Molecules that selectively inhibit histone deacetylase 6 relative to histone deacetylase 1

Patent metadata

Field	Value
Publication number	US-9499479-B2
Application number	US-201214349291-A
Country	US
Kind code	B2
Filing date	Oct 3, 2012
Priority date	Oct 3, 2011
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

Abstract

This invention provides a compound having the structure:

wherein
R 1 is H, halogen, —NR 5 R 6 , —NR 5 —C(═O)—R 6 , —NH—C(═O)—OR 7 , —OR 7 , —NO 2 , —CN, —SR 7 , —SO 2 R 7 , —CO 2 R 7 , CF 3 , —SOR 7 , —POR 7 , —C(═S)R 7 , —C(═O)—NR 5 R 6 , —CH 2 —C(═O)—NR 5 R 6 , —C(═NR 5 )R 6 , —P(═O)(OR 5 )(OR 6 ), —P(OR 5 )(OR 6 ), —C(═S)R 7 , C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, aryl, heteroaryl, or heterocyclyl,
wherein R 5 , R 6 , and R 7 and are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

m is an integer from 0 to 2;
R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl;
wherein X is Cl, Br, or F; R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Q is —Ar 1 —Z— or —Z—Ar 1 —Z—,
wherein Ar 1 is aryl or heteroaryl; and each occurrence of Z is independently present or absent, and when present is —O—, —S—, —CH 2 —, —C(O)— —NH—, —NH—NH—, —NHC(═O)—, —C(═O)NH—, —NHC(═O)CH 2 NH—, —NHC(═O)CH 2 C(═O)—, —N(OH)—, —CH 2 CH 2 — or —NHC(═O)CH═CH—; and

R 4 is alkyl, —OR 11 or —NH—OR 11 ,
wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl, and

when Q is —Ar 1 —Z—, Z is absent, Ar 1 is phenyl, R 2 and R 3 are H, n=1, and R 4 is —NHOH, then R 1 is other than carbazole, tetrahydro-β-carboline, tetrahydro-γ-carboline, —C(═O)—NR 5 R 6 and —NR 5 —C(═O)—R 6 , wherein one of R 5 or R 6 is quinoline and the other of R 5 or R 6 is H;

or a pharmaceutically acceptable salt thereof.

First claim

What is claimed is:

1. A compound having the structure:

wherein
R 1 is —NR 5 —C(═O)—R 6 or —C(═O)—NR 5 R 6 ,
wherein
R 5 is

R 6 is

wherein
X is a Cl, Br, or F; and
R 12 is H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

m is an integer from 0 to 2;
R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl;
wherein
X is Cl, Br, or F;
R 8 , R 9 and R 10 are each, independently, H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Q is —Ar 1 —Z— or —Z—Ar 1 —Z—,
wherein Ar 1 is

wherein X is a Cl, Br, or F; and

each Z is absent; and

R 4 is alkyl, —OR 11 or —NH—OR 11 ,
wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl,

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 having the structure:

wherein
R 1 is —NR 5 —C(═O)—R 6 or —C(═O)—NR 5 R 6 ,
wherein
R 5 is

R 6 is

wherein
X is a Cl, Br, or F; and
R 12 is H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

m is an integer from 0 to 2;
R 2 and R 3 are each, independently, H, halogen, —NH 2 , —CX 3 , —C(═O)OR 8 , C(═O)R 8 , —C(═O)NR 9 R 10 , C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroalkyl, aryl, heteroaryl, or heterocyclyl;
wherein
X is Cl, Br, or F;
R 8 , R 9 and R 10 are each, independently, H, C 1-5 alkyl, C 2-5 alkenyl, C 2-5 alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

Ar 1 is

wherein X is a Cl, Br, or F;

Z is absent; and
R 4 is —OR 11 or —NH—OR 11 ,
wherein R 11 is H, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, aryl, heteroaryl, or heterocyclyl,

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 ,
wherein R 4 is —OR 11 or —NH—OR 11 ,
wherein R 11 is H or CH 3 ,

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 2 ,
wherein R 4 is —OR 11 or —NH—OR 11 ,
wherein R 11 is H or CH 3 ,

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 ,
wherein m=1;
R 2 is H or CH 3 ; and
R 3 is H, CH 3 , Cl, Br, F, or CF 3 ,

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 2 ,
wherein m=1;
R 2 is H or CH 3 ; and
R 3 is H, CH 3 , Cl, Br, F, or CF 3 ,

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 ,
wherein
R 5 is

and
R 6 is

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 2 ,
wherein
R 5 is

and
R 6 is

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 having the structure:

or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

13. A method of inhibiting the activity of a histone deactylase in a cell comprising contacting the histone deacetylase with the compound of claim 1 so as to inhibit the activity of the histone deacetylase.

14. A method of inhibiting the activity of a histone deacetylase 6 (HDAC6) in a cell comprising contacting the histone deacetylase 6 with the compound of claim 1 so as to inhibit the activity of the histone deacetylase 6 in the cell.

15. A method of increasing accumulation of acetylated alpha tubulin in a cell comprising contacting the cell with the compound of claim 1 so as to increase the accumulation of acetylated alpha-tubulin in the cell.

16. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier.

17. A method of inhibiting the activity of a histone deactylase in a cell comprising contacting the histone deacetylase with the compound of claim 2 so as to inhibit the activity of the histone deacetylase.

18. A method of inhibiting the activity of a histone deacetylase 6 (HDAC6) in a cell comprising contacting the histone deacetylase 6 with the compound of claim 2 so as to inhibit the activity of the histone deacetylase 6 in the cell.

19. A method of increasing accumulation of acetylated alpha tubulin in a cell comprising contacting the cell with the compound of claim 2 so as to increase the accumulation of acetylated alpha-tubulin in the cell.

Assignees

• Breslow Ronald
• Marks Paul A
• Univ Columbia
• Sloan-Kettering Inst For Cancer Res

Inventors

• Breslow Ronald
• Marks Paul A

Classifications

• C07C259/10 Primary

  having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings · CPC title

• C07D215/40

  attached in position 8 · CPC title

• C07D209/08

  with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring · CPC title

• C07D209/24

  with an alkyl or cycloalkyl radical attached to the ring nitrogen atom · CPC title

• C07D215/06

  having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom · CPC title