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Macrocyclic isoquinoline peptide inhibitors of hepatitis C virus

a technology of macrocyclic isoquinoline and hepatitis c virus, which is applied in the direction of peptides, drug compositions, peptides, etc., can solve the problems that a large percentage of patients do not have a sustained reduction in viral load, and achieve the effect of inhibiting the function of ns3 proteas

Inactive Publication Date: 2006-11-16
BRISTOL MYERS SQUIBB CO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides new compounds that can inhibit the HCV NS3 protease, which is a key enzyme involved in the replication of the virus that causes hepatitis C. These compounds have improved potency and selectivity compared to existing drugs, and can be used in pharmaceutical compositions to treat patients infected with HCV. The invention also provides methods for inhibiting the NS3 protease and methods for treating patients with HCV. Overall, the invention provides better drugs for the treatment of hepatitis C.

Problems solved by technology

However, even with experimental therapeutic regimens involving combinations of pegylated alpha-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load.

Method used

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  • Macrocyclic isoquinoline peptide inhibitors of hepatitis C virus
  • Macrocyclic isoquinoline peptide inhibitors of hepatitis C virus
  • Macrocyclic isoquinoline peptide inhibitors of hepatitis C virus

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Representative Intermediates

Preparation of P2 Isoquinoline Intermediates for Incorporation into Compounds of Formula 1

[0167] Method A

Step 1:

[0168] To a solution of 3-methoxy cinnamic acid (11.04 g, 62 mmol) and triethylamine (12.52 g, 124 mmol) in acetone (80 mL) was added ethyl chloroformate (approximately 1.5 equivalents) dropwise at 0° C. After stirring at this temperature for 1 h, aqueous NaN3 (6.40 g, 100 mmol in 35 mL H2O; appropriate precautions must be taken when using sodium azide) was added dropwise and the reaction mixture was stirred for 16 h at the ambient temperature. Water (100 mL) was added to the mixture and the volatile was removed in vacuo. The resulting slurry was extracted with toluene (3×50 mL) and the combined organic layers were dried over MgSO4. This dried solution was added dropwise to a heated solution of diphenylmethane (50 mL) and tributylamine (30 mL) at 190° C. The toluene was distilled off as added. After complete addition, the r...

example 2

, Compound 1

Step 2A, Preparation of 2-(1-Ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester

[0329]

[0330] A stirred slurry of 4-(isoquinolin-1-yloxy)-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (5.69 g, 15.9 mmol) in 200 mL of methylene chloride was treated sequentially with diisopropylethylamine (13.8 mL, 79.0 mmol), HBTU (7.10 g, 18.7 mmol), HOBT.H2O (2.86 g, 18.7 mmol), and 1R,2S-1-amino-2-vinylcyclopropane carboxylic acid ethyl ester hydrochloride (3.19 g, 16.7 mmol). The gold homogeneous solution was stirred at rt under N2 for 18 h, and then concentrated in vacuo to give 10 g of a brown oil. This was partitioned between ethyl acetate and sat. aq. NaHCO3. The organic phase was washed with brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography (2-5% MeOH in methylene chloride) gave 5.5 g (70%) of 2-(1-ethoxycarbonyl-2-vinyl-cyclopropylcarbamoyl)-4-(isoquinolin-1-yloxy)-pyrrolidine-1-carboxylic...

example 3a

Preparation of Cyclopropylsulfonamide

[0339] Method A:

[0340] To a solution of 100 mL of THF cooled to 0° C. was bubbled in gaseous ammonia until saturation was reached. To this solution was added a solution of 5 g (28.45 mmol) of cyclopropylsulfonyl chloride (purchased from Array Biopharma) in 50 mL of THF, the solution warmed to rt overnite and stirred one additional day. The mixture was concentrated until 1-2 mL of solvent remained, applied on to 30 g plug of SiO2 (eluted with 30% to 60% EtOAc / Hexanes) to afford 3.45 g (100%) of cyclopropyl sulfonamide as a white solid. 1H NMR (Methanol-d4) δ 0.94-1.07 (m, 4H), 2.52-2.60 (m, 1H); 13C NMR (methanol-d4) δ 5.92, 33.01.

Method B:

Step 1: Preparation of N-tert-Butyl-(3-chloro)propylsulfonamide

[0341]

tert-Butylamine (3.0 mol, 315.3 mL) was dissolved in THF (2.5 L). The solution was cooled to −20° C. 3-Chloropropanesulfonyl chloride (1.5 mol, 182.4 mL) was added slowly. The reaction mixture was allowed to warm to rt and stirred for 2...

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Abstract

Macrocyclic isoquinoline peptides are disclosed having the general formula: A compound of formula I: wherein R1 to R9, Q and W are described in the description. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.

Description

CROSS REFERENCE TO RELATED APPLICATION [0001] This application is a divisonal of U.S. application Ser. No. 10 / 825,693, filed on Apr. 16, 2004, which claims priority to U.S. Provisional Application Ser. No. 60 / 463,423 filed Apr. 16, 2003.FIELD OF THE INVENTION [0002] The present invention is generally directed to antiviral compounds, and more specifically directed to compounds which inhibit the functioning of the NS3 protease (also referred to herein as “serine protease”) encoded by Hepatitis C virus (HCV), compositions comprising such compounds, and methods for inhibiting the functioning of the NS3 protease. BACKGROUND OF THE INVENTION [0003] HCV is a major human pathogen, infecting an estimated 170 million persons worldwide—roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma. (Lauer, G. M.; Walker, B. D. N. E...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12P13/04A61K38/00A61K38/12C07KC07K5/083C07K5/12C07K7/00C12P7/62C12P41/00
CPCA61K38/00C07K5/0804C12P7/62C12P13/04C12P41/005A61P1/16A61P31/14A61P31/22A61P43/00
Inventor LI, WENYING
Owner BRISTOL MYERS SQUIBB CO
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