BRD2879

BRD-K56962879-001-01-5
CAS 1304750-47-7
Chemical Formula: C30H38FN3O5S
Molecular Weight: 571.7084

3-cyclohexyl-1-(((4R,5R)-8-((3-fluorophenyl)ethynyl)-2-((S)-1-hydroxypropan-2-yl)-4-methyl-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4,5]oxathiazocin-5-yl)methyl)-1-methylurea

3-cyclohexyl-1-[[(4R,5R)-8-[2-(3-fluorophenyl)ethynyl]-2-[(2S)-1-hydroxypropan-2-yl]-4-methyl-1,1-dioxo-4,5-dihydro-3H-6,1$l^{6},2-benzoxathiazocin-5-yl]methyl]-1-methylurea

BRD2879 is a potent and cell-active inhibitor of IDH1-R132H with a markedly different structure from previously reported probes with (IC50 = 50 nM for inhibiting IDH1-R132H enzyme). BRD2879 represents a new structural class of mutant IDH1 inhibitors that, with optimization, may prove useful in the study of this enzyme and its role in cancer

The Eli and Edythe L. Broad Institute of MIT and Harvard (/ˈbroʊd/), often referred to as the Broad Institute, is a biomedical and genomic research center located in Cambridge, Massachusetts, United States. The institute is independently governed and supported as a 501(c)(3) nonprofit research organization under the name Broad Institute Inc.,^[1][2] and is partners with Massachusetts Institute of Technology, Harvard University, and the five Harvard teaching hospitals.

Mahmud M. Hussain

PAPER

Evidence suggests that specific mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2) are critical for the initiation and maintenance of certain tumor types and that inhibiting these mutant enzymes with small molecules may be therapeutically beneficial. In order to discover mutant allele-selective IDH1 inhibitors with chemical features distinct from existing probes, we screened a collection of small molecules derived from diversity-oriented synthesis. The assay identified compounds that inhibit the IDH1-R132H mutant allele commonly found in glioma. Here, we report the discovery of a potent (IC₅₀ = 50 nM) series of IDH1-R132H inhibitors having 8-membered ring sulfonamides as exemplified by the compound BRD2879. The inhibitors suppress (R)-2-hydroxyglutarate production in cells without apparent toxicity. Although the solubility and pharmacokinetic properties of the specific inhibitor BRD2879 prevent its use in vivo, the scaffold presents a validated starting point for the synthesis of future IDH1-R132H inhibitors having improved pharmacological properties.

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1

People

Stuart L. Schreiber

David Liu

CLICK ON IMAGES

1H NMR (300 MHz, CDCl3, 27 °C) δ 7.88 (d, J = 8.3 Hz, 1H), 7.39-7.27 (m, 3H), 7.22-7.14 (m, 2H), 7.12-7.03 (m, 1H), 4.57 (td, J = 9.5, 2.5 Hz, 1H), 4.35-4.23 (m, 2H), 3.97-3.78 (m, 2H), 3.74-3.60 (m, 2H), 3.51 (ddd, J = 12.3, 9.9, 4.0 Hz, 1H), 3.40 (dd, J = 15.8, 5.1 Hz, 1H), 3.18 (dd, J = 9.9, 2.9 Hz, 1H), 3.12 (dd, J = 14.4, 2.6 Hz, 1H), 2.66 (s, 3H), 2.30-2.16 (m, 1H), 2.06 (d, J = 12.2 Hz, 1H), 1.96 (d, J = 12.1 Hz, 1H), 1.69-1.58 (m,1H), 1.58-1.45 (m, 2H), 1.23 (d, J = 6.8 Hz, 3H), 1.40-0.97 (m, 5H), 0.94 (d, J = 7.0 Hz, 3H).

13C NMR (75 MHz, CDCl3, 27 °C) δ 164.20, 160.92, 157.74, 154.80, 134.60, 130.26, 130.15, 129.56, 128.62, 127.82, 127.77, 127.68, 126.90, 124.27, 118.81, 118.50, 116.63, 116.35, 91.32, 88.40, 85.60, 64.86, 58.03, 51.64, 49.88, 48.51, 36.73, 34.51, 34.35, 34.31, 25.72, 25.28, 25.23, 15.76, 15.05.

HRMS (ESI) calc’d for C30H38FN3O5S [M+H]+ : 572.2589. Found: 572.2588.

1H NMR PREDICT

13C NMR PREDICT

REFERENCES

Discovery of 8-Membered Ring Sulfonamides as Inhibitors of Oncogenic Mutant Isocitrate Dehydrogenase 1
Jason M. Law, Sebastian C. Stark, Ke Liu, Norah E. Liang, Mahmud M. Hussain, Matthias Leiendecker, Daisuke Ito, Oscar Verho, Andrew M. Stern, Stephen E. Johnston, Yan-Ling Zhang, Gavin P. Dunn, Alykhan F. Shamji, and Stuart L. Schreiber
Publication Date (Web): August 18, 2016 (Letter)
DOI: 10.1021/acsmedchemlett.6b00264

FC1=CC(C#CC2=CC(O[C@@H](CN(C(NC3CCCCC3)=O)C)[C@H](C)CN([C@@H](C)CO)S4(=O)=O)=C4C=C2)=CC=C1

PF-06273340

N-(5-(2-amino-7-(1-hydroxy-2-methylpropan-2-yl)-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)pyridin-3-yl)-2-(5-chloropyridin-2-yl)acetamide

CAS 1402438-74-7
Chemical Formula: C23H22ClN7O3
Molecular Weight: 479.925

• Originator Pfizer
• ClassAnalgesics; Small molecules
• Mechanism of ActionUndefined mechanism

• 06 Oct 2014 Pfizer plans a phase I trial in Pain (In volunteers) in the Netherlands (NCT02260947)
• 07 Aug 2014 Discontinued – Phase-I for Pain (In volunteers) in Belgium (PO)
• 07 Aug 2014 Discontinued – Phase-I for Pain (In volunteers) in Singapore (PO)

PF-06273340 is a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor with an excellent LipE profile (IC50 value: Trk-A = 6 nM; Trk-B = 4 nM; Trk-C = 3 nM). PF-06273340 has low metabolic turnover in HLM and hHep is a good substrate for efflux transporters P-gp (ER = 35.7) and BCRP (ER = 4.0) and has moderate passive permeability (RRCK Papp = 5.4 × 10−6 cm s−1). PF-06273340 is well-tolerated was selected as a candidate for clinical development.

Tropomyosin-related kinases (Trks) are a family of receptor tyrosine kinases activated by neurotrophins. Trks play important roles in pain sensation as well as tumour cell growth and survival signaling. Thus, inhibitors of Trk receptor kinases might provide targeted treatments for conditions such as pain and cancer. Recent developments in this field have been reviewed by Wang et al in Expert Opin. Ther.

Patents (2009) 19(3): 305-319 and an extract is reproduced below.

“1.1 Trk receptors

As one of the largest family of proteins encoded by the human genome, protein kinases are the central regulators of signal transduction as well as control of various complex cell processes. Receptor tyrosine kinases (RTKs) are a subfamily of protein kinases (up to 100 members) bound to the cell membrane that specifically act on the tyrosine residues of proteins. One small group within this subfamily is the Trk kinases, with three highly homologous isoforms: TrkA, TrkB, and TrkC. All three isofonns are activated by high affinity growth factors named neurotrophins (NT): i) nerve growth factor (NGF), which activates TrkA; ii) brain-derived neurotrophic factor (BDNF) and NT-4/5, which activate TrkB; and iii) NT-3, which activates TrkC. The binding of neurotrophins to the extracellular domain of Trks causes the Trk kinase to autophosphorylate at several intracellular tyrosine sites and triggers downstream signal transduction pathways. Trks and neurotrophins are well known for their effects on neuronal growth and survival.

1.2 Trks and cancer

Originally isolated from neuronal tissues, Trks were thought to mainly affect the maintenance and survival of neuronal cells. However, in the past 20 years, increasing evidence has suggested that Trks play key roles in malignant transformation, chemotaxis, metastasis, and survival signaling in human tumors. The association between Trks and cancer focused on prostate cancer in earlier years and the topic has been reviewed. For example, it was reported that malignant prostate epithelial cells secrete a series of neurotrophins and at least one Trks. In pancreatic cancer, it was proposed that paracrine and/or autocrine neurotrophin-Trk interactions may influence the invasive behavior of the cancer. TrkB was also reported to be overexpressed in metastatic human pancreatic cancer cells. Recently, there have been a number of new findings in other cancer settings. For example, a translocation leads to expression of a fusion protein derived from the W-terminus of the ETV9 transcription factor and the C-terminal kinase domain of TrkC. The resulting ETV6-TrkC fusions are oncogenic in vitro and appear causative in secretory breast carcinoma and some acute myelogenous leukemias (AML). Constitutively active TrkA fusions occurred in a subset of papillary thyroid cancers and colon carcinomas. In neuroblastoma, TrkB expression was reported to be a strong predictor of aggressive tumor growth and poor prognosis, and TrkB overexpression was also associated with increased resistance to chemotherapy in neuroblastoma tumor cells in vitro. One report showed that a novel splice variant of TrkA called TrkAIII signaled in the absence of neurotrophins through the inositol phosphate-AKT pathway in a subset of neuroblastoma. Also, mutational analysis of the tyrosine kinome revealed that Trk mutations occurred in colorectal and lung cancers. In summary, Trks have been linked to a variety of human cancers, and discovering a Trk inhibitor and testing it clinically might provide further insight to the biological and medical hypothesis of treating cancer with targeted therapies.

1.3 Trks and pain

Besides the newly developed association with cancer, Trks are also being recognized as an important mediator of pain sensation. Congenital insensitivity to pain with anhidrosis (CIPA) is a disorder of the peripheral nerves (and normally innervated sweat glands) that prevents the patient from either being able to adequately perceive painful stimuli or to sweat. TrkA defects have been shown to cause CIPA in various ethnic groups.

Currently, non-steroidal anti-inflammatory drugs (NSAIDs) and opiates have low efficacy and/or side effects (e.g., gastrointestinal/renal and psychotropic side effects, respectively) against neuropathic pain and therefore development of novel pain treatments is highly desired. It has been recognized that NGF levels are elevated in response to chronic pain, injury and inflammation and the administration of exogenous NGF increases pain hypersensitivity. In addition, inhibition of NGF function with either anti- NGF antibodies or non-selective small molecule Trk inhibitors has been shown to have effects on pain in animal models. It appears that a selective Trk inhibitor (inhibiting at least NGF’s target, the TrkA receptor) might provide clinical benefit for the treatment of pain. Excellent earlier reviews have covered targeting NGF/BDNF for the treatment of pain so this review will only focus on small molecule Trk kinase inhibitors claimed against cancer and pain. However, it is notable that the NGF antibody tanezumab was very recently reported to show good efficacy in a Phase II trial against osteoarthritic knee pain.”

International Patent Application publication number WO2009/012283 refers to various fluorophenyl compounds as Trk inhibitors; International Patent Application publication numbers WO2009/152087, WO2008/080015 and WO2008/08001 and WO2009/152083 refer to various fused pyrroles as kinase modulators; International Patent Application publication numbers WO2009/143024 and WO2009/143018 refer to various pyrrolo[2,3-d]pyrimidines substituted as Trk inhibitors; International Patent Application publication numbers WO2004/056830 and WO2005/1 16035 describe various 4-amino-pyrrolo[2,3- d]pyrimidines as Trk inhibitors. International Patent Application publication number WO201 1/133637 describes various pyrrolo[2,3-d]pyrimidines and pyrrolo[2,3-b]pyridines as inhibitors of various kinases.

US provisional application US61/471758 was filed 5^th April 2012 and the whole contents of that application in it’s entirety are herewith included by reference thereto.

Thus Trk inhibitors have a wide variety of potential medical uses. There is a need to provide new Trk inhibitors that are good drug candidates. In particular, compounds should preferably bind potently to the Trk receptors in a selective manner compared to other receptors, whilst showing little affinity for other receptors, including other kinase and / or GPC receptors, and show functional activity as Trk receptor antagonists. They should be non-toxic and demonstrate few side-effects. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated. They should preferably be e.g. well absorbed from the gastrointestinal tract, and / or be injectable directly into the bloodstream, muscle, or subcutaneously, and / or be metabolically stable and possess favourable pharmacokinetic properties.

Among the aims of this invention are to provide orally-active, efficacious, compounds and salts which can be used as active drug substances, particularly Trk antagonists, i.e. that block the intracellular kinase activity of the Trk, e.g. TrkA (NGF) receptor. Other desirable features include good HLM/hepatocyte stability, oral bioavailability, metabolic stability, absorption, selectivity over other types of kinase, dofetilide selectivity. Preferable compounds and salts will show a lack of CYP inhibition/induction, and be CNS- sparing.

SYNTHESIS

WO-2012137089-A1

https://www.google.com/patents/WO2012137089A1?cl=enhttps://www.google.com/patents/WO2012137089A1?cl=en

Sharanjeet Kaur Bagal,

Karl Gibson

Example 46: N-(5-{[2-Amino-7-(2-hydroxy-1 ,1-dimethylethyl)-7H-pyrrolo[2,3-d]pyrimidin-5- yl]carbonyl}pyridin-3-yl)-2-(5-chloropyridin-2-yl)acetamide

(5-Chloropyridin-2-yl)acetic acid (26.1 g, 152 mmol) (see Preparation 90) was added to (5-aminopyridin- 3-yl){7-(2-{[ferf-butyl(dimethyl)silyl]oxy}-1 , 1-dimethylethyl)-2-[(2,4-dimethoxybenzyl)ami

d]pyrimidin-5-yl}methanone (75.0 g, 130 mmol ) (see Preparation 51 ), 1-propylphosphonic acid cyclic anhydride (187 mL, 317 mmol, 50% solution in EtOAc) and triethylamine (61.9 mL, 444 mmol ) in THF (423 mL). The mixture was stirred at 25°C for 2 hours then saturated aqueous sodium bicarbonate (400 mL) was added and the organic layer was separated. The aqueous phase was extracted with EtOAc (400 mL) and all organic phases were combined and dried over sodium sulfate then evaporated in vacuo. The residue brown solid was dissolved in trifluoroacetic acid (300 mL) and the solution was stirred at 50°C for 3 hours then evaporated in vacuo. Methanol (1800 mL) was added to the residue and the mixture was filtered. The filtrate was evaporated in vacuo and azeotroped with ethanol (3 x 200 mL).

Potassium carbonate (87.7 g, mmol) was added to the crude trifluoroacetamide in methanol (300 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was poured into water (2000 mL) and filtered. The solid was washed with water (200 mL) then triturated with ethanol (2 x 200 mL at room temperature then 380 mL at 50°C) to afford the title compound as a yellow solid in 48% yield, 29.9 g. H NMR (400 MHz, DMSO-c/6) δ: 1.64 (s, 6H), 3.90 (d, 2H), 3.95 (s, 2H), 5.05 (t, 1 H), 6.54 (br s, 2H), 7.49 (d, 1 H), 7.69 (s, 1 H), 7.92 (dd, 1 H), 8.40 (m, 1 H), 8.56 (m, 1 H), 8.64 (d, 1 H), 8.94 (d, 1 H), 8.96 (s, 1 H), 10.71 (s, 1 H); LCMS (System 3): R_t = 9.92 min; m/z 480 [M+H]⁺.

PAPER

The Discovery of a Potent, Selective, and Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of Pain

Sarah E. Skerratt

MARK ANDREWS

Abstract

The neurotrophin family of growth factors, comprised of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4), is implicated in the physiology of chronic pain. Given the clinical efficacy of anti-NGF monoclonal antibody (mAb) therapies, there is significant interest in the development of small molecule modulators of neurotrophin activity. Neurotrophins signal through the tropomyosin related kinase (Trk) family of tyrosine kinase receptors, hence Trk kinase inhibition represents a potentially “druggable” point of intervention. To deliver the safety profile required for chronic, nonlife threatening pain indications, highly kinase-selective Trk inhibitors with minimal brain availability are sought. Herein we describe how the use of SBDD, 2D QSAR models, and matched molecular pair data in compound design enabled the delivery of the highly potent, kinase-selective, and peripherally restricted clinical candidate PF-06273340.

ADDITIONAL INFORMATION

The aqueous solubility of PF-06273340 is 131 μM, much improved over previous analogues, it is highly kinase-selective (Gini score of 0.92) and has no measurable activity at the hERG channel. PF-06273340 was profiled in a series of in vitro safety assays, showing little cytotoxicity in THLE or HepG2 cell lines (IC50 > 42 μM and >300 μM, respectively) and was evaluated for broader pharmacological activity in a panel of receptors, ion channels, and enzymes. In this broad panel, all IC50/Ki values were >10 μM except for COX-1 (IC50 = 2.7 μM) and dopamine transporter assays (Ki = 5.2 μM) and PDEs 4D, 5A, 7B, 8B, and 11 (54−89% inhibition at 10 μM). PF-06273340 was screened in the Invitrogen wide kinase panel of 309 kinases, and all were inhibited by <40% when tested at 1 μM except the following: MUSK (IC50 53 nM), FLT-3 (IC50 395 nM), IRAK1 (IC50 2.5 μM), MKK (90% @ 1 μM), and DDR1 (60% @ 1 μM).

REFERENCES

1: Skerratt SE, Andrews MD, Bagal SK, Bilsland J, Brown D, Bungay PJ, Cole S,
Gibson KR, Jones R, Morao I, Nedderman A, Omoto K, Robinson C, Ryckmans T,
Skinner K, Stupple PA, Waldron G. The Discovery of a Potent, Selective and
Peripherally Restricted Pan-Trk Inhibitor (PF-06273340) for the Treatment of
Pain. J Med Chem. 2016 Oct 21. [Epub ahead of print] PubMed PMID: 27766865.

Gareth Waldron

(-)-32 as an off-white solid.
Analytical data
LCMS 418 [M+H]+1
H NMR (400 MHz, DMSO-d6) δ 8.23 (s, 1H), 6.88 (d, J = 8.0 Hz, 1H), 6.68 (s, 1H), 6.61 (dd,J = 11.2, 2.0 Hz, 1H), 6.49-6.38 (m, 2H), 6.33 (s, 1H), 5.61 (m, 1H), 4.88 (s, 2H), 4.20(t, J = 4.3 Hz, 2H), 3.35-3.18 (m, 6H).
Optical rotation [α]D20 -38.5° (c = 0.107, DMSO)

PAPER

Discovery of Pyrazolopyrimidine Derivatives as Novel Dual Inhibitors of BTK and PI3Kδ

Son Pham

Associate Director, Medicinal Chemistry at Medivation

Roopa Rai

Sr. Director, Medicinal Chemistry at Medivation

 

Brahmam Pujala

Senior Research Scientist at Integral Biosciences

Ashu Gupta

Research Scientist at Integral Biosciences

Rambabu guguloth

Abstract

The aberrant activation of B-cells has been implicated in several types of cancers and hematological disorders. BTK and PI3Kδ are kinases responsible for B-cell signal transduction, and inhibitors of these enzymes have demonstrated clinical benefit in certain types of lymphoma. Simultaneous inhibition of these pathways could result in more robust responses or overcome resistance as observed in single agent use. We report a series of novel compounds that have low nanomolar potency against both BTK and PI3Kδ as well as acceptable PK properties that could be useful in the development of treatments against B-cell related diseases.

Monali Banerjee

Director, R&D

Ms. Banerjee has more than 10 years of research experience, during which she has held positions of increasing responsibility. Her past organizations include TCG Lifesciences (Chembiotek) and Sphaera Pharma. Ms. Banerjee is a versatile scientist with a deep understanding of the fundamental issues that underlie various aspects of drug discovery. At Curadev, she has been responsible for target selection, patent analysis, pharmacophore design, assay development, ADME/PK and in vivo and in vitro pharmacology. Ms. Banerjee holds a Masters in Biochemistry and a Bachelors in Chemistry both from Kolkata University.

Nidhi Adlaka & Neha Munjal are developing a bioprocess for butanediol. Over the next few decades, chemical routes of manufacture will gradually be replaced by more environment friendly biological methods.

Read more at:
http://economictimes.indiatimes.com/articleshow/47276311.cms?utm_source=contentofinterest&utm_medium=text&utm_campaign=cppst

Dr. Arjun Surya, CSO, Curadev enthralling participants with anecdotes of his entrepreneurial jrney in drugdiscovery

Manish Tandon

Co-founder Curadev Pharma Pvt Ltd

//////////////B-cell,  BCR,  BTK,  inhibitor,  p110δ,  PI3K,  pyrazolopyrimidine, Novel Dual Inhibitors, BTK , PI3Kδ, Medivation, Integral BioSciences,  Curadev, Fundación Ciencia y Vida, Departamento de Ciencias Biológicas,

Nc1ccc2CC(Cc2c1)n6nc(c3cc(F)c4OCCNc4c3)c5c(N)ncnc56

ZOPICLONE

Structural formula

UV- Spectrum

Conditions : Concentration – 1 mg / 100 ml
The solvent designation schedule	methanol	water	0.1М HCl	0.1M NaOH
maximum absorption	There  decay	303 nm	304 nm	277 nm  237 nm
	–	362	364	199 390
e	–	10500	10500	5800 11300

IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

MASS spectrum

Range
10 largest peaks:
Peak	42	56	99	112	139	143	217	245	246	247
Value	155	231	280	283	209	999	279	719	156	250

References

• UV and IR Spectra. H.-W. Dibbern, R.M. Muller, E. Wirbitzki, 2002 ECV

• NIST/EPA/NIH Mass Spectral Library 2008

• Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman. Academic Press, 2000.

• Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Brief background information

Salt	ATC	formula	MM	CASE
–	N05CF01	C 17 H 17 ClN 6 O 3	388.82 g / mol	43200-80-2

Application

• sedative

• hypnotic

Classes substance

• chlorine compounds

  • oxo

    • Esters of 1-piperazinecarboxylate

      • pyridines

        • Pirrolo [3,4-b] piraziny

Synthesis Way

Синтез a)

Trade names

country	Tradename	Manufacturer
Germany	Optydorm	DOLORGIET
	Somnosan	Hormos
	Ksimovan	Sanofi-Aventis
	Zop	HEXAL
	Zopi-cigar	Actavis
	various generic drugs
France	imovane	SanofiAventis
	Noktireks	Sanofi-Synthélabo
United Kingdom	Snowman	SanofiAventis
Italy	imovane	SanofiAventis
	tion	THERE
Japan	Amoʙan	Sanofi-Aventis; Chugai; Mitsubishi
Ukraine	imovane	Sanofi Winthrop Indastria, France
	various generic drugs

Formulations

• coated tablets 7.5 mg;

• Tablets 7.5 mg, 10 mg

References

• DOS 2 300 491 (Rhône-Poulenc; appl. 5.1.1973; F-prior. 7.1.1972, 9.9.1972).

• US 3 862 149 (Rhône-Poulenc; 21.1.1975; F-prior. 7.1.1972, 9.9.1972).

Two major zopiclone metabolites.

CAS Registry No.:	43200-80-2
Molecular Formula:	C17H17ClN6O3	Molecular Weight:	388.8
Compound Name:
zopiclone 1-piperazinecarboxylic acid, 4-methyl-, 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo(3,4-b)pyrazin-5-yl ester 4-methyl-1-piperazinecarboxylic acid 6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo(3,4-b)-pyrazin-5-yl ester 4-methyl-1-piperazinecarboxylic acid-6-(5-chloro-2-pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo(3,4-b)-pyrazin-5-yl ester 6-(5-chloro-2-pyridyl)-6,7-dihydro-7-oxo-5H-pyrrolo(3,4-b)pyrazin-5-yl 4-methyl-1-piperazinecarboxylate 6-(5-chloro-pyridin-2-yl)-5((4-methyl-1-piperazinyl)carbonyloxy)-7-oxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazine 6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo(3,4-b)pyrazin-5-yl 4-methylpiperazine-1-carboxylate amoban (R) imovane

Zopiclone (Imovance), 4-methyl-1-piperzinecarboxylic acid 6-(5-chloro-2- pyridinyl)-6,7-dihydro-7-oxo-5H-pyrrolo[3,4-b]pyrazin-5-yl ester (Figure 1) is one of the non benzodiazepine sedative-hypnotics of the cyclopyrrolone class, sold by Rhone-Poulene Company in France since 1987. Although structurally unrelated to benzodiazepines, its pharmacological profile is similar, exhibiting sedative-hypnotic, anxiolytic, myorelaxant, and anticonvulsant activity.[1] Other than the first generation barbiturates and the second-generation benzodiazepines, zopiclone, which is widely used in Europe as well as other regions worldwide,[2,3] as a representative of the third generation sedative-hypnotic drugs, has been shown to be free from residual effects on performance and psychological function the day after intake and from the risks of accumulation because of its short elimination half-life (3.5 to 6.5 hours).[3,4] It is indicated for the short term treatment of insomnia, transient, situational or chronic insomnia, and insomnia secondary to psychiatric disturbances.[3]

REFERENCES 1. Mann, K.; Bauer, H.; Hiemke, C.; Ro¨schke, J.; Wetzel, H.; Benkert, O. Acute, subchronic and discontinuation effects of zopiclone on sleep EEG and nocturnal melatonin secretion. Eur. Neuropsychopharm. 1996, 6 (3), 163– 168. Structure Elucidation of Sedative-Hypnotic Zopiclone 359 Downloaded by [Dalhousie University] at 22:10 19 December 2012

2. Le´ger, D.; Janus, C.; Pellois, A.; Quera-Salva, M.A.; Dreyfus, J.P. Sleep, morning alertness and quality of life in subjects treated with zopiclone and in good sleepers. study comparing 167 patients and 381 good sleepers. Eur. Psychiat. 1995, 10 (973) Suppl. 3, 99s – 102s.

3. Piperaki, S.; Parissi-Poulou, M. Enantiomeric separation of zopiclone, its metabolites and products of degradation on a b-cyclodextrin bonded phase. J. Chromatogr. A 1996, 729 (1 – 2), 19 – 28

Spectral Data Analyses and Structure Elucidation of Sedative‐Hypnotic Zopiclone

Xin Ming , Hongzhen Lian  & Wei Zhu

Pages 349-360 | Received 10 Sep 2006, Accepted 18 Oct 2006, Published online: 13 Oct 2010

• Download citation
• http://dx.doi.org/10.1080/10739140701255656

Zopiclone

Systematic (IUPAC) name
(RS)-6-(5-chloropyridin-2-yl)-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazin-5-yl 4-methylpiperazine-1-carboxylate
Clinical data
Trade names	Imovane, Zimovane
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	Oral tablets, 3.75 mg (UK), 5 or 7.5 mg
Legal status
Legal status	AU: S4 (Prescription only) UK: Class C (POM) US: Schedule IV
Pharmacokinetic data
Bioavailability	75-80%[1]
Protein binding	52–59%
Metabolism	Hepatic through CYP3A4and CYP2E1
Biological half-life	~5 hours (3.5–6.5 hours) ~7–9 hours for over 65
Excretion	Urine (80%)
Identifiers
CAS Number	43200-80-2
ATC code	N05CF01 (WHO)
PubChem	CID 5735
IUPHAR/BPS	7430
DrugBank	DB01198
ChemSpider	5533
UNII	03A5ORL08Q
KEGG	D01372
ChEBI	CHEBI:32315
ChEMBL	CHEMBL135400
PDB ligand ID	ZPC (PDBe, RCSB PDB)
Chemical data
Formula	C17H17ClN6O3
Molar mass	388.808 g/mol
3D model (Jmol)	Interactive image

REF http://shodhganga.inflibnet.ac.in/bitstream/10603/46826/9/09_part%20a%20section%202.pdf

////////////

Valdetamid (Valdetamide)

Structural formula

UV – spectrum

Conditions : Concentration – 50 mg / 100 ml
The solvent designation schedule	methanol	Water	0.1 M HCl	0.1M NaOH
maximum absorption	–	–	–	–
	–	–	–	–
ε	–	–	–	–

IR – spectrum

Wavelength (μm)
Wave number (cm -1 )

Range
10 largest peaks:
Peak	53	55	57	67	69	81	112	126	127	140
Value	152	848	115	141	929	156	286	999	338	238

References

• UV and IR Spectra. H.-W. Dibbern, RM Muller, E. Wirbitzki, 2002 ECV

• NIST / EPA / NIH Mass Spectral Library 2008

• Handbook of Organic Compounds. NIR, IR, Raman, and UV-Vis Spectra Featuring Polymers and Surfactants, Jr., Jerry Workman.Academic Press, 2000.

• Handbook of ultraviolet and visible absorption spectra of organic compounds, K. Hirayama. Plenum Press Data Division, 1967.

Brief background information

Salt	ATC	Formula	MM	CAS
–	N05C	C 9 H 17 NO	155.24 g / mol	512-48-1

Using

• hypnotic

Classes substance

• Amides

Synthesis Way

Synthesis of a)

Trade names

A country	Tradename	Manufacturer
Germany	Arantxa	Hoechst
	Betadorm-H	Woelm
	insomnia	ICN
	Nokturetten	Starke
	New Dolestan	Much
Ukraine	no	no

Formulations

• dragees 50 mg;

• 300 mg Tablets

References

• DRP 473 329 (IG Farben; appl 1925.).

• DRP 616 876 (IG Farben; appl 1930.).

• DRP 622 875 (IG Farben; appl 1931.).

• GB 253,950 (IG Farben; appl 1926;.. D-prior 1925).

1H NMR PREDICT

13C NMR PREDICT

Acetylcholine Chloride

2-acetyloxyethyl(trimethyl)azanium;chloride

60-31-1

Acetylcholine chloride is obtained as white or off-white hygroscopic crystals, or as a crystalline powder. The salt is odorless, or nearly odorless, and is a very deliquescent powder. Acetylcholine bromide is obtained as deliquescent crystals, or as a white crystalline powder. The substance is hydrolyzed by hot water and alkali

Chemistry

History

Laboratory Synthesis Of Acetylcholine chloride

Acetylcholine
IUPAC name	2-Acetoxy-N,N,N-trimethylethanaminium
Abbreviation	ACh
Sources	motor neurons, parasympathetic nervous system, brain
Targets	skeletal muscles, brain, many other organs
Receptors	nicotinic, muscarinic
Agonists	nicotine, muscarine, cholinesterase inhibitors
Antagonists	tubocurarine, atropine
Precursor	choline, acetyl-CoA
Synthesizing enzyme	choline acetyltransferase
Metabolizing enzyme	acetylcholinesterase
Database links
CAS Number	51-84-3
PubChem	CID: 187
IUPHAR/BPS	294
DrugBank	EXPT00412
ChemSpider	182
KEGG	C01996

1H NMR PREDICT

13 C NMR PREDICT

/////////CC(=O)OCC[N+](C)(C)C.[Cl-]

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SUGAMMADEX

WATCH OUT POST WILL BE UPDATED………

SUGAMMADEX

Sugammadex Sodium is the sodium salt form of the biologically inert, selective relaxant binding agent (SRBA) sugammadex, a modified, anionic gamma cyclodextrinderivative containing a hydrophilic exterior and a hydrophobic core, with neuromuscular blocking drug (NMBD) reversal activity. Upon administration, the negatively charged carboxyl-thio-ether groups of sugammadex selectively and reversibly bind to the positively charged quaternary nitrogen of a steroidal NMBD, which was administered at an earlier time for anesthetic purposes. The encapsulation of the NMBD by sugammadex blocks its ability to bind to nicotinic receptors in the neuromuscular junction and thereby reverses the NMBD-induced neuromuscular blockade. Sugammadex binds rocuronium, vecuronium, and to a lesser extent pancuronium.

Sugammadex is used to reverse neuromuscular blockade after administration of non-depolarizing neuromuscular-blocking agentssuch as vecuronium or rocuronium.

Pharmacology

Pharmacodynamics

Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery. This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions. These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the quaternary nitrogen of the target as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex’s binding encapsulation of rocuronium is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified steroid) bound within sugammadex’s lipophilic core, is rendered unavailable to bind to the acetylcholine receptor at the neuromuscular junction.

Left: Schematic of a sugammadex molecule encapsulating a rocuronium molecule.
Right: Space-filling model of a sugammadex sodium molecule in the same orientation.

Sugammadex, unlike neostigmine, does not inhibit acetylcholinesterase so cholinergic effects are not produced and co-administration of an antimuscarinicagent (glycopyrronium bromide or atropine) is not needed. Sugammadex might therefore be expected to have fewer adverse effects than the traditional reversal agents.

When muscle relaxant with rapid onset and short duration of action is required, there has been little choice apart from suxamethonium but this drug has important contraindications; for example, it can trigger malignant hyperthermia in susceptible individuals, it has a prolonged duration of action in patients with pseudocholinesterase deficiency and it causes an increase in plasma potassium concentration which is dangerous in some circumstances. Rocuronium has a comparably quick onset in high dose (0.6 mg kg⁻¹ to 1 mg kg⁻¹) and can be rapidly reversed with sugammadex (16 mg kg⁻¹), so this drug combination offers an alternative to suxamethonium.

‘Recurarisation’, a phenomenon of recurrence of neuromuscular block, may occur where the reversal agents wear off before a neuromuscular blocking drug is completely cleared. This is very unusual with all but the longest acting neuromuscular blocking drugs (such as gallamine, pancuronium or tubocurarine). It has been demonstrated to occur only rarely with sugammadex, and only when insufficient doses were administered.^[1] The underlying mechanism is thought to be related to redistribution of relaxant after reversal. It may occur for a limited range of sugammadex doses which are sufficient for complex formation with relaxant in the central compartment, but insufficient for additional relaxant returning to central from peripheral compartments.^[2]

Sugammadex has been shown to have affinity for two other aminosteroid neuromuscular blocking agents, vecuronium and pancuronium. Although sugammadex has a lower affinity for vecuronium than for rocuronium, reversal of vecuronium is still effective because fewer vecuronium molecules are present in vivo for equivalent blockade: vecuronium is approximately seven times more potent than rocuronium. Sugammadex encapsulates with a 1:1 ratio and therefore will adequately reverse vecuronium as there are fewer molecules to bind compared to rocuronium.^[3] Shallow pancuronium blockade has been successfully reversed by sugammadex in phase III clinical trials.^[4]

Efficacy

A study was carried out in Europe looking at its suitability in rapid sequence induction. It found that sugammadex provides a rapid and dose-dependent reversal of neuromuscular blockade induced by high-dose rocuronium.^[5]

A Cochrane review on sugammadex concluded that “sugammadex was shown to be more effective than placebo (no medication) or neostigmine in reversing muscle relaxation caused by neuromuscular blockade during surgery and is relatively safe. Serious complications occurred in less than 1% of the patients who received sugammadex. The results of this review article (especially the safety results) need to be confirmed by future trials on larger patient populations”.^[6]

Tolerability

Sugammadex was generally well tolerated in clinical trials in surgical patients or healthy volunteers. In pooled analyses, the tolerability profile of sugammadex was generally similar to that of placebo or neostigmine plus glycopyrrolate.^[7]

History

Sugammadex was discovered by the pharmaceutical company Organon at the Newhouse Research Site in Scotland.^[8] Organon was acquired by Schering-Plough in 2007; Schering-Plough merged with Merck in 2009. Sugammadex is now owned and sold by Merck.

The US Food and Drug Administration (FDA) initially rejected Schering-Plough’s New Drug Application for sugammadex in 2008,^[9] but finally approved the medication for use in the United States on December 15, 2015.^[10] Sugammadex was approved for use in the European Union on July 29, 2008.^[11]

SYNTHESIS

Sugammadex (Trade name: Bridion) is first disclosed in US6670340 assigned to Akzo Nobel. Sugammadex sodium was approved in EMEA as an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia in 2008 and is the first selective relaxant binding agent (SRBA).

Sugammadex sodium contains 8 recurring glucose units each with 5 asymmetric carbon atoms, in total 40 asymmetric carbon atoms for the whole molecule. Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery. The gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth carbon positions.

The US Patent 6670340 assigned to Akzo Nobel discloses a process for preparing Sugammadex sodium as depicted in Scheme-I:

Scheme-I

Sugammadex Sodium The first step in the process in the scheme-I involves the preparation of Vilsmeier Hack reagent by the reaction , of DMF, triphenylphosphine and Iodine. The triphenylphosphine oxide is formed as a byproduct of the first step. Removal of triphenylphosphine oxide from the product is very difficult from the reaction mass as it requires repeated washing with DMF under argon atmosphere, which leads to inconsistency in yield of final product Sugammadex. The second step involves the reaction of 6-perdeoxy-6-per-Iodo-Gamma cyclodextrin with 3-mercapto propionic acid in presence of alkali metal hydrides in an organic solvent to give 6-per-deoxy-6-per-(2-carboxyethyl)thio-y- cyclodextrin sodium salt.

The PCT publication WO2012/025937 discloses preparation of Sugammadex involving the reaction of gamma cyclodextrin with phosphorous halide in presence of organic solvent, thereby overcomes the formation of triphenyl phosphine oxide. The publication also discloses the use of 6-per deoxy-6-per- chloro-y-cyclodextrin in the preparation of the Sugammadex.

The purification techniques in the prior arts employ column chromatographic / membrane dialysis techniques which are costly and not convenient in large scale operations.

Sugammadex is a modified γ-cyclodextrin, with a lipophilic core and a hydrophilic periphery.

Sugammadex (designation Org 25969, trade name Bridion) is an agent for reversal of neuromuscular blockade by the agent rocuronium in general anaesthesia. It is the first selective relaxant binding agent (SRBA). This gamma cyclodextrin has been modified from its natural state by placing eight carboxyl thio ether groups at the sixth earbon positions. These extensions extend the cavity size allowing greater encapsulation of the rocuronium molecule. These negatively charged extensions electrostatically bind to the positively charged ammonium group as well as contribute to the aqueous nature of the cyclodextrin. Sugammadex’s binding encapsulation of rocuronium is one of the strongest among cyclodextrins and their guest molecules. The rocuronium molecule (a modified steroid) bound within Sugammadex’s lipophilic core, is rendered unavailable to bind to the acetylcholine receptor at the neuromuscular junction. Sugammadex sodium contains 8 recurring glucose units each with 5 asymmetric carbon atoms, in total 40 asymmetric carbon atoms for the whole molecule.

The Sugammadex was disclosed in US6670340 by Akzo Nobel. The process for preparing Sugammadex is there outlined as follows: (Scheme-I)

Scheme – 1 Suggamadex

above process step-1 involves the preparation of Vilsmeier Hack reagent by the reaction of DMF, triphenylphosphine and Iodine. Drawback associated with this step is formation of triphenylphosphine oxide as a byproduct. Removal of triphenylphosphine oxide is very difficult from the reaction; it requires repeated washing with DMF under argon atmosphere and leads to inconsistency in yield of final product. Due to this, process is lengthy and not feasible on commercial scale.

PATENT

https://www.google.com/patents/WO2012025937A1?cl=en

Suggamadex

The process of the invention is depicted in following

Formula – 1 Formula – lla

Scheme – III

scheme-IV

Suggamadex

Scheme – IV

[0018] The alkali metal hydrides are selected from the group consisting of sodium hydride, lithium hydride, potassium hydride preferably sodium hydride. [0019] The advantage of the present process is there that there is no formation of by product such as triphenylphosphine oxide, as present in prior art process. So, purification is not required which leads to better purity and yields for the intermediate as well as for final product.

[0020] Another advantage of the present invention is the significant difference between molecular weight of 6-per deoxy-6-per-chloro-y-cyclodextrin (Mol. wt. 1444) and the final product (Mol. wt. 2178). The use of 6-per deoxy-6-per- chforo-y-cyclodextrin instead of 6-per deoxy-6-per-bromo-y-cyclodextrin (Mol. wt. 1800) in the final stage^‘ of the process would extend the scope of selection of appropriate dialysis membranes with precise molecular weight cut off and there by facilitate efficient purification of Sugammadex. The invention is further illustrated with following non-limiting examples:

Example: 1 Preparation of 6-perdeoxy-6-per-bromo Gamma Cyclodextrin

[0021] A portion of phosphorous pentachloride (256.5 g) was added in DMF (300 ml) at 0-5°C. Mixture was stirred at 20-25°C for lhr. A solution of gamma- cyclodextrin (50 g) in DMF (400ml) was added to above solution at 5-10°C under nitrogen. Mixture was stirred at 65 -70°C 14 hrs. The reaction mixture was cooled to 20 – 25°C and DMF was removed under vacuum. The viscous residue was diluted with water. 5M NaOH solution was added dropwise to the above solution at 5-10°C until P^H=8, the resulting slurry was stirred for one hour at 20-25°C. The slurry was filtered under vacuum and washed with water and dried. The crude product was diluted with water and resulting slurry was stirred at 20-25^uC for one hour. The slurry was filtered under vacuum and the solid dried at 55- 60°C under vacuum for 12hrs. (Yield – 94 – 98%, purity-98.5% by HPLC) Example: 2 Preparation of Sugammadax

[0022] To a mixture of sodium hydride (24.4 g) in DMF (150 ml) at 0-5°C, a solution of 3-mercapto propionic acid (23.7 ml, 10 eq) in DMF (50 ml) was added slowly under argon maintaining the temperature below 10 C. The resulting mixture was stirred at 20 -25°C for 30 mins. Then 6-deoxy-6-chloro gamma cyclodextrin (40 g) in DMF (400 ml) was added slowly at 5-10°C under argon and the resulting mixture was heated to 70-75°C for 12 hrs. Reaction mixture was cooled to 20 -25°C and DMF removed partially under vacuum and the reaction mixture is diluted with ethanol (600 ml). The resulting precipitate was stirred at 20 – 25°C for 1 hr and filtered under vacuum and the solid dried to afford the crude Sugammadex (wet) (100 g). The crude product was purified over silica gel and sephadex G-25 column using water as eluent. (Yield 60%)

CLIP

PATENT

http://www.google.co.in/patents/WO2001040316A1?cl=en

PATENT

https://www.google.com/patents/WO2014125501A1?cl=enhttps://www.google.com/patents/WO2014125501A1?cl=en

FDA Orange Book Patents

References

BRIDION (sugammadex) injection, for intravenous use, contains sugammadex sodium, a modified gamma cyclodextrin chemically designated as 6^A,6^B,6^C,6^D,6^E,6^F,6^G,6^H-Octakis-S-(2-carboxyethyl)6^A,6^B,6^C,6^D,6^E,6^F,6^G,6^H-octathio-γ-cyclodextrin sodium salt (1:8) with a molecular weight of 2178.01. The structural formula is:

BRIDION is supplied as a sterile, non-pyrogenic aqueous solution that is clear, colorless to slightly yellow-brown for intravenous injection only. Each mL contains 100 mg sugammadex, which is equivalent to 108.8 mg sugammadex sodium. The aqueous solution is adjusted to a pH of between 7 and 8 with hydrochloric acid and/or sodium hydroxide. The osmolality of the product is between 300 and 500 mOsmol/kg.

BRIDION may contain up to 7 mg/mL of the mono OH-derivative of sugammadex [see CLINICAL PHARMACOLOGY]. This derivative is chemically designated as 6^A,6^B,6^C,6^D,6^E,6^F,6^G-Heptakis-S-(2carboxyethyl)-6^A,6^B,6^C,6^D,6^E,6^F,6^G-heptathio-γ-cyclodextrin sodium salt (1:7) with a molecular weight of 2067.90. The structural formula is:

Sugammadex

Clinical data
AHFS/Drugs.com	International Drug Names
License data	EU EMA: Bridion
Routes of administration	Intravenous
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Identifiers
CAS Number	343306-79-6
ATC code	V03AB35 (WHO)
PubChem	CID 6918584
ChemSpider	5293781
UNII	361LPM2T56
KEGG	D05940
ChEBI	CHEBI:90952
Chemical data
Formula	C72H104Na8O48S8
Molar mass	2178 g/mol
3D model (Jmol)	Interactive image
SMILES[hide] [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O=C([O-])CCSC[C@H]8O[C@@H]7O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@@H]1CSCCC(=O)[O-])O[C@H]2[C@H](O)[C@@H](O)[C@H](O[C@@H]2CSCCC(=O)[O-])O[C@H]3[C@H](O)[C@@H](O)[C@H](O[C@@H]3CSCCC(=O)[O-])O[C@H]4[C@H](O)[C@@H](O)[C@H](O[C@@H]4CSCCC(=O)[O-])O[C@@H]9[C@H](O[C@H](O[C@H]5[C@H](O)[C@@H](O)[C@H](O[C@@H]5CSCCC(=O)[O-])O[C@H]6[C@H](O)[C@@H](O)[C@H](O[C@@H]6CSCCC([O-])=O)O[C@H]8[C@H](O)[C@H]7O)[C@H](O)[C@H]9O)CSCCC(=O)[O-]

/////////SUGAMMADEX, Sugammadex Sodium, D05940, SUYDEX SODIUM, UNII-ERJ6X2MXV7, fda 2015, bridion, Org25969,  Org-25969, Org 25969,  361LPM2T56

O[C@@H]1[C@@H](O)[C@@H]2O[C@H]3O[C@H](CSCCC(O)=O)[C@@H](O[C@H]4O[C@H](CSCCC(O)=O)[C@@H](O[C@H]5O[C@H](CSCCC(O)=O)[C@@H](O[C@H]6O[C@H](CSCCC(O)=O)[C@@H](O[C@H]7O[C@H](CSCCC(O)=O)[C@@H](O[C@H]8O[C@H](CSCCC(O)=O)[C@@H](O[C@H]9O[C@H](CSCCC(O)=O)[C@@H](O[C@H]1O[C@@H]2CSCCC(O)=O)[C@H](O)[C@H]9O)[C@H](O)[C@H]8O)[C@H](O)[C@H]7O)[C@H](O)[C@H]6O)[C@H](O)[C@H]5O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O

O=C(O[Na])CCSC[C@@H]1OC(O[C@@H]2[C@H]([C@H](O)C(O[C@H]3[C@H](CSCCC(O[Na])=O)OC(O[C@H]4[C@H](CSCCC(O[Na])=O)OC5[C@@H](O)[C@@H]4O)[C@@H](O)[C@@H]3O)O[C@H]2CSCCC(O[Na])=O)O)[C@@H](O)[C@H](O)[C@H]1OC(O[C@@H](CSCCC(O[Na])=O)[C@H](OC6[C@@H](O)[C@H](O)[C@@H](OC7[C@@H](O)[C@H](O)[C@@H](OC8[C@@H](O)[C@H](O)[C@@H](O5)[C@H](CSCCC(O[Na])=O)O8)[C@H](CSCCC(O[Na])=O)O7)[C@H](CSCCC(O[Na])=O)O6)[C@H]9O)[C@H]9O

FDA approves Intrarosa for postmenopausal women experiencing pain during sex

The U.S. Food and Drug Administration approved Intrarosa (prasterone) to treat women experiencing moderate to severe pain during sexual intercourse (dyspareunia), a symptom of vulvar and vaginal atrophy (VVA), due to menopause. Intrarosa is the first FDA approved product containing the active ingredient prasterone, which is also known as dehydroepiandrosterone (DHEA).

Read more

http://www.fda.gov/newsevents/newsroom/pressannouncements/UCM529641.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

For Immediate Release

November 17, 2016

Release

The U.S. Food and Drug Administration approved Intrarosa (prasterone) to treat women experiencing moderate to severe pain during sexual intercourse (dyspareunia), a symptom of vulvar and vaginal atrophy (VVA), due to menopause. Intrarosa is the first FDA approved product containing the active ingredient prasterone, which is also known as dehydroepiandrosterone (DHEA).

During menopause, levels of estrogen decline in vaginal tissues, which may cause a condition known as VVA, leading to symptoms such as pain during sexual intercourse.

“Pain during sexual intercourse is one of the most frequent symptoms of VVA reported by postmenopausal women,” said Audrey Gassman, M.D., deputy director of the Division of Bone, Reproductive, and Urologic Products (DBRUP) in the Office of Drug Evaluation III in the FDA’s Center for Drug Evaluation and Research (CDER). “Intrarosa provides an additional treatment option for women seeking relief of dyspareunia caused by VVA.”

Efficacy of Intrarosa, a once-daily vaginal insert, was established in two 12-week placebo-controlled clinical trials of 406 healthy postmenopausal women, 40 to 80 years of age, who identified moderate to severe pain during sexual intercourse as their most bothersome symptom of VVA. Women were randomly assigned to receive Intrarosa or a placebo vaginal insert. Intrarosa, when compared to placebo, was shown to reduce the severity of pain experienced during sexual intercourse.

The safety of Intrarosa was established in four 12-week placebo-controlled trials and one 52-week open-label trial. The most common adverse reactions were vaginal discharge and abnormal Pap smear.

Although DHEA is included in some dietary supplements, the efficacy and safety of those products have not been established for diagnosing, curing, mitigating, treating or preventing any disease.

Intrarosa is marketed by Quebec-based Endoceutics Inc.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

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Dehydroepiandrosterone

Systematic (IUPAC) name
(3S,8R,9S,10R,13S,14S)-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-17-one; (1S,2R,5S,10R,11S,15S)-5-Hydroxy-2,15-dimethyltetracyclo[8.7.0.02,7.011,15]heptadec-7-en-14-one
Clinical data
Routes of administration	Oral
Legal status
Legal status	AU: S4 (Prescription only) CA: Schedule IV US: OTC
Pharmacokinetic data
Metabolism	Hepatic
Biological half-life	12 hours
Excretion	Urinary:?%
Identifiers
CAS Number	53-43-0
ATC code	A14AA07 (WHO) G03EA03 (WHO) (combination with estrogen)
PubChem	CID 5881
IUPHAR/BPS	2370
DrugBank	DB01708
ChemSpider	5670
UNII	459AG36T1B
ChEBI	CHEBI:28689
ChEMBL	CHEMBL90593
Synonyms	(3β)-3-Hydroxyandrost-5-en-17-one
Chemical data
Formula	C19H28O2
Molar mass	288.424 g/mol
3D model (Jmol)	Interactive image

 //////////////////

 FDA,  approves,  Intrarosa, postmenopausal women, pain during sex, prasterone, dehydroepiandrosterone,  (DHEA).

Filed under: FDA 2016 Tagged: (DHEA), Approves, dehydroepiandrosterone, fda, Intrarosa, pain during sex, postmenopausal women, prasterone

WO2016181313,  A PROCESS FOR THE PREPARATION OF SOFOSBUVIR INTERMEDIATES & ITS POLYMORPH

SINGH, Girij, Pal; (IN).
SRIVASTAVA, Dhananjai; (IN).
MEHARE, Kishor, Gulabrao; (IN).
MALIK, Vineet; (IN).
DEOKAR, Sharad, Chandrabhan; (IN).
DANGE, Abhijeet, Avinash; (IN)

SUCCESS QUOTIENT: Lupin chairman DB Gupta (sitting) with managing director Kamal K Sharma (centre), directors Vinita Gupta (right) and Nilesh Gupta.

The present invention provides a novel process for preparation N-[(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2) and resolving the formula 2 in the presence base to form N-[(S)-(2,3,4,5,6- Pentafluorophenoxy)phenoxyphosphinyl]-L-alanine 1-methylethyl ester (formula 2′).

Sofosbuvir is chemically named as (S)-isopropyl 2-((S)-(((2R,3R,4R,5R)-5-(2,4- dioxo3,4-dihydropyrimidin-l(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran- 2yl)methoxy)-(phenoxy)phosphorylamino)propanoate and is represented by the following chemical structure:

Formula 1

PCT publications WO2011123645 and WO2010135569 describes process for preparation of compound of formula 2′ by reacting isopropyl (chloro(phenoxy)phosphoryl)-L-alaninate and pentaflurophenol in the presence of base.

Formula 2′

Example-1:

Preparation of sodium 2,3,4,5,6-pentaflurophenolate using sodium hydride

10.2g of sodium hydride was dissolved in 100 ml anhydrous THF. This solution was slowly added to a solution of pentafluorophenol (50g) in THF (100ml), Reaction mass was stirred for 60-120 min at 25-30°C. Reaction mass was distilled under reduced pressure, obtained solid was dried under vacuum at 45-50°C (yield=55g, confirmed by IR)

Example-2:

Preparation of sodium 2,3,4,5,6-pentaflurophenolate using sodium methoxide

2,3,4,5, 6-pentafluorophenol (lOg) was dissolved in methanol (100ml), solution was cooled to 5-10°C. To this was added a solution of sodium methoxide in methanol. The reaction mass was stirred for 60-120 min at 25-30°C. Reaction mass was distilled under reduced pressure, obtained residue was striped with toluene. Obtained solid was dried under vacuum at 45-50°C (yield=l lg)

Example 3:

Preparation of sodium 2,3,4,5,6-pentaflurophenolate using sodium hydroxide

2,3,4,5, 6-pentafluorophenol (lOOg) dissolved in methanol (—ml), solution was cooled to 5-10°C. To this was added a solution of sodium hydroxide (— g) in methanol. The reaction mass was stirred for 60-120 min at 25-30°C. Reaction mass was distilled under reduced pressure, obtained residue was striped with dichloromethane. Obtained solid was dried under vacuum at 45-50°C (yield=— g)

Example 4:

Preparation of (2S)-isopropyl-2-((chloro(phenoxy)posphoryl)amino)propanoate:

phenyl phosphodichloridate (30.6g) was dissolved in dichloromethane , to this was added a solution of 1-alanine isopropyl ester free base (19.16g) in dichloromethane at-60°C under nitrogen. Solution of triethylamine (20.7ml) was added to above reaction mass. Reaction mass was stirredat -60°C for 30 min and then temperature was raised to 25 °C. Reaction mass was stirred at 20-25 °C for 60 min & filtered and washed with dichloromethane. Clear filtrate was distilled under reduced pressure obtained residue was stirred with diisopropyl ether & filtered. Clear filtrate was distilled under reduced pressure to get (2S)-isopropyl-2-((chloro(phenoxy)posphoryl)amino)propanoate compound.

Example 5:

Preparation of isopropyl ((perfluorophenoxy)(phenoxy)phosphoryl)-L-alaninate (formula 2):

(Formula 2)

Obtained (2S)-isopropyl-2-((chloro(phenoxy)phosphoryl)amino)propanoate (1.2 mol eq.) was dissolved in dichloromethane and cooled to 0-5°C under nitrogen atmosphere. To this was added solution of sodium 2,3,4,5,6-pentaflurophemolate (1 mol eq.) in tetrahydrofuran . Temperature of reaction mass was raised to 25°C and reaction mass was stirred for 3 hrs. After completion of reaction, reaction mass was distilled under reduced pressure & obtained residue was dissolved I ethyl acetate. Ethyl acetate layer was washed with water, dried over sodium sulfate & distilled off under reduced pressure. Diisopropyl ether was added to obtained residue and stirred for 60 min at 25 °C, obtained mass was filtered & washed with diisopropyl ether. Solid product was dried under vacuum at 40-45 °C .(yield=20g, enantiomer purity=93.45%)

Example 6:

Preparation of (S)-isopropyl 2-(((S)- (perfluorophenoxy)phenoxy)phosphoyl)amino)propanoate (Formula 2′):

Formula 2′

(2S)-isopropyl-2-((chloro(phenoxy)phosphoryl)amino)propanoate (1.2 mol eq.) was dissolved in tetrahydrofuran (3.5 volumes). The reaction mass was cooled to -10°C. Solution of sodium salt of pentafluorophenol (1 mol eq.) in tetrahydrofuran (3.5 volumes) was added dropwise to the reaction mass at -10°C. After completion of the reaction solvent was distilled off. Ethyl acetate and water were added to the reaction mass. Reaction mass was stirred, ethyl acetate layer was separated and washed with sodium bicarbonate solution and brine. Ethyl acetate layer was concentrated under reduced pressure. Reaction mass was stripped with n-hepatane to get crude product. Crude product was dissolved in Methyl tert-butyl ether and n-heptane (1 : 1 ratio). The pH of reaction mass was adjusted to pH 8 by using triethylamine. Reaction mass was stirred overnight. Solid mass was filtered and washed with a mixture of methyl tertiary-butyl ether: n-heptane (1 : 1). The obtained product was dissolved in ethyl-acetate and washed with water and 20% brine solution. Ethyl acetate layer was separated; solvent was distilled off under reduced pressure. Reaction mass was stripped with diisopropyl ether. Di-isopropyl ether was added to the reaction mass. Reaction mass was stirred at 45-50°C. Reaction mass was cooled to 5-10°C and stirred. The titled compound was isolated by filtration and washed with di-isopropyl ether. The titled compound was dried under reduced pressure at 40°C. Yield 66.81%.

Vinita Gupta, CEO, Lupin Pharmaceuticals Inc

Desh Bhandu Gupta- Founder and chairman of Lupin Limited

////////////LUPIN LIMITED, WO 2016181313,  NEW PATENT, SOFOSBUVIR

Doxercalciferol

• Molecular FormulaC₂₈H₄₄O₂
• Average mass412.648

Doxercalciferol (1α-hydroxyvitamin D2) is a commercially approved vitamin D derivative used to treat chronic kidney disease (CKD) patients whose kidneys cannot metabolically introduce a hydroxyl group at C1. A new process for the production of doxercalciferol from ergocalciferol was developed using a continuous photoisomerization of a known vitamin D intermediate as the key step, thus circumventing the limitations of batch photoisomerization processes. Doxercalciferol is produced in an overall yield of about 10% from ergocalciferol.

Doxercalciferol

1H NMR (CDCl3) δ 6.40 (d, 1H, J = 11.2), 6.04 (d, 1H, J = 11.2), 5.35 (s, 1H), 5.15–5.29 (m, 2H), 5.03 (s, 1H), 4.45 (dd, 1H, J = 7.3, 4.0), 4.21–4.31 (m, 1H), 2.81–2.90 (m, 1H), 2.62 (d, 1H, J = 13.3), 2.34 (dd, 1H, J = 13.3, 6.5), 1.83–2.11(m, 6H), 1.42–1.79 (m, 7H), 1.21–1.40 (m, 3H), 1.04 (d, 3H, J = 6.6), 0.94 (d, 3H, J = 6.8), 0.86 (t, 6H, J = 7.3), 0.58 (s, 3H) ppm.

References

Doxercalciferol

Names
IUPAC name (1S,3R,5Z,7E,22E)-9,10-Secoergosta-5,7,10,22-tetraene-1,3-diol
Other names 1-Hydroxyergocalciferol; 1-Hydroxyvitamin D2; 1α-Hydroxyergocalciferol; 1α-Hydroxyvitamin D2; Hectorol; TSA 840
Identifiers
CAS Number	54573-75-0
3D model (Jmol)	Interactive image
ChEMBL	ChEMBL1200810
ChemSpider	4444554
DrugBank	DB06410
ECHA InfoCard	100.170.997
IUPHAR/BPS	2790
PubChem	5281107
UNII	3DIZ9LF5Y9
InChI[show]
SMILES[show]
Properties
Chemical formula	C28H44O2
Molar mass	412.66 g·mol−1
Pharmacology
ATC code	H05BX03 (WHO)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

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NINTEDANIB ETHANESULPHONATE

NEW PATENT

WO2016178064, CLICK FOR PATENT

POLYMORPH OF NINTEDANIB ETHANESULPHONATE, PROCESSES AND INTERMEDIATES THEREOF

SUVEN LIFE SCIENCES LIMITED [IN/IN]; 5th floor, Serene Chamber, Road No.5, Off Avenue No. 7, Banjara Hills, Telangana Hyderabad 500034 (IN)

ARAVA, Veera Reddy; (IN).
GOGIREDDY, Surendra Reddy; (IN).
JASTI, Venkateswarlu; (IN)

DR VEERA ARAVA REDDY

Veerareddy Arava

Vice President

Suven Life Sciences Limited, Hyderabad · Research and Development

Surendra Reddy Gogireddy, Sr.Research Associate

Suven Life Sciences Limited, Hyderabad · Research and Development

JASTI, Venkateswarlu

The present invention provides novel crystalline Form of Nintedanib and process for its preparation. The present invention also provides to a novel process for the preparation of Nintedanib. The present invention further provides to novel intermediates used in the preparation of Nintedanib and process for their preparation.

Nintedanib inhibits multiple receptor tyrosine kinases (RTKs) and non-receptor tyrosine kinases (nRTKs).The chemical name of Nintedanib is lH-Indole-6-carboxylic acid, 2,3-dihydro-3-[[[4-[methyl-(4-methyl-l-iperazinyl)acetyl]amino]phenyl]amino]phenylmethylene] -2-oxo-,methylester, (3Z)-, ethanesulfonate (1 : 1) and is structurally represented by compound of Formula I.

Formula I

Nintedanib is marketed in the United States under the trade name OFEV and is indicated for the treatment of Idiopathic Pulmonary Fibrosis (IPF).

Nintedanib was first described and claimed in U.S. Pat.No. 6,762, 180 and EP 1224 170. These patents disclose a process for the preparation of Nintedanib as depicted in scheme I given below:

U.S.Pat.No. 8,067,617 discloses a process for the preparation of Nintedanib intermediate Enolindole derivative), which is shown in the scheme-II given below:

Scheme-II

U.S.Pat. No. 7,119,093 discloses Nintedanib monoethanesulphonate in crystalline form characterised by X-ray powder diffraction pattern having 2Θ values at 7.70, 8.78, 9.47, 9.82, 11.59, 11.93, 13.15, 13.69, 14.17, 16.32, 16.72, 16.92, 17.43, 17.77, 18.58, 18.81, 19.03, 19.73, 19.87, 20.03, 20.61, 20.83, 21.26, 21.76, 22.05, 22.19, 22.57, 23.10, 23.81, 24.69, 24.78, 24.91, 25.42, 26.24, 26.91, 27.19, 27.61, 27.95, 28.71, 29.25.

Polymorphism, the occurrence of different crystal forms, is a property of some molecules and molecular complexes. A single molecule may give rise to a variety of polymorphs having distinct crystal structures and physical properties like melting point, X-ray diffraction pattern, infrared absorption fingerprint and solid state NMR spectrum. One polymorph may give rise to thermal behaviour different from that of another polymorph. Thermal behaviour can be measured in the laboratory by such techniques as capillary melting point, thermo gravimetric analysis (“TGA”) and differential scanning calorimetry (“DSC”), which have been used to distinguish polymorphic forms.

The differences in the physical properties of different polymorphs results from the orientation and intermolecular interactions of adjacent molecules or complexes in the bulk solid. Accordingly, polymorphs are distinct solids sharing the same molecular Formula yet having distinct advantageous physical properties compared to other polymorphs of the same composition or complex. Hence there remains a need for polymorphic forms which have properties suitable for pharmaceutical processing on a commercial scale.

Considering the importance of Nintedanib, there exists a need to develop an alternate and improved process for the preparation of Nintedanib with better yield. Further, the process involved should be simple, convenient and cost-effective for large scale production. The inventors of the present invention during their continuous efforts also developed a novel high melting stable polymorphic form of Nintedanib ethanesulfonate.

EXAMPLES

Example 1: Process for the preparation of Nintedanib Monoethane Sulfonate:

Step-1: Preparation of methyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate: To the suspension of methyl 2-oxoindoline-6-carboxylate (50 gm, 0.261 mol) in IPA (350 ml) was added slowly SMO-powder (33.8 gm, 0.626 mol) and stirred for about 15 min. Benzyl chloride (44 g, 0.313 mol) was added after completion of the reaction at a reaction temperature of -5 to -10°C for about 5hrs. The reaction mixture was quenched into ice-water (700 ml) and acidified with Cone. HC1 (2.0-2.5 ml). Filtered the reaction mixture, washed with water (2X100 ml) and dried the precipitate to obtain crude product which can be recrystallized from acetonitrile (28 ml) to obtain methyl-3-(hydroxy(phenyl)methylene)-2- oxoindoline-6-carboxylate pure crystalline solid (32 gm) (61%) (HPLC purity >97%). The filtrate was evaporated in vacuum to give unreacted methyl 2-oxoindoline-6-carboxylate. MR: 216-223°C; IR (KBr, cm^“1): 3178, 1711, 1651; 1H-NMR (400 MHz, DMSO): δ 3.80 (s, 3H), 7.17 (s, 1H), 7.28-7.31 (m, 2H), 7.46-7.50 (m, 3H), 7.72 (d, 2H, J = 6.0 Hz), 9.52 (s, 1H), 11.53 (s, 1H); ¹³C-NMR (100 MHz, DMSO): δ 22.12, 52.41, 101.13, 111.13, 119.23, 123.06, 126.65, 127.06, 128.65, 129.21, 132.26, 134.47, 136.99, 166.58, 172.52 and 175.80; MS: m/z 294 [M]^“1

Step-2: Preparation of methyl-3-(acetoxy(phenyl)methylene)-l-acetyl-2-oxoindoline-6-carboxylate (Acetyl derivative):

To the suspension of methyl-3-(hydroxy(phenyl)methylene)-2-oxoindoline-6-carboxylate (45 gm, 0.1512 mol) in acetic anhydride (300 ml) was added pyridine (4.5g) slowly (drop-wise) and stirred the reaction at temperature of 0-5°C for about30 min. After completion of the reaction raised the temperature of the reaction mass to 75-80°C and stirred for about lhr. Cooled the reaction mass and stirred for about 30 min at 25-28°C, filtered, washed with hexane (100ml) and dried the precipitate to obtain methyl-3-(acetoxy(phenyl)methylene)-l-acetyl-2-oxoindoline-6-carboxylate.

MR: 226-229°C; IR (KBr, cm^“1): 3413, 1771, 1743, 1717, 1640; 1H-NMR (400 MHz, CDC1₃): δ 2.38 (s, 3H), 2.62 (s, 3H), 3.92 (s, 3H), 7.44 (m, 3H), 7.62 (d, 2H, J = 7.004 Hz), 7.68 (d, 1H, J = 8.12 Hz), 7.91 (d, 1H, J = 8.0 Hz), 8.90 (s, 1H); ¹³C-NMR (100 MHz, CDC13): δ 21.08, 21.38, 26.96, 52.25, 52.34, 115.17, 117.18, 121.33, 122.77, 125.82, 126.19, 126.56, 128.15, 128.87, 129.27, 129.34, 130.81, 130.90, 131.47, 131.82, 132.80, 138.55, 160.85, 165.95, 166.38, 166.42, 167.01, 170.67 and 170.76; MS: m/z 380 [M]⁺¹.

Step-3: Preparation of methyl- l-acetyl-3-(((4-(2-chloro-N-methylacetamido)phenyl)amino) (phenyl)methylene)-2-oxoindoline-6-carboxylate) (Chloroacetyl derivative) :

Suspension of methyl-3-(acetoxy(phenyl)methylene)- l-acetyl-2-oxoindoline-6-carboxylate (Acetyl derivative) (49gm, 0.129mol) and N-(4-aminophenyl)-2-chloro-N-methylacetamide(25.66gm, 0.129 mol) in a mixture of methanol (350 ml) and DMF (88 ml) was heated to 60-65°C stirred for about 12hr at the same temperature. After completion of the reaction cooled the reaction mass to room temperature and stirred for about 30min. Filtered the reaction mixture, washed with methanol (2X50ml) and dried the precipitate to obtainmethyl-l-acetyl-3-(((4-(2-chloro-N-ethylacetamido)phenyl)amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate).

MR: 247-250°C; IR (KBr, cm^“1): 3432, 1712, 1675, 1591; 1H-NMR (400 MHz, DMSO): δ 2.74 (s, 3H), 3.11 (s, 3H), 3.78(s, 3H), 3.87 (s, 2H), 5.75 (d, 1H, J = 8.08 Hz), 7.01 (d, 2H, J = 7.96 Hz), 7.22 (d, 2H, J = 6.08Hz), 7.36 (d, 1H, J = 8.48 Hz), 7.46 (d, 2H, J = 7.24 Hz), 7.54-7.64 (m, 3H), 8.74 (s, 1H0, 11.92 (s, 1H), ¹³C-NMR (100MHz, DMSO): δ 27.17, 37.76, 42.48, 52.40, 96.38, 116.17, 117.59, 124.80, 125.33, 125.68, 128.09, 129.00, 130.10, 131.35, 131.97, 134.05, 160.93, 165.63, 166.68, 168.49 and 171.28; MS: m/z 518 [M]⁺¹ and 520 [M]⁺¹.

Step-4: Preparation of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-lyl)acetamide) phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (Nintedanib free base):

Suspension of methyl- l-acetyl-3-(((4-(2-chloro-N-methylacetamido)phenyl)amino) (phenyl)methylene)-2-oxoindoline-6-carboxylate)(40 gm, 0.077ml) and N-methylpiperidine (23.24 gm, 0.232 mol) in a mixture of DMF (160 ml) was heated to a reaction temperature of 45-50°C for about l-2hrs. The reaction mixture was quenched into ice-water (1.6 Lt) and stirred for about lhr at 15-20°C. Filtered the reaction mixture mass washed with water and dried the precipitate to obtain crystalline crude solid (36 gm). Purified with acetonitrile to obtain Nintedanib free base (34 gm) as a yellow crystals (93.74%) (HPLC purity: >98%). MR: 240-246°C; IR (KBr, cm^“1): 3559, 3455, 2940, 2810, 1711, 1657; 1H-NMR (400 MHz, DMSO): δ 2.09 (s, 3H), 2.17 (s, 8H), 2.68 (s, 2H), 3.05 (s, 3H), 3.76 (s, 3H), 5.80 (d, 1H, J = 7.56 Hz), 6.86 (d, 2H, J = 6.72 Hz), 7.11 (d, 1H, J = 6.48 Hz), 7.17 (d, 2H, J = 7.68 Hz), 7.42-7.57 (m, 6H), 10.98 (s, 1H), 12.23 (s, 1H) ; ¹³C-NMR (100MHz, DMSO): δ 37.17, 46.18, 52.24, 52.79, 55.05, 59.68, 98.10, 109.94, 117.75, 121.96, 124.29, 124.52, 128.06, 128.90, 129.40, 129.92, 130.91, 132.50, 136.72, 140.66, 158.81, 166.84, 169.04 and 170.66; MS: m/z 540 [M]⁺¹.

Step-5: Preparation of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-lyl)acetamide) phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate ethane sulfonate salt:

Suspension of (Z)-methyl-3-(((4-(N-methyl-2-(4-methylpiperazin-l-yl)acetamide)phenyl) amino)(phenyl)methylene)-2-oxoindoline-6-carboxylate (36 gm, 0.066 mol) in methanol (237 ml) and water (2.88 ml)was heated to 60-65°C and aq. ethane sulfonic acid was added to the reaction mixture. The resulting solution was cooled to 50°C, seeds diluted with isopropanol (237 ml) was added. The reaction mixture was cooled at 0°C for lhr. Filtered the precipitate, washed with mixture of methanol and isopropanol (50 ml), dried to obtain crude Nintedanib monoethane sulfonate (36.6 gm) and crystallized from methanol (5 Vol) to

obtained pure Nintedanib monoethane sulfonate salt as yellow crystals (33 gm) (80%) (HPLC purity >99%).

DSC: 298°C; IR (KBr, cm-1): 3321, 3273, 1710, 1652, 1615, 1515, 1435, 1378, 1289, 1209, 1161, 1087; 1H-NMR (400 MHz, DMSO): δ 1.08 (t, 3H, J = 7.31 Hz), 2.41-2.47 (q, 2H), 2.50-3.16 (broad m, 13H), 3.37 (s, 3H), 3.76 (s, 3H), 5.82 (d, 1H, J = 7.88Hz), 6.87 (d, 2H, J = 7.36 Hz), 7.14-7.20 (m, 3H), 7.49 (s, 1H), 7.49 (d, 2H, J = 6.68 Hz), 7.56-7.63 (m, 3H), 9.45 (s, 1H), 10.99 (s, 1H), 12.25 (s, 1H), 13C-NMR (100 MHz, DMSO): δ 37.15, 42.79, 45.65, 49.40, 52.26, 53.10, 58.04, 98.25, 110.01, 117.78, 121.97, 124.32, 124.59, 128.27, 128.90, 129.36, 130.00, 131.00, 132.52, 136.79, 137.93, 140.00, 158.66, 166.85, 168.47 and 170.65; MS: m/z 540[M]⁺¹.

Example 2: Process for the preparation of Polymorph Form S of Nintedanib monoethanesulf onate :

Crude Nintedanib monoethane sulfonate was dissolved in methanol and heated to 60-64°C for about 15 min. After completion of the reaction cooled to room temperature for about lhr. Filtered the precipitate, washed with mixture of methanol (20ml) and isopropanol (30 ml) and dried to obtain pure crystalline solid (28 gm) (yield: 93.3%) with HPLC purity 99.72% and individual impurities 0.09%, 0.02% and 0.04%.

SUVEN, Chief executive and chairman Venkat Jasti

//////////WO2016178064,  POLYMORPH,  NINTEDANIB ETHANESULPHONATE, PROCESSES,  INTERMEDIATES, suven, new patent