GLUCAGON ANTAGONISTS

• US 20150087680A1
• Filed: 11/26/2014
• Published: 03/26/2015
• Est. Priority Date: 08/13/2008
• Status: Active Grant

• Current Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.)
• Original Assignee: Metabasis Therapeutics, Inc. (Ligand Pharmaceuticals, Inc.)
• Inventors: Gomez-Galeno, Jorge E., Hecker, Scott J., Dang, Qun, Reddy, Mali Venkat, Sun, Zhili, Grote, Matthew P., Nguyen, Thanh Huu, Lemus, Robert Huerta, Li, Haiqing
• Granted Patent: US 9,783,494 B2
• Time in Patent Office: Days
• US Class Current: 514/375
• CPC Class Codes: A61K 31/185 Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids hydroxamic acids A61K31/16; peroxy acids A61K31/327
• CPC Class Codes: A61K 31/423 condensed with carbocyclic rings
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 Antihypertensives
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2601/16 : the ring being unsaturated
• CPC Class Codes: C07C 309/15 : the nitrogen atom of at least one of the amino groups being part of any of the groups , X being a hetero atom, Y being any atom
• CPC Class Codes: C07D 263/57 : Aryl or substituted aryl radicals

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. Formula I

Claims

1. A compound of Formula I:

2. The compound of claim 1, wherein:

R⁴⁴ is H, CH₃ or CH₃CH₂;

R⁴⁵ 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_1-6alkyl, CF₃, F, CN or OCF₃;

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, CH₃, CF₃, OCF₃ or CN; and

R⁴⁶ is H, F, Cl, CH₃, CF₃, OCF₃ or CN.

3. The compound 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, CH3, CF3, OCF3 or CN.

4. The compound 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 compound of claim 1, wherein R⁴⁴ is H or CH₃.

6. The compound of claim 1, wherein R⁴⁴ is H.

7. The compound of claim 1, wherein R⁴⁵ is attached to the 3 (meta) or 4 (para) position.

8. The compound of claim 1, wherein R⁴⁵ 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_1-6alkyl or CF₃.

9. The compound of claim 1, wherein R⁴⁵ is substituted with one or more substituents independently selected from CH₃ and (CH₃)₃C—

.

10. The compound of claim 1, wherein R⁴⁵ is selected from (CH₃)₃CCH═

CH—

, t-butyl-cycloalkyl-, dimethyl-cycloalkyl-, t-butyl-cycloalkenyl-, dimethyl-cycloalkenyl-, bicycloalkenyl- or t-butyl-phenyl-.

11. The compound of claim 1, wherein R⁴⁵ 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, 4,4dipropylcyclohex-1-enyl, 4,4-dipropylcyclohexyl, 4,4-dimethylcyclohexa-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.

12. The compound of claim 1, wherein is R⁴⁵ is trans-t-butylvinyl, cis-4-t-butylcyclohexyl, trans-4-t-butylcyclohexyl, 4,4-dimethylcyclohexyl, (S)-4-t-butylcyclohex-1enyl, (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.

13. The compound of claim 1, wherein R⁴⁶ is H or CH₃.

14. The compound of claim 1, wherein the compound is selected from the group

15. The compound of claim 1, wherein the compound is:

16. A pharmaceutical composition comprising the compound of claim 1, and one or more pharmaceutically acceptable excipients or carriers.

17. The pharmaceutical composition of claim 16, further comprising a second therapeutic agent.

18. The pharmaceutical composition of claim 16, wherein the second therapeutic agent is an antidiabetic agent.

19. A pharmaceutical composition comprising the compound of claim 1 and cyclodextrin.

20. A method of treating one or more symptoms of a disease responsive to the modulation of a glucagon receptor in a subject, comprising administering to a subject in need thereof a compound of Formula I:

21. The method of claim 20, wherein the disease is at least one selected from the group consisting of obesity, type 1 diabetes, type 2 diabetes, gestational diabetes, ketoacidosis, nonketotic hyperosmolar coma, nonketotic hyperglycemia, hyperchoi esterolemia, dyslipidemia, arteriosclerosis, atherosclerosis, glucagonomas, acute pancreatitis, hypertension, cardiac hypertrophy, vascular restenosis, pancreatitis, retinopathy, nephropathy, neuropathy, accelerated gluconeogenesis, hyperlipidemia, hypertriglyceridemia, metabolic syndrome X, impaired glucose tolerance, stroke, coronary artery disease, cardiovascular disease

22. The method of claim 20, wherein the disease is type 1 diabetes or type 2 diabetes.

23. 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 of a subject, comprising administering to a subject in need thereof a compound of Formula I:

24. The method of claim 23, wherein the disease is at least one selected from the group consisting of obesity, type 1 diabetes, type 2 diabetes, gestational diabetes, ketoacidosis, nonketotic hyperosmolar coma, nonketotic hyperglycemia, hyperchoi esterolemia, dyslipidemia, arteriosclerosis, atherosclerosis, glucagonomas, acute pancreatitis, hypertension, cardiac hypertrophy, vascular restenosis, pancreatitis, retinopathy, nephropathy, neuropathy, accelerated gluconeogenesis, hyperlipidemia, hypertriglyceridemia, metabolic syndrome X, impaired glucose tolerance, stroke, coronary artery disease, cardiovascular disease

25. The method of claim 23, wherein the disease is type 1 diabetes or type 2 diabetes.