Glucagon antagonists
View Patent ↗Provided herein are compounds, including enantiomerically pure forms thereof, and pharmaceutically acceptable salts or co-crystals and prodrugs thereof which have glucagon receptor antagonist or inverse agonist activity. Further, provided herein are pharmaceutical compositions comprising the same as well as methods of treating, preventing, delaying the time to onset or reducing the risk for the development or progression of a disease or condition for which one or more glucagon receptor antagonist is indicated, including Type I and II diabetes, insulin resistance and hyperglycemia. Moreover, provided herein are methods of making or manufacturing compounds disclosed herein, including enantiomerically pure forms thereof, and pharmaceutically acceptable salts or Co-crystals and prodrugs thereof. Formula I
1. A compound of Formula I:
wherein
R 44 is H, CH 3 or CH 3 CH 2 ;
R 45 is C 1-6 -alkyl, alkenyl, alkoxy, C 3-6 -cycloalkyl, C 4-8 -cycloalkenyl, C 4-8 -bicycloalkenyl, aryl or heteroaryl, any of which can be optionally substituted with one or more substituents selected from C 1-6 alkyl, CF 3 , F, CN or OCF 3 ;
L is phenyl, indenyl, benzoxazol-2-yl, C 3-6 -cycloalkyl, C 4-8 -cycloalkenyl or C 4-8 -bicycloalkenyl, any of which can be optionally substituted with one or more substituents selected from F, Cl, CH 3 , CF 3 , OCF 3 or CN; and
R 46 represents one or more substituents selected from H, F, Cl, CH 3 , CF 3 , OCF 3 or CN;
or a pharmaceutically acceptable salt, solvate, or prodrug thereof having an optical purity of at least 95% of the R enantiomer.
2. The compound of claim 1 , wherein:
R 44 is H, CH 3 or CH 3 CH 2 ;
R 45 is C 1-6 -alkyl, alkenyl, alkoxy, C 3-6 -cycloalkyl, C 4-8 -cycloalkenyl, C 4-8 -bicycloalkenyl, aryl or heteroaryl, any of which can be optionally substituted with one or more substituents selected from C 1-6 alkyl, CF 3 , F, CN or OCF 3 ;
L is phenyl, indenyl, benzoxazol-2-yl or 4,4-dimethylcyclohexenyl, any of which can be optionally substituted with one or more substituents selected from F, Cl, CH 3 , CF 3 , OCF 3 or CN; and
R 46 is H, F, Cl, CH 3 , CF 3 , OCF 3 or CN.
3. The compound of claim 2 , wherein L is phenyl, benzoxazol-2-yl or 4,4-dimethylcyclohexenyl, any of which can be optionally substituted with one or more substituents selected from F, Cl, CH 3 , CF 3 , OCF 3 or CN.
4. The compound of claim 2 , wherein L is 4-chloro-2-methylphenyl, 4-methyl-2-benzoxazolyl, 2,4,6-trimethylphenyl, 2-benzoxazolyl, 4-chloro-3-methylphenyl or 4,4-dimethylcyclohexenyl.
5. The compound of claim 2 , wherein R 44 is H or CH 3 .
6. The compound of claim 2 , wherein R 45 is attached to the 3 (meta) or 4 (para) position.
7. The compound of claim 2 , wherein R 45 is alkenyl, C 3-6 -cycloalkyl, C 4-8 -cycloalkenyl, C 4-8 -bicycloalkenyl or phenyl, any of which can be optionally substituted with one or more substituents selected from C 1-6 alkyl or CF 3 .
8. The compound of claim 2 , wherein R 45 is substituted with one or more substituents independently selected from CH 3 and (CH 3 ) 3 C—.
9. The compound of claim 2 , wherein R 45 is selected from (CH 3 ) 3 CCH═CH—, t-butyl-cycloalkyl-, dimethyl-cycloalkyl-, t-butyl-cycloalkenyl-, dimethyl-cycloalkenyl-, bicycloalkenyl-or t-butyl-phenyl-.
10. The compound of claim 2 , wherein R 45 is trans-t-butylvinyl, cis-4-t-butylcyclohexyl, trans-4-t-butylcyclohexyl, 4,4dimethylcyclohexyl, cyclohex-1-enyl, (S)-4-t-butylcyclohex-1 -enyl, (R)-4-t-butylcyclohex-1 -enyl, 4,4-dimethylcyclohex-1 -enyl, 4,4-diethylcyclohex -1 -enyl, 4,4-diethylcyclohexyl, 4,4 dipropylcyclohex-1 -enyl, 4,4-dipropylcyclohexyl, 4,4-dimethylcyclo hexa-1,5 -dienyl, (1R,4 S)1,7,7-trimethylbicyclo [2.2.1]3-heptyl -2-ene, (1R,4R)-1,7,7-trimethylbicyclo[2.2.1]2-heptyl-2-ene, 2-methyl-4-chloro-phenyl, 2,4,6-trimethylphenyl or 4-t-butylphenyl.
11. The compound of claim 10 , wherein is R 45 is trans-t-butylvinyl, cis-4-t-butylcyclohexyl, trans-4-t-butylcyclohexyl, 4,4-dimethylcyclohexyl, (S)-4-t-butylcyclohex-lenyl, (R)-4-t-butylcyclohex-1 -enyl, 4,4-dimethylcyclohex-1 -enyl, (1R,4R)-1,7,7-trimethylbicyclo [2.2.1]2-heptyl-2-ene or 4-t -butylphenyl.
12. The compound of claim 2 , wherein R 46 is H or CH 3 .
13. The compound of claim 1 , wherein the compound is selected from the group
having an optical purity of at least 95% of the R enantiomer.
14. The compound of claim 1 , wherein the compound is:
and wherein the compound has an optical of at least 95% of the R enantiomer.
15. A pharmaceutical composition comprising the compound of claim 1 , and one or more pharmaceutically acceptable excipients or carriers.
16. The pharmaceutical composition of claim 15 , further comprising a second therapeutic agent.
17. The pharmaceutical composition of claim 16 , wherein the second therapeutic agent is an antidiabetic agent.
18. A method of treating one or more symptoms of a disease responsive to the modulation of a glucagon receptor in a subject, wherein the disease is diabetes, comprising administering to a subject in need thereof the compound of claim 1 .
19. A method of treating one or more symptoms of a disease responsive to a decrease in the hepatic glucose production or in the blood glucose level in a subject, wherein the disease is diabetes, comprising administering to a subject in need thereof the compound of claim 1 .