Patent EA-001485-B1 (EA)
Title: Benzyl(idene)-lactam derivatives, their preparation and their use as selective (ant)agonists of 5-ht1a and/or 5-ht1d
Inventor: HOWARD HARRY R
IPC: A61K31/445
Filed: 1997-02-03
Abstract: 1. A compound of the formula I, depicted below,   wherein R<1> is a 2-dimethylaminoethoxygroup or group of the formula G<1>, G<2>, G<3>, G<4> or G<5>, depicted below,   wherein E is oxygen, sulfur, SO or SO2; R<6> and R<7> are independently selected from hydrogen, (C1-C6) alkyl, [(C2-C4)alkyl]aryl wherein the aryl moiety is phenyl or naphthyl, and heteroaryl-(CH2)q wherein the heteroaryl moiety is selected from pyridyl, pyrimidyl, benzoxazolyl, benzothiazolyl, benzisoxazolyl and benzisothiazolyl and q is zero, one, two, three or four, and wherein said aryl and heteroaryl moieties 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 SOg(C1-C6)alkyl wherein g is zero, one or two; or R<6> and R<7> together form a 2 to 4 carbon atom chain; x is zero to eight; each R<13> is, independently, is (C1-C4)alkyl or a (C1-C4) methylene bridge from one of the ring carbons of the piperazine or piperidine ring of G<1> or G<2>, respectively, to the same or another ring carbon atom or a ring nitrogen atom of the piperazine or piperidine ring of G<1> or G<2>, respectively, having an available bonding site, or to a ring carbon of R<6> having an available bonding site; R<8> is selected from hydrogen and (C1-C3) alkyl; R<9> is selected from hydrogen and (C1-C6)alkyl; or R<6> and R<9>, together with the nitrogen atom to which they are attached, form a 5 to 7 membered ring; and p is one, two, or three; R<2> is hydrogen, (C1-C4)alkyl, phenyl or naphthyl, wherein said phenyl or naphthyl may optionally be substituted with one or more substituents, preferably from zero to three substituents, independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano and SOg(C1-C6)alkyl wherein g is zero, one or two; R<3> is (CH2)mB, wherein m is zero, one, two or three and B is hydrogen, phenyl, naphthyl or a 5 or 6 membered heteroaryl group containing from one to four hetero atoms in the ring (e.g., furyl, thienyl, pyridyl, pyrimidyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, etc.), and wherein each of the foregoing aryl and heteroaryl groups may optionally be substituted with one or more substituents, preferably from zero to three substituents, independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, cyano, hydroxy, COOH and SOg(C1-C6)alkyl wherein g is zero, one or two; Z is CR<4>R<5>, wherein R<4> and R<5> are independently selected from hydrogen, (C1-C6)alkyl and trifluoromethyl; or Z may be one of the aryl or heteroaryl groups referred to in the definition of B above and wherein two adjacent ring members of Z are also members of ring A; X is hydrogen, chloro, fluoro, bromo, iodo, cyano, (C1-C6)alkyl, hydroxy, trifluoromethyl, (C1-C6)alkoxy, SOg(C1-C6)alkyl wherein g is zero, one or two, CO2R<10> or CONR<11>R<12>; each of R<10>, R<11> and R<12> is selected, independently, from the radicals set forth in the definition of R<2>; or R<11> and R<12>, together with the nitrogen to which they are attached, form a 5 to 7 membered ring that may contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen; n is one, two, three or four; and the broken line indicates an optional double bond; with the proviso that n must be one when Z is a heteroaryl group; and with the proviso that when R<1> is 2-dimethylaminoethoxygroup, R<2> is hydrogen, m is zero, B is 3,4-dichlorophenyl group, X is hydrogen, each of R<4> and R<5> is hydrogen, n is two, and the broken line indicates a double bond; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R<1> is piperazinyl. 3. A compound according to claim 1 wherein Z is CH2. 4. A compound according to claim 1 wherein n is two or three. 5. A compound according to claim 1, wherein R<3> is substituted phenyl. 6. A compound according to claim 2, wherein Z is CH2. 7. A compound according to claim 6, wherein R<3> is substituted phenyl. 8. A compound according to claim 7, wherein n is two or three. 9. A compound according to claim 1, wherein said compound is selected from: 3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one; 6-chloro-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one; 5-chloro-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one; 1-methyl-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one; 3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-phenyl-1,3-dihydro-indol-2-one; 1-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one; 1-(3,4-dichlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1,3-dihydro-indol-2-one; 1-(4-chlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one; 1-(4-chlorobenzyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one; 1-(3,4-difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one; 1-(2,4-dichlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one; 1-(3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one; 1-(4-chlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one; 1-(3,4-dichlorobenzyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one; 1-(4-chlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one; 1-(3,4-dichlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one; 3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-phenyl-pyrrolidin-2-one; 3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-(4-trifluoromethylphenyl)-pyrrolidin-2-one; 1-(3,4-difluorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzyl]-pyrrolidin-2-one; 3-[2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one; 3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one; 3-[2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one; 1-(3,4-dichlorophenyl)-3-[2-(4-methylpiperazin-1-yl)-benzyl]-piperidin-2-one; 1-(4-methoxyphenyl)-3-[2-(4-methylpiperazin-1-yl)-benzylidene]-3,4-dihydro-1H-quinolin-2-one; 1-(3,4-diochlorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzyl]-piperidin-2-one; 3-[2-(4-methylpiperazin-1-yl)-benzyl]-1-phenyl-pyrrolidin-2-one; 3-[2-(4-methylpiperazin-1-yl)-benzylidene]-1-(p-tolyl)-pyrrolidin-2-one; 3-[4-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-1-phenyl-pyrrolidin-2-one; 1-(3,4-dichlorophenyl)-3-[2-fluoro-6-(4-methylpiperazin-1-yl)-benzylidene]-pyrrolidin-2-one; 1-(3,4-difluorophenyl)-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperine- 2-one; 1-[2-(4-chlorophenyl)ethyl]-3-[5-fluoro-2-(4-methylpiperazin-1-yl)-benzylidene]-piperidin-2-one; 1-(3,4-dichlorophenyl)-3-[2-(2-dimethylaminoethoxy)-benzylidene]-pyrrolidin-2-one; and 3-[2-(4-methylpiperazin-1-yl)-benzyl]-1-(4-trifluoromethylphenyl)-pyrrolidin-2-one; and the pharmaceutically acceptable salts of such compounds. 10. A pharmaceutical composition 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 where changes in motility and secretion are involved and chronic paroxysmal hemicrania and headache associated with vascular disorders in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier. 11. A pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by enhancing serotonergic neurotransmission in a mammal, comprising an amount of a compound according to claim 1 that is effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier. 12. A method 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, vacospasm, cerebellar ataxia, gastrointestinal tract disorders where changes in motility and secretion are involved and chronic paroxysmal hemicrania and headache associated with vascular disorders 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. 13. A method for treating or preventing a disorder or condition that can 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. 14. A pharmaceutical composition 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 where changes in motility and secretion are involved, and chronic paroxysmal hemicrania and heada