Glucagon antagonists

Patent metadata

Field	Value
Publication number	US-10076504-B2
Application number	US-201515317390-A
Country	US
Kind code	B2
Filing date	Jun 11, 2015
Priority date	Jun 12, 2014
Publication date	Sep 18, 2018
Grant date	Sep 18, 2018

Abstract

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.

First claim

What is claimed is:

1. An aqueous formulation comprising sulfobutylether 7-b-cyclodextrin and about 40 mg of 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.

2. The aqueous formulation 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 aqueous formulation of claim 1 , 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 aqueous formulation of claim 1 , 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 aqueous formulation of claim 1 , wherein R 44 is H or CH 3 .

6. The aqueous formulation of claim 1 , wherein R 45 is attached to the 3 (meta) or 4 (para) position.

7. The aqueous formulation of claim 1 , 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 aqueous formulation of claim 1 , wherein R 45 is substituted with one or more substituents independently selected from CH 3 and (CH 3 ) 3 C—.

9. The aqueous formulation of claim 1 , 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 aqueous formulation of claim 1 , wherein R 45 is trans-t-butylvinyl, cis-4-t-butylcyclohexyl, trans-4-t-butylcyclohexyl, 4,4-dimethylcyclohexyl, 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,4S)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 aqueous formulation of claim 1 , wherein R 45 is trans-t-butylvinyl, cis-4-t-butylcyclohexyl, trans-4-t-butylcyclohexyl, 4,4-dimethylcyclohexyl (S)-4-t-butylcyclohex-1-enyl, (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 aqueous formulation of claim 1 , wherein R 46 is 1-H or CH 3 .

13. The aqueous formulation of claim 1 , wherein the compound is selected from the group

14. The aqueous formulation of claim 1 , wherein the compound is

15. The aqueous formulation of claim 1 , wherein the compound is in the amount of 40 mg.

Assignees

• Ligand Pharm Inc

Inventors

• Zhi Lin

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title