SUBSTITUTED INDOLYL ALKYL AMINO DERIVATIVES AS NOVEL INHIBITORS OF HISTONE DEACETYLASE

• US 20090124646A1
• Filed: 07/25/2005
• Published: 05/14/2009
• Est. Priority Date: 07/28/2004
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Arts, Janine, Verdonck, Marc Gustaaf Celine, Angibaud, Patrick Rene, Pilatte, Isabelle Noelle Constance, Roux, Bruno, Van Emelen, Kristof, Ten Holte, Peter
• Granted Patent: US 8,193,205 B2
• Time in Patent Office: Days
• US Class Current: 514/275
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 491/04 Ortho-condensed systems
• CPC Class Codes: C07D 491/056 with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

This invention comprises the novel compounds of formula (I)

wherein R¹, R², R³, X and Y have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.

Claims

1. A compound of formula (I),

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein

each n is an integer with value 0, 1 or 2 and when n is 0 then a direct bond is intended;

each m is an integer with value 1 or 2;

each X is independently N or CH;

each Y is independently O, S, or NR⁴;

wherein

each R⁴ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_3-6cycloalkyl, C_3-6cycloalkylmethyl, phenylC_1-6alkyl, —

C(═

O)—

CHR⁵R⁶ or —

S(═

O)₂—

N(CH₃)₂;

wherein

each R⁵ and R⁶ is independently hydrogen, amino, C_1-6alkyl or aminoC_1-6alkyl; and

when Y is NR⁴ and R² is on the 7-position of the indolyl then R² and R⁴ together can form the bivalent radical

—

(CH₂)₂—

(a-1), or

—

(CH₂)₃—

(a-2);

R¹ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylsulfonyl, C_1-6alkylcarbonyl or mono- or di(C_1-6alkyl)aminosulfonyl;

R² is hydrogen, hydroxy, amino, halo, C_1-6alkyl, cyano, C_2-6alkenyl, polyhaloC_1-6alkyl, nitro, phenyl, C_1-6alkylcarbonyl, hydroxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkyloxy, or mono- or di(C_1-6alkyl)amino;

R³ is hydrogen, C_1-6alkyl, or C_1-6alkyloxy; and

when R² and R³ are on adjacent carbon atoms, they can form the bivalent radical —

O—

CH₂—

O—

.

2. A compound according to claim 1 wherein

each n is an integer with value 0 or 1;

each R⁴ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_3-6cycloalkyl or phenylC_1-6alkyl;

R¹ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylcarbonyl or C_1-6alkylsulfonyl; and

R² is hydrogen, halo, C_1-6alkyl, cyano, nitro, polyhaloC_1-16alkyl or C_1-6alkyloxy.

3. A compound according to claim 1 wherein

wherein each n is an integer with value 1;

each m is an integer with value 1;

each X is independently N;

each Y is independently NR⁴;

each R⁴ is C_1-6alkyl;

R¹ is hydrogen;

R² is hydrogen or halo; and

R³ is hydrogen.

5. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1.

6. A process of preparing a pharmaceutical composition as claimed in claim 5 wherein the pharmaceutically acceptable carriers and the compound as claimed in claim 5 are intimately mixed.

9. A combination of an anti-cancer agent and a HDAC inhibitor as claimed in claim 1.

10. A process for preparing a compound as claimed in claim 1, said process comprising the steps of:

a) reacting an intermediate of formula (II), wherein Q is tetrahydropyranyloxyaminocarbonyl, herein referred to as an intermediate of formula (II-a), with an appropriate acid, such as for example, trifluoro acetic acid, yielding a hydroxamic acid of formula (I)

b) reacting an intermediate of formula (II), wherein Q is C_1-2alkyloxycarbonyl, herein referred to as intermediates of formula (II-c), with hydroxylamine, in the presence of a base and in an appropriate solvent with the production of a hydroxamic acid of formula (I)

13. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 2.

14. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 3.

16. A combination of an anti-cancer agent and a HDAC inhibitor as claimed in claim 2.

17. A combination of an anti-cancer agent and a HDAC inhibitor as claimed in claim 3.

25. The combination of claim 9, wherein said anti-cancer agent is a DNA methyl transferase inhibitors.

28. A method of treating a disorder related to the abnormal growth of cells or the abnormal growth of transformed cells, in a mammalian subject in need of inhibition of such abnormal cell growth, comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

29. The method of claim 28 in which the abnormal growth of cells comprises cell growth independent of normal regulatory mechanisms, said mechanisms including the direct inhibition of tumour growth by growth arrest, terminal differentiation or apoptosis of cancer cells, and the indirect inhibition of tumour growth by inhibition of the neovascularization of tumours.

30. The method of claim 29 in which the abnormal growth of cells is c caused by histone deacetylase (HDAC) activity.

31. A method of inhibiting abnormal cellular proliferative conditions caused by histone deacetylase (HDAC) activity, in a human subject in need of inhibition of histone deacetylase (HDAC) activity, comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

32. A method of inhibiting tumor growth in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the compound of claim 1.

33. The method of claim 32 in which the tumor comprises lung cancer, adenocarcinoma lung cancer, non-small cell lung cancer, pancreatic cancer, exocrine pancreatic carcinoma, colon cancers, colon adenocarcinoma and colon adenoma, prostate cancer, advanced prostate cancer, hematopoietic tumours of lymphoid lineage, acute lymphocytic leukemia, B-cell lymphoma, Burkitt'"'"'s lymphoma, myeloid leukemias, acute myelogenous leukemia (AML), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumours of mesenchymal origin, fibrosarcomas, rhabdomyosarcomas, melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumours of the skin, keratoacanthomas, breast carcinoma, advanced breast cancer, kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.

4. A compound selected from the group consisting of compound No. 1a, compound No. 30, compound No. 39 and compound No. 50:

and the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof.

15. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 4.

18. A combination of an anti-cancer agent and a HDAC inhibitor as claimed in claim 4.

7-8. -8. (canceled)

11. A compound of formula (II),

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein

each n is an integer with value 0, 1 or 2 and when n is 0 then a direct bond is intended;

each m is an integer with value 1 or 2;

each X is independently N or CH;

each Y is independently O, S, or NR⁴;

wherein

each R⁴ is hydrogen, C_1-6alkyl, C_1-6alkyloxyC_1-6alkyl, C_3-6cycloalkyl, C_3-6cycloalkylmethyl, phenylC_1-6alkyl, —

C(═

O)—

CHR⁵R⁶ or —

S(═

O)₂—

N(CH₃)₂;

wherein

each R⁵ and R⁶ is independently hydrogen, amino, C_1-6alkyl or aminoC_1-6alkyl; and

when Y is NR⁴ and R² is on the 7-position of the indolyl then R² and R⁴ together can form the bivalent radical

—

(CH₂)₂—

(a-1), or

—

(CH₂)₃—

(a-2);

R¹ is hydrogen, C_1-6alkyl, hydroxyC_1-6alkyl, C_1-6alkylsulfonyl, C_1-6alkylcarbonyl or mono- or di(C_1-6alkyl)aminosulfonyl;

R² is hydrogen, hydroxy, amino, halo, C_1-6alkyl, cyano, C_2-6alkenyl, polyhaloC_1-6alkyl, nitro, phenyl, C_1-6alkylcarbonyl, hydroxycarbonyl, C_1-6alkylcarbonylamino, C_1-6alkyloxy, or mono- or di(C_1-6alkyl)amino;

R³ is hydrogen, C_1-6alkyl, or C_1-6alkyloxy;

when R² and R³ are on adjacent carbon atoms, they can form the bivalent radical —

O—

CH₂—

O—

; and

Q is C_1-12alkyloxycarbonyl, hydroxycarbonyl or tetrahydropyranyloxyaminocarbonyl.

12. A process for preparing a compound as claimed in claim 11, said process comprising the steps of:

a) reacting a compound of formula (II), wherein Q is hydroxycarbonyl, herein referred to as compounds of formula (II-b), with an intermediate of formula (III) in the presence of appropriate reagents such as N′

-(ethylcarbonimidoyl)-N,N-dimethyl-1,3-propanediamine, monohydrochloride (EDC) and 1-hydroxy-1H-benzotriazole (HOBT) with the formation of a compound of formula (II-a),

b) reacting an intermediate of formula (VI) with the appropriate carboxaldehyde of formula (V), wherein t is an integer with value 0 or 1, and when t is 0 then a direct bond is intended, in the presence of an appropriate reagent, with the formation of a compound of formula (II-a),

c) reacting a compound of formula (II), wherein Q is methyl- or ethyloxycarbonyl (C_1-2alkyl), herein referred to as compounds of formula (II-c), with an appropriate acidic solution or basic solution, with the formation of a compound of formula (II-b),

d) reacting the carboxylic acid ethyl ester of formula (IV) with the appropriate carboxaldehyde of formula (V), in the presence of an appropriate reagent, with the formation of a compound of formula (II-c),

e) reacting an intermediate of formula (XIV) with the appropriate intermediate of formula (XV), in the presence of an appropriate reagent, in a suitable solvent,

with the formation of a compound of formula (II-c),

f) reacting an intermediate of formula (X) with an intermediate of formula (XI) wherein W is an appropriate leaving group such as, for example, halo, e.g. fluoro, chloro, bromo or iodo, or a sulfonyloxy radical such as methylsulfonyloxy, with the formation of a compound of formula (II-c), or

g) reacting an intermediate of formula (XII) with an intermediate of formula (XIII), wherein W is an appropriate leaving group as described above, with the formation of a compound of formula (II-c).

19. A compound of the following structure:

and the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof.

21. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 19.

23. A combination of an anti-cancer agent and a HDAC inhibitor as claimed in claim 19.

26. The combination of claim 23, wherein said anti-cancer agent is a DNA methyl transferase inhibitors.

20. A compound selected from the group consisting of:

and the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof.

22. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 20

24. A combination of an anti-cancer agent and a HDAC inhibitor as claimed in claim 20.

27. The combination of claim 24, wherein said anti-cancer agent is a DNA methyl transferase inhibitors.