Cathepsin inhibitors

A cathepsin, compound technology, applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve problems such as inactivating proteins

Inactive Publication Date: 2006-10-04
MERCK FROSST CANADA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

All mutations identified to date in the cathepsin K gene are known to result in an inactive protein

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0249] N 1 -(cyanomethyl)-N 2 -Synthesis of -(2,2,2-trifluoro-1-phenylethyl)-L-leucine amide

[0250]

[0251] To a solution of L-leucine methyl ester hydrochloride (975 mg, 5.37 mmol) in dichloromethane (30 mL) was added 2,2,2-trifluoroacetophenone (0.75 mL, 5.34 mmol) and diisopropyl Ethylamine (3.5 mL, 20 mmol). TiCl dissolved in 0.45mL dichloromethane solution was added dropwise 4 (0.55 mL, 5.0 mmol), and the mixture was stirred overnight. Then add additional TiCl 4 (0.4 mL, 3.6 mmol), and the mixture was stirred for 3 h. Join NaCNBH 3 (1050 mg, 16.7 mmol) in methanol (20 mL), and the mixture was stirred for 2 h. Poured into 1N NaOH and extracted with ethyl acetate (2x). The organic phase was washed with 1N NaOH and brine, followed by MgSO 4 Dry and evaporate. Purification by ISCO column chromatography (30% to 90% ethyl acetate / hexanes gradient) yielded methyl N-(2,2,2-trifluoro-1-phenethyl)-L-white ester.

[0252] To a room temperature solution of methyl N-(...

Embodiment 2

[0256] N 2 -[1-(-4-Bromophenyl)-2,2,2-trifluoroethyl]-N 1 Synthesis of -(cyanomethyl)-L-leucine amide

[0257]

[0258] Using the method of Example 1, N 2 ~[1-(4-bromophenyl)-2,2,2-trifluoroethyl]-N 1 -(cyanomethyl)-L-leucine amide.

[0259] MS (-ESI): 403.9, 405.9 [M-1] -

Embodiment 3

[0261] N 1 -(cyanomethyl)-N 2 -{[4'-((methylsulfonyl))-1,1'-biphenyl-4-yl][4-((methylsulfonyl))phenyl]methyl}-L-leucine amide Synthesis

[0262]

[0263] Step 1: N-{(4-bromophenyl)[4-((methylsulfonyl))phenyl]methylene}-L-leucine methyl ester

[0264] (4-bromophenyl)[4-((methylsulfonyl))phenyl]methanone (202mg, 0.59mmol), L-leucine methyl ester hydrochloride (328mg, 2.0mmol) and camphorsulfonic acid (52 mg, 0.22 mmol in toluene was refluxed for 18 h using a Dean-Stark trap. The solvent was removed in vacuo and the residue was purified by chromatography using EtOAc and hexanes as eluents to afford the title compound along with the starting material ( A mixture of 4-bromophenyl)[4-((methylsulfonyl))phenyl]methanone in a ratio of 1:1.

[0265] Step 2: N-{(4-bromophenyl)[4-((methylsulfonyl))phenyl]methyl}-L-leucine methyl ester

[0266] To N-{(4-bromophenyl)[4-((methylsulfonyl))phenyl]methylene}leucine methyl ester and (4-bromophenyl Base)[4-((methylsulfonyl))phenyl]methan...

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Abstract

This invention relates to a novel class of compounds, represented by the formula (I) below, wherein the meanings of R1, R2, R3 and R4 are indicated therein, which are cysteine protease inhibitors, including but not limited to, inhibitors of cathepsins K, L, S and B. These compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis, osteoarthritis and rheumatoid arthritis.

Description

technical field [0001] The present invention relates generally to inhibitors of protein activity, and in particular to inhibitors of cathepsins. Background technique [0002] Many cathepsins belong to the papain superfamily of cysteine ​​proteases. These proteases play a role in the normal physiological as well as pathological degradation of connective tissue. Cathepsins play a pivotal role in intracellular protein degradation and turnover and remodeling. These cathepsins are naturally present in a variety of tissues. To date, many cathepsins have been identified and sequenced from many sources, for example, cathepsins B, F, H, L, K, S, W and Z have been cloned. In addition, the sequence of cathepsin K is disclosed in PCT Application WO 96 / 13523, published May 9, 1996 by Khepri Pharmaceuticals, Inc., which is hereby incorporated by reference in its entirety. Cathepsin L has a complex relationship with normal lysozyme proteolysis as well as several pathological states inc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C255/29C07C317/22C07C317/40C07D241/04C07D333/10C07C255/46C07C323/41C07D223/08C07D295/108C07D295/135C07D307/33C07D333/20C07K5/06
CPCC07D333/20C07K5/06191C07C255/29C07D307/33C07D401/12C07C323/41C07D295/135C07D223/08C07D295/108C07C255/24C07C2101/02C07D333/24C07C255/46C07C2601/02A61P19/02A61P19/10A61P29/00A61P43/00
Inventor C·拜利C·布拉克D·J·麦凯
Owner MERCK FROSST CANADA INC
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