New inhibitors of histone deacetylase

• US 20050107384A1
• Filed: 03/11/2003
• Published: 05/19/2005
• Est. Priority Date: 03/13/2002
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Verdonick, Marc Gustaaf Celine, Van Brandt, Sven Franciscus Anna, Roux, Bruno, Meerpoel, Lieven, Ten Holte, Peter, Dyatkin, Alexey Borisovich, Angibaud, Patrick Rene, Pilatte, Isabelle Noelle Constance
• Granted Patent: US 7,816,363 B2
• Time in Patent Office: Days
• US Class Current: 514/242
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• CPC Class Codes: A61K 31/435 having six-membered rings with one nitrogen as the only ring hetero atom
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
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• CPC Class Codes: A61K 31/472 Non-condensed isoquinolines, e.g. papaverine
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
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• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
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• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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• CPC Class Codes: C07D 211/14 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 211/58 : attached in position 4
• CPC Class Codes: C07D 213/78 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 217/02 : with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
• CPC Class Codes: C07D 217/04 : with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• CPC Class Codes: C07D 217/16 : substituted by oxygen atoms
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
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• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
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• CPC Class Codes: C12Q 1/48 : involving transferase

Abstract

This invention comprises the novel compounds of formula (I) wherein n, t, R¹, R², R³, R⁴, L, Q, X, Y, Z and 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),

2. A compound as claimed in claim 1 wherein n is 1 or 2;

t is 0, 1, 2 or 4;

each Q is

3. A compound as claimed in claim 1 wherein t is 1, 2, 3, or 4;

R¹ is —

C(O)NR⁷R⁸, —

C(O)—

C_1-6alkanediylSR⁹, —

NR¹⁰C(O)N(OH)R⁹, —

NR¹⁰OC(O)C_1-6alkanediylSR⁹, —

NR¹⁰C(O)C═

N(OH)R⁹ or another Zn-chelating-group wherein R⁷ and R⁸ are each independently selected from hydrogen, hydroxy, hydroxyC_1-6alkyl or aminoC_1-6alkyl;

R² is hydrogen, halo, hydroxy, amino, nitro, C_1-6alkyl, C_1-6alkyloxy, trifluoromethyl or di(C_1-6alkyl)amino;

-L- is a direct bond or a bivalent radical selected from C_1-6alkanediyl, C_1-6alkanediyloxy, amino or carbonyl;

R⁴ is hydrogen, hydroxy, amino, hydroxyC_1-6alkyl, C_1-6alkyl, C_1-6alkyloxy, arylC_1-6alkyl, aminocarbonyl, aminoC_1-6alkyl, C_1-6alkylaminoC_1-6alkyl or di(C_1-6alkyl)aminoC_1-6alkyl;

is a radical selected from (a-1), (a-3), (a-4), (a-5), (a-6), (a-7), (a-8), (a-9), (a-10), (a-11), (a-12), (a-13), (a-14), (a-15), (a-16), (a-17), (a-18), (a-19), (a-20), (a-21), (a-22), (a-23), (a-24), (a-25), (a-26), (a-28), (a-29), (a-30), (a-31), (a-32), (a-33), (a-34), (a-35), (a-36), (a-37), (a-38), (a-39), (a-40), (a-41), (a-42), (a-44), (a-45), (a-46), (a-47), (a-48) and (a-51);

each s is independently 0, 1, 2, 3 or 4;

R⁵ is hydrogen;

halo;

hydroxy;

amino;

nitro;

trihaloC_1-6alkyl;

trihaloC_1-6alkyloxy;

C_1-6alkyl;

C_1-6alkyloxy;

C_1-6alkylcarbonyl;

C_1-6alkyloxycarbonyl;

C_1-6alkylsulfonyl;

hydroxyC_1-6alkyl;

aryloxy;

di(C_1-6alkyl)amino;

cyano;

thiophenyl;

furanyl;

furanyl substituted with hydroxyC_1-6alkyl;

benzofuranyl;

imidazolyl;

oxazolyl;

oxazolyl substituted with aryl and C_1-6alkyl;

C_1-6alkyltriazolyl;

tetrazolyl;

pyrrolidinyl;

pyrrolyl;

morpholinyl;

C_1-6alkylmorpholinyl;

piperazinyl;

C_1-6alkylpiperazinyl;

hydroxyC_1-6alkylpiperazinyl;

C_1-6alkyloxypiperidinyl;

pyrazoly;

pyrazolyl substituted with one or two substituents selected from C_1-6alkyl or trihaloC_1-6alkyl;

pyridinyl;

pyridinyl substituted with C_1-6alkyloxy, aryloxy or aryl;

pyrimidinyl;

quinolinyl;

indole;

phenyl;

or phenyl substituted with one or two substituents independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl;

R⁶ is hydrogen;

halo;

hydroxy;

amino;

nitro;

trihaloC_1-6alkyl;

trihaloC_1-6alkyloxy;

C_1-6alkyl;

C_1-6alkyloxy;

C_1-6alkylcarbonyl;

C_1-6alkyloxycarbonyl;

C_1-6alkylsulfonyl;

hydroxyC_1-6alkyl;

aryloxy;

di(C_1-6alkyl)amino;

cyano;

pyridinyl;

phenyl;

or phenyl substituted with one or two substituents independently selected from halo, C_1-6alkyl, C_1-6alkyloxy or trifluoromethyl.

4. A compound as claimed in claim 1 wherein n is 1;

t is 0 or 1;

each Q is

6. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound according to claim 1.

7. A process of preparing a pharmaceutical composition as claimed in claim 6 wherein the pharmaceutically acceptable carriers and the compound according to claim 1 are intimately mixed.

10. A process for preparing a compound as claimed in claim 1, characterized by reacting an intermediate of formula (II) with an appropriate acid, such as for example, trifluoro acetic acid, yielding a hydroxamic acid of formula (I-a), wherein R¹ is —

C(O)NH(OH)

5. A compound selected from the group consisting of compounds No. 3, No. 4, No. 8, No. 5, No. 7, No. 6 and No. 9.

8. (canceled)

9. (canceled)

11. A method of detecting or identifying a HDAC in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound as defined in claim (I) and a HDAC.

12. (canceled)