WO1996024583A1

WO1996024583A1 - Novel benzamidine derivatives and medicinal composition thereof

Info

Publication number: WO1996024583A1
Application number: PCT/JP1996/000274
Authority: WO
Inventors: Seijiro Akamatsu; Yuzo Matsumoto; Masato Ichihara; Tomihisa Kawasaki; Seiji Kaku; Isao Yanagisawa
Original assignee: Yamanouchi Pharmaceutical Co., Ltd.
Priority date: 1995-02-10
Filing date: 1996-02-08
Publication date: 1996-08-15
Also published as: AU4633296A

Abstract

Benzamidine derivatives represented by general formula (I), salts thereof, hydrates thereof or solvates thereof; and medicinal compositions comprising the derivatives, salts, hydrates or solvates and pharmaceutically acceptable carriers: wherein R?1 and R2¿ represent each independently hydrogen or ester residue; X1 represents lower alkylene; X2 represents a single bond or lower alkylene; m represents 0, 1 or 2; and n represents 0 or 1, provided when m is 0, then n is 1. The compounds have a GPIIb/IIIa receptor antagonism and are useful as ameliorants for ischemic heart diseases, auxiliaries for cardiac or vascular surgical operation, ameliorants for cerebrovascular disorder, and ameliorants for peripheral arterial diseases.

Description

Description Novel benzamidine derivatives and pharmaceutical compositions thereof

The present invention relates to a novel benzamidine derivative or a salt thereof useful as a medicament, particularly a GPIb / la antagonist, and a pharmaceutical composition containing the compound.

Background art

Platelets have been discovered by Don ne in 1842 (CR Ac a d. Sci. (Paris) ±±, 336-368, 1842), a component in the blood that is necessary for hemostasis for a long time Has been treated as Today, platelets not only play a leading role in the hemostatic mechanism, but also the development of arteriosclerosis, which is attracting clinical attention, circulatory diseases including thrombotic diseases, cancer metastasis, inflammation, rejection after transplantation, and immune response It has been shown to be multifunctional, such as involvement, and thrombotic and ischemic diseases are being treated with drugs or physical methods to resume blood circulation. However, recently, after revascularization, platelet activation, adhesion, and aggregation are enhanced due to disruption of vascular tissue including endothelial cells or disruption of fibrinolysis / coagulation balance due to the drug itself. It has been discovered and is a clinical problem. For example, after re-communication was obtained by thrombolytic therapy using t-PA, etc., it was revealed that fibrinolytic ability and coagulability were activated, and systemic coagulation and fibrinolytic balance were destroyed. . Clinically, it causes reocclusion and is a major therapeutic problem. CI. Am. Coll. Cardiol. 1 ^, 616-623, 1988). On the other hand, PTCA therapy has rapidly spread to treatment of diseases based on coronary stenosis and aortic stenosis, such as angina pectoris and myocardial infarction, with some success. However, this therapy damages vascular tissues including endothelial cells, causing acute coronary occlusion and restenosis that occurs in nearly 30% of patients treated. Platelets play an important role in various thrombotic adverse effects (such as reocclusion) after such revascularization therapy. Therefore, the efficacy of antiplatelet agents is expected, but until the conventional antiplatelet agent proves to be effective enough. Has not been reached. GPIbZBIa is a platelet membrane glycoprotein that is a member of the integrin family (Blood, 80, 1386-1404.1992). This integrin binds to adhesion proteins such as fibrinogen and von Willebrand factor and plays an important role at the very end of platelet aggregation. Monoclonal antibodies against GPEb / EIa and peptide containing an RGD sequence have potent platelet aggregation inhibitory effects, some of which have already been tested in clinical trials. Non-peptide, low molecular weight GPlIbZlEa antagonists are described in JP-A-4-288051, JP-A-6-25227, and LeO et al. (Journal of Medicinal Chemistry, 35, 4393-4407, 1992) Published by. However, they are all intravenous and can only be used during the acute phase of the disease. In addition, although EP-A-542363 discloses a GPHbZHIa antagonist which can be orally administered, its oral activity is not sufficient, and a GP が which is more or less effective by oral administration is disclosed. There is a keen need for bZna antagonists. The compound of the present invention is a novel benzamidine derivative which has a different structure from the compound described in the above patent, exhibits a strong GP lb / Ha antagonistic activity even in particular by oral administration, and has excellent sustained action. is there. Disclosure of the invention

The present inventors have conducted intensive studies on the above compounds exhibiting 0 to 1) 1113 antagonistic activity, and as a result, have created novel benzamidine derivatives, and have found that these compounds have good properties. The inventors have found that they have an antagonistic action, and have completed the present invention.

That is, the present invention relates to a benzamidine derivative represented by the following general formula (I) or a salt thereof, and a pharmaceutical composition containing these compounds and a pharmaceutically acceptable carrier.

(0) „

(I) (The symbols in the above formula have the following meanings, respectively.

R], R ² : the same or different, a hydrogen atom or an ester residue,

X ': lower alkylene group,

X ² : a single bond or a lower alkylene group,

m: 0, 1 or 2,

n: 0 or 1, provided that when m = 0, n = 1. The same applies hereinafter. )

The compound of the present invention has a structural feature in that it has two carboxylic acid residues on the piperidine ring and one or two oxo groups on the Z or piperazin ring, and has a favorable structure caused by the structure. It has oral activity and sustained action.

Preferred compounds in the present invention compounds, the upper Ϊ himself general formula (I), R ', R 2 are the same or different and each represents a hydrogen atom, or, lower pole alkyl group, lower pole Aruke group, a lower alkynyl group, Halogeno lower alkyl, cycloalkyl, phenyl, naphthyl, indolyl, benzyl, lower alkoxybenzyl, nitrobenzyl, benzhydryl, lower alkoxybenzhydryl, lower alkanoyloxy极 alkyl group, lower alkenyloxy lower alkyl group, lower alkanol lower alkyl group, lower alkenoyl lower alkyl group, lower alkoxy lower alkanoyloxy lower alkyl group, lower alkoxy lower alkenyl lower alkyl group, lower 基Alkoxy lower alkyl group, lower alkoxy lower alkoxy Lower alkyl group, cycloalkyloxycarbonyloxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower alkoxy lower alkoxycarbonyloxy lower alkyl group, benzoyloxy lower alkyl group, di-lower alkylamino lower group選 Select from alkyl group, 2-year-old oxotetrahydrofuran-1-yl group, 2-oxo-2-alkyl-1,3-dioxolen-1-ylmethyl group, tetrahydrofuranylcarbonyloxymethyl group or 3-phthalidyl group Benzamidine derivative, salt, hydrate or solvate thereof, which is selected ester residue;

R ', R ² are the same or different and each represents a hydrogen atom or a lower alkyl group, a lower alkenyl group, a halogeno-lower alkyl group, lower pole alkoxy lower alkyl group, lower pole alkoxy A benzamidine derivative which is an ester residue selected from a cyclocarbonyloxy lower alkyl group, a phenyl group, a benzyl group or a lower alkoxybenzyl group, a salt thereof, a hydrate or a solvate thereof;

R 'and R ² are the same or different and are a hydrogen atom or a lower dialkyl group, a benzamidine derivative, a salt thereof, a hydrate thereof or a solvate thereof;

a benzamidine derivative wherein m = 0 and n = 1, a salt, hydrate or solvate thereof;

A benzamidine derivative, m = l or 2 and n = 0, a salt thereof, a hydrate thereof or a solvate thereof.

Hereinafter, the compound (I) of the present invention will be described in detail.

The term "lower" in the definition of the general formula in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified.

Therefore, in the formula (I), as the “lower alkylene group j” represented by X ¹ and X ^2, a linear or branched alkylene group having 1 to 6 carbon atoms is preferable. Methylene, ethylene, methylmethylene, trimethylene, propylene, 2-propylene, dimethylmethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene, 1-ethylethylene group, 2-ethylethylene group, 2,2-dimethylethylene group, 1-dimethylethylene group, ethylmethylmethylene group, propylmethylene group, pentamethylene group, 1-methyltetramethylene group, 2-methyltetramethylene group Group, 3-methyltetramethylene group, 4-methyltetramethylene group, 1,1-dimethyltrimethylene group, 2,2-dimethyltrimethylene group Methylene group, 3,3-dimethyltrimethylene group, 1,3-dimethyltrimethylene group, 2,3-dimethyltrimethylene group, 1,2-dimethyltrimethylene group, 1-ethyltrimethylene group, 1, 2-trimethylethylene, getylmethylene, 1-propylethylene, 2-propylethylene, butylmethylene, hexamethylene, 1-methylpentamethylene, 1,1-dimethyltetramethylene, 2, 2-dimethyltetramethylene group, 3, 3-dimethyltetramethylene group, 4,4-dimethyltetramethylene group, 1, 1, 3- Trimethyltrimethylene group, 1,1,2-trimethyltrimethylene group, 1,1,2,2-tetramethylethylene group, 1,1-dimethyl-2-ethylethylene group, 1,1-getylethylene group, 11 Provir trimethylene group, 2-propyltrimethylene group, 3-propyltrimethylene group, 1-butylethylene group, 2-butylethylene group, 1-methyl-1-propylethylene group, 2-methyl-2-propylethylene group A 1-methyl-2-propylethylene group, a 2-methyl-1-propylethylene group, a pentylmethylene group, a butylmethylmethylene group, an ethylpropylmethylene group and the like. Among them, a linear alkylene group having 1 to 3 carbon atoms, Methylene and ethylene groups are preferred.

A compound in which R ¹ and / or R ² is an ester residue itself becomes a drug as an active substance. In addition, these compounds are useful as prodrugs which are metabolized in vivo to become active carboxylic acid compounds, and are also useful as intermediates for synthesizing carboxylic acid compounds. Therefore, the `` ester residue '' in R ′ and R ² includes an ester residue known to those skilled in the art that can be metabolized and hydrolyzed in vivo and serve as a protecting group for Z or carboxyl group. . These ester residues include, for example, lower alkyl groups, lower alkenyl groups, lower alkynyl groups, halogeno lower alkyl groups, cycloalkyl groups, phenyl groups, naphthyl groups, indolyl groups, benzyl groups, lower alkoxybenzyl groups Group, nitrobenzyl group, lower alkoxybenzhydryl group, benzhydryl group, lower alkanoyloxy lower alkyl group, lower alkenoyloxy lower alkyl group, lower alkanoyl lower alkyl group, lower alkenoyl lower alkyl group, lower alkoxy lower极 Alkyloxy lower alkyl group, low 、 alkoxy lower alkoxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, cycloalkyloxycarbonyl lower alkyl group, Lower alkoxycarbonyloxy lower alkyl group, lower alkoxy lower alkoxy carbonyloxy lower alkyl group, benzoyloxy lower alkyl group, di lower alkylamino lower alkyl group, 2-oxotetrahydrofuran-1- Group, 2-oxo-1-5-alkyl-1, 3-dioxolen-1-ylmethyl group, tetrahydrofuranylcarbonyl Common ester residues such as a xylmethyl group or a 3-phthalidyl group are exemplified. Preferable are a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarboxy lower alkyl group, a phenyl group, a benzyl group and a lower alkoxybenzyl group. Preferably, it is a lower alkyl group.

Here, the “lower alkyl group” is a straight or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, and an isobutyl group. , Sec monobutyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl Xyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group , 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,2,2-trimethylpropyl group, 1,2,2-trimethylpropyl group 1 Echiru 1 one-methylpropyl group, and a 1-Echiru 2-methylpropyl group or the like. Particularly, a methyl group and an ethyl group are preferred. The lower alkyl group substituted with various substituents represented as ester residues of R ′ and R ² is a lower alkyl group in which any hydrogen atom of the lower alkyl group is substituted with each substituent. Show.

The “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a vinyl group, an aryl group, a 1-propenyl group, an isopropyl group, a 1-butenyl group. Group, 2-butenyl group, 3-butenyl group, 2-methyl-1-proproenyl group, 2-methylaryl group, 1-methyl-1-propenyl group, 1-methylaryl group, 1-pentenyl group, 2-pentenyl group And 11-hexenyl groups.

The “lower alkynyl group” is a straight-chain or branched alkynyl group having 2 to 6 carbon atoms, specifically, an ethynyl group, a 1-propynyl group, a 2-propynyl group, a 1-butynyl group, a 2-alkynyl group. Petenyl, 3-petynyl, 1-methyl-2-propynyl, 1 One pentynyl group and the like can be mentioned.

Examples of the “halogeno lower alkyl group” include groups in which one or more hydrogen atoms of the lower alkyl group have been replaced with a halogen atom consisting of a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Examples thereof include a chloromethyl group, a bromomethyl group, a fluoromethyl group, a trifluoromethyl group, a 1,1-dichloromethyl group, and a 1-chloro-2-bromoethyl group.

The "cycloalkyl group" in the "cycloalkyl group" or the "cycloalkyloxycarbonyldialkyl group" is a cycloalkyl group having 3 to 8 carbon atoms, and is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, Examples include a cyclohexyl group and a cycloheptyl group.

“Lower alkoxybenzyl group”, “Lower alkoxybenzhydryl group”, “Lower alkoxy lower alkanoyloxy lower alkyl group”, “Lower alkoxy lower 极 alkenoyloxy lower alkyl group J, ΓLower alkoxy lower alkyl group "," Lower alkoxy lower alkoxy lower alkyl group j "," lower alkoxy carbonyl lower alkyl group ", or" lower alkoxy lower J in "lower alkoxy lower alkoxy carbonyl lower alkyl group J", preferably an alkyl moiety A lower alkoxy group having the above-mentioned lower alkyl group; for example, a methoxy group, an ethoxyquin group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butkin group, a pentyloxy (amylo) group; B) group, isopentyloxy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 1-ethylpropoxy group, hexyloxy group, etc., especially methoxy group And ethoxy groups are preferred.

The `` lower alkanoyl group '' in the `` lower alkanoyl lower alkyl group j '', `` lower alkanoyloxy lower alkyl group J '' or `` lower alkoxy lower alkanoyloxy lower alkyl group '' is derived from a saturated aliphatic carboxylic acid. Lower acetyl group having 2 to 6 carbon atoms, for example, acetyl group, propionyl group, butyryl group, isobutyryl group, octyleryl group, isovaleryl group, vivaloyl group or hexanoyl group Preferred are aryl groups and the like.

The “lower alkenyl lower alkyl group”, the “lower alkenyloxy lower alkyl group” or the “lower alkenyl group” in the “lower alkoxy lower alkenoyloxy lower alkyl group J” has 3 to 3 carbon atoms. Six alkenoyl groups, for example, an acryloyl group, a crotonyl group, a maleoyl group and the like can be mentioned.

The “di-lower alkylamino group” in the “di-lower alkylamino lower alkyl group” means an amino group di-substituted by a specific group of the lower alkyl group, and specifically, for example, a dimethylamino group, a getylamino group, Examples thereof include symmetric or asymmetric di-lower alkylamino groups such as a mouth amino group, a diisopropylamino group, a dibutylamino group, a diisobutylamino group, an ethylmethylamino group, and a methylpropylamino group.

In the compound (I) of the present invention, a preferable compound is a compound represented by the general formula (la) wherein 111 = 0 or 1 = 1, or a compound represented by the general formula (111 = 1 or 2 and 11 = 0) Compounds represented by I b) are mentioned. OR ¹

(la)

(The symbols in the formula have the meanings described above.)

(lb)

(In the formula, X ¹ and R ¹ have the same meanings as above, and m ′ represents 1 or 2.)

Preferred compounds of the present invention are listed below.

4- [4- (4-Amidinophenyl) -1-piperazinyl] -1,3-piperidinediacetic acid, its optically active form, its salt, its hydrate or its solvate 4- [4- (4-Amidinophenyl) -1,2,5-dioxiz-1-piperazinyl] — 1-piperidineacetic acid, its optically active form, its salt, its hydrate or its solvate

4- [4- (4-Amidinophenyl) -1-3-oxo-1-piperazinyl] —1-piperidineacetic acid, an optically active form thereof, a salt thereof, a hydrate or a solvate thereof The compound of the present invention (I) At least one asymmetric carbon atom is present based on the presence of the piperidinyl group contained in the skeleton and the substituents thereof (the group represented by Formula 1 X ² —COOR ² ). Further, depending on the type of the substituent, the compound may have another asymmetric carbon atom. The compound of the present invention has optical isomers based on these asymmetric carbon atoms. Further, there may be a tautomer based on the presence of a carbonyl group in the substituent or a geometric isomer based on a double bond. The present invention includes all isolated forms or mixtures of these isomers.

The compound (I) of the present invention is preferably a salt capable of forming a salt. Such a salt is preferably an alkali metal such as a sodium salt, a potassium salt or a calcium salt, or an alkaline earth. Metal salts; hydrohalides such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide; carbonates, nitrates, perchlorates, sulfates, phosphates, etc. Inorganic acid salts; low-alkyl sulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; arylsulfonic acids such as benzenesulfonate and p-toluenesulfonate Salts; organic acid salts such as acid salts, trifluoroacetates, fumarate salts, succinates, citrates, tartrate salts, oxalates and maleates; and amino acids such as glutamates and asbalaginates To It can gel.

The present invention also includes hydrates, various pharmaceutically acceptable solvates and polymorphs of the compound (I) of the present invention.

It should be understood that the present invention is not limited to the compounds described in Examples below, but encompasses all of the benzamidine derivatives represented by the general formula (I) or pharmaceutically acceptable salts thereof. Is what you do.

(Manufacturing method)

The compound (I) of the present invention can be produced by applying various production methods. The typical manufacturing method is described below ₍

(I)

OR ² ) „

(I)

(Wherein, RR ² , m, n, X ¹ and X ² have the above-mentioned meanings.) The compound (I) having an amidino group can be synthesized by the following methods (i), (ii) and (iii). .

(i) Method of condensing nitrile into imidate followed by amine

Acetonitrile (ox) is treated with an alcohol such as methanol or ethanol at a temperature of TC to 0 ° C in the presence of hydrochloric acid gas in the presence of hydrochloric acid to form imidate, ammonia, ammonium carbonate, ammonium chloride, ammonium sulfate React with amines or amine salts such as methanol, ethanol, acetone, tetrahydrofuran and the like.

(ii) A method in which nitrile is converted to thioamide, then converted to thioimidate, and condensed with amine.

The nitrile form (I) is reacted with hydrogen sulfide in the presence of an organic base such as methylamine, triethylamine, pyridine or picoline to obtain a thioamide form. This thioamide form can also be obtained by reacting the nitrile form (Π) with 0,0-diethyl dithiophosphate in the presence of hydrogen chloride. The above thioamide form is reacted with a low alkyl halide such as methyl iodide or thiolated iodide to form a thioimidate form, and then an amine or an amine salt such as ammonia, ammonium carbonate, ammonium chloride or ammonium tallowate is added. Let react. As the solvent, methanol, ethanol, acetone, tetrahydrofuran, ethyl drunkate or the like is used.

(iii) Direct addition of amide, amine salt, metal amide or Grignard reagent to nitrile

Ammonitrile, ammonium chloride and ammonia, ammonium thiocyanate, alkyl ammonium thiocyanate, Me Al (C 1) NH ₂ , Na NH in a solvent suitable for nitrile form (H) or without solvent ₂ , can be synthesized by adding a reagent such as (CH ₃ ) ₂ NMgBr. As the solvent, chloroform, methanol, ethanol, acetone, tetrahydrofuran, toluene, dimethylformamide and the like are used. Further, as a catalyst, a base such as sodium hydride or an acid such as aluminum chloride or p-toluenesulfonic acid may sometimes significantly accelerate the reaction. The reaction can be carried out from cooling to room temperature to heating.

(Other manufacturing methods)

Carboxylic acid compounds in which R ¹ and Z or R ² are hydrogen atoms can be obtained by dissolving compound (I) in a suitable solvent and subjecting ordinary ester hydrolysis to basic, acidic, or neutral conditions. To be obtained.

By appropriately selecting the conditions, a carboxylic acid compound in which only one is a hydrogen atom can be obtained by hydrolysis. For example, on the one hand, ester residues that are susceptible to hydrolysis under acidic conditions (for example, tertiary butyl group) and on the other hand, ester residues that are susceptible to hydrolysis under base conditions (for example, methyl ester, ethyl ester) ) Can selectively hydrolyze only one of them depending on the hydrolysis conditions (acidic or basic conditions).

Further, by subjecting the carboxylic acid compound to an esterification reaction, a desired ester compound can be obtained. The esterification reaction is appropriately selected according to a conventional method. PC / JP In the compound of the present invention, a compound in which R ′ and Z or R ² is an ester residue can also be produced from a suitable alcohol by transesterification. For example, in the presence of an acid or base or other catalyst (for example, titanium (W) alkoxide), use a large excess of the alcohol form or remove the other alcohol form to the outside of the system to shift the equilibrium toward the production system. By doing so, a desired ester form can be obtained.

(Production method of raw material compounds)

Hereinafter, the method for synthesizing the starting compounds will be described.

(A)

(la) (W)

(la)

(Wherein, R ′, R ² , X ′, X ² , m and n have the above meanings.)

Compound (la) is obtained by dissolving compound (Ha) in a suitable solvent, reacting with compound (IV) amine to form a Schiff base, and then reducing the Schiff base. This Schiff base may be isolated or reduced without isolation.

As the solvent, an organic solvent inert to the reaction, for example, benzene, toluene, methanol, acetic acid and the like are used.

In the reaction, the compound (Ma) and the corresponding amount of the compound (IV) or one of the amines are used in a slight excess, preferably an acid catalyst such as p-toluenesulfonic acid, adipic acid, oxalic acid, pyridine hydrochloride, and acetic acid. Perform in the presence of (B)

(V) (lb)

(Wherein, R ′, R ² , X ′ and X ² have the above-mentioned meanings.)

The compound (ffib) is prepared by dissolving the compound (V) in a suitable solvent, and reacting with a suitable secondary amine to form an enamine, and then reacting the enamine with an alkyl acrylate.

(Eg, methyl acrylate) or a halogenated aliphatic carboxylic acid ester (eg, ethyl bromoacetate). Enamine may or may not be isolated.

(C)

(In the formula, X ¹ and X ² have the above-mentioned meaning, and R ³ and R ⁴ are the same or different and represent ester residues.)

The compound represented by the general formula (VDI) is obtained by reacting a carboxylic acid (VI) with a halogenated fatty acid-protected carboxylic acid ester (eg, ethyl bromoacetate) in the presence of a base (eg, lithium carbonate) to give a compound (VII). And subjecting this compound (II) to dealkoxycarbonylation under appropriate conditions. (D)

IY ¹ -A ³ -A ⁴ -Y ² (XII)

(0)

CN

(In the formula, one or two of A ^{1 to} A ⁴ represent a carbonyl group, and the other represent a methylene group, and Y represents a halogen atom, a hydroxyl group, a lower alkoxy group, a phenoxy group, an imidazolyl group, an arylsulfonyl group. alkoxy group means a de雜基de雠基such active carboxylic acid derivative, Upsilon ² is 'means a leaving group or a hydrogen atom and described ^{in, X' Y, X 2,} R 1 R 2, m 'And n have the above-mentioned meaning.)

The reaction of producing the compound (XI) by reacting the compound (K) with the compound (X) can be carried out in the same manner as in the aforementioned starting compound production method (A). The solvent, catalyst, reaction conditions and the like used in the reaction are the same as in (A) above.

Reactions for producing compound (XII I) from compound (XI) are shown in the following 1) to 3).

1) In the above compound (II), when Y ² is an alkyl derivative in which Y ² is the leaving group described for Y ′ and A ⁴ is a methylene group

This reaction may be performed according to a conventional N-alkylation reaction method. This reaction is carried out while stirring compound (XI) and a corresponding amount of compound (XII) in an inert solvent with cooling or heating. To accelerate the reaction, it is preferable to add a base (for example, an inorganic base such as potassium carbonate, sodium carbonate, sodium hydride, or an organic base such as triethylamine).

2) In the case of the above compound (XI I), a carboxylic acid derivative wherein Y ² is the leaving group described for Y ′ and A ⁴ is a carbonyl group

The amide compound (ΧΙΠ) can be obtained by carrying out an acylation reaction of an amine (XO with a carboxylic acid and its derivative (ΧΠ) in a suitable solvent. —Active esters obtained by reacting with phenolic compounds such as ditrophenol and N-hydroxyamine compounds such as N-hydroxysuccinimide and 1-hydroxybenbuttriazole; monoalkyl carbonates or organic compounds A mixed acid anhydride obtained by reacting with an acid, a phosphoric acid mixed acid anhydride obtained by reacting with diphenylphosphoryl chloride, or N-methylmorpholine; obtained by reacting an ester with hydrazine or alkyl nitrite Acid azides; acid halides such as acid chloride and acid promide; symmetrical acid anhydrides; The compound (ΧΠ Ο can also be obtained by an acylation reaction with carboxylic acid (XII) in a suitable solvent in the presence of a condensing agent. In this case, the condensing agent may be N, N-zinclohexylcarpoimide (DCC :), 1-ethyl-3- (3- (N, N-dimethylamino) propyl) carbodiimide, carbonyldiimidavour, diphenylphosphoryl azide (DPPA), and dimethylphosphoryl cyanide are preferred.

3) Of the above compounds (XI I), those wherein Y ² is a hydrogen atom and Y ⁴ is a carbonyl group Derivative derivatives

Compound (ΧΠ Ι) is obtained by dissolving the aldehyde compound (ΧΠ) in a suitable solvent, reacting with the amine of compound (XI), and reducing the resulting imidium ion. The reaction solvent, reducing agent, and reaction conditions are as described in (A) above.

(D) Cyclization to an oxobiperazine ring compound (E b) is carried out by reacting the precursor (X [I []) in a suitable solvent without a catalyst or in the presence of a suitable catalyst. At that time, the reaction can be carried out under ice cooling, at room temperature or under heating.

The compound of the present invention produced in this manner is isolated or purified as it is or subjected to a salt-forming treatment by a conventional method, and as a salt thereof. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, careful recrystallization, and various types of chromatography.

When the target compound of the present invention is an optical isomer, a racemic mixture can be prepared from the pure starting material having the desired stereostructure of the product, or the racemic mixture can be resolved at any convenient stage in the synthesis, with respect to the above process. It is also obvious to those skilled in the art that they can be obtained by performing Resolution of the final product, intermediate or starting material is accomplished by any suitable method apparent to one skilled in the art. Industrial applicability

The compound of the present invention has a platelet aggregation inhibitory action as a medicament, particularly an orally administrable GPU bZIIIa receptor antagonist, and ischemic heart disease (unstable angina, acute myocardial infarction, and its secondary prevention, After coronary artery bypass surgery, re-occlusion and restenosis after PTCA surgery, drugs for promoting coronary thrombolysis and preventing re-occlusion, adjuvant drugs during cardiac surgery or vascular surgery, cerebrovascular accident (transient cerebral ischemic attack) (TIA :), cerebral infarction, subarachnoid hemorrhage (blood vessel spasm)), and peripheral arterial disease (such as chronic arterial occlusion).

In particular, the compound of the present invention is excellent in oral absorbability, and is useful as a drug for improving the above-mentioned diseases not only in parenteral administration such as intravenous injection but also in oral administration. In addition, the compound of the present invention is excellent in the effect surrounding properties, and has high clinical utility. Further, the compound of the present invention Less toxic than compounds.

The pharmacological effects such as the platelet aggregation inhibitory effect of the compound of the present invention were confirmed by the following test methods.

Inhibition test of fibrinogen binding to purified GPπbZIIIa

GPEbZHa was purified according to the method of Fitzgera id. Fibrinogen was biotinylated using NHS-LC-Bi0tin (Pierec).

TBS (2 OmM Tr is -. HC 1 pH7 4, 15 OmM Na C 1, Im CaC 12, 1 mM Mg C 1 2) in 1 gZm 1 and the purified GPH b! 13 100 1 was added to a 96 we 1 1 plate (axi Sorp ™, Nc nc) and left at 4 eC for ^e . After washing once with TBS, 200 1 of 1% BS AZT BS was added, and the mixture was allowed to stand at 37 ° C for 1 hour. After removing the solution, specimen and Piochin reduction is added Fuiburino one Gen, 37 ^e C in for 3 hours the reaction was washed three more times with 0. 01% t we en 2 OZTBS . 0.1 Add 100% of streptavidin-biotinylated horseradish peroxidase complex (Amersham) diluted 1 000-fold with 1% BSA-no-TBS and react at room temperature for 30 minutes. Washed three times with T-TBS. The color was developed by adding 100 / zl of a 2,2'-azinobis-3-ethylbenzothiazoline 6-sulfonic acid solution (Bi0-Rad) and the absorbance at 414 nm was measured using a microplate reader. It was measured at 1.

As a result of the test for inhibiting the binding of fibrinogen to the purified GPEbZlIIa, the compound of the present invention exhibited good binding inhibition, and the compound of Example 8 exhibited an IC ₅ . The value was 8.4 nM, and the compound of Example 16 showed 10.4 nM. In addition, the above-mentioned European Patent which is a prior art

No. 542363, Example 15 Compound (hereinafter abbreviated as “preceding compound”) has an IC _so value of

68.8 nM.

Cynomolgus monkey _e X vi vo platelet aggregation inhibitory activity test

The cynomolgus monkey under mild anesthesia by intramuscular administration of keyumin hydrochloride was kept on an experimental table, and 3 mg of the compound of the present invention dissolved in 2 ml of distilled water was used in a rubber tube. And administered by gavage. Blood was collected from the femoral vein at a dose of 3 ml (including 1Z10 volume sodium citrate) before administration and after a certain period of time, and then the method of De Marco et al. (J. Clin. Inv. Est., 77, 1) Platelet-rich plasma (PRP) was prepared according to 272–1 277, 198 6). PRP was prepared at 3 × 10 ⁸ Zm 1 using an automatic hemocytometer (ΜΕΚ-5158, Nihon Kohden) and used. Platelet aggregation was induced using 20 uM ADP, 10 g of bovine tendon-derived collagen (Nikko Bioscience), and measured using a platelet aggregometer (NBS Hematrater 811, Nikko Bioscience). . P harmful activity was expressed as an inhibition rate (%) with respect to the maximum aggregation rate in an aggregation curve calculated using PRP of each animal before drug administration.

Table 1 shows the results of the above-mentioned cynomolgus monkey eXVivo platelet aggregation inhibitory activity test.

me an ± SEM (n = 3) As a result of the above-mentioned cynomolgus monkey exvivo platelet aggregation inhibitory activity test, the compound of the present invention showed a sufficient platelet aggregation inhibition ratio even after 12 hours of oral administration compared to the preceding compound .

As a result of the above pharmacological tests, it was found that the compound of the present invention inhibits fibrinogen binding to human platelets, has a good platelet aggregation inhibitory activity, and has good oral absorption and sustained action. confirmed.

A preparation containing one or more of the compound of the present invention or a salt thereof as an active ingredient is prepared by using a carrier, a shaping agent, and other additives commonly used in pharmaceutical preparations. Examples of carriers and excipients for pharmaceuticals include solid or liquid non-toxic pharmaceutical substances. These include, for example, lactose, magnesium stearate, starch, yunorek, gelatin, agar, pectin, acacia, olive oil, sesame oil, cocoa butter, ethylene glycol and the like, and other commonly used ones. Administration is oral, such as tablets, pills, capsules, granules, powders, and liquids, or parenteral administration, such as injections such as intravenous and intramuscular injections, suppositories, transdermal agents, and inhalants. May be used. The dose is determined as appropriate depending on the individual case, taking into account the symptoms, age of the subject of administration, gender, etc., but in the case of oral administration, it is usually about 0.01 mg / kg to 10 mg / kg / day for adults. This may be administered once or in 2-4 divided doses. In the case of intravenous administration depending on the symptoms, it is usually administered once or more than once a day in the range of 0.001 mg to 1 OmgZkg per adult. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail based on examples. The compound of the present invention is not limited to the compounds described in the following Examples, and furthermore, the compound represented by the general formula (I), a salt thereof, a hydrate thereof, a solvate thereof, a geometrical and optical isomer thereof The crystal includes all polymorphs.

The starting compounds of the compound of the present invention include novel compounds. Production examples of these compounds will be described as reference examples.

Reference example 1

1.85 g of ethyl 4-oxo-1-piperidine acetate and 1.1 g of pyrrolidine were dissolved in 50 ml of benzene and refluxed for 24 hours using a Dean-Stark apparatus. The reaction solution was concentrated, 50 m of benzene was added thereto, 1.7 g of methyl acrylate was added, and the mixture was refluxed for 48 hours. 7 ml of water was added to the reaction solution, and the mixture was refluxed for 2 hours, and the organic layer was separated. This was dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 50: 1) to give methyl 1-ethoxycarbonylmethyl 14-oxo-13-biperidine propionate. 1.8 g were obtained as oily substance.

Mass analysis (m / z): FAB ( Po s) 272 (M + + 1)

Nuclear magnetic resonance scan Bae spectrum (CDC 1 _3, TMS internal standard)

δ: 1.29C3H.t), 1.51-1.58 (1H.m) .2.06-2.13 (1H.ra) .2.31-2.48 (4H, m) .2.61 -2.74 (3H.m) .3.14-3.17 (2H.m) .3.36 (2H.d), 3.66 (3H.s) .4.20 (2H, q).

In the same manner as in Reference Example 1, the following compound of Reference Example 2 was obtained.

Reference example 2

Methyl 11- (tert-butoxycarbonylmethyl) 1-4-oxo 3-piperidinepropionate

Starting compound: tert-butyl 4 Okiso - 1 over piperidine § cetearyl Ichito Mass analysis (m / z): FAB ( Po s) 300 (M + + 1)

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

(5: 1.48 (9H.s), 1.50-1.59 (1H, m), 2.05-2.15 (1H, m) .2.30-2.46 (4H, m) .2.60 -2.70 (3H, m) .3.13-3.17 ( 2H, m) 3.25 (2H, d), 3.66 (3H, s).

Reference example 3

1.74 g of methyl l-ethoxycarbonylmethyl-4-oxo-3-piperidinepropionate Dissolve 1.2 g of 4- (1-piperazinyl) benzonitrile and 0.8 g of diacid in 50 ml of dichloromethane and add hydrogenated tria to it. 2.7 g of sodium ethoxyborohydride was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was neutralized with a 1 N aqueous solution of sodium hydroxide, and the organic layer was separated. This was dried over sodium sulfate and concentrated, and the residue was purified by silica gel column chromatography (eluent hexane: St-ethyl = 1: 1) to give methyl 4- [4- (4-cyanophenyl)]. [1-1 piperazinyl] 1.1 g of 1-ethoxyquincarbonylmethyl-3-piperidinepropionate was obtained.

Mass spectrometry value (mZz): FAB (Po s ) 44 3 (+ + 1)

Nuclear magnetic resonance scan Bae spectrum (CDC 1 _3, TMS internal standard)

δ: 1.28 (3Η, t) .1.66-1.77 (2H, m), 1.94-1.97 (3H, m) .2.05-2.08 (2H.m) .2.19- 2.24C1H, ra) .2.35-2.41 (2H. m) .2.53-2.58 (3H.m), 2.64-2.66 (2H.m), 2.94 (1H, d) .2.99 (1H.d), 3.15 (2H, dd) .3.32-3.36 (3H, m), 3.66 (3H.s), 3.33C2H. q), 6.85 (2H, d). 7.48 (2H. d).

In the same manner as in Reference Example 3, the following compound of Reference Example 4 was obtained.

Reference example 4 Methyl 4- [4- (4-cyanophenyl) -1-piperazinyl] — 1- (tert-butoxycarbonylmethyl) 1-3-piperidinepropionate

Mass analysis (m / z): FAB ( Po s) 47 1 (M + + 1)

Nuclear magnetic resonance scan Bae spectrum (CDC 1 _3, TMS internal standard)

(5: 1.47 (9H, s), 1.64-1.70 (1H, m), 1.75 (1H, d) .1.94-1.99 (3H, m), 2.03-2.09 (2H.m) 2.17-2.22 (1H.m) m) .2.35-2.42 (2H.m), 2.52-2.58 (3H, m), 2.63-2.67C2H.m), 2.92-2.97 (3H.m), 3.15 (1H, d), 3.33C3H, t) .3.66 (3H.s) .6.85 (2H.d), 7.48C2H.d). The compound of Reference Example 5 was obtained in the same manner as in Reference Example 1.

Reference example 5

t er t-Butyl 3- (2-methoxycarbonylethyl)-4-oxo-1-1-piperidinepropionate

Starting compounds: tert-butyl 4-oxo-11-piperidineprobionate and methylacrylate

Mass spectrometry value (mZz): FAB (Po s ) 31 4 (M + + 1)

Nuclear magnetic resonance spectrum (CDC 13, TMS internal standard)

δ 1.46C9H.s) .1.50-1.59 (1H.m) .2.04-2.13 (1H, m) .2.23 (1H.t) .2.34-2.5 (5H, m) .2,48-2.58 (3H , m), 2.75-2.80 (2H.m) .3.02-3.08 (2H.m) .3.66 (3H, s).

Reference example 6

Dissolve 9.65 g of methyl 4-oxo-l-biperidinecarboxylate monohydrochloride, 21.0 g of ethyl bromoacetate and 24.0 g of potassium carbonate in 20 Om1 of N, N-dimethylformamide, Stirred at room temperature overnight. 100 ml of water was added to the reaction solution, extracted with 500 ml of ethyl tallowate, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: black form) to obtain 9.0 g of ethyl 3-ethoxyquincarbylmethyl-3-methoxycarbonyl-2-oxo-1-biperidine acetate as an oily substance.

Mass spectrometry value (mZz): FAB (Po s ) 330 (M + + 1)

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

δ: 1.23-1.31 (6Η.m) .2.46-2.51 (1H.m) .2.71 (2H, dd), 2.91-2.96 (2H, m) .3.00 -3.08 (2H, m), 3.35-3.45 (2H, m) .3.79 (3H, s), 4.10-4.19 (4H, m).

Reference Example 7

Ethyl 3-ethoxycarbonyl methyl-3-methoxycarbonyl 2-oxo 4-piperidine acetate 1.0 g and lithium chloride 14 Omg were dissolved in N, N-dimethylformamide 1 Oml and refluxed for 48 hours. did. Water I 反応 was added to the reaction solution, extracted with 100 ml of ethyl acetate, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent: black-mouthed form) to obtain 40 mg of getyl 4-oxo-1,3-dipyridine diacetate as an oily substance.

Mass analysis (m / z): FAB ( Po s) 272 (M + + 1)

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

δ: 1.23-1.30 (6H.in) 2.18 (1H.dd) 2.36-2. 0 (1H.m), 2.50 (1H, t) 2.70-2.77 (3H, m), 3.13-3.26 (3H , m), 3.38 (2H.s), 4.09-4.22 (4H.m).

Reference Example 8

Dissolve 1.94 g of methyl 4-oxo-1,3-piperidinecarboxylate monohydrochloride, 1.68 g of sodium hydrogen carbonate and 1.67 g of ethyl bromoacetate in a mixed solvent of 32 ml of water and 8 ml of diethyl ether. Then, the mixture was stirred at room temperature overnight. 50 ml of ethyl acetate was added to the reaction solution, the organic layer was separated, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (eluent, black form to black form: methanol = 100: 1), and ethyl 3-methoxycarbo-2-ru 4-oxo-one piperidine acetate 1.5 g Was obtained as an oil. Mass analysis (m / z): FAB ( Po s) 244 (M + + 1)

Nuclear magnetic resonance scan Bae spectrum (CDC 1 _3, TMS internal standard)

δ: 1.29 (3Η.t) .2.45-2.47 (2H, m), 2.80C2H, t), 3.31 (2H, s) .3.36 (3H.s) .3.76 (3H.s), 4.20 (2H.q ).

In the same manner as in Reference Example 3, the compounds of Reference Example 9 (1) and (2) were obtained.

Reference Example 9

(1) tert-butyl 4- [4- (4-cyanophenyl) -111 piperazi Nyl] -1- (2-methoxycarbonylethyl) -1-piperidinepropionate

Starting compound: tert-butyl 3- (2-methoxycarbonylethyl)-4-oxo-l-biperidine propionate

Mass analysis (m / z): FAB ( Po s) 485 (M + + 1)

Nuclear magnetic resonance scan Bae spectrum (C DC 1 _3, TMS internal standard)

δ: 1.44C9H.s) .1.53-1.59C2H.m), 1.75 (1H, d) 1.89-2.05 (5H, m), 2.23-2.77 (11H, m) .2.87 (1H.d) .2.93 ( 1H.d), 3.32 (2H, d), 3.66 (3H, s) .6.85 (2H, d), 7.48 (2H.d).

(2) (Sat) 1-cis-1 getyl 4-1 [4- (4-cyanophenyl) -1-1-piperazinyl] -1,3-piperidine acetate

Starting compound: Jethyl 4-oxo-1,3-piperidine acetate

Reference example 10

(Sat) 1-cis-getyl 4- [4- (4-cyanophenyl) -1-biperazinyl] 4.0 g of 1,1,3-piperidine diacetate and (10) dibenbuyl D-3.4 g of tartaric acid Stethyl acid: diisopropyl It was dissolved in 140 ml of a mixed solvent of ether (1: 1) and subjected to fractional crystallization. The obtained crystals were repeatedly recrystallized several times with a mixed solvent of ethyl acetate: diisopropyl ether (1: 1) to give (+)-cis-ethyl-4-[4- (4-cyanophenyl) -1-1-piperazinyl] — 1, 3-piperidine diacetate (+)-dibenzoyl D-tartrate 69 mg (98.4% e.e.) was obtained.

Specific rotation _{_{_{(C 24 H 34 N 4 04}}} ; as a free Shiotai):

^{_{Non] 25 D = + 32.4 ° c}} = 1.00 (CHC 1 3)

Reference example 1 1

(Sat) 1-cis-getyl 4- [4- (4-cyanophenyl) -1-piperazinyl] 6.3 g of 1,1-piperidine diacetate and (1) 5.4 g of dibenzoyl-L-tartaric acid in ethyl acetate: diisopropyl ether The mixture was dissolved in 80 ml of a mixed solvent of (1: 1) and subjected to fractional crystallization. The obtained crystals are mixed with ethyl nitrate: diiso. Recrystallization was repeated several times with a mixed solvent of propyl ether (1: 1), and (1) 1-cis-ethyl 4- (4- (4-cyanophenyl) -1-1-piperazinyl) 1-1,3-piperidine diacetate (-) There was obtained 64 Omg (98.4% ee) of dibenbuyl L-tartrate.

Specific rotation _{_{_{(C 2 4 H 34 N 4}}} 0 *; as free Shiotai):

^{Non] 25 D = - 31.7 ° c} = l.67 (CHC 1 3)

Example 1

Methyl 4- [4- (4-cyanophenyl) -1-1-piperazinyl] -111-ethoxycarbonylmethyl-3-piperidinepropionate 55 Omg dissolved in 2 Oml of ethanol and chlorided at 110--20 ° C Hydrogen was bubbled in until saturated. After returning to room temperature and stirring overnight, the solvent was distilled off. The obtained residue was dissolved in 20 ml of ethanol, 1.0 g of ammonium carbonate was added, and the mixture was stirred at room temperature overnight. The solvent of the reaction mixture was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 10: 1), and ethyl 4 -— [4-—

(4-Amidinophenyl) -1-1-piperazinyl] -111-ethoxycarbonylmethyl-3-piperidinepropionate monohydrochloride (500 mg) was obtained.

Mass spectrometry value (mZz): FAB (Po s) 4 74 (M + + 1)

Nuclear magnetic resonance scan Bae spectrum (DMSO- d _6, TMS internal standard)

δ: 1.06C3H, t), 1.17-1.21 (4H.m) 1.40-2.30 (5H, m) .2.44-2.54C2H.m) 2.87 (1H.m), 3.15 (1H.dd), 3.17 ( 3H.d), 3.31 (3H, s) .3.36 (3H, brs), 3.2-3.47 (2H, m), 4.03-4.10 (4H.m) .4.34 (1H, t) .7.07 ( 2H.d), 7.75 (2H.d).

Example 2

Ethyl 4-1 [4- (4-amidinofenyl) -11-piperazinyl] -11-ethoxycarbonylmethyl-3-piperidinepropionate monohydrochloride 35 Omg is dissolved in 20 ml of ethanol and 1N aqueous sodium hydroxide solution 2. 5 ml was added and the mixture was stirred at room temperature for 5 hours. 2.5 ml of 1 N hydrochloric acid was added to the reaction mixture, and the solvent was distilled off. The residue was purified by HP-20 column chromatography (eluent water to water: methanol = 50: 1), and 4- (4-Amidinophenyl) 1-1-piperazinyl One hundred and one hundred and eighty-one carboxymethyl-3-biperidinepropionic acid monohydrochloride was obtained.

Mass spectrometry value (mZz): FAB (P 0 s) 4 1 8 (M + + 1)

Nuclear magnetic resonance spectrum (DMSO - d _6, TMS內部standard)

<5: 1.75 (1H.brs) .2.02-2.09 (2H, m) .2.38-2.45 (2H, m) .2.51-2.64 (2H.m), 3.0

4 (1H, d), 3.12C1H.t) .3.56 (2H, brs), 3.76C2H.d) .4. HUH, dd), 7.21 (2H.d), 7.81 (2

H, d), 8.87 (2H.s), 9.04 (2H.s).

Example 3

Methyl 4- [4- (4-cyanophenyl) 1-1-piperazinyl] 1-11 (tert-butoxycarbonylmethyl) 1-3-piperidinepropionate 1.lg and triethylamine 1 ml N, N-dimethylforma The solution was dissolved in 20 ml of mid and blown at room temperature until hydrogen sulfide was saturated. After stirring the mixture overnight at room temperature, 200 ml of a 2N aqueous sodium carbonate solution was added, and the mixture was extracted three times with 150 ml of ethyl nitrate. The collected organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated. The residue was dissolved in 100 ml of acetone, 0.3 ml of methyl iodide was added, and the mixture was refluxed for 1 hour and concentrated. The residue was dissolved in 50 ml of methanol, 1.5 g of ammonium St acid was added, and the mixture was refluxed for 2 hours and concentrated. The residue was purified by silica gel column chromatography (eluent: chloroform: methanol: 10: 1), and methyl 4- [4- (4- (amidinophenyl) -111-biperazinyl] -11- (tert-butoxycarbonylmethyl) 0.95 g of 13-piperidinepropionate monohydroiodide was obtained.

Mass spectrometry value (mZz): FAB (Po s ) 488 (M + + 1)

Nuclear magnetic resonance spectrum (DMSO- d _e, TMS internal standard)

δ: 1.06 (1H.m) .1.4K9H, s), 1.73-1.84 (3H, m), 1.90-2.15 (4H.m) .2.26-2.34

(1H.m) .2.85 (2H.d) .3.03 (2H, dd) .3.32-3.3 (10H.m) .3.59 (3H.s) .7.08 (2H.d) .7.7

2 (2H.d), 8.54 (2H, s) .8.90 (2H, s).

Example 4

Methyl 4- [4 -— (4-amidinofenyl) 1-1-piperazinyl] 1-111 0.45 g of (tert-butoxycarbonylmethyl) -3-piperidinepropionate monoiodide was dissolved in 50 ml of a 90% aqueous trifluoroacetic acid solution, and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was concentrated, and the residue was purified by HP-20 column chromatography (eluent water: methanol = 10: 1) to obtain 4- [4- (4-amidinofenyl) -11-piperazinyl] 1-1. 0.32 g of 3-methoxycarbonylethyl 1-piperidine succinate monotrifluoroacetate was obtained.

Mass spectrometry value (mZz): FAB (P 0 s) 4 32 (M + + 1)

Nuclear magnetic resonance scan Bae spectrum (DMSO- d _e, TMS internal standard)

<5: 1.18 (2H.t), 1.76 (1H, brs) 1.86 (1H.brs) 1.99 (2H, s), 2.20 (1H.m), 2.30 (1H.m), 2.42-2.50 (2H , m), 2.61-2.84 (2H.m) .3.33 (2H.brs), 3.44 (2H.brs), 3.63C3H, s), 4.03 (2H.q) .7.17 (2H.d), 7.80 (2H , d) .9.02 (4H, brs).

The following compounds of Examples 5 and 6 were obtained in the same manner as in Reference Example 3 and Example 1.

Example 5

(Sat) 1-cis-Jetyl 4- [4-1 (4-amidinofenyl) -1-1-piperazinyl] 1,1,3-piperidinediacetate monohydrochloride

Starting compound: Jechiru 4 one Okiso one 1, 3-piperidin-diacetate Mass analysis (m / z): FAB ( Po s) 4 60 (M + + 1)

Nuclear magnetic resonance spectrum (DMSO-cU, TMS internal standard)

6: 1.18 (6H.t) .1.69-1.83 (3H.m), 2.01-2.33 (5H.m) 2.66-2.87 (3H, m), 3.08- 3.23 (4H, m) .4.03-4.33 (4H .m), 7.06 (2H, d). 7.73 (2H, d).

Example 6

4- (4-amidinophenyl) -1-piperazinyl] -1-methoxycarbone-l-piperidine acetate monohydrochloride

Raw material compound: Ethyl 3-methoxycarbonyl 4 1-year-old oxo 11-biperidine acetate

Mass analysis (m / z): FAB ( Po s) 4 32 (M + + 1)

δ: 1.18 (3H.t), 1.67C1H, d), 2.17 (1H, q) .2.28-2.35 (2H, m), 2.85-2.87 (1H.m). 2.96-3.01 (2H.m), 3.21 (2H, q), 3.57 (2H, s), 4.07 (2H, q), 7.05 (2H, d) .7.75C2H.d), 8.71 (2H.s ), 8.99 (2H.s).

The following compound of Example 7 was obtained in the same manner as in Example 1.

Example 7

Ethyl 4- [4- (4-amidinofenyl) -1-1-piperazinyl] -1- (2-ethoxyquinone) 2-piperidinepropionate monohydrochloride Starting compound: tert-butyl 4- [4-1-1 (4-Cyanophenyl) 1-1-piperazinyl] 1-3- (2-Methoxycarbonylethyl) 1-1-piperidinepropionate

Mass spectrometry value (mZz): FAB (Po s ) 4 88 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (DMS0- d _e, TMS internal standard)

δ: 1.15-1.20C6H.m) .1.34-1.40 (1H, m) .1.69-1.96 (7H.m), 2.19-2.27 (1H, m).

2.35-2.43 (3H.m) .2.83-2.86 (2H, m), 3.97-4.11 (4H.m) .7.04 (2H, d) .7.74 (2H, d). In the same manner as in Example 2, the following compounds of Examples 8 to 10 were obtained.

Example 8

4- [4- (4-Amidinophenyl) -1-piperazinyl] 1,1,3-piperidindi-drussic acid monohydrochloride

Starting compound: Jethyl 4- [4- (4-amidinofenyl) -1-piperazinyl] -1-1,3-piperidine diacetate monohydrochloride

Mass spectrometry value (m / z): FAB (Po s) 4 04 (M ++ 1)

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

δ: 1.56 (1H.d), 2.01-2.03 (1H, m), 2.55-2.64 (6H.m), 2.82 (3H.brs) .3.20 (2H.brs) .7.1K2H, d), 7.76 (2H d) .8.87 (2H, brs) .8.97 (2H, brs).

Example 9

4- [4- (4-Amidinophenyl) -1-piperazinyl] -1-3-carboxy-1-piperidinediacid monohydrochloride

Raw material compound: Ethyl 4- [4- (4-amidinofenyl) -1-piperazinyl] -1-3-methoxycarbone 1-piperidine acetate monohydrochloride Mass spectrometry value (mZz): FAB (Po s ) 390 (M + + 1)

Nuclear magnetic resonance spectrum (DMSO - d _6, TMS internal standard)

δ: 7.08-7.13C2H.m) .7.75-7.81 (2H, m) .8.75 (2H, brs), 9.01 (2H, d).

Example 10

4- [4- (4-Amidinophenyl) 1-1-piperazinyl] 1-3- (2-carboxicetyl) 1-1-piperidinepropionic acid monohydrochloride

Starting compound: ethyl 4- [4- (4-amidinofenyl) — 1-biperazinyl] — 3- (2-ethoxycarbonylethyl) -1-piperidinepropionate Mass spectrometry (mZz): FAB (Po s) 432 (M ⁺⁺ 1)

Nuclear magnetic resonance spectrum (DMSO—, TMS internal standard)

δ: 1.70-1.72 (1H.m), 1.88-2.00 (2H.m) .2.39-2.46 (3H.m), 2.80 (2H, t) .2.93-3.04 (3H.m), 7.20 (2H.d ) .7.81 (2H.d), 8.93 (2H, brs) .9.05 (2H, brs).

Example 1 1

(+) —Cis-cetyl 4 -— [4- (4-cyanophenyl) -1-piperazinyl] -1,3-piperidinediacetate (+) — dibenzoyl-D-tartaric acid salt 66 Omg was dissolved in 20 ml of ethanol, and Hydrogen chloride was blown in until saturated with 10 to -2 O'C. After returning to room temperature and stirring overnight, the solvent was distilled off. The obtained residue was dissolved in 20 ml of ethanol, 1.0 g of ammonium carbonate was added, and the mixture was stirred at room temperature overnight. The solvent of the reaction mixture was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent: chloroform: methanol = 10: 1) to give (+)-cis-jethyl 4- [4— (4— Amidinophenyl) -1-pirazinyl] -1,3-piperidine diacetate monohydrochloride 30 Omg was obtained.

Mass spectrometry value (m / z): FAB (Po s) 4 60 ( ⁺ + 1)

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

δ: 1.18C6H, t) .1.33C1H.m) .1.76C1H.d), 2.02 (1Η.m), 2.13 (1Η.t) .2.21 (1Η, d), 2.77 (1H.d) 2.86 (1H.d), 3.15 (2H.dd) .4.03-4.08 (4H, m), 7.06 (2H, d) .7.73 (2H, d). Example 1 2 (+)-Cis-Jetyl 4- [4- (4-amidinophenyl) -11-biperazinyl]-1,3-piperidine diacetate monohydrochloride (28 Omg) was dissolved in 1N hydrochloric acid (1 Oml) and refluxed for 48 hours. The reaction mixture was distilled off, and the residue was prepared by ODS column chromatography (eluent: water), and (+)-cis-4-1 [4- (4-amidinophenyl) -11-piperazinyl] 1,3 —160 mg (98.2% ee) of piperidine diacetic acid trihydrochloride was obtained.

Specific rotation: [a] ²⁵ _D = + 3 1.2 ° c = 0.50 (MeOH)

Mass analysis (m / z): FAB ( Po s) 404 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (DMSO- d _e, TMS internal搮準)

δ: 7.15C2H, d), 7.82 (2H.d), 8.89 (2H, s) .9.11 (2H.s).

The following compounds of Example 14 were obtained in the same manner as in Examples 11 and 12.

Example 14

(-) —Cis 4 -— [4- (4-Amidinophenyl) -11-biverazinyl] 1-1,3-biperidinediacetate trihydrochloride (97.3% e.e.)

Starting compounds: (1-)-Jetyl 4-1 [4- (4-cyanophenyl) -1-1-piperazinyl] -1 3-Piperidine diacetate (1-) 1-cis-dibenzoyl-L-tartrate

Specific rotation: [H] ²⁵ D =-29.0 ° c = 0.50 (MeOH)

Mass analysis (m / z): FAB ( Po s) 404 (M + + 1)

Nuclear magnetic resonance spectrum (DMSO— _ds , TMS internal standard)

δ: 7.17C2H, d), 7.84 (2H.d) .8.90 (2H, s), 9.13 (2H.s).

Example 15-(1)

Dissolve 4.83 g of N- (tert-butoxycarbonyl) glycine in 50 ml of tetrahydrofuran, gradually add 13.73 g of 1, -carbonylbis-1H-imidazole, and allow to stand at room temperature for 3 hours. Stirred. After adding 10 g of p-aminobenzonitrile and stirring for 3 days, the solvent was distilled off under reduced pressure. Water was added to the residue, and the resulting crystals were collected, washed with a small amount of ethanol, dried under reduced pressure, and dried with 2- (tert-butoxycarbonylamino) -1-N- (4-cyanophenyl) ase 20.5 β I got Mass spectrometry value (mZz): FAB (Po s ) 276 (M + + 1)

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

6: 1.49C9H.s), 3.92 (2H, d), 5.18 (1H.brs), 7.61 (2H.d) .7.65 (2H, d) .8.59 (1H.brs)

Example 15 (2)

Under sealed condition, add 10 g of 2- (tert-butynecarbonylamino) -1-N- (4-cyanophenyl) acetamide, add 45.5 ml of 4N hydrogen chloride solution in ethyl acetate, and add 1 Stirred for 8 hours. The resulting crystals were taken into consideration, washed with ethyl acetate, and dried under reduced pressure to obtain 7.7 g of 2-amino-N- (4-cyanophenyl) acetamide monohydrochloride. To the 3.7 g, 58.8 m of a saturated aqueous sodium hydrogen carbonate solution and 20 ml of water were added, and the mixture was stirred for 1 hour. The resulting crystals were collected and dried under reduced pressure to give 2-amino-N- (4- 2.5 g of cyanophenyl) amide was obtained.

Mass spectrometry value (mZz): FAB (Po s ) 1 76 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal摞準)

δ: 1.68C2H, brs), 3.50 (2H.s), 7.61 (2H, d) .7.74 (2H.d) .9.75 (1H.brs) Example 15- (3)

Dissolve 1.83 g of 2-amino-1-N- (4-cyanophenyl) acetamide in 90 ml of methylene chloride and add ethyl 2- (4-oxo2-l-piperidine) acetate 3.10 g, drunk acid 4.4m] and 8.88 g of sodium triacetoxyborohydride were sequentially added, and the mixture was stirred for 1.5 hours. After concentration under reduced pressure, water and sodium carbonate were added to make the system alkaline, and the resulting crystals were collected. The crude crystals were dissolved in chloroform and washed with saturated saline. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Ether was added to the residue, and the resulting solid was collected to give 2.82 g of ethyl 4 -— [N— (4-cyanophenyl) potassium rubamoylmethylamino] -11-piperidine acetate.

Mass spectrometry value (mZz): APC I + Q IMS: 345

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

δ: 1.27C3H.t) .1.50-1.58 (2H, m) .1.67 (1H, brs) 1.88-1.90 (2H.m), 2.23-2.

3 o 27 (2H, m), 2.49-2.54 (1H, m) 2.95 (2H.m), 3.22 (2H.s), 3.2 (2H.s) 4.18 (2H.q), 7.62 (2H , d) .7.72 (2H, d), 9.69 (1H, brs)

Example 15-(4)

Ethyl 4- [N- (4-Cyanophenyl) pothambylmethylamino] 1-1-Biperidine Acetate 1.0 g, Clom Form 20 ml, Triethylamine 0.69 g in a solution of chloroacetyl chloride 0.52 g was gradually added, and the mixture was stirred for 30 minutes. Then, water and a saturated aqueous solution of sodium hydrogen carbonate were added. After liquid separation, the organic layer was concentrated under reduced pressure. The residue was subjected to silica gel chromatography (chloroform: methanol = 50: 1, v / v), and ethyl 4- [N-chloroacetyl-N— [N- (4-cyanophenyl) potumbamoylmethyl] amino] 1.19 g of 1-piperidine acetate was obtained.

Mass spectrometry value (mZz): FAB (Po s ) 4 2 1 (M + + 1)

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

δ: 1.28C3H.0, 1.80-1.82 (2H.m) 1.97-2.04 (2H.m), 2.38-2.42 (2H.m) .3.03-3.05 (2H.m), 3.25 (2H.s). 3.68-3.75C1H.m) .4.12 (2H, s), 4.19 (2H.q) .4.22 (2H, s), 7.53 (2H.d), 7.56C2H.d), 9.01 (1H, brs)

Example 15-(5)

Ethyl 4- [N-chloroacetyl-N- [N- (4-cyanophenyl) carbamoylmethyl] amino] 11-piperidine acetate 0.5 ^ is dissolved in N-dimethylformamide 20 ml and hydrogenated Sodium (60% oil) (0.090 g) was added, and the mixture was stirred for 4 hours while heating at 40 ° C to 50 ° C. A saturated aqueous solution of ammonium chloride was added, and the solution was concentrated under reduced pressure. Water was added. The resulting crystals were collected by filtration, recrystallized from ethanol, and ethyl 4- (4-cyanophenyl) -1,2,5- Dioki Two 1-piperazinyl] — 1-piperidine acetate 0.21 g was obtained.

Mass spectrometry value (mZz): FAB (Po s ) 385 (M + + 1)

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

δ 1.28 (3Η, 0.1.70-1.72 (2H, m) .1.85-1.93C2H.m) 2.36-2.0 (2H.m), 3.05 -3.07 (2H, m) .3.24 (2H.s) , 4.09 (2H.s), 4.20 (2H, q) .4.39 (2H.s), 4.44-4.51 (1H, m), 7.48 (2H.d), 7.72 (2H.d)

Example 15-(6)

Ethyl 4-1 [4-1 (4-Cyanophenyl) -1,2,5-dioxo1-1-Biberazinyl] -11-piperidine acetate 0.2 1 g of dry ethanol 20 ml 1 Hydrogen was blown for about one hour. The mixture was gradually returned to room temperature and stirred, and then concentrated under reduced pressure. 20 ml of dry ethanol and 1.56 g of ammonium carbonate were added to the residue, and the mixture was stirred for 3 days. After evaporating the solvent, the residue was subjected to silica gel column chromatography (chloroform: methanol = 5: 1, v / v) to give ethyl 4- [4- (4-amidinofenyl) -1,2,5-dioxo-1. 1-piperazinyl] -1-1-piperidine acetate monohydrochloride (0.17 g) was obtained.

Mass spectrometry value (mZz): FAB (Po s ) 4 02 (M + + 1)

Nuclear magnetic resonance spectrum (DMSO—ds, TMS internal standard)

δ: 1.20C3H.t), 1.53-1.55 (2H.m) .1.76-1.80 (2H.m), 2.28-2.32 (2H.m), 2.91-2.93 (2H.in), 3.24 (2H, s) .4.07-4.11 (4H, m) .4.15-4.19 (1H, m), 4.41 (2H.s), 7.65 (2H, d), 7.88 (2H.d) .9.20 (2H, brs), 9.39 (2H , brs).

Example 16

Ethyl 4- [4- (4-amidinophenyl) -1,2,5-dioxit-1-piperazinyl] -1-1-piperidine acetate monohydrochloride 0.08 9 g was dissolved in lm l of water, and water was cooled with ice. Lithium oxide monohydrate (0.017 g) was added. After stirring for 30 minutes under ice-cooling, add a saturated aqueous solution of ammonium chloride and perform ODS column chromatography.

H ₂ 〇 → H ₂ 0: MeOH = 3: 2, v / v), and then 4- [4- (4-amidinofenyl) -1,2,5-dioxo-1-piperazinyl] — 1-piperidine 0.027 g was obtained.

Mass analysis value (m / z): FAB (Po s) 374 ( ⁺ + 1)

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

δ: 1.85 (2Η, m), 2.13-2.19 (2H.ra), 3.22C2H.m) .3.58C2H.m), 4.11 (4H, brs) .4.44 (3H, brs) .7.66 (2H.d) .7.86 (2H.d), 9.07 (2H, brs) .9.31 (2H.brs) o

Example 17-(1) Ethyl 4- [N— (4-cyanophenyl) -rubamoylmethylamino] 1-piperidine acetate 1.0 g, methanol 1 Oml, chloroacetaldehyde (40% aqueous solution) 2.85 g To the mixed solution, 0.448 g of sodium cyanoborohydride and 0.57 g of drunk acid were sequentially added, followed by stirring for a while. After distilling off the solvent, the residue was added with chloroform and washed with a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was separated and decompressed. The residue was subjected to silica gel column chromatography (chloroform: methanol = 100: 1, v / v), and ethyl 4- [N- (2-chloroethyl) -N- [N- (4-cyanophenyl) power. Rubamoylmethyl] amino] -1-piperidine acetate 1.15 g was obtained.

Mass spectrometry value (mZz): FAB (Po s ) 4 07 (M + + 1)

Example 17-(2)

Ethyl 4— [N- (2-chloroethyl) -1-N— [N— (4-Cyanophenyl) potamyl]] amino-1-1-piperidine acetate 1.08] \ 1, N-dimethylformamide 30 ml Then, 0.18 g of sodium hydride (60% oil) was gradually added and stirred for 5 hours. A saturated aqueous solution of ammonium chloride was added, the solvent was distilled off, and then chloroform and a saturated aqueous solution of sodium hydrogencarbonate were added. The organic layer was concentrated under reduced pressure. Ether was added to the residue, and the resulting solid was collected to give 0.43 g of ethyl 4- [4- (4-cyanophenyl) -13-oxo-11-piperazinyl]-1-pyridinepyridine. .

Mass analysis (m / z): FAB ( Po s) 37 1 (M + + 1)

Nuclear magnetic resonance spectrum (CDC13, TMS internal standard)

δ 1.28 (3H.t) .1.65-1.71 (2H.m) .1.83-1.85 (2H, m) .2.24-2.28 (2H, m) .2.35- 2.39 (1H, m), 2.91-2.93 (2H.m) m), 3.01-3.04 (2H.m) .3.22 (2H, s) .3.46C2H, s), 3.71-3.73 (2H.m) .4.19 (2H, q) .7.49 (2H.d), 7.68 (2H.d)

The following compounds of Example 17- (3) were obtained in the same manner as in Example 15- (6).

Example 17-(3)

Ethyl 4- [4- (4-amidinophenyl) -1-3-oxo-1-piperazinyl] — 1-biperidine acetate monohydrochloride Starting compound: ethyl 4- [4- (4-cyanophenyl) -13-oxo-11-piperazinyl] -11-piperidine acetate

Mass spectrometry value (m / z): FAB (Po s) 388 (M ++ 1)

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

(5: 1.19 (3H.t), 1.43-1.47C2H.m) .1.77-1.80 (2H, m) .2.17-2.21 (2H, m) .2.29

(IH, m), 2.87-2.89 (4H, m) 3.19 (2H, s), 3.33 (2H, s), 3.70-3.72 (2H.m) .4.08 (2H.q).

7.65 (2H.d) .7.84 (2H, d), 9.01 (2H, brs) .9.32C2H.brs).

The following compound of Example 18 was obtained in the same manner as in Example 16.

Example 18

4- [4-1 (amidinophenyl) -1-3-oxo-1-piperazinyl] 1-1-piperidineacetic acid

Starting compound: ethyl 4- [4- (4-amidinofenyl) -1-3-oxo-1

-Piperazinyl] 1-piperidine acetate monohydrochloride

Mass analysis (m / z): FAB ( Po s) 360 (M + + 1)

Nuclear magnetic resonance spectrum (DMSO- d ₆ + TFA, TMS internal standard)

δ: 2.04C2H.m) .2.31 (2H, m) .3.13 (2H, m), 3.42 (1H.m), 3.59 (2H.m), 3.66 (2H, m) .3.97-4.02 (4H.m ) .4.16 (2H, brs) .7.64 (2H.d), 7.88 (2H, d), 9.09 (2H.brs) .9.32

(2H, brs)

The following compound of Example 191-1 (1) was obtained in the same manner as in Example 15- (3).

Example 19 (1)

Ethyl 4 — [[2- (4-cyanoanilino) ethyl] Amino] 1 1—piperidine acetate

Starting compound: Echiru 4 one C (2-aminoethyl) Amino] benzonitrile Mass spectrometry value (mZz): FAB (Po s ) 33 1 (M + + 1)

Nuclear magnetic resonance spectrum (CDC13, TMS II standard)

δ: 1.27 (3H, t), 1.43-1.51 (2H, m), 1.55 (1H.brs) 1.88-1.90 (2H, m) .2.23-2.

28 (2H, m) 2.47-2.51 (IH.m) .2.91-2.93 (4H, m) 3.19-3.21 (4H.m) 4.16-4.20 (2H, m).

4.9K1H.m) .6.57 (2H, d) .7.41 (2H, d) The following compound of Example 191-1 (2) was obtained in the same manner as in Example 15- (4). Example 19 1 (2)

Ethyl 4- [N— [2 -— (4-cyanoanilino) ethyl] —N—methoxalylamino] 1-piperidine acetate

Starting compound: Ethyl 4-C [2- (4-cyanoalumino) ethyl] amino]-1-biperidine acetate and methyl oxalyl chloride

Mass analysis (m / z): FAB ( Po s) 1 7 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal摞準)

δ 1.23-1.29 (3Η.m), 1.67-1.93 (4H.m) 2.20-2.33 (2H.m) 2.87-3.18C2H.m), 3.22 (2H, s), 3.35-3.60 (5H, m ), 3.90 (3H.s), 4.14-4.34 (2H, m), 4.97 (1H.m), 6.55-6.61 (2H, m), 7.38-7.45 (2H.m)

The following compounds of Example 19- (3) were obtained in the same manner as in Example 15- (5).

Example 19 (3)

4- (4- (4-Cyanophenyl) -1-2,3-dioxo-1-biperazinyl)-1-Piberidine acetate

Mass spectrometry value (mZz): FAB (Po s ) 385 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

δ: L28C3H.t) .1.75-1.78 (2H.m) .1.82-1.90 (2H.m), 2.33-2.38C2H.πθ, 3.04-3.06 (2Η.m) .3.23 (2Η, s), 3.63- 3.65 (2Η.m), 3.97-3.99 (2Η.m) .4.20 (2Η, q) .4.51-4.57 (1Η, m) .7.54 (2Η.d), 7.71 (2H.d)

The following compound of Example 191-1 (4) was obtained in the same manner as in Example 15- (6).

Example 19-(4)

Ethyl 4- [4- (4-amidinophenyl) -1,2,3-dioxo-2-1-pirazinyl〗 —1-bidinidine acetate monohydrochloride

Mass analysis (m / z): FAB ( Po s) 402 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (DMSO- d _e, TMS internal standard)

δ: 1.21 (3Η, t) .1.61 (2H.m), 1.77 (2H, m) .2.30 (2H, m), 2.94C2H.m) .3.32 (2H.s), 3.65C2H, m) .4.00 (2H, m) .4.11 (3H, m) .7.67 (2H.d), 7.91 (2H, d) The following compound of Example 20 was obtained in the same manner as in Example 16.

Example 20

4- [4- (4-amidinofenyl) -1,2,3-dioxo-1-piperazinyl] -1-piperidineacetic acid monohydrochloride

Mass spectrometry value (mZz): FAB (Po s ) 374 (M + + 1)

Nuclear magnetic resonance spectrum (DMSO- d _6, TMS internal standard)

(5: 1.63-1.65 (2H.m) .1.84- 1.86 (2H.m), 2.36-2.47 (2H.m), 3.07-3.09 (2H.m),

3.18 (2H, s) .3.63-3.65 (2H.m) .3.99-4.01 (2H.m), 4.23 (1H.m) .7.67 (2H, d) .7.86 (2H.d)

Example 15 The following compound of Example 21 (1) was obtained in the same manner as in 5- (4).

Example 2 1-(1)

Ethyl 4- [N-chloroacetyl-N- [2- (4-cyanoanilino) ethyl] amino] 1-piperidine acetate

Mass spectrometry value (mZz): FAB (Po s) 407 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

δ: 1.28 (3H, t), 1.75-1.77 (2H, m), 1.91-1.98 (2H.m), 2.33-2.37C2H.m) .3.04-3.06 (2H, m), 3.24 (2H, s) .3.31-3.34 (2H.m) .3.55-3.58 (2H.m), 4.12 (2H.s), 4.19 (2H, q) .5.06 (1H, m) .6.59 (2H.d) .7.41 (2H d)

Example 15 The following compounds of Example 21- (2) were obtained in the same manner as in 5- (5).

Example 2 1-(2)

Ethyl 4- [4- (4-cyanophenyl) -1-2-oxo-1-piperazinyl] ― 1-piperidine acetate

Mass spectrometry value (mZz): FAB (Po s ) 37 1 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (CDC 1 _3, TMS internal standard)

δ: 1.28C3H, t) .1.67-1.69C2H, m) .1.83-1.91 (2H.m) .2.31-2.35 (2H, m) .3.03-3.05 (2H, m) .3.22 (2H.s), 3.45-3.47 (2H.m), 3.55-3.57 (2H.m) .4.01 (2H.s), 4.17-4.22 (2H, q) .4, 52-4.59 (1H.m) .6.77 (2H.m) d), 7.53 (2H.d)

Example 15 The following compound of Example 21- (3) was obtained in the same manner as in 5- (6). Example 2 1-(3)

Ethyl 4- [4- (4-amidinophenyl) -1-2-oxo-1-biperazinyl] 1-1-piperidine acetate monohydrochloride

Mass analysis (m / z): FAB ( Po s) 388 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (DMSO- d _6, TMS internal standard)

δ: 1.20 (3H, t), 1.49-1.51 (2H.m) .1.72-1.77 (2H, m), 2.25-2.29 (2H.m), 2.90-2.92 (2H.m) .3.22 (2H, s ), 3.42-3.45 (2H.m), 3.61-3.63 (2H, m) .4.01 (2H.s) .4.07- 4.1K2H.q), 4.24 (1H.m) .7.02 (2H, d) .7.76 (2H.d)

The following compound of Example 22 was obtained in the same manner as in Example 16.

Example 22

4- [4- (4-Amidinophenyl) -1-oxo-1--1-piperazinyl] -1-piperidineacetic acid monohydrochloride

Mass analysis (m / z): FAB ( Po s) 360 (M + + 1)

Nuclear magnetic resonance scan Bae-vector (DMS0- d _6, TMS internal standard)

δ: 1.57-1.59 (2Η.m) .1.87-1.93 (2H.m) .2.55-2.59 (2H.m), 3.15-3.17 (2H, m). 3.25 (2H.s), 3.42-3.4 (2H, m) .3.63-3.65 (2H.m), 4.01 (2H, s) .4.32-4.37 (1H, m), 7.02 (2H.d), 7.79 (2H.d)

The chemical structural formula of the compound obtained in the above example is described below,

Puki

Other compounds of the present invention besides the examples described above are shown. These compounds can be synthesized using the above-mentioned production methods and synthetic routes and methods described in the Examples, and ordinary production methods known to those skilled in the art. Absent.

Compound 1

Ethyl 4-1 [4-1 (4-amidinophenyl) -1,3,5-dioxo-1-radiazine] 1-1-Piridine acetate

Compound 2

4-[4-(4-Amidinophenyl) 1,3,5-dioxo 1-piperazinyl] 1 1-piberidine

HN

H ₂ N

Claims

The scope of the claims

1. A benzamidine derivative represented by the following general formula (I), a salt, a hydrate or a solvate thereof.

OR ² ) _n

(I)

(The symbols in the formula have the following meanings, respectively.

R ¹ , R ² : the same or different and a hydrogen atom or an ester residue,

X ¹ : lower alkylene group,

X ² : a single bond or a lower alkylene group,

m: 0, 1 or 2,

n: 0 or 1, provided that when m = 0, n = l. )

2. R ', R ² are the same or different and each represents a hydrogen atom, or, lower pole alkyl group, a lower § alkenyl group, a lower alkynyl group, halogeno lower pole alkyl group, a cycloalkyl group, phenyl group, naphthyl group, indolyl group , Benzyl group, lower alkoxybenzyl group, nitrobenzyl group, benzhydryl group, lower alkoxybenzhydryl group, lower alkylyloxy lower alkyl group, lower alkenyloxy lower alkyl group, lower alkanol lower alkyl group, lower Alkenyl lower alkyl groups, lower alkoxy lower alkoxy groups, lower alkoxy groups, lower alkoxy lower alkyl groups, lower alkoxy lower alkyl groups, lower alkoxy lower alkoxy groups, cycloalkyloxy groups Nyloxy lower alkyl group, Lower alkoxycarbonyloxy lower alkyl group, lower alkoxy lower alkoxycarbonyl lower alkyl group, benzoyloxy lower alkyl group, lower dialkylamino lower alkyl group, 2-oxotetrahydrofuran-1-yl Claims that is an ester residue selected from a group, 2-oxo-5-alkyl-1,3,3-dioxolen-4-ylmethyl group, tetrahydrofuranylcarbonyloxymethyl group or 3-furidylidyl group. 2. The benzamidine derivative, a salt thereof, a hydrate thereof or a solvate thereof according to 1.

3. R ′ and R ² are the same or different and each represent a hydrogen atom, or a lower alkyl group, a lower alkenyl group, a halogeno lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyl lower alkyl group, 3. The benzamidine derivative, salt, hydrate or solvate thereof according to claim 1 or 2, which is an ester residue selected from a phenyl group, a benzyl group or a lower alkoxybenzyl group.

4. The benzamidine derivative, salt, hydrate or solvate thereof according to claim 1, wherein R ′ and R ² are the same or different and each is a hydrogen atom or a lower alkyl group.

5. The benzamidine derivative, salt, hydrate or solvate thereof according to claim 1, wherein m = 0 and n = 1.

6. The benzamidine derivative, salt, hydrate or solvate thereof according to claim 1, wherein m = 1 or 2, and n = 0.

7. 4- [4- (4-amidinofenyl) -1-biperazinyl] — 1,3-bipyridine diBt acid, its optically active form, its salt, its hydrate or its solvate.

8. (+)-cis-4-1 [4-1- (amidinophenyl) -1-piperazinyl] -1,3-piperidinediacid, a salt thereof, a hydrate or a solvate thereof.

9. (-) 1-cis-4-1 [4-1- (4-amidinofenyl) -1-1-piperazinyl] -1, 3-piperidinediacetic acid, salt, hydrate or solvate thereof.

10.4- [4- (4-amidinophenyl) -1,2,5-dioxo-1-biperazinyl] -1-piperidineacetic acid, its optically active form, its salt, its hydrate or its solvate.

1 1.4- [4- (4-amidinophenyl) -3- 3-okifu-1-biperazinyl] -1-piperidineacetic acid, its optically active form, its salt, its hydrate or its solvate

1 2. Benzamidine derivatives represented by the following general formula (I), salts thereof, and hydrates thereof Or a pharmaceutical composition _c containing a solvate thereof and a pharmaceutically acceptable carrier

(I)

(The symbols in the formula have the following meanings, respectively.

R ¹ , R ² : the same or different and a hydrogen atom or an ester residue,

X ′: lower alkylene group,

X ² : a single bond or a lower alkylene group,

m: 0, 1 or 2,

n: 0 or where n = 0 when m = 0. )

13. The pharmaceutical composition according to claim 12, which is a GPIb / Ia receptor antagonist.

14. The claim 13, wherein the GPIb / Ia receptor antagonist is an agent for improving ischemic heart disease, an auxiliary agent for cardiac surgery or vascular surgery, an agent for improving cerebrovascular disease, or an agent for improving peripheral arterial disease. Pharmaceutical composition.