SULFONYLAMINO-DERIVATIVES AS NOVEL INHIBITORS OF HISTONE DEACETYLASE

• US 20100234353A1
• Filed: 03/15/2010
• Published: 09/16/2010
• Est. Priority Date: 03/13/2002
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Van Heusden, Jimmy Arnold Viviane, Van Emelen, Kristof, Verdonck, Marc Gustaaf Celine, Van Brandt, Sven Franciscus Anna, Angibaud, Patrick René, Pilatte, Isabelle Noëlle Constance, Backx, Leo Jacobus Jozef, De Winter, Hans Louis Jos
• Granted Patent: US 8,163,733 B2
• Time in Patent Office: Days
• US Class Current: 514/217.40
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• 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 19/00 : Drugs for skeletal disorders
• 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 405/14 : containing three or more hetero rings
• 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, m, t, R¹, R², R³, R⁴, R⁵, 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

1-13. -13. (canceled)

14. A compound of formula (I),

15. A compound as claimed in claim 14 wherein n is 0, 1 or 2;

t is 0, 1, 2 or 3;

each is

16. A compound according to claim 14 wherein t is 0;

R¹ is —

C(O)NR⁸R⁹, —

C(O)—

C_1-6alkanediylSR¹⁰, —

NR¹¹C(O)N(OH)R¹⁰, —

NR¹¹C(O)C_1-6alkanediylSR¹⁰, —

NR¹¹C(O)C═

N(OH)R¹⁰ or another Zn-chelating-group wherein R⁹ and R⁹ 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;

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;

R⁵ is hydrogen;

17. A compound as claimed in claim 14 wherein

R⁸ and Ware each independently selected from hydrogen, hydroxy, hydroxyC_1-6alkyl, aminoC_1-6alkyl or aminoaryl;

R⁵ is hydrogen, C_1-6alkyl, C_3-10cycloalkyl, hydroxyC_1-6alkyl, C_3-10alkyloxyC_1-6alkyl or di(C_1-6alkyl)aminoC_1-6alkyl;

18. A compound as claimed in claim 14 wherein n is 1 or 2;

t is 0, 1, 2 or 3;

each Q is

19. A compound according to claim 14 selected from the following compounds No. 13, No. 15, No. 2, No. 5, No. 21, No. 4, No. 24, No. 32, No. 26, No. 36, No. 38, No. 39, No. 40, No. 41, No. 42, No. 43, No. 44 and No. 35.

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

21. A process of preparing a pharmaceutical composition as claimed in claim 20 wherein the pharmaceutically acceptable carriers and the compound are intimately mixed.

22. 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 14.

23. A process for preparing a compound as claimed in claim 14, 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)

24. 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 14 and a HDAC.

25. A combination of an anti-cancer agents and a compound of claim 14.