JPS6347707B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel substituted vinylcarboxylic acid derivative having an action of specifically inhibiting thromboxane A ₂ (TXA ₂ ) synthase, and a method for producing the same. The present inventors have discovered that prostaglandin H ₂ , which is a substrate for the synthase of thromboxane A ₂ (TXA ₂ ),
As a result of analyzing and considering the three-dimensional structural elements of (PGH ₂ ) from the standpoint of molecular orbital theory, and conducting various studies on the construction of a molecular model that inhibits thromboxane A ₂ synthase, we found that it has an unprecedented structure and pharmacological properties. The present inventors have discovered a group of novel derivatives that inhibit thromboxane _A2 synthetase and have completed the present invention. That is, the present invention provides: (1) General formula [In the formula, R ¹ is a pyridyl group, and R ² is a phenyl group or thienyl group that may have a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group, or a methylenedioxy group. , furyl group, naphthyl group,
benzothienyl group or pyridyl group, A is a sulfur atom, methylene group or general formula

[Formula] (where R ⁴ is a hydrogen atom or an acetyl group, m is 0 or 1), R ³ is a hydrogen atom or a lower alkyl group, and n is an integer from 0 to 6. ]
Substituted vinylcarboxylic acid derivative (2) represented by general formula (Each symbol in the formula has the same meaning as above) and the general formula (C ₆ H ₅ ) ₃ P—CH ₂ CH ₂ CH ₂ —(CH ₂ —) _o COOR ³・
X ^- () (wherein R ³ is a hydrogen atom or a lower alkyl group, X is a halogen atom, and n has the same meaning as above). Method for producing a compound represented by formula (), and (3) general formula (In the formula, R ¹ and R ² have the same meanings as above,
Z represents a halogen atom) and a compound represented by the general formula HY ¹ —(CH ₂ —) _o COOR ³ () [wherein R ³ and n have the same meanings as above,
Y ¹ is a sulfur atom or general formula

[Formula] (where R ⁴ and m have the same meanings as above) is shown. ] A method for producing a substituted vinylcarboxylic acid derivative represented by the general formula (), characterized by reacting the substituted vinyl carboxylic acid derivative with a compound represented by the formula (). In the general formulas (), () and (), R ¹ ,
The pyridyl group represented by R ² is 2-pyridyl, 3
-Pyridyl, 4-pyridyl may be used, and thienyl represented by R ² may be 2-thienyl, 3-pyridyl.
Thienyl and furyl are 2-furyl, 3-furyl, naphthyl is α-naphthyl, β-naphthyl, benzothienyl is 2-benzothienyl, 3-benzothienyl, 4-benzothienyl, 5-benzothienyl,
Either 6-benzothienyl or 7-benzothienyl may be used. Phenyl, thienyl represented by R ² ,
Examples of lower alkoxy groups as substituents of furyl, naphthyl, benzothienyl, and pyridyl include those having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, and t-butoxy. Examples of lower alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
Those having 1 to 5 carbon atoms, such as t-butyl, n-pentyl, and i-pentyl; examples of halogen atoms include fluorine, chlorine, and bromine; and examples of lower alkenyl groups, such as vinyl, aryl, and pentenyl. Examples include those having 2 to 5 carbon atoms. When phenyl, thienyl, furyl, naphthyl, benzothienyl, or pyridyl represented by R ² has a substituent, these substituents can be substituted at any position on the ring. In the general formulas (), () and (), the lower alkyl represented by R ³ is:
Examples include those having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, n-butyl, and t-butyl. The halogen atom represented by X in the general formula () or Z in the general formula () is,
Examples include chlorine and bromine. The compound represented by the general formula () may be an addition salt of a pharmacologically acceptable organic or inorganic acid, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, etc. , citric acid, succinic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, etc. Further, when R ³ of the compound () is a hydrogen atom, it may be an alkali metal salt such as a sodium salt or a potassium salt, or an alkaline earth metal salt such as a calcium salt. As a representative example of the compound (), for example, 7-
Phenyl-7-(3-pyridyl)-6-heptenoic acid, 8-phenyl-8-(3-pyridyl)-7-
Octenoic acid, 7-(2-thienyl)-7-(3-
pyridyl)-6-heptenoic acid, 8-(2-thienyl)-8-(3-pyridyl)-7-octenoic acid,
7-(2-naphthyl)-7-(3-pyridyl)-
Examples include 6-heptenoic acid. The substituted vinylcarboxylic acid derivatives of the present invention represented by the general formula () and their salts can be used for humans, cattle,
It has a strong inhibitory effect on thromboxane synthase, which is solubilized and fractionated from platelet microsomes of horses and other animals, and shows a strong inhibitory effect on the biosynthesis of thromboxane A ₂ (TXA ₂ ) in mammals including humans. In addition, the compound () of the present invention is a prostaglandin that exhibits an arterial smooth muscle relaxing effect, a platelet aggregation inhibiting effect, or an aggregated platelet re-dissociation effect.
Shows the effect of increasing the production efficiency of I ₂ (PGI ₂ ). That is, prostaglandin G ₂ (PGH ₂ ) or prostaglandin H ₂ (PGH ₂ ) is thromboxane.
A ₂ , prostaglandin _{I 2 and other} prostaglandins _. ) exhibits an inhibitory effect at extremely low concentrations (below 3×10 ^-8 mol), but on the other hand, it inhibits the synthesis of physiologically extremely useful prostaglandin I ₂ and other prostaglandin-converting enzymes, such as PGI ₂ synthesis. It shows almost no inhibitory effect on enzymes and prostaglandin synthase, but rather on PGH ₂ or PGG ₂
It has the effect of increasing the in vivo utilization efficiency of PGI 2 and enhancing the production of PGI ₂ . Thus, the substituted vinylcarboxylic acid derivative represented by the general formula () is prostaglandin I ₂
It specifically inhibits the action of thromboxane _{A 2 (} TXA 2 ) synthase without significantly affecting the action of (PGI ₂ ) synthetase or prostaglandin synthase (cyclooxygenase). Furthermore, the compound of the present invention is characterized in that it has extremely low toxic effects on rabbits, guinea pigs, dogs, etc., and has a wide range of toxicity and medicinally effective doses. Therefore, the compound according to the present invention has few side effects when used continuously for a long period of time, and is effective against thrombosis caused by platelet aggregation or ischemic diseases caused by vasospasm in the heart, brain, periphery, and circulatory system (e.g., myocardial infarction, stroke). ，
It is used in mammals, including humans, to prevent or treat vascular infarctions in the kidneys, lungs, etc., gastrointestinal ulcers, etc.). For example, the drug can be administered orally in the form of tablets, capsules, powders, granules, etc., or parenterally in the form of injections or pellets. Dosage is usually 1 per adult
The drug is administered orally at a dose of 50 to 500 mg per day, and parenterally at a dose of 50 to 200 mg per day in 2 to 4 divided doses. In the method for producing the compound represented by the general formula (), the reaction between the compound represented by the general formula () and the compound represented by the general formula () is usually carried out in a solvent in the presence of a base. As a base,
Examples include n-butyllithium, sodium hydride, tertiary butoxypotassium, and the like, among which n-butyllithium and sodium hydride are preferably used. Examples of the solvent include ether, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or a mixed solvent of two or more of these solvents. This reaction is preferably carried out under an atmosphere of dry inert gas (eg nitrogen gas, helium gas, etc.). Reaction temperature is -10℃~50℃, preferably 0℃
~30℃. The progress of this reaction can be determined by observing the disappearance of the characteristic color of phosphorane, and the reaction is usually completed in about 1 to 6 hours. Further, the reaction between the compound represented by the general formula () and the compound represented by the general formula () is usually carried out in a solvent in the presence of a base. Preferred examples of the base include sodium hydride, potassium tertiary butoxide, potassium carbonate, and sodium methoxide. Examples of solvents include ether,
Examples include tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, or a mixed solvent of two or more selected from these solvents. The reaction temperature is usually -10°C to 60°C, preferably 0°C to 30°C, and the reaction time is usually 1 to 3 hours. The substituted vinyl carboxylic acid derivative () produced in this manner can be separated and purified by conventional means such as extraction, concentration, crystallization, liquid chromatography, etc. Compound () belongs to trisubstituted olefin compounds and may exist in two types of geometric isomers. Separation of isomers may be performed by fractional crystallization or chromatography, if necessary. I can do it. When the compound represented by the general formula () is a carboxylic acid [R ³ in the formula () is a hydrogen atom], it can be esterified if necessary to form an ester [R ³ in the formula () is a lower alkyl group]. Conversely, when it is an ester, it can be converted into a free carboxylic acid if necessary. The compound represented by the general formula () can be obtained by reacting the compound () with vinyl magnesium halide to form the compound represented by the general formula (). It can be produced by obtaining a compound represented by (in the formula, each symbol has the same meaning as above) and then subjecting it to halogenation treatment. The reaction between the compound () and vinylmagnesium halide is carried out by -
It is carried out at 5°C to room temperature. The reaction of halogenating compound () is performed by adding thionyl chloride, thionyl bromide, phosphorus pentachloride, phosphorus trichloride, phosphorus tribromide, etc. to compound () in a solvent such as methylene chloride, chloroform, ether, isopropyl ether, etc. This is done by reacting a halogenating agent. Since the product of this reaction, compound (), is unstable, particular attention must be paid to the reaction temperature. The reaction temperature is usually about -20°C to 20°C. The halide () obtained in this way can be used in a condensation reaction with the compound () without purification. The compound of the general formula () is obtained by reacting an organolithium compound and an aldehyde compound, and then adding manganese dioxide or dimethyl sulfoxide-oxalic acid chloride to this compound, as shown in the following formula. It can be produced by reaction. The present invention will be explained in more detail by referring to Reference Examples, Examples, and Experimental Examples below. Reference example 1 Method A 3-bromopyridine (10.0
g, 63 mmole) in ether (200 ml),
Cooled to -30°C. A n-butyllithium hexane solution (1.62 molar concentration, 40 ml) was added dropwise to this solution over 10 minutes, and the mixture was stirred for 5 minutes under the same reaction conditions. A solution of p-isopropylbenzaldehyde (10.0 g, 67 mmole) in ether (20 ml) was added dropwise to this reaction solution over 5 minutes. Gradually raise the reaction temperature to room temperature, then add water (300 ml) to the reaction,
Ethyl acetate (300ml) was added to the product, and the product was extracted with ethyl acetate (300ml). Wash the organic layer with water,
After drying (magnesium sulfate), it was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography and developed with ethyl acetate to obtain the desired secondary alcohol (a-2 in Table 1) (9 g, 76%). . Table 1 summarizes the secondary alcohols (a-1 to a-22 in Table 1) produced according to the above method. Method B Benzothiophene (2.0 g, 14.9 mmole) was dissolved in tetrahydrofuran (6 ml) and ether (12 ml), and n-butyllithium hexane solution (1.62 molar concentration, 12.5 ml) was added dropwise at -20 to 0°C to form a blue solution. Summer. After 15 minutes, add a solution of nicotinaldehyde (1.6 g) in tetrahydrofuran (5 ml) to 0.
Added dropwise at ~25°C. After stirring the reaction for 1 hour, water (50 ml) was added to the reaction solution, and the product was extracted with ethyl acetate. The product was separated and purified according to a conventional method to obtain a secondary alcohol (a-23 in Table 1) (2.1 g). Physical properties and other properties are shown in Table 1.

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[Table] Reference Example 2 The alcohol compound (a) produced in Reference Example 1 can be converted into a carbonyl compound (a in Table 2) by producing it according to either Method A or Method B shown below. Obtained. Oxidation with manganese dioxide was applicable to all secondary alcohols (), and oxidation with dimethyl sulfoxide-oxalic acid chloride was applicable to all compounds except those containing a thiophene nucleus. Method A Alcohol (a-11) (4.0g, 21mmole)
was dissolved in methylene chloride (70 ml), manganese dioxide (13 g) was added, and the mixture was heated and stirred for 10 hours.
After the reaction, the manganese dioxide was separated, the manganese dioxide was thoroughly washed with ethyl acetate and acetone, the liquid was concentrated, and the product was recrystallized from a mixed solution of isopropyl ether and ethyl acetate to obtain the carbonyl form (a-12 in Table 2) ( 3g, 75%) was obtained. Method B Oxalic acid chloride (2.2 ml) was dissolved in methylene chloride (50 ml) and cooled to -60°C. A methylene chloride (5 ml) solution containing dimethyl sulfoxide (4 ml) was added dropwise to this solution within a temperature range of -60°C to -50°C. Next, alcohol (
A-2, 4.5 g, 20 mmole) in methylene chloride (50 ml) was added dropwise under the same temperature conditions over 10 minutes, and after another 15 minutes, triethylamine (15 ml) was gradually added, and the reaction took approximately 1 hour. The temperature was allowed to rise to room temperature. After the reaction, water (20 ml) was added, the solvent was concentrated under reduced pressure, and the residue was extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated under reduced pressure, and the product was purified by silica gel chromatography according to a conventional method to obtain carbonyl compounds (a-3, a-3 in Table 2,
4.3g, 98%) was obtained. The reaction was carried out according to the above two methods, and the carbonyl compounds shown in Table 2 (a-1 to a-
25) was manufactured.

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[Table] Example 1 Dimethyl sulfoxide (40
ml) was added with sodium hydride (1.0 g) and heated to 80°C for 30 minutes. After cooling the reaction to room temperature,
To this was added 5-carboxybentyltriphenylphosphonium bromide (9.5 g, 21 mmole) and stirred for 5 minutes. A solution of 3.7 g (0.02 mole) of 3-benzoylpyridine in tetrahydrofuran (10 ml) was added to the reaction mixture. After stirring at room temperature for 30 minutes, water (100 ml) was added, extracted twice with ethyl acetate (50 ml), and the aqueous solution was diluted with 2N hydrochloric acid to PH.
was adjusted to 6 and the product was extracted with ethyl acetate.
After washing the organic layer with water and drying (magnesium sulfate), the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel chromatography, and ethanol-ethyl acetate (1:
5), (E)+(Z)-7-(3-pyridyl)-7-phenyl-6-heptenoic acid (Table 3-
a-3, a-4) (4.5 g, 79%) was obtained. In Table 3-1 (a-1 to
a-10), Table 3-2 (b-11 to b-38), Table 3-3 (c-39 to c-41), and Table 3-4
Medium (d-42) was produced. Isomers can be separated using fractional crystallization or Lobar Lichroprep RP-8.
(40-63 μm manufactured by Merck & Co.) by liquid chromatography.

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[Table] *1: Isomers are indicated as E if the pyridine nucleus and hydrogen atom are in the same direction in the trisubstituted olefin bond, and Z if they are in the opposite direction.
The same applies to the table below.

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[Table] Similar numbers are used in the tables below.

[Table] *2: See Table 3-2

[Table] *2: See Table 3-2 Example 2 Phosphorus pentachloride (3.0 g, 14.2 mmole) was suspended in dichloromethane (4 ml) and 1-phenyl-1-
(3-pyridyl)-2-propen-1-ol (2.0 g, 9.5 mmole) in dichloromethane (20 ml)
The solution was added dropwise at 0°C. After the dropwise addition was completed, the mixture was stirred at room temperature for 1 hour, and washed with water and saturated sodium bicarbonate water in that order. Dry the organic layer (magnesium sulfate)
Thereafter, the solution was concentrated to about 20 ml at 30° C. or lower, and the solution was further dried using molecular sieves 4A. This solution is called solution (a). Separately, sodium hydride (400 mg, 10 mmole) was suspended in dimethylformamide (5 ml), and methyl metahydroxybenzoate (1.37 g, 9.0 mmole) was added at 0°C under an argon atmosphere.
A dimethylformamide (5 ml) solution of was added dropwise. After stirring at 0°C for 30 minutes, (a) solution was added dropwise, followed by
Stirred at room temperature for 1.5 hours. Pour the reaction into ice water,
The product was extracted with ethyl acetate, washed with water, dried (magnesium sulfate), and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography,
When developed with ether-ethyl acetate (7:3), 3
―[3-(3-pyridyl)-3-phenyl-2-
Methyl propenyloxybenzoate (f-56)
(3.0g, 92%) was obtained. The substituted vinyl carboxylic acid derivatives () produced according to Example 2 above are shown in Table 4-1 (e-43,
e-44, e-52), Table 4-2 (f-55~
f-63) and Table 6 (i-77, i-78). Example 3 3-[3-(3-pyridyl)-3-phenyl-
2-propenyloxy]methyl benzoate (f-
56, 1.5 g, 4.35 mmole) was dissolved in a mixture of water (3 ml) and methanol (10 ml), sodium hydroxide (700 mg, 17.5 mmole) was added, and the mixture was stirred at 60°C for 2 hours. After cooling, water was added to the reaction solution, the pH was adjusted to 5 with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was distilled off. The residue was subjected to silica gel column chromatography and developed with ethyl acetate to obtain the desired 3-
[3-(3-pyridyl)-3-phenyl-2-propenyloxy]benzoic acid (e-46) (1.15 g,
80%). The substituted vinyl carboxylic acid derivatives shown in Table 4-1 (
e-45 to e-51, e-53, e-54) were manufactured. Example 4 (E)-7-(3-pyridyl)-7-phenyl-6
- Heptenoic acid (a-4300mg) and 2N hydrochloric acid (5
ml) was added and dissolved, and then concentrated under reduced pressure. When the precipitated crystals were recrystallized from ethanol-isopropyl ether, (E)-7-(3-pyridyl)-7-phenyl-6-heptenoic acid hydrochloride (i-75) was obtained.
(285mg) was obtained. Melting point 163-165°C and other physical properties are shown in Table 6. Example 5 (E)-7-(3-pyridyl)-7-phenyl-6
- Add heptenoic acid (a-4) (560 mg) and sodium hydrogen carbonate (160 mg) to water (5 ml) to make a homogeneous solution, concentrate under reduced pressure, and powder with ethanol-isopropyl ether (E)-7- Sodium (3-pyridyl)-7-phenyl-6-heptenoate (i-76, 300 mg) was obtained. Physical properties and other properties are shown in Table 6. Example 6 (E+Z)-7-(3-pyridyl)-7-phenyl-6-heptenoic acid (a-3, a-4)
(0.5 g) was dissolved in ethyl acetate (50 ml), and a diazomethane ether solution was added under cooling. After the reaction, the solvent was concentrated, the residue was subjected to Rover column chromatography (RP-8), and (E)- and (Z)-
Methyl 7-(3-pyridyl)-7-phenyl-6-heptenoate (g-72) and (g-73) were separated. Substituted vinyl carboxylic acid derivatives (g-64 to g-74) were produced according to the reaction procedure of Example 6.
Table 5 shows these physical properties and other physical constants.

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[Table] *2: See Table 3-2

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[Table] *2: See Table 3-2

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[Table] Experimental example 1 Thromboxane A ₂ (TXA ₂ ) synthase inhibitory effect As a standard of TXA ₂ synthase, the method of Needleman et al. (Science 193 163,
Horse platelet microsomes treated with indomethacin (indomethacin-treated horse platelet microsomes: 1PM) prepared according to the method (1976) were used. First of all, IPM
Solutions containing various concentrations of drugs in 60μ of 50mM Tris buffer solution (PH7.5) (containing 140μg of protein)
60μ was added and left at room temperature for 5 minutes. Take 100μ of this mixture, add 20μ of a buffer solution containing 30ng of prostaglandin H ₂ (PGH ₂ ) under ice-cooling, and add 20μ of a buffer containing 30ng of prostaglandin H 2 (PGH 2 ).
The mixture was allowed to stand at ℃ for 5 minutes to generate thromboxane A ₂ (TXA ₂ ). After stopping _the reaction by adding 500μ of Tris buffer, the 50μ was used for radioimmunoassay of thromboxane B ₂ (TXB ₂ ), a stable metabolite of TXA 2 [Shibouta et al.
al) Biochem.Pharmacol. 28 3601 1979]. TXB ₂ in drug-free and drug-added groups
The inhibition rate (%) against TXA ₂ synthetase was determined from the difference in production ability. Table 7 shows the results for the following representative compounds.

[Table] Example 8 Promoting the utilization of prostaglandin H ₂ (PGH ₂ ) or prostaglandin G ₂ (PGG ₂ ) for the biosynthesis of vascular wall prostaglandin I ₂ (PGI ₂ ) Platelet aggregation experiments were conducted using Born ( (Nature 194 , 927 1962). 50mM Tris buffer solution (PH7.5) containing a fixed concentration of drug in 250μ of rabbit platelet-rich plasma prepared by a conventional method
25μ was added and stirred for 2 minutes. 1 mg of aorta section (containing PGI ₂ synthetase activity) taken from a rat was added to this mixture, and after 2 minutes, 25μ of arachidonic acid was added.
(0.21mM) was added to examine the platelet aggregation ability. 6 minutes after the addition of arachidonic acid, 20μ aliquots were collected from the reaction solution, and thromboxane B ₂ (a stable metabolite of TXB ₂ , TXA ₂ ) and 6-keto-prostaglandin were collected.
F ₁ 〓 (6-Keto-PGE ₁ 〓) (stable metabolite of PGI ₂ ) was measured by radioimmunoassay. [Shibouta et.al Biochem. Pharmacol. 28 ,
3601 (1979) Terashita et.al, Japan,
J.Pharmacol., 32 , 351 (1982)]. Platelet aggregation ability without and with addition of rat aorta sections
The production amounts of TXB ₂ and 6-Keto-PGF ₁ were compared. (Results) In Table 8, the platelet aggregation rate due to arachidonic acid (0.21mM) was
100%, at this time TXB ₂ generates 32ng, 6-
No formation of Keto-PGF ₁ was observed. When 10 ^-6 M of 7-phenyl-7-(3-pyridyl)-6-heptenoic acid (a-4) was applied, aggregation was slightly suppressed to 93%. At this time, TXB ₂ production was almost completely suppressed (2 ng). Addition of aorta slices suppressed aggregation to 70% and reduced TXB ₂ from 32 to 27 ng.
On the other hand, 6-Keto-PGF ₁ 〓 decreases from 0 to
increased to 22ng. In contrast, aortic fragments and
When 10 ^-6 M of ( _a -4) coexists, the aggregation rate is 31
% and at the same time, TXB ₂ production was completely suppressed, while 6-Keto-PGF ₁ 〓 was 22 to 38 ng.
There was a marked increase in From these results, the compound (a-
4) TXA ₂ from arachidonic acid in platelets
TXA ₂ precursor PGH ₂ ,
It is considered to promote and enhance the utilization of PGG ₂ for vascular PGI ₂ synthesis.

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Claims (1)

[Claims] 1. General formula [In the formula, R ¹ is a pyridyl group, and R ² is a phenyl group or thienyl group that may have a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group, or a methylenedioxy group. , a furyl group, a naphthyl group, a benzothienyl group, or a pyridyl group, Y is a sulfur atom, a methylene group, or the general formula [Formula] (wherein, R ⁴ is a hydrogen atom or an acetyl group, and m is 0 or 1). A substituted vinyl carboxylic acid derivative represented by the following group, R ³ is a hydrogen atom or a lower alkyl group, and n is an integer of 0 to 6. 2 General formula (In the formula, R ¹ is a pyridyl group, and R ² is a phenyl group or thienyl group that may have a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group, or a methylenedioxy group. , a furyl group, a naphthyl group, a benzothienyl group, or a pyridyl group) and the general formula (C ₆ H ₅ ) ₃ P—CH ₂ CH ₂ CH ₂ —(CH ₂ —) _o COOR ³・
A general ^formula characterized by reacting ^with a compound represented by A method for producing a substituted vinyl carboxylic acid derivative represented by the formula (wherein each symbol has the same meaning as above). 3 General formula (In the formula, R ¹ is a pyridyl group, and R ² is a phenyl group or thienyl group that may have a lower alkoxy group, a lower alkyl group, a halogen atom, a trifluoromethyl group, a lower alkenyl group, or a methylenedioxy group. , a furyl group, a naphthyl group, a benzothienyl group, or a pyridyl group, and Z represents a halogen atom) and the general formula HY ¹ -(CH ₂ -) _o COOR ³ [wherein, R ³ is a hydrogen atom or ^A lower alkyl group, Y ¹ is a sulfur atom or a group represented by the general formula A general formula characterized by reacting with a compound represented by A method for producing a substituted vinylcarboxylic acid derivative represented by the formula (wherein each symbol has the same meaning as above).