C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cystenine proteases

An amino acid, CH2OCO technology, used in the treatment of autoimmune diseases, in the field of pharmaceutical compositions containing these compounds, can solve problems such as obstacles

Inactive Publication Date: 2001-09-19
CONATUS PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

These undesired properties hinder the de...

Method used

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  • C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cystenine proteases
  • C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cystenine proteases
  • C-terminal modified oxamyl dipeptides as inhibitors of the ICE/ced-3 family of cystenine proteases

Examples

Experimental program
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preparation example 1

[0145] In the following examples, the proton NMR spectrum is measured at 300 MHz; the chemical shift value is reported for the low magnetic field of the internal standard tetramethylsilane. Preparation Example 1 (3S)-Amino-4-oxobutyric acid tert-butyl semicarbazone p-toluenesulfonate Part A: N-(benzyloxycarbonyl)-L-(N'-methyl-N'-methoxy) Asparagine β-tert-Butyl Ester

[0146] In 0℃ (ice bath) and nitrogen atmosphere, into N-(benzyloxycarbonyl)-L-aspartic acid β-tert-butyl ester (14.65g, 45.3mmol, Bachem) in dichloromethane (150mL) Add 1-hydroxybenzotriazole hydrate (7.29g, 47.6mmol, Aldrich), then add 1-ethyl-3-(3',3'-dimethyl-1'-aminopropyl) carbodiimide Amine hydrochloride (9.55 g, 49.8 mmol, Sigma). After stirring for 15 minutes at 0°C, N,O-dimethylhydroxylamine hydrochloride (5.10g, 52.3mmol, Aldrich) and N-methylmorphine (5.8ml, 53mmol, Aldrich) were added. After 3 hours, the mixture was allowed to warm to room temperature, and then stirred at room temperature for 16 hours. ...

preparation example 2

[0152] By conversion to the corresponding Mosher amide [1.05 equivalents (R)-(-)-α-methoxy-α-(trifluoromethyl)phenylacetyl chloride, 2.1 equivalents diisopropylethylamine (i-Pr2NEt) Dichloromethane solution, room temperature, 30 minutes], the optical purity of the product was detected. The target product has a double peak at 7.13 ppm (1H, d, J=2.4 Hz, CH=N), and the corresponding signal of its diastereomer is at 7.07 ppm. The optical purity of the title compound obtained by the above method is usually >95:5. Preparation Example 2 (3S)-(9-Fluorenylmethoxycarbonyl)amino-4-oxobutyrate tert-butyl semicarbazonyl-4-[2'-(4-ethyl-phenoxyacetic acid)] Preparation part A: 4-[2'-(N-tert-butoxycarbonyl)aminoethyl]phenoxyacetic acid, methyl ester

[0153] At room temperature and under a nitrogen atmosphere, to a suspension of 4-hydroxyphenethylamine (7.00g, 51.1mmol, Aldrich) in anhydrous dimethylformamide (50ml) was added di-tert-butyl dicarbonate (11.0g, 50.5mmol). After stirring at room te...

preparation example 3

[0161] Basically in accordance with the method of Thornberry et al. (Nature, 356:768:774 (1992)) and Nicholson et al. (Nature, 376:37-43 (1995)) (incorporated herein for reference), in a 96-well microtiter plate Recombinant ICE and CPP32 enzymes were used in the luciferase assay to determine the activity of the compound of formula 1. The substrate used for ICE analysis is acetyl-Tyr-Val-Ala-Asp-amino-4-methylcoumarin (AMC), and the substrate used for CPP32, Mch2, Mch3 and Mch5 analysis is acetyl-Asp -Glu-Val-Asp-amino-4-methylcoumarin. At room temperature, the enzyme reaction was repeated (in duplicate) in ICE buffer (25 mM HEPES, 1 mM EDTA, 0.1% CHAPS, 10% sucrose, pH 7.5) containing 2 mM DTT. The analysis is performed by mixing the following ingredients:

[0162] 50μl ICE, Mch2, Mch5, CPP32 (concentrations of 18.8, 38, 8.1 and 0.153nM) or Mch3 (18.8, 38, 8.1 and 0.153nM) in 50μl of ICE, Mch2, Mch5, CPP32 in ICE buffer containing 8.0 (ICE, Mch2, Mch3, CPP32) or 20 (Mch5) mM DTT U...

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Abstract

This invention is directed to novel oxamyl depeptide ICE/ced-3 family inhibitor compounds. The invention is also directed to pharmaceutical compositions containing these compounds, as well as to the use of such compositions in the treatment of patients suffering inflammatory, autoimmune and neurodegenerative diseases, for the prevention of ischemic injury, and for the preservation of organs that are to undergo a transplantation procedure.

Description

Background technique [0001] The present invention relates to a new class of compounds, which are inhibitors of interleukin-1 beta converting enzyme and related proteases (ICE / ced-3 family cysteine ​​proteases). The present invention also relates to pharmaceutical compositions containing these compounds and their use Method of drug-like composition. Background of the invention [0002] Interleukin-1 ("IL-1") is a major pro-inflammatory and immunomodulatory protein, which stimulates the differentiation and proliferation of fibroblasts, stimulates the production of prostaglandins, collagenase and phospholipase through synovial cells and chondrocytes, Degranulation of basophils and eosinophils and activation of neutrophils. Oppenheim, J.H. et al., Immunology Today, 7:45-56 (1986). Therefore, it is related to the pathogenesis of chronic and acute inflammation and autoimmune diseases. IL-1 is mainly produced by peripheral blood mononuclear cells, and this process forms part of the infl...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K31/16A61K31/33A61K38/05A61K38/06A61P7/06A61P9/10A61P25/28A61P29/00A61P37/06A61P43/00C07CC07C23/22C07C235/80C07C237/22C07C317/50C07D209/42C07D211/60C07D235/30C07D237/22C07D239/00C07D239/34C07D261/18C07D309/30C07D311/32C07F9/32C07F9/46C07K5/06C07K5/062C07K5/078
CPCC07D261/18C07F9/3264C07D209/42C07D211/60C07C237/22C07D235/30C07C2103/74C07C2101/14C07D239/34C07D311/32C07D309/30C07C2601/14C07C2603/74A61P25/28A61P29/00A61P37/06A61P43/00A61P7/06A61P9/10C07K5/06
Inventor D·S·卡拉尼沃斯克R·J·特南斯凯
Owner CONATUS PHARMA
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