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Silinane compounds as cysteine protease inhibitors

A compound, heterocycloalkyl technology, applied in the field of cysteine ​​protease

Inactive Publication Date: 2007-03-28
SCHERING AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, abnormal activity of cysteine ​​proteases, such as those caused by increased expression or enhanced activation, may lead to pathological consequences

Method used

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  • Silinane compounds as cysteine protease inhibitors
  • Silinane compounds as cysteine protease inhibitors
  • Silinane compounds as cysteine protease inhibitors

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Experimental program
Comparison scheme
Effect test

Embodiment approach

[0173] Although the broadest definition of the invention is given in the Summary of the Invention, certain compounds of the invention are preferred. For example:

[0174] A. A preferred group of compounds are those wherein E is -C(R 5 )(R 6 )X 1 compounds, of which:

[0175] R 5 is hydrogen or alkyl; and

[0176] R 6 is hydrogen, alkyl, -(alkylene)-OR 12 (where R 12 is hydrogen, alkyl or haloalkyl), cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl, where aryl radical, aralkyl, heteroaryl, heteroaralkyl, heterocycloalkyl or heterocycloalkylalkyl is optionally selected from one, two or three independently selected from alkyl, haloalkyl, alkoxy, R of hydroxy, haloalkoxy, halogen, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino or acyl a replace.

[0177] Preferred R 5 is hydrogen;

[0178] R 6 is an alkyl group, preferably ethyl or propyl, more preferably ethyl; and

[0179] ...

Embodiment 1

[0518] 1-(R)-morpholine-4-carboxylic acid [1-(4-cyano-1-ethylpiperidin-4-ylcarbamoyl)-2-(trimethylsilyl)ethyl]amide Synthesis

[0519]

[0520] step 1

[0521] (R)-2-Amino-3-trimethylsilylpropionic acid (0.320g, 2mmol) and N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA) (1.85g, 13mmol ) mixture was heated at 70 °C for 1 h. The reaction mixture was cooled and remaining MSTFA was removed in vacuo. Morpholinocarbonyl chloride (0.70ml, 6mmol) was added to the reaction mixture, heated at 70°C for 45 minutes, then cooled. Water and ice (25ml) were added to the reaction mixture and stirred until the evolution of carbon dioxide ceased. Extraction of this solution with ethyl acetate afforded 2-(R)-[(morpholine-4-carbonyl)amino]-3-(trimethylsilyl)propanoic acid (0.529 g), which was used without further purification in the following step.

[0522] step 2

[0523] To a solution of 2-(R)-[(morpholine-4-carbonyl)amino]-3-(trimethylsilyl)propanoic acid (140 mg, 0.51 mmol) in DM...

Embodiment 2

[0531] 1-(R)-morpholine-4-carboxylic acid [1-(4-cyano-1,1-dioxohexahydro-1λ6 Synthesis of -thiopyran-4-ylcarbamoyl)-2-(trimethylsilyl)ethyl]amide

[0532]

[0533] At room temperature, to the crude product 1-(R)-morpholine-4-carboxylic acid [1-(4-cyanothiopyran-4-ylcarbamoyl)-2-(trimethylsilyl) To a solution of ethyl]amide (260mg, 0.51mmol) in MeOH (15ml) was added potassium persulfate (469mg, 0.76mmol) in water (15ml). After 2 h, methanol was removed in vacuo and the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated. The residue was purified by silica gel chromatography to give the title compound (47mg). h 1 NMR (DMSO-d 6 ): δ8.39(1H, s), 6.5(1H, d, J=7.6Hz), 4.1(1H, m), 3.49(4H, t, J=4.4Hz), 3.4-3.1(6H, m) , 2.7-2.55 (2H, m), 2.5-2.4 (4H, m), 1.05-0.85 (2H, m), 0.008 (9H, s). MS: 429.2 (M-1), 43 1.1 (M+1), 453.2 (M+Na).

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Abstract

The present invention is directed 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 also directed to pharmaceutical compositions comprising these compounds and processes for preparing them. The present invention is also directed to the use of these inhibitors in combination with a therapy that causes a deleterious immune response in patients receiving the therapy.

Description

field of invention [0001] The present invention relates to compounds which are inhibitors of cysteine ​​proteases, especially cathepsins B, K, L, F and S, and which are therefore useful in the treatment of diseases mediated by these proteases. The invention also relates to pharmaceutical compositions containing these compounds and processes for their preparation. The invention also relates to the use of these inhibitors in patients receiving a therapy that results in an adverse immune response in combination with that therapy. technical background [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 the normal degradation and processing of proteins. However, abnormal activity of cysteine ​​proteases, such as those caused by increased expression or enhanced activation, may lead to pathological consequences. In this regard, certain cystein...

Claims

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Application Information

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IPC IPC(8): C07F7/08A61K45/00A61P29/00
Inventor 约翰·O.·林克迈克尔·格劳佩
Owner SCHERING AG
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