Derivatives amine and pharmaceutical composition based on them

 

(57) Abstract:

Derivatives amine of the formula I

< / BR>
where R is halogen, hydroxyl, C1-3-alkyl, C1-3-alkoxy; Q is a residue of formula (IIA), (IIB)

< / BR>
< / BR>
V is methylene or ethylene, X - C0-2-Allenova chain, X' - C1-4-Allenova chain, T is phenyl, pyridyl, pyrazinyl, benzo[b]furanyl, 1,4-benzodioxane, hintline, possibly substituted by halogen, metaxylem or trifluoromethyl, m = 0 or 1, and their pharmaceutically acceptable salts, have high affinity receptor 5-HT1and D2. 2 S. and 4 C.p. f-crystals, 1 table.

The invention relates to new fluorine-containing organic compounds, more specifically to an amine derivative having biological activity.

Known nitrogen-containing organic compounds, in particular N-heterocyclic compounds which possess biological activity and can be used as active substances in pharmaceutical compositions, manifesting, for example, the tool receptor 5-HT1Aand D2(see application EP N 0054304, published on 23 June 1982).

The objective of the invention is to expand the range of high-performance derivatives of the amine with DDPs is otvodkami amine of the formula (I)

< / BR>
where R is halogen, hydroxyl, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 atom mi carbon

Q is a divalent group of formula (IIa), (IIB),

< / BR>
< / BR>
where V is methylene or ethylene,

X - Allenova chain with 0 to 2 carbon atoms,

X' - Allenova chain with 1 to 4 carbon atoms,

the total number of carbon atoms in the residues X and X' is 3 or 4,

T is phenyl, pyridyl, pyrazinyl, benzo[b]furanyl, 1,4-benzodioxane, and hintline, unsubstituted or substituted by halogen, metaxylem or trifluoromethyl,

m - 0,1,

and their pharmaceutically acceptable salts.

In the first group of preferred compounds includes compounds in which R is hydroxyl, methoxy, fluorine or chlorine.

The second group of preferred compounds includes compounds in which T represents 2-pyridyl, 2-pyrazinyl, phenyl, 2,3-dihydro-benzo[b]furan-7-yl, 1,4-benzodioxan-5-yl or 4-hintline, unsubstituted or substituted by metaxylem, trifluoromethyl or halogen.

The third group of preferred compounds consists of the compounds selected from the group comprising: N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrazin-2-yl)piperid-4-yl] methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] METI azolin-4-yl)piperid-4-yl] methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl] methylamine; N-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-(1-phenylpiperidine-4-yl)methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(1,4-benzodioxan-5-yl)piperid-4-yl] methylamine; 1-[1-(1,4-benzodioxan-2-ylmethyl)piperid-4-yl] -N-(2-methoxyphenyl)methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(4-methoxyphenyl)piperid-4-yl] methylamine; N-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-N'-(2-methoxyphenyl)-1,3-propandiamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(3-methoxyphenyl)piperid-4-yl] methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-chlorophenyl)piperid-4-yl] methylamine; N-(5-fluoro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; N-(8-fluoro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; 1-[1-(2,3-dihydro-benzo[b]furan-7-yl)piperid-4-yl] -N-(8-methoxy-1,4-benzodioxan-2-ylmethyl)methylamine; N-(6-chloro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; N-(7-chloro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; N-(8-hydroxy-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; and their pharmaceutically acceptable salts that may be present in the form of individual enantiomers, racemates, or other mixtures of PPI, including:

(S)-(-)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)-piperid-4-yl]methylamine;

(R)-(+)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)-piperid-4-yl]methylamine;

(-)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl] methylamine in the form of dihydrochloride;

(+)-N-( 1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl] methylamine in the form of the dihydrochloride.

Compounds of General formula (I) may exist as salts with pharmaceutically acceptable acids. Examples of such acids are hydrochloride, hydrobromide, sulphates, methansulfonate, nitrates, maleate, acetates, citrates, fumarate, tartratami [e.g. (+)- tartratami, (-)-tartratami and their mixtures and racemates], succinate, benzoate and salt with amino acid such as, for example, glutamic acid. Compounds of General formula (I) and their salts may exist in the form of a solvate, for example, hydrates.

Compounds of General formula (I) can have one or more chiral centers, and exist in different optically active forms. If there is one chiral centre, the compounds of formula (I) exist in two enantiomeric forms and, therefore, the present invention covers both enantiomers and mixtures thereof. Individual enantiomers may be obtained WPI is but to divide, for example, by crystallization, the formation of derivatives or complexes of diastereomers, which can be divided, for example, by crystallization, gas-liquid chromatography or liquid chromatography, selective engagement of one enantiomer with an appropriate reagent, for example enzymatic esterification, or gas-liquid or liquid chromatography in a chiral environment, for example, chiral media, such as silicon dioxide, with the associated chiral ligand or in the presence of a chiral solvent. If desired enantiomer into another chemical form in one of the above methods, you must follow the selection of the desired enantiomeric form. It is also possible to synthesize the enantiomers by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by translation of one enantiomer into the other enantiomer due to the asymmetric rearrangement.

If compounds of General formula (I) have at least two chiral center, they are in the form of diastereoisomers which are separated by well-known specialist methods, such as chromatography or crystallization.

Some compounds of General formula (I) and their salts may exist in different crystalline forms, and therefore, this invention encompasses any crystal form and mixtures of these forms. Some compounds of General formula (I) and their salts may also exist in the form of a solvate, for example, hydrates, and therefore, this invention encompasses any MES and a mixture of the solvate.

A further object of the present invention is a pharmaceutical composition with affinity receptor 5-HT1Aand D2containing a therapeutically effective amount of the compounds of General formula (I) or its salt and a pharmaceutically acceptable diluent or carrier.

Used here, the term "active principle" means a compound of formula (I) or its salt. In the treatment, the active principle give orally, rectally, parenterally or topically, preferably orally. Thus the proposed pharmaceutical composition can be any standard form of therapeutic drug for oral, rectal, parenteral or topical application. As a pharmaceutically acceptable diluent or carrier offer the inhabitants of 0.1 to 99 wt.% the active agent. Usually it's in the form of a dosage unit. A dosage unit of the active agent is preferably 1 to 500 mg of the Target additives in containing the proposed connection compositions are well-known substances.

Examples of preferred compositions for oral villas are tablets, capsules, syrups, aqueous or oil suspensions. Target additives in such compositions are well-known substances. Tablets are prepared by mixing the active agent with an inert fillers, such as, for example, calcium phosphate, dezinfeciruyuhimi agents, such as, for example, corn starch, lubricants such as, for example, magnesium stearate, providing tableting proposed composition. Tablets may have prolonged action, i.e., can be performed so that the active principle is released within a certain time. For this purpose on the pill can be applied by known coating techniques, for example, phthalate cellulose acetate. In addition, it is possible to translate the proposed composition in capsules, for example, hard or soft gelatin which is prepared by known techniques and neobhodimo beginning.

Another composition for oral cottages is, for example, aqueous suspensions containing the active principle in an aqueous medium in the presence of a non-toxic suspending agent such as carboxymethyl cellulose sodium, and oily suspensions containing a compound of the above General formula (I) in a suitable vegetable oil, such as, for example, peanut butter.

The active principle can also be translated into granules, optionally with additional excipients. Granules may be applied directly by the patient, or they can be added to a suitable liquid carrier, such as, for example, water, before use. The granules may also contain pharmaceutically acceptable dezintegriruetsja agents, such as, for example, a granular mixture consisting of acids and salts of carbonic acid or bicarbonate, which facilitates dispersion in a liquid medium.

Suitable for rectal villas form the proposed compositions are, for example, suppositories that contain cocoa butter or polietilenglikoli basis.

Suitable for parenteral villas form the proposed compositions are, for example, sterile suspen the t matrix, in which the active principle dispersed in such a way that it is in contact with the skin so that the active substance may be absorbed transdermal. A suitable composition for transdermal application can be prepared by mixing the pharmaceutically active agent with a suitable carrier, such as, for example, mineral oil, petrolatum and/or wax, such as paraffin or beeswax, and is suitable for transdermal application accelerator, such as, for example, dimethyl sulfoxide or propylene glycol. But the active principle can also be dispersed in a pharmaceutically acceptable cream or the basis for ointments. In the case of topical application of the active principle must be kept in a suitable drug so that a therapeutically effective amount of the active agent is released over a desired period of time.

Compounds of the above General formula (I) can also be given by continuous infusion, for example, by intravenous infusion, or with the source placed inside the patient's body. These internal sources are, for example, implanted capacity, which contain subject infusion active nazvanie drugs can be a liquid, such as, for example, a suspension or solution in a pharmaceutically acceptable oil to be infusion of connection, for example, as a sparingly soluble in water derivative, such as, for example, salt or ester with dodecanol acid, or serving as the basis for subject infusion connections solid, for example, synthetic resin or wax. This base may be a single body containing the active principle, or series of bodies, each of which contains part appliciruemah active principle. The active principle must be an internal source so that a therapeutically effective amount of the active agent given during the desired period of time.

For some purposes it may be desirable that the composition comprises compounds of the above General formula (I) in the form of fine particles obtained, for example, by spraying.

The proposed pharmaceutical composition may also contain other pharmacologically active agent that is compatible with the compounds of the above General formula (I).

As mentioned above, the proposed pharmaceutical composition exhibits affinity against the AI. Necessary for the successful treatment of a number of active principle depends on a number of factors such as, for example, the patient's age, severity of disease, medical history, so in each case the doctor must find the suitable dosage. As a rule, new connections give in the amount of 1 - 1000 mg/day, preferably 5 to 500 mg/day as single dose or multiple doses, once or several times per day.

Below describes how to obtain the compounds of the above General formula (I).

The compounds of formula (I), where Q is a group of formula (IIA) can be obtained by reacting the compounds of formula (III)

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where R and m have the above values,

with the compound of the formula (IV)

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where n is 1 or 2, and X, X' and T have the above values,

with the subsequent interaction of the resulting imine with a reducing agent, such as, for example, sodium borohydride.

The compounds of formula (I), where Q is a group of formula (IIA) can also be obtained by reacting compounds of the above formula (III) with the compound of the formula (V)

< / BR>
where X, X' and n have the above values, a Y means a group to delete, such as, for example, toluene-4-sulfonyl is potassium.

In addition, compounds of General formula (I), where Q is a group of formula (IIa) can be obtained by reacting the compounds of formula (VI)

< / BR>
where X, X' and T have the above values,

with the compound of the formula (VII)

< / BR>
where R and m have the above values, a Z means a group to delete, such as, for example, toluene-4-sulfonyloxy.

if necessary, in an environment suitable solvent and in the presence of a base, e.g. potassium carbonate.

Compounds of General formula (I) can also be obtained by reacting the compounds of formula (VIII)

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where R and m have the above values,

with the compound of the formula (VI), followed by reduction of the resulting imine with a suitable reducing agent, such as, for example, sodium borohydride.

Compounds of General formula (III) can be obtained by restoring the connection of the formula (IX)

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where R and m have the above values,

a reducing agent, such as, for example, alumoweld lithium.

The compounds of formula (IX) can be obtained by reacting the compounds of formula (X)

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where R and m have the above values,

with a nitrile of the formula (XI)

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where Y is the group to delete, t>/P>The compounds of formula (III) can also be obtained from compounds of formula (XII)

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where R and m have the above meanings, and Deputy E together with the nitrogen atom to which it is linked, forms a cyclic imide, such as, for example, phthalimide, catalyzed by acid or base hydrolysis, or by cleavage reagent, for example, hydrazine hydrate.

The compounds of formula (XII) where the Deputy E together with the nitrogen atom to which it is linked, is phthalimide can be obtained by reacting the compounds of formula (VII), where Z is a removable group, such as, for example, toluene-4-sulfonyloxy, phthalimide potassium.

The compounds of formula (III) can also be obtained by restoring the compounds of formula (XIII)

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where R and m have the above meanings, with a suitable reducing agent, such as, for example, alumoweld lithium.

The compounds of formula (XIII) can be obtained by reacting the compounds of formula (XIV)

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where R and m have the above values, a L means an alkyl group with 1 to 6 carbon atoms, with ammonia.

The compounds of formula (IV) can be obtained by reacting the compounds of formula (XV)

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where X, X', T and n have the for example, bis(2-methoxyethoxy)alumoweld sodium, in the environment of the solvent, for example toluene.

The compounds of formula (XV) can be obtained by reacting the compounds of formula (XVI)

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where R6X, X' and n have the above meanings, with galoidzamyescyennykh aromatic compound, such as, for example, 2-aloperidin, for example, 2-chloropyridin, optionally in the presence of a base, such as, for example, triethylamine.

The compounds of formula (IV) may also be obtained by oxidation of compounds of formula (XVII)

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where X, X', T and n have the above meanings, with a suitable oxidizing agent, such as, for example, oxalicacid environment dimethyl sulfoxide.

The compounds of formula (V), where Y - toluene-4-sulfonyloxy can be obtained by reacting the compounds of formula (XVII) with the agent tiliouine, such as, for example, toluene-4-sulphonylchloride.

The compounds of formula (XVII) can be obtained by restoring the compounds of formula (XV) a reducing agent, such as, for example, alumoweld lithium, or by reacting with the compound of the formula (XVIII)

< / BR>
where X, X' and n have the above meanings, with galoidzamyescyennykh aromatic compound, such as, for example, 2-aloperidin,x2">

The compounds of formula (XVIII) can be obtained by restoring the compounds of formula (XVI), where R6- CNS group with 1 to 4 carbon atoms, with a reducing agent, such as, for example, alumoweld lithium.

The compounds of formula (VI) can be obtained by reacting the compounds of formula (XIX),

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where X and X' have the above values, a D - protective group, for example, methylbenzylidene or 4-nitrobenzylidene, with galoidzamyescyennykh aromatic compound, such as, for example, 2-aloperidin, for example 2-chloropyridin, optionally in the presence of a base, such as, for example, triethylamine, followed by removal of the protective group, for example, by acid catalyzed hydrolysis.

The compounds of formula (XIX) can be obtained by reacting the compounds of formula (XX)

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where X and X' have the above meanings, with a protective reagent, such as, for example, acetophenone or 4-nitrobenzaldehyde.

The compounds of formula (VI) can be obtained directly by reacting the compounds of formula (XX) with galoidzamyescyennykh aromatic compound, such as, for example, haloperidol, 2-chloropyridin, optionally in the presence of a base, such as, for example, the crystals (XVI), where R6- amino group, a reducing agent, such as, for example, alumoweld lithium.

The compounds of formula (VI) can also be obtained by reacting the compounds of formula (XXI)

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where X and X' have the above values, a G means hydrogen, with galoidzamyescyennykh aromatic compound, such as, for example, 2-chloropyridin, optionally in the presence of a base, such as triethylamine, followed by reduction using a reducing agent such as, for example, alumoweld lithium.

The compounds of formula (XXI), where G denotes hydrogen, can be obtained by reacting the compounds of formula (XXI), where G denotes alkyl or arylalkyl group, for example, benzyl, dealkylation agent, such as, for example, 1-chlorotalonil ether of Harborview acid, followed by cleavage obtained as an intermediate product of ester carbamino acid.

The compounds of formula (XX) can also be obtained by reacting the compounds of formula (XXI), where G is the amine protecting group, e.g. benzyl, with a reducing agent, such as, for example, alumoweld lithium, followed by removal of the protective group, for example by interacting with ant is the train partway through the recovery of the compounds of formula (XXII)

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where X, X', T and n have the above values, a reducing agent, such as, for example, a complex of borane and dimethyl sulfide or alumoweld lithium.

The compounds of formula (XXII), where the total number of carbon atoms in the radicals X and X' is 4, and T - aromatic group that does not contain a nitrogen atom, can be obtained by restoring the compounds of formula (XXIII)

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where n has the above meaning, and T - aromatic group that does not contain a nitrogen atom, a reducing agent, such as, for example, ammonium formate or hydrogen, in the presence of palladium on coal as a catalyst.

The compounds of formula (XXIII) can be obtained by the interaction of the compounds of formula (XXIV)

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where n has the above meaning, with a compound of formula (XXV)

T-NH2< / BR>
where T is an aromatic group containing a nitrogen atom, thus there is a rearrangement of 2,4-dinitroaniline.

The compounds of formula (XXIV) can be obtained by reacting 2,4-dinitrochlorobenzene with the compound of the formula (XXVI)

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where n has the above meaning.

The compounds of formula (VII), where Z means the toluene-4-sulfonyloxy can be obtained by reacting the compounds of formula (XXVI Foundation, for example, pyridine.

The compounds of formula (XXVII) can be obtained by recovery of the compounds of formula (XIV), where L denotes an alkyl group with 1 to 4 carbon atoms, a reducing agent, such as, for example, alumoweld lithium.

The compounds of formula (XXVII) can also be obtained by reacting the compounds of formula (XXVIII)

< / BR>
where Z is the group to delete, for example, chlorine or toluene-4-sulfonyloxy, with the compound of formula (X) in a suitable solvent, such as, for example, water or dimethylformamide, in the presence of a base, e.g. sodium hydroxide. In the case of enantiomerically pure forms of compounds of formula (XXVIII), such as, for example, (R)-glycidol-O-toluene-4-sulfonate, you can get a single enantiomer of compounds of formula (XXVII).

The compounds of formula (XXVII), where R means the CNS group with 1 to 3 carbon atoms, can be obtained in the alkylation of the corresponding compounds of formula (XXVII), where R is hydroxyl, by interacting with the alkylation agent, for example, methyliodide, in the presence of a base, such as, for example, sodium hydroxide.

The compounds of formula (VIII) can be obtained by oxidation of compounds of formula (XXVII), soedineniya formula (XIV), where m is 0, with a suitable reducing agent, such as, for example, bis(2-methoxyethoxy)alumoweld sodium, in the environment of the solvent, for example toluene.

The compounds of formula (XIV) can be obtained by reacting the compounds of formula (XXIX)

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where Y is a removable group, for example, bromine, a L - alkyl group with 1 to 6 carbon atoms, with a compound of formula (X) in the presence of a base, e.g. potassium carbonate.

The compounds of formula (I), where Q is a group of formula (IIB) can be obtained by reacting the compounds of formula (XXX)

< / BR>
where R, X, X', H and V have the above meanings, with galoidzamyescyennykh aromatic compound, such as, for example, 2-aloperidin, for example, 2-chloropyridin, optionally in the presence of a base, such as, for example, triethylamine.

The compounds of formula (XXX) can be obtained from compounds of formula (XXXI)

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where R, X, X' V and m have the above values, a D - protective group, for example, 5-chloro-2-oxybenzoates, catalyzed by acid or base hydrolysis.

The compounds of formula (XXXI) can be obtained by reacting the compounds of formula (XXXII)

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where X, X', V and D have the above meanings, with a compound of formula (VII) with (I) can be obtained by reacting the compounds of formula (XXXIII)

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where X, X' and V have the above meanings, with a protective reagent, such as, for example, 5-chlorosalicylaldehyde.

The compounds of formula (I), where Q is a group of formula (IIB) can also be obtained by reacting the compounds of formula (XXXIV)

< / BR>
where R, X, X', V and m have the above meanings, with a reducing agent, for example, a complex of borane and dimethyl sulfide.

The compounds of formula (XXXIV) can be obtained by reacting the compounds of formula (XXXV)

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where R, X, X' V and m have the above significance, with an agent in the formation of a mixed anhydride, such as, for example, a complex of ethyl ether of Harborview acid, optionally in the presence of a base, such as, for example, triethylamine, followed by interaction with the compound of the formula (XXV).

The compounds of formula (XXXV) can be obtained by hydrolysis of compounds of formula (XXXVI)

< / BR>
where R6- CNS group with 1 to 4 carbon atoms, with a base, such as, for example, potassium hydroxide.

The compounds of formula (XXXVI) can be obtained by reacting the compounds of formula (VII) with the compound of the formula (XVI), where R6- CNS group with 1 to 4 carbon atoms.

The ability connected experience designed to determine the ability of compounds to inhibit in vitro the binding of labeled tritium ligand with the receptor 5-HT, in particular with the receptor 5-HT1A.

Hippocampal tissue of the brain of male rats strain, Charles River CD, weighing 150 to 250 g of homogenized in cold as ice 50-mm buffer Tris-HCl pH value, equal to 7.7 (measured at a temperature of 25oC) taken in a weight ratio to the tissue, equal to 1:40 in terms of volume and centrifuged with a speed of 30,000 g at a temperature of 4oC for 10 minutes. The precipitate is again homogenized in the same buffer, incubated at temperature 37oC for 10 minutes and centrifuged with a speed of 30,000 g at a temperature of 4oC for 10 minutes. The resulting residue suspended in 50 mm buffer Tris-HCl pH value, equal to 7.7, containing 4 mmol of calcium dichloride, 0.1% of L-ascorbic acid and 10 mmol of pargyline as hydrochloride (which is equivalent to 6.25 mg wet tissue/ml) and immediately used in the experiment to determine binding. Aliquot amount (400 µl, which is equivalent to 2.5 mg of wet tissue per tube) the resulting suspension was applied to a tube containing 50 µl (2 nmol) of the ligand and 50 μl of distilled water (gender in a single concentration of 10-6mol or 10 different concentrations equal to 10-11- 10-3mol). As the ligand used [3H]8-hydroxy-2-(dipropylamino)tetralin. The mixture is incubated at a temperature of 25oC for 30 minutes, after which the incubation was stopped by rapid filtration.

Filters were washed in cold as ice buffer Tris-HCl, and dried. The filters were put in test tubes, which were added to scintillation fluid, after which the radioactivity was determined by liquid scintillation counting,% substitution of specific binding labeled with tritium ligand was calculated for a single concentration (10-6mol) of the investigated compounds. Was curves substitution for those compounds that were replaced by 50% the specific binding of labeled tritium ligand at a concentration of 10-6mol using the compounds in different concentrations. The concentration providing 50% inhibition of specific binding (IC50) was obtained from the curve. The braking coefficient (Ki) was determined using the following equation

< / BR>
where [ligand] means the concentration of labeled tritium ligand, a KDmeans the equilibrium constant for the dissociation of the ligand.

With the following experience designed to determine the ability of compounds to inhibit in vitro the binding of labeled tritium ligand with adrenoceptors, in particular with1-adrenoceptors.

The whole cortical tissue of the brain of male rats strain, Charles River CD, weighing 150 to 250 g of homogenized in cold as ice 50-mm buffer Tris-HCl pH value, equal to 7.6 (measured at a temperature of 25oC) taken in a weight ratio to the tissue, equal to 1:40 in terms of volume and centrifuged with a speed of 1,000 g at a temperature of 4oC for 10 minutes. The supernatant was centrifuged with a speed of 30,000 g at a temperature of 4oC for 10 minutes. The residue is homogenized in cold as ice 50-mm buffer Tris-HCl pH value, equal to 7.6 taken in a weight ratio to the tissue, equal to 1:40 in terms of volume, and centrifuged with a speed of 30,000 g at a temperature of 4oC for 10 minutes. Get final remainder homogenized in 50 mm buffer Tris-HCl pH value, equal to 7.6, (equivalent to 12.5 mg wet tissue/ml) and immediately used in the experiment to determine binding. Aliquot amount (400 µl, which is equivalent to 5 mg of wet tissue per tube) the resulting suspension was applied to a tube containing 50 ál (Noe binding) or 50 μl of the compounds (taken at a single concentration of 10-6mol or 10 different concentrations equal to 10-11-10-3mol). As the ligand used [7-methoxy-3H]prazosin. The mixture is incubated at a temperature of 30oC for 30 minutes, after which the incubation was stopped by rapid filtration.

Filters were washed in cold as ice buffer Tris-HCl, and dried. The filters were put in test tubes, which were added to scintillation fluid, after which the radioactivity was determined by liquid scintillation counting,% substitution of specific binding labeled with tritium ligand was calculated for a single concentration (10-6mol) of the investigated compounds. Was curves substitution for those compounds that were replaced by 50% the specific binding of labeled tritium ligand at a concentration of 10-6mol using the compounds in different concentrations. The concentration providing 50% inhibition of specific binding (IC50) was obtained from the curve. The braking coefficient (Ki) was determined using the following uravneniya

< / BR>
where [ligand] means the concentration of labeled tritium ligand, and KDmeans the equilibrium constant for the dissociation of the ligand.

The ability of soy is one designed to determine the ability of compounds to inhibit in vitro the binding of the ligand with adrenoceptors, in particular2- adrenoceptors.

The fabric of the anterior cortex of male rats strain, Charles River CD, weighing 150 to 250 g of homogenized in ice cold a 0.25-m sucrose, taken in a weight ratio to the tissue, which is 1:30 in terms of volume and centrifuged with a speed of 1,000 g at a temperature of 4oC for 12 minutes. The supernatant was kept on ice, and the residue was rehomogenization 0.25-m sucrose, taken in a weight ratio to the tissue, which is 1:15 in terms of volume, and centrifuged with a speed of 850 g at a temperature of 4oC for 12 minutes. The combined supernatant was diluted 5-mm buffer Tris-HCl-pH 7.5, containing 0.5 mol ethylendiaminetetraacetic acid, pH again brought to 7.5 (at a temperature of 25oC) the addition of 1 m sodium hydroxide until the weight ratio equal to 1:80 in terms of volume, and centrifuged with a speed of 30,000 g at a temperature of 4oC for 10 minutes. The resulting residue resuspendable in 50 mm buffer Tris-HCl-pH 7.5, containing of 5.68 mmol L-ascorbic acid and 5 mmol ethylendiaminetetraacetic KIS is Aravali with a speed of 30,000 g for 10 minutes. Get final remainder resuspendable in 50 mm buffer Tris-HCl-pH 7.5, containing of 5.68 mmol L-ascorbic acid and 5 mmol ethylendiaminetetraacetic acid (which is equivalent to 12.5 mg wet tissue/ml) and immediately used in the experiment to determine binding. Aliquot amount (400 µl, which is equivalent to 5 mg of wet tissue per tube) the resulting suspension was applied to a tube containing 50 μl (1 nmol) of the ligand and 50 μl of distilled water (total binding) or 50 μl (5 mmol) fentolamina (nonspecific binding) or 50 μl of the compounds (taken at a single concentration of 10-6mol or 10 different concentrations equal to 10-11-10-3mol). As the ligand used labeled with tritium idazoxan ((1,4-[6,7(n)-3H] benzodioxan-2-yl)-2-imidazolin as hydrochloride). The mixture is incubated at a temperature of 0oC for 75 minutes, after which the incubation was stopped by rapid filtration.

Filters were washed in cold as ice buffer Tris-HCl, and dried. The filters were put in test tubes, which were added to scintillation fluid, after which the radioactivity was determined by liquid scintillation counting,% substitution suenaga connection. Was curves substitution for those compounds that were replaced by 50% the specific binding of labeled tritium ligand at a concentration of 10-6mol using the compounds in different concentrations. The concentration providing 50% inhibition of specific binding (IC50) was obtained from the curve. The braking coefficient (Ki) was determined using the following equation

< / BR>
where [ligand] means the concentration of labeled tritium ligand, and KDmeans the equilibrium constant for the dissociation of the ligand.

The ability of compounds of the formula (I) to interact with dopamine receptors were identified using the following experience designed to determine the ability of compounds to inhibit in vitro the binding of labeled tritium ligand to dopamine receptors, in particular dopamine receptors D2.

Cut into strips brain tissue of male rats strain, Charles River CD, weighing 140 to 250 g of homogenized in cold as ice 50-molarnom buffer Tris-HCl pH value, equal to 7.7 at a temperature of 25oC, and centrifuged with a speed of 40,000 g for 10 minutes. The remainder resuspendable in Tris-buffered saline (50 mmol buffer Tris-HCl containing 120 mmol of sodium chloride ; H buffer at a temperature of 25oC is equal to 7.7) and again centrifugally with a speed of 40,000 g for 10 minutes. Get the final residue was kept at a temperature of -80oC. Before each test solid mass resuspendable in Tris-buffered saline (equivalent to 2 mg wet weight of tissue/ml). Aliquot amount (720 μl, which is the equivalent of 1.44 mg wet tissue per tube) the resulting suspension was applied to a tube containing 40 μl (1 nmol) of the ligand and 40 μl of Tris-saline buffer (total binding) or 40 μl (10 nmol) spiroperidol (nonspecific binding) or 40 μl of tested compound (taken at a single concentration of 10-6mol or 6 different concentrations equal to 10-11- 10-4mol). As the ligand used labeled with tritium (S)-sulpiride. The mixture is incubated at a temperature of 4oC for 40 minutes, after which the incubation was stopped by rapid filtration.

Filters were washed in cold as ice buffer Tris-HCl, and dried. The filters were put in test tubes, which were added to scintillation fluid and left for 20 hours, after which the radioactivity was determined by scintillation spectrophotometry,% substitution of specific binding mechen the curves and substitution for those compounds, which was replaced by 50% the specific binding of labeled tritium ligand at a concentration of 10-6mol using the compounds in different concentrations. The concentration providing 50% inhibition of specific binding (IC50) was obtained from the curve. The braking coefficient (Ki) was determined using the following uravneniya

< / BR>
where [ligand] means the concentration of labeled tritium ligand, and KDmeans the equilibrium constant for the dissociation of the ligand.

Values of Kidefined in the above-described tests for binding to 5-HT1A,1,2and D2for all target compounds obtained in the following examples 1 to 32, are given in table 1. In several cases the definition of Kiit was not possible, therefore, the value of Kigiven as "greater than" (>), obtained from applying the above formula to the highest concentration, which provides the substitution of the ligand by 50%.

% the values in table 1 refer to% final substitution when the concentration of the compound equal to 10-6the mole.

The invention is illustrated by the following examples which do not limit its scope. Target products in each of these examples were the nature of the DIMMs liquid chromatography, elemental analysis, spectroscopy, nuclear magnetic resonance, infrared spectroscopy.

Example 1.

A mixture of 14.3 g of chloropyrazine, of 14.25 g of 1-(piperid-4-yl)methylamine, 11.4 g of sodium carbonate and 100 ml of 3-methyl-1-butanol is stirred and heated under reflux for 64 hours, then cooled to room temperature and filtered. The solvent is removed in vacuum and the remaining oil is distilled to obtain 16.2 g of 1-[1-(pyrazin-2-yl)piperid-4-yl]methylamine as a pale yellow oil boiling within 136 -160oC/0.6 mbar.

The solution 60,25 g of toluene-4-sulphonylchloride in 75 ml of pyridine is added dropwise at a temperature of 20oC serves to mix a solution of 50 g of 1-(1,4-benzodioxan-2-yl)methanol in 100 ml of pyridine, and the mixture is stirred at room temperature for 18 hours, then poured onto an excess of ice and hydrochloric acid (5 mol). The resulting solid is collected by filtration, thoroughly washed with water and dried in vacuum to obtain 82.3 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate as a whitish solid with melting point: 75 - 78oC.

A mixture of 6.4 g of the obtained solid substance, 3.8 g of 1-[1-(pyrazin-2-yl)piperid-4-yl] methylamino for 70 hours, then cooled to room temperature and filtered. The solid is washed with a small amount of methanol, and the filtrate and washing liquid combine. The solvent is removed in vacuum, while getting the oil, which is ground to powder using diethyl ether, and the solution is filtered. The solvent is removed in vacuum to obtain 6.2 g of oil, which is purified by distillation in Kugeler, you get 4 grams of oil with a boiling point of ~ 220oC/0.13 mbar. The oil is dissolved in methanol, and the solution saturated with hydrogen chloride. The solvent is removed in vacuum to obtain resin, which is dissolved in 25 ml of hot ethanol and cooled on ice to obtain 4 g of yellow solid, which was collected by filtration and dried in vacuum. The solid is dissolved in water and the solution washed with ethyl acetate and alkalinized 5-molar aqueous solution of sodium hydroxide. The free base is extracted with ethyl acetate, and the resulting extracts are dried over magnesium sulfate. The solvent is removed in vacuum to obtain 2.55 g of oil, which is purified by flash-chromatography under reduced pressure over silica gel using as eluent a mixture of diethyl ether and methanol in the ratio aslo dissolved in 50 ml of ethanol, and the solution is saturated with hydrogen chloride to obtain solid, which is collected by filtration and dried in vacuum at a temperature of 80oC. Obtain 1.4 g 1, . 4-hydrochloride N-(1,4-benzodioxan-2-ylmethyl)-1- [1-(pyrazin-2-yl)piperid-4-yl] methylamine as a yellow solid with a melting point of 242 - 245oC.

Example 2.

A mixture of 8 g of pyridine-4-carboxamide and 40 g of 2,4-dinitrochlorobenzene is heated at a temperature of 95oC for 1 hour, cooled and suspended in a mixture of 60 ml of methanol and 600 ml of diethyl ether. The supernatant decanted, and the solid residue twice suspended in the same solvent mixture.

The solid residue is boiled in 100 ml of methanol, after which the reaction mixture is allowed to cool. The product is collected by filtration and dried in vacuum to obtain 15,35 g chloride 4-carbarnoyl-1-(2,4-dinitrophenyl)pyridinium in the form of a yellowish powder with a melting point of 236 - 238oC (Razlog.)

A mixture of 13.6 g of the chloride of 4-carbarnoyl-1-(2,4-dinitrophenyl)pyridinium, 10 ml of 2-methoxyaniline and 500 ml of methanol was stirred at room temperature for 16 hours, after which the solvent is removed in vacuum. Add diethyl ether containing a small amount of acetone, with the AI. Get 11.5g chloride 4-carbarnoyl-1-(2-methoxyphenyl)-pyridinium as a yellow solid with a melting point of 229 - 230oWith (Razlog.).

A mixture of 10.3 g of chloride 4-carbarnoyl-1-(2-methoxyphenyl)- pyridinium, 10 g of the catalyst in the form of a 10% palladium on coal, 20 g of ammonium formate and 200 ml of methanol was stirred at room temperature for 20 minutes, then heated under reflux for 3.5 hours. The cooled mixture is filtered, and the solvent is removed in vacuum to obtain 8.8 g of a bluish-gray solid.

A 0.75 g sample bluish-gray solids mixed with hot water, and the resulting solid is collected by filtration, dried in vacuo and crystallized from 2-propanol with the receipt of 0.13 g of gray solid [A] with a melting point of 176 - 180oC.

Other 8,05 g bluish-gray solids suspended in water and the product extracted 5 times with ethyl acetate, taken in an amount of 100 ml, the Extracts washed with water, dried over magnesium sulfate, and the solvent is removed in vacuum to obtain 5.0 g of a light brown solid with a melting point of 167 - 172oC, which is crystallized from 60 ml of 2-propanol. You get a 2.5 g is iesa after crystallization, evaporated, and the residue is crystallized from 10 ml of 2-propanol to obtain 0.5 g of a light brown solid [V] with a melting point of 176 - 180oC.

Products [A] , [B] and [B] together with the receipt of 3.1 g of 1-(2-methoxyphenyl)piperidine-4-carboxamide.

4 ml of a 10 m solution of the complex of borane and dimethyl sulfide in the dimethyl sulfide is added dropwise at a temperature of 15 - 20oC in nitrogen atmosphere served in a mixed solution of 2.6 g of 1-(2-methoxyphenyl)piperidine-4-carboxamide in 25 ml of tetrahydrofuran, and stir the mixture heated under reflux for 6 hours. The mixture is left to stand at room temperature for 16 hours, then the reaction stopped by slowly feeding the reaction mixture dropwise into an excess of ice and water. The aqueous mixture is acidified with 5-m hydrochloric acid, then alkalinized a 5 m aqueous solution of sodium hydroxide and the product extracted with diethyl ether. The extracts washed with water, then the product is extracted three times with 5-m hydrochloric acid, twice taken in an amount of 100 ml and once with 50 ml. of Acid extracts alkalinized a 5 m aqueous solution of sodium hydroxide and the product extracted with diethyl ether. The extracts are dried over the tov by chromatography on silica gel using as eluent a mixture of diethyl ether and methanol in the ratio 9:1. Silica gel is suspended in methanol, the mixture is heated under reflux for 10 minutes, allowed to cool and filtered. The solvent is removed in vacuum to obtain 0.65 g of 1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine in the form of butter.

A mixture of 0.65 g of 1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine, 0.95 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate (obtained similar to example 1 reception), 0.8 g of potassium carbonate, 0.01 g of potassium iodide and 20 ml of acetonitrile is stirred and heated under reflux for 20 hours, then filtered.

The solvent is removed in vacuum to obtain 1 g of oil, which is purified by flash chromatography on silica gel under reduced pressure using as eluent a mixture of diethyl ether and methanol in the ratio 9:1. The appropriate fractions are combined, the solvents removed in vacuo to obtain 0.6 g of oil which was dissolved in diethyl ether. The solution is saturated with hydrogen chloride, you get a solid, which is collected by filtration and dried in vacuum to obtain 0.5 g of the dihydrochloride of N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)-piperid-4-yl]methylamine as a white solid with a melting point of 219 - 223oC.

Stir a mixture of 3.5 g obtained in the previous phase oil, 5 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained similar to example 1 reception, 10 g of potassium carbonate and 50 ml of acetonitrile is heated under reflux for 24 hours, the solvent is removed in vacuo, and the residue is diluted with 100 ml of ethyl acetate. The resulting suspension is filtered, the solvent is removed in vacuum to obtain 6.6 g of a brown oil, which was purified by flash chromatography on silica gel using as eluent a mixture of diethyl ether and methanol in the ratio 9:1. The appropriate fractions are combined, the solvents removed in vacuo to obtain two products:

(1) 2.2 g of pale yellow oil, and

(2) 2.2 g of pale yellow oil.

Product (1) is dissolved in 50 ml of diethyl ether and the solution saturated with hydrogen chloride. The resulting solid collected by filtration is esta with a melting point of 241 - 243oC.

Product (2) is treated in a similar reception to obtain 1.9 g of a white solid with a melting point of 250 - 252oC.

Two products as solids are combined and suspended in a mixture of 20 ml ethanol and 20 ml of ethyl acetate. The mixture is heated under reflux for 5 minutes, after which she is allowed to cool to room temperature. The solid is collected by filtration, washed with ethyl acetate and dried in a vacuum at a temperature of 60oC with 3 g of 1,4-hydrochloride N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(3-chloropyrid-2-yl)piperid-4-yl] methylamine as a white solid with melting point: 251 - 253oC.

Example 4. A solution of 2.15 g of 1-(piperid-4-yl)methylamine in 20 ml of ethanol is served in a solution of 3.1 g of 4-chlorination and 6 ml of triethylamine in 50 ml of ethanol. The mixture is stirred at room temperature for 100 minutes, after which the product is collected by filtration, washed with little ethanol and dried in vacuum at a temperature of 60oC with 3 g of solid substance with a melting point of 226 - 227oC. the Solid is ground to powder with 100 ml of hot ethyl acetate, the resulting solid is collected by filtration as a white solid with a melting point of 231 - 232oC.

A solution of 1.2 g obtained in the previous phase solids in 250 ml of water alkalinized a 5 m aqueous solution of sodium hydroxide and the free base extracted with diethyl ether. The extract is dried over magnesium sulfate, and the solvent is removed in vacuum to obtain 1 g of oil.

A mixture of 1 g of the obtained in the previous phase of oil, 1.3 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained similar to example 1 reception, 1.1 g of potassium carbonate and 15 ml of acetonitrile is stirred and heated under reflux for 64 hours, then cooled and filtered. The solid residue was washed with diethyl ether and the filtrate and washing liquid combine. The solvents are removed in vacuo to obtain an orange oil, which was purified by flash chromatography on silica gel under reduced pressure using as eluent a mixture of diethyl ether and methanol in the ratio 9:1.

The appropriate fractions are combined and the solvents removed in vacuo to obtain 1.2 g of oil which was dissolved in diethyl ether. The solution is saturated with hydrogen chloride to obtain solid, which is collected by filtration and dried in vacuum to obtain 1 g b is actor saturated with hydrogen chloride, and the solvent is removed in vacuum. The residue is dissolved in a smaller amount of hot 2-propanol and the solution is allowed to cool to room temperature, and the precipitated mixture of white solid and resin. The mixture is gently heated and pounded into powder using before all brown resin was transferred into a white solid. The mixture is cooled, the solid is collected by filtration, washed with diethyl ether and dried in vacuum to obtain 0.6 g of the dihydrochloride of N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(hinzelin-4-yl)piperid-4-yl] methylamine as a white solid with a melting point of 210 to 216oC.

Example 5. A mixture of 19.4 g of 2-chloropyridine, of 14.25 g of 1-(piperid-4-yl)methylamine, 11.4 g of sodium carbonate and 100 ml of 3-methyl-1-butanol is stirred and heated under reflux for 16 hours, then filtered. The solvent is removed in vacuum to obtain an oil which is distilled to obtain the 5.65 g of 1-[1-(pyrid-2-yl)piperid-4-yl]methylamine in the form of a pale yellow oil boiling within 126 - 130oC/0.6 mbar.

A mixture of 3.4 g of oil, 5,7 r 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained similar to example 1 reception, 4.5 g of potassium carbonate and 45 ml of acetonitrile is stirred by Iconium oil, which is purified by flash chromatography on silica gel under reduced pressure using as eluent a mixture of diethyl ether and methanol in the ratio 9:1. The appropriate fractions are combined and the solvents removed in vacuo to obtain an oil, which was dissolved in diethyl ether. The solution is saturated with hydrogen chloride, you get a solid, which is collected by filtration, washed with diethyl ether and dried in vacuum to obtain the 3.65 g of the dihydrochloride of N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl] methylamine as a white solid with a melting point of 217 - 228oC.

Example 6. A mixture of 10 g of 8-hydroxy-1,4-benzodioxan-2-ylmethanol obtained by the method similar to the one described in U.S. patent N 3101354, 2.2 g of sodium hydroxide and 150 ml of water is stirred for 30 minutes, then cooled to a temperature of 0oC. are added dropwise 3.42 ml methyliodide, after which the mixture is heated to a temperature of 80oC and stirred for 4 hours. The mixture is cooled to room temperature and stirred for 16 hours. The product is extracted twice with ethyl acetate, taken in an amount of 200 ml, the combined extracts washed twice with a saturated solution of tirocinium 6,89 g of 1-(8-methoxy-1,4-benzodioxan-2-yl)methanol as a solid.

A solution of 5.84 g of toluene-4-sulphonylchloride in 10 ml drops of pyridine at a temperature of 10 - 15oC served in a solution of 5.0 g of 1-(8-methoxy-1,4-benzodioxan-2-yl)methanol in 30 ml of pyridine, and the mixture is stirred at room temperature for 20 hours. The mixture is poured onto excess ice and dilute hydrochloric acid. The resulting solid is collected by filtration, washed with water and dried in vacuum, obtaining of 6.61 g of 8-methoxy-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate as a white solid with a melting point of 66 - 68oC.

of 12.53 g of 1-(2-methoxyphenyl)piperidine-4-carboxamide, obtained by a similar technique to the method described in example 2, the portions served in a mixed suspension 4,36 g of lithium aluminum hydride in 900 ml of tetrahydrofuran in a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 72 hours. Add 5 ml of 5 m aqueous solution of sodium hydroxide and 5 ml of water, and the resulting solid removed by filtration. The solvent is removed from the filtrate in vacuo, and the residue is dissolved in 500 ml of ethyl acetate. The organic phase is twice washed with water, taken in an amount of 300 ml, dried over magnesium sulfate, and the solvent is removed in vacuum with receipt is the mixture of ethyl acetate and methanol in the ratio of 1:1. The silica gel from the column is suspended in methanol, and the mixture is heated under reflux for 3 hours, filtered, and the solvent is removed in vacuum to obtain 4.8 g of 1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine as a light brown oil.

Stir a mixture of 1.12 g of 8-methoxy-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate, 0.7 g of 1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine, 1 g of potassium carbonate and catalytic amounts of potassium iodide in 50 ml of acetonitrile is heated under reflux for 120 hours. The solvent is removed in vacuo, and the residue is dissolved in 100 ml of ethyl acetate. The solution was washed with 50 ml water and the product extracted three times with 5-m hydrochloric acid, taken in an amount of 70 ml of the Acid extracts are combined, washed with 50 ml of diethyl ether, alkalinized a 5 m aqueous solution of sodium hydroxide and extracted three times with ethyl acetate, taken in an amount of 200 ml Organic extracts are combined, dried over magnesium sulfate, and the solvent is removed in vacuum with the receipt of 0.85 g of light brown oil, which was dissolved in 30 ml of diethyl ether. In the solution serves the flow of gaseous hydrogen chloride. The resulting solid is collected by filetreepanel)piperid-4-yl] methylamine as a white solid with a melting point of 160oC (Razlog.)

Example 7. A mixture of 7.25 g of potassium carbonate and 200 ml of dimethylformamide is treated with ultrasound before getting muddy, containing the smallest particles in suspension. Added 5.8 g of catechin and 10 g of (R)-glycidyl-toluene-4-sulfonate, and the resulting mixture is stirred and heated at a temperature of 60oC for 36 hours. The mixture is allowed to cool, after which she served in 200 ml ice water and the product extracted three times with diethyl ether, taken in an amount of 300 ml combined extracts washed three times with brine, taken in an amount of 200 ml, dried over magnesium sulfate, and the solvent is removed in vacuo to obtain 7 g of white solid. The solid is crystallized from a mixture of ethyl acetate and petroleum ether beyond boiling point 40 - 60oC, you get a 3,47 g (S)-1,4-benzodioxan-2-ylmethanol as a white crystalline substance.

of 4.2 g of toluene-4-sulphonylchloride at a temperature of -10oC in nitrogen atmosphere served in a mixed solution of 3.3 g of (S)-1,4-benzodioxan-2-ylmethanol in 50 ml of pyridine. Mixture is allowed to warm to room temperature, stirred for another 60 hours, then served in 200 ml of ice water. The product is extracted three times with ethyl acetate, water taken, dried over magnesium sulfate, and the solvent is removed in vacuum. Get of 5.84 g of an orange oil which slowly overdevest. The oil is purified by crystallization from a mixture of diethyl ether and petroleum ether with a boiling within 40 - 60oC, you get two servings of white solids weight of 2.4 g and 1.2, 2.4 g of the obtained solids 3 times recrystallized from ethanol, the content of the desired (R)-isomer of the product in a solid each time becomes smaller, so the solid is not processed further. Royal solutions three recristallization, which is now mostly contain the desired (R)-isomer of the product are pooled, the solvent is removed in vacuo and the residue will recrystallized from ethanol to obtain 1.2 g of (R)-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate in the form of white crystals with a melting point of 105 - 107oC.

Stir a mixture of 0.84 g of 1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine obtained analogous to example 2 reception, 1.2 g of (R)-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate, 1 g of potassium carbonate and catalytic amounts of potassium iodide in 50 ml of acetonitrile for 90 hours, heated under reflux. The solvent is removed in vacuo, and the residue of razbam is 70 ml, the extracts are combined and alkalinized a 5 m aqueous solution of sodium hydroxide. The product is extracted three times with ethyl acetate, taken in an amount of 150 ml, the combined extracts washed twice with water, taken in an amount of 100 ml, dried over

magnesium sulfate, and the solvent is removed in vacuum. The residue is purified by flash chromatography on silica gel using ethyl acetate as eluent. The appropriate fractions are combined and the solvent is removed in vacuum to obtain a yellow oil, which crystallized when left to stand. The product is then recrystallized from ethyl acetate, thus receive 0,41 g (S)-(-)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine as light brown crystals with a melting point of 78 - 79oC []2D5-27,0o(C = 1,0, dichloromethane).

Example 8. 8 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained similar to example 1 reception portions over 30 minutes at a temperature of 100 - 140oC served in a solution of 4.9 g of N-[3-(trifluoromethyl)pyrid-2-yl]academia in 36 ml of xylene, the mixture is stirred at a temperature of 140oC for 6 hours and left to stand at room temperature for 48 hours.

With the magnesium, and the solvents removed in vacuo to obtain 7.4 g of a brown oil, which was purified by flash-chromatography under reduced pressure over silica gel using ethyl acetate as eluent. The appropriate fractions are combined and the solvent is removed in vacuum to obtain two fractions brown oil (fraction 1 - 1.35 g; fraction 2 - 0.6 g).

1.35 g of fraction 1 was dissolved in diethyl ether, the solution is saturated with hydrogen chloride to obtain solid, which is collected by filtration, suspended in 2-propanol for 5 minutes, heated under reflux, cooled, collected by filtration, washed with ethyl acetate and dried in a vacuum at a temperature of 40oC, you get a 1.4 g of beige solid with a melting point of 220 - 224oC.

0.6 g of fraction 2 was dissolved in diethyl ether and the solution saturated with hydrogen chloride to obtain solid, which is collected by filtration and dried in vacuum at a temperature of 45oC, you get a 0.7 g of brown solid. The solid is suspended in ethyl acetate for 5 minutes, heated under reflux, cooled, collected by filtration, suspended in propan-2-OLE what Etat and dried in a vacuum at a temperature of 45oC, you get a 0.55 g of beige solid with a melting point of 220 - 224oC.

Two portions of the resulting solids unite, pounded into powder and dried in vacuum to obtain 1.75 g of the dihydrochloride of N-(1,4-benzodioxan-2-ylmethyl)-N'-[3-(trifluoromethyl)-2-(pyridyl)] academia as a beige solid with a melting point of 222 - 224oC.

Example 9. 120 ml dimethylsulfate at a temperature of 70oC in nitrogen atmosphere for 1 hour dropwise serving stir in a mixture of 100 g of 1,6-dioxynaphthalene, 75 g of sodium hydroxide and 600 ml of water. The mixture is stirred at a temperature of 70oC for another 3 hours. Additionally serves 30 ml dimethylsulfate, and the mixture is stirred at room temperature for 16 hours, after which the mixture is diluted with 1000 ml of water. Product three times extracted with diethyl ether, taken in an amount of 500 ml, the extracts washed three times with water, taken in an amount of 500 ml, dried over magnesium sulfate, and the solvent is removed in vacuum. The residue is distilled to obtain 95 g of 1,6-dimethoxyaniline as oil boiling within 100 - 130oC/0.6 mbar, which, when left to stand, cures at room temperature.

220 ml of 2.5 is th solution of 95 g of 1,6-dimethoxyaniline in 1000 ml of tetrahydrofuran. Add 150 ml of N,N,N',N'-tetramethylethylenediamine, the mixture is stirred at room temperature for 20 hours, then cooled to a temperature of -20oC and poured onto 500 g of solid carbon dioxide. Upon completion of gas evolution, the mixture is diluted with 1000 ml of water, alkalinized 100 g of sodium carbonate, washed twice with diethyl ether, taken in an amount of 100 ml, and acidified with concentrated hydrochloric acid. The product is extracted with ethyl acetate, the extracts washed with brine, dried over magnesium sulfate, and the solvents removed in vacuo. The residue is crystallized from ethyl acetate to obtain solid, which is collected by filtration, dried under vacuum and triturated with getting 45.6 g of 3,8-dimethoxy-2-naphthoic acid in the form of a beige powder with a melting point of 151 - 153oC. When the concentration of the liquid receive the second portion of 5.4 g of 3,8-dimethoxy-2-naphthoic acid.

1.2 g of lithium in the form of a wire with a length of 27 cm and a diameter of 3.2 mm in small portions served in stir a mixture of 5 g of 3,8-dimethoxy-2-naphthoic acid, 45 ml of tetrahydrofuran, 10 ml of t-butanol and 130 ml of liquid ammonia until the blue colour remains within 5 minutes. Add 10 g of ammonium chloride and the ammonia give evaporate. Stateu, dried over magnesium sulfate, and the solvents removed in vacuo to obtain a yellow solid, which crystallized from aqueous methanol as 3.2 g of 8-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid in the form of shiny, yellowish tiles with a melting point of 136 to 138oC.

Above the reception is repeated with the use of 46 g of 3,8-dimethoxy-2-naphthoic acid, 400 ml of tetrahydrofuran, 100 ml of t-butanol, 1200 ml of liquid ammonia and 11 grams of lithium in the form of a wire with a length of 250 cm and a diameter of 3.2 mm Get 29,35 g of the product as yellowish tiles.

A solution of 5 g of 8-methoxy-1,2,3,4-tetrahydronaphthalen-2-carboxylic acid in 50 ml of tetrahydrofuran in a nitrogen atmosphere heated to boiling temperature, and added dropwise 5 ml of a 10 m solution of the complex of borane and dimethyl sulfide in dimethyl sulfide. The mixture for 5 hours gently heated under reflux, after which it was allowed to stand at room temperature for 16 hours, cooled on ice and stop the reaction by careful addition of water. The mixture is acidified with 5-m hydrochloric acid, heated for removing dimethyl sulfide, cool, alkalinized 5-molar aqueous solution of sodium hydroxide, and the product extragere the g 1-(8-methoxy-1,2,3,4-tetrahydronaphtyl-2-yl)methanol as a pale yellow syrup, which at room temperature slowly hardens.

A solution of 1.3 g of toluene-4-sulphonylchloride 1.4 ml of pyridine is added dropwise served in a mixed solution of 1.0 g of 1-(8-methoxy-1,2,3,4-tetrahydronaphtyl-2-yl)-methanol (2.4 ml of pyridine, and the mixture is stirred for 64 hours at room temperature and for 4 hours at a temperature of 35 - 52oC. the Mixture is poured into ice water and the product extracted with dichloromethane. The extracts are washed with ice cold 5-m hydrochloric acid and ice cold water, then dried over magnesium sulfate. The solvents are removed in vacuo obtaining of 1.15 g of orange oil.

Above the reception is repeated with the addition of a solution of 2.75 g of toluene-4-sulphonylchloride in 3.0 ml of dry pyridine in a solution of 2.2 g of alcohol in 5,15 ml of pyridine. The mixture is stirred for 6 hours at a temperature of 35 - 50oC, leave to stand over night at room temperature, and treated with the above-described technique of obtaining 2.8 g of orange oil.

The resulting orange oil weighing only 3,95 g are combined and dissolved in 75 ml of pyridine. Add a solution of 4.1 g of toluene-4-sulphonylchloride 4.5 ml of pyridine, the mixture is stirred at room temperature for 24 hours and under the oC, and the mixture is ground to powder before complete curing of the product. The solid is collected by filtration, washed with water and petroleum ether with a boiling within 40 - 60oC, and dried in a vacuum at a temperature of 45 - 50oC, to obtain 2.9 g of 8-methoxy-1,2,3,4-tetrahydronaphtyl-2-ylmethyl-toluene-4-sulfonate in the form of a solid substance with a melting point of 53 - 58oC.

of 15.4 g of fine powder of 2-chloropyrimidine for 40 minutes servings serves in hot, having a temperature of 95oC, stir a mixture of 30 g of 1-(piperid-4-yl)methylamine, 30 g of sodium carbonate and 100 ml of 3-methyl-1-butanol. The mixture is stirred at a temperature of 95oC for 18 hours, cooled, diluted with ethyl acetate and filtered. The solvents are removed in vacuo to obtain a dark brown oil, which is subjected to distillation to obtain 12.2 g of pale yellow oil boiling within 126-130oC/1 mbar. The oil was dissolved in diethyl ether and the solution saturated with hydrogen chloride. Add the ethanol, and the mixture is ground to powder to obtain solid, which is collected by filtration, washed with diethyl ether and dried in vacuum at 40 ° oC with the receipt of 9.75 g of the dihydrochloride of 1-[1-(pyrimidine-2-yl)pedicellaria 1-[1-(pyrimidine-2-yl)piperid-4-yl] methylamine alkalinized 5) aqueous solution of sodium hydroxide and the free base extracted twice with ethyl acetate, taken in an amount of 25 ml of the Extracts washed with water, dried over magnesium sulfate, and the solvents removed in vacuo to obtain 1.6 g of orange oil. Butter one portion served in a mixture of 2.9 g of 8-methoxy-1,2,3,4-tetrahydronaphtyl-2-ylmethyl-toluene-4-sulfonate, 2.5 g of potassium carbonate and 25 ml of acetonitrile, the mixture is stirred and heated under reflux in nitrogen atmosphere for 30 hours. The mixture is allowed to cool, filtered, and the filter cake washed with acetonitrile. The filtrate and washing liquid are combined and the solvent is removed in vacuum to obtain 3.2 g of orange oil.

The oil is purified by flash-chromatography under reduced pressure on silica gel using as eluent a mixture of diethyl ether and methanol in the ratio 9:1. The appropriate fractions are combined and the solvent is removed in vacuum to obtain 2.1 g of a yellow oil.

The oil was dissolved in 20 ml of 2-propanol and add 5 ml of concentrated hydrochloric acid. The solvent is removed to obtain a very hygroscopic solid, which is suspended in a 5 m aqueous solution of the hydroxide nvoy acid in 10 ml of methanol. The resulting solution was diluted with ethyl acetate and concentrated under reduced pressure until precipitation of a white solid. The solid is collected by filtration and crystallized from 50 ml of a mixture of ethyl acetate and denatured alcohol in the ratio of 4:1, you get a 1.1 g of a white solid with a melting point of 184 - 186oC, represents N-(8-methoxy-1,2,3,4-tetrahydronaphtyl-2-ylmethyl)-1-[1-(pyrimidine-2-yl)piperid-4-yl]methylamine in the form of 1,1-instead of the expected hydrochloride salt of fumaric acid.

Example 10. Recrystallization of the liquid remaining after the separation of the product described in example 9, again alkalinized a 5 m aqueous solution of sodium hydroxide and the free base extracted with ethyl acetate. The extracts washed with water, dried over magnesium sulfate, filtered, and the solvents removed in vacuo to obtain 0.35 g of N-(8-methoxy-1,2,3,4-tetrahydronaphtyl-2-yl-methyl)-1-[1-(pyrimidine-2-yl)piperid-4-yl]methylamine as a brown oil. The oil is dissolved in 14 ml of dichloromethane, and in the atmosphere of nitrogen added to 3.5 ml of 1 m solution trichromate boron in dichloromethane. The mixture is stirred under nitrogen atmosphere at room temperature for 24 hours, then add 5 ml of methanol. The mixture perei atmospheric pressure to obtain a green oil, which is grinded into powder with hot 2-propanol, you get 0.5 g of a pale brown solid with a melting point of 85 - 90oC.

When you try crystallization from a mixture of denatured alcohol and ethyl acetate in the ratio 1:2 are resin. In the result of desantirovaniya supernatant and titration of the residue with acetone receive solid, which is collected by filtration and dried in vacuum to obtain 0.14 g of dihydrobromide 7-{ N-[1-(pyrimidine-2-yl)piperid-4-ylmethyl]aminomethyl}-5,6,7,8-tetrahedronal-1-ol as a pale brown solid with a melting point of > 110oC (Razlog.)

Example 11. A mixture of 50 g of 3-methoxyphenol, 60 ml of etilenovogo ether, 250 ml of dichloromethane and 1.3 g of trichloroacetic acid was stirred at room temperature for 20 hours, diluted with 1000 ml of diethyl ether, washed twice with 0.5-m aqueous solution of sodium hydroxide, taken in an amount of 100 ml and once with 100 ml brine, dried over potassium carbonate and the solvent is removed in vacuum. Get 3-(1-ethoxyethoxy)anisole, which is used without further purification.

3-(1-ethoxyethoxy)anisole are dissolved in 750 ml of diethyl ether, and drops at room temperature is the temperature for 2 hours, cooled to a temperature of 10oC and drops add a solution of 94 g of dimethylformamide and 150 ml of diethyl ether. The mixture is stirred at room temperature for 2 hours, then poured on ice. The product is extracted with diethyl ether, the combined extracts dried over magnesium sulfate, and the solvents removed in vacuo. The residual oil is dissolved in 500 ml of methanol, and mix the solution is cooled in ice and strongly acidified with 2-m hydrochloric acid. The resulting solid is collected by filtration, washed with water, dried in vacuum over pjatiokisi phosphorus and crystallized from petroleum ether with a boiling within 60 - 80oC, you get a 16 g of 2-hydroxy-6-methoxy-benzaldehyde as a pale yellow needle-like substances with a melting point of 69 - 71oC.

The whole process is repeated using as the starting material of 111.2 g of 3-methoxyphenol. In the second stage of the process before adding ice, the reaction mixture is stirred for 16 hours at room temperature. As a result of crystallization from petroleum ether with a boiling within 40 - 60oC receive the product as the two parties pale yellow needle-like substances. Two parties unite, reki is elegida in the form of pale yellow needle-like substances.

The mixture 29,2 g 2-hydroxy-6-methoxybenzaldehyde, 7.5 g of 1,4-diazabicyclo[2.2.2] -octane and 100 ml of ethyl acrylate for 16 hours, heated at a temperature of 95oC. the Mixture is diluted with 500 ml of ethyl acetate, cooled to room temperature, washed twice with a saturated aqueous solution of sodium bicarbonate, taken in an amount of 100 ml, twice - 5-m hydrochloric acid, taken in an amount of 100 ml and twice with water, taken in an amount of 100 ml, dried over magnesium sulfate, and the solvent is removed in vacuum to obtain a brown oil.

The oil is dissolved in 500 ml of ethanol, and add 30 g of potassium hydroxide and 500 ml of water. The mixture is heated for 3 hours under reflux and allowed to stand at room temperature for 16 hours. The mixture is diluted with water, washed twice with diethyl ether, taken in an amount of 200 ml, and the concentrated hydrochloric acid is acidified to pH 1. Precipitated solid, which is collected by filtration, washed with water and ground to powder using diethyl ether, thus obtain 4.3 g of a pale brown solid. The viscous residue from the titration allowed to clot for 16 hours at room temperature, thus get another 0.9 for SVT-2H-1-benzopyran-3-carboxylic acid of melting point 209 - 211oC.

The mixture 12,25 g 5-methoxy-2H-1-benzopyran-3-carboxylic acid obtained by the method similar to the one described above, 3 g of 10% palladium on coal as a catalyst, and 250 ml of ethanol hydronaut at a pressure of 1 ATM for 1 hour. The absorption of hydrogen is carried out only slowly, so add another 3 g of the catalyst, and the hydrogenation continued for 5 hours. The mixture is filtered, and the solvent is removed in vacuo to obtain a semi-solid substance, which was crystallized from 2-propanol, you get a mass of pale yellow crystals, which izmenchivost, collected by filtration, washed with cold as ice 2-propanol, dried in vacuum, ground to powder, and dried again in a vacuum with the receipt of 7.4 g of 5-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid as a yellowish powder with a melting point of 147 - 150oC.

1 ml of 1 m solution of the complex of borane and dimethyl sulfide in dimethyl sulfide at room temperature in a nitrogen atmosphere served in a mixed solution of 1.0 g of 5-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid in 10 ml of tetrahydrofuran, and the mixture is heated for 5 hours under reflux, and then for 16 hours her leave to stand p is added dropwise water until the gas evolution stops, after which the mixture is acidified with 5-m hydrochloric acid and heated to a temperature of approximately 95oC with removal of dimethyl sulfide. The mixture is cooled on ice and alkalinized a 5 m aqueous solution of sodium hydroxide. The product is extracted with ethyl acetate, the extracts washed with saturated saline and dried over magnesium sulfate. The solvents are removed in vacuo to obtain 1 g of 1-(5-methoxy-3,4-dihydro-2H-1-benzopyran-3-yl)methanol as a pale yellow oil.

The above reaction is repeated using the remaining 6.0 g of 5-methoxy-3,4-dihydro-2H-1-benzopyran-3-carboxylic acid in 60 ml of tetrahydrofuran and 6 ml of the complex of borane and dimethyl sulfide. You get more of 5.6 g of 1-(5-methoxy-3,4-dihydro-2H-1-benzopyran-3-yl)methanol.

A solution of 8.1 g of toluene-4-sulphonylchloride in 9 ml of pyridine is added dropwise at room temperature and added to a solution of 6.5 g of 1-(5-methoxy-3,4-dihydro-2H-1-benzopyran-3-yl)methanol 15.2 ml of pyridine, after which the mixture is stirred for 3 hours at room temperature and left to stand for 16 hours at room temperature. Add 2.0 g of toluene-4-sulphonylchloride, the mixture is stirred at room temperature for 6 hours and left to stand for 72 kagerou with ethyl acetate. The extracts are washed with ice cold water, dried over magnesium sulfate, and the solvent is removed in vacuum to obtain 6.6 g of a yellow oil which is dissolved in 50 ml of dichloromethane. Add to 3.35 g of 4-(dimethylamine)pyridine. The solution is cooled to a temperature of 0oC, and one portion add 4.8 g of toluene-4-sulphonylchloride. The mixture is stirred at a temperature of 0oC, while toluene-4-sulphonylchloride soluble, then stop cooling, and the solution was stirred at room temperature for 16 hours. The mixture was vacuum concentrated to a volume of 20 ml, then diluted with ethyl acetate, thus precipitated white solid. The mixture is filtered, the filtrate is diluted with additional ethyl acetate to obtain a second batch of solids, and again filtered. The filtrate of the second batch is left to stand at room temperature for 72 hours to obtain a third precipitate solids, and again filtered. The solvents are removed in vacuo to obtain 7.0 g of 5-methoxy-3,4-dihydro-2H-1-benzopyran-3-ylmethyl-toluene-4-sulfonate as a yellow oil which is used without further purification.

A mixture of 7.0 g of 5-methoxy-3,4-dihydro-2H-1-benzopyran-3-ylmethyl-toluene-4-sulfonate, 5.6 g of potassium carbonate is Ilumina, obtained analogous to example 9. The mixture is stirred and heated under reflux in nitrogen atmosphere for 24 hours, after which the mixture is allowed to cool and filtered. The filter pad washed with acetonitrile, and the filtrate and washing liquid combine. The solvent is removed in vacuum to obtain 7.5 g of an orange oil, which was purified by flash-chromatography under reduced pressure over silica gel using as eluent a mixture of diethyl ether and methanol in the ratio 9:1. The appropriate fractions are combined and the solvents removed in vacuo to obtain two fractions of the oil in the form of 3.6 g of product with a small amount of impurities, and 1.5 g of pure product.

1.5 g of the obtained oil is dissolved in 40 ml of ethyl acetate and served in a solution of 0.45 g of fumaric acid and 20 ml of denatured alcohol. The resulting solution was diluted with ethyl acetate to a total volume of 100 ml and cooled to a temperature of 0oC. the resulting precipitate is collected by filtration, washed with ethyl acetate and dried in vacuum to obtain 1.5 g of N-(5-methoxy-3,4-dihydro-2H-1-benzopyran-3-ylmethyl)-1-[1-(pyrimidine-2-yl)piperid-4-yl] -methylamine in the form of monopolarity as white solids with technochange analogous to example 2 reception 35 ml of aniline and 1 l of methanol was stirred at room temperature for 48 hours. The resulting suspension for 1 hour, heated at a temperature of 50oC, cooled, and the solvent is removed in vacuum. The solid residue double-pounded into powder with acetone, taken in an amount of 1 liter, and then collected by filtration to obtain 33,24 g chloride 4-carbarnoyl-1-phenylpyridine with a melting point of 290 - 292oC.

A mixture of 13 g of the chloride of 4-carbarnoyl-1-phenylpyridine, 260 mg of 10% palladium on coal as a catalyst and 250 ml of ethanol hydronaut at room temperature and atmospheric pressure for 2 days. The solution is filtered on the silicate brand Celite and the filtrate concentrated to a volume of about 50 ml. of the Solution is cooled and the solid precipitate collected by filtration to obtain of 5.99 g 1-phenylpiperidine-4-carboxamide.

Consisting of Celite filter pad washed thoroughly with hot ethanol, and the solvent is removed in vacuum. The remainder unite with that obtained in the above stage of the filtrate, and the mixture for 0.5 hours, heated under reflux. Saducees upon further cooling, the solid is collected by filtration to obtain more of 3.42 g of 1-phenylpiperidine-4 is needful suspension of 0.5 g of lithium aluminum hydride in 100 ml dry tetrahydrofuran in a nitrogen atmosphere. The resulting suspension was stirred at room temperature for 2 hours, then heated under reflux for 2 hours. The mixture is cooled and successively add 0.5 ml water and 0.5 ml of concentrated sodium hydroxide solution. The resulting precipitate is removed by filtration silicate brand Celite. The filtrate is dried over magnesium sulfate, and the solvent is removed in vacuum with the receipt of 1.15 g of 1-(1-phenylpiperidine-4-yl)methylamine.

The above process is repeated using the starting materials in the above-stated amount, multiplied by the factor 4,33, you get a 5.1 g of 1-(1-phenylpiperidine-4-yl)methylamine.

Stir a mixture of 6 g of 1-(1-phenylpiperidine-4-yl)methylamine, 10,1 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained similar to example 1 reception, 15 g of potassium carbonate and acetonitrile within 72 hours, heated under reflux. The resulting mixture is cooled and filtered. The solvent is removed in vacuo, and the residue is dissolved in ethyl acetate. The solution is filtered on silica gel using as eluent 500 ml of ethyl acetate. The solvent is removed in vacuum. The residue is dissolved in diethyl ether, and the solution serves gaseous hydrogen chloride. Poluchenya in the ratio of 25:1 and again filtered with getting 5,64 g of the dihydrochloride of N-(1,4-benzodioxan-2-yl-methyl)-1-(1-phenylpiperidine-4-yl)methylamine as a white solid with a melting point of 278 - 280oC.

Example 13. A mixture of 3.5 g of 1,4-benzodioxan-5-ylamine (obtained by the method similar to the one described in J. Org. Chem., 1967, 3, page 1121), 6.8 g of chloride 4-carbarnoyl-1-(2,4-dinitrophenyl)pyridinium (obtained analogous to example 2 receive) and 150 ml of methanol is stirred for 16 hours at room temperature. Add 100 ml of methanol, and the resulting mixture heated under reflux for 3 hours, then allowed to stand for 2.5 days at room temperature. Add 0.35 g of 1,4-benzodioxan-5-ylamine, and the mixture is heated under reflux for 24 hours. The solvent is removed in vacuo, and the residue is ground to powder using diethyl ether. The resulting solid is crystallized from a mixture of 2-propanol and ethyl acetate in the ratio of 1:1, you get a pale yellow solid. The solvents in vacuum is removed from the filtrate, and the residue is ground to powder with acetone to obtain additional yellow solid, which unite with those obtained by crystallization of a solid substance thus obtain 3.57 g of a party (1).

A mixture of 3.0 g of 1,4-benzodioxan-5-ylamine, 5.8 g of chloride 4-carbarnoyl-1-(2,4-dinitrophenyl)pyridinium and 150 ml of methanol peremeshayt into powder using diethyl ether. Diethyl ether is decanted, and the solid residue is ground into powder with hot acetone. The resulting mixture is cooled and filtered, you get a lot (2) in the form of 5.30 g of a yellow solid.

Party (1) and (2) are combined and ground to powder with hot acetone. The mixture is cooled and the resulting solid is collected by filtration and dried in vacuum to obtain 8.7 g of the chloride of 1-(1,4-benzodioxan-5-yl)-4-carbamaepine as a yellow solid with a melting point of 256 - 258oC.

1.8 g of 10% palladium on coal as a catalyst in nitrogen atmosphere serves 2.0 g of the chloride of 1-(1,4-benzodioxan-5-yl)-4-carbamaepine. Add 3.5 g of ammonium formate, and with stirring, the resulting mixture dropwise serves 35 ml of methanol. The resulting mixture is heated for 3.5 hours under reflux. The ammonium formate, which crystallizes in the condenser, addition of 35 ml of methanol is recycled to the mixture. The mixture is cooled and filtered on the silicate brand Celite under nitrogen atmosphere. The filtrate is alkalinized with solid sodium bicarbonate, and the solvent is removed in vacuum. The residue is diluted with 100 ml water and the product extracted three times with dichloromethane, taken in the quantity out in vacuum to obtain 1.27 g of 1-(1,4-benzodioxan-5-yl)piperidine-4-carboxamide as a white solid with a melting point of about 194oC.

A mixture of 4.1 g of 1-(1,4-benzodioxan-5-yl)piperidine-4-carboxamide, obtained above, and 400 ml of tetrahydrofuran dropwise serving stir in a mixture of 1.2 g of lithium aluminum hydride in 100 ml of tetrahydrofuran in a nitrogen atmosphere. The resulting mixture is stirred for 2 hours at room temperature. Add 0.4 g of lithium aluminum hydride, and the resulting mixture is stirred for another 1.5 hours.

Add 3 ml water and 3 ml of concentrated sodium hydroxide solution, the mixture is stirred for 15 minutes and filtered on the silicate brand Celite.

The Celite pad washed with ethyl acetate. The filtrates are combined and the solvents removed in vacuo. The residue is dissolved in dichloromethane, the solution is dried over magnesium sulfate, filtered, and the solvent is removed in vacuum to obtain 4,19 g of 1-[1-(1,4-benzodioxan-5-yl)piperid-4-yl]methylamine as an orange oil which is used without further purification.

The mixture 4,19 g orange oil, 5.0 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained similar to example 1 reception, 4,32 g of potassium carbonate and 100 ml of acetonitrile is stirred at reflux for 30 hours, after which the mixture leaves the mind to obtain 8.0 g of orange oil.

The resulting oil purified by flash chromatography on silica gel, using as eluent consistently using a mixture of petroleum ether with a boiling within 40 - 60oC and ethyl acetate in the ratio of 1:1 mixture of petroleum ether with a boiling within 40 - 60oC and ethyl acetate in the ratio 1:2, ethyl acetate and then methanol. The solvents are removed from the appropriate fractions in vacuo, and 2.7 g of the resulting residue dissolved in a mixture of ethyl acetate and methanol. The solution is saturated with hydrogen chloride, the solvent is removed in vacuo, and the residue is crystallized from a mixture of methanol and ethyl acetate to obtain 2.6 g of the dihydrochloride of N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(1,4-benzodioxan-5-yl)piperid-4-yl] methylamine as a light pink solid with a melting point of 226 - 228oC.

Example 14. Stir a mixture of 0.89 g of 1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine obtained analogous to example 2 reception, 1.3 g (S)-1,4-benzodi-oxan-2-ylmethyl-toluene-4-sulfonate, 1 g of potassium carbonate and a few crystals of potassium iodide in 50 ml of acetonitrile within 72 hours, heated under reflux. The solvent is removed in vacuo, add 50 ml water and the product extracted three times with ethyl acetate, made Aut in vacuum. The product was then purified by flash chromatography on silica gel using ethyl acetate as eluent. The appropriate fractions are combined and the solvent is removed in vacuum, thus receive 0,69 g of a white crystalline solid. Solid 6 times recrystallized from ethanol to obtain 0.4 g of (R)-(+)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine with melting point is 79 - 82oC. []2D6= +25,6o(C = 1,0; dichloromethane).

Example 15. A mixture of 20.0 g of 2-(chloromethyl)-1,4-benzodioxane and 34,04 g ethyl-piperidine-4-carboxylate are stirred and heated at a temperature of 130oC for 3.5 hours. Upon cooling, the mixture is partially cured. Add 100 ml water and the product extracted three times with ethyl acetate, taken in an amount of 100 ml combined extracts dried over magnesium sulfate, filtered, and the solvent is removed in vacuum to obtain 35 g of a brown oil, which was purified by distillation to Kugeler. The fraction obtained after heating to a temperature of 250oC/5.3 mbar represents 31,5 g complex ethyl ester 1-(1,4-benzodioxan-2-ylmethyl)piperidine-4-carboxylic acid.

A solution of 5 g of complex ethyl ester 1-(1,4-benzodioxane in 50 ml of water. The mixture is stirred at room temperature for 1 hour, then heated for 6 hours under reflux. The solution is cooled, and the solvent is removed in vacuum. The residue is diluted with water, then neutralized with diluted hydrochloric acid. The product is extracted with ethyl acetate, and the extract is dried over magnesium sulfate. The solvent is removed in vacuum to obtain 0.28 g of crude 1-(1,4-benzodioxan-2-ylmethyl)piperidine-4-carboxylic acid. The aqueous phase is evaporated to dryness, and the residue twice pounded into powder using a mixture of dichloromethane and methanol in the ratio of 25:1, taken in an amount of 100 ml Inorganic residue is removed by filtration, and the solvent removed from the filtrate in vacuo to obtain more of 5.03 g of crude desired product which is used without further purification.

0.1 g of a complex of ethyl ether of Harborview acid dropwise served in a mixed solution of 0.28 g of 1-(1,4-benzodioxan-2-ylmethyl)piperidine-4-carboxylic acid and 0.12 g of triethylamine in 10 ml of chloroform at a temperature of 0oC. After 30 minutes, add a solution of 0.12 g of 2-methoxyaniline in 5 ml of chloroform, and the mixture is stirred at room temperature for 16 hours. The reaction mixture of posledovati dried over magnesium sulfate, the solvent is removed in vacuo, and the residue is subjected to elution on silicagel column using as eluent a mixture of petroleum ether with a boiling within 40 - 60oC and ethyl acetate in the ratio of 1: 1. The solvent is removed in vacuum to obtain 50 mg of 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide as a solid. The process described here is repeated with the use of original substances, taken in the above amount, multiplied by a factor of 9, with the following changes: after stirring at room temperature for 16 hours, the reaction mixture for 1 hour, heated to a temperature of 50oC. the Solvent is removed in vacuo, and the residue on silica gel elute as described above. You get more of 1.05 g of the target product.

0.5 ml of a 10 m solution of the complex of borane and dimethyl sulfide in the dimethyl sulfide is added dropwise in a nitrogen atmosphere served in a solution of 0.35 g of 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide in 25 ml of dry tetrahydrofuran, then the mixture for 2 hours, heated under reflux. The reaction mixture is cooled, and the solvents removed in vacuo. The resulting residue is carefully diluted with 70 ml of 1 m chlorotoluron is. the one solution of sodium hydroxide, after which the product is extracted with dichloromethane. The organic extract was washed with water, dried over magnesium sulfate, filtered, and the solvent is removed in vacuum to obtain 0.32 g of 1-[1-(1,4-benzodioxan-2-ylmethyl)piperid-4-yl] -N-(2-methoxyphenyl)methylamine. The process is repeated with the use of 1.37 g of 1-(1,4-benzodioxan-2-ylmethyl)-N-(2-methoxyphenyl)piperidine-4-carboxamide, obtained similarly as described above reception. The products of the two reactions are combined and dissolved in diethyl ether. In the solution serves gaseous hydrogen chloride, and 1.2 g of the resulting solid precipitate is collected by filtration. The solid is dissolved in 100 ml saturated aqueous sodium bicarbonate solution, and the resulting oil is extracted with ethyl acetate, taken in an amount of 100 ml Add an excess of a saturated solution of oxalic acid in ethyl acetate, the solid precipitate is collected by filtration and dried in vacuum at a temperature of 50oC obtaining 0,78 g of 1-[1-(1,4-benzodioxan-2-ylmethyl)piperid-4-yl]-N-(2-methoxyphenyl)methylamine in the form of mono-oxalate with a melting point of 215 - 218oC.

Example 16. A mixture of 50 g of the chloride of 4-carbarnoyl-1-(2,4-dinitrophenyl) pyridinium obtained analogous to example 2 method, 40 g of 4-Mitel removed in vacuum, and the residue is ground to powder using 1200 ml of hot diethyl ether. The suspension is cooled and filtered to obtain and 67.2 g of solid gold color. Solid will recrystallised of 1500 ml of denatured alcohol, you get a 45.6 g of dark yellow crystals. In the denatured alcohol is served diethyl ether and the resulting solid collected by filtration to obtain 3 g of the chloride of 4-carbarnoyl-1-(4-methoxyphenyl)pyridinium. 45.6 g of crystals suspended in 500 ml of acetone, and the mixture is heated under reflux for a few minutes, after which the mixture is filtered. The obtained solid substance for 16 hours and extracted with acetone in a Soxhlet extraction apparatus, removing neproreagirovavshimi original products. The resulting solid is dried in vacuum to obtain more of 31.8 g of chloride 4-carbarnoyl-1-(4-methoxyphenyl)pyridinium. Total yield: 34,8,

A suspension of 22.0 g of the chloride of 4-carbarnoyl-1-(4-methoxyphenyl)pyridinium 250 ml of methanol in the presence of 1.0 g of 10% palladium on coal as a catalyst for 2 days at room temperature and atmospheric pressure is subjected to hydrogenation. Add 0.75 g of catalyst, and after the hydrogenation can produce the t in vacuum. The residue is partitioned between water and a mixture of chloroform and methanol in a ratio of 19:1. The solvent from the organic phase removed in vacuo, and the residue is dried in vacuum over pjatiokisi phosphorus. You get 10 g of 1-(4-methoxyphenyl)piperidine-4-carboxamide as a white solid with a melting point of 178 - 181oC. 15 ml of a 10 m solution of the complex of borane and dimethyl sulfide in the dimethyl sulfide is added dropwise at a temperature of 15 - 20oC in nitrogen atmosphere serves to stir a suspension of 10 g of 1-(4-methoxyphenyl)piperidine-4-carboxamide in 95 ml of tetrahydrofuran. The mixture is heated for 4 hours under reflux, after which it was allowed to stand at room temperature for 16 hours. Add ice water to destroy excess reducing agent, after which the mixture is acidified with 5-m hydrochloric acid and washed with 200 ml of diethyl ether. The aqueous phase is alkalinized with concentrated aqueous solution of sodium hydroxide, after which the product three times extracted with diethyl ether, taken in an amount of 250 ml combined extracts dried over magnesium sulfate and the solvent is removed in vacuum. The residue is purified by flash chromatography on silica gel using as eluent dare in vacuum, thus obtain 0.5 g of 1-[1-(4-methoxyphenyl)-piperid-4-yl]methylamine as oil.

Stir a mixture of 0.42 g of 2-chloromethyl-1,4-benzodioxan, 0.5 g of 1-[1-(4-methoxyphenyl)piperid-4-yl] methylamine, 1.0 g of potassium carbonate in 50 ml of acetonitrile is heated under reflux for 7 hours. Type of 0.32 ml of triethylamine, and stirring is continued at reflux for 6 hours. Added 0.73 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained similar to example 1, and the mixture is stirred for 7 hours while heating under reflux. The solvent is removed in vacuum to obtain a yellow oil, which was purified by flash chromatography on silica gel using as eluent first dichloromethane and then a mixture of dichloromethane and denatured alcohol in a ratio of 19:1. Productstream fractions are collected, and the solvents removed in vacuo to obtain 0.20 g of butter gold color. The oil is dissolved in 50 ml of diethyl ether, and the solution serves gaseous hydrogen chloride. The resulting white solid is collected by filtration, washed with diethyl ether and immediately dried in vacuum, thus receive of 0.13 g of the dihydrochloride of N-(1,4-benzodia. peremeshivaemogo mixture of 26.8 g of N-(3-bromopropyl)phthalimide, and 24.6 g of 2 - methoxy-aniline and 60 ml of xylene for 4 hours, heated at a temperature of 140oC. After cooling, the solvent is removed in vacuum. A mixture of the obtained oil, 100 ml of denatured alcohol and 6.9 g of hydrazine hydrate for 1 hour with stirring is heated under reflux. The mixture is cooled and acidified with 5-m hydrochloric acid. A white precipitate is removed by filtration, and the solvent removed from the filtrate in vacuo. The residue is dissolved in 15 ml of water and alkalinized a 5 m aqueous solution of sodium hydroxide. The resulting oil is extracted twice with dichloromethane, taken in an amount of 50 ml, the Extracts dried, and the solvent is removed in vacuum to obtain 16.5 g low-viscous red oil. The resulting oil purified by flash chromatography on silica gel, using as eluent consistently applied dichloromethane, a mixture of dichloromethane and denatured alcohol in the ratio of 9: 1, and then methanol. The appropriate fractions are collected and the solvents removed in vacuo to obtain 8.5 g of N-(2-methoxyphenyl)-1,3-propandiamine as a low-viscosity oil is Golden in color.

Stir a mixture of 2.4 g of 8-methoxy-1,4-benzodioxan-2-kataliticheskogo amount of potassium iodide and 1.8 g of potassium carbonate in 120 ml of acetonitrile for 24 hours and heated under reflux. After cooling, the mixture is filtered and the solvent removed from the filtrate under vacuum, thus obtain 3.57 g of reddish oil. The resulting oil purified by flash chromatography on silica gel using as eluent a mixture of dichloromethane and denatured alcohol in a ratio of 19: 1. Productstream fractions are collected and the solvent is removed in vacuum to obtain 1.4 g of a yellow oil. The oil is dissolved in 50 ml of diethyl ether and the solution serves gaseous hydrogen chloride, you get a hygroscopic solid. Oil the solid is collected by filtration and partitioned between dilute aqueous solution of sodium hydroxide and dichloromethane. The organic phase is separated, dried over magnesium sulfate, and the solvent is removed in vacuum to obtain a yellow oil. The resulting oil is dissolved in 50 ml of diethyl ether, and the solution is added dropwise serves an excess of a saturated solution of maleic acid in diethyl ether. The resulting solid is collected by filtration and dried in vacuum to obtain 0.35 g of N-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-N'-(2-methoxyphenyl)-1,3-propandiamine in the form of maleate as a solid substance with a melting point of 59 - 62oC.

A suspension of 26 g of chloride 4-carbarnoyl-1-(3-methoxyphenyl)pyridinium 300 ml of methanol hydronaut until the absorption of hydrogen (i.e., within approximately 2 days) at room temperature and atmospheric pressure in the presence as catalyst of 2.0 g of 10% palladium on coal. The mixture is filtered, add an excess of triethylamine, and the solvent is removed in vacuum to obtain a pink solid, which was partitioned between water and chloroform. The organic phase is dried, and p the solid substance with a melting point of 153 - 156oC.

12,2 10 ml) solution of the complex of borane and dimethyl sulfide in the dimethyl sulfide is added dropwise at a temperature of 15 - 20oC in nitrogen atmosphere serves to stir a suspension of 8.0 g of 1-(3-methoxyphenyl)piperidine-4-carboxamide in 75 ml of tetrahydrofuran. The suspension gradually dissolves. When all of 12.2 ml of the above solution is submitted, the mixture is heated under reflux for 4 hours, after which it was allowed to stand at room temperature for 16 hours. The reaction is stopped by adding the reaction mixture dropwise to stirred mixture of ice and water. The aqueous mixture is acidified with dilute hydrochloric acid and washed with 200 ml of diethyl ether. Insoluble matter is removed by filtration and not processed further. The aqueous phase is alkalinized with concentrated aqueous solution of sodium hydroxide, cooled, and the product extracted three times with diethyl ether, taken in an amount of 250 ml combined extracts dried over magnesium sulfate, and the solvent is removed in vacuum with

obtain 4.7 g of an opaque oil. The resulting oil purified by flash chromatography on silica gel, using as eluent consistently using a mixture of dichloromethane and de is removed in vacuum to obtain 2.9 g of 1-[1-(3-methoxyphenyl)-piperid-4-yl]methylamine as the oil is Golden in color.

Stir a mixture of 4.2 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained similar to example 1 reception, 2.9 g of 1-[1-(3-methoxyphenyl)piperid-4-yl] methylamine and 4 g of potassium carbonate in 250 ml of acetonitrile is heated under reflux for 3 days. The potassium carbonate is removed by filtration and washed with acetonitrile. The solvent is removed from the filtrate under vacuum, thus obtain 6.0 g turbid oil, which is purified by flash chromatography on silica gel using as eluent a mixture of dichloromethane and denatured alcohol in a ratio of 19:1. Productstream fractions are collected and the solvents removed in vacuo to obtain 2.3 g of a yellow oil. The resulting oil was dissolved in diethyl ether, and the solution serves gaseous hydrogen chloride. The resulting white solid is collected by filtration, washed with diethyl ether and dried in vacuum to obtain 0,93 g of the hydrochloride of N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(3-methoxyphenyl)piperid-4-yl] methylamine as a solid substance with a melting point of 186 - 188oC.

Example 19. 1.5 g of racemic N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl] methylamine obtained by alkalizing dihydrochloride, polichinelles liquid chromatography on a column of brand Chiralcel OS internal dimensions 25 cm x 2 cm using as eluent a mixture of isohexane and ethanol in the ratio 1:1. The appropriate fractions are combined and the solvents removed in vacuo.

First elyuirovaniya fraction is dissolved in diethyl ether, the solution is saturated with hydrogen chloride and the resulting solid is collected by filtration and dried in vacuum to obtain 0.5 g of the dihydrochloride of (-)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl] methylamine as a white solid with a melting point of 228 - 232oC. []rDt= -63,0o(C = 1; methanol).

Example 20. Second elyuirovaniya fraction obtained as described in example 19 separation by preparative high performance liquid chromatography, dissolved in diethyl ether, the solution is saturated with hydrogen chloride, and the resulting solid is collected by filtration and dried in vacuum to obtain 0.55 g of the dihydrochloride of (+)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl] methylamine as a white solid with a melting point of 227 - 230oC. []rDt= +63,0o(c = 1; methanol).

Example 21. The second solution 12,88 g of 1-(6,7-dichloro-1,4-benzodioxan-2-yl)methanol obtained receiving the mixed solution of 12 g of toluene-4-sulphonylchloride in 21 ml of pyridine. The mixture is allowed to cool to room temperature and stirred for 60 hours, after which she served in 150 ml of water, acidified with concentrated hydrochloric acid and the product extracted 4 times with ethyl acetate, taken in an amount of 80 ml combined extracts washed twice with water, taken in an amount of 100 ml, and brine, dried over magnesium sulfate, and the solvent is removed in vacuum. Thus obtain 17.5 g of an orange oil which slowly solidifies. Solid double-pounded into powder using diethyl ether, taken in an amount of 100 ml, is collected by filtration and recrystallized from acetonitrile to obtain 6.6 g of 6,7-dichloro-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate as white crystals with a melting point of 124 - 125oC.

A mixture of 3 g of 6,7-dichloro-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate, of 1.65 g of 1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine obtained analogous to example 2 reception 2.1 g of potassium carbonate and 25 ml of dimethylformamide is stirred for 16 hours at a temperature of 85oC in nitrogen atmosphere, then served in 150 ml of water. The product is extracted 4 times with ethyl acetate, taken in an amount of 80 ml combined extracts washed twice with water, usathat whitish resin, which purify by flash chromatography on silica gel using as eluent a mixture of methanol and dichloromethane in the ratio of 1:20. The appropriate fractions are combined and the solvents removed in vacuo. Thus obtain 0.54 g of solid, which was dissolved in diethyl ether. In the solution serves excess ethereal solution of hydrogen chloride, after which the solvent is removed in vacuum. The residue is dried by azeotropic distillation using 2-propanol, grind into powder with hot ethanol, and the resulting solid is collected by filtration and dried in vacuum to obtain 280 mg of the hydrochloride of N-(6,7-dichloro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine with a melting point of 248 - 252oC (Razlog.).

Example 22. A mixture of 41 g of the chloride of 4-carbarnoyl-1-(2,4-dinitrophenyl)pyridinium and 20 g of 2-Chloroaniline in 500 ml of methanol is stirred for 24 hours at room temperature. The mixture is heated under reflux for a further 24 hours, then served another 10 g of 2-Chloroaniline. Continue to heat under reflux for a further 48 hours, then served another 10 g of 2-Chloroaniline. The mixture is heated for a further 48 hours, cooled, and the solvent is removed is t, and the solid is collected by filtration. The solid is dissolved in 100 ml of hot methanol, treated with active charcoal and filtered while hot. In the filtrate, 500 ml of hot ethyl acetate, and the solution is allowed to cool. The resulting solid is collected by filtration, washed with ethyl acetate and dried to obtain 23,69 g crude chloride 4-carbarnoyl-1-(2-chlorophenyl)pyridinium, which is used without further purification.

2.5 g of the crude product from the previous reaction in ethanol in the presence of 0.25 g of 10% rhodium on coal as a catalyst hydronaut at room temperature and atmospheric pressure for 7 hours, then served another 0.5 g of catalyst, and the hydrogenation continued for 8 hours. Add 0.5 g of catalyst, and the hydrogenation continued for 6 hours. The catalyst is removed by filtration silicate brand Celite, and the filtrate is alkalinized saturated aqueous sodium bicarbonate. The solvent is removed in vacuo, and the solid is crystallized from ethyl acetate, and insoluble inorganic substances are removed by filtration. Obtain 0.5 g of 1-(2-chlorophenyl)piperidine-4-carboxamide.

0.25 g of 1-(2-chlorophenyl)piperidine-4-carboxamide, obtained the RA complex of borane and dimethyl sulfide in dimethyl sulfide. The resulting solution is heated under reflux for 2 hours, after which the solvent is removed in vacuo, add 50 ml of 1 m hydrochloric acid, and the mixture is stirred at room temperature for 1 hour. The solution is alkalinized a 5 m aqueous solution of sodium hydroxide and the product extracted with diethyl ether. The extracts washed with water, dried over magnesium sulfate, and the solvent is removed in vacuum with getting to 0.19 g of 1-[1-(2-chlorophenyl)piperid-4-yl]methylamine as oil. The reaction is repeated using the original substances, taken in the above amount, multiplied by a factor of 4.4, while getting another 1.0 g of 1-[1-(2-chlorophenyl)piperid-4-yl]methylamine.

A mixture of 1.68 g of 1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained similar to example 1 reception, 1.8 g of 1-[1-(2-chlorophenyl)piperid-4-yl]methylamine and 10 g of potassium carbonate in 150 ml of acetonitrile under stirring for 24 hours, heated under reflux. In the reaction mixture serves 0.2 g of potassium iodide, with stirring at the reflux continued for another 24 hours. The cooled mixture is filtered and the solvent removed in vacuum from the filtrate. The residue is subjected to chromatography on silicogermanate 1:1. The solvent in a vacuum removed from the eluate, and transparent oily residue is dissolved in diethyl ether. Add an excess of ethereal solution of hydrogen chloride and the solvent is removed in vacuum with the receipt of 0.37 g of the hydrochloride of N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-chlorophenyl)piperid-4-yl] methylamine with a melting point of 275 - 278oC (Razlog.).

Example 23. to 18.3 ml of epichlorohydrin is added dropwise in a nitrogen atmosphere served in a solution of 10 g of 3-forkatana and 4,56 g of potassium hydroxide in 45 ml of water, and the mixture is heated under reflux for 4.5 hours. The mixture is cooled and the product extracted three times with ethyl acetate, taken in an amount of 50 ml Organic extract was successively washed with 25% aqueous solution of sodium hydroxide and brine, and dried over magnesium sulfate. The solvent is removed in vacuum to obtain 15.5 g of a crude mixture of 1-(5-fluoro-1,4-benzodioxan-2-yl)-methanol and 1-(8-fluoro-1,4 - benzodioxan-2-yl)methanol.

A solution of 15.5 g of a crude mixture of isomers obtained in the previous reaction, and 14,88 g of toluene-4-sulphonylchloride in 20 ml of pyridine is stirred at room temperature for 18 hours. Add 100 ml of water and extracted three times with ethyl acetate, taken in an amount of 50 ml. Organic what LifeCam magnesium. The solvent is removed in vacuo and the residue purified by flash chromatography on silica gel using as eluent a mixture of cyclohexane and diethyl ether in the ratio 1:1. The appropriate fractions are combined and the residue obtained by removal of solvent in vacuo, then purified by flash chromatography on silica gel using as eluent a mixture of cyclohexane and diethyl ether in the ratio of 7:3. The solvent is removed from the appropriate fractions in vacuo, thus obtain 4.5 g of a mixture of 5-fluoro-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate and 8-fluoro-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate.

Stir a mixture of 4.5 g of isomers obtained in the previous reaction, of 2.93 g of 1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine, 3,68 g of potassium carbonate and 100 ml of acetonitrile for 18 hours, heated under reflux. The cooled solution is purified using a strip of silica gel, using as eluent first mixture of ethyl acetate and petroleum ether with a boiling within 40 - 60oC in the ratio 2:1 to remove the remaining original toluene-4-sulfonate, and then pure ethyl acetate for the elution of the target product. The solvent is removed in vacuum, the OS is acaemy precipitate is collected by filtration and dried in vacuum to obtain 260 mg of the mixture of the hydrochloride of N-(5-fluoro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine hydrochloride and N-(8-fluoro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)-piperid-4-yl] methylamine with a melting point of 228 - 230oC.

Example 24. 2,32 g of epichlorohydrin is added dropwise served in a mixed solution of 4.0 g of 1,2-dioxynaphthalene and 4.0 g of potassium hydroxide in 32 ml of water, and the resulting mixture is stirred at a temperature of 60 - 80oC for 2.5 hours, after which the mixture is poured into 100 ml of water. Product 6 times extracted with diethyl ether, taken in an amount of 100 ml, and to increase the solubility add a small amount of methanol. The combined extracts are washed subsequently with 1-m aqueous solution of sodium hydroxide and water, and dried over magnesium sulfate. The solvent is removed in vacuum to obtain 4.0 g of crude 1-(oil[1,2-b] dioxane-2-yl)methanol as a dark oil which is used without further purification.

A solution of 4.0 g of crude product of the previous reaction and of 3.53 g of toluene-4-sulfonyl-chloride in 10 ml of pyridine is stirred at room temperature for 3 hours, then add another 200 mg of toluene-4-sulphonylchloride and the mixture is left to stand for 18 hours. The mixture is poured into 100 ml water and the product extracted three times with ethyl acetate, taken in an amount of 100 ml combined extracts washed twice with 5-m hydrochloric acid, taken in an amount of 100 ml, twice nassen the m magnesium. The solvent is removed in vacuum to obtain a red oil, which was purified by flash chromatography on silica gel using as eluent a mixture of cyclohexane and diethyl ether in the ratio of 85: 15. The solvent is removed from productstream fractions in vacuo, and the residue is crystallized from a mixture of diethyl ether and ethyl acetate with the receipt of 0.48 g of almost pure oil[1,2-b]dioxane-2-ylmethyl-toluene-4-sulfonate as a pink solid.

The reaction is repeated using the original substances, taken in the above amount, multiplied by the factor 4,15, you get more of 1.75 g of the product. The target products of the two reactions are combined and will recrystallized from ethyl acetate to obtain 1,38 g of a clear oil[1,2-b]dioxane-2-ylmethyl-toluene-4-sulfonate as a white solid with a melting point of 122 - 124oC.

A mixture of 1.32 g of the product of the previous reaction of 0.79 g of 1-[1-(2 - methoxyphenyl)-piperid-4-yl]methylamine, 1.0 g of potassium carbonate and 50 ml of acetonitrile is stirred and heated under reflux for 40 hours. The cooled mixture is filtered, the solvent is removed in vacuo, and the residue purified by flash chromatography on silica gel using ethyl acetate as CTB dissolved in ethyl acetate. The solution is saturated with hydrogen chloride and the resulting solid is collected by filtration and dried in vacuum to obtain 0,86 g of 1,3-hydrochloride 1-[1-(2-methoxyphenyl)piperid-4-yl] -N-(oil[1,2-b] dioxane-2-ylmethyl)of methylamine in the form of a hydrate with a melting point of 182 - 185oC.

Example 25. A mixture of 6.8 g of 2,3-dihydrobenzo[b]furan-7-ylamine obtained by the method similar to the one described in Tetrahedron Letters 1982, 23, page 147, of 14.7 g of chloride 4-carbarnoyl-1-(2,4-dinitrophenyl)pyridinium obtained similar to example 2, and 400 ml of methanol for 5 hours and stirred while heating under reflux, and then allowed to stand at room temperature and heated for 16 hours. The solvent is removed in vacuo, and the residue is ground to powder with hot acetone, cooled and filtered to obtain 11.5g chloride 1-(2,3-dihydrobenzo[b] furan-7-yl)-4-carbamaepine as a yellow solid with a melting point of 289 - 290oC.

12.7 g of the chloride of 1-(2,3-dihydrobenzo[b]furan-7-yl)-4-carbamaepine obtained similarly to the above-described reception in nitrogen atmosphere serves 12.3 g of 10% palladium on coal as a catalyst. Add to 23.5 g of ammonium formate, and under stirring peluchetaiwanes in the condenser ammonium formate add ~150 ml of methanol, and the resulting mixture is again fed to the reaction). After cooling, the mixture is filtered on the silicate brand Celite under nitrogen atmosphere, while paying attention to the fact that the catalyst cannot be dry, alkalinized with saturated sodium bicarbonate solution, the solvent is removed in vacuo, and the residue diluted with water. The product is extracted three times with dichloromethane, taken in an amount of 100 ml the combined organic extracts washed with water, dried over magnesium sulfate, filtered, and the solvent is removed in vacuum with the receipt of 7.75 g of pink solid. The resulting solid is ground to powder with hot ethyl acetate, cooled and filtered to obtain only 6.64 g of crude 1-[2,3-dihydrobenzo[b]furan-7-yl]piperidine-4-carboxamide as a light pink solid, which is used without further purification.

A solution of 6.6 g of a light pink solid in 500 ml of tetrahydrofuran is added dropwise in a nitrogen atmosphere serves to stir the mixture of 2.05 g of lithium aluminum hydride in 250 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature for 16 hours, then add 4 ml of water and 4 ml of concentrated aqueous solution of sodium hydroxide. The floor chamou mixture plumage is accelerate in dichloromethane. The solution is dried over magnesium sulfate, filtered, and the solvent is removed in vacuum to obtain 6,24 g of 1-[1-(2,3-dihydrobenzo[b]furan-7-yl)-piperid-4-yl]methylamine as an orange oil which is used without further purification.

The mixture 2,12 g of 8-methoxy-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate obtained analogous to example 6 reception, 1.4 g of 1-[1-(2,3-dihydrobenzo[b] -furan-7-yl)piperid-4-yl] methylamine, 1,67 g of potassium carbonate and 50 ml of acetonitrile is stirred at reflux for 4 days. The mixture is poured into 50 ml water and the product extracted three times with ethyl acetate, taken in an amount of 50 ml, the Extracts washed with 50 ml of brine, dried over magnesium sulfate, filtered, and the solvent is removed in vacuum to obtain resin, which is purified by flash chromatography on silica gel, using as eluent consistently apply a mixture of ethyl acetate and petroleum ether with a boiling within 60 - 80oC in the ratio 2:1, and then in a 1: 1 ratio. The solvent is removed from the appropriate fractions in vacuo, and the residue is dissolved in diethyl ether. Add an excess of ethereal solution of hydrogen chloride, after which the solvent is removed in vacuum to obtain 180 mg of the hydrochloride of 1 - substances with a melting point of 194 - 196oC.

Example 26. A mixture of 5.0 g of 4-chlormethine in 20 ml of 10% aqueous solution of potassium hydroxide is stirred in a nitrogen atmosphere, add 9.6 g of epichlorohydrin, and the mixture is heated at a temperature of 95oC for 4 hours. The mixture is cooled to room temperature, and the product extracted twice with diethyl ether, taken in an amount of 50 ml, the Extracts washed with 50 ml of a 5 m aqueous solution of sodium hydroxide and 50 ml of water, dried over magnesium sulfate, filtered, and the solvents removed in vacuo to obtain 8,24 g yellow oil.

The resulting oil purified by flash chromatography on silica gel, using as eluent consistently apply a mixture of petroleum ether with a boiling within 40 - 60oC and ethyl acetate in a ratio of 10:1, 4:1, then 1: 1, and end with ethyl acetate. The appropriate fractions are combined and the solvents removed in vacuo to obtain 6.0 g of beige solid.

A mixture of 6.0 g obtained in the previous phase of solids, 40 ml of pyridine and 17.1 g of toluene-4-sulphonylchloride stirred at room temperature for 16 hours, after which the mixture is poured into 200 ml of water. The product is extracted three times with ethyl acetate, taken in an amount of 100 ml, extracts the n aqueous solution of sodium bicarbonate, taken in an amount of 100 ml and once with 100 ml brine. The extracts are dried over magnesium sulfate, filtered, and the solvent is removed in vacuum to obtain is 11.39 g of yellow oil. The oil is purified by flash chromatography on silica gel using as eluent a mixture of cyclohexane and diethyl ether in the ratio of 85:15. The appropriate fractions are combined and the solvents removed in vacuo to obtain 8 fractions.

Fraction 4 recrystallized from diethyl ether obtaining of 0.44 g of a white solid substance which is a mixture of 7-chloro-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate and 6-chloro-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate in a ratio of 9:1.

Fractions 5 and 6 are combined and purified by flash chromatography on silica gel using as eluent a mixture of cyclohexane and diethyl ether in the ratio of 85:15, you get a 3 fractions a, B and C.

Faction And will recrystallized from diethyl ether to obtain 1.2 g of a white solid, which combine with recrystallization product fractions 4. You get a total yield 1.64 g of a mixture of isomers in a ratio of 9:1.

Stir a mixture of 1.5 g of the above combined solids of 0.93 g of 1-[1-(2-what military refrigerator. The mixture is cooled, filtered, and the solvents removed in vacuo. The residual oil purified by flash chromatography on silica gel using ethyl acetate as eluent. The resulting oil was dissolved in diethyl ether, and the solution serves gaseous hydrogen chloride, thus receive a colorless solid, which was collected by filtration, washed with ethyl acetate and dried to obtain 0.87 g of the mixture of the hydrochloride of N-(7-chloro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine in the form of a hydrate hydrochloride and N-(6-chloro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine in the form of hydrate in a ratio of about 9:1. Melting point: 237 - 240oC.

Example 27. Fraction 7, obtained in the first purification by chromatography, as described in the second stage of example 26, recrystallized from diethyl ether to obtain 0.21 g of a white solid, which combined with the fraction In the resulting purification by chromatography as described in example 26, with the General release of 1.40 g of a mixture of 7-chloro-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate and 6-chloro-1,4-benzodioxan-2-ylmethyl-toluene-4-sulfonate in a ratio of 4:6.

Stir the mixture 1,3 is toxigenic)piperid-4-yl] methylamine, 1.01 g of potassium carbonate and 80 ml of acetonitrile is heated under reflux for 30 hours. The cooled mixture is filtered, then the solvent is removed in vacuum to obtain an oil, which was purified by flash chromatography on silica gel using ethyl acetate as eluent. The solvent is removed from the appropriate fractions in vacuo, the resulting oil is dissolved in diethyl ether. The solution is saturated with hydrogen chloride and the resulting solid is collected by filtration and dried in vacuum to obtain 0,69 g of a mixture of 1,7-hydrochloride N-(7-chloro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine in the form of a hydrate and 1.7-hydrochloride N-(6-chloro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2- methoxyphenyl)piperid-4-yl] of methylamine in the form of hydrate in a ratio of about 4:6, with a melting point 237-240oC.

Example 28. 10 g of toluene-4-sulphonylchloride portions at a temperature of -10oC served in a mixed solution of 4.9 g of 1-(8-hydroxy-1,4-benzodioxan-2-yl)methanol in 50 ml of dry pyridine under nitrogen atmosphere. The solution is stirred for 4 hours, allowed to stand at room temperature for 48 hours, after which the solution serves in 100 ml of ice water. Water decanted from the resulting resin, the d magnesium sulfate, and the solvent is removed in vacuum to obtain a brown oil, which crystallized when left to stand. In the titration with the use of a mixture of ethanol and methanol in the ratio of 1:1 to obtain 1.6 g of crude [8-(toluene-4-sulfonate)-1,4-benzodioxan-2-yl] methyl toluene-4-sulfonate as a whitish solid, which is used without further purification.

A mixture of 1.6 g of a crude product of the previous reaction, to 0.72 g of 1-[1-(2-methoxy-phenyl)piperid-4-yl] methylamine, 1.0 g of potassium carbonate and catalytic amounts of potassium iodide in 50 ml of acetonitrile is heated under reflux for 72 hours. The solvent is removed in vacuo, and the residue is dissolved in 100 ml of ethyl acetate. The solution is washed with water, then the product is extracted three times with 5-m hydrochloric acid, taken in an amount of 70 ml combined extracts washed twice with ethyl acetate, taken in the quantity of 30 ml, alkalinized a 5 m aqueous solution of sodium hydroxide and the product extracted three times with ethyl acetate, taken in an amount of 150 ml Extracts are combined, dried over magnesium sulfate, and the solvent is removed in vacuum to obtain a yellow oil, which was purified by flash chromatography on silica gel with the E. The residual oil was dissolved in 20 ml of diethyl ether, and the solution serves gaseous hydrogen chloride. You get a whitish solid, which is collected by filtration and immediately dried in vacuum to obtain 0.15 g of dihydrochloride[2-({ [1-(2-methoxyphenyl)piperid-4-yl] methylamino} methyl)-1,4-benzodioxin-8-yl] toluene-4-sulfonate with a melting point of 225oC.

A solution of 1.0 g of potassium hydroxide 19.7 ml of water and 19.7 ml of ethanol in portions of about 10 ml at intervals of 15 minutes serves in 0.15 g of dihydrochloride[2-({ [1-(2-methoxyphenyl)piperid-4-yl] methylamino} methyl)-1,4-benzodioxin-8-yl]-toluene-4-sulfonate. The mixture is heated under reflux for 2.5 hours, cooled and neutralized glacial acetic acid. Product three times extracted with diethyl ether, taken in an amount of 100 ml, and the combined extracts leave to stand for 16 hours. The resulting precipitate is collected by filtration and dried to obtain 0.2 g of N-(8-hydroxy-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine as a colorless solid with a melting point of 116 - 119oC.

Example 29. This example illustrates the application of the proposed compounds for the manufacture of farmatsevticheskii any particular connection, representing the target product of one of the previous examples.

a) Capsules

10 weight. parts of the active principle intensively mixed in 240 weight. parts of lactose, and the resulting mixture is crushed, loaded into capsules of hard gelatin so that each capsule contains either a single dose or part of a unit dose of the active agent.

b) Tablets.

Tablet composition (in weight. part): 10 active principle, 190 lactose, 22 corn starch, 10-vinylpyrrolidone and 3 stearate prepared as follows.

The active principle, lactose and a portion of the corn starch are crushed, mixed and the resulting mixture granularit with a solution of polyvinylpyrrolidone in ethanol. After drying, the granules are mixed with magnesium stearate and the residual amount of corn starch. The resulting mixture was fed into the tablet press machine to obtain tablets, each of which contains either a single dose or part of a unit dose of the active agent.

C) coated Tablets.

Tablets are prepared in the same manner as described in paragraph (b). Then on the pill known techniques put a solution of 20% acetate phthalate is.

100 weight. parts of the active principle produce 1300 weight.parts of a mixture of triglycerides and the resulting mixture was transferred to suppositories, each containing a therapeutically effective amount of the active agent.

1. Derivatives amine of General formula (I)

< / BR>
where R is halogen, hydroxyl, alkyl with 1 to 3 carbon atoms, alkoxy with 1 to 3 carbon atoms;

Q is a divalent group of formula (IIa), (IIB)

< / BR>
< / BR>
where V is methylene or ethylene;

X - Allenova chain with 0 to 2 carbon atoms;

X' - Allenova chain with 1 to 4 carbon atoms, the total number of carbon atoms in the residues X and X' is 3 or 4;

T is phenyl, pyridyl, pyrazinyl, benzo[b]furanyl, 1,4-benzodioxane and hintline, unsubstituted or substituted by halogen, metaxylem or trifluoromethyl;

m is 0, 1,

and their pharmaceutically acceptable salts.

2. Derivatives amine of the formula (I) under item 1, where R is hydroxyl, methoxy, fluorine or chlorine.

3. Derivatives amine of the formula (I) under item 1, where T represents 2-pyridyl, 2-pyrazinyl, phenyl, 2,3-dihydrobenzo[b] furan-7-yl, 1,4-benzodioxan-5-yl or 4-hintline, unsubstituted or substituted by metaxylem, trifluoromethyl or halogen.

4. Derivatives amine of the formula 4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(3-chloropyrid-2-yl)piperid-4-yl] methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(hinzelin-4-yl)piperid-4-yl]methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl]methylamine; N-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-(1-phenylpiperidine-4-yl)methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(1,4-benzodioxan-5-yl)piperid-4-yl] methylamine; 1-[1-(1,4-benzodioxan-2-ylmethyl)piperid-4-yl] -N-(2-methoxyphenyl)methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(4-methoxyphenyl)piperid-4-yl] methylamine; N-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-N'-(2-methoxyphenyl)-1,3-propandiamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(3-methoxyphenyl)piperid-4-yl] methylamine; N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-chlorophenyl)piperid-4-yl] methylamine; N-(5-fluoro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; N-(8-fluoro-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; 1-[1-(2,3-dihydrobenzo[b] furan-7-yl)piperid-4-yl] -N-(8-methoxy-1,4-benzodioxan-2-ylmethyl)methylamine; N-(6-chloro-1,4-benzodioxan-2-ylmethyl)-1-[1-(methoxyphenyl)piperid-4-yl] methylamine; N-(7-chloro-1,4-benzodioxan-2-ylmethyl)-1-[1-(methoxyphenyl)piperid-4-yl] methylamine; N-(8-hydroxy-1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-amatou or other mixtures of enantiomers.

5. Derivatives amine of the formula (I) under item 4, selected from the group comprising (S)-(-)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl]methylamine; (R)-(+)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(2-methoxyphenyl)piperid-4-yl] methylamine; (-)-N-(1,4-benzodioxan-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl] methylamine as hydrochloride; (+)-N-(1,4-besticken-2-ylmethyl)-1-[1-(pyrid-2-yl)piperid-4-yl] methylamine in the form of the dihydrochloride.

6. Pharmaceutical composition with affinity receptor 5-HTIAand D2containing nitrogen-containing organic active ingredient and at least one pharmaceutically acceptable diluent or carrier, characterized in that as the nitrogen-containing organic active substances it contains a compound of General formula (I) under item 1 or its salt in an effective amount.

 

Same patents:

The invention relates to new derivatives of piperidine and piperazine of the formula I

< / BR>
where Ind is unsubstituted or one - or twofold substituted by Oh, OA, CN, Hal, COR2or CH2R indol-3-ilen balances;

R1is unsubstituted or once substituted with CN, CH2OH, CH2OA or COR2benzofuran-5-yl, 2, 3-dihydrobenzofuran-5-yl-, chroman-6-yl, chroman-4-one-6-yl, 3-chromen-6-yl or chromen-4-one-6-yl;

Q-CmH2m;

Z is N or CR3;

A is alkyl with 1-6 C-atoms;

Hal is F, Cl, Br or I;

R2-OH, OA, NH2, NHA or NA2;

R3Is H, OH or OA;

m is 2, 3 or 4,

and their physiological acceptable salts

The invention relates to the field of organic chemistry and pharmaceuticals, namely heterobicyclic compounds and pharmaceutical compositions based on them, as well as methods of producing these compounds

The invention relates to stereoisomerism forms of Itraconazole (X=CL) and saperconazole (X= F), which can be represented by the formula CIS-(I) that are listed in the text of the description, their pharmaceutically acceptable acid additive salt forms, and methods of producing these stereoisomeric forms and their complexes with cyclodextrin derivatives and pharmaceutical compositions containing the above-mentioned complexes with anti-fungal activity

The invention relates to piperazine derivatives or its salts, which are used as therapeutic agents for diseases of the circulatory organs and areas of the brain

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine

The invention relates to 2,3-dihydro-1,4-benzodioxin-5-yl-piperazinyl derivative of the formula I, where R1denotes halogen, lower alkyl or alkoxyl, or cyano; m = 1 or 2, n = 0 or 1, And - Allenova chain with 2 to 6 carbon atoms which may be substituted by one or two lower alkyl groups or one phenyl group; B is methylene, ethylene, carbonyl, sulfinil, sulfonyl or sulfur, or their salts with 5-HTIA-antagonistic activity

The invention relates to new 2,2-dialkyl - 2,2-dialkyl-3,4-dihydro-3 - hydroxy-2H-1-benzopyranyl and their salts, esters and N-oxides and to methods for their preparation, their use as pharmaceuticals and to the containing pharmaceutical compositions

The invention relates to antiparasitics agents and, in particular, to compounds related to the avermectins and milbemycin, but containing substituents at the 3-position

The invention relates to the field of medicine and for the pharmaceutical solution of antitumor action of its receipt and perfusion solution

The invention relates to pharmaceutical industry and relates to antitumor compositions containing the derivatives taxane

, 20-epoxy-1,2, 4,7; , 1013th- hexahydroxy-11-en-9-it is complex ester group in position 13 formed (2r, 2s)-n-hexanoyl-3 - phenylisoxazol, method thereof and pharmaceutical composition" target="_blank">

The invention relates to a new taxane, namely 4,10-diacetate 2-benzoate 5, 20-epoxy-1,2, 4,7, 1013th-hexahydroxy-11-EN-9-it is complex ester group in position 13 formed (2R, 2S)-N-hexanoyl-3-phenylisoxazol having the structural formula I, which are extracted from the bark of the roots of plants of the genus Taxus extraction

The invention relates to the field of macrolides

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)

wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

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