5-HT2C receptor agonists and compositions and methods of use

Patent metadata

Field	Value
Publication number	US-11608339-B2
Application number	US-202017073458-A
Country	US
Kind code	B2
Filing date	Oct 19, 2020
Priority date	Aug 19, 2016
Publication date	Mar 21, 2023
Grant date	Mar 21, 2023

Abstract

The present invention relates to compounds of Formula A and pharmaceutical compositions thereof that modulate the activity of the 5-HT2C receptor. Compounds of the present invention and pharmaceutical compositions thereof are directed to methods useful in the treatment of a 5-HT2C receptor-mediated disorder, such as, weight management, inducing satiety, and decreasing food intake, and for preventing and treating obesity, antipsychotic-induced weight gain, type 2 diabetes, Prader-Willi syndrome, tobacco/nicotine dependence, drug addiction, alcohol addiction and the like, obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders, urinary incontinence, psychiatric disorders (including schizophrenia, anorexia nervosa, and bulimia nervosa), Alzheimer disease, sexual dysfunction, erectile dysfunction, epilepsy, movement disorders (including parkinsonism and antipsychotic-induced movement disorder), hypertension, dyslipidemia, nonalcoholic fatty liver disease, obesity-related renal disease, and sleep apnea. Also provided are compositions comprising a compound herein, optionally in combination with a supplemental agent.

First claim

What is claimed is:

1. A compound selected from the group consisting of

Compound

No.
Chemical Structure
Chemical Name

106

(R)-4-benzyl- 6,6a,7,8,9,10- hexahydro-5H- pyrazino[1,2- a][1,8]naphthyridine

116

(R)-4-(2-fluorobenzyl)- 6,6a,7,8,9,10- hexahydro- 5H-pyrazino[1,2- a][1,8]naphthyridine

152

(R)-4-(3,3,3- trifluoropropyl)- 6,6a,7,8,9,10- hexahydro-5H- pyrazino[1,2-a]- [1,8]naphthyridine

175

(R)-7,7-dimethyl- 1,2,3,4,4a,5,6,7- octahydronaphtho[1,8- cd]azepine

176

(R)-4- (cyclobutylmethyl)- 6,6a,7,8,9,10- hexahydro- 5H-pyrazino[1,2- a][1,8]naphthyridine

and pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein the compound is selected from the group consisting of: (R)-4-benzyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 106), and pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 , wherein the compound is selected from the group consisting of: (R)-4-(2-fluorobenzyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 116), and pharmaceutically acceptable salts thereof.

4. The compound according to claim 1 , wherein the compound is selected from the group consisting of: (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 152), and pharmaceutically acceptable salts thereof.

5. The compound according to claim 1 , wherein the compound is selected from the group consisting of: (R)-7,7-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphtho[1,8-cd]azepine (Compound 175), and pharmaceutically acceptable salts thereof.

6. The compound according to claim 1 , wherein the compound is selected from the group consisting of: (R)-4-(cyclobutylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 176), and pharmaceutically acceptable salts thereof.

7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

8. A method for decreasing food intake in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of claim 1 .

9. A method for the treatment of type 2 diabetes, drug and alcohol addiction, or a seizure disorder in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a compound of claim 1 .

10. The method according to claim 8 , wherein the compound is selected from the group consisting of: (R)-4-benzyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 106), and pharmaceutically acceptable salts thereof.

11. The method according to claim 8 , wherein the compound is selected from the group consisting of: (R)-4-(2-fluorobenzyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 116), and pharmaceutically acceptable salts thereof.

12. The method according to claim 8 , wherein the compound is selected from the group consisting of: (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 152), and pharmaceutically acceptable salts thereof.

13. The method according to claim 8 , wherein the compound is selected from the group consisting of: (R)-7,7-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphtho[1,8-cd]azepine (Compound 175), and pharmaceutically acceptable salts thereof.

14. The method according to claim 8 , wherein the compound is selected from the group consisting of: (R)-4-(cyclobutylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 176), and pharmaceutically acceptable salts thereof.

15. The method according to claim 9 , wherein the compound is selected from the group consisting of: (R)-4-benzyl-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 106), and pharmaceutically acceptable salts thereof.

16. The method according to claim 9 , wherein the compound is selected from the group consisting of: (R)-4-(2-fluorobenzyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 116), and pharmaceutically acceptable salts thereof.

17. The method according to claim 9 , wherein the compound is selected from the group consisting of: (R)-4-(3,3,3-trifluoropropyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 152), and pharmaceutically acceptable salts thereof.

18. The method according to claim 9 , wherein the compound is selected from the group consisting of: (R)-7,7-dimethyl-1,2,3,4,4a,5,6,7-octahydronaphtho[1,8-cd]azepine (Compound 175), and pharmaceutically acceptable salts thereof.

19. The method according to claim 9 , wherein the compound is selected from the group consisting of: (R)-4-(cyclobutylmethyl)-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,8]naphthyridine (Compound 176), and pharmaceutically acceptable salts thereof.

20. A method for the treatment of obesity, comprising administering to said individual a therapeutically effective amount of a compound of claim 1 .

Assignees

• Arena Pharm Inc

Inventors

• Semple Graeme
• Ren Albert S
• Schrader Thomas O
• Kasem Michelle
• Zhu Xiuwen

Classifications

• C07D471/14 Primary

  Ortho-condensed systems · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P3/00 Primary

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• A61P25/34

  Tobacco-abuse · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title