Glucagon antagonists

• US 10,221,130 B2
• Filed: 09/29/2017
• Issued: 03/05/2019
• 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
• Primary Examiner(s): Gordon, Melenie L
• Assistant Examiner(s): Matos Negron, Taina D
• Application Number:
  US15/721,556
• Publication Number:
  US 20180022695A1
• Time in Patent Office: 522 Days
• Field of Search: 548224
• 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.

Claims

1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:

2. The pharmaceutical composition 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_1-6-alkyl, 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 pharmaceutical composition 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 pharmaceutical composition 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 pharmaceutical composition of claim 1, wherein R⁴⁴ is H or CH₃.

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

7. The pharmaceutical composition 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_1-6-alkyl or CF₃.

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

.

9. The pharmaceutical composition 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-.

10. The pharmaceutical composition of claim 1, wherein R⁴⁵ 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-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.

11. The pharmaceutical composition of claim 1, wherein R⁴⁵ is trans-1-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 pharmaceutical composition of claim 1, wherein R⁴⁶ is H or CH₃.

13. The pharmaceutical composition of claim 1, wherein the compound is selected from the group consisting of

14. The pharmaceutical composition of claim 1, wherein the compound is