Matrix metalloprotease inhibitors

Abstract

Compounds of the formula (I) and their pharmaceutically acceptable salts inhibit matrix metalloproteases, such as stromelysin, gelatinase, matrilysin and collagenase, and are useful in the treatment of mammals having disease-states alleviated by the inhibition of such matrix metalloproteases.

What is claimed is:  
     
         1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is mercapto, acetylthio, carboxy, hydroxycarbamoyl, N-hydroxyformamide, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, benzyloxycarbamoyl or a group of the formula  
                     
  where R 6  is aryl or heteroaryl;  
 R 2  is alkyl, cycloalkyl, aryl, heterocycloalkyl, or heteroaryl;  
 R 3  is alkyl, cycloalkyl, aralkyl, or heteroaralkyl;  
 R 7  is aryl, heteroaryl or heterocycloalkyl;  
 X is a group of the formula —(CH 2 ) m —Y—(CH 2 ) n —, where: 
 Y is O, S, or a single bond,  
 m is an integer from 0 to 4,  
 n is an integer from 0 to 4, and  
 m+n is an integer from 0 to 4;  
 
 p is an integer from 0 to 4, provided that R 2 —X is biphenylalkyl when p is not 0;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound or salt of  claim 1  wherein: R 1  is carboxy; R 3  is cyclohexyl; R 7  is optionally substituted phenyl or N-morpholino; X is propanyl; and p is 2 or 3.  
     
     
         3 . The compound or salt of  claim 2  wherein R 7  is 4-(aminosulfonyl)phenyl or N-morpholino.  
     
     
         4 . The compound or salt of  claim 1  wherein: R 2  is alkyl, optionally substituted phenyl, or a group of the formula:  
       
         
           
           
               
               
           
         
       
       where: 
 A is CH 2 , O, NH, S, CH 2 —CH 2 , or NH—CH 2 ;  
 R 10  is H, alkyl, alkoxy, alkylamino or acylamide; and  
 R 11  is H or halo;  
 R 7  is 4-pyridyl or optionally substituted phenyl; and p is 0.  
 
     
     
         5 . The compound or salt of  claim 4  wherein: R 1  is carboxy, hydroxycarbamoyl, or N-hydroxyformamide; R 2  is phenyl, biphenyl, 4-(pyridyl)phenyl, or 2-methylpropyl; R 3  is t-butyl, 4-aminobutyl, dimethylaminobutyl, 4-(N,N′diethylguanido)butyl, propyl, 2-methylpropyl, 1-hydroxyisopropyl, 1-hydroxyethyl, or cyclohexyl; and X is a single bond, ethylene or propanyl.  
     
     
         6 . The compound or salt of  claim 4  wherein R 2  is biphenyl.  
     
     
         7 . The compound or salt of  claim 6  wherein: R 1  is carboxy, N-hydroxyformamide, or hydroxycarbamoyl; R 3  is alkyl; and R 7  is 4-pyridyl.  
     
     
         8 . The compound or salt of  claim 7  wherein R 3  is t-butyl and X is propanyl.  
     
     
         9 . The compound or salt of  claim 8  wherein R 1  is carboxy.  
     
     
         10 . The compound or salt of  claim 8  wherein R 1  is N-hydroxyformamide.  
     
     
         11 . The compound or salt of  claim 8  wherein R 1  is hydroxycarbamoyl.  
     
     
         12 . The compound or salt of  claim 4  wherein: R 2  is a group of the formula:  
       
         
           
           
               
               
           
         
       
       where: 
 A is CH 2 ;  
 R 10  is H or acylamide; and  
 R 11  is H;  
 R 7  is optionally substituted phenyl; and  
 X is propanyl.  
 
     
     
         13 . The compound or salt of  claim 12  wherein: R 1  is carboxy, hydroxycarbamoyl, or N-hydroxyformamide; R 1  is alkyl; and R 7  is alkoxycarbonylphenyl.  
     
     
         14 . The compound or salt of  claim 13  wherein: R 1  is carboxy; R 3  is 2-methylpropyl; and R 7  is 4-(methoxycarbonyl)-phenyl.  
     
     
         15 . The compound or salt of  claim 6  wherein R 7  is optionally substituted phenyl.  
     
     
         16 . The compound or salt of  claim 15  wherein R 1  is carboxy; R 3  is alkyl or cycloalkyl; and X is propanyl.  
     
     
         17 . The compound or salt of  claim 16  wherein R 3  is cyclohexyl; and R 7  is 4-(hydroxyethylaminosulfonyl)phenyl or 4-(dimethylaminoethyl-aminosulfonyl)phenyl.  
     
     
         18 . The compound or salt of  claim 16  wherein R 3  is 4-(amino)butyl or 4-(isopropylamino) butyl; and R 7  is 4-(ethoxycarbonyl) phenyl.  
     
     
         19 . The compound or salt of  claim 16  wherein R 3  is 1-hydroxyisopropyl; and R 7  is phenyl.  
     
     
         20 . The compound or salt of  claim 16  wherein R 3  is tert-butyl.  
     
     
         21 . The compound or salt of  claim 20  wherein R 7  is 4-(N-morpholinopropylaminosulfonyl)phenyl.  
     
     
         22 . The compound or salt of  claim 20  wherein R 7  is 4-(methylaminosulfonyl)phenyl.  
     
     
         23 . The compound or salt of  claim 20  wherein R 7  is 4-(hydroxyethylaminosulfonyl)phenyl.  
     
     
         24 . The compound or salt of  claim 20  wherein R 7  is 4-(methylsulfinyl)phenyl.  
     
     
         25 . The compound or salt of  claim 4  wherein: R 1  is carboxy; R 2  is phenyl; R 3  is alkyl or cycloalkyl; and R 7  is optionally substituted phenyl.  
     
     
         26 . The compound or salt of  claim 25  wherein: R 3  is 4-(amino)butyl; R 7  is 4-(ethoxycarbonyl)phenyl; and X is propanyl.  
     
     
         27 . The compound or salt of  claim 25  wherein: R 3  is (N,N′-diethylguanido)N-butyl; R 7  is 4-(ethoxycarbonyl)phenyl; and X is propylene.  
     
     
         28 . The compound or salt of  claim 25  wherein: R 3  is cyclohexyl; R 7  is 4-(N″,N″-dimethylaminoethylaminosulfonyl)phenyl; and X is ethylene.  
     
     
         29 . The compound or salt of  claim 4  wherein: 
 R 1  is mercapto, carboxy, hydroxycarbamoyl, or N-hydroxyformamide;  
 R 2  is 2-methylpropyl;  
 R 3  is alkyl, cycloalkyl, or heteroaralkyl;  
 R 7  is optionally substituted phenyl; and  
 X is a single bond.  
 
     
     
         30 . The compound or salt of  claim 29  wherein: 
 R 1  is hydroxycarbamoyl;  
 R 3  is propyl, 2-methylpropyl, cyclohexyl or 3-methylindolyl; and  
 R 7  is 4-(methoxy)phenyl, 4-(carboxy)phenyl, 4-(methoxycarbonyl)phenyl or 4-(dimethylaminoethylcarbamoyl)phenyl.  
 
     
     
         31 . The compound or salt of  claim 30  wherein R 7  is 4-(dimethylaminoethylcarbamoyl)phenyl.  
     
     
         32 . The compound or salt of  claim 30  wherein R 7  is 4-(methoxycarbonyl)phenyl.  
     
     
         33 . The compound or salt of  claim 29  wherein: R 1  is N-hydroxyformamide; R 3  is 2-methylpropyl; and R 7  is 4-(methoxycarbonyl)phenyl.  
     
     
         34 . The compound or salt of  claim 29  wherein: R 1  is carboxy; R 3  is cyclohexyl or 2-methylpropyl; and R 7  is 4-(methoxycarbonyl)phenyl.  
     
     
         35 . The compound or salt of  claim 29  wherein: R 1  is mercapto; R 3  is 2-methylpropyl; and R 7  is 4-(methoxycarbonyl)phenyl.  
     
     
         36 . The compound or salt of  claim 4  wherein: 
 R 1  is carboxy; R 2  is 4-(2-hydroxyethyl)phenyl, 4-(2-hydroxypropyl)-phenyl, 4-(2-hydroxybutyl)phenyl, 4-pyridylphenyl, biphenyl, 4′-(aminoethoxy)biphenyl, 4′-(cyano)biphenyl, or 4′-(hydroxy)biphenyl;  
 R 3  is 2-methylpropyl; R 7  is 4-(methoxycarbonyl)phenyl; and X is propanyl.  
 
     
     
         37 . The compound or salt of  claim 36  wherein R 2  is 4-(pyridyl)phenyl.  
     
     
         38 . A pharmaceutical composition comprising a compound or salt of  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         39 . A method of inhibiting matrix metalloproteinase activity in a mammal comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of  claim 1 .  
     
     
         40 . A method of treating matrix metalloproteinase-mediated disorders selected from the group consisting of arthritis, abnormal wound healing, tissue ulceration, bone resorption disease, diabetes, tumor invasion, tumor metastasis and periodontal disease comprising administering to a mammal in need thereof a therapeutically effective amount of a compound or salt of  claim 1 .  
     
     
         41 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 2  is alkyl, aryl or heteroaryl; and  
 X is a group of the formula —(CH 2 ) m —Y—(CH 2 ) n , where: 
 Y is O, S, or a single bond,  
 m is an integer from 0 to 4,  
 n is an integer from 0 to 4, and  
 m+n is an integer from 0 to 4;  
 
 or R 2  and X together are lower alkenyl.  
 
     
     
         42 . A process for making a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  is aryl or heteroaryl, said process comprising hydrogenating a compound of the formula:  
       
         
           
           
               
               
           
         
       
       in the presence of a palladium/carbon catalyst.  
     
     
         43 . The process of  claim 42  wherein said compound of the formula:  
       
         
           
           
               
               
           
         
       
       is made by contacting N-(2R-(t-butoxycarbonyl)-methyl-4-pentenoyl)-4S-phenylmethyl-2-oxazolidinone with an R 2 -halide in the presence of a base and a palladium catalyst.  
     
     
         44 . A process for making a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  is aryl or heteroaryl, said process comprising contacting a compound of the formula:  
       
         
           
           
               
               
           
         
       
       with sodium hexamethyldisilazide and t-butylbromoacetate.  
     
     
         45 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  is aryl or heteroaryl.  
     
     
         46 . A process for making a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 2  is aryl or heteroaryl, said process comprising: 
 (a) contacting a compound of the formula:  
                     
 where R 2  is hydrogen, aryl or heteroaryl, with an excess of mesyl chloride in pyridine followed by refluxing under basic conditions, and  
 (b) where R 2  is hydrogen in step (a), reacting the product of step (a) with an aryl halide or a heteroaryl halide in the presence of a base and a palladium catalyst.  
 
     
     
         47 . A process for the preparation of a compound of formula (I)  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1  is mercapto, acetylthio, carboxy, benzyloxycarbamoyl, hydroxycarbamoyl, N-hydroxyformamide, alkoxycarbonyl, aralkoxycarbonyl, benzyloxycarbamoyl, or a thiomethylphosphinoyl group of the formula  
                     
 where R 6  is aryl or heteroaryl;  
 R 2  is alkyl, aryl, or heteroaryl;  
 R 3  is alkyl, cycloalkyl, aralkyl or heteroaralkyl;  
 X is a group of the formula —(CH 2 ) m —Y—(CH) n , where: 
 Y is O, S, or a single bond,  
 m is an integer from 0 to 4,  
 n is an integer from 0 to 4, and  
 m+n is an integer from 0 to 4;  
 
 R 7  is aryl, heteroaryl or heterocycloalkyl; and  
 p is an integer from 0 to 4;  
 said process comprising:  
 (A) contacting a compound of formula (D)  
                     
 with a compound of formula (P)  
                     
 where R 1  is alkoxycarbonyl, aralkoxycarbonyl, aryl- or heteroaryl-thiomethylphosphinoyl, or acetylthio;  
 in the presence of a base and an amide coupling reagent to give the corresponding compound of formula (I); or  
 (B) catalytically hydrogenating the corresponding compound where X and R 2  together are optionally aryl- or heteroaryl-substituted alkenyl; or  
 (C) treating a compound of formula (I), where R 1  is alkoxycarbonyl or aralkoxycarbonyl, under mild acidic conditions to give the corresponding compound of formula (I) where R 1  is carboxy; or  
 (D) contacting a compound of formula (I), where R 1  is carboxy, with O-benzylhydroxylamine to give the corresponding compound of formula (I) where R 1  is benzyloxycarbamoyl; or  
 (E) catalytically hydrogenating a compound of formula (I), where R 1  is benzyloxycarbamoyl, to give the corresponding compound of formula (I) where R 1  is hydroxycarbamoyl; or  
 (F) contacting a compound of formula (I), where R 1  is carboxy, with hydroxylamine to give the corresponding compound of formula (I) where R 1  is hydroxycarbamoyl; or  
 (G) catalytically hydrogenating a compound of the formula  
                     
 where BnO is benzyloxy, to give the corresponding compound of formula (I) where R 1  is N-hydroxyformamide; or  
 (H) treating a compound of formula (I), wherein R 1  is acetylthio, with ammonium hydroxide in a protic solvent to give the corresponding compound of formula (I) where R 1  is mercapto.