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Alpha ketoamide compounds as cysteine protease inhibitors

Technology of a compound, alkyl, in the field of alpha ketoamide compounds as cysteine ​​protease inhibitors

Inactive Publication Date: 2008-05-14
探索诊断投资有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, abnormal activity of cysteine ​​proteases, e.g. as a result of increased expression or enhanced activity, can have pathological consequences

Method used

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  • Alpha ketoamide compounds as cysteine protease inhibitors
  • Alpha ketoamide compounds as cysteine protease inhibitors
  • Alpha ketoamide compounds as cysteine protease inhibitors

Examples

Experimental program
Comparison scheme
Effect test

specific Embodiment approach

[0107] I. Certain compounds of formula (I) within the broadest ranges set forth in the Summary of the Invention are preferred. E.g:

[0108] (A) A preferred group of compounds is that wherein:

[0109] R 1 is hydrogen or methyl, preferably hydrogen;

[0110] R 2 is cyclopropyl, 1-phenethyl[-CH(C 6 h 5 )CH 3 ], or 1H-pyrazol-5-yl; preferably cyclopropyl.

[0111] (1) Among the above-mentioned preferred group (A) and the more preferred groups contained therein, the more preferred group of compounds is that wherein: R 3 is hydrogen and R 4 is an alkyl group, preferably methyl, ethyl, propyl or butyl, more preferably R 4 is ethyl or propyl.

[0112] (2) Among the above-mentioned preferred group (A) and the more preferred groups contained therein, the more preferred group of compounds is that wherein: R 3 is an alkyl group, preferably methyl or ethyl and R 4 is an alkyl group, preferably methyl, ethyl, propyl or butyl, more preferably R 4 is methyl. Preferably, R 3 a...

Embodiment 1

[0280] 2-oxo-3(S)-{3-(pyridin-3-ylmethylsulfonyl)-2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl ) ethylamino]-propionylamino} hexanoic acid cyclopropylamide synthesis

[0281]

[0282] step 1

[0283] Phthaloxaborane (19.4ml, 182mmol) in dichloromethane (15mL) was added dropwise to S-methyl CBS oxazoborane (13ml, 13mmol) and 2 at -78°C over 30min, 2,2,4'-Tetrafluoroacetophenone (18.2ml, 130.13mmol) in dichloromethane. The reaction mixture was stirred overnight at -78°C. The reaction mixture was quenched with 4N HCl (13 mL) in dioxane at -78 °C, warmed to room temperature and the solvent was removed under reduced pressure. Add 10% NaHSO to the concentrate 3 solution (200 mL) and the aqueous layer was extracted with hexane. The organic layer was washed with water and washed with MgSO 4 dry. The solvent was removed under reduced pressure to give 2,2,2-trifluoro-1(R)-(4-fluorophenyl)-ethanol as a colorless oil (90% e.e.).

[0284] step 2

[0285] at 0°C, in N 2 Add NaH (...

Embodiment 2

[0299] 2-Oxo-3(S)-3-[2(R)-(2,2,3,3,3-pentafluoropropylamino)-3-(pyridin-3-ylmethylsulfonyl)propionyl Synthesis of Amino]pentanoic Acid Cyclopropylamide

[0300]

[0301] step 1

[0302] To a solution of 2,2,3,3,3-pentafluoropropan-1-ol (1.5 g, 10.0 mmol) and DIPEA (6.1 ml, 35.0 mmol) in dichloromethane (75 mL) at -78°C was added trifluoro Methanesulfonic anhydride (1.78ml, 10.5mmol). After 2.5 h, S-tritylcysteine ​​was added all at once, and the reaction mixture was stirred at 0° C. for 80 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated on a rotovap. Ethyl acetate was added and the reaction mixture was washed with 1N HCl. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash chromatography (3 parts hexane / 1 part ethyl acetate + 1% acetic acid) to give 2(R)-(2,2,3,3,3-pentafluoropropylamino)- 3-Tritylsulfanylpropionic acid (3.29 g).

[0303] step 2

[0304] 2(R)-...

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Abstract

The present invention relates to compounds that are inhibitors of cysteine proteases, in particular, cathepsins B, K, L, F, and S and are therefore useful in treating diseases mediated by these proteases. The present invention is directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application 60 / 663,970, filed March 21, 2005, and US Provisional Patent Application 60 / 684,623, filed May 24, 2005, both of which are incorporated herein by reference. [0003] Statement Concerning Rights to Inventions Made Under Federally Sponsored Research or Development Not Applicable [0004] With respect to "sequence listings," table or computer program listing attachments filed on disc, not applicable technical field [0005] The present application relates to compounds which are inhibitors of cysteine ​​proteases, in particular inhibitors of cathepsins B, K, L, F and S, and are therefore useful in the treatment of diseases mediated by these proteases. The invention also relates to pharmaceutical compositions comprising these compounds and processes for their preparation. Background technique [0006] Cysteine ​​proteases represent a class of peptidases ...

Claims

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Application Information

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IPC IPC(8): C07C233/00C07C235/00C07C237/00C07C239/00
Inventor 迈克尔·格劳佩约翰·O·林克迈克尔·G·勒佩
Owner 探索诊断投资有限责任公司
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