Triazine compounds and pharmaceutical use thereof

Abstract

Provided is a compound having an mPGES-1 inhibitory activity and useful for the prophylaxis or treatment of pain, rheumatism, osteoarthritis, fever, Alzheimer's disease, multiple sclerosis, arteriosclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma and cancer including colorectal cancer. A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof: wherein each symbol is as defined in the SPECIFICATION.

1 . A compound represented by the formula [I] or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         X is CH or N, 
         ring Cy is 
         the formula: 
       
       
         
           
           
               
               
           
         
         or 
         the formula: 
       
       
         
           
           
               
               
           
         
         {wherein R 1  is
 (1) halogen, 
 (2) C 1-6  alkyl, 
 (3) cyano or 
 (4) haloC 1-4  alkyl, 
 R 2  is 
 (1) halogen, 
 (2) hydroxy, 
 (3) carboxy, 
 (4) C 1-6  alkyl, 
 (5) C 1-6  alkoxy, 
 (6) haloC 1-4  alkoxy, 
 (7) haloC 1-4  alkyl, 
 (8) C 1-6  alkyl-carbonyl, 
 (9) —C(O)NR a1 R a2  (R a1  and R a2  are each independently hydrogen or C 1-6  alkyl) or 
 (10) —(C n H 2n )—R b    
 (n is 1, 2, 3 or 4, —(C n H 2n )— may be straight or branched chain, and 
 R b  is 
 (a) hydroxy, 
 (b) carboxy, 
 (c) C 1-6  alkoxy, 
 (d) C 1-6  alkyl-carbonyloxy, 
 (e) —C(O)NR b1 R b2  (R b1  and R b2  are each independently hydrogen or C 1-6  alkyl), 
 (f) —OC(O)NR b3 R b4  (R b3  and R b4  are each independently hydrogen or C 1-6  alkyl), 
 (g) —NR b5 C(O)NR b6 R b7  (R b5 , R b6  and R b7  are each independently hydrogen or C 1-6  alkyl), 
 (h) —NR b8 R b9  (R b8  and R b9  are each independently hydrogen, C 1-6  alkyl or haloC 1-4  alkyl), 
 (i) —NR b10 S(O) 2 R b11  (R b10  and R b11  are each independently hydrogen, C 1-6  alkyl or C 3-7  cycloalkyl), 
 (j) —NR b12 C(O)OR b13  (R b12  is hydrogen or C 1-6  alkyl, and R b13  is C 1-6  alkyl), 
 (k) —NR b14 C(O)R b15  (R b14  is hydrogen or C 1-6  alkyl, and 
 R b15  is 
 (i) C 6-10  aryl, 
 (ii) C 1-8  alkyl (said C 1-8  alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of hydroxy, haloC 1-4  alkyl, C 1-6  alkoxy and C 6-10  aryl), 
 (iii) adamantyl or 
 (iv) C 3-7  cycloalkyl (said C 3-7  cycloalkyl is optionally substituted by 1, 2, 3 or 4 substituents selected from the group consisting of C 1-6  alkyl, halogen, hydroxyl C 1-6  alkyl and halo C 1-4  alkyl, and/or optionally form a fused ring with a benzene ring), or 
 R b14  and R b15  optionally form a 4-, 5- or 6-membered lactam together with the nitrogen atom that R b14  is bonded to and the carbon atom that R b15  is bonded to (said lactam is optionally substituted by 1, 2 or 3 C 1-6  alkyls, and/or optionally form a fused ring with a benzene ring), 
 (1) the formula: 
 
       
       
         
           
           
               
               
           
         
         wherein m2 and m3 are each independently 1, 2 or 3, m4 is 0, 1, 2, 3 or 4, R b16  is C 1-6  alkyl or C 1-6  alkoxy, and when m4 is 2, 3 or 4, each R b16  is selected independently or
 (m) the formula: 
 
       
       
         
           
           
               
               
           
         
         wherein m5 and m6 are each independently 1, 2 or 3, and R b17  is C 1-6  alkyl or C 1-6  alkoxy),
 R 3  is 
 (1) halogen, 
 (2) hydroxy, 
 (3) C 1-6  alkyl or 
 (4) —OR c  {R c  is C 1-6  alkyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (a) to (f); 
 (a) halogen, 
 (b) hydroxy, 
 (c) C 1-6  alkoxy, 
 (d) —C(O)NR c1 R c2  (R c1  and R c2  are each independently hydrogen or C 1-6  alkyl), 
 (e) C 6-10  aryl (said C 6-10  aryl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of 
 (i) halogen, 
 (ii) hydroxy, 
 (iii) C 1-6  alkyl, 
 (iv) C 1-6  alkoxy, and 
 (v) haloC 1-4  alkyl), and 
 (f) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms (said heteroaryl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of 
 (i) halogen, 
 (ii) hydroxy, 
 (iii) C 1-6  alkyl, 
 (iv) C 1-6  alkoxy, and 
 (v) haloC 1-4  alkyl)}, and 
 R 4  is 
 (1) hydrogen, 
 (2) halogen, 
 (3) C 1-6  alkyl or 
 (4) C 1-6  alkoxy}, 
 R 5  is 
 (1) halogen, 
 (2) hydroxy, 
 (3) C 1-6  alkylsulfanyl, 
 (4) C 1-6  alkyl (said C 1-6  alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of halogen, C 6-10  aryl and C 1-6  alkoxy), 
 (5) C 3-7  cycloalkyl, 
 (6) —OR d  {R d  is 
 (a) C 2-6  alkynyl, 
 (b) C 3-7  cycloalkyl optionally substituted by 1, 2 or 3 C 1-6  alkyls or 
 (c) C 1-8  alkyl (said C 1-8  alkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (i) to (v); 
 (i) halogen, 
 (ii) C 6-10  aryl, 
 (iii) C 1-6  alkoxy, 
 (iv) C 3-7  cycloalkyl (said C 3-7  cycloalkyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C 1-6  alkyl and haloC 1-4  alkyl), and 
 (v) 4-, 5- or 6-membered saturated heterocyclyl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms (said saturated heterocyclyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of C 1-6  alkyl and haloC 1-4  alkyl))} or 
 (7) the formula: 
 
       
       
         
           
           
               
               
           
         
         wherein R e  is
 (a) C 1-6  alkyl, 
 (b) C 3-7  cycloalkyl, 
 (c) 5- or 6-membered heteroaryl containing 1, 2 or 3 nitrogen atoms, oxygen atoms or sulfur atoms, or 
 (d) C 6-10  aryl (said C 6-10  aryl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of 
 (i) halogen, 
 (ii) C 1-6  alkyl, 
 (iii) haloC 1-4  alkyl, 
 (iv) C 1-6  alkoxy, and 
 (v) haloC 1-4  alkoxy), and 
 
         m1 is 0, 1, 2 or 3 and, when m1 is 2 or 3, each R 5  is selected independently, excluding 4,6-bis-(2,5-dimethyl-phenyl)-1,3,5-triazin-2-ol. 
       
     
     
         2 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein ring Cy is the formula: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 4  are as defined in  claim 1 . 
       
     
     
         3 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein ring Cy is the formula: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 3  and R 4  are as defined in  claim 1 . 
       
     
     
         4 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein X is CH. 
     
     
         5 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein X is N. 
     
     
         6 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 1  is
 (1) chloro, 
 (2) methyl, 
 (3) cyano or 
 (4) trifluoromethyl. 
 
     
     
         7 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 4  is hydrogen. 
     
     
         8 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 2  is
 —(C n H 2n )—R b  (n is 1 or 2, —(C n H 2n )— may be straight or branched chain, and R b  is
 (a) —C(O)NR b1 R b2 , 
 (b) —NR b5 C(O)NR b6 R b7 , 
 (c) —NR b10 S(O) 2 R b11  or 
 (d) —NR b14 C(O)R b15    
 
 (R b1 , R b2 , R b5 , R b6 , R b7 , R b10 , R b11 , R b14 , and R b15  are as defined in  claim 1 )). 
 
     
     
         9 . The compound according to  claim 8  or a pharmaceutically acceptable salt thereof, wherein R 2  is —CH 2 —R b  (R b  is as defined in  claim 8 ). 
     
     
         10 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein R 3  is
 (1) halogen, 
 (2) hydroxy, 
 (3) C 1-6  alkyl or 
 (4) —OR c  {R c  is C 1-6  alkyl optionally substituted by 1, 2 or 3 substituents selected from the group consisting of the following (a) to (f) 
 (a) halogen, 
 (b) hydroxy, 
 (c) C 1-6  alkoxy, 
 (d) —C(O)NR c1 R c2  (R c1  and R c2  are each independently hydrogen or C 1-6  alkyl), 
 (e) phenyl (said phenyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of 
 (i) halogen, 
 (ii) hydroxy, 
 (iii) C 1-6  alkyl, 
 (iv) C 1-6  alkoxy, and 
 (v) haloC 1-4  alkyl), and 
 (f) pyridyl (said pyridyl is optionally substituted by 1, 2 or 3 substituents selected from the group consisting of 
 (i) halogen, 
 (ii) hydroxy, 
 (iii) C 1-6  alkyl, 
 (iv) C 1-6  alkoxy, and 
 (v) haloC 1-4  alkyl)}. 
 
     
     
         11 . The compound according to  claim 1  or a pharmaceutically acceptable salt thereof, wherein m1 is 1, and
 R 5  is the formula: 
 
       
         
           
           
               
               
           
         
         wherein R e  is as defined in  claim 1 . 
       
     
     
         12 . A compound selected from the following formulas: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         13 . A pharmaceutical composition comprising the compound according to  claim 1  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         14 - 16 . (canceled) 
     
     
         17 . A method of inhibiting mPGES-1, comprising administering a pharmaceutically effective amount of the compound according to  claim 1  or a pharmaceutically acceptable salt thereof to a human. 
     
     
         18 . A method of treating or preventing pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma or cancer, comprising administering a pharmaceutically effective amount of the compound according to  claim 1  or a pharmaceutically acceptable salt thereof to a human. 
     
     
         19 . The method according to  claim 18  for treating or preventing glaucoma or ocular hypertension, further comprising administering a pharmaceutically effective amount of one or more kinds of other therapeutic agents for glaucoma to the human. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . A pharmaceutical composition comprising the compound according to  claim 12  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         23 . A method of inhibiting mPGES-1, comprising administering a pharmaceutically effective amount of the compound according to  claim 12  or a pharmaceutically acceptable salt thereof to a human. 
     
     
         24 . A method of treating or preventing pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, systemic scleroderma or cancer, comprising administering a pharmaceutically effective amount of the compound according to  claim 12  or a pharmaceutically acceptable salt thereof to a human. 
     
     
         25 . The method according to  claim 24  for treating or preventing glaucoma or ocular hypertension, further comprising administering a pharmaceutically effective amount of one or more kinds of other therapeutic agents for glaucoma to the human. 
     
     
         26 . A method of treating or preventing glaucoma or ocular hypertension, comprising administering a pharmaceutically effective amount of an mPGES-1 inhibitor to a human.