Heterocyclic NMDA antagonists

Patent metadata

Field	Value
Publication number	US-11834409-B2
Application number	US-202218087233-A
Country	US
Kind code	B2
Filing date	Dec 22, 2022
Priority date	Nov 14, 2019
Publication date	Dec 5, 2023
Grant date	Dec 5, 2023

Abstract

A compound of formula (I), or a salt thereof that may have an antagonistic action against an NMDA receptor that includes an NR2B subunit and may be useful as a prophylactic or therapeutic agent for depression, bipolar disorder, migraine, pain, a symptom peripheral to dementia, or the like.

First claim

What is claimed is:

1. A compound which is (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one or a salt thereof.

2. A compound which is crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at 8.5°±0.2°, 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2° degrees two theta.

3. A compound which is crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at at least three degrees two theta chosen from 8.5°±0.2°, 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2° degrees two theta.

4. A compound which is crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at at least four degrees two theta chosen from 8.5°±0.2°, 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2° degrees two theta.

5. A compound which is crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at 5.1°±0.2°, 10.3°±0.2°, 14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2° and 25.2°±0.2° degrees two theta.

6. A compound which is crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at at least three degrees two theta chosen from 5.1°±0.2°, 10.3°±0.2°, 14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2° and 25.2°±0.2° degrees two theta.

7. A compound which is crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at at least four degrees two theta chosen from 5.1°±0.2°, 10.3°±0.2°, 14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2° and 25.2°±0.2° degrees two theta.

8. A pharmaceutical composition comprising (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one or a salt thereof, and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition according to claim 8 , the pharmaceutical composition comprising crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at 8.5°±0.2°, 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2° degrees two theta, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 8 , the pharmaceutical composition comprising crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at at least three degrees two theta chosen from 8.5°±0.2°, 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2° degrees two theta, and a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 8 , the pharmaceutical composition comprising crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at at least four degrees two theta chosen from 8.5°±0.2°, 11.2°±0.2°, 13.5°±0.2°, 14.6°±0.2°, 14.9°±0.2°, 19.8°±0.2°, 21.5°±0.2° and 22.5°±0.2° degrees two theta, and a pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 8 , the pharmaceutical composition comprising crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at 5.1°±0.2°, 10.3°±0.2°, 14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2° and 25.2°±0.2° degrees two theta, and a pharmaceutically acceptable carrier.

13. The pharmaceutical composition according to claim 8 , the pharmaceutical composition comprising crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at at least three degrees two theta chosen from 5.1°±0.2°, 10.3°±0.2°, 14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2° and 25.2°±0.2° degrees two theta, and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition according to claim 8 , the pharmaceutical composition comprising crystalline (4S,5S)-1-({6-[4-(difluoromethyl)-2-fluorophenoxy]pyridin-3-yl}methyl)-4-hydroxy-5-methylpyrrolidine-2-one, characterized by a powder X-ray diffraction pattern comprising peaks at at least four degrees two theta chosen from 5.1°±0.2°, 10.3°±0.2°, 14.3°±0.2°, 16.5°±0.2°, 17.6°±0.2°, 22.3°±0.2° and 25.2°±0.2° degrees two theta, and a pharmaceutically acceptable carrier.

15. A compound which is (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidine-2-one or a salt thereof.

16. A compound which is crystalline (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at 7.4°±0.2°, 10.3°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 19.5°±0.2°, 20.6°±0.2° and 21.3°±0.2° degrees two theta.

17. A compound which is crystalline (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at at least three degrees two theta chosen from 7.4°±0.2°, 10.3°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 19.5°±0.2°, 20.6°±0.2° and 21.3°±0.2° degrees two theta.

18. A compound which is crystalline (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at at least four degrees two theta chosen from 7.4°±0.2°, 10.3°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 19.5°±0.2°, 20.6θ+0.2θ and 21.3°±0.2θ degrees two theta.

19. A pharmaceutical composition comprising (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidine-2-one or a salt thereof and a pharmaceutically acceptable carrier.

20. The pharmaceutical composition according to claim 19 , the pharmaceutical composition comprising crystalline (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at 7.4°±0.20, 10.3°±0.2°, 10.5°±0.20, 14.5°±0.20, 16.4°±0.20, 17.8°±0.20, 18.6°±0.20, 19.5°±0.20, 20.6°±0.2° and 21.3°±0.2° degrees two theta, and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 19 , the pharmaceutical composition comprising crystalline (5S)-1-{[2-(2,4-difluorophenoxy)pyrimidin-5-yl]methyl}-5-methylpyrrolidine-2-one characterized by a powder X-ray diffraction pattern comprising peaks at at least three degrees two thetas of 7.4°±0.2°, 10.3°±0.2°, 10.5°±0.2°, 14.5°±0.2°, 16.4°±0.2°, 17.8°±0.2°, 18.6°±0.2°, 19

Assignees

• Takeda Pharmaceuticals Co

Inventors

• Ikeda Shuhei
• Kamata Makoto
• Oguro Yuya
• Murakami Masataka
• Nakamura Minoru
• Yamaguchi Fumie
• Yukawa Takafumi

Classifications

• C07D207/263 Primary

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title