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Macrocyclic peptides active against the hepatitis C virus

A hepatitis virus, cycloalkyl technology, applied in the field of compounds, can solve problems such as reducing side effects

Inactive Publication Date: 2005-07-13
BOEHRINGER INGELHEIM CANADA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the side effects caused by IFN were not alleviated by using this combination therapy

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

Embodiment approach

[0071] Preferably, the above-mentioned compound of formula I, wherein R 1 is hydroxyl or NHSO 2 R 1A , where R 1A Yes (C 1-6 ) alkyl, (C 3-7 ) cycloalkyl or {(C 1-6 ) Alkyl-(C 3-7 )cycloalkyl}, which are optionally halogen, nitro or O-(C 1-6 ) Alkyl is substituted 1-3 times, or phenyl, which is optionally replaced by halogen, nitro, (C 1-6 ) Alkyl or O-(C 1-6 ) alkyl groups are substituted 1 to 3 times.

[0072] More preferred are compounds of I above, wherein R 1 is hydroxyl or NHSO 2 R 1A , where R 1A is methyl, ethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl, cyclohexylethyl, CCl 3 , CF 3 , phenyl, 2-fluorophenyl or 4-methylphenyl.

[0073] Most preferred are compounds of formula I as defined above, wherein R 1 is hydroxyl or NHSO 2 R 1A ; where R 1A is methyl, cyclopropyl, CF 3 or phenyl. Yujia R 1A For cyclopropyl.

[0074] R 1 Most preferred is hydroxyl.

[0075] R 2 Most preferred is cyclopentyl.

[0076] All compounds of formul...

Embodiment 1

[0110] Synthesis of dipeptide 1c

[0111]

[0112] 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 A mixture of DIPEA (113 mL, 649 mmol) in DMF (800 mL) was stirred at room temperature under nitrogen. After 3.5 hours, the solvent was evaporated and the residue was extracted with EtOAc. The extract was washed with hydrochloric acid (10%), saturated sodium bicarbonate and brine. The organic phase was then dried over magnesium sulfate, filtered and evaporated to an oil. After drying under high vacuum overnight (18 hours), dipeptide 1c was obtained as a yellow foam (72.0 g, 94%, purity >95% by HPLC).

Embodiment 2

[0114] Synthesis of dipeptide 2a

[0115]

[0116] Dipeptide 1c (72.0 g, 203 mmol), triphenylphosphine (63.94 g, 243.8 mmol, 1.2 eq) and 4-nitrobenzoic acid (41.08 g, 245.8 mmol, 1.2 eq) were dissolved in anhydrous THF (1.4 L). The stirred solution was cooled to 0 °C under nitrogen. DEAD (38.4 mL, 244 mmol, 1.2 equiv) was then added dropwise over 45 minutes and the reaction was allowed to warm to room temperature. After 4 hours, the solvent was evaporated and the residue was divided into four portions. Each aliquot was prepared on fine silica gel (10-40 micron mesh, column diameter 12 cm, column length 16 cm) with a gradient of 2:1 hexane / EtOAc to 1:1 hexane / EtOAc to pure EtOAc. Chromatographic eluent purification. Ester 2a was obtained as an amorphous white solid (108.1 g, quantitative yield) after evaporation of the solvent and drying under high vacuum at 70°C for 1 hour.

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Abstract

Compounds of formula (I): wherein R1 is hydroxyl or NHSO2R1A, wherein R1A is (C1-8) alkyl, (C3-7) cycloalkyl or {(C1-6) alkyl-(C3-7) cycloalkyl }, all of which are optionally substituted 1 to 3 times with halogen, cyano, nitro, O(C1-6) alkyl, amido, amino or phenyl, or R1A is C6 or C10 aryl, depending on Requires 1 to 3 substitutions with halogen, cyano, nitro, (C1-6) alkyl, O(C1-6) alkyl, amido, amino or phenyl; R2 is (C5-6) ring Alkyl and R3 are cyclopentyl; or a pharmaceutically acceptable salt thereof, useful as an HCV NS3 protease inhibitor.

Description

field of invention [0001] The present invention relates to a class of compound, its synthesis method, composition and method for treating hepatitis C virus (HCV) infection. Specifically, the present invention provides novel peptide analogs, pharmaceutical compositions containing the same and methods of using these analogs to treat HCV infection. Background of the invention [0002] Hepatitis C virus (HCV) is the major etiological agent of post-transfusion and socially acquired non-A non-B hepatitis worldwide. It is estimated that more than 200 million people in the world are infected by this virus. A high percentage of carriers become chronically infected, and most of them develop chronic liver disease, the so-called chronic hepatitis C. This group of people in turn becomes a high-risk group for serious liver diseases such as cirrhosis, hepatocellular carcinoma and liver disease leading to death. [0003] The mechanisms by which HCV establishes viral persistence and contr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K31/7052A61K38/00A61K38/21A61P31/14A61P43/00C07K5/078C07K5/083C07K5/087
CPCA61K38/00C07K5/0806C07K5/0812A61P31/12A61P31/14A61P43/00C07K5/12C07K5/06139C07K5/08
Inventor 蒙特斯·利纳斯-布鲁尼特维达·J·戈里斯
Owner BOEHRINGER INGELHEIM CANADA LTD
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