Substituted pyridazine compound
The object of the present invention is to provide a pharmaceutical composition, in particular, a compound suitable for prevention and/or treatment of an inflammatory disease and/or a neurodegenerative disease. The present inventors have extensively conducted studies for discovering a compound having an inhibitory action on NLRP3 inflammasome activation, and found that substituted pyridazine compound has an inhibitory action on NLRP3 inflammasome activation. In this way, the present invention has been attained. The substituted pyridazine compound of the present invention is expected to serve as a prophylactic and/or therapeutic drug for an inflammatory disease and/or a neurodegenerative disease.
1 . A compound of formula (I) or a salt thereof:
wherein
Ar is a group represented by the following formula (i) or (ii):
wherein * represents a bonding site to the pyridazine ring of formula (I);
L is C 1-6 alkylene or C 3-8 cycloalkylene;
R 1 is H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, cyano, —OR 7 , —N(C 1-6 alkyl) 2 , or heteroaryl optionally substituted with 1 to 4 C 1-6 alkyls;
R 2 is H, C 1-6 alkyl, C 3-8 cycloalkyl, aryl, cyano, —OR 7 , —N(C 1-6 alkyl) 2, —C(═O)O—C 1-6 alkyl, —C(═O)NR 8 R 9 , or heteroaryl optionally substituted with 1 to 4 C 1-6 alkyls;
R 3 is OH, —NHC(═O) R 10 or —OC(═O)—C 1-6 alkyl;
R 4 is halogen, —O—C 1-6 alkyl or halogeno C 1-6 alkyl;
R 5 is H, C 3-8 cycloalkyl or halogeno C 1-6 alkyl;
R 6 is H, halogen, —O—C 1-6 alkyl or halogeno C 1-6 alkyl;
R 7 is-C 1-6 alkylene-O—C 1-6 alkylene-aryl or halogeno C 1-6 alkyl;
R 8 and R 9 are the same or different, and each are H or C 1-6 alkyl; or R 8 and R 9 , together with a nitrogen atom to which R 8 and R 9 are bonded, form morpholine, piperazine or thiomorpholine, and the morpholine, piperazine or thiomorpholine is optionally substituted with C 1-6 alkyl; and
R 10 is C 1-6 alkyl, halogeno C 1-6 alkyl or C 3-8 cycloalkyl,
provided that when Ar is a group represented by formula (i) with R 5 being H, R 4 is halogeno C 1-6 alkyl, and one of R 1 and R 2 is a group other than H.
2 . The compound or a salt thereof according to claim 1 , wherein R 5 is C 3-8 cycloalkyl or halogeno C 1-6 alkyl.
3 . The compound or a salt thereof according to claim 2 , wherein R 3 is OH.
4 . The compound or a salt thereof according to claim 3 , wherein R 1 is H, C 1-6 alkyl or C 3-8 cycloalkyl, and R 2 is H, C 1-6 alkyl, C 3-8 cycloalkyl or cyano.
5 . The compound or a salt thereof according to claim 4 , wherein R 1 and R 2 are the same or different, and each are H or C 1-6 alkyl.
6 . The compound or a salt thereof according to claim 5 , wherein Ar is a group represented by formula (i).
7 . The compound or a salt thereof according to claim 6 , wherein each of R 4 and R 5 is halogeno C 1-6 alkyl.
8 . The compound or a salt thereof according to claim 5 , wherein Ar is a group represented by formula (ii).
9 . The compound or a salt thereof according to claim 8 , wherein R 6 is halogeno C 1-6 alkyl.
10 . The compound or a salt thereof according to claim 1 , wherein the compound is a compound selected from the following group of:
(2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4,5-dimethylpyridazin-3-yl}amino)propan-2-ol;
(2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)propan-2-ol;
(2R)-1-({6-[2,4-bis(trifluoromethyl)phenyl]-4-methylpyridazin-3-yl}amino)propan-2-ol;
2-(6-{[(2R)-2-hydroxypropyl]amino}-4-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol;
2-(6-{[(2R)-2-hydroxypropyl]amino}-5-methylpyridazin-3-yl)-5-(trifluoromethyl)phenol;
2-(6-{[(2R)-2-hydroxypropyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol;
rac-(1R,2R)-2-({6-[2,4-bis(trifluoromethyl)phenyl]-5-methylpyridazin-3-yl}amino)cyclohexan-1-ol;
rac-(1R,2R)-2-({6-[2,4-bis(trifluoromethyl)phenyl]-4-methylpyridazin-3-yl}amino)cyclohexan-1-ol; and
2-(6-{[(1R,2R)-2-hydroxycyclohexyl]amino}-4,5-dimethylpyridazin-3-yl)-5-(trifluoromethyl)phenol.
11 . A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients.
12 . A NLRP3 inflammasome activation inhibitor comprising the compound or a salt thereof according to claim 1 .
13 . A method of treating an inflammatory disease, comprising administering to a subject an effective amount of the compound of claim 1 , or a salt thereof.
14 . A method of treating a neurodegenerative disease, comprising administering to a subject an effective amount of the compound of claim 1 , or a salt thereof.
15 . A method of treating an inflammatory disease, comprising administering to a subject an effective amount of the pharmaceutical composition of claim 11 .
16 . A method of treating a neurodegenerative disease, comprising administering to a subject an effective amount of the pharmaceutical composition of claim 11 .