5′-carbamoyl-1,1′-biphenyl-4-carboxamide derivatives and their use as p38 kinase inhibitors

• US 7,396,843 B2
• Filed: 10/16/2002
• Issued: 07/08/2008
• Est. Priority Date: 10/17/2001
• Status: Expired due to Fees

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Bamford, Mark James, Angell, Richard Martyn, Walker, Ann Louise, Cockerill, George Stuart, Bamborough, Paul, Aston, Nicola Mary, Merrick, Suzanne Joy
• Primary Examiner(s): McKane; Joseph
• Assistant Examiner(s): CHUNG, SUSANNAH LEE
• Application Number:
  US10/492,699
• Publication Number:
  US 20050038014A1
• Time in Patent Office: 2,092 Days
• Field of Search: 514/343, 514/378, 514/408, 514/438, 514/461, 546/276.4, 548/240, 549/70, 549/497
• US Class Current: 514/343
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• 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 27/14 Decongestants or antiallergics
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• 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 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular 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 211/26 : with hydrocarbon radicals, substituted by nitrogen atoms
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 277/28 : Radicals substituted by nitrogen atoms
• CPC Class Codes: C07D 295/13 : to an acyclic saturated chain
• CPC Class Codes: C07D 295/135 : with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• CPC Class Codes: C07D 295/182 : Radicals derived from carboxylic acids
• CPC Class Codes: C07D 307/14 : Radicals substituted by nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 307/52 : Radicals substituted by nitrogen atoms not forming part of a nitro radical

Abstract

Compounds of formula (I):

or pharmaceutically acceptable salts or solvates thereof, and their use as pharmaceuticals, particularly as p38 kinase inhibitors.

Claims

1. A compound of formula (I):

2. A compound according to claim 1 wherein R1 is optionally substituted by up to three substituents selected from C_1-6alkyl, C_1-6alkoxy, oxy, halogen, hydroxyC_1-6alkyl, N(C_1-6alkyl)2, -CH2 —

N(C_1-6alkyl)₂, —

CO₂C_1-6alkyl, phenyl optionally substituted by halogen and benzyl optionally substituted by halogen and/or cyano.

3. A compound according to claim 1 wherein X is optionally substituted phenyl, and R1 is selected from optionally substituted pyrrolidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, oxadiazoly l, piperidinyl, piperazinyl, morpholino, pyridyl, pyrimidinyl, thienyl, imidazolidinyl, benzimidazolyl and quinolyl;

wherein the optional substituents for R1 are selected independently from C_1-6alkyl, C_1-6alkoxy, oxy, halogen, hydroxyC_1-6alkyl, —

N(C_1-6alkyl)₂ and —

CH2—

N(C_1-6alkyl)₂.

4. A compound according to claim 1 wherein X is a bond, and R1 is selected from an optionally substituted pyrrolidinyl, isoxazolyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, piperidinyl, piperazinyl, morpholino, pyridyl, tetrahydrofuranyl, tetrahydrothiophenyl and quinolyl;

wherein the optional substituents for R1 are selected independently from C_1-6alkyl, C_1-6alkoxy, oxy, halogen, hydroxyC_1-6alkyl, —

N(C_1-6alkyl)₂, —

CH₂—

N(C_1-6alkyl)₂, —

CO₂C_1-6alkyl, phenyl optionally substituted by halogen and benzyl optionally substituted by halogen and/or cyano.

5. A compound according to claim 1 wherein R² is selected from hydrogen, C_1-4alkyl and —

CH₂-cyclopropyl.

6. A compound according to claim 1 wherein m and n are independently selected from 0, 1 and 2, and the sum of m+n is from 0-3.

7. A compound according to claim 1 wherein R⁴ is selected from C_1-4alkyl, cyclopropyl, —

CH₂-cyclopropyl, pyridinyl and phenyl.

8. A compound according to claim 1 as defined in any one of Examples 1 to 2, or a pharmaceutically acceptable salt or solvate thereof.

9. A pharmaceutical composition comprising a compound according to claim 1 or a pharmnaceutically acceptable salt or solvate thereof, in admixture with one or more pharmnaceutically acceptable carriers, diluents or excipients.

10. A compound according to claim 2 wherein R¹ is an optionally substituted five- to seven-membered heterocyclic ring.

11. A compound according to claim 2 wherein R¹ is an optionally substituted five- to seven-membered heteroaryl ring.

12. A compound according to claim 2 wherein R¹ is an optionally substituted fused bicyclic ring.

13. A compound according to claim 2 wherein X is optionally substituted phenyl, and R¹ is selected from optionally substituted pyrrolidinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, tetrazolyl, oxazolyl, oxadiazolyl, piperidinyl, piperazinyl, morpholino, pyridyl, pyrimidinyl, thienyl, imidazolidinyl, benzimidazolyl and quinolyl;

wherein the optional substituents for R¹ are selected independently from C_1-6alkyl, C_1-6alkoxy, oxy, halogen, hydroxyC_1-6alkyl, —

N(C_1-6alkyl)₂ and —

CH₂—

N(C_1-6alkyl)₂.

14. A compound according to claim 2 wherein X is a bond, and R¹ is selected from an optionally substituted pyrrolidinyl, isoxazolyl, furyl, thienyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, oxadiazolyl, piperidinyl, piperazinyl, morpholino, pyridyl, tetrahydrofuranyl, tetrahydrothiophenyl and quinolyl;

wherein the optional substituents for R¹ are selected independently from C_1-6alkyl, C_1-6alkoxy, oxy, halogen, hydroxyC_1-6alkyl, —

N(C_1-6alkyl)₂, —

CH₂—

N(C_1-6alkyl)₂, —

CO₂C_1-6alkyl, phenyl optionally substituted by halogen and benzyl optionally substituted by halogen and/or cyano.

15. A compound according to claim 2 wherein R² is selected from hydrogen, C_1-4alkyl and —

CH₂-cyclopropyl.

16. A compound according to claim 13 wherein R² is selected from hydrogen, C_1-4alkyl and —

CH₂-cyclopropyl.

17. A compound according to claim 14 wherein R² is selected from hydrogen, C_1-4alkyl and —

CH₂-cyclopropyl.

18. A compound according to claim 2 wherein R⁴ is selected from C_1-4alkyl, cyclopropyl, —

CH₂-cyclopropyl, pyridinyl and phenyl.

19. A compound according to claim 3 wherein R⁴ is selected from C_1-4alkyl, cyclopropyl, —

CH₂-cyclopropyl, pyridinyl and phenyl.

20. A compound according to claim 4 wherein R⁴ is selected from C_1-4alkyl, cyclopropyl, —

CH₂-cyclopropyl, pyridinyl and phenyl.