JPH07149642A - Antithrombotic medicine - Google Patents

Abstract

PURPOSE:To obtain an antithrombotic medicine exhibiting excellent antithrombotic action and capable of using as a medicine for preventing and treating a vascular disease such as cardiac infarction and diabetic complication. CONSTITUTION:This antithrombotic medicine contains a 2,5-pyrrolidine-dione derivative of the formula (ring A is a tri-lower-alkoxyphenyl) or its pharmacologically permissible salt, preferably 3-[(E)-benzylidene]-4-[(E)-3,4,5- trimethoxy-benzylidene]-2,5-pyrrolidinedione as an active ingredient. The compound has excellent PA activity-promoting action and PAI-1 activity-inhibiting action and exhibits excellent antithrombotic action in either of oral administration and parental administration unlike a conventional well-known enzyme preparation. The dose of the compound is preferably 0.5-50mg/kg.day in oral administration and preferably 0.05-5mg/kg.day in parental administration. The antithrombotic medicine can be used also as a medicine for preventing re- obstruction after percutaneous coronary artery forming operation or after thrombolytic therapy or a medicine for preventing and treating arteriosclerosis.

Description

Detailed Description of the Invention

[0001]

This invention relates to antithrombotic agents.

[0002]

It is well known that thrombus causes various diseases such as myocardial infarction, stroke and pulmonary embolism. On the other hand, it is also known that plasmin in blood changes fibrin, which is a constituent component of thrombus, into a highly water-soluble fibrin degradation product, suppresses thrombus formation, and has a thrombolytic effect.

Further, plasminogen is converted to plasmin by plasminogen activator (PA) such as tissue plasminogen activator, urokinase, streptokinase, etc., so that enzyme preparations such as PA have been conventionally clot-formed. It is used for the suppression of thrombolysis and thrombolysis.

However, these preparations 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.

Recently, plasminogen activator inhibitors (PAI) such as plasminogen activator inhibitor (PAI) -1 which inhibits the action of PA.
Have been found to be involved in thrombus formation and lysis.

On the other hand, as a derivative of 2,5-pyrrolidinedione, N-methyl-3,4-dibenzylidene derivative [NOUVEAU J
OURRNAL DE CHIMIE), Vol. 1, N
o. 5, 413-418 (1977)], but no pharmacological activity of the compound is known.

[0007]

The present invention provides an excellent PA.
Has an activity promoting action and a PAI-1 activity inhibiting action, and
Different from the conventionally known enzyme preparations, the novel 2,5-which has an excellent antithrombotic effect by both oral administration and parenteral administration
The present invention provides an antithrombotic drug containing a pyrrolidinedione derivative as an active ingredient.

[0008]

The 2,5-pyrrolidinedione derivative, which is the active ingredient of the present invention, has the general formula [I]

[0009]

[Chemical 2]

(In the formula, ring A represents a tri-lower alkoxyphenyl group).

The 2,5-pyrrolidinedione derivative [I] or a pharmacologically acceptable salt thereof, which is the active ingredient of the present invention, has an excellent PA activity-promoting activity and PAI-1 activity-inhibiting activity, and has an antithrombotic effect. It is useful as a medicine.

Preferred compounds having a medicinal effect of the 2,5-pyrrolidinedione derivative [I] which is the active ingredient of the present invention include ring A having a 3,4,5-tri-lower alkoxyphenyl group and 2,3,4-triene. Lower alkoxyphenyl group, 2,
4,5-Tri-lower alkoxyphenyl group, 2,4,6-
Examples thereof include compounds having a tri-lower alkoxyphenyl group such as a tri-lower alkoxyphenyl group.

Examples of the compound of the present invention which is more preferable from the viewpoint of efficacy include compounds in which ring A is a 3,4,5-tri-lower alkoxyphenyl group, and particularly, compounds in which the tri-lower alkoxyphenyl group is a trimethoxyphenyl group, In particular, 3-[(E) -benzylidene] -4-[(E) -3,
4,5-Trimethoxybenzylidene] -2,5-pyrrolidinedione is preferred.

The 2,5-pyrrolidinedione derivative [I], which is the active ingredient of the present invention, contains 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 2,5-pyrrolidinedione derivative [I], which is the active ingredient of the present invention, the lower alkoxy group includes an alkoxy group having 1 to 6 carbon atoms, particularly 1 to 4 carbon atoms.

The 2,5-pyrrolidinedione derivative [I], which is the active ingredient of the present invention, can be used in medicinal use in the free form or in the form of its pharmacologically acceptable salt. Examples of the pharmacologically acceptable salt include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt, and the like.

The antithrombotic drug of the present invention can be administered orally or parenterally, and can be administered by a conventional method such as tablets, granules, capsules, powders, solutions, suspensions and injections. It can be used as an appropriate pharmaceutical preparation such as an agent and an injectable solution.

The dose of the 2,5-pyrrolidinedione derivative [I] or a pharmacologically acceptable salt thereof varies depending on the administration method, age / weight / condition of the patient or degree of disease, but is usually per day. In the case of oral administration, the dose is
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.

The 2,5-pyrrolidinedione derivative [I], which is the active ingredient of the present invention, is represented by the general formula [II]

[0020]

[Chemical 3]

(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 closure reaction of the carbamoyl compound Can be manufactured by.

The intramolecular ring-closing reaction can be carried out in a suitable solvent (eg,
It can be appropriately carried out in an organic solvent such as tetrahydrofuran or a mixed solvent of these organic solvents and water) in the presence of a base (for example, a lower alkyl-substituted alkali metal amide such as lithium diisopropylamide).

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

The starting compound [II] is, for example,
(1) Benzaldehyde or tri-lower alkoxybenzaldehyde and 3-lower alkoxycarbonyl-4-phenyl (or tri-lower alkoxyphenyl) -3-butenoic acid by condensation reaction with succinic acid di-lower alkyl ester, and then (2) ester The corresponding lower alkyl ester is prepared by a conventional method of compounding, and (3) this is reacted with tri-lower alkoxybenzaldehyde (or, when tri-lower alkoxybenzaldehyde is used in step (1), benzaldehyde is used in this step). The general formula [II
I]

[0025]

[Chemical 4]

(Wherein R ¹¹ and R ²¹ each represent a lower alkoxy group and the other represents a hydroxyl group, and ring A has the same meaning as described above).
Then, (4) compound [III], a salt thereof or a reactive derivative thereof can be reacted with ammonia for production.

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. Position (Z), or trans-coordination (E)
Represents that it may be.

Experimental Example 1 [plasminogen activator (PA) activity] Bovine carotid artery-derived endothelial cells were grown for 3 to 4 days in a growth medium (E'MEM + 10% fetal bovine serum) containing a specimen having a final concentration of 3 µM for one generation. After culturing, the obtained cell monolayer was washed twice with a serum-free medium. Add serum-free medium and add 3
Conditioned medium (CM) was prepared by incubating at 7 ° C. under 5% CO ₂ -95% air for 24 hours, and centrifuging the supernatant at 4 ° C. at 3,000 rpm for 10 minutes. The PA activity in CM was as follows: Wim
An's method (synthetic substrate method; Clin. Chim. Ac
ta, 127, 279, 1983).
The PA activity in CM was calculated from a standard curve prepared from known amounts of t-PA, and converted into PA activity per 10 ⁶ endothelial cells. The results are shown in Table 1 below as relative activity to PA activity in the absence of the sample.

[0029]

[Table 1]

Experimental Example 2 [plasminogen activator inhibitor (PA
I) -1 Activity Inhibitory Action] The final concentration of the sample is 0.1% Nikk
10 mg / 1 for ol (HCO-60, Nikko Chemicals)
The suspension was adjusted to 0 ml or 100 mg / 10 ml, and 10 ml / kg of the Wistar male rat was orally administered once a day for 8 days. Two hours after the final administration, blood was collected from the descending abdominal vein under anesthesia with sodium pentobarbital, and citric acid was added to the blood to prepare plasma. The PAI-1 activity in plasma was measured by the same method as in Experimental Example 1. The results are shown in Table 2 below as% inhibition when the PAI-1 activity of the control group administered with only the solvent was 100.

[0031]

[Table 2]

Production 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 distilled off. 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-butenoate is obtained as pale yellow crystals.

M. 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 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.

M. P. 179-180 ° C (recrystallized from ethyl acetate) (3) To a solution of 24.9 g of this product in 75 ml of tetrahydrofuran is added 15.6 ml of a 2N aqueous sodium hydroxide solution, and the mixture is heated under reflux for 1 hour. After cooling to room temperature, 2N hydrochloric acid 1
After adding 5.6 ml and concentrating under reduced pressure, trichloromethane is added, and after washing and drying, 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) in yellow. Obtained as plate crystals.

M. 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 ethyl acetate-n-hexane mixed solution) Production Example 2 (1) (Z) -3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester Production Example 1- (1) And (2), and processes (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 ethyl acetate-n-hexane mixed solution) (2) This product was treated in the same manner as in Production 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 ethyl acetate-n-hexane mixed solution) Production Example 3 (1) (E) -3-Methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester and 2,4,6-tri Methoxybenzaldehyde was treated in the same manner as in Production Example 1- (1) 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-
Production Example 1-Methyl Phenyl-3-butenoic Acid Ester
The same process as in (2) is performed to obtain (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 Production Example 1- (3) to give 3-[(E) -benzylidene] -4-[(E)-
2,4,6-Trimethoxybenzylidene] -2,5-pyrrolidinedione is obtained.

M. P. : 246-248 [deg.] C. Production Example 4 (1) (E) -3-Methoxycarbonyl-4- (3,3)
4,5-Trimethoxyphenyl) -3-butenoic acid methyl ester and benzaldehyde were treated in the same manner as in Production 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 Production 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 Production Example 1- (3) to give 3-
[(E) -Benzylidene] -4-[(E) -3,4,5
-Trimethoxybenzylidene] -2,5-pyrrolidinedione is obtained.

Production Example 5-8 (1) The corresponding raw material compounds and the corresponding benzaldehyde compounds obtained in Reference Examples 1 and 4-5 were treated in the same manner as in Production Example 1- (1), and the results shown in Table 3 below. Obtain the compound.

[0046]

[Table 3]

(2) The above product is treated in the same manner as in Production Example 1- (2) to obtain the compounds shown in Table 4 below.

[0048]

[Table 4]

(3) The above product is treated in the same manner as in Production Example 1- (3) to obtain the compounds shown in Table 5 below.

[0050]

[Table 5]

Reference Example 1 A solution of 16.8 g of potassium t-butylate 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. 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.

B. P. : 135-137 ° C (0.3 mm
Hg) 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 methyl ester. 2.3 g of ester are obtained as 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 compound was treated in the same manner as in Reference Example 1 to give the following 6th compound.
The compounds listed are obtained.

[0055]

[Table 6]

[0056]

The 2,5-pyrrolidinedione derivative [I] and the pharmaceutically acceptable salt thereof, which are the active ingredients of the present invention, have an excellent PA activity promoting action and PAI-1 activity inhibiting action, In addition, in rat venous thrombosis model, it exerts an excellent fibrinolysis-promoting action such as significantly reducing the thrombus weight, and also exhibits such action in both oral and parenteral administration. Furthermore, the 2,5-pyrrolidinedione derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, has low toxicity and high safety. For example, in rats, 3-[(E) -benzylidene] -4-[(E)-
3,4,5-trimethoxybenzylidene] -2,5-pyrrolidinedione 300 mg / kg orally,
No deaths were observed even after one month.

Therefore, the active ingredient of the present invention is useful as an antithrombotic drug, for example, myocardial infarction, stroke, pulmonary embolism,
It can be used as a prophylactic and therapeutic drug for vascular diseases such as deep vein thrombosis, peripheral arterial occlusion, angina pectoris, generalized intravascular blood coagulation and other venous occlusions, and diabetic complications. It can also be used as a preventive agent for re-occlusion after percutaneous coronary angioplasty or after thrombolytic therapy, and a therapeutic / preventive agent for arteriosclerosis.

Claims (7)

[Claims] 1. A compound represented by the general formula [I]: An antithrombotic agent comprising a 2,5-pyrrolidinedione derivative represented by the formula (wherein ring A represents a tri-lower alkoxyphenyl group) or a pharmacologically acceptable salt thereof as an active ingredient. 2. Ring A is 3,4,5-tri-lower alkoxyphenyl group, 2,3,4-tri-lower alkoxyphenyl group, 2,4,5-tri-lower alkoxyphenyl group or 2,4,6- The antithrombotic drug according to claim 1, which is a tri-lower alkoxyphenyl group. 3. The antithrombotic drug according to claim 1, wherein ring A is a 3,4,5-tri-lower alkoxyphenyl group. 4. The antithrombotic drug according to claim 1, 2 or 3, wherein both double bond sites have E-coordination. 5. The antithrombotic drug according to claim 1, wherein ring A is a trimethoxyphenyl group. 6. 3-[(E) -Benzylidene] -4-
[(E) -3,4,5-trimethoxybenzylidene]-
An antithrombotic drug comprising 2,5-pyrrolidinedione or a pharmacologically acceptable salt thereof as an active ingredient. 7. A preventive and / or therapeutic agent for myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, angina, generalized intravascular coagulation, venous obstruction or diabetic complications. The antithrombotic drug according to claim 1, 2, 3, 4, 5 or 6.