COMBINATIONS OF CLASS-I SPECIFIC HISTONE DEACETYLASE INHIBITORS WITH PROTEASOME INHIBITORS

• US 20090270419A1
• Filed: 09/11/2007
• Published: 10/29/2009
• Est. Priority Date: 09/15/2006
• Status: Abandoned Application

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Page, Martin John, Hellemans, Peter Willem Jan, Arts, Janine, Janicot, Michel Marie Francois
• Application Number:
  US12/441,236
• Publication Number:
  US 20090270419A1
• Time in Patent Office: Days
• US Class Current: 514/255.50
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 38/05 Dipeptides
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention is concerned with combinations of a proteasome inhibitor and a class-I specific histone deacetylase inhibitor for inhibiting the growth of tumor cells, useful in the treatment of cancer.

Claims

1. A combination of a proteasome inhibitor and a histone deacetylase inhibitor of formula (I)

the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein

is a radical selected from

R⁵ is selected from hydrogen;

thienyl;

thienyl substituted with di(C_1-6alkyl)aminoC_1-6alkyl, or C_1-16alkylpiperazinylC_1-6alkyl;

furanyl;

phenyl;

phenyl substituted with one substituents independently selected from di(C_1-4alkyl)aminoC_1-4alkyloxy, di(C_1-4alkyl)amino, di(C_1-4alkyl)aminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl(C_1-4alkyl)aminoC_1-4alkyl, pyrrolidinylC_1-4alkyl, pyrrolidinylC_1-4alkyloxy or C_1-14alkylpiperazinylC_1-4alkyl.

3. A combination as claimed in claim 1 wherein the histone deacetylase inhibitor of formula (I) is R306465 (Compound No. 6)

4. A combination as claimed in claim 1 wherein the proteasome inhibitor is bortezomib.

5. A combination as claimed in claim 1 in the form of a pharmaceutical composition comprising a proteasome inhibitor and a histone deacetylase inhibitor of formula (I) together with one or more pharmaceutical carriers.

6. A combination as claimed in claim 5 for simultaneous, separate or sequential use.

13. A method for the characterisation of a histone deacetylase inhibitor of formula (I) as defined in claim 1, either alone or in combination with a proteasome inhibitor, said method comprising the determination in a sample, of the amount of induction of acetylation of histones or other proteins, or of the induction of proteins functionally regulated by said acetylation.

14. A method for the characterisation of a histone deacetylase inhibitor of formula (I) as defined in claim 1, either alone or in combination with a proteasome inhibitor, comprising the determination in a sample of the amount of

a) induction of acetylation of histone 3, induction of acetylation of histone 4, or induction of p21 and

b) induction of acetylation of alpha-tubulin, induction of acetylation of Hsp 90, or induction of Hsp 70.

17. A combination as claimed in claim 3 wherein the proteasome inhibitor is bortezomib.

19. A combination as claimed in claim 3 in the form of a pharmaceutical composition comprising a proteasome inhibitor and a histone deacetylase inhibitor of formula (I) together with one or more pharmaceutical carriers.

20. A combination as claimed in claim 4 in the form of a pharmaceutical composition comprising a proteasome inhibitor and a histone deacetylase inhibitor of formula (I) together with one or more pharmaceutical carriers.

2. A combination of a proteasome inhibitor and a histone deacetylase inhibitor wherein the histone deacetylase inhibitor is selected from compounds No. 6 (R306465), No. 100, No. 104, No. 128, No. 144, No. 124, No. 154, No. 125, No. 157, No. 156, No. 159, No. 163, No. 164, No. 168, No. 169, No. 127, No. 171, No. 170, No. 172 and No. 173:

15. A combination as claimed in claim 2 wherein the histone deacetylase inhibitor of formula (I) is R306465 (Compound No. 6)

16. A combination as claimed in claim 2 wherein the proteasome inhibitor is bortezomib.

18. A combination as claimed in claim 2 in the form of a pharmaceutical composition comprising a proteasome inhibitor and a histone deacetylase inhibitor of formula (I) together with one or more pharmaceutical carriers.

7. (canceled)

8. (canceled)

9. A method for the treatment of acute lymphoblastic leukemia, acute myelogenous leukemia, acute promyelocytic leukemia, acute myeloid leukemia, acute monocytic leukemia, lymphoma, chronic B cell leukemia, chronic myeloid leukemia, chronic myeloid leukemia in blast crisis, Burkitt'"'"'s lymphoma and multiple myeloma in a subject in need of treatment, said method comprising administering a therapeutically effective amount of a histone deactylase inhibitor is a compound of formula (I):

the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein

is a radical selected from

R⁵ is selected from hydrogen;

thienyl;

thienyl substituted with di(C_1-6alkyl)aminoC_1-6alkyl, or C_1-16alkylpiperazinylC_1-6alkyl;

furanyl;

phenyl;

phenyl substituted with one substituents independently selected from di(C_1-4alkyl)aminoC_1-4alkyloxy, di(C_1-4alkyl)amino, di(C_1-4alkyl)aminoC_1-4alkyl, di(C_1-4alkyl)aminoC_1-4alkyl(C_1-14alkyl)aminoC_1-4alkyl, pyrrolidinylC_1-4alkyl, pyrrolidinylC_1-4alkyloxy or C_1-14alkylpiperazinylC_1-4alkyl.

11. The method of claim 9, wherein said method is for treatment of bortezomib resistant multiple myeloma.

12. The method of claim 9 further comprising the induction of hyperacetylation of histones or the induction of proteins functionally regulated by said acetylation for a beneficial effect for the treatment of human cancer.

10. A method for the treatment of drug resistant acute lymphoblastic leukemia, drug resistant acute myelogenous leukemia, drug resistant acute promyelocytic leukemia, drug resistant acute myeloid leukemia, drug resistant acute monocytic leukemia, drug resistant lymphoma, drug resistant chronic B cell leukemia, drug resistant chronic myeloid leukemia, drug resistant chronic myeloid leukemia in blast crisis, drug resistant Burkitt'"'"'s lymphoma and drug resistant multiple myeloma in a subject in need of treatment, said method comprising administering a therapeutically effective amount of a histone deactylase inhibitor is a compound of formula (I):

the pharmaceutically acceptable acid or base addition salts and the stereochemically isomeric forms thereof, wherein

is a radical selected from

R⁵ is selected from hydrogen;

thienyl;

thienyl substituted with di(C_1-6alkyl)aminoC_1-6alkyl, or C_1-6alkylpiperazinylC_1-6alkyl;

furanyl;

phenyl;

phenyl substituted with one substituents independently selected from di(C_1-4alkyl)aminoC_1-4alkyloxy, di(C_1-4alkyl)amino, di(C_1-4alkyl)aminoC_1-14alkyl, di(C_1-4alkyl)aminoC_1-4alkyl(C_1-4alkyl)aminoC_1-4alkyl, pyrrolidinylC_1-4alkyl, pyrrolidinylC_1-4alkyloxy or C_1-4alkylpiperazinylC_1-4alkyl.

21. The method of claim 10, wherein said method is for treatment of bortezomib resistant multiple myeloma.