Pyridine and Pyrimidine Derivatives as Inhibitors of Histone Deacetylase

• US 20090143401A1
• Filed: 01/16/2007
• Published: 06/04/2009
• Est. Priority Date: 01/19/2006
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Gaurrand, Sandrine Francoise Dominique, Angibaud, Patrick Rene, Marconnet-Decrane, Laurence Francoise
• Granted Patent: US 8,114,876 B2
• Time in Patent Office: Days
• US Class Current: 514/252.190
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• 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 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• 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 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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 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 213/82 : in position 3
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 403/12 : 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: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

This invention comprises the novel compounds of formula (I)

wherein R¹, R², R³ and X 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)

the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof, wherein

X is N or CH;

R¹ is hydroxy or a radical of formula (a-1)

wherein

R⁴ is hydroxy or amino;

R⁵ is hydrogen, thienyl, furanyl or phenyl and each thienyl, furanyl or phenyl is optionally substituted with one or two halo, amino, nitro, cyano, hydroxy, phenyl, C_1-6alkyl, (diC_1-6alkyl)amino, C_1-6alkyloxy, phenylC_1-6alkyloxy, hydroxyC_1-6alkyl, C_1-6alkyloxycarbonyl, hydroxycarbonyl, C_1-6alkylcarbonyl, polyhaloC_1-6alkyloxy, polyhaloC_1-6alkyl, C_1-6alkylsulfonyl, hydroxycarbonylC_1-6alkyl, C_1-6alkylcarbonylamino, aminosulfonyl, aminosulfonylC_1-6alkyl, isoxazolyl, aminocarbonyl, phenylC_2-6alkenyl, phenylC_3-6alkynyl or pyridinylC_3-6alkynyl;

R⁶, R⁷ and R⁸ are each independently hydrogen, amino, nitro, furanyl, halo, C_1-6alkyl, C_1-16alkyloxy, trifluoromethyl, thienyl, phenyl, C_1-16alkylcarbonylamino, aminocarbonylC_1-6alkyl or —

C≡

C—

CH₂—

R⁹;

wherein R⁹ is hydrogen, C_1-6alkyl, hydroxy, amino or C_1-6alkyloxy;

R² is amino, C_1-6alkylamino, arylC_1-6alkylamino, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, C_3-7cycloalkylamino, C_3-7cycloalkylC_1-6alkyamino, glutarimidyl, maleimidyl, phthalimidyl, succinimidyl, hydroxy, C_1-6alkyloxy, phenyloxy wherein the phenyl moiety in said phenyloxy group is optionally substituted with one or two substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy, cyano, C_1-6alkyloxycarbonyl and trifluoromethyl;

R³ is phenyl, naphthalenyl or heterocyclyl;

wherein

each of said phenyl or naphthalenyl groups is optionally substituted with one or two substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy, polyhaloC_1-6alkyl, aryl, hydroxy, cyano, amino, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, hydroxycarbonyl, C_1-6alkyloxycarbonyl, hydroxyC_1-6alkyl, C_1-6alkyloxymethyl, aminomethyl, C_1-6alkylaminomethyl, C_1-6alkylcarbonylaminomethyl, C_1-6alkylsulfonylaminomethyl, aminosulfonyl, C_1-6alkylaminosulfonyl and heterocyclyl;

aryl is phenyl or naphthalenyl;

wherein each of said phenyl or naphthalenyl groups is optionally substituted with one or two substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy, trifluoromethyl, cyano and hydroxycarbonyl; and

heterocyclyl is furanyl, thienyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolyl, oxazolyl, thiazolyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, triazinyl, trithianyl, indolizinyl, indolyl, indolinyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, purinyl, quinolizinyl, quinolinyl, cinnolinyl, phthlazinyl, quinazolinyl, quinoxalinyl or naphthyridinyl;

wherein each of said heterocyclyl groups is optionally substituted with one or two substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy, cyano, amino and mono-or di(C_1-4alkyl)amino.

2. A compound according to claim 1 wherein:

a) X is N;

b) R¹ is hydroxy;

c) R² is amino, C_1-6alkylcarbonylamino, C_1-6alkylsulfonylamino, phthalimidyl, succinimidyl or phenyloxy wherein the phenyl moiety in said phenyloxy group is optionally substituted with a halo substituent; and

d) R³ is phenyl optionally substituted with one or two substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy and polyhaloC_1-6alkyl.

3. A compound according to claim 1 wherein:

a) X is N;

b) R¹ is hydroxy;

c) R² is amino; and

d) R³ is phenyl optionally substituted with one substituent selected from halo and C_1-6alkyloxy.

5. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 1.

8. A method of treating in a subject a proliferative disease comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

9. A combination of an anti-cancer agent and a HDAC inhibitor as claimed in claim 1.

10. A process for preparing a compound as claimed in claim 1, said process comprising the steps of:

a) reacting an intermediate of formula (II) with an appropriate acid to form a compound of formula (I-a)

b) reacting an intermediate of formula (III) wherein M represents hydrogen or an alkali metal, with an intermediate of formula (IV) to form a compound of formula (I-b)

11. A compound of formula (B):

in which Q is C_1-2alkyloxycarbonyl, MO₂C (in which M is hydrogen or an alkali metal) or tetrahydropyranyloxyaminocarbonyl, R^2a is as defined for R² or alternatively is hydroxymethyl and X and R³ are as defined for formula (I) in claim 1, and the N-oxide forms, the pharmaceutically acceptable addition salts and the stereo-chemically isomeric forms thereof.

12. A process for preparing a compound as claimed in claim 11, said process comprising the steps of:

a) reacting an intermediate of formula (III) with an intermediate of formula (V) to form an intermediate of formula (B) in which Q is tetrahydropyranyloxyaminocarbonyl, represented by formula (II) below

b) reacting an intermediate of formula (VI) with an appropriate acidic solution or an appropriate alkali

metal base, to form an intermediate of formula (B) in which Q is MO₂C, represented by formula (III) below

c) reacting an intermediate of formula (X) with diisopropyl azodicarboxylate (DIAD), tri-n-butylphosphine (PBu₃) and an appropriate nucleophile R²H (XI) to form an intermediate of formula (B) in which Q is

C_1-2alkyloxycarbonyl, represented by formula (VI) below

d) reacting an intermediate of formula (XII) with 1,4-dioxane-2,5-diol and an appropriate boronic acid of formula (XV), wherein R³ is as defined above to form an intermediate of formula (B) in which Q is C_1-2alkyloxycarbonyl and R^2a is hydroxymethyl represented by formula (X) below

13. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 2.

14. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 3.

4. The compound that is Compound No. 2:

.

15. A pharmaceutical composition comprising pharmaceutically acceptable carriers and as an active ingredient a therapeutically effective amount of a compound as claimed in claim 4.

6. (canceled)

7. (canceled)