Method for producing high-purity prasugrel hydrochloride

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for producing prasugrel hydrochloride which involves the following stages: (i) chlorination of a compound described by formula (III) by addition of an chlorinating agent, optionally drop-by-drop, in a solvent; (ii) reaction of the prepared compound of formula (IV) and a compound described by general formula (V) where R means a protective group for hydroxyl, or its salt in a solvent in the presence of a base; (iii) acetylation of the prepared compound described by general formula (II) by reaction with an acetylation agent in a solvent in the presence of a base and an acetylation catalyst; and (iv) addition of hydrochloric acid, optionally drop-by-drop, to the prepared compound described by formula (I) in a solvent to produce prasugrel hydrochloride described by formula (1a), and differs by the fact that at the stage (i) temperature during addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C, and reaction temperature after addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C. The invention also concerns a product containing prasugrel hydrochloride and CATP in an amount no more than 0.3 %, to the pharmaceutical composition suitable for prevention or treatment of thrombosis or embolism on the basis of the specified product.

EFFECT: production of low-CATP prasugrel hydrochloride.

31 cl, 3 dwg, 1 tbl, 2 ex

 

The technical field to which the invention relates

The present invention relates to a method for producing high purity prasugrel hydrochloride.

The level of technology

The compound of the formula:

it is well known as prasugrel. It is known that prasugrel and its pharmaceutically acceptable salts inhibit platelet aggregation and is used as an active ingredient of medicines (in particular, antithrombotic or antiembolism funds) (patent document 1 or 2). However, to use prasugrel or its pharmaceutically acceptable salts as a drug is needed is a method of obtaining high purity of prasugrel or its pharmacologically acceptable salts.

Prasugrel hydrochloride represented by the formula:

can be obtained in the following way. In patent document 3 described in stage (i)-(iii), and in patent document 2 - stage (iv). However, none of these patent documents is not described by-product of satr.

In these formulas, R is a protective group for hydroxyl group.

Patent document 1: laid Japan patent No. Hei 6-41139.

Patent document 2: lined the Japan patent No. 2002-145883.

Patent document 3: international p is blackace No. WO 96/11203.

Description of the invention

Problem solved thanks to the present invention

The authors of the present invention found that the large-scale production prasugrel hydrochloride of the above leads to the formation of the final product, contaminated byproduct of satr, which previously was not known.

The present invention is to provide a method for obtaining high-purity prasugrel hydrochloride with reduced content of by-products, such as satr.

Means to solve the aforementioned problems

As a result of intensive studies, the method of obtaining high purity prasugrel hydrochloride with reduced content of by-products, such as satr, the authors of the present invention found that the temperature of the reaction at the stage of chlorination, as in stage (i) of the above method, it is possible to regulate with the aim of reducing the amount of by-product satr in prasugrel the hydrochloride, which is the destination of the connection. Thus was accomplished the present invention.

As for the reaction conditions at the stage of chlorination stage (i), in international publication no WO 96/11203, with the description of reference examples 12-1 and 12-2 shown that gloriouse reagent was added dropwise, maintaining the temperature of the liquid medium below 5ºC. After cachemonitor liquid medium was gradually increased to room temperature (20°C), the mixture was allowed to interact for 1.5 hours under stirring". Thus, previously believed that the reaction temperature after the addition, optionally dropwise, glorieuses agent, preferably, should be at room or higher. In the present invention, on the contrary, the reduction of the amount of side product satr in the target connection - prasugrel the hydrochloride is is possible due to regulation at the level of the low values of the reaction temperature after the addition, optionally dropwise, glorieuses agent, and the temperature during the addition, optionally dropwise, glorieuses agent.

The present invention provides a method of obtaining prasugrel hydrochloride, characterized by regulating the reaction temperature in stage (i)contained in the above-described method including steps (i)to(iv); high-purity prasugrel hydrochloride obtained in this way; the pharmaceutical composition (in particular, prophylactic or therapeutic agent for the treatment of diseases caused by thrombi or emboli), containing as an active component high-purity prasugrel hydrochloride; application of high-purity prasugrel hydrochloride for preparation of the above pharmaceutical compositions and method of prevention or treatment of diseases (in particular, is of rombase and embolism), including the introduction of warm-blooded animals (particularly humans) above pharmaceutical compositions containing the pharmacologically effective amount of high purity prasugrel hydrochloride.

The present invention is as follows.

(1) a Method of obtaining prasugrel hydrochloride, comprising the following stages:

(i) chlorination of compound (III) by adding to it glorieuses agent, optionally dropwise, in a solvent;

(ii) the interaction of the obtained compound (IV) with compound (V) or its salt in a solvent in the presence of a base;

(iii) acetylation of the obtained compound (II) by reacting the reaction with azetiliruet agent in a solvent in the presence of base and catalyst for the acylation; and

(iv) adding to the resulting compound (I) in the solvent of hydrochloric acid to obtain prasugrel hydrochloride,

characterized in that in stage (i) the temperature during the addition, optionally dropwise, glorieuses agent ranges from -20°C to 5°C and the reaction temperature after the addition, optionally dropwise, glorieuses agent ranges from -20°C to 5°C.

(2) a Way of getting under item (1), characterized in that in stage (i) the temperature during the addition, optionally dropwise, glorieuses agent is from -10°C to 5°C and the temperature of the PE the work after adding, optional dropwise, glorieuses agent is from -10°C to 5°C.

(3) the Way of getting p. (1), characterized in that in stage (i) the temperature during the addition, optionally dropwise, glorieuses agent ranges from -5°C to 5°C and the reaction temperature after the addition, optionally dropwise, glorieuses agent ranges from -5°C to 5°C.

(4) the Method of receiving according to any one of paragraphs.(1)to(3), characterized in that the temperature of the subsequent processing after the reaction in stage (i) is from -20°C to 15°C.

(5) the Method of receiving according to any one of paragraphs.(1)to(3), characterized in that the temperature of the subsequent processing after the reaction in stage (i) is from -10°C to 15°C.

(6) the Method of receiving according to any one of paragraphs.(1)to(3), characterized in that the temperature of the subsequent processing after the reaction in stage (i) is from 0°C to 15°C.

(7) the Method of receiving according to any one of paragraphs.(1)to(6), in which gloriouse agent is a chlorine gas.

(8) the Method of receiving according to any one of paragraphs.(1)to(7), in which R denotes a group of General formula:

where R1, R2and R3independently mean alkyl group containing from 1 to 10 carbon atoms, or aryl group.

(9) the Method of obtaining under item (8), in which R1, R2and R3independently mean alkyl groups is, containing from 1 to 5 carbon atoms, or phenyl group.

(10) the Method of receiving according to any one of paragraphs.(1)to(7), in which R is tert-butyldimethylsilyloxy group.

(11) the Method of receiving according to any one of paragraphs.(1)to(10), characterized in that the compound obtained of General formula (II) in stage (ii) is recrystallized from ethers or NITRILES.

(12) the Method of receiving according to any one of paragraphs.(1)to(10), characterized in that the compound obtained of General formula (II) in stage (ii) is recrystallized from acetonitrile.

(13) the Method of receiving according to any one of paragraphs.(1)to(12), in which acetylide agent is an acetic anhydride.

(14) the Method of receiving according to any one of paragraphs.(1)to(13), characterized in that the output stage (iii) compound corresponding to the formula (I), used in the next stage (iv) without purification.

(15) Prasugrel hydrochloride, characterized by a content of satr 0.3% or less, obtained by way of getting PP.(1)-(14).

(16) Prasugrel hydrochloride, characterized by a content of the satr of 0.1% or less, obtained by way of getting PP.(1)-(14).

(17) Prasugrel hydrochloride, characterized by a content of satr 0.04% or less, obtained by way of getting PP.(1)-(14).

(18) Prasugrel hydrochloride, characterized by a content of the satr of 0.03% or less, obtained by way of getting PP.(1)-(14).

(19) Prasugrel hydrochlor is d, characterized by the content of the satr of 0.02% or less, obtained by way of getting PP.(1)-(14).

(20) Prasugrel hydrochloride, characterized by a content of satr 0.3% or less.

(21) Prasugrel hydrochloride, characterized by a content of the satr of 0.1% or less.

(22) Prasugrel hydrochloride, characterized by a content of satr 0.04% or less.

(23) Prasugrel hydrochloride, characterized by a content of the satr of 0.03% or less.

(24) Prasugrel hydrochloride, characterized by a content of the satr of 0.02% or less.

(25) a Pharmaceutical composition comprising as an active ingredient prasugrel hydrochloride on PP.(15)-(24).

(26) a Preventive or therapeutic agent used for the treatment of warm-blooded animals diseases caused by thrombi or emboli containing as the active component prasugrel hydrochloride on PP.(15)-(24).

(27) a Preventive or therapeutic agent used to treat in humans thrombosis or embolism, comprising as an active component prasugrel hydrochloride on PP.(15)-(24).

In accordance with the present invention by a protective group for hydroxyl group" has no particular restrictions, provided that it is capable of during the reaction continuously to protect the hydroxyl group, in particular, this term refers to a protective group, the cat heaven can be derived in the course of this chemical stage, as hydrogenolysis, hydrolysis, electrolysis and photolysis. The protective group may, for example, be an aliphatic acyl group, including alkanoyloxy group, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoic, 8-methylnonanoic, 3-ethyloctanoic, 3,7-dimethyloctane, undecanoyl, dodecanoyl, tridecanol, deletion, pentadecanol, hexadecanol, 1-methylpentanol, 14-methylpentadiene, 13,13-dimethylcarbamoyl, heptadecanoyl, 15-methylhexadecanoic, octadecanoyl, 1-methylheptadecyl, nonadecanoic, eicosanoic or heneicosanol, alkylcarboxylic group, substituted carboxypropyl, such as succinoyl, glutaryl or adipoyl, alkylcarboxylic group, substituted atom(s) halogen, such as chloroacetyl, dichloroacetyl, trichloroacetyl or TRIFLUOROACETYL, saturated cyclic hydrocarbon-carbonyl, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl, cyclohexylcarbonyl or cyclooctylmethyl, alkylcarboxylic group, substituted lower alkoxygroup, such as methoxyacetyl or unsaturated alkylcarboxylic group, such as (E)-2-methyl-2-butenyl; aromatic acyl group, including arylcarbamoyl group such as the benzoyl, α-naphtol, β-oil is l, pyridyl, toenail or furoyl, halogenoalkanes group, such as 2-bromobenzoyl or 4-chlorobenzoyl, arylcarbamoyl group, a substituted lower alkyl group(s), such as 2,4,6-trimethylbenzoyl or 4-toluoyl, lower alkoxycarbonyl arylcarbamoyl group, such as 4-anisoyl, arylcarbamoyl group, substituted carboxypropyl, such as 2-carboxybenzoyl, 3-carboxybenzoyl or 4-carboxybenzoyl, nitride arylcarbamoyl group, such as 4-nitrobenzoyl or 2-nitrobenzoyl, arylcarbamoyl group, substituted lower alkoxycarbonyl, such as 2-(methoxycarbonyl)benzoyl or arylcarbamoyl group, substituted aryl, such as 4-phenylbenzyl; carboncillo group, including oksadiazoldiola group, such as (5-methyl-2-oxo-1,3-dioxolan-4-yl)methyl or (5-phenyl-2-oxo-1,3-dioxolan-4-yl)methyl; the remainder of the salt of a partial ester of succinic acid; a residue of salt of ester of phosphoric acid; forming an ester residue, such as an amino acid; karbamoilnuyu group; karbamoilnuyu group, substituted by one or two lower alkyl groups; group carbonylcontaining such as pivaloyloxymethyl; or a silyl group such as trimethylsilyl, triethylsilyl, Tripropylene, triisopropylsilyl, tert-butyldimethylsilyl or tert-buildif ililil. These protective groups are preferred silyl group; more preferred group represented the General formula:

where R1, R2and R3independently of one another denote an alkyl group containing from 1 to 10 carbon atoms, or aryl group, and preferably are, independently of one another, alkyl group containing from 1 to 5 carbon atoms, or phenyl group; and more preferred are tert-butyldimethylsilyloxy group.

In accordance with the present invention, "alkyl group comprising from 1 to 10 carbon atoms" may be an alkyl group with straight or branched chain, containing from 1 to 10 carbon atoms, such as, for example, methyl, ethyl, propyl (including its isomers), butyl (including each isomer), pentyl (including each isomer), hexyl (including each isomer), heptyl (including each isomer), octyl (including each isomer), nonyl (including each isomer) or decyl (including each isomer). Preferably it is an alkyl group containing from 1 to 5 carbon atoms; more preferably, methyl group, ethyl group, through the group (including isomers) or bucilina group (including each isomer); and more preferably, is a methyl group or a tert-bucilina group.

In choosing the accordance with the present invention, "aryl group" is, for example, a phenyl group, xylella group, biphenylene group, naftalina group, antenna group or phenanthroline group, and preferably, it aryl group comprising from 6 to 8 carbon atoms, more preferably phenyl group.

In the molecule of the compounds of the present invention may contain asymmetric carbon atom; and they may be due to its optical isomers (including diastereoisomers), which also form the compound of the present invention.

In accordance with the present invention the salt of the compound (V) may be a salt of an inorganic acid such as hydrochloride or sulfate; organic sulfonate, such as p-toluensulfonate or methanesulfonate; or an organic carboxylate, such as acetate or propionate. Salts of inorganic acids or organic sulfonates are preferred, more preferred, hydrochloride or p-toluensulfonate.

In accordance with the present invention "satr" means 2-acetoxy-5-[5-chloro-1-(2-forfinal)-2-oxobutyl]-4,5,6,7-tetrahydrothieno[3,2-C]pyridine represented by the formula:

In accordance with the present invention in satr has asymmetric carbon atom and can exist due to its optical isomers; any of e is their isomers and their mixtures are also included in satr, corresponding to the present invention.

The value of invention

In accordance with the present invention can be provided with high-purity prasugrel hydrochloride with a reduced content of impurities such as by-product of satr. In particular, the present invention provides the possibility of reducing the amount of by-product satr compared to other similar structure byproducts.

Brief description of drawings

Figure 1 represents the result of analyzing by liquid chromatography, prasugrel hydrochloride obtained in example 1;

Figure 2 represents the result of analyzing by liquid chromatography, prasugrel hydrochloride obtained in example 2;

Figure 3 represents the result of analyzing by liquid chromatography, prasugrel hydrochloride obtained in reference example 1.

Description of the preferred variant of the invention, the

The compound (III)used in stage (i) of the method of the present invention as a starting material, can be obtained by the method described in international publication no WO 96/11203.

The compound (V)used in stage (ii) of the method of the present invention as a starting material, can be obtained by a method described, for example, in international publications is no WO 96/11203.

The method of obtaining high purity prasugrel hydrochloride of the present invention is as follows.

Stage (i)

This stage represents the stage of chlorination of compound (III) by adding to it in a solvent, optionally dropwise, glorieuses reagent to obtain the compound (IV).

Used at this stage gloriouse agent can represent, for example, chlorine gas or sulfurylchloride; preferred is chlorine gas.

Used at this stage, the solvent has no particular restrictions, provided that it is to some extent dissolve the source material and did not inhibit this reaction. This solvent may constitute, for example, ether solvent such as tetrahydrofuran, diethyl ether or dioxane; halogenated solvent such as dichloromethane or 1,2-dichloroethane; an aromatic hydrocarbon solvent such as benzene, toluene or xylene; a nitrile solvent such as acetonitrile, propionitrile or benzonitrile; or an amide solvent such as dimethylformamide, dimethylacetamide or dimethylimidazolidin. Halogenated solvents are preferred, more preferred dichloromethane.

The number glorieuses agent used at this stage, usually sostav the et from 0.5 to 3 moles, preferably, from 0.8 to 2 moles, more preferably from 0.9 to 1.5 moles per 1 mol of compound (III).

During the addition, optionally dropwise, glorieuses agent at this stage the temperature of the reaction solution varies depending on the reagent, solvent, or the like; however, the typical temperature is between -20 ° C and up to 5 º C, preferably from -10 º C to 5 º C, more preferably from-5ºC to 5ºC.

Added, optionally dropwise, glorieuses agent at this stage varies depending on the type and quantity of glorieuses agent. However, it usually takes from 30 minutes to 24 hours, preferably from 1 hour to 12 hours, more preferably from 1 hour to 6 hours.

The reaction temperature after the addition, optionally dropwise, glorieuses agent at this stage varies depending on the reagent, solvent, etc. But it usually ranges from-20ºC up to 5 º C, preferably from -10 º C to 5 º C, more preferably from-5ºC to 5ºC.

The reaction time after the addition, optionally dropwise, glorieuses agent at this stage varies depending on the reagent, solvent, reaction temperature, etc. But it usually takes from 30 minutes to 12 hours, preferably from 1 hour to 6 hours, more preferably from 1 hour to 3 hours.

After completion of the reaction at this stage, connect the s (IV) can be allocated by the way, usually used in the field of organic synthesis. The reaction liquid may also be used directly in the next stage (ii) without isolation of compound (IV).

The temperature of the subsequent processing after the reaction at this stage is usually from -20 º C to 15 ° C, preferably from -10 º C to 15 ° C, more preferably, from 0 ° C to 15 ° C.

Stage (ii)

This stage represents the stage, including the production of compound (II) by reacting the compound (IV) with compound (V) or its salt in a solvent in the presence of a base.

The amount of compound (IV) at this stage is usually from 0.5 to 3 moles, preferably 0.8 to 2 moles, more preferably from 0.9 to 1.2 mol per 1 mol of compound (V).

Used at this stage, the solvent has no particular restrictions, provided that it is to some extent dissolve the source material and did not inhibit this reaction. This solvent may constitute, for example, ether solvent such as tetrahydrofuran, diethyl ether or dioxane; halogenated solvent such as dichloromethane or 1,2-dichloroethane; an aromatic hydrocarbon solvent such as benzene, toluene or xylene; a nitrile solvent such as acetonitrile, propionitrile or benzonitrile; or an amide solvent, that is Oh as dimethylformamide, dimethylacetamide or dimethylimidazolidin. Ether solvents, halogenated solvents, nitrile solvents, amide solvents are preferable, more preferable tetrahydrofuran, dichloromethane, acetonitrile or dimethylacetamide.

Used at this stage, the Foundation has certain limitations. Preferred tertiary amines, for example trialkylamines, such as triethylamine, tributylamine or diisopropylethylamine; or trialkylamine, such as diazabicyclo, databaseconnect or tetramethylethylenediamine preferred trialkylamine, even more preferred triethylamine, tributylamine or diisopropylethylamine.

The amount of base used at this stage, is usually from 0.5 to 3 moles, preferably from 0.5 to 2 moles, more preferably from 0.7 to 1.5 moles per 1 mol of compound (V).

At this stage, the promoting effect, as expected, has a presence in the reaction system ammonium salt or Quaternary ammonium salt.

Promoting the reaction of the additive may constitute, for example, Quaternary ammonium salts, including those of tetraalkylammonium halides with alkyl groups containing from 1 to 20 carbon atoms, such as chloride of Tetramethylammonium, bromide of Tetramethylammonium chloride to tetraethyl one, bromide of tetraethylammonium, tetrabutylammonium chloride, tetrabutylammonium bromide, or halides of trialkylaluminium with alkyl groups containing from 1 to 20 carbon atoms, such as chloride of trimethylantimony or chloride of triethylenediamine; bromides of alkali metals, including lithium bromide, sodium bromide, potassium bromide or cesium bromide; or iodides of alkali metals, including lithium iodide, sodium iodide, potassium iodide or cesium iodide. The preferred bromide of tetraethylammonium, tetrabutylammonium bromide or sodium iodide.

The amount of promoting the reaction of the additives used at this stage is usually from 0.01 to 5 moles, preferably from 0.1 to 2 Mols per 1 mol of compound (VI) for Quaternary ammonium salts and, usually, from 0.001 to 0.6 moles, preferably from 0.01 to 0.5 moles per 1 mol of compound (VI) to bromides of alkali metals or alkaline iodides of metals.

The reaction temperature in this stage varies depending on the reagent, solvent, etc. But it usually ranges from -20 º C to 100 º C, preferably from -10 º C to 70 º C, more preferably from 0 º C to 60 º C.

The reaction time at this stage varies depending on the reagent, solvent, reaction temperature, etc. But it usually takes from 30 minutes to 24 hours, preferably from 1 hour to 12 hours, more preferred the equipment, from 1 hour to 10 hours.

After completion of the reaction at this stage the compound (II) can be isolated by the method commonly used in the field of organic synthesis. The reaction liquid may also be used directly in the next stage (iii) without isolation of compound (II). However, it is preferable to separate the compound (II) and clean it by recrystallization. Due to this further reduced content of by-product satr in prasugrel the hydrochloride, which is the end product of the present invention, then you can expect to receive high-purity prasugrel hydrochloride.

The solvent used for the recrystallization of compound (II), with no particular restrictions, provided that it is to some extent dissolve the compound (II) and doesn't come with compound (II) in the reaction. This solvent may constitute, for example, ether solvent such as tetrahydrofuran, diethyl ether or dioxane; halogenated solvent such as dichloromethane or 1,2-dichloroethane; an aromatic hydrocarbon solvent such as benzene, toluene or xylene; a nitrile solvent such as acetonitrile, propionitrile or benzonitrile; or an amide solvent such as dimethylformamide, dimethylacetamide or dimethylimidazolidin. Ethereal solvents or realnye solvents are preferred, more preferred acetonitrile.

Temperature during recrystallization, usually from 30 º C to 80 ° C, preferably from -40 º C to 70 º C, more preferably from -40 º C to 60 º C. After dissolving, the solution is gradually cooled. Preferably, thereto was added a weak solvent (preferably water) at 30 º C, then the solution was subjected to cooling to a temperature of from-5ºC to 10ºC and stirring for from 1 hour to 6 hours. Also, if you want, you can add the seed crystal.

Stage (iii)

This stage represents the stage, including acetylation of compound (II) by carrying out the reaction with azetiliruet reagent in a solvent in the presence of base and catalyst for the acylation with the purpose of obtaining compound (I).

Used at this stage the catalyst for the acylation may represent, for example, 4-dialkylaminoalkyl, such as 4-dimethylaminopyridine, 4-diethylaminophenyl or 4-dipropylamine, and preferably is 4-dimethylaminopyridine.

The number of acylation catalyst used at this stage, is usually from 0.1 to 10 mol.% 1 mol of compound (II), the catalyst may be used in excess.

Used at this stage acetylide agent can represent, for example, acetic anhydride or ACET chlorid and preferably is acetic anhydride.

The amount of acetic anhydride used at this stage, usually from 1 to 10 moles, preferably 1 to 5 moles per 1 mole of compound (II).

Used at this stage, the solvent has no particular restrictions, provided that it is to some extent dissolve the source material and did not inhibit this reaction. This solvent may constitute, for example, ether solvent such as tetrahydrofuran, diethyl ether or dioxane; halogenated solvent such as dichloromethane or 1,2-dichloroethane; an aromatic hydrocarbon solvent such as benzene, toluene or xylene; a nitrile solvent such as acetonitrile, propionitrile or benzonitrile; or an amide solvent such as dimethylformamide, dimethylacetamide or dimethylimidazolidin. Ether solvents, halogenated solvents, nitrile solvents, amide solvents are preferable, more preferable tetrahydrofuran, dichloromethane, acetonitrile or dimethylacetamide.

Used at this stage, the Foundation has certain limitations. Preferred tertiary amines, for example, trialkylamine, such as triethylamine, tributylamine or diisopropylethylamine; or trialkylamine, such as Diaz is bicicletta, databaseconnect or tetramethylethylenediamine preferred trialkylamine, even more preferred triethylamine.

The amount of base used at this stage, usually from 1 to 10 moles, preferably 1 to 5 moles per 1 mole of compound (II).

The reaction temperature in this stage varies depending on the reagent, solvent, etc. But it usually ranges from -50 º C to 50 º C, preferably from -30 º C to 30 º C, more preferably from -20 º C to 20o C.

The reaction time at this stage varies depending on the reagent, solvent, reaction temperature, etc. But it usually takes from 30 minutes to 24 hours, preferably from 1 hour to 12 hours, more preferably from 1 hour to 6 hours.

After completion of the reaction at this stage, the compound (I) can be isolated by the method commonly used in the field of organic synthesis. The reaction liquid may also be used directly in the next stage (iv) without isolation of compound (I).

Stage (iv)

This stage is a stage that includes receiving prasugrel hydrochloride by adding to the compound (I) in the solvent of hydrochloric acid, optionally dropwise.

At this stage the addition of hydrochloric acid, optionally dropwise, can be carried out by adding an acid is added dropwise, or add it at once, or two, or more separate portions.

Used at this stage, the solvent has no particular restrictions, provided that it is to some extent dissolve the source material and did not inhibit this reaction. This solvent may constitute, for example, aliphatic hydrocarbons such as hexane, cyclohexane, heptane or ligroin, or petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, chlorobenzene or dichlorobenzene; simple ether, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane or dimethyl ether of diethylene glycol; a ketone, such as acetone, methyl ethyl ketone or diethylketone; ester such as ethyl acetate, propyl or butyl acetate; carboxylic acid such as acetic acid or propionic acid; NITRILES, such as acetonitrile or propionitrile. Ethers, ketones, esters, carboxylic acids or NITRILES are preferred; more preferred tetrahydrofuran, dioxane, acetone, methyl ethyl ketone, ethyl acetate, acetic acid or acetonitrile; even more preferred tetrahydrofuran, dioxane, acetic acid or acetone; most preferred is Elen acetone.

The reaction temperature in this stage varies depending on the reagent, solvent, etc. But it usually ranges from -20 º C to 100 º C, preferably from 0 º C to 70 º C, more preferably from 30 º C to 60 º C, most preferably from -40 º C to 55 º C.

The reaction time at this stage varies depending on the reagent, solvent, reaction temperature, etc. But it usually takes from 5 minutes to 10 hours, preferably from 10 minutes to 5 hours.

The preferred implementation of this stage is a process comprising dissolving the compound (I) in acetone, added dropwise to this solution half of the required number (usually required number equimolar thienopyridines form) of concentrated hydrochloric acid at a temperature of from 0 º C to 70 º C (preferably from 35 º C to 60 º C) for a time from 2 minutes to 10 minutes, if necessary, adding the seed crystal and the subsequent reaction at the same temperature, carried out for from 30 minutes to 2 hours, then adding dropwise the remaining necessary amount of concentrated hydrochloric acid for 30 minutes up to 2 hours and subsequent reaction at a temperature of from 0 º C to 70 º C (preferably from 25 to 55 º C), carried out for from 1 hour to 3 hours.

After the reaction at this stage prasugrel hydrochlor the d of the present invention are selected from the reaction mixture in the usual way. For example, the desired compound is obtained by filtering off the precipitated crystals after completion of the reaction or distillation of the solvent after the reaction. The obtained target compound, if necessary, may be subjected to further purification in the usual way, for example by recrystallization, precipitation or chromatography.

Prasugrel hydrochloride of the present invention can be left in the air or recrystallized to absorb water, causing it absorbs water and / or converted to hydrate; containing water connection is also prasugrel hydrochloride of the present invention. In addition, his MES containing any quantity of the solvent is also prasugrel hydrochloride of the present invention.

Content satr in prasugrel the hydrochloride was measured by liquid chromatography and expressed as percentage of area (%), reflecting the content of satr free prasugrel.

Content satr in high purity prasugrel the hydrochloride of the present invention usually is 0.3% or less, preferably, 0.1% or less, more preferably 0.04% or less, even more preferably of 0.03% or less, particularly preferably of 0.02% or less.

The purity prasugrel hydrochloride, i.e. the content of prasuhn the La, can be measured as described in regard to the content of satr.

The degree of purity high purity prasugrel hydrochloride in accordance with the present invention is typically 95% or more, preferably 97% or more, more preferably 99% or more.

High purity prasugrel hydrochloride obtained in the present invention, has excellent absorption in the oral cavity, the ability to activate metabolism and inhibit platelet aggregation, low toxicity and good stability during storage and manipulation, therefore, it is applicable as a drug (preferably, a prophylactic or therapeutic agent for the treatment of diseases caused by thrombi or emboli (in particular, a therapeutic agent), more preferably, a prophylactic or therapeutic agent to combat thrombosis and embolism (in particular, a therapeutic agent)). In addition, preferably the use of this drug to a warm-blooded animal, more preferably, for a person.

When used as a therapeutic or prophylactic agent for the treatment of these diseases is high-purity prasugrel hydrochloride of the present invention may be introduced by itself or in a mixture with a pharmaceutical is viable by excipients, diluent, etc. orally in the form of tablets, capsules, granules, powders, syrups and the like, or parenterally in the form of injections, suppositories, etc.

These songs get well-known methods using additives, including fillers (which may be, for example, organic fillers (e.g., derivatives of sugars, such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum Arabic; dextran; or pullulan); or inorganic fillers (e.g., derivatives, salts of silicic acid, such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate or aluminate metasilicate magnesium; phosphate, such as acidic calcium phosphate; carbonates such as calcium carbonate; or sulfates such as calcium sulfate)), lubricants (which may represent, for example, stearic acid; metal salts of stearic acid such as calcium stearate or magnesium stearate; talc; waxes, such as beeswax or spermaceti; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; D,L-leucine; laurilsulfate, such as laurylsulfate the sodium or valium magnesium; silicates such as silicic anhydride or hydrosilicate; or derivatives of starch, above), the binder (which may represent, for example, hydroxypropylcellulose, hypromellose, polyvinylpyrrolidone, macrogol or compounds similar to the above excipients, disintegrators (which may represent, for example, derivatives of cellulose, such as having the lowest Deputy hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose or having internal cross connections sodium carboxymethylcellulose; chemically modified starch/cellulose, such as carboximetilkrahmal, sodium salt of carboxymethyl amylum or poperechnyy polyvinylpyrrolidone; or derivatives of starch, as described above), emulsifying agents (which may represent, for example, colloidal clay, such as bentonite or veegum; metal hydroxides such as magnesium hydroxide or aluminum hydroxide; anionic surfactants such as sodium lauryl sulfate or calcium stearate; cationogenic surfactants, such as benzalconi chloride; nonionic surfactants such as polyoxyethyleneglycol ether, polyoxyethylene ether sorbitan and fatty acid or ester of sucrose and W is nuclear biological chemical (NBC acid), stabilizers (which may represent, for example, para-hydroxybenzoic esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenethyl alcohol; benzylaniline; phenols, such as phenol or cresol; thimerosal; along with dehydroacetic acid or sorbic acid), modifiers (which may be, for example, commonly used sweeteners, poikilitically or substances, corrective taste and smell) and thinners.

They used the number may vary depending on symptoms, age and the like, it is possible to introduce adults from one to seven times a day orally with a lower limit of a single dose of 0.1 mg (preferably 1 mg) and the upper limit of a single dose of 1000 mg (preferably 500 mg) or intravenously with a lower limit of a single dose of 0.01 mg (preferably, 0.1 mg) and the upper limit of a single dose of 500 mg (preferably, 250 mg) depending on the symptoms. Thus, the amount per dose for a person weighing 60 kg is 0,0017 mg/kg (preferably 0.017 mg/kg) as the lower limit and 17 mg/kg (preferably, 8,3 mg/kg) as the upper limit for oral administration and 0,00017 mg/kg (preferably 0,0017 mg/kg) as the lower limit and 8.3 mg/kg (preferably, 4,2 mg/kg) as the upper limit for intravenous injection.

EXAMPLES

Below, the present and the finding described in more detail with reference to examples, reference examples and test examples. However, they present invention is not limited.

Example 1

(1) 2-Fluoro-α-cyclopropanecarbonitrile (stage (i))

A mixture of 100 g cyclopropyl-2-forbindelsen and 886 g of dichloromethane was stirred under ice cooling with the purpose of obtaining a mixed solution. The obtained mixed solution was purged 3,98 g (0.1 equivalent) of gaseous chlorine for 20 minutes, maintaining the temperature of the solution is not higher than 5 º C, then stirred for 0.5 hours at the same temperature. Then the solution was purged of 39.8 g (1 equivalent) of gaseous chlorine in a period of 220 minutes at the same temperature, the reaction was conducted under stirring for one hour at the same temperature.

After completion of the reaction in the resulting reaction solution under stirring was added dropwise 236 g of 3% aqueous sodium thiosulfate solution, maintaining the solution temperature not higher than 15ºC. After adding the solution dropwise stirred for 10 minutes, then the liquid phase was separated. The obtained organic layer was washed sequentially 589 g pre-cooled 8% aqueous solution of sodium bicarbonate and 168 g of pre-cooled water, and then concentrated under reduced pressure to obtain 145 g of compound indicated in the title (the content of pure substance of 95.4 g, yield 80%), oily the second form. During these operations the temperature of the solution was maintained in the range from 0 ° C to 15 ° C.

(2) 2-(tert-Butyldimethylsilyloxy)-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine (stage ii))

To a mixture of 115 g of 5,6,7,7a-tetrahydro-4H-thieno[3,2-C]pyridine-2-he p-toluensulfonate, of 60.7 g of tert-butyldimethylchlorosilane and 277 g of dichloromethane was added 40,7 g of triethylamine, the mixture is then stirred at 25 º C for 1 hour with obtaining a mixed solution. To this stirred solution was added to 78.1 g of 2-fluoro-α-cyclopropanecarbonitrile obtained in paragraph (1), and 70.8 g of triethylamine and 1.57 g of sodium iodide, the reaction between them is then carried out with stirring for 1 hour at 45 º C and another 5 hours at 52º.

After completion of the reaction in the resulting reaction solution was added the total amount of phosphate buffer solution prepared by adding distilled water to 9,50 g KN2RHO4and 0.95 g of Na2HPO4·N2About to of the total weight 358 g, then the liquid phase was separated, then the aqueous layer was subjected to the reversible extraction of 116 g of dichloromethane. The obtained organic layers were combined and concentrated under reduced pressure until the volume balance is not reached 218 Jr. added 476 g of acetonitrile, after which the resulting mixture was concentrated under reduced pressure until the volume of the OST is TKA has not reached 517 ml To the obtained residue were added 238 g of acetonitrile and stirred at 30 º C for 30 minutes. Then added 122 g of water and stirred at 0 ° C for 3 hours. The precipitated crystals were separated by filtration, washed 69,0 g pre-cooled acetonitrile and dried under reduced pressure, getting 131 g of compound specified in the header.

(3) 2-Acetoxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine (stage iii))

To a mixture of 15.0 g of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine obtained in paragraph (2), 5.10 g of triethylamine, 41.3 mg of 4-dimethylaminopyridine and 75 g of acetonitrile dropwise added 3,90 g of a solution of acetonitrile, which was dissolved 4,13 g of acetic anhydride, the reaction mixture was carried out under stirring at 0 ° C for 1 hour.

After completion of the reaction in the resulting reaction solution was added 50.6 g of cold water and stirred at-15 ° C 30 minutes. The precipitated crystals were separated by filtration, washed mixed with a solution of 15.1 g of acetonitrile and 11.9 g of water and dried under reduced pressure, obtaining 10.8 g of the connection specified in the header.

The melting point of 122 to 124º.

(4) the Hydrochloride of 2-acetoxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (stage (iv))

To 8.00 g of 2-acetoxy-5-(α-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine, obtained in paragraph (3), and 398 mg of the activated clay was added 43 g of acetone, and then the resulting mixture was stirred at 32º. The reaction solution was filtered, the residue washed to 4.41 g of acetone, and then to this solution at 52º was added dropwise 1.12 g of 36%concentrated hydrochloric acid for one minute. As the seed crystals added 238 mg of B2 crystals obtained by the method described in laid the Japan patent No. 2002-145883, and then stirred at the same temperature for one hour. In addition, dropwise added 1.07 g of 36%concentrated hydrochloric acid for one hour, then the solution was stirred 2 hours at -40 ° C and 1 h at 30ºC. The precipitated crystals were separated by filtration, washed with 15.8 g of acetone, dried under reduced pressure at 50 º C for 5 hours, after receiving 8,03 g of compound specified in the header.

Melting point 194 to 197º.

Example 2

(1) 2-(tert-Butyldimethylsilyloxy)-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine (stage ii))

To 40,0 g of compound (II), not subjected to recrystallization obtained in example 1(2), added 252 g of acetonitrile, and then stirred at 50 º C for 10 minutes and cooled to 30ºC. Then to the solution dropwise over 30 minutes was added 40 g of water at the same temperature, then the solution was cooled to 0OC and stirred relieved by the same temperature for 3 hours. The precipitated crystals were separated by filtration, washed with 30 g of pre-cooled acetonitrile, dried under reduced pressure, obtaining of 37.6 g of compound specified in the header.

(2) 2-Acetoxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine (stage iii))

Using 22,5 g of 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine obtained in paragraph (1), carried out the reaction and post-treatment as described in example 1(3), having a 16.4 g of compound specified in the header.

The melting point of 122 to 124º.

(3) the Hydrochloride of 2-acetoxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (stage (iv))

Using 8.00 g of 2-acetoxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine obtained in paragraph (2), carried out the reaction and post-treatment as described in example 1(4), having 8,01 g of compound specified in the header.

The melting point of 192 to 196º.

Comparative example 1

(1) 2-Fluoro-α-cyclopropanecarbonitrile (stage (i))

A mixture of 100 g cyclopropyl-2-forbindelsen and 886 g of dichloromethane was stirred under ice cooling with the purpose of obtaining a mixed solution. The obtained mixed solution was purged 3,98 g (0.1 equivalent) of gaseous chlorine for 0 minutes maintaining the temperature of the solution is not higher than 5 º C, then stirred for 0.5 hours at the same temperature. Then the solution was purged of 39.8 g (1 equivalent) of gaseous chlorine in a period of 220 minutes at the same temperature, then the temperature of the solution gradually increased up to 20 ° C, the reaction was conducted under stirring for one hour.

After completion of the reaction in the resulting reaction solution under stirring was added dropwise to 500 ml of pre-cooled water, then the solution was stirred 10 minutes, the liquid phase was separated. The obtained organic layer was washed sequentially 833 ml of a saturated aqueous solution of sodium bicarbonate and 333 ml of water, then concentrated under reduced pressure to obtain 129 g of compound indicated in the title (the content of pure substance 96,1 g, yield 81%)in oily form.

(2) the Hydrochloride of 2-acetoxy-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (stage (ii)-(iv))

Using 105 g (content of pure substance to 78.3 g), 2-fluoro-α-cyclopropanecarbonitrile obtained in paragraph (1), carried out the reaction and post-treatment as described in example 1(2)-(4), having 8,10 g of compound specified in the header.

Melting point 194 to 196º.

Reference example 2

(Production of standard contaminants satr)

(1) -Chloro-1-(2-forfinal)pentane-2-he

To 5,00 g cyclopropyl-2-forbindelsen added 25 ml of 36%concentrated hydrochloric acid, after which the solution was stirred at 100 º C for 2.5 hours. After completion of the reaction, the reaction solution was cooled and added to it 50 ml of water and 50 ml of dichloromethane to separate phases. The obtained organic layer was washed with 50 ml of saturated aqueous sodium hydrogen carbonate solution, dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure, obtaining 6,70 g of compound indicated in the title, in oily form.

(2) 1,5-Dichloro-1-(2-forfinal)pentane-2-he

To 9,44 g of 5-chloro-1-(2-forfinal)pentane-2-it, obtained as described in paragraph (1), added 63 ml of dichloromethane, through the resulting solution was purged 119 ml of chlorine gas for 1 minute, maintaining the solution temperature is 15 ° C, then the solution was stirred at the same temperature for 0.5 hours. In addition, this solution was purged 1.19 liters of chlorine gas at the same temperature for 10 minutes, after which the solution was stirred at the same temperature for 1.5 hours to implement the response.

After completion of the reaction in the resulting reaction solution was added 22 ml of 3%aqueous solution of sodium sulfite to separate the aqueous phase. The obtained organic layer was successively washed with 56 ml of 8%aqueous solution of hydrocarbon is that of sodium, and 16 ml of water, dried with anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to distillation under reduced pressure, obtaining 3.80 g fractions containing the desired compound (100ºC-105º/48 PA). In addition, this fraction was purified on a chromatographic column filled with silica gel (eluent: n-hexane/ethyl acetate = 19/1 (about./vol.), getting to 1.21 g of compound specified in the header.

(3) 2-Acetoxy-5-(5-chloro-1-(2-forfinal)-2-oxobutyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine

Using 1,21 g of 1,5-dichloro-1-(2-forfinal)pentane-2-it is obtained in paragraph (2), carried out the reaction and post-treatment as described in example 1 (2) and (3)with 1,71 g of the crude material containing the connection specified in the header. In addition, this material was purified on a chromatographic column filled with silica gel (eluent: n-hexane/ethyl acetate = 5/1 → 3/1 (vol./vol.), receiving of 0.77 g of compound indicated in the title, in oily form.

Mass spectrum (Cl, mass/charge): 410 [M+H]+.

1H NMR spectrum (400 MHz, CDCl3) δ ppm: 1,97-2,05 (m, 2H), and 2.26 (s, 3H), 2,66 was 2.76 (m, 3H), and 2.79 (t, J=5.4 Hz, 2H), 2,85-2,90 (m, 1H), 3,43-3,59 (m, 4H), 4,74 (s, 1H), and 6.25 (s, 1H), 7,10-7,20 (m, 2H), 7,31 and 7.36 (m, 1H), 7,42-7,47 (m, 1H).

Test example 1

(Method of measuring the content of prasugrel and satr in prasugrel the hydrochloride)

The content of prasugrel and satr in prasugrel the hydrochloride is smerilli, as is described below.

In the mixed solution of acetonitrile-water (7:3) was dissolved 150 mg prasugrel hydrochloride to 100 ml With the following conditions 10 ál of this solution was subjected to analysis by liquid chromatography.

The measurement conditions (liquid chromatography)

Detector: ultraviolet absorptiometer (wavelength 240 nm)

Analytical column: Cadenza CD-C18, inner diameter 4.6 mm, length 15 cm, a particle size of 3 μm

Protective column: missing

The column temperature: -40 ° C

Mobile phase: 0.01 mol/l aqueous solution of potassium dihydrophosphate:tetrahydrofuran:acetonitrile in the ratio of 13:5:2 (about./about./about.)

Flow rate: 1.0 ml/min

Table 1
(Contents satr in prasugrel the hydrochloride)
Content (%) satr in prasugrel the hydrochloride
Example 10,031
Example 20,014
Reference example 10,042

The content of prasugrel and satr expressed in percent by area (%) when measured by the method described above liquid chromatography. The results zhidkokristallicheskogo analysis prasugrel guide is ochloride, obtained in examples 1 and 2 and reference example 1 are presented in figures 1, 2 and 3, respectively.

Content satr in the final product - prasugrel the hydrochloride was significantly lower in examples 1 and 2, in which the addition of gaseous chlorine and the subsequent reaction stage (i) was carried out at a lower temperature than in the reference example 1 in which the reaction after adding gaseous chlorine was carried out at room temperature. In addition, the contents satr in the final product - prasugrel the hydrochloride was lower than in example 2, in which 2-(tert-butyldimethylsilyloxy)-5-(α-cyclopropanecarbonyl-2-terbisil)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine obtained in stage (ii), was purified by recrystallization than in example 1, in which the recrystallization step was not performed.

Industrial applicability

Because the present invention provides high purity prasugrel hydrochloride with a reduced content of impurities such as by-product of satr, and how to obtain it.

1. The method of obtaining prasugrel hydrochloride, comprising the following stages:
(i) chlorination of compounds corresponding to the formula

by adding to it glorieuses agent, optionally dropwise, in a solvent;
(ii) the interaction of the compounds of the formula

with a compound corresponding to the General formula

where R is a protective group for hydroxyl,
or its salt in a solvent in the presence of a base;
(iii) acetylation of the obtained compounds corresponding to the General formula

where R has the same meaning indicated above,
by interacting reactions with azetiliruet agent in a solvent in the presence of base and catalyst for the acylation; and
(iv) adding hydrochloric acid, optionally dropwise, to the obtained compound corresponding to the formula

in a solvent to obtain prasugrel hydrochloride, corresponding to the formula

characterized in that in stage (i) the temperature during the addition, optionally dropwise, glorieuses agent ranges from -20°C to 5°C, and the reaction temperature after the addition, optionally dropwise, glorieuses agent ranges from -20°C to 5°C.

2. The method according to claim 1, characterized in that in stage (i) the temperature during the addition, optionally dropwise, glorieuses agent is from -10°C to 5°C, and the reaction temperature after the addition, optionally dropwise, glorieuses agent is from -10°C to 5°C.

3. The method according to claim 1, characterized in that in stage (i) temperature is during add, optional dropwise, glorieuses agent ranges from -5°C to 5°C, and the reaction temperature after the addition, optionally dropwise, glorieuses agent ranges from -5°C to 5°C.

4. The method according to claim 1, characterized in that the temperature of the subsequent processing after the reaction in stage (i) is from -20°C to 15°C.

5. The method according to claim 1, characterized in that the temperature of the subsequent processing after the reaction in stage (i) is from -10°C to 15°C.

6. The method according to claim 1, characterized in that the temperature of the subsequent processing after the reaction in stage (i) is from 0°C to 15°C.

7. The method according to claim 1, in which gloriouse agent is a chlorine gas.

8. The method according to claim 1, in which R denotes a group of General formula:

where R1, R2and R3independently mean alkyl group containing from 1 to 10 carbon atoms, or aryl group.

9. The method according to claim 8, in which R1, R2and R3independently mean alkyl group containing from 1 to 5 carbon atoms, or phenyl group.

10. The method according to claim 1, in which R is tert-butyldimethylsilyloxy group.

11. The method according to claim 1, characterized in that the compound obtained of General formula (II) in stage (ii) is recrystallized from ethers or NITRILES.

12. The method according to claim 1, great for the present, however, that the compound obtained of General formula (II) in stage (ii) is recrystallized from acetonitrile.

13. The method according to claim 1, in which acetylide agent is an acetic anhydride.

14. The method according to claim 1, characterized in that the output stage (iii) compound corresponding to the formula (I), used in the next stage (iv) without purification.

15. The product is suitable for the prevention or treatment of thrombosis or embolism, containing prasugrel hydrochloride and satr in the amount of not more than 0.3%, obtained by the method according to claim 1.

16. The product is suitable for the prevention or treatment of thrombosis or embolism, containing prasugrel hydrochloride and satr in the amount of not more than 0.1%, obtained by the method according to claim 1.

17. The product is suitable for the prevention or treatment of thrombosis or embolism, containing prasugrel hydrochloride and satr in the amount of not more than 0,04%obtained by the method according to claim 1.

18. The product is suitable for the prevention or treatment of thrombosis or embolism, containing prasugrel hydrochloride and satr in the amount of not more than 0.03%, obtained by the method according to claim 1.

19. The product is suitable for the prevention or treatment of thrombosis or embolism, containing prasugrel hydrochloride and satr in an amount not more than 0.02%, obtained by the method according to claim 1.

20. Pharmaceutical composition containing as an active ingredient the product PP-19.

21. Pharmaceutical composition containing as an active ingredient the product PP-19 intended for the prevention or treatment of warm-blooded animals diseases caused by thrombi or emboli.

22. The pharmaceutical composition intended for the prevention or treatment of a person thrombosis or embolism, comprising as active ingredient the product PP-19.

23. The use of a product according to any one of PP-19 for obtaining a medicinal product intended for the prevention or treatment of warm-blooded animals diseases caused by thrombi or emboli.

24. The use of a product according to any one of PP-19 for obtaining a medicinal product intended for the prevention or treatment of a person thrombosis or embolism.

25. The method of prevention or treatment of diseases caused by thrombi or emboli, including the introduction of a warm-blooded animal a pharmaceutical composition containing as an active ingredient a product according to any one of PP-19.

26. The method of prevention or treatment of diseases caused by thrombosis or embolism, comprising the administration to a human a pharmaceutical composition containing as an active ingredient a product according to any one of PP-19.



 

Same patents:

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SUBSTANCE: invention refers to organic chemistry, more specifically to a method of olanzapine purification which involves mixing olanzapine with an organic acid in an organic solvent or a mixture of organic solvents to prepare acid-additive olanzapine salt, precipitation and isolation of acid-additive olanzapine salt and transforming acid-additive olanzapine salt in olanzapine; the organic acid is carboxylic acid which is selected from the group including oxalic, fumaric and benzoic acid.

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38 cl, 1 tbl, 25 ex

FIELD: chemistry.

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6 cl, 19 ex, 1 tbl

FIELD: chemistry.

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Organic compounds // 2430921

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,

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17 cl, 8 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing prasugrel hydrochloride of the formula:

,

with low content of "ОХТР", involving preparation of free prasugrel containing "ОХТР" from 2-silyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, dissolving the obtained free prasugrel in an inert solvent and optionally adding hydrochloric acid in drops to the solution for reaction.

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2 cl, 6 dwg, 1 tbl, 2 ex

FIELD: chemistry.

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38 cl, 43 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting PI3 kinase inhibitor activity. In the formula (I), A represents a thiophen ring; n=1; R1 represents , where m=1; R30 represents H; R4 And R5 together with N atom whereto attached form a 5- or 6-members N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N and O which is unsubstituted or substituted by one or more substitutes selected from C1-6alkyl, C1-6alkoxy, -N(R"')-alk-OR, -alk-OR, -O-alk-OR, -alk-C(O)NR2, -C(O)NR2, -alk-Het, -N(R)-Het, -O-Het, -N(R)-C(O)- alk-OR, -NR-S(O)2R, -N(R)-alk-S(O)2R, -N(R)-alk-OR, -alk-NR'R", -N(R"')-S(O)2R, S(O)2R"', -S(O)2-alk-ORf 5- or 6-members N-containing heterocyclic group, 5- or 6-members N-containing heteroaryl group which includes 0 or 1 additional heteroatom selected from N, O or S, oxo(=O), -SO2NR2, -SO2-alk-NR2 where alk means a C1-6alkylene chain; Het means a 5- or 6-members N-containing heteroaryl group or furan optionally substituted by C1-6alkyl; R means H or C1-6alkyl, or when 2 groups R are bound with N, they together with N atom form a saturated 5- or 6-members N-containing heterocyclic group; each R' and R" means independently H, C1-6alkyl or C1-6alkoxy; R'" represents C1-6alkyl, a 5- or 6-merous saturated N-containing heterocyclic group, or a 5- or 6-merous N-containing heteroaryl group; R2 means where R6 and R7 together with N atom whereto attached form a morpholine group; R3 represents an indazole group.

EFFECT: development of the effective method of preparing the compounds of formula (I), and their application for preparing a drug, a pharmaceutical composition, and a method of inhibition.

10 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the new fused pyrimidines of formula (I) and to their pharmaceutically acceptable salts exhibiting P13 kinase inhibitor properties; in formula (I), A represents a thiophen ring; n=1; R1 represents a group of formula , where m=1; R30 represents hydrogen; R4 and R5 together with N atom whereto attached form a 5- or 6-members saturated N-containing heterocyclic group which includes 1 additional heteroatom selected from N which is unsubstituted or substituted by C1-C3alkyl which can be substituted by OH; S(O)2C1-3alkyl; C(O)N(diC1-C3alkyl); N(CH3)2; CON(CH3)-CH2CH2OCH3; N(CH3)-CH2CH2OCH3; -C(O)morpholine or morpholine; R2 is selected from where R6 and R7 together with nitrogen atom whereto attached form a morpholine group which is unsubstituted; and R3 represents an indole group which is unsubstituted.

EFFECT: production of the compounds of formula (I), a pharmaceutical composition, their application for preparing a drug and a method of inhibition.

9 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to condensed heterocyclic derivative, represented by formula (I): where ring A represents 5-member monocyclic heteroaryl, containing 1 or 2 heteroatoms, selected from N or S; RA represents lower alkyl group, optionally substituted with hydroxyl group, COW1, COOW1 or CONW2W3, in which W1-W3 independently represent a hydrogen atom or lower alkyl group; m represents integer 0 or 2; ring B represents benzene ring or thiophene ring; RB represents halogen atom, cyano group, lower alkyl group or OW4, in which W4 represents a hydrogen atom or lower alkyl group; n represents integer 0-2; E1 represents an oxygen atom; E2 represents an oxygen atom; U represents a single bond or lower alkelene group; X represents group, represented by Y, -CO-Y, -SO2-Y, -S-L-Y, -O-L-Y, -CO-L-Y, -SO-L-Y, -SO2-L-Y, -S-Z or -O-Z, in which L represents a lower alkylene group optionally substituted with halogen or hydroxy group; Y represents group, represented by Z or -NW7W8, where W7 and W8 independently represent a hydrogen atom, lower alkyl group or Z on condition that W7 and W8 are not simultaneously hydrogen atoms, or W7 and W8 can bind together with adjacent nitrogen atom with formation of cyclic amino group; Z represents cycloalkyl group, optionally condensed with phenyl and optionally substituted with phenyl group, optionally substituted with halogen or alkoxy group; 6-8-member heterocycoalkyl group, which has 1 heteroatom, selected from nitrogen atom or oxygen atom, optionally condensed with phenyl and optionally substituted with phenyl; phenyl group optionally substituted with a substituent, selected from group, consisting of a halogen atom, cyano group, alkyl group, optionally substituted with halogen atom, hydroxy group or alkoxy group, alkoxy group, optionally substituted with halogen atom, hydroxy group, alkoxy group, alkoxy-carbonyl-oxy group or acyloxy group, alkylthio group, carboxy group and alkoxy-carbonyl group; pyridyl; or its pharmaceutically acceptable salt. Invention also relates to pharmaceutical composition possessing antagonistic activity with respect to gonatotropin-releasing hormone, based on the claimed compound.

EFFECT: obtained are novel compounds and based on them pharmaceutical composition, which can be applied in medicine for prevention or treatment of a disease depending on sex hormones, which is selected from group, consisting of benign prostatic hypertrophy, hysteromyoma, endometriosis, premature puberty, prostate cancer, ovarian cancer and breast cancer.

29 cl, 112 tbl, 428 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to application of thienopyridone derivatives of formula (I), in which B represents CH, represents , or , R represents H, R1 and R2, independently on each other, represent H, linear or branched (C1-C4)alkyl, (C1-C4)cycloalkyl, halogen or together form group -(CH2)n-, where n=1- 4, R3 and R4, independently on each other, represent H, R6 represents H, X represents -O-, or their pharmaceutically acceptable salts for preparation of pharmaceutical composition.

EFFECT: obtaining pharmaceutical composition, suitable for treatment of diabetes, metabolic syndrome and obesity.

8 cl, 1 tbl, 210 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula in which R1 means hydrogen or alkyl with 1-4 carbon atoms, R2 means hydrogen and L means an alkandiyl group with 1-4 carbon atoms, one CH2-group in which can be substituted by with oxygen atom or a group of formula: or in which * means a conjunction with nitrogen atom, R3 means hydrogen, methyl, propane-2-yl, propane-1-yl, imidazol-4-ylmethyl, hydroxymethryl or 4-aminobutan-4-yl, or R3 is connected with R1 together with which forms (CH2)3- or (CH2)4- -group, R4 means hydrogen or methyl, R5 means alkyl with 1-4 carbon atoms, and R6 means hydrogen or alkyl with 1-4 carbon atoms, and also to its salt and to a method of preparing it.

EFFECT: there are prepared new compounds which can find application in medicine for treating and/or preventing diseases, first of all thromboembolic diseases.

5 cl, 4 tbl, 23 ex

FIELD: medicine.

SUBSTANCE: polypeptide, which is used in composition of pharmaceutical composition and in sets for screening of adhesion inhibitors of platelet adhesion or aggregation, is obtained in recombinant way applying matrix of cDNA of Anopheles stephensi salivary gland.

EFFECT: invention makes it possible to obtain polypeptide which possesses inhibiting activity with respect to platelet aggregation or inhibiting activity with respect to platelet adhesion.

10 cl, 4 dwg, 5 ex

FIELD: chemistry.

SUBSTANCE: described is a novel compound of general formula (I): oligosaccharide-spacer-antagonist GpIIb/IIIa (1), where the oligosacharride is a negatively charged pentasaccharide residue of formula (B) (B), where R1 denotes OCH3 or OSO3-. The charge is compensated for by positively charged counterions; the spacer is essentially a pharmacologically inactive binding residue having length of 10-35 atoms; the GpIIb/IIIa antagonist is a tirofiban residue (MK 383). The spacer includes a covalent bond with a biotin analogue of formula -(CH2)4-X-BT, where X=NH, N(1-4C)alkyl, -N-CH(CH2OH)-CH2-C(O)-NH-, -NH-CH(CH3)-CH2-C(O)-NH-, -NH-CH(COOH)-CH2-C(O)-NH- or -NH-CH(CH2COOH)-CH2-C(O)-NH-, and BT is a label ; or pharmaceutically acceptable salt thereof.

EFFECT: compounds have antithrombotic activity and can be used to treat or prevent thrombotic diseases.

8 cl, 7 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: inventions relate to methods of obtaining therapeutically effective medication for treatment and/or improvement of condition in case of disseminated intravascular clotting (DIC), methods of treatment and/or improvement of conditions in case of DIC of patients in whose plasma activity of antithombin constitutes 40% or less. Essence of invention consists in the fact that applied is thrombomodulin obtained by transfection of cells-hosts by means of DNA, which codes amino-acid sequence SEQ ID NO: 9 or 11.

EFFECT: improvement of condition in case of disseminated intravascular clotting.

10 cl, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

, where radicals are described in the claims, as well as to salts and hydrates of said compound or salts thereof. The invention also relates to pharmaceutical compositions and medicinal agents for treating diseases associated with thrombosis.

EFFECT: highly effective treatment.

35 cl, 1 tbl, 488 ex

FIELD: medicine.

SUBSTANCE: invention refers to treating the patients over 50 years old suffering secondary hypothyroidism progressing as a result of surgical management of chiasmatic-cellar tumours. That is ensured by administration of thyreohormones in dose increased every 2 months to a therapeutic dose and observed hypothyroidism correction. There are also evaluated thrombocyte aggregation, packed cell volume, and thrombocyte count. If observing spontaneous thrombocyte aggregation (STA) more than 1 %, adenosine diphosphate (ADP) thrombocyte aggregations more than 75 %, with normal or higher packed cell volume: than 50 % in male patients, than 42 % in female patients, with thrombocyte count either normal, or exceeding 320*109/l, the disaggregant Curantyl 75 mg/day is also prescribed to ensure hypothyroidism correction.

EFFECT: decreased thrombocyte aggregation, improved microcirculation processes, immune status that in turn enables reducing side effects of hormonotherapy and time of selection of thyreohormone dosage.

2 ex

FIELD: medicine.

SUBSTANCE: invention refers to Trecresan applications as an acid lipase activator.

EFFECT: invention enables extending the range of cholesterol-lowering drugs.

2 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention represents an ointment for chemical skin burn prevention containing Vaseline and target additives, differing by the fact that the target additives are chondroitin sulphate, lanolin. And the ointment ingredients are taken in certain proportions, wt %.

EFFECT: more effective chemical skin burn prevention in an individual.

2 cl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

in modification 11, characterised by the following spectral data in the near infrared region [cm-1]: 4086, 4228, 4418, 4457, 4634, 4905, 5846, 5911, 6026, 6081, 6582, as well as to the amorphous form of this compound, characterised by the following spectral data in the near infrared region [cm-1]: 4006, 4081, 4224, 4307, 4403, 4634, 4875, 5193, 5865, 6017, 6073, 6696, 7028, 8452, 8873.

EFFECT: novel polymorphous and amorphous form of compounds of formula I is obtained, having high solubility compared to the existing modification.

6 cl, 7 ex, 8 tbl, 9 dwg

FIELD: medicine.

SUBSTANCE: copolymers of hetero-chain aliphatic poly-N-oxides of general formula (I) , where R=N, CH; x=2-4; y=0, 2; n=10-1000; q=(0.1-0.9)n; z=(0.1-0.9)n. Copolymers possess anti-oxidant action, therapeutic action as detoxicant and immunomodelling agent. Copolymers of formula (I) can be used as immunomodulating carrier for obtaining vaccinating medication and as carrier of medications for obtaining medications.

EFFECT: copolymers of hetero-chain aliphatic poly-N-oxides represent novel class of compounds possessing wide spectrum of pharmacological and vaccinating action, aimed at increase of safety in application, increase of technological and economical effectiveness and ecological safety of production of medications.

20 cl, 2 dwg, 13 tbl, 22 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing prasugrel hydrochloride of the formula:

,

with low content of "ОХТР", involving preparation of free prasugrel containing "ОХТР" from 2-silyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, dissolving the obtained free prasugrel in an inert solvent and optionally adding hydrochloric acid in drops to the solution for reaction.

EFFECT: novel method of producing prasugrel with low content of impurities, specifically "ОХТР" by-product.

2 cl, 6 dwg, 1 tbl, 2 ex

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