Isoprenoid pathway inhibitors for stimulating cartilage growth

Abstract

Compounds of the formula wherein X in each of formulas (1) and (2) represents a substituted or unsubstituted alkylene, alkenylene, or alkynylene linker of 2-6C; Y is of the formula or a stereoisomer thereof, wherein R 1 is substituted or unsubstituted alkyl; each R 2 is independently H, hydroxy, alkoxy (1-6C) or lower alkyl (1-4C); R 3 is H, hydroxy, or alkoxy (1-6C); or Y is of the formula wherein each n is 1, Z is N, K comprises a substituted or unsubstituted aromatic carbocyclic or heterocyclic ring system which may optionally be spaced from the linkage position shown in formula (7) by a linker of 1-2C, or in formula (7), Z may be spaced from the carbon bonded to X by ═CR 6 — wherein R 6 is H or linear, branded or cyclic alkyl (1-6C), R 5 is H or linear, branched or cyclic alkyl, and R′ represents a cation, H or a substituted or unsubstituted alkyl group of 1-6C, promote bone formation and are thus useful in treating osteoporosis, bone fracture or deficiency, primary or secondary hyperparathyroidism, periodontal disease or defect, metastatic bone disease, osteolytic bone disease, post-plastic surgery, post-prosthetic joint surgery, and post-dental implantation. Also disclosed is a method to identify additional compounds which are inhibitors of enzymes in the isoprenoid scheme especially of HMG-CoA reductase which results in prenylation of proteins and in the synthesis of steroids or of inhibitors of their production which are useful in treating bone disorders.

1 . A method to enhance cartilage formation in a vertebrate animal which method comprises administering to a vertebrate subject in need of such treatment an amount of a composition comprising a statin compound of the formula:  
     
       
         
         
             
             
         
       
       wherein X in each of formulas (1) and (2) represents a substituted or unsubstituted alkylene, alkenylene, or alkynylene linker of 2-6C;  
       Y is of the formula  
       
         
           
           
               
               
           
         
       
       or a stereoisomer thereof,  
       wherein R 1  is substituted or unsubstituted alkyl;  
       each R 2  is independently H, hydroxy, alkoxy (1-6C) or lower alkyl (1-4C);  
       R 3  is H, hydroxy, or alkoxy (1-6C); or  
       Y is of the formula  
       
         
           
           
               
               
           
         
       
       wherein each n is 1,  
       Z is N,  
       K comprises a substituted or unsubstituted aromatic carbocyclic or heterocyclic ring system which may optionally be spaced from the linkage position shown in formula (7) by a linker of 1-2C, or in formula (7), Z may be spaced from the carbon bonded to X by ═CR 6 — wherein R 6  is H or linear, branded or cyclic alkyl (1-6C),  
       R 5  is H or linear, branched or cyclic alkyl, and  
       R′ represents a cation, H or a substituted or unsubstituted alkyl group of 1-6C,  
       wherein bone formation is effected.  
     
   
   
       2 . The method of  claim 1  wherein X is selected from the group consisting of —CH 2 CH 2 —; —CH═CH—; and —C≡C—.  
   
   
       3 . The method of  claim 2  wherein Y is of the formula 4(g) or a stereoisomer or mixture of stereoisomers thereof.  
   
   
       4 . The method of  claim 3  wherein R 1  alkyl 4-5C.  
   
   
       5 . The method of  claim 3  wherein each R 2  is independently H, methyl or hydroxy.  
   
   
       6 . The method of  claim 5  wherein each of R 2  is independently H or methyl.  
   
   
       7 . The method of  claim 2  wherein Y is of formula (7) as shown.  
   
   
       8 . The method of  claim 2  wherein Y is of formula (7) where Z is spaced from the carbon bonded to X by ═CR 6 —, wherein R 6  is H or linear, branched or cyclic alkyl (1-6C).  
   
   
       9 . The method of  claim 7  wherein K is a substituted or unsubstituted carbocyclic aromatic system.  
   
   
       10 . The method of  claim 8  wherein K is a substituted or unsubstituted carbocyclic aromatic system.  
   
   
       11 . The method of  claim 9  wherein K is p-fluorophenyl.  
   
   
       12 . The method of  claim 10  wherein K is p-fluorophenyl.  
   
   
       13 . The method of  claim 2  wherein Y is of formula (8).  
   
   
       14 . The method of  claim 13  wherein K is substituted pyrrole.  
   
   
       15 . The method of  claim 14  wherein said substitutions comprise aromatic systems.  
   
   
       16 . The method of  claim 15  wherein said substitutions comprise substituted and unsubstituted phenyl groups.  
   
   
       17 . The method of  claim 16  wherein said substitutions comprise p-fluorophenyl and phenyl.  
   
   
       18 . The method of  claim 13  wherein K is substituted pyridyl.  
   
   
       19 . The method of  claim 18  wherein the pyridyl is 2- pyridyl.  
   
   
       20 . The method of  claim 19  wherein the substitutions comprise alkyl (1-6c) and alkoxy (1-6c).  
   
   
       21 . The method of  claim 2  wherein said compound is atorvastatin, cerivastatin, lovastatin, mevastatin, simvastatin, fluvastatin, pravastatin or NK-104 in hydrolyzed or unhydrolyzed form.