JPH07165573A - Antithrombotic agent - Google Patents

Abstract

PURPOSE:To obtain an antithrombotic agent, containing a 3-butenoic acid derivative or its salt as an active ingredient, having excellent antithrombotic actions and useful for preventing and treating cardiac infarction, etc. CONSTITUTION:This antithrombotic agent contains a compound expressed by the formula (ring A is a tri-lower alkoxyphenyl; either of R<1> and R<2> is a lower alkoxy and the other is amino) or its salt as an active ingredient. The compound expressed by the formula has excellent promoting actions on the activity of plasminogen activators and inhibiting actions on the activity of plasminogen inhibitor-1 and is capable of manifesting excellent antithrombotic actions by either of the oral and parenteral administrations. Methyl (E)-2-[ (E)-3,4,5- trimethoxybenzyl idene]-3-carbamoyl-4-phenyl-3-butenoate is exemplified as the compound expressed by the formula. The daily dose thereof is 0.1-100mg/kg in the case of the oral administration and 0.01-10mg/kg in the case of the parenteral administration. The agent is useful for preventing and treating cardiac infarction, cerebral apoplexy, pulmonary embolism, deep venous thrombosis, peripheral arterial obstruction, angina pectoris, disseminated intravascular coagulation, venous occlusion, diabetic complications, etc.

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.

Meanwhile, NOUVEAU JOURNALDE CHIMI
E), Vol. 1, No. 5,413-418 (197)
7) discloses dibenzylidene succinic acid, but the pharmacological activity of the compound is unknown.

[0007]

The present invention provides an excellent PA.
Has an activity promoting action and a PAI-1 activity inhibiting action, and
Unlike conventionally known enzyme preparations, the present invention provides an antithrombotic drug containing a novel 3-butenoic acid derivative as an active ingredient, which exhibits an excellent antithrombotic effect in both oral administration and parenteral administration.

[0008]

The 3-butenoic acid derivative which is the active ingredient of the present invention has the general formula [I]

[0009]

[Chemical 2]

(Wherein 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).

The 3-butenoic acid derivative [I], which is the active ingredient of the present invention, has excellent PA activity-promoting activity and PAI-1 activity-inhibiting activity, and is useful as an antithrombotic drug.

A compound having a ring A of 3, is preferred as a compound having a pharmacological effect of the 3-butenoic acid derivative [I], which is the active ingredient of the present invention.
4,5-Tri-lower alkoxyphenyl group, 2,3,4-
Examples thereof include compounds having a tri-lower alkoxyphenyl group such as a tri-lower alkoxyphenyl group, a 2,4,5-tri-lower alkoxyphenyl group and a 2,4,6-tri-lower alkoxyphenyl group.

A ring A is more preferable as a compound more preferable in terms of efficacy.
Is a 3,4,5-tri-lower alkoxyphenyl group,
A compound in which R ¹ is a lower alkoxy group and R ² is an amino group, especially a compound in which a tri-lower alkoxyphenyl group is a trimethoxyphenyl group, a compound in which R ¹ is a lower alkoxy group and R ² is an amino group, particularly (E) -2 -[(E) -3,4,5
-Trimethoxybenzylidene] -3-carbamoyl-4
-Phenyl-3-butenoic acid methyl ester is preferred.

The 3-butenoic acid derivative [I], which is the active ingredient 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 3-butenoic acid 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 antithrombotic drug of the present invention can be administered orally or parenterally, and can be administered in a conventional manner 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 3-butenoic acid derivative [I] varies depending on the method of administration, the age / weight / condition of the patient, or the degree of disease, but the daily dose is usually, in the case of oral administration, 0.1-100 mg / kg, especially 0.5
~ 50 mg / kg, 0.01 ~ for parenteral administration
It is preferably 10 mg / kg, especially 0.05 to 5 mg / kg.

The 3-butenoic acid derivative [I], which is the active ingredient of the present invention, is, for example, a compound represented by the general formula [II]

[0019]

[Chemical 3]

(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 reaction thereof. It can be produced by reacting a sex derivative with ammonia.

For example, the condensation reaction between the reactive derivative of the compound [II] and ammonia can be carried out in a suitable solvent in the presence or absence of a deoxidizing agent (eg alkali metal hydroxide). As the reactive derivative, any of those commonly used for acid amide condensation, such as acid halide, can be used.

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 A corresponding lower alkyl ester is produced by a conventional method of chemical reaction, 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). Can be manufactured.

In the present specification, the structural formulas of compounds having a double bond (for example, compounds [I] and [II]) have a cis-coordination (Z) at the double bond site unless otherwise specified. Or may be a trans-coordination (E).

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 sample 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.

[0025]

[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.

[0027]

[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) Production Example 2 (Z) -3-methoxycarbonyl-4-phenyl-3-
Production Example 1- (1) and (2) of butenoic acid methyl ester
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) 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. Also, (E) -2-[(Z) -2,4,6-trimethoxybenzylidene] -3-carboxy-4-phenyl-3.
-Butenoic acid methyl ester was treated as in Preparation 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) 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. Production Example 5-8 (1) The corresponding raw material compounds and 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 following Table 3 was shown. The compound described is obtained.

[0038]

[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.

[0040]

[Table 4]

Reference Example 1 To a solution of 16.8 g of potassium t-butyrate in 150 ml of t-butyl alcohol, a solution of 15.9 g of benzaldehyde and 26.3 g of dimethyl succinate in 20 ml of t-butyl alcohol was added dropwise at room temperature with stirring. 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 5th compound.
The compounds listed are obtained.

[0045]

[Table 5]

[0046]

INDUSTRIAL APPLICABILITY The 3-butenoic acid derivative [I], which is the active ingredient of the present invention, has excellent PA activity-promoting activity and PAI-1 activity-inhibiting activity, and also significantly thrombus weight in rat venous thrombosis model. It exerts an excellent fibrinolysis-promoting action such as decreasing the amount of the drug, and exhibits such action in both oral and parenteral administration. Furthermore, 3 which is the active ingredient of the present invention
-The butenoic acid derivative [I] has low toxicity and high safety. For example, in a mouse, (E) -2-[(E) -3,
4,5-Trimethoxybenzylidene] -3-carbamoyl-4-phenyl-3-butenoic acid ethyl ester 300
When mg / kg was repeatedly administered by oral gavage for 1 week, no toxicologically significant change was observed.

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]: (In the formula, ring A is a tri-lower alkoxyphenyl group, and R ¹ and R ² are one lower alkoxy group and the other is an amino group.) An antithrombotic agent comprising a 3-butenoic acid derivative 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, 2,
It is a 4,6-tri-lower alkoxyphenyl group.
The described antithrombotic drug. 3. The antithrombotic drug 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. 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. An antithrombotic drug comprising (E) -2-[(E) -3,4,5-trimethoxybenzylidene] -3-carbamoyl-4-phenyl-3-butenoic acid methyl ester 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.