Condensed heterocyclic compounds, method of their production and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in medicine as cholinesterase inhibitors. The inventive Products: condensed heterocyclic compounds f-ly 1, where H is O, S, or R1- N , where R1- H, C1-C7- alkyl, C7-C10-aralkyl, C2-C8- alkylsulphonyl, R2- H, C7-C10-aralkyl And the benzene ring, K is a number from 0 to 3, m is from 0 to 5, n = 2 or its salt. Reagent 1: compound f-crystals II, where Y is halogen, Z Is an N - protective group. Reagent 2: compound f-crystals III. 3 C. and 28 C.p. f-crystals, 17 PL. .

The invention relates to novel condensed heterocyclic compounds or their salts. The compounds of this invention are useful as a drug and an inhibitor of cholinesterase and, in particular, as therapeutic and/or prophylactic agent against senile dementia, Alzheimer's disease and similar diseases.

In our time, the aging society offers a variety of tools that provide curative and preventive action in the case of senile dementia. It was found that physostigmine, a cholinesterase inhibitor natural origin, has a therapeutic and/or profile and, as a short duration of action, high toxicity and other imperfections.

Meanwhile were created artificial medicines, representing a variety of heterocyclic compounds, which can be used as cholinesterase inhibitors, depressants and similar preparations /for example, U.S. patents NN 4064255, 4208417, 4849431, 4895841 published unexamined patent application Japan N 169569/1990 and the application for the European patent N 378207/.

However, currently requires a more active connection with the greater duration of action, but is less toxic compared with the known compounds which have therapeutic and/or preventive effect against senile dementia.

The present invention provides a new class of compounds that are useful as inhibitors of cholinesterase and, in particular, as therapeutic and/or prophylactic agent against senile dementia, Alzheimer's disease and similar diseases.

The authors of the present invention investigated the connections that could be useful as a drug for improving functions of the Central nervous the diseases, resulting from ischemia of the brain, and managed to get a condensed compound of formula (I):

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in which X represents an oxygen atom, a sulfur atom, or R1N<, where R1represents a hydrogen atom, a hydrocarbon group which may be substituted, or acyl group which may be substituted, R2represents a hydrogen atom or a hydrocarbon group which may be substituted, ring a is a benzene ring which may be substituted, K is an integer from 0 to 3, m is an integer from 1 to 8, and n is an integer from 1 to 6, or its salt.

Connection /1/ or its salt according to the present invention is structurally characterized by the fact that the heterocycle containing a heteroatom / O, S or N/ and condensed to the benzene ring is a saturated ring and substitute group of the formula:

< / BR>
bonded directly to the carbon atom in the benzene ring. We believe that this connection is a completely new compound, which were not previously documented in the literature.

You should specify that in the above formula /1/ "hydrocarbon group" of the "hydrocarbon group which may be substituted" indicated by zemlevedenie groups in arbitrary combination.

Acyclic saturated hydrocarbon group includes C1-11alkyl group with straight or branched chain (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, n-hexyl/.

Acyclic unsaturated hydrocarbon group includes C2-4alkeneamine group /for example, vinyl, allyl, 2-butenyl/ and C2-4alkyl groups (for example, propargyl, 2-butinyl/.

The cyclic saturated hydrocarbon group includes C3-7monocyclic cycloalkyl group /for example, cyclobutyl, cyclopentyl, cyclohexyl/ and C8-14bridged cyclic saturated hydrocarbon group /for example, bicyclo [3. 2. 1]Oct-2-yl, bicyclo [3. 3. 1]ion-2-yl, adamantan-1-yl/.

Cyclic unsaturated hydrocarbon group include phenyl, naphthyl and the like groups.

"Hydrocarbon group" of the "carbon group which may be substituted" indicated by the symbols R1and R2may be arbitrarily combined hydrocarbon group of the above-mentioned acyclic, cyclic, saturated and unsaturated hydrocarbon groups, including C7-18aralkyl /same as phenyl C1-12alkyl and naphthyl C1-8alkyl, for example, L /such as aryl (C34-12alkenyl, for example, styryl, cinnamyl, 4-phenyl-2-butenyl, 4-phenyl-3-butenyl/, C8-18arylalkyl /such as aryl (C12-12quinil, for example, phenylethenyl, 3-phenyl-2-PROPYNYL, 3-phenyl-PROPYNYL/, C3-7cycloalkyl C1-6/for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylethyl, cycloheptylmethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl/ etc.

Preferred examples of the "hydrocarbon group" of the "hydrocarbon group which may be substituted" indicated by the symbol R1include C1-7alkyl group with straight or branched chain (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertbutyl, n-Patil, n-hexyl /or C7-10aracelio group/ for example, phenylmethyl, phenylethyl, phenylpropyl/, and preferred examples of the "hydrocarbon group" of the "hydrocarbon group which may be samedl).

Acyclic, saturated, unsaturated acyclic and cyclic saturated hydrocarbon groups mentioned above for the symbols R1and R2may be substituted by 1 to 5 substituents selected from the group including halogen (for example, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxy, C1-4alkoxy (for example, methoxy, ethoxy, propyloxy, bucalossi, isopropoxy/, C1-4alkylthio /for example, methylthio, ethylthio, propylthio/, amino, mono - or di - C1-4alkyl substituted an amino group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino/, cyclic amino group (for example, pyrrolidino, piperidino, morpholino/, C1-4alkylcarboxylic /for example, acetylamino, propionamido, bucillamine/, C1-4alkylsulfonamides/ for example, methylsulfonylamino, ethylsulfonyl/, C1-4alkoxycarbonyl /for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl/ hydroxycarbonyl, C1-6alkylaryl /for example, methylcarbamyl, ethylcarboxyl, propylmalonic/ carbarnoyl mono - or di - C1-4alkyl substituted carbarnoyl /for example, methylcarbamoyl, ethylcarbitol/, C1-6alkylsulfonyl /for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl/, etc.

Sitely in a cyclic unsaturated hydrocarbon group, denoted by the symbols R1and R2include C1-4alkyl /for example, methyl, ethyl, propyl, butyl), halogen (for example, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxy, C1-4alkoxy (for example, methoxy, ethoxy, propyloxy, bucalossi, isopropoxy/, C1-4alkylthio /for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio/, amino, mono - or di - C1-4alkyl substituted an amino group (for example, methylamino, ethylamino, propylamino, dimethylamino, diethylamino/, cyclic amino group (for example, pyrrolidino, piperidino, morpholino/, C1-4alkylcarboxylic /for example, acetylamino, propionamido, bucillamine/, aminocarbonyl, mono - or di-C1-4alkyl substituted aminocarboxylate /for example, methyl-aminocarbonyl, ethylenedicarboxylic, dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl/, C1-4alkylsulfonamides /for example, methyl-sulfonylamino, ethyl-sulfonylamino, propylsulfonyl/, C1-4alkoxycarbonyl /for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, isobutoxide/ hydroxycarbonyl C1-6alkylaryl /for example, methylcarbamyl, ethylcarboxyl, butylcarbamoyl/, C3-6cycloalkylcarbonyl /for example, cyclohexylcarbonyl, propellerblades, butylcarbamoyl, diethylcarbamoyl, dibutylbarbituric /and C1-6alkylsulfonyl /for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl/ and C3-6cycloalkylcarbonyl /for example, cyclopentylmethyl, cyclohexylsulfamic/ as well as phenyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl - C1-4allylcarbamate /for example, formethylcarbamoyl, phenylethanol, phenylpropionyl/ phenylcarbamoyl, phenyl-C1-4alkylcarboxylic /for example, phenylethylenediamine, phenylethylenediamine/ benzoyl-amino, phenyl-C1-4alkylsulfonyl /for example, phenylmethylsulfonyl, phenylethylamines/, phenylsulfonyl, phenyl-C1-4alkylsulfonyl /for example, phenylmethylsulfonyl, phenylalaline/, phenyl C1-4alkylsulfonamides /for example, phenylmethylsulfonyl, phenylethylenediamine/ or phenylcarbonylamino, which may have from 1 to 4 substituents selected, for example, from the group comprising C1-4alkyl groups such as methyl, ethyl, propyl, butyl, isopropyl, etc. C1-4CNS group, such as methoxy, ethoxy, n-propyloxy, isopropoxy, n-Butylochka etc., halogen, such as chlorine, bromine and iodine, hydroxy, benzyloxy, amino, mono - Il is l, similar to the above, and similar groups. A reasonable number of such substituents in the benzene ring, or a cyclic unsaturated hydrocarbon group is 1 to 3.

Arbitrarily combined hydrocarbon group denoted by the symbols R1and R2may be substituted by 1-5 substituents selected from the group comprising C1-4alkyl /for example, methyl, ethyl, propyl, butyl), halogen (for example, fluorine, chlorine, bromine, iodine, nitro, cyano, hydroxy, C1-4alkoxy (for example, methoxy, ethoxy, propyloxy, bucalossi, isopropoxy/, C1-4alkylthio /for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio/, amino, mono - or di - C1-4alkyl substituted by an amino group (for example, methylamino, ethylamino, propylamino, dimethylamine/, cyclic amino group (for example, pyrrolidino, piperidino, morpholino/, C1-4alkylcarboxylic /for example, acetylamino, propionamido, bucillamine/, aminocarbonyl, mono - or dis-C1-4alkyl substituted aminocarboxylate /for example, methylaminorex, ethylenedicarboxylic, dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl/, C1-4alkylsulfonamides /for example, methylsulfonylamino, ethylsulfonyl about isobutoxide/, hydroxycarbonyl, C1-6alkylaryl /for example, methylcarbamyl, ethylcarboxyl, butylcarbamoyl/, C3-6cycloalkylcarbonyl /for example, cyclohexylcarbonyl/, carbarnoyl, mono - or di - C1-4alkyl substituted carbarnoyl /for example, methylcarbamoyl, ethylcarbitol, propellerblades, butylcarbamoyl, diethylcarbamoyl, dibutylbarbituric/, C1-6alkylsulfonyl /for example, methylsulphonyl, ethylsulfonyl, propylsulfonyl/ and C3-6cycloalkylcarbonyl /for example, cyclopentylmethyl/, cyclohexylaniline/ as well as phenyl, naphthyl, phenoxy, benzoyl, phenoxycarbonyl, phenyl C1-4allylcarbamate /for example, formethylcarbamoyl, phenylethanol, phenylpropionyl/ phenylcarbamoyl, phenyl - C1-4alkylcarboxylic/ for example, phenylethylenediamine, phenylethylamine amino/, benzoylamine, phenyl - C1-4alkylsulfonyl /for example, phenylmethylsulfonyl, phenylethylamines/, phenylsulfonyl, phenyl C1-4alkylsulfonyl /for example, phenylmethylsulfonyl, phenylalaline/, phenyl C1-4alkylsulfonamides /for example, phenylmethylsulfonyl, phenylethylenediamine/ or phenylcarbonylamino, which may have from 1 to 4 substituents selected, for example, from the group wilnie group, such as methoxy, ethoxy, n-propyloxy, isopropoxy, n-Butylochka etc., halogen, such as chlorine, bromine and iodine, hydroxy, benzyloxy, amino, mono - or di - C1-4alkyl substituted an amino group, similar to the above, the nitro-group and C1-6alkylsulphonyl similar to the above, and similar groups.

"Acyl" of the" acyl group which may be substituted", marked by the symbol R1includes acyl group of the carboxylic acids (for example, formyl, C2-8alkyl - or phenylcarbonylamino groups such as acetyl, propionyl, butyryl, benzoyl, etc./, acyl group, sulfonic acids (for example, C1-7alkyl or phenylsulfonyl groups, such as methanesulfonyl, benzazolyl, paratoluenesulfonyl etc./, acyl group, phosphonic acids (for example, C1-7Alcide or phenylphosphine group; such as metaphosphoric, benzazolyl, and so on/ and substituted oxycarbonyl group /for example, C2-8allyloxycarbonyl or C7-8aracelikarsaalyna groups, such as methoxycarbonyl, tert-butyloxycarbonyl, benzyloxycarbonyl etc.

Each of these acyl groups can have from 1 to 3, preferably from 1 to 2 substituents, such as GoLoG or secondary amino group (for example, methylamino, ethylamino, propylamino, cyclohexylamino, dimethylamino, diethylamino, diisopropylamino, dicyclohexylamine/, C1-4CNS group /for example, methoxy, ethoxy, propoxy/ and similar groups.

X preferably represents R1N<, and the element R1preferably is hydrogen, methyl, ethyl, benzyl, acetyl, benzoyl, methoxycarbonyl or etoxycarbonyl.

R2preferably represents benzyl or naphthylmethyl group, which is unsubstituted or may be substituted by 1 or 2 substituents selected from the group including halogen (for example, fluorine, chlorine/, methyl, nitro and/or methoxy, with the preferred examples of R2include unsubstituted benzyl.

The substituent in ring A is preferably fluorine, chlorine, trifluoromethyl, methyl or methoxy, in which preference is given to fluorine.

Preferred values k and m are values, which together form an integer from 2 to 6, i.e., when

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form a 5-9 membered ring.

The preferred combination of values of k and m is this combination, when k equals 0, then m is equal to 2, 3, 4 or 5, if k rastenii heterocyclic ring, which is expressed by the formula

< / BR>
represent 2,3-dihydro-1H-indole, 1,2,3,4-tetrahydrothieno, 2,3,4 - 5-tetrahydro-1H-1-benzazepine, 2,3-dihydro-1H-isoindole, 1,2,3,4-tetrahydroisoquinoline, 2,3,4,5-tetrahydro-1H-2-benzazepin, 2, 3, 4, 5 - tetrahydro-1H-3-benzazepin, 1, 2, 3, 4, 5, 6 hexahydro-1-benzazocine, 1, 2, 3, 4, 5, 6 hexahydro-2-benzazocin, 1, 2, 3, 4, 5, 6 hexahydro-3-benzazocine, 2, 3, 4, 5, 6, 7 hexahydro-1H-1-benzazepin, 2, 3, 4, 5, 6, 7 hexahydro-1H-2-benzazepin, 2, 3, 4, 5, 6, 7 hexahydro-1H-3-benzazepin, 2, 3, 4, 5, 6, 7 hexahydro-1H-4-benzazocin.

The preferred oxygen-containing condensed heterocyclic ring, which is expressed by the formula

< / BR>
represent 2,3-dihydrobenzofuran, 1,3-dihydroisobenzofuran 3,4-dihydro-2H-1-benzopyran, 2, 3, 4, 5-tetrahydro-1-benzoxazin, 1, 3, 4, 5 - tetrahydro-2-benzoxazin, 1, 2, 4, 5 tetrahydro-3-benzoxazin, 3, 4, 5, 6 - tetrahydro-2H-1-benzoxazin, 3, 4, 5, 6 tetrahydro-1H-2-benzoxazin, 1, 4, 5, 6 tetrahydro-2H-3-benzoxazin, 2, 3, 4, 5, 6, 7 - hexahydro-1-benzoxazin, 1, 3, 4, 5, 6, 7 hexahydro-2-benzoxazin, 1, 2, 3, 4, 5, 6, 7 hexahydro-4-benzoxazin.

Preferred sulfur-containing condensed heterocyclic ring, which is expressed by the formula

< / BR>
represent 2,3-dihydro[b] thiophene, 1, 3,-dihydrobenzo[c]thiophene, 3,4-dividen, 1, 2, 4, 5 - tetrahydro-3-benzothiazin, 3, 4, 5, 6 tetrahydro-2H-1-benzothiazin, 3, 4, 5, 6 tetrahydro-1H-2-benzothiazin, 1, 4, 5, 6 tetrahydro-2H-3-benzothiazin, 2, 3, 4, 5, 6, 7 hexahydro-1-benzothiazin, 1, 3, 4, 5, 6, 7 - hexahydro-3-benzothiazin, 1, 2, 3, 5, 6, 7 hexahydro-4-benzothiazin.

Preferred heterocyclic rings, which is expressed by the formula

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in which each symbol has the above values include the

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where R3represents a hydrogen atom or a C1-3alkyl group, a C1-3an alkyl group denoted by the symbol R3includes methyl, ethyl, propyl and isopropyl.

A preferred example of the value of n is 1, 2 or 3, preference is given to 2.

Especially preferred are the following compounds of formula I and their salts. (see tab. 1 13).

Salt of the compounds (I) of the present invention is preferably a physiologically acceptable salt accession acid, the above salt includes salts formed with inorganic acids (for example, hydrochloric acid, phosphoric acid, Hydrobromic acid, sulfuric acid, and salts formed with organic acids (for example, acetic acid, Murata, methansulfonate acid, benzolsulfonat acid/.

In addition, if the connection /I/ according to the present invention has such an acid group COOH, the compound (I) may form a salt with an inorganic base (for example, sodium, potassium, calcium, magnesium, ammonia or an organic base (for example, triethylamine/.

The following describes a method of obtaining compound (I) or its salt of the present invention.

Although the following description of the method of obtaining applies not only to receive the connection /I/, and its salts, both of these compounds can be defined below as compounds /I/.

Connection /I/ can be obtained by the interaction of the compounds of formula (II):

< / BR>
in which Y represents halogen, n has the values listed in the formula (I), Z represents a protective group for protecting the amino group or its salt with the compound of the formula (III:

< / BR>
in which all symbols have the meanings indicated in the formula (I) or its salt, and removing the protective group of the obtained compound of the formula /IV/:

< / BR>
in which all symbols have the above values, or of its salts.

Y preferably represents chlorine, bromine or Joliet acetyl, benzoyl, formyl, methoxycarbonyl, tert-butoxycarbonyl or benzyloxycarbonyl, while preferred examples of Z include acetic and benzoyl.

The compound of formula (II) or its salt can be obtained by known methods or similar. For example, this connection can be obtained using the method described in Chemical Pharmaceutical Bulletin, 34, 3747-3761 /1986/.

The compound of formula (III or its salt can be obtained in accordance with known methods or similar methods. For example, this connection can be obtained using the methods described in journal of Organic Chemistry, 34, 2235 /1969/, Journal of the Organic Chemistry", 54, 5574 /1989/, Tetrahedron letters 35, 3023 /1977/, in Bulletin of the chemical society of Japan, 56, 2300 /1983/ etc.

The salt of the compound (II) or compound (III according to the present invention is preferably a physiologically acceptable salt accession acid. The above salt includes salts formed with inorganic acids (for example, hydrochloric acid, phosphoric acid, Hydrobromic acid, sulfuric acid, and salts formed with organic acids (for example, acetic acid, formic acid, propionic acid, fumaric acid, maleic Kista, methansulfonate acid, benzolsulfonat acid/.

The interaction between the compound (II) or its salt (for example, one of the salts described for formula (I) and compound (III or its salt can be carried out as follows. For example, compound (II) or its salt is subjected to interaction with the connection /III/ without solvent or in a solvent, optionally in the presence of acid or similar substances. Such acid may be a Lewis acid (for example, aluminium chloride, zinc chloride, titanium chloride/. The amount of this acid is usually 1 to 20 moles, preferably 2 to 10 mmol, in relation to one pray connection /II/. The solvent may be any conventional solvents used in chemical reactions, provided that it does not affect the course of the reaction. For example, the solvent can be used dichloromethane, dichloroethane, nitrobenzene, carbon disulfide. The reaction temperature is usually from -30 to 150oC, preferably from 20 to 100oC. the reaction Time is generally equal to 0.5 to 72 hours Connection /III/ or its salt is usually used in a ratio of 1 to 20 moles, preferably 1 to 5 moles, to one pray compound (II) or its salt.

< / BR>
the compounds of formula (II) can enter the em to be replaced. This position is usually the position of the atom 6, if the frame structure of the compound (III represents 1, 2, 3, 4 - tetrahydroquinolin /where ring A is unsubstituted/. However, it is also possible to receive and to highlight the connections that were formed during the introduction of the above groups in other provisions /provisions atoms 5, 7 and 8/.

Thus obtained compound /IV/ or its salt can be extracted and cleaned using known methods, such as concentration, regulation of pH, disproportionation, by solvent extraction, fractional distillation, distillation, crystallization, recrystallization, chromatography and the like methods. However, the reaction mixture can be directly used as a material for the next reaction stage.

The removal of the protective group from compounds /IV/ or its salts can be made by treating compounds /IV/ or its salt is kept in an aqueous solution of mineral acid, for example nitric acid, hydrochloric acid, Hydrobromic acid, innovata acid, sulfuric acid and/ or hydroxide of alkaline metal (for example, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide/ Tempe 1-100 equivalents, preferably 1-40 equivalents, to the compound /IV/ or its salt. The strength of the acid or base usually corresponds to 1-10 normality, preferably 4-10 normality. The reaction time, which depends on the reaction temperature, usually from 1 to 24 h, preferably from 2 to 10 o'clock

Thus obtained, the connection /I/ /R2=H/ can be extracted and cleaned using known methods, such as concentration, regulation of pH, disproportionation, by solvent extraction, fractional distillation, distillation, crystallization, recrystallization, chromatography and the like methods. However, the reaction mixture can be used directly as starting material for the next reaction stage.

Connection /I/, in which R2represents a group that is not a hydrogen atom, or its salt can be obtained by the interaction of compounds /I/ /R2=H/ or its salt with the compound of the formula J1/V/ which represents a hydrocarbon group which may be substituted, and the J1is tsepliaeva group.

Tsepliaeva group J1includes halogen /for example, chlorine, bromine, iodine/ C1-6alkylchlorosilanes, paratoluenesulfonyl/.

The interaction between connection /I/ /R2=H/ or its salt and the compound /V/ is carried out in a solvent or without solvent, and optionally in the presence of a base.

Above the base includes various inorganic bases such as sodium carbonate, potassium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, sodium methylate, sodium ethylate, sodium hydride, etc. and various organic bases, such as pyridine, 4-dimethylaminopyridine, triethylamine and the like bases. In the case of the use of a solvent, this solvent may represent lower alcohols, such as methanol, ethanol, propanol, isopropyl alcohol, n-butanol, tert-butanol etc., ethers such as dioxane, simple ether, tetrahydrofuran, etc., aromatic hydrocarbons such as toluene, benzene, xylene etc., amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide etc., esters such as ethyl acetate, butyl acetate, etc. which do not affect the course of the reaction. This reaction can be carried out in conditions of cooling /from 0 to 10oC/ at room temperature from 10 to 40oC/ or when heated from 40 to 120oC/, proli /V/ is usually used in preference from 0.3 to 5.0 moles pray one connection /I/ /R2=H/ or its salts. In the case of using the base as it is commonly applied in respect of more than one mole, preferably 1.1 to 5 moles, to one pray compounds of the formula /I/ /R2=H/ or its salts.

If desired, this reaction can be accelerated by carrying it in the presence of iodide, sodium iodide, potassium iodide, lithium or similar substances. In such cases, the iodide is commonly used in the ratio of 1 to 5 moles, preferably 1.2 to 1.5 mole, to one pray connections /V/. In addition, compound (I) or its salt can also be obtained by the interaction formula /VI/:

< / BR>
in which k, m, n, ring a and R2have the values indicated above, or its salt with the compound of the formula /VII/:

< / BR>
in which represents a hydrocarbon group which may be substituted, or alalou group which may be substituted, J1has the above meanings, in the presence of the same conditions that were described for the reaction between compound /I/ /R2=H/ or its salt and the compound /V/. The connection formula /VI/ or its salt can be obtained in accordance with the above methods or by hydrolysis of compounds /I/ /R2=H/, in which R1in which R1is acyl, or its salts with COI the dust from the connection /IV/ or its salts.

Connection /I/ can also be obtained by other known methods or similar methods /for example, compound (I) can be obtained by the reduction of compounds of formula IV, in which Z represents an acyl carboxylic acid, it also may be necessary to protect and unprotect such functional groups m connection /IV/, as a ketone, in the implementation of this method/.

If the thus obtained compound /I/ is the free base of the compound, it can be converted into a salt using known techniques. If the connection is salt, it can be converted into the free compound or into another salt by known methods. Thus obtained compound (I) or its salt can be extracted and cleaned using the above methods.

Connection /I/ or its salt of the present invention affects the Central nervous system of mammals, has a strong inhibitory effect on cholinesterase and has a significant impact on the factors that cause amnesia in humans and animals, for example mice/.

Connection /I/ or its salt of the present invention demonstrates excellent isbeing with physostigmine, at doses of impeding the development of amnesia, does not cause side effects on the peripheral nervous system, such as cramps, salivation and diarrhea, and, if it has such side effects, it is minimal. In addition, this compound is characterized by a long duration of action and low toxicity and high efficacy when administered orally. Acute toxicity of the compounds (I) or its salt of the present invention is observed at a dose of more than 100 mg/kg

Therefore, the connection /I/ or its salt of the present invention is useful as a drug that improves brain function in mammals, including humans.

Connection /I/ or its salt of the present invention can be used to treat diseases such as senile dementia, Alzheimer's disease, Huntington's chorea, hyperkinesis and manic syndrome, and prevention of these diseases.

Connection /I/ or its salt of the present invention is typically included in the composition together with a pharmaceutically acceptable excipient, and may be administered orally or parenterally to humans and other mammals.

Such pharmaceuti and so on/ or for parenteral administration (for example, suppositories, injections/. These drugs can be manufactured by the known methods. Although the dose depends on the type of disease and symptoms requiring treatment, the usual daily dose for oral administration for adults is from 0.01 to 100 mg, preferably from 0.1 to 30 mg, and preferably from 0.3 to 10 mg.

Following reference examples, working examples, examples of formulations and test examples are intended to further a more detailed illustration of the present invention, and in any case not be considered as examples, limit this invention.

In the examples and reference examples, the elution when performing chromatography on columns produced under controlled conditions by thin-layer chromatography, if no special instructions. Control by thin-layer chromatography is performed using kieselgel Merck 60 F254E. Merck/ as plates for thin-layer chromatography, the solvent for column elution as a developing solution and a UV detector for detection. As an additional detection method used the method, according to which spot on the plan and re-heated, the change of color in red reddish-purple color was recorded as a positive reaction. Thus identified and collected fractions containing the target compound. If no special instructions, as the silica gel for chromatography used kieselgel Merck 60 /70 to 230 mesh/ /E. Merck//.

The term "ambient temperature" or "room temperature" generally means a temperature of 5oC to 40oC, and the term "atmospheric pressure" means the pressure is approximately equal to one atmosphere.

If no special instructions, it means mass percent.

Reference primer.

1-acetyl-6-[3-/1-acetylpiperidine-4 - yl] -1-oxopropyl]-1,2,3,4-tetrahydroquinolin

< / BR>
/I/ in 300 ml of acetic acid was dissolved 33 g of ethyl- -/pyridine-4-yl/acrylate and produced the catalytic hydrogenation using platinum oxide as catalyst, at atmospheric pressure and a temperature of from 70 to 80oC. After adding 40 ml of acetic anhydride, the catalyst was filtered, and the solvent is kept at reduced pressure. The residue was dissolved in water and neutralized with potassium carbonate, after which the reaction product was extracted with di obtained with 44.8 g of oily product.

/2/ In 200 ml of methanol was dissolved 42,0 g of the above oil connections, after which was added a solution of 12.7 g of potassium hydroxide in 20 ml of water. This mixture was stirred 1.5 hours at a temperature of 50oC and 12 h at room temperature. The reaction mixture was neutralized with concentrated hydrochloric acid, and drove away the solvent. To the residue was added methanol, and then the insoluble substance was filtered. The filtrate was concentrated and the resulting crude crystals were collected by filtration, which allowed us to obtain 27 g of 3-/1-acetylpiperidine-4-yl/ propyl acid/ melting point 201-206oC/.

/3/ To 20 ml of thionyl chloride was added 3.8 g of 3-/1-acetylpiperidine-4-yl/ propionic acid in small portions under ice cooling, after which the mixture was stirred for 5 minutes, the Excess thionyl chloride and drove to the solid residue was added 15 g of carbon disulfide and 3.1 g of 1-acetyl - 1,2,3,4-tetrahydroquinoline, then gradually added 10.7 g of anhydrous aluminium chloride at room temperature. This mixture was heated under reflux for 2 h, and then poured into a mixture of ice water and was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and dissolve the compared//, that allowed us to obtain 1.4 g of colorless oil.

Elemental analysis for C21H28N2O3< / BR>
Calculated: C 70,76 H 7,92 N 7,86.

Found: C 70,68 H 7,80 N Of 7.64.

Reference example 2.

1-acetyl-6-[3-/1-acetylpiperidine-4-yl/-1 - oxopropyl-] 1,2,3,4-tetrahydroquinolin /A/ and 1-acetyl-7-[3-/1-acetylpiperidine-4 - yl/-1-oxopropyl]-1,2,3,4-tetrahydroquinolin /B/

/1/ To 100 ml of thionyl chloride was added 26 g of 3- /1-acetylpiperidine-4-yl/ propionic acid obtained according to reference example 1 3 /2/, in the form of small portions under ice cooling. This mixture was stirred for 5 min, after which the excess thionyl chloride drove away, and the solid residue was washed simple diethyl ether, which allowed us to obtain 26,4 g 3- /1-acetylpiperidine-4-yl/-propionitrile in the form of a pale yellow powder.

/2/ To a mixture of 42.5 G of 1-acetyl-1,2,3,4-tetrahydropyrazin and 30 ml of carbon disulfide was added 71 g of anhydrous aluminium chloride, and then added 26,4 g 3-/1-acetylpiperidine-4-yl/propionitrile at room temperature. This mixture was stirred for 16 h at room temperature, and then treated as in reference example 1-/3/, resulting in 25 g of a mixture of 1-acetyl-6-[3-/1-aceti-tetrahydroquinoline /B/ in the form of a pale yellow oil.

Elemental analysis for C21H28N2O3< / BR>
Calculated: C 70,76 H 7,92 N 7,86.

Found: C 70,81 H 7,69 N 7,83.

Reference example 3.

1-Acetyl-5-[3-/1-acetylpiperidine-4-yl/-1 - oxopropyl-] 2,3-dihydro-1H-indol

< / BR>
When performing the techniques described in reference example 2-/2/ using 24 g of 1-acetyl-2,3-dihydro-1H indole was obtained solid substance. This solid is recrystallized from a mixture of dichloromethane and simple diethyl ether with the formation of 26 g of colorless crystals with a melting point 148 149oC.

Elemental analysis for C20H26N2O3< / BR>
Calculated: C 70,15 H 7,65 N 8,18.

Found: C 69,97 H 7,71 N 7,98.

Reference example 4.

1-Acetyl-8[3-/1-acetylpiperidine-4-yl/-1 - oxopropyl] 2,3,4,5-tetrahydro-1H-1-benzazepin /A/ and 1-acetyl-7- [3-/1-acetylpiperidine-4-yl/1-oxopropyl] 2,3,4,5-tetrahydro-1H-1-benzazepin /B/

< / BR>
When performing the techniques described in reference example 2-/2/ with 8.7 g of 1-acetyl-2,3,4,5-tetrahydro-1H-1 - benzazepine were obtained solid substance, which is then recrystallized from a mixture of dichloromethane and simple diethyl ether with the formation of 6.5 g specified in Sagalova C22H30N2O3< / BR>
Calculated: C 71,32 H 8,16 N 7,56.

Found: C 71,10 H 8,21 N 7,6.

The mother liquor obtained in the recrystallization, which was purified by chromatography on columns /eluent: a mixture of ethyl acetate and methanol 100 1/, resulting 0,3 specified in the title compound B as a pale yellow oil.

Elemental analysis for C22H30N2O3< / BR>
Calculated: C 71,32 H 8,16 N 7,56.

Found: C 71,13 H 8,04 N 7,43.

Reference example 5.

8-[3-/1-acetylpiperidine-4-yl/-1 - oxopropyl] 2,3,4,5-tetrahydro-1H-1-benzazepin

< / BR>
When performing the techniques described in example 7-/1-/, using 2.2 g of the compound obtained according to example 17, there was obtained 2.1 g of colorless crystals with a melting point of 86 to 88 C.

Elemental analysis for C20H28N2O2< / BR>
Calculated: C 73,14 H 8,59 N 8,53.

Found: C 72,81 Scored 8.38 H N Of 8.47.

Reference example 6.

5[3-/1-Acetylpiperidine-4-yl/-1 - oxopropyl]1-ethyl-2,3-dihydro-1H-indol

< / BR>
In 10 ml of ethanol was dissolved 0.8 g 5[3 - /1-acetylpiperidine-4-yl-/1-oxopropyl] 2,3-dihydro-1H-indole, 2,1-g ethyliodide and 0.5 g of potassium carbonate, after h the residue was purified by chromatography on columns /eluent: a mixture of ethyl acetate and methanol 20:1/, that allowed us to obtain 0.85 grams specified in the title compounds as a pale yellow oil.

Elemental analysis for C20H28N2O2< / BR>
Calculated: C 73,14 H 8,59 N 8,53.

Found: C 73,03 H 8,54 N 8,56.

Reference example 7.

When performing the techniques described in reference example 6, using the compound obtained in example 14-/1/, were obtained the following compounds in the form of oil. (see tab. 14).

< / BR>
Reference example 8.

5[-3-/1-acetylpiperidine-4-yl/-1-oxopropyl]-2,3-dihydro-benzofuran

< / BR>
To 200 ml of 1,2-dichloroethane was added 9,65 g /44 mmole/ acid chloride 3-/1-acetylpiperidine-4-yl/propionic acid and 10365 g /89 mmol/ 2,3-dihydrobenzofuran. To this mixture was added 12,82, /96 mmol/ aluminium chloride in limited quantities, after which this mixture was stirred for 3 h at room temperature. The reaction mixture was poured into a mixture of ice water and was extracted with methylene chloride. The organic layers were combined and washed with water, and then dried over anhydrous sodium sulfate, after which drove the solvent. The residue was purified by chromatography on columns of silica gel /ethyl acetate/, which allowed us to obtain 10,47 g /78%/ 5[of diethyl ether resulted in the formation of colorless needles, melting point 93 95oC.

Elemental analysis for C18H23NO3< / BR>
Calculated: C 71,73 H 7,69 N 4,65.

Found: C 71,57 To 7.77 H N 4,58.

Reference example 9.

3-/1-benzoylpiperidine-4 - yl/propionic acid

< / BR>
/1/ In 100 ml of acetic acid was dissolved 12 g of ethyl -/pyridine-4-yl/acrylate, and then produced a catalytic reduction in the presence of 1 g of the oxide plate as a catalyst at atmospheric pressure and a temperature of 70 80oC. the Catalyst was filtered, the solvent is kept under reduced pressure, and the residue was dissolved in 100 ml of dioxane. To a dioxane solution was added 100 ml of an aqueous solution of 12 g of sodium bicarbonate and the mixture was stirred for 20 min at room temperature. To the mixture was added dropwise 8 ml of benzoyl chloride at room temperature, after which the mixture was stirred for two hours. The reaction product was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent drove with the formation of 17.5 g of ethyl-3-/1-benzoylpiperidine-4 - yl/propionate as a pale yellow oily product.

/2/ When performing the techniques described in example 1-a/2/ with ispolzovanie in the form of colorless crystals, melting point 153 155oC.

Elemental analysis for C15H19NO3< / BR>
Calculated: C 68,94 H 7,33 N Are 5.36.

Found: C 68,71 H 7,44 N 5,20.

Reference example 10.

3-methoxycarbonyl-2,3,4,5-tetrahydro-1H-3 - benzazepin

< / BR>
In 150 ml of water was dissolved 4,13 g /0,10 mol/ sodium hydroxide. To this solution was added 15,27 g /10,4 mmole/ 2,3,4,5 - tetrahydro-1H-3-benzazepine. The reaction mixture was cooled with ice was added dropwise to 7.9 ml of 0.10 mol/ methylcarbamate. This mixture was stirred for 2.5 h at room temperature, and then was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent drove away, resulting in 20,46 g /96%/ 3-methoxycarbonyl - 2,3,4,5-tetrahydro-1H-3-benzazepine in the form of colorless crystals. Recrystallization from a mixture of simple diethyl ether and n-hexane allowed to obtain colorless needles, melting point 53 54oC.

Elemental analysis for C12H15NO2< / BR>
Calculated: C 70,22 H 7,37 N 6,82.

Found: C 6 70,02 H 7,41 N 6,68.

Spravochnik example 11.

3 metastable-7-[3-/1-benzoylpiperidine-4 - yl/-1-oxopropyl] -2,3,4,5-tetrahydro-1H-3-benzazepin

< / BR>
the OIC acid, obtained in reference example 9. This mixture was stirred for 40 minutes at a temperature of 0oC, and then thionyl chloride drove away. The residue was dissolved in 20 ml of 1,2 dichloroethane and to this solution was added 0,81 g /3.9 mmole/ 3-methoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine, polcenigo in reference example 10. To this mixture was added to 1.75 g /13.1 mmole/ aluminum chloride in small portions. The resulting mixture was stirred at room temperature for one hour, then the reaction mixture was poured into a mixture of ice water and was extracted with dichloromethane. The organic layers were combined and washed once with water, then dried over anhydrous sodium sulfate, and then drove the solvent. Purification using chromatography on columns of silica gel was allowed to get 1,46 g /83%/ 3-methoxycarbonyl-7- [3-/1-benzoylpiperidine-4-yl/-1-oxopropyl-]2,3-4,5-tetrahydro-1H-3 - benzazepine. Recrystallization from a mixture of ethyl acetate and n-hexane resulted in the formation of colorless needles, melting point 120 123oC.

Elemental analysis for C27H32N2O4< / BR>
Calculated: C 72,30 H 7,19 N 6,25.

Found: C 71,99 H 7,22 N 6,12.

Reference example 12.

6-[3-/1-Acetylpiperidine-4-yl/-1-ACS who ridin-4-yl/propionitrile /2,18 g/ 1,2-dichloroethane /20 ml portions) was added aluminium chloride /3,2/ at a temperature of 10 15oC. This mixture was stirred at room temperature for 2 hours, heated under reflux for 2 h and was poured into a mixture of ice water. The resulting mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulfate and drove the solvent. The residue was purified by chromatography on columns of silica gel /manifested solvent: ethyl acetate/, the result of which was obtained 2.7 g specified in the title compounds as a pale yellow oil.

Elemental analysis for C19H25NO2< / BR>
Calculated: C 68,85 H 7,60 N To 4.23.

Found: C 68,66 H 7.62mm H 4,13.

Reference example 13.

2-acetyl-8-chloro-1,2,3,4-tetrahydroisoquinoline

< / BR>
To a mixture of 28.6 g of 8-chloro-1,2,3,4 of tetrahydroxyphenylchlorin in 140 ml of dichloromethane was added 140 ml of 1 n aqueous solution of NaON and 17.6 g of NaHCO. To this solution was added dropwise to 14.5 ml of acetic anhydride at a temperature of 5oC. This mixture was stirred at room temperature for 1 hour the Organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic extracts were washed with water, dried over anhydrous sodium sulfate. The solvent drove with obrazovanii>11H12ClNO

Calculated: C 63,01 H 5,77 N 6,68.

Found: C 62,82 H 5,86 N 6,56.

Reference example 14.

2-Acetyl-5-[3-[1-benzoylpiperidine-4 - yl/-1-oxopropyl] 8-chloro-1,2,3,4-tetrahydroisoquinoline

< / BR>
When performing the techniques described in reference example 11, using 21,0 g of compound obtained in reference example 13 was obtained 9.2 grams specified in the title compounds as a pale yellow oil.

Elemental analysis for C26H29ClN2O3< / BR>
Calculated: C 68,94 X 6,45, H 6,18.

Found: C 68,83 H 6:52 N 6,04.

Example 1.

6-[1-oxo-3-/piperidine-4-yl/-propyl]-1,2,3,4-tetrahydroquinolin

< / BR>
A mixture of 1.3 g of 1-acetyl-6-[3/1-acetyl - piperidine-4-yl/-1-oxo-propyl] 1,2,3,4-tetrahydroquinoline obtained in reference example 1 and 20 ml of concentrated hydrochloric acid was heated under reflux for 16 hours Then the reaction mixture was concentrated, and the residue was dissolved in water. This solution was washed with a simple ether, the pH of the aqueous layer was brought to 10 with 10% sodium hydroxide solution and was extracted with sodium, and the solvent is kept at reduced pressure, which allowed us to obtain 0.9 g of colorless oil.ujena: C 74,87 H 8,68 N 10,3.

Example 2.

6-[1-oxo-3-[1-/phenylmethyl/piperidine-4 - yl] propyl]-1,2,3,4-tetrahydronaphtalene

< / BR>
To a mixture of 1.3 g of 6-[1-oxo-3-/piperidine-4 - yl/-propyl]-1,2,3,4-tetrahydroquinoline 0.9 g of potassium carbonate and 10 ml of ethanol was added dropwise 2 ml of a solution of 0.74 g of benzylbromide in ethanol under cooling with ice. This mixture was stirred at room temperature for 2 h, and then deleted the solid substance and the solvent. The residue was purified by chromatography on columns/ eluent: a mixture of ethylacetate and methanol=20:1 /volumes/, after which the eluate containing the target compound were distilled to remove solvent. The residue was treated with 2.4 ml of 4 n solution of hydrochloride in methanol with the formation of solids. This solid substance was recrystallized from a mixture of methanol and simple ether, which allowed us to obtain 1.55 g of colorless powder with a melting point of 110 - 125oC /decomposition/.

Elemental analysis for C24H3N2O2HCl

Calculated: C 6,20 H 7,41 N To 6.43.

Found: C Of 66.00 H 7,35 N 6,22.

Example 3.

1-/phenylmethyl/-6-[3-1-/phenylmethyl/piperidine-4 - yl-] 1-oxopropyl] -1,2,3,4-tetrahydronaphtalene

< / BR>
To 5 ml of a solution of 0.5 g of 6[1-oxo-3-1 N, N-dimethylformamide was gradually added 40 ml of a sodium hydride /not containing oil/, after which the mixture was stirred at room temperature for 1 h To this solution was added dropwise to 0.22 g benzylbromide under ice cooling and the resulting mixture was stirred at room temperature for 6 hours the Reaction mixture was then treated as in example 2, and the residue was purified by chromatography on columns/ eluent: a mixture of ethyl acetate and methanol 20:1/ volume ratio. Eluent containing the target compound were distilled under reduced pressure to remove solvent and the resulting oil was treated with 0.7 ml of 4 N. the solution of hydrochloric acid in methanol, the resulting solid substance. This solid precrystallization from a mixture of ethanol and simple ether with the formation of 0.28 g of colorless crystals with a melting point 112 117oC /decomposition/.

Elemental analysis for C31H36N2O2HCl

Vaticano: C 70,85 H 7,29 N 5,33.

Found: C 70,81 H 7,12 N 5,18.

Example 4.

1-methyl-6-[3-[1-/phenylmethyl/piperidine-4 - yl] -1-oxopropyl-]1,2,3,4-tetrahydropyrimidine

< / BR>
To 3 ml of a solution of 0.2 g of 6-[3-[1-/penile 2, in N, N-dimethylformamide was gradually added 37 ml of a sodium hydride /not containing oil/. This mixture was stirred at room temperature for 1 h, then was added 62 mg under the conditions. The resulting mixture was stirred at room temperature for 6 h and at the end of this period were added in the order listed 15 mg of sodium hydride/ not containing oil and 40 ml of atilglukuronida. This mixture was stirred for 1 h, and then poured into a mixture of ice water and was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent is kept at reduced pressure. The residue was purified by chromatography on columns /eluent mixture of ethyl acetate and methanol 20:1/ volumes // and eluent mixture of ethyl acetate and methanol 20 1 /volumes // and the eluate containing the target compound were distilled under reduced pressure to remove solvent. The resulting oil was treated 0,23 ml of 4 N. the solution of hydrochloric acid in methanol, which allowed us to obtain 0.1 g of an amorphous powder.

Elemental analysis for C25H32N2O2HCl

Calculated: C 66,81 H A 7.62 N 6,23.

Found C 66,83 H At 7.55 N 6,09.

Example 5.

6-[1-oxo-3-[piperidine-4-yl/n is ispolnenii techniques described in example 1 using 23 g of the compound obtained according to reference example 2 was obtained of 16.9 g of a mixture of 6-[1-oxo-3-/piperidine-4-yl/- propyl]-1,2,3,4-tetrahydroquinoline /And/ and 7-[1-oxo-3-piperidine-4-yl/propyl] 1,2,3,4-tetrahydroquinoline /In/ in the form of a pale yellow oil.

Elemental analysis for C17H24N2O

Calculated C 74,96 H 7,88 N 10,29.

Found: C 74,69 H 8,90 N 10,2.2

Example 6.

6-[1-oxo-3-[1-/phenylmethyl/piperidine-4 - yl] propyl]-1,2,3,4-tetrahydroquinoline /And/ and 7-[1-oxo-3-[1-/phenylmethyl/- piperidine-4-yl]propyl-1,2,3,4-tetrahydroquinoline //

< / BR>
When performing the techniques described in example 2, using 1.8 g of the compound obtained in example 5 was obtained 1,82 g free base mixture specified in the title compounds a and B. the First collection of crystals /0.65 g/ calculation of this mixture in a simple diethyl ether, that is, 7-[1-oxo-3-[1-/phenylmethyl/piperidine-4-yl] propyl] 1,2,3; 4 - tetrahydroquinoline /melting point 132 135oC was treated with an equivalent amount of formovoy acid, resulting 0,69 g is specified in the header fumarata /In/ in the form of colorless crystals with a melting point of 175 177oC /decomposed the 7 H 7,16 N 5,85

Found: C 70,01 H 6,97 N 5,98

The mother liquor of the specified solution in simple diethyl ether was also concentrated with the formation of 0.7 g of 6-[1 - oxo-3-[1-/phenyl-methyl-piperidine-4-yl] propyl] -1,2,3,4-tetrahydroquinoline in the form of crystals melting point 126 129oC/. This collection of crystals was treated with an equivalent amount of fumaric acid, resulting in 0,78 g is specified in the header fumarata /A/ in the form of colorless crystals with a melting point 138 142oC /decomposition/.

Elemental analysis for C24H30N2O C4H4O4< / BR>
Calculated: C 70,27 H 7,16 N 5,85.

Found: C 70,13 H 7,13 N 5,77.

Example 7.

1-methyl-6-[1-oxo-3-/piperidine-4 - yl/propyl] -1,2,3,4-tetrahydroquinolin /A/ and 1-methyl-7-[1-oxo-3-/piperidine-4-yl/propyl]-1,2,3,4-tetrahydroquinolin /B/

< / BR>
/1/ To 40 ml of a solution of 14.2 g of the compound obtained in accordance with example 5, in dichloromethane was added dropwise 10 ml of a solution of 5.1 g of acetic anhydride in dichloromethane under ice cooling. This mixture then was stirred at room temperature for 10 min, after which it was washed with 10% sodium hydroxide solution and dried over anhydrous sodium sulfate. Then the distillate is -[1-oxo-3-/1-acetylpiperidine-4-yl/-propyl] -1,2,3,4-tetrahydroquinoline in the form of a colorless oil.

/2/ the Mixture of 7.1 g of the oil obtained in accordance with the option /1/ and 1.6 g of trimethyl phosphate was heated at a temperature of 190oC for 2 h After cooling to room temperature was added 20 ml of dichloromethane, and the aqueous solution of sodium hydroxide /NaOH/H2O 1,74 g /11 ml and the resulting mixture was heated under reflux for 2 hours, the dichloromethane Layer was washed with water and dried over anhydrous sodium sulfate, the solvent drove away. The residue was purified by chromatography on columns /eluent mixture of ethyl acetate and methanol 30 1/, the result of which was obtained 5.5 g of a mixture of 6-[3-/1-acetylpiperidine-4-yl/-1-oxopropyl-] 1 - methyl-1,2,3,4-tetrahydroquinoline and 7-[3-/1-acetylpiperidine-4-yl/-1-oxopropyl] -1-methyl-1,2,3,4-tetrahydroquinoline in the form of a pale yellow oil.

/3/ When performing the techniques described in example 1 with the use of 3.9 g of the oil obtained in accordance with option /2/ was obtained 3.2 g of the mixture specified in the title compounds as a pale yellow oil.

Elemental analysis for C18H26N2O

Calculated: C 75,48 H 9,15 N 9,78.

Found: C 75,21 H 9,06 N 9,8.

Example 8.

1-methyl-6-[1-oxo-3-[1-/phenylmethyl/piperidine-4 - yl] -propyl] -1,2,3,4-BR> When performing the techniques described in example 2, using 3.1 g of the compound obtained in accordance with example 7 was obtained 3.8 g of the free base mixture specified in the header of compounds A and B. This mixture was purified via chromatography/ eluent mixture of ethyl acetate and methanol 50 1/, which allowed us to obtain 1.6 g of 1-methyl-6-[1-oxo-3- [1-/phenylmethyl/piperidine-4-yl] propyl] -1,2,3,4-tetrahydroquinoline /colourless oil/ and 1.7 g of 1-methyl-7-[1-oxo-3-[1/phenylmethyl/piperidine-4-yl]propyl]-1,2,3,4-tetrahydroquinoline /colourless oil/.

Then 1.6 g of 1-methyl-6-[1-oxo-3-[1- /phenylmethyl/piperidine-4-yl]-]propyl] -1,2,3,4-tetrahydroquinoline was treated with an equivalent amount of fumaric acid with the formation of 1.7 g specified in the header fumarata /A/ in the form of colorless crystals with a melting point of 170 172oC /decomposition/.

Elemental analysis for C25H32N2O C4H4O4< / BR>
Calculated: C 70,71 H 7,37 N 5,69.

Found: C 70,61 H 7,24 N 5,63.

On the other hand 1.7 g of 1-methyl-7-[1-oxo-3- [1-/phenylmethyl/-piperidine-4-yl] propyl] -1,2,3,4-tetrahydroquinoline was treated with an equivalent amount of fumaric acid with the formation of 1.65 g is specified in the header fumarata /B/ in the form of colorless is B>32N2O C4H4O4< / BR>
Calculated: C 70,71 H 7,37 N 5,69.

Found: C 70,54 H 7,09 N 5,7.

Example 9.

1-phenylmethyl/-6-[1-oxo-3-/piperidine-4 - yl/-propyl]-1,2,3,4-tetrahydroquinolin /A/ and 1-/phenylmethyl/ -7-[1-oxo-3-/piperidine-4-yl/propyl]-1,2,3,4-tetrahydroquinolin /B/.

< / BR>
/I/ To a mixture of 5.2 g of the compound obtained in accordance with example 7-/1/, 3.0 g of potassium carbonate and 30 ml of ethanol was added dropwise 5 ml of a solution of 2.7 g of benzylbromide in ethanol under cooling with ice. This mixture was stirred at room temperature for 2 h, and then deleted the solid substance and the solvent. The residue was purified using chromatography /eluent: a mixture of ethyl acetate and methanol 20:1 /volumes/, the result of which was obtained 3.2 g of 7-[3-/1-acetylpiperidine-4-yl/-1 - oxopropyl] 1-/phenylmethyl/-1,2,3,4-tetrahydroquinoline/ colourless oil/ and 1.8 g of 6-[3-/1-acetylpiperidine-4-yl/-1-oxopropyl]-1,2,3,4 - tetrahydroquinoline.

/2/ the Mixture of 1.8 g of 6-[3-/1-acetylpiperidine-4 - yl/-1-oxopropyl]-1,2,3,4-tetrahydroquinoline obtained in accordance with the option /1/, of 1.03 g of potassium carbonate, 1,96 g benzylbromide and 20 ml of ethanol was heated under reflux for 5 h, and then deleted the solid substance and the solvent. Ostate the g 6[3-/1-acetylpiperidine-4-yl/-1-oxopropyl] 1-/phenylmethyl/-1,2,3,4 tetrahydroquinoline in the form of a colorless oil.

/3/ When performing the techniques described in example 1 with the use of 3.15 g of 7-[3-/1-acetylpiperidine-4-yl/-1-oxopropyl] -1-/phenylmethyl/ -1,2,3,4-tetrahydroquinoline obtained in accordance with the option /1/, there was obtained 2.8 g of 1-/phenylmethyl/-7-[1-oxo-3-/piperidine-4-yl/-propyl] -N 1,2,3,4-tetrahydroquinoline /In/ in the form of a pale yellow oil.

Elemental analysis for C24H30N2O

Calculated: C 7,52 H A 8.34 N 7,73.

Found: C 79,28 H 8,21 N To 7.59.

/4/ When performing the techniques described in example 1, using 1,9 g 6[3-/1-acetylpiperidine-4-yl/-1-oxopropyl]-1-/phenylmethyl/ -1,2,3,4-tetrahydroquinoline received in accordance with option /2/ was obtained 1.63 g /1-/phenylmethyl/-6-[1-oxo-3-/piperidine-4 - yl/propyl]-1,2,3,4-tetrahydroquinoline /A/ in the form of a pale yellow oil.

Elemental analysis for C24H30N2O

Calculated C 79,52 H A 8.34 N 7,73.

Found C 79,43 H 8,16 N Of 7.48.

Example 10.

1-/phenylmethyl/-6-[1-oxo-3-[1- /phenylmethyl/piperidine-4-yl] -propyl] -1,2,3,4-tetrahydroquinoline

< / BR>
When performing the techniques described in example 2, using 1.5 g of the compound obtained in accordance with example 9-/4/, there was obtained 1.6 g

/phenylmethyl/-6-[1-oxo-3-[1-/Tesla /1.6 g/ was treated with an equivalent amount of fumaric acid with the formation of 1.7 g specified in the header fumarata in the form of colorless crystals with a melting point 178-181oC /decomposition/.

Elemental analysis for C31H36N2O C4H4O4< / BR>
Calculated C 73,92 H 7,09 N 4,93.

Found C Of 7.64 H 7,22 N 4,84.

Example 11.

1-/phenylmethyl/-7-[1-oxo-3-[1-/phenylmethyl/piperidine-4 - yl] -propyl] -1,2,3,4-tetrahydroquinoline

< / BR>
When performing the techniques described in example 2, using a 2.75 g of the compound obtained in accordance with example 9-/3/ was obtained 2,95 g 1/phenylmethyl/-7- [1-oxo-3-[1-phenylmethyl/piperidine 4-yl]propyl]-1,2,3,4 - tetrahydroquinoline/ free/ base in the form of a colorless oil. This oil /2,95 g/ was treated with an equivalent amount of fumaric acid with the formation of 3.1 g specified in the header fumarata in the form of colorless crystals with a melting point 180-182oC /decomposition/.

Elemental analysis for C31H36N2O C4H4O4< / BR>
Calculated C 7,92 H 7,09 N 4,93.

Found C 73,72 H 7,02 N 4,86.

Example 12.

2,3-dihydro-5-[1-oxo-3-/piperidine-4-yl/propyl]-1H-indole

< / BR>
When performing the techniques described in example 1, using 10 g of the compound obtained according to reference example 3 was obtained a solid product, which is crystals with a melting point of 137-139oC.

Elemental analysis for C16H22N2O

Vicisano C 74,38 H 8,58 N 10,84.

Found C 74,11 H 8,75 N 10,67.

Example 13.

2,3-dihydro-5-[1-oxo-3-[1-/phenylmethyl/piperidine-4-yl] -propyl]-1H-indulgement

< / BR>
When performing the techniques described in example 2, using 2 g of the compound obtained in accordance with example 12 was obtained 2.3 g of the free base is specified in the header connection in the form of colorless crystals with a melting point 81-82 C. These crystals /2.3 g/ then was treated with an equivalent amount of fumaric acid with the formation of 2.6 g specified in the header fumarata in the form of colorless crystals with a melting point 150-153 C /decomposition/.

Elemental analysis for C23H28N2O C4H4O4< / BR>
Vicisano C 69,81 H 6,94 N 6,03.

Found C 69,68 H Of 6.71 N 5,93.

Example 14.

2,3-dihydro-1-methyl-5-[1-oxo-3[-1-/phenylmethyl/piperidine-4-yl]-propyl] -1H-indapurkat

< / BR>
/1/ when performing the techniques described in example 7-/1/ using 3 g of the compound obtained in accordance with example 12 was obtained 3.1 g of 5-[3-/1-acetylpiperidine-4-yl/1-oxopropyl-] 2,3 - dihydro-1H-indole in the form of the devil>2O2< / BR>
Calculated, C 71,97 H 8,05 N Was 9.33.

Found C 71,92 H 7,84 N 9,11.

/2/ When performing the techniques described in example 7-/2/ using 1.5 g of the compound obtained in accordance with the option /1/ was obtained 1.25 g 5[3-/1-acetylpiperidine-4-yl/-1-oxopropyl]- 2,2,-dihydro-1-methyl-1H-indenol in the form of a colorless oil.

/3/ When performing the techniques described in example 1 using 1.0 g of the compound obtained in accordance with option /2/ was obtained 0,83 g of 2,3-dihydro-1-methyl-5-[1-oxo-3- /piperidin-4-yl/propyl]1H-indenol in the form of a pale yellow oil.

Elemental analysis for C17H24N2O

Calculated: C 74,96 H 8,88 N 10,29.

Found: C 74,69 H 8,79 N 10,33.

/4/ When performing the techniques described in example 2 with the use of 0.53 g of the compound obtained in accordance with option /3/ was obtained 0.51 g of the free base specified in the title compounds as colorless oils. This oil /0.51 g/ was treated with an equivalent amount of fumaric acid, resulting in 0,57 specified in the header fumarata in the form of colorless crystals with a melting point 147-151oC /decomposition,

Elemental analysis for CN 5,80.

Example 15.

2,3-dihydro-5-[1-oxo-3[1-/phenylmethyl/piperidine-4-yl] propyl] -1- /phenylmethyl/-1H-indulgement

< / BR>
/1/ When performing the techniques described in example 9-/2/ using 0.65 g of the compound obtained in accordance with example 14-/1/, received 0,77 g 5[3-/1-acetylpiperidine-4-yl/-1-oxopropyl]-2,3-dihydro-1-/phenylmethyl/-1H-indenol in the form of a colorless oil.

/2/ When performing the techniques described in example 1 with the use of 0.67 g of the compound obtained in accordance with the option /1/, there was obtained 0.65 g of 2,3-dihydro-5[-1-oxo-3-/piperidine-4-yl/-propyl] -1-/phenylmethyl/-1H-indenol in the form of a yellow oil.

Elemental analysis for C23H28N2O

Calculated: C 79,27 H 8,10 N 8,04.

Found: C 79,03 H 8,05 N 8,13.

/3/ when performing the techniques described in example 2, using 0.64 g of the compound obtained in accordance with option /2/ was obtained 0.66 g of the free base specified in the title compounds as colorless oils. This oil /0,66 g/ was treated with an equivalent amount of fumaric acid, the result of which was obtained 0.75 g specified in the header of format in the form of colorless crystals with a melting point 153-156 C /decomposition/.

Found C To 73.65 H 6,80 N 5,00.

Example 16.

1-acetyl-6-[1-oxo-3-[1-/phenylmethyl/piperidine-4-yl] propyl]-1,2,3,4-tetrahydroquinoline

< / BR>
In 10 ml of dichloromethane was dissolved 0.5 g of 6[1-oxo-3- [1-phenylmethyl/piperidine-4-yl]propyl]-1,2,3,4-tetrahydroquinoline /free/ bottom, 0.28 g of acetic anhydride and 0.22 g of piperidine, and the solution was heated under reflux for 2 hours, the Solvent and excess reagents drove away under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with 10% sodium hydroxide, dried over anhydrous sodium sulfate and drove the solvent. This residue was purified using chromatography /eluent: a mixture of ethyl acetate and ethanol:1/, the result was obtained 0.45 g of the free base specified in the title compounds as colorless oils. This oil 0.45 g, was treated with an equivalent amount of fumaric acid with the formation of 0.53 g is specified in the header fumarata in the form of amorphous powder.

Elemental analysis for C26H32N2O2C4H4O4< / BR>
Calculated: C 69,21 H 6,97 N 5,38.

Found: C 69,23 H 6,87 N 6,40.

Example 17.

8-[1-oxo-3-/piperidine-4 - yl/propyl]-2,3,4,5-tetrahydro-1H-buenaga in accordance with reference example 4, there was obtained a viscous oil, which was led from the hexane with the formation of 5 4.6 g of pale yellow crystals with a melting point 104-107oC.

Elemental analysis for C18H26N2O

Calculated C 75,48 H 9,15 N 9,78.

Found: C 75,24 H A 9.09 N 9,66.

Example 18.

When performing the techniques described in example 1 using the compounds obtained according to reference examples 4, 6 and 7, were obtained the following compounds in the form of oils (see table. 15).

< / BR>
Example 19.

When performing the techniques described in example 13, using the compounds obtained in accordance with examples 12, 17 or 18, were obtained the following compounds (see table. 16,17).

< / BR>
Example 20.

2,3-dihydro-5-[1-oxo-3- /piperidine-4-yl/-propyl]bestfurniture

< / BR>
To 30 ml of concentrated hydrochloric acid was added to 5.00 g of 5-[3-/1-acetylpiperidine-4-yl/-1-oxopropyl] -2,3-dihydrobenzofuran and the resulting mixture was heated under reflux for 14 hours, the Reaction mixture was left to cool, and then podslushivaet diluted aqueous sodium hydroxide solution and was extracted with methylene chloride. Organic with the draw-5[1-oxo-3-/piperidine-4-yl/propyl]benzofuran /4/. The thus obtained solid substance was dissolved in methanol, treated with hydrogen chloride and recrystallized from a mixture of methanol and ethyl acetate, resulting in the obtained colorless needles, melting point 203 - 205oC /decomposition/.

Elemental analysis for C16H21N2O2HCl

Calculated C 64,97 H 7,50 N 4,74.

Found C 64,76 H Of 7.64 N 4,54.

Example 21.

2,3-dihydro-5-[1-oxo-3-[1 - phenylmethyl/piperidine-4-yl-[propyl]bestfurniture

< / BR>
In 30 ml of a mixture of tetrahydrofuran and ethanol /50/ 50 in volume/ added 1.52 g of 2,3-dihydro-5- [1-oxo-3-piperidine-4-yl-/propyl] benzofuran, and then 1,06 to potassium carbonate. The resulting mixture was cooled with ice was added dropwise a solution of 0.96 g of benzylbromide in ethanol /5 ml/. This mixture was stirred for 22 h at room temperature, and then drove the solvent. To the residue was added water, which was extracted with methylene chloride. The organic layers were combined and dried over anhydrous sodium sulfate, and then drove the solvent. The residue was purified by chromatography on columns of silica gel /ethyl acetate/ education 1.13 g /55% / 2,3 - dihydro-5-[1-oxo-3-[1-phenylmethyl/piperidine-4-from a mixture of ethanol and ethyl acetate, that allowed us to obtain colorless needles /Quaternary hydrate, melting point 143 144oC.

Elemental analysis for C23H27NO2HCl1/4H2O

Calculated C 70,75 Of 7.36 H N 3,59.

Found: C 70,49 H 7,26 N 3,62.

Example 22.

7-[1-oxo-3-[1-phenylmethyl/piperidine-4 - yl]-propyl]-2,3,4,5-tetrahydro-1H-3-benzenedicarboxamide

< / BR>
In nitrogen atmosphere of 0.48 g /1.1 mmole/ 3 - methoxycarbonyl-7-[3-/1-benzoylpiperidine-4-yl/-1-yl/-oxopropyl] -2,3,4,5-tetrahydro-1H-3-benzazepine obtained according to reference example 11, was dissolved in 5 ml of dry chloroform. To this solution was added 0.3 ml /2.1 mmole/ idolisation. This mixture was stirred for 2.5 h at a temperature of 50oC. the Reaction mixture was left to cool, after which it was added to 0.4 ml /10 mmol/ methanol. To the mixture was added dilute aqueous sodium hydroxide solution and aqueous sodium thiosulfate solution, and then made the extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent drove away. The residue was dissolved in 15 ml of dry tetrahydrofuran. To this solution was added to 0.13 g 03,4 mmole/ lithium aluminum hydride, and then the mixture was heated with abratt was dried over anhydrous sodium sulfate, and the solvent drove away. The residue was dissolved in methanol and treated with hcl, then drove the solvent with the formation of the hydrochloride. The hydrochloride was added to a mixture of 0.3 g /3 mmole/ chromic acid, 0.3 ml of concentrated sulfuric acid and 10 ml of an aqueous solution of acetone /1/1= 0 in the volume ratio/. The resulting mixture was stirred at room temperature for 24 h the Reaction mixture was poured into water and podslushivaet diluted aqueous sodium hydroxide solution, after which made the extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent drove away. The residue was purified by chromatography on columns of aluminum oxide, the result of which was obtained 0.31 g /76%/ 7-[1-oxo-3-[1-/phenylmethyl/piperidine-4-yl]propyl] -2,3,4,5-tetrahydro-1H-3 - benzazepine. This product was dissolved in methanol and treated 3 N. a solution of hydrochloric acid in methanol with the formation of the dihydrochloride as an amorphous powder.

Elemental analysis for C25H32N2O 2HCl2,5H2O

Calculated: C RUR 60,72 H 7,95 N 5,66.

Found: C 60,85 H 8,24 N 5,6.

Example 23.

3-methyl-7-[1-oxo-3-[1-/phenylmethyl/-piperidine-4-yl] -propyl]-2,3,4,5-tetrahydro-1H-3-b is uridin-4-yl/1-oxopropyl]-2,3,4,5-tetrahydro-1H-3 - benzazepine. To this solution was added 7 ml of ethylene glycol and 10 mg paratoluenesulfonyl, after which the mixture was heated under reflux for 2.5 hours To the reaction mixture were added saturated aqueous sodium bicarbonate solution and was extracted with simple diethyl ether. The extract was dried over anhydrous sodium sulfate, then the solvent drove away. The residue was purified by chromatography on columns of silica gel with formation of 1.22 g/94%/ 7-[2-[2- /1-benzoylpiperidine-4-yl] ethyl] -1,3-dioxolan-2-yl/-3-methoxycarbonyl-2,3,4,5-tetrahydro-1H-3-benzazepine. 1,03 g /2.1 mmole/ obtained above compound was dissolved in 15 ml of dry tetrahydrofuran and then to this solution was added 0.25 g /6.5 mmole/ lithium aluminum hydride. The reaction mixture was heated under reflux for 3 h, then added water and filtered. The filtrate was dried over anhydrous sodium sulfate, and then drove the solvent. The residue was dissolved in tetrahydrofuran and to this solution was added 5.6 ml of 1 n HCl solution, after which the mixture was stirred for 14,5 hours at room temperature. The reaction mixture was podslushivaet diluted aqueous sodium hydroxide solution and then was extracted with dichloromethane. The extract solution was dried relatively the hydrogen chloride with the formation of the dihydrochloride, which is then recrystallized from a mixture of ethanol and ethyl acetate, which allowed us to obtain 0.65 g /67%/ colorless needles, melting point 190 193oC.

Elemental analysis of C26H34N2O2HCl H2O

Calculated: C 64,86 H 7,95 Of 5.82.

Found: C 64,78 Of 7.90 H N 5,78.

Example 24.

2,3-dihydro-6-[1-oxo-3-/piperidine-4-yl/propyl]-1H-indole

< / BR>
/1/ To a mixture of 25 g of 2,3-dihydro-1-triptoreline, 25 g of acid chloride of 3-/1-acetylpiperidine-4-indole/ propionic acid and 120 ml of carbon disulfide was added 56 g of anhydrous aluminium chloride at room temperature, after which the mixture was heated under reflux for 30 hours. The reaction mixture was treated as in reference example 1-/3/-, resulting in 9.0 g of a mixture of 6-[3-/1-acetylpiperidine-4-yl/1-oxopropyl] -2,3-dihydro-1-TRIFLUOROACETYL-1H-indole and 5-[3/-/1-acetylpiperidine-4-yl/-1 - oxopropyl] -2,3-dihydro-1-TRIFLUOROACETYL-1H-indole as a pale yellow oily product.

/2/ Oily product obtained in accordance with the option /1/, were subjected to the same interaction as in example 1, the result of which was obtained 2,3-dihydro-6-[1-oxo-3-/piperidine-4-yl-propyl] -1 H - ingoldisthorpe. The mixture ecoville from a mixture of methanol and ethyl acetate with the formation of 2.5 g of the dihydrochloride specified in the title compound as a colourless powder, melting point 146 148oC. the thus Obtained powdery compound was dissolved in water, the pH of which was brought to 10 with 10% sodium hydroxide solution, and was extracted with dichloromethane. The extract solution was dried over anhydrous sodium sulfate, and the solvent is kept at reduced pressure, which allowed us to obtain 1.8 g specified in the title compounds as a pale yellow oily product.

Elemental analysis: for C16H22N2O

Calculated: C 74,38 H 8,58 N 10,84.

Found: C 74,32 H 8,66 N A 10.74.

Example 25.

2,3-dihydro-6-[1-oxo-3-[1-/phenylmethyl/- piperidine-4-yl] -propyl-1H-engulfment

< / BR>
When performing the techniques described in example 13, using 0.5 g of the compound obtained in accordance with example 24. There was obtained 0.55 g specified in the title compounds as colorless crystals, melting point 157 158oC.

Elemental analysis for C23H28N2O C4H4O4< / BR>
Calculated C 69,81 H 6,94 N 6,03.

Found C 69,65 H 6,87 N 5,76.

Example 26.

9[1-oxo-3-/piperidine-4-yl/propyl] 1,2,3,4,5,6-hexahydro-1-benzazocin

< / BR>
When performing techniques is oluce balance. This residue was subjected to the same interaction as in example 1, resulting mentioned in the title compound as a pale yellow oily product.

Elemental analysis for C19H28N2O

Calculated: C 75,95 H 9,39 N Was 9.33.

Found: C 75,73 H 9,38 N 9,10.

Example 27.

9-[1-oxo-3-[1-/phenylmethyl/piperidine-4-yl] propyl] -1,2,3,4,5,6 - hexahydro-1-benzazocine

< / BR>
When performing the techniques described in example 13, using 9-[1-oxo-3-/piperidine-4-yl/propyl] 1,2,3,4,5,6-hexahydro-1-benzazocine was obtained is listed in the title compound as colorless crystals.

Elementary analysis for C26H34N2O C4H4O4< / BR>
Calculated: C 71,12 H 7,56 N Of 5.53.

Found: C 70,98 To 7.61 H N 5,42.

Example 28.

1-acetyl-8-[1-oxo-3-[1-/phenylmethyl/piperidine-4-yl] -propyl] -2,3,4, 5-tetrahydro-1H-1-benzazepin

< / BR>
When performing the techniques described in example 16, using 0.3 g 8[1/oxo-3[1-phenylmethyl/piperidine-4-yl] propyl] -2,3,4,5 tetrahydro-1H-1-benzazepin, which is the free base of the compound obtained in accordance with example 19, the compound N 16, there was obtained 0.21 g of the criminal code of elementry analysis for C27H34N2O2< / BR>
Calculated C 77,48 H 8,19 N 6,69.

Found C 77,21 H 7,98 N 6,56.

Example 29.

3,4-dihydro-6-[1-oxo-3-piperidine-4-yl/propyl] -2H-1-benzothiadiazole

< / BR>
When the run described in example 1, using 2.5 g of the compound obtained in accordance with reference example 12 was obtained 2.4 g specified in the title compound as a colourless powder, melting point 196 199oC.

Elemental analysis for C24H29NOSHCl

Vaticano: C 62,65 H 7,42 N 4,30.

Found: C 62,61 H 7,33 N 4,27.

Example 30.

a 4.3-dihydro-6-[1-oxo-3-[1-/phenylmethyl/piperidine-4 - yl] -propyl]-2H-1-benzothiadiazole

< / BR>
When performing the techniques described in example 2 with the use of 0.83 g of the compound obtained according to example 29 was obtained 1.0 g specified in the title compound as a colourless powder, melting point 186 188oC.

Elemental analysis for C24H29NOSHCl

Calculated C 69,29 H 7,27 N 3,37.

Found C 69,31 H 7,22 N 3,27.

Example 31.

8-[1-oxo-3-/piperidine-4-yl/propyl] -2,3,4,5 - tetrahydro-1H-2-benzenedithiol /II/ and 7-[1-oxo-3-/piperidine-4-yl/-cnom example 1 using 5.0 g of 2-acetyl-2,3,4,5-tetrahydro-1H-benzazepine was obtained 4.7 g of viscous oil.

When performing the techniques described in example 1, using 4.5 g of the specified oil was obtained of 3.3 g of a pale yellow solid. This solid is recrystallized from methanol with the formation specified in the header connection /A/ in the form of a colourless powder, melting point > 300oC.

Elemental analysis for C18H26N2O2HCl

Calculated: C 60,17 H A 7.85 7,80.

Found: C 59,95 H 7,98 To 7.77.

The compound (B) was obtained as amorphous powder by concentrating the mother liquor, obtained by recrystallization of the compound (A) mentioned above.

Example 32.

8-[1-oxo-3-[1-/phenylmethyl/piperidine-4-yl] propyl-] -2-/phenyl methyl/-2,3,4,5-tetrahydro-1H-2-benzenedithiol /A/ and 9-[1 - oxo-3-[1-/phenylmethyl/piperidine-4-yl] propyl] -2,3,4,5-tetrahydro-1H-2 - benzenepropanoic /B/

< / BR>
When performing the techniques described in example 2, using 1.5 g of 8-[1-oxo-3-/piperidine-4-yl/propyl] -2,3,4,5-tetrahydro - 1H-2-benzenedicarboxamide obtained in accordance with example 31 was obtained 0.5 g specified in the header of soedinen> 8-[1-oxo-3-/1-/phenylmethyl/piperidine-4 - yl/propyl] -2-/phenylmethyl/-2,3,4,6-tetrahydro-1H-2-benzenedithiol /A/.

Elemental analysis for C32H38N2O2HCl

Calculated: C 71,23 H 7,47 N 5,19.

Found: C 66,72 H 7,69 N 6,01.

8-[1-oxo-3-/1-phenylmethyl/piperidine-4-yl-propyl] -2,3,4,5-tetrahydro-1H-2-benzenedithiol /B/

Elemental analysis for C25H32N2O2HCl

Calculated: C 66,81 H A 7.62 N 6,23.

Found: C 66,72 H 7,69 N 6,01.

Example 33.

8-chloro-5-[1-oxo-3-[1-/phenylmethyl/piperidine-4-yl]propyl] -1,2,3,4-tetrahydroisoquinolinium

< / BR>
Calculation of 5.99 g /13,22 mmole/ compound obtained in reference example 14, 198 ml of methanol was added to 99 ml of 1 n aqueous NaOH solution. This mixture was stirred at a temperature of 60oC for 5 hours After removal of methanol under reduced aqueous residue was extracted with dichloromethane. The extracts were dried over anhydrous sodium sulfate, and the solvent drove away. The residue was purified by chromatography on columns of silica gel /eluent: a mixture of ethyl acetate and methanol 7:3 / volumes// education 2,59 g of 5- [3-/1-benzoylpiperidine-4-yl/-1-oxopropyl] -8-chloro-1,2,3,4 - tetrahydrothieno.

To a solution of 1.23 ur 5oC, and the solvent drove away. The remaining oil was added 60 ml of solvent, of 0.21 ml of ethylene glycol and 57 mg of the monohydrate of paratoluenesulfonyl. This mixture was heated under reflux for 2 hours To the reaction mixture were added saturated aqueous solution of NaHCO3and was extracted with dichloromethane. The extracts were dried over anhydrous sodium sulfate, then the solvent was removed under reduced pressure. The residue was purified by chromatography on columns of silica gel /eluent mixture of ethyl acetate and methanol 7 3/ volumes/ with the formation of 1.31 g of 5-[2-2-/1-benzoylpiperidine-4-yl/ethyl]-1,3 - dioxolan-2-yl]-8-chloro-1,2,3,4-tetrahydroisoquinoline.

In a nitrogen atmosphere to a solution of 455 mg /1.0 mg/ obtained above compound in 10 ml of dry tetrahydrofuran was added 127 μl of chlorotrimethylsilane at a temperature of 5oC, after which the mixture was stirred at room temperature for 1 h Then the reaction mixture was added 190 mg of lithium aluminum hydride and the mixture was heated under reflux for 2.5 hours To the mixture was added water and the precipitate was removed by filtration. The filtrate was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. A mixture of the residue and 5 ml of 1N odogmalooli dilute aqueous NaOH solution, and then was extracted with dichloromethane. The extract was dried on anhydrous sodium sulfate, then the solvent was removed under reduced pressure, which allowed us to obtain 200 mg of a colorless oil, which was treated with 4 n HCl solution in methanol /2 equivalent/, resulting in 205 mg specified in the title compound as amorphous powder.

Elemental analysis for C24H29ClN2O2HCl

Calculated: C 61,35 H 6,65 N 5,96.

Found: C 61,42 H 6,69 N 5,91.

Example 34.

7,8-dibromo-8-[1-oxo-3-(phenylmethyl)piperidine-4 - yl)propyl)-2,3,4,5-tetrahydro-1H-benzazepine hydrochloride.

< / BR>
To a solution of 0.73 g of compound 16 (free from salt) obtained in example 19 in acetic acid (50 ml) and water (10 ml) is added bromine (0.68 g) under cooling with ice. After stirring for 1 h the solution was added 10% aqueous sodium hydroxide until disappears yellow staining. Extracted the product with dichloromethane and the extract washed with water, dried and evaporated in vacuo to obtain the product in the form of butter.

The residue is treated with ethanolic hydrochloric acid (two equivalents) and the resulting solid is recrystallized from ether methanes>H30Br2N2O

in which X is oxygen, sulfur or

< / BR>
where R1hydrogen, C1C7-alkyl, C7- C10-aralkyl or C2C8-acylcarnitine group;

R2hydrogen or C7C10-kalkilya group which may be substituted C1C4-alkyl, C1- C4-alkoxy, halogen, nitro, hydroxyl or C1- C4-alkylaminocarbonyl;

the ring is A benzene ring which may be substituted with halogen;

k 0 3, integer;

m 0 5, integer;

n 2

or its salt.

2. Connection on p. 1, in which X , where R1matter specified in paragraph 1.

2. Connection on p. 2, in which k is 0, m is 2 to 5, an integer.

4. Connection on p. 1, in which R1the hydrogen.

5. Connection on p. 1, in which R1C1C7-alkyl or C7C10-kalkilya group.

6. Connection on p. 1, in which R1C2- C8-acylcarnitine group.

7. Connection on p. 1, in which R2C7- C10-kalkilya group which may be substituted C1- C4-alkyl, C1C4-alkoxy, halogen, nitro, HYDR 1 5.

9. Connection on p. 1, where k 0 and m 2 5.

10. Connection on p. 1, in which X is oxygen, or R1matter specified in paragraph 1, k 0 2, m 2 5, n is 2 and R2hydrogen or C7C10-kalkilya group which may be substituted C1C4-alkyl, halogen, the nitro-group or C1C4-CNS group.

11. Connection on p. 1, in which R2benzyl group.

12. Connection on p. 1, in which the group

is

< / BR>
13. Connection on p. 1, in which the group

is

< / BR>
14. Connection on p. 1, in which the group

is

< / BR>
15. Connection on p. 1, in which the group

is

< / BR>
16. Connection on p. 1, in which the group

is

< / BR>
17. Connection on p. 1, in which the group

is

< / BR>
or

< / BR>
where R3hydrogen or C1C3is an alkyl group;

n 2;

R2benzyl group.

18. Connection on p. 1, which is 8-[1-oxo-3-[1-(phenylmethyl)piperidine-4-yl] - propyl]-2,3,4,5-tetrahydro-1H-1-benzazepin or its salt.

19. Connection on p. 1, which is 3-methyl-7- [1-oxo-3-[1-(phenylmethyl)piperidine-4-yl]-propyl]- 2,3,4,5-tetraethyl)piperidine-4-yl] propyl]-2,3,4,5-tetrahydro-1H-3-benzazepin or its salt.

21. Connection on p. 1, which is 9-[1-oxo-3-[1-(phenylmethyl)piperidine-4-yl] propyl]-1,2,3,4,5,6 - hexahydro-1-benzazocin or its salt.

22. Connection on p. 1, which is 7-[1-oxo-3-[1- (phenylmethyl)piperidine-4-yl] propyl] -2,3,4,5-tetrahydro-1H-1-benzazepin or its salt.

23. Connection on p. 1, which is 8-[1-oxo-3-[1- (phenylmethyl)piperidine-4-yl] propyl]-2,3,4,5 tetrahydro-1H-1-benzazepine fumarate.

24. Connection on p. 1, which is 3-methyl-7-[1-oxo-3- [1-(phenylmethyl)piperidine-4-yl] -propyl] -2,3,4,5-tetrahydro-1H-3-benzazepine the dihydrochloride.

25. Connection on p. 1, which is 7-[1-oxo-3- [1-(phenylmethyl)piperidine-4-yl] propyl] -2,3,4,5-tetrahydro-1H-3 - benzazepine fumarate.

26. Connection on p. 1, which is 9-[1-oxo-3-[1- (phenylmethyl)piperidine-4-yl] propyl] -1,2,3,4,5,6 - hexahydro-1-benzazocine fumarate.

27. Connection on p. 1, which is 7-[1-oxo-3-[1-(phenylmethyl)piperidine-4-yl] propyl] -2,3,4,5 - tetrahydro-1H-1-benzazepine fumarate.

28. A method of obtaining a condensed heterocyclic compounds of the formula I

< / BR>
in which X is oxygen, sulfur or

< / BR>
where R1hydrogen, CR2hydrogen or C7C10-kalkilya group which may be substituted C1C4-alkyl, C1- C4-alkoxy, halogen, nitro, hydroxyl or C1- C4-alkylaminocarbonyl;

the ring is A benzene ring which may be substituted with halogen;

k 0 3; m is 1 to 5; n 2

or their salts, characterized in that interact the compounds of formula III

< / BR>
in which all symbols have the listed values,

or its salt with the compound of the formula II

< / BR>
in which Y is halogen;

Z group protecting the amino group; n 2

or its salt, and removing the protective group, followed if necessary by the interaction of the compounds in which R2is hydrogen, with a compound of formula R2'Y', in which R2' - C7C10-kalkilya group which may be substituted C1C4-alkyl, C1C4-alkoxy, halogen, nitro, hydroxyl or C1C4-alkylaminocarbonyl, and Y' tsepliaeva group, or the interaction of the compounds in which X -

< / BR>
with the compound of the formula R1'Y', in which R1' C1- C7-alkyl, C7C1

30. The pharmaceutical composition inhibiting the cholinesterase containing the active substance on the basis of condensed heterocyclic compounds and pharmaceutically acceptable additives target, characterized in that as a condensed heterocyclic compounds it contains a compound of formula I or its pharmaceutically acceptable salt in an amount of 0.01 to 100 mg per dose.

31. Connection on p. 1, where k 0 2, m 2 5, R2is hydrogen or C7C10-kalkilya group which may be substituted C1C4-alkyl, halogen, nitro or C1- C4-alkoxygroup.

Priority points:

22.11.90 on PP.3, 12, 15 and 16;

14.01.91 on PP.2, 13, 14 and 17;

21.08.91 on PP.18, 22, 23 and 27;

24.09.91 on PP.1, 4 11, 19 21, 24 26, 28 31.

 

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The invention relates to new triazolo[4,3-a][1,4] benzodiazepine or a thieno[3,2-f][1,2,4]triazolo[4,3-a]benzodiazepines of General formula I

< / BR>
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The invention relates to a method for producing new derivatives triazolo-[4,3-a](1,4) benzodiazepines General formula I:

I,

where X is-CH=CH -, or S;

R1lower alkyl or trifluoromethyl;

R2chlorine or fluorine;

R3the radical of the formula R4-(CH2)nC or R5-O-CH2-C_C-, where n is the integer 0, 1 or 2;

R4phenyl or mono-, di-, or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms 0 or S, and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine,

R5phenyl or pyridylethyl provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5attached via a carbon to oxygen connection with RAG-antagonistic properties

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts

The invention relates to a method for production of new chemical compounds having pesticidal activity

The invention relates to a series of new derivatives of compounds known as "milbemycin", which are characterized by the presence of heterocyclic substituted mercaptoacetate group at the 13-position

The invention relates to a new method of obtaining the previously described connections of a number of dibenzo[b, e]pyrano[3,2-b]-1-benzopirilievyh salts of General formula (I),

< / BR>
where X 0;

R1a hydrogen atom;

R2-R4the atom of hydrogen or halogen, C1-C6alkyl or C1-C6alkoxygroup, the nitro-group;

R5, R6, R7the atom of hydrogen or C1-C6alkyl,

that exhibit fluorescent properties and are used as dyes for dyeing films and aminomethylating fibers (DOS 2942931 (1980), BASF, Erf

The invention relates to certain 13-alkyl-23-imino - 13-halogen-23-imino-LL-F28249-compounds and to their use for combating endo - and ectoparasitic infections and infestations in warm-blooded animals

The invention relates to a new class of pesticides, which are 1,4-bis-substituted-2,6,7-dioxabicyclo(2.2.2)octane

The invention relates to a series of new macrolide compounds that are chemically related to some well-known classes of macrolides, including milbemycin and avermectins

The invention relates to a derivative of pyrazine, which has antagonistic activity relative to the glutamate receptor, represented by the formula:

< / BR>
in which Z represents C or N, provided that two Z are nitrogen atoms; R1is:

< / BR>
in whichisor, R6represents H or alkyl, and R7and R8are each H, alkyl, nitro or phenyl, or alternatively, R7and R8taken together, represent butadiene or 1,4-butylene; R2and R3are each H, F, cyano, acyl, nitro, alkyl, morpholino or one of the above definitions for R1; R4and R5are each H, hydroxyl, alkyl, cycloalkyl, heterocycle, phenyl, or Y-substituted alkyl; Y represents a hydroxyl, acyloxy, F - substituted methyl, cycloalkyl, tetrahydrofuranyl, carboxyl, alkoxycarbonyl or

The invention relates to new triazolo[4,3-a][1,4] benzodiazepine or a thieno[3,2-f][1,2,4]triazolo[4,3-a]benzodiazepines of General formula I

< / BR>
where X is-CH=CH -, or S; R1- lower alkyl or trifluoromethyl; R2is chlorine or fluorine; R3is a radical of the formula R4-(CH2)n-CC - or R5-O-CH2-CC -, where n is an integer of 0,1 or 2; s is 0 or 1; R4is phenyl or mono-, di - or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms O or S and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine; R5is phenyl or pyridyl radical, provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5always attached through carbon to oxygen of communication, and in the presence of at least one asymmetric center, their enantiomers and racemates and pharmaceutically-acceptable salts accession acids exhibiting the properties of antagonists of platelet activating factor (PAF) and, respectively, with angioprotective, immunological, is omposition based on them
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