Hydroxytriazine compounds and pharmaceutical use thereof

Abstract

The present invention provides 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/or cancer including colorectal cancer. The present invention relates to a compound of formula [I-a], [I-b] or [I-c] or a pharmaceutically acceptable salt thereof: wherein each symbol is as defined in the specification.

1 . A compound of the formula [I-a], [I-b] or [I-c], or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is 
         (1) the formula: 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 1a  is C 1-4  alkyl, 
           R 1b  is C 1-4  alkyl or trifluoromethyl, and 
           R 1c  is 
           (a) CM alkyl, 
           (b) CM fluoroalkyl, 
           (c) CM alkoxy, or 
           (d) CM alkoxy CM alkyl, or 
         
         (2) the formula: 
       
       
         
           
           
               
               
           
         
         
           wherein 
           n is 1, 2, 3, 4 or 5, and 
           R 1d  is 
           (a) fluoro, 
           (b) C 1-4  alkyl, 
           (c) C 1-4  fluoroalkyl, 
           (d) CM alkoxy, or 
           (e) CM alkoxy CM alkyl, 
         
         R 2  is hydrogen or CM alkyl, 
         R 3  is 
         (1) hydrogen, 
         (2) halogen, 
         (3) CM alkyl, or 
         (4) CM alkoxy, 
         R 4  is 
         (1) the formula: 
       
       
         
           
           
               
               
           
         
         
           wherein 
           R 4a  is hydrogen, CM alkyl or CM alkoxy, or 
         
         (2) the formula: 
       
       
         
           
           
               
               
           
         
         R 5  is C 1-6  alkyl, 
         R 6  is 
         (1) C 1-6  alkyl, 
         (2) C 3-5  cycloalkyl, or 
         (3) CM alkoxy CM alkyl, and 
         X is CH 2  or O, 
         provided that when R 2  in the formula [I-a] is CM alkyl, then R 3  is hydrogen. 
       
     
     
         2 . The compound or pharmaceutically acceptable salt according to  claim 1 , wherein, in the formula [I-a],
 R 2  and R 3  are both hydrogens, and   R 4  is   (1) isopropyl or tert-butyl, or   (2) the formula:   
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound or pharmaceutically acceptable salt according to  claim 1 , wherein, in the formula [I-a],
 R 2  is hydrogen,   R 3  is chloro, and   R 4  is isopropyl.   
     
     
         4 . The compound or pharmaceutically acceptable salt according to  claim 1 , wherein X in the formula [I-b] is O. 
     
     
         5 . The compound or pharmaceutically acceptable salt according to  claim 1 , wherein, in the formula [I-c],
 R 2  is hydrogen, and   R 6  is 1-methylbutyl or n-hexyl.   
     
     
         6 . The compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 1  is the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1a  is CM alkyl, 
         R 1b  is CM alkyl or trifluoromethyl, and 
         R 1c  is 
         (b) difluoromethyl or trifluoromethyl, or 
         (c) methoxy. 
       
     
     
         7 . The compound or pharmaceutically acceptable salt according to  claim 1 , wherein R 1  is the formula: 
       
         
           
           
               
               
           
         
         wherein 
         n is 3, 4 or 5, and 
         R 1d  is 
         (a) fluoro, 
         (c) CM fluoroalkyl, 
         (d) methoxy, or 
         (e) methoxymethyl. 
       
     
     
         8 . The compound or pharmaceutically acceptable salt according to  claim 7 , wherein n is 3 or 4, and
 R 1d  is monofluoromethyl, difluoromethyl or trifluoromethyl.   
     
     
         9 . A compound selected from the following formulas: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         10 . A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt according to  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         11 .- 13 . (canceled) 
     
     
         14 . A method of inhibiting mPGES-1, which comprises administering a pharmaceutically effective amount of the compound or pharmaceutically acceptable salt according to  claim 1  to a human. 
     
     
         15 . A method of treating or preventing pain, rheumatism, fever, osteoarthritis, arteriosclerosis, Alzheimer's disease, multiple sclerosis, glaucoma, ocular hypertension, ischemic retinal disease, or systemic scleroderma and/or cancer, which comprises administering a pharmaceutically effective amount of the compound or pharmaceutically acceptable salt according to  claim 1  to a human. 
     
     
         16 . A method of treating or preventing glaucoma and/or ocular hypertension, which comprises administering a pharmaceutically effective amount of the compound or pharmaceutically acceptable salt according to  claim 1  and one or more kinds of other therapeutic agents for glaucoma to a human. 
     
     
         17 .- 18 . (canceled)