Pyrrolidine derivatives

Abstract

The present invention relates to pyrrolidine derivatives useful as inhibitors of metalloproteases, e.g. zinc proteases, and which are effective in treating disease states associated with vasoconstriction.

What is claimed is:  
     
         1 . A compound selected from the group consisting of compounds of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen, alkylcarbonyl, or arylcarbonyl;  
 R 2  is alkyl, alkenyl, alkinyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, alkylcarbonylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylsulfonyl, aryl, arylalkyl, arylalkoxyalkyl, aryl(alkoxycarbonyl)alkyl, arylcarbamoyl, diarylalkyl, aryl(carboxyalkyl)amide, arylamino, arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, or the group YR 2  is heterocyclyl or R 2  is a group of the formula  
                     
 R 3  is alkyl, alkylcycloalkyl, alkylcycloalkylalkyl, cycloalkyl, halogenalkyl, carboxyalkyl, aminoalkyl, dialkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl, arylalkyl, arylalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl, aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl, heteroarylalkyl, heterocyclyl or hetercycylalkyl, and  
 R 3  is hydroxy in case of X is SO 2 ;  
 R 4  is hydrogen in case m=1 or alkyl or hydrogen in case m=0;  
 R 5  is hydrogen, alkyl, aryl, or carboxyalkyl;  
 R 6  is hydrogen, alkyl, aryl, carboxyalkyl, arylcarbonyl, alkylcarbonyl, arylalkoxycarbonyl, or arylalkyl;  
 R 7  is hydrogen, aryl, alkyl, arylalkyl, heterocyclylalkyl, arylamino, alkyl(arylalkyl)amino, alkoxycarbonylalkyl, carboxyalkyl, or alkylthioalkyl;  
 R 8  is hydroxy, alkyl, aryl, cyanoalkyl, alkoxy, arylalkyl, arylalkoxy, mono- or dialkylamino, arylamino, aryl(alkyl)amino, cyanoalkylamino, arylalkyl(alkyl)amino, heteroaryl, heteroarylalkyl, or heterocyclyl;  
 X is —S(O) 2 —, —S(O) 2 —NH—, —C(O)—, —C(O)NR 5 —, or C(O)O—;  
 Y is —CH 2 , —O—, —NR 6 — or —S—; and  
 m and p independently are 0 or 1, n and q independently are 1, 2 or 3 and o is 0, 1 or 2 with the proviso that the sum of n, o and p is ≧2 and ≧3;  
 pharmaceutically acceptable esters, and pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound according to  claim 1  of formula III  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 4 , X and Y are as defined in formula (I).  
     
     
         3 . The compound according to  claim 1  wherein R 1  is hydrogen or alkylcarbonyl.  
     
     
         4 . The compound according to  claim 3  wherein said alkylcarbonyl is acetyl.  
     
     
         5 . The compound according to  claim 1  wherein R 1  is hydrogen.  
     
     
         6 . The compound according to  claim 1  wherein R 2  is aryl, arylalkyl, arylalkoxyalkyl, arylcarbamoyl, arylamino, arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl or heteroarylalkyl.  
     
     
         7 . The compound according to  claim 6  wherein R 2  is aryl, arylalkyl, arylcarbamoyl, arylamino, arylcarbonyl, arylsulfonyl or heteroarylalkyl.  
     
     
         8 . The compound according to  claim 7  wherein R 2  is arylalkyl.  
     
     
         9 . The compound according to  claim 8  wherein arylalkyl of R 2  is phenylalkyl or phenylalkyl substituted with 2 or 3 halogen atoms.  
     
     
         10 . The compound according to  claim 1  wherein R 3  is alkyl, halogenalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, cycloalkyl, halogenalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl, arylalkyl, arlyalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl, aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl, heteroarylalkyl or heterocyclyl.  
     
     
         11 . The compound according to  claim 10  wherein R 3  is alkyl, arylalkyl, arylcarbonylalkyl, aryloxylakyl, alkylcycloalkyl, alkylcycloylkylalkyl, cycloalkyl, heteroarylalkyl or halogenalkyl.  
     
     
         12 . The compound according to  claim 10  wherein R 3  is alkyl, arylalkyl, aryl, aryloxyalkyl or halogenalkyl.  
     
     
         13 . The compound according to  claim 1  wherein R 4  is hydrogen.  
     
     
         14 . The compound according to  claim 1  wherein X is —S(O) 2 —, —S(O) 2 —NH—, —C(O)NR 5 — or C(O)O—.  
     
     
         15 . The compound according to claims  14  wherein X is —S(O) 2 —, —C(O)NH— or C(O)O—.  
     
     
         16 . The compound according to  claim 1  wherein R 5 is hydrogen, alkyl or carboxyalkyl.  
     
     
         17 . The compound according to  claim 16  wherein R 5  is hydrogen.  
     
     
         18 . The compound according to  claim 1  wherein R 6  is hydrogen, alkyl or arylalkyl.  
     
     
         19 . The compound according to  claim 18  wherein R 6  is hydrogen.  
     
     
         20 . The compound according to  claim 1  wherein R 7  is hydrogen or aryl.  
     
     
         21 . The compound according to  claim 1  wherein R 8  is hydroxy or alkoxy.  
     
     
         22 . The compound according to  claim 1  wherein Y is —O—.  
     
     
         23 . The compound according to  claim 1  wherein Y is —NH—.  
     
     
         24 . The compound according to  claim 1  wherein 
 R 1  is hydrogen or alkylcarbonyl;  
 R 2  is arylalkyl which is phenylalkyl substituted with 2 or 3 halogen atoms;  
 R 3  is alkyl, aryl, arylalkyl, aryloxyalkyl or halogenalkyl;  
 X is —SO 2 —, —CONH—, —C(O)—O—; and  
 Y is —NH— or —O—.  
 
     
     
         25 . The compound according to  claim 24  wherein said alkylcarbonyl of R 1  is acetyl, and R 2  is difluorobenzyl or trifluorobenzyl.  
     
     
         26 . The compound according to  claim 1  of formula (IV)  
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , R 3 , R 4 , X and Y are as defined in formula (I).  
     
     
         27 . The compound according to  claim 1  selected from the group consisting of: 
 a) (3R,5S)-5-[(2,5-Difluoro-benzylamino)-methyl]-1-(naphthalene-2-sulfonyl)-pyrrolidine-3-thiol;  
 b) (2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid (2-fluoro-phenyl)-amide;  
 c) (2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid 4-methoxy-phenyl ester;  
 d) (2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid 4-fluoro-phenyl ester;  
 e) (2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid isopropyl ester;  
 f) (2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid naphthalen-2-yl ester;  
 g) (2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester;  
 h) (2S,4R)-2-[(2,5-Difluoro-benzylamino)-methyl]-4-mercapto-pyrrolidine-1-carboxylic acid butyl ester;  
 i) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid isopropyl ester;  
 j) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester;  
 k) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester;  
 l) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid butyl ester;  
 m) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-fluoro-phenyl ester;  
 n) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl ester;  
 o) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-bromo-phenyl ester;  
 p) (3R,5S)-1-(Butane-1-sulfonyl)-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol;  
 q) (3R,5S)-1-Methanesulfonyl-5-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-3-thiol;  
 r) (2S,4R)-4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic acid benzylamide;  
 s) 4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic acid butylamide;  
 t) 4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic acid (2-phenoxy-ethyl)-amide;  
 u) 4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic acid (2,2,2-trifluoro-ethyl)-amide;  
 v) 4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonic acid 4-fluoro-benzylamide;  
 w) 4-{[4-Mercapto-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-sulfonylamino]-methyl}-benzoic acid;  
 x) (2S,4R)-4-Acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2,3-dihydro-benzo[1,4]dioxin-5-yl ester;  
 y) (2S,4R)-4-Acetylsulfanyl-2-[(2,5-difluoro-benzylamino)-methyl]-pyrrolidine-1-carboxylic acid butyl ester; and  
 z) (2S,4R)-4-Acetylsulfanyl-2-(2,4,5-trifluoro-benzyloxymethyl)-pyrrolidine-1-carboxylic acid 2-methoxycarbonyl-phenyl ester.  
 
     
     
         28 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         29 . A dimeric form of a compound of formula I  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is hydrogen, alkylcarbonyl, or arylcarbonyl;  
 R 2  is alkyl, alkenyl, alkinyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, alkylcarbonylalkyl, alkylcycloalkyl, alkylcycloalkylalkyl, alkylsulfonyl, aryl, arylalkyl, arylalkoxyalkyl, aryl(alkoxycarbonyl)alkyl, arylcarbamoyl, diarylalkyl, aryl(carboxyalkyl)amide, arylamino, arylcarbonyl, arylsulfonyl, cycloalkyl, cycloalkylcarbonyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclylalkyl, or the group YR 2  is heterocyclyl or R 2  is a group of the formula  
                     
 R 3  is alkyl, alkylcycloalkyl, alkylcycloalkylalkyl, cycloalkyl, halogenalkyl, carboxyalkyl, aminoalkyl, dialkylaminoalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkinyl, aryl, arylalkyl, arylalkyl(alkoxycarbonyl)alkyl, arylcarbonylalkyl, aryloxyalkyl, arylalkenyl, aryl(alkoxycarbonyl)alkyl, heteroaryl, heteroarylalkyl, heterocyclyl or hetercycylalkyl, and  
 R 3  is hydroxy in case of X is SO 2 ;  
 R 4  is hydrogen in case m=1 or alkyl or hydrogen in case m=0;  
 R 5  is hydrogen, alkyl, aryl, or carboxyalkyl;  
 R 6  is hydrogen, alkyl, aryl, carboxyalkyl, arylcarbonyl, alkylcarbonyl, arylalkoxycarbonyl, or arylalkyl;  
 R 7  is hydrogen, aryl, alkyl, arylalkyl, heterocyclylalkyl, arylamino, alkyl(arylalkyl)amino, alkoxycarbonylalkyl, carboxyalkyl, or alkylthioalkyl;  
 R 8  is hydroxy, alkyl, aryl, cyanoalkyl, alkoxy, arylalkyl, arylalkoxy, mono- or dialkylamino, arylamino, aryl(alkyl)amino, cyanoalkylamino, arylalkyl(alkyl)amino, heteroaryl, heteroarylalkyl, or heterocyclyl;  
 X is —S(O) 2 —, —S(O) 2 —NH—, —C(O)—, —C(O)NR 5 —, or C(O)O—;  
 Y is —CH 2 , —O—, —NR 6 — or —S—; and  
 m and p independently are 0 or 1, n and q independently are 1, 2 or 3 and o is 0, 1 or 2  
 with the proviso that the sum of n, o and p is ≧2 and ≦3.