Macrocyclic peptides active against the hepatitis C virus

a peptide and macrocyclic technology, applied in the field of compound, can solve the problems of lack of effective, recommendation of immunoglobulin treatment, and lack of cellular and humoral immune responses in protecting against hcv infection and disease, and achieve the effects of not showing significant inhibitory activity, reducing the activity of ns3 protease, and enhancing the stability of the formulation compound or its delivery form

Inactive Publication Date: 2005-04-07
BOEHRINGER INGELHEIM INT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

One advantage of the present invention is that it provides tripeptide compounds that are inhibitory to the NS3 protease, an enzyme essential for the replication of the hepatitis C virus.
A further advantage of one aspect of the present invention resides in the fact that the compounds specifically inhibit the NS3 protease and do not show significant inhibitory activity against other serine proteases such as human leukocyte elastase (HLE), porcine pancreatic elastase (PPE), or bovine pancreatic chymotrypsin, or cysteine proteases such as human liver cathepsin B (Cat B).
Furthermore, the compounds are active in cell culture.
Included in the scope of the invention are compounds of formula (I):
The pharmaceutical composition of this invention may be administered orally, parentera

Problems solved by technology

A high percentage of carriers become chronically infected and many progress to chronic liver disease, so-called chronic hepatitis C. This group is in turn at high risk for serious liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death.
In addition, the roles of cellular and humoral immune responses in protection against HCV infection and disease have yet to be established.
Immunoglobulins have been reported for prophylaxis of transfusion-associated viral hepatitis, however, the Center for Disease Control does not presently recommend immunoglobulins treatment for this purpose.
The lack of an effective protective immune response is hampering the development of a vaccine or adequate post-exposure proph

Method used

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  • Macrocyclic peptides active against the hepatitis C virus
  • Macrocyclic peptides active against the hepatitis C virus
  • Macrocyclic peptides active against the hepatitis C virus

Examples

Experimental program
Comparison scheme
Effect test

example 1

A mixture of Boc-hydroxyproline 1a (50.0 g, 216 mmol), (1R,2S)-vinyl-ACCA hydrochloride 1b (42.25 g, 238 mmol), TBTU (76.36 g, 238 mmol) and DIPEA (113 mL, 649 mmol) in DMF (800 mL) was stirred at R.T. under a nitrogen atmosphere. After 3.5 h, the solvent was evaporated and the residue extracted with EtOAc and washed with hydrochloric acid (10%), saturated sodium bicarbonate and brine. The organic phase was then dried over magnesium sulfate, filtered and evaporated to afford an oil. Drying the oil overnight (18 h) under high vacuum gave the dipeptide 1c as a yellow foam (72.0 g, 94%, purity >95% by HPLC).

example 2

The dipeptide 1c (72.0 g, 203 mmol), triphenylphosphine (63.94 g, 243.8 mmol, 1.2 equiv.) and 4-nitrobenzoic acid (41.08 g, 245.8 mmol, 1.2 equiv) were dissolved in dry THF (1.4L) and the stirred solution cooled to 0° under a nitrogen atmosphere. DEAD (38.4 mL, 244 mmol, 1.2 equiv.) was then added dropwise over 45 min and the reaction allowed to warm to R.T. After 4 h, the solvent was evaporated and the residue divided into four portions. Each of these was chromatographed over fine silica gel (10-40 μm mesh, column diameter 12 cm, column length 16 cm) using a gradient of 2:1 hexane / EtOAc to 1:1 hexane / EtOAc to pure EtOAc. Ester 2a was obtained as an amorphous white solid after evaporation of the solvents and drying under high vacuum at 70° for 1 h (108.1 g, quantitative yield).

example 3

The nitrobenzoyl ester 2a (108.1 g, 203.1 mmol) was dissolved in THF (1.0L) and the resulting solution cooled to 0°. A solution of lithium hydroxide monohydrate (10.66 g, 253.9 mmol) in water (225 mL) was then added rapidly and the reaction stirred at 0° for 30 min. after which time the remaining base was neutralized with hydrochloric acid (1 N, 50.8 mL). Additional acid was slowly added until the yellow color dissipated (7 mL). The resulting mixture was then evaporated and the residue extracted with EtOAc (3×150 mL) and washed with saturated sodium bicarbonate (150 mL) and brine (150 mL). The organic phase was dried over magnesium sulfate-charcoal, filtered through diatomaceous earth and evaporated. Overnight drying of the residue under high vacuum yielded the alcohol 3a as a colorless foam (70.1 g, 98%, purity >99% by HPLC).

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Abstract

Compounds of formula (I):
wherein R1 is (C1-8)alkyl, (C3-7)cycloalkyl, {(C1-6)alkyl-(C3-7)cycloalkyl} or Het, which are all optionally substituted from 1 to 3 times with halo, cyano, nitro, O—(C1-6)alkyl, amido, amino or phenyl, or R1 is C6 or C10 aryl which is optionally substituted from 1 to 3 times with halo, cyano, nitro, (C1-6)alkyl, O—(C1-6)alkyl, amido, amino or phenyl; or a pharmaceutically acceptable salt thereof, useful as an inhibitor of the HCV NS3 protease.

Description

FIELD OF THE INVENTION The present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection. In particular, the present invention provides novel peptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection. BACKGROUND OF THE INVENTION Hepatitis C virus (HCV) is the major etiological agent of post-transfusion and community-acquired non-A non-B hepatitis worldwide. It is estimated that over 200 million people worldwide are infected by the virus. A high percentage of carriers become chronically infected and many progress to chronic liver disease, so-called chronic hepatitis C. This group is in turn at high risk for serious liver disease such as liver cirrhosis, hepatocellular carcinoma and terminal liver disease leading to death. The mechanism by which HCV establishes viral persistence and causes a high rate of chronic li...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K38/12C07K5/08
CPCC07K5/0802A61K38/00A61P31/14
Inventor LLINAS-BRUNET, MONTSEBAILEY, MURRAY D.
Owner BOEHRINGER INGELHEIM INT GMBH
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