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Elbasvir, MK 8742 ……….Anti-Hepatitis C Virus Drug in phase 2

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Elbasvir, MK 8742
1370468-36-2  cas

 methyl N-[(2S)-1-[(2S)-2-[4-[(6S)-3-[2-[(2S)-1-[(2S)-2-(methoxycarbonylamino)-3-methylbutanoyl]pyrrolidin-2-yl]-4H-imidazol-4-yl]-6-phenyl-6H-indolo[1,2-c][1,3]benzoxazin-10-yl]-2H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate
Methyl [(2S)-1-[(2S)-2-[4-[(6S)-3-[2-[(2S)-1-[(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl]pyrrolidin-2-yl]-1H-imidazol-4-yl]-6-phenylindolo[1,2-c][1,3]benzoxazin-10-yl]-1H-imidazol-2-yl]pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl]carbamate

Carbamic acid, N,​N‘-​[[(6S)​-​6-​phenyl-​6H-​indolo[1,​2-​c]​[1,​3]​benzoxazine-​3,​10-​diyl]​bis[1H-​imidazole-​5,​2-​diyl-​(2S)​-​2,​1-​pyrrolidinediyl[(1S)​-​1-​(1-​methylethyl)​-​2-​oxo-​2,​1-​ethanediyl]​]​]​bis-​, C,​C‘-​dimethyl ester

Carbamic acid, N,N’-(((6S)-6-phenyl-6H-indolo(1,2-c)(1,3)benzoxazine-3,10-diyl)bis(1H-imidazole-5,2-diyl-(2S)-2,1-pyrrolidinediyl((1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl)))bis-, C,C’-dimethyl ester
Dimethyl N,N’-(((6S)-6-phenylindolo(1,2-c)(1,3)benzoxazine-3,10-diyl)bis(1H-imidazole-5,2-diyl-(2S)-pyrrolidine-2,1-diyl((2S)-3-methyl-1-oxobutane-1,2-diyl)))dicarbamate
Methyl ((1S)-1-(((2S)-2-(4-((6S)-10-(2-((2S)-1-((2S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-imidazol-4-yl)-6-phenyl-6H-indolo(1,2-c)(1,3)benzoxazin-3-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)carbonyl)-2-methylpropyl)carbamate

MW 882.0171, C49 H55 N9 O7, 

UNII-632L571YDK

MERCK-PHASE 2

HCV NS5A Inhibitors 

patent….http://www.google.com/patents/WO2012040923A1?cl=en

MK-8742 is in phase II clinical development at Merck & Co. for the oral treatment of chronic hepatitis C infection in combination with MK-5172 and ribavirin. Phase I clinical trials are uongoing for the treatment of hepatitis C infected males. In 2013, breakthrough therapy designation was assigned to the compound.

MK-8742 is an inhibitor of Hepatitis C Virus (HCV) non-structural protein 5A (NS5A) that is being developed for the treatment of HCV infection. MK-8742 has broad, potent HCV genotypic activity in vitro against viral variants that are resistant to other NS5A inhibitors. MK-8742 exhibits potent antiviral activity during 5 days of monotherapy in patients with GT1 and GT3 chronic HCV infection. MK-8742 is currently in Phase IIB development.

ELBASVIR

MK-8742 is an inhibitor of Hepatitis C Virus (HCV) non-structural protein 5A (NS5A) that is being developed for the treatment of HCV infection. MK-8742 has broad, potent HCV genotypic activity in vitro against viral variants that are resistant to other NS5A inhibitors. MK-8742 exhibits potent antiviral activity during 5 days of monotherapy in patients with GT1 and GT3 chronic HCV infection. MK-8742 is currently in Phase IIB development.

http://www.natap.org/2012/EASL/EASL_46.htm

EASL1.gif

………………

http://www.google.com/patents/WO2012040923A1?cl=en

EXAMPLE 23

Preparation of Compound A

Figure imgf000117_0001

A mixture of Compound Int-19b (1.1 g, 3 mmol), (dibromomethyl)benzene (2.25 g, 9 mmol) and K2C03 (1.2 g, 9 mmol) in 15 mL of DMF was heated to 100 °C and allowed to stir at this temperature for 3 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo and the residue obtained was dissolved with

dichloromethane and water. The aqueous phase was extracted with dichloromethane. The combined organic extracts were washed with brine, dried over Na2S04, filtered and concentrated in vacuo. The resulting residue was purified using flash column

chromatography on silica gel to provide Compound Int-23a (380 mg, 28 %) as a white solid. 1H MR (CDCI3): δ 7.72 (bs, 1 H), 7.44 – 7.46 (d, J= 8.4 Hz, 1 H), 7.21 – 7.28 (m, 3 H), 7.09 – 7.12 (m, 3 H), 7.04 (s, 1 H), 6.99 – 7.01 (bs, J= 6.8 Hz, 2 H), 6.78 (s, 1 H), 6.63 – 6.65 (d, J = 8.4 Hz, 1 H). MS (ESI)

m/e (M+H+): 456. Step B – Pre aration of Compound Int-23b

Figure imgf000118_0001

lnt-23a lnt-23b

To a solution of Int-23a (456 mg, 1.0 mmol) in 1,4-dioxane was added bis pinacol borate (2.2 mmol) , Pd(dppf)Cl2 (0.04 mmol) and KOAc (4 mmol). The reaction mixture was put under N¾ heated to 110°C and allowed to stir at this temperature for 3 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, and the residue obtained was purified using column chromatography on silica gel to provide Compound Int- 23b (590 mg, 87 % yield). 1H MR (CDC13): δ 8.13 (s, 1 H), 7.60 (d, J= 7.6 Hz, 1 H), 7.52 (d, J= 8.0 Hz, 1H), 7.36 – 7.39 (m, 1 H), 7.14 -7.19 (m, 4 H), 6.93 – 6.95 (m, 3 H), 6.90 (s, 1 H), 1.26 – 1.29 (s, 24 H). MS (ESI) m / e (M+H+): 550.

– Pre aration of Compound Int-23c

Figure imgf000118_0002

lnt-23b lnt-23c

A suspension of Int-23b (550 mg, 1.0 mmol), tert-butyl 2-(2-bromo-lH- imidazol-5-yl) pyrrolidine- 1-carboxylate (2.4 mmol), Pd(dppf) Cl2 (200 mg), Na2C03 (3 mmol) and in THF/H20 (10: 1, 33 mL) was allowed to stir at reflux for about 15 hours under N2. The reaction mixture was cooled to room temperature and filtered, and the filtrate was washed with water (50 mL) and extracted with EtOAc (100 mL). The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified using column chromatography on silica gel to provide Compound Int-23c (160 mg). MS (ESI) m / e (M+H+): 768.

Preparation of Compound Int-23d

Figure imgf000119_0001

Int-23c (0.10 g, 0.13 mmol) was added to HCl/CH3OH (5 mL, 3M) and the resulting reaction was allowed to stir at room temperature for about 3 hours. The reaction mixture was then concentrated in vacuo to provide Compound Int-23d, which was used without further purification. MS (ESI) m / e (M+H+): 568.

– Preparation of Compound A

Figure imgf000119_0002

To a solution of Int-23d (56.8 mg, 0.10 mmol), (S)-2- (methoxycarbonylamino)-3-methylbutanoic acid (35.0 mg, 0.20 mmol) and DIPEA (0.8 mmol) in CH3CN (1 mL) was added BOP (98 mg, 0.22 mmol). The resulting reaction was allowed to stir at room temperature and monitored using LCMS. After LCMS showed the starting material to be consumed, the reactionmixture was filtered, and the filtrate was purified using HPLC to provide Compound A as a white solid. 1H MR (MeOD): δ 7.94 (s,

1 H), 7.85 (d, J= 8.0 Hz, 1 H), 7.74 (s, 1 H), 7.63 (s, 1 H), 7.48 (s, 1 H), 7.35 – 7.37 (m, 2 H), 7.31 (s, 1 H), 7.17 – 7.18 (m, 4 H), 7.11 (s, 1 H), 6.96 – 6.98 (d, J = 7.6 Hz, 2 H), 5.09 – 5.17

(m, 2 H), 4.13 (t, J= 8.0 Hz, 2 H), 3.99 (bs, 2 H), 3.78 (bs, 2 H), 3.56 (s, 6 H), 2.44 – 2.47 (m,

2 H), 1.92 – 2.19 (m, 8 H), 0.77 – 0.85 (m, 12 H). MS (ESI) m / e (M+H+): 882.

The diastereomers were separated on a chiral SFC column: Isomer A: 1H NMR (MeOD): δ 8.08 (s, 1H), 7.91 – 7.93 (m, 1 H), 7.72 (s, 1 H), 7.56 (s, 1 H), 7.24 – 7.43 (m, 7 H), 7.19 (s, 1 H), 7.03 – 7.05 (m, 2 H), 5.16 – 5.24 (m, 2 H), 3.81 – 4.21 (m, 6 H), 3.62 (s, 6 H), 2.52 – 2.54 (m, 2 H), 2.00 – 2.25 (m, 8 H), 0.84 – 0.91 (m, 12 H). MS (ESI) m/z (M+H)+: 882.

Isomer B: 1H NMR (MeOD): δ 7.90 (s, 1 H), 7.81 – 7.83 (m, 1 H), 7.72 (s, 1 H), 7.62 (s, 1 H), 7.45 (s, 1 H), 7.14 – 7.33 (m, 6 H), 7.09 (s, 1 H), 6.93 – 6.95 (m, 2 H), 5.06 – 5.14 (m, 2 H), 3.71 – 4.11 (m, 6 H), 3.52 (s, 6 H), 2.41 – 2.44 (m, 2 H), 1.90 – 2.15 (m, 8 H), 0.74 – 0.86 (m, 12 H). MS (ESI) m/z (M+H)+: 882.

……………………..

 Discovery of MK-8742: An HCV NS5A inhibitor with broad genotype activity
ChemMedChem 2013, 8(12): 1930

http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201300343/abstract

The NS5A protein plays a critical role in the replication of HCV and has been the focus of numerous research efforts over the past few years. NS5A inhibitors have shown impressive in vitro potency profiles in HCV replicon assays, making them attractive components for inclusion in all oral combination regimens. Early work in the NS5A arena led to the discovery of our first clinical candidate, MK-4882 [2-((S)-pyrrolidin-2-yl)-5-(2-(4-(5-((S)-pyrrolidin-2-yl)-1H-imidazol-2-yl)phenyl)benzofuran-5-yl)-1H-imidazole]. While preclinical proof-of-concept studies in HCV-infected chimpanzees harboring chronic genotype 1 infections resulted in significant decreases in viral load after both single- and multiple-dose treatments, viral breakthrough proved to be a concern, thus necessitating the development of compounds with increased potency against a number of genotypes and NS5A resistance mutations. Modification of the MK-4882 core scaffold by introduction of a cyclic constraint afforded a series of tetracyclic inhibitors, which showed improved virologic profiles. Herein we describe the research efforts that led to the discovery of MK-8742, a tetracyclic indole-based NS5A inhibitor, which is currently in phase 2b clinical trials as part of an all-oral, interferon-free regimen for the treatment of HCV infection.

see

Journal of Medicinal Chemistry (2014), 57(5), 1643-1672.

Want to know everything on vir series

click

http://drugsynthesisint.blogspot.in/p/vir-series-hep-c-virus-22.html

AND

http://medcheminternational.blogspot.in/p/vir-series-hep-c-virus.html

WO2010111483A1 * Mar 25, 2010 Sep 30, 2010 Merck Sharp & Dohme Corp. Inhibitors of hepatitis c virus replication
US20070049593 * Feb 23, 2005 Mar 1, 2007 Japan Tobacco Inc. Tetracyclic fused heterocyclic compound and use thereof as HCV polymerase inhibitor

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 29 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 29 year tenure till date Aug 2016, Around 30 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 25 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 13 lakh plus views on New Drug Approvals Blog in 212 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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