JPH09291081A - New 2,3-diketopiperazine derivative and its salt - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new 2,3-diketopiperazine derivative having a platelet aggregation-inhibiting action based on a glycoprotein IIb/IIIb receptor- antagonizing action and useful as a medicine for preventing and treating diseases relating to platelet aggregation, such as an antithrombotic agent. SOLUTION: A 2,3-diketopiperazine derivative of formula I (R<1> is amidino group which may be protected; R<2> is H, a carboxyl-protecting group; A is a lower alkyl which may be substituted; B is NH, etc.; Y is a lower alkylene which may be substituted; the broken line is a single bond or a double bond) or its salt. For example, 3-[[4-(4-amidinophenyl)-2,3-dioxopiperazin-1- yl]acetamide]-4-pentynic acid. The compound of formula I is obtained e.g. by a reaction scheme of formula II (R<1a> is protected amidino group; R<2a> is the same carboxy-protecting group as R<2> ; R<3> is H, a lower alkyl).

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention has the following general formula:

Embedded image "In the formula, R ¹ represents an amidino group which may be protected;
R ² is a hydrogen atom or a carboxyl protecting group; A is
An optionally substituted lower alkylene group; B is -N
H- or formula

Embedded image (In the formula, Z is a nitrogen atom or a carbon atom; n is 1 to
Indicates an integer of 3. ), Y represents an optionally substituted lower alkylene group; and broken lines represent a single bond or a double bond, respectively. New two or three represented by
-A diketopiperazine derivative or a salt thereof.

[0002]

BACKGROUND OF THE INVENTION Platelet aggregation plays an important role in thrombus formation and blood coagulation. When a blood vessel is damaged, platelets are activated by collagen or the like under the blood vessel, fibrinogen is bound to the platelet, that is, platelet aggregation occurs, and a thrombus is formed. The final step in the platelet aggregation process is the activation of the glycoprotein IIb / IIIa receptor on the platelet surface, which then binds fibrinogen. Therefore, glycoprotein IIb / IIIa
Inhibitors that prevent the binding of receptors to adhesion proteins such as fibrinogen are believed to be useful in preventing thrombus formation and blood coagulation.

When fibrinogen binds to the glycoprotein IIb / IIIa receptor, the amino acid sequence Arg-Gly-Asp-Ser on fibrinogen (hereinafter referred to as RGDS).
A portion is said to be its active site. for that reason,
As an antagonist of glycoprotein IIb / IIIa receptor,
RGDS analogs have been developed. Further, this is expected as a drug for suppressing metastasis of cancer cells.

[0004]

[Problems to be Solved by the Invention] As described above, peptide derivatives containing the amino acid sequence of Arg-Gly-Asp are known as antagonists. However, these are insufficient for use as pharmaceuticals in terms of oral absorbability and the like.

[0005]

[Means for Solving the Problems] Under these circumstances, as a result of intensive investigations, the present inventors have found that a novel 2,3-diketopiperazine derivative represented by the general formula [1] or a derivative thereof It was found that a salt has a platelet aggregation inhibitory action based on glycoprotein IIb / IIIa receptor antagonism, and is a compound useful as a prophylactic and therapeutic agent for diseases involving platelet aggregation such as antithrombotic agents. completed. Next, the present invention will be described in detail.

[0006]

BEST MODE FOR CARRYING OUT THE INVENTION In the present specification, unless otherwise specified, a halogen atom means a fluorine atom, a chlorine atom,
A bromine atom or an iodine atom; a lower alkyl group means, for example, a linear or branched chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl and hexyl. C _1-6 alkyl group; lower alkenyl group is, for example, C _1-6 alkenyl group such as vinyl, propenyl, butenyl; lower alkynyl group is, for example, C _1-6 such as ethynyl, propynyl, butynyl and the like. An alkynyl group; a lower alkylene group,
For example, methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, 1-methyltrimethylene, 1-ethyltriethylene, 1-isopropyltriethylene, 1,1-dimethyltrimethylene and 1,2-dimethyltrimethylene. the lower alkylenedioxy group, for example, a C _1-6 alkylenedioxy group such as methylenedioxy and ethylenedioxy; linear or branched C _1-6 alkylene group and a cycloalkyl group Is, for example, C _3-8 such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
A cycloalkyl group; an aryl group is, for example, a group such as a phenyl, tolyl and naphthyl group; a lower alkoxy group is a lower alkyl-O- group (lower alkyl is the above lower alkyl group). An aralkyl group is, for example, a group such as benzyl, benzhydryl, trityl and phenethyl; a heterocyclic group is, for example, furyl, pyrrolyl, imidazolyl, pyrazolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyridyl,
Piperidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, piperazinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, flazanyl, morphonylyl, furanyl, thienyl, pyranyl, thiopyranyl, benzothienyl, benzoimidazolyl, indolyl, benzothiadiazolyl, benzimidazolyl, benzimidazolyl. It means a 5-membered, 6-membered or condensed ring heterocyclic group containing one or more heteroatoms selected from oxygen, sulfur and nitrogen atoms as the heteroatoms constituting the ring such as naphthyridinyl and chromanyl. .

The lower alkylene group of Y is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a lower alkoxy group, a cycloalkyl group, an aryl group, an aralkyl group, a heterocyclic group, a carbamoyl group, or even if protected. It may be substituted with one or more groups selected from a good amino group, an optionally protected hydroxyl group, and an optionally protected carboxyl group. Further, the above-mentioned substituent of Y is further a halogen atom, a lower alkyl group, a lower alkoxy group, an optionally protected hydroxyl group,
It may be substituted with one or more groups selected from a lower alkylenedioxy group and an aralkyl group. The lower alkylene group of A is a lower alkyl group, a lower alkoxy group,
It may be substituted with one or more groups selected from a cycloalkyl group, an aryl group, an aralkyl group, a heterocyclic group and an optionally protected hydroxyl group. Further, the above-mentioned substituent of A may be further substituted with one or more groups selected from a halogen atom, a lower alkyl group, a lower alkoxy group, an optionally protected hydroxyl group and an aralkyl group. .

The protecting group for a carboxyl group includes all groups which can be used as a usual protecting group for a carboxyl group, for example, methyl, ethyl, n-propyl, iso-propyl, 1,1-dimethylpropyl, n. -Butyl and te
lower alkyl groups such as rt-butyl; aryl groups such as phenyl and naphthyl; benzyl, diphenylmethyl,
Aralkyl groups such as triphenylmethyl, p-nitrobenzyl, p-methoxybenzyl and bis (p-methoxyphenyl) methyl; acetylmethyl, benzoylmethyl,
lower alkyl groups substituted with an acyl group such as p-nitrobenzoylmethyl, p-bromobenzoylmethyl and p-methanesulfonylbenzoylmethyl; oxygen-containing heterocyclic groups such as 2-tetrahydropyranyl and 2-tetrahydrofuranyl; 2 Lower alkyl group substituted with halogen atom such as 1,2,2-trichloroethyl; lower alkylsilyl lower alkyl group such as 2- (trimethylsilyl) ethyl; acyloxy group such as acetoxymethyl, propionyloxymethyl and pivaloyloxymethyl A lower alkyl group substituted with nitrogen; a lower alkyl group substituted with a nitrogen-containing heterocyclic group such as phthalimidomethyl and succinimidomethyl; a cycloalkyl group such as cyclohexyl; methoxymethyl, methoxyethoxymethyl and 2
A lower alkyl group substituted with a lower alkoxy group such as-(trimethylsilyl) ethoxymethyl; a lower alkyl group substituted with an aralkyloxy group such as benzyloxymethyl; a lower alkylthio group such as methylthiomethyl and 2-methylthioethyl Lower alkyl group substituted with an arylthio group such as phenylthiomethyl; a lower alkenyl group such as 1,1-dimethyl-2-propenyl, 3-methyl-3-butynyl and allyl; and trimethylsilyl, triethyl Silyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-
Substituted silyl groups such as butyl methoxyphenyl silyl and the like can be mentioned.

The protecting group for the amidino group, amino group and imino group includes all groups which can be used as usual amino protecting groups, and examples thereof include trichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl and p-nitro. Benzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-, tri-) chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl, benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl, p-
Methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4- (phenylazo) benzyloxycarbonyl, 2-furfuryloxycarbonyl, diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl,
Acyl groups such as phthaloyl, succinyl, alanyl, leucyl, 1-adamantyloxycarbonyl and 8-quinolyloxycarbonyl; aralkyl groups such as benzyl, diphenylmethyl and trityl; 2-nitrophenylthio and 2,4-dinitrophenylthio Arylthio groups such as methanesulfonyl; arylsulfonyl groups such as p-toluenesulfonyl; lower alkylidene groups substituted with di-lower alkylamino such as N, N-dimethylaminomethylene; benzylidene, 2-hydroxy Benzylidene, 2-hydroxy-5-chlorobenzylidene and 2-hydroxy-
1-Alkylidene group such as naphthylmethylene; 3-
Nitrogen-containing heterocyclic alkylidene group such as hydroxy-4-pyridylmethylene; cyclohexylidene, 2-ethoxycarbonylcyclohexylidene, 2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene and 3,3-dimethyl-5. A cycloalkylidene group such as oxycyclohexylidene; a di-arylphosphoryl group such as diphenylphosphoryl; a di-alkylalkylphosphoryl group such as dibenzylphosphoryl; 5-methyl-2-oxo-2H-1,3-dioxole-4 And oxygen-containing heterocyclic alkyl groups such as -yl-methyl; and substituted silyl groups such as trimethylsilyl.

The hydroxyl-protecting group includes all groups which can be used as a usual hydroxyl-protecting group, for example, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 4-methoxybenzyl. Oxycarbonyl,
3,4-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, 2- (trimethylsilyl) ethoxycarbonyl, 2- (phenylsulfonyl) ethoxycarbonyl, 2- (triphenylphosphonyl) ethoxycarbonyl, 2-furfuryloxycarbonyl, 1-adamantyloxy Carbonyl, vinyloxycarbonyl, allyloxycarbonyl, S-benzylthiocarbonyl, 4-
Acyl groups such as ethoxy-1-naphthyloxycarbonyl, 8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pivaloyl and benzoyl; methyl, tert- Lower alkyl groups such as butyl, 2,2,2-trichloroethyl and 2-trimethylsilylethyl; lower alkenyl groups such as allyl; benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, aralkyl such as diphenylmethyl and trityl Groups; oxygen-containing and sulfur-containing heterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl and tetrahydrothiopyranyl; methoxymethyl, methylthiomethyl, benzyloxymethyl,
Lower alkyl groups substituted with lower alkoxy and lower alkylthio groups such as 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, 2- (trimethylsilyl) ethoxymethyl and 1-ethoxyethyl; alkylsulfonyl such as methanesulfonyl Groups; arylsulfonyl groups such as p-toluenesulfonyl; and such as trimethylsilyl, triethylsilyl, triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, diphenylmethylsilyl and tert-butylmethoxyphenylsilyl Examples thereof include a substituted silyl group.

As the salt of the compound of the general formula [1], there may be mentioned a salt of a generally known basic group such as amino group or acidic group such as carboxyl group. Examples of the salt in the basic group include salts with mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid; tartaric acid, formic acid, acetic acid, fumaric acid, maleic acid, citric acid, trichloroacetic acid and trifluoroacetic acid. Salts with organic carboxylic acids such as; and methanesulfonic acid, benzenesulfonic acid,
Salts with sulfonic acids such as p-toluene sulfonic acid, mesitylene sulfonic acid and naphthalene sulfonic acid, also,
Examples of the salt in the acidic group include salts with alkali metals such as sodium and potassium; salts with alkaline earth metals such as calcium and magnesium; ammonium salts; and trimethylamine, triethylamine,
Tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine, procaine,
Examples thereof include salts with nitrogen-containing organic bases such as dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N, N′-dibenzylethylenediamine, guanidine, hydrazine, quinine and cinchonine. Of the above-mentioned salts, pharmacologically acceptable salts are preferable as the salt of the compound of the general formula [1]. When isomers (for example, optical isomers, geometric isomers and tautomers) exist in the compound of the general formula [1] or a salt thereof, the present invention includes those isomers and includes a solvent. It includes hydrates, hydrates and crystals of various shapes.

Among the compounds of the present invention, B is --NH-; A
Is a lower alkylene group; R ¹ is an amidino group; the broken line is a single bond; Y is an optionally substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cycloalkyl, aryl, aralkyl, heterocyclic , A carbamoyl or amino group or a lower alkylene group which may be substituted with one or more groups selected from optionally protected amino, hydroxyl or carboxyl groups, particularly Y is a lower alkynyl group. Alternatively, a compound having a lower alkylene group substituted with a 5- or 6-membered heterocyclic group is preferable.

Among the compounds of the present invention, as typical compounds,
For example, the following compounds may be mentioned. 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -4-pentenoic acid 3-[[4- (4-amidinophenyl) -2,3 -Dioxopiperazin-1-yl] acetamido] -4-butenoic acid 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] butyric acid 3-[[ 4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamide] -3-
(Pyridin-3-yl) propionic acid 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamide] -3-
(Pyridin-4-yl) propionic acid 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamide] -3-
(Pyridin-2-yl) propionic acid 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamide] -3-
(Thiophen-2-yl) propionic acid 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -3-phenylpropionic acid

3-[[4- (4-amidinophenyl)
-2,3-Dioxopiperazin-1-yl] acetamido] -3- (4-fluorophenyl) propionic acid 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazine-1- Il] acetamide] -3-
(3-Methoxyphenyl) propionic acid-3- [3- [4- (4-amidinophenyl) -2,3
-Dioxopiperazin-1-yl] propionamide]
-4-Pentenoic acid 3- [3- [4- (4-amidinophenyl) -2,3
-Dioxopiperazin-1-yl] propionamide]
-4-butenoic acid 3- [3- [4- (4-amidinophenyl) -2,3
-Dioxopiperazin-1-yl] propionamide]
Butyric acid- [4-[[4- (4-amidinophenyl) -2,3-
Dioxopiperazin-1-yl] acetyl] piperazin-1-yl] acetic acid. [1-[[4- (4-amidinophenyl) -2,3-
Dioxopiperazin-1-yl] acetamido] piperidin-4-yl] acetic acid

Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be synthesized, for example, by the route shown below.

[0016]

(Equation 1)

[Wherein R ^1a represents a protected amidino group; R ^2a represents a carboxyl protecting group similar to R ² ; R ³
Is a hydrogen atom, lower alkyl; R ¹ , A, B, Y,
Z, n and the broken line have the same meaning as described above. "

(Production Method) The compound of the general formula [1a] is a compound of the general formula [3] or a reactive derivative of the amino group thereof, or a compound of the general formula [4] or a reactive derivative of the imino group thereof. It can be produced by reacting with the compound of the formula [2] or its reactive derivative at the carboxyl group.

Examples of the reactive derivative at the carboxyl group of the compound of the general formula [2] include acid halides, acid anhydrides, activated amides and activated esters.
Suitable examples of the reactive derivative include acid chloride; acid azide; acid (for example, dialkylphosphoric acid such as dimethylphosphoric acid and diethylphosphoric acid; diphenylphosphoric acid; phosphorus halide such as phosphorus oxychloride and phosphorus pentachloride). Acids; dialkyl phosphites such as dimethyl phosphite and diethyl phosphite; sulfonic acids such as sulphite, thiosulfuric acid, sulfuric acid and methane sulfonic acid; Aromatic carboxylic acids such as benzoic acid; mixed acid anhydrides with monoethyl carbonic acid, monoalkyl carbonic acid such as monoisobutyl carbonic acid); symmetrical acid anhydrides; imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H-benzotriazole Activated amide with; cyanomethyl ester, methoxymethyl ester , Vinyl esters, propargyl esters, p- nitrophenyl ester, 2,4
Dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, phenylthioester, p-nitrophenyl ester, pyranyl ester,
Pyridyl esters, activated esters such as 8-quinolylthioester; and esters with N-hydroxy compounds such as N, N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxy-1H-benzotriazole and the like. These reactive derivatives can be arbitrarily selected from among them depending on the kind of the compound of the general formula [2] used.

Suitable reactive derivatives at the amino group or imino group of the compound of general formula [3] or general formula [4] include compounds of general formula [3] or general formula [4] and aldehydes, ketones and the like. A Schiff base type imino group or an enamine type tautomer formed by the reaction with a carbonyl compound; a compound of the general formula [3] or [4] and bis (trimethylsilyl) acetamide, mono (trimethylsilyl) acetamide, bis A silyl derivative formed by reaction with a silyl compound such as (trimethylsilyl) urea; general formula [3] or general formula [4]
And a derivative formed by the reaction of the compound of (3) with phosphorus trichloride or phosgene.

The solvent used in this reaction may be any solvent which does not adversely affect the reaction, for example, water; ketones such as acetone; alcohols such as methanol and ethanol; aroma such as benzene, toluene and xylene. Group hydrocarbons; ethers such as dioxane, tetrahydrofuran, anisole, diethylene glycol diethyl ether and dimethyl cellosolve; nitriles such as acetonitrile; amides such as N, N-dimethylformamide and N, N-dimethylacetamide; methylene chloride, chloroform And halogenated hydrocarbons such as 1,2-dichloroethane; esters such as ethyl acetate; and heteroaromatics such as pyridine. These solvents may be used alone or in combination of two or more. hand Good.

In this reaction, when the compound of the general formula [2] is used in a free acid form, N, N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morphonylethylcarbodiimide; N-cyclohexyl-
N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide; N, N'-diisopropylcarbodiimide;N-ethyl-N'-(3
-Dimethylaminopropyl) carbodiimide; N, N'-
Carbonylbis (2-methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethyl; trialkylphosphorous acid; polyphosphoric acid ethyl ester; polyphosphoric acid Isopropyl ester; phosphorus oxychloride; phosphorus trichloride; thionyl chloride; oxalyl chloride; halogenated formic acid alkyl ester such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2
-Ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H -Benzotriazole; N, N-dimethylformamide and thionyl chloride, phosgene, chloroformic acid trichloromethyl ester,
The reaction is preferably carried out in the presence of a conventional condensing agent such as the so-called Vilsmeier reagent prepared by the reaction of phosphorus oxychloride and methanesulfonyl chloride.

Further, this reaction is carried out by sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, triethylamine,
N-methylmorpholine, diisopropylethylamine and 1,8-diazabicyclo- [5.4.0] undec-
It may be carried out in the presence of an inorganic or organic base such as 7-ene (DBU). The amount of the compound of the general formula [3] or [4] to be used is, relative to the compound of the general formula [2],
It is 1 to 20 times mol, preferably 1 to 3 times mol. These reactions are usually performed at -50 to 150 ° C, preferably at -30 to 100 ° C.
It may be carried out for 1 minute to 24 hours.

In the production method described above, the compounds of the general formulas [2], [3] and [4] and the general formula [2],
As the reactive derivative of the compound [3] or [4], a salt thereof can be used, and examples of the salt include the same as those described as the salt of the compound of the general formula [1]. Further, the compound of the general formula [1a] can be converted into a salt, and as the salt, the same salts as those described in the general formula [1] can be mentioned.

The compound of the general formula [1a] or a salt thereof thus obtained can be converted to the compound of the general formula [1] or a salt thereof by subjecting to a commonly known elimination reaction. Furthermore, the compound of the general formula [1] or a salt thereof is subjected to a known reaction such as oxidation, reduction, rearrangement, substitution, halogenation, dehydration or hydrolysis, or a combination thereof is appropriately used. Thus, the compound of the general formula [1] or a salt thereof can be derived.

Next, a method for producing the compound of the general formula [2] which is a raw material for producing the compound of the present invention will be explained. The compound of general formula [2] can be synthesized, for example, by the following production route.

[0027]

(Equation 2)

"Wherein R ⁴ is an imino protecting group; R ⁵ is
A carboxyl protecting group; X represents a leaving group; R ¹ ,
R ^1a , A and the broken line have the same meaning as described above. Examples of the imino protecting group include 2,4-dimethoxybenzyl group, trityl group and dimethyl tert-butylsilyl group, and examples of the leaving group include halogen atom, methanesulfonyl group and p-toluenesulfonyl group. Can be mentioned.

Next, each step will be described. (Production method) A compound of the general formula [5] is combined with sodium hydride,
A compound of the general formula [6] is obtained by reacting a compound of the general formula [6] in the presence of a base such as potassium tert-butoxide or potassium carbonate, and then a compound of the general formula [7] is prepared. [7] compound is reacted with hydrogen chloride in alcohol such as methanol or ethanol and then reacted with ammonium chloride, ammonium acetate or ammonia, etc. (b) In pyridine, the compound of general formula [7] is converted into hydrogen sulfide. And a base such as triethylamine to give a thioamide, which is methylated with methyl iodide in acetone and then reacted with ammonium acetate to convert the nitrile group into an amidino group, followed by deprotection of a known protecting group. By subjecting to a leaving reaction and further protecting the amidino group by a known method, the compound of the general formula [9]
Can be obtained.

Then, the compound of the general formula [9] is reacted with the compound of the general formula [10] or the general formula [11] in a polar solvent such as N, N-dimethylformamide in the presence of a general formula. The compound of [2a] is obtained. Examples of the base used in this reaction include potassium tert-butoxide, DBU, potassium carbonate and the like. Furthermore, the compound of the general formula [2] can be obtained by subjecting it to a known elimination reaction of a protecting group.

The compound of the general formula [5] is, for example,
It can be synthesized according to the method described in Pharmaceutical Journal, Vol. 99, No. 9, 929-935 (1979) and Japanese Examined Patent Publication No. 3-57913.

As described above, the general formula [1
a], [2], [2a], [3], [4], [5],
[6], [7], [8], [9], [10] and [1
1) [1] or salts thereof, if isomers (for example, optical isomers, geometric isomers and tautomers) exist, these isomers can be used, and solvates, hydrates And crystals of various shapes can be used.

Further, the general formulas [1a], [2] and [2]
a], [3], [4], [8], [9], [10] and [11] or a salt thereof has an amino group, an imino group, an amidino group, a carboxyl group or a hydroxyl group. In the compound, these groups can be previously protected with an ordinary protecting group, and after the reaction, these protecting groups can be removed by a method known per se. The compound of the general formula [1] or a salt thereof thus obtained is extracted,
It can be isolated and purified by a conventional method such as crystallization and / or column chromatography.

When the compound of the present invention is used as a medicine, excipients, carriers and diluents which are usually used for formulation may be appropriately mixed, and these may be used in the form of tablets or capsules according to a conventional method. It can be administered orally or parenterally in the form of a preparation, powder, syrup, granule, pill, suspension, emulsion, liquid, powder preparation, suppository, ointment or injection. In addition, the administration method, dose and frequency of administration can be appropriately selected according to the age, body weight and symptoms of the patient, and usually, for adults, oral or parenteral (for example, injection, infusion and rectal site administration). Daily administration), and 0.1 to 1000 mg may be divided into one to several divided doses and administered daily.

Next, the pharmacological action of the representative compounds of the present invention will be explained. (1) Inhibitory action on human platelet aggregation Blood: Blood collected from human cubital vein at 3.8% sodium citrate solution = 9: 1 (V / V) was centrifuged at room temperature to obtain platelet rich plasma and platelet poor plasma. Got Then
Platelet-rich plasma diluted with platelet-poor plasma to obtain a platelet count of 5 x 1
0 was adjusted to ⁸ / ml. 18.75 μl of the test drug dissolved in physiological saline was added to 150 μl of the adjusted platelet-rich plasma, and the mixture was stirred and kept warm at 37 ° C. After 3 minutes 18.75 μl of adenosine-5′-diphosphate (ADP) (final concentration:
3 μM) was added, and changes in transmitted light intensity caused by the aggregation were recorded with an aglycometer over time. The 50% inhibitory concentration (IC ₅₀ ) was defined as the concentration of the test drug showing 50% aggregation when the aggregation when only physiological saline was added was 100%. Table 1 shows the results.

[0036]

[Table 1] ------------------ Example No. 50% Inhibitory concentration (μM) ------------------ 0.53 14 0.32 16 0.35 17 1.50 19 0.92 20 0.48 −−−−−−−−−−−−−−−−

[0037]

EXAMPLES Next, the present invention will be explained with reference to reference examples and examples, but the present invention is not limited thereto. The mixing ratios in the eluent are all volume ratios, and the carrier in column chromatography is
Silica gel 60, 70 to 230 mesh (manufactured by Merck), and LC-SORB SP-B-ODS (manufactured by Chemco) was used as a carrier in reverse phase column chromatography. The symbols used in Reference Examples and Examples have the following meanings. d ₁ -TFA: deuterated trifluoroacetic acid d ₆ -DMSO: deuterated dimethylsulfoxide Et: ethyl t-Bu: tert-butyl DPM: diphenylmethyl Boc: tert-butoxycarbonyl Bz: benzyl

Reference Example 1 1- (4-cyanophenyl) -4- (2,4-dimethoxybenzyl) -2,3-dioxopiperazine 1- (2,4-dimethoxybenzyl) -2,3-di 51.3 g of oxopiperazine, 150 ml of N, N-dimethylformamide
And sodium hydride (60%, w / w,
(Oiliness) 8.54 g is added and stirred at 50 ° C for 30 minutes. Then 4
-Add 23.5 g of fluorobenzonitrile and stir at 100 ° C for 8 hours. The reaction solution is cooled to room temperature, poured into a mixture of 700 ml of water and 100 ml of toluene, and stirred at room temperature for 1 hour.
The precipitated crystals are collected by filtration, washed with water and toluene, and dried to give colorless crystals of 1- (4-cyanophenyl) -4.
52.7 g of-(2,4-dimethoxybenzyl) -2,3-dioxopiperazine are obtained. IR (KBr) cm ^-1 : ν _{C = O} 1695,1665 NMR (CDCl ₃ ) δ value: 3.4-4.3 (4H, m), 3.80 (3H, s), 3.82 (3H,
s), 4.66 (2H, s), 6.3-6.6 (2H, m), 7.1-7.9 (5H, m)

Reference Example 2 1- (4-amidinophenyl) -2,3-dioxopiperazine trifluoroacetate salt 1- (4-cyanophenyl) -4- (2,4-dimethoxybenzyl) -2, 20 g of 3-dioxopiperazine are suspended in 60 ml of ethanol and hydrogen chloride gas is bubbled through at 0-5 ° C. until it is saturated. After standing overnight at room temperature, the solvent is distilled off under reduced pressure. The obtained residue is dissolved in 120 ml of ethanol, 40 ml of 4.4N ammonia / ethanol solution is added, and the mixture is heated under reflux for 3 hours. The reaction solution is cooled to room temperature, the insoluble matter is filtered off, and the filtrate is concentrated under reduced pressure. The obtained solid is dissolved in 23 ml of anisole and 92 ml of trifluoroacetic acid and heated under reflux for 7 hours. Then, the solvent is distilled off under reduced pressure, 200 ml of ethyl acetate is added to the residue, and the mixture is stirred at room temperature for 1 hour. The precipitated crystals are collected by filtration and dried to give 19 g of 1- (4-amidinophenyl) -2,3-dioxopiperazine trifluoroacetate as pale yellow crystals. IR (KBr) cm ^-1 : ν _{C = O} 1685 NMR (d ₁ -TFA) δ value: 3.7-4.6 (4H, m), 7.73 (2H, d, J = 9Hz), 8.0
1 (2H, d, J = 9Hz)

Reference Example 3 1- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazine 1- (4-amidinophenyl) -2,3-dioxopiperazine trifluoroacetate (22 g) It is dissolved in a mixed solution of 100 ml of dioxane and 220 ml of water, 17.6 g of potassium carbonate and 14.5 g of di-tert-butyl dicarbonate are added, and the mixture is stirred at room temperature overnight. The reaction solution was adjusted to pH 7 with 2N hydrochloric acid, concentrated under reduced pressure to about half volume, and then 50 ml of chloroform was added. After stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration, washed successively with water and chloroform, and dried to give colorless crystals of 1- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazine. I get 15.5g. IR (KBr) cm ^-1 : ν _{C = O} 1720,1685 NMR (d ₆ -DMSO) δ value: 1.47 (9H, s), 3.2-4.3 (4H, m), 7.55 (2H,
d, J = 8Hz), 8.05 (2H, d, J = 8Hz), 8.7-9.3 (3H, m)

Reference Example 4 [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] acetic acid benzyl ester 1- (4-tert-butoxycarbonylamidinophenyl) -2 4.0 g of 3,3-dioxopiperazine was suspended in 40 ml of N, N-dimethylformamide, 2.02 g of potassium tert-butoxide and 2.68 ml of benzyl bromoacetate were added to this solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution is poured into a mixed solution of 200 ml of water and 50 ml of ethyl acetate, and the mixture is stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration, washed with water and ethyl acetate, and dried to give colorless crystals of [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] benzyl acetate. 3.7 g of ester are obtained. IR (KBr) cm ^-1 : ν _{C = O} 1755,1680 NMR (d ₆ -DMSO) δ value: 1.47 (9H, s), 3.6-4.3 (4H, m), 4.40 (2H,
s), 5.24 (2H, s), 7.1-7.8 (7H, m), 8.06 (2H, d, J = 8Hz), 9.06
(2H, brs)

Reference Example 5 3- [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl]
Propionic acid diphenylmethyl ester 1- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazine 1.1 g N, N-dimethylformamide 20 ml suspension containing acrylic acid diphenylmethyl ester 1.2 g and 1, 8-diazabicyclo [5.
4.0] Undec-7-ene (DBU) (0.26 g) was added, the mixture was stirred at room temperature for 2 hours, and then diluted with 20 ml of ethyl acetate. The precipitated crystals are collected by filtration, washed with ethyl acetate and dried,
Colorless crystals of 3- [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazine-1
-Yl] propionic acid diphenylmethyl ester 1.3 g is obtained. IR (KBr) cm ^-1 : ν _{C = O} 1730,1675 NMR (d ₆ -DMSO) δ value: 1.46 (9H, s), 2.7-3.0 (2H, m), 3.5-4.0
(6H, m), 6.83 (1H, s), 7.2-7.6 (12H, m), 8.00 (2H, d, J = 8.5H
z), 9.00 (2H, brs)

Reference Example 6 [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] acetic acid [4- (4-tert-butoxycarbonylamidinophenyl) -2, 3-Dioxopiperazin-1-yl] acetic acid benzyl ester (3.14 g) was added to N, N-dimethylformamide 63
Dissolve in 0.5 ml, add 0.5 g of 5% palladium carbon to this solution, and hydrogenate at room temperature and atmospheric pressure for 2 hours. After completion of the reaction, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. Ethyl acetate (10 ml) was added to the obtained residue, and the crystals were collected by filtration to give [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] acetic acid as pale yellow crystals.
Get 2.3 g. IR (KBr) cm ^-1 : ν _{C = O} 1690,1680 NMR (d ₆ -DMSO) δ value: 1.46 (9H, s), 3.6-4.4 (6H, m), 7.3-8.5
(7H, m)

Reference Example 7 3- [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl]
Propionic acid In the same manner as in Reference Example 6, 3- [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] propionic acid diphenylmethyl ester was used to give 3- [4- ( 4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazine-1
-Yl] propionic acid is obtained. IR (KBr) cm ^-1 : ν _{C = O} 1745,1675

Example 1 Ethyl 3-[[4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -4-pentanoic acid [4- (4- tert-Butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] acetic acid 2.1
A solution of 4 g and 1.16 ml of N-methylmorpholine in 20 ml of N, N-dimethylformamide is cooled to -50 ° C, 0.66 ml of isobutyl chlorocarbonate is added, and the mixture is stirred at -30 ° C for 30 minutes. Then, 0.75 g of ethyl 3-amino-4-pentanoate hydrochloride is added to this reaction solution, and the mixture is stirred at -30 ° C for 30 minutes, slowly warmed to room temperature, and stirred at the same temperature for 1 hour. After completion of the reaction, the reaction solution is poured into a mixed solution of 50 ml of water and 50 ml of ethyl acetate. The organic layer is separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent; chloroform: acetone = 3:
If purified in 1), 3-[[4- (4-tert
1.62 g of ethyl butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -4-pentinate are obtained. IR (KBr) cm ^-1 : ν _{C = O} 1735,1675 NMR (CDCl ₃ ) δ value: 1.28 (3H, t, J = 7Hz), 1.53 (9H, s), 2.41 (1
H, d, J = 2Hz), 2.75 (2H, d, J = 7Hz), 3.6-4.4 (11H, m), 5.09 (1
H, d, t, J = 2Hz, J = 7Hz), 7.44 (2H, d, J = 8Hz), 7.91 (2H, d, J = 8H
z)

Examples 2 to 6 In the same manner as in Example 1, the compounds shown in Table 2 are obtained.

[0047]

[Table 2]

The compound names and physical properties shown in Table 2 are shown below. -No.2 3-[[4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl]
Acetamido] propionic acid diphenylmethyl ester IR (KBr) cm ^-1 : ν _{C = O} 1740,1680 NMR (d ₆ -DMSO) δ value: 1.46 (9H, s), 2.4-2.8 (4H, m), 3.2- 4.2
(6H, m), 6.83 (1H, s), 7.2-8.4 (16H, m), 8.9-9.2 (1H, m) ・ No.3 3-[[4- (4-tert-butoxycarbonylamidinophenyl) -2,3-Dioxopiperazin-1-yl]
Acetamide] -3-phenylpropionate ethyl IR (KBr) cm ⁻¹ : ν _{C = O} 1735,1675 NMR (CDCl ₃ ) δ value: 1.20 (3H, t, J = 7Hz), 1.55 (9H, s), 2.85 (2
H, d, J = 7Hz), 3.4-4.4 (8H, m), 5.2-5.7 (1H, m), 7.0-9.0 (12
H, m) ・ No.4 3-[[4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl]
Acetamide] -4 _- Pentenoic acid ethyl IR (KBr) cm ^-1 : ν _{C = O} 1735,1685 NMR (d ₆ -DMSO) δ value: 1.19 (3H, t, J = 7Hz), 1.47 (9H, s) , 2.60
(2H, d, J = 6Hz), 3.6-4.3 (8H, m), 4.6-6.3 (4H, m), 7.60 (2H,
d, J = 9Hz), 8.10 (2H, d, J = 9Hz), 9.10 (3H, brs) ・ No.5 3-[[4- (4-tert-butoxycarbonylamidinophenyl) -2,3-di Oxopiperazin-1-yl]
Acetamide] ethyl butyrate IR (KBr) cm ^-1 : ν _{C = O} 1735,1685 NMR (d ₆ -DMSO) δ value: 0.9-1.7 (7H, m), 1.53 (9H, s), 2.2-2.7
(2H, m), 3.5-4.6 (8H, m), 6.2-6.5 (1H, m), 7.4-8.5 (4H, m),
8.8-9.3 (2H, brs) -No.6 3- (S)-[[4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazine-1
-Yl] acetamide] -4 _- ethylpentanoate IR (KBr) cm ^-1 : ν _{C = O} 1735,1675

Example 7 3-[[4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -3- (pyridin-3-yl) propionic acid Ethyl [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] acetic acid 0.5
g is dissolved in 10 ml N, N-dimethylformamide. To this was added 0.18 g of N-hydroxysuccinimide and N, N '.
-Add 0.66 g of dicyclohexylcarbodiimide and stir at room temperature for 3 hours. To this reaction solution was added 0.25 g of ethyl 3-amino-3- (pyridin-3-yl) propionate,
After standing overnight at room temperature, the solvent is distilled off under reduced pressure. Chloroform (20 ml) is added to the obtained residue and the insoluble matter is filtered off. Then, 10 ml of water is added to the filtrate and the pH is adjusted to 8 with a saturated aqueous sodium hydrogen carbonate solution. The organic layer is separated, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 10: 1) to give 3-[[4
-(4-tert-butoxycarbonylamidinophenyl)
-2,3-Dioxopiperazin-1-yl] acetamido] -3- (pyridin-3-yl) propionate ethyl ester
I get 0.37g. IR (KBr) cm ^-1 : ν _{C = O} 1730,1680 NMR (d ₆ -DMSO) δ value: 1.14 (3H, t, J = 6Hz), 1.46 (9H, s), 2.4-
2.6 (2H, m), 3.3-4.5 (8H, m), 5.1-5.6 (1H, m), 7.3-8.2 (6H,
m), 8.4-9.3 (5H, m)

Examples 8 to 10 The compounds shown in Table 3 are obtained in the same manner as in Example 7.

[0051]

[Table 3]

The compound names and physical properties shown in Table 3 are shown below. -No.8 3- [3- [4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] propionamido] -3- (pyridin-3-yl)
Ethyl propionate IR (KBr) cm ^-1 : ν _{C = O} 1740,1685,1670 NMR (d ₆ -DMSO-D ₂ O) δ value: 1.22 (3H, t, J = 7Hz), 1.46 (9H, s ),
2.4-2.6 (2H, m), 2.91 (2H, d, J = 8Hz), 3.2-4.4 (8H, m), 5.1-
5.4 (1H, m), 7.2-8.2 (6H, m), 8.4-8.7 (2H, m) ・ No.9 1-[[4- (4-tert-butoxycarbonylamidinophenyl) -2,3-di Oxopiperazin-1-yl]
Acetyl] -4-piperidine acetic acid diphenylmethyl ester IR (KBr) cm ^-1 : ν _{C = O} 1740,1675,1655 ・ No.10 4-[[4- (4-tert-butoxycarbonylamidinophenyl) -2, 3-Dioxopiperazin-1-yl]
Acetyl] -1-piperazine acetic acid benzyl ester IR (KBr) cm ⁻¹ : ν _{C = O} 1750,1675,1655

Example 11 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -4-pentenoic acid 3- [4- (4-tert-butoxy] Carbonylamidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -4-pentynate (1.2 g) was dissolved in chloroform (12 ml), and 4.4 N hydrogen chloride / dioxane solution (5.7 ml) was added.
And stir at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure, the obtained residue is dissolved in 10 ml of ethanol, 2.6 ml of 2N aqueous lithium hydroxide solution is added, and the mixture is stirred at room temperature for 30 minutes. The reaction solution was adjusted to pH 4 with 2N hydrochloric acid and purified by reverse phase column chromatography (eluent: 10% aqueous acetonitrile) to give colorless crystals of 3-[[4- (4-amidinophenyl) -2,3. 0.75 g of -dioxopiperazin-1-yl] acetamido] -4-pentynoic acid are obtained. IR (KBr) cm ^-1 : ν _{C = O} 1695,1655 NMR (d ₁ -TFA-CDCl ₃ ) δ value: 2.45 (1H, d, J = 2Hz), 3.00 (2H, d, J
= 6Hz), 3.9-4.5 (4H, m), 4.50 (2H, s), 5.0-5.4 (1H, m), 7.72
(2H, d, J = 8Hz), 7.96 (2H, d, J = 8Hz)

The compounds shown in Table 4 are obtained in the same manner as in Example 11.

[0055]

[Table 4]

The compound names and physical properties shown in Table 4 are shown below. -No.12 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -3-phenylpropionic acid IR (KBr) cm ^-1 : ν _{C = O} 1685 , 1655 NMR (d ₁ -TFA) δ value: 3.13 (2H, d, J = 7Hz), 4.20 (4H, brs), 4.50
(2H, s), 5.60 (1H, t, J = 7Hz), 7.40 (5H, s), 7.68 (2H, d, J = 8H
z), 7.96 (2H, d, J = 8Hz) ・ No.13 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -4-pentenoic acid IR (KBr) cm ^-1 : ν _{C = O} 1695,1670 NMR (d ₁ -TFA) δ value: 2.92 (2H, d, J = 6Hz), 3.9-4.8 (6H, m), 4.9
-6.1 (4H, m), 7.85 (2H, d, J = 8Hz), 8.00 (2H, d, J = 8Hz) ・ No.14 3-[[4- (4-amidinophenyl) -2,3- Dioxopiperazin _- ¹ -yl] acetamido] butyric acid IR (KBr) cm ⁻¹ : ν _{C = O} 1695,1655 NMR (d ₁ -TFA) δ value: 1.40 (3H, d, J = 6Hz), 2.6-3.0 (2H, m), 3.9
-5.0 (7H, m), 7.5-8.2 (4H, m) -No.15 3- (S)-[[4- (4-amidinophenyl) -2,
3-Dioxopiperazin-1-yl] acetamide]-
4-Pentenoic acid IR (KBr) cm ^-1 : ν _{C = O} 1695,1655 [α] _D (25 ° C) =-44 ° (c = 0.21,1N-HCl)

Example 16 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamide] -3-
(Pyridin-3-yl) propionic acid 3-[[4- (4-tert-butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl]
Acetamide] -3- (pyridin-3-yl) ethyl propionate (0.48 g) was dissolved in 50% ethanol aqueous solution (9.6 ml), lithium hydroxide monohydrate (0.053 g) was added, and the mixture was allowed to stand at room temperature for 30%.
After stirring for a minute, the solvent is distilled off under reduced pressure. To the obtained residue, 4.8 ml of 6N hydrochloric acid is added, stirred at room temperature for 2 hours, and then adjusted to pH 4 with a saturated sodium hydrogen carbonate aqueous solution. By purifying this solution by reverse phase column chromatography (eluent: 20% aqueous acetonitrile), colorless crystals of 3-
0.35 g of [[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] -3- (pyridin-3-yl) propionic acid are obtained. IR (KBr) cm ^-1 : ν _{C = O} 1695,1680 NMR (d ₆ -DMSO) δ value: 2.3-3.0 (2H, m), 3.3-4.6 (6H, m), 5.1-
5.4 (1H, m), 7.2-9.6 (13H, m)

Example 17 The following compound was obtained in the same manner as in Example 16. -3- [3- [4- (4-amidinophenyl) -2,3
-Dioxopiperazin-1-yl] propionamide]
-3- (pyridin-3-yl) propionic acid IR (KBr) cm ^-1 : ν _{C = O} 1685 NMR (d ₁ -TFA-D ₂ O) δ value: 2.7-3.1 (2H, m), 3.30 ( 2H, d, J = 8H
z), 3.7-4.3 (6H, m), 5.73 (1H, t, J = 8Hz), 7.3-8.3 (5H, m), 8.
7-8.9 (2H, m), 9.01 (1H, brs)

Example 18 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] propionic acid 3-[[4- (4-tert-butoxycarbonylamidino] Phenyl) -2,3-dioxopiperazin-1-yl]
Acetamido] propionic acid diphenylmethyl ester
After stirring a mixed solution of 0.15 g, 1.5 ml of anisole and 3 ml of trifluoroacetic acid at room temperature for 2 hours, the solvent is distilled off under reduced pressure. 10 ml of ethyl acetate and 5 ml of water are added to the obtained residue, the pH is adjusted to 5.5 with a saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer is separated. After concentrating the aqueous layer under reduced pressure to about half, reverse phase column chromatography (eluent;
Purification with 10% aqueous acetonitrile) gives 0.07 g of amorphous solid 3-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetamido] propionic acid. IR (KBr) cm ^-1 : ν _{C = O} 1675,1665 NMR (d ₁ -TFA) δ value: 2.5-3.2 (2H, m), 3.5-4.7 (8H, m), 7.5-8.
2 (4H, m)

Example 19 The following compound was obtained in the same manner as in Example 18. -1-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetyl] -4-piperidineacetic acid IR (KBr) cm ^-1 : ν _{C = O} 1685

Example 20 4-[[4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetyl] -1-piperazineacetic acid 4-[[4- (4-tert- Butoxycarbonylamidinophenyl) -2,3-dioxopiperazin-1-yl]
Acetyl] -1-piperazine acetic acid benzyl ester 0.26
A mixture of g, 5% -palladium on carbon (0.1 g) and N, N-dimethylformamide (2 ml) is hydrogenated at room temperature and atmospheric pressure for 2 hours. Then, the solvent is distilled off under reduced pressure, 3 ml of methylene chloride and 1 ml of trifluoroacetic acid are added to the obtained residue, the mixture is stirred at room temperature for 2 hours, and then the solvent is distilled off under reduced pressure. 5 ml of water was added to the obtained residue, and the pH was adjusted to 8 with a saturated sodium hydrogen carbonate aqueous solution, and then purified by reverse phase column chromatography (eluent; 10% acetonitrile aqueous solution) to give 4-[[ 0.08 g of 4- (4-amidinophenyl) -2,3-dioxopiperazin-1-yl] acetyl] -1-piperazine acetic acid is obtained. IR (KBr) cm ^-1 : ν _{C = O} 1685 NMR (d ₁ -TFA-D ₂ O) δ value: 3.4-4.4 (14H, m), 4.61 (2H, s), 7.68
(2H, d, J = 9Hz), 7.92 (2H, d, J = 9Hz)

[0062]

The compound of the present invention has an inhibitory action on platelet aggregation, and is useful as a prophylactic and therapeutic agent for diseases associated with platelet aggregation.

Continued Front Page (72) Inventor Hidetoshi Kaga 1-8 Toyojocho, Toyama City, Toyama Prefecture

Claims (16)

[Claims] 1. A compound of the general formula "In the formula, R ¹ represents an amidino group which may be protected;
R ² is a hydrogen atom or a carboxyl protecting group; A is
An optionally substituted lower alkylene group; B is -N
H- or the formula (In the formula, Z is a nitrogen atom or a carbon atom; n is 1 to
Indicates an integer of 3. ), Y represents an optionally substituted lower alkylene group; and broken lines represent a single bond or a double bond, respectively. And a 2,3-diketopiperazine derivative or a salt thereof. 2. The 2,3-diketopiperazine derivative or a salt thereof according to claim 1, wherein B is —NH—. 3. A 2,3-diketopiperazine derivative or a salt thereof according to claim 2, wherein A is a lower alkylene group. 4. The 2,3-diketopiperazine derivative or a salt thereof according to claim 3, wherein R ¹ is an amidino group. 5. The method according to claim 4, wherein the broken line is a single bond,
3-Diketopiperazine derivative or a salt thereof. 6. Y is an optionally substituted lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, cycloalkyl, aryl, aralkyl, heterocyclic, carbamoyl or amino group or optionally protected amino. A 2,3-diketopiperazine derivative or a salt thereof according to claim 5, which is a lower alkylene group which may be substituted with one or more groups selected from a hydroxyl group and a carboxyl group. 7. The 2,3-diketopiperazine derivative or a salt thereof according to claim 6, wherein Y is a lower alkynyl group which is substituted with an optionally substituted lower alkynyl, aryl or heterocyclic group. 8. The 2,3-diketopiperazine derivative or a salt thereof according to claim 7, wherein Y is a lower alkylene group substituted with a 5- or 6-membered heterocyclic group. 9. The 2,3-diketopiperazine derivative or a salt thereof according to claim 7, wherein Y is a lower alkylene group substituted with a lower alkynyl group. 10. B is of the formula: (In the formula, Z is a nitrogen atom or a carbon atom; n is 1 to
Indicates an integer of 3. 2. A 2,3-diketopiperazine derivative or a salt thereof according to claim 1, which is a group represented by: 11. The method according to claim 1, wherein Y is a lower alkylene group.
2. The 2,3-diketopiperazine derivative according to 0 or a salt thereof. 12. The 2,3-diketopiperazine derivative or a salt thereof according to claim 11, wherein R ¹ is an amidino group. 13. The 2,3-diketopiperazine derivative or a salt thereof according to claim 12, wherein the broken line is a single bond. 14. The 2,3-diketopiperazine derivative or a salt thereof according to claim 13, wherein Z is a carbon atom. 15. The 2,3-diketopiperazine derivative or salt thereof according to claim 13, wherein Z is a nitrogen atom. 16. The method according to any one of claims 1 to 15,
An antithrombotic agent containing a 3-diketopiperazine derivative or a salt thereof.