JPH09249646A - Fibrinogen receptor antagonistic substance and medicinal preparation with the same as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject substance antagonistic to fibrinogen receptor, having platelet coagulation inhibitory action, excellent in oral absorbability, thus useful for e.g. preventing platelet thrombosis, thromboembolic disorders etc., during and after the therapy of thrombolysis. SOLUTION: This substance is a compound (pharmaceutically permissible salt thereof) expressed by formula I [(A) is a structure of formula II, etc., (R4 is H, a lower alkyl, aralkyl, etc.); R1 and R2 are each H, a lower alkyl, etc.; R3 is H or a biodegradable carboxyl-protecting group], e.g. N-(4- amidinobenzoyl-2,2-dimethy1-3-penten-1-oyl)piperidine-4-acetate. This compound of formula I is obtained by respectively synthesizing an amidinophenyl-contg. unit of formula III and a piperidine-4-acetate unit of formula IV followed by condensing these units together.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel compound having an inhibitory action on platelet aggregation, a platelet aggregation inhibitor containing the compound as an active ingredient, a blood coagulation inhibitor for extracorporeal circulation, a coronary artery reocclusion inhibitor, and the like. It relates to a pharmaceutical preparation.

[0002]

2. Description of the Related Art Ischemic diseases of the circulatory system, such as myocardial infarction and cerebral stroke, are caused by obstruction of sufficient oxygen and nutrients to tissues and organs due to blockage of blood vessels by thrombus. Therefore, these diseases can be treated by inhibiting platelet aggregation. It is now known that platelet aggregation is caused by the binding of fibrinogen to the fibrinogen receptor glycoprotein "gpIIbIIIa" present on the surface of platelet membranes. As a substance that inhibits these two proteins, a peptide having an RGD sequence has been widely developed. Currently, the mainstream of drug development is to further induce a structure from a peptide structure containing a natural amino acid.
It is shifting to so-called peptidomimetics which has undergone modification, and these reports are reported in WO93 / 16697, EP0503548, WO93 / 08181.
Publication, WO93 / 08174 Publication, WO94 / 08
577 and EP 0505868. However, at present, there is a demand for the development of an oral platelet aggregation inhibitor that does not have the pain sensation of an injection and is easy to take. Oral drugs generally require a compound having a long-lasting action and a stable chemical structure in vivo, but an enzyme that decomposes a peptide bond exists in the body, and therefore a compound having a peptide bond is Not suitable for long acting drugs due to their low stability. Also,
The stability and absorbability of compounds in the digestive tract must also be taken into consideration, but in general, oral absorbability is due to the hydrophobicity of the molecule, and therefore the compound itself has a peptide bond that is hydrophilic. The group is also not suitable as an oral drug.

[0003]

Therefore, an object of the present invention is to provide a novel platelet aggregation inhibitor compound that antagonizes the fibrinogen receptor and has high stability, and a platelet aggregation inhibitor containing the same as an active ingredient. .

[0004]

[Means for Solving the Problems] The inventors of the present invention have made extensive studies in view of the above-mentioned problems, and as a result, have further promoted the concept of conventional peptidomimetics and have a higher structure by constructing a skeleton of a compound with a carbon bond. It was found that the stability was obtained, and that by maintaining the carbon atoms at the α-position and β-position of the amidinophenyl group in a plane, the conventional platelet aggregation inhibitory activity was greatly exceeded, and the present invention was completed. That is, the present invention provides a compound represented by the general formula [I] and a pharmaceutically acceptable salt thereof.

[0005]

Embedded image

{In formula [I], (A) is represented by formula [II] and formula [I
II] or a structure represented by the formula [IV]. (However, the bonds on the * side of formulas [II], [III], and [IV] are represented by formula [I]
A bond on the * side of the middle (A) and a bond on the ** side are located on the ** side of the (A) in the formula [I]. ) Further, R ₁ and R ₂ each independently represent a hydrogen atom, a lower alkyl or a biodegradable amino group-protecting group. R ₃ represents a hydrogen atom or a protecting group for a carboxyl group which is degradable in a living body}.

[0007]

Embedded image

{In the formula [II], R ₄ represents a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl, aralkyl or carboxyalkyl. X in formula [III],
Y's each represent a carbon atom, and the bond between them represents a single bond or a double bond. In formula [IV], Z represents an oxygen or nitrogen atom, R ₅ represents a hydrogen atom, a lower alkyl or aryl group, and does not exist when Z 2 is an oxygen atom. ｝.

The present invention also provides a pharmaceutical preparation such as a platelet aggregation inhibitor, a blood coagulation inhibitor for extracorporeal circulation and a coronary artery reocclusion inhibitor, which contains the above compound or a pharmaceutically acceptable salt thereof as an active ingredient. Pharmaceutical formulations are also provided.

The present invention will be described in detail below. In the general formula [I], suitable “biodegradable amino-group protecting groups” for R ₁ and R ₂ include all amino-group protecting groups known to be biodegradable. But specifically, "Development of pharmaceuticals" No. 13
Vol., "Drug Delivery Method" (edited by Hitoshi Sezaki, Hirokawa Shoten, published in July 1989), it may be a protective group having a bonding mode as shown in Table 2.29 on page 116, such as an acetyl group. Examples thereof include an acyl group, an amino acid having a free carboxylic acid and a protected amino acid thereof, a carbamate such as benzyloxycarbonyl, 1-acyloxyalkyloxycarbonyl and the like. Particularly, an acetoxymethyloxycarbonyl group, a 1-acetoxyethyloxycarbonyl group and the like are preferable. R ₃ represents a hydrogen atom or a protecting group for a carboxyl group which can be decomposed in a living body. The protective group for a carboxyl group that is degradable in a living body may specifically have a bond mode such as an ester bond or a peptide bond, and may be a methyl ester, an ethyl ester, a sugar having a free hydroxyl group, or a derivative thereof, or The amino acid which has a free amino group, its protected amino acid, etc. can be mentioned.

In formula [II], a suitable "lower alkyl" for R ₄ is straight-chain alkyl having 1 to 7 carbon atoms, but branched alkyl or cyclic alkyl may be used. Considering steric hindrance, preferred alkyl is methyl, ethyl and propyl, and most preferred alkyl is methyl. In addition, linear ones are preferable to branched and cyclic ones. R ₄
Suitable "lower alkenyl" is straight-chain alkenyl having 2 to 7 carbon atoms, but may be branched alkenyl or cyclic alkenyl. Considering steric hindrance, preferred alkenyl is vinyl or propenyl. R ₄ suitable ”
"Lower alkynyl" is straight-chain alkynyl having 3 to 7 carbon atoms, but may be branched alkynyl. In view of steric hindrance, preferable alkynyl is propynyl. Suitable "alkalkyl" for R ₄ is , An alkyl group having an aryl group at the terminal and consisting of 1 to 3 carbon atoms, preferably benzyl or phenethyl, and the terminal aryl group may be phenyl or a condensed polycyclic hydrocarbon (eg, naphthyl, anthranyl). Well, in this case,
It may have a substituent on the aromatic ring, and in this case, the substituent is preferably lower alkyl, halogen, nitro, amino, carboxy, hydroxy (lower) alkyl, hydroxy or protected hydroxy. Suitable for R ₄ "carboxyalkyl" is an alkyl group having a carboxyl group at the terminal of a linear or branched alkyl group consisting of carbon atoms 3-7 is preferably carboxyalkyl group is carboxymethyl group.

In the general formula [III], X and Y are both carbon atoms, and the bond between them is a single bond or a double bond,
Double bonds are more desirable. In the general formula [IV], when Z is an oxygen atom, R ₅ does not exist, but when Z is a nitrogen atom, R ₅ represents a hydrogen atom, a lower alkyl or an aryl group. Suitable "lower alkyl" for R ₅ is linear alkyl having 1 to 7 carbon atoms, but may be branched alkyl or cyclic alkyl. Suitable "aryl groups" for R ₅ may be phenyl or fused polycyclic hydrocarbons (eg naphthyl, anthranyl), where substituents on the aromatic ring include lower alkyl, halogen, nitro, amino, carboxy,
It may have hydroxy (lower) alkyl, hydroxy or protected hydroxy.

Suitable pharmaceutically acceptable salts of the target compound described in the present invention are usual non-toxic salts such as salts with inorganic bases such as alkali metal salts (eg sodium salt, potassium salt etc.), alkaline earth salts. Metal salts (eg calcium salt, magnesium salt etc.); ammonium salts; organic bases such as organic amines (eg triethylamine, pyridine, picoline, ethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine etc.) Salts; inorganic acid addition salts (eg hydrochloride, hydrobromide, sulfate, phosphate, etc.); organic carboxylic acid or sulfonic acid addition salts (eg formate, acetate, propionate, trifluoroacetic acid) Salt, maleate, malate, tartrate, succinate, citrate,
Methanesulfonate, benzenesulfonate, p-toluenesulfonate, glycolate, etc.); basic or acidic amino acids (eg arginine, aspartic acid,
A salt with a base or an acid addition salt such as a salt with glutamic acid).

The compounds of the present invention can be synthetically prepared. Hereinafter, the production method of the compound of the present invention will be described in detail. The compound of the present invention can be produced by synthesizing its structure into two parts and combining the respective units. The two moieties are an amidinophenyl-containing moiety (a) located on the * side of general formula [I] and a piperidine-4-acetic acid moiety (b) located on the ** side. After synthesizing these units by an appropriate method, they can be produced by the general method described below. Furthermore, with respect to the unit a, condensation may be performed as a corresponding synthetic precursor, that is, a 4-cyanophenyl-containing moiety, and the cyano group may be subsequently converted to an amidino group.

[0015]

Embedded image

The two amino acid-like units can be synthesized by methods commonly used in peptide chemistry, eg, "the peptide".
(The Peptides) "Volume 1 [Schroder and Luhke, Acad
emicPress, New York, USA (1966)], "Basics and experiments of peptide synthesis" [Nobuo Izumiya et al., Maruzen Co., Ltd. (1985)
Year)] and the like. As a general method, an azide method, an acid halide method, an acid anhydride method, a carbodiimide method, a carbodiimide-additive method, an active ester method, a carbonylimidazole method, a redox method, an enzyme method, a method using Woodward reagent K, etc. It can be illustrated. These condensation reactions are usually performed in a solvent. As the solvent,
For example, chloroform, dichloromethane, ethyl acetate,
N, N-dimethylformamide, dimethyl sulfoxide, pyridine, dioxane, tetrahydrofuran, N-
Mention may be made of methylpyrrolidone, water, methanol and the like, or mixtures thereof. Further, the reaction temperature of the condensation reaction can be carried out in the range of −30 ° C. to 50 ° C. as in the usual case.

Before carrying out these condensation reactions, a protecting means such as a carboxyl group, an amino group, a hydroxyl group or an amidino group which does not participate in the condensation reaction can be provided by a generally known means. Conversely, a carboxyl group or an amino group directly involved in the condensation reaction can be activated. As a protecting group used for protecting functional groups not involved in the condensation reaction of each unit, a protecting group usually used in organic chemistry, for example, `` Protective Groups in Organic Synthesis (Protective Group
ps in Organic Synthesis) [Greene, John Wiley & S
ons, Inc. (1981)] and the like.

Examples of the protective group for the carboxyl group include various commonly known protective groups such as various methyl ester, ethyl ester, benzyl ester, p-nitrobenzyl ester, t-butyl ester and cyclohexyl ester. Examples of the amino group-protecting group include a benzyloxycarbonyl group, a t-butoxycarbonyl group, an isobornyloxycarbonyl group and a 9-fluorenylmethoxycarbonyl group.
Examples of the hydroxyl-protecting group include t-butyl group, benzyl group, trimethylsilyl group, tetrahydropyranyl group and the like. As the protecting group for the amidino group,
For example, a benzyloxycarbonyl group etc. can be mentioned.

With respect to the compound of the present invention thus produced, generally known separation and purification means can be used after completion of the above series of reactions. For example, extract,
The compound of the present invention can be obtained in a more pure form by partitioning, reprecipitation, recrystallization, column chromatography and the like.

Next, a method of synthesizing each unit will be described. Among the units a, those in which (A) is represented by the formula [II] are
It can be obtained from commercially available isobutyryl chloride by appropriately performing esterification, aldol condensation, oxidation, reduction, dehydration, deprotection reaction and the like.

[0021]

[Chemical 6]

Examples of the organic base used in the reaction 1-1 include diisopropylethylamine, triethylamine,
3 such as dicyclohexylmethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non-5-ene, triethylenediamine
It is a primary amine, more preferably triethylamine. Preferred solvents include chloroform, dichloromethane, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, pyridine, dioxane, tetrahydrofuran, diethyl ether and the like, more preferably dichloromethane, pyridine and tetrahydrofuran, most preferably It is dichloromethane.

Sources of the desired enolate anions used in Reactions 1-2 include diisopropylamine,
Examples thereof include lithium, sodium, and potassium salts of diethylamine, dicyclohexylamine, hexamethyldisilazane, and the like, with lithium salt of diisopropylamine being more preferable. At this time, as a desirable solvent, dichloromethane, tetrahydrofuran, diethyl ether,
Examples thereof include dimethoxyethane, and more preferably tetrahydrofuran. The reaction temperature is -8
0 ° C to 30 ° C is preferable.

In Reactions 1-3, chromic acid oxidation using Jones reagent, pyridinium chlorochromate, pyridinium dichromate, etc., oxidation using dimethyl sulfoxide such as Swan oxidation, oxidation using sulfur trioxide pyridinium salt, and desmartin oxidation are preferable. But,
Chromic acid oxidation and swan oxidation are more preferable, and chromic acid oxidation using Jones reagent is the most preferable. Preferred solvents in this case include dichloromethane, tetrahydrofuran, diethyl ether, dimethoxyethane, acetone and the like, and more preferably acetone. The reaction temperature is preferably 0 ° C to 50 ° C.

The reaction conditions of reaction 1-4 differ only in the aldehyde used as the raw material, and the conditions such as solvent, reaction time and reaction temperature are preferably in accordance with reaction 1-2.

As a method for carrying out the reaction 1-5, diisopropylethylamine, triethylamine, dicyclohexylmethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.
[0] A method of reacting various acid chloride reagents such as p-toluenesulfonyl chloride, methanesulfonyl chloride, acetyl chloride in the presence or the presence of a tertiary amine such as non-5-ene or triethylenediamine.
Treatment with hydrochloric acid, sulfuric acid, nitric acid, etc., diisopropylethylamine, triethylamine, dicyclohexylmethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,5-diazabicyclo [4.3.0] non- Examples thereof include a method of treating with a tertiary amine such as 5-ene and triethylenediamine, but a method of reacting various acid chloride reagents is preferable, and a method of reacting methanesulfonyl chloride in a pyridine solvent is more preferable. .
The reaction temperature is preferably 0 ° C to 50 ° C, and the reaction time is preferably 1 hour to 24 hours.

In Reactions 1-6, a hydride-donating reagent such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, or sodium cyanocyanoborohydride is added to chloroform, dichloromethane, pyridine,
Dioxane, tetrahydrofuran, diethyl ether,
It is preferable to react in a solvent such as methanol or ethanol, but it is more preferable to treat sodium borohydride in methanol, and to add cerium trichloride heptahydrate to add sodium borohydride in methanol. Is most desirable.

In reaction 1-7, the compound having a hydroxyl group obtained in reaction 1-6 is used as a corresponding alkoxide, and lower alkyl, lower alkenyl, lower alkynyl corresponding to R ₄ , or methyl, ethyl, propyl, trimethylsilylethyl, etc. Is a reaction in which a halide of carboxyalkyl protected with is reacted to form an ether bond.
As a reagent for forming an alkoxide, a hydride of a metal such as lithium hydride, sodium hydride, potassium hydride or calcium hydride is preferable, and sodium hydride is more preferable. Preferred solvents include chloroform, dichloromethane, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, pyridine, dioxane, tetrahydrofuran, diethyl ether and the like, more preferably dichloromethane and tetrahydrofuran, and most preferably tetrahydrofuran. is there. The halide of carboxyalkyl protected with lower alkyl, lower alkenyl, lower alkynyl, or methyl, ethyl, propyl, trimethylsilylethyl and the like is preferably the chloride, bromide or iodide of the alkyl, more preferably bromide. The reaction temperature is preferably −80 ° C. to 30 ° C., and the reaction time is preferably 1 hour to 24 hours.

Reactions 1-8 hydrolyze the t-butyl ester under acidic conditions, the preferred acid being hydrochloric acid,
Sulfuric acid, nitric acid, trifluoroacetic acid and acetic acid are used, but trifluoroacetic acid is more preferable. Preferred solvents include chloroform, dichloromethane, ethyl acetate, N,
Examples thereof include N-dimethylformamide, dimethylsulfoxide, pyridine, dioxane, tetrahydrofuran, diethyl ether, and more preferably dichloromethane. Further, these acids and a solvent may be mixed and used at an appropriate ratio, and it is most preferable to use trifluoroacetic acid itself as a solvent. The reaction temperature is preferably -20 ° C to 30 ° C, and the reaction time is 1
0 minute to 120 minutes is preferable.

Among the units a, those in which (A) is represented by the formula [III] can be obtained from commercially available neopentyl glycol monohydroxypivalate according to the following formula.

Embedded image

The protecting group (R ₆ ) used in the reaction 2-1 is methyl ether, ethyl ether, propyl ether, methoxymethyl ether, methoxyethoxymethyl ether, 1-ethoxyethyl ether, trimethylsilylethyl ether, tetrahydropyranyl ether. , Benzyl ether and the like are preferable, and methoxymethyl ether is more preferable. In addition, it is preferable to add an organic base to the reaction system. Examples of the organic base used include diisopropylethylamine, triethylamine, dicyclohexylmethylamine, pyridine, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1, Tertiary amines such as 5-diazabicyclo [4.3.0] non-5-ene and triethylenediamine are preferred,
More preferred is triethylamine. Preferred solvents include chloroform, dichloromethane, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, pyridine, dioxane, tetrahydrofuran, diethyl ether and the like, more preferably dichloromethane, pyridine and tetrahydrofuran, most preferably It is dichloromethane.

In the reaction 2-2, a hydride-donating reagent such as lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride and sodium cyanoborohydride is added to chloroform, dichloromethane, pyridine and
Dioxane, tetrahydrofuran, diethyl ether,
The reaction is preferably performed in a solvent such as methanol or ethanol, but it is more preferable to mix lithium aluminum hydride in diethyl ether. The reaction temperature is preferably -20 ° C to 30 ° C, and the reaction time is 1 minute. ~ 60
Minutes are preferred.

In the reaction 2-3, chromic acid oxidation using Jones reagent, pyridinium chlorochromate, pyridinium dichromate, etc., oxidation using dimethyl sulfoxide such as Swan oxidation, oxidation using sulfur trioxide pyridinium salt, and desmartin oxidation are preferable. But,
More preferred is swan oxidation. The reaction conditions of the reaction 2-4 are different only in the starting materials, and the conditions such as the solvent, the reaction time, the reaction temperature and the like are preferably the same as those of the reaction 1-2. The reaction conditions of Reactions 2-5 are different only in the starting materials, and the solvent,
The conditions such as reaction time and reaction temperature are preferably in accordance with Reaction 1-5.

Reaction 2-6 hydrolyzes the hydroxyl-protecting group under acidic conditions. Preferred acids are hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid and acetic acid, with hydrochloric acid being more preferred. Preferred solvents include chloroform, dichloromethane, ethyl acetate, N, N-dimethylformamide, dimethylsulfoxide, pyridine, dioxane, tetrahydrofuran, diethyl ether, ethanol, methanol, water and the like, and more preferably methanol. Further, these acids and a solvent may be mixed in an appropriate ratio, and most preferably, 6M hydrochloric acid is used in methanol. The reaction temperature is preferably -20 ° C to 30 ° C, and the reaction time is 10
Minutes to 120 minutes are preferred.

In Reaction 2-7, Jones reagent, lithium, sodium and potassium salts such as permanganate and dichromic acid are used in a solvent such as dichloromethane, tetrahydrofuran, diethyl ether, dimethoxyethane, acetone, acetic acid and water. It is preferred that the Jones reagent be used in acetone. The reaction temperature is preferably -20 ° C to 30 ° C, and the reaction time is 1 minute to 12
0 minutes is preferred. In addition, pyridinium chlorochromate, chromic acid oxidation using pyridinium dichromate, oxidation using dimethylsulfoxide such as swan oxidation, oxidation using sulfur trioxide pyridinium salt, Dess-Martin oxidation, etc., once via an aldehyde,
Thereafter, a method of oxidizing the carboxylic acid with sodium chlorite, silver nitrate or the like may be used.

After the reaction 2-5, at any stage,
The double bond existing in the compound may be reduced to a methylene group by catalytic hydrogen reduction using palladium / charcoal, platinum oxide or the like as a catalyst, and the solvent at this time is dichloromethane, tetrahydrofuran, diethyl ether, dimethoxyethane. , Acetone, acetic acid, ethanol, methanol, water and the like are preferably used, but these solvents may be mixed and used at an appropriate ratio. More preferably, palladium / charcoal is used with a mixture of methanol and acetic acid. The reaction conditions thereafter are as follows: Reactions 2-6, 2
It is preferable to comply with -7. In addition, of the unit a,
The compound (A) represented by the formula [III] can also be obtained from commercially available isobutyryl chloride according to the following formula.

[0037]

Embedded image

The esterification of the reaction 3-1 is preferably according to the reaction 1-1. The carbon-increasing reaction of Reaction 3-2 is different only in the starting material, and the reaction conditions are preferably in accordance with Reaction 1-2. The reaction conditions of Reaction 3-3 are preferably the same as those of Reaction 1-2 except that the starting materials are different. Reaction 3-4
It is preferable that the reaction conditions are the same as those in Reactions 1-5 except that the starting materials are different. The reaction conditions of Reaction 3-5 are preferably the same as those of Reaction 1-8 except that the starting materials are different.

After the reaction 3-4, at any stage,
The double bond existing in the compound may be reduced to a methylene group by catalytic hydrogen reduction using palladium / charcoal, platinum oxide or the like as a catalyst, and the solvent at this time is dichloromethane, tetrahydrofuran, diethyl ether, dimethoxyethane. , Acetone, acetic acid, ethanol, methanol, water and the like are preferably used, but these solvents may be mixed and used at an appropriate ratio. It is more preferred to use palladium / charcoal mixed with methanol and acetic acid. The reaction conditions thereafter are preferably in accordance with Reactions 3-5.

The unit (a) represented by the formula [IV] among the units a can be obtained from commercially available isobutyryl chloride according to the following formula.

[0041]

Embedded image

The reaction 4-1 is preferably similar to the reaction 1-1. The reaction 4-2 is preferably according to the reaction 3-2. Reaction 4-3 is preferably according to reaction 3-3.
Reaction 4-4 is different only in the starting material, and the reaction conditions are preferably in accordance with Reaction 1-3.

Reaction 4-5 is a reaction to form an isoxazole or pyrazole ring using hydrazine having a hydrogen atom corresponding to R ₅ or a lower alkyl or aryl group as a reagent. The reaction is preferably carried out under acidic conditions, and the acid used is preferably hydrochloric acid, sulfuric acid, nitric acid, trifluoroacetic acid or acetic acid, more preferably hydrochloric acid. Preferred solvents include chloroform, dichloromethane, ethyl acetate,
N, N-dimethylformamide, dimethylsulfoxide, pyridine, dioxane, tetrahydrofuran, diethyl ether, t-butanol, ethanol, methanol, water and the like can be mentioned, but ethanol is more preferable. Further, these acids and a solvent may be mixed in an appropriate ratio, and most preferably 6M hydrochloric acid is used in ethanol. The reaction temperature is -2
The temperature is preferably 0 ° C to 120 ° C, and the reaction time is preferably 2 hours to 50 hours. Reaction 4-6 differs only in the starting material, and the reaction conditions are preferably in accordance with Reaction 3-5.

The unit b is obtained by reduction of the corresponding 4-carboxyalkylpyridine, or oxidation of the hydroxyl group of 4-hydroxyalkylpyridine having the same number of side chain carbon atoms including the carbon of carboxylic acid, and reduction of the pyridine ring. It can be easily obtained by

The compound of the present invention is effective as a platelet aggregation inhibitor for the treatment or prevention of various diseases caused by platelet aggregation or caused by it. In particular, it is effective as a drug for inhibiting or preventing blood vessel obstruction due to thrombus formation, such as myocardial infarction and cerebral infarction. In addition, thrombolysis in coronary arteries during myocardial infarction. Reperfusion by thrombolytic drugs such as urokinase and acute reocclusion inhibitors after percutaneous coronary angioplasty (PTCA) to thrombolytic therapy to infarct lesions. It is effective as an occlusion inhibitor and also as a blood coagulation inhibitor during medical procedures involving extracorporeal blood circulation. The compound of the present invention can also be applied to cell adhesion inhibitors, anti-inflammatory agents, anti-rheumatic agents, therapeutic agents for osteoporosis, cancer metastasis inhibitors, and the like.

When the compound of the present invention obtained as described above is used as, for example, the above blood coagulation inhibitor,
As the active ingredient, it is preferable to prepare a formulation containing the compound of the present invention or a pharmaceutically acceptable salt thereof together with a solid or liquid pharmaceutical carrier or diluent, that is, together with an excipient, a stabilizer and the like. In the formulation, the ratio of the active ingredient to the carrier component can be varied between 1 and 90% by weight. The dosage form and dosage form of the preparation can be granules, fine granules, powders, tablets, capsules, pills or liquids. Further, it can be administered orally as it is, and can be administered as an injection by intravenous administration, intramuscular administration, or subcutaneous administration. When used as an injection, the compound of the present invention can be prepared as a powder for injection at the time of use.

Organic or inorganic, solid or liquid pharmaceutical carriers or diluents suitable for oral, enteral or parenteral administration can be used to prepare the platelet aggregation inhibitors of the present invention. . Water, gelatin, lactose,
Starch, magnesium stearate, talc, animal and vegetable fats and oils, benzyl alcohol, gum, polyalkylene glycol, petroleum resin, coconut oil, lanolin and other carriers used in medicine are all carriers or dilutions of the platelet aggregation inhibitor of the present invention. It can be used as an agent. Further, a stabilizer, a wetting agent or an emulsifier can be added, and a salt can be used as an auxiliary agent as an osmotic pressure adjusting agent or a pH adjusting agent.

Further, in the treatment of various diseases, the blood coagulation inhibitor of the present invention contains, in addition to the above-mentioned active ingredients, other pharmaceutically active ingredients, such as other types of platelet aggregation-inhibiting ingredients, if necessary. It can also be included.

When in the form of granules, fine granules, powders, tablets, or capsules, the active ingredient is added in an amount of 5 to 80.
It is preferable to contain it by weight percent. In the case of a liquid preparation, it is preferable to contain the above-mentioned active ingredient in a ratio of 1 to 30% by weight. Furthermore, among parenteral administration preparations, when used as an injection, it is preferable to contain the active ingredient in a proportion of 1 to 10% by weight. In the case of oral administration, the clinical dose is 500 per day for adults as the above active ingredient.
It is preferable to take ~ 1000 mg orally. However, the dosage can be appropriately increased or decreased depending on the age, symptoms, etc. of the patient. The platelet aggregation inhibitor of the present invention described above,
Although it is possible to administer once a day, it is also possible to administer an appropriate interval in 2 to 3 divided doses. Further, when used as an injection, it is preferable that the above-mentioned active ingredient be administered to an adult at a dose of 1 to several 100 mg per dose. Also,
The administration can be performed once or continuously by means such as infusion. When the compound of the present invention is used for extracorporeal circulation, it can be used in the form of the above injection. The dose also depends on the dose of the above-mentioned injection.

[0050]

BEST MODE FOR CARRYING OUT THE INVENTION Formula [II], Formula [III] of the present invention,
The compound represented by the formula [IV] type is a compound in which a portion in which a peptide bond is used in the conventional technique is converted into a carbon bond. By converting into a carbon bond, the hydrophobicity of the compound is increased, and the in vivo stability and the oral absorption ability, which are problems in the conventional techniques, can be improved. Furthermore, by introducing a dimethyl group and an appropriate substituent at the 2- and 3-positions of amidinopentenoic acid, the platelet aggregation inhibitory activity can be improved. Therefore, the compound of the present invention is greatly advantageous not only in prolonging the action time of the drug and the oral absorption ability, but also in terms of the platelet aggregation inhibitory activity.

The compound that antagonizes the fibrinogen receptor has a basic site and an acidic site in the molecule with a certain spatial distance, and it is necessary that these bind to the receptor.

In the compound of the present invention, the basic site corresponds to the amidino group and the acidic site corresponds to acetic acid bonded to the 4-position of piperidine. As can be seen from Comparative Examples 1 and 2, the three-dimensional structure at the 5-position is greatly involved in the platelet aggregation inhibitory activity. Therefore, the 3rd, 4th and 5th positions of the amidinophenylpentanoic acid skeleton
Of the three carbon atoms, the compound represented by the formula [II] type maintains the conformational planarity at the 3, 4, and 5 positions, and the compound represented by the formula [III] type maintains the conformational planarity at the 4, 5 position. Introduced possible sp2 carbon. By introducing sp2 carbon at the 5-position, the mobility of a compound having a linear structure with a high degree of freedom can be regulated and the three-dimensional molecular structure can be fixed. That is, it enables stable retention of the three-dimensional structure required for high activity expression, and enhances the binding ability with the receptor. From the above viewpoint, s at the α-position of the amidinophenyl group
The introduction of p2 carbon is extremely important for enhancing the ability of the compound to suppress platelet aggregation, and the novel compound of the present invention is clearly significant as a fibrinogen receptor antagonist.

[0053]

The present invention will be specifically described below with reference to examples and comparative examples, but the present invention is not limited to these examples. <Synthesis of Compound> [Example 1] N- (4-amidinobenzoyl-2,2
-Dimethyl-3-pentene-1-oil) piperidine-
Synthesis of 4-acetic acid

[0054]

Embedded image

(1) Synthesis of 2,2-dimethyl-3-methoxymethoxypropanal Neopentyl glycol mono (hydroxypivalate) 2
To a solution of 5.0 g (123 mmol) of dehydrated dichloromethane in 400 ml, triethylamine 51 ml (3 equivalents) and chloromethyl methyl ether 28 ml (3 equivalents) were sequentially added at 0 ° C., and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure, acidified with 2M hydrochloric acid, and extracted twice with diethyl ether. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated under reduced pressure. Crude product
Obtained 39.98 g. This was dissolved in 300 ml of diethyl ether, 5.1 g (1.2 equivalents) of lithium aluminum hydride was added at 0 ° C, and the mixture was stirred at 0 ° C for 10 minutes. Excess lithium aluminum hydride was decomposed with 4M aqueous sodium hydroxide solution, filtered through Celite, and the solvent was distilled off under reduced pressure to give crude product 3
Obtained 6.62 g.

A solution of 33 g (260 mmol) of oxalyl dichloride in 500 ml of dehydrated dichloromethane was added with 30 ml of dimethyl sulfoxide (423 m
(mol) was added dropwise at -78 ° C, and the mixture was stirred for 10 minutes. A solution of 36.62 g of the above crude product in 40 ml of dehydrated dichloromethane was added dropwise to this reaction solution at −78 ° C., and the mixture was stirred for 10 minutes. After adding 100 ml of triethylamine and heating to room temperature and stirring for 10 minutes, 2M hydrochloric acid was added and the reaction solution was concentrated. The mixture was extracted twice with diethyl ether, the extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated under reduced pressure. The product was purified by a silica gel column, and 35.50 g (yield 99%) of 2,2-dimethyl-3-methoxymethoxypropanal was obtained from the outflow portion of hexane-ethyl acetate (4: 1). ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 9.57 (1H, s), 4.59 (2H, s), 3.55 (2H,
s), 3.33 (3H, s), 1.11 (6H, s)

(2) 1- (4-cyanophenyl) -5-
Methoxymethoxy-4,4-dimethyl-2-pentene-
Synthesis of 1-one To a solution of 26.15 g (180 mmol) of 4-cyanoacetophenone in 400 ml of dehydrated tetrahydrofuran, 90 ml of a solution of 2M lithium diisopropylamide in tetrahydrofuran at -78 ° C (1.0 ml
(5 equivalents) was added dropwise and stirred for 0.5 hours. 2,2 in this solution
-Dimethyl-3-methoxymethoxypropanal 25.0 g
30 ml of a dehydrated tetrahydrofuran solution of (171 mmol) was added dropwise at -78 ° C, and the mixture was stirred for 1 hour. A saturated ammonium chloride aqueous solution was added to the reaction solution, the temperature was raised to room temperature, and the solvent was concentrated under reduced pressure.
The reaction mixture was acidified with 2M hydrochloric acid and then with diethyl ether.
Extracted twice. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with a cotton plug, and the solvent was evaporated under reduced pressure. Crude purification was performed using a silica gel column, and 18.70 g of a crude purified product was obtained from the outflow portion of hexane-ethyl acetate (3: 1). To 180 ml of a dehydrated pyridine solution of 18.70 g of this crude product, 25 ml (5 equivalents) of methanesulfonyl chloride was added at 0 ° C., and the temperature was raised to room temperature.
Stir overnight. Under ice-cooling, excess methanesulfonyl chloride was decomposed with water, and the reaction solution was concentrated under reduced pressure. The reaction solution was acidified with 2M hydrochloric acid and then extracted twice with diethyl ether.
The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated under reduced pressure. Purify with a silica gel column, and use 1- (4-cyanophenyl) -5 from the hexane-ethyl acetate (8: 1) outlet.
8.57 g (yield 17%) of -methoxymethoxy-4,4-dimethyl-2-penten-1-one was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 8.00 (2H, d, 8 Hz), 7.78 (2H, d, 8 Hz),
7.13 (1H, d, 16 Hz), 6.82 (1H, d, 16 Hz), 4.62 (2
H, s), 3.42 (2H, s), 3.35 (3H, s), 1.19 (6H, s) MS: 295.9 [(M + Na) ⁺ , base]

(3) 1- (4-cyanophenyl) -4,
Synthesis of 4-dimethyl-5-hydroxy-2-penten-1-one 1- (4-cyanophenyl) -5-methoxymethoxy-
4,4-Dimethyl-2-penten-1-one 8.57 g (31.4
30 ml of 6M hydrochloric acid was added to 100 ml of a methanol solution of
The mixture was heated under reflux at 10 ° C for 10 minutes. The reaction solution was concentrated under reduced pressure and extracted twice with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate,
A cotton plug was filtered and the solvent was distilled off under reduced pressure. Purify with a silica gel column, and from the hexane-ethyl acetate (2: 1) outlet, 1-
4.46 g (yield 62%) of (4-cyanophenyl) -4,4-dimethyl-5-hydroxy-2-penten-1-one was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 7.98 (2H, d, 8 Hz), 7.76 (2H, d, 8 Hz),
7.07 (1H, d, 16 Hz), 6.82 (1H, d, 16 Hz), 3.50 (2
H, s), 1.15 (6H, s)

(4) Synthesis of 4-cyanobenzoyl-2,2-dimethyl-3-pentenoic acid 1- (4-cyanophenyl) -4,4-dimethyl-5-
Hydroxy-2-penten-1-one 1.00 g (4.37 mmol)
The Jones reagent was added to 50 ml of the acetone solution of 1 at 0 ° C. with stirring until the reaction solution became orange. Excess Jones reagent was decomposed with isopropyl alcohol, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, filtered through Celite, and the solvent was evaporated under reduced pressure. The residue was dissolved in 1M aqueous sodium hydroxide solution, washed with diethyl ether, the aqueous layer was acidified with hydrochloric acid, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with a cotton plug, and the solvent was evaporated under reduced pressure. 4-cyanobenzoyl-2,2-dimethyl-3-
954 mg of pentenoic acid (yield 90%) was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 8.01 (2H, d, 8 Hz), 7.80 (2H, d, 8 Hz),
7.23 (1H, d, 16 Hz), 6.88 (1H, d, 16 Hz), 1.49 (6
H, s)

(5) N- (4-cyanobenzoyl-2,
Synthesis of methyl 2-dimethyl-3-pentene-1-oil) piperidine-4-acetate 4-cyanobenzoyl-2,2-dimethyl-3-pentenoic acid 954 mg (3.93 mmol) in dehydrated dichloromethane 10 ml
To this, 2086 mg (1.2 equivalents) of BOP reagent and 820 μl of diisopropylethylamine were added at 0 ° C., the temperature was raised to room temperature, and the mixture was stirred for 0.5 hours. Methyl piperidine-4-acetate hydrochloride 2080 mg
The aqueous solution of ammonia (2.8 equivalents) was extracted once with ethyl acetate, the extract was dried over sodium sulfate, filtered through a cotton plug, and the solvent was evaporated under reduced pressure. This residue was dissolved in 5 ml of dehydrated dichloromethane, added to the above reaction solution, and stirred overnight. Aqueous citric acid solution was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated under reduced pressure.
Purified with silica gel column, hexane-ethyl acetate
(3: 1) From the outlet, N- (4-cyanobenzoyl-2,2
-Dimethyl-3-pentene-1-oil) piperidine-
1013 mg (yield 67%) of 4-methyl acetate was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 8.02 (2H, d, 9 Hz), 7.82 (2H, d, 9 Hz),
7.35 (1H, d, 15 Hz), 6.88 (1H, d, 15 Hz), 3.8-4.8
(2H, br), 3.66 (3H, s), 2.78 (2H, m), 2.24 (2h, d,
7 Hz), 2.02 (1H, m), 1.74 (2H, br d, 13 Hz), 1.45
(6H, s), 1.12 (2H, br dq, 3, 13 Hz) MS: 404.9 [(M + Na) ⁺ , base]

(6) Synthesis of title compound N- (4-cyanobenzoyl-2,2-dimethyl-3-
Pentene-1-oil) piperidine-4-methyl acetate 24
After adding 1 ml of triethylamine to 9 mg (0.65 mmol) of a dehydrated pyridine solution, 20% hydrogen sulfide gas was blown into the solution at room temperature for 20 minutes. After stirring overnight, the solvent was distilled off under reduced pressure, and the residue was azeotropically distilled with toluene until the odor of pyridine disappeared. The residue is acetone
It was dissolved in 40 ml, 4 ml of iodomethane was added, and the mixture was refluxed at 65 ° C for 15 minutes. The solvent was evaporated under reduced pressure, the residue was dissolved in 40 ml of methanol, 300 mg of ammonium acetate was added, and the mixture was refluxed at 80 ° C for 0.5 hr. After distilling off the solvent under reduced pressure, the residue was purified by a silica gel column, and N- (4-amidinobenzoyl-2,2-dimethyl-3) was extracted from the chloroform-methanol (10: 1) outlet.
209 mg (yield 81%) of methyl- (pentene-1-oil) piperidine-4-acetate was obtained. Methyl N- (4-amidinobenzoyl-2,2-dimethyl-3-pentene-1-oil) piperidine-4-acetate 200 mg (0.50 mmol) in methanol 1
Dissolve in 2 ml, add 1.5 ml of 4M sodium hydroxide aqueous solution,
The mixture was stirred at room temperature for 2 hours. Acetic acid was added to the reaction solution to neutralize it, and the solvent was distilled off under reduced pressure. The residue was dissolved in 1M acetic acid aqueous solution and subjected to high performance liquid chromatography (HPLC) [ODS 5C (μbondasp
here, φ19 mm × 150 mm), distilled water-acetonitrile (0.1%
TFA-containing), gradient (1% / min), 17 ml / min]. The 23% acetonitrile fraction was freeze-dried to obtain 26.6 mg of the title compound. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 8.10 (2H, d, 9 Hz), 7.43 (2H, d, 9 Hz),
7.31 (1H, d, 16 Hz), 7.04 (1H, d, 16 Hz), 4.0-4.6
(2H, br), 2.7-3.0 (2H, br), 2.18 (2H, d, 7 Hz), 1.
85-2.05 (1H, m), 1.74 (2H, br d, 12 Hz), 1.43 (6H,
s), 1.10 (2H, br q, 12 Hz) MS: 386.2 [(MH) ⁺ , base]

[Example 2] N- (4-amidinobenzoyl-2,2-dimethylbutanoyl) piperidine-4-
Acetic acid synthesis

[0063]

Embedded image

(1) Synthesis of Title Compound 1.00 g of the compound of Example 1- (3) was dissolved in 30 ml of methanol, 100 μl of acetic acid and 100 mg of palladium-charcoal were added, and the mixture was stirred at room temperature for 2 days under a hydrogen atmosphere. This was filtered and the solvent was distilled off under reduced pressure. Purification with a silica gel column, 0.61 g of 4-cyanobenzoyl-2,2-dimethylbutanoic acid from the outlet of ethyl acetate-hexane (1: 4) (yield 60
%)Obtained. Thereafter, the same operations as in Examples 1- (4), (5), and (6) were performed, and the product was purified by high performance liquid chromatography. 120 mg of the title compound was obtained from the 27% acetonitrile fraction. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 8.17 (2H, d, 9 Hz), 7.90 (2H, d, 9 Hz),
4.41 (2H, br d, 13 Hz), 3.06 (2H, br t, 7 Hz), 2.8
7 (2H, br t, 13 Hz), 2.20 (2H, d, 7 Hz), 2.04 (2H,
br t, 7 Hz), 2.02 (1H, m), 1.80 (2H, br d, 14 H
z), 1.32 (6H, s), 1.14 (2H, br q, 14 Hz) MS: 388.1 [(MH) ⁺ , base]

Example 3 N- (5- (4-amidinophenyl) -3-hydroxy-2,2-dimethyl-4-
Synthesis of (pentene-1-oil) piperidine-4-acetic acid

[0066]

Embedded image

(1) Synthesis of t-butyl 2,2-dimethylacetoacetate t-Butyl isobutyrate 15.86 g of dehydrated tetrahydrofuran 45
To the 0 ml solution, at −78 ° C., 60 ml (1.07 equivalent) of a 2M solution of lithium diisopropylamide in tetrahydrofuran was added dropwise.
Stirred for hours. 6.76 ml of acetaldehyde in this solution
13.52 ml of dehydrated tetrahydrofuran solution (1.1 equivalent) -78
The mixture was added dropwise at ° C and stirred for 1.5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, the temperature was raised to room temperature, and the solvent was concentrated under reduced pressure. The reaction mixture was acidified with 2M hydrochloric acid and then with ethyl acetate.
Extracted twice. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with a cotton plug, and the solvent was evaporated under reduced pressure. It was roughly purified by a silica gel column, and a crude product of t-butyl 2,2-dimethyl-3-hydroxy-butanoate was obtained from an ethyl acetate-chloroform (1: 5) outflow portion. This was dissolved in 200 ml of acetone, and the Jones reagent was added at 0 ° C. with stirring until the reaction solution became orange. The excess Jones reagent was decomposed with isopropyl alcohol, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, filtered through Celite, and the solvent was concentrated under reduced pressure. The residue was extracted twice with diethyl ether. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate,
A cotton plug was filtered and the solvent was distilled off under reduced pressure. Purify with a silica gel column, and use 2,2 from the outlet of ethyl acetate-hexane (1:20).
T-butyl dimethylacetoacetate (19.08 g, yield 90%) was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 2.09 (3H, s), 1.39 (9H, s), 1.24 (6H, s) MS: 208.9 [(M + Na) ⁺ , base], 241.0 [(M + Na + MeOH) ⁺ ]

(2) 5- (4-cyanophenyl) -2,
Synthesis of t-butyl 2-dimethyl-3-oxo-4-pentenoate 21.54 g (116 mmo) of t-butyl 2,2-dimethylacetoacetate
l) in a solution of 500 ml of dehydrated tetrahydrofuran at -78 ° C
61 ml (1.05 equivalent) of a tetrahydrofuran solution of M lithium diisopropylamide was added dropwise, and the mixture was stirred at -40 ° C for 0.5 hour. To this solution, 16.0 g of 4-cyanobenzaldehyde (1.
60 ml of a dehydrated tetrahydrofuran solution (05 equivalents) was added dropwise at -78 ° C, and the mixture was stirred for 1.5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, the temperature was raised to room temperature, and the solvent was concentrated under reduced pressure.
The reaction solution was acidified with 2M hydrochloric acid and then extracted twice with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with a cotton plug, and the solvent was evaporated under reduced pressure. Purified with silica gel column, ethyl acetate-hexane (1: 1)
From the outlet, t-butyl 5- (4-cyanophenyl-5-hydroxy-3-oxo-2,2-dimethylpentanoate)
15.24 g (yield 41%) was obtained.

To 130 ml of a dehydrated pyridine solution of 10.24 g (34.2 mmol) of t-butyl 5- (4-cyanophenyl-5-hydroxy-3-oxo-2,2-dimethylpentanoate) was added 0 ° C.
Then, 13 ml (5 equivalents) of methanesulfonyl chloride was added, the temperature was raised to room temperature, and the mixture was stirred overnight. Under ice-cooling, excess methanesulfonyl chloride was decomposed with water, and the reaction solution was concentrated under reduced pressure. The reaction solution was acidified with 2M hydrochloric acid and then extracted twice with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine,
After drying over anhydrous magnesium sulfate, a cotton plug was filtered and the solvent was distilled off under reduced pressure. After purification with a silica gel column of hexane-ethyl acetate (6: 1), recrystallization from hexane was performed, and t-butyl 5- (4-cyanophenyl) -2,2-dimethyl-3-oxo-4-pentenoate 7.40 was obtained. g (yield 72%) was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃, ref: TMS = 0.00) δ (ppm); 7.69 (2H, d, 10 Hz), 7.65 (1H, d, 16 H
z), 7.61 (2H, d, 10 Hz), 6.92 (1H, d, 16 Hz), 1.43
(9H, s), 1.43 (3H, s), 1.40 (3H, s) MS: 322.2 [(M + Na) ⁺ , base], 354.1 [(M + Na + MeOH) ⁺ ]

(3) N- (5- (4-cyanophenyl)
-3-Hydroxy-2,2-dimethyl-4-pentene-
Synthesis of 1-oil) piperidine-4-methyl acetate 5- (4-cyanophenyl) -2,2-dimethyl-3-
T-Butyl oxo-4-pentenoate 0.50 g (1.67 mmol)
Was mixed with 15 ml of trifluoroacetic acid and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure. Then, methyl 5- (4-cyanophenyl) -3-hydroxy-2,2-dimethyl-4-pentene-1-oilpiperidine-4-acetate was obtained in the same manner as in Example 1- (5). Add this to methanol 30
It was dissolved in ml, cerium chloride heptahydrate (750 mg) was added, and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was cooled to 0 ° C, 126 mg (2 equivalents) of sodium borohydride was added, and the mixture was stirred for 0.5 hours.
The reaction mixture was concentrated under reduced pressure, acidified with citric acid, and then extracted twice with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated under reduced pressure. After purification with a silica gel column of hexane-ethyl acetate (6: 1), recrystallization with hexane and N- (5- (4-
601 mg (yield 94%) of methyl cyanophenyl) -3-hydroxy-2,2-dimethyl-4-pentene-1-oil) piperidine-4-acetate was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 7.60 (2H, d, 9 Hz), 7.49 (2H, d, 9 Hz),
6.69 (1H, d, 16 Hz), 6.49 (1H, dd, 16, 7 Hz), 4.40
(2H, m), 4.32 (1H, d, 7 Hz), 3.69 (3H, s), 2.85-2.
95 (2H, m), 2.28 (2H, d, 7 Hz), 2.02 (1H, m), 1.82
(2H, m), 1.35 (3H, s), 1.30 (3H, s), 1.12-1.35 (2
H, m) MS: 407.1 [(M + Na) ⁺ , base]

(4) Synthesis of title compound The procedure of Example 1- (6) was repeated and purification was carried out by high performance liquid chromatography. 35 mg of the title compound was obtained from the 24% acetonitrile fraction. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 7.75 (2H, d, 8 Hz), 7.62 (2H, d, 8 Hz),
6.76 (1H, d, 16 Hz), 6.54 (1H, d, 16 Hz), 4.52 (1
H, d, 6 Hz), 4.47 (2H, br d, 14 Hz), 2.88 (2H, br
t, 14 Hz), 2.23 (2H, d, 7 Hz), 2.04 (1H, m), 1.81
(2H, br d, 14 Hz), 1.32 (3H, s), 1.28 (3H, s), 1.
20 (2H, br q, 14 Hz) MS: 388.1 [(MH) ⁺ , base]

Example 4 Synthesis of N- (5- (4-amidinophenyl) -3-methoxy-2,2-dimethyl-4-pentene-1-oil) piperidine-4-acetic acid

[0073]

Embedded image

(1) 5- (4-cyanophenyl) -2,
Synthesis of t-butyl 2-dimethyl-3-methoxy-4-pentenoate 1.00 g (3.34 mmol) of the compound of Example 3- (2) was dissolved in 20 ml of methanol, and 1.50 g (1.2 equivalents) of cerium chloride heptahydrate.
Was added and stirred at room temperature for 0.5 hours. The reaction solution was cooled to 0 ° C, 253 mg (2 equivalents) of sodium borohydride was added, and the mixture was stirred for 10 minutes. Acidify the reaction mixture with hydrochloric acid, and then add 2 with ethyl acetate.
Extracted times. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered through a cotton plug, and the solvent was evaporated under reduced pressure. Dissolve the residue in 20 ml of dehydrated tetrahydrofuran, 0 ℃
Sodium hydride (160 mg, 1.2 equivalents) was added and the mixture was stirred for 20 minutes. Methyl iodide (3 ml) was added to the reaction solution, and the mixture was stirred at room temperature overnight. After the excess sodium hydride was decomposed with water, the reaction solution was concentrated under reduced pressure, acidified with hydrochloric acid, and then extracted twice with ethyl acetate. The extract was washed with saturated saline,
After drying over anhydrous magnesium sulfate, a cotton plug was filtered and the solvent was distilled off under reduced pressure. Purified with a hexane-ethyl acetate (5: 1) silica gel column to give 5- (4-cyanophenyl) -2,2.
-Dimethyl-3-methoxy-4-pentenoate t-butyl
929 mg (yield 85%) was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ° C) δ (ppm); 7.62 (2H, d, 9 Hz), 7.48 (2H, d, 9 Hz),
6.60 (1H, d, 16 Hz), 6.23 (1H, dd, 16, 8 Hz), 3.92
(1H, d, 8 Hz), 3.31 (3H, s), 1.46 (9H, s), 1.17 (3
H, s), 1.09 (3H, s) MS: 338.2 [(M + Na) ⁺ , 370.2 [(M + Na + MeOH) ⁺ ]

(2) Synthesis of title compound 5- (4-cyanophenyl) -2,2-dimethyl-3-
929 mg of t-butyl methoxy-4-pentenoate was mixed with 10 ml of trifluoroacetic acid and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure. Thereafter, the same operations as in Examples 1- (5) and (6) were performed, and the product was purified by high performance liquid chromatography. The title compound (183 mg) was obtained from the 28% acetonitrile fraction. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C.) δ (ppm); 7.77 (2 H, d, 8 H
z), 7.66 (2H, d, 8 Hz),
6.75 (1H, d, 16 Hz), 6.37
(1H, dd, 16, 8 Hz), 4.47
(2H, br d, 14 Hz), 4.09
(1H, d, 8 Hz), 3.31 (3H,
s), 2.88 (2H, br t, 12 H
z), 2.23 (2H, d, 7 Hz),
2.03 (1H, m), 1.81 (2H, br
d, 13 Hz), 1.32 (3H, s),
1.25 (3H, s), 1.19 (2H,
br q, 13 Hz) MS: 402.2 [(MH) ⁺ , base].

Example 5 Synthesis of N- (5- (4-amidinophenyl) -3-ethoxy-2,2-dimethyl-4-pentene-1-oil) piperidine-4-acetic acid

[0077]

Embedded image

(1) Synthesis of title compound The procedure of Example 4 was repeated and purification was carried out by high performance liquid chromatography. The title compound (179 mg) was obtained from the 32% acetonitrile fraction. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 7.76 (2H, d, 8 Hz), 7.65 (2H, d, 8 Hz),
6.73 (1H, d, 16 Hz), 6.38 (1H, dd, 16, 7 Hz), 4.49
(2H, br d, 14 Hz), 4.17 (1H, d, 7 Hz), 3.60 (1H, d
q, 9, 7 Hz), 3.40 (1H, dq, 9, 7 Hz), 2.87 (2H, br
q, 13 Hz), 2.23 (2H, d, 7 Hz), 2.03 (1H, m), 1.81
(2H, br d, 14 Hz), 1.32 (3H, s), 1.26 (3H, s), 1.18
(3H, t, 7 Hz), 1.10-1.26 (2H, m) MS: 416.4 [(MH) ⁺ , base]

Example 6 N- (5- (4-amidinophenyl) -3- (2-propynyloxy) -2,2-
Dimethyl-4-pentene-1-oil) piperidine-4
-Synthesis of acetic acid

[0080]

Embedded image

(1) Synthesis of title compound Purification by high performance liquid chromatography was performed in the same manner as in Example 4. The title compound (183 mg) was obtained from the 30% acetonitrile fraction. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 7.77 (2H, d, 8 Hz), 7.67 (2H, d, 8 Hz),
6.78 (1H, d, 16 Hz), 6.37 (1H, dd, 16, 7 Hz), 4.43
-4.55 (2H, m), 4.47 (1H, d, 7 Hz), 4.25 (1H, dd, 1
6, 2 Hz), 4.08 (1H, dd, 16, 2 Hz), 2.90 (2H, br q,
13 Hz), 2.88 (1H, t, 2 Hz), 2.24 (2H, d, 7 Hz),
2.04 (1H, m), 1.81 (2H, br d, 13 Hz), 1.34 (3H, s),
1.28 (3H, s), 1.22 (2H, br q, 13 Hz) MS: 426.0 [(MH) ⁺ , base]

Example 7 N- (5- (4-amidinophenyl) -3-benzyloxy-2,2-dimethyl-
Synthesis of 4-pentene-1-oil) piperidine-4-acetic acid

[0083]

Embedded image

(1) Synthesis of title compound The same operation as in Example 4 was carried out and the product was purified by high performance liquid chromatography. 46 mg of the title compound was obtained from the 36% acetonitrile fraction. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 7.78 (2H, d, 8 Hz), 7.67 (2H, d, 8 Hz),
7.23-7.38 (5H, m), 6.78 (1H, d, 16 Hz), 6.43 (1H,
dd, 16, 8 Hz), 4.62 (1H, d, 12 Hz), 4.26-4.47 (2H,
m), 4.39 (1H, d, 12 Hz), 4.32 (1H, d, 7 Hz), 2.73
(2H, br q, 13 Hz), 2.68 (2H, br q, 13 Hz), 2.16
(2H, d, 7 Hz), 1.94 (1H, m), 1.70 (2H, br d, 13 H
z), 1.32 (3H, s), 1.26 (3H, s), 1.07 (2H, m) MS: 478.2 [(MH) ⁺ , base]

Example 8 Synthesis of N- (5- (4-amidinophenyl) -3-carboxymethoxy-2,2-dimethyl-4-pentene-1-oil) piperidine-4-acetic acid

[0086]

Embedded image

(1) Synthesis of title compound The procedure of Example 4 was repeated and the product was purified by high performance liquid chromatography. The title compound (48 mg) was obtained from the 22% acetonitrile fraction. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 7.77 (2H, d, 8 Hz), 7.67 (2H, d, 8 Hz),
6.77 (1H, d, 16 Hz), 6.37 (1H, dd, 16, 8 Hz), 4.42
-4.56 (2H, m), 4.39 (1H, d, 8 Hz), 4.12 (1H, d, 17
Hz), 4.04 (1H, d, 17 Hz), 2.90 (2H, br t, 14 Hz),
2.24 (2H, d, 8Hz), 2.04 (1H, m), 1.81 (2H, br d, 1
3 Hz), 1.41 (3H, s), 1.30 (3H, s), 1.11-1.30 (2H,
m) MS: 446.1 [(MH) ⁺ , base]

Example 9 N- (5- (4-amidinophenyl) -3-hexyloxy-2,2-dimethyl-
Synthesis of 4-pentene-1-oil) piperidine-4-acetic acid

[0089]

Embedded image

(1) Synthesis of title compound The same operation as in Example 4 was carried out and the product was purified by high performance liquid chromatography. 4 mg of the title compound was obtained from the 45% acetonitrile fraction. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 7.76 (2H, d, 8 Hz), 7.64 (2H, d, 8 Hz),
6.73 (1H, d, 16 Hz), 6.37 (1H, dd, 16, 7 Hz), 4.50
(2H, br d, 13 Hz), 4.16 (1H, d, 7 Hz), 3.55 (1H, d
t, 10, 5 Hz), 3.33 (1H, dt, 10, 5 Hz), 2.87 (1H,
q, 12 Hz), 2.23 (2H, d, 7 Hz), 2.03 (1H, m), 1.81
(2H, br d, 13 Hz), 1.56 (2H, m), 1.27-1.42 (4H,
m), 1.31 (3H, s), 1.27 (3H, s), 1.19 (2H, br q, 13
Hz), 0.89 (3H, t, 7 Hz) MS: 472.3 [(MH) ⁺ , base]

Example 10 Synthesis of N- (2,2-dimethyl (5- (4-amidinophenyl) -3-isoxazolylacetyl)) piperidine-4-acetic acid

[0092]

Embedded image

(1) Synthesis of 4-cyanobenzoyl-3-oxo-2,2-dimethylbutanoic acid t-butyl 5- (4-cyanophenyl) -5 of Example 3- (2)
To a solution of tert-butyl hydroxy-3-oxo-2,2-dimethylpentanoate (5.00 g, 15.8 mmol) in 80 ml of acetone,
The Jones reagent was added with stirring until the reaction liquid turned orange. The excess Jones reagent was decomposed with isopropyl alcohol, the reaction solution was neutralized with saturated aqueous sodium hydrogen carbonate, filtered through Celite, and the solvent was concentrated under reduced pressure. The residue was extracted twice with diethyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered with a cotton plug, and the solvent was evaporated under reduced pressure. Recrystallization from hexane was carried out and t-butyl 4-cyanobenzoyl-3-oxo-2,2-dimethylbutanoate 3.
44 g (yield 69%) was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 7.99 (2H, d, 8 Hz), 7.80 (2H, d, 8 Hz),
6.29 (1H, s), 1.51 (9H, s), 1.50 (6H, s) MS: 339.9 [(M + Na) ⁺ , base]

(2) 5- (4-cyanophenyl) -3-
Synthesis of (1-t-butoxycarbonyl-1-methyl) ethyl isoxazole 2.55 g (8.1 mmol) of 4-cyanobenzoyl-3-oxo-2,2-dimethylbutanoate t-butyl was dissolved in 35 ml of ethanol to give hydroxyl. 3.5 g of amine was added and the mixture was stirred at 55 ° C. for 3 hours. The reaction solution was distilled off under reduced pressure, the residue was dissolved in 20 ml of t-butyl alcohol and refluxed for 4 hours. The reaction solution was extracted twice with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous sodium sulfate, filtered through a cotton plug, and the solvent was evaporated under reduced pressure. 5- (4-cyanophenyl)-
2.26 g (yield 89%) of 3- (1-t-butoxycarbonyl-1-methyl) ethylisoxazole was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 7.93 (2H, d, 9 Hz), 7.75 (2H, d, 9 Hz),
6.47 (1H, s), 1.63 (6H, s), 1.44 (9H, s) MS: 313 (MH ⁺ ), 257, 212, 172, and 57 (base)

(3) Synthesis of title compound The same operation as in Example 4 was carried out and the product was purified by high performance liquid chromatography. 42 mg of the title compound was obtained from the 26% acetonitrile fraction. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 8.11 (2H, d, 9 Hz), 7.92 (2H, d, 9 Hz),
6.92 (1H, s), 2.77 (2H, m), 2.17 (2H, d. 7 Hz), 1.
93 (1H, m), 1.66 (2H, m), 1.64 (6H, s), 1.03 (2H, m
m) MS: 399.2 [MH ⁺ , base]

Example 11 Synthesis of N- (2,2-dimethyl (N ¹ -phenyl-3- (4-amidinophenyl) pyrazolyl) acetyl) piperidine-4-acetic acid

[0097]

Embedded image

(1) (5- (4-cyanophenyl) -3
Synthesis of-(1-t-butoxycarbonyl-1-methyl) ethyl-N ¹ -phenyl) pyrazole The compound of Example 10- (1) (0.5 g, 0.50 mmol) was dissolved in ethanol (10 ml), and phenylhydrazine hydrochloride (87 mg) was added. In addition, the mixture was refluxed at 60 ° C for 1 hour. The reaction solvent was gradually replaced with 1,4-dioxane and further refluxed for 3 hours. The mixture was further refluxed with m-xylene for 3 hours, and the reaction solution was concentrated under reduced pressure. The mixture was extracted with ethyl acetate, the extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered with a cotton plug, and the solvent was evaporated under reduced pressure. Purify with a silica gel column of hexane-ethyl acetate (6: 1) to give (5- (4-cyanophenyl) -3- (1
-T-butoxycarbonyl-1-methyl) ethyl-N ¹
0.18 g (yield 60%) of -phenyl) pyrazole was obtained. ¹ H-NMR (270 MHz, CDCl ₃ , 27 ℃) δ (ppm); 7.96 (2H, d, 10 Hz), 7.77 (2H, d, 10 H
z), 6.70 (1H, s), 1.47 (6H, s), 1.39 (9H, s) MS: 387 (M ⁺ ), 286, and 57 (base)

(2) Synthesis of title compound The same operation as in Example 4 was carried out and the product was purified by high performance liquid chromatography. 84 mg of the title compound was obtained from the 26% acetonitrile fraction. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 8.09 (2H, d, 9 Hz), 7.85 (2H, d, 9 Hz),
7.52 (2H, m), 7.42 (3H, m), 7.03 (1H, s), 4.11 (1
H, m), 3.84 (1H, m), 2.79 (1H, m), 2.26 (1H, m), 2.
18 (2H, d, 7 Hz), 1.98 (1H, m), 1.46-1.74 (8H, m),
1.06 (2H, m) MS: 474.4 [MH ⁺ , base]

Comparative Example 1 Synthesis of 5- (4-amidinophenyl) -2,2-dimethyl-5-hydroxy-3-pentene-1-oilpiperidine-4-acetic acid

[0101]

[Chemical 21]

(1) Synthesis of Title Compound To 60 ml of a dehydrated pyridine solution containing 759 mg (1.99 mmol) of the compound of Example 1- (5), 2 ml of triethylamine was added, and then 20% hydrogen sulfide gas was blown for 15 minutes at room temperature. It is. After stirring overnight, the solvent was distilled off under reduced pressure, and the residue was azeotropically distilled with toluene until the odor of pyridine disappeared. The residue was dissolved in 40 ml of acetone, 4 ml of iodomethane was added, and the mixture was refluxed at 65 ° C for 15 minutes. The solvent was evaporated under reduced pressure, the residue was dissolved in 40 ml of methanol, 300 mg of ammonium acetate was added, and the mixture was refluxed at 80 ° C for 0.5 hr. After distilling off the solvent under reduced pressure, the residue was purified by a silica gel column, and N- (4-amidinobenzoyl-2,2-dimethyl-3-pentene-1-oil) piperidine-4 was extracted from the chloroform-methanol (10: 1) outlet. -465 mg (59% yield) of methyl acetate was obtained. Of them, 93 mg (0.23 mmol) was dissolved in methanol,
39 mg of sodium borohydride was added, and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was made basic with 1M aqueous sodium hydroxide solution and extracted twice with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, filtered through a cotton plug, and the solvent was evaporated under reduced pressure to give a residue (27 mg). 2 ml of this
, 0.5M of 4M sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 1 hour. Acetic acid was added to the reaction solution to neutralize it, and the solvent was distilled off under reduced pressure. Dissolve the residue in 1M aqueous acetic acid and perform high performance liquid chromatography (HPLC) [ODS 5C (μbondasphe
re, φ19 mm × 150 mm), distilled water-acetonitrile (0.1% TF
A), gradient (1% / min), 17 ml / min]. The 21% acetonitrile fraction was freeze-dried to obtain 2.0 mg of the title compound. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 7.77 (2H, d, 9 Hz), 7.59 (2H, d, 9 Hz),
5.99 (1H, dd, 16, 1 Hz), 5.60 (1H, dd, 16, 8 Hz),
5.26 (1H, d, 8 Hz), 4.1-4.4 (2H, br), 2.6-2.8 (2H,
br), 2.12 (2H, br d, 10 Hz), 1.91 (1H, m), 1.61
(2H, m), 1.27 (6H, s), 0.95 (2H, m) MS: 404.4 [(MH) ⁺ , base]

Comparative Example 2 Synthesis of N- (5- (4-amidinophenyl) -2,2-dimethyl-3-methoxypentanoyl) piperidine-4-acetic acid

[0104]

Embedded image

79 mg (0.20 mmol) of the compound of Example 4 was dissolved in 3 ml of methanol, 100 μl of acetic acid and 30 mg of palladium-charcoal were added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 2 days. This was filtered and the solvent was distilled off under reduced pressure. High performance liquid chromatography (HPLC) [ODS 5C (μbond asphere, φ1
9 mm × 150 mm), distilled water-acetonitrile (containing 0.1% TFA), gradient (1% / min), 17 ml / min]. The 28% acetonitrile fraction was freeze-dried to obtain 72 mg of the title compound. ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 7.74 (2H, d, 8 Hz), 7.47 (2H, d, 8 Hz),
4.41 (2H, m), 3.49 (3H, s), 3.48 (1H, dd, 8, 4 H
z), 2.70-3.03 (4H, m), 2.22 (2H, d, 7 Hz), 2.01 (1
H, m), 1.66-1.85 (4H, m), 1.27 (3H, s), 1.21 (3H,
s), 1.12 (2H, m) MS: 404.4 [(MH) ⁺ , base]

Comparative Example 3 Synthesis of N- (N-4-amidinobenzoyl-β-alanyl) -4-piperidineacetic acid

[0107]

Embedded image

(1) Synthesis of title compound Nt-butoxycarbonyl-β-alanine was prepared in Example 1.
The same operation as- (5) was performed to obtain methyl N- (Nt-butoxycarbonyl-β-alanyl) -4-piperidine acetate. This was mixed with 15 ml of trifluoroacetic acid and stirred at room temperature for 20 minutes. The solvent was distilled off under reduced pressure. Hereinafter, in the same manner as in Examples 1- (5) and (6), 56.0 mg of the title compound was obtained.
I got ¹ H-NMR (270 MHz, CD ₃ OD, 27 ° C) δ (ppm); 1.12 (1H, dq, 4, 13 Hz), 1.20 (1H, dq,
4, 13 Hz), 1.80 (2H, brt, 16 Hz), 1.94-2.05 (1H,
m), 2.21 (2H, d, 7 hz), 2.65 (1H, dt, 3, 13 Hz),
2.68-2.80 (2H, m), 3.10 (1H, dt, 3, 13 Hz), 3.66
(2H, t, 14 Hz), 3.97 (1H, d, 13 Hz), 4.51 (1H, br
d, 13 Hz), 7.88 (2H, dt, 2, 8 Hz), 8.00 (2H, dt,
2, 8 Hz) MS: 361.6 [(M + Na) ⁺ , base]

Test Example Platelet Aggregation Inhibitory Ability of the Present Invention (In-vitro Human Platelet Aggregation Using PRP) A healthy male who has not taken any drug for at least 2 weeks was used as a subject. Blood sampling is 1/10 with needle # 19
Using a plastic syringe in which a volume of 3.8% sodium citrate aqueous solution had been put in advance, it was performed from the vein of the lower abdomen on an empty stomach. Immediately after blood collection, the two solutions were mixed by gently stirring the syringe. Centrifuge this blood for 15 minutes at room temperature (1100rpm, 250g), stop the rotation without braking,
The supernatant was taken with a Komagome pipette and stored as platelet rich plasma ((PRP) at room temperature. After centrifugation, the remaining blood was further centrifuged at room temperature for 15 minutes (3500 rpm, 1500 g) and stopped without braking. After the preparation of PRP, the platelet count was measured and the platelet count was 2 × 10 ⁸
The experiments described below were carried out only with respect to the number of cells / ml or more.

Platelet aggregation was performed using an 8-channel platelet aggregometer (Hematracer, Nikoh Bioscience, Tokyo, Japa
n) was used to measure the change in light transmittance of PRP. First, put 200 μl of PRP and PPP in a glass cuvette and incubate at 37 ℃. Then, measure the transmittance and measure the transmittance of PPP to 100%.
%, And the transmittance of PRP was 0%. Next, 10 μl of physiological saline or physiological saline containing a sample was added to PRP and incubated at 37 ° C. for 1 minute, and then 10 μl of 100 μg / ml collagen solution was added (final concentration 5 μg / ml) to induce aggregation,
After that, the transmittance was measured for 7 minutes. The experiment was carried out by first confirming that aggregation occurred using collagen and ADP, and was carried out only when the maximum aggregation rate of collagen was 70% or more.

The sample was dissolved in physiological saline so as to have a concentration of 2.2 × 10 ⁻² M, and a 2-fold dilution series was prepared based on this and used in the experiment. 10 for samples insoluble in saline
It was dissolved in physiological saline containing% dimethyl sulfoxide.
The result was calculated according to the following formula.

[0112]

[Equation 1]

A graph was prepared in which the aggregation inhibition rate was plotted against the concentration of the sample, and from this figure, the concentration at which aggregation was suppressed by 50%
(IC ₅₀ ) was calculated. The following table shows the IC ₅₀ of each sample.

[Table 1] The activity values of Examples 9 to 11 were almost the same.

[0114]

INDUSTRIAL APPLICABILITY According to the present invention, there is provided a platelet aggregation inhibitor that antagonizes the fibrinogen receptor and has a high platelet aggregation inhibitory activity, and that is excellent in in vivo stability against proteolytic enzymes and in oral absorbability. Provided. The formulation comprises:
Prevention of platelet thrombosis, thromboembolism and reocclusion during and after thrombolysis treatment and prevention of platelet thrombosis, thromboembolism and reocclusion after angioplasty of coronary arteries and other arteries and after coronary artery bypass treatment, It is very effective in preventing unstable angina, preventing myocardial infarction, improving peripheral blood flow, and suppressing blood coagulation during extracorporeal circulation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical display location C07D 413/06 211 211 C07D 413/06 211 (72) Inventor Ishitaka Weitaka Ida, Nakahara-ku, Kawasaki City, Kanagawa Prefecture 1618 Nippon Steel Corporation Technology Development Headquarters (72) Inventor Atsushi Katada 1618 Ida, Nakahara-ku, Kawasaki City, Kanagawa Prefecture

Claims (5)

[Claims] 1. A compound represented by the following general formula [I] and a pharmaceutically acceptable salt thereof. Embedded image {In the formula [I], (A) represents a structure represented by the formula [II], the formula [III], or the formula [IV]. (However, the formula [II],
The bonds on the * side of [III] and [IV] are located on the * side of (A) in formula [I], and the bonds on the ** side are located on the ** side of (A) in formula [I]. ) Further, R ₁ and R ₂ each independently represent a hydrogen atom, a lower alkyl or a biodegradable amino group-protecting group. R ₃ represents a hydrogen atom or a protecting group for a carboxyl group which is degradable in a living body}. Embedded image {In the formula [II], R ₄ represents a hydrogen atom, lower alkyl, lower alkenyl, lower alkynyl, aralkyl or carboxyalkyl. In formula [III], both X and Y represent carbon atoms, and the bond between them represents a single bond or a double bond. In formula [IV], Z represents an oxygen or nitrogen atom,
R ₅ represents a hydrogen atom, a lower alkyl or aryl group, and does not exist when Z 2 is an oxygen atom. ｝. 2. A pharmaceutical preparation containing the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 3. The pharmaceutical preparation according to claim 2, which is a platelet aggregation inhibitor. 4. The pharmaceutical preparation according to claim 2, which is a blood coagulation inhibitor for extracorporeal circulation. 5. The pharmaceutical preparation according to claim 2, which is a coronary artery reocclusion inhibitor.