Method of producing dihydroquinazolines

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing dihydroquinazolines of formula (I), which are used to prepare medicinal agents. In formula

Ar denotes phenyl, possibly substituted with a C1-C4alkoxy group, R1 and R2 are selected from hydrogen, C1-C4alkoxy group and trifluoromethyl, R3 is selected from C1-C4 alkoxy group and trifluoromethyl, R4 denotes hydrogen or C1-C4alkyl, R5 denotes hydrogen or C1-C4alkyl, each of R6 R7 and R8 denotes hydrogen or halogen. The method involves hydrolysis of an ester of a compound of formula (II) in which Ar, R1, R2, R3, R4, R5, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, with a base or acid, where the compound of formula (II) obtained from reaction of a compound

of formula (III), is used, in which R1, R2, R3, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, in the presence of a base, with a compound of formula (IV) in which Ar, R4 and R5 are as described above. The method simplifies extraction of products.

EFFECT: invention also relates to novel intermediate compounds and a method of obtaining said compounds.

11 cl, 5 dwg, 24 ex

 

The present invention relates to a method of producing dihydroquinazolines, which are used for preparing medicines.

Compounds obtained by the method proposed in the present invention, suitable for use as antiviral agents, in particular to combat cytomegaloviruses, as described in WO 04/072048 and WO 04/096778.

Synthesis of dihydroquinazolines described in these documents, start with a 2-halogen-substituted aniline (A), which through a combination of the HEC in turn derived 2-aminoborane acid (In). By reaction with triphenylphosphine in carbon tetrachloride get phosphinite (C), which is then injected into the reaction with the isocyanate with the release of triphenylphosphine and getting carbodiimide (D). The reaction of the carbodiimide (D) with the amine formed dihydroquinazolines ether (E), which is separated into the enantiomers by chromatography on chiral phase. Then under standard conditions carry out the hydrolysis in dihydroquinazolines acid (F1). The synthesis is illustrated below, schemes 1 and 2.

Scheme 1:

Scheme 2

The above stages of the reaction when conducted in an industrial scale are associated with significant risk and by-product formation, as well as the stoichiometric quantities of the organic waste. When using fashinoned (C) and carbodiimide (D) during the formation of intermediate reaction products containing highly reactive functional groups, resulting in a significant amount of side products. These by-products can be separated only with a very tedious chromatographic purification or time-consuming process of extraction.

In addition, during the reaction of compounds of formula (C) with the formation of the compounds of formula (D) in stoichiometric quantities formed triphenylphosphine, chromatographic separation of the desired product is a time-consuming procedure. Chromatography is a particularly unsuitable for the synthesis of compounds on an industrial scale, because it requires a lot of time and is labor-intensive and use large quantities of solvents.

Separation of enantiomers of compounds of formula (E) is performed using time-consuming chromatography on chiral phase and at the same time as the waste is allocated unwanted R-enantiomer.

The present invention was based on the task of developing industrially applicable method of producing dihydroquinazolin formula (I), in particular, (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid, in which the address is s the disadvantages of the above stages of the prior art and which does not form undesirable waste - The R-enantiomer.

In the context of the present invention this problem is solved as described below. The following schemes 3 and 4 illustrate the separate stages of the reaction.

Scheme 3:

Scheme 4:

According to the invention it has been unexpectedly found that the compounds of formula (I) can be obtained by the method proposed in the present invention, i.e. by the reaction of 2-halogen-substituted aniline with isocyanate followed by reaction Hake with alkylacrylate, preferably methyl acrylate, and thus it is possible to avoid the formation of fashinoned and carbodiimide as reactive intermediates and the formation of stoichiometric amounts of triphenylphosphine respectively.

In addition, according to the invention it has been unexpectedly found that compounds of intermediate stages to form crystals and can be cleaned using crystallization without chromatography or extraction and thus it is possible industrial application of these stages of the method.

In addition, according to the invention it has been unexpectedly found that the structural unit of methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl} acetate can be efficiently synthesized using ortho palladiana. In this case, N-(2-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)is enyl]urea is injected into the reaction with methyl acrylate and oxidizing reagent in the presence of acid and get methyl-(2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}acrylate. Then slyvania cycle tetrahydroquinazoline carried out in an alkaline medium.

In addition, according to the invention it has been unexpectedly found that alkyl-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate, preferably methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate, can be divided into the enantiomers by crystallization with (28,38)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid.

In addition, according to the invention it has been unexpectedly found that the R-enantiomer alkyl-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate, preferably methyl {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate can be racemethionine in alkaline medium during the formation of acid after hydrolysis alkylboron or methyl ester and after re-esterification can be separated by crystallization with (2S,3S)-2,3-bis[(4-methylbenzoyl)-oxy]succinic acid and increases total output of the S-enantiomer.

When more detailed description of the proposed in the present invention is a method of obtaining the compounds of formula (I)

in which

AG denotes aryl, where aryl can contain from 1 is about 3 substituents and the substituents independently of one another selected from the group includes alkyl, alkoxygroup, formyl, carboxylate, alkylsulphonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy-group, amino group, alkylamino, aminocarbonyl and the nitro-group, where the alkyl may contain from 1 to 3 substituents, and the substituents independently of one another selected from the group comprising halogen, amino, alkylamino, the hydroxy-group and aryl, or two of the substituents of the aryl together with the carbon atoms to which they are linked, form a 1,3-dioxolane ring, a cyclopentane ring or cyclohexane ring, and optionally contained the third substituent independently selected from the specified group

R1denotes hydrogen, amino, alkyl, alkoxygroup, alkylamino, allylthiourea, cyano, halogen, the nitro-group or trifluoromethyl,

R2denotes hydrogen, alkyl, alkoxygroup, allylthiourea, cyano, halogen, the nitro-group or trifluoromethyl,

R3denotes an amino, alkyl, alkoxygroup, alkylamino, allylthiourea, cyano, halogen, the nitro-group, trifluoromethyl, alkylsulfonyl or alkylaminocarbonyl

or

one of the radicals R1, R2and R3denotes hydrogen, alkyl, alkoxygroup, cyano, halogen, the nitro-group or trifluoromethyl and the other two together with the carbon atoms to which they shall vasani, form a 1,3-dioxolane ring, a cyclopentane ring or cyclohexane ring,

R4denotes hydrogen or alkyl,

R5denotes hydrogen or alkyl

or

the radicals R4and R5in piperazinovom ring associated with facing each other with the carbon atoms form a methylene bridge, which is optionally substituted 1 or 2 metal bands,

R6denotes hydrogen, alkyl, alkoxygroup, allylthiourea, formyl, carboxylate, aminocarbonyl, alkylsulphonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy-group or a nitro-group,

R7denotes hydrogen, alkyl, alkoxygroup, allylthiourea, formyl, carboxylate, alkylsulphonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy-group or a nitro-group

and

R8denotes hydrogen, alkyl, alkoxygroup, allylthiourea, formyl, carboxylate, alkylsulphonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxy-group or a nitro-group,

includes hydrolysis of ester compounds of the formula (II)

in which

AG, R1, R2, R3, R4, R5, R6, R7and R8have the above meanings, and

R9stands With1-C4-alkyl,

using osnovaniya acid.

The compound of formula (II) can be obtained by the reaction of compounds of formula (III)

in which

R1, R2, R3, R6, R7and R8have the above meanings, and

R9stands With1-C4-alkyl,

in the presence of base

with the compound of the formula (IV)

in which

AG, R4and R5have the above values.

The compound of formula (III) can be obtained by the reaction of compounds of formula (V)

,

in which

R1, R2, R3, R6, R7and R8have the above meanings, and

R9stands With1-C4-alkyl,

with phosphorus oxychloride, trichloride phosphorus or pentachloride phosphorus in the presence of a base.

The compound of formula (V) can be obtained by the reaction of compounds of formula (VI)

in which

R1, R2, R3, R6, R7and R8have the above meanings, with a compound of the formula

in which

R9stands With1-C4-alkyl,

in the presence of a palladium catalyst and base.

Compounds of formula (IV), (VI) and (IX) are known to the specialist in the art or can be obtained on icnam techniques known from the literature.

In an alternative method, the compound of formula (V) can be obtained by the reaction of compounds of formula (VII)

in which

R1, R2, R3, R6, R7and R8have the above values,

in the first stage with a compound of formula (IX) in acetic acid in the presence of a palladium catalyst, an oxidizing reagent and acid to obtain the compounds of formula (VIII)

in which

R1, R2, R3, R6, R7and R8have the above meanings, and

R9stands With1-C4-alkyl,

and in the second stage with the basis of obtaining the compounds of formula (V).

The compounds of formula (VII) are known to the specialist in the art or can be obtained by conventional methods known from the literature.

In a preferred embodiment of the present invention in the method of synthesis of the radical R9in the compounds of formula (II), (III), (V), (VIII) and (IX) denotes methyl.

In addition, the present invention relates to compounds of the formula (III)

in which

R1, R2, R3, R6, R7and R8have the above meanings, and

R9stands With1-C4-alkyl.

Connection is ormula (III) in which R 9denotes methyl, are preferred.

In addition, the present invention relates to compounds of the formula (V)

in which

R1, R2, R3, R6, R7and R8have the above meanings, and

R9stands With1-C4-alkyl.

The compounds of formula (V)in which R9denotes methyl, are preferred.

In a particularly preferred embodiment of the present invention the compound of formula (I) represents the following connection:

{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid

In a particularly preferred embodiment of the present invention the compound of formula (II) represents the following connection:

methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate

In a particularly preferred embodiment of the present invention the compound of formula (III) is the following connection:

methyl 2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}-acetate

In a particularly preferred variant of the OS the implement of the present invention the compound of formula (IV) is the following connection:

1-(3-methoxyphenyl)piperazine

In a particularly preferred embodiment of the present invention the compound of formula (V) represents the following connection:

methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate

In a particularly preferred embodiment of the present invention the compound of formula (VI) represents the following connection:

N-(2-bromo-6-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea

In a particularly preferred embodiment of the present invention the compound of formula (VII) represents the following connection:

N-(2-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea

In a particularly preferred embodiment of the present invention the compound of formula (VIII) represents the following connection:

methyl-(2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}acrylate

In a particularly preferred embodiment of the present invention the compound of formula (IX) represents the following connection:

MMA

Hydrolysis of ester with the unity of formula (II) with the formation of the compounds of formula (I) is conducted by the reaction of compounds of formula (II) with a base in an inert solvent, in the temperature range from 18 up to the boiling point of the solvent, preferably from 18 to 50°C., particularly preferably from 20 to 30°C, at atmospheric pressure within, for example, from 0.5 to 10 hours, preferably for 1 to 5 hours

Bases are, for example, hydroxides of alkali metals such as sodium hydroxide, lithium hydroxide or potassium hydroxide, or carbonates of alkali metals such as cesium carbonate, sodium carbonate or potassium carbonate, or alkoxides such as sodium methoxide or potassium methoxide or ethoxide sodium or atoxic potassium, and the basis is not necessarily contained in the aqueous solution.

Inert solvents are, for example, ethers, such as 1,2-dimethoxyethane, dioxane, tetrahydrofuran, dimethyl ether glycol or dimethyl ether of diethylene glycol, alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol or tert-butanol, or water, or mixture of solvents.

Sodium hydroxide in water and dioxane is preferred.

Hydrolysis of ester compounds of the formula (II) in the compound of formula (I) is conducted by the reaction of compounds of formula (II) with an acid in a solvent in the presence of water, in the temperature range from 18°C to the boiling point of the solvent, preferably from 18 to 50°C., particularly preferably from 20 to 30°C, at atmospheric pressure for for example, from 0.5 to 48 hours, preferably for from 5 to 24 hours

Acids in the solvent are, for example, hydrochloric acid, sulfuric acid or phosphoric acid in dioxane or tetrahydrofuran.

Hydrochloric acid in dioxane is preferred.

The synthesis of compounds of formula (II) from compounds of formula (III) and compounds of formula (IV) in the presence of base is carried out in an inert solvent, in the temperature range from 40°C to the boiling point of the solvent, preferably at the boiling temperature of the solvent at atmospheric pressure, within, for example, from 5 to 48 hours, preferably for from 10 to 24 hours

Bases are, for example, amides such as sodium amide, bis(trimethylsilyl)amide lithium or diisopropylamide lithium, or amines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1-(3-methoxyphenyl)piperazine or triethylamine, or other bases such as tert-piperonyl potassium or sodium hydride.

Inert solvents are, for example, chlorobenzene, or ethers, such as 1,2-dimethoxyethane, dioxane, dimethyl ether glycol or dimethyl ether of diethylene glycol.

DBU in dioxane is preferred.

The reaction of the compound of formula (V) with a compound of the formula (III) is conducted by the reaction of compounds of formula (V) with phosphorus oxychloride, trichloro the om phosphorus or pentachloride phosphorus, the reaction with phosphorus oxychloride is preferred, in the presence of a base in an inert solvent, in the temperature range from 40°C to the boiling point of the solvent, preferably at the boiling temperature of the solvent at atmospheric pressure, within, for example, from 5 to 48 hours, preferably for from 10 to 24 hours

Bases are, for example, amines, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine or triethylamine, or amides such as sodium amide, bis(trimethylsilyl)amide lithium or diisopropylamide lithium, or other bases such as tert-piperonyl potassium.

Inert solvents are, for example, hydrocarbons, such as benzene, xylene, toluene or chlorobenzene.

DBU in chlorobenzene is preferred.

The reaction of the compound of formula (VI) with a compound of the formula (V) is conducted by the reaction of compounds of formula (VI) with the compound of the formula (IX) in the presence of a palladium catalyst and a base in an inert solvent, in the temperature range from 40°C to the boiling point of the solvent, preferably at the boiling temperature of the solvent at atmospheric pressure, within, for example, from 5 to 48 hours, preferably for from 10 to 24 hours

Palladievye catalysts are, for example, bis(triphenylphosphine)palladium(II)chloride, tetrakis(triphenyltin is n)palladium(0), bis(Tris(o-tolyl)phosphine)palladium(II)chloride or palladium catalyst derived from bis(acetonitrile)dichloropalladium or palladium acetate(II) and a ligand, for example, Tris(o-tolyl)phosphine, triphenylphosphine or diphenylphosphinite.

Bases are, for example, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, or diisopropylethylamine.

Inert solvents are, for example, ethers, such as 1,2-dimethoxyethane, dioxane, dimethyl ether glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, xylene or toluene, or other solvents, such as isobutyronitrile, acetonitrile, nitrobenzene, dimethylformamide, dimethylacetamide, dimethylsulfoxide or N-organic.

Palladium catalysts derived from bis(acetonitrile)dichloropalladium and Tris(o-tolyl)phosphine and triethylamine in isobutyronitrile are preferred.

The reaction of the compound of formula (VII) with a compound of formula (VIII) is conducted by the reaction of compounds of formula (VII) with the compound of the formula (IX) in acetic acid in the presence of a palladium catalyst, an oxidizing reagent and acid, in a temperature range from 0 to 50°C, preferably at room temperature, at atmospheric pressure, within, for example, from 5 to 48 hours, preferably for from 10 to 24 hours

Palladievye katal the traffic jams are, for example, a palladium salt such as palladium chloride(II)acetylacetonate, palladium(II)acetate, palladium(II) or tetrachloropalladate sodium palladium(II) acetate is preferred.

Oxidizing agents are, for example, p-benzoquinone or peroxides, such as hydrogen peroxide, tert-butylhydroperoxide or perborate sodium, or a complex of sulfur trioxide with pyridine, manganese dioxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), peroxodisulfate sodium or oleum (fuming sulfuric acid); p-benzoquinone, peroxodisulfate sodium or oleum (fuming sulfuric acid) is preferred and oleum is especially preferred.

Acids are, for example, methanesulfonate acid, triftormetilfullerenov acid or substituted benzosulfimide acid, such as, for example, 4-methylbenzenesulfonic acid, 4-chlorobenzenesulfonic acid or 4-nitrobenzenesulfonate acid or concentrated sulphuric acid to form oleum; triftormetilfullerenov acid or sulfuric acid in the form of oleum are preferred, oleum is especially preferred.

The reaction of the compound of formula (VIII) with a compound of the formula (V) is conducted by the reaction of compounds of formula (VIII) with a base in an inert solvent, in the temperature range from 40°C to the boiling point of RA is the solvent, preferably at the boiling temperature of the solvent at atmospheric pressure, within, for example, from 1 to 48 hours, preferably for from 2 to 14 hours

Bases are, for example, carbonates of alkali metals such as cesium carbonate, sodium carbonate or potassium carbonate, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), triethylamine, or diisopropylethylamine; potassium carbonate or DBU is preferred.

Inert solvents are, for example, ethers, such as 1,2-dimethoxyethane, dioxane, dimethyl ether glycol or dimethyl ether of diethylene glycol, or a hydrocarbon, such as benzene, xylene or toluene, or ketones, such as acetone or methyl isobutyl ketone (MIBK), or other solvents, such as isobutyronitrile, acetonitrile, chlorobenzene, nitrobenzene, dimethylformamide, dimethylacetamide, dimethylsulfoxide, N is an organic or tetrahydrothiophene-1,1-dioxide (sulfolane); acetone is preferred.

In addition, the present invention relates to a method for separation of enantiomers (C1-C4)-alkyl-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate and allocation (C1-C4)-alkyl-(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate, characterized in that the rat is practical ester crystallized with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid. Crystallization was carried out in the temperature range from 0 to 25°C in ethyl acetate. Sol S-enantiomer precipitates out of solution first.

Method of separating enantiomers of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate and excretion of methyl-(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate, characterized in that the racemic ester is crystallized with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid is preferred. Crystallization was carried out in the temperature range from 0 to 25°C in ethyl acetate. Sol S-enantiomer precipitates out of solution first.

In addition, the present invention relates to salts (C1-C4)-alkyl-(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid.

In addition, the present invention relates to salts of methyl-(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (2S,3S)-2,3 bis[(4-methylbenzoyl)oxy]succinic acid.

In addition, the present invention relates to a method of racemization (C1-C4)-alkyl-(R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydrobenzo the Jn-4-yl} acetate, characterized in that

in the first stage alkilany ester hydrolyzing the acid,

in the second stage acid racemized using sodium methoxide or ethoxide sodium and in the third stage, the acid is re-converted into alkilany ester.

The way racemization methyl-(R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate, characterized in that

in the first stage of the methyl ester hydrolyzing the acid in the second stage acid racemized using sodium methoxide or ethoxide sodium and

in the third stage, the acid is re-converted into the methyl ester is preferred.

Hydrolysis in the first stage using acid or base is conducted under the same reaction conditions as in the hydrolysis of ester compounds of the formula (II), to obtain the compounds of formula (I).

Racemization in the second stage is carried out by heating the acid with sodium methoxide or ethoxide sodium, and preferably using at least 2 equivalents of base and sodium methoxide or ethoxide sodium optional use in ethanol solution in the solvent by boiling under reflux at atmospheric pressure, within, for example, from 36 to 72 h, preferably for 50 to 70 hours

Solvents JW is Auda, for example, ethers, such as 1,2-dimethoxyethane, dioxane, dimethyl ether glycol or dimethyl ether of diethylene glycol, hydrocarbons such as benzene, xylene or toluene, or other solvents, such as isobutyronitrile, acetonitrile or dimethyl sulfoxide; acetonitrile is preferred.

The esterification in the third stage is carried out, for example, by the reaction of the acid with sulfuric acid in methanol or another alcohol by boiling under reflux at atmospheric pressure, within, for example, from 12 to 48 h, preferably for 20 to 30 p.m.

In addition, the present invention relates to a method of racemization (1-C4)-alkyl-(R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate, characterized in that

alkilany ester is introduced into reaction with a base in an inert solvent.

The way racemization methyl-(R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5 -(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate, characterized in that

methyl ester is introduced into reaction with a base in an inert solvent is preferred.

The reaction is carried out in the temperature range from 40°C to the boiling point of the solvent, preferably at the boiling temperature of the solvent at atmospheric Yes the tion, during, for example, from 5 to 48 hours, preferably within 12 to 24 hours

Bases are, for example, organic bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or tetramethylguanidine; DBU is preferred.

Inert solvents are, for example, hydrocarbons, such as benzene, xylene or toluene, or other solvents, such as isobutyronitrile; isobutyronitrile is preferred.

Compounds described in the context of the method proposed in the present invention can also be in the form of their salts, solvate or solvate of salt.

Compounds described in the context of the method proposed in the present invention, depending on its structure may be present in stereoisomeric forms (enantiomers, diastereoisomers). Therefore, the method proposed in the present invention, also includes obtaining and applying enantiomers or diastereoisomers and appropriate mixtures thereof. Stereoisomers homogeneous components can be isolated from such mixtures of enantiomers and/or diastereoisomers according to the methods known to the expert of the art.

Compounds described in the context of the method proposed in the present invention, depending on its structure can also be in the form of their tautomers.

Salts, pre is deferential in the context of the present invention, are physiologically acceptable salts of used compounds obtained by the method proposed in the present invention.

Physiologically acceptable salts of the compounds used in the method proposed in the present invention, and obtained by this method include the salts of the accession of inorganic acids, carboxylic acids and sulphonic acids, e.g. salts of hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, econsultancy acid, toluensulfonate acid, benzosulfimide acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid and benzoic acid. Physiologically acceptable salts of the compounds used in the method proposed in the present invention, and obtained by this method, also include salts of conventional bases such as, for example and preferably, alkali metal salts (e.g. sodium and potassium salts), salts of alkaline earth metals (e.g. calcium salts and magnesium), and ammonium salts, derived from ammonia or organic amines containing from 1 to 16 C atoms, such as, for example and preferably, ethylamine, diethylamine, triethylamine, ethyldiethanolamine, monoethanol the min, diethanolamine, triethanolamine, dichlorohexane, dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine, dehydroabietylamine, arginine, lysine, Ethylenediamine, methylpiperidin.

The solvate in the context of the present invention means those forms of the compounds used in the method proposed in the present invention, and obtained by this method, which is in solid or liquid state, form a complex by coordination with solvent molecules. Hydrates are a special form of a solvate, in which coordination takes place with water.

In the context of the present invention "racemic" means that the compounds are not contained in enantiomerically pure form, i.e. compounds are present as mixtures of (S)- and (R)-enantiomers. Therefore, the ratio of the number (S)-enantiomer to the amount of (R)-enantiomer is not permanent. A mixture of (S)-enantiomer to (R)-enantiomers in a ratio of 1:1 is preferred.

In the context of the present invention, unless otherwise specified, the substituents have the following values.

Alkyl by itself and "alkyl" in alkoxygroup, alkylamino, allylthiourea, alkylcarboxylic, alkylsulfonyl, alkoxycarbonyl and alkylaminocarbonyl means a linear or branched alkyl radical, typically containing from 1 to 6 ("C1-C6-alkyl"), preferably from 1 to 4, more p is edocfile - from 1 to 3 carbon atoms, for example and preferably methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.

Alkoxygroup for example and preferably means a methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, tert-butoxypropyl, n-phenoxypropan or n-hexachrome.

Alkylamino means alkylamino radical containing 1 or 2 alkyl substituent (chosen independently from each other), for example and preferably methylaminopropyl, ethylamino, n-propylamino, isopropylamino, tert-butylamino, n-pentylamine, n-hexylamine, N,N-dimethylaminopropyl, N,N-diethylaminopropyl, N-ethyl-N-methylaminopropyl, "N-methyl-N-n-propylamino, N-isopropyl-N-n-propylamino, N-tert-butyl-N-methylaminopropyl, N,N-ethyl-N-n-pentylamine or N-n-hexyl-N-methylaminopropyl. C1-C3-Alkylamino means, for example, monoalkylamines radical containing from 1 to 3 carbon atoms, or dialkylamino radical containing from 1 to 3 carbon atoms in the alkyl substituent.

Allylthiourea, for example and preferably, means metalcorp, ethylthiourea, n-PropertyGroup, isopropylthio, tert-butylthiourea, n-intelligroup or n-vexillographer.

Alkylsulphonyl, for example and preferably, means ethylcarboxyl, ethylcarbazole, n-propylboronic, isopropylcarbonate, tert-butylcarbamoyl, n-internabonal or n-hexylcaine.

Alkylsulfonyl, for example and preferably, means methylsulphonyl, ethylsulfonyl, n-propylsulfonyl, isopropylphenyl, tert-butylsulfonyl, n-peterculter or n-hexylsilane.

Alkoxycarbonyl, for example and preferably, means methoxycarbonyl, etoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl, n-phenoxycarbonyl or n-hexoxyethanol.

Alkylaminocarbonyl means alkylaminocarbonyl radical containing 1 or 2 alkyl substituent (chosen independently from each other), for example and preferably methylaminomethyl, ethylaminomethyl, n-propylaminosulfonyl, isopropylaminocarbonyl, tert-butylaminoethyl, n-intramyocellular, n-exelonexelon, N,N-dimethylaminomethyl, N,N-diethylaminomethyl, N-ethyl-N-methylaminomethyl, N-methyl-N-n-propylaminosulfonyl, N-isopropyl-N-n-propylaminosulfonyl, N-tert-butyl-N-methylaminomethyl, N-ethyl-N-n-intramyocellular or N-n-hexyl-N-methylaminoethanol. With1-C3-Alkylaminocarbonyl, for example, means monoalkylbenzenes containing from 1 to 3 carbon atoms, or dialkylaminoalkyl radical containing from 1 to 3 carbon atoms in alkylene the Deputy.

Aryl means a mono - or bicyclic aromatic carbocyclic radical, typically containing from 6 to 10 carbon atoms; for example and preferably phenyl or naphthyl.

Halogen means fluorine, chlorine, bromine or iodine,

The present invention is described below with the help of a non-limiting preferred examples and comparative examples. Unless otherwise noted, all quantitative values are given in mass percent.

Typical embodiments of the

List of abbreviations:

Atsn acetonitrile

IAD-ER-floorelectrospray ionization at atmospheric pressure in the positive ion mode (in MS)

IAD-ER-neg. electrospray ionization at atmospheric pressure, in the negative ion mode (in MS)

HEE, NH3chemical ionization (using ammonia)

DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

DMAP 4-(dimethylamino)pyridine

DMSO dimethyl sulfoxide

Assembly external standardization

h hour(s)

HPLC high performance liquid chromatography

MIBK methylisobutylketone

min minutes

MS mass spectroscopy

NMR spectroscopy nuclear magnetic resonance

RTretention time (in HPLC)

General HPLC methods:

Method 1 (HPLC): Instrument:HP 1050 with detection at multiple wavelengths; column: Phenomenex-Prodigy ODS (3) 100A, 150 mm×3 mm, 3 μm; eluent A: (1.0 g KN2RHO4+1,0 ml of N3RHO4) / l of water, eluent b: acetonitrile; gradient mode: 0 min 10% B, 25 min 80% B, 35 min 80% B; flow rate: 0.5 ml/min; temperature: 45°C.; UV detection: 210 nm.

Method 2 (HPLC): Instrument: HP 1050 with detection at multiple wavelengths; column: chiral AD-H, 250 mm×4.6 mm, 5 μm; eluent A: n-heptane+0.2% diethylamine, eluent b: isopropanol+0.2% diethylamine; gradient mode: 0 min 12.5% In 30 min (12.5%; flow rate: 1 ml/min; temperature: 25°C; UV detection: 250 nm.

For the S-enantiomer shows positive values of EI, (enantiomeric excess), for the R-enantiomer shows negative values of EI.

Method 3 (HPLC): Instrument: HP 1050 with detection at multiple wavelengths; column: chiral AD-H, 250 mm×4.6 mm, 5 μm; eluent A: n-heptane + 0.2% diethylamine, eluent b: isopropanol + 0.2% diethylamine; gradient mode: 0 min 25% B, 15 min, 25% B; flow rate: 1 ml/min; temperature: 30°C.; UV detection: 250 nm.

For the S-enantiomer shows positive values of EI, for the R-enantiomer shows negative values of EI.

Method 4 (HPLC): Instrument: HP 1100 with detection at multiple wavelengths; column: Phenomenex-Prodigy C8, 150 mm×3 mm, 5 μm; eluent A: (1,36 g KN2RHO4+1,15 g of 85% H2RHO4)/l of water, eluent b: acetonitrile; gradient the tunes: 0 min 10% B, 20 min 80% B, 30 min 80% B; flow rate: 0.5 ml/min; temperature: 40°C.; UV detection: 210 nm.

The above outputs are not adjusted for the content.

Figure 5:

Synthesis of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid

Example 1

N-(2-Bromo-6-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea

2-Methoxy-5-triftormetilfullerenov (274,3 g) dissolved in acetonitrile (1 l), then added 2-bromo-6-ftoranila (200 g) and washed with acetonitrile (50 ml). The obtained clear solution is stirred at the boil under reflux (about 85°C) for 38 h, then concentrated in vacuo at 40°C and receive a viscous suspension. The solid is collected by filtration with suction, washed with acetonitrile (260 ml) cooled to 0-5°C) and dried overnight at 45°C in a vacuum drying Cabinet with supply of nitrogen. So just get 424,3 g of N-(2-bromo-6-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea as solid substances, which corresponds to 99.2% of theoretical yield.

1H NMR (300 MHz, d6-DMSO): δ = 8,93 (s, 1H), 8,84 (s, 1H), charged 8.52 (d,3J=2,3, 2H), 7,55 (d2J=7,7, 1H), 7,38-7,26 (m, 3H), 7,22 (d2J=8,5, 1H), 4.00 points (s, 3H) ppm million;

MS (IAD-ER-floor.): m/z=409 [(M+N)+, 100%];

HPLC (methods is 1): R T=22,4 and 30.6 minutes

Example 2

N-(2-Bromo-6-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea (alternative synthesis)

2-Methoxy-5-triftormetilfullerenov (1.19 kg) melted at about 35°C and dissolved in acetonitrile (4.2 l), then added 2-bromo-6-ftoranila (870 g) and washed with acetonitrile (380 ml). The obtained clear solution was stirred at 74-88°C for 45 h, then concentrated in vacuo (200 mbar) at 50°C and receive viscous suspension (the number of distillate is 4.4 l). It is diluted at room temperature diisopropyl ether (1.5 l), the solid is collected by filtration with suction, washed with diisopropyl ether (1,15 l) and dried to constant weight (24 h) at 45°C in a vacuum drying Cabinet with supply of nitrogen. Thus receive only 1.63 kg of N-(2-bromo-6-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea as solid substances, which corresponds to 87.5% of theoretical yield.

HPLC (method 1): RT=22,6 and 30.8 minutes

Example 3

Methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl} acetate

N-(2-Bromo-6-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea (300 g) is suspended in isobutyronitrile (1.2 l) under nitrogen atmosphere, then in the order added triethylamine (210 ml), bis(acetonitrile)dichloropalladium (7.5 g), Tris-(the-tolyl)phosphine (18.0 g) and methyl acrylate (210 ml). The resulting suspension is stirred while boiling under reflux (about 102°C) for 16 h and then cooled to room temperature. Add water (1.2 l) and the mixture is stirred at room temperature for 1 h, then the solid is collected by filtration with suction and washed with a mixture of water/methanol (1:1, 300 ml) and acetonitrile (100 ml). The residue is dried overnight at 45°C in a vacuum drying Cabinet with supply of nitrogen. So just get 208 g of methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl} acetate in the form of solids, which corresponds to 68.5% of theoretical yield.

1H NMR (300 MHz, d6-DMSO): δ=9,73 (s, 1H), 7,72 (d2J=7,3, 1H), 7,71 (s, 1H), 7,33 (d2J=9,3, 1H), 7,15 (dd,2J=9,6,2;=8,6, 1H), 7,01 (d2J=7,3, 1H), 6,99-6,94 (m, 1H), 5,16 (t2;=5,9, 1H), 3,84 (s, 3H), 3,41 (s, 3H), of 2.81 (dd,2J=15,4,2]=5,8, 1H), 2,62 (dd,2J - 15,4,2J=6,3, 1H) ppm million;

MC (IAD-ER-floor.): m/z=413 [(M+N)+, 100%], 825 [(2M+N)+14%];

HPLC (method 1): RT=19,3 min; Pd (ICP): 16000 ppm million

Example 4

Methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl} acetate (alternative synthesis)

N-(2-Bromo-6-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea (2.5 kg) suspended in isobutyronitrile (9 l) under nitrogen atmosphere, then in the order added triethyl is min (1,31 kg), bis(acetonitrile)dichloropalladium (64,9 g), Tris(o-tolyl)phosphine (149 g) and methyl acrylate (1,59 kg). The resulting suspension was stirred at 90-100°C for 22 h, then cooled to room temperature. Add water (9 l) and the mixture is stirred at room temperature for 1 h, then the solid is collected by filtration with suction and washed with a mixture of water/methanol (1:1, 2.5 l) and acetonitrile (850 ml). The residue is dried overnight at 45°C in a vacuum drying Cabinet to constant weight (21 h) with supply of nitrogen. So just get 1,90 kg of methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate in the form of solids, which corresponds to a rate of 74.9% of theoretical yield.

HPLC (method 1): RT=19,4 minutes

Example 5

Methyl-{2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate/chlorination

The solution 2,84 kg of methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate in 14.8 liters of chlorobenzene is refluxed and the solvent is distilled until the termination of water. The mixture is cooled to 120°C. for 10 minutes add 3,17 kg of phosphorus oxychloride, and then for another 10 minutes add 2,10 kg DBU. The mixture is refluxed for 9 hours

For treatment the mixture is Hledat to 40°C, is stirred overnight and the contents of the vessel are added to 11.4 l of water, the temperature of which is pre-set to 40°C. During the addition the need to maintain the internal temperature of equal to 40-45°C. the Mixture is allowed to cool to room temperature, add 11.4 l of dichloromethane, the mixture is filtered through filter Cup Seitz and the phases are separated. The organic phase is washed with 11.4 l of water, 11.4 l of a saturated aqueous solution of sodium bicarbonate and again with the help of 11.4 liters of water. The organic phase is concentrated in vacuo in a rotary evaporator and the resulting residue (2.90 kg) used in the next stage without additional processing.

1H NMR (300 MHz, d6-DMSO): δ=7,93-of 7.82 (m, 2H), 7,38 (d,2J=8,9, 1H), 7,17 (m, 2H), 6,97-6,91 (m, 1H), 5,45 and of 5.29 (m and t2J=5,4, 1H), 3,91 and of 3.84 (2s, 3H), of 3.48 (s, 3H), of 3.0 to 2.6 (m, 2H) ppm million;

MS (HI, NH3): m/z=431 [(M+N)+, 100%];

HPLC (method 1): RT=23,5 min; typical value for Pd (ICP): 170 ppm million

Example 6

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate/amination

Methyl-{2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (52,5 g) is dissolved in 1,4-dioxane (100 ml), then at room temperature was added 3-methoxyphenylpiperazine (25,8 g) and DBU (20.4 g)and the temperature rises. The mixture is stirred at the boil under reflux for 22 h, then cooled to room temperature, diluted with ethyl acetate (500 ml) and water (200 ml) and the phases are separated. The organic phase is washed with 0,2 N. hydrochloric acid (three times 100 ml) and water (200 ml), dried over sodium sulfate and concentrated in a rotary evaporator. So get all of 62.5 g of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetates the form of a solid foam material, which is introduced into the reaction in the form of the crude product without further purification. HPLC (method 1): RT=16,6 min

Example 7

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate/ignoreaction chlorination+amination

Methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl} acetate (50.0 g) was dissolved in chlorobenzene (300 ml), then the chlorobenzene was partially evaporated (50 ml). The mixture is cooled to 120°C, was added DBU (36,9 g), then when 120-128°C for 10 min was added phosphorus oxychloride (33,4 ml). The mixture is stirred while boiling under reflux (about 130°C) for 9 hours and Then the mixture is cooled to 40°C, slowly at 40-45°C. add water (200 ml), the mixture is cooled to room temperature and Rabba is given in dichloromethane (200 ml), extracted under stirring and then the phases are separated. The organic phase is washed with water (200 ml), saturated aqueous sodium hydrogen carbonate (200 ml) and again water (200 ml), dried over sodium sulfate, concentrated in a rotary evaporator and then dried at 50°C in high vacuum. The remainder of 48.1 g) dissolved in chlorobenzene (20 ml), then the solution was diluted with 1,4-dioxane (80 ml) and at room temperature was added 3-methoxyphenylpiperazine (23,6 g) and DBU (18.7 g) and the temperature rises. The mixture is stirred at the boil under reflux for 22 h, then cooled to room temperature, diluted with ethyl acetate (500 ml) and water (200 ml) and the phases are separated. The organic phase is washed with 0,2 N. hydrochloric acid (three times 100 ml) and water (200 ml), dried over sodium sulfate and concentrated in a rotary evaporator. So get all of 55.6 g of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetates the form of a solid foam material, which is introduced into the reaction in the form of the crude product without further purification.

HPLC (method 1): RT=16,2 minutes

Example 8

(±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl} acetic acid hydrolysis of the racemate

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (64 g) was dissolved in 1,4-dioxane (450 ml) and 1 N. solution of sodium hydroxide (325 ml) and stirred at room temperature for 2 h, then part of the solvent (400 ml) is distilled off at 30°C in vacuum. Then add toluene (300 ml) and the phases are separated. The aqueous phase is washed with toluene (twice 150 ml)then the combined organic phases are re-extracted with 1 N. a solution of sodium hydroxide (50 ml). The pH of the combined aqueous phase was adjusted to 7.5 with 2 N. hydrochloric acid (150 ml), then added MILK (150 ml). The phases are separated, the aqueous phase is re-extracted with MIBK (150 ml), then the combined phase in MIBK dried over sodium sulfate and concentrated at 45°C. Thus receive a total of 64 g of (±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid in quantitative yield as an amorphous solid.

HPLC (method 1): RT=14,9 minutes

Scheme 6:

Separation of enantiomers of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate

Example 9

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)Fe is Il]-3,4-dihydroquinazolin-4-yl} acetate (28,38)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1)/crystallization

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (62.5 g, crude product) are dissolved in ethyl acetate (495 ml) and filtered. To the filtrate add (28,38)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (42,0 g), the mixture is stirred at room temperature for 30 min, then make a seed crystal of methyl {8-fluoro-2- [4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (28,38)-2,3-bis[(4-methylbenzoyl)oxy]-amber acid (salt composition 1:1) (165 mg) and stirred at room temperature for 3 days, then cooled to 0-3°C and stirred for another 3 hours, the Suspension is collected by filtration with suction and washed with cold ethyl acetate (0-10°C, 35 ml). The crystals are dried at 40°C for 18 h in a vacuum drying Cabinet with supply of nitrogen. So get all of 37.1 g of salt in the form of solids, which corresponds to a 30.4% of theoretical yield for the three stages (chlorination, amination and crystallization) in terms of the racemate or of 60.8% in terms of the obtained S-enantiomer.

1H NMR (300 MHz, d6-DMSO): δ=of 7.90 (d,2J=7,8, 4H), 7,56 (d2J=8,3, 1H), 7,40 (d2J=7,8, 4H), 7,28-7,05 (m, 4H), 6,91-6,86 (m, 2H). 6,45 (d2J=8,3, 1H), 6,39-6,36 (m, 2H), of 5.82 (s, 2H), 4,94 (m, 1H), 4,03 (q2J=7,1, 2H), 3,83 (brs, 3H), of 3.69 (s, 3H), of 3.64 (s, 3H), 3,47-to 3.36 (m, 8H and the ode, 2H), 2,98-of 2.81 (m, 5H), 2,58-2,52 (m, 1H), 2,41 (s, 6H), of 1.99 (s, 3H), of 1.18 (t,2J=7,2, 3H) ppm million;

HPLC (method 1): RT=16,6 and 18.5 minutes

Example 10

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (28,38)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1)/recrystallization

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (28,38)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) cases (36.8 g) is suspended in ethyl acetate (370 ml) and dissolved by boiling under reflux (77°C.). The mixture is slowly cooled down to room temperature. At this time there is spontaneous crystallization. The suspension is stirred at room temperature for 16 h, then cooled to 0-5°C and stirred for another 3 hours, the Suspension is collected by filtration with suction and washed with cold ethyl acetate (0-10°C, two times 15 ml). The crystals are dried at 45°C for 18 h in a vacuum drying Cabinet with supply of nitrogen. So get all of 33.6 g of salt in the form of solids, which corresponds to 91.3 percent of theoretical yield. HPLC (method 1): RT=16,9 and 18.8 min;

HPLC (method 3): 99.9% of EI.

Example 11

(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}UKS is SNA acid

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (28,38)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) (10.1 g, containing 14 ppm million Pd) is suspended in ethyl acetate (100 ml) and shaken with saturated aqueous sodium bicarbonate (100 ml)until both phases is clear. The phases are separated and the organic phase was concentrated in a rotary evaporator. The residue is dissolved in 1,4-dioxane (100 ml) and 1 N. the solution of sodium hydroxide (31,2 ml) and stirred at room temperature for 3 hours and Then the pH value was adjusted to 7.5 with 1 N. hydrochloric acid (about 17 ml), add MILK (80 ml) and then the pH re-adjusted to 7.0 with 1 N. hydrochloric acid (about 2 ml). The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The residue is dissolved in ethanol (40 ml) and concentrated, then dissolved in ethanol (40 ml) and concentrated and dried at 50°C in high vacuum. The hardened foamed substance dried at 45°C for 18 h in a vacuum drying Cabinet with supply of nitrogen. So get all of 5.05 g (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid in the form of amorphous solids, h which corresponds to about 85.0 per cent of theoretical yield.

1H NMR (300 MHz, d6-DMSO): δ=7,53 (d2J=8,4, 1H), 7,41 (brs, 1H), 7,22 (d2J=8,5, 1H), 7,09-7,01 (m, 2H), 6,86 (m, 2H), 6,45 (dd,2J=8,2,3J=1,8, 1H), 6,39-6,34 (m, 2H), 4,87 (t2J=7,3, 1H), 3,79 (brs, 3H), 3,68 (s, 3H), 3,50-to 3.38 (m, 4H), 2,96-of 2.75 (m, 5H), a 2.45-2.40 a (m, 1H) ppm million;

MC (IAD-ER-neg.): m/z=571 [(M-N), 100%];

HPLC (method 1); RT=15,1 min;

HPLC (method 2): 99,8% EI; Pd (ICP): <1 ppm million

Example 12

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate(2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1)/crystallization of R-isomer from the mother liquor

The mother liquor after crystallization of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (28,38)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) and shaken with saturated aqueous sodium bicarbonate (1.5 l), the phases are separated and the organic phase is shaken out twice with dilute saturated aqueous sodium bicarbonate (1.5 liters). The phases are separated and the organic phase is dried over sodium sulfate and concentrated in a rotary evaporator. The remainder (EUR 188.4 g) dissolved in ethyl acetate (1.57 in l), then add (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (121,7 g) and the mixture is stirred at room temperature for 10 minutes Then see the camping contribute seed methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) (0,38 g) and stirred at room temperature for 18 h, then cooled to 0-3°C and stirred for another 3 hours, the Suspension is collected by filtration with suction and washed with cold ethyl acetate (0-10°C, 500 ml). The crystals are dried at 40°C for 18 h in a vacuum drying Cabinet with supply of nitrogen. Thus receive a total of 160 grams of salt in the form of solids.

HPLC (method 1): RT=16,6 and 18.5 min;

HPLC (method 3): -99,0% of EI.

Example 13

(R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid/take the R-isomer

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (2R,3R)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) (170 g) is suspended in ethyl acetate (850 ml) and shaken with saturated aqueous sodium bicarbonate solution (850 ml)until both phases will not be transparent (about 5 minutes). The phases are separated and the solvent of the organic phase at atmospheric pressure replace with 1,4-dioxane to a final temperature equal to 99°C (portions of distilled off just to 2.55 l of solvent and use of 2.55 l of 1,4-dioxane). The mixture is cooled to room temperature and stirred at room temperature for 18 h with 1 N. a solution of sodium hydroxide (525 ml). Then the pH value was adjusted to 7.5 with the help of the concentrated hydrochloric acid (about 35 ml), add MILK (850 ml) and then the pH re-adjusted to 7.0 with concentrated hydrochloric acid (about 10 ml). The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The residue is dissolved in ethanol (350 ml) and concentrated, then dissolved in ethanol (350 ml) and concentrated at 50°C. Thus receive all of 91.6 g (R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid in the form of amorphous solids, which corresponds to 91.6% of theoretical yield.

HPLC (method 1): RT=14,8 minutes

Example 14

{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid/racemization R-enantiomer

(R)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid (50 g) dissolved in acetonitrile (500 ml) and added sodium methoxide (30% in methanol, 32,4 ml) and the mixture is then stirred at the boil under reflux for 60 hours After cooling to room temperature the mixture is concentrated to half volume in vacuo, then the pH value adjusted to 7.5 using hydrochloric acid (20%, about 20 ml) was added, MIBK (200 ml) and the pH value of the mixture is re-adjusted to 7 using chloride is hydrogen acid (20%). The phases are separated and the organic phase is dried over sodium sulfate and concentrated in a rotary evaporator and get a solid foamed substance. The residue is dissolved in ethanol (150 ml) and concentrated, then dissolved in ethanol (150 ml) and kontsentriruitesi granted only to 54.2 g of (±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid as an amorphous solid in quantitative yield.

HPLC (method 1): RT=14,9 min;

HPLC (method 4): 80,8 wt.%.

Example 15

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate/etherification of the racemate

(±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid (54 g) was dissolved in methanol (540 g), then added concentrated sulfuric acid (a 7.85 ml). The mixture is stirred at the boil under reflux for 26 h, then cooled and concentrated in vacuo to approximately one third of the initial volume. Add water (150 ml) and dichloromethane (150 ml), then the phases are separated. The organic phase is extracted with saturated sodium hydrogen carbonate solution (twice in 140 ml), dried over sodium sulfate and concentrate and get the foam residue. It twice consecutively Rast is oraut in ethanol (150 ml) and concentrated and then dried for 18 hours under vacuum with a flow of nitrogen. So get all of 41.6 g of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate in the form of amorphous solids, which corresponds to 75.2% of theoretical yield.

HPLC (method 1): RT=16,8 min;

HPLC (method 4): 85,3 wt.%;

HPLC (method 3): -8,5% of EI.

Example 16

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1)/crystallization esterified racemate

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (41,0 g) is suspended in ethyl acetate (287 ml), then added (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (27.5 g). The mixture is stirred at room temperature for 30 min, then make a seed crystal of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) (0.08 g). The suspension is stirred at room temperature for 16 h, then cooled to 0-5°C and stirred for another 3 h, then the solid is collected by filtration with suction and washed with cold ethyl acetate (0-10°C, four times in 16 ml). The crystals are dried the ri 45°C for 18 h in a vacuum drying Cabinet with supply of nitrogen. So get all of 25.4 g of salt in the form of solids, which corresponds to 37,4% of theoretical yield.

HPLC (method 1): RT=16,9 and 18.8 min;

HPLC (method 4): with 99.5 wt.%;

HPLC (method 3): 99.3% of EI.

Example 17

(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl} acetic acid hydrolysis of crystalline product

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) (25,1 g) is suspended in ethyl acetate (250 ml) and shaken with saturated aqueous sodium bicarbonate (250 ml)until both phases are not will become transparent. The phases are separated and the organic phase was concentrated in a rotary evaporator. The residue is dissolved in 1,4-dioxane (250 ml) and 1 N. the solution of sodium hydroxide (77,4 ml) and stirred at room temperature for 18 hours and Then the pH value was adjusted to 7.5 with 1 N. hydrochloric acid (about 50 ml), MILK (240 ml) was added and then the pH re-adjusted to 7.0 with 1 N. hydrochloric acid (approximately 15 ml). The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The residue is dissolved in ethanol (90 ml) and concentrated, then dissolved in ethanol (90 ml) and concentrate the. The hardened foamed substance dried at 45°C for 18 h in a vacuum drying Cabinet with supply of nitrogen. Thus get a total of 12 g of (S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid in the form of amorphous solids, which corresponds to 81.2% of theoretical yield.

HPLC (method 1): RT=15,1 min;

HPLC (method 2): 97.5% of EI.; Pd (ICP): <20 ppm million

An alternative method of racemization:

Example 18

(±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid hydrolysis of concentrated R-isomer obtained from the mother liquor after crystallization

The mother liquor after crystallization 207 g of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate(2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) and shaken with saturated aqueous sodium bicarbonate (500 ml), the phases are separated and the organic phase is shaken with diluted twice with saturated aqueous solution of sodium bicarbonate (500 ml). The phases are separated and the organic phase is dried over sodium sulfate and concentrated in a rotary evaporator. The residue is dissolved in ethanol (500 ml) and concentrated in a rotary evaporator and receive solid spin the TES substance. It is dissolved in 1,4-dioxane (1.6 l) and 1 N. the solution of sodium hydroxide (1.04 million liters) and stirred at room temperature for 18 h, then added toluene (1.5 l) and the phases are separated. The pH value of the aqueous phase adjusted to equal 14 to 8 with hydrochloric acid (20%, about 155 ml), then added MILK (1.25 l) and the pH value of the mixture is re-adjusted to 7 with hydrochloric acid (20% to about 25 ml). The phases are separated and the organic phase is dried over sodium sulfate and concentrated in a rotary evaporator and get a solid foamed substance. It is dried at 45°C for 18 h in a vacuum drying Cabinet with supply of nitrogen. So get all 150 g {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl} acetic acid in the form of (R/S) of the mixture in the form of an amorphous solid.

HPLC (method 2): -14,6% of EI.

Example 19

(±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid/racemization

{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid (150 g, R/S-a mixture of 14.6% of EI) is dissolved in acetonitrile (1.5 l) and added sodium methoxide (30% in methanol, 97,2 ml) and the mixture is then stirred at the boil under reflux for 77 hours After ohlazhdeniya room temperature the mixture is concentrated to half volume in vacuum and then the pH value was adjusted equal to from 13 to 7.5 using hydrochloric acid (20%, approximately 80 ml), added MIBK (0.6 l) and the pH value of the mixture is re-adjusted to 7 with hydrochloric acid (20%, about 3 ml). The phases are separated and the organic phase is dried over sodium sulfate and concentrated in a rotary evaporator and get a solid foamed substance. The residue is dissolved in ethanol (500 ml) and concentrated, then dissolved in ethanol (500 ml) and concentrated, then dried for 18 h at 45°C in a vacuum drying Cabinet with supply of nitrogen. Just obtain 148 g of (±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl} acetic acid in the form of amorphous solids, which corresponds to 98,7% of theoretical yield.

HPLC (method 2): 1,5% of EI.

Example 20

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate (etherification)

(±)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-(2-methoxy-5-triptoreline)-3,4-dihydroquinazolin-4-yl}acetic acid (148 g) was dissolved in methanol (1480), then added concentrated sulfuric acid (21,5 ml). The mixture is stirred while boiling under reflux for 6 h, then cooled and concentrated in vacuo to approximately one third of the initial volume. Add water (400 ml) and dichloromethane (400 ml), then the phases are separated. The organic phase extragere is a saturated solution of sodium bicarbonate (twice) 375 ml, diluted with 300 ml of water), dried over sodium sulfate and concentrate and get the foam residue. It twice successively dissolved in ethanol (400 ml) and concentrated and then dried under vacuum for 18 h with a flow of nitrogen. So get just 124 g of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate in the form of amorphous solids, which corresponds to 81.9% of theoretical yield.

HPLC (method 1): RT=16,9 min;

Example 21

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1)/crystallization esterified racemate

Methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) (123 g, 14.4% of EI) is suspended in ethyl acetate (861 ml) and filtered, then added (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (82.5 g). The mixture is stirred at room temperature for 30 min, then make a seed crystal of methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (28,38)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) (0.2 g). The suspension is stirred at room temperature for 4 days, then concentrated to about 600 ml and re-make the seed methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetate (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid (salt composition 1:1) (0.24 g). The suspension is stirred at room temperature for 1 week, cooled to 0-5°C and stirred for another 3 h, then the solid is collected by filtration with suction and washed with cold ethyl acetate (0-10°C, 4×40 ml). The crystals are dried at 45°C for 18 h in a vacuum drying Cabinet with supply of nitrogen. Thus receive only 11.8 g of salt in the form of solids, which corresponds to 5.8% of theoretical yield.

Scheme 7:

Example 22

N-(2-Forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea

2-Methoxy-5-triftormetilfullerenov (1057,8 g) dissolved in acetonitrile (4240 ml), then added 2-ftoranila (540,8 g) and washed with acetonitrile (50 ml). The obtained clear solution is stirred at the boil under reflux (about 82°C) for 4 h, and then make the seed at about 78°C and stirred for approximately 15 minutes, the Suspension is cooled to 0°C. and the product collected by filtration with suction and p is washed with acetonitrile (950 ml cooled to 0-5°C). The product is dried overnight at 45°C in a vacuum drying Cabinet with supply of nitrogen. So just get 1380,8 g of N-(2-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea as solid substances, which corresponds to 86.4% of theoretical yield.

1H NMR (500 MHz, d6-DMSO): δ=9,36 (s, 1H), 9,04 (s, 1H), 8,55 (d, l,7 H2, 1H), 8,17 (t, 8,2Hz, 1H), 7,33 (d, 8,5Hz, 1H), 7,20-7,26 (m, 2H), 7,14 (t, 7,6Hz, 1H), 7,02 (m, 1H), of 3.97 (s, 3H) ppm million;

MC (IAD-ER-floor.): m/z 329(M+H)+, 100%];

HPLC: RT=48,7 minutes

Instrument: HP 1100 with detection at multiple wavelengths; column:

Phenomenex-Prodigy ODS (3) 100A, 150 mm×3 mm, 3 μm; eluent A: (1,36 g KN2RHO4+0.7 ml of N3RHO4)/l of water, eluent b: acetonitrile; gradient mode: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; flow rate: 0.5 ml/min; temperature: 55°C; UV detection: 210 nm.

Example 23

Methyl-(2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}acrylate

N-(2-Forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea (0,225 kg) dissolved in acetic acid (6.75 l) and added palladium acetate (30,3 g). Then add 65% oleum (of 247.5 g) and methyl acrylate (90 g) is then added. The solution was stirred at room temperature overnight. Then acetic acid (3740 g) is distilled off at about 30°and about 30 mbar. To the suspension was added water 2.25 liters) and the mixture is stirred for about 1 h The product is collected by filtration with suction, washed twice with water (0.5 l) and dried at 50°C overnight in a vacuum drying Cabinet with supply of nitrogen. So just get 210,3 g of methyl-(2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl}acrylate in the form of solids, which corresponds to 72.2% of theoretical yield.

1H NMR (300 MHz, d6-DMSO): δ=9,16 (s, 1H), 8,84 (s, 1H), 8,45 (d, l,7Hz, 1H), 7,73 (m, 2H), 7,33 (m, 3H), 7,22 (d, 8,6Hz, 1H), 6,70 (d, 16Hz, 1H), 3,99 (s, 3H), 3,71 (s, 3H) ppm million;

MC (IAD-ER-floor.): m/z=429,9 [(M+NH4)+]; 412,9 [(M+H)+]

HPLC: RT=46,4 minutes

Instrument: HP 1100 with detection at multiple wavelengths; column: Phenomenex-Prodigy ODS (3) 100A, 150 mm×3 mm, 3 μm; eluent A: (1,36 g KN2RHO4+0.7 ml of N3RHO4)/l of water, eluent b: acetonitrile; gradient mode: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; flow rate: 0.5 ml/min; temperature: 55°C; UV detection: 210 nm.

Example 24

Methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl} acetate

Methyl-(2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)amino] phenyl }acrylate (50 g) is suspended in acetone (1.2 l) and added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.7 g). The suspension is refluxed (about 56°C) and stirred for 4 h Obtained clear solution is altroot warm through diatomaceous earth (5 g). The diatomaceous earth was washed with warm acetone (100 ml). Then acetone (550 g) is distilled off. The resulting suspension is cooled to 0°C for 3 h and stirred. The product is collected by filtration with suction, washed twice with cold acetone (50 ml) and dried at 45°C overnight in a vacuum drying Cabinet with supply of nitrogen. So get all of 44.5 g of methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate in the form of solids, which corresponds to 89% of theoretical yield.

1H NMR (300 MHz, d6-DMSO): δ=9,73 (s, 1H), 7,72 (d2J=7,3, 1H), 7,71 (s, 1H), 7,33 (d2J=9,3, 1H), 7,15 (dd,2J=9,6,2J=8,6, 1H), 7,01 (d1J=7,3, 1H), 6,99-6,94 (m, 1H), 5,16 (t2J=5,9, 1H), 3,84 (s, 3H), 3,41 (s, 3H), of 2.81 (dd,2J=15,4,2J=5,8, 1H), 2,62 (dd,2J=15,4,2J=6,3, 1H) ppm million;

MC (IAD-ER-floor.): m/z=413(M+H)+, 100%], 825 [(2M+N)+, 14%];

HPLC: RT=37,1 minutes

Instrument: HP 1100 with detection at multiple wavelengths; column: Phenomenex-Prodigy ODS (3) 100A, 150 mm×3 mm, 3 μm; eluent A: (1,36 g KN2RHO4+0.7 ml of N3RHO4)/l of water, eluent b: acetonitrile; gradient mode: 0 min 20% B, 40 min 45% B, 50 min 80% B, 65 min 80% B; flow rate: 0.5 ml/min; temperature: 55°C; UV detection: 210 nm.

1. The method of obtaining the compounds of formula (I)

where AG denotes aryl, where aryl represents phenyl, long is Ino substituted C 1-C4alkoxygroup,
R1and R2selected from hydrogen, C1-C4alkoxygroup and trifloromethyl,
R3selected from C1-C4alkoxygroup and trifloromethyl,
R4denotes hydrogen or C1-C4alkyl,
R5denotes hydrogen or C1-C4alkyl,
R6denotes hydrogen or halogen,
R7denotes hydrogen or halogen and
R8denotes hydrogen or halogen,
by hydrolysis of ester compounds of the formula (II)

in which Ar, R1, R2, R3, R4, R5, R6, R7and R8have the above values and
R9stands With1-C4-alkyl,
with a base or acid, when used as a compound of the formula (II)obtained by the reaction of compounds of formula (III),
in which R1, R2, R3, R6, R7and R8have the above values and
R9stands With1-C4-alkyl,
in the presence of a base with the compound of the formula (IV)
,
in which Ar, R4and R5have the above values.

2. The method according to claim 1, characterized in that the compound of formula (III) according to claim 1 get the reaction of the compounds of formula (V)
,
in which 1, R2, R3, R6, R7and R8have the meanings indicated in claim 1, and
R9stands With1-C4-alkyl,
with phosphorus oxychloride, trichloride phosphorus or pentachloride phosphorus in the presence of a base.

3. The method according to claim 2, characterized in that the compound of formula (V) according to claim 2 get the reaction of the compounds of formula (VI)
,
in which R1, R2, R3, R6, R7and R8have the meanings specified in claim 2,
with the compound of the formula
,
in which R9stands With1-C4-alkyl,
in the presence of a palladium catalyst and base.

4. The method according to claim 2, characterized in that the compound of formula (V) according to claim 2 get the reaction of the compounds of formula (VII)
,
in which R1, R2, R3, R6, R7and R8have the meanings specified in claim 2,
in the first stage with a compound of formula (IX) in acetic acid in the presence of a palladium catalyst, an oxidizing reagent and acid to obtain the compounds of formula (VIII)
,
in which R1, R2, R3, R6, R7and R8have the meanings specified in claim 2, and
R9stands With1-C4-alkyl,
and in the second stage, with base connection form is s (V).

5. The method according to one of claims 1 to 4, characterized in that the compound of formula (I) is a
{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetic acid

the compound of formula (II) is a methyl{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate

the compound of formula (III) is methyl-2-chloro-8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate

the compound of formula (IV) represents a 1-(3-methoxyphenyl)piperazine

the compound of formula (V) is a
methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate

the compound of formula (VI) is an N-(2-bromo-6-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea

the compound of formula (VII) represents an N-(2-forfinal)-N'-[2-methoxy-5-(trifluoromethyl)phenyl]urea

the compound of formula (VIII) represents a methyl(2E)-3-{3-fluoro-2-[({[2-methoxy-5-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenyl} acrylate

the compound of formula (IX) pre who is a MMA
.

6. Method of separating enantiomers (C1-C4)-alkyl-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate and allocation (C1-C4)-alkyl-(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate, characterized in that the racemic ester is crystallized with (2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid.

7. Methyl-(S)-{8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5 - (trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl}acetate(2S,3S)-2,3-bis[(4-methylbenzoyl)oxy]succinic acid.

8. The compound of formula (III)
,
in which R1, R2, R3, R6, R7and R8have the meanings indicated in claim 1, and
R9stands With1-C4-alkyl.

9. The connection of claim 8, characterized in that it represents a methyl{8-fluoro-3-[2-methoxy-5-(trifluoromethyl)phenyl]-2-oxo-3,4-dihydroquinazolin-4-yl}acetate

10. The compound of formula (V)
,
in which R1, R2, R3, R6, R7and R8have the meanings indicated in claim 1, and
R9stands With1-C4-alkyl.

11. The connection of claim 10, characterized in that it represents a methyl{8-fluoro-3-[2-met the xylose-5-(trifluoromethyl)phenyl]-2-oxo-1,2,3,4-tetrahydroquinazolin-4-yl}acetate
.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I): where: A is a monocyclic or polycyclic aryl or heteroaryl group, where the heteroaryl radical denotes a 5-10-member cyclic system containing at least one heteroaromatic ring and containing at least one heteroatom selected from O, S and N; optionally substituted with one or more substitutes independently selected from a group comprising halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, C1-4alkoxy and a hydroxyl group; B is a monocyclic nitrogen-containing heteroaryl group, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from S and N; optionally substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-4alkyl, C3-8cycloalkyl, C3-8cycloalkyl-C1-4alkyl, aryl and C1-8alkylthio; either a) R1 is a group of formula: -L-(CR'R")n-G, where L is a binding group selected from a group consisting of a direct bond, -(CO)-, -(CO)NR'- and -SO2-; R' and R" is independently selected from hydrogen atoms; n assumes values from 0 to 1; and G is selected from a group consisting of a hydrogen atom and C1-4alkyl, aryl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O, S and N; C3-8cycloalkyl and saturated heterocyclic groups, where heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one or two carbon atoms are substituted with a N heteroatom; where alkyl, C3-8cycloalkyl, aryl or heteroaryl groups are unsubstituted or substituted with one or more substitutes selected from halogen atoms; and R2 is a group selected from hydrogen atoms, halogen atoms and C1-4alkyl, C2-5alkynyl, C1-4alkoxy, -NH2 and cyano groups, where alkyl and alkynyl groups may be unsubstituted or substituted with one aryl group; or b) R2, R1 and -NH- group to which R1 is bonded form a group selected from groups of formulae and , where: Ra is selected from a hydrogen atom or groups selected from C1-4alkyl, C3-8cycloalkyl, aryl, aryl-C1-4alkyl, heteroaryl, where the heteroaryl radical denotes a 5-6-member heteroaromatic ring containing at least one heteroatom selected from O and N; saturated heterocyclic rings, where the heterocyclic group denotes a non-aromatic saturated 6-member carbocyclic ring in which one carbon atom is substituted with a heteroatom selected from O and N; and C1-4alkylthio; where the aryl or heteroaryl groups are unsubstituted or substituted with one or more groups selected from halogen atoms, cyano group, trifluoromethoxy and carbamoyl; Rb denotes hydrogen; and pharmaceutically acceptable salts thereof and N-oxides; provided that the compound is not selected from N-[6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]benzamide, and N-[3-ethoxycarbonyl-6-(1-methyl-1H-indol-3-yl)-5-pyridin-2-ylpyrazin-2-yl]formamide. The invention also relates to a pharmaceutical composition, use of compounds in any of claims 1-20, a method of treating a subject, as well as a composite product.

EFFECT: obtaining novel biologically active compounds having adenosine A2B receptor antagonist activity.

27 cl, 160 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: in formula (I) Cy1 is a 6-member heterocyclyl containing N as a heteroatom, a 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteroatoms selected from N, S and O, phenyl or phenyl condensed with a 5-member heterocycle containing O as a heteroatom, each optionally having 1-3 identical or different substituting Cy1 groups which are: (C1-C6)-acyl, cyano, carboxy, hydroxy, (C1-C6)alkylsulphonyl, (C3-C6)-cycloalkyl, a 6-member heterocyclyl containing 1-2 heteroatoms selected from O and N, phenyl, a 5-member heteroaryl containing 1-3 heteroatoms selected from N, S and O, Y1Y2N-, Y1Y2NC(=O)-, Y1Y2NSO2-, (C1-C6)-alkyl-SO2-N(R5)-C(=O)-, R6-C(=O)-N(R5)-, R7-NH-C(=O)-NH-; (C1-C6)-alkoxycarbonyl; (C1-C6)-alkyl, which optionally contains 1-3 identical or different substitutes which are halogen, carboxy, cyano, hydroxy, Y1Y2N-, Y1Y2N-C(=O)-, R6-C(=O)-N(R5)-, R8-SO2-N(R5)-C(=O)-, 5-member heterocyclyl, containing N as a heteroatom, 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; or (C1-C6)-alkoxycarbonyl; as well as (C1-C6)-alkoxy which optionally have 1-3 identical or different substitutes which are carboxy, (C1-C6)-alkoxycarbonyl, cyano, 3-member heterocyclyl containing O as a heteroatom, or 5-member heteroaryl containing 1-3 heteroatoms selected from N and O; where phenyl or heteroaryl fragments in the substituting Cy1 groups optionally and independently have substitutes represented by hydroxy, (C1-C6)-alkyl, (C1-C6)-alkoxy, carboxy, (C1-C6)-alkoxycarbonyl or R8-SO2-N(R5)-C(=O)-; and where cycloalkyl fragments in the substituting Cy1 groups which optionally and independently have substitutes represented by (C1-C6)-alkoxy, carboxy; Cy2 is a 9-member cycloalkenyl, phenyl, 5,6-member monocyclic or 9,10-member bicyclic heteroaryl containing 1-3 heteratoms selected from N, S and O, or phenyl condensed with a 5,6-member heterocycle containing 1-2 heteroatoms selected from N and O, each independently and optionally having 1-3 identical or different substitutes represented by (C1-C6)-alkoxy, (C1-C3)-alkyl, hydroxy, halogen, halogen-(C1-C6)-alkoxy, nitro, Y1Y2N-; L1 is an alkylene with a straight or branched chain containing 1-6 carbon atoms, optionally substituted carboxy; or L1 is -CH2-(C1-C5)halogenalkylene; L2 is a bond, -O- or -CH2-O-. Other values of radicals are given in the formula of invention.

EFFECT: novel compounds have prostaglandin D2 receptor antagonist properties, can be used in treating primarily allergic disorders such as allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, food allergy and other diseases.

39 cl, 1 tbl, 99 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or pharmaceutically acceptable salts, solvates or tautomers thereof, where substitute M is selected from groups D1 and D2, having structural formulae given below, and R1, E, A and X are as described in the formula of invention. Disclosed also are pharmaceutical compositions which contain these compounds, methods for synthesis of these compounds, intermediate compounds and synthesis methods thereof, as well as use of compounds of formula (I) in preventing or treating diseases mediated by CDK kinases, GSK-3 kinases or Aurora kinases.

EFFECT: high effectiveness of the compounds.

40 cl, 8 dwg, 18 tbl, 84 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a pyridazine compound of formula (1), in which R1 is a chlorine atom, bromine atom, C1-C4 alkyl group of C1-C4 alkoxy group, R2 is a C1-C4 alkyl group, R3 is a halogen atom, m equals 0 or 1, Q is a 6-member aromatic heterocyclic group selected from a pyridyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group, wherein the said aromatic heterocyclic group is optionally substituted with at least one substitute selected from a group comprising halogen atoms, C1-C4 alkyl group optionally substituted with at least one halogen atom, and C1-C4 alkoxy group optionally substituted with at least one halogen atom. This compound has excellent plant disease suppression.

EFFECT: compound can be used plant disease control.

10 cl, 11 tbl, 56 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or pharmaceutically acceptable salt thereof; where Q is selected from a group consisting of R1 denotes H; each R2 independently denotes ZR; each JQ independently denotes ZQ, MQ, (LQ)-ZQ or (XQ)-MQ; each LQ and XQ independently denotes C1-6alkyl, where each carbon of the alkyl group is independently substituted in up to 2 cases -NR-, -NHR-, -NRC(O)O-; where each XQ is independently and optionally substituted with 0-2 JXQ; each ZR and ZQ independently denotes H; a C1-6alkyl group, a 5-7-member saturated or completely unsaturated monocyclic ring, having 0-2 nitrogen atoms; or a 9-member saturated bicyclic ring system having 1 nitrogen atom; where each is ZQ independently and optionally substituted with 0-3 JZQ; MQ denotes halogen, CN or N(R)2; each JLQ, JXQ and JZQ independently denotes V, M, (LV)-V, (LM)-M, halogen, C1-3alkoxy; each R independently denotes H, C1-6alkyl group; each LV and LM independently denotes C1-6alkyl, interrupted in up to 1 case by -C(O)-; where each V independently denotes H; C1-6alkyl group, a 5-6-member saturated or completely unsaturated monocyclic ring; where each V is independently or optionally substituted with 0-1 JV; each JV denotes NH2; each M independently denotes halogen, OH, O(C1-6alkyl), NH2, provided that when R1 and R2 - H, Q is not The invention also relates to a composition based compounds of formula I, a method of inhibiting activity of Aurora B protein kinase, FLT-3 protein kinase, a method of treating a proliferative disorder, particularly leukaemia or lymphoma and a method of producing compounds of formula I.

EFFECT: novel benzimidazole derivatives are obtained, which can be used as inhibitors of protein kinase Aurora B and FLT-3.

28 cl, 2 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound of formula pharmaceutically acceptable salt or solvate of a compound or salt (I), ring Q represents optionally substituted monocyclic or condensed (C6-C12)aryl or optionally substituted monocyclic or condensed heteroaryl where said substitutes are chosen from: halogen; (C1-C6)alkyl optionally substituted by 1-3 halogen atoms; (C1-C6)alkylsulphonyl; phenyl optionally substituted by 1 or 2 substitutes chosen from halogen, (C1-C6)alkyl which can be substituted by 1-3 halogen atoms, groups (C1-C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and (C1-C6)alkylthio; monocyclic or condensed heteroaryl optionally substituted by halogen; or oxo; Y1 represents a bond or -NR6-CO-, where R6 represents hydrogen, ring A represents optionally substituted a nonaromatic heterocyclyldiyl where said substitutes are chosen from (C1-C6)alkyl optionally substituted by groups hydroxy, (C1-C6)alkylamino, di(C1-C6)alkylamino, morpholino, (C1-C6)alkylaminocarbonyl, di(C1-C6)alkylaminocarbonyl; cyano; (C3-C6)cycloalkyl; (C1-C6)alkoxy; (C1-C6)alkoxy(C1-C6)alkyl; phenyl; benzyl; benzyloxymethyl; thienyl; 4-8-members monocyclic nonaromatic heterocycle having 1 or 2 heteroatoms chosen from N or O, and optionally substituted by 1 or 2 substitutes chosen from (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkoxy(C1-C6)alkyl and oxo; (C1-C6)alkylamino; di(C1-C6)alkylamino; a group of formula: -Y2Z'- represents a group of formula: [Formula 2] each R7 independently represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of R8 and R9 independently represents hydrogen or (C1-C6)alkyl, n is equal to an integer 0 to 3, Z1 represents a bond, -O-, -S- or-NR9 - where R9 represents hydrogen, (C1-C6)alkyl, acyl or (C1-C6)alkylsulphonyl, ring B represents optionally substituted aromatic carbocyclediyl or optionally substituted aromatic heterocyclediyl where said substitutes are chosen from (C1-C6)alkyl, halogen, (C1-C6)alkoxy and oxo; Y3 represents a bond optionally substituted (C1-C6)alkylene or (C3-C6)cycloalylene, optionally interrupted -O- or optionally substituted (C2-C6)alkenylene where said substitutes are chosen from (C1-C6)alkyl, (C3-C6)cycloalkyl, halogen and (C1-C6)alkoxycarbonyl; Z2 represents COOR3; R3 represents hydrogen or (C1-C6)alkyl.

EFFECT: preparation of new compounds.

30 cl, 9 tbl, 944 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel benzimidazole and indole derivatives or pharmaceutically acceptable salts of general formula 1, where m assumes values from 0 to 2; n equals 1, X denotes: -NRa-; -CRbRc-; or -C(O)-; where: Ra is hydrogen or C1-6alkyl; Rb is hydrogen or C1-6alkyl; Rc is hydrogen, C1-6alkyl, hydroxy; or Ar denotes: phenyl, possibly substituted with 1-2 halogens; or isoxazole, possibly substituted with C1-6alkyl; R1 is a group of formula p assumes values from 1 to 3; Y denotes: -O-; -NRd-; or -CReRf-; where Rd, Re and Rf each independently denotes hydrogen or C1-6alkyl; each R2 independently denotes: halogen; C1-6alkyl; R3 and R4 each independently denotes hydrogen or C1-6alkyl; R5 and R6 each independently denotes; and R7 and R8 each independently denotes hydrogen or C1-6alkyl; or one of R7 and R8 and one of R5 and R6 together with atoms to which they are bonded can form a 4-6-member ring; or one of R7 and R8 together with Rd and atoms to which they are bonded can form a 6-7-member ring; or one of R7 and R8 and one of Re and Rf together with atoms to which they are bonded can form a 5-6-member ring. The invention also relates to a pharmaceutical composition based on compounds of formula I-VI and use of the compounds of formula I-VI.

EFFECT: obtaining novel benzimidazole and indole derivatives with selective 5-and/or 6-HT2A receptor antagonist properties.

27 cl, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel AMPA receptor antagonists - 1H-quinazoline-2,4-dione derivatives, selected from the group: N-(6-imidazol-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,4]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-pyrrolidin-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-azetidin-1-yl-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(7-nitro-2,4-dioxo-6-[1,2,3]triazol-1-yl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide; N-(6-morpholin-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; (2,4-dioxo-6-[1,2,4]triazol-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)amide ethanesulphonic acid; N-(6-imidazol-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(2,4-dioxo-6-thiomorpholin-4-yl-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide; N-(6-[1,4]oxazepan-4-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)methanesulphonamide and N-(6-azetidin-1-yl-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl)-methanesulphonamide and physiologically acceptable salts thereof.

EFFECT: compounds can be used in treating such diseases as epilepsy and schizophrenia.

9 cl, 106 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula: or to its pharmaceutically acceptable salt, where: Ar2 represents phenyl or pyridyl, each of which is substituted by 0-4 substituents, independently selected from R2; X and Z represent N; Y represents CRX; D represents N; F represents N, CH or carbon, substituted by substituent, representing R1 or R10; Rx in each case is independently selected from hydrogen, halogen, C1-C4alkyl, amino, cyano and mono- or di-(C1-C4alkyl)amino; R1 represents 0-3 substituents, independently selected from: (a) halogen, cyano and nitro; (b) groups of formula -Q-M-Ry; R10 represents one substituent, selected from: (a) groups of formula -Q-M-Ry; so that R10 is not hydroxy, amino or unsubstituted group, selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkinyl, C1-C6aloxy, C2-C6alkyl, ether, C2-C6alkanoyl, C3-C6alcanone, C1-C6halogenalkyl, C1-C6halogenoalkoxy, mono- or di-(C1-C6alkyl)amino, C1-C6alkylsulfonyl, mono- or di-(C1-C6alkyl)aminosulfonyl or mono- or di-(C1-C6alkyl)aminocarbonyl; each Q is independently selected from C0-C4alkylene; each M is independently absent or is selected from O, C(=O), OC(=O), C(=O)O, S(O)m, N(RZ), C(=O)N(Rz), C(=NH)N(Rz), N(Rz)C(=O), N(Rz)C(=NH), N(Rz)S(O)m, S(O)mN(Rz) and N[S(O)mRz]S(O)m, where m equals 2; and Rz in each case is independently selected from hydrogen, C1-C8alkyl and groups, which taken together with Ry, form possibly substituted (4-7)-member heterocycle; and each Ry independently represents hydrogen, C1-C8halogenalkyl, C1-C8alkyl, C2-C8alkenyl, (C3-C8carbocycle)C0-C4alkyl, ((4-7)-member heterocycle)C0-C4alkyl or taken together with Rz forms (4-7) member heterocycle, where each alkyl, carbocycle and heterocycle is substituted by 0-4 substituents, independently selected from hydroxy, halogen, amino, cyano, nitro, -COOH, aminocarbonyl, aminosulfonyl, C1-C6alkyl, C3-C7cecloalkyl, C2-C6alkyl ether, C1-C6alkanoyl, C1-C6alkylsulfonyl, C1-C8alkoxy, C1-C8hydroxyalkyl, mono- and di-(C1-C6alkyl)aminocarbonyl, mono- and di-(C1-C6alkyl)aminosulfonyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkanoylamino and phenyl; so that Ry is not hydrogen, if Q represents C0alkyl and M is absent; each R2: (a) is independently selected from (1) hydroxyl, amino, cyano, halogen, -COOH, nitro and (2) C1-C6alkyl, (C3-C8cycloalkyl)C0-C4alkyl, C1-C6halogenalkyl; R3 is selected from: (1) hydrogen; (2) C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl; and (3) groups of formula: where L represents C0-C6alkylene; R5 and R6: (a) are independently selected from C1-C12alkyl, (C3-C8cycloalkyl)C0-C4alkyl; or (b) are combined with formation of (4-6)-member heterocycle, containing one or two heteroatoms independently selected from O and N; and where each of (2) and (3) is substituted by 0-4 substituents, independently selected from: C1-C6alkyl and (C3-C8cycloalkyl)C0-C2alkyl, each of which is substituted by 0-4 secondary substituents, independently selected from hydroxy, C1-C4alkyl and C1-C4alkoxy; and R4 represents 0-2 substituents, independently selected from C1-C3alkyl.

EFFECT: claimed are pharmaceutical compositions for modulation of capsaicin receptor activity and methods of applying said compounds for treatment of such disorders as pain, itch, cough, hiccup, urinary incontinence or obesity.

65 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula [I-D1] or pharmaceutically acceptable salt thereof,

,

where each symbol is defined in the claim. The invention also relates to pharmaceutical compositions containing said compound and having HCV polymerase inhibiting activity.

EFFECT: disclosed compound exhibits anti-HCV activity, based on HCV polymerase inhibiting activity and is useful as an agent for preventing and treating hepatitis C.

32 cl, 497 tbl, 1129 ex

The invention relates to new nitrogen-containing heterocyclic compounds, in particular to derive hinzelin or benzodiazepina.beloe acid formula

(I) where R is hydrogen, halogen, lower alkyl or lower alkoxygroup;

And group O or S;

In group-CH2-CH2or СНR1where R1means hydrogen, lower alkyl or hydroxyl;

X is oxygen or the group NH

The Y group of the formula)qwhere R2means lower alkyl, q is 2 or 3, and their salts, in particular physiologically tolerable salts, which possess pharmacological activity, in particular activity antimuskarinovoe act occurs, and therefore can be used to treat diseases of the gastrointestinal tract and respiratory tract

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds with formula I where R1, R2, R3 and Y together with a formula I residue, are compounds, chosen from a group given in the formula of invention, or to their pharmaceutically used and split esters, or to their acid-additive salts, which promote release of parathyroid hormone.

EFFECT: compounds can be used for making medicinal agents, with antagonistic properties towards calcium sensitive parathyroid gland receptor for treating diseases mediated by effect of parathyroid hormone.

7 cl, 179 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with compounds of formula IV , or their acidoadditive salts, methods of their obtaining and application while applying medicinal preparation for treating osseous diseases associated with increased calcium loss or resorption or when the stimulation of osteogenesis and fixation of bone calcium are required.

EFFECT: higher efficiency.

6 cl, 190 ex

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

The invention relates to new nitrogen-containing heterocyclic compounds, in particular to derive hinzelin or benzodiazepina.beloe acid formula

(I) where R is hydrogen, halogen, lower alkyl or lower alkoxygroup;

And group O or S;

In group-CH2-CH2or СНR1where R1means hydrogen, lower alkyl or hydroxyl;

X is oxygen or the group NH

The Y group of the formula)qwhere R2means lower alkyl, q is 2 or 3, and their salts, in particular physiologically tolerable salts, which possess pharmacological activity, in particular activity antimuskarinovoe act occurs, and therefore can be used to treat diseases of the gastrointestinal tract and respiratory tract

FIELD: organic chemistry of heterocyclic compounds, pharmacy.

SUBSTANCE: invention relates to new bicyclic heteroaromatic compounds of the general formula (I): wherein R1 represents phenyl optionally substituted with NHR5 or OR5; R2 represents (C1-C4)-alkyl or phenyl; R5 represents phenylcarbonyl, (C4-C6)-heterocycloalkylcarbonyl, (C2-C8)-alkenylsulfonyl and others; Y represents nitrogen atom (N); Z represents -NH2 or -OH. A represents sulfur atom (S) or a bond; B represents -N(H) or oxygen atom (O); X1-X2 represent C=C, -NH-C(O), C=N and others; Proposed compounds show agonistic activity with respect to LH receptor and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 34 ex

FIELD: organic chemistry, amino acids.

SUBSTANCE: invention proposes the novel derivatives of phenylalanine of the formula (I) and (II) possessing with antagonistic activity with respect to α4-integrin. Derivatives of phenylalanine are used as therapeutic agents in different diseases associated with α4-integrin.

EFFECT: valuable medicinal properties of compounds.

37 cl, 30 tbl, 215 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with compounds of formula IV , or their acidoadditive salts, methods of their obtaining and application while applying medicinal preparation for treating osseous diseases associated with increased calcium loss or resorption or when the stimulation of osteogenesis and fixation of bone calcium are required.

EFFECT: higher efficiency.

6 cl, 190 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds with formula I where R1, R2, R3 and Y together with a formula I residue, are compounds, chosen from a group given in the formula of invention, or to their pharmaceutically used and split esters, or to their acid-additive salts, which promote release of parathyroid hormone.

EFFECT: compounds can be used for making medicinal agents, with antagonistic properties towards calcium sensitive parathyroid gland receptor for treating diseases mediated by effect of parathyroid hormone.

7 cl, 179 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing dihydroquinazolines of formula (I), which are used to prepare medicinal agents. In formula

Ar denotes phenyl, possibly substituted with a C1-C4alkoxy group, R1 and R2 are selected from hydrogen, C1-C4alkoxy group and trifluoromethyl, R3 is selected from C1-C4 alkoxy group and trifluoromethyl, R4 denotes hydrogen or C1-C4alkyl, R5 denotes hydrogen or C1-C4alkyl, each of R6 R7 and R8 denotes hydrogen or halogen. The method involves hydrolysis of an ester of a compound of formula (II) in which Ar, R1, R2, R3, R4, R5, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, with a base or acid, where the compound of formula (II) obtained from reaction of a compound

of formula (III), is used, in which R1, R2, R3, R6, R7 and R8 are as described above and R9 denotes C1-C4-alkyl, in the presence of a base, with a compound of formula (IV) in which Ar, R4 and R5 are as described above. The method simplifies extraction of products.

EFFECT: invention also relates to novel intermediate compounds and a method of obtaining said compounds.

11 cl, 5 dwg, 24 ex

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