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HCV NS3 Protease Inhibitors

a protease inhibitor and hcv technology, applied in the field of macrocyclic compounds, can solve the problems of limited clinical benefit, no established hcv vaccine, and treatment of hcv infection, and achieve the effect of reducing the likelihood or severity of one or more symptoms

Inactive Publication Date: 2010-04-22
MERCK SHARP & DOHME CORP +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0069]The present invention also includes pharmaceutical compositions containing a compound of the present invention and methods of preparing such pharmaceutical compositions. The present invention further includes methods of treating or reducing the likelihood or severity of one or more symptoms of HCV infection.

Problems solved by technology

Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population.
Current treatments for HCV infection, which are restricted to immunotherapy with recombinant interferon-α alone or in combination with the nucleoside analog ribavirin, are of limited clinical benefit.
Moreover, there is no established vaccine for HCV.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

(2R,4S,7S,16E)-7-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxamide

[0390]

Step 1: 1-t-Butyl 2-methyl(2S,4R)-4-[(3-bromopyridin-2-yl)oxy]pyrrolidine-1,2-dicarboxylate

[0391]

[0392]To a solution of 1-t-butyl 2-methyl(2S,4S)-4-{[(4-bromophenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.718 g, 3.70 mmol) and 3-bromopyridin-2-ol (0.773 g, 4.44 mmol) in NMP (18.50 mL) under N2, CS2CO3 (1.808 g, 5.55 mmol) was added. The mixture was then heated to 40° C. After 17 hours, the reaction was complete, and H2O and EtOAc were added. The organic layer was then extracted with H2O (3×), NaHCO3 (2×) and brine (2×). The organic layer was dried over MgSO4, and the solvent was removed in vacuo. The crude product was purified on SiO2 (gradient elution, 0-40% EtOAc / hexanes) to yield 1.04 g of the title compound. LRMS ESI+ ((M-Boc)+H)+ 301.2.

Step 2: 1-t-B...

example 2

(2R,4S,7S,16E)-7-t-Butyl-N-((1R,2R)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-ethylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15-decahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxamide

[0404]

[0405]To a solution of a portion of the product from Example 1, Step 6 (90 mg, 0.196 mmol) in DMF (2.2 mL), Intermediate A3 (63 mg, 0.235 mmol), DIEA (0.137 mL, 0.78 mmol), and HATU (97 mg, 0.255 mmol) was added. After 1 hour, the mixture was partitioned between EtOAc and 1N HCl. The organic layer was separated, dried over MgSO4, and the solvent was removed in vacuo. The crude product was purified on SiO2 (gradient elution, 0-70% EtOAc / hexanes) to yield 110 mg of the title compound. LRMS ESI+ (M+H)+ 674.4.

example 3

[0406](2R,4S,7S)-7-t-Butyl-N-((1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropyl)-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxamide

Step 1: Methyl (2R,4S,7S)-7-t-butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxylate

[0407]

[0408]To a solution of a portion of the product from Example 1, Step 5 (200 mg, 0.422 mmol) in EtOAc (4.5 mL), 10% Pd / C (22.5 mg, 0.021 mmol) was added. The mixture was then place under H2, stirred for 17 hours, and filtered through a pad of glass wool. The solvent was then removed in vacuo to yield 195 mg of the title compound. LRMS ESI+ (M+H)+ 476.4.

Step 2: (2R,4S,7S)-7-t-Butyl-6,9-dioxo-3,4,6,7,8,9,12,13,14,15,16,17-dodecahydro-2H,11H-2,5-methanopyrido[2,3-k][1,10,3,6]dioxadiazacyclononadecine-4-carboxylic acid

[0409]

[0410]To a solution of a portion of the product from Step 1 (190 mg...

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Abstract

The present invention relates to macrocyclic compounds of formula (I) that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, their synthesis, and their use for treating or preventing HCV infections.

Description

FIELD OF THE INVENTION[0001]The present invention relates to macrocyclic compounds that are useful as inhibitors of the hepatitis C virus (HCV) NS3 protease, the synthesis of such compounds, and the use of such compounds for treating HCV infection and / or reducing the likelihood or severity of symptoms of HCV infection.BACKGROUND OF THE INVENTION[0002]Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, estimated to be 2-15% of the world's population. There are an estimated 3.9 million infected people in the United States alone, according to the U.S. Center for Disease Control, roughly five times the number of people infected with the human immunodeficiency virus (HIV). According to the World Health Organization, there are more than 170 million infected individuals worldwide, with at least 3 to 4 million people being infected each year. Once inf...

Claims

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Application Information

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IPC IPC(8): A61K31/439C07D513/18C07D513/08A61K31/407A61K31/4748A61P31/12
CPCA61K38/00C07D498/08C07D498/18C07K5/0804C07K5/0806C07K5/0808C07K5/0812A61K31/407A61K31/4192A61K31/437A61K31/439C07D498/22A61P31/12A61P31/14A61P43/00A61K31/12A61K38/06A61K45/06
Inventor LIVERTON, NIGEL J.SUMMA, VINCENZODI FRANCESCO, MARIA EMILIAFERRARA, MARCOGILBERT, KEVIN F.HARPER, STEVENMCCAULEY, JOHN A.MCINTYRE, CHARLES A.PETROCCHI, ALESSIAPOMPEI, MARCOROMANO, JOSEPH J.RUDD, MICHAEL T.BUTCHER, JOHN W.HOLLOWAY, M. KATHARINE
Owner MERCK SHARP & DOHME CORP
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