Biphenylcarboxylic amide derivatives as p38-kinase inhibitors

• US 7,151,118 B2
• Filed: 10/16/2002
• Issued: 12/19/2006
• Est. Priority Date: 10/17/2001
• Status: Expired due to Fees

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Bamford, Mark James, Angell, Richard Martyn, Walker, Ann Louise, Cockerill, George Stuart, Bamborough, Paul, Aston, Nicola Mary, Lainé, Dramane Ibrahim, Flack, Stephen Sean
• Primary Examiner(s): McKane, Joseph K.
• Assistant Examiner(s): CHU, YONG LIANG
• Application Number:
  US10/492,697
• Publication Number:
  US 20050020540A1
• Time in Patent Office: 1,525 Days
• Field of Search: 548/143, 514/364
• US Class Current: 514/617
• 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 25/00 Drugs for disorders of the nervous system
• 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 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• 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 37/04 : Immunostimulants
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 39/02 : Antidotes
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• 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 213/81 : Amides; Imides
• 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 261/18 : Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
• CPC Class Codes: C07D 307/46 : Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
• 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 333/38 : 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 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links

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, imidazolidinyl, pyrazolyl, tetrazolyl, oxazolyl, oxadiazolyl, piperidinyl, piperazinyl, morpholino, pyridyl, pyrimidinyl, thienyl, 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 R⁴ is selected from —

(CH₂)rphenyl optionally substituted by R⁵ and/or R⁶ and —

(CH₂)_rheteroaryl optionally substituted by R⁵ and/or R⁶.

7. A compound according to claim 6 wherein R⁴ is —

(CH₂)_rheteroaryl optionally substituted by R⁵ and/or R⁶.

8. A compound according to any claim 1 wherein m and n are independently selected from 0, 1 and 2, and the sum of m+n is from 0–

3.

9. A process for preparing a compound according to claim 1 which comprises:

reacting a compound of formula (XIV)

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

11. A compound according to claim 1 which is:

N-(6-Methyl-4′

-{[3-(4-methylpiperazin-1-yl)propylamino]carbonyl}-1,1′

-biphenyl-3-yl)-2-pyrrolidin-1-ylisonicotinamide;

N-{4′

-[(3-Imidazol-1-ylpropylamino)carbonyl]-6-methyl-1,1′

-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide;

N-{4′

-[(3-Imidazol-1-ylpropylamino)carbonyl]-6-methyl-1,1′

-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide;

N-{6-Methyl-4′

-[(4-methylpiperazin-1-yl)carbonyl]-1,1′

-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide;

N-(4′

-{[3-(4-Methylpiperazin-1-yl)propylamino]carbonyl}-6-methyl-1,1′

-biphenyl-3-yl)-3-furamide;

N-(6-Methyl-4′

-{[(3-morphlin-4-ylmethylbenzyl)amino]carbonyl}-1,1′

-biphenyl-3-yl)-3-furamide;

N-[4′

-({[(1-t-Butyloxycarbonylpiperidin-4-yl)methyl]amino}carbonyl)-6-methyl-1,1′

-biphenyl-3-yl]-3-furamide;

N-(6-Methyl-4′

-{[2-(4-methylpiperazin-1-yl)anilino]carbonyl)}-1,1′

-biphenyl-3-yl)-3-furamide;

N-(6-Methyl-4′

-{[2-(4-methylpiperazin-1-ylmethyl)anilino]carbonyl}-1,1′

-biphenyl-3-yl)-3-furamide;

N-(6-Methyl-4′

-{[3-(4-methylpiperazin-1-yl)anilino]carbonyl}-1,1′

-biphenyl-3-yl)-3-furamide;

N-(6-Methyl-4′

-{[2-(2-morpholin-4-ylethyl)anilino]carbonyl}-1,1′

-biphenyl-3-yl)-3-furamide;

N-4′

-{[(3-Imidazol-1-ylpropyl)amino]carbonyl}-6-methyl-1,1′

-biphenyl-3-yl)-3-furamide;

N-(6-Methyl-4′

-{[(3-morpholin-4-ylpropyl)amino]carbonyl}-1,1′

-biphenyl-3-yl)-3-furamide;

N-[6-Methyl-4′

-({[4-(4-methylpiperazin-1-yl)benzyl]amino}carbonyl)-1,1′

-biphenyl-3-yl]thiophene-3-carboxamide;

N-{6-Methyl-4′

-[({3-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)carbonyl]-1,1′

-biphenyl-3-yl}thiophene-3-carboxamide;

N-[6-Methyl-4′

-({[4-(4-methylpiperazin-1-yl)benzyl]amino}carbonyl)-1,1′

-biphenyl-3-yl]isoxazole-3-carboxamide;

N-[6-Methyl-4′

-({[3-(morpholin-4-ylmethyl)benzyl]amino}carbonyl)-1,1′

-biphenyl-3-yl]-3-furamide;

tert-butyl 4-[({[5′

-(3-furolyamino)-2′

-methyl-1,1′

-biphenyl-4-yl]-carbonyl}amino)methyl]piperdine-1-carboxylate;

N-[6-Methyl-4′

-({[2-(4-methylpiperazin-1-yl)phenyl]amino}carbonyl)-1,1′

-biphenyl-3-yl]-3-furamide;

N-{6-Methyl-4′

-[({2-[(4-methylpiperazin-1-yl)methyl]phenyl}amino)carbonyl]-1,1′

-biphenyl-3-yl}-3-furamide;

N-[6-Methyl-4′

-({[3-(4-methylpiperazin-1-yl)phenyl]amino}carbonyl)-1,1′

-biphenyl-3-yl]-3-furamide;

N-(6-Methyl-4′

-{[(3-morpholin-4-ylpropyl)amino]carbonyl}-1,1′

-biphenyl-3-yl)-3-furamide;

N-[4′

-({[3-(1H-Imidazol-1-yl)propyl]amino}carbonyl)-6-methyl-1,1′

-biphenyl-3-yl]-3-furamide;

N-[4′

-({[3-(1H-Imidazol-1-yl)propyl]amino}carbonyl)-6-methyl-1,1′

-biphenyl-3-yl]thiophene-3-carboxamide;

tert-Butyl 4-{[({2′

-methyl-5′

-[(thien-3-ylcarbonyl)amino]-1,1′

-biphenyl-4-yl}carbonyl)amino]methyl}piperidine-1-carboxylate;

N-(6-Methyl-4′

-{[(3-morpholin-4-ylpropyl)amino]carbonyl}-1,1′

-biphenyl-3-yl)thiophene-3-carboxamide;

N-[6-Methyl-4′

-({[3-(4-methylpiperazin-1-yl)propyl]amino}carbonyl)-1,1′

-biphenyl-3-yl]thiophene-3-carboxamide;

N-[6-Methyl-4′

-({[2-(4-methylpiperazin-1-yl)ethyl]amino}carbonyl)-1,1′

-biphenyl-3-yl]thiophene-3-carboxamide;

N-[6-Methyl-4′

-({[3-(4-methylpiperazin-1-yl)phenyl]amino}carbonyl)-1,1′

-biphenyl-3-yl]isoxazole-5-carboxamide;

or

or a pharmaceutically acceptable salt or solvate thereof.

12. A compound according to claim 7 wherein the heteroaryl is furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazinyl.

13. A compound according to claim 7 wherein the heteroaryl is furyl, thienyl, isoxazolyl or pyridyl.

14. A compound according to claim 13 wherein the heteroaryl is optionally substituted by —

(CH₂)_sNR⁹R¹⁰.

15. A compound according to claim 12 wherein R² is hydrogen, W is methyl, and X and V are hydrogen.