5-HT2C receptor agonists and compositions and methods of use

Patent metadata

Field	Value
Publication number	US-10272094-B2
Application number	US-201615748205-A
Country	US
Kind code	B2
Filing date	Jul 28, 2016
Priority date	Jul 31, 2015
Publication date	Apr 30, 2019
Grant date	Apr 30, 2019

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 compound selected from compounds of Formula A, 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;
X is O or C(R 4 R 5 );
Y is O or C(R 6 R 7 );
wherein if X is O, Y is (CR 6 R 7 );
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.

2. The compound of claim 1 , wherein the compound is 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.

3. The compound 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.

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

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

6. The compound 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 8 cycloalkyl.

7. The compound of claim 6 , wherein R 2 and R 3 are each H.

8. The compound of claim 6 , wherein R 2 and R 3 are each methyl.

9. The compound 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.

10. The compound of claim 9 , wherein R 2 and R 3 taken together with the carbon connecting them form a 3-membered spirocyclic carbocyclic ring.

11. The compound of claim 1 , wherein X is CR 4 R 5 and 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.

12. The compound of claim 11 , wherein R 4 and R 5 are each methyl.

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

14. The compound of claim 13 , wherein R 4 and R 5 taken together with the carbon connecting them form a 3-membered spirocyclic carbocyclic ring.

15. The compound of claim 1 , wherein X is CR 4 R 5 , 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.

16. The compound of claim 1 , wherein X is CR 4 R 5 , 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.

17. The compound of claim 1 , wherein Y is CR 6 R 7 and R 6 and R 7 are each H.

18. The compound of claim 1 , wherein Y is CR 6 R 7 and R 6 and R 7 taken together with the carbon connecting them form a 3- to 6-membered spirocyclic carbocyclic ring.

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

20. The compound of claim 1 , wherein R 8 and R 9 are each H.

21. The compound of claim 2 , wherein the compound of Formula I is selected from compounds of Formula Ia, and pharmaceutically acceptable salts, solvates, and hydrates thereof:

wherein:
R 1 is selected from: H, C 1 -C 6 alkyl, halogen, O—C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl;
and
R 4 and R 5 are the same and each is H, C 1 -C 6 alkyl, 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.

22. The compound of claim 21 , wherein the compound of Formula Ia is selected from compounds of Formula Ia-i, and pharmaceutically acceptable salts, solvates, and hydrates thereof:

23. The compound of claim 21 , wherein the compound of Formula Ia is selected from compounds of Formula Ia-ii, and pharmaceutically acceptable salts, solvates, and hydrates thereof:

24. The compound of claim 2 , wherein the compound of Formula I is selected from compounds of Formula Ib, and pharmaceutically acceptable salts, solvates, and hydrates thereof:

wherein:
R 1 is selected from: H, C 1 -C 6 alkyl, halogen, O—C 1 -C 6 alkyl, and C 3 -C 8 cycloalkyl;
R 4 and R 5 are the same and each is H, C 1 -C 6 alkyl, 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;
and
n is 1, 2, 3, or 4.

25. The compound of claim 24 , wherein the compound of Formula Ib is selected from compounds of Formula Ib-i, and pharmace

Assignees

• Arena Pharm Inc

Inventors

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

Classifications

• A61K31/55 Primary

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

• C07D223/32

  containing carbocyclic rings other than six-membered · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title

• C07D491/052

  the oxygen-containing ring being six-membered · CPC title