US 2006/0235021 A1 · Phenylpyridazine derivatives as ligands for gaba receptors

Abstract

A class of 4-phenylpyridazine derivatives of Formula (I), being selective ligands for GABAA receptors, in particular having high affinity for the α2 and/or α3 and or α5 subunit thereof, are accordingly of benefit in the treatment and/or prevention of adverse conditions of the central nervous system, including anxiety, convulsions and cognitive disorders.

Claims14

Dependent claims

1-13. (canceled)

A compound of formula I, or an N-oxide thereof or a pharmaceutically acceptable salt thereof:

wherein:
X1 represents hydrogen, halogen, C1-6 alkyl, trifluoromethyl or C1-6 alkoxy;
X2 represents hydrogen or halogen;
Z represents hydrogen, halogen, cyano, cyanomethyl, trifluoromethyl, nitro, hydroxy, C1-6 alkoxy, formyl, C2-6 alkoxycarbonyl, or an optionally substituted aryl, heteroaryl or heteroaryl(C1-6)alkoxy group;
R1 represents hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, —ORa, —OSO2CF3, —SRa, —SORa, —SO2Ra, —SO2NRaRb, —NRaRb, —NRaCORb, —NRaCO2Rb, —CORa, —CO2Ra, —CONRaRb or —CRa═NORb;
R2 represents hydrogen or C2-6 alkoxycarbonyl;
and
Ra and Rb independently represent hydrogen, hydrocarbon or a heterocyclic group.

5 more elements

A compound which is selected from:

3,5-diphenylpyridazine-4-carboxylic acid ethyl ester;
3,5-diphenylpyridazine-4-carboxylic acid methyl ester;
3,5-diphenylpyridazine;
5-[2-fluoro-3-(pyridin-3-yl)phenyl]3-phenylpyridazine;
5-(3-isopropoxyphenyl)-3-phenylpyridazine;
3-(6-phenylpyridazin-4-yl)benzaldehyde;
4,2′-difuoro-5′-(6-phenylpyridazin4-yl)biphenyl-2-carbonitrile;
5-(3-cyanophenyl)-3-phenylpyridazine;
5-(3-bromophenyl)-3-phenylpyridazine;
3-phenyl-5-[3-(pyridin-3-yl)phenyl]pyridazine;
3-phenyl-5-(3-[1,2,4]triazol-4-ylphenyl)pyridazine;
5-[2,4-difluoro-3-(pyridin-4-yl)phenyl]-3-phenylpyridazine;
5-[3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl]-3-phenylpyridazine;
6,2′-difluoro-5′-(6-phenylpyridazin-4-yl)biphenyl-2-carbonitrile;
5-[4-fluoro-3-(pyridin-4-yl)phenyl]-3-phenylpyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-phenylpyridazine;
3-phenyl-5-[3-(pyridin-2-ylmethoxy)phenyl]pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-4-yl)phenyl]-3-phenylpyridazine;
5-[2-fluoro-3-(pyridin-4-yl)phenyl)-3-phenylpyridazine;
5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-3-phenylpyridazine;
5-[4-fluoro-3-(pyridin-3-yl)phenyl]-3-phenylpyridazine;
[3-(6-phenylpyridazin-4-yl)phenyl)acetonitrile;
2-fluoro-5-(6-phenylpyridazin-4-yl)benzonitrile;
5-(3-nitrophenyl)-3-phenylpyridazine;
3-(6-phenylpyridazin-4-yl)benzoic acid methyl ester;
3-(6-phenylpyridazin-4-yl)benzaldehyde;
5-(3-fluorophenyl)-3-phenylpyridazine;
3-phenyl-5-(3-trifluoromethylphenyl)pyridazine;
5-(3-methoxyphenyl)-3-phenylpyridazine;
5,2′-difluoro-5′-(6-phenylpyridazin-4-yl)biphenyl-2-carbonitrile;
3,2′-difluoro-5′-(6-phenylpyridazin-4-yl)biphenyl-2-carbonitrile;
5-(4-fluoro-3-methoxyphenyl)-3-phenylpyridazine;
6,2′-difluoro-5′-[6-(4-fluorophenyl)pyridazin-4-yl]biphenyl-2-carbonitrile;
4-fluoro-3′-(6-phenylpyridazin-4-yl)biphenyl-2-carbonitrile;
6,2′-difluoro-5′-[6-(thien-2-yl)pyridazin-4-yl]biphenyl-2-carbonitrile;
6,2′-difluoro-5′-[6-(4-methoxyphenyl)pyridazin-4-yl]biphenyl-2-carbonitrile;
5′-[6-(3-chlorophenyl)pyridazin-4-yl]-6,2′-difluorobiphenyl-2-carbonitrile;
6,2′-difluoro-5′-[6-(pyridin-3-yl)pyridazin-4-yl]biphenyl-2-carbonitrile;
5′-[6-(4-chlorophenyl)pyridazin-4-yl]-6,2′-difluorobiphenyl-2-carbonitrile;
6,2′-difluoro-5′-[6-(pyridin-4-yl)pyridazin-4-yl]biphenyl-2-carbonitrile;
5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-3-(4-fluorophenyl)-pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(2-fluorophenyl)pyridazine;
5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-3-(2-fluorophenyl)-pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(pyridin-3-yl)pyridazine;
5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-3-(3-fluorophenyl)-pyridazine;
3-(2,4-difluorophenyl)-5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-pyridazine;
5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-3-(3-methoxyphenyl)-pyridazine;
6,2′-difluoro-5′-[6-(2-fluorophenyl)pyridazin-4-yl]biphenyl-2-carbonitrile;
6,2′-difluoro-5′-[6-(3-fluorophenyl)pyridazin-4-yl]biphenyl-2-carbonitrile;
3-[6-(3-fluorophenyl)pyridazin-4-yl]benzonitrile;
3-[6-(2-fluorophenyl)pyridazin-4-yl]benzonitrile;
3-[6-(4-fluorophenyl)pyridazin-4-yl]benzonitrile;
3-[6-(4-methoxyphenyl)pyridazin-4-yl]benzonitrile;
3-[6-(3,4-difluorophenyl)pyridazin-4-yl]benzonitrile;
3-[6-(2,4-difluorophenyl)pyridazin-4-yl]benzonitrile;
5′-[6-(2-chlorophenyl)pyridazin-4-yl]-6,2′-difluorobiphenyl-2-carbonitrile;
3-(4-methoxyphenyl)-5-phenylpyridazine;
4-fluoro-3′-[6-(4-methoxyphenyl)pyridazin-4-yl]biphenyl-2-carbonitrile;
5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-3-(4-methoxyphenyl)-pyridazine;
3-(4-chlorophenyl)-5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-pyridazine;
2-{5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]pyridazin-3-yl}-5-fluorobenzonitrile;
3-(4-chlorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(furan-3-yl)pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(furan-2-yl)pyridazine;
3-(2,3-difluorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(thien-3-yl)pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(thien-2-yl)pyridazine;
3-(2,5-difluorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-pyridazine;
3-(3,4-difluorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-pyridazine;
4-{-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]pyridazin-3-yl}benzonitrile;
N-[5-(3-bromophenyl)pyridazin-3-yl]-N-methylamine;
N-[5-(3-bromophenyl)pyridazin-3-yl]-N-isopropylamine;
N-[5-(3-bromophenyl)pyridazin-3-yl]-N-cyclopropylamine;
N-allyl-N-[5-(3-bromophenyl)pyridazin-3-yl]amine;
N-[5-(3-bromophenyl)pyridazin-3-yl]-N-ethylamine
N-benzyl-N-[5-(3-bromophenyl)pyridazin-3-yl]amine;
N-[5-(3-bromophenyl)pyridazin-3-yl]-N-(2-methoxybenzyl)amine;
5-(3-bromophenyl)-3-(2,5-dihydropyrrol-1-yl)pyridazine;
5-(3-bromophenyl)-3-ethoxypyridazine;
3-allyloxy-5-(3-bromophenyl)pyridazine;
3-(6-isopropylaminopyridazin-4-yl)benzonitrile;
3-(6-benzylaminopyridazin-4-yl)benzonitrile;
3-[6-(2-methoxybenzylamino)pyridazin-4-yl]benzonitrile;
3-(6-benzyloxypyridazin-4-yl)benzonitrile;
3′-(6-ethylaminopyridazin-4-yl)-4-fluorobiphenyl-2-carbonitrile;
4-fluoro-3′-(6-isopropylaminopyridazin-4-yl)biphenyl-2-carbonitrile;
4-fluoro-3′-(6-propylaminopyridazin-4-yl)biphenyl-2-carbonitrile;
3′-(6-cyclopropylaminopyridazin-4-yl)-4-fluorobiphenyl-2-carbonitrile;
3′-(6-allylaminopyridazin-4-yl)-4-fluorobiphenyl-2-carbonitrile;
p3′-(6-benzylaminopyridazin-4-yl)-4-fluorobiphenyl-2-carbonitrile;
4-fluoro-3′-(6-methylaminopyridazin-4-yl)biphenyl-2-carbonitrile;
4-fluoro-3′-(6-methoxypyridazin-4-yl)biphenyl-2-carbonitrile;
3′-(6-ethoxypyridazin-4-yl)-4-fluorobiphenyl-2-carbonitrile;
3′-(6-benzyloxypyridazin-4-yl)-4-fluorobiphenyl-2-carbonitrile;
5-(4-fluoro-3-hydroxyphenyl)-3-phenylpyridazine;
5-[4-fluoro-3-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)phenyl)-3-phenylpyridazine;
5-[4-fluoro-3-(1-methyl-3-trifluoromethyl-1H-pyrazol-4-ylmethoxy)phenyl]-3-phenylpyridazine;
5-[4-fluoro-3-(pyridin-4-ylmethoxy)phenyl]-3-phenylpyridazine;
5-[4-fluoro-3-(pyridin-3-ylmethoxy)phenyl]-3-phenylpyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(pyridin-4-yl)pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(pyrazin-2-yl)pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(thiazol-2-yl)pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(pyridin-2-yl)pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(3-fluoropyridin-4-yl)pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-3-(1H-[1,2,3]triazol-4-yl)pyridazine;
5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]pyridazine-3-carboxylic acid ethyl ester;
5-[3-(3,5-difluoropyridin-2-yl)-4-fluorophenyl]-3-(2-fluorophenyl)-pyridazine-1-oxide;
3-(2,6-difluorophenyl)-5-[4-fluoro-3-(3-fluoropyridin-2-yl)phenyl]-pyridazine;
and pharmaceutically acceptable salts thereof.

106 more elements

Dependencies are inferred from the claim text.

Phenylpyridazine derivatives as ligands for gaba receptors

Life of this patent

Phenylpyridazine derivatives as ligands for gaba receptors

Life of this patent

Abstract

Claims14