Metopimazine

RP-9965, EXP-999, NG-101

l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide

• Isonipecotamide, 1-[3-[2-(methylsulfonyl)phenothiazin-10-yl]propyl]- (7CI,8CI)
• 1-[3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
• 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]-4-piperidinecarboxamide
• 1-[3-[2-(Methylsulfonyl)phenothiazin-10-yl]propyl]isonipecotamide
• 2-Methylsulfonyl-10-[3-(4-carbamoylpiperidino)propyl]phenothiazine

• EXP 999
• Metopimazine
• RP 9965
• Vogalene
• metopimazine (gastroparesis), Neurogastrx

Sanofi (Originator)
Teva

Treatment of Nausea and Vomiting, APPROVED

Dopamine D3 receptor antagonist; Dopamine D2 receptor antagonist

Gastroprokinetic

Metopimazine (INN) is a phenothiazine antiemetic.

Metopimazine is an established antiemetic that has been approved and marketed for many years in Europe for the treatment of acute conditions. The compound does not cross the blood-brain-barrier, and is therefore free from central side effects, and is not associated with cardiovascular side effects

In May 2016, preclinical data were presented at the 2016 DDW in San Diego, CA. In rats, po NG-101 and domperidone did not penetrate the brain at therapeutically relevant concentrations, unlike metoclopramide. In dogs, the amplitude and frequency of antral contractions were increased by NG-101, whereas in rats, po metopimazine resulted in an increase in gastric emptying of solid foods. The blood-brain barrier was not readily crossed and there was no interaction with 5-HT3 or 5-HT4 receptors by NG-101 unlike metoclopramide and domperidone, respectively

In July 2014, preclinical data were published. Metopimazine at 1mg/kg increased gastric motility in hound dogs. In studies in rodents, metopimazine at 3 and 10 mg/kg increased gastric emptying by 18 and 40%, respectively, compared with vehicle control

There is an increasing demand for antiemetic agents because of the most troublesome adverse effects of chemotherapy-induced nausea and emesis during cancer treatment.

However, the objective of complete prevention of emesis in all patients remains elusive. Therefore, there is a great demand for both development of (i) new antiemetic agents and (ii) new manufacturing processes for existing antiemetic agents. Metopimazine is an existing dopamine D₂-receptor antagonist with potent antiemetic properties. It is chemically known as l-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide , which belongs to nitrogen- and sulfur-containing tricyclic compounds (phenothiazine class of drugs) with interesting biological and pharmacological activities.

Recently, it has been found that Metopimazine plays a key role as an alternative to Ondansetron in the prevention of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving moderate to high emetogenic noncisplatin-based chemotherapy.It has been used in France for many years for the prevention and treatment of nausea and vomiting under the brand name of Vogalene

In 1959, the first synthesis and manufacture process of Metopimazine  was reported by Jacob et al.The synthesis starts from the protection of 2-(Methylsulfanyl)-10H-phenothiazine..Jacob, R. M.; Robert, J. G. German Patent No. DE1092476, 1959.

Later, in 1990, Sindelar et al. reported a modified process , which starts from synthesis of 4-(2-fluorophenylthio)-3-nitrophenylmethylsulfone..Sindelar, K.; Holubek, J.; Koruna, I.; Hrubantova, M.; Protiva, M. Collect. Czech. Chem. Commun. 1990, 55, 1586– 1601, DOI: 10.1135/cccc19901586

In 2010, Satyanarayana Reddy et al. reported a modified synthetic route which starts from either N-protection using acetyl chloride or N-alkylation using dihalopropane of 2-(methylsulfanyl)-10H-phenothiazine ..Satyanarayana Reddy, M.; Eswaraiah, S.; Satyanarayana, K. Indian Patent No. 360/CHE/2010 A, Aug 19, 2011.

Synthesis of 1-(3-[2-(methylsulfonyl)-10H-phenothiazin-10-yl]propyl)piperidine-4- carboxamide (1)-Metopimazine: Pale yellow color solid, yield. 65% (82 g), DSC 189 °C.

1H NMR (400 MHz, DMSO-d6, δ/ppm): 7.44 (d, 1H, arom H, J = 8.8 Hz), 7.37 (d, 2H, arom H, J = 8.0 Hz), 7.24 (t, 1H, arom H, J = 7.6 Hz), 7.16 (m, 2H, -NH2), 7.1 (d, 1H, arom H, J = 8.4 Hz), 6.99 (t, 1H, arom H, J = 7.6 Hz), 6.68 (s, 1H, arom H), 3.99 (t, 2H, -NCH2, J = 6.4 Hz), 3.23 (s, 3H, -S-CH3), 2.8-2.73 (m, 2H, -CH2-), 2.36 (t, 2H, -CH2-, J = 6.8 Hz), 2.02-1.96 (m, 1H, -CH-), 1.84-1.78 (m, 4H, 2-CH2-), 1.61-1.58 (m, 2H, -CH2-), 1.48-1.44 (m, 2H, – CH2-).

13C NMR (100 MHz, DMSO-d6, δ/ppm): 176.52, 145.41, 143.5, 140.12, 130.47, 128.03, 127.50, 127.25, 123.23, 122.16, 120.59, 116.38, 113.24, 54.82, 52.97, 44.64, 43.47, 41.7, 28.59, 23.52.

MS m/z (ESI): 446.21 (M+H)+.

SYNTHESIS

PATENT

IN 201641043070

IN 2013CH05689

IN 2013CH00361

IN 2010CH00360

DE 1092476/US 3130194

PAPER

A Simple and Commercially Viable Process for Improved Yields of Metopimazine, a Dopamine D₂-Receptor Antagonist

Venumanikanta Karicherla, Kumar Phani, Mohan Reddy Bodireddy, Kumar Babu Prashanth, Madhusudana Rao Gajula^*, and Kumar Pramod^*

Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, Fourth Phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore, Karnataka 560 105, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00052

*E-mail: pramodkumar@microlabs.in. Tel: 0811 0415647, ext. 245. Mobile No.: +91 9008448247., *E-mail: gmadhusudanrao@yahoo.com.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.7b00052

An efficient, practical, and commercially viable manufacturing process was developed with ≥99.7% purity and 31% overall yield (including four chemical reactions and one recrystallization) for an active pharmaceutical ingredient, called Metopimazine (1), an antiemetic drug used to prevent emesis during chemotherapy. The development of two in situ, one-pot methods in the present synthetic route helped to improve the overall yield of 1 (31%) compared with earlier reports (<15%). For the first time, characterization data of API (1), intermediates, and also possible impurities are presented. The key process issues and challenges were addressed effectively and achieved successfully.

Synthesis of 1-(3-[2-(Methylsulfonyl)-10H-phenothiazin-10-yl]propyl)-4-piperidinecarboxamide (1), Metopimazine

 

Metopimazine

Clinical data
AHFS/Drugs.com	International Drug Names
ATC code	A04AD05 (WHO)
Identifiers
IUPAC name[show]
CAS Number	14008-44-7
PubChem CID	26388
ChemSpider	24584
UNII	238S75V9AV
ChEMBL	CHEMBL398615
ECHA InfoCard	100.034.367
Chemical and physical data
Formula	C22H27N3O3S2
Molar mass	445.6 g/mol
3D model (Jmol)	Interactive image
SMILES[hide] O=S(=O)(c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCC(C(=O)N)CC4)C

//////////////Metopimazine, Dopamine D₂-Receptor Antagonist, 14008-44-7, sanofi, teva, RP-9965, Nausea and Vomiting, EXP-999, NG-101, metopimazine, gastroparesis, Neurogastrx

NC(=O)C1CCN(CC1)CCCN2c4ccccc4Sc3ccc(cc23)S(C)(=O)=O

USA Viewership touched 3 lakhs on New Drug Approvals

https://newdrugapprovals.org/

Total 16.9 lakhs in 213 countries

BMS 986205

CAS: 1923833-60-6

Phase 1 cancer

BMS-986205, ONO-7701,  F- 001287

• Molecular Formula C₂₄H₂₄ClFN₂O
• Average mass 410.912 Da

• Originator Bristol-Myers Squibb
• Class Antineoplastics
• 01 Feb 2016 Phase-I/II clinical trials in Cancer (Combination therapy, Late-stage disease, Second-line therapy or greater) in Canada (PO) (NCT02658890)
• 31 Jan 2016 Preclinical trials in Cancer in USA (PO) before January 2016
• 01 Jan 2016 Bristol-Myers Squibb plans a phase I/IIa trial for Cancer (Late-stage disease, Combination therapy, Second-line therapy or greater) in USA, Australia and Canada (PO) (NCT02658890)

Hilary Beck

EX Principal Investigator, Company NameFLX Bio, Inc., 

CURRENTLY Director, Medicinal Chemistry at IDEAYA Biosciences, IDEAYA Biosciences, The University of Texas at Austin

Brian Wong

Chief Executive Officer at FLX Bio, Inc.

Bristol-Myers Squibb, following its acquisition of Flexus Biosciences, is developing BMS-986205 (previously F- 001287), the lead from an immunotherapy program of indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors for the potential treatment of cancer. In February 2016, a phase I/IIa trial was initiated .

BMS-986205 (ONO-7701) is being evaluated at Bristol-Myers Squibb in phase I/II clinical trials for the oral treatment of adult patients with advanced cancers in combination with nivolumab. Early clinical development is also ongoing at Ono in Japan for the treatment of hematologic cancer and for the treatment of solid tumors.

In April 2017, data from the trial were presented at the 108th AACR Annual Meeting in Washington DC. As of February 2017, the MTD had not been reached, but BMS-986205 plus nivolumab treatment was well tolerated, with only two patients discontinuing treatment due to DLTs. The most commonly reported treatment-related adverse events (TRAEs) were decreased appetite, fatigue, nausea, diarrhea, and vomiting. Grade 3 TRAEs were reported in three patients during the combination therapy; however, no grade 3 events were reported during BMS-986205 monotherapy lead-in. No grade 4 or 5 TRAEs were reported with BMS-986205 alone or in combination with nivolumab

Indoleamine 2,3-dioxygenase (IDO; also known as IDOl) is an IFN-γ target gene that plays a role in immunomodulation. IDO is an oxidoreductase and one of two enzymes that catalyze the first and rate-limiting step in the conversion of tryptophan to N-formyl-kynurenine. It exists as a 41kD monomer that is found in several cell populations, including immune cells, endothelial cells, and fibroblasts. IDO is relatively well-conserved between species, with mouse and human sharing 63% sequence identity at the amino acid level. Data derived from its crystal structure and site-directed mutagenesis show that both substrate binding and the relationship between the substrate and iron-bound dioxygenase are necessary for activity. A homolog to IDO (ID02) has been identified that shares 44% amino acid sequence homology with IDO, but its function is largely distinct from that of IDO. (See, e.g., Serafini P, et al, Semin. Cancer Biol, 16(l):53-65 (Feb. 2006) and Ball, H.J. et al, Gene, 396(1):203-213 (Jul. 2007)).

IDO plays a major role in immune regulation, and its immunosuppressive function manifests in several manners. Importantly, IDO regulates immunity at the T cell level, and a nexus exists between IDO and cytokine production. In addition, tumors frequently manipulate immune function by upregulation of IDO. Thus, modulation of IDO can have a therapeutic impact on a number of diseases, disorders and conditions.

A pathophysiological link exists between IDO and cancer. Disruption of immune homeostasis is intimately involved with tumor growth and progression, and the production of IDO in the tumor microenvironment appears to aid in tumor growth and metastasis. Moreover, increased levels of IDO activity are associated with a variety of different tumors (Brandacher, G. et al, Clin. Cancer Res., 12(4): 1144-1151 (Feb. 15, 2006)).

Treatment of cancer commonly entails surgical resection followed by chemotherapy and radiotherapy. The standard treatment regimens show highly variable degrees of long-term success because of the ability of tumor cells to essentially escape by regenerating primary tumor growth and, often more importantly, seeding distant metastasis. Recent advances in the treatment of cancer and cancer-related diseases, disorders and conditions comprise the use of combination therapy incorporating immunotherapy with more traditional chemotherapy and radiotherapy. Under most scenarios, immunotherapy is associated with less toxicity than traditional chemotherapy because it utilizes the patient’s own immune system to identify and eliminate tumor cells.

In addition to cancer, IDO has been implicated in, among other conditions, immunosuppression, chronic infections, and autoimmune diseases or disorders (e.g. , rheumatoid arthritis). Thus, suppression of tryptophan degradation by inhibition of IDO activity has tremendous therapeutic value. Moreover, inhibitors of IDO can be used to enhance T cell activation when the T cells are suppressed by pregnancy, malignancy, or a virus (e.g., HIV). Although their roles are not as well defined, IDO inhibitors may also find use in the treatment of patients with neurological or neuropsychiatric diseases or disorders (e.g., depression).

Small molecule inhibitors of IDO have been developed to treat or prevent IDO-related diseases. For example, the IDO inhibitors 1-methyl-DL-tryptophan; p-(3-benzofuranyl)-DL-alanine; p-[3-benzo(b)thienyl]-DL-alanine; and 6-nitro-L-tryptophan have been used to modulate T cell-mediated immunity by altering local extracellular concentrations of tryptophan and tryptophan metabolites (WO 99/29310). Compounds having IDO inhibitory activity are further reported in WO 2004/094409.

In view of the role played by indoleamine 2,3-dioxygenase in a diverse array of diseases, disorders and conditions, and the limitations (e.g., efficacy) of current IDO inhibitors, new IDO modulators, and compositions and methods associated therewith, are needed.

In April 2017, preclinical data were presented at the 108th AACR Annual Meeting in Washington DC. BMS-986205 inhibited kynurenine production with IC50 values of 1.7, 1.1 and > 2000 and 4.6, 6.3 and > 2000 nM in human (HeLa, HEK293 expressing human IDO-1 and tryptophan-2, 3-dioxygenase cell-based assays) and rat (M109, HEK293 expressing mouse ID0-1 and -2 cell-based assays) respectively. In human SKOV-3 xenografts (serum and tumor) AUC (0 to 24h; pharmacokinetic and pharmacodynamic [PK and PD])) was 0.8, 4.2 and 23 and 3.5, 11 and 40 microM h, respectively; area under the effect curve (PK and PD) was 39, 32 and 41 and 60, 63 and 76% kyn, at BMS-986205 (5, 25 and 125 mg/kg, qd×5), respectively

In April 2017, preclinical data were presented at the 253rd ACS National Meeting and Exhibition in San Francisco, CA. BMS-986205 showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. A good pharmacokinetic profile was seen at oral and iv doses in rats, dogs and monkeys. The compound showed good oral exposure and efficacy in in vivo assays

Preclinical studies were performed to evaluate the activity of BMS-986205, a potent and selective optimized indoleamine 2, 3-dioxygenase (IDO)- 1inhibitor, for the treatment of cancer. BMS-986205 inhibited kynurenine production with IC50 values of 1.7, 1.1 and > 2000 and 4.6, 6.3 and > 2000 nM in human (HeLa, HEK293 expressing human IDO-1 and tryptophan-2, 3-dioxygenase cell-based assays) and rat (M109, HEK293 expressing mouse ID0-1 and -2 cell-based assays) respectively. BMS-986205 was also found to be potent when compared with IDO-1from other species (human < dog equivalent monkey equivalent mouse > rat). In cell-free systems, incubation of inhibitor lead to loss of heme absorbance of IDO-1 which was observed in the presence of BMS-986205 (10 microM), while did not observed with epacadostat (10 microM). The check inhibitory activity and check reversibility (24 h after compound removal) of BMS-986205 was found to be < 1 and 18% in M109 (mouse) and < 1 and 12% SKOV3 (human) cells, respectively. In human whole blood IDO-1, human DC mixed lymphocyte reaction and human T cells cocultured with SKOV3 cells- cell based assays, BMS-986205 showed potent cellular effects (inhibition of kynurenine and T-cell proliferation 3H-thymidine) with IC50 values of 2 to 42 (median 9.4 months), 1 to 7 and 15 nM, respectively. In human SKOV-3 xenografts (serum and tumor) AUC (0 to 24h; pharmacokinetic and pharmacodynamic [PK and PD])) was 0.8, 4.2 and 23 and 3.5, 11 and 40 microM h, respectively; area under the effect curve (PK and PD) was 39, 32 and 41 and 60, 63 and 76% kyn, at BMS-986205 (5, 25 and 125 mg/kg, qd×5), respectively. In vivo human-SKOV3 and hWB-xenografts, IC50 values of BMS-986205 were 3.4 and 9.4 NM, respectively. The ADME of BMS-986205 at parameters iv/po dose was 0.5/2, 0.5/1.5 and 0.5/1.2 mg/kg, respectively; iv/clearance was 27, 25 and 19 ml, min/kg, respectively; iv Vss was 3.8, 5.7 and 4.1 l/kg, respectively; t1/2 (iv) was 3.9, 4.7 and 6.6 h, respectively; fraction (po) was 64, 39 and 10%, respectively. At the time of presentation, BMS-986205 was being evaluated in combination with nivolumab.

The chemical structure and preclinical profile was presented for BMS-986205 ((2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide), a potent IDO-1 inhibitor in phase I for the treatment of cancer. This compound showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. The pharmacokinetic profile in rats dosed at 0.5 mg/kg iv and 2 mg/kg po, with clearance, Vss, half-life and bioavailability of 27 ml/min/kg, 3.8 l/kg, 3.9 h and 4%, respectively; in dogs at 0.5 iv and 1.5 po mg/kg dosing results were 25 ml/min/kg, 5.7 l/kg, 4.7 h and 39%; and, in cynomolgus monkeys with the same doses as dogs results were 19 ml/min/kg, 4.1 l/kg, 6.6 h and 10%, respectively. The compound showed good oral exposure and efficacy in in vivo assays.

BMS-986158: a BET inhibitor for cancerAshvinikumar Gavai of Bristol Myers Squibb (BMS) gave an overview of his company’s research into Bromodomian and extra-terminal domain (BET) as oncology target for transcriptional suppression of key oncogenes, such as MYC and BCL2. BET inhibition has been defined as strong rational strategy for the treatment of hematologic malignancies and solid tumors. From crystal-structure guided SAR studies, BMS-986158, 2-{3-(1,4-Dimethyl-1H-1,2,3-triazol-5-yl)-5-[(S)-(oxan-4-yl)(phenyl)methyl]-5H-pyrido[3,2-b]indol-7-yl}propan-2-ol, was chosen as a potent BET inhibitor, showing IC50 values for BRD2, BRD3 and BRD4 activity of 1 nM; it also inhibited Myc oncogene (IC50 = 0.5 nM) and induced chlorogenic cancer cell death. In vitro the compound also displayed significant cytotoxicity against cancer cells.  When administered at 0.25, 0.5 and 1 mg/kg po, qd to mice bearing human lung H187 SCLC cancer xenograft, BMS-986158 was robust and showed efficacy as a anticancer agent at low doses. In metabolic studies, it showed t1/2 of 36, 40 and 24 min in human, rat and mice, respectively, and it gave an efflux ratio of 3 in Caco-2 permeability assay. In phase 1/II studies, BMS-986158 was well tolerated at efficacious doses and regimens, and drug tolerable toxicity at efficacy doses and regimens. Selective Itk inhibitors for inflammatory disordersThe development of highly selective Itk inhibitors for the treatment of diseases related to T-cell function, such as inflammatory disorders, was described by Shigeyuki Takai (Ono Pharmaceutical). Inhibitory properties of a hit compound, ONO-8810443, were modified via X-ray structure and Molecular Dynamics stimulation to get ONO-212049 with significant kinase selectivity (140-fold) against Lck, a tyrosine kinase operating upstream of Itk in the TCR cascade. Further modifications identified final lead compound ONO-7790500 (N-[6-[3-amino-6-[2-(3-methoxyazetidin-1-yl)pyridin-4-yl]pyrazin-2-yl]pyridin-3-yl]-1-(3-methoxyphenyl)-2,3-dimethyl-5-oxopyrazole-4-carboxamide), which selectively inhibited Itk (IC50 = < 0.004 microM) over Lck (IC50 = 9.1 microM; SI 2000-fold) and suppressed Jurkat T-cell proliferation (IC50 = 0.014 microM). This compound suppressed alphaCD3/CDP28 CD4+T-cell stimulation (IC50 = 0.074 microM) with selectivity over PMA/Ionomycin (IC50 = > 10 microM). ONO-7790500 also exhibited in vivo IL-2 inhibitory properties (62% inhibition at 30 mg/kg po) in mice. In pharmacokinetic studies in balb/c mice, the compound administered orally (10 mg/kg) showed a Cmax of 1420 ng/ml, AUClast of 11,700 ng*h/ml, t1/2 of 5.3 h and oral bioavailability of 68%. Administration iv at 0.3 mg/kg gave an AUC last of 610 ng*h/ml, t1/2 of 3.8 h, Vss of 1260 ml/kg and Cl of 5.1 ml/min/kg. ADMET data showed ONO-7790500 did not have relevant activity in cytochromes and hERG channels (IC50 > 10 microM) in toxicological studies, and gave a PAMPA value of 5.0 x 10(-6) cm/s. Fused imidazole and pyrazole derivatives as TGF-beta inhibitorsDual growth and differentiation factor-8 (GDF-8; also known as myostatin) and TGF-beta inhibitors were described. Both targets belong to TGF-beta superfamily consisting of a large group of structurally related cell regulatory proteins involved in fundamental biological and pathological processes, such as cell proliferation or immunomodulation. Myostatin (GDF8) is a negative regulator negative regulator of skeletal muscle growth and has also been related to bone metabolism. Investigators at Rigel Pharmaceuticals found that compounds designed to be GDF-8 inhibitors were able to inhibit TGF-beta as well, this could be an advantage for the treatment of diseases associated with muscle and adipose tissue disorders, as well as potentially immunosuppressive disorders. Jiaxin Yu from the company described  new fused imidazole derivatives, of which the best compound was 6-[2-(2,4,5-Trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl]quinoxaline. This compound was very potent at TGF-beta Receptor Type-1 (ALK5) inhibition with an IC50 value of 1nM. In an in vivo mouse assay this compound showed good activity at 59.7 mg/kg, po, and good plasma exposure; inhibition of GDF-8 and TGFbeta growth factors was 90 and 81.6 %, respectively.Rigel’s Ihab Darwish described a series of fused pyrazole derivatives, with the best compound being 6-[2-(2,4-Difluorophenyl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl][1,2,4]triazolo[1,5-a]pyridine. This compound showed an IC50 of 0.06 and 0.23 microM for GDF-8 and TGFbeta, respectively, in the pSMAD (MPC-11) signaling inhibition test. The compound had a good pharmacokinetic profile, with 40% of bioavailability in mice after a 5-mg/kg po dose. An iv dose of 1 mg/kg showed t1/2 of 0.7 h and Vss of 1.0 l/h/kgDiscovery of selective inhibitor of IDO BMS-986205 for cancerIndoleamine-2,3-dioxygenase (IDO)-1 enzyme initiates and regulates the first step of the kynurenine pathway (KP) of tryptophan metabolism, and evidence has shown that overexpression of IDO-1 in cancer tumors is a crucial mechanism facilitating tumor immune evasion and persistence. The chemical structure and preclinical profile of BMS-986205 was presented by Aaron Balog from BMS. BMS-986205 ((2R)-N-(4-Chlorophenyl)-2-[cis-4-(6-fluoroquinolin-4-yl)cyclohexyl]propanamide),  is a potent IDO-1 inhibitor in phase I for the treatment of cancer. This compound showed potent and selective inhibition of IDO-1 enzyme (IC50 = 1.7nM) and potent growth inhibition in cellular assays (IC50 = 3.4 nM) in SKOV3 cells. The pharmacokinetic profile in rats dosed at 0.5 mg/kg iv and 2 mg/kg po, with clearance, Vss, half-life and bioavailability of 27 ml/min/kg, 3.8 l/kg, 3.9 h and 4%, respectively; in dogs at 0.5 iv and 1.5 po mg/kg dosing results were 25 ml/min/kg, 5.7 l/kg, 4.7 h and 39%; and, in cynomolgus monkeys with the same doses as dogs results were 19 ml/min/kg, 4.1 l/kg, 6.6 h and 10%, respectively. The compound showed good oral exposure and efficacy in in vivo assays.Three further reports have been published from this meeting .The website for this meeting can be found at https://www.acs.org/content/acs/en/meetings/spring-2017.html.

SYNTHESIS

1 Wittig  NaH

2 REDUCTION H2, Pd, AcOEt, 4 h, rt, 50 psi

3 Hydrolysis HCl, H2O, Me2CO, 2 h, reflux

4  4-Me-2,6-(t-Bu)2-Py, CH2Cl2, overnight, rt

5 SUZUKI AcOK, 72287-26-4, Dioxane, 16 h, 80°C

6  Heck Reaction,  Suzuki Coupling, Hydrogenolysis of Carboxylic Esters, Reduction of Bonds, HYDROGEN

7 Et3N, THF, rt – -78°C , Pivaloyl chloride, 15 min, -78°C; 1 h, 0°C ,THF, 0°C – -78°C, BuLi, Me(CH2)4Me, 15 min, -78°C, R:(Me3Si)2NH •Na, THF, 10 min, -50°C , HYDROLYSIS,  (PrP(=O)O)3, C5H5N, AcOEt, 5 min, rt

Patent

WO2016073770

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=289DBE79BEFC6ADC558C89E7A74B19DB.wapp2nB?docId=WO2016073770&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example 19

(i?)-N-(4-chlorophenyl)-2- c 5-4-(6-fluoroquinolin-4-yl)cyclohexyl)propanamide

Example 19 : (i?)-N-(4-chlorophenyl)-2-(cz5-4-(6-fluoroquinolin-4- yl)cyclohexyl)propanamide

[0277] Prepared using General Procedures K, B, E, L, M, N, and O. General Procedure L employed 2-(4-(6-fluoroquinolin-4-yl)-cyclohexyl)acetic acid (mixture of

diastereomers), and ( ?)-2-phenyl-oxazolidinone. General Procedure M employed the cis product and iodomethane. The auxiliary was removed following General Procedure N and the desired product formed employing General Procedure O with 4-chloroaniline.

Purified using silica gel chromatography (0% to 100% ethyl acetate in hexanes) to afford Example 19. 1H NMR of czs-isomer (400 MHz; CDC1₃): δ 9.14 (s, 1H), 8.70 (d, J= 4.6 Hz, 1H), 8.06 (dd, J= 9.2 Hz, J= 5.6 Hz, 1H), 7.58-7.64 (m, 3H), 7.45 (ddd, J= 9.3 Hz, J= 7.8 Hz, J= 2.7 Hz, 1H), 7.19-7.24 (m, 2H), 7.15 (d, J= 4.6Hz, 1H), 3.16-3.26 (m, 1H), 2.59-2.69 (m, 1H), 2.08-2.16 (m, 1H), 1.66-1.86 (m, 7H), 1.31-1.42 (m, 1H), 1.21 (d, J= 6.8Hz, 3H) ppm. m/z 411.2 (M+H)⁺.

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Juan Jaen

Jordan Fridman

Chief Scientific Officer at FLX Bio, Inc.

Rekha Hemrajani

Chief Operating Officer at FLX Bio, Inc

Max Osipov

////////////////PHASE 1, BMS 986205, 1923833-60-6, BMS-986205, ONO-7701,Bristol-Myers Squibb,  Antineoplastics,  F- 001287

 C[C@H]([C@H]1CC[C@@H](C2=CC=NC3=CC=C(F)C=C23)CC1)C(NC4=CC=C(Cl)C=C4)=O

Wrapping up #MEDI‘s 1st time disclosures is Aaron Balog of @bmsnews talking about an IOD-1 inhibitor to treat cancer #ACSSanFran

The U.S. Food and Drug Administration today expanded the approved use of Kalydeco (ivacaftor) for treating cystic fibrosis. The approval triples the number of rare gene mutations that the drug can now treat, expanding the indication from the treatment of 10 mutations, to 33. The agency based its decision, in part, on the results of laboratory testing, which it used in conjunction with evidence from earlier human clinical trials. The approach provides a pathway for adding additional, rare mutations of the disease, based on laboratory data.

“Many rare cystic fibrosis mutations have such small patient populations that clinical trial studies are not feasible,” said Janet Woodcock, M.D., director of the FDA’s Center for Drug Evaluation and Research. “This challenge led us to using an alternative approach based on precision medicine, which made it possible to identify certain gene mutations that are likely to respond to Kalydeco.

Cystic fibrosis affects the cells that produce mucus, sweat and digestive juices. These secreted fluids are normally thin and slippery due to the movement of sufficient ions (chloride) and water in and out of the cells. People with the progressive disease have a defective cystic fibrosis transmembrane conductance regulator (CFTR) gene that can’t regulate the movement of ions and water, causing the secretions to become sticky and thick. The secretions build up in the lungs, digestive tract and other parts of the body leading to severe respiratory and digestive problems, as well as other complications such as infections and diabetes.

Results from an in vitro cell-based model system have been shown to reasonably predict clinical response to Kalydeco. When additional mutations responded to Kalydeco in the laboratory test, researchers were thus able to extrapolate clinical benefit demonstrated in earlier clinical trials of other mutations. This resulted in the addition of gene mutations for which the drug is now indicated.

Kalydeco, available as tablets or oral granules taken two times a day with fat-containing food, helps the protein made by the CFTR gene function better and as a result, improves lung function and other aspects of cystic fibrosis, including weight gain. If the patient’s genotype is unknown, an FDA-cleared cystic fibrosis mutation test should be used to detect the presence of a CFTR mutation followed by verification with bi-directional sequencing when recommended by the mutation test instructions for use.

Cystic fibrosis is a rare disease that affects about 30,000 people in the United States.Kalydeco is indicated for patients aged 2 and older who have one mutation in the CFTR gene that is responsive to drug treatment based on clinical and/or in vitro (laboratory) data. The expanded indication will affect another 3 percent of the cystic fibrosis population, impacting approximately 900 patients. Kalydeco serves as an example of how successful patient-focused drug development can provide greater understanding about a disease. For example, the Cystic Fibrosis Foundation maintains a 28,000-patient registry, including genetic data, which it makes available for research.

Common side effects of Kalydeco include headache; upper respiratory tract infection (common cold) including sore throat, nasal or sinus congestion, or runny nose; stomach (abdominal) pain; diarrhea; rash; nausea; and dizziness. Kalydeco is associated with risks including elevated transaminases (various enzymes produced by the liver) and pediatric cataracts. Co-administration with strong CYP3A inducers (e.g., rifampin, St. John’s wort) substantially decreases exposure of Kalydeco, which may diminish effectiveness, and is therefore not recommended.

Kalydeco is manufactured for Boston-based Vertex Pharmaceuticals Inc.

PRESENTING 2 MOLECULES………..I AM NOT SURE WHICH IS TITLE MOLECULE

EMAIL ME amcrasto@gmail.com

2-[(3R)-3alpha-Aminopiperidino]-3-(2-butynyl)-5-(4-methyl-2-quinazolinylmethyl)-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidine-4-one

CAS 1428445-40-2

REF Bioorganic & Medicinal Chemistry (2013), 21(7), 1749-1755.

NEXT ONE………………

CAS 1415912-31-0

TILOGLIPTIN

HWH-ZGC-2-143

Guangzhou Institutes of Biomedicine and Health

Chia Tai Tianqing Pharmaceutical Group Co Ltd;

Non-insulin dependent diabetes

Dipeptidyl peptidase IV inhibitor (oral, type 2 diabetes),

DPP-IV inhibitors (oral, type 2 diabetes), Guangzhou Institutes of Biomedicine and Health/Jiangsu Chia Tai Tianqing Pharmaceutical ; HWH-ZGC-2-143 ;

Novel polymorphic forms of thiadiazole derivatives, preferably aglucin, sitagliptin, saxagliptin, vildagliptin, levaratine, useful for treating type II diabetes. Guangzhou Institutes of Biomedicine and Health , in collaboration with Jiangsu Chia Tai Tianqing Pharmaceutical , is investigating tilogliptin , an oral dipeptidyl peptidase IV inhibitor and a pyrrolopyrimidine analog, for treating type 2 diabetes.

As of June 2017, Centaurus BioPharma is developing diabetes therapy, CT-1006 and CT-1005 (in preclinical development) for treating diabetes mellitus.

See WO2016019868, claiming novel citric acid salt of 8-((R)-3-amino-piperidin-1-yl)-1-([1,2,5]-thiadiazolo [3,4-b] pyridine-5methyl)-7-(2-butyn-1-yl)-3-methyl-xanthine, coassigned to Lianyungang Runzhong Pharmaceutical .

PATENT

WO2016019868

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2016019868

PATENT

WO 2017088790

Centaurus BioPharma Co Ltd; Chia Tai Tianqing Pharmaceutical Group Co Ltd

N[C@@H]1CCCN(C1)C5=Nc4ccn(Cc3nc2ccccc2c(C)n3)c4C(=O)N5CC#CC

N[C@@H]1CCCN(C1)c5nc4c(C(=O)N(Cc2ccc3nsnc3n2)C(=O)N4C)n5CC#CC

HNIW, CL-20

• Molecular FormulaC₆H₆N₁₂O₁₂
• Average mass438.185 Da
• 1,3,4,7,8,10-hexanitrooctahydro-1H-5,2,6-(epiminomethanetriylimino)imidazo[4,5-b]pyrazine
  CAS 135285-90-4

• Hexanitrohexaazaisowurtzitane
• 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane
• Octahydro-1,3,4,7,8,10-hexanitro-5,2,6-(iminomethenimino)-1H-imidazo[4,5-b]pyrazine
• HNIW
• 六硝基六氮杂异伍兹烷

ABOUT AUTHOR

Tomasz Gołofit

Thermochemistry, Physical Chemistry, Materials Chemistry

Staff Paweł Maksimowski Wincenty Skupiński Wojciech Pawłowski Waldemar Tomaszewski Tomasz Gołofit Katarzyna Cieślak

Faculty of Chemistry, Division of High Energetic Materials, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland

Hexanitrohexaazaisowurtzitane /ˈhɛksɑːˈnaɪtroʊˈhɛksɑːˌæzɑːˌaɪsoʊˈvʊərtsɪteɪn/, also called HNIW and CL-20, is a nitroamine explosive with the formula C₆H₆N₁₂O₁₂. The structure of CL-20 was first proposed in 1979 by Dalian Institute of Chemical Physics.^[1]In 1980s, CL-20 was developed by the China Lake facility, primarily to be used in propellants. It has a better oxidizer-to-fuel ratio than conventional HMX or RDX. It releases 20% more energy than traditional HMX-based propellants, and is widely superior to conventional high-energy propellants and explosives.

Industrial production of CL-20 was achieved in China in 2011, and it was soon fielded in propellant of solid rockets.^[2] While most development of CL-20 has been fielded by the Thiokol Corporation, the US Navy (through ONR) has also been interested in CL-20 for use in rocket propellants, such as for missiles, as it has lower observability characteristics such as less visible smoke.^[3]

CL-20 has not yet been fielded in any production weapons system, but is undergoing testing for stability, production capabilities, and other weapons characteristics.

Synthesis

THEN CONVERTED TO CL20, HNIW

Synthesis of CL20, HNIW

505	Synthesis of CL-20: By oxidative debenzylation with cerium(IV) ammonium nitrate (CAN)   IPC: Int.Cl.8 C07D		A simple debenzylation approach has been discussed for the synthesis of hexanitrohexaazaisowurtzitane (HNIW or CL-20) one of the most powerful high explosives of today with cerium ammonium (IV) nitrate.
	G M Gore, R Sivabalan*, U R Nair, A Saikia, S Venugopalan & B R Gandhe

First, benzylamine (1) is condensed with glyoxal (2) under acidic and dehydrating conditions to yield the first intermediate compound.(3). Four benzyl groups selectively undergo hydrogenolysis using palladium on carbon and hydrogen. The amino groups are then acetylated during the same step using acetic anhydride as the solvent. (4). Finally, compound 4 is reacted with nitronium tetrafluoroborate and nitrosonium tetrafluoroborate, resulting in HNIW.^[4]

(3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane

• Molecular FormulaC₆H₆N₁₂O₁₂
• Average mass438.185 Da
• (3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecan
  (3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane
  (3R,9R)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatétracyclo[5.5.0.0^3,11.0^5,9]dodécane
  5,2,6-(Iminomethanetriylimino)-1H-imidazo[4,5-b]pyrazine, octahydro-1,3,4,7,8,10-hexanitro-, (5R,7aR)-

(3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane

• Molecular FormulaC₆H₆N₁₂O₁₂
• Average mass438.185 Da
• (3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecan
  (3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^3,11.0^5,9]dodecane
  (3R,5S,9R,11S)-2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatétracyclo[5.5.0.0^3,11.0^5,9]dodécane
  5,2,6-(Iminomethanetriylimino)-1H-imidazo[4,5-b]pyrazine, octahydro-1,3,4,7,8,10-hexanitro-, (3aR,5S,6R,7aS)

Cocrystal product with HMX

In August 2012, Onas Bolton et al. published results showing that a cocrystal of 2 parts CL-20 and 1 part HMX had similar safety properties to HMX, but with a greater firing power closer to CL-20. ^[5][6]

Cocrystal product with TNT

In August 2011, Adam Matzger and Onas Bolton published results showing that a cocrystal of CL-20 and TNT had

The synthesis of 2,4,6,8,10,12-hexabenzyl-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.0^5,9.0^3,11]-dodecane (HBIW) is the first stage in the production of 2,4,6,8,10,12-hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.05,9.03,11] dodecane (CL-20), which is the most potent explosive known today. Because of the high performance characteristics of CL-20, a number of research projects are being conducted worldwide on CL-20 synthesis, properties and applications

Scale-Up Synthesis of Hexabenzylhexaazaisowurtzitane, an Intermediate in CL-20 Synthesis

Tomasz Gołofit^*† , Paweł Maksimowski^† , Piotr Szwarc^‡, Tomasz Cegłowski^‡, and Joanna Jefimczyk^†

^† Faculty of Chemistry, Division of High Energetic Materials, Warsaw University of Technology, Noakowskiego 3, 00-664 Warsaw, Poland

^‡Chemical Works “NITRO−CHEM” S.A., Wojska Polskiego 65 A, 85−825 Bydgoszcz, Poland

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00101

*E-mail: tomgol@ch.pw.edu.pl.

After successful synthesis of hexabenzylhexaazaisowurtzitane (HBIW) on a laboratory scale (0.25 L reactor), it was performed on a multilaboratory scale (10 L reactor) and subsequently in an experimental installation in which a 300 L reactor was built. Seven syntheses were carried out in the unit on a pilot scale to produce 250 kg of HBIW. The pilot-scale syntheses ran with a yield comparable to those observed for the processes conducted on a large-laboratory scale. Some modifications were suggested that allowed for reduction of the HBIW weight unit by approximately 50%

HBIW was 89%. FTIR υ (cm^–1): 3022, 2835, 1954, 1669, 1602, 1492, 1451, 1396, 1351, 1302, 1264, 1208, 1169, 1140, 1122, 1072, 1057, 1028, 1017, 986, 926, 896, 828, 792, 781, 749, 732, 698. ¹H NMR (CDCl₃, 400 MHz): δ 7.39–7.42 (m, 30 H, phenyl CH), 4.33 (s, 4 H, CH2), 4.26–4.27 (d, 8 H, CH2), 4.21 (s, 4 H, CH), 3.75 (s, 2, H, CH).

References

1. Jump up^ 王征, 和霄雯 (2016-04-19). “北理工的爆轰速度 中国力量的可靠基石”. 北京理工大学新闻网.
2. Jump up^ 黎轩平 (2016-04-23). ““我们要在宇宙空间占一个位置！””. 北京理工大学新闻网.
3. Jump up^ Yirka, Bob (9 September 2011). “University chemists devise means to stabilize explosive CL-20”. Physorg.com. Retrieved 8 July 2012.
4. Jump up^ Nair, U. R.; Sivabalan, R.; Gore, G. M.; Geetha, M.; Asthana, S. N.; Singh, H. (2005). “Hexanitrohexaazaisowurtzitane (CL-20) and CL-20-based formulations (review)”. Combust. Explos. Shock Waves. 41 (2): 121–132. doi:10.1007/s10573-005-0014-2.
5. Jump up^ High Power Explosive with Good Sensitivity: A 2:1 Cocrystal of CL-20:HMX, Crystal Growth & Design (American Chemical Society), 2012, 12 (9), pp 4311–4314, DOI: 10.1021/cg3010882, Publication Date (Web): August 7, 2012, accessed 7 September 2012
6. Jump up^ Powerful new explosive could replace today’s state-of-the-art military explosive, SpaceWar.com, 6 September 2012, accessed 7 September 2012
7. Jump up^ Angewandte Chemie International Edition
8. Jump up^ Things I Won’t Work With: Hexanitrohexaazaisowurtzitane

Further reading

• Bolton, Onas; Adam J. Matzger (September 12, 2011). “Improved Stability and Smart-Material Functionality Realized in an Energetic Cocrystal”. Angewandte Chemie. 123 (38): 9122–9125. doi:10.1002/ange.201104164. Retrieved 8 July 2012.
• Lowe, Derek (11 November 2011) “Things I won’t work with: Hexanitrohexaazaisowurtzitane”

////////////////CL 20, 135285-90-4, HNIW

Hexanitrohexaazaisowurtzitane

Names
IUPAC name 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazatetracyclo[5.5.0.03,11.05,9]dodecane
Other names CL-20 Hexanitrohexaazaisowurtzitane 2,4,6,8,10,12-Hexanitro-2,4,6,8,10,12-hexaazaisowurtzitane Octahydro-1,3,4,7,8,10-hexanitro-5,2,6-(iminomethenimino)-1H-imidazo[4,5-b]pyrazine HNIW Octahydro-1,3,4,7,8,10-hexanitro-5,2,6-(iminomethenimino)-1H-imidazo[4,5-b]pyrazine 5,2,6-(Iminomethenimino)-1H-imidazo[4,5-b]pyrazine, octahydro-1,3,4,7,8,10-hexanitro- isowurtzitane, hexanitrohexaaza- Octahydro-1,3,4,7,8,10-hexanitro-5,2,6-(iminomethenimino)-1H-imidazo(4,5-b)pyrazine
Identifiers
CAS Number	135285-90-4
3D model (JSmol)	Interactive image Interactive image
Abbreviations	CL-20, HNIW
ChEBI	CHEBI:77327
ChemSpider	8064994  9223599 (3R,9R)-dodec  9594121 (3R,5S,9R,11S)- dodec
ECHA InfoCard	100.114.169
PubChem CID	9889323 11048432 (3R,9R)-dodec 11419235 (3R,5S,9R,11S)- dodec
InChI[show]
SMILES[show]
Properties
Chemical formula	C 6N 12H 6O 12
Molar mass	438.1850 g mol−1
Density	2.044 g cm−3
Explosive data
Detonation velocity	9.38 km s−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

• 1.Bayat, Y.; Malmir, S.; Hajighasemali, F.; Dehghani, H. Cent. Eur. J. Energy Mater. 2015, 12, 439– 458
• 2.Bayat, Y.; Zarandi, M.; Khadiv-Parsi, P.; Salimi, A. Cent. Eur. J. Energy Mater. 2015, 12, 459– 472
• 3.Gołofit, T.; Zyśk, K. J. J. Therm. Anal. Calorim. 2015, 119, 1931– 1939, DOI: 10.1007/s10973-015-4418-2
• 4.Maksimowski, P.; Adamiak, J. Propellants, Explos., Pyrotech. 2010, 35, 353– 358, DOI: 10.1002/prep.200900057

Lisdexamfetamine

• Molecular FormulaC₁₅H₂₅N₃O
• Average mass263.379 Da

(2S)-2,6-diamino-N-[(2S)-1-phenylpropan-2-yl]hexanimidic acid

H645GUL8KJ

L-lysine-(+)-amphetamine

NRP104|Vyvanse®

UNII:H645GUL8KJ

UNII-H645GUL8KJ

Vyvanse®

CAS 608137-33-3

(2S)-2,6-Diamino-N-[(1S)-1-methyl-2-phenylethyl]hexanamide dimethanesulfonate

https://www.google.com/patents/WO2005032474A2

Applicants:	NEW RIVER PHARMACEUTICALS INC. [US/US]; The Governor Tyler, 1881 Grove Avenue, Radford, VA 24141 (US) (For All Designated States Except US). MICKLE, Travis [US/US]; (US) (For US Only). KRISHNAN, Suma [US/US]; (US) (For US Only). MONCRIEF, James, Scott [US/US]; (US) (For US Only). LAUDERBACK, Christopher [US/US]; (US) (For US Only). MILLER, Christal [US/US]; (US) (For US Only)
Inventors:	MICKLE, Travis; (US). KRISHNAN, Suma; (US). MONCRIEF, James, Scott; (US). LAUDERBACK, Christopher; (US). MILLER, Christal; (US)

MICKLE, Travis
Dr. Travis Mickle founded KemPharm, Inc. in late 2006. Prior to KemPharm, from January 2003 to October 2005, Dr. Mickle was Director of Drug Discovery and Chemical Development at New River Pharmaceuticals where he also served in a variety of other senior research roles since joining the firm in 2001. During his tenure at New River, Dr. Mickle was responsible for creating a strong preclinical and clinical pipeline of drugs in the areas of ADHD, pain and thyroid dysfunction. His contributions included, as principal inventor, the discovery and development of lisdexamfetamine dimesylate, the highly successful therapy for the treatment of ADHD known as Vyvanse®. In addition, Dr. Mickle was an active participant in FDA and DEA meetings representing the company’s discovery/chemistry group and was also called in as a critical scientific resource during New River’s financings and strategic partnering discussions. Before his departure, Dr. Mickle played an integral part in New River’s development into a successful publicly-traded company which was subsequently acquired for $2.6 billion by its marketing partner, Shire PLC. Dr. Mickle is also the author of more than 150 US and international patents and patent applications, as well as several research papers. Dr. Mickle holds a Ph.D in Bio-Organic Chemistry from the University of Iowa.

ABOUT SUMA KRISHNAN

Mrs. Krishnan has served as our Senior Vice President — Regulatory Affairs since 2012. From 2009 to 2011, Mrs. Krishnan served as Senior Vice President of Product Development at Pinnacle Pharmaceuticals, Inc. From 2007 to 2009, she served as Chief Financial Officer of Light Matters Foundation. Previously, Mrs. Krishnan was Vice President, Product Development at New River Pharmaceuticals Inc. from September 2002 until its acquisition by Shire plc in April 2007.

Mrs. Krishnan has 22 years’ experience in drug development. Prior to serving at New River Pharmaceuticals Inc., Mrs. Krishnan served in the following capacities: Director, Regulatory Affairs at Shire Pharmaceuticals, Inc., a specialty pharmaceutical company; Senior Project Manager at Pfizer, Inc., a multi-national pharmaceutical company; and a consultant at the Weinberg Group, a pharmaceutical and environmental consulting firm.

Mrs. Krishnan began her career as a discovery scientist for Janssen Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson, a multi-national pharmaceutical company, in May 1991. Mrs. Krishnan received an M.S. in Organic Chemistry from Villanova University, an M.B.A. from Institute of Management and Research (India) and an undergraduate degree in Organic Chemistry from Ferguson University (India).

Lisdexamfetamine (contracted from L–lysine–dextroamphetamine) is a prodrug of the central nervous system (CNS) stimulantdextroamphetamine, a phenethylamine of the amphetamine class that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and binge eating disorder.^[4][5] Its chemical structure consists of dextroamphetamine coupled with the essential amino acid L-lysine. Lisdexamfetamine itself is inactive prior to its absorption and the subsequent rate-limited enzymaticcleavage of the molecule’s L-lysine portion, which produces the active metabolite (dextroamphetamine).

Lisdexamfetamine can be prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) in adults and children six and older, as well as for moderate to severe binge eating disorder in adults.^[4] The safety and the efficacy of lisdexamfetamine dimesylate in children with ADHD three to five years old have not been established.^[6]

Lisdexamfetamine is a Class B/Schedule II substance in the United Kingdom and a Schedule II controlled substance in the United States (DEA number 1205)^[7] and the aggregate production quota for 2016 in the United States is 29,750 kilograms of anhydrous acid or base.^[8] Lisdexamfetamine is currently in Phase III trials in Japan for ADHD.^[9]

Uses

Medical

Lisdexamfetamine is used primarily as a treatment for attention deficit hyperactivity disorder (ADHD) and binge eating disorder;^[4] it has similar off-label uses as those of other pharmaceutical amphetamines.^[4][5] Long-term amphetamine exposure at sufficiently high doses in some animal species is known to produce abnormal dopamine system development or nerve damage,^[10][11] but, in humans with ADHD, pharmaceutical amphetamines appear to improve brain development and nerve growth.^[12][13][14] Reviews of magnetic resonance imaging (MRI) studies suggest that long-term treatment with amphetamine decreases abnormalities in brain structure and function found in subjects with ADHD, and improves function in several parts of the brain, such as the right caudate nucleus of the basal ganglia.^[12][13][14]

Reviews of clinical stimulant research have established the safety and effectiveness of long-term continuous amphetamine use for the treatment of ADHD.^[15][16][17] Randomized controlled trials of continuous stimulant therapy for the treatment of ADHD spanning two years have demonstrated treatment effectiveness and safety.^[15][17] Two reviews have indicated that long-term continuous stimulant therapy for ADHD is effective for reducing the core symptoms of ADHD (i.e., hyperactivity, inattention, and impulsivity), enhancing quality of life and academic achievement, and producing improvements in a large number of functional outcomes^{[note 1]} across nine outcome categories related to academics, antisocial behavior, driving, non-medicinal drug use, obesity, occupation, self-esteem, service use (i.e., academic, occupational, health, financial, and legal services), and social function.^[16][17] One review highlighted a nine-month randomized controlled trial in children with ADHD that found an average increase of 4.5 IQ points, continued increases in attention, and continued decreases in disruptive behaviors and hyperactivity.^[15] Another review indicated that, based upon the longest follow-up studies conducted to date, lifetime stimulant therapy that begins during childhood is continuously effective for controlling ADHD symptoms and reduces the risk of developing a substance use disorder as an adult.^[17]

Current models of ADHD suggest that it is associated with functional impairments in some of the brain’s neurotransmitter systems;^[18] these functional impairments involve impaired dopamine neurotransmission in the mesocorticolimbic projection and norepinephrine neurotransmission in the noradrenergic projections from the locus coeruleus to the prefrontal cortex.^[18]Psychostimulants like methylphenidate and amphetamine are effective in treating ADHD because they increase neurotransmitter activity in these systems.^[19][18][20] Approximately 80% of those who use these stimulants see improvements in ADHD symptoms.^[21] Children with ADHD who use stimulant medications generally have better relationships with peers and family members, perform better in school, are less distractible and impulsive, and have longer attention spans.^[22][23] The Cochrane Collaboration‘s reviews^{[note 2]} on the treatment of ADHD in children, adolescents, and adults with pharmaceutical amphetamines stated that while these drugs improve short-term symptoms, they have higher discontinuation rates than non-stimulant medications due to their adverse side effects.^[25][26] A Cochrane Collaboration review on the treatment of ADHD in children with tic disorders such as Tourette syndrome indicated that stimulants in general do not make tics worse, but high doses of dextroamphetamine could exacerbate tics in some individuals.^[27]

Individuals over the age of 65 were not commonly tested in clinical trials of lisdexamfetamine for ADHD.^[4] Lisdexamfetamine is being investigated for possible treatment of cognitive impairment associated with schizophrenia and excessive daytime sleepiness.^[28]

Cognitive

In 2015, a systematic review and a meta-analysis of high quality clinical trials found that, when used at low (therapeutic) doses, amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults;^[29][30] these cognition-enhancing effects of amphetamine are known to be partially mediated through the indirect activation of both dopamine receptor D₁ and adrenoceptor α₂ in the prefrontal cortex.^[19][29] A systematic review from 2014 found that low doses of amphetamine also improve memory consolidation, in turn leading to improved recall of information.^[31] Therapeutic doses of amphetamine also enhance cortical network efficiency, an effect which mediates improvements in working memory in all individuals.^[19][32]Amphetamine and other ADHD stimulants also improve task saliency (motivation to perform a task) and increase arousal (wakefulness), in turn promoting goal-directed behavior.^[19][33][34] Stimulants such as amphetamine can improve performance on difficult and boring tasks and are used by some students as a study and test-taking aid.^[19][34][35]Based upon studies of self-reported illicit stimulant use, 5–35% of college students use diverted ADHD stimulants, which are primarily used for performance enhancement rather than as recreational drugs.^[36][37][38] However, high amphetamine doses that are above the therapeutic range can interfere with working memory and other aspects of cognitive control.^[19][34]

Physical

Amphetamine is used by some athletes for its psychological and athletic performance-enhancing effects, such as increased endurance and alertness;^[39][40] however, non-medical amphetamine use is prohibited at sporting events that are regulated by collegiate, national, and international anti-doping agencies.^[41][42] In healthy people at oral therapeutic doses, amphetamine has been shown to increase muscle strength, acceleration, athletic performance in anaerobic conditions, and endurance (i.e., it delays the onset of fatigue), while improving reaction time.^[39][43][44] Amphetamine improves endurance and reaction time primarily through reuptake inhibition and effluxion of dopamine in the central nervous system.^[43][44][45] Amphetamine and other dopaminergic drugs also increase power output at fixed levels of perceived exertion by overriding a “safety switch” that allows the core temperature limit to increase in order to access a reserve capacity that is normally off-limits.^[44][46][47] At therapeutic doses, the adverse effects of amphetamine do not impede athletic performance;^[39][43] however, at much higher doses, amphetamine can induce effects that severely impair performance, such as rapid muscle breakdown and elevated body temperature.^[48][49][43]

Available forms

Vyvanse capsules are available in doses of 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, and 70 mg of the active ingredient, lisdexamfetamine dimesylate.^[50] Vyvanse capsules contain several inactive ingredients, including microcrystalline cellulose, croscarmellose sodium, and magnesium stearate.^[50] The capsule shells contain gelatin and titanium dioxide, and may contain FD&C Red 3, FD&C Yellow 6, FD&C Blue 1, black iron oxide, and yellow iron oxide.^[50]

DESCRIPTION/SYNTHESIS

Lisdexamfetamine dimesylate is approved and marketed in the United States for the treatment of attention-deficit hyperactivity disorder in pediatric patients. The active compound lisdexamfetamine contains D-amphetamine covalently linked to the essential amino acid L-lysine. Controlled release of D-amphetamine, a psychostimulant, occurs following administration of lisdexamfetamine to a patient. The controlled release has been reported to occur through hydrolysis of the amide bond linking D-amphetamine and L-lysine.

A procedure for making lisdexamfetamine hydrochloride is described in U.S. Pat. No. 7,223,735 to Mickle et al. (hereinafter Mickle). The procedure involves reacting D-amphetamine with (S)-2,5-dioxopyrrolidin-1-yl 2,6-bis(tert-butoxycarbonylamino)hexanoate to form a lysine-amphetamine intermediate bearing tert-butylcarbamate protecting groups. This intermediate is treated with hydrochloric acid to remove the tert-butylcarbamate protecting groups and provide lisdexamfetamine as its hydrochloride salt. However, this procedure suffers several drawbacks that are problematic when carrying out large scale reactions, such as manufacturing scale, to prepare lisdexamfetamine.

Lisdexamphetamine of formula I, is a conjugate of D-amphetamine and L-lysine and is chemically named as (2S)-2,6-diamino-N-[(lS)-methyl-2-phenylethyl]hexan amide.

Formula- I

Amphetamines stimulate central nervous system (CNS). Amphetamine is prescribed for treatment of various disorders, including attention deficit hyperactivity disorder (ADHD), obesity, nacrolepsy. It is approved as lisdextamphetamine dimesylate of formula IA and

Formula- IA

marketed under trade name Vyvanse for treatment of attention-deficit hyperactivity disorder in pediatric patients.

L-Lysine-D-amphetamine and its pharmaceutically acceptable salts were first disclosed in US patent 7,662,787 wherein it is exemplified as hydrochloride salt. Process for preparation of L- lysine-D-amphetamine includes reaction of BOC-Lys-(BOC)-hydroxysuccinimido ester with D-amphetamine in dioxane using diisopropyl ethyl amine (DIPEA) as a base to obtain BOC- protected lisdexamphetamine which is then purified using flash chromatography and further reacted with a mixture of 4M hydrochloric acid /dioxane to yield L-lysine-D-amphetamine hydrochloride. The process is as shown in following scheme:

4M HCI/dioxane

In equivalent patent US 7,659,253, process for preparation of mesylate salt is disclosed as shown below.

NHS;DCC;

isopropyl acetate

-50°C, 2 hr

Process includes preparation of BOC-Lys-(BOC)-hydroxysuccinimido ester wherein use of reagents like N-hydroxy-succinimide (NHS) and Ν,Ν-dicyclohexyl- carbodimiide (DCC) is carried out, The above processes involve use of flash column chromatography to purify crude BOC- protected L-lysine-D-amphetamine intermediate. Use of column chromatography is very cumbersome, tedoius and time consuming, therefore not advisable at commercial scale. Further Ν,Ν-dicyclohexylcarbodimiide is known to be highly toxic and moisture sensitive compound, and its use leads to formation of a large amount of Ν,Ν-dicyclohexyl urea (DCU) as bye product which has to be removed from reaction mixture.. Therefore use of DCC is not advisable at industrial scale.

International patent publication WO 2010/042120 discloses a process for preparing L-lysine- D-amphetamine or its salts by reacting D-amphetamine with protected lysine or its salt by using an alkylphosphonic acid anhydride as coupling agent in presence of a base and solvent. The process is as shown in following scheme:

The application discloses use of alkylphosphonic acid anhydrides, which are expensive, and needs additional testing to show absence of phosphic impurities in intermediate or final compound to meet regulatory requirements. So it is not appealing to use alkylphosphonic anhydrides for scale up operations.

International patent publication WO2010/148305 discloses a process for preparation of lisdexamphetamine by removal of chlorine from Ν,Ν’-bistrifluoroacetyl-chloro- lisdexamphetamine by using hydrogenation catalyst like Pd/C, under hydrogen gas to form Ν,Ν’-bistrifluoroacetyl-lisdexamphetamine which on further deprotection by using deprotecting agent to form lisdexamphetamine. Alternatively first deprotection by using deprotecting agent and then chlorine is removed by using hydrogenation catalyst like Pd/C under hydrogen gas. The process involves additional steps of inserting chloro group and thereafter removing chloro group; further Pd/C is an expensive reagent, hence not attractive option from cost point of view.

It is therefore, necessary to overcome problems associated with prior art and to provide an efficient process for preparation of lisdexamphetamine and its pharmaceutically acceptable salts using easily available, less expensive, easy to handle raw materials and avoid use of column chromatography.

PATENT

https://www.google.com/patents/US20120157706

• • Example IPreparation of N,N′-Biscarbobenzyloxy-Lisdexamfetamine (LDX-(Cbz)2)

General Experimental Procedure: In an appropriately sized, inert jacketed reactor charge 378.3 g of Cbz-Lys(Cbz)-OSu and 2309 g of isopropyl acetate. Heat the stirred slurry to ˜50° C. In a second reactor mix 100.0 g of D-amphetamine into 165 g of isopropyl acetate. Add the D-amphetamine solution to the batch over 1.75-2.25 hours. After the addition is complete stir the heterogeneous mixture at 50-55° C. until the reaction is complete by HPLC analysis. Charge 1197 g of methanol and heat the batch at a vigorous reflux 1 hour. Cool the batch to 45-55° C. over 2 hours then hold at temperature for 14-16 hours. Cool the batch to 15-25° C. at a rate of 5-10° C. per hour. Filter the slurry. Rinse the wet cake with 449 g of methanol and dry on the filter under nitrogen. To a clean, dry reactor charge the crude solids and 1642 g of methanol. Stir the slurry and heat to a vigorous reflux for 2 hours. Cool the batch to 45-55° C. over 1-2 hours then hold at temperature 12-16 hours. Continue cooling to 15-25° C. at a rate of 5-10° C. per hour. Filter the slurry and wash the wet cake with 547 g of methanol. Vacuum dry the wet cake at ˜55° C. to give product as a white to off-white solid (332 g, 88 mol %).

The crude LDX-(Cbz)product isolated from the reaction mixture by crystallization had a purity of 99.96% according to HPLC analysis.¹H NMR analysis of crude LDX-(Cbz)₂product revealed the presence of 0.57% by weight N-hydroxysuccinimide. The purified LDX-(Cbz)₂product obtained by re-crystallization from methanol had a purity of 99.99% according to HPLC analysis.¹H NMR analysis of the purified LDX-(Cbz)₂product obtained by re-crystallization from methanol revealed that the amount of N-hydroxysuccinimide in the purified LDX-(Cbz)₂product was reduced to 0.05% by weight.

Example 2Preparation of Lisdexamfetamine Dimesylate

General Experimental Procedure: In an appropriately sized, inert autoclave charge 100.0 g of LDX-(Cbz)2, 1 g of 10% (50% wet) palladium on carbon and 607.5 g of n-butanol. Stir the mixture under 100-150 psi of hydrogen at 80-85° C. until the reaction is complete by HPLC analysis. Heat the batch to 95-97° C. and hot filter. Transfer the product rich filtrate to an appropriately sized glass reactor. Charge 7.6 g of methanesulfonic acid maintaining a batch temperature of 32-38° C. To the resulting solution add 1.3 g of LDX-2MSA seed crystal. Stir the batch 4-16 hours at 32-38° C. Charge 30.4 g of methanesulfonic acid to the slurry over not less than 2 hours maintaining a batch temperature of 32-38° C. After the addition stir 1-2 hours at 32-38° C. Charge 436 g of isopropyl acetate over not less than 2 hours, then stir 1-2 hours at 32-38° C. Cool the batch to 15-25° C. and hold 1 hour. Filter the slurry. Wash the wet cake with a premixed combination of n-butanol (91.5 g) and isopropyl acetate (32.7 g) followed by a wash of isopropyl acetate (87.2 g). Vacuum dry the wet cake at ˜50° C. to give product as a white to off-white solid (78.8 g, 92 mol %).

PATENT

WO 2017098533

Sun Pharmaceutical Industries Ltd

Process for preparation of lisdexamphetamine and its salts via a novel aziridine intermediate is claimed. Lisdexamphetamine attention deficit hyperactivity disorder (ADHD). Represents the first patenting to be seen from Sun pharmaceutical that focuses on lisdexamphetamine. At the time of publication Pawar and Patel are affiliated with Chattem chemicals .

PATENT

WO 2005032474

IN 2011DE02040

WO 2013011526

IN 2009CH01986

WO 2010042120

PATENT

https://www.google.com/patents/WO2013011526A1?cl=en

Formula II A

Formula IV

Formula IVA

EXAMPLES

Examplel Preparation of 2,6-bis-tertiarvbutoxycarbonylamino hexanoic acid

To a solution of L-lysine monohydrochloride (25g, 0.14mol) and sodium hydroxide (15g) in water (250 ml), ditertiary butyl dicarbonate (70.0 g, 0.32 mol) was added at 15-25°C. The temperature was slowly raised to 55-60 °C and the reaction mixture was stirred for 12 hours.. After completion of reaction, ( monitored by TLC), the reaction mixture was cooled to 10-

15°C and pH was adjusted to 2.5-3.5 with 2N hydrochloric acid. The reaction mass’ was then extracted with dichloromethane (2 x 125 ml) and combined organic layer was successively washed with water (150 ml) and brine (150 ml). Dichloromethane layer was distilled under vacuum at 30-40 °C to obtain 29.7g of title compound as a viscous oily mass having purity 96.5% by HPLC.

Example 2: Preparation of (5-tert-butoxycarbonylamino-5-(l-methyl-2-phenyl- ethylcarba moyl)-pentyll-carbamic acid tert-butyl ester;

To a solution of 2,6-bis-tertbutoxy carbonylamino hexanoic acid (7.5g) in dichloromethane (150 ml) , triethyl amine (8.0 ml) was added at 25-30°C and the reaction mixture was stirred for 15 minutes. The solution was cooled to -15 to -10°C and isobutylchloroformate (4.35 g) was slowly added under nitrogen atmosphere and stirred for 30 minutes at -15°C to – 10°C. A solution of D-amphetamine (3.85 g) in dichloromethane (10 ml) was slowly added and. the reaction mixture was stirred at 15 to -10°C for 60 minutes. The reaction completion was checked by TLC. After completion of the reaction temperature was raised to 25-30°C and reaction mixture was successively washed with 0.5 N hydrochloric acid solution (2 x 75 ml), sodium bicarbonate solution (5%w/w 75ml), water (50 ml) and brine solution (50 ml). The combined dichloromethane layer was dried over sodium sulfate (10.0 g) and distilled at 30- 40°C to obtain a semisolid compound which was stirred with a mixture of n-heptane (85 ml) and ethyl acetate (5ml) at 25-30°C for 30 minutes. The solid, thus obtained, was filtered and dried to get 10.21 g of title compound having purity 89.77% by HPLC. The crude compound was dissolved in ethanol (45ml) at 50-55°C and water (50ml) was added. The reaction mixture was slowly cooled to 35-40°C, stirred for 30 minutes. The solid, thus obtained, was filtered and dried to get 7.35g of pure title compound as a white crystalline solid having purity 99.5 % by HPLC.

Example 3: Preparation of lisdexamphetamine dimesylate

(5-Tert-butoxycarbonylamino-5-( 1 -methyl-2-phenyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester (2.5g,) was dissolved in a mixture of isopropyl alcohol (10ml) and ethyl acetate (10ml) at 40-45°C and the reaction mass was cooled to 15-20°C. To this cold solution, methane sulphonic acid (2.5g) was added slowly and stirred for 12 hours at 15- 20°C. The reaction completion was checked by HPLC. The resulting solid was filtered, washed with a mixture of chilled isopropyl alcohol (5ml) and ethyl acetate (5ml) and dried under vacuum to obtain 1.68 g of title compound as a white crystalline solid having purity 99.72 % by HPLC.

Example 4: Preparation of lisdexamphetamine dimesylate:

(5-Tert-butoxycarbonylamino-5-( 1 -methyl-2-phenyl-ethylcarbamoyl)-pentyl]-carbamic acid tert-butyl ester (2.5 g,) was dissolved in ethanol (20 ml) at 25-30°C. To the reaction mixture, methane sulphonic acid (2.5 g) was slowly added and the reaction mixture was heated to 55- 60°C and stirred for 3 hours at 55-60°C. The reaction mixture was cooled to 25-30°C, stirred for 2 hours, filtered, washed with ethanol (10ml) and dried under vacuum to obtain 1.55g of lisdexamphetamine dimesylate having purity 99.61 % by HPLC.

Example 5: Purification of lisdexamphetamine dimesylate

Lisdexamphetamine dimesylate (1.40g,) was dissolved in ethanol (10 ml) at 50-55 °C and ethyl acetate (10 ml) was slowly added at 50-55 °C. The reaction mixture was cooled to 20- 25°C and stirred for 30 minutes. The resulting solid was filtered, washed with a mixture of ethanol and ethyl acetate (3 ml, 1: 1) and dried under vacuum at 55-60°C to obtain 1.28g of pure lisdexamphetamine dimesylate as a white crystalline solid having purity 99.90 % by HPLC.

Example 6: Preparation of lisdexamphetamine dimesylate

To a stirred solution of L-lysine monohydrochloride (50g) and sodium hydroxide (30 g) in water (500ml) at 15-25°C, ditertbutyl dicarbonate(140g) was added. The temperature was slowly raised to 55-60°C and reaction mixture was stirred for 12 hours. After completion of reaction, the reaction mixture was cooled to 10-15°C and pH was adjusted to 2.5-3.5 with 2N hydrochloric acid. The reaction mixture was then extracted with dichloromethane (2 x 250 ml) and combined dichloromethane layer was successively washed with water (300 ml) and brine (300 ml). To the organic layer triethyl amine (58g) in dichloromethane (500 ml) was added. The solution was cooled to -15 to -20°C and isobutylchloroformate (42.5 g) was slowly added at -15 to -20°C and stirred for 1 hour. A solution of D-amphetamine (41.85 g) in dichloromethane (100 ml) was slowly added to reaction mixture at -15 to -20 °C and stirred. After completion of the reaction, the reaction mixture was successively washed with 0.5 N hydrochloric solution (2 x 450 ml), sodium bicarbonate solution (5%w/w, 450 ml), water (450 ml) and brine solution (450 ml). The organic layer was dried over sodium sulfate and distilled under vacuum at 30-40°C to afford a residue. To this residue, ethanol (480 ml) was added followed by slow addition of methane sulphonic acid (55 g) under nitrogen atmosphere. The reaction temperature was raised 55-60°C and after completion of reaction, the reaction mixture was cooled to 20-25°C and stirred for 2 hours. The resulting solid was filtered, washed with ethanol (50 ml) and suck dried for 30 minutes, further washed with ethanol and dried to obtain lisdexamphetamine dimesylate.

Mechanism of action

Pharmacodynamics of amphetamine in a dopamine neuron
v · t · e

via AADC

Amphetamine enters the presynaptic neuron across the neuronal membrane or through DAT. Once inside, it binds to TAAR1 or enters synaptic vesicles through VMAT2. When amphetamine enters synaptic vesicles through VMAT2, it collapses the vesicular pH gradient, which in turn causes dopamine to be released into the cytosol (light tan-colored area) through VMAT2. When amphetamine binds to TAAR1, it reduces the firing rate of the dopamine neuron via potassium channels and activates protein kinase A (PKA) and protein kinase C (PKC), which subsequently phosphorylate DAT. PKA-phosphorylation causes DAT to withdraw into the presynaptic neuron (internalize) and cease transport. PKC-phosphorylated DAT may either operate in reverse or, like PKA-phosphorylated DAT, internalize and cease transport. Amphetamine is also known to increase intracellular calcium, an effect which is associated with DAT phosphorylation through a CAMKIIα-dependent pathway, in turn producing dopamine efflux.

Lisdexamfetamine is an inactive prodrug that is converted in the body to dextroamphetamine, a pharmacologically active compound which is responsible for the drug’s activity.^[119] After oral ingestion, lisdexamfetamine is broken down by enzymes in red blood cells to form L-lysine, a naturally occurring essential amino acid, and dextroamphetamine.^[4] The conversion of lisdexamfetamine to dextroamphetamine is not affected by gastrointestinal pH and is unlikely to be affected by alterations in normal gastrointestinal transit times.^[4][120]

The optical isomers of amphetamine, i.e., dextroamphetamine and levoamphetamine, are TAAR1 agonists and vesicular monoamine transporter 2 inhibitors that can enter monoamine neurons;^[121][122] this allows them to release monoamine neurotransmitters (dopamine, norepinephrine, and serotonin, among others) from their storage sites in the presynaptic neuron, as well as prevent the reuptake of these neurotransmitters from the synaptic cleft.^[121][122]

Lisdexamfetamine was developed with the goal of providing a long duration of effect that is consistent throughout the day, with reduced potential for abuse. The attachment of the amino acid lysine slows down the relative amount of dextroamphetamine available to the blood stream. Because no free dextroamphetamine is present in lisdexamfetamine capsules, dextroamphetamine does not become available through mechanical manipulation, such as crushing or simple extraction. A relatively sophisticated biochemical process is needed to produce dextroamphetamine from lisdexamfetamine.^[120] As opposed to Adderall, which contains roughly equal parts of racemic amphetamine and dextroamphetamine salts, lisdexamfetamine is a single-enantiomer dextroamphetamine formula.^[119][123] Studies conducted show that lisdexamfetamine dimesylate may have less abuse potential than dextroamphetamine and an abuse profile similar to diethylpropion at dosages that are FDA-approved for treatment of ADHD, but still has a high abuse potential when this dosage is exceeded by over 100%.^[120]

Pharmacokinetics

The oral bioavailability of amphetamine varies with gastrointestinal pH;^[118] it is well absorbed from the gut, and bioavailability is typically over 75% for dextroamphetamine.^[124] Amphetamine is a weak base with a pK_a of 9.9;^[125]consequently, when the pH is basic, more of the drug is in its lipid soluble free base form, and more is absorbed through the lipid-rich cell membranes of the gut epithelium.^[125][118] Conversely, an acidic pH means the drug is predominantly in a water-soluble cationic (salt) form, and less is absorbed.^[125] Approximately 15–40% of amphetamine circulating in the bloodstream is bound to plasma proteins.^[126]

The half-life of amphetamine enantiomers differ and vary with urine pH.^[125] At normal urine pH, the half-lives of dextroamphetamine and levoamphetamine are 9–11 hours and 11–14 hours, respectively.^[125] An acidic diet will reduce the enantiomer half-lives to 8–11 hours; an alkaline diet will increase the range to 16–31 hours.^[127][128] The biological half-life is longer and distribution volumes are larger in amphetamine dependent individuals.^[128] The immediate-release and extended release variants of salts of both isomers reach peak plasma concentrations at 3 hours and 7 hours post-dose respectively.^[125] Amphetamine is eliminated via the kidneys, with 30–40% of the drug being excreted unchanged at normal urinary pH.^[125] When the urinary pH is basic, amphetamine is in its free base form, so less is excreted.^[125] When urine pH is abnormal, the urinary recovery of amphetamine may range from a low of 1% to a high of 75%, depending mostly upon whether urine is too basic or acidic, respectively.^[125] Amphetamine is usually eliminated within two days of the last oral dose.^[127]

The prodrug lisdexamfetamine is not as sensitive to pH as amphetamine when being absorbed in the gastrointestinal tract;^[129] following absorption into the blood stream, it is converted by red blood cell-associated enzymes to dextroamphetamine via hydrolysis.^[129] The elimination half-life of lisdexamfetamine is generally less than one hour.^[129]

CYP2D6, dopamine β-hydroxylase (DBH), flavin-containing monooxygenase 3 (FMO3), butyrate-CoA ligase (XM-ligase), and glycine N-acyltransferase (GLYAT) are the enzymes known to metabolize amphetamine or its metabolites in humans.^{[sources 9]} Amphetamine has a variety of excreted metabolic products, including 4-hydroxyamphetamine, 4-hydroxynorephedrine, 4-hydroxyphenylacetone, benzoic acid, hippuric acid, norephedrine, and phenylacetone.^{[125][127][134]} Among these metabolites, the active sympathomimetics are 4‑hydroxyamphetamine,^[138] 4‑hydroxynorephedrine,^[139] and norephedrine.^[140] The main metabolic pathways involve aromatic para-hydroxylation, aliphatic alpha- and beta-hydroxylation, N-oxidation, N-dealkylation, and deamination.^[125][127] The known metabolic pathways, detectable metabolites, and metabolizing enzymes in humans include the following:

Metabolic pathways of amphetamine in humans^{[sources 9]}

4-Hydroxyphenylacetone

Phenylacetone

Benzoic acid

Hippuric acid

Amphetamine

Norephedrine

4-Hydroxyamphetamine

4-Hydroxynorephedrine

Para-
Hydroxylation

Para-
Hydroxylation

Para-
Hydroxylation

CYP2D6

CYP2D6

unidentified

Beta-
Hydroxylation

Beta-
Hydroxylation

DBH

DBH

Oxidative
Deamination

FMO3

Oxidation

unidentified

Glycine
Conjugation

XM-ligase
GLYAT

The primary active metabolites of amphetamine are 4-hydroxyamphetamine and norephedrine;^[134] at normal urine pH, about 30–40% of amphetamine is excreted unchanged and roughly 50% is excreted as the inactive metabolites (bottom row).^[125] The remaining 10–20% is excreted as the active metabolites.^[125] Benzoic acid is metabolized by XM-ligase into an intermediate product, benzoyl-CoA,^[136] which is then metabolized by GLYAT into hippuric acid.^[137]

Chemistry

Comparison to other formulationsLisdexamfetamine dimesylate is a water-soluble (792 mg/mL) powder with a white to off-white color.^[50]

Lisdexamfetamine dimesylate is one marketed formulation delivering dextroamphetamine. The following table compares the drug to other amphetamine pharmaceuticals.

History, society, and culture

Lisdexamfetamine was developed by New River Pharmaceuticals, who were bought by Shire Pharmaceuticals shortly before lisdexamfetamine began being marketed. It was developed for the intention of creating a longer-lasting and less-easily abused version of dextroamphetamine, as the requirement of conversion into dextroamphetamine via enzymes in the red blood cells increases its duration of action, regardless of the route of ingestion.^[148] The drug lisdexamfetamine dimesylate is the first prodrug of its kind.

On 23 April 2008, Vyvanse received FDA approval for the adult population.^[149] On 19 February 2009, Health Canada approved 30 mg and 50 mg capsules of lisdexamfetamine for treatment of ADHD.^[150] On 8 February 2012, Vyvanse received FDA approval for maintenance treatment of adult ADHD.^[151] In February 2014, Shire announced that two late-stage clinical trials had shown that Vyvanse was not an effective treatment for depression.^[152] Lisdexamfetamine was granted approval in a number of European countries for the treatment of ADHD in children and adolescents over the age of 6 years, as well as adults who are continuing treatment from childhood, after a positive outcome of the regulatory procedure.^[153] Shire also recently announced receipt of a positive result from a European decentralised procedure for lisdexamfetamine for adult patients with ADHD in the United Kingdom, Sweden and Denmark, expanding the indication of lisdexamfetamine to include newly diagnosed adult patients.^[154]

In January 2015, lisdexamfetamine was approved by the U.S. Food and Drug Administration for treatment of binge eating disorder in adults.^{[28][155][156]}

In January 2017, a new dosage form of lisdexamfetamine in the form of a chewable tablet (as opposed to a capsule) was approved by the FDA.^[157]

Brand names

Lisdexamfetamine is sold as Tyvense (IE), Elvanse (UK), Venvanse (BR), Vyvanse (CA, US).^[158]

Clinical research

Some clinical trials that used lisdexamfetamine as an add-on therapy with a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI) for treatment-resistant depression indicated that this is no more effective than the use of an SSRI or SNRI alone.^[159] Other studies indicated that psychostimulants potentiated antidepressants, and were under-prescribed for treatment resistant depression. In those studies patients showed significant improvement in energy, mood, and psychomotor activity.^[160]

Notes

References

Lisdexamfetamine

Clinical data
Trade names	Tyvense, Elvanse, Venvanse, Vyvanse
AHFS/Drugs.com	Monograph
MedlinePlus	a607047
License data	US FDA: Lisdexamfetamine
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Dependence liability	Physical: none Psychological: moderate
Addiction liability	Moderate
Routes of administration	Oral (capsules)
ATC code	N06BA12 (WHO)
Legal status
Legal status	AU: S8 (Controlled) CA: Schedule I DE: Anlage III (Special prescription form required) UK: Class B US: Schedule II In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	96.4%[1]
Metabolism	Hydrolysis by enzymes in red blood cells initially. Subsequent metabolism follows Amphetamine#Pharmacokinetics.
Onset of action	2 hours[2][3]
Biological half-life	≤1 hour (prodrug molecule) 9–11 hours (dextroamphetamine)
Duration of action	12 hours[2][3]
Excretion	Renal: ~2%
Identifiers
IUPAC name[show]
Synonyms	Vyvanse
CAS Number	608137-32-2 [IUPHAR]
PubChem CID	11597698
IUPHAR/BPS	7213
DrugBank	DB01255
ChemSpider	9772458
UNII	H645GUL8KJ
ChEMBL	CHEMBL1201222
Chemical and physical data
Formula	C15H25N3O
Molar mass	263.378 g/mol
3D model (Jmol)	Interactive image

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CC(CC1=CC=CC=C1)NC(=O)C(CCCCN)N