Pyridine and pyrimidine derivatives as inhibitors of histone deacetylase

• US 8,101,616 B2
• Filed: 01/16/2007
• Issued: 01/24/2012
• Est. Priority Date: 01/19/2006
• Status: Active Grant

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Angibaud, Patrick René, Marconnet-Decrane, Laurence Françoise Bernadette, Arts, Janine
• Primary Examiner(s): RAO, DEEPAK R
• Application Number:
  US12/160,133
• Publication Number:
  US 20090005393A1
• Time in Patent Office: 1,834 Days
• Field of Search: 544/295, 544/365, 514/252.14, 514/253.13
• US Class Current: 514/252.14
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/08 Bronchodilators
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/10 Anti-acne agents
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• 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 27/16 Otologicals
• 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 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• 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 9/04 : 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 213/82 : in position 3
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

Abstract

This invention comprises the novel compounds of formula (I)

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹ 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)

2. A compounds according to claim 1 wherein:

a) X is N or CH;

b) R¹ is phenyl optionally substituted with one or two substituents each independently selected from halo, C_1-6alkyl, C_1-6alkyloxy, polyhaloC_1-6alkyl or aryl;

c) R² is —

CH₂—

R¹⁰ or —

C(═

O)—

R¹¹;

d) each R¹⁰ is independently selected from hydrogen, hydroxy, C_1-6alkyloxy, C_1-6alkyloxyC_1-6alkyloxy, C_1-6alkylcarbonyloxy, N-methylpiperazinyl, morpholinyl, or imidazolyl;

e) each R¹¹ is independently selected from C_1-6alkylamino, C_1-6cycloalkylamino, hydroxyC_1-6alkylamino, di(C_1-6alkyl)aminoC_1-6alkylamino or morpholinyl;

f) R³ is hydrogen;

g) R⁴ is hydrogen or C_1-6alkyl;

h) R⁵ is amino;

i) R⁶ is hydrogen or thienyl; and

j) R⁷, R⁸ and R⁹ are each hydrogen.

3. A compound according to claim 1 wherein:

a) X is N;

b) R¹ is phenyl;

c) R² is —

CH₂—

R¹⁰ wherein R¹⁰ is hydroxy or C_1-6alkyloxy;

d) R³ is hydrogen;

e) R⁴ is hydrogen;

f) R⁵ is amino;

g) R⁶ is hydrogen or thienyl; and

h) R⁷, R⁸ and R⁹ are each hydrogen.

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.

6. A method of treating ovarian cancer in a subject in need of such treatment comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A combination of an anti-cancer agent and a compound of claim 1.

8. A process for preparing a compound according to claim 1, said process comprising:

reacting an intermediate of formula (II) wherein M represents hydrogen or an alkali metal with a compound of formula (III), in the presence of a base;

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

10. 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. A compound having the following structure:

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