Sertaconasole mononitrate process and sertaconasole mononitrate monohydrate

FIELD: chemistry.

SUBSTANCE: invention refers to Sertaconasole mononitrate process by reaction of 1-(2,4-dichlorphenyl)-2-(1H-imidazole-1-yl)ethanol and 3-bromomethyl-7-chlorbenzo[b]thiophene with tetrabutylammonium hydrosulphate and sodium hydroxide in toluene at 30-45°C. Produced free base of Sertaconasole is transferred into Sertaconasole mononitrate monohydrate with the latter being transferred into Sertaconasole mononitrate. There is disclosed and characterised intermediate Sertaconasole mononitrate monohydrate.

EFFECT: method allows simplifying process technology considerably.

6 cl, 5 dwg, 2 tbl, 2 ex

 

The technical field to which the invention relates.

The present invention relates to a method for imidazole compounds, namely sertaconazole, and its salts and pseudopolymorphs.

The level of technology

Sertaconazole (WHO-INN) is an antifungal agent, is widely used in the treatment of infections caused by fungi and yeast in humans and animals. The name "sertaconazole" means 1-[2-(7-chlorobenzo[b]thiophene-3-yl-methoxy)-2-(2,4-dichlorophenyl)ethyl]-1H-imidazole. Usually sertaconazole used as Mononitrate salt (I).

Specification EP 151477 describes obtaining Mononitrate sertaconazole (I) by reaction of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (II) with sodium hydride and 3-methyl bromide-7-chlorobenzo[b]thiophene (III) in hexamethylphosphoramide (NMRA) and processing the resulting free-base sertaconazole nitric acid.

Specification CN 1358719 (CAPLUS 2003:711267) describes the synthesis of Mononitrate sertaconazole (I) by esterification of 3-methyl bromide-7-chlorobenzo[b]thiophene (III) 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (II) at a molar ratio of 1:1 in the system toluene-water (3:1 by volume) in the presence of sodium hydroxide and 50% solution of tetrabutylammonium chloride (IV, Z=Cl) at 80°C for 4 hours, followed extraction with ethyl ether to obtain the free base sertaconazole, education salts when inter is actvie with nitric acid and recrystallization from 95% ethanol. The final contents of Mononitrate sertaconazole in the product, thus obtained, is >98.5 per cent.

The molecular formula is shown in figure 1/I-V.

The disclosure and implementation of inventions

The present invention relates to a new chemical process of obtaining Mononitrate sertaconazole (I).

In particular, the invention includes the process of obtaining Mononitrate sertaconazole (I), which is more efficient than that described in EP 151477 and CN 1358719, and which may unexpectedly produce Mononitrate sertaconazole (I) clinical quality standard (>99.5%pure). In this context, the Mononitrate of sertaconazole (I) clinical quality standard means the material is of sufficient purity for introducing people. The particle size of the product obtained in this way is 10 μm or less for at least 40% (by volume) of the total sample and 30 μm or less for at least 95% (by volume) of the total sample, which is a material suitable for direct use in pharmaceutical compositions.

Unlike specifications EP 151477, the process of the present invention does not require the use of hazardous solvents, such as hexamethylphosphoramide known as a chemical mutagen (The Merck Index, page 844, 13 th Edition, 2001, Merck&Co., Inc.), and ethyl ester, known as flammable and is vzryvoopasnaya liquid (ibid, page 677). Moreover, the process of the present invention is much more effective than described in the specification CN 1358719 (CAPLUS 2003:711267)as stoichiometric amount of raw materials required to obtain 1000 g of the final Mononitrate sertaconazole (I)is lower than the number used in the CN 1358719 (table 1).

Table 1.
Basic stoichiometric differences to obtain 1000 g of Mononitrate sertaconazole (I).
SubstanceThe present inventionCN 1358719
The reagent (II), {1-(2,4-Dichlorophenyl)-2-(1H-imidazol-1-yl)-ethanol}2,40 mol3,39 mol
The reagent (III), {3-methyl bromide-7-chlorobenzo[b]thiophene}2,62 mol3,39 mol
The catalyst (IV, Z=HSO4, Cl) {Tetrabutylammonium}0,121 mol {Z=HSO4}0,488 mol {Z=Cl}
The molar ratio of IV:II0,0500,144

A key stage in the process includes the t dehydrogenation immediate precursor, Mononitrate sertaconazole (V) monohydrate, the Mononitrate of sertaconazole (I).

Mononitrate sertaconazole monohydrate (V) has not been described previously and is also part of the present invention. Mononitrate sertaconazole monohydrate (V) can also be called poliforum of Mononitrate sertaconazole.

In a preferred embodiment, the dehydrogenation is carried out in a mixture of ethanol and water at 75-80°C, and slow addition (6-8 hours) this solution to aqueous solution of nitric acid, cooled to 5-15°C, filtration, drying at 60-70°C, screening and final drying at 80-90°C. thus Obtained Mononitrate sertaconazole (I) has sufficient purity and proper particle size for direct use in pharmaceutical compositions. Getting Mononitrate sertaconazole monohydrate (V) includes in the first stage, the reaction of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (II) with excess 3-methyl bromide-7-chlorobenzo[b]thiophene (III) in the presence of hydrosulphate of tetrabutylammonium (IV, Z=HO4S) and sodium hydroxide in toluene at 30-45°C, followed by addition of water, cooling the mixture to a temperature of 0-15°C., filtering, washing the obtained solid material with water and toluene, boiling free base sertaconazole in absolute ethanol until dissolved, by heating the mass at 60-80°C and add the group of water, further cooled to 5-15°C., filtering the obtained solid product and washing it with a mixture of ethanol and water, re-dissolving the obtained pure free base of sertaconazole in absolute ethanol at 70 to 80°C., cooling the mixture to a temperature of 65-75°C., followed by addition of 60% aqueous solution of nitric acid, maintaining at this temperature for 10-20 minutes at pH below 2, cooling the mixture to 5-15°C and maintaining at this temperature for 30 minutes to 2 hours, followed by filtration and washing with getting Mononitrate sertaconazole monohydrate (V).

In another embodiment, the molar ratio of reagent II: reagent III is from 0.85 to 0.95.

In another embodiment, the molar ratio of catalyst (IV, Z=HSO4to the limiting reagent (II) is from 0.025 up to 0.060.

In another embodiment, the molar ratio of catalyst (IV, Z=HSO4to the limiting reagent (II) from to 0,045 0,055. In the most preferred embodiment, the molar ratio of catalyst (IV, Z=HSO4to the limiting reagent (II) is 0,050.

Pharmaceutical compositions means for external use, such as bath additives, creams, gels, ointments, pastes for skin, medical adhesive tapes, foam for skin, shampoos, solutions for cooking sprays for leather, suspension for cooking sprays for skin powders for the preparation of sprays to the and liquid for skin solutions for skin, suspensions for skin emulsion for skin powders for the skin, cutaneous patches, Collodi, medical lipsticks, poultices, sticks to leather, sponge leather, impregnated dressings and the like; vaginal preparations such as vaginal creams, vaginal gels, vaginal creams, vaginal foam, vaginal fluids, vaginal suspension, vaginal emulsion, tablets for the preparation of vaginal fluids, vaginal suppositories, solid vaginal capsules, soft vaginal capsule, vaginal tablet, effervescent vaginal tablets, medical vaginal swabs vaginal delivery system and the like; preparations for the mouth and throat, such as a liquid for rinsing, concentrates to rinse, powders for the preparation of solutions for mouthwashes, tablets for the preparation of solutions for rinsing, the solutions to the mucous membrane of the throat, suspension for the mucous membrane of the throat, drops to the mucous membrane of throat sprays mucous membrane of the throat, sublingual sprays, liquids for mouth rinses, tablets for the preparation of solutions for rinsing the mouth, solutions for gums, gels for the mucous membrane of the throat, the paste for the mucous membrane of the throat, gels, gums, toothpaste, gum, sublingual tablets, the medicine-adhesive tablet for slow dissolution in the buccal pocket tablet on which I slow dissolution in the buccal pocket, pellet, extruded pellet, lozenges and the like;

dental medicines such as dental gels, dental sticks, tooth paste, tooth powders, dental solutions, dental suspension, dental emulsions, toothpaste and the like.

Another option of the present invention is the Mononitrate of sertaconazole (I), characterized by a particle size of 10 μm or less for at least 40% of the total sample and 30 μm or less for at least 95% of the total sample.

Another option of the present invention is the Mononitrate of sertaconazole monohydrate (V).

The present invention will be described hereinafter in more detail by the following examples. Technical boundaries of the present invention is not limited by these examples.

Example 1

Mononitrate sertaconazole monohydrate (V) (pseudopolymorphs of Mononitrate sertaconazole)

A 2-liter flask was loaded 308 ml of toluene, 100 g of 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (II) (0,389 mol) and 6.67 g of tetrabutylammonium hydrosulfate (IV, Z=HSO4) (0,0196 mol). Then added 155 g of sodium hydroxide (purity, 49%; 1,905 mol). The mixture was heated to 35-40°C. and stirred for 15 minutes. A solution consisting of 111,11 g 3-methyl bromide-7-chlorobenzo[b]thiophene (III) (0,425 mol) and 595 ml of toluene, was added for at least 30 minutes while holding the temperature of the reaction mixture between 37 and 40°C. After adding the system is kept at 37-40°C in t is an increase of 2.5 hours and then added water (635 ml). The mixture was cooled to 5-10°C. and the precipitated sertaconazole was filtered and washed with water and cold toluene (5-10°C), getting to $ 179.7 g of crude free base of sertaconazole (of 161.7 g in the dry state).

The obtained free base sertaconazole were loaded into a 2-liter reactor containing 848 ml of absolute ethanol. The mixture was heated until complete dissolution. Then the reaction mixture was heated to a temperature of 68-72°C. and was added 236 ml of water. The mixture was cooled to 10°C and kept at this temperature for 1 hour. The resulting solid was filtered and washed with pre-cooled to 10°With 160 ml of absolute ethanol and 51 ml of water. There was obtained crude (177, 9mm g) of pure free base of sertaconazole (158 g in the dried state). Net free base sertaconazole were loaded into a 2-liter reactor and was again dissolved in 932 ml of absolute ethanol at 75°C. the Mixture is then cooled to a temperature of 67-70°C was added a solution containing of 53.7 g (0,512 mol) of 60% nitric acid in 193 ml of water. Temperature stabilized for 15 minutes, checking that the pH was below 2. The mixture was cooled to 10°C. and kept for 1 hour. The precipitated substance was filtered and washed with water, getting 215,9 g Mononitrate sertaconazole monohydrate (V) (pseudopolymorphs of Mononitrate sertaconazole). Output 88,7%.

Analytical data

IR (infra-red spectra roscopy): Used Magna-IR Nicolet 550 spectrometer with database software Omnic of 2.1. The obtained IR spectrum of Mononitrate sertaconazole monohydrate (V) in comparison with Mononitrate sertaconazole (I) is shown in figure 2.

DSC (differential scanning calorimetry): Used instrument Mettler TA-8000, which includes DSC-820 and TG-50 and scales MT-5, supplied with the database software TAS 810 1,1. A sample of the product from 1 to 5 mg were weighed into 40 µl aluminum crucibles, subject to the following conditions.

Temperature range 110-180°C

Heating rate: 10°C/min

The flow of nitrogen: 100 ml/min

The results obtained DSC Mononitrate sertaconazole monohydrate (V) in comparison with Mononitrate sertaconazole (I) is shown in figure 3.

Microscopy: Used unit Nikon Eclipse E-600 with polarised light, equipped with a heating surface Linkam THMS 600, database Linksys and image processing program. Some of the product particles suspended in mineral oil on the glass and the sample is examined under magnification, depending on the size of the particles, and the use of polarized light or without it. Micrograph of Mononitrate sertaconazole monohydrate (V) and Mononitrate sertaconazole (I) is shown in figure 4.

The diffraction of x-rays. Used appliance Siemens D-500 for measuring the x-ray diraction processes in the powders. Diffraction patterns of Mononitrate sertaconazole monohydrate (V) and mononitrotoluene (I) is shown in figure 5. The data crystal and structural refinement for Mononitrate sertaconazole monohydrate (V) are shown in Table 2.

C=15,990(3) Å
Table 2
The data crystal and structural refinement Mononitrate sertaconazole monohydrate (V)
Empirical formulaC20H15Cl3N2OS. HNO3. H2O
Weight according to the formula518,78
Temperature293(2) K
Wavelength0,71069 Å
Crystal systemMonoclinic
Space groupP21/c
The parameters of the crystal cella=16,049(2) Åα=90°
b=8,946(7) Åβ=102,046(7)°
γ=90°
Volume2245(2) Å3
Z4
Density(calculated)1,535 mg/m3
The absorption coefficient0,540 mm-1
The size of the crystal0,1×0,1×0,2 mm
Theta limits the accumulation of dataFrom 1.30 to 30,07°
Limits index-3≤h≤16, -12≤k≤12, -22≤I≤21
The received reflections11440
Independent reflections5861 [R(int)=0,1748]
Method of refiningPolnomatrichnym the method of least squares on F2
Data/restraints/parameters3246/1/336
Greater the F 20,980
Final R indices [I > 2σ(I)]R1=0,0644,WR2=0,1302
The R indices (all data)R1=0,3270, WR2=0,2365
The extinction coefficient0,0000(6)
The highest diffraction peak and the pit0,356 and -0,429 E. Å3

Example 2

Mononitrate sertaconazole (I)

Mononitrate sertaconazole monohydrate (V) (215,9 g, 0,344 mol), obtained as described above was dissolved in 991 ml of absolute ethanol and 150 ml of water. The mixture was heated at 75-80°C and then added to another solution was cooled to 10°C and containing 2.8 liters of water and 1.7 g of 60%nitric acid for about 6-8 hours. At the end of the addition the mixture was stirred for 15 minutes at 10°C. the resulting material was filtered, dried at 65°C, sieved and finally dried at 85°C with getting 162,2 g Mononitrate sertaconazole (I). The output of 93.9 per cent. The total yield of 83.3%. The particle size was 10 μm to 40% of the total sample and 30 μm for 95% of the total sample. TPL 158-160°C. the Content of Mononitrate sertaconazole the resulting product was >99.5%pure.

1. Method received what I Mononitrate sertaconazole (I), in which first carried out a chemical reaction 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethanol (II) with 3-methyl bromide-7-chlorobenzo[b]thiophene (III) in the presence of tetrabutylammonium hydrosulfate (IV) and sodium hydroxide in toluene at 30-45°C, then add water to the mixture, it is cooled to a temperature of 0-15°C. and then the solid is separated by filtration and washed with water and toluene; and thus obtained the free base sertaconazole mixed with absolute ethanol and heated the flask under reflux until dissolved; the mixture is heated to 60-80°C. and to it was added water, then the mixture is cooled to 5-15°C; the resulting solid is separated by filtration and washed with a solution of ethanol in water; the resulting pure free base of sertaconazole dissolved in absolute ethanol at 70-80°C, the mixture is cooled to 65-75°C., add a solution containing 60% nitric acid in water, and kept at this temperature for 10-20 min, maintaining the pH below 2; the mixture is cooled to 5-15°C and maintained at this temperature from 30 minutes to 2 h; then the solid is separated by filtration and washed with getting Mononitrate sertaconazole monohydrate (V); and then the Mononitrate of sertaconazole monohydrate is dissolved in a solution of ethanol in water, the mixture is heated to 75-80°C and add to cooled to 5-15°C aqueous solution azo is Noah acid, filtered, dried at 60-70°C, sieved and finally dried at 80-90°C.

2. The method according to claim 1, in which the molar ratio of reagent reagent II to III is from 0.85 to 0.95.

3. The method according to claim 1 or 2, in which the molar ratio of the catalyst (IV) to the limiting reagent II is from 0.025 up to 0.060.

4. The method according to claim 3, in which the molar ratio of the catalyst (IV) to the limiting reagent II is to 0,045 0,055.

5. The method according to claim 3, in which the molar ratio of the catalyst (IV) to the limiting reagent II is 0,050.

6. Mononitrate sertaconazole monohydrate (V).



 

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16 cl, 1 tbl, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

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

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thien-3-yl-sulfonylamino(thio)carbonyl-triazolin(thi)ons of general formula I

(wherein Q represents oxygen or sulfur; R1 represents unsubstituted alkyl; R2 represents hydrogen, halogen, unsubstituted alkyl; R3 represents hydrogen, halogen, alkyl optionally substituted with alkoxy, alkoxy or arylthio, optionally substituted with alkoxy or halogen, unsubstituted cycloalkyl or cycloalkyloxy, or unsubstituted arylalkoxy or aryloxy; R4 represents unsubstituted alkyl, alkoxy, dialkylamino, cycloalkyl) and their salts. Compounds of present invention are useful as herbicide agents. Also disclosed is herbicide composition and new synthetic intermediates for compounds of formula I.

EFFECT: new compounds and intermediates thereof with herbicide activity.

16 cl, 13 tbl, 67 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to new substituted thienyl(amino)sulfonylureas of formula I ,

wherein A represents nitrogen or methane; Q represents direct bond or imino; R1 represents fluorine, chlorine, bromine, unsubstituted C1-C4-alkyl, C1-C4-alkoxyl optionally substituted with halogen, unsubstituted C1-C4-alkylthio, or di(C1-C4-alkyl)amino; R2 represents hydrogen or C1-C4-alkyl. Compounds of present invention are useful as herbicide agents.

EFFECT: new compounds with herbicide activity.

5 cl, 11 tbl, 5 ex

FIELD: organic chemistry, pharmaceutical industry, medicine.

SUBSTANCE: invention relates to new derivatives of S-substituted N-1-[(hetero)aryl]alkyl-N'-1-[(hetero)aryl]alkylisothioureas of general formula I

in form of free base and salts with pharmaceutically accepted acids, as well as racemate, individual optical isomers or mixture thereof. In formula R1, R2, R3, R4, Y and Z are as described in specification. Compounds of present invention are capable to potentiate (positively modulate) AMPA/KA glutamate receptors and simultaneously to block transmembrane currents induced by activation of NMDA glutamate receptors. Also disclosed are method for production of said compounds, including optical isomers; pharmaceutical composition; method for investigation of glutamatergic system, and method for Alzheimer's disease, treatment; as well as method for extreme retentiveness of memory by administering of effective amount of claimed compounds.

EFFECT: new pharmaceutically active compounds for Alzheimer's disease treatment.

23 cl, 1 tbl, 11 ex

FIELD: pharmaceutical industry, in particular new bioactive chalcones.

SUBSTANCE: invention relates to new chalcones of formula I

, pharmaceutically acceptable salts or solvates thereof, wherein Ar is optionally substituted C5-C10-carbocycle group or 5- or 6-membered heterocycle group having sulfur atom in cycle, and Ar substituents are selected independently from Cl, Br, F, CN, SCH3 and OR10, wherein R10 is linear or branched C1-C6-hydrocarbon; R is OH or R10; R2 and R3 are independently phenyl, saturated linear or branched C1-C6-hydrocarbon, or R2 and R3 together with carbon atom attached thereto form 5- or 6-membered carbocycle group with the proviso, that in compounds where R is OH and both R2 and R3 are methyl, Ar is not phenyl, 4-chlorophenyl, 4-chlorophenyl, 4-methylphenyl, 2-chlorophenyl, 3,4-dimethoxyphenyl, or 4-methoxyphenyl. Also disclosed are drug component for treatment or prophylaxis of neoplasm and pharmaceutical compositions with antiproliferation effect based on compounds of formula I.

EFFECT: new chalcone derivatives with value bioactive action.

26 cl, 2 tbl, 22 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

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

11 cl, 7 tbl, 353 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to new amide derivatives of general formula I

1, as well as to pharmaceutical acceptable salts or cleaving in vivo esters thereof. Claimed compounds are capable to inhibit cytokine production due to inhibition of p38 kinase action and are useful in treatment of various diseases such as inflammation or allergic disorders. Also are disclosed methods for production the same, pharmaceutical composition and method for inhibition of TNFα cytokine production. In formula I X is -NHCO- or -CONH-; m = 0-3; R1 is halogen, C1-C6-alkoxy, N-(C1-C6)-alkyl-di{(C1-C6)-alkyl]-amino-(C2-C6)-alkylamino, or heterocyclyl, heterocyclyl-(C1-C6)-alkyl, heterocyclyloxy, heterocyclyl-(C1-C6)-alkoxy, heterocyclylamino, N-(C1-C6)-alkylheterocyclylamino, heterocyclyl-(C1-C6)-alkylamino, N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino, heterocyclylcarbonylamino, heterocyclylsulfonylamino, N-heterocyclylsulfamoyl, heterocyclyl-(C2-C6)-alkanoylamino, heterocyclyl-(C1-C6)-alkoxy-(C1-C6)-alkyl, heterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, or N-(C1-C6)-alkylheterocyclyl-(C1-C6)-alkylamino-(C1-C6)-alkyl, wherein any of heterocylyl in R1 optionally may contain 1 or 2 substituents selected from oxo- or thioxogroup; n = 0-2; R2 is hydrogen or C1-C6-alkyl; R2 is hydrogen, C1-C6-alkyl or C1-C6-alkoxy; q = 0-4; Q is aryl, aryloxy, etc.

EFFECT: new inhibitors of cytokine production.

13 cl, 8 tbl, 20 ex

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