US2002065264A1PendingUtilityA1

Cysteine protease inhibitors containing heterocyclic leaving groups

50
Priority: Dec 8, 1993Filed: Jun 11, 2001Published: May 30, 2002
Est. expiryDec 8, 2013(expired)· nominal 20-yr term from priority
Inventors:Mary P. ZimmermanRobert E. Smith, Iii
A61P 31/12A61P 43/00A61P 35/00A61P 9/08A61P 9/10A61P 33/02A61P 9/00A61P 37/08A61P 29/00A61P 25/02A61P 27/14A61P 27/12A61P 27/02A61P 25/28A61K 47/62A61K 31/443C07D 307/62C07D 207/16A61K 31/505C07D 295/215A61K 31/35A61K 31/40C07D 213/80C07D 239/34A61K 31/34C07D 309/38A61K 31/5375C07D 307/60C07D 213/64A61K 31/44C07D 307/58A61P 1/02C07D 405/12Y02A50/30
50
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Claims

Abstract

A class of cysteine protease inhibitors which inactivate a cysteine protease by covalently bonding to the protease and releasing a heterocyclic leaving group is presented. The cysteine protease inhibitors of the present invention comprise a first portion which targets a desired cysteine protease and positions the inhibitor near the thiolate anion portion of the active site of the protease, and a second portion which covalently bonds to the cysteine protease and irreversibly deactivates that protease by providing a carbonyl or carbonyl-equivalent which is attacked by the thiolate anion of the active site of the cysteine protease to sequentially cleave a heterocyclic leaving group. The heterocyclic leaving group of the protease inhibitor is of the formula: —O— Het, where Het is a heterocycle having 4-7 atoms in the ring, with at least one of the heterocycle atoms being N, O or S.

Claims

exact text as granted — not AI-modified
What is claimed is:  
     
         1 . Cathepsin inhibitors of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 B is H or an amino acid blocking group for an N-terminal amino acid nitrogen;  
 R 1  is the amino acid side chain of the P 1  amino acid residue;  
 R 2  is the amino acid residue of the P 2  amino acid;  
 R 3  is the amino acid residue of the P 2  amino acid;  
 n is 0 or 1;  
 m is 0 or 1; and  
 Het is a hetrerocyclic leaving group;  
 wherein the heterocyclic leaving group includes a four-, five-, six- or seven-membered ring having at least one C and at least one of N, O or S in the ring.  
 
     
     
         2 . A cathepsin inhibitor according to  claim 1  wherein n is 0 and m is 1.  
     
     
         3 . A cathepsin inhibitor according to  claim 2  wherein R 2  is the residue of phenylalanyl (Phe).  
     
     
         4 . A cathepsin inhibitor according to  claim 3  wherein R 1  is a side chain such that the P amino acid residue is the residue of homophenylalanyl (HPhe).  
     
     
         5 . A cathepsin inhibitor according to  claim 4  wherein B is Mu.  
     
     
         6 . A cathepsin dipeptidyl peptidase inhibitor according to  claim 1  wherein B=H.  
     
     
         7 . A cathespin inhibitor according to  claim 5  wherein Het is a benzo-fused heterocycle.  
     
     
         8 . A cathespin inhibitor according to  claim 5  wherein Het is dihydropyrone.  
     
     
         9 . A cathespin inhibitor according to  claim 5  wherein Het is hydroxyproline or a salt, or extended peptide thereof.  
     
     
         10 . A cathespin inhibitor according to  claim 5  where Het is a pyrone.  
     
     
         11 . A cathespin inhibitor according to  claim 5  wherein Het is a pyridine.  
     
     
         12 . A cathespin inhibitor according to  claim 5  wherein Het is pyrimidine.  
     
     
         13 . A cathespin inhibitor according to  claim 5  wherein Het is a furan.  
     
     
         14 . A cathespin H inhibitor according to  claim 6  wherein Het is a member of the group consisting of pyrone, pyridine, pyrimidine, furan or proline derivatives.  
     
     
         15 . A cathespin H inhibitor according to  claim 7  wherein Het is a pyrone, pyridine, pyrimidine, furan or proline derivative and B=H, n=0 and m=0.  
     
     
         16 . A composition according to  claim 1 , and further including a pharmaceutically acceptable carrier.  
     
     
         17 . Cathepsin inhibitors of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 B is H or an amino acid blocking group for an N-terminal amino acid nitrogen;  
 R 1  is the amino acid side chain of the P 1  amino acid residue;  
 R 2  is the amino acid residue of the P 2  amino acid;  
 R 3  is the amino acid residue of the P 2  amino acid;  
 n is 0 or 1;  
 m is 0 or 1; and  
 Het is a hetrerocyclic leaving group;  
 wherein the heterocyclic leaving group includes a four-, five-, six- or seven-membered ring having at least one C and at least one of N, O or S in the ring.  
 
     
     
         18 . A cysteine protease inhibitor, comprising: 
 (a) a first portion which targets a desired cysteine protease and positions tile inhibitor near the thiolate anion portion of the active site of the protease;    (b) a second portion which covalently bonds to the cysteine protease and irreversibly deactivates that protease by providing a carbonyl or carbonyl-equivalent which is attacked by the thiolate anion of the active site of the cysteine protease to sequentially cleave a heterocyclic leaving group;    said heterocyclic leaving group being of the formula:   —O— Het wherein Het is a heterocycle having 4-7 members in the ring, with at least one of the heterocycle members being N, O or S.      
     
     
         19 . A method of treating a patient for a medical condition, said method comprising administering to the patient a therapeutically effective amount of a composition of the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 B is H or an amino acid blocking group for an N-terminal amino acid nitrogen;  
 R 1  is the amino acid side chain of the P 1  amino acid residue;  
 R 2  is the amino acid residue of the P 2  amino acid;  
 R 3  is the amino acid residue of the P 2  amino acid;  
 n is 0 or 1;  
 m is 0 or 1; and  
 Het is a heterocyclic leaving group;  
 wherein the heterocyclic leaving group includes a four-, five-, six- or seven-membered ring having at least one C and at least one of N, O or S in the ring.  
 
     
     
         20 . The method of  claim 19  wherein the medical condition is myocardial infarction.  
     
     
         21 . The method of  claim 19  wherein the medical condition is inflammation.  
     
     
         22 . The method of  claim 19  wherein the medical condition is a dystrophic disease.  
     
     
         23 . The method of  claim 19  wherein the medical condition is rheumatoid arthritis.  
     
     
         24 . The method of  claim 19  wherein the medical condition is pneumocytis carinii.  
     
     
         25 . The method of  claim 19  wherein the medical condition is schistosomiasis.  
     
     
         26 . The method of  claim 19  wherein the medical condition is trypanosoma cruzi.  
     
     
         27 . The method of  claim 19  wherein the medical condition is trypanosoma brucei brucei.  
     
     
         28 . The method of  claim 19  wherein the medical condition is  Crithidia fusiculata.    
     
     
         29 . The method of  claim 19  wherein the medical condition is malaria.  
     
     
         30 . The method of  claim 19  wherein the medical condition is periodontal disease.  
     
     
         31 . The method of  claim 19  wherein the medical condition is metachromatic leukodystrophy.  
     
     
         32 . The method of  claim 19  wherein the medical condition is muscular dystrophy.  
     
     
         33 . The method of  claim 19  wherein the medical condition is cancer metathesis.  
     
     
         34 . The method of  claim 19  wherein the medical condition is viral infection.  
     
     
         35 . The method of  claim 19  wherein the medical condition is kidney disease.  
     
     
         36 . The method of  claim 19  wherein the medical condition is multiple sclerosis, peripheral nervous neuropathy or the like.  
     
     
         37 . The method of  claim 19  wherein the medical condition is polymyositis.  
     
     
         38 . The method of  claim 19  wherein the medical condition is a neurogenic disorder.  
     
     
         39 . The method of  claim 19  wherein the medical condition is Alzheimer's disease.  
     
     
         40 . The method of  claim 19  wherein the medical condition is leukemia.  
     
     
         41 . The method of  claim 19  wherein the medical condition is cataracts.  
     
     
         42 . The method of  claim 19  wherein the medical condition is an allergy.  
     
     
         43 . The method of  claim 19  wherein the medical condition is ischemia.  
     
     
         44 . The method of  claim 19  wherein the medical condition is bone resorption (osteo arthritis).  
     
     
         45 . The method of  claim 19  wherein the therapeutic composition includes a pharmaceutically acceptable carrier.

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