Derivatives of 1,3-substituted of cycloalkene and cycloalkane in the form of mixtures of isomers or individual isomers, or their hydrates, or salts

 

(57) Abstract:

Usage: in medicine as an antipsychotic, and antihypertensive agents. The essence of the invention: derivatives of 1,3-substituted of cycloalkene and cycloalkane F.-ly (I) Z-CH2-Y, where Z and Y - see below, R is phenyl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, 2-, 4 - or 5-pyrimidinyl, 2 - or 3-thienyl, 3-indolyl, 2-, 3 - or 4-chinoline, m is the number 1, 2 or 3. Reagent 1: compound f-crystals (II). Reagent 2: RM, where R has the above meanings, M is a magnesium halide or lithium. Reaction conditions: in a medium solvent such as tetrahydrofuran at 0oC, followed by treatment of the resulting product with acid, for example triperoxonane. 7 C.p. f-crystals, 2 PL.

The invention relates to new cycloalkenes and cycloalkanes, suitable as pharmaceutically active substances, more particularly to derivatives of 1,3-substituted of cycloalkene and cycloalkane formula (I)

Z-CH2-Y (I)

where Z stands for a group

< / BR>
where

where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, dysoxylum, by hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted go substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is the number 1, 2, or 3, or group

< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

mixtures of their isomers or individual isomers, its hydrates and salts, in particular pharmaceutically acceptable acid additive salts.

Compounds of General formula (I) can be used as antipsychotic drugs for the treatment of psychosis, such as, for example, schizophrenia. They can also be used as antihypertensive funds and for the treatment of disorders resulting from dopaminergicescoe activation.

Thus, the compounds according to the invention can be used as a means for treatment-related hyperprolactinemia diseases, such as, for example, galactorrhea, amenorea, disorders of menstruation and sexual dysfunction, as well as to treat certain disorders of the Central nervous system, such as, n is" to characterize the compounds of formula (I) refers to straight or branched hydrocarbon residue with 1 to 6 carbon atoms. Examples are, for example, methyl, ethyl, n-propyl, isopropyl, n - butyl, sec.-butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl, etc.

Under "aryl" refers to aromatic residue, which is a radical, unsubstituted or substituted by 1 to 4 substituents from the group comprising lower alkyl, lower alkoxyl, lower thioalkyl, hydroxyl, halogen, trifluoromethyl, amino, lower alkylamino or lower dialkylamino, or 1,3-benzodioxol-5-yl.

Under "lower alkoxyl" and "toolboxitem" refers to O-alkyl or S-alkyl residues having 1 to 6 carbon atoms. By "halogen" refers to fluorine, chlorine, bromine or iodine.

Under the following by the term "alkali metal" means a metal of group IA of the Periodic system. Examples are, for example, lithium, sodium, potassium.

Under the following by the term "alkaline earth metal" means a metal of group IIA of the Periodic system. Examples are, for example, calcium, barium, strontium, magnesium.

Pharmaceutically acceptable acid additive salts of compounds of General formula (I) are salts resulting from interaction with non-toxic inorganic KIS is Hydrobromic acid, uudistoodetena acid, phosphoric acid, etc., acid, and salt, obtained as a result of interaction with non-toxic organic acids such as, for example, aliphatic mono - and dicarboxylic acids, substituted phenyl alkenylboronic acid, oxyalkylene acid, delanceboy acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc., acids. Thus, the salts are, for example, sulfates, pyrosulfite, bisulfate, sulfites, bisulfite, nitrates, phosphates, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphates, chlorides, bromides, iodides, acetates, propionate, caprylate, isobutyrate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, salt almond acid, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalates, bansilalpet, toluensulfonate, phenylacetate, citrates, lactates, maleate, tartratami, methanesulfonate, etc., the Invention also encompasses salts with amino acids such as, for example, arginate etc., gluconate, galacturonase.

Acid additive salts of basic compounds of formula (I) are obtained by the interaction of the free base with a sufficient number of VC is dividing the free base by known techniques. The free base is slightly different from the corresponding salt in parts of certain physical properties, such as solubility in polar solvents. But mostly salts exhibit the same biological activity as the corresponding free base.

Some compounds of General formula (I) may exist in resolutiony forms, and solvated forms, including hydrated forms. In General, the solvated forms, including gidratirovannye form, show the same activity as nonsolvated form of the proposed compounds. So they are also covered by the present invention.

Some compounds of General formula (I) have asymmetric carbon atoms, i.e. have optical centers. So as racemates and individual enantiomers are covered by the present invention. In addition, some compounds of General formula (I) may exist as a mixture of CIS - and TRANS-isomers or in the form of separate CIS - and TRANS - isomers. As mixtures of these isomers and individual isomers are also covered by the present invention.

Preferred compounds of General formula (I) are compounds in which R is phenyl, nasalcrom, amino group, a lower alkylaminocarbonyl, lower dialkylamino, 2 -, or 3-pyridyl, unsubstituted or substituted lower alkyl, lower alkoxyl or halogen, 2 - or 3 - thienyl, unsubstituted or substituted lower alkyl, lower alkoxyl or halogen, 2-, 3 - or 5-pyrimidinyl, 2-, 3 - or 4-chinoline, 3-indolyl or a group of the formula

< / BR>
Y is a group of the formula

< / BR>
where R is the specified value, and m is 1 or 2.

Other preferred compounds of General formula (I) are compounds in which R is phenyl, unsubstituted or substituted n-halogen, p-metaxylem, o - or p-lower alkyl, mono - or denissa alkylaminocarbonyl in p-position, 2 -, or 3 - pyridyl, 2 - or 3-thienyl, 5-pyrimidinyl, 3-chinoline, 3-indolyl or a group of the formula

< / BR>
Y is a group of the formula

where R is the specified value, and m is 2.

Further preferred compounds of General formula (I) are compounds in which R is phenyl, unsubstituted or substituted lower alkyl, lower alkoxyl, lower dialkoxy, halogen, hydroxyl, dihydroxyl, amino, lower alkylamino, lower dialkylamino group, 2 -, or 3-pyridyl, unsubstituted or substituted lower alkyl, lower alkoxyl or Galaico inil, 2-, 3 - or 4-chinoline, 3-indolyl or a group of the formula

< / BR>
Y - group

where R is the specified value, and m=1 or 2.

In an additional preferred group of compounds of General formula (I) include compounds in which R is phenyl, unsubstituted or substituted n-halogen, p-metaxylem, o - or p - lower alkyl, mono - or denissa alkylaminocarbonyl in p-position, 2 -, or 3-pyridyl, 2 - or 3-thienyl, 5-pyrimidinyl, 3-chinoline, 3 - indolyl or a group of the formula

< / BR>
Y is a group of the formula

where R is the specified value, and m=2.

As preferred compounds include:

()-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3 - cyclohexen-1-yl)methyl] pyridine,

()-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-2-cyclohexen-1-yl) methyl] pyridine,

()-1,2,3,6-tetrahydro-4-phenyl-1-[[3-thienyl)-3-cyclohexen - 1-yl]methyl] pyridine,

()-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-2-cyclohexen - 1-yl] methyl]pyridine,

()-1-[[3-(4-forfinal)-3-cyclohexen-1-yl] -methyl] -1,2,3,6 - tetrahydro-4-phenylpyridine,

()-1-[[3-4-forfinal)-2-cyclohexen-1-yl] -methyl-1,2,3,6 - tetrahydro-4-phenylpyridine,

()-1-[(3-phenyl-3-cyclohexen-1-yl)-methyl]-4-(2 - pyridinyl)piperazine,

()-1-[(3-phenyl-2-cyclohexen-1-yl)methyl]-4- (2-pyridinyl)piperazine,

()-1-[[3-(4-forfinal)-is)piperazine,

(+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1 - yl)methyl]pyridine,

(-)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl] pyridine,

monohydrochloride (R)-1-[[3-(4-chlorophenyl)-3-cyclohexen-1-yl] methyl] -1,2,3,6-tetrahydro-4-phenylpyridine,

(R)-1-[[3-(4-chlorophenyl)-2-cyclohexen-1-yl] methyl] -1,2,3,6-tetrahydro-4-phenylpyridine,

(R)-1-[[3-(4-forfinal)-3-cyclohexen-1-yl] methyl]- 1,2,3,6-tetrahydro-4-phenylpyridine,

(R)-1,2,3,6-tetrahydro-[3-(4-were)-3-cyclohexen-1-yl] methyl] -4-phenylpyridine,

monohydrochloride (R)-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-3 - cyclohexen-1-yl]methyl]pyridine,

monohydrochloride (R)-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-2 - cyclohexen-1-yl]methyl]pyridine,

monohydrochloride (R)-1,2,3,6-tetrahydro-1-[[3-(4-methoxyphenyl)-3-cyclohexen-1-yl]methyl]-4-phenylpyridine,

monohydrochloride (R)-3-[5-[(3,6-dihydro-4-phenyl-1-(2H)- pyridinyl)methyl] -1-cyclohexen-1-yl]pyridine

the dihydrochloride (R)-3-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl]- 1 - cyclohexen-1-yl]pyridine,

(R)-1,2,3,6-tetrahydro-1-[[3-2-were)-2-cyclohexen-1-yl] methyl] - 4-phenylpyridine,

(R)-1,2,3,6-tetrahydro-1-[[3-2-were)-3-cyclohexen-1-yl] methyl] -4-phenylpyridine,

monohydrochloride (R)-5-[5-[(3,6-dihydro-4-phenyl-1-(2H)- pyridinyl) methyl] -1-cyclog is Medina

(R)-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(3-thienyl)-2-cyclohexen-1-yl] methyl]pyridine,

(R)-4-[5-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1-cyclohexen-1-yl]-N,N-dimethylbenzenamine,

(R)-4-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1 - cyclohexen-1-yl]-N,N-dimethylbenzenamine,

(R)-3-[5-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1 - cyclohexen-1-yl]-quinoline,

(R)-3-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1 - cyclohexen-1-yl]-quinoline,

monohydrochloride (R)-1-[[3-(1,3-benzodioxol-5-yl)-3-cylohexane-1 - yl] methyl]-1,2,3,6-tetrahydro-4-phenylpyridine,

(1S-CIS)-N-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] cyclohexyl] - benzamide,

monohydrochloride (1R-CIS)-1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenylcyclohexyl)methyl]pyridine,

monohydrochloride (1R-TRANS)-1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenylcyclohexyl)methyl]pyridine,

(R)-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]-4-(2-pyridinyl)piperazine,

the dihydrochloride ()-1-phenyl-4-[(3-phenyl-3-cyclohexen-1-yl) methyl]piperazine,

()-2-[4-[[3-phenyl-3-cyclohexen-1-yl)methyl]-1-piperazinil] pyrimidine,

monohydrochloride ()-1,2,3,6-tetrahydro-1-[(3-phenyl-3 - cyclohexen-1-yl)methyl]-4-(2-thienyl)pyridine,

()-1-[(3-phenyl-3-cyclopenten-1-yl)methyl]-4-(2-pyridinyl) piperazine,

()-3-5-[(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)methyl] -1 - Zeh preferred compound is (+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine.

The compounds of formula (I) are valuable dofaminergicheskie funds, as appropriate tests revealed that they have dopaminergicescoe activity. Thus the compounds of formula (I) were studied in terms of their ability to inhibit locomotor activity in mice and rats, which is a measure of antipsychotic activity. This experience was carried out in accordance with the data of I. R. Meklina and others, Pharmacology, Biochemistry and Behavior, volume 8, pages 97 - 99, 1978. In addition, the compounds of formula (I) were studied in terms of their ability to bind dopamine receptors, which was determined by inhibition of binding of [3H]spiroperidol in accordance with the data D. Grigoriadis and P. Simen, Journal of Neurochemistry, vol 44, pp. 1925 - 135, 1985, and also in terms of their ability to synthesize dopamine in rats in accordance with the data of I. P. Walters and R. Mouth X, Naunyn-Schmiedeberg''s Archives of Pharmacology, volume 296, pages 5 - 14, 1976. In table. 1 summarizes data for dopaminergicescoe activity falling under the formula (1) compounds. Specified there a conditional reduction in CT50in µmol means the concentration of the compounds to achieve 50% inhibition.

In table. 2 summarizes the comparative data on activity Izvestiya

< / BR>
or

< / BR>
p=0, 1, or 2, and the proposed connections in the following, examples 1 and 4, which correspond to the formula

< / BR>
where W is the specified value, q is 0 or 1.

Comparison of the data table. 2 shows that the proposed 1,3-substituted compounds exhibit better activity than the known 1,4-substituted compounds.

Compounds of General formula (Ia)

Za-CH2-Y (Ia)

where Zagroup

< / BR>
where R is aryl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted or substituted lower alkyl or halogen, 2 - or 3-furanyl, unsubstituted or substituted lower alkyl or halogen, 2-, 4 - and 5-thiazolyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline, and m is 1, 2 or 3, or a group of the formula

< / BR>
where R and m have the above meanings;

Y - group

where R is the specified value, or group

< / BR>shall be provided by reacting the compounds of formula (II)

< / BR>
where Y and m have the above values,

with a compound of General formula (III)

R-M (III)

where R is the specified value, and M is a magnesium halide or lithium,

in the environment of a solvent, such as, for example, tetrahydrofuran, at a temperature of about 0oC for about 30 to 120 min and subsequent interaction with acid, such as, for example, triperoxonane acid, in the environment of a solvent, such as, for example, chloroform, at about room temperature for about 2 to 24 hours

The target product is isolated in free form or in pharmaceutically acceptable acid salt additive, optionally in the form of mixtures of isomers or of individual isomers.

The reaction is preferably carried out in an environment of tetrahydrofuran at a temperature of about 0oC for about one hour with subsequent interaction with triperoxonane acid in the environment of chloroform at about room temperature for about 18 hours

The compounds of formula (IB)

Zb-CH2-Ya(IB)

where Zbgroup

< / BR>
where R and m have the above meanings;

Yagroup

where R and has the specified value,

or their pharmaceutically SUB>-Ya(IB)

where Zaand Yahave the specified values,

with hydrogen in the presence of a catalyst, such as, for example, palladium on charcoal, in a solvent environment, such as, for example, methanol.

The reaction is preferably carried out in an environment of methanol in the presence of palladium on coal.

The compounds of formula (Iك)

Zb-CH2-Y (Iك)

where Zband Y have the above meanings, can be obtained by reacting the compounds of formula (IV)

< / BR>
where R, Y and m have the above values,

with regenerating agent such as, for example, triethylsilane in trifluoroacetic acid.

The reaction is preferably carried out by triethylsilane in trifluoroacetic acid.

The compound of formula (IV) can be obtained by reacting the compounds of formula (II) with the compound of the formula (III) in a solvent such as, for example, tetrahydrofuran, at a temperature of about 0oC for 30 - 120 minutes the Reaction is preferably carried out in an environment of tetrahydrofuran at a temperature of about 0oC for about 1 h

The compound of formula (II)

< / BR>
where Y and m have the above meanings, can be obtained by reacting orectolobidae acid, in the environment of a solvent, such as, for example, acetone.

The reaction is preferably carried out with diluted hydrochloric acid in the medium of acetone.

The compound of formula (V) can be obtained by reacting the compounds of formula (VI)

< / BR>
where Y and m have the above values,

with reactive hydride, such as, for example, aluminum hydride, in an environment of a solvent, such as, for example, tetrahydrofuran.

The reaction is preferably carried out by a hydride of aluminium in the environment of tetrahydrofuran.

In addition, the compounds of formula (V) can be obtained by reacting the compounds of formula (VII)

< / BR>
where m is the specified value,

with p-toluensulfonate in the presence of a base, such as, for example, pyridine, and subsequent interaction with the compound of the formula (VIII)

HY (VIII)

where Y is the specified value.

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

< / BR>
where m is the specified value,

with thionyl chloride or ethyl or isobutyl)-chloroformiate and the compound of the formula (VIII) in the presence of a base, such as, for example, triethylamine, in a solvent environment, such as, maprotiline carry isobutylparaben in the presence of triethylamine in an environment dichloromethane at a temperature of approximately 25oC for about 4 h

The compound of formula (VII) can be obtained by reacting the compounds of formula (IX) with reactive hydride, such as, for example, alumoweld lithium, in an environment of a solvent, such as, for example, tetrahydrofuran.

The reaction is preferably carried out with lithium aluminum hydride in an environment of tetrahydrofuran.

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

< / BR>
where m is the specified value, with acid, such as, for example, water chlorotoluron acid, and subsequent interaction with ethylene glycol in the presence of acid, such as, for example, p-toluensulfonate, in the environment of a solvent, such as, for example, benzene. The reaction is preferably carried out a 10% aqueous hydrochloric acid and subsequent interaction with ethylene glycol is carried out in the presence of p-toluenesulfonic acid in the environment of benzene.

In addition, the compounds of formula (IV) can be obtained by reacting the compounds of formula (XI)

< / BR>
where R1is alkyl with 1 to 6 carbon atoms, and m is the specified value,

with base, such as, for example, alkali metal hydroxide, for example, hydroxide h the solvent, such as, for example, benzene.

The reaction is preferably carried out with sodium hydroxide and subsequent interaction with ethylene glycol is carried out in an environment of benzene.

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

< / BR>
where m is the specified value,

with potassium cyanide in the presence of acid, such as, for example, sulfuric acid, in an environment of water, or trimethylsilylcyanation in the presence of a Lewis acid such as, for example, zinc chloride.

The reaction is preferably carried out by trimethylsilylcyanation in the presence of chloride of zinc.

The compound of formula (Ia)

where R and Y have the above values,

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

< / BR>
R where has the specified value,

with the compound of the formula (XIV)

< / BR>
where Y has the above meaning,

in the presence of a base, such as, for example, triethylamine, in a solvent environment, such as, for example, dichloromethane, at temperatures of about 0 to 50oC for 1 to 72 hours

The reaction is preferably carried out in the presence of triethylamine in an environment dichloromethane at temperatures of approximately 25oC for the presence of ammonium acetate in a solvent environment, such as, for example, ethanol, at temperatures of about 0 to 50oC for 1 to 72 hours

The reaction is preferably carried out by cyanoborohydride sodium in the environment of methanol in the presence of ammonium acetate at a temperature of approximately 25oC for about 4 h

Compounds of formula (III), (VIII), (XI),(XII) and (XIII) are either widely known or can be obtained by known methods.

The compound of formula (I), which represents the racemate, can be divided into its enantiomers by known methods, for example, with the use of optically active acids. So, for example, received diastereomeric salt can be divided by crystallization and known techniques to allocate in the form of optically active (+)- and (-)-enantiomers. So, for example, () is the compound of formula (I) is treated with (R)-(-)-1,1' -binaphthyl-2,2'-diyl-hydrogenphosphate in the environment of a solvent, such as, for example, acetonitrile, and the resulting diastereomer salt is subjected to interaction with the bottom, such as, for example, alkali metal hydroxide, e.g. sodium hydroxide, to obtain (+)-compounds of formula (I). Similarly, we can obtain the (-) compound of formula (I). In this case, applying (S)-(+)-1,1'-binaphthyl-2,2'- diyl-hydrogenphosphate.

PI parenteral villas. Such preparations contain compounds of the formula (I) or its pharmaceutically acceptable salt as an active principle.

For the preparation of pharmaceutical compositions proposed connection mixed by known methods with a solid or liquid pharmaceutically acceptable carriers. Solid preparations are, for example, powders, tablets, pills, capsule, suppositories, and dispersible granules. As a solid carrier can be used one or more substances which may also act as diluents, flavoring substance, solvent, wetting agent, suspending agent, binder, preservative, dezintegriruetsja tablets substances substances for encapsulation of the active agent. In the case of the powder carrier is a finely ground solid is available in the form of a mixture with finely ground active early. In the case of tablets, the active principle is mixed with a suitable carrier in suitable proportions in order to obtain tablets of desired sizes and configurations.

The powders and tablets preferably contain about 5 to 70% of the active principle. Suitable carriers are, for example, magnesium carbonate, magnesium stearate, talc, sugar, La the avco wax, butter, cocoa, etc. substances.

Suppositories can do due to the fact that the low-melting wax, such as, for example, a mixture of glycerides of fatty acids or cocoa butter, is first diluted and stirring, the resulting homogeneous melt is dispersed active principle. The resulting homogeneous melt is poured into molds of suitable size, where it is cooled.

As liquid preparations can be called solutions, suspensions and emulsions, for example, aqueous solutions or solutions of water and propylene glycol. For parenteral injection, liquid preparations are a solution in aqueous polyethylene glycol.

Suitable for oral application of aqueous solutions can be obtained by dissolving the active agent in water and adding suitable target additives, such as, for example, colorants, flavoring agents, stabilizers, thickeners.

Suitable for oral application of aqueous suspensions can be obtained by dispersing finely ground active principle in water in the presence of viscous substances, such as, for example, natural or synthetic gums, resins, methylcellulose, carboxymethylcellulose sodium and others well known suspendresume and is in fluid immediately prior to oral application. Such fluids are solutions, suspensions and emulsions. In addition to the active principle, these preparations may contain colouring agents, flavouring agents, stabilizers, buffers, natural or synthetic sweeteners, dispersants, thickeners, promoting solubilization agents and similar substances.

To achieve the desired therapeutic effects of the proposed connection is usually used in daily doses of about 1 to 50 mg/kg body weight of the patient, preferably 5 to 25 mg/kg body weight of the patient. However, these doses can be rejected as upwards and downwards depending on the age and General condition of the patient, severity of disease, appliciruemah connections, etc. circumstances. The person skilled in the art can determine the appropriate dosage in any specific case. Usually do that at the beginning of treatment give small doses of proposed connections that are less than the optimum dose. Then gradually increase the dose to achieve the optimal therapeutic effect.

Obtaining compounds of formula (I) is illustrated by the following examples.

Example 1

()-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-(or 2-)cicognolo in the following example A, in 400 ml of tetrahydrofuran was added dropwise in a nitrogen atmosphere a solution 9,13 ml of 3.0 m bromide vinylmania in diethyl ether at a temperature of 0oC. the resulting mixture was stirred at room temperature for one hour, then cooled in an ice bath and add 250 ml of 10% aqueous hydrochloric acid. The solvent is evaporated in vacuum and the residue is mixed with a solution of chloroform and 5% aqueous ammonium hydroxide. The organic extract is dried over magnesium sulfate and filtered. The filtrate is treated 4,2 ml triperoxonane acid and stirred at room temperature overnight. The solvent is evaporated in vacuum and the residue is mixed with a solution of ethyl acetate and 5% aqueous ammonium hydroxide. The organic extract is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by chromatography under pressure. Gain of 3.9 g of a whitish solid with so pl. 90 - 95oC, representing ()-1,2,3,6-Tetra-hydro-4-phenyl-1-[(3-phenyl-3-cyclohexen - 1-yl)methyl] pyridine (compound of example 1), and 2.7 g of a reddish-brown solid with so pl. 124 - 126oC, representing ()-1,2,3,6 - tetrahydro-4-phenyl-1- [(3-phenyl-2-cyclohexen-1-yl) methyl]pyridine (compound of example 1A).

Example 2

()-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-3-cyclohexen - 1-yl]methyl]pyridine

Reddish-brown solid with so pl. 97 - 99oC.

Example 2A

(-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-2-cyclohexen - 1-yl] methyl]pyridine

Whitish solid with so pl. 123 - 127oC.

Example 3

()-1-[[3-(4-forfinal)-3-cyclohexen-1-yl] methyl] -1,2,3,6-tetrahydro - 4-phenylpyridine

Whitish solid with so pl. 116 - 126oC.

Example 3A

()-1-[[3-4-forfinal)-2-cyclohexen-1-yl] methyl] -1,2,3,6-tetrahydro - 4-phenylpyridine

Yellowish solid with so pl. 159 - 162oC.

Example 4

()-1-[(3-phenyl-3-(or 2-)cyclohexen-1-yl] methyl] -4- (2-pyridinyl)piperazine

In a nitrogen atmosphere to a solution 5,14 g 3-[[4-(2-pyridinyl)piperazinil]methyl]cyclohexanone obtained in the following example B in 250 ml of tetrahydrofuran was added dropwise at a temperature of 0oC to 23.5 ml of a 2.0 m solution finelite in a mixture of cyclohexane and diethyl ether in the ratio of 70 : 30. The resulting solution was stirred at a temperature of 0oC for 1 h, then was added dropwise to 250 ml of a saturated solution of potassium phosphate. The solvent is evaporated in vacuum, the residue is alkalinized konzentrierte and filtered. The solution of the filtrate in a 250 ml chloroform containing 14,5 ml triperoxonane acid, stirred at room temperature under nitrogen atmosphere for 12 hours, the Solvent is evaporated in vacuum, the residue is dissolved in 250 ml of thioacetate and sequentially washed with 1 N. solution of sodium hydroxide and salt solution, taken in an amount of 250 ml of an ethyl acetate extract is dried over magnesium sulfate, filtered and concentrated. The crude product is purified by chromatography under pressure on silica gel using as eluent a mixture of 90% of hexanol and 10% ethyl acetate. You get a whitish solid with so pl. 96 - 98oC, representing ()-1-[(3-phenyl-3-cyclohexen-1-yl)methyl] -4-(2-pyridinyl)piperazine (compound of example 4), as well as a whitish solid with so pl. 78 - 82oC, representing ()-1-[(3-phenyl-2-cyclohexen-1 - yl)methyl] -4-(2-pyridinyl)piperazine (compound of example 4A).

Using the suitable starting compound, as in example 4 to obtain the compound of examples 5 and 5A.

Example 5

()-1-[[3-(4-forfinal)-3-cyclohexen-1-yl] methyl] -4- (2-pyridinyl)piperazine

Whitish solid with so pl. 116 - 118oC.

Example 5A

()-1-[[3-(4-forfinal)-2-cyclohexen-1-yl] methyl] -4- (hydro-4-phenyl-1-[[(3-phenyl-3 - cyclohexen-1-yl] methyl] pyridine

5.31g solution ()-1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-3-cyclohexen-1-yl] methyl] pyridine in example 1 in 50 ml of acetonitrile is treated with a solution is 4.21 g (R)-(-)-1,1'-binaphthyl-2,2'-diihydrocodeine of sodium in 50 ml of a mixture of ethanol and methylene chloride in a 1 : 1 ratio. The solution volume reduced to 50 ml by boiling on the steam bath. In the cooling get a whitish solid, which is recrystallized twice from 95% ethanol. Get 5,11 g of a white solid substance with so pl. 227 - 234oC, which is mixed with chloroform and 10% aqueous solution of sodium hydroxide. The resulting mixture was filtered through diatomaceous earth brand Celite and the resulting layers separated. The organic extracts are dried over magnesium sulfate, filtered and evaporated in vacuum. Receive (+)- 1,2,3,6-tetrahydro-4-phenyl-1-[[(3-phenyl-3-cyclohexen-1 - yl] methyl]pyridine as a whitish solid with so pl. 94 - 96oC

[]D= +64,4(C = 1,12; chloroform).

Example 6A

(-)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1 - yl)methyl] pyridine

Repeat example 6 with the only difference that instead of (R)-(-)-1,1'-binaphthyl-2,2'-diyl-hydrogenphosphate use (S)-(+)-1,1'-binaphthyl-2,2'-diyl-hydrogen-phosphate. This produces the]D= +63,7(C = 1,095; chloroform).

Example 7

(R)-1-[[3-4-chlorophenyl)-3-(or 2-)cyclohexen-1-yl] methyl] -1,2,3,6 - tetrahydro-4-phenylpyridine

1.50 g (R)-1,2,3,6 - tetrahydro-4-phenyl-1-[(3-oxocyclohexyl)methyl]pyridine obtained according to the following example, in 40 ml of tetrahydrofuran was added dropwise to 11,1 ml of bromide 4-chloraniline in 30 ml of diethyl ether in a nitrogen atmosphere at a temperature of 0oC, after which the reaction mixture is stirred for 1 h was Added 100 ml of saturated aqueous ammonium chloride, the organic layer was washed with 100 ml of brine, dried over magnesium sulfate, filtered and evaporated. Get to 2.41 g of a yellow foam, which was dissolved in 100 ml of 1,2-dichloroethane and 2.14 ml triperoxonane acid, after which the mixture is boiled for 1 h, the Solvent evaporated, the residue treated with 100 ml of 2 n sodium carbonate, extracted twice with dichloromethane, taken in an amount of 75 ml, the extracts washed with 75 ml of brine, dried over magnesium sulfate, filtered and evaporated. Get a white solid, which was purified by column chromatography on silica gel using as eluent a mixture of 5-7% ethyl acetate and hexane. Get 0,875 g of a whitish solid matter what pyridine (compound of example 7), and 0,875 g (R)- [[3-(4-chlorophenyl)-2 - cyclohexen-1-yl]methyl]-1,2,3,6-tetrahydro-4-phenylpyridine with so pl. 157 - 161oC, which is also a whitish substance.

Using the suitable starting compound, analogously to example 7 receive connection examples 8 -18.

Example 8

(R)-1-[[3-(4-forfinal)-3-cyclohexen-1-yl] methyl)-1,2,3,6 - tetrahydro-4-phenylpyridine

White solid with so pl. 130 - 132oC.

Example 9

(R)-1,2,3,6-tetrahydro-1-[[3-(4-were)-3-cyclohexen-1-yl] methyl] -4-phenylpyridine

White solid with so pl. of 101.5 - 103,5oC.

Example 10

Monohydrochloride (R)-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-3-cyclohexen-1 - yl]methyl]-pyridine

White solid with so pl. 223 - 225oC.

Example 10A

Monohydrochloride (R)-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-2-cyclohexen-1-yl] methyl]pyridine

White solid with so pl. 227 - 230oC.

Example 11

Monohydrochloride (R)-1,2,3,6-tetrahydro-1-[[3-(4-methoxyphenyl)-3-cyclohexen-1-yl]methyl] -4-phenylpyridine

White solid with so pl. 201 - 205oC.

Example 12

Monohydrochloride (R)-3-[5-[(3,6-dihydro-4-phenyl-1-(2H)pyridinyl) methyl] -1-cyclohexen-1-yl]pyridine

Bel-(2H)-pyridinyl) methyl] -1-cyclohexen-1-yl]pyridine

White solid with so pl. 249 - 253oC.

Example 13

Monohydrochloride (R)-1,2,3,6-tetrahydro-1-[[3-(2-were)-2-cyclohexen-1-yl] methyl] -4-phenylpyridine and monohydrochloride (R)-1,2,3,6-tetrahydro-1-[[3-(2- were)-3-cyclohexen-1-yl] methyl] -4-vinylpyridine with a ratio of 2 : 1

The mixture is a white solid with so pl. 213 - 215oC.

Example 14

Monohydrochloride (R)-5-[5-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl) methyl] -1-cyclohexen-1-yl]pyrimidine

White solid with so pl. 192 - 194oC.

Example 14a

Monohydrochloride (R)-5-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl) methyl] -1-cyclohexen-1-yl]pyrimidine

White solid with so pl. > 220oC.

Example 15

(R)-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(3-thienyl)-2 - cyclohexen-1-yl] methyl]pyridine

White solid with so pl. 126 - 128oC.

Example 16

(R)-4-[5-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)-methyl] -1-cyclohexen - 1-yl]-N,N-dimethylbenzenamine

White solid with so pl. 126 - 127oC.

Example 16A

(R)-4-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1-cyclohexen-1-yl]-N,N-dimethylbenzenamine

White solid with so pl. 158 - 160oC.

Example 17

(R)-3-[5-[(3,6-�SUP>C.

Example 17A

(R)-3-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)-methyl] -1-cyclohexen - 1-yl]-quinoline

White solid with so pl. 134 - 136oC.

Example 18

Monohydrochloride (R)-1-[[3-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl)-methyl]- 1,2,3,6-tetrahydro-4-phenylpyridine

White solid with so pl. 210 - 112oC.

Example 19

(1S-CIS)-N-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl) methyl]cyclohexyl] benzamide

A mixture of 2.0 g of (R)- 1,2,3,6-tetrahydro-4-phenyl-1- [(3-oxocyclohexyl)methyl] pyridine obtained in the following example, 5,72 g of ammonium acetate and 0,311 g cyanoborohydride of sodium in 40 ml of methanol is stirred at a temperature of 25oC for 2 h the Solvent is evaporated, the residue is treated with 300 ml of 2 n sodium carbonate and extracted three times with trichloromethane, taken in an amount of 100 ml, the Extracts washed with 200 ml of brine, dried over magnesium sulfate, filtered and evaporated. The resulting yellow oil purified by liquid chromatography on silica gel using as eluent a mixture of dichloromethane, methanol and ammonium hydroxide in the ratio of 40 : 8 : 1. Receives a yellow oil, to which is added 0,753 ml of triethylamine, 0,684 ml benzylchloride, 50 mg of 4-(N,N-dimethylamino)pedubast 100 ml of 2 N. sodium carbonate, the organic layer is separated, dried over magnesium sulfate, filtered and evaporated. Receives a yellow solid, which was purified by liquid chromatography on silica gel using as eluent of 3% methanol in dichloromethane. Gain of 0.62 g of (1S - CIS)-N-[3-[(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)methyl] -cyclohexyl] benzamide as a white solid with so pl. 200 - 204oC.

Example 20

Monohydrochloride (1R-CIS) and (1R-TRANS)-1,2,3,6-tetrahydro-4-phenyl-1- [(3-phenyl-cyclohexyl)methyl]pyridine

0.75 g obtained in the following example, G (R)-3-phenyl-3 - cyclohexen - carboxylic acid in 75 ml of isopropanol is subjected to hydrogenation 0.1 g of 10% palladium on coal under pressure 3,55 kg/cm2within 24 hours the Mixture is filtered and evaporated to obtain a colorless oil, to which is added 0,839 g dicyclohexylcarbodiimide in 10 ml of dichloromethane, the coefficient was 0.796 g of 1,2,3,6-tetrahydro-4-phenylpyridine as hydrochloride, 0,549 g of the hydrate oxibendazole and 1.13 ml of triethylamine in 20 ml dichloromethane. The resulting mixture is stirred overnight, then filtered, sequentially washed with 2 N. hydrochloric acid (2 x 100 ml), 100 ml of 2 n sodium carbonate and 100 ml of brine, dried over su is on silica gel using as eluent a mixture of 60 100% ethyl acetate in hexane. Get 0,325 g of colorless oil and 0,692 g waxy solids. The solid is dissolved in 5 ml of tetrahydrofuran and added to 75 g of lithium aluminum hydride in 2 ml of tetrahydrofuran, pretreated 87 mg of aluminum chloride in 2 ml of diethyl ether at a temperature of 0oC, after which the mixture is stirred for 1 h, add 90 ml of water and 0.38 ml of 20% sodium hydroxide and the resulting mixture is filtered and evaporated. Receives a yellow oil which is purified by liquid chromatography on silica gel using as eluent 10% ethyl acetate in hexane. The resulting yellow oil is dissolved in 10 ml of diethyl ether and 2 ml of ethanol, then add a 1.46 ml of 1 m hydrogen chloride in diethyl ether. The resulting salt is collected, washed with diethyl ether and dried at a temperature of 50oC in high vacuum. Get 0,498 g monohydrochloride (1R-CIS)-1,2,3,6 - tetrahydro-4-phenyl-1-[(3-phenylcyclohexyl)methyl] pyridine as a whitish solid with so pl. 200 - 202oC. Similarly treated 0,325 g of the above-mentioned colorless oil. You get 0.152 g of monohydrochloride (1R-TRANS)- 1,2,3,6-tetrahydro-4 - phenyl-1-[(3-phenylcyclohexyl)meteological-1-yl)methyl]-4-(2-pyridinyl)piperazine

0,506 g dicyclohexylcarbodiimide in 10 ml of dichloromethane is added to 0,414 g obtained in the following example, G (R)-3-phenyl-3 - cyclohexenecarboxylic acid, 0,410 g 2-pyridinediamine and of 0.332 g of the hydrate oxibendazole in 40 ml of dichloromethane. The resulting mixture is stirred overnight, then filtered and evaporated. The residue is dissolved in ethyl acetate, filtered, sequentially washed with saturated sodium bicarbonate, 5% citric acid, 2 N. sodium carbonate, brine, dried over magnesium sulfate, filtered and evaporated. Receives a yellow solid, which was dissolved in 5 ml of tetrahydrofuran, the resulting solution was added 78 mg of lithium aluminum hydride in 5 ml of tetrahydrofuran, pre-treated with 90 mg of aluminum chloride in 5 ml of diethyl ether at a temperature of 0oC, after which the mixture was stirred for 2 hours Add 0.1 ml of water and 0.4 ml of 25% sodium hydroxide, after which the mixture is filtered, washed with saline, dried over magnesium sulfate, filtered and evaporated. Receives a yellow oil which is purified by liquid chromatography on silica gel using as eluent 50% ethyl acetate in hexane. Get 0,22 g (R)-1-[(3 - phenyl-3-cyclohexen-1-yl)m is p 22

The dihydrochloride ()-1-phenyl-4-[(3-phenyl-3-cyclohexen-1 - yl)methyl] -piperazine

A solution of 0.75 g obtained in the following example G 3-phenyl-3 - cyclohexenecarboxylic acid, 0.66 g of 1-phenylpiperazine, 0.55 g of hydrate oxibendazole and 0.57 ml of triethylamine in 10 ml of dichloromethane cooled to a temperature of 0oC, treated with 0.84 g of dicyclohexylcarbodiimide and the reaction mixture stirred for 1 h at a temperature of 0oC and then at a temperature of 25oC during the night. The reaction mixture was filtered, successively washed with 1 N. hydrochloric acid (2 x 100 ml) 100 ml saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and evaporated. Receives a yellow oil, which was purified column chromatography on silica gel size 230 - 400 mesh using as eluent a mixture of ethyl acetate and chloroform in the ratio of 1 : 4. Obtain 1.0 g of the amide as a white solid, which was dissolved in 5 ml of tetrahydrofuran. The resulting solution was added to 0.33 g of lithium aluminum hydride in 20 ml of tetrahydrofuran, pre-treated 0.33 g of aluminium chloride in 20 ml of diethyl ether at a temperature of 0oC, after which the reaction mixture allowed to warm to a temperature of 25s and then adding 4 ml of 10% sodium hydroxide and the resulting mixture is stirred at a temperature of 25oC for 2 h After filtering through Celite and evaporation receive a white solid, which was dissolved in 30 ml of diethyl ether, filtered, and add 3 ml of 1 m hydrogen chloride in diethyl ether. The resulting salt is collected, washed with diethyl ether and dried in high vacuum at a temperature of 50oC. Obtain 0.88 g of the dihydrochloride ()-1-phenyl-4- [(3 - phenyl-3-cyclohexen-1-yl)methyl] -piperazine as a whitish solid with so pl. 212 - 214oC.

Using the suitable starting compound, analogously to example 22 to obtain the compounds of examples 23 and 24.

Example 23

()-2-[4-[[3-phenyl-3-cyclohexen-1-yl)methyl]-1-piperazinil] pyrimidine

As white solids with so pl. 68 - 70oC.

Example 24

Monohydrochloride ()-1,2,3,6-tetrahydro-1-[(3-phenyl-3-cyclohexen-1-yl) methyl]-4-(2-thienyl)pyridine

As white solids with so pl. 238 - 240oC (receipt using 1,2,3,6-tetrahydro-(2-thienyl)pyridine).

Example 25

()-1-[(3-phenyl-3-cyclopenten-1-yl)methyl]-4- (2-pyridinyl)piperazine

Repeat example 22 with the only difference that the use of 3-phenyl-C-cyclopentanecarbonyl acid obtained in the following example, the emer 26

()-3-[5-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)-methyl] -1-cyclohexen-1-yl] -1H-indole

A mixture of 1.00 g of 3-phenyl-3-cyclohexenecarboxylic acid obtained in the following example G of 0.48 g of indole and 1.20 g of sodium methylate in 10 ml of methanol is heated under reflux for 60 h in nitrogen atmosphere. Then the reaction mixture is concentrated to half the original volume, after which the resulting suspension is filtered, the solid is collected, dissolved in chloroform and purified by liquid chromatography on silica gel using as eluent a mixture of chloroform, methanol and ammonium hydroxide in the ratio 95 : 5 : 0.1 to. Thus obtain 0.21 g()-3-[5-[(3,6-dihydro-4-phenyl-1(2H)- pyridinyl)methyl]-1-cyclohexen-1-yl]-1H-indole as a whitish solid with so pl. 174oC.

Obtaining parent compounds

An example of a

3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl]-cyclohexanone

Stage A: Obtaining 1,4-dioxaspiro[4,5]decane-7-carboxylic acid

A mixture of 101.7 g complex ethyl ester 3-oxo-cyclohexanecarbonyl acid, of 38.9 g of ethylene glycol and 5.5 g of p-toluenesulfonic acid in 1000 ml of benzene is heated under reflux for 4 h, after which the solution is cooled, washed with 1 N. hydroxide is passed dissolved in 1000 ml of ethanol, process of 25.3 g of sodium hydroxide in 250 ml of water and heated under reflux for 2.5 hours, the Reaction mixture was concentrated in vacuo, cooled in an ice bath and acidified to pH 2 cold as ice 1 N. aqueous solution of hydrochloric acid. Extracted twice with chloroform, taken in an amount of 500 ml, dried over magnesium sulfate and concentrated in vacuum. Get 99,3 g of target compound as a yellowish oil, which according to gas chromatography has a purity of 98%.

Stage B: Obtain 1-(1,4-dioxaspiro[4,5[Oct-7 - ylcarbonyl)-1,2,3,6-tetrahydro-4-phenylpyridine

The solution of 99.3 g obtained at the stage And 1,4-dioxaspiro[4,5]decane-7-carboxylic acid and to 80.8 g of triethylamine in 1000 ml of dichloromethane cooled in an ice bath, and then in an atmosphere of nitrogen was added dropwise to 80.1 g of isobutylacetate. After 30 min was added dropwise within 2 hours the solution up 84.7 g of 4-phenyl-1,2,3,6-tetrahydropyridine in 500 ml of dichloromethane. The reaction mixture was stirred at room temperature for additional 2 h and then the solvent is removed in vacuo, the residue suspended in 100 ml of ethyl acetate, cooled to a temperature of 0oC, sequentially washed with cold as ice 1 N. aqueous solution chloritoid the t purified flash chromatography on silica using as eluent a mixture of hexane and ethyl acetate in a ratio of 3 : 1. Get 107,1 g of target compound as a yellow oil. Rf= 0,4; a mixture of methanol and chloroform in a ratio of 1 : 99. Mass spectrum (electron ionization): 327 (M, 26,1%), 141 (100%).

Stage: Obtain 1-(1,4-dioxaspiro[4,5]Dec-7-ylmethyl)-1,2,3,6-tetrahydro-4-phenylpyridine

The solution 14,54 g of aluminum chloride in 500 ml of original diethyl ether was added dropwise to a suspension 12,41 g of lithium aluminum hydride in 500 ml of tetrahydrofuran. The reaction mixture was stirred at room temperature for 30 min, then added dropwise to the solution obtained in stage 6 1-(1,4 - dioxaspiro[4,5] Dec-7 - ylcarbonyl)-1,2,3,6-tetrahydro-4-phenylpyridine in 500 ml of tetrahydrofuran. The resulting mixture was stirred at room temperature overnight, then carefully add 13 ml of water followed by the addition of 59 ml of 25% aqueous sodium hydroxide solution. The resulting mixture was stirred at room temperature for 2 h, filtered through Celite and concentrated in vacuum. Get 90,40 g of target compound as a yellowish oil with a value of Rf=0,2 (a mixture of methanol and chloroform in a ratio of 1 : 99).

Stage D: 3-[(3,6-dihydro-4-phenyl-1(2H)- pyridinyl)methyl]cyclohexanone

The solution to 90.4 g obtained but hydrochloric acid is heated under reflux for 2 h in nitrogen atmosphere, then the solvent is evaporated in vacuum and the residue is mixed with a mixture of ethyl acetate and a dilute solution of ammonium hydroxide. The organic extract is dried over magnesium sulfate and concentrated. Get 68,9 g of target compound as a light pink solid with so pl. 56 - 59oC. Mass spectrum (electron ionization): 269 (m, 41%), 172 (100%).

Example B

3-[[4(2-pyridinyl)piperazinil]methyl]cyclohexanone

Stage A: Obtain 1-(1,4-dioxaspiro[4,5]Dec-7-ylcarbonyl)-4-(2-pyridinyl)-piperazine

Repeat stage B of example a with the only difference that apply 10 g obtained in stage a of example And 1,4-dioxaspiro[4,5]decane-7-carboxylic acid, 8 g of triethylamine, 7.9 g of isobutylacetate and 8.3 g of 1-(2-pyridyl)piperazine. You get to 9.8 g of the target compound as an oil.

Stage B: Obtain 1-(1,4-dioxaspiro[4,5]Dec-7-ylmethyl)-4- (2-pyridinyl)-piperazine

Repeat stage In the example And with the only difference that apply 40,22 g obtained at the stage And 1-(1,4 - dioxaspiro[4,5]Dec-7-ylcarbonyl)-4-(2-pyridinyl)-piperazine, of 5.39 g of aluminum chloride and 4.61 in g of lithium aluminum hydride. You get 35,66 g of target compound as an oil.

Stage b: 3-[[4[(2 - pyridinyl)PIP the military to stage B 1-(1,4-dioxaspiro[4,5]Dec-7-ylmethyl)-4-(2-pyridinyl) piperazine and 50 ml of 10% aqueous hydrochloric acid. Thus obtain 6.4 g of the target compound as white solids with so pl. 86 - 90oC.

The example IN

(R)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-oxocyclohexyl)methyl]pyridine

41,53 g dicyclohexylcarbodiimide in 400 ml of dichloromethane is added to 98,22 g (R)-3-oxocyclohexanecarboxylic acid in the form of brezinova salt, 39,39 g of the hydrochloride 1,2,3,6-tetrahydro-4-phenylpyridine, 27,20 g of the hydrate of oxide of benzotriazole and 28,07 g of triethylamine in 1000 ml of dichloromethane, and then stirred over night. The reaction mixture is filtered and evaporated to obtain a brown solid, which is suspended in 100 ml of ethyl acetate, filtered, sequentially washed with twice 500 ml of 2 N. hydrochloric acid, 500 ml of 2 n sodium carbonate and 500 ml of brine, dried over magnesium sulfate, filtered and evaporated. Get 55,87 g butter, served in 150 ml of dichloromethane, and then stirred with 40 ml of 2-methoxy-1,3-dioxolane and 1 ml of methansulfonate at room temperature for three days. The resulting mixture was washed with 150 ml of 2 n sodium carbonate, dried over magnesium sulfate, filtered and evaporated. Receives a yellow oil, which was dissolved in 200 ml of tetrahydrofuran and the resulting solution is added to of 7.48 g is l diethyl ether at a temperature of 0oC, and stirred at a temperature of 0oC for 2 hours Add 2 ml of water and 10 ml of 25% sodium hydroxide, after which the mixture is filtered and evaporated. The resulting residue is heated under reflux in an environment 300 ml of acetone and 300 ml of 2 N. hydrochloric acid for 6 hours the Solvent was mostly evaporated and the residue is treated with 500 ml of 2 n sodium carbonate. The resulting mixture is shaken out three times three-chlormethine, taken in an amount of 300 ml, the resulting extracts are dried over magnesium sulfate, filtered and evaporated. The residue is purified by column chromatography on 250 g of silica gel using as eluent a mixture of 50% ethyl acetate in hexane. Get 39,40 g yellow wax with the rate of rotation + 15,2o(C = 1.00; methanol).

Example D

(R)-3-phenyl-3-cyclohexanecarbonyl acid

Stage A: Obtaining complex ethyl ester tetrahydro-2-oxo-2H - Piran-3 - carboxylic acid

3.0 g of metallic sodium are dissolved in 60 ml of absolute ethanol under nitrogen atmosphere and the resulting solution concentrated in vacuo. To get solid ethanolate sodium add 50 ml of diethylmalonate and 0.5 g of valerolactone and the resulting solution is heated at an oil bath temperature of 130oC. Ethanol from up to 150oC, with 11 ml of distillate is collected to a temperature of 120oC. In the distillation of the formed solid substance. The reaction mixture is cooled and diluted with 100 ml of diethyl ether, after which the mixture is filtered and the solid residue washed with diethyl ether. The residue is stirred with 80 ml of water and 8 ml of acetic acid, after which the reaction mixture is extracted with 100 ml diethyl ether. The extracts are dried over magnesium sulfate and concentrated. Get to 13.1 g of oil, which is subjected to vacuum distillation. You get 9,1 g complex ethyl ester tetrahydro - 2-oxo-2H - Piran-3-carboxylic acid with so Kip. 115 - 118oC (0.5 mm RT.cent.).

Stage B: 3-(benzoylmethyl)tetrahydro-2H-Piran-2-it

4,32 g complex ethyl ester tetrahydro - 2-oxo-2H-Piran-3 - carboxylic acid in 10 ml of tetrahydrofuran was added dropwise to 1.0 g of sodium hydride as a 60% dispersion in oil, washed with hexane, suspended in 10 ml of tetrahydrofuran, under nitrogen atmosphere with stirring. The reaction mixture is stirred until the evolution of gas, then add to 4.98 g of freshly distilled bromoacetophenone in 10 ml of tetrahydrofuran and the resulting mixture is heated on an oil bath with a temperature of 65oC techestva, therefore, before heating it is recommended to wait until the decay of the initial reaction). After cooling, the reaction mixture was added to 150 ml of diethyl ether and 100 ml of dilute aqueous potassium carbonate solution. The ether layer is successively washed with 10% aqueous potassium carbonate solution, water and saturated aqueous sodium chloride, then dried over magnesium sulfate and the solvent is removed in vacuum. Get to 6.58 g of an orange-red oil which was stirred with 50 ml of tetrahydrofuran and 50 ml of 1 m hydrochloric acid, and then heated under reflux on an oil bath with a temperature of 79oC for 45 hours, the Tetrahydrofuran is removed in vacuo, the residue is extracted twice with dichloromethane in an amount of 50 ml, the extract is dried over magnesium sulfate and concentrated in vacuum. Get 5,70 g of oil which crystallized from 30 ml of a mixture of hexane and ethyl acetate in the ratio of 1 : 1. The resulting crystals are filtered, washed with a mixture of hexane and ethyl acetate in the ratio of 1 : 1 and hexane, followed by vacuum drying. Get at 2.59 g of 3-(benzoylmethyl)tetrahydro - 2H-Piran-2-it is as white solids with so PL 93 - 94oC.

Stage: Obtain 3-phenyl-3-cyclohexadiene mix and, stirring, is heated in a nitrogen atmosphere in an oil bath with a temperature of 170oC for 2 h the resulting cooling of the vitreous solid is crushed to obtain a powder which is dissolved in 50 ml of dry dimethyl sulfoxide and add 30 ml of dry tetrahydrofuran. The resulting solution is cooled to a temperature of 10oC and stirring in nitrogen atmosphere, was added dropwise at a temperature below 18oC and 18.6 ml of 2 m dimethylsilane sodium in dimethyl sulfoxide obtained by dissolving sodium hydride in dimethyl sulfoxide at a temperature of 80oC for 1 - 2 hours the resulting solution was stirred at a temperature of 25oC for 2 h, after which the sulfoxide is distilled in a vacuum to a temperature of 80oC. the resulting residue is added to 100 ml dichloromethane and 100 ml of water containing 2 g of potassium carbonate. The aqueous layer was washed with 50 ml of dichloromethane, and then acidified with concentrated hydrochloric acid and twice extracted with dichloromethane in an amount of 70 ml of the Extract is dried over magnesium sulfate and concentrated in vacuum. Get 3,76 g of oil, which is purified on 25 g of silica gel using a mixture of chloroform and ethyl acetate in the ratio of 1 : 1 with subsequent thickening. Get 2,56 g texana. Get 2,02 g 3 - phenyl-3 - cyclohexenecarboxylic acid as white solids with so pl. 111 - 112oC. as a result of thickening of the supernatant solution to 5 ml get another 0.45 g of the target product with so pl. 107 - 111oC.

Stage G: Division 3-phenyl-3-cyclohexenecarboxylic acid

8,1 g obtained at the stage of 3-phenyl-3-cyclohexenecarboxylic acid was dissolved in 20 ml of 2-butanone, then add 4,85 g (S)- -methylbenzylamine in 10 ml of 2-butanone. Precipitated salt, add 200 ml of 2-butanone and the mixture is heated in order to dissolve the salt. In the cooling to a temperature of 25oC salt is recrystallized and collect. After drying receive 10,02 grams of salt, which is recrystallized five times from 2-butanone, resulting in a gain of 3.14 g of a white powder, which is suspended in ethyl acetate and washed with 2 N. hydrochloric acid. An ethyl acetate layer is dried over magnesium sulfate, filtered and evaporated. Receive (R)-3-phenyl-3-cyclohexenecarboxylic acid as a white powder with so pl. 77 - 80oC.

Example D

3-phenyl-3-cyclopentanecarbonyl acid

Stage a: 3-(benzoylmethyl)-4,5-dihydro-2(3H)-furanone

To stir at a temperature of 40ooC for 2 h, after which it is subjected to fractional distillation. When 100 - 120oC/0.8 mm RT.article get 74,8 g fraction, representing colorless oil. of 10.5 g of this oil was stirred in 125 ml of tetrahydrofuran in a nitrogen atmosphere is cooled by a bath of dry ice and acetone, and then added dropwise 33 ml of 1.6 m n-utility in hexano, and the internal temperature of the support below the 50oC. the Reaction mixture was stirred for 15 h and add to 5.08 g-methylene - butyrolactone in 20 ml of tetrahydrofuran, and the internal temperature of the support below - 64oC. the Reaction mixture was stirred for 30 min and heated to a temperature of 50oC, then add 100 ml of an aqueous solution of ammonium chloride and the reaction mixture is stirred for 5 minutes Twice extracted with diethyl ether in an amount of 200 ml, the extracts dried over magnesium sulfate, filtered and evaporated. The resulting residue is stirred in 45 ml of ethanol containing 12 ml of 5% sulfuric acid for 20 minutes Add 250 ml of water and the mixture extracted three times with chloroform, taken in an amount of 100 ml, the extracts dried over magnesium sulfate, filtered and evaporated the 120 - 180oC and a pressure of 1 mm RT.article Get 8,61 g of oil, which solidified upon standing. The resulting solid is recrystallized from a mixture of ethyl acetate and hexane. Get 6,27 g 3-(benzoylmethyl)-4,5-dihydro - 2-(3H)-furanone with so pl. 77 - 79oC.

Stage B: 3-phenyl-3-cyclopentanecarbonyl acid

5,00 g obtained at the stage And 3-(benzoylmethyl)-4,5-dihydro-2(3H)- furanone mixed with to 8.41 g of triphenylphosphine hydrobromide and the resulting mixture is heated to a temperature of 170oC on an oil bath in a nitrogen atmosphere for 1 h Then the reaction mixture is cooled and transferred into a powder which is dissolved in 50 ml of dimethyl sulfoxide and diluted with 30 ml of tetrahydrofuran. The resulting solution is stirred in a nitrogen atmosphere and cooled in an ice bath. Within 20 min was added dropwise 25 ml of 2 m dimethylsilane sodium (see stage b of example G), while the internal temperature of the support below the 14oC. the Reaction mixture is stirred at a temperature of 25oC for 2 h and the solvents evaporated. The resulting residue is treated with 80 ml of water containing 10 ml of a saturated aqueous solution of sodium bicarbonate, then extracted three times with dichloromethane, taken in an amount of 50 ml, the Extracts washed is centered hydrochloric acid. The aqueous layers extracted three times with dichloromethane, taken in an amount of 50 ml, the extracts dried over magnesium sulfate, filtered and evaporated. Get a brown oil which is purified on 30 g of silica gel using a mixture of chloroform and ethyl acetate in the ratio of 2 : 1. Obtain 3.1 g of 3-phenyl-3 - cyclopentanecarbonyl acid as a brown solid.

1. Derivatives of 1,3-substituted of cycloalkene and cycloalkane General formula I

Z - CH2- Y

where Z is the group

< / BR>
where R is phenyl, 2-, 3 - or 4-pyridinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-, 4 - or 5-pyrimidinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2-pyrazinyl, unsubstituted or substituted lower alkyl, lower alkoxyl, hydroxyl or halogen, 2 - or 3-thienyl, unsubstituted or substituted lower alkyl or halogen, 3-indolyl, 2-, 3 - or 4-chinoline;< / BR>
m = 1, 2, or 3,

or group

< / BR>
< / BR>
< / BR>
in which R and m have the above meanings;

Y - group

< / BR>
where R is the specified value,

in the form of mixtures of isomers or individual isomers, or their hydrates, or salts.

2. Derivatives of 1,3-substituted PWM alkoxyl, lowest dialkoxy, halogen, hydroxyl, dihydroxyl, amino group, lower alkylamino, lower dialkylamino, 2 -, or 3-pyridyl, unsubstituted or substituted lower alkyl, lower alkoxyl or halogen, 2 - or 3-thienyl, unsubstituted or substituted lower alkyl, lower alkoxyl or halogen, 2-, 3 - or 5-pyrimidinyl, 2-, 3 - or 4-chinoline, 3-indolyl, or a group of the formula

< / BR>
Y is a group of the formula

< / BR>
where R has the specified value, m = 1 or 2.

3. Derivatives of 1,3-substituted of cycloalkene and cycloalkane formula I on p. 2, in which R is phenyl, unsubstituted or substituted n-halogen, p-metaxylem, 0 - or p-lower alkyl, mono - or denissa alkylaminocarbonyl in p-position, 2 -, or 3-pyridyl, 2 - or 3-thienyl, 5-pyrimidinyl, 3-chinoline, 3-indolyl or a group of the formula

< / BR>
Y is a group of the formula

< / BR>
where R is the specified value; m = 2.

4. Derivatives of 1,3-substituted of cycloalkene and cycloalkane formula I on p. 3, representing a compound selected from the group comprising ()-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine; ()-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-2-cyclohexen-1-yl)methyl]pyridine; ()-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-3-cyclohexen-1-yl] -methyl] the h-1-yl] -methyl] -1,2,3,6-tetrahydro-4-phenylpyridine; ()-1-[[3-(4-forfinal)-2-cyclohexen-1-yl] methyl] -1,2,3,6-tetrahydro-4-phenylpyridine; ()-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl] pyridine; (-)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl] pyridine; monohydrochloride (R)-1-[[3-(4-chlorophenyl)-3-cyclohexen-1-yl] methyl] -1,2,3,6-tetrahydro-4 - phenylpyridine; (R)-1-[[3-(4-chlorophenyl)-2-cyclohexen-1-yl] methyl]-1,2,3,6-tetrahydro-4 - phenylpyridine; (R)-1-[[3-(4-forfinal)-3-cyclohexen-1-yl] methyl] -1,2,3,6-tetrahydro-4 - phenylpyridine; (R)-1,2,3,6-tetrahydro-[3-(4-were)-3-cyclohexen-1-yl] methyl] -4 - phenylpyridine; monohydrochloride (R)-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-3-cyclohexen-1-yl] methyl] pyridine; monohydrochloride (R)-1,2,3,6-tetrahydro-4-phenyl-1-[[3-(2-thienyl)-2-cyclohexen-1-yl] methyl]pyridine; monohydrochloride (R)-1,2,3,6-tetrahydro-1-[[3-(4-methoxyphenyl)-3-cyclohexen-1-yl]methyl]-4-phenylpyridine; monohydrochloride (R)-3-[5-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1-cyclohexen-1-yl] pyridine; hydrochloride (R)-3-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1-cyclohexen-1-yl] pyridine; R)-1,2,3,6-tetrahydro-1-[[3-(2-were)-2-cyclohexen-1-yl] methyl] -4-phenylpyridine; (R)-1,2,3,6-tetrahydro-1-[[3-(2-were)-3-cyclohexen-1-yl] methyl] -4-phenylpyridine; monohydrochloride (R)-5-[5-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl]-1-cyclohexen-1-yl] pragito-4-phenyl-1-[[3-(3-thienyl)-2-cyclohexen-1-yl] methyl] pyridine; (R)-4-[5-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl]-1-cyclohexen-1-yl]-N,N-dimethylbenzylamine; (R)-4-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1-cyclohexen-1-yl]-N,N-dimethylbenzylamine; (R)-3-[5-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1-cyclohexen-1-yl]quinoline; (R)-3-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] -1-cyclohexen-1-yl]quinoline; monohydrochloride (R)-1-[[3-(1,3-benzodioxol-5-yl)-3-cyclohexen-1-yl] methyl] -1,2,3,6-tetrahydro-4-phenylpyridine; (1S-CIS)-N-[3-[(3,6-dihydro-4-phenyl-1-(2H)-pyridinyl)methyl] cyclohexyl] benzamide; monohydrochloride (1R-CIS)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenylcyclohexyl)methyl] pyridine; monohydrochloride (1R-TRANS)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenylcyclohexyl)methyl] pyridine; monohydrochloride ()-1,2,3,6-tetrahydro-1-[(3-phenyl-3-cyclohexen-1-yl)methyl] -4-(2-thienyl)pyridine; ()-3-[5-[(3,6-dihydro-4-phenyl-1(2H)-pyridinyl)methyl]-1-cyclohexen-1-yl]-1H-indole.

5. Derived 1,3-substituted of cycloalkene formula I on p. 1, representing the (+)-1,2,3,6-tetrahydro-4-phenyl-1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine.

6. Derivatives of 1,3-substituted of cycloalkene and cycloalkane formula I under item 1, in which R is phenyl, unsubstituted or substituted lower alkyl, lower alkoxyl, lower dialkoxy, halogen, hydroxyl, dihydroxyl, aminor the PWM-alkyl, lowest alkoxyl or halogen, 2 - or 3-thienyl, unsubstituted or substituted lower alkyl, lower alkoxyl or halogen, 2-, 3 - or 5-pyrimidinyl, 2-, 3 - or 4-chinoline, 3-indolyl or a group of the formula

< / BR>
Y is a group of the formula

< / BR>
where R is the specified value, m = 1 or 2.

7. Derivatives of 1,3-substituted of cycloalkene and cycloalkane formula I under item 1, in which R is phenyl, unsubstituted or substituted n-halogen, p-metaxylem, o - or p-lower alkyl, mono - or denissa alkylaminocarbonyl in p-position, 2 -, or 3-pyridyl, 2 - or 3-thienyl, 5-pyrimidinyl, 3-chinoline, 3-indolyl or a group of the formula

< / BR>
Y is a group of the formula

< / BR>
where R is the specified value, m = 2.

8. Derivatives of 1,3-substituted of cycloalkene formula I on p. 1 representing ()-1-[(3-phenyl-3-cyclohexen-1-yl)-methyl] -4-(2-pyridinyl)piperazine; ()-1-[(3-phenyl-2-cyclohexen-1-yl)-methyl] -4-(2-pyridinyl)piperazine; ()-1-[[3-(4-forfinal)-3-cyclohexen-1-yl]methyl]-4-(2-pyridinyl) piperazine; ()-1-[[3-(4-forfinal)-2-cyclohexen-1-yl]methyl]-4-(2-pyridinyl) piperazine; (R)-1-[(3-phenyl-3-cyclohexen-1-yl)-methyl]-4-(2-pyridinyl)piperazine, dihydrochloride ()-1-phenyl-4-[(3-phenyl-3-cyclohexen-1-yl)methyl]piperazine; ()-2-[4-[[3-phenyl-3-cyclohexen-1-yl)methyl]-1-piperazinil] pyrimidine; ()-1

 

Same patents:

The invention relates to a method for producing (+) (2R)-endo-norbornene and (-)-(2S)-endo-norbornene and their subsequent transformations, respectively, in pharmaceuticals, 5-(3-[(2S)-endo-norbornene and their subsequent transformations, respectively, in pharmaceuticals, 5-(3-[(2S)-Exo-bicyclo [2.2.1] gate-2-yloxy] - 4-methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2 (1H)he is of the formula:

,

and its enantiomer, 5-(3- [(2R.) -Exo-bicyclo [2.2.1.]hept-2 - yloxy]- 4 - methoxyphenyl)-3,4,5,6-tetrahydropyrimidin-2 (1H)-he, of the formula:

The invention relates to new derivatives isoindoline General formula:

< / BR>
in which the radicals R represent hydrogen atoms or together form a single bond; the radical R' represents a hydrogen atom or easily removable and the radicals R" are identical, represent phenyl radicals which may be substituted by a halogen atom or a methyl radical in the ortho - or meta-position, as well as their salts

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds

The invention relates to piperazinone derivatives, to processes for their production, to their use and to the containing pharmaceutical compositions

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

The invention relates to the field of chemistry, to a method for the chemical substance that manifests anthelminthic properties, and can be used in agriculture to treat animals

The invention relates to organic chemistry, and in particular to methods obtain 1-ethyl-6-fluoro-7-(piperazinil-1)-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid (norfloxacin) formula 1

which is a synthetic antibiotic with a broad spectrum of antibacterial activity, is among the five most active fluoroquinolones (ciprofloxacin, pefloxacin, norfloxacin, enoxacin, ofloxacin) and used as an antibiotic of the fourth generation

The invention relates to new derivatives of benzimidazole, method of production thereof and their use as medicines

The invention relates to new pyridinesulfonamide General formula I or their acceptable for agriculture salts, have a weed-killing activity, as well as to a method for their production and compositions for combating the growth of unwanted vegetation

The invention relates to new derivatives of arylsulfonamides, namely, potassium salt of N-(4,6-dimethylpyrimidin-2-yl)-N'-/2- (methoxycarbonyl)phenylsulfonyl/urea (potassium salt of sulfometuron-methyl), which may find application in forestry planting cedar (Siberian pine, Korean) and non-agricultural land use as a herbicide

The invention relates to a series of substituted 5-arylpyrimidines, to methods for their preparation, to pharmaceutical remedies containing these compounds and to their use in therapy, in particular in the treatment of a range of diseases and disorders of the Central nervous system (CNS)

The invention relates to new derivatives of sulfamethoxypyrazine and herbicides containing them as active ingredients
Up!