New salt morpholinomethyl, the method of production thereof, pharmaceutical composition and method of treatment

 

The invention relates to pharmaceutically acceptable salts of the compounds of formula (I) or solvate specified salts in which the compound of formula (I) is in the form of (R)-enantiomer, (S)-enantiomer or the racemate. Describes pharmaceutically acceptable salt of the compounds of formula I or MES specified salts in which the compound of formula I is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

provided that

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-(2S,3S)-tartrate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,1,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-(2R,3R)-tartrate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-1,2-etandisulfonat,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl-D-gluconate,

(R)-N-[5-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-(S)-maleate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium and

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium

excluded. Also describes a pharmaceutical composition based on salt and/or solvate under item 1 to 9, having a selective action on the subgroup of receptors 5-hydroxytryptamine, the method of treatment based on the use of salt and/or solvate under item 1 to 9, and the method of obtaining salt or MES the compounds of formula I. the Technical result obtained new salt and solvate of biologically active compounds. 4 N. and 27 C.p. f-crystals, 1 Il., 1 PL.

The present invention relates to novel pharmaceutically acceptable salts of N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl in the form of (R)-enantiomer, (S)-enantiomer or racemate or in form of a solvate of these salts, the method of production thereof, pharmaceutical compositions containing the salt or the solvate, and to the use of these active salt or solvate in therapy.

The purpose of the invention making the action on the subgroup of receptors 5-hydroxytryptamine, denote the h5-HT1Breceptor (formerly h5-HT1D-receptors) in mammals, including humans, and of these compounds are easy to manufacture pharmaceutical compositions.

In addition, the purpose of the invention is to provide compounds with therapeutic activity in oral administration.

Prior art

Different classes piperazineethanesulfonic derived benzanilide as antagonists of 5-HT1Ddescribes, inter alia, in EP 533266, EP 533267, EP 533268, GB 2273930 and WO 95/11243.

WO 94/13659 describes a very broad class of condensed benzodiazipine with para-substituted radicals of piperidine or piperazinil in the aromatic ring, and claimed that this class of compounds is associated with 5-HT1A-receptor.

WO 94/21619 describes a fully aromatic naphthalene cyclic system, which may be substituted piperidines or piperazinilnom group, and States that these compounds are strong agonists and antagonists of serotonin (5-HT1).

EP 402923 describes substituted 2-aminoalkyl or allenamento group derivatives of 1,2,3,4-tetrahydronaphthalene with additional the dopamine.

Background of the invention

Various Central nervous system disorders, such as depression, fear and so on, as it turns out, involve damage to the neurotransmitters noradrenaline (NA) and/or 5-hydroxytryptamine (5-HT), the latter also known as serotonin. It is believed that the drugs most often used to treat depression work by improving the transmission of nerve impulses from either or both of these physiological agonists. It turns out that the increase in 5-HT neurotransmission, first of all, the effect on depressed mood and anxiety, while increasing noradrenergic neurotransmission effect on the symptoms of retardation, occurring in patients who are prone to depression.

Suppose that the activity of serotonin, or 5-HT, it is understood in many different types of mental disorders. For example, suppose that the increased activity of 5-HT is associated with fear, while the decrease in the allocation of 5-HT is associated with depression. In addition, serotonin is involved in such different States as eating disorders, gastrointestinal disorders, cardiovascular regulation, and sexual behavior.

The compounds of formula I, described below, in the main phoria depends on pH, i.e., the speed is different in the stomach and intestines. From the point of view of the pharmaceutical composition is very difficult to dissolve the base fast enough to keep it dissolved in the gastric juice until absorbed a sufficient amount of the substance.

5-HT receptors

Different effects of 5-HT may be associated with the fact that serotonergic neurons stimulate the secretion of several hormones, such as cortisol, prolactin,-endorphin, vasopressin and others. It turns out that the selection of each of these additional hormones is regulated on a specific basis of several different subtypes of receptors 5-HT (serotonin). Using the methods of molecular biology to date, these receptors have been classified as 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6and 5-HT7and 5-HT1the receptor is further divided into 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1Eand 5-HT1Fsubtypes. Each receptor subtype is involved in various function of serotonin and has various properties.

Regulation of transmission of nerve impulse 5-HT

The allocation of 5-HT at nerve endings is regulated by feedback two subtypes of 5-quiet when stimulation of 5-HT reduces the pulse duration of 5-HT neurons, whereby reducing the secretion of 5-HT at nerve endings. Another subtype of inhibitory 5-HT receptors is located on 5-HT nerve endings, h5-HT1Breceptors in rodents r5-HT1Breceptors), which regulate synaptic concentration of 5-HT, controlling eye-catching number of 5-HT. Antagonist data limit autoreceptors, thus, increases the number of 5-HT, the selected nerve impulses, which has been shown in experiments both in vitro and in vivo.

The use of antagonist limit h5-HT1Bautoreceptors, respectively, will increase synaptic 5-HT concentration and to improve the transmission of nerve impulses in the 5-HT system. Thus, it will create an antidepressant effect, making it useful as a drug for the treatment of depression.

There are also other localization h5-HT1Bsubtype receptor. It turns out that a huge portion of the data postsynaptic receptors located on the nerve endings of other neural systems (the so-called heteroreceptors). Since h5-HT1Bthe receptor mediates inhibitory reactions, the antagonist of this receptor subtype may also increase the secretion of other neurotransmitters, mikologicakim tests can be divided into full agonists, partial agonists and antagonists.

Description of the invention

The purpose of the present invention is to provide compounds having a selective action on the h5-HT1Breceptor, preferably antagonistic properties, as well as having good bioavailability and from which it is possible to easily manufacture of pharmaceutical compositions. Compounds according to the invention unexpectedly decided the above problem, because they quickly dissolve and supported in dissolved form in the gastric juice after absorbed a sufficient amount of the substance.

Accordingly, the present invention provides pharmaceutically acceptable salts of the compounds of formula I, or a solvate of the specified salts in which the compound of formula I is in the form of (R)-enantiomer, (S)-enantiomer or the racemate

provided that

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-(2S,3S)-tartrate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-(2R,3R)-tartrate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl-D-gluconate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-(S)-maleate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium and

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium

excluded, and salts show a strong selective effect on the h5-HT1B-receptor, easy to manufacture pharmaceutical compositions, and they also show sufficient bioavailability upon oral administration.

Preferred enantiomers are (R)-enantiomers.

The preferred compounds are (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl-L-lactate, (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium, (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-Tamil]-4-morpholinobenzenediazonium.

To obtain non-toxic pharmaceutically acceptable additive salts of acids of the present invention can be used both organic and inorganic acids. Examples of acids are sulfuric, nitric, phosphoric, oxalic, hydrochloric, formic, Hydrobromic, citric, acetic, lactic, tartaric, dibenzoyltartaric, diatsetilvinny, Panova, ethicality, sulfamic, succinic, propionic, glycolic, malic, gluconic acid, pyruvic acid, phenylacetic, 4-aminobenzoic, Anthranilic, salicylic, 4-aminosalicylic, 4-hydroxybenzoic, 3,4-dihydroxybenzene, 3,5-dihydroxybenzene, 3-hydroxy-2-naphthoic, nicotine, methansulfonate, econsultancy, hydroxyethanesulfonic, benzolsulfonat, p-toluensulfonate, sulfanilic, naphthalenesulfonate, ascorbic, cyclohexylsulfamate, fumaric, maleic and benzoic acid. The compound of the formula I can form a Hemi-, mono-, Queen -, di - or triple salt or any intermediate combination of salts of the above acids, if they are suitable. These salts can easily be obtained by methods known from the prior art.

The preferred solvate according to this invention are hydrate the GKO get ways known from the prior art.

Pharmaceutical compositions

In a second aspect the present invention provides an easily manufactured pharmaceutical composition comprising as active ingredient a therapeutically effective amount of pharmaceutically acceptable salts of the compounds of formula I or of the specified MES salt in the form of an enantiomer or racemate, or a combination of such salts and/or solvate, optionally together with diluents, excipients or inert carriers.

In accordance with the present invention the compound according to the invention will normally be administered orally, rectally or by injection, in the form of a pharmaceutical formulation comprising the active ingredient, or a pharmaceutically acceptable non-toxic additive salts of acids, such as hydrochloride, hydrobromide, lactates, acetates, phosphates, sulfates, sulfamates, citrates, tartratami, oxalates and similar, either in the form of MES of such salt in a pharmaceutically acceptable dosage form. Dosage form may be a solid, semisolid 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 of drugs is advised to make a pharmaceutical formulation, containing compound according to the invention, in dosage units for oral use, the selected compound can be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder in the form of gelatin or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and similar, and then pressed into tablets. If you want a tablet shell, kernel, prepared as described above, can be coated with a concentrated sugar solution which contains, for example, Arabian gum, gelatin, talc, titanium dioxide and similar. Alternative tablets may be coated with a polymer known to the person skilled in the art, dissolved in a volatile organic solvent or mixture of organic solvents. These coatings can add dyes to easily distinguish between tablets containing different active substances or different number of active connections.

For the manufacture of soft gelatin capsules, the active substance can be mixed, for example, vegetable oil is any of the above excipients for tablets, for example lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. In addition, the liquid or semi-solid drugs can be filled hard gelatin capsules.

Dosage forms for rectal injection can be a solution or suspension of, or can be prepared in the form of suppositories comprising the active substance in a mixture with a neutral fat base, or gelatin rectal capsules comprising the active substance in a mixture with vegetable oil or paraffin oil. Liquid preparations for oral administration can be in the form of syrups or suspensions, for example solutions containing from about 0.1% to about 20% by weight of the active substances described here, and the rest is sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, corrigentov, saccharin and carboxymethylcellulose as a thickening agent or other excipients known to the person skilled in the art.

Solutions for parenteral administration by injection can be prepared in aqueous solution modorator the ome 10% by weight. These solutions may also contain stabilizing agents and/or buffering agents and may be conveniently provided in ampoules with different uniform doses.

Suitable daily doses of the compounds according to the invention in therapeutic treatment of humans is approximately 0.01 to 100 mg/kg body weight by oral administration and 0.001-100 mg/kg body weight at parenteral administration.

The connection according to the invention can be used in combination with an inhibitor of the reuptake of 5-HT, such as fluoxetine, paroxetine, citalopram, clomipramine, sertraline, alaproclate or fluvoxamine, preferably paroxetine or citalopram. Another possible combination is the use of compounds according to the invention together with a monoamine oxidase inhibitor such as moclobemide, tranylcypromine, brofaromine or phenelzine, preferably moclobemide or phenelzine. Another possible combination is a compound of the invention together with 5-HT1Asubstance-antagonist, such as compounds described in WO 96/33710, preferably (R)-5-carbarnoyl-3-(N,N-dicycloverine)-8-fluoro-3,4-dihydro-2H-1-benzopyran.

Medical and pharmaceutical use

In a further aspect the present invention provides the use of the respectfully as antagonists, and use for the treatment of disorders mediated by 5-hydroxytryptamine. Examples of such disorders include CNS disorders such as depression, major depressive disorder, major depressive episodes, dysthymia, seasonal affective disorder, depressive phase of bipolar disorder), anxiety (obsessive convulsive disorder, panic disorder with/without agoraphobia, social phobia, specific phobia, a disorder associated with generalized fear disorders, post-traumatic stress disorder), disorders associated with changes in personality (disorders of impulse control, trichotillomania), obesity, anorexia, bulimia, premenstrual syndrome, sexual dysfunction, alcoholism, tobacco addiction, autism, attention deficit disorder, a disorder associated with increased activity, migraine, memory impairment (memory loss associated with age, presenilny and senile dementia), pathological aggression, schizophrenia, endocrine disorders (for example, a buildup of lactic acid in the blood), stroke, dyskinesia, Parkinson's disease, disorders of thermoregulation, pain, hypertension. Other examples of disorders where made, lung cancer).

Methods of obtaining

The present invention also relates to methods of preparing compounds according to the invention.

Methods of obtaining intermediates

(i) Benzilidene the compounds of formula II or in the form of the racemate or enantiomer

a suitable reagent for benzylidene, for example a benzyl halide such as benzyl bromide or benzyl chloride, or activated alcohol, for example, Basilicata or benzalconium, it is possible to obtain the compound of formula III. The reaction can be carried out using the salt or the base of the compound (II) in an appropriate solvent, for example N,N-dimethylformamide, acetone or acetonitrile, with an appropriate base, for example NaOH, NaHCO3To2CO3or trialkylamines, such as triethylamine, at a temperature in the range from 20 to 150C. the Presence of a suitable catalyst, such as potassium iodide or sodium iodide may increase the reaction rate.

(ii) Demethylation of compounds of formula III

processing the connection with the acidic reagent, such as aqueous solution of HBr, HI, NWG/CH3COOH, VVG3, ll3, pyridine-HCl or main NAA solvent receive the compound of formula IV. Suitable solvents may be methylene chloride or chloroform, and the reaction may occur between -78 and +60C.

(iii) the Conversion of compounds of formula IV to the compound of formula V

conduct the reaction with the compound of the formula VI

where X denotes a leaving group, for example halogen, such as chlorine, bromine or iodine, or an alkane - or arenesulfonic, such as p-toluensulfonate, and Raand Rbrepresent hydrogen or a lower alkyl group, for example methyl. The process can be done with the salt of the compounds of formula IV obtained by reaction with a base, such as2CO3, Na2CO3, KOH, NaOH, BuLi or NaH. The reaction can be carried out in a suitable solvent, for example an aprotic solvent such as dioxane, N,N-dimethylformamide, tetrahydrofuran, toluene, benzene, or petroleum ether, and the reaction may occur between 20 and 150C.

(iv) the Rearrangement of compounds of formula V to the compound of formula VII

can be carried out in a suitable solvent, for example an aprotic solvent such as N,N-dimethylformamide, dioxane, 1,1,3,3-tetramethylene the CO3, CON, tert-piperonyl NaH or potassium, at a temperature in the range of 20 and 150C.

The presence of solvent, co-solvent, such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone or triamide hexamethylphosphoric acid, in an appropriate concentration can increase the reaction rate.

(v) Hydrolysis of compounds of formula VII to the compound of formula VIII can be carried out in acidic conditions using acids such as H2SO4, HCl or NVG, in a suitable solvent, such as H2O, ethanol, methanol or their mixtures, and the reaction may occur between 20 and 100With, or under alkaline conditions using bases such as NaOH or KOH, in a suitable solvent, for example N2O, ethanol, methanol or their mixtures, and the reaction may occur between 20 and 100C.

(vi) the Conversion of compounds of formula VIII to the compound of formula IX

can be accomplished by conducting the reaction with the compound of the formula 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 a binding reagent, such as N,N’, carbonelli is of imida suitable regenerating agent, for example LiAlH4, in an appropriate solvent, for example diethyl ether or tetrahydrofuran, at temperatures between 20With the temperature and reflux distilled.

(vii) Halogenoalkane the compounds of formula IX

to obtain the compounds of formula XI can be electrophilic substitution on the aromatic group, using a suitable halogenation reagents such as Br2, Cl2, I2, ICl or SO2Cl2. The reaction can be performed using the compound IX in the form of a salt or base in an appropriate solvent, for example acetic acid, a mixture of HCl/ethanol or water in the presence of or without a suitable base, such as alkali metal acetate such as sodium acetate, and at a reaction temperature between -20C and room temperature.

(viii) the Conversion of compounds of formula XI to the compound of formula XII can be performed metal-halogen exchange reaction in an appropriate anhydrous solvent such as tetrahydrofuran or diethyl ether, using suitable alkyllithium or metal, for example butyllithium, lithium or magnesium turnings, followed by quenching>/img>With up to room temperature, followed by cleavage of benzyl groups by hydrogenation over an appropriate catalyst containing palladium, rhodium, platinum or Nickel, in a suitable solvent, for example acetic acid or ethanol, and at a reaction temperature between 20 IC.

The way the final product

Another objective of the invention is the method of obtaining the compounds according to the invention by acylation of compounds of formula XII

activated 4-martinbentley acid and reaction of the base with an organic or inorganic acid to obtain the salt in solvated or resolutional form.

Thus, the acylation can be carried out by reaction of the compound of formula XII with an acid chloride or acid bromide 4-martinbentley acid in a suitable solvent, such as methylene chloride or chloroform with a suitable base, such as trialkylamine, such as triethylamine, at temperatures between -20With the temperature and reflux distilled, or activating carboxylate function in 4-martinbentley acid activating reagent, such as N,N’-carbonyldiimidazole, N,N’-dicyclohexylcarbodiimide solvent, such as N,N-dimethylformamide or tetrahydrofuran and the reaction may be carried out at a temperature between 20 and 150C.

Further, the pharmaceutically acceptable salt of the compounds of formula I can be obtained by reaction of the base with the appropriate acid in a suitable solvent, such as alcohol, for example methanol, ethanol or 2-propanol, or other appropriate solvent such as water, ethyl acetate, hexane, tetrahydrofuran, acetone, acetonitrile, chloroform or mixtures thereof. The process can be performed at different temperatures between -30C and temperature of reflux distilled. Formed in the above way salt can be obtained in the form of MES.

Working examples

The following examples illustrate, but not limit the invention.

Example 1

(R)-2-N,N-Dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalen

To a solution of (R)-8-methoxy-2-amino-1,2,3,4-tetrahydronaphthalene hydrochloride (24 g, 0.11 mol) in acetonitrile (600 ml) is added potassium carbonate (53 g, to 0.39 mol), potassium iodide (catalytic amount) and benzyl bromide (34 ml, 0.28 mol). The reaction mixture is stirred at the boil under reflux for a period equal to 35 hours.

After the sediment filter and acetonitrile in the at (Na2SO4) and is evaporated in vacuum, obtaining the crude product, which was purified on a column of silica gel using a mixture of hexane/ethyl acetate (3:1) as eluent. Yield 36 g (91%) indicated in the title compound as white solid. Tpl.=105-107C; []21D+124(C 1.0, chloroform); SEU (70 eV) m/z (relative intensity) 357 (100, M+).

Example 2

(R)-7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthol

(R)-2-N,N-Dibenzylamino-8-methoxy-1,2,3,4-tetrahydronaphthalen (43 g, 0.12 mol) is dissolved in diethyl ether (800 ml) and added dropwise an excess of ethereal Hcl solution. The precipitate is filtered off and dried in vacuum, obtaining a white solid. This crude product (42 g, 0.11 mol) is dissolved in anhydrous methylene chloride (1 l) and cooled to -60C. To the solution is added dropwise tribromide boron (16 ml, 0.15 mol), dissolved in anhydrous methylene chloride (100 ml). The reaction temperature allowed to reach -5With and support her during the night. It chilled in an ice bath, the solution is added dropwise a 2 M aqueous solution of ammonium hydroxide, and the mixture is extracted twice with methylene chloride. The combined balance. Chromatography on silica gel (eluent: methylene chloride) to give 34 g (93% yield) specified in the title compound as a viscous clear oil. []21D+118(1.5; chloroform); SEU (70 eV) m/z (relative intensity) 343 (53, M+).

Example 3

(R)-2-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy)-2-methylpropanamide

(R)-2-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthol (10 g, 29 mmol) stirred in anhydrous dioxane (150 ml) with sodium hydride (80% in oil, 0.96 g, 32 mmol) over 1 hour. Add 2-bromo-2-methylpropanamide (4.8 g, 29 mmol, described Coutts I. G. C.; Southcott M. R. J. Chem. Soc. Perkin. Trans.1, 1990, 767-770), and the reaction mixture is heated at 100C for 2.5 hours. After cooling, the precipitated sodium bromide is filtered off, the filtrate is evaporated in vacuo and the residue partitioned between water and methylene chloride. The organic phase is separated, dried (Na2SO4), filtered and evaporated, obtaining the crude product, which was purified on a column of silica gel using methylene chloride as eluent. The output of 9.6 g (76%) indicated in the title compound as white crystals.pl.=125-126C; []21D+98To a solution of (R)-2-(7-N,N-dibenzylamino-5,6,7,8-tetrahydro-1-naphthyloxy)-2-methylpropanamide (9,1 g, 21 mmol) in anhydrous 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (10 ml) and dry N,N-dimethylformamide (100 ml) is added sodium hydride (80% in oil, 1.4 g, 47 mmol) and the reaction mixture is heated at 130C for 8 hours. The solution is poured into a mixture of ice and water and extracted three times with ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and evaporated in vacuum. Chromatography on silica gel (eluent: chloroform/ethanol saturated NH3; 100:0,5) gives 7.6 g (84% yield) as white crystals. Tpl.=134-135C; []21D+130(1,1; chloroform); SEU (70 eV) m/z (relative intensity) 428 (1, M+).

Example 5

(R)-2-N,N-Dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalen

(R)-N-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-2-hydroxy-2-methylpropionamide) (7,4 g, 17 mmol) dissolved in a mixture of ethanol (200 ml) and 20% aqueous Hcl (300 ml) and refluxed for 8 hours. The ethanol is evaporated in vacuo, the remaining solution was twice washed with diethyl ether and cooled in an ice bath. After alkalizing 45% of the water is2SO4), filtered and evaporated in vacuum. Purification on a column of silica gel using chloroform as eluent, gives 3.8 g (76% yield) specified in the title compound as light brown oil. []21D+124(from 0.9; chloroform); SEU (70 eV) m/z (relative intensity) 342 (92, M+).

Example 6

(R)-1-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-4-N-methylpiperazine-2,6-dione

To a stirred suspension methyliminodiacetic acid (2.7 g, 18 mmol) in anhydrous tetrahydrofuran (250 ml) is added 1,1’-carbonyldiimidazole (6.0 g, 37 mmol). The reaction mixture is refluxed for 1.5 hours. Then add (R)-2-N,N-dibenzylamino-8-amino-1,2,3,4-tetrahydronaphthalen (5.7 g, 17 mmol) and stirring while boiling under reflux continued for 17 hours. Add an additional amount of 1,1’-carbonyldiimidazole (2.9 g, 18 mmol) and boiling under reflux continued for another 17 hours. The solvent is evaporated in vacuum and the crude product is purified on a column of silica gel using a mixture of chloroform/ethanol saturated NH3(100 level:0.5) as eluent. Yield 6.6 g (87%) specified in the connection header in relative intensity) 453 (8, M+).

Example 7

(R)-2-N,N-Dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-1-(7-N,N-Dibenzylamino-5,6,7,8-tetrahydro-1-naphthyl)-4-methylpiperazine-2,6-dione (1.4 g, 3.1 mmol) are added to a suspension of sociallyengaged (or 0.57 g, 15 mmol) in anhydrous diethyl ether (70 ml). The reaction mixture is refluxed for 7 hours. The reaction is quenched by adding water (0,60 ml), 15% aqueous sodium hydroxide solution (0,60 ml) and again water (1.8 ml). The mixture is filtered, dried (Na2SO4) and evaporated in vacuo. Purification on a column of silica gel using a mixture of chloroform/ethanol saturated NH3(100:2) as eluent, gives 1.0 g (79% yield) specified in the title compound as a viscous oil. []21D+53(0.5; chloroform); SEU (70 eV) m/z (relative intensity) 425 (2, M+).

Example 8

(R)-5-Bromo-2-N,N-dibenzylamino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

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 acetic acid (100 ml) in one portion add bromine (370 ml, 7.2 mmol) and the reaction mixture is stirred for 5 minutes the Solvent is evaporated in vacuum and the memory is alkalinized 2 M aqueous solution of sodium hydroxide and the phases are separated. The organic phase is dried (Na2SO4), filtered and evaporated in vacuum, obtaining the crude product, which was purified on a column of silica gel using a mixture of chloroform/ethanol saturated NH3(100:2) as eluent. Output 2 g (61%) of a viscous brown oil; SEU (70 eV) m/z (relative intensity) 503 and 505 (0,6, M+).

Example 9

(R)-2-N,N-Dibenzylamino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N,N-Dibenzylamino-5-bromo-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (16 g, 0.31 mol) is dissolved in freshly tetrahydrofuran (300 ml) and cooled to -78With under argon. To the solution are added dropwise n-utility (19 ml, 1.6 M in hexane, 0.31 mol) over 45 min at a maximum temperature of -76C. the Dark green solution is stirred for additional 20 minutes. Added dropwise a solution of methyliodide (1.9 ml, 0.31 mol) in freshly tetrahydrofuran (10 ml) for 25 minutes at a maximum temperature of -74With, to the disappearance of the green color. The reaction mixture was stirred at -78C for 50 min and at 0With over 50 minutes the Reaction is quenched with isopropyl alcohol (SHL separated and the organic layer was washed with saturated salt solution (brine) (30 ml). After drying (Na2SO4) and evaporate the solvent in vacuo obtain 15 g of the crude product. Purification through column chromatography with silica gel using a mixture of ethyl acetate/triethylamine (100:1) as eluent gives 11 g (82% yield) specified in the title compound as a brown oil. MSAU (70 eV) m/z (relative intensity) 439 (5, M+); []22D+86(from 0.05; l3).

Example 10

(R)-2-Amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen

(R)-2-N,N-Dibenzylamino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (28 g, 64 mmol) is dissolved in acetic acid (280 ml) and loaded into a glass autoclave(1 liter). Add 10% Pd on charcoal (2.8 g, containing 50% N2O). The reaction mixture was stirred at 70C and at hydrogen pressure of 5 bar (5105PA) for 3.5 hours. The catalyst is filtered off and the solvent is evaporated in vacuum. The residue is distributed between ethyl acetate (400 ml) and water (100 ml) and cooled in an ice bath. The regulate pH value to 12 by adding aqueous NaOH (45%), and divide phase. The aqueous phase extravert with ethyl acetate (22SO4). Evaporation of the solvent in vacuo gives 18 g (99% yield) specified in the title compound as a brown oil. MSAU (70 eV) m/z (relative intensity) 259 (34, M+); []22D-1,1(from 0.09; l3).

Example 11

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

4-Morpholinomethyl acid (23.3 g, 113 mmol, described in J. Degutis, Rasteikiene L., Degutiene A. Zh. Org. Khim. 1978, 14(10), 2060-2064) and 1,1’-carbonyldiimidazole (19.2 g, 118 mmol) dissolved in anhydrous N,N-dimethylformamide (250 ml), stirred at 75C for 2 h and cooled to room temperature. To the solution was added (R)-2-amino-5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalen (27.8 g, 107 mmol) dissolved in anhydrous N,N-dimethylformamide (250 ml). The reaction mixture is stirred for 58 hours, getting a white suspension. The precipitate is filtered off and dried in vacuum, obtaining 13.3 g of the crude product. The mother liquid is concentrated until dry in a vacuum, receiving 65 g of the crude substance, which partitioned between CH2Cl2(500 ml) and H2O (70 ml). The organic layer was washed with H2O (70 ml) and saturated salt solution (2pl.=236-237With; SEU (70 eV) m/z (relative intensity) 448 (3, M+); []22D-60(from 0.15; l3).

Salt (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl

All melting temperature is determined using differential scanning calorimetry (DSC). The rate of temperature rise is 10With in a minute, starting from room temperature. The samples examined in aluminum cups with nitrogen purge.

Example 12

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl-L-lactate

To the warm solution of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl (1.0 g, 2.2 mmol) in methanol (40 ml) is added L-lactic acid (240 mg, 2.7 mmol) and the solution is allowed to cool to room temperature. The solvent is evaporated in vacuo and the white residue is dissolved in 2-propanol (20 ml) under heating. After adding diethyl ether (10 ml), the solution is allowed to cool to room temperature. The precipitate is filtered off and dried in vacuum, obtaining 360 ml (30% o calculated for C27H36N4O2CH3H6About3, %: 66,9; N 7,9; N 10,4. Found, %: From 66.6; H 7,9; N 10,3.

Example 13

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl-L-ascorbate

To the warm solution of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl (1.0 g, 2.2 mmol) in methanol (30 ml) add a solution of L-ascorbic acid (475 mg, 2.7 mmol) in methanol (20 ml) and the solution is allowed to cool to room temperature. Approximately 25 ml of the solvent is evaporated in vacuum and the remaining solution (25 ml) maintained at room temperature for 2.5 hours. The crystals are filtered and dried in vacuum, obtaining 1.3 g (92% yield) specified in the title compound as a pale gray crystals. Tpl.=235-245C.

Elemental analysis calculated for C27H36N4O2CH6H8About6HN2O, %: FROM 61.7; H TO 7.2; N, 8,7. Found, %: C 61,9; H 7,0; N, 8,9.

Example 14

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium

To the boiling solution of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl (1.0 g, 2.2 mmol) in ethanol (50 ml) add a solution of salicylic acid (400 mg, 2.9 mmol) and the second temperature. The solution is placed in the refrigerator for two days. The crystals are filtered and dried in vacuum, obtaining 1.2 g (86% yield) specified in the title compound as white crystals. Tpl.=235-240C.

Elemental analysis calculated for C27H36N4O2CH7H6About3, %: FROM 69.6; H 7,2; N OF 9.6. Found, %: C 69,5; N 7,2; N 9,5.

Example 15

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium

To a hot solution of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl (1.0 g, 2.2 mmol) in ethanol (50 ml) is added a hot solution of glycolic acid (200 mg, 2.6 mmol) in ethanol (10 ml). The solvent was concentrated in vacuo and the remaining solution (20 ml) add boiling ethyl acetate until the solution is not turbid. After boiling for several minutes the solution is cooled and placed in the refrigerator overnight. The crystals are filtered and dried in vacuum, obtaining 1.0 g (83% yield) specified in the title compound as white crystals.

Elemental analysis calculated for C27H36N4O2CH7H6About3HN2O, %: FROM 62.1; H 7,9; N AND 10.0. Found, %: From 62.7; H 7,7; N 9,6.

Example 16

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4 ftil]-4-morpholinomethyl (2.0 g, 4.5 mmol) dissolved in anhydrous tetrahydrofuran (55 ml) and added dropwise an ethereal solution NVG until the solution becomes acidic. A white solid is filtered off, washed with diethyl ether and dried, obtaining the crude solid. Conduct recrystallization of the crude solid from a mixture of absolute ethanol/ethyl acetate, getting 0,78 g (29% yield) of white transparent crystals. Tpl.=250-265C. Elemental analysis calculated for C27H38VG2N4O2, %: From 53.1; H 6,3; VG 26,2; N Is 9.2. Found, %: 53,0; H 6,4; VG 26,3; N 9,0.

Example 17

(R)-N-[5-Methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl (2.0 g, 4.5 mmol) dissolved in anhydrous tetrahydrofuran (55 ml) and added dropwise an ethereal solution of Hcl until the solution becomes acidic. A white solid is filtered off, washed with diethyl ether and dried, obtaining the crude hygroscopic solid. Double-spend recrystallization of the crude solid from a mixture of ethanol/ethyl acetate, getting 0.11 g (16% yield) small solid white crystals.

Elemental analysis calculated for C27H38The imidazole (16.3 g, 239 mmol) was dissolved in isopropanol (170 ml) and added dropwise Hydrobromic acid (34%, wt./wt., in acetic acid, 49.5 ml, 218 mmol). This solution is added to a suspension of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl (89.2 g, 198 mmol) in isopropanol (710 ml) at 40C. After complete addition the mixture is refluxed for 3 hours. After cooling to 0The crystals are collected by filtration and dried at 60With in a vacuum, getting to 98.5 g (93,6% yield) of the crude monohydrobromide.

Conduct recrystallization of the crude monohydrobromide (96,6 g, 182 mmol) obtained above, from 95% ethanol (5% water.about., 598 ml) and ethyl acetate (2280 ml) at 60-70And the suspension is slowly cooled to -10With before filtering. The crystals are collected by filtration and dried at 60With in a vacuum, getting 87,7 g (91% yield) of pale pink crystals. Tpl.=265C (with decomposition).

1H NMR (300 MHz, DMSO-d6): 8,24 (d, J=7.5 Hz, 1H), 7,86 (d, J=8 Hz, 2H), 6,92-was 7.08 (m, 1H), 7,01 (d, J=7.5 Hz, 1H), 6,98 (d, J=8 Hz, 1H), 6,86 (d, J=8 Hz, 1 the field of allocation of [3N]-5-HT from the posterior part of the cerebral cortex of Guinea pigs

[3N]-5-HT released by the electric field stimulation of the slices posterior part of the cerebral cortex of Guinea pigs that were pre-incubated with [3N]-5-HT. This selection is similar to selection caused by nerve stimulation, i.e. associtations allocation of serotonergic nerve endings, depending on the presence of CA2+in the medium for incubation. Selection 5-HT is regulated at the level of the nerve endings by autoreceptors, in Guinea pigs (just as it is in humans), belonging to the h5-HT1Bsubtype receptors. Thus, agonists h5-HT1Breceptors, reduce the number of [3N]-5-HT, the selected stimulation field, whereas antagonists of this type of receptors increase the allocation. Test compounds by this method, therefore, is a convenient method of test to determine the effectiveness and functionality of the new substances as agonists and antagonists h5-HT1Bthe receptor.

Methods and materials

The buffer composition (mm) Panso3(25), NaH2PO4HN2O (1,2), NaCl (117), KCl (6), MgSO4x7H2O (1,2), CaCl2(1,3), EDTU Na2(0,03). Buffer the first temperature, but increases approximately to 7.4 at 37C.

Preparation of sections of the occipital part of cerebral cortex

Guinea pigs (200-250 g) decapitate and remove the entire brain. The occipital part of the cerebral cortex dissected and cut into sections for 0.44 mm apparatus for making sections Il-wain. The white part of the tissue should be carefully removed with tweezers before making cuts. Slices incubated in 5 ml of buffer in the presence of 5 mm parkeringsomrede. After incubation with 0.1 mm3N]-5-HT for another 30 min, the slices are transferred into a test tube for testing and washed three times with the same volume of buffer. The slices are transferred to a chamber for superfusion plastic pipette and washed for 40 minutes buffer in the presence of absorption inhibitor citalopram 2.5 μm with a flow of 0.5 ml/min.

Electrical stimulation of the allocation of the 5-HT

The buffer after superfusion collected in 2 ml fractions. Cuts stimulate electricity with a chain of pulses with a frequency of 3 Hz, with a duration of 2 MS and a current of 30 mA for 3 min during the 4-th and 13-th fractions. Test drugs add 8 fractions to the end of the experiment.

Results

The first electric (or+) stimulation leads to a standard which enables antagonist h5-HT1Bthat leads to a dose-dependent increase (S2after the second stimulation. Cm. a drawing.

The ratio of S2/S1that is the percentage of released [3N]-5-HT when the second stimulus (S2) divided by this value when the first stimulus (S1), used for evaluating the effect of the drug on the release of transmitter.

Determination of the solubility of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl and its corresponding salts

Method

The excess of (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl or its corresponding salts added to purified water. The solution is stirred overnight in a water bath, maintained at 25With using a thermostat (Julabo SW and U3, 60 movements/min). A saturated solution centrifuged and filtered through a filter of 0.45m Gelman GHP Acrodisc, dilute and analyze GPIH.

Results

Solubility in water at 25From the Foundation, (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl 0,034 mg/ml

Solubility in water at 25

From the above comparison between the connection base and near its typical salts clear that the salts of the compounds of formula (I) are more soluble in water compared to the base and thus they are more suitable for pharmaceutical formulations.

Claims

1. Pharmaceutically acceptable salt of the compounds of formula I or MES specified salts in which the compound of formula I is in the form of [(R)-enantiomer, (S)-enantiomer or the racemate

provided that

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-(2S,3S)-tartrate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,1,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-(2R,3R)-tartrate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-1,2-etandisulfonat,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morphonuclear,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium-(S)-maleate,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium,

(R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium

eliminated.

2. Pharmaceutically acceptable salt under item 1, in which the compound of formula I is (R)-enantiomer or the specified MES salt.

3. Salt or MES under item 1, which is (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl L-lactate or MES.

4. Salt or MES under item 1, which is (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl L-ascorbate or its MES.

5. Salt or MES under item 1, which is (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium or MES.

6. Salt or MES under item 1, which is (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium or MES.

7. Salt or MES under item 1, which predstavljajut.

8. Salt or MES under item 1, which is (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinobenzenediazonium or MES.

9. Salt or MES under item 1, which is (R)-N-[5-methyl-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydro-2-naphthyl]-4-morpholinomethyl the dihydrochloride or its MES.

10. Pharmaceutical composition having a selective action on the subgroup of receptors 5-hydroxytryptamine, comprising as active ingredient a therapeutically effective amount of salt and/or MES according to any one of paragraphs.1-9, or a combination of such salts and/or solvate, optionally together with diluents, excipients or inert carriers.

11. The pharmaceutical composition according to p. 10 for the treatment of disorders mediated by 5-hydroxytryptamine.

12. The pharmaceutical composition according to any one of p. 10 or 11 for the treatment of depression, anxiety, disorders associated with changes in personality, obesity, anorexia, bulimia, premenstrual syndrome, sexual dysfunction, alcoholism, tobacco addiction, autism, attention deficit disorder associated with increased activity, migraine, memory disorders, pathological aggression, schizophrenia, endocrine is Jania urine, vasospasm and control of tumor growth.

13. Pharmaceutical composition for p. 12 for the treatment of main depressive disorders.

14. Salt or MES under item 1 as defined in any of paragraphs.1-9, for use in therapy.

15. Salt or MES under item 1, as defined in paragraph 14, for use in the treatment of disorders of the Central nervous system.

16. Salt or MES under item 1, as defined in paragraph 15, for use in the treatment of depression, anxiety, disorders associated with changes in personality, obesity, anorexia, bulimia, premenstrual syndrome, sexual dysfunction, alcoholism, tobacco addiction, autism, attention deficit disorder associated with increased activity, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, disorders of thermoregulation, pain, hypertension.

17. Salt or MES under item 1, as defined in paragraph 16, for use in the treatment of main depressive disorders.

18. Salt or MES under item 1, as defined in paragraph 14, for use in the treatment of urinary incontinence, vasospasm and control of tumor growth.

19. Salt or MES under item 1, as defined in paragraph 14, for use in the treatment of disorders mediated agonist.

21. Salt or MES as defined in any of paragraphs.1-9, which can be used in the manufacture of a medicinal product for the treatment of disorders of the Central nervous system and/or urinary incontinence, vasospasm and control of tumor growth.

22. Salt or MES under item 21, which can be used in the manufacture of a medicinal product for the treatment of depression, anxiety, disorders associated with changes in personality, obesity, anorexia, bulimia, premenstrual syndrome, sexual dysfunction, alcoholism, tobacco addiction, autism, attention deficit disorder associated with increased activity, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, disorders of thermoregulation, pain, hypertension.

23. Salt or MES under item 22, which can be used in the manufacture of a medicinal product for the treatment of main depressive disorders.

24. Salt or MES as defined in any of paragraphs.1-9, which can be used in the manufacture of a medicinal product for the treatment of disorders mediated by 5-hydroxytryptamine.

25. Salt or MES on p. 24, where salt or MES, is definitely the Noi nervous system and/or urinary incontinence, vasospasm and control of tumor growth by administration to a mammal, including man, in need of such treatment, a therapeutically effective amount of salt or MES as defined in any of paragraphs.1-9.

27. The method according to p. 26 treatment of depression, anxiety, disorders associated with changes in personality, obesity, anorexia, bulimia, premenstrual syndrome, sexual dysfunction, alcoholism, tobacco addiction, autism, attention deficit disorder associated with increased activity, migraine, memory disorders, pathological aggression, schizophrenia, endocrine disorders, stroke, dyskinesia, Parkinson's disease, disorders of thermoregulation, pain, hypertension.

28. The method according to p. 27 treatment of main depressive disorders.

29. The method according to p. 26 treatment of disorders mediated by 5-hydroxytryptamine.

30. The method according to p. 29, in which salt or MES according to any one of paragraphs.1-9 are used as h5-HT1Bantagonist.

31. The method of obtaining salts of the compounds of formula I or of the specified MES salt p. 1 by acylation of compounds of formula XII

activated 4-martinbentley acid and reaction of the base with an organic or inorganic acid to obtain the

 

Same patents:

The invention relates to imidazole derivative of the formula (I), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to a method for producing compounds of formula I:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid, R1means phenyl or a straight or branched alkyl or alkenyl and R2means hydrogen or acetyl, which comprises: (a) simultaneous protection of the hydroxyl groups in positions 7 and 10 10-deacetylbaccatin III trichloroethylene derivatives with obtaining the compounds of formula III:

b) subsequent etherification of the hydroxyl group of the compounds of formula III in position 13 interaction with the compound of the formula VII:

where R is tert-butoxycarbonyl, benzoyl or the remainder of the straight or branched aliphatic acid and R1means phenyl or a straight or branched alkyl or alkenyl, obtaining the compounds of formula IV:

(C) removing trichloroethylene protective groups of the compounds of formula IV with connection inflectional acetylation of the hydroxyl group in position 10 of the compounds of formula V to obtain the compounds of formula VI:

e) acid hydrolysis oxazolidinone ring compounds of the formula VI to obtain the compounds of formula I

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to omega-Amida N-arylsulfonamides formula I

and/or stereoisomeric forms of the compounds I and/or physiologically acceptable salts of the compounds I where R1means phenyl, phenyl, substituted once with halogen, the rest of the heterocycle of the following groups: morpholine, pyrrolidine; R2means N; R3means -(C1-C4)-alkyl-C(O)-N(R6)-R7where R6and R7together with the nitrogen to which they are bound, form a residue of formula IIa, IIe

moreover, in formula IIa, IIe q indicates an integer of zero or 1, Z denotes the carbon atom or a covalent bond, and R8means a hydrogen atom or halogen, or R3means -(C1-C4)-alkyl-C(O)-Y, where Y means the remainder of the formula IIC or IId

moreover, in formulas IIc and IId, R8means H or halogen, R9means H, or R3means -(C1-C4)-alkyl-C(O)-N(R9)-(CH2)about-N(R4)-R5and R9has the above values, means the integer 2 and R is substituted by-O-, And means covalent bond, B means -(CH2)m- where m is zero, X is-CH=CH-

The invention relates to new derivatives of 1,3-diaryl-2-pyridin-2-yl-3-(pyridine-2-ylamino)propanol of the formula (I)

where Z denotes-NH-(C1-C16-alkyl)-(C=O)-; -(C=O)-(C1-C16-alkyl)-(C=O)-;

-(C=O)-phenyl-(C=O)-; AND1AND2AND3AND4denote independently of each amino-acid residue, E represents-SO2-R4and-CO-R4; R1- phenyl, thiazolyl, oxazolyl, thienyl, thiophenyl and others, R2- N., HE, CH2HE, OMe; R3Is h, F, methyl, OMe; R4denotes -(C5-C16-alkyl), -(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylen)-R5, -(C=O)-(C0-C16-alkylene)-NH-R5and others, R5denotes-COO-R6, -(C=O)-R6-(C1-C6-alkylen)-R7, phenyl, naphthyl and others, R6denotes H, -(C1-C6) alkyl; R7denotes H, -(C1-C7-cycloalkyl, phenyl, naphthyl and others, l, q, m, n, o, p denote 0 or 1, and l+q+m+n+o+p is greater than or equal to 1, and their pharmaceutically acceptable salts

Thrombin inhibitors // 2221808
The invention relates to compounds of formula I, the values of the radicals defined in the claims and their pharmaceutically acceptable salts

The invention relates to new derivatives of benzothiadiazole, benzoxazoles and benzodiazines formula I in free base form or in the form of a pharmaceutically acceptable acid salt additive that can be used as an anxiolytic drug in the treatment of any condition, which is associated with increased endogenous levels of CRF or in which violated the regulation of the hPa system (hypothalamic - pituitary), or various diseases that are caused by CRF1or the manifestation of which contributes CRF1such as arthritis, asthma, allergies, anxiety, depression, etc

The invention relates to derivatives of N-(4-carbamimidoyl) glycinamide formula (I), where E denotes hydrogen or HE, Q denotes hydrogen or alkyl, R is aryl, cycloalkyl or alkyl substituted radicals R1, R2, R3, R1denotes hydrogen, COOH, COO-alkyl or aryl, R2denotes hydrogen, aryl, cycloalkyl or heteroaryl, R3denotes hydrogen, aryl or HE (in any position other thanposition relative to the nitrogen atom is attached to an alkyl group R) or optional substituted by an amino group, three of the radicals X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rd), Ra-Rddenote H, HE, NO2dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkylated, heteroarylboronic, geterotsiklicheskikh, COOH, COO-alkyl, NH-SO2-alkyl, NH-SO2-aryl, two adjacent groups Ra-Rbdenote alkylenedioxy, G1and G2denote hydrogen, HE, the invention relates to intermediate compounds of the formula (IV), (V), (VI) used in the methods of making compounds of formula (I), and are in взаимодействCN, the nitrile of formula (IV) is transformed into amidinopropane C(N-G1)NH-G2

The invention relates to new compounds of the formula (I), where R1is hydrogen or a fragment of ester, E is hydrogen or hydroxy, three of X1-X4denote the group of C(Ra), C(Rb) or C(Rc), and the fourth represents C(Rdor N, where Ra-Rdis hydrogen, alkenyl, quinil, alkenylacyl, alkoxy, alkylamino, alkoxyalkyl, alkoxyalkanols, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, alkyl, alkoxycarbonylmethyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, allylurea, allylthiourea, alkylsulfonamides, alkylsulfonyl, aminoethoxy, arylalkyl, Allakaket, arylalkyl, arylalkylamine, arylcarboxylic, arylcarboxamide, aryloxy, aryloxyalkyl, arylsulfonyl, arylsulfonamides, carboxy, carboxylic, substituted alkyl, substituted amino, halogen, substituted halogen, cycloalkyl, substituted cycloalkyl, hydroxy, substituted hydroxy, heterocycle, substituted heterocycle, or two adjacent groups of Ra-Rdtogether form the fragment condensed di - or monooxygenase ring or aryl ring

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to new derivatives of 4-(1-piperazinil)benzoic acid of formula I in which Ar represents a mono-, di - or tricyclic aryl having from 6 to 14 carbon atoms, while Ar may have from 1 to 3 substituents selected from the group comprising (C1-C8)alkyl, (C1-C8)alkoxy, halogen, trifluoromethyl; R1selected from the group comprising a hydrogen atom, cycloalkyl containing from 3 to 8 carbon atoms, (C6-C14)aryl, heteroaryl(C1-C6)alkyl, and heteroaryl selected from the group comprising furyl; R2and R3is hydrogen, a solvate and a pharmaceutically acceptable salt

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to a method of production of new chemical compounds, diamine consisting of aromatic and cycloaliphatic fragments, specifically disodium salt of N,N-bis-(4-amino-2-sulfophenyl)piperazine, which can be used as a monomer in producing high-strength heat-resistant cation-exchange materials

The invention relates to new biologically active compounds, in particular to new pyridone derivative exhibiting analgesic activity

The invention relates to organic chemistry and pharmacology, and relates new connection - 1-(1,1-dissociator-3)-2-morpholinobenzenediazonium hydrochloride, increasing resistance to acute hypoxia with hypercapnia

The invention relates to compounds of formula (I)

< / BR>
in which Ar1denotes a heterocyclic group, which represents a pyrazole which may be substituted by one or more radicals R1, R2or R3; Ar2denotes phenyl, naphthyl or tetrahydronaphthyl, each of which optionally is substituted by one to three groups R2; L denotes a saturated or unsaturated, branched or unbranched carbon C1-C10chain; in which one or more methylene groups are optionally independently replaced by O, NH or S, and in which the linking group is optionally substituted by 0-2 of doxography; Q has a value selected from a range of: a) phenyl, naphthyl, pyridine, imidazole, Piran, etc. b) tetrahydropyran, morpholine, thiomorpholine, thiomorpholine and t

The invention relates to amide derivative of the formula I

< / BR>
where R3represents (1-6C)alkyl or halogen; m is 0, 1, 2 or 3; R1represents hydroxy, halogen, trifluoromethyl, nitro, amino, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)quinil, (1-6C)alkoxy, (1-6C)alkylamino, di-[(1-6C)alkyl] amino, amino-(2-6C)alkylamino, (1-6C)alkylamino-(2-6C)alkylamino etc
Up!