JPH05279309A - 3-butenoic acid derivative and its production - Google Patents

Abstract

PURPOSE:To provide a new 3-butenoic acid derivative exhibiting excellent antithrombotic action by oral administration as well as parenteral administration, useful as an antithrombotic agent and also as an intermediate for other antithrombotic agent having excellent antithrombotic action. CONSTITUTION:The 3-butenoic acid derivative expressed by formula I [ring A is tri(lower alkoxy)phenyl; one of R<1> and R<2> is alkoxy and the other is NH2), e.g. (E)-2-[(E)-3,4,5-trimethoxybenzylidene]-3-carbamoyl-4-phenyl-3-butenoic ac id methyl ester. The compound can be produced by reacting a new compound of formula II (one of R<11> and R<12> is lower alkoxy and the other is OH), its salt or its reactive derivative with ammonia. A compound of formula III having excellent antithrombotic action can be produced by the intramolecular cyclization of the objective compound. The new compound of formula II used as a starting compound can be produced from benzaldehyde or a tri(lower alkoxy)benzaldehyde and a succinic acid di(lower alkyl) ester with three steps.

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 drawback that they are rapidly decomposed in blood and lose their drug efficacy, and that they can be used for pharmaceutical 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]

[Chemical 5]

(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 an amino group).

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
Examples thereof include compounds having a tri-lower alkoxyphenyl group such as a 5-tri-lower alkoxyphenyl group and a 2,4,6-tri-lower alkoxyphenyl group.

The object [I] of the present invention includes all four stereoisomers based on two double bonds and mixtures thereof. In the case of using it for pharmaceutical use, those having both double bond sites having E-coordination among them exhibit more excellent drug efficacy. Further, those having a ring A of 3,
It is a 4,5-tri-lower alkoxyphenyl group, R ¹ is a lower alkoxy group, and R ² is an amino group.

In the object [I] of the present invention, the lower alkoxy group has 1 to 6 carbon atoms, especially 1 to 1 carbon atoms.
The alkoxy group of 4 is mentioned.

When the object [I] of the present invention is used for medicinal purposes, it can be used either orally or parenterally, and is mixed with an excipient suitable for oral or parenteral administration,
It can be used as a pharmaceutical preparation. Also, the pharmaceutical formulation is
It may be a solid preparation such as tablets, capsules and powders, or a liquid preparation such as a solution, suspension and 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 the daily dose is usually 0.1 to 100 mg / k in the case of oral administration.
g, especially 0.5 to 50 mg / kg, 0.01 to 10 mg / kg, especially 0.05, for parenteral administration
It is preferably ˜5 mg / kg.

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

[0012]

[Chemical 6]

(In the formula, 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.),
It can be produced by reacting the salt or its reactive derivative with ammonia.

The condensation reaction of butenoic acid ester compound [II] or a salt thereof with ammonia can be carried out in a suitable solvent in the presence of a dehydrating agent. Examples of the dehydrating agent include dicyclohexylcarbodiimide and carbonyldiimidazole. 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 these salts are preferably used as a free carboxylic acid in advance in the reaction with ammonia. .. The condensation reaction between the reactive derivative of compound [II] and ammonia 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, N-dialkylaniline, pyridine and the like.

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 carried out under cooling from the boiling point of the solvent, for example, -20 ° C to 100 ° C, especially -10 ° C.
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 activity. For example, by subjecting the target compound [I] to an intramolecular ring closure reaction,

[0017]

[Chemical 7]

A 2,5-pyrrolidinedione derivative represented by the formula (wherein ring A has the same meaning as described above) can be used. The intramolecular ring closure reaction can be suitably carried out in the presence of a base (for example, 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- by a condensation reaction of benzaldehyde or tri-lower alkoxybenzaldehyde with di-lower alkyl succinate.
After preparing phenyl (or tri-lower alkoxyphenyl) -3-butenoic acid, (2) a corresponding lower alkyl ester is produced by a conventional method of esterification, and (3) this is tri-lower alkoxybenzaldehyde (or step (1)). When tri-lower-alkoxybenzaldehyde is used in the above step, it can be produced by reacting with benzaldehyde in this step). The condensation reaction steps (1) and (3) can be suitably carried out in a suitable solvent in the presence of a base (for example, an alkali metal alcoholate) under cooling to heating, for example, at -20 ° C to the boiling point of the solvent. In the present specification, compounds having a double bond (for example, compounds [I], [II], [II]
The structural formula [I]) indicates that the coordination at the double bond site may be cis coordination (Z) or trans coordination (E), unless otherwise specified.

[0019]

【Example】

Example 1 (1) 23.1 g of (E) -3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester and 3,4,4.
A solution of 19.4 g of 5-trimethoxybenzaldehyde in 100 ml of t-butyl alcohol is added dropwise to a solution of 11.1 g of potassium t-butyrate in 100 ml of t-butyl alcohol under stirring at room temperature, 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 and dried, and the solvent is evaporated. The residue was crystallized with diethyl ether to give (E) -2-
[(E) -3,4,5-trimethoxybenzylidene]-
25.7 g of methyl 3-carboxy-4-phenyl-3-butenoic acid are obtained as pale yellow crystals. Yield: 65% M.I. P. 153 ° -154 ° C. (recrystallized from a mixed solution of ethyl acetate-isopropyl ether) (2) To a solution of 25.7 g of this product in 50 ml of trichloromethane, 4.7 ml of thionyl chloride was added dropwise under ice-cooling. Then, after adding 1 drop of dimethylformamide, 3
Heat to reflux for 0 minutes. After cooling the reaction solution to 25 ° C or lower,
Add dropwise to 20 ml of concentrated aqueous ammonia with vigorous stirring. After stirring for 30 minutes as it is, the organic layer is separated, washed and dried, and then the solvent is distilled off. The residue was crystallized from diethyl ether and collected by filtration (E) -2-[(E) -3,4,
5-Trimethoxybenzylidene] -3-carbamoyl-
4-phenyl-3-butenoic acid methyl ester 24.9 g
Is obtained as pale yellow crystals. Yield: 97% P. 179-180 ° C (recrystallized from ethyl acetate)

Example 2 (Z) -3-methoxycarbonyl-4-phenyl-3-
Butenoic acid methyl ester was used in Examples 1- (1) and (2).
The same process as in (Z) -2-[(E) -3,4,5
-Trimethoxybenzylidene] -3-carbamoyl-4
-Phenyl-3-butenoic acid methyl ester is obtained as colorless crystals. M. P. : 144-146 ° C (recrystallized from a mixed solution of ethyl acetate-n-hexane)

Example 3 (1) (E) -3-Methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester and 2,4,6-trimethoxybenzaldehyde were prepared in the same manner as in Example 1- (1). Treated to give (E) -2-[(E) -2,4,6-trimethoxybenzylidene] -3-carboxy-4-phenyl-3-butenoic acid methyl ester (foam) and (E)-.
2-[(Z) -2,4,6-trimethoxybenzylidene] -3-carboxy-4-phenyl-3-butenoic acid methyl ester (MP: 208-210 ° C.) is obtained. (2) (E) -2-[(E) -2,4,6-trimethoxybenzylidene] -3-carboxy-4-phenyl-3
-Butenoic acid methyl ester was treated as in Example 1- (2) to give (E) -2-[(E) -2,4,6-trimethoxybenzylidene] -3-carbamoyl-4-phenyl-3. -Obtaining butenoic acid methyl ester. M. P. 173-174 ° C. Also, (E) -2-[(Z) -2,4,6-trimethoxybenzylidene] -3-carboxy-4-phenyl-3.
-Butenoic acid methyl ester was treated as in Example 1- (2) to give (E) -2-[(Z) -2,4,6-trimethoxybenzylidene] -3-carbamoyl-4-phenyl-. 3-butenoic acid methyl ester is obtained. M. P. 169-171 ° C (recrystallized from a mixed solution of ethyl acetate-n-hexane)

Example 4 (1) (E) -3-Methoxycarbonyl-4- (3,3)
4,5-Trimethoxyphenyl) -3-butenoic acid methyl ester and benzaldehyde were treated as in Example 1- (1) to give (E) -2-[(E) -benzylidene] -3-carboxy. -4- (3,4,5-Trimethoxyphenyl) -3-butenoic acid methyl ester is obtained. M. P. : 131-133 ° C. (2) This product was treated in the same manner as in Example 1- (2),
(E) -2-[(E) -Benzylidene] -3-carbamoyl-4- (3,4,5-trimethoxyphenyl) -3
-Obtaining butenoic acid methyl ester. M. P. : 121-122 ° C. Example 5-8 (1) The corresponding starting material compounds and the corresponding benzaldehyde compounds obtained in Reference Examples 1 and 4-5 were treated in the same manner as in Example 1- (1), and the following Table 1 was shown. The compound described is obtained.

[0023]

[Table 1]

(2) The above product is treated in the same manner as in Example 1- (2) to obtain the compounds shown in Table 2 below.

[0025]

[Table 2]

Reference Example 1 A solution of 16.8 g of potassium t-butyrate in 150 ml of t-butyl alcohol was added dropwise with 20 ml of a solution of 15.9 g of benzaldehyde and 26.3 g of dimethyl succinate in t-butyl alcohol under stirring at room temperature. Then, stir for 30 minutes. The reaction solution is poured into 200 ml of ice water and extracted with isopropyl ether. Aqueous layer pH 2-3
Adjusted to, and extracted with ethyl acetate, washed the ethyl acetate layer,
Dry and evaporate the solvent. The residue is dissolved in 75 ml of methanol, 10.9 ml of thionyl chloride is added dropwise under ice cooling, the mixture is left at room temperature overnight, and then the solvent is distilled off. Isopropyl ether is added to the residue, washed and dried, and then the solvent is distilled off. By distilling the residue under reduced pressure, (E)-
23.2 g of 3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester are obtained as a colorless oil. Income: 66% B. P. : 135-137 ° C (0.3 mmHg)

Reference Example 2 21.2 g of benzaldehyde and 40.9 g of succinic acid dimethyl ester were treated in the same manner as in Reference Example 1 and purified by silica gel to give (Z) -3-methoxycarbonyl-4-phenyl-3-butenoic acid. 2.3 g of methyl ester are obtained as a colorless syrup.

Reference Example 3 3,4,5-Trimethoxybenzaldehyde and succinic acid dimethyl ester were treated in the same manner as in Reference Example 1 (E).
-3-Methoxycarbonyl-4- (3,4,5-trimethoxyphenyl) -3-butenoic acid methyl ester is obtained as a pale yellow syrup. Reference Example 4-5 The corresponding starting material compound was treated in the same manner as in Reference Example 1, and the following third
The compounds listed are obtained.

[0029]

[Table 3]

[0030]

INDUSTRIAL APPLICABILITY The 3-butenoic acid derivative [I], which is the object of the present invention, has an excellent antithrombotic action 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 after thrombolytic therapy. The object [I] of the present invention is another pharmaceutical compound such as 3- (benzylidene)-, which has an excellent antithrombotic effect.
It can also be used as a synthetic intermediate for 4- (tri-lower-alkoxybenzylidene) -2,5-pyrrolidinedione.

Claims (5)

[Claims] 1. A compound represented by 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 an amino group.) A 3-butenoic acid derivative. 2. The compound according to claim 1, wherein both double bond sites have E-coordination. 3. The compound according to claim 2, wherein ring A is a 3,4,5-tri-lower alkoxyphenyl group, R ¹ is a lower alkoxy group and R ² is an amino group. 4. A compound represented by 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) a butenoic acid ester compound represented by the formula (1), a salt thereof or a reactive derivative thereof, and ammonia are reacted with each other, the compound represented by the general formula [I] (In the formula, ^one of R ¹ and R ² represents a lower alkoxy group and the other represents an amino group, and ring A has the same meaning as described above.). 5. A compound represented by the general formula [II]: (In the formula, ring A is a tri-lower alkoxyphenyl group, R ¹¹
One of R ²¹ l and R ²¹ l represents a lower alkoxy group and the other represents a hydroxyl group. ) The butenoic acid ester compound or its salt shown by these.