VMAT2 inhibitor compounds and compositions thereof

• US 11,040,970 B2
• Filed: 04/17/2018
• Issued: 06/22/2021
• Est. Priority Date: 04/19/2017
• Status: Active Grant

• Current Assignee: Neurocrine Biosciences Inc.
• Original Assignee: Neurocrine Biosciences Inc.
• Inventors: Harriott, Nicole, Hettinger, Donald, Branum, Shawn, Culhane, Jeffrey C.
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US16/606,191
• Publication Number:
  US 20200131173A1
• Time in Patent Office: 1,162 Days
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

Provided is a compound selected from compounds of Formula (I) and pharmaceutically acceptable salts, solvates, and hydrates thereof: (I) wherein R¹, R², R³ and R⁴ are as defined herein. Such compounds are inhibitors of the vesicular monoamine transporter 2 (VMAT2) and have utility for treating, for example, neurological and psychiatric diseases and disorders. Also disclosed are compositions containing such compounds in combination with a pharmaceutically acceptable carrier, as well as methods relating to their use in subjects in need thereof.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

2. The compound of claim 1, selected from a compound of Formula (II) or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

3. The compound of claim 1, wherein R² is C_1-4 saturated alkyl.

4. The compound of claim 3, wherein R² is methyl.

5. The compound of claim 2, wherein R³ is methyl, ethyl, n-propyl, iso-propyl, iso-butyl, or neo-pentyl.

6. The compound of claim 5, wherein R³ is methyl.

7. The compound of claim 2, wherein R⁴ is C_1-6 saturated alkyl.

8. The compound of claim 2, wherein R⁴ is iso-butyl, neo-pentyl, —

CH₂-cyclopropyl, or —

CH₂-cyclobutyl.

9. The compound of claim 1, selected from a compound of Formula (V) or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

10. The compound of claim 1, selected from a compound of Formula (VI) or a pharmaceutically acceptable salt, solvate, or hydrate thereof:

11. The compound of claim 2, wherein R¹ is lower alkyl or lower cycloalkyl, wherein each lower alkyl and lower cycloalkyl is independently unsubstituted or substituted with one or more halo, cyano, or lower alkoxy.

12. The compound of claim 2, wherein R¹ is methyl, ethyl, n-propyl, iso-propyl, iso-butyl, neo-pentyl, —

(CH₂)₃CH₂F, —

(CH₂)₂CH₂F, —

CH₂CH₂F, —

(CH₂)₄CF₃, —

(CH₂)₃CF₃, —

(CH₂)₂CF₃, —

CH₂CF₃, cyclopropyl, cyclobutyl, —

CH₂-cyclopropyl, —

CH₂-cyclobutyl, or —

CH₂-cyclopentyl.

13. The compound of claim 2, wherein R¹ is C_1-4 saturated alkyl substituted with C_1-4 saturated alkoxy, R¹ is C_1-4 saturated alkyl substituted with a cyano group, or R¹ is lower cycloalkylalkyl substituted with halo.

14. The compound of claim 13, wherein R¹ is —

CH₂CH₂OCH₃ or R¹ is —

CH₂CH₂CH₂CN.

15. The compound of claim 13, wherein R¹ is:

16. The compound of claim 1, selected from

17. The compound of claim 1, selected from

18. The compound of claim 17, selected from

19. The compound of claim 18, which is a diphosphate salt, or a solvate or hydrate thereof.

20. The compound of claim 17, selected from

21. The compound of claim 17, which is

22. The compound of claim 17, which is

23. The compound of claim 17, which is

24. A pharmaceutical composition comprising one or more compounds of claim 2 in combination with one or more pharmaceutically acceptable excipients and/or diluents.

25. A process for preparing a composition comprising admixing a compound of claim 2 and one or more pharmaceutically acceptable excipients and/or diluents.

26. A process for preparing a compound of Structure vi having formula:

27. The process of claim 26, wherein:

in step a) the reacting the compound of Structure iii, or a salt thereof, under reductive amination conditions comprises reacting the compound of Structure iii, or a salt thereof, with paraformaldehyde in the presence of acetic acid, and then treating with a reducing agent;

in step b) cyclizing the compound of Structure iv, or a salt thereof, under acidic conditions comprises reacting the compound of Structure iv with concentrated sulfuric acid; and

in step c) the reducing the compound of Structure v, or a salt thereof, is performed using a reducing agent where the reducing agent is lithium aluminum hydride.

28. A process for preparing Compound 11-2 having formula:

29. The process of claim 28, wherein:

in step a) the reacting the compound of Structure 11b, or a salt thereof, under reductive amination conditions comprises reacting the compound of Structure 11b, or a salt thereof, with 2,2-dimethoxyacetaldehyde in the presence of acetic acid, and then treating with sodium cyanoborohydride;

in step b) the reacting the compound of Structure 11c, or a salt thereof, under reductive amination conditions comprises reacting the compound of Structure 11c, or a salt thereof, with paraformaldehyde in the presence of acetic acid, and then treating with sodium cyanoborohydride;

in step c) the cyclizing the compound of Structure 11d, or a salt thereof, under acidic conditions comprises treating the compound of Structure 11d, or a salt thereof, with concentrated sulfuric acid; and

in step d) the reducing the compound of Structure 11e, or a salt thereof, is performed using a reducing agent where the reducing agent is lithium aluminum hydride.