CN102199163A - 2-hydroxy tetrahydrothiophene derivative, preparation method thereof and application thereof in pharmacy - Google Patents

Abstract

The invention discloses a series of 2-hydroxy tetrahydrothiophene derivatives, a preparation method thereof and application thereof in pharmacy; and the derivatives are compounds shown in the formula I. The experimental results of pharmacodynamics show that the compounds I in the formula I have obvious effect of inhibiting the congregation of blood platelets; the aggregation effect of blood platelet resistance of most of compounds is obviously better than that of clopidogrel; and the activity of individual compound is stronger than prasugrel. The compounds in the formula I can be used for preparing medicines for preventing or treating related diseases such as thrombus and embolism. The invention also provides a preparation method of the compounds in the formula I.

Description

2-Hydroxytetrahydrothienopyridine derivative and its preparation method and application in pharmacy

technical field

The invention relates to the field of medicinal chemistry, in particular to a series of 2-hydroxythienopyridine derivatives. The invention also discloses a preparation method and medical application of the above compounds.

Background technique

Myocardial infarction is one of the diseases with the highest fatality rate in the world today, and it is mainly caused by coronary artery thrombosis. After atherosclerotic plaque rupture causes endothelial injury, platelets will adhere to the subendothelial matrix and aggregate with each other to form a thrombotic obstructive surface, which will further cause vascular obstruction (Nature Reviews, 2010, 9, 154-169). In view of the key role played by platelets in the process of thrombus formation, the combined application of anti-platelet aggregation drugs aspirin and clopidogrel is considered to be the "standard treatment" for the clinical treatment of acute coronary syndrome, but clinical data show that 15%~ 40% of patients have no effect on this treatment, and such patients have a high possibility of thrombosis and myocardial infarction after stent placement (Circulation, 2000, 102, 624-629). Moreover, these two anti-platelet first-line drugs have some defects. First, aspirin, as the basic anti-platelet drug, has a long history, but there is a risk of recurrence, that is, some so-called "aspirin resistance (also known as aspirin treatment response variation) "In the patients who cannot effectively inhibit platelet aggregation, it is estimated that 5%-60% of those who take drugs (Mayo Clin Proc, 2006, 81:518-526). Clopidogrel, as the second-generation P2Y ₁₂ receptor antagonist, is the most widely used anti-platelet aggregation drug in the world. Clopidogrel is a prodrug, which undergoes two-step oxidative metabolism in the liver P450 enzyme system Produce active metabolites, active metabolites form covalent bonds with P2Y ₁₂ receptors on the surface of platelets, and inhibit platelet aggregation by antagonizing P2Y ₁₂ receptors. Clopidogrel has many clinical defects, including relatively long onset time (approx. 6h after taking the drug), the elimination time is longer (5-7 days), and there are large individual differences between patients (Circulation.2004; 109: 166-171), about 21% of patients have "clopidogrel resistance" Phenomenon.

Prasugrel is a third-generation P2Y ₁₂ receptor antagonist. It is also a prodrug that irreversibly inhibits P2Y ₁₂ receptors after being metabolized by liver CYP3A4 into an active product. Because prasugrel can be rapidly metabolized to form active metabolites, and the original structure of clopidogrel methyl ester is changed to carbonyl cyclopropane structure, which avoids the esterolysis effect of liver esterase, so its oral bioavailability is greater than that of clopidogrel Improvement (J Thromb Haemost. 2007, 5, 1545-51). Clinical trials have also proved that in healthy volunteers, patients with coronary heart disease and interventional surgery, prasugrel has faster, more sustained and stronger platelet inhibition than standard or higher doses of clopidogrel. Although prasugrel can inhibit platelet aggregation faster and more effectively, the stronger its antiplatelet effect is, the more likely it is to cause bleeding. In the phase III clinical TRITON-TIMI38 trial of 13,608 intermediate-risk to high-risk patients who planned to undergo coronary intervention therapy, the incidence of major bleeding in the prasugrel group was 2.4 higher than that in the clopidogrel treatment group. % vs. 1.8%; and life-threatening bleeding was also higher in the prasugrel group, 1.4% vs. 0.9% (P=0.01), which included nonfatal bleeding (1.1% vs. 0.9%, P=0.23) and fatal bleeding (0.4% vs. 0.1%, P=0.002), therefore, in the elective interventional treatment of acute coronary syndrome, prasugrel can significantly reduce the incidence of ischemic events, including stent thrombosis, compared with clopidogrel, but its Increased risk of bleeding (N Eng J Med.2007357(20):2001-2015). Other adverse reactions of prasugrel are thrombocytopenia and neutropenia.

Patents US4051141, US4075215, US4529596, and US5288726 all disclose a series of tetrahydrothienopyridine compounds, which have the ability to inhibit platelet aggregation. Patent US5288726 discloses prasugrel and its structural analogues, and discloses the activity and preparation method of prasugrel pharmaceutical salts in patents WO2004098713A2 and WO2006135605A2, and states that the activity of prasugrel pharmaceutical salts is stronger than that of prasugrel Gray's free base, but the article also points out that prasugrel hydrochloride is easily degraded and oxidized, which requires higher conditions in its preparation process, including temperature, humidity, inert gas environment, etc. And the storage process brings great difficulties. Based on the above defects, the development of anti-platelet aggregation drugs that can reduce coronary thrombosis and avoid bleeding side effects, and are chemically stable and convenient for industrial production is the current focus of the development of this type of drugs.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the above-mentioned deficiencies of clopidogrel and prasugrel, to design and synthesize various ester derivatives of novel 2-hydroxytetrahydrothienopyridines, so as to develop new 2-hydroxytetrahydrothienopyridine derivatives with good curative effect, small side effects and A stable anti-platelet aggregation drug.

The invention discloses a series of compounds of the general formula I and pharmaceutically acceptable salts and solvates thereof. The compounds shown have a good effect of inhibiting platelet aggregation.

Wherein, ^R represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile, nitro, amino, amido, sulfonylamino, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy , carboxyl, methoxyl, ethoxyl, straight or branched alkyl, alkenyl or alkynyl with 1 to 6 carbons;

^R2 represents C1～C6 alkyl, C3～C7 cycloalkyl, C1～C4 alkoxy, C3～C7 cycloalkoxy;

R ³ is an unsubstituted or X-substituted linear or branched alkyl group of 1 to 10 carbons, OR ⁴ , NR ⁵ R ⁶ , phenyl, Y-substituted phenyl, styryl, 4-hydroxybenzene Vinyl, 4-hydroxy-3-methoxystyryl, 3-pyridyl, alkenyl or alkynyl; where X is fluorine, chlorine, bromine, iodine, nitrile, nitro, amino, amido, sulfonyl Amylamino, trifluoromethyl, mercapto, hydroxy, acetoxy, methoxy, ethoxy, carboxyl, methoxyacyl, ethoxyacyl, aryloxy, phenyl, or Y-substituted phenyl; Y is fluorine , chlorine, bromine, iodine, nitrile, nitro, amino, amido, sulfonylamino, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxyl or ethyl Oxyacyl, and the Y group is at the 2, 3 or 4 position of the benzene ring;

并且当R1为氟或氯时，同时R2为环丙烷或乙烷时，R4不为叔丁基。R ⁴ is a straight chain or branched chain alkyl or benzyl group with 1 to 10 carbons; R ⁵ and R ⁶ are straight or branched chain alkyls with 1 to 6 carbons, or NR ⁵ R ⁶ is

And when R1 is fluorine or chlorine, and R2 is cyclopropane or ethane, R4 is not tert-butyl.

In the compound of formula I of the present invention, R ¹ is preferably 2-fluoro, 2-chloro, 2-bromo, 2-nitrile or 2-trifluoromethyl.

In the compound of formula I of the present invention, R ¹ is more preferably 2-fluoro, 2-chloro.

Preferred ^R in the compound of formula I of the present invention is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclopropyl Each of butoxy and cyclohexyl can be substituted by one or more halogen atoms.

In the compound of formula I of the present invention, R ² is more preferably ethyl, cyclopropyl, methoxy.

In the compound of formula I of the present invention, R ³ is preferably OR ⁴ , NR ⁵ R ⁶ , R ⁴ is a straight chain or branched chain alkyl or benzyl group with 1 to 6 carbons; R ⁵ and R ⁶ are 1 to 6 carbons Straight chain or branched chain alkyl, or NR ⁵ R ⁶ is

In the compound of formula I of the present invention, R ³ is more preferably OR ⁴ , NR ⁵ R ⁶ , R ⁴ is methyl, ethyl, isopropyl, isobutyl, n-hexyl, benzyl; R ⁵ and R ⁶ are methyl , Ethyl.

Preferred compounds of the present invention are as follows:

2-Methoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-1;

2-Ethoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-2;

2-isopropoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-3;

2-isobutoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-4;

2-tert-butoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-5;

2-n-hexyloxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-6;

2-Benzyloxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-7;

2-N,N-Dimethylaminocarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-8.

The compound of the present invention also includes the pharmaceutically acceptable salt of the compound of formula I, including but not limited to the acid addition salt formed by the compound of the present invention and the following acids: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid , acetic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, pamoic acid (pamoic acid), oxalic acid, or succinic acid.

Another object of the present invention is to provide the preparation method of 2-hydroxytetrahydrothienopyridine derivative formula I compound, following reaction formula:

method 1)

Specifically include the following steps:

(1) the compound of formula II reacts with the compound of formula III or its salt (their molar ratio is 1:2～2:1) in the presence of alkali (consumption is 1～10 equivalents of the compound of formula II), and obtains the compound of formula IV or its salt, the solvent used is selected from benzene, toluene, chloroform, n-hexane, cyclohexane, methylene chloride, 1,2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate A mixed solvent of one or more of esters, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, ether, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide, preferably N, N-dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane; the base used can be triethylamine, diisopropylethylamine, 1,8-diazacyclo[5,4,0]undeca En-7, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate; the reaction temperature is from minus 20°C to 100°C, preferably from 10°C to 60°C; the salt of the compound of formula III is selected from its hydrochloride, para Tosylate, acetate, sulfate, phosphate, trifluoromethanesulfonate, oxalate, methanesulfonate, benzenesulfonate or hydrobromide, the preparation of the compound of formula III can refer to the patent US4740510 .

(2) compound of formula IV or its salt and compound of formula V (their mol ratio is 1: 1～1: 10) react under the presence of alkali (consumption is 1～10 equivalents of compound of formula IV), obtain the compound of formula I The reaction solvent adopted is selected from benzene, toluene, chloroform, n-hexane, cyclohexane, methylene chloride, 1,2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate, propyl acetate A mixed solvent of one or more of esters, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, ether, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide, preferably tetrahydrofuran, acetonitrile or N, N-dimethylformamide; the base used is selected from triethylamine, sodium hydride, potassium hydride, 1,8-diazacyclo[5,4,0]undecene-7, pyridine, diisopropyl ethylamine, lithium diisopropylamide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium tert-butoxide or sodium tert-butoxide; the reaction temperature is minus 20°C to 100°C, preferably 0°C to 50°C.

In the above reaction formula, R ¹ , R ² , and R ³ are as defined in the compound of formula I above; X is a halogen atom.

method(2)

Specifically include the following steps:

The compound of formula II reacts with the compound of formula VI or its salt in the presence of alkali to obtain the compound of formula I. The solvent used is selected from benzene, toluene, chloroform, normal hexane, hexanaphthene, dichloromethane, 1,2-dichloro Ethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, diethyl ether, acetonitrile, N,N-dimethylformamide or di Methylsulfoxide or a mixed solvent of one or more of them, preferably N, N-dimethylformamide, tetrahydrofuran, acetonitrile or methylene chloride; the base used is selected from triethylamine, diisopropylethyl Amine, 1,8-diazacyclo[5,4,0]undecene-7, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate; the reaction temperature is minus 20°C to 100°C, the preferred temperature is 10°C to 60°C; the salt of the compound of formula VI is selected from its hydrochloride, p-toluenesulfonate, acetate, sulfate, phosphate, trifluoromethanesulfonate, oxalate, methanesulfonate, besylate or hydrobromide;

In the above reaction formula, R ¹ , R ² , R ³ and X are as defined in the compound of formula I and formula II above. The preparation of the compound of formula VI or its salt can be carried out with reference to the method of patent US5190938.

The preparation of the enantiomers of the compound of general formula I of the present invention can be carried out with reference to the above method (1) and method (2).

Another object of the present invention is to provide the use of the 2-hydroxytetrahydrothienopyridine derivative compound of formula I in pharmacy. The results of pharmacodynamic experiments show that the compound of the general formula I of the present invention has a significant inhibitory effect on platelet aggregation, and the anti-platelet aggregation effect of some compounds is obviously better than that of clopidogrel. The above experimental results suggest that the compound of the present invention or a pharmaceutically acceptable salt thereof can be used for the preparation of drugs for the prevention or treatment of thrombosis and embolism-related diseases, especially for the preparation of prevention or treatment of atherosclerotic diseases, myocardial infarction, stroke, Drugs for ischemic cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or thrombosis after coronary intervention.

Description of drawings

Fig. 1 is the proton nuclear magnetic resonance spectrum of compound I-1;

Fig. 2 is the proton nuclear magnetic resonance spectrum of compound 1-2;

Fig. 3 is the proton nuclear magnetic resonance spectrum of compound 1-3;

Fig. 4 is the proton nuclear magnetic resonance spectrum of compound I-4;

Fig. 5 is the proton nuclear magnetic resonance spectrum of compound 1-6;

Fig. 6 is the proton nuclear magnetic resonance spectrum of compound I-7;

Fig. 7 is the proton nuclear magnetic resonance spectrum of compound 1-8;

Detailed ways

The content of the present invention is specifically described below by way of examples. In the present invention, the following examples are for better illustration of the present invention, and are not intended to limit the scope of the present invention.

Example 1

5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-2-oxo-2,4,5,6,7,7a-hexahydrothieno[3,2-c]pyridine (IV-1)

(5.4g, 0.02mol) of α-cyclopropylcarbonyl-2-fluorobenzyl bromide (II-1) and (4.5g, 0.02mol) of 2-oxo-2,4,5,6,7,7a - Hexahydrothieno[3,2-c]pyridine hydrochloride (III-1) into a 250mL reaction flask, add 100mL CH ₃ CN as a solvent, add KHCO ₃ (5.1g, 0.05mol), in a nitrogen protected Stirring at 40°C for 24 hours under the same conditions, the TLC detection reaction was almost complete, the reaction solution was poured into 500mL water, extracted with ethyl acetate (3×50mL), dried over anhydrous sodium sulfate, evaporated to dryness to obtain a crude product, and flash column chromatography Analysis (petroleum ether: ethyl acetate = 4:1) gave 3.2 g (IV-1) of light yellow oil, yield: 48%. ¹ H-NMR (300MHz, CDCl ₃ ) δppm: 0.82～0.90(m, 2H), 1.03～1.07(m, 2H), 1.21～1.26(m, 1H), 1.86～2.01(m, 1H), 2.04～ 2.15(m, 1H), 2.28～2.40(s, 1H), 2.49～2.57(m, 1H), 2.84～3.10(m, 2H), 3.89～3.97(m, 1H), 4.85(d, 1H, J =8.04MHz), 6.03(d, 1H, J=6.24MHz), 7.12～7.40(m, 4H); ¹³ C-NMR (75MHz, CDCl ₃ ) δppm: 11.69, 12.14, 18.75, 33.78, 48.61, 50.94, 53.15, 70.89, 115.84, 124.55, 126.72, 130.49, 130.83, 159.64, 162.92, 167.36, 198.60, 206.73. ESI-MS m/z: 332.2[M+H] ⁺ .

Example 2

2-Methoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I-1)

(110 mg, 0.33 mmol) of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3, 2-c] Pyridine-2(4H)-one (IV-1) was added to a 10mL reaction flask, 5mL CH ₃ CN was added as a solvent, and (168μL, 1.2mmol) triethylamine was added, stirred at room temperature for 10min, and the reaction The system was lowered to 0°C, slowly added (93.5 μL, 1.2 mmol) of methyl chloroformate (V-1) dropwise at this temperature, after the dropwise addition was completed, it was allowed to rise to room temperature naturally, stirred at room temperature for 3 h, and detected by TLC The reaction was basically completed, and the reaction solution was poured into 30 mL of saturated _NaHCO solution, extracted with ethyl acetate (3×15 mL), dried over anhydrous sodium sulfate, evaporated to dryness to obtain a crude product, and subjected to flash column chromatography (petroleum ether: ethyl acetate ester = 8:1) to obtain a transparent oily substance, which was ground in diethyl ether to obtain 90 mg of a white solid, mp: 127°C-128°C, yield: 69.7%. ¹ H-NMR (300MHz, CDCl ₃ ) δppm: 0.82～0.87(m, 2H), 0.95～1.07(m, 2H), 2.22～2.26(m, 1H), 2.81(m, 3H), 2.92～2.95( m, 1H), 3.49～3.56(m, 2H), 3.90(s, 3H), 4.87(s, 1H), 6.30(s, 1H), 7.09～7.21(m, 2H), 7.30～7.37(m, 1H), 7.46～7.51 (m, 1H); ¹³ C-NMR (75MHz, CDCl ₃ ) δppm: 11.58, 12.14, 18.45, 24.81, 48.40, 50.37, 55.83, 71.27, 112.51, 115.73, 116.03, 124.49, 125.78, 130.10, 130.20, 150.53, 153.25, 159.69, 162.97, 207.14; ESI-MS m/z: 390.1[M+H] ⁺ , HRMS Calcd for C ₂₀ H ₂₁ FNO ₄ S[M+H] ⁺ m/z 390.1175 , found 390.1178.

Example 3

2-Ethoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I-2)

method 1:

Referring to Example 2, methyl chloroformate was replaced by ethyl chloroformate, separated by column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a colorless transparent oil, which was ground in ether to obtain White solid (I-2), mp: 89°C-90°C, yield: 70.2%. ¹ H-NMR (300MHz, CDCl ₃ ) δppm: 0.84～0.87(m, 2H), 1.04(m, 2H), 1.37(t, 3H, J=7.08MHz), 2.23(m, 1H), 2.82(m , 3H), 2.96(m, 1H), 3.57(m, 2H), 4.31(q, 2H, J=7.08MHz), 4.88(s, 1H), 6.29(s, 1H), 7.09～7.20(m, 2H), 7.30～7.34(m, 1H), 7.48～7.52(m, 1H); ¹³ C-NMR (75MHz, CDCl ₃ ) δppm: 11.59, 12.16, 14.09, 18.46, 24.76, 48.42, 50.37, 65.48, 71.23 , 112.36, 115.73, 124.55, 125.66, 129.21, 130.22, 130.77, 150.57, 152.57, 159.69, 162.97, 207.11; ESI-MS m/z: 404.1[M+H] ⁺ , HRMS Calcd for C ₂₁ H ₂₃ FNO ₄ S [M+H] ⁺ m/z 404.1332, found 404.1336.

Method 2:

100 mg (0.3 mmol) of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3,2- c] Pyridin-2(4H)-one (IV-1), 95mg (0.36mmol) 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-ylethoxycarbonyl ester salt Add salt (III-2) and 75.1mg (0.75mmol) potassium bicarbonate into a 10mL reaction flask, add 5mL CH ₃ CN as a solvent, protect the reaction system with nitrogen, stir at 40°C for 24h, TLC detection reaction is basically complete, The reaction solution was poured into 50 mL of water, extracted with ethyl acetate (3×10 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude product, which was separated by flash column chromatography (petroleum ether:ethyl acetate=8:1) to obtain A colorless transparent oil, which was ground in diethyl ether to obtain a white solid (I-2), mp: 89°C-90°C, yield: 40%.

Example 4

2-isopropoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I-3 )

Referring to Example 2, methyl chloroformate was replaced by isopropyl chloroformate, separated by column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a colorless transparent oil, which was ground in diethyl ether, A white solid (I-3) was obtained, mp: 120°C-122°C, yield: 79.3%. ¹ H-NMR (300MHz, CDCl ₃ ) δppm: 0.82～0.89(m, 2H), 0.99～1.07(m, 2H), 1.36(d, 6H, J=6.24MHz), 2.23(m, 1H), 2.82 ～2.95(m, 4H), 3.57(m, 2H), 4.88(s, 1H), 4.93～5.01(m, 1H), 6.29(s, 1H), 7.09～7.21(m, 2H), 7.26～7.37 (m, 1H), 7.47～7.52 (m, 1H); ¹³ C-NMR (75MHz, CDCl ₃ ) δppm: 11.61, 12.18, 18.43, 21.61, 24.79, 48.42, 71.28, 74.00, 112.21, 115.73, 116.03, 121.16 , 124.50, 125.59, 129.11, 130.09, 130.74, 150.56, 152.02, 159.67, 162.95, 207.28; ESI-MSm/z: 418.1[M+H] ⁺ , HRMS Calcd for C ₂₂ H ₂₅ FNO ₄ S[M+H] ⁺ m/z 418.1488, found418.1491.

Example 5

2-isobutoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I-4 )

Referring to Example 2, methyl chloroformate was replaced by isobutyl chloroformate and separated by column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a colorless transparent oil (I-4), yield: 35%. ¹ H-NMR (300MHz, CDCl ₃ ) δppm: 0.82～0.89(m, 2H), 0.93～0.99(m, 6H), 1.05～1.07(m, 2H), 1.89～2.08(m, 1H), 2.23( m, 1H), 2.82～2.95(m, 4H), 3.28(m, 2H), 3.56(m, 1H), 4.03(d, 2H, J=6.6MHz), 4.88(s, 1H), 6.30(s , 1H), 7.10～7.18(m, 2H), 7.21～7.31(m, 1H), 7.33～7.49(m, 1H); ¹³ C-NMR(75MHz, CDCl ₃ )δppm: 11.55, 12.12, 18.43, 18.78 , 19.13, 24.84, 27.71, 48.40, 50.39, 71.16, 75.38, 112.33, 115.71, 116.01, 124.47, 130.05, 130.71, 150.59, 152.74, 159.69, 162.97, 183.79, 204.19 H] ⁺ , HRMS Calcd for C ₂₃ H ₂₇ FNO ₄ S[M+H] ⁺ m/z 432.1645, found 432.1647.

Example 6

2-tert-butoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I-5 )

(150 mg, 0.45 mmol) of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3, 2-c] Pyridine-2(4H)-one (IV-1) was added to a 10mL reaction flask, 5mL N,N-dimethylformamide was added as a solvent, and (30mg, 0.75mmol) NaH was added at 0°C , the reaction system naturally rose to room temperature, stirred at room temperature for 0.5h, then added (300mg, 1.37mmol) di-tert-butyl dicarbonate (V-5) to the reaction system, stirred at room temperature for 3h, TLC detection reaction was substantially complete, The reaction solution was poured into 30 mL of ice water, extracted with ethyl acetate (3×15 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude product, which was obtained by flash column chromatography (petroleum ether:ethyl acetate=10:1) to obtain a transparent Oil 113 mg (I-5), yield: 58%. ¹ H-NMR (300MHz, CDCl ₃ ) δppm: 0.83～0.89(m, 2H), 1.03～1.09(m, 2H), 1.54(s, 9H), 2.23(m, 1H), 2.83～2.98(m, 4H), 3.60(m, 2H), 4.92(s, 1H), 6.28(s, 1H), 7.09～7.19(m, 2H), 7.21～7.31(m, 1H), 7.33～7.53(m, 1H) ; ¹³ C-NMR (75MHz, CDCl ₃ ) δppm: 11.68, 12.23, 18.51, 24.55, 27.40, 27.58, 48.46, 50.33, 71.08, 84.67, 112.01, 115.76, 116.06, 124.63, 130.34, 130.69, 1ES, 7; -MS m/z: 432.2[M+H] ⁺ , HRMS Calcd for C ₂₃ H ₂₇ FNO ₄ S[M+H] ⁺ m/z 432.1645, found 432.1658.

Example 7

2-n-hexyloxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I-6)

Referring to Example 2, methyl chloroformate was replaced by n-hexyl chloroformate, separated by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain a colorless transparent oil (I-6), yield: 82 %. ¹ H-NMR (300MHz, CDCl ₃ ) δppm: 0.84～0.91(m, 5H), 1.02～1.11(m, 2H), 1.25～1.39(m, 6H), 1.67～1.76(m, 2H), 2.23～ 2.26(m, 1H), 2.80～2.94(m, 4H), 3.48～3.60(m, 2H), 4.22～4.26(m, 2H), 4.86(s, 1H), 6.29(s, 1H), 7.08～ 7.20(m, 2H), 7.29～7.36(m, 1H), 7.46～7.51(m, 1H); ¹³ C-NMR(75MHz, CDCl ₃ ) δppm: 11.53, 12.10, 13.91, 18.38, 22.43, 24.90, 25.23 , 28.41, 30.28, 48.40, 50.41, 69.62, 71.38, 112.34, 115.70, 116.00, 124.47, 125.71, 130.08, 130.69, 150.52, 152.70, 159.68, 162.95, 207.36] [M4-MS m ⁺ , HRMS Calcd for C ₂₅ H ₃₁ FNO ₄ S[M+H] ⁺ m/z 460.1958, found 460.1955.

Example 8

2-Benzyloxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I-7)

Referring to Example 2, methyl chloroformate was replaced by benzyl chloroformate, separated by column chromatography (petroleum ether: ethyl acetate = 8: 1) to obtain a yellow transparent oil (I-7), yield: 9.5% . ¹ H-NMR (300MHz, CDCl ₃ ) δppm: 0.86～0.88(m, 2H), 1.06(m, 2H), 2.23(m, 1H), 2.82～2.95(m, 4H), 3.56(m, 2H) , 4.88(s, 1H), 5.27(s, 2H), 6.31(s, 1H), 7.10～7.49(m, 9H); ¹³ C-NMR(75MHz, CDCl ₃ ) δppm: 11.61, 12.18, 18.44, 24.83 ，48.40，50.37，70.94，112.47，115.73，124.53，126.17，126.95，128.45，128.49，128.62，128.69，128.90，129.02，130.14，130.38，130.71，130.91，152.60，159.67，162.95；ESI-MS m/z： 466.1[M+H] ⁺ , HRMS Calcd for C ₂₆ H ₂₅ FNO ₄ S[M+H] ⁺ m/z 466.1488, found 466.1486.

Example 9

2-N,N-Dimethylaminocarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (I-8)

(150 mg, 0.45 mmol) of 5-(2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl)-5,6,7,7a-tetrahydrothieno[3, 2-c] Pyridine-2(4H)-one (IV-1) was added to a 10mL reaction flask, 5mL N,N-dimethylformamide was added as a solvent, and (30mg, 0.75mmol) NaH was added at 0°C , the reaction system naturally rose to room temperature, stirred at room temperature for 0.5h, slowly added dropwise N,N-dimethylformyl chloride (128μL, 2.0mmol) (V-8), stirred at room temperature for 3h, TLC detection reaction was basically completed, The reaction solution was poured into 30 mL of ice water, extracted with ethyl acetate (3×15 mL), dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude product, which was obtained by flash column chromatography (petroleum ether:ethyl acetate=5:1) to obtain a transparent The oil was triturated in diethyl ether to obtain 105 mg of white solid (I-8), mp: 108°C-109°C, yield: 57.7%. ¹ H-NMR (300MHz, CDCl ₃ ) δppm: 0.79～0.91(m, 2H), 0.99～1.07(m, 2H), 2.24～2.33(m, 1H), 2.80～2.94(m, 4H), 3.02( d, 6H, J=14.49MHz), 3.49～3.61(m, 2H), 4.85(s, 1H), 6.20(s, 1H), 7.08～7.20(m, 2H), 7.27～7.36(m, 1H) , 7.49～7.54 (m, 1H); ¹³ C-NMR (75MHz, CDCl ₃ ) δppm: 11.50, 12.11, 18.29, 24.86, 36.36, 36.87, 48.49, 50.32, 71.43, 111.67, 115.67, 115.98, 124.42, 125.2 130.02, 130.63, 151.12, 153.53, 159.69, 162.96, 207.47. ESI-MSm/z: 403.1[M+H] ⁺ , HRMS Calcd for C ₂₁ H ₂₄ FN ₂ O ₃ 8[M+H] ⁺ m/z 403.1492 , found 403.1495

Example 10

Antiplatelet Aggregation Activity Test

Drugs and preparations: the positive drugs were clopidogrel sulfate and prasugrel free base. The positive drug and the test compound were formulated into a suspension with 0.5% CMC-Na (sodium carboxymethylcellulose) for administration to animals.

0.5% carboxymethyl cellulose, China Pharmaceutical (Group) Shanghai Chemical Reagent Company.

ADP, Sigma, USA.

Animals: Wistar rats, 200-250g, male, provided by the Experimental Animal Center of Shandong University, certificate of conformity:

SCXK (Lu) 20090001

Instrument: platelet aggregation analyzer (560Ca), CHRONO-LOG, USA

Method: Referring to the BORN nephelometric method (Nature, 1962, 194(4832): 927), the compound of the present invention (prepared in the above examples) was tested for its anti-platelet aggregation pharmacological activity. The clumping agent adenosine diphosphate (ADP) is added to platelet-rich plasma (PRP) and stirred to allow platelets to aggregate. Aggregation of platelets causes a change in optical density, which can be detected by a spectrophotometer. This assay can evaluate platelet aggregation induced by in vivo or in vitro administration of a test compound.

Anti-platelet aggregation activity test: the rats were randomly divided into groups, and the test compound (suspended with 0.5% carboxymethyl cellulose before use) was administered by intragastric administration, and the dose was 3 mg/kg, and the blank control group was administered orally with the same volume 0.5% CMC-Na. After 2 hours, blood was taken from the abdominal aorta (anesthetized by intraperitoneal injection of pentobarbital sodium), anticoagulated with 3.8% sodium citrate, the ratio of whole blood to anticoagulant was 9:1, and centrifuged at 1000rpm for 7min to prepare platelet-rich plasma ( PRP). Adjust PRP with platelet-poor plasma (PPP) to keep the platelet count at 2×10 ⁶ /ml. Add PRP into the test cup, incubate at 37°C for 10min, adjust to zero with PRP, adjust to 100% with PPP, use ADP (final concentration: 5μM) as the inducer, and measure the platelet aggregation percentage with a platelet aggregometer according to the turbidimetric method, and use t- Test for statistical comparison. The inhibition rate of platelet aggregation was calculated according to the following formula: inhibition rate of platelet aggregation (%)=[1-(aggregation percentage of administration tube/aggregation percentage of control tube)]×100%.

The results (see Table 1) showed that most of the tested compounds showed stronger anti-platelet aggregation activity than clopidogrel, and some compounds had stronger activity than prasugrel. It shows that the novel antiplatelet compound provided by the present invention has good development prospects.

Table 1. Inhibition of platelet aggregation after oral administration of test compounds in rats

Claims (10)

1. 2-hydroxytetrahydrothienopyridine derivatives shown in formula I and pharmaceutically acceptable salts thereof:

Wherein, ^R represents hydrogen, fluorine, chlorine, bromine, iodine, nitrile, nitro, amino, amido, sulfonylamino, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy , carboxyl, methoxyl, ethoxyl, straight or branched alkyl, alkenyl or alkynyl with 1 to 6 carbons; R ² represents C1～C6 alkyl, C3～C7 cycloalkyl, C1～C4 alkoxy, C3～C7 cycloalkoxy; R ³ represents unsubstituted or X-substituted linear or branched chain alkyl with 1 to 10 carbons, OR ⁴ , NR ⁵ R ⁶ , phenyl, Y-substituted phenyl, styryl, 4-hydroxystyrene Base, 4-hydroxy-3-methoxystyryl, 3-pyridyl, alkenyl or alkynyl; where X is fluorine, chlorine, bromine, iodine, nitrile, nitro, amino, amido, sulfonyl Amino, trifluoromethyl, mercapto, hydroxyl, acetoxy, methoxy, ethoxy, carboxyl, methoxyl, ethoxyl, aryloxy, phenyl or Y-substituted phenyl; Y is fluorine, Chlorine, bromine, iodine, nitrile, nitro, amino, amido, sulfonylamino, trifluoromethyl, mercapto, hydroxy, acetoxy, methoxy, ethoxy, carboxyl, methoxyl, or ethoxy Acyl, and the Y group is at the 2, 3 or 4 position of the benzene ring; R ⁴ represents a straight chain or branched chain alkyl group or benzyl group with 1 to 10 carbons; R ⁵ and R ⁶ are straight chain or branched chain alkyl groups with 1 to 6 carbons, or NR ⁵ R ⁶ is And when R1 is fluorine or chlorine, and R2 is cyclopropane or ethane, R4 is not a tert-] group. 2. according to the 2-hydroxy tetrahydrothienopyridine derivatives of claim 1, it is characterized in that, in the compound of formula I, ^R is fluorine, chlorine, bromine, nitrile or trifluoromethyl; ^R is methyl , ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclohexyl, methoxy, ethoxy, isopropoxy, cyclopropoxy, cyclobutoxy, cyclohexyloxy, each group Can be substituted by one or more halogen atoms; R ³ is OR ⁴ , NR ⁵ R ⁶ , R ⁴ is straight chain or branched chain alkyl or benzyl with 1 to 6 carbons; R ⁵ and R ⁶ are 1 to 6 straight-chain or branched-chain alkyl of carbons, or NR ⁵ R ⁶ is

3. according to the 2-hydroxy tetrahydrothienopyridine derivatives of claim 1, it is characterized in that, in described formula I compound R ¹ is fluorine, chlorine; R ² is ethyl, cyclopropyl, methoxy; R ² is ethyl, cyclopropyl, methoxy; R ³ is OR ⁴ , NR ⁵ R ⁶ , R ⁴ is methyl, ethyl, isopropyl, isobutyl, n-hexyl, benzyl; R ⁵ , R ⁶ is methyl, ethyl. 4. according to the 2-hydroxytetrahydrothienopyridine derivative according to any one of claims 1-3, it is characterized in that, said derivative comprises the pharmaceutically acceptable salt of formula I compound, comprises formula I compound and following Acid addition salts formed from acids: hydrochloric acid, hydrobromic acid, sulfuric acid, citric acid, tartaric acid, phosphoric acid, lactic acid, acetic acid, maleic acid, fumaric acid, malic acid, mandelic acid, methanesulfonic acid, benzenesulfonic acid, p- Toluenesulfonic acid, pamoic acid (pamoic acid), oxalic acid, or succinic acid. 5. 2-hydroxytetrahydrothienopyridine derivatives according to claim 1, characterized in that said derivatives comprise the following compounds: 2-Methoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-1; 2-Ethoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-2; 2-isopropoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-3; 2-isobutoxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-4; 2-n-hexyloxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-6; 2-Benzyloxycarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-7; 2-N,N-Dimethylaminocarbonyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine I-8. 6. the preparation method of 2-hydroxytetrahydrothienopyridine derivative as claimed in claim 1, following reaction formula: Specifically include the following steps: (1) the compound of formula II reacts with the compound of formula III or its salt (their molar ratio is 1:2～2:1) in the presence of alkali (consumption is 1～10 equivalents of the compound of formula II), and obtains the compound of formula IV or its salt, the solvent used is selected from benzene, toluene, chloroform, n-hexane, cyclohexane, methylene chloride, 1,2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate A mixed solvent of one or more of esters, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, ether, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide, preferably N, N-dimethylformamide, tetrahydrofuran, acetonitrile or dichloromethane; the base used can be triethylamine, diisopropylethylamine, 1,8-diazacyclo[5,4,0]undeca En-7, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate; the reaction temperature is from minus 20°C to 100°C, preferably from 10°C to 60°C; the salt of the compound of formula III is selected from its hydrochloride, para Tosylate, acetate, sulfate, phosphate, trifluoromethanesulfonate, oxalate, methanesulfonate, benzenesulfonate or hydrobromide, the preparation of the compound of formula III can refer to the patent US4740510 . (2) compound of formula IV or its salt and compound of formula V (their mol ratio is 1: 1～1: 10) react under the presence of alkali (consumption is 1～10 equivalents of compound of formula IV), obtain the compound of formula I The reaction solvent adopted is selected from benzene, toluene, chloroform, n-hexane, cyclohexane, methylene chloride, 1,2-dichloroethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate, propyl acetate A mixed solvent of one or more of esters, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, ether, acetonitrile, N,N-dimethylformamide or dimethyl sulfoxide, preferably tetrahydrofuran, acetonitrile or N, N-dimethylformamide; the base used is selected from triethylamine, sodium hydride, potassium hydride, 1,8-diazacyclo[5,4,0]undecene-7, pyridine, diisopropyl ethylamine, lithium diisopropylamide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, potassium tert-butoxide or sodium tert-butoxide; the reaction temperature is minus 20°C to 100°C, preferably 0°C to 50°C; In the above reaction formula, R ¹ , R ² , and R ³ are as defined in the compound of formula I above; X is a halogen atom. 7. the preparation method of 2-hydroxytetrahydrothienopyridine derivative formula I compound as claimed in claim 1, following reaction formula:

Include the following steps: The compound of formula II reacts with the compound of formula VI or its salt in the presence of alkali to obtain the compound of formula I. The solvent used is selected from benzene, toluene, chloroform, normal hexane, hexanaphthene, dichloromethane, 1,2-dichloro Ethane, methyl tert-butyl ether, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, methanol, ethanol, acetone, tetrahydrofuran, diethyl ether, acetonitrile, N,N-dimethylformamide or di Methylsulfoxide or a mixed solvent of one or more of them, preferably N, N-dimethylformamide, tetrahydrofuran, acetonitrile or methylene chloride; the base used is selected from triethylamine, diisopropylethyl Amine, 1,8-diazacyclo[5,4,0]undecene-7, potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate; the reaction temperature is minus 20°C to 100°C, the preferred temperature is 10°C to 60°C; the salt of the compound of formula VI is selected from its hydrochloride, p-toluenesulfonate, acetate, sulfate, phosphate, trifluoromethanesulfonate, oxalate, methanesulfonate, besylate or hydrobromide; In the above reaction formula, R ¹ , R ² , R ³ and R ⁷ are as defined in the compound of formula I and formula II above. 8. Use of the 2-hydroxytetrahydrothienopyridine derivative according to any one of claims 1-3 in the preparation of medicines for preventing or treating thrombosis and embolism-related diseases. 9. purposes as claimed in claim 8, is characterized in that, is used for the preparation prevention or treatment atherosclerotic disease, myocardial infarction, apoplexy, ischemic cerebral thrombosis, peripheral arterial disease, acute coronary syndrome or coronary intervention Post-thrombotic drugs. 10. A pharmaceutical composition for preventing or treating thrombosis and embolism-related diseases, characterized in that the pharmaceutical composition contains a compound of formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

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