Methods and Compositions for the Treatment of Body Weight Related Disorders

Abstract

The present invention relates to methods for reducing body weight in an animal in need thereof via administration of a therapeutically effective amount of a compound having a general tripartite structure A-B-C. In the tripartite structure A, B, and C are identical or non-identical structures, for example, but not limited to, heterocyclic, phenyl or benzyl ring structures with or without substitutions and are described in detail herein. The methods may utilize particular compounds, for example, having a piperidinyl, a pyrrolinyl or pyridinyl A ring, a thiazole B ring, and a phenyl C ring which may be further substituted independently. Also provided are methods for increasing thermogenesis without reducing lean body mass during weight loss in an animal by administering of a therapeutically effective amount of the compounds described.

What is claimed is: 
     
         1 . A method for reducing body weight in an animal in need thereof, comprising the step of administering to the animal, in a pharmaceutically acceptable medium, a therapeutically effective amount of a compound having the structure:
 A-B-C   wherein A is a pyridine or a substituted pyridine, a piperidine or a substituted piperidine, a pyrrolidine or a substituted pyrrolidine, a thiazole or a substituted thiazole, a phenyl ring or a substituted phenyl ring;   B is a thioazole or a substituted thioazole, a piperazine or a substituted piperazine, a phenyl ring or a substituted phenyl ring; and   C is a phenyl ring or a substituted phenyl ring, a pyridine or a substituted pyridine, a thioazole or a substituted thioazole;   or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof.   
     
     
         2 . The method of  claim 1 , wherein the chemical structure is: 
       
         
           
           
               
               
           
         
         wherein m is 0 or 1; 
         R 5  is H, —OH, —O—C 1-3  alkoxy, —OC(O)R 7  or halogen, wherein said halogen is preferably bromine; 
         R 7  is C 1 -C 3  alkyl or aryl, —OCH 2 —C(O)OR 8 ; 
         R 8  is H or C 1 -C 3  alkyl, —NHR 9 ; 
         R 9  is H, C 1 -C 4  alkyl, alkylcyclopropane, benzyl, —NHC(O)C 1 -C 3  amide, —NHC(O)O—R 10  carbamate; 
         R 10  is tert-butyl or fluorenylmethyl or —NH—SO 2 —R 11  sulfonamide; 
         R 11  is alkyl or aryl; 
         R 6  is alkyl or R 12 OC(O)—; and 
         R 12  is C 3 -C 5  alkyl or aryl; or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof. 
       
     
     
         3 . The method of  claim 1 , wherein the chemical structure is: 
       
         
           
           
               
               
           
         
         wherein R 5  is H, —OH, —O—C 1-3  alkoxy, —OC(O)R 7  or halogen; 
         R 7  is C 1 -C 3  alkyl or aryl, —OCH 2 —C(O)OR 8 ; 
         R 8  is H or C 1 -C 3  alkyl, —NHR 9 ; 
         R 9  is H, C 1 -C 4  alkyl, alkylcyclopropane, benzyl, —NHC(O)C 1 -C 3  amide, —NHC(O)O—R 10  carbamate; 
         R 10  is tert-butyl or fluorenylmethyl or —NH—SO 2 —R 11  sulfonamide; 
         R 11  is alkyl or aryl; 
         R 13  is nitrogen or methylene; 
         n is 0 or 1 and when n is 1, Z is —C═O; 
         A is 
       
       
         
           
           
               
               
           
         
       
       and
 R 14  is H or C 1 -C 3  alkyl group; or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof. 
 
     
     
         4 . The method of  claim 1 , wherein the chemical structure is: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof. 
       
     
     
         5 . A method for increasing thermogenesis without reducing lean body mass during weight loss in an animal, comprising the step of administering to the animal, in a pharmaceutically acceptable medium, a therapeutically effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
         wherein m is 0 or 1; 
         R 5  is H, —OH, —O—C 1-3  alkoxy, —OC(O)R 7  or halogen, wherein said halogen is preferably bromine; 
         R 7  is C 1 -C 3  alkyl or aryl, —OCH 2 —C(O)OR 8 ; 
         R 8  is H or C 1 -C 3  alkyl, —NHR 9 ; 
         R 9  is H, C 1 -C 4  alkyl, alkylcyclopropane, benzyl, —NHC(O)C 1 -C 3  amide, —NHC(O)O—R 10  carbamate; 
         R 10  is tert-butyl or fluorenylmethyl or —NH—SO 2 —R 11  sulfonamide; 
         R 11  is alkyl or aryl; 
         R 6  is alkyl or R 12 OC(O)—; and 
         R 12  is C 3 -C 5  alkyl or aryl; or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof. 
       
     
     
         6 . The method of  claim 5 , wherein said compound is administered in a composition which is in the form of a food, an animal feed material, or a medicine. 
     
     
         7 . The method of  claim 5 , wherein the compound increases the expression of a uncoupling protein selected from the group consisting of uncoupling protein 1, uncoupling protein 2 and uncoupling protein 3. 
     
     
         8 . The method of  claim 5 , wherein the animal suffers from a weight-related condition selected from the group consisting of obesity, hypertension, arteriosclerosis, asthma, hyperlipidemia, hyperinsulinemia, non-alcoholic fatty liver and type 2 diabetes caused by insulin resistance. 
     
     
         9 . The method of  claim 5 , further comprising providing to the animal a second therapy selected from a lifestyle modification, an antihyperglycemic agent, insulin, glucagon-like peptide (GLP), a dipeptidyl peptidase-4 inhibitor, a thiazolidinedione, a lipid lowering compound, and a combination of two or more thereof. 
     
     
         10 . A method for increasing thermogenesis without reducing lean body mass during weight loss in an animal, comprising the step of administering to the animal, in a pharmaceutically acceptable medium, a therapeutically effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
         wherein R 5  is H, —OH, —O—C 1-3  alkoxy, —OC(O)R 7  or halogen; 
         R 7  is C 1 -C 3  alkyl or aryl, —OCH 2 —C(O)OR 8 ; 
         R 8  is H, C 1 -C 3  alkyl, or —NHR 9 ; 
         R 9  is H, C 1 -C 4  alkyl, alkylcyclopropane, benzyl, —NHC(O)C 1 -C 3  amide, or —NHC(O)O—R 10  carbamate; 
         R 10  is tert-butyl or fluorenylmethyl or —NH—SO 2 —R 11  sulfonamide; 
         R 11  is alkyl or aryl; 
         R 13  is nitrogen or methylene; 
         n is 0 or 1 and when n is 1, Z is —C═O; 
         A is 
       
       
         
           
           
               
               
           
         
       
       and
 R 14  is H or C 1 -C 3  alkyl group; or a pharmaceutically acceptable salt or a stereoisomer thereof or a combination thereof. 
 
     
     
         11 . The method of  claim 10 , wherein said compound is administered in a composition which is in the form of a food, an animal feed material, or a medicine. 
     
     
         12 . The method of  claim 10 , wherein the compound increases the expression of a uncoupling protein selected from the group consisting of uncoupling protein 1, uncoupling protein 2 and uncoupling protein 3. 
     
     
         13 . The method of  claim 10 , wherein the animal suffers from a weight-related condition selected from the group consisting of obesity, hypertension, arteriosclerosis, asthma, hyperlipidemia, hyperinsulinemia, non-alcoholic fatty liver and type 2 diabetes caused by insulin resistance. 
     
     
         14 . The method of  claim 10 , further comprising providing to the animal a second therapy selected from a lifestyle modification, an antihyperglycemic agent, insulin, glucagon-like peptide (GLP), a dipeptidyl peptidase-4 inhibitor, a thiazolidinedione, a lipid lowering compound, and a combination of two or more thereof.