MXPA98007983A - Lact derivatives - Google Patents

Abstract

A compound of the formula wherein R1, R2, R3, A, X, z, n and the broken line are defined as in the specification, these compounds are useful as psychotherapeutic agents

Description

PERIY? PQS PE LACTAflA BACKGROUND PE THE INVENTION The present invention relates to lactam derivatives "to processes and intermediates for their preparation" to pharmaceutical compositions containing them and to their use in medicine. The compounds of the present invention include selective serotonin receptor agonists and antagonists 1 < 5-HTx) f specifically »from one of the two 5-HTiA and 5-HTXD receptors. They are useful in the treatment or prevention of migraine »depression and other disorders for which 5-HTj agonists or antagonists are indicated. The publication of European patent 434,561» published on June 26, 1991 »refers to 7-alkyl. alkoxy and l- (4-substituted-e-piperaz m "l) -naphthalenes substituted with hydroxy The compounds are called 5-HTx agonists and antagonists useful for the treatment of migraine» depression »anxiety» schizophrenia »stress and pain The publication of the European patent 343.050 »published on November 23, 1989» refers to l - (- 4-ßubstituido-1-piperazinyl) -naphthalenes unsubstituted in composition 7 »halogenated and substi tuted with methoxy as ligands Useful 5-HTXA Therapeutics Glennon §t al .. refers to 7-methoxy-1- (Al-piperazinyl) -naphthalene as a useful 5-HT ... ligand, in its article "5-HT-D Serotonin Receptor "» Clinical Drug Res. Dev. 22.25-36 (1991) The article by ßlennon "Serotonin Receptors: Clinical Implantations" »Neuroscience and Behavoral Reviews 14. 35-47 (1990)» refers to the pharmacological effects associated with serotonin receptors including appetite suppression »therregulation, cardio effects vasculareß / hypothermia sleep »psychosis» anxiety »depression» nausea »emesis» Alzheimer's disease »Parkinson's disease and Huntington's disease. It is well established that ligands with high affinity for 5-HT ^ receptors have a therapeutic value for the treatment of human disorders caused by imbalance or serotonin. Worldwide patent application WO 95/31988 »published November 30, 1995» refers to the use of 5-HT antagonists or in combination with a 5-HTXA antagonist to treat CNS disorders such as depression »generalized anxiety »Obsessive-compulsive disorders» post-traumatic stress disorders »memory disorders» anorexia nervosa and bulima nervosa »Parkinßon disease. tardive dyskinesias »endocrine disorders such as hyperprolactinemia» vasospasm (particularly in the cerebral vascular system) and hypertension »disorders of the gastrointestinal tract where changes in modality and secretion are involved» as well as sexual dysfunction.

G. Maura e_t al. »J.IMeuroche» 66 < D »pags. 203-209 (1996) »have indicated the administration of selective agonists for 5-HTXA receptors or for 5-HT A and 5-HTiD receptors. it could represent a great improvement in the treatment of human cerebral ataxias »a many-faceted syndrome for which no established therapy is available.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of the formula I "represented below" wherein R * is a group of the formula Gx »Ga» G3 > G "» or Gß »represented later» G4 5S where E eß oxygen »sulfur» SO or S0a; R * and R "* are independently selected from hydrogen" alkyl (Cx-Cß> Calkyl (aC ^) 1 aryl "where the aryl radical is phenyl or naphthyl and heteroaryl -CH2), where the heteroaryl radical it is selected from pyridyl, pyrimidyl, benzoxazo, and q is zero, one, three, or four, and wherein said aryl and heteroaryl radicals may be optionally substituted with one or more substituents, preferably from zero to three independently selected substituents. between chloro »fluoro» bromo, iodo »alkyl (C -Cβ), alkoxy < CX-Cß), trifluoromethyl lo-cyano &Subalkyl < CX-Cß). where g is zero» one or two; or R * and R "7 together form a chain of 2 to 4 carbons, x is zero to eight, each Rxa is» independently »alkyl (Ca-C ^) or a methylene bridge (C -C ^) between one of the carbons of the piperazine ring or the piperidine ring of G or Gß "respectively" and the same or another ring carbon "or a nitrogen of the piperazine ring or of piperidine of G * or Ga" respectively »having a available linkage "or a ring carbon of R" having a binding site available; R * is selected from nitrogen and alkyl (C -Ca); R "is selected from nitrogen and alkyl (Cx-Cß); or Rß and R *. together with the nitrogen atom to which they are attached »form a ring of 5 to 7 members; and p is one »two or three» R * is hydrogen »alkyl (C -C ^). phenyl or naphthyl. wherein said phenyl may optionally be substituted with one or more substituents. preferably from zero to three substituents. independently selected from chlorine. fluoro. bromine »iodo» alkyl (C -Cβ) »(Cx-Cß)» trifluoromethyl »alkoxy and SOβalkyl (Cx-Cß)» where g is zero one or two; Ra is (CHa) mB > where rn is zero »one» two or three and B is hydrogen »phenyl» naphthyl or a 5- or 6-membered heteroaryl group containing 1 to 4 ring heteroatoms (eg, furyl »thienyl, pyridyl, pyrimidyl, thiazolyl) Pyrazolyl, isothiazole, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, etc.). and wherein each of the above 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 »alk (Cx-Cß). alkoxy (Cx-Cß), trifluoromethyl »cyano and SOßalqu lo (Cx-Cß>, where g is zero, one or two; 2 is CR- * R". where R- * and Rβ are independently selected from hydrogen »alkyl (Cx-Cß) and trifluoromethyl; or Z may be one of the aryl or heteroaryl groups mentioned in the definition of B above and where two adjacent members of the ring are Z are also members of the A ring; X is hydrogen, chlorine. fluorine »bromine» iodine »alkyl (Cx-Cß). alco? i (Cx-Cß>, trifluoromethyl, cyano, and SOßalkyl (C -Cß) »where g is zero, one or two» COaR * 0 ° CONRXiRX !? »each from Rio, R * x and R * is selected »Irrespective of the radicals indicated in the definition of Ra, or R and RAar» together with the nitrogen to which they are attached, they form a ring of 5 to 7 members which can contain from zero to four heteroatoms selected from nitrogen »sulfur and oxygen. for example, wherein R? - ^ R "* is pyrrolidinyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholyl, hexamethyliminyl, diazepinyl, oxazepinyl, thiazepinyl, oxadiazepine, thiadiazepinyl or triazepinyl. "n is one, two" three or four, and the dotted line indicates an optional double bond, with the proviso that n must be one when Z is an aryl or heteroaryl group "and pharmaceutically acceptable salts thereof. Below are more specific embodiments ace of groups GA and G *.

G1-. Gx-b Gl- < Gl-d: 1-, Gl-f G ^ g G2-h G2-a The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable addition salts of the aforementioned base compounds of this invention »are those which form non-toxic acid addition salts, ie» salts containing pharmacologically acceptable anions »such as the hydrochloride, hydrobromide salts. yohydrate nitrate, sulfate, bisulfate, acid citrate, tartrate, bitartrate. succinate. maleate fumarate »gluconate. saccharate. benzoate, methanesulfonate. ethanesulfonate. benzenesulfonate. p-toluenesulfonate and pamoate Let say, l-l-met len-bis (2-hydroxy-2-naphthoate) 3. The invention also relates to base addition salts of formula I. The chemical bases which can be used as reagents for preparing pharmaceutically acceptable base salts of the compounds of formula I which are acidic in nature, are those which form non-toxic base salts. with such compounds. Such non-toxic base salts include, but are not limited to, those obtained from pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), addition salts of ammonium or of water-soluble amines such as N-methyglucamine- (meglumine) "the lower alkanolammonium salts and other salts of pharmaceutically acceptable organic amine bases. The compounds of this invention include all stereoisomers and all optical isomers of the compounds of formula I (for example, R and S enantiomers) as well as racemic mixtures, diastereomers and other mixtures of such isomers. Unless otherwise indicated "the alkyl and alkenyl groups mentioned herein" as well as the alkyl radicals of other groups mentioned herein (eg, alkoxy) may be linear or branched, and may also be cyclic (eg. cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or can be linear or branched and contain cyclic radicals. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine. Preferred compounds of formula I include those in which RA is piperazinyl. Preferred compounds of formula I also include those in which Z is CHa. Preferred compounds of formula I also include those in which R * is substituted phenyl. Examples of preferred specific compounds of the formula I are the following: 3-C2- (4-methylpiperaz-1-l) -benz-1-ideno-1 -3-dihydro-indol-2-one »6-C1-gold-3 -C2- (-methylpiperazin-li 1) -benzyl 1 ideno3-1.3-dihydro-1-one-1-one; 5-chloro-3-C2- (4-methyl-1-perazin-1-yl) -benzyl-1-idene-1-1.3-dihydro-indo-1-one-one; 1-methyl-3-C2- (4-methylpiperazin-1-yl) -benzyl-1-idene 3-1.3-dihydro-indol-2-one; 3-C2- (4-methyl-piperazin-1-yl) -benzylidene-Jl-phenyl-1,3-dihydro-indo-1-2-one »l- (3,4-dichlorophen-1) -3-C2- (4-methylpiperazine) -l-il) -benz 1 i denoD-pi rro1 i di n-2-one; l- (3 »4-dichlorobenzyl) -3-C2- (4-met lpiperazin-1-yl) -benzyl-1 ideno-1 -3-dihydro-indol-2-one; l- (4-chlorobenzyl > -3-C2- (4-methylpiperazin-1-l) -benzyl ideno-D-pyrrolidin-2-one; l- (4-chlorobenzyl) -3-C5-fluoro-2- (4-methypiperazine) 1-i 1) -benzyl 1 i deno-pi rro1 idin-2-one; l- (3 »4-difluorophenyl) -3-C2- (4-methylpiperazin-li 1) -benzyl 1 i denoD-pi rro1 n-2-one; l- (2 »4-dichlorobenzyl) -3-C2- (4-methylpiperazin-1-yl) -benzyl 1 -deno-D-pi rro1 i di n-2-one; 1- (3» 4-dichlorophenyl) -3-C5-fluoro-2- (4-methylpiperazin-1-yl) -benzyl-1 ideno-3-pyrro1-idin-2-one »l- (4-chlorobenzyl) -3- 2- (4- meti piperazin-1-i 1) -benzyl 1 i denoD-pi peridin-2-one; l- (3 »4-dichlorobenzl) -3-C2- (4-methylpiperazin-1-l) -benzl ideno3 -piper din-2-one; l- (4-c lorophenyl) -3-C5-fluoro-2- (4-methylpiperazin-1-l) -benzyl-1 ideno-3-piperidin-2-one; l- (3,4 -dichlorophen 1) -3-C5-fluoro-2- (4-methyl-piperazin-1-yl) -benzyl-1-idene-piperidin-2-one; 3-C2- (-methyl-piperazyl-1-benzyl) 1 ideno3-1-fe nor 1-pyrrole idin-2-one; 3- 2- (-meti Ipiperazi n-l-1) -benz i 1 ideno3-1- (4-trifluoromethyl-1-phenyl-1-pyrrolidin-2-one; l- (3 »4-difluorophenyl) -3-C2- (4-methylpiperazin-li 1) -benzyl 1 -pyrrolidin-2-one» 3-C2- (4-methylpiperazin-1-yl) -benzyl ideno3-pyrrole idin-2-one; 3-C5-fluoro-2- (4-methypiperazyl-1-yl) -benzyl ideno-3-pyrrole din-2-one; 3-C2- (4-meti Ipiperazi n-l-i 1) -benci lideno3-piperidin-2-one; 1- (3,4-dichlorophen-1) -3-C2- (4-methyl-piperazin-1-yl) -benzyl-piperidin-2-one; l- (4-oxyphenyl) -3-C2- (4-methylpiperazin-1-yl) -benzyl-1-ideno-3-4-dihydro-1H-qui no1-n-2-one »l- ( 3,4-dichlorophen-1) -3-C5-fluoro-2- (4-methylpiperazin-1-yl) -benz-13-piperidin-2-one; 3-C2- (4-methyl-piperazin-1-) - benz 13-1-pheny1-pyrrolidin-2-one »3-C2- (4-methy1 piperazyl n1) -benzyl 1 ideno3-1- (p-tol i1) -pyrrole din-2-one; 3-C4-fluoro-2- (4-methylpiperaz nl-yl) -benzyl ideno3-l-pheni 1-pi rro1 idi n-2-one; l- (3 »4-d chloropheni 1) -3-2-fluoro-6- (4-methyl-1-piperazin-1-yl) -benzyl-idene-3-pyrrolidi-2-one; l- (3 »4-difluoropheni 1) -3-C5-fluoro-2- (4-methylpiperaz n-1-yl) -benzyl idene -piperin-2-one; l-C2- (4-chlorophenyl) eti 13-3-C5-fluoro-2- (4-methylpiperazin-1-yl) -benzyl idene -piperidin-2-one; l- (3 »4-dichlorophenyl) -3-C2- (2-dimethylaminoethoxy) -benzyl-1-ideno-3-pi rrol id n-2-one» and 3-C2- (4-methylpiperazin-1-yl) benzyl 3- 1- (4-trifluoromethylphenyl) -pyrrol idin-2-one. Other compounds of formula I include the following: l- (3 »4-dichlorophenyl) -3-C2- (4-methy1piperazin-1-y1) -benzylidene-azet-di-2-one; l- (3,4-dichlorophenyl-3-C2- (4-methylpiperazin-1-yl) -benzyl-1-idene-3-azepin-2-one; l- (3 »4-di chlorophenyl) -3-Cl-C2- (4 -meti Ipiperazi nli 1) -feni 13eti 1.}. -pi rrol idin-2-ona; l- (3 »4-dichlorophenyl) -3-Cl-C2- (4-meti Ipiperazi nli 1) -phenylDethyl-piperidin -2-one »l- (3» 4-dichloropheni 1) -3-Cl-C2- (4-methypiperazyl) 1-phenyl-1,3-idene.} -pyrrol idin-2-one; dichlorophenyl) -3-Cl-C2- (4-methylpiperazin-li 1) -phen-1-eti 1 ideno-piperidin-2-one; l- (3 »4-dichlorophenyl) -3-CC2- (4-methylpiperazine) -1-i 1) -pheni 13-phenylimmethylene. Pyrrol-idin-2-one; l- (3 »4-dichlorophenyl) -3-C2-C (2-dimethylaminoeti 1) -methyl-1-non-benzylidene} -pyrrole n-2-one; l- (3 »4-dichlorophen 1> -3-C2- (pi rol din-li-letoxy) -benzyl-1-ideno-3-pi rro1-id-2-one; l- (3» 4-dichlorophenyl) -3 -C2- (2-dimet laminoeti lamino) -benzyl 1 ideno3-pi rro1 id n-2-one; 2- (3 »4-di chlorophenyl) -3-C2- (2-dimethylaminoeti lami no) -benz 1 ideno-3-pyrro1-id n-2-one; 2- (3'-4-d-chlorophenyl) -4-C2- (4-methyl-1-piperazyl-1-benzyl-idene-3-octahydro-isoquinol-3-one »l- (3 »4-dichlorophenyl) -3-C2-I4-meti Ipiperazi nli 1) -benz i 1 ideno3-oc ahydro-qui nol in-2-one; l- (3 »4-dichlorophenyl) -3-C2- (4-methyl-piperazin-1-yl) -benzyl-idene-3-octahydro-indol-2-one» and l- (3,4-dichlorophen-1) -5,5-dimethyl -3-C2- (4-methylpiperazin-1-y1) -benzyl deno3-pyrrole idin-2-one. The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from hypertension »depression» generalized anxiety disorders »phobias (eg» agoraphobia »social phobia and simple phobias)» post-traumatic stress syndrome » disorders of personality cancellation »premature ejaculation» eating disorders (for example »anorexia nervosa and bulimia nervosa)» obesity »chemical dependencies (for example» addictions to alcohol »to cocaine» to heroin, to phenolbarbitol, to nicotine and benzodiazepines) • cluster headache »migraine» pain Alzheimer's disease »obsessive-compulsive disorders» panic disorders »memory disorders (for example» dementia »disorders in babies and memory loss associated with age), diseases of Parkinson's disease (for example »dementia in Parkinson's disease» induced neuroleptic parkinsonism and d delayed iskinesias) »endocrine disorders (for example» hyperprolactinemia) »vasospasm (particularly in the vascular system of the brain)» cerebellar ataxia. Gastrointestinal tract disorders including changes in motility and secretion »hermicrania paroxis al chronic and headache associated with vascular disorders in a mammal» preferably in a human »comprising an amount of a compound of the formula io a pharmaceutically acceptable salt of the same »effective in the treatment or prevention of such disorder or condition and a pharmaceutically acceptable vehicle. The present invention also relates to a pharmaceutical composition for the treatment or prevention of a disorder or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal »preferably in a human» comprising an amount of a compound of the formula I Or a pharmaceutically acceptable salt thereof effective in the treatment or prevention of such disorder or condition and a pharmaceutically acceptable carrier. Examples of such disorders and conditions are those listed in the previous paragraph.

The present invention also relates to a method of treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorders, phobias (e.g., agoraphobia, social phobia and simple phobias), post-traumatic stress syndrome. of personality cancellation »premature ejaculation» eating disorders (for example »anorexia nervosa and bulimia nervosa)» obesity »chemical dependencies (for example, additions to alcohol, cocaine» to heroin »to phenolbarb tol. nicotine and benzodiazepines) »cluster headache» migraine »pain, Alzheimer's disease, obsessive-compulsive disorders, panic disorders, memory disorders (for example» dementia, amnestic disorders and memory loss associated with age), Parkinson's disease (eg, dementia, Parkinson's disease, induced neuroleptic parkinsonism and tardive dyskinesias), after endocrine lathes (for example, hyperprolactinemia). vasospasm (particularly in the vascular system of the brain). cerebellar ataxia. gastrointestinal tract disorders including changes in motility and secretion, chronic paroxysmal hemicrania and headache associated with vascular disorders in a mammal, preferably in a human being »which comprises administering to a mammal in need of such treatment or prevention» an amount of a compound of the formula I "or a pharmaceutically acceptable salt thereof" which is effective in the treatment or prevention of such disorder or condition. The present invention also relates to a method of treating or preventing a disorder or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal, preferably in a human being which comprises administering to a mammal in need of such treatment or prevention. , an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, which is effective in the treatment or prevention of such disorder or condition. The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from hypertension »depression» generalized anxiety disorders, phobias (eg, agoraphobia »social phobia and simple phobias), post-traumatic stress syndrome, disorders of annulation of the ad person, premature ejaculation, eating disorders (for example »anorexia nervosa and bulimia nervosa)» obesity »chemical dependencies (for example» addictions to alcohol »to cocaine» to heroin »to phenol barbitol» to nicotine and benzodiazepines) »cluster headache» migraine »pain» Alzheimer's disease »obsessive-compulsive disorders» panic disorders, memory disorders (for example, dementia, amnestic disorders and memory loss associated with age) , Parkinson's diseases (for example, dementia in Parkinson's disease, neuroleptic induced pair induction and dyskinesias late), endocrine disorders (eg, hyperprolactinemia), vasospasm (particularly in the vascular system of the brain), cerebellar ataxia, gastrointestinal tract disorders including changes in motility and secretion, chronic paroxysmal hemicrania, and headache associated with vascular disorders in a mammal, preferably in a human being »comprising an amount effective to antagonize or agonize the serotonin receptor» of a compound of the formula I »or a pharmaceutically acceptable salt thereof» and a pharmaceutically acceptable carrier. The present invention also relates to a pharmaceutical composition for the treatment or prevention of a disorder or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal "preferably in a human" comprising an amount effective to antagonize or agonize the receptor of the serotonin "of a compound of the formula I" or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The present invention also relates to a method for treating or preventing a disorder or condition selected from hypertension »depression» generalized anxiety disorders »phobias (for example» agoraphobia »social phobia and simple phobias), post-traumatic stress syndrome. disorders of personality cancellation »sexual dysfunction (for example» premature ejaculation), eating disorders (for example »anorexia nervosa and bulimia nervosa). obesity, chemical dependencies (for example, addictions to alcohol, cocaine, heroin, phenolbarbitol, nicotine, and benzodiazepines). cluster headache, migraine, pain, Alzheimer's disease »obsessive-compulsive disorders» panic disorders »memory disorders (for example, dementia, amnestic disorders and memory loss associated with age), Parkinson's diseases (for example, dementia in Parkinson's disease, induced neuroleptic parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinemia). vasospasm (particularly in the vascular system of the brain), cerebellar ataxia. Gastrointestinal tract disorders including changes in motility and secretion, chronic paroxysmal hemicrania and headache associated with vascular disorders in a mammal, preferably in a human being, which comprises administering to a mammal that requires such treatment or prevention, an effective amount for antagonizing or agonizing the serotonin receptor, a compound of formula I or a pharmaceutically acceptable salt thereof. The present invention also relates to a method of treating or preventing a disorder or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal, preferably in a human being, which comprises administering to a mammal that requires such treatment or prevention, a an amount effective to antagonize or agonize the serotonin receptor, a compound of the formula I or a pharmaceutically acceptable salt thereof. The present invention relates to a pharmaceutical composition for the treatment or prevention of a tracheobron or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal »preferably in a human being, comprising: a) a pharmaceutically acceptable carrier; b) A compound of formula I or a pharmaceutically acceptable salt thereof; and O a 5-HT reuptake inhibitor. preferably sertral na. or a pharmaceutically acceptable salt thereof; wherein the amounts of the active compoundsß (ie, the compound of formula I and the 5-HT reuptake inhibitor) are such that the combination is effective in the treatment or prevention of such disorder or condition. The present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal, preferably in a human being, which comprises administering to a mammal that requires such treatment or prevention: a) a compound of the formula I, defined above, or a pharmaceutically acceptable salt thereof; and b) a 5-HT reuptake inhibitor, preferably sertraline »or a pharmaceutically acceptable salt thereof» where the amounts of the active compounds (ie »the compound of formula I and the 5-HT reuptake inhibitor. ) are such that the combination is effective in the treatment or prevention of such disorder or condition. The present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal »preferably a human being» which comprises administering to said mammal that requires such treatment or prevention: a) a 5-HTXA antagonist or a pharmaceutically acceptable salt thereof; and b) a 5-HTXD antagonist or a pharmaceutically acceptable salt thereof; wherein the amounts of each active compound (e.g., the 5-HTXA antagonist and the 5-HT antagonist) are such that the combination is effective in the treatment or prevention of such a tracheal or condition. "Augmented Serotonergic Neurotransmission" as used herein refers to the enhancement or enhancement of the neuronal process by which a pre-synaptic cell releases serotonin upon excitation and crosses the synapse to stimulate or inhibit the post-synaptic cell. "Chemical dependency" as used herein means an abnormal desire or craving for »or an addiction to a drug or drug. Such drugs or drugs are generally administered to the affected individual by any of a variety of means of administration "including oral, parenteral, nasal or inhalation routes. They are examples of chemical dependencies which can be treated by the processes of the present invention, dependencies of alcohol, nicotine, cocaine, heroin, phenol barbitol and benzodiazepines (for example, Val ium (trademark)). "Treatment of a chemical dependency," as used herein, means reducing or alleviating such dependence. ßertraline »(lS-cis) -4- (3» 4-dichlorophenyl) -1,2,3 », 4-tetrahydro-N-methyl-1-naphthalenamine. as used in this document, it has the chemical formula Cx-, H ^ -NCl ^ and the following structural formula l its synthesis is described in U.S. Patent 4,536,518, assigned to Pfizer Inc. Sertraline hydrochloride is useful as an antidepressant and an anotonic agent, and is also useful in the treatment of depression, chemical dependencies »obsessive-compulsive anxiety disorders» phobias »panic disorders» post-traumatic eßtreß disorders and early ejaculation.

DETAILED DESCRIPTION OF THE INVENTION The compounds of the formula I can be prepared according to the following reaction and discussion schemes. Unless otherwise indicated, R * to RAat, Gx to Gß. X »A» B »E» Z »n. m »p. q and g "and structural formula I in the reaction schemes and in the discussion shown below, are as defined above.

SCHEME 1 IA IB < R3 not K > SCHEME 2 XV IB III < Rl = GJ H) SCHEME 2 (CONTINUED) III (R1 = 6d, R * H) (Scheme 1) III < Rl = 6Z, R * not H) (Scheme 1) IR or 18 SCHEME 3 XIV butyl-lithium XVI (R2 = G2) Scheme 1 illustrates a procedure for synthesizing compounds of the formula I »wherein the broken line represents a carbon-carbon double bond and R1 is a group of the formula Gx» Ga »G **» or Gß. Referring to Scheme 1, a compound of the formula II is reacted wherein Q is a suitable leaving group (for example, chloro, fluoro, bromo, mesylate, tosy ato, etc.) with a compound of the formula R * H 'wherein R3- is a group of the formula G * »G3» G ** »or Gß, in the presence of a base» to form the corresponding compound of formula III. The reaction is generally carried out at a temperature of from about 0 ° C to about 140 ° C "preferably at about the reflux temperature" in a polar solvent, such as dimethyl sulfoxide (DMSO). N.N-dimethyl Iformam gives 8DMF) »N» N-di met l acetamide (DMA) 0 N-methyl 1-2-pyrrolidone (NMP) »preferably (DMF). Suitable laß baßes include anhydrous sodium carbon (Na2COa) > potassium carbonate (KaCOß). sodium hydroxide (NaOH) and potassium hydroxide (KOH) »as well as tertiary amines such as pyrrolidine» triethylamine and pyridine. Anhydrous potassium carbonate is preferred. The compounds of the formula III can be converted into compounds of the formula I "wherein R * is other than hydrogen (ie, compounds of the formula IB" as depicted in Scheme 1) "by subjecting them to an aldol condensation or a Witting reaction. For example, in the case of an aldol condensation, a compound of the formula III can be reacted with a compound of the formula in the presence of a "bar" to form an intermediate to the dicole of the formula V »which can be directly added or converted» to the same reaction stage »in a compound of the formula IB by loss of water. The degree of completion of the conversion of the compound of formula III to the aldol product of formula IB can be determined using one or more analytical techniques such as thin layer chromatography (tick) or mass spectrometry. In some cases it may be possible or desirable to isolate the intermediate of formula V. In such a case, the compound of formula V can be converted to formula IB by water use using technique which is familiar to those skilled in the art, for example »by heating to the reflux temperature of a solution of the compound of the formula V in a solvent such as benzene» toluene oxylene »in the presence of a catalytic amount of benzene or p-toluene-sulfonic acid» ensuring the elimination of the water generated. Such water removal techniques may include the use of molecular sieves or a Dean-Stark trap to isolate the water created as an azeotrope with the solvent.

The aldol reaction is typically carried out in a polar solvent such as DMSO, DMF, tetrahydrofuran (THF), methanol or ethanol, at a temperature of from about -25 ° C to about BO ° C. Preferably, this reaction is carried out in THF at about 25 ° C. Suitable bases for use in the aldol formation stage include K3COa, Na2COa, sodium hydride (NaH), pyrrolidine and piperidine. Sodium hydride is preferred. In "Modern Synthetic Reactions» "Herbert O. House» 29. Edition »W.A. Benjamin. Menlo Park »California 1972» pages 629-682 »condensations are described. Compounds of the formula I in which R 3 is hydrogen (compueßtoß of the formula A "as shown in Scheme 1) can be prepared by an aldol condensation in a manner analogous to that described above for the formation of compounds of the formula IB »But using as the starting material a compound of the formula IV in which R * is hydrogen or -C (= 0) RA3, where R ^ is (C-C) alkyl or trifluoromethyl. The compounds of the formula IA can be converted to compounds of the formula IB by reaction of the mißmoß with a compound of the formula R * Y wherein Y is a leaving group and is defined as Q that has been defined above. These reactions can be carried out in a solvent such as di- (alkyl) ether, THF »DMF, DMA or DMSO, preferably DMF, in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydride» potassium hydride »sodium hydroxide or potassium hydroxide, preferably sodium hydride. The reaction temperatures may vary from about 0 ° C to about 150 ° C. preferably between about 25 ° C and about the reflux temperature of the solvent. Alternatively, the compound of formula IV can be converted to a compound of formula IB by means of an olefination of Wittig »as described in Helvetica Chimica Acta» 1963 »46 ,. 1580 and is represented below.

IV L = H XII XI L = c e.g. Br) Thus, the compound of formula IV can be converted into the corresponding bromide of formula XI using conventional bromination conditions. followed by treatment with triphenylphosphine in anhydrous THF to form the intermediate of formula XII. The compound of formula XII can then be treated with a strong base (for example aqueous Na ~ CO.) To generate the corresponding phosphonium ylide »which can then be reacted with the appropriate intermediate of formula I. This transformation is described in A Maercker. Organic Reaction® 1965. 14. 270. Compounds of formula I in which the dotted line represents a single carbon-carbon bond can be prepared by hydrogenation of the corresponding compounds in which the broken line represents a double link that are well known for conventional loe that are well known to the specials in the art. For example "reduction of the double bond with hydrogen gas (H can be performed. Taleß using catalysts such as palladium on carbon (Pd / C), palladium on barium sulfate (Pd / Ba ^ SO ^), platinum on carbon (Pt / C). or tris (triphenylphosphine) rhodium (Wilkinson's catalyst). in an appropriate solvent such as methanol. ethanol, THF, dioxane or ethyl acetate, at a pressure of about 1 to about 5 atmospheres and a temperature of about 10 ° C to about 60 ° C, as described in Catalyze Hydrogenation in Organic Svnthesiß, Paul Rylander, Academic Press Inc., San Diego, 1979, pages 31-63 The following conditions are preferred: Pd on carbon, methanol at 25 ° C. ° C and a hydrogen gas pression 344.73 kPa. This method also provides for introduction of hydrogen isotopes (i.e., deuterium »tritium) .¡¡ replaced. by aHa or" H., in the above method. a alternative procedure that employs the use of reagents such as ammonium formate and Pd / C in methanol »at reflux temperature» under an atmosphere of inert gas (eg »nitrogen gas or argon) is also effective in reducing the carbon-carbon double bond of the compounds Formula I. Another alternative procedure includes the selective reduction of the carbon-carbon double bond using samarium and iodine or samarium iodide (Sml-) in methanol or ethanol "at approximately room temperature" as described by R. Yanada et al. .. Synlett. , 1995 »pages. 443-4. The starting materials of the formula II and IV are available on the market or are known in the art. For example, compounds of formula II in which Rs is hydrogen are readily available from commercial sources or can be prepared using methods described in the chemical literature. They can also be prepared from the corresponding carboxylic acids or ester (ie, formula II in which R * = OH or O-alkyl), which are available on the market. Eßtoß acid or esters can be reduced to the corresponding alcohols of formula XIII, represented below "wherein Q is defined as for formula II" using one or more of a variety of reducing agents and conditions "depending on the nature of the sust QY X listeners Q Such reducing agents include sodium borohydride (NaBH ^) »sodium cyanoborohydride (NaCNBHa). lithium aluminum hydride (LiAlH.,) and borane in THF (BHa-THF) in solvents such as methanol. ethanol. THF diethyl ether and dioxane. Oxidation of the alcohol of formula XIII to the corresponding aldehyde of formula II. You can be accomplished using a selective oxidizing agent such as Jones reagent (chromate hydrogen (H ^ CrO ^). chromate pyridinium (PCC) or magnesium (MnO_a) dioxide. They can easily see references for taleß conversions (eg " KB W lberg Oxidation in Organic Chemistry, Part A. Academic Preßß Inc. NY 1965. pp. 69-72) The starting materials of formula IV can be prepared by various methods, including the procedures described in the literature, for example. the compounds of formula Iv in Z is an aromatic ring and n- = l (i.e., 3-dihydro-indol-2-one and substituted analogues thereof), are commercially available or can be prepared using methods described in »for example» H.R. Howard and R. Sarges, Patent of the United States of 4,476,307 or October of 1984. A process for preparing the starting materials of formula IV in which Z is CR-'R "and n is one» or three , includes the condensation of a cyclic lactone of the formula VIII with an amine of the formula H ^ NR3 »as it moves further» in the presence of a strong mineral acid such as hydrochloric acid (HCl). (Véaße MJ Kornet »J Pharm. Sci. »1979. 6B (3) .350; and J. Het. Chem. 1966, 3. 311).

IV IVB As an alternative, the compound of formula IV in which R 3 is hydrogen (compound of formula IVA) can be alkylated to form the corresponding compounds in which R 3 is not hydrogen (compounds of formula IB) using conventional techniques available for the special ißtaß in the art, for example by (a) generation of the desired compound anion of formula IVA using a strong base / polar solvent such as NaH / THF, NaH / DMF or n-buty 1-lithium / THF (n) -buLi / THF) at a temperature from about -30 ° C to about the reflux temperature of the solvent "for a period of about 5 minutes to about 24 hours" and (b) treatment of the anion with an alkylating agent of the formula R ^ in which Y is a leaving group such as chlorine »bromine» iodine or mesylate This process is shown below.

[VR IVB (R3 = H) (R3 not = H) The above conversion of the compounds of formula IVA to formula VB can also be achieved using transfer catalysis conditions of faßeß as described by Takahata e_t § .. »Heterocycles» 1979. 12 (11), p. 1449-1451. The compounds of formula RAH used in the preparation of intermediates of formula III. they can be easily purchased or can be prepared using conventional methods of organic synthesis known to those skilled in the art, and methods adapted from methods described in the chemical literature. For example »the preparation of the compounds of formula RXH» in which R * eß G * - »can real zarße using the following reaction sequence, starting with N-tert-butoxycarbonyl piperazine available on the market (VI): V I V I I The alkylation of the compound of formula VI with a compound of the formula R * Y wherein Y is defined as above and R * is alkyl (Cx-Cß). arylalkyl (Cß-C "> where the aryl radical phenyl or naphthyl or heteroary lo- (CHa,) ,," where q eß zero »one» doß »three or four, and the heteroaryl radical is selected from pyrid »Pyrimidyl, benzoxazole ilo» benzothiazolyl, benzoisoxazole and benzoisothiazolyl »in the presence of an acid scavenger, (eg» sodium bicarbonate (NaHCOa) »potassium bicarbonate (KHCOa), sodium carbonate (Na2COa) or potassium carbonate (KJCO) ) »In a polar solvent such as acetone, at a temperature of about 10 ° C to about the reflux temperature of the solvent» will produce the intermediate of formula VII The removal of the tert-butoxycarbonyl group can be carried out using acidic conditions, example, HBr in acetic acid or trifluoroacetic acid until the reaction is considered complete The compounds of formula III in which R x e β tetrahydropyridone or piperidine and R 2 e β hydrogen, can be prepared from 2-bromobenza lehido, which is available on the market »as depicted in Scheme 2. Referring to Scheme 2» the compound of formula II ß converts first to a protected aldehyde or ketone of the formula XIV »where p represents the aldehyde radical or whole protected ketone, using procedures well known in the art. For example, the 1,3-dioxolane derivative of the aldehyde or ketone can be prepared according to the process described by J.E. Colé et al. »J. Chem. Soc.» 1962 »p. 244 »by refluxing a solution of the aldehyde of formula II and l-3-propanediol in anhydrous benzene with a catalytic amount of p-toluenesulfonic acid. When Ra of formula II is not hydrogen, the ketone can be protected by an appropriate protective group. Appropriate protecting groups can be chosen from many such groups based on the presence and nature of the substituent x. Examples of suitable protecting groups β can be found in T.W. Greene »Protecting Groups in Organic Synthesis, John W Law and Sons» New York, 19B1. The most preferred protecting groups are those which are resistant to catalytic hydrogenation (e.g., 1 »3-dioxolane) and» therefore allowing a further reduction »ßi eß neceßario. of the carbon-carbon double bond of the tetrahydropyridines of formula XVI. The compounds of the formula XIV can then be treated with vin leßtannanoß of formula XV. for example »1-B0C-4-trimeti leßtanni l-l» 2 »5» 6-tetrahydropyridine (BOC = tert-butoxycarboni lo). in the presence of a catalyst »to form the corresponding compound of formula XVIA. Palladium is the preferred catalyst (for example) (PHaP) ^ Pd or Pda (dba) a) »where dba = di-1-idenoacetone. This reaction can be carried out as described in "Palladium-catalyzed V nylation of Organic Halides" in Organic Reactions, Vol 27 »p. 345-390 »W.G. Dauben »Ed.» John Wiley and Sons »Inc., New York» New York. 1982. The compounds of formula III in which R is piperidine (G3) »can be prepared by catalytic hydrogenation of the tetrahydropyridine of formula XVIA of the previous paragraph» using conventional methods known in the art »generally using palladium on carbon as a catalyst» for form the corresponding compounds of the formula XVIB. This reaction is typically carried out in an inert solvent, such as ethanol or ethyl acetate, with or in a protic acid such as acetic acid or HCl. Acetic acid is preferred.Loe protecting groups in G2 (ie, BOC) can be removed using one or more of the techniques described in Greene. mentioned above, for example, by stirring the compound of formula XVI in ethyl acetate and 3M hydrochloric acid at about room temperature the aldehyde or ketone, P, can be converted to the unprotected ketone or aldehyde of the formula -C (= 0 ) Ra, using one or more of the deßcritaß technique in Greene, for example, by stirring a solution of the compound of formula XVI in THF and 554 hydrochloric acid at room temperature, for 20 hours. The compounds of the formula XIV of the above reaction scheme can also be treated with alkyl lithium reagents, for example butyllithium, εec-butyl-1-1-thio or tert-butyl-lithium. preferably butyl lithium in an inert solvent, as shown in Scheme 3 »to form the intermediate lithium anion of formula XVII. Suitable solvents for this reaction include. for example. ether or tetrahydrofuran. preferably tetrahydrofuran. The reaction temperature may vary between about -110 ° C and about 0 ° C. The intermediate lithium anionis of formula XVII can then be further reacted with a suitable electrophile, the selection of which depends on the pre-existence and nature of the receptor. The ectrophilic agents suitable for use in the preparation of compounds of formula III in which R x is a group of the formula G 3 include, for example, derivative, carbonyl or alkylating agents (for example, 1-BOC-4-piperidone). In case an aldehyde or ketone is used as an electrophile, the hydroxy group has to be removed from the intermediate of formula XVIII as shown below, to form the corresponding compound of formula II BO C XV I J i l l (R1 = G2) This step can be carried out by one of several conventional methods known in the art. For example, a carbonyl derivative such as xanthate can be prepared and removed by the radical-free process, of which both are known to those skilled in the art. Alternatively, the hydroxyl group can be removed by reduction with a hydride source such as trieti Isi la or under acidic conditions using, for example, trifluoroacetic acid or boron trifluoride. The reduction reaction can be carried out in the pure state or in a solvent such as methylene chloride. A further alternative may be to convert the hydroxyl group to a suitable leaving group, such as tosylate or chloride, using conventional procedures known in the art, and then remove the leaving group with a nucleophilic hydride, such as, for example, lithium hydride. and aluminum. This latter reaction is typically carried out in an inert solvent such as ether or tetrahydrofuran. In addition, a reducing agent can be used to remove the benzyl ester reductively. Suitable reducing agent agents include, for example, Raney nickel in ethanol and sodium or 1 in liquid ammonia. Another alternative method for removing the hydroxyl group is to first dehydrate the alcohol of formula VIII to form an olefin with a reagent such as Burgenss salt (J. Org. Chem .. 1973. 38, 26) and then catalytically hydrogenating the double bond under conventional with a catalyst such as palladium on carbon. The alcohol can also be dehydrated to form the olefin by treatment with an acid such as p-toluenesulfonic acid. The compounds of the formula III in which R e G3 and R * is hydrogen »can be converted into the corresponding compounds of the formula III in which R is G3 and R * is other than hydrogen» by reaction of the mißmoß with a compueßto of the formula RβY »as previously described» to prepare compounds of the formula VII. Unless otherwise indicated, the pressure of each of the above reactions is not critical. Usually. the reactions will be carried out at a pressure of about one to about three atmospheres, preferably at ambient pressure (approximately one atmosphere). The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable ßal and then simply convert the latter into the compound of free base by treatment with an alkaline reagent "and subsequently converting the free baße into a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are easily prepared by treating the base compound with a substantially equivalent amount of the chosen organic or mineral acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. . After careful evaporation of the solvent, the desired solid salt is obtained. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, ie, salts containing pharmacologically acceptable anions such as saltse hydrochloride. »Hydrobromide» hydroiodide »nitrate» sulfate or bisulfate »phosphate or phosphate acid» acetate »lactate» citrate »or acid citrate» tartrate or bitartrate »ßuccinate» maleate »fumarate» gluconate »saccharate. benzoate, methanesulfonate and patoate Cs say »1, '-methyl-bis- (2-hydroxy-3-naphthoate) 3. The compounds of formula 1 which are also acidic in nature, for example, when R3 includes a COOH or tetrazole radical, they can form salts of bases with various pharmacologically acceptable cations. The examples of such salts include the alkali metal or alkaline earth metal salts and, in particular, the sodium and potassium salts. These salee are all prepared by conventional techniques. The chemical baaes that are used as reagents for preparing the laß salee of pharmaceutically acceptable bases of this invention are those which form non-toxic base salts with those with the acidic compounds described herein in formula 1. These non-toxic base salts include laß. derived from pharmacologically acceptable cations such as ßodio »potassium» calcium and magnesium »etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the pharmacologically acceptable cations described and the subsequent evaporation of the resulting solution to the dryness »preferably» under reduced pressure. As an alternative they can also be prepared by mixing together lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxides and then evaporating the resulting solution to dryness in the same manner as indicated above. In any case, they preferably employ stoichiometric amounts of reagents to ensure the completion of the reaction and maximum yields of the products. The compounds of formula 1 and their pharmaceutically acceptable saltse (hereinafter collectively referred to as "loe compueßto activeß") are useful psychotherapeutics and are potent agonists and / or antagonists of the serotonin A (5-HTXA) receptors and / or of the serotonin ID (5-HTxo). The active compoundsßßß useful in the treatment of hypertension »depression» generalized anxiety disorder «phobias (for example» agoraphobia »social phobia and simple phobias)» post-traumatic stress syndrome »disorders of personality annulment» sexual dysfunction ( for example premature ejaculation), eating disorders (for example, anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (for example, "alcohol addictions" to cocaine, heroin, phenolbarbitol, nicotine and laß benzodiazepines). ) »Cluster headache» migraine »pain» Alzheimer's disease »obsessive-compulsive disorder» panic disorder »memory disorders (for example» dementia in Parkinson's disease »induced neuroleptic parkinsonism and tardive dyskinesiaß) endocrine traßtornoß (for example» hyperprolactinemia ) »Vasospasm (particularly in the vascular system of the brain), cerebellar ataxia ar »gastrointestinal tract disorders including changes in motility and secretion» chronic paroxysmal hemicrania and headache associated with vascular disorders. These compounds are also useful as vasodi 1 atadoreß. The affinities of the compounds of this invention for the various serstonin-1 receptors can be determined using conventional radioligand binding assays as described in the literature. The affinity of 5-HTXA can be measured using the procedure of Hoyer et al. (Brain Res. »1986» 376. 85). The affinity of 5-HTxo can be measured using the procedure of Heuring and Peroutka (J. Neurosoi .. 19T7, 7. 894). The in vitro activity of the compounds of the present invention at the 5-HT D binding site can be determined according to the following procedure. Bovine caudal tissue is homogenized and suspended in 20 volumes of a buffer containing 50 mM TRIS-hydrochloride (tris Chidroximeti 1 Daminometano hydrochloride) at a pH of 7.7. Then the homogenate is centrifuged at 45,000 G for 10 minutes. The supernatant is then discarded and the resulting pellet is resuspended in approximately 20 volumes of 50 mM TRIS-hydrochloride buffer (HCl) at pH 7"7. This suspension then it is pre-incubated for 15 minutes at 37 ° C »after which the suspension is centrifuged again at 45,000 G for 10 minutes and the supernatant is discarded. The resulting pellet (approximately 1 gram) is resuspended in 150 ml of a 15 mM TRIS hydrochloride (HCl) buffer containing 0.01 percent ascorbic acid with a final pH of 7: 7 and which also contains 10 μM pargyline. and 4 mM calcium chloride (CaClw). The suspension is kept on ice at least 30 minutes before use. The inhibitor »control or vehicle is then incubated according to the following procedure. To 50 μl of a solution of 20 percent dimethylsulfoxide (DMSO) / 80 percent distilled water, add 200 μl of tritiated 5-hydroxytryptamine (2 nM) in a 50 mM TRIS hydrochloride buffer containing 0.01 percent acid. ascobic at pH 7 »7 and also containing 10 μM pargyline and 4 mM calcium chloride» máß B-hydroxy-DPAT (dipropylaminotetral ina) 100 nM and 100 nM meßulergine. To this mixture 750 μl of bovine caudal tissue are added and the resulting suspension is stirred vertically to ensure a homogeneous suspension. After the suspension, incubate in a shaking water bath for 30 minutes at 25 ° C. After completing the incubation »the suspension is filtered using glass fiber filters (for example» Whatman GF / B-filters ™). Then, the sediment is washed three times with four ml of a 50 mM TRIS-hydrochloride buffer at pH 7.7. The sediment is then placed in a scintillation vial with 5 ml of scintillation fluid (aquasol 2MC) and left to stand overnight. The percentage of inhibition can be calculated for each dose of the compound. After that, a CI value can be calculated from the percentage value of inhibition. The activity of the compounds of the present invention with respect to the 5-HTXA binding capacity can be determined according to the following procedure. Rat cerebral cortex tissue is homogenized »it is divided into samples of batches of 1 gram and these are diluted with 10 volumes of sucrose solution 0, 32 M. The suspension is then centrifuged at 900 G for 10 minutes. The supernatant is separated and recentrifuged at 7,000 G for 15 minutes. The supernatant ß desencha and the sediment is re-suspended in 10 volumes of 15 mM TRIS-hydrochloride at pH 7.5. The suspension is allowed to incubate for 15 minutes at 37 ° C. After completing the pre-incubation, the suspension is centrifuged at 70,000 G for 15 minutes and the b-phenatant is desected. The resulting silyl sediment is resuspended in a buffer of 50 mM TRIS-hydrochloride at pH 7.7 »containing 4 mM calcium chloride and 0.01% ascorbic acid. The tissue is stored at -70 ° C until it is ready for an experiment. The tissue can be thawed immediately before use, diluted with 10 μM pargyline and kept on ice. The tissue is then incubated according to the following procedure. Fifty microliters of control »inhibitor or vehicle (final concentration of 1% DMSO) are prepared at various dosages. To this solution, add 200 μl of tritiated DPAT at a concentration of 1.5 nM in a buffer of 50 mM TRIS-hydrochloride at pH 7.7 »containing 4 mM calcium chloride» 0.1% percent ascorbic acid and pargyline. To this solution is then added 750 μl of tissue and the resulting suspension is stirred vertically to ensure homogeneity. The suspension is then incubated in a shaking water bath for 30 minutes at 37 ° C. The solution is then filtered "is washed twice with 4 ml of 10 mM TRIS-hydrochloride at pH 7.5" containing 154 mM sodium chloride. The percent inhibition is calculated for each dose of the control compound or vehicle. The ICβ values are calculated from the percentage inhibition value. The compounds of formula 1 of the present invention described in the following examples were tested for affinity for 5-HTXA and 5-HTXB using the above-mentioned processes. All said compounds had IC.sub.o values less than 0.60 μM for affinity for 5-HT.sub.x and value of CI.sub.o or less than 1.0 μM for the affinity for 5-HTXA. The antagonist and antagonist activities of the compounds of the invention at the 5-HTXA and 5-HTxo receptors can be determined using a single saturating concentration according to the following procedure. Male Hartley guinea pigs are decapitated and the 5-HT A receptors of the hippocampus are dissected, while 5-HTxo receptors are obtained by cutting at 350 mM in a Mcllwain tissue cutter and obtaining by dissection the black substance of the appropriate cuts. The individual tissues are homogenized in 5 mM HEPES buffer containing 1 M EGTA (pH 7 »5) using a manual glass-Teflon * homogenizer and centrifuging at 35,000 x g for 10 min at 4 ° C. The sediments are resuspended in 100 mM HEPES containing 1 mM EGTA (pH 7 »5) to a final protein concentration of 20 mg (hippocampus) or 5 mg (substantia nigra) of proteins per tube. The following agents are added so that the reaction mixture in each tube contains 0.2 mM MgCla 2. 0.5 mM ATP »1.0 mM cAMP» 0.5 mM IBMX »10 mM phosphocreatine» 0.31 mg / ml creatine phosphokinase »GTP 100 μM and 0.5-1 microcurie of aC3 P3-ATP (30 Ci / mmol: NEG-003 - New England Nuclear) . Incubation ße starts by the addition of tissue to microcentrifuge tubes if they are liquefied (in triplicate) at 30 ° C for 30 minutes. Each tube receives 20 μl of tissue. 10 μl of drug or buffer (at a final concentration 10X). 10 μl of 32 nM agonist or buffer (at a final concentration 10X). 20 μl of forskolin (final concentration 3 μM) and 40 μl of the above reaction mixture. Incubation is terminated with the addition of a 100 μl solution of 2% SDS, 1.3 mM cAMP. 45 mM APT containing 40,000 dp of C3H-l-cAMP (30 Ci / mmol: NET-275 - New England Nuclear) to control the recovery of cAMP from laß colu naß. The separation of -33P_I-ATP and C33P3-cAMP is carried out using the procedure of Solomon et al. J. Analytical Biochemistry. 1974. §§ »541-548. The radioactivity is quantified by liquid scintillation counting. Maximum inhibition is defined by 10 μM (R) -B-OH-DPAT for 5-HTXA and 320 nM 5-HT receptors for 5-HTxo receptors. Deßpuéß the inhibitions are calculated, in percentages, produced by the enßayo compounds in relation to the inhibitory effect of (R) -B-OH-DPAT for 5-HT-XA 05-HT receptorreß for 5-HTxo receptors. The inverse of agonißtaß-induced inhibition of the activity of adenylate cyclase stimulated by forskolin is calculated in relation to the agonist effect of 32 nM. The compounds of the invention can be tested for in vivo activity for hypothermia induced by 5-HTXD agonists in guinea pigs according to the following procedure. Hartley guinea pig males from Charles River. weighing 250-275 grams after arrival and 300-600 grams at the time of testing, they serve as subjects in the experiment. The guinea pigs are caged under conventional laboratory conditions from 7 to 7 a.m. haßta laß 7 p.m. with a lighting program for at least 7 days before the experimentation. Food and water are available adl ibitum until the time of the trial. The compounds of the invention can be administered in the form of a solution in a volume of 1 ml / kg. The used vehicle is varied depending on the solubility of the compound. The test compounds are typically administered either 60 minutes orally (po) or 0 minutes subcutaneously (sc) before the 5-HTXD agonist, which is administered at a dose of 5.6 mg / kg, sc. take the first reading of the temperature, each guinea pig is placed in a transparent plastic shoe box containing wood chips and a metal grid floor and allowed to acclimate to the medium for 30 minutes. The animals are then returned to the same shoe box after each temperature reading. Before each measurement of temperature, each animal is held firmly with one hand for a period of 30 seconds. A digital thermometer with a small probe for animaleß is used for the temperature measurements. The ßonda is made of semi-flexible nylon with an epoxy tip. The temperature probe is inserted 6 cm deep into the rectum and held there for 30 seconds or until it obtains a stable record. Then the temperatures are recorded. In the p.o. evaluation experiments, a reading of the "pre-drug" base temperature is made at -90 minutes, the test compound is administered at -60 minutes and an additional reading is taken at -30 minutes. Afterwards, administer the 5-HT agonist or at 0 minutes and take the temperatures 30 »60» 120 and 240 minutes later. In the subcutaneous evaluation experiments », a reading of the pre-drug basal temperature is performed at -30 minutes. The enßayo compound and the 5-HTxo agonists are co-administered and temperatures 30, 60, 120 and 240 minutes later are taken.

The data are analyzed with a double-way analysis of variance with repeated measurements in the post hoc analysis of Newman-Keuls. The active compounds of the invention can be evaluated as anti-migraine agents by testing the degree to which they mimic sumatriptan in the contraction of the isolated dog saphenous vein strip CP.P.A. Humphrey et al .. Br. J. Pharmacol .. 94. 1128 (1988) 3. This effect can be blocked with metiotepin. a known serotonin antagonist. It is known that sumatriptan is useful in the treatment of migraine and that it produces a selective increase in vascular resistance of the carotid in an anesthetized dog. The pharmacological basis for the efficacy of sumatriptan has been discussed in W. Fenwick e al .. Br. J. Pharmacol .. 96. 83. (1989). The affinity of the 5-HTxo receptor. of serotonin can be determined by in vitro receptor binding assays. as described for the 5-HTXA receptor when cutting? of rat as a source of receptor and C3H3-B-0H-DPAT as radio! igando CD. Hoyer et al. Eur. J. Pharm .. 118. 13 (1985) 3 and as it has been described for the 5-HTxo receptor using bovine caudal tissue as the source of the receptor and C3H serotonin as radiolying CR.E. Heurüng and S.J. Peroutka J. Neuroscience. 7_. 894 (1987). Of the active compounds tested. allß had a CIß value, in all tests, of 1 μM or less. The compounds of formula I can be advantageously used together with one or more other therapeutic agents, for example, different antidepressant agents such as tricyclic antidepressants, (eg, amitriptyline, dotiepin, doxepin, trimipramine, butryipine, clomipramine, desipramine, imipraraine, iprindol, lofepramine. nortriptylane or protriptiline) »monoamine oxidase inhibitors (eg» isocarboxazid »phenelzine or trani I cyclopramine) or 5-HT reuptake inhibitors (eg» fluvoxamine »sertraline» fluoxetine or paroxetine) and / or with antiparsonic agents such as antiparkinsonianoß dopaminergic agents (for example »levodopa, preferably together with a peripheral decarboxylase inhibitor, for example» benserazide or carbidopa »or with a dopamine agonist» for example, bromocriptine, 1-isuride or pergolide). It is to be understood that the present invention encompasses the use of a compound of general formula (I) or a physiologically acceptable ßal or solvate thereof, in combination with one or more therapeutic agents β-dißtintoß. The compounds ß of the formula I and ß-ß-ß-ß-ß-ß-ß-ß-ß-ß-ß in addition to a 5-HT reuptake inhibitor (eg ß fluvoxaraine »sertraline» fluoxetine or paroxetine), preferably sertraline or a pharmaceutically acceptable or polymorph salt thereof (the combination of a compound of formula I with a 5-HT reuptake inhibitor is referred to herein as an "active combination"), they are pßicoterapéuticoß útileß and can be used in the treatment or prevention of disorders, whose treatment or prevention is facilitated increasing serotonergic neurotransmission (eg, hypertension »depression» generalized anxiety disorder »phobias» post-traumatic stress syndrome »personality annulment disorder, sexual dysfunction, eating disorders, obesity, chemical dependencies» cluster headache, migraine , pain, Alzheimer's disease, obsessive-compulsive disorders, trauma panic disorders »memory disorders (for example» dementia »amnesic traßtornoß and memory loss associated with age)» Parkinson's diseases (for example »dementia in Parson's disease. Pair neuroleptic induced induction and tardive dyskinesias), endocrine disorders (for example »hyperprolactinemia)» vasospasm (particularly in the cerebral vascular system) »cerebellar ataxia» gastrointestinal tract disorders including changes in motility and secretion »paroxysmal hi icrania Chronic and headache associated with vascular disorders. The inhibitors of the reuptake of serotonin (5-HT) »preferably sertraline. present a positive activity against depression; chemical dependencies; generalized anxiety disorders. agoraphobia »simple phobias» social phobia and post-traumatic stress disorders »obsessive-compulsive traumatisms, disturbance of abnormality of prematurity and premature ejaculation in mammals, including human beings, due in part to their ability to block ßinaptosomal uptake of the serotonin United States Patent 4,536,518 describes the synthesis and pharmacological composition of sertraline for depression and is therefore incorporated by reference in its entirety. The activity of the active combination as antidepressants and the related pharmacological properties can be determined by the procedures (1) - (4) shown below "which are described in Koe" B. and others. »Journal of Pharmacology and Experimental Therapeutics. 226 (3), 686-700 (1983). Specifically, the activity can be determined by studying (1) its ability to affect ratoneß efforts to escape from a water reservoir ("desperate behavior" test of Porsolt mice), (2) its ability to enhance behavioral symptoms induced by 5-hydroxy tryptophan in mice in vivo. (3) its ability to antagonize the serotonin destruction activity of p-chloroamphetamine hydrochloride in rat brain in vivo and (4) its ability to block the uptake of serotonin »norepinephrine and dopamine by rat brain synaptoßomal cells in vitro. The ability of the active combination to counteract the hypother iß produced by reserpine in mice in vivo can be determined in accordance with the procedures described in US Pat. 4,029,731. The compositions of the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active ingredients of the invention can be formulated for parenteral oral (eg intravenous) intramuscular or subcutaneous oral or intranasal administration, or for rectal administration, or in a form suitable for administration by inhalation or insufflation. For oral administration, the pharmaceutical compositions may take the form of, for example, "tablets" or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (eg, progelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl hypro-elose); fillers (eg »lactose» microcrystalline cellulose or calcium phosphate); lubricants (for example »magnesium stearate» talc or silica); disintegrants (eg, potato starch or sodium starch glycolate) or humectants (eg, sodium lauryl sulphate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of. for example, solutions, syrups or suspensions, or they can be presented as a dry product to be constituted with water or other suitable vehicle before the use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspension agent (eg, sorbitol syrup, hypromellose or hydrogenated edible fats); emulsifying agents (for example, lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily steamers or ethyl alcohol); and preservatives (for example, methyl or propyl p-hydroxybenzoates or sorbic acid). For buccal administration, the composition may take the form of tablets or lozenges formulated in a conventional manner. The active compounds of the invention can be used for parenteral administration by injection. including the use of conventional catheterization or infusion techniques. The formulations for injection may be presented in the form of unit-β-dozification. for example, in blister or in containers of several doses »with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending and stabilizing and / or dispersing agents. As an alternative »the active ingredient can be in powder form for reconstitution with a suitable vehicle» for example »sterile water ßin pyrogens, antee of the ußo. The active compounds of the invention can also be formulated in rectal compositions such as suppository or retention enemas, eg containing suppository bases or retention enemas for example containing conventional suppository bases such as cocoa butter or other glyceride. . For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently in the form of a solution or suspension of a container with a spray pump that is pressed or pumped by the patient or in the form of a spray presentation. aerosol from a pre-pressurized container or a nebulizer, with the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosing unit can be determined by having a valve to supply a measured quantity. The pressurized container or the nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (manufactured eg for gelatin) can be formulated for ußarße in an inhaler or insufflator containing a powder mixture of a compound of the invention and a suitable powder baεe such as lactose or starch. A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to an average adult human, for the treatment of the aforementioned drugs (e.g., migraine) is 0.1 to 200 mg of the active ingredient per dose unit, which can be admired, for example, from 1 to 4 times a day. Aerosol formulations for the treatment of the aforementioned disorders (e.g., migraine) in a medium human ßer preferably dispose thereof so that each metered dose or "pulsation" of aerosol contains from 20 μg to 1,000 μg of the compound of the invention. The overall daily dose with an aerosol will be within the range of 100 μg to 10 mg. The administration can be carried out several times a day »for example» 2 »3» 4 or 8 times »administering for example» 1 »2 or 3 doses each time. In relation to the use of an active compound of this invention with a reuptake inhibitor of 5-HT "preferably sertraline" for the treatment of subjects having any of the above disorders "it should be noted that these compounds can be administered alone or in combination with pharmaceutically acceptable vehicles by any of the routes indicated previously "and that each administration can be carried out in single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, ie. can be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspensions, injectable solutions, elixirs, syrups and the like. Such vehicles include solid diluents or fillers »sterile aqueous media and various non-toxic organic solvents» etc. In addition »such oral pharmaceutical formulations can be conveniently sweetened and / or flavored by means of various agents of the type usually employed for such purposes. In general, the compounds of formula I are present in such dosage form at concentration levels ranging from about 0.554 to about 909- by weight of the total composition, ie, in amounts which are sufficient to provide the dosage. desired unit and the 5-HT reuptake inhibitor. preferably sertraline. it is present in such dosage form at concentration levels which vary approximately between 0.554 and about 90J4 by weight of the total composition, ie, in amounts that are sufficient to provide the desired unit doεification. A proposed daily doßiß of an active compound of this invention in the combination formulation (a formulation containing an active compound of this invention and a 5-HT reuptake inhibitor) for oral administrationparenteral »rectal or oral to a medium adult human ßer for the treatment of the aforementioned disorders» is approximately 0.01 mg to about 2,000 mg »preferably from about 0.1 mg to about 200 mg of active ingredient of formula I per unit dose »That you can administer» for example »from 1 to 4 times per day. A proposed daily dose of a 5-HT reuptake inhibitor "preferably sertraline" in the combination formulation for oral, parenteral or buccal administration "to a medium adult human ßer for the treatment of the aforementioned traducers" of approximately Ol mg to about 2 »OOO mg» preferably from about 1 mg to about 200 rag of the 5-HT reuptake inhibitor per unit dose »which may be administered» for example »from 1 to 4 times per day. A preferred proportion of doßiß between βertralin and an active compound of this invention in the combination formulation for oral, parenteral or buccal administration to a medium adult human being for the treatment of the aforementioned tracheostomes, is from about 0.00005 to about 20,000. preferably from about 0.25 to about 2,000. The aerosol combination formulations for the treatment of the aforementioned trays in a medium adult human being preferably have such that each medium dose or "pulsation" of aerosol contains from about 0.01 μg to about 1,000 μg of the active compound of This invention is preferably from about 1 μg to about 10 mg of such compound. The administration can be carried out several times a day »for example» 2. 3. 4 or 8 times »administering, for example. 1. 2 or 3 doses each time. Aerosol formulations for the treatment of the aforementioned disorders in an average adult human being are preferably arranged so that each medium dosiß or "pulsation" of aerosol contains from about 0.01 mg to about 2000 mg of a reuptake inhibitor. 5-HT »preferably sertraline. preferably from about 1 mg to about 200 mg of sertraline. The administration can be carried out several times a day, for example, 2 »3» 4 or 8 times »administering for example» 1 »2 or 3 doses each time. As previously indicated "a 5-HT reuptake inhibitor" preferably sertraline. together with compoundβ of formula I. Easily adapts for the therapeutic use as an antidepressant agent. In general, eßtaß antidepressant compositions containing a 5-HT reuptake inhibitor. preferably ßertraline and a compound of formula I are normally administered in docification ranging from about 0.01 mg to about 100 mg per kg of body fat per day of a 5-HT reuptake inhibitor. preferably ßertralina. preferably from about 0.1 mg to about 10 mg per kg of body fat per day of sertraline; with from about 0.001 mg to about 100 mg per kg of body weight and per day of a compound of formula I »preferably from about 0.01 mg to about 10 mg per kg of body weight and per day of a compound of formula I Variations will necessarily appear depending on the traitors of the subject being treated and the particular administration route chosen. The following examples illustrate the preparation of the compounds of the present invention. The melting points are uncorrected. The NMR data are presented in parts per million (or) and are referred to the deuterium synchronization signal of the sample solvent (deuterium chloroform unless otherwise specified). Specific rotations were measured at room temperature using the sodium D line (589 nm). Commercial reagents were used without further purification. THF refers to tetrahydrofuran. DMF refers to N »-dimeti Iformamide. Chromatography refers to column chromatography performed using 32-63 μm silica gel and performed under nitrogen pressure conditions (flash chromatography). Ambient temperature refers to 20-25 ° C. All non-aqueous reactions were conducted under a nitrogen atmosphere for convenience and to maximize yields. Concentration at reduced pressure means that a rotary evaporator was used.

AXIS? PLQ I 3 ^ - < 4 ^? NipiPragi? ^ L-ii) -0en ^ «ana Under nitrogen. 2- (4-methyl-1-1-piperazinyl) -benzaldehyde (0.152 g »0.75 g, 0.75 mmol) were introduced into a round bottom flask equipped with a condenser and a magnetic stir bar. oxindole (0.104 g »0.7B mmoles)» pyrrolidine (62 μl) and ethanol (7.0 ml). The mixture was refluxed for 16 hours, cooled and evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer was washed with saturated aqueous sodium chloride (NaCl), dried over magnesium sulfate (MgSO 4), filtered and taken up in 437 mg of silica gel. Elution with ethyl acetate (EtOAc) (125 ml) »methanol 154 (CHaOH) in EtOAc (100 ml), CH0H at 254 in EtOAc (100 ml) and CHa0H at 454 + triethylamine at 154 (EtaN) in EtOAc ( 50 ml). provided 280 mg of a yellow solid. Recrystallization from hot CHa0H afforded the title product »mp. 226-228 ° C. NMR (CDC13, 250 MHz) or 7.93 (1H »S)» 7.84 (1H, 8 broad) »7» 79 (1H. Dd). 7.66 (1H, d.J = 7.94 Hz) »7.42 (1H» dt) »7.12-7.03 (2H, m). 6 »91-6» 84 (2H »m)» 3.06 (4H »t)» 2.66-2.53 (4H, m), 2.35 (3H, s). Elemental Analysis: Calculated for CaoHaxNa0-0,5 H20: C 73.15, H 6.75, N 12.79. Found. "C 73.00, H 6.51, N 13.01 In the same way, the following analogues of Example 2-6 were prepared: EXAMPLE 2 Fifi-3-C2- (-methylpiperazin-1-yl) -1-benzyl-1-ideno-3, 3-dihydro-indo-1-one-dihydrate hydrochloride p.f. 265-267 ° C (CHaCla). PBMS: 354 (M * l). Elemental analysis calculated for CaoHaoC1Na, 0-HC1-2Ha0: C 56.34, H 5.91. N, 9.86. Found: C 56.83, H 5.90, N 10.07.

EJEHP Q a l-met? L-3-C2- Hydrochloride < 4-methylPiperazin-l-? 1) - benz? Deno3-1.3-d? idro-? ndo --- 2-or-a hydrate p.f. 120 ° C decomp. (Et ^ CHa-Cl ,,. PBMS: 334 (rV) Elemental analysis calculated for CaxHaaNa0-HCl-2.5 H ^ O: C 60.79, H 7.04, N 10.13 Found: C 61 » 04 »H 6.69, N 10.18.

EXAMPLE 4. - E2- < ^^ ilPipgra-sir ^? - > -.?ft ^^ indol-2-one hemihydrate p.f. 171-172 ° C (EtOAc). PBMS: 369 (rV). Elemental analysis calculated for CaßHaßNa0-O »52Ha0: 77.20, H 6.48. N, 10.39. Found: C 77.31, H 6.43, N 10.39.

EEMPO 15 l- (3,4-Dic1orobenci1) -3-C2- (4-mß i Ipíperazi -l-i 1) - p.f. 120-124 ° C (EtOAc: Hexanes). PBMS: 478 (M- *). Elemental analysis calculated for Ca rHaBCl_tN_B0: C 7.78, H 5.27, N 8.78. Found: C 67.85, H 5.41, N 8 »53.

EXAMPLE < s 5-C1oR - »- C2- (4-m-t i Ipiperazin-l-i 1) -benzyl 1 ideno3-1.3-dihydro-indol-2-one p.f. 235-237 ° C (MeOH). PBMS 354 (M-3-). Elemental analysis calculated for CaoHaoClNa0: C 7.89 »H 5.70. N, 11.88. Found: C 67.39, H 5.67, N 11.81.

EXAMPLE 7 l- (3.4 ~ Dichloropheni 1) -3-C2- (4-methi lPiPßrazin-l-i 1) -bßnci 1 ideno3-pyrrolidin -? - Qna hswi hi r s Under nitrogen, in a 3-neck flask equipped with a stirrer, thermometer and condenser, they added 12.8 g (0.321 mol) of NaH (dispersion to 6054 in oil) and 2165 ml of anhydrous THF. After cooling to 0 ° C, a solution of 48.8 g (0.212 mmoles) of l- (3,4-dichlorophenyl) -pyrrole idin-2-one and 42.7 g (0.209 mmoles) was added under ice-bath cooling. of 2- (4-methyl-1-piperazinyl) -benzaldehyde in 1300 ml of THF. After the addition, the mixture was refluxed for 7 hours and then concentrated in vacuo to a dark brown residue, which was triturated with hot EtOAc to 1054: hexanes. The remaining residue was filtered and dried in air until η obtained 95.6 g of a chestnut solid which was recrystallized from 16 1 MeOH to yield 24.2 g of an off-white solid. Additional recrystallization from CHCla: MeOH gave the title product as an off-white solid, 14.4 g, m.p. 224-225 ° C. PBMS: 416 (MA>, 418, 420 AH-NMR (CDCla, 250 MHz) or 7.98 (1H, d, J = 2.6 Hz), 7.82 (1H, tf J = 2.7 HZ ) »7.70 (1H» dd) »7» 4B-7.41 (2H. M), 7.34 (1H, dt), 7.09 (2H, d, J = 7.8 Hz), 3.91 (2H) , t, J-6.8 Hz), 3.23-3.14 (2H, m), 3.00, (4H, m Sim), 2.63 (4H, broad s), 2.35, OH. ). 6B Elemental analysis: calculated for CaaHaaNa0Cla-0 »5 Ha0: C 62.12, H 5.69, N 9.88. Found: C 62.06, H 5.39, N 9.69. Additional collections of the title product were also isolated from the mother liquors conserved laß recrystallizations. The free base was converted to the hydrochloride salt by dissolving the base in methanol and adding IN HCl in EtOAc to precipitate the salt recrystallized from methanol: Etw0 to give a crystalline white solid, m.p. 177-179 ° C Elemental analysis calculated for CaaHaaNaOCla-HCl -1.5 Ha0: C 55.07. H 5.67, N 8.76. Found: C 55.22. H 5.61, N 8.73. They also prepared the following compound of Example 8-28 by the same procedure: EXAMPLE 8 l- (2,4-Dic1oro eni1) -3-C2- (4-methylPiperazin-l-i1) -benz 1 idenoJpi rol idin-2-one p.f. 228-229 ° C. PBMS: 416 (M - * -). Elemental analysis calculated for CaaHaaNa0Cla: C 63.47. H 5.57. N 10 »09. Found: C 63.30 »H 5.53. N, 10.12.

EXAMPLE 9 l- (3. -Di luorophenyl) -3-C2- (4-mßt lPiPßrazin-l-i1) - ba ci 1 ideno3-pyrro1 idin-2-one p.f. 228-229 ° C. PBMS: 384 (M **). Elemental analysis calculated for CaaHaaFNaO • l / 3Ha0: C 67.85. H 6.13. N 10.79. Found: C 67.99, H 6.02, N 10.86.

EXAMPLE 10 l- (3,4-Dichlorophenn) -3-i: 5-f1uoro-2- (4-pyridylPiPerazin-1-yl) -benzyl-1-idno-3-pyrro-1-idirv-2-one hydrate p. . 228-229 ° C. PBMS: 434 (m- *) Elemental analysis calculated for CaaHaaClaFNa0 «0.5 Ha0: C 59.60, H 5.23, N 9.48. Found: C 59.67, H 5.02, N 9.44. EXAMPLE -LA- < -Cloro indigo) -3-C2- (4-mct lPiperazir? -l-i1) -benci1 ideno-pperi in-g-ona p.f. 117-178 ° C (EtOAc). PBMS: 396 (- =.

EXAMPLE 12 A- < 3r4-pi? IQrQfenil --h-C2- (4 ^ me? N? Erazir ^ 3 »-n) - & e? Ci í enQ- iperid n-2-ona p.f. 138-139. 5 ° C (EtOAc). PBMS: 430 (M **).

EXAMPLE 13 1- (Chloroenyl) -3-C5-1uoro-2- < 4- ethylPi g azi-l-i1) - benz 1 ideno3-pjperidi -2-one p.f. 158-159 ° C (EtaO). PBMS: 414 (M **).

EXAMPLE 14 1-, 3-4-D? Chloroanyl) -3-C5-f1uoro-2- (4-m? IlPi arazir-l-i1) -benzyl 1-one o3-piperidin-2-one p.f. 161-162 ° C (EtOAC). PBMS: 448 (M **).

EXAMPLE 1S ana p.f. 178-179. 5 ° C. PBMS: 348 (M "*) Elemental analysis calculated for CaaHaaNa ?: C 76.05, H 7.25.N 12.09 Found: c 76.36» H 6.90 »N 12.18.

EXAMPLE 6 3- C2- (4-Me i 1piparazin-l-i1) -banci 1 ideno3-1- (4- rif 1 v-orome-ti ifem'l? -pyrrol? 'D? N-2-one) p.f. 185-186.5 ° C. PBMS: 416 (M ** -). Elemental analysis calculated for CaaHa * »FaNaO: C 66.49» H 5.82, N 10.11. Found: C 66.42. H 5.85, N 10.18.

EXAMPLE 17 3-C2- (4-MethylPiPerazin-l-i 1) -benzyl 1-idane-1-p-to 1 and Ipyrrole-2-one p.f. 165-1G7 ° C. PBMS: 362 < M- *). Elemental analysis calculated for CaaHa ^ Na0 • O, 25 Ha0: C 75.48 H 7.57, N 11.48. Found: C 75 »68» H 7.56 »N 11» 39.

EXAMPLE 18 l- (4-Chloroenyl) -3-C2- (4-methylPiperazin-1-yl) -benzylidene-3-pyrrolidin-2-one p.f. 1B8-190 ° C. PBMS: 382 < M ** > . Elemental analysis calculated for CaaH2 C1 a0 * O »25 C ^ HaOa: C 68.39» H 6 »49. N, 10.40. Found: C 68.24. H 6.62. N 10.18. (Compound containing 0.25 moles of ethyl acetate) t? tJ i SS J? í um? m 3-C4-nuoro-2- < 4-w-? Ti Ipipcrazin-l-i 1) -bßnci 1 ideno3-1-fani 1- pyrrol idln-2-one p.f. 199-200 ° C. PBMS: 366 (M **).

EXAMPLE 20 1- (3,4-Dichlorophysi 1) -3-C2-f1uoro-6- (4-p-e ilP perazi-l-i1) -benzyl 1 ideno-3-pyrro1 idin-2-one p.f. 170-171 ° C. PBMS: 434 (M ** -). Elemental analysis calculated for CaaHaaClaFNa ?: C 60 »84. H 5-11- N 9.67. Found: C 60.77 »H 5» 07 »N 9» 62.

EXAMPLE 21 l- < 3t4-pjf l g Qf and i t ^ - 1; 5-f TMor-2 < -we npiperasi - i) - peno i deno -pjperidi -2-9na p.f. 168-170 ° C (MeOH-'Et ^ O). PBMS: 416 < m- *).

EXAMPLE 22 l-t; 2-H-Ct ofenyl? Eti 3-3-C5-p''vor-2- ^ -flipiphenyl ^ in-l-i1? - banc 1 ideno3-pjperidin-2-one p.f. 88-90 ° C (Et «0). PBMS: 442 (M ** -).

EXAMPLE 23 l- (4 ~ C1-benzene-1) -3-C2- (4-aati-1-piperazin-1-yl) -benzyl-3-pi-rol-in-2-one p.f. 129-130 ° C. PBMS: 396 (M - * -).

EXAMPLE 2 l- (4-Chlorobenzyl) -3-C5-f1uoro-2- < 4 - na ilPiperazi -l-i1) - Penoi1 ideno3-pirro1 idin-2-one p.f. 131-132 ° C. PBMS: 414 (m *).

EXAMPLE 25 l- (3l, 4-Dic1orobanci1) -3-C2- (4-matilPiperazin-l-i1) - Penei 1 ideno3-p rr 1 idin-2-one p.f. 118-119 ° C. PBMS: 430 (M-A). Elemental Analysis calculated for CaaHaBC1aNaO * 0 »25 H..0: C 63.52, H 5.91, N 9.66. Found: C 63.38, H 5, B5, N 9 »67.

EXAMPLE 26 l- (3,4-Dichlorobanzyl) -3-C2- (4-methylPiPcrazin-l-i1) - banc 1 ideno3-piperidin-2-one PBMS: 444 (- *).

EXAMPLE 27 l- (3.-D? Chloro enyl) -3-C2- < 2-dimati lamínoetox) -bßnci lideno3- prroli i -2-ona p.f. 111-112 ° C (free base) »241-242 ° C (ßal HCl). PBMS: 405 (M + a-> Elemental Analysis calculated for CaxHaaClaNaOa: C 62.23, H 5.47, N 6.91, Found: C 62.42, H 5.46, N 6.86.

EXAMPLE 29 l- (3t4-piffiQroeni1) ---; d- «ffe il-2-H-! I» e-tylPperaz -l-i - banci 1 ida o3-pirro1 idin-2-one p.f. 149-150 ° C. PBMS: 430 (M-t- *).

EXAMPLE 29 l- (3,4-Difluorofani 1) -3-C2- < 4-meti Ipiperazin-l-i 1-benzyl 13-pyrrolidin-2-one A mixture of l- (3,4-difluoropheni-1) -3-C2- (4-methylpiperazin-1-yl) -benzyl-1-ideno-3-pyrrole-n-2 was heated at reflux under nitrogen for 18 hours. ona (125 mg, 0.326 mmol), ammonium formate (411 mg, 6.53 mmol) and 1054 palladium on carbon (40 mg) in 30 ml of anhydrous methanol. After cooling, the catalyst was removed in vacuo and the residue was treated with saturated aqueous sodium bicarbonate and methylene chloride. The organic layer was removed, combined with a second extraction of the aqueous layer with more methylene chloride, washed with saturated aqueous sodium chloride (NaCl) and dried. The solvent was removed again in vacuo to give the crude product as a white solid (111 mg). This solid was dissolved in hot ethyl acetate and crystallized by the addition of a few drops of hexanoe. The product of the tistle »29 mg, has a p.f. of 130-131 ° C. From the filtrate, also obtained a second harvest of the product as indicated above, 50 mg, m.p. 130-131 ° C. Mass spectrum: 386 (M * x). - Í-RMN (CDC1, 250 MHZ)? 7.75 (1H, m), 7.33-7.00 (6H, m), 3.71-3.60 (2H, m), 3.39 (1H, dd, J = 13.5, 4.2 Hz) , 3.08 (1H, m), 2.93 (4H, dd »J = 8.8» 4.2 Hz). 2 »78 (1H» dd »J = 13» 5, 10 »2 Hz). 2.59 (4H, broad s), 2.36 (3H, s), 2.17-2.01 (1H, m), 1.94-1.76 (1H, m). Elemental Analysis: Calculated for CaaHaßFaNa0: C 68.55, H 6.54 »N 10.90. Found: C 68.55. H 6.53. N 10.90.

EXAMPLE 30 3-C2- (4-Meti ipiperaz n-l-i 1) -benzyl-13-phenyl-1-pyrrole idin-2-one In a manner similar to the procedure of Example 29. 3-C2-4-meti Ipiperazi nli 1) -benzylidene-3-l-phenyl-pyrrole-idin-2-one was converted to 3-C2- (4-methypiperazine-li 1) ) -benz 13-phenyl-pyrrolidin-2-one, mp 104-105 »5 ° C. Mass spectrum: 350 (M * x). AH-NMR (CDCl ..,. »250 MHz) or 7.68 (2H, dd, J = 8» 7 »1.1 HZ), 7.39 (2H, t), 7.26-7.03 (5H, m), 3.76-3.69 (2H, m), 3.40 (1H, dd, J = 13.5, 3.9 Hz), 3.06 (1H, m), 2.96 (4H, dd »J = 5.2, 3.5 HZ) »2.81 (1H, dd, J = 13.5, 3.9 Hz). 2.59 (4H, 8 wide), 2.36 (3H, S), 2.16-2.00 (1H, m), 1 »94-1» 76 (1H.m).

E.IfflPlO 31 Hydrochloride gives 3-C2- (4-me i Ipiperaz -l-i 1) -benz 1-l- (4-trifluoromet 1-pheny1) -pyrrolidin-2-one ihydrate It was converted to 3-C2- (4-meti Ipiperazin-li 1) -benci lideno3-1- (4-trifluoromethyl-phenyl-1) -pyrrole-idin-2-one in 3-C2- (4-methylpiperazin-1-yl) hydrochloride) benzyl-1- (4-trifluoromethylphenyl) -pyrrole idin-2-one hemihydrate. p.f. 181- 1B3 ° C. Mass spectrum: 418 (M "» -?). - "- H-NMR (DMSO-dß, 250 MHz) or 10.61 (1H.s wide), 7.91 (2H, d, J-8.5 HZ), 7.72 (2H, d, J = B »9 Hz). 7.30-7.IB (2H.m). 7. 18-7.03 (2H, m), 3.73 (2H, t, J- = 6.7 Hz), 3.50-3.33 (2H, m), 3.22-2.94 (8H, m), 2.78 (3H.S), 2.70 (1H, dd, J = 13.7, 10.2 HZ). 2.03 (1H, m), 1.74 (1H, m). Elemental Analysis: Calculated for CaaHaßNa0FaHCll / 2Ha ?: C 59.67, H 6.10, N 9.08. Found: C 59.84 »H 6.06. N B .96.

E.iumium 32 Chlorhydrate or of l-C3y4-pioiophenyl -3-C2- < 4-ffic-tilPiperazin-l-i 1 > -Pention 13-p per i -2 -one A solution of l- (3,4-dichloropheni-1) -3-C2- (4-methyl-piperazyl-1) benzyl-idene-piperi-di-n-2-one (260 mg, 0.60 mmol) in 20 ml of methanol was combined. . with 100 mg of palladium on 1054 on carbon and ß hydrogenated on a Parr shaker to 344, 73 kPa for a total of 4 hours. The catalyst was then removed by filtration through diatomaceous earth and the solvent removed in vacuo to give a yellow gummy residue. Chromatography (silica gel) eluting with 554 methanol (CHaOH / methylene chloride 9554 (CHaCla) gave a clear product »70 mg» in the form of a clear gum which was dissolved in dry ethyl ether (EtOAc) and treated with ethyl ether saturated with HCl to produce the hydrochloride salt »61 mg» mp 106-108 ° C. The mass spectrum: 432 (M "* -?) 434.

E. Example 33 l-C3r4-dichloropheni l) -3-C5-fl-liKro-2- < 4- ffiet i iperaei - -i i? - enci i 3-peper d n-2-one Using a procedure similar to that of Example 32, l- (3 »4-dichloropheni 1> -3-C5-fluoro-2- (4-methyl-piperazin-1-yl) -benzylidene-pipep) was reduced. 2-one (270 mg »0.6 mmol) after 18 hours to give» after conversion to the hydrochloride salt, l-C3.4-dichlorophenyl) -3-C5-fluoro-2- (4- hydrochloride meti Ipiperazi nli 1) -benc? "13-piperi di n-2-one. p.f. 83-85 ° C. in the form of a white solid. Mass spectrum: 450 (M - * - *). 452

Claims (24)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula I »represented below» where R is a group of the formula 6a- »G *. Ga, S * or Qß, represented below »

• VVV

G4 G5 in reads that E is oxygen »sulfur» SO or S0a »R * and R" 7 are selected, independently »from hydrogen, alkyl (C, -Cß), [alkyl (Ca-C ^) 3 aryl» where the aryl radical phenyl or naphthyl and heteroaryl-1CHa, wherein the heteroaryl radical is selected from pyridyl, pyrimidyl, bezoxazole, benzothiazolyl, benzoisoxazole, and benzoisothiazolyl, and is zero, one, two, three, or four; aryl and heteroaryl radicals can optionally be substituted with one or more substituents »independently selected from chloro fluoro, bromo, iodo, alkyl (Cx-Cß), alkoxy (Cx-Cm), trifluoromethyl, cyano and SOaalkyl (Cj ^ -C ,,,, where g eß zero, one or two, or Rß and R "r together form a chain of 2 to 4 carbons, x is zero to eight, each R is independently, alkyl (Cx-C ^) or a methylene bridge (Cx-C ^) between one of the carbons of the piperazine ring or the piperidine ring of Qx or Ga, respectively, and the same or another carbon the ring, or a nitrogen of the piperazine ring or the piperidine ring of Gx or Ga, respectively having an available binding site, or a ring carbon of R "having an available binding site; Rm is selected from hydrogen and alkyl < CX-Ca); R9 is selected from hydrogen and alkyl (Cx-Cß); or R * and R9t together with the nitrogen atom to which they are attached. they form a ring of 5 to 7 members; and p is one. two and three; R * eβ hydrogen, alkyl (C -C ^). phenyl or naphthyl. wherein said phenyl or naphthyl optionally may be substituted with one or more substituents, preferably from zero to three substituents »independently selected from chloro» fluoro »bromo» iodo »alkyl (Cx-Cß). alkoxy (C -Cβ) »trifluoromethyl» cyano and S0ßalkyl, IC ^ -C ^). where g is zero one or two »Ra is (CHa) mB» where m is zero »one» two or three and B eß hydrogen »phenyl» naphthyl or a 5- or 6-membered heteroaryl group containing from one to four heteroatoms in the ring (for example »furyl» thienyl, pyridyl »pyrimidyl» thiazolyl »pyrazolyl» isothiazolyl, oxazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazole, etc.), and where each of the above aryl and heteroaryl groups optionally it may be substituted with one or more substituents, preferably from zero to three substituents independently selected from chloro, fluoro. bromine, iodine »alkyl (Cx-Cß). alkoxy (Cx-Cß). trifluoromethyl. cyano. hydroxy. COOH and SOβalkyl (Cx-Cß). where g is zero, one or two; 2 is CR-'R "wherein R- * and RB are independently selected from hydrogen, (C-C) alkyl and trifluoromethyl; or Z may be one of the aryl or heteroaryl groups mentioned in the definition of B above, and where two members of ring A; X e β hydrogen »chloro, fluoro, bromo» iodo »cyano» (Cx-Cβ) alkyl, hydroxy, trifluoromethyl, alkoxy (C -Ca), -S0ßalkyl (Cx-Cß) where g eß zero, one or doß »CO ^ .RO or CONR ^ -R"; each of RÍO, RA and R-a. »is selected» independently »between the radicaleß indicated in the definition of Ra; or R and R ** », together with the nitrogen to which they are attached» form a 5- to 7-membered ring that can contain from zero to four heteroatoms selected from nitrogen, sulfur and oxygen, n is one, two, three or four; and the dotted line indicates an optional double bond; with the proviso that n must be one when Z is a heteroaryl group; or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1, wherein R is piperazinyl. 3. A compuesta according to claim 1,

4. A compuesta according to claim 1, wherein n eß doß or three.

5. A compound according to claim 1, wherein R is substituted phenyl.

6. A compound according to claim 2, wherein Z is CH_ ..

7. A compound according to claim 6 »wherein R3 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-C2- (4-methylpiperazin-1-yl) -benzyl-1 ideno3-l »3-dihydro-indol-2-one; 6-cl-3-C2- (4-methy1piperazi n-1-y1) -benzyl lead -1 »3-dihydro-indol-2-one; 5-Chloro-3-C2- (4-methyl-piperazin-1-yl) -benzyl-1-idene-3'-3-dihydro-indo-1-one-one; 1-methy1-3-C2- (4-methypiperazin-1-yl) -benzyl lead -1 »3-dihydro-i ndol-2-one; 3-C2- (4-methi Ipiperazi n-1-yl) -benzyl lead -1-phenyl-1-1.3-dihydro-indol-2-one; l- (3,4-dic lorophenyl) -3-C2- (4-methy1 piperazyl n-1-yl) -benzylidene-3-pyrrole idin-2-one; l- (3,4-Dichlorobenzyl) -3-C2- (4-methyl-1-piperazin-1-yl) -benzylidene-1,3-dihydro-indol-2-one; 1- (4-Chlorobenzyl) -3-C2- (4-methylpiperazin-1-yl) -benzyl-1-idene-3-pyrro1-idin-2-one; l- (4-chlorobenzyl) -3-C5-fluoro-2- (4-methyl-1-piperazin-1-yl) -benzyl-ideno-3-pyrrole-idin-2-one; 1- (3,4-difluorophenyl) -3-C2- (4-methypiperazin-1-yl) -benzyl-1 ideno-pyrrolidin-2-one; 1-4,4-dichlorobenzyl) -3-C2- (4-methypiperazin-1-yl) -benzyl-deno-pyrrolidin-2-one; 1- (3,4-dichloropheni-1) -3-C5-fluoro-2- (4-methyl-piperazin-1-yl) -benzyl-ideno-pyrrolidin-2-one; 1- (4-chlorobenz 1) -3-2- (4-methypiperazin-1-yl) -benzyl-1 ideno-piperidyl-2-one; l- (3,4-dichlorobenzyl) -3-C2- (4-methylpiperazin-1-y1) -benzyl-1 idene -piperidin-2-one; 1- (4-chloropheni-1) -3-C5-f1-uoro-2- (4-methyl-1-piperazin-1-yl) -benzyl-1-idene-pi-peridin-2-one; l- (3,4-dichlorophenyl) -3-C5-fluoro-2- (4-methylpiperazin-1-yl) -benzylidene »3-piperidin-2-one; 3-C2- (4-methyl-1-piperazin-1-yl) -benzyl-1 ideno-3-l-phenyl-1-pyrrole idin-2-one; 3-C2- (4-methypiperazin-1-yl) -benzyl-1-ideno-1- (4-trifluoromethyl-1-phenyl) -pyrrole-idin-2-onß; l- (3 »4-di-luo-phenyl) -3-C2- (4-methyl-piperazin-1-yl) -benzyl-3-pyrrole-idin-2-one; 3-C2- (4-methyl-piperazin-li-1) ) -benzyl 1 ideno-3-pyrrole din-2-one; 3-C5-fluoro-2- (4-methypiperazyl 1) -benzylidene-pyrrolidin-2-one; 3-C2- (4-methylpiperazin-li 1) ) -benzyl i deno3-pi peri din-2-one; l- (3 »4-dichloropheni 1) -3-C2- (4-methy1piperazin-li 1) -benzyl 13-piperidin-2-one; (4-methoxypheni 1) -3-C2- (4-methyl-1-piperazin-li 1) -benzyl 3 -3.4-dihydro-lH-quinoline-2-one; 1- (3,4-dic1-orofeni-1) -3-C5- f1uoro-2- (4-methy1 piperazyl n1) -benzyl-piperidin-2-one »3-C2- (4-methypiperazyl nl 1) -benzyl 3-1-pheny1-pyrrole idin-2-one; 3-C2- (4-methylpiperazin-1-yl) -benzyl 1 ideno3-l- (p-tol i 1) -pyrrole idin-2-one; 3-C4-f1uoro-2- (4-methylpiperazin- li 1) -benzyl-1-idene-1-phenyl-1-pyrrole-idin-2-one; l- (3,4-dichlorophen-1) -3-C2-fluoro-6- (4-methyl-1-piperazin-li-1) -benzyl-idene -pyrrolidin-2-one; l- (3,4-difluorophenyl) -3-C5-fluoro-2- (4-methylpiperazin-li 1) -benzylidene-3-piperine-2-one; l-C2 - (4-Cl oropheni 1) eti 1 -3-C5-f1-uoro-2- (4-methyl-1-piperazin-1-yl) -benzyl-1-idene-3-piperidin-2-one; 1- (3,4-dic 1 -ophenone 1) -3-C2- (2-dimethylaminoethoxy) -benzyli deno3-pyrrole idin-2-one; and 3-C2- (4-methi Ipiperazi n-l-i 1) benzyl 3-l- (4-trifluoromethyl-lfeni 1) -pyrrol idin-2-one; and the pharmaceutically acceptable salts of said compounds.

10. A pharmaceutical composition for treating or preventing a disorder or condition selected between hypertension, depression, traßtornoß of generalized anxiety, phobias, post-traumatic stress syndrome, disorders of personality annulment, premature ejaculation, eating disorders, obesity chemical dependence, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorders, panic disorders, memory disorders, Parkinson's disease »endocrine traßtornoß» vasospasm »cerebellar ataxia, gaßtrointeßtinal tract disordersß including changes in motility and in the chronic »chronic paroxysmal hemicrania and headache associated with vascular disorders in a mammal» comprising a quantity of a compound according to claim 1 which is effective in the treatment or prevention of such a tracheal or condition and a pharmaceutically vehicle acceptable.

11. A pharmaceutical composition for treating or preventing a tracheopathy or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal "comprising an amount of a compound according to claim 1 which is effective in the treatment or prevention of such disorder or condition and a pharmaceutically acceptable vehicle.

12. The use of a compound according to claim 1 to prepare a composition for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorders, phobias »post-traumatic stress syndrome» personality disorder disorders »premature ejaculation» eating disorders, obesity, chemical dependence, cluster headache, migraine, pain, Alzheimer's disease »disorders obsessive-compulsive, panic disorders, memory disorders, Parkinson's disease »endocrine traßtornoß» vasospasm »cerebellar ataxia» disorders of the gaßtrointeßtinal tract including changes in motility and secretion »chronic paroxysmal hemicrania and headache associated with vascular disorders, in a mammal.

13. The use of a compound according to claim 1, for preparing a composition for treating or preventing a disorder or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal.

14. A pharmaceutical composition for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorders, phobias »poßt-traumatic stress syndrome, disorders of personality annulment, premature ejaculation, traßtornoß of feeding, obesity »Chemical dependencies, cluster headache, migraine» pain »Alzheimer's disease. obsessive-compulsive disorder, panic disorder, memory traßtornoß, Parkinson's disease. endocrine traßtornoß, vasospasm. cerebellar ataxia. Gastrointestinal tract disorders including changes in motility and secretion, chronic paroxysmal hemicrania and headache associated with vascular disorders in a mammal, comprising an 8B an effective amount to antogonize or agonize the serotinin receptor of a compound according to claim 1 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by increasing serotonergic neurotransmission. in a "memory" comprising an amount effective to antagonize or agonize the serotinin receptor of a compound according to claim 1 and a pharmaceutically acceptable carrier.

16. The use of a compound according to claim 1 which antagonizes or agonizes the serotonin receptor "to prepare a composition for treating or preventing a disorder or condition selected from hypertension, depression, generalized anxiety disorders, phobias, post-traumatic stress »disorders of personality cancellation, sexual dysfunction, eating disorder, obesity, chemical dependency, cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorders, panic disorders» memory disorders »Parsin's disease» endocrine disruptors »vasospasm» cerebellar ataxia »traßtornoß of the gastrointestinal tract including changes in motility and secretion» chronic paroxysmal hemicrania and headache associated with vascular disorders »in a mammal.

17. The method of a method according to claim 1 which antagonizes or agonizes the serotonin receptor "to prepare a composition for treating or preventing a disorder or condition that can be treated or prevented by increasing serotonergic neurotransmission" in a mammal.

18. A pharmaceutical composition for treating or preventing a tracheopathy or condition that can be treated or prevented by increasing serotonergic neurotransmission in a mammal "comprising: a) a pharmaceutically acceptable carrier; b) a compound according to claim 1; and c) a 5-HT reuptake inhibitor or a pharmaceutically acceptable salt thereof; wherein the amounts of the active compounds are such that the combination is effective in the treatment or prevention of such disorder or condition.

19. The use of a compound according to claim 1 in combination with a 5-HT reuptake inhibitor or a pharmaceutically acceptable ßal thereof, for preparing a composition for treating or preventing a disorder or condition that can be treated or prevent it by increasing serotonergic neurotransmission, in a mammal.

20. The method of a 5-HTXA antagonist or a pharmaceutically acceptable salt thereof, in combination with a 5-HTXD antagonist or a pharmaceutically acceptable salt thereof, for preparing a composition for treating or preventing a disorder or condition that it can be treated or prevented by increasing ßerotonergic neurotransmission, in a mammal.

21. - A pharmaceutical composition according to claim 18, wherein the inhibitor of the reuptake of 5-HT eß sertraline or a pharmaceutically acceptable ßal of the same.

22. The nail according to claim 19, wherein the 5-HT reuptake inhibitor is sertraline or a pharmaceutically acceptable salt thereof.

23. The method of a compound according to claim 1, in combination with a 5-HT reuptake inhibitor or a pharmaceutically acceptable salt thereof, for preparing a composition for treating or preventing a disorder or condition selected from hypertension. , depression, generalized anxiety disorder, phobias, post-traumatic stress syndrome, personality cancellation disorders »sexual dysfunction» breast cancer »obesity, chemical dependencies» cluster headache »migraine, pain, Alzheimer's disease. Obsessive-Compulsive Disorders. traßtornoß of panic, memory disorder, Parkinson's disease. traßtornoß endocrinoß »vasospasm, cerebellar ataxia, disorders of the gastrointestinal tract including changes in motility and secretion, chronic paroxysmal hemicrania and headache associated with vascular disorders, in a mammal.

24. The use of a 5-HTXA antagonist or a pharmaceutically acceptable salt thereof, in combination with a 5-HTxo antagonist or a pharmaceutically acceptable salt thereof, for preparing a composition for treating or preventing a disorder or condition selected between hypertension, depression, generalized anxiety disorders »phobias» post-traumatic stress syndrome, personality annulment disorder, sexual dysfunction, breast cancer, obesity, chemical dependence, headache in recimos, migraine, pain, Alzheimer's disease , obsessive-compulsive disorders. panic disorders, endocrinoß disorder, vasospasm, cerebellar ataxia, gausstrointeßtinal tract disorders, including changes in motility and secretion, chronic paroxysmal hemicrania, and aßociated headache with vascular traßtornoß, in a mammal.