Di-fluoro containing compounds as cysteine protease inhibitors

Technology of a compound, amino group, in the field of difluorinated compounds as cysteine ​​protease inhibitors

Inactive Publication Date: 2011-04-13
VIROBAY INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, aberrant activity of cysteine ​​proteases (e.g. due to incr...

Method used

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  • Di-fluoro containing compounds as cysteine protease inhibitors
  • Di-fluoro containing compounds as cysteine protease inhibitors
  • Di-fluoro containing compounds as cysteine protease inhibitors

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0122] In a particular aspect, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein:

[0123] R 1 Is hydrogen or alkyl;

[0124] R 2 Is hydrogen, alkyl, haloalkyl, carboxyalkyl, alkoxycarbonylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, Heterocyclylalkyl, cyano or -alkylene-XR 9 (Where X is -O-, -NR 10 -, -CONR 11 -, -S(O) n1 -, -NR 12 CO-, -CO- or -C(O)O-, where n1 is 0-2, and R 9 , R 10 , R 11 And R 12 Independently hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl), wherein R 2 The aromatic ring or alicyclic ring in is optionally divided by one, two or three R a Replace, the R a Independently selected from alkyl, haloalkyl, alkoxy, hydroxy, haloalkoxy, halogen, carboxy, alkoxycarbonyl, amino, monosubstituted amino, disubstituted amino, nitro, aryloxy, benzyloxy, Acyl or arylsulfonyl, and further wherein R a The aromatic rin...

Embodiment 1

[0217] Synthesis Example 1-Scheme 1

[0218]

[0219] Scheme 1, Step 1: Synthesis of 1-aminocyclopropane nitrile hydrochloride (1-aminocyclopropane nitrile hydrochloride is commercially available)

[0220]

[0221] At room temperature and nitrogen, in a 2L Erlenmeyer flask, benzophenone imine (25g, 0.138mol, Aldrich) and aminoacetonitrile hydrochloride (25g, 0.270mol, Lancaster) in dichloromethane (1000mL) The mixture was stirred for five days. The reaction mixture was filtered to remove the precipitated ammonium chloride, and the filtrate was evaporated to dryness in vacuum. The obtained residue was dissolved in ether (400 mL) and washed with water (200 mL) and brine. After drying over magnesium sulfate, the solution was evaporated to give (dibenzylidene amino)-acetonitrile (47.89 g).

[0222] Under nitrogen, an aqueous solution (91mL) of sodium hydroxide (91g, 2.275mol) in a 2L flask was cooled on ice, and then benzyltriethylammonium chloride (2.0g, 0.0088mol, Aldrich) and (dib...

Embodiment 2

[0224] Synthesis Example 2: Scheme 2

[0225]

[0226] Scheme 2, Step 1: Synthesis of methyl (S)-2-(benzyloxycarbonylamino)-4-chloro-4-oxobutanoate

[0227]

[0228] See Synth. Comm. 1993, 23(18):2511-2526. Dissolve N-benzyloxycarbonyl-L-aspartic acid 2-methyl ester (5g, 17.7mmol) in 30ml anhydrous THF, and add 2 Stir at 0°C. At 0°C, thionyl chloride (10.5 g, 88.5 mmol, 5 equivalents) was added to the solution with a syringe, and the solution was refluxed for one hour. The solvent was removed under vacuum and the product was crystallized from dichloromethane / hexane to give methyl 2(S)-2-benzyloxycarbonylamino-3-chlorocarbonylpropionate.

[0229] 1 H NMR(400MHz, CDCl 3 )δ3.48(dd, 1H, J=18.5Hz, J=3.7Hz), 3.56(dd, 1H, J=18.5Hz, J=3.7Hz), 3.74(s, 3H), 4.58(m, 1H) , 5.10 (s, 2H), 5.72 (d, 1H), 7.30-7.35 (m, 5H) ppm.

[0230] Scheme 2, Step 2: (S)-2-(Benzyloxycarbonylamino)-4-oxo-5-phenylpentanoic acid methyl ester

[0231]

[0232] A solution of lithium bromide (2.2g, 25.44mmol, 2.4 equi...

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PUM

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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 directed to pharmaceutical compositions comprising these compounds and processes for preparing them.

Description

Background technique [0001] The present invention relates to compounds that act as inhibitors of cysteine ​​proteases (especially cathepsins B, K, L, F, and S) and thus can be used to treat diseases mediated by these proteases. The present invention also relates to pharmaceutical compositions containing these compounds and methods for their preparation. [0002] Cysteine ​​proteases represent a class of peptidases characterized by the presence of cysteine ​​residues at the catalytic site of the enzyme. Cysteine ​​proteases are involved in the normal degradation and processing of proteins. However, the abnormal activity of cysteine ​​proteases (for example due to increased expression or increased activation) can have pathological consequences. In this regard, certain cysteine ​​proteases are associated with various disease states including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic brain White matt...

Claims

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Application Information

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IPC IPC(8): A01N57/00A61K31/66
CPCC07C255/46C07C2101/02A61P9/10A61P11/06A61P17/02A61P17/06A61P19/02A61P21/04A61P25/00A61P25/04A61P29/00A61P37/00A61P43/00C07C2601/02
Inventor 约翰·O·林克克雷格·J·莫斯曼刘捷禹顺亨
Owner VIROBAY INC
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