Pyridazinone compounds and their use as DAAO inhibitors

Patent metadata

Field	Value
Publication number	US-9931340-B2
Application number	US-201615014336-A
Country	US
Kind code	B2
Filing date	Feb 3, 2016
Priority date	Aug 22, 2011
Publication date	Apr 3, 2018
Grant date	Apr 3, 2018

Abstract

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein R 1 and R 2 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy:

First claim

The invention claimed is:

1. A method of treating at least one symptom or condition associated with schizophrenia comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof,

wherein
R 1 is chosen from a hydrogen or fluorine atom or a trifluoromethyl group;
R 2 represents a group —X—Y—R 3 ;
X and Y each independently are chosen from a bond, an oxygen atom, or a group —C(O), —S(O) n , —C(O)NR 4 , —S(O) 2 NR 4 , —NR 4 ,

or —CR 4 R 5 —, with the proviso that X and Y cannot both simultaneously represent a bond, and if X and Y are both not a bond, then at least one of X and Y represents —CR 4 R 5 —;
n is chosen from 0, 1 or 2;
each R 4 independently is chosen from a hydrogen atom or a C 1 -C 6 alkyl or C 1 -C 6 haloalkyl group;
each R 5 independently is chosen from a hydrogen atom, a C 1 -C 6 alkyl or C 1 -C 6 haloalkyl group or ═CH—;
R 3 is chosen from a 3- to 10-membered saturated or unsaturated carbocyclic or heterocyclic ring system, wherein the ring system is unsubstituted or substituted by at least one substituent chosen from halogen, hydroxyl, cyano, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulphinyl, C 1 -C 6 alkylsulphonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkoxycarbonyl, amino (—NH 2 ), —CON(R 6 ) 2 , C 1 -C 6 alkylamino, di-(C 1 -C 6 alkyl)amino, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylmethyl, —[O] p —(CH 2 ) q —O—R 7 or a 4- to 6-membered saturated or unsaturated heterocyclic ring, which is unsubstituted or substituted with at least one substituent chosen from C 1 -C 4 alkyl or C 1 -C 4 alkoxy;
each R 6 independently is chosen from a hydrogen atom or a C 1 -C 6 alkyl group;
p is chosen from 0 or 1;
q is chosen from 1, 2, 3 or 4; and
R 7 is chosen from a C 1 -C 6 alkyl group.

2. The method according to claim 1 , wherein the at least one symptom is a positive symptom of schizophrenia.

3. The method according to claim 1 , wherein the at least one symptom is a negative symptom of schizophrenia.

4. The method according to claim 2 , wherein the positive symptom of schizophrenia is chosen from hearing voices that others do not experience, seeing hallucinations, or cognitive impairment associated with schizophrenia.

5. The method according to claim 4 , wherein the positive symptom of schizophrenia is cognitive impairment associated with schizophrenia.

6. The method according to claim 1 , wherein the compound of formula (I) is chosen from:
4-Hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one,
6-[2-(4-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-2-yl]ethyl}pyridazin-3(2H)-one,
6-[(4-Chlorobenzyl)sulfanyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[6-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one,
6-[2-(3-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(2-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(3, 5-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(3,4-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one,
4-Hydroxy-6-{2-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one,
4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one,
6-(2-Cyclohexylethyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Cyclopropylethyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Cyclopentylethyl)-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-[2-(4-methoxycyclohexyl)ethyl]pyridazin-3(2H)-one,
6-[2-(2,4-Difluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-{2-[3-(Difluoromethyl)phenyl]ethyl}-4-hydroxypyridazin-3(2H)-one,
6-Benzyl-4-hydroxypyridazin-3(2H)-one,
6-[2-(3-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-(1-phenylcyclopropyl)pyridazin-3(2H)-one,
4-[2-(5-Hydroxy-6-oxo-1,6-dihydropyridazin-3-yl)ethyl]benzonitrile,
6-[2-(3-Fluoro-4-methylphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(4-Fluoro-3-methylphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(3,4-Dimethoxyphenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[3-(trifluoromethoxy)phenyl]ethyl}pyridazin-3(2H)-one,
6-[2-(4-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
6-[2-(2-Chlorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[2-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one,
6-(4-Difluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one,
6-(4-(Trifluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one,
6-(3-(Difluoromethoxy)phenethyl)-4-hydroxypyridazin-3(2H)-one,
6-[1-(4-Fluorophenyl)cyclopropyl]-4-hydroxypyridazin-3(2H)-one,
6-[1-(4-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{1-[3-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one,
4-Hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one,
6-((Cyclopropylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one,
6-((Cyclohexylmethyl)(methyl)amino)-4-hydroxypyridazin-3(2H)-one,
6-(3-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(4-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(Cyclohexylmethyl)-4-hydroxypyridazin-3(2H)-one,
6-(4-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Chloro-6-fluorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(3-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(2-Fluorobenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(4-Methylbenzyl)-4-hydroxypyridazin-3(2H)-one,
6-(3-Methylbenzyl)-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-(3-(trifluoromethyl)benzyl)pyridazin-3(2H)-one,
4-Hydroxy-6-{2-[5-(trifluoromethyl)pyridin-3-yl]ethyl}pyridazin-3(2H)-one,
4-Hydroxy-6-[2-(oxan-4-yl)ethyl]pyridazin-3(2H)-one,
6-{[(4-Fluorophenyl)methyl](methyl)amino}-4-hydroxy-pyridazin-3(2H)-one,
6-[2-(2,6-Difluorophenyl)ethyl]-4-hydroxy-pyridazin-3(2H)-one,
6-[2-(2-Chloro-6-fluorophenyl)ethyl]-4-hydroxy-pyridazin-3(2H)-one,
6-{[3,5-bis(Trifluoromethyl)phenyl]methyl}-4-hydroxypyridazin-3(2H)-one,
6-(1-Phenylethyl)-4-hydroxypyridazin-3(2H)-one,
6-(Cyclopropylmethyl)-4-hydroxy-2,3-dihydropyridazin-3-one,
4-Hydroxy-6-{-[4-(trifluoromethyl)phenyl]cyclopropyl}-2,3-dihydropyridazin-3-one,
6-{2-[2-Chloro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one,
6-{2-[2-Fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one,
6-{2-[3,5-bis(Trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one,
6-{2-[2,4-bis(Trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydro-pyridazin-3-one,
6-{2-[3,4-bis(Trifluoromethyl)phenyl]ethyl}4-hydroxy-2,3-dihydropyridazin-3-one,
4-Hydroxy-6-(3-methyl-4-(trifluoromethyl)phenethyl)pyridazin-3(2H)-one,
3,4-bis(Benzyloxy)-6-((3-chloro-4-(trifluoromethyl)phenyl)ethyl)pyridazine,
4-Hydroxy-6-{2-[2-methyl-4-(trifluoromethyl)phenyl]ethyl}-2,3-dihydropyridazin-3-one,
6-{2-[3,5-Difluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one, and
6-{2-[3-Fluoro-4-(trifluoromethyl)phenyl]ethyl}-4-hydroxy-2,3-dihydropyridazin-3-one,
or a pharmaceutically acceptable salt thereof.

7. The method according to claim 6 , wherein the compound of formula (I) is chosen from:
6-[2-(4-Fluorophenyl)ethyl]-4-hydroxypyridazin-3(2H)-one,
4-Hydroxy-6-{2-[4-(trifluoromethyl)phenyl]ethyl}pyridazin-3(2H)-one, and
6-(4-Chlorobenzyl)-4-hydroxypyridazin-3(2H)-one,
or a pharmaceutically acceptable salt thereof.

8. The metho

Assignees

• Takeda Pharmacuetical Company Ltd
• Takeda Pharmaceuticals Co

Inventors

• Farnaby William
• Fieldhouse Charlotte
• Hazel Katherine
• Kerr Catrina
• Kinsella Natasha
• Livermore David
• Merchant Kevin
• Miller David

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/02

  without antiinflammatory effect · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title