Cyclic aminosilane or its physiologically acceptable additive salt of the acid

 

(57) Abstract:

Usage: in medicine, in particular, as substances having antihypoxic, anticholinesterase activity, activity against swelling of the brain. The inventive cyclic aminosilane formula where B is pyridyl, piperidyl or pyrrolidinyl, each of which may be substituted by lower alkyl, lower alkylcarboxylic, carbobenzoxy, afterburner (nisei) alkyl, phenylketone (lower) alkyl, phenylcarbamoyl (lower) alkyl or phenyl (lower) alkyl, each of which may be substituted by a halogen atom or lower alkoxy, p = 1 or 2, A communication or two - or trivalent aliphatic C1-6is a hydrocarbon residue which may be substituted by lower alkyl, OXO, hydroximino or hydroxy, either simple or double bond, provided that when a is a bond, means a simple link, R2and R3- independently a hydrogen atom or lower alkyl which may be substituted by phenyl or piperidino, provided that both R2and R3are not a hydrogen atom, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, piperazinonyl is diphenyl (lower) alkyl, or its physiologically acceptable additive salt of the acid. 10 table.

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

B A N where - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group; means either simple or double bond, provided that when a represents a bond, means a simple bond; R2and R3independently mean a hydrogen atom or a lower alkyl group which may be substituted by phenyl or piperidino group, provided that both R2and R3are not hydrogen atoms, or R2and Rthe new, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid.

The compound of formula I and its salt have antihypoxic, anticholinesterase activity, activity against swelling of the brain and are effective for the treatment of various symptoms caused by hypoxia or ischemia of the brain, in particular swelling of the brain.

Currently available means of therapeutic treatment aimed at the treatment of edema of the brain associated with increased intracranial pressure caused by brain tumor, injury or cerebral ischemia, assume excessive introduction of corticosteriods and etilenglikolevye therapy using osmotic pressure, however, there is still no sufficiently effective therapeutic tools or tools that do not have side effects.

The purpose of the invention to provide a new class of compounds that can be used as therapeutic agents aimed at receivemtu against swelling of the brain. In addition, it was found that among the various kinds of compounds (1), compounds in which the Aza-heterocyclic group with 5-6 members, a substituted benzyl group, which itself can be substituted in the N position, possess besides a strong anticholinesterase activity.

When using the invention in the treatment of swelling of the brain, the cerebral microcirculation, for example, with increasing erythrocyte deficiency, acute brain symptoms of hemorrhage, as well as protection from the death of nerve cells, or as cholinesterase-vast funds, particularly preferred are compounds (1) having the formula (1' )

R N(CH2)lDN (l') where R1is a hydrogen atom or a benzyl group which may be substituted; l is an integer from 0 to 4 and D' is a group of the formula--,--, or-CH2-, and R'2and R'3are independently1-6-alkyl group or together form a cyclic amino group together with the adjacent nitrogen atom, or their salts.

In particular, compounds in which b is N-benzylamino piperidinyloxy group, possess satisfactory activity against holinesse - times.

More FAV"1is a benzyl group, and D' is the CO-, i.e. compounds of the formula

CHN(CH2)lCON (l) where l, R'2and R'3defined, or their salts.

For use in the treatment of edema of the brain, acute symptoms of brain hemorrhage or stroke, or for treatment of disorders of the microcirculation of the brain, as well as to protect nerve cells or brain cells from death and so on, more preferred are the compounds of formula (I'), where R1is a hydrogen atom, and l = 0, i.e. the compounds of formula

NDN (l"') where D', R'2or R'3defined, or their salts.

In relation to therapeutic activity in the treatment of brain edema and acute cerebral symptoms especially valuable are the compounds of formula (I'), where R1is a hydrogen atom, l = 0 and D' is-CH2- or their salts.

Compounds of the present invention can be obtained not only in the form of compounds of formula (I), but also in the form of acid additive salts, in particular their physiologically acceptable acid additive salts. Examples of such acid additive salts can serve as inorganic acid salts (e.g. salts of hydrochloric acid, sulfuric acid, nitric key is lots propionic acid, fumaric acid, maleic acid, tartaric acid, citric acid, malic acid, oxalic acid, benzoic acid, methanesulfonic acid, benzosulfimide acid).

Methods for obtaining compounds of the invention.

Among the specific compounds of formula (I), corresponding to the invention, the compounds of formula

R7NDN (la) where R7means substituting group in the N-position, if the ring R7-N is saturated and denotes acyl group which may be substituted and which is included in the definition of R1; D means the relationship or1-5-alkylenes group which may be substituted by hydrocarbon residues, oxo and/or hydroxy; R2, R3m = 1 or 0 and p are defined, can be obtained by using the reaction, for example, the compounds of formula (II)

R7ND--X (ll) where D, R7and m are defined above and X is halogen, for example chlorine, bromine, iodine, for example, with the compound of formula (III):

[Y]p(III) where R is defined, and Y is a halogen atom, e.g. fluorine, chlorine, bromine, iodine obtaining the compounds of formula (IV)

RND[Yp] (lV) where D, R7, Y, m, and p are defined, and then by using the specified reaction soy is The compound of formula (II) can be obtained by known or an equivalent method. For example, compound (II) can be obtained by the method described in Chemical Pharmaceutical Bulletin , 3747-3761, 1986.

The reaction between the compound (II) and compound (III) can be carried out per se in the standard way. For example, the compound (II) interacts with the compound (III) or in the absence of solvent or in a solvent, and if necessary, in the presence of acid or similar Acid may be a Lewis acid such as aluminum chloride, zinc chloride, titanium chloride or similar Solvent may be any of the standard solvents, unless it inhibits the reaction. For example, the reaction can be carried out in dichloromethane, dichloroethane, nitrobenzene, carbon disulfide, or etc., at a temperature of, generally, about-30-150aboutWith, and preferably about 20-100aboutC. For each mol of compound (II) is mainly used for about 1-20 mol of compound (III), and preferably about 2-5 mol. The reaction between the compound (IV) and compound (V) can also be carried out per se in the standard way. For example, the compound (IV) reacts with the compound (V) or in a solvent or in the absence of solvent, at a temperature of around 50-300aboutWith, and preferably about 20-200aboutC. the Solvent can be any of the standard, clonicel, dimethylformamide, N-organic, dimethylsulfoxide, etc. If necessary, this reaction may proceed in the presence of organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine and etc., inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc., sodium hydride, potassium hydride, etc.

For each mol of compound (IV) is mainly used for about 1-10 mol of compound (V), and preferably about 2-4 mol of compound (V). Reaction time is mostly about 1-48 hours, preferably 10-20 hours

Among the various kinds of compounds (I), the compounds of formula (Ib)

HNDN (lb) where D, R2, R3, m and p are defined, provided that a hydrogen atom in the N-position of the ring is available only if the specified ring is saturated; can be obtained by processing the above-mentioned compound (Ia) with an acid or a base. Thus, the compound (Ia) is treated in an aqueous solution of mineral acid (e.g. nitric acid, hydrochloric acid, Hydrobromic acid, innovate acid, sulfuric acid, etc. or water is. ) at a temperature of, generally, 10-150aboutWith, preferably 50-100aboutC. the Ratio of acid or base to the compound (Ia) is mainly 10 to 100 equivalents, and preferably 20 to 40 equivalents. The strength of the acid or base is preferably about 1-10 N. , and more preferably about 4-10 N. the reaction Time mainly is about 1-24 h, and preferably, about 2-10 hours, although it depends on the reaction temperature.

The compounds of formula (Ic)

R7NDN (lc) where D, R2, R3, R7, m and p are defined, can be obtained by recovering the compounds of formula (Ia) using standard methods. For example, compound (Ia) is subjected to catalytic recovery in solvent using hydrogen in the presence of a catalyst. The solvent may be any standard solvent for chemical reactions, if it has no effect on the reaction undesirable way. For example, the reaction may proceed in water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane, etc., using palladium, rhodium, platinum, skeletal Nickel hydrogenation catalyst or other catalysts, at a temperature of, generally, about -10about< the, and if necessary in the presence of acid. These acids may be a mineral acid (e.g. hydrochloric acid, nitric acid, phosphoric acid, Hydrobromic acid) or organic acid (e.g. acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonate acid, toluensulfonate acid and so on). The compound (Ic) can also be obtained by treating compound (Ia) with a metal hydride (for example, a hydride diisobutylaluminum, triphenylimidazole and so on), metallovedenie complex compounds (for example, alumoweld sodium, alumoweld lithium, triaxiality sodium, etc.,), DIBORANE or substituted borane (e.g., sodium borohydride). These metal compounds are used mainly in the ratio of 0.3 to 5 mol, preferably 1-2 mol per mol of compound (Ia). The solvent may be any standard solvent for chemical reactions, if only he has no undesirable influence on the reaction. For example, the reaction may proceed in proton solvent (e.g. water, methanol, ethanol, propanol, etc.,) or an aprotic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane, etc.,) is where D, R2, R3, m and p are defined, can be obtained by treating the compounds of formula (Ic) acid or base or by restoring the compounds of formula (Ib) using standard procedures. Acid or base that can be used in the above processing, the compounds of formula (Ic) include mineral acid (e.g. nitric acid, hydrochloric acid, Hydrobromic acid, innovate acid, sulfuric acid, etc.,), hydroxide of alkali metals (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.,). This processing may be carried out in an aqueous solution of acid or base at a temperature of 10-150aboutWith, and preferably 50-100aboutC. the Strength of the acid or base, basically, is about 1 to 10 n, preferably 4-10 N. the Specified acid or base, mainly used in proportions of about 20-40 equivalents relative to the compound (Ic). The response time is mainly 1-24 hours, preferably about 2-10 hours, although it depends on the reaction temperature. As for the above-mentioned standard method recovery compounds (Ib), the used solvent can be any standard solvent for himt, for example, water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane, etc. as a catalyst can be used, for example, palladium, rhodium, platinum or skeletal Nickel catalyst for hydrogenation. The reaction may proceed in the presence of the specified catalyst at a temperature of about-10-100aboutWith, and preferably about 20-50aboutWith, when the hydrogen pressure of 1-100 atmospheres, and preferably 1-5 ATM, and if necessary, in the presence of acid. Used acid may be a mineral acid (e.g. hydrochloric acid, nitric acid, phosphoric acid, Hydrobromic acid, etc. or an organic acid (e.g. acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonate acid, toluensulfonate acid and so on ). Compound (Id) can also be obtained by treating compound (Ib) with a metal hydride (for example, a hydride diisobutylaluminum, triphenylimidazole and so on ), metallovedenie complex compounds such as alumalite lithium, alumoweld sodium, triaxiality sodium), DIBORANE or substituted borane (e.g., sodium borohydride) in a solvent. The solvent may be ispolzovatsya for the reaction. Thus, this processing may be done in proton solvent (e.g. water, methanol, ethanol, propanol, etc.,) or an aprotic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane, etc.,) at a temperature of mostly-10-200aboutWith, and preferably 20-100aboutC.

The compounds of formula (Ie)

R7NDCHN (le) where D, R2, R3, R7, m and p are defined, can be obtained by recovering the compounds of formula (Ia) or (Ic). As a solvent in this reaction may be used with any standard solvent for chemical reactions, if only he has no undesirable influence on the reaction. Such a solvent can be, for example, water, methanol, ethanol, dimethylformamide, tetrahydrofuran and dioxane. This reaction may proceed in such a solvent in the presence of a catalyst, e.g. palladium, rhodium, platinum or skeletal Nickel hydrogenation catalyst at a temperature of, generally, about-10-100aboutWith, and preferably about 20-50aboutWith under a hydrogen pressure of 1-100 bar, preferably 1-5 ATM, and if necessary, in the presence of acid. Used acid may be a mineral acid, for example, chlorite the PTA for example, acetic acid, propionic acid, tartaric acid, benzoic acid, methanesulfonate acid.

The compounds of formula (If)

HNDCHN (lf) where D, R2, R3, m and p are defined, can be obtained by treating compound (Ie) with an acid or a base. For example, the compound (Ie) can be treated with mineral acid (e.g. nitric acid, hydrochloric acid, Hydrobromic acid, innovate acid, sulfuric acid, etc. or an alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, etc.,) at a temperature of, generally, 10-150aboutWith, preferably 50-100aboutC. the Strength of the acid or base, basically, is about 1 to 10 n, preferably about 4-10 N. the reaction Time mainly is 1-24 hours, and preferably about 2-10 hours, and depends on the reaction temperature.

The compounds of formula (Ig)

R7NDN (lg) where D, R2, R3, R7, m and p are defined, R8similar R5and R6i.e. is a hydrogen atom, a hydroxyl group or a C1-3is an alkyl group; can be obtained by using the reaction of compounds of formula (Ia) with the compound of the formula (VI)

R8MgZ (VI) where R8the definition is clonage product using hydrogen in the presence of a catalyst. The reaction between the compound (Ia) and compound (VI) can be carried out in an aprotic solvent such as tetrahydrofuran, ethyl ether, isopropyl ether, dimethoxyethane, benzene, or similar, at a temperature of, generally, about 50-100aboutWith, and preferably about 0-50aboutC. Catalytic reduction with hydrogen can be carried out in a solvent such as water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane, etc., in the presence of a catalyst, e.g. palladium, rhodium, or skeletal Nickel hydrogenation catalyst, at a temperature of about-10-100aboutWith, and preferably about 20-50aboutWith, when the hydrogen pressure of 1-10 ATM, and preferably 1-5 ATM, and, if necessary, in the presence of acid. This acid can be a mineral acid (e.g. hydrochloric acid, nitric acid, phosphoric acid, Hydrobromic acid) or organic acid (e.g. acetic acid, tartaric acid, benzoic acid, methanesulfonic acid, toluensulfonate acid).

The compounds of formula (Ih)

HNDN (lh) where D, R2, R3, R8, m and p are defined, can be obtained by treating the compounds of formula (Ig) Ki nitric acid, hydrochloric acid, Hydrobromic acid, innovate acid, sulfuric acid) or alkali metal hydroxide (e.g. sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide) at a temperature of, generally, 10-150aboutWith, and preferably 50-100aboutC. the Strength of the acid or base is 1 to 10 n, preferably 4-10 N. the Specified acid or base used in the ratio of about 20-40 equivalents relative to the compound (Ig). The reaction time is about 1-24 hours, preferably 2-10 hours

The compounds of formula (Ii)

R1NN (li) R1, R2, R3, p, and m are defined, can be obtained e.g. by reaction of compounds of formula (VII)

R1NO (Vll) where R1and m is defined, for example, with the compound of formula (VIII)

N (Vlll) where R2, R3, p and x are defined, and by the reaction of dehydration of the reaction product.

The reaction between the compounds (VII) and (VIII) can be carried out in an aprotic solvent such as ethyl ether, tetrahydrofuran, dioxane or similar , using alkylate (for example, n-utility, isobutyrate and so on ) at a temperature of, generally, about-78-20aboutWith, and preferably about-78-(-50)aboutC. On each is 2">

The dehydration reaction can be carried out in a solvent that is commonly used in such reactions, if only he does not exert undesirable influence on the reaction, for example, such as an aromatic solvent (benzene, toluene, xylan, and so on) and ether solvents (tetrahydrofuran, dioxane, etc.,), and if necessary in the presence of an acid catalyst such as toluensulfonate acid, concentrated sulfonic acid, etc. at elevated temperatures of 50-150aboutC. this reaction can also be carried out by heating the compound in a mineral acid (e.g. nitric acid, hydrochloric acid, Hydrobromic acid, sulfuric acid) at 50-110aboutC.

The compounds of formula (Ij)

HNN (lj) where R2, R3, p, and m are defined, can be obtained by treating the compounds of formula (Ij) with an acid or a base or restoration of the same compound (Ii) in a standard way. Acid or base that can be used in the specified processing of compound (Ii) can be, among others, mineral acid (e.g. nitric acid, hydrochloric acid, Hydrobromic acid, innovata acid, sulfuric acid, etc.,) or the Hydra is similar). This processing can also be carried out in an aqueous solution of the specified acid or base at a temperature of 10-150aboutWith, and preferably 50-100aboutC. the Strength of the acid or base may be about 1-10 N. , and preferably about 4-10 N. the Specified acid or base is used usually in a proportion of about 20-40 equivalents relative to the compound (Ij). The reaction time mainly is about 1-24 hours, preferably 2-10 hours

As for the standard method recovery compounds (Ij), then it can be used with any standard solvent for organic reactions, such as water, methanol, ethanol, dimethylformamide, tetrahydrofuran, dioxane, etc., and the reaction may proceed in the specified solvent in the presence of palladium, rhodium, platinum, skeletal Nickel hydrogenation catalyst, or other catalyst at a temperature of about-10-100aboutWith, and preferably about 20-50aboutWith, when the hydrogen pressure of 1-100 bar, preferably 1-5 ATM, and if necessary, in the presence of acid. Mentioned acid may be a mineral acid (e.g. hydrochloric acid, nitric acid, phosphoric acid, Hydrobromic acid) or PR is methanesulfonic acid, toluensulfonate acid).

The compounds of formula (Ik)

HNAN (1k) where A, R2, R3, p, and m are defined, can be obtained by a method in which the compound of formula (Ic) or (Id) is subjected to dehydration reaction.

This dehydration reaction can be carried out in any standard solvent that does not adversely affect the reaction, for example in an aromatic solvent such as benzene, toluene, xylene, etc., and essential solvent, such as tetrahydrofuran, dioxane, etc. at an elevated temperature of 50-150aboutWith and, if necessary, in the presence of an acid catalyst such as toluensulfonate acid, sulfuric acid, etc., this reaction can also be carried out by heating the mixture at 50-110aboutWith a mineral acid such as sulfuric acid, hydrochloric acid, Hydrobromic acid, sulfuric acid, etc.

The compounds of formula (Il)

RAN (ll) where R'1similar R1whose definition is given, with the exception of the hydrogen atom, i.e., in other words hydrocarbon residue which may be substituted, or acyl group which may be substituted, and R2, Ris an Association of the formula (IX)

R1X (IX) where R'1and X is defined.

The reaction of the compound (Ib), (Id), (Ie), (Ih), (Ij) or (Ik) c compound (IX) can be carried out in any solvent that is commonly used for chemical reactions, i.e. proton solvent (e.g. water, methanol, ethanol, propanol, etc.,) or in an aprotic solvent (e.g. ethyl ether, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile) at a temperature of mostly-10-200aboutWith, and preferably 20-100aboutC.

If necessary, this reaction may be carried out in the presence of organic bases such as pyridine, 4-dimethylaminopyridine, triethylamine, triethylenediamine, tetramethylethylenediamine and etc., inorganic bases such as sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, etc. or a metal hydride such as sodium hydride, potassium hydride, etc., For each mol of compound (Ib), (Id), (Ie), (Ih), (Ij) or (Ik) we have, basically, about 1-10 mol, preferably 1-2 mol of compound of formula (IX). The reaction time mainly is about 1-48 hours, preferably about 1-10 hours

Therefore, among the compounds (I), compound (I') may be the floor of the cylinder, and Y is halogen; which can be obtained by using the reaction of compounds of formula

R-N(CH2X

where R'7and M are defined, and X is a halogen; with a compound of the formula

Y (lll') where Y is defined; with a compound of the formula

HN (V) where R'2and R'3defined, with the aim of obtaining the compounds of formula

R-N(CH2)N (la') where all symbols are listed; 2) processing the specified compounds of formula (Ia') with an acid or a base to obtain the compounds of formula

HN(CH2)N (lb'); where all symbols are defined; 3) recovery of the compounds of formula (Ia') c in order to obtain the compounds of formula

R-N(CH2)N (lc'); where all symbols are defined; 4) treatment of certain compounds of formula (Ic' ) with an acid or a base or recovery of the compounds of formula (Ib') c in order to obtain the compounds of formula

HNCH2)N (ld') where all symbols are defined; 5) recovery of the compounds of formula (Ia') or (Ic') c in order to obtain the compounds of formula

RN(CH2)l+1N (le') where all symbols are defined; 6) treatment of certain compounds of formula (Ie') with an acid or a base to obtain the compounds of formula

HN(CH2)N (lf') where all symbols are defined; (IX) R1and X is defined, with the aim of obtaining the compounds of formula

RN(CH)DN (ll') where all symbols are defined.

Specific conditions for the respective reactions 1-7 defined in the description of the method of obtaining the compounds (Ia), (Ib), (Ic), (Id), (Ie), (If) and (1l).

As shown in the following examples, cyclic amino compounds (I), in particular the compound (I"'), and salts of the invention possess strong activity against hypoxia in mice and activity against brain edema in rats.

Clinical condition or disease against which it can be used cyclic amino compounds (I) and salts of the invention include, among other various symptoms associated with cerebral hypoxia and ischemia, various symptoms associated with increased intracranial pressure caused by a tumor or injury, or other diseases such as brain swelling, acute symptoms and residual effects of a cerebral hemorrhage, disorders of consciousness and dementia. Thus, cyclic amino compounds (I) and salts of the invention are aimed at prevention and treatment of these symptoms and diseases.

The invention allows to obtain valuable medicines to address acute brain sent is DSTV to protect nerve/brain cells.

In using the compounds of the invention in the treatment of acute symptoms caused by bleeding in the brain, and disorders of cerebral circulation, such as increased erythrocyte deficiency, or for the prevention and treatment of complications of cerebral hemorrhage, and also to protect nerve cells from death, or so on, including the treatment of edema of the brain, the said compound can be administered to the mammal, including humans, orally or parenterally in the form of various dosage forms such as tablets, granules, capsules, injections and suppositories. Dosage depends on the type of disease, the patient's condition and other factors. However, the usual dose for adults is largely 0.1 mg to 3 g per day, and preferably 0.3 to 300 mg / day, and more preferably 3-50 mg per day for administration by injection, preferably 1 mg to 1 g, and most preferably 10-300 mg for oral administration.

Some compounds of the invention, such as compound (I) and their salts have effects on the Central nervous system of mammals and, with a strong activity against cholinesterase show activity against different types of amnesia in humans and animals (e.g. mice).

Thus, the compounds of the invention can be used as drugs that enhance brain function in mammals, including humans.

Compounds of the invention can also be used for treatment and prevention of diseases such as, for example, senile dementia, Alzheimer's disease, Huntington's chorea, hyperkinesis and mania.

When using compounds of the invention as a means for improving brain function, the specified connection can be administered to the mammal, including humans, orally or parenterally in the form of various dosage forms such as tablets, granules, capsules, injectable solutions, and suppositories. Although the dose of the medication depends on the type of disease, condition of the patient and so on, the usual daily DMG.

Examples of obtaining and testing of connections in detail illustrate the implementation of the invention, but they should not be regarded as some of the limitations of possible options for practical implementation of the invention.

In the description of the invention uses the following abbreviations: AC is acetyl, BZ is benzoyl, Bz1 - benzyl, Cbz - benzyloxycarbonyl, - phenyl.

The term "room temperature" means about 10-30aboutC.

P R I m e R 1.

AcNN 1-Acetyl-4-(4-piperidinomethyl)Piperi - DIN.

The mixture of 3.73 g of 1-acetyl-4-(4-forestsoil) of piperidine and 3.0 ml of piperidine was stirred for 24 h at 100aboutWith, and then was dissolved in 100 ml of ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution and water, respectively, and the organic layer was dried with anhydrous magnesium sulfate. Then the solvent was removed, and the residue was recrystallized from ETHYLACETYLENE, which was obtained 3.7 g of target compound in the form of colourless crystals with a melting point 122-125aboutC.

Elemental analysis of C19H26N2O2< / BR>
Calculated, %: C 72,58; H a 8.34; N 8,91

Found, %: C 72,61; H 8,28; N 8,73

P R I m m e R 2.

AcNNO 1-A of 2.6 ml of the research, was stirred for 24 h at 100aboutWith, and then the reaction mixture was dissolved in 100 ml of ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate solution and water, respectively, and the organic layer was dried with anhydrous magnesium sulfate. Then the solvent was removed and the oily residue was purified using column chromatography on silica gel (elwira mixture of methanol and dichloromethane 1:19, Rev./vol.), the result that was obtained 2.4 g of target compound in the form of butter.

Elemental analysis: C18H24N2O3< / BR>
Calculated, %: C 68,33; H 7,65; N cent to 8.85

Found, %: C 68,49; H Rate Of 7.54; N 8,53.

P R I m e R 3.

CbZNN 1 Carbobenzoxy-4-(4-pyrrolidinones)- piperidine.

A mixture containing 4.1 g of 1-carbobenzoxy-4-(4-forestsoil)of piperidine and 8 ml of pyrrolidine, was stirred for 24 h at 100aboutWith, and then the reaction mixture was treated in a manner similar to that described in example 2, which was obtained 3.2 g of target compound in the form of butter.

Elemental analysis: C24H28N2O3< / BR>
Calculated, %: C 73,44; H 7,20; N 7,14

Found, %: C 73,19; H 7,16; N OF 7.23

P R I m e R 4. Compounds shown in table. 1, were obtained, mainly, by the way, zoilus] PI - peridin.

A mixture containing 2.67 g of 1-acetyl-4-(2,4-differentail)of piperidine and 5.0 ml of piperidine was stirred for 24 h at 100aboutWith, and then the reaction mixture was processed as described in example 2, resulting in a received 3,3 g of target compound in the form of butter.

Elemental analysis: C24H35N3O2< / BR>
Calculated, %: C 72,51; H 8,87; N 10,57

Found, %: C 72,32; H 8,63; N OF 10.58

P R I m e R 6.

AcNNBzl 1-Acetyl-4-[2,4-di[(4-benzyl)piperidino]- benzoyl]piperidine.

A mixture containing 2.67 g of 1-acetyl-4-(2,4-differentail)of piperidine and 8.8 ml of 4-benzylpiperidine, was stirred for 24 h at 100aboutWith, and then the reaction mixture was treated in a manner similar to that described in example 2, which was obtained 4.1 g of target compound in the form of butter.

Elemental analysis: C38H47N3O2< / BR>
Calculated, %: C 78,99; H 8,20; N 7,27

Found, %: C 79,10; H 8,39; N 7,15

P R I m e R 7.

1-Acetyl-3-(4-piperidinomethyl)Piperi - DIN.

A mixture containing of 3.73 g of 1-acetyl-3-(4-forestsoil)of piperidine and 5 ml of piperidine was stirred for 24 h at 100aboutWith, and then the reaction mixture was treated in the manner described in example 1. The residue was recrystallized

Elemental analysis: C19H28N2O2< / BR>
Calculated, %: C 72,58; H a 8.34; N 8,91

Found, %: C 72,52; H of 8.06; N 8,73

P R I m e R 8.

HNN2HCl 4--methyl-4-pyrrolidinones)piperidin - dihydrochloride.

The metal magnesium (2 g) was added to dry ethyl ether (30 ml) and then added iodomethane until until used magnesium. To this solution was added to 1.96 g of 1-carbobenzoxy-4-(4-pyrrolidinones)piperidine obtained in accordance with the description in example 3, after which the mixture was heated in a flask under reflux for 2 hours Then to this reaction mixture was added an aqueous solution of ammonium chloride, and the precipitate was filtered. The filtrate was extracted with dichloromethane and the solvent is then drove away. The residue was purified using column chromatography on silica gel (eluent:methanol:dichloromethane = 1:100, V/V) and the resulting oily substance (0.7 g) was dissolved in a mixture of methanol (50 ml) and 1H-methanol hydrochloric acid (2 ml), followed by addition of 10% palladium charcoal. Catalytic reduction was conducted in a stream of hydrogen at atmospheric pressure and ambient temperature for 20 hours After completion of the reaction the catalyst was removed, and the Dogo substances.

Elemental analysis: C17H28Cl2N2< / BR>
Calculated, %: C 61,62; H charged 8.52; N 8,45

Found, %: C 61,39; H of 8.37; N 8,48

P R I m e R 9.

4-(4-piperidinomethyl)piperidine.

The mixture containing the value of 4.76 g of 4-(4-forestsoil)pyridine and 9.8 ml of piperidine was stirred for 24 h at 100aboutS, after which the reaction mixture was treated in a manner similar to that described in example 3, and was received with 5.3 g of the target compound as a yellow oily substance.

Elemental analysis: C17H18N2O

Calculated, %: C 76,66; H for 6.81; N 10,52

Found, %: C 76,70; H 6,79; N 10,56

P R I m e R 10.

4-(4-piperidinomethyl)of the piperidine dihydrochloride

1-acetyl-4-(4-piperidinylmethyl)piperidine 0,63 g, obtained by the method described in example 1, was dissolved in 10 ml of concentrated hydrochloric acid and the resulting solution was stirred for 3 h at 100aboutC. the solvent is Then drove away under reduced pressure, and the residue was recrystallized from ethanol, resulting in a received 0.5 g of colorless crystals with a melting point 256-264aboutC.

Elemental analysis: C17H26Cl2N2O

Calculated, %: C $ 59.13 USD; H to 7.59; N 8,11

Found, %: C 58,92; H 7,44; N 8,31

P R I m e R and m e R 12.

4-[-hydroxy-4-piperidino)benzyl] Piri - DIN hydrochloride.

In 30 ml of ethanol was dissolved 2.66 g of 4-(4-piperidinomethyl)pyridine obtained in accordance with the description in example 9, and then added 1.0 ml of concentrated hydrochloric acid. Using as catalyst 10% palladium charcoal, spent catalytic reduction at atmospheric pressure and ambient temperature for 5 hours After completion of the reaction the catalyst and the solvent was consistently removed, and the residue was recrystallized from a mixture of ethanol and ethyl acetate, which was obtained 1.3 g of colorless crystalline substance with a melting point 151-154aboutC.

Elemental analysis: C17H22Cl2N2O

Calculated, %: C 59,83; H 6,50; N 8,21

Found, %: C 59,70; H to 6.39; N 8,14

P R I m e p 13.

4-[ -hydroxy-4-piperidino)benzyl]Pipa - ridine hydrochloride.

In a mixture solvent of ethanol (10 ml) and water (1 ml) was dissolved 1.04 g of 4-(4-piperidinomethyl)piperidine hydrochloride, obtained in accordance with the description in example 10, and then to this solution drop by drop) was added to 0.44 g of sodium borohydride at room temperature. The resulting mixture was stirred for 4 h at Immorali in dichloromethane 50 ml Then nerastvorimaya substance was filtered, was added 2 ml of 4 N. methanol hydrochloric acid and the solvent drove away. The residue was recrystallized from ethanol, resulting in the obtained 1.4 g of colorless crystalline substance with a melting point 205-217aboutC.

P R I m e R 14. Compounds shown in table. 3 were obtained, mainly, in a way similar to that described in example 13.

P R I m e R 15.

1-Acetyl-4-(4-dimethylaminobenzoyl)Pipa - ridin.

5.49 g of 1-acetyl-4-(4-dimethylaminobenzoyl)piperidine (compound 4), obtained in example 4 was dissolved in 100 ml of ethanol and then added concentrated hydrochloric acid (2 ml). Using as catalyst 10% palladium charcoal, spent catalytic reduction for 48 h at ambient temperature and atmospheric pressure. After completion of the reaction the solvent is kept off, and the oily residue was dissolved in ethyl acetate (100 ml). The solution was washed with saturated aqueous sodium bicarbonate solution and then water, and dried with anhydrous magnesium sulfate. Then the solvent is kept off, and the oily residue was subjected to chromatography on a column of silica gel (eluent:methanol:dichloro the VA.

Elemental analysis: C16H24N2O

Calculated, %: C 73,81; H 9,29; N 10,76

Found, %: C 73,57; H 9,36; N 10,90

P R I m e R 16. Compounds shown in table. 4, were obtained by the method basically similar to that described in example 15.

P R I m e R 17

CHNHCl 1-Acetyl-3-(4-piperidinomethyl)Piperi - DIN monohydrochloride.

1-Acetyl-3-(4-piperidinomethyl)PI - peridin obtained in example 7, was treated in a manner similar to that described in example 15, resulting in a received target compound, which was converted into hydrochloride. After which he obtained 1.1 g of colorless amorphous solid.

Elemental analysis: C19H29ClN2O

Calculated, %: C 67,74; H 8,68; N 8,31

Found, %: C 67,91; H 8,73; N 8,28

P R I m e R 18.

AcNCHNNH2HCl 1-Acetyl-4-(4-piperidinomethyl)Piperi - DIN hydrochloride.

4.8 g of 1-acetyl-4-(4-piperidinomethyl)piperidine (compound 2) obtained in example 4 was dissolved in 100 ml of ethanol and then added 3.5 ml of concentrated hydrochloric acid. The reaction mixture was treated in a manner similar to that described in examples 15-17, and received solid, which was recrystallized from a mixture of ethanol and ethyl acetate. The resulting floor is entry analysis: C18H29Cl2N3O

Calculated, %: C 57,75; H 7,81; N 11,22

Found, %: C 57,51; H 7,60; N 11,37

P R I m e R 19.

AcNCHNNBzl 1-Acetyl-4-(4-benzylpiperazine)PI - peridin.

of 1.16 g of 1-acetyl-4-(4-piperidinomethyl)piperidine hydrochloride, obtained in example 18, was dissolved in 20 ml of ethanol and then added to 1.38 g of potassium carbonate and 0.4 ml of benzylbromide. The mixture was heated in a flask under reflux for 20 h, nerastvorim the residue was filtered. The solvent is then drove away, and was allocated an oily substance, which was purified using chromatography on a column of silica gel (eluent:methanol: dichloromethane = 1:19, V/V), resulting in a received target compound in the form of colorless oily substance.

Elemental analysis: C25H33N3O

Calculated, %: C 76,69; H 8,50; N OF 10.73

Found, %: C 76,82; H 8,59; N 10,59

P R I m e R 20.

HNCHN 2HCl 4-(4-dimethylaminobenzoyl)of the piperidine dihydrochloride.

3.5 g of 1-acetyl-4-(4-dimethylaminobenzoyl)piperidine obtained in example 15, was dissolved in 30 ml of concentrated hydrochloric acid and the resulting solution was stirred for 20 h at 100aboutC. the solvent is Then drove away, and the remainder is in the form of oil chromatography is what got the target compound in the form of an amorphous solid.

Elemental analysis: C14H24Cl2N2< / BR>
Calculated, %: C 57,73; H 8,31; N 9,62

Found, %: C 57,49; H 8,24; N 9,68

P R I m e R 21. Compounds shown in table. 5 were obtained, mainly, in a way similar to that described in example 20.

P R I m e R 22.

3-(4-piperidinomethyl)of the piperidine dihydrochloride.

1-acetyl-3-(4-piperidinomethyl)Pipa - ridin monohydrochloride (1.40 g) obtained in example 17, was treated in a manner similar to that described in example 20, the result of which was obtained 0.8 g of colorless amorphous solid.

Elemental analysis: C17H28Cl2N2< / BR>
Calculated, %: C 61,62; H charged 8.52; N 8,45

Found, %: C 61,40; H 8,31; N 8,60

P R I m e R 23.

CH2)2NCHN 1-(4-Methyl)pentanoyl-4-(4-piperidine - ZIL)piperidine.

of 0.85 g of 4-(4-piperidinomethyl)piperidine dihydrochloride (compound 1) obtained in example 21 was dissolved in 10 ml of dimethylformamide and then added to 1.02 ml of triethylamine, 0,42 g isocaproate acid and 0.6 g of diethylthiophosphate. The mixture was stirred for 2 hours at room temperature, the solvent drove away. The oily residue was purified using chromatography on a column of silica gel (eluent:metago substances.

Elemental analysis: C23H36N2O

Calculated, %: C 77,48; H 10,18; N 7,86

Found, %: C 77,57; H 10,13; N OF 7.96

P R I m e R 24.

(CH2)3NCHN2HCl 1-(4-Methyl)pentyl-4-(4-piperidinomethyl) piperidine dihydrochloride.

0.7 g of 1-(4-methyl)pentanoyl-4-(4-piperidinomethyl)piperidine obtained in example 23 was dissolved in 30 ml of tetrahydrofuran, and then added to 0.23 g of lithium aluminum hydride. The mixture was heated in a flask with reflux condenser for 10 min, then was added to 0.45 ml of water and 0.33 ml of 10% aqueous solution of sodium hydroxide. The mixture was stirred for 1 h at room temperature, and the undissolved precipitate was filtered. To the filtrate was added 5 ml of 1 N. hydrochloric acid and the solvent drove away. The solid residue was recrystallized from dioxane and received 0.66 g of colorless crystalline substance with a melting point 174-178aboutC.

Elemental analysis: C23H40Cl2N2< / BR>
Calculated, %: C 66,49; H 9,70; N 6,72

Found, %: C 66,43; H at 9.53; N 6,54

P R I m e R 25.

HNCHN2HCl 4-(4-pyrrolidinones)of the piperidine dihydrochloride.

In a mixture of solvents (20 ml) of ethanol and 20 ml of water was added 3.33 g of 4-(4-pyrrolidinones)piperidine, dihydrochloride recovery at atmospheric pressure and ambient temperature for 2 hours After completion of the reaction the solvent is kept off, and the residue was dissolved in a saturated aqueous solution of sodium chloride. The solution was made basic by adding solid sodium bicarbonate and was extracted with acetonitrile. The extract was dried with anhydrous sodium sulfate, and the solvent drove away. Then was added a 2n-methanol hydrochloric acid to the oily residue, the solvent is kept off, and the residue was recrystallized from a mixture of ethyl ether and methanol, resulting in a received 0.4 g of colorless crystalline substance with a melting point of 152-154aboutC.

Elemental analysis: C16H24CL2N2< / BR>
Calculated, %: C 60,56; H compared to 8.26; N 8,83

Found, %: C 60,40; H 8,45; N 8,70

P R I m e R 26.

HNCHN2HCl 4-(4-homopiperazines)of the piperidine dihydrochloride.

4-(4-homopiperazines)Piperi - DIN the dihydrochloride 3.6 g (compound 2) obtained in example 11 was subjected to catalytic reduction with manner similar to that described in example 25, and the resulting reaction product was purified using chromatography on a column of silica gel (eluent:n-butanol: acetic acid:ethyl acetate:water= 1:1:1:1). Fractions rich in the desired compound were combined and dissolve the resulting received 0.7 g of colorless amorphous solid.

Elemental analysis: C18H30Cl2N2< / BR>
Calculated, %: C 62,60; H 8,62; N 8,11

Found: C 62,37; H at 8.36; N 7,92

P R I m e R 27.

NN 2HCl 4-[-hydroxy-4-dimethylamino)benzyl]Piri - Dina dihydrochloride. 1) a Mixture of 2.38 g of 4-(4-forestsoil)pyridine and 7 ml of 50% aqueous dimethylamine was stirred for 24 h at room temperature, and then was added 100 ml of ethyl acetate. The mixture was washed with saturated aqueous sodium bicarbonate solution and the organic layer was dried with anhydrous sodium sulfate. The solvent is kept off, and the residue was recrystallized from a mixture of ethanol and ethyl acetate, which was obtained 1.1 g of 4-(4-dimethylaminobenzoyl)pyridine as a light yellow crystalline substance with a melting point 122-124aboutC. 2) 4-(4-dimethylaminobenzoyl)pyridine (1.0 g) was treated in a manner similar to that described in example 12, and was obtained 1.1 g of the target compound as a light yellow crystalline substance with a melting point 133-136aboutC.

Elemental analysis: C14H18Cl2N2O

Calculated, %: C 55,83; H 6,01; N OF 9.30

Found, %: C 55,83; H 6,21; N 9,07

P R I m e R 28.

NCHN 4-(4-dimethylaminobenzoyl)pyridine fumarate.

1,25 g of 4-[(--is islote, and then added a 1.75 g format ammonium. Using as catalyst 10% palladium carbon, the resulting mixture was stirred for 30 min at 110aboutWith a stream of nitrogen. Then the catalyst was filtered, and the solvent drove away. The remaining oily substance was dissolved in a saturated aqueous solution of sodium chloride, and the resulting solution was made basic by adding solid sodium bicarbonate and was extracted with acetonitrile. The solvent is then drove away, and the remaining oily substance was purified using chromatography on a column of silica gel eluent: ethyl acetate. The obtained oily compound was converted to the fumarate by standard procedures. The result was obtained 1.2 g of a pale-yellow crystalline substance with a melting point 132-134aboutC.

Elemental analysis of C18H20N2O4< / BR>
Calculated, %: C 65,84; H 6,14; N 8,53

Found, %: C 65,89; H is 6.19; N 8,31

P R I m e R 29

AcNCHN 1-Acetyl-4-[4-(N-benzyl-N-ethylamino)Ben - ZIL]piperidine.

3.13 g of 1-acetyl-4-[4-(ethylamino)benzyl]piperidine (compound 8) obtained in example 16, was dissolved in 30 ml of ethanol and then added of 3.31 g of potassium carbonate and 1.43 ml of benzylbromide. The mixture was heated in a flask with obramleniy the residue was purified using chromatography on a column of silica gel eluent:ethyl acetate, the result that was obtained 3.8 g of the target compound as colorless oily substance.

Elemental analysis of C23H30N2O

Calculated, %: C unchanged at 78.81; H 8,63; N 7,99

Found, %: C 78,53; H 8,68; N 7,75

P R I m e R 30.

HNCHN 4-[4-(N-Benzyl-N-ethylamino)benzyl]Pipa - ridin fumarate.

3.5 g of 1-acetyl-4-[4-(N-benzylamino)benzyl]piperidine obtained in example 29 was dissolved in 30 ml of concentrated hydrochloric acid and the resulting solution was stirred for 24 h at 100aboutC. the solvent is Then drove away, and the oily residue was dissolved in water and made basic by adding solid sodium bicarbonate. The solution was extracted with dichloromethane and the extract was dried with anhydrous magnesium sulfate. The solvent is then drove away, and the remaining compound was converted to the fumarate using standard procedures. The resulting product was recrystallized from a mixture of ethanol and ethyl acetate, which was obtained 2.0 g of the target compound as a colourless crystalline substance with a melting point 128-130aboutC.

Elemental analysis: C25H32N2O4< / BR>
Calculated, %: C 70,73; H 7,60; N 6,60

Found, %: C 70,96; H a 7.62; N 6,57

P R I m e R 31.

Elemental analysis: C18H27N3O2< / BR>
Calculated, %: C 68,11; H to 8.57; N 13,24

Found, %: C 67,86; H 8,51; N MADE 13.36

P R I m e R 32.

HNN 3HCl 4-[2,4-bis(dimethylamino)benzoyl]Piperi - DIN trihydrochloride.

1-Acetyl-4-[2,4-[bis-(dimethylamino)] - benzoyl] piperidine (1.8 g) obtained in example 31, was treated in a manner similar to that described in example 10, resulting in received of 1.37 g of the target compound as a colourless crystalline substance with a melting point 211-214aboutC.

Elemental analysis: C16H28Cl3N3O

Calculated, %: C 49,94; H 7,33; N 10,92

Found, %: C 49, 80mm; H 7,16; N A 10.74

P R I m e R 33.

AcNCHN 1-Acetyl-4-[2,4-bis-(dimethylamino)benzyl] - piperidine.

1-acetyl-4-[2,4-[bis-(dimethylamino)Ben zoilus] piperidine (6,34 g) obtained in preeminene in the form of a colorless oily substance.

NMR (CDCl3): 1,0-1,5 (2H, m), of 1.5-1.9 (3H, m), 2,04 (3H, s), 2,3-2,7 (1H, m), 2,53 (2H, d), 2.63 in (6N, (C), is 2.8-3.2 (1H, m), 2,92 (6N, (C), 3,6-3,9 (1H, m), 4,4-4,7 (1H, m), 6,4-6,6 (2H, m), 6,9-7,1 (1H, m).

P R I m e R 34.

HNCHN 3HCl 4-[2,4-bis-(dimethylamino)benzyl]Piperi - DIN trihydrochloride

1-Acetyl-4-[2,4-[bis-(dimethylamino)- benzyl] piperidine (2.4 g) obtained in example 33, was treated in a manner similar to that described in example 20, the result of which was obtained 2.1 g of the target compound as colorless amorphous solid connections.

Elemental analysis: C16H30Cl3N3< / BR>
Calculated, %: C 51,83; H 8,15; N 11,33

Found, %: C 51,87; H 8,10; N 11,22

P R I m e R 35.

CH3CH2NCHN 1-Ethyl-4-(4-dimethylaminobenzoyl)Piperi - DIN fumarate.

2.6 g of 1-acetyl-4-(4-dimethylaminobenzoyl)piperidine obtained in example 15, was dissolved in tetrahydrofuran (30 ml) and then was added 0.56 g of lithium aluminum hydride. The mixture was stirred under heating for 30 min, then was added to 1.1 ml of water and 0.9 10% aqueous solution of sodium hydroxide. The resulting mixture was stirred for 1 h at room temperature and the undissolved residue was filtered. The solvent is then drove away under reduced pressure, and the residue was diluted dichlormethane the / establishment, which was converted into the fumarate in a standard way. This product was recrystallized from a mixture of ethanol and ethyl acetate, which was obtained target compound in the form of a colorless crystalline substance with a melting point 128-132aboutC.

Elemental analysis: C20H30N2O4< / BR>
Calculated, %: C 66,27; H a 8.34; N 7,73

Found, %: C 66,37; H 8,21; N 7,71

P R I m e R 36.

CH2NCHN 1-Benzyl-4-(4-dimethylaminobenzoyl)Pipa - ridin fumarate.

1-Benzoyl-4-(4-dimethylaminobenzoyl)piperidine (1.3 g) was obtained from 4-(4-dimethylaminobenzoyl)piperidine dihydrochloride example 20 and benzoyl chloride in the standard way per se, were processed by the method similar to that described in example 35, and was obtained 0.45 g of target compound in the form of colorless crystals with a melting point 182-183aboutC.

Elemental analysis: C25H32N2O4< / BR>
Calculated, %: C 70,73; H 7,60; N 6,60

Found, %: C 70,79; H 7,35; N 6,52

P R I m e R 37.

1-Acetyl-3-(4-dimethylaminobenzoyl)Pipa - ridin.

1). A mixture containing 2,49 g of 1-acetyl-3-(4-forestsoil)of piperidine and 8 ml of 50% aqueous dimethylamine was stirred for 5 days at room temperature, and then was added a saturated aqueous solution of sodium bicarbonate. Races which was purified using chromatography on silica gel (eluent:ethyl acetate), the result that was obtained 2.6 g of 1-acetyl-3-(4-dimethylaminobenzoyl)piperidine as a pale yellow oil. 2). 1-Acetyl-3-4-dimethylaminobenzoyl piperidine 2.5 g was treated in a manner similar to that described in example 15, and received 2.0 g of colorless oily substance.

NMR (CDCl3): 1,0-1,4 (2H, m), 1,4-1,9 (3H, m), a 2.01 (3H, s), 2,3-3,2 (2H, m), of 2.45 (2H, d), 2,90 (6N, (C), and 3.4 to 3.8 (1H, m), 4,3-4,6 (1H, m), 6,6-6,8 (2H, m), 6,9-7,1 (2H, m).

P R I m e R 38.

CHN 3-(4-dimethylaminobenzoyl)piperidine fumarate.

1-Acetyl-3-(4-dimethylaminobenzoyl)PI - peridin (2.55 g) obtained in example 37, was treated in a manner similar to that described in example 30, and obtained 1.3 g of colorless crystalline substance with a melting point 142aboutC.

Elemental analysis: C18H26N2O4< / BR>
Calculated, %: C 64,65; H to 7.84; N SCORED 8.38

Found, %: C 64,68; H of 7.75; N 8,24

P R I m e R 39.

AcNCHN 1-Acetyl-4-(4-dimethylaminobenzoyl - Tyl)piperidine. 1). 31,2 g (N-acetylpiperidine-4-yl)acetic acid was dissolved in 100 ml of thionyl chloride and the resulting solution was stirred for 10 minutes, the Excess thionyl chloride and drove to the oily residue was added 60 ml of vorobtsova. Then while cooling with ice was gradually added to 42.1 g of the chloride of al the hydrated product was poured into ice water and was extracted with ethyl acetate. The extract was dried and the solvent is kept, resulting in received 30 g of 1-acetyl-4-(4-forosensualelite)piperidine as a brown oily substance. 2). A mixture of 1.84 g of 1-acetyl-4-4-forosensualelite of piperidine and 6 ml of 50% aqueous dimethylamine was stirred for 3 days at room temperature and then processed in the manner described in example 1, which was obtained 1.8 g of colorless crystalline substance with a melting point of 136aboutC.

Elemental analysis: C17H24N2O2< / BR>
Calculated, %: C 70,80; H 8,39; N 9,71

Found, %: C 70,85; H 8,43; N 9,79

P R I m e R 40.

HNCHN 2HCl 4-(4-dimethylaminobenzoyl)Piperi - DIN the dihydrochloride.

1.73 g of 1-acetyl-4-(4-dimethylaminobenzoyl)piperidine obtained in example 39 was dissolved in 30 ml of concentrated hydrochloric acid and was stirred for 15 h at 100aboutC. the solvent is Then drove away and the residue was recrystallized from a mixture of ethanol and ethyl acetate, which was obtained 1.7 g of colorless crystalline substance with a melting point 251-255aboutC.

Elemental analysis: C15H24Cl2N2O

Calculated, %: C 56,43; H 7,58; N 8,77

Found, %: C 56,25 containing 1.84 g of 1-acetyl-4-(4-forosensualelite)of piperidine and 5 ml of piperidine was stirred under heating for 20 hours at 100aboutC. After completion of the reaction, the reaction mixture was diluted with saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. After osushivaniya solvent drove, oily residue was purified using chromatography on a column of silica gel (eluent: ethyl acetate) and result was obtained 2.2 g of a light yellow oily substance.

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

Found, %: C 72,98; H 8,45; N SCORED 8.38

P R I m e R 42.

HNCHN 2HCl 4-(4-piperidinylmethyl)of the piperidine dihydrochloride.

1-Acetyl-4-(4-piperidinomethyl-Tyl)piperidine (1,71 g) obtained in example 41, was treated by the method described in example 10, and received of 1.93 g of a colorless crystalline substance with a melting point 228-234aboutC.

Elemental analysis: C18H28Cl2N2O

Calculated, %: C 60,16; H a 7.85; N 7,80

Found, %: C 59,91; H 7,65; N 7,71

P R I m e R 43.

AcNCH2CHN 1-Acetyl-4-[2-(4-dimethylaminophenyl)ethyl] piperidine.

1-Acetyl-4-(4-dimethylaminobenzoyl - methyl)piperidine (1.1 g) obtained in example 39, was treated by the method described in example 15, which was obtained 0.7 g of colorless Crist is2O

Calculated, %: C 74,41; H of 9.55; N OF 10.21

Found, %: C 74,58; H for 9.64; N TO 10.09

P R I m e R 44.

HNCH2CHN 4-[2-(4-dimethylaminophenyl)ethyl]piperidin - fumarate.

1-Acetyl-4-[2-(4-dimethylaminophenyl)- ethyl]piperidine (0.5 g) obtained in example 43 was treated by the method described in example 30, and received 0.5 g of colorless crystalline substance with a melting point 182aboutC.

Elemental analysis: C19H28N2O4< / BR>
Calculated, %: C 65,49; H 8,10; N 8,04

Found, %: C 65,32; H of 7.95; N 8,17

P R I m e R 45.

HNCHN 4-(4-dimethylaminobenzoyl)piperidine fumarate.

4-(4-dimethylaminobenzoyl)piperidine hydrochloride, obtained in example 20 was treated in the standard way and get the corresponding fumarate. As a result of recrystallization from ethanol was obtained a colorless crystalline substance with a melting point 178-180aboutC.

Elemental analysis: C18H26N2O4< / BR>
Calculated, %: C 64,65; H to 7.84; N SCORED 8.38

Found, %: C 64,94; H 7,72; N 8,50

P R I m e R 46.

CH2NN 2HCl 1-Benzyl-4-(4-dimethylaminophenyl)-1,2,3,6 - tetrahydropyridine the dihydrochloride.

A solution of 10 g of p-bromo-N,N-dimethylaniline in 100 ml of tetrahydrofuran was cooled amasyali for 10 min at -78aboutWith, after which was added 9.5 g of N-benzyl-4-piperidone. Then the mixture was stirred for 1 h Specified, the reaction mixture was diluted with 100 ml saturated aqueous solution of sodium chloride and was obtained organic layer. From the specified layer drove the solvent and the oily residue was added 200 ml of concentrated hydrochloric acid. Stirring, the mixture was heated for 6 h at 100aboutC. And finally, the solvent is kept off, the residue was recrystallized from methanol, resulting in a received 14 g of a colorless crystalline substance with a melting point 229-232aboutC.

Elemental analysis: C20H26Cl2N2< / BR>
Calculated, %: C 65,75; H 7,17; N TO 7.67

Found, %: C 65,49; H 7,03; N 7,74

P R I m e R 47.

HNN 2HCl 4-(4-dimethylaminophenyl)of the piperidine dihydrochloride.

1-Benzyl-4-(4-dimethylaminophenyl)-1, 2,3,6-tetrahydropyridine the dihydrochloride (3,65 g) obtained in example 46 was dissolved in a solvent mixture of 20 ml ethanol and 5 ml of water. Using as catalyst 10% palladium carbon, and the mixture was subjected to catalytic recovery for 10 h at atmospheric pressure and ambient temperature. Then the catalyst was filtered, and the solvent drove away. is bauleni solid sodium bicarbonate and was extracted with acetonitrile. The extract was dried and added to 5 ml of 2 N. ethanol hydrochloric acid. Finally, the solvent is kept off, the residue was recrystallized from ethanol and obtained 1.2 g of colorless crystals with a melting point 215-220aboutC.

Elemental analysis: C13H22Cl2N2< / BR>
Calculated, %: C 56,32; H 8,00; N 10,10

Found, %: C 56,41; H 7,86; N 9,85

P R I m e R 48.

AcNCHN 1-Acetyl-4-[2-hydroxy-2(4-dimethylamino - phenyl)ethyl]piperidine.

In a solvent mixture consisting of 60 ml of ethanol and 30 ml of water, was dissolved with 2.93 g of 1-acetyl-4-(4-dimethylaminobenzoyl)piperidine obtained in example 39, and at room temperature was slowly added 1 g of sodium borohydride. The reaction mixture was diluted with dichloromethane and water and the organic layer was dried with anhydrous magnesium sulfate. The solvent is then drove away, and the oily residue was purified using column chromatography on silica gel (eluent:ethyl acetate), resulting in the obtained pale-yellow solid with a melting point 119-120aboutC.

Elemental analysis: C17H26N2O2< / BR>
Calculated, %: C 70,31; H 9,02; N 9,65

Found, %: C 70,17; H 9,03; N 9,62

P R I m e R 49.

HNCH=CHN 2HCl 4-[2-(4 zentrierung hydrochloric acid, 2 ml of water and 10 ml of ethanol was dissolved 1.0 g of 1-acetyl-4-[2-hydroxy-2-(4-dimethylaminophenyl)ethyl] piperidine obtained in example 48, and the mixture was heated while stirring at 100aboutC for 15 h and Then the solvent is kept off, and the residue was recrystallized from a mixture of ethanol and ethyl acetate, which was obtained 0.6 g of colorless crystalline substance with a melting point 220-245aboutC.

Elemental analysis: C15H24Cl2N2< / BR>
Calculated, %: C 59,41; H 7,98; N 9,24

Found, %: C 59,70; H 7,19; N 8,98

P R I m e R 50.

HNCHN 2HCl 4-(4-Pyrrolidinedione)of the piperidine dihydrochloride

1-Acetyl-4-(4-pyrrolidinones)piperidine (2.0 g) (compound 13) obtained in example 4 was treated in the manner described in example 44, the result of which was obtained 1.1 g of an amorphous solid.

Elemental analysis: C16H24Cl2N2< / BR>
Calculated, %: C 60,95; H to 7.67; N 8,88

Found, %: C 60,75; H to 7.61; N 8,76

P R I m e R 51.

HN CHN 2HCl 4-(4-homopiperazines)Piperi - DIN the dihydrochloride.

1-Acetyl-4-(4-homopiperazines) piperidine (2.0 g) (compound 14) obtained in example 4 was treated in a manner similar to that described in example 59, CEG 2
N2< / BR>
Calculated, %: C 62,97; H by 8.22; N 8,16

Found, %: C 62,67; H 8,13; N 8,04

P R I m e R 52.

AcNCH2CHN 1-Acetyl-4-[2-(4-dimethylaminobenzoyl)- ethyl]piperidine.

1) 33 g of ethyl -(pyridin-4-yl)acrylate was dissolved in 300 ml of acetic acid and using platinum as a catalyst, was carried out by catalytic reduction at atmospheric pressure and a temperature of 70-80aboutC. After adding 40 ml of acetic anhydride, the catalyst is filtered off and the solvent is removed under reduced pressure. The precipitate is dissolved in water and neutralized with potassium carbonate, and the resulting product was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, the solvent drove and got to 44.8 g of oily substance.

2) 42.9 g of the obtained oil was dissolved in 200 ml of methanol, and then was added a solution of 12.7 g of potassium hydroxide in 20 ml of water. The mixture was stirred for 1.5 h at 50aboutWith and for 12 h at room temperature. Then the reaction mixture was neutralized with concentrated hydrochloric acid and the solvent drove away. The residue was diluted with methanol, and nerastvorim the residue was filtered. Then the filtrate was concentrated and the resulting crude is of 201-206aboutC.

3) the Procedure described in example 39 was repeated, using 26.7 g (N-acetylpiperidine-4-yl)propionic acid, resulting in received of 26.1 g of 1-acetyl-4-[2-(4-forestsoil)ethyl] piperidine as colorless crystals with a melting point 95-96aboutC.

Elemental analysis: C16H20FNO2< / BR>
Calculated, %: C 69,29; H 7,27; N OF 5.05

Found, %: C 69,16; H of 7.36; N 4,99

4) a Mixture containing 3.2 g of 1-acetyl-4-[2-(4-forestsoil)ethyl]piperidine and 10 ml of 50% aqueous dimethylamine was heated at 100aboutWith stirring for 6 h, and then were processed by the method described in example 37, the result of which was obtained 1.6 g of colorless crystalline substance with a melting point 148-160aboutC.

Elemental analysis: C18H26N2O2< / BR>
Calculated, %: C 71,49; H 8,67; N 9,26

Found, %: C 71,54: H 8,86; N 9,15

P R I m e R 53.

HNCHN 4-(4-Pyrrolidinecarbonyl)Piperi - DIN.

1-Acetyl-4-(4-pyrrolidinedione - Tyl)piperidine (1.0 g) obtained by the method similar to that described in example 41, was treated in a manner similar to that described in example 10, and get the corresponding hydrochloride, which was dissolved in aqueous saturated solution of chlorite is scrap. The extract was dried and the solvent drove away. The residue was recrystallized from ethyl acetate, which was obtained 0.7 g of colorless solid with a melting point of 144-145aboutC.

Elemental analysis: C17H24N2O

Calculated, %: C 74,96; H 8,88; N 10,28

Found, %: C 75,06; H 8,62; N 10,37

P R I m e R 54.

AcNCH2CHN 1-Acetyl-4-[2-(4-pyrrolidinones)ethyl] piperidine

The procedure described in example 53 was repeated using 3.2 g of 1-acetyl-4-[2-(4-forestsoil)ethyl] piperidine, which was obtained 2.7 g of colorless oily substance.

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

Found, %: C 73,19; H of 8.40; N, 8.34 PER

P R I m e R 55.

HNCH2CHN 2HCl 4-[2-(4-Dimethylaminobenzoyl)ethyl]Piperi - DIN the dihydrochloride.

1-Acetyl-4-[2-(4-dimethylaminobenzoyl) ethyl]piperidine obtained in example 53, was treated by the method described in example 10, which was obtained white solid with a melting point 182-183aboutC.

Elemental analysis: C16H26Cl2N2O

Calculated, %: C 57,66; H 7,86; N 8,40

Found, %: C 57,53; H 7,86; N 8,49

P R I m e R 56.

HNCH]piperidine, obtained in example 54 was treated by the method described in example 10, which was obtained a colorless crystalline substance with a melting point 207-209aboutC.

Elemental analysis: C18H28Cl2N2O

Calculated, %: C 60,16; H a 7.85; N 7,80

Found, %: C 60,22; H of 7.70; N 7,71

P R I m e R 57.

AcNCH2CH2CHN 1-Acetyl-4-[3-(4-dimethylaminophenyl)Pro - MPI]piperidine.

1-Acetyl-4-[2-(4-dimethylaminobenzoyl) ethyl] piperidine (3.6 g) obtained in example 52, was treated by the method described in example 15, which was obtained 2.6 g of colorless oily substance.

NMR (CDCl3): 0,8-1,8 (9H, m) to 2.06 (3H, s), 2,5-2,7 (1H, m), 2,47 (2H, t), 2,7-3,2 (1H, m), 2,85 (6N, (C), 3,6-3,9 (1H, m), 4,4-4,7 (1H, m), 6,6-6,8 (2H, m), 6,9-7,1 (2H, m).

P R I m e R 58.

HNCH2CH2CHN

1-Acetyl-4-[3-(4-dimethylaminophenyl)propyl]piperidine (2.4 g) obtained in example 57, was treated by the method described in example 30, the result of which was obtained 1.6 g of colorless crystalline substance with a melting point 158-160aboutC.

Elemental analysis: C20H30N2O4< / BR>
Calculated, %: C 66,27; H a 8.34; N 7,73

Found, %: C 66,23; H 8,17; N 7,74

P R I m e R 59.

CH2NCHabout
C. the solvent is Then drove away, and the residue was recrystallized from a mixture of methanol and ether, resulting in the received 9,13 g of a colorless crystalline substance with a melting point 188-181aboutC.

2) the Obtained crystals (the ceiling of 5.60 g) was dissolved in 30 ml of dioxane and then added 4,07 g benzylbromide and 3.45 g of potassium carbonate. The mixture was heated for 3 hours at 90aboutWith, and the solvent drove away. The residue was diluted with water and was extracted with ether, and the organic layer was washed with water and dried. The solvent is kept off, and the residue was recrystallized from a mixture of dichloromethane and n-hexane, resulting in received 6,72 g of 1-benzyl-4-[2-(4-forestsoil)ethyl]piperidine as colorless crystals with a melting point 65-67aboutC.

Elemental analysis: C21H24FNO

Calculated, %: C 77,51; H 7,43; N 4,30

Found, %: C 77,74; H 7,47; N 4,32

3) a Mixture containing 0.5 g of 1-benzyl-4-[2-(4-forestsoil)ethyl]piperidine and 2 ml of pyrrolidine, was heated for 24 h at 150aboutC, and the reaction mixture was subjected to distribution between ethyl acetate and saturated aqueous rectorville of ethyl acetate which was obtained 0.7 g of colorless crystals with a melting point of 144-145aboutC.

Elemental analysis: C25H32N2O

Calculated, %: C 79,75; H to 8.57; N 7,44

Found, %: C 79,54; H 8,56; N 7,46

P R I m e R 60. Compounds shown in table. 6, obtained mainly by the method similar to that described in example 59.

P R I m e R 61.

CH2NCHN

1-Benzyl-4-[4-pyrrolidinedione - til]piperidine.

Using 2.0 g of 4-(4-pyrrolidinecarbonyl)piperidine obtained in example 53 was repeated the procedure benzylidene described in example 59(2), which was obtained 1.8 g of colorless crystals with a melting point 110-112aboutC.

Elemental analysis: C24H30N2O

Calculated, %: C 79,52; H a 8.34; N 7,73

Found, %: C 79,55; H 8,35; N TO 7.77

P R I m e R 62.

NCH2CHN 1-o-Methoxybenzyl-4-[2-(4-pyrrolidinone - zoilus)ethyl]piperidine.

Using 4-[2-(4-pyrrolidinones)ethyl] piperidine the dihydrochloride obtained in example 56, and p-methoxime - sybreed, repeated the procedure p-methoxybenzylamine described in example 59, resulting in the obtained colorless crystals with a melting point of 89-91aboutC.

Elemental analysis: C26H32N2O2< / BR>
Calculated, %: C 76,81; H 8,43; N 6,89

By the way, is similar to that described in example 59, obtained target compound in the form of colorless crystals with a melting point 102-103aboutC.

Elemental analysis: C26H34N2O

Calculated, %: C 79,96; H 8,77; N 7,17

Found, %: C 79,75; H 8,86; N 7,02

P R I m e R 64.

NN 1-[(Oil-2-yl)carbonylmethyl]-4-(4-dime - thelaminated)piperidine fumarate.

4-(4-dimethylaminobenzoyl)of the piperidine dihydrochloride (compound 5), obtained in example 11 was treated with ethyl acetate and an aqueous solution of sodium hydroxide, resulting in received a free 4-(4-dimethylaminobenzoyl)piperidine, and then 2,04 g of this compound and 2,19 g of 2-bromoacetylation was dissolved in n-butanol (30 ml). To the resulting solution were added 0.2 g of potassium iodide and 2.95 g of sodium bicarbonate, and then the mixture was heated, with stirring, at 100aboutC for 3 hours the Solvent is kept off, and the residue was diluted with water (50 ml) and was extracted with chloroform. The solvent is then drove away. The oily residue was purified using chromatography on a column of silica gel (eluent:methanol-dichloromethane = 1:19, V/V) and the solvent was removed. The oily residue was dissolved in methanol, then was added 0.51 g of fumaric acid was dissolved, and razmetnoga crystalline substance with a melting point 170-185aboutWith (Razlog. ).

Elemental analysis: C30H32N2O6< / BR>
Calculated, %: C 69,75; H 6,24; N 5,42

Found, %: C 69,80; H x 6.15; N 5,56

P R I m e R 65.

NCHN [1-(Oil-2-yl)carbonylmethyl]-4-(4-dime - thiaminases)]-piperidine fumarate.

Using 4-(4-dimethylaminobenzoyl)of the piperidine dihydrochloride obtained in example 20 was repeated the procedure of example 64 was obtained colorless crystals, melting at 190-193aboutC.

Elemental analysis: C30H34N2O5.

Calculated, %: C 71,69; H 6,82; N 5,57.

Found, %: C 71,54; H 6,87; N 5,46.

P R I m e R 66.

ClNCHN

[1-(4-chlorbenzoyl)-4-(4-dimethyl - aminobenzyl)]piperidine fumarate.

4-(4-Dimethylaminobenzoyl)of the piperidine dihydrochloride obtained in example 20 was converted into the free compound similar to the description in example 64, 3.27 g of the resulting 4-(4-dimethylaminobenzoyl)of piperidine and 2.8 ml of triethylamine was dissolved in dioxane (20 ml). This solution was added drop by drop into a solution of dioxane (30 ml) containing 3.5 g of p-chlorophenethylamine, and the mixture was stirred for 10 min at room temperature. The solvent is then drove away, the residue was diluted with 1N-aqueous solution of hydroxide hydroxide is yiali. The oily residue was purified using chromatography on a column of silica gel, and then turned to fumarate by analogy to the description in example 64. After recrystallization specified fumarata of ethyl acetate was obtained 1.1 g of colorless crystals with a melting point 131-132aboutC.

Elemental analysis: C26H31ClN2O5< / BR>
Calculated, %: C 64,12; H 6.42 per; N 5,75

Found, %: C 64,05; H 6,45; N OF 5.83

P R I m e R 67.

Cl-CHCHN[1-[(2-(4-Chloro)phenyl-2-hydroxy]ethyl]-4-(4 - dimethylaminobenzoyl)piperidine

[1-(4-chlorobenzoyl)-4-(4-dimethylaminobenzoyl)] piperidine fumarate obtained in example 66 was converted into the free compound by the method described in example 64, resulting in received [1-(4-chlorobenzoyl)-4-(4-dimethylaminobenzoyl)piperidine. Then of 1.65 g of this compound was dissolved in ethanol (50 ml) and water (50 ml). To the obtained solution was gradually added 0.51 g of sodium borohydride, which promotes the separation of the precipitates. The reaction system was stirred for 2 h at room temperature, and after this time the solvent is kept off, and the residue was diluted with water (100 ml) and was extracted with chloroform (100 ml). The extract was dried with anhydrous magnesium sulfate, and the " substance with a melting point of 159-160aboutC.

Elemental analysis: C22H29ClN2O

Calculated, %: C 70,85; H to 7.84; N 7,51

Found, %: C, 70.62 per; H 7,83; N 7,27

P R I m e R 68.

HN N 4-(4-Dimethylaminobenzylidene)piperidine fumarate.

In 20 ml of benzene added 1.35 g of 4-[(-hydroxy-4-dimethylamino)benzyl] PI - peridine hydrochloride synthesized in example 14 (compound 5), and 0.6 g of aluminum chloride, and the resulting suspension was stirred for 24 h at 80aboutC. Then there was added 50 ml of 1 N. aqueous solution of sodium hydroxide and 50 ml of ethyl acetate, resulting in the obtained organic layer was dried with anhydrous magnesium sulfate. The solvent is then drove away, and the oily residue was dissolved in methanol (20 ml). To this solution was added 0.7 g of fumaric acid, and the solvent drove away. Finally, the residue was recrystallized from ethanol and obtained 1.4 g of colorless crystalline substance with a melting point 181-184aboutC.

Elemental analysis: C18H24N2O4< / BR>
Calculated, %: C 65,04; H 7,28; N 8,43

Found, %: C 65,92; H 7,14; N 8,50

P R I m e R 69.

CH2NCH2CH2CHN 1-Benzyl-4-[3-(4-pyrrolidinones)Pro - MPI]piperidine fumarate.

platinum oxide, was carried out by catalytic reduction at atmospheric pressure and 45-50aboutC. After adding 100 ml of acetic anhydride, the catalyst was filtered, and the solvent is kept at reduced pressure. The residue was dissolved in ethanol, was added 5 drops of concentrated hydrochloric acid and the mixture was heated in a flask under reflux for 1 h Then the solvent is kept under reduced pressure, and the residue was diluted with water, neutralized with potassium carbonate and was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, and the solvent drove away, resulting in received 10 g of oily substance.

2) Using 10 g of the specified substances, repeating the procedure of example 52-2), resulting in received of 8.1 g of 4-(N-acetylpiperidine-4-yl)butyric acid as a viscous oily substance.

3) Using 2.15 g of 4-(N-acetylpiperidine-4-yl)butyric acid, repeating the procedure described in example 39, resulting in a received 1,95 g of 1-acetyl-4-[3-(4-forestsoil)propyl] piperidine as a colourless crystalline substance with a melting point 77-78aboutC.

Elemental analysis: C17H22FNO2< / BR>
Calculated, %: C 70,08; H to 7.61 N 4,81
aboutC.

Elemental analysis: C22H26FNO

Calculated, %: C 77,84; H 7,72; N 4,13

Found, %: C sideways range between 77.90; H 7,76; N 3,84

5) To a solution of 1-benzyl-4-[3-(4-forestsoil)propyl]piperidine (0.6 g) synthesized in accordance with the specified description, in dioxane (1 ml) was added 3 ml of pyrrolidine and the mixture was heated for 16 h at 100aboutC. then POWTECH crystals with a melting point 115-116aboutC.

Elemental analysis: C26H34N2O

Calculated, %: C 79,96; H 8,77; N 7,17

Found, %: C 79,95; H 8,83; N 7,03

6) Obtained 1-benzyl-4-[3-(4-pyrrolidinones)propyl] piperidine (0.55 g) was treated with one equivalent of fumaric acid (0.16 g) and the reaction product was recrystallized from ethanol, resulting in the obtained 0.7 g of 1-benzyl-4-[3-(4-pyrrolidinones)propyl]piperidine fumarata in the form of a colorless crystalline substance with a melting point of 220-222aboutC.

Elemental analysis: C26H34N2O C4H4O4< / BR>
Calculated, %: C 71,12; H 7,56; N OF 5.53

Found, %: C 71,19; H EUR 7.57; N OF 5.53

P R I m e R 70.

CH2NCH2CH2CHN 1-Benzyl-4-[3-(4-dimethylaminobenzoyl)- propyl]piperidine fumarate

1) Using 1-benzyl-4-[3-(4-forestsoil)propyl]piperidine synthesized in example 69(4), repeating the procedure of example 69(5) was obtained 1-benzyl-4-[3-(4-dimethylaminobenzoyl)propyl] piperidine as colorless crystals with a melting point 83-85aboutC.

Elemental analysis: C24H32N2O

Calculated, %: C 79,08; H cent to 8.85; N 7,69

Found, %: C 79,01; H 8,72; N 7,55

2) the compound Obtained was treated with one equivalent of panromantic)propyl] Piperi - DIN fumarate as colorless crystals with a melting point 210-211aboutC.

Elemental analysis: C24H32N2O C4H4O4< / BR>
Calculated, %: C 69,98; H of 7.55; N OF 5.83

Found, %: C 69,71; H 7,44; N 5,62

P R I m e R 71.

CH2NCH2CH2CH2CH

1-Benzyl-4-[4-(4-pyrrolidinones - butyl)piperidine]fumarate.

1) To an ethanol solution of ethoxide sodium obtained from 1.4 g of sodium and 200 ml of ethanol, were added are 5.36 pyridine-4-aldehyde and 27 g of (3-methoxycarbonyl-2-propenyl) triphenylphosphine bromide and the resulting mixture was left for 3 days at room temperature. The solvent is then drove away under reduced pressure, and the residue was dissolved in water and acidified with 10% hydrochloric acid (pH about 5). The solution was washed with ethyl acetate, and the aqueous layer was made basic (pH about 8) 10% aqueous solution of sodium hydroxide and was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, and the solvent is kept at reduced pressure, which was obtained 7.0 g of methyl 5-(pyridin--4-yl)-2,4-pentadienoic in the form of an oily substance.

2) Using 7.0 g of methyl 5-(pyridin-4-yl)-2,4-pentadienoic, repeating the procedure of example 69(1) and (2), which was obtained 6.5 g of 5-(N-acetylpiperidine-4-yl)valerianic acid in the form of hygroscopicity-4-yl)valerianic acid, repeating the procedure described in example 39, the result of which was obtained 1.6 g of 1-acetyl-4-[4-(4-forestsoil)butyl]piperidine as colorless crystals with a melting point 98-100aboutC.

Elemental analysis: C18H24FNO2< / BR>
Calculated, %: C 70,79; H a 7.92; N 4,59

Found, %: C 70,75; H 7,88; N 4,60

4) Using 1.5 g of 1-acetyl-4-[4-(4-forestsoil)butyl] piperidine, repeating the procedure described in example 69(4), resulting in a received 1.45 g of 1-benzyl-4-[4-(4-forestsoil)butyl piperidine in the form of colorless crystals with a melting point 67-68aboutC.

Elemental analysis: C23H28FNO

Calculated, %: C 78,15; H 7,98; N 3,96

Found, %: C 78,06; H 7,78; N 3,83

5) Using 0.6 g of the obtained 1-benzyl-4-[4-(4-forestsoil)butyl] piperidin - on, repeating the procedure described in example 69(5), resulting in received of 0.57 g of 1-benzyl-4-[4-(4-pyrrolidinones)BU Tyl]piperidine as colorless crystals with a melting point of 129-131aboutC.

Elemental analysis: C27H36N2O

Calculated, %: C 80,15; H 8,97; N 6,92

Found, %: C 80,04; H 8,89; N 6,85

6) Obtained 1-benzyl-4-[4-(4-pyrrolidinones)butyl]piperidine (0.5 g) was treated with one equivalent of fumaric acid (0.14 g is l]piperidine fumarata in the form of colorless crystals with a melting point of 183-185aboutC.

Elemental analysis: C27H36N2O C4H4O4< / BR>
Calculated, %: C 71,51; H 7,74; N 5,38

Found, %: C 71,45; H a 7.85; N 5,23

P R I m e R 72.

CH2NCH2CH2CH2CH 1-Benzyl-4-[4-(4-dimethylaminobenzoyl)BU Tyl]piperidine fumarate.

1) Using 1-benzyl-4-[4-(4-forestsoil)butyl] piperidine synthesized in example 71(4), repeating the procedure described in example 69(5), which was obtained 1-benzyl-4-[4-(4-dimethylaminobenzoyl)butyl]piperidine as colorless crystals with a melting point 121-123aboutC.

Elemental analysis: C25H34N2O

Calculated, %: C 79,32; H 9,05; N 7,40

Found, %: C 79,09; H 8,98; N 7,27

2) the compound Obtained was treated with one equivalent of fumaric acid and the reaction product was led from ethanol, resulting in the obtained 1-benzyl-4-[4-(4-dimethylaminobenzoyl)BU Tyl]piperidine fumarate as colorless crystalline compound with a melting point 143-145aboutC.

Elemental analysis: C25H34N2OC4H4O4< / BR>
Calculated, %: C 70,42; H 7,74; N 5,66

Found, %: C 70,29; H of 7.64; N 5,49

P R I m e R 73.

CH2NCHN 1-Benzyl-4-(4-dimethy is (0.55 g), obtained in example 40 were subjected to basiliani in accordance with the description in example 59(2), and then treated with one equivalent of fumaric acid, which was obtained 0.7 g of colorless crystalline substance with a melting point 245-247aboutC.

Elemental analysis: C22H28N2OC4H4O4< / BR>
Calculated, %: C 69,01; H 7,13; N IS 6.19

Found, %: C 68,95; H? 7.04 baby mortality; N 6,05

P R I m e R 74.

CH2NN 1-Benzyl-4-(4-pyrrolidinones)Pipa-ridin.

4-(4-Pyrrolidinones)of the piperidine dihydrochloride obtained in example 11(1) (0.66 g) were subjected to basiliani the method described in example 59(2), resulting in a received 0.5 g of colorless crystalline substance with a melting point 154-156aboutC.

Elemental analysis: C23H28N2O

Calculated, %: C 79,27; H 8,10; N 8,04

Found, %: C 79,23; H 8,03; N 8,03

P R I m e R 75.

CH2NN 1-Benzyl-4-(4-dimethylaminobenzoyl)Pipa - ridin fumarate.

4-(4-Dimethylaminobenzoyl)of the piperidine dihydrochloride, synthesized in example 11(5) were subjected to basiliani manner similar to that described in example 59(2), and then treated with one equivalent of fumaric acid in achiev>Elemental analysis: C21H26N2OC4H4O4< / BR>
Calculated, %: C 68,47; H 6,90; N 6,39

Found, %: C 68,35; H 6,74; N 6,32

P R I m e R 76.

CH2NCH2CHN 1-Benzyl-4-[3-hydroxyimino-3-(4-pyrrole - disofenin)propyl piperidine

To a solution (20 ml) containing 0.8 g of 1-benzyl-4-[2-(4-pyrrolidinones)ethyl] piperidine obtained in example 59, and 0.7 g of hydroxylaminopurine in ethanol was added drop by drop a solution (7 ml) 1.4 g of potassium hydroxide in methanol, stirring at 50-55aboutC. Then the mixture was heated at 50-55aboutC for 1 h and after this time, this mixture was added 200 ml of ice water. The resulting precipitate was collected by filtration, washed and dissolved in dichloromethane. The solution was dried with anhydrous sodium sulfate, the solvent is kept under reduced pressure and the obtained crystalline substance. Specified substance was recrystallized from a mixture of dichloromethane and ether and was obtained 0.55 g of colorless crystals with a melting point 153-158aboutC.

Elemental analysis: C25H33N30< / BR>
Calculated, %: C 76,69; H 8,50; N OF 10.73

Found, %: C 76,53; H 8,43; N 10,65

P R I m e R 77.

CH2NCH2CHN 1-Benzyl-4-[3-hydroxy-3-(4-shall obavljale 0.6 g of 1-benzyl-4-[2-(4-pyrrolidinones)ethyl]piperidine, synthesized in example 59, and the resulting mixture was stirred for 30 min at room temperature. Then there was carefully added water to decompose the excess reagent, and then the reaction product was extracted with dichloromethane. The extract was dried with anhydrous sodium sulfate, and the solvent is kept under reduced pressure, resulting in the obtained crude crystals. After recrystallization from a mixture of ether and hexane were obtained 0.5 g of colorless crystals with a melting point of 93-95aboutC.

Elemental analysis: C25H34N2O

Calculated, %: C 79,32; H 9,05; N 7,40

Found, %: C 79,04; H 9,18; N 7,24

P R I m e R 78.

CH2NCH N (E)-1-Benzyl-4-[3-(4-pyrrolidinyl)-2-propen-1-yl]piperidine

To an ethanol solution (10 ml), 0.3 g of 1-benzyl-4-[3-hydroxy-3-(4-pyrrolidino - phenyl)propyl]piperidine synthesized in example 77, was added one drop of concentrated hydrochloric acid and the resulting mixture was heated in a flask under reflux for 30 minutes Then the solvent is kept under reduced pressure, and the residue was dissolved in dichloromethane. The solution was washed with water and the solvent is kept under reduced pressure, resulting in a received neojidannaia 115-117aboutC.

Elemental analysis: C25H32N2< / BR>
Calculated, %: C 83,28; H of 8.95; N TO 7.77

Found, %: C 82,96; H 9,05; N 7,62

Experimental example.

1. Effect against hypoxia.

Of male mice (strain ICR/Jcl, age: 5-6 weeks) were divided into two groups, i.e. the control group and the group treated with the medication. The desiccator was subjected to decompression to obtain an internal pressure of 35 mm RT.article using a vacuum pump, and then was connected to two executors containing mice of the two groups. After the establishment of equilibrium between the internal pressure of executores measured time before the onset of respiratory arrest each mouse in each group, which was seen as a time of survival. Then, taking the average survival time in the control group as 100, the received time of survival for the group treated with the medicinal product, expressed as a percentage (table. 7). The test vehicle was administered intraperitoneally 30 min before inducing hypoxia. The control group was injected with saline.

2. Action against swelling of the brain.

Rats-males (Wistar/Tcl, age: 11 weeks) did an incision in the neck under anesthesia with ether, and legerov the Yu in reverse order from the external carotid artery and in the beginning of the internal carotid artery. Then, in the internal carotid artery through the cannula was poured suspension of carbon microspheres (diameter of 50 µm and 10 µm) in 20% dextran over a period of about 10 seconds at 72 h after injection, the brain was removed and divided into left and right hemisphere. Then determined the content of water, sodium and ions in each hemisphere. The test drug was administered intraperitoneally 30 min prior to injection of the microspheres, and 5 h after infusion, i.e., twice a day, morning and afternoon, until the end of the experiment. For the control group used 5% Arabian gum. The results of the tests are presented in table. 8.

3. Activity against cholinesterase.

In the study of the proposed connection on the activity against cholinesterase used acetyl-[3H]-acetylcholine. Thus, as the source cholinesterase used S1-the fraction of a homogenate of cerebral cortex from male Wistar rats, and acetyl-[3H]-acetylcholine, which is used as substrate, and the test compound were incubated for 30 min, and after completion of the reaction was added a toluene scintillator. The mixture was shaken and using a scintillation counter measured the radioactivity of the reaction product [50
), are presented in table. 9.

4. Effect on copolymerization failure of spontaneous alteration in the T-maze.

Nootropic effect of the proposed connection (example 59) was investigated, using as an indicator of spontaneous alternation in rats (Murray and Bibiger, Behav Neurosci. , 23-32, 1986). In this experiment used rats, whose age was nine weeks. Feeding the animals was restricted so that the body weight of the rats decreased to about 80% by weight with free feeding. Then began the preparation of rats for the experiment. The training consisted of 11 experiments. In the first experiment one fodder pellet (45 mg) were placed in each trough installed at the end of two branches, allowing the rat to choose any of them for a meal. In the next 10 experiments, i.e., from the second and the eleventh specified food was placed only on the end opposite the selected rat directly to this. The choice of edges, where was located the food was regarded as a normal reaction. In each experiment for obtaining food the rat was first placed in a separate compartment and after 15 opened the door and let the animal free, as she ate the pellet in the case of a correct choice, or after it has reached the trough in the case of a wrong choice. In the tests used only those rats that the number of correct election was not less than 80%. Scopolamine was administered intraperitoneally at a dose of 0.3 mg/kg 30 min before the start of the experiment, and the test compound (example 59) was administered orally 30 min prior to injection of scopolamine. The experimental results were expressed in number of correct responses. To analyze differences between groups used the t-test (two steps) of the student. In the first experiment used 7-9 rats, and in the second experiment used 12-14 rats. The results are presented in table. 10, the results of the second experiment are shown in parentheses.

The proposed connection (example 59), depending on its doses counteracts the decrease of the degree of correct reactions caused by scopolamine, and shows a significant improvement effect at the dose of 10 mg/kg Example of obtaining compositions 1. (1) 4-(4-Dimethylaminobenzoyl) of the piperidine dihydrochloride (compound of example 20) 50 g (2) Lactose 198 g (3) Corn starch 50 g (4) magnesium Stearate 2 g

The ingredients (1) and (2) was mixed with 20 g of corn starch and e is Lyali 15 g of corn starch and the ingredient (4), then this mixture was compressed and received 1000 tablets of 5 mm diameter, each of which contained 50 mg of the ingredient (1). An example of obtaining the compositions 2.

2 g of 4-(4-dimethylaminobenzoyl)piperidine dihydrochloride and 1.25 g of mannitol was dissolved in water, the pH of the resulting solution was brought to a value of 5-7 using 0.1 G. of NaOH, and the total volume to 100 ml Then the solution was filtered through 0.2 micron bacterial filter and was divided into 100 vials, each of which contained 1 ml

Cyclic aminosilane General formula

B A N

where B is Peregrina group, piperidinyl group or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner(lower)alkyl group, phenylketone(lower)alkyl group, phenylcarbamoyl(lower)alkyl group or phenyl(lower)alkyl group, each of which may be substituted with halogen or lower alkoxygroup;

p = 1 or 2;

A connection, or two- , or trivalent aliphatic C1- C6a hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino - or hydroxy-group;

- simple B>3is independently hydrogen or a lower alkyl group which may be substituted by phenyl group or piperidino group, provided that both R2and R3are not hydrogen, or R2and R3together with the adjacent nitrogen atom form piperidino group, hexamethyleneimino, morpholino group, pyrolidine group, pieperazinove group or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl(lower)alkyl group, a lower alkylcarboxylic group or diphenyl(lower)alkyl group,

or its physiologically acceptable additive salt of the acid.

Priority signs:

13.01.89 when B - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner(lower)alkyl group, phenylketone(lower)alkyl group, phenylcarbamoyl(lower)alkyl group or phenyl(lower)alkyl group, each of which may be substituted with halogen or lower alkoxygroup, p = 1 or 2, A is a divalent aliphatic C1- C6hydrocarbon residue, which may adored or a lower alkyl group, or together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine group, pieperazinove group or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl(lower)alkyl group, a lower alkylcarboxylic group or diphenyl(lower)alkyl group;

12.07.89 when A connection or trivalent aliphatic C1- C6a hydrocarbon residue which may be substituted by a lower alkyl group, oxo - or hydroxy-group,

- double bond, R2and R3- lower alkyl group which is substituted by phenyl group or piperylenes group;

12.01.90 when A two - or trivalent aliphatic C1- C6hydrocarbon residue, which is substituted by gidroksilaminopurina.

 

Same patents:

The invention relates to new imidazole derivative of General formula I

where R1-COOH or the group< / BR>
R2=H-C3H7or n-C4H9;

R3-Cl, CF3C2F5C6H5or COOH;

R4-COOH, CHO, or CH2HE, provided that

a) when R4-CH2OH, R3-C2F5and R2-n-C3H7,

b) when R3-COOH, R4also is COOH,

b) when R2-n-C3H7, R3-C2F5and R4-COOH, R1is the groupwhich inhibit the action of the hormone angiotensin and can be used in medicine

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

The invention relates to new chemical compounds, namely hydrochloridum derivatives of 1-benzyl-4-indane)-methylpiperidine formula IHClwhere R1- H or methoxy;

R2is methylene;

n is an integer 1 or 2, which have a high and strictly selective antiacetylcholinesterase activity and can find application in medicine

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes N-substituted azaheterocyclic carboxylic acids and their esters of the formula (I):

wherein R1 and R2 represent independently hydrogen, halogen atom, NR6R7 or (C1-C6)-alkyl; Y represents >N-CH2 or >C=CH2- wherein only underlined atom is a component of the ring system; X represents -O-, -S-, -CH2CH2- wherein R6 and R7 represent independently (C1-C6)-alkyl; r = 1, 2 or 3; Z represents heterocycle taken among formulas (a), (b), (c), (d), (f), (k), (g) and (j) given in the invention claim. Also, invention relates to a method for their preparing and pharmaceutical composition based on compounds of the formula (I). Invention describes a method for inhibition of neurogenous pain, inflammation and blood glucose level increase to patient by administration to patient the effective dose of compound of the formula (I). Compounds of the formula (I) elicit ability to inhibit the neurogenous pain and blood glucose enhanced level.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 1 tbl, 30 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to treatment of patients suffering from diseases associated with pathologic activity of matrix proteases. Treatment involves administration of compounds depicted by general formula (I).

EFFECT: increased treatment efficiency.

136 cl, 448 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes applying N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazol-3-carboxamide or its salt for manufacturing a medicinal agent used for treatment of nicotine dependence and/or symptoms of nicotine withdrawal syndrome and a method for help in ceasing using tobacco. The claimed compound is known as antagonist of central cannabinoid receptors and agent used for treatment of disorders associated with using psychoactive substances. Indicated compounds are effective with respect to complete or partial tobacco abstinence with elimination of attenuation of nicotine withdrawal syndrome and patients show reduced weight loss or its absence.

EFFECT: valuable medicinal properties of antagonist.

3 cl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel perfluorinated cycle-containing tertiary amines of the general formula (1): wherein n = 1; m = 2 or 3; X means or and to a mixture of perfluorinated cycle-containing tertiary amines of the general formula (1) wherein n = 1; m = 2 or 3; X means or where at n = 1 Y means CF3 and at n = 2 Y means F as a base for gas-transferring emulsions. Proposed compounds are similar by their physicochemical properties, in particular, by critical temperature dissolving in hexane. Properties of these compounds provide the improved homogeneity of fluorocarbon phase of emulsions and to enhance stability of emulsion particles stabilized with block-copolymer of ethylene oxide and propylene oxide and in the absence of toxicity for small and large animals. Also, invention relates to a method for preparing perfluorinated cycle-containing tertiary amines of the general formula (1) by electrochemical fluorination of p-piperidinoheptafluorotoluene in anhydrous hydrogen fluoride.

EFFECT: improved preparing method and valuable properties of compounds.

4 cl, w dwg, 3 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and their acid-additive and basic salts as FAAH enzyme inhibitors, method of producing said compounds, a pharmaceutical composition based on said compounds and their use, as well as to intermediate compounds of formula (IIa). In general formula (I) , m is an integer ranging from 1 to 4; n is equal to 1 or 2; o is equal to 1 or 2; A is selected from one or several groups X, Y; X denotes a methylene group optionally substituted with one group which is C1-6-alkyl; Y denotes a C2-alkynylene group; B denotes a covalent bond or C1-6-alkylene group; G denotes a covalent bond, an oxygen atom; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes a group selected from oxazolyl, isoxazolyl, thiazolyl, phenyl, pyridinyl, naphthyl, quinolinyl, isoquinolinyl; R5 denotes a halogen atom, a cyano group, C1-6-alkyl, C1-6-alkoxy, C1-6-fluoroalkyl, C1-6-fluroalkoxy, NR7R8; R6 denotes a phenyl group, phenyloxy or pyrimidinyloxy; where R6 group(s) can be substituted with one or two R5 groups which are identical or different from each other; R7 and R8 independently denote a C1-6-alkyl group; R2 denotes a hydrogen atom; R3 denotes a hydrogen atom or C1-C6-alkyl group. In general formula (IIa) , m is an integer ranging from 1 to 2; n equals 2, o equals 2; A denotes X, X denotes a methylene group; B denotes a C1-6-alkylene group; G denotes a covalent bond; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes phenyl; R5 denotes a halogen atom, C1-6alkoxy; R6 denotes a phenyl group; R2 denotes a hydrogen atom.

EFFECT: compounds can be used for treating and preventing diseases mediated by FAAH enzyme activity, such as acute and chronic pain, dizziness, vomiting, nausea, disrupted eating behaviour, neurologic and psychiatric pathologies, acute and chronic neurodegenerative diseases etc.

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I): where: n equals 1 or 3; R1 denotes H, straight or branched (C1-C7)alkyl, (C2-C4)alkenyl, (C2-C4)alkynyl; X denotes H, either one or more substitutes selected from halogen atoms and the following groups: CF3, straight or branched (C1-C6)alkyl, (C1-C6)alkoxy; R2 denotes H, one or more substitutes selected from halogen atoms, CF3, straight or branched (C1-C6)alkyls, (C1-C6)alkoxy, -NR3R4, -SO2NR3R4, -CONR3R4, where R3 and R4 each independently denotes H, straight or branched (C1-C6)alkyl, in form of a base or additive salt with an acid.

EFFECT: formula I compounds are inhibitors of glycine glyt 1 and/or glyt 2 carriers, which enables their use in preparing a pharmaceutical composition and a medicinal agent.

1 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of ethylenediamine derivatives (4), having a halogenated carbamate group and an acyl group, involving catalytic hydrogenation of aminonitrile with a halogen-substituted carbamate group in the presence of an acid and then acylation of the formed amino derivative. The initial aminonitrile may be obtained with high output by reacting an amino acid amide with a halogen-substituted carbamating agent in the presence of water and then reacting the formed amide, which has a halogen-substituted carbamate group, with a reducing agent such as a Wilsmeyer reagent.

EFFECT: high yield.

22 cl, 45 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel 3,4-substituted pyrrolidine derivatives of general formula or pharmaceutically acceptable salts thereof, where R1 is an acyl selected from values given paragraph 1 of the formula of invention; R2 is unsubstituted C1-C4-alkyl or C3-C7-cycloalkyl; R3 is a fragment selected from a group of fragments of formulae: (a), (b),

(c) and (f), where any of the fragments of formulae given above (a), (b) and (f), the star (*) indicates a bond of the corresponding fragment R3 with the molecule residue in formula I; Ra denotes N-C1-C4-alkylaminocarbonyl, N-phenylaminocarbonyl, N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl- C1-C4-alkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C1-C4-alkyl)-N-(C3-C7-cycloalkyl-C1-C4-alkyl)aminocarbonyl, N,N-di-(C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(phenyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl-C1-C4-alkyl)aminocarbonyl, N-(C3-C7-cycloalkyl)-N-(tetrahydropyranyl)aminocarbonyl or hydrogen; Rb and Rc are independently selected from a group comprising unsubstituted C1-C4-alkyl, unsubstituted monocyclic aryl, unsubstituted monocyclic heterocyclyl, unsubstituted or substituted monocyclic C3-C7-cycloalkyl, unsubstituted aryl- C1-C4-alkyl, usubstituted monocyclic C3-C7-cycloalkyl- C1-C4-alkyl, hydrogen or acyl, where the acyl is selected from values given in paragraph 1 of the formula of invention; or Rb and Rc together may form a 6-member nitrogen-containing ring which may be unsubstituted or disubstituted with =O; Rd in the fragment of formula (c) denotes a phenyl or phenyl-C1-C4-alkyl; Re denotes hydrogen or C1-C4-alkyl; and m equals 2; each of R4 and R5 denotes hydrogen; and T denotes methylene. The invention also relates to the pharmaceutical composition based on the compound of formula I and a method of treating hypertension using the compound of formula I.

EFFECT: novel pyrrolidine derivatives having renin inhibiting activity are obtained.

7 cl, 19 tbl, 37 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of novel 4-(azacycloalkyl)phthalonitriles. Novel 4-(azacycloalkyl)phthalonitriles of general formula

are obtained. The method of obtaining said compounds involves nucleophilic substitution of the bromine atom in 4-bromophthalonitrile (BPN) with N,N-cycloalkyleneamines.

.

The reaction takes place in the presence of a deprotonation agent K2CO3 and a catalytic complex Cul/dipyridyl formed in situ at temperature 90-95°C for 12 hours. Molar ratio of reactants BPN: amine: Cul: dipyridyl: K2CO3=1:1.2:0.1:0.1:1.5. After the reaction, the mixture is cooled and filtered. The filtered residue is washed with water and recrystallised.

EFFECT: obtaining novel 4-(azacycloalkyl)phthalonitriles using a method which is safe for this class of compounds.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where: n equals 0, 1, 2; G denotes CH2, CHR3; R1 denotes H, C1-C6-alkyl, C3-C6-alkenyl, -CH2Ph; R2, R3, R4 independently denote H, CH3, -CH2F, -CHF2, CF3; A denotes 1,4-Ph, 1,3-Ph, which can be optionally substituted with 1-4 substitutes selected from halogen, C1-C4-alkyl, C1-C4alkoxy, fluorinated C1-C4-alkyl and fluorinated C1-C4alkoxy; E denotes NR5, where R5 denotes H, C1-C3-alkyl; Ar denotes a radical of formula

and

where: Ra denotes halogen, C1-C6-alkyl, fluorinated C1-C6-alkyl, C1-C6-alkoxy, fluorinated C1-C6-alkoxy, phenyl sulphonyl, CN, -NR6R7, where R6 and R7, together with an N atom, form a 5- or 6-member saturated ring or denotes a 5-member saturated or unsaturated aromatic or non-aromatic heterocyclic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heterocyclic ring can carry 1, 2 or 3 substitutes selected from halogen and C1-C6-alkyl, or denotes a 6-member saturated heterocyclic ring containing, as ring members, one N and one O atom; Rb and Rc independently denote H, halogen, CH3, OCH3, CH2F, OCH2F, CHF2, OCHF2, CF3, OCF3, CH2CH2F, OCH2CH2F, CH2CHF2, OCH2CHF2, CH2CF3 or OCH2CF3; Rd denotes Ra or a 5- or 6-member heteroaromatic ring containing, as ring members, 1, 2 or 3 heteroatoms selected from N, O and S, and where the heteroaromatic ring can carry 1 substitute selected from C1-C6-alkyl and C1-C6-alkylthio; Re denotes H or is defined as Ra; Rf is defined as Ra; k equals 0, 1, 2, 3; j equals 0, 1, 2, 3, 4; provided that Ra does not denote F, CH2F, CHF2, CF3, OCF3, if A denotes 1,4-Ph, Ar denotes a radical of formula (A) and Rb and Rc denote H, halogen; except compounds, where R1 denotes propyl, G denotes CH2, n equals 1, A denotes 1,4- Ph, E denotes NH, Ar denotes a radical of formula (F) and Rd denotes halogen, C1-C6-alkyl, C2-C6-alkenyl or a 5-member heteroaromatic ring; and physiologically acceptable acid addition salts thereof.

EFFECT: compounds exhibit 5HT6 receptor simulating activity, which allows for their use in a pharmaceutical composition.

25 cl, 6 tbl, 107 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula l , where a and b are independently equal to 0-5; R1 and R2 independently denote -C1-4alkyl, CN, halogen, -ORa, -CH2OH, Ra independently denotes H, C1-4alkyl; R3 denotes -C(O)NR3aR3b, -CN; R3a and R3b denote H; R5 denotes -C1-6alkyl; Q denotes -C0-5-alkylene-Q'-C0-1alkylene-, Q' denotes -CH2-, -CH=CH-, -C≡C-, -O-, -S-, -S(O)-, -SO2-, -C(O)-, -OC(O)-, -C(O)O-, -NRQ1C(O)-, -C(O)NRQ1-, -NRQ2-C(O)-NRQ3-, -C=N-O-, -S-S- and -C(=N-O-RQ4)-, RQ1 denotes H; RQ2 and RQ3 denote H; RQ4 denotes -C1-4alkyl, benzyl; e equals 0-5; R6 independently denotes halogen, -C1-4alkyl, -C0-4alkylene-OH, CN, -C (O)O-C1-4alkyl, -O-C1-4alkyl, -S-C1-4alkyl, -NH-C(O)-C1-4alkyl, -N (C1-4alkyl)2 and -N+(O)O; where the alkyl group in R6 is optionally substituted with 1-5 F atoms; one -CH2- group in Q is optionally substituted with one -OH; or a pharmaceutically acceptable salt or zwitterion form thereof.

EFFECT: compounds exhibit antagonistic activity towards muscarinic receptors, which enables their use to produce pharmaceutical compositions for treating lung diseases such as chronic obstructive pulmonary disease and asthma.

32 cl, 16 ex

Up!