HYDROXYTRIAZINE COMPOUNDS AND PHARMACEUTICAL USE THEREOF
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)