JP2541420B2 - 3-Butenoic acid derivative and process for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel 3-butenoic acid derivative useful as an antithrombotic drug and as a synthetic intermediate thereof, and a process for producing the same.

[0002]

BACKGROUND ART It is well known that thrombus causes various diseases such as myocardial infarction, stroke, pulmonary embolism, etc. Therefore, enzyme preparations such as tissue plasminogen activator, urokinase and streptokinase have been conventionally used. Widely used to prevent blood clots. However, these drugs have the disadvantage that they are rapidly degraded in the blood and lose their medicinal effect, and can be used for medical use only by parenteral administration. On the other hand, NOUVEAU JOURNAL
DE CHIMIE), Vol. 1, No. 5,413
-418 (1977) discloses dibenzylidene succinic acid, but no pharmacological activity of the compound is known.

[0003]

INDUSTRIAL APPLICABILITY The present invention is useful as an antithrombotic drug which can be used by oral administration or parenteral administration per se, and is an excellent antithrombotic drug 2,5-
The present invention provides a novel 3-butenoic acid derivative which is also useful as a synthetic intermediate for a pyrrolidinedione derivative.

[0004]

The 3-butenoic acid derivative according to the present invention has the general formula [I]

[0005]

Embedded image

(In the formula, ring A is a tri-lower alkoxyphenyl group, R ¹ and R ^{2 each} represent a lower alkoxy group and the other represents a group represented by the formula: —NHR ³ , and R ³ has a substituent. Represents a lower alkyl group which may be substituted, a hydroxyl group, a lower alkoxy group which may have a substituent or an amino group which may have a substituent).

Specific examples of the object [I] of the present invention include:
Ring A is a 3,4,5-tri-lower alkoxyphenyl group,
2,3,4-tri-lower alkoxyphenyl group, 2,4
Tri-lower alkoxyphenyl groups such as 5-tri-lower alkoxyphenyl group and 2,4,6-tri-lower alkoxyphenyl group, wherein R ³ is 1) hydroxyl group, lower alkoxy group, phenyl group and nitrogen atom-containing 6-membered heterocycle Group 1 selected from formula groups (eg, pyridyl group, morpholino group, etc.)
A lower alkyl group which may have three, 2) a hydroxyl group,
Examples thereof include a compound which is 3) a lower alkoxy group which may be substituted with a phenyl group, or 4) an amino group which may be substituted with a lower alkyl group.

The object [I] of the present invention may have four types of stereoisomers based on two double bonds, and the present invention includes both of these stereoisomers and mixtures thereof.

In the object [I] of the present invention, specific examples of the lower alkyl group and the lower alkoxy group include an alkyl group and an alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms.

The object [1] of the present invention can be used for medicinal use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Examples of the pharmacologically acceptable salt include hydrochloride, hydrobromide, sulfate, maleate, oxalate and the like.

The object [I] of the present invention and a pharmaceutically acceptable salt thereof can be used either orally or parenterally for pharmaceutical use, and are suitable for oral or parenteral administration. It can be mixed with an agent and used as a pharmaceutical preparation. Further, the pharmaceutical preparation may be a solid preparation such as a tablet, a capsule or a powder, or a liquid preparation such as a solution, a suspension or an emulsion. Further, for parenteral administration, it can be used in the form of injection. The dose varies depending on the age, weight, condition of the patient or the degree of disease, but usually the daily dose is, in the case of oral administration,
0.1-100 mg / kg, especially 0.5-50 mg
/ Kg, 0.01 to 10 mg / in the case of parenteral administration
It is preferably kg, especially 0.05 to 5 mg / kg.

According to the present invention, the target [I] is, for example, a compound of the general formula [II]

[0013]

[Chemical 6]

[Wherein one of R ¹¹ and R ²¹ represents a lower alkoxy group and the other represents a hydroxyl group, and ring A has the same meaning as described above], a salt thereof or a reactive derivative thereof. , The general formula [III]

[0015]

Embedded image NH ₂ R ³ [III]

It can be produced by condensing with an amine compound represented by the formula (wherein R ³ has the same meaning as described above).

The condensation reaction of the butenoic acid ester compound [II] or its salt and the amine compound [III] can be carried out in a suitable solvent in the presence of a dehydrating agent. As the dehydrating agent, for example, dicyclohexylcarbodiimide,
Carbonyldiimidazole and the like can be mentioned. As the salt of the butenoic acid ester compound, a conventional salt such as an alkali metal salt or an alkaline earth metal salt can be used, and when these salts are reacted with an amine compound, they are previously subjected to the reaction as a free carboxylic acid. preferable. In addition, the compound [I
The condensation reaction between the reactive derivative of I] and the amine compound can be carried out in a suitable solvent in the presence or absence of a deoxidizing agent. As the reactive derivative, for example, any of those commonly used for acid amide condensation such as acid halide, mixed acid anhydride and active ester can be used. Examples of the deoxidizing agent include alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogen carbonate, trialkylamine, N,
Examples thereof include N-dialkylaniline and pyridine.

The reaction solvent may be any inert solvent which does not adversely influence the reaction, and preferred examples thereof include trichloromethane, dichloromethane, dioxane and tetrahydrofuran. This condensation reaction is performed under cooling to the boiling point of the solvent, for example, -20 ° C to 100 ° C, especially -10 ° C to
It can be suitably carried out at 70 ° C.

The thus-obtained object of the present invention can be used not only as a pharmaceutical compound itself, but also as a synthetic intermediate for a 2,5-pyrrolidinedione derivative having an excellent antithrombotic effect. For example, by subjecting the target compound [I] to an intramolecular ring closure reaction, a compound of the general formula [IV]

[0020]

Embedded image

A 2,5-pyrrolidinedione derivative represented by the formula (wherein rings A and R ³ have the same meanings as described above) can be used. The intramolecular ring closure reaction can be suitably carried out in the presence of a base (for example, an alkali metal hydroxide) in a suitable solvent, under cooling to heating, for example, at -60 ° C to 150 ° C.

The starting compound [II] of the present invention is a novel compound, for example, (1) 3-lower alkoxycarbonyl-4-phenyl by a condensation reaction of benzaldehyde or tri-lower alkoxybenzaldehyde and di-lower alkyl succinate. (Or tri-lower alkoxyphenyl) -3-butenoic acid, and then (2) a corresponding lower alkyl ester is produced by a conventional esterification method. (3) This is tri-lower alkoxybenzaldehyde (or step (1) When tri-lower-alkoxybenzaldehyde is used, it can be produced by reacting with benzaldehyde in this step). The condensation reaction steps (1) and (3) are carried out in the presence of a base (for example, an alkali metal alcoholate) in a suitable solvent, under cooling to heating, for example, at -20.
C. to the boiling point of the solvent can be suitably carried out.

In the present specification, the structural formulas of compounds having a double bond (for example, compounds [I], [II] and [IV]) have a coordinate at the double bond site unless otherwise specified. It means that it may be in the cis configuration (Z) or in the trans configuration (E).

[0024]

【Example】

Example 1 (1) To a solution of 16.8 g of potassium t-butyrate in 150 ml of t-butyl alcohol, 15.15% of benzaldehyde was added.
A solution of 9 g and 26.3 g of dimethyl succinate in 20 ml of t-butyl alcohol is added dropwise with stirring at room temperature, and then stirred for 30 minutes. The reaction solution was added to ice water 200
Pour into ml and extract with isopropyl ether. The aqueous layer is adjusted to pH 2-3, extracted with ethyl acetate, the ethyl acetate layer is washed, dried, and the solvent is distilled off. The residue was dissolved in 75 ml of methanol and thionyl chloride 1 was added under ice-cooling.
0.9 ml is added dropwise and left overnight at room temperature, after which the solvent is distilled off. After adding isopropyl ether to the residue, washing and drying, the solvent is distilled off. The residue is distilled under reduced pressure to obtain 23.2 g of (E) -3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester as a colorless oil. Yield: 66% B. P. : 135 = 137 ° C. (0.3 mmHg)

(2) A solution of 23.1 g of this product and 19.4 g of 3,4,5-trimethoxybenzaldehyde in 100 ml of t-butyl alcohol was added to 1 part of potassium t-butyrate.
It is added dropwise to a solution of 1.1 g of t-butyl alcohol in 100 ml at room temperature with stirring, and then stirred for 1 hour. The reaction solution is poured into 200 ml of cold water and extracted with isopropyl ether. The aqueous layer is adjusted to pH 2-3, extracted with ethyl acetate, the ethyl acetate layer is washed, dried, and the solvent is distilled off. By washing the residue with diethyl ether,
25.7 g of (E) -2-[(E) -3,4,5-trimethoxybenzylidene] -3-carboxy-4-phenyl-3-butenoic acid methyl ester are obtained as pale yellow crystals. Yield: 65% M.D. P. : 153-154 ° C (recrystallized from ethyl acetate-isopropyl ether)

(3) This product 6.0 g of trichloromethane 3
To 0 ml solution, under ice cooling, thionyl chloride 1.1 ml
Is dripped. Then, after adding 2 drops of dimethylformamide, the mixture is refluxed for 30 minutes. After cooling the reaction solution to 25 ° C. or lower, it is dropped into 10 ml of a 40% aqueous solution of methylamine with vigorous stirring. After stirring for 30 minutes as it is, the organic layer is separated, washed, dried, and the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent: trichloromethane: acetone = 5: 1) to give (E) -2-[(E) -3,4,5-trimethoxybenzylidene] -3. 5.4 g of -methylcarbamoyl-4-phenyl-3-butenoic acid methyl ester are obtained as crystals. Yield: 87% M.I. P. : 155-157 ° C (recrystallized from ethyl acetate-n-hexane)

Example 2-17 The corresponding starting compound was treated in the same manner as in Example 1 to give the following first compound:
And the compounds shown in Table 2 are obtained.

[0028]

[Table 1]

[0029]

[Table 2]

[0030]

INDUSTRIAL APPLICABILITY The 3-butenoic acid derivative [I], which is the object of the present invention, has an excellent antithrombotic effect both in oral and parenteral administration, and as an antithrombotic drug, for example, myocardial infarction
Stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion,
It can be used as a prophylactic and therapeutic drug for vascular diseases such as angina, sepsis and other vein occlusions and diabetic complications. It can also be used as a preventive agent for reocclusion after percutaneous coronary angioplasty or thrombolytic therapy. Further, the object [I] of the present invention is another antithrombotic drug having an excellent antithrombotic action, for example, the general formula [IV]

[0031]

[Chemical 9]

(In the formula, rings A and R ³ have the same meanings as described above) and can be used as a synthetic intermediate for a 2,5-pyrrolidinedione derivative.

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Claims (4)

(57) [Claims] 1. A compound of the general formula [I] (In the formula, ring A is a tri-lower alkoxyphenyl group, and ^one of R ¹ and R ² is a lower alkoxy group and the other is of the formula: —NH
Represents a group represented by R ^3, R ³ which may have optionally substituted lower alkyl group, a hydroxyl group, an optionally substituted lower alkoxy group or a substituent amino Represents a group. ) The 3-butenoic acid derivative or its salt shown by these. 2. The compound according to claim 1, wherein ring A is a 3,4,5-tri-lower alkoxyphenyl group. 3. R ³ is 1) a hydroxyl group, a lower alkoxy group,
A lower alkyl group optionally having 1 to 3 groups selected from a phenyl group and a nitrogen atom-containing 6-membered heterocyclic group, 2)
The compound according to claim 1 or 2, which is a hydroxyl group, 3) a lower alkoxy group optionally substituted with a phenyl group, or 4) an amino group optionally substituted with a lower alkyl group. 4. A compound of the general formula [II] (In the formula, ring A is a tri-lower alkoxyphenyl group, R ¹¹
One of R ²¹ and R ²¹ represents a lower alkoxy group and the other represents a hydroxyl group. ), A salt thereof or a reactive derivative thereof, and a compound represented by the general formula [III]: embedded image NH ₂ R ³ [III] (wherein R ³ is a lower alkyl group which may have a substituent). , A hydroxyl group, a lower alkoxy group which may have a substituent or an amino group which may have a substituent.), And the product is converted to a salt thereof if desired. Of the general formula [I] (In the formula, ^one of R ¹ and R ² represents a lower alkoxy group and the other represents a group represented by the formula: —NHR ³ , and ring A and R ³
Has the same meaning as above. The manufacturing method of the 3-butenoic acid derivative or its salt shown by these.