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Haloalkyl containing compounds as cysteine protease inhibitors

A technology of halogenated alkyl and compounds, which is applied in the field of cysteine ​​proteases, and can solve problems such as increased expression

Inactive Publication Date: 2006-07-26
维罗湾公司
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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. due to increased expression or enhanced activation, can have pathological consequences

Method used

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  • Haloalkyl containing compounds as cysteine protease inhibitors
  • Haloalkyl containing compounds as cysteine protease inhibitors
  • Haloalkyl containing compounds as cysteine protease inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0138] Certain compounds of formula (I) within the broad scopes and preferred embodiments set forth in the Summary of the Invention are preferred. For example:

[0139] A. A preferred group of compounds wherein R 1 and R 2 those for hydrogen.

[0140] B. Another preferred group of compounds is that wherein R 1 and R2 together with the carbon atoms to which they are attached are optionally replaced by one or two R b Those of substituted cycloalkylene, R b independently selected from alkyl, halo, dialkylamino, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, alkoxycarbonyl, or aryloxycarbonyl. Preferably, R 1 and R 2 Together with the carbon atom to which they are attached, form cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene optionally substituted by the groups described immediately above. More preferably, R 1 and R 2 Together with the carbon atoms they are attached to form cyclopropylene, cyclobutylene, cyclopentylene, cyclohexyl...

Embodiment A

[0373] Synthesis of 2(RS)-benzyloxycarbonylamino-4(RS)-(2-methoxyphenyl)pentanoic acid

[0374]

[0375] To d,l-2-methoxy-α-methylbenzyl alcohol (0.5 g, 3.29 mmol) was added 48% aq. HBr (2 mL) and the reaction mixture was stirred rapidly for 1.5 hours. Dilute the reaction mixture with n-hexane (30mL), wash with water, MgSO 4Dry, filter, and evaporate in vacuo. Crude d,l-2-methoxy-α-methylbenzyl bromide was added to tributyltin hydride (0.67 mL, 2.49 mmol), Z-dehydroalanine methyl ester (0.25 g, 1.06 mmol), and 2,2'-azobisisobutyronitrile (15 mg, 0.09 mmol) in benzene (5 mL). The reaction mixture was heated at 80° C. for 5 hours under nitrogen atmosphere. Benzene was removed in vacuo and the residue was dissolved in methanol (20 mL). 2N KOH (5 mL) was added and the mixture was stirred rapidly at room temperature overnight. Methanol was removed in vacuo and the residue was diluted with water (20 mL). The aqueous solution was washed with ether to remove the tin by-produc...

Embodiment 1

[0476] N-(1-cyanocyclopropyl)-3-phenylmethanesulfonyl-2(R)-(2,2,2-trifluoro-1(RS)-thiophen-2-ylethylamino)propane Amide synthesis

[0477]

[0478] step 1

[0479] To a cold (0 °C), stirred solution of 2(R)-amino-3-phenylmethanesulfanylpropionic acid (commercially available) (4.01 g, 19.0 mmol) in methanol (100 mL) was introduced HCl gas 15 min, the reaction mixture was sealed and stirring continued at room temperature overnight. The solvent was then evaporated under vacuum to give methyl 2(R)-amino-3-phenylmethanesulfanylpropionate hydrochloride (4.98 g) in quantitative yield.

[0480] step 2

[0481] 2(R)-Amino-3-phenylmethanesulfanylpropanoic acid methyl ester hydrochloride (4.95 g, 18.9 mmol) containing p-toluenesulfonic acid (0.19 g) and Trifluoroacetaldehyde methyl hemiacetal (3.12 g, 24.0 mmol) mixture overnight. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 100% sodium bicarbonate, and then washed with water. Dry the organic phase (...

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Abstract

The present invention relates to compounds substituted by haloalkyl of the following formula (I), wherein R 7 Represents haloalkyl, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 8 The definition is the same as the claims. The compounds are inhibitors of cysteine ​​proteases, especially cathepsins B, K, L, F and S, and are therefore useful in the treatment of diseases mediated by these proteases. The invention also discloses pharmaceutical compositions including these compounds and their references.

Description

technical field [0001] The present invention relates to compounds which are inhibitors of cysteine ​​proteases, in particular cathepsins B, K, L, F, and S, and are thus useful in the treatment of diseases mediated by these proteases. The invention also relates to pharmaceutical compositions comprising these compounds and methods of preparing them. Background technique [0002] Cysteine ​​proteases represent a class of peptidases characterized by the presence of a cysteine ​​residue in the catalytic site of the enzyme. Cysteine ​​proteases are involved in normal protein degradation and processing. However, abnormal activity of cysteine ​​proteases, for example due to increased expression or enhanced activation, can have pathological consequences. In this regard, certain cysteine ​​proteases have been associated with a variety of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachroma...

Claims

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Application Information

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IPC IPC(8): C07C255/46C07C317/48C07C323/60C07D213/12C07D241/12C07D309/14C07D333/20C07D335/02A61P17/06A61P37/00A61K31/277
Inventor 约翰·O·林克克雷格·J·莫斯曼禹顺亨希拉·M·齐普费尔
Owner 维罗湾公司
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