N-substituted indole-3-glycinamide and drug, possess antiasthmatic, antiallergic and immunosuppressive/immunomodulatory effect, the method of obtaining compounds(options) and the method of obtaining drug

 

(57) Abstract:

The invention relates to N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl; R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen, or R1presents arylamination-2-methylprop-1-ilen group, or R and R1together with the nitrogen atom to which they are attached, form a loop piperazine is )alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium residue; R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)alkyl, or R3is cyclopentanecarbonitrile; Z denotes Oh, and alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert-butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, and their pharmaceutically acceptable salts with acids. Connection with the specified activity can be used to obtain a drug. 4 N. and 3 C.p. f-crystals, 5 PL.

The technical field to which the invention relates.

And ladyship asthma, antiallergic and immunosuppressive/immunomodulatory effect.

The level of technology.

Indole-3-glycinamide are pharmaceutically dynamic active compounds and are widely used as starting compounds for the synthesis of pharmaceutical chemistry.

In the patent application NL (Netherlands) 6502481 described compounds with anti-inflammatory and antipyretic properties and exhibiting analgetic activity.

In the British patent application GB-PS 1028812 derivatives indolyl-3-Glyoxylic acid and the above-mentioned amides are considered as analgesics, anticonvulsants and-adrenergic compounds.

In article G. Domschke et al. (Ber., 94, 2353 (1961) described 3-intelligibility that are not described from the perspective of pharmacology.

E. Walton et al. (J. Med. Chem., 11, 1252 (1968) reported derivatives indolyl-3-Glyoxylic acid, which inhibit glitserofosfatdegidrogenazy and lactate dehydrogenase.

In European patent application EP 0675110 A1 describes amides 1H-indole-3-Glyoxylic acid, which has inhibitory effect on SPLA2 and used in the treatment of septic shock, pancreatitis, allergic rhinitis and rheumatoid arthritis.

In addition, the object of the invention is to develop a chemical method of obtaining such compounds, methods of processing of new compounds in herbal medicines, as well as ways to obtain their dosage forms.

The subject invention are compounds of General formula I

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl;

R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6

R7denotes phenyl or pyridinyl;

R2means (C1-C6)alkyl, which optionally contains a phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium balance;

R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)-alkyl, or R3is cyclopentanecarbonitrile;

Z means OF,

and their pharmaceutically acceptable salts with acids.

The terms alkyl-, alkanol-, alkoxy - or alkylamino refer to the residues R, R1, R2, R3, R4, R5, R6, R7and means ordered as "unbranched" and "branched" alkyl groups, for example, unbranched group" means methyl, ethyl, n-propyl, n-butyl, n-hexyl, and as a "branched" Ala the R, chlorine, bromine or iodine. "Alkoxygroup" means, for example, methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan.

Compounds according to the invention can be used in the form of salts of the adducts with acids, for example salts of mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid; salts of organic acids such as acetic acid, lactic acid, malonic acid, maleic acid, fumaric acid, gluconic acid, glucuronic acid, citric acid, albanova acid (4,4’-Methylenebis(3-hydroxy-2-naphthenic acid)), methansulfonate acid, triperoxonane acid and succinic acid.

The compounds of formula I and their salts are biologically active. The compounds of formula I can be entered as medicine both in free form and in the form of salts with physiologically tolerated acids.

The compounds can be administered orally, parenterally, intravenously, subcutaneously or through the respiratory tract.

Thus, the invention relates also to pharmaceutical preparations having anti-asthmatic, anti-allergic and immunosuppressive/immunomodulatory effect and containing, at mkokotoni and, if necessary, pharmaceutically applicable substances - the carrier and/or diluent or excipient. In addition, the invention concerns a method of obtaining these drugs.

As the dosage forms are used, for example, tablets, pills, capsules, solutions or capsules, suppositories, patches, inhalation compositions, suspensions, creams and ointments.

The invention also relates to a method for obtaining N-substituted indole-3-glycinamido formula I, where R, R1, R2, R3, R4and Z have the above values, namely, that derived indole of formula IV

where R3and R4have the above values,

mix with the ground, suspended in proton dipolar, aprotic or nonpolar organic solvent, and with a reactive compound containing a residue R2where R2have the above values, and get the derived 1-indole of formula V

where R2, R3and R4have the above values,

which is mixed with an aprotic or nonpolar organic solvent and a reactive compound of the formula VI

(C-Z-Hal)2

where Z is an oxygen atom and Hal m ilitary a product of primary or secondary amine of the formula VII

HNRR1

where R and R1have the above values,

in aprotic or dipolar aprotic solvent and produce the target compound of formula I.

The invention also concerns a method for obtaining N-substituted indole-3-glycinamido formula I, where R, R1, R2, R3, R4and Z have the above values, namely, that derived indole of formula IV

where R3and R4have the above values,

mix in aprotic or non-polar solvent with a reactive compound of the formula VI

(C-Z-Hal)2

where Z is an oxygen atom, and Hal means halogen, selected from the group consisting of fluorine, chlorine, bromine or iodine,

handle the product in aprotic or dipolar aprotic solvent and a primary or secondary amine of the formula VII

HNRR1

where R and R1have the above values,

then the derived 3-indole of formula VIII

where R, R1, R3, R4and Z have the above meaning,

mix in the presence of the suspended Foundation in proton dipolar, aprotic or nonpolar organic races of the values, and produce the target compound of formula I.

Compounds according to the invention have good anti-asthmatic, anti-allergic and immunosuppressive/immunomodulatory effect, for example, in transplantation and diseases, such as psoriasis, rheumatoid diseases and chronic polyarthritis, which was investigated on the following pharmacological models.

The suppression of the "late stage" of eosinophilia with bronchoalveolar lavage (BAL) within 24 hours after allergies provoked in Guinea pigs.

Male Guinea pigs (200-250 g, Dunkin Hartley Shoe) actively sensibiliser the ovalbumin subcutaneously (10 µg ovalbumin + 1 mg Al(Oh)3and after 2 weeks again subjected to immunization. One week after immunization with ovalbumin in animals cause allergies by ovalbumin (0.5% solution) inhalation method for 20-30 seconds. After 24 hours, animals are killed by cordozo urethane, bleed and performed bronchoalveolar lavage (BAL) 25 ml of 0.9% saline solution. Lavanya washings are combined and centrifuged for 10 minutes at 400 g, the precipitate is suspended in 1 ml of 0.9% saline solution. The number of eosinophils count in the microscope it Floxin, which is a reagent that selectively coloring eosinophils. They expect the number of eosinophils in BAL for each animal and eosinophilia Express the value (millions/animal). For each group, calculate the average and standard deviation. The percentage inhibition of eosinophilia for the group of animals treated with the test compound is determined by the following formula:

(A-b)-(b-C)/(a-C)x100 = % suppression

where And eosinophilia in a group of untreated animals with provoked allergies

In - eosinophilia in the group treated animals and

With eosinophilia in the control group of animals provoked without allergies.

To prevent death 2 hours before the provocation of allergic animals treated with N1antagonists of histamine (azelastin, 0.01 mg/kg orally). Test compounds or indifferent based drug administered 4 hours after provocation allergies. The percentage inhibition of eosinophilia in BAL calculated for groups of 6-10 animals. The data obtained are summarized in table 1.

Method for determining the activity of peptidyltransferase (RR) and suppression of the activity.

PPI-activity cycle is no isomerization of the substrate, then it becomes available for chymotrypsin and the cleavage of the chromophore (p-nitroaniline). To determine the suppression of PPI activity in the presence of substance use recombinant cyclophilin In person (sur). The interaction of sur with the potential inhibitor is carried out as follows.

The solution of purified sur In a certain concentration incubated in the presence of 1 μm of the substance within 15 minutes. PPI-initiate the reaction by adding to the reaction mixture of the substrate solution, HEPES buffer, chymotrypsin and either the test sample or a control sample. Under these conditions, the reaction obeys the law of the first order with a rate constant

KOBS=Kabout+Kfarms,

where Kospontaneous isomerization TOfarmsthe rate of isomerization catalyzed by PPI.

The magnitude of the absorption corresponding to the number derived chromophore, measured at a constant reaction temperature equal to 10C, using the spectrophotometer Beckman DU 70.

The observed residual activity of different substances compared with ticlopidine treated only with solvent. Results expressed as % residual activity. As a standard connection uspomena gel in the presence of SDS-PAGE.

The colorimetric method is based on using MTT) for non-radioactive determination of cell proliferation and viability.

MTT is used to quantify cell proliferation and activation, for example, with the help of growth factors and cytokines, such as IL-2 and IL-4, as well as for quantitative evaluation of antiproliferative or toxic effect.

The method is based on the cleavage of the yellow salt of tetrazole MTT before the formation of a purple-red crystals formazan in the presence of metabolically active cells.

Cells grown in 96-well the tablet to cell cultures and incubated with yellow MTT solution for about 4 hours. After this period, the formed purple-red crystals of salt formazan that do not dissolve in aqueous solution, but which can be dissolved by adding reagent to dissolve and after incubation over night. The amount of dissolved salts formazan determined spectrophotometrically using the reader for enzyme-linked immunosorbent assay (ELISA). The increase in the number of living cells results in increasing the overall metabolic activity in the sample. This increase directly correlates with the number ="ptx2">

The method of obtaining the compounds according to the invention described in the following schemes 1 and 2, provides a brief description of the synthesis. All connections can be obtained on the schemes or in the same way.

Compounds of General formula I are synthesized according to the following scheme 1. The following diagram illustrates the synthesis of compounds according to example 1.

A brief description of obtaining compounds of General formula I according to scheme 1.

Stage 1

For synthesis, you can use a derivative of indole or without substituents or a substituent at position C-2, or with one or more substituents in the phenyl cycle. A derivative of indole dissolved in proton, dipolar aprotic or nonpolar organic solvent, for example isopropanol, tetrahydrofuran, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-organic, dioxane, toluene or methylene chloride, and the solution slowly added dropwise in a nitrogen atmosphere to a stoichiometric amount or excess of the stoichiometric amount of the base suspension loaded in a three-neck flask, such as sodium hydride, the powder potassium hydroxide, tert-butyl potassium, dimetilan aralkyl or heteroarylboronic, and in the appropriate case type catalyst, for example copper, and the reaction mixture was kept, for example, from 30 minutes to 12 hours at the temperature of the reaction mixture from 0 to 120C, preferably from 30 to 80, more preferably from 50 to 65 degree Celsius. After completion of the reaction, the reaction mixture is added to the water. The solution is extracted with, for example, diethyl ether, dichloromethane, chloroform, methyl tert-butyl ether or tetrahydrofuran, and in each case the organic phase is dried with anhydrous sodium sulfate. The organic phase was concentrated in vacuo, the residue is crystallized by rubbing or oily residue is purified by recrystallization, distillation or column chromatography or thin-layer chromatography on silica gel or aluminium oxide. As the mobile phase used, for example, a mixture of dichloromethane and diethyl ether in the ratio 8:2 (about./about.) or a mixture of dichloroethane and ethanol in the ratio of 9:1 (vol./vol.).

Stage 2

N-substituted indole, obtained in the above stage 1, is dissolved in an aprotic or nonpolar organic solvent, for example diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylene chloride or chloroform,at a stoichiometric quantity or 60% excess oxalicacid in aprotic or non-polar solvent, for example in diethyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane, toluene, xylene, methylene chloride or chloroform, and the temperature of the reaction mixture is maintained within the range from -5 to-20C. Then the reaction mixture is heated for from 30 minutes to 5 hours at a temperature of from 10 to 130C, preferably from 20 to 80, preferably from 30 to 50C. After completion of the reaction the solvent is distilled off. The remnant chloride indolyl-3-Glyoxylic acid obtained according to this method, dissolved in an aprotic solvent, such as tetrahydrofuran (THF), dioxane, diethyl ether, toluene, or a dipolar aprotic solvent, for example dimethylformamide, dimethylacetamide or dimethyl sulfoxide, is cooled to a temperature of from 10 to 15 SECONDS, preferably from -5 to 0C and the reaction mixture is added a solution of primary or secondary amine in a diluent in the presence of an acid acceptor. As a diluent is used, the solvents used for dissolving chloride indolyl-3-Glyoxylic acid. As the acid acceptor used triethylamine, pyridine, dimethylaminopyridine, a basic ion exchanger, sodium carbonate, potassium carbonate, powdered potassium hydroxide, and reaccreditation from 20 to 80C, particularly preferably from 40 to 60C. The reaction mixture was incubated for 1-3 hours, 24 hours at room temperature, then the hydrochloride of the acid acceptor is removed by filtration, the filtrate was concentrated in vacuo and the residue is recrystallized from an organic solvent or purified by column chromatography on silica gel or aluminium oxide. As the mobile phase used, for example, a mixture consisting of dichloromethane and ethanol (95:5, vol/vol.).

Information confirming the possibility of carrying out the invention.

Explanation of examples.

The following compounds were obtained using the above General principles for stages 1 and 2, which are the basis of the synthesis of 1, the corresponding chemical names below. Table 3 presents the structure of the substituents R1-R4and Z of the compounds of the General formula I, as well as the melting point of these compounds.

Example 1. N-(Pyridine-4-yl)-[1-(4-terbisil)indol-3-yl]glyoxylate.

Stage 1. 1-(4-Terbisil)indole.

The solution 11,72 g (0.1 mol) of indole in 50 ml of dimethyl sulfoxide is added to a mixture of 2.64 g of sodium hydride (0.11 mol, suspension in mineral oil) in 100 ml of dimethyl sulfoxide. Reactionsto heated to 60C, leave overnight and then with stirring, poured into 400 ml of water. The resulting mixture was repeatedly extracted with methylene chloride (final volume 150 ml), the organic phase is separated and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is distilled in high vacuum.

Output 21,0 g (96% of theory). So Kip. (0.5 mm) 140 C.

Stage 2. N-(Pyridine-4-yl)-[1-(4-terbisil)indol-3-yl]glyoxylate.

A solution of 4.75 g (21.1 mmol) of 1-(4-terbisil)indole in 25 ml of ether was added dropwise to a solution of 2.25 ml of oxalicacid in 25 ml of ether at 0C under nitrogen atmosphere. Heated for 2 hours under reflux and the solvent is distilled off. Then to the residue was added 50 ml of THF, the solution is cooled to-5 ° C and added dropwise a solution of 4.66 g (x 49.5 mmol) of 4-aminopyridine in 200 ml of THF. The reaction mixture is heated for 3 hours under reflux and left overnight at room temperature. 4-Aminopyridine hydrochloride is filtered off, the filter cake washed with THF, the filtrate was concentrated in vacuo and the residue is recrystallized from ethyl acetate.

Output to 7.09 g (90% of theory). So pl. 225-S.

Elemental analysis

Calculated, %: C 70,77; N 4,32; N 11,25.

Found, %: C 71,09; N 4,36; N Of 11.26.

Example 2. N the amide.

Example 4. N-(Pyridine-3-yl)-(1-benzyliden-3-yl)glyoxylate.

Example 5. N-(Pyridine-3-yl)-[1-(2-Chlorobenzyl)indol-3-yl]glyoxylate.

Example 6. N-(4-Forfinal)-[1-(4-terbisil)indol-3-yl]glyoxylate.

Example 7. N-(4-Nitrophenyl)-[1-(4-terbisil)indol-3-yl]glyoxylate.

Example 8. N-(2-Chloropyridin-3-yl)-[1-(4-terbisil)indol-3-yl]glyoxylate.

Example 9. N-(Pyridine-4-yl)-(1-benzyliden-3-yl)glyoxylate.

Example 10. N-(Pyridine-4-yl)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylate.

Example 11. N-(4-Forfinal)-[1-(2-pyridylmethyl)indol-3-yl]glyoxylate.

Example 12. N-(4-Forfinal)-[1-(3-pyridylmethyl)indol-3-yl]glyoxylate.

Example 13. N-(Pyridine-4-yl)-[1-(4-Chlorobenzyl)indol-3-yl]glyoxylate.

Example 14. N-(Pyridine-4-yl)-[1-(2-Chlorobenzyl)indol-3-yl]glyoxylate.

Example 15. N-(Pyridine-2-yl)-[1-(4-terbisil)indol-3-yl]glyoxylate.

Example 16. N-(Pyridine-4-yl)-[1-(2-pyridylmethyl)indol-3-yl]glyoxylate.

Example 17. (4-Phenylpiperazin-1-yl)-[1-(4-terbisil)indol-3-yl]glyoxylate.

Example 18. N-(Pyridine-2-yl)-(1-benzyliden-3-yl)glyoxylate.

Example 19. N-(Pyridine-4-yl)-[1-(4-terbisil)-6-ethoxycarbonylmethyl-3-yl]glyoxylate.

Example 20. N-(Pyridine-4-yl)-[1-(4-terbisil)-5-etox nileminowa-3-yl]glyoxylate.

Example 22. [4-(Pyridin-4-yl)piperazine-1-yl]-[1-(4-terbisil)indol-3-yl]glyoxylate.

Example 23. N-(3,4,5-Trimethoxybenzyl)-N-(arylamination-2-methylprop-1-yl)-[1-(4-terbisil)indol-3-yl]glyoxylate.

Example 24. N-(Pyridine-4-yl)-[1-(4-terbisil)-5-methoxyindol-3-yl]glyoxylate.

Example 25. N-(Pyridine-4-yl)-[1-(4-terbisil)-5-hydroxyindole-3-yl]glyoxylate.

Example 26. N-(Pyridine-4-yl)-[1-(4-terbisil)-5-ethoxycarbonylmethyl-3-yl]glyoxylate.

The preliminary stage of the synthesis of compounds of General formula I obtained according to scheme 1 (see table 3).

All of the original compounds used in the final stages of the synthesis of compounds according to examples 1-22 and 24-26 are commercial preparations.

Further compounds of General formula I were obtained according to scheme 2, which shows the synthesis of compounds according to example 27.

Brief description of producing compounds of the formula I according to scheme 2.

Stage 1. The solution derived indole containing substituted or unsubstituted in position C-2 phenyl ring, slowly added dropwise to a solution of oxalicacid in aprotic or non-polar solvent, such as diethyl ether, methyl tert-butyl ether is killgore in equimolar ratio from up to 60% excess of the stoichiometric amount. Then the reaction mixture is heated for 1 to 5 hours at a temperature of from 10 to 120C, preferably from 20 to 80, particularly preferably from 30 to 60, and the solvent is distilled off. The residue containing chloride (indol-3-yl)Glyoxylic acid, is dissolved or suspended in an aprotic solvent, such as THF, dioxane, diethyl ether, toluene, or a dipolar aprotic solvent, for example dimethylformamide, dimethylacetamide or dimethyl sulfoxide, is cooled to a temperature of from -10 to +10 ° C, preferably from -5 to 0C and add a solution of primary or secondary amine in a diluent in the presence of an acid acceptor. As a diluent for use generally accepted for dissolution "of chlorides indolyl-3-Glyoxylic acid solvents. As the acid acceptor used triethylamine, pyridine, dimethylaminopyridine, a basic ion exchanger, sodium carbonate, potassium carbonate, powdered potassium hydroxide, and add the primary and secondary amines in excess. The reaction is carried out at a temperature of from 0 to 120C, preferably from 20 to 80, particularly preferably from 40 to 60C. The reaction mixture was kept at this temperature for 1-4 hours, then at room temperature for the Aquum and spend cleaning compounds by recrystallization from an organic solvent or by column chromatography on silica gel or aluminium oxide. As the mobile phase used, for example, a mixture of dichloromethane and ethanol (10:1, vol/vol.).

Stage 2. "Indole-3-yl-Glyoxylic" obtained by the above method in stage 1, is dissolved in proton, dipolar aprotic or an organic solvent, such as isopropanol, THF, dimethylsulfoxide, dimethylformamide, dimethylacetamide, N-organic, dioxane, toluene or dichloromethane and slowly added dropwise to a suspension of a base such as sodium hydride, powdered potassium hydroxide, of potassium tert-butylate, dimethylaminopyridine or sodium amide, in an appropriate solvent. The suspension is loaded into a three-neck flask in the stoichiometric ratio or in excess of the stoichiometric ratio. All reactions carried out in nitrogen atmosphere. Then add the desired alkyl-, aralkyl or heteroarylboronic without solvent or diluent, which, for example, is used for dissolution of the indol-3-yl-glycinamide", if necessary add a catalyst, for example copper, the reaction mixture was kept for some time, for example from 30 minutes to 12 hours, and keep the temperature from 0 to 120C, preferably from 30 to 80, particularly preferred is diethyl ether, dichloromethane, chloroform, methyl tert-butyl ether, THF or n-butanol and the organic phase is dried with anhydrous sodium sulfate.

The organic phase was concentrated in vacuo, the resulting residue is crystallized by rubbing or oily residue is purified by distillation or column or thin-layer chromatography on silica gel or aluminium oxide. As the mobile phase used, for example, a mixture of methylene chloride and diethyl ether in the ratio 8:2 (about./about.) or a mixture of methylene chloride and ethanol in the ratio of 9:1 (vol./vol.).

Comments to the example.

The following compounds were obtained using the above General principles for stages 1 and 2, which are the basis of the scheme of synthesis of 2. These compounds were also synthesized according to scheme 1 and are presented in table 3. Starting compound to obtain these compounds result from table 4.

Example 27. N-(Pyridine-4-yl)-[1-(4-(tormentil)indol-3-yl]glyoxylate (end stage analogously to example 1).

Stage 1. N-(Pyridine-4-yl)-(indol-3-yl)glyoxylate.

A solution of 10 g (85,3 mmol) of indole in 100 ml of ether is slowly added dropwise to a solution of 9 ml of oxalicacid in 100 ml of anhydrous ether. The reaction mixture is ri-5S suspension of 12 g (127,9 mmol) of 4-aminopyridine in 500 ml of THF, the reaction mixture is heated under stirring for 3 hours at boiling under reflux and maintained at room temperature during the night. The reaction mixture is filtered, the residue is treated with water and dried compound purified by column chromatography on silica gel (Kieselgel 60, manufactured by Fa. Merck AG, Darmstadt). As mobile phase a mixture of methylene chloride and ethanol (10:1, vol/vol.).

The output of 9.8 g (43.3% of theory). So pl. from S.

Stage 2. N-(Pyridine-4-yl)-1-[4-(tormentil)indol-3-yl]glyoxylate.

Obtained in stage 1 N-(pyridin-4-yl)-(indol-3-yl)glyoxylate process according to the stage of benzylidene" (page 8, step 1) 4-formanilide and allocate the resulting connection.

Exit 41% of theory.

So pl. 224-S.

Elemental analysis

Calculated, %: C 70,77; N 4,32; N 11,25.

Found, %: C 70,98; N 4,40; N 11,49.

Example 28. N-(4-Nitrophenyl)-[1-(4-terbisil)indol-3-yl]glyoxylate (the last stage, analogously to example 7).

Example 29. N-(4-Forfinal)-[1-(4-terbisil)indol-3-yl]glyoxylate (the last stage, analogously to example 6).

Example 30. N-(Pyridine-3-yl)-[1-(4-terbisil)indol-3-yl]glyoxylate (the last stage, the analogues of the 2, table 4).

Example 31. N-(Pyridine-4-yl)-(indol-3-yl)glyoxylate.

Example 32. N-(4-Nitrophenyl)-(indol-3-yl)glyoxylate.

Example 33. N-(4-Forfinal)-(indol-3-yl)glyoxylate.

Example 34. N-(Pyridine-3-yl)-(indol-3-yl)glyoxylate.

These studies of acute toxicity in animal models.

The study was conducted using compound D-24851, representing N-(pyridin-4-yl)-[1-(4-Chlorobenzyl)indol-3-yl]glyoxylate obtained in example 13, according to the invention.

According to the Protocol of the study of acute toxicity in mice and rats animals injected oral (p/o) unit dose of a compound D-24851. Interval dose for mice is from 100 to 2150 mg/kg p/O. Rats males and females administered 100 mg/kg, 464 mg/kg, 681 mg/kg and 1000 mg/kg Males impose additional 215 and 31.6 mg/kg Compound D-24851 for the successful introduction of suspended with telazol (R).

Mouse. Dose of 215 mg/kg p/o males and 464 mg/kg p/o females did not cause any systemic toxicity. Lethal dose LD10and LD50and the coefficients of the reduction are given in table 5.

The rats. Dose of 215 mg/kg p/o males and 31.6 mg/kg in females did not cause any systemic toxicity. Letal the>P CLASS="ptx2">1. N-substituted indole-3-glycinamide General formula I, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory action:

where R is hydrogen, (C1-C6)alkyl, and the alkyl group optionally contains one phenyl substituent, which, in turn, optionally contains at least one Deputy, selected from the group comprising halogen, methoxy, ethoxy, (C1-C6)alkyl;

R1means phenyl cycle containing at least one Deputy, selected from the group comprising (C1-C6)alkoxy, hydroxy, nitro, (C1-C6)alkoxycarbonyl one or fluorine, or R1represents the balance of the pyridine of the formula II

where the carbon atoms 2, 3 and 4 of the remaining pyridine optionally have the same or different substituents R5and R6and R5and R6denote (C1-C6)alkyl or halogen; or

R1presents arylamination-2-methyl-prop-1-ilen group; or

R and R1together with the nitrogen atom to which they are attached, form a loop piperazine of formula III

where R7about the contains phenyl residue, which, in turn, optionally substituted with halogen, methoxy group or ethoxypropane, or related to R2(C1-C6)alkyl group optionally substituted 2-, 3 - or 4-pyridinium balance;

R3and R4are the same or different substituents and represent hydrogen, hydroxy, (C1-C6)alkoxy, (C1-C3)alkoxycarbonyl or (C1-C3)alkoxycarbonyl(C1-C3)-alkyl, or R3is cyclopentanecarbonitrile;

Z means OF,

moreover, alkyl, alkoxy or alkylamino mean as an unbranched group, such as methyl, ethyl, n-propyl, n-butyl, n-hexyl and branched alkyl groups such as isopropyl or tert. butylene group; halogen means fluorine, chlorine, bromine or iodine and alkoxygroup means methoxy, propoxy, butoxy, isopropoxy, isobutoxy or phenoxypropan, as well as their pharmaceutically acceptable salts with acids.

2. Connection on p. 1, characterized in that they are

N-(pyridine-4-yl)-[1-(4-terbisil)-indol-3-yl]-Glyoxylic,

N-(pyridine-4-yl)-(1-methyl-indol-3-yl)-Glyoxylic,

N-(pyridine-3-yl)-[1-(4-(-3-yl)-[1-(2-Chlorobenzyl)-indol-3-yl]-Glyoxylic,

N-(4-forfinal)-[1-(4-terbisil)-indol-3-yl]-Glyoxylic,

N-(4-nitrophenyl)-[1-(4-terbisil)-indol-3-yl]-Glyoxylic,

N-(2-chloropyridin-3-yl)-[1-(4-terbisil)-indol-3-yl]-Glyoxylic,

N-(pyridine-4-yl)-(1-benzyliden-3-yl]-Glyoxylic,

N-(pyridine-4-yl)-[1-(3-pyridylmethyl)-indol-3-yl]-Glyoxylic,

N-(4-forfinal)-[1-(2-pyridylmethyl)-indol-3-yl]-Glyoxylic

N-(4-forfinal)-[1-(3-pyridylmethyl)-indol-3-yl]-Glyoxylic

N-(pyridine-4-yl)-[1-(4-Chlorobenzyl)-indol-3-yl]-Glyoxylic,

N-(pyridine-4-yl)-[1-(2-Chlorobenzyl)-indol-3-yl]-Glyoxylic,

N-(pyridine-2-yl)-[1-(4-terbisil)-indol-3-yl]-Glyoxylic,

N-(pyridine-4-yl)-[1-(2-pyridylmethyl)-indol-3-yl]-Glyoxylic,

(4-phenyl-piperazine-1-yl)-[1-(4-terbisil)-indol-3-yl]-Glyoxylic,

N-(pyridine-2-yl)-(1-benzyliden-3-yl)-Glyoxylic,

[4-(pyridin-4-yl)-piperazine-1-yl]-[1-(4-terbisil)-indol-3-yl]-Glyoxylic,

N-(pyridine-4-yl)-[1-(4-terbisil)-6-ethoxycarbonyl-indol-3-yl]-Glyoxylic,

N-(pyridine-4-yl)-[1-(4-terbisil)-5-ethoxycarbonyl-indol-3-yl]-Glyoxylic,

N-(pyridine-4-yl)-[1-(4-terbisil)-6-cyclopentanecarbonyl-indol-3-yl]-Glyoxylic,

N-(3,4,5-trimethoxybenzyl)-N-(allylamino the XI-indol-3-yl]-Glyoxylic,

N-(pyridine-4-yl)-[1-(4-terbisil)-5-hydroxy-indol-3-yl]-Glyoxylic or

N-(pyridine-4-yl)-[1-(4-terbisil)-5-ethoxycarbonylmethyl-indol-3-yl]-glyoxylate.

3. Drug, possess Antiasthmatic, antiallergic and immunosuppressive/immunomodulatory effect, containing as active substance at least one connection on p. 1, a carrier and/or diluent and excipient.

4. Drug under item 3, made in the form of tablets, pills, capsules, solutions, capsules, suppositories, patches, inhalation compositions, suspensions, creams or ointments.

5. The method of obtaining the drug product described in paragraph 3, including a joint treatment of the active substances with carriers and/or diluents and excipients.

6. The method of obtaining N-substituted indole-3-glycinamido formula I under item 1 or 2, where R, R1, R2, R3, R4and Z are specified in paragraph 1 values, namely, that derived indole of formula IV

where R3and R4have the specified values,

mix with the ground, suspended in proton dipolar, aprotic or non-polar body is Azania values, and get the derived 1-indole of formula V

where R2, R3and R4have the specified values,

which is mixed with an aprotic or nonpolar organic solvent and a reactive compound of the formula VI

(C-Z-Hal)2,

where Z is an oxygen atom;

Hal denotes a halogen selected from the group consisting of fluorine, chlorine, bromine or iodine,

then processed the product of primary or secondary amine of the formula VII

HNRR1,

where R and R1have the specified values,

in aprotic or dipolar aprotic solvent and produce the target compound of formula I.

7. The method of obtaining N-substituted indole-3-glycinamido formula I under item 1 or 2, where R, R1, R2, R3, R4and Z are specified in paragraph 1 values, namely, that derived indole of formula IV

where R3and R4have the specified values,

mix in aprotic or non-polar solvent with a reactive compound of the formula VI

(C-Z-Hal)2,

where Z is an oxygen atom;

Hal means halogen, selected from the group consisting of fluorine, chlorine, bromine or iodine,

HNRR1,

where R and R1have the specified values,

then the derived 3-indole of formula VIII

where R, R1, R3, R4and Z have the abovementioned meaning,

mix in the presence of the suspended Foundation in proton dipolar aprotic or nonpolar organic solvent with a reactive compound containing a residue R2where R2has the specified values, and produce the target compound of formula I.

 

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< / BR>
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