Orexin receptor antagonists
The disclosures herein relate to novel compounds of formula wherein W, X and Y 1 , Y 2 , Y 3 and Y 4 are defined herein, and their use in treating, preventing, ameliorating, controlling or reducing the risk of neurological or psychiatric disorders associated with orexin receptors.
1. A method of treatment of a disorder, wherein the disorder is insomnia, a headache disorder, obesity, a movement disorder, an anxiety disorder, a panic disorder, a binge eating disorder, a compulsive disorder, an impulse control disorder and Alzheimer's disease, comprising administering an effective amount of the compound of formula (1) to a subject in need thereof, wherein the compound of formula (1) is
wherein
Y 2 , Y 3 are independently a carbon or a nitrogen atom; and Y 4 is C-alkyl, C-halogen, C—H or N; and
W is a methylene group substituted by substituted aryl, or optionally substituted heteroaryl or heterocycloalkyl moiety, wherein the substituents and optional substituents forming part of W are selected from the group consisting of halo, alkyl, hydroxyl and alkoxy; and
X comprises an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl moiety, wherein X is not cyclopropyl and wherein the optional substituents forming part of X are selected from the group consisting of fluoro, chloro, bromo, iodo, oxo, C 1-4 alkyl, C 1-4 alkylsulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulphonyl, C 3-6 cycloalkyl, hydroxy, C 1-4 alkoxy, cyano, nitro, amino, C 1-4 alkylamino, C 2-4 alkenylamino, di-C 1-4 alkylamino, C 1-4 acylamino, phenyl, phenylamino, benzoylamino, benzylamino, phenylamido, carboxy, C 1-4 alkoxycarbonyl, phenyl-C 1-10 alkoxycarbonyl, carbamoyl, mono-C 1-4 carbamoyl, di-C 1-4 carbamoyl and any of the above in which a hydrocarbyl moiety is itself substituted by halo, cyano, hydroxy, C 1-2 alkoxy, amino, nitro, carbamoyl, carboxy or C 1-2 alkoxycarbonyl.
2. The method of claim 1 wherein Y 1 is nitrogen.
3. The method of claim 1 wherein Y 4 is CH or N.
4. The method of claim 1 , wherein X is an optionally substituted heteroaryl or heterocycloalkyl moiety.
5. The method of claim 4 , wherein X is selected from
6. The method of claim 1 , wherein the disorder is migraine, cluster headache or other headache disorders.
7. The method of claim 1 , wherein the disorder is obesity.
8. The method of claim 1 , wherein the disorder is movement disorders, anxiety disorders, panic disorders, binge eating disorder, compulsive disorders, impulse control disorders, or Alzheimer's disease.
9. The method of claim 6 , wherein the headache disorder is migraine or cluster headache.
10. The method of claim 1 wherein the compound is selected from the group consisting of
4-(1,3-benzodioxol-5-ylmethyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(3,4-dimethoxyphenyl)-4-(3-fluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(3,5-dimethoxyphenyl)-4-(3-methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
3-{[2-(3,4-dimethoxyphenyl)-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl]methyl}benzonitrile,
4-benzyl-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(3,5-dimethoxyphenyl)-4-(3-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(3,4-dimethoxyphenyl)-4-(4-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(3,4-dimethoxyphenyl)-4-(4-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(3-bromobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3 (4H)-one 1,1-dioxide,
4-(3-fluoro-4-methoxybenzyl)-2-(3-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(3-ethylphenyl)-4-(3-fluoro-4-methoxybenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(3-fluorobenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(3,5-dimethoxyphenyl)-4-(2-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-fluorobenzyl)-2-(3-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(3,5-dimethoxyphenyl)-4-(2-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chlorobenzyl)-2-(3,5-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
methyl 3-{[2-(3,5-dimethoxyphenyl)-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl]methyl}-4-methoxybenzoate,
2-(3,4-dimethoxyphenyl)-4-(2-methylbenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chlorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-4-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chlorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-fluorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(4-chlorophenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-phenyl-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(4-ethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(4-acetylphenyl)-4-(2-chloro-6-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(3-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(2,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(2-ethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(3,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(2-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(3-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(4-ethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(2,3-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(4-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-benzyl-4-(2-chloro-6-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(5-chloro-2-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(3-chlorophenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(3-fluoro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(4-fluorophenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(2,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(2,5-difluorophenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(3-ethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-[4-(propan-2-yl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-4-fluorobenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2,5-dimethylbenzyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
methyl 3-({2-[3-(methylsulfanyl)phenyl]-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl}methyl)-4-methoxybenzoate,
4-(2-fluorobenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-methylbenzyl)-2-(3-chloro-4-methylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chlorobenzyl)-2-(3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-fluorobenzyl)-2-(3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-fluorobenzyl)-2-(3,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-benzyl-4-(2-chlorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chlorobenzyl)-2-(3,4-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
methyl 3-{[2-(3,4-dimethoxyphenyl)-1,1-dioxido-3-oxo-2,3-dihydro-4H-1,2,4-benzothiadiazin-4-yl]methyl}-4-methoxybenzoate,
4-(Cyclobutylmethyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(Cyclohexylmethyl)-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
7-Fluoro-4-[1-(2-fluorophenyl)ethyl]-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-Chloro-6-fluorobenzyl)-2-(cyclohexylmethyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-{[4-(2,6-Difluorobenzyl)-1,1-dioxido-3-oxo-3,4-dihydro-2H-1,2,4-benzothiadiazin-2-yl]methyl}-2-fluorobenzonitrile,
4-(2,6-Difluorobenzyl)-2-[2-(3-methoxyphenyl)ethyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
2-(3,4-Dimethoxyphenyl)-4-(2-fluorobenzyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2,6-Dichlorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-Chloro-6-fluorobenzyl)-2-(3,5-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2,6-Dichlorobenzyl)-2-(3,5-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(3-Chloro-2-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(4-Chloro-2-fluorobenzyl)-2-(3,4-dimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-Chloro-6-fluorobenzyl)-2-{3-[(trifluoromethyl) sulfanyl]phenyl}-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-Chloro-6-fluorobenzyl)-7-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2,6-Difluorobenzyl)-2-{3-[(trifluoromethyl) sulfanyl]phenyl}-2H-1,2,4-benzothiadiazin-3 (4H)-one 1,1-dioxide,
4-(2-Chloro-6-fluorobenzyl)-6-fluoro-2-[3-(methylsulfanyl)phenyl]-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2,6-Dimethylbenzyl)-2-(3,4-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-Chloro-6-fluorobenzyl)-2-(3,4,5-trimethoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-Fluoro,6-methylbenzyl)-2-(3,4-methoxyphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-Chloro-4-fluorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide,
4-(2-chloro-6-fluorobenzyl)-2-(4-methoxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide, and
4-(2-Chloro-6-fluorobenzyl)-2-(4-hydroxy-3,5-dimethylphenyl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide.