JPH05194404A - Carbostyril derivative - Google Patents

Abstract

PURPOSE:To provide the subject new carbostyril derivatives excellent in thromboxane A2 antagonism, useful for treatment and prevention of diseases and symptoms caused by thromboxane A2, e.g. thrombosis, vasospasm and asthma and excellent in safety. CONSTITUTION:Compounds of formula I (R<1> is H or a lower alkyl; R<2> and R<3> are H, OH, a lower alkyl or together form CO; X is H or a halogen; Y is CH2COOH or OCH2COOH; Formula II is a single bond or a double bond) or their pharmaceutically permissible salts e.g. {5-[2-(4- chlorobenzenesulfonylamino)ethyl]carbostyril-8-yl]oxyacetic acid} of formula III. In case of Y=OCH2COOH, the above-mentioned compound can be produced by four steps from a compound of formula IV (Bz is benzyl) (through compounds of formulae V to VII (tBu is t-butyl; R<4> is a lower alkyl). In addition, the dosage of the compound of formula I required for improving or preventing the above- mentioned diseases is generally 1 to 1000mg, preferably 5 to 500mg per day per an adult in oral administration.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention is excellent in thromboxane A.
A novel carbostyril derivative or a salt thereof that strongly antagonizes the action of ₂ (hereinafter referred to as TXA ₂ ), and is useful for treating and preventing thrombosis, vasospasm, asthma, and other disease symptoms caused by TXA ₂ .

[0002]

_2. Description of the Related Art TXA ₂ is a metabolite of arachidonic acid widely distributed in various animal organs such as liver, kidney, lung and brain, and strongly aggregates platelets and contracts blood vessels. Is known (Arachidonic acid cascade and drugs, Yamazo Shozo (1985)).

TXA ₂ is also known to exhibit a strong contractile action on bronchi and tracheal smooth muscle. TX like this
A ₂ is considered to be involved in a wide range of pathological conditions, for example,
Myocardial infarction, angina, thrombosis, transient cerebral ischemia, migraine,
It is known to be involved in pathological conditions such as cerebral hemorrhage, cerebral infarction, atherosclerosis, peripheral circulatory failure, hypertension, pulmonary embolism, bronchial asthma, bronchitis, pneumonia, nephritis, hepatitis and shock.

[0004]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention Therefore, by antagonizing TXA ₂ , a therapeutic effect on the above-mentioned diseases is expected, and many studies have been conducted so far. For example,
JP-A-56-100757 discloses 4- [2- (4-chlorobenzenesulfonylamino) as a compound that antagonizes TXA _2.
Ethyl] phenylacetic acid derivatives have been reported. However, it is not always satisfactory in terms of efficacy, duration of action, and side effects as a drug.

[0005]

[Means for Solving the Problems] The inventors of the present invention have synthesized various carbostyril derivatives for the purpose of solving the above problems and conducted extensive evaluation, and as a result, described in JP-A-56-100757. The inventors have found a group of novel carbostyril derivatives having a stronger TXA ₂ antagonistic action than the compounds, and completed the present invention. That is, the invention has the general formula (I)

[0006]

[Chemical 3]

(Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² and R ³ represent hydrogen atoms, a hydroxyl group or a lower alkyl group at the same time or differently, or form a carbonyl group together. , X represents a hydrogen atom or a halogen atom, and Y represents —CH ₂ —COOH or —OCH.
Represents _2- COOH,

[0008]

[Chemical 4]

Represents a single bond or a double bond. ), A carbostyril derivative or a pharmaceutically acceptable salt thereof. As the lower alkyl group in the present invention,
Examples thereof include linear or branched alkyl groups having 1 to 4 carbon atoms, and methyl, ethyl, propyl, butyl groups and isomers thereof are preferable. Examples of the halogen atom include chlorine, bromine, fluorine or iodine atom. When R ² and R ³ in the general formula (I) represent a hydroxyl group, one of them is preferably a different group. Inventive Compound (I)
May have an asymmetric carbon atom, and thus optical isomers or stereoisomers may exist, but the present invention also includes these isomers. Compound (I) of the present invention
Can be produced by the method described below. Manufacturing method A

[0010]

[Chemical 5]

(In the formula, tBu represents a t-butyl group, Bn represents a benzyl group, R ⁴ represents a lower alkyl group, and R ^{1 represents}
And X are as defined above. ) Compound (II) in an inert solvent such as acetic acid, ethanol, tetrahydrofuran, dichloroethane or dichloromethane, for example, inorganic bases such as ammonium acetate, potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate or triethylamine, pyridine, It is condensed with a nitroalkane, preferably nitromethane, nitroethane, nitropropane or nitrobutane in the presence of an organic base such as ethylenediamine in a temperature range of 25 to 120 ° C. Then, the nitro group and the olefin moiety of the product (III) are reduced and debenzylated to give an amine derivative. Then, preferably in the presence of bases, di-t-
Compound (IV) is obtained by protecting the amino group with butyl carbonate or the like.

The hydroxyl group of compound (IV) is preferably a base,
For example, in the presence of sodium hydride, potassium hydroxide, sodium hydroxide, potassium carbonate and the like, in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dimethylformamide and the like, halogenated acetic acid ester such as bromoacetic acid ester is condensed. Compound (V),
Under acidic conditions, for example, hydrochloric acid, sulfuric acid, trifluoroacetic acid or a mixture of these acids and a suitable solvent, preferably methylene chloride, the deprotection reaction of the amino group is carried out, for example, sodium hydroxide, potassium carbonate, sodium hydrogencarbonate, etc. In the presence of the inorganic bases or organic bases such as triethylamine and pyridine, the desired product (Ia) can be produced by condensation with a desired sulfonyl chloride and deesterification reaction. In addition, the target compound (Ib) can be produced by reducing the double bond of the compound (V) by a general method and then performing a deesterification reaction in the same manner as above. Manufacturing method B

[0013]

[Chemical 6]

(In the formula, R ¹ , R ⁴ , X, tBu and Bn have the same meanings as above.) After the compound represented by the general formula (VI) is subjected to the reformattsky reaction to give the compound (VII) ,
A dehydroxylation reaction and a reductive debenzylation reaction are performed, and then the phenolic hydroxyl group is protected with a suitable protecting group such as an arylmethyl group, preferably a benzyl group, a p-methoxybenzyl group or a 3,4-dimethoxybenzyl group, The resulting compound (VIII) undergoes Curtius rearrangement to give compound (I
X). Metal catalyst, in a suitable solvent such as methanol, ethanol, ethyl acetate, tetrahydrofuran, etc.
For example, palladium, platinum, etc. are reductively debenzylated under atmospheric pressure at room temperature, and then the phenolic hydroxyl group is reacted with a desired halogenated acetic acid ester according to the production method A to obtain the compound (X). Can be synthesized. The ester can be hydrolyzed with an acid to deprotect the amino group and then condensed with a sulfonyl chloride to produce the desired product (Ic). Manufacturing method C

[0015]

[Chemical 7]

(In the formula, R ¹ , R ⁴ , X and Bn have the same meanings as described above.) The compound represented by the general formula (VI) is subjected to Curtius rearrangement to give a compound (XI). The compound (XII) is obtained by subjecting the compound to debenzylation reaction and alkylation reaction, and then hydrolyzed with an alkali to give a sulfonamide, whereby the desired product (Id) can be produced. Manufacturing method D

[0017]

[Chemical 8]

(In the formula, R ⁴ , X, tBu and Bn have the same meanings as described above.) Compound (XV) was condensed with sodium diformylamide to protect the amino group produced as an acid, and the compound (XVI) was prepared. According to the method B, the desired product (Ie) and the desired product (If) can be produced via the compound (XVII).

The compound (I) of the present invention thus obtained
Is useful as a platelet aggregation inhibitor because it has an excellent TXA ₂ antagonism as described below, and is highly safe.For example, cerebral thrombosis, coronary artery thrombosis, pulmonary embolism, chronic arterial occlusion, thrombotic pulse. It can be used for treating and preventing thrombosis and embolism such as ductitis. Further, the compound (I) of the present invention and a salt thereof can be used for the treatment, alleviation and prevention of myocardial ischemia, unstable angina, coronary artery spasm, cerebral vasospasm after subarachnoid hemorrhage, cerebral hemorrhage, asthma and the like. ..

The compound (I) of the present invention can be used in medicinal use either in a free form or a salt thereof. When used for pharmaceutical use, the salts are preferably pharmacologically acceptable, for example, inorganic salts such as sodium salts, potassium salts, calcium salts, magnesium salts or ammonium salts, pyridine salts, triethylamine salts, ethanolamine salts, basic salts. Organic salts such as amino acid salts are preferred.

The compound (I) of the present invention or a salt thereof can be used as a preparation for oral administration or parenteral administration by incorporating a pharmaceutically acceptable auxiliary agent. As a preparation for oral administration, the above compound is added as a suitable additive, for example, lactose, mannitol, corn starch, excipients such as crystalline cellulose, cellulose derivative, gum arabic,
Tablets when properly combined with a binder such as gelatin, a disintegrant such as carboxymethylcellulose calcium, a talc, a lubricant such as magnesium stearate, and the like,
It can be made into powder, granules and capsules. Also,
These solid preparations can be made into enteric preparations by using a coating base such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, and methacrylate copolymer. Liquid preparations for oral administration include emulsions, solutions, suspensions, syrups, elixirs and the like, and may include generally used inert diluents such as purified water and ethanol. The composition may contain, in addition to the inert diluent, auxiliary agents such as a wetting agent, a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative. In addition, an aerosol formulation formulated by a known method can also be used. As a preparation for parenteral administration, a liquid for injection can be prepared by combining, for example, water, ethanol, glycerin, a conventional surfactant and the like. Furthermore, an inhalant, a liquid for external use, an eye drop, a nasal drop, and a coating agent such as an ointment can be prepared by a known method.

The dose of the compound (I) of the present invention required for the therapeutic or prophylactic effect on the above-mentioned diseases varies depending on its formulation form, administration form, age and symptoms, but the daily oral dose for an adult is usually 1 ~ 1000 mg, preferably 5
It is 500 mg. The administration method can be divided into 2 to 3 times daily.

Next, the usefulness of the compound of the present invention will be described with reference to test examples. Test Example 1 Blood was collected from the ear vein or abdominal aorta of a rabbit using a syringe containing 1/10 volume of 3.8% sodium citrate. Blood was centrifuged at 160 xg for 12 minutes at room temperature, and the supernatant was used as platelet rich plasma (PRP). An equal volume of washing medium containing 2 mM of EDTA was added to PRP, and the mixture was centrifuged at 2000 xg for 10 minutes to separate platelets. The obtained platelet precipitate was washed several times with Ca ²⁺ -free washing medium. Washed platelets Ca
²⁺ resuspended in medium 1 mM concentration particle counter (PC
-601, Elma Koki Co., Ltd.), and the same medium was used to prepare a platelet count of 5 × 10 ⁵ cells / μl. 250 μl of the prepared washed platelet suspension was placed in a silicon-coated glass cylindrical cuvette, mounted on a platelet aggregometer (HEMA TRACER PAT-6A; Nikko Bioscience), and 10 μl of the test drug was added and 2 minutes later. 10 μl of agglutinin was added to measure platelet aggregation. Results (50%
The inverse logarithm of inhibitory concentration: pIC ₅₀ value) is shown in Table 1.

[0024]

[Table 1]

Toxicity test ICR mice aged 4 to 5 weeks were used as one group consisting of 10 mice. Each Example compound was suspended in 10% gum arabic and then orally administered at a dose of 1000 mg / kg, respectively, and observed for 72 hours.
As a result, no deaths were observed under the above conditions.

[0026]

EXAMPLES The present invention will now be specifically described with reference to Reference Examples and Examples, but the present invention is not limited thereto. The production intermediate of the compound (I) of the present invention is shown as a reference example. Example 1 (Production method A) {5- [2- (4-chlorobenzenesulfonylamino)
Ethyl] carbostyryl-8-yl} oxyacetic acid

[0027]

[Chemical 9]

Step 1 41 g of (8-benzyloxycarbostyryl-5-yl) glyoxal was suspended in methanol, 6.2 g of sodium borohydride was added under ice cooling, and the mixture was stirred for 30 minutes. After returning to room temperature and further stirring for 1 hour, the reaction solution was concentrated,
It was added to 1.8 l of saline. After extraction with a mixed solution of n-butanol and ethyl acetate and evaporation of the solvent, the residue was subjected to silica gel column chromatography (chloroform: methanol = 5:
Purified in 1), the obtained crystals are 300 ml of methanol and 85 of water.
Suspended in a mixed solution of ml, and under ice cooling, sodium periodate 16.5
g was added. After stirring at room temperature for 2 hours, 1.2 l of water was added, and the obtained crystals were recrystallized from acetic acid to give 8-benzyloxy-
20.4 g of 5-formylcarbostyril was obtained. Yield 58%. Melting point: 147 to 149 ° C MS (m / z): 279 (M ⁺ ) IR (KBr) cm ^-1 : 1685,1650

Step 2 16.1 g of 8-benzyloxy-5-formylcarbostyril obtained in Step 1 was suspended in 60 ml of acetic acid, and 30 ml of nitromethane was added.
And 11.5 g of ammonium acetate were added, and the mixture was stirred at 110 ° C. for 6 hours. After cooling, 600 ml of water was added, and the obtained crystals were recrystallized from acetic acid to obtain 16.6 g of 8-benzyloxy-5- (2-nitroethylene) carbostyril. Yield 89%. Melting point (decomposition point): 200 to 230 ° C MS (m / z): 322 (M ⁺ ) IR (KBr) cm ^-1 : 1700,1630

Step 3 16.6 g of 8-benzyloxy-5- (2-nitroethylene) carbostyryl obtained in Step 2 was added to dimethylformamide.
The mixture was suspended in a mixed solution of 85 ml and 85 ml of methanol, and 5.2 g of sodium borohydride was added under ice cooling. The mixture was stirred at 5-10 ° C for 3 hours, added to 1.7 l of saline, and the obtained crystals were recrystallized from a mixed solution of ethyl acetate and ethanol to give 1-3.8 g of 8-benzyloxy-5- (2-nitroethyl) carbostyril. Obtained. Yield 83%. Melting point: 178 to 179 ° C MS (m / z): 324 (M ⁺ ) IR (KBr) cm ^-1 : 1650,1545

Step 4 14.6 g of 8-benzyloxy-5- (2-nitroethyl) carbostyril obtained in Step 3 was suspended in 300 ml of acetic acid to obtain 10
% Palladium on carbon 3g, 40 ℃ under normal pressure hydrogen atmosphere
It was stirred for 14 hours. After filtering the reaction solution, the solvent was distilled off. The residue was dissolved in 600 ml of methanol, and 6.3 g of triethylamine and di-t-butyl carbonate were cooled under ice.
20.7 g was added. After stirring under ice cooling for 1.5 hours, 26 ml of 40% methylamine was added and stirred at room temperature for 30 minutes, and the solvent was distilled off. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 7: 1), and the obtained crystals were recrystallized from a mixed solution of ethyl acetate and ethanol to give 8-hydroxy-5- [2- (t 7.8 g of -butoxycarbonylamino) ethyl] carbostyril were obtained. Yield 57%. Melting point (decomposition point): 194 to 197 ° C MS (m / z): 304 (M ⁺ ) IR (KBr) cm ^-1 : 3380,1680,1650

Step 5 6.4 g of 8-hydroxy-5- [2- (t-butoxycarbonylamino) ethyl] carbostyryl obtained in Step 4 was dissolved in 35 ml of dimethylformamide and potassium carbonate 5.9
g and 3.9 g of ethyl α-bromoacetate were added and the mixture was allowed to stand at room temperature for 24 hours.
Stir for hours. Add 400 ml of water and extract with ethyl acetate,
After evaporating the solvent, the obtained crystals were washed with isopropyl ether to obtain 6.1 g of ethyl {5- [2- (t-butoxycarbonylamino) ethyl] carbostyryl-8-yl} oxyacetate. Yield 74%. Melting point: 168 to 170 ° C MS (m / z): 390 (M ⁺ ) IR (KBr) cm ^-1 : 3260,1750,1690,1655

Step 6 2.6 g of ethyl {5- [2- (t-butoxycarbonylamino) ethyl] carbostyryl-8-yl} oxyacetate obtained in Step 5 was suspended in 14 ml of methylene chloride, and triturated under ice cooling. 8 g of fluoroacetic acid was added dropwise. After stirring under ice cooling for 5 hours,
Methylene chloride 100 ml, potassium carbonate 13.7 g, water 80 ml, 4
-1.5 g of chlorobenzenesulfonyl chloride was added, and the mixture was stirred at room temperature for 1 hour. The organic layer is separated, washed with water and dried,
The solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 7: 1), and the obtained crystals were recrystallized from a mixed solution of ethyl acetate and ethanol to give {5- [2- (4-chlorobenzenesulfonylamino)]. 2.2 g of ethyl] carbostyryl-8-yl} oxyacetate was obtained. Yield 71%. Melting point: 152-153 ° C MS (m / z): 464 (M ⁺ ) IR (KBr) cm ^-1 : 3300,1755,1650

Step 7 {5- [2- (4-chlorobenzenesulfonylamino) ethyl] carbostyryl-8-yl} obtained in Step 6
2.1 g of ethyl oxyacetate was suspended in 60 ml of methanol, and 5
10 ml of sodium hydroxide N were added. After stirring at room temperature for 1 hour, the solvent was evaporated, and the residue was acidified by adding 3N hydrochloric acid. The precipitated crystals are recrystallized from acetic acid, {5- [2-
1.9 g of (4-chlorobenzenesulfonylamino) ethyl] carbostyryl-8-yl} oxyacetic acid was obtained. yield
96%. Melting point: 250 ° C. or higher MS (m / z): 437 (M ⁺ +1) IR (KBr) cm ⁻¹ : 3275,1735,1630 NMR (DMSO-d ₆ ) δ: 13.2 (brs, 1H), 10.69 (b
rs, 1H), 7.90 (d, 1H), 7.85 (t, 1H), 7.69
(D, 2H), 7.58 (d, 2H), 7.04 (d, 1H), 6.93
(D, 1H), 6.54 (d, 1H), 4.81 (s, 2H), 3.05 ~
2.85 (m, 4H)

1 g of the title compound obtained in step 7 was dissolved in 2 ml of 10% sodium hydroxide and purified by HP-20 column to obtain 0.8 g of sodium salt (amorphous powder). IR (KBr) cm ^-1 : 3250,1655,1605 Example 2 (Production method A) {5- [2-benzenesulfonylamino) ethyl] carbostyryl-8-yl} oxyacetic acid

[0036]

[Chemical 10]

The title compound was prepared according to the method of Example 1. Melting point: 261-264 ° C MS (m / z): 384 (M ⁺ -18) IR (KBr) cm ^-1 : 3240,1730,1630 NMR (DMSO-d ₆ ) δ: 13.0 (brs, 1H), 10.70. (B
rs, 1H), 7.88 (d, 1H), 7.80 to 7.70 (m, 3H), 7.
65 to 7.50 (m, 3H), 7.04 (d, 1H), 6.92 (d, 1
H), 6.54 (d, 1H), 4.79 (s, 2H), 3.05 to 2.85
(M, 4H) Sodium salt (colorless crystal) Melting point (decomposition point): 230 to 239 ° C IR (KBr) cm ^-1 : 3250,1650,1600 Example 3 (Production method B) {5- [2- (4 -Chlorobenzenesulfonylamino-
1-methyl) ethyl] carbostyryl-8-yl} oxyacetic acid

[0040]

[Chemical 11]

Step 1 20 g of 5-acetyl-8-benzyloxycarbostyril
Was suspended in 150 ml of tetrahydrofuran, 17.4 g of zinc powder was added, and 30 ml of ethyl α-bromoacetate was added dropwise at 40 to 65 ° C over about 30 minutes. After refluxing for 30 minutes and cooling, the reaction solution was mixed with 10% sulfuric acid 1
In addition to 1, the mixture was extracted with ethyl acetate and the solvent was distilled off. The obtained crystals were recrystallized from a mixed solution of ethyl acetate, ethanol and n-hexane to give ethyl 3-hydroxy-3- (8-benzyloxycarbostyryl-5-yl) butanoate.
22.8 g was obtained. Yield 88%. Melting point: 150 to 151 ° C MS (m / z): 381 (M ⁺ ) IR (KBr) cm ^-1 : 3340,1725,1635

Step 2 6.2 g of ethyl 3-hydroxy-3- (8-benzyloxycarbostyryl-5-yl) butanoate obtained in Step 1 was suspended in 120 ml of toluene, and 10 g of anhydrous magnesium sulfate and p-toluenesulfonic acid were suspended. 1.2 g was added and refluxed for 14 hours. After cooling, it was filtered, washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, dried, and the solvent was evaporated. The obtained residue was dissolved in a mixed solution of 90 ml of ethanol and 30 ml of ethyl acetate, 0.3 g of platinum dioxide was added, and under a hydrogen atmosphere at atmospheric pressure,
Stir at room temperature for 4 hours. After filtering the reaction solution, the solvent was distilled off, and the obtained crystals were recrystallized from hydrous ethanol to give 3
3.9 g of ethyl (8-hydroxycarbostyryl-5-yl) butanoate was obtained. Yield 89%. Melting point: 229 to 230 ° C MS (m / z): 275 (M ⁺ ) IR (KBr) cm ^-1 : 3150,3050,1725,1625

Step 3 3- (8-Hydroxycarbostyryl-5 obtained in Step 2
-Yl) Ethyl butanoate (1.0 g) was suspended in acetone (20 ml), potassium carbonate (0.6 g) and benzyl bromide (0.5 ml) were added, and the mixture was refluxed for 1.5 hours. After cooling, the solvent was distilled off, 1N hydrochloric acid (20 ml) was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and the solvent was evaporated. The residue was subjected to silica gel column chromatography (methylene chloride:
Purified with methanol = 100: 1) and
It was dissolved in a mixed solution of 10 ml of N sodium hydroxide and 2 ml of tetrahydrofuran and stirred at 60 ° C. for 1 hour. After cooling, 1N hydrochloric acid was added to make the mixture acidic, and the precipitated crystals were recrystallized from ethanol to obtain 0.9 g of 3- (8-benzyloxycarbostyryl-5-yl) butanoic acid. Yield 73%. Melting point: 223 to 227 ° C MS (m / z): 337 (M ⁺ ) IR (KBr) cm ^-1 : 1700,1640

Step 4 1.6 g of 3- (8-benzyloxycarbostyryl-5-yl) butanoic acid obtained in Step 3 was suspended in 40 ml of t-butanol, and 0.8 ml of triethylamine and 1.1 ml of diphenylphosphoric acid azide were added. Refluxed for 19 hours. After cooling, the solvent was distilled off and the residue was purified by silica gel column chromatography (methylene chloride: methanol = 100: 1).
-Benzyloxy-5-[(2-t-butoxycarbonylamino-1-methyl) ethyl] carbostyril 1.6 g
Got Yield 84%. MS (m / z): 408 (M ⁺ ) IR (KBr) cm ^-1 : 3420,1700,1660

Step 5 3.3 g of 8-benzyloxy-5-[(2-t-butoxycarbonylamino-1-methyl) ethyl] carbostyril obtained in Step 4 was dissolved in 60 ml of ethanol to obtain 0.15 g of 10% palladium carbon. Was added and the mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere at atmospheric pressure. After filtering the reaction solution, the solvent was distilled off, and the obtained crystals were recrystallized from water-containing methanol to give 5- [2-
2.2 g of (t-butoxycarbonylamino-1-methyl) ethyl] -8-hydroxycarbostyril was obtained. Yield 86%. Melting point: 199 to 201 ° C MS (m / z): 318 (M ⁺ ) IR (KBr) cm ^-1 : 3350,1685,1640

Step 6 1.4 g of 5- [2- (t-butoxycarbonylamino-1-methyl) ethyl] -8-hydroxycarbostyryl obtained in Step 5 was suspended in 30 ml of acetone, and 0.8 g of potassium carbonate was added.
g and 0.6 ml of α-bromoacetate were added and the mixture was refluxed for 2 hours. After cooling, the solvent was distilled off, 1N hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline,
After drying, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography, {5- [2- (t
1.6 g of ethyl-butoxycarbonylamino-1-methyl) ethyl] carbostyryl-8-yl} oxyacetate was obtained. Yield 87%. MS (m / z): 404 (M ⁺ ) IR (KBr) cm ^-1 : 3240,1750,1650

Step 7 From ethyl {5- [2- (t-butoxycarbonylamino-1-methyl) ethyl] carbostyryl-8-yl} oxyacetate obtained in Step 6, Step 6 and Step 7 of Example 1 were carried out. The title compound was prepared according to the method. Melting point: 248 to 252 ° C MS (m / z): 432 (M ⁺ -18) IR (KBr) cm ^-1 : 3450,3280,1745,1640 NMR (DMSO-d ₆ ) δ: 13.14 (brs, 1H) ， 10.67
(Brs, 1H), 7.98 (d, 1H), 7.85 (t, 1H), 7.69
(D, 2H), 7.60 (d, 2H), 7.07 (d, 1H), 6.98
(D, 1H), 6.55 (d, 1H), 4.80 (s, 2H), 3.45 ~
3.27 (m, 1H), 3.03 to 2.82 (m, 2H), 1.20 (d, 3)
H) Sodium salt (amorphous powder) IR (KBr) cm ^-1 : 3250,1661,1605 Example 4 (Production method B) {5-[(2-benzenesulfonylamino-1-methyl) ethyl] carbostyryl- 8-yl} oxyacetic acid

[0048]

[Chemical 12]

The title compound was prepared according to the method of Example 3. Melting point: 246 to 253 ° C MS (m / z): 416 (M ⁺ ) IR (KBr) cm ⁻¹ : 3280, 1735, 1635 NMR (DMSO-d ₆ ) δ: 13.14 (brs, 1H), 10.68
(Brs, 1H), 7.99 (d, 1H), 7.80 to 7.72 (m, 3
H), 7.65 ~ 7.52 (m, 3H), 7.07 (d, 1H), 6.97
(D, 1H), 6.55 (d, 1H), 4.80 (s, 2H), 3.46 ~
3.30 (m, 1H), 2.98 to 2.78 (m, 2H), 1.21 (d, 3
H) Sodium salt (amorphous powder) IR (KBr) cm ^-1 : 3250,1655,1603 Example 5 (Production method C) {5- [2- (4-chlorobenzenesulfonylamino-
1-Hydroxy-1-methyl) ethyl] carbostyryl-8-yl} oxyacetic acid

[0050]

[Chemical 13]

Step 1 10.5 g of ethyl 3-hydroxy-3- (8-benzyloxycarbostyryl-5-yl) butanoate obtained in Step 1 of Example 3 was mixed with 30 ml of ethanol and 100 parts of 1N sodium hydroxide.
It was dissolved in a mixed solution of ml and stirred at 50 ° C. for 3 hours. After cooling, concentrated sulfuric acid was added to acidify, the precipitated crystals were suspended in 100 ml of toluene, 4.6 ml of triethylamine and 5.6 ml of diphenylphosphoric acid azide were added, and the mixture was refluxed for 17 hours. After cooling, the precipitated crystals were recrystallized from ethanol to give 5- (8-benzyloxycarbostyryl-5-yl) -5-methyl-2-
8.1 g of oxazolidone was obtained. Yield 84%. Melting point: 232 to 233 ° C MS (m / z): 350 (M ⁺ ) IR (KBr) cm ^-1 : 3200,1745,1645

Step 2 From 5- (8-benzyloxycarbostyryl-5-yl) -5-methyl-2-oxazolidone obtained in Step 1, according to the method of Step 6 and step 7 of Example 3, −
(8-ethoxycarbonylmethoxycarbostyryl-5
-Yl) -5-methyl-2-oxazolidone was prepared. MS (m / z): 346 (M ⁺ ) IR (KBr) cm ^-1 : 3380,1740,1650

Step 3 0.9 g of 5- (8-ethoxycarbonylmethoxycarbostyryl-5-yl) -5-methyl-2-oxazolidone obtained in Step 2 was dissolved in 30 ml of 1N sodium hydroxide, 10 ml of ether and p- 0.8 g of chlorobenzenesulfonyl chloride was added, and the mixture was stirred for 2 hours. The aqueous layer was separated, acidified by adding concentrated sulfuric acid, and the precipitated crystals were recrystallized from hydrous ethanol to obtain 0.8 g of the title compound. Yield 66%. Melting point: 240-242 ° C MS (m / z): 467 (M ⁺ +1) IR (KBr) cm ^-1 : 3445,3250,1754,1634 NMR (DMSO-d ₆ ) δ: 13.0 (brs, 1H), 10.50 (b
rs, 1H), 8.70 (d, 1H), 7.65 (d, 2H), 7.63
(T, 1H), 7.55 (d, 2H), 7.05 (d, 1H), 7.01
(D, 1H), 6.45 (d, 1H), 5.54 (brs, 1H), 4.82
(S, 2H), 3.15 (dd, 1H), 3.07 (dd, 1H), 1.58
(S, 3H) Sodium salt (amorphous powder) IR (KBr) cm ^-1 : 3300,1655,1603 Example 6 (Production method C) {5- [2- (4-chlorobenzenesulfonylamino-
2-Methyl) ethyl] carbostyryl-8-yl} oxyacetic acid

[0054]

[Chemical 14]

Step 1 17.5 g of 8-benzyloxy-5-formylcarbostyryl obtained in Step 1 of Example 1 was dissolved in 180 ml of tetrahydrofuran.
Then, 16.3 g of zinc dust was added thereto, and 32 ml of ethyl α-bromopropionate was added dropwise thereto at 60 to 68 ° C over 30 minutes. After refluxing for 1.5 hours, the mixture was added to 1.5 l of 10% sulfuric acid and extracted with ethyl acetate. The extract was washed with saturated saline and dried, and the solvent was distilled off. The obtained crystals were recrystallized from a mixed solution of ethyl acetate and n-hexane to obtain 18.7 g of ethyl 3-[(8-benzyloxycarbostyryl-5-yl) -3-hydroxy-2-methyl] propionate. Yield 78%. Melting point: 144 to 160 ° C MS (m / z): 381 (M ⁺ ) IR (KBr) cm ^-1 : 3297,1732,1644

Step 2 From the ethyl 3-[(8-benzyloxycarbostyryl-5-yl) -3-hydroxy-2-methyl] propionate obtained in Step 1 to the method of Steps 2 to 7 of Example 3. The title compound was prepared accordingly. Melting point: 250 ° C. or higher MS (m / z): 432 (M ⁺ ) IR (KBr) cm ⁻¹ : 3270, 1734, 1638 NMR (DMSO-d ₆ ) δ: 13.04 (brs, 1H), 10.53
(Brs, 1H), 7.84 (d, 1H), 7.82 (d, 1H), 7.40
(ABq, 4H), 6.91 (ABq, 4H), 6.48 (d, 1H), 3.
35 to 3.20 (m, 1H), 2.85 (dd, 1H), 2.77 (dd, 1
H), 1.08 (d, 3H) sodium salt (colorless crystals) Melting point: 224 to 236 ° C IR (KBr) cm ^-1 : 3318,1655,1597 Example 7 (Production method C) {5- [2- (4 -Chlorobenzenesulfonylamino-
1,2-Dimethyl) ethyl] carbostyryl-8-yl}
Oxyacetic acid

[0057]

[Chemical 15]

The title compound was prepared from 5-acetyl-8-benzyloxycarbostyril according to the method of Example 3. Melting point: 251-255 ° C. MS (m / z): 464 (M ⁺ ) IR (KBr) cm ⁻¹ : 3310,1736,1636 NMR (DMSO-d ₆ ) δ: 13.09 (brs, 1H), 10.58
(Brs, 1H), 8.04 (d, 1H), 7.67 (d, 1H), 7.61
(D, 2H), 7.52 (d, 2H), 7.05 (d, 1H), 6.95
(D, 1H), 4.81 (s, 2H), 3.50 to 3.25 (m, 2H),
1.19 (d, 3H), 0.80 (d, 3H) sodium salt (amorphous powder) IR (KBr) cm ⁻¹ : 3250,1663,1603 Example 8 (Production method D) [5- (4-chlorobenzenesulfonylamino) Acetyl) carbostyryl-8-yl] oxyacetic acid

[0059]

[Chemical 16]

Step 1 24.5 g of (8-benzyloxy-5-bromoacetyl) carbostyril was suspended in 180 ml of dimethylformamide,
8.9 g of sodium diformylamide was added under ice cooling, and the mixture was stirred at room temperature for 4 hours. The crystals thus obtained were suspended in 100 ml of ethanol, 100 ml of 18% hydrochloric acid ethanol was added, and the mixture was refluxed for 1 hour. After cooling, the precipitated crystals were suspended in dimethylformamide, and di-t-butyl carbonate 8.8
g and 13 ml triethylamine were added. After stirring for 1 hour, the precipitated crystals were added to 500 ml of ice water and recrystallized from water-containing ethanol to obtain 13.2 g of (8-benzyloxy-5-t-butoxycarbonyl) carbostyril. Yield 72%. Melting point: 184 to 185 ° C MS (m / z): 408 (M ⁺ ) IR (KBr) cm ^-1 : 3500,3360,1700,1680,1665

Step 2 From the (8-benzyloxy-5-t-butoxycarbonylaminoacetyl) carbostyril obtained in Step 1, according to the methods of Step 5 and Step 6 of Example 3, [5- (t-
Butoxycarbonylaminoacetyl) carbostyryl-
Ethyl 8-yl] oxyacetate was produced. Melting point: 160 to 162 ° C MS (m / z): 404 (M ⁺ ) IR (KBr) cm ^-1 : 3362,1750,1705,1685,1643

Step 3 The title compound was prepared from ethyl [5- (α-t-butoxycarbonylaminoacetyl) carbostyryl-8-yl] oxyacetate obtained in Step 2 according to the method of Step 7 of Example 3. did. Melting point: 250 ° C. or higher MS (m / z): 451 (M ⁺ ) IR (KBr) cm ⁻¹ : 3350, 1734, 1686, 1643 NMR (DMSO-d ₆ ) δ: 13.0 (brs, 1H), 11.02 ( b
rs, 1H), 8.28 (t, 1H), 8.24 (d, 1H), 7.80
(D, 2H), 7.75 (d, 1H), 7.62 (d, 2H), 7.17
(D, 1H), 6.62 (d, 1H), 4.97 (s, 2H), 4.46
(D, 2H) Sodium salt (amorphous powder) IR (KBr) cm ^-1 : 3300,1673,1655,1601 Example 9 (Production method D) {5- [2- (4-chlorobenzenesulfonylamino-
1-hydroxy) ethyl] carbostyryl-8-yl}
Oxyacetic acid

[0063]

[Chemical 17]

Step 1 2.0 g of ethyl [5- (t-butoxycarbonylaminoacetyl) carbostyryl-8-yl] oxyacetate obtained in Step 2 of Example 8 was suspended in 20 ml of ethanol and, under ice cooling,
0.2 g of sodium borohydride was added and stirred for 50 minutes. After distilling off the solvent, the mixture was extracted with ethyl acetate, washed with saturated saline and dried, and then the solvent was evaporated. The obtained crystals were recrystallized from a mixed solution of ethyl acetate and isopropyl ether to give {5
1.6 g of ethyl [-(2- (t-butoxycarbonylamino-1-hydroxy) ethyl] carbostyryl-8-yl} oxyacetate was obtained. Yield 81%. Melting point: 197 to 198 ° C MS (m / z): 406 (M ⁺ ) IR (KBr) cm ^-1 : 3332,1738,1703,1649

Step 2 {5- [2- (t-butoxycarbonylamino-1-hydroxy) ethyl] carbostyryl-8-obtained in Step 1
The title compound was prepared from ethyl oxyacetate according to the method of Step 7 of Example 3. Melting point: 230 to 236 ° C MS (m / z): 453 (M ⁺ +1) IR (KBr) cm ^-1 : 3500 to 3000, 1732, 1651 NMR (DMSO-d ₆ ) δ: 12.60 (brs, 1H), 10.69
(Brs, 1H), 8.06 (sd, 1H), 7.92 (t, 1H), 7.
70 (d, 2H), 7.59 (d, 2H), 7.10 (ABq, 2H), 6.
56 (d, 1H), 5.68 (d, 1H), 5.05 to 4.96 (m, 1
H), 4.82 (s, 2H), 2.96 (t, 2H) sodium salt (colorless crystals) Melting point: 200 to 220 ° C IR (KBr) cm ^-1 : 3400,1655,1603 Example 10 (Production method A) { 5-[(2-benzenesulfonylamino) ethyl]-
3,4-Dihydrocarbostyryl-8-yl} oxyacetic acid

[0066]

[Chemical 18]

Step 1 {5-[(2-benzenesulfonylamino) ethyl] carbostyryl-8-prepared according to the method of Example 1.
1.0 g of ethyl oxyacetate was suspended in 10 ml of methanol, 0.5 g of magnesium metal was added and the mixture was refluxed for 3 hours.
After cooling, the solvent was distilled off, 6N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried and the solvent was evaporated. Silica gel column chromatography of the residue (methylene chloride: methanol = 5
The resulting crystals were recrystallized from a mixed solution of ethyl acetate and n-hexane to give {5-[(2-benzenesulfonylamino) ethyl] -3,4-dihydrocarbostyryl-8- 0.45 g of methyl oxyacetate was obtained. yield
35%. Melting point: 200 to 205 ° C MS (m / z): 418 (M ⁺ ) IR (KBr) cm ^-1 : 3266,1734,1701

Step 2 According to the method of Step 7 of Example 1 from methyl {5-[(2-benzenesulfonylamino) ethyl] -3,4-dihydrocarbostyryl-8-yl} oxyacetate obtained in Step 1. To produce the title compound. Melting point: 203 to 204 ° C MS (m / z): 405 (M ⁺ +1) IR (KBr) cm ^-1 : 3312,3202,1718,1653 NMR (DMSO-d ₆ ) δ: 12.17 (brs, 1H), 10.26
(Brs, 1H), 7.83 to 7.71 (m, 3H), 7.68 to 7.52
(M, 3H), 6.73 (ABq, 2H), 4.45 (s, 2H), 2.93
-2.73 (m, 4H), 2.63 (t, 2H), 2.28 (t, 2H) sodium salt (amorphous powder) IR (KBr) cm ^-1 : 3250,1655,1602 Example 11 {5- [2- (4-chlorobenzenesulfonylamino)
Ethyl] carbostyryl-8-yl} acetic acid

[0069]

[Chemical 19]

Step 1 Under ice cooling, 13.0 g of potassium nitrate was suspended in 270 ml of sulfuric acid,
Add 29.3 g of diethyl 1,4-benzenediacetate little by little and add 2
Stir for 0 minutes. The reaction solution was added to 1 l of ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and the solvent was evaporated. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and the obtained crystals were recrystallized from isopropyl ether to give 2-
31.8 g of diethyl nitro-1,4-benzenediacetate was obtained.
Yield 92%. Melting point: 48 to 49 ° C MS (m / z): 295 (M ⁺ ) IR (nujol) cm ^-1 : 1735,1535

Step 2 10.5 g of diethyl 2-nitro-1,4-benzenediacetate obtained in Step 1 was dissolved in 90 ml of tetrahydrofuran, and a solution of 2.80 g of potassium hydroxide in 20 ml of ethanol was added dropwise under ice cooling. After stirring under ice-cooling for 3 hours, the mixture was added to ice water, acidified with hydrochloric acid and extracted with ethyl acetate. After drying the organic layer, the solvent was evaporated and the residue was subjected to silica gel column chromatography (chloroform: methanol = 1.
The crystals obtained were purified by 0: 1) and recrystallized from a mixed solution of ethyl acetate and isopropyl ether to obtain 4.18 g of (4-ethoxycarbonylmethyl-3-nitrophenyl) acetic acid. Melting point: 96.5-97.2 ° C MS (m / z): 267 (M ⁺ ) IR (KBr) cm ^-1 : 3000,1720,1695,1525

Step 3 3.17 g of (4-ethoxycarbonylmethyl-3-nitrophenyl) acetic acid obtained in Step 2 was dissolved in 20 ml of thionyl chloride and refluxed for 1 hour. After cooling, excess thionyl chloride was distilled off, the residue was dissolved in methylene chloride, and the solution was added dropwise to 40 ml of concentrated ammonia under ice water. After stirring for 2 hours, the mixture was extracted with a large amount of methylene chloride, and the solvent was distilled off. The obtained crystals were recrystallized from a mixed solution of ethyl acetate and isopropyl ether to give (4-ethoxycarbonylmethyl-3-nitrophenyl) acetamide.
2.46 g were obtained. Melting point: 145 to 146 ° C MS (m / z): 220 (M ⁺ −46) IR (KBr) cm ⁻¹ : 3440,3310,1722,1664,1530

Step 4 3.13 g of (4-ethoxycarbonylmethyl-3-nitrophenyl) acetamide obtained in Step 3 was added to 160 ml of methanol.
Was dissolved in 10% palladium carbon (400 mg), and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere at atmospheric pressure. After filtering the reaction solution, the solvent was distilled off and the obtained crystals were recrystallized from a mixed solution of ethyl acetate and hexane to obtain 2.53 g of (3-amino-4-ethoxycarbonylmethylphenyl) acetamide. Melting point: 118 to 120 ° C MS (m / z): 236 (M ⁺ ) IR (KBr) cm ^-1 : 3390,3190,1735,1650,1625

Step 5 2.74 g of (3-amino-4-ethoxycarbonylmethylphenyl) acetamide obtained in Step 4 was added to 130 ml of methylene chloride.
The mixture was dissolved in ml, 2.88 g of 3,3-diethoxypropionic acid and 3.70 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was washed successively with 0.1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate and water, dried and the solvent was evaporated. The obtained crystals were recrystallized from a mixed solution of ethyl acetate and ethanol to obtain 3.54 g of [4-ethoxycarbonylmethyl-3- (3,3-diethoxypropionylamino) phenyl] acetamide. Melting point: 176 to 177 ° C MS (m / z): 380 (M ⁺ ) IR (KBr) cm ^-1 : 3380,3300,3200,1735,1650

Step 6 [4-Ethoxycarbonylmethyl-3-obtained in Step 5
5.17 g of (3,3-diethoxypropionylamino) phenyl] acetamide was dissolved in 50 ml of sulfuric acid under cooling with ice,
Stir for hours. The reaction solution was added to ice water, ethyl acetate, n-
It was extracted sequentially with butanol, dried and the solvent was distilled off. The obtained crystals were recrystallized from ethanol to obtain 1.02 g of (5-carbamoylmethylcarbostyryl-8-yl) acetic acid. Melting point (decomposition point): 222 to 223 ° C MS (m / z): 288 (M ⁺ ) IR (KBr) cm ^-1 : 3450,3320,3200,1710,1650

Step 7 680 mg of (5-carbamoylmethyl-8-yl) carbostyril obtained in Step 6 was suspended in 15 ml of dioxane, 456 mg of sodium borohydride was added, and 721 mg of acetic acid was added dropwise under stirring with ice cooling. After stirring at 95 ° C. for 2.5 hours, 5 ml of water was added to the reaction solution and concentrated. Furthermore, 10 ml of water, 670 mg of potassium carbonate, and 20 ml of methylene chloride were added, and the mixture was stirred 4-
615 mg of chlorobenzenesulfonyl chloride was added. After stirring at room temperature for 1 hour, the organic layer was separated, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1), and the obtained crystals were recrystallized from ethanol, {5- [2- (4
250 mg of ethyl -chlorobenzenesulfonylamino) ethyl] carbostyryl-8-yl} acetate was obtained. Melting point: 184 to 185 ° C MS (m / z): 448 (M ⁺ ) IR (KBr) cm ^-1 : 3320,1725,1650

Step 8 1.54 g of ethyl {5- [2- (4-chlorobenzenesulfonylamino) ethyl] carbostyryl-8-yl} acetate obtained in Step 7 was suspended in 30 ml of methanol and 4 ml of 20% sodium hydroxide was added. In addition, it stirred at 60 degreeC for 1 hour. The solvent was distilled off, the residue was dissolved in 5 ml of water, and concentrated hydrochloric acid was added to acidify the mixture. The precipitated crystals are recrystallized from ethanol, {5-
1.30 g of [2- (4-chlorobenzenesulfonylamino) ethyl] carbostyryl-8-yl} acetic acid was obtained. Melting point (decomposition point): 223 to 225 ° C MS (m / z): 420 (M ⁺ ) IR (KBr) cm ^-1 : 3280,1720,1650 NMR (DMSO-d ₆ ) δ: 12.40 (brs, 1H) ， 10.96
(Brs, 1H), 7.93 (d, 1H), 7.88 (brs, 1H), 7.
73 (d, 2H), 7.61 (d, 2H), 7.26 (d, 1H), 6.94
(D, 1H), 6.51 (d, 1H), 3.91 (s, 2H), 3.05 ~
2.85 (m, 4H) sodium salt (amorphous powder) IR (KBr) cm ^-1 : 3281,1676,1559

Formulation Example 1 20 g of the compound of Example 1, 315 g of lactose, 125 g of corn starch and 25 g of crystalline cellulose were uniformly mixed, and 7.5
% Hydroxypropyl cellulose aqueous solution 200ml,
Using an extrusion granulator, granules were formed using a screen with a diameter of 0.5 mm, immediately rounded by a marumerizer, and dried to obtain granules.

Formulation Example 2 20 g of the compound of Example 7, 100 g of lactose, 36 g of corn starch, 30 g of crystalline cellulose, 10 g of carboxymethyl cellulose calcium, 4 g of magnesium stearate.
Are evenly mixed, and one tablet is pressed with a single punch tableting machine using a punch with a diameter of 7.5 mm.
It was a 200 mg tablet.

Formulation Example 3 40 g of the compound of Example 11, 232 g of lactose, 108 g of corn starch and 20 g of polyvinylpyrrolidone were uniformly mixed, 180 ml of 70% (v / v) isopropyl alcohol was added, and the mixture was extruded into a granulator having a diameter of 0.8 mm. Granules were made using a screen, immediately rounded with a marumerizer, and dried to give granules. Then, fill the granules with a No. 2 hard gelatin capsule.

[0082]

The compound of the present invention and its salt are excellent
It has a TXA ₂ antagonistic action, and is useful as a platelet aggregation inhibitor because of its high safety, for example, cerebral thrombosis, coronary thrombosis, pulmonary embolism, chronic arterial occlusion, thrombosis such as thromboangiitis, It can be used for the treatment and prevention of embolism. Further, the compound of the present invention and a salt thereof can also be used for the treatment, alleviation and prevention of myocardial ischemia, unstable angina, coronary artery spasm, cerebral vasospasm after subarachnoid hemorrhage, cerebral hemorrhage, asthma and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI Technical display location C07D 215/26 (72) Inventor Hiromasa Kami 2512-1 Zuma, Oshikiri, Konan-cho, Osato-gun, Saitama Prefecture Zeria Shinyaku Kogyo Co., Ltd. Central Research Center (72) Inventor Hiroki Sato Oshikiri, Osa-gun, Saitama Prefecture Oshikiri 2512-1 Zeria Shinyaku Kogyo Co., Ltd. Central Research Center

Claims (2)

[Claims] 1. A compound represented by the general formula (I): (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group,
R ² and R ³ are the same or different and are a hydrogen atom, a hydroxyl group,
A lower alkyl group, or together form a carbonyl group, X represents a hydrogen atom or a halogen atom, Y is -CH ₂ -COOH or -OCH ₂ -COO
H is shown below. Represents a single bond or a double bond. ) A carbostyril derivative represented by the formula) or a pharmaceutically acceptable salt thereof. 2. A thromboxane antagonist comprising the compound according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.