JPH07165574A - 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 NHR<3>; R<3> is a lower alkyl, OH, a lower alkoxy or 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 the parenteral administrations. 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 and diabetic complications.

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 present invention has the general formula [I]

[0009]

[Chemical 2]

(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. 3-butenoic acid derivative represented by 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, or a pharmacology thereof. Relates to an antithrombotic drug comprising a salt that is chemically acceptable as an active ingredient.

The 3-butenoic acid derivative [I] or a pharmaceutically acceptable salt thereof, 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. Is.

Specific examples of the 3-butenoic acid derivative [I] which is the active ingredient of the present invention include ring A having 3,4,5-tri-lower alkoxyphenyl group and 2,3,4-tri-lower alkoxyphenyl group. A tri-lower alkoxyphenyl group such as a 2,4,5-tri-lower alkoxyphenyl group or a 2,4,6-tri-lower alkoxyphenyl group, wherein R ³ is 1).
A lower alkyl group optionally having 1 to 3 groups selected from a hydroxyl group, a lower alkoxy group, a phenyl group and a nitrogen atom-containing 6-membered heterocyclic group (eg, pyridyl group, morpholino group, etc.), 2) hydroxyl group Examples thereof include compounds which are 3) a lower alkoxy group optionally substituted with a phenyl group, or 4) an amino group optionally substituted with a lower alkyl group.

Of these 3-butenoic acid derivatives [I], those which are preferable from the viewpoint of medicinal effects are ring A having 3,4,5-tri-lower alkoxyphenyl group and R ³ having 1) 1 to 3 hydroxyl groups. Examples thereof include a lower alkyl group which may be substituted, 2) hydroxyl group, 3) lower alkoxy group or 4) an amino group which may be substituted with a lower alkyl group.

The 3-butenoic acid derivative represented by the general formula [I], which is the active ingredient of the present invention, includes all four stereoisomers based on two double bonds and a mixture 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 an active ingredient of the present invention, specific examples of the lower alkyl group and the lower alkoxy group include 1 to 6 carbon atoms, especially 1 carbon atom.
To 4 alkyl groups and alkoxy groups.

The 3-butenoic acid derivative [I], which is the active ingredient of the present invention, can be used in medicinal use either in the free form or in the form of its pharmacologically acceptable salt. Examples of the pharmaceutically acceptable salt include, for example, hydrochloride, hydrobromide,
Examples thereof include inorganic acid salts such as sulfates, maleic acid salts, and organic acid salts such as oxalates.

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 3-butenoic acid derivative [I] or a pharmacologically acceptable salt thereof varies depending on the administration method, age / body weight / condition of the patient or degree of disease, but the daily dose is usually , 0.1-10 in the case of oral administration
It is preferably 0 mg / kg, especially 0.5 to 50 mg / kg, and 0.01 to 10 mg / kg, especially 0.05 to 5 mg / kg for parenteral administration.

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

[0020]

[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 reactive derivative thereof. , The general formula [III]

[0022]

[Chemical 4]

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

For example, the condensation reaction between the reactive derivative of the compound [II] and the amine compound can be carried out in a suitable solvent (eg trichloromethane) 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.

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], [II], and [IV]) have cis-coordination at the double bond site unless otherwise specified. Position (Z), or trans-coordination (E)
Represents that it may be.

Experimental Example [Plasminogen Activator (PA) Activity] Bovine carotid artery-derived endothelial cells were cultured for one to three days in a growth medium (E'MEM + 10% fetal calf serum) containing a specimen with a final concentration of 3 μM for 3 to 4 days. Thereafter, 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.

[0028]

[Table 1]

Production 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 succinic acid dimethyl ester in 20 ml of t-butyl alcohol is added dropwise with stirring at room temperature, and then stirred for 30 minutes. The reaction solution is 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 and dried, and then 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, 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, 23.2 g of (E) -3-methoxycarbonyl-4-phenyl-3-butenoic acid methyl ester was obtained as a colorless oil.

Yield: 66% B. P. : 135-137 ° C. (0.3 mmHg) (2) 23.1 g of this product and 19.4 g of 3,4,5-trimethoxybenzaldehyde in t-butyl alcohol 10
0 ml of solution was added with 11.1 g of t-butyrate potassium.
-Add dropwise to a 100 ml solution of butyl alcohol at room temperature with stirring and then stir for 1 hour. The reaction solution is cold water 2
Pour into 00 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 and dried, and then the solvent is distilled off. By washing the residue with diethyl ether, (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% P. 153-154 ° C (recrystallized from ethyl acetate-isopropyl ether) (3) To a solution of 6.0 g of this product in 30 ml of trichloromethane, 1.1 ml of thionyl chloride was added dropwise under ice cooling. Then add 2 drops of dimethylformamide and then add 3
Reflux for 0 minutes. After cooling the reaction solution to 25 ° C or lower, 40
% Aqueous solution of methylamine and added dropwise 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. By purifying the residue by silica gel column chromatography (elution solvent: trichloromethane: acetone = 5: 1),
(E) -2-[(E) -3,4,5-Trimethoxybenzylidene] -3-methylcarbamoyl-4-phenyl-
5.4 g of 3-butenoic acid methyl ester are obtained as crystals.

Yield: 87% M. P. 155-157 ° C. (recrystallized from ethyl acetate-n-hexane) Production Example 2-17 The corresponding starting material compound was treated in the same manner as Production Example 1, and the following second
And the compounds listed in Table 3 are obtained.

[0033]

[Table 2]

[0034]

[Table 3]

[0035]

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 excellent in both oral and parenteral administration. It has a thrombotic effect.

The active ingredient of the present invention has low toxicity and high safety as a medicine. For example, (E) -2-[(E) -3,4,5-trimethoxybenzylidene] -3- (2,3-dihydroxypropyl), which is the active ingredient of the present invention.
Carbamoyl-4-phenyl-3-butenoic acid methyl ester was orally administered to mice at a dose of 300 mg / kg, and the mice were observed for 3 days, but no death was observed.

Therefore, the active ingredient of the present invention is useful as an antithrombotic drug, for example, myocardial infarction, cerebral stroke, pulmonary embolism, deep vein thrombosis, peripheral arterial occlusion, angina, generalized intravascular. It can be used as a preventive and therapeutic drug for vascular diseases such as blood coagulation 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 treatment, and a therapeutic / preventive agent for arteriosclerosis.

Claims (6)

[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 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. [3] An antithrombotic drug comprising a 3-butenoic acid derivative or a pharmacologically acceptable salt thereof represented by the formula (1) as an active ingredient. 2. The antithrombotic drug 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 antithrombotic drug 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. R ³ is 1) a lower alkyl group which may have 1 to 3 hydroxyl groups, 2) a hydroxyl group, 3) a lower alkoxy group or 4) an amino group which may be substituted with a lower alkyl group. The antithrombotic drug according to claim 1 or 2. 5. The antithrombotic drug according to claim 1, 2, 3 or 4, wherein both double bond sites have E-coordination. 6. A prophylactic / 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, or 5.