Heterocyclic amide derivatives for the treatment of diabetes and other diseases

Abstract

The present invention relates to methods of treating breast cancer, diabetes, and/or related metabolic disorders with certain substituted heterocycles of Formula (200), wherein B, H, I, J and K together with the Ar 5 form a ring containing at least one amide residue, and W, X, Y and Z together form a 2,4-thiazolidinedione, 2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one residue; or a pharmaceutically acceptable salt thereof.

1 . A method of treating type 2 Diabetes comprising administering to a mammal diagnosed as needing such treatment one or more compounds a compound of Formula (200):  
     
       
         
         
             
             
         
       
       wherein:  
       a) the B, H, I, J and K residues are independently selected from —C(O)—, —C(S)—, —O—, —S—, —N(R 101 )—, —N(R 102 )—, —C(R 103 )(R 104 )—, —C(R 105 )(R 106 ), or —C(R 107 )(R 108 )— residues, and from zero to two of the B, H, I, J or K residues can be absent; wherein: 
 i) R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107  and R 108  are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic residue comprising 1 to 12 carbon atoms; or two of the R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107  and R 108  residues can be connected together to form an exocyclic substituent residue comprising 1 to 6 ring carbon atoms and from 0 to 3 optional ring heteroatoms selected from O, S, or N; and  
 ii) B, H, I, J and K together with the Ar 5  form a ring containing at least one amide residue having the formula  
                     
  wherein R x  is a R 101  or R 102  residue;  
 
       b) Ar 5  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl residue comprising from 3 to 6 ring carbon atoms and from 0 to 3 optional ring heteroatoms selected from O, S, or N;  
       c) Ar 6  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl residue comprising from 2 to 6 ring carbon atoms and from 0 to 3 optional ring heteroatoms selected from O, S, or N;  
       d) R 109  is hydrogen, hydroxy, or an organic residue comprising 1 to 10 carbon atoms;  
       e) ----- is either present or absent;  
       f) W, X, Y and Z form a 2,4-thiazolidinedione, 2-thioxo-thiazolidine-4-one, 2,4-imidazolidinedione or 2-thioxo-imidazolidine-4-one residue;  
       or a pharmaceutically acceptable salt thereof, in an amount effective to treat type 2 diabetes.  
     
   
   
       2 . The method of  claim 1  wherein the radical:  
     
       
         
         
             
             
         
       
     
     has the structure:  
     
       
         
         
             
             
         
       
     
     wherein R 101  is selected from hydrogen or an organic radical comprising 1 to 12 carbon atoms, and wherein R 103 , R 104 , R 105 , R 106 , and R 110  are independently selected from hydrogen or alkyls comprising 1 to 4 carbon atoms.  
   
   
       3 . The method of  claim 1  wherein the radical:  
     
       
         
         
             
             
         
       
     
     has the structure:  
     
       
         
         
             
             
         
       
     
     wherein R 101 , R 103 , R 104 , R 105 , R 106 , and R 110  are independently selected from hydrogen or alkyls comprising 1 to 4 carbon atoms.  
   
   
       4 . The method of  claim 1  wherein the radical:  
     
       
         
         
             
             
         
       
     
     has the structure:  
     
       
         
         
             
             
         
       
     
     wherein R 101  and R 110  are an alkyl comprising 1 to 4 carbon atoms.  
   
   
       5 . The method of  claim 1  wherein Ar 6  comprises a phenyl ring.  
   
   
       6 . The method of  claim 5  wherein the Ar 6  ring is substituted with one, two or three substituents independently selected from halogens or a radical comprising 1 to 4 carbon atoms selected from an alkyl, a haloalkyl, an amino, a mono-substituted amino, a di-substituted amino, an alkoxy, or a haloalkoxy.  
   
   
       7 . The method of  claim 1  wherein Ar 6  comprises a pyridyl ring.  
   
   
       8 . The method of  claim 7  wherein the Ar 6  ring is substituted with one, two or three substituents independently selected from halogens or a radical comprising 1 to 4 carbon atoms selected from an alkyl, a haloalkyl, an amino, a mono-substituted amino, a di-substituted amino, an alkoxy, or a haloalkoxy.  
   
   
       9 . The method of  claim 1  wherein Ar 6  has the structure:  
     
       
         
         
             
             
         
       
     
     wherein R 125 , R 126 , R 127  and R 128  are substituents independently selected from hydrogen, halogen, nitro, hydroxyl, amino, or an organic radical comprising 1 to 4 carbon atoms.  
   
   
       10 . The method of  claim 9  wherein R 125  is not hydrogen.  
   
   
       11 . The method of  claim 10  wherein R 125  is an alkyl, substituted alkyl, haloalkyl, alkoxy, substituted alkoxy, haloalkoxy, halogen, amino, mono-substituted amino, or disubstituted amino radical comprising 1 to four carbons.  
   
   
       12 . The method of  claim 1  wherein Ar 6  has the structure:  
     
       
         
         
             
             
         
       
     
     wherein R 126 , R 127  and R 128  are independently or together hydrogen or halogen.  
   
   
       13 . The method of  claim 1  wherein ----- is present.  
   
   
       14 . The method of  claim 1  wherein R 109  is hydrogen.  
   
   
       15 . The method of  claim 1  wherein the heterocycle comprising W, X, Y and Z has the structure  
     
       
         
         
             
             
         
       
     
   
   
       16 . The method of  claim 1  in the form of a salt wherein the heterocycle comprising W, X, Y and Z forms an anion having the structure:  
     
       
         
         
             
             
         
       
     
   
   
       17 . A method of treating breast cancer comprising administering to a mammal diagnosed as needing such treatment a compound having the formula 5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione, or a pharmaceutically acceptable salt thereof, in an amount effective to treat breast cancer.  
   
   
       18 . A method of treating Type 2 Diabetes comprising administering to a human diagnosed as needing such treatment, 
 a compound having the formula 5-[3-(1-Ethyl-4,4,6-trimethyl-2-oxo-1,2,3,4-tetrahydro-quinolin-7-yl)-4-trifluoromethoxy-benzylidene]-thiazolidine-2,4-dione or a pharmaceutically acceptable salt thereof, in an amount effective to decrease serum glucose levels by at least about 5% and also decrease serum triglyeride levels by at least about 5%.    
   
   
       19 . A method of treating hypercholesterolemia comprising administering to a mammal diagnosed as needing such treatment one or more compounds having the structure:  
     
       
         
         
             
             
         
       
       wherein  
       a) Ar 5  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
       b) B, H, I, J and K are independently selected from —C(O)—, —C(S), —O—, —S—, —N(R 101 )—, —N(R 102 )—, —C(R 103 )(R 104 )—, —C(R 105 )(R 106 )—, or —C(R 107 )(R 108 )—, wherein one, or two of B, H, I, J or K can optionally be absent; and 
 i) R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107  and R 108  are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic radical comprising 1 to 12 carbon atoms;  
 ii) two of B, H, I, J and K form at least one radical having the structure:  
                     
  wherein R x  is a R 101  or R 102  radical;  
 iii) Ar 5  together with B, H, I, J and K comprise from 2 to 24 carbon atoms;  
 
       c) Ar 6  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl comprising from 2 to 18 carbon atoms;  
       d) R 109  is hydrogen, hydroxy, or an organic radical comprising 1 to 10 carbon atoms;  
       e) ----- is either present or absent;  
       f) HAr is a heterocycle having the structure:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       20 . The method of  claim 19  wherein the one or more compounds or salts are applied in an amount effective to decrease serum cholesterol levels by at least about 5%.  
   
   
       21 . A method of treating dyslipidemia comprising administering to a mammal diagnosed as needing such treatment one or more compounds having the structure:  
     
       
         
         
             
             
         
       
       wherein  
       a) Ar 5  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
       b) B, H, I, J and K are independently selected from —C(O)—, —C(S), —O—, —S—, —N(R 101 )—, —N(R 102 )—, —C(R 103 )(R 104 )—, —C(R 105 )(R 106 )—, or —C(R 107 )(R 108 )—, wherein one, or two of B, H, I, J or K can optionally be absent; and 
 i) R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107  and R 108  are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic radical comprising 1 to 12 carbon atoms;  
 ii) two of B, H, I, J and K form at least one radical having the structure:  
                     
  wherein R x  is a R 101  or R 102  radical;  
 iii) Ar 5  together with B, H, I, J and K comprise from 2 to 24 carbon atoms;  
 
       c) Ar 6  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl comprising from 2 to 18 carbon atoms;  
       d) R 109  is hydrogen, hydroxy, or an organic radical comprising 1 to 10 carbon atoms;  
       e) ----- is either present or absent;  
       f) HAr is a heterocycle having the structure:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, in an amount effective to decrease serum triglyceride levels in the animal.  
     
   
   
       22 . The method of  claim 21 , wherein the one or more compounds or salts are applied in an amount effective to decrease triglyceride levels by at least about 5%.  
   
   
       23 . A method of treating type 2 Diabetes comprising administering to a mammal diagnosed as needing such treatment one or more compounds having the structure:  
     
       
         
         
             
             
         
       
       wherein  
       a) Ar 5  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
       b) B, H, I, J and K are independently selected from —C(O)—, —C(S), —O—, —S—, —N(R 101 )—, —N(R 102 )—, —C(R 103 )(R 104 )—, —C(R 105 )(R 106 )—, or —C(R 107 )(R 108 )—, wherein one, or two of B, H, I, J or K can optionally be absent; and 
 i) R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107  and R 108  are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic radical comprising 1 to 12 carbon atoms;  
 ii) two of B, H, I, J and K form at least one radical having the structure  
                     
  wherein R x  is a R 101  or R 102  radical;  
 iii) Ar 5  together with B, H, I, J and K comprise from 2 to 24 carbon atoms;  
 
       c) Ar 6  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl comprising from 2 to 18 carbon atoms;  
       d) R 109  is hydrogen, hydroxy, or an organic radical comprising 1 to 10 carbon atoms;  
       e) ----- is either present or absent;  
       f) HAr is a heterocycle having the structure:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, in an amount effective to treat type 2 diabetes.  
     
   
   
       24 . The method of  claim 23 , wherein the one or more compounds or salts are applied in an amount effective to decrease blood glucose levels by at least about 5%.  
   
   
       25 . A method of treating Type 2 Diabetes comprising administering to a human diagnosed as needing such treatment one or more compounds having the structure:  
     
       
         
         
             
             
         
       
       wherein  
       a) Ar 5  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
       b) B, H, I, J and K are independently selected from —C(O)—, —C(S)—, —O—, —S—, —N(R 101 )—, —N(R 102 )—, —C(R 103 )(R 104 )—, —C(R 105 )(R 106 )—, or —C(R 107 )(R 108 )—, wherein one, or two of B, H, I, J or K can optionally be absent; and 
 i) R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107  and R 108  are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic radical comprising 1 to 12 carbon atoms;  
 ii) two of B, H, I, J and K form at least one radical having the structure:  
                     
  wherein R x  is a R 101  or R 102  radical;  
 iii) Ar 5  together with B, H, I, J and K comprise from 2 to 24 carbon atoms;  
 
       c) Ar 6  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl comprising from 2 to 18 carbon atoms;  
       d) R 109  is hydrogen, hydroxy, or an organic radical comprising 1 to 10 carbon atoms;  
       e) ----- is either present or absent;  
       f) HAr is a heterocycle having the structure:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, in an amount effective to decrease serum glucose levels by at least about 5% and also decrease serum triglyeride levels by at least about 5%.  
     
   
   
       26 . A method of treating breast cancer comprising administering to a mammal diagnosed as needing such treatment one or more compounds having the structure:  
     
       
         
         
             
             
         
       
       wherein  
       a) Ar 5  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl;  
       b) B, H, I, J and K are independently selected from —C(O)—, —C(S)—, —O—, —S—, —N(R 101 )—, —N(R 102 )—, —C(R 103 )(R 104 )—, —C(R 105 )(R 106 )—, or —C(R 107 )(R 108 )—, wherein one, or two of B, H, I, J or K can optionally be absent; and 
 i) R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107  and R 108  are independently selected from hydrogen, hydroxyl, a halogen, amino, or an organic radical comprising 1 to 12 carbon atoms;  
 ii) two of B, H, I, J and K form at least one radical having the structure:  
                     
  wherein R x  is a R 101  or R 102  radical;  
 iii) Ar 5  together with B, H, I, J and K comprise from 2 to 24 carbon atoms;  
 
       c) Ar 6  is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl comprising from 2 to 18 carbon atoms;  
       d) R 109  is hydrogen, hydroxy, or an organic radical comprising, 1 to 10 carbon atoms;  
       e) ----- is either present or absent;  
       f) HAr is a heterocycle having the structure:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, in an amount effective to treat the breast cancer.