Piperazinyl-, piperidinyl- and morpholinyl-derivatives as novel inhibitors of histone deacetylase
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Abstract
This invention comprises the novel compounds of formula (I)
wherein t, R1, R2, 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.
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Citations
14 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, 13, 14)
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2. A compound as claimed in claim 1 wherein
R3 and R4 are each independently selected from hydrogen, hydroxy, hydroxyC1-6alkyl, aminoC1-6alkyl or aminoaryl; -
3. A compound as claimed in claim 1 wherein
t is 0; -
R1 is —
C(O)NR3R4, —
C(O)—
C1-6alkanediylSR7, —
NR8C(O)N(OH)R7, —
NR8C(O)C1-6alkanediylSR7, or —
NR8C(O)C═
N(OH)R7 wherein R3 and R4 are each independently selected from hydrogen, hydroxy, hydroxyC1-6alkyl or aminoC1-6alkyl;
R2 is hydrogen, hydroxy, amino,hydroxyC1-6alkyl, C1-6alkyl, C1-6alkyloxy, arylC1-6alkyl, aminocarbonyl, aminoC1-6alkyl, C1-6alkylaminoC1-6alkyl or di(C1-6alkyl)aminoC1-6alkyl; -L- is a bivalent radical selected from —
NHC(O)—
or —
NHSO2—
;
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4. A compound as claimed in claim 1 wherein t is 0 or 1;
- each Q is
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5. A compound as claimed in claim 1 wherein t is 1;
- each Q is
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6. A compound according to claim 1 selected from the group consisting of compounds:
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7. A pharmaceutical composition comprising a pharmaceutically acceptable carrier, and as an active ingredient a therapeutically effective amount of a compound of claim 1.
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8. A process of preparing a pharmaceutical composition as claimed in claim 7 wherein the pharmaceutically acceptable carriers and the compound are mixed.
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9. A method of treating ovarian cancer comprising administering to a patient in need of such treatment, an anti-proliferative disease-effective amount of a compound of claim 1.
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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);
- C(O)NH(OH);
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11. 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 labeled compound as defined in claim 1 and a HDAC.
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12. A pharmaceutical composition comprising an anti-cancer agent and a compound of claim 1.
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13. A pharmaceutical composition comprising pharmaceutically acceptable carriers, and a therapeutically effective amount of a compound of claim 6 as an active ingredient.
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14. A pharmaceutical composition comprising an anti-cancer agent and a compound of claim 6.
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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
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Primary Examiner(s)Young, Shawquia
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Application NumberUS12/539,682Publication NumberTime in Patent Office1,455 DaysField of Search544/122, 544/330, 546/192US Class Current514/237.2CPC 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 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 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 1/44 : involving esteraseC12Q 1/48 : involving transferase