MXPA01007403A - New morpholinobenzamide salts - Google Patents

Abstract

The present invention relates to pharmaceutically acceptable salts of the compound of formula (I) or solvates of said salt in which the compound of formula (I) is as the (R)-enantiomer, the (S)-enantiomer or the racemate, a process for their preparation, pharmaceutical formulations containing said therapeutically active compounds and to the use of said active compounds in therapy.

Description

NEW SALTS OF MORFOLINOBENZAMIDA Field of the Invention The present invention relates to novel pharmaceutically acceptable salts of N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4 -morpholinobenzamide as the enantiomer. { R), the enantiomer (S) or the racemate or as solvates of the salts, a process for their preparation, pharmaceutical formulations containing the salts or solvates and the use of the active salts or solvates in the therapy. An object of the invention is to provide compounds for therapeutic use, especially compounds that have a selective effect on a subgroup of 5-hydroxytryptamine receptors, designated the h5-HTa receptor (previously called the 5-HT? Dp receptor). ) in mammals including man, the compounds that are easily formulated in pharmaceutical formulations. It is also an object of the invention to provide compounds with a therapeutic effect after oral administration.

Prior Art The different classes of benzanilide derivatives substituted with piperazinyl as 5-HT ?D antagonists are REF: 131292 describe in inter alia EP 533266, EP 533267, EP 533268, GB 2273930 and WO 95/11243. WO 94/13659 discloses an extremely broad class of benzo fused compounds having a piperidyl or piperazinyl radical for substituted on the aromatic ring, the class of compounds being established to bind to the 5-HTiA receptor. WO 94/21619 discloses a fully aromatic naphthalene ring system which can be substituted with a piperidyl or piperazinyl group, it was also established that the compounds are potent serotonin agonists and antagonists (5HT?). Patent EP 402923 discloses 1, 2, 3, 4-tetrahydronaphthalene derivatives substituted with 2-aminoalkyl or aromatic alkylene having an additional nitrogen substitution at the 5-position on the tetralin ring, the compounds acting as dopamine agonists.

Background of the Invention Several disorders of the central nervous system such as depression, anxiety, etc., appear to involve the alteration of the neurotransmitters noradrenaline (NA) and / or 5-hydroxytryptamine (5-HT), the latter also known as serotonin. It is believed that the drugs most frequently used in the treatment of depression act by improving the neurotransmission of either or both of these physiological agonists. It seems that the increase in neurotransmission of 5-HT mainly affects depressed mood and anxiety, while the increased neurotransmission of norepinephrine affects the delay symptoms that occur in depressed patients. It is believed that the activity of serotonin, or 5-HT, is involved in many different types of psychiatric disorders. For example, it is believed that an increase in the activity of 5-HT is associated with anxiety, while the decrease in the release of 5-HT has been associated with depression. Serotonin has also been implicated in diverse conditions such as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behavior. The compound of formula I below in base form has an extremely low solubility in water and a slow release rate, the rate being pH dependent, ie the speed is different in the stomach and intestines. From a pharmaceutical formulation point of view it is very difficult to dissolve the base fast enough and keep it dissolved in the gastric juice until a sufficient amount of the substance has been absorbed.

The 5-HT receptors The various effects of 5-HT can be related to the fact that serotonergic neurons stimulate the secretion of various hormones, for example, cortisol, prolactin, β-endorphin, vasopressin and others. The secretion of each of these other hormones appears to be regulated on a specific basis by several different 5-HT (serotonin) receptor subtypes. To date, these receptors have been classified as 5-HT ?, 5-HT2, 5-HT3, 5-HT4, 5-HTs, 5-HT6 and 5-HT7 with the receptor of 5-HT? it has also been divided into the subtypes 5-HT? A, 5-HT? B, 5-HT1D, 5-HT? E and 5-HT? F. Each receptor subtype is involved in a different function of serotonin and has different properties.

Regulation of the transmission of 5-HT The release of 5-HT at the nerve terminals is regulated by feedback by two different subtypes of 5-HT receptors. The inhibitory 5-HTαA autoreceptors are located in the cellular bodies in the raphé nuclei which with the stimulation by the 5-HT decrease the propagation of impulses in the 5-HT neurons and due to that they reduce the liberation of 5-HT in the nerve terminals. Another subtype of inhibitory 5-HT receptors is located at the nerve terminals of 5-HT, the 5-HTIB receptors (in rodents the receptors of r5-HT? B) which regulate the synaptic concentration of 5-HT by controlling the amount of 5-HT that is released. An antagonist of those terminal auto-receptors in this manner increases the amount of 5-HT released by nerve impulses which has been shown in both in vitro and in vivo experiments. The use of a terminal 5-HTiB auto-receptor antagonist will therefore increase the synaptic 5-HT concentration and increase the transmission in the 5-HT system. In this way, an antidepressant effect would be produced making it useful as a medication for depression. There are also other locations of the 5-HT1B receptor subtype. A large part of these post-synaptic receptors appear to be located in the nerve terminals of other neuronal systems (commonly called hetero-receptors). Since the h5-HT1B receptor mediates inhibitory responses, an antagonist of this receptor subtype could also increase the release of other neurotransmitters than 5-HT. According to well-known and recognized pharmacological tests, compounds having h5-HT ?B activity can be divided into full agonists, partial agonists and antagonists.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graphical representation in which the fractions of release of [H3] -5-HT produced as a result of electrical stimulation are shown.

Description of the Invention The objective of the present invention is to provide compounds having a selective effect on the h5-HT1B receptor, preferably antagonistic properties, as well as having good bioavailability and which can be easily formulated in pharmaceutical formulations. The compounds according to the invention have surprisingly solved the above problem since they dissolve fast enough and remain dissolved in the gastric juice until a sufficient amount of the substance has been absorbed.

Accordingly, the present invention provides pharmaceutically acceptable salts of the compound of the formula I or solvates of the salt in which the compound of the formula I is as the (R) -enantiomer, the (S) -enantiomer or the racemate.

(I) with the proviso that they are excluded (25, 3S) - (R) -N- [5-methyl-! - (4-methyl-piperazin-1-yl) -1, 2, 3, -tetrahydro-2-naphthyl acid tartrate ] -4-morpholinobenzamide, . { 2R, 3R) - (R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1, 2, 3, 4-tetrahydro-2-naphthyl] -4-morpholinobenzamide acid tartrate, benzenesulfonate of. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, Acid 1,2-ethanedisulfonate. { R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4- orfolinobenzamide, acid maleate. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, acid sulfate. { R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, D-gluconate of. { R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, acid succinate. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, methanesulfonate of. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (Sj-acidic acid of { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, diacid citrate of (i?) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2, 3, -tetrahydro-2-naphthyl] -4-morpholinobenzamide and hydrochloride. { R) -N- _5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, the salts having a high selective effect in the h5-HT1B receptor, are easily formulated in pharmaceutical formulations and also show sufficient bioavailability after oral administration. The preferred enantiomers are the enantiomers . { R). Preferred compounds are L-lactate. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, dibromohydrate. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,4,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, monobromide hydrate. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide and dihydrochloride of. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide. Both organic and inorganic acids can be used to form pharmaceutically acceptable, non-toxic acid addition salts according to the invention. Illustrative acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, hydrobromic, citric, acetic, lactic, tartaric, dibenzoyltartaric, diacetyltartaric, palmoic, ethanedisulfonic, sulfamic, succinic, propionic, glycolic, malic, gluconic, pyruvic, phenylacetic acids , 4-aminobenzoic, anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3,4-dihydroxybenzoic, 3,5-dihydroxybenzoic, 3-hydroxy-2-naphthoic, nicotinic, methanesulfonic, ethanesulfonic, hydroxyethane sulfonic, benzenesulfonic, p -toluenesulfonic, sulfanilic, naphthalenesulfonic, ascorbic, cyclohexyl sulfamic, fumaric, maleic and benzoic. The compound of the formula I can form hemi-, mono-, sesqui-, di- or friesal or any other salt combination existing between the above acids, if applicable. These salts are readily prepared by methods known in the art. The preferred solvates of this invention are hydrates. Other solvates can be formed from solvents such as ethyl acetate, ethanol or acetone. The solvates of the salts are readily prepared by methods known in the art.

Pharmaceutical Formulations In a second aspect, the present invention provides easily formulated pharmaceutical formulations comprising as active ingredient a therapeutically effective amount of a pharmaceutically acceptable salt of the compound of the formula I or a solvate of the salt as an enantiomer or a racemate, or a combination of such salts and / or solvates, optionally in association with inert diluents, excipients or carriers. In accordance with the present invention, the compound of the invention will normally be administered orally, rectally or by injection, in the form of pharmaceutical formulations comprising the active ingredient either as a non-toxic, pharmaceutically acceptable acid addition salt. , for example hydrochlorides, hydrobromides, lactates, acetates, phosphates, sulphates, sulphamates, citrates, tartrates, oxalates and the like or as a solvate of such salt in a pharmaceutically acceptable dosage form. The dosage form can be a solid, semi-solid or liquid preparation. Usually, the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% "by weight for the proposed preparations for injection and between 0.2 and 50% by weight for the preparations suitable for oral administration To produce pharmaceutical formulations containing the compound of the invention in the form of dosage units for oral application, the selected compound can be mixed with a solid excipient., for example lactose, sucrose, sorbitol, mannitrol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidone and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then compress into tablets. If coated tablets are required, the cores, prepared as described above, can be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatin, talcum, titanium dioxide and the like. Alternatively, the tablet can be coated with a polymer known to the person skilled in the art, dissolved in an easily volatile organic solvent or a mixture of organic solvents. Pigments can be added to these coatings in order to easily distinguish between tablets containing different active substances or different amounts of the active compound. For the preparation of soft gelatine capsules, the active substance can be mixed with, for example, a vegetable oil or polyethylene glycol. The hard gelatine capsules may contain granules of the active substance using either the excipients mentioned above for the tablets for example lactose, sucrose, sorbitol, mannitol, starches (for example potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. You can also fill liquids or semisolids of the drug in hard gelatin capsules. Dosing units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fat base, or rectal gelatin capsules comprising the active substance in admixture with vegetable oil or paraffin oil. Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.1% to about 20% by weight of the active substance described herein, the remainder being sugar and a mixture of ethanol, water, glycerol and. propylene glycol. Optionally, such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent or other excipients known to the person skilled in the art.

Solutions for parenteral applications by injection can be prepared in an aqueous solution of a pharmaceutically acceptable water soluble salt of the active substance, preferably in a concentration of about 0.1% to about 10% by weight. These solutions may also contain stabilizing agents and / or buffering agents and may conveniently be provided in several ampoules of dosage units. Suitable daily doses of the compound of the invention in the therapeutic treatment of humans are approximately 0.01-100 mg / kg of body weight in peroral administration and 0.001-100 mg / kg of body weight in parenteral administration. The compound of the invention can be used in combination with an inhibitor of 5-HT uptake, such as fluoxetine, paroxetine, citalopram, clomipramine, sertraline, alaproclate or fluvoxamine, preferably paroxetine or citalopram. Another possible combination is to use the compound of the invention together with an inhibitor of the monoamine oxidase, such as moclobe ida, tranylcypramine, brofaromide or phenelzine, preferably moclobemide or phenelzine. Yet . Another possible combination is the compound of the invention together with a 5-HT? A / antagonist such as the compounds described in WO 96/33710, preferably. { R) -5-carbamoyl-3- (N, N-dicyclobutylamino) -8-fluoro-3,4-dihydro-2-yl-benzopyran.

Medical and Pharmaceutical Use In a further aspect, the present invention provides the use of the compounds of the invention in therapy as antagonists of h5-HT-_B, partial agonists or full agonists, preferably as antagonists and the use in the treatment of disorders mediated by 5-hydroxytryptamine. Examples of such disorders are disorders in the CNS such as disorders in mood (depression, major depressive disorder, major depressive episodes, dysthymia, seasonal affective disorder, depressive phases of bipolar disorder), anxiety disorders (compulsive disorder obsessive, panic disorder with / without agoraphobia, social phobia, specific phobia, generalized anxiety disorder, post-traumatic stress disorder), personality disorders (impulse control disorders, trichotillomania), 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 hyperprolactinaemia) apoplexy, dyskinesia, Parkinson's disease, thermoregulation, pain, hypertension Zion. Other examples of disorders mediated by hydroxytryptamine are urinary incontinence, vasospasm, and tumor growth control (eg, lung carcinoma). Methods of Preparation The present invention also relates to processes for preparing the compounds of the invention.

Methods of Preparation of Intermediate Products (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 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 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, N-dimethylformamide, acetone or acetonitrile with a suitable base, for example? AOH,? AHC03, K2C03 or a trialkylamine such as triethylamine at a 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. (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 acidic reagent such as aqueous HBr, Hl, HBr / CH3COOH, BBr3, A1C13, pyridine-HCl or with a basic nucleophilic reagent such as CH3C6H4S ~ or C2H5S ~ in a suitable solvent. Suitable solvents may be methylene chloride or chloroform and the reaction may occur between -78 ° C and + 60 ° C. (iii) The conversion of the compound of the formula IV to a compound of the formula V (TV) (V) it can be carried out by reaction with a compound of formula VI (VI) where X represents a leaving group, for example, a halogen such as chlorine, bromine or iodine or an alkane- or arenesulfonyloxy group such as a p-toluenesulfonyloxy group and Ra and Rb are hydrogen or a lower alkyl group, for example 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 (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 suitable base, for example K2C03, KOH, potassium ter-butoxide or? aH at a temperature within 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 an appropriate concentration in a solvent can increase the speed 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 H2SO, HCl or HBr in a suitable solvent, for example H20, ethanol, methanol or mixtures thereof and the reaction may occur between + 20 ° C and + 100 ° C or under basic conditions using bases such as? aOH or KOH in a suitable solvent, for example, H20, ethanol, methanol or mixtures thereof and the reaction may occur between + 20 ° C and 100 ° C. (iv) The conversion of the compound of formula VIII to a compound of formula IX (HIV) (IX) it can be carried out by reaction with a compound of formula X.

(X) 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 LiAlH4 in a solvent for example diethyl ether or tetrahydrofuran at a temperature between + 20 ° C and reflux. (vii) Halogenation of the compound of formula IX (IX) (XI) to obtain a compound of formula XI can be made 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 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 at a temperature of reaction between -20 ° C and at room temperature.

(XI) (ID (viii) Conversion of the compound of the formula XI to a compound of the formula XII 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 the treatment with methyl iodide and the reaction can be carried out at a reaction temperature within, from the range of -78 ° C to room temperature, followed by the division 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.

Final Product Preparation Method Another object of the invention is a process for the preparation of the compound of the invention by the acylation of a compound of the formula XII, (XH) (i) with activated 4-morpholinobenzoic acid and. by reacting the base with an organic or inorganic acid to form the salt with or without a solvate. In this way, the acylation can be carried out by reacting the compound of the formula XII with the acid chloride or acid bromide of 4-morpholinobenzoic acid in a suitable solvent such as methylene chloride or chloroform with a suitable base, for example trialkylamine such as triethylamine at a temperature between -20 ° C and at reflux temperature or by activation of the carboxylic acid function in 4-morpholinobenzoic acid with an activating reagent such as N, N-carbonyldiimidazole, N, N-dicyclohexylcarbodiimide or diphenylphosphinic chloride with or without 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. In addition, the pharmaceutically acceptable salt of the compound of the formula I can be obtained by reaction of the base with the appropriate acid in a suitable solvent such as an alcohol, for example, methanol, ethanol or 2-propanol or other suitable solvent such as water, ethyl acetate, hexane, tetrahydrofuran, acetone, acetonitrile, chloroform or mixtures thereof. The process can be carried out at various temperatures between -30 and reflux. The salt formed in the above process can be formed as a solvate.

Work Examples The following examples will describe, but will not limit, the invention.

Example 1 (I?) -2-N, N-Dibenzylamino-8-methoxy-l, 2,3,4-tetrahydronaphthalene To a solution of hydrochloride of. { R) -8-methoxy-2-amino-1,2,3,4-tetrahydronaphthalene (24 g, 0.11 mol) in acetonitrile (600 L) were added potassium carbonate (53 g, 0.39 mol), potassium iodide ( catalytic amount) and benzyl bromide (34 mL, 0.28 moles). The reaction mixture was stirred at reflux for a period of 35 hours. After the precipitated product was filtered and the acetonitrile was removed in vacuo, the residue was partitioned between diethyl ether and water. The organic phase was separated, dried (Na2SO4) 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 +).

Example 2 (R) -7-N, N-Dibenzylamino-5,6,7,8-tetrahydro-l-naphthol The (?) -2-N, N-dibenzylamino-8-methoxy-2,3, 4-tetrahydronaphthalene (43 g, 0.12 mol) was dissolved in diethyl ether (800 mL) and an excess of an ethereal HCl solution was added dropwise. The precipitated product was filtered and dried in vacuo to give a white solid. This crude product (42 g, 0.11 mol) was dissolved in anhydrous methylene chloride (1 L) and cooled to -60 ° C. To the solution was added dropwise boron tribromide (16 mL, 0.15 mol), dissolved in anhydrous methylene chloride (100 mL). The reaction temperature was allowed to reach -5 ° C and remained there overnight. To the ice-cooled solution, a solution of 2 M aqueous ammonium hydroxide was added dropwise and the mixture was extracted twice with methylene chloride. The combined organic phases were dried (Na2SO4), filtered and the solvent was 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: [a] 21D + 118 ° (c 1.5, chloroform): EIMS (70 eV) m / z (relative intensity) 343 (53, M +).

Example 3 (R) -2- (7-N, N-Dibenzylamino-5, 6, 7, 8-tetrahydro-l-naphthyloxy) -2-methylpropanamide The (i?) -2-N, N-dibenzylamino-5 , 6,7, 8-tetrahydro-l-naphthol (10 g, 29 mmol) was stirred in anhydrous dioxane (150 mL) with sodium hydride (80% in oil, 0.96 g, 32 mmol) for 1 hour. 2-Bromo-2-methylpropanamide (4.8 g, 29 mmol); described in: Coutts, I. G. C; Southcott, M.R. J. Chem. Soc. Perkin Trans. 1 1990, 767-770) was added and the reaction mixture was heated at 100 ° C for 2.5 hours. After cooling, the precipitated sodium bromide was filtered off completely, the filtrate was evaporated in vacuo and the residue was partitioned between water and methylene chloride. The organic phase was separated, dried (Na 2 SO), filtered and evaporated to give a crude product which was purified on a column of 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 (70eV) m / z (relative intensity) 428 (13, M +).

Example 4 (R) -N- (7-N, N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl) -2-hydroxy-2-methylpropanamide To a solution of (R) -2- ( 7-N, N-dibenzylamino-5, 6, 7, 8-tetrahydro-l-naphthyloxy) -2-methylpropanamide (9.1 g, 21 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro- 2 (li?) - anhydrous pyrimidone (10 mL) and dry N, N-di-ethylformamide (100 mL) were added with 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 (? A2S04), filtered and evaporated in vacuo. Chromatography on silica (eluent: chloroform / methanol saturated with NH3; 100: 0.5) gave 7. 6 g (84% yield) as white crystals; p.f. 134-135 ° C; [a] 21D + 130 ° (c 1.1, chloroform): EIMS (70eV) m / z (relative intensity) 428 (1, M +).

Example 5 (R) -2-N, N-Dibenzylamino-8-amino-l, 2,3, -tetrahydronaphthalene The (i?) -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 ethanol (200 L) and an aqueous solution of HCl 20% (300 mL) 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 in 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 (? A2S04), 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 ( 70eV) m / z (relative intensity) 342 (92, M +).

Example 6 (i.) -1- (7-N, N-Dibenzylamino-5,6,7,8-tetrahydro-l-naphthyloxy) -4-2-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 anhydrous tetrahydrofuran (250 mL). The reaction mixture was heated to reflux for 1.5 hours. He . { R) -2-N, N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalene (5.7 g, 17 mmol) was then added and 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 silica gel column using chloroform / ethanol saturated with? H3 (100: 0.5) as the eluent. Yield: 6.6 g (87%) of the title compound as an oil: [a] 21D + 90 ° (c 0.52, chloroform): EIMS (70eV) m / z (relative intensity) 453 (8, M +).

Example 7 (jR) -2-N / N-Dibenzylamino-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene The (J.) -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 anhydrous diethyl ether (70 L). The reaction mixture was heated to reflux for 7 hours. The reaction was quickly cooled by the addition of water (0.60 mL), 15% aqueous sodium hydroxide (0.60 L) and again water (1.8 mL). The mixture was filtered, dried (Na2SO4) 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 (70eV) m / z (relative intensity) 425 (2, M +).

Example 8 (R) -5-Bromo-2-N, 27-dibenzylamino-8- (4-methyl-pyridin-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 (2.8 g, 6.5 mmol) and sodium acetate (6.8 g, 83 mmol) in bromine (100 mL) was added bromine (370 mL, 7.2 mmol) in one 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 in an ice bath. The aqueous phase was alkalized with a 2M aqueous solution of sodium hydroxide and the phases were separated.

The organic phase was dried (Na2SO4), 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: 2 g (61%) of a viscous brown oil: EIMS (70eV) m / z (relative intensity) 503 and 505 (0.6, M +).

Example 9 (R) -2 -ST, N-Dibenzylamino-5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydronaphthalene El. { R) -2-N, N-dibenzylamino-5-bromo-8- (4-methylpiperazin-1-yl) -1,2,4,4-tetrahydronaphthalene (16 g, 0.31 mol) was dissolved in freshly distilled tetrahydrofuran ( 300 mL) and cooled to -78 ° C under argon. To the solution was added n-butyl lithium (19 L, 1.6M in hexane, 0.31 mol), dropwise over 45 minutes at a maximum temperature of -76 ° C. The dark green solution was stirred for an additional 20 minutes. A solution of methyl iodide (1.9 mL, 0.31 mol) in freshly distilled tetrahydrofuran (10 mL) was added dropwise over 25 minutes at a maximum temperature of -74 ° C, causing the green color to disappear. The reaction mixture was stirred at -78 ° C for 50 minutes and at 0 ° C for 50 minutes. The reaction was quenched with i-propyl alcohol (3 mL) and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (300 mL) and H20 (30 mL) and the phases were separated and the organic layer was washed with brine (30 mL). After drying (Na2SO), and evaporation of the solvent in vacuo, 15 g of a crude product were obtained. Purification by column chromatography on silica using ethyl acetate / triethylamine (100: 1) as the eluent gave 11 g (82% yield) of the title compound as a brown oil: EIMS (70eV) m / z ( relative intensity) 439 (5, M +); [a] 22D + 86 ° (c 0.05, CHC13).

Example 10 (R) -2-Amino-5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-naphthalene The (i) -2-N, N-dibenzylamino -5-Methyl-8- (4-methyl-piperazin-1-yl) -1,2,4,4-tetrahydronaphthalene (28 g, 64 mmol) was dissolved in acetic acid (280 mL) and loaded in a glass autoclave. Büchi (1 L). Palladium 10% on charcoal (2.8 g, containing H20 50%) was added. The reaction mixture was stirred at 70 ° C and at a hydrogen pressure of 5 bar for 3.5 hours. The catalyst was completely filtered and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (400 mL) and water (100 mL) and cooled in an ice bath. The pH was adjusted to 12 by the addition of aqueous NaOH (45%) and the phases were separated. The aqueous phase was back extracted with ethyl acetate (2 x 100 mL) and the combined organic layer was washed with brine (50 mL) and dried (Na 2 SO). Evaporation of the solvent in vacuo gave 18 g (99% yield) of the title compound as a brown oil. EIMS (70eV) m / z (relative intensity) 259 (34, M +); [a] 22D -1.1 ° (c 0.09, CHC13).

Example 11 (R) -N- [5-Methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide 4-morpholinobenzoic acid (23.3 g, 113 mmol, described in: Degutis, J .: Rasteikiene, L., Degutiene, A. Zh. Org. Khim. 1978, 14 (10), 2060-2064) and 1,1'-carbonyldiimidazole (19.2 g, 118 mmoles) dissolved in anhydrous N, N-dimethylformamide (250 mL), stirred at 75 ° C for 2 hours and cooled to room temperature. The solution was added. { R) -2-amino-5-? R-ethyl-8- (4-methylpiperazin-1-yl) -1,2,4,4-tetrahydronaphthalene (27.8 g, 107 mmol) dissolved in anhydrous N, N-dimethylformamide (250 mL). The reaction mixture was stirred for 58 hours giving a thick white suspension. The precipitated product was completely filtered and dried in vacuo to give 13.3 g of a crude product. The mother liquor was concentrated to dryness in vacuo yielding 65 g of a crude material which was divided between CH2C12 (500 mL) and H20 (70 mL). The organic layer was washed with H20 (70 mL) and brine (2 x 70 L) and dried (Na2S04). The solvent was evaporated in vacuo giving 40 g. The two portions were combined and recrystallized, three times, with anhydrous methanol to give 33.6 g (70% yield) of the title compound as white needles: m.p. 236-237 ° C; EIMS (70 eV) m / z (relative intensity) 448 (3, M +); [a] D22 -60 ° (c 0.15, CHC13).

Salts of (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2-, 3,4-tetrahydro-2-na tyl] -4-morinobenzamide. All melting points were determined using Differential Exploration Calorimetry (DSC). The temperature exploration speed was 10 ° C per minute starting from room temperature. The samples were analyzed in aluminum trays with non-fixed lids under nitrogen.

Example 12 L-Lactate of (R) -N- [5-Methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide To one solution hot from. { R) -N- [5-Methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (1.0 g, 2.2 mmol) in methanol ( 40 mL) was added L-lactic acid (240 mg, 2.7 mmol) and the solution was allowed to cool to room temperature. The solvent was evaporated in vacuo and the white residue was dissolved in 2-propanol (20 mL) under heating. After the addition of diethyl ether (10 mL), the solution was allowed to cool to room temperature. The precipitated product formed was completely filtered and dried in vacuo to give 360 mg (30% yield) of the desired product as white crystals: m.p. 130-140 ° C. Analysis Calculated for C27H36N4? 2xC3H603: C, 66.9; H, 7.9; N, 10.4. Found: C, 66.6; H, 7.9; N, 10.3.

Example 13 L-Ascorbate of (R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -morpholinobenzamide To a hot solution of (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,4,4-tetrahydro-2-naphthyl] -4- orfolinobenzamide (1.0 g, 2.2 mmol) in methanol (30 mL) was added a solution of L-ascorbic acid (475 mg, 2.7 mmol) in methanol (20 mL) and the solution was allowed to cool to room temperature. Approximately 25 mL of the solvent was evaporated in vacuo and the remaining solution (25 mL) was allowed to stand at room temperature for 2.5 hours. The crystals were filtered and dried in vacuo to give 1.3 grams (92% yield) of the title compound as light gray crystals. p.f. 235-245 ° C. Analysis Calculated for C27H36N4? 2xC6H806xH20: C, 61.7; H, 7.2; N, 8.7. Found: C, 61.9; H, 7.0; N, 8.9.

Example 14 (R) -N- [5-Methyl-8- (4-methyl-piperazin-1-yl) -1,2,3-tetrahydro-2-naphthyl] -4-morpholinobenzamide salicylate. To a boiling solution of. { R) -N- [5-Methyl-8- (4-methyl-piperazin-1-yl) -1,2,4,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (1.0 g, 2.2 mmol) in ethanol ( 50 mL) was added a solution of salicylic acid (400 mg, 2.9 mmol) in ethanol (10 L). The solvent was concentrated in vacuo and the remaining solution (20 mL) was allowed to cool to room temperature. The solution was put in the freezer during the weekend. The crystals were filtered and dried in vacuo to give 1.2 grams (86% yield) of the title compound as white crystals: m.p. 235-240 ° C. Analysis Calculated for C27H36 4? 2xC7H6? 3: C, 69.6; H, 7.2; N, 9.6. Found: C, 69.5; H, 7.2; N, 9.5.

Example 15. Glycolate of (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide.

To a hot solution of (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (1.0 g, 2.2 mmol) in ethanol (50 mL) was added a hot solution of glycolic acid (200 mg, 2.6 mmol) in ethanol (10 mL). The solvent was concentrated in vacuo and to the remaining solution (20 mL) boiling ethyl acetate was added until the solution was cloudy. After boiling for a few minutes, the solution was cooled and placed in the refrigerator overnight. The crystals were filtered and dried in vacuo to give 1.0 grams (83% yield) of the title compound as white crystals. Analysis Calculated for C27H36? 402xC7H6? 3x2H20: C, 62.1; H, 7.9; ?, 10.0. Found: C, 62.7; H, 7.7; ?, 9.6. Example 16 (R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1 -hydrobromide., 2,3, 4-tetrahydro-2-naphthyl] -4-morpholinobenzamide La. { R) -N- [5-Methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (2.0 g, 4.5 mmol) was dissolved in anhydrous tetrahydrofuran (55 mL) and a solution of ethereal HBr was added until the solution was acidic. The white solid was filtered, washed with diethyl ether and dried to give the crude solid. The crude solid was recrystallized with pure ethanol / ethyl acetate to give 0.78 g (29% yield) of clear white crystals: m.p. 250-265 ° C. Calculated Analysis for C27H38Br2N402: C, 53.1; H, 6.3; Br, 26.2; N, 9.2. Found: C, 53.0; H, 6.4; Br, 26.3; N, 9.0.

Example 17 (R) ~ N ~ [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3-tetrahydro-2-naphthyl] -morpholinobenzamide dihydrochloride La. { R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,4,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (2.0 g, 4. 5 mmoles) was dissolved in anhydrous tetrahydrofuran (55 mL) and a solution of ethereal HCl was added until the solution was acidic. The white solid was filtered, washed with diethyl ether and dried to give a crude hygroscopic solid. The crude solid was recrystallized, twice, with ethanol / ethyl acetate to give 0.11 g (16% yield) of hard, small white crystals: Analysis Calculated for C27H38C12N402: C, 62.2; H, 7. 3; Cl, 13.6; N, 10.7. Found: C, 62.1; H, 7.4; Cl, 13.4; N, 10.8.

EXAMPLE 18 (j) -N- [5-Methyl-8- (4-methyl-piperazin-1-yl) -1,2,4,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide monobromhydrate.

The imidazole (16.3 g, 239 mmol) was dissolved in isopropanol (170 mL) and hydrobromic acid (34% w / w in acetic acid, 49.5 mL, 218 mmol) was added dropwise. This solution was added to a thick suspension of. { R) -N- [5-Methyl-8- (4-methyl-piperazin-1-yl) -1,2,4,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide (89.2 g, 198 mmol) in isopropanol ( 710 mL) at 40 ° C. After the addition was complete, the mixture was refluxed for 3 hours. After cooling to 0 ° C, the crystals were collected by filtration and dried at 60 ° C under vacuum to give 98.5 g (93.6% yield) of crude monobromhydrate. The above crude monobromhydrate (96.6 g, 182 mmol) was recrystallized with 95% ethanol (5% v / v water, 598 mL) and ethyl acetate (2280 mL) at 60-70 ° C and the slurry was slowly cooled to -10 ° C before filtration. The crystals were collected by filtration and dried at 60 ° C under vacuum to give 87.7 g (yield 91%) of slightly pink crystals: m.p. 265 ° C (decom.). RM? X (300 MHz, DMSO- 6) d 8.24 (d, J = 7.5 Hz, 1 H), 7.86 (d, J = 8 Hz, 2 H), 6.92-7.08 (m, 1 H), 7.01 (d, J = 7.5 Hz, 1 H), 6.98 (d, J = 8 Hz, 1 H), 6.86 (d, J = 8 Hz, 1 H), 3.61-4.07 (m, 5 H), 2.42-3.61 (m , 16 H), 2.84 (s, 3 H), 2.00-2.20 (m, 1 H), 2.15 (s, 3 H), 1.63-1.88 (m, 1 H).

PHARMACOLOGY Electric field stimulation of the release of [3H] -5-HT from the occipital cortex of guinea pigs [3H] -5-HT is released by stimulating electric field slices of the occipital cortex of guinea pigs which have been pre-incubated with [3 H] -5-HT. This release is similar to that caused by nerve stimulation, ie the exocytotic release of the serotonergic nerve terminals, depending on the presence of Ca2 + in the incubation medium. The release of 5-HT is regulated at the level of nerve terminals by autoreceptors, in guinea pigs (as in humans) corresponds to the subtype of the h5-HT1B receptor. Thus, the agonists of the h5-HT? B receptors reduce the amount of [3 H] -5-HT released by field stimulation while the release is increased by antagonists of this type of receptor. Testing the compounds with this method is therefore a convenient selection technique for determining the potency and functional effect of the new agonists and antagonists of the h5-HT1B receptor.

Materials and Methods Buffering composition (mM) NaHCO3 (25), NaH2P04, H20 (1.2), NaCl (117), KCl (6), MgSO4x7H20 (1.2), CaCl2 (1.3), EDTA Na2 (0.03). The buffer substance was gassed for at least 30 minutes before use. The pH of the buffer substance is about 7.2 at room temperature but is raised to about 7.4 at 37 ° C.

Preparation of occipital cortical slices The guinea pigs (200-250 g) were decapitated and the whole brain was removed. The occipital cortex was dissected and cut into 0.4x4 mm slices with a Mcllwain mincer. The white part of the tissue had to be carefully removed with tongs before slicing. The slices were incubated in 5 ml of the buffer substance 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 buffering substance. The slices were transferred to the superfusion chambers with a plastic pipette and washed for 40 minutes with the buffer substance in the presence of the 2.5 μM citalopram uptake inhibitor at a flow rate of 0.5 ml / minute.

Electrical stimulation of the release of 5-HT The superfused buffer substance was collected in fractions of 2 L. The slices were stimulated by electricity with a pulse train of frequency of 3 Hz, duration 2 ms and current 30 mA for 30 minutes in fractions 4a and 13a. The tested drugs were added from the 8th fraction at the end of the experiment.

Results A first electrical stimulation (or K +) results in a normal amount of [3H] -5-HT released (Si). Before the first and second stimulation, the h5-HT ?B antagonist is added to the media, which results in a dose that depends on the increase in the release (S2) after the second stimulation. See Figure 1. The relation of S2 / Sj, 1a which is the percentage of [3H] -5-HT released in the second stimulation (S2) divided by that of the first stimulation (SL), was used to estimate the effects of the drug in the transmitter release.

Determination of the solubility of (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2, 3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide and its salts Corresponding Method Excess of (i?) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide or its salts were added to purified water. The solution was stirred overnight in a water bath, kept at 25 ° C when using a thermostat (Julabo SW and U3, 60 strokes / min.). The saturated solution was centrifuged and filtered through a Gelman GHP Acrodisc® 13 0.45 Dm filter, diluted and subjected to a test by CLAP.

Results Solubility in water at 25 ° C for the base, (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1, 2, 3, 4-tetrahydro-2-naphthyl] - 4- Orfolinobenzamide. 0.034 mg / mL Solubility in water at 25 ° C for the different salts of (i?) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide.

Salt (Example] Solubility mg / mL L-Lactate 18. L-Ascorbate 4.2 Salicylate 0.29 Glycolate / 23.6 Dibromhydrate 4.6 It is clear from the above comparison between the base compound and a number of salts representative thereof that the salts of the compound according to formula (I) to a greater degree are more soluble in water compared to the base and from this are more suitable for the preparation of pharmaceutical formulations.

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 (31)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. A pharmaceutically acceptable salt of the compound of the formula I or a solvate of the salt, characterized in that the compound of the formula I is as the enantiomer { R), the (S) -enantiomer or the racemate. (D with the condition that they be excluded (2S, 3S) -acid tartrate. { R) -N- [5-methyl-i- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide ,. { 2R, 3R) -acid tartrate. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, benzenesulfonate of (i?) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, 1, 2-ethanedisulfonate acid of. { R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, acid maleate of (í.) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, acid sulfate. { R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, D-gluconate of (f.) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3-tetrahydro-2-naphthyl] -4-morpholinobenzamide, acid succinate of (..) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (_) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,4,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, (S) -maleate acid of (R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide, diacid citrate of. { R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,4,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide and hydrochloride. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide.
2. 2. A pharmaceutically acceptable salt according to claim 1, characterized in that the compound of the formula I is an enantiomer. { R) or a solvate of salt.
3. 3. A salt or solvate according to claim 1, characterized in that it is L-lactate of (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3,4 -tetrahydro-2-naphthyl] -4-morpholinobenzamide or a solvate thereof.
4. 4. A salt or solvate according to claim 1, characterized in that it is L-ascorbate of . { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide or a solvate thereof.
5. 5. A salt or solvate according to claim 1, characterized in that it is salicylate of. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide or a solvate thereof.
6. 6. A salt or solvate according to claim 1, characterized in that it is glycolate of (R) -N- [5-methyl-8- (4-methylpiperazin-1-yl) -1,2,3, 4-tetrahydro -2-naphthyl] -4-morpholinobenzamide or a solvate thereof.
7. 7. A salt or solvate according to claim 1, characterized in that it is (i?) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-dibromohydrate. tetrahydro-2-naphthyl] -4-morpholinobenzamide or a solvate thereof.
8. 8. A salt or solvate according to claim 1, characterized in that it is monohydrochloride of. { R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide or a solvate thereof.
9. 9. A salt or solvate according to claim 1, characterized in that it is dihydrochloride of (R) -N- [5-methyl-8- (4-methyl-piperazin-1-yl) -1,2,3,4-tetrahydro-2-naphthyl] -4-morpholinobenzamide or a solvate thereof.
10. 10. A pharmaceutical formulation, characterized in that it comprises as an active ingredient a therapeutically effective amount of the salt or solvate according to any of claims 1-9 or a combination of such salts and / or solvates, optionally in association with diluents, excipients or inert carriers.
11. 11. A pharmaceutical formulation according to claim 10, characterized in that it is for use in the treatment of disorders mediated by 5-hydroxytryptamine.
12. 12. A pharmaceutical formulation according to any of claims 10 or 11, characterized in that it is for use in the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, alterations sexual, alcoholism, tobacco abuse, autism or, attention deficit, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain, hypertension, urinary incontinence, vasospasm and control of tumor growth.
13. 13. A pharmaceutical formulation according to claim 12, characterized in that it is for use in the treatment of a major depressive disorder.
14. A salt or solvate according to claim 1, as defined in any of claims 1-9, characterized in that it is for use in therapy.
15. 15. A salt or solvate according to claim 1, as defined in claim 14, characterized in that it is for use in the treatment of disorders in the central nervous system.
16. 16. A salt or solvate according to claim 1, as defined in claim 15, characterized in that it is for use in the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia , premenstrual syndrome, sexual alterations, alcoholism, tobacco abuse, autism, attention deficit, disorder of overactivity, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, apoplexy, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain, hypertension.
17. 17. A salt or solvate according to claim 1, as defined in claim 16, characterized in that it is for use in the treatment of a major depressive disorder.
18. 18. A salt or solvate according to claim 1, as defined in claim 14, characterized in that it is for use in the treatment of urinary incontinence, vasospasm and control of tumor growth.
19. 19. A salt or solvate according to claim 1, as defined in claim 14, characterized in that it is for use in the treatment of disorders mediated by 5-hydroxytryptamine.
20. 20. A salt or solvate according to claim 19, characterized in that it is for use as an antagonist of h5-HT? B.
21. 21. The use of a salt or solvate according to any of claims 1-9 in the preparation of a medicament for the treatment of disorders in the central nervous system and / or urinary incontinence, vasospasm and growth control of tumors
22. 22. The use of a salt or solvate according to claim 21 in the preparation of a medicament for the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual alterations , alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain, hypertension.
23. 23. The use of a salt or solvate according to claim 22, in the preparation of a medicament for the treatment of a major depressive disorder.
24. 24. The use of a salt or solvate according to any of claims 1-9 in the preparation of a medicament for the treatment of disorders mediated by 5-hydroxytryptamine.
25. 25. The use according to claim 24 wherein the salt or solvate according to any of claims 1-9 is used as an antagonist
26. 26. A method for the treatment of disorders in the central nervous system and / or urinary incontinence, vasospasm and ruminant growth control by administering to a mammal, including man in need of such treatment, a therapeutically effective amount of a salt or solvate according to any of claims 1-9.
27. 27. A method according to claim 26, characterized in that it is for the treatment of mood disorders, anxiety disorders, personality disorders, obesity, anorexia, bulimia, premenstrual syndrome, sexual alterations, alcoholism, tobacco abuse, autism, attention deficit, hyperactivity disorder, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, apoplexy, dyskinesia, Parkinson's disease, thermoregulatory disorders, pain, hypertension.
28. 28. A method according to claim 27, characterized in that it is for the treatment of a major depressive disorder.
29. 29. A method according to claim 26, characterized in that it is for the treatment of disorders mediated by 5-hydroxytryptamine.
30. 30. A method according to claim 29, characterized in that the salt or solvate according to any of claims 1-9 is used as an antagonist of h5-HT? B.
31. 31. A process for the preparation of the salt of the compound of the formula I or the solvate of the salt according to claim 1 by the acylation of a compound of the formula XII, (XH) (i) with activated 4-morpholinobenzoic acid and reacting the base with an organic or inorganic acid to form the salt with or without a solvate.