Pyridine derivatives useful as cyclooxygenase inhibitor
A compound of the formula (I): wherein R 1 is hydrogen, halogen, carbamoyl, cyano, formyl, or lower alkyl optionally substituted with halogen, amino or a protected amino; R 2 is hydrogen, halogen, cyano or lower alkoxy; R 3 is phenyl or pyridyl, each of which is substituted with lower alkoxy; and R 4 is lower alkoxy; provided that either R 1 or R 2 is hydrogen, then the other is other than hydrogen, or its salts, which are useful as a medicament.
1 .- 17 . (canceled)
18 . A method for selecting a selective cylcooxygenase-I inhibitor, which lacks gastrointestinal disorders, by assessing whether cycloxygenase-II vs. cyclooxygenase-I IC 50 values ratio is higher than 30 in a whole blood assay and whether the cyclooxygenase-II IC 50 value thereof is higher than 0.2 μm in whole blood assay.
19 . The method of claim 18 , wherein said ratio of said IC 50 value for inhibition of cyclooxygenase-II to said IC 50 value for inhibition of cyclooxygenase-I is higher than 50.
20 . The method of claim 18 , wherein said ratio of said IC 50 value for inhibition of cyclooxygenase-II to said IC 50 value for inhibition of cyclooxygenase-I is higher than 100.
21 . The method of claim 18 , wherein said IC 50 value for inhibition of cyclooxygenase-II of said selective cyclooxygenase-I inhibitor is higher than 0.5 μm.
22 . The method of claim 18 , wherein said selective cyclooxygenase-I inhibitor is a compound of the formula (1), or a salt thereof:
wherein
R 1 is hydrogen, halogen, carbamoyl, cyano, formyl, or lower alkyl optionally substituted with halogen, amino or a protected amino;
R 2 is hydrogen, halogen, cyano or lower alkoxy;
R 3 is phenyl or pyridyl, each of which is substituted with lower alkoxy; and
R 4 is lower alkoxy;
provided that either R 1 or R 2 is hydrogen, then the other is other than hydrogen.
23 . The method of claim 22 , wherein:
R 1 is halogen, carbamoyl, cyano, formyl, or lower alkyl optionally substituted with halogen, amino or a protected amino;
R 2 is hydrogen;
R 3 is phenyl substituted with lower alkoxy, or pyridyl substituted with lower alkoxy; and
R 4 is lower alkoxy.
24 . The method of claim 22 , wherein:
R 1 is hydrogen;
R 2 is halogen, cyano or lower alkoxy;
R 3 is phenyl substituted with lower alkoxy; and
R 4 is lower alkoxy.
25 . The method of claim 22 , wherein:
R 1 is cyano, or lower alkyl optionally substituted with halogen, amino or a protected amino;
R 2 is halogen, cyano or lower alkoxy;
R 3 is phenyl substituted with lower alkoxy; and
R 4 is lower alkoxy.
26 . The method of claim 22 , wherein:
R 1 is cyano;
R 2 is chlorine;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
27 . The method of claim 22 , wherein:
R 1 is —CONH 2 ;
R 2 is chlorine;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
28 . The method of claim 22 , wherein:
R 1 is —CONH 2 ;
R 2 is hydrogen;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
29 . The method of claim 22 , wherein:
R 1 is cyano;
R 2 is hydrogen;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
30 . The method of claim 22 , wherein:
R 1 is hydrogen;
R 2 is cyano;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
31 . The method of claim 22 , wherein:
R 1 is cyano;
R is methoxy;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
32 . The method of claim 22 , wherein:
R 1 is —CHO;
R 2 is hydrogen;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
33 . The method of claim 22 , wherein:
R 1 is —CHF 2 ;
R 2 is hydrogen;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
34 . The method of claim 22 , wherein:
R 1 is —CH 2 NH 2 ;
R 2 is hydrogen;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
35 . The method of claim 22 , wherein:
R 1 is —CH 2 N(CH 3 ) 2 ;
R 2 is hydrogen;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
36 . The method of claim 22 , wherein:
R 1 is —CH 2 NH—CO—NHCH 3 ;
R 2 is hydrogen;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
37 . The method of claim 22 , wherein:
R 1 is —CH 3 ;
R 2 is hydrogen;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
38 . The method of claim 22 , wherein:
R 1 is chlorine;
R 2 is hydrogen;
R 3 is p-methoxyphenyl; and
R 4 is methoxy.
39 . The method of claim 22 , wherein:
R 1 is cyano;
R 2 is hydrogen;
R 3 is 2-methoxypyrid-3-yl; and
R 4 is methoxy.