Inhibitors of histone deacetylase

Patent metadata

Field	Value
Publication number	US-2016272579-A1
Application number	US-201415034276-A
Country	US
Kind code	A1
Filing date	Nov 5, 2014
Priority date	Nov 5, 2013
Publication date	Sep 22, 2016
Grant date	—

Abstract

The present invention relates to compounds which inhibit histone deacetylase activity and methods of synthesizing these compounds. The present invention also relates to pharmaceutical compositions containing these compounds. The present invention also relates to methods of treating and preventing hematological cell proliferative disorders, such as multiple myeloma, by administering these compounds and pharmaceutical compositions to subjects in need thereof.

First claim

1 . A compound of formula I:

wherein;
Ar is unsubstituted or substituted phenyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyrimidinyl, unsubstituted or substituted pyridinyl, unsubstituted or substituted quinolinyl, unsubstituted or substituted isoquinolinyl, unsubstituted or substituted quinazolinyl, or unsubstituted or substituted quinoxalinyl;
R 1 and R 2 are each independently H, hydroxyl, cyano, halogen, unsubstituted or substituted amino, unsubstituted or substituted C 1 -C 6 alkyl, or unsubstituted or substituted C 1 -C 6 alkoxy;
each R is independently hydroxyl, cyano, halogen, unsubstituted or substituted amino, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, or unsubstituted or substituted C 6 -C 10 aryl; and
x is 0, 1, 2, or 3;
provided that when Ar is unsubstituted pyrazinyl, x is not 0,

or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

2 . The compound of claim 1 , wherein Ar is substituted phenyl.

3 . The compound of claim 1 , wherein Ar is unsubstituted or substituted pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.

4 . The compound of claim 1 , wherein Ar is unsubstituted or substituted pyrimidin-5-yl.

5 . The compound of claim 1 , wherein Ar is unsubstituted or substituted pyrazinyl.

6 . The compound of claim 1 , wherein R 1 is H and R 2 is hydroxyl or unsubstituted or substituted amino.

7 . The compound of claim 1 , wherein R 1 is halogen and R 2 is hydroxyl or unsubstituted or substituted amino.

8 . The compound of claim 1 , wherein R 2 is H and R 1 is halogen.

9 . The compound of claim 1 , wherein x is 1, 2, or 3.

10 . The compound of claim 1 , having formula Ia, Ib, or Ic:

wherein;
Ar is unsubstituted or substituted phenyl, unsubstituted or substituted pyrazinyl, unsubstituted or substituted pyrimidinyl, or unsubstituted or substituted pyridinyl;
R 1 and R 2 are each independently H, hydroxyl, cyano, halogen, unsubstituted or substituted amino, unsubstituted or substituted C 1 -C 6 alkyl, or unsubstituted or substituted C 1 -C 6 alkoxy;
each R is independently hydroxyl, cyano, halogen, unsubstituted or substituted amino, unsubstituted or substituted C 1 -C 6 alkyl, unsubstituted or substituted C 1 -C 6 alkoxy, or unsubstituted or substituted C 6 -C 10 aryl;
Y is halogen;
x is 0, 1, 2, or 3; and
xt is 0, 1, 2, or 3,
provided that when Ar is unsubstituted pyrazinyl, xt is not 0, or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

11 . The compound of claim 1 , selected from the group consisting of

or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof.

12 . The compound of claim 1 , wherein the compound is an inhibitor of a histone deacetylase.

13 . The compound of claim 12 , wherein the compound is a selective class-I histone deacetylase inhibitor.

14 . The compound of claim 13 , wherein the compound is a selective histone deacetylase 1, 2, and 3 inhibitor.

15 . The compound of claim 14 , wherein the compound is a selective histone deacetylase 3 inhibitor.

16 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, ester, solvate or prodrug thereof, and a pharmaceutically acceptable carrier.

17 . A method of treating a hematological cell proliferative disorder in a subject, comprising administering to the subject an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt, ester, solvate, or prodrug thereof, and a pharmaceutically acceptable carrier.

18 . The method of claim 17 , wherein the hematological cell proliferative disorder is a multiple myeloma.

19 . The method of claim 18 , further comprising administering to the subject a second therapeutic agent.

20 . The method of claim 19 , wherein the second therapeutic agent is selected from the group consisting of an HDAC inhibitor, a proteasomal inhibitor, a deubiquitinase inhibitor, a demethylase inhibitor, an endoplasmic reticulum (ER) stressor, a JNK inhibitor, and a caspase inhibitor.

21 . The method of claim 20 , wherein the second therapeutic agent is a proteasomal inhibitor.

22 . The method of claim 21 , wherein the proteasomal inhibitor is bortezomib.

Assignees

• Dana Farber Cancer Inst Inc
• Massachusetts Gen Hospital

Inventors

• Mazitschek Ralph
• Hideshima Teru
• Anderson Kenneth C
• Haggarty Stephen J
• Ghosh Balaram

Classifications

• A61K31/505

  Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim · CPC title

• C07D213/82

  in position 3 · CPC title

• C07C237/40 Primary

  having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring · CPC title

• A61K31/4409

  only substituted in position 4, e.g. isoniazid, iproniazid · CPC title

• A61K31/167 Primary

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title