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AUR 101
AUR101-201
ANTIINNFLAMATORY
AUR-101, a ROR gamma inverse agonist for autoimmune disorders like psoriasis
AUR-101 is an ROR-gammaT inverse agonist in phase II clinical development at Aurigene for the treatment of patients with moderate-to-severe chronic plaque-type psoriasis.
Aurigene Announces First Patient Dosed with AUR101 in Phase II Study in Patients with Moderate to Severe Psoriasis
Bangalore, February 17, 2020 — Aurigene, a development stage biotechnology company, today announced dose administration for the first patient in INDUS-2, a Phase II double blind placebo-controlled three-arm study of AUR101 in patients with moderate to severe psoriasis. AUR101 is an oral small molecule inverse agonist of RORγ and has shown desirable pharmacodynamic modulation of IL-17 and acceptable safety in a completed Phase I human study conducted in Australia.
“The initiation of this Phase II study under a US FDA IND represents a significant milestone for Aurigene, as it marks the first program which Aurigene has led from the bench side to the clinic all by itself,” said Murali Ramachandra, PhD, Chief Executive Officer of Aurigene. “We look forward to producing important clinical data by the end of 2020 to guide our future development plans and demonstrating Aurigene’s unique expertise in conducting Proof-of-Concept studies in a quality and fast-paced manner.”
About AUR101-201 and the Phase II Study of AUR101 in Patients with Moderate to Severe Psoriasis
The purpose of the Phase II multi-center, blinded, placebo-controlled, three-arm study is to evaluate the clinical activity of AUR101 in patients with moderate to severe psoriasis. In two of the arms, AUR101 will be administered twice daily, at 400 mg PO BID and 600 mg PO BID, for 12 weeks. Patients in the third arm will receive matched blinded placebo in a double dummy fashion. The trial is listed at clinicaltrials.gov with identifier NCT04207801.
About Aurigene
Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY,NYSE: RDY). Aurigene is focused on precision- oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene currently has several programs from its pipeline in clinical development. Aurigene has also submitted an IND to DCGI, India for a Phase IIb/III trial of CA-170, a dual inhibitor of PD-L1 and VISTA, in non-squamous NSCLC. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has partnered with many large and mid-pharma companies in the United States and Europe and has 15 programs currently in clinical development. For more information, please visit Aurigene’s website at https://www.aurigene.com/.
CLIP
Signalling of multiple interleukin (IL)-17 family cytokines via IL-17 receptor A drives psoriasis-related inflammatory pathways
M.A.X. Tollenaere,J. Hebsgaard,D.A. Ewald,P. Lovato,S. Garcet,X. Li,S.D. Pilger,M.L. Tiirikainen,M. Bertelsen,J.G. Krueger,H. Norsgaard,First published: 01 April 2021 https://doi.org/10.1111/bjd.20090Citations: 2Funding sources LEO Pharma A/S funded this study.Conflicts of interest M.A.X.T., J.H., D.A.E., P.L., S.D.P., M.L.T., M.B. and H.N. are employees of LEO Pharma. J.G.K. received grants paid to his institution from Novartis, Pfizer, Amgen, Lilly, Boehringer, Innovaderm, BMS, Janssen, AbbVie, Paraxel, LEO Pharma, Vitae, Akros, Regeneron, Allergan, Novan, Biogen MA, Sienna, UCB, Celgene, Botanix, Incyte, Avillion and Exicure; and personal fees from Novartis, Pfizer, Amgen, Lilly, Boehringer, Biogen Idec, AbbVie, LEO Pharma, Escalier, Valeant, Aurigene, Allergan, Asana, UCB, Sienna, Celgene, Nimbus, Menlo, Aristea, Sanofi, Sun Pharma, Almirall, Arena and BMS.Data Availability Statement The gene array dataset described in this publication has been deposited in NCBI’s Gene Expression Omnibus and is accessible through GEO Series accession number GSE158448 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE158448).
10:35 Small Molecule Inhibitors of RORgamma and IRAK4 for the Treatment of Autoimmune Disorders
Image may be NSFW. Clik here to view.Susanta Samajdar, Ph.D., Director, Medicinal Chemistry, Aurigene Discovery Technologies Limited
Although biologics such as anti-TNFα antibody are fairly successful in the treatment of autoimmune disorders, there is significant unmet need due to heterogeneity in diseases and lack of response to established therapies in some patients. While biologics typically target one cytokine signaling pathway, small molecule therapeutics directed towards intracellular target(s) can interfere in the signaling from multiple cytokines potentially leading to improved response. Development of small molecule oral inhibitors of IRAK4 and RORgamma to target TLR/IL-R and Th17 pathway respectively will be discussed.
This application claims the benefit of Indian provisional application number 5641/CHE/2013 filed on 06th December 2013 which hereby incorporated by reference.
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Novel inhibitor of programmed cell dealth-1 (PD-1)
CA-170 (also known as AUPM170 or PD-1-IN-1) is a first-in-class, potent and orally available small molecule inhibitor of the immune checkpoint regulatory proteins PD-L1 (programmed cell death ligand-1), PD-L2 and VISTA (V-domain immunoglobulin (Ig) suppressor of T-cell activation (programmed death 1 homolog; PD-1H). CA-170 was discovered by Curis Inc. and has potential antineoplastic activities. CA-170 selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation. Curis is currently investigating CA-170 for the treatment of advanced solid tumours and lymphomas in patients in a Phase 1 trial (ClinicalTrials.gov Identifier: NCT02812875).
Curis and Aurigene Announce Amendment of Collaboration for the Development and Commercialization of CA-170
– Aurigene to fund and conduct a Phase 2b/3 randomized study of CA-170 in patients with non-squamous non-small cell lung cancer (nsNSCLC) –
– Aurigene to receive Asia rights for CA-170; Curis entitled to royalty payments in Asia –
LEXINGTON, Mass., February 5, 2020 /PRNewswire/ — Curis, Inc. (NASDAQ: CRIS), a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, today announced that it has entered into an amendment of its collaboration, license and option agreement with Aurigene Discovery Technologies, Ltd. (Aurigene). Under the terms of the amended agreement, Aurigene will fund and conduct a Phase 2b/3 randomized study evaluating CA-170, an orally available, dual inhibitor of VISTA and PDL1, in combination with chemoradiation, in approximately 240 patients with nonsquamous non-small cell lung cancer (nsNSCLC). In turn, Aurigene receives rights to develop and commercialize CA-170 in Asia, in addition to its existing rights in India and Russia, based on the terms of the original agreement. Curis retains U.S., E.U., and rest of world rights to CA-170, and is entitled to receive royalty payments on potential future sales of CA-170 in Asia.
In 2019, Aurigene presented clinical data from a Phase 2a basket study of CA-170 in patients with multiple tumor types, including those with nsNSCLC. In the study, CA-170 demonstrated promising signs of safety and efficacy in nsNSCLC patients compared to various anti-PD-1/PD-L1 antibodies.
“We are pleased to announce this amendment which leverages our partner Aurigene’s expertise and resources to support the clinical advancement of CA-170, as well as maintain our rights to CA-170 outside of Asia,” said James Dentzer, President and Chief Executive Officer of Curis. “Phase 2a data presented at the European Society for Medical Oncology (ESMO) conference last fall supported the potential for CA-170 to serve as a therapeutic option for patients with nsNSCLC. We look forward to working with our partner Aurigene to further explore this opportunity.”
“Despite recent advancements, patients with localized unresectable NSCLC struggle with high rates of recurrence and need for expensive intravenous biologics. The CA-170 data presented at ESMO 2019 from Aurigene’s Phase 2 ASIAD trial showed encouraging results in Clinical Benefit Rate and Prolonged PFS and support its potential to provide clinically meaningful benefit to Stage III and IVa nsNSCLC patients, in combination with chemoradiation and as oral maintenance” said Kumar Prabhash, MD, Professor of Medical Oncology at Tata Memorial Hospital, Mumbai, India.
Murali Ramachandra, PhD, Chief Executive Officer of Aurigene, commented, “Development of CA-170, with its unique dual inhibition of PD-L1 and VISTA, is the result of years of hard-work and commitment by many people, including the patients who participated in the trials, caregivers and physicians, along with the talented teams at Aurigene and Curis. We look forward to further developing CA-170 in nsNSCLC.”
About Curis, Inc.
Curis is a biotechnology company focused on the development of innovative therapeutics for the treatment of cancer, including fimepinostat, which is being investigated in combination with venetoclax in a Phase 1 clinical study in patients with DLBCL. In 2015, Curis entered into a collaboration with Aurigene in the areas of immuno-oncology and precision oncology. As part of this collaboration, Curis has exclusive licenses to oral small molecule antagonists of immune checkpoints including, the VISTA/PDL1 antagonist CA-170, and the TIM3/PDL1 antagonist CA-327, as well as the IRAK4 kinase inhibitor, CA- 4948. CA-4948 is currently undergoing testing in a Phase 1 trial in patients with non-Hodgkin lymphoma. In addition, Curis is engaged in a collaboration with ImmuNext for development of CI-8993, a monoclonal anti-VISTA antibody. Curis is also party to a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are commercializing Erivedge® for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at http://www.curis.com.
About Aurigene
Aurigene is a development stage biotech company engaged in discovery and clinical development of novel and best-in-class therapies to treat cancer and inflammatory diseases and a wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (BSE: 500124, NSE: DRREDDY, NYSE: RDY). Aurigene is focused on precision- oncology, oral immune checkpoint inhibitors, and the Th-17 pathway. Aurigene currently has several programs from its pipeline in clinical development. Aurigene’s ROR-gamma inverse agonist AUR-101 is currently in phase 2 clinical development under a US FDA IND. Additionally, Aurigene has multiple compounds at different stages of pre-clinical development. Aurigene has partnered with many large and mid-pharma companies in the United States and Europe and has 15 programs currently in clinical development. For more information, please visit Aurigene’s website at https://www.aurigene.com/
Curis with the option to exclusively license Aurigene’s orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field
Addressing immune checkpoint pathways is a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients.
Through its collaboration with Aurigene, Curis is now engaged in the discovery and development of the first ever orally bioavailable, small molecule antagonists that target immune checkpoint receptor-ligand interactions, including PD-1/PD-L1 interactions. In the first half of 2016, Curis expects to file an IND application with the U.S. FDA to initiate clinical testing of CA-170, the first small molecule immune checkpoint antagonist targeting PD-L1 and VISTA. The multi-year collaboration with Aurigene is focused on generation of small molecule antagonists targeting additional checkpoint receptor-ligand interactions and Curis expects to advance additional drug candidates for clinical testing in the coming years. The next immuno-oncology program in the collaboration is currently targeting the immune checkpoints PD-L1 and TIM3.
In November 2015, preclinical data were reported. Data demonstrated tha the drug rescued and sustained activation of T cells functions in culture. CA-170 resulted in anti-tumor activity in multiple syngeneic tumor models including melanoma and colon cancer. Similar data were presented at the 2015 AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Conference in Boston, MA
By August 2015, preclinical data had been reported. Preliminary data demonstrated that in in vitro studies, small molecule PD-L1 antagonists induced effective T cell proliferation and IFN-gamma production by T cells that were specifically suppressed by PD-L1 in culture. The compounds were found to have effects similar to anti-PD1 antibodies in in vivo tumor models
(Oral Small Molecule PD-L1/VISTAAntagonist)
Certain human cancers express a ligand on their cell surface referred to as Programmed-death Ligand 1, or PD-L1, which binds to its cognate receptor, Programmed-death 1, or PD-1, present on the surface of the immune system’s T cells. Cell surface interactions between tumor cells and T cells through PD-L1/PD-1 molecules result in T cell inactivation and hence the inability of the body to mount an effective immune response against the tumor. It has been previously shown that modulation of the PD-1 mediated inhibition of T cells by either anti-PD1 antibodies or anti-PD-L1 antibodies can lead to activation of T cells that result in the observed anti-tumor effects in the tumor tissues. Therapeutic monoclonal antibodies targeting the PD-1/PD-L1 interactions have now been approved by the U.S. FDA for the treatment of certain cancers, and multiple therapeutic monoclonal antibodies targeting PD-1 or PD-L1 are currently in development.
In addition to PD-1/PD-L1 immune regulators, there are several other checkpoint molecules that are involved in the modulation of immune responses to tumor cells1. One such regulator is V-domain Ig suppressor of T-cell activation or VISTA that shares structural homology with PD-L1 and is also a potent suppressor of T cell functions. However, the expression of VISTA is different from that of PD-L1, and appears to be limited to the hematopoietic compartment in tissues such as spleen, lymph nodes and blood as well as in myeloid hematopoietic cells within the tumor microenvironment. Recent animal studies have demonstrated that combined targeting/ blockade of PD-1/PD-L1 interactions and VISTA result in improved anti-tumor responses in certain tumor models, highlighting their distinct and non-redundant functions in regulating the immune response to tumors2.
As part of the collaboration with Aurigene, in October 2015 Curis licensed a first-in-class oral, small molecule antagonist designated as CA-170 that selectively targets PD-L1 and VISTA, both of which function as negative checkpoint regulators of immune activation. CA-170 was selected from the broad PD-1 pathway antagonist program that the companies have been engaged in since the collaboration was established in January 2015. Preclinical data demonstrate that CA-170 can induce effective proliferation and IFN-γ (Interferon-gamma) production (a cytokine that is produced by activated T cells and is a marker of T cell activation) by T cells that are specifically suppressed by PD-L1 or VISTA in culture. In addition, CA-170 also appears to have anti-tumor effects similar to anti-PD-1 or anti-VISTA antibodies in multiple in vivo tumor models and appears to have a good in vivo safety profile. Curis expects to file an IND and initiate clinical testing of CA-170 in patients with advanced tumors during the first half of 2016.
Image may be NSFW. Clik here to view.Jan 21, 2015
Curis and Aurigene Announce Collaboration, License and Option Agreement to Discover, Develop and Commercialize Small Molecule Antagonists for Immuno-Oncology and Precision Oncology Targets
— Agreement Provides Curis with Option to Exclusively License Aurigene’s Antagonists for Immuno-Oncology, Including an Antagonist of PD-L1 and Selected Precision Oncology Targets, Including an IRAK4 Kinase Inhibitor —
— Investigational New Drug (IND) Application Filings for Both Initial Collaboration Programs Expected this Year —
— Curis to issue 17.1M shares of its Common Stock as Up-front Consideration —
— Management to Host Conference Call Today at 8:00 a.m. EST —
LEXINGTON, Mass. and BANGALORE, India, Jan. 21, 2015 (GLOBE NEWSWIRE) — Curis, Inc. (Nasdaq:CRIS), a biotechnology company focused on the development and commercialization of innovative drug candidates for the treatment of human cancers, and Aurigene Discovery Technologies Limited, a specialized, discovery stage biotechnology company developing novel therapies to treat cancer and inflammatory diseases, today announced that they have entered into an exclusive collaboration agreement focused on immuno-oncology and selected precision oncology targets. The collaboration provides for inclusion of multiple programs, with Curis having the option to exclusively license compounds once a development candidate is nominated within each respective program. The partnership draws from each company’s respective areas of expertise, with Aurigene having the responsibility for conducting all discovery and preclinical activities, including IND-enabling studies and providing Phase 1 clinical trial supply, and Curis having responsibility for all clinical development, regulatory and commercialization efforts worldwide, excluding India and Russia, for each program for which it exercises an option to obtain a license.
The first two programs under the collaboration are an orally-available small molecule antagonist of programmed death ligand-1 (PD-L1) in the immuno-oncology field and an orally-available small molecule inhibitor of Interleukin-1 receptor-associated kinase 4 (IRAK4) in the precision oncology field. Curis expects to exercise its option to obtain exclusive licenses to both programs and file IND applications for a development candidate from each in 2015.
“We are thrilled to partner with Aurigene in seeking to discover, develop and commercialize small molecule drug candidates generated from Aurigene’s novel technology and we believe that this collaboration represents a true transformation for Curis that positions the company for continued growth in the development and eventual commercialization of cancer drugs,” said Ali Fattaey, Ph.D., President and Chief Executive Officer of Curis. “The multi-year nature of our collaboration means that the parties have the potential to generate a steady pipeline of novel drug candidates in the coming years. Addressing immune checkpoint pathways is now a well validated strategy to treat human cancers and the ability to target PD-1/PD-L1 and other immune checkpoints with orally available small molecule drugs has the potential to be a distinct and major advancement for patients. Recent studies have also shown that alterations of the MYD88 gene lead to dysregulation of its downstream target IRAK4 in a number of hematologic malignancies, including Waldenström’s Macroglobulinemia and a subset of diffuse large B-cell lymphomas, making IRAK4 an attractive target for the treatment of these cancers. We look forward to advancing these programs into clinical development later this year.”
Dr. Fattaey continued, “Aurigene has a long and well-established track record of generating targeted small molecule drug candidates with bio-pharmaceutical collaborators and we have significantly expanded our drug development capabilities as we advance our proprietary drug candidates in currently ongoing clinical studies. We believe that we are well-positioned to advance compounds from this collaboration into clinical development.”
CSN Murthy, Chief Executive Officer of Aurigene, said, “We are excited to enter into this exclusive collaboration with Curis under which we intend to discover and develop a number of drug candidates from our chemistry innovations in the most exciting fields of cancer therapy. This unique collaboration is an opportunity for Aurigene to participate in advancing our discoveries into clinical development and beyond, and mutually align interests as provided for in our agreement. Our scientists at Aurigene have established a novel strategy to address immune checkpoint targets using small molecule chemical approaches, and have discovered a number of candidates that modulate these checkpoint pathways, including PD-1/PD-L1. We have established a large panel of preclinical tumor models in immunocompetent mice and can show significant in vivo anti-tumor activity using our small molecule PD-L1 antagonists. We are also in the late stages of selecting a candidate that is a potent and selective inhibitor of the IRAK4 kinase, demonstrating excellent in vivo activity in preclinical tumor models.”
In connection with the transaction, Curis has issued to Aurigene approximately 17.1 million shares of its common stock, or 19.9% of its outstanding common stock immediately prior to the transaction, in partial consideration for the rights granted to Curis under the collaboration agreement. The shares issued to Aurigene are subject to a lock-up agreement until January 18, 2017, with a portion of the shares being released from the lock-up in four equal bi-annual installments between now and that date.
The agreement provides that the parties will collaborate exclusively in immuno-oncology for an initial period of approximately two years, with the option for Curis to extend the broad immuno-oncology exclusivity.
In addition Curis has agreed to make payments to Aurigene as follows:
for the first two programs: up to $52.5 million per program, including $42.5 million per program for approval and commercial milestones, plus specified approval milestone payments for additional indications, if any;
for the third and fourth programs: up to $50 million per program, including $42.5 million per program for approval and commercial milestones, plus specified approval milestone payments for additional indications, if any; and
for any program thereafter: up to $140.5 million per program, including $87.5 million per program in approval and commercial milestones, plus specified approval milestone payments for additional indications, if any.
Curis has agreed to pay Aurigene royalties on any net sales ranging from high single digits to 10% in territories where it successfully commercializes products and will also share in amounts that it receives from sublicensees depending upon the stage of development of the respective molecule. About Immune Checkpoint Modulation and Programmed Death 1 Pathway
Modulation of immune checkpoint pathways has emerged as a highly promising therapeutic approach in a wide range of human cancers. Immune checkpoints are critical for the maintenance of self-tolerance as well as for the protection of tissues from excessive immune response generated during infections. However, cancer cells have the ability to modulate certain immune checkpoint pathways as a mechanism to evade the immune system. Certain immune checkpoint receptors or ligands are expressed by various cancer cells, targeting of which may be an effective strategy for generating anti-tumor activity. Some immune-checkpoint modulators, such as programmed death 1 (PD-1) protein, specifically regulate immune cell effector functions within tissues. One of the mechanisms by which tumor cells block anti-tumor immune responses in the tumor microenvironment is by upregulating ligands for PD-1, such as PD-L1. Hence, targeting of PD-1 and/or PD-L1 has been shown to lead to the generation of effective anti-tumor responses. About Curis, Inc.
Curis is a biotechnology company focused on the development and commercialization of novel drug candidates for the treatment of human cancers. Curis’ pipeline of drug candidates includes CUDC-907, a dual HDAC and PI3K inhibitor, CUDC-427, a small molecule antagonist of IAP proteins, and Debio 0932, an oral HSP90 inhibitor. Curis is also engaged in a collaboration with Genentech, a member of the Roche Group, under which Genentech and Roche are developing and commercializing Erivedge®, the first and only FDA-approved medicine for the treatment of advanced basal cell carcinoma. For more information, visit Curis’ website at www.curis.com.
About Aurigene
Aurigene is a specialized, discovery stage biotechnology company, developing novel and best-in-class therapies to treat cancer and inflammatory diseases. Aurigene’s Programmed Death pathway program is the first of several immune checkpoint programs that are at different stages of discovery and preclinical development. Aurigene has partnered with several large- and mid-pharma companies in the United States and Europe and has delivered multiple clinical compounds through these partnerships. With over 500 scientists, Aurigene has collaborated with 6 of the top 10 pharma companies. Aurigene is an independent, wholly owned subsidiary of Dr. Reddy’s Laboratories Ltd. (NYSE:RDY). For more information, please visit Aurigene’s website at http://aurigene.com/.
WO2011161699, WO2012/168944, WO2013144704 and WO2013132317 report peptides or peptidomimetic compounds which are capable of suppressing and/or inhibiting the programmed cell death 1 (PD1) signaling pathway.
The compound was synthesised using similar procedure as depicted in Example 2 for synthesising compound 2 using Image may be NSFW. Clik here to view. instead of H-Ser(‘Bu)-0’Bu (in synthesis of compound 2b) to yield 0.35 g crude material of the title compound. The crude solid material was purified using preparative HPLC described under experimental conditions. LCMS: 361.2 (M+H)+, HPLC: tR = 12.19 min.
(5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydrofuran-2-yl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid 106560-14-9[RN] 4-Thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-, (5R,6S)- 6α-[(R)-1-hydroxyethyl]-2-[(R)-tetrahydrofuran-2-yl]pen-2-em-3-carboxylic acid 4-Oxofenretinide 4-Oxo-N-(4-hydroxyphenyl)retinamide 6α-[(1R)-1-hydroxyethyl]-2-[(2R)-tetrahydrofuran-2-yl]-2,3-didehydropenam-3-carboxylic acid 7305146 [Beilstein] FaropenemCAS Registry Number: 106560-14-9 CAS Name: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid Additional Names: fropenem; (5R,6S,8R,2¢R)-2-(2¢-tetrahydrofuryl)-6-hydroxyethylpenem-3-carboxylate Molecular Formula: C12H15NO5S Molecular Weight: 285.32 Percent Composition: C 50.51%, H 5.30%, N 4.91%, O 28.04%, S 11.24% Literature References: Orally active, b-lactamase stable, penem antibiotic.Prepn: M. Ishiguro et al.,EP199446; eidem,US4997829 (1986, 1991 both to Suntory); eidem,J. Antibiot.41, 1685 (1988).Pharmacokinetics: A. Tsuji et al.,Drug Metab. Dispos.18, 245 (1990). In vitro antimicrobial spectrum: J. M. Woodcock et al.,J. Antimicrob. Chemother.39, 35 (1997). b-Lactamase stability: A. Dalhoff et al., Chemotherapy (Basel)49, 229 (2003).HPLC determn in plasma: R. V. S. Nirogi et al., Arzneim.-Forsch.55, 762 (2005). Clinical trial in urinary tract infections: S. Arakawa et al.,Nishinihon J. Urol.56, 300 (1994); in bacterial sinusitis: R. Siegert et al., Eur. Arch. Otorhinolaryngol.260, 186 (2003). Derivative Type: Sodium salt CAS Registry Number: 122547-49-3 Additional Names: Furopenem Manufacturers’ Codes: ALP-201; SUN-5555; SY-5555; WY-49605 Trademarks: Farom (Daiichi) Molecular Formula: C12H15NNaO5S Molecular Weight: 308.31 Percent Composition: C 46.75%, H 4.90%, N 4.54%, Na 7.46%, O 25.95%, S 10.40% Properties: [a]D22 +60° (c = 0.10). Optical Rotation: [a]D22 +60° (c = 0.10) Derivative Type: Daloxate CAS Registry Number: 141702-36-5 CAS Name: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-7-oxo-3-[(2R)-tetrahydro-2-furanyl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester Additional Names: faropenem medoxomil Manufacturers’ Codes: Bay-56-6854; SUN-208 Trademarks: Orapem (Replidyne) Molecular Formula: C17H19NO8S Molecular Weight: 397.40 Percent Composition: C 51.38%, H 4.82%, N 3.52%, O 32.21%, S 8.07% Literature References: Prepn: H. Iwata et al., WO9203442; eidem, US5830889 (1992, 1998 both to Suntory). Properties: Pale yellow crystals. Therap-Cat: Antibacterial (antibiotics). Keywords: Antibacterial (Antibiotics); ?Lactams; Penems.
The sodium salt faropenem sodium, available under the trade name Farom, has been marketed in Japan since 1997. (CID 636379 from PubChem)
The prodrug form faropenem medoxomil[4] (also known as faropenem daloxate) has been licensed from Daiichi Asubio Pharma by Replidyne, which plans to market it in conjunction with Forest Pharmaceuticals. The trade name proposed for the product was Orapem, but company officials recently announced this name was rejected by the FDA.[5]
Clinical use
As of 8 September 2015, Faropenem has yet to receive marketing approval in the United States, and was submitted for consideration by the United States Food and Drug Administration (FDA) on 20 December 2005. The new drug application dossier submitted included these proposed indications:
acute bacterial sinusitis
community-acquired pneumonia
acute exacerbations of chronic bronchitis
uncomplicated skin and skin structure infections
urinary tract infections
History
The FDA refused to approve faropenem, an antibiotic manufactured by Louisville-based Replidyne. The FDA said the drug was “nonapprovable”, but did not refer to specific safety concerns about the product. The company will have to conduct new studies and clinical trials, lasting an estimated two more years, to prove the drug treats community-acquired pneumonia, bacterial sinusitis, chronic bronchitis, and skin infections.[citation needed]
In India it is available as Farobact 200/300ER CIPLA.
PATENT
https://patents.google.com/patent/WO2008035153A2/enFaropenem is an orally active β-lactam antibiotic belonging to the penem group. Faropenem is chemically known as 6-(l-hydroxyethyl)-7-oxo-3-(oxolan-2-yl)-4-thia-l-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid. The known forms of Faropenem are Faropenem sodium and the prodrug form, FaropenemMedoxomil (also known as Faropenem Daloxate). In view of the importance of the compound of the formula (I), several synthetic procedures to prepare the compound have been reported.US 4,997,829 provides process for the preparation of faropenem according to the following scheme. The process is exemplified with the allyl protected carboxyl group. One of the process involves the reaction of A- acetoxyazetidinone with tetrahydrothiofuroic acid, condensation with allyl glyoxalate in refluxing benzene, chlorination with thionyl chloride, reaction of triphenylphosphine with lutidine in hot THF, cyclization in refluxing toluene, deprotection of silyl protecting group with tetrabutylammonium fluoride, treating with triphenylphosphine and, treating with sodium 2-ethylhexanoate and (PP^)4Pd to result faropenem sodium. The process exemplified utilizes benzene as solvent, which is not environmentally acceptable. Tetrabutylammonium fluoride was used as desilylating agent that is expensive. Even though the description teaches that optically active compounds can be employed, the examples utilized the dl-compound of tetrahydrothiofuroic acid further requiring resolution.
Methods are provided for the synthesis of series of penem compounds in J Antibiotics 1988, 41(11), 1685-1693. The provided methods utilize sulfonylazetidinone as the starting materials. As one of the procedures gives lesser yield, another procedure was adopted which uses silver salts.Japanese patent, JP2949363 describes a process for deallylation and salt formation with an alkali metal salt of carboxylic acid in the presence of a catalytic amount of palladium complex for the preparation of faropenem.EP410727 describes a process for removing allyl group from a penem compound using cyclic 1,3-diketone such as dimedone.The yield and quality of the final product is always less in the above prior art methods. With the continued research, the present inventors have undertaken extensive studies for developing a process for the preparation of compound of formula (I), which is commercially viable, involves simple techniques such as crystallizations, with improved yields and quality of the product, and with lesser reaction time. None of the prior art suggests or teaches the techniques provided herein.The process is shown in Scheme-I as given below:
One-pot process for the preparation of Faropenem sodium:Sodium salt of R(+)-tetrahydrofuran-2-thiocarboxylic acid (67 g) in aqueous acetone was added slowly to a solution of AOSA (100 g) in acetone (200 mL) and stirred for 3 h at pH 8.0 to 8.5 using sodium bicarbonate solution.After completion of the reaction, the product was extracted with toluene. The combined toluene layer was washed with saturated sodium bicarbonate solution and brine solution. Toluene was removed under vacuum completely and the mass obtained, 3-(l’-tert-butyldimethylsilyloxyethyl)-4-(2′- tetrahydrofuranoylthio)-2-azetidinone was directly taken for next step.3-(r-tert-Butyldimethylsilyloxyethyl)-4-(2′-tetrahydrofuranoylthio)-2- azetidinone obtained was dissolved in toluene (1000 mL) and cooled to -10 to -5 °C under nitrogen. Triethylamine (124 mL) was added to it followed by allyl oxalyl chloride (82 g) at -10 to- 5 0C for 2 h. After completion of the reaction, cold water was added to the mass and washed with dilute hydrochloric acid and sodium bicarbonate solution. Toluene layer was separated and washed with purified water. The toluene layer containing compound of formula (VI) was concentrated under vacuum at 50 to 60 °C and taken for next step as such.Compound of formula (VI) (150 g) was dissolved in triethyl phosphite (150 mL), heated to 60 0C and stirred under nitrogen atmosphere. Toluene (3000 mL) was added, heated to 100 to 110 °C and stirred for 20- 24 h. Toluene was distilled under vacuum completely. Product obtained, allyl (1 ‘R,2″R,5R,6S)-6-(l 5-tert-butyldimethylsilyloxyethyl)-2-(2″-tetrahydrofuranyl) penem-3-carboxylate (VII) was directly taken for next step.Compound (VII) obtained was dissolved in DMF (700 mL) at 30 °C.Ammonium hydrogen difluoride (80 g) and NMP (210 mL) were added and stirred at room temperature for 25 to 35 h. The reaction mass was quenched into a mixture of water-ethyl acetate and stirred at room temperature. The ethyl acetate layer was separated and the aqueous layer extracted with ethyl acetate. ■ The combined ethyl acetate layer was washed with water followed by saturated sodium bicarbonate solution. The ethyl acetate layer was charcoal treated. The ethyl acetate layer containing allyl (l’R,2″R,5R,6S)-6-(l’-hydroxyethyl)-2-(2″- tetrahydrofuranyl)penem-3-carboxylate (XII) was partially distilled and taken for the next step.The ethyl acetate layer containing compound of formula (XII), Pd/C, sodium bicarbonate and purified water (1000 mL) were taken in an autoclave and maintained 5 to 10 kg pressure of hydrogen gas for 2-5 h. After completion of the reaction the Pd/C was filtered off and ethyl acetate layer separated. The pH of the mass was adjusted to 1.5 and extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate twice. The combined ethyl acetate layer was carbon treated. Sodium-2-ethylhexanoate in ethyl acetate was added slowly and stirred. The precipitated title compound was filtered under vacuum, washed with acetone and dried. Dry weight of the product: 65-75 g.Example 9Purification of Faropenem sodiumCrude Faropenem sodium (50 g) was dissolved in purified water (200 mL) at 25-30 0C. The solution was charcoalised. Acetone (1500 mL) was added. The reaction mass was stirred further for 10 min. The precipitated solid was cooled to 0 —2 °C then filtered, washed with acetone and dried at room temperature. Weight of pure Faropenem sodium is 43 to 46 g (Purity 99.95%).Example 9aPurification of Faropenem sodiumCrude Faropenem sodium (50 g) was dissolved in purified water (200 mL) at 25-30 °C. Acetone (150O mL) was added. The reaction mass was stirred further for 10 min. The precipitated solid was cooled to 0-2 °C then filtered, washed with acetone and dried at room temperature. Weight of pure Faropenem sodium is 43 to 46 g (Purity 99.95%).
PATENT
https://patents.google.com/patent/CN103880864B/enFaropenem sodium is developed by Japanese Suntory companies, and first penemss antibiosis in listing in 1997 Element, it are similar to the several carbapenem antibiotics for listing, strong with has a broad antifungal spectrum, antibacterial activity, to beta-lactamase Stably, the features such as also having good action to extended spectrumβ-lactamase producing strains, citrobacter, enterococcus and anaerobe etc.. It is first orally active, penems antibiotics stable to beta-lactamase in the world so far.Its structural formula As follows： Report about Faropenem sodium preparation method is a lot, mainly has several as follows：1st, J. Antibiotics 1988, the method that reports in 41,1685, see below row reaction equation: Acyl group substitution reaction is carried out in the basic conditions with 4-AA and three beneze methane thiols and obtains thio trityl as protecting group Aza cyclo-butanone, then when 2-TETRAHYDROFUROYL chlorine is connected with lactams, using silver nitrate as condensing agent, but nitric acid Silver is expensive, and cost is too high, while the silver chloride for generating is difficult to filter, is not suitable for large-scale production.2nd, the classical preparation method of United States Patent (USP) US4997829 report：There is acyl with (R) tetrahydrofuran -2- thiocarboxylic acids Base substitution reaction generates thioesters, then through condensation, chlorine replacement, intramolecular Witting cyclization, slough hydroxyl protecting group and carboxylic Base protection group obtains product, and this synthetic route yield is very low, while side chain is thio-compoundss, abnormal smells from the patient is extremely smelly, and prepares complexity, There is-fixed harm to human body and environment.It is also required in chloro building-up process using pungent thionyl chloride, these factors are all It is unfavorable for industrialized production 3rd, the method that reports in Chinese patent CN1314691 is as follows： Said method route is shorter, is produced using one kettle way, more convenient.But said method is related to some other salt such as acetate using heavy metal palladium in last operation The deprotecting regent of compound and triphenyl phosphorus together as pi-allyl, metal palladium reagent is expensive, while triphenyl phosphorus are most More difficult removing in step afterwards, increases operation difficulty, affects product quality.Allyloxy is used easily to produce as protection group simultaneously A kind of double bond olefinic polymerization species impurity of life, affects product quality, reduces yield.Embodiment one(R) tetrahydrofuran -2- thiocarboxylic acids (198g, 1.5 mol) are put in 3L reaction bulbs, plus 1 mol/L hydrogen-oxygens Change sodium body lotion (I.5 L) to be adjusted at 5 DEG C of pH 9- 10,0-, Deca 4AA（287g, 1. 0mo l) acetone (1 L) Solution, drop are finished, and are adjusted to pH 8 or so, 2 h of room temperature reaction with 1 mol/L sodium hydroxide. and add water (500 ml) dilution, second Acetoacetic ester (600 ml x3) is extracted, and merges organic layer, successively with 5 % sodium bicarbonate solutions (300 ml x 2) and water (300 m1 x 2) is washed, and anhydrous sodium sulphate is dried, and is filtered, and filtrate concentrates, and obtains pale yellow oil (about 360 g), directly Input the next step.Embodiment twoThe mixing of concentrated solution as obtained above, triethylamine (l70g, 1.7 mol) and dichloromethane (1.5 L), 0-5 DEG C Deca chlorine oxalic acid is finished to p-Nitrobenzyl (414.1 g, 1 .7 mo l), drop, and equality of temperature reacts 2 h, and add water (1 L) dilution, Extracted with dichloromethane (500 ml x 4), merge organic layer, molten with water (300m1 x 2) and 5 % sodium bicarbonate successively Liquid (300 m1 x 2) is washed, anhydrous sodium sulfate drying, is filtered, and concentration obtains pale yellow oil (about 530g), direct plunges into The next step..Embodiment threeAbove-mentioned gained grease, dimethylbenzene (4L) and NSC 5284 (500ml) are mixed, heating reflux reaction 5h , reduce pressure and boil off dimethylbenzene and NSC 5284, residue ethyl acetate-hexane (1：5,1 L) recrystallization, obtain yellowish Color solid (334.3g, 61%, in terms of 4AA).Example IVAbove-mentioned solid (0.60 mol of 330g.) is dissolved in methanol (2 L), adds 1.0M hydrochloric acid (0.4 L), adds palladium carbon （15.0 g）, hydrogen is passed through, 40 DEG C of stirrings, response time are 16 h, and the pressure of system is 4atm, after reaction terminates, crosses and filters Catalyst is removed, is concentrated.Embodiment fiveThe product obtained after above-mentioned concentration is dissolved in tetrahydrofuran 600ml, the 2 ethyl hexanoic acid sodium of 100.0g is added Tetrahydrofuran（200ml）And water（200 ml）Mixed solution, 2 h are stirred at room temperature, have faint yellow solid generate, filter, be method Faropenem crude product 147.0g.Embodiment sixBy above-mentioned solid deionized water（2200ml）Acetone is slowly added under dissolved solution, stirring to start to become to solution Muddiness, when about adding acetone 750ml, solution starts to become cloudy, and stops adding, and continues stirring and allows its crystallize overnight, sucking filtration, acetone Washing, dries, and obtains the Faropenem sodium fine work 125.0g of white.
Syn
AU 8654460; EP 0199446; JP 1994128267; US 4997829
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This compound is prepared by several related ways: 1) The reaction of silylated azetidinone (I) with tetrahydrofuran-2-thiocarboxylic acid (II) by means of NaOH in THF – water gives the azetidinone thioester (III), which is condensed with allyl glyoxylate in refluxing benzene yielding the hydroxyester (IV). The reaction of (IV) with SOCl2 affords the chloroester (V), which by reaction with triphenylphosphine by means of lutidine in hot THF is converted into the phosphoranylidene derivative (VI). The elimination of the silyl protecting group of (VI) with tetrabutylammonium fluoride gives the azetidinone (VII), which is cyclized in refluxing toluene yielding the (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxyli c acid allyl ester (VIII). Finally, this compound is hydrolyzed with triphenylphosphine, sodium 2-ethylhexanoate and Pd-tetrakis(triphenylphosphine). 2) The condensation of the silver salt of protected azetidinone (IX) with tetrahydrofuran-2(R)-carbonyl chloride (X) also yields the phosphoranylidene salt (VI). 3) Phosphoranylidene ester (VI) can also be cyclized first in refluxing benzene yielding the silylated penem ester (XI), which is deprotected with tetrabutylammonium fluoride to (VIII). 4) The hydrolysis of allyl ester (VIII) to the final product can also be performed with paladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethylacetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene, or ethylene glycol dimethyl ether. 5) The preceding hydrolysis can also be performed with triphenylphosphine and paladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone.
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Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanyl-azetidinone (II), which is converted into the silver salt (III) by reaction with AgNO3. Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) — obtained by treatment of carboxylic acid (V) with thionyl chloride — providing the azetidinone thioester (VI). Coupling of azetidinone (VI) with allyl oxalyl chloride (VII) in CH2Cl2 by means of Et3N, followed by intramolecular Wittig cyclization by means of triethyl phosphite in refluxing xylene, affords penem (VIII). Alternatively, compound (VIII) can also be obtained as follows: Substitution of phenyl sulfonyl group of azetidinone (X) by tritylmercaptan by means of NaOH in acetone/water provides tritylsulfanyl-azetidinone (XI), which is condensed with allyl oxalyl chloride (VII) by means of DIEA in CH2Cl2 to give the oxalyl amide (XII). Compound (XII) is then treated with AgNO3 and pyridine in acetonitrile, providing the silver mercaptide (XIII), which is acylated with tetrahydrofuran-2(R)-carbonyl chloride (IV) in acetonitrile to afford the penem precursor (XIV). Penem (VIII) is obtained by intramolecular Wittig cyclization of (XIV) with P(OEt)3 in refluxing xylene. Finally, faropenem sodium can be obtained by removal of the tbdms protecting group of (VIII) by means of either Et3N tris(hydrogen fluoride) in ethyl acetate or tetrabutylammonium fluoride (TBAF) and HOAc in THF to give compound (IX). This is followed by allyl ester group removal of (IX), which can be performed under several different conditions: i) triphenylphosphine, sodium 2-ethylhexanoate and palladium tetrakis(triphenylphosphine); ii) palladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)-5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethyl acetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene or ethylene glycol dimethyl ether; iii) triphenylphosphine and palladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone; or iv) palladium acetate in the presence of P(OBu)3 and sodium propionate in THF.
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Treatment of the silylated azetidinone (I) with tritylmercaptan affords the tritylsulfanylazetidinone (II), which by reaction with AgNO3 is converted into the silver salt (III). Compound (III) is coupled with tetrahydrofuran-2(R)-carbonyl chloride (IV) ?obtained by treatment of carboxylic acid (V) with thionyl chloride ?to provide the azetidinone thioester (VI). Alternatively, compound (VI) can be obtained by condensation of tetrahydrofuran-2(R)-thiocarboxylic S-acid (VII) ?obtained by treatment of carboxylic acid (V) with hydrogen sulfide ?with silylated azetidinones (I) or (VIII) by means of NaOH in THF/water. Condensation of azetidinone thioester (VI) with allyl glyoxylate (IX) in refluxing benzene gives the hydroxy ester (X), which is treated with SOCl2 to yield the chloro ester (XI). Reaction of compound (XI) with triphenylphosphine and lutidine in hot THF provides the phosphoranylidene derivative (XII), which is converted into (5R,6S)-6-[1(R)-hydroxyethyl]-2-[2(R)-tetrahydrofuryl]penem-3-carboxylic acid allyl ester, faropenem allyl ester (XIII) by removal of the silyl protecting group with tetrabutylammonium fluoride, followed by cyclization in refluxing toluene. Compound (XII) can also be obtained by condensation of the silver salt of protected azetidinone (XIV) with tetrahydrofuran-2(R)-carbonyl chloride (V).
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Alternatively, faropenem allyl ester (XIII) can also be prepared by cyclization of compound (XII) in refluxing benzene to yield silylated penem allyl ester (XV), which is then deprotected with either tetrabutylammonium fluoride in AcOH or triethylamine tris(hydrogen fluoride) in methyl isobutyl ketone or toluene. Penem (XV) can also be synthesized by several related ways: a) By coupling of azetidinone (VI) with allyl oxalyl chloride (XVI) in CH2Cl2 by means of Et3N, followed by intramolecular Wittig cyclization by means of triethyl phosphite in refluxing xylene. b) Substitution of phenyl sulfonyl group of azetidinone (VIII) by tritylmercaptan by means of NaOH in acetone/water provides tritylsulfanyl-azetidinone (II), which is condensed with allyl oxalyl chloride (XVI) by means of DIEA in CH2Cl2 to give the oxalyl amide (XVII). Compound (XVII) is then treated with AgNO3 and pyridine in acetonitrile to provide the silver mercaptide (XVIII), which is acylated with tetrahydrofuran-2(R)-carbonyl chloride (IV) in acetonitrile to afford the penem precursor (XIX). Finally, compound (XV) is obtained by intramolecular Wittig cyclization of (XX) with P(OEt)3 in refluxing xylene.
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Hydrolysis of faropenem allyl ester (XIII) to faropenem sodium (XX) can be performed under several different conditions: i) triphenylphosphine, sodium 2-ethylhexanoate and palladium tetrakis(triphenylphosphine); ii) palladium tetrakis(triphenylphosphine) and sodium 4-(methoxycarbonyl)- 5,5-dimethylcyclohexane-1,3-dione enolate in several different solvents such as methyl acetate, ethyl acetate, tetrahydrofuran, dioxane, sec-butanol, acetonitrile, acetone, 2-butanone, 1,2-dichloroethane, chlorobenzene, toluene, or ethylene glycol dimethyl ether; iii) triphenylphosphine and palladium tetrakis(triphenylphosphine) with sodium propionate, sodium acetate or sodium lactate in tetrahydrofuran or acetone; and iv) palladium acetate in the presence of P(OBu)3 and sodium propionate in THF. Finally, faropenem daloxate can be directly obtained from faropenem sodium (XX) by esterification with 4-(iodomethyl)-5-methyl-1,3-dioxol-2-one (XXI) in DMF.
PATENT
https://patents.google.com/patent/CN103059046A/enFaropenem (Faropenem), chemistry (5R, 6S)-6-[(1R)-hydroxyethyl by name]-2-[(2R)-and tetrahydrofuran (THF)] penem-3-carboxylic acid list sodium salt, by the first exploitation listing in 1997 years of Japanese Suntory company.This medicine is a kind of atypical beta-lactam penems antibiotics, has very strong anti-microbial activity, especially to the anti-microbial activities of the anerobes such as the gram positive organisms such as golden Portugal bacterium, penicillin-fast streptococcus pneumoniae, streptococcus faecium and bacteroides fragilis apparently higher than existing cynnematin, anti-gram-negative bacteria is active similar to oral cephalosporin, and is stable to various β-lactamases.Various clinical studyes show that this medical instrument has clinical effectiveness good, safe, the advantage that renal toxicity and neurotoxicity are little.Its structural formula is as follows: For synthesizing of Faropenem, existing many reports in the prior art, for example CN101125857A has reported following synthetic route: Take (3R, 4R)-3-[(R)-1-tert-butyl dimethyl silica ethyl]-4-[(R)-and acetoxyl group] nitrogen heterocyclic din-2-ketone is as starting raw material, and warp gets intermediate compound I with R-(+)-sulfo-tetrahydrofuran (THF)-2-formic acid condensation; Intermediate compound I is carried out acylation reaction with monoene propoxy-oxalyl chloride under the catalysis of alkali, get intermediate II; Intermediate II cyclization under the effect of triethyl-phosphite gets intermediate III; Intermediate III is sloughed hydroxyl protecting group through the effect of tetrabutylammonium, gets intermediate compound IV; Intermediate compound IV decarboxylize protecting group under [four (triphenylphosphine)] palladium and triphenylphosphine effect gets Faropenem.Find that after deliberation the method for the present synthetic Faropenem of reporting is all similar with the disclosed method of above-mentioned CN101125857A, all need remove in two steps the protecting group of hydroxyl and carboxyl, reaction scheme is longer.When removing above-mentioned protecting group, need to use a large amount of tetrabutylammonium and [four (triphenylphosphine)] palladium and triphenylphosphine; these reagent costs are high, toxicity is large; be unfavorable for large industrial production; and can introduce the heavy metal palladium; so that the heavy metal remnants in the Faropenem exceed standard, be not suitable for the production of bulk drug.And when adopting aforesaid method deprotection base, the yield in per step only can reach 60%-75%, has further increased production cost.Embodiment 6The preparation of FaropenemWith intermediate 3(364.5g, 0.8mol) use the 700mL acetic acid ethyl dissolution, to open and stir, 0 ℃ of lower dropping with the 36g trifluoroacetic acid after the dilution of 100mL ethyl acetate dripped off in 1 hour, 0 ℃ of lower reaction 2h that continues.Stopped reaction stirs the sodium bicarbonate aqueous solution of lower dropping 5%, until reaction solution pH is neutral.Emit water layer from the reactor lower end, discard.In reactor, add gradually the ethanolic soln of sodium bicarbonate, until till no longer including solid and separating out.Suction filtration, filter cake gets white solid powder 230g(productive rate 93.7% with acetone-water (10:3, v/v) recrystallization), M.P. 163-164 ℃, detect through HPLC, purity is 99.8%Reference examples 1(5R, 6S)-6-[(R)-1-hydroxyethyl]-2-[(R)-and the 2-TETRAHYDROFUROYL sulfenyl] preparation of penem-3-carboxylic acid propyleneWith (5R, 6S)-6-[(R)-the 1-tert-butyl dimethyl silica ethyl]-2-[(R)-and the 2-TETRAHYDROFUROYL sulfenyl] penem-3-carboxylic acid propylene (150g, 0.342mol) and ammonium bifluoride (59.5g, 1.025mmol) add successively among the 400mL DMF, 55～60 ℃ were reacted 5 hours, stopped reaction, suction filtration, filtrate adds water 800ml, uses ethyl acetate extraction, and organic phase is washed with 5% sodium hydrogen carbonate solution, anhydrous sodium sulfate drying, concentrated, gained incarnadine oily matter gets yellow solid 73g through the petrol ether/ethyl acetate recrystallization, yield 66%.Reference examples 2The preparation of Faropenem(the 5R that reference examples 1 is prepared, 6S)-6-[(R)-the 1-hydroxyethyl]-2-[(R)-and the 2-TETRAHYDROFUROYL sulfenyl] penem-3-carboxylic acid propylene (73g, 0.224mol), 6.5g triphenylphosphine, 6.5g [four (triphenylphosphine)] palladium adds among the 500mL methylene dichloride l successively, the ethyl acetate solution that adds the 2 ethyl hexanoic acid sodium preparation of 500mL 0.5M, stirring at room 1 hour, stopped reaction adds 15mL water in reaction solution, stir 30min, suction filtration, this solid is dissolved in the 100mL water again, adds decolorizing with activated carbon 30min, filter, filtrate adds in the 500mL acetone, place crystallization, get Faropenem 66g, yield 96%.Find that by contrast the total recovery that two steps of reference examples remove hydroxyl and carboxyl-protecting group only has about 63.4%, and single stage method of the present invention removes the yield of hydroxyl and carboxyl-protecting group and can reach more than 90%.Preparation method of the present invention can the one-step removal hydroxyl and carboxyl on protecting group, shortened the production cycle, the deprotecting regent cost is low, toxicity is little, can not cause heavy metal remaining, and have higher reaction yield, is fit to very much the industrial production of raw material medicine.
Patent
Publication numberPriority datePublication dateAssigneeTitleCN1939924A *2006-09-082007-04-04鲁南制药集团股份有限公司Industrial production of Fallopeinan sodiumWO2008035153A2 *2006-08-022008-03-27Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of beta-lactam antibioticCN103059046A *2013-01-282013-04-24苏州二叶制药有限公司Preparation method of faropenemFamily To Family CitationsCN100522975C *2007-08-232009-08-05东北制药集团公司沈阳第一制药厂Method for preparing faropenemPublication numberPriority datePublication dateAssigneeTitleCN1884284A *2005-06-212006-12-27浙江金华康恩贝生物制药有限公司Process for the preparation of sodium faropenemCN1939924A *2006-09-082007-04-04鲁南制药集团股份有限公司Industrial production of Fallopeinan sodiumCN101125857A *2007-08-232008-02-20东北制药集团公司沈阳第一制药厂Method for preparing faropenemWO2008035153A2 *2006-08-022008-03-27Orchid Chemicals & Pharmaceuticals LimitedProcess for the preparation of beta-lactam antibiotic
EP0410727A1 *1989-07-261991-01-30Suntory LimitedProcesses for removing allyl groupsUS4997829A *1985-03-091991-03-05Suntory LimitedPenem compounds, and use thereofEP0574940A1 *1992-06-181993-12-22Tanabe Seiyaku Co., Ltd.Method for removing the protecting group for carboxyl groupWO2007039885A1 *2005-10-052007-04-12Ranbaxy Laboratories LimitedA process for the preparation of faropenemFamily To Family Citations Publication numberPriority datePublication dateAssigneeTitleCN102964357A *2012-11-112013-03-13苏州二叶制药有限公司Faropenem sodium and tablet thereofCN103059046A *2013-01-282013-04-24苏州二叶制药有限公司Preparation method of faropenemCN103880864A *2014-03-252014-06-25江苏正大清江制药有限公司Method for synthesizing faropenem sodiumCN104086516A *2014-07-182014-10-08成都樵枫科技发展有限公司Synthetic method of R-(+)-sulfotetrahydrofuran-2-formic acidCN101941981B *2009-07-032015-01-21湖南华纳大药厂有限公司Catalyst composition and method for preparing faropenem sodiumCN106860405A *2015-12-142017-06-20山东新时代药业有限公司A kind of faropenem sodium granules and preparation method thereofCN108840877A *2018-06-122018-11-20赤峰迪生药业有限责任公司A kind of preparation method of oxygen cephalosporin intermediate
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CAS-RN
Formula
Chemical Name
CAS Index Name
504-29-0
C5H6N2
2-aminopyridine
2-Pyridinamine
7790-94-5
ClHO3S
chlorosulfonic acid
Chlorosulfuric acid
56946-84-0
C5H5Cl2NO2S2
2,5-dichloro-N-methyl-3-thiophenesulfonamide
3-Thiophenesulfonamide, 2,5-dichloro-N-methyl-
3172-52-9
C4H2Cl2S
2,5-dichlorothiophene
Thiophene, 2,5-dichloro-
SYN Synthesis of lornoxicam (DE2838851)
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The sulfonation of 2,5-dichlorothiophene (I) with ClSO3H -SOCl2 gives 2,5-dichlorothiophene-3-sulfonic acid chloride (II), which by reaction with methylamine in CHCl3 yields the corresponding methylamide (III). The carboxylation of (III) with butyllithium and CO2 in ether affords 5-chloro-3-(N-methylsulfamoyl)thiophene-2-carboxylic acid (IV), which is esterified with PCl5 and methanol to the methyl ester (V). The condensation of (V) with methyl iodoacetate (VI) by means of NaH in DMF gives 5-chloro-3-[N-(methoxycarbonylmethyl)-N-methylsulfamoyl]thiophene-2-carboxylic acid methyl ester (VII), which is cyclized with sodium methoxide in methanol yielding 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylic acid methyl ester 1,1-dioxide (VIII). Finally, this compound is treated with 2-aminopyridine (IX) in refluxing xylene.
Lornoxicam is an NSAID indicated in the treatment of mild to moderate pain, as well as rheumatoid arthritis and osteoarthritis.
It was patented in 1977 and approved for medical use in 1997.[1] Brand names include Xefo and Xefocam among others.
Lornoxicam (chlortenoxicam) is a new nonsteroidal anti-inflammatory drug (NSAID) of the oxicam class with analgesic, anti-inflammatory and antipyretic properties. Lornoxicam differs from other oxicam compounds in its potent inhibition of prostaglandin biosynthesis, a property that explains the particularly pronounced efficacy of the drug. Lornoxicam is approved for use in Japan.
Medical uses
Lornoxicam is used for the treatment of various types of pain, especially resulting from inflammatory diseases of the joints, osteoarthritis, surgery, sciatica, and other inflammations.[2]
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Contraindications
The drug is contraindicated in patients who must not take other NSAIDs, possible reasons including salicylate sensitivity, gastrointestinal bleeding and bleeding disorders, and severe impairment of heart, liver or kidney function. Lornoxicam is not recommended during pregnancy and breastfeeding and is contraindicated during the last third of pregnancy.[2]
Adverse effects
Lornoxicam has side effects similar to other NSAIDs, most commonly mild ones like gastrointestinal disorders (nausea and diarrhea) and headache. Severe but seldom side effects include bleeding, bronchospasms and the extremely rare Stevens–Johnson syndrome.[2]
The present invention relates to the prepn. of high purity loroxicam. In particular, the prepn. method comprises a step of taking 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-Me thiazinecarboxylate-1,1-dioxide and 2-amino pyridine is used as the raw material and xylene is used as the solvent undergoes distn. reaction with solid acid catalyst, mixed gas obtained by the distn. reaction is condensed to obtain a condensate and solid acid catalyst is used to adsorb methanol in the condensate and the adsorbed condensate is recycled, filtering and refining to obtain loroxicam. The present inventive method distills out the methanol produced by the reaction to promote the pos. progress of the reaction and then catalyzes the absorption of methanol by H2SO4/MxOy solid super acid, so that the xylene returned to the reaction system does not contain methanol, which reduces the coking of the reaction, thereby improving product quality and yield. The prepd. lornoxicam has high purity, which can reach more than 99.9%, reduces the amt. of solvent and also suitable for industrial prodn.
PATENT
CN 112592356
The present invention relates to the prepn. of lornoxicam. In particular, the prepn. method comprises a step of taking 6-chloro-4-hydroxy-2-methyl-2-H-thieno[2,3-e]-1,2-thiazidecarboxylic acid Me ester-1,1-dioxide and 2-aminopyridine as raw materials, xylene is used as solvent, adding stabilizer, and carrying out aminolysis reaction, the solvent was removed by concn. under reduced pressure, adding org. solvent to make the slurry, filtering and refining to obtain lornoxicam. The inventive method uses p-toluene sulfonic acid as a stabilizer, while lowering the reaction temp., it promotes the reaction to proceed forward, and improve the product quality and yield; at the same time reduce the amt. of industrial solvents, the post-treatment process is optimized and the cost of the three wastes treatment is reduced.
Example: 1Preparation of 6-chloro-4-hydroxy-l,l-dioxo-l,2-dihydro-lX6-thieno [2,3-e][l,2] thiazine-3-carboxylic acid methyl ester To the mixture of methanol ( 1000 ml) and 5-chloro-3-(methoxy carbonyl methyl sulfamoyl)-thiophene-2-carboxylicacid methyl ester ( 100 g ,0.305 moles), added sodium methoxide solution (200 ml ) at 25-30°C over a period of 30-45 min. The resulting mixture was stirred for 60 min at same temperature; allowed to heat at 65-75°C and stirred for 10-12 hrs. After completion of reaction, methanol was distilled out under reduced pressure to obtained titled residual product which is directly used to next step
(Example-2). Example: – 2:Preparation of 6-chloro-4-hydroxy-2-methyl-l,l-dioxo-l,2-dihydro-U6- thieno[2,3-e][l,2] thiazine-3-carboxylic acid methyl ester 6-chloro-4-hydroxy-1,1 -dioxo-1,2-dihydro-1 X,6-thieno [2,3-e][ 1,2] thiazine-3-carboxylic acid methyl ester was suspended in DM water (500 ml) and cooled to 10-15° C, dimethyl sulphate ( 70 g) was slowly added to the mixture at 10-15°C in 30 min. The reaction mixture was raised to 25-30°C and maintained for 2-3 hours at same temperature. After completion of reaction, mixture was cooled to 10-15°C, methylene dichloride (1600 ml) was added, reaction mixture pH was adjust to 1.0 -2.0 with hydrochloric acid at 10-15° C, stir reaction mixture to separate the layers. The methylene dichloride layer was distilled out completely at below 30°C to get an residue, followed by addition of methanol (60 ml) and distilled out methanol completely under vacuum at below 50°C to get an residue; further it was crystallized by addition of methanol 190 ml and stirred for 30 min at 50-55°C; cooled the reaction mixture at 25-30°C and stirred for 60 min at same temperature. The resultant solid was filtered, washed with methanol (40 ml) and dried at 50-55°C for 4 – 6 hrs to obtain the titled product
Example: 3Preparation of 6-Chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e]-l,2-thiazine-3-carboxamide 1,1-dioxide (Lornoxicam) 6-chloro-4-hydroxy-2-methyl-l, 1 -dioxo-1,2-dihydro-l X.6-thieno[2,3-e][l ,2] thiazine-3-carboxylic acid methyl ester ( 50 g 0.161 moles) was suspended in O-xylene (500 ml) and allow to stirred at 70-75°C to obtained clear solution. To this clear solution slowly added the mixture of THF ( 50 ml) solution of 2-Amino pyridine ( 14 g ) and ethyl magnesium bromide 2 molar solution (100 ml) at 70-75°C and allow to stirred for 3-4 hrs at same temperature. After completion of reaction, the dilute hydrochloric acid was added to the mixture at 10-15°C and stirred for 60 min. The resultant solid was filtered, washed with water (100 ml) to obtain crude Lornoxicam.
Example: 4Preparation of 6-Chloro-4-hydroxy-2-methyl-N-2-pyridinyl-2H-thieno[2,3-e)-l,2-thiazine-3-carboxamide 1,1-dioxide (Lornoxicam) 6-chloro-4-hydroxy-2-methyl-l,l-dioxo-l,2-dihydro-R6-thieno[2,3-e][l,2] thiazine-3-carboxylic acid methyl ester ( 50 g 0.161 moles) was suspended in O-xylene (500 ml) and allow to stirred at 70-75°C to obtained clear solution. To this clear solution slowly added the mixture of THF ( 50 ml) solution of 2-Amino pyridine ( 14 g ) and isopropyl magnesium bromide 2 molar solution (100 ml) at 70-75°C and allow to stirred for 3-4 hrs at same temperature. After completion of reaction, the dilute hydrochloric acid was added to the mixture at 10-15°C and stirred for 60 min. The resultant solid was filtered, washed with water (100 ml) to obtain crude Lornoxicam.
Example: 5Purification of Lornoxicam.The crude Lornoxicam was suspended in methanol (500 ml) and cooled to 5-10°C, resulting suspension was basified to pH 11-13 by using sodium hydroxide solution to get clear solution; followed by filtration through hyflo bed; the obtain filtrate was acidified to pH 4.5 – 5.0 with dil. HC1 (1:1) at 5-10°C; stirred the slurry for 30 min. at 5-10°C. The resultant solid was filtered, washed with DM water (100 ml) and dried at 50-55°C to obtained pure Lornoxicam.
.EXAMPLES:Preparation of Lornoxicam crudeExample ITo 1200ml o-xylene, 20gm Methyl-6-chloro-4-hydroxy-2-methyl-2//-thieno [2, 3-e] [1, 2] thiazine-3- carboxyate 1,1-dioxide and 6.44gm 2-aminopyridine was added. The reaction mass was stirred under nitrogen atmosphere. Temperature was raised to 140-145°C and maintained for 6hrs. The reaction mass was cooled to 30-35°C and nitrogen was removed. Reaction mass was further stirred for 3hrs- Filtered and washed twice with 50ml of o-xylene. 19.8gm of crude Lornoxicam was obtained. Purification of Lornoxicam crude
Example 219.8gm of crude Lornoxicam was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around Ihr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C, til! the reaction mass reached pH of 2-3, and then stirred for around I hi*. The reaction mass was cooled to room temperature, filtered, and then washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 19.1 gm of pure Lornoxicam was obtained. (HPLC purity- 99.95%)
Example 3!7.9gm of crude Lornoxicam (prepared as per example 1) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around Ihr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C till the reaction mass reached pH of 2-3, and then stirred for around Ihr. The reaction mass was cooled to room temperature, filtered and then washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 17.2 gm of pure Lornoxicam was obtained. (HPLC purity- 99.9%) clear solution and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around lhr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C, till the reaction mass reached pH of 2-3, and then stirred for around lhr. The reaction mass was cooled to 30-35°C, filtered and then washed with 1:1 mixture of isopropyl alcohol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 4.85 gm of pure Lornoxicam was obtained. (HPLC purity- 99.8%)
Example 55 gm of crude Lornoxicam (prepared as per example 1) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and ethanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 5% activated charcoal was further added. The reaction mass was heated to 50-55°C and stirred for around lhr followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added at 50-55° C, til! the reaction mass reached pH of 2-3 and then stirred for around lhr. The reaction mass was cooled to 30-35°C and filtered, washed with 1:1 mixture of ethanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 4.8 gm of pure Lornoxicam was obtained. (HPLC purity- 99.8%)
Example 619.4 gm of crude Lornoxicam (prepared as per example I) was added to the solvent mixture of water (5 vol with respect to Lornoxicam) and methanol (10 vol with respect to Lornoxicam) under stirring. Subsequently 48% sodium hydroxide was added to form a clear solution, and 20% activated charcoal was further added. The reaction mass was stirred for around lhr at room temperature followed by filtration through Hyflo. To the filtrate, mixture of hydrochloric acid and water in the ratio of 1:1 was added till the reaction mass reached pH of 2-3 and then stirred for around 1 hr. The reaction mass was * filtered and washed with 1:1 mixture of methanol and water. Purified wet Lornoxicam was dried at 60-65°C for 6-8hrs. 18.9 gm of pure Lornoxicam was obtained. (HPLC purity- 99.3%).
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2-propylpentanoic acid, DIVALPROEX SODIUM, 76584-70-8, Valproate semisodium, Epival, Depakote, Sodium divalproate, Semisodium Valproate, Abbott 50711, ValdisovalValproic Acid CAS Registry Number: 99-66-1 CAS Name: 2-Propylpentanoic acid Additional Names: 2-propylvaleric acid; di-n-propylacetic acid Trademarks: Convulex (Pharmacia); Depakene (Abbott) Molecular Formula: C8H16O2 Molecular Weight: 144.21 Percent Composition: C 66.63%, H 11.18%, O 22.19% Literature References: Antiepileptic; increases levels of g-aminobutyric acid (GABA) in the brain. Prepn: B. S. Burton, Am. Chem. J.3, 385 (1882); E. Oberreit, Ber.29, 1998 (1896); M. Tiffeneau, Y. Deux, Compte Rend.212, 105 (1941). Anticonvulsant activity: H. Meunier et al.,Therapie18, 435 (1963). Toxicity data: Jenner et al.,Food Cosmet. Toxicol.2, 327 (1964). Comprehensive description: Z. L. Chang, Anal. Profiles Drug Subs.8, 529-556 (1979). Review of teratogenicity studies: H. Nau et al.,Pharmacol. Toxicol.69, 310-321 (1991); R. Alsdorf, D. F. Wyszynski, Expert Opin. Drug Safety4, 345-353 (2005). Review of pharmacology and clinical experience in epilepsy: E. M. Rimmer, A. Richens, Pharmacotherapy5, 171-184 (1985); in psychiatric disease: D. R. P. Guay, ibid.15, 631-647 (1995); in migraine prophylaxis: C. E. Shelton, J. F. Connelly, Ann. Pharmacother.30, 865-866 (1996). Review of pharmacodynamics and mechanisms of action: W. Löscher, Prog. Neurobiol.58, 31-59 (1999). Properties: Colorless liquid with characteristic odor. bp 219.5°. nD24.5 1.425. d40 0.9215. pKa 4.6. Very sol in organic solvents. Soly in water: 1.3 mg/ml. LD50 orally in rats: 670 mg/kg (Jenner). Boiling point: bp 219.5° pKa: pKa 4.6 Index of refraction:nD24.5 1.425 Density: d40 0.9215 Toxicity data: LD50 orally in rats: 670 mg/kg (Jenner) Derivative Type: Sodium salt (1:1) CAS Registry Number: 1069-66-5 Additional Names: Sodium valproate Trademarks: Depacon (Abbott); Depakin (Sanofi-Synthelabo); Dépakine (Sanofi-Aventis); Epilim (Sanofi-Aventis); Ergenyl (Sanofi-Synthelabo); Leptilan (Dolorgiet); Orfiril (Desitin) Molecular Formula: C8H15NaO2 Molecular Weight: 166.19 Percent Composition: C 57.82%, H 9.10%, Na 13.83%, O 19.25% Properties: White, odorless, crystalline, deliquescent powder. pKa 4.8. Hygroscopic. One gram is sol in 0.4 ml water; 1.5 ml ethanol; 5 ml methanol. Practically insol in common organic solvents. LD50 orally in mice: 1700 mg/kg (Meunier). pKa: pKa 4.8 Toxicity data: LD50 orally in mice: 1700 mg/kg (Meunier) Derivative Type: Sodium salt (2:1) CAS Registry Number: 76584-70-8 Additional Names: Sodium hydrogen bis(2-propylpentanoate); divalproex sodium; valproate semisodium Manufacturers’ Codes: Abbott 50711 Trademarks: Depakote (Abbott); Valcote (Abbott) Molecular Formula: C16H31NaO4 Molecular Weight: 310.40 Percent Composition: C 61.91%, H 10.07%, Na 7.41%, O 20.62% Derivative Type: Magnesium salt Trademarks: Depamag (Sigma-Tau) Molecular Formula: C16H30MgO4 Molecular Weight: 310.71 Percent Composition: C 61.85%, H 9.73%, Mg 7.82%, O 20.60% Therap-Cat: Anticonvulsant; antimanic; antimigraine.Keywords: Anticonvulsant; Antimigraine; Antimanic.
Synthesis Reference
Daniel Aubert, Francis Blanc, Henri Desmolin, Michel Morre, Lucette Sindely, “Valproic acid preparations.” U.S. Patent US5017613, issued January, 1965.
https://patents.google.com/patent/WO2007004238A2/enDivalproex sodium is one of the most widely used epileptic agents presently available in the market. Both the constituents, valproic acid and sodium valproate themselves have also been used for the treatment of epileptic seizures and convulsions. But their utility has remained restricted since valproic acid is a liquid and is difficult to formulate for an oral dosage form whereas sodium valproate is a hygroscopic solid with poor stability characteristics. Divalproex sodium is an oligomer having 1:1 molar ratio of valproic acid and sodium valproate containing 4 to 6 units. The relevant prior art includes US 4,988,731 (’73I) relates to a non-hygroscopic stable sodium hydrogen divalproate oligomer. Its probable structure is shown in Fig 1
Fig 1 – Divalproex sodiumWhere M is a about 2.As can be seen from the displayed structure, one mole each of the valproic acid forms coordinate bonds with the sodium of the sodium valproate molecule, and the valproate ion is ionically bonded to the sodium atom. The structure is thus consistent with the unique characteristic of the compound. However the preferred mode of representing Divalproex sodium is by reference to single compound of the formula{(CH3CH2CH2)2CHCO2} {(CH3CH2CH2)2CHCO2}Na, HThe said patent also describes two alternative processes for the preparation of the oligomer. According to one aspect, the oligomer is produced by dissolving sodium valproate and valproic acid in equimolar amount in acetone and crystallizing from chilled acetone at around O0C. Alternatively Divalproex sodium can be isolated from a two component liquid medium, which includes acetone where in half equivalent of NaOH to the valproic acid present, preferable as a solution in an acetone miscible solvent eg. water. The new compound can be recovered from the liquid phase by evaporating the solvent(s) and, if desired, the new compound can be recrystallized, for instance from acetonitrile or others or the material may be spay-dried, lyophilized or purified by chromatography.US ‘731 claims yield of 90% of theory.Drawbacks of the above mentioned reported methods for the preparation of Divalproex sodium described in US 4988731 are difficult to reproduce on a large scale and provides inconsistent yields and the material obtained is not always free flowing in nature. The process involves the crystallization of a 1:1 mixture of valproic acid and sodium valproate from a chilled solution of acetone, followed by washing with chilled acetone. Divalproex sodium is as such fairly soluble in acetone at temperatures above 1O0C and extreme care has to be. taken while performing washing with chilled acetone as any rise in temperature would lead to the loss of yield. This problem actually comes to the fore while scaling up the process during commercialization since during centrifugation of the large volume the temperature of the mixture rises and acetone has to be cooled below O0C, which require large amount of liquid nitrogen or dry ice. Moreover it was also observed that due to the cooled nature of the solvent, the isolated Divalproex sodium absorbs considerable amount of moisture and therefore requires longer time to dry eventually leading to longer time cycle for the otherwise simple single step process. Also the high moisture content in the recovered acetone makes it unsuitable for reuse. Alternatively, to avoid absorption of water, the centrifugation had to be carried out under a blanket of dry nitrogen gas. These additional infrastructural loads add to input costs eventually making the otherwise single step low cost process becoming uncompetitive and economically unviable.Similarly the other process involves the addition of half molar equivalent of sodium hydroxide dissolved in water to valproic acid and the solvent has to be evaporated to obtain crude product, which has to be recrystallized to get Divalprox of the desired specification. The process is operationally tedious and requires the reduction in the level of water in the reaction mass via evaporation of the solvent followed by re- crystallization from acetonitrile making the process lengthy and economically unviable. There is therefore a need for operationally making this single step process more efficient and high yieldingExample I:To lOOg of Valproic acid with stirring at 20-300C, powdered NaOH ( 13g; half molar) is added & the resulting reaction mixture is stirred at 40-500C for 1 hr. Then acetonitrile(600ml) is added to obtain clear solution at 40-500C and the solution is charcoalized at 40-500C followed by filtration at 40-500C through hyflo-bed. The resultant reaction mixture was stirred at 10-200C for 2-3 hr. The solid , thus obtained, was filtered and product was dried at 40-450C for 10-12 hr. (102.25g, 95%)Example II;To lOOg of Valproic acid with stirring at 20-300C, powdered NaOH (13g; half molar) is added & the resulting reaction mixture is stirred at 30-400C for 1 hr. Then acetone (600ml) is added to obtain clear solution at 30-400C and the material is charcoalized at 30-400C followed by filtration through hyflo-bed. The resultant reaction solution was stirred at -5°C to -1O0C for 2-3 hr. The solid , thus obtained, was filtered and product was dried at 40-450C for 10-12 hr. ( 55g, 51.11%) Example III:To a solution of Valproic acid (10Og) in dichloromethane (200ml) at 20-300C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 30- 400C for 1 hr to get clear solution. Then acetonitrile (600ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-50C for 2-3 hr followed by filtration. The product was dried at 40-450C for 10-12 hr. (10Og; 93%)Example IV:To a solution of Valproic acid (10Og) in diisopropyl ether(200ml) at 20-300C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-500C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-50C for 2-3 hr followed by filtration. The product was dried at 40-450C for 10-12 hr. (104g; 96.65%)Example V:To a solution of Valproic acid (10Og) in methyl tertiary butyl ether(200ml) at 20- 300C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-500C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-50C for 2-3 hr followed by filtration. The product was dried at 40-450C for 10-12 hr. (102g;94.79%)Example VI:To a solution of Valproic acid (10Og) in toluene (200ml) at 20-300C, powdered caustic (13g ; half molar) is added & the reaction mixture is stirred at 40-500C for 1 hr to get clear solution. Then acetonitrile (800ml) is added to it inorder to crystallize the product. The solid, thus obtained, is further stirred at 0-50C for 2-3 hr followed by filtration. The product was dried at 40-450C for 10-12 hr. (101g; 93.87%)Example VII: A mixture of sodium valproate (6Og) and valproic acid (52.04g) was taken in acetonitrile (800ml) and heated at reflux to obtain a clear solution, which was filtered through hyflo-bed to remove suspended particles. Then the solution was stirred at 10- 200C for 2-3 hr. The solid, thus obtained, was filtered and washed with acetonitrile (100ml). The product was dried at 40-450C for 10-12 hr. (105g ; 93.75%)Example VIII;To a solution of valproic acid (10Og) in methanol (200ml) at 20-300C5 caustic (13g; half molar) is added & the reaction mixture is stirred at 20-300C for 1 hr. Then the methanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring. The reaction mixture was further stirred at 0-50C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-45°C for 10-12 hr.(102g; ~ 95%) Example IX:To a solution of valproic acid (10Og) in methanol (200ml) at 20-300C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-300C for 1 hr. Then the methanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -1O0C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-450C for 10-12 hr.(54g; ~ 50.11%)Example X:To a solution of valproic acid (10Og) in ethanol (200ml) at 20-300C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-300C for 1 hr. Then the ethanol was recovered at reduced pressure and acetonitrile (600ml) is added to it with stirring.The reaction mixture was further stirred at 0-50C for 2-3 hr. The solid, thus obtained, is filtered, washed with acetonitrile (100ml) and product was dried at 40-450C for 10-12 hr.(101g; ~ 93.87%)Example XI: To a solution of valproic acid (10Og) in ethanol (200ml) at 20-30°C, caustic (13g; half molar) is added & the reaction mixture is stirred at 20-300C for 1 hr. Then the ethanol was recovered at reduced pressure and acetone (600ml) is added to it with stirring. The reaction mixture was further stirred at -5°C to -100C for 2-3 hr. The solid, thus obtained, is filtered, washed with chilled acetone (100ml) and product was dried at 40-450C for 10-12 hr.(55g; ~ 51%)ADVANTAGES:> The process is high yielding. > The process produces Divalproex sodium with improved flowability.> The process produces Divalproex sodium that is non-hygroscopic and more stable.> The process is industrially feasible, precise, reproducible and does not require sophisticated infrastructure.
Divalproex Sodium is a stable coordination compound comprised of sodium valproate and valproic acid with anticonvulsant and antiepileptic activities. Divalproex dissociates to the valproate ion in the gastrointestinal tract. This agent binds to and inhibits gamma-aminobutyric acid (GABA) transaminase and its anticonvulsant activity may be exerted by increasing brain concentration of GABA and by inhibiting enzymes that catabolize GABA or block the reuptake of GABA into glia and nerve endings. Divalproex may also work by suppressing repetitive neuronal firing through inhibition of voltage-sensitive sodium channels.
Valproate semisodium is a mixture of valproic acid and its sodium salt in a 1:1 molar ratio. It is used for the management and treatment of seizure disorders, mania, and prophylactic treatment of migraine headache. It has a role as an antimanic drug, an anticonvulsant and a GABA agent. It contains a valproic acid and a sodium valproate.
Divalproex sodium, valproate sodium, and valproic acid, are all similar medications that are used by the body as valproic acid. Therefore, the term valproic acid will be used to represent all of these medications in this discussion.
Common side effects of valproate include nausea, vomiting, sleepiness, and dry mouth.[2] Serious side effects can include liver failure, and regular monitoring of liver function tests is therefore recommended.[2] Other serious risks include pancreatitis and an increased suicide risk.[2] Valproate is known to cause serious abnormalities in babies if taken during pregnancy,[2][3] and as such it is not typically recommended for women of childbearing age who have migraines.[2]
Valproate was first made in 1881 and came into medical use in 1962.[7] It is on the World Health Organization’s List of Essential Medicines[8] and is available as a generic medication.[2] It is marketed under the brand names Depakote, among others.[2] In 2018, it was the 131st most commonly prescribed medication in the United States, with more than 5 million prescriptions.[9][10]
There is limited evidence that adding valproate to antipsychotics may be effective for overall response and also for specific symptoms, especially in terms of excitement and aggression. Valproate was associated with a number of adverse events among which sedation and dizziness appeared more frequently than in the control groups.[18]
showOutcomeFindings in wordsFindings in numbersQuality of evidence
Valproate is also used to prevent migraine headaches. Because this medication can be potentially harmful to the fetus, valproate should be considered for those able to become pregnant only after the risks have been discussed.[22]
There is evidence that valproic acid may cause premature growth plate ossification in children and adolescents, resulting in decreased height.[26][27][28][29] Valproic acid can also cause mydriasis, a dilation of the pupils.[30] There is evidence that shows valproic acid may increase the chance of polycystic ovary syndrome (PCOS) in women with epilepsy or bipolar disorder. Studies have shown this risk of PCOS is higher in women with epilepsy compared to those with bipolar disorder.[31] Weight gain is also possible.[32]
Valproate causes birth defects;[33] exposure during pregnancy is associated with about three times as many major abnormalities as usual, mainly spina bifida with the risks being related to the strength of medication used and use of more than one drug.[34][35] More rarely, with several other defects, including a “valproate syndrome”.[36] Characteristics of this valproate syndrome include facial features that tend to evolve with age, including a triangle-shaped forehead, tall forehead with bifrontal narrowing, epicanthic folds, medial deficiency of eyebrows, flat nasal bridge, broad nasal root, anteverted nares, shallow philtrum, long upper lip and thin vermillion borders, thick lower lip and small downturned mouth.[37] While developmental delay is usually associated with altered physical characteristics (dysmorphic features), this is not always the case.[38]
Children of mothers taking valproate during pregnancy are at risk for lower IQs.[39][40][41] Maternal valproate use during pregnancy increased the probability of autism in the offspring compared to mothers not taking valproate from 1.5% to 4.4%.[42] A 2005 study found rates of autism among children exposed to sodium valproate before birth in the cohort studied were 8.9%.[43] The normal incidence for autism in the general population is estimated at less than one percent.[44] A 2009 study found that the 3-year-old children of pregnant women taking valproate had an IQ nine points lower than that of a well-matched control group. However, further research in older children and adults is needed.[45][46][47]
Sodium valproate has been associated with paroxysmal tonic upgaze of childhood, also known as Ouvrier–Billson syndrome, from childhood or fetal exposure. This condition resolved after discontinuing valproate therapy.[48][49]
Women who intend to become pregnant should switch to a different medication if possible or decrease their dose of valproate.[50] Women who become pregnant while taking valproate should be warned that it causes birth defects and cognitive impairment in the newborn, especially at high doses (although valproate is sometimes the only drug that can control seizures, and seizures in pregnancy could have worse outcomes for the fetus than exposure to valproate). Studies have shown that taking folic acid supplements can reduce the risk of congenital neural tube defects.[22] The use of valproate for migraine or bipolar disorder during pregnancy is contraindicated in the European Union, and the medicines are not recommended for epilepsy during pregnancy unless there is no other effective treatment available.[51]
Elderly
Valproate in elderly people with dementia caused increased sleepiness. More people stopped the medication for this reason. Additional side effects of weight loss and decreased food intake were also associated with one-half of people who become sleepy.[22]
Excessive amounts of valproic acid can result in sleepiness, tremor, stupor, respiratory depression, coma, metabolic acidosis, and death.[54] In general, serum or plasma valproic acid concentrations are in a range of 20–100 mg/l during controlled therapy, but may reach 150–1500 mg/l following acute poisoning. Monitoring of the serum level is often accomplished using commercial immunoassay techniques, although some laboratories employ gas or liquid chromatography.[55] In contrast to other antiepileptic drugs, at present there is little favorable evidence for salivary therapeutic drug monitoring. Salivary levels of valproic acid correlate poorly with serum levels, partly due to valproate’s weak acid property (pKa of 4.9).[56]
Valproate inhibits CYP2C9, glucuronyl transferase, and epoxide hydrolase and is highly protein bound and hence may interact with drugs that are substrates for any of these enzymes or are highly protein bound themselves.[24] It may also potentiate the CNS depressant effects of alcohol.[24] It should not be given in conjunction with other antiepileptics due to the potential for reduced clearance of other antiepileptics (including carbamazepine, lamotrigine, phenytoin and phenobarbitone) and itself.[24] It may also interact with:[22][24][62]
Aspirin: may increase valproate concentrations. May also interfere with valproate’s metabolism.
Benzodiazepines: may cause CNS depression and there are possible pharmacokinetic interactions.
Carbapenem antibiotics: reduce valproate levels, potentially leading to seizures.
Cimetidine: inhibits valproate’s metabolism in the liver, leading to increased valproate concentrations.
Erythromycin: inhibits valproate’s metabolism in the liver, leading to increased valproate concentrations.
Ethosuximide: valproate may increase ethosuximide concentrations and lead to toxicity.
Felbamate: may increase plasma concentrations of valproate.
Mefloquine: may increase valproate metabolism combined with the direct epileptogenic effects of mefloquine.
Primidone: may accelerate metabolism of valproate, leading to a decline of serum levels and potential breakthrough seizure.
Rifampicin: increases the clearance of valproate, leading to decreased valproate concentrations
Warfarin: valproate may increase free warfarin concentration and prolong bleeding time.
Zidovudine: valproate may increase zidovudine serum concentration and lead to toxicity.
Pharmacology
Pharmacodynamics
Although the mechanism of action of valproate is not fully understood,[24] traditionally, its anticonvulsant effect has been attributed to the blockade of voltage-gated sodium channels and increased brain levels of gamma-aminobutyric acid (GABA).[24] The GABAergic effect is also believed to contribute towards the anti-manic properties of valproate.[24] In animals, sodium valproate raises cerebral and cerebellar levels of the inhibitory synaptic neurotransmitter, GABA, possibly by inhibiting GABA degradative enzymes, such as GABA transaminase, succinate-semialdehyde dehydrogenase and by inhibiting the re-uptake of GABA by neuronal cells.[24]
Prevention of neurotransmitter-induced hyperexcitability of nerve cells, via Kv7.2 channel and AKAP5, may also contribute to its mechanism.[63] Also, it has been shown to protect against a seizure-induced reduction in phosphatidylinositol (3,4,5)-trisphosphate (PIP3) as a potential therapeutic mechanism.[64]
It also has histone-deacetylase-inhibiting effects. The inhibition of histone deacetylase, by promoting more transcriptionally active chromatin structures, likely presents the epigenetic mechanism for regulation of many of the neuroprotective effects attributed to valproic acid. Intermediate molecules mediating these effects include VEGF, BDNF, and GDNF.[65][66]
Taken by mouth, valproate is rapidly and virtually completely absorbed from the gut.[71] When in the bloodstream, 80–90% of the substance are bound to plasma proteins, mainly albumin. Protein binding is saturable: it decreases with increasing valproate concentration, low albumin concentrations, the patient’s age, additional use of other drugs such as aspirin, as well as liver and kidney impairment.[73][74] Concentrations in the cerebrospinal fluid and in breast milk are 1 to 10% of blood plasma concentrations.[71]
In adult patients taking valproate alone, 30–50% of an administered dose is excreted in urine as the glucuronide conjugate.[75] The other major pathway in the metabolism of valproate is mitochondrial beta oxidation, which typically accounts for over 40% of an administered dose.[75] Typically, less than 20% of an administered dose is eliminated by other oxidative mechanisms.[75] Less than 3% of an administered dose of valproate is excreted unchanged (i.e., as valproate) in urine.[75] Only a small amount is excreted via the faeces.[71]Elimination half-life is 16±3 hours and can decrease to 4–9 hours when combined with enzyme inducers.[71][74]
Valproic acid was first synthesized in 1882 by Beverly S. Burton as an analogue of valeric acid, found naturally in valerian.[76] Valproic acid is a carboxylic acid, a clear liquid at room temperature. For many decades, its only use was in laboratories as a “metabolically inert” solvent for organic compounds. In 1962, the French researcher Pierre Eymard serendipitously discovered the anticonvulsant properties of valproic acid while using it as a vehicle for a number of other compounds that were being screened for antiseizure activity. He found it prevented pentylenetetrazol-induced convulsions in laboratory rats.[77] It was approved as an antiepileptic drug in 1967 in France and has become the most widely prescribed antiepileptic drug worldwide.[78] Valproic acid has also been used for migraine prophylaxis and bipolar disorder.[79]
Limited (depends on the seizure type; it can help with certain kinds of seizures: drug-resistant epilepsy, partial and absence seizures, can be used against glioblastoma and other tumors both to improve survival and treat seizures, and against tonic–clonic seizures and status epilepticus).[81][82][83][84]
Weak evidence. Not recommended for agitation in people with dementia.[90] Increased rate of adverse effects, including a risk of serious adverse effects.[90]
In 2012, pharmaceutical company Abbott paid $1.6 billion in fines to US federal and state governments for illegal promotion of off-label uses for Depakote, including the sedation of elderly nursing home residents.[110][111]
Valproate exists in two main molecular variants: sodium valproate and valproic acid without sodium (often implied by simply valproate). A mixture between these two is termed semisodium valproate. It is unclear whether there is any difference in efficacy between these variants, except from the fact that about 10% more mass of sodium valproate is needed than valproic acid without sodium to compensate for the sodium itself.[114]
Depalept and Depalept Chrono (extended release tablets) are equivalent to Epilim and Epilim Chrono above. Manufactured and distributed by Sanofi-Aventis.
Mexico – Epival and Epival ER (extended release) by Abbott Laboratories
United Kingdom – Depakote (for psychiatric conditions) and Epilim (for epilepsy) by Sanofi-Aventis and generics
United States – Depakote and Depakote ER (extended release) by Abbott Laboratories and generics[22]
India – Valance and Valance OD by Abbott Healthcare Pvt Ltd, Divalid ER by Linux laboratories Pvt Ltd, Valex ER by Sigmund Promedica, Dicorate by Sun Pharma
Germany – Ergenyl Chrono by Sanofi-Aventis and generics
Chile – Valcote and Valcote ER by Abbott Laboratories
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
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^ Guo CY, Ronen GM, Atkinson SA (2002). “Long-term valproate and lamotrigine treatment may be a marker for reduced growth and bone mass in children with epilepsy”. Epilepsia. 42 (9): 1141–7. doi:10.1046/j.1528-1157.2001.416800.x. PMID11580761. S2CID25499280.
^ Bilo, Leonilda; Meo, Roberta (October 2008). “Polycystic ovary syndrome in women using valproate: a review”. Gynecological Endocrinology. 24 (10): 562–70. doi:10.1080/09513590802288259. PMID19012099. S2CID36426338.
^ Koch S, Göpfert-Geyer I, Jäger-Roman E, et al. (February 1983). “[Anti-epileptic agents during pregnancy. A prospective study on the course of pregnancy, malformations and child development]”. Dtsch. Med. Wochenschr. (in German). 108 (7): 250–7. doi:10.1055/s-2008-1069536. PMID6402356.
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^ Luat, AF (20 September 2007). “Paroxysmal tonic upgaze of childhood with co-existent absence epilepsy”. Epileptic Disorders. 9(3): 332–6. doi:10.1684/epd.2007.0119 (inactive 31 May 2021). PMID17884759.
^ Mock CM, Schwetschenau KH (2012). “Levocarnitine for valproic-acid-induced hyperammonemic encephalopathy”. Am J Health Syst Pharm. 69 (1): 35–39. doi:10.2146/ajhp110049. PMID22180549.
^ Matsuoka M, Igisu H (1993). “Comparison of the effects of L-carnitine, D-carnitine and acetyl-L-carnitine on the neurotoxicity of ammonia”. Biochem. Pharmacol. 46 (1): 159–164. doi:10.1016/0006-2952(93)90360-9. PMID8347126.
^ Jump up to:abcdef Haberfeld H, ed. (2021). Austria-Codex (in German). Vienna: Österreichischer Apothekerverlag. Depakine chrono retard 300 mg Filmtabletten.
^ Kumar, S.; Wong, H.; Yeung, S. A.; Riggs, K. W.; Abbott, F. S.; Rurak, D. W. (2000). “Disposition of valproic acid in maternal, fetal, and newborn sheep. II: Metabolism and renal elimination”. Drug Metabolism and Disposition: The Biological Fate of Chemicals. 28(7): 857–864. PMID10859160.
^ Schneemann; Young, Lloyd; Koda-Kimble, Mary Anne, eds. (2001). Angewandte Arzneimitteltherapie (in German). Springer. pp. 28–29. ISBN3540413561.
^ Vasudev K, Mead A, Macritchie K, Young AH (2012). “Valproate in acute mania: is our practice evidence based?”. Int J Health Care Qual Assur. 25 (1): 41–52. doi:10.1108/09526861211192395. PMID22455007.
^ Bond DJ, Lam RW, Yatham LN (2010). “Divalproex sodium versus placebo in the treatment of acute bipolar depression: a systematic review and meta-analysis”. J Affect Disord. 124 (3): 228–334. doi:10.1016/j.jad.2009.11.008. PMID20044142.
^ Candelaria M, Herrera A, Labardini J, González-Fierro A, Trejo-Becerril C, Taja-Chayeb L, Pérez-Cárdenas E, de la Cruz-Hernández E, Arias-Bofill D, Vidal S, Cervera E, Dueñas-Gonzalez A (2011). “Hydralazine and magnesium valproate as epigenetic treatment for myelodysplastic syndrome. Preliminary results of a phase-II trial”. Ann. Hematol. 90 (4): 379–387. doi:10.1007/s00277-010-1090-2. PMID20922525. S2CID13437134.
^ Bug G, Ritter M, Wassmann B, Schoch C, Heinzel T, Schwarz K, Romanski A, Kramer OH, Kampfmann M, Hoelzer D, Neubauer A, Ruthardt M, Ottmann OG (2005). “Clinical trial of valproic acid and all-trans retinoic acid in patients with poor-risk acute myeloid leukemia”. Cancer. 104 (12): 2717–2725. doi:10.1002/cncr.21589. PMID16294345. S2CID1802132.
^ Kuendgen A, Schmid M, Schlenk R, Knipp S, Hildebrandt B, Steidl C, Germing U, Haas R, Dohner H, Gattermann N (2006). “The histone deacetylase (HDAC) inhibitor valproic acid as monotherapy or in combination with all-trans retinoic acid in patients with acute myeloid leukemia”. Cancer. 106 (1): 112–119. doi:10.1002/cncr.21552. PMID16323176. S2CID43747497.
^ Coronel J, Cetina L, Pacheco I, Trejo-Becerril C, González-Fierro A, de la Cruz-Hernandez E, Perez-Cardenas E, Taja-Chayeb L, Arias-Bofill D, Candelaria M, Vidal S, Dueñas-González A (2011). “A double-blind, placebo-controlled, randomized phase III trial of chemotherapy plus epigenetic therapy with hydralazine valproate for advanced cervical cancer. Preliminary results”. Med. Oncol. 28 Suppl 1: S540–6. doi:10.1007/s12032-010-9700-3. PMID20931299. S2CID207372333.
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Publication numberPriority datePublication dateAssigneeTitleCA1144558A *1979-10-221983-04-12Francis E. FischerProcess for making sodium hydrogen divalproateUS4988731A *1979-08-201991-01-29Abbott LaboratoriesSodium hydrogen divalproate oligomerUS5212326A *1979-08-201993-05-18Abbott LaboratoriesSodium hydrogen divalproate oligomerWO2001032595A1 *1999-11-022001-05-10Cilag AgMethod for producing compounds of the valproinic acidUS20030018215A1 *2001-06-292003-01-23Procos S.P.A.Process for the preparation of sodium divalproatePublication numberPriority datePublication dateAssigneeTitleUS20110040122A1 *2009-08-112011-02-17Sci Pharmtech, Inc.Method for preparing metal salt of valproic acidCN102942467A *2012-10-172013-02-27山东方明药业集团股份有限公司Preparation method of divalproex sodiumCN103183600A *2011-12-302013-07-03北大方正集团有限公司Method for preparing divalproex sodium
CAS Registry Number: 137-58-6 CAS Name: 2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide Additional Names: 2-diethylamino-2¢,6¢-acetoxylidide; w-diethylamino-2,6-dimethylacetanilide; lignocaine Trademarks: Cuivasil (IDC); Lidoderm (Hind); LidoPosterine (Kade); Vagisil (Combe) Molecular Formula: C14H22N2O Molecular Weight: 234.34 Percent Composition: C 71.75%, H 9.46%, N 11.95%, O 6.83% Literature References: Long-acting, membrane stabilizing agent against ventricular arrhythmia. Originally developed as a local anesthetic. Prepn: N. M. Löfgren, B. J. Lundqvist, US2441498 (1948 to Astra); A. D. H. Self, A. P. T. Easson, GB706409 (1954 to May & Baker); I. P. S. Hardie, E. S. Stern, GB758224 (1956 to J. F. Macfarlane & Co.); Zhuravlev, Nikolaev, Zh. Obshch. Khim.30, 1155 (1960). Toxicity studies: E. R. Smith, B. R. Duce, J. Pharmacol. Exp. Ther.179, 580 (1971); G. H. Kronberg et al.,J. Med. Chem.16, 739 (1973). Review of pharmacokinetics: N. L. Benowitz, W. Meister, Clin. Pharmacokinet.3, 177 (1978). Review of action as local anesthetic: Löfgren, Studies on Local Anesthetics: Xylocaine, A New Synthetic Drug (Hoeggstroms, Stockholm, 1948); Cooper, Pharm. J.171, 68 (1953). Reviews of anti-arrhythmic agents: J. L. Anderson et al.,Drugs15, 271 (1978); L. H. Opie, Lancet1, 861 (1980); E. Carmeliet, Ann. N.Y. Acad. Sci.427, 1 (1984). Comprehensive description: K. Groningsson et al.,Anal. Profiles Drug Subs.14, 207-243 (1985); M. F. Powell, ibid.15, 761-779 (1986). Review of use in treatment of postherpetic neuralgia: P. S. Davies, B. S. Galer, Drugs64, 937-947 (2004).Properties: Needles from benzene or alcohol, mp 68-69°. bp4 180-182°; bp2 159-160°. Insol in water. Sol in alcohol, ether, benzene, chloroform, oils. Partition coefficient (octanol/water, pH 7.4): 43. Melting point: mp 68-69° Boiling point: bp4 180-182°; bp2 159-160° Log P: Partition coefficient (octanol/water, pH 7.4): 43 Derivative Type: Hydrochloride CAS Registry Number: 73-78-9; 6108-05-0 (monohydrate) Trademarks: Basicaina (Galenica); Batixim (So.Se.); Dynexan (Kreussler); Heweneural (Hevert); Licain (DeltaSelect); Lidesthesin (Ritsert); Lidofast (Angelini); Lidoject (Hexal); Lidrian (Baxter); Odontalg (Giovanardi); Sedagul (Wild); Xylocaine (AstraZeneca); Xylocard (AstraZeneca); Xylocitin (Jenapharm); Xyloneural (Strathmann) Molecular Formula: C14H22N2O.HCl Molecular Weight: 270.80 Percent Composition: C 62.09%, H 8.56%, N 10.34%, O 5.91%, Cl 13.09% Properties: Crystals, mp 127-129°; monohydrate, mp 77-78°. Very sol in water, alcohol; sol in chloroform. Insol in ether. pH of 0.5% aq soln: 4.0-5.5. LD50 in mice (mg/kg): 292 orally (Smith, Duce); 105 i.p.; 19.5 i.v. (Kronberg). Melting point: mp 127-129°; mp 77-78° Toxicity data: LD50 in mice (mg/kg): 292 orally (Smith, Duce); 105 i.p.; 19.5 i.v. (Kronberg) Therap-Cat: Anesthetic (local); antiarrhythmic (class IB). Therap-Cat-Vet: Anesthetic (local). Keywords: Anesthetic (Local); Antiarrhythmic.
https://patents.google.com/patent/CN102070483B/en#:~:text=The%20method%20comprises%20the%20following,as%20solvent%20and%20carbonate%20isPreparation method of the present invention, it can be two-step approach, comprises the steps:1) 2,6-xylidine is dissolved in the acetone, adds carbonate then, the back that stirs drips chloroacetyl chloride, and 20～35 ℃ (room temperature) be stirring reaction 3h down; After-filtration is finished in reaction, and after filter cake was washed with water to filtrate and is neutrality, drying made intermediate chloracetyl-2, the 6-xylidine, and yield is about about 94%; 2) intermediate that step 1) is made is dissolved in the acetone, adds carbonate then, and the back that stirs drips diethylamine, back flow reaction 8h; After-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.Wherein, in the step 1) 2, the mol ratio of 6-xylidine, chloroacetyl chloride and carbonate is 1: 1.2～1.7: 1.3～2.0, is preferably 1: 1.5: 1.6. Step 2) intermediate chloracetyl-2 in, the mol ratio of 6-xylidine, diethylamine and carbonate is 1: 1.5～2.5: 1.2～2.0, is preferably 1: 2: 1.5.In addition, preparation method of the present invention owing to all be that solvent, carbonate are catalyzer with acetone in the two-step reaction, therefore can further optimize reaction process on the basis of two-step approach, namely the intermediate of Sheng Chenging needn’t pass through aftertreatment, prepares lignocaine by one kettle way.Described one kettle way comprises the steps: 2,6-xylidine is dissolved in the acetone, adds carbonate then, after stirring, drips chloroacetyl chloride, and 20～35 ℃ (room temperature) be reaction 3h down; After reaction is finished, without processing, directly drip diethylamine, back flow reaction 8h, after-filtration is finished in reaction, and filtrate is recrystallization, drying after removing solvent under reduced pressure, makes lignocaine.Wherein, described 2, the mol ratio of 6-xylidine, chloroacetyl chloride, diethylamine and carbonate is 1: 1.2～1.7: 1.5～2.5: 2.5～3.5, is preferably 1: 1.5: 2: 2.5. In addition, preparation method of the present invention adopts TLC monitoring reaction progress, and the developping agent of TLC is sherwood oil: ethyl acetate (V/V)=3: 1.The invention has the advantages that, the method synthesis technique for preparing lignocaine of the present invention is simple, do not need in the intermediate aftertreatment first pickling numerous and diverse step of alkali cleaning again, avoided unnecessary loss, therefore the yield of the intermediate that makes of the inventive method and lignocaine is all higher, and the lignocaine purity that makes is good, reaches more than 99%, has favorable industrial application prospect; In addition, the inventive method uses acetone to make solvent, and this solvent is nontoxic substantially non-stimulated, and can recycle, and is environmentally friendly. EmbodimentBelow further specify the present invention by specific embodiment, but be not used for limiting the scope of the invention. Embodiment 1 two-step approach prepares lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 200g salt of wormwood again, and mechanical stirring evenly back drips 100mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 156g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 94%, fusing point is 145.0～147.0 ℃.2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 112g salt of wormwood, drips the 60g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 90g white powder, is lignocaine, yield is 95%, and fusing point is 67.0～68.0 ℃, and content is 99.05%. Embodiment 2 two-step approachs prepare lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 163g salt of wormwood again, and mechanical stirring evenly back drips 80mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 136g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 82%, fusing point is 145～146 ℃. 2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 90g salt of wormwood, drips the 45g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 84g white powder, is lignocaine, yield is 89%, and fusing point is 66～67 ℃, and content is 99.15%. Embodiment 3 two-step approachs prepare lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineAdd 102g 2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, adds 250g salt of wormwood again, and mechanical stirring evenly back drips 113mL chloroacetyl chloride (1.5h drips off), (20 ℃) stirring reaction 3h under the room temperature; Reaction finishes the back suction filtration, and filter cake is washed with water to filtrate and is neutral, and under 100 ℃ of temperature dry 1 hour then, make the 150g white powder, be intermediate chloracetyl-2,6-xylidine, yield are 90%, fusing point is 147～148 ℃. 2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL acetone, and the dissolving back adds 150g salt of wormwood, drips the 75g diethylamine fast, back flow reaction 8h; Reaction finishes the back suction filtration, and filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, uses 150mL sherwood oil recrystallization then, suction filtration, vacuum-drying 6h under 40 ℃ of temperature makes the 88g white powder, is lignocaine, yield is 93%, and fusing point is 68～69 ℃, and content is 98.75%. Embodiment 4 one kettle ways prepare lignocaineIn the 5000mL there-necked flask, add 305g 2, the 6-xylidine, make solvent with 2000mL acetone, add 700g salt of wormwood again, mechanical stirring evenly back slowly drips 230mL chloroacetyl chloride (1.5h drips off), room temperature (35 ℃) is stirring reaction 3h down, and TLC point plate (use sherwood oil: ethyl acetate (V/V)=3: 1 is made developping agent) demonstration reacts completely; Dropwise 5 50g diethylamine then, the back back flow reaction 8h that stirs, TLC monitoring (developping agent is the same) shows and reacts completely; The reaction solution suction filtration, filtrate is removal of solvent under reduced pressure under 40 ℃ of temperature, gets light yellow solid, uses sherwood oil recrystallization secondary then, makes 482g white lignocaine crystal, and total recovery is 82%, and fusing point is 68.0～69.0 ℃, and content is 99.75%. Comparative example 1 existing method prepares lignocaine1) intermediate chloracetyl-2, the preparation of 6-xylidineIn the 1000mL there-necked flask, with 102g 2, the 6-xylidine is dissolved in the 400mL glacial acetic acid, stirs slowly to add the 100mL chloroacetyl chloride down, is heated to 45 ℃, adds 200g solid sodium acetate (containing crystal water) then, reaction 2h; After reaction finished, ice bath was cooled to below 10 ℃, suction filtration, filter cake is washed with water to filtrate and is neutral, and drying is 1 hour under 100 ℃ of temperature, makes the 111g white powder, be intermediate chloracetyl-2,6-xylidine, yield are that 67% fusing point is 145.0～148.0 ℃. 2) preparation of lignocaineAdd 80g intermediate chloracetyl-2 in the 1000mL there-necked flask, the 6-xylidine is made solvent with 400mL toluene, and the dissolving back drips 60g diethylamine, back flow reaction 3.5h fast; After reaction finished, ice bath was cooled to 5 ℃, suction filtration, filtrate is used the 3mol/L hcl as extraction agent, and the acid solution that extraction is obtained is cooled to 10 ℃ then, stirs slowly to add 6mol/L KOH solution down, be alkalescence (pH8～9) to solution, with pentane extraction, organic layer was after washing, Anhydrous potassium carbonate drying after ice bath was cooled to 20 ℃, vapor bath is steamed and is desolventized, make the 74g white powder, be lignocaine, yield is 78%, fusing point is 66.0～67.0 ℃, and content is 97.15%.Embodiment 1 compares with comparative example 1, its intermediate chloracetyl-2, and the yield of 6-xylidine obviously improves, and reaches 94%, and the total recovery of final product lignocaine also is significantly improved, and the content of lignocaine is brought up to about 99%.Embodiment 4 compares with comparative example 1, and the total recovery of lignocaine is significantly improved, and reach 82%, and content is brought up to more than 99%. Though above with a general description of the specific embodiments, the present invention is described in detail, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention. CLIPhttps://www.cerritos.edu/chemistry/chem_212/Documents/Lab/10_lidocaine.pdf
Procedure: (1st week)A: Synthesis of 2,6-Dimethylaniline via Reduction of 2,6-Dimethylnitrobenzene 1. Dissolve1.0 g of 2,6-dimethylnitrobenzene in 10 mL of glacial acetic acid in a 50 mL Erlenmeyer flask. 2. In a 25 mL flask, dissolve 4.6 grams of SnCl2 · 2H2O in 8 mL of concentrated HCl, inside the fume hood. 3. Add the SnCl2 solution in one portion to the nitroxylene solution, magnetically swirl and mix, and let the mixture stand for 15 minutes. 4. Cool the mixture and collect the crystalline salt (dimethylaniline in the salt form: C6H5NH3 +Cl- ) in a Buchner funnel. 5. Transfer the moist crystals to an Erlenmeyer flask, add 5-10 mL of water, and make the solution strongly basic (to remove the acid and change C6H5NH3 +Clback intoC6H5NH2) by adding 30% KOH solution (12 to 17 mL required). 6. After cooling extract with three 10 mL portions of ether, rinse the ether extracts twice with 10 mL of water, and dry over K2CO3. 7. Evaporate the dried and filtered solution to an oil, transfer and rinse into a 50 mL Erlenmeyer flask, complete evaporation, weigh, and calculate the %yield of 2,6-dimethylaniline. B: Synthesis of α-Chloro-2,6-dimethylacetanilide (prepare for a steam bath ahead of time) 1. For every 7 grams (from this step on, you need to calculate proportionally how much you need to add according to the actual weight that you got) of dimethylaniline from the previous step, add 50 mL of glacial acetic acid, and 7.2 g (or 5.2 mL) of chloroacetyl chloride, in that order. 2. Warm the solution on a steam bath to (40–50)ºC, remove, and add a solution of 1 gram of sodium acetate in 100 mL of water. 3. Cool the mixture and collect the product in a Buchner funnel. 4. Transfer the product to a disk of medium–sized filter paper, finely divide it with a spatula, and let air dry until the next laboratory period. 5. Upon drying, measure the mass and the melting point. Also, calculate the % yield. B: Synthesis of α-Chloro-2,6-dimethylacetanilide (prepare for a steam bath ahead of time) 1. For every 7 grams (from this step on, you need to calculate proportionally how much you need to add according to the actual weight that you got) of dimethylaniline from the previous step, add 50 mL of glacial acetic acid, and 7.2 g (or 5.2 mL) of chloroacetyl chloride, in that order. 2. Warm the solution on a steam bath to (40–50)ºC, remove, and add a solution of 1 gram of sodium acetate in 100 mL of water. 3. Cool the mixture and collect the product in a Buchner funnel. 4. Transfer the product to a disk of medium–sized filter paper, finely divide it with a spatula, and let air dry until the next laboratory period. 5. Upon drying, measure the mass and the melting point. Also, calculate the % yield. D. Synthesis of the bisulfate salt of lidocaine 1. Dissolve the lidocaine in ether (10 mL per gram of lidocaine) and add 2 mL of 2.2 M sulfuric acid in ethanol per gram of lidocaine. 2. Stir and scratch with a glass rod to mix and induce crystallization. 3. Dilute the mixture with an equal volume of acetone to aid filtration and collect the salt in a small Buchner funnel. 4. Rinse the solid on the funnel with a few milliliters of acetone and air dry and weigh the product. 5. Calculate the % yield of this step. *** Overall % Yield The overall % YCLIPhttp://home.sandiego.edu/~khuong/chem302L/Handouts/Lidocaine_handout_Su07.pdfSynthetic Strategy Lidocaine will be prepared via a three-step linear synthesis starting from 2,6-dimethylnitrobenzene. The reduction of 2,6-dimethylnitrobenzene 1 with three equivalents of stannous chloride (SnCl2) yields the ammonium salt 2. It is very important that the reaction mixture is strongly acidic during this reaction because the reduction of nitrobenzene using different reducing reagents and conditions can afford a variety of functional groups: nitroso, hydroxylamine (zinc dust, pH 4), azoxy (sodium arsenite), azo (zinc, weakly basic), or hydrazo (zinc, strongly basic). In industrial settings, often iron or tin with hydrochloric acid is used instead of stannous chloride because iron and tin are cheaper, but the reduction takes much longer. In the workup portion of the reaction, the ammonium salt 2 is reacted with an aqueous potassium hydroxide solution, liberating the free 2,6-dimethylaniline 3 in an acid-base reaction.
The reaction of 3 with the bifunctional α-chloroacetyl chloride leads to α-chloro-2,6-dimethylacetanilide 4. A slight excess of the acid chloride is used to ensure the complete conversion of the amine to the amide. The formation of the amide is a result of the significantly higher reactivity (~106 times) of the acyl chloride over the alkyl chloride. The addition of sodium acetate solution avoids the formation of HCl which would protonate unreacted 3 causing it to co-precipitate with the desired product 4.
In the last step, diethylamine performs a nucleophilic substitution (SN2) on the remaining alkyl chloride. Diethylamine serves both as a nucleophile to form lidocaine 5, and as acid scavenger, leading to formation of NH2Et2 + Cl- in this reaction. Since diethylamine is not a very strong nucleophile, it is used in excess here to improve the yield and speed up the reaction. The unreacted amine is later removed by extraction with water. The aqueous extraction of lidocaine with acid separates the unreacted chloroanilide 4 and the lidocaine. After addition of a strong base like aqueous potassium hydroxide, crude lidocaine is obtained.
Procedure Synthesis of 2,6-dimethylaniline (3) Dissolve 15 g of SnCl2•2H2O in 27 mL of concentrated hydrochloric acid. If necessary, heat the mixture gently. Add this solution in one portion to a solution of 3 mL of 2,6-dimethylnitrobenzene in 34 mL of glacial acetic acid. Swirl the resulting mixture and then allow it to stand for 15 minutes before placing the mixture in an ice bath. Collect the formed precipitate by vacuum filtration. Place the wet precipitate obtained above in a beaker and add 20 mL of water. Neutralize the acidic mixture by carefully adding an 8 M aqueous potassium hydroxide with continuous stirring until basic to litmus. Place the mixture in an ice bath. Upon cooling to room temperature, extract the mixture three times with diethyl ether. Combine the organic layers and wash them twice with water and once with brine. Dry the organic layer over anhydrous potassium carbonate. Decant away from the drying agent and evaporate the diethyl ether from a dry, preweighed flask using a rotary evaporator. The oily residue will be your crude product 3. Obtain and record the following information: 1. crude product description (co2. crude weight/percent yieldSynthesis of α-chloro-2,6-dimethylacetanilide (4) Dissolve 3 in 17 mL of glacial acetic acid. Add 1.1 equivalents (based on the moles of 3) of α-chloroacetyl chloride to this solution. Heat the solution to 40-50 o C for ten minutes to complete the reaction. Upon cooling, add a solution of ~3.3 g sodium acetate trihydrate in 67 mL water and then place the resulting mixture in an ice bath. Collect the precipitate by vacuum filtration. Rinse the filter cake with copious amounts of water in order to remove the acetic acid. It is important that the product be completely free of acetic acid after this step (why?). The pH of the individual water rinses can be checked with litmus paper to determine if the product is acid free. Allow for the product to air-dry on a watch glass until the next meeting. There is a reasonable chance that you will not obtain a precipitate as described above. If this is the case, you can try “seeding” using a small sample of authentic product from a classmate. If this does not work, check the TLC to be sure that you have formed product and devise an extractive workup that will separate the unreacted aniline 3 from the desired product 4. (Make sure you understand how to do this even if you obtain a precipitate in the first place). After the aqueous workup and following removal of solvent, you should obtain a solid. If not, check the TLC, using a sample of authentic product from a classmate as a standard. If the product appears relatively pure, you can continue even though the material is not a solid. Obtain and record the following information: 1. crude product description (color, physical state, etc.) 2. crude weight/percent yield 3. mp (if a solid) 4. TLC analysis 5. IR (check for presence of amide functional group) Synthesis of lidocaine; α-(N,N-diethylamino)-2,6-dimethylacetanilide (5). In a round bottom flask, dissolve α-chloro-2,6-dimethylacetanilide 4 in 17 mL of toluene. Before continuing, spot several (4 to 5) TLC plates in advance with this solution of 4. Provide three lanes and spot the 4 on the “SM” and “CO-SPOT” lanes. You will use these plates to monitor the progress of this reaction. Add three equivalents of diethylamine to the round bottom flask, and reflux the mixture vigorously until the reaction is complete. The amount of time required for complete reaction depends on many factors but it will likely take anywhere from more than a few minutes up to several hours. If the reaction is not complete when your lab period ends, you can stopper the reaction and reflux it for additional time at the next period. Usually a white precipitate forms during the reflux. Upon cooling, transfer the reaction mixture to a separatory funnel and extract the mixture three times with water. Next, extract the organic layer with two portions of 3 M hydrochloric acid. Cool the combined acidic aqueous extracts in an ice bath and then add 8 M aqueous potassium hydroxide slowly until the mixture is strongly basic again. The formation of a thin, dark yellow oily layer on top or a white solid is observed at this point. Place the mixture in an ice bath. Once the mixture is chilled, try to initiate the crystallization of the final product if no solid has formed at this point. Collect the obtained precipitate by filtration using a Büchner funnel. Wash it with twice with water and then press it as dry as possible. Obtain and record the following information: 1. crude product description (color, physical state, etc.) 2. crude weight/percent yield 3. TLC analysis Recrystallize the crude product from hexanes. Regardless of the final physical state of your product (solid or oil), obtain and record the following: 1. pure product description (color, physical state, etc.) 2. pure product weight/percent yield 3. overall (three-step) percent yield (from starting material 1) 4. TLC analysis 5. melting point (if a solid) 6. IR 7. 1 H and 13C NMR spectra of lidocaine will be given to you. Turn in a sample of your final product.
1H NMR
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13C NMR
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MS
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IR KBR
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Lidocaine is an antiarrhythmic medicine and also serves as a local anaesthetic drug. It is utilized in topical application to relieve pain, burning and itching sensation caused from skin inflammations. This drug is mainly used for minor surgeries. Figure 1 shows the 1H NMR spectrum of 200 mM lidocaine in CDCl3.
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Figure 1. Proton NMR spectrum of 200 mM lidocaine in CDCl3.
1H NMR Relaxation
Figures 2, 3 and 4 show the relaxation time measurements. It can be seen that the relaxation times are shortest for the CH2 protons and longest for the CH protons. The first data point amplitude increases with the number of protons for the related peak.
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Figure 2. Proton T1 relaxation time measurement of 200 mM lidocaine in CDCl3.
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Figure 3. Proton T2 relaxation time measurement of 200 mM lidocaine in CDCl3.
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Figure 4. COSY spectrum of 200 mM lidocaine in CDCl3. The cross-peaks and corresponding exchanging protons are labeled by colour-coded arrows and ellipses.
2D COSY
Figure 4 shows the 2D COSY spectrum where two spin systems (6,7,8) to (10,11) can be clearly seen. For instance, the methyl groups at 10 and 11 positions bond to aromatic protons at 6 and 8 positions, while the methyl groups at 16 and 17 positions bond to the ethylene groups at 14 and 15 positions. No coupling occurs at positions (6,7,8) to (16,17) or (14,15).
2D Homonuclear J-Resolved Spectroscopy
The chemical shift in the 2D homonuclear j-resolved spectrum appears along the direct (f2) direction and the effects of coupling between protons appear along the indirect (f1) dimension. This enables the assignment of chemical shifts of multiplets and may help in measuring unresolved couplings. Also, a decoupled 1D proton spectrum is produced by the projection along the f1 dimension. The 2D homonuclear j-resolved spectrum of lidocaine, plus the 1D proton spectrum (blue line) are shown in Figure 5.
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Figure 5. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl3. The multiplet splitting frequencies for different couplings are colour- coded.
The projection which is vertical reveals how the multiplets disintegrate into a single peak, which makes the 1D spectrum more simplified. Peak multiplicities are produced by vertical traces from peaks in the 2D spectrum and help in determining the frequencies of proton-proton coupling. When coupling frequencies are compared between different peaks, information can be obtained regarding which peaks are bonded to each other. Also, Information regarding the coupling strength can be obtained from the size of the coupling frequencies. These couplings substantiate the results of the COSY experiment.
However, in this experiment, the effects of second order coupling appear in the f1 direction as additional peaks which are equidistant from the coupling partners detached from the zero frequency in the f1 dimension. These peaks provide proof of second order coupling partners, but are generally considered as artifacts. Figure 6 shows these coupling partners and additional peaks marked by colour-coded arrows and ellipses.
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Figure 6. Homonuclear j-resolved spectrum of 200 mM lidocaine in CDCl3 showing the extra peaks due to strong couplings.
1D 13C Spectra
Figure 7 shows the 13C NMR spectra of 1 M lidocaine in CDCl3. Since the 1D Carbon experiment is highly susceptible to the 13C nuclei in the specimen, it easily and clearly resolves 9 resonances. In this experiment, only carbons coupled to protons are seen.
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Figure 7. Carbon spectra of 1 M lidocaine in CDCl3.
Given the fact that the DEPT spectra do not display the peaks at 170 and 135ppm, they must be part of quaternary carbons. The DEPT-135 and the DEPT-45 experiments provide signals of CH3, CH2 and CH groups, while the DEPT-90 experiment provides only the signal of CH groups. However, in DEPT-135 the CH2 groups occur as negative peaks. It can thus be summed up that the peaks between 45 and 60ppm belong to ethylene groups; the peaks between 10 and 20ppm are part of the methyl groups; and the peaks between 125 and 130ppm belong to methyne groups. A similar study can be carried out on the C and CH peaks.
Heteronuclear Correlation
The Heteronuclear Correlation (HETCOR) experiment identifies the proton signal that appears along the indirect dimension and the carbon signal along the direct dimension. Figure 8 shows the HETCOR spectrum of 1 M lidocaine in CDCl3. in the 2D spectrum, the peaks reveal which proton is attached to which carbon. This experiment helps in resolving assignment uncertainty from the ID carbon spectra.
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Figure 8. HETCOR spectrum of 1 M lidocaine in CDCl3.
Heteronuclear Multiple Quantum Coherence
Heteronuclear Multiple Quantum Coherence (HMQC) is similar to the HETCOR experiment and is utilized to associate proton resonances to the carbons that are coupled directly to those protons. But in the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 9 shows the HMQC spectrum of 1 M lidocaine in CDCl3. In the 2D spectrum, the peaks show which proton is attached to which carbon. For conclusive peak assignment, a similar study with the HETCOR spectrum can be carried out.
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Figure 9. HMQC spectrum of 1 M lidocaine in CDCl3.
Heteronuclear Multiple Bond Correlation
The Heteronuclear Multiple Bond Correlation (HMBC) experiment can be employed to achieve long-range correlations of proton and carbon via two or three bond couplings. Similar to the HMQC experiment, the proton signal appears along the direct dimension and the carbon signal along the indirect dimension. Figure 10 shows the HMBC spectrum of 1 M lidocaine in CDCl3.
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Figure 10. HMBC spectrum of 1 M lidocaine in CDCl3, with some of the long-range couplings marked.
The couplings amid the molecular positions appear analogous to the couplings seen in the COSY spectrum; however, the HMBC also displays couplings to quaternary carbons, which are not seen either in HMQC or COSY experiments. In addition, there is a correlation between protons and carbons. This is attributed to three-bond bonding from 14 and 15 and vice versa, as shown in light green in Figure 1.
SYN
Synthesis of lidocaine T. J. Reilly (1999). “The Preparation of Lidocaine”. J. Chem. Ed.76 (11): 1557.
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CLIP
The Present Synthesis Of Lidocaine Begins With 2,6-Dimethylnitrobenzene (1). This Compound Can Be Made From 1,3-Dimethylbenzene, Also Known As M-Xylene, Which Is More Difficult To Make. Luckily,
This problem has been solved!
See the answer
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The present synthesis of lidocaine begins with 2,6-dimethylnitrobenzene (1). This compound can be made from 1,3-dimethylbenzene, also known as m-xylene, which is more difficult to make. Luckily, m-xylene is commercially available, so a synthesis of 1 from m-xylene is a practical alternative if one wants to begin the synthesis of lidocaine with m-xylene. Suppose you want to prepare 1 from m-xylene. Show with chemical equations the reagents that you would use, and the possible isomers that would result.
2. The practical transformation of 1 into 3 is carried out by the following scheme:
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Suppose you dissolve the solid precipitate of 2 in water, but forget to include the KOH in the second step above. What would happen after the extraction with ether? Give your answer in terms of what would be found in the ether layer, and in the aqueous layer.
3. Suppose you’re out of acetic acid (CH3COOH) and decide to use ethanol (CH3 CH2OH) as the solvent in the transformation of 3 into 4. Would this be a wise choice, and why?
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4.The amide 4 has a nitrogen attached to the benzene ring, and a chlorine attached to a primary carbon. Yet, it doesn’t react with itself in a nucleophilic displacement. Why is the nitrogen in the amide not nucleophilic? Give your answer in terms of the resonance forms of amides in general:
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5. In the reaction below, what factors come into play to favor attack of the aniline 3 on the carbonyl carbon of the acid chloride (carbon 1 in red), rather than at the a-carbon (carbon 2 in red)?
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6. Before carrying out the transformation below, compound 4 and the glassware used must be oven-dried. What would happen if the reaction was attempted using wet 4?
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7.In the reaction below, what factors come into play to favor attack of diethylamine on the a-carbon (carbon 1 in red), rather than on the amide C=O carbon (carbon 2 in red)?
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8. In the reaction below, why does the amine nitrogen (#1 in red) undergo protonation with H2SO4 preferentially over the amide nitrogen (#2 in red)? In other words, why is nitrogen 1 basic, but nitrogen 2 is not?
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9.Lidocaine and other drugs containing amino groups are usually marketed as their hydrochloride or hydrogen sulfate salts, rather than as “free amines.” Provide two reasons why this practice makes sense.
10.Although lidocaine is marketed as its hydrochloride salt, it doesn’t exhibit the same level of physiological activity as the free amine. The free amine is more lipophilic and diffuses across a neuron cell membrane more rapidly than the ionic salt, resulting in a more rapid onset of anesthesia. Therefore, sodium bicarbonate (NaHCO3) is added to a solution of lidocaine prior to injection. How does the addition of sodium bicarbonate promote a faster anesthetic effect?
CLIP
CLIP
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Lidocaine, also known as lignocaine and sold under the brand name Xylocaine among others, is a local anesthetic of the aminoamide type. It is also used to treat ventricular tachycardia.[7][8] When used for local anaesthesia or in nerve blocks, lidocaine typically begins working within several minutes and lasts for half an hour to three hours.[8][9] Lidocaine mixtures may also be applied directly to the skin or mucous membranes to numb the area.[8] It is often used mixed with a small amount of adrenaline (epinephrine) to prolong its local effects and to decrease bleeding.[8]
If injected intravenously, it may cause cerebral effects such as confusion, changes in vision, numbness, tingling, and vomiting.[7] It can cause low blood pressure and an irregular heart rate.[7] There are concerns that injecting it into a joint can cause problems with the cartilage.[8] It appears to be generally safe for use in pregnancy.[7] A lower dose may be required in those with liver problems.[7] It is generally safe to use in those allergic to tetracaine or benzocaine.[8] Lidocaine is an antiarrhythmic medication of the class Ib type.[7] This means it works by blocking sodium channels and thus decreasing the rate of contractions of the heart.[7] When injected near nerves, the nerves cannot conduct signals to or from the brain.[8]
Lidocaine was discovered in 1946 and went on sale in 1948.[10] It is on the World Health Organization’s List of Essential Medicines.[11] It is available as a generic medication.[8][12] In 2018, it was the 233rd most commonly prescribed medication in the United States, with more than 2 million prescriptions.[13][14]
Medical uses
Local numbing agent
The efficacy profile of lidocaine as a local anaesthetic is characterized by a rapid onset of action and intermediate duration of efficacy. Therefore, lidocaine is suitable for infiltration, block, and surface anaesthesia. Longer-acting substances such as bupivacaine are sometimes given preference for spinal and epidural anaesthesias; lidocaine, though, has the advantage of a rapid onset of action. Adrenaline vasoconstricts arteries, reducing bleeding and also delaying the resorption of lidocaine, almost doubling the duration of anaesthesia.
Lidocaine is one of the most commonly used local anaesthetics in dentistry. It can be administered in multiple ways, most often as a nerve block or infiltration, depending on the type of treatment carried out and the area of the mouth worked on.[15]
For surface anaesthesia, several formulations can be used for endoscopies, before intubations, etc. Buffering the pH of lidocaine makes local numbing less painful.[16] Lidocaine drops can be used on the eyes for short ophthalmic procedures. There is tentative evidence for topical lidocaine for neuropathic pain and skin graft donor site pain.[17][18] As a local numbing agent, it is used for the treatment of premature ejaculation.[19]
An adhesive transdermal patch containing a 5% concentration of lidocaine in a hydrogel bandage, is approved by the US FDA for reducing nerve pain caused by shingles.[20] The transdermal patch is also used for pain from other causes, such as compressed nerves and persistent nerve pain after some surgeries.
A 2013 review on treatment for neonatal seizures recommended intravenous lidocaine as a second-line treatment, if phenobarbital fails to stop seizures.[22]
Other
Intravenous lidocaine infusions are also used to treat chronic pain and acute surgical pain as an opiate sparing technique. The quality of evidence for this use is poor so it is difficult to compare it to placebo or an epidural.[23]
Inhaled lidocaine can be used as a cough suppressor acting peripherally to reduce the cough reflex. This application can be implemented as a safety and comfort measure for patients who have to be intubated, as it reduces the incidence of coughing and any tracheal damage it might cause when emerging from anaesthesia.[24]
For gastritis, drinking a viscous lidocaine formulation may help with the pain.[27]
Adverse effects
Adverse drug reactions (ADRs) are rare when lidocaine is used as a local anesthetic and is administered correctly. Most ADRs associated with lidocaine for anesthesia relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, and allergic reactions only rarely occur.[28] Systemic exposure to excessive quantities of lidocaine mainly result in central nervous system (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. ADRs by system are:
CNS excitation: nervousness, agitation, anxiety, apprehension, tingling around the mouth (circumoral paraesthesia), headache, hyperesthesia, tremor, dizziness, pupillary changes, psychosis, euphoria, hallucinations, and seizures
CNS depression with increasingly heavier exposure: drowsiness, lethargy, slurred speech, hypoesthesia, confusion, disorientation, loss of consciousness, respiratory depression and apnoea.
Skin: itching, depigmentation, rash, urticaria, edema, angioedema, bruising, inflammation of the vein at the injection site, irritation of the skin when applied topically
ADRs associated with the use of intravenous lidocaine are similar to toxic effects from systemic exposure above. These are dose-related and more frequent at high infusion rates (≥3 mg/min). Common ADRs include: headache, dizziness, drowsiness, confusion, visual disturbances, tinnitus, tremor, and/or paraesthesia. Infrequent ADRs associated with the use of lidocaine include: hypotension, bradycardia, arrhythmias, cardiac arrest, muscle twitching, seizures, coma, and/or respiratory depression.[29]
It is generally safe to use lidocaine with vasoconstrictor such as adrenaline, including in regions such as the nose, ears, fingers, and toes.[30] While concerns of tissue death if used in these areas have been raised, evidence does not support these concerns.[30]
Interactions
Any drugs that are also ligands of CYP3A4 and CYP1A2 can potentially increase serum levels and potential for toxicity or decrease serum levels and the efficacy, depending on whether they induce or inhibit the enzymes, respectively. Drugs that may increase the chance of methemoglobinemia should also be considered carefully. Dronedarone and liposomalmorphine are both absolutely a contraindication, as they may increase the serum levels, but hundreds of other drugs require monitoring for interaction.[31]
Contraindications
Absolute contraindications for the use of lidocaine include:
Heart block, second or third degree (without pacemaker)
Intra-articular infusion (this is not an approved indication and can cause chondrolysis)
Porphyria, especially acute intermittent porphyria; lidocaine has been classified as porphyrogenic because of the hepatic enzymes it induces,[34] although clinical evidence suggests it is not.[35]Bupivacaine is a safe alternative in this case.
Impaired liver function – people with lowered hepatic function may have an adverse reaction with repeated administration of lidocaine because the drug is metabolized by the liver. Adverse reactions may include neurological symptoms (e.g. dizziness, nausea, muscle twitches, vomiting, or seizures).[36]
Overdosage
Overdoses of lidocaine may result from excessive administration by topical or parenteral routes, accidental oral ingestion of topical preparations by children (who are more susceptible to overdose), accidental intravenous (rather than subcutaneous, intrathecal, or paracervical) injection, or from prolonged use of subcutaneous infiltration anesthesia during cosmetic surgery.
Such overdoses have often led to severe toxicity or death in both children and adults. Lidocaine and its two major metabolites may be quantified in blood, plasma, or serum to confirm the diagnosis in potential poisoning victims or to assist forensic investigation in a case of fatal overdose.
Lidocaine is often given intravenously as an antiarrhythmic agent in critical cardiac-care situations.[37] Treatment with intravenous lipid emulsions (used for parenteral feeding) to reverse the effects of local anaesthetic toxicity is becoming more common.[38]
Lidocaine alters signal conduction in neurons by prolonging the inactivation of the fast voltage-gated Na+ channels in the neuronal cell membrane responsible for action potential propagation.[40] With sufficient blockage, the voltage-gated sodium channels will not open and an action potential will not be generated. Careful titration allows for a high degree of selectivity in the blockage of sensory neurons, whereas higher concentrations also affect other types of neurons.
The same principle applies for this drug’s actions in the heart. Blocking sodium channels in the conduction system, as well as the muscle cells of the heart, raises the depolarization threshold, making the heart less likely to initiate or conduct early action potentials that may cause an arrhythmia.[41]
Pharmacokinetics
When used as an injectable it typically begins working within four minutes and lasts for half an hour to three hours.[8][9] Lidocaine is about 95% metabolized (dealkylated) in the liver mainly by CYP3A4 to the pharmacologically active metabolitesmonoethylglycinexylidide (MEGX) and then subsequently to the inactive glycine xylidide. MEGX has a longer half-life than lidocaine, but also is a less potent sodium channel blocker.[42] The volume of distribution is 1.1 L/kg to 2.1 L/kg, but congestive heart failure can decrease it. About 60% to 80% circulates bound to the protein alpha1 acid glycoprotein. The oral bioavailability is 35% and the topical bioavailability is 3%.
The elimination half-life of lidocaine is biphasic and around 90 min to 120 min in most patients. This may be prolonged in patients with hepatic impairment (average 343 min) or congestive heart failure (average 136 min).[43] Lidocaine is excreted in the urine (90% as metabolites and 10% as unchanged drug).[44]
History
Lidocaine, the first aminoamide–type local anesthetic, was first synthesized under the name ‘xylocaine’ by Swedish chemist Nils Löfgren in 1943.[45][46][47] His colleague Bengt Lundqvist performed the first injection anesthesia experiments on himself.[45] It was first marketed in 1949.
Society and culture
Dosage forms
Lidocaine, usually in the form of its hydrochloride salt, is available in various forms including many topical formulations and solutions for injection or infusion.[48] It is also available as a transdermal patch, which is applied directly to the skin.
Lidocaine hydrochloride 2% epinephrine 1:80,000 solution for injection in a cartridge
Lidocaine is often added to cocaine as a diluent.[54][55] Cocaine and lidocaine both numb the gums when applied. This gives the user the impression of high-quality cocaine, when in actuality the user is receiving a diluted product.[56]
^ Jump up to:abc J. P. Nolan; P. J. F. Baskett (1997). “Analgesia and anaesthesia”. In David Skinner; Andrew Swain; Rodney Peyton; Colin Robertson (eds.). Cambridge Textbook of Accident and Emergency Medicine. Project co-ordinator, Fiona Whinster. Cambridge, UK: Cambridge University Press. p. 194. ISBN9780521433792. Archived from the original on 2017-09-08.
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06.
^ Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 22. ISBN9781284057560.
^ Cepeda MS, Tzortzopoulou A, Thackrey M, Hudcova J, Arora Gandhi P, Schumann R (December 2010). Tzortzopoulou A (ed.). “Adjusting the pH of lidocaine for reducing pain on injection”. The Cochrane Database of Systematic Reviews (12): CD006581. doi:10.1002/14651858.CD006581.pub2. PMID21154371.(Retracted, see doi:10.1002/14651858.cd006581.pub3. If this is an intentional citation to a retracted paper, please replace{{Retracted}} with {{Retracted|intentional=yes}}.)
^ Sinha S, Schreiner AJ, Biernaskie J, Nickerson D, Gabriel VA (November 2017). “Treating pain on skin graft donor sites: Review and clinical recommendations”. The Journal of Trauma and Acute Care Surgery. 83 (5): 954–964. doi:10.1097/TA.0000000000001615. PMID28598907. S2CID44520644.
^ Biller JA (2007). “Airway obstruction, bronchospasm, and cough”. In Berger AM, Shuster JL, Von Roenn JH (eds.). Principles and practice of palliative care and supportive oncology. Hagerstwon, MD: Lippincott Williams & Wilkins. pp. 297–307. ISBN978-0-7817-9595-1. Inhaled lidocaine is used to suppress cough during bronchoscopy. Animal studies and a few human studies suggest that lidocaine has an antitussive effect…
^ Birsa LM, Verity PG, Lee RF (May 2010). “Evaluation of the effects of various chemicals on discharge of and pain caused by jellyfish nematocysts”. Comp. Biochem. Physiol. C. 151 (4): 426–30. doi:10.1016/j.cbpc.2010.01.007. PMID20116454.
^ Morabito R, Marino A, Dossena S, La Spada G (Jun 2014). “Nematocyst discharge in Pelagia noctiluca (Cnidaria, Scyphozoa) oral arms can be affected by lidocaine, ethanol, ammonia and acetic acid”. Toxicon. 83: 52–8. doi:10.1016/j.toxicon.2014.03.002. PMID24637105.
^ James G. Adams (2012). “32”. Emergency Medicine: Clinical Essentials. Elsevier Health Sciences. ISBN9781455733941. Archived from the original on 2017-09-08.
^ Jump up to:ab Nielsen LJ, Lumholt P, Hölmich LR (October 2014). “[Local anaesthesia with vasoconstrictor is safe to use in areas with end-arteries in fingers, toes, noses and ears]”. Ugeskrift for Laeger. 176(44). PMID25354008.
^“Lidocaine – N01BB02”. Drug porphyrinogenicity monograph. The Norwegian Porphyria Centre and the Swedish Porphyria Centre. Archived from the original on 2014-04-20. strong clinical evidence points to lidocaine as probably not porphyrinogenic
^ Khan, M. Gabriel (2007). Cardiac Drug Therapy (7th ed.). Totowa, NJ: Humana Press. ISBN9781597452380.
^ Baselt R (2008). Disposition of Toxic Drugs and Chemicals in Man(8th ed.). Foster City, CA: Biomedical Publications. pp. 840–4. ISBN978-0-9626523-7-0.
^ Picard J, Ward SC, Zumpe R, Meek T, Barlow J, Harrop-Griffiths W (February 2009). “Guidelines and the adoption of ‘lipid rescue’ therapy for local anaesthetic toxicity”. Anaesthesia. 64 (2): 122–5. doi:10.1111/j.1365-2044.2008.05816.x. PMID19143686. S2CID25581037.
^ Carterall, William A. (2001). “Molecular mechanisms of gating and drug block of sodium channels”. Sodium Channels and Neuronal Hyperexcitability. Novartis Foundation Symposia. 241. pp. 206–225. doi:10.1002/0470846682.ch14. ISBN9780470846681.
^ Jump up to:ab Löfgren N (1948). Studies on local anesthetics: Xylocaine: a new synthetic drug (Inaugural dissertation). Stockholm, Sweden: Ivar Heggstroms. OCLC646046738.[page needed]
^ Löfgren N, Lundqvist B (1946). “Studies on local anaesthetics II”. Svensk Kemisk Tidskrift. 58: 206–17.
^ Pupka A, Sikora J, Mauricz J, Cios D, Płonek T (2009). “[The usage of synthol in the body building]”. Polimery W Medycynie. 39(1): 63–5. PMID19580174.
^ Bernardo NP; Siqueira MEPB; De Paiva MJN; Maia PP (2003). “Caffeine and other adulterants in seizures of street cocaine in Brazil”. International Journal of Drug Policy. 14 (4): 331–4. doi:10.1016/S0955-3959(03)00083-5.
US patent 2441498, Nils Magnus Loefgren & Bengt Josef Lundqvist, “Alkyl glycinanilides”, published 1948-05-11, issued 1948-05-11, assigned to ASTRA APOTEKARNES KEM FAB
Ropivacaine CAS Registry Number: 84057-95-4 CAS Name: (2S)-N-(2,6-dimethylphenyl)-1-propyl-2-piperidinecarboxamide Additional Names: (S)-(-)-1-propyl-2¢,6¢-pipecoloxylidide; l-N-n-propylpipecolic acid-2,6-xylidide Manufacturers’ Codes: LEA-103 Molecular Formula: C17H26N2O, Molecular Weight: 274.40 Percent Composition: C 74.41%, H 9.55%, N 10.21%, O 5.83% Literature References: Prepn: A. F. Thuresson, C. Bovin, WO8500599 (1985 to Apothekernes); H.-J. Federsel et al.,Acta Chem. Scand.B41, 757 (1987).Physicochemical properties: G. R. Strichartz et al.,Anesth. Analg.71, 158 (1990).HPLC determn in human plasma: Z. Yu et al.,J. Chromatogr. B654, 221 (1994). In vitro metabolism: Y. Oda et al.,Anesthesiology82, 214 (1995). Clinical pharmacokinetics: D. J. Kopacz et al.,ibid.81, 1139 (1994). Toxicity study in sheep: A. C. Santos et al.,ibid.82, 734 (1995). Clinical evaluation in relief of surgical pain: I. Cederholm et al.,Reg. Anesth.19, 18 (1994); B. Johansson et al.,Anesth. Analg.78, 210 (1994); labor pain: R. Stienstra et al.,ibid.80, 285 (1995). Properties: Crystals from toluene, mp 144-146°. [a]D25 -82.0° (c = 2 in methanol). pKa 8.16. Distribution coefficient (1-octanol/aq buffer, pH 7.4): 115.0. Melting point: mp 144-146° pKa: pKa 8.16 Optical Rotation: [a]D25 -82.0° (c = 2 in methanol) Derivative Type: Hydrochloride CAS Registry Number: 98717-15-8 Trademarks: Naropin (AstraZeneca) Molecular Formula: C17H26N2O.HCl, Molecular Weight: 310.86 Percent Composition: C 65.68%, H 8.75%, N 9.01%, O 5.15%, Cl 11.40% Properties: Crystals from isopropyl alcohol, mp 260-262°. [a]D25 -6.6° (c = 2 in water). Melting point: mp 260-262° Optical Rotation: [a]D25 -6.6° (c = 2 in water) Derivative Type: Hydrochloride monohydrate CAS Registry Number: 132112-35-7 Properties: Crystals from acetone + water, mp 269.5-270.6°. [a]D20 -7.28° (c = 2 in water). Melting point: mp 269.5-270.6° Optical Rotation: [a]D20 -7.28° (c = 2 in water) Therap-Cat: Anesthetic (local). Keywords: Anesthetic (Local).Product Ingredients
Ropivacaine is an analgesic drug used for local or regional anesthesia for surgery and short-term management of pain.Ropivacaine is an aminoamide local anaesthetic drug commonly marketed by AstraZeneca under the trade name Naropin. It is present as a racemic mixture of the enantiomers containing equal proportions of the “S” and “R” forms. The marketed form contains the single S-enantiomer as the active ingredient.
Ropivacaine hydrochloride hydrate was first approved by the U.S. Food and Drug Administration (FDA) on September 26, 1996, then approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) in April 4, 2001. It was developed by AstraZeneca, then marketed as Naropin® by APP Pharmaceuticals, LLC. in the US and as Anapeine® by AstraZeneca in JP.
Ropivacaine is a local anaesthetic drug belonging to the amino amide group. It is indicated for the production of local or regional anesthesia for surgery and for acute pain management.
Naropin® is available as injection solution for intravenous use, containing 2, 5, 7.5 or 10 mg of Ropivacaine hydrochloride one mL. Common concentration is 7.5 mg/mL, and the maximum single dose is 200 mg.
https://patents.google.com/patent/WO1985000599A1/enA large variety of N-alkyl-pipecolic acid amides have been synthesized. A number of these compounds have found use as local anesthetics, such as Mepivacaine, namely the racemate of N-methylpipecolic–acid-2,6-xylidide:
References disclosing homologs of this series of compounds include U.S. Patent 2,799,679; British Patent 775,749; British Patent 775,750; British Patent 800,565; British Patent 824,542; British Patent 869,978; British Patent 949,729; U.S. Patent 4,110,331; and U.S. Patent 4,302,465.There is a summary paper dealing with these types of anesthetics, and related compounds in a paper in Acta Che ica Scandinavica 11, (1957) No. 7 pp. 1183-1190 by Bo Thuresson af Ekenstam et al.There is a discussion of the“ effect of optical isomers in related compounds in J. Med. Chem., 14 (1971) pp. 891-892 entitled “Optical Isomers Of Mepivacaine And Bupivacaine” by Benjamin F. Tullar; Acta Pha m. Suecica, 8 (1971) pp. 361- 364 entitled “Some Physicochemical Properties Of The Racemates And The Optically Active Isomers Of Two Local Anaesthetic Compounds”, by . Friberger et al -.; Acta Pharmacol et Toxicol, 31 (1972). pp. 273-286 entitled “Toxicological And Local Anaesthetic Effects Of Optically Active Isomers Of Two Local Anaesthetic Compounds”, by G. Aberg; Annual Review Of Pharmacology, 9 (1969) pp. 5Q3-520 entitled “Duration Of Local Anaesthesia”, by F.P. Luduena and Acta Pharmacol, et Toxicol, 41 (1977). pp. 432-443 entitled “Studies On The Duration Of Local Anaesthesia: Structure/Activity Relationships In A Series Of Homologous Local Anaesthetics”, by G. Aberg et al.
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Route 3
Reference：1. J. Labelled Compd. Rad. 1987, 24, 521-528.Route 4
Reference：1. CN104003930A.
https://patents.google.com/patent/CN104003930A/enRopivacaine (Ropivacaine) is the long-acting local anesthetics of amide derivatives of Novel pure levo form of Astra drugmaker of Sweden listing in 1996, there is analgesia and anesthesia dual function, be widely used in nerve block anesthesia, local infiltration anesthesia and epidural anesthesia , be particularly useful for Postoperative Analgesia After and obstetrical analgesia.On piperidine ring in ropivacaine structure, having a chiral carbon atom, is chipal compounds, and levoisomer is low compared with dextrorotatory isomer toxicity, and action effect is good.Ropivacaine HCL is the hydrochloride of ropivacaine, and chemistry is by name: (-)-(S)-N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-carboxamide hydrochloride, molecular formula is C 17 h 26 n 2 oHCl, structural formula:At present, in prior art, the synthetic method of ropivacaine mainly contains:Taking L-2-piperidine formyl chlorine as starting raw material, through phosphorus pentachloride or sulfur oxychloride acidylate, then with the condensation of 2,6-xylidine, and then react and obtain ropivacaine with n-propyl bromide.Although this method production technique is simple, reactions steps is also shorter, but commercially available L-2-piperidine carboxylic acid average price is 4～5 times of racemization Pipecolic Acid, raw materials cost is too high, and may there is racemization phenomenon in subsequent reactions process, affect optical purity of products, for example US Patent No. 4695576 and “Chinese Medicine magazine” o. 11th in 2012 “Ropivacaine HCL a synthetic” literary composition and Chinese patent CN201310041390.2 all adopt this kind of method.”synthetic chemistry” the 14th the 4th phase of volume “Synthesis of Ropivacaine Hydrochloride by Triphosgene” in 2006 and Hunan University’s Master’s thesis “synthesising process research of Ropivacaine HCL and” disclose the synthetic method of another ropivacaine, the Pipecolic Acid that adopts inexpensive racemization is raw material, prepare Ropivacaine HCL through reactions such as amidation, alkylations, use triphosgene or thionyl chloride to prepare acyl chlorides, but triphosgene danger in the time of storage and aftertreatment is larger, is not suitable for suitability for industrialized production; And partial condition in the latter’s method (reagent that the pH separating as intermediate (I) and reagent, catalyzer and recrystallization are used etc.) haves much room for improvement,under its test conditions, be difficult to take into account high purity and high yield simultaneously, according to prior art, the separation of ropivacaine raceme is also not ideal.The preparation method of embodiment 1, a kind of Ropivacaine HCL, comprises the steps:(1) preparation of intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea10.0g2-piperidine carboxylic acid, 160ml toluene are added in 500ml reaction flask.Pass into HCl gas, to pH2, be warming up to 48 ± 2 DEG C, add 1.5mlDMF, drip 11.2g (1.2 equivalent) sulfur oxychloride and 20ml toluene mixture liquid, drip and finish, be incubated 48 ± 2 DEG C of reaction 3h.Drip 2 of 4.0 equivalents, 6-xylidine and 20ml toluene mixture liquid, be incubated 58 ± 2 DEG C of reaction 3h.Filter, obtain yellow-green colour wet product 65g, dry to obtain gray solid 56g, solid is added in 280ml purified water, stir the molten reaction solution that obtains; 10%NaOH solution is slowly dropped in reaction solution, adjust pH to 4.5-5.0, use 100ml toluene wash , layering, retains water layer, continues to adjust pH to 9-10 with 10%NaOH solution, adds 100ml methylene dichloride.Layering, gets organic layer,and water layer continues to use 50ml dichloromethane extraction, merges organic layer, adds anhydrous sodium sulfate dehydration, 40 DEG C of concentrating under reduced pressure.Obtain pale yellow oily liquid body 15.5g, yield 86.2%, is intermediate (I) N-( 2,6-dimethyl benzene)-2-piperidyl urea.(2) preparation of intermediate (II) N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amideIntermediate 15.5 g of (the I) Dissolved in 60mlDMF IS, ADDS 8.9gK 2 cO . 3 , 8.2 g of drip (1.0 equivalent)-n-propyl bromide, and drip BE Finishing After Warming up to 78 ± 2 of DEG C, Insulation Reaction 2H; Ice Bath is down to room temperature, filters, and filtrate is added in 150ml frozen water, separates out a large amount of white solids, filter, dry, obtain white solid 17.4g, yield 95.0%, is intermediate (II) N-(2, 6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide.(3) preparation of left-handed ropivacaine tartrate17.4g intermediate (II) is dissolved in 100ml Virahol, heats up 40 DEG C and stir molten; Treat entirely moltenly, add successively 1.80g (0.1 equivalent) titanium isopropylate, 1.91g (0.2 equivalent) D-tartrate, be warming up to backflow, after solution clarification, continue reaction 2h; Be cooled to 30 DEG C of crystallizatioies, filter, 75 DEG C of oven dry, obtain white solid 8.7g, and yield 39.2% is left-handed ropivacaine tartrate; After testing, ropivacaine purity 99.02%, dextrorotatory isomer per-cent 0.98%.(4) preparation of Ropivacaine HCL crude productLeft-handed 8.7g ropivacaine tartrate is joined in 50ml Virahol, be warming up to 50 DEG C, drip concentrated hydrochloric acid, surveying pH is 1～2, insulation reaction 2h.Be cooled to 0 DEG C of crystallization, separate out a large amount of white solids, filter, dry, obtain white solid 6.6g, yield 85.5%, is Ropivacaine HCL crude product.After testing, ropivacaine purity 99.11%, dextrorotatory isomer per-cent 0.89%.(5) refining6.6g crude product and 40ml dehydrated alcohol-concentrated hydrochloric acid mixed solution (20:1) are added in reaction flask, be heated to 50 DEG C and make to dissolve; Complete molten after, naturally cool to room temperature, ice-water bath is cooled to 0 DEG C, crystallization 2h; Filter, 5ml mixed solution washing for filter cake, obtains wet product, dries, and obtains white solid 6.0g, and yield 91.7%, is Ropivacaine HCL fine work.After testing, ropivacaine purity 99.91 %, dextrorotatory isomer per-cent 0.09%.The preparation method of embodiment 2, a kind of Ropivacaine HCLStep is as follows:(1) preparation of intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea100.0g2-piperidine carboxylic acid, 1600ml toluene are added in 3000ml reaction flask.Pass into HCl gas, to pH2 left and right, be warming up to 45～50 DEG C, add 15mlDMF, drip 111.5g (1.2 equivalent) sulfur oxychloride and 200ml toluene mixture liquid, drip and finish, be incubated 50-55 DEG C of reaction 3h.Drip 2 of 4.0 equivalents, 6-xylidine and 200ml toluene mixture liquid, be incubated 55～60 DEG C of reaction 2h.Filter, obtain the about 660g of yellow-green colour wet product, dry to obtain gray solid 545g, solid is added in 3000ml purified water, stir the molten reaction solution that obtains; 10%NaOH solution is slowly dropped in reaction solution, adjust pH to 4.5～5.0 , use 1000ml toluene wash, layering, retains water layer, continues to adjust pH to 9～10 with 10%NaOH solution, adds 1000ml methylene dichloride.Layering, gets organic layer,and water layer continues to use 750ml dichloromethane extraction, merges organic layer, adds anhydrous sodium sulfate dehydration, 40 DEG C of concentrating under reduced pressure.Obtain the about 151.8g of pale yellow oily liquid body, yield 84.5%, is intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea.(2) preparation of intermediate (II) N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amideIntermediate 150.0 g (the I) Dissolved in 600mlDMF IS, ADDS 86.5gK 2 cO . 3 , drip 95.4 g (1.2 equivalent)-n-propyl bromide, and drip BE Finishing After Warming up to 85 ~ 90 of DEG C, Insulation Reaction 2H; of Be Down to room temperature, filter, filtrate is added in 1500ml frozen water, separate out a large amount of white solids, filter, dry, obtain the about 167.6g of white solid, yield 94.6%, is intermediate (II) N-(2, 6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide.(3) preparation of left-handed ropivacaine tartrate160.0g intermediate (II) is dissolved in 1000ml Virahol, heats up 50 DEG C and stir molten; Treat entirely moltenly, add successively 16.58g (0.1 equivalent) titanium isopropylate, 43.8g (0.5 equivalent) D-tartrate, be warming up to backflow, after solution clarification, continue reaction 3h; Cooling, is down to 30-35 DEG C of crystallization, filters, and 75 DEG C of oven dry, obtain white solid 84.2g, and yield 41.3% is left-handed ropivacaine tartrate; After testing, ropivacaine purity 98.97%, dextrorotatory isomer per-cent 1.03%.(4) preparation of Ropivacaine HCL crude productLeft-handed 80.0g ropivacaine tartrate is joined in 500ml Virahol, be warming up to 50 DEG C, drip concentrated hydrochloric acid, surveying pH is 1～2, insulation reaction 4h.Be cooled to 0～5 DEG C of crystallization, separate out a large amount of white solids, filter, dry, obtain the about 61.6g of white solid, yield 86.5%, is Ropivacaine HCL crude product.After testing, ropivacaine purity 99.07%, dextrorotatory isomer per-cent 0.93%.(5) refining60.0g crude product and 500ml dehydrated alcohol-concentrated hydrochloric acid mixed solution (20:1) are added in reaction flask, be heated to 50 DEG C and make to dissolve; Complete molten after, cooling crystallization, ice-water bath is cooled to 0-5 DEG C, crystallization 4h; Filter, a small amount of cold mixed solution washing for filter cake, obtains wet product, dries, and obtains white solid 55.6g, and yield 92.7%, is Ropivacaine HCL fine work.After testing, ropivacaine purity 99.87%, dextrorotatory isomer per-cent 0.13%.The preparation method of embodiment 3, a kind of Ropivacaine HCLStep is as follows:(1) preparation of intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea10.0g2-piperidine carboxylic acid, 160ml toluene are added in 500ml reaction flask.Pass into HCl gas, to pH3 left and right, be warming up to 48 ± 2 DEG C, add 1.5mlDMF, drip 9.3g (1.0 equivalent) sulfur oxychloride and 20ml toluene mixture liquid, drip and finish, be incubated 48 ± 2 DEG C of reaction 2h.Drip 2 of 4.0 equivalents, 6-xylidine and 20ml toluene mixture liquid, be incubated 58 ± 2 DEG C of reaction 3h.Filter, obtain yellow-green colour wet product 63.6g, dry to obtain gray solid 55g, solid is added in 280ml purified water, stir the molten reaction solution that obtains; 10%NaOH solution is slowly dropped in reaction solution, adjust pH to 4.5-5.0, use 100ml toluene wash, layering, retains water layer, continues to adjust pH to 9-10 with 10%NaOH solution, adds 100ml methylene dichloride.Layering, gets organic layer,and water layer continues to use 50ml dichloromethane extraction, merges organic layer, adds anhydrous sodium sulfate dehydration, 40 DEG C of concentrating under reduced pressure.Obtain the about 14.8g of pale yellow oily liquid body, yield 82.4%, is intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea.(2) preparation of intermediate (II) N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amideIntermediate 14.8 g of (the I) Dissolved in 60mlDMF IS, ADDS 8.5gK 2 cO . 3 , 7.8 g of drip (1.0 equivalent)-n-propyl bromide, and drip After Finishing of DEG BE Warming up to 75 C, Reaction Insulation 2H; IS Down Ice Bath to room temperature, filters, and filtrate is added in 150ml frozen water, separates out a large amount of white solids, filter, dry, obtain the about 16.0g of white solid, yield 91.5%, is intermediate (II) N-(2 ,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide.(3) preparation of left-handed ropivacaine tartrate15g intermediate (II) is dissolved in 100ml Virahol, heats up 40 DEG C and stir molten; Treat entirely moltenly, add successively 1.72g (0.1 equivalent) titanium isopropylate, 1.82g (0.2 equivalent) D-tartrate, be warming up to backflow , after solution clarification, continue reaction 1h; Be cooled to 32 DEG C of crystallizatioies, filter, 75 DEG C of oven dry, obtain white solid 7.5g, and yield 39.2% is left-handed ropivacaine tartrate; After testing, ropivacaine purity 98.92 %, dextrorotatory isomer per-cent 0.99%.(4) preparation of Ropivacaine HCL crude productLeft-handed 7.5g ropivacaine tartrate is joined in 50ml Virahol, be warming up to 40 DEG C, drip concentrated hydrochloric acid, surveying pH is 1～2, insulation reaction 1h.Be cooled to 0 DEG C of crystallization, separate out a large amount of white solids, filter, dry, obtain the about 5.7g of white solid, yield 85.3%, is Ropivacaine HCL crude product.After testing, ropivacaine purity 99.12%, dextrorotatory isomer per-cent 0.96%.(5) refining5.7g crude product and 40ml dehydrated alcohol-concentrated hydrochloric acid mixed solution (20:1) are added in reaction flask, be heated to 50 DEG C and make to dissolve; Complete molten after, naturally cool to room temperature, ice-water bath is cooled to 0 DEG C, crystallization 2h; Filter, 10ml mixed solution washing for filter cake, obtains wet product, dries, and obtains white solid 5.5g, and yield 92.1%, is Ropivacaine HCL fine work.After testing, ropivacaine purity 99.92 %, dextrorotatory isomer per-cent 0.15%.The preparation method of embodiment 4, a kind of Ropivacaine HCLStep is as follows:(1) preparation of intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea10.0g2-piperidine carboxylic acid, 160ml toluene are added in 500ml reaction flask.Pass into HCl gas, to pH3 left and right, be warming up to 48 ± 2 DEG C, add 1.5mlDMF, drip 10.2g (1.1 equivalent) sulfur oxychloride and 20ml toluene mixture liquid, drip and finish, be incubated 48 ± 2 DEG C of reaction 6h.Drip 2 of 4.0 equivalents, 6-xylidine and 20ml toluene mixture liquid, be incubated 58 ± 2 DEG C of reaction 8h.Filter, obtain yellow-green colour wet product 64.2g, dry to obtain gray solid 55.6g, solid is added in 280ml purified water, stir the molten reaction solution that obtains; 10%NaOH solution is slowly dropped in reaction solution, adjust pH to 4.5-5.0 , use 100ml toluene wash, layering, retains water layer, continues to adjust pH to 9-10 with 10%NaOH solution, adds 100ml methylene dichloride.Layering, gets organic layer,and water layer continues to use 50ml dichloromethane extraction, merges organic layer, adds anhydrous sodium sulfate dehydration, 40 DEG C of concentrating under reduced pressure.Obtain the about 14.9g of pale yellow oily liquid body, yield 82.9%, is intermediate (I) N-(2,6-dimethyl benzene)-2-piperidyl urea.(2) preparation of intermediate (II) N-(2,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amideIntermediate 14.9 g of (the I) Dissolved in 60mlDMF IS, ADDS 8.5gK 2 cO . 3 , 7.8 g of drip (1.0 equivalent)-n-propyl bromide, and drip After Finishing of DEG BE Warming up to 75 C, Reaction Insulation 2H; IS Down Ice Bath to room temperature, filters, and filtrate is added in 150ml frozen water, separates out a large amount of white solids, filter, dry, obtain the about 16.1g of white solid, yield 92.0%, is intermediate (II) N-(2 ,6-3,5-dimethylphenyl)-1-n-propyl piperidines-2-methane amide.(3) preparation of left-handed ropivacaine tartrate15g intermediate (II) is dissolved in 100ml Virahol, heats up 60 DEG C and stir molten; Treat entirely moltenly, add successively 1.72g (0.1 equivalent) titanium isopropylate, 1.82g (0.2 equivalent) D-tartrate, be warming up to backflow , after solution clarification, continue reaction 4h; Be cooled to 30 DEG C of crystallizatioies, filter, 75 DEG C of oven dry, obtain white solid 7.6g, and yield 39.7% is left-handed ropivacaine tartrate; After testing, ropivacaine purity 99.01 %, dextrorotatory isomer per-cent 1.05%.(4) preparation of Ropivacaine HCL crude productLeft-handed 7.6g ropivacaine tartrate is joined in 50ml Virahol, be warming up to 40 DEG C, drip concentrated hydrochloric acid, surveying pH is 1～2, insulation reaction 4h.Be cooled to 5 DEG C of crystallizatioies, separate out a large amount of white solids, filter, dry, obtain the about 5.7g of white solid, yield 85.3%, is Ropivacaine HCL crude product.After testing, ropivacaine purity 99.06%, dextrorotatory isomer per-cent 0.95%.(5) refining5.7g crude product and 40ml dehydrated alcohol-concentrated hydrochloric acid mixed solution (volume ratio 20:1) are added in reaction flask, be heated to 80 DEG C and make to dissolve; Complete molten after, naturally cool to room temperature, ice- water bath is cooled to 5 DEG C, crystallization 2h; Filter, 10ml mixed solution washing for filter cake, obtains wet product, dries, and obtains white solid 5.2g, and yield 91.2%, is Ropivacaine HCL fine work.After testing, ropivacaine purity 99.81%, dextrorotatory isomer per-cent 0.11%.The optical isomer method for detecting purity of left-handed ropivacaine tartrate, Ropivacaine HCL crude product and the Ropivacaine HCL purified product obtaining in above-described 1-4 is: measure according to high performance liquid chromatography (annex VD), with alpha- acid glycoprotein post (AGP, 100mm × 4.0mm, 5 μ m are suitable for); Agilent-1260 type high performance liquid chromatograph; (get potassium primary phosphate 2.72g with Virahol-phosphate buffered saline buffer, the 800ml that adds water dissolves, regulating pH value with 0.1mol/L sodium hydroxide solution is 7.1, be diluted with water to 1000ml) be (10:90) moving phase, detection wavelength is: 210nm, column temperature: 30 DEG C, flow velocity 1.0ml/min, limit is: dextrorotatory isomer must not be greater than 0.5%. PATENThttps://patents.google.com/patent/CN109503465A/enThe embodiment of 1 intermediate (-) of-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamideL- piperidinecarboxylic acid hydrochloride (30.00g, 0.18mol), toluene are sequentially added in three mouthfuls of reaction flasks of 500ml cleaning N,N-Dimethylformamide (1ml), thionyl chloride (25.85g, 0.2 2mol) is added in (300ml) , stirring.It finishes, is warming up to 50~55 DEG C insulation reaction 3 hours.Snubber device is added to vacuumize 1 hour.The toluene solution of 2,6- dimethylaniline is added dropwise (2,6- dimethylanilines (109.75g , 0.91mol) are mixed with toluene (60ml)).It finishes, 60 DEG C of insulation reaction 2.0h.Cooling It to 20~30 DEG C, is added purified water (300ml), water phase is collected in layering; Fresh toluene (300ml), 10% hydrogen-oxygen is added in water phase Change sodium regulation system pH=6- 7, water phase is collected in layering; Water phase 10% sodium hydroxide regulation system pH=11~12,room temperature Stirring 4 hours, filter, purified water (150ml) elute filter cake, filter cake in 60 DEG C of air dry ovens it is dry 35.88g (yield 85%, HPLC purity 94.023% is calculated by areas of peak normalization method) .The purification of 2 intermediate (-) of-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide1 gained intermediate (-) of embodiment-(2S)-N- (2,6- diformazan is sequentially added in three mouthfuls of reaction flasks of 100ml cleaning Base phenyl) piperidines -2- formamide (5.00g, 21.52mmol), ether (50ml), stir and are warming up to reflux, flow back insulated and stirred 1 Hour, it is cooled to room temperature, insulated and stirred 1 hour, is filtered, ether (10ml) elutes filter cake, and filter cake is dry in 50 DEG C of air dry ovens Dry 2 hours 2.66g (yield 53.2% calculates HPLC purity 99.837% by areas of peak normalization method), map is shown in attached drawing 1.The purification of 3 intermediate (-) of-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide1 gained intermediate (-) of embodiment-(2S)-N- (2,6- diformazan is sequentially added in three mouthfuls of reaction flasks of 100ml cleaning Base phenyl) piperidines -2- formamide (5.00g, 21.52mmol), isopropyl ether (50ml), stir and are warming up to reflux, reflux heat preservation is stirred It mixes 1 hour, is cooled to room temperature, insulated and stirred 1 hour, filters, isopropyl ether (10m l) elutes filter cake, and filter cake is dry in 50 DEG C of air blast Dry 2 hours 3.45g of dry case (yield 69.0% calculates HPLC purity 99.332% by areas of peak normalization method).Map is shown in attached Fig. 2.The purification of 4 intermediate (-) of-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide1 gained intermediate (-) of embodiment-(2S)-N- (2,6- diformazan is sequentially added in three mouthfuls of reaction flasks of 100ml cleaning Base phenyl) piperidines -2- formamide (5.00g, 21.52mmol), methyl tertiary butyl ether(MTBE) (50ml), stir and are warming up to reflux, flow back Insulated and stirred 1 hour, be cooled to room temperature, insulated and stirred 1 hour, filter, methyl tertiary butyl ether(MTBE) (10ml) elutes filter cake, filter cake in Dry 2 hours 4.75g (yield 95% calculates HPLC purity 99.709% by areas of peak normalization method) of 50 DEG C of air dry ovens, Map is shown in attached drawing 3.5 intermediate (-) of embodiment-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide preparation and purificationA) the preparation of intermediate (-)-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamideL- piperidinecarboxylic acid hydrochloride (3kg, 18.1mol), toluene (30L) are added in 50L reaction kettle, N, N- is added in stirring Dimethylformamide (1L), thionyl chloride (2.59kg, 21.8mol). It finishes, is warming up to 50~55 DEG C of insulation reactions 3 hours. Snubber device is added to vacuumize 6 hours.Be added dropwise 2,6- dimethylaniline toluene solution (2,6- dimethylanilines (11kg, It 90.8mol) is mixed with toluene (6L)).It finishes, 60 DEG C of insulation reaction 2.0h. 20~30 DEG C are cooled to, is added purified water (30L), Water phase is collected in layering; Water phase is added fresh toluene (30L) , 10% sodium hydroxide regulation system pH=6-7, and water is collected in layering Phase; 10% sodium hydroxide regulation system pH=11~12 of water phase, are stirred at room temperature 4 hours, filter,purified water (15L) elution filter Cake, filter cake in 60 DEG C of air dry ovens it is dry 3.52kg (yield 84%, by areas of peak normalization method calculate HPLC purity 98.092%), map is shown in attached drawing 4.B) the purification of intermediate (-)-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamideIntermediate (-)-(2S)-N- (2,6- 3,5-dimethylphenyl) piperidines -2- formamide (3. is sequentially added in 50L reaction kettle 5kg, 15.1mol), methyl tertiary butyl ether(MTBE) (35L), stirring is warming up to reflux, flows back insulated and stirred 1 hour, be cooled to room temperature, guarantor Temperature stirring 1 hour, filters, and methyl tertiary butyl ether(MTBE) (7L) elutes filter cake, and filter cake is in the dry 8 hours 3.3kg of 50 DEG C of air dry ovens (yield 94% calculates HPLC purity 99.889% by areas of peak normalization method), map is shown in attached drawing 5.
Ropivacaine is the S-enantiomer of an N-alkyl pipecoloxylidine derivative, which is the first local anesthetic with chiral activity, and is widely used in clinical infiltration anesthesia, conduction anesthesia and epidural anesthesia. It has a long of local anesthesia and analgesic effect. However, ropivacaine also has serious safety risks in clinical practice. When the concentration of ropivacaine in human blood is too high, it may cause toxicity to the cardiovascular and central nervous system, and even cause allergic reactions in some patients. Thus far, the mechanism of the effect of ropivacaine on local anesthesia is not clear. Ropivacaine is a multitarget drug that acts on the gamma-aminobutyric acid a receptor (GABAA-R) and N-methyl-D-aspartate acid receptor (NDMA-R). Sodium (Na+) channels are a key target of local anesthetics and these two receptors regulate sodium channels. Previous studies on the structural modification of ropivacaine mainly focused on the substitution of –CH3 on the phenyl group or the substitution of –CH2CH2CH3 on piperidine with different alkyl groups. In 2017, Wen L. et al.69 reported the design and synthesis of ropivacaine analogues for local anesthesia. In the process of structural design, they used ropivacaine as the lead compound to design two series of compounds, 4a–4q (17 new substituted imines). In the first series of compounds, 4a–4i, different substituents were selected to replace –CH2CH2CH3 on piperidine. In the second series of compounds, 4j–4q, the methyl groups were replaced by –CF3 at the o-positions, m-positions and p-positions. Meanwhile, the –CH2CH2CH3 on piperidine ring was also substituted and modified. The process for the synthesis of the target compounds is shown in Scheme 8. The synthetic route takes piperic acid (compound 1) as the starting material, hydrochloric acid and sulfoxide chloride as additives, and toluene as the reaction solvent to convert compound 1 into acyl chloride salt (compound 2). Compound 2 was then treated with substituted aniline and reacted at 58 °C for 5 h to form compounds 3a–3i and 3j–3q. Finally, bromoalkyl and hydrochloric acid were used to treat compounds 3a–3i and 3j–3q. Potassium carbonate (K2CO3) was used as an acid dressing agent and dimethylformamide (DMF) as the reaction solvent in N-alkylation reaction. The N-alkylation reaction lasted 10 h at 80 °C, and the salt reaction lasted 5 min at room temperature to obtain the final target compounds 4a–4q. The total yield of the target compounds ranged from 17.5% to 87.7%. The synthetic route has the advantages of mild reaction conditions, cheap reagents and simple operation. However, using this synthetic route, the total yield of some products is too low, and too low yield will bring great problems to the synthesis cost, which needs to be further optimized in follow-up work. In the evaluation of the local anesthesia effect, sciatic nerve block activity, infiltration anesthesia activity, corneal anesthesia activity and spinal cord anesthesia activity were used as evaluation indexes. Ropivacaine was used as a positive control substance to test the local anesthesia activity in vitro. Firstly, the local anesthesia effect of all the target compounds 4a–4q was screened by a sciatic nerve block test in toads in vitro (Table 6). The preliminary screening results in vitro showed that these compounds increased the blocking effect of the sciatic nerve on electrical stimulation, with ED50 values ranging from 0.012 to 0.64 (positive control for ropivacaine was 0.013), with the highest activity shown by compound 4b. In terms of latent period, that of target compounds 4a–4q ranged from 27.7 to 59.4 min. Based on the results of the preliminary in vitro screening, compounds 4a, 4b, 4c, 4j and 4l were selected to test the efficacy of invasive anesthesia in guinea pigs. The results of the infiltration anesthesia test showed that the local anesthetic effect of compounds 4c and 4l was similar to that of the positive control ropivacaine, and the local anesthetic activity of other compounds was lower than that of the positive control. Furthermore, compounds 4a, 4b, 4c, 4j and 4l were used to test the local surface anesthesia effect of these compounds (Table 7). The results of the surface anesthesia test showed that compound 4l had a similar local anesthetic effect as the positive control ropivacaine, while the effect of the other compounds was poor in comparison with the positive control. Finally, compounds 4a, 4b, 4c, 4j and 4l were tested for spinal anesthesia in order to further study their local surface anesthesia effect. The experimental results showed that the ED50 produced by compounds 4l and 4b was 5.02 and 7.87, respectively, while the effects of compounds 4a, 4c and 4j were poor. The evaluation of local anesthesia in vitro found that compound 4l had the best activity, and thus molecular docking of compound 4l and ropivacaine was conducted to further study its local anesthesia mechanism. The molecular docking results showed that compound 4l interacts with receptor proteins of VGSC, GABAA-R and NDMA-R, which may help optimize and predict the activity of these ropivacaine analogues as potential local anesthetics.
Scheme 8 Reagents and conditions: (a) (i) HCl,PhCH3, r.t., 1 h; (ii) PhCH3, SOCl2, 55 °C, 1 h; (b) substituted anilines, 58 °C, 5 h; and (c) (i) RBr, K2CO3, DMF, 80 °C, 10 h; (ii) HCl, r.t., 5 min.
SYN
Prepn: A. F. Thuresson, C. Bovin, WO 8500599 (1985 to Apothekernes); H.-J. Federsel et al., Acta Chem. Scand. B41, 757 (1987).
Ropivacaine hydrochloride was synthesized from L-2-pipecolic acid by successive reaction with SOCl2 and 2,6-dimethylaniline at 40 °C under ultrasonic irradiation to yield L-N-(2,6-dimethylphenyl)piperidin-2-carboxamide (4), and 4 was reacted with 1-bromopropane at 50 °C for 1 h under ultrasonic irradiation. The effects of reaction solvent, temperature and time under ultrasonic irradiation were investigated. Compared with conventional methods, present procedures have the advantages in milder conditions, shorter reaction time and higher yields. The total yield was 67.5%, [α]25 D= – 6.6°(c = 2, H2O).
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Ropivacaine (3.1.37) (Naropin) is the pure S(–)-enantiomer of propivacaine released for clinical use in 1996. It is a long-acting, well tolerated local anesthetic agent and first produced as a pure enantiomer. Its effects and mechanism of action are similar to other local anesthetics working via reversible inhibition of sodium ion influx in nerve fibers. It may be a preferred option among other drugs among this class of compounds because of its reduced CNS and cardiotoxic potential and its lower propensity for motor block in the management of postoperative pain and labor pain [48–58].
The synthesis of ropivacaine (3.1.37) was carried out starting with l-pipecolic acid (3.1.34), prepared by a resolution of (±)-pipecolic acid with (+)-tartaric acid, which was dissolved in acetyl chloride and converted to acid chloride (3.1.35) with phosphorus pentachloride. The obtained compound (3.1.35) dissolved in toluene a solution of 2,6-xylidine (3.1.28) dissolved in the mixture of equal volumes of acetone, and N-methyl-2-pyrrolidone was added at 70°C to give (+)-l-pipecolic acid-2,6-xylidide (3.1.36). Reaction of this compound with propyl bromide in presence of potassium carbonate in i-PrOH/H2O gave the desired ropivacaine (3.1.37) [59] (Scheme 3.6).
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Another approach for the synthesis of ropivacaine (3.1.37) was proposed via a resolution of enantiomers of chiral pipecolic acid-2,6-xylidide [60].
SYN
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Scheme 21. Generation of ‘cation pool’ and its applications.
Reproduced from Yoshida, J.; Suga, S.; Suzuki, S.; et al. J. Am. Chem. Soc. 1999, 121, 9546–9549, and Shankaraiah, N.; Pilli, R. A.; Santos, L. S. Tetrahedron Lett. 2008, 49, 5098–5100.
The synthesis of ropivacaine is achieved in only three steps, as in the previous example, comprised of a resolution of a racemic, commercially available starting material (pipecoloxylidide) followed by an N-alkylation and the final precipitation of the product as its HCl salt.14,24 Focusing on the middle step—the attachment of a propyl moiety onto the piperidine nitrogen—this reaction when developed in the laboratory and scaled up to maximum pilot plant volume (1000 L) behaved very well (Scheme 3). Thus, boiling the reaction mixture (reactants in a H2O/organic solvent mixture in the presence of a solid inorganic base) for an extended period of time (6 h) at high temperature (100 °C), the transformation was considered complete once a sample of the process solution showed <1% of remaining starting material. In preparation for launch, the method that had been thoroughly investigated and tested over a number of years and proven reliable on scale up had to be validated in the authentic 4000 L production equipment. Much to our surprise (and shock) we, however, found that the reaction came to a complete stand still long before reaching the expected end point. With a large amount of un-reacted starting material (30–40%) we were facing a situation that had never occurred during the lengthy development phase and this put the whole project in a very critical state as we were not able to reproduce the manufacturing method.
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Ropivacaine was developed after bupivacaine was noted to be associated with cardiac arrest, particularly in pregnant women. Ropivacaine was found to have less cardiotoxicity than bupivacaine in animal models.
Clinical use
Contraindications
Ropivacaine is contraindicated for intravenous regional anaesthesia (IVRA). However, new data suggested both ropivacaine (1.2-1.8 mg/kg in 40ml) and levobupivacaine (40 ml of 0.125% solution) be used, because they have less cardiovascular and central nervous system toxicity than racemic bupivacaine.[1]
Adverse effects
Adverse drug reactions (ADRs) are rare when it is administered correctly. Most ADRs relate to administration technique (resulting in systemic exposure) or pharmacological effects of anesthesia, however allergic reactions can rarely occur.
Systemic exposure to excessive quantities of ropivacaine mainly result in central nervous system (CNS) and cardiovascular effects – CNS effects usually occur at lower blood plasma concentrations and additional cardiovascular effects present at higher concentrations, though cardiovascular collapse may also occur with low concentrations. CNS effects may include CNS excitation (nervousness, tingling around the mouth, tinnitus, tremor, dizziness, blurred vision, seizures followed by depression (drowsiness, loss of consciousness), respiratory depression and apnea). Cardiovascular effects include hypotension, bradycardia, arrhythmias, and/or cardiac arrest – some of which may be due to hypoxemia secondary to respiratory depression.[2]
As for bupivacaine, Celepid, a commonly available intravenous lipid emulsion, can be effective in treating severe cardiotoxicity secondary to local anaesthetic overdose in animal experiments[4] and in humans in a process called lipid rescue.[5][6][7]
References
^ (Basic of Anesthesia, Robert Stoelting, page 289)
^ Rosenblatt MA, Abel M, Fischer GW, Itzkovich CJ, Eisenkraft JB (July 2006). “Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest”. Anesthesiology. 105 (1): 217–8. doi:10.1097/00000542-200607000-00033. PMID16810015.
^ Litz RJ, Popp M, Stehr SN, Koch T (August 2006). “Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion”. Anaesthesia. 61 (8): 800–1. doi:10.1111/j.1365-2044.2006.04740.x. PMID16867094. S2CID43125067.
External links
“Ropivacaine”. Drug Information Portal. U.S. National Library of Medicine.
Publication numberPriority datePublication dateAssigneeTitleUS4695576A *1984-07-091987-09-22Astra Lake Medel AktiebolagLNn-propylpipecolic acid-2,6-xylidideUS20050065345A1 *2001-09-102005-03-24Toshio TsuchidaMethod for producing pipecolamide derivativeCN103086954A *2013-02-042013-05-08Shandong Pharmaceutical Industry Research InstituteMethod for preparing ropivacaineCN104003930A *2014-06-132014-08-27Shandong Alura Pharmaceutical Research and Development Co., Ltd.Method for preparing hydrochloric acid ropivacaineCN107325041A *2017-06-202017-11-07Guangzhou Tonghui Pharmaceutical Co., Ltd.A kind of preparation method of Ropivacaine HCL
Non-Patent
TitleNAGULA SHANKARAIAH, etc.: “Enantioselective total syntheses of ropivacaine and its analogues”, “TETRAHEDRON LETTERS” *Liu Yi, et al.: “Synthesis of Ropivacaine Hydrochloride”, “Chinese Journal of Pharmaceutical Industry” *Ye Jiao, et al.: “Synthesis of Ropivacaine Hydrochloride by Triphosgene Method”, “Synthetic Chemistry” *Jiang Yao: “Study on the Synthetic Process of Ropivacaine Hydrochloride and Bupivacaine Hydrochloride”, “Engineering Science and Technology Series Ⅰ” *
Thuresson, B. and Egner, B.P.H.; U.S. Patent 2,792,399; May 14, 1957; assigned to AB Bofors, Sweden. Thuresson, B. and Pettersson, B.G.; US. Patent 2,955.1 11; October 4,1960; assigned to AB Bofors, Sweden., US2955111
SYN
British Patent 869,978 (1959).
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SYN
Bupivacaine, N-2,6-(dimethyl)1-butyl-2-piperidincarboxamide (2.2.7), is chemically similar to mepivacaine and only differs in the replacement of the N-methyl substituent on the piperidine ring with an N-butyl substituent. There are also two suggested methods of synthesis. The first comes from α-picolin-2,6-xylidide (2.2.4). The alkylation of the last with butyl bromide gives the corresponding pyridine salt (2.2.6). Finally, it is reduced by hydrogen using platinum oxide as a catalyst into a piperidine derivative—bupivacaine [13,16].
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The other method results directly from the piperidine-2-carboxylic acid chloride, which is reacted with 2,6-dimethylaniline. The resulting amide (2.2.8) is further alkylated with butyl bromide to bupivacaine [17–19].
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Like lidocaine and mepivacaine, bupivacaine is used in infiltration, spinal, and epidural anesthesia in blocking nerve transmission. Its most distinctive property is its long-lasting action. It is used for surgical intervention in urology and in lower thoracic surgery from 3 to 5 h in length, and in abdominal surgery lasting from 45 to 60 min. It is used to block the trifacial nerve, the sacral and brachial plexuses, in resetting dislocations, in epidural anesthesia, and during Cesarian sections. The most common synonym for bupivacaine is marcaine.
SYN
3.7 Bupivacaine (21293) and Levobupivacaine (1976)
Bupivacaine (3.1.41) (Marcaine) is a local anesthetic of great potency and long duration that has been widely used for years, but it has cardio and CNS toxic sideeffects. For many years it was nearly the only local anesthetic applicable to almost all kinds of loco-regional anesthetic techniques, and nowadays, in many occasions, it is still the only alternative available [61–64].
Bupivacaine is currently used in racemic form. At high doses, however, the racemate is potentially hazardous due to toxicity problems.
Currently, racemic bupivacaine (3.1.41) is produced from picolinic acid (3.1.38) either by reduction to pipecolic acid (3.1.39) and then, after conversion to corresponding acid chloride (3.1.40) coupling with 2,6-xylidine to give pipecolic acid-2,6-xylidide (3.1.33), or by reducing the pyridyl amide (3.1.43) prepared from picolinic acid chloride (3.1.42) over platinum oxide. The amide intermediate (3.1.33), which can also be used to prepare the anesthetics ropivacaine (3.1.37) and mepivacaine (3.1.31), was transformed to desired bupivacaine (3.1.41) either by direct alkylation using butyl bromide and potassium carbonate or by reductive amination using butyraldehyde [45,59,65–69] (Scheme 3.7).
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Enantiomers of bupivacaine can be prepared via diastereomeric salt resolution with tartaric acid or by resolution of the amide (3.1.33) with O,O-dibenzoyl tartaric acid followed by alkylation [47,70].
One of enantiomers, S(–) isomer of the racemic bupivacaine (levobupivacaine), has equal potency but less cardiotoxic and CNS effects in comparison with both R(+) bupivacaine and bupivacaine racemate. The reduced toxicity of levobupivacaine (3.1.48) gives a wider safety margin in clinical practice [71,72].
Stereospecific synthesis of levobupivacaine from (S)-lysine have been proposed (Scheme 3.8).
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Treatment of N-CBZ (S)-lysine (3.1.44) with sodium nitrite in acetic acid yields the acetate (3.1.45). The prepared acetate (3.1.45) was then coupled with dimethyl aniline using N,N′-dicyclohexylcarbodiimide to give the amide (3.1.46) in good yield. The acetate group was then converted into the tosylate (3.1.47), which was deprotected and cyclized stereospecifically in one-pot reaction to give the amide (3.1.33) in high yield. Alkylation is easily achieved using an alkyl bromide and K2CO3 without any racemization. Alkylation can also be carried out using butyraldehyde/formic acid although the former is a much simpler process [73] (Scheme 3.8).
SYN
WO 9611181
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Levobupivacaine has been obtained by two different ways: 1) The deamination of N-benzoyloxycarbonyl-L-lysine (I) with NaNO2/acetic acid gives 6-acetoxy-2(S)-(benzyl-oxycarbonylamino)hexanoic acid (II), which is amidated with 2,6-dimethylaniline (III) and dicyclohexylcarbodiimide (DCC) to the expected amide (IV). The deacetylation of (IV) with K2CO3 in methanol affords compound (V), which is tosylated as usual with tosyl chloride giving intermediate (VI), which is stereospecifically cyclized by means of K2CO3 in ethanol yielding N-(2,6-dimethyl-phenyl)piperidine-2 (S)-carboxamide (VII). Finally, this compound is alkylated with butyl bromide and K2CO3 or by reductoalkylation with butyraldehyde. 2) The amidation of piperidine-2-carboxylic acid (VIII) with 2,6-dimethylaniline (III) by means of SOCl2 in toluene gives the corresponding amide (IX), which is alkylated with butyl bromide as before yielding racemic bupivacaine (X) (3). This compound is then submitted to optical resolution by treatment with (S,S)-(?-tartaric acid followed by crystallization of the resulting tartrate and acidification with HCl in isopropanol.
SYN
Org Process Res Dev 2000,4(6),530
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Improved yield in the synthesis of levobupivacaine. An improved yield in the synthesis of levobupivacaine can be obtained by recovering the unwanted (R)-enantiomer side product in the optical resolution of the racemic bupivacaine. The treatment of (R)-(I) with refluxing propionic acid causes its racemization, yielding racemic-(I) (bupivacaine), which is then submitted to a new optical resolution process using dibenzoyl-L-tartaric acid.
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Bupivacaine is a local anesthetic used in a wide variety of superficial and invasive procedures.
Bupivacaine, marketed under the brand name Marcaine among others, is a medication used to decrease feeling in a specific area.[4] In nerve blocks, it is injected around a nerve that supplies the area, or into the spinal canal’s epidural space.[4] It is available mixed with a small amount of epinephrine to increase the duration of its action.[4] It typically begins working within 15 minutes and lasts for 2 to 8 hours.[4][5]
Possible side effects include sleepiness, muscle twitching, ringing in the ears, changes in vision, low blood pressure, and an irregular heart rate.[4] Concerns exist that injecting it into a joint can cause problems with the cartilage.[4] Concentrated bupivacaine is not recommended for epidural freezing.[4] Epidural freezing may also increase the length of labor.[4] It is a local anaesthetic of the amide group.[4]
Bupivacaine is indicated for local infiltration, peripheral nerve block, sympathetic nerve block, and epidural and caudal blocks. It is sometimes used in combination with epinephrine to prevent systemic absorption and extend the duration of action. The 0.75% (most concentrated) formulation is used in retrobulbar block.[12] It is the most commonly used local anesthetic in epidural anesthesia during labor, as well as in postoperative pain management.[13] Liposomal formulations of bupivacaine (brand name EXPAREL) have shown to be more effective in providing pain relief than plain solutions of bupivacaine.[14][15]
Bupivacaine (Posimir) is indicated in adults for administration into the subacromial space under direct arthroscopic visualization to produce post-surgical analgesia for up to 72 hours following arthroscopic subacromial decompression.[16][17]
Contraindications
Bupivacaine is contraindicated in patients with known hypersensitivity reactions to bupivacaine or amino-amide anesthetics. It is also contraindicated in obstetrical paracervical blocks and intravenous regional anaesthesia (Bier block) because of potential risk of tourniquet failure and systemic absorption of the drug and subsequent cardiac arrest. The 0.75% formulation is contraindicated in epidural anesthesia during labor because of the association with refractory cardiac arrest.[18]
Adverse effects
Compared to other local anaesthetics, bupivacaine is markedly cardiotoxic.[19] However, adverse drug reactions (ADRs) are rare when it is administered correctly. Most ADRs are caused by accelerated absorption from the injection site, unintentional intravascular injection, or slow metabolic degradation. However, allergic reactions can rarely occur.[18]
Clinically significant adverse events result from systemic absorption of bupivacaine and primarily involve the central nervous system (CNS) and cardiovascular system. CNS effects typically occur at lower blood plasma concentrations. Initially, cortical inhibitory pathways are selectively inhibited, causing symptoms of neuronal excitation. At higher plasma concentrations, both inhibitory and excitatory pathways are inhibited, causing CNS depression and potentially coma. Higher plasma concentrations also lead to cardiovascular effects, though cardiovascular collapse may also occur with low concentrations.[20] Adverse CNS effects may indicate impending cardiotoxicity and should be carefully monitored.[18]
Animal evidence[22][23] indicates intralipid, a commonly available intravenous lipid emulsion, can be effective in treating severe cardiotoxicity secondary to local anaesthetic overdose, and human case reports of successful use in this way.[24][25] Plans to publicize this treatment more widely have been published.[26]
Pregnancy and lactation
Bupivacaine crosses the placenta and is a pregnancy category C drug. However, it is approved for use at term in obstetrical anesthesia. Bupivacaine is excreted in breast milk. Risks of discontinuing breast feeding versus discontinuing bupivacaine should be discussed with the patient.[18]
Bupivacaine binds to the intracellular portion of voltage-gated sodium channels and blocks sodium influx into nerve cells, which prevents depolarization. Without depolarization, no initiation or conduction of a pain signal can occur.
Pharmacokinetics
The rate of systemic absorption of bupivacaine and other local anesthetics is dependent upon the dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the preparation.[28]
Onset of action (route and dose-dependent): 1-17 min
Duration of action (route and dose-dependent): 2-9 hr
Half life: neonates, 8.1 hr, adults: 2.7 hr
Time to peak plasma concentration (for peripheral, epidural, or caudal block): 30-45 min
Like lidocaine, bupivacaine is an amino-amide anesthetic; the aromatic head and the hydrocarbon chain are linked by an amide bond rather than an ester as in earlier local anesthetics. As a result, the amino-amide anesthetics are more stable and less likely to cause allergic reactions. Unlike lidocaine, the terminal amino portion of bupivacaine (as well as mepivacaine, ropivacaine, and levobupivacaine) is contained within a piperidine ring; these agents are known as pipecholyl xylidines.[13]
Society and culture
Legal status
On 17 September 2020, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Exparel, intended for the treatment of post-operative pain.[29] The applicant for this medicinal product is Pacira Ireland Limited.[29] Exparel liposomal was approved for medical use in the European Union in November 2020.[30]
Levobupivacaine is the (S)-(–)-enantiomer of bupivacaine, with a longer duration of action, producing less vasodilation. Durect Corporation is developing a biodegradable, controlled-release drug delivery system for after surgery. It has currently[when?] completed a phase-III clinical trial.[31]
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06.
^ Jump up to:ab Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 22. ISBN9781284057560.
^ de La Coussaye, J. E.; Eledjam, J. J.; Brugada, J.; Sassine, A. (1993). “[Cardiotoxicity of local anesthetics]”. Cahiers d’Anesthésiologie. 41 (6): 589–598. ISSN0007-9685. PMID8287299.
^ Weinberg, GL; VadeBoncouer, T; Ramaraju, GA; Garcia-Amaro, MF; Cwik, MJ. (1998). “Pretreatment or resuscitation with a lipid infusion shifts the dose-response to bupivacaine-induced asystole in rats”. Anesthesiology. 88 (4): 1071–5. doi:10.1097/00000542-199804000-00028. PMID9579517. S2CID1661916.
^ Weinberg, G; Ripper, R; Feinstein, DL; Hoffman, W. (2003). “Lipid emulsion infusion rescues dogs from bupivacaine-induced cardiac toxicity”. Regional Anesthesia and Pain Medicine. 28 (3): 198–202. doi:10.1053/rapm.2003.50041. PMID12772136. S2CID6247454.
^ Rosenblatt, MA; Abel, M; Fischer, GW; Itzkovich, CJ; Eisenkraft, JB (July 2006). “Successful use of a 20% lipid emulsion to resuscitate a patient after a presumed bupivacaine-related cardiac arrest”. Anesthesiology. 105 (1): 217–8. doi:10.1097/00000542-200607000-00033. PMID16810015.
^ Litz, RJ; Popp, M; Stehr, S N; Koch, T. (2006). “Successful resuscitation of a patient with ropivacaine-induced asystole after axillary plexus block using lipid infusion”. Anaesthesia. 61 (8): 800–1. doi:10.1111/j.1365-2044.2006.04740.x. PMID16867094. S2CID43125067.
CAS Registry Number: 155213-67-5 CAS Name: (5S,8S,10S,11S)-10-Hydroxy-2-methyl-5-(1-methylethyl)-1-[2-(1-methylethyl)-4-thiazolyl]-3,6-dioxo-8,11-bis(phenylmethyl)-2,4,7,12-tetraazatridecan-13-oic acid 5-thiazolylmethyl ester Additional Names: (2S,3S,5S)-5-[N-[N-[[N-methyl-N-[(2-isopropyl-4-thiazolyl)methyl]amino]carbonyl]valinyl]amino]-2-[N-[(5-thiazolyl)methoxycarbonyl]amino]-1,6-diphenyl-3-hydroxyhexane Manufacturers’ Codes: A-84538; Abbott 84538; ABT-538 Trademarks: Norvir (Abbott) Molecular Formula: C37H48N6O5S2 Molecular Weight: 720.94 Percent Composition: C 61.64%, H 6.71%, N 11.66%, O 11.10%, S 8.90% Literature References: Peptidomimetic HIV-1 protease inhibitor. Prepn: D. J. Kempf et al.,WO9414436; eidem,US5541206 (1994, 1996 both to Abbott). Antiretroviral spectrum, pharmacokinetics: idemet al.,Proc. Natl. Acad. Sci. USA92, 2484 (1995). Structural model for drug resistance: M. Markowitz et al.,J. Virol.69, 701 (1995). HPLC determn in biological fluids: R. M. W. Hoetelmans et al.,J. Chromatogr. B705, 119 (1998). Review of clinical experience: A. P. Lea, D. Faulds, Drugs52, 541-546 (1996). Clinical trial with nucleoside analogs in HIV-infected children: S. A. Nachman et al.,J. Am. Med. Assoc.283, 492 (2000). Clinical trial with lopinavir, q.v., in HIV infection: S. Walmsley et al.,N. Engl. J. Med.346, 2039 (2002). Therap-Cat: Antiviral. Keywords: Antiviral; Peptidomimetics; HIV Protease Inhibitor.Company：Abbvie (Originator)Sales：$389 Million (Y2012); Image may be NSFW. Clik here to view. $419 Million (Y2011);ATC Code：J05AE03
Ritonavir was first approved by the U.S. Food and Drug Administration (FDA) on March 1, 1996, then approved by European Medicine Agency (EMA) on August 26, 1996, and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on September 25, 1998. It was developed and marketed as Norvir® by Abbvie.
Ritonavir is an HIV protease inhibitor. It is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection.
Norvir® is available as solution for oral use, containing 80 mg of free Ritonavir per mL. The recommended dose is 600 mg twice-day with meals for adult patients. Ritonavir is an HIV protease inhibitor used in combination with other antivirals in the treatment of HIV infection.
Common side effects include nausea, vomiting, loss of appetite, diarrhea, and numbness of the hands and feet.[2] Serious side effects include liver problems, pancreatitis, allergic reactions, and arrythmias.[2] Serious interactions may occur with a number of other medications including amiodarone and simvastatin.[2] At low doses it is considered to be acceptable for use during pregnancy.[4] Ritonavir is of the protease inhibitor class.[2] Typically, however, it is used to inhibit the enzyme that metabolizes other protease inhibitors.[5] This inhibition allows lower doses of these latter medication to be used.[5]
The first report of a new protease inhibitor candidate lopinavir (34.1.21) seems to be Abbott’s patent [134].
The core of lopinavir is identical to that of ritonavir. The 5-thiazolyl end group in ritonavir was replaced by the phenoxyacetyl group, and the 2-isopropylthiazolyl group in ritonavir was replaced by a modified valine in which the amino terminus had a six-membered cyclic urea attached.
Synthetic strategy employed for the synthesis of multikilogram quantities of lopinavir is very similar to that implemented for ritonavir (34.1.22), but using the protected version (34.1.79) of the “core” diamino alcohol (34.1.55), which was sequentially acylated with the acid chlorides of (S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoic acid (34.1.89) and 2-(2,6-dimethylphenoxy)acetic acid (34.1.94) [135,136].
The bulk synthesis of protected diamino alcohol (34.1.79) was proposed [137,138] by a method closely related to the method [122,123] for ritonavir. For that purpose L-phenylalanine (34.1.74) was sequentially trialkylated with benzyl chloride using a K2CO3/water system at reflux to produce a tribenzylated product (34.1.75). A solution with generated acetonitrile anion in THF was added to the benzylated product (34.1.75) at less than −40°C to yield the cyanomethylketone (34.1.76), which was exposed to Grignard reagent–benzyl magnesium chloride to produce an enaminone (34.1.77). No racemization was observed in these two steps. The addition of the obtained enaminone (34.1.77) in THF/PrOH to a solution of NaBH4 and MsOH in THF at 5°C produced an intermediate aminoketone (34.1.78). No further reduction of the keto group occurs under these conditions. Reduction of the keto group could proceed by addition of a preformed solution of sodium tris(trifluoroacetoxy)borohydride in tetrahydrofuran [NaBH3(OTFA)], which produces a mixture of amino alcohols composed of 93% of the desired (2S)-5-amino-2-(dibenzylamino)-1,6-diphenylhexan-3-ol (34.1.79) along with 7% of the three undesired diastereomers. The crude mixture was debenzylated (Pd-C, HCONH4), and the product was purified by precipitation from iPrOH/HCl (aq) to produce (34.1.55) in greater than 99% purity and in high yield (Scheme 34.8.).
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An efficient synthesis of each of the side chain moieties and their coupling with the “core” diamino alcohol derivatives was developed as follows: (S)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanoic acid (34.1.85) was prepared starting from L-valine (34.1.80), which was first converted to N-phenoxycarbonyl-L-valine (34.1.82) with phenylchloroformate (34.1.81). Accurate pH monitoring (pH 9.5 to 10.2) was necessary and LiOH was found to be a superior base. Control of pH was essential as the valine dimer and its derivatives were formed as reaction byproducts outside of this pH margin. LiCl was added to provide a lower freezing point to the aqueous solution and neutral Al2O3 was added to prevent gumming and emulsion formation during the course of the reaction.
Treatment of N-phenoxycarbonyl-L-valine (34.1.82) with 3-chloropropylamine hydrochloride (34.1.3) and solid NaOH in THF produced the unisolated salt of chloropropylurea (34.1.84), which was then treated with t-BuOK, effecting cyclization to produce the desired acid (34.1.85) in 75 to 85% yield and in greater than 99% enantiomeric excess. Acylation of (34.1.79) with synthesized acid (34.1.85) was initially achieved by well-known peptide coupling methods. Optimization of this transformation allowed the discovery of a more cost-effective method for implementing acyl chloride (34.1.86), which was easily prepared using thionyl chloride in THF at room temperature.
The reaction of dibenzylamino alcohols (34.1.79) with acyl chloride (34.1.86) in the presence of 3.0 equivalents of imidazole in EtOAc and DMF produced acylated intermediate (34.1.87) as a mixture of diastereomers, which, without any further purification, was subjected to debenzylation with Pd/C and HCO2NH4 in MeOH at 50°C, which proceeded without significant complications to produce (34.1.88).
Exposure of crude (34.1.88) to L-pyroglutamic acid (34.1.89) in dioxane at 50°C followed by cooling, allowed for the isolation of (S)-N-((2S,4S,5S)-5-amino-4-hydroxy-1,6-diphenylhexan-2-yl)-3-methyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanamide (34.1.90) pyroglutamic salt as virtually a single diastereomer in high yield (Scheme 34.9.).
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Acyl chloride (34.1.92) was prepared by the reaction of 2-(2,6-dimethylphenoxy)acetic acid (34.1.91) with thionyl chloride in EtOAc, at room temperature adding a single drop of DMF, and warming the slurry to 50°C, which produced a clear solution of (34.1.92) that was used in the subsequent acylation of amine (34.1.90). Reaction of pyroglutamate salt (34.1.90) with acyl chloride (34.1.95) in ethyl acetate under Schotten-Baumann reaction conditions (use of a two-phase solvent system) in the presence of a water solution of NaHCO3 for liberation of free amine, produced the desired lopinavir (34.1.21) in high yield and purity (Scheme 34.10.).
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Lopinavir is a novel and strong protease inhibitor developed from ritonavir with high specificity for HIV-1 protease [139-141]. It is indicated, in combination with other antiretroviral agents, for the treatment of HIV-1 infection. Numerous clinical trials have shown that lopinavir/ritonavir (Kaletra) is highly effective as a component of highly active antiretroviral therapy [142,143].
Ritonavir is indicated in combination with other antiretroviral agents for the treatment of HIV-1-infected patients (adults and children of two years of age and older).[1][2]
Ritonavir (CAS Number [155213-67-5]), the structural formula of which is given below,is an inhibitor of human HIV protease which was described for the first time by Abbott in International Patent Application WO 94/14436, together with the process for the preparation thereof.
[0002] In the synthesis scheme given in WO 94/14436, Ritonavir is manufactured starting from valine and from compounds 1, 4 and 7, the structural formulae of which are also given below.
[0003] The synthesis process in question was subsequently optimised in its various parts by Abbot, who then described and claimed the individual improvements in the patent documents listed below: US 5,354,866, US 5,541,206, US 5,491,253, WO98/54122, WO 98/00393 and WO 99/11636.
[0004] The process for the synthesis of Ritonavir carried out on the basis of the above-mentioned patent documents requires, however, a particularly large number of intermediate stages; it is also unacceptable from the point of view of so-called “low environmental impact chemical synthesis” (B.M.Trost Angew. Chem. Int. Ed. Engl. (1995) 34, 259-281) owing to the increased use of activating groups and protective groups which necessitate not inconsiderable additional work in disposing of the by-products of the process, with a consequent increase in the overall manufacturing costs.
[0005] The object of the present invention is therefore to find a process for the synthesis of Ritonavir which requires a smaller number of intermediate stages and satisfies the requirements of low environmental impact chemical synthesis, thus limiting “waste of material”.
[0006] A process has now been found which, by using as starting materials the same compounds as those used in WO 94/14436, leads to the formation of Ritonavir in only five stages and with a minimum use of carbon atoms that are not incorporated in the final molecule.
EXAMPLESStage 1
[0014] ReagentMolecular weightAmountMmolEq.Amine 1464.6515 g32.2821Val-NCA 2142.136.9 g48.5471.5Triethylamine101.194.5 ml32.2831 (d = 0.726) Dichloromethane 108 ml Sol. 0.3 M
[0015] Compound Val-NCA 2 was added to a solution of amine 1 (note 1, 2) in dichloromethane (60 ml) at -15°C under nitrogen followed by a solution of triethylamine in dichloromethane (48 ml) (note 3). The reaction mixture was maintained under agitation at from -15° to -13°C for two hours (note 4). The solution was used directly for the next stage without further purification.
Note 1. Amine 1 was prepared using the procedure described in A.R. Haight et al. Org. Proc. Res. Develop. (1999) 3, 94-100.
Note 2. Amine 1 was a mixture of stereoisomers with a ratio of 80 : 3.3 : 2.1 : 1.9.
Note 3. This solution was added dropwise over a period of 25 minutes.
Note 4. HPLC analysis after 2 hours: Amide 3 70.2 % – starting material 4.3 %
Stage 2
[0016] ReagentMolecular weightAmountMmolEq.Amine 3 Solution from stage 1563.78 32.2821Triethylamine101.19 (d = 0.726)2.6 ml18.6540.6Bis(trichloromethyl) carbonate (BTC)296.753.5 g11.7940.36dichloromethane 65 ml N-Methyl-4-aminomethyl-2-isopropylthiazole 4170.275.5 g32.2821triethylamine101.196.9 ml49.5041.5 (d = 0.726) Dichloromethane 52 ml
[0017] The triethylamine was added slowly to the solution of amine 3 resulting from stage 1 and this mixture was in turn added slowly to a solution of BTC in dichloromethane (65 ml) at from -15° to -13°C and the reaction mixture was maintained under agitation at that temperature for 1.5 hours (note 1). A solution of amine 4 and triethylamine in dichloromethane (52 ml) was then added slowly to the reaction mixture (note 2) and maintained under agitation at that temperature for one hour (note 3). The reaction was stopped with water (97 ml) and the two phases were separated. The organic phase was washed with a 10% aqueous citric acid solution, filtered over Celite and evaporated with a yield of 25 g of crude urea 5 which was purified by flash chromatography on silica gel (eluant: toluene – ethyl acetate 6:4) to give 9.4 g of pure compound 5 (total yield of the two stages 38%) (note 4).
Note 1. HPLC analysis after 1.5 hours of the reaction stopped in tert-butylamine: Amide 3 = 0.41 % – intermediate isocyanate = 61.3 %
Note 2. The solution of amine 4 was added over a period of approximately 20 minutes.
[0018] ReagentMolecular weightAmountMmolEq.Urea 5760.053.5 g4.6051Pd(OH)2/C 20% 5.25 g 30% w/wAcetic acid 31 ml Sol. 0.15 M
[0019] The Pearlman catalyst (note 1) was added to a solution of urea 5 in acetic acid and the mixture was hydrogenated for 5 hours at from 4 to 4.5 bar and from 78 to 82°C (note 2). The catalyst was filtered and the solvent was removed under reduced pressure. The crude product was dissolved in water (35 ml), the pH was adjusted to a value of 8 with NaOH, and extracted with CH2Cl2 (2×15 ml). The organic phase was washed with water (10 ml) and the solvent was evaporated under reduced pressure with a yield of 1.8 g of amine 6 as a free base which was used for the next stage without further purification (note 3, 4).
Note 1. Of the various reaction conditions tested, such as HCOONH4/Pd-C in MeOH, H2/Pd-C in methanol, H2Pd-C/CH3SO3H in methanol, H2/Pd(OH)2/C in methanol, etc., the best conditions we have found hitherto are those described in this Example.
[0021] A solution of the chloride of compound 7 in ethyl acetate was treated with an aqueous sodium bicarbonate solution. The phases were separated and the organic phase was added to a solution of amine 6 in ethyl acetate. The reaction mixture was heated at 60°C for 12 hours, then concentrated; ammonia was added and the solution was maintained under agitation for 1 hour. The organic phase was washed with a 10% aqueous potassium carbonate solution (3x5ml) and with a saturated sodium chloride solution (5 ml); the solvent was removed under reduced pressure. The crude product was purified by flash chromatography on silica gel (eluant ethyl acetate) to give 900 mg of pure Ritonavir (total yield of the two stages 27 %) (note 1).
Ritonavir induces CYP 1A2 and inhibits the major P450 isoforms 3A4 and 2D6.[according to whom?][medical citation needed] Concomitant therapy of ritonavir with a variety of medications may result in serious and sometimes fatal drug interactions.[11] The list of clinically significant interactions of ritonavir includes the following drugs:
Mechanism of action
Ritonavir was originally developed as an inhibitor of HIV protease, one of a family of pseudo-C2-symmetric small molecule inhibitors.
Ritonavir is now rarely used for its own antiviral activity but remains widely used as a booster of other protease inhibitors. More specifically, ritonavir is used to inhibit a particular enzyme, in intestines, liver, and elsewhere, that normally metabolizes protease inhibitors, cytochrome P450-3A4 (CYP3A4).[16] The drug binds to and inhibits CYP3A4, so a low dose can be used to enhance other protease inhibitors. This discovery drastically reduced the adverse effects and improved the efficacy of protease inhibitors and HAART. However, because of the general role of CYP3A4 in xenobiotic metabolism, dosing with ritonavir also affects the efficacy of numerous other medications, adding to the challenge of prescribing drugs concurrently.[medical citation needed][17][better source needed]
Pharmocodymanics and pharmacokinetics
The capsules of the medication do not have the same bioavailability as the tablets.[2]
New HIV infections and deaths, before and after the FDA approval of “highly active antiretroviral therapy”,[18] of which saquinavir and ritonavir were key as the first two protease inhibitors.[medical citation needed] As a result of the new therapies, HIV deaths in the United States fell dramatically within two years.[18]
Ritonavir is manufactured as Norvir by AbbVie, Inc..[citation needed] The US Food and Drug Administration (FDA) approved ritonavir on March 1, 1996,[19] making it the seventh U.S.-approved antiretroviral drug and the second U.S.-approved protease inhibitor (after saquinavir four months earlier).[citation needed] As a result of the introduction of new “highly active antiretroviral thearap[ies]”—of which the protease inhibitors ritonavir and saquinavir were critical[citation needed]—the annual U.S. HIV-associated death rate fell from over 50,000 to about 18,000 over a period of two years.[20][21]
In 2003, Abbott (now AbbVie, Inc.) raised the price of a Norvir course from US$1.71 per day to US$8.57 per day, leading to claims of price gouging by patients’ groups and some members of Congress. Consumer group Essential Inventions petitioned the NIH to override the Norvir patent, but the NIH announced on August 4, 2004, that it lacked the legal right to allow generic production of Norvir.[22]
In 2014, the FDA approved a combination of ombitasvir/paritaprevir/ritonavir for the treatment of hepatitis C virus (HCV) genotype 4,[3] where the presence of ritonavir again capitalizes on its inhibitory interaction with the human drug metabolic enzyme CYP3A4.
Polymorphism and temporary market withdrawal
Ritonavir was originally dispensed as an ordinary capsule that did not require refrigeration. This contained a crystal form of ritonavir that is now called form I.[23] However, like many drugs, crystalline ritonavir can exhibit polymorphism, i.e., the same molecule can crystallize into more than one crystal type, or polymorph, each of which contains the same repeating molecule but in different crystal packings/arrangements. The solubility and hence the bioavailability can vary in the different arrangements, and this was observed for forms I and II of ritonavir.[24]
During development—ritonavir was introduced in 1996—only the crystal form now called form I was found; however, in 1998, a lower free energy,[25] more stable polymorph, form II, was discovered. This more stable crystal form was less soluble, which resulted in significantly lower bioavailability. The compromised oral bioavailability of the drug led to temporary removal of the oral capsule formulation from the market.[24] As a consequence of the fact that even a trace amount of form II can result in the conversion of the more bioavailable form I into form II, the presence of form II threatened the ruin of existing supplies of the oral capsule formulation of ritonavir; and indeed, form II was found in production lines, effectively halting ritonavir production.[23] Abbott (now AbbVie) withdrew the capsules from the market, and prescribing physicians were encouraged to switch to a Norvir suspension.[citation needed]
The company’s research and development teams ultimately solved the problem by replacing the capsule formulation with a refrigerated gelcap.[when?][citation needed] In 2000, Abbott (now AbbVie) received FDA-approval for a tablet formulation of lopinavir/ritonavir (Kaletra) which contained a preparation of ritonavir that did not require refrigeration.[26]
Research
In 2020, the fixed-dose combination of lopinavir/ritonavir was found not to work in severe COVID-19.[27] In the trial the medication was started around thirteen days after the start of symptoms.[27] Virtual screening of the 1930 FDA-approved drugs followed by molecular dynamics analysis predicted ritonavir blocks the binding of the SARS-CoV-2 spike (S) protein to the human angiotensin-converting enzyme-2 (hACE2) receptor, which is critical for the virus entry into human cells.[28]
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
^ Hsieh, Yi-Ling; Ilevbare, Grace A.; Van Eerdenbrugh, Bernard; Box, Karl J.; Sanchez-Felix, Manuel Vincente; Taylor, Lynne S. (2012-05-12). “pH-Induced Precipitation Behavior of Weakly Basic Compounds: Determination of Extent and Duration of Supersaturation Using Potentiometric Titration and Correlation to Solid State Properties”. Pharmaceutical Research. 29 (10): 2738–2753. doi:10.1007/s11095-012-0759-8. ISSN0724-8741. PMID22580905. S2CID15502736.
^ The CDC, in its Morbidity and Mortality Weekly Report, ascribes this to “highly active antiretroviral therapy”, without mention of either of these drugs, see the preceding citation. A further citation is needed to make this accurate connection between this drop and the introduction of the protease inhibitors.
^ Lüttge, Andreas (February 1, 2006). “Crystal dissolution kinetics and Gibbs free energy”. Journal of Electron Spectroscopy and Related Phenomena. 150 (2): 248–259. doi:10.1016/j.elspec.2005.06.007.
^“Kaletra FAQ”. AbbVie’s Kaletra product information. AbbVie. 2011. Archived from the original on 7 July 2014. Retrieved 5 July2014.
Chemburkar, Sanjay R.; Bauer, John; Deming, Kris; Spiwek, Harry; Patel, Ketan; Morris, John; Henry, Rodger; Spanton, Stephen; et al. (2000). “Dealing with the Impact of Ritonavir Polymorphs on the Late Stages of Bulk Drug Process Development”. Organic Process Research & Development. 4 (5): 413–417. doi:10.1021/op000023y.
External links
“Ritonavir”. Drug Information Portal. U.S. National Library of Medicine.
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Molecular FormulaC12H17NO2
Average mass207.269 Da
CICLOPIROX(6-Cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone) 2(1H)-Pyridinone, 6-cyclohexyl-1-hydroxy-4-methyl- 249-577-2[EINECS] 29342-05-0[RN] KS-5085, циклопирокс , سيكلوبيروكس , 环吡酮 , Ciclopirox CAS Registry Number: 29342-05-0 CAS Name: 6-Cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridinone Molecular Formula: C12H17NO2 Molecular Weight: 207.27 Percent Composition: C 69.54%, H 8.27%, N 6.76%, O 15.44% Literature References: Broad spectrum antimycotic agent with some antibacterial activity. Prepn: G. Lohaus, W. Dittmar, ZA6906039; eidem,US3883545 (1970, 1975 both to Hoechst). In vitro study: eidem,Arzneim.-Forsch.23, 670 (1973). Series of articles on pharmacokinetics, pharmacology, teratology, toxicity studies: Oyo Yakuri9, 57-115 (1975), C.A.83, 53159d, 53538b, 53539c, 71844c, 90833q (1975). Series of articles on chemistry, mechanism of action, toxicology, clinical trials: Arzneim.-Forsch.31, 1309-1386 (1981). Toxicity data: H. G. Alpermann, E. Schutz, ibid. 1328. Review: S. G. Jue et al.,Drugs29, 330-341 (1985). Review of clinical experience in seborrheic dermatitis: A. Starova, R. Aly, Expert Opin. Drug Saf.4, 235-239 (2005). Properties: Solid, mp 144°. Melting point: mp 144°
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Derivative Type: Ethanolamine salt (1:1) CAS Registry Number: 41621-49-2 Additional Names: Ciclopirox olamine Manufacturers’ Codes: HOE-296 Trademarks: Batrafen (HMR); Brumixol (Bruschettini); Ciclochem (Novag); Dafnegin (Poli); Loprox (HMR); Micoxolamina (Domp?; Mycoster (Fabre) Molecular Formula: C14H24N2O3 Molecular Weight: 268.35 Percent Composition: C 62.66%, H 9.01%, N 10.44%, O 17.89% Properties: LD50 in mice, rats (mg/kg): 2898, 3290 orally (Alpermann, Schutz). Toxicity data: LD50 in mice, rats (mg/kg): 2898, 3290 orally (Alpermann, Schutz)
///////////////////////////////////////////////////////////////////////////////////////////////////// Ciclopirox (sometimes known by the abbreviation CPX[2]) is a synthetic antifungal agent for topical dermatologic treatment of superficial mycoses. It is most useful against Tinea versicolor. It is sold under many brand names worldwide.[1]
In addition to other formulations, ciclopirox is used in lacquers for topical treatment of onychomycosis (fungal infections of the nails). A meta-analysis of the six trials of nail infections available in 2009 concluded that they provided evidence that topical ciclopirox had poor cure rates and that amorolfine might be substantially more effective, but more research was required.
“Combining data from 2 trials of ciclopiroxolamine versus placebo found treatments failure rates of 61% and 64% for ciclopiroxolamine. These outcomes followed long treatment times (48 weeks) and this makes ciclopiroxolamine a poor choice for nail infections. Better results were observed with the use of amorolfine lacquer; 6% treatment failure rates were found after 1 month of treatment but these data were collected on a very small sample of people and these high rates of success might be unreliable.”[4]
Pharmacology
Pharmacodynamics
In contrast to the azoles and other antimycotic drugs, the mechanism of action of ciclopirox is poorly understood.[5] However, loss of function of certain catalase and peroxidase enzymes has been implicated as the mechanism of action, as well as various other components of cellular metabolism. In a study conducted to further elucidate ciclopirox’s mechanism, several Saccharomyces cerevisiae mutants were screened and tested. Results from interpretation of the effects of both the drug treatment and mutation suggested that ciclopirox may exert its effect by disrupting DNA repair, cell division signals and structures (mitotic spindles) as well as some elements of intracellular transport.[6]
It is currently being investigated as an alternative treatment to ketoconazole for seborrhoeic dermatitis as it suppresses growth of the yeast Malassezia furfur. Initial results show similar efficacy to ketoconazole with a relative increase in subjective symptom relief due to its inherent anti-inflammatory properties.[7]
Chemistry
Ciclopirox is a considered a hydroxypyrimidine (sic) antifungal agent.[citation needed] Structurally, ciclopirox is the N-oxide of a 2-hydroxypyridine derivative and therefore ought to be termed a hydroxypyridine antifungal agent. Additionally, the structure as drawn above is the lactam tautomer and indicates the molecule being an N-Hydroxy-2-pyridone. Hence the classification of ciclopirox as a 2-pyridone antifungal agent.
Ciclopirox is used clinically as ciclopirox olamine, the olaminesalt of ciclopirox.
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SYNTHESIS
SYN
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SYN
W. Dittmar, E. Druckrey andBroad spectrum antimycotic agent with some antibacterial activity. Prepn: G. Lohaus, W. Dittmar, ZA 6906039; eidem, US 3883545 (1970, 1975 both to Hoechst). In vitro study: eidem, Arzneim.-Forsch. 23, 670 (1973).
H. Urbach, J. Med. Chem., 17, 753 (1974); W. Dittmar and G. Lohaus,
German Patent 2,214,608 (1973); Chem. Abstr., 79: 146419w (1973).
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SYN
ethanolamine (CAS NO.: ), with other names as 6-Cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridinone 2-aminoethanol, could be produced through the following synthetic routes.
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Compound can be prepared in two different ways: 1) The reaction of methyl 5-oxo-5-cyclohexyl-3-methylpentenoate (I) with NH2OH gives the corresponding oxime (II), which is then cyclized to 6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridone (III). Finally, this compound is salified with ethanolamine (IV). 2) Compound (III) can also be obtained by reaction of 6-cyclohexyl-4-methyl-2-pyron (V) with hydroxylamine hydrochloride in hot 2-aminopyridine.
The molecule 6-cyclohexyl-1-hydroxy-4-methylpyridin-2(1H)-one, also known as Ciclopirox, is a commercially available antifungal agent as an olamine salt. Ciclopirox olamine has been used to treat superficial mycoses and Tinea versicolor following topical application to the skin. Following enteral administration, ciclopirox undergoes significant first-pass effect resulting in low oral bioavailability. The oral route of administration is also associated with gastrointestinal toxicities observed in animals and humans limiting its benefit in animal and human health applications. Ciclopirox olamine has poor solubility, limiting opportunities to deliver the antifungal agent via parenteral administration of suitably potent solutions and suspensions. As such, it would be beneficial to configure ciclopirox for improved water solubility in order to deliver the drug by parenteral routes of administration.
Saikawa, I., Takano, S., Yoshida, C., Takashima, 0..Momonoi, K., Kuroda, S., Komatsu, M., Yasuda, T.and Kodama, Y.; British Patent 1,508,071; April 19,1978; assigned to Toyama Chemical Co., Ltd. and U.S. Patent 4,110,327; August 29,1978; also assigned to Toyama Chemical Co., Ltd.
logP
-0.74
HANSCH,C ET AL. (1995)
Cefoperazone CAS Registry Number: 62893-19-0 CAS Name: (6R,7R)-7-[[(2R)-[[(4-Ethyl-2,3-dioxo-1-piperazinyl)carbonyl]amino](4-hydroxyphenyl)acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acidAdditional Names: 7-[D-(-)-a-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-a-(4-hydroxyphenyl)acetamido]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-3-cephem-4-carboxylic acid Molecular Formula: C25H27N9O8S2 Molecular Weight: 645.67 Percent Composition: C 46.50%, H 4.21%, N 19.52%, O 19.82%, S 9.93% Literature References: Broad spectrum third generation cephalosporin antibiotic. Prepn: I. Saikawa et al.,BE837682; eidem,US4410522 (1976, 1983 both to Toyama); eidem,Yakugaku Zasshi99, 929 (1979). Stability in aq soln: eidem,ibid. 1207. In vitro activity: M. V. Borobio et al.,Antimicrob. Agents Chemother.17, 129 (1980). Kinetics in rats: J. Fabre et al.,Schweiz. Med. Wochenschr.110, 264 (1980); in humans: A. F. Allaz, ibid.109, 1999 (1979). Review of pharmacology and therapeutic efficacy: R. N. Brogden et al.,Drugs22, 423-460 (1981). Symposium on clinical studies: ibid. Suppl. 1, 1-124. Properties: Crystals from acetonitrile/water, mp 169-171° (hydrated). Stable at pH 4.0-7.0; slightly unstable in acid; highly unstable in alkaline soln. Melting point: mp 169-171° (hydrated) Derivative Type: Sodium salt CAS Registry Number: 62893-20-3 Manufacturers’ Codes: CP-52640-2; T-1551 Trademarks: Bioperazone (Biopharma); Cefazone (Firma); Cefobid (Pfizer); Cefobine (Pfizer); Cefobis (Pfizer); Cefogram (Metapharma); Cefoneg (Tosi); Cefosint (Proter); Dardum (Lisapharma); Farecef (Lafare); Kefazon (Esseti); Novobiocyl (Francia); Pathozone (Pfizer); Peracef (Pfizer); Perocef (Pulitzer); Tomabef (Aandersen) Molecular Formula: C25H26N9NaO8S2 Molecular Weight: 667.65 Percent Composition: C 44.97%, H 3.93%, N 18.88%, Na 3.44%, O 19.17%, S 9.61% Therap-Cat: Antibacterial., Therap-Cat-Vet: Antibacterial. Keywords: Antibacterial (Antibiotics); ?Lactams; Cephalosporins.
Cefoperazone is a third-generation cephalosporinantibiotic, marketed by Pfizer under the name Cefobid. It is one of few cephalosporin antibiotics effective in treating Pseudomonas bacterial infections which are otherwise resistant to these antibiotics.
Cefoperazone is a broad-spectrum cephalosporin antibiotic used for the treatment of bacterial infections in various locations, including the respiratory tract, abdomen, skin, and female genital tracts.
Cefoperazone is a semisynthetic broad-spectrum cephalosporin proposed to be effective against Pseudomonas infections. It is a third-generation antiobiotic agent and it is used in the treatment of various bacterial infections caused by susceptible organisms in the body, including respiratory tract infections, peritonitis, skin infections, endometritis, and bacterial septicemia. While its clinical use has been discontinued in the U.S., cefoperazone is available in several European countries most commonly under the product name, Sulperazon.
English: I. Saikawa, S. Takano, Y. Shuntaro, C. Yoshida, 0.
Takashima, K. Momonoi, S. Kuroda, M. Komatsu, T. Yasuda, and Y. Kodama, German Offen., DE 2,600,880 (1977); Chem.
Abstr., 87_, 184533b (1977).
SYN
Following is one of the synthesis routes: alpha-(4-Ethyl-2,3-dioxo-1-piperazinocarbonylamino)-p-hydroxyphenylacetic acid (I) is condensed with 7-amino-3-[(1-methyl-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (II) in the presence of ethyl chlorocarbonate and N,O-bis(trimethylsilyl)acetamide in acetonitrile to produce Cefoperazone sodium.
Cefoperazone, (6R,7R)-7-[(R)-2-(4-ethyl-2,3-dioxo-1-piperazincarboxamido)-2-(p-hydroxyphenyl)acetamido]-3-[[(1-methyl-1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-2-carboxylic acid (32.1.2.84), is synthesized by acylating 7-amino-3-(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl-3-cefem-4-carboxylic acid (32.1.2.24) with a mixed anhydride synthesized from ethyl chloroformate and α-(4-ethylpiperazin-2, 3-dion-1-carbonylamino)-4-hydroxyphenylacetic acid (32.1.2.83), which in turn is synthesized from 4-ethylpiperazin-2,3-dion-1-carboxylic acid (32.1.1.29) and the sodium salt of 4-hydroxyphenylglycine [163–168].
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Cefoperazone also has a broad spectrum of antimicrobial action, including most clinically significant microorganisms: Gram-positive, Gram-negative, aerobic, and anaerobic. It is stable with respect to most beta-lactamases of Gram-positive and Gram-negative bacteria.
Cefoperazone is used for bacterial infections of the lower respiratory tract, urinary and sexual tracts, bones, joints, skin, soft tissues, abdominal, and gynecological infections. Synonyms of this drug are cefazon, cefobid, cefobis, and many others.
Spectrum of bacterial susceptibility
Cefoperazone has a broad spectrum of activity and has been used to target bacteria responsible for causing infections of the respiratory and urinary tract, skin, and the female genital tract. The following represents MIC susceptibility data for a few medically significant microorganisms.
Cefoperazone exerts its bactericidal effect by inhibiting the bacterialcell wall synthesis, and sulbactam acts as a beta-lactamase inhibitor, to increase the antibacterial activity of cefoperazone against beta-lactamase-producing organisms.
^ Stork CM (2006). “Antibiotics, antifungals, and antivirals”. In Nelson LH, Flomenbaum N, Goldfrank LR, Hoffman RL, Howland MD, Lewin NA (eds.). Goldfrank’s toxicologic emergencies. New York: McGraw-Hill. p. 847. ISBN0-07-143763-0. Retrieved 2009-07-03.
Prilocaine is a local anesthetic used in dental procedures.
A local anesthetic that is similar pharmacologically to lidocaine. Currently, it is used most often for infiltration anesthesia in dentistry. (From AMA Drug Evaluations Annual, 1992, p165)
Image may be NSFW. Clik here to view.1 H-nuclear magnetic resonance ( 1 H-NMR) spectra of prilocaine solution after sterilization with the assignment of the prilocaine hydrogens. [Prilocaine] = 5 mM, 20°C, 500 MHz.
English: N. Lofgren and C. Tegner, Acta Chem. Scand., 14, 486 (1960). DOI number: 10.3891/acta.chem.scand.14-0486
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SYN
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SUN
Prilocaine, 2-(propylamino)-o-propiontoluidine (2.2.14), is structurally related to the exact same group as ethidocaine, yet it differs structurally in that during synthesis, o-toluidine is used instead of 2,6-dimethylaniline, and instead of a butyric acid, a fragment of propionic acid, and a terminal propylethylamine group is replaced with a propylamine group. In order to synthesize prilocaine, o-toluidine is reacted with bromopropionyl bromide, and the resulting bromopropionyltoluidide (2.2.13) is then reacted with propylamine, which gives prilocaine [22,23].
CAS Registry Number: 103577-45-3 CAS Name: 2-[[[3-Methyl-4-(2,2,2-trifluoro-ethoxy)-2-pyridinyl]methyl]sulfinyl]-1H-benzimidazole Additional Names: 2-(2-benzimidazolylsulfinylmethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine Manufacturers’ Codes: A-65006; AG-1749 Trademarks: Agopton (Takeda); Lansox (Takeda); Lanzor (Aventis); Limpidex (Sigma-Tau); Ogast (Takeda); Prevacid (TAP); Takepron (Takeda); Zoton (Wyeth) Molecular Formula: C16H14F3N3O2S, Molecular Weight: 369.36 Percent Composition: C 52.03%, H 3.82%, F 15.43%, N 11.38%, O 8.66%, S 8.68% Literature References: Gastric proton-pump inhibitor. Prepn: A. Nohara, Y. Maki, EP174726; eidem,US4628098 (both 1986 to Takeda).HPLC determn in plasma: T. Uno et al., J. Chromatogr. B816, 309 (2005). Pharmacology: H. Satoh et al.,J. Pharmacol. Exp. Ther.248, 806 (1989). Mechanism of action study: H. Nagaya et al.,ibid.252, 1289 (1990). Clinical pharmacology and effect on human gastric acid secretion: P. Müller et al.,Aliment. Pharmacol. Ther.3, 193 (1989). Review of pharmacology and clinical experience: H. D. Langtry, M. I. Wilde, Drugs54, 473-500 (1997). Comparative clinical trial with esomeprazole in erosive esophagitis: C. W. Howden et al., Clin. Drug Invest.22, 99 (2002). Properties: mp 178-182° (dec). Melting point: mp 178-182° (dec) Therap-Cat: Antiulcerative., Keywords: Antiulcerative; Gastric Proton Pump Inhibitor.
Lansoprazole was patented in 1984 and came into medical use in 1992.[6] It is available as a generic medication.[3] In 2017, it was the 188th most commonly prescribed medication in the United States, with more than three million prescriptions.[7][8]
Helicobacter pylori infection, alongside antibiotics (adjunctive treatment), treatment to kill H. pylori causing ulcers or other problems involves using two other drugs besides lansoprazole known as “triple therapy“, and involves taking twice daily for 10 or 14 days lansoprazole, amoxicillin, and clarithromycin
It is a racemic 1:1 mixture of the enantiomersdexlansoprazole and levolansoprazole.[17] Dexlansoprazole is an enantiomerically pure active ingredient of a commercial drug as a result of the enantiomeric shift. Lansoprazole’s plasma elimination half-life (1.5 h) is not proportional to the duration of the drug’s effects to the person (i.e. gastric acid suppression).[18]
Lansoprazole , available in the name of Selanz SR, was originally synthesized at Takeda and was given the development name AG 1749.[19] Takeda patented it in 1984 and the drug launched in 1991.[20] In the United States, it was approved for medical use in 1995.[21]
The lansoprazole molecule is off-patent and so generic drugs are available under many brand names in many countries;[22] there are patents covering some formulations in effect as of 2015.[23] Patent protection expired on 10 November 2009.[24][25]
Availability
Since 2009, lansoprazole has been available over the counter (OTC) in the U.S. as Prevacid 24HR[26][27] and as Lansoprazole 24HR.[28] In Australia, it is marketed by Pfizer as Zoton.[citation needed]
i. 2,3-dimethyl-4-nitropyridine-1-oxide is reacted with 2,2,2-trifluoroethanol in presence of potassium carbonate to give 2,3-dimethyl-4-(2,2,2-trifluoro-ethoxy)pyridine-1-oxide.
ii. The compound so formed is treated with acetic anhydride in acidic conditions followed by nutrilizing with sodium hydroxide solution to get 2-hydroxymethyl-3-methyl-4-(2,2,2-trifluoroethoxy)-pyridine
iii. Last is treated with thionyl chloride followed by reaction with 2-mercaptobenzimidazole to get 2-[3-methyl-4-(2,2,2-trifluoroethoxy)pyrid-2-ylmethylthio]benzimidazole.
iv. Above formed compound is reacted with m-chloro-perbenzoic acid to get lansoprazole.[2]
Lansoprazole (37.3) is the second approved gastric acid pump inhibitor. The common approach for the synthesis of lansoprazole involves coupling of mercapto-benzimidazole (37.24) with a new 2-chloromethylpyridine derivative (37.32) followed by oxidation of the prochiral sulfide group with m-chloroperbenzoic acid or hydrogen peroxide was first disclosed by Nohara and Maki [73], with followed improvements in patents [74-78] and briefly summed up in papers [79-80].
Lansoprazole synthesis is represented on the Scheme 37.4.
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In principle it repeats the synthesis Scheme of omeprazole, differing in details and characteristics, for example, in place of 2,3,5-collidine (37.15) as a starting material, 2,3-lutidine (37.27) was selected, and the methoxy group in the fourth position of pyridine ring was replaced by the 2,2,2-trifluoroethoxy group.
Another interesting approach has been demonstrated [81]. In this case, 2-chloromethyl-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (37.32) was prepared starting with 3-picoline (37.34), which was oxidized using peracids (i.e., m-chloroperoxybenzoic acid) to produce 3-methylpyridineN-oxide (37.35). The obtained product was nitrated with fuming nitric acid to produce 3-methyl-4-nitropyridine N-oxide (37.36). The prepared N-oxide was treated with dimethylsulfate at 65 to 70°C to form N-methoxypyridinium salt (37.37), the aqueous solution of which on cooling was treated with sodium cyanide to produce an after formation of intermediate (37.38) and elimination of methanol 2-cyano-3-methyl-4-nitropyridine (37.39). This method for the synthesis of 2-cyanopyridines via addition of cyanide ion to N-alkoxy-quaternary salts of pyridines, supplements the plethora of Reissert-Kaufmann reactions in the quinoline and isoquinoline series previously described [82]. The nitro group in (37.39) was replaced by the 2,2,2-trifluoroethoxy group by a direct reaction with sodium trifluoroethoxide in trifluoroethanol that produced ether (37.40). The next step—transformation of nitrile group in prepared 2-cyanopyridine (37.40) to 2-carboxypyridine (37.41)—was carried out in a one-pot procedure by heating the 2-cyano compound in the presence of concentrated sulfuric acid followed by reaction of the intermediate amide with sodium nitrite under aqueous acidic conditions [83,84]. The obtained acid was esterified in methanol with a catalytic amount of sulfuric acid to produce ester (37.42). The ester (37.42) was reduced by NaBH4, producing the above-described 2-hydroxymethyl- pyridine derivative (37.31) followed by a reaction with thionyl chloride in dioxane that produced the required 2-chloromethylpyridine compound (37.32). Direct reaction of the last with 2-mercaptobenzimidazole (37.34) in methanol, even without use of any base, produced a sulfide (37.33) in high yield. The oxidation of the last to lansoprazole (37.3) has been carried out by various oxidants and catalysts, which, together with the desired sulfoxide, produced a certain amount of overoxidized product. Oxidizing sulfide (37.33) with a new oxidation method made up of the use of the composite metal oxide catalyst, LiNbMoO6, in methanol and 35% H2O2 as an oxidant sulfide (37.33) was successfully oxidized to desired lansoprazole (37.3) (Scheme 37.5.).
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Lansoprazole is the second inhibitor of the gastric H+/K+-ATPase to be marketed for the treatment of peptic ulcer disease and reflux esophagitis, erosive esophagitis, and Zollinger-Ellison syndrome. It is an inhibitor of gastric acid secretion and also exhibits antibacterial activity against H. pylori in vitro. More common side effects of lansoprazole are diarrhea and skin rash or itching. Less-common side effects are abdominal pain, joint pain, nausea, vomiting, and increased or decreased appetite [85-91].
SYN
AU 8545895; EP 0174726; ES 8607288; JP 1986050978; US 4628098; US 4689333
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The condensation of 2,3-dimethyl-4-nitropyridine N-oxide (I) with 2,2,2-trifluoroethanol (II) by means of K2CO3 in hot HMPT gives 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine N-oxide (III), which by isomerization in acetic anhydride at 100 C is converted to 2-(hydroxymethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (IV). The reaction of (IV) with SOCl2 in refluxing CHCl3 affords the corresponding chloromethyl derivative (V), which is condensed with 2-mercaptobenzimidazole (VI) by means of sodium methoxide in refluxing methanol to yield 2-(2-benzimidazolylthiomethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridin (VII). Finally, this compound is oxidized with m-chloroperbenzoic acid in CHCl3.
SYN
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SYN
Chemical Synthesis
Similar to the synthesis of the chiral sulfoxide of armodafinil vide supra, the preparation of the chiral sulfoxide of lansoprazole utilized the catalytic oxidation method developed by Kagan and co-workers (the Scheme). Two routes have been reported that describe the preparation of dexlansoprazole on large scale. The first route developed by Takeda reacts commercially available thioether 29, also used to make lansoprazole, under the Kagan asymmetric oxidation conditions and the alternative route utilizes the cheaper commercial intermediate nitrosulfide 30 in the analogous asymmetric oxidation by Kagan). Thus, the catalyst complex consisting of (+)-DET, Ti(OiPr)4 and water was formed in the presence of thioether 29 in toluene at 30–40°C. The reaction mixture was then cooled to 5 °C and DIPEA and cumene hydroperoxide (CMHP) were added to give, after aqueous work-up and in situ crystallization from the organic layer, dexlansoprazole (VI) in 98% ee. No yield was given in the patent. An alternate, but similar, sequence was also described wherein the nitrosulfide intermediate 30 was subjected to similar oxidative conditions that gave intermediate nitro compound 31 in 80% yield and 98% ee. Compound 31 was treated with KOH and trifluoroethanol to provide dexlansoprazole (VI).
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R-(+)-Lansoprazole Preparation Products And Raw materials
PATENT
https://patents.google.com/patent/WO2008087665A2/enA number of substituted 2-(2-pyridylmethyl) sulfinyl-lH-benzimidazole derivatives are reported as gastric proton pump inhibitors. These benzimidazole derivatives include lansoprazole, omeprazole, pantoprazole, and rabeprazole. The Lansoprazole is generally represented by the following chemical formula I
US 4,628,098 & 4,689,333 describes lansoprazole having its chemical name (2-[[[3-methyl-4-(2, 2, 2-trifluoro-ethoxy)-2-pyridinyl] methyl] sulfinyl]-lH-benzimidazole. As a characteristic shared with other benzimidazole derivatives (e.g., omeprazole and pantoprazole), lansoprazole can inhibit gastric acid secretion, and thus commonly used as an antiulcer agent. Several methods for preparing Lansoprazole are known. The majority of these methods involve the use of a lansoprazole precursor that contains a thioether group. The thioether group is oxidized in the last step of preparation to form the lansoprazole. These patents (‘098 and ‘333) further describes the oxidation of the thioether group using m-chloroperbenzoic acid, per acid, sodium bromite, sodium hypochlorite, or hydrogen peroxide as the oxidizing agent and the reaction solvent is halogenated hydrocarbon, ether, amide, alcohol, or water.US 6,002,011 describe the crystallization of Lansoprazole from the same ethanol: water system, containing traces of ammonia. This patent discloses a reslurry method in water, which permits to obtain more stable “solvent free” Lansoprazole. This patent fails to disclose the level of purity for Lansoprazole. In addition, the ethanol and water are difficult to eliminate. Even after intensive drying, Lansoprazole still contains solvent and is unstable under storage. US 6,180,652 describe the presence of sulfone derivative. Formation of sulfone derivative brings about the drawback of low yield of the desired sulfoxide. Although attempts have been made to separate the sulfone derivative from Lansoprazole, it is not a simple task, given their very similar structures and physicochemical properties. This patent also describes a method for separation of Lansprazole from its sulfone derivative, by converting to an acetone complex of the Lansoprazole salt & hence is purified in this method. Lansoprazole and other 2-(2- pyridylmethyl) sulfinylbenzimidazole derivatives tend to lose stability and undergo decomposition when contaminated with traces of a solvent, particularly water, in their crystal structure. It is desirable that the benzimidazole crystals be solvent free (i.e., residual solvent should be reduced to a minimum).US 6,909,004 describes the method of purifying Lansoprazole, comprising the steps of: a) providing a solution of lansoprazole in a solvent selected from an organic solvent or a mixture of organic solvent and water in the presence of an amine compound; b) combining the provided solution with an acid, and c)isolating the purified Lansoprazole. The amine compound is present in 1:1, mole: mole, ratio relative to the lansoprazole. Solution is in an organic solvent selected from the group consisting of alcohols, acetone, 2-butanone, dimethylformamide and tetrahydrofuran. The alcohol consisting of ethanol, methanol, n-propanol, & iso-propanol.US 7022859 & US 7060837 provides a method for preparing a substantially pure Lansoprazole containing less than about 0.2% (wt/wt) impurities including sulfone/sulfide derivatives. The present invention also provides a process for recrystallizing Lansoprazole to obtain a Lansoprazole containing less than about 0.1% (wt/wt) water.US 2004/010151 disclose a method of preparing crystalline Lansoprazole form A, comprising the steps of: a) preparing a solution of Lansoprazole in a solvent selected from the group consisting of methanol, n-butanol, acetone, methylethylketone, ethyl acetate, dimethyl sulfoxide, dimethylforniamide and their mixtures optionally with water; and b) isolating crystalline Lansoprazole form A.US 2005/020638 describe the process of preparing a stable Lansoprazole, comprising the steps of: a) crystallizing a Lansoprazole from an organic solvent or a mixture of organic solvent and water in the presence of a weak base; and b) isolating a stable Lansoprazole. An amorphous form of Lansoprazole prepared by spray drying method has been described (Farm. Vest. vol. 50, p. 347 (1999)). Curin et al. describe an ethanole solvate form and an ethanole-hydrate form of Lansoprazole (Farm. Vest. vol. 48, pp. 290-291 (1997). Kotar et al. describe two lansoprazole polymorphs, designated as crystalline Lansoprazole forms A and B, (Eur. J. Pharm. Sci. vol. 4, p. 182 (1996 Supp). According to Kotar, each of the crystalline Lansoprazole forms A and B exhibits a different DSC curve. In fact, crystalline Lansoprazole form B is unstable and can undergo a solid-solid transition to form crystalline Lansoprazole form A. No XRD data for crystalline Lansoprazole forms A and B, and fails to disclose processes for preparing these crystalline forms. No indication was found in the literature regarding the existence of other crystalline Lansoprazole forms other than the known forms A, B, ethanolate and ethanolate- hydrate.WO 00/78729 is discloses a phenomenon of polymorphism in Lansoprazole. The crystalline forms , I and II. The form I find application as an active ingredient of pharmaceutical compositions.WO 03/082857 disclose a method of preparing crystalline Lansoprazole form A, comprising the steps of: a) preparing a solution of Lansoprazole in a solvent selected from the group consisting of methanol, n-butanol, acetone, methylethylketone, ethyl acetate, dimethyl sulfoxide, dimethylformamide and their mixtures optionally with water; and b) isolating crystalline Lansoprazole form A.WO 2004/046135 describe the process for preparing a stable Lansoprazole compound, comprising the steps of: a) crystallizing a Lansoprazole from an organic solvent or a mixture of organic solvent and water in the presence of an amine; and b) isolating a stable Lansoprazole compound, wherein the stable Lansoprazole compound comprises greater than 500 ppm and not more than about 3,000 ppm water.Since proton pump inhibitors of the benzimidazole-type are very susceptible to degradation under acidic or neutral conditions, the reaction mixture is usually worked-up under basic conditions. These basic conditions may decompose any unwanted oxidizing agent still present in the reaction mixture and may also neutralize any acid formed when the oxidizing agent is consumed in the oxidation reaction. The main problem with the oxidation reaction to convert the sulfide intermediates of formula (II) into the sulfoxide compounds of formula (I) is over- oxidation, i.e. oxidation from sulfoxides of formula (I) to sulfones of formula (III) ; N-oxide of formula (IV) & chlorinating impurities ( V).The formation of sulfones of formula (III) due to over-oxidation is almost impossible to avoid and can be kept to a minimum by performing the oxidation reaction at a low temperature and restricting the amount of oxidizing agent. Typically the amount of oxidizing agent is less than 1 molar equivalent of the starting material, i.e. sulfide intermediates of formula (II), which inevitably results in a less than 100% conversion of starting material. Usually the amount of oxidizing agent is a compromise between maximum conversion of starting material, maximum formation of sulfoxides of formula (I) and minimum formation of unwanted sulfones of formula (III). Chlorinating impurities (V) are observed when chlorinating oxidizing agent such as sodium hypochlorite is used for oxidation reaction. Furthermore removal of the sulfones of formula (III) & chlorinating impurities (V) has often proved to be difficult, time-consuming and costly, in particular when high performance chromatography on an industrial scale is needed. Another problem with the benzimidazole-type is very susceptible to degradation when exposed to high temperatures for removal of solvents during distillation.Thus, there is continuing need to obtain 2-(2-pyridylmethyl) sulfϊnyl-lH-benzirnidazoles (e.g., Lansoprazole) that are free of contaminants including sulfone and sulfide derivatives. There has also -been a long-felt need for a method to prepare Lansoprazole having reduced water content (<0.1% wt/wt water).SCHEME : ]
SULPHIDE (II)+ Chlorinated Impurities(V)General Example10 g of 2- [3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methylthio-lH-benzimidazole was suspended in 100 ml chloroform and cooled to -100C. To the above suspension 3.4 g m- chloroperbenzoic acid solution in chloroform was added over a period of 2 hrs at -10 C. After completion of reaction, reaction mass was added to sodium bicarbonate solution (500 ml) and both layers were separated. Organic layer was washed with 2 x 50 ml of hypo solution followed by washing with 3 x 200 ml sodium bicarbonate solution. Both the layers were separated. Chloroform layer was washed with sodium bicarbonate solution (0.5%; 500 ml) at room temperature. Various co-solvents mentioned in Table- 1 were added to organic layer cool slowly to -10 to 100C. Filtered and washed with chilled chloroform (10 ml) followed by sodium bicarbonate solution (0.5%, 100 ml) & dried to get pure Lansoprazole.SYNhttp://www.ijmca.com/File_Folder/116-120.pdf
Publication numberPriority datePublication dateAssigneeTitleUS4628098A *1984-08-161986-12-09Takeda Chemical Industries, Ltd.2-[2-pyridylmethylthio-(sulfinyl)]benzimidazolesWO2004018454A1 *2002-08-212004-03-04Teva Pharmaceutical Industries Ltd.A method for the purification of lansoprazoleUS20040049045A1 *2000-12-012004-03-11Hideo HashimotoProcess for the crystallization of (r)-or (s)-lansoprazole Publication numberPriority datePublication dateAssigneeTitleWO2012004802A12009-07-072012-01-12Council Of Scientific & Industrial ResearchContinuous flow process for the preparation of sulphoxide compoundsCN107964005A *2017-11-102018-04-27扬子江药业集团江苏海慈生物药业有限公司A kind of preparation method of Lansoprazole
sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate CAS Registry Number: 577-11-7 CAS Name: Sulfobutanedioic acid 1,4-bis(2-ethylhexyl) ester sodium salt Additional Names: sulfosuccinic acid 1,4-bis(2-ethylhexyl) ester S-sodium salt; bis(2-ethylhexyl)sodium sulfosuccinate; dioctyl sodium sulfosuccinate; sodium dioctyl sulfosuccinate; DSS Trademarks: Aerosol OT (Cyanamid); Colace (Roberts); Comfolax (Searle); Coprola (Dunster); Dioctylal (Continental Pharma); Dioctyl (Medo); Diotilan (Chinoin); Disonate (Lannett); Doxinate (Hoechst); Doxol (Blair); Dulcivac (Harvey); Jamylène (Thaplix); Molatoc; Molcer (Wallace); Nevax; Regutol (Schering-Plough); Soliwax (Concept Pharm.); Velmol (Berlex); Waxsol (Norgine); Yal (Ritter) Molecular Formula: C20H37NaO7S Molecular Weight: 444.56 Percent Composition: C 54.03%, H 8.39%, Na 5.17%, O 25.19%, S 7.21% Literature References: Prepn: Jaeger, US2028091; US2176423 (1936, 1939, both to Am. Cyanamid). Structure and wetting power: Caryl, Ind. Eng. Chem.33, 731 (1941). Comprehensive description: S. Ahuja, J. Cohen, Anal. Profiles Drug Subs.2, 199-219 (1973); 12, 713-720 (1983). For structure see Docusate calcium. Properties: Available as wax-like solid, usually in rolls of tissue-thin material; also as 50-75% solns in various solvents. Soly in water (g/l): 15 (25°), 23 (40°), 30 (50°), 55 (70°). Sol in CCl4, petr ether, naphtha, xylene, dibutyl phthalate, liq petrolatum, acetone, alcohol, vegetable oils. Very sol in water + alcohol, water + water-miscible organic solvents. Stable in acid and neutral solns; hydrolyzes in alkaline solns. Derivative Type: Docusate potassium CAS Registry Number: 7491-09-0 Trademarks: Rectalad (Carter-Wallace) Molecular Formula: C20H37KO7S Molecular Weight: 460.67 Percent Composition: C 52.14%, H 8.10%, K 8.49%, O 24.31%, S 6.96% NOTE: Ingredient of the laxative Peri-Colace (Roberts) which also contains casanthranol.Use: Sodium salt as pharmaceutic aid (surfactant); as wetting agent in industrial, pharmaceutical, cosmetic and food applications; dispersing and solubilizing agent in foods; adjuvant in tablet formation. Therap-Cat: Stool softener. Therap-Cat-Vet: Stool softener. Keywords: Laxative/Cathartic.
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Docusate Calcium CAS Registry Number: 128-49-4 CAS Name: Sulfobutanedioic acid 1,4-bis(2-ethylhexyl)ester calcium salt Additional Names: bis[2-ethylhexyl]calcium sulfosuccinate; calcium dioctyl sulfosuccinate; dioctyl calcium sulfosuccinate Trademarks: Surfak (HMR) Molecular Formula: C40H74CaO14S2 Molecular Weight: 883.22 Percent Composition: C 54.40%, H 8.44%, Ca 4.54%, O 25.36%, S 7.26% Literature References: Prepd from dioctyl sodium sulfosuccinate dissolved in isopropanol and from calcium chloride dissolved in methanol: Klotz, US3035973 (1962 to Lloyd Brothers). Properties: White precipitate. Sol in mineral and vegetable oils, liq polyethylene glycol. Practically insol in glycerol. Claimed to have greater surface-active wetting properties than the sodium salt. NOTE: Ingredient of Doxidan (HMR) which also contains phenolphthalein. Therap-Cat: Stool softener. Keywords: Laxative/Cathartic.
Synthesis of Trihexyltetradecylphosphonium octylsulfosuccinate [P6, 6, 6, 14][docusate]
SYN
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Docusate is the common chemical and pharmaceutical name of the anionbis(2-ethylhexyl) sulfosuccinate, also commonly called dioctyl sulfosuccinate (DOSS).[2][3][4]
Sodium docusate was patented in 1937 by Coleman R. Caryl and Alphons O. Jaeger for American Cyanamid,[3] which commercialized it for many years as a detergent under the brand name Aerosol OT.
Its use for the treatment of constipation was first proposed in 1955 by James L. Wilson and David G. Dickinson,[4] and quicky popularized under the name Doxinate.[13]
Medical use
Constipation
The main medical use of docusate sodium is to treat constipation, acting as a laxative and stool softener. In painful anorectal conditions such as hemorrhoid and anal fissures, it can help avoid pain caused by straining during bowel movements.
When administered by mouth, a bowel movement often occurs in 1 to 3 days,[1] while rectal use may be effective within 20 minutes.[14]
Sodium docusate is recommended as a stool softener for children.[1]
However, its effectiveness for constipation is poorly supported by evidence.[7][8] Multiple studies have found docusate to be no more effective than a placebo for improving constipation.[7][8][9][10] Others have found it to be less useful for the treatment of chronic constipation than psyllium.[10][15][16]
The medication may be given to people who are receiving opioid medication, although prolonged use may cause irritation of the gastrointestinal tract.[10][16]
Other medical uses
Docusate sodium, when used with ear syringing, may help with earwax removal, particularly in the case of impaction.[17]
When taken by mouth it should be ingested with plenty of water.
Side effects
Side effects are uncommon and typically mild,[1] and may include stomach pain, abdominal cramps or diarrhea,[1] Efficacy decreases with long-term use, and may cause poor bowel function.[11]
Serious allergic reactions may occur with the drug. The most severe side effect of docusate, although very rare, is rectal bleeding.[21]
Interactions
Docusate might increase resorption of other drugs, for example, dantron (1,8-dihydroxyanthraquinone).[16]
Mechanism of action
Docusate sodium works by allowing more water to be absorbed by the stool.[11][22]
Docusate does not stay in the gastrointestinal tract, but is absorbed into the bloodstream and excreted via the gallbladder[16] after undergoing extensive metabolism.
The effect of docusate may not necessarily be all due to its surfactant properties. Perfusion studies suggest that docusate inhibits fluid absorption or stimulates secretion in the portion of the small intestine known as the jejunum.
Pharmaceutical brand names
In the U.S., docusate sodium for pharmaceutical use is available under multiple brand names: Aqualax, Calube, Colace, Colace Micro-Enema, Correctol Softgel Extra Gentle, DC-240, Dialose, Diocto, Dioctocal, Dioctosoftez, Dioctyn, Dionex, Doc-Q-Lace, Docu Soft, Docucal, Doculax, Docusoft S, DOK, DOS, Doss-Relief, DSS, Dulcolax – Stool Softener (not to be confused with another drug marketed under the Dulcolax brand, bisacodyl, which is a stimulant laxative), Ex-Lax Stool Softener, Fleet Sof-Lax, Genasoft, Kasof, Laxa-basic, Modane Soft, Octycine-100, Pedia-Lax, Preferred Plus Pharmacy Stool Softener, Regulax SS, Sulfalax Calcium, Sur-Q-Lax, Surfak Stool Softener, and Therevac-SB. Generic preparations are also available.
In the UK, dioctyl sodium sulfosuccinate is sold under the brand name Docusol (Typharm Ltd) and DulcoEase (Boehringer Ingelheim).
In Australia, dioctyl sodium sulfosuccinate is sold as Coloxyl and Coloxyl with senna.
In India, preparations include Laxatin by Alembic, Doslax by Raptakos Laboratories, Cellubril by AstraZeneca, and Laxicon by Stadmed.
Other uses
Dioctyl sodium sulfosuccinate is used as a surfactant in a wide range of applications, often under the name Aerosol-OT.[4][23] It is unusual in that it is able to form microemulsions without the use of co-surfactants, and it has a rich variety of aqueous-phase behavior including multiple liquid crystalline phases.[24]
Food additive
Dioctyl sodium sulfosuccinate has been approved by the US FDA as a “generally recognized as safe” (GRAS) additive.[25] It is used in a variety of food products, as a surface active agent, stabilizer, thickener, wetting agent, processing aid, solubilizing agent, emulsifier, and dispersant. The highest amount found in food products is 0.5% by weight, which include pasteurized cheese spreads, cream cheeses and salad dressings.[26] The FDA also approved its use as a wetting agent or solubilizer for flavoring agents in carbonated and non-carbonated drinks at levels up to 10 parts per million.[25]
As a surfactant, docusate sodium is or has been commercialized under many brand names, including DSSj Aerosol OT, Alphasol OT, Colace, Complemix, Coprol, Dioctylal, Dioctyl-Medo Forte, Diotilan, Diovac, Disonate, Doxinate, Doxol, Dulsivac, Molatoc, Molofac, Nevax, Norval, Regutol, Softili, Solusol, Sulfimel DOS, Vatsol OT, Velmol, and Waxsol[28]
Ingestion may cause the side effects described above, such as diarrhea, intestinal bloating, and occasionally cramping pains. Dioctyl sodium sulfosuccinate is not known to be carcinogenic, mutagenic, or teratogenic.[29]
In a 2010 study, dioctyl sodium sulfosuccinate exhibited higher toxicity against bacteria (Vibrio fischeri, Anabaena sp.) and algae (Pseudokirchneriella subcapitata) than did a number of fluorinated surfactants (PFOS, PFOA, or PFBS). Measuring bioluminescence inhibition of the bacteria and growth inhibition of the algae, the LD50 were in the range of 43–75 mg/l. Combinations of the fluorinated compounds with dioctyl sodium sulfosuccinate showed mid to highly synergistic effects in most settings, meaning that such combinations are significantly more toxic than the individual substances.[30]
Freshwater species
The substance is highly toxic for rainbow trout with a median lethal concentration (LC50) of 0.56 mg/l after 48 hours for the pure substance. It is only slightly to moderately toxic for rainbow trout fingerlings, and slightly toxic for harlequin rasboras (LC50 27 mg/l of a 60% formulation after 48 hours).
^World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06.
^ Jump up to:abcd Ramkumar D, Rao SS (April 2005). “Efficacy and safety of traditional medical therapies for chronic constipation: systematic review”. The American Journal of Gastroenterology. 100 (4): 936–71. PMID15784043.
^ Friedman M (October 1956). “Dioctyl sodium sulfosuccinate (doxinate) in chronic functional constipation”. American Practitioner and Digest of Treatment. 7 (10): 1588–91. PMID13362832.
^ Mahadevan U, Kane S (July 2006). “American gastroenterological association institute medical position statement on the use of gastrointestinal medications in pregnancy”. Gastroenterology. 131(1): 278–82. doi:10.1053/j.gastro.2006.04.048. PMID16831610.
3055-99-0 Chemical Formula: C30H62O10 Exact Mass: 582.4343Polidocanol CAS Registry Number: 9002-92-0 CAS Name: a-Dodecyl-w-hydroxypoly(oxy-1,2-ethanediyl) Additional Names: polyethylene glycol (9) monododecyl ether; dodecyl alcohol polyoxyethylene ether; hydroxypolyethoxydodecane; laureth 9; polyoxyethylene lauryl ether Trademarks: Aethoxysklerol (Kreussler); Aetoxisclerol (Dexo); Atlas G-4829 (ICI); Hetoxol L-9 (Heterene Chem.)Line Formula: C12H25(OCH2CH2)nOH Literature References: Contains an average of nine ethylene oxide units and has an average mol wt ~600. Prepd by reaction of ethylene oxide and dodecyl alcohol: Pertsemlides, Soehring, Arzneim.-Forsch.10, 990 (1960). Toxicology: H. S. Zipf et al.,ibid.7, 162 (1957). Review of clinical experience: P. M. Goldman, J. Dermatol. Surg. Oncol.15, 204-209 (1989). Properties: Sol in water, ethanol, toluene. Miscible with hot mineral, natural and synthetic oils; with fats and fatty alcohols. LD50 in mice (mg/kg): 1170 orally, 125 i.v. (Zipf). Toxicity data: LD50 in mice (mg/kg): 1170 orally, 125 i.v. (Zipf) Use: Solvent; nonionic emulsifier; pharmaceutic aid (surfactant); spermaticide. Therap-Cat: Anesthetic (topical); antipruritic; sclerosing agent. Keywords: Anesthetic (Local); Antipruritic; Sclerosing Agent.
Polidocanol is a local anaesthetic and antipruritic component of ointments and bath additives. It relieves itching caused by eczema and dry skin. It is formed by the ethoxylation of dodecanol. The substance is also used as a sclerosant, an irritant injected to treat varicose veins, under the trade names Asclera, Aethoxysklerol and Varithena. Polidocanol causes fibrosis inside varicose veins, occluding the lumen of the vessel, and reducing the appearance of the varicosity. The FDA has approved polidocanol injections for the treatment of small varicose (less than 1 mm in diameter) and reticular veins (1 to 3 mm in diameter). Polidocanol works by damaging the cell lining of blood vessels, causing them to close and eventually be replaced by other types of tissue.
Jiang, Zhongxing; Yu, Zeqiong. Process for preparation of monodisperse nona-polyethylene glycol dodecyl alcohol monoether and sulfate. Assignee Wuhan University, Peop. Rep. China. CN 106316802. (2017).
Sclerotherapy
Polidocanol is also used as a sclerosant, an irritant injected to treat varicose veins, under the trade names Asclera, Aethoxysklerol[4] and Varithena.[5] Polidocanol causes fibrosis inside varicose veins, occluding the lumen of the vessel, and reducing the appearance of the varicosity.
The FDA has approved polidocanol injections for the treatment of small varicose (less than 1 mm in diameter) and reticular veins (1 to 3 mm in diameter). Polidocanol works by damaging the cell lining of blood vessels, causing them to close and eventually be replaced by other types of tissue.[6][7] Polidocanol in the form of Varithena injected in the greater saphenous vein can cause the eruption of varicose and spider veins throughout the lower leg. This procedure should be done with caution and with the knowledge that the appearance of the leg may be forever compromised.
On March 30th,2010 the FDA approved Polidocanol under the trade name Asclera. Polidocanol is a sclerosing agent indicated to treat uncomplicated spider veins (varicose veins ≤1 mm in diameter) and uncomplicated reticular veins (varicose veins 1 to 3 mm in diameter) in the lower extremities. Varicose veins develop when the small valves inside the veins no longer work properly, allowing the blood to flow backwards and then pool in the vein. When injected intravenously, Polidocanol works by locally damaging the endothelium of the blood vessel, causing platelets to aggregate at the site of damage and attach to the venous wall. Eventually, a dense network of platelets, cellular debris and fibrin occludes the vessel, which is then replaced with connective fibrous tissue. As one would expect for this type of molecule and also the mechanism of action, there is believed to be no specific molecular target for Polidocanol. Polidocanol is a large ‘small molecule’ drug (Molecular Weight of 583 g.mol-1), with a mean half-life of 1.5 hr. Polidocanol is administrated intravenously and the strength of the solution and the volume injected depend on the size and extent of the varicose veins. Thus, the recommended dosage is 0.1 to 0.3 mL for each injection (Asclera 0.5% for spider veins and Asclera 1% for reticular veins) into each varicose vein, and a maximum recommended volume per treatment session of 10 mL. Polidocanol’s chemical structure is 2-[2-[2-[2-[2-[2-[2-[2-[2-(dodecyloxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethanol. It is a non-ionic detergent, similar to polyethylene glycol (PEG) in structure, consisting of two components, a polar hydrophilic (dodecyl alcohol) and an apolar hydrophobic (polyethylene oxide – the part in brackets in the chemical structure) chain.
^ Star P, Connor DE, Parsi K (April 2018). “Novel developments in foam sclerotherapy: Focus on Varithena® (polidocanol endovenous microfoam) in the management of varicose veins”. Phlebology. 33 (3): 150–162. doi:10.1177/0268355516687864. PMID28166694.
^ Gao Z, Zhang Y, Li W, Shi C (January 2018). “Effectiveness and safety of polidocanol for the treatment of hemangiomas and vascular malformations: A meta-analysis”. Dermatologic Therapy. 31 (1). doi:10.1111/dth.12568. PMID29082587.
4-Undecanol, 7-ethyl-2-methyl-, hydrogen sulfate, sodium salt (1:1) 7-Ethyl-2-methyl-4-undecyl sulfate sodium salt UNII:Q1SUG5KBD6 натрия тетрадецилсульфат [Russian] [INN] تتراديسيل سولفات صوديوم [Arabic] [INN] 十四烷硫酸钠 [Chinese] [INN] CAS Registry Number: 139-88-8 CAS Name: 7-Ethyl-2-methyl-4-undecanol hydrogen sulfate sodium salt Additional Names: 7-ethyl-2-methyl-4-hendecanol sulfate sodium salt; sodium 2-methyl-7-ethyl-4-undecyl sulfate; sodium 7-ethyl-2-methylundecyl-4-sulfate Trademarks: Sotradecol (Elkins-Sinn); Tergitol 4; Trombavar; Trombovar Molecular Formula: C14H29NaSO4, Molecular Weight: 316.43 Percent Composition: C 53.14%, H 9.24%, Na 7.27%, S 10.13%, O 20.22% Properties: White, waxy solid. Sol in water, alcohol, ether. The pH of a 5% soln is from 6.5 to 9.0. Surface tension (dynes/cm) of aq soln at 25°: 56.5 dynes/cm (0.05% w/w); 52 (0.10%); 47 (0.20%); 40 (0.50%); 35 (1.0%). LD50 orally in rats: 4.95 g/kg, H. F. Smyth, C. P. Carpenter, J. Ind. Hyg. Toxicol.30, 63 (1948). Toxicity data: LD50 orally in rats: 4.95 g/kg, H. F. Smyth, C. P. Carpenter, J. Ind. Hyg. Toxicol.30, 63 (1948) Use: Wetting agent. Therap-Cat: Sclerosing agent., Keywords: Sclerosing Agent.
Synonyms of Sodium Tetradecyl Sulfate [INN]
4-Ethyl-1-isobutyloktylsiran sodny
EINECS 205-380-3
Natrii tetracylis sulfas
Natrii tetradecylis sulfas
Natrii tetradecylis sulfas [Latin]
Natrii tetradecylsulfas
NSC 755887
Obliterol
Sodium sotradecol
Sodium tetradecyl sulfate
Sotradecol
Tergitol
Tergitol 4
Tergitol anionic 4
Tergitol penetrant 4
Tetradecilsulfato sodico
Tetradecilsulfato sodico [Spanish]
Tetradecyl sulfate de sodium
Trombovar
UNII-Q1SUG5KBD6
Varicol
An anionic surface-active agent used for its wetting properties in industry and used in medicine as an irritant and sclerosing agent for hemorrhoids and varicose veins.
Sodium tetradecyl sulfate is an anionic surfactant which occurs as a white, waxy solid. The structural formula is as follows:
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C14H28NaS04 7-Ethyl -2-methyl -4-hendecanol sulfate sodium salt MW 316.44Sotradecol® (sodium tetradecyl sulfate injection) is a sterile nonpyrogenic solution for intravenous use as a sclerosing agent.
1% (10 mg/mL): Each mL contains sodium tetradecyl sulfate 10 mg, benzyl alcohol 0.02 mL and dibasic sodium phosphate, anhydrous 4.0 mg in Water for Injection. pH 7.9; monobasic sodium phosphate and/or sodium hydroxide added, if needed, for pH adjustment.
3% (30 mg/mL): Each mL contains sodium tetradecyl sulfate 30 mg, benzyl alcohol 0.02 mL and dibasic sodium phosphate, anhydrous 9.0 mg in Water for Injection. pH 7.9; monobasic sodium phosphate and/or sodium hydroxide added, if needed, for pH adjustment.
Sodium tetradecyl sulfate (STS) is a commonly used synonym for 7-ethyl-2-methyl-4-undecanyl sulfate sodium salt[1] which is anionicsurfactant that is the active component of the sclerosant drug Sotradecol. It is commonly used in the treatment of varicose and spider veins of the leg, during the procedure of sclerotherapy.[2] Being a detergent, its action is on the lipid molecules in the cells of the vein wall, causing inflammatory destruction of the internal lining of the vein and thrombus formation eventually leading to sclerosis of the vein. It is used in concentrations ranging from 0.1% to 3% for this purpose. It is occasionally used for the treatment of stabilisation of joints that regularly dislocate, particularly in patients with Ehlers-Danlos syndrome.[3] In the UK, Ireland, Italy, Australia, New Zealand and South Africa, it is sold under the trade-name Fibro-Vein in concentrations of 0.2%, 0.5%, 1.0%, and 3%.[4]
^ Jenkinson HA, Wilmas KM, Silapunt S (November 2017). “Sodium Tetradecyl Sulfate: A Review of Clinical Uses”. Dermatologic Surgery. 43 (11): 1313–1320. doi:10.1097/DSS.0000000000001143. PMID28430735.
In a quest of novel antispasmodic agents with antimicrobial properties, the present study describes design and synthesis of novel analogs for veratric acid ester 4-[ethyl-{2-(4- methoxyphenyl)-1-methylethyl} amino] butan-1-ol, an antispasmodic drug which is expected to be a potent antimicrobial agent may be due to the presence of two benzene rings and a secondary or tertiary nitrogen in the basic structural framework of the molecule. The reaction between substituted 2-ethylamino-1-(4’-methoxyphenyl) propane and various haloaryl benzoates derivatives obtained from reaction between different homologs of benzoic acid and dibromoalkanes in a two step process to give corresponding structurally diverse analogs of lead compound has been achieved. The structures of these novel analogs were confirmed by different structure elucidation techniques. All the compounds have been screened for their anti-spasmodic activity and the study extended further to evaluate their sedative, antibacterial and antifungal potency. The novel analogs of lead compound exhibited pronounced antispasmodic activities and also gave encouraging results of antimicrobial and sedative activity as anticipated.
General method of preparation of veratric acid ester 4-[ethyl-{2-(4-methoxyphenyl)-1- methylethyl} amino] butan-1-ol hydrochloride (5) and its analogs (5a-5p) A mixture of compound (3) (149 g, 0.47 mol) and Compound (4) (183 g, 0.95 mol) in ethyl methyl ketone (MEK) was refluxed for a period of 30 h at 75-80oC. The progress of the reaction was monitored by TLC to ensure formation of product and complete conversion of starting. On reaction completion solvent was distilled off and water (750 ml) was added to the reaction mass followed by toluene (300 ml). The resulting solution was cooled to 30oC and stirred for 30 minutes before layer separation. The organic layer was washed further with water (2×100 ml) and dried over sodium sulphate. To the organic layer IPA-HCl (72 g, 20 %) was added till pH is acidic (2-2.5).The product precipitated as solid hydrochloride salt was isolated by filtration and recrystallized from methanol. Yield: 181 g, 82% m.p., 105-107°C.
Antispasmodic drugs relieve cramps or spasms of the stomach, intestines, and bladder. Antispasmodics are classes (group) of drugs that can help to control some symptoms that arise from the gut, in particular, gut spasm. There are two main types namely “Antimuscarinics” and “Smooth muscle relaxants”. Antispasmodics are commonly used in “Irritable bowel syndrome” (IBS) to help relieve some of the symptoms of IBS such as spasm (colic), bloating and abdominal (stomach) pain and to reduce the motility (movement) of the intestines (gut) [1].
After understanding further the medicinal importance of antispasmodics and their ever increasing demand worldwide, we pursue to undertake the detailed synthetic and pharmacological study of antispasmodics to identify novel candidates as potential drug substances. Our parallel interest also lies on identifying novel antimicrobials since over the years; antibiotics are known to be the major protective agents against bacterial infections. However, the usage of antibiotics and antibacterial chemotherapeutics is becoming more and more restricted in the present age, despite the fact that there exist a large number of antibiotics. This is largely attributed to the emergence of drug-resistant bacteria, which render even some of the most broad spectrum antibiotics ineffective. In addition, most antibiotics have side effects. Thus, it becomes essential to investigate newer drugs with less resistance. Different studies on search of newer antimicrobials and antibacterial have revealed that moderate to remarkable antimicrobial or antibacterial action is present in several compounds, belonging to various pharmacological categories, such as antihistamines [2-4], tranquilizers [5], antihypertensive [6], anti-psychotics [7-11] anti-spasmodic [12] and anti-inflammatory agents [13]. Such compounds, having antibacterial properties in addition to their predesignated pharmacological actions, are termed as non-antibiotics [12]. Many of these compounds possess two or three benzene rings and nitrogen in the secondary or tertiary state in their molecular structure which is expected to be one of the bases for exhibiting antimicrobial potency [14]. Based on this rationale and to pursue our interest to identify newer antispasmodic agents with sedative and antimicrobial properties
[1] M. H. Pittler, E. Ernst, Am. J. Gastroenterol., 1998, 93 (7), 1131–5. [2] S. G. Dastidar, P. K. Saha, B. Sanyamat, A. N. Chakrabarty, J. Appl. Bacteriol., 1976, 41, 209- 214. [3] D. Chattopadyay, S. G. Dastidar, A. Chakrabarty, Arzneimittelforschang, 1988, 38, 869-872. [4] A. Chakrabarty, D. P. Acharya, D. K. Neogi, S. G. Dastidar, Indian J. Med. Res., 1989, 89, 233-237. [5] S. K. Dash, S. G. Dastidar, A. Chakrabarty, Indian J. Exp. Biol., 1977, 15, 324-326. [6] S. G. Dastidar, U. Mondal, S. Niyogi, A. Chakrabarty, Indian J. Med. Res., 1986, 84, 142- 147. [7] J. Molnar, Y. Mandi, J. Kiral, Acta Microbiol Acad Sci Hung., 1976, 23, 45-54. [8] J. E. Kristiansen, Acta Pathol. Microbial Immunol. Scand., 1992, 100 (Suppl. 30), 7-14 [9] S. G. Dastidar, A. Chaudhury, S. Annadurai, M. Mookerjee, A. Chakrabarty, J. Chemother., 1995, 7, 201-206. [10] V. Radhakrishnan, K. Ganguly, M. Ganguly, S. G. Dastidar, A. Chakrabarty, Indian J. Exp. Biol., 1999, 37, 671-675. [11] P. Bourlioux, J. M. Moreaux, W. J. Su, H. Boureau, Acta Pathol. Microbial. Immunol Scand., 1992, 100 (Suppl. 30), 40-43. [12] S. G. Dastidar, A. Chakrabarty, J. Molnar, N. Motohashi, National Institute of Science Communication (NISCOM), New Delhi, 1998, pp. 15. [13] S. Annadurai, S. Basu, S. Ray, S. G. Dastidar, A. C
Mebeverine is a drug used to alleviate some of the symptoms of irritable bowel syndrome. It works by relaxing the muscles in and around the gut.[1]
Medical use
Mebeverine is used to alleviate some of the symptoms of irritable bowel syndrome (IBS) and related conditions; specifically stomach pain and cramps, persistent diarrhoea, and flatulence.[2]
Data from controlled clinical trials have not found a difference from placebo or statistically significant results in the global improvement of IBS.[3][4]
It has not been tested in pregnant women nor in pregnant animals so pregnant women should not take it; it is expressed at low levels in breast milk, while no adverse effects have been reported in infants, breastfeeding women should not take this drug.[1]
Adverse effects
Adverse effects include hypersensitivity reactions and allergic reactions, immune system disorders, skin disorders including hives, oedema and widespread rashes.[2]
Additionally, the following adverse effects have been reported: heartburn, indigestion, tiredness, diarrhoea, constipation, loss of appetite, general malaise, dizziness, insomnia, headache, and decreased pulse rate.[1]
Mebeverine can, on highly rare occasions, cause drug-induced acute angle closure glaucoma.[5]
Mechanism of action
Mebeverine is an anticholinergic but its mechanism of action is not known; it appears to work directly on smooth muscle within the gastrointestinal tract and may have an anaesthetic effect, may affect calcium channels, and may affect muscarinic receptors.[2]
It is metabolized mostly by esterases, and almost completely. The metabolites are excreted in urine.[2]
Mebeverine exists in two enantiomeric forms. The commercially available product is a racemic mixture of them. A study in rats indicates that the two have different pharmacokinetic profiles.[6]
History
It is a second generation papaverine analog, and was first synthesized around the same time as verapamil.[7]
^ Hatami M, Farhadi K, Tukmechi A (August 2012). “Fiber-based liquid-phase micro-extraction of mebeverine enantiomers followed by chiral high-performance liquid chromatography analysis and its application to pharmacokinetics study in rat plasma”. Chirality. 24(8): 634–9. doi:10.1002/chir.22057. PMID22700279.
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DOMPERIDONE
Molecular FormulaC22H24ClN5O2
Average mass425.911 Da
1H-Benzimidazol-2-ol, 5-chloro-1-[1-[3-(2-hydroxy-1H-benzimidazol-1-yl)propyl]-4-piperidinyl]- 260-968-7[EINECS] 2H-Benzimidazol-2-one, 5-chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl]-1,3-dihydro- 4-(5-Chloro-2-oxo-1-benzimidazolinyl)-1-[3-(2-oxobenzimidazolinyl)propyl]piperidine 57808-66-9[RN]домперидон دومبيريدون 多潘立酮 CAS Registry Number: 57808-66-9 CAS Name: 5-Chloro-1-[1-[3-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)propyl]-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one Additional Names: 5-chloro-1-[1-[3-(2-oxo-1-benzimidazolinyl)propyl]-4-piperidyl]-2-benzimidazolinone Manufacturers’ Codes: R-33812 Trademarks: Euciton (Roux-Ocefa); Evoxin (Sterling Winthrop); Gastronorm (Janssen); Mod (Irbi); Motilium (Janssen); Nauzelin (Janssen); Peridon (Italchimici); Peridys (Robapharm) Molecular Formula: C22H24ClN5O2 Molecular Weight: 425.91 Percent Composition: C 62.04%, H 5.68%, Cl 8.32%, N 16.44%, O 7.51% Literature References: A novel in vitro dopamine antagonist with antinauseant properties.Prepn: J. Vandenberk et al.,DE2632870; eidem,US4066772 (1977, 1978 both to Janssen). Pharmacology: C. Ennis et al.,J. Pharm. Pharmacol.31, Suppl., 14P (1979). Gastrokinetic properties: J. M. Van Neuten et al.,Life Sci.23, 453 (1978). 3H-domperidone studies: M. P. Martres et al.,ibid. 1781; M. Baudry et al.,Arch. Pharmacol.308, 231 (1979). Clinical studies: A. J. Reyntjens et al.,Arzneim.-Forsch.28, 1194 (1978); D. B. Wilson, J. W. Dundee, Anaesthesia34, 765 (1979). Review of pharmacology, pharmacokinetics and therapeutic efficacy: R. N. Brogden et al.,Drugs24, 360-400 (1982). Properties: Crystals from DMF/water, mp 242.5°. Melting point: mp 242.5° Therap-Cat: Antiemetic. Keywords: Antiemetic; Dopamine Receptor Antagonist.
Domperidone (7.1.6) (Motilium), a peripherally selective D2-like receptor antagonist, regulates the motility of the gastric and small intestinal smooth muscles and has been shown to have some effects on the motor function of the esophagus. It effectively prevents bile reflux but does not affect gastric secretion. As a result of the blockade of dopamine receptors in the chemoreceptor trigger zone it also has an antiemetic activity. Domperiodone provided relief of such symptoms as anorexia, nausea, vomiting, abdominal pain, early satiety, bloating, and distension in patients with symptoms of diabetic gastropathy. It also provided short-term relief of symptoms in patients with dyspepsia or gastroesophageal reflux, prevented nausea and vomiting associated with emetogenic chemotherapy, and prevented the gastrointestinal and emetic adverse effects of antiparkinsonian drugs. Because domperidone does not readily cross the blood brain barrier and does not inhibit dopamine receptors in the brain, reports of adverse effects on the CNS, such as dystonic reactions, are rare [52–61]. Domperidone is widely used in many countries and can now be officially prescribed to patients in the United States. There are very few treatment options currently available for patients with gastrointestinal motility disorders, especially for patients with gastroparesis. Domperidone has been successfully used in the United States and in many countries as a second-line treatment option for the treatment of gastroparesis.
Synthesis of domperidone (7.1.6) started with arylation of ethyl 4-aminopiperidine-1-carboxylate (7.1.28) with 1,4-dichloro-2-nitrobenzene (7.1.29) on heating at 150°C in cyclohexanol in the presence of sodium carbonate and potassium iodide (in a later disclosure in toluene in presence of sodium carbonate [62]) to give compound (7.1.30), which on reflux in 48% hydrobromic acid solution yielded N-(4-chloro-2-nitrophenyl)piperidin-4-amine (7.1.31). The obtained product was alkylated with 1-(3-chloropropyl)-1,3-dihydro-2H-benzo[d]imidazol-2-one (7.1.32) on reflux in MBIK in the presence of sodium carbonate and potassium iodide to give compound (7.1.33). The ring closure could be effected by heating o-phenylene diamine (7.1.33) with an appropriate cyclizing agent, such as phosgene, urea, potassium isocyanate [63], and the like. In this patent potassium isocyanate dissolved in water was carefully added to a solution of compound (7.1.34) in 10 N hydrochloric acid solution (exothermic reaction) to give desired domperidone (7.1.6) [64,65] (Scheme 7.4).
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Medical uses
Nausea and vomiting
There is some evidence that domperidone has antiemetic activity.[10] It is recommended by the Canadian Headache Society for treatment of nausea associated with acute migraine.[11]
Gastroparesis
Gastroparesis is a medical condition characterised by delayed emptying of the stomach when there is no mechanical gastric outlet obstruction. Its cause is most commonly idiopathic, a diabetic complication or a result of abdominal surgery. The condition causes nausea, vomiting, fullness after eating, early satiety (feeling full before the meal is finished), abdominal pain and bloating.
However, increased rate of gastric emptying induced by drugs like domperidone does not always correlate (equate) well with relief of symptoms.[14]
Parkinson’s disease
Parkinson’s disease is a chronic neurological condition where a decrease in dopamine in the brain leads to rigidity (stiffness of movement), tremor and other symptoms and signs. Poor gastrointestinal function, nausea and vomiting is a major problem for people with Parkinson’s disease because most medications used to treat Parkinson’s disease are given by mouth. These medications, such as levodopa, can cause nausea as a side effect. Furthermore, anti-nausea drugs, such as metoclopramide, which do cross the blood–brain barrier may worsen the extra-pyramidal symptoms of Parkinson’s disease.
Domperidone can be used to relieve gastrointestinal symptoms in Parkinson’s disease; it blocks peripheral D2 receptors but does not cross the blood–brain barrier in normal doses (the barrier between the blood circulation of the brain and the rest of the body) so has no effect on the extrapyramidal symptoms of the disease.[15]
The hormone prolactin stimulates lactation (production of breast milk). Dopamine, released by the hypothalamus stops the release of prolactin from the pituitary gland. Domperidone, by acting as an anti-dopaminergic agent, results in increased prolactin secretion, and thus promotes lactation (that is, it is a galactogogue). Domperidone moderately increases the volume of expressed breast milk in mothers of preterm babies where breast milk expression was inadequate, and appears to be safe for short-term use for this purpose.[18][19][20] In the United States, domperidone is not approved for this or any other use.[21][22]
A study called the EMPOWER trial was designed to assess the effectiveness and safety of domperidone in assisting mothers of preterm babies to supply breast milk for their infants.[23] The study randomized 90 mothers of preterm babies to receive either domperidone 10 mg orally three times daily for 28 days (Group A) or placebo 10 mg orally three times daily for 14 days followed by domperidone 10 mg orally three times daily for 14 days (Group B). Mean milk volumes at the beginning of the intervention were similar between the 2 groups. After the first 14 days, 78% of mothers receiving domperidone (Group A) achieved a 50% increase in milk volume, while 58% of mothers receiving placebo (Group B) achieved a 50% increase in milk volume.[24]
To induce lactation, domperidone is used at a dosage of 10 to 20 mg 3 or 4 times per day by mouth.[25] Effects may be seen within 24 hours or may not be seen for 3 or 4 days.[25] The maximum effect occurs after 2 or 3 weeks of treatment, and the treatment period generally lasts for 3 to 8 weeks.[25] A 2012 review shows that no studies support prophylactic use of a galactagogue medication at any stage of pregnancy, including domperidone.[26]
Reflux in children
Domperidone has been found effective in the treatment of reflux in children.[27] However some specialists consider its risks prohibitory of the treatment of infantile reflux.[28]
Domperidone use is associated with an increased risk of sudden cardiac death (by 70%)[33] most likely through its prolonging effect of the cardiac QT interval and ventricular arrhythmias.[34][35] The cause is thought to be blockade of hERGvoltage-gated potassium channels.[36][37] The risks are dose-dependent, and appear to be greatest with high/very high doses via intravenous administration and in the elderly, as well as with drugs that interact with domperidone and increase its circulating concentrations (namely CYP3A4 inhibitors).[38][39] Conflicting reports exist, however.[40] In neonates and infants, QT prolongation is controversial and uncertain.[41][42]
UK drug regulatory authorities (MHRA) have issued the following restriction on domperidone in 2014 due to increased risk of adverse cardiac effects:
Domperidone (Motilium) is associated with a small increased risk of serious cardiac side effects. Its use is now restricted to the relief of nausea and vomiting and the dosage and duration of use have been reduced. It should no longer be used for the treatment of bloating and heartburn. Domperidone is now contraindicated in those with underlying cardiac conditions and other risk factors. Patients with these conditions and patients receiving long-term treatment with domperidone should be reassessed at a routine appointment, in light of the new advice.
However, a 2015 Australian review concluded the following:[39]
Based on the results of the two TQT (the regulatory agency gold standard for assessment of QT prolongation) domperidone does not appear to be strongly associated with QT prolongation at oral doses of 20 mg QID in healthy volunteers. Further, there are limited case reports supporting an association with cardiac dysfunction, and the frequently cited case-control studies have significant flaws. While there remains an ill-defined risk at higher systemic concentrations, especially in patients with a higher baseline risk of QT prolongation, our review does not support the view that domperidone presents intolerable risk.
In healthy volunteers, ketoconazole increased the Cmax and AUC concentrations of domperidone by 3- to 10-fold.[44] This was accompanied by a QT interval prolongation of about 10–20 milliseconds when domperidone 10 mg four times daily and ketoconazole 200 mg twice daily were administered, whereas domperidone by itself at the dosage assessed produced no such effect.[44] As such, domperidone with ketoconazole or other CYP3A4 inhibitors is a potentially dangerous combination.[44]
A single 20 mg oral dose of domperidone has been found to increase mean serum prolactin levels (measured 90 minutes post-administration) in non-lactating women from 8.1 ng/mL to 110.9 ng/mL (a 13.7-fold increase).[7][48][49][50] This was similar to the increase in prolactin levels produced by a single 20 mg oral dose of metoclopramide (7.4 ng/mL to 124.1 ng/mL; 16.7-fold increase).[49][50] After two weeks of chronic administration (30 mg/day in both cases), the increase in prolactin levels produced by domperidone was reduced (53.2 ng/mL; 6.6-fold above baseline), but the increase in prolactin levels produced by metoclopramide, conversely, was heightened (179.6 ng/mL; 24.3-fold above baseline).[7][50] This indicates that acute and chronic administration of both domperidone and metoclopramide is effective in increasing prolactin levels, but that there are differential effects on the secretion of prolactin with chronic treatment.[49][50] The mechanism of the difference is unknown.[50] The increase in prolactin levels observed with the two drugs was, as expected, much greater in women than in men.[49][50] This appears to be due to the higher estrogen levels in women, as estrogen stimulates prolactin secretion.[51]
For comparison, normal prolactin levels in women are less than 20 ng/mL, prolactin levels peak at 100 to 300 ng/mL at parturition in pregnant women, and in lactating women, prolactin levels have been found to be 90 ng/mL at 10 days postpartum and 44 ng/mL at 180 days postpartum.[52][53]
1978 – On 3 January 1978 Domperidone was patented in the United States under patent US4066772 A. The application has been filed on 17 May 1976. Jan Vandenberk, Ludo E. J. Kennis, Marcel J. M. C. Van der Aa and others has been cited as the inventors.
1979 – Domperidone marketed under trade name “Motilium” in Switzerland and (Western) Germany.[61]
Janssen Pharmaceutical has brought domperidone before the United States Federal Drug Administration (FDA) several times, including in the 1990s.
2014 – In April 2014 Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) published official press-release suggesting to restrict the use of domperidone-containing medicines. It also approved earlier published suggestions by Pharmacovigilance Risk Assessment Committee (PRAC) to use domperidone only for curing nausea and vomiting and reduce maximum daily dosage to 10 mg.[9]
It was reported in 2007 that domperidone is available in 58 countries, including Canada,[65] but the uses or indications of domperidone vary between nations. In Italy it is used in the treatment of gastroesophageal reflux disease and in Canada, the drug is indicated in upper gastrointestinal motility disorders and to prevent gastrointestinal symptoms associated with the use of dopamine agonist antiparkinsonian agents.[66] In the United Kingdom, domperidone is only indicated for the treatment of nausea and vomiting and the treatment duration is usually limited to 1 week.
In the United States, domperidone is not currently a legally marketed human drug and it is not approved for sale in the U.S. On 7 June 2004, FDA issued a public warning that distributing any domperidone-containing products is illegal.[67]
It is available over-the-counter to treat gastroesophageal reflux and functional dyspepsia in many countries, such as Ireland, the Netherlands, Italy, South Africa, Mexico, Chile, and China.[68]
Domperidone is not generally approved for use in the United States. There is an exception for use in people with treatment-refractory gastrointestinal symptoms under an FDA Investigational New Drug application.[1]
^ Jump up to:abcdefghijklmnopqrs Reddymasu, Savio C.; Soykan, Irfan; McCallum, Richard W. (2007). “Domperidone: Review of Pharmacology and Clinical Applications in Gastroenterology”. The American Journal of Gastroenterology. 102 (9): 2036–2045. ISSN0002-9270. PMID17488253.
^“БРЮЛІУМ ЛІНГВАТАБС” [BRULIUM LINGUATABS]. Нормативно-директивні документи МОЗ України (in Ukrainian). 18 March 2014. Retrieved 29 May 2015.
^ Jump up to:ab Reddymasu SC, Soykan I, McCallum RW. (2007). “Domperidone: review of pharmacology and clinical applications in gastroenterology”. Am J Gastroenterol. 102 (9): 2036–45. PMID17488253.
^ Stevens JE, Jones KL, Rayner CK, Horowitz M (June 2013). “Pathophysiology and pharmacotherapy of gastroparesis: current and future perspectives”. Expert Opinion on Pharmacotherapy. 14(9): 1171–86. doi:10.1517/14656566.2013.795948. PMID23663133. S2CID23526883.
^ Silvers D, Kipnes M, Broadstone V, Patterson D, Quigley EM, McCallum R, Leidy NK, Farup C, Liu Y, Joslyn A (1998). “Domperidone in the management of symptoms of diabetic gastroparesis: efficacy, tolerability, and quality-of-life outcomes in a multicenter controlled trial. DOM-USA-5 Study Group”. Clinical Therapeutics. 20 (3): 438–53. doi:10.1016/S0149-2918(98)80054-4. PMID9663360.
^ Janssen P, Harris MS, Jones M, Masaoka T, Farré R, Törnblom H, Van Oudenhove L, Simrén M, Tack J (September 2013). “The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis”. The American Journal of Gastroenterology. 108 (9): 1382–91. doi:10.1038/ajg.2013.118. PMID24005344. S2CID32835351.
^ Grzeskowiak LE, Lim SW, Thomas AE, Ritchie U, Gordon AL (February 2013). “Audit of domperidone use as a galactogogue at an Australian tertiary teaching hospital”. Journal of Human Lactation. 29 (1): 32–7. doi:10.1177/0890334412459804. hdl:2440/94368. PMID23015150. S2CID26535783.
^ Donovan TJ, Buchanan K (2012). “Medications for increasing milk supply in mothers expressing breastmilk for their preterm hospitalised infants”. The Cochrane Database of Systematic Reviews. 3 (3): CD005544. doi:10.1002/14651858.CD005544.pub2. PMID22419310.
^ Asztalos EV, Campbell-Yeo M, da Silva OP, Ito S, Kiss A, Knoppert D, et al. (EMPOWER Study Collaborative Group) (2017). “Enhancing human milk production with Domperidone in mothers of preterm infants”. Journal of Human Lactation. 33 (1): 181–187. doi:10.1177/0890334416680176. PMID28107101. S2CID39041713.
^ Leelakanok N, Holcombe A, Schweizer ML (2015). “Domperidone and Risk of Ventricular Arrhythmia and Cardiac Death: A Systematic Review and Meta-analysis”. Clin Drug Investig. 36 (2): 97–107. doi:10.1007/s40261-015-0360-0. PMID26649742. S2CID25601738.
^ van Noord C, Dieleman JP, van Herpen G, Verhamme K, Sturkenboom MC (November 2010). “Domperidone and ventricular arrhythmia or sudden cardiac death: a population-based case-control study in the Netherlands”. Drug Safety. 33 (11): 1003–14. doi:10.2165/11536840-000000000-00000. PMID20925438. S2CID21177240.
^ Johannes CB, Varas-Lorenzo C, McQuay LJ, Midkiff KD, Fife D (September 2010). “Risk of serious ventricular arrhythmia and sudden cardiac death in a cohort of users of domperidone: a nested case-control study”. Pharmacoepidemiology and Drug Safety. 19(9): 881–8. doi:10.1002/pds.2016. PMID20652862. S2CID20323199.
^ Jump up to:ab Buffery PJ, Strother RM (2015). “Domperidone safety: a mini-review of the science of QT prolongation and clinical implications of recent global regulatory recommendations”. N. Z. Med. J. 128(1416): 66–74. PMID26117678.
^ Djeddi D, Kongolo G, Lefaix C, Mounard J, Léké A (November 2008). “Effect of domperidone on QT interval in neonates”. The Journal of Pediatrics. 153 (5): 663–6. doi:10.1016/j.jpeds.2008.05.013. PMID18589449.
^ Sakamoto Y, Kato S, Sekino Y, Sakai E, Uchiyama T, Iida H, Hosono K, Endo H, Fujita K, Koide T, Takahashi H, Yoneda M, Tokoro C, Goto A, Abe Y, Kobayashi N, Kubota K, Maeda S, Nakajima A, Inamori M (2011). “Effects of domperidone on gastric emptying: a crossover study using a continuous real-time 13C breath test (BreathID system)”. Hepato-gastroenterology. 58 (106): 637–41. PMID21661445.
^ Parkman HP, Jacobs MR, Mishra A, Hurdle JA, Sachdeva P, Gaughan JP, Krynetskiy E (January 2011). “Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side-effects”. Digestive Diseases and Sciences. 56 (1): 115–24. doi:10.1007/s10620-010-1472-2. PMID21063774. S2CID39632855.
^ Jump up to:abcdef Brouwers JR, Assies J, Wiersinga WM, Huizing G, Tytgat GN (1980). “Plasma prolactin levels after acute and subchronic oral administration of domperidone and of metoclopramide: a cross-over study in healthy volunteers”. Clin. Endocrinol. 12 (5): 435–40. doi:10.1111/j.1365-2265.1980.tb02733.x. PMID7428183. S2CID27266775.
^Hospital Formulary. HFM Publishing Corporation. 1991. p. 171. Domperidone, a benzimidazole derivative, is structurally related to the butyrophenone tranquilizers (eg, haloperidol (Haldol, Halperon]).
^ Jump up to:abc Sneader, Walter (2005). “Plant Product Analogues and Compounds Derived from Them”. Drug discovery : a history. Chichester: John Wiley & Sons Ltd. p. 125. ISBN978-0-471-89979-2.
^“Domperidone”. Pharmaceutical Manufacturing Encyclopedia, 3rd Edition (Vol. 1-4). William Andrew Publishing. 2013. p. 138. ISBN9780815518563. Retrieved 12 December 2014.
^ Reddymasu SC, Soykan I, McCallum RW (2007). “Domperidone: review of pharmacology and clinical applications in gastroenterology”. Am. J. Gastroenterol. 102 (9): 2036–45. PMID17488253.
^ Hofmeyr, G. J.; Van Iddekinge, B.; Van Der Walt, L. A. (2009). “Effect of domperidone-induced hyperprolactinaemia on the menstrual cycle; a placebo-controlled study”. Journal of Obstetrics and Gynaecology. 5 (4): 263–264. doi:10.3109/01443618509067772. ISSN0144-3615.
UK: POM (Prescription only)US: Not approved for use or salePrescription medicine (Rx only):Pakistan, India, Australia, Canada, Israel, Belgium, France, Netherlands; over-the-counter: Egypt, Ireland, Italy, Japan, South Africa, Switzerland, Kuwait, China, Russia, Slovakia, Ukraine[2] Mexico, Thailand, Malta, South Korea, and Romania[3]
Hydroxypioglitazone is a member of the class of thiazolidenediones that is the hydroxy derivative of pioglitazone. It has a role as a human xenobiotic metabolite. It is a member of thiazolidinediones, a member of pyridines and an aromatic ether. It derives from a pioglitazone.
OriginatorIDIBELL
DeveloperMinoryx Therapeutics
ClassNeuroprotectants; Phenyl ethers; Pyridines; Small molecules; Thiazolidinediones
Mechanism of ActionPeroxisome proliferator-activated receptor gamma agonists
Orphan Drug StatusYes – Adrenoleucodystrophy; Friedreich’s ataxia
Phase II/IIIAdrenoleucodystrophy
Phase IIFriedreich’s ataxia
PreclinicalCNS disorders
23 Sep 2020Leriglitazone receives Rare Pediatric Disease designation from the US FDA for X-linked adrenoleukodystrophy before September 2020
23 Sep 2020Minoryx Therapeutics licenses leriglitazone to Sperogenix Therapeutics in China, Hong Kong and Macau for X-linked adrenoleukodystrophy (X-ALD)
14 Sep 2020Minoryx Therapeutics completes the phase II FRAMES trial in Friedreich’s ataxia (In adolescents, In adults) in Spain, Germany, France and Belgium (PO) (NCT03917225)
Leriglitazone (Hydroxypioglitazone), a metabolite of pioglitazone. Leriglitazone (Hydroxypioglitazone) PioOH is a PPARγ agonist, stabilizes the PPARγ activation function-2 (AF-2) co-activator binding surface and enhances co-activator binding, affording slightly better transcriptional efficacy. Leriglitazone (Hydroxypioglitazone) binds to the PPARγ C-terminal ligand-binding domain (LBD) with Ki of 1.2 μM，induces transcriptional efficacy of the PPARγ (LBD) with EC50 of 680 nM.
Leriglitazone is under investigation in clinical trial NCT03917225 (A Clinical Study to Evaluate the Effect of MIN-102 on the Progression of Friedreich’s Ataxia in Male and Female Patients).
Treatment of X-Linked Adrenoleukodystrophy
PATENT
WO 9218501
WO 9322445
PAPER
Chemical & Pharmaceutical Bulletin (1995), 43(12), 2168-72
The metabolites of (±)-5-[p-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2, 4-thiazolidinedione (1, pioglitazone), which is a representative insulin-sensitizing agent, were synthesized to confirm their structures and for studies of their pharmacological properties. Of the metabolites identified, a compound hydroxylated at the 2-position of the ethoxy chain (3) and compounds oxygenated at the ethyl side chain attached to the pyridine ring (4, 5) were found to be active, although the potency was slightly lower than that of the parent compound.
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PAPER
Journal of Medicinal Chemistry (1996), 39(26), 5053-5063.
Pioglitazone (5-(4-(2-(5-ethyl-2-pyridyl)ethoxy)benzyl)-2,4-thiazolidinedione, 2) is a prototypical antidiabetic thiazolidinedione that had been evaluated for possible clinical development. Metabolites 6−9 have been identified after dosing of rats and dogs. Ketone 10 has not yet been identified as a metabolite but has been added to the list as a putative metabolite by analogy to alcohol 6 and ketone 7. We have developed improved syntheses of pioglitazone (2) metabolites 6−9 and the putative metabolite ketone 10. These entities have been compared in the KKAy mouse model of human type-II diabetes to pioglitazone (2). Ketone 10 has proven to be the most potent of these thiazolidinediones in this in vivo assay. When 6−10 were compared in vitro in the 3T3-L1 cell line to 2, for their ability to augment insulin-stimulated lipogenesis, 10 was again the most potent compound with 6, 7, and 9 roughly equivalent to 2. These data suggest that metabolites 6, 7, and 9 are likely to contribute to the pharmacological activity of pioglitazone (2), as had been previously reported for ciglitazone (1).
PATENT
WO 2015150476
Compound 5-[4-[2-(5-(1 -hydroxyethyl)-2-pyridinyl)ethoxy]benzyl]-2,4-thiazolidinedione of formula (1 ) can be prepared according to Scheme 1 (see e.g. J.Med.Chem. 1996, 39(26),5053).
Yet another method to prepare mixtures (c) – comprising compound (2) and (4) – and (d) – comprising compounds (3) and (5) – (scheme 3), includes the resolution of the racemic mixture VIII using the already described methods (chiral HPLC separation, enzymatic resolution, chiral resolution, etc) followed by double bond reduction in each of the enantiomers Villa and Vlllb.
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Scheme 4
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Compounds of formula (2), (3), (4) and (5) may be obtained from mixtures (c) and (d) (Scheme 45) by chiral HPLC separation. Alternatively, the desired enantiomerically pure compounds can be prepared by chiral synthetic procedures known to those skilled in the art (for example: asymmetric hydrogenolysis of the corresponding single isomer of compound VI).
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HPLC Method
Column: Symmetry Shield RP-18, 5 μηη (4.6 x 250 mm); wavelength: 210 nm; flow: 1 mL/min; run time: 28 min; mobile phase-gradient: (t/%B): 0/10, 8/10, 12/60, 16/80, 20/80, 24/10, 28/10 [A: Water (potassium dihydrogen o-phosphate (pH~3)), B: Acetonitrile]
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A mixture of compounds (2) and (4) (mixture (c)) and a mixture of compounds (3) and (5) (mixture (d)) were prepared according to Scheme 7.
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Example 6: Preparation of diastereomeric mixtures D-1 and D-2 of M-IV:
Scheme 1 :
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Ent-1 (VIII) Ent-2 (VIII)
Step 3 Step 3
MIV D-1 MIV D-2
Step 1 : Synthesis of compound VIII: HCI (48 ml, 2N) was added to a solution of compound VI (10 g, 0.024 mol) in methanol (200 ml) and the mixture was heated to reflux. After 4 h of reflux, the reaction mixture was cooled to r.t. and concentrated under reduced pressure to afford a yellow solid. The solid was suspended in water (70 ml) and neutralized using a saturated NaHC03 solution. The resulting pale yellow precipitate was collected by filtration and vacuum dried to afford compound VIII (7.5 g; 84% yield).
ES-MS [M+1]+: 371.0.
Step 2: Chiral prep. HPLC
Compound VIII (1 .0 g) was dissolved in a mixture containing equal volumes of acetonitrile, methanol and dichloromethane; injected (150 μΙ injections) in chiral prep-HPLC column (Chiralpak-IA 250 x 20 mm, 5 micron) and separated [Mobile phase- n-Hexane/0.05% Et3N in EtOH (50:50); flow Rate: 18ml/min; run time: 60 min]. The fractions containing the enantiomers Villa and Vlllb were separately concentrated under reduced pressure to minimum volume and the respective residues were diluted with EtOAc (100 ml), followed by water (50 ml). The resultant organic phases were
dried over anhydrous Na2S04 and concentrated to afford compounds Villa and Vlllb as off-white solids. Enantiomers Villa and Vlllb were isolated but the absolute configuration of each enantiomer has not been determined.
Step 3: A solution of NaBH4 (77 mg, 2.02 mmol) in 0.1 N NaOH (2 ml) was added slowly to a stirred solution of compound Ent-1 (VIII) (250 mg, 0.675 mmol), dimethylglyoxime (32 mg, 0.27 mmol) and CoCI2.6H20 (16 mg, 0.067 mmol) in a mixture of water (10 ml), THF (10 ml) and 1 M NaOH (0.5ml) solution at 10 °C, and the reaction mixture was stirred at r.t. for 1 h. After color of the reaction medium faded, additional quantity of NaBH4 (26 mg, 0.675 mmol) and CoCI2.6H20 (16 mg, 0.067 mmol) were added and stirring was continued at r.t. [additional quantities of CoC|2 and NaBH4 were added at 12 h intervals till the starting material was consumed, as monitored by LCMS]. After 90-96 h, the reaction mixture was neutralized with AcOH (pH~7); diluted with water (10 ml) and extracted in EtOAc (3 χ 50 ml). The combined organic extract was dried over anhydrous Na2S04 and concentrated to afford crude compound which was purified by flash column chromatography (Si02; 4% methanol in CH2CI2) to afford diastereomeric mixture of MIV D-1 (125 mg) as off-white solid.
Synthesis of D-2 MIV
Step 3: A solution of NaBH4 (72 mg, 1 .921 mmol) in 0.1 N NaOH (2 ml) was added slowly to a stirred solution of compound Ent-2 (VIII) (237 mg, 0.64 mmol), dimethylglyoxime (30 mg, 0.256 mmol) and CoCI2.6H20 (15 mg, 0.064 mmol) in a mixture of water (10 ml), THF (10 ml), and 1 M NaOH (0.5ml) solution at 10 °C, and the
reaction mixture was stirred at r.t. for 1 h. After color of the reaction medium faded, additional quantity of NaBH4 (24 mg, 0.64 mmol) and CoCI2.6H20 (15 mg, 0.064 mmol) were added and stirring was continued at r.t. [additional quantities of CoCI2.6H20 and NaBH4 were added at 12 h intervals till the starting material was consumed, as monitored by LCMS]. After 96 h, the reaction mixture was neutralized with AcOH (pH~7); diluted with water (10 ml) and extracted in EtOAc (3 χ 50 ml). The combined organic extract was dried over anhydrous Na2S04 and concentrated to afford crude compound, which was purified by flash column chromatography (Si02; 4% methanol in CH2CI2) to afford diastereomeric mixture of MIV D-2 (100 mg) as off-white solid.
Diastereomeric mixtures D-1 and D-2 of MIV correspond to mixtures (c) and (d) described above, but the specific diastereomers present in each diastereomeric mixture have not been assigned.
Example 7: in vitro ADME and toxicological characterization
Protocol: The assays performed include cytochrome P450 inhibition with the different isoforms, microsomal and hepatocyte stability, neurotoxicity in neural cells and hERG safety assays using a patch clamp electrophysiology measurement (FDA Draft Guidance for Industry. Drug Interaction Studies – Study Design, Data Analysis, Implications for Dosing, and Labelling Recommendations 2012, The European Medicines Agency (EMA) Guideline on the Investigation of Drug Interactions Adopted in 2012, Schroeder K et al. 2003 J Biomol Screen 8 (1 ); 50-64, Barter ZE et al. 2007
Curr Drug Metab 8 (1 ); 33-45, LeCluyse EL and Alexandre E 2010 Methods Mol Biol 640; 57-82). The results indicate a safe and favourable ADME profile for the compounds of the invention.
Example 8: The brain plasma ratios of Pioglitazone, MIV, Mill and Mil following oral dosing of a single administration of Pioglitazone at 4.5 mg/kg in male C57BL/6 mice.
The brain-plasma ratio was calculated based on levels of Pioglitazone, MIV, Mill and Mllin plasma and brain quantified at C max (maximal concentration) following oral dosing of a single administration of Pioglitazone at 4.5 mg/kg in male C57BL/6 mice. The percentage brain plasma ratio was 9, 13, 7 and 1 %, respectively, for Pioglitazone, Mil and Mill as shown in the Figure 4. Thus, active metabolites Mill and Mil crossed the BBB at much lower extent than Pioglitazone as it was predicted based on the physicochemical properties of the compounds (see Tablel ). In contrast, unexpectedly metabolite MIV crossed the BBB in a higher percentage than the parent compound Piolgitazone
The calculations of the both indexes (ClogP and QPIogBB) for Pioglitazone and its metabolites Mil and Mill are shown in Table 1 . For both indexes the 2 metabolites are lower than for pioglitazone, suggesting for Mil, and Mill a less favored penetration and distribution within CNS.
TABLE 1
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PATENT
WO 2018116281
https://patents.google.com/patent/WO2018116281A1/enPioglitazone is a “dirty” drug which is converted to many metabolites in vivo. The metabolic pathway of pioglitazone after oral administration has been studied in several animal species and in humans and the metabolites have been described in the literature (see e.g. Sohda et al, Chem. Pharm. Bull., 1995, 43(12), 2168-2172) and Maeshiba et al, Arzneim.-Forsch/Drug Res, 1997, 47 (I), 29-35). At least six metabolites have been identified, named M-I to M-VI. Amongst these metabolites, M-II, M-III and M-IV show some pharmacological activity but are less active than Pioglitazone in diabetic preclinical models.
[0005] 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione has the following structure:
[0006] Tanis et al. (J. Med. Chem. 39(26 ):5053-5063 (1996)) describe the synthesis of 5-[[4-[2-[5-( 1 -hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione as follows:Scheme 1
[0007] Tanis et al. describe that the intermediate 14 was obtained in a 27% yield by reacting compound 13 in an aqueous 37% formaldehyde at 170°C for 6 hours. In this process, 5-[[4- [2-[5-( 1 -hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (compound 6 in Scheme 1) was obtained in a 2.47% overall yield.[0008] WO 2015/150476 Al describes the use of 5-[[4-[2-[5-(l-hydroxyethyl)-2- pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione, and its pharmaceutically acceptable salts, in the treatment of central nervous system (CNS) disorders. WO 2015/150476 Al describes that 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione was prepared according to the process of Tanis et al. (supra) where the intermediate corresponding to compound 14 of Tanis et al. was prepared similarly at 160°C for 5 hours providing a 17% yield. The overall yield of 5-[[4-[2-[5-(l-hydroxyethyl)-2- pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione was about 1.5%.[0009] Due to the low yield of the intermediate 2-[5-(l-methoxymethoxy-ethyl)pyridine-2- yl]ethanol, the process step for preparing this intermediate is critical for the overall yield of the product, 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione. In addition, the prior art process to obtain compound 14 is difficult to scale because the reaction is carried out in a pressure vessel at a very high temperature and it is a very dirty reaction.[0010] Accordingly, the processes described in the art afford the product 5-[[4-[2-[5-(l- hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione only in a very low overall yield and, therefore, they are not suitable for large scale synthesis. In addition, the prior art process employs CH3OCH2CI, a known carcinogen, for protecting the hydroxyl group in the key intermediate. There is a need for an improved process for synthesizing 5- [[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione, and its pharmaceutically acceptable salts.Formula I illustrated by Scheme 2:Scheme 2 r
I (HCI salt)[0255] In another embodiment, the disclosure provides a process for preparing the compound of Formula I illustrated by Scheme 3 : Scheme 3C
[0256] In another embodiment in Scheme 3, step c, the order of mixing of the reagents can be as follows: 1. n-BuLi, 2. ethylene oxide, and 3. Cul. This order of mixing is described in Example 2.[0257] In the step a, 2,5-dibromopyridine (1) is reacted with i-PrMgCl in THF and then further with acetaldehyde to obtain compound 2. The reaction mixture is preferably filtered over Celite® after the reaction to remove most of the salts. In one embodiment, the addition of acetaldehyde is conducted at a temperature between -15°C and -10°C to control the exothermic reaction. [0258] In the step b, compound 2 is reacted with TBDMS-C1 in the presence of imidazole having DMF as a solvent. The crude product 3 is advantageously purified by a short plug filtration.[0259] In the step c, the hydroxyl protected compound 3 is reacted with ethylene oxide in the presence of n-BuLi and Cu(I)iodide while maintaining the reaction temperature, i.e., the reaction mixture temperature, below -20°C. In one embodiment, the reaction temperature is maintained below -55°C while adding n-BuLi and Cu(I)iodide into the reaction mixture. In another embodiment, the temperature of the reaction mixture is maintained below -55°C while adding n-BuLi, followed by ethylene oxide and then Cu(I)iodide into the reaction mixture. In another embodiment, the temperature of the reaction mixture is maintained below -55°C while adding n-BuLi into the reaction mixture, followed by ethylene oxide. In this embodiment, Cu(I)iodide is added then into the reaction mixture while the reaction mixture temperature is maintained below -20°C, and preferably below -55 °C. The reaction mixture is then allowed to slowly warm to room temperature after the addition of the reagents and stirred at room temperature, e.g., 20-25°C, overnight. This process is described in detail in Example 2. After the reaction, the complexed copper is advantageously removed by washing with 10% ammonia. The crude compound 4 can be purified by column chromatography to give >99% pure product with a yield of about 52%.[0260] The following examples are illustrative, but not limiting, of the methods of the present invention. Suitable modifications and adaptations of the variety of conditions and parameters normally encountered in clinical therapy and which are obvious to those skilled in the art in view of this disclosure are within the spirit and scope of the invention.ExamplesCOMPARATIVE EXAMPLE 1Synthesis of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]- 2,4-thiazolidinedione (9a) according to the process described in WO 2015/150476 Al Scheme 4
8a 9a[0261] (a) Synthesis of l-(6-methyl-pyridin-3-yl)-ethanol (3a)[0262] LiHMDS (1.0 M in tetrahydrofuran, 463 ml, 0.463 mol) was added drop wise to a cooled solution of methyl 6-methylnicotinate (la) (20 g, 0.132 mol) and ethyl acetate (82 g, 0.927 mol) in dimethylformamide at -50°C; gradually raised the temperature to room temperature and stirred at the same temperature. After 1 h, the reaction mixture was cooled to 0°C; slowly diluted with 20% sulphuric acid and heated to reflux. After 4 h, the reaction mixture was cooled to room temperature, and further to 0°C and basified with potassium carbonate. The reaction medium was diluted with water and extracted in ethyl acetate (3×50 mL). Combined organic extract was dried over sodium sulphate and concentrated to afford crude l-(6-methylpyridin-3-yl)ethan-l-one (2a) (20.0 g) which was taken to the next step without any purification. ES-MS [M+l]+: 136.1.Sodium borohydride (2.3 g, 0.06 mol) was added in small portions over 30 min, to a solution of compound 2a (16.4 g, 0.121 mol) in ethanol (160 mL) at 0°C and the reaction mixture was stirred at same temperature. After 1 h, the reaction mixture was diluted with sodium bicarbonate solution (sat) (2×200 mL) and extracted with dichloromethane (2×500 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford a pale yellow oil, which was purified by flash column chromatography (5% methanol/dichloromethane) to afford compound 3a (17.0 g; 93% yield over 2 steps) as a pale yellow oil. ES-MS [M+l]+: 138.1. 1H NMR (400 MHz, CDC13): δ 8.35 (d, J = 2.0 Hz, 1H), 7.63 (dd, J = 8.0, 2.4 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 4.89 (q, J = 6.5 Hz, 1H), 3.30 (br s, 1H), 2.50 (s, 3H), 1.48 (d, J = 6.5 Hz, 3H).[0263] (b) Synthesis of 5-(l-methoxymethoxy-ethyl)-2-methyl-pyridine (4a):Compound 3a (15 g, 0.109 mol) was added, drop wise, to a cooled suspension of sodium hydride (6.56 g, 0.164 mol) in tetrahydrofurane (150 mL) and stirred at 0°C. After 30 min, chloromethyl methyl ether (13.2 g, 0.164 mol) was added drop wise while stirring and keeping the internal temperature around 0°C. After addition is over, the reaction mixture was stirred at the same temperature for 1 h. The reaction was quenched with ice cold water (80 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford an orange color oil, which was purified by flash column chromatography (1% methanol/dichloromethane) to afford compound 4a (10.0 g; 51% yield) as a pale yellow oil. ES-MS [M+l]+: 182.2. 1H NMR (400 MHz, CDC13): δ 8.45 (d, J = 2.0 Hz, 1H), 7.56 (dd, J = 8.0, 2.0 Hz, 1H), 7.14 (d, J = 8.0 Hz, 1H), 4.75 (q, J = 6.4 Hz, 1H), 4.57 (ABq, 2H), 3.36 (s, 3H), 2.53 (s, 3H), 1.48 (d, J = 6.6 Hz, 3H).[0264] (c) Synthesis of 2-[5-(l-methoxymethoxy-ethyl)-pyridin-2-yl]-ethanol (5a):A mixture of compound 4a (7.0 g, 0.0386 mol) and 37% formaldehyde solution (5.8 g, 0.077 mol) was heated to 160°C in a sealed glass tube for 5 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford a crude compound which was purified by flash column chromatography (1% methanol/dichloromethane) to afford compound 5 (1.2 g; 17% yield) as pale yellow oil. ES-MS [M+l]+: 212.1. 1H NMR (400 MHz, CDC13): δ 8.42 (d, J = 2.0 Hz, 1H), 7.65 (dd, J = 8.0, 2.4 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.72 (q, J = 6.6 Hz, 1H), 4.65 (t, J = 5.6 Hz, 1H), 4.52 (ABq, 2H), 3.73 (m, 2H), 3.24 (s, 3H), 2.86 (t, J = 7.2 Hz, 2H), 1.49 (d, J = 6.4 Hz, 3H).[0265] The total yield for compound 5a from compound la was 8% molar.[0266] (d) Synthesis of 4-{2-[5-(l-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}- benzaldehyde (6a): Methanesulphonylchloride (1.19 g, 0.01 mol) was added, drop wise, to a cooled suspension of compound 5a (1.7 g, 0.008 mol) and triethylamine (1.79 ml, 0.013 mol) in dichloromefhane (20 mL) at 0°C and stirred at same temperature for 1 h. The reaction mixture was diluted with water (50 mL) and extracted with dichloromethane (3×50 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford 2-(5-(l-(methoxymethoxy)ethyl)pyridin-2-yl)ethyl methanesulfonate (2.04 g; 88% yield) as a yellow oil, which was taken to next step without purification. ES-MS [M+l]+: 290.[0267] 2-(5-(l-(methoxymethoxy)ethyl)pyridin-2-yl)ethyl methanesulfonate was added (2.3 g, 0.008 mol) to a stirred suspension of 4-hydroxybenzaldehyde (1.65 g, 0.0137 mol) and potassium carbonate (1.86 g, 0.0137 mol) in mixture of toluene (25 mL) and ethanol (25 mL); stirred at 85°C for 5 h. After consumption of the starting materials, the reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extract was washed with water; dried over anhydrous sodium sulphate and concentrated to afford a crude dark yellow liquid. The crude was purified by flash column chromatography (1% methanol/dichloromethane) to afford compound 6a (1.5 g; 60% yield) as pale yellow liquid. ES-MS [M+l]+: 316.1.[0268] (e) Synthesis of 5-(4-{2-[5-(l-methoxymethoxy-ethyl)-pyridin-2-yl]-ethoxy}- benzylidene)-thiazolidine-2,4-dione (7a):Piperidine (80 mg, 0.95 mmol) was added to a solution of compound 6a (0.6 g, 1.9 mmol) and thiazolidine-2,4-dione (0.22 g, 1.9 mmol) in ethanol (15 mL) and the mixture was heated to reflux overnight. After 15 h, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to afford crude mixture, which was purified by flash column chromatography (2% methanol/dichloromethane) to afford compound 7 (500 mg; 64% yield) as a yellow solid. ES-MS [M+l]+: 415.1. 1H NMR (400 MHz, DMSO-d6): δ 12.25 (br s, 1H), 8.47 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 8.0, 2.0 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 8.8 Hz, 2H), 4.73 (m, 1H), 4.60-4.40 (m, 4H), 4.22 (t, J = 6.2 Hz, 1H), 3.24 (s, 3H), 3.20 (t, J = 6.8 Hz, 2H), 1.41 (d, J = 6.0 Hz, 3H).[0269] (f) Synthesis of 5-(4-{2-[5-(l-hydroxy-ethyl)-pyridin-2-yl]-ethoxy}-benzyl)- thiazolidine-2,4-dione (9a): [0270] A solution of sodium borohydride (115 mg, 3.017 mmol) in 0.2N sodium hydroxide(1.2 mL) was added slowly to a stirred solution of compound 7 (0.5 g, 1.207 mmol), dimethylglyoxime (42 mg, 0.36 mmol) and C0CI2.6H2O (23 mg, 0.096 mmol) in a mixture of water (6 mL): tetrahydrofurane (6 mL) and 1M sodium hydroxide (1 mL) solution at 10°C and after addition, the reaction mixture was stirred at room temperature. After 1 h, the reaction color lightened and additional quantities of sodium borohydride (46 mg, 1.207 mmol) and C0CI2.6H2O (22 mg, 0.096 mmol) were added and stirring was continued at room temperature. After 12 h, the reaction was neutralized with acetic acid (pH~7); diluted with water (10 mL) and extracted in ethyl acetate (3×50 mL). The combined organic extract was dried over anhydrous sodium sulphate and concentrated to afford crude compound 8a, 5-(4- (2-(5-(l-(methoxymethoxy)ethyl)pyridin-2-yl)ethoxy)benzyl)thiazolidine-2,4-dione, (0.4 g) as pale yellow semi solid, which was taken to next step without purification. ES-MS [M+l]+: 417.5.[0271] 2N HC1 (2 mL) was added to a solution of compound 8a (0.4 g, 0.96 mmol) in methanol (20 ml) and the mixture was heated to reflux. After 4 h, the reaction mixture was cooled to room temperature and then concentrated under reduced pressure to afford a residue which was dissolved in water and the solution was neutralized using sodium bicarbonate solution (sat). The resulting white precipitate was collected by filtration to afford compound 9a (250 mg; 56% yield over 2 steps) as an off-white solid. ES-MS [M+l]+: 373.4. 1H NMR (400 MHz, DMSO-de): δ 12.00 (br s, -NH), 8.46 (d, J = 2.0 Hz, 1H), 7.66 (dd, J = 8.0, 2.4 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.13 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.25 (d, J = 4.4 Hz, 1H), 4.86 (m, 1H), 4.75 (m, 1H), 4.30 (t, J = 6.8 Hz, 2H), 3.30 (m, 1H), 3.14 (t, J = 6.4 Hz, 2H), 3.04 (m, 1H), 1.34 (d, J = 6.4 Hz, 3H).[0272] The overall yield of compound 9a was 1.5% molar.EXAMPLE 2Synthesis of 2-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-l-ol[0273] The synthesis of 2-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-l-ol was conducted according to the Scheme 5 using the reagents and solvents listed in Table 1 below: Scheme 5TBDMS-CI OTBDMS 1 . n-BuLi, <-55°C OTBDMSImidazole
[0274] The 1H-NMR spectra were recorded with Agilent MercuryPlus 300 NMR spectrometer.[0275] LC-MS data were obtained on an Agilent 1290 series with UV detector and HP 6130MSD mass detector using as column Waters XB ridge BEH XP (2.1 x 50 mm; 2.5 μιτι) and as eluent Ammonium acetate (10 mM); Water/ Methanol/ Acetonitrile.[0276] (a) l-(6-bromopyridin-3-yl)ethan-l-ol (2)[0277] A 20 L vessel was placed under nitrogen atmosphere and charged with tetrahydrofuran (5.5 L) and 2,5-dibromopyridine (1) (2000 g, 8.44 mol, 1.0 eq) (OxChem Corporation). The mixture was cooled to -10°C and isopropyl magnesium chloride (20% in THF, 6.02 L, 11.82 mol, 1.4 eq) (Rockwood Lithium) was added slowly over 1 h, keeping the reaction temperature below 5°C. After addition, the cooling bath was removed and the temperature was kept below 30°C (some additional cooling was needed to achieve this) and the reaction mixture was stirred overnight. After 16 h, a sample was taken; quenched with saturated aqueous ammonium chloride and extracted with methyl tert-buty\ ether (TBME). The TBME was evaporated under vacuum. 1H-NMR in deuterated chloroform showed complete conversion.[0278] The reaction mixture was cooled to -15°C and a solution of acetaldehyde (472 g,10.72 mol, 1.27 eq) (Acros) in tetrahydrofuran (200 mL) was added dropwise, while keeping temperature below -10°C. After the addition was complete, the cooling bath was removed and the temperature was allowed to rise to maximum of 5-8°C. After 1.5 h, a sample was taken and the reaction was quenched with aqueous ammonium chloride as described above. 1H-NMR showed the reaction was complete.[0279] Two batches were combined for work up.[0280] The reaction mixture was quenched by pouring the mixture into a solution of aqueous ammonium chloride (1 kg in 5 L water) and stirred for 15 min, filtered over Celite and rinsed thoroughly with toluene. The filtrate was transferred to a separation funnel and the obtained two layers system was separated. The aqueous layer was extracted with toluene (2 L). The combined organic layers were dried over sodium sulfate and filtered. Evaporation of the filtrate to dryness under vacuum yielded 3.49 kg (99%) of the desired crude material. XH NMR (300 MHz, CDC13): δ 8.30 (d, J = 2.5 Hz, 1H), 7.59 (dd, J = 8.0, 2.5 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 4,91 (q, J = 6.5 Hz, 1H), 1.49 (d, J = 6.5 Hz, 3H).[0281] (b) 2-bromo-5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridine (3)[0282] A 50 L reactor under nitrogen atmosphere was charged with compound 2 (10.0 kg, around 49.5 mol) and DMF (16 L). The mixture was cooled to 10°C and imidazole (6.74 kg, 99 mol, 2.0 eq) (Apollo Scientific Ltd.) was added portion wise within 30 min. The mixture was cooled to 0°C and TBDMS-Cl (7.46 kg, 49.5 mol, 1.0 eq) (Fluorochem) was added portion wise within 5 h, keeping the temperature below 3°C. The mixture reaction temperature was allowed to reach room temperature and stirred overnig ht. H NMR of a sample showed complete conversion.[0283] The reaction mixture was transferred to a 100 L extraction-vessel and the product was extracted with heptane (2×7.5 L, 10 L). The combined heptane-layers were washed with water (2×6 L, 3 L) to remove small amounts of DMF, dried over sodium sulfate and evaporated under vacuum to give crude compound 3 (15.5 kg, 49.0 mol) in a 99.0% yield. This crude product was purified by a short plug filtration, using 10 kg silica/heptane and eluted with heptane (approx. 50 L). The product-fractions were combined and evaporated under vacuum to give 12.0 kg of purified compound 3 (38 mol) as a brown oil in a 76.8% molar yield. (Average yield for 3 experiments was 78%). HPLC-MS: Rt= 2.6 min, M+l=316.1 and 318.1; 1H NMR (300 MHz, CDC13): δ 8.55 (d, J = 2.2 Hz, 1H), 7.54 (dd, J = 8.2, 2.2 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 4,86 (q, J = 6.5 Hz, 1H), 1.40 (d, J = 6.5 Hz, 3H), 0.88 (s, 9H), 0.02 (d, J = 26 Hz, 2x3H).[0284] (c) 2-(5-(l-((tert-butyldimethylsilyl)oxy)ethyl)pyridin-2-yl)ethan-l-ol (4)[0285] The ethylene oxide solution in diethylether was prepared in advance. Diethylether(1.2 L) in a 3 L three-necked flask was cooled at -65 °C and ethylene oxide (462.3 g, 10.5 mol, 1.06 eq) (Linde) was added and stirred at -70°C. Alternatively, the ethylene oxide solution can be made at about -20°C and then added gradually to the reaction mixture having a temperature at about -60°C. [0286] To a solution of 2-bromo-5-(l-((ieri-butyldimethylsilyl)oxy)ethyl)pyridine (3) (3.13 kg, 9.90 mol, 1.0 eq) in diethylether (7.5 L) cooled at -59°C, n-butyllithium (4 L, 10.0 mol, 2.5M in hexanes, 1.01 eq) (Aldrich Chemistry) was added while keeping temperature between -58°C and -62°C. After addition, the mixture was stirred for 1 h while keeping temperature between -60°C and -68°C. The upfront prepared ethylene oxide solution was added at once to the reaction mixture, while temperature was around -62°C. Subsequently, copper(I) iodide (962.3 g, 5.05 mol, 0.51 eq) (Acros Organics) was added in portions of 120 g, every 10 min, keeping the temperature between -61°C and -63°C. Stirring was continued for 1 h after addition keeping temperature between -61°C and -63°C. The cooling bath was removed and allowing the temperature to rise to about 15°C and further to 25 °C with a water bath overnight.[0287] Workup: The reaction-mixture was poured into a solution of 1 kg ammonium- chloride in 5 L water and stirred for 30 min, then the layers were separated. The organic layer was washed with aqueous ammonium hydroxide (10%, 2.5 L, 4x) to remove Cu-complex (blue color disappeared). The combined organic layers were dried over sodium sulfate and evaporated to give 3.12 kg (max. 9.90 mol) crude compound 4 as a brown oil. The crude compound was purified over 20 kg silica (heptane/EtOAc) by eluting with 80 L heptane/EtOAc, 20 L EtOAc, 25 L EtOAc/MeOH 95/5, 25 L EtOAc/MeOH 9/1 and 10 L EtOAc/MeOH 8/2, to give 1.47 kg of purified compound 4 (5.22 mol) as a brown oil (with tendency to solidify) in a 52.7% average molar yield (HPLC-purity of 99.5%). (Average yield over 12 experiments 52%). HPLC-MS: Rt= 2.3 min, M+l=282.1; 1H NMR (300 MHz, CDC13): δ 8.42 (d, J = 2.1 Hz, 1H), 7.61 (dd, J = 8.3, 2.1 Hz, 1H), 7.11 (d, J = 8.3 Hz, 1H), 4,88 (q, J = 7.0 Hz, 1H), 4.01 (t, J=6.0 Hz, 2 H), 3.00 (t, J=6.0 Hz, 2 H), 1.41 (d, J =7.0 Hz, 3H), 0.90 (s, 9H), 0.02 (d, J = 26 Hz, 2x3H).[0288] Another 2.5% of the product was isolated by re -purifying impure product fraction.The total yield of compound 4 from compound 1 was 39.6% molar.EXAMPLE 3Synthesis of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]- 2,4-thiazolidinedione hydrochloride (9) 2. Sodium bisulfiteethanol/water mixture
step h[0289] The 1H-NMR spectra were recorded with a 400 MHz Avance Bruker NMR spectrometer. LC-MS data were obtained on a Agilent Technologies 6130 Quadrapole LC/MS using as column Agilent XDB-C18 and as eluent 0.1% formic acid (aq) and 0.05% formic acid in acetonitrile.[0290] Steps d and e: Synthesis of 4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2- pyridinyl] ethoxy] -benzaldehyde (6)[0291] To a well stirred solution of 5-[[[(l,l-dimethylethyl)dimethylsilyl]-oxy]ethyl]-2- pyridineethanol (4) (obtained as described in Example 2) (1.91 kg) in toluene (8.6 L) at 5°C were added sodium hydroxide (30% aqueous, 2.79 L) and tetrabutylammonium bromide (7.2 g). p-Toluenesulfonyl chloride (1.62 kg) was next added in portions during 5 min. After the addition, the reaction mixture was allowed to reach room temperature in 0.5 h and stirred at this temperature for 18 h. Water (7.3 L) was then added and the mixture was mixed well. Once the solids were dissolved, the layers were allowed to settle and the organic layer was separated. This organic phase was washed with water (5.7 L, 2x), followed by washing with a solution of sodium chloride (57 g) in water (5.7 L). The solvents were concentrated at reduced pressure to an amount of 2.5 kg of a brown oil (compound 5).[0292] To this well stirred brown oil were added subsequently ethanol (7.8 L), water (0.86L), 4-hydroxybenzaldehyde (0.88 kg) and potassium carbonate (1.17 kg) and then the mixture was heated at 75 °C for 18 h. Then, the solvent was evaporated while adding toluene (7.7 L) during 6 h and then the reaction mixture was allowed to cool. At 30°C, water (7.6 L) was added, stirred until all solids were dissolved and the mixture was cooled to room temperature. The layers were allowed to settle and separated. The organic layer was washed with water (7.6 L). The first aqueous extract was extracted with toluene (2.8 L) and this organic extract was used to also extract the aqueous washing. The organic extracts were combined and concentrated under vacuum to give 3.49 kg of a black oil (crude title compound 6).[0293] 1.73 kg of this black oil was dissolved in ethanol (0.74 L) and added to a well stirred solution of sodium bisulfite (1.36 kg) in a mixture of water (3.27 L) and ethanol (0.74 L). The container of the black oil was rinsed with ethanol (0.37 L) twice and these two rinses were also added to the bisulfite reaction mixture. After 75 min, heptane (5.3 L) was added, well mixed for 5 min, and the layers were allowed to settle and separated. To the organic layer was added a solution of sodium bisulfite (0.55 kg) in water (2.65 L), and ethanol (1.06 L). After stirring for 30 min, the layers were allowed to settle and separated. The two bisulfide aqueous extracts were combined and flasks rinsed with water (2.12 L). Next, toluene (4.5 L) and heptane (4.5 L) were added, the mixture was well stirred and the pH was adjusted to 12 using sodium hydroxide (10% aq) (temperature became 32°C). After stirring for an additional 5 min, the layers were allowed to settle and separated at 30°C. The aqueous layer was extracted with a mixture of toluene (1.5 L) and heptane (3.0 L). The layers were separated and the organic layers were combined. The combined organic layers were washed with water (5 L, 2x) and concentrated under vacuum to give the purified title compound 6. This procedure was repeated with another 1.73 kg of the black oil (crude title compound 6) to give in total 2.77 kg of 4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2- pyridinyl]ethoxy]-benzaldehyde (6) as brown oil which contained 24% m/m of toluene according to 1H NMR (yield = 80%, calculated from compound 4 and corrected for residual toluene). [0294] 1H NMR (CDC13) δ: 0.00 (s, 3H), 0.09 (s, 3H), 0.91 (s, 9H), 1.44 (d, = 6 Hz, 3H),3.30 (t, = 7 Hz, 2H), 4.47 (t, = 7 Hz, 2H), 4.92 (q, = 6 Hz, 1H), 6.99 – 7.30 (m, 3H), 7.62- 7.67 (m, 1H), 7.80 – 7.85 (m, 2H), 8.5- 8.54 (m, 1H) and 9.88 (s, 1H).[0295] LC-MS; rt 7.5 min: ES: M+ 387, 386.[0296] Step f: Synthesis of (5Z)-5-[[4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione (7)[0297] A solution of 4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]- ethoxy]-benzaldehyde (6) (2.75 kg, containing 24% m/m of toluene) and piperidine (6.0 g) in methanol (3.16 L) was concentrated at 40°C under reduced pressure. The residue was dissolved in methanol (10.4 L) and 2,4-thiazolidinedione (759 g) and piperidine (230 g) were added. The mixture was heated at 47°C. After 25 h, the reaction mixture was allowed to cool to room temperature. The mixture was kept at pH 5-6 by adjusting it with acetic acid, if necessary. After a night at room temperature, water (1.56 L) was added and the suspension was stirred at room temperature for additional 2 h. The solids were isolated by filtration, washed with methanol (1 L, 2x) and dried under vacuum to give crude compound 7 (1.65 kg). The crude compound was mixed with methanol (10 L) and dichloromethane (8.6 L) and heated at 32°C until all solids dissolved. Then, the solvents were removed by distillation until the temperature of the mixture reached 34°C at a pressure of 333 mbar. Then, it was allowed to cool to room temperature overnight and stirred at 2°C for additional 2 h. The solids were isolated by filtration, washed with methanol (0.5 L, 2x) and dried under vacuum to give title compound 7 (1.50 kg) (yield = 61%).[0298] 1H NMR (CDCI3) δ 0.00 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.43 (d, = 6 Hz, 3H),3.32 (t, = 7 Hz, 2H), 4.48 (t, = 7 Hz, 2H), 4.92 (q, = 6 Hz, 1H), 6.95 – 7.00 (m, 2H), 7.24 – 7,28 (m, 1H), 7.38 – 7.42 (m, 2H), 7.67 (s, 1H), 7.69 – 7.73 (m, 1H) and 8.48 (d, = 3 Hz, 1H).[0299] LC-MS; rt 7.5 min: ES: M+ 487, 486, 485.[0300] Step g: Synthesis of 5-[[4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]ethyl]-2- pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione (8)[0301] To a stirred suspension of (5Z)-5-[[4-[2-[5-[[[(l,l-dimethylethyl)dimethylsilyl]oxy]- ethyl]-2-pyridinyl]ethoxy]phenyl]methylene]-2,4-thiazolidinedione (7) (10 g) in THF (10 mL) and sodium hydroxide (IN aq, 21 mL) was added of a solution of cobalt chloride (26 mg) and of dimethylglyoxime (930 mg) in THF (2.3 mL) and water (1.0 mL). Then the suspension was put under a nitrogen atmosphere by applying the sequence of vacuum and flushing with nitrogen (4x). Thereafter, the suspension was heated to 30°C. Then, a stock solution of sodium borohydride was prepared by dissolving sodium borohydride (2.7 g) in a mixture of water (15.8 mL) and a solution of sodium hydroxide (1 N aq, 3.5 mL), which was put under a nitrogen atmosphere by applying a sequence of vacuum and flushing with nitrogen (3x). This was added to the suspension of compound 7 at a rate of 4.5 mL/h. Simultaneously, nitrogen gas-saturated acetic acid was added to the suspension at a rate of 0.7 mL/h to maintain a pH of 10.0-10.5. After 1 h 30 min the rate of addition of the sodium borohydride solution and acetic acid were both reduced by half. Next, 3 h 45 min after start of addition, the addition of sodium borohydride and acetic acid were stopped. The mixture was allowed to cool down to room temperature and acetone (2.5 mL) was added over a period of 1 minute. After stirring the reaction mixture for 15 min acetic acid was added until the pH was 5.5-6.0 (about 3 mL required). Next, a mixture of ethyl acetate/toluene (1/3 v/v, 30 mL) was added, well mixed and layers were allowed to settle. The aqueous layer was separated and washed with ethyl acetate/toluene (1/3 v/v, 10 mL). Both organic extracts were pooled and water (40 mL) was added, well mixed and layers were allowed to settle. The pH of the aqueous layer was adjusted to 5.5-6 using saturated sodium hydrogen carbonate solution (aq) and again mixed with the organic layer. Layers were allowed to settle and the organic layer was separated and concentrated under vacuum to give 11.09 g of yellow oil (crude mixture containing title compound 8 and its borane complex). Several batches were combined for work up.33.1 g of the crude mixture containing title compound 8 and its borane complex (not corrected for residual solvents) was dissolved in toluene (30 mL) and filtered. The filtrate was submitted to column chromatography (silica gel, gradient of toluene to toluene/ethyl acetate 1/1) to give 30.0 g of mixture of 5-[[4-[2-[5-[[[(l,l- dimethylethyl)dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione (8) and its borane complex as a slightly yellow oil (yield = 100% from compound 4, not corrected for residual solvents). [0303] 1H NMR (CDC13) δ: -0.03 – 0.10 (m, 6H), 0.87 – 0.93 (m, 9H), 1.42 (d, / = 6 Hz, 3H),3.05-3.71 (m, 4H), 4.30 – 4.51 (m, 3H), 4.87 – 4.94 (m, 1H), 6.82 – 6.88 (m, 2H), 7.10-7.92 (m, 5H), 8.49 (d, / = 3 Hz, 0.6H) and 8.72 (brs, 0.4H).[0304] LC-MS; rt 6.8 min: ES: M+ 489, 488, 487, M“ 487, 486, 485; rt 8.1 min: ES M“ 501,500, 499, 498, 485.[0305] Step h: Synthesis of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]- methyl]-2,4-thiazolidinedione hydrochloride (9)[0306] To a stirred solution of the mixture of (5-[[4-[2-[5-[[[(l,l-dimethylethyl)- dimethylsilyl]oxy]ethyl]-2-pyridinyl]ethoxy]phenyl]methyl]-2,4-thiazolidinedione and its borane complex (8) (5.17 g) in methanol (25.2 mL) at 22°C was added hydrochloric acid (30%, 2.75 mL) in about 5 min to give a temperature rise to 28°C. This solution was heated to 40 °C. Three hours after addition, the 11 g of volatiles were removed under reduced pressure. Then, acetonitrile (40.3 mL) was added and the mixture was heated at reflux for 0.5 h. Next, the suspension was allowed to cool down to room temperature and stirred for 1 h at room temperature. Solids were isolated by filtration, washed with a mixture of acetonitrile/water (20/1 v/v, 10 mL) and with acetonitrile (10 mL) and dried under vacuum at 40 °C to give 4.00 g of white solids (crude 9) (yield = 77%, not corrected for residual solvents).[0307] Purification of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]methyl]-2,4- thiazolidinedione hydrochloride (9):[0308] The crude mixture of 5-[[4-[2-[5-(l-hydroxyethyl)-2-pyridinyl]ethoxy]phenyl]- methyl]-2,4-thiazolidinedione hydrochloride (3.95 g, crude 9) was dissolved in methanol/water (7/2 v/v, 80 mL) by heating it to 49°C. To this solution was added washed norit (obtained by heating a suspension of norit (6 g) in methanol/water (7/2 v/v, 90 mL) at 45°C for 1 h, then isolating the norit by filtration and washing it twice with methanol/water (7/2 v/v, 30 mL) and drying it under vacuum at 40°C). Equipment was rinsed with methanol/water (7/2 v/v, 18 mL). After 0.5 h of stirring at 46°C, the warm suspension was filtered to remove the norit and filter was washed twice with methanol/water (7/2 v/v, 18 mL). The filtrate was concentrated under vacuum at a bath temperature of 60°C to a mass of 11.8 g (1 v of compound and 2 v of water). To the suspension was added butanone (19.7 mL, 5 v) and the mixture was heated at a bath temperature of 95°C. Under distillation at a constant volume, butanone (95 mL) was added. Next, heating was stopped and the suspension was allowed to reach room temperature in about 0.5 h. Subsequently it was stirred for 0.75 h at room temperature. The solids were isolated by filtration, washed with a mixture of butanone/water (95/5 v/v, 18 mL) and butanone (18 mL) and dried under vacuum at 40°C to give 3.57 g of compound 9 as white solids (yield = 91%).[0309] 1H NMR (DMSO-de): δ 12.00 (br s, -NH), 8.71 (d, = 2.0 Hz, 1H), 8.45 (dd, = 8.3,1.7 Hz, 1H), 7.98 (d, = 8.3 Hz, 1H), 7.15 (d, = 8.7 Hz, 2H), 6.88 (d, = 8.7 Hz, 2H), 5.57 (s, OH), 4.95 (q, = 6.5 Hz, 1H), 4.86 (dd, = 8.9, 4.4 Hz, 1H), 4.40 (t, = 6.3 Hz, 2H), 3.49 (t, = 6.2 Hz, 2H), 3.29 (dd, = 14.2, 4.4 Hz, 1H), 3.06 (dd, = 14.2, 9.0 Hz, 1H), 1.41 (d, = 6.5 Hz, 3H).[0310] LC-MS; rt 3.5 min: ES: M+ 374, 373, M“ 372, 371.EXAMPLE 4Conditions tested in the preparation of compound 5 in the Step d[0311] The conditions described in Table 2 below were tested in the step d in the preparation of compound 5 from compound 4 providing a good yield of compound 5:Table 2Entry Reaction Conditions Amount of p-Ts-Cl / Eq1 Toluene/water/Bu4NBr/NaOH 1.052 1.083 1.074 1.07+0.035 1.076 Et3N / DCM 1.187 1.408 Pyridine / DCM 1.40 EXAMPLE 5Conditions tested in the preparation of compound 6 in the Step e[0312] The conditions described in Table 3 below were tested in the step e in the preparation of compound 6 from compound 5 providing a good yield of compound 6:Table 3
Compound 1 is administered to the subject. The structure of 5-[[4-[2-[5-(l -hydroxy ethyljpyri din-2 – yl]ethoxy]phenyl]methyl]-l,3-thiazolidine-2,4-dione is:
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[0047] The present disclosure encompasses the use of stereoisomers of 5-[[4-[2-[5-(l- hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-l,3-thiazolidine-2,4-dione. 5-[[4-[2-[5- (l-hydroxyethyl)pyridin-2-yl]ethoxy]phenyl]methyl]-l,3-thiazolidine-2,4-dione has two asymmetric centers and thus four stereoisomers are possible as follows:
RP-12146 is an oral poly (ADP-ribose) polymerase (PARP) inhibitor in phase I clinical development at Rhizen Pharmaceuticals for the treatment of adult patients with locally advanced or metastatic solid tumors.
Solid TumorExtensive-stage Small-cell Lung CancerLocally Advanced Breast CancerMetastatic Breast CancerPlatinum-sensitive Ovarian CancerPlatinum-Sensitive Fallopian Tube CarcinomaPlatinum-Sensitive Peritoneal Cancer
Poly(ADP-ribose) polymerase (PARP) defines a family of 17 enzymes that cleaves NAD+ to nicotinamide and ADP-ribose to form long and branched (ADP-ribose) polymers on glutamic acid residues of a number of target proteins, including PARP itself. The addition of negatively charged polymers profoundly alters the properties and functions of the acceptor proteins. Poly(ADP-ribosyl)ation is involved in the regulation of many cellular processes, such as DNA repair, gene transcription, cell cycle progression, cell death, chromatin functions and genomic stability. These functions have been mainly attributed to PARP-1 that is regarded as the best characterized member of the PARP family. However, the identification of novel genes encoding PARPs, together with the characterization of their structure and subcellular localization, have disclosed different roles for poly(ADP-ribosyl)ation in cells, including telomere replication and cellular transport.
Recently, poly(ADP-ribose) binding sites have been identified in many DNA damage checkpoint proteins, such as tumor suppressor p53, cyclin-dependent kinase inhibitor p21Cip1/waf1, DNA damage recognition factors (i.e., the nucleotide excision repair xeroderma pigmentosum group A complementing protein and the mismatch repair protein MSH6), base excision repair (BER) proteins (i.e. DNA ligase III, X-ray repair cross-complementing 1, and XRCC1), DNA-dependent protein kinase (DNA-PK), cell death and survival regulators (i.e.,
NF-kB, inducible nitric oxide synthase, and telomerase). These findings suggest that the different components of the PARP family might be involved in the DNA damage signal network, thus regulating protein-protein and protein-DNA interactions and, consequently, different types of cellular responses to genotoxic stress. In addition to its involvement in BER and single strand breaks (SSB) repair, PARP-1 appears to aid in the non-homologous end-joining (NHEJ) and homologous recombination (HR) pathways of double strand breaks (DSB) repair. See Lucio Tentori et al., Pharmacological Research, Vol. 45, No. 2, 2002, page 73-85.
PARP inhibition might be a useful therapeutic strategy not only for the treatment of BRCA mutations but also for the treatment of a wider range of tumors bearing a variety of deficiencies in the HR pathway. Further, the existing clinical data (e.g., Csaba Szabo et al., British Journal of Pharmacology (2018) 175: 192-222) also indicate that stroke, traumatic brain injury, circulatory shock and acute myocardial infarction are some of the indications where PARP activation has been demonstrated to contribute to tissue necrosis and inflammatory responses.
As of now, four PARP inhibitors, namely olaparib, talazoparib, niraparib, and rucaparib have been approved for human use by regulatory authorities around the world.
Patent literature related to PARP inhibitors includes International Publication Nos. WO 2000/42040, WO 2001/016136, WO 2002/036576, WO 2002/090334, WO2003/093261, WO 2003/106430, WO 2004/080976, WO 2004/087713, WO 2005/012305, WO 2005/012524, WO 2005/012305, WO 2005/012524, WO 2005/053662, W02006/033003, W02006/033007, WO 2006/033006, WO 2006/021801, WO 2006/067472, WO 2007/144637, WO 2007/144639, WO 2007/144652, WO 2008/047082, WO 2008/114114, WO 2009/050469, WO 2011/098971, WO 2015/108986, WO 2016/028689, WO 2016/165650, WO 2017/153958, WO 2017/191562, WO 2017/123156, WO 2017/140283, WO 2018/197463, WO 2018/038680 and WO 2018/108152, each of which is incorporated herein by reference in its entirety for all purposes.
There still remains an unmet need for new PARP inhibitors for the treatment of various diseases and disorders associated with cell proliferation, such as cancer.
Abstract 1233: Preclinical profile of RP12146, a novel, selective, and potent small molecule inhibitor of PARP1/2
Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Debnath Bhuniya, Gayatriswaroop Merikapudi, Sridhar Veeraraghavan and Swaroop VakkalankaProceedings: AACR Annual Meeting 2021; April 10-15, 2021 and May 17-21, 2021; Philadelphia, PA
Abstract
Background: Poly (ADP-ribose) polymerase (PARP) activity involves synthesis of Poly-ADP ribose (PAR) polymers that recruit host DNA repair proteins leading to correction of DNA damage and maintenance of cell viability. Upon combining with DNA damaging cytotoxic agents, PARP inhibitors have been reported to demonstrate chemo- and radio-potentiation albeit with incidences of myelosuppression. A need therefore exists for the development selective PARP1/2 inhibitors with a high therapeutic window to fully exploit their potential as a single agent or in combination with established therapy across various tumor types. Additionally, with the emerging concept of ‘synthetic lethality’, the applicability PARP inhibitors can be expanded to cancers beyond the well-defined BRCA defects. Herein, we describe the preclinical profile of RP12146, a novel and selective small molecule inhibitor of PARP1 and PARP2.
Methods: Enzymatic potency was evaluated using a PARP Chemiluminescent Activity Assay Kit (BPS biosciences). Cell growth was determined following incubation with RP12146 in BRCA1 mutant and wild-type cell lines across indications. Apoptosis was evaluated following incubation of cell lines with compound for 120 h, subsequent staining with Annexin-V-PE and 7-AAD, and analysis by flow cytometry. For cell cycle, cells were incubated with compound for 72 h, and stained with Propidium Iodide prior to analysis by flow cytometry. Expression of downstream PAR, PARP-trapping, phospho-γH2AX and cleaved PARP expression were determined in UWB1.289 (BRCA1 null) cells by Western blotting. Anti-tumor potential of RP12146 was tested in OVCAR-3 Xenograft model. Pharmacokinetic properties of the molecule were also evaluated. Results: RP12146 demonstrated equipotent inhibition of PARP1 (0.6 nM) and PARP2 (0.5 nM) with several fold selectivity over the other members of the PARP family. Compound caused a dose-dependent growth inhibition of both BRCA mutant and non-mutant cancer cell lines with GI50 in the range of 0.04 µM to 9.6 µM. Incubation of UWB1.289 cells with RP12146 caused a G2/M arrest with a corresponding dose-dependent increase in the percent of apoptotic cells. Expression of PAR was inhibited by 86% at 10 nM with a 2.3-fold increase in PARP-trapping observed at 100 nM in presence of RP12146. A four-fold increase in phospho-γH2AX and > 2-fold increase in cleaved PARP expression was observed at 3 µM of the compound. RP12146 exhibited anti-tumor potential with TGI of 28% as a single agent in OVCAR-3 xenograft model. Efficay was superior compared to Olaparib tested at an equivalent dose. Pharmacokinetic studies in rodents indicated high bioavailability with favorable plasma concentrations relevant for efficacy
Conclusions: Data demonstrate the therapeutic potential of RP12146 in BRCA mutant tumors. Testing in patients is planned in H1 2021.
Citation Format: Srikant Viswanadha, Satyanarayana Eleswarapu, Kondababu Rasamsetti, Debnath Bhuniya, Gayatriswaroop Merikapudi, Sridhar Veeraraghavan, Swaroop Vakkalanka. Preclinical profile of RP12146, a novel, selective, and potent small molecule inhibitor of PARP1/2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1233.
Rhizen Pharmaceuticals AG Announces First Patient Dosing in a Phase I/Ib Study of Its Novel PARP Inhibitor (RP12146) in Patients With Advanced Solid Tumors
RHIZEN’S PARP INHIBITOR EFFORTS ARE PART OF A LARGER DDR PLATFORM THAT ALSO INCLUDES AN EARLY STAGE POLθ-DIRECTED PROGRAM; PLATFORM ENABLES PROPRIETARY IN-HOUSE COMBINATIONS
Rhizen Pharma commences dosing in a phase I/Ib trial to evaluate its novel PARP inhibitor (RP12146) in patients with advanced cancers.
Rhizen indicated that RP12146 has comparable preclinical activity vis-à-vis approved PARP inhibitors and shows improved preclinical safety that it expects will translate in the clinic.
The two-part multi-center phase I/Ib study is being conducted in Europe and is designed to initially determine safety, tolerability and MTD/RP2D of RP12146 and to subsequently assess its anti-tumor activity in expansion cohorts with HRR mutation-enriched ES-SCLC, ovarian and breast cancer patients.
RP12146 is part of a larger DDR platform at Rhizen that includes a preclinical-stage Polθ inhibitor program; the DDR platform enables novel, proprietary, in-house combinations
November 01, 2021 07:24 AM Eastern Daylight Time
BASEL, Switzerland–(BUSINESS WIRE)–Rhizen Pharmaceuticals AG (Rhizen), a Switzerland-based privately held, clinical-stage oncology & inflammation-focused biopharmaceutical company, announced today that it has commenced dosing in a multi-center, phase I/Ib trial to evaluate its novel poly (ADP-ribose) polymerase (PARP) inhibitor (RP12146) in patients with advanced solid tumors. This two-part multi-center phase I/Ib study is being conducted in Europe and has been designed to initially determine safety, tolerability, maximum tolerated dose (MTD), and/or recommended phase II dose (RP2D) of RP12146 and to subsequently assess its anti-tumor activity in expansion cohorts with HRR mutation-enriched ES-SCLC, ovarian and breast cancer patients.
“Our PARP program is foundational for our DDR platform efforts and will be the backbone for several novel proprietary combinations that we hope to bring into development going forward.”
Rhizen indicated that RP12146 has shown preclinical activity and efficacy comparable to the approved PARP inhibitor Olaparib, and shows improved safety as seen in the preclinical IND-enabling toxicology studies; an advantage that Rhizen hopes will translate in the clinical studies. Rhizen also announced that its PARP program is part of a larger DNA Damage Response (DDR) platform effort, which includes a preclinical-stage polymerase theta (Polθ) inhibitor program. Rhizen expects the platform to enable novel proprietary combinations of its PARP and Polθ assets given the mechanistic synergy and opportunity across PARP resistant/refractory settings.
“PARP inhibitors are a great success story in the DNA damage response area, but they are not without safety concerns that have limited realization of their full potential. Although our novel PARP inhibitor is competing in a crowded space, we expect its superior preclinical safety to translate into the clinic which will differentiate our program and allow us to extend its application beyond the current landscape of approved indications and combinations”, said Swaroop Vakkalanka, Founder & CEO of Rhizen Pharma. Swaroop also added that “Our PARP program is foundational for our DDR platform efforts and will be the backbone for several novel proprietary combinations that we hope to bring into development going forward.”
About Rhizen Pharmaceuticals AG.:
Rhizen Pharmaceuticals is an innovative, clinical-stage biopharmaceutical company focused on the discovery and development of novel oncology & inflammation therapeutics. Since its establishment in 2008, Rhizen has created a diverse pipeline of proprietary drug candidates targeting several cancers and immune associated cellular pathways.
Rhizen has proven expertise in the PI3K modulator space with the discovery of our first PI3Kδ & CK1ε asset Umbralisib, that has been successfully developed & commercialized in MZL & FL by our licensing partner TG Therapeutics (TGTX) in USA. Beyond this, Rhizen has a deep oncology & inflammation pipeline spanning discovery to phase II clinical development stages.
Rhizen is headquartered in Basel, Switzerland.
REF
Safety, Pharmacokinetics and Anti-tumor Activity of RP12146, a PARP Inhibitor, in Patients With Locally Advanced or Metastatic Solid Tumors….https://clinicaltrials.gov/ct2/show/NCT05002868
Susanta Samajdar, Ph.D., Director, Medicinal Chemistry, Aurigene Discovery Technologies Limited
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