Patent EA-002157-B1 (EA)
Title: Aralkyl and aralkylidene heterocyclic lactams and imides
Inventor: HOWARD HARRY RALPH
IPC: C07D417/04
Filed: 1997-09-08
Abstract: 1 A piperazinyl- benzylidene lactam compounds of the formula   wherein R<1> is piperazin-1-yl or piperazin-1-yl substituted in position 4 with (C1-C4) alkyl; R2 is hydrogen; R3 is -(CH2)mB, wherein m is zero or one and B is hydrogen, phenyl, optionally substituted with one or more substituents independently selected from halogen, (C1-C6) alkyl or trifluoromethyl; X is hydrogen or halogen; Y is a heteroalkyl bridge that, together with the atoms to which it is attached, forms a five to six membered heterocycle containing two to heteroatoms selected from the group consisting of 1 ,3-thiazolidin-2, 4-dion-5-yl, 1,3-imidazolidin-2, 4-dione-5-yl, morpholin-3-yl and thiomorpholin-3-one-2-yl, or pharmaceutically acceptable salts thereof. 2.A compound according to claim 1, wherein R<1> is   wherein R<6> is methyl. 3. A compound according to claim 2, wherein Y together, with the atoms to which it is attached, forms thiomorpholin-3-on-2-yl. 4. A compound according to claim 1, wherein R<3> is optionally substituted phenyl or (CH2)-optionally substituted phenyl. 5. A compound according to claim 2, wherein R<3> is optionally substituted phenyl or -(CH2)-optionally substituted phenyl. 6. A compound according to claim 3, wherein R<3> is optionally substiluted phenyl or-(CH2)-optionally substituted phenyl. 7. A compound according to claim 1, wherein said compound is selected from the group consisting of: 3-(4-chlorobenzyl)-5-[2-(4-methylpiperazin-1yl)-benzylidene]-imidazolidine-2,4dione; 3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-1yl)-benzylidene]-imidazolidine-2,4dione; 3-(4-chlorobenzyl)-5-[2-(4-methylpiperazin-1yl)-benzylidene]-thiazolidine-2,4dione; 4-benzyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorobenzyl)-2-[2-(4-methylpiperazin-1yl)-benzylidene]-thiomorpholin-3one, 3-(4-chlorophenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylldene]-thiazolidlne-2,4- dione; 3-(4-trifluoromethylphenyl)-5-[2-(4-methylpiperazin-1-yl)-benzylidene]thiazolidine-2,4-dione; 2-[2-(4-methylpiperazin-1-yl)-benzylidene]-4-(4-trifluoromethylphenyl)thiomorpholin-3-one; 2-12-(4-methylpiperazin-l-yl)-benzylidene]-thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-fluoro-6-(4-methylpiperazin-1-yl)-benzylidene]thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-morpholin-3one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin3-one; 4-(3,4-dichlorophenyl)-2-[2-(4-methylpiperazin-1-yl)-benzyl]-thiomorpholin-3-one; 4-methyl-2-[2-(4-methylpiperazin-1-yl)-benzylidene]-thiomorpholin-3-one; and 4-(3,4-dichlorophenyl)-2-(2-piperazin-1-ylbenzylidene)-thiomorpholin-3-one . and the pharmaceutically acceptable salts of such compounds. 8. A compound of the formula:   wherein R<1>, R<2>, R<3>, X and Y are as defined in claim 1. 9. A compound according to claim 8, wherein said compound is selected from the group consisting of: 4-benzyl-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl} thiomorpholin-3 one; 4-(3,4-dichlorobenzyl)-2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl} thiomorpholin-3-one; 2-{hydroxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl}-4-(4-trifluoromethylphenyl). thiomorpholin-3-one; 2-(hydrnxy-[2-(4-methylpiperazin-1-yl)-phenyl]methyl} thiomorpholin-3-one; 4-(3,4-dichlorophenyl)-2-{[2-fluoro-6-(4-methylpiperazin-1-yl)-hydroxymethyl} thiomorpholin-3-one; 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-(hydroxy-[2-(4-methylpiperazin-1 -yl)-phenyl]-methyl) thiomorpholin-3-one; 10. A pharmaceutical composition having a binding activity to serotonine -1 (5-HT1) receptors, comprising, as an active ingredient, an effective amount of a compound of formula I according to claim 1 in combination with a pharmaceutically acceptable carrier. 11. A composition according to claim 10 further comprising a 5-HT re-uptake inhibitor or a pharmaceutically acceptable salt thereof 12. A composition according to claim 11, wherein the S-HT re-uptake inhibitor is sertraline or a pharmaceutically acceptable salt thereof. 13. A method for treating or preventing a disorder or condition that carn be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising administering to a mammal in need of such treatment or prevention an amount of a compound according to claim 1 that is effective in treating or preventing such disorder or condition or compositions according to any of claims 10 to 12. 14. A method accordind to claim 13 for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, 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, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette syndrome, trichotillomania, kleptomania, male impotence, cancer, chronic paroxysmal hemicrania and headache.