Derivatives of cyclic amide or its pharmacologically acceptable salt with antiacetylcholinesterase activity

 

(57) Abstract:

Usage: in medicine, in particular as substances with antiacetylcholinesterase activity. The inventive product - derived cyclic amide f-ly 1 R1-(CH2)n-Z, where R1- one of the groups - 2H-3,4-dihydro-1,3-benzoxazin-2-he, 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-he N-5,6,7,8-tetrahydropyrido[3,2-b] azepin-8-he, 2H-3,4-dihydropyrido[3,2-e] -1,3-azepin-2-tion or-2-it, pyrrolidino[3,4-b] pyrazin-5-Oh, 1H-2,3,4,5-tetrahydrothieno[3,2-b] indole-2-it, 8H-4,5,6,7-tetrahydrothieno[3,2-b] thiophene-7-he 4H-pyrazolo[5,4-e] benzazepin-9-he, isoindoline-1,3-dione, benzoxazolyl-2-he may substituted lower alkelai, alkoxy, halogen, nitro, carboxy, benzene or benzoyl; n = 0, 1 to 6; Z is a group of f-crystals of 2 or 3 (2) or (3), where R2- phenyl, you can haloethanol, C5-C6-cycloalkyl or a radical of pyridine, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene; m is 1 to 3; R3- lower ALK is rohinson-2-he-or-2,4-dione, R2and R4are neither phenyl nor haloperidolum, or their pharmacologically acceptable salts. table 1.

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 -(CH3is 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.

With the rapid growth in the number of very elderly requires the creation of a medical treatment of senile dementia (senile dementia), such as disease Alzheimer.

Although there are attempts by various treatments senile dementia using drugs, yet the treatment is quite effective for these diseases.

Various studies are in progress for the development of therapeutics for these diseases. In particular, the development of the precursors of acetylcholine and acetylcholinesterase inhibitors has been changed, because the disease of Alzheimer accompanied by cerebral cholinergic hypofunction, and they are on the current analysis. Typical examples of inhibitors of anticholinergic istia are still insufficient and in fact, they have adverse reactions. Thus, they currently are not decisive therapeutic means.

The goal can be achieved through the use of derivatives of General formula I, below. In particular, the compounds of the invention represented by structural formula I have such properties that they have a potent, highly selective antiacetylcholinesterase activity to increase the amount of acetylcholine in the brain that they are effective in the treatment of models of memory impairment and their effect lasts for a long period of time and that they have a higher security than the same properties of physostigmine, often used in this field. Thus, the present invention is extremely valuable.

Compounds of the invention was found on the basis of inhibition of acetylcholinesterase and, therefore, they are effective in the treatment and prevention of various diseases caused by the failure of the Central functions of choline, i.e. the absence of acetylcholine as a neurotransmitter in vivo.

Typical examples of such diseases include dementia (slalom is it Huntington, the disease Peak and late dyskinesia (a complication of long-term administration of neuroleptics).

Therefore, the aim of the invention is the development of new derivatives of piperidine, suitable for use as a medicinal product and is particularly effective in the treatment and prevention of diseases of the Central nervous system.

The term "lower alkyl group" in this definition includes a linear-chain and branched alkyl groups having 1-6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl (amyl), isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl-1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylbutyl-1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl-, 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 3,2-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl. Preferred among them are methyl, ethyl, sawn and the isopropyl group, the most desirable are methyl group and ethyl group.

The term "lower alkoxy group" refers to plateline among them low alkoxygroup include methoxy-, ethoxy and n - propoxy groups.

The compounds of formula I can be obtained by similar chemical production methods:

The method of obtaining A.

When R1represents a group derived from compounds of cyclic amide selected from tetrahydroquinazoline, asterolecaniidae, benzylpiperidine and benzoylpiperidine, the connection can be obtained in the following way

( where n represents an integer from 1 to 6, R2is the same as defined above, and l represents a halogen atom.

Namely 9-Aza-1-benzophenon-2-he (II) is condensed with a compound of General formula (III) in the presence of, for example, sodium hydride, in a solvent, for example dimethylformamide, in the conventional method, to obtain the specified (target) compound of General formula (IV).

When R1is a monovalent group derived from compounds of cyclic amide other than as described above, the source compound of the formula

is replaced by tetrahydroquinazoline, benzylpiperidine or benzoylpiperidine, which is condensed with the compound of General formula III to obtain easy target connection.

A method of obtaining a B.


where n and R2are as defined above.

Namely complex fluids General formula (Y) is subjected to reaction with piperidine derivative of General formula (YI) by heating in a suitable solvent inert to the reaction, or in the absence of any solvent to obtain the compound of chinatron (YII), which is one of the target compounds.

The method of obtaining Century

When R1in General formula I represents a group derived from tetrahydroquinazoline, tetrahydropyrimidine, or tetrahydropyrimidine, the connection can also be obtained in the following way: (VIII) where n and R2are as defined above.

Namely, N-ACI-derivatives of the General formula (YIII) is condensed with an amine of General formula (YI) in a solvent such as tetrahydrofuran, and the condensate is additionally subjected to reaction with 1,1-carbonyl diimidazol to get the connection I, which is one of the target compounds.

The method of obtaining,

When R1in General formula I represents a monovalent group derived from substituted or unsubstituted of tetrahydroisoquinoline, the connection can be obtained also p is silovogo aldehyde of General formula XI is condensed with an amine of General formula VI in a solvent, such as methanol, in the condensate restore using natrojarosite to obtain compound XI. The connection is subjected to reaction with 1,1-carbonyl diimidazol, in a solvent such as tetrahydrofuran, to obtain the compound XIII, which is one of the specified compounds.

The method of obtaining D.

When R1in General formula I represents a group derived from substituted or unsubstituted of tetrahydrobenzaldehyde, and R2represents a substituted or unsubstituted arylmethyl, furylmethyl or thienylmethyl group or the like, the compound can also be obtained in the following way

where n and R2are as defined above, a represents a protective group, such as methoxymethyl or methoxyethoxymethyl group.

Namely, the derivative of salicylic acid of General formula XIV and the amine of General formula VI is condensed with, for example, 1,1-carbonyl diimidazol in a solvent such as tetrahydrofuran, and the protective group is removed with acid, such as hydrochloric acid to obtain the compound XY. This compound is subjected to reaction with 1,1-carbonyl diimidazol in a solvent such as tetrahydrofuran is.

When R1in General formula I represents a group derived from substituted or unsubstituted of tetrahydrobenzaldehyde, and R2is cycloalkylation, 1,3-dioxolane-2-ylmethylene or tetrahydropyranyloxy group or the like, the compound can also be obtained in the following way:

where n and R2are as defined above. Namely, the derivative of salicylic acid of General formula XVII and the amine of General formula VI is condensed, for example, 1,1-carbonyl diimidazol in a solvent such as tetrahydrofuran to obtain a compound XVIII and the protective group is removed from it by a catalytic reduction carried out in the presence of PD-C or the like of the catalyst, in a solvent such as methanol. This compound is subjected to reaction with 1,1-carbonyl diimidazol in a solvent such as tetrahydrofuran to obtain a compound XIX, which is one of the target compounds.

The method of obtaining railway

When R1in General formula I represents a group derived from substituted or unsubstituted of tetrahydroquinazoline or tetrahydropyridine, the connection can also be obtained in the following way:

g the th formula VI in a solvent such as methanol, and the condensate is recovered using natrojarosite to get the connection XXII, which undergoes reaction with 1,1-carbonyl diimidazol in a solvent such as tetrahydrofuran to obtain a compound XXIII, which is one of the target compounds.

The method of obtaining the HW

When R1in General formula I represents a group derived from a substituted or an unsubstituted tetrahydroquinoxalin-2, or tetrahydrobenzoic-2,4-dione, the compound can also be obtained in the following way:

where n and R2is as defined above, and L represents a carbonyl or methylene group.

Namely, the connection of the cyclic amide of General formula XXIY is condensed with an alcohol of General formula XXY in a solvent such as tetrahydrofuran, in the presence of DBP-diethyl ester of azodicarboxylic acid or diisopropyl ester of azodicarboxylic acid and triphenylphosphine to obtain a connection XXYI, which is one of the target compounds.

The method of obtaining And.

When R1 in the General formula I represents a group derived from a substituted or an unsubstituted tetrahydroquinoxalin-2-or 2-benzac is, the AK defined above, and R3represents a protective group such as benzyl, methoxymethyl or methoxyethoxymethyl group.

Namely, the amine of General formula XXYII is condensed with a carboxylic acid of General formula XXVIII, to obtain the amide compound XXIY and the protective group is removed to obtain a connection XXX, which is restored by using sociallyengaged in a solvent such as tetrahydrofuran, to obtain the amine XXXI. This compound is subjected to reaction with 1,1-carbonyl diimidazol in a solvent such as tetrahydrofuran or acetonitrile, to obtain the compound XXXII, which is one of the target compounds.

The compounds of formula I or their salts accession acid obtained as described above are effective in the treatment of senile dementia, in particular diseases of Alzheimer.

Following the results of pharmacological tests illustrate the usefulness of the compounds of General formula I and their salts accession acid.

Experimental example 1.

In vitro ingibirovanie action of acetylcholinesterase.

Esterna activity was determined by using ekolin as a substrate, sample and NB were added to the brain homogenate of mice and this mixture was incubated. The yellow product formed by the reaction produced thiocholine with NB, was determined on the basis of changes in the spectrum of the absorption at 412 nm, to evaluate the activity of acetylcholine-esterase.

Inhibition of the activity of acetylcholine-esterase image was expressed as the concentration inhibiting activity by 50% (IC50). The results are given in table. 1.

From the above pharmacological experimental examples, it is obvious that the derivatives of piperidine derivatives of the invention have a potent inhibitory effect on acetylcholinesterase.

Derivatives of cyclic amide obtained according to the invention have characteristics such that their structure is completely different from the structure of the conventional inhibitors acetylcholinesterase, they have a potent inhibitory effect on acetylcholinesterase, the difference between the target effect and a similar effect on acetylcholinesterase is quite significant, the effect lasts for a long period of time, they are quite stable compounds with high solubility in water, which is useful what neither are essentially free from the first patefacta (passing effect) and that they have a high rate of migration in the brain.

Thus, the aim of the invention is to develop new compounds effective in the treatment of dementia and the effects of diseases of the cerebral blood vessels.

Compounds of the invention are effective in the treatment, prevention, remission (temporary disappearance of symptoms), improve (positive dynamics of the disease) and so on , senile dementia, in particular, diseases of the cerebral blood vessels caused by presbyopia of Alzheimer, cerebral stroke (intracerebral cruiseline or cerebral infarction, atherosclerosis and outer head injury, and negligence, rasstroistva speech, weak will, emotional rasstroistva, inability to become sosredotochennymi (stationary) state of galucinacii and Breda and changes in behavior due to the effects of encephalitis and cortical paralysis.

Compounds of the invention are effective in the treatment of presbyterie of Alzheimer and horei Huntington's disease Peak and tardive dyskinesia (OS is e drug for such disease, they are oral or parenteral. Usually they are given by parenteral administration such as intravenous, subcutaneous or intramuscular injection, or in the form of suppositories or tablets under the tongue. The dose of the compounds is not particularly limited because it varies depending on symptoms, age, sex, liquid mass and the sensitivity of the patient, drug, period, and reception intervals, properties, composition and type of drug and type of active ingredient. Usually, however, they are given in the amount of from about 0.1 to 3000 mg, preferably from about 1 to 100 mg, per day (from 1 to 4 times a day).

P R I m e R 1. Hydrochloride 2-/2-(1-benzyl-4-piperidyl)-ethyl/-5-methoxy-2H-3,4-di - hydro-1,3-benzoxazin - 2-it:

< / BR>
To 1,87 g of 1-benzyl-4-(2-amino-ethyl)-piperidine add 10 ml of methanol to obtain a solution, and to this solution add a solution of 0.53 g of 6-methoxysalicylaldehyde aldehyde in 10 ml of methanol. The mixture is stirred at room temperature for 30 min, and then cooled with ice. To the mixture add natrojarosite small portions to effect recovery. The solvent is distilled off and to the residue water is added. After extraction ethylacetate, followed by drying over 450 ml of tetrahydrofuran and added to the mixture 2,77 N, N-carbonyldiimidazole. The mixture is heated at the boiling reverse drains phlegmy for 1 h, the Solvent is distilled off and the thus obtained oily substance is purified by column chromatography on silica gel. The reaction product is converted into its hydrochloride in the usual method to obtain 0.31 g of target compound in a colorless amorphous form. Melting point: amorphous substance. Molecular formula: C23H28N2O3HCl NMR (l3) :

1,20-2,12 (N, multiplet), 2,84 (2H, broadened doublet), 3,37-of 3.54 (4H, multiplet), of 3.80 (3H, singlet), the 4.29 (2H, singlet), is 6.54 (1H, Quartet, j = 2.1 Hz and 8.2 Hz), 7.04-7.18 (7H, multiplet). Mass spectrum: (M + 1+) = 381.

P R I m m e R 2. Hydrochloride 3-[2-(1-benzyl-4-piperidyl)-ethyl] -2H-3,4-dihydro-1,3-Ben - oxazin - 2-it.

< / BR>
To 0,954 g of 1-benzyl-4-(2-amino-ethyl)-piperidine add 6 ml of methanol to obtain a solution, and to the solution add a solution of 0.53 g of salicylic aldehyde in 6 ml of methanol. The mixture is stirred at room temperature for 30 min, and then cooled with ice. To the mixture in small portions add natrojarosite to effect recovery, the Solvent is distilled off and to the residue water is added. After extraction with ethyl acetate viscivorus in 15 ml of acetonitrile and added to the mixture of 2.58 g N, N-carbonyldiimidazole. The mixture is heated at boiling point with reverse drains phlegmy for 1 h, the Solvent is distilled off and the thus obtained oily substance is purified column chromatography on silica gel. The reaction product is converted into its hydrochloride in the usual method to obtain 0.68 g of the target compound as a colourless, amorphous substance. Melting point: 209,8-210aboutC. Molecular formula: C22H26N2O2HCl NMR (l3) :

1,24-2,08 (N, multiplet), and 2.83 (2H, broadened doublet), of 3.45 (2H, singlet), of 3.46 (2H, triplet, j = 7.5 Hz), to 4.38 (2H, singlet), 6,89-7,34 (N, multiplet).

Mass spectrum: (M + 1+) = 351.

P R I m e R 3. Hydrochloride 3-[2-(1-benzyl-4-piperidyl)-ethyl] -2H-3,4-dihydro-1,3-Ben - oxazin-2,4-dione:

< / BR>
In 70 ml of tetrahydrofuran was dissolved 2.15 g of 4-[2-(2-hydroxyethylamino)-ethyl] -1-benzylpiperidine and add to the mixture of 2.06 g of N, N'-carbonyldiimidazole. The mixture is heated at the boiling reverse drains phlegmy within 24 hours the Solvent is distilled off and the thus obtained oily substance is purified column chromatography on silica gel. The reaction product is converted into its hydrochloride in the usual method to obtain 2.14 g of the target connection is ula: C22H24N2O3HCl NMR (l3) :

1,24-2,19 (N, multiplet), of 2.86 (2H, broadened doublet), of 3.46 (2H, singlet), was 4.02 (2H, triplet, j : I = 7.5 Hz), 7,14 and 7.36 (7H, multiplet), to 7.59 (1H, Quartet, j = 1,8 Hz and 9.0 Hz), 8,00 )1H, Quartet, j = 1,8 Hz and 8.0 Hz).

Mass spectrum: (M + 1+) = 365.

P R I m e R 4. Dichlorhydrate 3-[2-(4-pyridylmethyl)-4-piperidyl] -ethyl] -2H-3,4-di - hydro-1,3 - benzoxazin-2-it.

< / BR>
To 0,83 g of 1-(4-pyridylmethyl)-4-(2-amino-ethyl)-piperidine add 10 ml of methanol to obtain a solution, and to this solution add a solution to 0.63 g of 5-methoxysalicylaldehyde aldehyde in 5 ml of methanol. The mixture is stirred at room temperature for 30 min, and then cooled with ice. To the mixture in small portions add natrojarosite to effect recovery. The solvent is distilled off and to the residue water is added. After extraction with ethyl acetate and drying over magnesium sulfate the solvent is distilled off. Thus obtained oily reaction product was dissolved in 20 ml of acetonitrile and added to the mixture of 2.28 g of N, N'-carbonyldiimidazole. The mixture is heated at the boiling reverse drains phlegmy for 4 hours the Solvent is distilled off and the thus obtained oily substance is purified using colonosopy from a mixture of methanol-ether, to obtain 0.35 g of the target compound in the form of colorless needle-like crystals. Melting point: 132,2-132,8aboutC (decomp. ). Molecular formula: C22H27N3O32HCl. NMR (l3) :

1,20-2,13 (N, multiplet), 2,82 (2H, broadened doublet), of 3.46 (2H, singlet), of 3.48 (2H, triplet, j = 7.5 Hz), of 3.75 (3H, singlet), 4,18 (2H, singlet), to 6.58 (1H, two doublet, j = 2,8 Hz and 8.5 Hz), 6,79 (1H, doublet, j = 2,8 Hz), 6,92 (1H, doublet, j = 8.5 Hz), 7.23 percent (2H, doublet, I = 6.2 Hz), 8,48 (2H, doublet, j = 6.2 Hz).

Mass spectrum: (M + 1+) = 382.

P R I m e R 5. Hydrochloride 3-[2-[1-(1,3-dioxolane-2-ylmethyl)-4-piperidine] -ethyl] -6-methoxy - 2H-3,4-dihydro-1,3-benzoxazin-2-it:

< / BR>
In 10 ml of methanol is dissolved 0,70 g 5-methoxysalicylaldehyde aldehyde and a solution of 1.28 g of 1-(1,3-dioxolane-2-ylmethyl)- 4-(2-amino-ethyl)-piperidine in 10 ml of methanol is added to a given solution. The mixture is stirred at room temperature for 1 h and then added to the mixture natrojarosite while cooling with ice until then, until there is no longer yellow staining. The reaction mixture was concentrated under reduced pressure and to the mixture is added 150 ml of a saturated aqueous solution of sodium bicarbonate. After extraction twice with 100 ml of methylene chloride, followed by washing with 150 the tion concentrated under reduced pressure. Thus obtained oily reaction product is dissolved in 100 ml of acetonitrile and added to the mixture 2,98 g N, N'-carbonyldiimidazole. The mixture is heated at the boiling reverse drains phlegmy for 3 h, and then allowed to cool to room temperature. After concentration under reduced pressure, to the residue is added 200 ml of ethyl acetate, the mixture is washed with 200 ml saturated aqueous sodium bicarbonate solution and then with 200 ml of a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, followed by concentration under reduced pressure, the residue is purified by column chromatography on silica gel (methylene chloride: methanol = 100: 1). Thus obtained white solid is recrystallized from a mixture of ethyl acetate/hexane, to obtain 1.30 grams of white crystals. The reaction product is converted into its hydrochloride to get 1,43 g (yield: 75% ) of target compound in amorphous form. Melting point: amorphous substance. Molecular formula: C22H28N2O5HCl. NMR (l3) :

1,30-of 1.41 (3H, multiplet), to 1.60 (2H, two doublet), 1,72 (2H, doublet), to 2.06 (2H, triplet), of 2.56 (2H, doublet), 2,98 (2H, doublet), 3,49 (2H, two doublet), of 3.78 (3H, singlet

Mass spectrum: (M + 1+) = 377. P R I m e R 6. Hydrochloride 3-[2-(1-cyclopentylmethyl-4-piperidyl)-ethyl] -2H-3,4-dihydro-1,3 - benzoxazin-2,4-dione:

In 50 ml of methanol is dissolved of 0.91 g of 4-[2-(2-benzyloxy-5-methoxybenzamido)-ethyl] -1-cyclopentenopyridine and to the solution add 0,07 10% Pd-C. the Mixture is stirred at room temperature in hydrogen atmosphere for 1 h Used PD-C is removed by filtration and the solvent is distilled off to obtain a pale yellow oily substance. This substance add 30 ml of tetrahydrofuran to obtain a solution, and to the solution was added 0.65 g of N, N'-carbonyldiimidazole. The mixture is heated at the boiling reverse drains phlegmy for 13 hours the Solvent is distilled off and the thus obtained oily substance is purified by column chromatography on silica gel. This substance is converted into its hydrochloride in the usual manner and recrystallized from a mixture of methanol/ether to obtain 0.39 g of target compound in the form of colorless needle-like crystals. Melting point: 213,5-214,1aboutC. Molecular formula: C22H30N2O4HCl. NMR (l3) :

1,17-to 1.21 (2H, multiplet), 1,36-of 1.39 (3H, multiplet), 1,50-1,68 (6N, multiplet), 1,74-to 1.79 (4H, multipl is, ,06 (2H, multiplet), 7,19 (1H, doublet, j = 9,2 Hz), 7,25 (1H, two doublet, j = 3.2 Hz and 9.2 Hz), was 7.45 (1H, doublet, j = 3.2 Hz).

Mass spectrum: (M + 1+) = 387.

P R I m e R 7. Hydrochloride 3-[2-[1-(1,3-dioxolane-2-ylmethyl)-4-piperidyl] -ethyl] -2H - 3,4-dihydro - 1,3-benzoxazin-2,4-diene:

< / BR>
In 30 ml of methanol is dissolved 0,99 g of 4-[2-(2-benzyloxy-5-methoxybenzoyl-amino)- ethyl] -1-(1,3-dioxolane-2 - ylmethyl)-piperidine and added to a solution of 0.11 g of 10% PD-C. the Mixture is stirred at room temperature in a hydrogen atmosphere for 2 hours Used PD-C is removed by filtration and the solvent is distilled off to obtain 0,82 g of light yellow oily substance. To it add 30 ml of tetrahydrofuran to obtain a solution, and added 0.71 g of N, N'-carbonyldiimidazole. The mixture is heated at the boiling reverse drains phlegmy for 20 hours the Solvent is distilled off and the thus obtained oily substance is purified by column chromatography on silica gel. The substance is converted into its hydrochloride in the usual way and recrystallized from a mixture of methanol/ether to obtain of 0.85 g of the target compound as colorless needles. Melting point: 155, 3mm-156,8aboutC. Molecular formula: C20H26N2O6HCl. NMR (,0 Hz), of 2.56 (2H, doublet, j = 4.4 Hz), 3,50 (2H, broadened doublet), a 3.87 (3H, singlet), 3,82-3,90 (2H, multiplet), 3,92-to 3.99 (2H, multiplet), a 4.03-4,07 (2H, multiplet), 5,00 (1H, triplet, j = 4.4 Hz), 7,10 (1H, doublet, j = 9,2 Hz), 7,16 (1H, Quartet, j = 2,8 Hz and 9.2 Hz), 7,35 (1H, doublet, I = 2,8 Hz).

Mass spectrum: (M + 1+) = 391.

P R I m e R 8. Dichlorhydrate 5-[2-(1-benzyl-4-piperidyl)-ethyl] -5H-6,7,8,9-Tetra - hydroperiod-[3,2-b] - azepin-6-it.

< / BR>
0.73 g of sodium hydride was washed with n-hexane, and then suspended in 1 ml of N, N-dimethylformamide (DMF) and the suspension is stirred under cooling with ice. To the suspension is added dropwise a solution of 0,989 5H-6,7,8,9-tetrahydropyrido-[3,2-b] -azepin-6-she's in 15 ml of DMF. The mixture is stirred for 20 min at 60aboutC. the reaction Product is again cooled with ice, and add to it of 2.51 g of the hydrochloride of 1-benzyl-4-(2-chloroethyl)-piperidine. The mixture is stirred for 2.5 h, maintaining the external temperature at 60aboutC. the Solvent is distilled off and to the residue water is added. After extraction with methylene chloride, followed by washing with saturated aqueous sodium chloride solution and drying over magnesium sulfate, the solvent is distilled off. Thus obtained oily reaction product is purified by column chromatography n is inane in the form of colorless, amorphous substances. Temperature melting point: amorphous substance. Molecular formula: C23H29N3OHCl. NMR (l3) :

1,21-2,04 (N, multiplet), and 2.26 (4H, broadened singlet), 2,82 (4H, broadened doublet), 3,44 (2H, singlet), 3,81 (2H, broadened triplet), 7,08 was 7.45 (7H, multiplet), 8,30 (1H, two doublet, j = 1.3 Hz and 4.6 Hz).

Mass spectrum: (M+= 363 (D1-E1).

P R I m e R 9. Hydrochloride 3-[2-(1-benzyl-4-piperidyl)-ethyl] -2H-3,4-dihydro-6-methyl - pyrido- [2,3-e] -meta-oxazin-2-thione.

HCl< / BR>
The Schiff's base obtained by boiling under reflux 0.50 g of 3-hydroxy-6-methyl-2-pyridinecarboxylic - degidi and 1.00 g of 1-benzyl-[4-(2-amino-ethyl)] -piperidine in methanol, add an excessive amount of natrojarosite. The mixture is stirred at room temperature for 30 min and the reaction mixture was poured 0.2 N. aqueous solution of sodium hydroxide. After extraction with a mixture of ethyl acetate/diethyl ether, followed by washing with a saturated solution of sodium chloride, drying over anhydrous magnesium sulfate and distillation of the solvent under reduced pressure, the residue is dissolved in 30 ml of acetonitrile. To the solution was added to 2.00 g of 1,1'-thiocarbonyldiimidazole and the reaction is carried out at straccia a mixture of ethyl acetate/diethyl ether, followed by washing with saturated sodium chloride solution and drying over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure. The residue is purified by column chromatography on silica gel (methylene chloride: methanol = = 97: 3). Received blue oily substance is transformed into its hydrochloride and treat Narita SX-2, to obtain 0.40 g of the target compound as pale yellow crystals (yield: 26% ). Melting point: 138-139aboutC (decomp. ). Molecular formula: C22H27N3OSHCl. NMR (l3) :

1,16-2,10 (N, multiplet), 2,49 (3H, singlet), 2,64-of 2.97 (2H, multiplet), 3,47 (2H, singlet), of 3.96 (2H, triplet), of 4.49 (2H, singlet), 6,95-7,40 (7H, multiplet).

Mass spectrum: (M + 1+) = 382.

P R I m e R 10. Fumarate 3-[2-[4-[(1-benzyl)-piperidin] ] -ethyl] -pyrazino-[2,3-d] PI rimidine - 2,4-dione.

< / BR>
In 200 ml of acetonitrile is suspended 5 g of 3-aminopyrazine-2-carboxylic acid and 6.7 g of 1,1'-carbonyldiimidazole and the suspension is heated at the boiling reverse drains phlegmy within 6 hours Undissolved part is removed by filtration and the residue is cooled to room temperature. Thus obtained crystals are removed by filtration, to obtain 3.5 g prot 1.5 g of the thus obtained derivative elimidate and 1.4 g of 2-[4-[(1-benzyl)-piperidin] ] -ethylamine and the solution stirred at room temperature overnight. The tetrahydrofuran is distilled off under reduced pressure and the residue purified by column chromatography on silica gel (methylene chloride: methanol = 9: 1) to obtain 1.9 g of the amide compounds.

In 50 ml of acetonitrile and 50 ml of tetrahydrofuran was dissolved 1.9 g of amide compound and 2.2 g of 1,1'-carbonyldiimidazole and the solution is heated at the boiling reverse drains phlegmy for 26 hours the Solvent is distilled off under reduced pressure and to the residue water is added. After extraction with methylene chloride and drying over magnesium sulfate the reaction product is purified by column chromatography on silica gel (methylene chloride: methanol = 10: 1) to extract 1.5 grams of amide compounds and to obtain 150 mg of the reaction product. The reaction product is converted into its fumarate usual method to obtain a powder target connection. Melting point: 223-226aboutC (decomp. ). Molecular formula: C20H23N5O2x C4H4O4.

NMR (l3) :

1,08-2,20 (N, multiplet), was 2.76-is 3.08 (2H, multiplet), 3,52 (2H, singlet), 3,80-4,24 (2H, multiplet), 6,32 (1H, broadened singlet), 6,92-to 7.32 (5H, multiplet), charged 8.52 (2H, singlet).

Mass spectrum: (M + 1+) = 366.

P R I m e R 11. 1 4.8 g of anhydride 2,3-pyrazinecarboxamide acid and 7 g of 2-[4-[(1-benzyl)-piperidin] ] -ethylamine in 70 ml of toluene is heated at the boiling reverse drains phlegmy within 2 hours The reaction mixture is cooled to room temperature and filtered extract 10 g of the thus obtained N-[2-[4-(1-benzyl)-piperidin] ] -ethyl] -2-PIR incarbone-3-carboxylic acid.

1,76 g thus obtained amido-carboxylic acid are heated at 70aboutWith in 25 ml of acetic anhydride for 30 min Volatile matter is distilled off under reduced pressure and the residue is subjected to azeotropic distillation with toluene, and then the subsequent reaction without further purification.

Thus obtained crude reaction product was dissolved in 20 ml of tetrahydrofuran, and to the mixture are added dropwise at room temperature for 2 min with 2 ml of 3 M solution methylacrylamide in the air. The mixture is stirred at room temperature for 30 min and to this mixture an aqueous solution of ammonium chloride. After extraction with methylene chloride followed by drying over magnesium sulfate, the reaction product is purified by column chromatography on silica gel (methylene chloride: methanol = 9: 1) to obtain 0.15 g of the target compound. Melting point: amorphous substance. Molecular formula: C21H26N4O2.

NMR (l3) :

1,00-2,24 (NR> Mass spectrum: (M + 1+) = 367.

P R I m e R 12. Fumarate 1-[2-[4-[(1-benzyl)-piperidin] ] -ethyl] -7-Methylenebis - Zino-[2,3-c] - pyrrolidin-2-it.

< / BR>
In 3 ml of acetic anhydride was dissolved 0.1 g 1-[2-[4-[(1-benzyl)-piperidin] ] -ethyl] -7-hydroxy-7-methylpiperazine-[2,3 - C] -pyrrolidin-2-she and the solution is heated at the boiling reverse drains phlegmy within 3.5 h of the Volatile matter is distilled off under reduced pressure and the residue purified by column chromatography on silica gel (methylene chloride: methanol = 9: 1) to obtain 0.06 g of the reaction product. His turn in the corresponding fumarate usual method to obtain the target compound. Melting point: amorphous substance. Molecular formula: C21H24N4O x xC4H4O4.

NMR (l3) :

1,04-2,20 (N, multiplet), 2,68 totaling 3.04 (2H, multiplet), of 3.48 (2H, singlet), 3,76-Android 4.04 (2H, triplet), 5,04-5,12 (1H, doublet), 5,72-5,80 (1H, doublet), 7,12-7,40 (5H, multiplet), 8,64-8,80 (2H, two doublet).

Mass spectrum: (M + 1+) = 349.

P R I m e p 13. Hydrochloride 1-[2-[4-[(1-benzyl)-piperidin] ] -ethyl] - 4-benzylpyrrolidine-2-it.

< / BR>
(1) Synthesis of 1-[2-[4-[(1-benzyl)-piperidin] ] -ethyl] -pyrrolidin-2-he - 4-carboxylic acid.

1-benzylpiperidine. The reaction mixture is extracted with water and the aqueous layer washed with methylene chloride. The water is distilled off under reduced pressure and the residue is subjected to azeotropic distillation with toluene to obtain 27 g of the crude carboxylic acid.

(2) Synthesis of hydrochloride 1-[2-[4-[(1-benzyl)-piperidin] ] -ethyl] -4 - benzylpyrrolidine-2-it:

< / BR>
In 80 ml of methylene chloride was dissolved 4.3 g of the crude carboxylic acid obtained in the above method (1), and to the solution at room temperature for 5 minutes and added dropwise 5 ml of chloride tiomila. The mixture is stirred for additional 10 min at room temperature and the volatile matter is distilled off under reduced pressure.

The residue is dissolved in 70 ml of methylene chloride and to the solution was added 12 ml of benzene and cooled with ice. To the mixture for 5 min add 5.5 g aluminum chloride. After stirring at room temperature overnight, the reaction mixture was poured on ice, alkalinized with sodium hydroxide, extracted with methylene chloride and dried over magnesium sulfate. Methylene chloride is distilled off under reduced pressure, and 6 g of crude reaction product is purified by column chromatography on silica gel (chlorite is at in the usual way, to obtain the target compound as a hygroscopic amorphous substance. Melting point: amorphous substance. Molecular formula: C25H30N2O2HCl. NMR (l3) :

1,00-4,28 (2HE, multiplet),? 7.04 baby mortality of 6.68 (8H, multiplet), 7,72-8,00 (2H, multiplet).

Mass spectrum: (M + 1+) = 391.

P R I m e R 14. Hydrochloride 1-[2-[4-[(1-benzyl)-piperidin] ] -ethyl] -4-benzylphenol - DIN-2-it.

< / BR>
In 10 ml of methanol is dissolved 0,58 g 1-[2-[4-[(1-benzyl)-piperidin] ] -ethyl] -4-benzoyl - pyrrolidin-2-it, and to the solution at room temperature add 60 mg of natrojarosite. The mixture is stirred for 10 minutes, the Methanol is distilled off under reduced pressure and to the residue water is added. After extraction with methylene chloride followed by drying over magnesium sulfate, distilled under reduced pressure, methylene chloride. The reaction product is purified by column chromatography on silica gel (methylene chloride: methanol = 9: 1) to obtain 0,41 g of the alcohol compound in the form of a colorless, viscous, oily mixture of two isomers, which is subjected to the subsequent reaction without separation.

In 5 ml of pyridine is dissolved 0,41 g of the alcohol compound obtained above, and to rastovac for 3 hours and add water to the mixture. After extraction with ethyl acetate followed by drying over magnesium sulfate, distilled under reduced pressure, ethyl acetate. The reaction product is purified by column chromatography on silica gel (methylene chloride: methanol = 95: 5) to obtain 0.4 g thiocarbonate compound as a brown oil.

In 9 ml of toluene dissolving 0.39 g obtained above thiocarbonates connection and to the solution add 0.5 ml of anti-hydride and a catalytic amount of 2,2'-azobis-(isobutyronitrile). The mixture is heated at 70-80aboutC for 8 hours, the Toluene is distilled off under reduced pressure and the residue purified by column chromatography on silica gel (chloride stands: methanol = 9: 1) to obtain 0.12 g of the free base. This base is converted into its hydrochloride in the usual way to get targeted amorphous compound. Melting point: amorphous substance. Molecular formula: C25H32N2OHCl. NMR (l3) :

1,16-3,48 (20N, multiplet), 3,52 (2H, singlet), 7,00-7,40 (10H, multiplet).

Mass spectrum: M+= 376 (FD).

P R I m e R 15. Hydrochloride 3-[2-[1-(1,3-dioxolane-2-ylmethyl)-4-piperidine] -ethyl] -5-methoxy-1,2,3,4 - tetrahydroquinazoline-2,4-dione.

HCl20H27N3O5HCl. NMR (l3) :

1,20-2,20 (N, multiplet), 2,60 (2H, doublet), 2,98 (2H, doublet), 3,69-4,20 (6N, multiplet), of 3.97 (3H, singlet), to 5.03 (1H, multiplet), 6,56-6,74 (2H, multiplet), to 7.50 (1H, two doublet).

Mass spectrum: (M + 1+) = 390.

P R I m e R 16. Hydrochloride 3-[2-[1-(1,3-dioxolane-2-ylmethyl)-4-piperidyl] -ethyl] - 1,2,3,4 - tetrahydroquinazolin-2-it.

CH3OHCl

To 1.04 g of 1-(1,3-dioxolane-2-ylmethyl)-4-(2-amino-ethyl)-piperidine is added 15 ml of methanol to obtain a solution, and to anatoy temperature for 0 min and cooled with ice. To the reaction mixture in portions of natrojarosite to effect recovery. The solvent is distilled off and to the residue water is added. After extraction with ethyl acetate followed by drying over magnesium sulfate, the solvent is distilled off and the resulting oily substance was dissolved in 30 ml of tetrahydrofuran. To the solution was added to 2.42 g of N, N'-carbonyldiimidazole and heated at the boiling reverse drains phlegmy for 2.5 hours the Solvent is distilled off and the resulting oily substance is purified by column chromatography on silica gel. The reaction product is converted into its hydrochloride in the usual method to get to 0.19 g of the target compound as a pale yellow amorphous substance.

Melting point: amorphous substance. Molecular formula: C20H29N3O5HCl.

NMR (l3) :

1,20-to 1.38 (3H, multiplet), 1,52-and 1.54 (2H, broadened Quartet), 1,71 (2H, broadened doublet), 2,04 (2H, triplet, j = = 9,2 Hz), of 2.54 (2H, doublet, j = 4.6 Hz), 2,97 (2H, broadened doublet), 3,44 (2H, triplet, j = 7.4 Hz), 3,66 (3H, singlet), 3,80-a-3.84 (2H, multiplet), 3,92-of 3.95 (2H, multiplet), at 4.99 (1H, triplet, I = 4,6 Hz), to 6.57 (1H, doublet, j = 3.2 Hz), 6,62 (1H, doublet, j = 8,4 Hz), 6,70 (1H, Quartet, j = 3.2 Hz and 8.4 Hz).

Mass spectrum: the in-2,4-dione.

CH3OHCl

To 0,83 g of 1-(1,3-dioxolane-2-ylmethyl)-4-(2-amino-ethyl)-piperidine add 10 ml of tetrahydrofuran to obtain a solution and to the solution was added with 0.93 g of 1-(2-amino-5-methoxybenzophenone)-imidazole. The mixture is stirred. To the solution was added 1.26 g of N, N'-carbonyldiimidazole and the mixture is heated at the boiling reverse drains phlegmy for 19 hours, the Solvent is distilled off and the resulting oily substance is purified by column chromatography on silica gel. The reaction product is converted into its hydrochloride in the usual way to get to 0.30 g of the target compound as a pale yellow amorphous substance.

Melting point: amorphous substance. Molecular formula: C20H27N3O5HCl.

NMR (l3) :

of 1.36 (3H, broadened singlet), 1,59-of 1.64 (2H, multiplet), to 1.76 (2H, broadened doublet), was 2.05 (2H, broadened triplet), 2,53 (2H, doublet, j = 4.6 Hz), 2,98 (2H, broadened doublet), 3,80-a 3.83 (2H, multiplet), 3,83 (3H, singlet), 3,91-of 1.93 (2H, multiplet), 4,08 (2H, broadened triplet), to 4.98 (1H, triplet, j = 4.6 Hz), ? 7.04 baby mortality (1H, doublet, j = 8,8 Hz), 7,18 (1H, Quartet, j = 2,8 Hz and 8.8 Hz), 7,49 (1H, doublet, j = 2,8 Hz), 11,05 (1H, broadened singlet).

Mass spectrum: (M + 1+) = 390.

P R I m e R s 18-75. The following connection is tx2">

The temperature of the melt: amorphous substance. Molecular formula: C27H33N3OHCl. NMR (l3) :

1,2-2,1 (M, multiplet), 2,31 (4H, broadened singlet), 2,78 (4H, broadened doublet), to 3.41 (2H, singlet), to 3.67 (3H, singlet), 3,90 (2H, broadened triplet), 7,02-7,46 (N, multiplet).

Mass spectrum: M+= 415 (FD).

Melting point: amorphous substance. Molecular formula: C22H28N2OSHCl. NMR (l3) :

1,18-2,01 (N, multiplet), and 2.26-of 2.30 (4H, multiplet), 2,68-is 2.88 (4H, multiplet), to 3.41 (2H, singlet), to 3.67 (2H, broadened triplet), 6,79 (1H, doublet, j = 5.7 Hz), 7,00 (1H, doublet, j = 5.7 Hz), 7,18 (5H, singlet).

Mass spectrum: M+= 368 (FD).

Melting point: amorphous substance. Molecular formula: C23H29N3OHCl.

NMR (l3) :

1,20-1,86 (N, multiplet), 2,24-to 2.29 (4H, multiplet), 2,59-of 2.81 (4H, multiplet), of 3.43 (2H, singlet), of 4.05 (2H, broadened triplet), 7,01 (1H, two doublet, j = 4,9 Hz and 7.5 Hz), 7,20 (5H, singlet), 7,46 (1H, two doublet, j = 1.8 Hz and 7.5 Hz), 8,29 (1H, two doublet, j = 1.8 Hz and 4.9 Hz).

Mass spectrum: (M + 1+) = 364 (FAB).

Melting point: amorphous substance. Molecular formula: C27H32N4OHCl.

NMR (l3) :

1,24-2,04 (11N,), a 7.62 (1H, two doublet, j= 2,8 Hz and 5.5 Hz).

Mass spectrum: (M + 1+) = 429 (FAB).

Melting point: 217,6-218,8aboutMolecular formula: C23H28N2O2HCl. NMR (l3) :

1,16-2,04 (11N, multiplet), and 2.83 (2H, broadened doublet), is 2.40 (2H, triplet, j = 7,2 Hz), 2,43 (2H, singlet), 4,39 (2H, singlet), 6,88-7,35 (M, multiplet).

Mass spectrum: M+= 364 (D1-E1)

Melting point: amorphous substance. Molecular formula: C21H25N2O32HCl. NMR (l3) :

1,28-2,04 (N, multiplet), 2,85 (2H, broadened doublet), of 2.45 (2H, singlet), of 2.50 (2H, triplet, j = 7,3 Hz), 4,49 (2H, singlet), 7,02-to 7.32 (7H, multiplet), 8,24 (1H, two doublet, j = 2.1 Hz and 4.1 Hz).

Mass spectrum: (M + 1+) = 352 (FAB)

Melting point: of 209.5-210,7aboutMolecular formula: C23H28N2O3HCl. NMR (l3) :

1,22-2,12 (N, multiplet), 2,89 (2H, broadened doublet), of 3.48 (2H, triplet, j= 7,3 Hz, 3,51 (2H, singlet), 3,76 (3H, singlet), 4,35 (2H, singlet), 6,59 (1H, two doublet, j = 2,8 Hz and 13.1 Hz), 6,94 (1H, doublet, j = 13.1 Hz), 7.18 in-7,38 (6N, multiplet).

Mass spectrum: (M + 1+) = 381 (FAB).

Melting point: amorphous substance. Molecular formula: C23H28N2O3HCl. NMR (l3) :

Mass spectrum: (M + 1+) = 381 (FAB).

melting point: 209,8-210,9aboutC (decomp. ). Molecular formula: C23H28N2O3HCl. NMR (l3) :

1,19-2,11 (N, multiplet), 2,87 (2H, broadened doublet), of 3.43 (2H, triplet, j = 7.5 Hz), 3,48 (2H, singlet), of 3.94 (3H, singlet), 4,35 (2H, singlet), 6,60 (1H, two doublet, IK = 2,6 Hz and 9.8 Hz), 6,78 (1H, doublet, j = 2.6 Hz), 6,91 (1H, doublet, j = 9.8 Hz), 7,24 (5H, singlet).

Mass spectrum: (M + 1+) = 381 (FAB)

Melting point: amorphous substance. Molecular formula: C23H26N2OHCl. NMR (l3) :

1,18-2,11 (N, multiplet), 2,85 (2H, broadened doublet), 3,47 (2H, singlet), 3,76 (2H, triplet, j = 7,3 Hz), 4,78 (1H, doublet, I = 2,3 Hz), 5,14 (1H, doublet, I = 2,3 Hz), 7,24 (5H, singlet), 7,38-7,81 (4H, multiplet).

Mass spectrum: (M + 1+) = 347 (FAB)

Melting point: amorphous substance. Molecular formula: C24H30N2O4HCl. NMR (l3) :

1,24-2,12 (9G, multiplet), is 2.88 (2H, broadened doublet), 3,38 of 3.56 (4H, multiplet in), 3.75 (3H, singlet), of 3.78 (3H, singlet), 4,24 (2H, singlet), x 6.15 (1H, broadened singlet), 7,20-7,30 (6N, broadened singlet).

Mass spectrum: (M + 1+) = 441 (FAB)

Melting point: 220,5-221,8aboutWith MOLEKULYaRNAYa (4H, multiplet), to 4.38 (2H singlet), of 6.96 (1H, broadened singlet), 7,29 (6N, broadened singlet).

Mass spectrum: (M + 1+) = 419 (FAB).

Melting point: amorphous substance. Molecular formula: C21H23Cl2N3O2:

1,20-1,12 (N, multiplet), 2,78 (2H, broadened doublet), 3,36-of 3.53 (4H, multiplet), 4,36 (2H, singlet), 6,92 (1H, doublet, j = 2.3 Hz), 7,08-7,28 (3H, multiplet), to 8.41 (2H, doublet, j = 8.5 Hz).

Mass spectrum: (M + 1+) = 420 (FAB).

Melting point: 231,1-232,3aboutC (decomp. ). Molecular formula: C22H25N3O4HCl.

NMR (l3) :

1,16-2,09 (N, multiplet), 2,84 (2H, broadened doublet), 2,40-of 2.56 (4H, multiplet), 4,47 (2H, singlet), 7,06 (1H, doublet, j = = 9,3 Hz), 7.23 percent (5H, singlet), of 7.97 (1H, doublet, j = 2.6 Hz), 8,08 (1H, two doublet, j = 2,6 Hz and 9.3 Hz).

Mass spectrum: (M + 1+) = 396 (FAB).

Melting point: 225,3-227,1aboutC (decomp. ). Molecular formula: C22H25ClN2O2:

1,20-2,08 (N, multiplet), and 2.83 (2H, broadened doublet), 3,35-to 3.52 (4H, multiplet), to 4.33 (2H, singlet), 6,85 (1H, doublet, j = = 9,0 Hz),? 7.04 baby mortality (1H, two doublet, j = 2,8 Hz and 9.0 Hz), 7,22 (6N, broadened singlet).

Mass spectrum: (M + 1+) = 385 (FAB).

Melting point: amorphous substance. is, broadened singlet), 3,36-to 3.52 (4H, multiplet), 3,81 (6N, singlet), or 4.31 (2H, singlet), 6,47 (1H, doublet, j = 1,8 Hz), 7,22 (6N, broadened singlet).

Mass spectrum: (M + 1+) = 411 (FAB).

Melting point: 189,1-189,8aboutC. Molecular formula: C21H24N4O42HCl. NMR (l3) :

1,21-2,15 (N, multiplet), 2,82 (2H, broadened doublet), 3,42-3,62 (4H, multiplet), 4,56 (2H, singlet), 7,06 (1H, doublet, j = = 8,2 Hz), from 7.24 (2H, doublet, IK = 6.2 Hz), 8,03-8,15 (2H, multiplet), 8,44 (2H, doublet, j = 6.2 Hz).

Mass spectrum: (M + 1+) = 397 (FAB).

Melting point: amorphous substance. Molecular formula: C22H27N3O22HCl. NMR (l3) :

1,16-2,07 (N, multiplet), 2,82 (2H, broadened doublet), 3,32-of 3.48 (4H, multiplet), to 3.92 (2H, broadened singlet), 4,24 (2H, singlet), 6,30 (1H, doublet, j = 2.3 Hz), 6,46 (1H, Quartet, j = 2.3 Hz and 8.7 Hz), 6,72 (1H, doublet, j = 8.7 Hz), 7,22 (5H, broadened singlet).

Mass spectrum: (M + 1+) = 366 (FAB).

ONH melting point: amorphous substance. Molecular formula: C24H29N3O3HCl. NMR (l3) :

1,16-2,12 (N, multiplet), and 2.14 (3H, singlet), 2,84 (2H, broadened doublet), of 3.45 (4H, broadened singlet), to 4.33 (2H, singlet), is 6.78 (1H, doublet, j = 9.5 Hz), 7,14-7,28 (6N, multiplet), 7,63 (1H, broadened sin is the substance. Molecular formula: C23H26N2O3HCl. NMR (l3) :

1,24-2,12 (N, multiplet), is 2.40 (3H, singlet), of 2.86 (2H, broadened doublet), 3,47 (2H, singlet), of 4.00 (2H, broadened triplet), 7,00-7,44 (7H, multiplet), 7,76 (1H, broadened singlet).

Mass spectrum: (M + 1+) = 379 (FAB).

Melting point: 195,1-195,8aboutMolecular formula: C23H26N2O4HCl. NMR (l3) :

of 1.34 (3H, broadened singlet), of 1.65 (2H, broadened singlet), of 1.74 (2H, broadened singlet), of 1.95 (2H, broadened triplet), 2,87 (2H, broadened doublet), of 3.48 (2H, singlet), 3,86 (3H, singlet), of 4.05 (2H, extended triplet, j = 2.0 Hz and 7.2 Hz), 7,19 (1H, doublet, j = 9.4 Hz), 7,24 (1G, Quartet, j = 3.0 Hz, 9.4 Hz), 7,31 (5H, broadened singlet), was 7.45 (1H, doublet, j = 3.0 Hz).

Mass spectrum: (M + 1+) = 395 (FAB).

Melting point: 199,5-200,4aboutC. Molecular formula: C22H23FN2O3HCl. NMR (l3) :

of 1.34 (3H, broadened singlet), 1,63-of 1.66 (2H, multiplet), 1,73-to 1.77 (2H, multiplet), of 1.95 (2H, broadened triplet), of 2.86 (2H, broadened doublet), of 3.48 (2H, singlet), Android 4.04 (2H, doublet and triplet, j = 4.0 Hz and 5.2 Hz), 7.23 percent-7,28 (6N, multiplet), 7,37-7,42 (1H, multiplet), 7,71-7,73 (1H, multiplet).

Mass spectrum: (M + 1+) = 383 (FAB).

Melting point: -1,41 (3H, multiplet), 1,60-of 1.66 (2H, broadened Quartet of 1.73 to 1.76 (2H, broadened doublet), to 2.06 (2H, triplet, I = 11.2 Hz), to 2.55 (2H, doublet, j = 4.4 Hz), 2,98 (2H, broadened doublet), 3,83-3,86 (2H, multiplet), 3,94-3,98 (2H, multiplet), was 4.02-4,06 (2H, multiplet), 4.09 to (1H, triplet, j = 4.4 Hz), 7,25-7,28 (1H, multiplet), 7,37-7,42 (1H, multiplet), 7,72 (1H, Quartet, j = 2,6 Hz and 7.2 Hz).

Mass spectrum: (M + 1+) = 379 (FAB).

Melting point: 210,5-211,4aboutMolecular formula: C22H32N2O3HCl. NMR (l3) :

1,15-1,20 (2H, multiplet), 1,25-to 1.38 (3H, multiplet), 1,51-1,60 (6N, multiplet), 1,72-of 1.78 (4H, multiplet), of 1.93 (2H, triplet, j = 9.6 Hz), to 2.06 (1H, multiplet in), 2.25 (2H, two doublet, j = 2.0 Hz and 7.2 Hz), 2.91 in (2N, broadened doublet), 3,45-to 3.49 (2H, multiplet in), 3.75 (3H, singlet), to 4.38 (2H, singlet), 6, 58 (1H, singlet), 6,76 (1H, doublet, j = 10.0 Hz), 6,91 (1H, doublet, j = 10.0 Hz).

Mass spectrum: (M + 1+) = 373 (FAB).

Melting point: 206,5-207,8aboutMolecular formula: C23H34N2O3HCl. NMR (l3) :

0,81-0,89 (2H, multiplet), 1,09 is 1.23 (3H, multiplet), of 1.23 and 1.35 (2H, multiplet), of 1.46 (1H, multiplet), 1,54 to 1.76 (10H, multiplet), of 1.84 (2H, broadened triplet), of 2.08 (2H, doublet, IK = 7,2 Hz), 2,84 (2H, broadened doublet), 3,49 (2H, multiplet), 3,76 (3H, singlet), to 4.41 (2H, singlet), 6,60 (1H, doublet, I = 2,8 Hz), 6, C melting point: 205,9-207,2aboutC (decomp. ). Molecular formula: C23H32N2O4HCl. NMR (l3) :

from 0.84 to 0.92 (2H, multiplet), 1,15-1,25 (3H, multiplet), 1,36-of 1.42 (2H, multiplet) and 1.51 (1H, multiplet), 1,63-of 1.78 (10H, multiplet), of 1.93 (2H, triplet, j = a 10.6 Hz), of 2.15 (2H, doublet, j = 7,2 Hz), 2.91 in (2N, broadened doublet), a 3.87 (3H, singlet), 4,06 (2H, multiplet), 7,19 (1H, doublet, j = 8,8 Hz), to 7.25 (1H, two doublet, j = 2,8 Hz and 8.8 Hz), was 7.45 (1H, doublet, j = 2,8 Hz).

Mass spectrum: (M + 1+) = 401 (FAB).

Melting point: 119,5-120,8aboutC. Molecular formula: C21H26N2O4x C4H4O4< / BR>
NMR (l3) :

of 1.28 and 1.33 (3H, multiplet), 1,58-of 1.62 (2H, multiplet), and 1.63 and 1.75 (2H, multiplet), of 1.93 (2H, broadened triplet), 2,90 (2H, broadened doublet), 3,37 (2H, singlet), 3,50 (2H, multiplet), of 3.78 (3H, singlet), to 4.41 (2H, singlet), 6,38 (1H, two doublet, j = 0.8 Hz and 1.6 Hz), 6,60 (1H, doublet, j = 2,8 Hz), 6,79 (1H, two doublet, j = 2,8 Hz and 8.8 Hz), to 6.95 (1H, doublet, j = 8,8 Hz), 7,32 (1H, two doublet, I = 0,8 Hz and 1.6 Hz), 7,37 (1H, triplet, j = 1.6 Hz).

Mass spectrum: (M + 1+) = 371 (FAB).

Melting point: 155, 3mm-156,0aboutC. Molecular formula: C21H24N2O5x C4H4O4. NMR (l3) :

1,30 was 1.43 (3H, multiplet), 1,62 by 1.68 (2H, multiplet), of 1.76 and 1.80 (2H, multipliable, I = 3.2 Hz), of 6.31 (1H, two doublet, j = 3.2 Hz and 6.4 Hz), 7,19 (1H, doublet, j = 8,8 Hz), 7,20-7,28 (2H, multiplet), was 7.36-7,37 (1H, multiplet), was 7.45 (1H, doublet, j = 3.2 Hz).

Mass spectrum: (M + 1+) = 385 (FAB).

Melting point: 162,9-163,6aboutC. Molecular formula: C21H23N2O5x C4H4O4. NMR (l3) :

1,30-to 1.38 (3H, multiplet), 1,62-of 1.66 (2H, multiplet), 1,77-to 1.79 (2H, multiplet), was 1.94 (2H, broadened triplet), 1,90 (2H, broadened doublet), 3,37 (2H, singlet), a 3.87 (3H, singlet), of 4.05 (2H, multiplet), 6,38 (1H, broadened singlet), 7,19 (1H, doublet, IK = 9,2 Hz), 7,32 (1H, broadened singlet), 7,37 (1H, broadened singlet), 7,44 (1H, doublet, j = 2,8 Hz).

Mass spectrum: (M + 1+) = 385 (FAB).

Melting point: 113,3-113,8aboutC. Molecular formula: C21H26N2O4x C4H4O4. NMR (l3) :

1,31-to 1.38 (3H, multiplet), 1,56-of 1.62 (2H, multiplet), at 1.73 (2H, broadened doublet), of 1.97 (2H, triplet, j = 11.0 in Hz), is 2.88 (2H, broadened doublet), of 3.48 (2H, multiplet), 3,51 (2H, singlet), of 3.77 (3H, singlet), and 4.40 (2H, singlet), 6,18 (1H, doublet, j = 3.2 Hz), 6,30 (1H, two doublet, I = 2,0 Hz and 3.2 Hz), 6,59 (1H, doublet, j = 2,8 Hz), 6,79 (1H, two doublet, I = 2,8 Hz and 8.8 Hz), 6,93 (1H, doublet, j = 8,8 Hz), was 7.36 (1H, doublet, j = 2.0 Hz).

Mass spectrum: (M + 1+) = 37 2 x C4H4O4< / BR>
NMR (l3) :

1,31-of 1.36 (3H, multiplet), 1,69 to 1.76 (4H, multiplet), of 1.95 (2H, broadened triplet), is 2.88 (2H, broadened doublet), 3,49 (2H, singlet), 3,85 (2H, triplet, j = 7.4 Hz), to 6.95 (1H, doublet, j = 7,6 Hz), 7,10-7,31 (8H, multiplet).

Mass spectrum: (M + 1+) = 337 (FAB).

HClMelting point: 217,9-219,2aboutC (decomp. ). Molecular formula: C20H22N2O2HCl.

NMR (l3) :

1,72-of 1.78 (2H, multiplet), 1,84-of 1.94 (2H, multiplet), 2,11-of 2.16 (2H, multiplet), 2,99 (2H, broadened doublet), 3,52 (2H, singlet), to 4.33 (1H, multiplet), 4,39 (2H, singlet), 7,03 (1H, doublet, j = 8.0 Hz), 7,10-7,11 (2H, multiplet), 7,24-7,33 (6N, multiplet).

Mass spectrum: (M + 1+) = 323 (FAB).

Melting point: 178,5-179,1aboutC. Molecular formula: C21H26N2O3S x C4H4O4.

NMR (l3) :

1,28-to 1.38 (3H, multiplet), 1,57-to 1.61 (2H, multiplet), 1,71-of 1.73 (2H, multiplet), to 1.98 (2H, broadened triplet), only 2.91 (2H, broadened doublet), of 3.48 (2H, multiplet), 3,70 (2H, singlet), 3,76 (3H, singlet), 4,39 (2H, singlet), 6,59 (1H, doublet, j = 1.2 Hz), 6,78 (1H, two doublet, j = 1.2 Hz and 8.8 Hz), 6,88-6,94 (3H, multiplet), 7,20 (1H, doublet, j = 4,8 Hz).

Mass spectrum: M+= 386 (D1-E1).

Temperature >

NMR (l3) :

1,24-of 1.36 (3H, multiplet), 1,61-to 1.63 (2H, multiplet), 1,72-of 1.74 (2H, multiplet), with 1.92 (2H, broadened triplet), 2,89 (2H, broadened doublet), 3,48-of 3.53 (2H, multiplet), 3,53 (2H, singlet), of 3.78 (3H, singlet), to 4.41 (2H, singlet), 6,60 (1H, doublet, j = 2,8 Hz), 6,79 (1H, two doublet, j = 2,8 Hz and 8.8 Hz), of 6.96 (1H, doublet, j = 8,8 Hz), 7,05 (1H, two doublet, j = 0.8 Hz and 5.0 Hz), 7,11 (1H, broadened singlet), 7,25-7,27 (1H, broadened singlet).

Mass spectrum: M+= 386 (D1-E1).

C HClMelting point: amorphous substance. Molecular formula: C20H28N2O5HCl. NMR (l3) :

1,26 was 1.43 (3H, multiplet), 1,59-to 1.67 (2H, multiplet), of 1.74 (2H, broadened doublet), of 2.08 (2H, triplet), of 2.56 (2H, doublet), of 3.00 (2H, doublet), 3,52 (2H, triplet), 3,83-3,90 (2H, multiplet), 3,86 (3H, singlet), 3,92-4,00 (2H, multiplet), 4,37 (2H, singlet), 5,00 (1H, two doublet), 6,63 )2N, two doublet), 7,21 (1H, triplet).

Mass spectrum: (M + 1+) = 377 (FAB).

C melting point: 194-195aboutC. Molecular formula: C23H25N2O4FHCl. NMR (l3) :

1,30-of 1.41 (3H, multiplet), 1,62 is 1.70 (2H, multiplet), to 1.76 (2H, broadened doublet), of 1.97 (2H, triplet), to 1.87 (2H, doublet), of 3.48 (2H, singlet), 3,88 (3H, singlet), 4,07 (2H, two doublet), 6,92 (1H, triplet), 7,03-7,10 (2H, multiplet), 7,18-7,29 (3H, mulC. Molecular formula: C23H27N2O3FHCl. NMR (l3) :

1,22-of 1.39 (3H, multiplet), 1,58-of 1.65 (2H, multiplet), 1,72 (2H, broadened doublet), a 1.96 (2H, triplet), 2,84 (2H, doublet), of 3.46 (2H, singlet), 3,50 (2H, triplet), of 3.78 (3H, singlet), to 4.41 (2H, singlet), 6,60 (1H, doublet), 6,79 (1H, two doublet), 6,90-6,98 (2H, multiplet), 7,02-7,10 (2H, multiplet), 7,20-7,30 (1H, multiplet).

Mass spectrum: (M + 1+) = 399 (FAB).

Melting point: 100-101oC. Molecular formula: C20H28N2O5.

NMR (l3) :

1,30-of 1.41 (3H, multiplet), to 1.60 (2H, two doublet), 1,72 (2H, doublet), to 2.06 (2H, triplet), of 2.56 (2H, doublet), 2,98 (2H, doublet), 3,49 (2H, two doublet), of 3.78 (3H, singlet), 3,82-4,00 (4H, multiplet), to 4.41 (2H, singlet), 5,00 (1H, triplet), 6,60 (1H, doublet), 6,79 (1H, two doublet), to 6.95 (1H, doublet).

Mass spectrum: (M + 1+) = 377 (FAB).

Melting point: 243 - 244aboutC (decomp. ). Molecular formula: C21H24N2O2HCl. NMR (l3) :

1,25-2,48 (7H, multiplet), 2,72-to 3.02 (2H, multiplet), 3,32 (2H, doublet), of 3.48 (2H, singlet), 4,42 (2H, singlet), 6,98-7,40 (M, multiplet).

Mass spectrum: M+= 336 (FD).

Melting point: 264-265aboutC (decomp. ). Molecular formula: C21H23N2Omultiplet).

Mass spectrum: M++ 1 = 416 (FD).

M+- 1 = 414 (FD).

Melting point: 261-263aboutC (decomp. ). Molecular formula: C21H25N3O2HCl. NMR (l3) :

1,16-of 2.26 (7H, multiplet), 2,48 (3H, singlet), was 2.76 was 3.05 (2H, multiplet), 3,32 (2H, doublet), of 3.54 (2H, singlet), 4,48 (2H, singlet), 6,92-7,34 (7H, multiplet).

Mass spectrum: M+= 351 (FD).

Melting point: 116-117aboutC. Molecular formula: C20H21N2O2Br:

1,58-2,48 (6N, multiplet), 2,84-3,18 (2H, multiplet), 3,51 (2H, singlet), Android 4.04-4,30 (1H, multiplet), 4,32 (2H, singlet), at 6.84 (1H, doublet), 7,14-7,40 (7H, multiplet).

Mass spectrum: M+- 1 = 402 (FD)

M+- 1 = 400 (FD).

Melting point: 250-252aboutC (decomp. ). Molecular formula: C20H23N3O2HCl. NMR (l3) : 1,60-2,40 (6N, multiplet), 2,48 (3H, singlet), 2,84-of 3.12 (2H, multiplet), 3,52 (2H, singlet), Android 4.04-4,32 (1H, multiplet), to 4.41 (2H, singlet), 6,88-7,16 (2H, multiplet), 7,25 (5H, broadened singlet).

Mass spectrum: M+= 337 (FD).

Melting point: 210-213aboutC (decomp. ). Molecular formula: C22H27N3O2HCl. NMR (l3) :

1,16-2,15 (N, multiplet), 2,48 (3H, singlet), 2,70-2,96 (2H, multi is 366 (FAB).

< / BR>
Melting point: 183-184aboutC (decomp. ). Molecular formula: C21H26N4O2x 3/2C4H4O4.

NMR (l3) :

1,08-2,20 (N, multiplet), 2,49 (3H, singlet), 2,64-2,96 (2H, multiplet), 3,44 (2H, singlet), 3,50 (3H, triplet), 4,47 (2H, singlet), 6,88-7,30 (4H, multiplet), 8,44 (2H, doublet).

Mass spectrum: M++ 1 = 367 (FAB).

Melting point: 111aboutC. Molecular formula: C19H27N3O4.

NMR (l3) :

1.27mm and 1.80 (7H, multiplet), of 2.08 (2H, triplet), of 2.53 (3H, singlet), to 2.57 (2H, doublet), 2,99 (2H, doublet), 3,55 (2H, triplet), 3,80-Android 4.04 (4H, multiplet), 4,51 (2H, singlet), 5,00 (1H, triplet), 7,06 (1H, doublet), from 7.24 (1H, doublet).

Mass spectrum: M++ 1 = 362 (FAB).

HCl melting point: 70aboutC. Molecular formula: C22H25N3O3HCl. NMR (l3) :

1,24-of 1.40 (3H, multiplet), 1,62-of 1.84 (4H, multiplet), 1,88-2,05 (2H, triplet), 2,70 (3H, singlet), 2,87 (2H, doublet), of 3.48 (2H, singlet), 4.09 to (2H, triplet), 7,20 and 7.36 (5H, multiplet, of 7.48 (1H, doublet), 7,53 (1H, doublet).

Mass spectrum: M++ 1 = 380 (FAB).

NHClMelting point: 233-235aboutC. Molecular formula: C23H26N2O2HCl. NMR (l3) :

Mass spectrum: (M + 1+) = 363 (FAB).

Melting point: 158-160aboutC (decomp. ). Molecular formula: C18H26N4O3x C4H4O4< / BR>
NMR (l3) :

1,20-1,40 (3H, multiplet), 1,47 is 1.60 (2H, multiplet), 1,65-of 1.78 (2H, multiplet), 2,00 and 2.13 (2H, broadened triplet), 2,53-2,78 (2H, doublet), 2,93-3,03 (2H, doublet), 3,40-3,50 (2H, multiplet), of 3.80-4.00 points (4H, multiplet), to 4.41 (2H, singlet), to 4.98 (1H, triplet), 6,90-6,87 (1H, two doublet), 7,31-7,37 (1H, multiplet), 8,20-of 8.27 (1H, multiplet), remaining 9.08 (1H, singlet).

Mass spectrum: (M + 1+) = 347 (FAB).

Melting point: 262-263aboutC (decomp. ). Molecular formula: C18H24N4O42HCl. NMR (l3) :

1,30-1,45 (2H, multiplet), 1,50-of 1.85 (5H, multiplet), 2,00-of 2.15 (2H, broadened triplet), 2,52-2,60 (2H, doublet), 2,95 was 3.05 (2H, broadened doublet), 3,80-4,15 (6N, multiplet), free 5.01 (1H, triplet), 7,20-7,27 (1H, multiplet), 8,42-of 8.47 (1H, multiplet), 8,70 is 8.75 (1H, multiplet), 10,96 (1H, broadened singlet),< / BR>
Mass spectrum: (M + 1+) = 361 (FAB).

Melting point: 166-168aboutC. Molecular formula: C19H24N4O6HCl. NMR (l3) :

1,23-to 1.45 (2H, multiplet), 1,50-1,80 (5H, multiplet), 2,00 and 2.13 (2H, broadened triplet), 2,53-2,60 (2H, doublet), 2,95 was 3.05 (2H, broadened doublet), 3,80-4, inglet).

Mass spectrum: (M + 1+) = 405 (FAB).

2HClMelting point: 235-238aboutWith rasl. ). Molecular formula: C21H22F2N4O2:

NMR (l3 :

1,08-2,24 (N, multiplet), 2,64 totaling 3.04 (2H, multiplet), of 3.48 (2H, singlet), 3,92-4,24 (2H, multiplet), 6,52-to 7.00 (3H, multiplet), 7,12-7,40 (1H, two doublet), 8,32-charged 8.52 (1H, two doublet), 8,56-8,72 (1H, two doublet).

Mass spectrum: (M + 1+) = 401 (FAB).

Melting point: 245-247aboutC (decomp. ). Molecular formula: C23H26N4O22HCl. NMR (l3) :

1,08-2,24 (N, multiplet), was 2.76 of 3.28 (4H, multiplet), 3,80-4,20 (2H, multiplet), 6,04-only 6.64 (2H, multiplet), 7,00-7,40 (6N, multiplet), 8,24-8,48 (1G, two doublet), 8,56-8,76 (1H, two doublet).

Mass spectrum: (M + 1+) = 391 (FAB) .

Melting point: 182-184aboutC. Molecular formula: C20H23N5O2x C4H4O4< / BR>
NMR (l3) :

1,08-2,28 (N, multiplet), 2,64-of 3.00 (2H, multiplet), 3,44 (2H, singlet), 3,84-4,20 (2H, multiplet), 7,00 was 7.36 (3H, multiplet), 8,24-8,80 (4H, multiplet).

Mass spectrum: (M + 1+) = 366 (FAB).

2HClMelting point: 220aboutC (decomp. ). Molecular formula: C21H23FN4O22(2H, multiplet), 6,76 and 7.36 (5H, multiplet), 8,28-8,48 (1H, two doublet), 8,60-8,76 (1H, multiplet). Mass spectrum: (M + 1+) = 383 (FAB).

Melting point: 220-222aboutC (decomp. ). Molecular formula: C21H24N4O22HCl. NMR (l3) :

1,00-2,20 (N, multiplet), 2,60-of 3.00 (2H, multiplet), 3,44 (2H, singlet), 3,88-4,20 (2H, multiplet), 7,08 and 7.36 (6N, multiplet), 8,28-8,48 (1H, two doublet), 8,60-8,76 (1H, two doublet).

Mass spectrum: (M + 1+) = 365 (FAB).

N HClMelting point: amorphous substance. Molecular formula: C27H34N2O3HCl. NMR (l3) :

1,04-2,20 (N, multiplet), 2,56-of 3.00 (4H, multiplet), 3,12-3,80 (6N, multiplet), 3,88-4,32 (3H, multiplet), 6,72-7,72 (N, multiplet).

Mass spectrum: M+= 434 (FD).

Melting point: amorphous substance. Molecular formula: C27H34N2O3HCl. NMR (l3) :

1,00-2,40 (N, multiplet), 2,48 totaling 3.04 (4H, multiplet), is 3.08-4,28 (N, multiplet), 6,80-7,00 (2H, doublet), 7,08 and 7.36 (5H, multiplet), 7,72-of 7.96 (2H, doublet).

Mass spectrum: M+= 434 (FD).

Melting point: 138,8-139,2aboutC. Molecular formula: C21H28N2O5x C4H4O4.

NMR (l3) :

Mass spectrum: M+= 389 (FAB).

HOOC melting point: 152-152,8aboutC. Molecular formula: C21H30N2O4x C4H4O4< / BR>
NMR (l3) :

1,30-2,10 (13H, multiplet), 2,18 is 2.51 (2H, multiplet), a 3.01 (2H, broadened triplet), 3,49 (2H, multiplet), 3,70-3,68 (1H, multiplet), of 3.77 (3H, singlet), 3,82-3,88 (1H, multiplet), 4,01-4,08 (1H, multiplet), to 4.41 (2H, singlet), 6,64-6,84 (2H, multiplet), 6,94-of 6.96 (1H, multiplet).

Mass spectrum: M+= 375 (FAB).

COOH melting point: 171,8-172,2aboutC. Molecular formula: C22H28N2O4.

NMR (l3) :

1,31-to 1.38 (3H, multiplet), 1,58 by 1.68 (4H, multiplet), 1,86 is 2.00 (2H, multiplet), a 2.01 (3H, singlet), is 2.88 (2H, broadened doublet), of 3.46 (2H, singlet), 3,50 (2H, broadened triplet), of 3.78 (3H, singlet), and 4.40 (2H, singlet), 6,60 (1H, doublet, j = 2,8 Hz), 6,72 (1H, doublet, j= 1.4 Hz), 6,79 (1H, two doublet, I = 2,8 Hz and 9.0 Hz), to 6.95 (1H, doublet, j = 9.0 Hz), 7,28 (1H, doublet, j = 1.4 Hz).

Mass spectrum: M+= 385 (FAB).

HOOC melting point: 190,2-190,8aboutC. Molecule The>1,32-to 1.38 (3H, multiplet), 1,62-of 1.66 (2H, multiplet), 1,72-to 1.79 (2H, multiplet), 1,99 (2H, broadened triplet), 292 (2H, broadened doublet), 3,71 (2H, singlet), a 3.87 (3H, singlet), was 4.02-of 4.05 (2H, multiplet), 6,88-of 6.90 (1H, multiplet), 7,18-7,26 (4H, multiplet), 7,43-7,46 (1H, multiplet).

Mass spectrum: M+= 101 (FAB).

COOH melting point: 197,2-198,0aboutC. Molecular formula: C21H24N2O4S x C4H4O4.

NMR (l3) :

1,33-to 1.38 (3H, multiplet), 1,62-to 1.67 (2H, multiplet), a 1.75-of 1.78 (2H, multiplet), of 1.95 (2H, broadened triplet), 2,89 (2H, broadened doublet), 3,52 (2H, singlet), a 3.87 (3H, singlet), Android 4.04-4,07 (2H, multiplet), 7,05 (1H, doublet, j = 4,8 Hz), 7,10 (1H, broadened singlet), 7,19 (1H, doublet, j = 8,8 Hz), of 7.23-7,27 (2H, multiplet), was 7.45 (1H, doublet, j = = 2,8 Hz).

Mass spectrum: M+= 401 (FAB).

P R I m e R 81. Fumarate[(N-benzyl-N-methyl)-5-aminopentyl] -6-methoxy-2H-3,4-di - hydro - 1,3-benzoxazin-2-it:

CH3O

To of 1.62 g of 1-benzyl-1-methyl-1,5-diaminopentane add 10 ml of methanol to obtain a solution, which was stirred at room temperature. To the solution was added to 0.98 ml of 5-methoxysalicylaldehyde aldehyde and the solution is stirred as such for 20 minutes the Reaction mixture is cooled with ice and add small p is eshiwani at room temperature for additional 30 min, the solvent is distilled off. To the mixture is added saturated aqueous sodium bicarbonate solution and ethyl acetate and the solution thoroughly mixed. So produced organic layer is separated. The aqueous layer was extracted with ethylacetate. The organic layer and the extract unite together and washed with a saturated aqueous solution of common salt. After drying over magnesium sulfate the solvent is distilled off. To the residue add 30 ml of tetrahydrofuran to obtain a solution. To the solution add 1,91 g of N, N-carbonyldiimidazole, and the resulting solution was heated at the boiling reverse drains phlegmy for 3 hours the Solvent is distilled off. Thus obtained oily reaction product is purified by column chromatography on silica gel to obtain 1.44 g of colorless oily reaction product, which is dissolved in methanol. To the solution was added a solution of 0.45 g of fumaric acid in methanol. The solvent is distilled off to obtain 1.89 g of the above compound as a colorless amorphous substance. Melting point: amorphous substance. Molecular formula: C22H28N2O3x C4H4O4.

NMR (l3) :

1,33-of 1.41 (2H, multiplet), 1,52 is 1.70 (4H,2H, singlet), 6,59 (1H, doublet, j = 2,8 Hz), to 6.80 (1H, two doublet, j = 2,8 Hz and 8.8 Hz), of 6.96 (1H, doublet, j = 8,8 Hz), 7,21-7,30 (5H, multiplet).

Mass spectrum: M+= 369 (FAB).

P R I m e R 82. Fumarate [(N-benzyl-N-methyl)-5-aminopentyl] -6-methoxy-2H-3,4-di-hydro-1,3 - benzoxazin-2,4-dione.

< / BR>
To of 1.57 g of 2-methoxymethyl-5-methoxybenzoic acid, add 10 ml of tetrahydrofuran to obtain a solution. To the solution add 1,91 g of N, N-carbonyldiimidazole and the resulting solution was stirred at room temperature for 15 minutes a Solution of 1.43 g of 1-benzyl-1-methyl-1,5-diaminopentane in 5 ml of tetrahydrofuran is added to the mixture. After stirring for an additional 13 h, the solvent is distilled off. The residue is cooled with ice and add to the mixture of 8.3 ml of 5 N. hydrochloric acid and 5 ml of methanol. The resulting solution was stirred at room temperature for 4.5 hours, the Methanol is distilled off under reduced pressure and the residue is cooled with ice. the pH of the reaction mixture is adjusted to 8 with sodium bicarbonate. After extraction with ethyl acetate twice, followed by washing with a saturated aqueous solution of common salt and dried over magnesium sulfate, drives away the solvent. To the residue add 30 tetrahydrofuran, to get the war drains phlegmy for 16 PM The solvent is distilled off. Thus obtained oily reaction product is purified by column chromatography on silica gel to obtain 2.16 g of colorless oily reaction product, which is dissolved in pentanol. To the solution was added a solution of 0.66 g of fumaric acid in methanol. The solvent is distilled off to obtain 2,82 g of the named compound as a colorless amorphous substance. Melting point: amorphous substance. Molecular formula: C22H26N2O4x C4H4O4.

NMR (l3) :

of 1.40 (2H, broadened quintet), of 1.57 (2H, broadened quintet), 1,72 (2H, broadened quintet), 2,17 (3H, singlet), is 2.37 (2H, triplet, j = 7,2 Hz), 3,47 (2H, singlet), a 3.87 (3H, singlet), a 4.03 (2H, triplet, j = 7,6 Hz), 7.18 in-7,44 (8H, multiplet).

Mass spectrum: M+= 383 (FAB).

(M + 1+).

P R I m e R s 83-87. The following connections get in the same way as in Examples 81 and 82.

HOOC melting point: amorphous substance. Molecular formula: C18H26N2O5x C4H4O4.

NMR (l3) :

1,49-of 1.74 (4H, multiplet), 2,32 (3H, singlet), 2,48 (2H, triplet, j = 7,2 Hz), to 2.57 (2H, doublet, j = 4.5 Hz), 3, = 4.5 Hz), 6,59 (1H, doublet, j = 3.2 Hz), 6,79 (1H, two doublet, j = 3.2 Hz and 8.8 Hz), of 6.96 (1H, doublet, j = 8,8 Hz).

Mass spectrum: M+= 351 (FAB)

(M + 1+)

Melting point: amorphous substance. Molecular formula: C21H26N2O2x C4H4O4.

NMR(l3) :

of 1.03 (3H, triplet, j= 7,2 Hz) and 1.51 (2H, quintet, j = 7,6 Hz) of 1.66 (2H, quintet, j = 7,6 Hz), 2,46 (2H, triplet, j = 7,2 Hz), 2,50 (2H, Quartet, j = 7.5 Hz), 3,42 (2H, triplet, j = 7,6 Hz), of 3.54 (2H, singlet), 4,39 (2H, singlet), 6,99-7,11 (4H, multiplet), 7,19-to 7.32 (5H, multiplet).

Mass spectrum: M+= 339 (FAB).

(M + 1+).

Melting point: amorphous substance.

Molecular formula: C21H26N2O5x C4H4O4.

NMR (l3) :

of 1.06 (3H, triplet, j = 7,2 Hz), of 1.37 (2H, quintet, j = 7.2 Hz), 1,45 is 1.58 (2H, multiplet), 1,72 (2H, quintet, j = 7.5 Hz), 2,43 (2H, triplet, j = 7,6 Hz), of 2.51 (2H, Quartet, j = 7,2 Hz), to 3.64 (2H, singlet), a 3.87 (3H, singlet), a 4.03 (2H, triplet, IK = 7.5 Hz), x 6.15 (1H, doublet, j = 3.0 Hz), 6,30 (1H, two doublet, j = 3.2 Hz and 2.0 Hz), 7,20 (1H, doublet, j = 8,8 Hz), 7,25 (1H, two doublet, j = 3.0 Hz and 8.8 Hz), 7,34 and 7.36 (1H, multiplet), 7,46 (1H, doublet, j = 3.2 Hz).

Mass spectrum: M+= 387 (FAB)

(M + 1+)

Melting point: and the x2">

NMR (l3) :

of 1.05 (3H, triplet, j = 7,1 Hz), 1,33-to 1.38 (4H, multiplet), 1,45-of 1.53 (2H, multiplet), 1,62 is 1.70 (2H, multiplet), 2,43 (2H, triplet, j = 7.4 Hz), 2,53 (2H, Quartet, j = 7,1 Hz), of 3.45 (2H, triplet, j = 7,6 Hz), with 3.79 (2H, singlet), 4,42 (2H, singlet), to 6.80 (3H, multiplet), 7,07-7,10 (1H, multiplet), 7,18-7,24 (2H, multiplet).

Mass spectrum: M+= 407 (FAB)

(M + 1+).

Melting point: amorphous substance Molecular formula: C20H24ClN3O3x CH4H4O4< / BR>
NMR (l3) :

of 1.05 (3H, triplet, j = 7,2 Hz), of 1.39 (2H, broadened quintet), and 1.56 (2H, broadened quintet), 1,72 (2H, broadened quintet), 2,33 (2H, triplet, j = 7,2 Hz), of 2.51 (2H, Quartet, j = 7,2 Hz), to 3.64 (2H, singlet), 4,06 (2H, triplet, j = 7,6 Hz), x 6.15 (1H, doublet, j = 3,4 Hz), of 6.29 (1H, two doublet, I = 2,0 Hz and 3.4 Hz), 7,05 (1H, doublet, j = 8,8 Hz), 7,35 (1H, two doublet, j = 0.8 Hz and 2.0 Hz), 7,54 (1H, two doublet, I = 2,3 Hz and 8.8 Hz), 8,10 (1H, doublet, j = 2.3 Hz).

Mass spectrum: M+= 390 (FAB)

(M + 1+). (56) Ellman, G. L. et al. Biochem Pharmacol, 1961, v. 7, R. 88-95.

Derivatives of cyclic amide of General formula

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 - tetrahydro - is 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 9H - 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 - e) benzazepin - 9 - it, isoindoline-1,3 - dione, benzoxazolyl - 2 - it, unsubstituted or substituted lower alkyl, lower alkoxygroup, a halogen, a nitro-group, amino group, acetylamino, carboxy, benzoyl or benzyl;

n= 0 - 6 - integer;

Z is a group of formula A or B:

N-(CH2)mR2(A)

or

-(CH2)p-R4(B)

where R2is phenyl, substituted with halogen, phenyl, C5- C6-cycloalkyl or a radical of pyridine, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene;

m= 1 - 3 - integer;

R3is lower alkyl;

R4is phenyl or a radical of dioxolane, furan or thiophene;

p = 1,

if R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R

 

Same patents:

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: 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: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes 2-phenyl-substituted imidazotriazinones of the general formula (I): wherein R1 and R2 mean independently linear (C1-C4)-alkyl; R3 and R4 are similar or distinct and represent hydrogen atom or linear or branched (C1-C4)-alkenyl or (C1-C4)-alkoxy-group, linear or branched (C1-C6)-alkyl chain that can be broken by oxygen atom, and/or it can comprise from to some similar or different the following substitutes: methoxy-, hydroxy-, carboxyl, linear or branched (C1-C4)-alkoxycarbonyl, and/or residues of formulae -SO3H, -(A)a-NR7R8, -O-CO-NR7'R8', and/or wherein A means a number 0 or 1; A means residue -CO or -SO2; R7 and R8 mean hydrogen atom (H), cyclopentyl, cyclohexyl, cycloheptyl, phenyl, piperidinyl or pyridyl that can be substituted with different substitutes, methoxy-, (C1-C6)-alkyl and others; R7' and R8' mean (C1-C6)-alkyl. Also, other values of radicals R3 and R4 are given, a method for their preparing and a pharmaceutical composition. Described compounds are inhibitors of phosphodiesterases and can be used in manufacturing agents showing an anti-thrombosis, anti-proliferative, anti-vasospastic and vasodilating effect.

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

10 cl, 6 tbl, 337 ex

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

SUBSTANCE: invention relates to new derivatives of propene carboxylic acid amidooximes of the formula (I):

wherein R means phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R' means hydrogen atom (H); R4 and R5 mean independently of one another H, (C1-C5)-alkyl, phenyl that is substituted optionally with 1-3 substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; or R4 and R5 in common with adjacent nitrogen atom form 5- or 6-membered saturated or unsaturated heterocyclic group that can comprise additional nitrogen atom or oxygen atom as a heteroatom and it can be condensed with benzene ring, and heterocyclic group and/or benzene ring can comprise one or two substitutes wherein substitute means (C1-C2)-alkyl or (C1-C2)-alkoxy-group; R1 and R2 mean H; R3 means H, OH; or R1 in common with R2 forms carbonyl group wherein carbon atom is joined with oxygen atom adjacent with R1 and with nitrogen atom adjacent with R2; R3 means H, OH; or R2 means H; and R1 in common with R3 form a valence bond between oxygen atom adjacent with R1 and carbon atom adjacent with R3; and its geometric isomers and/or optical isomers, and/or its pharmaceutically acceptable acid-additive salts. Compounds of the formula (I) inhibit activity of poly(adenisone diphosphate ribose) polymerase and can be used in pharmaceutical composition in treatment of states based on inhibition of this enzyme activity, and in treatment of states associated with oxygen insufficiency of heart and brain. Also, invention describes methods for preparing compounds of the formula (I).

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

9 cl, 1 tbl, 41 ex

Antagonist npy y5 // 2264810

FIELD: medicine, pharmacology.

SUBSTANCE: the present innovation deals with applying pharmaceutical composition as an antagonist of NPY Y5 receptor that contains the compound of formula I

, moreover, it deals with compounds of formula I and method for treating obesity and suppressing food intake, as well.

EFFECT: higher efficiency of therapy.

18 cl, 13 ex, 6 tbl

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

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

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: pharmaceutics.

SUBSTANCE: the present innovation deals with surgical, antiseptic, antiphlogistic and wound-healing glue that contains collagen hydrolyzate, sodium salt of alginic acid, catapol, dioxidin, poviargol; additionally, it contains glycerol, nipagin, nipasol and aqueous solution of sodium hypochlorite. The innovation provides increased antimicrobial activity and regulation of biodegradation rate of covering depending upon the level of inflammatory process in the wound that leads to faster wound healing.

EFFECT: higher efficiency of application.

4 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes using the compound (R/S)-(-/+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or their salts for preparing a medicinal agent. This agent is used in treatment of extrapyramidal motor disorders, in particular, in treatment of unfavorable effects of anti-parkinsonic preparations and using (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman in combination with an anti-parkinsonic preparation for preparing the combined medicinal agent. Also, invention relates to a pharmaceutical composition for treatment of extrapyramidal disorders and a set of the same designation. Proposed compounds are able to prevent catalepsy caused by usual anti-dopaminergic preparations and they are strong agonists of 5-HT1A-receptors in combination with antagonism to dopamine D2-receptors and interaction with D3-receptors that provides positive effects on extrapyramidal system in treatment of dyskinesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to cyclopentyl compounds of the general formula (I): wherein X means carbon (C), nitrogen (N) or oxygen (O) atom; Y means O; Z means C; R1 means hydrogen atom, -(C0-C6)-alkyl-W-(C1-C6)-alkyl-, -(C0-C6)-alkyl-W-(C0-C6)-alkyl-(C3-C7)-cycloalkyl-(C0-C6)-alkyl wherein alkyl and cycloalkyl are optionally substituted with 1-7 independent substitutes chosen from hydroxy-group, -O-(C1-C3)-alkyl, trifluoromethyl, (C1-C3)-alkyl; W means a simple bond, -O-, -CO-, -CO2-, -CONR10- or -NR9-; R2 means -(C0-C6)-alkyl, (C0-C6)-alkyl-W-(C1-C6)-alkyl or (C0-C6)-alkyl-W-(C3-C7)-cycloalkyl wherein (C1-C6)-alkyl, (C3-C7)-cycloalkyl are optionally substituted with 1-6 substitutes chosen from halogen atom, trifluoromethyl, -(C1-C6)-alkyl; R3 means hydrogen atom, -(C0-C6)-alkyl-phenyl, -(C0-C6)-alkyl-heterocycle, -(C0-C6)-alkyl-(C3-C7)-cycloalkyl, -(C0-C6)-alkyl-CO2R10, -(C0-C6)-alkyl-(alkene)-CO2R10, -(C0-C6)-alkyl-SO3H, -(C0-C6)-alkyl-W-(C0-C4)-alkyl, -CONR10N10- or -NR10CO2R10-, -NR10-(C0-C3)-alkyl-CO2R10- wherein phenyl and heterocycle, cycloalkyl or (C0-C6)-alkyl are optionally substituted with 1-5 independent substitutes chosen from halogen atom, trifluoromethyl, hydroxy-group, (C1-C3)-alkyl, -O-(C0-C3)-CO2R10, -CN, =O, -NR10R10, -CONR10R10, -SO3-R10 or -(C0-C3)-alkyl-heterocycle and wherein phenyl can be condensed with heterocycle that the latter can be substituted with 1-2 hydroxyl groups; R4 is absent if X represents O or N, or if a double bond joints carbon atoms to which R3 and R6 are added, or R4 means hydroxy-group, -(C0-C6)-alkyl, -CN, -(C0-C3)-CO2R10; or R3 and R4 are combined and form 1H-indenyl, 2,3-dihydro-1H-indenyl, cyclopentanyl or cyclohexanyl ring wherein this obtained cycle is optionally substituted with 1-5 substitutes chosen independently from hydroxy-group, (C1-C3)-alkyl, -O-(C1-C3)-alkyl and -(C0-C3)-CO2R10; or R3 and R5, or R4 and R6 are combined and form phenyl or heterocyclic ring wherein this ring is optionally substituted with 1-7 independent substitutes chosen from hydroxy-group, (C1-C3)-alkyl, -O-(C1-C3)-alkyl, -CO2R10; R5 and R6 mean independently hydrogen atom, hydroxy-group, (C1-C6)-alkyl or (C0-C6)-alkyl-CO2R10; if Z means C then R7 means hydrogen atom, (C1-C6)-alkyl; R8 means hydrogen atom; R10 means hydrogen atom, -(C1-C6)-alkyl, benzyl, phenyl or -(C0-C6)-alkyl-(C3-C6)-cycloalkyl; n1 and n2 = 0, 1 or 2 independently and the sum n1 + n2 = 0, 1, 2 or 3; a dotted line represents a simple or double bond, and other

compounds of this series. Also, invention relates to a pharmaceutical composition modulating activity of chemokine receptors, a method for modulation of activity of chemokine receptors in mammals, and to a method for treatment, improving, regulating or decreasing risk of inflammatory and immunoregulatory disorder or disease. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

21 cl, 4 tbl, 81 ex

Up!