Chemokine receptor antagonist and medical use thereof

Abstract

The present invention relates to a compound represented by formula (I), a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof, and medical use thereof (the symbols in the formula are as described in the specification). The compound represented by formula (I) has chemokine receptor (especially in CCR4 and/or CCR5) antagonistic activity. Therefore it is useful for prevention and/or treatment of a chemokine receptor-mediated disease such as inflammatory and/or allergic diseases [systemic inflammatory response syndrome (SIRS), anaphylaxis, anaphylactoid reaction, allergic angiitis, transplant rejection reaction, hepatitis, nephritis, nephropathy, pancreatitis, rhinitis, arthritis, inflammatory ocular disease, inflammatory bowel disease, disease in cerebro and/or circulatory system, respiratory disease, dermatosis, autoimmune disease, and the like], infection [viral disease (human immunodeficiency virus infection, acquired immunodeficiency syndrome, SARS, etc.), and the like], and the like.

1 . A compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein ring A, ring B and ring D are each independently an optionally substituted cyclic group; J is a bond or a spacer having 1 to 8 atom(s) in its main chain; and G is a bond or a spacer having 1 to 4 atom(s) in its main chain, 
         a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein ring D is an optionally substituted monocyclic hetero ring. 
     
     
         3 . The compound according to  claim 2 , wherein ring D is an optionally substituted pyrazine ring. 
     
     
         4 . The compound according to  claim 2 , wherein ring D is an optionally substituted pyridine ring. 
     
     
         5 . The compound according to  claim 1 , wherein ring D is an optionally substituted bicyclic hetero ring. 
     
     
         6 . The compound according to  claim 5 , wherein ring D is an optionally substituted cyclic group selected from the group of the following (a) to (y), and wherein, when an arrowhead binds to J, another one binds to G: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The compound according to any one of  claims 3 ,  4  and  6 , wherein the substituent(s) of ring D is one or two substituent(s) selected from the group consisting of halogen atom and methyl substituted by 1 to 3 of halogen atom(s). 
     
     
         8 . The compound according to  claim 1 , wherein J is —O—CH 2 —, —NHCH 2 —, —NHCO— or —C≡C—, wherein ring A binds to right side of each group. 
     
     
         9 . The compound according to  claim 1 , wherein ring A is a 5- to 10-membered cyclic group. 
     
     
         10 . The compound according to  claim 1 , wherein ring A is a 8- to 10-membered bicyclic ring. 
     
     
         11 . The compound according to  claim 9 , wherein ring A is an optionally substituted benzene ring, pyridine ring, 3,4-dihydro-2H-1,4-benzoxaxazine ring, 1,2,3,4-tetrahydro-1,8-naphthyridine ring, quinoline ring, 1,2,3,4-tetrahydroisoquinoline ring, pyrazole ring or thiazole ring. 
     
     
         12 . The compound according to  claim 11 , wherein the substituent(s) of ring A is one to three substituent(s) selected from the group consisting of chlorine atom, methoxy, 2-(dimethylamino)ethoxy, piperidin-4-ylmethoxy, 1-methylpiperidin-4-ylmethoxy, methyl, t-butoxycarbonyl and phenyl. 
     
     
         13 . The compound according to  claim 1 , wherein G is —NHSO 2 —, and wherein the nitrogen atom binds to ring D. 
     
     
         14 . The compound according to  claim 1 , wherein ring B is an optionally substituted C3-8 monocyclic aromatic carbon ring or an optionally substituted monocyclic aromatic hetero ring having 1 to 4 nitrogen atom(s), 1 or 2 oxygen atom(s) and/or 1 or 2 sulfur atom(s) as a hetero atom(s). 
     
     
         15 . The compound according to  claim 14 , wherein ring B is an optionally benzene ring or thiophene ring. 
     
     
         16 . The compound according to  claim 14 , wherein the substituent(s) of ring B is one or two substituent(s) selected from the group consisting of halogen atom and methyl substituted by 1 to 3 of halogen atom(s). 
     
     
         17 . The compound according to  claim 1 , which is represented by formula (I-1): 
       
         
           
           
               
               
           
         
         wherein R1 is the substituent(s) of ring D depicted in  claim 1 , m is 0 or an integer of 1 to 3, and other symbols have the same meanings as  claim 1 . 
       
     
     
         18 . The compound according to  claim 1 , which is represented by formula (I-4): 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as  claim 1  or  17 . 
       
     
     
         19 . The compound according to  claim 1 , which is selected from the group consisting of
 N-[5-bromo-3-({3-[2-(dimethylamino)ethoxy]-4-methoxybenzyl}oxy)pyridin-2-yl]-4-methylbenzenesulfonamide;   3-chloro-N-[3-({4-chloro-3-[(1-methylpiperidin-4-yl)methoxy]benzyl}oxy)-5-methylpyrazin-2-yl]-2-methylbenzenesulfonamide;   2-chloro-N-[3-({4-chloro-3-[(1-methylpiperidin-4-yl)methoxy]benzyl}oxy)-5-methylpyrazin-2-yl]-2-methylbenzenesulfonamide;   3-chloro-2-methyl-N-[5-methyl-3-(quinolin-2-ylmethoxy)pyrazin-2-yl]benzenesulfonamide;   2-chloro-N-[3-({3-[2-(dimethylamino)ethoxy]-4-methoxybenzyl}oxy)quinoxalin-2-yl]benzenesulfonamide;   N-[3-({4-chloro-3-[(1-methylpiperidin-4-yl)methoxy]benzyl}oxy)-5-methylpyrazin-2-yl]-4-methylbenzenesulfonamide;   N-[3-({4-chloro-3-[(1-methylpiperidin-4-yl)methoxy]benzyl}oxy)-5-methylpyrazin-2-yl]-2-(trifluoromethyl)benzenesulfonamide;   3-chloro-2-methyl-N-{5-methyl-3-[(2-methyl-1,2,3,4-tetrahydro-7-isoquinolinyl)methoxy]-2-pyrazinyl}benzenesulfonamide;   N-[5-bromo-3-({4-chloro-3-[(1-methyl-4-piperidinyl)methoxy]benzyl}oxy)-2-pyrazinyl]-4-methylbenzenesulfonamide;   3-chloro-N-{3-[(3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl)methoxy]-5-methyl-2-pyrazinyl}-2-methylbenzenesulfonamide;   3-chloro-2-methyl-N-{5-methyl-3-[(2-phenyl-1,3-thiazol-4-yl)methoxy]-2-pyrazinyl}benzenesulfonamide;   tert-butyl 7-{[(6-bromo-3-{[(4-methylphenyl)sulfonyl]amino}-2-pyrazinyl)oxy]methyl}-3,4-dihydro-2(1H)-iso quinoline carboxylate;   N-[5-chloro-3-({3-[2-(dimethylamino)ethoxy]-4-methoxybenzyl}oxy)-2-pyridinyl]-4-methylbenzenesulfonamide and   3-chloro-N-[5-chloro-3-({3-[2-(dimethylamino)ethoxy]-4-methoxybenzyl}oxy)-2-pyridinyl]-2-methylbenzenesulfonamide.   
     
     
         20 . A pharmaceutical composition which comprises a compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein all symbols have the same meanings as  claim 1 , 
         a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 
       
     
     
         21 . The pharmaceutical composition according to  claim 20 , which is a chemokine receptor antagonist. 
     
     
         22 . The pharmaceutical composition according to  claim 21 , wherein chemokine receptor is CCR4 and/or CCR5. 
     
     
         23 . The pharmaceutical composition according to  claim 21 , which is an agent for prevention and/or treatment of a chemokine receptor-mediated disease. 
     
     
         24 . The pharmaceutical composition according to  claim 23 , wherein the chemokine receptor-mediated disease is inflammatory disease, allergic disease, metabolism/endocrine-related disease, cancer and/or infectious disease. 
     
     
         25 . The pharmaceutical composition according to  claim 23 , wherein the chemokine receptor-mediated disease is asthma, pulmonary fibrosis, atopic dermatitis, infection of human immunodeficiency virus, acquired immunodeficiency syndrome and/or transplant rejection reaction. 
     
     
         26 . The pharmaceutical composition according to  claim 20 , which is a function inhibitor of effector cell. 
     
     
         27 . The pharmaceutical composition according to  claim 26 , wherein the function of effector cell is cell migration, increase of vascular permeability, infiltration to tissue, accumulation to tissue, release of humoral factor and/or expression of cell surface antigen. 
     
     
         28 . A method for prevention and/or treatment of a chemokine receptor-mediated disease in a mammal, which comprises administering to a mammal an effective amount of a compound represented by formula (I) depicted in  claim 1 , a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof. 
     
     
         29 . Use of a compound represented by formula (I) depicted in  claim 1 , a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof for the manufacture of an agent for prevention and/or treatment of a chemokine receptor-mediated disease. 
     
     
         30 . A medicament, which comprises a compound represented by formula (I) depicted in  claim 1 , a salt thereof, an N-oxide thereof, a solvate thereof or a prodrug thereof in combination with one or two or more of selected from the group consisting of bronchodilator, steroid, nonsteroidal antiinflammatory drug, leukotriene receptor antagonist, phosphodiesterase inhibitor, immunosuppressive drug, antiallergic drug, mediator release inhibitor, antihistamine drug, metabolism accelerator, protease inhibitor, reverse transcriptase inhibitor, integrase inhibitor, fusion inhibitor, interferon, aldose reductase inhibitor, cannabinoid-2 receptor stimulator, adrenocorticotropic hormone, metalloprotease inhibitor, prostaglandin, disease modifying antirheumatic drug, antiinflammatory enzyme drug, cartilage protective drug, T-cell suppressor, TNFα inhibitor, IL-1 inhibitor, IL-6 inhibitor, interferon γ stimulator, NF-κB inhibitor and/or chemokine antagonist.