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Novel compounds and compositions as cathepsin inhibitors

a technology of cathepsin inhibitors and compounds, applied in the field of peptidases, can solve the problems of pathological consequences and the erratic activity of cysteine proteases, and achieve the effect of preventing, inhibiting or ameliorating the pathology and/or symptomatology of the diseas

Inactive Publication Date: 2007-03-01
SANYO ELECTRIC CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The aberrant activity of cysteine proteases, e.g., as a result of increase expression or enhanced activation, however, may have pathological consequences.

Method used

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  • Novel compounds and compositions as cathepsin inhibitors
  • Novel compounds and compositions as cathepsin inhibitors
  • Novel compounds and compositions as cathepsin inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-butyl]-3-benzylsulfonyl-2-benzylsulfonylmethyl-propionamide

[0520]

[0521] A mixture comprised of 3-benzylsulfanyl-2-benzylsulfanylmethyl-propionic acid (0.239 g, 0.719 mmol), prepared as in Reference 1, in methylene chloride (6 mL), HOBt hydrate (0.11 g, 0.719 mmol), EDC (0.18 g, 0.939 mmol), hydroxy amine (0.19 g, 0.86 mmol) and 4-methylmorpholine (0.075 mL) was stirred at room temperature for 1 hour and then poured into cold 1N aqueous hydrochloric. The product was extracted with ethyl acetate and the extracts were washed with saturated aqueous sodium chloride and then dried over magnesium sulfate. The solvent was removed by rotary evaporation at reduced pressure and the residue was chromatographed on silica gel eluting with ethyl acetate / hexane to give N—[(S)-1-(1-Benzooxazol-2-yl-1-hydroxy-methyl)-butyl]-3-benzylsulfanyl-2-benzylsulfanylmethyl-propionamide (0.217 g).

[0522] A solution of N—[(S)-1-(1-Benzooxazol-2-yl-1-hydroxy-methyl)-butyl]...

example 2

N-Cyanomethyl-4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzyl-sulfonylmethyl)-butyramide

[0535]

[0536] A mixture comprised of 4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzylsulfonylmethyl)-butyric acid (200 mg, 0.47 mmol), prepared as in reference 5, EDC (200 mg, 1.05 mmol), HOBt (200 mg, 1.3 mmol), and aminoacetonitrile hydrochloride (150 mg, 1.6 mmol) was treated with dichloromethyl (4 mL) and 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with water (30 mL), saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate and evaporated under vacuum. The product was crystallized from ethyl acetate / hexane to yield N-cyanomethyl-4-morpholin-4-yl-4-oxo-2-(2-trifluoromethyl-benzyl-sulfonylmethyl)-butyramide (156 mg) as a yellowish solid; 1H NMR: (DMSO) 8.87 (t, J=5.5 Hz, 1H), 7.81-7.57 (m, 4H), 4.74 (d, J=14.5 Hz, 1H), 4.67 (d, J=14.5 Hz, 1H), 4.13 (d, J=5.5 Hz,...

example 3

N—[(S)-1-(1-Benzooxazol-2-yl-methanoyl)-propyl]-4-morpholin-4-yl-4-oxo-2-benzylsulfonylmethyl-butyramide

[0540]

[0541] A mixture comprised of 4-Morpholin-4-yl-4-oxo-2-(benzyl-sulfonylmethyl)-butyric acid (300 mg, 0.84 mmol), EDC (250 mg, 1.3 mmol), HOBt (250 mg, 1.6 mmol) and (2S)-2-amino-1-benzooxazol-2-yl-butan-1-ol (250 mg, 1.2 mmol) was treated with dichloromethyl (4 mL) followed by 4-methylmorpholine (0.5 mL). The mixture was stirred at ambient temperature for 2 hours. After dilution with ethyl acetate (150 mL), the solution was washed with 1N aqueous HCl, water, saturated aqueous NaHCO3 solution and brine, dried with magnesium sulfate and evaporated under vacuum. The crude product was dissolved in dry dichloromethyl (10 mL) and 1,1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one (Dess-Martin periodinane) (500 mg, 1.2 mmol) was added. After stirring at ambient temperature for 1 hour, the mixture was diluted with ethyl acetate (150 mL) and treated with 0.26M Na2S2O3 solution...

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Abstract

The present invention relates to novel selective cathepsin S inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

Description

[0001] This application is based on and claims priority from U.S. Provisional Application Ser. No. 60 / 257,603 filed on Dec. 22, 2000.THE INVENTION [0002] This Application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsin S. DESCRIPTION OF THE FIELD [0003] 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 associated with the normal degradation and processing of proteins. The aberrant activity of cysteine proteases, e.g., as a result of increase expression or enhanced activation, however, may have pathological consequences. In this regard, certain cysteine proteases are associated with a number of disease states, including arthritis, muscular dystrophy, inflammation, tumor invasion, glomerulonephritis, malaria, periodontal disease, metachromatic leukodystrophy a...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/501A61K31/50A61K31/4965A61K31/497C07D417/02C07D413/02A61K31/165C07D295/18A61K31/277A61K31/423A61K31/4245A61K31/425A61K31/437A61K31/454A61K31/5375A61K31/5377A61K31/55A61P3/10A61P9/10A61P11/00A61P11/06A61P17/00A61P19/02A61P21/04A61P25/00A61P25/28A61P29/00A61P37/02A61P37/08A61P43/00C07C317/44C07C317/50C07C323/60C07D205/08C07D205/085C07D207/24C07D207/26C07D207/273C07D213/40C07D223/10C07D223/12C07D263/06C07D263/32C07D263/56C07D271/06C07D271/10C07D277/26C07D277/64C07D285/08C07D295/185C07D413/04C07D413/12C07D498/04
CPCA61K31/5375A61K31/5377C07C317/44C07C323/60C07D205/08C07D207/24C07D207/273C07D213/40C07D223/10C07D223/12C07D263/32C07D263/56C07D271/06C07D271/10C07D277/26C07D277/64C07D285/08C07D295/185C07D413/04C07D413/12A61P1/02A61P11/00A61P11/06A61P13/12A61P17/00A61P19/02A61P21/00A61P21/04A61P25/00A61P25/28A61P29/00A61P33/06A61P35/00A61P37/02A61P37/08A61P43/00A61P9/10A61P3/10Y02A50/30
Inventor GRAUPE, MICHAELPATTERSON, JOHNALDOUS, DAVIDTHURAIRATNAM, SUKANTHINITIMM, ANDREASLINK, JOHNLI, JIAYAOPICKETT, STEPHENHALLEY, FRANKLAI, JUSTINE
Owner SANYO ELECTRIC CO LTD
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