Glucose metabolism modulating compounds

Abstract

The present invention provides, inter alia, dihydropyridone compounds and compositions, including analogs of a vesicular monoamine transporter type 2 (VMAT2) antagonist. The present invention also provides methods of using such compounds/analogs for modulating glucose levels, and/or preventing, treating, or ameliorating the effects of diabetes and hyperglycemia.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 6 , and R 7  are independently selected from the group consisting of H, halogen, hydroxyl, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, C 1-8 alkoxy, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, C 1-4 aralkyl, residues of glycolic acid, ethylene glycol/propylene glycol copolymers, carboxylate, ester, amide, carbohydrate, amino acid, alditol, OC(X) 2 COOH, SC(X) 2 COOH, NHCHXCOOH, COY, CO 2 Y, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, propylphthalimide, and thioether; 
         R 4  and R 5 , which are attached to one or more positions of at least one carbon atom of the respective rings, are independently selected from the group consisting of H, halogen, hydroxyl, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, C 1-8 alkoxy, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, C 1-4 aralkyl, residues of glycolic acid, ethylene glycol/propylene glycol copolymers, carboxylate, ester, amide, carbohydrate, amino acid, alditol, OC(X) 2 COOH, SC(X) 2 COOH, NHCHXCOOH, COY, CO 2 Y, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, propylphthalimide, and thioether; 
         X is selected from the group consisting of H, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, and alkylheterocycle, wherein each alkyl, carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, and alkylheterocycle is optionally substituted with at least one substituent; 
         Y is selected from the group consisting of H, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle, and heteroaromatic, wherein each alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle, and heteroaromatic is optionally substituted with at least one substituent; and 
         --- is an optional bond, wherein the optional bond is a single bond or a double bond; 
       
       or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
     
     
         2 . The compound according to  claim 1 , wherein the compound has formula II: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 8  and R 9  are independently selected from the group consisting of H, halogen, C 1 -C 8  alkyl, C 1 -C 8 alkenyl, and C 1 -C 8 alkynyl; 
         R 4  and R 5 , which are attached to one or more positions of at least one carbon atom of the respective rings, are independently selected from the group consisting of H, halogen, hydroxyl, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, and C 1-8 alkoxy; and 
         --- is an optional bond, wherein the optional bond is a single bond or a double bond; 
       
       or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
     
     
         3 . The compound according to  claim 2 , wherein the compound has formula III: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , and R 3  are independently selected from the group consisting of H, C 1 -C 8 alkyl, C 1 -C 8 alkenyl, and C 1 -C 8 alkynyl; and 
         --- is an optional bond, wherein the optional bond is a single bond or a double bond; 
       
       or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
     
     
         4 . The compound according to  claim 3 ,
 wherein R 1  is selected from the group consisting of H, C 1 -C 8 alkyl, C 1 -C 8 alkenyl, and C 1 -C 8 alkynyl;   R 2  and R 3  are selected from the group consisting of H and C 1 alkyl; and   --- is a single bond if R 2  or R 3  is not H.   
     
     
         5 . The compound according to  claim 4 , wherein the compound is compound 15: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
     
     
         6 . The compound according to  claim 1 , wherein the compound has formula IV: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 8 , and R 9  are independently selected from the group consisting H, halogen, hydroxyl, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, C 1-8 alkoxy, 3- to 8-membered carbocyclic or heterocyclic, aryl, heteroaryl, C 1-4 aralkyl, residues of glycolic acid, ethylene glycol/propylene glycol copolymers, carboxylate, ester, amide, carbohydrate, amino acid, alditol, OC(X) 2 COOH, SC(X) 2 COOH, NHCHXCOOH, COY, CO 2 Y, sulfate, sulfonamide, sulfoxide, sulfonate, sulfone, thioalkyl, thioester, propylphthalimide, and thioether; 
         X is selected from the group consisting of H, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, and alkylheterocycle, wherein each alkyl, carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, and alkylheterocycle is optionally substituted with at least one substituent; 
         Y is selected from the group consisting of H, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle, and heteroaromatic, wherein each alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheterocycle, and heteroaromatic is optionally substituted with at least one substituent; 
       
       or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound according to  claim 6 , wherein R 1  is —CH 2 —CH—(CH 3 ) 2 . 
     
     
         8 . The compound according to  claim 6 , wherein R 8  is methyl. 
     
     
         9 . The compound according to  claim 6 , wherein R 9  is methyl. 
     
     
         10 . The compound according to  claim 6 , wherein both R 8  and R 9  are methyl. 
     
     
         11 . The compound according to  claim 6 , wherein R 1  is selected from the group consisting of C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, and C 1-8 alkoxy and R 8  and R 9  are both methyl. 
     
     
         12 . The compound according to  claim 6 , which is compound 8: 
       
         
           
           
               
               
           
         
       
       or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
     
     
         13 . A compound having the structure (1): 
       
         
           
           
               
               
           
         
       
       or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof. 
     
     
         14 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         15 . A method for modulating blood glucose levels in a subject comprising administering to a subject an effective amount of the compound according to  claim 1 . 
     
     
         16 . A method for preventing, treating, or ameliorating the effects of diabetes in a subject comprising administering to a subject an effective amount of the compound according to  claim 1 . 
     
     
         17 . A method for preventing, treating, or ameliorating the effects of hyperglycemia comprising administering to a subject an effective amount of the compound according to  claim 1 . 
     
     
         18 . A method for modulating blood glucose levels in a subject comprising administering to a subject an effective amount of the pharmaceutical composition according to  claim 14 . 
     
     
         19 . A method for preventing, treating, or ameliorating the effects of diabetes in a subject comprising administering to a subject an effective amount of the pharmaceutical composition according to  claim 14 . 
     
     
         20 . A method for preventing, treating, or ameliorating the effects of hyperglycemia comprising administering to a subject an effective amount of the pharmaceutical composition according to  claim 14 . 
     
     
         21 . A method for modulating blood glucose levels in a subject comprising administering to a subject an effective amount of the compound according to  claim 1  or a pharmaceutical composition thereof, which compound or composition interacts with VMAT2 to provide the modulation. 
     
     
         22 . A method for preventing, treating, or ameliorating the effects of diabetes in a subject comprising administering to a subject an effective amount of the compound according to  claim 1  or a pharmaceutical composition thereof, which compound or composition interacts with VMAT2 to provide the prevention, treatment, or amelioration of the effects of diabetes in the subject. 
     
     
         23 . A method for preventing, treating, or ameliorating the effects of hyperglycemia comprising administering to a subject an effective amount of the compound according to  claim 1  or a pharmaceutical composition thereof, which compound or composition interacts with VMAT2 to provide the prevention, treatment, or amelioration of the effects of hyperglycemia in the subject.