Patent NZ-334215-A (NZ)
Title: Aralkyl and aralkylidene heterocyclic lactams and imides useful as psychotherapeutic agents
Inventor: HOWARD HARRY RALPH
IPC: C07D417/04
Filed: 1997-09-08
Abstract: Compounds of the formula I are selective agonists and antagonists of serotonin 1 (5-HT1) receptors, specifically of one or both of the 5-HT1A and 5-HT1D receptors, wherein: R1 is a group of formula G1, G2, G3, G4, G5, G6 or G7; R2 is hydrogen, (C1-C4)alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and -SO4k(C1-C6)alkyl, wherein k is zero, one or two; R3 is -(CH2)mB, wherein m is 0 to 3 and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered heteroaryl group containing from 1 to 4 heteroatoms in the ring, and wherein each of the foregoing phenyl, naphthyl and heteroaryl groups may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6) alkoxy-(C1-C6)alkyl-, trifluoromethyl, trifluoromethoxy, cyano, hydroxy -COOH and -SOn(C1-C6)alkyl wherein n is 0, 1 or 2;  X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C1-C6)alkyl, hydroxy, trifluoromethyl, (C1-C6)alkoxy, -SOt(C1-C6)alkyl, wherein t is zero one or two, -CO2R' or -CONR11R12; and Y is an optionally substituted (C1-C4) heteroalkyl bridge that, together with the atoms to which it is attached, forms a 5 to 7 membered heterocycle containing 2 to 4 heteroatoms. Examples of the compounds of formula I include: 4-(3,4-dichlorophenyl)-2-(hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]-methyl}morpholin-3-one; 2-{[2,4-dibromo-6-(4-methylpiperazin-1-yl)-phenyl]-hydroxymethyl}-4-(3,4dichlorophenyl)-thiomorpholin-3-one; 4-(3,4-Dichlorophenyl)-2-[3-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]- thiomorpholin-3-one; 4-(3,4-Dichlorophenyl)-2-(2-[4-(2-methoxyethyl)piperazin- 1-yl]-benzylidene}- thiomorpholin-3-one; 4-(3-Chlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3- one; 2-[2-Chloro-6-(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)thiomorpholin-3-one; 4-Benzo[1,3]dioxol-5-yl-2-[2-(3,5-dimethylpiperazin-1-yl)-benzylidene]thiomorpholin-3-one; 3-(3,4-Dichlorophenyl)-5-[2-(4-methylpiperazin-1 -yl)-benzylidene]-thiazolidin-4- one; 3-[4-(3 ,4-Dichlorophenyl)-3-oxo-thiomorpholin-2-ylidenemethyl]-6-dimethylamino-2-(4-methylpiperazin-1-yl)-benzonitrile; 2-[4-Bromo-2 -(4-methylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)thiomorpholin-3-one; 4-(3,4-Difluorophenyl)-2-[2-(3,4,5-trimethylpiperazin-1-yl)-benzylidene]thiomorpholin-3-one; 4-(3,4-Dichlorophenyl)-2-[2-(octahydropyrido[1 ,2-a]pyrazin-2-yl)-benzylidene]thiomorpholin-3-one; 2-[2-(4-Cyclopropylpiperazin-1 -yl)-benzylidene]-4-pyridin-3-yl-thiomorpholin-3one; 4-(3,4-Difluorophenyl)-2-[2-(2,5-dimethylpiperazin-1-yl)-benzylidene]thiomorpholin-3-one; 4-Benzo[1,3]dioxol-5-yl-2-[2-(4-cyclopropylpiperazin-1-yl)-benzylidene]- thiomorpholin-3-one; 2-[2-( 3, 5-Dimethylpiperazin-1 -yl)-benzytidene]-4-(4-fluorophenyl)-thiomorpholin-3- one; 4-(3,4-Dichlorophenyl)2-[2-(2,4,6-trimethylpiperazin-1-yl)-benzylidene]thiomorpholin-3-one; and 2-[2-(4-Cyclopropylpiperazin-1-yl)-benzylidene]-4-(3,4-dichlorophenyl)thiomorpholin-3-one. These compounds may be used for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, memory disorders, Parkinson's diseases, endocrine disorders, vasospasm, cerebellar ataxia, gastrointestinal tract disorders, schizophrenia, premenstrual syndrome, Fibromyalgia Syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and headache in a mammal.