PPAR gamma ligands

Abstract

The present invention discloses a method for treating osteoporosis by administration of a PPAR gamma antagonist.

What is claimed is:  
     
         1 . A compound of the following formula  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof,  
         where n is2,3, or 4,  
         R 1  is hexyl, heptyl, or C 4—6  alkyl-phenyl,  
         R 2  is butyl or benzyl optionally substituted with 1 or 2 halogen,  
         R 3  is butyl, benzyl optionally substituted with a trifluoromethyl group or with 1 to 3 halogen, —C 4 H 8 OH, p-pyridyl, o-pyridyl, ethylpropionate, propyl, ethyl acetate, o-thiophenmethyl, 2,3-methylenedioxobenzyl, 2-thiazolemethyl, 2-furfuryl,  
         R 4  is —COOH, —NHC(O)NH 2 , —NHS(CH 3 )O 2 , —S(NH 2 )O 2 , hydantoin, —OH, —OCH 2 CO 2 H, —OCH 2 CONH 2 , —OCH 3 ,  
         R 5  is hydrogen or R 5  and R 4  are bonded together to form a methylenedioxo ring.  
       
     
     
         2 . The compound of  claim 1  wherein R 3  is butyl, benzyl optionally substituted with 1 or 2 halogen, or p-pyridyl.  
     
     
         3 . A compound of claims  1  or  2  wherein the stereochemistry around the 2 and 5 carbon atoms is such that the compound is the trans pair of the (2S, 5S) enantiomer and the (2R, 5R) enantiomer.  
     
     
         4 . A compound of  claim 3  wherein the stereochemistry around the 2 and 5 carbon atoms is such that the compound is the (2S,5S) enantiomer.  
     
     
         5 . The compound of  claim 1  wherein said compound is selected from the group consisting of 
 4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S,5S)-4- 0 (4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzyacetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-hexyl-4-oxo-5-thiazolidine N,N-dibutylacetamide,  
 (2S*,5S*)-4-(2-(4-carboxyphenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2R*,5S*)-4(2-(4-carboxyphenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(2-(4-carboxyphenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-di-(3-iodo)benzylacetamide,  
 (2S*,5S*)-4-(3-(4-carboxyphenyl)propyl)-2-heptyl-4-oxo-5-thiazolidine N,N-benzylacetamide,  
 (2S*,5S*)-4-(4-(4carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-di-(3-benzylacetamide,  
 (2S*,5S*)-4-(2-(4-carboxyphenyl)ethyl)-2-(6-phenylhexyl)-4-oxo-5-thiazolidine N,N-dibenzyiacetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-(6-phenylhexyl)-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 4-(4-(4-carboxyphenyl)butyl)-2-(4-phenylbutyl)-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(2-(4-ureidophenyl)ethyl)-2-octyl-4oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(2-(4-methylsuffonamidophenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(2-(4-aminosuffonylphenylethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-hepyl-4-oxo-5-thiazolidine N-benzyl-N-(4-trifluorobenzyl)acetamide,  
 (2R*,S*)-4-(4-(4-carboxyphenyl)butyl)-2-hepyl-4-oxo-5-thiazolidine N-benzyl-N-(4-trifluorobenzyl)acetamide,  
 (2S*,5S*)-4-(2-(4-(3-hydantoino)phenyl)ethyl)-2-octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S,5S*)-4-(2-(3,4-dioxomethylenephenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(4-(4-arboxyphenyl)butyl)-2-octyl-4-oxo-5-thiazolidine N-benzyl-N-(4-hydroxybutyl)acetamide,  
 (2S*,5S*)-4-(2-(3,4dioxomethylenephenyl)ethyl)-2octyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(4-pyridyl)acetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-pyridyl)acetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-ethoxycarboxyethyl)acetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-butylacetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-isopropylacetamide,  
 (2S*,5S*)-4-(2-(4-hydroxyphenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5thiazoildne N-benzyl-N-ethoxycarboxymethylacetamide,  
 (2S*,5S*)-4-(4-(4arboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-di-(4-fluorobenzyl)acetamide,  
 (2S*,5S*)-4-(2-(4-carboxymethoxyphenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(2-(4-carboxyamidomethoxyphenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(2-(4-methoxyphenyl)ethyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-thienylmethyl)acetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2,3-dioxomethylenebenzyl)acetamide,  
 (2S*,S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazoidine N-benzyl-N-(2-thiazolemethyl)acetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-furfuryl)acetamide,  
 and pharmaceutically acceptable salts and solvates thereof.  
 
     
     
         6 . The compound of  claim 1  wherein said compound is selected from the group consisting of 
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S,5S)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N,N-dibenzylacetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-hexyl-4-oxo-5-thiazolidine N,N-dibutylacetamide,  
 (2S*,5S*)-4-(4(4-carboxyphenyl)butyl)-2octyl-4-oxo-5-thiazolidine N-benzyl-N-(4-hydroxybutyl)acetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenylbutyl)-2-heptyloxo-5thiazolidine N-benzyl-N-(4-pyridyl)acetamide,  
 (2S*,5S*)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thiazolidine N-benzyl-N-(2-thiazolemethyl)acetamide,  
 and pharmaceutically acceptable salts and solvates thereof.  
 
     
     
         7 . A pharmaceutical composition comprising a compound according to any of claims  1 - 6 .  
     
     
         8 . A pharmaceutical composition according to  claim 6  further comprising a pharmaceutically acceptable diluent or carrier.  
     
     
         9 . A compound according to any of claims  1 - 6  for use in therapy.  
     
     
         10 . A method for the prevention or treatment of a PPARgamma mediated disease or condition comprising administration of a therapeutically effective amount of a compound of any of claims  1 - 6 .  
     
     
         11 . The method of  claim 10  wherein said disease or condition is diabetes, obesity, dyslipidemia, metabolic syndrome, osteoporosis, acne, cardiovascular disease, inflammation, or cancer.  
     
     
         12 . The method of  claim 10  wherein said disease or condition is osteoporosis.  
     
     
         13 . A method for the prevention or treatment of osteoporosis comprising administration of a therapeutically effective amount of a PPARgamma antagonist.  
     
     
         14 . The method of  claim 13  wherein said antagonist is a compound of any of claims  1 - 6 .  
     
     
         15 . Use of a compound of any of claims  1 - 6  for the manufacture of a medicament for the prevention or treatment of a PPARgamma mediated disease or condition.  
     
     
         16 . Use according to  claim 15  wherein said disease or condition is diabetes, obesity, dyslipidemia, metabolic syndrome, osteoporosis, acne, cardiovascular disease, inflammation, or cancer.  
     
     
         17 . Use according to  claim 16  wherein said disease or condition is osteoporosis.  
     
     
         18 . Use of a PPARgamma antagonist compound for the manufacture of a medicament for the prevention or treatment of osteoporosis.  
     
     
         19 . Use according to  claim 18  wherein said antagonist is a compound according to any of claims  1 - 6 .  
     
     
         20 . A method for identifying compounds that will be useful for the treatment of a PPAR gamma mediated disease or condition, comprising the step of binding a compound of  claim 1  to PPAR gamma.  
     
     
         21 . The method of  claim 20  wherein said disease or condition is diabetes, impaired glucose tolerance, obesity, or a cardiovascular disorder.  
     
     
         22 . A method for treating a PPAR gamma mediated disease or condition comprising administration of a therapeutically effective amount of a compound that was identified as useful for such treatment by the method of  claim 20 .  
     
     
         23 . The method of  claim 22  wherein said disease or condition is diabetes, impaired glucose tolerance, obesity, or a cardiovascular disorder.  
     
     
         24 . Use of a compound identified by the method of  claim 20  for the manufacture of a medicament for use in the treatment of a PPAR mediated disease or condition.  
     
     
         25 . Use according to  claim 24  wherein the PPAR mediated disease or condition is diabetes, impaired glucose tolerance, obesity or a cardiovascular disorder.  
     
     
         26 . A method for identifying compounds which would be useful in the treatment of osteoporosis comprising the step of determining whether a compound antagonises PPAR gamma.