Substituted derivative of emininently and pharmaceutical composition based on it

 

(57) Abstract:

Describes the new substituted derivative of emininently General formula I or its salt, where R1represents a group which can be converted into amedieval group in vivo and selected from hydroxyamides or lower alkoxycarbonylmethyl; R2and R3are the same or different and each represents a carboxyl group or lower (alkoxy)carbonyl group; X1and X2are the same or different and each represents a lower alkylenes group; m is 0 or 1, n is 0 or 1, provided that when m is 0, n is 1, which has antagonistic activity against receptor GPIIb/IIIA, which can be used as a drug to relieve ischemic heart disease, as an aid for heart or vascular operations, medicines to relieve cardiovascular diseases and drugs for relief of peripheral arterial disease. In addition, the connection can be used as prodrugs possessing extremely high oral absorption SPE C.p. f-crystals, 1 Il., 9 table.

The technical field

The present invention relates to new substituted derivatives of emininently and their salts, which can be used as medicines, particularly as antagonists GPIIb/IIIa.

Prior art

For a long time after opening, Donne made in 1842 (see C. R. Acad. Sci. (Paris), 14, 336-368, 1842), platelets were considered as a component of blood necessary for hemostasis. Currently, it is found that platelets not only play a major role in the mechanism of hemostasis of blood, but also multiple functions upon the occurrence of arteriosclerosis, disorders of the cardiovascular system, including thrombotic disorders, cancer metastasis, inflammation, rejection after transplantation, and immunoreactive, etc. that are clinically significant. Thrombotic and ischemic disorders treated by restoring blood flow, using drugs or by physical means. However, it has recently been found to be clinically problematic phenomenon, namely, that after the restoration of blood flow, tissue damage blood vessels, including endothelial village funds, and so p. , enhances activation, adhesion and aggregation of platelets. For example, it was found that after the restoration of blood flow in the thrombolytic therapy with tissue plasminogen activator (t-PA) or etc., is activated fibrinolytic and coagulating activity, destroying the system balance between fibrinolysis and coagulation. Clinically, it causes a re-occlusion and therefore represents a serious problem in therapy (see J. Am. Coil. Cardiol., 12, 616-623, 1988). On the other hand, the popularity of percutaneous intraluminal coronary angioplasty (PTCA), giving some degree of good results in the treatment of disorders caused by coronary stenosis and Archostemata, such as angina, myocardial infarction, etc. However, this therapy leads to serious problems, damaging the tissue of the blood vessels, including endothelial cells, causing acute coronary obstruction and even re-stenosis, occurring in approximately 30% of medical cases. After this therapy to restore blood platelets play a major role in various thrombotic disorders (e.g., re-occlusion). So with these disorders tut satisfactory efficiency. GPIIb/IIIa is a membrane glycoprotein of platelets belonging to the integrin family (see Blood, 80, 1386-1404, 1992). Integrin is associated with adhesive proteins such as fibrinogen, factor von Willebrand and so on, and plays an important role in the terminal when the aggregation of blood platelets. Monoclonal antibodies directed against GPIIb/IIIa, peptides having the sequence RGD, and so on, exhibit high inhibitory activity against platelet aggregation. Some of them are already undergoing clinical trials.

Ones, low molecular weight antagonists GIIb/IIIa is known from Japanese patent application 4-288051 (antagonists of the fibrinogen receptor sulfonamida, presents the following link:

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and published Japanese patent application 6-25227 (cyclic imino-derivatives, represented by the following link:

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and described in Leo et al., (see JournaL of Medicinal Chemistry, 35, 4393-4407, 1992), where as an example the following connection:

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Pieperazinove derivatives of acetic acid following General formula are described in the published patent application PCT WO 93/10091:

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where X1and Y1identical or different, represent CH or N;

X2dostavljati a CH;

Z=N or N+R5< / BR>
R1represents a hydrogen atom or a hydroxyl,

C1-4alkyl or 2,2,2-triptoreline group;

R2represents a hydrogen atom or, when both X1and X2= CH, may also represent a fluorine atom, chlorine or bromine, or C1-4alkyl group;

R3represents a hydrogen atom or, when both Y1and Y2=N, can also be a C1-4alkyl or hydroxymethylene group;

R4represents a hydrogen atom or, when Z=N, R4can also be C1-4alkyl group;

R5represents a C1-4alkyl or phenyl C1-4alkyl group;

R6represents an atom of hydrogen, C1-4alkyl group.

However, the compounds disclosed in the above application, are inhibitors of platelet aggregation. There is a great need for antagonists GPIIb/IIIa, which has sufficient security in a wide range of concentration and a certain effect when administered orally.

Description of the invention

This invention discloses new benzamidine derivative having the following formula, UNT (Japanese patent application N Hei-8-333342, kokai).

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where R1and R2have the same or different values, and each of them represents a hydrogen atom or essential balance;

X1represents the lowest alkylenes group;

X2represents a single bond or lower alkylenes group;

m = 0, 1, or 2;

n = 0 or 1, provided that n = 1 when m = 0.

As a result of further extensive studies, it was found that the new substituted derivatives of emininently obtained by transformation of these derivatives emininently in prodrugs for amedieval group, have an extremely high oral absorption capacity and duration, which led to the creation of this invention.

Thus, the present invention relates to substituted derivatives of emininently having the following General formula (I) and their salts, and pharmaceutical compositions comprising such compounds together with pharmaceutically acceptable carriers.

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The symbols in the above formula have the following meanings:

R1the group, which can be turned into amedieval group in vivo;

R2and R3same or different is at the carboxy group in vivo;

X1and X2- same or different, each represents a lower alkylenes group;

m = 0, 1, or 2;

n = 0 or 1, provided that n = 1 when m = 0.

In the following formulas, the symbols have the same meaning.

Compounds according to this invention, which are structurally characterized by the fact that the substituent R1in the benzene group is a group which can be converted into amedieval group in vivo, thus, these compounds are prodrugs. As noted above, such conversion into the prodrug leads to extremely high oral absorption and concomitant prolonged action. The second characteristic is that (1) these compounds have two carboxyl groups or a group which can be converted into a carboxy group in vivo in piperidinium ring, and/or (2) these compounds have one or two carbonyl group in piperazinovom ring. On the basis of this link structure according to this invention have excellent antagonizers action against GPIIb/IIIa.

The preferred compounds of this invention of the above General formula (I) are the following:

for the a group which can be converted into a carboxy group in vivo (i.e., compounds that were converted into prodrugs, as amedieval group, and carboxyl group (so-called double proletarienne connection));

- substituted derivatives of emininently or their salts, where R1that can be turned into amedieval group in vivo, represents a group selected from hydroxyamides, low alkoxycarbonylmethyl, low alkoxyamino and lower alkanolamides;

- substituted derivatives of emininently or their salts, where R2and R3that can be converted into a carboxy group in vivo, represents a group selected from lower alkoxycarbonyl group, a lower alkoxy-lower alkoxycarbonyl group, a lower alkoxy-lower alkoxy-lower alkoxycarbonyl group, halogeno lowest alkoxycarbonyl group, lower alkenylcarbazoles group, a lower alkanoyloxy lowest alkoxycarbonyl group, a lower alkanoyl-hydroxy-lower alkoxycarbonyl group, a lower alkanoyl lowest alkoxycarbonyl group, a lower alkanoyl lowest alkoxycarbonyl group, a lower alkoxy-lower Alka is lower alkoxy-lower alkoxycarbonyl-hydroxy-lower alkoxycarbonyl group, di-lower alkylamino lowest alkoxycarbonyl group, cycloalkylcarbonyl lowest alkoxycarbonyl group, lower alkoxyalkanols group, nitrobenzisoxazole group, lower alkoxyalkanols group, benzylaminocarbonyl group, benzoyloxy-lower alkoxycarbonyl group, 2-oxo-tetrahydrofuran-5 - jocstarbunny group, 2-oxo-5-alkyl-1,3-dioxolan-4-ylmethoxycarbonyl group, tetrahydroprotoberberine group and 3-feliciasteinberg group; and

- substituted derivatives of emininently or their salts, where m = 1.

More preferred compounds are substituted derivatives of emininently or their salts, where m = 1 and n = 0.

Especially preferred compounds are the compounds listed below, or their salts:

ethyl-4-[4-(4-hydroxylaminopurine)-3-oxo-1-piperazinil] -1-piperidineacetate, methyl 4-[4-(4-hydroxylaminopurine)-3-oxo-1-piperazinil]-1 - piperidineacetate, ethyl 4-[4-(4-methoxycarbonylaminophenyl)-3-oxo-1-piperazinil] -1-piperidineacetate, methyl 4-[4-(4-methoxycarbonylaminophenyl)-3-oxo-1-piperazinil] -1-piperidineacetate and ethyl 4-[4-(4 - ethoxycarbonylphenyl)-3-is ethyl 4-[4-(4-hydroxylaminopurine)-3-oxo-1-piperazinil]-1-piperidineacetate or its salts.

Other preferred compounds include substituted derivatives of emininently or their salts, where m = 0 and n = 1, in particular, substituted derivatives of emininently or their salts, where R2and R3represents a group which can be converted into a carboxy group in vivo.

Next, the compound (I) according to this invention are described in detail.

Unless otherwise specified, the term "lower" used in this description for the definitions of the substituents in the General formula, refers to linear or branched carbon chain having from 1 to 6 carbon atoms.

Accordingly, the "lower Allenova group" represented by X1and X2in the General formula (I), represents a linear or branched alkylenes group having from 1 to 6 carbon atoms, and its examples include methylene group, ethylene group, metilbutilovy group, trimethylene group, propylene group, 2-propylene group, dimethylmethylene group, tetramethylene group, 1-methyltrienolone group, 2-methyltrienolone group, 3-methyltrienolone group, 1-ethylethylene group, 2-ethylethylene group, 2,2-dimethylethylene group, 1,1-dimethylethylene Gruppo, 2-methyltetrahydro group, 3-methyltetrahydro group, 4-methyltetrahydro group, 1,1-dimethyltrimethylene group, 2,2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, 1,3-dimethyltrimethylene group, 2,3-dimethyltrimethylene group, 1,2-dimethyltrimethylene group, 1-ethyltrimethylammonium group, 1,1,2-trimethylethylene group, diethylethylene group, 1-propylethylene group, 2-propylethylene group, butylmethylamine group, hexamethylene group, 1-methylpentylamino group, 1,1-dimethyltrimethylene group, 2,2-dimethyltrimethylene group, 3,3-dimethyltrimethylene group, 4,4-dimethyltrimethylene group, 1,1,3-trimethylethylene group, 1,1,2-trimethylethylene group, 1,1,2,2 - tetramethylene group, 1,1-dimethyl-2-ethylethylene group, 1,1-diethylethylene group, 1-propyltrimethylammonium group, 2-propyltrimethylammonium group, 3-propyltrimethylammonium group, 1-butylamino group, 2-butylamino group, 1-methyl-1-propylethylene group, 2 - methyl-2-propylethylene group, 1-methyl-2-propylethylene group, 2-methylpropylamine group, inteletravel group, butylmethylamine group, ethylpropylamine group, etc. Solee preferred are a methylene group and ethylene group.

"The group that can be converted into amedieval group in vivo" R1and "group that can be converted into a carboxy group in vivo" R2and/or R3represent groups that are part of the connection, which may be an active agent in medicines, or group, which is part amidnogo prodrugs, which can be metabolized in vivo to obtain amidnogo compounds as the active substance in the first case, or group, which is part of a carboxylic acid prodrugs, which can be metabolized in vivo to form compounds of carboxylic acid as the active substance in the latter case.

"The group that can be converted into amedieval group in vivo", and "group that can be converted into a carboxy group in vivo, can be determined by introducing the compounds according to this invention to a human or other animal, and analysis metabolized product using conventional analytical methods. In other words, the first can be defined as a compound that amedieval group after metabolism in vivo, and the second can be defined as a connection with in amedieval group in vivo R1includes substituted amidinopropane, which can be hydrolyzed in the metabolism in vivo, i.e., group forming prodrug based on amedieval group. Substituted medinova group includes hydroxyamides, lower alkoxycarbonylmethyl, lower alkoxyamino and lower alkanolamides. Preferred are hidroximetilpropan and lower alkoxycarbonylmethyl, and particularly preferred is hidroximetilpropan.

"The group that can be converted into a carboxy group in vivo" R2and/or R3includes substituted hydroxyl group that can be hydrolyzed in the metabolism in vivo, i.e., group forming prodrug, based on the carboxyl group. Substituted carboxyl group includes unsubstituted lower alkoxycarbonyl group and a substituted lower alkoxycarbonyl group with a straight chain, for example lower alkoxy-lower alkoxycarbonyl group, a lower alkoxy-lower alkoxy-lower alkoxycarbonyl group, halogeno lowest alkoxycarbonyl group, lower altneratively group, a lower alkanoyloxy lowest alkoxycarbonyl group, a lower alkanoyl lowest alkoxycarbonyl group, lower alkoxy-lower alkanoyloxy lowest alkoxycarbonyl group, a lower alkoxycarbonyl lowest alkoxycarbonyl group, a lower alkoxy-lower alkoxycarbonyl lowest alkoxycarbonyl group, di-lower alkylamino lowest alkoxycarbonyl group, cycloalkylcarbonyl lowest alkoxycarbonyl group, lower alkoxyalkanols group, nitrobenzyloxy-carbonyl group, a lower alkoxyalkanols group, benzylaminocarbonyl group, benzoyloxy-lower alkoxycarbonyl group, 2-oxitetraciclina-5-intoxicatingly group, 2-oxo-5-alkyl-1,3-dioxolan-4-ylmethoxycarbonyl group, tetrahydroprotoberberine group and 3-phthalimidomethyl group. The preferred groups are unsubstituted lower alkoxycarbonyl group and a substituted lower alkoxycarbonyl group with a straight chain, for example lower alkoxy-lower alkoxycarbonyl group, a lower alkoxy-lower alkoxy-lower alkoxycarbonyl group, halogeno lowest alkoxycarbonyl group, lower altneratively group, a lower alkanoyloxy lowest alkoxycarbonyl group, a lower alkanoyloxy-n alkoxycarbonyl group, lower alkoxy-lower alkanoyloxy lowest alkoxycarbonyl group, a lower alkoxycarbonyl lowest alkoxycarbonyl group, a lower alkoxy-lower alkoxycarbonyl lowest alkoxycarbonyl group, di-lower alkylamino lowest alkoxycarbonyl group, cycloalkylcarbonyl lowest alkoxycarbonyl group, 2-oxo-5-alkyl-1,3-dioxolan-4-ylethoxy-carbonyl group and a 3-feliciasteinberg group. The preferred group is the lowest alkoxycarbonyl group, and especially preferred are methoxycarbonyl group and ethoxycarbonyl group.

"Lower alkyl group" includes, for example, methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, Deut.-boutelou group, tert.-boutelou group, pentelow group, isopentyl group, neopentyl group, tert.-pentelow group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropylene group, hexoloy group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dibutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyloxy group, etc.

"Lower CNS group" corresponds to a hydroxyl group, a hydrogen atom which is substituted by the above lower alkyl group such as a methoxy group, ethoxypropan, propoxylate, isopropoxide, butoxypropan, isobutoxy, Deut. -butoxypropan, tert.-butoxypropan, pentyloxy(amyloxy) group, isopentylamine, tert.-pentyloxy, neopentadactyla, 2-methylbutoxy, 1,2-DIMETHYLPROPANE, 1-ethylpropoxy, hexyloxy etc., preferably a methoxy group, ethoxypropan and tert.- butoxypropan.

"Lower alcoolica group preferably has from 2 to 6 carbon atoms (e.g. acetyl, propionyl, pivaloyl, etc.,); "lower alcoolica group preferably has from 3 to 6 carbon atoms (calolina group, crotonoideae group, miliolina group, etc.,); "cycloalkyl group preferably has from 3 to 8 carbon atoms, more preferably from 3 to 6 carbon atoms (for example, cyclopropyl, cyclopentyl, cyclohexyl, etc.,).

"Lower Alchemilla group" LASS="ptx2">

"Halogeno-lower alkyl group" corresponds to the above-mentioned lower alkyl group in which one or more hydrogen atoms replaced by an atom(s) halogen, and includes pharmacylow group, chloromethylene group, bromatology) group, iodomethyl group, 1-chloroethyl group, 2-chloroanilino group, di-chloromethylene group, triptorelin group, dichloromethyl group, etc.

In the main structure of compound (I) according to this invention a residue represented by the formula

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means oxopiperidine ring or dioxopiperazinyl ring.

Examples oxopiperidine ring in accordance with this application to the following:

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Among these rings are preferred rings, presents

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and most preferred is a ring represented by

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Compounds (I) according to this invention have at least one asymmetric carbon atom, depending on the structure piperidinyloxy group and her Deputy (group-X2-R3). Depending on the various substituents of the compounds (I) may have additional asymmetric atom(s) of carbon. The compounds of this invention may exist in VI the tautomeric isomers depending on carbonyl groups or amidinopropane in Vice, and also in the form of geometrical isomers depending on the double bonds. This invention includes all selected isomers of these optical isomers, tautomeric isomers and geometric isomers, and mixtures thereof.

Compounds (I) according to this invention can be converted into a salt. Examples of preferred salts include salts of alkaline or alkaline earth metals, such as salts of sodium, potassium and calcium, and hydrogen halides), such as hydrogen fluoride, hydrogen chloride, hydrogen bromide and hydrogen iodide; salts with inorganic acids, such as carbonates, nitrates, perchlorates, sulfates and phosphates; lower alkyl sulphonates, such as methanesulfonate, triftoratsetata and econsultancy; arylsulfonate, such as benzosulfimide and p-toluensulfonate; salts with organic acids, such as fumarate, succinate, citrates, tartratami, oxalates and maleate; salts with amino acids, such as glutamate and aspartate.

In addition, this invention also includes hydrates and pharmaceutically acceptable solvate of the compounds (I) and polymorphic isomers of the compounds (I) according to this invention. In fact, the invention is not limited to the compounds listed asepticheski acceptable salt.

Ways to get

Some typical methods for producing compounds according to this invention is shown below.

The first method of obtaining

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In the formula, R2, R3X1X2, m and n have the meanings specified above. R1ameans hydroxyamides or lower alkoxyamino group.

The compound (Ia) according to this invention can be obtained by the reaction of nitrile compound (II) with hydroxylaminopurine or lower alkoxilierungen in an appropriate solvent in the presence of a base. The appropriate solvent is preferably a solvent inert to the reaction. Examples of such inert solvents include methanol, ethanol, dimethylformamide, dimethylacetamide, tetrachlorethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, dimethoxymethane, diethoxymethane, ethyl acetate, benzene, toluene, acetonitrile, dimethyl sulfoxide, etc. as well as mixtures of solvents. A suitable solvent is selected depending on various reaction conditions.

Examples of bases include sodium, sodium hydride, sodium methoxide, ethoxide sodium, potassium carbonate, triethylamine, pyridine, etc., Etc the led of sodium.

The reaction can normally be performed at room temperature by heating or by heating under reflux, preferably at reflux.

The second way of obtaining

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In the formula, R2, R3X1X3, m and n have the meanings specified above. R4means lower alkoxycarbonyl group or lower alkanoyloxy group. R1bmeans lower alkoxycarbonylmethyl group or lower alkanolamide group.

Y represents a leaving group such as halogen atom, hydroxyl group, lower alkoxygroup, fenoxaprop, imidazolidine group, arylsulfonate and outgoing group of active carboxylic acid derivative.

The compound (Ib) according to this invention can be obtained by the reaction of amidinothiourea (III) with compound (IV) in the presence of an appropriate base. Examples of appropriate bases include the above base, preferably sodium hydroxide, potassium carbonate and triethylamine. In this reaction can be used solvents. Examples of the solvents above. Examples of preferred solvents include not the active carboxylic acid derivative include active esters, obtained by reaction with a phenolic compound such as p-NITROPHENOL or similar, or with N-hydroxyamino compound, such as N-hydroxysuccinimide, 1-hydroxybenzotriazole or etc.; mixed acid anhydrides obtained by reaction with monoalkylammonium or organic acid, and mixed phosphoryl anhydrides obtained by reaction with diphenylphosphinylchloride and N-methylmorpholine; azides acids obtained by reaction of the ester with hydrazine or alkylation; galodamadruga, such as acid anhydrides, acid bromides, and so on; symmetric acid anhydrides, etc.

Other ways to get

Among compounds (I) according to this invention compounds having carboxyl group, such as R2and/or R3can be obtained by dissolving the corresponding compounds having a group which can be converted into a carboxy group in vivo, such as R2and/or R3, in a suitable solvent with subsequent conventional ester hydrolysis in basic, acidic or neutral conditions.

Examples of bases used in the basic conditions include the hydroxides of sodium, potassium, lithium, barium, etc., Examples of acids used in acid conditions include acid, Lui is islote. In neutral conditions can be used halogen ions (e.g., iodide and lithium bromide), alkali metal salts (for example, thiol and selenol), edotreotide and enzymes (e.g., esterase).

Examples of the solvent used in the reaction include water, alcohol (e.g. methanol and ethanol), acetone, dioxane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethyl sulfoxide, formic acid, acetic acid, pyridine, lutidine, kallidin, etc. described Above, commonly used solvents can be used in a mixture with water.

The reaction is usually carried out at room temperature, but sometimes it should be performed under ice cooling, or when heated, therefore, the reaction is carried out at a temperature selected accordingly.

The selection of appropriate conditions for hydrolysis of the substituted carboxylic acid compounds having only one carboxyl group. For example, the ether compound in which one of the ether the residue is easily hydrolyzed in acidic conditions (for example, tert.-bucilina group, or so on), and other essential balance easily hydrolyzed in basic conditions (for example, methyl ether, ethyl ether or similar), hydralicious when you select the CLASS="ptx2">

If desired, compounds of carboxylic acids may be further tarifitsirovana with obtaining the desired esters. The etherification can be carried out in the usual way under appropriate conditions selected.

Compounds according to this invention, where R2and/or R3represents a group which can be converted into a carboxy group in vivo, can be also obtained internal transesterification with suitable alcohols. For example, a large excess of the alcohol used for transesterification carried out in the presence of acid, base or any other catalyst (for example, an alkoxide of titanium (IV)), or other alcohols produced during the reaction, is removed from the reaction system, thus shifting the equilibrium of the reaction towards the desired ether compound.

The method of obtaining the source connections

Methods for obtaining compounds used as starting compounds, are described below.

The method of obtaining AND

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In the formula, R3, R4X1and X2have the values specified above.

The compound (VII) can be obtained by dissolving compound (VI) in an appropriate solvent followed recriticality) or halogenated alkyl (e.g., ethylbromoacetate) to the enamine. The enamine can be used after isolation or without isolation.

Examples of the secondary amine include pyrrolidine, piperidine, morpholine, diethylamine and Diisopropylamine.

Examples of the solvent include toluene, benzene, chlorobenzene, etc. in Addition to these commonly used solvents, the reaction can be carried out in any other organic solvents, provided that the solvent does not render harmful influence on the reaction.

The reaction is carried out with removal from the system water generated upon receipt of the enamine, by adding a water-absorbent agent, such as potassium hydroxide, molecular sieves, and so on , or use traps Dean-stark (apparatus for azeotropic dehydration). During the reaction preferably support the azeotropic temperature or boiling point.

Way to get IN

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In the formula, R3, R4X1X2, m and n have the meanings specified above.

The compound (II) obtained by dissolution of the compound (VIII) in a suitable solvent followed by reaction with the amine compound (IX) to obtain a Schiff's base, which is then restored after isolation or without isolation.

The reaction is carried out in such a way that the compound (VIII) is reacted with reactive with the corresponding amount of amine compounds (IX) or, alternatively, using a small excess of one of them, in the presence of an acid catalyst such as p-toluensulfonate acid, adipic acid, oxalic acid, pyridine hydrochloride, acetic acid or so on, depending on the reaction conditions, it is preferably carried out with the destruction of the system of water by adding a water-absorbent agent, such as potassium hydroxide, molecular sieves, and so on, or use traps Dean-stark (apparatus for azeotropic dehydration). The reaction is usually carried out at temperatures below room temperature, however, depending on the reaction conditions can be performed at the azeotropic temperature or boiling point.

Restoration of Schiff bases carried out by adding a reducing agent, such as a metal hydride complex (e.g. borohydride sodium, borohydride lithium, cyanoborohydride sodium and triacetoxyborohydride sodium), borane or similar, to the reaction Rast is the same or different values, each of them represents a carbonyl or methylene group; Y1represents the same leaving group, and Y, a Y2represents the same leaving group, and Y1or a hydrogen atom.

During this reaction, the compound (XI) is reacted with the amine compound (X) to obtain compound (XII).

(1) the Above compound (XI) represents an alkyl derivative, where Y2- withdrawing group, and4- methylene group.

This reaction can be carried out under conditions conventional N-alkylation. The reaction is carried out, stirring the amine compounds (X) and the reaction equivalent amount of compound (XI) in an inert solvent under cooling or heating. To promote the reaction, it is desirable to add a base (e.g. an inorganic base such as potassium carbonate, sodium carbonate, sodium hydride or etc., or an organic base such as triethylamine or etc.) to the reaction system.

(2) the Above compound (XI) is a carboxylic acid derivative, where Y2- withdrawing group, and4- carbonyl group.

The amide compound (XII) is obtained by acylation minisode carboxylic acids include active esters, described above under the Second method of manufacture, and the amide compound (XII) is also obtained by acylation in carboxylic acid (XI) and a condensing agent in a suitable solvent. The condensing agent used in the reaction preferably represents N,N-dicyclohexylcarbodiimide, 1-ethyl-3-(3-(N, N-dimethylamino)propyl) carbodiimide, carbonyldiimidazole, di-phenylphosphonite, diethylphosphonate or etc.

The reaction is usually conducted in a solvent with cooling or at room temperature. Used solvents are organic solvents that do not participate in the reaction, such as dimethylformamide, dimethylacetamide, dioxane, tetrahydrofuran, diethyl ether, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, acetonitrile, dimethyl sulfoxide, etc., and also mixtures of solvents. These organic solvents may be appropriately selected depending on the applied method. Depending on the type of acylation reaction sometimes must be performed in conditions of dehydration. In addition, depending on the applied method to ensure the smooth passage of the reaction is preferably done in presumo base as a solvent.

(3) When the above compound (XI) is an aldehyde, where Y2is a hydrogen atom, and4- carbonyl group.

The compound (XII) is obtained by dissolution of the derived aldehyde in a suitable solvent, subjecting it to reaction with the amine (X), and then restoring the received ion imine. In this reaction applies the reaction solvent, reducing agent and reaction conditions described above in the section "Method of production".

Method of application D

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In the formula A1-A4, Y1and m have the meanings specified above.

To obtain the compound (IX) with (di)oxopiperidin ring with cyclization precursor (XII) is treated in a suitable solvent in the presence of a suitable catalyst or without him. These reactions are carried out under ice cooling, at room temperature or when heated.

Examples of solvents include dimethylformamide, dimethylacetamide, dimethylsulfoxide, tetrachlorethane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, dioxane, dimethoxymethane, dimethoxyethane, benzene, chlorobenzene, toluene, water, acetic anhydride, alcohols, etc. that are selected are appropriate to the OPA include a base (for example, sodium hydride, potassium hydride, n-utility, Deut.-utility, tert.-piperonyl potassium bis(trimethylsilyl)amide, potassium diisopropylamide lithium, sodium methoxide, potassium hydroxide, potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, triethylamine, diisopropylethylamine, dimethylaminopyridine), salts (such as sodium acetate and potassium acetate) and acid (such as sulfuric acid and hydrochloric acid).

The method of obtaining E

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In the formula A1-A4X1X2, Y1, Y2, R2, R3, m and n have the meanings specified above.

In the same way as described in the section "Method of production", the compound (X) and the compound (VII) is subjected to the reaction of obtaining compound (XIII).

The solvent, catalyst and reaction conditions are the same as described above in the section "Method of production".

In the same way as described in the section "Method of obtaining, from the compound (XIII) are obtained compound (XIV). The solvent, catalyst, reaction conditions, etc. are the same as described above in the section "Method of production".

Cyclization with the formation of (di)oxopiperidine rings can be conducted as described in the section "Method of gaining the CLASS="ptx2">

The way of getting F

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In the formula, R2, R3X1X2, m and n have the meanings specified above.

Compound (III) having amedieval group, can be obtained in accordance with one of the following methods (i), (ii) and (iii).

(i) Method of conversion of nitrile in imidate with subsequent condensation with the amine.

The connection of the nitrile (II) is subjected to reaction with an alcohol, such as methanol, ethanol and so forth, in the presence of gaseous hydrogen chloride at a temperature of from -40oC and 0oC obtaining imidate, which is then subjected to reaction with ammonia, an amine or amine salt, such as carbonate, chloride, ammonium acetate or similar as solvent for the reaction using methanol, ethanol, acetone, tetrahydrofuran or etc.

(ii) Method of conversion of nitrile in tioned, and then in thioimidate with subsequent condensation with the amine.

The connection of the nitrile (II) is subjected to reaction with hydrogen sulfide in the presence of organic bases such as methylamine, triethylamine, pyridine, picoline or so on, to obtain the compounds thioamide. This connection can also be obtained by reaction of the compound of the nitrile (II) with O-diethyldithiophosphate in the presence of SSIM haloalkyl, such as methyliodide, ethyliodide or so on, obtaining of thioimidate, which is then subjected to reaction with ammonia or an amine, or amine salt, such as carbonate, chloride, ammonium acetate or similar as solvent for the reaction using methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, or etc.

(iii) a Method of directly adding the amine, amine salt, amide metal or Grignard reagent to a nitrile.

Reagent, such as ammonia, ammonium chloride with ammonia, ammonium thiocyanate, a thiocyanate of alkylamine, MeAI(Cl)NH2, NaNH2, (CH3)2NMgBr or similar, add to the connection of the nitrile (II) in an appropriate solvent or without him. As the solvent used chloroform, methanol, ethanol, acetone, tetrahydrofuran, toluene, dimethylformamide or so on the Addition of the catalyst base, such as sodium hydride or etc., or acid such as aluminium chloride, p-toluensulfonate acid or similar, to the reaction system in some cases significantly speeds up the reaction. The reaction can be conducted under cooling or at room temperature or when heated.

The way to obtain G

< / BR>
< / BR>
In the formula, R2, R3X1X2and n have the meanings specified is(XIIIa) with a dialdehyde in an appropriate solvent.

The reaction can be conducted under cooling with ice, at room temperature or when heated.

Examples of the solvent include a mixed solvent of tetrahydrofuran-water, dimethylformamide, dimethylsulfoxide, 1-methyl-2-pyrrolidin, dioxane, dimethoxyethane, alcohols, etc. that may be properly selected depending on various reaction conditions.

The method of obtaining H

< / BR>
< / BR>
In the formula a1AND2X1X2, Y2, R2, R3and n have the meanings specified above.

This reaction process is intended to obtain the compound (XIII) by reaction of the compound (XV) and compound amine (XVI).

1) If in the above compound (XV) Y2= Y1, a a2represents a methylene group, the reaction is carried out by the method described in (1) "Method of obtaining.

2) If in the above compound (XV) Y2= Y1, a a2represents a carbonyl group, the reaction is carried out by the method described in 2) in the Method of obtaining C".

3) If in the above compound (XV) Y2represents a hydrogen atom, and2represents a carbonyl group, the reaction propositionem way isolated and purified using any conventional chemical method, including, for example, extraction, precipitation, fractional chromatography, recrystallization, etc., in Addition, the compounds of this invention can be converted into a desired salt by conventional salt formation reactions.

Industrial applicability

Compounds according to this invention can be used as input oral antagonists of the receptor GPIIb/IIIa, especially inhibitor of platelet aggregation, including, for example, drugs for relief of ischemic heart disease (angina, caused by anxiety, acute myocardial infarction), and also to prevent subsequent secondary complications, postoperative re-obstruction and restenosis occurring after coronary artery bypass or percutaneous intraluminal coronary angioplasty (PTCA), as well as to stimulate coronary thrombolite and prevention of re-obstruction occurring after coronary thrombolite and so on); as an aid in cardiac and vascular operations; medicines for alleviating cardiovascular diseases (prikhodyashcheisya vessels, and so on); and as medicines for relief of peripheral artery disease (chronic arterial obstruction, and so on).

Since the compounds according to this invention can be particularly useful as prodrugs in our previous application (unexamined published Japanese patent application N 8-333342) and is therefore useful as medicines to facilitate the above diseases, not only by parenteral administration, such as intramuscular injection, but also for oral administration. In addition, since the retention time of the Compound in plasma increased with the introduction of compounds according to this invention in the form of prodrugs, the pharmaceutical activity of the compounds according to this invention is a lengthy and clinical utility of these compounds is high. Moreover, the toxicity of the compounds according to this invention is much lower toxicity of commonly used compounds.

The action of the compounds according to this invention on the inhibition of platelet aggregation and their utility as prodrugs confirmed by the following test methods.

Metabolic test for the active substance (what about the dose of 10 mg/kg in aqueous solution, and then 48 hours after introduction of selected blood. After centrifugation the plasma was separated and then stored at -20oC until analysis. The connection (connection name: 4-in/4-lidinopril/-3-oxo-1-piperazinil/-1-piperidinyloxy acid, unexamined published Japanese patent application N 8-333342), which is an active substance obtained as a metabolite of the Compound of Example 2, was determined by the method of liquid chromatography high resolution with obtaining pharmacokinetic parameters. These hounds dogs also introduce the Compound a at a dose of 10 mg/kg, and then measure the concentration in the plasma. Pharmacokinetic parameters of the Connection And after the introduction of the Compound of Example 2 and the Connection And compared between them. Table 1 shows the pharmacokinetic parameters of plasma Compound 1 in plasma, and the drawing shows the profile of plasma concentration of the Compound And the time after oral administration.

Table 1 includes the pharmacokinetic parameters of the Compounds in plasma after oral administration of the Compounds of Example 2 and the Connection And hounds dogs at a dose of 10 mg/kg (average from three animals standard deviation), and the drawing shows the concentration profile in the p the possible Connection Example 2 is more than three times the area after the introduction of Compound A. t1/2Connection And significantly increased after oral administration of it in the form of Compounds of Example 2. Confirmed that not only increases the bioavailability, but also the duration of the Connection And in the plasma with the introduction of it in the form of Compounds of Example 2, intended for double prodrugs of Compounds A.

Activity by inhibition of platelet aggregation ex vivo in Cynomolgus monkeys

Cynomolgus monkeys, slightly shot by intramuscular injection of ketamine hydrochloride, fixed on the desktop and via a gastric tube injected into their stomachs sample compounds according to this invention, dissolved or suspended in a solution of methylcellulose at a dose of 1 mg/kg Before the introduction and after the introduction, over time, through the femoral vein of the animal selected 3 ml of blood (containing 1/10 volume of sodium citrate). Using the method of De Marco et al. (see J. Clin. Invest., 77, 1272-1277, 1986), from the blood receiving platelet-rich plasma. Before using using an automatic counter blood cells (Model MEK-5158, manufactured by Nihon Koden Co.) this plasma was adjusted to 3108Jr. Then, with the aim of platelet aggregation stimulator add 20 μm adenosine 5'-di-phosphate and 10 maraut using the respective device (NBS Hematracer 801, produced by Niko Bioscience Co.). Activity by inhibition of platelet aggregation the compounds represented by percentage of inhibition relative to the maximum percentage aggregation of each animal before adding the compounds.

The test results are shown in Table 2 together with the results for Compound a, which is an active substance according to this invention.

As shown by the above results, the compounds of this invention have a high ratio of platelet aggregation/inhibition even in comparison with the active ingredient Compound A. in Addition, in the case of using the prodrugs in this application the ratio of platelet aggregation/inhibition were well preserved after 9, 12 and 24 hours after injection, confirming the fact that this compound has a sufficient duration of action.

Incidentally, as described in our previous application, the connection active substance according to this demand perfectly inhibits the binding of GPIIb/IIIa with fibrinogen, thus the connection per se exhibits inhibitory activity against platelet aggregation. Accordingly, it is obvious that connected, described above, which is confirmed by the results of metabolic test of the active substance in plasma, and have effect, inhibiting platelet aggregation, based on the inhibitory activity against the binding of fibrinogen to GPIIb/IIIa.

As shown by the above results of pharmacological test, the compounds of this invention have good bioavailability and duration of action. Accordingly confirmed that the compounds according to this invention can be preferably used as prodrugs especially double.

Pharmaceutical compositions comprising one or more compounds and their salts according to this invention as the active ingredient may be formulated with carriers, fillers and other additives commonly used in the compositions.

Used in carriers and excipients can be solid or liquid non-toxic pharmaceutically acceptable substances. Examples of such carriers and excipients include lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum Arabic, olive oil, sesame oil, cacao butter, ethylene glycol and others commonly used in dannok, capsules, granules, powders, liquids etc., or parenterally in the form of intravenous or intramuscular injections, suppositories, transdermal preparations, pharmaceutical forms for inhalation, vnutrikitayskoy injections etc. Dose of the composition is determined for each individual patient depending on its condition, age, sex, etc. But in General oral dose for adults is approximately from 0.1 to 100 mg/kg/day and be entered for one or 2-4 times. When intravascular injection of the composition, depending on the condition of the patient, the dose is generally from about 0.001 to 10 mg/kg and placed in one or more doses per day.

Solid composition used for oral administration in accordance with this invention, has the form of tablets, powders, granules, etc. In such solid compositions one or more active substances are mixed with at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid or magnesium aluminate. Typically, the composition may contain additives other than the inert diluent, such as a lubricating substance (for example, is chose) and the agent, accelerating the solubilization (e.g., glutamic and aspartic acid). If necessary, tablets or pills may be coated with a film of gastric or Intercollege substances, such as sucrose, gelatin, hydroxypropylcellulose, phthalate of hydroxypropylmethylcellulose or etc.

Liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. and contains a generally used inert diluent such as purified water or ethanol. In addition to the inert diluent, this composition may also contain auxiliary agents such as wetting, suspendisse agent, etc. and sweetening agents, corrigentov, fragrances and preservatives.

Injections for parenteral administration include aseptic aqueous or anhydrous solutions, suspensions and emulsions. Examples of the diluent used in aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of the diluent used in anhydrous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oil (e.g. olive is such as an antiseptic, humectant, emulsifier, dispersant, stabilizer (e.g., lactose), and the agent, accelerating the solubilization (e.g., glutamic and aspartic acid). Such compositions are sterilized by filtration through a filter that removes bacteria, the addition of antimicrobial drug or irradiation. Alternatively, they may be used in the form of sterile solid compositions and after their dissolution in sterile water or a sterile solvent before use.

Preferred embodiments of the invention

The present invention is described in more detail using the following Examples. However, the compounds according to this invention is not limited to the compounds specified in the Examples, and include all compounds of the above General formula (I), their salts, hydrates, solvate, tautomers, geometrical and optical isomers, and polymorphic isomers.

Comparative Example 1

Methyl 4-oxo-3-piperidinecarboxylate hydrochloride (9,65 g), 21,0 g of ethyl bromoacetate and 24.0 g of potassium carbonate are dissolved in 200 ml of N,N-dimethylformamide, and the solution was stirred at room temperature overnight. Then to the reaction liquid was added 100 ml of water and the mixture of extragenic purified column chromatography on silica gel (solvent for elution: chloroform), getting 9.0 g of ethyl 3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-1 - piperidineacetate in the form of an oily substance.

Mass spectrum (m/z): FAB (Pos.) 330 (M++ 1)

NMR spectrum (CDCl3, TMS internal standard):

: of 1.23 to 1.31 (6H, m), 2,46 is 2.51 (1H, m), a 2.71 (2H, DD), 2.91 in-2,96 (2H, m), 3.00 and-is 3.08 (2H, m), 3,35 is-3.45 (2H, m), with 3.79 (3H, s), 4,10-4,19 (4H, m)

Comparative Example 2

Ethyl 3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-1-piperidineacetate (1/0 g) and 100 mg of lithium chloride dissolved in 10 ml of N,N-dimethylformamide, and the solution is boiled with a reverse refrigeration for 48 hours. Then to the reaction liquid, add 10 ml of water, and the mixture is extracted with 100 ml of ethyl acetate. The obtained extract was dried over sodium sulfate and concentrated. The resulting residue is purified column chromatography on silica gel (solvent for elution: chloroform) to give 400 mg diethyl-4-oxo-1,3-piperidineacetate in the form of an oily substance.

Mass spectrum: (m/z): FAB (Pos.) 272 (M++ 1)

NMR spectrum (CDCl3, internal standard TMS):

: 1,23-of 1.30 (6H, m) to 2.18 (1H, DD), a 2.36-2.40 a (1H, m), 2,50 (1H, t), 2,70-2,77 (3H, m), 3,13-3,26 (3H, m) to 3.38 (2H, s), 4.09 to 4,22 (4H, m).

Comparative Example 3

Diethyl 4-oxo-1,3-piperidineacetate (28 g), 19 g of 4-(1-piperazinil)benzonitrile and 6 g of acetic acid the Oh temperature for 24 hours. The reaction liquid is neutralized with an aqueous solution of 1N sodium hydroxide, and then separate the organic layer. This layer is dried over sodium sulfate and concentrated, and the resulting residue purified by chromatography on silica gel (solvent for elution: hexane: ethyl acetate = 1:1) to give 13 g of diethyl 4-[4-(4-cyanophenyl)-1-piperazinil]-1,3-piperidineacetate.

Comparative Example 4

Diethyl 4-[4-(4-cyanophenyl)-1-piperazinil]-1,3 - piperidine-acetate (8.2 g) was dissolved in 100 ml of ethanol, and at a temperature of from -10oC to -20o0 purge hydrogen chloride up to saturation. The solution is heated to room temperature and stirred overnight, and the solvent is removed by evaporation. Thus obtained residue is dissolved in 100 ml of ethanol, added 9.0 g of ammonium carbonate, and the mixture is stirred at room temperature overnight. The solvent is removed from the reaction mixture by evaporation, and the resulting residue is purified column chromatography on silica gel (solvent for elution: chloroform:methanol = 10:1) to give 4.4 g diethyl-4-[4-(4-AMINOPHENYL)-1-piperazinil]-1,3-piperidineacetate hydrochloride.

Mass spectrum: (m/z): FAB (Pos.) 460 (M++ 1)

NMR spectrum: (DMSO-d6internal stagnantly Example 5

N-(tert. -butoxycarbonyl) glycine (14,83 g) dissolved in 50 ml of tetrahydrofuran, gradually add 1,1'-carbonylbis-1H - imidazole (13,73 g) and the mixture is stirred at room temperature for 3 hours. Then add 10 g of p-aminobenzonitrile, and the mixture is stirred for 3 days. Then the solvent is removed by evaporation under reduced pressure. Educated thus the crystals are collected by filtration, washed with a small amount of ethanol, and then dried under reduced pressure, obtaining of 20.5 g of 2-(tert. -butoxycarbonylamino)-N-(4-cyanophenyl)-ndimethylacetamide.

Mass spectrum (m/z): FAB 276 (M +H)+< / BR>
NMR spectrum (CDCl3, internal standard TMS):

: for 1.49 (9H, s) to 3.92 (2H, d), is 5.18 (1H, sh.C.), to 7.61 (2H, d), the 7.65 (2H, d), 8,59 (1H, sh.sec.)

Comparative Example 6

A solution of ethyl acetate (to 45.5 ml) of 4N solution of hydrogen chloride is added to 10 g of 2-(tert.-butoxycarbonylamino)-N-(4-cyanophenyl)ndimethylacetamide in a closed vessel, and the mixture is stirred for 18 hours. The resulting crystals are collected by filtration, washed with ethyl acetate, and then dried under reduced pressure, obtaining of 7.7 g of 2-amino-N-(4-cyanophenyl)ndimethylacetamide hydrochloride. Then 58,8 ml aqueous saturated solution of sodium bicarbonate and 20 ml of water is added to 3.7 g is the growth collected by filtration and dried under reduced pressure, receiving 2.5 g of 2-amino-N-(4-cyanophenyl)ndimethylacetamide.

Mass spectrum (m/z): FAB 176 (M + H)+< / BR>
NMR spectrum (CDCl3, internal standard TMS):

: 1,68 (2H, sh.C.), to 3.50 (2H, s), to 7.61 (2H, d), 7,74 (2H, d), of 9.75 (1H, sh.sec.)

Comparative Example 7

2-Amino-N-(4-cyanophenyl)ndimethylacetamide (1,83 g) dissolved in 90 ml of methylene chloride, in turn, add 3,10 g of ethyl 2-(4-oxo-1-piperidine)acetate, 4,4 ml of acetic acid and 8,88 g triacetoxyborohydride sodium, and the mixture is stirred for 1.5 hours. After concentrating the mixture under reduced pressure, water is added and the sodium carbonate to alkalizing the system. Then the resulting crystals are collected by filtration. The crude crystals are dissolved in chloroform and washed with brine. The obtained organic layer is dried over anhydrous sodium sulfate, and the filtrate concentrated under reduced pressure. To the obtained residue is added ether and the resulting solid is collected by filtration, getting 2,82 g of ethyl 4-[N-(4-cyanophenyl)carbamoylmethyl]-1-piperidineacetate.

Mass spectrum (m/z): APCI + QIMS: 345

NMR spectrum (CDCl3, internal standard TMS):

: of 1.27 (3H, t), 1,50 is 1.58 (2H, m), 1,67 (1H, sh.E.), 1,88-1,90 (2H, m), 2,23-of 2.27 (2H, m), 2,49-of 2.54 (1H, m), 2,95 (2H, m), up 3.22 (2H, s), 3,42 (2H, s), 4,18 (2H, HF), a 7.62 (2H, d), 7,72 (2H, d),given in turn to a stirred solution of 1.0 g of ethyl 4-[N- (4-cyanophenyl)carbamoylmethyl]-1-piperidineacetate, 10 ml of methanol and 2.85 g of chloroacetaldehyde (40% aqueous solution), and the mixture is stirred over night. The solvent is removed by evaporation, add chloroform, and the mixture was washed with saturated aqueous sodium bicarbonate. The obtained organic layer was separated and concentrated under reduced pressure. The resulting residue is subjected to column chromatography on silica gel (solvent for elution: chloroform: methanol = 100:1, vol/vol.), getting to 1.15 g of ethyl 4-[M-(2 - chloroethyl)-N-[N-(4-cyanophenyl)carbamoylmethyl]amino]-1-piperidineacetate.

Mass spectrum (m/z): FAB 407 (M+H)+< / BR>
Comparative Example 9

Ethyl 4-[N-(2-chloroethyl)-N-[N-(4-cyanophenyl)-carbamoylmethyl] -amino] -1-piperidineacetate (1.08 g) was dissolved in 30 ml of N,N-dimethylformamide, gradually add 0.18 g of sodium hydride, and the mixture is stirred for 5 hours. Add saturated aqueous solution of ammonium chloride, and the solvent is removed by evaporation. Then add chloroform and saturated aqueous sodium hydrogen carbonate solution, the mixture is subjected to separation by liquid-liquid, and the obtained organic layer is concentrated under reduced pressure. To the obtained residue is added ether and the resulting solid is collected by filtration, SUP>+< / BR>
NMR spectrum (CDCl3, internal standard TMS):

: of 1.28 (3H, t), 1,65-1,71 (2H, m), 1,83-of 1.85 (2H, m), 2,24-of 2.28 (2H, m), 2,35-2,39 (1H, m), 2.91 in-of 2.93 (2H, m), 3,01 totaling 3.04 (2H, m), up 3.22 (2H, s), of 3.46 (2H, c), 3,71-to 3.73 (2H, m). 4,19 (24, kV), 7,49 (2H, d), to 7.68 (2H, d).

The method described in Comparative Example 4, the receive connection of Comparative Example 10.

Comparative Example 10

Ethyl 4-[4-(4-amidinophenoxy)-3-oxo-1-piperazinil]-1-piperidine-acetate hydrochloride

Parent compound: ethyl 4-[4-(4-cyanophenyl)-3-oxo-1-piperazinil]-1-piperidineacetate

Mass spectrum (m/z): FAB 388 (M + H)+< / BR>
NMR spectrum: (DMSO-d6, internal standard TMS):

: to 1.19 (3H, t), of 1.43 to 1.47 (2H, m), is 1.77 and 1.80 (2H, m), 2,17-of 2.21 (2H, m) to 2.29 (1H, m), 2,87-2,89 (4H, m), 3,19 (2H, s) to 3.33 (2H, s), 3,70-and 3.72 (2H, d), 4,08 (2H, HF), the 7.65 (2H, d), to 7.84 (2H, d), 9,01 (2H, SHS), to 9.32 (2H, CL).

The method described in Comparative Example 9, to obtain the compound of Comparative Example 11.

Comparative Example 11

Methyl 4-[4-(4-cyanophenyl)-3-oxo-1-piperazinil] -1-piperidineacetate

Source connection: methyl 4-[N-(2-chloroethyl)-N-[N-(4-cyanophenyl)carbamoylmethyl]amino]-1-piperidineacetate

Mass spectrum (m/z): FAB (Pos.) 357 (M++ 1)

NMR spectrum (CDCl3, internal standard TMS):

: 1,63-of 1.73 (2H, m), 1,83 is 1.86 (2H, m), 2,22-of 2.28 (2H, m), 2,33-to 2.41 (1H, m), 2.91 in-of 2.93 (2H, get the compound of Comparative Example 12.

Comparative Example 12

Methyl 4-[4-(4-amidinophenoxy)-3-oxo-1-piperazinil] -1-piperidineacetate hydrochloride

Source connection: methyl 4-[4-(4-cyanophenyl)-3-oxo-1-piperazinil]-1-piperidineacetate

Mass spectrum (m/z): FAB (Pos.) 374 (M++ 1)

NMR spectrum: (DMSO-d6, internal standard TMS):

: to 1.47 (2H, m), 1,79-of 1.81 (2H, m), 2.21 are 2,31 (3H, m), 2,89 (4H, m) to 3.34 (4H, m), 3,62 (3H, s), 3,71-to 3.73 (2H, m), the 7.65 (2H, d), 7,88 (2H, m), 9.28 are (2H, CL), 9,43 (2H, CL)

Comparative Example 13

Ethyl 4-[[2-(4-cyanoaniline)ethyl] amino]-1-piperidineacetate (1.0 g) is dissolved in a mixed solvent consisting of 10 ml of tetrahydrofuran and 10 ml of water, add 0,69 ml dialdehyde (40%, aqueous), and the mixture is stirred at room temperature for 15 hours. The solvent is evaporated and the residue extracted with ethyl acetate. The organic layer is successively washed with saturated aqueous sodium bicarbonate and brine. The organic layer is dried over anhydrous magnesium sulfate, and the solvent is evaporated. The resulting crude crystals recrystallized from toluene-hexane, obtaining 0,86 g of ethyl 4-[4-(4-cyanophenyl)-3-oxo-1-piperazinil]-1-piperidineacetate.

Mass spectrum (m/z): FAB 371 (M+H)+< / BR>
An NMR spectrum: (CDCl3, internal standard TMS):

: of 1.28 (3H, t), of 1.5-1.9 (4H, m is ID hydroxylamine (700 mg) was dissolved in 100 ml of ethanol and at room temperature add 680 mg ethoxide sodium. After 5 minutes add 2.2 g ()-CIS-diethyl-4-[4-(4-cyanophenyl)-1-piperazinil]-1,3-piperidineacetate, and the mixture is refluxed over night. The reaction solution is concentrated and add 200 ml of water and the mixture is extracted with 300 ml of chloroform. The extract was dried over sodium sulfate, concentrated, and then purified column chromatography on silica gel (solvent for elution: chloroform:methanol= 50:1 - 20:1), receiving 1.5 g ()-CIS-diethyl-4-[4-(4-hydroxynicotinic)-1-piperazinil]-1,3-piperidineacetate.

Mass spectrum (m/z): FAB (Pos.) 476 (M++ 1)

NMR spectrum (CDCl3, internal standard TMS):

: 1,24 of 1.28 (6H, m), 1,76-of 1.78 (1H, m), 2.06 to 2,11 (1H, m), 2.21 are of 2.30 (2H, m), 2,55-2,75 (7H, m), 4,06-4,22 (4H, m), 4,80 (2H, s), to 6.88 (2H, d), 7,51 (2H, d)

Example 2

Ethanol (38 ml) of 0.90 g of hydroxylamine hydrochloride and 1.64 g of triethylamine are added to 3.0 g of ethyl 4-[4-(4-cyanophenyl)-3-oxo-1-piperazinil]-1-piperidineacetate and the mixture is refluxed for 3 hours. The resulting crystals are collected by filtration at a temperature of about 30oC and recrystallized from a mixture of chloroform:ethanol, receiving of 2.27 g of ethyl 4-[4-(4-hydroxynicotinic)-3-oxo-1-piperazinil]-1-piperidineacetate

Elemental analysis (for C20H29N5O4
: to 1.19 (3H, t), of 1.39 to 1.48 (2H, m), is 1.77 and 1.80 (2H, m), 2,16-of 2.21 (2H, m), 2,24-of 2.27 (1H, m), 2,83-2,89 (4H, m), 3,19 (2H, s), or 3.28 (2H, s), 3,62-the 3.65 (2H, m), 4,08 (2H, q), of 5.81 (2H, s), 7,34 (2H, d), to 7.67 (2H, d), for 9.64 (1H, s)

The method described in Example 1, to obtain the compound of Example 3.

Example 3

Methyl 4-[4-(4-hydroxynicotinic)-3-oxo-1-piperazinil] -1-piperidineacetate

Source connection: methyl 4-[4-(4-cyanophenyl)-3-oxo-1-piperazinil]-1-piperidineacetate

Elemental analysis (for C19H27N5O40,25 H2O)

Calculated: C(%) 56,63; H(%) 7,13; N(%) 17,38.

Found: C(%) 56,81; H(%) 6,79; N(%) 17,26.

NMR spectrum (CDCl3, internal standard TMS):

: 1,73 is 1.86 (4H, m), 2,22-of 2.28 (2H, m), 2,34-to 2.41 (1H, m), 2,87-2,89 (2H, m), 3,02 was 3.05 (2H, m) of 3.25 (2H, s), of 3.45 (2H, s), 3,62-the 3.65 (2H, m), of 3.73 (3H, s), a 4.83 (2H, CL), 7,32 (2H, d), a 7.62 (2H, d)

Example 4

()-CIS-Diethyl-4-[4-(4-hydroxynicotinic)-1-piperazinil]-1,3-piperidineacetate (1.5 g) is dissolved in 50 ml of 1N hydrochloric acid and the solution refluxed overnight. The reaction mass is concentrated, and the concentrate purified ODS column chromatography (solvent for elution: water and water: ethanol = 1: 1) to give 100 mg of trihydrochloride ()-CIS-4-[4-(4-hydroxynicotinic)-1-piperazinil]-1-[(etoxycarbonyl) methyl]piperidine-3-acetic acid.

M), 1,98 is 2.01 (1H, m), 1,10-2,19 (2H, m) 4,06 (2H, HF), 5,62 (2H, s), 6.89 in (2H, d), 7,51 (2H, d), was 9.33 (1H, s)

Example 5

()-CIS-Diethyl-4-[4-hydroxynicotinic)-1-piperazinil] -1,3-piperidineacetate (1.5 g) is dissolved in 50 ml of 1N hydrochloric acid and the solution refluxed overnight. The reaction mass is concentrated, and the concentrate purified ODS column chromatography (solvent for elution: water) to give 450 mg of trihydrochloride ()-CIS-4-[4-(4-hydroxynicotinic)-1,3-piperidineacetic acid.

Mass spectrum (m/z): FAB (Pos.) 420 (M++ 1)

NMR spectre (DMSO-d6) internal standard TMS):

: to 7.15 (2H, d), 7,71 (2H, d), 11,09 (1H, s)

Example 6

()-CIS-Diethyl-4-[4-(4-AMINOPHENYL)-1-piperazinil]-1,3-piperidineacetate hydrochloride (1.5 g) is dissolved in 150 ml of methylene chloride, add 300 mg of methylchloroform and 30 ml of 0.2 N aqueous solution of sodium hydroxide, and the mixture is stirred at room temperature for 1 hour. The organic layer is separated, washed twice with water, dried over sodium sulfate, and then concentrated. The resulting residue is purified column chromatography on silica gel (solvent for elution: chloroform:methanol = 50:1) to give 850 g ()-CIS-diethyl-4-[4-(4-methoxycarbonylaminophenyl)-1-piperazinyl]-1,3-Piper TMS):

1,24 of 1.28 (6H, m), 1,47 - to 1.59 (3H, m), 1.77 in (1H, d), 2.06 to 2,11 (1H, m), 2.21 are 2,30 (2H, d), 2,54-2,60 (3H, m), 2.63 in-a 2.71 (4H, m), 2,88-2,95 (2H, m), 3,17 (2H, HF), or 3.28 (4H, t), of 3.78 (3H, s), 4,06-4,19 (4H, m), 6,87 (2H, d), 7,81 (2H, d)

The method described in Example 6, to obtain the compound of Example 7.

Example 7

Ethyl 4-[4-(4-methoxycarbonylaminophenyl)-3-oxo-1-piperazinil] -1-piperidineacetate

Parent compound: Ethyl 4-[4-(4-amidinophenoxy)-3-oxo-1-piperazinil]-1-piperidineacetate

Elemental analysis (for C22H31N5O5)

Calculated: C(%) 59,31; H(%) 7,01; N(%) 15,72.

Found: C(%) 59,02; H(%) 7.03 Is; N(%0 15,63.

NMR spectrum (CDCl3, internal standard TMS):

: of 1.28 (3H, t), and 1.63 and 1.75 (2H, m), 1,83 is 1.86 (2H, m), 2,22-of 2.28 (2H, m), - 2,33-to 2.41 (1H, m), 2,90 of 2.92 (2H, m), 3,01 totaling 3.04 (2H, m), 3,23 (2H, s), of 3.45 (2H, s), 3,69-and 3.72 (2H, m), of 3.78 (3H, s), 4,19 (2H, HF), 4,70 (2H, d), of 7.90 (2H, d)

Example 8

Ethyl 4-[4-(4-hydroxynicotinic)-3-oxo-1-piperazinil] -1-piperidineacetate (0.8 g) is dissolved in 8 ml of water and cooled with ice add the monohydrate of lithium hydroxide. The mixture is stirred for 30 minutes while cooling with ice, add saturated aqueous solution of ammonium chloride and concentrate mixture. The resulting crystals are collected by filtration, getting to 0.67 g of 4-[4-(4-hydroxynicotinic)-Z-oxo - 1-piperazinil] -1-piperidineacetic acid.

Found: C(%) 55,14; H(%) 6,6; N(%) 18,00.

NMR spectrum: (DMSO-d6+ CF3COOD, internal standard TMS):

: 2,11-and 2.14 (2H, m), of 2.38 (2H, m), 3,17 (2H, m), 3,64-of 3.77 (5H, m), 4.04 the-4,07 (2H, m), 4,18 (4H, m), the 7.65 (2H, d), 7,83 (2H, d)

The method described in Example 6, to obtain compounds of Examples 9 and 10.

Example 9

Methyl 4-[4-(4-methoxycarbonylaminophenyl)-3-oxo-1-piperazinil] -1-piperidineacetate

Source connection: methyl 4-[4-(4-amidinophenoxy)-3-oxo-1-piperazinil] -1-piperidineacetate hydrochloride

Elemental analysis (for C21H29N5O50,25 H2O)

Calculated: C(%) 0 57,85; H(%) 6,82; N(%) 16,06.

Found: C(%) 57,70; H(%) 6,60; N(%) 16,20

NMR spectrum (CDCl3internal standard TMS):

: 1,63-of 1.73 (2H, m), 1,83 is 1.86 (2H, m), 2,22-of 2.28 (2H, m), 2,34-to 2.40 (1H, m), 2,89 of 2.92 (2H, m), 3.00 and-3,03 (2H, m), 3,24 (2H, s), of 3.45 (2H, s), 3,70 (2H, m), of 3.73 (3H, s), of 3.78 (3H, s), 7,40 (2H, d), of 7.90 (2H, d)

Example 10

Ethyl 4-[4-(4-ethoxycarbonylphenyl)-3-oxo-1-piperazinil] -1 - piperidineacetate

Source connection: ethyl-[4-(4-amidinophenoxy)-3-oxo-1-piperazinil]-1-piperidineacetate hydrochloride

Elemental analysis (for C23H33N5O50,25 H2O)

Calculated: (%) 59,53; H(%) 7,28; N(%) 15,09.

Found: C(%) 59,61; H(%) 7,13; N(%) 15,08.

NMR spectrum (CDCl3internal hundred who 2H, C), 3,70-to 3.73 (2H, m), 4,17-of 4.25 (4H, m), the 7.43 (2H, d), to $ 7.91 (2H, d).

The chemical structures of the compounds obtained in the above Examples shown in Tables 3 and 4.

In addition to the above compounds included in the Examples in Tables 5-9 presents other compounds according to this invention. These compounds can be synthesized without special experiments in accordance with any of the above methods and production processes, as well as their modifications, known to specialists in this field.

1. Substituted derivative of emininently following General formula I or its salt:

< / BR>
in which R1represents a group which can be converted into amedieval group in vivo and selected from hydroxyamides or lower alkoxycarbonylmethyl;

R2and R3are the same or different and each represents a carboxyl group or lower(alkoxy)carbonyl group;

X1and X2are the same or different and each represents a lower alkylenes group;

m = 0 or 1;

n = 0 or 1, provided that when m = 0, then n is equal to 1.

2. Substituted derivative of emininently or its salt under item 1, which is what yl)-3-oxo-1-piperazinil] -1-piperidineacetate, ethyl 4-[4-(4-methoxycarbonylaminophenyl)-3-oxo-1-piperazinil] -1-piperidineacetate, methyl 4-[4-(4-methoxycarbonylaminophenyl)-3-oxo-1-piperazinil] -1-piperidineacetate and ethyl 4-[4-(4-ethoxycarbonylphenyl)-3-oxo-1-piperazinil]-1-piperidineacetate.

3. Substituted derivative of emininently or its salt under item 1, which is ethyl 4-[4-(4-hydroxylaminopurine)-3-oxo-1-piperazinil] -1-piperidineacetate.

4. The pharmaceutical composition exhibiting inhibitory activity against platelet aggregation, characterized in that it comprises an effective amount of substituted derivative emininently General formula I under item 1 or its salt and a pharmaceutically acceptable carrier.

5. The pharmaceutical composition according to p. 4, characterized in that it exhibits the property antagonist receptor GPIIb/IIIa.

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
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