Derivatives of n-phenylglycine, the method of production thereof and pharmaceutical composition having an affinity for cck receptors and gastrin

 

(57) Abstract:

Usage: in biology and medicine. The essence of the invention: derivatives of N-phenylglycinate General formula I:

R4-H(CHR1COR2)-COCH2NHCOR3,

where R1= hydrogen, (NISS. )alkyl; R2= (ness.)alkoxy or NR5R6; R3= chinolin or phenylaminopropyl, in which phenyl is substituted by one or more substituents selected from halogen, lower alkyl, (lower)ancilliary, carboxyl, monoxi (lower)alkyl, (lower)alkoxycarbonyl, oxyimino(lower)alkyl, tetrazolyl-5-(NISS. )alkyl, (NISS. )alkyl-COOH, -O-(ness.)alkyl-COOH, -CH=SSOON, (ness.)Ala. SO3H; X=hydrogen, NISS.alkyl; R4=phenyl, substituted by halogen, (ness.)the alkyl, (NISS. )alkoxy, hydroxyl; polyflor(ness.)alkyl or (ness.)alkoxy, NO2, (NISS. )alkylthio, (ness.)alkoxycarbonyl, carboxyl, acylamino, methylendioxy, triptoreline, phenoxy, phenyl, di(ness.)alkylamino or CONRaRbwhere Ra= ness. alkyl, Rb= phenyl, or Raand Rbtogether with the nitrogen to which they are attached, form: 1,2,3,4-tetrahydroquinolin-1-OIC, 3,3-di(NISS. )alkylpiperidines, 3,4-dihydro-2H-benzoxazinone or morpholinyl cmom nitrogen, to which they are attached, form a: 3,3-di(NISS. )alkylpiperidines cycle, 3,4-di-hydro-2H-benzothiazin-1,4-new cycle, 1,2,3,4-tetrahydroquinolin-1-OIC cycle. Reagent II - isocyanate: CONR9. Reagent III - amino derivatives: R4-N[CH(R1)COR2]-COCH2NH2. The resulting product is optionally subjected to hydrolysis: compound I is isolated in the form of ester or in free form. If I R3= phenylaminopropyl with substituted phenyl ring, the corresponding ester is subjected to hydrolysis. If I R4= phenyl, substituted hydroxy-group, is subjected to the hydrolysis of the corresponding compound I, where R4= phenyl, substituted lower alkoxygroup. Pharmacological composition having affinity to receptors of CCK and gastrin, containing as the active agent I in a single dose of 10-500 mg of 4 s and 3 C.p. f-crystals, 2 tab.

The invention relates to the synthesis of biologically active compounds, in particular to new derivatives of N-phenylglycinate formula

< / BR>
the way they are received and to farbkomposition based on them.

In the formula (I):

R1hydrogen, (ness.)alkyl;

R2(ness.)alkoxy or NR5R6,

where R5(ness.)alkyl, and R6Fenena too, form 3,3-di(ness.) alkylpiperidines cycle, 3,4-dihydro-2H-benzothiazin-1,4-new cycle or 1,2,3,4-tetrahydroquinolin-1-Oy loop;

R3chinolin or phenylaminopropyl,

in which phenyl substituted by one or more substituents selected from halogen, lower alkyl, (ness.)alkylthio, carboxyl, monoxi(ness.) of alkyl, (ness.)alkoxycarbonyl, oxyimino(ness.)of alkyl, tetrazolyl-5-(NISS. )alkyl, (NISS. )-alkyl-COOH, -O-ness. alkyl-COOH, -CH=CH-COOH, NISS.Ala. SO3H,

X is hydrogen, lower alkyl,

R4phenyl, substituted by halogen, (ness.)the alkyl, (ness.) alkoxy, hydroxyl, polyflor(ness.)by alkyl, nitro, (ness.)alkylthio, (NISS. )alkoxycarbonyl, carboxyla, group acylamino, methylendioxy, polyflor(ness.)alkoxy, triptoreline, phenoxy, phenyl, benzyl, phenylamino, dialkylamino or group CONRaRbin which

Raness. alkyl, Rbphenyl,

or Raand Rbtogether with the nitrogen

to which they are attached and form a 1,2,3,4-tetrahydroquinolin-1-OIC, 3,3-di(NISS. )alkylpiperidines, 3,4-dihydro-2H-benzoxazinone or morpholinyl cycle.

The invention relates also to a method for producing derivatives of N-phenylglycinate General formula I (SUB>9(II)

in which R9represents a phenyl radical (substituted if necessary by one or more substituents selected among halogen atoms and alkyl, alkoxy, alkylthio-, nitro, acyl, cyano, sulfanilic, benzoline, alkoxycarbonyl, AK-O-AC, 5-tetrazole and 5-tetraallylsilane radicals), with the amino derivatives of the formula

< / BR>
in which R1, R2and R4have the same meanings as described above, produce the target product, and optionally the compound of formula I, in which R4is phenyl, substituted by alkoxygroup, is subjected to hydrolysis to obtain the compound I in which R4is phenyl, substituted by hydroxyl, and/or, if necessary, is subjected to hydrolysis of compound I containing the ester group to obtain compound I in the form of the corresponding acid.

This reaction is carried out usually in an inert solvent such as tetrahydrofuran, dimethylformamide, a chlorinated solvent (e.g. chloroform, 1,2-dichloroethane), aromatic solvents (e.g. benzene, toluene) at a temperature that is between 10oC and the boiling point of the solvent.

E R. Richter et coll. The Chemistry of Cyanate and their thio derivatives. S. Patai, part 2, Wiley, New York, or are commercial.

Derivatives with formula (III) can be obtained by application or adaptation of the method described in the examples or the method described in the article by T. Wieland et coll. Justus Liebigs Ann. Chem. or in the adaptation of the Gabriel method (Gibson et coll. Angew. Chem. Int. Ed. 7, 919 (1968)), which is that the effect of the hydrazine with the formula

H2N-OTHER10(IV)

in which R10represents a hydrogen atom or a methyl radical, derived from the formula:

< / BR>
in which R1, R2and R4have the same meanings as in the formula (I).

This reaction is carried out preferably in an inert solvent, such as alcohol (e.g. methanol, ethanol) or a chlorinated solvent (e.g. chloroform, dichloromethane) at a temperature that is between the 0oC and the boiling point of the solvent.

The compounds of formula (I) can be purified using conventional known methods, for example, crystallization, chromatography, extraction, etc.

The compounds of formula (I) have interesting pharmacological properties. These compounds have great sledstvenii violations associated with CCK and gastrinom, at the level of the nervous system and gastrointestinal system.

Thus, these compounds can be used for the treatment or prevention of psychoses, disorders related to anxiety, Parkinson's disease, retarded dyskinesia, a syndrome irritable colon, acute pancreatitis, ulcers, disorders of intestinal obstruction, some tumors of the lower esophagus, colon and intestines, and also as a regulator of appetite.

These compounds have also potentialities effect on the analgesic activity of narcotic and non-narcotic drugs.

The affinity of compounds with formula (I) to CCK receptors was determined according to the method similar to the method of work S. Saito et coll. (J. Nenro. Chem. 37, 483-490 (1981)) at the level of the cerebral cortex at the level of the pancreas.

In these tests the value of C150for compounds with formula (I) is usually equal to or less than 1000 nm.

On the other hand, it is known that compounds that recognize the Central CCK receptors have similar specificity with respect to the gastrin receptors in the gastrointestinal tract (Bock et coll. J. Med. Chem. 32,16-23 (1989); Reyfeld et coll. Am. d. Their value DL50normally exceeds the amount of 40 mg/kg by subcutaneous mice.

Of particular interest are compounds of formula (I) for which:

R1represents a hydrogen atom;

R2is alkoxyalkyl or a radical-NR5R6;

R3is phenylaminopropyl (phenyl ring which is substituted by one or more substituents selected among alkyl, monohydrocalcite, carboxy -, noos-AK-radicals);

R4represents a phenyl radical substituted by one or more substituents selected among halogen atoms and alkoxy-, hydroxy-, alkoxycarbonyl and R5R6N-CO-radicals.

P R I m e R 1. To a solution containing 1.25 g of 2-/2-amino-N-(3-chlorophenyl)-acetamido/tert-butyl acetate in 20 cm3anhydrous tetrahydrofuran is added at a temperature close to 20oC, 0.6 g of isocyanate 3-methylphenyl. The resulting solution was stirred for 4 h at a temperature close to 20oC, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residual liquid oil is purified by chromatography on 150 g of silica (0,063-0.2 mm) in number of operasie only the desired product, are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After crystallization in isopropyl ether obtain 0.8 g of 2-{N-(3-chloranil-2-[3-(3-were)-ureido]-acetamido}-tert-butyl acetate, melting at 110oC.

2-/2-Amino-N-(3-chlorophenyl)-acetamido/tert-butyl acetate can be obtained in the following way: to a solution containing 2.4 g 2-/N-(3-chlorophenyl)-2-telemediated/tert-butyl acetate in 40 cm3methanol was added 0.75 g of hydrazine hydrate. The reaction mixture is stirred at a temperature of education phlegmy for 3 h, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residue is mixed with 100 cm3diethyl ether, then the insoluble product is separated by filtration, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get so 1.3 g 2-/2-amino-N-(3-chlorophenyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(3-Chlorophenyl)-2-telemediated/tert-butyl acetate can be obtained in the following way. To survive in an argon atmosphere to a solution containing 4.8 g of 2-/3-chlorophenyl/-amino-tert-buck 20oC, a solution containing 6.2 g of 2-palmitoylethanolamide 20 cm31,2-dichloroethane. The resulting solution was stirred for 3 h at a temperature close to 20oC, then to it was added 50 cm3water. The aqueous phase is separated by decantation, then restrained 2 times in 50 cm31,2-dichloroethane. The organic phases are combined, washed with 2 times 10 cm3water, dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the liquid oil is purified by chromatography on 200 g of silica (0,063-0.2 mm) in a column 2.5 cm in diameter (eluent: cyclohexane-ethyl acetate(50:50 by volume), collecting fractions of 25 cm3. Fractions 3 through 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 2.6 g of 2-N-(3-chlorophenyl)-2-telemediated/tert-butyl acetate in the form of liquid oil, used in this manner as it is, for the subsequent syntheses.

2-/3-Chlorophenyl/amino-tert-butyl acetate can be obtained in the following way: to a solution containing 7.6 g of 3-Chloroaniline in 60 cm3acetonitrile, was added 5.9 g of bromoacetate tert-butyl. The resulting solution peremeshaem filtration and washed by 30 cm3acetonitrile. The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residual liquid oil is dissolved in 150 cm3dichloromethane and the resulting solution was washed 4 times for 15 cm3water. The organic phase is dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get that way of 8.1 g of 2-/3-chlorophenyl/-aminobutyl-tert-acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-Phthalimidomethyl can be obtained according to the method described in the article by W. Grassmann et E. Schulte-Uebbing, Chem. Ber. 83, 244-247 (1950).

P R I m m e R 2. Conducting the synthesis according to the method similar to that described in example 1, but based on 2.5 g 2-/2-amino-N-(2-forfinal)-acetamido/tert-butyl acetate and 1.2 g of isocyanate 3-methylphenyl, obtained after recrystallization in diisopropyl ether to 1.75 g of 2-{N-/2-forfinal/-2-/3-(3-were)-ureido/-acetamido}-tert-butyl acetate, melting at 148oC.

2-/2-Amino-N-(2-forfinal)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/2-amino-N-(3-chlorophenyl)-acetamido/tert-butylated the t thus 2.7 g / 2-/2-amino-N-(2-forfinal)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Forfinal)-2-telemediated/tert-butyl acetate can be obtained in the following way. To distance in an argon atmosphere to a solution containing 3.3 grams 2-/2-forgenerating/tert-butyl acetate in 60 cm31,2-dichloroethane, was added 1.3 g of sodium bicarbonate, then drop by drop at a temperature close to 20oC, a solution containing 3.1 g of 2-palmitoylethanolamide 10 cm31,2-dichloroethane. The resulting solution was stirred for 3 h at a temperature close to 20oC, then to it was added 20 cm3water. The aqueous phase is separated by decantation, then restrained 2 times in 100 cm31,2-dichloroethane. The organic phases are combined, dried on magnesium sulfate, filtered, then concentrated to dryness at 40oC and under reduced pressure (2.7 kPa). After recrystallization in petroleum ether get so 4.9g 2-/N-(2-forfinal)-2-telemediated/tert-butyl acetate, melting at 140oC.

2-/2-Forfinal/-amino-tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/3-chlorpheniramine/tert-butyl acetate, but on the basis of a 2.45 g of 2-flora g 2-/2-forfinal/-amino-tert-butyl acetate, melting at 70oC.

P R I m e R 3. Conducting the synthesis according to the method similar to that described in example 1, but on the basis of 6.6 g of 2-/2-amino-N-(4-methoxyphenyl)-acetamido/tert-butyl acetate and 3 g of isocyanate 3-methylphenyl, obtained after recrystallization in acetonitrile, 1.7 g of 2-{N-/4-methoxyphenyl/-2/3-(3-were)-ureido/-acetamido}-tert - butyl acetate, melting at 158oC.

2-/2-Amino-N-(4-methoxyphenyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/2-amino-N-(3-chlorophenyl)-acetamido/tert-butyl acetate, but according to 11.7 g of 2-N-(4-methoxyphenyl)-2-telemediated/tert-butyl acetate and 1.75 g of hydrazine hydrate. Get so 7 g 2-/2-amino-N-(4-methoxyphenyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(4-Methoxyphenyl)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 2 to obtain 2-/2-phthalimido-N-(2-forfinal)-acetamido/tert-butyl acetate, but on the basis of 6.7 g of 2-/4-methoxybenzylamine/tert-butyl acetate, 2.5 g of sodium bicarbonate and 6.25 g of 2-palmitoylethanolamide. Get this obim, as it is, for the subsequent syntheses.

2-(4-Methoxybenzylamine)-tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/3-chlorophenyl/-amino-tert-butyl acetate, but on the basis of 7.3 g of 4-methoxyaniline and 5,95 g bromoacetate tert-butyl. Get so 7.2 g of 2-(4-methoxybenzylamine)-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 4. Conducting the synthesis according to the method similar to that described in example 1, but from 2 g of 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate and 0.8 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate 1.35 g 2-{2-/3-(3-were)-ureido/-N-/2-trifloromethyl/-acetamido} - tert-butyl acetate, melting at 163oC.

2-/2-Amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate can be obtained in the following way. To a solution containing 4.4 g of 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate in 50 cm3ethanol was added 105 g of hydrazine hydrate. The reaction mixture was stirred for 3 h at a temperature close to 20oC, then concentrated to dryness under reduced pressure, delaetsa by filtration. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 2.1 g of 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/2-Phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate can be obtained in the following way. To survive in an argon atmosphere to a solution containing 5 g of 2-phthalimido-N/2-trifloromethyl/-ndimethylacetamide 50 cm3anhydrous tetrahydrofuran, are added at a temperature close to 10oC, 0.7 g of an oil suspension of sodium hydride (50 wt.) and stir the resulting suspension for 1 h at a temperature close to 20oC. and Then added to the solution containing 2,75 g bromoacetate tert-butyl 10 cm3anhydrous tetrahydrofuran, and continue stirring for 3 h at a temperature close to 20oC. the Reaction mixture was then prilisaetsa to the mixture, cooled to a temperature close to 0oC, which contains 20 cm3water and 200 cm3ethyl acetate. The aqueous phase is separated by decantation and restrained 2 times in 20 cm3ethyl acetate. The organic phases are combined, washed with 3 times 25 cm3pa) and at 40oC. thus Receive the 4.4 g 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2 Phthalimido-N/2/trifloromethyl/-ndimethylacetamide can be obtained as follows. To survive in an argon atmosphere to a solution containing 3.6 g of 2-triphtalocyaninine 50 cm3dichloromethane, was added 2.2 g of triethylamine, then, maintaining the temperature in the region of 20oC, a solution containing 4.6 g of 2-palmitoylethanolamide 25 cm3dichloromethane. The resulting solution was stirred for 3 h at a temperature close to 20oC, then add to it 25 cm3water. The resulting solid product is separated by filtration, washed 3 times for 5 cm3dichloromethane, then 3 x 10 cm3water and dried in air. The organic phase of the filtrate is separated by decantation, washed with 2 times 10 cm3distilled water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the resulting solid product combined with the previous one, and all paracrystalline in ethyl acetate. Receive the same is 5. Conducting the synthesis according to the method similar to that described in example 1, but on the basis of 3.4 g of 2-/2-amino-N-(3-trifloromethyl)-acetamido/tert-butyl acetate and 1.4 g of isocyanate 3-methylphenyl, obtained after recrystallization in diisopropyl ether to 1.75 g 2-{2-/3-(3-were)-ureido/-N-/3-trifloromethyl/-acetamido} -tert-butyl acetate, melting at 125oC. 2-/2-amino-N-(3-trifloromethyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 3 g 2-/2-phthalimido-N-(3-trifloromethyl)-acetamido/tert-butyl acetate and 3.2 g of hydrazine hydrate. Get so 3.5 g 2-/2-amino-(3-trifloromethyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/2-Phthalimido-N-(3-trifloromethyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 3 g 2-/-phthalimido-N-(3-trifloromethyl)-acetamido/tert-butyl acetate and 3.2 g of hydrazine hydrate. Get so the th such as it is, for the subsequent syntheses.

2-/2-Phthalimido-N-(3-trifloromethyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 4.8 g of 2-phthalimido-N-/3-trifloromethyl/-ndimethylacetamide, 0.7 g of an oil suspension of sodium hydride (50 wt.) and 2.75 g of bromo-tert-butyl acetate. Get so 5,1 g 2-/2-phthalimido-N-(3-trifloromethyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2 Phthalimido-N-/3-trifloromethyl/-ndimethylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-cryptomaterial/-ndimethylacetamide, but on the basis of 3.6 g of 3-triphtalocyaninine, 2.2 g of triethylamine and 4.6 g of 2-palmitoylethanolamide. After recrystallization in ethyl acetate thus receive the 4.8 g of 2-phthalimido-N-/3-trifloromethyl/-ndimethylacetamide, melting at 170oC.

P R I m e R 6. Conducting the synthesis according to the method similar to that described in example 1, but on the basis of 3.1 g of 2-/2-amino-N-/3-were/-acetamido/tert-butyl acetate and 0.52 g of isocyanate 3-lpanel/-acetamido)-tert-butyl acetate, melting at 97oC.

2-/2-Amino-N-(3-were)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 7.5 g 2-/N-(3-were)-2-telemediated/tert-butyl acetate and 1.84 g of hydrazine hydrate. Get so 3.5 g 2-/2-amino-N-(3-were)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2//N-(3-Were)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 12.5 g of N-/3-were/-2-palmitoylated, of 2.45 g of an oil suspension of sodium hydride (50 wt.) and 8.3 g of bromo-tert-butyl acetate. After recrystallization in diisopropyl ether get so 7.6 g of 2-N-(3-were)-2-telemediated/tert-butyl acetate, melting at 166oC.

N-/3-Were/-2-phthalimidobutyl can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-trifloromethyl/-acetone 12.7 g of N-/3-were/-2-palmitoylated, melting at 207oC.

P R I m e R 7. Conducting the synthesis according to the method similar to that described in example 1, but from 1.6 g 2-/2-amino-N-(3-methoxyphenyl)-acetamido/-N-methyl-N-phenylacetamide and 0.67 g of isocyanate 3-methylphenyl, obtained after recrystallization in acetonitrile, 1.2 g of 2-{N-(3-methoxyphenyl)-2-[3-were)-ureido] -acetamido} -N-methyl-N-phenylacetamide, melting at 179oC.

2-/2-Amino-N-(3-methoxyphenyl)-acetamido/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 2.3 g of 2-N-(3-methoxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide and 0.75 g of hydrazine hydrate. Get so 1.6 g 2-/2-amino-N-(3-methoxyphenyl)-acetamido/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(3-Methoxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but according to 9.15 g N-/3-methoxyphenyl/-2-palmitoylated, 1.6 g of an oil suspendablethread/-N methylphenylacetic resin, used as it is, for the subsequent syntheses.

N-/3-Methoxyphenyl/-2-phthalimidobutyl can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-trifloromethyl/-ndimethylacetamide, but based on 6,15 g 3-methoxyaniline, 5.6 g of triethylamine and 11.2 g of 2-palmitoylethanolamide. 12.3 g of 2-phthalimido-N-/3-methoxyphenyl)-ndimethylacetamide, melting at 186oC, get that way after recrystallization in acetonitrile.

P R I m e R 8. Conducting the synthesis according to the method similar to that described in example 1, but on the basis of 4.9 g of 2-[2-amino-N-(3-triptoreline)-acetamido] -tert-butyl acetate and 2 g of isocyanate 3-methylphenyl, obtained after recrystallization in diisopropyl ether, 1.56 g of 2-/2-(3-were)-ureido)-N-(3-triptoreline)-acetamido/tert - butyl acetate, melting at 140oC.

2-[Amino-N-(3-trifloromethyl)-acetamido] -tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 9 g 2-/2-phthalimido-N-(3-triptoreline)-acetamido/tert-butyl acetate and 2.9 g of hydrazine hydrate. Get so 5,2 g 2-/2-AMB, for subsequent syntheses.

2-/2-Phthalimido-N-(3-triptoreline)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 16.5 g of 2-phthalimido-N-/3-triptoreline/-ndimethylacetamide, 2.3 g of an oil suspension of sodium hydrate (50 wt.) and 9.2 g of bromo-tert-butyl acetate. Get so 9,1 g 2-/2-phthalimido-N-(3-triptoreline)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2 Phthalimido-N-/3-triptoreline/-ndimethylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-trifloromethyl/-ndimethylacetamide, but based on 8.1 g of 3-triptorelin, of 5.1 g of triethylamine and 11.2 g of 2-palmitoylethanolamide. Get that way 16.7 g of 2-phthalimido-N-/3-triptoreline/-ndimethylacetamide, melting at 235oC.

P R I m e R 9. Conducting the synthesis according to the method similar to that described in example 1, but from 3.6 g 2-/2-amino-N-(2-ethoxycarbonylphenyl)-acetamido/tert-butyl acetate and 1.42 g of isocyanate 3-methylphenyl, obtained after recrystallization in disegna at 142oC.

2-/2-Amino-N-(2-ethoxycarbonylphenyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but based on 6,13 g 2-/-N-(2-ethoxycarbonylphenyl)-2-telemediated/tert-butyl acetate and 1.98 g of hydrazine hydrate. Get so 3.6 g 2-/2-amino-N-(2-ethoxycarbonylphenyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Ethoxycarbonylphenyl)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/-tert-butyl-acetate, but on the basis of 7,7 g N-/2-ethoxycarbonylphenyl/2 telemediated, 1,26 oil suspension of sodium hydride (50 wt.) and 4.3 g of bromoacetate tert-butyl. After recrystallization in diisopropyl ether get so 6,1 g 2-/N-(2-ethoxycarbonylphenyl)-2-telemediated/tert-butyl acetate, melting at 127oC.

N-/2-Ethoxycarbonylphenyl/-2-phthalimidobutyl can be obtained by the method similar to that described in example 4 for the floor and 5.6 g of 2-palmitoylethanolamide. Get so 7,7 g N-/2-ethoxycarbonylphenyl/-2-palmitoylated, melting at 187oC.

P R I m e R 10. Conducting the synthesis according to the method similar to that described in example 1, but on the basis of 4.7 g of 2-/2-amino-N-(2-acetylaminophenol)-acetamido)-acetate tert-butyl and 2 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate 3.6 g of 2-{N-/2-acetylaminophenol/-2-/3-(3-were)ureido/-acetamido}-tert-butyl acetate, melting at 185oC.

2-/2-Amino-N-(2-acetylaminophenol)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 7.2 g 2-/N-(2-acetamidophenyl)-2-telemediated/tert-butyl acetate and 2.4 g of hydrazine hydrate. Thus receive the 4.8 g of 2-/2-amino-N-(2-acetylaminophenol)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Acetamidophenyl)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but based on Tata tert-butyl. After recrystallization in ethyl acetate get so 8 g 2-/N-(2-acetamidophenyl)-2-telemediated/tert-butyl acetate, melting at 170oC.

N-/2-Acetylaminophenol/-2-phthalimidobutyl can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-trifloromethyl/-ndimethylacetamide, but on the basis of 6 g of 2-acetylaminofluorene, of 4.05 g of triethylamine and 9.6 g of 2-palmitoylethanolamide. Thus receive the 12.5 g of N-/2-acetylaminophenol/-2-palmitoylated, melting at 270oC.

P R I m e R 11. Conducting the synthesis according to the method similar to that described in example 1, but on the basis of 4.8 g of 2-/2-amino-N-(2-chlorophenyl)-acetamido/tert-butyl acetate and 2.35 g of isocyanate 3-methylphenyl, obtained after recrystallization in a mixture of ethyl acetate and methanol (80:20 by volume), 1.4 g of 2-{N-/2-chlorophenyl/-2-/3-(3-were)-ureido/acetamido}-tert-butyl acetate, melting at 148oC.

2/2-Amino-N-(2-chlorophenyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/2-amino-N - (3-chlorophenyl)-acetamido/tert-butyl acetate, but from 9,12 g 2-/N-(2-chlorophenyl)-2-telemediated/tert-butyl acetate liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Chlorophenyl)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 2 to obtain 2-/N-(2-forfinal)-2-telemediated/tert-butyl acetate, but on the basis of 8 g 2-/2-chlorophenyl/-amino-tert-butyl acetate, 3.1 g of sodium bicarbonate and 7.4 g of 2-palmitoylethanolamide. After recrystallization in a mixture of ethyl acetate and cyclohexane (70:30 by volume), obtain 10.6 g of 2-N-(2-chlorophenyl)-2-telemediated/tert-butyl acetate, melting at 164oC.

2-/2-Chlorophenyl/-amino-tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/3-chlorophenyl/-amino-tert-butyl acetate, but according to 19.1 g of 2-Chloroaniline and 9.75 bromoacetate tert-butyl. Get so 9.3 g 2-/2-chlorophenyl/-amino-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 12. Conducting the synthesis according to the method similar to that described in example 1, but from 2.4 g 2-/2-amino-N-(3,4-methylenedioxyphenyl)-acetamido/tert-butyl acetate and 1 g of isocyanate 3-methylphenyl, obtained after recrystallization in what I 142oC.

2/2-Amino-N-(3,4-methylenedioxyphenyl)-acetamido/tert-butyl acetate can be obtained in the following way: to a solution containing 4.6 g of 2-/N-(3,4-methylenedioxyphenyl)-2-telemediated/tert-butyl acetate in 70 cm3dichloromethane is added at a temperature close to 0oC, 1.45 g of methylhydrazine. The reaction mixture was stirred for 16 h at a temperature close to 20oC, then for 2 hours at a temperature of education phlegmy dichloromethane and cooled to a temperature close to 20oC. Add 50 cm3water and separated by decanting the aqueous phase, which restrained 2 times 40 cm3dichloromethane. The organic phases are combined, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the liquid oil is purified by chromatography on 50 g of silica (0,063-0.2 mm) in a column 2 cm in diameter (eluent: ethyl acetate-methanol (90:10 by volume), collecting fractions of 20 cm3. Fractions 11 to 22 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 1.85 g 2-/2-amino-N-(3,4-methylenedioxyphenyl)-acetamido/tert-butyl acetate in the form of liquid mA is methazolamide/tert-butyl acetate can be obtained by the method, similar to that described in example 2 to obtain 2-/N-(2-forfinal)-2-telemediated/tert-butyl acetate, but on the basis of 5,15 g 2-/3,4-methylenedioxyphenyl/-amino-tert-butyl acetate and 1.9 g of sodium bicarbonate and 4.6 g of 2-palmitoylethanolamide. After recrystallization in ethyl acetate to obtain 8 g of 2-/N-(3,4-methylenedioxyphenyl)-2-telemediated/tert-butyl acetate, melting at 166oC.

2-/3,4-Methylenedioxyphenyl/-amino-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/3-chlorophenyl/-amino-tert-butyl acetate, but on the basis of 9 g of 3,4-methylenedioxyaniline and 5.9 g of bromo-tert-butyl acetate. After recrystallization in petroleum ether get so 5,2 g 2-/3,4-methylenedioxyphenyl/-amino-tert-butyl acetate, melting at 80oC.

P R I m e p 13. To a solution containing 0.7 g 2-/2-amino-N-(4-dimethylaminophenyl)-acetamido/tert-butyl acetate in 15 cm3anhydrous tetrahydrofuran, are added at a temperature close to 20oC, 0.35 g of isocyanate 3-methylphenyl. The resulting solution was stirred for 3 h at a temperature close to 20oC, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After the cross is tamido} tert-butyl acetate, melting at 105oC.

2-/2-Amino-N-(4-dimethylaminophenyl)-acetamido/tert-butyl acetate can be obtained in the following way: to a solution containing 1 g 2-/N-(4-dimethylaminophenyl)-2-telemediated/tert-butyl acetate in 20 cm3methanol was added 0.15 g of hydrazine hydrate. The reaction mixture is stirred at a temperature of education phlegmy for 3 h, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residue is mixed with 75 cm3diethyl ether, and the insoluble product is separated by filtration. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 0.7 g 2-/2-amino-N-(4-dimethylaminophenyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(4-Dimethylaminophenyl)-2-telemediated/tert-butyl acetate can be obtained in the following way. To survive in an argon atmosphere to a solution containing 2.6 g 2/4-dimethylaminophenyl/-amino-tert-butyl acetate in 20 cm31,2-dichloroethane, was added 1.4 g of triethylamine, then drop by drop at a temperature close to 20oC, a solution containing 3.1 g of 2-palmitoylethanolamide 20 C, then thereto was added 25 cm3water. The aqueous phase is separated by decantation, then restrained 2 times 50 cm31,2-dichloroethane. The organic phases are combined, washed with 2 times 10 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the liquid oil is purified by chromatography on 100 g of silica (0,063-0.2 mm) in a column 2 cm in diameter (eluent: dichloromethane-methanol (98:2 volume), collecting fractions 15 cm3. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 1.1 g 2-/N-(4-dimethylaminophenyl)-2-phthalimide tamido/tert-butyl acetate, melting at 170oC.

2-/4-Dimethylaminophenyl/-amino-tert-butyl acetate can be obtained in the following way. To a suspension containing 6.3 g of dichlorhydrate 4-dimethylaminopyridine 50 cm3acetonitrile is added at a temperature close to 10oC and 6.1 g of triethylamine. The suspension obtained is stirred at a temperature close to 20oC, for 30 min, then added 3 g of bromoacetate tert-butyl, and the reaction mixture paramasivam filtration and washed through a 15 cm3acetonitrile, the filtrates are combined and concentrated under reduced pressure (2.7 kPa) and at 40oC. the Residual liquid oil is dissolved in 100 cm3dichloromethane and the solution obtained is washed 4 times for 10 cm3. The organic phase is dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) at 40oC. thus Receive the 2.6 g of 2-/4-dimethylaminophenyl/-amino-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 14. Conducting the synthesis according to the method similar to that described in example 11, but according to 5.1 g of 2-/2-amino-N-(3-methylthiophenyl)-acetamido/tert-butyl acetate and 2.2 g of isocyanate 3-methylphenyl, obtained after recrystallization in a mixture of diisopropyl ether and ethyl acetate (80: 20 by volume), 2.6 g 2-{2-/3-(3-were(ureido/-N-(3-methylthiophenyl)-acetamido}tert - butyl acetate, melting at 135oC.

2-/2-Amino-N-(3-methylthiophenyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/2-amino-N-(3-chlorophenyl)-acetamido/tert-butyl acetate, but on the basis of 7.6 g of 2-N-(3-methylthiophenyl)-2-telemediated/ - the way of 5.1 g of 2-/2-amino-N-(3-methylthiophenyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(3-Methylthiophenyl)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/N-(3-chlorophenyl)-2-telemediated/tert-butyl acetate, but on the basis of 6.8 g of 2-/3-methylthiophenyl/-amino-tert-butyl acetate, 3 g of triethylamine and 6 g of 2-palmitoylethanolamide. After crystallization in isopropyl ether get so 7.6 g of 2-N-(3-methylthiophenyl)-2-telemediated/tert-butyl acetate,melting at 141oC.

2-/3-Methylthiophenyl/-amino-tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/3-chlorophenyl/-amino-tert-butyl acetate, but on the basis of an 8.4 g of 3-methylthioinosine and 5.9 g of bromoacetate tert-butyl. Get that image of 6.8 g of 2-/3-methylthiophenyl/-amino-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 15. Conducting the synthesis according to the method similar to that described in example 11, but on the basis of 3.4 g of 2-/2-amino-N-(2-chlorophenyl)-acetamido/-N-methyl-N-phenylacetamide and 1.4 g of isocyanate 3-methylphenyl, obtained after recrystallization in acetonitrile 2.2 g 2">

2-/2-Amino-N-(2-chlorophenyl)-acetamido/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 5.6 g of 2-N-(2-chlorophenyl)-2-telemediated/-N-methyl-N-phenylacetamide and 1.9 g of hydrazine hydrate. Get so 3,3 g 2-/2-amino-N-(2-chlorophenyl)-acetamido/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Chlorophenyl)-2-telemediated/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of the 7.4 g of 2-phthalimido-N/2-chlorophenyl)-ndimethylacetamide, 1.3 g of an oil suspension of sodium hydride (50 wt.) and 5.9 g of 2-bromo-N-methyl-N-phenylacetamide. After recrystallization in ethyl acetate get so 5,7 g 2-/N-(2-chlorophenyl)-2-telemediated/-N-methyl-N-phenylacetamide, melting at 168oC.

2 Phthalimido-N/2-chlorophenyl/-ndimethylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-trifloromethyl/-ndimethylacetamide, but based on the 3.8 is aminoacidemia, melting at 250oC.

2-Bromo-N-methyl-N-phenylacetamide can be obtained according to the method described in C. A. Bischoff. Chem. Ber. 34, 2125 (1901).

P R I m e R 16. Conducting the synthesis according to the method similar to that described in example 11, but judging from 4.2 g of 2-/2-amino-N-(2-methoxyphenyl)-acetamido/tert-butyl acetate and 1.9 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate, 3 g of 2-{N-/2-methoxyphenyl/-2-/3-(3-were)ureido/-acetamido}-tert - butyl acetate, melting at 171oC.

2-/2-Amino-N-(2-methoxyphenyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/2-amino-N-(3-chlorophenyl)-acetamido/tert-butyl acetate, but on the basis of 8,4 g 2-/N-(2-methoxyphenyl)-2-telemediated/tert-butyl acetate, 3 g of hydrazine and carrying out the synthesis at a temperature close to 20oC. Get thus of 4.2 g of 2-[2-amino-N-(2-methoxyphenyl)-acetamido]-tert-butyl acetate, in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Methoxyphenyl)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/N-(3-chlorophenyl)-2-palmitoylethanolamide. After recrystallization in diisopropyl ether get so 8,4 g 2-/N-(2-methoxyphenyl)-2/-telemediated/tert-butyl acetate, melting at 144oC.

2-/2-Methoxyphenyl/-amino-tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/3-chlorophenyl/-amino-tert-butyl acetate, but on the basis of the 7.4 g of 2-methoxyaniline and 5.9 g of bromoacetate tert-butyl. Get so 6.4g 2-/2-methoxyphenyl/-amino-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 17. To survive in an argon atmosphere to a suspension containing 3.7 g of 2-/3-(3-were)-ureido/-acetic acid in 230 cm31,2-dichloroethane is added at a temperature close to 20oC, 4.5 g 2-/4-nitrophenyl/-amino-tert-butyl acetate. The reaction mixture is heated under stirring to form phlegmy solvent. Then add drop by drop, maintaining the temperature of education phlegmy, 2,12 g sulphonylchloride. Upon completion of addition, continue heating at a temperature of education phlegmy for 10 min, then the reaction mixture is cooled to a temperature close to 10oC, and prilisaetsa to the solution, steriade the times by 50 cm31,2-dichloroethane. The organic phases are combined, washed 3 times with 20 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residue is purified by chromatography on 200 g of silica (0,063-0.2 mm) in a column with a diameter of 3.5 cm (eluent: cyclohexane-ethyl acetate (50:50 by volume), collecting fractions at 30 cm3. Fractions 16 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in ethyl acetate to obtain 2.9 g 2-{ 2-/3-(3-were)-ureido/-N-/4-nitrophenyl/-acetamido}-tert-butyl acetate, melting at 152oC.

2-/4-Nitrophenyl/-amino-tert-butyl acetate can be obtained in the following way. A mixture of 6.9 g of 4-nitroaniline,19,5 g of bromoacetate tert-butyl and 9,24 g of sodium bicarbonate is heated with stirring in an argon atmosphere at 160oC for 2 h 30 min, then cooled to a temperature close to 20oC, and prilisaetsa to a mixture consisting of 150 cm3water and 150 cm3ethyl acetate. The aqueous phase is separated by decantation and restrained 3 times by 50 cm3ethyl acetate. The organic phases are combined, washed 3 times p is the situation (2.7 kPa) and at 40oC. After recrystallization in a mixture of ethyl acetate and cyclohexane (50:50 by volume), gain of 7.7 g of 2-/4-nitrophenyl/-amino-tert-butyl acetate, melting at 124oC.

2-/3-(3-Were)-ureido/acetic acid can be obtained in the following way. To a solution containing 7.5 g of glycine and 8.4 g of sodium bicarbonate in 250 cm3water is added at a temperature close to 20oC, 13.3 g of isocyanate 3-methylphenyl. The reaction mixture is stirred for 18 hours at a temperature close to 20oC, then the insoluble product is separated by filtration and washed with 2 times 30 cm3water, then 2 times in 30 cm3ethyl acetate. The filtrates are combined, the aqueous phase is separated by decantation and acidified using 5 N. aqueous solution chloroethanol acid to pH values close to 1. The resulting solid product is separated by filtration, washed with 2 times 30 cm3water, then 2 times in 30 cm3ethyl acetate and dried in air. Get so 16.3 g of 2-/3-(3-were)-ureido/-acetic acid, melting at 225oC.

P R I m e R 18. Conducting the synthesis according to the method similar to that described in example 17, but on the basis of 1.04 g of 2-/3-(3-torment after recrystallization in acetonitrile, 0.3 g of 2-{ N-/2,3-dichlorophenyl/-2-/3-(3-were)-ureido/-acetamido} -tert-butyl acetate, melting at 135oC.

2-/2,3-Dichlorophenyl/-amino-tert-butyl acetate can be obtained in the following way: to a solution containing 32,4 g of 2,3-dichloraniline 100 cm3acetonitrile is added at a temperature close to 20oC, with 16.8 g of sodium bicarbonate, then a solution containing 39 g of bromoacetate tert-butyl 50 cm3acetonitrile. The reaction mixture is stirred at a temperature of education phlegmy within 48 h, then cooled to a temperature close to 20oC. the Insoluble product is separated by filtration and washed by 50 cm3acetonitrile. The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residue is purified by chromatography on 300 g of silica (0,063-0.2 mm) in a column of diameter 4 cm (eluent: cyclohexane-ethyl acetate (90: 10 by volume), collecting fractions of 50 cm3. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 33 g 2-/2,3-dichlorophenyl/-amino-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 19. Conducting the synthesis in which the notes, 4.3 g of 2-/2-bromophenyl/-amino-tert-butyl acetate and 2 g of sulphonylchloride, obtained after recrystallization in a mixture of diisopropyl ether and acetonitrile (80:20 by volume), 0.6 g of 2-{N-/2-bromophenyl)-2-/3-(3-were)-ureido/-acetamido} -tert-butyl acetate, melting at 158oC.

2-/2-Bromo-phenyl/-amino-tert-butyl acetate can be obtained by the method similar to that described in example 18 to obtain 2-/2,3-dichlorophenyl/-amino-tert-butyl acetate, but on the basis of 34.4 g of 2-bromoaniline, and 8.4 g of sodium bicarbonate and 19.5 g of bromoacetate tert-butyl. Get so 17,4 g 2-/2-bromophenyl/-aminoacetate tert-butyl in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 20. Conducting the synthesis according to the method similar to that described in example 17, but based on 2,08 g 2-/3-(3-were)-ureido/-acetic acid, of 3.07 g of 2-/3-trifloromethyl/-amino-tert-butyl acetate and 1.3 g of sulphonylchloride, obtained after recrystallization in diisopropyl ether 0.8 g 2-{2-/3-(3-were)ureido/-N-/3-trifloromethyl)-acetamido}-tert-butyl acetate, melting at 112oC.

2-/3-Trifloromethyl/-amino-tert-butyl acetate can be obtained according to the method, analog,3 g of 3-cryptomaterial, of 8.4 g of sodium bicarbonate and 19.5 g of bromoacetate tert-butyl. Get so 25,5 g 2-/3-trifloromethyl/-aminoacetate tert-butyl in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 21. To a solution containing 5.5 g of 2-N-(2-were)-2-telemediated/tert-butyl acetate in 90 cm3dichloromethane is added at a temperature close to 0oC, 2,13 g methylhydrazine. The reaction mixture is stirred for 30 hours at a temperature close to 20oC, then for 1 h at a temperature of education phlegmy. After you add 100 cm3water, stirred and separated by decanting the aqueous phase, which restrained 2 times in 60 cm3dichloromethane. The organic phases are combined, washed 2 times for 15 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 2-/2-amino-N-(2-were)-acetamido/tert-butyl acetate in the form of liquid oil, which is dissolved in 40 cm3anhydrous tetrahydrofuran. To this solution was added 1.77 g of the isocyanate 3-methylphenyl, then stirred the reaction mixture for 1 h at a temperature close in petroleum ether gain of 1.05 g of 2-{N-/2-were/-2-/3-(3-were)-ureido/-acetamido} -tert-butyl acetate, melting at 133oC.

2/N-(2-Were)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-N-(3-chlorophenyl)-2-telemediated/-acetate tert-butyl, but on the basis of the 5.2 g of 2-/2-were/aminoacetate tert-butyl, 2.6 g of triethylamine and 5.3 g of 2-palmitoylethanolamide. After recrystallization in ethyl acetate get so 5.5 g of 2-N-(2-were)-2-telemediated/tert-butyl acetate, melting at 140oC.

2-/2-Were/-amino-tert-butyl acetate can be obtained by the method similar to that described in example 18 to obtain 2-/2,3-dichlorophenyl/-amino-tert-butyl acetate, but on the basis of 6.4 g of 2-methylaniline, 2.5 g of sodium bicarbonate and 5.85 g of bromo-tert-butyl acetate. Get so 5,2 g 2-/2-were/-amino-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 22. Spend the synthesis according to the method similar to that described in example 17, but on the basis of 1.8 g of 2-/4-chlorophenyl/-amino-tert-butyl acetate, 1.56 g of 2-/3-(3-were)-ureido/-acetic acid and 0,89 g of thionyl chloride. The resulting product was then purified by chromatography on 60 g Kremennaya excess nitrogen pressure value of 40 kPa and collecting fractions of 20 cm3. Fractions 21 to 25 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After crystallization in acetonitrile obtain 0.5 g of 2-(N-/4-chlorophenyl/-2-/3-(3-were)-ureido/-acetamido)-tert-butyl acetate, melting at 125oC.

2-/4-Chlorophenyl/-amino-tert-butyl acetate can be obtained in the following way: to a solution containing 12.7 g of 4-Chloroaniline in 100 cm3acetonitrile, was added 9.7 g bromo-tert-butyl acetate and stirred the mixture at a temperature of education phlegmy for 3 hours, the Insoluble product is separated by filtration, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the resulting product was then purified by chromatography on 150 g of silica (0,065 0.2 mm) in a column 2 cm in diameter (eluent: cyclohexane-ethyl acetate (70: 30 by volume), collecting fractions of 20 cm3. After concentration under reduced pressure (2.7 kPa) and at 40oC obtain 11.9 g of 2-/4-chlorophenyl/-amino-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 23. Spend the synthesis according to the method similar to that described in example 1, but from 2.3 g of 2-/2-amino-N-(3-methoxyphenyl)-AI on 150 g of silica (0.04 to 0,063 mm), located in a column with a diameter of 3.5 cm (eluent: cyclohexane-ethyl acetate (70:30 by volume)), applying excess nitrogen pressure value of 40 kPa and collecting fractions of 20 cm3. Fractions 10 to 16 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in diisopropyl ether obtain 2.2 g of 2-{N-/3-methoxyphenyl/-2-/3-(3-were)-ureido/-acetamido} -tert - butyl acetate, melting at approximately the 60oC.

2-/2-Amino-N-(3-methoxyphenyl)acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/2-amino-N-(3-chlorophenyl)-acetamido/tert-butyl acetate, but on the basis of 3.4 g) 2-/N-(3-methoxyphenyl)-2-telemediated/tert-butyl acetate and 0.8 g of hydrazine hydrate. Get so 2.0 g 2-/2-amino-N-(3-methoxyphenyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(3-Methoxyphenyl)-2-telemediated/tert-butyl acetate can be obtained in the following way: to a solution containing 6.3 g of 2-/2-chloro-N-(3-methoxyphenyl)-acetamido/tert-butyl acetate in 100 cm3of dimethylformamide, was added 7.5 g of phthalimide in the hydroxide solution to the>water. The insoluble product is separated by filtration, washed 3 times in 60 cm3water and dried in air. After recrystallization in diisopropyl ether obtain 6.7 g of 2-N-(3-methoxyphenyl)-2-telemediated/tert-butyl acetate, melting at 138oC.

2-/2-Chloro-N-(3-methoxyphenyl)-acetamido/tert-butyl acetate can be obtained in the following way. To stand at a temperature close to the 15oC, the solution containing 7.9 g of 2-/3-methoxyphenyl/-amino-tert-butyl acetate and 6.7 g of triethylamine in 50 cm31,2-dichloroethane, was added 5.7 g of chlorine-acetylchloride. The mixture was stirred for 6 h at a temperature close to 60oC. After cooling, the mixture is washed 3 times in 100 cm3water. The organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in diisopropyl ether get so 6.3 g 2-/2-chloro-N-(3-methoxyphenyl)-acetamido/tert-butyl acetate, melting at 110oC.

2-/3-Methoxyphenyl/-amino-tert-butyl acetate can be obtained by the method similar to that described in example 1 to obtain 2-/3-chlorophenyl)-aminoacetate tert-butyl, but on the basis of 12.4 g of 4-methoxy who 063-0,200 mm), located in a column with a diameter of 7.0 cm (eluent: dichloromethane), collecting fractions of 60 cm3. Fractions 10 to 20 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get that way of 9.8 g of 2-/3-methoxyphenyl)-aminoacetate tert-butyl in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 24. To a solution containing 1.2 g of 2-{N-(4-dimethylaminophenyl)-2-[(1-imidazolyl)-carboxamido] -acetamido} -tert-butyl acetate in 30 cm3toluene is added 0,83 g 3-methylthioinosine, and the mixture is stirred at a temperature of education phlegmy within 4 hours After cooling, add 30 cm3ethyl acetate, then the resulting solution was washed sequentially through 30 cm3water, 2 times 30 cm31 N. solution chloroethanol acid, 2 times 30 cm3saturated aqueous sodium hydrogen carbonate solution and by 30 cm3saturated aqueous solution of sodium chloride. The organic phase is dried on magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residue is purified by chromatography on 100 g of silica (0,065-0,200 mm) in a column with a diameter of 2.7 cm (eluent: met nnom pressure (2.7 kPa) and at 40oC. After recrystallization in acetonitrile obtain 0.40 g of 2-{N-/4-dimethylaminophenyl/-2-/3-(3-methylthiophenyl)-ureido/-acetamido}- tert-butyl acetate, melting at 160oC.

2-{ N-/4-Dimethylaminophenyl/-2-/(1-imidazolyl)-carboxamido/(acetamido} -tert-butyl acetate can be obtained in the following way. To a solution containing of 0.58 g of N,N'-diimidazole 20 cm3anhydrous tetrahydrofuran is added a solution containing 1.2 g 2-/2-amino-N-(4-dimethylaminophenyl)-acetamido/tert-butyl acetate in 15 cm3anhydrous tetrahydrofuran. The solution is stirred for 3 h at a temperature close to 20oC, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residue is dissolved in 30 cm3ethyl acetate and the resulting solution was washed sequentially: 4 x 20 cm3water and by 25 cm3saturated aqueous solution of sodium chloride. The organic phase is dried on magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in ethyl acetate was obtained 1.2 g of 2-{N-/4-dimethylaminophenyl/-2-/(1-imidazolyl)-carboxamid/-acetamido} -tert - butyl acetate, melting at 110oC.

P R I m e R 25. To piretanide/tert-butyl acetate in 35 cm31,2-dichloroethane is added 0.55 g of triethylamine, then 0.9 g of 2-indocarbocyanine dissolved in 35 cm31,2-dichloroethane. The reaction mixture is stirred for 18 hours at a temperature close to 25oC. Then add 250 cm3dichloromethane, then 125 cm3saturated aqueous solution of sodium bicarbonate. The organic phase is washed 2 times in 125 cm3water, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in ethyl acetate to obtain 0.35 g of N-[N-(4-dimethylamino-N-tert-butoxycarbonylmethylene)-carbonylmethyl]-2 - indocarbocyanine, melting at 230oC.

2-Indocarbocyanine can be obtained as follows. To a suspension containing 1.85 g of 2-indolocarbazoles acid at 40 cm3anhydrous diethyl ether at a temperature close to 5oC, add 0.1 cm3of dimethylformamide, then 1.5 g of oxalicacid dissolved in 10 cm3anhydrous diethyl ether. The reaction mixture is stirred at a temperature close to the 25oC for 2 h, the Ether phase is concentrated to dryness under reduced pressure (2.7 kPa) and at 30oC. thus Receive the 1.8 g 2-indycars who yl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl]- ureido}-ethylbenzoic 75 cm3a mixture of water-tetrahydrofuran, dioxane (30:40:30 by volume), add 5 cm31 N. aqueous sodium hydroxide solution. The mixture is stirred for 16 hours at a temperature close to 25oC, then concentrated to a volume of about 40 cm3under reduced pressure (2.7 kPa) and 10oC. the resulting solution was diluted by 50 cm3water, washed with 2 times 50 cm3ethyl acetate, acidified to pH 3 with 4 n solution chloroethanol acid and extracted 2 times in 30 cm3ethyl acetate. The organic phases are combined, washed by 30 cm3water, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 30oC. After recrystallization in a mixture acetonitrile (90:10 by volume) to obtain 0.9 g of 3-{3-[N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl]- ureido}-benzoic acid, melting at 222oC.

3-{3-[N-(3-Methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl] -ureido} -ethyl benzoate can be obtained as follows: to a solution containing 2.1 g of 2-N-(3-methoxyphenyl)-isocyanatoacetate-/-N-methyl-N-phenylacetamide 80 cm3anhydrous tetrahydrofuran, probably is centered to dryness under reduced pressure (2.7 kPa) and at 40oC. the resulting crude product was then purified by chromatography on 80 g of silica (0,065-0.20 mm) in a column 2.5 cm in diameter (eluent: methanol-dichloromethane(20:80 by volume)), applying excess nitrogen pressure value of 40 kPa and collecting fractions of 80 cm3. Fractions 8 to 11 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get that way of 1.9 g of 3-{3-[N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl]- ureido}-ethyl benzoate in the form of a substance of the type "meringue", used as it is, for the subsequent syntheses.

2-/N-(3-Methoxyphenyl)-isocyanatoacetate/-N-methyl-N-phenylacetamide can be obtained as follows. To stand at a temperature close to 5oC, the solution containing 1.55 g of 2-/3-methoxyphenyl/-amino-N-methyl-N-phenylacetamide and 0.5 g of pyridine in 30 cm3anhydrous tetrahydrofuran, was added 0.87 g of isocyanatoacetate dissolved in 10 cm3anhydrous tetrahydrofuran, then the mixture was stirred for 3 h at a temperature close to 25oC. the Insoluble product is separated by filtration, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 30oC. Receive such obrazki, as it is, for the subsequent syntheses.

2-/3-Methoxyphenyl/-amino-N-methyl-N-phenylacetamide can be obtained as follows. To a solution containing 5.2 g of 2-N-(3-methoxyphenyl)-trifurcated/-N-methyl-N-phenylacetamide 80 cm3ethanol is added at a temperature close to 20oC 14.2 cm32 N. an aqueous solution of sodium hydroxide. The reaction mixture is stirred at a temperature of education phlegmy for 5 min, then the ethanol is removed by evaporation under reduced pressure (2.7 kPa) and at 40oC. To the residue is added 150 cm3ethyl acetate and the separated aqueous fraction by decanting. The organic phase is washed 5 times with 20 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residual liquid oil is purified by chromatography on 100 g of silica (0,063-0.2 mm) in a column 2.5 cm in diameter (eluent: dichloromethane), collecting fractions of 20 cm3. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 2.5 g of 2-/3-methoxyphenyl/-amino-N-methyl-N-phenylacetamide in the form of liquid oil, ispolzuemuyu can be obtained as follows. To survive in an argon atmosphere to a solution containing 5 g of N-/3-methoxyphenyl/-trifurcated 80 cm3anhydrous tetrahydrofuran, are added at a temperature close to 10oC, 1.4 g of an oil suspension of sodium hydride (50 wt.) and stir the resulting suspension for 30 min at a temperature close to 20oC. and Then added to the solution containing 7.9 g of 2-bromo-N-methyl-N-phenylacetamide 50 cm3anhydrous tetrahydrofuran and heated at a temperature of education phlegmy with stirring for 5 hours Then the reaction mixture is cooled to a temperature close to 20oC, and prilisaetsa to a mixture consisting of 100 cm3water and 150 cm3ethyl acetate. The aqueous phase is separated by decantation and restrained 2 times in 100 cm3ethyl acetate. The organic phases are combined, washed with 3 times 100 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at a temperature of 40oC. the liquid oil is purified by chromatography on 100 g of silica (0,063-0.2 mm) in a column with a diameter of 3.5 cm (eluent: dichloromethane), collecting fractions of 20 cm3. The fractions containing only the desired product are pooled is ethoxyphenyl)-trifurcated/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

N-/3-Methoxyphenyl/-triptorelin can be obtained as follows. To an anhydrous solution containing 3.1 g of 3-methoxyaniline 25 cm3pyridine is added at a temperature close to -20oC, 5,25 g triperoxonane anhydride. The reaction mixture was stirred for 30 min at temperatures approaching -20oC, then for 1 h at a temperature close to 0oC, and prilisaetsa to 150 cm3water, cooled to a temperature close to 0oC. Insoluble liquid oil is extracted by 200 cm3diethyl ether, and the organic phase is washed with 2 times 30 cm31 N. aqueous solution chloroethanol acid, then 2 times in 30 cm3water, dried on magnesium sulfate and concentrated under reduced pressure (2.7 kPa) and at 30oC to dryness. Get so 5.7 g of N-/3-methoxyphenyl/-trifurcated in the form of liquid oil, used as it is, for the subsequent syntheses.

2-Bromo-N-methyl-N-phenylacetamide can be obtained as follows. To a solution containing 10.7 g of N-methylaniline in 65 cm3dichloromethane, are added successively at temperaturen. The resulting suspension stirred for 2 h at a temperature close to 20oC, then it added to 25 cm3water. The aqueous phase is separated by decantation and restrained 2 times 15 cm3dichloromethane. The organic phases are combined, washed with 3 times 25 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. To a residual liquid oil add 100 cm3anhydrous diethyl ether: insoluble product is separated by filtration and washed with 3 times 15 cm3diethyl ether. The filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get that way of 20.5 g of 2-bromo-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

Isocyanatoacetate can be obtained according to the method described in the article Yoshio Iwakura et Coll. J. Org. Chem. 30, 1158 (1965).

P R I m e R 27. To a solution containing 4.8 g of 2-{-2-amino-N-[2-(3,3-dimethylpiperidino)-carbonitrile] -acetamido} - tert-butyl acetate in 40 cm3anhydrous tetrahydrofuran, are added at a temperature close to 20oC, 1.2 g of isocyanate 3-IU is controlled to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residual liquid oil is purified by chromatography on 150 g of silica (0,063-0.2 mm) in a column with a diameter of 3.5 cm (eluent: dichloromethane-methanol (98:2 by volume), collecting fractions of 50 cm3. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in ethyl acetate to obtain 3.2 g of 2-{N-[2-(3,3-dimethylpiperidino)-carbonitrile] -2-[3-(3-were)-ureido]-acetamido}-tert-butyl acetate, melting at 207oC.

2-{ 2-Amino-N-[2-(3,3-dimethylpiperidino)-carbonitrile] -acetamido} - tert-butyl acetate can be obtained in the following way. To a solution containing 6.3 g of 2-{N-[2-(3,3-dimethylpiperidino)-carbonitrile]-2-telemediated} tert-butyl acetate in 100 cm3methanol was added to 1.9 g of hydrazine hydrate. The reaction mixture is heated at a temperature of education phlegmy for 4 h, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residual liquid oil is dissolved in 200 cm3ethyl acetate and the resulting solution was added 50 cm3water. The aqueous phase is separated by decantation, then restrained 2 times in 30 cm3ethyl acetate. Organic Interoute to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 4.8 g of 2-{-2-amino-N-[2-(3,3-dimethylpiperidino)-carbonitrile]-acetamido}-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-{ N-[2-(3,3-Dimethylpiperidino)-carbonitrile] -2-telemediated} - tert-butyl acetate can be obtained in the following way. To survive in an argon atmosphere to a solution containing 8,4 g N-/2-(3,3-dimethylpiperidino)-carbonitril/-2-telemediated 100 cm3anhydrous tetrahydrofuran, are added at a temperature close to 10oC of 1.05 g of an oil suspension of sodium hydride (50 wt.) and the resulting mixture was stirred for 1 h at a temperature close to 20oC. and Then added to the solution containing 4.5 g of bromoacetate tert-butyl 25 cm3anhydrous tetrahydrofuran, and stirred for further 3 h at a temperature close to 20oC, then 4 hours at a temperature of education phlegmy solvent. Then the reaction mixture prilisaetsa to cooled to a temperature close to 0oC, a mixture consisting of 30 cm3distilled water and 200 cm3ethyl acetate. The aqueous phase is separated by decantation and restrained 2 times in 20 cm3ethyl acetate. The organic phases are combined, about the reduced pressure (2.7 kPa) and at 40oC. thus Receive the 6.5 g of 2-{N-/2-(3,3-dimethylpiperidino)-carbonitril/-2-telemediated} acetate tert-butyl in the form of an amorphous solid used as it is, for the subsequent syntheses.

N-/2-(3,3-Dimethylpiperidino)-carbonitril/-2-phthalimidobutyl can be obtained as follows. To survive in an argon atmosphere to a solution containing 7 g of 2-(3,3-dimethylpiperidino)-carbonylation 150 cm3dichloromethane is added to 3.3 g of triethylamine, then, maintaining the temperature in the region of 20oC, a solution containing 6.8 g of 2-phthalimidomethyl 100 cm3dichloromethane. The resulting solution was stirred for 3 h at a temperature close to 20oC, then to it was added 100 cm3water and 150 cm3dichloromethane. The aqueous phase is separated by decantation and restrained 2 times 50 cm3dichloromethane. The combined organic phases are washed 3 times by 75 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in ethyl acetate get so 10.4 g of N-/2-(3,3-dimethylpiperidino)-carbonitril/-2-palmitoylated, melting at 158oC.

36 N. aqueous solution chloroethanol acid was added 16.7 g of 2-/3,3-dimethylpiperidino/-carbonyldiimidazole, maintaining the temperature in the region 40oC. Then the reaction mixture is heated at a temperature close to 85oC for 1 h and 30 min, then cooled to a temperature close to 20oC, and prilisaetsa to a mixture consisting of 300 cm3water and 250 cm3dichloromethane which was cooled to a temperature close to 0oC. the Mixture podslushivaet by adding 11 N. water solution of ammonia until a pH close to 9. The aqueous phase is separated by decantation and restrained 2 times in 100 cm3dichloromethane. The organic phases are combined, washed 4 times in 100 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get that way 14.2 g 2-/3,3-dimethylpiperidino/-carbonylation in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/3,3-Dimethylpiperidino/-carbonitriles can be obtained as follows. To a solution containing 7.9 g of 3,3-dimethylpiperidine and 7.7 g of triethylamine in 100 cm3dichloromethane is added at a temperature, nl is foreseen within 2 hours at a temperature of, close to the 20oC, then prilisaetsa to a mixture consisting of 75 cm3water and 100 cm3dichloromethane. The aqueous phase is separated by decantation and restrained 2 times 50 cm3dichloromethane. The organic phases are combined, washed with 3 times 30 cm3then by 30 cm31 N. aqueous solution chloroethanol acid and 3 times by 25 cm3water, dried on magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get so 16,8 g 2-/3,3-dimethylpiperidino/-carbonyldiimidazole in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 28. Conducting the synthesis according to the method similar to that described in example 27, but on the basis of 2.5 g of 2-{-2-amino-N-[2(N-methylaniline)-carbonitrile] -acetamido} -tert-butyl acetate and 0,83 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate and 1.9 g of 2-{N-[2-(N-methylaniline)-carbonitrile] -2-[3-(3-were)-ureido] -acetamido}-tert-butyl acetate, melting at 145oC.

2-{2-Amino-N-/2-(N-methylaniline)-carbonitril/-acetamido}-tert - butyl acetate can be obtained by the method similar to that described in example 27 for p-(N-methylaniline)-carbonitril/-2-telemediated} -tert-butyl acetate and 0,93 g of hydrazine hydrate. Get so 2.5 g of 2-{2-amino-N-/2-(N-methylaniline)-carbonitril/-acetamido} -tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-{ N-/2-(N-Methylaniline)-carbonitril/-2-telemediated} -tert-butyl acetate can be obtained by the method similar to that described in example 27 to obtain 2-{N-/2-(3,3-dimethylpiperidino)-carbonitril/2-telemediated}-tert-butyl acetate, but on the basis of 8,3 g N-/2-(N-methylaniline)-carbonitril/-2-palmitoylated, 1.1 g of an oil suspension of sodium hydride (50 wt.) and 4.5 g of bromoacetate tert-butyl. After recrystallization in ethyl acetate get so 3.4 g of 2-{N-/2-(N-methylaniline)-carbonitril/-2-phthalimidobutyl)-tert-butyl acetate, melting at 160oC.

N-/2-(N-Methylaniline)-carbonitril/-2-phthalimidobutyl can be obtained by the method similar to that described in example 27 to obtain the N/2-(3,3-dimethylpiperidino)-carbonitril/-2-palmitoylated, but on the basis of 6.8 g of 2-/N-methylaniline/-carbonylation, and 3.3 g of triethylamine and 6.8 g of 2-palmitoylethanolamide. After recrystallization in ethyl acetate get so 10.8 g of N-/2-(N-methylaniline)-carbonitril/-2-palmitoylethanolamide to that described in example 27 to obtain 2-/3,3-dimethylpiperidino/-carbonylation, but on the basis of 50 g digidrirovannoe chloride divalent tin, 70 cm36 N. aqueous solution chloroethanol acid and 17.5 g of 2-/N-methylaniline/-carbonyldiimidazole. After recrystallization in diisopropyl ether get so 10.3 g 2-/N-methylaniline/-carbonylation, melting at 127oC.

2-/N-Methylaniline/-carbonitriles can be obtained by the method similar to that described in example 27 to obtain 2-/3,3-dimethylpiperidino/-carbonyldiimidazole, but on the basis of 7.2 g of N-methylaniline, and 7.7 g of triethylamine and 13.6 g of 2-nitrobenzotrifluoride. Get so 17,7 g 2-/N-methylaniline/-carbonyldiimidazole in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 29. Conducting the synthesis according to the method similar to that described in example 27, but from 2 g of 2-{2-amino-N-[1,2,3,4-tetrahydro-1-chinolin)-carbonitrile] -acetamido} -tert-butyl acetate and 0.63 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate, 1.2 g 2-{2-[3-(3-were)-ureido] -N-2-(1,2,3,4-tetrahydro-1-chinolin)-carbonitrile] -acetamido}tert-butyl acetate, melting at t can be obtained by the method, similar to that described in example 27 to obtain 2-{2-amino-N-/2-(3,3-dimethylpiperidino)-carbonitril/-acetamido} -tert-butyl acetate, but on the basis of 4.4 g of 2-{2-phthalimido-N-[2-(1,2,3,4-tetrahydro-1-chinolin)-carbonitrile] -acetamido}-tert-butyl acetate and 1.2 g of hydrazine hydrate. Thus receive the 2.1 g of 2-{2-amino-N-[2-(1,2,3,4-tetrahydro-1-chinolin)-carbonitrile] -acetamido} -tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-{ 2-Phthalimido-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-carbonitril/- acetamido} -tert-butyl acetate can be obtained by the method similar to that described in example 27 to obtain 2-{N-/2-(3,3-dimethylpiperidino)-carbonitril/-2-telemediated}-tert-butyl acetate, but according to 31.5 g of 2-phthalimido-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-carbonitril/-ndimethylacetamide, 3.75 g of an oil suspension of sodium hydride (50 wt.) and 16.1 g of bromine tert-butyl acetate. After recrystallization in ethyl acetate get that way of 26.5 g of 2-{2-phthalimido-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-carbonitril/-acetamido}-tert-butyl acetate, melting at 150oC.

2 Phthalimido-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-carbonitril/-ndimethylacetamide can be obtained by the method similar to that is based on a 20.2 g 2-/1,2,3,4-tetrahydro-1-chinolin/-carbonylation, of 9.1 g of triethylamine and 19.7 g of 2-palmitoylethanolamide. After recrystallization in ethyl acetate get so 31.6 2 phthalimido-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-carbonitril/-ndimethylacetamide, melting at 130oC.

2-/1,2,3,4-Tetrahydro-1-chinolin/-carbonitrile can be obtained by the method similar to that described in example 27 to obtain 2-/3,3-dimethylpiperidino/-carbonylation, but on the basis of 114 g digidratirovannogo chloride divalent tin, 140 cm36 N. aqueous solution chloroethanol acid and 39.7 g 2-/1,2,3,4-tetrahydro-1-chinolin/-carbonyldiimidazole. After recrystallization in ethyl acetate get so 20,2 g 2-/1,2,3,4-tetrahydro-1-chinolin/-carbonylation, melting at 102oC.

2-/1,2,3,4-Tetrahydro-1-chinolin/-carbonitriles can be obtained by the method similar to that described in example 27 to obtain 2-/3,3-dimethylpiperidino/-carbonyldiimidazole, but on the basis of 20 g of 1,2,3,4-tetrahydroquinoline, 16.5 g of triethylamine and 29.7 g of 2-nitrobenzaldehyde. After recrystallization in ethyl acetate get so 39,7 g 2-/1,2,3,4-tetrahydro-1-chinolin/-carbonyldiimidazole, melting at 155oC.

P R I m e R 30. To a solution containing 2,6 Ute at a temperature close to the 20oC, 1.07 g of isocyanate 3-methylphenyl. The resulting solution was stirred for 2 h at a temperature close to 20oC, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residual liquid oil is purified by chromatography on 150 g of silica (0,063-0.2 mm) in a column 2 cm in diameter (eluent: cyclohexane-ethyl acetate (50:50 by volume), collecting fractions of 20 cm3. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in ethyl acetate get to 1.15 g of 2-{ N-/2-anilinophenol/-2-/3-(3-were)-ureido/acetamido}-tert-butyl acetate, melting at 180oC.

2/2-Amino-N-(2-anilinophenol)-acetamido/tert-butyl acetate can be obtained in the following way. To a solution containing 4,2 g 2-/N-(2-anilinophenol)-2-telemediated/-acetate tert-butyl 100 cm3methanol was added 1.3 g of hydrazine hydrate. The reaction mixture was stirred for 5 h at a temperature close to 20oC, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residue is processed using a 200 cm3diethyl ether, and the insoluble product is P>C. thus Receive the 2.6 g of 2-/2-amino-N-(2-anilinophenol)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Anilinophenol)-2-telemediated/tert-butyl acetate can be obtained in the following way. To survive in an argon atmosphere to a solution containing 8.7 g of N-/2-anilinophenol/-2-telemediated 100 cm3anhydrous tetrahydrofuran, are added at a temperature close to 10oC, 1.1 g of an oil suspension of sodium (50 wt.) and stir the resulting suspension for 1 h at a temperature close to 20oC. and Then added to the solution containing 4.6 g of bromoacetate tert-butyl 20 cm3anhydrous tetrahydrofuran (THF) and continue stirring for 3 h at a temperature close to 20oC. the Reaction mixture was then prilisaetsa to cooled to a temperature close to 0oC, a mixture consisting of 100 cm3water and 200 cm3ethyl acetate. The aqueous phase is separated by decantation and restrained 2 times in 20 cm3ethyl acetate. The organic phases are combined, washed with 3 times 25 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and eghosa at 205oC.

N-/2-Anilinophenol/-2-phthalimidobutyl can be obtained as follows. To survive in an argon atmosphere to a solution containing 9.2 grams of N-phenyl-1,2-diaminobenzene and 5.1 g of triethylamine in 60 cm3dichloromethane is added, maintaining the temperature within the 20oC, a solution containing 11.2 g of 2-palmitoylethanolamide 60 cm3dichloromethane. The resulting solution was stirred for 2 h at a temperature close to 20oC, then to it was added 100 cm3water. The aqueous phase is separated by decantation, then restrained 2 times 50 cm3dichloromethane. The organic phases are combined, washed with 2 times 30 cm3water, dried on magnesium sulfate, filtered, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in ethyl acetate get so 8.8 g of N-/2-anilinophenol/-2-palmitoylated, melting at 191oC.

P R I m e R 31. To survive in an argon atmosphere to a solution containing 1.1 g of 3-/1-hydroxyethyl/-aniline in 20 cm3anhydrous tetrahydrofuran, are added at a temperature close to 20oC, 3 g 2-/N-(3-methoxyphenyl)-isocyanatoacetate/-N-methyl-N-phenylacetamide. Received Meganom pressure (2.7 kPa) and at 40oC. the Residual liquid oil is purified by chromatography on 150 g of silica (0,063-0.2 mm) in a column 2.5 cm in diameter (eluent: dichloromethane-methanol (98:2 by volume), collecting fractions of 20 cm3. The fractions containing only the desired product are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in diisopropyl ether obtain 1.7 g 2-{2-[3-/3-(1-hydroxyethyl)-phenyl/-ureido]-N-/3-methoxyphenyl/-acetamido}-N-methyl-N-phenylacetamide-/RS/, melting at 115oC.

P R I m e R 32. Conducting the synthesis according to the method similar to that described in example 31, but from 0,86 g 3-/1-hydroxyethyl/-aniline and 2.8 g of 2-/N-(2-ethoxycarbonylphenyl)-isocyanatoacetate/-N-methyl-N-phenylacetamide, obtained after recrystallization in ethyl acetate 2 g 2-{2-[3-/3-(1-hydroxyethyl)-phenyl/-ureido] -N-/2-ethoxycarbonylphenyl/-acetamido} -N-methyl-N-phenylacetamide, melting at 195oC.

2-/N-(2-Ethoxycarbonylphenyl/-isocyanatoacetate/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 26 to obtain 2-/N-(3-methoxyphenyl)-isocyanatoacetate/-N-methyl-N-phenylacetamide, but from 1.1 g of isocyanatoacetate 2.2 g 2-/2-evildevil)-isocyanatoacetate/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/2-Ethoxycarbonylphenyl/-amino-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 26 to obtain 2-/3-methoxyphenyl/-amino-N-methyl-N-phenylacetamide, but on the basis of 3.1 g of 2-/N-(2-ethoxycarbonylphenyl)-triptoreline/-N-methyl-N-phenylacetamide and 7.5 cm32 N. an aqueous solution of sodium hydroxide. Get thus, 2.2 g 2-/2-ethoxycarbonylphenyl/-amino-N-methyl-N-phenylacetamide, melting at 100oC.

2-/N-(2-Ethoxycarbonylphenyl)-trifurcated/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 26 to obtain 2-/N-(3-methoxyphenyl)-triptoreline/-N-methyl-N-phenylacetamide, but on the basis of 5.8 g of 2-triptoreline ethyl and 1.3 g of an oil suspension of sodium hydrate (50 wt.) and 7.3 g of bromo-N-methyl-N-phenylacetamide. Get so 5,7 g 2-/N-(2-Ethoxycarbonylphenyl)-trifurcated/-N-methyl-N-phenylacetamide, melting at 95oC.

2-Triptoreline ethyl can be obtained by the method similar to that described in example 26 to obtain the N-/3-methoxyphenyl/-trifurcated, but from 4.1 g of 2-amentia, melting at 78oC.

P R I m e R 33. Conducting the synthesis according to the method similar to that described in example 31, but from 0,86 g 3-hydroxymethylbilane and 2.9 g of 2-/N-(2-ethoxycarbonylphenyl)-isocyanatoacetate/-N-methyl-N-phenylacetamide, obtained after recrystallization in ethyl acetate 2-{N-/2-ethoxycarbonylphenyl/-2-/3-(3-hydroxymethylene)-ureido/- acetamido}-N-methyl-N-phenylacetamide, melting at 184oC.

P R I m e R 34. Conducting the synthesis according to the method similar to that described in example 31, but from 1.1 g of 3-hydroxymethylbilane and 3.2 g of 2-N-(3-methoxyphenyl)-isocyanatoacetate/-N-methyl-N-phenylacetamide, obtained after recrystallization in ethyl acetate 2.6 g 2-{2-/3-(3-hydroxymethylene)-ureido/-N-/3-methoxyphenyl/-acetamido} -N-methyl-N-phenylacetamide, melting at 142oC.

P R I m e R 35. Conducting the synthesis according to the method similar to that described in example 27, but on the basis of 3.1 g of 2-/2-amino-N-(3-ethoxycarbonylphenyl)-acetamido/-N-methyl-N-phenylacetamide and 1.2 g of isocyanate 3-methylphenyl, obtained after recrystallization in diisopropyl ether, 2 g of 2-{N-/3-ethoxycarbonylphenyl/-2-/3-(3-were)-ureido/-acetamido}-N-methyl-N-phenylacetamide, melting at 88oC.

2-/2-Amino-N-(is that described in example 27 to obtain 2-{2-amino-N-/2-(3,3-dimethylpiperidino)-carbonitril/-acetamido} -tert-butyl acetate, but judging from 4.2 g of 2-N-(3-ethoxycarbonylphenyl)-2-telemediated/-N-methyl-N-phenylacetamide and 1.25 g of hydrazine hydrate. Get so 3 g 2-/2-amino-N-(3-ethoxycarbonylphenyl)-acetamido/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(3-Ethoxycarbonylphenyl)-2-telemediated/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 27 to obtain 2-{N-/2-3,3-dimethylpiperidino)-carbonitril/-2-telemediated} -tert-butyl acetate, but based on a 3.9 g of N-(3-ethoxycarbonylphenyl/-2-palmitoylated, 0.64 g of an oil suspension of sodium hydride (50 wt.) and 3.3 g of 2-bromo-N-methyl-N-phenylacetamide. Get so 4,2 g 2-/N-(3-ethoxycarbonylphenyl)-2-telemediated/-N-methyl-N-phenylacetamide.

N-/3-Ethoxycarbonylphenyl/-2-phthalimidobutyl can be obtained by the method similar to that described in example 27 to obtain the N/2-(3,3-dimethylpiperidino)-carbonitril/-2-palmitoylated, but starting from 5 g of 3-aminobenzoate ethyl, 3,9 g of triethylamine and 8.1 g of 2-palmitoylethanolamide. After recrystallization in ethyl acetate get so 8.7 g of N-/3-ethoxycarbonylphenyl/-2-telemediated the Isan in example 26, but based on 0.5 g of 3-{N-/N-methyl-N-phenylcarbamoyl/-2-/3-(3-were)-ureido/acetamido}-ethylbenzoic and 1 cm31 N. aqueous sodium hydroxide solution. Get so 0.3 g of 3-{N-/N-methyl-N-phenylcarbamoyl/-2-/3-(3-were)-ureido/-acetamido} -benzoic acid, melting at 140oC.

P R I m e R 37. Spend the synthesis according to the method similar to that described in example 26, but on the basis of a 2.45 g of 3-{3-/N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/-ureido} -phenylethylamine and 4.6 cm31 N. aqueous sodium hydroxide solution. Get so 1.6 g of 3-{ 3-/N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/-ureido}-phenylacetic acid, melting at 120oC.

3-{ 3-/N-(3-Methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/- ureido} -fenilatilamin can be obtained by the method similar to that described in example 26 to obtain 3-{3-/N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/-ureido)-ethylbenzoic, but on the basis of 2.4 g 2-/N-(3-methoxyphenyl)-isocyanatoacetate/-N-methyl-N-phenylacetamide and 1.1 g of 3-aminophenethyl-acetate. The crude product is purified by chromatography on 60 silica (0,063-0.2 mm) in the column with the diameter of Auda and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get that way of 2.45 g of 3-{ 3-/N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/- ureido} -phenylethylamine in the form of amorphous powder, used as it is, for the subsequent syntheses.

3-Aminophenylacetate can be obtained as follows. To a solution containing 2.0 g of 3-nitrophenylacetate 20 cm3ethanol was added 0.1 g of palladium deposited on activated charcoal containing 5% Suspension stirred for 2 h at a temperature close to 25oC in hydrogen atmosphere (100 kPa). The catalyst is separated by filtration, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 1.7 g of 3-aminophenylacetate in the form of liquid oil, used as it is, for the subsequent syntheses.

3-Nitrophenylacetate ethyl can be obtained according to the method described in the article Segers et A. Bruylants, Bul. Soc. Chim. Belg. 64, 87 (1955).

P R I m e R 38. To survive in the atmosphere of nitrogen to a solution containing 1.2 g of tribromide boron 20 cm3dichloromethane, at a temperature close to -55oC, was added for 5 min, the suspension containing 0.8 g of 3-{3-/N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbanilate is at a temperature close to -55oC, then for 20 h at a temperature close to 20oC. Then add 20 cm3water, then 5 cm31 N. aqueous sodium hydroxide solution. The organic phase is separated by decantation, the aqueous phase is washed 2 times with 20 cm3ethyl acetate, then acidified using 5 cm31 N. aqueous solution chloroethanol acid. The formed precipitate is separated in the filtration, washed 3 times for 5 cm3water and dried in air. Get so 0.3 g of 3-{3-/N-(3-hydroxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/-ureido}-phenylacetic acid, melting at 148oC.

P R I m e R 39. Conducting the synthesis according to the method similar to that described in example 1, but from 1.2 g 2-/2-amino-N-(2-were)-acetamido/-N-methyl-N-phenylacetamide and 1.3 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate, 2.3 g of 2-{N-/2-were/-2-/3-were)-ureido/-acetamido} -N-methyl-N-phenylacetamide, melting at 193oC.

2-/2-Amino-N-(2-were)-acetamido/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-A1,2 g of hydrazine hydrate. Get so 3.8 g of 2-[2-amino-N-(2-were)-acetamido] -N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Were)-2-telemediated/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 5.9 g of N-/2-were/-2-palmitoylated and 1.15 g of an oil suspension of sodium hydride (50 wt.) and 6.8 g of 2-bromo-N-methyl-N-phenylacetamide. After recrystallization in diisopropyl ether get so 7,1 g 2-/N-(2-were)-2-telemediated/-N-methyl-N-phenylacetamide, melting at 120oC.

N-/2-Were/- 2-phthalimidobutyl can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-trifloromethyl/-ndimethylacetamide, but on the basis of the 5.4 g 2-methylaniline, 6.6 g of triethylamine and 13.4 g of 2-palmitoylethanolamide. After recrystallization in ethyl acetate receive thus to 14.4 g of N-/2-were/-2-palmitoylated, melting at 254oC.

P R I m e R 40. Conducting the synthesis according to the method similar to that described in example 1, but iChat after recrystallization in ethyl acetate, 1.5 g of 2-{N-/2-methoxyphenyl/-2-/3-(3-were)-ureido/-acetamido} -N-methyl-N-phenylacetamide, melting at 212oC.

2-/2-Amino-N-(2-methoxyphenyl)-acetamido/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 4.0 g 2-/N-(2-methoxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide and 1.3 g of hydrazine hydrate. Get so 2.0 g 2-/2-amino-N-(2-methoxyphenyl)-acetamido/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-N-(2-Methoxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 6.2 g of N-/2-methoxyphenyl/-2-palmitoylated and 1.15 g of an oil suspension of sodium hydride (50 wt.) and 6.8 g of 2-bromo-N-methyl-N-phenylacetamide. After recrystallization in ethyl acetate get so 5,1 g 2-/N-(2-methoxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide, melting at 199oC.

N-/2-Methoxyphenyl/-2-phthalimidobutyl can be obtained by the method similar to that described in example 4 to obtain 2-nafta is acetylchloride. After recrystallization in acetonitrile get thus 14.6 g of N-/2-methoxyphenyl/-2-palmitoylated, melting at 211oC.

P R I m e R 41. Conducting the synthesis according to the method similar to that described in example 1, but on the basis of 4.7 g of 2-/2-amino-N-(2-phenoxyphenyl)-acetamido/tert-butyl acetate and 1.9 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate 1.7 g 2-{2-/3-(3-were)-ureido/-N-/2-phenoxyphenyl/-acetamido}-tert - butyl acetate, melting at 204oC.

2-/2-Amino-N-(2-phenoxyphenyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 6.3 g of 2-/N-(2-phenoxyphenyl)-2-telemediated/tert-butyl acetate and 2 g of hydrazine hydrate. Get so 4.7g 2-/2-amino-N-(2-phenoxyphenyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Phenoxyphenyl)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, Notre-butyl acetate. Get so 7,1 g 2-/N-(2-phenoxyphenyl)-2-telemediated/tert-butyl acetate, melting at 145oC.

N-/2-Phenoxyphenyl/-2-phthalimidobutyl can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N-(2-trifloromethyl)-ndimethylacetamide, but on the basis of 4.6 g of 2-phenoxyimino, 2.5 g of triethylamine and 5.6 g of 2-palmitoylethanolamide. Get so 8,3 g N-/2-phenoxyphenyl/-2-palmitoylated, melting at 143oC.

P R I m e R 42. Conducting the synthesis according to the method similar to that described in example 1, but from 5.8 g of 2-/2-amino-N-(2-biphenylyl)-acetamido)-acetate tert-butyl and 2.3 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate 3.7 g of 2-{N-/2-biphenylyl/-2-/3-(3-were)-ureido/acetamido}-tert-butyl acetate, melting at 177oC.

2-/2-Amino-N-(2-biphenylyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 7.5 g 2-/N-(2-biphenylyl)-2-telemediated/tert-butyl acetate and 2.4 g of hydrazine hydrate. Get so 5,8 g 2-/2-amino-N-(2-biphenylyl)-acetamido/tre is/N-(2-Biphenylyl)-2-telemediated/tert-butyl acetate can be obtained by the method, similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 6.5 g of N-/2-biphenylyl/-2-palmitoylated, 0.87 g of an oil suspension of sodium hydride (50 wt.) and 3.6 g of bromoacetate tert-butyl. Get so 8 g 2-/N-(2-biphenylyl)-2-telemediated/tert-butyl acetate, melting at 145oC.

N-(2-Biphenylyl)-2-phthalimidobutyl can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-trifloromethyl/-ndimethylacetamide, but judging from 4.2 g of 2-aminobiphenyl, 2.7 g of triethylamine and 5.6 g of 2-palmitoylethanolamide. Get that image of 7.1 g of 2-phthalimido-N/2-biphenylyl/-ndimethylacetamide, melting at 204oC.

P R I m e R 43. Conducting the synthesis according to the method similar to that described in example 1, but from 8,1 g 2-/2-amino-N-(2-benzoylphenyl)-acetamido/tert-butyl acetate and 3 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate and 6.6 g of 2-{N-/2-benzylphenol/-2-/3-(3-were)-ureido/-acetamido}-tert-butyl acetate, melting at 183oC.

2-/2-Amino-N-(2-benzoylphenyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described-benzoylphenyl)-2-telemediated/tert-butyl acetate and 3.5 g of hydrazine hydrate. Get so 8,1 g 2-/2-amino-N-(2-benzoylphenyl)-acetamido-tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Benzoylphenyl)-2-phthalimido-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 9.3 g of N-/2-benzylphenol/-2-palmitoylated, 1.4 g of an oil suspension of sodium hydride (50 wt.) and 5.9 g of bromo-tert-butyl acetate. Get that way 11.3 g 2-/N-(2-benzoylphenyl)-2-telemediated/tert-butyl acetate, melting at 190oC.

N-/2-Benzylphenol/-2-phthalimidobutyl can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-trifloromethyl/-ndimethylacetamide, but on the basis of 4.6 g of 2-benzylaniline, 3 g of triethylamine and 7.3 g of 2-palmitoylethanolamide. Get so 9.3 g of N-/2-benzylphenol/-2-palmitoylated, melting at 232oC.

P R I m e R 44. Conducting the synthesis according to the method similar to that described in example 1, but based on 3,3 g 2-/2-amino-N-(3-ethoxycarbonylphenyl)-acetamido/tert-butyl acetate and 1.3 g of isocyanate 3-methylphenyl, Polo/-acetamido} -tert-butyl acetate, melting at 71oC.

2-/2-Amino-N-(3-ethoxycarbonylphenyl)-acetamido/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but starting from 5 g 2-/N-(3-ethoxycarbonylphenyl)-2-telemediated/tert-butyl acetate and 1.6 g of hydrazine hydrate. Get so 3,3 g 2-/2-amino-N-(3-ethoxycarbonylphenyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(3-ethoxycarbonylphenyl)-2-telemediated/tert-butyl acetate can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 6 g of N-/3-ethoxycarbonylphenyl/-2-palmitoylated, 1 g of an oil suspension of sodium hydride (50 wt.) and 4 g of bromo-tert-butyl acetate. Get so 5,1 g 2-/N-(3-ethoxycarbonylphenyl)-2-telemediated/tert-butyl acetate in the form of liquid oil, used as it is, for the subsequent syntheses.

N-/3-Ethoxycarbonylphenyl/-2-phthalimidobutyl can be obtained by the method similar to that described in 2.4 g of triethylamine and 5.8 g of 2-palmitoylethanolamide. Get so 6.2 g of N-/3-ethoxycarbonylphenyl/-2-palmitoylated, melting at 219oC.

P R I m e R 45. Conducting the synthesis according to the method similar to that described in example 1, but from 2.25 g 2/2-amino-N-(2-ethoxycarbonylphenyl)-acetamido/-N-methyl-N-phenylacetamide and 0.88 g of isocyanate 3-methylphenyl, obtained after recrystallization in ethyl acetate, 1.6 g of 2-{N-/2-ethoxycarbonylphenyl/-2-/3-(3-were)-ureido/-acetamido} - N-methyl-N-phenylacetamide, melting at 201oC.

2-/2-Amino-N-(2-ethoxycarbonylphenyl)-acetamido/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 3.0 g 2-/N-(2-ethoxycarbonylphenyl)-2-telemediated/-N-methyl-N-phenylacetamide and 0.9 g of hydrazine hydrate. Get so 2.25 g 2-/2-amino-N-(2-ethoxycarbonylphenyl)-acetamido/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(2-Ethoxycarbonylphenyl)-2-telemediated/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-phthalimido-N-(2-tripto the g oil suspension of sodium hydride (50 wt.) and 5.25 g of 2-bromo-N-methyl-N-phenylacetamide. After recrystallization in ethyl acetate get so 3.0 g 2-/N-(2-ethoxycarbonylphenyl)-2-telemediated/-N-methyl-N-phenylacetamide, melting at 202oC.

N-/2-Ethoxycarbonylphenyl/-2-phthalimidobutyl can be obtained by the method similar to that described in example 4 to obtain 2-phthalimido-N/2-trifloromethyl/-ndimethylacetamide, but from 4.1 g of 2-aminobenzoate ethyl, 2.8 g of triethylamine and 5.6 g of 2-palmitoylethanolamide. After recrystallization in ethyl acetate get so 8.7 g of N-/2-ethoxycarbonylphenyl/-2-palmitoylated, melting at 197oC.

P R I m e R 46. Conducting the synthesis according to the method similar to that described in example 27, but from 2 g of 2-{2-amino-N-/2-(N-methylaniline)-carbonitril/-acetamido} -N-methyl-N - phenylacetamide and 0.62 g of isocyanate 3-methylphenyl, obtain 1.45 g of 2-{N-[2-(N-methylaniline)-carbonitrile]-2-[3-(3-were)-ureido]- acetamido}-N-methyl-N-phenylacetamide, melting at 140oC.

2-{ 2-Amino-N-/2-(N-methylaniline)-carbonitril/-acetamido} -N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 27 to obtain 2-{2-amino-N-/2-(3,3-dimethylpiperidino)-carbonitril/-acetamido} -tert-butyl is 0.75 g of hydrazine hydrate. Get thus 2 g of 2-{2-amino-N-/2-(N-methylaniline)-carbonitril/-acetamido}-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

N-Methyl-2-{ N-/2-(N-methylaniline)-carbonitril/-2-telemediated}-N-phenylacetamide can be obtained as follows. To a suspension containing 8,3 g N-/2-(N-methylaniline)-carbonitril/-2-palmitoylated and 3 g of potassium carbonate in 50 cm3N,N-dimethylformamide, is added at a temperature close to 20oC, a solution containing 4,6 2-bromo-N-methyl-N-phenylacetamide 25 cm3N, N-dimethylformamide. The resulting mixture was stirred for 120 h, then prilisaetsa to 800 cm3water. The insoluble product is separated by filtration, washed 4 times in 100 cm3water, dried in air and purified by chromatography on 90 g of silica (0.04 to 0,063 mm) in a column with a diameter of 3.2 cm (eluent: dichloromethane), by collecting fractions of 50 cm3. Fractions with 60-90 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at the 50oC. thus Receive the 2.8 g of N-methyl-2-{N-/2-(N-methylaniline)-carbonitril/-2-telemediated}-N-phenylacetamide in the form of amorphous solids, the, similar to that described in example 27, but on the basis of 1.45 g of 2-amino-N-/3,3-dimethylimidodicarbonimidic/-N-/2-(N-methylaniline)-carbonitril/-ndimethylacetamide and 0.63 g of 3-isocyanatoacetate, get 1 g of 3-{3-N-(3,3-dimethylimidodicarbonimidic)-N-[2-(N-methylaniline)-carbonitrile] -carbonylmethyl} -ureido-ethylbenzoic, melting at 225oC.

2-Amino-N-(3,3-dimethylimidodicarbonimidic/-N-/2-(N-methylaniline)-carbonitril/-ndimethylacetamide can be obtained by the method similar to that described in example 27 to obtain 2-{2-amino-N-/2-(3,3-dimethylpiperidino)-carbonitril/-acetamido} -tert-butyl acetate, but on the basis of 2.3 g of N-(3,3-dimethylimidodicarbonimidic)-N/2-(N-methylaniline)-carbonitril/-2-palmitoylated and 0.6 g of hydrazine hydrate. Get so 1.45 g of 2-amino-N-/3,3-dimethylimidodicarbonimidic/-N-/2-(N-methylaniline)-carbonitril/-ndimethylacetamide as liquid oil, used as it is, for the subsequent syntheses.

N/a 3.3-Dimethylimidodicarbonimidic/-N-/2-(N-methylaniline)-carbonitril/-2-phthalimidobutyl can be obtained as follows. To a solution containing 6.8 g of 2-{N-/2-(N-methylaniline)-carbonitril/-2-telemediated} -acetic acid and 30 mg of N,N-dimethyl-4-the P>C, 2.35 g of N,N'-diaminostilbene and 1.6 g of 3,3-dimethylpiperidine. The mixture is stirred for 70 hours at a temperature close to 20oC, then concentrated to dryness under reduced pressure (2.7 kPa) and at the 50oC. the Residue is dissolved in 250 cm3dichloromethane, and the resulting solution is washed 2 times with 75 cm31 N. aqueous sodium hydroxide solution, then through a 100 cm3water. The organic phase is dried on magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) and at 60oC. thus Receive the 6.6 g N/a 3.3-dimethylimidodicarbonimidic/-N-/2-(N-methylaniline)-carbonitril/-2-palmitoylated, melting at 180oC.

2-{ N-/2-(N-methylaniline)-carbonitril/-2-telemediated} acetic acid can be obtained in the following way. The solution containing 7.9 g of 2-{ N-/2-(N-methylaniline)-carbonitril/-2-telemediated}- tert-butyl acetate in 30 cm3triperoxonane acid, is stirred at a temperature close to 20oC for 24 h, then prilisaetsa 50 cm3water. The aqueous phase is extracted 3 times with 250 cm3dichloromethane. The organic phases are combined, washed 2 times with 150 cm3water, dried at Sul is OK processed using a 100 cm3petroleum ether, and the insoluble product is separated by filtration and dried under reduced pressure (15 kPa) and at 30oC. thus Receive the 6.8 g of 2-{N-/2-(N-methylaniline)-carbonitril/-2-telemediated} -acetic acid as an amorphous solid used as it is, for the subsequent syntheses.

P R I m e R 48. Conducting the synthesis according to the method similar to that described in example 27, but on the basis of 1.8 g 2-/2-amino-N-(2-tertbutoxycarbonyl)-acetamido/tert-butyl acetate and 0.64 g of isocyanate 3-methylphenyl get 1.3 g 2-{2-[3-(3-were)-ureido]-N-(2-tert-butoxycarbonylmethyl)-acetamido}-tert-butyl acetate, melting at 146oC.

2-/2-Amino-N-(2-tert-butoxycarbonylmethyl)-acetamido/tert - butyl acetate can be obtained by the method similar to that described in example 27 to obtain 2-{2-amino-N-/2-(3,3-dimethylpiperidino)-carbonitril/-acetamido}-tert-butyl acetate, but on the basis of 2.4 g 2-/2-phthalimido-N-(2-tert-butoxycarbonylmethyl)-acetamido/tert - butyl acetate and 0.7 g of hydrazine hydrate. Get so 1.8 g 2-/2-amino-N-(2-tert-butoxycarbonylmethyl)-acetamido/tert-butyl acetate in the form of liquid oil, used as it is for sweat to be obtained by the method, similar to that described in example 46 to obtain 2-{N-/2-(N-methylaniline)-carbonitril/-2-telemediated}-N-methyl-N-phenylacetamide, but on the basis of 3.8 g of 2-/2-telemediated/-benzoate-tert-butyl, 2.15 g of bromoacetate tert-butyl and 1.5 g of potassium carbonate. Get thus 2 g 2-/2-phthalimido-N-(2-tert-butoxycarbonylmethyl)-acetamido/tert - butyl acetate, melting at 143oC.

2-/2-Telemediated/-tert-butyl-benzoate can be obtained by the method similar to that described in example 27 to obtain the N/2-(3,3-dimethylpiperidino)-carbonitril/-2-palmitoylated, but on the basis of 3.3 grams of anthranilate tert-butyl, 4,96 g of 2-palmitoylethanolamide and 2.24 g of triethylamine. Get so 5,6 g 2-/2-telemediated/-benzoate tert-butyl, melting at 159oC.

Anthranilate tert-butyl can be obtained according to the method described in the article by W. E. Gaines, N. B. Carson, J. Econ. Entomol. 39, 763 (1946).

P R I m e R 49. To a solution containing 1.7 g of 2-{2/(1-imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-acetamido} -N-methyl-N-phenylacetamide 35 cm3toluene, was added 1.1 g of 2-/3-AMINOPHENYL)-ethanol. The mixture is heated at a temperature of education phlegmy for 4 h, then concentrated to dryness under pangmalaysia by 20 cm32 N. an aqueous solution chloroethanol acid, then 2 times to 25 cm3. The organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the resulting crude product was then purified by chromatography on 50 g of silica (0,065-mm 0,205), located in a column with a diameter of 2.1 cm (eluent: ethyl acetate-ethanol (95:5 by volume), collecting fractions of 20 cm3. Fractions 4 to 6 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in a mixture of diisopropyl ether and ethyl acetate (90:10 by volume), gain of 0.85 g 2-{2-[3-/3-(2-hydroxyethyl)-phenyl/-ureido]-N-(3-methoxyphenyl)-acetamido}-N-methyl-N-phenylacetamide, melting at 90oC.

2-{2-(1-Imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-acetamido}-N-methyl-N-phenylacetamide can be obtained as follows. To a solution containing 3,0 N, N'-diimidazole 30 cm3anhydrous tetrahydrofuran is added a solution containing 3,1 2-/2-amino-N-(3-methoxyphenyl)-acetamido/-N-methyl-N-phenylacetamide 30 cm3anhydrous tetrahydrofuran. The solution is stirred for 16 hours at a temperature close to 25oC, then concentrated to dryness under p is romihaitza consistently 4 times in 30 cm3water and by 30 cm3saturated aqueous solution of sodium chloride. The organic phase is dried on magnesium sulfate, the flow is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in ethyl acetate to obtain 3.5 g of 2-{2-/(1-imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-acetamido} -N-methyl-N-phenylacetamide, melting at 130oC.

2-/3-AMINOPHENYL/-ethanol can be obtained according to the method described in the article Century. rnmalm et coll. Acta Pharm. Suedica, 11, 33, (1974).

P R I m e R 50. Spend the synthesis according to the method similar to that described in example 26, but from 2 g of 2-{3-[3-N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/- ureido] -phenyl} -methyl propionate (RS) and 3.8 cm31 N. aqueous sodium hydroxide solution. Get so 1.3 g of 2-{3-/3-/N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/ -ureido] -phenyl} -propionic acid (RS), melting at 127oC.

2-{ 3-[3-N-(3-Methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/-ureido] -phenyl} -methyl propionate (RS) can be obtained by the method similar to that described in example 49 to obtain 2-{2-[3-/3-(2-hydroxyethyl)-phenyl/-ureido]-N-/3-methoxyphenyl/- acetamido}-N-methyl-N-FeNi is a and 2.1 g of 2-/3-AMINOPHENYL/-methyl propionate (RS). The resulting crude product was then purified by chromatography on 50 g of silica (0,065-0,200 mm) in a column 2.5 cm in diameter (eluent: methylene chloride-ethyl acetate (60:40 by volume), collecting fractions of 50 cm3. Fractions 5 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 2.1 g of 2-{3-[3-N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl/-ureido] -phenyl} -methyl propionate (RS) in the form of a substance of the type "meringue", used as it is, for the subsequent syntheses.

2-/3-AMINOPHENYL/-methyl propionate (RS) can be obtained as follows. To a solution containing 4 g of 2-/3-nitrophenyl/-methyl propionate (RS) 50 cm3ethanol was added 0.3 g of palladium deposited on activated charcoal containing 5% Suspension stirred for 2 h at a temperature close to 25oC in hydrogen atmosphere (100 kPa). Then the catalyst is separated by filtration, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get that way of 3.3 g of 2-/3-AMINOPHENYL/-methyl propionate (RS) in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/3-Nitrophenyl/-methyl-propionate (RS) can be half Astor, containing 5 g of 2-/3-nitrophenyl/-propionitrile-(RS) 40 cm3of methanol. The resulting mixture is stirred at a temperature of education phlegmy for 30 min, and then the insoluble product is separated by filtration. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Crude product is purified by chromatography on 80 g of silica (0,065-0,200 mm) in a column with a diameter of 3.5 cm (eluent: petroleum ether-ethyl acetate (80:20 by volume), collecting fractions of 100 cm3. Fractions 1 and 2 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. Get so 4.0 g of 2-/3-nitrophenyl/-methyl propionate (RS) in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/3-Nitrophenyl/-propionitrile-(RS) can be obtained according to the method described in the article by E. Felder et coll. J. Med. Chem. 13, 559, (1970).

P R I m e R 51. Spend the synthesis according to the method similar to that described in example 49, but on the basis of 1.7 g of 2-{2-/(1-imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-acetamido}-N - methyl-N-phenylacetamide and 1.4 g of 5-/3-aminobenzyl/-tetrazole. The resulting crude product was then purified by chromatography on 40 g of silica (0,065-0,200 mm) in the colon which 23 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in a mixture of ethyl acetate-diisopropyl ether (10:90 by volume) thus receive the 0.2 g of 2-{ N-/3-methoxyphenyl/-2-{ 3-[3-/(5-tetrazolyl)-methyl-phenyl]-ureido}-acetamido} -N-methyl-N-phenylacetamide, melting at 120oC.

5-/3-Aminobenzyl/-tetrazol can be obtained as follows. To a solution containing 3.9 g of 5-/3-nitrobenzyl/-tetrazole 80 cm3ethanol was added 0.3 g of palladium deposited on activated charcoal containing 5% Suspension stirred for 2 h at a temperature close to 25oC in hydrogen atmosphere (100 kPa). The catalyst is separated by filtration, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 3.1 g 5-/3-aminobenzyl/-tetrazole, melting at 140oC.

5-/3-Nitrobenzyl/-tetrazol can be obtained as follows. To a solution containing 1.6 g of 3-nitrophenylacetonitrile 25 cm3anhydrous DMF (dimethylformamide), gain of 1.43 g of sodium azide and 1,17 g anhydrous ammonium chloride. The mixture is stirred at a temperature close to 100oC for 22 h, then concentrated to dryness under reduced pressure (1.2 kPa) and at 80oC. the resulting residue is extracted by the P>3
of methylene chloride. The combined organic phases are dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 35oC. Get so 1.6 g 5-/3-nitrobenzyl/-tetrazole, melting at 140oC.

3-Nitrophenylacetonitrile can be obtained as follows. To a solution containing 20.6 g of 3-nitrobenzylamine 120 cm3methanol, add 20 cm38.5 M aqueous solution of potassium cyanide. The mixture is stirred at a temperature of education phlegmy for 4 h, then concentrated to dryness under reduced pressure (2.7 kPa) and at 45oC. the Residue is extracted by 200 cm3diethyl ether and 150 cm3water. The organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 35oC. the resulting crude product was then purified by chromatography on 50 g of silica (0,065-0,200 mm) in a column 2 cm in diameter (eluent: methylene chloride), collecting fractions at 30 cm3. Fractions 4 to 9 are combined and concentrated under reduced pressure (2.7 kPa) and at 40oC. Get so 11 g 3-nitrophenylacetonitrile, melting at 60oC.

P R I m e R 52. Spend the synthesis according to the method, the l/-acetamido}-N-methyl-N-phenylacetamide and 0.6 g of 3-aminophenylalanine. The crude product is purified by chromatography on 40 g of silica (0,065-0,200 mm) in a column 2 cm in diameter (eluent: ETANA-ethyl acetate (5: 95 by volume), collecting fractions of 10 cm3. Fractions 7 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in a mixture of ethyl acetate-diisopropyl ether (80: 20 by volume) to obtain 0.2 g 2-{2-/3-(3-hydroxymethylene)-ureido/-N-/3-hydroxyphenyl/-acetamido} -N-methyl-N-phenylacetamide, melting at 160oC.

2-{ 2-/(1-Imidazolyl)-carboxamido/-N-/3-hydroxyphenyl/-acetamido} -N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 49 to obtain 2-{2-/(1-imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-acetamido} -N-methyl-N-phenylacetamide, but on the basis of 0.9 g of 2-amino-N-(3-hydroxyphenyl)-acetamido/-N-methyl-N-phenylacetamide and 0.7 g of N, N'-diimidazole. Get so 0.9 g of 2-{2-/(1-imidazolyl)-carboxamido/-N-/3-hydroxyphenyl/-acetamido}-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/2-Amino-N-/3-hydroxyphenyl/-acetamido/-N-methyl-N-phenylacetamide can be obtained by the method similar to that of g 2-/N-(3-hydroxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide and 0.45 g of hydrazine hydrate. Get so 0.9 g 2-/2-amino-N-(3-hydroxyphenyl)-acetamido/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(3-Hydroxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide can be obtained as follows. To survive in the atmosphere of nitrogen at a temperature close to -50oC, 1 M solution volume of 13.3 cm3tribromide boron in methylene chloride was added over 10 min a solution containing 2 g 2-/N-(3-methoxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide 20 cm3of methylene chloride. The resulting mixture was stirred for 30 minutes at a temperature close to -50oC, then 16 hours at a temperature close to 20oC. Then add 25 cm3water, then 25 cm3of methylene chloride. The organic phase is separated by decantation, washed 4 times in 30 cm3water, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 0.9 g 2-/N-(3-hydroxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 53. Spend the synthesis according to the method similar to the one the cat is Anata 3-methylphenyl. The resulting crude product was then purified by chromatography on 40 g of silica (0,065-0,200 mm) in column (diameter 2.0 cm (eluent: cyclohexane-ethyl acetate (30:70 by volume), collecting fractions of 20 cm3. Fractions 5 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in a mixture of ethyl acetate-diisopropyl ether (10: 90 by volume) to obtain 0.3 g of 2-{N-/3-ethoxyphenyl/-2-/3-(3-were)-ureido/-acetamido}-N-methyl-N-phenylacetamide, melting at 98oC.

2-/2-Amino-N-(3-ethoxyphenyl)-acetamido/-N-methyl-N-phenylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 1.2 g 2-/N-(3-ethoxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide and 0.28 g of hydrazine hydrate. Get thus 1 g 2-/2-amino-N-(3-ethoxyphenyl)-acetamido/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

2-/N-(3-Ethoxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide can be obtained as follows. To a solution containing 2.7 g of 2-N-(3-hydroxyphenyl)-2-telemediated/-N-methyl-N-Federatsii of sodium hydride (50 wt.). The suspension is stirred for 30 minutes at a temperature close to 10oC, then add 1.0 g of ethyliodide. The mixture is stirred for 2 hours at a temperature close to 25oC, then prilisaetsa to a mixture consisting of 150 cm3water and 200 cm3ethyl acetate. The organic phase is separated by decantation, washed with 2 times 100 cm3water, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 35oC. the Crude product is purified by chromatography on 50 g of silica (0,063-0.2 mm) in a column 2.5 cm in diameter (eluent: cyclohexane-ethyl acetate (40: 60 by volume), collecting fractions of 20 cm3. Fractions 4 through 7 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 1.2 g 2-/N-(3-ethoxyphenyl)-2-telemediated/-N-methyl-N-phenylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 54. Spend the synthesis according to the method similar to that described in example 1, but on the basis of 0.8 g 2-/2-amino-N-(3-methoxyphenyl)-acetamido/-N-/2-forfinal/-N methylacetamide and 0.32 g of isocyanate 3-methylphenyl. The resulting product was then purified by chromatography on 40 g of cremaschi 20 cm3. Fractions 8 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in a mixture of diisopropyl ether-acetonitrile (90: 10 by volume) to obtain 0.7 g of N-/2-forfinal/-2-{N-/3-methoxyphenyl/-2-/3-(3-were)-ureido/-acetamido} -N-methylacetamide, melting at 110oC.

2-/2-Amino-N-(3-methoxyphenyl)-acetamido/-N-/2-forfinal/-N-methylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido)-acetate tert-butyl, but on the basis of 6.2 g of N-/2-forfinal/-2-/N-(3-methoxyphenyl)-2-telemediated/-N methylacetamide and 1.3 g of hydrazine hydrate. Get so 4.0 g 2-/2-amino-N-(3-methoxyphenyl)-acetamido/-N-/2-forfinal/-N methylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

N-/2-Forfinal/-2-/N-(3-methoxyphenyl-2-telemediated/-N-methylacetamide can be obtained as follows. To a suspension containing 9.2 grams of 2-(N-(3-methoxyphenyl)-2-telemediated/-acetic acid in 150 cm31,2-dichloroethane is added 3.5 g of oxalicacid, then 0.2 cm3of dimethylformamide. The mixture is stirred for 2 hours at a temperature of, blizman. The solution is stirred for 2 hours at a temperature close to 25oC, then washed with 2 times 100 cm3water. The organic phase is dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the resulting crude product was then purified by chromatography on 80 g of silica (0,065-0,200 mm) in a column with a diameter of 4.0 cm (eluent: methylene chloride-methanol (98:2 by volume), collecting fractions at 30 cm3. Fractions 5 to 13 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 6.2 g of N-/2-forfinal/-2-/N-(3-methoxyphenyl)-2-telemediated/-N methylacetamide matter type "meringue", used as it is, for the subsequent syntheses.

2-/N-(3-Methoxyphenyl)-2-telemediated/acetic acid can be obtained in the following way. To a solution containing 19 g of 2-N-(3-methoxyphenyl)-2-telemediated/-acetate tert-butyl 220 cm3dichloromethane is added to 32.9 g triperoxonane acid. The resulting solution was stirred at a temperature of education phlegmy for 4 h, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. After recrystallization in diisopropyl is="ptx2">

2-Fluoro-N-methylaniline may be obtained in the following way. To stand at a temperature close to the 25oC, the suspension containing 4.9 g of lithium aluminum hydride in 100 cm3anhydrous tetrahydrofuran is added over 15 min a solution containing 12.2 g of 2-performanced 100 cm3anhydrous tetrahydrofuran. The mixture is stirred at a temperature close to the 25oC, within 3 hours After cooling to a temperature close to 5oC, was added sequentially: 5,7 cm3water, 4.2 cm35 N. aqueous sodium hydroxide solution, then 19 cm3water. The resulting suspension stirred for 30 min, then add 150 cm3diethyl ether. The insoluble product is separated by filtration, and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. the Residue is dissolved in 60 cm3dichloromethane solution and dried on magnesium sulfate, then concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 7.2 g of 2-fluoro-N-methylaniline in the form of liquid oil, used as it is, for the subsequent syntheses.

2-Performanceline can be obtained as follows. To a solution containing 10.8 g of sodium methylate usuwania phlegmy for 2 h, driving the formed methanol, then concentrated to dryness under reduced pressure (0.01 kPa) and at 60oC. the Residue is extracted by 1 l of water and 300 cm3diethyl ether. The organic phase is separated by decantation, dried on magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa) and at 30oC. thus Receive the 12.2 g of 2-performanced in the form of liquid oil, used as it is, for the subsequent syntheses.

P R I m e R 55. Spend the synthesis according to the method similar to that described in example 26, but on the basis of 3.1 g of 3-{3-[N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxyethyl/-N-/3 - methoxyphenyl/-carbonylmethyl] -ureido}-ethyl-benzoate and 5.5 cm31 N. aqueous sodium hydroxide solution. Get so 1.6 g of 3-{3-[N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxoethyl/-N-3-methoxyphenyl/-carbonylmethyl] -ureido} -benzoic acid, melting at 165oC.

3-{ 3-[N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxyethyl/-N-/3-methoxyphenyl/-carbonylmethyl] -ureido} -ethylbenzoic can be obtained by the method similar to that described in example 49 to obtain 2-{2-[3-/3-(2-hydroxyethyl)-phenyl/-ureido] -N-/3-methoxyphenyl/-acetamido} -N-methyl-N-phenylacetamide, but on the basis of 3,g 3-aminobenzoate ethyl. The resulting product was then purified by chromatography on 150 g of silica (0,065-0,200 m) in column 5 cm in diameter (eluent: methylene chloride-ethyl acetate (70:30 by volume), collecting fractions at 30 cm3. Fractions 24 to 36 are combined and concentrated to dryness under reduced pressure (2.7 kPa) and at 40oC. thus Receive the 3.2 g of 3-{ 3-[N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxoethyl/-N-/3-methoxyphenyl/-carbonylmethyl] -ureido} -ethylbenzoic matter type "meringue", used as it is, for the subsequent syntheses.

N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxoethyl/-2-/(1 - imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-ndimethylacetamide can be obtained by the method similar to that described in example 49 to obtain 2-{2-/(1-imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-acetamido} -N-methyl-N-phenylacetamide, but on the basis of 3.6 g of 2-amino-N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxoethyl/-N-/3-methoxyphenyl)-ndimethylacetamide and 2.6 g of N,N'-diimidazole. Get so 3.1 g of N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxoethyl/-2-/(1-imidazolyl)-carboxamido/-N-/3-methoxyphenyl)-ndimethylacetamide in the form of amorphous powder, used as it is, for the subsequent syntheses.

2-Amino-N-/2-(3,4-dihydro-1,4-2H-benzothiazepine 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido)-acetate tert-butyl, but on the basis of 8.0 g N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxoethyl/-N-/3 - methoxyphenyl/-2-palmitoylated and 1.6 g of hydrazine hydrate. Get so 5.9 g of 2-amino-N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxoethyl/-N-/3-methoxyphenyl-ndimethylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

N-/2-(3,4-Dihydro-1,4-2H-benzothiazin-4-yl)-2-oxoethyl/-N-/3 - methoxyphenyl/-2-phthalimidobutyl can be obtained by the method similar to that described in example 54 to obtain the N/2-forfinal/-2-/N-(3-methoxyphenyl)-2-telemediated/-N-methyl-ndimethylacetamide, but on the basis of 9.2 grams 2-/N-(3-methoxyphenyl)-2-telemediated/-acetic acid, 3.5 g of oxalicacid, 3.8 g of 3,4-dihydro-1,4-2H-benzothiazin and 2 g of pyridine. After recrystallization in a mixture of acetonitrile-isopropyl ether (35:65 by volume) gain of 8.2 g of N-/2-(3,4-dihydro-1,4-2H-benzothiazin-4-yl)-2-oxoethyl/-N-/3-methoxyphenyl/-2-palmitoylated, melting at 150oC.

3,4-Dihydro-1,4-2H-benzothiazin can be obtained according to the method described in the article by C. C. J. Culvenor et coll. J. Chem. Soc. 278 (1949).

P R I m e R 56. Spend the synthesis according to the method similar to that described in example 26, but on the basis of 0.7 g of 3-{3-/N-/3-methoxyphenyl/-N-/2-(1,2,3,4-tetrahydro-1-Pinochet thus 0.2 g of 3-{3-[N-/3-methoxyphenyl-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-2-oxoethyl/- carbonylmethyl]-ureido}-benzoic acid, melting at 190oC.

3-{ 3-[N-/3-methoxyphenyl/-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-2-oxoethyl/-carbonylmethyl] -ureido} -benzoate of ethyl can be obtained by the method similar to that described in example 49 to obtain 2-{2-[3-/3-(2-hydroxyethyl)-phenyl/-ureido] -N-/3-methoxyphenyl/-acetamido}-N-methyl-N-phenylacetamide, but on the basis of 1.2 g of 2/(1-imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-2-oxoethyl/-ndimethylacetamide and 0.85 grams 3-aminobenzoate ethyl. The resulting product was then purified by chromatography on 40 g of silica (0,065-0,200 mm) in a column 2 cm in diameter (eluent: methylene chloride-ethyl acetate (70:30 by volume), collecting fractions of 20 cm3. Fractions 31 to 40 are combined and concentrated to dryness under reduced pressure (2.4 kPa) and at 40oC. thus Receive the 0.7 g of 3-{3-[N-/3-methoxyphenyl/-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-2-oxoethyl/-carbonylmethyl] -ureido} -ethylbenzoic matter type "meringue", used as it is, for the subsequent syntheses.

2-/(1-Imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-N-/2-(1,2,3,4 - tetrahydro-1-chinolin)-2-oxoethyl/-ndimethylacetamide can be obtained by the method similar to that described in example 49 to obtain 2-{2-/(1-imidazolyl)-carboxamid the hydro-1-chinolin)-2-oxoethyl/- ndimethylacetamide and 4.2 g of N,N'-diimidazole. Get so 2.3 g of 2/(1-imidazolyl)-carboxamido/-N-/3-methoxyphenyl/-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-2-oxoethyl/-ndimethylacetamide matter type "meringue", used as it is, for the subsequent syntheses.

2-Amino-N-/3-methoxyphenyl/-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-2 - oxoethyl/-ndimethylacetamide can be obtained by the method similar to that described in example 4 to obtain 2-/2-amino-N-(2-trifloromethyl)-acetamido/tert-butyl acetate, but on the basis of 8.5 g of N-/3-methoxyphenyl/-2-phthalimido-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-2 - oxoethyl/-ndimethylacetamide and 1.7 g of hydrazine hydrate. Get thus 5 g of 2-amino-N-/3-methoxyphenyl/-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-2-oxoethyl/-ndimethylacetamide in the form of liquid oil, used as it is, for the subsequent syntheses.

N-/3-Methoxyphenyl/-2-phthalimido-N-/2-(1,2,3,4-tetrahydro-1-chinolin)-2 - oxoethyl/-ndimethylacetamide can be obtained by the method similar to that described in example 54 to obtain the N/2-forfinal/-2-/N-(3-methoxyphenyl)-2-phthalimido-acetamido/-N methylacetamide, but on the basis of 8.0 g of 2-N-(3-methoxyphenyl)-2-telemediated/-acetic acid, 3.0 g of oxalicacid, 3.5 g of 1,2,3,4-tetrahydroquinoline and 1.8 g of pyridine. Get so 8.8 g of N-/3-methoxyphenyl/-2-phthalimido-N syntheses.

Working in the same manner but using the corresponding source, you receive the following connections:

A) +2(S)-{ 3-{ 3-{[N-(3-methoxyphenyl)-N-1-(N-methyl-N-phenylcarbamoyl)-(R, S)-ethyl] -carbamoylmethyl} -ureido} phenyl}-propionic acid, melting at 151oC;

B) 2-fluoro-5-{ 3-[N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)- carbonylmethyl]-ureido}-benzoic acid, melting at 140oC;

C) potassium Sol-{3-[N-(3-methoxyphenyl)-N-/N-methyl-N-phenylcarbamoyl)carbamoylmethyl)] -ureido} phenyl}-methanesulfonic acid, melting at 180oC;

D) potassium salt of 1-{3-{3-[N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbamoylmethyl] ureido} phenyl}-econsultancy acid, melting at 190oC;

E) methyl-2-{3-{3-[N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl]-ureido}phenyl}-propionate, melting at 160oC;

F) /E/-2-{ 2-{3-[3-(1-acetimidoyl)phenyl]-ureido}-N-(3-methoxyphenyl)-acetamido}-N-methyl-N-phenylacetamide, melting at 188oC;

G) 3-{ 3-[N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl]-ureido}-venexiana acid, melting at 118oC;

H) 3/E/-{ 3-[N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl]-ureido}-cinnamic acid, melting p is carbamylethyl} ureido} phenyl}-propionic acid, melting at 135-140oC;

J) 2/S/-{ 3-{3-{[N-(2-morpholinoethyl)-N-tert-butoxycarbonylmethyl] carbonylmethyl}ureido}phenyl}-propionic acid, melting at 135oC.

Activity and toxicity of the examples given in table. 1.

The invention relates also to medicines, consisting of at least one compound with formula (I) in pure form or in the form of a composition in which it associated with any other pharmaceutically compatible product, the latter may be inert or physiologically active. Medicinal product according to the invention can be applied to oral, parenteral, rectal or topical route.

As solid compositions for oral administration may be tablets, pills, powders (gelatin capsules, pills or granules. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica. These compositions can also contain substances that differ from diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a protective coating is AMB pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerin, liquid vegetable oil or paraffin oil. These compositions may contain substances that differ from diluents, for example wetting, sweetening, thickening, flavouring or stabilizing compounds.

Sterile compositions for parenteral administration may be preferably aqueous solutions or non-aqueous solutions, suspensions or emulsions. As a solvent or carrier, you can use water, propylene glycol, polyethylene glycol, liquid vegetable oils, in particular olive oil, suitable for injectable organic esters, for example etiloleat, or other suitable organic solvents. These compositions can also contain additives, in particular wetting, isotonic, emulsifying, dispersing and stabilizing agents. Sterilization may be performed in various ways, for example by especisally filtering, by introducing into the composition stabiliziruyushchikh agents, as a result of irradiation or by heating. They can also be prepared in the form of sterile solid compositions, which can rectorates is edenia are candles or rectal capsules, which contain in addition to the active compounds are neutral substances such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

Compositions for topical injection can be, for example, creams, ointments, lotions, eye drops, means for mucous membrane of the throat and mouth, nasal drops or aerosols.

In therapeutic practice for people of the compounds according to the invention is particularly useful in the treatment and prevention of disorders associated with CCK and gastrinom at the level of the nervous system and gastrointestinal system. Therefore, these compounds can be used for the treatment and prevention of psychoses, disorders related to anxiety, Parkinson's disease, retarded dyskinesia, a syndrome irritable colon, acute pancreatitis, ulcers, disorders of intestinal obstruction, some tumors of the lower esophagus, colon and intestines and as potentialization analgesic activity of narcotic and non-narcotic pain medicines, as well as regulators of appetite.

Doses depend on the desired effect, on the duration of treatment and on the used route of administration: they usually Costablanca.

In the General case, the treating physician will determine the appropriate dosage depending on the age, weight and all other factors inherent to the patient to be treated.

The following examples illustrate compositions according to the invention.

P R I m e R A. In accordance with the usual method of preparing gelatin capsules 50 mg dosage of compounds having the following composition mg:

3-{ 3-/N-(3-Methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/- ureido}-benzoic acid 50

Cellulose 18

Lactose 55

Colloidal silica 1

Sodium carboximetilkrahmal 10

Talc 10

Magnesium stearate 1

P R I m e R C. In accordance with a conventional method to prepare tablets with 50 mg dosage of active compound, having the following composition mg:

2-{ (N-/2-(3,3-Dimethylpiperidino)-carbonitril/-2-/3-(3-were)- ureido/-acetamido}-tert-butyl acetate 50

Lactose 104

Cellulose 40

Pariston 10

Sodium carboximetilkrahmal 22

Talc 10

Magnesium stearate 2

Colloidal silica 2

A mixture consisting of hydroxyethylcellulose, glycerin, and titanium oxide (72,0: 3,5:24,5) in number, shall communicate the weight of one end covered with a thin protective layer tabla the output has the following composition, mg:

3-{ 3-/N-(3-methoxyphenyl)-N-(N-methyl-N-phenylcarbamoyl)-carbonylmethyl/-ureido}-phenylacetic acid, 10

Benzoic acid 80

Benzyl alcohol is 0.06 cm3< / BR>
Sodium benzoate 80

95% ethanol 0.4 cm3< / BR>
Sodium hydroxide 24

Propylene glycol 1.6 cm3< / BR>
Water in a quantity sufficient to bring the volume Up to 4 cm3< / BR>
BIOLOGICAL TESTS

Materials and methods

M a t e R I a l s. Mice Swiss-Webster male (weighing 25-35 g) were kept under 24oC under a 12-h cycles of change of light and darkness (9 h 21 h), fed a diet of Purina chon for rats and supplied water to drink ad libitum. Pure natural pork cholecystokinin (CCK33) received from the laboratory of gastrointestinal hormones, Karolinska Institute, Stockholm, Sweden. Synthetic CCK8and desulfuromonas CCK8(DCCA8) were obtained from Sguibb Institute for medical research, Princeton, new Jersey. Sodium salt of N2, O2-dibutyryl-guanosine-3,5-cyclic monophosphoric acid (dibutyryl-cyclic GMP), sodium salt of N6, O2-dibutyryl-adenosine-3,5-monophosphoric acid (dibutyryl-cyclic AMP), cyclic GMP, 4-(2-hydroxyethyl)-1-piperazine-econsultancy acid (G Is From. St. Louis, Missouri. Synthetic Three-Met-ASP-Hairdryer-amide (CCK4) purchased from Research firm Plus Danville, new Jersey. N-Succinimidyl-3-(4-hydroxy, 5-1251-iodophenyl)propionate (1251-NR reagent) was purchased from firms Amercham Arlington heights, Illinois. CCK33was codiroli to a specific activity of 200 to 300 Ci/g by conjugation with1251-BH reagent, as described in detail in SanKarah and others 1979 Labeled CCK33is referred to below as1251-BH-CCK.

P R and g o t o l e n g t C a t n I. Mice were decapitated between 9: 30 and 11 o'clock the Whole brain was removed and placed in 0.9% NaCl at 4oC. the cerebral Cortex was dissected in ice and homogenized in 10 volumes of 50 mm Tris buffer (pH 7.4) at 4oC using a homogenizer with glass cups, coated with Teflon, and seven knives at 1600 rpm the homogenate was centrifuged at 42 000 q for 15 min at 4oC. the Precipitate is then resuspendable in the same amount of the above-mentioned Tris-buffer and recentrifuged under the same conditions. Sediment suspended in 1 ml of incubation medium, the concentration of the protein in the membrane suspension was determined by Lowry method (Lowry and others, 1951), and then drove her to 0.58 mg/ml

Pancreatic particles were prepared similar obra.

With in I s C a n and e125-BH-CCK. The composition of the incubation medium, which was used in experiments to study the binding125-BH-CCK, was as follows: 118,0 mm NaCl; 4,7 mm KCl; 5.0 mm MgCl2; 1.0 mm AGTEK; 10.0 mm HEPES; 5.0 mg/ml BSA and 0.25 mg/ml bacitracin. When studied pH values between 5 and 6, instead of GAPES used succinic acid. Other changes to the composition of the incubation medium are marked in the text.

In most experiments, freshly prepared membrane (105 mg protein) were incubated in plastic microcentrifuge tubes in 300 l of incubation medium with 50 PM1251-BH-CCK at the 24oC. To determine nonspecific binding was added 1 mm of CCK8. Each study was performed in three replications. In a certain period of time (usually 120 min) the tubes were centrifuged at 10 000 q on microcentrifuge Beckman for 1 min at 24oC. Nadeshiko then used to determine the decay of1251-BH-CCK. Sediments were washed ice-cold incubation medium and was recentrifuged for 15 s at 24oC. the Tip of the tube was broken off, and the radioactivity was measured in a gamma scintillation counter. Nonspecific binding was determined by subtraction of specific binding of the X100 mm plastic tubes. The total volume was 4.2 ml, and the final concentration of protein1251-BH-CCK and CCK8was the same as in the other experiments. After a certain period of time, 200 ml of the incubation mixture was removed, centrifuged at 10 000 q on microcentrifuge Beckman 152, washed and counted as described above. To determine the dissociation associated1251-BH-CCK added CCK8at a concentration of 1 to the incubation mixture, which was pre-incubated for 60 min with1251-BH-CCK. Incubation was continued for another 120 min, then after a certain period of time, taking aliquots, centrifuged and counted as described above.

P and s p and d1251-BH-CCK. After incubation with1251-BH-CCK aliquots of 100 ml of medium was added to 0.5 ml of 20% trichloroacetic acid (THUK) together with 0.4 ml of medium containing 5 mg/ml BSA as a protein carrier. After incubation in ice for 30 min the mixture was centrifuged at 1 000 q for 5 min at 4oC, and the radioactivity nadeshiko and sediment was measured using a scintillation gamma counter. The decay of1251-BH-CCK was calculated as a percentage of the total radioactivity in the environment, not besieged THUC. First label to precipitate more than 95% and this value and not the1251-BH-CCK with particles of the cerebral cortex of mice initially studied at the 24oC and pH 7.4, conditions, usually demonstrates a specific and saturable binding to the particles of the cerebral cortex of mice. Under these conditions, specific binding was observed, but was accompanied by the decay of1251-BH-CCK-label (PL. 2). Adding to the environment bacitracin, an inhibitor of amino peptidases reduce the collapse of the label depending on the concentration. In the presence of 0.25 mg/ml bacitracin binding of CCK almost doubled, however, when further increasing the concentration of bacitracin binding was decreased (table. 2). Therefore, all subsequent studies were performed at a concentration of bacitracin in the environment of 0.25 mg/ml

1. Derivatives of N-phenylglycinate General formula I

< / BR>
where R1hydrogen, (lower)alkyl;

R2(lower)alkoxy or NR5R6where R5- (lower)alkoxy, R6phenyl, possibly substituted by halogen, or R5and R6together with the nitrogen atom to which they are attached to form 3,3-di(lower)alkylpiperidines cycle, 3,4-dihydro-2H-benzothiazin-1,4-new cycle or 1,2,3,4-tetrahydroquinolin-1-new cycle;

R3chinolin or phenylaminopropyl, in which phenyl Zam is, monoxi(ness.)of alkyl, (ness.)alkoxycarbonyl, oxyimino(ness.)of alkyl, tetrazolyl-5-(ness.)of alkyl, (ness.)alkyl-COOX, -O-(NISS. )alkyl-COOX, -CH CH COOH, (ness.)alkyl SO3H;

X is hydrogen, lower alkyl; R4=phenyl, substituted by halogen, (ness.)the alkyl, (ness.)alkoxy, hydroxyl, polyflor(ness.)by alkyl, nitro, (ness.)alkylthio, (NISS. )alkoxycarbonyl, carboxyla, acylamino, methylendioxy, polyflor(NISS. )alkoxy, triptoreline, phenoxy, phenyl, benzyl, phenylamino, di(NISS. )alkylamino or CONRaRbwhere Ralower alkyl, Rbphenyl, or Raand Rbtogether with the nitrogen to which they are attached, form a 1,2,3,4-tetrahydroquinolin-1-OIC, 3,3-di(NISS. )alkylpiperidines, 3,4-dihydro-2H-benzoxazinone or morpholinyl cycle.

2. Derivatives of N-phenylglycinate General formula I on p. 1, wherein R1hydrogen, R2NR5R6and R5and R6together with the nitrogen atom to which they are attached to form 3,3-dimethylpiperidino cycle, 1,2,3,4-tetrahydro-1-quinoline cycle or 3,4-dihydro-2H-benzothiazin-1,4-new cycle, R3phenylaminopropyl, in which phenyl is substituted by (ness.)alkoxycarbonyl or carboxyla, R4is phenyl, substituted (lower) alkoxy is named General formula I through p. 1, wherein R1hydrogen, R2(ness.)alkoxygroup or NR5R6and R5lower alkyl, R6phenyl, possibly substituted by halogen, R3phenylaminopropyl, phenyl ring which is substituted by lower alkyl, monoxi(lower)alkyl, carboxyla or group (NISS. )alkyl-COOH, R4phenyl, substituted by halogen, (lower)alkoxygroup, hydroxyl, (lower)alkoxycarbonyl, or CONRaRbwhere Ra(lower)alkyl, Rbphenyl, or Randand Rbtogether with the nitrogen atom to which they are attached, form a 1,2,3,4-tetrahydroquinolin-2,3,3-di(NISS. )alkylpiperidines, 3,4-dihydro-2H-benzoxazin or morpholine.

4. The method of obtaining derivatives of N-phenylglycinate General formula I

< / BR>
where R1hydrogen or (ness.)alkyl;

R2(ness.)alkoxy or NR5R6where R5- (ness.)alkyl, and R6phenyl, possibly substituted by halogen, or R5and R6together with the nitrogen atom to which they are attached to form 3,3-dialkylimidazolium cycle, 3,4-dihydro-2H-benzothiazin-1,4-new cycle or 1,2,3,4-tetrahydroquinolin-1-new cycle;

R3chinolin or phenylaminopropyl, in which phenyl is substituted by one or more substituents, silt, oxyimino(NISS. )alkyl, tetrazolyl-5-(ness.)of alkyl, (ness.)Ala COOX, -O-(NISS. )Ala COOX, -CH CH COOX, and (ness.)Ala SO3H;

R4phenyl, substituted by halogen, (ness.)the alkyl, (ness.)alkoxy, hydroxyl, polyflor(ness.)by alkyl, nitro, (ness.)alkylthio, (NISS. )alkoxycarbonyl, carboxyla, acylamino, methylendioxy, polyflor(NISS. )alkoxy, triptoreline, phenoxy, phenyl, benzyl, phenylamino, di(NISS. )alkylamino or CONRaRbwhere Ra- (ness.)alkyl, and Rbphenyl, or Raand Rbform together with the nitrogen to which they are attached, 1,2,3,4-tetrahydroquinolin-1-OIC, 3,3-dialkylimidazolium, 3,4-dihydro-2H-benzoxazinone or morpholinyl cycle

characterized in that they are subjected to the interaction of the isocyanate of the formula

OCN R9,

where R9phenyl radical, substituted if necessary by one or more substituents selected among halogen atoms and (NISS. )alkyl, (NISS. )alkoxy-, (NISS. )alkylthio-, nitro, acyl, cyano, sulfanilic, benzoline, (ness.)alkoxycarbonyl, (ness.)-ALK-O-(NISS. )Ala, 5-tetrazolyl and tetrazolyl-5-(ness.) alkyl radicals,

with amino derivatives of the formula

< / BR>
where R1, R2and R4have ukazaniya.)alkoxygroup, subjected to hydrolysis to obtain the compound I where R4phenyl, substituted by hydroxyl, and/or, if necessary, is subjected to hydrolysis of compound I containing the ester group to obtain compound I in the form of the corresponding acid.

5. The method of obtaining derivatives of N-phenylglycinate General formula I under item 1, for which R3is phenylaminopropyl, the phenyl ring of which is substituted by at least one radical-type carboxy-, (ness.)Ala COOH, -O-(NISS)-Ala COOH, -CH CH COOH and/or R4represents a phenyl radical substituted by carboxypropyl, characterized in that it is subjected to hydrolysis of the corresponding ester.

6. The method of obtaining derivatives of N-phenylglycinate General formula I under item 1, for which R4represents a phenyl radical substituted by a hydroxy-group, wherein subjected to hydrolysis of the corresponding connection, for which R4represents a phenyl radical, substituted lower alkoxygroup.

7. Pharmacological composition having means for receptor cholecystokinin and gastrin, containing the active principle and a pharmaceutically acceptable additive, wherein the Oze 10 500 mg.

Priority signs:

07.03.90 when R1hydrogen or alkyl radical, R2radical alkoxy or NR5R6where R5the alkyl radical and R6the phenyl radical, if necessary substituted by a halogen atom, or R5and R6form together with the nitrogen atom to which they are linked, a cycle 3,3-dialkylamino, 3,4-dihydro-2H-1,4-benzothiazine or 1,2,3,4-tetrahydro-1-chinoline, R3radical chinoline or phenylamino, in which phenyl is substituted by one or more substituents selected among halogen, alkyl, and R4the radical is phenyl, substituted with halogen, alkyl, alkoxy, nitro, alkylthio, alkoxycarbonyl, acylamino, methylendioxy, triptoreline, triptoreline, phenoxy, phenyl or benzyl;

16.10.90 when R1a hydrogen atom or an alkyl radical, R2radical alkoxy or NR5R6where R5the alkyl radical and R6the phenyl radical, if necessary substituted by a halogen atom, or R5and R6form together with the nitrogen atom to which they are linked, a cycle 3,3-dialkylamino, 3,4-dihydro-2H-1,4-benzothiazine or 1,2,3,4-tetrahydro-1-chinoline, or R3radical chinoline or phenylamino, in which phenyl is substituted by one or more of samesexmarriage, ALK-COOX, -ALK-COOH, -CH CH COOX and ALK-SO3H, R4the radical phenyl, substituted hydroxy, cryptometrics, triptoreline, phenylamino, dialkylamino or CONRaRbwhere Rathe alkyl radical and Rbthe radical phenyl, or Raand Rbform together with the nitrogen atom to which they are linked, a cycle 1,2,3,4-tetrahydro-1-chinolin or 3.3-dialkylamino, or R3radical, phenylamino, in which phenyl is substituted by one or more substituents selected among carboxy, monohydrocalcite, alkoxycarbonyl, hydroxyarylalkyl, -ALK-COOX or-ALK-COOX, -CH CH - COOX and ALK-SO3H, R4the radical is phenyl, substituted with halogen, alkyl, alkoxy, hydroxy, triptoreline, nitro, alkylthio, alkoxycarbonyl, carboxy, acylamino, methylendioxy, triptoreline, triptoreline, phenoxy, phenyl, benzyl, phenylamino, dialkylamino or-CONRaRbwhere Rathe alkyl radical, Rbthe radical phenyl, or Raand Rbform together a cycle 1,2,3,4-tetrahydro-1-chinolin or 3.3-dialkylamino;

05.03.91 when R1a hydrogen atom or an alkyl radical, R2radical alkoxy or NR5R6where R5the alkyl radical and R6the phenyl radical, if necessary substituted Dino, 3,4-dihydro-2H-1,4-benzothiazine or 1,2,3,4-tetrahydro-1-chinoline, or R3radical 5-tetracoralla and R4the radical is phenyl, substituted with halogen, alkyl, alkoxy, hydroxy, triptoreline, nitro, alkylthio, alkoxycarbonyl, carboxy, acylamino, methylendioxy, triptoreline, triptoreline, phenoxy, phenyl, benzyl, phenylamino, dialkylamino or CONRaRbwhere Rathe alkyl radical and Rbrepresents a phenyl radical, or Raand Rbform together with the nitrogen atom to which they are linked, a cycle 1,2,3,4-tetrahydro-1-chinolin, 3,3-dialkylamino, 3,4-dihydro-benzoxazine or morpholino, or R3radical chinoline or phenylamino, in which phenyl is substituted by one or more substituents selected among halogen, alkyl, alkylthio, carboxy, monohydrocalcite, alkoxycarbonyl, hydroxyarylalkyl, 5-tetracoralla, ALK-COOX, -O-ALK-COOX, -CH=CH-COOX and ALK-SO3H, and R4radical CONRaRbwhere Raand Rbform together with the nitrogen atom to which they are linked, a cycle of 3,4-dihydro-2H-benzoxazine or morpholino.

 

Same patents:

The invention relates to new biologically active compounds derived boron-containing peptides and pharmaceutical composition having inhibitory activity to trypsinogen serine proteases, which can find application in biology and medicine

The invention relates to new derivatives of dipeptides with pharmacological activity, and the way they are received, and may find application in medicine

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to applying compounds of the formula (I) for preparing an antibacterial composition and veterinary composition eliciting with the enhanced activity.

EFFECT: valuable properties of agents.

4 cl, 3 tbl, 78 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to macrocyclic peptides of the general formula (I): wherein W means nitrogen atom (N); R21 means hydrogen atom (H), (C1-C6)-alkoxy-, hydroxy-group or N-(C1-C6-alkyl)2; R22 means hydrogen atom (H), (C1-C6)-alkyl, CF3, (C1-C6)-alkoxy-group, (C2-C7)-alkoxyalkyl, C6-aryl or Het wherein het means five- or six-membered saturated or unsaturated heterocycle comprising two heteroatoms taken among nitrogen, oxygen or sulfur atom and wherein indicated Het is substituted with radical R24 wherein R23 means hydrogen atom (H), -NH-C(O)-R26, OR26, -NHC(O)-NH-R26, -NHC(O)-OR26 wherein R26 means hydrogen atom, (C1-C6)-alkyl; R3 means hydroxy-group or group of the formula -NH-R31 wherein R31 means -C(O)-R32, -C(O)-NHR32 or -C(O)-OR32 wherein R32 means (C1-C6)-alkyl or (C3-C6)-cycloalkyl; D means a saturated or unsaturated alkylene chain comprising of 5-10 carbon atoms and comprising optionally one-three heteroatoms taken independently of one another among oxygen (O), sulfur (S) atom, or N-R41 wherein R41 means hydrogen atom (H), -C(O)-R42 wherein R42 means (C1-C6)-alkyl, C6-aryl; R4 means hydrogen atom (H) or one-three substitutes at any carbon atom in chain D wherein substitutes are taken independently of one another from group comprising (C1-C6)-alkyl, hydroxyl; A means carboxylic acid or its alkyl esters or their derivatives. Invention relates to pharmaceutical compositions containing indicated compounds and eliciting activity with respect to hepatitis C virus and these peptides inhibit activity of NS3-protease specifically but don't elicit significant inhibitory activity with respect to other serine proteases.

EFFECT: valuable biochemical and medicinal properties of peptides.

106 cl, 9 tbl, 61 ex

FIELD: organic chemistry, medicine, pharmacy.

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

wherein r = 1, 2 or 3; s = 0; t = 0; R1 is taken among group including R11-CO and R12-SO2- wherein R11 is taken among group including (C6-C14)-aryl, (C1-C8)-alkyloxy-group wherein all given group are unsubstituted or substituted with a single or some similar or different substitutes R40; R12 means (C6-C14)-aryl wherein indicated group is unsubstituted or substituted with a single or some similar or different substituted R40; R2 means R21(R22)CH-, R23-Het-(CH2)k-, R23(R24)N-(CH2)m-D-(CH2)n- or R25(R26)N-CO-(CH2)p-D-(CH2)q- wherein D means bivalent residue -C(R31)(R32)-, bivalent (C6-C14)-arylene residue or bivalent residue obtained from aromatic group Het comprising 5 or 6 atoms in cycle among them 1 or 2 are similar or different cyclic heteroatoms taken among group including nitrogen and sulfur atoms; numbers k, m, n, p and q = 0, 1, 2; R21 and R22 that are independent of one another can be similar or different and taken among group including hydrogen atom, (C1-C12)-alkyl, (C6-C14)-aryl and so on; R23 means hydrogen atom, R27-SO2- or R28-CO-; R24, R25 and R26 mean hydrogen atom; R27 is taken among group including (C1-C8)-alkyl, (C6-C14)-aryl and so on; R28 is taken among group including R27, (C1-C8)-alkyloxy-group; R31 and R32 mean hydrogen atom; R40 is taken among group including halogen atom, hydroxy-, (C1-C8)-alkyloxy-group, (C1-C8)-alkyl, (C6-C14)-aryl and so on; R91, R92, R93 and R96 means hydrogen atom; R95 means amidino-group; R97 means R99-(C1-C8)-alkyl; R99 is taken among group including hydroxycarbonyl- and (C1-C8)-alkyloxycarbonyl-; Het means saturated, partially unsaturated or aromatic monocyclic structure comprising from 3 to 6 atoms in cycle among them 1 or 2 are similar or different heteroatoms taken among group comprising nitrogen and sulfur atoms; in all its stereoisomeric forms and also their mixtures in any ratios, and its physiologically acceptable salts. Invention proposes a method for preparing compound of the formula (I). Also, invention proposes a pharmaceutical preparation eliciting inhibitory activity with respect to factor VIIA and containing at least one compound of the formula (I) and/or its physiologically acceptable salts and pharmaceutically acceptable carrier. Invention provides preparing compounds of the formula (I) eliciting power anti-thrombosis effect and useful for treatment and prophylaxis of thrombosis-embolic diseases.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 70 ex

FIELD: organic chemistry and drugs.

SUBSTANCE: New class of compounds of general formula 1, where R has formula 2 or 3; other residues are as described in claim of invention is disclosed. Said compounds are interleikyn-1β converting enzyme (ICE) inhibitors and have specific structural and physicochemical properties. Invention also relates to pharmaceutical composition containing said compounds. Compounds and composition of present invention are particularly useful in ICE activity inhibition and thereby can be used as drug for treating of diseases mediated by IL-1, apoptosis, IGIF and IFN-γ, as well as inflammations, autoimmune diseases, bone-destructive disorder, infections, disorder associated with cell proliferation, degenerative and necrotic disorders. Uses of claimed compounds and compositions as well as methods for production of N-acylamino compounds also are disclosed.

EFFECT: effective interleikyn-1beta converting enzyme inhibitors.

64 cl, 35 ex, 35 tbl, 21 dwg

FIELD: medicine, gastroenterology.

SUBSTANCE: traditional eradication therapy should be supplemented with licopid at the dosage of 10 mg per os once daily before breakfast for 10 d. The present innovation prevents transfer of microorganisms into inactive form, accelerates restoration of mucosal epithelial layer in gastroduodenal area, provides complete eradication of microorganisms, that in its turn, favors to prevent disease exacerbation and restoration of gastroduodenal functions.

EFFECT: higher efficiency of therapy.

3 dwg, 2 ex

FIELD: biotechnology, biochemistry.

SUBSTANCE: invention relates to producing the biologically active complex eliciting antioxidant and immunomodulating activity and used in medicine, cosmetics, veterinary science and food industry. The biologically active complex preparing by enzymatic hydrolysis of muscle tissue represents complex of biologically active compounds involving carnosine and anserine in the amount 85-97 wt.-% of the native content of these components in poultry muscle tissue, 1-7 weight parts of amino acids, 0.5-12 weight parts of oligopeptides of molecular mass 10 kDa, not above, and 0.1-15 weight parts of cyclic and polycyclic phenolic compounds as measured for 1 weight part of carnosine and anserine in the complex. This complex is prepared by enzymatic hydrolysis of milled and homogenized water muscle tissue in preferable dilution homogenate with water in the range 0.2-0.6 and with using proteolytic enzymes in the amount 2-5 wt.-% of the protein content and working at pH 4.5-8.5 and at enhanced temperature being preferably at 45-65°C. Product is isolated as extract or powder prepared in drying the extract. Invention provides enhancing effectiveness of the claimed complex.

EFFECT: improved method for preparing, valuable properties of complex.

7 cl, 6 tbl, 6 ex

FIELD: medicine, cardiology, gastroenterology.

SUBSTANCE: invention relates to a method for treatment of ulcer-erosion injures in gastroduodenal region in patients with arterial hypertension. Method involves detection of immune disturbances and carrying out the combined immunomodulating therapy and hypotensive therapy. Immunocorrecting complex consists of licopide, cortexinum, vetoronum TK in arterial hypertension of I-II degree and comprises superlymph additionally in arterial hypertension of III degree. Method provides attaining optimal results in treatment for relatively short time due to adequate immunocorrection in such patients.

EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new inhibitors of thrombin of the formula (I)

,

method for their preparing, intermediate compounds used for their preparing of the formula (II)

and a pharmaceutical composition comprising compounds of the formula (I). Invention provides enhancing effectiveness in inhibition of thrombin.

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

23 cl, 61 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a combined medicinal agent used in treatment of arterial hypertension. The proposed agent comprises the combination of enalapril maleate and hydrochlorothiazide as an active component, and also sodium hydrocarbonate, starch, lactose, iron oxide and stearate as accessory substances. The proposed agent is stable in storage and releases the active component easily.

EFFECT: improved and valuable properties of agent.

8 cl, 1 tbl, 5 ex

FIELD: veterinary science, pharmacy.

SUBSTANCE: invention proposes a composition for antioxidant protection of cells, tissues and a whole body against hyperproduction of free radicals in acute inflammation, chemical thermal and radiation damages. The composition comprises peroxyredoxin Prx VI and, additionally, lipoic acid and pharmaceutically acceptable additives. The composition comprises peroxyredoxin Prx VI and dihydrolipoic acid taken in the effective amount in the ratio peroxyredoxin Prx VI to dihydrolipoic acid in the range (w/w) from 1:1 to 50:1 wherein peroxyredoxin Prx VI can represents human recombinant peroxyredoxin Prx VI. Also, invention relates to a method for enhancing antioxidant protection of mammals involving delivery of indicated pharmaceutical composition is carried out into intercellular space of tissue, organ or a whole body of mammal. The delivery can be carried out by passive or active diffusion in application or spraying, by parenteral or endolumbal administration by injection, by parenteral administration, infusion, inhalation, drainage, by sublingual, vaginal or rectal administration, by nasal or ophthalmic drops. Except for, the delivery can be carried out with using other therapeutic agent, in particular, interferon simultaneously. Invention provides prophylaxis of secondary alternative damages, recovery of epithelial tissue, protection of biomacromolecules against effect of irradiation.

EFFECT: valuable medicinal properties of composition.

6 cl, 9 tbl, 11 dwg, 45 ex

FIELD: synthesis of biologically active compounds.

SUBSTANCE: invention provides 1,5-benzothiazepines of general formula I (formulae presented below), in which Rv and Rw are independently selected from hydrogen and C1-C5-alkyl; one of Rx and Ry represents hydrogen or C1-C6-alkyl and the other hydroxy or C1-C6-alkoxy; Rz is selected from halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1 of invention; v is a number from 0 to 5; one of R4 and R5 represents group of general formula IA; R3 and R6 and the second from R4 and R5 are independently selected from hydrogen, halogen, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulfamoyl, C1-C6-alkyl, and other residues indicated in claim 1; R3 and R6 and the second from R4 and R5 being optionally substituted by one or several R16 groups at their carbon atoms; D represents -O-, -N(Ra)-, -S(O)b- or -CH(Ra)-, wherein Ra is hydrogen or C1-C6-alkyl; and b=0-2; ring A represents aryl or heteroaryl and is optionally substituted by one or several substituents selected from R17; R7 represents hydrogen, C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R18; R8 represents hydrogen or C1-C4-alkyl; R9 represents hydrogen or C1-C4-alkyl; R10 represents hydrogen or C1-C4-alkyl, carbocyclyl, or heterocyclyl and is optionally substituted by one or several substituents selected from R19; R11 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORc)(ORd), -P(O)(OH)(ORc), -P(O)(OH)(Rd), or -(O)(ORc)(Rd), wherein Rc and Rd are independently selected from C1-C6-alkyl; or R11 represents group of general formula IB, in which X is -N(Rq)-, N(Rq)C(O)-, -O-, or -S(O)a, wherein a=0-2; and Rq is hydrogen or C1-C4-alkyl; R12 represents hydrogen or C1-C4-alkyl; R13 and R14 are independently selected from hydrogen, C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R23 can be optionally independently substituted by one or several substituents selected from R20; R15 represents carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORe)(ORf), -P(O)(OH)(ORe), -P(O)(OH)(Re), or -P(O)(ORe)(Rf), wherein Re and Rf are independently selected from C1-C6-alkyl; or R15 represents group of general formula IC, in which R24 is selected from hydrogen and C1-C4-alkyl; R24 is selected from hydrogen, C1-C4-alkyl carbocyclyl, heterocyclyl, and R27, of which C1-C4-alkyl, carbocyclyl, heterocyclyl, or R27 can be optionally independently substituted by one or several substituents selected from R28; R26 is selected from carboxy, sulfo, sulfino, phosphono, tetrazolyl, -P(O)(ORg)(ORh), -P(O)(OH)(ORg), -P(O)(OH)(Rg), or -P(O)(ORg)(Rh), wherein Rg and Rg are independently selected from C1-C6-alkyl; p=1-3; wherein meanings for R13 can be the same or different; q=0-1; r=0-3; wherein meanings for R14 can be the same or different; m=0-2; wherein meanings for R10 can be the same or different; n=1-3; wherein meanings for R7 can be the same or different; z=0-3; wherein meanings for R25 can be the same or different; R16, R17, and R18 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N,N-(di-C1-C4-alkyl)amino, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, and N,N-(di-C1-C4-alkyl)sulfamoyl; wherein R16, R17, and R18 can be optionally independently substituted by one or several of R21 at their carbon atoms; R19, R20, R23, R27, and R28 are independently selected from halogen, nitro, cyano, hydroxy, carbamoyl, mercapto, sulfamoyl, C1-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4-alkoxy, C1-C4-alkanoyl, C1-C4-alkanoyloxy, N-(C1-C4-alkyl)amino, N.N-(di-C1-C4-alkyl)amino, C1-C4-alkanoylamino, N-(C1-C4-alkyl)carbamoyl, N,N-(di-C1-C4-alkyl)carbamoyl, C1-C4-alkyl-S(O)a (wherein a=0-2), C1-C4-alkoxycarbonyl, N-(C1-C4-alkyl)sulfamoyl, N,N-(di-C1-C4-alkyl)sulfamoyl, carbocyclyl, heterocyclyl, sulfo, sulfino, amidino, phosphono, -P(O)(ORa)(ORb), -P(O)(OH)(ORa), -P(O)(OH)(Ra), or -P(O)(ORa)(Rb), wherein Ra and Rb are independently selected from C1-C6-alkyl and wherein R19, R20, R23, R27, and R28 can be optionally independently substituted by one or several of R22 at their carbon atoms; R21 and R22 are independently selected from halogen, hydroxy, cyano, carbamoyl, mercapto, sulfamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy, methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulfinyl, mesyl, N-methylsulfamoyl, N,N-dimethylsulfamoyl; or pharmaceutically acceptable salt thereof, solvate, or salt solvate. Described are also method for preparing compounds of formula I, pharmaceutical compositions based on compounds I, and a method for achieving inhibiting effect relative to interscapular brown adipose tissue (IBAT), and intermediates. (I), (IA), (IB), (IC).

EFFECT: expanded synthetic possibilities in the 1,5-benzothiazepine series.

36 cl, 121 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein R1 and R2 are chosen independently from (C1-C4)-alkyl; R3 represents hydrogen atom or hydroxy-group; R4 represents (C1-C4)-alkyl; R5 represents hydroxy-group, or to its pharmaceutically acceptable salts, esters or amides. Also, invention relates to using these compounds as inhibitors of bile acids transfer in ileum for treatment of hyperlipemia. Also, invention describes methods for synthesis of these compounds and pharmaceutical compositions comprising thereof.

EFFECT: improved methods of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

12 cl, 2 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: present invention refers to bioactive compounds of formula (Ic) , pharmaceutical compositions and application at cancer treatment, where R2-R7, X2, R, Q, G, J, L and M represent values estimated in invention formula and description.

EFFECT: production of compounds which can be used for anticancer medical product.

55 cl, 19 ex

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