Carbonylamino-derivatives as novel inhibitors of histone deacetylase
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Abstract
This invention comprises the novel compounds of formula (I)
wherein n, m, t, R1, R2, R3, R4, R5, L, Q, X, Y and
have defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.
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Citations
12 Claims
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1. A compound of formula (I),
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
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2. A compound as claimed in claim 1 wherein:
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R8 and R9 are each independently hydrogen, hydroxy, hydroxyC1-6alkyl, aminoC1-6alkyl or aminoaryl; R5 is hydrogen, C1-6alkyl, C3-10cycloalkyl, hydroxyC1-6alkyl, C1-6alkyloxyC1-6alkyl or di(C1-6alkyl)aminoC1-6alkyl;
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3. A compound as claimed in claim 1 wherein t is 0;
- m is 0;
R1 is —
C(O)NR8R9, —
C(O)—
C1-6alkanediylSR10, —
NR11C(O)N(OH)R10, —
NR11C(O)C1-6alkanediylSR10, or —
NR11C(O)C═
N(OH)R10 wherein R8 and R9 are each independently hydrogen, hydroxy, hydroxyC1-6alkyl or aminoC1-6alkyl;R2 is hydrogen, halo, hydroxy, amino, nitro, C1-6alkyl, C1-6alkyloxy, trifluoromethyl or di(C1-6alkyl)amino; -L- is a direct bond or a bivalent radical that is C1-6alkanediyl, C1-6alkanediyloxy, amino or carbonyl; R4 is hydrogen, hydroxy, amino, hydroxyC1-6alkyl, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl, aminocarbonyl, aminoC1-6alkyl, C1-6alkylaminoC1-6alkyl or di(C1-6alkyl)aminoC1-6alkyl; R5 is hydrogen;
- m is 0;
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4. A compound as claimed in claim 1 wherein n is 1;
- m is 0 or 1;
t is 0, 1 or 2;
R1 is —
C(O)NH(OH);
R2 is hydrogen or C1-6alkyl;
-L- is a direct bond;
R4 is hydrogen;
R5 is hydrogen;
- m is 0 or 1;
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5. A compound as claimed in claim 1 wherein n is 1;
- m is 0 or 1;
t is 0, 1 or 2;R1 is —
C(O)NH(OH);
R2 is hydrogen;
-L- is a direct bond;
R4 is hydrogen;
R5 is hydrogen;
- m is 0 or 1;
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6. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1.
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7. A process of preparing a pharmaceutical composition as claimed in claim 6 wherein the pharmaceutically acceptable carriers and a compound are intimately mixed.
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8. A method of treating ovarian carcinoma comprising administering to a patient in need of such treatment a compound of claim 1.
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9. A process for preparing a compound as claimed in claim 1, comprising characterized by reacting an intermediate of formula (II) with an acid yielding a hydroxamic acid of formula (I-a)
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10. A method of detecting or identifying a histone deacetylase (HDAC) in a biological sample comprising detecting or measuring the formation of a complex between a compound as defined in claim 1, which compound has been labeled and a HDAC.
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11. A composition comprising an agent effective for treating cancer and a compound of claim 1.
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12. The process of claim 9 wherein the acid is trifluoro acetic acid (CF3COOH).
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2. A compound as claimed in claim 1 wherein:
Specification
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Current AssigneeJanssen Pharmaceutica NV (Johnson & Johnson)
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Original AssigneeJanssen Pharmaceutica NV (Johnson & Johnson)
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InventorsVan Emelen, Kristof, Verdonck, Marc Gustaaf Celine, Van Brandt, Sven Franciscus Anna, Backx, Leo Jacobus Jozef
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Primary Examiner(s)RAO, DEEPAK R
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Application NumberUS13/280,207Publication NumberTime in Patent Office505 DaysField of Search546/205, 546/168, 546/174, 546/256, 514/319, 514/237.2, 514/256, 514/318, 514/314, 544/129, 544/335US Class Current514/319CPC Class CodesA61K 31/40 having five-membered rings ...A61K 31/402 1-aryl substituted, e.g. pi...A61K 31/435 having six-membered rings w...A61K 31/4427 containing further heterocy...A61K 31/454 containing a five-membered ...A61K 31/4545 containing a six-membered r...A61K 31/472 Non-condensed isoquinolines...A61K 31/495 having six-membered rings w...A61K 31/496 Non-condensed piperazines c...A61K 31/506 not condensed and containin...A61K 31/5377 not condensed and containin...A61K 31/55 having seven-membered rings...A61K 45/06 Mixtures of active ingredie...A61P 1/04 for ulcers, gastritis or re...A61P 11/00 Drugs for disorders of the ...A61P 11/02 Nasal agents, e.g. deconges...A61P 11/06 AntiasthmaticsA61P 13/08 of the prostateA61P 13/10 of the bladderA61P 13/12 of the kidneysA61P 15/00 : Drugs for genital or sexual...A61P 17/00 : Drugs for dermatological di...A61P 17/04 : AntipruriticsA61P 17/06 : AntipsoriaticsA61P 17/10 : Anti-acne agentsA61P 17/14 : for baldness or alopeciaA61P 17/16 : Emollients or protectives, ...A61P 19/02 : for joint disorders, e.g. a...A61P 19/06 : Antigout agents, e.g. antih...A61P 21/04 : for myasthenia gravisA61P 25/00 : Drugs for disorders of the ...A61P 25/16 : Anti-Parkinson drugsA61P 25/28 : for treating neurodegenerat...A61P 27/02 : Ophthalmic agentsA61P 27/06 : Antiglaucoma agents or mioticsA61P 29/00 : Non-central analgesic, anti...A61P 3/10 : for hyperglycaemia, e.g. an...A61P 31/18 : for HIVA61P 35/00 : Antineoplastic agentsA61P 35/02 : specific for leukemiaA61P 37/02 : ImmunomodulatorsA61P 37/04 : ImmunostimulantsA61P 37/06 : Immunosuppressants, e.g. dr...A61P 37/08 : Antiallergic agents antiast...A61P 43/00 : Drugs for specific purposes...A61P 5/00 : Drugs for disorders of the ...A61P 9/00 : Drugs for disorders of the ...A61P 9/02 : Non-specific cardiovascular...A61P 9/08 : Vasodilators for multiple i...A61P 9/10 : for treating ischaemic or a...C07D 207/09 : Radicals substituted by nit...C07D 207/14 : Nitrogen atoms not forming ...C07D 211/14 : with hydrocarbon or substit...C07D 211/58 : attached in position 4C07D 213/78 : Carbon atoms having three b...C07D 217/02 : with only hydrogen atoms or...C07D 217/04 : with hydrocarbon or substit...C07D 217/16 : substituted by oxygen atomsC07D 239/42 : One nitrogen atom nitro rad...C07D 295/155 : with the ring nitrogen atom...C07D 295/26 : Sulfur atomsC07D 307/68 : Carbon atoms having three b...C07D 401/04 : directly linked by a ring-m...C07D 401/12 : linked by a chain containin...C07D 401/14 : containing three or more he...C07D 403/04 : directly linked by a ring-m...C07D 403/12 : linked by a chain containin...C07D 405/06 : linked by a carbon chain co...C07D 405/14 : containing three or more he...C07D 409/12 : linked by a chain containin...C07D 409/14 : containing three or more he...C07D 413/04 : directly linked by a ring-m...C07D 413/12 : linked by a chain containin...C07D 471/04 : Ortho-condensed systemsC07D 471/10 : Spiro-condensed systemsC07D 513/04 : Ortho-condensed systemsC12Q 1/34 : involving hydrolaseC12Q 1/48 : involving transferaseG01N 2333/98 : acting on amide bonds in li...G01N 33/573 : for enzymes or isoenzymes