JPH11171770A - New heterocyclic compound having antiplatelet action - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having an antiplatelet action. SOLUTION: A compound of formula I [A, B, D, E and F are each CR<1> , CR<1> R<2> (R<1> and R<2> are each H or a lower alkyl), N or the like; G is (CO) or the like; J is CHX (X is pyridyl or the like) or the like; K is CH=CR<4> COOR<3> (R<3> is H or the like; R' is a lower alkyl or the like) or the like; (p) is 1 or 2]. For example, 2- 4-[1-(3-pyridyloxy)-2-[4-(4-pyridyl) piperaziny]lethyl]phenoxy}acetic acid. The compound of formula I (J is CHX) is obtained, for example, by reacting a compound of formula II with a compound of formula III in the presence of a base, reducing the obtained compound of formula IV and subsequently subjecting the obtained compound of formula V to a Mitsunobu reaction, etc. The compound is effective for treating and preventing thrombosis diseases, especially cerebral infarction, myocardial infarction, stenocardia, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a nitrogen-containing heterocyclic compound which inhibits platelet aggregation, and a pharmaceutical composition comprising at least one of these compounds as an active ingredient, which is effective for the treatment and prevention of thrombotic diseases. About things.

[0002]

2. Description of the Related Art With changes in eating habits and the elderly population, circulatory diseases are increasing, and it is considered that thrombus accounts for about 50% of the diseases. Platelets, which are plasma components, are greatly involved in thrombus formation in vivo. Therefore, for the treatment and prevention of thrombotic diseases, drugs that suppress platelet function and inhibit platelet aggregation, such as aspirin, which suppresses cyclooxygenase, ticlopidine, which activates adenylcyclase, and thromboxane A
Osagrel and the like that inhibit the synthase ₂ are used in clinical practice.

In recent years, the analysis of glycoproteins on platelet membranes has been advanced,
It was revealed that a membrane glycoprotein called GPIIb / IIIa functions as a fibrinogen receptor. Therefore, it has been expected that this antagonist to GPIIb / IIIa is effective as a platelet aggregation inhibitor having a new mechanism of action in the treatment and prevention of the above thrombotic diseases (Trends in
Pharmacological Science, 13, 413 pages, 19
1992). Compounds having this antagonistic activity include monoclonal antibodies (Ann. New York Acad. Sci., Vol. 614,
193 page, 1991), arginine-glycine-
Tripeptide derivatives consisting of aspartic acid (J. Med.
Chem., 35, 2040, 1992), and amidinophenyl derivatives (J. Med. Chem., 35, 4393).
J., 1992, JP-A-4-264068, JP-A-4-
334351, EP483636, EP502536,
EP525629, EP529858, EP53798
0, WO9307867, WO9404722, etc.) and tyrosine derivatives (J. Med. Chem., 35, 4640 pages).
Di, 1992), piperidine derivative (EP51283)
1, EP540334, EP578535, etc.) and pyridyl piperazine derivatives (WO942834, WO942)
2835 etc.) are known, and the present inventors have already
Effective compounds have been found in O942159 and WO9602503.

On the other hand, thromboxane A ₂ (TXA ₂ ) is one of metabolites of arachidonic acid and has physiological activities such as platelet aggregation and vascular smooth muscle contraction. Excessive production of TXA ₂ in the body causes platelet aggregation, vascular occlusion, vasospasm or bronchoconstriction, and is known to cause angina, myocardial infarction, cerebral infarction or bronchial asthma. I have. Therefore, it is expected that the TXA ₂ synthase inhibitor will be useful as a prophylactic or therapeutic agent for the above-mentioned angina pectoris, myocardial infarction, cerebral infarction or bronchial asthma. Conventionally, compounds having a TXA ₂ synthase inhibitory activity include, for example, ozagrel (The Merck In
dex, 11th edition, p. 6935) and dazoxiben (Drug o)
f the Future, vol. 6, p. 693, 1981), pyridine derivatives (JP-A-60-28963, JP-A-60-1)
55555, JP-A-62-87570, JP-A-7-17
9425).

[0005]

As a therapeutic or prophylactic agent for a thrombotic disease, development of a drug having no side effects such as bleeding and having high action selectivity has been desired. A GPIIb / IIIa antagonist is sufficient for platelet aggregation inhibitory activity alone, but unfortunately cannot exert its effect on vascular lesions such as vasospasm.

[0006]

Means for Solving the Problems Accordingly, the present inventors have developed a GP.
An attempt was made to solve the above-mentioned problem by having both IIb / IIIa antagonistic activity and TXA ₂ synthase inhibitory activity. The present inventors have already found a compound having both GPIIb / IIIa antagonism and TXA ₂ synthase inhibitory activity in Japanese Patent Application No. 8-78004, and as a result of various studies, have found an effective present compound. In addition, improvement in oral absorbability can be expected due to increase in fat solubility. Accordingly, an object of the present invention is to provide a novel compound having an antiplatelet effect.

Another object of the present invention is to provide a pharmaceutical composition comprising the novel compound having the above-mentioned action. Another object of the present invention is to provide a method for treating or preventing a thrombotic disease, which comprises administering a novel compound having the above action. Furthermore, the present invention
It is an object of the present invention to provide a use of a novel compound having the above action for the manufacture of a pharmaceutical composition used for treating or preventing thrombotic diseases.

The heterocyclic compound according to the present invention is an imidazole or pyridine derivative represented by the following general formula (I) or (II), and pharmacologically acceptable salts and solvates thereof.

Embedded image (I) [In the above formula, A, B, D, E, and F may be the same or different, and -CR ¹ =, -CR ¹ R ^2- , -N
＝, —NR ¹ — or a bond (where R ¹ and R ² may be the same or different and each represents a hydrogen atom or a lower alkyl group), and G represents —CR ¹ R ² — or — (CO) —.
Wherein R ¹ and R ² represent the same meaning as described above,
J is -CHX- or -C (= CH-Y)-(where X
Represents a pyridyloxy group, a pyridyl group, a pyridylalkyl group, an imidazolyl group or an imidazolylalkyl group, and Y represents a pyridyl group or a pyridylalkyl group.
The stands, K is a group -Z- (CH ₂₎ qCOOR ³ or -
CH = CR ⁴ COOR ³ (where Z is —O— or a bond, R ³ is a hydrogen atom, a lower alkyl group or an ester residue that can be removed under physiological conditions, and R ⁴ is a hydrogen atom or a lower alkyl group And q represents an integer of 1 to 4.)
And p represents 1 or 2. ]

[0009]

Embedded image (II) wherein G ′ represents —CH ₂ — or — (CO) —, J ′ represents —CHX— (where X represents a 3-pyridyloxy group or 1-imidazolylmethyl group) or -C
(= CH-Y)-(where Y represents a 3-pyridyl group)
The stands, K is a group -Z- (CH ₂₎ qCOOR ³ or -
CH = CR ⁴ COOR ³ (where Z is —O— or a bond, R ³ is a hydrogen atom, a lower alkyl group or an ester residue that can be removed under physiological conditions, and R ⁴ is a hydrogen atom or a lower alkyl group And q represents an integer of 1 to 4.)
And p represents 1 or 2. ]

[0010]

DETAILED DESCRIPTION OF THE INVENTION Compounds of general formula (I) or (II) As used herein, the term "lower alkyl" as a group or part of a group refers to straight or branched chain carbon atoms having 1 to 1 carbon atoms.
6, preferably 1 to 4 alkyl groups.

In the general formula (I), R ¹ and R ² represent a hydrogen atom or a lower alkyl group. One or more hydrogen atoms of the lower alkyl group may be substituted, and specific examples of the substituent include a hydroxyl group and a halogen atom (preferably,
Examples thereof include a chlorine atom, a bromine atom, and a fluorine atom) amino group and a lower alkylamino group (preferably, methylamino, ethylamino, propylamino, dimethylamino, and diethylamino).

Examples of A, B, D, E, and F in the general formula (I) are those in which A, B, D, E, and F represent -CR ¹ =,
-CR ¹ R ² -or a bond, or one of B, D, and E is -N =, -NR ^1- , and the rest are -CR ¹ =,
—CR ¹ R ² — or a bond. Specific preferred examples include pyridylpiperazinyl and pyridylhomopiperazinyl (the binding positions of these are 2
Position, position 3, and position 4), pyrimidinylpiperazinyl, pyrimidinylhomopiperazinyl, tetrahydropyrimidinylpiperazinyl, tetrahydropyrimidinylhomopiperazinyl (the bonding positions thereof are as follows:
And 5).

Preferred examples of the lower alkyl group represented by R ¹ and R ² in the group —CR ¹ R ² — represented by G in the general formula (I) include methyl, ethyl, n-propyl, iso-propyl and n. -, Iso-, sec-, t-butyl and the like.

Preferred examples of X in the group -CHX- and -C (= CH-Y)-represented by J in the general formula (I) are 3-pyridyloxy, 3-pyridylmethyl, 1-
Imidazolyl, 1-imidazolylmethyl and the like,
Preferred examples of Y include 3-pyridyl and the like.

Groups of the general formulas (I) and (II) represented by K: -Z- (CH ₂ ) qCOOR ^3- , -CH ＝ CR ⁴ COO
In R ³ —, Z represents an oxygen atom or a bond, preferably an oxygen atom. Also, q preferably represents 1 or 2. Preferred examples of the lower alkyl group represented by R ³ and R ⁴ include methyl, ethyl, n-propyl, iso-propyl, n-, iso-, sec- and t-butyl. R ³ can represent an ester residue that can be removed under physiological conditions, and specific examples thereof include:
Examples include a pivaloyloxymethyl group, a 1- (cyclohexyloxycarbonyloxy) ethyl group, and a (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group.

The compounds according to the invention can be in the form of their salts. Such salts include pharmacologically acceptable non-toxic salts. Preferred examples thereof include inorganic salts such as sodium salt, potassium salt, magnesium salt and calcium salt, and acid addition salts such as trifluoroacetate, hydrochloride, sulfate, oxalate, methanesulfonate and citrate. , Glutamate, and amino acid salts such as aspartate.

The compounds according to the invention can also be solvates thereof. Preferred solvates include hydrates and ethanol solvates.

Synthesis of compound of general formula (I) The compound according to the present invention can be synthesized by the following method. As the protecting group for the carboxyl group used in the following synthesis method, a normal protecting group used for peptide synthesis can be used, but a methyl group, an ethyl group, a t-butyl group, a benzyl group, a p-methoxy group are preferable. Examples include a benzyl group, a p-nitrobenzyl group, an allyl group, and a benzhydryl group.

(1) When the compound is represented by the general formula (I) and J is -CHX-

Embedded image A compound represented by the formula (III) (where A, B, D, E, F and p represent the above-mentioned meanings) and a compound represented by the formula (IV) (where K represents the above-mentioned meaning) In a solvent that does not participate in the reaction in the presence of a base for 0.5 to 24 hours, preferably 0.5 to 10 hours, at 0 to 100 ° C., preferably 0 to 30 ° C. Equation (V)
In formula (IV) L represents a halogen atom (preferably a chlorine atom, a bromine atom) or group -OR ^5,. The R ^5, methanesulfonyl group, etc. p- toluenesulfonyl group can be used. Next, the compound represented by the formula (V) is reduced to a general formula (VI) according to a conventional method, and the compound of the general formula (I) can be obtained by a Mitsunobu reaction.
That is, in a solvent not involved in the reaction, in the presence of triphenylphosphine, or tributylphosphine and diethyl azodicarboxylate, or 1,1 ′-(azodicarbonyl) dipiperidine, an alcohol and, for example, pyridyl alcohol for 10 minutes to 24 hours, Preferably 1 to 12
The reaction is carried out at a temperature of 0 to 100 ° C., preferably 20 to 80 ° C. for a time, and the protecting group is removed as necessary, whereby the compound of the general formula (I) can be obtained. In this case, in the group -CHX- represented by J in the general formula (I), preferable examples represented by X are 1-imidazolyl and 3-pyridyloxy.

The compound represented by the formula (IV) can be obtained by converting a compound such as 4-hydroxyacetophenone to W
It can be synthesized according to O9421599 and Japanese Patent Application No. 8-78004.

When X is an imidazolyl group in the group —CHX— represented by J in the general formula (I), the imidazole carboxylate or imidazole aldehyde is used to form M.
The compound of general formula (I) can be obtained by performing an isunobu reaction and performing deesterification or dealdehyde. In addition, EP683156, WO9421
599, Chem. Pharm. Bull. , 44 volumes,
The compound of general formula (I) can also be obtained according to the method described on page 1510, 1996.

In the group —CHX— represented by J in the general formula (I), when X is a pyridyl group or a pyridylalkyl group, those described in JP-A-4-270265, JP-A-5-43547 and WO9
The compound of the general formula (I) can be obtained according to the method described in U.S. Pat.

[0023]

Embedded image When X in the group -CHX- represented by J in the general formula (I) is an imidazolylmethyl group, the group represented by the formula (VII) [wherein R ¹ ,
K represents the above-mentioned meaning, and M represents a group generally used as a protecting group for a hydroxyl group (preferably, acetyl, methoxymethyl, methoxyethoxymethyl, tetrahydropyranyl, methanesulfonyl, p-toluenesulfonyl, benzyl) A) in the presence of a base in a solvent that does not participate in the reaction for 0.5 to 24 hours, preferably 0.5 to 10 hours.
The reaction is carried out at 0 to 100 ° C., preferably 0 to 30 ° C., to give formula (VIII). Then, for example, R ⁵
Formula (IX) is obtained by reacting the compound represented by Cl and a base in the same manner. Further, the above equation (V)
By reacting imidazole in the same manner as in the above case, it can be led to the formula (X). After reducing the ester by a conventional method and further protecting the hydroxyl group, deprotection of the phenolic hydroxyl group and introduction of K are performed to obtain the formula (XII).
Then, the compound of the general formula (I) can be obtained in exactly the same manner as in the case of the above formula (V). By hydrolyzing the ester of the compound represented by the formula (X) without reducing it to form a carboxylic acid, and performing a reaction with the formula (III) according to a conventional method, G of the general formula (I) becomes-(CO )-Can be obtained. Here, the compound represented by the formula (VII) is prepared by the method described in Chem. Pharm. Bull., Vol. 41, 1990.
Page, 1993.

(2) When the compound is represented by the general formula (I) and J is -C (= CH-Y)-In the above reaction from (VII) to (VIII), instead of paraformaldehyde By using, for example, pyridyl aldehyde, the compound of the general formula (I) can be obtained. In this case, the group represented by J in the general formula (I)
Preferred examples of Y represented by C (= CH-Y)-include 3-pyridyl and the like.

In the above-mentioned production methods, the synthesis order is determined so that no side reaction occurs in the functional groups not involved in the reaction, and the functional groups are protected with appropriate protecting groups so that undesired reactions do not proceed. It will be apparent to those skilled in the art that this may be the case.

Use of Compound / Pharmaceutical Composition The compound according to the present invention is a platelet membrane protein, GPIIb / IIIa.
Inhibits platelet aggregation by inhibiting binding to fibrinogen. Furthermore, by inhibiting TXA ₂ synthase, it can be expected that the production of TXA ₂ is suppressed, and the release of various cytokines from platelets and the spasm of blood vessels are suppressed. Therefore, the compounds according to the present invention and pharmacologically acceptable salts thereof are thrombotic diseases caused by platelet aggregation, especially cerebral infarction, myocardial infarction, angina,
It is effective for treating and preventing diseases such as peripheral arterial occlusion.

The pharmaceutical composition containing the compound according to the present invention and a pharmacologically acceptable salt thereof as an active ingredient is orally or parenterally (eg, intravenous, intramuscular, subcutaneous, rectal, transdermal) Administration) can be administered to humans and non-human animals.

Therefore, the pharmaceutical composition containing the compound according to the present invention as an active ingredient is made into an appropriate dosage form depending on the administration route, and specifically, mainly injections such as intravenous injection and intramuscular injection, capsules and tablets. , Granules, powders, pills, fine granules, toro
Tablets and the like, oral preparations, rectal administration preparations, oily suppositories, aqueous suppositories and the like can be prepared in any form. These various preparations are commonly used excipients, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, dispersants,
It can be manufactured by a conventional method using a buffer, a preservative, a solubilizing agent, a preservative, a flavoring agent, a soothing agent, a stabilizer and the like. The non-toxic additives that can be used include, for example, lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose or a salt thereof, gum arabic, polyethylene glyco- Syrup, petrolatum, glycerin, ethanol, propylene glycol,
Citric acid, sodium chloride, sodium sulfite, sodium phosphate and the like.

The content of the compound according to the present invention in the pharmaceutical composition varies depending on the dosage form, but is usually 1 to 7 in the total composition.
0% by weight, preferably about 5 to 50% by weight. The dosage is appropriately determined in consideration of the usage, the age of the patient, the sex, the degree of the symptoms, and the like. For the treatment of thrombotic diseases, usually about 0.1 to 1000 mg per adult daily, preferably Is a dosage of 1 to 200 mg, which can be administered once or several times a day.

[0030]

EXAMPLES Examples and test examples are shown below, but the present invention is not limited to these.

Test Example 1 Platelet Aggregation Inhibiting Activity The platelet aggregation inhibiting effect of the compound of the present invention was evaluated using human PR.
The examination was performed using P (platelet-rich plasma). 9 volumes of blood were collected from a vein of a normal human (male) using a syringe containing 1 volume of 3.8% sodium citrate, and 10 volumes at 170 × g.
After centrifugation at room temperature for 1 minute, the obtained supernatant was separated and used as PRP. The remaining blood from which the PRP was collected was collected at 2700 xg for 1
After centrifugation for 5 minutes, the supernatant was separated as platelet poor plasma (PPP). The platelet aggregation test was performed using an aggregometer (PAM-8C) manufactured by Mevanix. The test substance is
It was dissolved in physiological saline, 0,1N hydrochloric acid-physiological saline or 1N aqueous sodium hydroxide solution-physiological saline. Also,
The preincubation time between the test substance and PRP is 2
Minutes. ADP (CHRONO-PAR REAGENTS)
384 ADP, CHRONO-LOG Corp.) was used after being diluted with physiological saline to a final concentration of 5 μM. From the following formula, the platelet aggregation inhibitory activity was A when no test compound was added.
It was determined as the inhibition rate against the platelet aggregation effect of DP.

The platelet aggregation inhibitory activity of the compound according to the present invention is as shown below.

Test Example 2 Platelets GPIIb / IIIa and fibrino
The inhibitory effect of the compound according to the present invention on the binding between platelet GPIIb / IIIa and fibrinogen was determined by using the biotinylated human fibrinogen as a ligand for human platelet GPIIb / II.
The study was performed using the Ia solid phase receptor binding experimental system. First,
Human platelet GPIIb / IIIa was prepared according to the method of Pytela, R et al. (Scienc
e, 231, 1559-1561 (1986)). That is, 0.2% (w / v) Gluco
TBS containing se (0.15 M NaCl / 50 mM T
ris-HCl buffer (pH 7.5)), and the resulting pellet was added to the same amount of 50 mM Octylglucoside, 2 mM
TBS containing PMSF was added to solubilize the membrane protein at 4 ° C. for 20 minutes. The extract was centrifuged at 3500 × g for 20 minutes at 4 ° C., and 1 mM CaCl ₂ and 1 mM were added to the obtained supernatant.
mM MgCl ₂ was added to obtain a sample for affinity chromatography. 50 mM Octylglucoside in advance
TB containing 1 mM CaCl ₂ and 1 mM MgCl ₂
The solubilized protein solution was adsorbed on a GRGDSPK-Sepharose column equilibrated with S (buffer solution A).
After washing with buffer A, the adsorbed GPIIb / IIIa was eluted with buffer A containing 2 mM GRGDDSPK peptide. GRGDSPK-Sepharose was prepared by coupling the GRGDSPK peptide with CNBr-activated Sepharose 4B (Pharmacia) according to the manufacturer's instructions. Next, a binding test of human platelet GPIIb / IIIa solid phase receptor was performed according to the method of Mori et al. (Journal of the Japanese Society of Thrombosis and Hemostasis, 2 (4), 323-329 (1991)). Purified human platelet GPIIb / IIIa was prepared at 2 μg / ml and adsorbed to a 96-well microtiter plate in 50 μl portions at 4 ° C. overnight. 1 mM CaCl ₂ and 1 mM MgCl ₂
After washing with TBS containing 1%, 1% bovine serum albumin
The solution was added in an amount of 00 μl each and blocking was further performed at 4 ° C. overnight. TBS containing 0.01% Tween 20 (TBS-T
After washing with ween 20), 50 μl of biotinylated fibrinogen adjusted to 1 μg / ml was added thereto, and 50 μl of the test compound adjusted to each concentration was simultaneously added thereto, followed by reaction at room temperature for 4 hours. After washing with TBS-Tween 20, peroxidase-labeled avidin was washed with TBS for 4 days.
000-fold dilutions were added in 50 μl aliquots,
Allowed to react for minutes. After washing with TBS-Tween 20, 1 m of peroxidase substrate buffer diluted 10 times was added.
g / ml ABTS (2,2'-Azino-bis (3-ethylbenzthiazol
A solution in which ine-6-sulfonic acid was dissolved was added in an amount of 50 μl, and the mixture was reacted for 5 minutes. The reaction was stopped by adding 50 μl of 0.1 M citrate buffer (pH 4.3) containing 0.05% NaN _3, and the absorbance at 415 nm was measured. The binding inhibition rate was calculated by the following equation.

Platelets GPIIb / IIIa of the compounds according to the invention
The effect of inhibiting the binding of to fibrinogen is as follows.

Test Example 3 Thromboxane A ₂ (TXA ₂ )
Synthase Inhibitory Activity The TXA ₂ synthase inhibitory activity of the compound according to the present invention was measured by the method of Li et al.
It went according to. 10 μg of human TXA ₂ synthase (B
50 mM Tris-HCl buffer (0.IOMOL).
PH 7.5, 25 ° C. containing 1 M NaCl) 100 μ
Then, 10 μl of the test drug solution was added to 1 l, and the mixture was incubated at 25 ° C. for 3 minutes. Next, 2 μl of a 50 μg / ml PGH ₂ solution (Cayman Chemical) was added to start the enzymatic reaction, and the reaction was performed at 25 ° C. for 3 minutes.
The reaction was stopped by adding 10 μl of an aqueous M ferrous chloride solution.
After standing at room temperature for 15 minutes, the mixture was centrifuged at 4 ° C. at 3000 × g for 10 minutes, and the supernatant was used as a sample for TXB ₂ quantification. TX
B ₂ The amount of Thromboxane B2 Enzyme
Immunoassay Kit (Cayman C
Chemical Co., Ltd.). After performing the color reaction, the absorbance at 415 nm was measured using a microplate reader (Corona Electric, MTP-32). T
The XA ₂ synthase activity inhibition rate is calculated by the following equation,
A 50% inhibitory concentration value was determined by a regression line. Inhibition rate (%) = (1−B / A) × 100 A: Amount of TXB ₂ produced without addition B: Amount of TXB ₂ produced when test substance is added

The TXA ₂ synthase inhibitory activity of the compound according to the present invention is as shown below.

Example 1 Ethyl 2- [4- [1- (3-
Pyridyloxy) -2- [4- (4-pyridyl) pipera
Dinyl] ethyl] phenoxy] acetate (a) 4-pyridylpiperazine (2 g: JP-A-6-19)
2225) was dissolved in acetonitrile (80 ml), a solution of ethyl 2- [4- (2-bromoethyl) phenoxy] acetate (2.01 g) in acetonitrile (40 ml) was added, and the mixture was stirred at room temperature overnight. The insolubles were removed from the reaction solution by filtration, the filtrate was concentrated, re-extracted with dichloromethane, washed with water, dried over sodium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography (80 g, chloroform: methanol = 9: 1) to give ethyl 2- [4-
1.378 g (54.7 g of [2- [4- (4-pyridyl) piperazinyl] acetyl] phenoxy] acetate
%)Obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J
= 7.1 Hz), 2.72 (4H, t, J = 5.1H)
z), 3.41 (4H, t, J = 5.1 Hz), 3.8
2 (2H, s), 4.28 (2H, q, J = 7.1H
z), 4.69 (2H, s), 6.66 (2H, d, J
= 6.4 Hz), 6.95 (2H, d, J = 8.9H)
z), 8.01 (2H, d, J = 8.9 Hz), 8.2
6 (2H, d, J = 6.4 Hz) TSPMS (m / z): 384 (M ⁺⁺ 1)

(B) The compound obtained in the above (a) (1.
378 g) was dissolved in ethanol (30 ml), sodium borohydride (63.3 mg) was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated, extracted with ethyl acetate, and washed with a saturated saline solution and then with water. After drying over sodium sulfate, the solvent was distilled off and ethyl 2- [4- [1-hydroxy-
864 mg (66.9%) of 2- [4- (4-pyridyl) piperazinyl] ethyl] phenoxy] acetate was obtained. ¹ H-NMR (CDCl ₃ ) δ: 1.30 (3H, t, J
= 7.1 Hz), 2.53 (1H, s), 2.55 (1
H, d, J = 2.7 Hz), 2.59 (2H, brt,
J = 10.9Hz), 2.87 (2H, brt, J = 1
0.9 Hz), 3.38 (4H, dt, J = 3.9,
6.1 Hz), 4.27 (2H, q, J = 7.1H)
z), 4.62 (2H, s), 4.75 (1H, dd,
J = 5.5, 8.2 Hz), 6.67 (2H, d, J =
6.6 Hz), 6.90 (2H, d, J = 8.6H)
z), 7.31 (2H, d, J = 8.6 Hz), 8.2
9 (2H, d, J = 6.6 Hz) TSPMS (m / z): 386 (M ⁺⁺ 1)

(C) The compound (32) obtained in the above (b)
8 mg) was dissolved in a mixed solvent of benzene (10 ml) and tetrahydrofuran (10 ml), and tributylphosphine (0.315 ml) was added under ice-cooling, followed by 3-hydroxypyridine (121.4 mg) and further 1,1′-.
(Azodicarbonyl) dipiperidine (322.1 mg)
Was added and stirred at room temperature overnight. The reaction solution was concentrated, extracted with ethyl acetate, and washed with a saturated saline solution and then with water. After drying over sodium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (30 g, chloroform: methanol = 9: 1) to give 132.2 mg of the title compound.
(33.6%). ¹ H-NMR (CD ₃ OD) δ: 1.23 (3H, t, J
= 7.1 Hz), 2.99 (2H, dd, J = 3.0, 1
3.7 Hz), 3.06 (2H, s), 3.28-3.
35 (2H, m), 3.81 (4H, brt, J = 3.
7 Hz), 4.18 (2H, q, J = 7.1 Hz),
4.67 (2H, s), 5.68 (1H, dd, J =
3.0, 8.8 Hz), 6.92 (2H, d, J = 8.
8 Hz), 7.18 (2H, d, J = 7.6 Hz),
7.27 (1H, dd, J = 4.8, 8.6 Hz),
7.39 (2H, d, J = 8.8 Hz), 7.42 (1
H, d, J = 2.7 Hz), 8.07 (1H, d, J =
4.2Hz), 8.15 (2H, d, J = 7.6H)
z), 8.24 (1H, s) TSPMS (m / z): 463 (M ⁺⁺ 1)

Example 2 2- [4- [1- (3-pyridi)
Luoxy) -2- [4- (4-pyridyl) piperazini
[Ethyl] phenoxy] acetic acid The compound (30 mg) obtained in Example 1 was dissolved in ethanol (2 ml), a 1N aqueous sodium hydroxide solution (0.195 ml) was added, and the mixture was stirred at room temperature overnight. After concentrating the reaction solution, adding water and neutralizing with a 1N aqueous hydrochloric acid solution,
Washed with ethyl acetate and then with chloroform. The aqueous layer was concentrated, extracted with ethanol, further concentrated, and lyophilized to give 27.8 mg (98.7%) of the title compound. ¹ H NMR (D ₂ O) δ: 2.64 (1 H, dd, J =
2.3, 13.7 Hz), 2.70-2.76 (4H,
m), 3.06 (1H, dd, J = 9.6, 13.7H
z), 3.48-3.54 (4H, m), 4.42 (2
H, s), 5.56 (1H, dd, J = 2.3, 8.8)
Hz), 6.92 (4H, d, J = 8.8 Hz), 7.
22-7.27 (1H, m), 7.35 (4H, d, J
= 8.5 Hz), 8.07 (2H, brd, J = 13.
0 Hz), 8.21 (1H, s) TSPMS (m / z): 435 (M ⁺⁺ 1)

Example 3 Ethyl 2- [4- [1- (imi
Dazolylmethyl) -2- [4- (4-pyridyl) pipera
Dinyl] ethyl] phenoxy] acetate (a) Ethyl 2- [4- (methoxymethoxy) phenyl] acetate (10.1 g) and paraformaldehyde (1.35 g) were dissolved in dimethyl sulfoxide (45 ml), and 0.5N sodium An ethanol solution of ethoxide (4.5 ml) was added, and the mixture was stirred at room temperature for 4 hours. Acetic acid (4.5 ml) and water (100 ml) were added to the reaction solution, and extracted with ethyl acetate. The extract was washed with water, saturated aqueous sodium hydrogen carbonate and saturated saline, dried over magnesium sulfate, and the solvent was distilled off. Purification by silica gel column chromatography (350 g, n-hexane: ethyl acetate = 2: 1) gave ethyl 3-hydroxy-
7.80 g (68.2%) of 2- [4- (methoxymethoxy) phenyl] propanoate were obtained. ¹ H NMR (CDCl ₃ ) δ: 1.23 (3H, t, J =
7.1 Hz), 2.22 (1H, t, J = 6.3H)
z), 3.47 (3H, s), 3.75-3.83 (2
H, m), 4.04-4.25 (3H, m), 5.16
(2H, s), 7.00 (2H, d, J = 8.5H)
z), 7.19 (2H, d, J = 8.5 Hz) TSPMS (m / z): 255 (M ⁺⁺ 1)

(B) The compound obtained in the above (a) (7.
80 g) was dissolved in methylene chloride (75 ml), and triethylamine (5.1 ml) and methanesulfonyl chloride (2.8 ml) were added under ice-cooling, followed by stirring at room temperature for 1 hour. Water and methylene chloride were added to the reaction solution, and the organic layer was further washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was treated with acetone (150
ml), sodium carbonate (6.52 g), imidazole (10.5 g), sodium iodide (91 m
g) was added and the mixture was stirred for 2.5 hours under reflux with heating. Further, imidazole (10.5 g) was added, and the mixture was stirred for 1.5 hours. The reaction solution was subjected to suction filtration, the filtrate was concentrated, and then ethyl acetate was added to the residue. After washing with water and saturated saline and drying over sodium sulfate, the solvent was distilled off. Silica gel column chromatography (300 g, methylene chloride: methanol = 2
0: 1) to give ethyl 3-imidazolyl-2- [4
9.24 g (98.9%) of-(methoxymethoxy) phenyl] propanoate were obtained. ¹ H NMR (CDCl ₃ ) δ: 1.17 (3H, t, J =
7.1 Hz), 3.45 (3H, s), 3.87 (1
H, dd, J = 6.3, 8.5 Hz), 4.06-4.
20 (3H, m), 4.59 (1H, dd, J = 8.
5,13.9 Hz), 5.16 (2H, s), 6.84
(1H, s), 7.00 (3H, m), 7.16 (2
H, d, J = 8.8 Hz), 7.35 (1 H, s) TSPMS (m / z): 305 (M ⁺⁺ 1)

(C) Lithium aluminum hydride (1.
90 g) were suspended in tetrahydrofuran (65 ml), and the compound (7.61) obtained in the above (b) was suspended under ice cooling.
A solution of g) in tetrahydrofuran (60 ml) was added dropwise over 30 minutes. The mixture was further stirred for 1 hour under ice cooling. The reaction solution was slowly poured into a cold saturated aqueous ammonium chloride solution (125 ml). After insolubles were filtered off through celite, the mixture was extracted with ethyl acetate. After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off to give 3-imidazolyl-2.
-[4- (methoxymethoxy) phenyl] propane-1
6.19 g (94.4%) of all were obtained. . ¹ H NMR (CDCl ₃ ) δ: 1.79 (1 H, br
s), 3.13 (1H, m), 3.48 (3H, s),
3.77 (2H, d, J = 6.3 Hz), 4.16 (1
H, dd, J = 7.6, 13.9 Hz), 4.38 (1
H, dd, J = 6.3, 13.9 Hz), 5.16 (2
H, s), 6.80 (1H, s), 7.00 (3H,
m), 7.05 (2H, d, J = 8.5 Hz), 7.3
1 (1H, s) TSPMS (m / z): 263 (M ⁺⁺ 1)

(D) The compound obtained in the above (c) (5.
59 g) was dissolved in pyridine (40 ml), acetic anhydride (2.2 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure to obtain 7.53 g (quant.) Of 3-imidazolyl-2- [4- (methoxymethoxy) phenyl] propyl acetate. ¹ H NMR (CDCl ₃ ) δ: 2.07 (3H, s),
3.29 (1H, m), 3.48 (3H, s), 4.1
4 (1H, dd, J = 8.0, 14.1 Hz), 4.2
3-4.32 (3H, m), 5.16 (2H, s),
6.72 (1H, s), 6.99 (5H, m), 7.2
5 (1H, s) TSPMS (m / z): 305 (M ⁺⁺ 1)

(E) The compound obtained in the above (d) (7.
53 g) was dissolved in methylene chloride (100 ml), trifluoroacetic acid (16.5 ml) was added under ice cooling, and the mixture was stirred at room temperature for 2.5 hours. Further, trifluoroacetic acid (8.2
ml) and stirred for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with methylene chloride. After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off. Purification by silica gel column chromatography (250 g, methylene chloride: methanol = 30: 1-10: 1) gave 4.52 g (81.5%) of 2- (4-hydroxyphenyl) -3-imidazolylpropyl acetate. ¹ H NMR (CDCl ₃ ) δ: 2.12 (3H, s),
3.15-3.24 (1H, m), 4.09 (1H, d
d, J = 8.3, 13.9 Hz), 4.22-4.38
(3H, m), 6.67 (4H, d, J = 2.4H
z), 6.84 (1H, s), 6.90 (1H, s),
7.02 (1H, s) TSPMS (m / z): 261 (M ⁺⁺ 1)

(F) The compound obtained in the above (e) (1.
04 g) was dissolved in acetone, and potassium carbonate (608 m
g) and ethyl chloroacetate (0.43 ml) were added. After stirring at 60 ° C. for 3 hours, potassium carbonate (608 mg) and ethyl chloroacetate (0.43 m
l) was added and the mixture was stirred at 60 ° C for 12 hours. After insoluble matter was removed from the reaction solution by filtration through Celite, the filtrate was concentrated. Ethyl acetate and a 10% aqueous solution of ammonium chloride were added to the residue.
The organic layer was separated and the aqueous layer was further extracted with ethyl acetate.
After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off. Purification by silica gel column chromatography (85 g, methylene chloride: methanol = 50: 1) gave ethyl 2-
820 mg of [4- [2-acetyloxy-1- (imidazolylmethyl) ethyl] phenoxy] acetate (5 mg
9.2%). ¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J =
7.1 Hz), 2.07 (3H, s), 3.25-3.
33 (1H, m), 4.13 (1H, dd, J = 7.
8, 13.9 Hz), 4.23-4.32 (5H,
m), 4.60 (2H, s), 6.69 (1H, s),
6.85 (2H, d, J = 8.8 Hz), 6.97 (1
H, s), 7.00 (2H, d, J = 8.8 Hz),
7.22 (1H, s) TSPMS (m / z): 347 (M ⁺⁺ 1)

(G) Compound (82) obtained in the above (f)
0 mg) was dissolved in ethanol (12 ml), potassium carbonate (360 mg) was added, and the mixture was stirred at room temperature for 4 hours. After insoluble matter was removed from the reaction solution by filtration through Celite, the filtrate was concentrated. Water was added to the residue and extracted with methylene chloride. The extract was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off. The product was purified by silica gel column chromatography (25 g, methylene chloride: methanol = 25: 1).
-[4- [2-hydroxy-1- (imidazolylmethyl) ethyl] phenoxy] acetate was 420 mg (5 mg).
8.2%). ¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J =
7.1 Hz), 1.86 (1H, brs), 3.08-
3.16 (1H, m), 3.77 (2H, m), 4.1
5 (1H, dd, J = 7.6, 13.9 Hz), 4.2
7 (2H, q, J = 7.1 Hz), 4.37 (1H, d
d, J = 6.6, 13.9 Hz), 4.60 (2H,
s), 6.73 (1H, s), 6.86 (2H, d, J
= 8.8 Hz), 6.96 (1H, s), 7.05 (2
H, d, J = 8.8 Hz), 7.29 (1H, s) TSPMS (m / z): 305 (M ⁺⁺ 1)

(H) The compound (19) obtained in the above (g)
7 mg) was dissolved in methylene chloride (3 ml), and triethylamine (0.18 ml) and methanesulfonyl chloride (0.075 ml) were added under ice-cooling, followed by stirring at room temperature for 2 hours. Under ice-cooling, saturated aqueous sodium hydrogen carbonate was added to the reaction solution, extracted with methylene chloride, washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off to remove ethyl 2- [4- [1- (imidazolylmethyl). 249 mg (quan) of 2- (methylsulfonyloxy) ethyl] phenoxy] acetate
t. )Obtained. ¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J =
7.1 Hz), 2.95 (3H, s), 3.32-3.
40 (1H, m), 4.21 (1H, dd, J = 7.
6, 14.3 Hz), 4.27 (2H, q, J = 7.1)
Hz), 4.32-4.40 (4H, m), 4.60
(2H, s), 6.74 (1H, s), 6.87 (2
H, d, J = 8.8 Hz), 6.99 (1H, s),
7.01 (2H, d, J = 8.8 Hz), 7.24 (1
H, s) TSPMS (m / z): 383 (M ⁺⁺ 1)

(I) The compound (30) obtained in the above (h)
mg) and 4-pyridylpiperazine (38 mg) were suspended in toluene (1 ml) and stirred at 80 ° C for 3 hours. The residue obtained by concentrating the reaction solution was subjected to PTLC (Merck
5744; methylene chloride: methanol = 5: 1) to give 8.2 mg (23.3%) of the title compound. ¹ H NMR (CDCl ₃ ) δ: 1.30 (3H, t, J =
7.1 Hz), 2.47-2.55 (3H, m), 2.
63-2.72 (3H, m), 3.11-3.20 (1
H, m), 3.35 (4H, m), 4.18 (1H, d
d, J = 7.3, 13.6 Hz), 4.22-4.32
(3H, m), 4.60 (2H, s), 6.59 (1
H, s), 6.66 (2H, d, J = 6.3 Hz),
6.84 (2H, d, J = 8.8 Hz), 6.94 (2
H, d, J = 8.8 Hz), 6.94 (1H, s),
7.17 (1H, s), 8.27 (2H, d, J = 6.
3 Hz) TSPMS (m / z): 450 (M ⁺⁺ 1)

Example 4 2- [4- [1- (imidazoli)
Methyl) -2- [4- (4-pyridyl) piperazini
[Ethyl] phenoxy] acetic acid / hydrochloride The compound (27 mg) obtained in Example 3 (i) was dissolved in ethanol (1 ml), and a 1N aqueous sodium hydroxide solution (0.075 ml) was added under ice-cooling. Stirred at room temperature for 4 hours. The reaction solution was concentrated, water (0.4 ml) was added to the residue, and 1N hydrochloric acid (0.2 ml) was added under ice cooling. The residue obtained by concentrating this solution was subjected to LH-20 (water: methanol).
= 1: 1) to give 24 mg of the title compound.
(80.9%). ¹ H NMR (D ₂ O) δ: 2.79 (4H, m), 3.0
2 (1H, m), 3.28 (1H, brt, J = 9.8
Hz), 3.48 (1H, m), 3.64 (4H, br)
s), 4.23 (1H, dd, J = 11.0, 13.4)
Hz), 4.36 (2H, s), 4.50 (1H, d
d, J = 4.6, 13.4 Hz), 6.80 (2H,
d, J = 8.8 Hz), 6.95 (2H, d, J = 7.
6 Hz), 7.07 (2H, d, J = 8.8 Hz),
7.20 (2H, brs), 7.98 (2H, d, J =
7.6 Hz), 8.08 (1H, brs) TSPMS (m / z): 422 (M ⁺⁺ 1)

Example 5 Ethyl 2- [4- [2-oxo]
-1- (3-pyridylmethylene) -2- [4- (4-pi
Lysyl) piperazinyl] ethyl] phenoxy] acetate
In preparative (a) Example 3 (a) and the same method, using 3-pyridyl aldehyde in place of paraformaldehyde, ethyl 2- [4- (methoxymethoxy) phenyl] -3-
8.21 g of (3-pyridyl) -2-propenoate
(77.1%). ¹ H NMR (CDCl ₃ ) δ: 1.32 (3H, t, J =
7.1 Hz), 3.51 (3H, s), 4.28 (2
H, q, J = 7.1 Hz), 5.20 (2H, s),
7.03 (2H, d, J = 8.8 Hz), 7.07 (1
H, dd, J = 4.6, 7.8 Hz), 7.12 (2
H, d, J = 8.8 Hz), 7.28 (1H, m),
7.74 (1H, s), 8.39-8.43 (2H,
m) TSPMS (m / z): 314 (M ⁺⁺ 1)

(B) Compound (50) obtained in the above (a)
1 mg) in ethanol (8 ml), and the mixture was dissolved in ice-cooled 5N
An aqueous sodium hydroxide solution (0.64 ml) was added, and the mixture was stirred at room temperature for 18 hours. The reaction solution was concentrated, water was added to the residue, and the mixture was washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid (2.7 ml) and saturated with sodium chloride.
Extracted with diethyl ether. After drying this solution over sodium sulfate, the solvent is distilled off to give 2- [4- (methoxymethoxy) phenyl] -3- (3-pyridyl)-.
447 mg (97.9%) of 2-propenoic acid were obtained. ¹ H NMR (CDCl ₃ ) δ: 3.50 (3H, s),
5.20 (2H, s), 7.06 (2H, d, J = 8.
8 Hz), 7.11 (1H, dd, J = 4.9, 7.8)
Hz), 7.16 (2H, d, J = 8.8 Hz), 7.
31 (1H, m), 7.87 (1H, s), 8.46
(2H, m) TSPMS (m / z): 286 (M ⁺⁺ 1)

(C) Compound (35) obtained in the above (b)
6 mg) in dimethylformamide (7 ml)
Under ice cooling, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (660 mg), triethylamine (0.35 m
l) was added and the mixture was stirred for 1 hour under ice cooling. This solution was added to a solution of 4-pyridylpiperazine (264 mg) in dimethylformamide (5 ml) under ice cooling, and the mixture was stirred at room temperature for 1 hour. Methylene chloride and water were added to the reaction solution, the organic layer was separated, and the aqueous layer was extracted with methylene chloride. The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate and saturated saline. After drying over sodium sulfate, the solvent was distilled off. Purification by silica gel column chromatography (30 g, methylene chloride: methanol = 20: 1) gave 2- [4- (methoxymethoxy) phenyl]-
511 mg of 3- (3-pyridyl) -1- [4- (4-pyridyl) piperazinyl] -2-propen-1-one
(95.0%). ¹ H NMR (CDCl ₃ ) δ: 3.13 (2H, br
s), 3.35 (2H, brs), 3.48 (3H,
s), 3.61 (2H, brs), 3.82 (2H, b
rs), 5.17 (2H, s), 6.62 (2H, d,
J = 6.6 Hz), 6.70 (1H, s), 6.98
(2H, d, J = 8.8 Hz), 7.12 (1H, d
d, J = 4.9, 8.0 Hz), 7.23 (2H, d,
J = 8.8 Hz), 8.43 (1H, m), 8.29
(2H, d, J = 6.6 Hz), 8.42-8.45
(2H, m) TSPMS (m / z): 431 (M ⁺⁺ 1)

(D) In the same manner as in Example 3 (e), the compound (450 mg) obtained in (c) above was used in place of the compound obtained in Example 3 (d),
-(4-hydroxyphenyl) -3- (3-pyridyl)
361 mg (89.0%) of -1- [4- (4-pyridyl) piperazinyl] -2-propen-1-one was obtained. ¹ H NMR (CDCl ₃ ) δ: 3.04 to 3.90 (8
H, m), 6.57 and 6.62 (2H, d, J = 6.5.
6Hz), 6.67 and 6.90 (1H, s), 6.7
4 and 6.84 (2H, d, J = 8.5 Hz), 7.10
and 7.36 (2H, d, J = 8.5 Hz), 7.18an
d7.26 (1H, dd, J = 4.9, 8.0 Hz),
7.50 and 7.81 (1H, m), 8.23-8.3
0 (2H, m), 8.41 and 8.47 (1H, dd,
J = 1.5, 4.9 Hz), 8.43 and 8.65 (1
H, d, J = 2.1 Hz) TSPMS (m / z): 387 (M ⁺⁺ 1)

(E) Compound (36) obtained in the above (d)
0 mg) was dissolved in dimethylformamide (10 ml), potassium carbonate (160 mg) and ethyl chloroacetate (0.11 ml) were added, and the mixture was stirred at room temperature for 8 hours. Methylene chloride and water were added to the reaction solution, the organic layer was separated,
After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off. Silica gel column chromatography (18 g, methylene chloride: methanol: aqueous ammonia = 250: 5: 0.
1-75: 2.5: 0.1) to give 247 mg (56.1%) of the title compound. ¹ H NMR (CDCl ₃ ) δ: 1.29 and 1.30 (3
H, t, J = 6.5 Hz), 3.07-3.93 (8
H, m), 4.26 and 4.28 (2H, q, J = 6.5)
Hz), 4.61 and 4.65 (2H, s), 6.56a
nd 6.63 (2H, d, J = 7.0 Hz), 6.71an
d 6.94 (1H, s), 6.86 and 6.95 (2H,
d, J = 8.9 Hz), 7.10 and 7.25 (1H, d
d, J = 4.6, 7.7 Hz), 7.24 and 7.47
(2H, d, J = 8.9 Hz), 7.39 and 7.82
(1H, m), 8.24-8.33 (2H, m), 8.
42 and 8.49 (1H, dd, J = 1.5, 4.6H
z), 8.43 and 8.67 (1H, d, J = 2.2H
z) TSPMS (m / z): 473 (M ⁺⁺ 1)

Example 6 2- [4- [2-oxo-1-]
(3-pyridylmethylene) -2- [4- (4-pyridi
L) Piperazinyl] ethyl] phenoxy] acetic acid / hydrochloride The compound obtained in Example 5 (e) in place of the compound obtained in Example 3 (i) in the same manner as in Example 4 (36.
5 mg) to give 39 mg of the title compound.
(97.6%). ¹ H NMR (D ₂ O) δ: 3.42 (2H, brt, J =
5.3 Hz), 3.66-3.79 (6H, m), 4.
42 (2H, s), 6.83 (2H, d, J = 8.5H)
z), 6.85 (1H, s), 6.89 (2H, d, J
= 7.1 Hz), 7.14 (2H, d, J = 8.5H)
z), 7.77 (1H, brs), 7.96 (2H,
d, J = 7.1 Hz), 8.21 (2H, d, J = 7.8)
Hz), 8.48 (2H, brs) TSPMS (m / z): 445 (M ⁺⁺ 1)

[0057]

The compound according to the present invention is excellent in platelet aggregation inhibitory activity, has no side effects due to bleeding or lack of selectivity of the inhibitory effect, and is also effective for platelet aggregation such as vasospasm. An inhibitor can be provided.

 ──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Naoko Kamien, 760 Shiokaoka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside the Pharmaceutical Research Institute, Meiji Seika Co., Ltd. Address Meiji Seika Co., Ltd., Pharmaceutical Research Laboratory (72) Inventor Emiko Hatsushiba 760, Shiokaokacho, Kohoku-ku, Yokohama, Kanagawa Prefecture Meiji Pharmaceutical Research Institute, Inc.

Claims (7)

[Claims] 1. An imidazole or pyridine derivative represented by the following general formula (I) and a pharmacologically acceptable salt and solvate thereof. Embedded image (I) [wherein A, B, D, E, and F may be the same or different, and represent -CR ¹ =, -CR ¹ R ^2- , -N =, -NR ¹ -or a bond ( Here, R ¹ and R ² may be the same or different and each represent a hydrogen atom or a lower alkyl group), and G represents —CR ¹ R ² — or — (CO) — (where R ¹ and R ² represent J represents -CHX- or -C (= CH-Y)-(where X is
Represents a pyridyloxy group, a pyridyl group, a pyridylalkyl group, an imidazolyl group or an imidazolylalkyl group, and Y represents a pyridyl group or a pyridylalkyl group.
The stands, K is a group -Z- (CH ₂₎ qCOOR ³ or -CH = C
R ⁴ COOR ³ (where Z represents —O— or a bond, R ³ represents a hydrogen atom, a lower alkyl group or an ester residue which can be removed under physiological conditions, and R ⁴ represents a hydrogen atom or a lower alkyl group. , Q represents an integer of 1 to 4), and p represents 1 or 2. ] 2. An imidazole or pyridine derivative represented by the following general formula (II), and pharmacologically acceptable salts and solvates thereof. Embedded image (II) wherein G ′ represents —CH ₂ — or — (CO) —, J ′ represents —CHX— (where X represents a 3-pyridyloxy group or a 1-imidazolylmethyl group) or −C (=
CH-Y) - (wherein Y represents represents) a 3-pyridyl group, K is a group -Z- (CH ₂₎ qCOOR ³ or -CH = C
R ⁴ COOR ³ (where Z represents —O— or a bond, R ³ represents a hydrogen atom, a lower alkyl group or an ester residue which can be removed under physiological conditions, and R ⁴ represents a hydrogen atom or a lower alkyl group. , Q represents an integer of 1 to 4), and p represents 1 or 2. ] 3. The compound according to claim 1, which is 2- [4- [1- (3-pyridyloxy) -2- [4- (4-pyridyl) piperazinyl] ethyl] phenoxy] acetic acid. 4. The compound according to claim 1, which is 2- [4- [1- (imidazolylmethyl) -2- [4- (4-pyridyl) piperazinyl] ethyl] phenoxy] acetic acid. 5. The compound according to claim 1, which is 2- [4- [2-oxo-1- (3-pyridylmethylene) -2- [4- (4-pyridyl) piperazinyl] ethyl] phenoxy] acetic acid. 6. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 or a pharmacologically acceptable salt or solvate thereof together with a pharmacologically acceptable carrier. 7. The pharmaceutical composition according to claim 6, which is effective for treating and preventing thrombotic diseases.