Thiol sulfonamide metalloprotease inhibitors

Abstract

This invention is directed to proteinase (protease) inhibitors, and more particularly to thiol sulfonamide inhibitors for matrix metalloproteinase 13(MMP-13), compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, processes for the preparation of proteinase inhibitors and processes for treating pathological conditions associated with pathological matrix metalloproteinase activity related to MMP-13.

1 . A compound or a pharmaceutically acceptable salt thereof, wherein: 
 the compound corresponds in structure to formula Ia, IIa, or IIIa:                          R 1  is a substituted phenyl    R 1  has a length greater than that of a saturated four carbon chain and shorter than that of a saturated eighteen carbon chains;    when rotated about an axis drawn through the SO 2 -bonded 1-position and the 4-position of the phenyl, R 1  defines a three-dimensional volume whose widest dimension has the width of about one phenyl ring to about three phenyl rings in a direction transverse to the axis of rotation;    R 1  comprises no heterocyclyl substituent;    R 2  is selected from the group consisting of hydrido, C 1 -C 6 -alkyl, phenyl-C 1 -C 4 -alkyl, C 2 -C 4 -alkyl substituted by amino, C 2 -C 4 -alkyl substituted by mono-substituted amino, and C 2 -C 4 -alkyl substituted by di-substituted amino, wherein: 
 the substituent(s) on the mono-substituted or di-substituted amino nitrogen is/are independently selected from the group consisting of C 1 -C 6 -alkyl, aralkyl, C 5 -C 8 -cycloalkyl, and C 1 -C 6 :alkanoyl;  
   R 2  can be hydrido only when R 1  is 4-(phenylazo)phenyl;    R 4  is selected from the group consisting of hydroxycarbonyl, aminocarbonyl, and C 1 -C 6 -alkyl;    W is selected from the group consisting of oxygen and sulfur; and    R 9  is selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and phenyl.    
     
     
         2 . The compound or salt according to  claim 1 , wherein R 1  has a length greater than that of a pentyl group and less than the length of a lauryl group.  
     
     
         3 . The compound or salt according to  claim 1 , wherein R 1  is phenyl substituted at its 4-position with a substituent selected from the group consisting of phenyl, alkyl comprising an unbranched chain of 3 to about 7 carbon atoms, alkoxy comprising an unbranched chain of 3 to about 7 carbon atoms, phenoxy, phenylthioxy, phenylazo, and benzamido.  
     
     
         4 . A compound or a pharmaceutically acceptable salt thereof, wherein: 
 the compound corresponds in structure to formula Ib, IIb, or IIIb:                          PhR 11  is phenyl substituted with R 11  at the 4-position;    R 11  is selected from the group consisting of C 3 -C 8 -alkoxy, C 3 -C 8 -alkyl, phenoxy, phenylthioxy, benzamido, phenylazo, and phenyl;    R 2  is selected from the group consisting of hydrido and C 1 -C 6 -alkyl;    R 2  can be hydrido only when R 11  is phenylazo;    R 4  is selected from the group consisting of C 1 -C 6 -alkyl and carbamido; and    R 9  is selected from the group consisting of C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, and phenyl.    
     
     
         5 . The compound or salt according to  claim 4 , wherein R 9  is selected from the group consisting of phenyl, methyl, ethyl, methoxy, and ethoxy.  
     
     
         6 . The compound or salt according to  claim 4 , wherein R 11  is selected from the group consisting of phenoxy, phenylthioxy, benzamido, phenylazo, and phenyl, wherein: 
 the phenoxy, phenylthioxy, benzamido, phenylazo, or phenyl is substituted at the 3- or 4-position, or both, with a single atom or a non-heterocyclyl substituent comprising a longest chain of up to five atoms, excluding hydrogen.    
     
     
         7 . The compound or salt according to  claim 6 , wherein R 11  is selected from the group consisting of phenoxy, phenylthioxy, benzamido, phenylazo, or phenyl, wherein: 
 the phenoxy, phenylthioxy, benzamido, phenylazo, or phenyl is substituted at the 4-position with a substituent selected from the group consisting of halogen, C 1 -C 4 -alkoxy, C 1 -C 4 -alkyl, dimethylamino, and carboxy-C 1 -C 2 -alkyl.    
     
     
         8 - 19 . (canceled)  
     
     
         20 . The compound or salt according to  claim 1 , wherein the compound corresponds in structure to formula (Ia):  
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound or salt according to  claim 20 , wherein R 4  is selected from the group consisting of aminocarbonyl and methyl.  
     
     
         22 . The compound or salt according to  claim 20 , wherein R 2  is phenylmethyl.  
     
     
         23 . The compound or salt according to  claim 20 , wherein R 2  is selected from the group consisting of methyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, and N,N-dimethyl-2-aminoethyl.  
     
     
         24 . The compound or salt according to  claim 1 , wherein the compound corresponds in structure to formula (IIa):  
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound or salt according to  claim 24 , W is oxygen.  
     
     
         26 . The compound or salt according to  claim 1 , wherein the compound corresponds in structure to formula (IIIa):  
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound or salt according to  claim 1 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         28 . The compound or salt according to  claim 27 , wherein the compound corresponds in structure to a formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . The compound or salt according to  claim 28 , wherein the compound corresponds in structure to the following formula:  
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound or salt according to  claim 4 , wherein the compound corresponds in structure to formula (Ib):  
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound or salt according to  claim 30 , wherein R 4  is selected from the group consisting of aminocarbonyl and methyl.  
     
     
         32 . The compound or salt according to  claim 30 , wherein R 2  is phenylmethyl.  
     
     
         33 . The compound or salt according to  claim 30 , wherein R 2  is selected from the group consisting of methyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, and N,N-dimethyl-2-aminoethyl.  
     
     
         34 . The compound or salt according to  claim 4 , wherein the compound corresponds in structure to formula (IIb):  
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound or salt according to  claim 34 , wherein W is oxygen.  
     
     
         36 . The compound or salt according to  claim 4 , wherein the compound corresponds in structure to formula (IIIb):  
       
         
           
           
               
               
           
         
       
     
     
         37 . A method for treating a mammal having a condition associated with pathological matrix metalloprotease activity, wherein the process comprises administering to the mammal an effective amount of the compound or salt of  claim 1 .  
     
     
         38 . A method for treating a mammal having a condition associated with pathological matrix metalloprotease activity, wherein the process comprises administering to the mammal an effective amount of the compound or salt of  claim 4 .  
     
     
         39 . A method for treating a mammal having a condition associated with pathological matrix metalloprotease activity, wherein the process comprises administering to the mammal an effective amount of the compound or salt of  claim 20 .  
     
     
         40 . A method for treating a mammal having a condition associated with pathological matrix metalloprotease activity, wherein the process comprises administering to the mammal an effective amount of the compound or salt of  claim 28 .  
     
     
         41 . A method for treating a mammal having a condition associated with pathological matrix metalloprotease activity, wherein the process comprises administering to the mammal an effective amount of the compound or salt of  claim 30 .  
     
     
         42 . A pharmaceutical composition, wherein the composition comprises a compound according to  claim 1  (or a pharmaceutically acceptable salt thereof) dissolved or dispersed in a pharmaceutically acceptable carrier.  
     
     
         43 . A pharmaceutical composition, wherein the composition comprises a compound according to  claim 4  (or a pharmaceutically acceptable salt thereof) dissolved or dispersed in a pharmaceutically acceptable carrier.  
     
     
         44 . A pharmaceutical composition, wherein the composition comprises a compound according to  claim 20  (or a pharmaceutically acceptable salt thereof) dissolved or dispersed in a pharmaceutically acceptable carrier.  
     
     
         45 . A pharmaceutical composition, wherein the composition comprises a compound according to  claim 28  (or a pharmaceutically acceptable salt thereof) dissolved or dispersed in a pharmaceutically acceptable carrier.  
     
     
         46 . A pharmaceutical composition, wherein the composition comprises a compound according to  claim 30  (or a pharmaceutically acceptable salt thereof) dissolved or dispersed in a pharmaceutically acceptable carrier.