Histone deacetylase inhibitors

Patent metadata

Field	Value
Publication number	US-9908899-B2
Application number	US-201615337354-A
Country	US
Kind code	B2
Filing date	Oct 28, 2016
Priority date	Feb 28, 2011
Publication date	Mar 6, 2018
Grant date	Mar 6, 2018

Abstract

The compounds provided herein are phenyl analine amides and are useful for inhibiting histone deacteylase (“HDAC”) enzymes, such as HDAC1, HDAC2, and HDAC3.

First claim

We claim:

1. A method of inhibiting HDAC1, HDAC2, or HDAC3 in a subject, comprising administering to the subject an effective amount of a compound having a structure of formula (II):

wherein:
R A is H or F;
R C is H, Cl, or F;
Het is selected from oxetanyl, azetindinyl, piperidinyl, and 8-azabicyclo[3.2.1]octanyl, and when Het is azetindinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, the ring nitrogen is substituted with R B ; and
R B is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, C 1 -C 3 alkylene-phenyl, or C 1 -C 3 alkylene-pyridyl; wherein the phenyl or pyridyl ring is optionally substituted with methyl;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein R A is H.

3. The method of claim 1 , wherein R A is F.

4. The method of claim 1 , wherein Het is oxetanyl.

5. The method of claim 1 , wherein Het is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl.

6. The method of claim 1 , wherein Het is azetindinyl or piperidinyl.

7. The method of claim 1 , wherein R B is C 1-6 alkyl, C 1-6 hydroxyalkyl, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -pyridyl, and the pyridyl is optionally substituted with methyl.

8. The method of claim 1 , wherein R B is methyl, CH 2 C(CH 3 ) 3 , CH 2 C(CH 3 ) 2 OH, CH 2 -cyclopropyl, CH 2 -phenyl, CH 2 -pyridyl, or CH 2 -methylpyridyl.

9. The method of claim 1 , wherein Het is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl; and R B is C 1-6 alkyl, C 1-6 hydroxyalkyl, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -pyridyl, or CH 2 -methylpyridyl.

10. The method of claim 9 , wherein Het is azetindinyl, and R B is C 1-6 alkyl, CH 2 C(CH 3 ) 2 OH, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -methylpyridyl.

11. The method of claim 9 , wherein Het is piperidinyl, and R B is C 1-6 alkyl, CH 2 C(CH 3 ) 2 OH, CH 2 -cyclopropyl, CH 2 -phenyl, CH 2 -pyridyl, or CH 2 -methylpyridyl.

12. The method of claim 9 , wherein Het is 8-azabicyclo [3.2.1]octanyl and R B is C 1-6 alkyl.

13. The method of claim 1 , wherein the subject suffers from a neurological disease.

14. The method of claim 13 , wherein the neurological disease is Friedreich's ataxia.

15. A method of treating a neurological disease or disorder selected from Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Alzheimer's disease; cutaneous T-cell lymphoma; a B cell lymphoma; colorectal cancer; psoriasis; rheumatoid arthritis; osteoarthritis; a long-term memory impairment condition; or a drug addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound having a structure of formula (II):

wherein:
R A is H or F;
R C is H, Cl, or F;
Het is selected from oxetanyl, azetindinyl, piperidinyl, and 8-azabicyclo[3.2.1]octanyl, and when Het is azetindinyl, piperidinyl, or 8-azabicyclo[3.2.1]octanyl, the ring nitrogen is substituted with R B ;
R B is C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 3 alkylene-C 3 -C 6 cycloalkyl, C 1 -C 3 alkylene-phenyl, or C 1 -C 3 alkylene-pyridyl; wherein the phenyl or pyridyl ring is optionally substituted with methyl;

or a pharmaceutically acceptable salt thereof.

16. The method of claim 15 , wherein Het is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl.

17. The method of claim 15 , wherein Het is azetindinyl or piperidinyl.

18. The method of claim 15 , wherein R B is C 1-6 alkyl, C 1-6 hydroxyalkyl, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -pyridyl, wherein the pyridyl is optionally substituted with methyl.

19. The method of claim 15 , wherein Het is azetindinyl, piperidinyl, or 8-azabicyclo [3.2.1]octanyl; and R B is C 1-6 alkyl, CH 2 C(CH 3 ) 2 OH, CH 2 -cyclopropyl, CH 2 -phenyl, or CH 2 -pyridyl, wherein the pyridyl is optionally substituted with methyl.

20. A method of treating a neurological disease or disorder selected from Friedreich's ataxia, myotonic dystrophy, spinal muscular atrophy, fragile X syndrome, Huntington's disease, spinocerebellar ataxia, Kennedy's disease, amyotrophic lateral sclerosis, spinal and bulbar muscular atrophy, and Alzheimer's disease; cutaneous T-cell lymphoma; a B cell lymphoma; colorectal cancer; psoriasis; rheumatoid arthritis; osteoarthritis; a long-term memory impairment condition; or a drug addiction in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

21. The method of claim 20 , wherein the disease or disorder is Friedreich's ataxia.

22. A method of inhibiting HDAC1, HDAC2, or HDAC3 in a subject, the method comprising administering to the subject an effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

23. The method of claim 22 , wherein the subject suffers from a neurological disease.

24. The method of claim 23 , wherein the neurological disease is Friedreich's ataxia.

Assignees

• Biomarin Pharm Inc

Inventors

• Jacques Vincent
• Rusche James R
• Peet Norton P
• Singh Jasbir

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P31/04

  Antibacterial agents · CPC title

• A61P25/34

  Tobacco-abuse · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title