Ethynyl derivatives

Patent metadata

Field	Value
Publication number	US-11059766-B2
Application number	US-201715829481-A
Country	US
Kind code	B2
Filing date	Dec 1, 2017
Priority date	Jun 3, 2015
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

The present invention relates to ethynyl derivatives of formula Iwith variables as defined herein, or to a pharmaceutically acceptable acid addition salt thereof.Compounds of formula I are metabotropic glutamate receptor antagonists (negative allosteric modulators) for use in the treatment of, e.g., anxiety and pain, depression, Fragile-X syndrome, autism spectrum disorders, Parkinson's disease, and gastroesophageal reflux disease (GERD).

First claim

The invention claimed is:

1. A compound of formula I

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen or F; and
n is 1 or 2.

2. A compound selected from the group consisting of:
(1S,5R)-2-methyl-4-(5-(phenylethynyl)pyridin-2-yl)-2,4-diazabicyclo[3.2.O]heptan-3-one;
(1R,5S)-2-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0] heptan-3-one;
(1R,5S)-2-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0] heptan-3-one; and
(1R,5S)-2-(5-((2,5-difluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0]heptan-3-one;
or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , wherein the compound is (1S,5R)-2-methyl-4-(5-(phenylethynyl)pyridin-2-yl)-2,4-diazabicyclo[3.2.0] heptan-3-one; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 , wherein the compound is (1R,5S)-2-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.O]heptan-3-one; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 2 , wherein the compound is (1R,5S)-2-(5-fluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.O]heptan-3-one; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 2 , wherein the compound is (1R,5S)-2-(5-((2,5-difluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0]heptan-3-one; or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert excipient.

8. A pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a therapeutically inert excipient.

9. The pharmaceutical composition of claim 8 , wherein the compound of the composition is (1S,5R)-2-methyl-4-(5-(phenylethynyl)pyridin-2-yl)-2,4-diazabicyclo[3.2.0]heptan-3-one, or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition of claim 8 , wherein the compound of the composition is (1R,5S)-2-(5-((4-fluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0]heptan-3-one, or a pharmaceutically acceptable salt thereof.

11. The pharmaceutical composition of claim 8 , wherein the compound of the composition is (1R,5S)-2-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0]heptan-3-one, or a pharmaceutically acceptable salt thereof.

12. The pharmaceutical composition of claim 8 , wherein the compound of the composition is (1R,5S)-2-(5-((2,5-difluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0]heptan-3-one, or a pharmaceutically acceptable salt thereof.

13. A method for the treatment of anxiety and pain, depression, Fragile-X syndrome, an autism spectrum disorder, Parkinson's disease, or gastro- esophageal reflux disease (GERD) in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

14. A method for the treatment of anxiety and pain, depression, Fragile-X syndrome, an autism spectrum disorder, Parkinson's disease, or gastro- esophageal reflux disease (GERD) in a patient, the method comprising administering to the patient in need thereof an effective amount of a compound of claim 2 , or a pharmaceutically acceptable salt thereof.

15. The method of claim 14 , wherein the administered compound is (1S,5R)-2-methyl-4-(5-(phenylethynyl)pyridin-2-yl)-2,4-diazabicyclo[3.2.0]heptan-3-one, or a pharmaceutically acceptable salt thereof.

16. The method of claim 14 , wherein the administered compound is (1R,5S)-2-(5((4-fluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0]heptan-3-one, or a pharmaceutically acceptable salt thereof.

17. The method of claim 14 , wherein the administered compound is (1R,5S)-2-(5-((3-fluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0]heptan-3-one, or a pharmaceutically acceptable salt thereof.

18. The method of claim 14 , wherein the administered compound is (1R,5S)-2-(5-((2,5-difluorophenyl)ethynyl)pyridin-2-yl)-4-methyl-2,4-diazabicyclo[3.2.0]heptan-3-one, or a pharmaceutically acceptable salt thereof.

Assignees

• Hoffmann La Roche

Inventors

• Jaeschke Georg
• Lindemann Lothar
• Ricci Antonio
• Vieira Eric

Classifications

• C07D401/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/4439 Primary

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• A61P1/00

  Drugs for disorders of the alimentary tract or the digestive system · CPC title

• C07D213/81

  Amides; Imides · CPC title

• A61K31/44

  Non condensed pyridines; Hydrogenated derivatives thereof · CPC title