Isoxazolidine compounds useful in the treatment of diabetes, hyperlipidemia, and atherosclerosis in mammals

Abstract

The subject invention provides pharmaceutical compounds useful in the treatment of Type II diabetes. These compounds are advantageous because they are readily metabolized by the metabolic drug detoxification systems. Particularly, isoxazolidine compounds which have been designed to include esters within the structure of the compounds are provided. This invention is also drawn to methods of treating disorders, such as diabetes, comprising the administration of therapeutically effective compositions comprising compounds which have been designed to be metabolized by serum or intracellular hydrolases and esterases. Pharmaceutical compositions of the isoxazolidine compounds are also taught.

We claim:  
     
         1 . A compound comprising  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B may be the same or different and are CH 2 , CO, N, NO, NH, SO 0-2 , or O;  
 F is O;  
 D 1 -D 6  can be the same or different and are CH, N, S, or O;  
 E can be a substituent attached to one or more of the atoms located at D 1 -D 6 ;  
 P and Q can be a double bond; or  
 P, Q, and E can be the same or different and are a moiety selected from the group consisting of H, C 1-10  alkyl, substituted alkyl groups, substituted or unsubstituted carboxylic acids, substituted or unsubstituted carboxylic esters, halogen, carboxyl, hydroxyl, phosphate, phosphonate, aryl, CN, OH, COOH, NO 2 , NH 2 , SO 2-4 , C 1-20  heteroalkyl, C 2-20  alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C 1-20  alkyl-aryl, C 2-20  alkenyl-aryl, heteroaryl, C 1-20  alkyl-heteroaryl, C 2-20  alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C 1-20  alkyl-heteroycloalkyl, and C 1-20  alkyl-cycloalkyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of C 1-6  alkyl, halogen, OH, NH 2 , CN, NO 2 , COOH, or SO 2-4 ;  
 X is —OH, —COOH, or a substituted carboxylic group comprising OOC— or COO— and said substituted carboxylic group is attached to D 1 ;  
 and analogs, derivatives, or salts of the compound of Formula I.  
 
     
     
         2 . The compound according to  claim 1 , wherein said substituted carboxylic acid group is selected from the group consisting of alkyloxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, arylcarbonyloxy, heteroalkyloxycarbonyl, heteroalkylcarbonyloxy, heteroaryl-oxycarbonyl, heteroarylcarbonyloxy, each of which is, optionally, substituted with C 1-10  alkyl, CN, COOH, NO 2 , NH 2 , SO 2-4 , C 2-20  heteroalkyl, C 2-20  alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C 1-20  alkyl-aryl, C 2-20  alkenyl-aryl, heteroaryl, C 1-20  alkyl-heteroaryl, C 2-20  alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C 1-20  alkyl-heteroycloalkyl, and C 1-20  alkyl-cycloalkyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of C 1-6  alkyl, halogen, OH, NH 2 , CN, NO 2 , COOH, or SO 2-4 .  
     
     
         3 . The compound according to  claim 1 , wherein said heterocyclic groups are selected from the group consisting of morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine or thiadiazoline.  
     
     
         4 . The compound according to  claim 2 , wherein said heterocyclic groups are selected from the group consisting of morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine, and thiadiazoline.  
     
     
         5 . A composition comprising a carrier and a compound comprising  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B may be the same or different and are CH 2 , CO, N, NO, NH, SO 0-2 , or O;  
 F is O;  
 D 1 -D 6  can be the same or different and are CH, N, S, or O;  
 E can be a substituent attached to one or more of the atoms located at D 1 -D 6 ;  
 P and Q can be a double bond; or  
 P, Q, and E can be the same or different and are a moiety selected from the group consisting of H, C 1-10  alkyl, substituted alkyl groups, substituted or unsubstituted carboxylic acids, substituted or unsubstituted carboxylic esters, halogen, carboxyl, hydroxyl, phosphate, phosphonate, aryl, CN, OH, COOH, NO 2 , NH 2 , SO 2-4 , C 1-20  heteroalkyl, C 2-20  alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C 1-20  alkyl-aryl, C 2-20  alkenyl-aryl, heteroaryl, C 1-20  alkyl-heteroaryl, C 2-20  alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C 1-20  alkyl-heteroycloalkyl, and C 1-20  alkyl-cycloalkyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of C 1-6  alkyl, halogen, OH, NH 2 , CN, NO 2 , COOH, or SO 2-4 ;  
 X is —OH, —COOH, or a substituted carboxylic group comprising OOC— or COO— and said substituted carboxylic group is attached to D 1 ;  
 and analogs, derivatives, or salts of the compound of Formula I.  
 
     
     
         6 . The composition according to  claim 5 , wherein said substituted carboxylic acid group is selected from the group consisting of alkyloxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, arylcarbonyloxy, heteroalkyloxycarbonyl, heteroalkylcarbonyloxy, heteroaryl-oxycarbonyl, heteroarylcarbonyloxy, each of which is, optionally, substituted with C 1-10  alkyl, CN, COOH, NO 2 , NH 2 , SO 2-4 , C 1-20  heteroalkyl, C 2-20  alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C 1-20  alkyl-aryl, C 2-20  alkenyl-aryl, heteroaryl, C 1-20  alkyl-heteroaryl, C 2-20  alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C 1-20  alkyl-heteroycloalkyl, and C 1-20  alkyl-cycloalkyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of C 1-6  alkyl, halogen, OH, NH 2 , CN, NO 2 , COOH, or SO 2-4 .  
     
     
         7 . The composition according to  claim 5 , wherein said heterocyclic groups are selected from the group consisting of morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine or thiadiazoline.  
     
     
         8 . The composition according to  claim 5 , wherein said carrier is a pharmaceutically acceptable carrier.  
     
     
         9 . A method of treating diabetes, atherosclerosis, hypercholesterolemia, or hyperlipidemia comprising the administration of a therapeutically effective amount of the composition comprising a carrier and a compound comprising  
       
         
           
           
               
               
           
         
       
       wherein 
 A and B may be the same or different and are CH 2 , CO, N, NO, NH, SO 0-2 , or O;  
 F is O;  
 D 1 -D 6  can be the same or different and are CH, N, S, or O;  
 E can be a substituent attached to one or more of the atoms located at D 1 -D 6 ;  
 P and Q can be a double bond; or  
 P, Q, and E can be the same or different and are a moiety selected from the group consisting of H, C 1-10  alkyl, substituted alkyl groups, substituted or unsubstituted carboxylic acids, substituted or unsubstituted carboxylic esters, halogen, carboxyl, hydroxyl, phosphate, phosphonate, aryl, CN, OH, COOH, NO 2 , NH 2 , SO 2-4 , C 1-20  heteroalkyl, C 2-20  alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C 1-20  alkyl-aryl, C 2-20  alkenyl-aryl, heteroaryl, C 1-20  alkyl-heteroaryl, C 2-20  alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C 1-20  alkyl-heteroycloalkyl, and C 1-20  alkyl-cycloalkyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of C 1-6  alkyl, halogen, OH, NH 2 , CN, NO 2 , COOH, or SO 2-4 ;  
 X is —OH, —COOH, or a substituted carboxylic group comprising OOC— or COO— and said substituted carboxylic group is attached to D 1 ;  
 and analogs, derivatives, or salts of the compound of Formula I.  
 
     
     
         10 . The method according to  claim 9 , wherein said substituted carboxylic acid group is selected from the group consisting of alkyloxycarbonyl, alkylcarbonyloxy, aryloxycarbonyl, arylcarbonyloxy, heteroalkyloxycarbonyl, heteroalkylcarbonyloxy, heteroaryl-oxycarbonyl, heteroarylcarbonyloxy, each of which is, optionally, substituted with C 1-10  alkyl, CN, COOH, NO 2 , NH 2 , SO 2-4 , C 1-20  heteroalkyl, C 2-20  alkenyl, alkynyl, akynyl-aryl, alkynyl-heteroaryl, aryl, C 1-20  alkyl-aryl, C 2-20  alkenyl-aryl, heteroaryl, C 1-20  alkyl-heteroaryl, C 2-20  alkenyl-heteroaryl, cycloalkyl, heterocycloalkyl, C 1-20  alkyl-heteroycloalkyl, and C 1-20  alkyl-cycloalkyl, any of which may be, optionally, substituted with a moiety selected from the group consisting of C 1-6  alkyl, halogen, OH, NH 2 , CN, NO 2 , COOH, or SO 2-4 .  
     
     
         11 . The method according to  claim 9 , wherein said heterocyclic groups are selected from the group consisting of morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine or thiadiazoline.  
     
     
         12 . The method according to  claim 10 , wherein said heterocyclic groups are selected from the group consisting of morpholine, triazole, imidazole, pyrrolidine, piperidine, piperazine, pyrrole, dihydropyridine, aziridine, thiazolidine, thiazoline, thiadiazolidine, and thiadiazoline.  
     
     
         13 . The method according to  claim 9 , wherein said carrier is a pharmaceutically acceptable carrier.  
     
     
         14 . The method according to  claim 9 , wherein A is NH; B is C═O; P and Q are a double bond or H; D 1 -D 6  are C (carbon), E is hydrogen; X is selected from the group consisting of: COOH, OH,  
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound according to  claim 1 , wherein A is NH; B is C═O; P and Q are a double bond or H; D 1 -D 6  are C (carbon), E is hydrogen; X is selected from the group consisting of: COOH, OH,  
       
         
           
           
               
               
           
         
       
     
     
         16 . The composition according to  claim 5 , wherein A is NH; B is C═O; P and Q are a double bond or H; D 1 -D 6  are C (carbon), E is hydrogen; X is selected from the group consisting of: COOH, OH,