CN116947858A - Compounds selectively inhibiting four amino acid modifications of ADP, preparation and application thereof - Google Patents

Compounds selectively inhibiting four amino acid modifications of ADP, preparation and application thereof Download PDF

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CN116947858A
CN116947858A CN202310854644.6A CN202310854644A CN116947858A CN 116947858 A CN116947858 A CN 116947858A CN 202310854644 A CN202310854644 A CN 202310854644A CN 116947858 A CN116947858 A CN 116947858A
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张筱宜
杨一帆
赵明
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Capital Medical University
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Abstract

The invention discloses a four-amino acid modified tetracyclic compound capable of selectively inhibiting adenosine diphosphate, which has a structure shown in the specification, wherein amino acids represented by AA in the formula are L-Ser residues, L-Glu residues, L-Lys residues and L-Tyr residues respectively. Experiments prove that the adenosine diphosphate selective inhibitor has good anti-arterial thrombosis effect. Therefore, the invention provides an effective technical means for resisting arterial thrombosis.

Description

Compounds selectively inhibiting four amino acid modifications of ADP, preparation and application thereof
Technical Field
The present invention relates to four amino acid modified tetracyclic compounds that selectively inhibit adenosine diphosphate, to processes for their preparation and to their use in the treatment of arterial thrombotic disorders. Experiments prove that the adenosine diphosphate selective inhibitor has good anti-arterial thrombosis effect. The invention belongs to the field of biological medicine.
Background
Arterial embolism has become one of the diseases with high morbidity and mortality. Arterial thrombosis is responsible for transient ischemic attacks, acute coronary syndromes, myocardial infarction and atrial fibrillation. Between 18% and 47% of patients with atrial fibrillation suffer from coronary artery disease, and about 20% of patients with atrial fibrillation associated with coronary artery disease receive percutaneous coronary intervention. Arterial thrombosis is also responsible for prosthetic heart valves, arteriovenous fistulae and other post-operative arterial thrombosis and unstable angina. For example, following liver transplant surgery, the patient is at risk of arterial thrombosis of the liver. In addition, patients with antiphospholipid syndrome are also at risk of arterial thrombosis. Arterial thrombosis is associated with platelet aggregation. Inducers that generally induce platelet aggregation include Platelet Activating Factor (PAF), adenosine Diphosphate (ADP), thrombin (TH), and Arachidonic Acid (AA). The search for selective inhibitors of platelet activating factor, adenosine diphosphate, thrombin and arachidonic acid is an important direction in the study of anti-arterial thrombosis drugs. The inventors have screened in a study for a tetracyclic compound that selectively inhibits the amino acid modification of Adenosine Diphosphate (ADP)
The tetracyclic compounds show excellent anti-arterial thrombotic activity as demonstrated by data on the rat silk-method arterial thrombosis model. Based on these findings, the inventors have proposed the present invention.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a tetracyclic compound for selectively inhibiting amino acid modification of adenosine diphosphate. Experiments prove that the amino acid modified tetracyclic compound prepared by the invention has excellent anti-arterial thrombosis effect. In order to achieve the object, the present invention adopts the following technical means.
The first technical means is to provide the tetracyclic compound for selectively inhibiting the amino acid modification of adenosine diphosphate, wherein the structure of the compound is as follows:
wherein AA is an L-Ser residue, an L-Glu residue, an L-Lys residue or an L-Tyr residue.
The second technical means is to provide a method for preparing the amino acid modified tetracyclic compound, which comprises the following steps:
1 preparing 3S-tetrahydro-beta-carboline-3-carboxylic acid;
2 preparing 3S-tetrahydro-beta-carboline-3-carboxylic acid methyl ester;
3 preparation of 3S-2-Boc-Asp (OCH) 3 ) -tetrahydro- β -carboline-3-carboxylic acid methyl ester;
4 preparation of 3S-2-Asp (OCH) 3 ) -tetrahydro- β -carboline-3-carboxylic acid methyl ester;
5 preparing an acetylmethyl ester group substituted tetracyclic compound;
6 preparing an acetoxy substituted tetracyclic compound;
7 preparing acetyl-Ser-OBzl, acetyl-Glu-OBzl, acetyl-Lys-OBzl and acetyl-Tyr-OBzl substituted tetracyclic compound;
8 preparation of acetyl-Ser, acetyl-Glu, acetyl-Lys and acetyl-Tyr substituted tetracyclic compounds.
The third technical means provides the use of the amino acid modified tetracyclic compound as an Adenosine Diphosphate (ADP) selective inhibitor.
The fourth technical means is to confirm the selective inhibition of adenosine diphosphate-induced platelet aggregation by the acetamido-substituted tetracyclic compound.
The fifth technical means is to confirm the excellent inhibitory effect of the acetamido-substituted tetracyclic compound on arterial thrombosis.
Drawings
FIG. 1 is a synthetic scheme of amino acid modified tetracyclic compounds selectively inhibiting adenosine diphosphate i) CH 2 O,H 2 SO 4 ；ii)SOCl 2 ,CH 3 OH; iii) DCC, HOBt, N-methylmorpholine, boc-Asp (OMe); iv) ethyl acetate solution of hydrogen chloride 4N; v) CH 3 OH, N-methylmorpholine; vi) 2N NaOH, CH 3 OH；vii)H 2 Palladium on carbon.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention.
Example 1 preparation of 3S-tetrahydro-beta-carboline-3-carboxylic acid (1)
To 400mL of water was slowly added 0.2mL of concentrated sulfuric acid. To the resulting aqueous dilute sulfuric acid solution was added 5.0g (24.5 mmol) of L-Trp, and the solution was sonicated until the L-Trp was completely dissolved. To the resulting solution was added 10mL of an aqueous formaldehyde solution having a concentration of 30% -40%. The reaction mixture was stirred at room temperature for 5-6 hours, and the disappearance of L-Trp was monitored by thin layer chromatography (ethyl acetate/diethyl ether, 20/1) to terminate the reaction. And (3) slowly dropwise adding concentrated ammonia water into the reaction solution, adjusting the pH to 6, and standing for 30-40 minutes. The precipitate formed was filtered off and washed with water, and the colorless solid filtered off was spread on a petri dish and dried in air to give 5.05g (95%) of the title compound as a colorless solid. ESI (m/e): 217[ M+H ]] + 。
Example 2 preparation of 3S-tetrahydro-beta-carboline-3-carboxylic acid methyl ester (2)
SOCl was slowly added to a solution of 3.3g (15 mmol) of 3S-tetrahydro-beta-carboline-3-carboxylic acid in methanol at 0deg.C 2 . The reaction mixture was stirred at 0deg.C for 6 hours, no HCl gas was released from the reaction mixture, and slow precipitation of solids was observed in the reaction mixture, and the disappearance of 3S-tetrahydro-beta-carboline-3-carboxylic acid was monitored by thin layer chromatography (ethyl acetate/diethyl ether, 20/1), and the reaction was terminated. The reaction solution was concentrated to dryness under reduced pressure. The residue was repeatedly washed with saturated aqueous sodium chloride solution and filtered to give 3.2g (92%) of the title compound as colorless powder. ESI (m/e) 231[ M+H ]] + 。
EXAMPLE 3 preparation of 3S- [2-Boc-Asp (OCH) 3 )]-tetrahydro-beta-carboline-3-carboxylic acid methyl ester (3)
At 0deg.C to 3.2g (13.9 mmol) of 3S-tetrahydro-beta-carboline-3-carboxylic acid methyl ester and 3.4g (13.9 mmol) of Boc-Asp (OCH) 3 ) And 150mL of anhydrous tetrahydrofuran was added 2.0g (14.8 mmol) of N-hydroxybenzotriazole (HOBt), 3.1g (14.8 mmol) of Dicyclohexylcarbodiimide (DCC). The reaction mixture was stirred for 30 minutes at 0 ℃. The pH was then adjusted to 8 with N-methylmorpholine (NMM). The reaction mixture was stirred for 6 hours at 0deg.C, and the disappearance of 3S-tetrahydro-beta-carboline-3-carboxylic acid methyl ester was monitored by thin layer chromatography (ethyl acetate/methanol, 20/1), and the reaction was terminated. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure toThe mixture was dried and the residue was dissolved in 200mL ethyl acetate. The resulting solution was washed with 5% aqueous sodium hydrogencarbonate (30 mL. Times.3), saturated aqueous sodium chloride (30 mL. Times.3), 5% aqueous hydrochloric acid (30 mL. Times.3) and saturated aqueous sodium chloride (30 mL. Times.3) in this order. 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 5.9g (93%) of the title compound as colorless powder. ESI (m/e) 460[ M+H ]] + 。
EXAMPLE 4 preparation of 3S- [2-Asp (OCH) 3 )]-tetrahydro-beta-carboline-3-carboxylic acid methyl ester (4)
5.9g (12.9 mmol) of 3S- [2-Boc-Asp (OCH) 3 )]-tetrahydro-beta-carboline-3-carboxylic acid methyl ester in 50mL of ethyl acetate solution of hydrogen chloride (4N), the reaction mixture was stirred at room temperature for 60 minutes. Thin layer chromatography (ethyl acetate/methanol, 20/1) gave 3S- [2-Boc-Asp (OCH) 3 )]-tetrahydro-beta-carboline-3-carboxylic acid methyl ester disappears, terminating the reaction. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 50mL of ethyl acetate and concentrated under reduced pressure. This operation was repeated 5 times to obtain 5.8g (98%) of the title compound as a colorless powder. ESI (m/e) 460[ M+H ]] + 。
EXAMPLE 5 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetic acid methyl ester (5)
4.10g (8.9 mmol) of 3S- [2-Asp (OCH) 3 )]The solution of methyl-tetrahydro-beta-carboline-3-carboxylate and 30mL ethyl acetate is stirred at 30 ℃ for 60 minutes to complete the cyclization reaction. 1.9g (70%) of the title compound are obtained as a colourless powder. ESI (m/e) 327[ M+Na ]] + 。
Example 6 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetic acid (6)
1.1g (3.6 mml) (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6 are reacted at 0 DEG C]Pyrido [3,4-b]Indole-1, 4-dione-3-acetic acid methyl ester was dissolved with 20mL of methanol, 2N aqueous sodium hydroxide solution was added dropwise to the solution to adjust the pH of the reaction solution to 12, the reaction solution was stirred for another 3 hours, and (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] was monitored by thin layer chromatography (ethyl acetate/methanol, 20/1)]Pyrido [3,4-b]Indole-1, 4-dione-3-acetic acid methyl ester disappeared, stopping the reaction. The reaction solution is diluted firstAdjusting pH to 2 with hydrochloric acid, and concentrating under reduced pressure. To the residue was added 50mL of distilled water, and the resulting mixture was extracted with ethyl acetate (30 mL. Times.3). The ethyl acetate extracts were combined and washed with saturated aqueous sodium chloride (30 mL. Times.3). The ethyl acetate extract was dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to obtain 0.91g (87%) of the title compound as colorless powder. R is R f =0.35 (dichloromethane/methanol, 5/1). MP 228-232 ℃.(c=0.5, methanol). ESI (m/e) 313[ M-H ]] - 。 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝11.04(s,1H),8.23(s,1H),7.44(d,J＝7.5Hz,1H),7.33(t,J＝7.5Hz,1H),7.06(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),5.38(d,J＝17.1Hz,1H),4.25(dd,J＝3.9Hz,J＝11.4Hz,1H),4.20(d,J＝17.1Hz,1H),4.16(d,J＝15.0Hz,1H),3.18(dd,J＝3.3Hz,J＝14.7Hz,1H),2.97(t,J＝13.5Hz,1H),2.51(d,J＝10.5Hz,2H)。 13 C NMR(75MHz,DMSO-d 6 ):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。
EXAMPLE 7 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetyl-Ser-OBzl (7 a)
Using the reaction conditions and operation of example 2, 570mg (1.82 mmol) of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6]Pyrido [3,4-b]Indole-1, 4-dione-3-acetic acid (6) and 672mg (1.82 mmol) Ser-OBzl gave 368mg (50%) of the title compound as colorless solid. ESI (m/e) 513[ M+Na ]] + 。
Example 8 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetyl-Glu-OBzl (7 b)
Using the reaction conditions and operation of example 2, 570mg (1.82 mmol) of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6]Pyrido [3,4-b]Indole-1, 4-dione-3-acetic acid (6) and 936mg (1.82 mmol) Glu-OBzl gave 1.08g (87%) of the title compound as colorless solid. ESI (m/e) 645[ M+Na ]] + 。
EXAMPLE 9 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetyl-Lys-OBzl (7 c)
Using the reaction conditions and operation of example 2, 570mg (1.82 mmol) of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6]Pyrido [3,4-b]Indole-1, 4-dione-3-acetic acid (6) and 987mg (1.82 mmol) Lys-OBzl gave 867mg (85%) of the title compound as a colorless solid. ESI (m/e) 544[ M+Na ]] + 。
Example 10 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetyl-Tyr-OBzl (7 d)
Using the reaction conditions and operation of example 2, 570mg (1.82 mmol) of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6]Pyrido [3,4-b]Indole-1, 4-dione-3-acetic acid (6) and 806mg (1.82 mmol) of Tyr-OBzl gave 435mg (53%) of the title compound as colorless solid. ESI (m/e) 589[ M+Na ]] + 。
EXAMPLE 11 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetyl-Ser (8 a)
80mg of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6]Pyrido [3,4-b]Indole-1, 4-dione-3-acetyl-Ser-OBzl (7 a) was dissolved in 15mL of methanol, 30mg of palladium on carbon was added, the reaction was continued with hydrogen for 2 hours, TLC detection of 7a disappeared, filtration, repeated washing of the cake with methanol, concentration of the filtrate under reduced pressure, and drying with diethyl ether to colorless powder, giving 48mg (88%) of the title compound as a colorless solid. R is R f =0.20 (dichloromethane/methanol, 5/1), mp 189-194 ℃.(c=0.5, methanol). ESI (m/e) 399.1299[ M-H ]] - 。IR(KBr):3327,2927,1625,1332,1126,744cm -1 。 1 HNMR(500MHz,DMSO-d 6 ):δ/ppm＝8.202(m,1H),8.173(m,1H),7.444(d,J＝7.5Hz,1H),7.340(d,J＝7.5Hz,1H),7.705(t,J＝8.0Hz,1H),6.996(d,J＝7.5Hz,1H),5.398(d,J＝16.5Hz,1H),4.270(m,2H),4.184(d,J＝17.0Hz,1H),3.618(m,1H),3.522(m,1H),3.160(m,1H),3.038(t,J＝14.0Hz,1H),2.756(m,2H)。 13 CNMR(125MHz,DMSO-d 6 ):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。
EXAMPLE 12 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetyl-Glu (8 b)
Using the reaction conditions and procedures of example 11, a reaction consisting of 100mg (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6]Pyrido [3,4-b]Indole-1, 4-dione-3-acetyl-Glu-OBzl gave 78mg (93%) of the title compound as a colorless solid. R is R f =0.35 (dichloromethane/methanol, 5/1), mp:172-176 ℃.(c=0.5, methanol). ESI (m/e) 441.1405[ M-H ]] - 。IR(KBr):3300,2953,1716,1643,1332,1203,744cm -1 。 1 HNMR(DMSO-d 6 ,300MHz):δ/ppm＝10.927(S,1H),8.210(m,2H),7.443(d,J＝7.8Hz,1H),7.333(d,J＝7.8Hz,1H),7.071(t,J＝7.5Hz,1H),6.990(t,J＝7.2Hz,1H),5.392(d,J＝16.8Hz,1H),4.206(m,4H),3.167(m,1H),3.007(m,1H),2.687(m,2H),2.226(t,J＝7.5Hz,2H),1.914(m,1H),1.783(m,1H)。 13 CNMR(75MHz,DMSO-d 6 ):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。
EXAMPLE 13 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetyl-Lys (8 c)
Using the reaction conditions and operation of example 11, a reaction consisting of 160mg (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6]Pyrido [3,4-b]Indole-1, 4-dione-3-acetyl-Lys-OBzl gave 130mg of the title compound as a colorless solid. R is R f =0.25 (dichloromethane/methanol, 5/1), mp:202 ℃.(c=0.5, methanol). ESI (m/e) 440.1928[ M-H ]] - 。IR(KBr):3348,2927,1647,1332,1004,744cm -1 。 1 H NMR(DMSO-d 6 ,300MHz):δ/ppm＝11.06(s,1H),8.314(d,J＝7.5Hz,1H),8.248(s,1H),7.944(s,3H),7.455(d,J＝7.5Hz,1H),7.341(d,J＝7.8Hz,1H),7.067(t,J＝7.5Hz,1H),6.986(t,J＝7.2Hz,1H),5.395(d,J＝16.8Hz,1H),4.256(m,2H),4.175(d,J＝16.5Hz,1H),4.103(m,1H),3.174(m,1H),3.046(t,J＝7.2Hz,1H),2.702(m,4H),1.580(m,4H),1.271(m,2H)。 13 CNMR(75MHz,DMSO-d 6 ):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。
EXAMPLE 14 preparation of (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6] pyrido [3,4-b ] indole-1, 4-dione-3-acetyl-Tyr (8 d)
Using the reaction conditions and procedures of example 11, a reaction consisting of 100mg (3S, 12 aS) -2,3,6,7,12 a-hexahydropyrazino [1',2':1,6]Pyrido [3,4-b]Indole-1, 4-dione-3-acetyl-Tyr-OBzl gave 60mg of the title compound as a colorless solid. R is R f =0.25 (dichloromethane/methanol, 5/1), mp 189-194 ℃.(c=0.5, methanol). ESI (m/e) 475.1612[ M-H ]] - 。IR(KBr):3307,2922,1643,1516,1332,1126cm -1 。 1 H NMR(DMSO-d 6 ,300MHz):δ/ppm＝10.971(s,1H),8.213(m,1H),7.450(d,J＝8.0Hz,1H),7.340(d,J＝8.0Hz,1H),7.076(t,J＝7.5Hz,1H),6.998(t,J＝7.5Hz,1H),6.934(d,J＝9.0Hz,2H),6.611(d,J＝9.0Hz,2H),5.387(d,J＝16.5Hz,1H),4.270(m,3H),4.175(d,J＝16.5Hz,1H),3.185(m,1H),3.023(m,1H),2.852(dd,J＝5.5Hz,J＝13.5Hz,1H),2.734(dd,J＝8.0Hz,J＝14.0Hz,1H),2.654(m,2H)。 13 CNMR(75MHz,DMSO-d 6 ):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。
Example 15 evaluation of anti-platelet aggregation Activity
Fresh pig carotid blood was anticoagulated with 3.8% sodium citrate (1/9 by volume). Platelet Rich Plasma (PRP) was obtained by centrifugation at 1000g for 10 min, and Platelet Poor Plasma (PPP) was obtained by centrifugation at 3000g for 10 min. Modulation of enrichment with platelet-poor plasmaPlatelet plasma, the number of platelets in platelet rich plasma is adapted to determine anti-platelet aggregation activity. 8a-d are dissolved in physiological saline. To the turbidimetric tube was added 0.24mL of conditioned platelet rich plasma, followed by 5. Mu.L of physiological saline solution or 8a-d of physiological saline solution (5. Mu.L, concentration 0.1. Mu.M, 10. Mu.M, 15. Mu.M, 20. Mu.M). The absorbance baseline was adjusted, and 5. Mu.L of physiological saline solution of four inducers was added to observe the maximum aggregation rate (Am) of platelets within 5 minutes. The four inducers were platelet activating factor (PAF, final concentration 50. Mu.M), adenosine diphosphate (ADP, final concentration 500. Mu.M), thrombin (TH, final concentration 50 IU/L) and arachidonic acid (AA, final concentration 7.5 mg/mL). The maximum aggregation rate is a value corresponding to the peak of the aggregation curve. Each concentration was measured in parallel 6 times to form a platelet aggregation curve. IC for inhibiting platelet-activating factor, adenosine diphosphate, thrombin and arachidonic acid induced platelet aggregation by 8a-d as determined from platelet aggregation curve 50 (see Table 1). The data in Table 1 show that 8a-d inhibits ADP-induced platelet aggregation IC 50 At minimum, 8a-d are selective inhibitors of ADP.
Tables 18 a-d IC inhibiting 4 inducer-induced platelet aggregation 50 (mean.+ -. SD, μM)
n＝6
EXAMPLE 16 evaluation of anti-arterial thrombotic Activity
1) Drawing a polyethylene tube into a thin tube with one end being a bevel, wherein the fixed length is 10.0cm, and the thin tube is respectively used for inserting a right jugular vein (with thicker tube diameter) and a left carotid artery (with thinner tube diameter); the length of the middle polyethylene tube is 8.0cm, the thrombus line is pressed in the carotid artery intubation direction, and heparin is filled in the tube before intubation.
2) Male SD rats weighing 200+ -20 g were acclimatized and fasted for one day prior to surgery. The animals were randomized into physiological saline groups (blank control, oral dose of 0.3mL/100g,10 rats), aspirin groups (positive control, oral dose of 167. Mu. Mol/kg,10 rats), and 8a-d physiological saline solution groups (oral dose of 1nmol/kg,10 rats). After 30 minutes of oral administration, the rats were anesthetized with 20% uratam solution (7 mL/kg) and surgery was started after 2 minutes. The method comprises the steps of lying a rat on the back on a fixed plate in an operation, cutting neck skin, separating a right common carotid artery and a left jugular vein, pressing down a wire for accurate weighing by a blood vessel, ligating a distal end, cutting a small opening at the distal end of the vein, inserting a cannula into the vein end, injecting heparin, then taking down a syringe for injecting heparin, tying a wire for fixing, clamping an artery proximal end by an artery clamp, cutting a small opening at the distal end of the artery, ligating the artery end, loosening the artery clamp after the tying is fixed, and establishing an extracorporeal circulation bypass. After 15 minutes of circulation, veins are cut off to observe whether blood circulation is normal, if blood circulation is normal, a silk thread with thrombus is taken out from an arterial end, non-coagulated blood is sucked by filter paper, the silk thread with thrombus is accurately weighed, the weight of the silk thread with thrombus is subtracted from the weight of the silk thread, and the weight of thrombus is obtained, and data are listed in Table 2.
TABLE 2 influence of 8a-d on arterial thrombosis in rats
a) The ratio p to physiological saline is less than 0.01; b) The ratio p with physiological saline is more than 0.05; n=10
The thrombus weights in the table indicate that 8a-d are effective in inhibiting arterial thrombosis in rats at 1nmol/kg oral dose (p <0.01 to normal saline). This is an unexpected technical effect.

Claims (5)

1. A tetracyclic compound selectively inhibiting amino acid modification of adenosine diphosphate, characterized in that the tetracyclic compound has the following structural formula,
wherein the amino acid represented by AA is selected from the group consisting of L-Ser residue, L-Glu residue, L-Lys residue and L-Tyr residue.
2. The tetracyclic compound of claim 1, wherein the process for preparing the compound comprises the steps of:
1) Preparing 3S-tetrahydro-beta-carboline-3-carboxylic acid;
2) Preparing 3S-tetrahydro-beta-carboline-3-carboxylic acid methyl ester;
3) Preparation of 3S-2-Boc-Asp (OCH) 3 ) -tetrahydro- β -carboline-3-carboxylic acid methyl ester;
4) Preparation of 3S-2-Asp (OCH) 3 ) -tetrahydro- β -carboline-3-carboxylic acid methyl ester;
5) Preparing an acetylmethyl ester group substituted tetracyclic compound;
6) Preparing an acetate substituted tetracyclic compound;
7) Preparing acetyl-Ser-OBzl, acetyl-Glu-OBzl, acetyl-Lys-OBzl and acetyl-Tyr-OBzl substituted tetracyclic compound;
8) Preparation of acetyl-Ser, acetyl-Glu, acetyl-Lys-and acetyl-Tyr substituted tetracyclic compounds.
3. The tetracyclic compound of claim 1 or 2, characterized by its use in a pharmaceutical agent for selectively inhibiting adenosine diphosphate.
4. The use of a tetracyclic compound according to claim 3, in a medicament for selectively inhibiting adenosine diphosphate-induced platelet aggregation.
5. The use of a tetracyclic compound according to claim 1 or 2, for the preparation of an anti-arterial thrombosis medicament.
CN202310854644.6A 2023-07-12 2023-07-12 Compounds selectively inhibiting four amino acid modifications of ADP, preparation and application thereof Pending CN116947858A (en)

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