INHIBITORS OF HISTONE DEACETYLASE

• US 20100010004A1
• Filed: 09/16/2009
• Published: 01/14/2010
• Est. Priority Date: 03/13/2002
• Status: Active Grant

• Current Assignee: Alexey Borisovich Dyatkin, Kristof Van Emelen, Lieven Meerpoel, Marc Gustaaf Celine Verdonck, Patrick René Angibaud, Sven Franciscus Anna Van Brandt
• Original Assignee: Alexey Borisovich Dyatkin, Kristof Van Emelen, Lieven Meerpoel, Marc Gustaaf Celine Verdonck, Patrick René Angibaud, Sven Franciscus Anna Van Brandt
• Inventors: ANGIBAUD, Patrick René, MEERPOEL, Lieven, VAN EMELEN, Kristof, VAN BRANDT, Sven Franciscus Anna, VERDONCK, Marc Gustaaf Celine, DYATKIN, Alexey Borisovich
• Granted Patent: US 8,455,498 B2
• Time in Patent Office: Days
• US Class Current: 514/252.140
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/402 1-aryl substituted, e.g. piretanide
• 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
• 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 31/472 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
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• 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
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 : Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 : Antipruritics
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 17/10 : Anti-acne agents
• CPC Class Codes: A61P 17/14 : for baldness or alopecia
• CPC Class Codes: A61P 17/16 : Emollients or protectives, e.g. against radiation
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• 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
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/00 : Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 207/09 : Radicals substituted by nitrogen atoms, not forming part of a nitro radical
• CPC Class Codes: C07D 207/14 : Nitrogen atoms not forming part of a nitro radical
• 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
• CPC Class Codes: C07D 295/155 : with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/26 : Sulfur atoms
• CPC Class Codes: C07D 307/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 513/04 : Ortho-condensed systems
• CPC Class Codes: C12Q 1/34 : involving hydrolase
• CPC Class Codes: C12Q 1/48 : involving transferase

Abstract

This invention comprises the novel compounds of formula (I)

wherein n, R¹, R², R³, R⁴, 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

1-12. -12. (canceled)

13. A compound of formula (I),

14. A compound as claimed in claim 13 wherein

R¹ is —

C(O)NR⁵R⁶, —

C(O)—

C_1-6alkanediylSR⁷, —

NR⁸C(O)N(OH)R⁷, —

NR⁸C(O)C_1-6alkanediylSR⁷, —

NR⁸C(O)C═

N(OH)R⁷ or another Zn-chelating-group wherein R⁵ and R⁶ 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;

R³ is hydrogen, C_1-6alkyl, arylC_2-6alkenediyl, furanylcarbonyl, naphthalenylcarbonyl, —

C(O)phenylR⁹, C_1-6alkylaminocarbonyl, aminosulfonyl, arylaminosulfonyl, aminosulfonylamino, di(C_1-6alkyl)aminosulfonylamino, di(C_1-6alkyl)aminoC_1-6alkyl, C_1-12alkylsulfonyl, di(C_1-6alkyl)aminosulfonyl or pyridinylcarbonyl wherein each R⁹ is independently selected from phenyl;

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

or thiophenyl; and

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.

15. A compound as claimed in claim 13 wherein n is 0 or 1;

each R¹ is —

C(O)NH(OH) or —

NHC(O)C_1-6alkanediylSH;

R² is hydrogen or nitro;

R³ is C_1-6alkyl, arylC_2-6alkenediyl, furanylcarbonyl, naphthalenylcarbonyl, C_1-6alkylaminocarbonyl, aminosulfonyl, di(C_1-6alkyl)aminosulfonylaminoC_1-6alkyl, di(C_1-6alkyl)aminoC_1-6alkyl, C_1-12alkylsulfonyl, di(C_1-6alkyl)aminosulfonyl, trihaloC_1-6alkylsulfonyl, di(aryl)C_1-6alkylcarbonyl, thiophenylC_1-6alkylcarbonyl, pyridinylcarbonyl or arylC_1-6alkylcarbonyl;

R⁴ is hydrogen;

when R³ and R⁴ are present on the same carbon atom R³ and R⁴ together may form a bivalent radical of formula (a-1) wherein R¹⁰ is aryl;

or when R³ and R⁴ are present on adjacent carbon atoms R³ and R⁴ together may form a bivalent radical of formula (b-1).

16. A compound as claimed in claim 13 wherein n is 1;

each Z is nitrogen;

R¹ is —

C(O)NH(OH);

R² is hydrogen;

R³ is naphthalenylcarbonyl,

C_1-12alkylsulfonyl or di(aryl)C_1-6alkylcarbonyl; and

R⁴ is hydrogen.

17. A compound according to claim 13 selected from the following compounds

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

19. A process of preparing a pharmaceutical composition as claimed in claim 18 wherein the pharmaceutically acceptable carriers and the compound are intimately mixed.

20. The method of treating proliferative disease comprising administering to a patient in need of such treatment, an anti-proliferative disease-effective amount of a compound of claim 13.

21. A process for preparing a compound as claimed in claim 13, 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)

22. A method of detecting or identifying a histone deactylase (HDAC) in a biological sample comprising detecting or measuring the formation of a complex between a labelled compound as defined in claim 13 and a HDAC.

23. A combination of anti-cancer agents and a compound of claim 13.