4-(benzimidazolyl-methylamino)benzamidine synthesis method

FIELD: chemistry.

SUBSTANCE: invention relates to a method for synthesis of substituted 4-(benzimidazol-2-ylmethylamino)benzamidine of formula (I) or its physiologically compatible salt, in which R1 is a C1-C3alkyl group, R2 is a R21NR22 group, where R21 denotes a C1-C3alkyl group substituted with a C1-C3alkoxycarbonyl group, and R22 denotes a pyridinyl group, and R3 is a C1-C8alkoxycarbonyl group having thrombin inhibiting and thrombin clotting time prolonging activity. The method involves a step (a) where phenyldiamine of formula (II) in which R1 and R2 assume values given for formula (I), reacts with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid. At step (b), the obtained product of formula (III), in which R1 and R2 assume values given for formula (I), is hydrogenated and then at step (c), if necessary, the obtained product of formula (I), in which R3 is hydrogen, reacts with a compound of formula R3-X (IV), in which R3 assumes values given for formula (I), and X denotes an acceptable leaving group, and then converted to a physiologically compatible salt if necessary. The invention also relates to novel intermediate products - formula (III) compound, in which R1 and R2 assume values given for formula (I), as well as to 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, 4-(1,2,4-oxadiazol-5-on-3-yl)aniline and toluene sulphonate N-(2-pyridinyl)-N-(2-ethoxycarbonylethyl)amide 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl carboxylic acid.

EFFECT: agents are highly effective.

12 cl, 2 dwg, 6 ex

 

Background of invention

1. The technical field to which the invention relates.

The present invention relates to a method for producing optionally substituted 4-(benzimidazole-2-ylmethylamino)benzamidine, namely, that

(a) optionally suitably substituted diaminobenzene subjected to the condensation reaction with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid,

(b) thus obtained product hydronaut and

(C) if necessary, carbonyliron amedieval group.

2. The level of technology

Substituted (4-(benzimidazole-2-ylmethylamino)benzamidine, especially N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide 1-methyl-2-[N-[4-(N-n - getselectionrange)phenyl]aminomethyl]benzimidazole-5-icarbonell acids, already known from the publication WO 98/37075 for their use as active substances possessing inhibiting thrombin and increasing the duration of the thrombin time action.

The main indication for the use of the chemical formula I is prevention of postoperative deep vein thrombosis.

In the specified publication WO 98/37075 substituted (4-(benzimidazole-2-ylmethylamino)benzamidine offered by the interaction of the corresponding substituted (4-(benzimidazole-2-ylmethylamino)benzonitrile with ammonia. This JV is the FDS associated with significant production and technical costs and with the formation of large quantities of acids, want to dispose of.

The present invention was based on the objective to develop a method of obtaining substituted (4-(benzimidazole-2-ylmethylamino)benzamidine, which would avoid the need for the above, is associated with high production and technical costs of the stage.

Summary of the invention

With the invention it has been unexpectedly found that substituted 4-(benzimidazole-2-ylmethylamino)benzamidine can be obtained with high yield and low cost of auxiliary substances,

(a) exposing optional appropriately substituted diaminobenzene the condensation reaction with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid,

(b) Giriraja thus obtained product and

(C) if necessary, carbanilide amedieval group, preferably alkylhalogenide in the presence of a base, primarily vexillifera.

Another object of the invention is a new, generated during implementation of the proposed in the invention method, the intermediate products of the formula (III)

in which R1and R2have the values listed below for compounds of formula (I)and 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid and 4-(1,2,4-oxadiazol-5-on-3-yl)what Nilin.

Detailed description of the invention

In a preferred embodiment, the invention features a method of obtaining optionally substituted 4-(benzimidazole-2-ylmethylamino)benzamidine formula (I)

in which R1represents a C1-C6alkyl or C3-C7:cycloalkyl group,

R2represents a

1) C1-C6is an alkyl group or a C3-C7cycloalkyl group, optionally substituted C1-C3alkyl group, which in turn may be optionally substituted carboxyl group, or translated in vivo in carboxypropyl group, or

2) R21NR22group,

R21stands With1-C6alkyl group which may be substituted by carboxypropyl, C1-C6alkoxycarbonyl group, benzyloxycarbonyl group, C1-C3alkylsulfonamides group, vinylsulfonylacetamido group, triftormetilfullerenov, triftormetilfullerenov group or 1H-tetrazolyl group,

substituted by a hydroxy-group, phenyl-C1-C3alkoxygroup, carboxy-C1-C3alkylaminocarbonyl, C1-C3alkoxycarbonyl-C1-C3-alkylaminocarbonyl, N-(C1-C 3alkyl)carboxy-C1-C3alkylaminocarbonyl or N-(C1-C3alkyl)-C1-C3alkoxycarbonyl-C1-C3alkylaminocarbonyl2-C4alkyl group, while in the above groups located directly next to the nitrogen atom of the α-carbon atom may not be substituted, or optionally substituted C1-C3alkyl group piperidinyloxy group, and

R22denotes a hydrogen atom, a C1-C6alkyl group, optionally substituted C1-C3alkyl group With3-C7cycloalkyl group3-C6alkenylphenol or3-C6alkylamino group, while unsaturated fragment cannot be directly connected to the nitrogen atom, R21NR22group,

optionally substituted by a fluorine atom, chlorine or bromine, C1-C3alkyl group or a C1-C3alkoxygroup phenyl group, optionally substituted C1-C3alkyl group, benzyl, oxazolidinyl, isoxazolyl, thiazolidine, isothiazolinone, pyrazolidine, pyridinoline, pyrimidinyl, personilnya, pyridazinyl, pyrrolidinyl, thienyl or imidazolidinyl group or

R21and R22together with located between the nitrogen atom represent optional is substituted on carboxypropyl or 1-C4alkoxycarbonyl group 5-7-membered cycloalkanones, which can be optionally condensed phenyl ring, and

R3represents a hydrogen atom, a C1-C9alkoxycarbonyl, cyclohexyloxycarbonyl, phenyl-C1-C3alkoxycarbonyl, benzoyloxy, n-C1-C3alkylbetaine or pyridinoyl group, with ethoxyline fragment in position 2 of the above With1-C9alkoxycarbonyl group may optionally be substituted

C1-C3alkylsulfonyl or 2-(C1-C3alkoxy)ethyl group,

namely, that at the stage of (a) phenyldiamine formula (II)

in which R1and R2have the above for formula (I) values, is subjected to the interaction with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, and then the thus obtained product of formula (III)

in which R1and R2have the above for formula (I) values, at the stage (b) hydronaut and then at the stage (C) if necessary, thus obtained compound of formula (I)in which R3represents hydrogen, is subjected to the interaction with the compound of the formula (IV)

in which R3has Azania for formula (I) values, and X denotes acceptable leaving group.

In a particularly preferred variant of the invention proposes a method of producing compounds of the formula (I), in which

R1represents a C1-C3alkyl group,

R2is an R21NR22group,

R21stands With1-C3alkyl group which may be substituted by carboxypropyl or C1-C3alkoxycarbonyl group, and

R22denotes a hydrogen atom, a C1-C3alkyl group, optionally substituted C1-C3alkyl group pyridinyl group, and

R3represents a hydrogen atom or a C1-C8alkoxycarbonyl group.

In the most preferred embodiment, the invention features a method of obtaining the compounds of formula (I), in which

R1represents a methyl group,

R2is an R21NR22group,

R21denotes an ethyl group, a substituted ethoxycarbonyl group, and

R22denotes pyridine-2-ilen group, and

R3represents hexyloxymethyl group.

The following are the preferred options (a)-(D) proposed in the invention method.

(A) a condensation Reaction in stage (a) is carried out in the Pris is under an inert diluent and binding water (water-absorbing) agent.

Appropriately substituted diaminobenzene formula (II) are known, for example, from the publication WO 98/37075 or you can get them as described in this publication. Particularly preferable to use amides of 3-amino-4-methylaminoethanol acids, especially N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide 3-amino-4-methylaminoethanol acid.

As inert diluents can be used aprotic non-polar solvents, such as aliphatic or aromatic, optionally halogenated hydrocarbons, aprotic polar solvents, such as ethers and/or amides, respectively, lactams, and/or mixtures thereof. As the aprotic nonpolar solvents, it is preferable to use a branched or unbranched5-C8aliphatic alkanes,4-C10cycloalkanes, C1-C6aliphatic halogenoalkane,6-C10aromatic alkanes or mixtures thereof. Particularly preferable to use alkanes such as pentane, hexane or heptane, cycloalkanes, such as cyclohexane or methylcyclohexane, halogenoalkane, such as dichloromethane, aromatic alkanes, such as benzene, toluene or xylene, or mixtures thereof. As aprotic solvents you can use a simple polar esters, such as those rehydrator (THF), methyltetrahydrofuran, dioxane, tert-butyl methyl ether or dimethoxyethane ether, amides, such as dimethylformamide, or lactams such as N-organic.

As water-bonding agents can be used hygroscopic salts, inorganic or organic acids, respectively, their anhydrides, anhydrides of inorganic or organic acids, anhydrides alkanephosphonic acid, molecular sieves or derivatives of urea. Preferred 1,1'-carbonyldiimidazole and anhydrides alkanephosphonic acid, and particularly preferred anhydrides alkanephosphonic acids.

In one preferred options 1,1'-carbonyldiimidazole suspended in THF and heated. Then add 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid. Next add the appropriately substituted diaminobenzene in THF. The reaction mixture is stirred at a temperature of about 50°C, and then after adding acetic acid concentrate that is mixed with water and the solid is filtered off, washed and dried.

In another, particularly preferred embodiment, the anhydrides alkanephosphonic acids in the presence of organic bases, preferably tertiary amines, such as DIPEA (diisopropylethylamine), added to a solution of 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenyl) - Rev. Ino]acetic acid and appropriately substituted diaminobenzene in THF. The reaction mixture is preferably stirred at a temperature in the range of -10 to 50°C, and then after adding acetic acid concentrate. Then mixed with ethanol and filtered while hot. Then precipitated precipitated from the cooled solution, the substance is filtered off, washed and dried.

(B) Hydrogenation in stage (b) is conducted in the presence of an inert diluent and a catalyst for hydrogenation.

Particularly preferred variant, in which the hydrogenation is carried out at a temperature in the range from 0 to 100°C., preferably from 0 to 50°C., especially from 10 to 30°C.

Preferred further variant, in which the hydrogenation is carried out at a pressure in the range from 0.5 to 100 bar, preferably from 1 to 10 bar, especially at a pressure of from 1 to 2 bar.

As inert diluents can be used proton solvents, such as alcohols, carboxylic acids and/or water, and aprotic polar solvents, such as ethers and/or amides, respectively, lactams, and/or mixtures thereof. All solvents if necessary, you can add water. As proton solvents are preferably branched or unbranched1-C8the alkanols, C1-C3carboxylic acid or mixtures thereof. Especially preferable to use the lowest sleep is you, such as methanol, ethanol, n-propanol and isopropanol, carboxylic acids such as formic acid, acetic acid and propionic acid, or mixtures thereof. As reaction medium is particularly preferable to use ethanol and/or acetic acid, which may optionally contain water. As aprotic solvents you can use a simple polar ethers such as tetrahydrofuran and dimethoxyethane ether, amides, such as dimethylformamide, or lactams such as N-organic. It is preferable to use solvents with low Flammability (flame retardant solvents).

For use as hydrogenation catalysts suitable, generally, transition metals, such as Nickel, platinum or palladium, or their salts or oxides. Preferred Raney Nickel, platinum oxide and palladium on an inert carrier, especially palladium on charcoal (Pd/C).

The preferred ways in which the product from step (a) and the hydrogenation catalyst used in the hydrogenation in a mass ratio between 1:1 to 1000:1, preferably from 5:1 to 100:1.

In one of the preferred variants of the product from step (a) is dissolved in ethanol and after adding acetic acid hydronaut when the pressure in the of aroda 2 bar at room temperature in the presence of water-wetted 10%Pd/C. Then the catalyst is filtered off and add n-toluensulfonate acid dissolved in 90 ml of ethanol either in 90 ml of water.

It is preferable to use an aqueous solution and is toluensulfonate acid. Toilet obtained 4-(benzimidazole-2-ylmethylamino)benzamidine precipitates, which is filtered off and washed with several portions of ethanol.

In one particularly preferred variants of the product from step (a) dissolved in a mixture of ethanol and water and hydronaut under hydrogen pressure of 2 bar at room temperature in the presence of water-wetted 10%Pd/C. Then the catalyst is filtered off and add n-toluensulfonate acid (in solid form or dissolved in 90 ml of ethanol and 90 ml of water). It is preferable to use n-toluensulfonate acid in solid form. Toilet obtained 4-(benzimidazole-2-ylmethylamino)benzamidine precipitates, which is filtered off and washed with several portions of ethanol.

(C) To obtain 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid 4-(1,2,4-oxadiazol-5-on-3-yl)aniline is subjected to interaction with ether 2-halogenase acid, preferably ethyl ether bromoxynil acid, in the presence of a weak base, preferably a tertiary amine, such as triethylamine or carbonate of an alkali metal, such, n is the sample, as sodium carbonate, in an inert solvent and the resulting ester 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid omelet.

As inert diluents can be used proton solvents, such as alcohols and/or water, and aprotic polar solvents, such as ethers and/or amides, respectively, lactams, and/or mixtures thereof. All solvents if necessary, you can add water. As proton solvents, it is preferable to use water or a branched or non-branched C1-C8the alkanols or mixtures thereof. Particularly preferable to use water or lower alcohols, such as methanol, ethanol, n-propanol and isopropanol, or mixtures thereof. As reaction medium is particularly preferable to use ethanol, which may optionally contain water. Equally you can use isopropanol, optionally together with water. However, the most suitable solvent is water. As aprotic solvents you can use a simple polar ethers such as tetrahydrofuran and dimethoxyethane ether, amides, such as dimethylformamide, or lactams such as N-organic.

In one particularly preferred options ethyl ester bromoxynil acid is dobavlaut in metered quantities to a suspension of 4-(1,2,4-oxadiazol-5-on-3-yl)aniline and sodium carbonate in a mixture of water and isopropanol or preferably in a mixture of water and ethanol and peremeshivajutsa cooling, the suspension is subjected to vacuum filtration, washed with several portions of water and ethanol and dried.

The saponification is preferably carried out in proton solvent using a hydroxide of alkali or alkaline earth metal, especially lithium hydroxide, sodium or potassium.

In one particularly preferred options ester 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid are suspended in water, preferably, however, in a mixture of water and ethanol and at room temperature slowly mixed with an aqueous solution of NaOH. The suspension thus becomes a slurry which is heated to between 45 and 75°C. the thus Obtained solution is mixed with Hcl to achieve a pH of about 5 or preferably 3. The solid is isolated and washed with cold water and cold ethanol and MTBE (methyl tert-butyl ether).

(G) To obtain 4-(1,2,4-oxadiazol-5-on-3-yl)aniline, the reaction of 4-aminophenylamino subjected to interaction with dialkylammonium, preferably with dimethylcarbonate or diethylcarbamoyl, in the presence of a base, preferably of an alcoholate of an alkali metal, especially sodium methylate, ethylate sodium or tert-butanolate potassium.

The oxime of 4-aminophenylamino can be obtained, for example, the interaction of 4-aminobenzonitrile with hydroxylamine hydrochloride.

In one particularly preferred variant is now the methylate or sodium, preferably sodium ethylate at a temperature of 65-75°C, more preferably 70-75°C. add to the suspension of the oxime of 4-aminophenylamino in ethanol and then washed with ethanol. After 15-minute stirring added dropwise diethylcarbamyl or preferably dimethylcarbonate. After a reaction time within 2-4 hours the mixture is cooled and the ethanol is distilled off at a pressure of 120 mbar and 40°C. the Residue is dissolved in water and after heating the pH by adding policecontributing sodium hydroxide solution set to a value of 10-12, then acidification with concentrated hydrochloric acid set to a value less than 6, preferably less than 4, particularly preferably a value of 2-3, and slowly cooled. The solution thus becomes a suspension, which was filtered and washed several times with cold water and ethanol.

Obtaining required for use as an intermediate product 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid 4-aminobenzonitrile illustrated by the following reaction scheme.

Scheme I

(Enclosed in square brackets, unmarked intermediate products in some cases may be different in different options proposed in the invention method. The following diagram illustrates the preferred option.)

Getting 4-(benzimidazole-2-ylmethylamino)is benzamidine in the example illustrated in the following reaction scheme.

Separate the reaction mixture can be subjected to conventional processing, consisting, for example, in the Department of auxiliary reaction substances, the removal of the solvent and the allocation of the remaining net final product by crystallization, distillation, extraction or chromatography.

Upon completion of the above-described method thus obtained compound of formula (I) can be converted into its physiologically compatible salt. Physiologically compatible salt can be a salt with inorganic or organic acids or in the presence of the connection carboxypropyl with inorganic or organic bases. As acids suitable for the formation of such salts, are suitable, for example, methanesulfonate acid, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid. As grounds, suitable for the formation of these salts, are suitable, among other things, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine. The compound of the formula (5) it is preferable to translate his mesilate.

Below proposed in the invention method is illustrated in more detail by examples. These examples of the nose illustrate the invention and do not limit its scope.

Examples

Used above and in the following description, the abbreviations have the following meanings:

Asónacetic acid
AAMBCN-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide 3-amino-4-methylaminoethanol acid
The OED1,1'-carbonyldiimidazole
DIPEAdiisopropylethylamine
EAthe ethyl acetate
EtOHethanol
HClhydrochloric acid
MTBEmethyl tert-butyl ether
NaOHsodium hydroxide
N-MPN-organic
The APFpapapostolou anhydride
PTSCn-toluensulfonate acid
CTroom temperature
THFdifferent.decomposition

Example 1

Getting 4-(1,2,4-oxadiazol-5-on-3-yl)aniline (1)

Option 1

Obtaining the compounds (1A)

In the reaction vessel pre-placed 118,6 g (1 mol) of 4-aminobenzonitrile and 68,9 g (of 0.65 mol) of sodium carbonate in 500 ml of ethanol and 100 ml of water and heated to 60°C. To this suspension is slowly added dropwise to 76.4 g (1.1 mol) of hydroxylamine hydrochloride dissolved in 100 ml of water. The mixture is then left to mix overnight at 60°C. Then, while cooling the mixture to 0-5°C in the sediment appears solid, which is filtered off and washed several times with a total of 150 ml of cold water and 100 ml of cold ethanol. In conclusion, washed with 50 ml of MTBE, to deliver to 178.4 g of wet product. This product is dried in vacuum at 35°C.

Output: 135,4 g of substance a light beige color (89.5% of theory), tPL>169, 5mm°C (decomp.), purity: >98%, of the peak area on GHUR-the chromatogram.

Obtaining the compound (1V)

To a suspension of 60.5 g of the product (1A) (0,4 mol) in 400 ml of ethanol at 70-75°C portions add 25,02 g (0,46 mole) of sodium methylate and washed with 20 ml ethanol. After 15 minutes of stirring are added dropwise 47,25 g (0.4 mole) of diethylmalonate. After reaction for 3 h the mixture is cooled to 40°C. and the ethanol is distilled p and a pressure of 120 mbar and 40°C. The result is a dark residue. This residue is dissolved at 40-45°C in 350 ml of water and after heating to 70°C pH value at first due to slow add policecontributing sodium hydroxide solution set to 11, and then by acidification with concentrated hydrochloric acid set at 5.5 and slowly cooled. Solution into the suspension, which was filtered and washed several times with a total of 150 ml of cold water and 50 ml ethanol. In this way receive 88,7 g wet matter, which is dried in vacuum at 35°C.

Yield: 62 g of dark matter (87.5% of theory), tPL>178°C (decomp.), purity: >98% by peak area at GHUR-the chromatogram.

Option 2

Obtaining the compounds (1A)

In the reaction vessel pre-placed 41,3 g (0,35 mol) of 4-aminobenzonitrile and 36.5 g (of 0.53 mol) of hydroxylamine hydrochloride in 175 ml of ethanol and heated to 60°C. To this suspension is slowly added dropwise USD 170.1 g (of 0.53 mol) of a solution of sodium methylate (approximately 21%in ethanol). The mixture is then left to mix overnight at 60°C. Then, while cooling the mixture to 0-5°C in the sediment appears solid, which is filtered off and washed several times with a total of 70 ml of cold ethanol. The result is about 86 g of wet product. This product is directly used in the subsequent the overall reaction.

Obtaining the compound (1V)

To a suspension of 86 g of the product (1A) in 270 ml of ethanol added 32 g (0,35 mol) of dimethylcarbonate. Then, at 65-75°C. add 125 g (range 0.38 mol) of a solution of sodium methylate (approximately 21%in ethanol) and washed with 20 ml ethanol. After reaction for 3 h the mixture is cooled to 40°C. and the ethanol is distilled off at a pressure of 120 mbar and 40°C. the result is a dark residue. This residue is dissolved at 40-45°C and 280 ml of water and after heating to 70°C pH value at first due to slow add policecontributing sodium hydroxide solution set to 11, and then by acidification with concentrated hydrochloric acid set at 3-4 or preferably 2-3, and slowly cooled. The solution thus becomes a suspension, which was filtered and washed several times with a total of 50 ml of cold water and 20 ml ethanol. In this way receive approximately 88 g wet matter, which is dried in vacuum at temperatures up to 50°C.

Yield: 48 g of substance beige (77.5% of theory), tPL>178°C (sec.), purity: >98% by peak area at GHUR-the chromatogram.

Example 2

Getting 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid (1)

Option 1

Obtaining the compounds (2A)

At room temperature to a suspension 70,86 g (0.4 mole) of the product (1B) and 26.5 g (0.25 mole) of carbonate intothree is in 600 ml of a mixture of water and isopropanol is metered to 83.5 g (0.5 mole) of ethyl ether bromoxynil acid and the mixture is left to mix overnight. The reaction mixture acquires the color from reddish-brown to orange. Cooled to 0°C. the suspension is subjected to vacuum filtration, washed with several portions of 300 ml of water and 150 ml of ethanol (106 g wet substances light brown) and dried in vacuum at 35°C.

Output: 92,44 g of a brownish substance (87.7% of theory), tPL>186,1°C (decomp.), purity: >98% by peak area at GHUR-the chromatogram.

Obtaining compound (2B)

Obtained above by ether (2A) (86,9 g of 0.33 mole) is suspended in 400 ml of water at RT to a suspension is slowly added dropwise to 120 g of 45%NaOH. Suspension turns in the solution acquires a reddish color (pH of 12.5). Next heated to a temperature of about 60°C and amyraut within 1 h the resulting solution portions mixed with Hcl (37%, or preferably with concentrated Hcl) to achieve pH 5. The mixture is then cooled to 0°C. the Solid is separated by vacuum filtration and washed with several portions a total of 400 ml of cold water, and 40 ml of cold ethanol and MTBE. The result of 81.4 g wet dark matter. In conclusion, this substance is dried in vacuum at 35°C.

Output: to 76.7 g of the desired substance (98% of theory), tPL>193°C (decomp.), purity: >99% by peak area at GHUR-the chromatogram.

Option 2

Receiving the connection is s (2A)

At 45°C to a suspension of 53.2 g (0,3 mol) of the product (1B) and 19.1 g (0,18 mol) of sodium carbonate in 500 ml of a mixture of water and ethanol in a ratio ranging from 90:10 to 95:5) type of 60.2 g (of 0.36 mol) of ethyl ether bromoxynil acid and, if necessary, leave the mix overnight. The reaction mixture acquires the color from reddish-brown to orange. Cooled to 0°C. the suspension is subjected to vacuum filtration, washed with several portions of 100 ml of ethanol and dried in vacuum at temperatures up to 50°C.

Output: 69,5 g of substance beige-brown (87.7% of theory), tPL>186,1°C (decomp.), purity: >98% by peak area at GHUR-the chromatogram.

Obtaining compound (2B)

Obtained above by ether (2A) (86,9 g of 0.33 mole) is suspended in 400 ml of water or preferably in a mixture of ethanol and water (in the ratio 1:1) and at RT to a suspension slowly added dropwise to 120 g of 45%NaOH. Suspension turns in the solution acquires a reddish color (pH of 12.5). Next, it is heated to a temperature of about 60°C and amyraut within 1 h the resulting solution portions mixed with Hcl (37%, or preferably with concentrated Hcl) to achieve pH 3. The mixture is then cooled to 0°C. the Solid is separated by vacuum filtration and washed with several portions a total of 400 ml of cold water, and 40 is l cold ethanol. The result of 81.4 g wet substances. This substance is dried in vacuum at 35°C.

Output: to 76.7 g of the desired substance (98% of theory), tPL>193°C (decomp.), purity: >99% by peak area at GHUR-the chromatogram.

Example 3

Obtaining N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide 1-methyl-2-[N-[4-(1,2,4-oxadiazol-5-on-3-yl)phenyl]aminomethyl]benzimidazole-5-icarbonell acid (3)

Option a: use the OED as agent combination

11,35 g (70 mmol) of 1,1'-carbonyldiimidazole suspended in 100 ml of THF and heated to 50°C. Then the suspension portions add 14,23 g (60,5 mmole) of the product (2B). Further, when heated to 50°C in 37 ml of THF was dissolved 17.1 g (50 mmol) AAMBC. After about 90 min, the suspension is added to a solution AAMBC and washed with 20 ml THF. The reaction mixture is stirred for about 18 h and then after adding 100 ml of acetic acid is heated under reflux, driving away in this way THF. After approximately 1 hour and stirred into 400 ml of water and stirred. The solution is cooled, precipitated in the sediment solid pink color is filtered off and washed with two portions of 20 ml of water, and then dried in vacuum at temperatures up to 50°C. the Selected substance is a diacetate of compound (3).

Yield: 24.8 g of the desired substance (75% of theory), tPL>167°C. with decomp. (according to the differential scan is ment calorimetry), purity: >95% of the peak area on GHUR-the chromatogram.

Option B: use the APF as an agent combination

of 34.2 g (0.1 mole) AAMBC, 27.5 g (0.12 moles) of the product (2B) and 30.3 g (to 0.23 mole) of DIPEA previously added to 170 ml of THF and cooled to a temperature slightly below room temperature. To this mixture is added 85 g (0,13 mol) APF (in the form of an approximately 50%solution in EA). The mixture is stirred for 90 min, after which the solvent is distilled off. After this type of 73.5 g of acetic acid and heated to an internal temperature of 90°C. Then mixed with 400 ml of ethanol or preferably with 400 ml of a mixture of ethanol and water (in a ratio of approximately 85:15) and filtered while hot. The solution is cooled, precipitated precipitated solid is filtered off, washed with two portions of 50 ml of ethanol and finally dried in vacuum at temperatures up to 50°C. the Selected substance is a diacetate of compound (3).

Yield: 56 g of the desired substance (85% of theory), tPL>167°C. with decomp. (according to differential scanning calorimetry), purity: >95% of the peak area on GHUR-the chromatogram.

Option b: using pualeilani as agent combination

96 g (0,41 mole) of the product (2B) are suspended at 0°C in 250 ml of N-MP and 550 ml of THF. The liquid suspension is successively mixed with 48 g (0.4 mole) of pivaloate and 52 g (0.4 mole) of DIPEA and p is remediat within 30 minutes Then add 125 g (of 0.36 mol) AAMBC dissolved in 800 ml of acetic acid and the reaction mixture for 3 hours, heated under reflux. Under low vacuum distilled THF and at elevated temperatures added to 1600 ml of water. The solid is isolated by 5°C, washed with 550 ml of water and during the night dried in a drying Cabinet with air circulation at a temperature up to 50°C.

Output: 183 g (76% of theory), purity: >95% of the peak area on GHUR-the chromatogram.

Example 4

Obtaining N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide 1-methyl-2-[N-[4-lidinopril]aminomethyl]benzimidazole-5-icarbonell acid (4)

Option a: the hydrogenation of the compound (3) in ethanol

of 37.3 g (of 56.4 mmole) of the compound (3) is dissolved in 900 ml of ethanol and after adding 10 ml of acetic acid hydronaut at RT and under hydrogen pressure of 2 bar in the presence of 4 g of hydrated water 10%Pd/C. Then the catalyst is filtered off and added 17 g (89,4 mmole) PTSC dissolved in 180 ml of ethanol. Precipitated in the sediment toilet connection (4) is filtered off and washed with several portions of 150 ml of ethanol. The result is a moist substance, which is dried in vacuum at 30°C.

Output: 34,5 g of the desired substance in a light beige color (91.3% of theory), tPL187°C (according to differential scanning calorimetry), purity: >98% by peak area at GHUR-chromatograms is.

Option B: hydrogenation of compound (3) in a mixture of ethanol and water

of 37.3 g (of 56.4 mmole) of the compound (3) is dissolved in 400 ml of a mixture of ethanol and water (in the ratio 90:10) and hydronaut at RT and under hydrogen pressure of 2 bar in the presence of 4 g of hydrated water 10%Pd/C. Then the catalyst is filtered off and added to 11.5 g (to 60.6 mmole) PTS. When the concentration in the sediment falls toilet connection (4). The suspension is cooled, the desired substance is filtered off and washed with several portions of 150 ml of a mixture of ethanol and water. The result is a moist substance, which is dried in vacuum at 35°C.

Output: 33,7 g of substance a light beige color (89% of theory), tPL187°C (according to differential scanning calorimetry), purity: >98% by peak area at GHUR-the chromatogram.

Option b: hydrogenation of compound (3) in a mixture of THF and water

30.0 g (of 45.3 mmole) of the compound (3) was dissolved at RT in 90 ml of a mixture of THF and water (in the ratio 1:1), mixed with 4 g of hydrated water 10%Pd/C and hydronaut at a pressure of 4 bar and a temperature of 60°C. the Catalyst is filtered off, washed with about 40 ml of a mixture of THF and water (in the ratio 1:1) and the filtrate without further processing used in the next stage, respectively, similar to the above procedure allocate by the addition of 13.6 g (72 mmole) PTSC dissolved in 100 ml water, and cooling.

Example 5

On the doctrine of N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide 1-methyl-2-[N-[4-(N-n-getselectionrange)phenyl]aminomethyl]benzimidazole-5-icarbonell acid (5)

Obtained in example 4, the compound is subjected by well-known methods interaction with vexillifera in the presence of an appropriate base.

Option a: the acylation of the compound (4) in a mixture of acetone and water

55 g (81.9 mmole) of the compound (4), dissolved in 437 ml of acetone and 273 ml of water, mixed in the presence of 34 g (246 mmol) of potassium carbonate at a temperature of about 15°from 16.4 g (99,6 mmole) of vexillifera. Upon completion of the reaction, precipitated precipitated product is filtered off and washed with a mixture of acetone and water. If necessary, the product can be reused by heating to dissolve in approximately 270 ml of acetone and then filtered. After filtration, the desired substance is again crystallized by adding 220 ml of water. The selected substance is dried in vacuum at 45°C.

Output: 42-48 g (82-94% of theory).

Option B: the acylation of the compound (4) in a mixture of acetone and water with the separation of the phases

55 g (81.9 mmole) of the compound (4), dissolved in 437 ml of acetone and 273 ml of water, mixed in the presence of 67 g (486 mmol) of potassium carbonate at a temperature of about 15°from 16.4 g (99,6 mmole) of vexillifera. Upon completion of the reaction, the suspension is heated to about 50°C. After separation of the phases the aqueous phase is discarded, and the acetone is replaced by 440 ml of ethyl acetate. Separated then the aqueous phase is discarded and the organic phase is several portions sequentially washed with RA who bavendam solution of potassium carbonate and water. The product is crystallized by cooling, is isolated and washed with ethyl acetate. The selected substance is dried in vacuum at 45°C.

Output: 42-48 g (82-94% of theory).

Example 6

Receiving nelfinavir N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide 1-methyl-2-[N-[4-(N-n-getselectionrange)phenyl]aminomethyl]benzimidazole-5-icarbonell acid (5)

100 g (0,16 mol) of the compound (5) is dissolved by heating in 890 ml of acetone and mixed with a solution of 15 g (0,16 mol) methanesulfonic acid in 200 ml of acetone. Then the solution is filtered and after you add 77 ml of acetone is cooled to about 20°C. Precipitated precipitated product is isolated and washed with acetone. Finally the product is dried in a vacuum drying Cabinet at temperatures up to 50°C.

Output: 90-98% (103-113 g).

1. The method of obtaining substituted 4-(benzimidazole-2-ylmethylamino)benzamidine formula (I)

or its physiologically compatible salt,
in which R1represents a C1-C3alkyl group,
R2is an R21NR22group,
R21represents C1-C3alkyl group, substituted C1-C8alkoxycarbonyl group, and
R22means pyridinyl group, and
R3represents a C1-C8alkoxycarbonyl group, namely, that at the stage of (a) Fe is Indiamen formula (II)

in which R1and R2have the above for formula (I) values, is subjected to the interaction with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, and then the thus obtained product of formula (III)

in which R1and R2have the above for formula (I) values, at the stage (b) hydronaut and then at the stage (C) if necessary, thus obtained compound of formula (I)in which R3represents hydrogen, is subjected to the interaction with the compound of the formula (IV)

in which R3is indicated for formula (I) values, and X denotes acceptable leaving group, and optionally converted into a physiologically compatible salt.

2. The method according to claim 1 for obtaining compounds of formula (I), in which
R1represents a methyl group,
R2is an R21NR22group,
R21denotes an ethyl group, a substituted ethoxycarbonyl group, and
R22denotes pyridine-2-ilen group, and R3represents hexyloxymethyl group.

3. The method according to claim 1, characterized in that the condensation reaction in stage (a) is carried out in the presence of an inert diluent and water-bonding agent.

4. The method according to claim 1, characterized in that the guide is the key to stage (b) is conducted in the presence of an inert diluent and a catalyst for hydrogenation.

5. The method according to claim 1, characterized in that in stage (a) using 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, obtained by the interaction of 4-(1,2,4-oxadiazol-5-on-3-yl)aniline with ether 2-halogenase acid in the presence of a weak base, with subsequent saponification of the resulting ester 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid.

6. The method according to claim 5, characterized in that 4-(1,2,4-oxadiazol-5-on-3-yl)aniline is produced by interaction of the oxime of 4-aminophenylamino with dialkylammonium in the presence of a base.

7. The method according to claim 1, characterized in that the compound of formula (I) then turn in a physiologically compatible salt.

8. The method according to claim 7, wherein the physiologically compatible salt is a methanesulfonate.

9. The compound of formula (III)

in which R1and R2have mentioned in one of claims 1 and 2 values.

10. 2-[4-(1,2,4-Oxadiazol-5-on-3-yl)phenylamino]acetic acid.

11. 4-(1,2,4-Oxadiazol-5-on-3-yl)aniline.

12. Toluensulfonate N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide 1-methyl-2-[N-[4-lidinopril]aminomethyl]benzimidazole-5-icarbonell acid formula



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrimidine derivatives having FAK inhibitory activity of formula (I), where R0 is hydrogen; R1 is a 5- or 6-member heterocycle containing 1 or 2 nitrogen atoms substituted with (C1-C7)alkyl, hydroxyl group, dialkylamino group or a 6-member heterocycle containing one nitrogen atom; R2 is hydrogen; R3 is carbamoyl substituted once or twice with (C1-C7)alkyl; a 5-member heterocycle containing 4 nitrogen atoms; SO2N(R12)R13, where R12 is hydrogen or (lower)alkyl, and R13 is hydrogen, (C1-C7)alkyl, (C1-C7)alkoxy(C1-C7)alkyl, di(C1-C7)alkylamino(C1-C7)alkyl, hydroxy(C1-C7)alkyl, or R12 and R13 together a nitrogen atom with which they are bonded form a 6-member heterocycle containing two nitrogen atoms, where the said heterocycle is not substituted or substituted with (C1-C7)alkyl; R4 is hydrogen; R5 is a halide; R6 is hydrogen; R7 is hydrogen; (C1-C7)alkoxy; carbamoyl which is not substituted or substituted with (lower)alkyl; a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with di(C1-C7)alkylamino, (C1-C7)alkyl, hydroxy, 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms, unsubstituted or substituted with (C1-C7)alkyl; 6-member heterocycle-oxy containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen ring atoms which is not substituted or substituted with (C1-C7)alkyl; R8 is hydrogen; halide; (C1-C7)alkoxy, carbamoyl unsubstituted or substituted with (C1-C7)alkyl; heterocycle(C1-C7)alkyloxy, where heterocycle denotes a 5-member heterocycle containing 1 nitrogen ring atom, unsubstituted or substituted with (C1-C7)alkyl; 5- or 6-member heterocycle containing 1 or 2 nitrogen or oxygen atoms, unsubstituted or substituted with one or two substitutes independently selected from hydroxy, (C1-C7)alkyl, aminocarbonyl and (C1-C7)alkylamino; 6-member heterocycle-oxy, containing 1 nitrogen ring atom, unsubstituted or substituted 1-5 times with (C1-C7)alkyl or di(C1-C7)alkylamino; or R7 and R8 together with atoms with which they are bonded form a 6-member heterocycle containing two nitrogen or oxygen atoms, unsubstituted or substituted once or twice with (C1-C7)alkyl or oxo group; R9 is hydrogen; R10 is (C1-C7)alkoxy, as well as to their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition and synthesis method.

EFFECT: novel compounds have useful biological activity.

4 cl, 167 ex

FIELD: medicine.

SUBSTANCE: invention relates to novel pyrimidine derivatives of formula (I) or their pharmaceutically acceptable salts which possess inhibiting activity with respect to focal adhesion kinase (FAK), proteintyrosinekinase ZAP-70, receptor of insulin-like growth factor 1 (IGF-1R), tyrosinekinase activity of anaplastic lymphoma (ALK) and fusion protein NPM-ALK. In formula (I) , R0, R1 and R2 independently represent hydrogen, C1-C8 alkyl, 5- or 6-member heterocycle, containing 1,2 or 3 heteroatoms, selected from N, O and S, C1-C8alkoxy group, C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, halogen, carbamoyl, sulphamoyl, etc.; R3 represents C1-C8alkylsulphinyl, C1-C8alkylsulphonyl, C5-C10arylsulphonyl, carbamoyl or sulphamoyl; R4 represents hydrogen or C1-C8alkyl; R5 represents chlorine or bromine; R6 represents hydrogen; R7, R8, R9 and R10 independently represent C1-C8alkyl, C5-C10aryl, possibly substituted by 5- or 6-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N, O and S, where substituents are selected from C1-C8alkyl, hydroxy, hydroxy-C1-C8alkyl, C1-C8alkoxy C1-C8alkyl, cyano, oxo, C1-C8alkylamino, diC1-C8alkylamino, carbamoyl, C1-C8alkylcaronyl, 5-10-member heterocycle, containing 1, 2 or 3 heteroatoms, selected from N and O, which is probably substituted by C1-C8alkyl; C1-C8alkoxy group, halogen- C1-C8alkoxy group, etc; A represents C. Invention also relates to pharmaceutical composition and to application of compounds of formula (I) for preparation of medication.

EFFECT: novel compounds possess useful biologic activity.

15 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: invention relates to crystalline 1-[2-(4-benzyl-4-hydroxypiperidin-1-yl)-ethyl]-3-(2-methylquinolin-4-yl)-urea of formula I

,

in monosulphate trihydrate form. The invention also relates to a composition based on the said compound which has antagonistic effect on urotensin.

EFFECT: obtaining a novel compound and compositions based on said compound, which can be used in medicine as neurohormonal antagonists.

8 cl, 3 dwg, 5 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids. The substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids of general formula 1 and their pharmaceutically acceptable salts and/or hydrates , where: R1 is an amino group substitute selected from hydrogen; optionally substituted C1-C5 alkyl; optionally substituted C1-C5 alkylsulphonyl, optionally substituted arylsulphonyl or optionally substituted heterocyclylsulphonyl; acyl; R2 is an alkyl substitute selected from hydrogen, substituted amino group, optionally substituted hydroxy group, substituted mercapto group, substituted alkylamino group; R3 is hydrogen, C1-C3 alkyl; R4 is a substitute selected from hydrogen, C1-C3 alkyl substituted with an amino group, optionally substituted with phenyl or heterocyclyl; R5 is one or more substitutes of the cyclic system selected from trifluoromethyl, carboxyl, alkyloxycarbonyl, possibly substituted aryl, heterocyclyl, substituted aminomethyl, cyano group, or R5 is hydrogen provided that when R1 is a substitute selected from hydroxy-substituted C1-C3 alkyl, amino-substituted C1-C3 alkyl, and R2, R3, R4 and R6 are as described above, or R2 is an alkyl substitute selected from substituted amino group, optionally substituted hydroxy group, substituted mercapto group, substituted alkylamino group, and R1, R3, R4 and R6 are as described above; or R5 is fluorine.

EFFECT: obtaining novel substituted 2-(5-hydroxy-2-methyl-1H-indol-3-yl)acetic acids which have antiviral activity, especially against the influenza virus and hepatitis C virus (HCV).

19 cl, 3 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (1) , where substitutes are as defined in paragraph 1 of the invention. The compounds have fungicide properties. The method of obtaining formula (1) compounds is described, in which n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining novel compounds which can be used as fungicides.

24 cl, 312 tbl, 14 ex

Amide derivatives // 2396259

FIELD: chemistry.

SUBSTANCE: claimed invention relates to compound of formula I where m equals 0 or 1; R1 represents halogeno, (C1-6)alkyl, (C1-6)alkoxy, amino-(C2-6)alkoxy, (C2-6)alkylamino-(C2-6)alkoxy, di-[(C1-6)alkyl]amino-(C2-6)alkoxy, (C1-6)alkoxy-(C2-6)alkoxy, carbamoyl-(C1-6)alkoxy, N-(C1-6)alkylcarbamoyl-(C1-6)alkoxy, amino-(C1-6)alkyl, (C1-6)alkylamino-(C1-6)alkyl, di(C1-6)alkyl]amino-(C1-6)alkyl, carbamoyl-(C1-6)alkyl, N-(C1-6)alkylcarbamoyl-(C1-6)alkyl, (C1-6)alkoxy-(C2-6)alkylamino, heteroaryloxy, heterocyclyl-(C1-6)alkyl, heterocyclyloxy or heterocyclyl-(C1-6)alkoxy, and where any heteroaryl or heterocyclyl group in substituent R1 probably can have 1 or 2 substituents, selected from hydroxy, halogeno, (C1-6)alkyl, (C1-6)alkoxy, (C2-6)alkanoyl, hydroxy-(C1-6)alkyl, (C1-6)alkoxy-(C1-6)alkyl, and where any of determined above R1 substituents, which contains CH2 group bound with 2 carbon atoms, or group CH3, bound with an atom of carbon or nitrogen, probably can have on each said CH2 or CH3 group one or more substituents, selected from halogeno, hydroxy, amino, oxo, (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkinyl,. (C3-6)cycloalkyl, (C3-6)cycloalkoxy, (C1-6)alkoxy, (C1-6)alkoxy-(C1-6)alkyl, (C1-6)alkylsulphamoyl, heteroaryl, heteroaryl-(C1-6)alkyl and heterocyclyl, and where any heterocyclyl group in substituent R1 probably can have 1 or 2 oxo or tioxo substituents; R2 represents (C1-6)alkyl; R3 represents hydrogen; R4 represents (C3-6)cycloalkyl, (C1-6)alkyl or heteroaryl, and R4 probably can be substituted with one or more substituents, selected from halogeno, (C1-6)alkyl, (C1-6)alkoxy; and R5 represents hydrogen, halogeno or (C1-6)alkyl; or its pharmaceutically acceptable salt, to method of obtaining said compounds, to pharmaceutical composition for application in treatment of diseases mediated by based on them cytokines. Invention also relates to methods of inhibiting p38α-kinase enzymes, TNFα production and production of cytokines.

EFFECT: obtained and described are novel compounds, which can be applied in treatment of medical conditions mediated by cytokines.

14 cl, 31 ex, 9 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1), their tautomers and pharmaceutically acceptable salts. The disclosed compounds have thromobopoietin receptor agonist properties. In formula (1) , A is a nitrogen atom or CH, when A is a nitrogen atom, B is NR9 (where R9 is a C1-10 alkyl group), and when A is CH, B is a sulphur atom, R1 is a phenyl group (the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10 alkyl groups and C1-10 alkoxy groups (C1-10 alkyl groups and C1-10 alkoxy groups are unsubstituted or substituted with one or more halogen atoms)), L1 is bond, X is OH, R2 is a C1-10 alkyl group, L2 is a bond, L3 is NH, L4 is a bond or NH, Y is a sulphur atom, and when L4 is a bond, R3 is a piperidinyl group, a piperazinyl group (the piperidinyl group and the piperazinyl group are substituted with substitutes selected from a group containing C1-10 alkoxycarbonyl groups, carboxyl group, hydroxyl groups, di-C1-10 alkylaminocarbonyl groups, C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups (C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups are substituted with a substitute selected from a group containing pyridyl groups, hydroxyl groups and carboxyl groups)), or when L4 is NH, R3 is a C1-10 alkyl group (C1-10 alkyl group is substituted with a substitute selected from a group containing C1-10 alkoxy groups, C1-10 alkoxycarbonyl groups or carboxyl groups).

EFFECT: obtaining a thrombopoietin receptor activator which is a formula (1) compound and a medicinal agent which contains the disclosed compound as an active ingredient.

10 cl, 3 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I') which have inhibitory effect on ALK kinase: , where n' is selected from 1 and 2; R'2 is selected from halogen; R'3 is selected from -S(O)2NR'5R'6, -S(O)2R'6 and -C(O)NR'5R'6, where R'5 is selected from hydrogen and C1-6alkyl, and R'1 is selected from C1-6alkyl; and R'1 is selected from phenyl which is substituted with 3 radicals independently selected from C2-6alkoxy group, C1-6alkyl, -X'R'4 and -OXR'4, where X' denotes a bond, and R'4 is selected from piperazinyl, piperidinyl, pyrrolidinyl, morpholino, where R'4 can be optionally substituted with 1-3 radicals independently selected from C1-6 alkyl, provided that the following compound is excluded .

EFFECT: design of a method of inhibiting and using compounds for making a medicinal agent for treating diseases which respond to ALK kinase inhibition.

7 cl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

Cytokine inhibitors // 2394029

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I) and their pharmaceutically acceptable salts and acids. In formula (I) , Ar1 is an aromatic carbocycle substituted with one R1 and where Ar1 is independently substituted with two R2; R1 is J-N(Ra)-(CH2)m-, N(J)2-(CH2)m-, NH2C(O)-, J-N(Ra)-C(O)-, J-S(O)m-N(Ra)-, J-N(Ra)-S(O)m-; Q is CRP; Y is -N(Rx)-; where Ra, Rp, Rx and Ry each independently denotes hydrogen or (C1-C5)alkyl; X is O-; W is N or CH, m independently equals 0, 1 or 2; J is selected from (C1-C10)alkyl, optionally substituted Rb; R2 is selected from (C1-C6)alkyl or (C1-C4)alkoxy, optionally partially or completely halogenated; R3, R4 and R5 are each independently selected from hydrogen or (C1-C6)alkyl; R6 is optionally bonded in the ortho- or meta-position to the nitrogen atom of the said ring and is selected from a bond, -O-, O-(CH2)1-5-, -NH-, -C(O)-NH-, branched or straight (C1-C5)alkyl; and where each R6 is further optionally covalently bonded to groups selected from hydrogen, -NR7R8, (C1-C3)alkyl, heteroaryl(C0-C4)alkyl, where the heteroaryl is pyrimidine, and heterocyclyl(C0-C4)alkyl, where the heterocyclyl is selected form morpholine, pyrrolidine, piperazinyl, optionally substituted with (C1-C6)alkyl; R7 and R8 each independently denote hydrogen or branched or straight (C1-C5)alkyl; and Rb is selected from hydrogen, (C1-C5)alkyl, amino, (C1-C5)alkylamino, (C1-C5)dialkylamino. The invention also relates to a pharmaceutical composition containing a pharmaceutically effective amount of the formula (I) compound, to use of the disclosed compounds to prepare a pharmaceutical composition and to a method of obtaining formula (I) compounds.

EFFECT: disclosed compounds have cytokine inhibiting properties.

13 cl, 3 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to the obtaining of the new derivatives of benzamide of the formulas (I), which possess the activating influence on glucokinase, which can be used for treating of diabetes and obesity: where X1 and X2 represent oxygen, R1 represents alkylsufonyl, alkaneyl, halogen or hydroxyl; R2 represents alkyl or alkenyl, R3 represents alkyl or hydroxyalkyl, ring A represents phenyl or pyridyl, the ring B represents thiazolyl, thiadiazolil, isoxazoleyl, pyridothiazolyl or pyrazolyl, in which the atom of carbon of ring B, which is connected with the atom of nitrogen of the amide group of the formula(I), forms C=N bond with ring B.

EFFECT: obtaining new bioactive benzamides.

12 cl, 166 ex, 4 tbl

FIELD: organic chemistry, medicine, pharmacology.

SUBSTANCE: invention relates to new derivatives of carbamic acid esters of the general formula (I):

and their pharmaceutically acceptable salts eliciting activity with respect to metabotropic glutamate receptors mGlu of group I that can be used for treatment of acute and/or chronic neurological disorders. In the general formula (I) R1 means hydrogen atom or (C1-C7)-alkyl; R2 and R2' mean independently of one another hydrogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom or trifluoromethyl; X means oxygen (O), sulfur (S) atom or two hydrogen atoms not forming a bridge; A1/A2 mean independently of one another phenyl or 6-membered heterocycle comprising 1 or 2 nitrogen atom; B represents group of the formula:

wherein R3 means (C1-C7)-alkyl and others; Y means -O-, -S- or a bond; Z means -O- or -S-; or B means 5-membered heterocyclic group of formulae: (a) , (b) , (c) or (d) . Also, invention relates to methods for preparing compounds and to a medicinal agent based on thereof.

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

22 cl, 1 tbl, 2 sch, 78 ex

FIELD: medicine.

SUBSTANCE: invention can be used for intravascular thrombocyte activity (ITA) normalisation in the patients with arterial hypertension (AH) and impaired glucose tolerance (IGT). Substance of the declared method consists in the prescription in the case patients of morning exercises, therapeutic gymnastics, graduated physical exercises throughout the day, daily swimming in a pool for at least 20 minutes in day, and the administration of Metformin 500 mg twice a day and Lisinopril 10 mg a day in the morning for 1 month.

EFFECT: combined application of all components of the therapeutic complex allows reducing risk of thrombotic complications due to ITA normalisation in the AH and IGT patients to be transferred to the level close to that in healthy people for 1 month.

1 ex

Anticoagulant // 2399377

FIELD: medicine, pharmaceutics.

SUBSTANCE: anticoagulant exhibiting a thrombin and factor Xa inhibiting activity represents a solution of biologically active birch bark complex prepared by water extraction of ground birch bark on boiling, concentration of aqueous extract and sodium chloride saturation, sediment discharge, ethyl acetate extraction of filtrate, concentration of filtrate, dilution with chloroform, sediment filtration and dissolution to ensure final concentration of 1.0-251.2 mcg/ml, effective for thrombin activity inhibition, and final concentration of 0.1-851.0 mcg/ml, effective for blood coagulation factor Xa activity inhibition.

EFFECT: invention allows implementing thrombin activity inhibition.

3 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is offered a method for preparing low-molecular heparins by enzymatic degradation. For enzymatic depolymerisation, immobilised lysozyme is used.

EFFECT: prepared low-molecular heparin shows higher inhibitor activity with respect to blood coagulation factor Xa and lower inhibitor activity with respect to thrombin in comparison with initial heparin.

2 tbl, 3 ex

Rgd-like peptides // 2396271

FIELD: chemistry.

SUBSTANCE: invention discloses novel synthetic RGD-like peptides capable of dose-dependant inhibition of thrombocyte aggregation.

EFFECT: obtaining novel compounds capable of dose-dependant inhibition of thrombocyte aggregation.

2 tbl, 1 ex

Novel compounds // 2395511

FIELD: chemistry.

SUBSTANCE: present invention relates to novel xanthine derivatives of general formula (I) and their pharmaceutically acceptable salts which have HM74A receptor activity, which can be used in therapy for treating diabetic dyslipidemia, combined dyslipidemia, heart failure, hypercholesteremia, atherosclerosis, arteriosclerosis, hypertriglyceridemia, type II sugar diabetes, type I diabetes, insulin resistance, hyperlipidemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, stenocardia, chronic kidney disease, peripherical vascular disease or stroke. In compounds of formula (I) , R1 is hydrogen or methyl; R2 is unsubstituted H-C4-6 alkyl; and R3 is chlorine.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on the said novel xanthine derivatives.

15 cl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzene derivatives of general formula (I) or salts thereof: [Chem. 12]

(Symbols in the given formula have the following values X1:-NR12-C(=O)- or -C(=O)-NR12-, X2 : -NR13 -C(=O)-, Ring A is a 6-member ring, if necessary having 1 or 2 double bonds and if necessary having 1-3 heteroatoms selected from N, O, Ring B is a benzene ring or a 6-member heteroaryl ring having 1-3 heteroatoms selected from N, R is a hydrogen atom or a residue of β-D- glucopyranoside uronic acid; R1-R8 are identical or different and each denotes a hydrogen atom, a halogen atom, -O-(lower alkyl), R9-R11 are identical or different and each denotes a hydrogen atom, lower alkyl, -O-(lower alkyl), -(CH2)n-N(lower alkyl)2, -(CH2)n-NH(lower alkyl), -(CH2)n-N(lower alkyl) (if necessary substituted with -C=O; a 6-member heterocycle having 1-3 heteroatoms selected from N, S, O) -(CH2)n-(C=O)-N(lower alkyl)2, -(CH2)n-(C-O)-N(lower alkyl) (if necessary substituted with -C=O, alkyl, a 6-member heterocycle having 1-3 heteroatoms selected from N) -(CH2)n- if necessary substituted with alkyl, -COCH3, -SO2CH3, -COOCH3, -C=O, CF3, -OCH3, OH, halogen; 5-7-member heterocycle having 1-3 heteroatoms selected from N, S, O), -(CH2)n-O- (if necessary substituted with alkyl; 6-member heterocycle having 1-3 heteroatoms selected from N), n is an integer from 0 to 3, R12 and R13 denote a hydrogen atom, provided that in R1-R11, when two lower alkyls are bonded to a nitrogen atom, they can together form a 3-8-member nitrogen-containing heterocycle.) The invention also relates to benzene derivatives of general formula (II), to a pharmaceutical composition, as well as to use of the said compounds.

EFFECT: obtaining novel biologically active compounds which are active as inhibitors of activated blood-coagulation factor X.

16 cl, 365 ex, 42 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and concerns a solid dosage form that exhibits the antiaggregatory activity and contains, wt %: clopidogrel hydrosulfate - 15-45; microcrystalline cellulose - 7-20; talc-1-3; sodium croscarmellose - 1-4; low-molecular polyvinylpyrrolidone - 0.3-10; stearic acid and/or its salts - 0.5-1; lactose - the rest, and a coating that contains, wt %: titanium dioxide - 8-30; polyethylene glycol - 6-28; talc - 5-25; carmine - 0.3-2.5; yellow aluminium lake - 0.05-1; red aluminium lake - 0.01-0.5; quinoline yellow aluminium lake - 0.01-0.05; polyvinyl alcohol - the rest. There is also disclosed a method for preparing the presented solid dosage form.

EFFECT: preparation of the solid dosage form that exhibits the antiaggregatory activity.

7 cl, 2 tbl

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