Nitrogen-containing heterocyclic compounds in the form of a racemate or a single enantiomer, are inhibitors of leukotriene biosynthesis

 

(57) Abstract:

The object of the present invention are nitrogen-containing heterocyclic compounds of General formula 1

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where X is oxygen or sulfur, Y is carbon or nitrogen, Z is carbon or nitrogen, and Y and Z are not simultaneously mean a nitrogen, R1and R2independent from each other and denote hydrogen, alkyl with 1-6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1-6 carbon atoms, a group - CO2R7where R7means hydrogen or alkyl with 1-6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine - group-NR10R11where R10and R11denote hydrogen or alkyl with 1-6 carbon atoms, group-C(O)R12where R12means alkyl with 1-6 carbon atoms, group-SO2R12where R12has the specified value, - NHC(O)R12where R12has the specified value, - NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R14independent from each other and denote hydrogen or alkyl with 1-6 carbon atoms, R3- methyl with 1-4 carbon atoms and alkoxy with 1-4 carbon atoms, group SO2R12where R12has the specified value,-NHC(O)R12where R12has the specified value, - NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1 - piperidinyl, 2-, 3 - or 4 - pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1-4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1-4 carbon atoms in each alkyl group, or alkilany ether with 1-4 carbon atoms, R4an ester of formula - CO2R16where R16means alkyl with 1-4 carbon atoms, the amide of formula - C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1-2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolyl, 2-imidazole, unsubstituted or substituted at the nitrogen by methyl group, 2-imidazole, unsubstituted or substituted in position 4 with stands, a ketone of the formula C(O)R19OR20where R20means alkyl with 1-3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20))2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylaminopropyl-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3, R5and R6independent from each other and denote hydrogen or methyl, n is 0,1 or 2, provided that the substituents are not simultaneously have the following meanings; Y and Z is carbon, R1or R2is hydrogen, halogen, alkyl with 1-4 carbon atoms, alkoxy with 1-4 carbon atoms, cyano, nitro, trifluoromethyl, R3is unsubstituted phenyl and R4group - C(O)OR16, where R16means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'where R18and R19'denote hydrogen, alkyl with 1-6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyano or C(S)NH2'or Y and Z is carbon, R2- group C(O)OCH3', R1and R2is hydrogen and R3-4 oksifenil, unsubstituted phenyl and 4-imidazole, wabl.

The invention relates to new chemical substances, which have valuable pharmacological properties, more particularly to a nitrogen-containing heterocyclic compounds of General formula I

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent from each other and denote hydrogen, alkyl with 1 to 6 carbon atoms, halogen, trifluoromethyl, nitrile, alkoxy with 1 to 6 carbon atoms, a group of CO2R7where R7means hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)NR8R9where R8and R9not dependent from each other and denote hydrogen, alkyl with 1 to 3 carbon atoms, methoxy or together with the nitrogen form a morpholine, pyrrolidine or piperidine-NR10R11where R10and R11denote hydrogen or alkyl with 1 to 6 carbon atoms, group-C(O)R12where R12means alkyl with 1 to 6 carbon atoms, group-SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has a specified value, and-SO2NR13R14where R13and R14independent from each other and denote hydrogen or a group including halogen, trifluoromethyl, alkyl with 1 to 4 carbon atoms and alkoxy with 1 to 4 carbon atoms, a group of SO2R12where R12has the specified value, -NHC(O)R12where R12has the specified value, -NHSO2R12where R12has the specified value, -SO2NR13R14where R13and R14have a specified value, a nitrogroup, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, pyrrolidine, imidazole, unsubstituted or substituted at the nitrogen by alkyl with 1 to 4 carbon atoms, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or alkilany ether with 1 to 4 carbon atoms;

R4an ester of formula-CO2R16where R16means alkyl with 1 to 4 carbon atoms, the amide of formula C(O)NR17R18where R17and R18independent from each other and denote hydrogen, alkyl with 1 to 2 carbon atoms, methoxy or together with the nitrogen form a morpholine, piperidine or pyrrolidine, phenyl, unsubstituted or substituted by residues from the group comprising halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, 4-pyrazolyl, 2-imidazole, unsubstituted or substituted at the nitrogen mutilin/SUB> means alkyl with 1 to 3 carbon atoms, phenyl or 1-Mei-2-yl, a simple ester of the formula-CH2OR20where R20means alkyl with 1 to 3 carbon atoms, thioether formula-CH2SR20where R20has the specified value, the group CH2SO2CH3amines of the formula-CH2N(R20)2where R20has the specified value, the remainder of the formula-CH2NHC(O)R21where R21means methyl, amino or methylamino - group-CH2NHSO2Me2where Me denotes methyl carbamate of the formula CH2OC(O)NHCH3;

R5and R6independent from each other and denote hydrogen or methyl;

n is 0,1 or 2,

Provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-C(O)OR16'where R16'means hydrogen, alkyl, alkenyl or quinil, group-C(O)N(R18')(R19'), where R18'and R19'denote hydrogen, alkyl with 1 to 6 carbon atoms, phenyl, alkoxy or together with the nitrogen form pyrrolidine, piperidine or morpholine, cyano or-C(S)NH2or Y and Z is carbon, R
in the form of a racemate or an individual enantiomers and their salts, are inhibitors of leukotriene biosynthesis.

New connections can be obtained well-known literature methods. So, for example, the compounds can be obtained by reacting substituted 2-chlorobenzoxazole, 2-chlorobenzothiazole, 2-chloronitrobenzene or 2-chlordiazepoxide with an amine, amino acid or a complex ester of the amino acids. This synthesis is illustrated by the following scheme AND

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The reaction according to the scheme And can be carried out in an inert solvent such as, for example, methylene chloride, toluene or dimethyl sulfoxide, in the presence of a basic catalyst such as, for example, triethylamine or galidakis sodium. The optimal choice of solvent and catalyst depends on the type of reagents.

In addition, to obtain compounds of General formula (I) can also be applied to the modification of a known literature method of obtaining 2-aminobenzothiazoles. This synthesis is illustrated by the following scheme B.

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According to the scheme B interact substituted isothiocyanate with amine or a complex ester of the amino acids in the medium of a suitable inert solvent such as, for example the house or bromine in the environment of another inert solvent such as, for example, a simple diethyl ether or chlorobenzene.

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The synthesis according to the scheme can be applied to obtain such compounds of General formula I, in which X is sulfur, and Z is nitrogen. Thus haloaluminate turn to isothiocyanate, for example by interacting with thiophosgene in the presence of a base such as, for example sodium carbonate, in an inert solvent. As a result of interaction of isothiocyanate with the amine in an inert solvent receive triazolopyridine. When using 2-chloro-3-aminopyridine with certain additional substituents receive the intermediate thiourea after completion of the reaction with isothiocyanates. In this case, the cyclization to triazolopyridine can be accomplished by heating in an inert solvent in the presence of acid or basic catalyst, for example in the presence of ethanolic hydrochloric acid or potassium carbonate, in an environment of dimethylformamide.

Isomeric triazolopyridine can be obtained by cyclization of pyridine, substituted in position 3 by halogen and in position 2 of thiourea. Another synthesis proceeds according to the following scheme,

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According to the scheme G replaced the original PI is and in the presence of potassium carbonate. The intermediate 2-amino-3-kalaidjian can be obtained, for example, by the synthesized unsubstituted or substituted 2-aminopyridine. Isothiocynate can be obtained according to the above scheme Century.

The compound of General formula I, in which R4means acid residue or ester, can be converted into a compound of General formula I, in which R4means amide, metronidazol, a ketone, a simple ester or thioether. The possibility of such translation are illustrated by the diagram D.

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Used in scheme D. abbreviations stand for: CDI carbonylcyanide, DMF is dimethylformamide, THF tetrahydrofuran, Et is ethyl.

Reactions included in the scheme D, a well-known specialist.

With regard to the stereochemistry obtained by the methods described above of compounds of formula I, the following shall be indicated. If the source amines used according to schemes a and B represent the pure enantiomers, I get the target product as a single enantiomer. The target product has either the R configuration or the S configuration at the asymmetric carbon. If the starting amine is a racemate, i.e. a mixture of R and S isomers, the target product is obtained in the form of a racemate. Racemizes the ay dissolution diastereomeric salt, chromatography on a chiral column, and so on

In this description to denote the enantiomers of amino acids using the letters D and L, and the racemates denote DL.

Obtaining new compounds of General formula (I) is illustrated by the following examples.

Example 1. 3,82 g (32.1 mmol) of thionyl chloride drops added to 3.2 g(of 10.7 mmol) of the hydrochloride DL-N-(benzothiazol-2-yl) phenylalanine, suspended in 200 ml of ethanol. The reaction mixture is heated under reflux for 4 h, and then dried, the residue is dissolved in 75 ml of ethyl acetate twice extrahiert 50 ml saturated sodium carbonate solution and once with 50 ml saturated sodium chloride solution, dried over sodium sulfate and concentrated. The product is recrystallized from ethanol. Get 2.25 g (6,9 mmol) of the product so pl. 137 139oC. (Yield: 64%).

Example 2. Complex ethyl ester of DL-N-(6-isopropylthiazole-2-yl)-4-chlorophenylalanine.

5 g (of 18.9 mmol) of the hydrochloride complex ethyl ester of DL-4-chlorophenylalanine transferred to the free base using triethylamine. A solution of free base in 75 ml simple diethyl ether are added to a solution of 4-isopropylbenzylamine 150 ml simple diethyl ether and R is sa add. The reaction mixture is stirred for 4.5 hours at a temperature of 12oC, and then filtered, the filtrate concentrated and the resulting foamy residue is stirred with petroleium ether while cooling with ice. Get 6,1 g (15.1 mmol, 80%) of N-(4-isopropylphenyl)-N'-[2-(4-chlorophenyl)-1-(etoxycarbonyl)ethyl] thiourea with so pl. 73 75oC.

6 g (of 14.8 mmol) of the intermediate product is dissolved in 25 ml of chlorobenzene and cooled to a temperature of 0oC in an ice bath. Drops added 2.76 g (to 20.4 mmol) sulfurylchloride in 5 ml of chlorobenzene. After 5.5 hours, the reaction mixture was concentrated, the residue is dissolved in 150 ml ethyl acetate, washed first with a saturated solution of sodium carbonate and then with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The product is crystallized from ethanol. Get 4,07 g (10.1 mmol), 68%) of the product so pl. 105 107oC.

Similarly receive connections, are summarized in tables 1 to 5.

Example 3. N'-methylamide L-N-(5 - methylbenzothiazol-2-yl)cyclohexylamine.

A solution of 1.08 g (3.6 mmol) of L-N-(5 - methylbenzothiazol-2-yl)cyclohexylamine in 15 ml of methylene chloride cooled in an ice bath. Portions added 0.88 g (5.4 mmol) of carbonyldiimidazole. After an hour in the reaction mixture is poured gas is m solution of sodium chloride, dried over sodium sulfate and concentrated. The resulting product was then purified by chromatography on silica gel using as eluent a mixture of metilenhloride and methanol in a ratio of 99 to 1. As a result of recrystallization from isopropanol obtain 0.2 g of the target product with so pl. 202 204oC.

Similarly receive connections are summarized in table 6.

Example 4. 2-(2-cyclohexyl-1 - phenyl)ethylaminoethanol.

A mixture of 1.12 g (7.3 mmol) of 2-chlorobenzoxazole, 1,48 g (7.3 mmol) of 2-cyclohexyl-1-phenethylamine and 0.88 g (8,8 mmol) of triethylamine in 305 ml of methylene chloride is heated under reflux for 31 hours, the Reaction mixture is diluted with 50 ml of methylene chloride, successively extracted with 50 ml of water, 50 ml of 1N hydrochloric acid, 50 ml saturated sodium chloride, dried over sodium sulfate and concentrated. The obtained solid is recrystallized from ethanol. Obtain 1.4 g (4.4 mmol, 60%) of the desired product with so pl. 129 131oC.

Similarly receive connections are summarized in table 7.

Example 5. L-2-[2-cyclohexyl-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethyl]amino-5-methylbenzotriazole.

The variance of 0.47 g of 60% sodium hydride in mineral oil (0.28 g of 11.8 mmol git - yl)cyclohexylamine and several molecular sieves in the environment of 20 ml of tetrahydrofuran and the reaction mixture heated under reflux for two hours in nitrogen atmosphere. The reaction mixture is poured into water and extracted with ethyl acetate. An ethyl acetate phase is dried over sodium sulfate and concentrated. The resulting product was then purified by chromatography on silica gel using as eluent a mixture of methylene chloride and methanol in a ratio of 99 to 1. After mixing with petroleum ether obtain 70 mg of the desired product as white solids with so pl. 118 119oC.

Example 6. 3-[(6-isopropylthiazole-2-yl) amino]-4-phenylbutane-2-it.

A solution of 2 g (5.9 mmol) of N-(6 - isopropylthiazole-2-yl) phenylalanine in 60 ml of tetrahydrofuran cooled to a temperature of -5oC in a salt-ice bath under nitrogen atmosphere. Then add a solution of 26 ml of cases (36.4 mmol) metallice in diethyl ether. Two hours quickly add 10 ml (78 mmol) of chlorotrimethylsilane and the reaction mixture is heated to room temperature. Then the reaction mixture is treated with 1N hydrochloric acid and the product extracted with diethyl ether, dried over sodium sulfate and concentrated. In the purification by chromatography on silica gel using as eluent methylene chloride and recrystallization from ethanol 0.75 g (2.2 mmol, 38%) of the desired product with so pl. 107 110oC.

amino]thiazolo[5,4-b]pyridine.

A mixture of 1.28 g (10 mmol) 3-amino-2-chloropyridine, 2.1 g (20 mmol) of sodium carbonate and 1.38 g (12 mmol) of thiophosgene in 50 ml of methylene chloride is stirred at room temperature overnight. The reaction mixture is poured into water and extracted with methylene chloride. The combined organic extracts washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The resulting oil purified by chromatography on silica gel using as eluent petroleum ether. Get a 1.6 (9.4 mmol, 94%) disocyanate.

0,516 g (to 3.02 mmol) disocyanate added to a mixture of 0.66 g (a 2.75 mmol) of the hydrochloride of 2-cyclohexyl-1-phenethylamine and 0,278 g (a 2.75 mmol) of triethylamine in 25 ml of tetrahydrofuran. The reaction mixture is heated under reflux for two hours, pour in water and extracted with diethyl ether. The organic extracts are washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated. As a result of recrystallization of the residue from a mixture of methylene chloride and petroleum ether get 0.625 g (of 1.84 mmol, 67%) of the product so pl. 146-148oC.

Example 8. 2-[(2-cyclohexyl-1-(2-pyridyl)ethyl]amino]-6-methylthiazole-[4,5-b] pyridine.

3,19 g of bromine drops add is at room temperature, the reaction mixture was sequentially extracted with a saturated solution of sodium carbonate and sodium thiosulfate solution. The combined aqueous extracts washed with methylene chloride and the combined organic extracts washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated. Get 3,59 g crude product which is purified by chromatography on silica gel using as eluent petroleum ether, to which is added increasing the number of methylene chloride (0-40%). Get 3,05 g amino-3-bromo-5-picoline with so pl. 68-70oC.

To 2,84 g (15 mmol) of the above product in 50 ml of methylene chloride with the addition 3,18 g (30 mmol) of sodium carbonate added 2,07 g (18 mmol) of thiophosgene. The reaction mixture was stirred at room temperature overnight, after which it is extracted with water, the aqueous phase is extracted with methylene chloride, the combined organic extracts are washed with saline, dried over magnesium sulfate and concentrated. Get isothiocyanate that crystallized when standing. Gain of 3.9 g of the product (IR 2050 cm-1).

To a solution of 1.0 g (4.3 mmol) of isothiocyanate and 1.04 g (4.3 mmol) of 2-cyclohexyl-1-phenethylamine in 50 ml of dry tetrahydrofuran add 438 mg (4.3 mmol) of triethylamine. The resulting reaction mixture is heated from the reverse holodilniki heaven crystallized when standing.

A mixture of 540 mg (1.15 mmol) of thiourea and 317 mg (2.3 mmol) of potassium carbonate in 10 ml of dimethylformamide is heated under reflux overnight, after which it was poured into water and extracted three times with diethyl ether and once with methylene chloride. The organic extracts are washed with sodium chloride solution, dried over sodium sulfate and concentrated. Obtain 450 mg of the product, which is recrystallized from a mixture of methylene chloride, diethyl ether and petroleum ether. Obtain 210 mg of the product so pl. 213-214oC.

Similarly receive connections are summarized in table 14.

Pharmacology.

Inhibition of leukotriene biosynthesis in polymorpho-nuclear leukocytes of man.

Inhibition of leukotriene biosynthesis determine due to the fact that they measure the capacity of the investigated connec - tions to the inhibition of leukotriene production from endogenous arachidonic acid in leukocytes from the peripheral blood of man.

In a Cup with 48 cells served a solution of the compound with subsequent up - Addendum polymorphically of human leukocytes in number 1,5x106cells/cells from peripheral blood. Cup pretrial incubated at a temperature of 28oatie 2.5 Ámol within 10 minutes The reaction is stopped by adding a solution etilenditiodiuksusnoi acid (final concentration 10 mmol) followed by centrifugation speeds of 1500 rpm and at a temperature of 10oC. the Supernatant stored at -70oC. the Concentration of leukotriene determine the known methods. The CT value50(= concentration of inhibition, i.e., the concentration of tested compound in which leukotriene biosynthesis is inhibited by 50%) are estimated using nonlinear regression analysis.

The results of the experiment are summarized in tables 15 and 16.

Caused by antigen narrowing of the bronchi in Guinea pigs

This experience allows us to identify the ability of compounds to inhibit leukotriene component caused by antigen narrowing of the bronchi. Male Guinea pigs actively sensitized against egg albumin, after which they were given mepyramine and indometacin (for blockade of histamine and components metabolite cyclo-oxygenase), and also investigated the connection (in the form containing freon and ethanol aerosol). The Guinea pig was charged antigen (by inhalation egg albumin). Pulmonary function was measured using oscillography. The results you experience the tion, compared to control animals who were given a placebo.

The results of the experiment are summarized in table 17.

Caused by antigen release of mediator in primates.

This experience enables us to determine the ability of compounds to inhibit formation of leukotriene C4in the lungs of allergic monkeys after loading of the antigen. After anesthesia, the animals were held intubation, after which the animals were given an extract of Ascaris suum in aerosol form. After 20 min was performed bronchoalveolar washing and the amount of leukotriene C4was determined by radioimmunoassay analysis. The compounds were added in the form of an aerosol for 10 min prior to loading of the antigen. Their action was defined as the percentage inhibition of the formation of leukotriene C4compared to control animals who were given a placebo. The results of the experiment are summarized in table 18.1

Nitrogen-containing heterocyclic compounds of General formula

< / BR>
where X is oxygen or sulfur;

Y is carbon or nitrogen;

Z is carbon or nitrogen, and Y and Z are not simultaneously mean nitrogen;

R1and R2independent of each other, hydrogen, C1- C6-alkyl, halogen, trifluoromethyl, cyano, nitro, C1- >9where R8and R9independent of each other, hydrogen, C1C3or together with the nitrogen form a morpholine group-NHC(O)R10where R10C1C6- alkyl, -NHSO2R10where R10has the specified value, or-SO2NR11R12where R11and R12independent of each other, hydrogen or C1- C6-alkyl;

R3cyclohexyl, phenyl, unsubstituted or substituted by residues from the group comprising halogen, C1C4-alkoxyl, group-NHSO2R10where R10has a specified value; the nitro-group, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, thiomorpholine, imidazole, substituted at the nitrogen C1C4-alkyl, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or C1< / BR>
C4-alkilany ether;

R4an ester of formula-CO2R13where R13- C1C4-alkyl, amide of formula-C(O)NR14R15where R14and R15independent of each other, hydrogen, C1- C3-alkyl, methoxy, or together with the nitrogen form a piperidine; phenyl, unsubstituted or substituted by residues from the group comprising halogen and C1C4-alkoxy, 3-methyl-1,2,4-oxadiazol-5-yl, 2 - or ly C(O)R16where R16C1- C3-alkyl, phenyl or 1-Mei-2-yl; a simple ester of the formula-CH2OR17where R17C1C3-alkyl; tiefer formula CH2SR17where R17has a specified value; a group-CH2SO2CH3; amine of formula-CH2N(R17)2where R17has a specified value; a residue of formula-CH2NHC(O)R18where R18methyl or amino; a group-CH2NHSO2Me2where Me is methyl; carbamate of the formula-CH2OC(O)NHCH3;

R5and R6independent of each other, hydrogen or methyl;

n is 0, 1 or 2,

provided that the substituents are not simultaneously have the following meanings: Y and Z is carbon, R1or R2hydrogen, halogen, C1C4-alkyl, C1C4-alkoxy, cyano, nitro, trifluoromethyl, R3unsubstituted phenyl and R4group-CO2R13where R13C1C4-alkyl; the group-C(O)N(R14)(R15), where R14and R15hydrogen, C1C3-alkyl, phenyl, methoxy, or together with the nitrogen form a piperidine, or Y and Z is carbon, R4-C(O)OCH3, R1and R2the hydrogen and R3unsubstituted phenyl,

in the form of a racemate or a single enantiomer, awlays the EPA, Y is carbon or nitrogen, Z is carbon, or nitrogen, R1and R2independent of each other, hydrogen, C1C6-alkyl, halogen, trifluoromethyl, cyano, nitro, C1- C6the alkoxy group-CO2R7where R7hydrogen or C1C6-alkyl; the group-C(O)NR8R9where R8and R9independent of each other, hydrogen, C1C3-alkyl, or together with the nitrogen form a morpholine; group-NHC(O)R10where R10C1C6-alkyl, -NHSO2R10, R10has the specified value, or-SO2NR11R12where R11and R12independent of each other, hydrogen or C1- C6-alkyl, R3cyclohexyl, phenyl, unsubstituted or substituted by residues from the group comprising halogen, C1C4-alkoxyl, group-NHSO2R10where R10has a specified value; the nitro-group, 1-piperidinyl, 2-, 3 - or 4-pyridine, morpholine, imidazole, substituted at the nitrogen C1C4-alkyl, R4ester of the formula CO2R13where R13C1C4-alkyl; amide of formula-C(O)NR14R15where R14and R15independent of each other, hydrogen, C1C3-alkyl, methoxy, or together with the nitrogen form a piperidine; phenyl, sesameseed-5-yl, 2 - or 3-thienyl, 2-, 3 - or 4-pyridyl, a ketone of the formula C(O)R16where R16C1C3-alkyl, phenyl or 1-Mei-2-yl, R5and R6independent of each other, hydrogen or methyl, n is 0, 1 or 2, in the form of a racemate or a single enantiomer;

04.09.92. when X is oxygen or sulfur, Y is carbon or nitrogen, Z is carbon or nitrogen, R1and R2independent of each other, hydrogen, C1C6-alkyl, halogen, trifluoromethyl, cyano, nitro, C1- C6the alkoxy group-CO2R7where R7hydrogen or C1C6-alkyl; the group-C(O)NR8R9where R8and R9independent of each other, hydrogen, C1C3-alkyl or together with the nitrogen form a morpholine; group-NHC(O)R10where R10- C1C6-alkyl; -NHSO2R10where R10has a specified value; or-S2NR11R12where R11and R12independent of each other, hydrogen or C1C6-alkyl, R3thiomorpholine, 2-thiazole, 2-methyl-4-thiazole, dialkylamino with 1 to 4 carbon atoms in each alkyl group, or C1- C4-alkilany ether, R42-thiazole, unsubstituted or substituted in position 4 with stands, a simple ester of the formula-CH2OR17where R17C1C3-Alki is B> amines of the formula-CH2N(R17)2the remainder of the formula-CH2NHC(O)R18where R18is methyl; group-CH2NHSO2Me2where Me is methyl; carbamate of the formula-CH2OC(O)NHCH3, R5and R6- independent of each other, hydrogen or methyl, n is 0, 1 or 2, in the form of a racemate or a single enantiomer;

23.09.92 when R44-pyrazole, or a group-CH2NHC(O)R18where R18amino.

 

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The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

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aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

The invention relates to new heterocyclic derivatives of substituted 2-acylamino-5-thiazolo exhibiting affinity to the receptor cholecystokinin and gastrin to a method for producing such compounds and to pharmaceutical compositions based on

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to a series of new piperidyl - occaisonally and khinuklidinilbenzilata derivatives that can be used in the treatment and prevention of various disorders, especially senile dementia / including disease of Alzheimer/
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