Nitrogenous heterocyclic derivative and medicine containing the same as an active ingredient

• US 8,604,207 B2
• Filed: 11/21/2012
• Issued: 12/10/2013
• Est. Priority Date: 09/13/2004
• Status: Expired due to Fees

• Current Assignee: ONO Pharmaceutical Company Limited
• Original Assignee: ONO Pharmaceutical Company Limited
• Inventors: Shibayama, Shiro, Nishizawa, Rena, Takaoka, Yoshikazu
• Primary Examiner(s): Mabry, John
• Application Number:
  US13/682,784
• Publication Number:
  US 20130085275A1
• Time in Patent Office: 384 Days
• Field of Search: 546/224, 514/330
• US Class Current: 546/224
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• 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 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 211/58 attached in position 4
• 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 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• 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 409/14 containing three or more hetero rings
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

A compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof:

(wherein each symbol is as defined in the description.) The compounds represented by formula (I) has the antagonistic activity against CCR5, so they are useful in preventing and/or treating CCR5-related diseases, for example, various inflammatory diseases (asthma, nephritis, nephropathy, hepatitis, arthritis, rheumatoid arthritis, rhinitis, conjunctivitis, inflammatory bowel disease such as ulcerative colitis, etc.), immunological diseases (autoimmune diseases, rejection in organ transplantation (rejection of graft of solid organ, rejection of graft of pancreatic islet cells in therapy for diabetes, graft-versus-host disease, etc.), immunosuppression, psoriasis, multiple sclerosis, etc.), infectious diseases (infection with human immunodeficiency virus, acquired immunodeficiency syndrome, infection with RSV, etc.), allergic diseases (atopic dermatitis, urticaria, allergic bronchopulmonary aspergillosis, allergic eosinophilic gastroenteritis, etc.), cardiovascular diseases (arteriosclerosis, ischemic reperfusion injury, etc.), acute respiratory distress syndrome, shock accompanying bacterial infection, diabetes, cancer metastasis and so on.

Claims

1. The compound, which is selected from the group consisting of:

(5) 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluoro-N-methylbenzamide,

(8) N-butyl-N′

-(2,4-difluorophenyl)-N-(1-{4-[4-(4-morpholinylsulfonyl)phenoxy]benzyl }-4-piperidinyl)urea,

(11) N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl }[4-(methylsulfanyl)phenyl]amino }-1-piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide,

(12) N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl }[3-(methylsulfanyl)phenyl]amino }-1-piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide,

(14) N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl }[4-(methylsulfinyl)phenyl]amino }-1-piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide,

(15) N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl }[3-(methylsulfinyl)phenyl]amino }-1-piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide,

(16) N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl }[4-(methylsulfonyl)phenyl]amino }-1-piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide,

(17) N-(4-{4-[(4-{{[(4-fluorophenyl)amino]carbonyl }[3-(methylsulfonyl)phenyl]amino }-1-piperidinyl)methyl]phenoxy }phenyl)methanesulfonamide,

(18) N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)-1-piperidinyl]methyl}phenoxy)-3-methoxyphenyl]methanesulfonamide,

(21) 5-[({butyl[1-(4-{2-methoxy-4-[(methylsulfonyl)amino]phenoxy }benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluorobenzamide,

(22) 5-[({butyl[1-(4-{2-chloro-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluorobenzamide,

(23) 4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)-1-piperidinyl]methyl}phenoxy)-N-(2-hydroxyethyl)benzenesulfonamide,

(24) 4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)-1-piperidinyl]methyl }phenoxy)-N- [2- (dimethylamino)ethyl]benzenesulfonamide,

(25) N-{4-[4-({4-[{[(2,4-difluorophenyl)amino]carbonyl }(phenyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,

(26) 4-(4-{[4- (butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)-1-piperidinyl]methyl}phenoxy)-N-methylbenzenesulfonamide,

(27) 4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)-1-piperidinyl]methyl}phenoxy)-N,N-dimethylbenzenesulfonamide,

(28) 4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl }amino)-1-piperidinyl]methyl}phenoxy)-N-(2-methoxyethyl)benzenesulfonamide,

(32) 5-({[butyl(1-{4-[4-(4-morpholinylsulfonyl)phenoxy]benzyl }-4-piperidinyl)amino]carbonyl }amino)-2,4-difluorobenzamide,

(34) 5-[({butyl[1-(4-{2,6-dimethyl-4-[(methylsulfonyl)amino]phenoxy }benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluorobenzamide,

(35) 5-[({butyl[1-(4-{4-[methyl(methylsulfonyl)amino]phenoxy }benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluorobenzamide,

(36) 5-[({butyl[1-(4-(4-{4-[(methylsulfonyl)amino]phenzyl}benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluorobenzamide,

(38) 5-({[(1-{4-[4-(aminosulfonyl)phenoxy]benzyl}-4-piperidinyl) (butyl)amino]carbonyl }amino)-2,4-difluorobenzamide,

(39) 5-[({butyl[1-(4-{4-[(methylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluorobenzamide,

(40) 5-[({butyl[1-(4-{4-[(dimethylamino)sulfonyl]phenoxy}benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluorobenzamide,

(41) N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-3-methylphenyl]methanesulfonamide,

(42) 5-[({butyl[1-(4-{2-methyl-4- [(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,

(43) 4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]benzoic acid,

(46) 5-({[butyl(1-{4-[4-(methylsulfonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,

(47) 4-[4-({4[{[(4-fluorophenyl)amino]carbonyl }(phenyl)amino]-1-piperidinyl}methyl)phenoxy]benzoic acid,

(48) 4-[4-({4- [({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoic acid,

(49) 4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-chlorobenzoic acid,

(50) 4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-nitrobenzoic acid,

(51) 5-[({butyl[1-(4-{3-methoxy-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,

(52) 5-[({butyl[1-(4-{3-chloro-4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,

(57) 5-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino }carbonyl)(butyl)amino]-1-piperidinyl }methyl)phenoxy]-2-[(methylsulfonyl)amino]benzoic acid,

(58) 2-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino }carbonyl)(butyl)amino]-1-piperidinyl }methyl)phenoxy]-5-[(methylsulfonyl)amino]benzoic acid,

(59) N-[4-(4-{[4-(butyl{[(3,4-dicyanophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl }phenoxy)phenyl]methanesulfonamide,

(60) N-[4-(4-{[4-(butyl{[(4-cyano-2,5-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)phenyl]methanesulfonamide,

(62) 3-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl }amino)benzamide,

(63) 4-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]benzamide,

(64) N-{4-[4-({4-[butyl({[2,4-difluoro-5-(4-morpholinylcarbonyl) phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,

(65) 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-(2-methoxyethyl)benzamide,

(66) 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluoro-N,N-dimethylbenzamide,

(67) 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluoro-N-(2-hydroxyethyl)benzamide,

(72) 5-[({2-butynyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-2,4-difluorobenzamide,

(73) 2,4-difluoro-5-({[[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](propyl)amino]carbonyl }amino)benzamide,

(74) N-{4-[4-({4-[butyl({[2,4-difluoro-5-(hydroxymethyl)phenyl]amino}carbonyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}methanesulfonamide,

(101) 4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl}phenoxy)-N-[2-(dimethylamino)ethyl]benzenesulfonamide,

(103) 5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino}carbonyl)amino]-N-[2-(dimethylamino)ethyl]-2,4-difluorobenzamide,

(105) methyl 4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]-3-methoxybenzoate,

(107) methyl N-[4-(4-{[4-(butyl{[(2,4-difluorophenyl) amino]carbonyl}amino)piperidin-1-yl]methyl}phenoxy)phenyl]-N-(methylsulfonyl)glycinate,

(108) methyl N-{4-[4({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino}carbonyl)(butyl)amino]piperidin-1-yl}methyl)phenoxy]phenyl}-N-(methylsulfonyl)glycinate,

(116) 5-({[(1-{4-[4-(aminocarbonyl)-2-methoxyphenoxy]benzyl}-4-piperidinyl) (butyl)amino]carbonyl}amino)-2,4-difluorobenzamide,

(117) 5-{[(butyl{1-[4(2-methoxy-4-{[(2-methoxyethyl)amino]carbonyl }phenoxy)benzyl]-4-piperidinyl }amino)carbonyl]amino }-2,4-difluorobenzamide,

(118) 5-({[butyl(1-{4-[2-methoxy-4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl }amino)-2,4-difluorobenzamide,

(119) [[4-(4-{[4-(butyl{[(2,4-difluorophenyl)amino]carbonyl}amino)-1-piperidinyl]methyl }phenoxy)phenyl](methylsulfonyl)amino]acetic acid,

(120) [{4-[4-({4-[({[5-(aminocarbonyl)-2,4-difluorophenyl]amino }carbonyl)(butyl)amino]-1-piperidinyl}methyl)phenoxy]phenyl}(methylsulfonyl)amino]acetic acid,

(122) 5-({[(1-{4-[4-(aminocarbonyl)phenoxy]benzyl}-4-piperidinyl)(butyl)amino]carbonyl}amino)-2,4-difluorobenzamide,

(123) 5-({[butyl(1-{4[4-(4-morpholinylcarbonyl)phenoxy]benzyl}-4-piperidinyl)amino]carbonyl}amino)-2,4-difluorobenzamide,

(124) 2-{5-[({butyl[1-(4-{4-[(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl]amino }carbonyl)amino]-2,4-difluorophenyl }acetamide,

(208) 2-chloro-5-({[[1-(4-{4- [(methylsulfonyl)amino]phenoxy}benzyl)-4-piperidinyl](phenyl)amino]carbonyl}amino)benzamide,

(212) 2-[4-({4-[{[(4-fluorophenyl)amino]carbonyl }(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,

(230) 2-[4-({4-[[({4-fluoro-3-[(methylsulfonyl)amino]phenyl}amino)carbonyl](phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide, and

(234) 2-[4-({4-[({[3-(acetylamino)-4-fluorophenyl]amino}carbonyl)(phenyl)amino]-1-piperidinyl}methyl)phenoxy]-5-[(methylsulfonyl)amino]benzamide,

or a salt thereof.

2. A pharmaceutical composition, which comprises the compound according to claim 1, or a salt thereof.