Treatment of neuroblastoma with histone deacetylase inhibitors

Patent metadata

Field	Value
Publication number	US-2016339022-A1
Application number	US-201615130351-A
Country	US
Kind code	A1
Filing date	Apr 15, 2016
Priority date	Apr 17, 2015
Publication date	Nov 24, 2016
Grant date	—

Abstract

Provided herein are combinations comprising an HDAC inhibitor and retinoic acid for the treatment of neuroblastoma in a subject in need thereof. Also provided herein are methods for treating neuroblastoma in a subject in need thereof, comprising administering to the subject an effective amount of the above HDAC inhibitor or combination, comprising administering to the subject in need thereof an effective amount of the above HDAC inhibitor or combination. Also provided herein is a method for predicting whether a neuroblastoma patient will respond to treatment with a combination comprising an HDAC inhibitor and retinoic acid.

First claim

1 - 10 . (canceled)

11 . A method for treating neuroblastoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination comprising an HDAC inhibitor or a pharmaceutically acceptable salt thereof, and retinoic acid or a pharmaceutically acceptable salt thereof.

12 . The method of claim 11 , wherein the retinoic acid is ATRA.

13 . The method of claim 11 , wherein the HDAC inhibitor is an HDAC1/2 inhibitor.

14 . The method of claim 11 , wherein the HDAC inhibitor is a compound of Formula I:

or a pharmaceutically acceptable salt thereof,
wherein,
ring B is aryl or heteroaryl;
R 1 is an aryl or heteroaryl, each of which may be optionally substituted by OH, halo, or C 1-6 -alkyl; and
R is H or C 1-6 -alkyl.

15 . The method of claim 14 , wherein R 1 is an aryl or heteroaryl, each of which is substituted by halo.

16 . The method of claim 15 , wherein the compound of Formula I is:

or a pharmaceutically acceptable salt thereof.

17 . The method of claim 13 , wherein the HDAC1/2 inhibitor is an HDAC1/2-specific inhibitor.

18 . The method of claim 17 , wherein the HDAC1/2-specific inhibitor is a compound of Formula II:

or a pharmaceutically acceptable salt thereof,
wherein,
R 1 is aryl or heteroaryl;
R 2 and R 3 are each independently selected from C 3-6 -cycloalkyl, C 1-6 -alkyl-OR 6 , C 1-6 -alkyl-C 3-6 -cycloalkyl, C 1-6 -alkyl-heterocycloalkyl, C 2-6 -alkenyl;
R 6 is H or C 1-6 -alkyl; and
R 7 is H or C 3-6 -cycloalkyl.

19 . The method of claim 18 , wherein the compound of Formula II is:

or a pharmaceutically acceptable salt thereof.

20 . The method of claim 11 , wherein the HDAC inhibitor is:

or a pharmaceutically acceptable salt thereof.

21 . The method of claim 11 , wherein the subject was previously refractory to ATRA.

22 - 35 . (canceled)

36 . A method for treating neuroblastoma in a subject in need thereof comprising administering to the subject a therapeutically effective amount of an HDAC1/2 inhibitor inhibitor or a pharmaceutically acceptable salt thereof.

37 - 40 . (canceled)

41 . The method of claim 36 , wherein the HDAC1/2 inhibitor is an HDAC1/2-specific inhibitor.

42 . The method of claim 41 , wherein the HDAC1/2-specific inhibitor is a compound of Formula II:

or a pharmaceutically acceptable salt thereof,
wherein,
R 1 is aryl or heteroaryl;
R 2 and R 3 are each independently selected from C 3-6 -cycloalkyl, C 1-6 -alkyl-OR 6 , C 1-6 -alkyl-C 3-6 -cycloalkyl, C 1-6 -alkyl-heterocycloalkyl, C 2-6 -alkenyl;
R 6 is H or C 1-6 -alkyl; and
R 7 is H or C 3-6 -cycloalkyl.

43 . The method of claim 42 , wherein the compound of Formula II is:

or a pharmaceutically acceptable salt thereof.

44 . The method of claim 36 , wherein the HDAC1/2 inhibitor is:

or a pharmaceutically acceptable salt thereof.

45 . The method of claim 36 , further comprising administering to the subject a therapeutically effective amount of all-trans-retinoic acid or 13-cis-retinoic acid, or pharmaceutically acceptable salts thereof.

Assignees

• Acetylon Pharmaceuticals Inc

Inventors

• Tamang David Lee
• Jones Simon S
• Yang Min

Classifications

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/505 Primary

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

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/203

  Retinoic acids {; Salts thereof} · CPC title

• A61P35/00

  Antineoplastic agents · CPC title