WO2018133765A1 - Method for preparing lactamide-based benzoic acid and applications thereof - Google Patents

Abstract

The preset invention relates to a new medical use of a chiral compound. The chemical name is R-/S-2-lactamide-based benzoic acid, having a structural formula shown below. The compound is originally extracted from a secondary metabolite of microorganisms, and can be obtained by means of chemical synthesis. Initial pharmacological experiments showed that the compound has good analgesic and anti-inflammatory activities, and had less stimulation a gastrointestinal tract. Recent studies show that an enantiomer of the compound has better antiplatelet agglutination and antithrombotic activities, and the compound is expected to become a new nonsteroidal antiplatelet agglutination and antithrombotic drug.

Description

Preparation method and application of 2-lactamaminobenzoic acid Technical field

The invention belongs to the field of pharmaceutical synthesis and pharmacology, and relates to a preparation method and application of 2-lactamaminobenzoic acid, in particular to (R)-2-lactamidobenzoic acid (R-HPABA) and (S)-2-milk Preparation of amidobenzoic acid (S-HPABA) and new medical uses.

Background technique

It is well known that although chiral compounds have the same physicochemical properties, their pharmacodynamics, pharmacokinetics (absorption, distribution, metabolism and excretion) and even toxicological properties may be different, especially when these processes involve large organisms. When molecules (enzymes, carriers, receptors, etc.) interact, different enantiomers of chiral compounds may exhibit different characteristics.

At present, many antithrombotic drugs have been developed and applied, and are classified into antiplatelet agglutination drugs, anticoagulants and thrombolytic drugs according to their target and mechanism of action. Among them, aspirin and clopidogrel are clinically recognized drugs for the treatment of platelet aggregation-related diseases, such as in the treatment of thrombosis and atherosclerosis. The above-mentioned similar drugs have been extensively studied in antithrombotic and have been clinically applied for a long time, but there are side effects such as narrow therapeutic window, bleeding risk, drug resistance, and other unexpected drug interactions have been the focus of attention.

2-Amilylaminobenzoic acid is a new compound isolated from the metabolites of microorganisms and can be obtained by chemical synthesis without the stimulating effect of gastrointestinal tract like aspirin. It has a promising medical use.

Summary of the invention

It is an object of the present invention to provide a process for the preparation of (R)-2-lactamidobenzoic acid and (S)-2-lactoamidobenzoic acid.

It is an object of the present invention to provide a new medical use of (R)-2-lactamidobenzoic acid and (S)-2-lactamidobenzoic acid.

It is also an object of the present invention to provide novel pharmacological activities of (R)-2-lactamidobenzoic acid and (S)-2-lactamidobenzoic acid a pair of chiral enantiomers.

Still another object of the present invention is to provide the use of (R)-2-lactamidobenzoic acid and (S)-2-lactamidobenzoic acid for the preparation of an antiplatelet aggregation or antithrombotic drug.

The present invention provides a benzoic acid compound having the following formula:

Where R ₁ =—H; —Na; —(CH ₂ )n—CH ₃ (n=0 to 3)

R ₂ =—H; —CH ₃ ;—(CH ₂ )n—CH ₃ (n=0～2)

R ₃ =—H; —F;—Cl;—Br

R ₄ =—H; —F;—Cl;—Br

R ₅ =—H; —F; —Cl;—Br.

Specifically, the present invention provides the compound (R)-2-lactoamidobenzoic acid and (S)-2-lactoamidobenzoic acid having the following structure, and the English name is R-/S-2-lactoylaminobenzoic acid:

The (R)-2-lactamidobenzoic acid and (S)-2-lactamidobenzoic acid are respectively:

The (R)-2-lactamidobenzoic acid or (S)-2-lactamidobenzoic acid provided by the invention has the following specific steps:

(a) L-lactic acid (IIa) or D-lactic acid (IIb) and acetyl chloride (III) in anhydrous tetrahydrofuran or acetic anhydride to obtain intermediate (IV), the reaction temperature and reaction time are 10 to 40 ° C and 2 to 15 hours, the ratio of L-lactic acid (or D-lactic acid) to acetyl chloride substance is 0.3 to 0.5:1;

(b) The intermediate (IVa, IVb) is reacted with thionyl chloride to obtain an intermediate (Va, Vb), the reaction temperature and the reaction time are 40 to 80 ° C and 1 to 4 hours;

(c) The intermediate (Va, Vb) is reacted with methyl anthranilate (VI) under anhydrous diethyl ether to form an intermediate (VIIa, VIIb) in an amount ratio of from 1 to 3:5. The temperature is 10 to 40 ° C, and the reaction time is 1 to 24 hours;

(d) Intermediate (VIIa, VIIb) is reacted with potassium carbonate solution in methanol to give intermediate (VIIIa, VIIIb), intermediate (VIIIa, VIIIb) is reacted with sodium hydroxide solution in tetrahydrofuran to give R-/S-HPABA (Ia, Ib), reaction temperature 15 to 35 ° C, reaction time 1 to 20 hours; or intermediate (VIIa, VIIb) and sodium hydroxide solution in tetrahydrofuran and methanol directly to obtain R-/S-HPABA (Ia, Ib), the reaction temperature is 10 to 40 ° C, and the reaction time is 1 to 24 hours.

In the above step (d), there are two methods for obtaining 2-lactamamidobenzoic acid; the organic solvents used in the two methods are tetrahydrofuran and methanol, and the former is reacted with a potassium carbonate solution, and the ratio of the substances is from 1 to 2:5. The latter is reacted with a sodium hydroxide solution in an amount ratio of 1 to 2:5.

In the above step (d), the reaction is completed, extracted with dichloromethane and adjusted to pH 1-4 with hydrochloric acid.

In the above synthesis method, the raw materials, intermediates and reaction routes involved are as follows:

In the present invention, the (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid has remarkable antiplatelet aggregation and antithrombotic activity. Moreover, the raw materials for preparation thereof are widely used, the cost is not high, and it has no stimulating effect on the stomach, and has superior advantages compared with aspirin, and has a very promising application prospect.

DRAWINGS

Figure 1 is a graph showing the platelet toxicity of (R)-2-lactamidobenzoic acid and (S)-2-lactamylbenzoic acid.

Figure 2 is a graph showing the effect of (R)-2-lactamidobenzoic acid and (S)-2-lactamidobenzoic acid on cyclooxygenase-1 (COX-1) activity.

detailed description

The present invention is more specifically described by the following examples, but is not intended to limit the invention.

Example 1. Preparation of (S)-2-lactamidobenzoic acid by chemical synthesis

1.1 Reagents: L-lactic acid, methyl anthranilate, acetyl chloride, thionyl chloride, tetrahydrofuran, anhydrous diethyl ether, methanol, dichloromethane, ethyl acetate

1.2 Synthesis method:

1.2.1 Synthesis of intermediate (IVa)

12.0 g (133.3 mmol) of L-lactic acid was added to a 250 ml three-neck reaction flask, 24 ml of anhydrous tetrahydrofuran was added, and 19.2 ml (266.6 mmol) of acetyl chloride was added dropwise with stirring at -10 to 0 ° C, and then stirred at room temperature for 5 hours, and decompressed at 35 ° C. It was concentrated to give 14.6 g of a colorless oily liquid, yield: 83.2%.

1.2.2 Synthesis of intermediate (Va)

14.6 g (110.6 mmol) of the intermediate (IVa) was taken in a 250 ml reaction flask, 48 ml of thionyl chloride was added, and the mixture was reacted at 50 ° C for 2 h, and concentrated under reduced pressure at 40 ° C to give a pale yellow oily liquid 15.6 g, yield 93.7%.

1.2.3 Synthesis of intermediate (VIIa)

Take 60.0 g (395.8 mmol) of methyl anthranilate (VI) in a 500 ml reaction flask, add 150 ml of anhydrous ether, and add 15.6 g (103.7 mmol) of the intermediate (Va) with stirring at -10 °C. After 3 h, it was suction filtered, and the filtrate was washed with EtOAc, EtOAc EtOAc.

Synthesis of 1.2.4(S)-2-lactoamidobenzoic acid (Ia)

12.0g (45.28mmol) of the intermediate (VIIa) was taken in a 250ml reaction flask, 60ml of methanol was added, and the potassium carbonate solution was added dropwise at room temperature, stirred for 2 hours, and extracted with ethyl acetate 150 ml three times. (VIIIa), ie, 9.2 g of methyl 2-lactamamidobenzoate, yield 89.1%, MS (ESI): m/z = 223.0624; 9.0 g (40.36 mmol) of intermediate (VIIIa) in 250 ml reaction flask Add 60 ml of tetrahydrofuran, add sodium hydroxide solution at room temperature, stir for 1.5 h, extract 150 ml of dichloromethane, and discard the dichloromethane extract. The aqueous phase is adjusted to pH 1-4 with hydrochloric acid, and the crystals are allowed to stand. Filtration and drying gave 7.51 g of 2-lactic acid aminobenzoic acid in a yield of 88.9%.

12.7g (47.92mmol) of the intermediate (VIIa) was taken in a 500ml reaction flask, 60ml of tetrahydrofuran and 40ml of methanol were added. The sodium hydroxide solution was added dropwise at room temperature, stirred for 3 hours, extracted with dichloromethane 200 ml three times, and dichloromethane was discarded. The liquid and the aqueous phase were adjusted to pH 1-4 with hydrochloric acid, and crystals were allowed to stand still, filtered, and dried to obtain 8.79 g of S-2-lactic acid aminobenzoic acid, yield 87.8%.

Table 1. ¹ H-NMR and ¹³ C-NMR spectra of (S)-2-lactamidobenzoic acid

MS data: For this compound, its high resolution mass spectrum gave the molecular ion peak ESI-MS (positive ion mode): 232.0582 [M+Na] ⁺ , molecular formula: C ₁₀ H ₁₁ O ₄ N.

Example 2. Preparation of (R)-2-lactamidobenzoic acid by chemical synthesis

The method was the same as the 1.2 synthesis method except that L-lactic acid was replaced by D-lactic acid. According to the synthesis method of S-2-lactic acid aminobenzoic acid, 8.50 g of R-2-lactic acid aminobenzoic acid was obtained, and the total yield was 52.9%.

Example 3. Anti-platelet aggregation activity of (R)-2-lactamidobenzoic acid and (S)-2-lactamidobenzoic acid

3.1 reagent

Aspirin (ASP, purity >99.5%), (R)-2-lactamaminobenzoic acid (homemade, optical purity >99.3%), (S)-2-lactamidobenzoic acid (homemade, optical purity >98.8%) ), dimethyl sulfoxide (DMSO), adenosine diphosphate (ADP), collagen (COLL), arachidonic acid (AA), thromboxane B ₂ (TXB ₂ ) enzyme-linked immunosorbent assay kit, 6-ketone -Prostaglandin F1α (6-keto-PGF1α) enzyme-linked immunosorbent assay kit, epoxidase-1 (COX-1) enzyme-linked immunosorbent assay kit, lactate dehydrogenase (LDH) assay kit, carboxymethyl fiber Sodium (CMC-Na).

3.2 experimental animals

Japanese white rabbit, male, SPF grade, weight 2-3kg, SCXK2014-0002.

KM mice, male, SPF grade, body weight 18-22 g, SCXK 2015-0001.

SD rats, male, weighing 220-250 g, SCXK 2015-0001.

3.3 Experimental methods

3.3.1 Antiplatelet aggregation

Blood was taken from the rabbit ear vein, and anti-coagulation with 3.8% sodium citrate (volume ratio of whole blood to anticoagulant 9:1) was performed at room temperature (500-800 rpm/min, 10 min) to prepare platelet-rich plasma. PRP). After PRP was isolated, platelet-poor plasma (PPP) was prepared by centrifugation (3000 rpm/min, 10 min) and adjusted to 0 with PPP. Take PRP 200μL and add 5μL of equimolar R-/S-HPABA DMSO solution. The blank control group and the same volume of medium DMSO were incubated for 2min. Then, ADP20μL, AA20μL and COLL20μL were used as inducers to measure platelet aggregation reaction. analysis.

3.3.2 platelet toxicity test

Lactate dehydrogenase (LDH) is considered to be an indicator of cell viability. Therefore, this test evaluates (R)-2-lactamidobenzoic acid or (S)-2-lactoamidobenzene by measuring the release of LDH. Formic acid is toxic to platelets. (R)-2-lactamaminobenzoic acid or (S)-2-lactamylbenzoic acid (150 μg/mL) was incubated with PRP for different times and assayed using the LDH Toxicity Assay Kit according to the instructions. The extent of LDH release is expressed as a percentage of the maximum release (0.3% Triton X-100).

3.3.3 Determination of bleeding time

KM mice were randomly divided into 8 groups of 8 animals each. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid in low, medium and high dose groups (50, 100 and 200 mg/ Kg), CMC-Na (blank control). The drug was administered by intragastric administration once a day for 7 days. Urethane was anesthetized (1 g/kg, i.p.) 1 h after the last administration. A length of about 5 mm was cut from the tip of the mouse and rapidly inserted into physiological saline at 37 °C. The time from the start of bleeding to the second bleeding within 15 minutes was observed and recorded.

3.3.4 Determination of clotting time

The experimental grouping and administration were as shown in 1.3.3, and urethane was anesthetized 1 hour after the last administration. Use a capillary eyelid to collect blood, drop two drops on both ends of the clean slide, start timing, pick it with a fine needle every 30 seconds, until the bloodshot stops, the time required is the clotting time.

3.3.5 Determination of plasma thromboxane B ₂ (TXB ₂ ) and 6-keto-prostaglandin F1α (6-keto-PGF1α)

SD rats were randomly divided into 8 groups, 5 in each group. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid in low, medium and high dose groups (50, 100 and 200 mg/ Kg), CMC-Na (blank control). The drug was administered by intragastric administration once a day for 7 days. Urethane was anesthetized (1 g/kg, ip) 1 h after the last administration. Blood was taken from the abdominal aorta, PRP was prepared, and stored at -20 °C before analysis. The concentrations were determined by the TXB ₂ and 6-keto-PGF1α enzyme-linked immunosorbent kit according to the instructions.

3.3.6 Determination of cyclooxygenase-1 (COX-1) activity

SD rats were randomly divided into 4 groups, 5 in each group. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamidobenzoic acid or (S)-2-lactamidobenzoic acid (200 mg/kg), CMC-Na (blank control) . The drug was administered by intragastric administration once a day for 7 days. Urethane was anesthetized (1 g/kg, i.p.) 1 h after the last administration. Blood was taken from the abdominal aorta, PRP was prepared, and stored at -20 °C before analysis. The concentration was determined by the COX-1 enzyme-linked immunosorbent assay kit according to the instructions.

3.4 Experimental results

3.4.1 Antiplatelet aggregation

The experimental results are shown in Table 2-4.

Table 2. R-/S-HPABA on ADP-induced platelet aggregation in rabbits

**P<0.01vs blank control group

Table 3. R-/S-HPABA on COLL-induced platelet aggregation in rabbits

*P<0.05vs blank control group

Table 4. R-/S-HPABA on AA-induced platelet aggregation in rabbits

*P<0.05vs blank control group

As can be seen from Table 2-4, (R)-2-lactamidobenzoic acid or (S)-2-lactamamidobenzoic acid was significantly different from the control group in the action of antiplatelet aggregation with aspirin. The effect is comparable and there is no significant difference in the effect between the two enantiomers.

The experimental results of the present invention indicate that (R)-2-lactamidobenzoic acid or (S)-2-lactoamidobenzoic acid has a certain anti-platelet aggregation effect.

3.4.2 Determination of platelet toxicity by R-/S-HPABA

The experimental results are shown in Fig. 1. As can be seen from Fig. 1, (R)-2-lactamidobenzoic acid or (S)-2-lactamidobenzoic acid has no significant difference compared with the control group, and two pairs There was no significant difference in the roles between the morphogens.

The experimental results of the present invention indicate that (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid is not toxic to platelets, and its antiplatelet aggregation is not caused by cytotoxicity.

3.4.3 Determination of bleeding time and clotting time

The experimental results are shown in Table 5.

Table 5. Effect of R-/S-HPABA on bleeding time and clotting time

^* p<0.05vs. blank control group

As can be seen from Table 5, (R)-2-lactamidobenzoic acid or (S)-2-lactamaminobenzoic acid was significantly different from the control group, and the effect was comparable to that of aspirin, and two There was no significant difference in the effects between the enantiomers.

The experimental results of the invention showed that R-/S-2-lactamamidobenzoic acid prolonged the clotting time and prolonged the bleeding time, but did not significantly prolong, so there was no risk of bleeding.

3.4.4 Determination of plasma thromboxane B ₂ (TXB ₂ ) and 6-keto-prostaglandin F1α (6-keto-PGF1α)

The experimental results are shown in Table 6.

Table 6. Effect of R-/S-HPABA on TXB ₂ and 6-keto-PGF1α

^* p<0.05vs. blank group.

As can be seen from Table 6, (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid significantly inhibited the production of thromboxane B ₂ and increased the 6-keto group compared with the blank group. - Formation of prostaglandin F1α.

3.4.5 Determination of cyclooxygenase-1 (COX-1) activity

The experimental results are shown in Fig. 2. As can be seen from Fig. 2, (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid and aspirin can significantly inhibit COX-1 compared with the control group. Active, and the effect of S-2-lactamidobenzoic acid is comparable to that of aspirin, and the effect is superior to R-2-lactamidobenzoic acid.

The experimental results of the present invention indicate that the anti-platelet aggregation of (R)-2-lactamidobenzoic acid or (S)-2-lactoamidobenzoic acid may further inhibit thromboxane by inhibiting the activity of cyclooxygenase-1. Generation of A ₂ (precursor compound of TXB ₂ ).

Example 4. Antithrombotic activity of (R)-2-lactamidobenzoic acid or (S)-2-lactamidobenzoic acid

4.1 reagent

Aspirin (ASP, purity >99.5%), (R)-2-lactamaminobenzoic acid (homemade, optical purity >99.3%), (S)-2-lactamidobenzoic acid (homemade, optical purity >98.8%) ), sodium carboxymethyl cellulose (CMC-Na).

4.2 experimental animals

KM mice, male, SPF grade, body weight 18-22 g, SCXK 2015-0001.

SD rats, male, weighing 220-250 g, SCXK 2015-0001.

4.3 Experimental methods

4.3.1 Collagen-adrenalin-induced pulmonary thrombosis

KM mice were randomly divided into 8 groups of 10 animals each. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid in low, medium and high dose groups (50, 100 and 200 mg/ Kg), CMC-Na (blank control). The drug was administered by intragastric administration once a day for 7 days. One hour after the last administration, a mixture of collagen (500 μg/kg) and epinephrine (50 μg/kg) was injected into the tail vein to induce pulmonary thrombosis. The number of mice with hemiplegia, death or recovery within 15 min was observed and recorded. Inhibition rate (%) = ((number of deaths in the blank group - number of deaths in the administration group) / number of deaths in the blank group) x 100%.

4.3.2 carotid thrombosis

SD rats were randomly divided into 8 groups, 5 in each group. Grouped as follows: aspirin 100 mg/kg (positive control), (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid in low, medium and high dose groups (50, 100 and 200 mg/ Kg), CMC-Na (blank control). The drug was administered by intragastric administration once a day for 7 days. Urethane was anesthetized (1 g/kg, ip) 1 h after the last administration. Arterial thrombosis was induced by carotid artery threading. After 3 hours of operation, arterial thrombosis (about 1 cm) was cut, and the filter paper was blotted dry and heavy. Inhibition rate (%) = (AA ₁ ) / A × 100%, the wet weight of the thrombus in the A blank group, and A ₁ represents the wet weight of the thrombus in the administration group.

4.4 Experimental results

4.4.1 Collagen-adrenalin-induced pulmonary thrombosis

The experimental results are shown in Table 7.

Table 7. Effect of R-/S-HPABA on collagen-adrenalin-induced pulmonary thrombosis

^* p < 0.05 vs. aspirin group.

^# P ^<0.05vs. Same concentration S-HPABA.

As can be seen from Table 7, (R)-2-lactamidobenzoic acid or (S)-2-lactoamidobenzoic acid can significantly improve the recovery rate of pulmonary thrombosis compared with the blank group. Compared with aspirin, medium and high doses of (R)-2-lactamidobenzoic acid and high doses of (S)-2-lactamidobenzoic acid are superior to aspirin, and medium and high doses (R) The -2-lactamidobenzoic acid acts more than the same concentration of S-2-lactamamibenzoic acid.

The experimental results of the present invention indicate that (R)-2-lactamidobenzoic acid or (S)-2-lactamidobenzoic acid has an anti-pulmonary thrombosis effect. Its antithrombotic effect may be produced by its anti-platelet aggregation.

4.4.2 carotid thrombosis

The experimental results are shown in Table 8.

Table 8. Effect of R-/S-HPABA on carotid artery thrombosis

^* p < 0.01 vs. blank group.

As can be seen from Table 8, (R)-2-lactamidobenzoic acid or (S)-2-lactamidobenzoic acid was able to significantly inhibit the weight of arterial thrombus as compared with the blank group. The effect is comparable to that of aspirin and there is no significant difference between the two enantiomers.

The experimental results of the present invention indicate that (R)-2-lactamaminobenzoic acid or (S)-2-lactamidobenzoic acid has an anti-arterial thrombus effect. Its antithrombotic effect may be produced by its anti-platelet aggregation.

Claims (10)

a benzoic acid compound having the following formula or a salt thereof

Where R ₁ =—H; —Na; —(CH ₂ ) _n —CH ₃ (n=0 to 3) R ₂ =—H; —CH ₃ ; —(CH ₂ ) _n —CH ₃ (n=0～2) R ₃ =—H; —F;—Cl;—Br R ₄ =—H; —F;—Cl;—Br R ₅ =—H; —F; —Cl;—Br. R)-2-lacylaminobenzoic acid or (S)-2-lactamidobenzoic acid or a salt thereof having the following structure:

A pharmaceutical composition comprising the compound of claim 1 or 2 or a salt thereof and a pharmaceutically acceptable carrier. A method of preparing a compound according to claim 2, comprising the steps of: (a) L-lactic acid or D-lactic acid (IIa or IIb) and acetyl chloride (III) to give intermediates (IVa, IVb); (b) the intermediate (IVa, IVb) is reacted with thionyl chloride to give the intermediate (Va, Vb); (c) intermediate (Va, Vb) and methyl anthranilate (VI) are reacted in an organic solvent to form an intermediate (VIIa, VIIb); (d) The intermediate (VIIa, VIIb) is reacted with an alkali carbonate solution to obtain an intermediate (VIIIa, VIIIb), or the intermediate (VIIa, VIIb) is reacted with an alkali hydroxide solution to obtain R-/S-2-lactamamidobenzene. Formic acid (Ia, Ib);

The process according to claim 4, wherein the step (a) is carried out in anhydrous tetrahydrofuran or acetic anhydride, and the molar ratio of L-lactic acid or D-lactic acid to acetyl chloride is from 0.3 to 0.5:1. The preparation method according to claim 4, wherein the molar ratio of the intermediate (Va, Vb) to the methyl anthranil (VI) in the step (c) is from 1 to 3:5, and the organic solvent is Anhydrous ether. The preparation method according to claim 4, wherein in the step (d), (VIIa, VIIb) is reacted with a potassium carbonate solution in methanol, and the intermediate (VIIa, VIIb) is reacted with a sodium hydroxide solution in tetrahydrofuran and The amount ratio of the compound of the formula (VIIa, VIIb) to the potassium carbonate is from 1 to 2:5; the ratio of the amount of the compound of the formula (VII) to the sodium hydroxide is from 1 to 2:5; the step (d) After the reaction was completed, it was extracted with dichloromethane and the pH was adjusted to 1-4. Use of the compound of claim 1 or 2 or the composition of claim 3 for the preparation of an anti-platelet agglutination and antithrombotic drug. The use according to claim 8, wherein the medicament is administered via the following routes of administration: intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, buccal, rectal or a combination thereof. The use according to claim 8, wherein said platelet aggregation and thrombosis include venous thrombosis, arterial thrombosis, capillary thrombosis or coronary heart disease, ischemic cerebrovascular disease, pulmonary embolism, angina pectoris, atherosclerosis, Thrombosis caused by cardiovascular and cerebrovascular diseases associated with thrombosis in myocardial infarction.

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