Method of obtaining 2-anilinopyrimidines or their salts (options)

FIELD: chemistry.

SUBSTANCE: invention pertains to a new method of obtaining derivatives of N-phenyl-2-pyrimidineamine (2-anilinopyrimidine) with general formula (I), which have a wide spectrum of biological effects and can be used mainly, for treating various types of tumours, leucaemia, cerebral ischemia, vascular stenosis and other diseases. In general formula (I) , R1 represents a pyridyl or its oxide bonded to a carbon atom, which can be substituted with a low alkyl or alkoxy, each of R2 and R3 independently represents hydrogen, branched of unbranched low alkyl, phenyl, unsubstituted of substituted with a haloid, R4 represents hydrogen, unbranched or branched low alkyl, R5 represents hydrogen, low alkyl, possibly substituted with halogen atoms. Other representations of radical are given in the formula of invention. The method involves the following stages: A) reaction of urea, mainly in a basic medium with N,N-dialkyamino-1-(3-pyridyl)-2-propene-1-ono with general formula II: with obtaining of the corresponding dihydropyrimidinone with general formula (III) B) oxidation of compound (III) by proton oxidation, with obtaining of the corresponding hydroxypyrimidine with formula IV , C) activation of the hydroxy group in the obtained compound IV , for example, treatment using sulphohalide R'SC2Hal or anhydride R'(SO2)2O, with obtaining of a compound with general formula V , where R' represents aryl of low alkyl, D) reaction of the obtained compound V with the corresponding aromatic amino compound with formula VI , with obtaining of compound with formula (I) and subsequent possible conversion of the obtained compounds to other compounds with general formula (I).

EFFECT: method allows for excluding use of toxic compounds and simplifies the process.

13 cl, 13 ex

 

The invention relates to a new method of obtaining 2-anilinopyrimidines General formula (I)

where R1means associated carbon atom of the pyridyl or its oxide, which may be substituted by lower alkyl or alkoxy, each of R2and R3independently means hydrogen, a branched or unbranched lower alkyl, phenyl, unsubstituted or substituted by halogen, R4is hydrogen, unbranched or branched lower alkyl, R5is hydrogen, lower alkyl, possibly substituted by halogen atoms, R6and R8is hydrogen, lower alkoxy, branched or unbranched lower alkyl, R7- lower alkyl, lower alkoxy, halogen-lower alkyl, halogen-lower alkoxy, nitro, carboxy, amino or the residue of formula II-N(R9)-C(=O)-R10, -C(=O)-NR9R10, -CH2-NR9R10, -OCH2-NR9R10-, NR9SO2-R10where R9 -hydrogen or R9and R10together with the nitrogen atom form piperidino, piperazinone with the second nitrogen atom Deputy, selected from lower alkyl or lower acyl, or R10means associated carbon atom of the pyridyl, thienyl, cyclohexyl, naphthyl or phenyl, optionally substituted by halogen, cyano, lower alkoxy, lower alkyl, carboxy or 4-methylpiperazine the sludge, R is hydrogen, lower alkyl,

or their pharmaceutically acceptable salts or isomers.

Part of the compounds of this group, the way they are received and application is known as in the technical and patent literature (see, for example, Zoltan Szakacs, Szabocs Beni et al. J. Med. Chem. 2005, 48, p.249-255, patents of the Russian Federation 2125992, 2208012, the application of the RF 2003103848, 2005129100, patents US 6096753, 4438117, bids US 2003/0069425, US 2004/0102453, US 2006/0223818, WO 2002/022597, WO 2004/029038, WO 2005/095379, WO 2005/0108358, WO 2005/095379, WO 2006/069525, WO 2006/117185, WO 2006/223817, WO 2006/071130, CA 2443092, DE 1271116, PL 370264).

Derivatives anilinopyrimidines have a broad spectrum of biological activity, but mainly are substances with antitumor activity. Some of them are well-known tools, such as imatinib, which can be used to treat leukemia, cerebral ischemia, vascular stenosis and other

To obtain the derivative anilinopyrimidines previously known methods mainly use reaction pyrimidinamine compounds with aniline derivatives or turning anilinopyrimidines in other derivatives (for example, see WO 2004/029038, WO 2006/071130, US 20060149061, RF application 2005129100). There are also known methods that include obtaining initial pyrimidine derivative, including the formation of the pyrimidine ring (see, for example, US 2004/0102453, US 2003/0069425, RF 2125992). In addition, it is known for various crystal is logical forms derived pyrimidinones and salts.

The most complete method for the synthesis of derivatives of 2-anilinopyrimidines formula I

or pyridyloxy, a method described in the patent of Russian Federation №2125992.

According to this method of N,N-dialkylamino-1-(3-pyridyl)-2-propen-1-it formula III

enter into interaction with the corresponding nitrophenylamino obtained from cyanamide and the corresponding nitroaniline derivative, followed by reduction of the nitro group in the presence of palladium.

The resulting derived anilinopyrimidines formula I, where R1= pyridyl, if necessary, oxidizing adharmasya acid to obtain the compound I where R1=N-oxidability, to obtain the compound I where R7- the remainder of the formula N(R9)-C(=O)-R10the aniline-pyrimidine of the formula V, where R16= amino group, is subjected to the interaction with the compound of the formula VI BUT-C(=O)-R10.

Considering the known method provides for obtaining N,N-dialkylamino-1-(3-pyridyl)-2-propen-1-she (III) the interaction of the ketone VII of the formula R1-CO-CH2-R2and dimethylacetal N,N-dimethylformamide or dimethylacetal of ndimethylacetamide, or N,N-dialkylamino-1-(3-pyridyl)-2-propen-1-he (III) can be obtained in the conversion of compound VII complex ester of the formula 3-C(=O)och2CH3and reaction of the resulting product with an appropriate amine.

The described known method has a number of shortcomings that hinder its use in industrial production. First of all, its implementation requires the use of toxic substances, such as cyanamide, volatile solvents (e.g., diethyl ether, acetone, hexane), presence of palladium to restore the nitro group to the amino group, the use of aggressive fluids.

Difficulties in technological design lead to insufficiently high yield of products as intermediate stages, to the total yield of the target product. In addition, the quality of the products, including the target product, also not high enough, as evidenced by the variation in the melting temperature by 4-5 degrees.

The task of the invention is to develop a new and improved method of producing anilinopyrimidines devoid of these shortcomings. The method according to the invention eliminates toxic substances and allows to obtain the derivatives of anilinopyrimidines with good yield and quality required.

The method of obtaining compounds of General formula I according to the invention comprises the following stages:

A) interaction of urea in the basic environment, such as environment Speer is a new solution of an alkali metal, with N,N-dialkylamino-1-(3-pyridyl)-2-propen-1-one of formula II

where R1means associated carbon atom of the pyridyl which may be substituted by lower alkyl or alkoxy, each of R2and R3independently mean hydrogen, branched or unbranched lower alkyl, phenyl, unsubstituted or substituted by halogen, with the receipt of dihydropyrimidinase General formula (III)

where R1-R3have the above values,

B) oxidation of the compound (III) proton oxidizing agent to obtain the corresponding hydroxypyrimidine formula IV

where R1-R3have the above values,

C) activating the resulting compound IV hydroxy-group, for example, by treatment with sulfoselenides R′SO2Hal or anhydride R′(SO2)2O obtaining the compounds of formula V

where R′ means aryl or lower alkyl,

G) the interaction of the compounds V with the corresponding aromatic aminoguanidinium formula VI

thus R4-R8have the meanings specified for formula I above,

and, if necessary, functional groups not participating in the reaction, protected, removed the eating of protective groups, if they are, and getting anilinopyrimidines formula (I).

Compounds where R is hydrogen, can be proaccelerin, for example, dimethylsulfate.

The compounds obtained can be isolated in free form or in the form of salts, including pharmaceutically acceptable salts.

If necessary, the resulting compound can be converted one group to another.

The obtained compound (I), where R1- pyridyl, can be treated with an oxidant, such as adharmasya acid, to obtain compounds in which R1means N-oxidability.

The compound of formula (I), where R7- halogen-lower alkyl, halogen-lower alkoxy, carboxypropyl, when interacting with the amine HNR9R10can be converted to the corresponding aminoalkyl, aminoethoxy or aminocoumarin.

Or can be subjected to acylation or sulfonylamino free amino group.

The compound of formula (I), where R7means phenyl, substituted amino group, can be braziliano, for example, an acid of the formula HOC(=O)-R10or its activated derivative, where R10have the above values.

According to the invention can be obtained imatinib: 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidine-2-ylamino)phenyl]benzamide or its salt selected from nelfinavir, hydrochloride, digit the chloride, tosilata or besilate and other

Can be also obtained new compounds corresponding to the General formula

where the values of the radicals R is hydrogen, lower alkyl, R1, R2above, L is N(R9)-C(=O)-, -C(=O)-NR9-, -CH2-NR9-, -OCH2-NR9-, -NR9SO2-.

According to the invention also received new source of compounds of formula V.

Salt obtained according to the invention, are known acid additive salts such as mono-, di - or trihydrochloride, mesylates, tozilaty, besylate, maleate, fumarate, succinate, pamoate, formate, malonate, salt benzoic acid, 1,5-dentalinsurance, salicylate, lactate, mandelate, ascorbate, vanillate, sulphates, picrate and other salts.

Salt can also be formed with alkali or alkaline earth metals. Salt can also be used for purification of the compounds obtained.

Stage A) is carried out in the presence of proton compound and a metal salt, possibly in the presence of a solvent. As proton connections can be used organic or inorganic acid, such as acetic, hydrochloric, sulfuric, nitric, phosphoric acid. As a salt of the metal m which may be used chloride of copper(II), chloride iron(II). Proton compound may be used in amounts of from 0.01 to 1 mole taken on the ketone, salt of a metal from 0.001 to 0.1 mole on the original ketone.

Stage A) can be carried out in the absence or presence of a solvent, for example a lower alcohol, such as methanol, ethanol, n-butanol, isopropyl alcohol, acetonitrile, dichloroethane, ethers, such as tetrahydrofuran.

As the proton acid in stage B) can be used inorganic acids such as sulphuric, nitric or phosphoric. The oxidation can be carried out in a solvent or without it.

The amount of acid used may be from 1 to 5 moles per 1 mole dihydropyrimidinase the compounds of formula III.

The solvent can be used carboxylic acids such as acetic, propionic, butyric, separately or in combination in amounts of from 0.1 to 5 ml per 1 g dihydropyrimidinase connection depending on the homogeneity and dispersion of the reaction mass. The oxidation can be carried out in the atmosphere of inert gas, possibly in the presence of a reaction initiator, such as sodium nitrite, at a temperature from 0 to 50°C. carrying out the process at room temperature.

Stage C) is preferably carried out in the presence of a base such as carbonate, bicarbonate alkaline m is metal, tert-butoxide or sodium methoxide or potassium hydroxide, or a tertiary amine such as triethylamine or pyridine, possibly in an inert gas environment at a temperature of from 0 to 50°C, preferably at room temperature.

As an agent, activating the hydroxy-group stage), you can use alkanesulfonyl, such as methanesulfonate, methansulfonate, triftormetilfullerenov, or chloride, propanesulfonyl, benzosulphochloride, naphthalenesulfonate, p-toluensulfonate and other

As sulfonic anhydrides can be used methansulfonate, benzosulfimide, p-toluensulfonate, triftormetilfullerenov anhydrides. These agents can be used in an amount of from 1 to 8 moles per 1 mole hydroxypyrimidinone connections.

The reaction can be carried out in the presence or in the absence of solvents, such as water, acetone, tetrahydrofuran, ethyl - or butyl acetate, in amounts depending on the homogeneity and dispersion of the reaction medium.

Possible activation of the hydroxy-group of pyrimidine compounds by replacement of the hydroxy-group on halogen using, for example, phosphorus oxychloride.

The reaction in stage D) can be performed in the environment of the solvent, optionally in the presence of bases, such as described above, at a temperature of about the 15 to 150° C. we can also carry out this stage in the two-phase system in the presence of a phase transfer catalyst in amounts of from 0.01 to 0.05 mol per 1 mol of 2-substituted pyrimidine compounds. As the phase transfer catalyst can be used Quaternary ammonium compounds such as tetraethylammonium bromide or chloride, benzyltriethylammonium chloride, dodecyltrimethylammonium chloride or hexadecyltrimethylammonium chloride.

Below are examples, but not limiting the present invention. The structure and quality of the products confirmed chromatography, IR - and NMR-spectroscopy.

Example 1.

A. Obtain 4-(3-pyridinyl)-3,4-2(1H)-dihydropyrimidin-2-it.

In a three-neck 2-liter flask equipped with stirrer, thermometer and reflux condenser, placed in 350 ml of ethanol, add 1.0 mol of 3-dimethylamino-(3-pyridyl)-2-propen-1-it, 1.3 mol of urea, 0.01 mol of copper chloride and sulphuric acid, heated under reflux for one hour at a temperature of 65-68°C, cooled to room temperature. Bring the solution pH to 5. The precipitation is sucked off over a Buechner funnel. The obtained wet solid is dissolved in a mixture of methanol-dichloromethane, the solution is injected into a column with silica gel and elute the product with a mixture of chloroform : methanol : water 65:25:4. The eluate evaporated on the river is again evaporator, get the title compound, yield of about 68% in the calculation of the original urea.

B. Obtain 6-(3-pyridinyl)-2-dihydropyrimidine.

In a three-neck 2-liter flask equipped with stirrer, condenser and potassium chloride tube, was placed 500 ml of absolute ethanol, add 23 g (1.0 mol) granulated metallic sodium and upon completion of the reaction through the funnel for the introduction of solids quickly add 60,0 g (1 mol) of urea, stirred for 10 minutes, enter 150 g (1.0 mol) of 3-dimethylamino-(3-pyridyl)-2-propen-1-she heated under reflux overnight, cooled to room temperature. To the resulting clear solution was added glacial acetic acid to pH 5. The precipitation is sucked off over a Buechner funnel. The obtained wet solid is dissolved in a mixture of methanol-dichloromethane, the solution is injected into a column with silica gel and elute the product with a mixture of chloroform : methanol : water 65:25:4. The eluate evaporated on a rotary evaporator to yield the title compound, yield of about 68% for urea.

Example 2. Getting 4-(3-pyridinyl)-2-hydroxypyrimidine.

In a three-neck glass flask with a capacity of 100 ml equipped with a stirrer and a thermometer, placed 22 ml (0, 03 mol) of nitric acid (60-61%, beats. weight of 1.38). To nitric acid is added slowly at room temperature of 5.1 g (0,03 mole) of 4-(3-pyridinyl)-3,4-2(1H)-Digue is dropyridine-2-it, the mixture is stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was neutralized by placing it in 280 ml of a saturated aqueous solution of sodium bicarbonate. The product is extracted with ethyl acetate. Organic liquid portion is separated, concentrated under reduced pressure and the residue is crystallized from toluene. Get the target product with a yield of about 92% in terms of the initial 4-(3-pyridinyl)-3,4-2(1H)-dihydropyrimidin-2-it. Similarly receive 4-(6-methoxypyridine-3-yl)-3,4-2(1H)-dihydropyrimidin-2-it.

Example 3. Getting 2-chloro-4-(3-pyridinyl)pyrimidine.

In a three-neck glass flask with a capacity of 250 ml, equipped with a stirrer, thermometer and reflux condenser, was placed 10 g (0,343 mole) of 4-(3-pyridinyl)-2-hydroxypyrimidine and 34 ml of 0.37 mole) of phosphorus oxychloride. The mixture is heated to 100-106°With over one and a half hours under reflux. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into a mixture of water and ice. The resulting aqueous mixture is neutralized with saturated aqueous sodium bicarbonate solution. The product is extracted with ethyl acetate. An ethyl acetate layer is separated, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. Dried an ethyl acetate layer is filtered and concentrated under reduced pressure, get the with the release of 90% of 2-chloro-4-(3-pyridinyl)pyrimidine as a yellow foam.

Can be similarly obtained

2-chloro-5-methyl-4-(3-pyridinyl)pyrimidine,

2-chloro-4-(4-methoxy-3-pyridinyl)pyrimidine,

2-chloro-6-(4-forfinal)-4-(3-pyridinyl)pyrimidine.

Example 4. Getting 4-(3-pyridinyl)-2-(napa-toluensulfonate)pyrimidine.

In a glass three-neck flask with a capacity of 250 ml, equipped with a stirrer, thermometer and reflux condenser, are placed 3.4 g (0,02 mol) of 4-(3-pyridyl-2-hydroxypyrimidine, 2.9 g (0,026 mol) of triethylamine and 40 ml of acetonitrile. The process is conducted in a nitrogen atmosphere. The mixture is cooled to 0-5°and slowly, dropwise, with stirring, 40 g (0,022 mol) napa-toluensulfonate, the reaction is carried out at 20-25°without stirring, for one hour. After completion of the reaction to the mixture of 25 ml of water and the product extracted with toluene, the organic layer was separated, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The dried mixture is filtered, concentrated under reduced pressure. The residue is crystallized from ethanol. Get 6-(3-pyridinyl)-2-(napa-toluensulfonate)-pyrimidine as a colourless product with a yield of 88% based on 4-(3-pyridyl)-2-hydroxypyrimidine.

Example 5. Getting 4-(6-methoxypyridine-3-yl)-2-methanesulfonylaminoethyl.

In a glass flask with a capacity of 250 ml, equipped with a stirrer, thermometer and reflux condenser, are placed 5.6 g (0,03 mole of 6-(6-methoxypyridine-3-yl)-2-hydroxypyrimidine, 3.0 g (0,03 mole) of triethylamine and 50 ml of toluene. The mixture in the flask is cooled to 0-5°in an ice bath. To the cooled mixture is added slowly to 5.4 g (0,03 mole) methanesulfonamido anhydride and the resulting mixture was continued to stir for 3 hours at the same temperature. After completion of the reaction the mixture was added 90 ml of water. From the aqueous reaction mixture is separated liquid organic part, which is then concentrated under reduced pressure. The remainder of the cleaning column chromatography on silica gel (column: Wako Gel C-2QO; eluent: hexane/ethyl acetate (volume ratio 8:2)).

Receive 4-(6-methoxypyridine-3-yl)-2-methanesulfonylaminoethyl with the release of 78% (based on 4-(6-methoxypyridine-3-yl)-2-hydroxypyrimidine).

Similar conditions obtain

5-methyl-4-(3-pyridinyl)-2-methanesulfonylaminoethyl,

4-(6-methoxy-3-pyridinyl)-2-methanesulfonylaminoethyl,

6-(4-forfinal)-4-(6-methoxypyridine-3-yl)-2-methanesulfonylaminoethyl.

Example 6. Getting 4-(N-oxido-3-pyridinyl)-5-methyl-2-(napa-toluensulfonate) pyrimidine.

0,068 moles of 4-(3-pyridinyl)-5-methyl-2-(napa-toluensulfonate) pyrimidine are suspended in 5 ml of methylene chloride and mixed with 0,071 the moles of 3-chloroperbenzoic acid. The mixture was kept under stirring at room temperature for 3 hours. After filtration and thin-layer chromatography (methylene is lorid : methanol : 25%aqueous ammonia solution =90:10:1) residue receive a 4-(N-oxido-3-pyridinyl)-5-methyl-2-(napa-toluensulfonate)pyrimidine with a yield of about 90%.

Example 7. Getting 4-(6-methoxypyridine-3-yl)-2-(3-AMINOPHENYL)pyrimidinamine.

In a glass flask with a volume of 50 ml equipped with a stirrer, thermometer and addition funnel, place (0,0163 mol) 6-(4-methoxypyridine-3-yl)-2-methanesulfonylaminoethyl. To the flask is added slowly (0,0652 mol) of m-phenylenediamine in an aqueous solution of sodium bicarbonate. Upon cooling, the mixture is stirred for one hour at the same temperature. The product, 6-(6-methoxypyridine-3-yl)-2-(3-AMINOPHENYL)pyrimidinamine allocate. The yield was 77% (counting on the original 6-(6-methoxypyridine-3-yl)-2-methanesulfonylaminoethyl).

Similarly, selecting appropriate source reagents, protective groups, solvents and ratios, get

4-(3-pyridinyl)-2-(5-amino-2-were)pyrimidinamine,

4-(4-methoxypyridine-3-yl)-2-(5-carboxyphenyl)pyrimidinamine,

4-(3-pyridinyl)-2-(5-carboxyphenyl)pyrimidinamine,

4-(3-pyridinyl)-2-(5-carboxy-4-were)pyrimidinamine,

4-(3-pyridinyl)-2-(5-amino-2-were)pyrimidinamine,

4-(3-pyridinyl)-2-(5-amino-2-isopropylphenyl)pyrimidinamine,

4-(6-methoxypyridine-3-yl)-2-(5-amino-2-isopropylphenyl)pyrimidinamine.

Example 8. Getting 4-(4-methoxypyridine-3-yl)-2-(4-formlistener.handleevent)pyrimidinamine.

0,019 moles of 4-(4-methoxypyridine-3-yl)-2-(3-AMINOPHENYL)pyrimidinamine dissolved in 2.5 ml of pyridine and add the keys is 0.023 mmole 4-ftormetilirovaniya. The mixture is stirred overnight at ambient temperature. Add 5 ml of water, cooled to -5°and filtered. After washing with water and drying obtain the target product, which is subjected to chromatography on silica gel with a mixture of chloroform-methanol at a volume ratio of 9:1, gives a single spot.

Similarly, using appropriate reagents and conditions, receive

4-(pyridin-3-yl)-2-(4-formlistener.handleevent)pyrimidinamine,

4-(pyridin-3-yl)-2-(4-chlorocarbonylsulfenyl)pyrimidinamine,

2-(3-chlorocarbonylsulfenyl)pyrimidinamine.

Example 9. Getting 6-(4-forfinal)-4-(6-isopropylpyridine-3-yl)-2-triftormetilfullerenov.

In a glass flask of 300 ml equipped with a stirrer, thermometer and reflux condenser, are placed 0.03 mmole of 6-(4-forfinal)-2-hydroxy-4-(6-isopropylpyridine-3-yl)pyrimidine, of 0.03 mol of triethylamine and 150 ml of toluene. The mixture in the flask is cooled to 0°in an ice bath. To the cooled mixture is added slowly 0.03 mmole triftormetilfullerenov anhydride and the resulting mixture is subjected to reaction for 3 hours at the same temperature. After completion of the reaction the mixture was added 90 ml of water, stirred and separated organic liquid part. The latter is dried over magnesium sulfate and concentrate under reduced pressure. OST the current purified column chromatography on silica gel (column: Wako Gel C-2QO; eluent: hexane/ethyl acetate (volume ratio 8:2)). Get 6-(4-forfinal)-4-(6-isopropylpyridine-3-yl)-2-triftormetilfullerenov. The yield was 74% (in terms of the initial 6-(4-forfinal)-2-hydroxy-4-(6-isopropylpyridine-3-yl)pyrimidine).

Example 10. Getting 6-(4-forfinal)-2-hydroxy-4-(6-isopropylpyridine-3-yl)-pyrimidine.

In a glass flask with a volume of 50 ml equipped with a stirrer and thermometer, is placed 0.01 mol 6-(4-forfinal)-4-(6-isopropylpyridine-3-yl)-3,4-2(1H)-dihydropyrimidine obtained in the same manner as in example 1, and 5 ml of acetic acid. To this mixture, slowly add 0.05 mol of nitric acid (60-61%, Udis 1,38). This mixture is then added 0.01 mol of sodium nitrite and conducting the reaction for one hour at room temperature. After completion of the reaction, the reaction mixture was neutralized by pouring it into 50 ml of saturated aqueous sodium bicarbonate solution. The reaction mixture was then extracted with ethyl acetate. Organic liquid portion is separated and concentrated under reduced pressure. The residue is crystallized from toluene. The crystalline product is collected on a filter and washed with toluene to obtain 6-(4-forfinal)-2-hydroxy-4-(6-isopropylpyridine-3-yl)pyrimidine in the form of a crystalline product. The yield was 90% (based on the amount of 6-(4-forfinal)-4-(6-isopropylpyridine-3-yl)-3,4-2(1H)-dihydropyrimido what it is).

Example 11. Benzamidophenyl-4-(4-methoxypyridine-3-yl)pyrimidine-2-ylamine.

0.05 m 4-(4-methoxypyridine-3-yl)-2-(3-AMINOPHENYL)pyrimidinamine injected into the interaction in the aquatic environment with 0.06 mole of acid chloride of benzoic acid, using as a condensing agent dicyclohexylcarbodiimide. Get chromatographic clean benzamidophenyl 4-(4-methoxypyridine-3-yl)pyrimidine-2-ylamine with the release of 69%.

Example 12. Getting 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-(pyridin-3-yl)pyrimidine-2-ylamino)phenyl]benzamide.

To 0,025 mol of 4-(3-pyridinyl)-2-(5-amino-2-were)pyrimidinamine obtained in the conditions of example 7 add to 0.03 mole of 4-(4-methylpiperazine)of benzoyl chloride in a solution of pyridine in a stream of argon at a temperature of 45°C for 5 hours. The solvent is distilled off, to the residue add 250 ml of water and alkalinized to pH 10. The product is extracted with dichloromethane (2×200 ml). Dry the extract over sodium sulfate, filtered, the solvent is distilled off. To the residue are added 50 ml of ethyl acetate and filtered, the residue washed with ethyl acetate. Dried, yielding the desired product with a yield of 65%. TPL 212-213°C.

Example 13. Getting 4-[(piperidine-1-ylmethyl)-N-[4-methyl-3-[(4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide.

0.1 mol of (4-chloromethyl)-N-[4-methyl-3-[(4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]benzamide in a solution of dichloromethane EXT the keys under stirring to 0.12 mole of 4-methylpiperidine. The process is conducted at room temperature, stirring constantly, in the presence of triethylamine. After the reaction mixture was washed with water, the organic layer is separated, dried over sodium sulfate and evaporated on a rotary evaporator under reduced pressure. Get almost pure product (according to IR - and NMR-spectroscopy). The yield of the target product 67%.

1. The method of obtaining derivatives of N-phenyl-2-pyrimidinamine General formula (I)

where R1means associated carbon atom of the pyridyl or its oxide, which may be substituted by lower alkyl or alkoxy, each of R2and R3independently mean hydrogen, branched or unbranched lower alkyl, phenyl, unsubstituted or substituted by halogen, R4is hydrogen, unbranched or branched lower alkyl, R5is hydrogen, lower alkyl, possibly substituted by halogen atoms, R6and R8is hydrogen, lower alkoxy, branched or unbranched lower alkyl, R7- lower alkyl, lower alkoxy, halogen-lower alkyl, halogen-lower alkoxy, nitro, carboxy, amino, or a residue of formula II-N(R9)-C(=O)-R10, -C(=O)-NR9R10, -CH2-NR9R10, -OCH2-NR9R10-, NR9SO2-R10where R9hydrogen or R9and R10together with at the IOM nitrogen form piperidino, piperazinone with the second nitrogen atom Deputy, selected from lower alkyl or lower acyl, or R10means associated carbon atom of the pyridyl, thienyl, cyclohexyl, naphthyl or phenyl, optionally substituted by halogen, cyano, lower alkoxy, lower alkyl, carboxy or 4-methylpiperazine, R is hydrogen or lower alkyl,

or their pharmaceutically acceptable salts or isomers, comprising the following stages:

A) interaction of urea in the core c (N,N-dialkylamino-1-(3-pyridyl)-2-propen-1-one of formula II

where R1means associated carbon atom of the pyridyl which may be substituted by lower alkyl or alkoxy, each of R2and R3independently means hydrogen, a branched or unbranched lower alkyl, phenyl, unsubstituted or substituted by halogen,

with the receipt of dihydropyrimidinase General formula (III)

where R1-R2have the above values,

B) oxidation of the compound (III) proton oxidizing agent to obtain the corresponding hydroxypyrimidine formula IV

where R1-R3have the above values,

C) activation in the resulting soybean is ininii IV hydroxy-group, for example, the processing sulfoselenides R′SO2Hal or anhydride R′(SO2)2O obtaining the compounds of formula V

where R′ means aryl or lower alkyl,

G) the interaction of the compounds V with the corresponding

aromatic aminoguanidinium formula VI

thus R4-R8have the meanings specified for formula I, in which, if necessary, functional groups not participating in the reaction, protected, followed by removal of protective groups, if any, of obtaining anilinopyrimidines formula (I), if necessary, the resulting compound of formula (I), where R1-pyridyl, can be treated with an oxidant, such as adharmasya acid, to obtain compounds in which R1means N-oxidability, or compound I, where R means hydrogen, and are subjected to alkylation of the compounds where R is lower alkyl, or a compound of formula (I), where R7- halogen-lower alkyl, halogen-lower alkoxy, carboxypropyl, when interacting with the amine HNR9R10can be converted to the corresponding aminoalkyl, aminoethoxy or aminocoumarin, or the compound of formula (I), where R7means a primary or secondary amino group, to be the up to the acylation or sulfonylamino the corresponding amides or sulfonamides and selection of products in free form or in the form of salts, including pharmaceutically active salts.

2. The method according to claim 1, characterized in that the compound of formula (I), where R7means phenyl, substituted amino group, treated with acid of the formula HOC(=O)-R10or its activated derivative, where R10have the above values.

3. The method according to claim 1 or 2, whereby the compound of formula (I), where R7- halogen-lower alkyl, are subjected to interaction with a secondary amine HNR9R10.

4. The method according to claim 1 or 2, which receive the connection, in which R3or R4or R8mean isopropyl.

5. The method according to claim 1 or 2, according to which it is obtained 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[[(4-pyridin-3-yl)pyrimidine-2-yl]amino]phenyl]benzamide or its salt.

6. The method according to claim 5, according to which are salt selected from nelfinavir, hydrochloride, dihydrochloride, tosilata or besilate.

7. The method according to claim 1, characterized in that the compound of General formula

8. The method according to any one of claims 1 and 7, characterized in that the compound of General formula

9. The method according to claim 1, characterized in that the compound of General formula

10. The method according to claim 1, characterized in that conduct the activation of the hydroxy-group in which the Association IV treatment sulfoselenides R′ SO2Hal or anhydride R′(SO2)2O obtaining the compounds of formula V

where R′ means aryl or lower alkyl,

with the subsequent interaction of the compounds V with the corresponding aromatic aminoguanidinium formula VI

thus R4-R8have the meanings specified for formula I, in which, if necessary, functional groups not participating in the reaction, protected, followed by removal of protective groups, if any, of obtaining anilinopyrimidines formula (I), if necessary, the resulting compound of formula (I), where R1- pyridyl, can be treated with an oxidant, such as adharmasya acid, to obtain compounds in which R1means N-oxidability, or the compound of formula (I), where R7means a primary or secondary amino group, and are subjected to acylation or sulfonylamino the corresponding amides or sulfonamides and selection of products in free form or in the form of salts, including pharmaceutically active salts.

11. The method of obtaining 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[[(4-pyridin-3-yl)pyrimidine-2-yl]amino]phenyl]benzamide or its salts, which consists in the fact that the compound of formula V

where R1mean 3-pyridyl, each of R2and R3means hydrogen, R′ means aryl or lower alkyl,

subjected to interaction with 2-methyl-1,3-phenylenediamine of the formula VI′

where R7means amino, R4means methyl, R5, R6, R8is hydrogen, R is hydrogen,

obtaining the compounds of formula VII

where R1- pyridyl, R7means amino, R4means methyl, R, R2, R3, R5, R6, R8- hydrogen, which is subjected to interaction with acid or its activated derivative of General formula: X-C(=O)-R10,

where R10means phenyl, substituted 4-methylpiperazine, X IS Oh or halogen,

and the selection of the target product in free form or in pharmaceutically acceptable salt.

12. The method according to claim 10, characterized in that receive a 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-[[(4-pyridin-3-yl)pyrimidine-2-yl]amino]phenyl]benzamide in the form of a hydrochloride, dihydrochloride, besilate or nelfinavir.

13. The method according to claim 10, characterized in that as starting compound is used as a compound of formula V obtained according to claim 1.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) or their pharmaceutically acceptable salts, where R1 and R2 are H or Me; R3 is H, hydroxy or (1-4C)alkoxi; R4 is H, OH, (1-4C)alkoxi; R5 is OH, (1-4C)alkoxi or R7; provided the R4 is H, then R5 differs from OH or (1-4C)alkoxi; R6 is (2-5C)heteroaryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, bromine or chlorine; (6C)aryl, not necessarily substituted with one or more substitutes, selected from (1-4C)alkyla, (1-4)C-alkoxi, bromine, chlorine, phenyl or (1-4C) (di)alkylamino; (3-8C)cycloalkyl, (2-6C)heterocycloalkyl or (1-6C)-alkyl; R7 is amino, (di)(1-4C)alkylamino, (6C)arylcarbonylamino, (2-5C)heteroarylcarbonylamino, (2-5C)heteroaryl-carbonylokxi, R8-(2-4C)alkoxi, R9-methylamino or R9-methoxi; R8 is amino, (1-4C)alkoxi, (di)(1-4C)-alkylamino, (2-6C)-heterocycloalkyl, (2-6C)heterocycloalkylcarbonylamino or (1-4C)-alkoxicarbonylamino; and R9 is aminocarbonyl, (di)(1-4C)alkylaminocarbonyl, (2-5C)heteroaryl or (6C)aryl. The invention also relates to the pharmaceutical composition which contains the said derivatives, and to the application of the derivatives in fertility modulating.

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

15 cl, 51 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of quinoline with general formula Ia or Ib their stereoisomers and pharmaceutical salts, where X represents oxygen or sulphur, Z-CH2, Y-NO2, -C(O)OR5, -NR5SO2R5, -SO2R5 (for Ia) and -NO2 or -C(O)OR5 (for Ib). Description is also given of the method of obtaining Ia and Ib compounds, pharmaceutical compositions based on them, and their use when making medicinal preparations.

EFFECT: compounds can be used for treating lesions, related to inhibition of migration of magrophage, for example, during treatment of septic shock or arthritis.

175 cl, 16 tbl, 22 ex, 16 dwg

FIELD: chemistry.

SUBSTANCE: invention pertains to new 2,4-substituted indole with formula: I, its pharmaceutically accepted salt, where R1 represents phenyl, optionally substituted with one or two substitutes, chosen from a group, consisting of a halogen, C1-12alkyl, halogen C1-12alkyl, or represents thienyl; R2 represents residue of a saturated ring, consisting of six ring atoms, one or two of which are nitrogen atoms, and the others are carbon atoms, optionally substituted with one or two C1-12alkyls; R represents H, C1-12alkyl; R4 represents H; p represents 1 or 2; n represents 0,1 or 2. The compounds have antagonistic activity to the "5-ГТ6" receptor, which allows to use in pharmaceutical mixtures.

EFFECT: use in pharmaceutical mixtures.

10 cl, 7 dwg, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrrolidinium of the general formula (I): possessing antagonistic effect with respect to muscarinic receptors M3 wherein B means phenyl or thienyl group; each radical among R1, R2 and R means independently hydrogen, fluorine, chlorine atom or hydroxyl; n means a whole number from 0 to 1; A means group chosen from groups -CH2 and -O-; m means a whole number from 0 to 6; R means (C1-C8)-alkyl; X- represents a pharmaceutically acceptable anion of mono- or multibasic acid, and involving all separate stereoisomers and their mixtures. Also, invention relates to methods for synthesis of such compounds, pharmaceutical compositions containing such compounds and to their using in therapy as antagonists of muscarinic receptors M3.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

17 cl, 51 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention describes novel compounds of the general formula (I): wherein R1 means quinolinyl possibly substituted with (C1-C5)-alkoxy-group, isoquinolinyl, quinoxalinyl, pyridinyl, pyrazinyl, benzyl possibly substituted with halogen atom, naphthalinyl, thiophenyl, furanyl, cinnolyl, phenylvinyl, quinolylvinyl or 4-oxo-4H-chromenyl possibly substituted with halogen atom, (C1-C5)-alkyl or (C1-C5)-alkoxy-group; R2, R5, R8 and R11 mean hydrogen atom; R3 and R4 mean halogen atom, (C1-C5)-alkoxy-group; R6 and R7 mean hydrogen atom (H) or (C1-C5)-alkyl or form in common radical -CH2-CH2-; R9 and R10 mean (C1-C5)-alkoxy-group; m and n mean a whole number from 0 to 4 independently; X means -CH2- or sulfur atom (S). Also, invention describes their pharmaceutically acceptable salts, a method for their preparing and pharmaceutical composition based on thereof. Proposed compounds are inhibitors of P-glycoprotein, enhance bioavailability of anti-cancer drug and can be used in medicine.

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

7 cl, 3 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (IA): or the formula (IB): wherein B means hydrogen atom or lower alkyl; A means an unsubstituted or substituted cyclic group chosen from compounds of the following formulae: (a) (b) (c) (d) (e) (f) (g) (h) (i) (j) and (k) wherein R1-R4 mean independently of one another hydrogen atom, halogen atom, -CF3, -CHF2, -C(CH3)F2, (C3-C6)-cycloalkyl, lower alkoxy-group, lower alkyl, -OCF3 or phenyl; R5-R10 means independently of one another hydrogen atom, halogen atom, lower alkoxy-group, lower alkyl or -CHF2; R11-R16 mean independently of one another hydrogen atom, halogen atom, alkoxy-group or lower alkyl; R17 means halogen atom or -CHF2; R18-R20 mean independently of one another hydrogen atom, lower alkoxy-group or lower alkyl, and to their pharmaceutically acceptable acid-additive salts. Also, invention relates to a medicinal agent possessing the selective effect of blockers of NMDA receptors of subtype 2B. Invention provides synthesis of novel biologically active compounds and medicinal agents based on thereof.

EFFECT: valuable medicinal properties of compounds and drugs.

6 cl, 180 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

FIELD: organic chemistry, pharmaceutical chemistry, pharmacology, medicine.

SUBSTANCE: invention relates to novel derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d): wherein R means C2H5, R1 means , n = 1 (Ia); R means n-C3H7, R1 means Br, n = 1 (Ib); R means hydrogen atom (H), R1 means -SCH2CONHNH2, n = 0 (Ic); R means H, R1 means -SCH2CONHNH2, n = 2 (Id). Proposed compounds possess the greater hemorheological activity as compared with that of pentoxyphylline and lower toxicity. Invention provides synthesis of novel and not described previously derivatives of 3-methyl-7-(thietanyl-3)-xanthine of formulae (Ia, b, c, d) possessing hemorheological activity.

EFFECT: improved method of synthesis, valuable medicinal property of compounds.

2 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I) or their pharmaceutically acceptable salts wherein R1 and R2 are similar or different and chosen independently from group comprising aryl and heteroaryl. Each of them as a substitute comprises optionally from one to sic groups chosen from group comprising the following groups: (a) halogen atom; (b) -OCF3 or -OCHF2; (c) -CF3; (d) -CN; (e) alkyl; (f) R18-heteroaljyl; (k) hydroxyl; (l) alkoxyl comprising cyclopropylmethoxyl, and (s) trifluoroalkoxyl; R3 means hydrogen atom (H); R4, R5, R7 and R8 are similar or different and chosen independently from group comprising H, -OH, alkyl, heteroalkyl and

under condition that if Z and/or X means nitrogen atom (N) then all radicals R4, R5, R7 and R8 don't mean -OH; R6 means -C(O)R15; R9 and R10 mean H; R11 is chosen from group comprising H and alkyl; R12 is chosen from group comprising H and alkyl; R13 is chosen from group comprising alkyl and alkoxyl; R14 means H; R15 is chosen from group comprising -NR16R17, -OR16 and alkyl wherein R16 and R17 are similar or different and chosen independently from group comprising H and alkyl; R18 means a substitute chosen from group comprising lower alkyl, halogen alkyl, halogenalkyl, alkoxycarbonyl, dialkylamino-group and piperidinyl; X and Z are similar or different and chosen independently from carbon atom (C) and N. Proposed compounds possess properties of inhibitor of 17β-hydroxysteroid dehydrogenase of type 3. Also, invention describes a pharmaceutical composition based on compound of the formula (I).

EFFECT: valuable medicinal and biochemical properties of compound and pharmaceutical composition.

16 cl, 23 tbl, 651 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to derivatives of quinoline with general formula Ia or Ib their stereoisomers and pharmaceutical salts, where X represents oxygen or sulphur, Z-CH2, Y-NO2, -C(O)OR5, -NR5SO2R5, -SO2R5 (for Ia) and -NO2 or -C(O)OR5 (for Ib). Description is also given of the method of obtaining Ia and Ib compounds, pharmaceutical compositions based on them, and their use when making medicinal preparations.

EFFECT: compounds can be used for treating lesions, related to inhibition of migration of magrophage, for example, during treatment of septic shock or arthritis.

175 cl, 16 tbl, 22 ex, 16 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to heterocyclic compounds with general formula (I) or its pharmaceutically acceptable salts; and including its any stereoisomer forms;X and Y are independently N or CR1; Z represents S, O, NR1 or CR12;every R1-R6 represent independently H or not influencing substitute, which is alkyl (C1-10), allkenyl (C2-10), alkynil (C2-10), aryl ("C'5-12), arylalkyl, arylalkenyl or arylalkynil, each of which can not obligatorily contain one or more heteroatoms selected from O, S and N and each of which can be substituted further one; or not obligatorily substituted forms of acyl, arylacyl, alkyl,alkenyl alkynyl or arylsulphonyl or their forms which contain heteroatoms in alkyl,alkynyl or aryl fragments or representing OR, SR, NR2, COOR, CONR2, where R is N or alkyl alkenyl, alkynyl, or aryl not obligatorily substituted, as defined above, when C is a substituted atom not influencing substitute can be a halohen, OOCR, NROCR, where R is H or its substitute shown above, or can equal 0; nl is equal to 0-4; n2 is equal to 0-1, where * means that CR5=CR5 can be substituted by C=C; n3 is equal to 0-4;where nl+n2+n3 exceeds or equals 2; b is equal to 0-2; where the following combinations of R-groups can be associated with cycle formation, which can saturated or unsaturated R2-R2, one R2+R3, R3+ one R4, R4+R4, one R5 + the other R5, one R5 + one R6 and R6+R6; where cycle can not be aromatic, when the cycle formation components are represented by two R5; and where, when n2 is unity 1, neither of n1 nor n3 can be equal to 0, the invention also relates to pharmaceutical composition, based on these compounds, possessing a modulating ability relative to CXCR4- and/or CCRS-receptor; to modulation method CXCR4- and/or CCRS-receptor; to method of treatment of a statec described by unusual activity CXCR4- and/or CCR5-receptor and application of the described compounds for production of pharmaceutical.

EFFECT: new compounds feature useful biological properties.

36 cl, 171 ex

FIELD: chemistry.

SUBSTANCE: invention presents several polymorphous forms and an amorphous form of {2-fluorine-5-[3-((E)-2-pyridine-2-ilvinyl)-1N-indazole-6-ilamine]phenyl}amide 2, 5-dimethyl-2N-pyrazole-3-carbonic acid, a pharmaceutical formula containing such polymorphous or amorphous forms, as well as ways of using such pharmaceutical formulas for therapy of ill conditions mediated by protein kinases such as cancer and other pathological conditions associated with undesirable angiogenesis and/or cell proliferation, as well as the mode of modulating protein kinase receptor activities on the basis of the polymorphous forms.

EFFECT: obtained polymorphous forms possess improved solubility and biological accessibility when taken per os.

22 cl, 40 dwg, 18 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I or pharmaceutically suitable salt or solvate thereof, where dashed line stands for additional bond, а is a number from 0 to 2, b is a number from 0 to 2, n is 2, p is 2, r is 1, М1 stands for nitrogen, М2 stands for С(R3), X stands for either a bond or alkylene group with number of carbon atoms from 1 to 6, Y stands for -С(О)- group, Z stands for a bond, or alkylene group with number of carbon atoms from 1 to 6, or alkenylene group with number of carbon atoms from 1 to 6, or -С(O)-, -CH(CN)-, -SO2- or СН2С(O)NR4- group, R1 stands for groups, R2 stands for six-membered heteroaryl ring with one or two heteroatoms chosen independently of each other from either nitrogen atom or N-O group, other atoms of the cycle being carbon, five-membered heteroaryl ring with one, two, three or four heteroatoms chosen independently of each other from nitrogen, oxygen or sulphur, other atoms of the cycle being carbon, R32 stands for substituded quinoline group, R32 stands for substituted aryl group, heterocycloalkyl group, cycloalkyl group with number of carbon atoms from 3 to 6, alkyl group with number of carbon atoms from 1 to 6, group, where the said six-membered heteroaryl ring or the said five-membered heteroaryl ring may be R6-substituted, R12 independently of others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group or fluorine atom, provided in case R12 stands for hydroxyl or fluorine the rest of R12 cannot be bonded to a nitrogen-bonded carbon atom, or two R12 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjaicent carbon atoms of the ring, R13 independently of the others is chosen from an alkyl group with number of carbon atoms from 1 to 6, hydroxyl group, alcoxy group with number of carbon atoms from 1 to 6, or fluorine atom, provided in case R13 stands for hydroxyl or fluorine the rest of R13 cannot be bonded to a nitrogen-bonded carbon atom, or two R13 substituents form an alkyl bridge with number of carbon atoms from 1 to 2, which bonds two non-adjacent carbon atoms of the ring. See description for meaning of the other structural elements. Invention relates also to pharmaceutical compositions, as well as to application of compounds of formula I.

EFFECT: preparation of novel biologically active substances and pharmaceutical compositions.

20 cl, 659 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to derivatives of quinazoline of the general formula (I): and their pharmaceutically acceptable salts and in vivo hydrolyzed esters as aurorakinase inhibitors and their using, to a method for inhibition and pharmaceutical composition based on thereof, and to a method for their synthesis. In compound of the general formula (I) X represents -NR6 wherein R6 represents hydrogen atom or (C1-C6)-alkyl; R5 represents group of the formula (a): or (b): wherein * means a point for adding to group X in compound of the formula (I); R1, R2, R3 and R4 are chosen independently from hydrogen atom or -X1R9 wherein X1 represents -O-, and R9 is chosen from one of the following groups: (1) hydrogen atom or (C1-C5)-alkyl; (3) (C1-C5)-alkyl-X3R20 wherein X3 represents -O- or -NR25 wherein R25 represents hydrogen atom, (C1-C3)-alkyl or (C1-C3)-alkoxy-(C2-C3)-alkyl, and R20 represents hydrogen atom, (C1-C3)-alkyl, cyclopentyl, cyclohexyl or 5- or 6-membered saturated heterocyclic group with 1 or 2 heteroatoms that are chosen independently from nitrogen atom (N) wherein (C1-C3)-alkyl group can carry 1 or 2 substitutes that are chosen from oxo, hydroxy group, halogen atom and (C1-C4)-alkoxy group, and wherein cyclic group can carry 1 or 2 substitutes that are chosen from (C1-C4)-alkyl; (4) (C1-C5)-alkyl-X4-(C1-C5)-alkyl-X5R26 wherein X4 and X5 can be similar or different, and each means -O- or -NR31- wherein R31 represents hydrogen atom, (C1-C3)-alkyl or (C1-C3)-alkoxy-(C2-C3)-alkyl, and R26 represents hydrogen atom or (C1-C3)-alkyl; (5) R32 wherein R32 represents 5- or 6-membered saturated heterocyclic group added through carbon atom or nitrogen atom with 1 or 2 heteroatoms that are chosen independently from oxygen (O), sulfur (S) and N atoms wherein heterocyclic group can carry 1 or 2 substitutes that are chosen from hydroxy, (C1-C4)-alkyl, (C1-C4)-hydroxyalkyl, (C1-C4)-alkoxy, (C1-C4)-alkoxy-(C1-C4)-alkyl; (6) (C1-C5)-alkyl-R32 wherein R32 is given above; (18) (C1-C5)-alkyl optionally substituted with 1, 2 or 3 halogen atoms; (19) (C1-C5)-alkyl-X10-(C1-C5)-alkyl-X11R90 wherein X10 and X11 that can be similar or different each means -O- or -NR95- wherein R95 represents (C1-C5)-alkyl, (C1-C3)-alkyl substituted with 1, 2 or 3 halogen atoms, (C1-C4)-alkyl or (C1-C4)-alkoxy groups, (and wherein 2 (C1-C4)-alkoxy groups by (C1-C4)-alkyl groups alkoxy can form in common 5- or 6-membered saturated heterocyclic group that comprises 2 oxygen atoms), (C2-C5)-alkenyl, (C2-C5)-alkynyl, (C3-C6)-cycloalkyl, (C3-C6)-cycloalkyl-(C1-C3)-alkyl or (C1-C3)-alkoxy-(C2-C3)-alkyl; R90 represents hydrogen atom or (C1-C3)-alkyl; (22) (C1-C5)-alkyl-R96 wherein R96 represents 5- or 6-membered heterocyclic group that can be saturated or unsaturated (added through carbon or nitrogen atom) with 1 or 2 heteroatoms that are chosen independently from N wherein heterocyclic group can carry 1 or 2 substitutes that are chosen from (C1-C4)-hydroxyalkyl, (C1-C4)-alkyl, hydroxy and (C1-C4)-alkoxy-(C1-C4)-alkyl, and wherein R60 represents hydrogen atom; R61 represents group of the subformula (k): wherein p represents 0 or 1; q represents 1; R'1 and R''1 represent independently hydrogen atom or (C1-C10)-alkyl; T represents C=O; V represents -N(R63)R64 wherein R63 represents -(CH2)q'R70 or phenyl optionally substituted with 1 or 2 groups chosen independently from halogen atom, (C1-C4)-alkyl, (C1-C4)-alkoxy, trifluoromethyl, trifluoromethoxy, nitro, difluoromethyl, difluoromethoxy and cyano group; R64 represents hydrogen atom or (C1-C3)-alkyl; q' = 0; R70 represents -K-J wherein K represents a bond, and J represents phenyl optionally substituted with 1, 2 or 3 groups that are chosen from halogen atom, (C1-C3)-alkyl, cyano, (C1-C3)-alkoxy, and R62 represents hydrogen atom. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by aurorakinase activity, for example, proliferative diseases, such as cancer.

EFFECT: valuable medicinal properties of compounds.

32 cl, 7 tbl, 2 sch, 147 ex

FIELD: organic chemistry, chemical technology, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a method for synthesis of compound of the formula (I): or its pharmaceutically acceptable salt, ether, ester, amide, hydrate or solvate wherein each R1, R2 and R3 is chosen independently from group consisting of hydrogen atom (H), (C1-C6)-alkyl, (C3-C6)-cycloalkyl, halogen atom, cyano, -CF3, difluoromethoxy, trifluoromethoxy, -O-(C1-C6)-alkyl, -O-(C3-C6)-cycloalkyl and -NR12R13; wherein R4 represents -(CR5R6)mH or -(CR7R8)n (4-10-membered) aromatic or nonaromatic heterocycle comprising one or more heteroatoms each of them is chosen from oxygen (O), sulfurs (S) and nitrogen (N) atoms, and wherein m represents a whole number in the range from 1 to 5, and wherein n represents a whole number in the range from 0 to 5, wherein indicated 4-10-membered aromatic heterocycle is substituted possibly with 1-3 substitutes R9, and wherein indicated 4-10-membered nonaromatic heterocycle is substituted possibly with 1-3 substitutes R10 by any position and substituted possibly with 1-3 substitutes R11 by any position but not adjacent or directly bound to heteroatom; wherein Each R5, R6, R7 and R8 is chosen independently from group consisting of H and (C1-C6)-alkyl; wherein each R9 is chosen independently from H, (C1-C6)-alkyl, (C3-C6)-cycloalkyl, cyano, -CF3, difluoromethoxy, trifluoromethoxy, -O-(C1-C6)-alkyl, -O-(C3-C6)-cycloalkyl and -NR14R15; wherein each R10 is chosen independently from H, (C1-C6)-alkyl and (C3-C6)-cycloalkyl; wherein each R11 is chosen from halogen atom, cyano, -CF3, difluoromethoxy, trifluoromethoxy, -O-(C1-C6)-alkyl, -O-(C3-C6)-cycloalkyl and -NR16R17; wherein R12, R13, R14, R15, R16 and R17 are chosen independently from group consisting of H, (C1-C6)-alkyl and (C3-C6)-cycloalkyl wherein each abovementioned (C1-C6)-alkyl, (C3-C6)-cycloalkyl, -O-(C1-C6)-alkyl and -O-(C3-C6)-cycloalkyl substitutes wherein they present can be substituted independently with substitutes in the amount from 1 to 3 and chosen independently from group consisting of halogen atom, cyano, amino, (C1-C6)-alkylamino, [(C1-C6)-alkyl]-amino, perhalogen-(C1-C6)-alkyl, perhalogen-(C1-C6)-alkoxy, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, hydroxy and (C1-C6)-alkoxy. Method of synthesis involves interaction of compound of the formula (II): wherein BOC represents tert.-butoxycarbonyl, and R1, R2, R3 and R4 are given above for compound of the formula (I) with metal alkoxide in the presence of water to obtain compounds of the formula (I). Invention provides a novel method for synthesis of compounds of the formula (I) that are useful in treatment of cells anomalous growth, such as cancer, in mammals.

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

12 cl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to therapeutic agents showing effectiveness in treatment of pain, cancer, cerebrospinal sclerosis, Parkinson's disease, Huntington's chorea and/or Alzheimer's disease. Invention describes compound of the formula (I): or its pharmaceutically acceptable salts wherein RF1 and RF2 represent independently electron-acceptor groups; Z is chosen from O=; R1 is chosen from (C1-C10)-alkyl, heterocyclyl-(C1-C6)-alkyl, substituted heterocyclyl-(C1-C6)-alkyl; R2 is chosen from (C1-C6)-alkyl; X represents bivalent (C1-C10)-group that separates groups added to it by one or two atoms; Ar represents bivalent (C4-C12)-aromatic group, and Y is chosen from =CH=. Also, invention describes fields wherein compounds of the formula (I) are used, a pharmaceutical composition based on thereof, and methods for their synthesis. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy, chemical technology.

SUBSTANCE: invention relates to novel substituted esters of 1H-indol-3-carboxylic acids of the general formula (1): or their racemates, or their optical isomers, or their pharmaceutical acceptable salts and/or hydrates. Compounds can be used in treatment of such diseases as infectious hepatitis, human immunodeficiency, atypical pneumonia and avian influenza. In compound of the general formula (1) R1, R41 and R42 each represents independently of one another a substitute of amino group chosen from hydrogen atom, optionally linear or branched alkyl comprising 3-12 carbon atoms, optionally substituted cycloalkyl comprising 3-10 carbon atoms, optionally substituted aryl or optionally substituted and possibly an annelated heterocyclyl that can be aromatic or nonaromatic and comprising from 3 to 10 carbon atom in ring with one or some heteroatoms chosen from nitrogen oxygen or sulfur atoms; or R41 and R42 in common with nitrogen atom to which they are bound form 5-10-membered azaheterocycle or guanidyl through R41 and R42; R2 represents an alkyl substitute chosen from hydrogen atom, optionally substituted mercapto group, optionally substituted amino group, optionally substituted hydroxyl; R3 represents lower alkyl; R5 represents a substitute of cyclic system chosen from hydrogen atom, halogen atom, cyano group, optionally substituted aryl or optionally substituted and possibly an annelated heterocycle that can be aromatic or nonaromatic and comprising from 3 to 10 atoms in ring with one or some heteroatoms chosen from nitrogen, oxygen or sulfur atoms. Also, invention relates to methods for treatment, drugs and pharmaceutical compositions using compounds of this invention.

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

22 cl, 3 tbl, 8 dwg, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 3-hydrozy-2-pyridone represented by the formula (I): wherein R1 means aryl optionally substituted with one or more alkyl group; R2 means hydrogen atom; each R3 and R4 is taken independently of one another from hydrogen atom, alkyl, alkylheteroaryl and aralkyl group; or R3 and R4 in common with nitrogen atom bound with them form heteroaryl or heterocycloaryl substitute optionally substituted with one halogen atom, alkoxy group, aryl, heteroaryl and heterocycloalkyl; R5 and R6 mean hydrogen atom. Also, invention relates to using the compound by any claims among 1-7 for preparing pharmaceutical compositions showing antibacterial properties, and to above said pharmaceutical compositions. Invention provides synthesis of novel compounds possessing useful biological properties, and a pharmaceutical composition based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

9 cl, 8 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and/or stereomer form of compound of the formula (I), and/or physiologically compatible salt of compound of the formula (I) wherein X and M are similar or different and mean independently of one another nitrogen atom (N) or -CH; R1 and R11 are similar or different and mean independently of one another: (1.) hydrogen atom; (2.) fluorine (F), chlorine (Cl), iodine (J) or bromine (Br) atom; R2 means: (1.) heteroaryl residue of group comprising 1,3,4-oxadiazole, oxadiazolylidinedione, oxadiazolone, thiazole, and heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another: (1.1.) keto-group; (2) -C(O)-R5 wherein R5 means hydrogen atom or -(C1-C4)-alkyl, or (3.) -C(O)-N(R7)-R8 wherein R7 and R8 mean independently of one another hydrogen atom, -(C1-C4)-alkyl-OH, -O-(C1-C4)-alkyl or -(C1-C4)-alkyl; R3 means hydrogen atom or -(C1-C4)-alkyl; R4 means: (1.) heteroaryl residue of group comprising thiazole, isothiazole, pyridine, pyrazine, pyrimidine wherein heteroaryl residue is unsubstituted or 1-3-times substituted independently of one another with -(C1-C5)-alkyl, halogen atom, trifluoromethyl, or (2.) aryl residue of group comprising phenyl. Also, invention relates to a method for preparing a medicinal agent and to using compounds based on the formula (I) possessing activity with respect to IkB kinase. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical agent.

6 cl, 67 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

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