N-substituted heterocycles for the treatment of hypercholesteremia, dyslipidemia and other metabolic disorders; cancer, and other diseases

Abstract

The present invention relates to certain compounds of Formula (I) which can be useful in the treatment of diseases, such as, cancer, metabolic disorders, Type 2 Diabetes, dyslipidemia and/or hyperchloesterolemia:

1 . A compound having the formula  
     
       
         
         
             
             
         
       
     
     wherein, 
 a) “ ” is absent or present;  
 b) Ar 1  has from six to 25 carbon atoms and has the formula  
                     
 wherein R 101 , R 102 , R 103 , R 104 , R 105 , R 106 , R 107 , R 108 , R 110 , R 111  or R 112  are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, arylsulfonamide, alkylurea, arylurea, alkylcarbamate, arylcarbamate, aryl, heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide;  
 c) Ar 2  comprises from four to twenty carbon atoms and an aryl ring or heteroaryl ring, and  
 d) R 1  is hydrogen or a substituted or unsubstituted organic radical comprising from one to four carbon atoms;  
 e) R 2  is a substituted or unsubstituted organic radical comprising one to twelve carbon atoms;  
 f) W is —S—, —O— or —N—R 3  wherein R 3  is hydrogen, or a substituted or unsubstituted radical comprising from one to 12 carbon atoms; and  
 g) X is O or S;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . The compound of  claim 1 , wherein R 2  is an alkyl or substituted alkyl group.  
   
   
       3 . The compound of  claim 1 , wherein R 2  is a —CH 2 CO 2 H group.  
   
   
       4 . The compound of  claim 1 , wherein “ ” is present.  
   
   
       5 . The compound of  claim 1 , wherein R 1  is hydrogen.  
   
   
       6 . The compound of  claim 1 , wherein W is —S—.  
   
   
       7 . The compound of  claim 1 , wherein X is —O—, or —S—.  
   
   
       8 . The compound of  claim 1 , wherein X is —O—.  
   
   
       9 . The compound of  claim 1 , wherein W is —S—, and X is —O—.  
   
   
       10 . The compound of  claim 1 , wherein W is —S—, and X is —S—.  
   
   
       11 . The compound of  claim 1 , wherein Ar 2  is an aryl ring optionally substituted with one, two, or three substituent groups independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, haloalkyl, haloalkoxy, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide groups.  
   
   
       12 . The compound of  claim 1 , wherein Ar 2  has the structure  
     
       
         
         
             
             
         
       
     
     wherein R 15 , R 16 , and R 17  are independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide radicals.  
   
   
       13 . The compound of  claim 1 , wherein Ar 2  has the structure  
     
       
         
         
             
             
         
       
     
   
   
       14 . The compound of  claim 1 , wherein Ar 2  is a heteroaryl ring optionally substituted with one, two, or three substituent groups independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide radicals.  
   
   
       15 . The compound of  claim 1 , wherein Ar 2  has the structure  
     
       
         
         
             
             
         
       
     
     wherein x is one or two, and R 15 , and R 16  are independently selected from inorganic radicals selected from halogen, cyano, nitro, hydroxyl, amino, and from organic radicals comprising from one to four carbon atoms independently selected from alkyl, substituted alkyl, acyloxy, alkoxy, substituted alkoxy, acyl, mono-substituted amino, di-substituted amino, carboxy, carboalkoxy, alkylcarboxamide, or dialkylcarboxamide groups.  
   
   
       16 . The compound of  claim 15 , wherein Ar 2  comprises a heteroaryl ring having the structure  
     
       
         
         
             
             
         
       
     
   
   
       17 . A pharmaceutical composition for administration in mammals comprising one or more pharmaceutically acceptable carriers and one or more compounds of  claim 1  in an amount effective for treating obesity, modulating lipid metabolism, carbohydrate metabolism, lipid and carbohydrate metabolism, or adipocyte differentiation.  
   
   
       18 . A method of modulating lipid and carbohydrate metabolism comprising administering to a mammal diagnosed as needing such modulation one or more compounds having the structure:  
     
       
         
         
             
             
         
       
     
     wherein, 
 a) “ ” is absent or present;  
 b) Ar 1  has from six to 25 carbon atoms and has the formula  
                     
 wherein R 5  and R 6  together with the aromatic ring form a five, six, or seven membered non-aromatic ring which can optionally comprise one, or two ring heteroatoms independently selected from O, S, N, and NR N , wherein R N  is hydrogen, hydroxyl, halogen, amino, or an organic radical comprising one to twelve carbon atoms; and wherein R 7  and R 8  are independently selected from hydrogen, alkyl, substituted alkyl, amino, mono-substituted amino, or di-substituted amino;  
 c) Ar 2  comprises from four to twenty carbon atoms and an aryl ring or heteroaryl ring, and  
 d) R 1  is hydrogen or a substituted or unsubstituted organic radical comprising from one to four carbon atoms;  
 e) R 2  is a substituted or unsubstituted organic radical comprising one to twelve carbon atoms;  
 f) W is —S—, —O— or —N—R 3  wherein R 3  is hydrogen, or a substituted or unsubstituted radical comprising from one to 12 carbon atoms; and  
 g) X is O or S;  
 or a pharmaceutically acceptable salt thereof in an amount effective to provide such modulation.  
 
   
   
       19 . 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) “ ” is absent or present;  
 b) Ar 1  has from six to 25 carbon atoms and has the formula  
                     
 wherein R 5  and R 6  together with the aromatic ring form a five, six, or seven membered non-aromatic ring which can optionally comprise one, or two ring heteroatoms independently selected from O, S, N, and NR N , wherein R N  is hydrogen, hydroxyl, halogen, amino, or an organic radical comprising one to twelve carbon atoms; and wherein R 7  and R 8  are independently selected from hydrogen, alkyl, substituted alkyl, amino, mono-substituted amino, or di-substituted amino;  
 c) Ar 2  comprises from four to twenty carbon atoms and an aryl ring or heteroaryl ring, and  
 d) R 1  is hydrogen or a substituted or unsubstituted organic radical comprising from one to four carbon atoms;  
 e) R 2  is a substituted or unsubstituted organic radical comprising one to twelve carbon atoms;  
 f) W is —S—, —O— or —N—R 3  wherein R 3  is hydrogen, or a substituted or unsubstituted radical comprising from one to 12 carbon atoms; and  
 g) X is O or S;  
 or a pharmaceutically acceptable salt thereof in an amount effective to decrease blood sugar levels of the mammal.  
 
   
   
       20 . The method of  claim 19 , wherein the compound is applied in an amount effective to to decrease blood sugar levels by at least about by at least 5%.  
   
   
       21 . The method of  claim 19 , wherein the mammal is a human.  
   
   
       22 . A method of treating obesity in mammals comprising administering to a mammal diagnosed as needing such treatment one or more compounds having the structure:  
     
       
         
         
             
             
         
       
     
     wherein, 
 a) “ ” is absent or present;  
 b) Ar 1  has from six to 25 carbon atoms and has the formula  
                     
 wherein R 5  and R 6  together with the aromatic ring form a five, six, or seven membered non-aromatic ring which can optionally comprise one, or two ring heteroatoms independently selected from O, S, N, and NR N , wherein R N  is hydrogen, hydroxyl, halogen, amino, or an organic radical comprising one to twelve carbon atoms; and wherein R 7  and R 8  are independently selected from hydrogen, alkyl, substituted alkyl, amino, mono-substituted amino, or di-substituted amino;  
 c) Ar 2  comprises from four to twenty carbon atoms and an aryl ring or heteroaryl ring, and  
 d) R 1  is hydrogen or a substituted or unsubstituted organic radical comprising from one to four carbon atoms;  
 e) R 2  is a substituted or unsubstituted organic radical comprising one to twelve carbon atoms;  
 f) W is —S—, —O— or —N—R 3  wherein R 3  is hydrogen, or a substituted or unsubstituted radical comprising from one to 12 carbon atoms; and  
 g) X is O or S;  
 or a pharmaceutically acceptable salt thereof in an amount effective to decrease or prevent weight gain in diabetic db/db mice or ob/ob mice.  
 
   
   
       23 . The method of  claim 22 , wherein the compound is applied in an amount effective to decrease or prevent weight gain by at least about by at least 5%.  
   
   
       24 . A compound having the formula  
     
       
         
         
             
             
         
       
     
     wherein, 
 a) “ ” is absent or present;  
 b) Ar 1  has from six to 25 carbon atoms and has the formula  
                     
 wherein R 200 , R 201 , R 202 , R 203 , R 204 , R 205 , R 206 , R 207 , R 208 , R 209 , and R 210  are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, alkyl, substituted alkyl, haloalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, acyloxy, amino, mono-substituted amino, di-substituted amino, alkylsulfonamide, substituted alkylsulfonamide, arylsulfonamide, heteroarylsulfonamide, alkylurea, alkylthiourea, arylurea, acyl, substituted acyl, alkylcarbamate, arylcarbamate, alkylthiocarbamate, substituted alkylthiocarbamate, arylthiocarbamate, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, haloalkoxy, thioalkyl, alkylsulfoxide, alkylsulfonyl, thiohaloalkyl, carboxy, carboalkoxy, alkylcarboxamide, substituted alkylcarboxamide, dialkylcarboxamide or substituted dialkylcarboxamide radicals;  
 c) Ar 2  comprises from four to twenty carbon atoms and an aryl ring or heteroaryl ring, and  
 d) R 1  is hydrogen or a substituted or unsubstituted organic radical comprising from one to four carbon atoms;  
 e) R 2  is a substituted or unsubstituted organic radical comprising one to twelve carbon atoms;  
 f) W is —S—, —O— or —N—R 3  wherein R 3  is hydrogen, or a substituted or unsubstituted radical comprising from one to 12 carbon atoms; and  
 g) X is O or S;  
 or a pharmaceutically acceptable salt thereof.