Glucose metabolism modulating compounds
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 hyper-glycemia.
1. A compound of 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 not present wherein for every occurrence of the C1-C8alkyl, C1-C8alkenyl, or C1-C8alkynyl is an unsubstituted C1-C8alkyl, an unsubstituted C1-C8alkenyl, or an unsubstituted C1-C8alkynyl;
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 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 not present;
or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
3. The compound according to claim 2 ,
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; and
R 2 and R 3 are selected from the group consisting of H and C 1 alkyl.
4. A compound of formula IV:
wherein R 1 , R 8 , and R 9 are independently selected from the group consisting of H, halogen, C 1-8 alkyl, C 1-8 alkenyl, C 1-8 alkynyl, and C 1-8 alkoxy;
or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
5. The compound according to claim 4 , wherein R 1 is —CH 2 —CH—(CH 3 ) 2 .
6. The compound according to claim 4 , wherein R 8 is methyl.
7. The compound according to claim 4 , wherein R 9 is methyl.
8. The compound according to claim 4 , wherein both R 8 and R 9 are methyl.
9. The compound according to claim 4 , 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.
10. The compound according to claim 4 , which is compound 8:
or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
11. A compound having the structure (1):
or an enantiomer, optical isomer, diastereomer, N-oxide, crystalline form, hydrate, or pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound according to any one of claim 1 , 4 or 10 .