MXPA00002612A - A COMBINATION OF A 5-HT REUPTAKE INHIBITOR AND A h5-HT1B - Google Patents

Abstract

The invention relates to a combination of a first component (a) which is a 5-HT reuptake inhibitor and a second component (b) which is selective h5-HT1B antagonist or partial agonist having formula (I) wherein X is CH2, O;Y is CONH, NHCO;R1 is H, C1-C6 alkyl, C3-C6 cycloalkyl;R2 is H, C1-C6 alkyl, C1-C6 alkoxy, halogen;R3 is (1), (2), (3), CF3;R4 and R5 independently are H, or C1-C4 alkyl, as racemate, R-enantiomer or S-enantiomer, and said components (a) and (b) being in the form of free bases, solvents or pharmaceutically acceptable salts thereof, the preparation thereof, pharmaceutical formulations containing said combinations, use of and method of treatment of affective disorders such as depression, anxiety and OCD with said combination as well as kit containing said combination.

Description

COMBINATION OF AN INHIBITOR OF RECOVERY OF 5-HT AND AN ANTAGONIST OR PARTIAL AGONIST OF H5-HT? B FIELD OF THE INVENTION The present invention relates to a product comprising a combination of a 5-HT reuptake inhibitor (SSRI) 'and a selective partial agonist or antagonist of the H5-HTaB receptor, more specifically a derivative of 1, 2, 3, 4-tetrahydronaphthalene or 3,4-dihydro-2H-l-benzopyran, substituted with piperidyl or piperazinyl, whereby each of the components are the shape of the free bases, solvates or pharmaceutically acceptable salts thereof. The present invention also relates to a process for the preparation of the combination of the invention, the pharmaceutical formulation comprising the combination, and the use of said combination either by concomitant administration or separate administration as an improvement in the treatment of affective disorders, such as depression, anxiety, obsessive-compulsive disorder (OCD), etc. 25 REF .: 32957 ? sP Éssar »: BACKGROUND OF THE INVENTION Today, it is generally considered that antidepressants, including selective serotonin reuptake inhibitors (5-HT) (SSRIs), take 2 to 4 weeks to reach their full clinical effect. In contrast, collateral effects occur immediately. Thus, the slow onset of action of antidepressants leads to a vulnerable period for patients in which they experience the side effects, but not the therapeutic effects of the drugs. There is often a heavy burden on the attending physician to persuade the patient to continue with the treatment during this period. In addition, in suicidal patients, since the onset of action is gradual, they can regain initiative without experiencing complete reversal symptoms, leading to a window of risk for suicide and a frequent requirement for hospitalization. An antidepressant with rapid onset of action may not only be beneficial because of the more rapid reduction of symptoms, but could also be more acceptable to patients and physicians, and reduce the need and duration of hospitalization. The same prolonged period to achieve the full clinical effect has been shown in the treatment of other disorders of the condition such as anxiety and OCD.

BRIEF DESCRIPTION OF THE INVENTION The present invention is directed in part to a combination of SSRI and a 5HT? B receptor antagonist. Advantageously, treatment with the combination results in an increased synaptic concentration of 5-HT. The SSRIs decrease the release of 5-HT in the 5-HT neurons via a negative feedback reaction partly mediated by the terminal receptors of h5-HT? B. By inhibiting the terminal auto-receptors of h5-HT? S, selective receptor antagonists counteract the decrease in 5-HT release caused by the 5-HT reuptake inhibitors. This indicates that a selective blockade of the terminal auto-receptors by an h5-HTIB antagonist may have a clinical potential to improve the efficiency of the 5-HT reuptake inhibitors (S? RIs) and offer a new reason for the Quick start of effective actions, for example antidepressant actions.

The combination Thus, by combining a first component (a) which is an inhibitor-of reuptake of 5-HT with a second component (b) which is an antagonist or partial agonist of h5-HT? B having the formula I wherein X is CH2, O; And it's CONH, NHCO; Ri is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms; R2 is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen; R3 is R4 and Rs are independently hydrogen or alkyl of 1 to 4 carbon atoms, As racemate, R enantiomer or S enantiomer and components (a) and (b) are in the form of free bases, solvates, preferably hydrates or pharmaceutically acceptable salts thereof, a rapid onset of action will occur and consequently, a more effective treatment of the patients. In other preferred embodiments of the second component (b) are those compounds of the formula I wherein X is CH2, and of those compounds, the compounds wherein Y is NHCO, and of those compounds, the compounds wherein R3 is morpholino. The compounds wherein Ri is hydrogen, methyl or ethyl and wherein R2 is hydrogen, methyl, ethyl, methoxy or bromine, are preferred.

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Preferred compounds having the formula I are: (R) -N- [8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [8- (4-ethylpiperazin-1-yl) -l, 2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [5-methoxy-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [5-ethyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [5-ethyl-8- (4-methyl-1-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] - (4-morpholinocarbonyl) benzamide; (R) -N- [5-methoxy-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morphorocarbonyl-1-benzamide; (R) -N- [5-bromo-8- (piperaz m-1 -i 1) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; N- [5-Bromo-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [5-Bromo-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-tr? Fluoromethyl-benzamide; (R) -N- [5-methy1-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; N- (4-morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-l, 2,3,4-tetrahydronaphthalene-2-carboxamide; (R) -N- (4-morpholinophenyl) -8- (4-methylpiperazyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide, (S) -N- (4-morpholinophenyl) ) -8- (4-methy1-piperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide; (R) -N- (morpholinocarbonylphenyl) -8- (4-methylpiperazin-1-yl) -5-methoxy-l, 2,3,4-tetrahydronaphthalene-2-carboxamide; (S) -N- [5- (4-methyIpiperazin-l-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-morpholinobenzamide; (S) -N- [5- (4-methylpiperazin-l-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (4-piperidon-1-yl) benzamide; (S) -N- [8-Methyl-5- (4-methyl-piperazin-l-yl) -3,4-dihydro-2H-l-benzopyran-3-yl] -4- (dimethylaminocarboni 1) benzamide; N- [4- (4-morpholinyl) phenyl] -8-methoxy-5- (-methyl-1-piperazin-1-yl) -3,4-dihydro-2H-l-benzopyran-3-carboxamide.

Particularly preferred compounds are (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (R) -N- [ 5-methoxy-8- (4-methi Ipiperazin-1-yl) -1, 2, 3, 4-tetrahydro-2-naphthyl] -4-morpholinobenzamide and (R) -N- [5-methyl-8- ( 4-methylpiperazin-1-yl) -1,2, 3, -tetrahydro-2-naphthyl] -4-morpholinobenzamide. The compounds of the formula I as (R) -enantiomers, (S) -enantiomers or racemates may exist in the form of a free base or a pharmaceutically acceptable salt or hydrate thereof. In the present context alkyl of 1 to 6 carbon atoms can be linear or branched.

Alkyl of 1 to 6 carbon atoms can be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, i-pentyl, t-pentyl, neo-pentyl, n-hexyl or i-hexyl. Alkyl of 1 to 4 carbon atoms is preferred, and methyl and ethyl are especially preferred. In the present context alkyl of 1 to 4 carbon atoms can be linear or branched.

Alkyl of 1 to 4 can be methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl or t-butyl.

Methyl and ethyl are preferred. In the present context cycloalkyl of 3 to 6 carbon atoms can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In the present context, alkoxy of 1 to 6 carbon atoms can be linear or branched. Alkoxy of 1 to 6 carbon atoms can be methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, t-pentyloxy, neo-pentyloxy, n-hexyloxy or i-hexyloxy. Alkoxy of 1 to 4 carbon atoms is preferred and methoxy is especially preferred. In the present context, halogen can be fluorine, chlorine, bromine or iodine, wherein bromine is preferred. The known, suitable 5-HT reuptake inhibitors (SSRIs) that are going to be used are norzimeldine, fluoxetine, paroxetine, citalopram, clomipramine, setralin, fluvoxamine, alaproclate, preferably citalopram or paroxetine, but component (a) in the combination according to the invention is not limited only to these SSRIs. The combination according to the present invention can exist in a pharmaceutical formulation comprising the first active component (a) and the second active component (b), or in two different pharmaceutical formulations, one for the first active component (a) and one for the second active component (b). The pharmaceutical formulation can be in the form of tablets or capsules, powders, mixtures, solutions or other forms suitable for the pharmaceutical formulation. The combination of the present invention can be prepared by the incorporation of a 5-HT reuptake inhibitor that is incorporated in the same formulation as a selective h5-HT? B antagonist as defined above, for example by mixing "n" a conventional way. The present invention also includes a method for improving the onset of therapeutic action, by concomitant administration of a combination of a first component (a) which is a 5-HT reuptake inhibitor and a second component (b) which is a selective antagonist of h5-HT? B, as defined above. A further embodiment of the present invention is a kit that contains the combination of a first component (a) which is a 5-HT reuptake inhibitor, and a second component (b) which is a selective antagonist of h5- HT? B as defined above. The equipment may include an instruction for use.

Pharmaceutical Formulations According to the present invention, the compounds in combination will normally be administered orally, rectally or by injection, in the form of pharmaceutical formulations comprising the active ingredient either as a free base, solvates for example hydrates or an addition salt of non-toxic, pharmaceutically acceptable acid, for example the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulfate, sulfamate, citrate, tartrate, oxalate salt and the like in a pharmaceutically acceptable dosage form. The dosage form can be a solid, semi-solid or liquid formulation. Usually the active substances will constitute between 0.1 and 99% by weight of the formulation, more specifically between 0.5 and 20% by weight for the formulations intended for injection and between 0.2 and 50% by weight for the formulations suitable for oral administration. The pharmaceutical formulation comprises the active ingredients optionally in association with adjuvants, diluents, excipients and / or inert carriers.

To produce pharmaceutical formulations of the combination of the invention in the form of unit doses for oral application, the selected compounds can be mixed with a solid excipient, for example lactose, sucrose, sorbitol, mannitol, starches such as potato starch, starch. of corn or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidone, disintegrants for example sodium starch glycolate, cross-linked PVP, sodium croscarmellose and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and similar, and then compressed to form tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talcum, titanium dioxide, and the like. Alternatively, the tablets may be coated with a polymer known to the person skilled in the art, wherein the polymer is dissolved in an easily volatile organic polymer or a mixture of organic solvents. Dyestuffs can be added to these coatings in order to easily distinguish between tablets containing different active substances or different amounts of the active compounds. For the formulation of soft gelatine capsules, the active substances can be mixed, for example, with a vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the active substances using any of the aforementioned excipients for tablets, for example lactose, sucrose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. Also liquids or semi-solids of the drug can be filled into hard gelatin capsules. The dosage units for rectal application can be solutions or suspensions or they can be prepared in the form of suppositories comprising the active substances in a mixture with a natural fatty base, or rectal gelatin capsules comprising the active substances in mixture with oil vegetable or paraffin oil. Liquid formulations for oral application may be in the form of syrups or suspensions, for example solutions of about 0.2% to about 20% by weight of the active substances described herein, the remainder being sugar and a mixture of ethanol, water , glycerol and propylene glycol. Optionally, such liquid formulations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent or other excipients known to a person skilled in the art. Solutions for parenteral application by injection can be prepared in an aqueous solution of a pharmaceutically acceptable salt, soluble in water, of the active substances, preferably in a concentration of about 0.5% to about 10% by weight. These solutions may also contain stabilizing agents and / or buffering agents and may optionally be provided in various unit dose vials. Suitable daily doses of the compounds in the combination of the invention in the therapeutic treatment of humans are from about 0.01 to 100 mg / kg of body weight in the peroral administration, and from 0.001 to 100 mg / kg of body weight in the administration parenteral The daily doses of the active h5-HT? B antagonist may differ greatly from the daily doses of the SSRIs, but the doses may also be the same for both active compounds.

Medical and Pharmaceutical Use In a further aspect the present invention provides the use of the combination of a first component (a) which is a 5-HT reuptake inhibitor with a second component (b) which is an antagonist or selective partial agonist of h5 -HT? B, preferably an antagonist, having the formula I as defined herein, and the use in the treatment of disorders mediated by 5-hydroxytryptamine, such as affective disorders. Examples of affective disorders are disorders in the central nervous system (CNS) such as mood disorders (depression, major depressive episodes, dysthymia, seasonal affective disorder, depressive phases of bipolar disorder), anxiety disorders (obsessive-compulsive disorder, disorder of panic with / without agoraphobia, social phobia, specific phobia, generalized anxiety disorder, post-traumatic stress disorder), personality disorders (impulse control disorders, tricotelomania). Other disorders in the central nervous system such as obesity, anorexia, bulimia, premenstrual syndrome, sexual disturbances, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders (memory impairment) associated with age, presenile and senile dementia), pathological aggression, schizophrenia, endocrine disorders (for example hyperprolactinemia), stroke, dyskinesia, Parkinson's disease, thermoregulation, pain, hypertension can also be treated with the combination described in this . Examples of other disorders mediated by hydroxytryptamine are urinary incontinence, vasospasm and tumor growth control (eg, lung carcinoma) and it may also be possible to treat these with the combination described herein.

Method of Preparation of Intermediaries 1. In the case where Y is NHCO and X is CH2 or 0. i) Benzylation of the compound of formula II, either as a racemate or as an enantiomer, (II) to obtain a compound of the formula III it can be carried out by reaction with a suitable benzylating agent for example a benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol for example benzyl mesylate or benzyl tosylate . The reaction can be carried out using a salt or the base of compound II in a suitable solvent, for example N, -dimethylformamide, acetone or acetonitrile with a suitable base for example NaOH, NaHCO 3, K 2 CO 3 or a trialkylamine such as triethylamine at a ^^. At the same temperature within the range of + 20 ° C to + 150 ° C. The presence of a suitable catalyst, for example potassium iodide or sodium iodide, can increase the speed of the reaction. The nitrogen in compound II can also be protected by reductive alkylation with an arylaldehyde in the presence of a reducing agent such as sodium cyanoborohydride, sodium borohydride or catalytically with hydrogen and a suitable catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent, for example tetrahydrofuran, dioxane, methanol or ethanol. A proton donor such as p-toluenesulfonic acid can be used to catalyze the formation of the imine / enamine, and adjusting the pH to slightly acidic by an appropriate acid such as acetic acid can accelerate the reaction, resulting in the compound III. ii) The demethylation of the compound of the formula III (III) to obtain a compound of the formula IV can be carried out by treating the compound with an acid reagent such as aqueous HBr, Hl, HBr / CH3COOH, BBr3, A1C13, pyridine hydrochloride or with a basic nucleophilic reagent such as CH3C6H4S ~ or C2H5S "in a suitable solvent The suitable solvents can be methylene chloride or chloroform and the reaction can occur between -78 ° C and + 60 ° C. iii) Conversion of the compound of the formula IV to a compound of the formula V IV); it can be carried out by reaction with a compound of formula VI (SAW) with L meaning a leaving group, for example a halogen such as chlorine, bromine or iodine or an alene- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and Ra and Rb are hydrogen and a lower alkyl group eg methyl. The process can be carried out with a salt of the compound of formula IV obtained by reaction with a base such as K2CO3, Na2CO3, KOH, NaOH, BuLi or NaH. The reaction can be conducted in a suitable solvent for example an aprotic solvent such as dioxane, N, N-dimethylformamide, tetrahydrofuran, toluene, benzene or petroleum ether, and the reaction can occur between + 20 ° C and + 150 ° C. iv) The rearrangement of a compound of the formula V to a compound of the formula VII Í & S? JS ^^ a ^^^ « (V) (VII) - can be carried out in a suitable solvent for example an aprotic solvent such as N, N-dimethylformamide, dioxane, 1, 1,3,3-tetramethylurea, tetrahydrofuran or hexamethylphosphoric triamide with a base suitable for example K2C03, KOH, potassium tert-butoxide or sodium hydride at a temperature in the range of + 20 ° C to + 150 ° C. The presence of a cosolvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidone or hexamethylphosphoric triamide in appropriate concentration in the solvent may increase the rate of the reaction. v) The hydrolysis of a compound of the formula VII to a compound VIII can be carried out under acidic conditions using acids such as H2S0, HCl or HBr in a suitable solvent for example H20, ethanol, methanol or mixtures thereof, and the reaction can occur between + 20 ° C and + 100 ° C or under basic conditions using bases such as sodium hydroxide or potassium hydroxide in a suitable solvent for example water, ethanol, methanol or mixtures thereof and the reaction can occur between + 20 ° C and + 100 ° C. - - vi) The conversion of the compound of the formula VIII to a compound of the formula IX (VIII) (IX) it can be carried out by a) the reaction with a compound of the formula X (X) where Ri is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms. The process can be carried out in a suitable solvent for example an aprotic / anhydrous solvent such as tetrahydrofuran or N, N-dimethylformamide in the presence of the coupling reagent such as N, N'-carbonyldiimidazole and the reaction can occur between + 20 ° C and + 130 ° C. The reaction is followed by reduction of the imide with a suitable reducing agent, for example LiAlH in a suitable solvent, for example diethyl ether or tetrahydrofuran at a temperature between + 20 ° C and reflux, or b) by reaction with a compound of the formula XI (XI) where L means a leaving group, for example a halogen such as chloride or bromide or an alene or arenesulfonyloxy such as the p-toluenesulfonyloxy group and Ri is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms. carbon. The process can be carried out in a suitable solvent such as ethanol, butanol, N, N-dimethylformamide, acetonitrile or a mixture of water and acetonitrile with a suitable base, for example potassium carbonate, sodium hydrogen carbonate and potassium hydroxide. and the reaction can occur between + 20 ° C and + 150 ° C. The conversion of a compound of the formula IX, where Ri is hydrogen, to an alkylated compound of the formula IX, where Ri is alkyl of 1 to 6 carbon atoms, can be carried out by the use of a suitable alkylating reagent such as Ri-L, where L is a suitable leaving group, for example a halogen such as chlorine, bromine or iodine or an alene- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and Ri is alkyl of 1 to 6 carbon atoms. The reaction can be carried out in a suitable solvent such as N, N-dimethylformamide, acetone, acetonitrile or tetrahydrofuran with a suitable base such as potassium carbonate., sodium carbonate, sodium hydroxide or a trialkylamine such as triethylamine. The reaction can be conducted at a temperature between + 20 ° C and + 120 ° C, or the conversion of a compound of the formula IX, where R 1 is hydrogen, to an alkylated compound of the formula IX, where Ri is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, can be carried by reductive alkylation with a compound Ri-CHO, wherein Rt is hydrogen or alkyl of 1 to 5 carbon atoms, or with a cyclic ketone of 3 to 6 carbon atoms, in the presence of a reducing agent, such as sodium cyanoborohydride, sodium borohydride, or catalytically with H2 and a suitable catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent for example tetrahydrofuran, dioxane , methanol or ethanol. A proton donor such as p-toluenesulfonic acid can be used to catalyze the formation of the imma / enamine, and adjusting the pH to slightly acidic by an appropriate acid such as acetic acid, can accelerate the reaction. vil) The halogenation of the compound of the formula IX, where Ri is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (IX) (XII) to obtain a compound of the formula XII can be carried out by aromatic electrophilic substitution using a suitable halogenating agent such as Br2, Cl2, I2, IC1 or S02C12. The reaction can be carried out using the salt or base of compound IX in a suitable solvent for example acetic acid, HCl / ethanol or water, with or without a suitable base, for example alkali metal acetate such as sodium acetate and a reaction temperature between -20 ° C and room temperature.

(XII) (XIII) viii) The conversion of the compound of the formula XII to a compound of the formula XIII, where Ri is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms and R2 is alkyl of 1 to 6 carbon atoms. carbon, can be carried out by a metal-halogen exchange, in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether, using a suitable alkyl lithium or a metal, for example butyllithium, lithium or magnesium chips, followed by treatment with appropriate alkyl halide such as methyl iodide, ethyl bromide or propyl iodide and the reaction can be carried out at a reaction temperature within the range of 78 ° C to room temperature, followed by cleavage. of the benzyl groups - by hydrogenation on a suitable catalyst containing palladium, rhodium, platinum or nickel, in a suitable solvent, for example acetic acid or ethanol and at a reaction temperature between + 20 ° C and + 120 ° C, or treatment with other electrophiles such as acetaldehyde or methyl chloroformate and after this the appropriate treatment. The reaction can be carried out at a reaction temperature within the range of -78 ° C to room temperature. In the case where acetaldehyde is used as the electrophile, the above reaction is followed by the reduction of the benzyl alcohol and the cleavage of the benzyl groups by hydrogenation on a suitable catalyst containing palladium, rhodium, platinum or nickel, in a suitable solvent for example acetic acid or ethanol and the reaction can occur between + 20 ° C and + 120 ° C. In the case where methyl chloroformate is used as the electrophilic, the above reaction is followed by the reduction of the methyl ester in a suitable solvent such as diethyl ether or tetrahydrofuran with an appropriate reducing agent such as lithium aluminum hydride, and the reaction can occur between + 20 ° C and reflux, followed by the cleavage of the benzyl groups and the reduction of the benzyl alcohol by hydrogenation on a suitable catalyst containing palladium, rhodium, platinum or nickel, in a suitable solvent, for example acid acetic or ethanol and the reaction can occur between + 20 ° C and + 120 ° C. When Ri is hydrogen, the nitrogen of the piperazine is protected with an appropriate protecting group before the lithiation step such as a benzyl group or other protecting group known to a person skilled in the art and then removed by methods known to a person skilled in the art. experience in the art, resulting in the compound of formula XIII. ix) The conversion of a compound of the formula XIII, where Ri is hydrogen, to a compound of the formula XIV, (XIII) (XIV) where Rc is a suitable protecting group, it can be carried out by protecting the piperazine ring in a suitable solvent, for example methylene chloride or chloroform, with a suitable protective reagent, for example di-tert-butyl dicarbonate with a Suitable base for example triethylamine or potassium carbonate and at a temperature between -20 ° C and + 60 ° C.

.- ^ AA.-.- S-.

(IX) (xv) x) The conversion of the compound of formula IX, where Ri is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, to a compound of formula XV, where Ri is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, can be carried out by cleavage of the benzyl groups by hydrogenation over a suitable catalyst containing palladium, rhodium, platinum or nickel, in a suitable solvent, for example acetic acid or ethanol and the reaction can occur between + 20C and + 120 ° C. & fej «a &agaisis¡» .taja? jf > "Xi) The conversion of a compound of the formula IX wherein Ri is hydrogen, to a compound of the formula XVI (IX) (XVI) where Rc means a suitable protecting group, it can be carried out by: a) hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent for example acetic acid or ethanol at a reaction temperature between + 20 ° C and + 120 ° C, or b) debenzylation in a suitable solvent such as methanol in the presence of ammonium formate and Pd / C at a reaction temperature between + 20 ° C and reflux.

Said reaction is followed by protection of the piperazine ring in a suitable solvent, for example methylene chloride or chloroform, with an appropriate protective agent for example di-tert-butyl dicarbonate with a suitable base, for example triethylamine or potassium carbonate and a temperature between -20 ° C and + 60 ° C. xii) Halogenation of the compound of the formula XV, where Ri is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, (XV) (XVII) to obtain a compound of formula XVII can be carried out by electrophilic aromatic substitution using a suitable halogenating agent such as Br2, Cl2, I2, IC1 or S02C12. The reaction can be carried out using the salt or base of compound XV in a suitable solvent for example acetic acid, HCl / ethanol or water with or without a suitable base for example alkali metal acetate such as sodium acetate and at a temperature of reaction between -20 ° C and room temperature. xiii) The conversion of a compound of the formula XVII, where R? is hydrogen, to a compound of formula XVIII, (XVII (XVIII) where Rc is a suitable protecting group, can be carried out by protecting the piperazine ring in a suitable solvent, for example methylene chloride or chloroform with a suitable protective reagent, for example di-ter dicarbonate. -butyl with a suitable base for example triethylamine or potassium carbonate and at a temperature between -20 ° C and + 60 ° C. xiv) The halogenation of the compound of the formula XIX, where R2 is alkoxy of 1 to 6 carbon atoms (when X is O described in: Thorberg, S-0 et al.

Acta Pharm. Suec. 1987 24, 169-182; when X is CH2 commercially available) either as a racemate or as an enantiomer (XIX); ?? ) to obtain a compound of formula XX, can be made by aromatic electrophilic substitution using a suitable halohalogenation agent such as Br2, Cl2, I2, IC1 or S02C12. The reaction can be carried out using the salt or base of compound XIX in an appropriate solvent, for example acetic acid, HCl / ethanol or water with or without a suitable base for example alkali metal acetate such as sodium acetate and at a reaction temperature between -20 ° C and room temperature.

(XXI) (xv) The benzylation of the compound of formula XX, either as a racemate or as an enantiomer, to obtain a compound of formula XXI by reaction with a suitable benzylating agent, for example benzyl halide such as benzyl bromide or benzyl chloride or an activated alcohol for example benzyl mesylate or benzyl tosylate. The reaction can be carried out using the salt or base of the compound of the formula XX in a suitable solvent for example N, N-dimethyl formamide, acetone or acetonitrile with a suitable base such as triethylamine, NaOH, NaHCO 3 or K 2 CO 3 at a temperature within the range + 20 ° C to + 150 ° C. The presence of a suitable catalyst eg alkali metal halide such as potassium iodide or sodium iodide can increase the speed of the reaction.

(XXI (XXII xvi) The conversion of the compound of the formula XXI to a compound of the formula XXII, where Ri is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms and R2 is alkoxy of 1 to 6 carbon atoms carbon, can be carried out by reaction with a compound of formula XXIII, where Ri is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms.

H I R, (XXIII) The process can be carried out in a suitable solvent, for example an aprotic solvent such as benzene, toluene, dioxane, tetrahydrofuran or N, N-dimethylformamide with a suitable base such as sodium tert-butoxide or bis (trimethylsilyl) amide. lithium in the presence of a suitable palladium catalyst such as PdZ2, L'2Pd (0) or LAPdZ2 where Z means a halogen such as chlorine or bromine and L 'means a suitable ligand such as triphenylphosphine, tri-o-tolyl phosphine, tpfurylphosphine , tri-phenylarsine or dibenzylideneacetone and with or without an addition of a ligand L "such as triphenylphosphine, tri-o-tolylphosphine, trifurylphosphine, 2,2'-bis (diphenylphosphino) -1,1-biphenylene (either as a racemate or as an enantiomer) or triphenylarsine and the reaction can occur at a temperature between + 20 ° C and + 150 ° C. xvii) The conversion of the compound of the formula XXII to a compound of the formula XXIV ; xx? v) where Ri is hydrogen, alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms and R2 is alkoxy of 1 to 6 carbon atoms, it can be carried out by hydrogenation using a catalyst containing palladium, platinum, rhodium or nickel in a suitable solvent for example acetic acid or ethanol at a reaction temperature between + 20 ° C and + 120 ° C. xviii) The conversion of a compound of the formula XXIV, where Ri is hydrogen, to a compound of the formula XXV, (XXIV) (XXV) where Rc is a suitable protecting group, it can be carried out by protecting the piperazine ring in a suitable solvent for example methylene chloride or chloroform with an appropriate protective reagent for example di-tert-butyl dicarbonate with a suitable base example triethylamine or potassium carbonate and at a temperature between -20 ° C and + 60 ° C.

(XV¡ .XXVI) xix) The conversion of a compound of formula XV, wherein Ri is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, to a compound of formula XXVI, wherein Y is NHCO and R3 is as defined in the general formula I above, can be carried out by acylation with an appropriate benzoic acid of the formula XXVII, activated as an acid chloride in a suitable solvent such as methylene chloride or chloroform with a suitable base for example trialkylamine such as triethylamine or using a benzoic acid of the formula XXVII with an activation reagent for example N, N '-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide or diphenylphosphinic chloride with a suitable base such as N-methylmorpholine in a suitable solvent such as N , N-dimethylformamide or tetrahydrofuran and the reaction can be conducted at a temperature between + 20 ° C and + 150 ° C. 2. In the case where Y is CONH and X is CH2 or O. i) The nitration of a compound of the formula XXVIII, wherein R2 is alkoxy of 1 to 6 carbon atoms, either as a racemate or as an enantiomer, to obtain a compound of the formula XXIX, (XXVIII) (XXIX; where Rd is alkyl of 1 to 6 carbon atoms, it can be carried out by aromatic electrophilic substitution using a suitable nitrating reagent such as nitric acid or nitric acid and sulfuric acid, in a suitable solvent for example acetic acid, acetic anhydride or water, at a reaction temperature between -20 ° C and room temperature. ii) The hydrolysis of a compound of the formula XXIX can be carried out under acidic conditions using acids such as H2SO4, HCl, HBr, in a suitable solvent such as H20, ethanol, methanol, acetic acid or mixtures thereof and the The reaction can occur at a temperature between + 20 ° C and the reflux temperature or under basic conditions using bases such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, ethanol, methanol or mixtures thereof, and the reaction can occur at a temperature between + 20 ° C and reflux, resulting in a compound of formula XXX.

(XXX) (XXXI iii) The conversion of a compound of the formula XXX, where R 2 is alkoxy of 1 to 6 carbon atoms, to a compound of the formula XXXI, where Y is CONH and R 2 is alkoxy of 1 to 6 carbon atoms, can be carry out by activating the acid functional group of a compound of the formula XXX as an acid halide such as an acid chloride with a suitable base such as a trialkylamine, for example triethylamine or by the use of an activation reagent such such as N, N'-carbonyldiimidazole, N, N-dicyclohexylcarbodiimide or diphenylphosphinic chloride with a suitable base such as N-methylmorpholine in a suitable solvent, for example methylene chloride, chloroform, toluene, N, N-dimethylformamide, dioxane or tetrahydrofuran followed by the addition of an appropriate aniline XXXII, where R3 is as defined in formula I above. The reaction can occur between 0 ° C and + 120 ° C. iv) The conversion of the compound of the formula XXXI to a compound of the formula XXXIII, (XXXIII) where Y is CONH and R3 is as defined in general formula I, it can be carried out by hydrogenation using a catalyst containing palladium, platinum or nickel in a suitable solvent such as ethanol, methanol or acetic acid, at a temperature of reaction between + 20 ° C and + 120 ° C; or the reduction with sodium dithionite in an appropriate solvent. 3. The conversion of a compound of the formula XXXIV to a compound of the formula XXXV XXX IV xxxv - can be carried out by: a) hydrolysis of the nitrile in the compound of the formula XXXIV in a suitable solvent such as aqueous methanol or aqueous ethanol in the presence of a suitable base such as sodium hydroxide or potassium hydroxide, at a reaction temperature between room temperature and reflux, followed by b) hydrolysis of the above-formed amide and the ketal under acidic conditions in a suitable solvent such as aqueous methanol, aqueous ethanol or water in the presence of a suitable acid such as HCl or HBr at a reaction temperature between room temperature and Reflux.

Methods of Preparation of Final Products Yet another object of the invention is a process A (?), A (ii), B or C for the preparation of the compound of the formula I by A (i) acylation, in the case where Ri is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms, Y is NHCO and X, R 2 and R 3 are as defined in formula I above, of a compound of formula A, (A) I) with an activated benzoic acid of the formula XXVII or by the use of a benzoic acid of the formula XXVII with an activation reagent. Thus, acylation according to process A (i) can be carried out with an appropriate benzoic acid of the formula XXVII, where R3 is as defined in formula I above, activated as an acid chloride in a solvent further suitable such as methylene chloride or chloroform with a suitable base for example trialkylamine such as triethylamine at a temperature between -20 ° C and the reflux temperature, or by the use of a benzoic acid of the formula XXVII, where R3 is as defined in formula I above, with an activating reagent for example N, N '-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide or diphenylphosphinic chloride with a suitable base such as N-methylmorpholine in a suitable solvent such as N, N -dimethylformamide or tetrahydrofuran and the reaction can be conducted at a temperature between + 20 ° C and + 150 ° C.

A (ii) the allylation, in the case where Ri is hydrogen, Y is NHCO, Rc is a protective group and X, R2 and R3 are as «^» I »w¡? Íi« «as defined in general formula I above, of a compound of formula B (B) (I) Thus, the acylation according to process A (ii) can be carried out with an appropriate benzoic acid of the formula XXVII, where R3 is as defined in formula I above, activated as an acid chloride in a solvent suitable such as methylene chloride or chloroform with a sdecueda base for example trialkylamine, such as triethylamine at a temperature between -20 ° C and the reflux temperature, or by the use of a benzoic acid of the formula XXVII, where R3 is as defined in formula I above, with an activation reagent for example N, N'-carbonyldiimidazole, N, N'-dicyclohexylcarbodiimide or diphenylphosphinic chloride with a suitable base such as N - ::? E _l? U ?? phytin in a suitable bulvent such as N, N-dimethylformamide or tetrahydrofuran. and the reaction can be conducted at a temperature between- + 20 ° C and + 150 ° C followed by removal of the protective group Re? -tj-.ui? tt; hydrolysis in a suitable solvent such as methylene chloride or chloroform, with a suitable acid such as trifluoroacetic acid at a temperature between + 20 ° C and + 60 ° C.

B the reaction, in the case where Y is CONH, X, Rlf R2 and Rj are as defined in general formula I above, Gglii ^ agi : c) (I with a compound of formula XI wherein L is a leaving group. In this way, the reaction according to process B can be carried out with a compound of formula XI wherein Ri is as defined in general formula I above and L is a leaving group, for example halogen such as chloro or bromine or an alean- or arensul foniloxy group such as the p-toluenesulphonyloxy group. The process can be carried out in a suitable solvent such as ethanol, butanol, N, N-dimethe formamide, acetomtplo or a -a », mixture of water and acetonitrile with or without a base, for example, potassium carbonate, sodium acid carbonate or potassium hydroxide and the reaction can occur between + 20 ° C and + 150 ° C the reaction, in the case where Y is NHCO, R2 is halogen and X, Ri and R3 are as defined - in general formula I above, a compound of formula D (GAVE) with a suitable halogenating agent such as Br2, Cl2, I2, IC1, or S02C12.

In this way, the reaction according to process C can be carried out by aromatic electrophilic substitution using a suitable halogenating agent such as Br2, Cl2, I2, IC1, or S02C12. The reaction can be carried out using the salt or base of compound D, in a suitable solvent for example acetic acid, HCl / ethanol or water with or without a suitable base, for example alkali metal acetate such as acetate of sodium and at a reaction temperature between -20 ° C and room temperature.

Work examples Preparation of Intermediates and Initial Materials for 5-HT1B Antagonists Preparation 1 (R) -2-N, N-dibenzylamino-8-methoxy-l, 2,3,4-tetrahydrone allene To a solution of (R) -8-methoxy-2-amino-1,2,3-tetrahydronaphthalene hydrochloride (24 g, 0.11 mol) in 600 ml of acetonitrile was added potassium carbonate (53 g, 0.39 mol), potassium iodide (catalytic amount) and benzyl bromide (34 ml, 0.28 mol). The reaction mixture was stirred at reflux for a period of 35 hours. After the precipitate was filtered and the acetonitrile was removed in vacuo, the residue was partitioned between diethyl ether and water. The organic phase was separated, dried over sodium sulfate and evaporated in vacuo to give a crude product which was purified on a column of silica gel using hexane / ethyl acetate. (3: 1) as the eluent. Yield: 36 g (91%) of the title compound as a white solid: m.p. 105-107 ° C; [a] 21D + 124 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 357 (100, M +).

Preparation 2 (R) -7-N, N-dibenzylamino-5,6,7,8-tetrahydro-l-naphthol The (R) -2-N, N-dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalene (43 g, 0.12 mol) was dissolved in 800 ml of diethyl ether and an excess of an ethereal solution was added. of HCl, drop by drop. The precipitate was filtered and dried in vacuo to give a white solid. This crude product (42 g, 0.11 mol) was dissolved in 1 liter of anhydrous methylene chloride and cooled to -60 ° C. To the solution was added boron tribromide (16 ml, 0.15 mol), dissolved in 100 ml of anhydrous methylene chloride, added dropwise. The reaction temperature was allowed to reach -5 ° C and was kept there overnight. To the ice-cooled solution was added dropwise a 2 M sodium hydroxide aqueous solution and the mixture was extracted, twice, with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and the solvent removed in vacuo to give a crude residue. Chromatography on silica (eluent: methylene chloride) gave 34 g (93% yield) of the title compound as a clear viscous oil: [α] 21D + 118 ° (c 1.5, chloroform); EIMS (70 eV) m / z (relative intensity) 343 (53, M +).

Preparation 3 (R) -2- (7-N, N-dibenzylamino-5, 6,7, 8-tetrahydro-1 na tyloxy) -2-methylpropanamide The (R) -2-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (10 g, 29 mmol) was stirred in 150 ml of anhydrous dioxane with sodium hydride (80% strength). oil, 0.96 g, 32 mmol) for 1 hour. 2-Bromo-2-methylpropanamide (4.8 g, 29 mmol) was added; described in: Coutts, I.G.C .; Southcott, M.R. J. Ch em. Soc. Perkin Trans. 1 1990, 767-770) and the reaction mixture was heated at 100 ° C for 2.5 hours. After cooling, the precipitated sodium bromide was filtered, the filtrate was evaporated in vacuo and the residue was partitioned between water and methylene chloride. The organic phase was separated, dried over sodium sulfate, filtered and evaporated to give a crude product which was purified on a column on silica gel, using methylene chloride as the eluent. Yield: 9.6 g (76%) of the title compound as white crystals: m.p. 125-126 ° C; [a] 21D + 98 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative intensity) 428 (13, M +).

Preparation 4 (R) -N- (7-N, N-dibenzylamino-5, 6,7, 8-tetrahydro-1-na tyl) -2-hydroxy-2-methylpropanamide To a solution of (R) -2- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy) -2-methylpropanamide (9.1 g, 21 mmol) in 10 ml of 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidone anhydrous and 100 ml of anhydrous N, N-dimethylformamide was added sodium hydride (80% in oil, 1.4 g, 47 mmol) and the reaction was heated to 130 ° C for 8 hours. The solution was poured into a mixture of ice and water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. Chromatography on silica (eluent: chloroform / ethanol saturated with NH3; 100: 0.5) gave 7.6 g (84% yield) as white crystals: m.p. 134-135 ° C; [a] 21D + 130 ° (c 1.1, chloroform); EIMS (70 eV) m / z (relative intensity) 428 (1, M +).

Preparation 5 (R) -2-N, N-dibenzylamino-8-amino-l, 2,3,4-tetrahydronaphthalene The (R) -N- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -2-hydroxy-2-methylpropionamide (7.4 g, 17 mmol) was dissolved in a mixture of 200 ml of ethanol and 300 ml of a 20% aqueous HCl solution and heated to reflux for 8 hours.

The ethanol was evaporated in vacuo and the remaining solution was washed twice with diethyl ether and cooled on an ice bath. After alkalization with a 45% aqueous solution of sodium hydroxide, the mixture was extracted with methylene chloride. The combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. Purification on a column of silica gel using chloroform as the eluent gave 3.8 g (76% yield) of the title compound as a light brown oil: [a] 21D + 124 ° (c 0.9, chloroform); EIMS ( 70 eV) m / z (relative intensity) 342 (92, M +).

Preparation 6 (R) -1- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naph il) -4-N-methylpiperazin-2,6-dione 1, 1 '-carbonyldiimidazole (6.0 g, 37 mmol) was added to a stirred suspension of methyliminodiacetic acid (2.7 g, 18 mmol) in 250 ml of anhydrous tetrahydrofuran. The reaction mixture was heated to reflux for 1.5 hour. Then (R) -2-N, N-dibenzylamino-8-amino-1, 2,3,4-tetrahydronaphthalene (5.7 g, 17 mmol) was added and the stirring at reflux was continued for 17 hours. An additional amount of 1,1 '-carbonyldiimidazole (2.9 g, 18 mmol) was added and heating to reflux was continued for another 17 hours. The solvent was evaporated in vacuo and the crude product was purified on a column of silica gel using chloroform / ethanol saturated with NH3 (100: 0.5) as the eluent. Yield: 6.6 g (87%) of the title compound as an oil: i n [a] A + 90 ° (c 0.52, chloroform); EIMS (70 eV) m / z (relative intensity) 453 (8, M +).

Preparation 7 (R) -2-N, N-Dibenzylamino-8- (-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene The (R) -1- (7-N, N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -4-methylpiperazine-2,6- dione (1.4 g, 3.1 mmol) was added. to a suspension of lithium aluminum hydride (0.57 g, 15 mmol) in 70 ml of anhydrous diethyl ether. The reaction mixture was heated to reflux for 7 hours. The reaction was quenched by the addition of 0.60 ml of water, 0.C0 ml of 15% aqueous sodium hydroxide and again with 1.8 ml of water. The mixture was filtered, dried over sodium sulfate and evaporated in vacuo. Purification on a silica gel column using chloroform / ethanol saturated with NH3 (100: 2) as the eluent gave 1.0 g (79% yield) of the title compound as a viscous oil: [a] 21D + 53 ° ( c 0.5, chloroform); EIMS (70 eV) m / z (relative intensity) 425 (2, M +).

Preparation 8 (R) -5-bromo-2-N, N-dibenzylamino-8- (4-methyl-piperazin-1-yl) -l, 2,3,4-tetrahydronaf alene To a solution of (R) -2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (2.8 g, 6.5 mmol) and sodium acetate ( 6.8 g, 83 mmol) in 100 ml of acetic acid, bromine (370 μl., 7.2 mmol) in a single portion and the reaction was stirred for 5 minutes. The solvent was evaporated in vacuo and the remaining solid was partitioned between water and methylene chloride and cooled on an ice bath. The aqueous phase was made alkaline with 2 M aqueous sodium hydroxide solution and the phases were separated. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give a crude product which was purified on a column of silica gel using chloroform / ethanol saturated with NH3 (100: 2) as the eluent. Performance. 2 g (61%) of a viscous brown oil: EIMS (70 eV) m / z (relative intensity) 503 and 505 (0.6, M +).

Preparation 9 (R) -2-N, N-dibenzylamino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaf alene The (R) -2-N, N-dibeneylamino-8-amino-1, 2,3,4-tetrahydronaphthalene (9.8 g, 39 mmol) and the bis- (2-chloroethyl) amine hydrochloride (5.5 g, 32 mmol) were dissolved in 80 ml of N-butanol. The reaction mixture was stirred at 100 ° C and after 65 hours the mixture was filtered and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as the eluent gave 6.0 g (51% yield) of the title compound as a viscous oil: [a] 2A > + 72 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 411 (2, M +).

Preparation 10 (R) -2-amino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene To a solution of (R) -2-N, N-dibenzylamino-8- (piperazin-1-yl) -1,2,4,4-tetrahydronaphthalene (5.5 g, 13 mmol) in 400 ml of methanol was added formate of ammonium (20 g, 0.32 mmol) and 1.9 g of 10% palladium on activated carbon. The mixture was heated to reflux for 1 hour and the palladium was then filtered. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and a 2M ammonium hydroxide solution. The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to give a crude product. which was purified on a column of silica gel using chloroform / ethanol / concentrated ammonium hydroxide (80: 20: 2.5) as the eluent. Yield 2.4 g (76%) of the title compound as an oil: [a] 21D + 9.9 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 231 (24, M +). d Preparation 11 (R) -2-amino-5-bromo-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene The title compound was prepared from (R) -2-amino-8- (piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene following the general method of preparation 8. Purification on a column of silica gel using methylene chloride / ethanol / concentrated ammonium hydroxide (80: 20: 2) as the eluent gave 0.8 g (67% yield) of a viscous light brown oil: [a] 21D- 6.2 ° (c = 1, chloroform); EIMS (70 eV) m / z ^ relative intensity) 309 and 311 (3.5, M +) Preparation 12 (R) -4- (7-amino-4-bromo-5,6,7,8-tetrahydro-1-naphthyl) piperazine-1-carboxylic acid tert-butyl ester To an ice-cooled solution of (R) -2-amino-5-bromo-8- (piperazin-1-yl) -1, 2, 3, 4-tetrahydronaphthalene (0.8 g, 2.6 mmol) and triethylamine (0.53 ml) 3.9 mmol) in 50 ml of methylene chloride . ».- ^ * > A £ tt s & j & e% sg: f £ y¿ * y¡z * and < Di-tert-butyl dicarbonate (0.56 g, 2.6 mmol) dissolved in 10 ml of methylene chloride was added. After the addition, the reaction was allowed to stir at room temperature for 1 hour. 10 ml of water were added and the mixture was cooled on an ice bath. The aqueous phase was made alkaline with a 2 M aqueous solution of sodium hydroxide and the phases were separated. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give a crude product which was purified on a column on silica gel using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5). as the eluent. Yield: 0.41 g (38%) of a viscous colorless oil: [a] 21D + 13 ° (c = 1, chloroform); EIMS (70 eV) m / z (relative intensity) 409 and 411 (75, M +).

Preparation 13 (R) -N- [5-Bromo-8- (4-tert-butyloxycarbonylpiperazin-1-yl) -l, 2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide 4-Morpholinobenzoic acid (0.50 g, 2.4 mmol, described in: Degutis, J., Rasteikiene, L .; Degutiene, A. Zh. Org. Khim. 1978, 14 (10), 2060-2064) was dissolved in 10 ml of thionyl chloride. After 2 minutes, the thionyl chloride was evaporated in vacuo and the residue was treated with toluene and again the solvent was evaporated in vacuo. The crude acid chloride (81 mg, 0.36 mmol) was dissolved in 10 ml of methylene chloride and added dropwise to a solution of (R) -4- (7-amino-4-bromo-5,6). 7, 8-tetrahydro-l-naphthyl) piperazine-1-tert-butyl carboxylate (140 mg, 0.34 mmol) and triethylamine (71 μl, 0.51 mmol) in 10 ml of methylene chloride. After the addition, the reaction was stirred at room temperature for 15 minutes and then washed with a dilute aqueous solution of sodium hydrogen carbonate and the phases were separated. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo and the residue was purified on a column of silica gel using chloroform / ethanol saturated with NH3 (100: 2) as the eluent. Yield: 160 mg (79%) of a viscous colorless oil: [a] 21D-ll ° (c = 1, chloroform); TSPMS m / s (relative intensity) 599 and 601 (35, M 1).

Preparation 14 (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene To a solution of (R) -2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,4,4-tetrahydronaphthalene (4.0 g, 9.4 mmol) in 2-50 ml of methanol was added aluminum formate (14 g, 56 mmol) and 10% palladium on activated carbon (1.4 g). The mixture was heated to reflux for 3 hours and the palladium was then filtered. The solvent was evaporated in vacuo and the residue was partitioned between methylene chloride and a 2M ammonium hydroxide solution. The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to give a crude product. which was purified on a column of silica gel using chloroform / methanol / concentrated ammonium hydroxide (90: 9: 0.5) as the eluent. Yield: 1.9 g 83%) as an oil [a] 1D-2.7 (c 1.0 chloroform); EIMS (70 eV) m / z (relative intensity) 245 (5, M +).

Preparation 15 (R) -2-amino-5-bromo-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene The title compound was prepared from (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene following the general method of Preparation 8. Purification over a silica gel column using chloroform / ethanol / concentrated ammonium hydroxide (80: 20: 2) as the eluent gave 630 mg (89% yield) of a viscous colorless oil: EIMS (70 eV) m / z (relative intensity ) 323 and 325 (20, M +).

Preparation 16 (R) -2-amino-8-bromo-5-methoxy-l, 2,3,4-tetrahydronaphthalene hydrochloride The hydrochloride of (R) -2-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene (5.0 g, 23 mmol) was dissolved in 300 ml of acetic acid under nitrogen atmosphere. Sodium acetate (5.5 g, 70 mmol) was added and then one-portion bromine (3.5 g, 23 mmol) was added. The mixture was stirred for 5 minutes at room temperature. The solvent was removed in vacuo to give a solid residue which was partitioned between ethyl acetate and 2M sodium hydroxide. The layers were separated and the aqueous phase was extracted twice with ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solvent was removed in vacuo to give a brown oily residue. The hydrochloride salt was precipitated from diethyl ether / methylene chloride by the addition of HCl in diethyl ether (3 M): yield 7.7 g (94%). Recrystallization from methanol gave the title compound as needle crystals: m.p. 264 + 265 ° C; [a] 21D + 54 ° (c 1, MeOH); EIMS (70 eV) m / z (relative intensity) 257 (30, M +, 81Br), 255 (31, M +, 79Br).

Preparation 17 (R) -8-bromo-2-N, N-dibenzylamino-5-methoxy-1, 2,3,4-tetrahydronaphthalene (R) -2-amino-8-bromo-5-methoxy-1,2,3,4-tetrahydronaphthalene hydrochloride (4.5 g, 17.5 mmol), benzyl bromide (6.6 g, 38 mmol), potassium carbonate (9.7 g, 70 mmol) and potassium iodide (100 mg, catalytic amount) were mixed with 250 ml of acetonitrile under nitrogen atmosphere and heated to reflux for 18 hours. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and ammonia (2M). The layers were separated and the organic layer was dried over magnesium sulfate. The solvent was removed in vacuo to give a residue which was purified by flash chromatography on silica gel using hexane / methylene chloride 8: 2 as the eluent. The title compound was obtained as an oil. Yield 7.5 g (98%): [a] 21D + 87 ° (c 1, MeOH); EIMS (70 eV) m / z (relative intensity) 437 (12, M +, 81Br), 435 (13, M +, 79Br).

Preparation 18 (R) -2-, N-Dibenzylamino-5-methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene To a solution of (R) -8-bromo-2-N, N-dibenzylamino-5-methoxy-1,2,3,4-tetrahydronaphthalene (19 g, 44 mmol) in 500 ml of anhydrous toluene under an argon atmosphere N-methylpiperazine (5.9 ml, 53 mmol), tris (dibenzylideneacetone) dipalladium (0) (0.41 g, 0.44 mmol), (R) -BINAP (0.82 g, 1.3 mmol) and sodium tert-butoxide (0.40 mg) were added. , 4.2 mmol). The dark solution was stirred at 85 ° C for 23 hours and then cooled, filtered and evaporated in vacuo. Purification on a silica gel column using chloroform / ethanol saturated with NH3 (100: 2 = as the eluent gave 19 g - (9-7% yield) of a viscous colorless oil: [a] 21D + 72 ° ( c = 1, chloroform), EIMS (70 eV) m / z (relative intensity) 455 (15, M +).

Preparation 19 (R) -2-amino-5-methoxy-8- (4-methylpiperazin-1-yl) 1,2,3,4-tetrahydronaphthalene The title compound was prepared from (R) -2-N, N-dibenzylamino-5-methoxy-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene following the general method of Preparation 10. Yield: 5.3 g (82%) of a colorless viscous oil: [a] 21D + 20 ° (c = ll, chloroform); EIMS (70 eV) m / z (relative intensity) 275 (53, M +).

Preparation 20 Methyl 5-methoxy-8-nitro-1, 2,3, 4-tetrahydronaphthalene-2-carboxylate Methyl 5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.1 g, 5 mmol, described in: Johnson, DW; Mander, LN Aus t., J. Ch., -19-74, 8, 1277-1286) dissolved in acetic anhydride (20 ml), treated with 0.4 ml of 70% nitric acid at 0 ° C for 1 hour and the mixture was poured into ice water and diethyl ether. The organic phase was separated, evaporated in vacuo and the residue was triturated with diisopropyl ether to yield 0.27 g (20%) of the title compound as crystals: m.p. 100-104 ° C; EIMS (70 eV) m / z (relative intensity) 265 (35, M +).

Preparation 21 -methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid A mixture of methyl 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylate (1.9 g, 7.1 mmol) in 20 ml of methanol and 10 ml of 2 M NaOH was heated to reflux for 1.5 hours and the solvent was evaporated in vacuo. The residue was taken up in ethyl acetate and acidified. The organic phase was separated and dried, and evaporated in vacuo to provide. 1.7 g (95% yield) of crystals: m.p. (after recrystallization from diisopropyl ether / ethanol) 189-190 ° C; EIMS (70 eV) m / z (relative intensity) 251 (30, M +). - - Preparation 22 N- (4-morpholinophenyl) -5-methox? -8-n? Tro-1, 2,3,4-tetrahydronaphthalene-2-carboxamide A mixture of 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.3 g, 5 mmol), 20 ml of toluene and thionyl chloride (1.8 ml, 25 mmol) it was heated at 80 ° C for 1 hour. The solvents were removed in vacuo and the residue, dissolved in 10 ml of methylene chloride, was added to a solution of 4-morpholinoaniline (890 mg, 5 mmol) and triethylamine (1.0 g, 10 mmol) in 20 ml of sodium chloride. methylene at 0 ° C. The mixture was stirred at 20 ° C for 2 hours, water was added and the precipitate was filtered to yield 1.9 g (90%) of the product from ^^^^^ ^^^^^^ title as crystals: p.f. 251-253; EIMS (70 eV) m / z (relative intensity) 411 (100, M +).

Preparation 23 5 N- (4-morpholinophenyl) -8-amino-5-methoxy-1, 2,3,4-tetrahydronaphthalene-2-carboxamide A solution of N- (4-morpholinophenyl) -5-10-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxamide (2.05 g, 5 mmol) and sodium dithionite (3.5 g, 20 mmol) in N, N-dimethyl formamide (20 ml) and 2 ml of water was heated at 90 ° C for 7 hours. After cooling, the reaction mixture was divided Between water and ethyl acetate, the phases were separated and the organic phase was washed twice with water and evaporated in vacuo. The residue was triturated with diisopropyl ether / ethyl acetate to give 1.4 g (72% yield) of the title product as crystals: p.f. 219-222 ° C; EIMS (70 eV) m / z (relative intensity) 381 (70, M +).

S & l fifift¡ «Bfe Preparation 24 N- (4-morpholinocarbonylphenyl) -5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxamide A mixture of 5-methoxy-8-nitro-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid (1.0 g, 4 mmol), 20 ml of toluene, 10 drops of N, N-dimethylformamide and chloride of thionyl (1.5 ml, 20 mmol) was heated at 60 ° C for 1 hour. The solvents were removed in vacuo and the residue, dissolved in 20 ml of methylene chloride, was added to a solution of 4-aminobenzoylmorphol (820 mg, 4 mmol, described in: Devlin JPJ Ch., Soc. Perkin Trans I, 1975, 830-841) and triethylamine (800 mg, 8 mmol) in 30 ml of methylene chloride at 5 ° C. After stirring at 20 ° C for 2 hours, water was added and the organic phase was separated, dried and the solvent was removed in vacuo. The oily residue was crystallized from diisopropyl ether / ethyl acetate to provide 1.2 g (73% yield) of the title compound as crystals: m.p. 186-189 ° C; EIMS (70 eV) m / z (relative intensity) 439 (20, M +).

Preparation 25 N- (morpholinocarbonylphenyl) -8-amino-5-methoxy-1, 2,3,4-tetrahydronaphthalene-2-carboxamide A solution of N- (4-morpholinocarbonylphenyl) -5-methoxy-8-nitro-l, 2,3,4-tetrahydronaphthalene-2-carboxamide (1.3 g, 2.8 mmol) and sodium dithionite (2.0 g, 11 mmol) in 20 ml of N, N-dimethylformamide and 2.5 ml of water was heated at 85 ° C for 3 hours. After cooling, the reaction mixture was partitioned between water and ethyl acetate, the phases were separated and the organic phase was washed twice with water and evaporated in vacuo. The organic phase was dried and evaporated. The residue was treated with diisopropyl ether to give 310 mg (30% yield) of the title product as crystals: EIMS (70 eV) m7z (relative intensity) 409 (100, M +).

Preparation 26 (R) -2-N, N-Dibenzylamino-5- (1-hydroxyethyl) -8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene The (R) -5-bromo-2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (1.4 g, 2.8 mmol) was dissolved in 100 - ml of freshly distilled tetrahydrofuran, was flooded with argon and cooled to -78 ° C. To the solution was added tert-butyllithium (2.6 ml, 1.4 M in pentane, 3.7 mmol) and the reddish solution was stirred at room temperature for 10 minutes. Acetaldehyde (320 μl, 5.7 mmol) was added and the reaction mixture was stirred at -78 ° C for 10 minutes, at 0 ° C for 2 hours and at room temperature for 10 minutes. The reaction was quenched with water and the solvent was evaporated in vacuo. The residue was partitioned between 100 ml of diethyl ether and 20 ml of 2M NH3 and the aqueous phase was extracted with 20 ml of diethyl ether. The combined organic layers were washed with 20 ml of brine, and dried over magnesium sulfate. The solvent was evaporated to give 2.0 g of a crude product. Purification by column chromatography on silica gel using chloroform / methanol / concentrated NH3 (95: 5: 0.5) as the eluent gave 910 mg (68% yield) of the title compound as a yellowish foam: ESI m / z ( relative intensity) 470 (100, M + l).

Preparation 27 (R) -2-amino-5-ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene The (R) -2-N, N-dibenzylamino-5- (1-hydroxyethyl) -1,2,3,4-tetrahydronaphthalene (1.6 g, 3.4 mmol) was dissolved in 80 ml of acetic acid and stirred at 100 ° C for 2 hours. The solvent was evaporated in vacuo and the residue was dissolved in 150 ml of methanol. Palladium 10% was added over 600 mg of mineral coal and the solution was flooded with nitrogen. To the solution was added ammonium formate (1.7 g, 28 mmol) and the reaction mixture was stirred at 65 ° C for 2 hours. The catalyst was filtered and the solvent was evaporated in vacuo to give 1.3 g of a crude product. The residue was partitioned between 120 ml of methylene chloride and 30 ml of 2 M NH 3. The organic phase was washed with 20 ml of brine and dried over magnesium sulfate. The solvent was evaporated under vacuum to - ^ ^ - § * ^ yield 740 mg (79% yield) of the title compound as a semi-crystalline white solid: EIMS (70 eV) m / z (relative intensity) 273 (24, M +).

Preparation 28 (R) -N- [8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide To an ice-cooled solution of (R) -2-amino-8- (4-methylpiperazin-1-yl) -1,2,4,4-tetrahydronaphthalene 110 mg, 0.44 mmol) triethylamine (91 μL, 0.66 mmol) in 20 ml of methylene chloride was added dropwise 4- (trifluoromethyl) benzoyl chloride (96 mg, 0.46 mmol) in 5 ml of methylene chloride. After the addition, the reaction was allowed to stir at room temperature for 15 minutes and then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried over sodium sulfate, filtered and evaporated in vacuo to give a crude product which was purified on a column of silica gel using chloroform / ethanol saturated with NH3 (100: 2) as the eluent. Yield: 150 mg (81%) of the title compound as white crystals: m.p. 203-204 ° C; [a] 2A > -20 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 417 (10, M +).

Preparation 29 (R) -2-N, N-dibenzylamino-5-hydroxymethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydrona The (R) -5-bromo-2-N, N-dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (800 mg, 1.6 mmol) was dissolved in 80 ml of freshly distilled tetrahydrofuran, was flooded with argon and cooled to -78 ° C. To the solution was added tert-butyllithium (1.5 ml, 1.4 M in pentane, 2.1 mmol) and the reaction mixture was stirred at room temperature for 10 minutes. Methyl chloroformate (250 μL, 3.2 mmol) was added and the reaction mixture was stirred at -78 ° C for 50 minutes and at 0 ° C for 1 hour. The reaction was quenched with water and the solvent was evaporated in vacuo. The residue was partitioned between 90 ml of diethyl ether and 2 M NH 3 (15 ml). The organic layer was washed with 10 ml of brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give 770 mg of a crude product. Purification by column chromatography on silica gel using chloroform / methanol / concentrated NH3 (250: 5: 0.5) as the eluent gave 610 mg of (R) -5-carboxymethyl-2-N, N-dibenzylamino-8- ( 4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (containing 13% of the corresponding 5-hydrogen analog) as a yellowish oil: EIMS (70 eV) m / z (relative intensity) 483 (1, -M +). The methyl ester (610 mg, 1.1 mmol) was dissolved in 35 ml of freshly distilled tetrahydrofuran and lithium aluminum hydride (120 mg, 3.1 mmol) was added. The reaction mixture was stirred at 45 ° C for 2 hours followed by cooling to room temperature. The reaction was quenched with 120 μl of water, with 120 μl of 15% NaOH and 240 μl of water followed by stirring the suspension at room temperature for 2.5 hours. The precipitate was filtered and the solvent was evaporated in vacuo to give 730 mg of a crude product. Purification by column chromatography on a silica gel column using chloroform / methanol / concentrated NH3 (95: 5: 0.5) as the eluent gave 360 mg (50% yield) of the title compound as a white foam: EIMS ( 70 eV) m / z (rel ative intensity) 455 (1, M +); [a] 21D + 44 (c 0.12, chloro form).

Preparation 30 (R) -2-amino-5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene The (R) -2-N, N-dibenzylamino-5-hydroxymethyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (360 mg, 0.78 mmol) was dissolved in 35 ml of methanol, 10% palladium on 170 mg of mineral coal was added and the solution was flushed with nitrogen. To the solution was added ammonium formate (390 mg, 6.2 mmol) and the reaction mixture was stirred at 65 ° C for 13 hours. The catalyst was filtered and the solvent was evaporated in vacuo to give 220 mg of a residue. The crude hydroxymethyl compound was dissolved in 25 ml of acetic acid, 10% palladium on charcoal (60 mg) was added and the solution was flooded with hydrogen. The reaction mixture was hydrogenated at room temperature and at atmospheric pressure for 4 hours. The catalyst was filtered and more 10% palladium on carbon (160 mg) was added followed by hydrogenation at room temperature and at atmospheric pressure for 24 hours. The catalyst was filtered and the solvent was evaporated in vacuo. The residue was partitioned between 70 ml of diethyl ether and concentrated NH3 and the organic phase was washed with 5 ml of brine. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give 120 mg (61% yield) of the title compound as a semi-crystalline white solid: EIMS m / z (relative intensity) 259 (20%). , M +); [a] 21D-1 ° (c 0.09, chloroform).

Preparation 31 (S) -3-N, N-dibenzylamino-5-methoxy-3,4-dihydro-2H-l-benzopyran hydrochloride (S) -3-amino-5-methoxy-3,4-dihydro-2H-l-benzopyran (45 g, 0.25 mol, described in WO93 / 07135), K2C03 (120 g, 0.87 mol) and benzyl bromide (65 ml, 0.55 mol) were mixed in 1000 ml of acetonitrile under nitrogen atmosphere. The reaction mixture was heated to reflux for 45 hours. The mixture was filtered and the solvent was removed in vacuo, and the residue was partitioned between diethyl ether and saturated aqueous NaCl. The layers were separated and the organic phase was dried over magnesium sulfate and filtered, followed by precipitation of the hydrochloride salt at room temperature. Yield: 99 grams (99%). An analytical sample was transferred to the base: [a] 21D + 116 ° (c 1.0, chloroform). EIMS (70 eV) m / z (relative intensity) 359 (28, M +).

Preparation 32 (S) -3-N, N-dibenzylamino-5-hydroxy-3,4-dihydro-2H-l-benzopyran The hydrochloride of (S) -3-N, N-dibenzylamino-5-methoxy? -3,4-dihydro-2H-1-benzopyran (67 g, 0.17 mol) was dissolved in 500 ml of methylene chloride under an argon, and the solution cooled to -75 ° C. Boron tribromide (32 ml, 0.34 mol) was added dropwise in 5 minutes. The temperature was left after it reached slowly + 5 ° C, and the reaction was stirred overnight. The reaction mixture was carefully quenched with a 2 M aqueous solution of NH3 under agitation. The layers were separated and the aqueous phase was extracted twice with methylene chloride. The organic layers were combined, - - £? If they were washed with brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo to give a brown oily residue which was purified by flash chromatography on a column of silica gel using chloride of methylene as the eluent. Yield: 50 g (86%) of the title compound: [α] 21 D + 109 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 345 (5, M +).

Preparation 33 (S) -2- (3-N, N-dibenzylamino-3,4-dihydro-2H-l-benzopyran-5-yloxy) -2-methylpropanamide The (S) -3-N, N-dibenzylamino-5-hydroxy-3,4-dihydro-2H-l-benzopyran (50 g, 0.14 mol) was dissolved in 450 ml of 1,4-dioxane anhydrous under nitrogen atmosphere. A dispersion of sodium hydride (60-65% in oil, 6.1 g, 0.15 mol) was added in portions. The mixture was stirred for 1 hour at room temperature. Dark green 2-bromo-2-methylpropanamide (24 g, 0.14 mol, Coutts, IGC, Southcott, MRJ Ch em. Soc. Perki n Tran 1, 1990, 767-771) was added to the dark green solution and heated to reflux. with agitation for 3 hours. An additional amount of sodium hydride (60-65% in oil, 2.8 g, 70 mmol) and 2-bromo-2-methylpropanamide (4.6 g, 28 mmol) was added in portions and heating to 60 ° C was continued by 17 hours After cooling, a small amount of 10 ml of methanol was added and the solution was filtered and the solvent was removed in vacuo. The residue was partitioned between 500 ml of ethyl acetate and 50 ml of an aqueous solution of NaHCO 3. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo to give a brown residue which was crystallized from ethyl acetate / hexane. Yield: 45 g (71%) of the title compound as a white solid: m.p. 133-134 ° C; [a] 21D + 99 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 430 (9, M +).

Preparation 34 (S) -5-amino-3-N, N-dibenzylamine-3,4-dihydro-2H-l-benzopyran To a solution of (S) -2- (3-N, N-dibenzylamino-3,4-dihydro-2H-l-benzopyran-5-yloxy) - ^ il Sf ^^^ 2-methylpropanamide (46 g, 0.11 mol) in 450 ml of anhydrous N, N-dimethylformamide and 45 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone was added sodium hydride (60-65% in oil, 8.5 g, 0.21 mol) in portions under nitrogen atmosphere. The reaction mixture was heated to 110 ° C with stirring for 13 hours. The mixture was allowed to cool, and the solution was partitioned between 400 ml of ethyl acetate and 200 ml of 2 M NH 3. The layers were separated and the aqueous layer was extracted with 150 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to give a brown oil. EIMS (70 eV) m / z (relative intensity) 430 (3, M +). The material obtained (0.11 mol) was dissolved in 350 ml of ethanol. 250 ml of a 6 M HCl solution was added, and the reaction mixture was heated to reflux for 16 hours. After stirring, the mixture was cooled to 35 ° C, the ethanolic solvent was removed in vacuo, and ethyl acetate was added to the aqueous remanents. The mixture was cooled on ice, and a concentrated NH3 solution was slowly added with stirring. The layers were separated, and the aqueous layer was extracted with another portion of ethyl acetate. The combined organic layers were dried over magnesium sulfate and the solvent was removed in vacuo to give a brown oil which was purified on a short column of silica gel (eluent: hexane / ethyl acetate; 8: 2) providing 25 g (68% yield) of the desired compound as a light yellow oil. The product crystallized slowly after standing in the refrigerator. An analytical sample was recrystallized from diethyl ether / petroleum ether: m.p. 101-103 ° C; [a] 21D + 123 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 344 (17, M +).

Preparation 35 (S) -1- (3-N, N-dibenzylamino-3,4-dihydro-2H-l-benzopyran-5-yl) -4-methylpiperazin-2,6-dione To a dispersion of N-methyliminodiacetic acid (6.90 g, 46.9 mmol) in 575 ml of anhydrous tetrahydrofuran was added 1,1'-carbonyldiimidazole (15.2 g, 93.9 mmol) and the mixture was heated at reflux for 2 hours under nitrogen atmosphere . A solution of (S) -5-amino-3-N, N-dibenzylamino-3,4-dihydro-2H-1-benzopyran (15.0 g, 42.7 mmol) in 120 ml of tetrahydrofuran was added, with stirring in 0.5 hours . The reaction mixture was heated to reflux for 28 hours, then allowed to cool, and the solvent was removed in vacuo. The residue was purified on a short column of silica gel (eluent: methylene chloride and ethyl acetate) to give 14.1 g (71% yield) of the title compound as a light yellow solid: m.p. sinters at more than 60 ° C; [a] 21-D + -89 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 455 (8, M +).

Preparation 36 (S) -3-N, N-dibenzylamino-5- (4-methylpiperazin-1-yl) 3,4-dihydro-2H-l-benzopyran To a solution of (S) -1- (3-N, N-dibenzylamino-3,4-dihydro-2H-l-benzopyran-5-yl) -4-met-piperazin-2,6-dione (25.4 g , 55.8 mmol) in 800 ml anhydrous diethyl ether was added lithium aluminum hydride (9.30 g, 246 mmol) in portions. The reaction mixture was refluxed for 6.5 hours under nitrogen atmosphere and stirred overnight at room temperature. The mixture was cooled in an ice bath, and 10 ml of water was added followed by a 15% aqueous solution of 10 ml of sodium hydroxide and another portion of more than 30 ml of water. The precipitate was filtered and washed with several portions of hot tetrahydrofuran. The organic layers were combined, and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform / ethanol; 95: 5 + 0.5% concentrated NH3) to yield 13.6 g (57% yield) of the title compound as a light yellow oil: [a] 25D + 63 ° (c 1.0, methanol); EIMS (70 eV) m / z (relative intensity) 427 (5, M +).

Preparation 37 (S) -3-amino-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran To a solution of (S) -3-N, N-dibenzylamino-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (2.6 g, 6.2 mmol) in 100 ml of anhydrous methanol was added 10% palladium on activated carbon (0.97 g) and ammonium formate (3.1 g, 49 mmol) under nitrogen atmosphere. The reaction mixture was heated to 50 ° C with stirring overnight. The solution was filtered through Celite®, and the solvent was removed in vacuo. The residue was partitioned between 20 ml of a 2M NH 3 solution and 100 ml of ethyl acetate. The layers were separated, and the aqueous layer was extracted with 3 50 ml portions of ethyl acetate. The combined organic phases were dried over sodium sulfate, and the solvent was removed in vacuo to give 1.4 g (89% yield) of the title compound as a pale yellow oil: [a] 21D-15 ° (c 1.0, cloprofoam ); EIMS (70 eV) m / z (relative intensity) 247 (74, M +).

Preparation 38 4- (4-p? Peridon-l-yl) benzoic acid A solution of 10 ml of 2M sodium hydroxide, 4- (8-aza-l, 4-dioxaspiro [4.5] dec-8-yl) benzonitrile (820 mg, 3.36 mmol, described in: Taylor EC; Skotnicki JS Syn th esi s 1981, 8, 606-608), and 7.5 ml of ethanol was heated to reflux for 3 hours. The external heating was stopped, and the reaction mixture was stirred overnight at room temperature. The ethanolic solvent was removed in vacuo, and the remnants were acidified to pH 4 with a 2 M HCl solution, followed by extraction with 50 ml of ethyl acetate. The layers were separated, and the pH was adjusted to pH 6 with a 2 M sodium hydroxide solution followed by another extraction with 50 ml of ethyl acetate. The combined organic layers were concentrated in vacuo, and the solid residue was dissolved in 10 ml of a 6M HCl solution. The reaction mixture was heated at 75 ° C for 2.5 hours and then at 55 ° C overnight. The temperature rose to 75 ° C for 2 hours, and the reaction mixture was allowed to cool. The pH was adjusted to pH 4 and the solution was extracted with 50 ml of ethyl acetate. The layers were separated and another extraction was carried out at pH 5. The combined organic layers were dried over anhydrous magnesium sulfate, and the solvent was removed in vacuo. The crude product was recrystallized from ethyl acetate to give 300 mg (41% yield) of the title compound as yellowish crystals: m.p. Sinters at more than 215 ° C; EIMS (70 eV) m / z (relative intensity) 219 (100, M +).

Preparation 39 (S) -3-N, N-Dibenzylamino-8-iodo-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-l-benzopyran The (S) -3-N, N-dibenzylamino-5- (4-methylpiperizin-1-yl) -3,4-dihydro-2H-l-benzo-l-pyran (6.90 g, 16 mmol) and Sodium (1.5 g, 18 mmol) was dissolved in 430 ml of acetic acid. To the solution was added iodine monochloride (18 ml, 1M, 18 mmol) and the reaction mixture was stirred at room temperature, protected from light, for 24 hours. Iodine monochloride (2.5 ml, 1 M, 2.5 mmol) was added followed by stirring for 3 hours. The solvent was evaporated in vacuo and the residue was partitioned between 800 ml of methylene chloride and 120 ml of 2 M NaOH. The aqueous phase was extracted with 100 ml of methylene chloride and the combined organic layers were washed with 2 portions of 100 ml. ml of brine and dried over magnesium sulfate. Evaporation of the solvent gave 8.6 g of a crude product. Purification by column chromatography on silica using ethyl acetate / ethanol (saturated with ammonia) (25: 1) as the eluent gave 4.1 g (43% yield) of the title compound (containing about 7% of the starting material) as a yellowish solid: EIMS (70 eV) m / z (relative intensity) 553 (15, M +). The product was used in the next step without further purification attempts.

Preparation 40 (S) -8-carboxymethyl-3-N, N-dibenzylamino-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-l-benzopyran (S) -3-N, N-Dibenzylamino-8-iodo-5- (4-methylpiperazin-1-yl) -3, -dihydro-2H-l-benzopyran (2.6 g, 4.8 mmol) was dissolved in 100 ml of N, N-dimethylformamide and was flushed with carbon monoxide. Palladium acetate was added to the solution (110 mg, 0.48 mmol), 1,3-bis (di phenyl phosphino) propane (200 mg, 0.48 mmol), 25 ml of methanol and triethylamine (3.3 ml, 24 mmol). The mixture was extracted with carbon monoxide at 90 ° C and at atmospheric pressure for 8 hours. The solution was filtered, the solvent was evaporated. The residue was co-evaporated with 2 x 50 ml portions of xylene and partitioned between 300 ml of methylene chloride and 50 ml of 2 M NH3. The aqueous phase was extracted with 50 ml of methylene chloride and the combined organic layers were washed with 2 50 ml portions of brine, dried over magnesium sulfate. The solvent was evaporated giving 4.0 g of a crude product. Purification by column chromatography on silica using methylene chloride / ethanol (saturated with ammonia) (50: 1) as the eluent gave 1.7 g (68% yield) of the title compound (containing - about 5% of the analogue). -H corresponding) as a yellowish solid: EIMS (70 eV) m / z (relative intensity) 485 (8, M +). The product was used in the next step without further attempts at purification.

Preparation 41 (S) -3-N, N-dibenzylamino-8-hydroxymethyl-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-l-benzopyran (S) -8-carboxymethyl-3-N, N-dibenzylamino-5- (methylpiperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (490 mg, 1.0 mmol) was dissolved in 40 ml of anhydrous tetrahydrofuran and lithium aluminum hydride (76 mg, 2.0 mmol) was added in portions. The reaction mixture was stirred at 45 ° C for 4 hours and cooled to room temperature. The reaction was quenched by the addition of 76 μl of water, 76 μl of 15% sodium hydroxide and 225 μl of water, and stirred for 18 hours. The white precipitate was filtered and the solution was dried over magnesium sulfate. The solvent was evaporated in vacuo to give 520 mg of a crude product. Purification by column chromatography on silica using chloroform / -ethanol (saturated with ammonia) (15: 1) as the eluent gave 390 mg (85% yield) of the title compound containing about 8% of the corresponding 8-methylated analog ) as a yellowish oil: EIMS (70 eV) m / z (relative intensity) 457 (15, M +).

Preparation 42 (S) -3-amino-8-methyl-1-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran The (S) -3-N, N-dibenzylamino-8-hydroxymethyl-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran (420 mg, 0.90 mmol) was dissolved in 60 ml of methanol and ammonium formate (460 mg, 7.3 mmol) was added. The solution was flushed with nitrogen and palladium on mineral charcoal (120 mg, 10%) was added. , ^ a »fife? ag¡? g * fe? ~., -, ~.-The reaction mixture was stirred at 50 ° C for 16 hours. The catalyst was filtered and the solvent was evaporated in vacuo to give 260 mg of a crude product. The residue was dissolved in 50 ml of acetic acid and palladium on charcoal (120 mg, 10%) was added. The reaction mixture was hydrogenated at room temperature and at atmospheric pressure for 46 hours. The catalyst was filtered and the solvent was e-vaporized in vacuo. The residue was partitioned between 120 ml of ethyl acetate and 10 ml of 2 M NaOH and the aqueous phase was extracted with 10 ml of ethyl acetate. The combined organic layers were washed with 5 ml of brine, dried over magnesium sulfate and the solvent was evaporated in vacuo to give 200 mg of a crude product. Purification by preparative thin layer chromatography on silica using chloroform / ethanol (saturated with ammonia) (10: 1) as the eluent gave 150 mg (64% yield) of the title compound as an oil: EIMS (70 eV) m / z (relative intensity) 261 (100, M +).

Preparation 43 Ethyl ester of 8-methoxy-5-nitro-3,4-dihydro-2H-l-benzopyran-3-carboxylic acid To a stirred solution of the ethyl ester of 8-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (5.5 g, 23 mmol, described in: Thorberg, S-0 et al., Acta Pharm. Suez 1987, 24, (4), 169-182) in 50 ml of methylene chloride at 0 ° C was added dropwise 2 ml of 65% HN03. The solution was stirred at room temperature for 2 hours and washed with water. The organic phase was dried and the solvent was evaporated in vacuo. The residue was treated with 30 ml of diisopropyl ether and 5 ml of ethyl acetate to yield 1.5 g (5.3 mmol) of crystals of the 6-nitro isomer. The mother liquor was purified by column chromatography using diisopropyl ether as the eluent to give 1.3 g (20% yield) of the title compound: m.p. 66-68 ° C; EIMS (70 eV) m / z (relative intensity) 281 (100, M +).

Preparation 44 8-methoxy-5-nitro-3,4-dihydro-2H-l-benzopyran-3-carboxylic acid A mixture of 8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid ethyl ester (5.8 g, 21 mmol) in 150 ml of -et-anol and 15 ml of hydroxide of 2 M sodium was heated to reflux for 30 minutes. The solvent was evaporated in vacuo and the residue dissolved in water. Acidification to pH 2 and extraction with ethyl acetate provided by evaporation of the solvent in vacuo gave 4.9 g (94% yield) of the title compound: m.p. 181-183 ° C; EIMS (70 eV) m / z (relative intensity) 253 (55, M +).

Preparation 45 N- [4- (4-morpholinyl) phenyl] -8-methoxy-5-nitro-3,4-dihydro-2H-l-benzopyran-3-carboxamide To a solution of 8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid (2.5 g, 10 mmol) in 40 ml of toluene and 1 ml of N, N-dimethylformamide thionyl chloride (3.6 ml, 50 mmol) was added. The reaction mixture was heated to reflux for 2 hours and the solvent was removed in vacuo. The residual acid chloride was added to a solution of 4- (1-morpholino) aniline (1.78 g, 10 mmol, described in: Devlin, JP et al., J. Chem. Soc. Perki. Trans. 1, 1975, 830-841) and triethylamine (2.0 g, 20 mmol) in 30 ml of methylene chloride and stirred at 0 ° C for 10 minutes and for 1 hour at room temperature. The solvent was removed in vacuo and the residue was dissolved in ethyl acetate and washed with 2 M sodium hydroxide. Evaporation of the solvent in vacuo afforded 1.5 g (36% yield) of the title compound as white crystals mp 238- 240 ° C, EIMS 70 eV) m / z (relative intensity) 413 (5, M +).

Preparation 46 N- [4- (4-morpholinyl) phenyl] -5-amino-8-methoxy-3,4-dihydro-2H-l-benzopyran-3-carboxamide To a solution of N- [4- (4-morpholinyl) phenyl] -8-methoxy-5-nitro-3,4-dihydro-2H-1-benzopyran-3-carboxamide (1.2 g, 2.9 mmol) in 10 ml A solution of sodium dithionite (2.1 g, 12 mmol) in 5 ml of water was added to the N, N-dimethylformamide, and the mixture was stirred at 55 ° C for 3 minutes. hours and the solvent was removed in vacuo The residue was purified by column chromatography on silica gel using ethyl acetate as the eluent to provide 273 mg of the title compound (55% yield): EIMS (70 eV) m / z (relative intensity) 383 (100, M +).

Preparation of the 5-HT ?B antagonist compounds described herein Example 1 (R) -N- [8- (piperazin-1-yl) -1, 2, 3, 4-tetrahydro-2-naphthyl] -4-morpholinobenzamide To an ice-cooled solution of (R) -N- [8- (4-tert-butyloxycarbonylpiperazin-1-yl) -1,2,3-tetrahydro-2-naphthyl] -4-morpholinophenylcarboxamide (1.0 g, 2 mmol) in 100 ml of methylene chloride was added 3 ml of trifluoroacetic acid. The reaction was stirred at room temperature for 7 hours. The solvent was evaporated in vacuo and the residue was dissolved in 20 ml of water, made alkaline with a 2 M aqueous sodium hydroxide solution and extracted twice with methylene chloride. The phases were separated, the combined organic phases were dried over sodium sulfate, filtered and evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as the eluent gave 580 mg (70% yield) of the title compound as white crystals: m.p. 202-203 ° C; [a] 21D-56 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 420 (5, M +).

Example 2 (R) -N- [8- (4-ethylpiperazin-1-yl) -1, 2, 3, 4-tetrahydro-2-naphthyl] -4-morpholinobenzamide To a solution of the (R) -N-8- (piperazin-1-yl) -l, 2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (90 mg, 0.21 mmol) in 20 ml of acetone was added potassium carbonate (44 mg, 0.32 mmol) and iodoethane (26 μl, 0.32 mmol) and the reaction was stirred for 48 hours at room temperature. The reaction mixture was filtered and the solvent was evaporated in vacuo. The residue was partitioned between methylene chloride and water, the phases were separated, and the organic phase was dried over sodium sulfate, filtered and evaporated in vacuo. Purification on a silica gel column using chloroform / ethanol saturated with NH3 (100: 3) as the eluent gave 63 mg (66% yield) of the title compound as white crystals: m.p. 204-206 ° C; [a] 21D-67 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 448 (21, M +).

Example 3 (R) -N- [5-methoxy -8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide To a solution of 4-morpholinobenzoic acid (0.92 g, 4.5 mmol, described in: Degutis, J .; Rasteikiene, L .; Degutiene, A. Zh. Org. Khim. 1978, 14 (10), 2060-2064) in 75 ml of anhydrous N, N-dimethyl formamide was added 1, 1'-carbonyldiimidazole (0.76 g, 4.8 mmol) and the reaction was heated to 75 ° C. When the evolution of carbon dioxide had ceased (after 45 minutes), the reaction was cooled to room temperature and a solution of (R) -2-amino-5-methoxy-8- (4-methylpiperazine-1) was added. -yl) -1, 2, 3, 4-tetrahydronaphthalene (1.2 g, 4.2 mmol) dissolved in 20 ml of anhydrous N, N-dimethylformamide. The reaction was allowed to stir at room temperature for 48 hours and the solvent was evaporated in vacuo. Purification on a column of silica gel using chloroform / methanol / concentrated ammonium hydroxide (180: 5: 0.5) as the eluent, -s-eguided by recrystallization from ethyl acetate and a few drops of methanol, gave 1.0 g (53% yield) of white crystals: mp 237-238 ° C [a] 21D-40 ° (c = 1, chloroform); EIMS (70 eV) m / z (relative intensity) 464 (5, M +).

Example 4 (R) -N- [5-ethyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide 4-Morpholinobenzoic acid (64 mg, 0.31 mmol) was dissolved in 1 ml of anhydrous N, N-dimethylformamide and added 1, 1'-carbonyldiimidazole (52 mg, 0.32 mmol). The reaction mixture was stirred at 75 ° C for 1 hour and cooled to room temperature. A solution of (R) -2-amino-5-ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (80 mg, 0.29 mmol) in 3 ml of N, N anhydrous dimethylformamide and the reaction mixture was stirred at room temperature for 14 hours. The solvent was evaporated and the residue was dried in vacuo. The crude product was purified by preparative TLC on silica using chloroform / methanol / concentrated NH3 (95: 5: 0.5) as the eluent which gave 85 mg (59% yield) of the title compound as a white solid: m.p. 234 ° C (decomposes); EIMS (70 eV) m / z (relative intensity) 462 (27, M +); [a] 21D-48 ° (c 0.09, chloroform).

Example 5 (R) -N- [5-ethyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonyl) benzamide 4-Morpholinocarbonylbenzoic acid (180 mg, 0.77 mmol, described in: J. Med. Ch., 1994 37 (26), 4538-4554) and 1,1 '-carbonyldiimidazole (130 mg, 0. 80 mmol) was dissolved in 3 ml of N, N-dimethylformamide and stirred at 75 ° C for 2 hours.

After cooling to room temperature, a solution of (R) -2-amino-5-ethyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (200 mg, 0.73 mmol) in anhydrous N, N-dimethylformamide and the reaction mixture was stirred for 60 hours. The solvent was evaporated in vacuo and the residue was partitioned between 60 ml of methylene chloride and 5 ml of 2 M NH3. The organic phase was washed with 10 ml of brine and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 360 mg of a crude product. Purification by column chromatography on silica using chloroform / methanol / concentrated NH3 (95: 5: 0.5) as the eluent afforded 240 mg (65% yield) of the title compound as a white solid: m.p. 213-214 ° C; EIMS (70 eV) m / z (relative intensity) 490 (27, M +); [a] 21D-28 ° (c 0.15, chloroform).

Example 6 (R) -N- [5-methoxy -8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonylbenzamide The title compound was prepared from (R) -2-amino-5-methoxy-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydronaphthalene following the general method of Preparation 16. Purification on a column of silica gel using chloroform / methanol / concentrated ammonium hydroxide (96: 4: 0.3) as the eluent, gave after recrystallization from ethyl acetate / diethyl ether, 93 mg (52% yield) of white crystals: mp 209-210 ° C; [a] 21D-18 ° (c = 1, chloroform); EIMS (70 eV) m / z (relative intensity) 492 (36, M +).

Example 7 (R) -N- [5-Bromo-8- (piperazin-1-y1) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide To an ice-cooled solution of (R) -N- [5-bromo-8- (4-tert-butyloxycarbonylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (150 mg, 0.26 mmol) in 20 ml of methylene chloride was added trifluoroacetic acid (0.7 ml). The reaction was stirred at room temperature for 20 hours. The solvent was evaporated in vacuo and the residue was dissolved in 20 ml of water, made alkaline with a 2 M aqueous solution of sodium hydroxide and extracted with methylene chloride. The phases were separated and the organic phase was dried over sodium sulfate, filtered and evaporated in vacuo. The residue was purified on a column of silica gel using chloroform / methanol / concentrated ammonium hydroxide (90: 10: 1) as the eluent. Yield: 94 mg (72%) of white crystals: m.p. 228-229 ° C; [a] 21D-6 ° (c = 1, chloroform); EIMS (70 eV) m / z (relative intensity) 498 and 500 (1.5, M + -). - Example 8 (R) -N- [5-Bromo-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide The title compound was prepared from (R) -2-amino-5-bromo-8- (-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene following the general method of Preparation 16 Purification on a column of silica gel using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 1) as the eluent, gave 100 mg (62% yield) of white crystals: mp 245-246 ° C; [a] 21D-23 ° (c = 1, chloroform); EIMS (70 eV) m / z (relative intensity) 512 and 514 (1, M +).

Example 9 (R) -N- [5-Bromo-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethyl-benzamide (R) -N- [8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethylbenzamide (80 mg, 0.19 mmol) -and -200 mg of sodium acetate were dissolved in 3 ml of acetic acid and the mixture was stirred at room temperature. Bromine was added dropwise (34 mg, 0.21 mmol) to the reaction mixture and the mixture was stirred for 2 hours at room temperature. 100 ml of a 2 M sodium hydroxide solution was added, and the mixture was extracted with 2 50 ml portions of diethyl ether. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification on a column of silica gel using methylene chloride / ethanol saturated with NH3 (94: 6) as the eluent gave 80 mg (85% yield) of the title compound as a white solid: m.p. 229-230 ° C; [a] 21D-5.4 ° (c = 1, chloroform); EIMS (70 eV) m / z (relative intensity) 495 and 497 (3, M +).

Example 10 (R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naph il] -4-morpholinobenzamide The 4-morpholinobenzoic acid (92 mg, 0.44 mmol) was dissolved in 2 ml of anhydrous N, N-dimethylformamide and flushed with nitrogen. To the solution was added 1,1 '-carbonyldiimidazole (76 mg, 0.47 mmol) and the reaction mixture was stirred at 75 ° C for 1.5 hour. The solution was cooled to room temperature and (R) -2-amino-5-methyl-8- (-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene (110 mg, 0.42 mmol) was added. dissolved in 2 ml of N, N-dimethyl formamide. The solution was stirred at room temperature for 30 hours. The solvent was evaporated in vacuo giving 290 mg of a crude product. Purification by preparative thin layer chromatography (TLC) on silica gel using chloroform / methanol / concentrated NH3 (95: 5: 0.5) as the eluent afforded 145 mg (73% yield) of the title compound as a white solid: pf > 231 ° C (decomposes); EIMS (70 eV) m / z (relative intensity) 448 (3, M +); [a] 21D-60 ° (c 0.15, chloroform).

Example 11 N- (4-morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide A solution of N- (4-morpholinophenyl) -8-amino-5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide (1.4 g, 3.5 mmol), bis- (2-chloroethyl) hydrochloride ) -methylamine (960 mg, 5 mmol) and sodium hydrogen carbonate (420 mg, 5 mmol) in 30 ml of n-butanol was heated at 90 ° C for 5 hours. After cooling, 30 ml of 2 M ammonium hydroxide was added and the mixture was heated at 50 ° C for 1 hour. The phases were separated, evaporated in vacuo and the mixture was heated at 50 ° C for 1 hour. The phases were separated, evaporated in vacuo and purified by flash chromatography on a silica gel column with chloroform / ethanol / concentrated sodium hydroxide 90/10 / 0.3 as the eluent. Yield: 320 mg (20%) of the title compound: m.p. 230.232 ° C; EIMS (70 eV) m / z (relative intensity) 464 (75, M +).

Chromatographic Preparation of the Enantiomers of N- (4-morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide The N- (4-morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-l, 2,3,4-tetrahydronaphthalene-2-carboxamide (5 mg) was dissolved in 4 ml of eluent, consisting of acetonitrile and phosphate buffer pH 3.0, μ = 0.1 (62.5: 37.5, v / v). This solution was purified on a Nucleosil 7 Cie column (25 x 250 mm) with the previous mobile phase to eliminate impurities eluting at the end. The fractions collected from the main component were concentrated under reduced pressure at 35-39 ° C. The residue was dissolved in 30 ml of the eluent composed of 10 mM ammonium acetate, diethylamine and acetic acid (4000 + 2 + 2, v / v / v, pH 5.26) and the chiral half-preparation of the N-enantiomers. (4-morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide was carried out on a semi-preparative Chiral AGP column (10 x 150 mm) using a protection column of the same stationary phase. A flow rate of 2 ml / minute was used and the detection was verified at 260 nanometers. The fractions of both enantiomers were separately collected and concentrated to a volume of approximately 5 ml under reduced pressure at 35-39 ° C. The concentrated fractions were adjusted to pH 10-11 with 5 M sodium hydroxide and extracted with chloroform. The two organic phases were washed with water and dried with anhydrous magnesium sulfate. After being filtered through glass wool, the organic filtrates were evaporated in vacuo affording the two enantiomers as two slightly yellow solids.

Example 12 N- (morpholinocarbonylphenyl) -8- (4-methylpiperazin-1-yl) -5-methoxy? -l, 2,3,4-tetrahydronaphthalene-2-carboxamide A solution of N- (morpholmocarbonylphenyl) -8-amino-5-methoxy-l, 2,3,4-tetrahydronaphthalene-2-carboxamide (280 mg, 0.69 mmol), bis (2-chloroethyl) methylamine hydrochloride (190 mg, 1.0 mmol) and sodium hydrogen carbonate (84 mg, 1.0 mmol) in 20 ml of n-butanol was heated at 90 ° C for 5 hours. After cooling, 100 ml of 2 M ammonium hydroxide was added and the mixture was heated at 50 ° C for 1 hour. The organic phase was evaporated in vacuo and the residue was purified by flash chromatography on a silica gel column using chloroform / ethanol / concentrated ammonium hydroxide (90: 10: 0.5) as eluent to yield 60 -mg- (18%) of the title compound; EIMS (70 eV) m / z (relative intensity) 492 (50, M +).

Example 13 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-l-benzopyran-3-yl] -4-morpholinobenzamide A solution of 4-morpholinobenzoic acid (380 mg, 1.83 mmol, described in: Degutis, J .; Rasteikiene, L .; Degutiene, A. Zh. Org. Khim. 1978, 14 (10), 2060-2064) and 1,1 '-carbonyldiimidazole (310 mg, 1.92 mmol) in 12 ml of anhydrous N, N-dimethyl formamide was stirred at 75 ° C for 30 minutes. The mixture was allowed to cool, after which a solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3, -dihydro-2H-1-benzopyran (430 mg, 1.74 g) was added. mmol) in 8 ml of N, N-dimethylformamide. The reaction mixture was stirred at room temperature for 3 days. Another portion of 1,1 '-carbonyldiimidazole (57 mg, 0.35 mmol) was added, and the mixture was stirred for an additional 3.5 hours. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (eluent: chloroform / ethanol; 93: 7 + 0.5% -NH3) yielding 513 mg (68% yield) of the title compound as a white solid: pf 210-212 ° C; [a] 22D-145 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity 436 (65, M +).

Example 14 (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (4-piperidon-1-yl) -benzamide A solution of 1,1 '-carbonyldiimidazole (116 mg, 0.716 mmol) and 4- (4-piperidon-1-yl) benzoic acid (150 mg, 0.683 mmol) in 5 ml of anhydrous N, N-dimethylformamide was stirred at 75 ° C for 50 minutes. The mixture was allowed to cool, and a solution of (S) -3-amino-5- (4-methylpiperazin-1-yl) -3, -dihydro-2H-1-benzopyran (161 mg, 0.651 mmol) was added.

S ^-N, N-dimethylformamide (4 ml). The reaction mixture was stirred at room temperature for 8 days. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica (eluent: chloroform / ethanol, 90:10 + 0.5% concentrated NH3) to afford 54 mg (19% yield) of the title compound as a solid white: pf 222-225 ° C (decomposes); [a] 22D-1-36 ° (c 0.30, chloroform); TSPMS (70 eV) m / z 449 (M + l).

Example 15 (S) -N- [8-Methyl-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (dimethylaminocarbonyl) benzamide 4- (Dimethylaminocarbonyl) benzoic acid (Jurewicz, AT; US Patent No. 3,607,918, 1971) (38 mg, 0.20 mmol) and 1,1'-carbonyldiimidazole (34 mg, 0.21 mmol) were dissolved in N, N-dimethylformamide anhydrous (4 ml) and stirred at 75 ° C for 1.5 hours. The reaction mixture was cooled to room temperature and a solution of (S) -3-amino-8-methyl-5- (4-methylpiperazin-1-yl) -3, -dihydro-2H-l-benzopyran ( 49 mg, 0.19 mmol) in 5 ml of anhydrous N, N-dimethylformamide. The reaction mixture was stirred at 50 ° C for 14 hours and the solvent was evaporated in vacuo to give 120 mg of the crude product. Purification by preparative thin layer chromatography using chloroform / methanol / concentrated NH3 (95: 5: 0.5) as the eluent gave 40 mg (48% yield) of the title compound as a white foam: EIMS (70 eV) m / z (relative intensity) 436 - (26, M +); [a] 21D-9 ° (c 0.20, chloroform).

Example 16 N [4- (4-morpholinyl) phenyl] -8-methoxy -5- (4-yl-piperazin-1-yl) -3,4-dihydro-2H-l-benzopyran-3-carboxamide A solution of N- [4- (4-morpholinyl) phenyl] -5-amino-8-methoxy-3,4-dihydro-2H-l-benzopyran-3-carboxamide (270 mg, 0.7 mmol, bis hydrochloride) (2-Chloroethyl) -methylamine (288 mg, 1.5 mmol) and sodium hydrogen carbonate (126 mg, 1.5 mmol) in 10 ml of n-butanol was stirred at 90 ° C for 2.5 hours.10 ml of ammonia 2 was added M at 50 ° C, the mixture was cooled and the phases were separated.The organic phase was evaporated in vacuo and the residue was purified by column chromatography on silica gel using ethyl acetate / triethylamine. (100: 8) as the eluent affording 170 mg (50% yield) of the title compound as white crystals: m.p. 202-204 ° C; EIMS (70 eV) m / z (relative intensity) 466 (100, M +).

Example 17 (R) -N- [8- (4-methyIpiperazin-1-yl) -1,2, 3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide To a solution of 4-morpholinobenzoic acid (0.89 g, 4.3 mmol, described in: Degutis, J., Rasteikiene, L., Degutiene, A. Zh. Org. Khim. 1978, 14 (10), 2060-2064) in 30 ml of anhydrous N, N-dimethylformamide was added 1,1'-carbonyldiimidazole (0.73 g, 4.3 mmol) and the reaction was heated to 75 ° C. When the evolution of carbon dioxide had ceased (after 30 minutes), the reaction was cooled to room temperature and a solution of (R) -2-amino-8- (4-methyl-piperazin-1-yl) -1 was added. , 2,3, 4 -tetrahydronaphthalene (1.0 g, 4.1 mmol) in 5 ml of anhydrous N, N-dimethylformamide. The reaction was allowed to stir at room temperature for 24 hours and the solvent was evaporated in vacuo. Purification on a silica gel column using chloroform / methanol / concentrated ammonium hydroxide (95: 5: 0.5) as the eluent gave 1.5 g (85% yield) of the title compound as white crystals: m.p. 230-231 ° C; [a] 1D-49 ° (c 1.0, chloroform); EIMS (70 eV) m / z (relative intensity) 434 (10, M +). - - Pharmacology Methods for testing i) Functional h5-HT? B receptor assay In order to evaluate the antagonist properties of the 5-HT1B receptor, the standard assay using the electric field stimulation of the release of [3H] -5-HT from the occipital cortex of guinea pigs can be used. teafaani.'g 'Methods and Materials Buffer composition (mM): NaHCO3 (25), NaH2PO4 «H20 (1.2), NaCl (117), KCl (6), MgSO4x7H20 (1.2), CaCl2 (1.3), EDTA Na2 (0.03). The damper is gasified for at least 30 minutes before use. The buffer's pH is about 7.2 at room temperature, but it rises - up to about 7.4 at 37 ° C. 10 Preparation of slices of occipital cortex Guinea pigs weighing 200 to 250 g were decapitated and their brains were removed complete. The occipital cortex was dissected and cut into 0.4x4 mm slices with a Mcll ain shredder. The white part of the tissue was carefully removed with tongs before slicing. The slices were incubated in 5 ml of buffer in the presence of 5 mM pargyline chloride. After incubation with 0.1 mM [3H] -5-HT for another 30 minutes the slices were transferred to a test tube and washed three times with the same volume of shock absorber. The slices were transferred to the E £ -atsáí3 &S £ -í- -MSets &ii. - .- «Ja & wffiMfttiSHte '" superfusion chambers with a plastic pipette and were washed for 40 minutes with the buffer in the presence of the uptake inhibitor, citalopram (2.5 μM) with a flow of 0.5 ml / minute .

Electrical stimulation of 5-HT release The superfused buffer was collected in 2 ml fractions. The slices were stimulated with electricity with a pulse train of frequencies of 3 Hz, for 2 milliseconds and a current of 30 mA for 3 minutes in the 4? and 13th fractions. The tested drugs were added from the 8th fraction until the end of the experiment.

Results A first electrical stimulation (or K +) resulted in a standard amount of [3H] -5-HT released (Si). Between the first and second stimulations the h5-HT ?B antagonist is added to the medium, which results in an increase, dependent on the dose, of the release (S2) during the second stimulation. The S2 / S ratio? t ^? A U ityX ^ M ^ If it is the percent of [3H] -5-HT released in the second stimulation (S2) stimulation (Si), which was used to estimate the effects of the drug on the release of the transmitter. See Figure 1. ii) Effects of antagonists / partial agonists of the h5-HTj.B receptor in combination with c n -SSRIs, measured by microdialysis in guinea pig brain The effects of different antagonists of the h5-HT? B receptor in combination with a selective inhibitor of serotonin reuptake on extracellular levels of 5-HT in the frontal cortex of guinea pigs are measured by microdialysis. Dunkin Hartley male guinea pigs (Charles River, Sweden), weighing 270-500 g, were anesthetized intramuscularly with a 1: 3 v / v mixture of Rompun® veterinary grade (20 mg / ml) and veterinary grade Ketalar® (50 mg / ml), and placed in a stereotaxic structure. A unilateral guide cannula was carefully implanted into the frontal cortex using the following stereotaxic coordinates with respect to the bregma: AP: +4.5 mm, L: -2.0 mm and DV: 0 mm from the brain surface. The animals were allowed to recover for 2 to 7 days before the experiment was carried out. The day before the beginning of the dialysis sample collection, microdialysis probes were inserted with 3 mm membranes inside the guide cannula. The probes were perfused with Ringer's solution at a flow rate of 2.0 μl / minute and samples were collected every 20 minutes. Compound A (a selective serotonin reuptake inhibitor, SSRI) was administered at 0 minutes and compound B, C, D or E (an antagonist of h5-HT? B or saline) was administered 60 minutes after . All drugs were administered simultaneously. The content of 5-HT was analyzed by high performance liquid chromatography (HPLC) with electrochemical detection. For data analysis, the average value of 5-HT from 3 to 4 samples collected prior to drug administration was defined as 100% (baseline) and the following samples expressed as the percent of this value. 12.3 Results Figure 2 shows the effects of compound A in combination with compound B, C, D or E on the extracellular levels of 5-HT in the frontal cortex of guinea pigs, as measured by microdialysis. The data are the mean + S.E.M .; n = 5.6. The arrows indicate the administration of the drug. Compound A: Citalopram Compound B: (R) -N-. { 5-methoxy-8- (-? Aet ilpiperazin-1-yl) -1, 2, 3, 4-tetrahydro-2-naphthyl] -4- morpholinobe zamide Compound C: Saline Compound D: (R) -N- [8- (-met? Ipiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- morpholinobenzamide Compound E: (R) -N- [5-methyl-8- (4 -met ilpiperazin-1-yl) -1, 2, 3, 4-tetrahydro-2-naphthyl] -4- orfolinobenzamide It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (20)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A combination of a first component (a) which is a 5-HT reuptake inhibitor, with a second component (b) which is an antagonist or selective partial agonist of h5-HT? B, which has the formula I (I) characterized in that X is CH2, O; And it's CONH, NHCO; Ri is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms; R2 is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen; R3 is -N O -C -C (O) -N O -CF. -C (O) NR4R R4 and Rs are independently hydrogen or alkyl of 1 to 4 carbon atoms, such as racemate, R enantiomer or S enantiomer, and the components (a ^ and (b) are in the form of free bases, solvates, or pharmaceutically acceptable salts of the same.

2. A combination according to claim 1, characterized in that the second component (b) is a compound of the formula I wherein X is CH23.

A combination according to claim 2, characterized in that the second component (b) is a compound of the formula I wherein Y is NHCO.

4. A combination according to claim 3, characterized in that the second component (b) is a compound of the formula I wherein R3 is morpholmo.

5. A combination according to any of claims 1 to 4, characterized in that the second component (b) is a compound of the formula I wherein RT. is hydrogen / methyl or ethyl and R2 is hydrogen, methyl, ethyl, methoxy or bromo.

6. A combination according to claim 1, characterized in that the second component (b) is a compound selected from: (R) -N- [8- (piperazin-1-yl) -1,2,3, 4-tetrahydro- 2-naphthyl] -4-morpholinobenzamide; (R) -N- [8- (4-ethylpiperazin-1-yl) -l, 2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [8- (4-methylpiperazin-1-yl) -1,2, 3, -tetrahydro-2-naphthyl] -4-morpholmobenzamide; (R) -N- [5-methoxy-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [5-ethyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [5-ethyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonyl) -benzamide; (R) -N- [5-methoxy-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinocarbonylbenz-amide; (R) -N- [5-bromo-8- (piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; N- [5-Bromo-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; (R) -N- [5-Bromo-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-trifluoromethyl-benzamide; (R) -N- [5-methi 1-8- (4-meth ipiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide; N- (4-morpholinophenyl) -8- (4-methypiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide; (R) -N- (4-morpholinophenyl) -8- (4-methylpiperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide, (S) -N- (4-morpholino-phenyl) -8- (4-methyl-piperazinyl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide; (R) -N- (morpholinocarbonylphenyl) -8- (4-methylpiperazin-1-yl) -5-methoxy-1,2,3,4-tetrahydronaphthalene-2-carboxamide; (S) -N- [5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4-morpholinobenzamide; (S) -N- [5- (4-methylp? Perazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (4-piperidon-1-yl) benzam to; (S) -N- [8-methyl-5- (4-methyl-piperazin-1-yl) -3,4-dihydro-2H-1-benzopyran-3-yl] -4- (dimethylaminocarbonyl) benzamide; N- [4- (4-morpholinyl) phenyl] -8-methoxy-5- (4-methyl-l-piperazin-1-yl) -3,4-dihydro-2H-l-benzopyran-3-carboxamide .

7. A combination according to claim 6, characterized in that the second component (b) is a compound selected from (R) -15 N- [8- (4-methyl-piperazin-1-yl) -l, 2,3,4- tetrahydro-2-naphthyl] -4-morpholmobenzamide, (R) -N- [5-methoxy-8- (4-methylp? perazin-1-yl) -1, 2, 3, 4-tetrahydro-2-naphthyl] -4- morpholinobenzamide and (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -l, 2, 3, 4-tetrahydro-2-naphthyl] -4- 20 morpholinobenzamide.

8. The combination according to any of claims 1 to 7, characterized in that the reuptake inhibitor | a ^ ij j ^ ¿j¡ ^ de 5-HT is fluoxetine, paroxetine, citalopram, clomipramine, sertraline or fluvoxamine.

9. The use of the combination according to any of claims 1 to 8, for the manufacture of a medicament for the treatment of affective disorders.

10. The use of the combination according to claim 9, for the manufacture of a medicament for the treatment of depression.

11. A method for the treatment of affective disorders, characterized in that the combination defined in accordance with any of claims 1 to 8 is administered to a patient suffering from them.

12. A method for the treatment of depression, characterized in that the combination defined in accordance with any of claims 1 to 8 is administered to a patient suffering from it.

13. A pharmaceutical formulation, characterized in that the active ingredients are the combination defined according to any of claims 1 to 8, optionally in association with adjuvants, diluents, excipients and / or inert carriers.

14. A pharmaceutical formulation according to claim 13, characterized in that the first component (a) is concomitantly administered with the second component (b).

15. A pharmaceutical formulation according to any of claims 13 to 14, for use in the treatment of affective disorders.

16. A pharmaceutical formulation according to claim 15, for use in the treatment of depression.

17. A process for the preparation of a combination according to claim 1, characterized in that a 5-HT reuptake inhibitor as defined according to any of claims 1 or 8, is incorporated within the same pharmaceutical formulation as a antagonist or selective partial agonist of 5-HT? B, as defined according to any of claims 1 to 7.

18. A process for the preparation of the combination according to claim 1, characterized in that a 5-HT reuptake inhibitor according to any of claims 1 or 8, is incorporated within the same pharmaceutical formulation, and an antagonist or Selective partial agonist of 5-HT? B, as defined according to any of claims 1 to 7, is in a pharmaceutical formulation.

19. A kit, characterized in that it contains the combination of a first component (a) which is a 5-HT reuptake inhibitor as defined in accordance with any one of claims 1 or 8, and a second component (b) which is an antagonist or selective partial agonist of 5-HT ?B as defined according to any one of claims 1 to 7, optionally with instructions for use.

20. A method for improving the initiation of therapeutic action by concomitant administration of a first component (a), which is a 5-HT reuptake inhibitor as defined in any one of claims 1 or 8, and a second component (b) which is a selective partial antagonist or agonist of 5-HT ?B as defined in accordance with any of claims 1 to 7. COMBINATION OF A 5-HT RECAPTATION INHIBITOR AND AN ANTAGONIST OR PARTIAL AGONIST OF h5-HT1B SUMMARY OF THE INVENTION The invention relates to a combination of a first component (a) which is a 5-HT reuptake inhibitor, and a second component (b) which is an antagonist or partial selective agonist of h5-HT? B which has the formula (I), wherein X is CH2, 0; And it's CONH, NHCO; Ri is H, - alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms; R2 is H, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen; R3 is (1), (2), (3), CF3; R 4 and R 5 independently are hydrogen or alkyl of 1 to 4 carbon atoms, as racemate, R enantiomer or S enantiomer and components (a) and (b) are in the form of the free bases, solvates or pharmaceutically acceptable salts of the same, the preparation thereof, the pharmaceutical formulations containing said combinations, the use of and a method of treating affective disorders such as depression, anxiety and OCD, with said combination, as well as the equipment containing said combination. - ^ LL L ^^ ÍSÍ