5-HT2C receptor agonists and compositions and methods of use

Patent metadata

Field	Value
Publication number	US-10624900-B2
Application number	US-201916299880-A
Country	US
Kind code	B2
Filing date	Mar 12, 2019
Priority date	Jul 31, 2015
Publication date	Apr 21, 2020
Grant date	Apr 21, 2020

Abstract

Provided in some embodiments are compounds of Formula A, as defined herein, that modulate the activity of 5-HT2C receptor. Also provided in some embodiments are methods, such as, for 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, pathological gambling, reward deficiency syndrome, and sex addiction), obsessive-compulsive spectrum disorders and impulse control disorders (including nail-biting and onychophagia), sleep disorders (including insomnia, fragmented sleep architecture, and disturbances of slow-wave sleep), 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.

First claim

What is claimed is:

1. A process for preparing a compound selected from compounds of Formula I, and pharmaceutically acceptable salts, solvates, and hydrates thereof:

wherein:
R 1 is selected from: H, C 1 -C 6 alkyl optionally substituted with one or more halogens, halogen, O—C 1 -C 6 alkyl optionally substituted with one or more halogens, and C 3 -C 8 cycloalkyl;
R 2 and R 3 are each independently H, C 1 -C 6 alkyl optionally substituted with one or more halogens, or C 3 -C 8 cycloalkyl; or R 2 and R 3 taken together with the carbon connecting them form a 3- to 6-membered spirocyclic carbocyclic ring;
R 4 and R 5 are each independently H, C 1 -C 6 alkyl optionally substituted with one or more halogens, or C 3 -C 8 cycloalkyl; or R 4 and R 5 taken together with the carbon connecting them form a 3- to 6-membered spirocyclic carbocyclic ring;
or R 2 and R 5 are each H and R 3 and R 4 taken together with the carbons connecting them form a 3- to 6-membered carbocyclic ring;
R 6 and R 7 are each independently H, C 1 -C 6 alkyl optionally substituted with one or more halogens, or C 3 -C 8 cycloalkyl; or R 6 and R 7 taken together with the carbon connecting them form a 3- to 6-membered spirocyclic carbocyclic ring;
and
R 8 and R 9 are each independently H, C 1 -C 6 alkyl optionally substituted with one or more halogens, or halogen,
wherein the process comprises reacting a compound of the formula

wherein R 10 is benzyl optionally substituted with one or more halogens with a compound of the formula

to form a compound of the formula

2. The process of claim 1 , wherein R 10 is 3,4-dichlorobenzyl.

3. The process of claim 1 , wherein the compound of the formula

is reacted with a compound of the formula

in the presence of an acid.

4. The process of claim 1 , further comprising removing the group

in the compound of the formula

to form the compound selected from compounds of Formula I, and pharmaceutically acceptable salts, solvates, and hydrates thereof.

5. The process of claim 4 , wherein removing the group

comprises treating the compound of the formula

with a reducing agent.

6. The process of claim 5 , wherein the reducing agent comprises aluminum.

7. The process of claim 2 , further comprising admixing the compound selected from compounds of Formula I, and pharmaceutically acceptable salts, solvates, and hydrates thereof compound with a pharmaceutically acceptable carrier, to form a pharmaceutical composition.

8. The process of claim 1 , wherein R 1 is H, C 1 -C 6 alkyl, halogen, O—C 1 -C 6 alkyl, or C 3 -C 8 cycloalkyl.

9. The process of claim 1 , wherein R 1 is C 1 -C 6 alkyl substituted with one or more halogens.

10. The process of claim 1 , wherein R 1 is H, methyl, ethyl, fluorine, chlorine, bromine, methoxy, or cyclopropyl.

11. The process of claim 1 , wherein R 2 and R 3 are each independently H, C 1 -C 6 alkyl optionally substituted with one or more halogens, or C 3 -C 5 cycloalkyl.

12. The process of claim 11 , wherein R 2 and R 3 are each H.

13. The process of claim 11 , wherein R 2 and R 3 are each methyl.

14. The process of claim 1 , wherein R 2 and R 3 taken together with the carbon connecting them form a 3- to 6-membered spirocyclic carbocyclic ring.

15. The process of claim 14 , wherein R 2 and R 3 taken together with the carbon connecting them form a 3-membered spirocyclic carbocyclic ring.

16. The process of claim 1 , wherein R 4 and R 5 are each independently H, C 1 -C 6 alkyl optionally substituted with one or more halogens, or C 3 -C 8 cycloalkyl.

17. The process of claim 16 , wherein R 4 and R 5 are each methyl.

18. The process of claim 1 , wherein R 4 and R 5 taken together with the carbon connecting them form a 3- to 6-membered spirocyclic carbocyclic ring.

19. The process of claim 18 , wherein R 4 and R 5 taken together with the carbon connecting them form a 3-membered spirocyclic carbocyclic ring.

20. The process of claim 1 , wherein R 2 and R 5 are each H, and R 3 and R 4 taken together with the carbons connecting them form a 3- to 6-membered carbocyclic ring.

21. The process of claim 1 , wherein R 2 and R 5 are each H, and R 3 and R 4 taken together with the carbons connecting them form a 5-membered carbocyclic ring.

22. The process of claim 1 , wherein R 6 and R 7 are each H.

23. The process of claim 1 , wherein R 6 and R 7 taken together with the carbon connecting them form a 3- to 6-membered spirocyclic carbocyclic ring.

24. The process of claim 1 , wherein R 8 and R 9 are each independently H or halogen.

25. The process of claim 1 , wherein R 8 and R 9 are each H.

Assignees

• Arena Pharm Inc

Inventors

• Lehmann Juerg
• Feichtinger Konrad
• Ren Albert S
• Semple Graeme

Classifications

• C07D223/32

  containing carbocyclic rings other than six-membered · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• A61K31/55 Primary

  having seven-membered rings, e.g. azelastine, pentylenetetrazole · CPC title

• C07D223/16 Primary

  Benzazepines; Hydrogenated benzazepines · CPC title