JP2003089687A - New butadiene derivative, method for producing the same and synthetic intermediate therefor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new butadiene derivative having excellent inhibitory actions, or the like, on type 1 plasminogen activator inhibitor (PAI-1) and useful as a prophylactic or a therapeutic agent for myocardial infarction, intraatrial thrombus in artial fibrillation, arteriosclerosis such as atherosclerosis, angina pectoris, cerebral apoplexy, pulmonary embolus, deep venous thrombosis (DVT), disseminated intravascular coagulation (DIC), diabetic complications, restenosis, after percutaneous transluminal coronary angioplasty (PTCA), to provide a method for producing the same and to obtain a synthetic intermediate therefor. SOLUTION: The butadiene derivative is represented by formula [I] (wherein, R<1> denotes hydrogen atom or a lower alkyl group; R<2> denotes a lower alkyl group; R<3> denotes a lower alkoxy group; R<4> denotes hydrogen atom or a lower alkyl group; and R<5> denotes a lower alkyl group) or its pharmacologically acceptable salt. The method for producing the butadiene derivative or its pharmacologically acceptable salt is also provided.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel butadiene derivative, a process for producing the same, and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art In a living body, a fibrinolytic (fibrinolytic) system plays an important role in lysis of thrombus, destruction and repair of tissues, migration of cells and the like. The fibrinolytic system is activated by the conversion of plasminogen into plasmin by the plasminogen activator (PA). Type 1 plasminogen activator inhibitor (PA
I-1) controls this fibrinolytic system at the initiation stage and is considered to be involved in the formation and progress of various pathological conditions such as thrombosis, diabetes and arteriosclerosis. Therefore, compounds that inhibit PAI-1 production are considered to be useful as prophylactic / therapeutic agents for thrombosis, diabetic complications, arteriosclerosis, and the like.

On the other hand, European Patent Publication No. 563798 discloses that
As an antithrombotic drug, (1E, 3E) -1- (3,4,5-
Trimethoxyphenyl) -2-methoxycarbonyl-3
-[N- (4-pyridylmethyl) carbamoyl] -4-
Although phenylbutadiene and the like are described, there is no specific disclosure about a compound in which the substituent on the carbamoyl group bonded to the 3-position of butadiene is a 2-lower alkylpyridyl group, and further, at the 1-position of butadiene. Nothing is disclosed about a compound having a carboxyl group on the benzene ring to be bonded. Further, the compounds described in the European publication have room for further improvement in terms of bioavailability and stability.

Further, WO 97/36864 discloses (1Z, 3E) -1-methyl-1- (3,5-dimethoxyphenyl) -2-methoxycarbonyl-3- [N.
-(4-Pyridyl) aminocarbonyl] -4- (3,4
-Methylenedioxyphenyl) butadiene, (1Z, 3
E) -1-Methyl-1- (3,4,5-trimethoxyphenyl) -2-methoxycarbonyl-3- [N- (4-
Pyridyl) aminocarbonyl] -4- (3,4-methylenedioxyphenyl) butadiene and the like are described, but a compound having a carboxyl group on the benzene ring bonded to the 1-position of butadiene as disclosed in the present invention is disclosed. However, a compound in which the substituent on the carbamoyl group bonded to the 3-position of butadiene is a 2-lower alkylpyridyl group is not specifically disclosed.

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a novel butadiene derivative having high safety as a medicine, a process for producing the same, and a synthetic intermediate thereof.

[0006]

As a result of earnest research, the present inventor has found that 1) the stereo structure of the butadiene skeleton is (1Z, 3E).
And 2) has a carboxyl group on the benzene ring bonded to the 1-position of the butadiene skeleton, and 3) has a substituent on the carbamoyl group bonded to the 3-position of the butadiene skeleton is 2-
A novel butadiene derivative, which is a lower alkylpyridyl group, inhibits the production of PAI-1 and has an excellent antithrombotic effect, etc., and also has bioavailability and stability,
The present invention has been completed by finding that it is also excellent in terms of toxicity and the like.

That is, the present invention has the general formula [I]:

[0008]

[Chemical 8]

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a lower alkyl group, R ³ represents a lower alkoxy group, R ⁴ represents a hydrogen atom or a lower alkyl group, and R ⁵ represents a lower alkyl group.) A new butadiene derivative represented by
The present invention relates to a pharmacologically acceptable salt thereof and a method for producing the salt.

Among the object compounds [I] of the present invention, preferred compounds include R ¹ as a hydrogen atom, R ² as a methyl group,
Examples thereof include a compound in which R ³ is a methoxy group, R ⁴ is a methyl group, and R ⁵ is a methyl group.

Among the object compounds [I] of the present invention, more preferred compounds include (1Z, 3E) -1-methyl-
1- (4-carboxyphenyl) -2-methoxycarbonyl-3- (2-methylpyridin-4-yl) aminocarbonyl-4- (3-methoxyphenyl) butadiene or a pharmacologically acceptable salt thereof can be mentioned. .

A compound of the general formula [II], which is a synthetic intermediate of the object compound [I] of the present invention:

[0013]

[Chemical 9]

(In the formula, R ⁴⁰ represents a lower alkyl group,
Other symbols have the same meanings as described above), or a carboxylic acid compound or a salt thereof is also a novel compound.

The object compound [I] of the present invention or its synthesis
Intermediate [II] is R¹, R^Two, R ^Three, R^Four, R⁴⁰Oh
And / or R⁵When the above substituent has an asymmetric atom,
Multiple stereoisomers (diastereomers) based on the asymmetric atom
Isomers, optical isomers) of the present invention
Is any one of these stereoisomers or its
It includes any of the mixtures.

The object compound [I] of the present invention or a pharmaceutically acceptable salt thereof has an excellent PAI-1 production inhibitory action. Therefore, myocardial infarction, atrial thrombosis in atrial fibrillation, arteriosclerosis such as atherosclerosis, angina, stroke, pulmonary embolism, deep vein thrombosis (DVT), disseminated intravascular coagulation (DIC) ), Diabetic complications, restenosis after percutaneous coronary angioplasty (PTCA), venous embolism after high-risk surgery such as orthopedic surgery or abdominal surgery, acute coronary syndrome (unstable angina, non-Q wave) Myocardial infarction, etc.), venous thrombosis in cancer patients, cerebral embolism from atrial fibrillation, hepatic vein occlusion after hematopoietic stem cell transplantation, pulmonary fibrosis, peritoneal sclerosis in patients with peritoneal dialysis, septic shock, organs (kidneys, etc.) It is considered to be useful as a preventive or therapeutic agent for rejection after transplantation, cancer metastasis, and the like. The object compound [I] of the present invention or a pharmaceutically acceptable salt thereof also has an anti-inflammatory effect. Furthermore, the object compound [I] of the present invention has the following bioavailability:
Excellent in stability. Moreover, the object compound [I] of the present invention has low toxicity when used as a medicine,
It also has the feature of high safety. In particular, it is extremely excellent in terms of toxicity, and, for example, in an inhibitory effect test on liver microsomal P450, the inhibitory effect (toxicity) is extremely weak. It is also excellent in terms of toxicity to chromosomes.

The object compound [I] of the present invention can be used in medicinal use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmaceutically acceptable salt include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate and methanesulfone. Examples thereof include acid salts, benzene sulfonates, organic acid salts such as tosylate salts and maleate salts, and the like. Further, when it has a substituent such as a carboxyl group, a salt with a base (for example, an alkali metal salt such as sodium salt, potassium salt or the like, or an alkaline earth metal salt such as calcium salt) is included.

The object compound [I] of the present invention or a salt thereof includes any of its inner salt, adduct, solvate or hydrate thereof.

The object compound [I] of the present invention or a pharmacologically acceptable salt thereof can be administered orally or parenterally, and also tablets, granules, capsules, powders and injections. , Can be used as a conventional pharmaceutical preparation such as an inhalant.

The dose of the object compound [I] of the present invention or a pharmacologically acceptable salt thereof is determined by the administration method, patient age,
Although it depends on the body weight and condition, an injection is usually about 0.01 to 10 mg / kg, especially about 0.05 to 5 mg / kg per day, and an oral preparation is usually
About 0.1-100 mg / kg per day, especially about 0.
It is preferably about 5 to 50 mg / kg. <Production Method of Butadiene Derivative> According to the present invention, the butadiene derivative which is the target compound can be produced by the following [Method A] to [Method C], but is not limited thereto. [Method A] In the target compound [I] of the present invention, R ⁴ is a lower alkyl group, that is, the compound of the general formula [I-
a]:

[0021]

[Chemical 10]

(In the formula, R ⁴⁰ represents a lower alkyl group,
Other symbols have the same meanings as described above), and the butadiene derivative represented by the general formula [II]:

[0023]

[Chemical 11]

(However, the symbols have the same meanings as above)
A carboxylic acid compound represented by or a salt thereof, or a reactive derivative thereof (for example, an acid halide, a mixed acid anhydride, etc.), and a compound represented by the general formula [III]:

[0025]

[Chemical 12]

(However, the symbols have the same meanings as above)
It can be produced by reacting with an amine compound represented by or a salt thereof.

When the carboxylic acid compound [II] is reacted with the amine compound [III], the reaction can be carried out in a solvent in the presence or absence of a condensing agent, a base and an activator. Examples of the condensing agent include dicyclohexylcarbodiimide (DCC) and 1-ethyl-3.
-(3-dimethylaminopropyl) carbodiimide / hydrochloride (WSC / HCl), diphenylphosphoryl azide (DPPA), carbonyldiimidazole (CDI),
Examples thereof include diethyl cyanophosphonate (DEPC), diisopropylcarbodiimide (DIPCI), benzotriazol-1-yloxy-trispyrrolidinophosphonium hexafluorophosphate (PyBOP), and the like. Examples of the activator include 1-hydroxybenzotriazole (HOBt), hydroxysuccinimide (HOSu), dimethylaminopyridine (DMAP),
1-hydroxy-7-azabenzotriazole (HOA
t), hydroxyphthalimide (HOPht), pentafluorophenol (Pfp-OH) and the like.
Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0] -7-undecene (DB
U), pyridine, N, N-dimethylaminopyridine and the like.

When the acid halide which is a reactive derivative of the carboxylic acid compound [II] is reacted with the compound [III], the carboxylic acid compound [II] is first converted into a conventional halogenating agent (eg, thionyl chloride or oxalyl chloride). , Phosphorus oxychloride, phosphorus (III) chloride, phosphorus (III) bromide
Etc.) to form an acid halide, and then the acid halide may be reacted with the amine compound [III] in a solvent in the presence or absence of a base. Examples of the base include triethylamine, diisopropylethylamine,
4-methylmorpholine, 1,8-diazabicyclo [5,
4,0] -7-undecene (DBU), pyridine, N,
N-dimethylamino pyridine etc. are mentioned.

When the mixed acid anhydride, which is a reactive derivative of the carboxylic acid compound [II], is reacted with the compound [III], first, the carboxylic acid compound [II] and a chlorocarbonic acid ester (for example, chlorocarbonic acid) are reacted. Ethyl, isobutyl chlorocarbonate, etc.), sulfonic acid halide derivatives (eg, methanesulfonyl chloride, p-toluenesulfonyl chloride, etc.), and various acid halide derivatives are reacted in the presence of a base (eg, triethylamine, pyridine, etc.) and mixed. Then, the mixed acid anhydride is treated with an amine compound [I] in a solvent in the presence or absence of a base.
II]. Examples of the base include triethylamine, diisopropylethylamine, 4-methylmorpholine, 1,8-diazabicyclo [5,4,0]
-7-Undecene (DBU), pyridine, N, N-dimethylaminopyridine and the like can be mentioned.

The solvent used in the above reaction is
Any solvent that does not adversely affect the reaction may be used, for example,
Examples thereof include methylene chloride, chloroform, N, N-dimethylformamide, N, N-dimethylacetamide, tetrahydrofuran, toluene, benzene, 1,2-dichloroethane, 1-methylpyrrolidinone, ethyl acetate, and mixed solvents thereof. [Method B] Of the target compounds of the present invention, compounds of the general formula [I] in which R ¹ is a hydrogen atom, that is, general formula [Ic]:

[0031]

[Chemical 13]

(However, the symbols have the same meanings as described above.)
The butadiene derivative represented by the general formula [Ib]:

[0033]

[Chemical 14]

(In the formula, R ¹⁰ represents a lower alkyl group,
Other symbols have the same meanings as described above) and can be produced by treating the compound or salt thereof with an acid or a base.

This reaction can be carried out in a solvent in the presence of an acid or a base. The solvent may be any solvent that does not adversely affect the reaction, for example, chloroform,
Examples thereof include methylene chloride, tetrahydrofuran, dioxane, methanol, ethanol, water, a mixed solvent thereof, and the like. Examples of the acid include hydrochloric acid, sulfuric acid, trifluoroacetic acid, hydrochloric acid-dioxane, hydrochloric acid-methanol, p.
-Toluenesulfonic acid, methanesulfonic acid, etc. are mentioned. Examples of the base include sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. [Method C] Among the target compounds of the present invention, compounds of the general formula [I] in which R ⁴ is a hydrogen atom, that is, general formula [Id]:

[0036]

[Chemical 15]

(However, the symbols have the same meanings as above)
The butadiene derivative represented by the general formula [Ib]:

[0038]

[Chemical 16]

(However, the symbols have the same meaning as above)
It can be produced by treating the compound represented by or a salt thereof with an acid or a base.

This reaction can be carried out in a solvent in the presence of an acid or a base. The solvent may be any solvent that does not adversely affect the reaction, and for example, those exemplified as the solvent that can be used in the above [Method B] can be appropriately used. Also, as the acid or base, those exemplified in the above [Method B] can be appropriately used. <Production Method of Raw Material Compound [II]> The raw material compound [II] is
For example, it can be manufactured according to the following method.

[0041]

[Chemical 17]

(However, the symbols have the same meanings as above.) The reaction for producing the compound [VI] from the compound [IV] and the compound [V] is a conventional Stobbe Reactio reaction.
It can be carried out under the condition of n), that is, in the presence of a base in a solvent. The solvent may be any solvent that does not adversely affect the reaction, and examples thereof include methanol, ethanol, isopropyl alcohol, tert-butyl alcohol, benzene, toluene, xylene, and tetrahydrofuran. Examples of the base include organic bases such as potassium tert-butoxide, sodium methoxide and sodium ethoxide, and inorganic bases such as sodium hydroxide and potassium hydroxide.

The reaction for producing compound [VIII] from compound [VI] and compound [VII] can be carried out under conventional esterification reaction conditions. For example, a method of reacting with a lower alcohol [VII] in the presence of an acid catalyst (eg concentrated sulfuric acid, concentrated hydrochloric acid, polyphosphoric acid, etc.), compound [VI]
The method of reacting with the lower alcohol [VII] in the presence of a base (eg, triethylamine, pyridine, etc.) after the carboxyl group of is once converted into an acid halide with a halogenating agent (eg, thionyl chloride, oxalyl chloride, etc.) Can be mentioned.

The reaction for producing the compound [II] from the compound [VIII] and the compound [IX] can be carried out under the usual Stobbe reaction conditions. The reaction solvent and the base are the same as those of the compound [IV] and the compound [V].
The solvents and bases that can be used in the reaction for producing [I] can be appropriately used. <Production Method of Raw Material Compound [III]> Raw Material Compound [III]
Can be produced, for example, according to the following method.

[0045]

[Chemical 18]

(Where the symbols have the same meanings as described above) The reaction for producing compound [III] from compound [X] is as follows:
It can be carried out in a solvent in the presence of a reducing agent. The solvent may be any solvent that does not adversely affect the reaction,
For example, acetic acid, methanol, ethanol, dioxane,
Tetrahydrofuran etc. are mentioned. As a reducing agent,
For example, palladium / carbon-hydrogen, palladium / carbon-
Formic acid, Raney nickel-hydrogen, lithium aluminum hydride, sodium borohydride and the like can be mentioned. Also,
This reaction can be carried out under normal pressure or increased pressure.

In producing the above-mentioned target compound, not only each intermediate compound shown in the above chemical reaction formula but also its salt or its reactive derivative may be appropriately used as long as it does not adversely affect the reaction. it can.

Further, in the production of the target compound and the starting compound of the present invention, when the starting compound or each intermediate has a functional group, appropriate protection of each functional group is carried out by a conventional synthetic chemistry method other than those shown above. A group may be introduced, and if necessary, those protecting groups may be appropriately removed.

In the target compound or starting material compound of the present invention, examples of the alkyl include linear or branched ones having 1 to 16 carbon atoms, and particularly 1 carbon atom.
~ 8 are mentioned. Examples of lower alkyl or lower alkoxy include linear or branched ones having 1 to 6 carbon atoms, and particularly ones having 1 to 4 carbon atoms. Examples of the halogen atom include fluorine, chlorine, bromine and iodine.

[0050]

Example 1 (1) 100 g of 4-acetylbenzoic acid was mixed with 5 methylene chloride.
Suspended in 00 ml, 64 ml of oxalyl chloride at room temperature,
After adding 4.7 ml of N, N-dimethylformamide,
Stir at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, 250 ml of chloroform and 175 ml of tert-butyl alcohol are added to the residue to dissolve it, and 156 ml of pyridine is added dropwise under water cooling (12 ° C.). After stirring at room temperature for 30 minutes, the reaction solution was concentrated under reduced pressure, the residue was dissolved in toluene, and 2M
Wash with hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution, and brine in this order. The organic layer is dried over magnesium sulfate, concentrated under reduced pressure, hexane is added to the precipitated crystals, and the mixture is stirred under ice cooling. The precipitated crystals are collected by filtration, washed with cold hexane, and dried under reduced pressure to give 96.82 g (yield 69%) of 4-acetylbenzoic acid tert-butyl ester. Mp: 59-60 ° C (2) Dimethyl succinate 773 g was added to methanol 600 m.
Dissolve in 1, and add 850 ml of 28% sodium methoxide-methanol solution, and heat and reflux for 30 minutes. After cooling the reaction solution to 65 ° C., m-anisaldehyde 600 m
A solution of g in methanol (300 ml) is added dropwise over 30 minutes. The reaction solution is heated under reflux for 3 hours, allowed to cool, and concentrated under reduced pressure. 2 L of water was added to the residue and washed with chloroform (1.5
L × 2). Concentrate hydrochloric acid 44 in the aqueous layer while stirring under ice cooling.
After dropwise adding 1 ml, the mixture is extracted with 4 L of ethyl acetate, washed with 3 L of brine, and dried with magnesium sulfate. The organic layer is concentrated under reduced pressure to obtain 1075 g of residual crude carboxylic acid compound. The residue was dissolved in 2.4 L of methanol and concentrated sulfuric acid 24.
Add 5 ml, heat under reflux for 3 hours, allow to cool, and concentrate under reduced pressure. Ethyl acetate (4 L) is added to the residue, and the mixture is washed with water (3 L), saturated aqueous sodium hydrogen carbonate solution (3 L × 3), and brine (3 L) in this order. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was distilled under reduced pressure (Bp: 145-150 ° C /
1 mmHg) to give (E) -2 as a pale yellow oil.
747 g (yield 64%) of-(3-methoxybenzylidene) -succinic acid dimethyl ester are obtained. (3) 30 g of 2-methyl-4-nitropyridine-N-oxide was dissolved in 330 ml of acetic acid, and 10% palladium /
After adding 20 g of carbon (Pd / C) (wet), catalytic hydrogenation under pressure is carried out using Parr. Two
After 4 hours, bubbling the reaction solution with nitrogen for 30 minutes,
Palladium on carbon is removed by filtration. Acetic acid is distilled off from the filtrate, and a saturated aqueous potassium carbonate solution is added to the residue to make it alkaline.
Tetrahydrofuran is added to this and the mixture is vigorously stirred, then the insoluble matter is filtered off and washed with tetrahydrofuran. Extract with tetrahydrofuran (× 2) and evaporate the solvent. Toluene is added to the residue and water is azeotropically distilled to obtain a precipitated solid. Methylene chloride is added to this solid to dissolve it, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals were triturated with diisopropyl ether, and the obtained crystals were dried by blowing air at 50 ° C. overnight to obtain 18.7 g (yield 88%) of 4-amino-2-methylpyridine. Mp: 86-88 ° C (4) 10.0 g of the compound obtained in (2) above and 8.33 g of the compound obtained in (1) above were dissolved in 55 ml of tert-butyl alcohol, and tert-butoxypotassium was added thereto. 67 g of tert-butyl alcohol 40 ml solution was added dropwise (under nitrogen atmosphere, under ice cooling: internal temperature 2
1-23 ° C) and 20 ° C for 2 hours. 0.87 ml of acetic acid is added to the reaction solution, and the mixture is concentrated under reduced pressure. Toluene is added to the residue, and the mixture is azeotropically distilled. 1.69 g of potassium tert-butoxide was added to this under ice cooling, and the mixture was stirred at 20 ° C. for 1 hour. After adding 2.8 ml of acetic acid thereto, the organic layer is washed with brine, 1M hydrochloric acid, water and brine in this order, dried over magnesium sulfate and concentrated under reduced pressure.
The residue was dissolved in 200 ml of diisopropyl ether, and 28% sodium methoxide-methanol solution under ice cooling.
After dropwise adding 1 g, the mixture is stirred at room temperature overnight. The precipitated crystals were collected by filtration, washed with diisopropyl ether, and dried by blowing air (50
(C)) to obtain (1Z, 3E) -1-methyl-1
-(4-Tert-butoxycarbonylphenyl) -2
-Methoxycarbonyl-4- (3-methoxyphenyl)
Butadiene-3-carboxylic acid sodium salt 6.58 g
(Yield 37%) is obtained. Mp:> 196 ° C (decomposition) (5) 152 g of the compound obtained in (4) above was suspended in chloroform, and 37.8 ml of oxalyl chloride, N, N-.
Add 2.51 ml of dimethylformamide, and add 1 at 50 ° C.
Stir for hours. The reaction mixture is concentrated under reduced pressure, chloroform is added, and the mixture is concentrated under reduced pressure again. Tetrahydrofuran 1.
5 L was added, and a solution of 41.7 g of the compound obtained in (3) above in 200 ml of tetrahydrofuran was added dropwise with stirring under ice-cooling. At the same temperature, after adding 3.96 g of N, N-dimethylaminopyridine, triethylamine 67.2 m
1 is added dropwise (internal temperature 7-10 ° C). 40 at room temperature
After stirring for a minute, concentrate under reduced pressure. The residue was dissolved in ethyl acetate, washed with brine (× 3), dried over magnesium sulfate, and concentrated under reduced pressure to give (1Z, 3E) -1-methyl-1- (4-tert-butoxycarbonylphenyl). 2-Methoxycarbonyl-3- (2-methylpyridin-4-yl) aminocarbonyl-4- (3-methoxyphenyl) butadiene is obtained as a crude product. (6) Chloroform 30 is added to the crude product obtained in (5) above.
0 ml of a 4 M hydrogen chloride-dioxane solution (1 L) is added, and the mixture is stirred at room temperature overnight. The precipitated crystals were collected by filtration and washed with tetrahydrofuran, and the crude crystals were subjected to silica gel column chromatography (developing solvent; chloroform: methanol = 2).
0: 1) and recrystallized from methanol to give (1Z, 3E) -1-methyl-1- (4-carboxyphenyl) -2-methoxycarbonyl-3- (2-methylpyridine-4-). Ayl) aminocarbonyl-4- (3
-Methoxyphenyl) butadiene / hydrochloride 86.4 g
(Yield 51%) is obtained. Mp: 232 ° C (decomposition)

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 7/02 A61P 7/02 9/10 9/10 103 103 11/00 11/00 37/00 37 / 00 43/00 111 43/00 111 F term (reference) 4C055 AA01 BA02 BA05 BA06 CA01 DA53 DB02 DB11 FA15 FA32 4H006 AA01 BJ50 BP30 BS10 BS70 KC14 KC30 KF00

Claims (6)

[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 represents a lower alkyl group, R ³ represents a lower alkoxy group, R ⁴ represents a hydrogen atom or a lower alkyl group, and R ⁵ represents a lower alkyl group). A butadiene derivative or a pharmacologically acceptable salt thereof. 2. R ¹ is a hydrogen atom, R ² is a methyl group, R ³
Is a methoxy group, R ⁴ is a methyl group, and R ⁵ is a methyl group. 3. (1Z, 3E) -1-methyl-1- (4
-Carboxyphenyl) -2-methoxycarbonyl-3
-(2-Methylpyridin-4-yl) aminocarbonyl-4- (3-methoxyphenyl) butadiene or a pharmaceutically acceptable salt thereof. 4. The general formula [II]: (Wherein R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a lower alkyl group, R ³ represents a lower alkoxy group, and R ⁴⁰ represents a lower alkyl group) or a salt thereof, or a reaction thereof. Of the general formula [II
I]: (Wherein R ⁵ represents a lower alkyl group) is reacted with an amine compound or a salt thereof to give a product as a pharmacologically acceptable salt, if desired. -A]: (However, symbols have the same meanings as described above), and a process for producing a butadiene derivative or a pharmaceutically acceptable salt thereof. 5. A compound represented by the general formula [Ib]: Wherein R ¹⁰ is a lower alkyl group, R ² is a lower alkyl group, R ³ is a lower alkoxy group, R ⁴⁰ is a lower alkyl group, and R ⁵ is a lower alkyl group. Alternatively, the compound of the general formula [Ic] is characterized in that it is treated with a base, and the product is converted into a pharmacologically acceptable salt if desired. (Wherein R ⁴ represents a hydrogen atom or a lower alkyl group, and other symbols have the same meanings as described above), and a method for producing a pharmaceutically acceptable salt thereof. 6. A compound represented by the general formula [II]: (In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, R ² represents a lower alkyl group, R ³ represents a lower alkoxy group, and R ⁴⁰ represents a lower alkyl group) or a salt thereof.