Novel compounds and compositions as protease inhibitors

a technology of protease inhibitors and compounds, applied in the direction of dipeptides, peptide/protein ingredients, depsipeptides, etc., can solve the problems of pathological consequences and the activeness of cysteine proteases, and achieve the effect of preventing, inhibiting or ameliorating the pathology and/or symptomatology of the diseas

Inactive Publication Date: 2003-05-15
AXYX PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

0022] A second aspect of this invention is a pharmaceutical composition which contains a compound of Formula I or a N-oxide derivative, prodrug derivative, individual isomer or mixture of isomers or a pharmaceutically acceptable salt thereof in admixture with one or more suitable excipients.
0023] A third aspect of this invention is a method of treating a disease in an anim

Problems solved by technology

The aberrant activity of cysteine proteases, e.g., as a result of increase ex

Method used

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  • Novel compounds and compositions as protease inhibitors
  • Novel compounds and compositions as protease inhibitors
  • Novel compounds and compositions as protease inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 1

Benzyl 1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamoyl)-3-methylbutylcarba-mate

[0204] 26

[0205] A mixture comprised of magnesium turnings (235 mg, 9.58 mmol) and mercuric chloride (35 mg, 0.13 mmol) in dry THF under nitrogen was cooled to between -10 and -20.degree. C. and chloromethoxymethane (0.75 mL, 9.58 mmol) was added. The mixture was stirred for 6 hours while the temperature was allowed to warm to between -8 and 0.degree. C. The mixture was then cooled to -78.degree. C. and stirred while a solution comprised of benzyl 1-[1-(N-methoxy-N-methylcarbamoyl)-3-phenylpropylcarb-amoyl]-3-methylbutylcarbamate (500 mg, 1.08 mmol) in anhydrous THF (6 mL) was added. The mixture was allowed to warm slowly over approximately 12 hours and then the reaction was quenched with ammonium chloride solution and then extracted with ethyl acetate. The ethyl acetate was dried (MgSO.sub.4), filtered and concentrated. Product was purified from the residue by flash column chromatography eluting with 33:1...

example 2

3S-(2S-Benzyloxycarbonylamino-4-methylpentanoylamino)-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate (Compound 7),

[0212] 27

[0213] A solution comprised of (S)-2-benzyloxycarbonylamino-4-methylpentan-oic acid (0.20 g, 0.76 mmol) in THF (5 mL) was cooled to -10.degree. C. and then 4-methylmorpholine (84 .mu.L, 0.76 mmol) and isobutyl chloroformate (99 .mu.L, 0.76 mmol) were added. The mixture was stirred for 5 minutes and then (S)-3-amino-2-oxo-5-phenylpentyl 2,5-dichlorobenzoate toluenesulfonic acid salt (0.41 g, 0.76 mmol) and 4-methylmorpholine (84 .mu.L, 0.76 mmol) were added sequentially. The mixture was stirred for 45 minutes and then ethyl acetate (30 mL) was added. The mixture was washed with 1M hydrochloric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL), dried (MgSO.sub.4), filtered and concentrated. The residue was crystallized from CH.sub.2Cl.sub.2 / ether to provide 3S-(2S-benzyloxycarbonylamno-4-methylpe-ntanoylamino)-2-oxo-5-phenylpentyl 2,5-dichlorobe...

example 3

Benzyl 1S-(3-hydroxy-2-oxo-1S-phenethylpropylcarbamovl)-3-methylbutylcarba-mate

[0281] 28

[0282] Potassium carbonate (31 mg, 0.225 mmol) was added to a solution comprised of the 3S-- (2S-benzyloxycarbonylamino-4-methylpentanoylamino)--2-oxo-5-phenylpentyl 2,5-dichlorobenzoate (0.92 g, 1.5 mmol), provided as in Example 2, in 1:1 methanol / THF (40 mL). The mixture was stirred for 60 minutes and then 1M hydrochloric acid (2 mL) was added. The mixture was concentrated in vacuo at room temperature and the residue was dissolved in ethyl acetate (40 mL). The solution was washed with 1M hydrochloric acid (5 mL) and saturated aqueous sodium bicarbonate (5 mL), dried (MgSO.sub.4), filtered and concentrated. Product was purified from the residue by flash chromatography (50% CH.sub.2Cl.sub.2 / ethyl acetate) to provide benzyl 1S-(3-hydroxy-2-oxo -1S-phenethylpropylcarbamoyl)-3-methyl-butylcarbamate (0.37 g, 0.84 mmol) in approximately a 3:1 mixture of (S,S)- to (S,R)-diastereomers. .sup.1H NMR (CDCl...

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Abstract

The present invention relates to novel cysteine protease inhibitors; the pharmaceutically acceptable salts and N-oxides thereof; their uses as therapeutic agents and the methods of their making.

Description

[0001] This application claims the benefit under 35 U.S.C. Sec. 119 (e)(1) of prior filed U.S. Provisional Application No. 60 / 124,529 filed Mar. 15, 1999.THE INVENTION[0002] This application relates to compounds and compositions for treating diseases associated with cysteine protease activity, particularly diseases associated with activity of cathepsins B, K, L or 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, ...

Claims

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Application Information

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IPC IPC(8): C07B53/00C07B61/00C07C231/02C07C233/31C07C235/78C07C237/08C07C237/12C07C237/36C07C253/30C07C255/57C07C269/06C07C271/22C07C271/34C07C273/18C07C275/24C07C275/34C07C275/42C07C311/03C07C311/19C07C313/06C07C317/28
CPCC07C235/78C07C317/28C07C275/24C07C271/22
Inventor BUYSSE, ANN M.MENDONCA, ROHAN V.PALMER, JAMES T.TIAN, ZONG-QIANGVENKATRAMAN, SHANKAR
Owner AXYX PHARMA INC
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