JP2564781B2 - 2,5-Pyrrolidinedione derivative and method for producing the same - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 2,5-pyrrolidinedione derivative having an antithrombotic effect and a method 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, as a derivative of 2,5-pyrrolidinedione, an N-methyl-3,4-dibenzylidene derivative [NOUVEAU JOURNAL DE CHIMI
E), Vol. 1, No. 5,413-418 (197
7)] is known, but no pharmacological activity of the compound is known.

[0003]

DISCLOSURE OF THE INVENTION The present invention provides a novel compound having an excellent antithrombotic activity and which can be used in both oral administration and parenteral administration, unlike conventional enzyme preparations. Is.

[0004]

The 2,5-pyrrolidinedione derivative according to the present invention has the general formula [I]

[0005]

[Chemical 4]

(In the formula, ring A represents a tri-lower alkoxyphenyl 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 are 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. Among them, the compounds that are preferable in terms of drug efficacy are those in which both double bond sites have E-coordination.

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

The object [I] of the present invention can be used in medicinal use in the free form or in the form of its pharmacologically acceptable salt. Pharmaceutically acceptable salts include, for example, sodium salts, alkali metal salts such as potassium salts,
Examples thereof include alkaline earth metal salts such as calcium salts.

The object [I] of the present invention and a pharmaceutically acceptable salt thereof can be administered orally or parenterally, and can be mixed with an excipient suitable for oral or parenteral administration. And can be 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 and degree of disease of the patient, 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 compound [I] is, for example, a compound represented by the general formula [II]

[0012]

Embedded image

(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.) Intramolecular ring-closing reaction of the carbamoyl compound Can be manufactured by.

The intramolecular ring closure reaction can be appropriately carried out in the presence of a base in a suitable solvent. Examples of the base include alkali metal, alkali metal hydroxide, alkali metal hydride, alkali metal alcoholate, lower alkyl-substituted alkali metal amide such as lithium diisopropylamide, lower alkyl alkali metal such as n-butyllithium, and tri-lower alkylamine. Organic amines such as 1,8-diazabicyclo [5.4.0] undec-7-ene can be preferably used.

The solvent may be an inert solvent which does not adversely influence the reaction, and examples thereof include organic solvents such as tetrahydrofuran, dioxane, methanol, ethanol and dimethylformamide, and mixed solvents of these organic solvents and water. . The reaction can be widely carried out under cooling to under heating, for example, -60 ° C to 150 ° C, especially 20 ° C to 15 ° C.
It can be suitably carried out at 0 ° C.

When the desired product [I] is obtained as a mixture of stereoisomers in the above reaction, it can be separated by a conventional method such as silica gel column chromatography, if necessary.

The starting compound [II] of the present invention is a novel compound, for example, (1) 3-lower alkoxycarbonyl-4-phenyl by a condensation reaction between 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 is reacted with benzaldehyde in this step) to give a compound of the general formula [III]

[0018]

[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.), And then (4) ) Compound [III], a salt thereof or a reactive derivative thereof can be produced by reacting with ammonia. 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. On the other hand, in the condensation reaction step (4), when using the compound [III] or a salt thereof, in the presence of a dehydrating agent (for example, dicyclohexylcarbodiimide), or when using a reactive derivative of the compound [III], a deoxidizing agent ( It can be carried out in the presence or absence of (for example, alkali metal hydroxide), and these reactions can be carried out in a suitable solvent under cooling to the boiling point of the solvent, for example, -20 ° C to 100 ° C. In addition, in the present specification, the structural formulas of compounds having a double bond (for example, compounds [I], [II], and [III]) have cis-coordination at the double bond site unless otherwise specified. It represents that it may be (Z) or may be a trans-coordination (E).

[0020]

【Example】

Example 1 (1) (E) -3-Methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester 23.1 g and 3,4.
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-butylate 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 from diethyl ether to give (E) -2-
[(E) -3,4,5-trimethoxybenzylidene]-
25.7 g of methyl 3-carboxy-4-phenyl-3-butenoic acid ester are obtained as pale yellow crystals. Yield: 65% M.D. 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-water 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,
It is dripped into 20 ml of concentrated aqueous ammonia 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 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% M.P. P. 179-180 ° C (recrystallized from ethyl acetate)

(3) In a solution of 24.9 g of this product in 75 ml of tetrahydrofuran, 2N aqueous sodium hydroxide solution (15.
Add 6 ml and heat to reflux for 1 hour. After cooling to room temperature,
After adding 15.6 ml of 2N hydrochloric acid and concentrating under reduced pressure, trichloromethane is added, washed and dried, and then the solvent is distilled off. The residue was recrystallized from ethyl acetate to give 3-[(E)-
Benzylidene] -4-[(E) -3,4,5-trimethoxybenzylidene] -2,5-pyrrolidinedione 17.
6 g are obtained as yellow platelets. Yield: 77% M.P. P. 158-159 ° C. The recrystallized mother liquor was purified by silica gel column chromatography to give 3-[(E) -benzylidene] -4-[(Z) -3,
4,5-Trimethoxybenzylidene] -2,5-pyrrolidinedione is obtained as orange crystals. M. P. : 193-195 ° C (recrystallized from a mixed solution of ethyl acetate-n-hexane)

Example 2 (1) (Z) -3-Methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester was treated in the same manner as in Examples 1- (1) and (2) to give (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) (2) This product was treated in the same manner as in Example 1- (3) to give 3-
[(Z) -Benzylidene] -4-[(E) -3,4,5
-Trimethoxybenzylidene] -2,5-pyrrolidinedione is obtained as yellow crystals. M. P. 176-178 ° 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-butenoic acid methyl ester is obtained. M. P. 173-174 ° C (3) The above product was treated in the same manner as in Example 1- (3) to give 3-[(E) -benzylidene] -4-[(E)-.
2,4,6-Trimethoxybenzylidene] -2,5-pyrrolidinedione is obtained. M. P. : 246-248 ° C

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
To obtain butenoic acid methyl ester. M. P. : 121-122 ° C (3) This product was treated in the same manner as in Example 1- (3) to give 3-
[(E) -Benzylidene] -4-[(E) -3,4,5
-Trimethoxybenzylidene] -2,5-pyrrolidinedione is obtained. Example 5-8 (1) The corresponding raw material compounds obtained in Reference Examples 1 and 4-5 and the corresponding benzaldehyde compound were treated in the same manner as in Example 1- (1) to obtain the compounds shown in Table 1 below. .

[0025]

[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.

[0027]

[Table 2]

(3) The above product is treated in the same manner as in Example 1- (3) to obtain the compounds shown in Table 3 below.

[0029]

[Table 3]

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, and the mixture is left at room temperature overnight, and then the solvent is distilled off. After adding isopropyl ether to the residue, washing and drying, 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. Yield: 66% B. P. : 135-137 ° C (0.3mmHg)

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 obtain (Z) -3-methoxycarbonyl-4-phenyl-3-putenoic acid. 2.3 g of methyl ester are obtained as a colorless syrup.

Reference Example 3 3,4,5-Trimethoxybenzaldehyde and dimethyl succinate 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 4th
The compounds listed are obtained.

[0033]

[Table 4]

[0034]

INDUSTRIAL APPLICABILITY The 2,5-pyrrolidinedione derivative [I] and the pharmacologically acceptable salt thereof, which are the objects of the present invention, exhibit an excellent antithrombotic effect in both oral and parenteral administration, As a thrombotic drug, for example, myocardial infarction, stroke,
Pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, angina,
It can be used as a prophylactic and therapeutic drug for vascular diseases such as 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.

Claims (4)

(57) [Claims] 1. A compound of the general formula [I] (In the formula, ring A represents a tri-lower alkoxyphenyl group.) A 2,5-pyrrolidinedione derivative or a pharmaceutically acceptable salt thereof. 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. 4. A compound of the general formula [II] (In the formula, ring A is a tri-lower alkoxyphenyl group, and R ¹ and R ² each represent a lower alkoxy group, and the other represents an amino group.) The carbamoyl compound represented by Is a pharmaceutically acceptable salt thereof, and is represented by the general formula [I] (Wherein the symbols have the same meanings as described above), or a method for producing a 2,5-pyrrolidinedione derivative or a pharmaceutically acceptable salt thereof.