Four amino acid modified compounds selectively inhibit adp, and their preparation and use

Abstract

The application discloses four kinds of tetra-cyclic compounds with selective adenosine diphosphate inhibition, which have the following formula structure, wherein the amino acids represented by AA are L-Ser residues, L-Glu residues, L-Lys residues and L-Tyr residues respectively, the application discloses a preparation method of the tetra-cyclic compounds and application of the tetra-cyclic compounds in treating arterial thrombosis diseases. Experiments prove that the adenosine diphosphate selective inhibitor has good anti-arterial thrombosis effect. Thus, the application provides an effective technical means for resisting arterial thrombosis.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of amino acid modified tetraloop compound selectively inhibiting adenosine diphosphate, to its preparation method and application in treating arterial thrombosis.The experiment proves that the adenosine diphosphate selective inhibitor of the present application has good anti-arterial thrombosis effect.The present application belongs to the field of biological medicine. BACKGROUND

[0002] Arterial embolism has become one of the diseases with high incidence and high mortality.Arterial thrombosis is responsible for transient ischemic attack, acute coronary syndrome, myocardial infarction and atrial fibrillation.In atrial fibrillation, 18%-47% of patients have coronary artery disease, and about 20% of patients with atrial fibrillation accompanied by coronary artery disease receive percutaneous coronary intervention.Arterial thrombosis is also responsible for arterial thrombosis after artificial heart valve, arteriovenous fistula and other surgeries, and unstable angina.For example, after liver transplantation surgery, patients face the risk of liver arterial thrombosis.In addition, patients with antiphospholipid syndrome also face the risk of arterial thrombosis.Arterial thrombosis is associated with platelet aggregation.Inducers that usually induce platelet aggregation include platelet activating factor (PAF), adenosine diphosphate (ADP), thrombin (TH) and arachidonic acid (AA).Finding selective inhibitors of platelet activating factor, adenosine diphosphate, thrombin and arachidonic acid is an important direction of anti-arterial thrombosis drug research.In the research, the inventors screened a kind of amino acid modified tetraloop compound selectively inhibiting adenosine diphosphate

[0003] The data on rat wire method arterial thrombosis model show that the tetraloop compound shows excellent anti-arterial thrombosis activity.According to these findings, the inventors propose the present application. SUMMARY

[0004] The technical problem to be solved by the present application is to provide an amino acid modified tetraloop compound selectively inhibiting adenosine diphosphate.The experiment proves that the amino acid modified tetraloop compound prepared by the present application has excellent anti-arterial thrombosis effect.In order to achieve the purpose, the present application adopts the following technical means.

[0005] The first technical means is to propose the amino acid modified tetraloop compound selectively inhibiting adenosine diphosphate of the present application, and the structure of the compound is as follows:

[0006]

[0007] In the formula, AA is L-Ser residue, L-Glu residue, L-Lys residue or L-Tyr residue.

[0008] The second technical means is to provide a method for preparing the amino acid modified tetrahydroisoquinoline compound, which comprises the following steps:

[0009] 1. Preparation of 3S-tetrahydro-β- carbolin-3-carboxylic acid;

[0010] 2. Preparation of 3S-tetrahydro-β-carbolin-3-carboxylic acid methyl ester;

[0011] 3. Preparation of 3S-2-Boc-Asp(OCH3)- tetrahydro-β-carbolin-3-carboxylic acid methyl ester;

[0012] 4. Preparation of 3S-2-Asp(OCH3)- tetrahydro-β-carbolin-3-carboxylic acid methyl ester;

[0013] 5. Preparation of acetylmethyl ester substituted tetrahydroisoquinoline compound;

[0014] 6. Preparation of acetoxy substituted tetrahydroisoquinoline compound;

[0015] 7. Preparation of acetyl-Ser-OBzl, acetyl-Glu-OBzl, acetyl-Lys-OBzl and acetyl-Tyr-OBzl substituted tetrahydroisoquinoline compound;

[0016] 8. Preparation of acetyl-Ser, acetyl-Glu, acetyl-Lys and acetyl-Tyr substituted tetrahydroisoquinoline compound.

[0017] The third technical means provides the use of the amino acid modified tetrahydroisoquinoline compound in selective inhibition of adenosine diphosphate (ADP).

[0018] The fourth technical means is to confirm the selective inhibitory effect of the acetyl amino acid substituted tetrahydroisoquinoline compound on adenosine diphosphate induced platelet aggregation.

[0019] The fifth technical means is to confirm the excellent inhibitory effect of the acetyl amino acid substituted tetrahydroisoquinoline compound on arterial thrombosis. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 Synthetic route of amino acid modified tetrahydroisoquinoline compound for selective inhibition of adenosine diphosphate: i) CH2O, H2SO4; ii) SOCl2, CH3OH; iii) DCC, HOBt, N-methyl morpholine, Boc-Asp(OMe); iv) hydrogen chloride in ethyl acetate 4N; v) CH3OH, N-methyl morpholine; vi) 2N NaOH, CH3OH; vii) H2, palladium on carbon. DETAILED DESCRIPTION

[0021] To further illustrate the application, a series of examples are given below. These examples are purely illustrative and are only used to specifically describe the application and should not be understood as limiting the application.

[0022] Example 1 Preparation of 3S-Tetrahydro-β-carboline-3-carboxylic acid (1)

[0023] To 400 mL of water was added 0.2 mL of concentrated sulfuric acid slowly. To the resulting dilute sulfuric acid solution was added 5.0 g (24.5 mmol) of L-Trp and sonicated until the L-Trp was completely dissolved. To the resulting solution was added 10 mL of a 30-40% concentration of formaldehyde in water. The reaction mixture was stirred at room temperature for 5-6 hours and thin layer chromatography (ethyl acetate / ether, 20 / 1) indicated that the L-Trp was gone and the reaction was terminated. Concentrated ammonia was added slowly to the reaction mixture and the pH was adjusted to 6. The resulting precipitate was allowed to settle for 30-40 minutes. The precipitate was filtered off and washed with water. The colorless solid was spread out on a petri dish and allowed to dry in air to give 5.05 g (95%) of the title compound as a colorless solid. ESI (m / e): 217 [M+H] + .

[0024] Example 2 Preparation of 3S-Tetrahydro-β-carboline-3-carboxylic acid methyl ester (2)

[0025] To a solution of 3.3 g (15 mmol) of 3S-Tetrahydro-β-carboline-3-carboxylic acid in methanol was added SOCl2slowly at 0°C. The reaction mixture was stirred at 0°C for 6 hours. The reaction mixture was no longer releasing HCl gas and a solid was slowly precipitating. Thin layer chromatography (ethyl acetate / ether, 20 / 1) indicated that the 3S-Tetrahydro-β-carboline-3-carboxylic acid was gone and the reaction was terminated. The reaction mixture was concentrated to dryness under reduced pressure. The residue was washed repeatedly with saturated aqueous sodium chloride solution and filtered to give 3.2 g (92%) of the title compound as a colorless powder. ESI (m / e): 231 [M+H] + .

[0026] Example 3 Preparation of 3S-[2-Boc-Asp(OCH3)]-tetrahydro-β-carboline-3-carboxylic acid methyl ester (3)

[0027] To a solution of 3.2 g (13.9 mmol) of 3S-tetrahydro-β-carboline-3-carboxylic acid methyl ester and 3.4 g (13.9 mmol) of Boc-Asp(OCH3) in 150 mL of dry tetrahydrofuran at 0 °C was added 2.0 g (14.8 mmol) of N-hydroxybenzotriazole (HOBt), 3.1 g (14.8 mmol) of dicyclohexylcarbodiimide (DCC). The reaction mixture was stirred at 0 °C for 30 minutes. The pH was then adjusted to 8 with N-methylmorpholine (NMM). The reaction mixture was stirred at 0 °C for 6 hours and thin layer chromatography (ethyl acetate / methanol, 20 / 1) indicated that 3S-tetrahydro-β-carboline-3-carboxylic acid methyl ester was consumed and the reaction was terminated. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The residue was dissolved in 200 mL of ethyl acetate. The resulting solution was washed successively with 5% aqueous sodium bicarbonate solution (30 mL x 3), saturated aqueous sodium chloride solution (30 mL x 3), 5% aqueous hydrochloric acid solution (30 mL x 3), and saturated aqueous sodium chloride solution (30 mL x 3). The ethyl acetate layer was separated, dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 5.9 g (93%) of the title compound as a colorless powder. ESI (m / e) 460 [M+H] + .

[0028] Example 4 Preparation of 3S-[2-Asp(OCH3)]-tetrahydro-β-carboline-3-carboxylic acid methyl ester (4)

[0029] A solution of 5.9 g (12.9 mmol) of 3S-[2-Boc-Asp(OCH3)]-tetrahydro-β-carboline-3-carboxylic acid methyl ester in 50 mL of hydrogen chloride in ethyl acetate (4 N) was stirred at room temperature for 60 minutes. Thin layer chromatography (ethyl acetate / methanol, 20 / 1) indicated that 3S-[2-Boc-Asp(OCH3)]-tetrahydro-β-carboline-3-carboxylic acid methyl ester was consumed and the reaction was terminated. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in 50 mL of ethyl acetate and concentrated under reduced pressure. This procedure was repeated five times to give 5.8 g (98%) of the title compound as a colorless powder. ESI (m / e) 460 [M+H] + .

[0030] Example 5 Preparation of (3S,12aS)-2,3,6,7,12,12a-hexahydropyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetic acid methyl ester (5)

[0031] A solution of 4.10 g (8.9 mmol) of 3S-[2-Asp(OCH3)]-tetrahydro-β- carbolin-3-carboxylic acid methyl ester in 30 mL of ethyl acetate was stirred at 30°C for 60 minutes to complete the cyclization reaction. 1.9 g (70%) of the title compound was obtained as a colorless powder. ESI (m / e) 327 [M+Na] + .

[0032] Example 6 Preparation of (3S,12aS)-2,3,6,7,12,12a-hexahydro-pyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetic acid (6)

[0033] A solution of 1.1 g (3.6 mml) of (3S,12aS)-2,3,6,7,12,12a-hexahydro-pyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetic acid methyl ester in 20 mL of methanol was dissolved at 0°C, and 2N aqueous sodium hydroxide solution was added dropwise to adjust the pH of the reaction solution to 12. The reaction solution was stirred for another 3 hours, and thin layer chromatography (ethyl acetate / methanol, 20 / 1) showed that (3S,12aS)-2,3,6,7,12,12a-hexahydro-pyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetic acid methyl ester disappeared, and the reaction was terminated. The reaction solution was first adjusted to pH 2 with dilute hydrochloric acid, and then concentrated under reduced pressure. 50 mL of distilled water was added to the residue, and the resulting mixture was extracted with ethyl acetate (30 mL x 3). The ethyl acetate extracts were combined and washed with saturated aqueous sodium chloride solution (30 mL x 3). The ethyl acetate extracts were dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.91 g (87%) of the title compound as a colorless powder. Rf = 0.35 (dichloromethane / methanol, 5 / 1). Mp: 228-232°C. f = 0.35 (dichloromethane / methanol, 5 / 1). Mp: 228-232°C. (c = 0.5, methanol). ESI (m / e) 313 [M-H] - . 1H NMR (300 MHz, DMSO-d6): δ / ppm = 11.04 (s, 1 H), 8.23 (s, 1 H), 7.44 (d, J = 7.5 Hz, 1 H), 7.33 (t, J = 7.5 Hz, 1 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.95 (t, J = 7.5 Hz, 1 H), 5.38 (d, J = 17.1 Hz, 1 H), 4.25 (dd, J = 3.9 Hz, J = 11.4 Hz, 1 H), 4.20 (d, J = 17.1 Hz, 1 H), 4.16 (d, J = 15.0 Hz, 1 H), 3.18 (dd, J = 3.3 Hz, J = 14.7 Hz, 1 H), 2.97 (t, J = 13.5 Hz, 1 H), 2.51 (d, J = 10.5 Hz, 2 H). 13 C NMR (75 MHz, DMSO-d6): δ / ppm = 172.44, 165.97, 165.05, 135.96, 129.84, 126.35, 120.86, 118.55, 117.53, 111.03, 105.70, 55.61, 52.35, 40.64, 26.43.

[0034] Example 7 Preparation of (3S,12aS)-2,3,6,7,12,12a-hexahydropyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetyl-Ser-OBzl (7a)

[0035] Using the reaction conditions and procedure of Example 2, 570 mg (1.82 mmol) of (3S,12aS)-2,3,6,7,12,12a-hexahydropyrazino[l',2':l,6]pyrido[3,4-b]indole-l,4-dione-3-acetic acid (6) and 672 mg (1.82 mmol) of Ser-OBzl gave 368 mg (50%) of the title compound as a colorless solid. ESI (m / e) 513 [M+Na] + .

[0036] Example 8 Preparation of (3S,12aS)-2,3,6,7,12,12a-hexahydropyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetyl-Glu-OBzl (7b)

[0037] Using the reaction conditions and procedure of Example 2, 570 mg (1.82 mmol) of (3S, 12aS)-2,3,6,7,12,12a-hexahydro-pyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetic acid (6) and 936 mg (1.82 mmol) of Glu-OBzl afforded 1.08 g (87%) of the title compound as a colorless solid. ESI (m / e) 645 [M+Na] + .

[0038] Example 9 Preparation of (3S, 12aS)-2,3,6,7,12,12a-hexahydro-pyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetyl-Lys-OBzl (7c)

[0039] Using the reaction conditions and procedure of Example 2, 570 mg (1.82 mmol) of (3S, 12aS)-2,3,6,7,12,12a-hexahydro-pyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetic acid (6) and 987 mg (1.82 mmol) of Lys-OBzl afforded 867 mg (85%) of the title compound as a colorless solid. ESI (m / e) 544 [M+Na] + .

[0040] Example 10 Preparation of (3S, 12aS)-2,3,6,7,12,12a-hexahydro-pyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetyl-Tyr-OBzl (7d)

[0041] Using the reaction conditions and procedure of Example 2, 570 mg (1.82 mmol) of (3S, 12aS)-2,3,6,7,12,12a-hexahydro-pyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetic acid (6) and 987 mg (1.82 mmol) of Lys-OBzl afforded 867 mg (85%) of the title compound as a colorless solid. ESI (m / e) 544 [M+Na] + .

[0042] Example 11 Preparation of (3S, 12aS)-2,3,6,7,12,12a-hexahydro-pyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetyl-Ser (8a)

[0043] Dissolve 80 mg of (3S,12aS)-2,3,6,7,12,12a-hexahydropyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-ethyl-Ser-OBzl (7a) in 15 mL of methanol and add 30 mg of palladium on carbon, continuously pass hydrogen gas, react for 2 hours, TLC test for disappearance of 7a, filter, rinse the filter cake with methanol repeatedly, concentrate the filtrate under reduced pressure, dry with ether to colorless powder, obtain 48 mg (88%) of the title compound as a colorless solid. R f = 0.20 (dichloromethane / methanol, 5 / 1), Mp: 189-194 °C. (c = 0.5, methanol). ESI (m / e) 399.1299 [M-H] - . IR (KBr): 3327, 2927, 1625, 1332, 1126, 744 cm -1 . 1 HNMR (500 MHz, DMSO-d6): δ / ppm = 8.202 (m, 1H), 8.173 (m, 1H), 7.444 (d, J = 7.5 Hz, 1H), 7.340 (d, J = 7.5 Hz, 1H), 7.705 (t, J = 8.0 Hz, 1H), 6.996 (d, J = 7.5 Hz, 1H), 5.398 (d, J = 16.5 Hz, 1H), 4.270 (m, 2H), 4.184 (d, J = 17.0 Hz, 1H), 3.618 (m, 1H), 3.522 (m, 1H), 3.160 (m, 1H), 3.038 (t, J = 14.0 Hz, 1H), 2.756 (m, 2H). 13 CNMR (125 MHz, DMSO-d6): δ / ppm = 172.28, 169.31, 165.15, 136.34, 130.16, 121.49, 119.18, 111.53, 106.30, 72.70, 61.80, 60.67, 56.26, 47.99, 33.79, 32.72, 26.68, 25.31, 24.90.

[0044] Example 12 Preparation of (3S,12aS)-2,3,6,7,12,12a-hexahydropyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-ethyl-Glu (8b)

[0045] Using the reaction conditions and procedure of Example 11, 78 mg (93%) of the title compound was prepared from 100 mg of (3S,12aS)-2,3,6,7,12,12a- hexahydropyrazino[l',2':l,6]pyrido[3,4-b]indole-l,4-dione-3-acetyl-Glu-OBzl as a colorless solid. Rf= 0.35 (dichloromethane / methanol, 5 / 1), Mp: 172-176 °C. f = 0.35 (dichloromethane / methanol, 5 / 1), Mp: 172-176 °C. (c = 0.5, methanol). ESI (m / e) 441.1405 [M-H] - IR (KBr): 3300, 2953, 1716, 1643, 1332, 1203, 744 cm -1 . 1 HNMR (DMSO-d6, 300 MHz): δ / ppm = 10.927 (S, 1H), 8.210 (m, 2H), 7.443 (d, J = 7.8 Hz, 1H), 7.333 (d, J = 7.8 Hz, 1H), 7.071 (t, J = 7.5 Hz, 1H), 6.990 (t, J = 7.2 Hz, 1H), 5.392 (d, J = 16.8 Hz, 1H), 4.206 (m, 4H), 3.167 (m, 1H), 3.007 (m, 1H), 2.687 (m, 2H), 2.226 (t, J = 7.5 Hz, 2H), 1.914 (m, 1H), 1.783 (m, 1H). 13 CNMR (75 MHz, DMSO-d6): δ / ppm = 174.12, 173.55, 169.34, 166.57, 165.08, 136.43, 130.28, 126.81, 121.49, 119.18, 118.09, 111.52, 106.26, 56.22, 52.01, 51.60, 48.97, 40.77, 30.51, 26.91, 26.69.

[0046] Example 13 (3S,12aS)-2,3,6,7,12,12a-hexahydropyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetyl-Lys(8c)

[0047] Using the reaction conditions and procedure of Example 11, 130 mg of the title compound was prepared from 160 mg of (3S,12aS)-2,3,6,7,12,12a- hexahydropyrazino[l',2':l,6]pyrido[3,4-b]indole-l,4-dione-3-acetyl-Lys-OBzl as a colorless solid. Rf= 0.35 (dichloromethane / methanol, 5 / 1), Mp: 172-176 °C. f= 0.25 (dichloromethane / methanol, 5 / 1), Mp: 202 °C. (c = 0.5, methanol). ESI (m / e) 440.1928 [M-H] - . IR (KBr): 3348, 2927, 1647, 1332, 1004, 744 cm -1 . 1 H NMR (DMSO-d6, 300 MHz): δ / ppm = 11.06 (s, 1H), 8.314 (d, J = 7.5 Hz, 1H), 8.248 (s, 1H), 7.944 (s, 3H), 7.455 (d, J = 7.5 Hz, 1H), 7.341 (d, J = 7.8 Hz, 1H), 7.067 (t, J = 7.5 Hz, 1H), 6.986 (t, J = 7.2 Hz, 1H), 5.395 (d, J = 16.8 Hz, 1H), 4.256 (m, 2H), 4.175 (d, J = 16.5 Hz, 1H), 4.103 (m, 1H), 3.174 (m, 1H), 3.046 (t, J = 7.2 Hz, 1H), 2.702 (m, 4H), 1.580 (m, 4H), 1.271 (m, 2H). 13 CNMR (75 MHz, DMSO-d6): δ / ppm = 173.94, 169.24, 166.68, 165.00, 136.39, 130.30, 126.83, 121.46, 119.15, 118.10, 111.60, 106.28, 56.24, 52.12, 30.94, 26.91, 26.59, 22.77, 21.56.

[0048] Example 14 Preparation of (3S,12aS)-2,3,6,7,12,12a-hexahydropyrazino[l',2':l,6]pyrido[3,4- b]indole-l,4-dione-3-acetyl-Tyr (8d)

[0049] Using the reaction conditions and procedure of Example 11, 60 mg of the title compound was prepared from 100 mg of (3S,12aS)-2,3,6,7,12,12a- hexahydropyrazino[l',2':l,6]pyrido[3,4-b]indole-l,4-dione-3-acetyl-Tyr-OBzl as a colorless solid. Rf = 0.25 (dichloromethane / methanol, 5 / 1), Mp: 189-194 °C. f = 0.25 (dichloromethane / methanol, 5 / 1), Mp: 202 °C. (c = 0.5, methanol). ESI (m / e) 440.1928 [M-H] -IR (KBr): 3307, 2922, 1643, 1516, 1332, 1126 cm -1 . 1 H NMR (DMSO-d6, 300 MHz): δ / ppm = 10.971 (s, 1H), 8.213 (m, 1H), 7.450 (d, J = 8.0 Hz, 1H), 7.340 (d, J = 8.0 Hz, 1H), 7.076 (t, J = 7.5 Hz, 1H), 6.998 (t, J = 7.5 Hz, 1H), 6.934 (d, J = 9.0 Hz, 2H), 6.611 (d, J = 9.0 Hz, 2H), 5.387 (d, J = 16.5 Hz, 1H), 4.270 (m, 3H), 4.175 (d, J = 16.5 Hz, 1H), 3.185 (m, 1H), 3.023 (m, 1H), 2.852 (dd, J = 5.5 Hz, J = 13.5 Hz, 1H), 2.734 (dd, J = 8.0 Hz, J = 14.0 Hz, 1H), 2.654 (m, 2H). 13 CNMR (75 MHz, DMSO-d6): δ / ppm = 173.33, 169.43, 166.71, 165.03, 156.53, 143.97, 136.16, 130.56, 121.49, 119.18, 118.10, 115.36, 111.54, 106.29, 72.70, 65.53, 56.26, 36.55, 26.50.

[0050] Example 15 Evaluation of anti-platelet aggregation activity

[0051] Fresh porcine carotid artery blood was collected and anticoagulated with 3.8% sodium citrate (1 / 9 by volume). Platelet-rich plasma (PRP) was obtained by centrifugation at 1000g for 10 minutes and platelet-poor plasma (PPP) was obtained by centrifugation at 3000g for 10 minutes. The PRP was adjusted with PPP to give a platelet count suitable for the determination of anti-platelet aggregation activity. 8a-d was dissolved in saline. To a cuvette was added 0.24 mL of adjusted PRP and 5 μL of either saline or a solution of 8a-d in saline (5 μL, 0.1 μM, 10 μM, 15 μM, 20 μM). The baseline absorbance was adjusted and 5 μL of a solution of one of the four inducers was added to observe the maximum aggregation (Am) of the platelets over 5 minutes. The four inducers were platelet-activating factor (PAF, final concentration 50 μM), adenosine diphosphate (ADP, final concentration 500 μM), thrombin (TH, final concentration 50 IU / L) and arachidonic acid (AA, final concentration 7.5 mg / mL). The maximum aggregation was the value corresponding to the peak of the aggregation curve. The platelet aggregation curve was determined in sextuplicate for each concentration. From the platelet aggregation curves it was determined that 8a-d inhibited platelet aggregation induced by PAF, ADP, TH and AA with IC 50 (see Table 1). The data in Table 1 show that 8a-d has the lowest IC 50 value for inhibition of ADP-induced platelet aggregation and is a selective inhibitor of ADP.

[0052] Table 1 IC50values for inhibition of platelet aggregation induced by four inducers by 8a-d 50 (mean ± SD, μM)

[0053]

[0054]

[0055] n = 6

[0056] Example 16 Evaluation of anti-arterial thrombosis activity

[0057] 1) A polyethylene tube was cut to a length of 10.0 cm with a bevelled end for the right jugular vein (thicker tube) and left carotid artery (thinner tube). The middle section of the polyethylene tube was cut to a length of 8.0 cm and a thrombosis thread was placed in the tube in the direction of the carotid artery cannula. The tube was filled with heparin before cannulation.

[0058] 2) Male SD rats with body weight of 200±20g were acclimated and fasted for one day before operation. They were randomly divided into normal saline group (blank control, oral dose of 0.3mL / 100g, 10 rats), aspirin group (positive control, oral dose of 167μmol / kg, 10 rats), and normal saline solution of 8a-d group (oral dose of 1nmol / kg, 10 rats). After 30 minutes of oral administration, the rats were anesthetized by intraperitoneal injection of 20% urethane solution (7mL / kg), and the operation was started 2 minutes later. During the operation, the rats were placed on a fixed plate in a supine position, the skin of the neck was cut, the right common carotid artery and the left jugular vein were separated, a precisely weighed silk thread was pressed under the blood vessels, the distal end was ligated, a small incision was made at the distal end of the vein, a cannula was inserted into the vein end, heparin was injected, then the heparin syringe was removed, the thread was fixed, the arterial clip was clamped at the proximal end of the artery, a small incision was made at the distal end of the artery, the artery end was ligated, the thread was fixed, and the arterial clip was loosened to establish an extracorporeal circulation bypass. After 15 minutes of circulation, the vein was cut to observe whether the blood circulation was normal. If the blood circulation was normal, the silk thread with thrombus was removed from the artery end, the uncoagulated blood was absorbed with filter paper, the weight of the silk thread with thrombus was accurately measured, the weight of the thrombus was obtained by subtracting the weight of the silk thread from the weight of the silk thread with thrombus, and the data were listed in Table 2.

[0059] Table 2 Effect of 8a-d on rat arterial thrombosis

[0060]

[0061] a) p<0.01 compared with normal saline; b) p>0.05 compared with normal saline; n=10

[0062] The thrombus weight in the table shows that 8a-d effectively inhibits rat arterial thrombosis at an oral dose of 1nmol / kg (p<0.01 compared with normal saline). This is an unexpected technical effect.

Claims

1. Amino acid modified tetraloop compounds that selectively inhibit adenosine diphosphate characterized in that, The structural formula of the tetra-cyclic compound is as follows, In the formula, AA represents an amino acid selected from the group consisting of L-Ser residue, L-Glu residue, L-Lys residue and L-Tyr residue.

2. Process for the preparation of the tetracyclic compounds according to claim 1, characterized in that, The method comprises the following steps: 1) preparing 3S-tetrahydro-β-carboline-3-carboxylic acid; 2) preparing 3S-tetrahydro-β-carboline-3-carboxylic acid methyl ester; 3) preparing 3S-2-Boc-Asp(OCH3)-tetrahydro-β-carboline-3-carboxylic acid methyl ester; 4) preparing 3S-2-Asp(OCH3)-tetrahydro-β-carboline-3-carboxylic acid methyl ester; 5) preparing acetylmethyl ester-substituted tetra-cyclic compound; 6) preparing acetic acid-substituted tetra-cyclic compound; 7) preparing tetra-cyclic compound substituted with -CH2CO-Ser-OBzl, -CH2CO-Glu-OBzl, -CH2CO-Lys-OBzl and -CH2CO-Tyr-OBzl; 8) preparing tetra-cyclic compound substituted with -CH2CO-Ser, -CH2CO-Glu, -CH2CO-Lys- and -CH2CO-Tyr.

3. Use of the tetra-cyclic compound of claim 1 in the preparation of a drug for selectively inhibiting adenosine diphosphate.

4. Use of the tetra-cyclic compound of claim 1 in the preparation of a drug for selectively inhibiting adenosine diphosphate-induced platelet aggregation.

5. Use of the tetra-cyclic compound of claim 1 in the preparation of an anti-arterial thrombosis drug. ​ ​

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