JPH08333341A - New piperazine derivative or its salt - Google Patents

Abstract

PURPOSE: To obtain a new compound having platelet aggregation inhibiting action based on GPIIb/IIIa antagonism, useful as an antithromobotic agent and orally administrable. CONSTITUTION: This piperazine derivative is expressed by formula I [X<1> is an alkylene group; X<2> is a single bond or an alkylene group; R<1> and R<2> are each amidino group, hydroxyl group, an aryl group, a heteroaryl group, CONHR<3> , SOn R4 , COOR<5> , etc.: R<3> is H, carboxyl group or an alkyl group which may be substituted by COOR<6> ; R<4> is an aryl group; R<5> and R<6> are each H or an ester residue; (n) is 0, 1 or 2], e.g. ethyl 4-[4-(4-amidinophenyl)-1-piperazinyl]-1- ethoxycarbonylmethyl-3-piperidinepropionate hydrochloride. The derivative of formula I is obtained by reacting an alcohol such as methanol with a nitrile compound expressed by formula II in the presence of chlorine gas at -40 deg.C to 0 deg.C, imidating the nitrile compound and reacting the imidated compound with amine such as ammonia or an amine salt.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to pharmaceuticals, especially GPIIb.
/ IIIa Novel piperazine derivative useful as an antagonist or a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Platelets have been discovered by Donne in 1842 (CR Acad. Sci.
ris) 14 , 336-368, 1842), for a long time,
It has been treated as a component of blood necessary for hemostasis. Today, platelets not only play a major role in the hemostatic mechanism, but are also clinically noticed. The establishment of arteriosclerosis, cardiovascular disease including thrombotic diseases, cancer metastasis, inflammation, rejection after transplantation, and further to immune reaction. It has been clarified that it has multiple functions such as involvement, and for thrombotic diseases and ischemic diseases, treatment for resuming blood circulation is performed by drugs or physical methods. However, recently after revascularization,
It has been a clinical problem that a phenomenon in which platelet activation, adhesion, and aggregation is accelerated due to disruption of vascular tissue including endothelial cells or disruption of fibrinolysis / coagulation balance by the drug itself has been discovered. For example, it has become clear that after recanalization is obtained by thrombolytic therapy using t-PA or the like, the fibrinolytic and coagulant functions are activated and the coagulation / fibrinolytic balance of the whole body is disrupted. It causes re-occlusion clinically and is a serious problem in treatment (J. Am. Coll. Cardio.
l. 12 , 616-623, 1988). On the other hand, PTCA therapy has been rapidly popularized for the treatment of diseases based on coronary stenosis and aortic stenosis such as angina and myocardial infarction, and has achieved some results. However, this therapy damages vascular tissues including endothelial cells, and acute coronary occlusion, and restenosis that occurs in nearly 30% of the treated cases have become serious problems. Platelets play an important role in various thrombotic adverse effects (such as re-occlusion) after such revascularization therapy. Therefore, although antiplatelet agents are expected to be effective, conventional antiplatelet agents have not been proved to have sufficient effects. GPIIb
/ IIIa is a platelet membrane glycoprotein that is a member of the integrin family (Blood, 80 , 1386-1.
404, 1992). This integrin binds to adhesion proteins such as fibrinogen and von Willebrand factor,
It aims at an important function at the extreme end of platelet aggregation. GPI
Monoclonal antibodies against Rb / IIIa and RGD
Peptides containing sequences have a strong inhibitory effect on platelet aggregation, and some of them have already undergone clinical trials. Non-peptide and low molecular weight GPIIb / II
Ia antagonists are disclosed in JP-A-4-288051 and JP-A-6
No. 25227, and also LeO et al. (Journ
al of Medicinal Chemistr
y, 35 , 4393-4407, 1992). However, these are all intravenous solutions and can only be used in the acute phase of the disease. Further, European Patent Publication No. 542363 discloses an orally administrable GPIIb / IIIa antagonist.
The oral activity is not sufficient, and further, a GPIIb / IIIa antagonist having an obvious effect upon oral administration is eagerly desired. The compound of the present invention has a different structure from the compounds described in the above-mentioned patents, and has a strong G group even in oral administration.
It is a novel piperazine derivative showing PIIb / IIIa antagonistic activity.

[0003]

As is clear from the above description, at present, the creation of a novel novel GPIIb / IIIa antagonist that can be orally administered remains an important medical problem.

[0004]

That is, the present invention relates to a piperazine derivative represented by the following general formula (I) or a salt thereof.

[0005]

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

X ^{1 is a} lower alkylene group, X ^{2 is a} single bond or a lower alkylene group, R ¹ and R ^{2 are the} same or different and are represented by an amidino group, a hydroxyl group, an aryl group, a heteroaryl group, and a formula --CONHR ^3. Group, a group represented by the formula —SO _n R ⁴ or a formula —COOR ⁵
A group represented by, R ^3: a hydrogen atom, a carboxyl group, or the formula -COOR ⁶
A lower alkyl group which may be substituted with a group represented by
Aryl group or aralkyl group, R ^4: aryl groups, R ^5, R ^6: identical or different, represent a hydrogen atom or an ester residue, n: 0, 1 or 2) groups R ¹ is represented by the formula -COOR ⁵ Sometimes, the compounds of the present invention are represented by the following general formula (Ia).

[0008]

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(In the formula, R ¹ , R ² , R ⁵ , X ¹ and X ² have the above-mentioned meanings.) The compound (I) of the present invention is described in detail below.

“Lower” in the definition of general formulas herein
The term, unless otherwise specified, means a straight or branched carbon chain having 1 to 6 carbon atoms.

Therefore, in the formula (I), the "lower alkylene group" represented by X ¹ and X ² is preferably a linear or branched alkylene group having 1 to 6 carbon atoms. Include methylene group, ethylene group, methylmethylene group, trimethylene group, propylene group, 2-propylene group, dimethylmethylene group, tetramethylene group, 1-methyltrimethylene group, 2-methyltrimethylene group, 3-methyltrimethylene group. Methylene group, 1-ethylethylene group, 2-ethylethylene group, 2,2-dimethylethylene group, 1,1-dimethylethylene group, ethylmethylmethylene group, propylmethylene group, pentamethylene group, 1-methyltetramethylene group ，
2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene 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-ethyltrimethylene group, 1,1,2-trimethylethylene group, diethylmethylene group, 1-propylethylene group, 2-propylethylene group, butylmethylene group, hexamethylene group, 1- Methyl pentamethylene group, 1,1-dimethyltetramethylene group, 2,2-dimethyltetramethylene group, 3,3-dimethyltetramethylene group, 4,4-dimethyltetramethylene group, 1,1,3-trimethyltrimethylene group Group 1,
1,2-trimethyltrimethylene group, 1,1,2,2-
Tetramethylethylene group, 1,1-dimethyl-2-ethylethylene group, 1,1-diethylethylene group, 1-propyltrimethylene group, 2-propyltrimethylene group, 3
-Propyltrimethylene group, 1-butylethylene group, 2
-Butylethylene group, 1-methyl-1-propylethylene group, 2-methyl-2-propylethylene group, 1-methyl-2-propylethylene group, 2-methyl-1-propylethylene group, pentylmethylene group, butyl Examples thereof include a methylmethylene group and an ethylpropylmethylene group. Among them, a linear alkylene group having 1 to 3 carbon atoms, particularly a methylene group and an ethylene group are preferable.

A compound in which R ¹ or R ² is a group represented by the formula —COOR ⁵ and R ⁵ is an ester residue is itself a drug as an active substance. In addition, a compound in which R ⁵ is an ester residue is useful as a prodrug that is metabolized in vivo to become a carboxylic acid compound of the active substance,
It is also useful as a synthetic intermediate for carboxylic acid compounds. The “ester residue” for R ⁵ or R ^{6 includes} an ester residue that is metabolized and hydrolyzed in vivo and an ester residue that can serve as a protective group for a carboxyl group. For example, lower alkyl group, lower alkenyl group, halogeno lower alkyl group, cycloalkyl group, lower alkoxybenzyl group, nitrobenzyl group, lower alkoxybenzhydryl group, benzhydryl group, lower alkanoyloxy lower alkyl group, lower alkenoyl lower alkyl group. , Cycloalkyloxycarbonyloxy lower alkyl group, lower alkenoyloxy lower alkyl group, lower alkoxy lower alkanoyloxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxy lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, lower Alkoxy lower alkoxycarbonyloxy lower alkyl group, benzoyloxy lower alkyl group, di-lower alkylamino lower alkyl group, 2-oxotetrahydrofuran 5-yl group, 2-oxo -5
-Alkyl-1,3-dioxolen-4-ylmethyl group, tetrahydrofuranylcarbonyloxymethyl group,
Examples include common ester residues such as 3-phthalidyl group. Particularly preferred is a lower alkyl group.

In the present invention, examples of the "lower alkyl group" include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl 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 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,
Examples thereof include a 1,2,2-trimethylpropyl group, a 1,2,2-trimethylpropyl group, a 1-ethyl-1-methylpropyl group, and a 1-ethyl-2-methylpropyl group. Particularly, a methyl group and an ethyl group are preferable.

The "lower alkenyl group" is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl group, allyl group, 1-propenyl group, isopropenyl group, 1-butenyl group. Group, 2-butenyl group, 3-butenyl group, 2-methyl-1-propenyl group, 2-methylallyl group, 1-methyl-1-propenyl group, 1-methylallyl group, 1-pentenyl group, 2-pentenyl group, 1-hexenyl group etc. can be mentioned.

In the ester residue, a lower alkanoyl group having 2 to 6 carbon atoms (eg acetyl, propionyl, pivaloyl etc.) and a lower alkenoyl group having 3 to 6 carbon atoms (eg acryloyl,
(Crotonoyl, maleoyl, etc.), cycloalkyl groups having 3 to 8 carbon atoms, particularly those having 3 to 6 carbon atoms (eg, cyclopropyl, cyclopentyl, cyclohexyl, etc.), lower alkoxy groups having 1 to 6 carbon atoms.
Preferable examples are ones, especially one to four (eg, methoxy, ethoxy, etc.).

The "aryl group" for R ¹ , R ² , R ³ or R ⁴ means an aromatic hydrocarbon group, preferably an aryl group having 6 to 14 carbon atoms. Specifically, a phenyl group, a tolyl group, a xylyl group, a biphenyl group, a naphthyl group, an indenyl group, an anthryl group, and a phenanthryl group are preferable, and a phenyl group or a naphthyl group is more preferable.

The heterocyclic aryl group for R ¹ or R ² is a furyl group, thienyl group, pyrrolyl group, imidazolyl group, virazolyl group, isothiazolyl group, isoxazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, pyrazinyl group. Group, indolyl group, indazolyl group, indolizinyl group, quinolyl group, isoquinolyl group,
Quinazolinyl group, quinolidinyl group, quinoxalinyl group,
Cinnolinyl group, benzimidazolyl group, imidazopyridyl group, benzofuranyl group, dihydrobenzofuranyl group, naphthyridinyl group, 1,2-benzisoxazolyl group, benzoxazolyl group, benzothiazolyl group, oxazolopyridyl group, isothiazolo Examples thereof include a pyridyl group and a benzothienyl group.

The "aralkyl group" for R ³ means a group in which any hydrogen atom of the "lower alkyl group" is substituted with the "aryl group". Specific examples thereof include a benzyl group and a naphthylmethyl group.

The "lower alkyl group, aryl group or aralkyl group substituted with a group represented by the formula --COOR ⁶ " in R ³ is any of the above "lower alkyl group", "aryl group" or "aralkyl group" Hydrogen atom of formula −
It means a group substituted with a group represented by COOR ⁶ .

The compound (I) of the present invention has at least two asymmetric carbon atoms based on the presence of the piperidinyl group and its substituent (the group represented by formula -X ² -R ² ) which the basic skeleton has. However, it may further have an asymmetric carbon atom depending on the kind of the substituent. The compound of the present invention has optical isomers based on these asymmetric carbon atoms. Further, there may be tautomers based on the presence of a carbonyl group in a substituent or geometric isomers based on a double bond. The present invention includes all isolated forms or mixtures of these isomers.

The compound (I) of the present invention can be made into a salt, and as such a salt, a salt of alkali metal or alkaline earth metal such as sodium salt, potassium salt or calcium salt is preferable. Hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide; inorganic salts such as carbonates, nitrates, perchlorates, sulphates and phosphates Lower alkyl sulfonates such as methane sulfonate, trifluoromethane sulfonate, ethane sulfonate; aryl sulfonates such as benzene sulfonate, p-toluene sulfonate; fumarate, succinate Salt, citrate, tartrate, oxalate,
Mention may be made of organic acid salts such as maleates; and amino acid salts such as glutamate and aspartate.

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

Needless to say, the present invention is not limited to the compounds described in the examples below, but is not limited to the piperazine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. It includes all.

(Production Method) A typical production method of the compound of the present invention will be illustrated and described below.

Manufacturing method 1

[0026]

[Chemical 4]

(In the formula, R ¹ , R ² , X ¹ and X ² have the above-mentioned meanings.) The compound (I) having an amidino group is represented by the following (i), (i
It can be synthesized by the methods i) and (iii).

(I) After converting the nitrile into an imidate,
Method of condensing with amine In the presence of hydrochloric acid gas, nitrile compound (II) is treated with an alcohol such as methanol or ethanol at -40 ° C to 0 ° C to form an imidate, and then ammonia, ammonium carbonate, ammonium chloride, ammonium acetate, etc. The amine or amine salt is reacted. As the solvent, methanol,
Ethanol, acetone, tetrahydrofuran, etc. are used.

(Ii) Method of converting nitrile to thioamide, then converting to thioimidate and condensing with amine The nitrile compound (II) is treated with hydrogen sulfide in the presence of an organic base such as methylamine, triethylamine, pyridine or picoline to give thioamide. Get the body. This thioamide compound was converted to dithiophosphoric acid in the nitrile compound (II) in the presence of hydrogen chloride.
It can also be obtained by reacting o, o-diethyl.

The thioamide compound is reacted with a lower alkyl halide such as methyl iodide or ethyl iodide to form a thioimidate compound, and then reacted with an amine or an amine salt such as ammonia, ammonium carbonate, ammonium chloride or ammonium acetate. As the solvent, methanol,
Ethanol, acetone, tetrahydrofuran, ethyl acetate, etc. are used.

(Iii) Method of directly adding amine, amine salt, metal amide, Grignard reagent to nitrile Ammonia, ammonium chloride and ammonia, ammonium thiocyanate, thiocyanate in a solvent suitable for nitrile (II) or without solvent. Alkylammonium acid, M
eAl (Cl) NH ₂ , NaNH ₂ , (CH ₃ ) ₂ NMgB
It can be synthesized by adding a reagent such as r. As the solvent, chloroform, methanol, ethanol, acetone, tetrahydrofuran, triene, dimethylformamide, etc. are used. In addition, a base such as sodium hydride or an acid such as aluminum chloride or p-toluenesulfonic acid as a catalyst may significantly accelerate the reaction. The reaction can be carried out under cooling or at room temperature or under heating.

Manufacturing method 2

[0033]

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(In the formula, X ¹ and X ² have the above-mentioned meanings. R ⁷ and R ⁸ are the same or different and mean an ester residue.) Carbonyl in which R ⁷ and R ⁸ are hydrogen atoms Acid compound (Ic)
Is prepared by dissolving the ester compound (Ib) in a suitable solvent,
Obtained by conventional ester hydrolysis under basic, acidic or neutral conditions.

On the other hand, the ester compound (Ib) can be obtained by dissolving the carboxylic acid compound (Ic) in a suitable solvent and carrying out a normal ester synthesis reaction under basic, acidic or neutral conditions.

Under basic conditions, bases such as sodium hydroxide, potassium hydroxide, lithium hydroxide and barium hydroxide can be used. Under acidic conditions, Lewis acids such as hydrochloric acid, sulfuric acid and boron trichloride, acids such as trifluoroacetic acid and p-toluenesulfonic acid can be used. Under neutral conditions, halogen ions such as lithium iodide, lithium bromide, alkali metal salts of thiols and senorails, iodotrimethylsilane, and enzymes such as esterases can be used. As the solvent, water, alcohol (for example, methanol, ethanol), acetone, dioxane, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, dimethylsulfoxide, formic acid, pyridine acetate, lutidine, collidine and the like are used. The above-mentioned conventional solvent may be a mixture with water.

The reaction usually proceeds at room temperature, but there are some that need to be carried out under ice cooling, and some that require heating.
The method is appropriately selected according to a conventional method.

By appropriately selecting the conditions, a carboxylic acid compound of which only one is a hydrogen atom can be obtained by hydrolysis. For example, an ester residue (eg, tert-butyl group) that is susceptible to hydrolysis under acidic conditions on one side and an ester residue (eg, methyl ester, ethyl ester) that is susceptible to hydrolysis under basic conditions on the other side. When used, only one of them can be selectively hydrolyzed depending on the hydrolysis condition (acidic or basic condition).

Among the compounds of the present invention, the compound in which R ¹ or R ² is an ester residue can also be produced from a suitable alcohol by a transesterification reaction. For example, in the presence of an acid or a base or other catalyst (for example, titanium (IV) alkoxide), a large excess of alcohol is used, or the other alcohol that is produced is removed from the system, and the equilibrium is biased to the production system. The desired ester form can be obtained.

The compound of the present invention produced by the above method is
It can be isolated and purified by known methods such as extraction, precipitation, fractionation chromatography, fractional crystallization and recrystallization. Further, the compound of the present invention can be converted into a desired salt by subjecting it to an ordinary salt formation reaction.

The method of synthesizing the raw material compounds will be described below.

[0042]

[Chemical 6]

(In the formula, R ¹ , R ² , X ¹ and X ² have the above-mentioned meanings.) The compound (II) is prepared by dissolving the compound (IV) in a suitable solvent to obtain the amine of the compound (V). It is obtained by reacting with Schiff base to produce a Schiff base, and then reducing the Schiff base. The Schiff base may be isolated or may be reduced without isolation.

As the solvent, an organic solvent inert to the reaction,
For example, benzene, toluene, xylene, methanol, ethanol, isopropanol, methylene chloride, dichloroethane, chloroform, acetic acid, etc. are used.

In the reaction, the compound (IV) and the corresponding amount of the compound (V) amine, or one of them is used in a slight excess,
It is preferably carried out in the presence of an acid catalyst such as p-toluenesulfonic acid, adipic acid, oxalic acid, pyridine hydrochloride and acetic acid. Depending on the reaction conditions, a hygroscopic agent such as potassium hydroxide or molecular sieves may be added, or a Dean-Stark trap (azeotropic dehydrator) may be used to carry out the reaction while removing generated water out of the system. Is advantageous. The reaction temperature is usually set at room temperature, and depending on the reaction conditions, set at an azeotropic or reflux temperature.

In order to reduce the Schiff base, it is preferable to add a reducing agent to the reaction solution in the first stage in advance. As the reducing agent, for example, a metal hydride complex such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or borane is used.

[0047]

[Chemical 7]

(In the formula, X ¹ , X ² , R ³ and R ⁷ have the above-mentioned meanings.) The carboxylic acid derivative (III) or its reactive derivative is
R ³ -NH ₂ and is normal condensation reaction, the amide compound (I
d) can be obtained.

Examples of the reactive derivative of the compound (III) include common esters such as carboxylic acid methyl ester, ethyl ester, isobutyl ester and tert-butyl ester; acid halides such as acid chloride and acid bromide; acid azides; p. -Active esters obtained by reacting with phenol compounds such as nitrophenol and N-hydroxylamine compounds such as 1-hydroxysuccinimide and 1-hydroxybenzotriazole; symmetric acid anhydrides; halocarboxylic acids such as alkyl carbonate halides Mixed acid anhydrides such as organic acid mixed acid anhydrides obtained by reacting with alkyl ester or bivaloyl halide, and phosphoric acid mixed acid anhydrides obtained by reacting with diphenylphosphoryl chloride or N-methylmorpholine ; Are mentioned.

When the carboxylic acid is reacted with a free acid or when the active ester is reacted without isolation, dicyclohexylcarbodiimide, carbonyldiimidazole, diphenylphosphoryl azide, diethylphosphoryl cyanide or 1-ethyl-3- It is preferable to use a condensing agent such as (3-dimethylaminopropyl) carbodiimide / hydrochloride.

Particularly, in the present invention, the acid chloride method,
A method of reacting in the presence of an active esterifying agent and a condensing agent and a method of treating an ordinary ester with an amine are advantageous because they can be easily and easily used as the compound of the present invention.

The reaction varies depending on the reactive derivative and the condensing agent used, but is usually a halogenated hydrocarbon such as dichloromethane, dichloroethane or chloroform, an aromatic hydrocarbon such as benzene, toluene, xylene, ether, tetrahydrofuran, etc. Ethers, esters such as ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, and other inert organic solvents in the reaction, depending on the reactive derivative, under cooling, under cooling to room temperature, or under room temperature to heating To be done.

In the reaction, the substituted aniline (II
I) is used in excess or is reacted in the presence of a base such as N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, picoline and lutidine. May be advantageous in facilitating the reaction. Pyridine can also be the solvent.

[0054]

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(In the formula, R ⁷ , R ⁸ , X ¹ and X ² have the above-mentioned meanings. One of R ^7a and R ^8a is a hydrogen atom and the other is an ester residue.) Compound (IIc) is obtained by using only one ester of the raw material (IIa) as a carboxylic acid and then selectively reducing the group represented by the formula —COOR ^8a , that is, the carboxylic acid or ester moiety to alcohol.

On the other hand, a raw material (IIa) into which an ester residue (such as a tert-butyl group) that is susceptible to hydrolysis under acidic conditions or an ester residue (such as a benzyl group) that can be converted into a carboxylic acid by hydrogenation is introduced is used. When used, the half ester compound (II
b) can be obtained.

When R ^8a of compound (IIb) is a hydrogen atom, that is, when it is a carboxylic acid, the ester is not reduced and only the carboxylic acid is reduced (for example, mixed acid anhydride of Yamada et al. And then reducing with sodium borohydride). On the other hand, compound (IIb)
When R ^{8a of} is an ester residue, the compound (XII) can be obtained by using a method in which the carboxylic acid is not reduced and only the ester is reduced (for example, reduction with lithium borohydride). .

[0058]

[Chemical 9]

(In the formula, R ¹ , R ² , X ¹ and X ² have the above meanings.) The compound (IV) can be synthesized by the following method (A) or (B).

(A) Compound (IV) is compound (VI)
Is dissolved in a suitable solvent to form an enamine by reacting with a suitable secondary amine, and then the enamine is treated with an alkyl acrylate (eg, methyl acrylate) or a halogenated aliphatic carboxylic acid ester (eg, ethyl bromoacetate). It is obtained by The enamine may or may not be isolated.

As the secondary amine, pyrrolidine, piperidine, morpholine, diethylamine, diisopropylamine and the like can be used.

The solvent used in the reaction includes toluene, benzene, chlorobenzene and the like. In addition to the above-mentioned conventional solvents, the reaction can be carried out in any organic solvent as long as it does not adversely affect the reaction.

The reaction is carried out by adding a hygroscopic agent such as potassium hydroxide or molecular sieves, or by using a Dean-Stark trap (azeotropic dehydrator) to produce enamine. It is removed outside the system. The reaction temperature is preferably set at an azeotropic or reflux temperature.

(B) Compound (IV) is compound (VI)
Is dissolved in a suitable solvent, reacted with a base, and then alkyl halide (eg ethyl bromoacetate) or alkyl acrylate (eg methyl acrylate)
It is obtained by acting.

As the base, sodium hydride, potassium hydride, potassium tert. -Butoxide, sodium methoxide, sodium ethoxide, n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like can be used.

As the solvent used in the reaction, N.I. Examples include N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, methylene chloride, benzene, toluene, pyridine, acetone, 2-butanone.

The reaction usually proceeds at room temperature, but there are some that need to be carried out under ice cooling, and some that require heating.
The method is appropriately selected according to a conventional method.

[0068]

[Chemical 10]

(In the formula, X ¹ , X ² , R ⁷ and R ⁸ have the above-mentioned meanings.) The compound represented by the general formula (IX) is a carboxylic acid (VI).
A halogenated aliphatic carboxylic acid ester (eg, ethyl bromoacetate) is allowed to act on I) in the presence of a base (eg, potassium carbonate) to obtain a compound (VIII), and the compound (VIII) is dealkoxycarbonylated under appropriate conditions. It can be obtained by

Step 1 Compound (VIII) is prepared by reacting compound (VII) in an appropriate solvent such as N, N-dimethylformamide, acetonitrile or the like with 2 equivalents or excess of halogenated aliphatic carboxylic acid relative to compound (VII). It is obtained by reacting an acid ester in the presence of a suitable base. As the base, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydride, potassium ter
t-Butoxide or the like is used.

Step 2 Dealkoxycarbonylation of compound (VII) is carried out by using an acid (for example, hydrochloric acid, sulfuric acid, acetic acid, p-).
Toluenesulfonic acid, trifluoroacetic acid, etc.), base (eg sodium hydroxide, potassium hydroxide, sodium ethoxide, pyridine etc.), or metal salt (eg sodium chloride, lithium chloride etc.) is dissolved or suspended in a suitable solvent. It is turbid and is made to act at room temperature or under heating conditions. Alternatively, decarboxylation proceeds by simply heating compound (VII) in a suitable solvent. As the solvent, a suitable solvent such as N, N-dimethylformamide, dimethylsulfoxide, ethylene glycol, acetonitrile, hexamethylphosphoramide or the like is used.

[0072]

[Chemical 11]

(In the formula, R ¹ , R ⁵ , X ¹ and X ² have the above-mentioned meanings.) The compound (X) is prepared by dissolving the compound (VI) in a suitable solvent and reacting with a base. , A halogenated aliphatic carboxylic acid ester (eg ethyl bromoacetate).

As the base, sodium hydride, potassium hydride, potassium tert. -Butoxide, sodium methoxide, sodium edoxide, n-butyllithium, sec-butyllithium, lithium diisopropylamide and the like can be used.

The solvent used in the reaction includes N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, 1,2-dimethoxyethane, acetonitrile, methylene chloride, benzene, toluene, pyridine, acetone, 2-butanone and the like. . The reaction usually proceeds at room temperature, but some reactions need to be carried out under ice cooling or some require heating.

[0076]

[Chemical 12]

(In the formula, R ² , R ⁵ , X ¹ and X ² have the above-mentioned meanings.) The compound (XII) is prepared by using a halogenated aliphatic carboxylic acid ester (such as ethyl bromoacetate) as the raw material (XI). ) Is subjected to the Schotten-Baumann reaction.

That is, the compound (XII) is a starting material (X
I) is dissolved in a mixed solvent of an appropriate solvent (eg, acetone, diethyl ether, etc.) and water, and the halogenated aliphatic carboxylic acid ester is allowed to cool to room temperature or with ice in the presence of an appropriate base (eg, sodium hydrogencarbonate). It is obtained by reacting under.

[0079]

The compound of the present invention is a GPI that can be orally administered.
It has an inhibitory effect on platelet aggregation as an Ib / IIIa receptor antagonist, and ischemic heart disease (unstable angina, acute myocardial infarction, and its secondary prevention, coronary artery bypass surgery, P
Re-occlusion and restenosis after TCA, promotion of coronary thrombolysis and prevention of re-occlusion) improver, adjuvant during cardiac surgery or vascular surgery, cerebrovascular disorder (transient cerebral ischemic attack (TIA), cerebral infarction, It is useful as an agent for improving subarachnoid hemorrhage (vasospasm) and an agent for improving peripheral arterial disease (chronic arterial occlusion).

Particularly, the compound of the present invention is excellent in oral absorbability and is useful as a remedy for the above-mentioned diseases not only by intravenous administration but also by oral administration. In addition, the compounds of the present invention include compounds having excellent durability upon oral administration.

The pharmacological effects of the compounds of the present invention, such as the platelet aggregation inhibitory action, were confirmed by the test methods described below.

Fibrinogen binding to human platelets Blood obtained by puncture of the cubital vein was converted into ACD fluid (50 whole blood).
10 ml at 900 rpm and mixed with 10 ml)
Centrifuge for minutes to obtain platelet rich plasma (PRP). PRP10
Add 100 μl of 1M citric acid to ml and mix to 200
The platelet precipitate was collected by centrifugation at 0 rpm for 15 minutes. 0.
Modified HEPES-Ty containing 35% BSA
The suspension was suspended in rode's buffer (pH 6.4), apyrase was added, and the mixture was kept at 37 ° C for 10 minutes. The same operation is performed again to wash the platelets, and then the modified HE
PES-Tyrode's buffer (pH 7.
4), and the number of platelets was measured with an automatic hemocytometer (MEK-5158, Nihon Kohden). 166,000 / μ
15 μl of 10 U / ml thrombin (Mochida Pharmaceutical Co., Ltd.), 15 μl of 100 μM argatroban (Mitsubishi Kasei, Daiichi Pure Chemicals), 15 μl of sample solution or solvent, and 15 μl of 200 μg / ml ¹²⁵ I-human fibrinogen to 90 μl of platelet suspension. Mix in the tube and leave at room temperature for 30 minutes. Nonspecific binding is 10
The measurement was performed by adding 15 μl of mg / ml human fibrinogen. In advance, 200 μl of 20% sucrose
Add 1 reaction solution to an elongated 0.4 ml tube containing
Overlay with 00 μl, centrifuge at 12000 rpm for 2 minutes, cut the tip of the container containing the platelet pellet, and measure the amount of bound fibrinogen with a γ-counter. The value obtained by subtracting the radioactivity of non-specific binding from the radioactivity of ¹²⁵ I-fibrinogen apparently bound to platelets was defined as the specific binding.

Human Platelet Aggregation Inhibitory Activity Blood was collected from healthy persons (adults, boys) with 1/10 volume sodium citrate, and the method of De Marco et al. (J.C.
lin. Invest, 77, 1272-1277, 1
986), and platelet rich plasma was prepared. PRP is
Using an automatic blood cell counter (MEK-5158, Nihon Kohden), it was prepared at 3 × 10 ⁸ / ml and used. As the agglutinating agent ADP and bovine tendon-derived collagen, products of Nikko Bioscience were used. Platelet aggregation was measured using a platelet aggregometer (NBS Hematracer 801, Nikko Bioscience). That is, PRP (80 μl)
After incubating the sample and solvent (10 μl) for 3 minutes at 37 ° C., add 10 μl of ADP (2-3 μM) or collagen (1-2 μg / ml) and record the change in transmitted light for 5 minutes. Aggregation inhibition (%) was calculated.

Cynomolgus monkey ex vivo platelet aggregation inhibition
A cynomolgus monkey anesthetized by intramuscular administration of the harmfully active ketamine hydrochloride was held on a laboratory table and the compound of the present invention dissolved in distilled water was forcibly administered intragastrically at a dose of 2 ml / kg using a rubber catheter. 3 ml of blood (including 1/10 volume sodium citrate) was collected from the femoral vein before administration and after a certain period of administration, and 300,000 / μl of PRP was prepared according to the method described above (human PRP preparation method), and ADP was used.
Platelet aggregation was measured using (20 μM) and CG (10 μg / ml) as inducers. The inhibitory activity was represented by the inhibition rate (%) with respect to the maximum aggregation rate before aggregation of each animal.

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

[0086]

EXAMPLES The production examples of the compounds of the present invention will be described below as specific examples, and will be specifically described. Further, there are novel compounds as raw material compounds of the compound of the present invention, and production examples of these compounds will be described as reference examples.

Reference Example 1 Ethyl 4-oxo-1-piperidine acetate 1.8
5 g 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 ml of benzene and 1.7 g of methyl acrylate were added thereto, 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 then 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) and methyl 1-
1.8 g of ethoxycarbonylmethyl-4-oxo-3-piperidine propionate was obtained as an oily substance.

Mass spectrometry value (m / z): FAB (Pos)
272 (M + 1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.29 (3H, t), 1.51-1.58 (1
H, m), 2.06-2.13 (1H, m), 2.31
-2.48 (4H, m), 2.61-2.74 (3H,
m), 3.14-3.17 (2H, m), 3.36 (2
H, d), 3.66 (3H, s), 4.20 (2H,
q).

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

Reference Example 2 Methyl 1- (tert-butoxycarbonylmethyl)
-4-oxo-3-piperidine propionate Raw material compound: tert-butyl 4-oxo-1-piperidine acetate Mass spec (m / z): FAB (Pos) 300 (M
+1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.48 (9H, s), 1.50-1.59 (1
H, 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 (2
H, d), 3.66 (3H, s).

Reference Example 3 Methyl 1-ethoxycarbonylmethyl-4-oxo-
3-piperidine propionate 1.74 g, 4- (1-
Piperazinyl) benzonitrile 1.2g and acetic acid 0.8g
Was dissolved in 50 ml of dichloromethane, 2.7 g of sodium triacetoxyborohydride was added thereto, and the mixture was stirred at room temperature for 2 hours.
Stir for 4 hours. The reaction solution was neutralized with 1N-sodium hydroxide aqueous solution and then 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: ethyl acetate = 1: 1) and methyl 4- [4- (4-cyanophenyl) -1.
-Piperazinyl] -1-ethoxycarbonylmethyl-3
-1.1 g of piperidine propionate was obtained.

Mass spectrum (m / z): FAB (Pos)
443 (M + 1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.28 (3H, t), 1.6-1.77 (2
H, m), 1.94-1.97 (3H, m), 2.05
-2.08 (2H, m), 2.19-2.24 (1H,
m), 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), 3.33 (2H, q),
6.85 (2H, d), 7.48 (2H, d).

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

Reference Example 4 Methyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -1- (tert-butoxycarbonylmethyl) -3-piperidine propionate Raw material compound: methyl 1- (tert-butoxy) Carbonylmethyl) -4-oxo-3-piperidine propionate Mass Spec (m / z): FAB (Pos) 471 (M
+1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.47 (9H, s), 1.64-1.70 (1
H, m), 1.75 (1H, d), 1.94-1.99.
(3H, m), 2.03 to 2.09 (2H, m), 2.
17-2.22 (1H, m), 2.35-2.42 (2
H, m), 2.52-2.58 (3H, m), 2.63
-2.67 (2H, m), 2.92-2.97 (3H,
m), 3.15 (1H, d), 3.33 (3H, t),
3.66 (3H, s), 6.85 (2H, d), 7.4
8 (2H, d).

Reference Example 5 Ethyl 4-oxo-1-piperidine acetate 5.5
5 g and pyrrolidine 3.3 g were melt | dissolved in benzene 100 ml, and it refluxed for 24 hours using the apparatus of Dean-Stark. The reaction solution was concentrated, 100 ml of benzene and 3.18 g of acrylonitrile were added thereto, and the mixture was refluxed for 48 hours. 10 ml of water was added to the reaction solution, and the mixture was refluxed for 2 hours, and then 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: ethyl acetate = 1: 1), and ethyl 3
3.1 g of-(2-cyanoethyl) -4-oxo-1-piperidine acetate was obtained as an oily substance.

Mass spectrum (m / z): GC / MS 23
8 (M ⁺ ) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.29 (3H, t), 1.50 to 1.57 (1
H, m), 2.06 to 2.13 (1H, m), 2.36
Up to 2.40 (1H, m), 2.46 to 2.53 (3H,
m), 2.66 to 2.80 (3H, m), 3.16 to
3.19 (2H, m), 3.39 (2H, s), 4.2
0 (2H, q).

The following Reference Examples 6 to 9 were carried out in the same manner as in Reference Example 5.
Was obtained.

Reference Example 6 tert-butyl 4-oxo-3- [2- (2-pyridyl) ethyl] -1-piperidine acetate Raw material compound: tert-butyl 4-oxo-1-piperidine acetate and 2-vinylpyridine Mass Analytical value (m / z): FAB (Pos) 319 (M
⁺ +1) Reference Example 7 tert-butyl 4-oxo-3- (2-phenylsulfonylethyl) -1-piperidine acetate Raw material compound: tert-butyl 4-oxo-1-piperidine acetate and phenylvinyl sulfone Mass spectrum (m / Z): FAB (Pos) 382 (M
⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.47 (9H, s), 1.61 to 1.70 (1
H, m), 1.99 to 2.09 (1H, m), 2.29.
˜2.35 (1H, m), 2.39 (1H, t), 2.
58 to 2.73 (3H, m), 3.06 to 3.16 (3
H, m), 3.24 (2H, s), 3.27 to 3.35.
(1H, m), 7.58 (2H, t), 7.66 (1
H, t), 7.91 (2H, d).

Reference Example 8 tert-butyl 3- (2-methoxycarbonylethyl) -4-oxo-1-piperidine propionate Raw material compound: tert-butyl 4-oxo-1-piperidine propionate and methyl acrylate Mass spectrometry Value (m / z): FAB (Pos) 314 (M
⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.46 (9H, s), 1.50 to 1.59 (1
H, m), 2.04 to 2.13 (1H, m), 2.23
(1H, t), 2.34 to 2.45 (5H, m), 2.
48-2.58 (3H, m), 2.75-2.80 (2
H, m), 3.02 to 3.08 (2H, m), 3.66
(3H, s).

Reference Example 9 tert-butyl 1-ethoxycarbonylmethyl-4
-Oxo-3-piperidine propionate Raw material compound: ethyl 4-oxo-1-piperidine acetate and tert-butyl acrylate Mass spec (m / z): CI-MS 314 (M ⁺⁺ )
1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.29 (3H, t, J = 7.2 Hz), 1.43
(9H, s), 1.95 to 3.25 (11H, m),
3.35 (2H, s), 4.20 (2H, q, J = 7.
2 Hz).

Reference Example 10 Methyl 4-oxo-3-piperidinecarboxylate monohydrochloride 9.65 g, ethyl bromoacetate 21.0 g and potassium carbonate 24.0 g were dissolved in 200 ml of N, N-dimethylformamide, and the mixture was stirred at room temperature overnight. It was stirred. 100 ml of water was added to the reaction solution and extracted with 500 ml of ethyl acetate,
This was dried over sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (eluent, chloroform) to obtain 9.0 g of ethyl 3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-1-piperidine acetate as an oily substance.

Mass spectrometric value (m / z): FAB (Pos)
330 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.23 to 1.31 (6H, m), 2.46 to 2.
51 (1H, m), 2.71 (2H, dd), 2.91
~ 2.96 (2H, m), 3.00 to 3.08 (2H,
m), 3.35 to 3.45 (2H, m), 3.79 (3
H, s), 4.10 to 4.19 (4H, m).

Reference Example 11 1.0 g of ethyl 3-ethoxycarbonylmethyl-3-methoxycarbonyl-4-oxo-1-piperidine acetate and 140 mg of lithium chloride were dissolved in 10 ml of N, N-dimethylformamide and refluxed for 48 hours. Water (10 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 ml), dried over sodium sulfate and concentrated.

The residue was purified by silica gel column chromatography (eluent, chloroform) and diethyl 4
-Oxo-1,3-piperidine diacetate 400 mg
Was obtained as an oily substance.

Mass spectrum (m / z): FAB (Pos)
272 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.23 to 1.30 (6H, m), 2.18 (1
H, dd), 2.36 to 2.40 (1H, m), 2.5
0 (1H, t), 2.70 to 2.77 (3H, m),
3.13-3.26 (3H, m), 3.38 (2H,
s), 4.09 to 4.22 (4H, m).

Reference Example 12 Methyl 4-oxo-3-piperidinecarboxylate monohydrochloride 1.94 g, sodium hydrogencarbonate 1.68 g and ethyl bromoacetate 1.67 g were dissolved in a mixed solvent of water 32 ml-diethyl ether 8 ml, Stir overnight at room temperature. 50 ml of ethyl acetate was added to the reaction solution, the organic layer was separated, dried over sodium sulfate and then concentrated. The residue was purified by silica gel column chromatography (eluent, chloroform-chloroform: methanol = 100: 1) and ethyl 3-methoxycarbonyl-4-oxo-
1.5 g of 1-piperidine acetate was obtained as an oily substance.

Mass spectrum (m / z): FAB (Pos)
244 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.29 (3H, t), 2.45 to 2.47 (2
H, m), 2.80 (2H, t), 3.31 (2H,
s), 3.36 (3H, s), 3.76 (3H, s),
4.20 (2H, q). Reference Example 13 Ethyl 3- (2-cyanoethyl) -4-oxo-1-
3.1 g of piperidine acetate, 2.4 g of 4- (1-piperazinyl) benzonitrile and 1.56 g of acetic acid were dissolved in 50 ml of dichloromethane, 5.5 g of sodium triacetoxyborohydride was added thereto, and the mixture was stirred at room temperature for 24 hours. . The reaction solution was neutralized with 1N-sodium hydroxide aqueous solution and then 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: ethyl acetate = 1: 1), ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl. ] 1.0 g of -3- (2-cyanoethyl) -1-piperidine acetate was obtained.

Mass spectrum (m / z): FAB (Pos)
410 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.28 (3H, t), 1.61 to 1.65 (2
H, m), 1.79 (1H, d), 1.96 to 1.98.
(1H, m), 2.04 to 2.15 (3H, m), 2.
19-2.25 (1H, m), 2.46-2.66 (6
H, m), 2.93 (1H, d), 2.99 to 3.38.
(7H, m), 4.11 to 4.22 (2H, m), 6.
85 (2H, d), 7.49 (2H, d).

The following Reference Example 14 was carried out in the same manner as Reference Example 13.
~ 15 compounds were obtained.

Reference Example 14 tert-butyl 4- [4- (4-cyanophenyl)
-1-Piperazinyl] -3- (2-methoxycarbonylethyl) -1-piperidine propionate Raw material compound: tert-butyl 3- (2-methoxycarbonylethyl) -4-oxo-1-piperidine propionate Mass spectrometry Value (m / z): FAB (Pos) 485 (M
⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.44 (9H, s), 1.53 to 1.59 (2
H, m), 1.75 (1H, d), 1.89 to 2.05
(5H, m), 2.23 to 2.77 (11H, m),
2.87 (1H, d), 2.93 (1H, d), 3.3
2 (2H, d), 3.66 (3H, s), 6.85 (2
H, d), 7.48 (2H, d).

Reference Example 15 tert-butyl 4- [4- (4-cyanophenyl)
-1-Piperazinyl] -1-ethoxycarbonylmethyl-3-piperidine propionate Raw material compound: tert-butyl 1-ethoxycarbonylmethyl-4-oxo-3-piperidine propionate and 4- (1-piperazinyl) benzonitrile elemental analysis (as _{C 27 H 40 N 4 O 4} ) C (%) H (%) N (%) theoretical values 66.92 8.32 11.56 Found 66.62 8.36 11.33 mass spectrometry Value (m / z): FAB (Pos) 485 (M
⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.29 (3H, t, J = 7.2 Hz), 1.44
(9H, s), 1.65 to 3.40 (22H, m),
4.19 (2H, q, J = 7.2Hz), 6.85 (2
H, d, J = 9.0 Hz), 7.48 (2H, d, J =
9.0 Hz). Reference Example 16 tert-butyl 4- [4- (4-cyanophenyl)
-1-Piperazinyl] -1-ethoxycarbonylmethyl-3-piperidine propionate (485 mg) in 1,4-
It was dissolved in 5 ml of dioxane. 4 normal hydrogen chloride / 1,4
-10 ml of dioxane was added, and the mixture was stirred at room temperature overnight.
The solvent of the reaction solution was distilled off, the obtained residue was suspended in 20 ml of 1,4-dioxane, and the solvent was distilled off. The same operation was repeated twice with 20 ml of toluene to give 4- [4- (4-cyanophenyl) -1-piperazinyl] -1-ethoxycarbonylmethyl-3-piperidinepropionic acid dihydrochloride as white crystals. Obtained.

Mass spectrum (m / z): FAB (Pos)
429 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.26 (3H, t, J = 7.2 Hz), 1.90.
~ 4.35 (22H, m), 4.23 (2H, q, J =
7.2 Hz), 7.14 (2H, d, J = 9.1H)
z), 7.67 (2H, d, J = 8.8Hz).

Reference Example 17 2.0 g of the product of Reference Example 16 and triethylamine 4.8
g was suspended in 50 ml of tetrahydrofuran, a solution of ethyl chloroformate (500 mg) in tetrahydrofuran was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 30 minutes. This reaction solution was added with an aqueous solution of sodium borohydride (400 mg) (1
0 ml) was added dropwise at a temperature of 10 ° C to 15 ° C, and the mixture was stirred at room temperature for 4 hours. The reaction solution was adjusted to pH 5 with 1N hydrochloric acid and washed with 100 ml of ethyl acetate. The pH of the aqueous layer was adjusted to 8 with 1N aqueous sodium hydroxide solution, and ethyl acetate
After extraction with 1, the extract was dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (eluent, chloroform-chloroform: methanol = 50: 1) and ethyl 4- [4- (4-cyanophenyl) -1.
-Piperazinyl] -3- (3-hydroxypropyl)-
1-piperidine acetate was obtained.

Mass spectrometric value (m / z): FAB (Pos)
415 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.27 (3H, t), 1.49 to 1.52 (1
H, m), 1.61 to 2.24 (8H, m), 2.61
(3H, t), 3.28 to 3.33 (3H, m), 3.
68 (1H, t), 4.18 (2H, q), 6.85
(2H, d), 7.49 (2H, d).

Reference Example 18 1.50 g of the product of Reference Example 16 was dissolved in 30 ml of N, N-dimethylformamide to give triethylamine 0.92.
ml, 1-hydroxybenzotriazole 687 mg and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide monohydrochloride 631 mg were sequentially added, and the mixture was stirred at room temperature for 80 minutes. To this, 0.36 ml of benzylamine was added, and the mixture was further stirred at room temperature overnight. The solvent of the reaction solution was distilled off, and the obtained residue was suspended in 500 ml of ethyl acetate,
Filtered. The organic layer is saturated aqueous sodium hydrogen carbonate solution 40
It was washed with 0 ml and saturated saline 400 ml. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was subjected to silica gel column chromatography (eluent, chloroform: methanol = 200: 1 to 100:
Purified in 1), ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-benzylcarbamoylethyl) -1-piperidine acetate 1.01
g was obtained.

Elemental analysis value (as C ₃₀ H ₃₉ N ₅ O ₃ ) C (%) H (%) N (%) Theoretical value 69.61 7.59 13.53 Experimental value 69.29 7.64 13. 47 Mass spectrum (m / z): FAB (Pos) 518 (M
⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.23 (3H, t, J = 7.2 Hz), 1.70
˜3.40 (22H, m), 4.09 (2H, q, J =
7.0 Hz), 4.43 (2H, d, J = 5.5H
z), 6.14 to 6.42 (1H, m), 6.83 (2
H, d, J = 8.9 Hz), 7.29 (5H, s),
7.49 (2H, d, J = 9.0 Hz).

The following Reference Example 19 was carried out in the same manner as Reference Example 18.
~ 21 compounds were obtained.

Reference Example 19 Ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-carbamoylethyl) -1-piperidine acetate Raw material compound: product of Reference Example 16 Elemental analysis value ( _{C 23 H 33 N 5 O 3} · 0.4H as _{2 O) C (%) H} (%) N (%) theoretical values 63.54 7.84 16.10 Found 63.65 7.79 15.84 Mass spectrum (m / z): FAB (Pos) 428 (M
⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.28 (3H, t, J = 7.2 Hz), 1.66
˜3.38 (22H, m), 4.17 (2H, q, J =
7.2 Hz), 5.25 (1 H, s), 6.10 (1
H, s), 6.84 (2H, d, J = 9.1 Hz),
7.49 (2H, d, J = 9.0 Hz).

Reference Example 20 Ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-methylcarbamoylethyl)-
1-piperidine acetate Raw material compound: product of Reference Example 16 Elemental analysis value (as C ₂₄ H ₃₅ N ₅ O ₃ .0.55H ₂ O) C (%) H (%) N (%) theoretical value 63.85 8.06 15.51 Experimental value 63.94 7.90 15.51 Mass spectrometry value (m / z): FAB (Pos) 442 (M
⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.28 (3H, t, J = 7.2 Hz), 1.78
˜3.38 (22 Hm), 2.79 (3 H, d, J =
4.9 Hz), 4.18 (2H, q, J = 7.2H
z), 5.86 to 6.16 (1H, m), 6.84 (2
H, d, J = 9.1 Hz), 7.49 (2H, d, J =
9.0 Hz).

Reference Example 21 Ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-ethoxycarbonylmethylcarbamoylethyl) -1-piperidine acetate Raw material compound: product of Reference Example 16 Element analysis _{(C 27 H 39 N 5 O} 5 · 0.2H 2 as O) C (%) H ( %) N (%) theoretical values 62.70 7.68 13.54 Found 62.67 7.56 13.51 Mass spectrum (m / z): FAB (Pos) 514 (M
⁺ +1) Nuclear magnetic resonance spectrum (CDCl _3, TMS internal standard) δ: 1.28 (3H, t , J = 7.3Hz), 1.28
(3H, t, J = 7.0Hz), 1.65 to 1.78
(2H, m), 1.97 to 2.07 (6H, m), 2.
17 to 2.22 (1H, m), 2.33 to 2.39 (1
H, m), 2.46 to 2.50 (1H, m), 2.53
Up to 2.65 (4H, m), 2.92 to 2.94 (1H,
m), 3.05 (1H, d, J = 17.0 Hz), 3.
25 (1H, d, J = 16.5Hz), 3.31-3.
33 (4H, m), 3.96 (1H, dd, J = 17.
8 Hz, 5.3 Hz), 4.07 (1H, dd, J = 1)
8.5 Hz, 5.5 Hz), 4.13 to 4.23 (4
H, m), 6.43 (1H, m), 6.84 (2H,
d, J = 9.0 Hz), 7.48 (2H, d, J = 9.
0 Hz).

Reference Example 22 501 mg of the product of Reference Example 16 was suspended in 5 ml of methylene chloride under an argon stream and cooled with ice. To this, 0.60 ml of a methylene chloride solution of oxalyl chloride (2 mol / L) and a catalytic amount of N, N-dimethylformamide were added, and the mixture was cooled with ice.
Stir for 0 minutes. The solvent of the reaction solution was evaporated, the obtained residue was suspended in 5 ml of methylene chloride, 0.10 ml of aniline and 0.17 ml of triethylamine were added, and the mixture was stirred at room temperature for 1 hour and 50 minutes. The solvent of the reaction solution was distilled off, the residue was suspended in 100 ml of ethyl acetate, 100 ml of saturated aqueous sodium hydrogen carbonate solution, 100 ml of saturated saline solution, and 10 ml of saturated saline solution.
It was washed successively with 0 ml. The organic layer was dried over magnesium sulfate and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 200: 1 to 100: 1) and purified with ethyl acetate.
4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-phenylcarbamoylethyl) -1-
421 mg of piperidine acetate was obtained.

Mass spectrometric value (m / z): FAB (Pos)
504 (M ⁺ +1) Nuclear magnetic resonance spectrum (CDCl ₃ , TMS internal standard) δ: 1.30 (3H, t, J = 7.7 Hz), 1.60
~ 3.45 (22H, m), 4.22 (2H, q, J =
6.9 Hz), 6.83 (2H, d, J = 8.1H
z), 6.97 to 7.62 (5H, m), 7.48 (2
H, d, J = 8.1 Hz), 8.11 (1 H, m).

Example 1

[0124]

[Chemical 13]

Methyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -1-ethoxycarbonylmethyl-3-piperidine propionate (550 mg) was dissolved in ethanol (20 ml) and hydrogen chloride was added at -10 to -20 ° C. Bubbling until saturated. After returning to room temperature and stirring overnight, the solvent was distilled off. The obtained residue is ethanol 20
It was dissolved in ml, 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), ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl. ] -L-Ethoxycarbonylmethyl-3-piperidine propionate monohydrochloride 500 mg was obtained.

Mass spectrometric value (m / z): FAB (Pos)
474 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.06 (3H, t), 1.17-1.21 (4
H, m), 1.40-2.30 (5H, m), 2.44
-2.54 (2H, m), 2.87 (1H, m), 3.
15 (1H, dd), 3.17 (3H, d), 3.31
(3H, s), 3.36 (3H, brs), 3.42-
3.47 (2H, m), 4.03-4.10 (4H,
m), 4.34 (1H, t), 7.07 (2H, d),
7.75 (2H, d).

Example 2

[0128]

Embedded image

Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -1-ethoxycarbonylmethyl-3-piperidinepropionate monohydrochloride 350 m
g was dissolved in 20 ml of ethanol, 2.5 ml of a 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 5 hours.
2.5 ml of 1N hydrochloric acid was added to the reaction solution, the solvent was distilled off, and the residue was purified by HP-20 column chromatography (eluent water-water: methanol = 50: 1) to give 4- [4-
(4-Amidinophenyl) -1-piperazinyl] -1-
180 mg of carboxymethyl-3-piperidine propionic acid monohydrochloride was obtained.

Mass spectrometric value (m / z): FAB (Pos)
418 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.75 (1H, brs), 2.02 to 2.09
(2H, m), 2.38-2.45 (2H, m), 2.
51-2.64 (2H, m), 3.04 (1H, d),
3.12 (1H, t), 3.56 (2H, brs),
3.76 (2H, d), 4.14 (4H, dd), 7.
21 (2H, d), 7.81 (2H, d), 8.87
(2H, s), 9.04 (2H, s).

Example 3

[0132]

[Chemical 15]

Methyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -1- (tert-butoxycarbonylmethyl) -3-piperidine propionate (1.1 g) and triethylamine (1 ml) were added to N.V. It was dissolved in 20 ml of N-dimethylformamide, and hydrogen sulfide was blown into it at room temperature until it was saturated. After stirring overnight at room temperature, 200 ml of 2N sodium carbonate aqueous solution was added, and ethyl acetate was added to 150
Extract 3 times with ml. The collected organic layer was washed with saturated brine, 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. 50 ml methanol residue
The resulting mixture was dissolved in, 1.5 g of ammonium acetate was added, and the mixture was refluxed for 2 hours and then concentrated. The residue was purified by silica gel column chromatography (eluent chloroform: methanol = 10: 1) and methyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -1- (tert-butoxycarbonylmethyl)- 0.95 g of 3-piperidine propionate monohydrogen iodide salt was obtained.

Mass spectrometric value (m / z): FAB (Pos)
488 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.06 (1H, m), 1.41 (9H, 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
-3.43 (10H, m), 3.59 (3H, s),
7.08 (2H, d), 7.72 (2H, d), 8.5
4 (2H, s), 8.90 (2H, s).

Example 4

[0136]

Embedded image

Methyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -1- (tert-butoxycarbonylmethyl) -3-piperidine propionate Monohydrogen iodide (0.45 g) was added to 90% trifluoro. It was dissolved in 50 ml of an aqueous acetic acid solution and 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 give 4- [4- (4-amidinophenyl) -1-piperazinyl] -3-methoxy. 0.32 g of carbonylethyl-1-piperidineacetic acid monotrifluoroacetate was obtained.

Mass spectrometric value (m / z): FAB (Pos)
432 (M + 1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.18 (2H, t ). 1.76 (1H, br
s), 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), 3.63 (3H, s), 4.03
(2H, q), 7.17 (2H, d), 7.80 (2
H, d), 9.02 (4H, brs).

Example 5 870 mg of ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-cyanoethyl) -1-piperidineacetate was dissolved in 20 ml of ethanol, and the temperature was from -10 ° C to -20. Bubbling with hydrogen chloride at 0 ° C. was 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 solution was distilled off, and the obtained residue was purified by silica gel column chromatography (eluent, chloroform: methanol = 10: 1) and ethyl 3- (2-amidinoethyl) -4- [4- (4-amidinophenyl) -1-
1.0 g of piperazinyl] -1-piperidine acetate dihydrochloride was obtained.

Mass spectrometric value (m / z): FAB (Pos)
444 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.20 (3H, t), 1.40 (1H, br)
s), 1.75 to 1.97 (4H, m), 2.18 (2
H, t), 2.39 (1H, brs), 2.93 (2
H, t), 3.17 (1H, d), 4.07 to 4.15.
(2H, m), 7.06 (2H, d), 7.81 (2
H, d), 8.82 (2H, brs), 8.93 (2
H, brs), 9.11 (4H, brs).

In the same manner as in Reference Example 13 and Example 5, the following compounds of Examples 6 to 9 were obtained.

Example 6 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- [2- (2-pyridyl) ethyl]-
1-piperidine acetate dihydrochloride raw material compound: tert-butyl 4-oxo-3- [2
-(2-Pyridyl) ethyl] -1-piperidine acetate Mass spec (m / z): FAB (Pos) 479 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.20 (3H, t), 1.40 to 1.46 (1
H, m), 1.73 to 2.12 (6H, m), 2.38.
~ 2.43 (3H, m), 2.63 ~ 2.66 (1H,
m), 2.89 to 2.91 (2H, m), 3.01 (1
H, d), 4.10 (2H, q), 7.04 (2H,
d), 7.18 (1H, t), 7.24 (1H, d),
7.67 to 7.71 (1H, m), 8.46 (1H,
d), 8.82 (2H, s), 9.03 (2H, s).

Example 7 Diethyl 4- [4- (4-amidinophenyl) -1-
Piperazinyl] -1,3-piperidine diacetate monohydrochloride Raw material compound: diethyl 4-oxo-1,3-piperidine diacetate Mass spec (m / z): FAB (Pos) 460 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.18 (6H, t), 1.69 to 1.83 (3
H, m), 2.01 to 2.33 (5H, m), 2.66
-2.87 (3H, m), 3.08-3.23 (4H,
m), 4.03 to 4.33 (4H, m), 7.06 (2
H, d), 7.73 (2H, d).

Example 8 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3-methoxycarbonyl-1-piperidine acetate monohydrochloride Raw material compound: ethyl 3-methoxycarbonyl-4-oxo-1 -Piperidine acetate Mass spec (m / z): FAB (Pos) 432 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.18 (3H, t), 1.67 (1H, d),
2.17 (1H, q), 2.28 to 2.35 (2H,
m), 2.85 to 2.87 (1H, m), 2.96 to
3.01 (2H, m), 3.21 (2H, q), 3.5
7 (2H, s), 4.07 (2H, q), 7.05 (2
H, d), 7.75 (2H, d), 8.71 (2H,
s), 8.99 (2H, s).

Example 9 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-phenylsulfonylethyl)
-1-Piperidine acetate monohydrochloride raw material compound: tert-butyl 4-oxo-3- (2
-Phenylsulfonylethyl) -1-piperidine acetate Mass spec (m / z): FAB (Pos) 542 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.19 (3H, t), 1.66 to 1.76 (2
H, m), 1.87 to 2.11 (4H, m), 2.3
6 (3H, brs), 2.84 to 2.86 (1H,
m), 4.08 (2H, q), 7.06 (2H, d),
7.63-7.75 (5H, m), 7.91 (2H,
d), 8.58 (2H, brs), 8.96 (2H, b
rs).

Similar to Example 5, the following Examples 10 to 10
16 compounds are obtained.

Example 10 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-ethoxycarbonylethyl)
-1-Piperidine propionate monohydrochloride Raw material compound: tert-butyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-methoxycarbonylethyl) -1-piperidine propionate Mass Analysis value (m / z): FAB (Pos) 488 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.15 to 1.20 (6H, m), 1.34 to 1.
40 (1H, m), 1.69 to 1.96 (7H, m),
2.19 to 2.27 (1H, m), 2.35 to 2.43
(3H, m), 2.83 to 2.86 (2H, m), 3.
97 to 4.11 (4H, m), 7.04 (2H, d),
7.74 (2H, d).

Example 11 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (3-hydroxypropyl) -1-
Piperidine acetate monohydrochloride Raw material compound: ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (3-hydroxypropyl) -1-piperidine acetate Mass spec (m / z): FAB ( Pos) 432 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.19 (3H, t), 1.31 to 1.60 (5
H, m), 1.72 (1H, d), 1.80 (1H, b
rs), 1.93 (1H, d), 2.03 to 2.12
(2H, m), 2.88 to 2.90 (2H, m), 3.
14 (2H, dd), 4.08 (2H, q), 7.06
(2H, d), 8.74 (2H, brs), 9.00
(2H, brs).

Example 12 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-benzylcarbamoylethyl) -1-piperidine acetate monohydrochloride Raw material compound: ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-benzylcarbamoyl-ethyl)] - 1-piperidine acetate elemental analysis (as _{C 30 H 42 N 6 O 3} · 1.2HCl · 1.5H 2 O ) C (%) H (%) N (%) Cl (%) theoretical value 59.51 7.69 13.88 7.03 experimental value 59.64 7.53 13.73 6.87 mass spectrometry value (m / Z): FAB (Pos) 535 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.19 (3H, t, J = 7.3Hz), 1.40
~ 1.42 (1H, m), 1.73 to 1.83 (4H,
m), 1.91 to 1.93 (1H, m), 2.05
2.07 (1H, m), 2.11 to 2.16 (2H,
m), 2.26 to 2.29 (1H, m), 2.46 to
2.51 (4H, m), 2.86 to 2.92 (2H,
m), 3.10 (1H, d, J = 16.5 Hz), 3.
22 (1H, d, J = 16.5 Hz), 3.28 to 3.
31 (4H, m), 4.08 (2H, q, J = 7.2H
z), 4.25 (2H, d, J = 6.0 Hz), 7.0
5 (2H, d, J = 9.0 Hz), 7.21 to 7.26
(3H, m), 7.30 to 7.33 (2H, m), 7.
74 (2H, d, J = 8.5Hz), 8.29 (1H,
m), 8.57 (2H, s), 8.95 (2H, s).

Example 13 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-carbamoylethyl) -1-
Piperidine acetate monohydrochloride Raw material compound: Ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-carbamoylethyl) -1-piperidine acetate Mass spec (m / z): FAB ( Pos) 445 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.20 (3H, t, J = 7.0Hz), 1.43
(1H, m), 1.75 to 2.18 (9H, m), 2.
50 to 2.56 (4H, m), 2.88 (2H, m),
3.10 (1H, d, J = 16.0 Hz), 3.22
(1H, d, J = 16.5 Hz), 3.29 to 3.35.
(4H, m), 4.09 (2H, q, J = 7.2H
z), 6.63 (1H, s), 7.07 (2H, d, J
= 8.5 Hz), 7.21 (1 H, s), 7.76 (2
H, d, J = 9.0 Hz), 8.74 (2H, s),
9.00 (2H, s).

Example 14 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-methylcarbamoylethyl)
-1-Piperidine acetate monohydrochloride and methyl 4-
[4- (4-amidinophenyl) -1-piperazinyl]
-3- (2-Methylcarbamoylethyl) -1-piperidine acetate monohydrochloride raw material compound: ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-methylcarbamoylethyl)]- 1-piperidine acetate mass spectrometry value (m / z): FAB (Pos) 459 (R
= Et, M ⁺ +1) 445 (R = Me, M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.19 (1.8H, t, J = 7.0Hz), 1.
42 (1H, m), 1.75 to 2.18 (9H, m),
2.50 to 2.56 (4H, m), 2.55 to 2.56
(3H, s), 2.87 (2H, m), 3.08-3.
15 (1H, m), 3.21 to 3.24 (1H, m),
3.32 to 3.44 (4H, m), 3.62 (1.2
H, s), 4.09 (1.2H, q, J = 7.2H
z), 7.07 (2H, d, J = 10.0 Hz), 7.
71 (1H, s), 7.77 (2H, d, J = 10.0
Hz), 8.83 (2H, s), 9.04 (2H,
s).

Example 15 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-methoxycarbonylmethylcarbamoylethyl) -1-piperidine acetate monohydrochloride, methyl [4- [4 -(4-amidinophenyl)-
1-Piperazinyl] -3- (2-ethoxycarbonylmethylcarbamoylethyl) -1-piperidine acetate monohydrochloride and methyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-methoxycarbonyl Methylcarbamoylethyl) -1-piperidine acetate monohydrochloride raw material compound: ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-ethoxycarbonylmethylcarbamoylethyl) -1-piperidine acetate mass Analytical value (m / z): FAB (Pos) 517 (R
¹ = Me, R ² = Et or R ¹ = Et, R ² = Me, M ⁺ +
1) 503 (R ¹ = R ² = Me, M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.17 to 1.20 (1.5H, t, J = 7. 0H
z), 1.43 (1H, m), 1.77 (3H, m),
1.86 (1H, m), 1.92 (1H, m), 2.0
5 to 2.07 (1H, m), 2.13 to 2.16 (2
H, m), 2.25 to 2.28 (1H, m), 2.49
~ 2.54 (4H, m), 2.90 to 2.92 (2H,
m), 3.12-3.26 (2H, m), 3.29-
3.35 (4H, m), 3.62 (4.5H, s),
3.81 (2H, d, J = 6.0 Hz), 4.03 to
4.09 (1H, q, J = 7.0Hz), 7.07 (2
H, d, J = 9.0 Hz), 7.75 (2H, d, J =
9.5 Hz), 8.22 (1 H, m), 8.69 (2
H, s), 8.98 (2H, s).

Example 16 Ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-phenylcarbamoylethyl) -1-piperidine acetate monohydrochloride Raw material compound: ethyl 4- [4- (4-cyanophenyl) -1-piperazinyl] -3- (2-phenylcarbamoyl-ethyl) -1-piperidineacetate elemental analysis (as _{C 29 H 40 N 6 O 3} · 1.5HCl · 1.4H 2 O) C (%) H (%) N (%) Cl (%) Theoretical value 58.00 7.43 13.99 8.85 Experimental value 58.12 7.33 13.78 9.02 Mass spec value (m / z): FAB (Pos) 521 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.20 (3H, t, J = 7.0Hz), 1.43
~ 1.44 (1H, m), 1.75 to 1.77 (1H,
m), 1.87 to 1.99 (5H, m), 209 to 2.
17 (2H, m), 2.28 to 2.31 (1H, m),
2.45 to 256 (4H, m), 2.88 to 2.90
(1H, m), 2.93 to 2.95 (1H, m), 3.
13 (1H, d, J = 16.5Hz), 3.24 (1
H, d, J = 16.5 Hz), 3.29 to 3.31 (4
H, m), 4.09 (2H, q, J = 6.8 Hz),
7.02 to 7.04 (3H, m), 7.27 to 7.30
(2H, m), 7.60 (2H, d, J = 8.0H
z), 7.74 (2H, d, J = 9.0 Hz), 8.6
7 (2H, s), 8.97 (2H, s), 9.91 (1
H, s).

Example 17 Ethyl 3- (2-amidinoethyl) -4- [4- (4
-Amidinophenyl) -1-piperazinyl] -1-piperidine acetate dihydrochloride (500 mg) in ethanol 20
Dissolve in 3 ml and add 1N aqueous sodium hydroxide solution 3
ml was added, and the mixture was stirred at room temperature for 5 hours. 3 ml of 1N hydrochloric acid was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. 3 ml of 1N hydrochloric acid was added to the reaction solution, the solvent was distilled off, and the residue was subjected to ODS column chromatography (eluent, water → water: methanol =
95: 5) and purified by 3- (2-amidinoethyl)-
150 mg of 4- [4- (4-amidinophenyl) -1-piperazinyl] -1-piperazineacetic acid dihydrochloride were obtained.

Mass spectrometric value (m / z): FAB (Pos)
416 (M ⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 2.09~2.40 (3H, m ), 2.80~2.
84 (1H, m), 3.19 (3H, brs), 3.8
7 (1H, d), 4.12 (3H, brs), 7.18
(2H, d), 7.85 (2H, d), 8.84 (2
H, brs), 8.94 (2H, brs), 9.16
(2H, brs), 9.29 (2H, brs).

Example 18 The same procedure as in Example 17 was repeated except that the starting materials of Example 17 were used and the product was purified by ODS column chromatography to give 4- [4- (4-
Amidinophenyl) -1-piperazinyl] -3- (2-
Carbamoylethyl) -1-piperazineacetic acid monohydrochloride Mass spec (m / z): FAB (Pos) 417 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.77 to 2.33 (5H, m), 3.01 (1
H, d), 6.68 (1H, brs), 7.09 (2
H, d), 7.24 (1H, brs), 7.74 (2
H, d), 8.63 (2H, brs), 8.97 (2
H, brs).

Example 19 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- [2- (2-pyridyl) ethyl] -1-piperidineacetic acid dihydrochloride Raw material compound: ethyl 4- [ 4- (4-amidinophenyl) -1-piperazinyl] -3- [2- (2-pyridyl) ethyl] -1-piperidine acetate Mass spec (m / z): FAB (Pos) 451 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.53 to 1.56 (1H, m), 1.82 (1
H, d), 1.92 to 1.97 (2H, m), 2.09
(1H, brs), 2.29 (1H, d), 2.35
(1H, t), 2.50 to 2.51 (5H, m), 2.
66 to 2.72 (1H, m), 2.93 to 3.03 (2
H, m), 3.12 to 3.33 (7H, m), 7.05.
(2H, d), 7.19 (1H, dd), 7.27 (1
H, d), 7.68 to 7.71 (1H, m), 7.76
(2H, d), 8.48 (1H, d), 8.87 (2
H, brs), 9.01 (2H, brs).

Example 20 4- [4- (4-amidinophenyl) -1-piperazinyl] -1,3-piperidinediacetic acid monohydrochloride starting material compound: diethyl 4- [4- (4-amidinophenyl) -1- Piperazinyl] -1,3-piperidine diacetate monohydrochloride Mass spec (m / z): FAB (Pos) 404 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.56 (1H, d), 2.01 to 2.03 (1
H, m), 2.55 to 2.64 (6H, m), 2.82
(3H, brs), 3.20 (2H, brs), 7.1
1 (2H, d), 7.76 (2H, d), 8.87 (2
H, brs), 8.97 (2H, brs).

Example 21 4- [4- (4-amidinophenyl) -1-piperazinyl] -3-carboxy-1-piperidineacetic acid monohydrochloride Raw material compound: ethyl 4- [4- (4-amidinophenyl)- 1-piperazinyl] -3-methoxycarbonyl-
1-piperidine acetate monohydrochloride Mass spec (m / z): FAB (Pos) 390 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 7.08 to 7.13 (2H, m), 7.75 to 7.
81 (2H, m), 8.75 (2H, brs), 9.0
1 (2H, d).

Example 22 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-phenylsulfonylethyl) -1-piperidineacetic acid monohydrochloride Raw material compound: ethyl 4- [4- ( 4-amidinophenyl) -1-piperazinyl] -3- (2-phenylsulfonylethyl) -1-piperidine acetate monohydrochloride Mass spec (m / z): FAB (Pos) 514 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 7.09 (2H, brs), 7.66 to 7.69
(2H, m), 7.73 to 7.80 (3H, m), 7.
93 (2H, d), 8.84 (2H, brs), 9.0
6 (2H, brs).

Example 23 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-carboxyethyl) -1-piperidinepropionic acid monohydrochloride Raw material compound: ethyl 4- [4- ( 4-amidinophenyl) -1-piperazinyl] -3- (2-ethoxycarbonylethyl) -1-piperidine propionate monohydrochloride Mass spec (m / z): FAB (Pos) 432 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.70 to 1.72 (1H, m), 1.88 to 2.
00 (2H, m), 2.39 to 2.46 (3H, m),
2.80 (2H, t), 2.93 to 3.04 (3H,
m), 7.20 (2H, d), 7.81 (2H, d),
8.93 (2H, brs), 9.05 (2H, br)
s).

Example 24 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (3-hydroxypropyl) -1-piperidineacetic acid monohydrochloride Raw material compound: ethyl 4- [4- (4 -Amidinophenyl) -1-piperazinyl] -3- (3-hydroxypropyl) -1-piperidine acetate monohydrochloride Mass spec (m / z): FAB (Pos) 404 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.36 to 1.39 (1H, m), 1.56 (1
H, brs), 1.64 to 1.66 (2H, m), 1.
96 (1H, d), 2.06 (1H, brs), 3.1
1 (1H, brs), 7.11 (2H, d), 7.79
(2H, d), 8.84 (2H, brs), 9.05
(2H, brs).

Example 25 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-benzylcarbamoylethyl) -1-
Piperidine acetic acid raw material compound: ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-benzylcarbamoylethyl) -1-piperidine acetate monohydrochloride Mass spec (m / z): FAB (Pos) 507 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d _6, TMS internal standard) δ: 1.36~1.42 (1H, m ), 1.69 (1
H, m), 1.81 (3H, m), 1.90 (1H,
m), 1.96 to 1.98 (1H, m), 2.03 (1
H, m), 2.15 (1H, m), 2.31 (1H,
m), 2.47 to 2.50 (4H, m), 2.73 to
2.81 (2H, m), 2.94 (1H, m), 3.0
3 to 3.05 (1H, m), 3.30 (4H, m),
4.25 (2H, d, J = 5.0Hz), 7.03 (2
H, d, J = 10.0 Hz), 7.19 to 7.31 (5
H, m), 7.71 (2H, d, J = 10.0Hz),
8.40 (1H, m).

Example 26 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-methylcarbamoylethyl) -1-piperidineacetic acid Raw material compound: product of Example 14 Mass spectrum ( m / z): FAB (Pos) 431 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ + TFA, TM
S internal standard) δ: 1.76 (1H, m), 1.99 to 2.05 (2
H, m), 2.30 to 2.31 (1H, m), 2.41
~ 2.51 (4H, m), 2.60 to 2.61 (3H,
s), 3.03 to 3.05 (1H, m), 3.09 to
3.13 (1H, m), 3.55 (2H, m), 3.7
1 to 3.74 (1H, m), 4.07 to 4.19 (4
H, m), 7.22 (2H, d, J = 10.0Hz),
7.81 (2H, d, J = 10.0Hz), 7.94-
7.95 (1H, m), 8.88 (2H, s), 9.0
4 (2H, s).

Example 27 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-carboxymethylcarbamoylethyl) -1-piperidineacetic acid Raw material compound: product of Example 15 Elemental analysis value _{(C 23 H 34 N 6 O} 5 · 1.9H as _{2 O) C (%) H} (%) N (%) theoretical values 54.30 7.49 16.52 Found 54.30 7.42 16. 52 Mass spectrometry value (m / z): FAB (Pos) 475 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ + TFA, TM
S internal standard) δ: 1.76 (1H, m), 1.98 (2H, m),
2.37 (2H, m), 2.45 (2H, m), 2.9
7 (3H, m), 3.47 to 3.49 (1H, m),
3.66-3.68 (2H, m), 3.72-3.82
(2H, m), 3.99 to 4.05 (4H, m), 7.
20 (2H, d, J = 5.0Hz), 7.80 (2H,
d, J = 5.0 Hz), 8.38 (1H, m), 8.8
5 (2H, s), 9.03 (2H, s).

Example 28 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-phenylcarbamoylethyl) -1-
Piperidine acetic acid raw material compound: ethyl 4- [4- (4-amidinophenyl) -1-piperazinyl] -3- (2-phenylcarbamoylethyl) -1-piperidine acetate monohydrochloride Mass spec (m / z): FAB (Pos) 493 (M
⁺ +1) Nuclear magnetic resonance spectrum (DMSO-d ₆ , TMS internal standard) δ: 1.44 (1H, m), 1.70 (1H, m),
1.85 (3H, m), 1.94 (3H, m), 2.2
6 (1H, m), 2.63 to 2.66 (1H, m),
2.82 to 2.85 (1H, m), 2.88 (1H,
m), 3.17 (1H, m), 6.97 to 7.03 (3
H, m), 7.24 to 7.27 (2H, m), 7.64
(2H, d, J = 10.0Hz), 7.70 (2H,
d, J = 10.0 Hz), 10.36 (1H, m).

Tables 1 to 4 show the chemical structural formulas of the compounds obtained in Examples 5 to 28.

[0168]

[Table 1]

[0169]

[Table 2]

[0170]

[Table 3]

[0171]

[Table 4]

Example 1-1 whose chemical structural formulas are listed below.
The compounds of 1 to 24 can be easily produced by substantially the same method as described in the above-mentioned examples or production methods, or by applying some modifications obvious to those skilled in the art to them.

[0173]

[Table 5]

[0174]

[Table 6]

[0175]

[Table 7]

 ─────────────────────────────────────────────────── ─── Continuation of front page (72) Inventor Tomihisa Kawasaki 1-18-5 Sengen, Tsukuba-shi, Ibaraki Prefecture 1-18-5 Palace Happiness 203 (72) Inventor Seiji Karai 378-1, Takaoka-cho, Hamamatsu-shi, Shizuoka Sky Hills Kaisei Nibankan 401 ( 72) Inventor Isao Yanagisawa 2-22-8 Shakujidaidai, Nerima-ku, Tokyo

Claims (1)

[Claims] 1. A piperazine derivative represented by the following general formula (I) or a salt thereof. Embedded image (The symbols in the above formula have the following meanings respectively. X ¹ : lower alkylene group, X ² : single bond or lower alkylene group, R ¹ , R ² : same or different, amidino group, hydroxyl group, aryl group , A heteroaryl group, a group represented by the formula —CONHR ³ , a group represented by the formula —SO _n R ⁴ , or a formula —COOR ⁵
A group represented by, R ^3: a hydrogen atom, a carboxyl group, or the formula -COOR ⁶
A lower alkyl group which may be substituted with a group represented by
Aryl group or aralkyl group, R ^4: aryl groups, R ^5, R ^6: identical or different, represent a hydrogen atom or an ester residue, n: 0, 1 or 2)