Piperazinil and piperidinemethanol and their pharmaceutically acceptable salts, pharmaceutical composition and method of enhancing serotonergic neurotransmission

 

(57) Abstract:

Piperazinil and piperidinemethanol General formula:

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and their pharmaceutically acceptable salts, where R1and R2- H, halogen, CF3C1-C4-alkoxy, and R1and R2cannot simultaneously denote H, and R1and R2if they are adjacent carbon atoms may together form a bridge-0-(CH2)n-0-, where n is an integer from 1 to 3; R3- H, C1-C4-alkyl; R4and R5- H, C1-C4-alkyl or phenyl; Y Is N or CH; Ar is phenyl, 2-thienyl or substituted phenyl of the formula - (C6H4XpX1qwhere the substituents X and X1- halogen, nitro, C1-C4-alkyl, C1-C4-alkoxy, and X and X1together form a bridge-0-(CH2)nwhere n is an integer from 1 to 3; p and q are integers from 0 to 5, and p + q5; disclosed pharmaceutical composition having activity to bind to the serotonin 5-HTIAthe receptor contains a substance of the formula I, and a method of treatment of serotonergic neurotransmission by introducing compounds I. 3 C. and 14 C.p. f-crystals.

The invention mainly relates to biologically active piperazinil and piperidine preparation and use. In some preferred technical solutions the invention relates to a derivative of 1,4-disubstituted piperazine or piperidine, in which the substituent in the 4 position is a benzyl or substituted benzyl, and the substituent in the 1 position is a 4-(1-aryl-cyclohexane-1-ol). These compounds and other structurally related have unique serotonergic profile, which makes them useful for the treatment of anxiety. In U.S. patent No. 4 957 921 Caprathe, etc. describe a series piperazinil-cyclohexanol compounds represented by structural formula A.

Formula A:

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where n takes a value from 0 to 4, Ar and Ar1are aryl or heterocyclic rings.

As you can see on the basis of chemical structures, previously described compounds chemically different from these compounds, because they are the aryl - or heteroaryl-piperazines, while real connection represents a benzyl or heteroaromatic-piperazines (when in formula I, below, Y N) or piperidine (when in formula I, below, Y, CH). In addition, the previously described compounds are biologically different from these compounds, because they have toplistreversal side effects, such as catalepsy. On the contrary, these compounds are serotonergic agents, devoid dopaminergically properties and properties, often related to disorders of the musculoskeletal system. In U.S. patent N 4975445 Caprathe, and others describe a series piperazinil-cyclohexenone compounds of General formula B:

Formula B:

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where R1is aryl or heterocyclic ring, and is 0-2 and n is 0-4. These compounds on the structure and biological activity are also different from these compounds. Connections referenced chemically represents aryl-piperazines, while these compounds are benzyl or heteroaromatic-piperazines. From a biological point of view on dopaminergic properties they differ from the compounds of the invention, which possess serotonergic activity. In addition, are avoided musculoskeletal disorders associated with dopaminergic agents, when the compounds of the invention are applied.

In its broadest aspect the invention relates to certain compounds, which are substituted benzyl - or heteroaromatic-piperazinil cyclohexane or substituted benzyl or heteroaryl. The compound corresponds to the formula I:

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where R1and R2independently selected from H, halogen, CF3or C1-4alkoxy groups, except that R1and R2at the same time cannot be H; and R1and R2when are next door, can form a bridge (n=1-3); R3is H or C1-4by alkyl; R4and R5independently selected from H, C1-4the alkyl or phenyl; Y is N or CH; and Ar is a heteroaryl ring or a substituted or unsubstituted phenyl ring.

The compounds of formula I include all pharmaceutically acceptable salt and/or solvate. The invention also encompasses all stereoisomers of the compounds of formula I.

Pharmaceutically acceptable salt, based on the formula I, can be obtained by using inorganic and organic acids, such as sulfurylase, phosphoric, hydrochloric, Hydrobromic, uudistoodetena, citric, acetic, fumaric, cinnamic, almond, nitrogen, mucus, setinova, palmitic, enanthic and others.

R1and R2can either separately or in combination to be halogen-free. The preferred Halogens are Cl and F, but F is preferable. the, to only one of them was alkoxy. Preferred alkoxy groups are those which contain not more than two carbon atoms. Thus, methoxy, ethoxy are the preferred solutions for R1and R2.

The most suitable compounds in which one of R1and R2are F, and the other OCH3.

R1and R2when located on adjacent carbon atoms, may form a bridging group. Preferably, when a group contains from 3 to 5 atoms, and 2 of the terminal oxygen separated -(CH2)n- (n=1-3) chain. Most preferably, when the compounds contain bridges.

R3can be H or alkyl. Preferably, when R3is 6 or contains not more than two carbon atoms. Therefore, preferably, when R3is H, CH3or C2H5most preferably, when H and CH3.

R4and R5as described above, is chosen independently from H, C1-4the alkyl or phenyl. Preferably, when at least one of R4and R5is H and the other is H or C1-2the alkyl (i.e., H, CH3or C2H5). Most preferably, when both R4

Y can be N or CH. When it can be one or the other, it is preferable to use piperidine (where Y=CH).

Ar may be any of a number of compounds, based on the phenyl or heteroaryl rings. Used heteroaryl groups include 2-thienyl, 2-furanyl and 1-methyl-2-pyrrolyl.

Ar may also be an unsubstituted phenyl group or substituted phenyl group of the General formula II

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where X and X1can be a halogen (preferably Cl or F), nitro, amino, carboxamide, C1-4alkyl, C1-4CNS, C1-4haloalkyl, C1-4alkylthio or similar groups, or X and X1may form together a bridge (n=1-3). p and q can take values from 0 to 5 when p+q5.

Ar can also be a heteroaryl group. Acceptable heteroaryl group containing O, S and/or N and include 3 - and 4-pyridinyl, 2-thienyl, 2-furanyl and 1-methyl-2-pyrrolyl and similar groups.

There are several groups of preferred compounds which correspond to formula I.

The first group are those compounds in which R1=F, R2and R3=H and X=H, F, Cl, Br or OCH3.

The second group is one in which R1=F, R2and R32O - bridge and at least one of X and X1is OCH3.

Still other groups containing molecules, in which R1forms-OCH2O - bridge, R3=C1and X and X1both are F.

The two most preferred groups of compounds are those in which either:

(a) R1and R2form-OCH2O - bridge, and X is F or OCH3or (b) R1or R2is F or CF3and at least one of X and X1is F.

Preferred compounds of formula I include:

Z-1-(1,3-benzodioxol-5-yl)-5-[4-(phenylmethyl)-1-piperidinyl] cyclohexanol;

Z-1-(4-methoxyphenyl)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperazinil] cyclohexanol;

Z-1-(4-methoxyphenyl)-4-[4-(phenylmethyl)-1-piperazinil]cyclohexanol;

Z-1-(4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl]-4-(phenylmethyl)piperazine;

Z-1-(1,4-benzodioxan-6-yl)-4-[4-(phenylmethyl)-1-piperazinil]cyclohexanol;

E-1-(1,4-benzodioxan-6-yl)-4-[4-(phenylmethyl)-1-piperazinil]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(3-methoxyphenyl)methyl]-1 - piperazinil] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(3-forfinal)methyl] -1 - piperazine is benzodioxol-5-yl)-4-[4-[(2-were)methyl] -1 - piperazinil] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2-nitrophenyl)methyl] -1 - piperazinil] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2-chlorophenyl)methyl] -1 - piperazinil] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(2-thienylmethyl)-1-piperazinil]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(2,5-dichlorophenyl)methyl]-1 - piperazinil] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(2,5-differenl)methyl]-1 - piperazinil] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,3-differenl)methyl] -1 - piperazinil]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(3,5-differenl)methyl] -1 - piperazinil]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2-itfinal)methyl] -1 - piperazinil]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(1,3-benzodioxol-4-yl)methyl] -1 - piperazinil]cyclohexanol;

Z-1-(4-forfinal-4-[4-[(3-methoxyphenyl)methyl]-1-piperazinil]cyclohexanol;

Z-1-(4-forfinal-4-[4-[(2-chlorophenyl)methyl]-1-piperazinil]cyclohexanol;

Z-1-(4-forfinal-4-[4-[(2,5-differenl)methyl] -1-piperazinil] cyclohexanol;

Z-1-[(4-trifluoromethyl)phenyl] -4-[4-[(2-chlorophenyl)methyl] -1-piperazinil] - cyclohexanol;

Z-1-[(4-trifluoromethyl)phenyl] -4-[4-[(3-methoxyphenyl)methyl]-1-piperazinil] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4[(2-fluoro-5-methoxyphenyl)methyl]-1-piperazine is-benzodioxan-6-yl)-4-[4-[(3-methoxyphenyl)methyl] -1-piperazinil] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(3-methoxyphenyl)methyl] -1-piperidinyl] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5-differenl)methyl]-1-piperidinyl] cyclohexanol;

Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl] -4-[(3-methoxyphenyl)methyl]piperidine;

Z-1-[4-1,4-benzodioxan-6-yl)-4-methoxy-1-cyclohexyl]-4-[3-(methoxyphenyl)methyl]piperidine fumarate;

Z-1-[4-(1,3-benzodioxol-5-yl)-4-methoxy-1-cyclohexyl] -4-[(2,5-differenl)methyl]piperidine fumarate;

Z-1-(4-forfinal)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol;

Z-1-(4-forfinal)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol;

Z-1-(4-forfinal)-4-[4-[(2,5-differenl)methyl]-1-piperidinyl] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2-bromophenyl)methyl]-1-piperazinil]cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(diphenylmethyl)-1-piperazinil] cyclohexanol;

Z-1-(1,3-benzodioxol-5-yl)-4-[4-(1-phenylethyl)-1-piperazinil]cyclohexanol;

Z-1-[4-(4-forfinal)-4-methoxy-1-cyclohexyl] -4-(3-methoxyphenyl)methyl] piperazine;

Z-1-[4-(4-forfinal)-4-methoxy-1-cyclohexyl] -4-[(3-methoxyphenyl)methyl] piperazine and the like.

Another aspect of the invention relates to a method for treatment of suffering from anxiety or panic disorder, which flucuatuations it acceptable salt, formed upon accession acid.

Although the dosage and dosage regimen in each case must be carefully regulated, using professional sounding and considering the age, weight and health status of the patient, route of admission, the nature and severity of the disease, the daily dose is from 0.01 to 10 mg/kg, preferably from 0.1 to 2 mg/kg, when receiving parenteral, and from 1 to 50 kg/kg when administered orally. For some cases a significant therapeutic effect can be obtained at lower doses, in other cases require higher doses. A systematic method refers to oral, rectal, transnasal, transdermal and parentalia (i.e., intramuscular, intravenous and subcutaneous). It is generally considered that, when the connection is made orally, a greater amount of active agent required to achieve the same effect, if the same amount taken parenterale. According to good clinical practice, it is preferable to make these connections on the concentration level at which receive effective calming effect without any harmful or adverse side effects.

redtwo, or in a mixture with other therapeutic means. Therapeutically they are usually given as a pharmaceutical composition, comprising a sedative number of the compounds of formula I or their pharmaceutically acceptable salt and a pharmaceutically acceptable carrier. The pharmaceutical composition that provides from 1 to 500 kg of active ingredient per unit dose are preferred and are usually prepared in the form of tablets, pellets, capsules, powders, aqueous or maslinic suspensions, syrups, Alexiou and water solutions.

Compounds of the invention are also useful in doses above for prophylactic treatment of migraine (i.e., to prevent headaches migraines). The nature of applied pharmaceutical composition depends of course on the desired path of treatment. For example, oral compositions may be in the form of tablets or capsules and may contain conventional excipient, such as binding agents (i.e., starch) and wetting agents (i.e., sodium lauryl sulphate). Solutions or suspensions of the compounds of formula I with an acceptable pharmaceutical packaging used for parenteral compositions, such as aqueous solution for intravenous injection or an oily suspension for vnutrimy the MA:

Examples 1 and 2.

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The diagram illustrates the preparation of intermediates PA through condensation of cyclohexane-1,4-dione mono-ethylene Catala 4-arylmaleimides or 1-arylmethylidene under conditions of reductive alkylation, such as isopropyl titanium/NaBH4cyanoborohydride sodium, triacetoxyborohydride sodium, etc. Received ketals break down in acidic environments such as acetone/HCl, THF/HCl, acetone/H2SO4, THF/H2SO4, dioxane/HCl, etc. Can also apply other methods known in the literature.

SCHEMA:

Examples 3, 4 and 7-10.

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Intermediate compound PV is prepared as shown in Scheme C. the reaction of cyclohexane-1,4-dione of ion-atelectasia with ORGANOMETALLIC reagents such as Grignard reagents, arily lithium, etc., receive a 4-aryl-4-hydroxy-cyclohexanone ketals III BC These reactions are usually carried out in solvents such as tetrahydrofuran, diethyl ether, dimethoxyethane, dioxane, ethylene glycol dimethyl ether, etc. at a temperature of from -80 to 30oC. Ketals break down in the presence of acid catalyst and receive a 4-aryl-hydroxycyclohexanone Ro. Acids suitable for this hydrolysis are, n entina etc.

SCHEME g:

Examples 5 and 6.

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Preparation of Z-1-aryl-4-piperazinylcarbonyl shown in the Diagram, the 4-Aryl-4-hydroxycyclohexanone PV, prepared according to the Scheme described in, recovery combined with ion-protected Piraino, such as carbobenzoxy, under normal conditions, as described previously in Scheme a, and get protected Z-1-aryl-4-piperidinemethanol. Other acceptable protected groups for piperazine are, but are not limited to, methylcarbamate, ethylcarbamate, tert.BUTYLCARBAMATE, acetyl, formyl, propionyl, metalfoil, n-toluensulfonyl, benzyl, suitable substituted benzyl, etc., 1-Aryl-4-piperazinecarboxamide usually obtained as a mixture of destroydb that can successfully divide by methods known in the literature. These methods include, but are not limited to, recrystallization, chromatographic accommodation, using simple absorbate, such as silica (silicon oxide), aluminum oxide, etc., Protected Z-1-aryl-4-piperazinecarboxamide released from the protecting groups using methods known in the literature. These methods include, but are not limited to, catalytic reduction, restoration of molten Michelle otseplena etc.

SCHEME d:

Examples 11-13.

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Scheme d illustrates the preparation of substituted arylmethylidene. By the reaction of either pyridine-4-aldehyde-or 4-cyanopyridine with suitable ORGANOMETALLIC reagents such as Grignard reagents, arily lithium etc. is received intermediate the alcohol and the ketone shown in the Diagram D. These organometallics reaction is usually carried out as described for Scheme C. the Intermediate alcohol and ketone to restore substituted arylmethyl-pyridine under conditions well known in the literature. Such conditions catalytic reduction include catalysts such as palladium on carbon, etc., and a source of hydrogen such as hydrogen gas, ammonium salt of formic acid or hydrazine ammonium, etc., With further recovery of pyridine is usually in acidic conditions, using a catalyst such as palladium oxide, etc. get the desired substituted - arylmethylidene.

SCHEME:

Example 14.

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In the Diagram shown getting substituted arylmethylidene. Suitable substituted killdevil recovery combined with piperazine or ion-protected piperazine, such as carbobenzoxy. Other acceptable protecting group to the piperazine described for Scheme C. Protected arylmethylidene released from the protecting groups by conventional means described for Scheme C. in Contrast, a suitable substituted arylmethyl halide lamp can be used for alkylation of piperazine in standard conditions, as described more fully for the Schema,

SCHEME W:

Examples 15-18 and 20.

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In the Diagram W retrieves the desired 1-aryl-4-/4-arylmethyl-1-piperidinyl/cyclohexanol and 1-aryl-4-/4-arylmethyl-1-piperazinil/cyclohexanol 1A by adding organometallics reagents, such as Grignard reagents or arily lithium, etc., to 4-/4-arylmethyl-1-piperidinyl/cyclohexanone and 4-/4-arylmethyl-1-piperazinyl/cyclohexanone. The reaction can be carried out in an inert solvent, such as tetrahydrofuran, diethyl ether, dimethoxyethane, diethylene glycol, dimethyl ether, etc., at temperatures from -100 to 25oC. the Right connections get usually in the form of diastereoisomeric mixtures, which can be divided as described for Scheme d above.

SCHEME C:

Example 19.

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Getting 1-/4-aryl-4-alkoxy-1-cyclohexyl/-4-/arylmethyl/-piperidinol and 1/4-aryl is analy and 1-aryl-4-/4-arylmethyl-1-piperazinil/cyclohexanol 1A react with an alkylating agent and a suitable base in an appropriate solvent, such as tetrahydrofuran, dimethyl ether, dimethylformamide, dimethylacetamide, dimethylsulfoxide, dioxane, dimethoxyethane, ethylene glycol, dimethyl ether, etc., and obtaining the desired product 1B. Suitable bases include, but are not limited to, sodium hydride, potassium hydride, calcium hydride, lithium hydride, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, butyl lithium, methyl lithium, phenyl lithium, etc., Alkylating agents include, but are not limited to, methyl iodide, ethyl iodide, dimethylsulfate, diethylsulfate, propyl iodide, propyl bromide, methyl triftorbyenzola, ethyl triftorbyenzola, methyl triptorelin, ethyl triptorelin, etc. Can be used other methods known in the literature.

The SCHEME is to:

Examples 21-27.

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In the Diagram it shows the derivation of the 1-aryl-4-/4-arylmethyl-1-piperazinil/cyclohexanol 1A /Y= N/ 1-aryl-4-piperazinylcarbonyl D. 1-aryl-piperazinecarboxamide can alkylaromatic under standard conditions known in the literature, such as using arylmethyl halide compounds, arylmethyl para-toluensulfonate, arylmethyl methosulphate, etc. in the presence of bases, that is an, acetone, dichloroethane, dimethylformamide, dimethylacetamide, dimethyl sulfoxide, etc., in Addition, as the base can also be used sodium carbonate, potassium bicarbonate, sodium bicarbonate, triethylamine, Tripropylamine, tributylamine, pyridine, etc., in addition, 1-aryl-4-piperazinil-cyclohexanol PA can be restorative alkilirovanny aryl aldehydes using cyanoborohydride sodium, triacetoxyborohydride sodium, lithium borohydride, sodium borohydride, sodium borohydride/isopropyl titanium and similar regenerative agents, to obtain the 1-aryl-4-/4-arylmethyl-1-piperazinil/cyclohexanol 1A. Arylketones can be used instead of arilaldegidov to obtain 1-aryl-4-[4-/1-aryl-1-alkyl/piperazinil]cyclohexanol.

Alternative 1-aryl-4-/4-arylmethyl-1-piperazinil/cyclohexanol 1A can be obtained from 1-aryl-4-piperazinylcarbonyl PV through preparation of an aryl carboxamide, followed by recovery of the product 1A. Suitable conditions for obtaining the amides include the reaction of an aryl halide compound with 1-aryl-4-piperazinylcarbonyl in the presence of an acceptable base, such as triethylamine, Tripropylamine, tributylamine, pyridine, potassium carbonate, sodium carbonate, Gran, dimethoxyethane, benzene, toluene, xylene, acetonitrile, acetone, dioxane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc., the Reaction is usually carried out at temperatures from 30 to 120oC. the Aryl carboxamide can also be obtained by the reaction arylcarboxylic acids combining agent such as carbonyl diimidazole, followed by reaction with 1-aryl-4-piperazinylcarbonyl PA. In addition, arylcarboxamide can be obtained by the reaction of 1-aryl-4-piperazinylcarbonyl with ether arylcarbamoyl acid in an acceptable solvent such as acetonitrile, acetone, dioxane, tetrahydrofuran, dimethoxyethane, benzene, toluene, xylene, dichloroethane, dimethylformamide, dimethylacetamide, dimethylsulfoxide, etc., at temperatures from 25 to 150oC. Intermediate arylcarboxamide can be restored reagents such as lithium aluminum hydride, diisobutylaluminium hydride, DIBORANE, sodium bis/2-methoxyethoxy/aluminum hydride, etc. in a suitable solvent, such as tetrahydrofuran, dimethoxyethane, diethyl ether, dioxane, benzene, toluene, xylene, diethylene glycol, dimethyl ether, etc., the Recovery can be performed at temperatures from 0 to 120oC. you Can also use other met this invention, methods for their preparation and their biological activity will be better appreciated upon consideration of the following examples, which are presented here only to illustrate, but not limit the invention. In the following examples, temperatures are in degrees Celsius and the melting temperature is inaccurate. If you have not installed specifically, all percentages given here as a weight percentage relative to the total weight of the composition.

The following examples describe in detail the receipt of each method, compounds of the formula I and also synthetic intermediate product of formula II. Obviously based on literature data that the modification of both materials and techniques will allow you to obtain other compounds similar to the above.

A. the production of intermediate compounds of formula P.

Some typical procedures for obtaining synthetic intermediate compounds above are given here below. Most of the source materials and some intermediate compounds are either industrial or methods of obtaining them are available in the chemical literature, allowing them full qualified use.

Example 1. 4-[4-/Phenylmethyl/-1-piperidinyl]cyclohexanone (PA; Y CH)
the tilen of Catala (7,81 g, 50 mmol) and gently heated. After stirring for 18 h yellow oil was diluted with ethanol (100 ml) and added NaBH4(2 g). The mixture is stirred for 4 hours and add water (10 ml) for deposition of TiO2. The mixture is filtered and the filtrate is concentrated under vacuum and get $ 15.87 with g (100%) crude ketal intermediate compounds in the form of tanning solid. This intermediate compound is stirred in a mixture of THF (75 ml) and 50% H2SO4(75 ml) for 20 hours the Acid is neutralized NaOH /50%/ and Na2CO3when cooled in a water bath. The ketone is extracted with ether and concentrated in vacuo. This yellow oil is dispersed on the kugelrohr apparatus and receive a colorless oil, which solidified upon standing and get 8,30 g (61,3%) of the ketone as colorless crystals.

Example 2. 4-[4-/Phenylmethyl/-1-piperazinil]cyclohexanone (PA; Y N).

Isopropyl titanium /IV/ (74 ml) are added to a mixture of 1-benzylpiperazine (35.2 g, 200 mmol) and 1,4-cyclohexandione monoethylene Catala (31,2 g, 200 mmol) and stirred until then, until it is observed absorption ketone in the IR spectra. The yellow oil was diluted with ethanol (200 ml) and added NaBH4(7.6 g, 200 mmol). The mixture is stirred for 16 hours and add water (37 ml) for ogadeniyaay IN HCI. Acid leaching process K2CO3and the basic mixture is extracted with methylene chloride. The extracts are dried over K2CO3and concentrate under vacuum, get 56,5 g Catala, which is stirred in a mixture of THF (300 ml) and 50% H2SO4(300 ml) for 2 hours the Solution was diluted with water (500 ml) and carefully treated with H2CO3. The basic mixture is extracted with ether and the extract was dried over sodium sulfate. After concentrating the extract under vacuum and recrystallization from isopropyl ether to give the product (41 g, 71% so pl. 83-85oC).

Example 3. 8-/1,3-Benzodioxol-5-yl/-1,4-dioxaspiro[4,5]Decan-8-ol (CHF).

To a solution of 1,4-cyclohexanedione of monoelemental (31,2 g, 0.2 mmol) in 100 ml dry THF added at -60oC solution of Grignard reagent prepared from magnesium metal (7.2 g, 0.3 mmol) and 5-bromo-1,3-benzodioxol (60,3 g, 0.3 mmol). The mixture is heated to 25oC and quenched with a saturated solution of NH4Cl and extracted with ether. The extracts are dried over Na2SO4and the solvent is removed under vacuum. The residue is recrystallized from isopropyl ether and receive the product (47,5 g, 85% so pl. 103-104oC).

Example 4. 4-/1,3-benzodioxol-5-yl/-4-hydroc the l of acetone, 1 ml 12 NHCI and 50 ml of water is stirred for 2 hours After dilution extension 50 ml of water collect solid and receive the product (4.0 g, 95% so pl. 166-168oC).

Example 5. Phenylmethyl Z-4[4-/1,3-benzodioxol-5-yl/-4-hydroxycyclohexyl]-1-piperidinecarboxylate (GHG) emissions.

A mixture of phenylmethyl 1 piperidinecarboxylate (5,65 g of 25.7 mmol), isopropylate titanium /IV/(17 ml, 50 mmol) and 4-/1,3-benzodioxol-5-yl/-4-hydroxycyclohexanone (6.0 g, of 25.7 mmol) is stirred for 18 hours the Mixture is dissolved in 50 ml of ethanol and add sodium borohydride (1.0 g, of 25.7 mmol). After stirring for 16 h the mixture was quenched with 15% solution of sodium hydroxide (6 ml). The mixture is filtered and the filtrate concentrated under vacuum. The residue is acidified INHCl and get a solid substance. The solid is collected and suspended in water. The mixture is treated with sodium hydroxide and extracted with methylene chloride. The extract was dried over Na2SO4and concentrate under vacuum. The residue is recrystallized from isopropyl ether and receive the product (2.4 g, 22% so pl. 122-124oC).

Analysis for C25H30N2O50.5 H2O:

Calculated C 67,10; H 6,99; N 6,26;

Found, C 67,18; H 6,8; N 6,26.

Example 6. Z-1/1,3-benzodioxol-5 - yl/-4-/1-piperazinecarboxamide (0,44 g, 1 mmol) and 10% palladium on charcoal (0.1 g) is subjected to hydrogenization for 1 h, the Catalyst is filtered off and the filtrate concentrated under vacuum. The residue is recrystallized from isopropylacetate and receive the product (0,30 g, 93.5 per cent so pl. 198-199oC).

Analysis for: C17H24N2O3:

Calculated C 65,16; H 8,05; N 8,94;

Found, C 65,27; H Of 7.69; N 8,83.

Example 7. 8-/4-forfinal/-1,4 - dioxaspiro[4,5]Decan-8-ol.

This compound is obtained from 1,4-cyclohexandione monoethylene Catala (6,24 g, 40 mmol) and 4-forfinal magnesium bromide (60 mmol) by the method of example 3. The crude product is recrystallized from hexane and receive the product in (8.9 g, 88%).

Example 8. 8-[/4-Trifluoromethyl/phenyl]-1,4-dioxaspiro[4,5]Decan-8-ol.

This compound is obtained from 1,4-cyclohexandione monoethylene Catala (310,9 g, 70 mmol) and the Grignard reagent prepared from 4-bromobenzonitrile (25,0 g, 110 mmol) and magnesium (2.7 g, 110 mmol) by the method of example 3. The crude product is recrystallized from petroleum ether and receive the product (20 g, 94,8%).

Analysis for C15H17F3O3:

Calculated With 59,60; H 5,67;

Found, C 59,77; H 5,62.

Example 9. 4-/4-Forfinal/-4-hydroxycyclohexanone.

oC).

Analysis for C12H13FO2:

Calculated With 69,22; H 6,30;

Found, C 69,32; H 6,34.

Example 10. 4-[4-/Trifluoromethyl/phenyl]-4-hydroxycyclohexanone.

This compound is obtained from 8-[4-trifluoromethyl/phenyl] -1,4-dioxaspiro [4,5] Decan-8-ol (10 g, 33 mmol) by the method of example 4. The crude product is recrystallized from isopropyl ether and receive the product (7.5 g, 90.4 percent ).

Analysis for C13H13F3O2:

Calculated With 60,47; H 5,71;

Found, C 60,63; H 4,99.

Example 11. 4-/3-Methoxybenzyl/piperidine.

Stage I.

To a solution of 4-cyanopyridine in THF add the Grignard reagent prepared from 3-bromoanisole time (37.4 g, 200 mmol) and magnesium (4.8 g, 200 mmol) in THF (400 ml) at -78oC. the Solution is heated to 25oC and quenched with a solution of ammonium chloride. The organic layer is separated and washed with water and 3N hydrochloric acid. Acid washing is stirred for 0.5 h and neutralized with 50% sodium hydroxide solution. The basic mixture is extracted with ether. The extracts are dried and concentrated under vacuum. The crude substance is recrystallized is 25 g) is added to a mixture of 4-/2-methoxybenzoyl/-pyridine (27 g, 127 mmol) and 10% palladium on charcoal (7 g) in acetic acid (250 ml). The mixture is heated vertical refrigerator for 15 hours the Mixture is cooled and diluted with an equal volume of methylene chloride. The catalyst was removed and the solution concentrated under vacuum. The residue is dissolved in water and treated with sodium hydroxide. The mixture is extracted with ether. The extracts are dried and concentrated under vacuum and obtain raw 4-/3-methoxybenzyl/pyridine (25 g, 98.8 per cent), which is used without purification in the next stage.

Stage 3.

A mixture of 4-/3-methoxybenzyl/pyridine (25 g, 126 mmol) and platinum oxide (2.4 g) in acetic acid (250 ml) is subjected to hydrogenation for 2 hours, the Catalyst was removed and the solution concentrated under vacuum. The residue is dissolved in water and the solution is treated with sodium hydroxide. The basic mixture is extracted with ether. The extracts are dried and concentrated under vacuum. The residue is dispersed under vacuum and get 4-/3-methoxybenzyl/piperidine in the form of oil (22,6 g, 87,). Hydrochloric acid sample is prepared in ether (so pl. 146-147oC).

Analysis for C13H19NOHCI:

Calculated With 64,59; H a 8.34; N 5,80;

Found, C 64,38; H A 8.34; N 5,66.

Example 12. 4-/2.5-Diferensial/piperidine.

Stage 1.

Stage 2.

A mixture of 4-/2.5-differentail/pyridine (7,3 g, 33.3 mmol) and 10% palladium on charcoal in triperoxonane acid (50 ml) is subjected to hydrogenation for 24 hours, the Catalyst was removed and the solution concentrated under vacuum. The residue is dissolved in water and treated with sodium hydroxide. The basic mixture is extracted with ether and the ether extracts are concentrated under vacuum. Crude 4-/2.5-diferensial/pyridine used in the next stage without purification.

oC). Hydrochloric acid sample get in the air (so pl. 146-147oC).

Analysis for C12H15H2N. HCl:

Calculated C 58,19; H of 6.52; N 5,66;

Found, C 58,14; H 6,56; N 5,59.

Example 13. 4-/2-fluoro-5-methoxybenzyl/piperidine.

Stage 1.

Butyl lithium (47,5 ml 2,22 M solution, is 105.6 mmol) is added slowly to a solution of pentamethyldiethylenetriamine (15 ml) and 4-fernicola (12,61 g, 0.1 mol) in THF (150 ml) at -70oC. the Solution is stirred for 2 h at -75oC and -75oC add a solution of pyridine-4-aldehyde (of 9.55 ml, 0.1 mol) in THF. The mixture is slowly heated to 25oC and then quenched with ammonium chloride solution. The mixture is diluted with ethyl acetate and the organic layer separated. The organic layer is washed with water and 3N hydrochloric acid. Acid washing is then treated with sodium hydroxide and extracted with ether and the ether solution concentrated under vacuum. The crude product is recrystallized from 80% ethane is output).

Stage 2.

Mix /2-fluoro-5-methoxyphenyl/-4-pyridinemethanol and 10% palladium on charcoal in triperoxonane acid is subjected to hydrogenation analogously as in example 12, step 2. The catalyst is removed and the solution concentrated under vacuum. The residue is dissolved in water and treated with sodium hydroxide. The basic mixture is extracted with ether and the ether extracts are concentrated in vacuo. Crude 4-/2-fluoro-5-methoxybenzyl/pyridine is used without purification in the next stage.

Stage 3.

A mixture of 4-/2-fluoro-5-methoxybenzyl/pyridine (7.7 g, 35.5 mmol) and platinum oxide (0.7 g) in acetic acid is subjected to hydrogenation for 3 hours, the Catalyst was removed and acetic acid is removed under vacuum. The residue is dissolved in water and the solution is treated with sodium hydroxide. The basic mixture is extracted with ether. The extracts are dried and concentrated under vacuum. The residue is dispersed under vacuum and get the product (6 g, 75,9%).

Example 14. 4-/2-Fluoro-5-methoxybenzyl/piperazine.

A solution of 2-formyl-4-methoxyphenol (5.0 g, 33 mmol I. Organic Chem. 53/14/, R 3145, 1988), piperazine (25,88 g, 3 mol) and Lamborghini sodium is 3.08 g, 50 mmol) in ethanol (400 ml) is heated under reflux for 18 hours Then araneida. Methylenechloride extracts are concentrated under vacuum and the residue is dissolved in INHCl. The acidified solution is extracted with methylene chloride and then treated with the hydrochloride of sodium. The product is extracted from the aqueous basic solution with methylene chloride. Concentrating methylenechloride extracts under vacuum to give the product as a slightly yellow oil (3,63 g, 50%).

C. Obtaining compounds of Formula I.

Example 15. Z-I-/I 3-Benzodioxol-5-yl/-4-[4-/phenylmethyl/-1-piperidinyl] cyclohexanol.

A solution of 4-[4-/phenylmethyl)-1-piperazinyl] cyclohexanone (2.5 g, 9,23 mmol) in dry THF (20 ml) are added to a Grignard reagent prepared from magnesium metal (0.50 g, 20,5 mmol) and 5-bromo-1,3-benzodioxole (2,84 g, 14.1 mmol) in dry THF (25 ml). The reaction mixture was stirred for 1 h before quenching with saturated NH4Cl and extraction with ether. The ether extracts dried tsolkas and concentrate under vacuum. The crude product is recrystallized twice from 20% ethyl acetate/n-hexane and dried under vacuum, get fluffy white crystals (1.25 g, 34.5 per cent so pl. 187-190,5oC).

Analysis for C25H31NO3:

Calculated C 76,30; H 7,94; N 3,56;

Found: C 76,30; H 8,11; N 3,76.

from the Grignard reaction of 4-methoxy-fenermine bromide (10 mmol) with 4 - [4-/phenylmethyl/-1-piperidinyl]-cyclohexanone (5.9 mmol) analogously to the method above. The crude product is recrystallized twice from 10% ethyl acetate/C-hexane and get a white crystalline flakes (0.50 g, 22% so pl. 177-179oC).

Analysis for C25H33NO2:

Calculated With 79,11; H 8,77; N 3,69;

Found, C 79,41; H 8,82; N 3,64.

Example 17. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-/phenylmethyl/-1-piperazinil] cyclohexanol.

This connection get the Grignard reaction of 1,3-benzodioxol-5-yl-magnesium bromide with 4-[4-/phenylmethyl/-1-piperazinil]cyclohexanone is similar to the method above. The crude product is recrystallized from isopropylacetate and get the product with 22% of output (so pl. 167-168oC).

Analysis for C24H30N2O3:

Calculated C 73,07; H to 7.67; N 7,11;

Found, C 73,05; H To 7.67; N 7,09.

Example 18. Z-1-/4-Methoxyphenyl/-4-[4-/phenylmethyl/-1-piperazinil]-cyclohexanol.

This compound is obtained from the Grignard reaction of 4-methoxy-fenermine bromide with 4-[4-/phenylmethyl/-1-piperazinil]-cyclohexanone similar to the method above. The crude substance is recrystallized from isopropylacetate and get the product with 50% output (so pl. 179-180oC).

Analysis for C24H30N2O2:

Calculated C 75,76; H the l/piperazine.

Sodium hydride (0.1 g, 2.5 mmol) are added to a solution of Z-1-/1,3-benzodioxol-5-yl/-4-[4-/phenylmethyl/-1-piperazinil] cyclohexanol (1.0 g, 2.5 mmol) in dry THF (10 ml). After stirring for 1 h the mixture is cooled to 5oC and add logmean (0.36 g, 2.5 mmol) the mixture is stirred for 18 hours the Mixture was diluted with water (25 ml) and extracted with CH2Cl2. The extracts are dried over Na2SO4and concentrate under vacuum. Insoluble Quaternary organic food is removed by grinding to a powder with isopropanol. The isopropanol is then removed under vacuum. The source material is removed by rubbing with ether and the ethereal filtrate is passed through a chromatographic column filled with silica gel, using methanol (CH2Cl21:50), get a solid (50 mg, 5% of T. pl. 108-109oC).

Analysis for C25H32N2O30.5 H2O:

Calculated C 71,91; H of 7.97; N OF 6.71;

Found, C 71,71; H 7,50; N 6,62.

Example 20. Z-1-/1,4-Benzodioxan-6-yl/-4-[4-/phenylmethyl/-1-piperazinil] cyclohexanol and E-1-/1,4-Benzodioxan-6-yl/-4-[4-/phenylmethyl/-1-piperazinil] cyclohexanol.

These compounds get the Grignard reaction of 1,4-benzodioxan-6-yl-magnesium bromide and 4-[4-/phenylmethyl/-1-piperazinil] Ziklag is 24% output (so pl. 178-179oC).

Analysis for C25H32N2>O30,05 H2O:

Calculated With 73,34; H to $ 7.91; N 6,85;

Found, C 73,04; H To $ 7.91; N 7,25.

E-isomer is separated from the mother liquor of the connections shown above, using a chromatographic column with silica gel, using as eluent methanol/methylene chloride (1:50), receive the E-isomer from 3.4% output (so pl. 126-128oC/.

Analysis for C25H32N2O30,05 H2O:

Calculated C 73,34; H to $ 7.91; N 6,85;

Found, C 72,90; H To $ 7.91; N 7,25.

Example 21. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperazinil]cyclohexanol.

A mixture of 3-methoxybenzyl chloride (0.24 g, 1.5 mmol), Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinil)cyclohexanol (0.45 g, 1.5 mmol) and excess potassium carbonate in acetonitrile (20 ml) is heated under reflux for 72 hours Insoluble compounds are removed, the solution is concentrated under vacuum and the residue is recrystallized from isopropyl acetate and receive the product (0,38 g, 60.3 per cent so pl. 166-167oC).

Analysis for C25H32N2O4:

Calculated C 70,73; H 7,60; N 6,60;

Found, C 70,58; H 7,47; N 6,51.

Example 22. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-(3-forfinal)methyl] -1- -Pieper is anola and 3-terbisil chloride analogously to example 21. The crude product is recrystallized from isopropylacetate and receive a white solid (74,1% so pl. 159-160oC).

Analysis for C24H29FN2O30,2 H2O:

Calculated C 69,28; H 7,13, N 6,74;

Found, C 68,97; H Of 6.96; N 6,58.

Example 23. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-[(2-forfinal)methyl] -1- -piperazinil]cyclohexanol.

This compound is obtained from Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinil)of cyclohexanol and 2-terbisil chloride analogously to example 21. The crude product is recrystallized on isopropylacetate and receive a white solid (72,5% so pl. 160-161oC).

Analysis for C24H29FN2O3:

Calculated C 69,88; H to 7.09; N 6,62;

Found, C 69,79; H 7,08; N 6,62.

Example 24. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-[(2-were)methyl]-1-piperazinil]-cyclohexanol.

This compound is obtained from N-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinil)of cyclohexanol and 2-methylbenzyl chloride analogously to example 21. The crude product is recrystallized from isopropylacetate and receive a white solid (82% so pl. 168-170oC).

Analysis for C25H32N2O30,2 H2O:

Calculated C 72,86; H of 7.93; N 6,80;

H2O 0,87;

Found, C 73,02; H To $ 7.91; N.

This compound is obtained from Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinil)of cyclohexanol and 2-nitrobenzyl chloride analogously to example 21. The crude product is recrystallized from isopropylacetate and receive a white solid (72,7% so pl. 200-201oC).

Analysis for C24H29N3O5:

Calculated C 65,59; H 6,66; N TO 9.57;

Found, C 65,51; H 6,69; N 9,45.

Example 26. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-(2-thienylmethyl)-1-piperazinil] cyclohexanol.

A solution of Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinil)cyclohexanol (0.6 g, 2 mmol), thiophene-2-carboxaldehyde (0,22 g, 2 mmol) and cyanoborohydride sodium (0.12 g, 2 mmol) in ethanol is heated under reflux for 36 hours To the solution was added water (5 ml) and the ethanol removed under vacuum. The residue is extracted with methylene chloride. The extracts are dried over Na2SO4and concentrate under vacuum. The crude product is recrystallized from isopropylacetate and get a solid beige color (0.39 g, and 48.8% of T. pl. 161-163oC).

Analysis for C22H28N2O3S:

Calculated C 65,97; H 7,05; N 6,97;

Found, C 65,94; H 7,05; N 6,97.

Example 27. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-(2-chlorophenyl)methyl]-1-piperazinil]-cyclohexanol.

oC).

Analysis for C24H29ClN2O3:

Calculated C 67,21; H 6,82; N 6,54;

Found, C 66,89; H 6,86; N 6,51.

Example 28. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-[(2,5-dichlorophenyl)methyl]-1-piperazinil]-cyclohexanol.

This compound is obtained from Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinil)cyclohexanol and 2.5-dichlorobenzyl chloride analogously to example 21. The crude product is recrystallized from isopropyl ether and receive a white solid (65,2% so pl. 158-159oC).

Analysis for C24H28Cl2N2O3:

Calculated C 62,20; H 6,09; N 6,05;

Found, C 62,26; H 6,11; N Of 6.96.

Example 29. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-[(2,5-differenl)methyl]-1 - piperazinil]cyclohexanol.

This compound is obtained from Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinil) cyclohexanol and 2.5-diferensial bromide analogously to example 21. The crude product is recrystallized from isopropylacetate and receive a white solid (46,0% so pl. 154-156oC).

Analysis for C24H28F2N2O30,2 H2O:

Calculated With 71,68; H 7,87; N 6,97;

Found, C 71,57; NTO the connection is obtained from Z-1-(4-forfinal)-4-(1-piperazinil)of cyclohexanol and 2-Chlorobenzyl chloride analogously to example 21. The crude product is recrystallized from isopropylacetate and receive a white solid (80.2% of so pl. 164-165oC).

Analysis for C23H28CIFN2O:

Calculated C 68,56; H 7,00; N 6,95;

Found, C 68,28; H 6,92; N 6,86.

Example 36. Z-1-(4-Forfinal)-4-[4-[(2,5-differenl)methyl]-1-piperazinil] cyclohexanol.

This compound is obtained from Z-1-(4-forfinal)-4-cyclohexanol and 2.5-diferensial bromide analogously to example 21. The crude product is recrystallized from isopropylacetate and receive a white solid (84.3 percent so pl. 149-151oC).

Analysis for C23H27F3N2O0,5 H2O:

Calculated C 66,81; H 6,83; N IS 6.78;

Found, C 66,46; H 6,50; N 6,64.

Example 37. Z-1-[(4-Trifluoromethyl)phenyl]-4-[4-(2-chlorophenyl)methyl]-1-piperazinil]cyclohexanol.

This compound is obtained from Z-1-[(4-trifluoromethyl)phenyl]-4-(1-piperazinil)of cyclohexanol and 2-Chlorobenzyl chloride analogously to example 21. The crude product is recrystallized from isopropyl ether and receive solid beige color (45,2% so pl. 161-162oC).

Analysis for C24H28CIF3N2O:

Calculated C 63,64; H 6,23; N IS 6.19;

Found, C 63,26; H 6,27; N 6,20.

Example 38. Z-1-[(4-Cryptomate tormentil)phenyl]-4-hydroxycyclohexanone, isopropylate titanium, sodium borohydride and (3-methoxybenzyl)piperazine as in example 5. The crude product is recrystallized from isopropyl ether and receive solid beige color (46,4% so pl. 131-132oC).

Analysis for C25H31F3N2O30.5 H2O:

Calculated C 72,61; H 8,13; N 3,14;

Found, C 72,33; H 7,94; N To 3.02.

Example 42. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidine]cyclohexanol.

This compound is obtained from 4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexanone, isopropyl titanium, sodium borohydride and 4-(3-methoxybenzyl)piperidine analogously to example 5. The crude product is recrystallized from isopropylacetate and receive a white solid (4.9 percent so pl. 164-165oC).

Analysis for C26H33NO4:

Calculated C 73,73; H a 7.85; N 3,31;

Found, C 73,45; H 7,88; N 3,20.

Example 43. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-[(2,5-differenl)methyl]-1-piperidinyl]cyclohexanol.

This compound is obtained from 4-(1,3-benzodioxol-5-yl)-4-hydroxycyclohexanone, isopropyl titanium, sodium borohydride and 4-(2,5-diferensial)piperidine analogously to example 5. The crude product is recrystallized from isopropyl ether and receive>Calculated C 60,91; H for 6.81; N 3,26;

Found, C 69,82; H Of 6.71; N 3,24.

Example 44. Z-1-[4-(1,3-Benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[(3-methoxyphenyl)methyl]piperidine.

This compound is obtained from 4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl, isopropyl titanium, sodium borohydride and 4-(3-methoxybenzyl)piperidine analogously to example 5. The crude product is recrystallized from hexane and receive a white solid (78% so pl. 89-90oC).

Analysis for C27H35NO4:

Calculated With 74,11; H of 8.06; N 3,20;

Found, C 73,89; H 8,00; N 3,15.

Example 45. Z-1-[4-(1,4-Benzodioxan-6-yl)-4-methoxy-1-cyclohexyl]-4-[3-(methoxyphenyl)methyl]piperidine fumarate.

This compound is obtained from 4-(1,4-benzodioxan-6-yl)-4-methoxycyclohexanone, isopropyl titanium, sodium borohydride and 4-(3-methoxybenzyl)piperidine analogously to example 5. The crude product is converted into salt fumarata in ethyl acetate-methanol and receive a white solid (16.7% of so pl. 165-170oC).

Analysis for C28H37NO4C4H4O4:

Calculated C 67,70; H 7,28; N 2,47;

Found, C 67,29; H 7,10; N, 2,46.

Example 46. Z-1-[4-(1,3-Benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[2,5-differenl)methyl]piperidine fumarate.

Analysis for C26H31F2NO3C4H4O40,1 H2O:

Calculated C 64,18; H 6,32; N 2,50;

Found, C 63,93; H 6,27; N, 2,53.

Example 47. Z-1-(4-forfinal)-4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanol.

This compound is obtained from 4-(4-forfinal)-4-hydroxycyclohexanone, isopropyl titanium, sodium borohydride and 4-benzylpiperidine analogously to example 5. The crude product is recrystallized from isopropylacetate and receive a white solid (44.4% of so pl. 160-161oC).

Analysis for C24H30FNO0,2 H2O:

Calculated C 77,67; H compared to 8.26; N 3,78;

Found, C 77,74; H 8,13; N Of 3.78.

Example 48. Z-1-(4-forfinal)-4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl] cyclohexanol.

This compound is obtained from 4-(4-forfinal)-4-hydroxycyclohexanone, isopropyl titanium, sodium borohydride and 4-(3-methoxybenzyl)piperidine analogously to example 5. The crude product is recrystallized from isopropylacetate and receive a white solid (12.5 percent so pl. 169-170oC).

Analysis for C24H32FNO20.5 H2O:

Calculated C 73,86; H 8,18; N 3,45;

ol.

This compound is obtained from 4-(4-forfinal)-4-hydroxycyclohexanone, isopropyl titanium, sodium borohydride and 4-(2,5-diferensial)piperidine analogously to example 5. The crude product is recrystallized from isopropyl ether and receive a white solid (61.5% of so pl. 162-163oC).

Analysis for C24H28F3NO:

Calculated C 71,44; H 7,00; N 3,47;

Found, C 71,23; H 7,12; N 3,42.

Example 50. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-[(2-bromophenyl)methyl]-1 - piperazinil]cyclohexanol.

This compound is obtained from Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperidinyl)of cyclohexanol and 2-bromobenzyl bromide analogously to example 21. The crude product is recrystallized from isopropylacetate and receive a white solid (84,5% so pl. 169-170oC).

Analysis for C24H29BrN2O3:

Calculated C 60,90; H 6,18; N OF 5.92;

Found, C 61,26; H Of 6.26; N Of 5.82.

Example 51. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-(diphenylmethyl)-1-piperazinil]-cyclohexanol.

This compound is obtained from Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinil)cyclohexanol and chloritrimeton analogously to example 21. The crude product is recrystallized from isopropylacetate and get a white kristali (87,8% so pl. 210-211oC).

26; N 5,96.

Example 52. Z-1-(1,3-Benzodioxol-5-yl)-4-[4-(1-phenylethyl)-1-piperazinil] cyclohexanol.

This compound is obtained from Z-1-(1,3-benzodioxol-5-yl)-4-(1-piperazinil)cyclohexanol, isopropylate titanium, sodium borohydride and acetophenone analogously to example 5. The crude product is recrystallized from isopropylacetate and receive a white solid (90% so pl. 177-178oC).

Analysis for C25H32N2O30,3 H2O:

Calculated C 72,86; H of 7.93; N 6,80;

Found, C 72,74; H 7,76; N 6,76.

Example 53. Z-1-[4-(4-forfinal)-4-methoxy-1-cyclohexyl]-4-[(3-methoxy-phenyl)methyl]piperazine.

Stage 1.

Sodium hydride (1.27 g, and 31.7 mmol) are added to a solution of 8-(4-forfinal)-1,4-dioxaspiro[4,5] Decan-8-yl (8.0 g, 10 mmol) in THF (100 ml) and the mixture stirred for 16 h under reflux for 4 hours the Solution is cooled to 25oC and add itmean (6.75 g, or 47.6 mmol). The mixture is stirred for 112 h and concentrated under vacuum. The residue is suspended in water and the mixture extracted with methylene chloride. The extracts are dried, concentrated under vacuum and receive 8-(4-forfinal)-1,4-dioxaspiro[4,5]Decan-8-yl methyl ether (98,8% so pl. 52-54oC).

Stage 2.

Stage 3.

A mixture of 4-(4-forfinal)-4-methoxycyclohexanone (2.2 g, 10 mmol), phenylmethyl 1 piperidinecarboxylate (2.2 g, 10 mmol), isopropylate titanium (IV) (3,7 ml, 11 mmol) are mixed, so that it entered into the reaction, and restore sodium borohydride (0.4 g, 10 mmol) as in example 5. The crude product was then purified through column chromatography with silica gel using eluent methanol-methylene chloride (1: 50), and get phenylmethyl [4-(4-forfinal)-4-methoxy-1-cyclohexyl]-1-piperidinecarboxylate (35,7% so pl. 68-69oC).

Stage 4.

A mixture of phenylmethyl [4-(4-forfinal)-4-methoxy-1-cyclohexyl]-1-piperidinecarboxylate (1,25 g, 2.9 mmol) and 10% palladium on charcoal (0.2 g) in methanol is subjected to hydrogenation for 2 hours, the Catalyst was removed and the solution concentrated under vacuum. The substance is recrystallized from hexane, to obtain 1-[4-(4-forfinal)-4-methoxy-1-cyclohexyl]piperazine (73%).

Stage 5.

A mixture of 1-[4-(4-forfei the action, as in example 13. The crude material is recrystallized from hexane and receive the product (37,8% so pl. 92-93oC).

Analysis for C24H33FN2O2:

Calculated C 72,79; H 8,07; N 6,80;

Found, C 72,73; H 8,15; N Of 6.71.

Example 54. Z-1-[4-(4-forfinal)-4-methoxy-1-cyclohexyl]-4-[(2-chlorophenyl) methyl]piperazine.

A mixture of 1-(4-forfinal)-1-methoxypiperidine (0.33 g, 1.1 mmol) and 2-Chlorobenzyl chloride (0.18 g, 1.1 mmol) is subjected to interaction as described in example 13. The crude product is recrystallized from hexane and receive the product (44,4% so pl. 66-67oC).

Analysis for C24H30FN2O:

Calculated C 68,25; H 7,31; N 6,64;

Found, C 68,07; H 7,18; N 6,50.

The table shows the in vitro activity of receptor binding compounds obtained in examples 15-52.

Below are the in vivo activity of the compounds obtained in examples 7-50 in experiments on the contact behavior of rats:

in vivo Activity

Example Experiments on contact interaction rats (active dose), mg/kg:

15 0,01-1

17 0,1-1,0

18 0,1-1,0

19 0,1

20-Z 0,001-0,01

36 0.01 to 10

44 0,001-0,01

49 0,1

50 0,01-0,1

Compounds of the invention, the selection of opposing and partially with a means to behold what their disorder, such as anxiety and panic disorder, and it is known that antagonists of 5-HTIAreceptor clinically effective in the treatment of anxiety (D. P. Taylor, "Serotonin Agent in Anxiety, Annals of the New York acadewy of Seieuces rol 600 eutitled: The Neurophurmacology of Serotonin" PP 545-557, October 15, 1990). Further, there is evidence that 5-HTIAagents can be useful in the prophylactic treatment of migraine (y Pascual auol Y. Berciauo "Au Open Yrial of Buspirone in Migraine Prophylaxis. Preliminay Report", Chimical Neuropharmacolody 14:3, 1991, PP 245-250).

Thus it is clear that the compounds of the invention can be used to treat disorders such as anxiety, panic disorder, obsessivecompulsive disorder and depression, as well as for the prophylactic treatment of migraine.

in vitro 1050test values for the binding of 5-HTIAreceptor was determined for representatives of the compounds of formula I by the method of S. Y. Peroutka, Besearch 344, 167, 1985); with only minor modifications. TC50test values lower than 100 nm, considered to reflect the activity of 5-HTIAthe receptor. Connection with values 1C50lower than 20 nm and are the preferred compounds.

The problem of contact interaction is an in vivo model of anxiety (A. P. Guy and C. R. Gardner, "Pharmacological characterization of a modified social interaction model and they are injected subcutaneously in doses of 0.1-1.0 mg/kg, thus providing additional evidence that these compounds will be useful in the treatment of anxiety and panic disorders.

It is also known that agents that interact with dopaminergic receptors can cause movement disorders and other extrapyramidal side effects (R. J. Baldessarini, "Drigs and the Preatment of Psychiatric Disorders", in "Goodman and Gilman's: The Pharmacologic Basis of Therapeutics", 8 th ed. p.428, A. G. Goodman, T. W. Rall, A. S. Nies, and P. Taylor, Editor,Pergamon Press, $no Fairiview Park, N. Y. 1990).

Compounds of the invention are inactive for dopaminergic receptors at doses are used to treat disorders such as anxiety, thus the risk of extrapyramidal side effects is small.

1C50test values for the binding of D2receptor for representatives of the compounds of formula I were determined by the method of Durt, Crees and Snyder,molecular Pharmacology, 12, 800, 1976); Greese, Burt and Snyder 196, 326, 1977); and Greese, Burt and Snyder, Science 192, 481, 1976).

Test 1C50values greater than 1,000 nm, viewed as inertness to the D2receptor, indicating that the risk of extrapyramidal side effects is small. Connection with values 1C50greater than 1,000 nm and are the preferred compounds. Blagorazumnyi from the substance of the invention.

1. Piperazinil and piperidinemethanol General formula I

< / BR>
where R1and R2independently from each other H, halogen, CF3C1C4-alkoxy, except that R1and R2may not simultaneously denote h, and R1and R2if they are adjacent carbon atoms may together form a bridge-O-(CH2)n-O-, where n is an integer from 1 to 3;

R3N or1WITH4-alkyl;

R4and R5independently H, C1WITH4-alkyl or phenyl;

Y is N or CH;

Ar phenyl-2-thienyl or substituted phenyl of the formula

< / BR>
where X and X1halogen, nitro, C1WITH4-alkyl, C1WITH4-alkoxy, or X and X1together form a bridge-O-(CH2)nO-, where n is an integer from 1 to 3;

p and q are integers from 0 to 5, and p + q 5,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, wherein R1and R2together form a bridge-O-(CH2)n-O-, where n is an integer from 1 to 3.

3. Connection on p. 2, wherein each R3, R4and R5H.

4. Connection on p. 3, wherein Y is CH.

5. Connection on p. 4, characterized in that -[4- (phenylmethyl)-1-piperidinyl]-cyclohexanol.

6. Connection on p. 4, characterized in that it is a Z-1- (1,3-benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperidinyl] cyclohexanol.

7. Connection on p. 4, characterized in that Z represents-1-(4-forfinal)-4-[4-[(2,5- differenl)- methyl]-1-piperidinyl]-cyclohexanol.

8. Connection on p. 4, characterized in that ctor represents Z-1-[4-(1,3 - benzodioxol-5-yl)-4-methoxy-1-cyclohexyl] -4-[(3 - methoxyphenyl)methyl]piperidine.

9. Connection on p. 3, characterized in that Y represents n

10. Connection on p. 9, characterized in that Z represents-1-(4-forfinal)-4-[4-[ (2,5-differenl)methyl]-1-piperazinyl]cyclohexanol.

11. Connection on p. 9, characterized in that Z represents-1- (1,3-benzodioxol-5-yl)-4-[4-[(2-fluoro-5-methoxyphenyl)methyl] -1-piperazinil] cyclohexanol.

12. Connection on p. 9, characterized in that Z represents-1-(4-forfinal)-4-[4- [(2-fluoro-5-methoxyphenyl)-methyl]-1-piperazinil]cyclohexanol.

13. Connection on p. 1, characterized in that it denotes a compound selected from the group consisting of:

Z-1-(1,3 - benzodioxol-5-yl) -4-[4-(phenylmethyl)-1-piperazinil]-cyclohexanol; Z-1-(4 - methoxyphenyl)-4-[4-(phenylmethyl)-1-piperazinyl] cycle- (phenylmethyl)-1-piperazinil] -cyclohexanol; Z-1-(1,3 - benzodioxol-5-yl)-4-[4-[(3-methoxyphenyl)methyl] -1-piperazinil] cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(3- forfinal)methyl] -1-piperazinil] cyclohexanol; Z-1-(1,3 - benzodioxol-5-yl)-4-[4-[(2-forfinal)methyl] -1-piperazinil] cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2- were)methyl] -1-piperazinil]cyclohexanol; Z-1-(1,3 - benzodioxol-5-yl)-4-[4-[(2-nitrophenyl)methyl]-1-piperazinil] cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2- chlorophenyl)methyl] -1-piperazinil] cyclohexanol; Z-1-(1,3 - benzodioxol-5-yl)-4-[4-(phenylmethyl)-1-piperazinyl] -cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4- [4-(phenylmethyl)-1-piperazinil] -cyclohexanol; Z-1- [4-(1,3-benzodioxol-5-yl)-4-methoxycyclohexyl] -4-(phenylmethyl) piperazine; Z-1- (1,3-benzodioxol-5-yl)-4-[4-[(2,5- differenl)methyl]-1-piperazinil]cyclohexanol; Z-1-(4 - forfinal)-4- [4-[(2,5-differenl)methyl]-1-piperazinyl] cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2-fluoro-5 - methoxyphenyl)methyl] -1-piperazinil] cyclohexanol; Z-1-(4 - forfinal)-4-[4-[(2-fluoro-5-methoxyphenyl)methyl] -1-piperazinil] cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5- differenl)methyl] -1-piperidinyl] cyclohexanol; Z-1-[4-(1,3 - benzodioxol-5-yl)-4-methoxy-1-cyclohexyl] -4-[(3 - methoxyphenyl)methyl] -piperidine; Z-1-(4-forfinal)-4- [4-(phenylmethyl)-1-piperidinyl]�-4-[4-[(2- bromophenyl)methyl]-1-piperazinil]cyclohexanol.

14. Connection on p. 1, characterized in that it denotes a compound selected from the group consisting of Z-1-(1,3-benzodioxol-5-yl)-4-[4- (phenylmethyl)-1-piperazinil] -cyclohexanol; Z-1-(1,3 - benzodioxol-5-yl)-4-[4-[(2,5-dichlorophenyl)methyl] -1-piperazinil] cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5- differenl)methyl] -1-piperazinil] cyclohexanol; Z-1-(1,3 - benzodioxol-5-yl)-4-[4-[(2,3-differenl)methyl] -1-piperazinil] cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(3,5- differenl)methyl]-1-piperazinil] cyclohexanol; Z-1-(1,3 - benzodioxol-5-yl)-4-[4-[(2-itfinal)methyl] -1-piperazinil] cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(1,3- benzodioxol-4-yl)methyl]-1-piperazinil]cyclohexanol; Z-1- (1,3-benzodioxol-5-yl)-4-[4-(2-fluoro-5-methoxyphenyl)-methyl] -1-piperazinil]cyclohexanol; Z-1-(1,4-benzodioxan-6-yl)- 4-[4-[(3-methoxyphenyl)methyl]-1-piperidinyl]cyclohexanol; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2,5-differenl)methyl] -1 - piperidinyl] cyclohexanol; Z-1-[4-(1,3-benzodioxol-5-yl)- 4-methoxy-1-cyclohexyl] -4-[(3-methoxyphenyl)methyl]piperidine; Z-1-[4-(1,4-benzodioxan-6-yl)-4-methoxy-1-cyclohexyl] -4- [(3-methoxyphenyl)methyl]piperidine fumarate; Z-1-[4-(1,3 - benzodioxol-5-yl)-4-methoxy-1-cyclohexyl]-4-[2,5 - differenl)methyl]piperidine fumarate; Z-1-(1,3-benzodioxol-5-yl)-4-[4-[(2-bromophenyl)methyl] -1-piperazinil)-4- [4-(1-phenylethyl)-1-piperazinil]-cyclohexanol.

15. Connection on p. 1, characterized in that it denotes a compound selected from the group consisting of: Z is 1-(4-forfinal)-4-[4- [(3-methoxyphenyl)methyl] -1-piperazinil] -cyclohexanol; Z-1- (4-forfinal)-4-[4-[(2-chlorophenyl)methyl] -1-piperazinil] cyclohexanol; Z-1-(4-forfinal)-4-[4-[(2,5-differenl) methyl] -1-piperazinil]cyclohexanol; Z-1-(4-forfinal)-4- [4-[(2-fluoro-5-methoxyphenyl)methyl] -1-piperazinil] cyclohexanol; Z-1-(4-forfinal)-4-(4-phenylmethyl)-1-piperidinyl] cyclohexanol; Z-1-(4-forfinal)-4-[4-[(3- methoxyphenyl)methyl]-1-piperidinyl]-cyclohexanol; Z-1-(4 - forfinal)-4-[4-[(2,5-differenl)methyl] -1-piperidinyl]- cyclohexanol; Z-1-[4-(4-forfinal)-4-methoxy-1 - cyclohexyl]-4-[(3-methoxyphenyl)methyl]piperazine.

16. Pharmaceutical composition having activity of binding of serotonergic 5-HTIAreceptor containing the active ingredient and pharmaceutically acceptable carrier, wherein the active component contains a compound of formula I, described in paragraph 1, in a pharmaceutically effective amount.

17. The way to increase serotonergic neurotransmission by introducing compounds having means for serotonergic receptors, wherein the administered compound I on p. 1

 

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