CN102212068A - Thiophene derivative and its preparation method and application in medicine - Google Patents

Abstract

The invention relates to a medicinal compound, a preparation method thereof and application thereof in medicaments, in particular to a structural compound of a thiophene derivative shown as a formula or pharmaceutically acceptable salt and optical isomer thereof, and a medicinal composition containing the structural compound. The thiophene derivative compound has good antithrombotic effect and higher application value in the field of medicines.

Description

Thiophene derivative and its preparation method and application in medicine

technical field

The invention relates to a medicinal compound, its preparation method and application in medicine, in particular to a new class of thiophene derivatives, its preparation method and application.

Background technique

Cardiovascular and cerebrovascular diseases are common and frequently-occurring diseases that seriously endanger human health. With the aging of the social population, the incidence rate is increasing day by day. According to statistics, 16 million people around the world die from various cardiovascular and cerebrovascular diseases every year, which is the number one killer threatening human health.

Thromboembolism is one of the important factors leading to cardiovascular and cerebrovascular diseases. Coronary artery disease and its corresponding ischemic complications can cause a variety of clinical syndromes, such as stroke, myocardial infarction or peripheral arterial disease. The main cause is the formation of A blood clot blocks a blood vessel, causing severe ischemia. Thromboembolic diseases with coronary thrombosis and cerebral thrombosis as the core also have high morbidity and mortality in my country. Therefore, preventing thrombosis has become one of the most popular research topics in the field of cardiovascular diseases today. At present, there are three main categories of anticoagulant drugs, antiplatelet aggregation drugs and thrombolytic drugs used in clinical treatment of thrombotic diseases.

Adenosine diphosphate (ADP) is an important agonist for the activation of platelets and the amplification of aggregation effects. By blocking the ADP receptors to inhibit the action of platelets, it has become an important way to prevent pathological thrombosis (coronary heart disease, cerebrovascular disease, pulmonary embolism, thrombophlebitis). etc.) and myocardial infarction, unstable angina pectoris, peripheral vascular disease, congestive heart failure, etc., antiplatelet aggregation drugs as ADP receptor antagonists have received extensive attention from the medical community. The currently clinically used ADP receptor antagonists include ticlopyridine, clopidogrel and prasugrel, all of which have certain defects. Therefore, it is necessary to search for new compounds of this type.

US 4,529,596, US 4,740,510 and US 5,288,726 disclose compounds of similar structure.

Contents of the invention

The purpose of the present invention is to provide a new class of thiophene derivatives with antithrombotic effect and their

Pharmaceutically acceptable salts and optical isomers, the structural formula of which is shown in (I).

Wherein, R ₁ is: C ₁ -C ₃ alkyl;

R ₂ is: hydrogen, chlorine, fluorine;

R ₃ is: C ₁ -C ₄ alkyl.

In the present invention, a C ₁ -C ₃ alkyl group as a group or part of a group refers to a branched or straight chain alkyl group containing up to 3 carbon atoms, including methyl, ethyl, propyl, Isopropyl, preferably methyl, ethyl. C ₁ -C ₄ alkyl as a group or part of a group means a branched or straight chain alkyl group containing up to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl and tert-butyl, preferably methyl, ethyl.

In the present invention, the described thiophene derivatives are preferably:

α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-chlorophenylacetic acid methyl ester,

α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-chlorophenylacetic acid ethyl ester,

α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-fluorophenylacetic acid methyl ester,

α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-fluorophenylacetic acid ethyl ester,

α-(2-propionyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-phenylacetic acid methyl ester or

α-[2-Isobutyryloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl]-phenylacetic acid ethyl ester.

In the present invention, the pharmaceutically acceptable salts are thiophene derivatives and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, Organic acids such as maleic acid, maleic acid, lactic acid, malic acid, tartaric acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, picric acid or methanesulfonic acid, salts of acidic amino acids such as aspartic acid or glutamic acid .

The present invention also relates to a pharmaceutical composition, which comprises a therapeutically effective amount of the above-mentioned thiophene derivatives or their pharmaceutically acceptable salts, optical isomers and pharmaceutically acceptable carriers. In the present invention, the pharmaceutically acceptable carrier refers to the conventional drug carrier in the pharmaceutical field, such as diluent, excipient (such as water, etc.), binder (such as cellulose derivatives, gelatin, polyvinylpyrrolidone, etc. ), fillers (such as starch, etc.), disintegrating agents (such as calcium carbonate, sodium bicarbonate). In addition, other auxiliary agents, such as flavoring agents and sweetening agents, can also be added to the composition.

The pharmaceutical composition of the present invention can be administered orally to patients in need of treatment. For oral administration, it can be prepared into conventional solid preparations such as tablets or capsules. Various dosage forms of the pharmaceutical composition of the present invention can be prepared by conventional methods in the field of pharmacy, wherein the content of the active ingredient is 0.1-99.9%, preferably 0.5-90%.

A further object of the present invention is to provide the preparation method of the thiophene derivative of the present invention, specifically as follows:

In an organic solvent, in the presence of a basic catalyst, react the compound of general formula (II) with different acid anhydrides (R ₁ CO-O-COR ₁ ) to prepare the compound shown in formula (I);

The compound of general formula (II) can refer to existing method, is prepared by compound (III) and compound (IV) reaction such as:

In the above structural formula, R ₁ is: C ₁ -C ₃ alkyl;

R ₂ is: hydrogen, chlorine, fluorine;

R ₃ is: C ₁ -C ₄ alkyl.

The basic catalyst is one or both of organic base triethylamine and 4-dimethylaminopyridine.

The organic solvent is one of dichloromethane, chloroform and dimethylformamide.

The reaction temperature is 10°C-40°C.

In the above preparation method, compound (III) is a key raw material. You can buy its hydrochloride from the market, neutralize it with alkali or react it directly with its hydrochloride. The difference is that when directly reacting with its hydrochloride, the added amount (number of moles, mol) of the organic base is 1-1.2 times of its hydrochloride amount (number of moles, mol) III Preparation of free base: will buy The III hydrochloride, dissolved in water, adjusted the pH to alkaline with saturated potassium carbonate aqueous solution under cooling, extracted with dichloromethane, dried with a desiccant, and evaporated to exhaust the solvent under reduced pressure.

In the above-mentioned preparation method, the key intermediate compound (IV) can refer to the method provided by EP420706, EP465358 and J.Org.Chem.1968.33 (6): 2565-2566, synthesized according to the following route:

Specific operation:

Use ortho-substituted benzaldehyde (1) as raw material to obtain α-bromo-ortho-substituted phenylacetic acid (2), and then react with alcohol (R ₃ OH) to obtain α-bromo-ortho-substituted phenylethyl Ester (IV).

Compound III reacts with the compound of general formula (IV) to prepare the compound shown in formula (II), which is essentially the reaction of secondary amine and (substituted) bromoalkane to generate tertiary amine, which is a class of classic organic chemical reaction, similar to The reaction of has been reported in the literature, and it is used for the preparation of the compound shown in formula (II) after improvement.

The compound shown in (I) formula of the present invention reacts with inorganic acid or organic acid to generate salt with chemical conventional method, and the mol ratio of compound shown in (I) formula of the present invention and inorganic acid or organic acid is 1: 1-1.2, preferably equimolar, to prevent the residue of acid and affect the quality of salt. The solvent for salt formation is absolute ethanol, ethyl acetate, acetone, methanol, etc.

The compound of the formula (I) structure of the present invention contains a chiral carbon, in addition to directly forming a salt with a pharmaceutically acceptable organic acid or inorganic acid, it can be separated with a pharmaceutically acceptable organic acid or inorganic acid after resolution by an acidic resolving agent. Salt formation of accepted organic or inorganic acids is a common method in organic synthesis and is familiar to those skilled in the art. Acidic resolving agents include (-)-camphor-10-sulfonic acid, (+)-camphor-10-sulfonic acid, (+)-tartaric acid, etc. For example, α-(2-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-chlorophenylacetic acid methyl ester, the following iso Construct:

As another example, α-(2-acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-ethyl o-fluorophenylacetate is resolved into the following isomers body:

A further object of the present invention is to provide the application of the compound represented by formula (I) of the present invention or its pharmaceutically acceptable salts, optical isomers and mixtures thereof in the preparation of medicaments for treating thromboembolic diseases. In particular, these substances should be suitable for the effective prophylaxis and/or treatment of thromboembolic diseases and at least to some extent avoid the disadvantages of the prior art, wherein "thromboembolic diseases" are to be understood in the present invention in particular as serious diseases, Such as myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis.

The positive progress effect of the present invention is that: the thiophene derivatives shown in formula (I) and their pharmaceutically acceptable salts and optical isomers of the present invention have good antithrombotic effect or at least avoid to a certain extent The deficiencies known in the prior art, such as activity, toxicity, etc., were overcome.

Detailed ways

The present invention is further illustrated below by means of examples, but the invention is not therefore limited to the scope of the examples.

In the following method examples, the melting point of the compound is measured with a capillary melting point analyzer, and the thermometer is not calibrated; ¹ HNMR is measured by a VarianAM-400 nuclear magnetic resonance instrument, with TMS as the internal standard, and the chemical shift is expressed in δ (ppm); elemental analysis Measured by a PerKin-240C elemental analyzer (PerKin, USA); the mass spectrum was determined by a Q-TOF mass spectrometer; the specific rotation was determined by a Perkin Elmer P-341 polarimeter.

The silica gel used in column chromatography was produced by Qingdao Ocean Chemical Factory.

Comparative Example 1: α-bromo-o-chlorophenylacetic acid (2a)

Add 56.4g of o-chlorobenzaldehyde and 101g of tribromomethane into 120ml of isopropyl ether, add 100g of potassium hydroxide and 10g of an aqueous solution (350ml) of benzyltriethylamine chloride, lower the temperature, and react at -5°C-0°C for 25 hours , add 320ml of water and 200ml of isopropyl ether, stir for 30 minutes, stand still, separate the organic phase, extract the water layer three times with 60ml of isopropyl ether, acidify the water layer with concentrated hydrochloric acid, extract three times with 600ml of toluene, and combine the toluene layers , washed 3 times with water, 3×40ml, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 62.9 g of solid, with a yield of 50.3%. The obtained crude product was directly used in the next reaction without further purification.

The synthesis method of 2b-2c is the same as that described in Comparative Example 1, except that o-chlorobenzaldehyde is changed into: o-fluorobenzaldehyde and benzaldehyde.

2b: α-bromo-o-fluorophenylacetic acid, yield 61.8%.

2c: α-Bromophenylacetic acid, yield 54.5%.

Comparative Example 2: α-bromo-o-chlorophenylacetic acid methyl ester (IVa)

Dissolve 50 g of α-bromo-o-chlorophenylacetic acid in 190 ml of methanol, add 30 g of concentrated sulfuric acid, and reflux for 4 hours. After the reaction is complete, evaporate the solvent under reduced pressure, add 100 ml of isopropyl ether and 100 ml of water, separate the organic phase, and anhydrous Dry over sodium sulfate and concentrate under reduced pressure to obtain 47g of α-bromo-o-chlorophenylacetic acid methyl ester (IVa), yield 89%, ¹ HNMR (DMSO) δppm 7.71(d, 1H), 7.19-7.22(m, 3H) , 5.58(s, 1H), 3.69(s, 3H). The synthesis method of IVc and IVe is the same as that described in Comparative Example 2, except that α-bromo-o-chlorophenylacetic acid is changed to: α-bromo-o-fluorophenylacetic acid and α-bromo-phenylacetic acid.

The synthesis method of IVb is the same as that described in Comparative Example 2, except that methanol is changed to ethanol.

IVd, the synthetic method of IVf is the same as the method described in Comparative Example 2, only that α-bromo-o-chlorophenylacetic acid is changed to: α-bromo-o-fluorophenylacetic acid, α-bromophenylacetic acid, and methanol Change to ethanol.

IV b: ethyl α-bromo-o-chlorophenylacetate, the yield is 88.5%. ¹ H NMR (DMSO) δppm 7.70 (d, 1H), 7.18-7.23 (m, 3H), 5.56 (s, 1H), 4.23 (m, 2H), 1.32 (t, 3H).

IV c: methyl α-bromo-o-fluorophenylacetate, yield 91.7%. ¹ H NMR (DMSO) δ ppm 7.60 (m, 1H), 7.49 (d, 1H), 7.24 (d, 1H), 7.08 (s, 1H), 5.59 (s, 1H), 3.70 (s, 3H). .

IV d: ethyl α-bromo-o-fluorophenylacetate, yield 90.2%. ¹ H NMR (DMSO) δppm7.60 (m, 1H), 7.49 (d, 1H), 7.24 (d, 1H), 7.08 (s, 1H), 5.59 (s, 1H), 4.25 (m, 2H), 1.35 (t, 3H).

IV e: methyl α-bromophenylacetate, yield 87.1%. ¹ H NMR (DMSO) δppm 7.28-7.34 (m, 3H), 7.26 (m, 2H), 5.52 (s, 1H), 3.61 (s, 3H).

IV f: ethyl α-bromophenylacetate, yield 89.3%. ¹ H NMR (DMSO) δppm 7.28-7.34 (m, 3H), 7.26 (m, 2H), 5.52 (s, 1H), 4.19 (m, 2H), 1.26 (t, 3H).

Comparative Example 3: α-[2-oxo- _2,4,5,6,7,7a -hexahydrothieno[3,2-c]pyridin-5-yl]-o-chlorophenylacetic acid methyl ester (IIa)

Dissolve 30g of 2-oxo- _2,4,5,6,7,7a -hexahydrothieno[3,2-c]pyridine (III) in 300ml of methanol, and add 53g of α-bromo Methyl o-chlorophenylacetate (IIIa) and 24g sodium bicarbonate were heated to 80°C and reacted for 6 hours, cooled to room temperature, filtered to remove inorganic salts, evaporated the solvent under reduced pressure, added 450ml ethyl acetate and 250ml water, separated The organic layer was washed twice with 100 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain 52 g of light yellow oil with a yield of 64.6%. EI-MS (m/z): 337.1 (M ⁺ ).

Take a small amount of the above light yellow oil, dissolve it in acetone, and adjust the pH to 2 with hydrochloric acid ethanol solution to obtain a white solid, M.P 130°C-131.5°C.

II c, the synthetic method of II e is the same as the method described in Comparative Example 3, and α-bromo-o-chlorophenylacetic acid methyl ester is changed into successively: α-bromo-o-fluorophenylacetic acid methyl ester, α-bromo-phenylacetic acid methyl ester.

II c: α-[2-Oxo-2,4,5,6,7,7a- _{hexahydrothieno} [3,2-c]pyridin-5-yl]-o-fluorophenylacetic acid methyl ester. Yield 56.4%, EI-MS (m/z): 321.1 (M ⁺ ).

II e: α-[2-Oxo-2,4,5,6,7,7a- _{hexahydrothieno} [3,2-c]pyridin-5-yl]-phenylacetic acid methyl ester. Yield: 61.8%, EI-MS (m/z): 303.1 (M ⁺ ).

II b, II d, the synthetic method of II f are the same as the method described in Comparative Example 3, and α-bromo-o-chlorophenylacetic acid methyl ester is changed into successively: α-bromo-o-fluorophenylacetic acid methyl ester, α-bromo methyl phenylacetate; meanwhile, methanol was replaced by ethanol.

II b: ethyl α-[2-oxo-2,4,5,6,7,7a- _{hexahydrothieno} [3,2-c]pyridin-5-yl]-o-chlorophenylacetate. Yield 58.2%, EI-MS (m/z): 351.1 (M ⁺ ).

II d: ethyl α-[2-oxo-2,4,5,6,7,7a- _{hexahydrothieno} [3,2-c]pyridin-5-yl]-o-fluorophenylacetate. Yield: 60.1%, EI-MS (m/z): 335.1 (M ⁺ ).

II f: ethyl α-[2-oxo-2,4,5,6,7,7a- _{hexahydrothieno} [3,2-c]pyridin-5-yl]-phenylacetate. Yield: 66.7%, EI-MS (m/z): 317.1 (M ⁺ ).

Example 1: α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-chlorophenylacetic acid methyl ester (compound 1)

3.4 g of α-[2-oxo- _2,4,5,6,7,7a -hexahydrothieno[3,2-c]pyridin-5-yl]-o-chlorophenylacetic acid methyl ester (II _a ) was dissolved in 80ml of dichloromethane, under the protection of high-purity nitrogen, 2g of triethylamine was added, 1.6g of acetic anhydride was added at room temperature, stirred for 6 hours, then separated by silica gel column chromatography, eluent: dichloromethane- Ethyl acetate 9:2 (volume ratio) to obtain 1.6 g of product.

Elemental analysis, C ₁₈ H ₁₈ ClNO ₄ S:

Calculated C, 56.91; H, 4.78; C1, 9.33; N, 3.69;

Found C, 56.79; H, 4.70; C1, 9.23; N, 3.51.

EI-MS (m/z): 379.1 (M ⁺ ).

Dissolve the obtained oil in 5 times the amount of acetone (mass/volume ratio, g/ml), and dropwise add equimolar concentrated sulfuric acid at 5°C-10°C under stirring to obtain the sulfate salt.

Example 2: α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-chlorophenylacetic acid ethyl ester (compound 2)

α-[2-Oxo- _2,4,5,6,7,7a -hexahydrothieno[3,2-c]pyridin-5-yl]-o-chlorophenylacetic acid ethyl ester (II b) 1.8 g, dissolved in 50 ml of chloroform, under the protection of high-purity nitrogen, add 1 g of 4-dimethylaminopyridine, add 1.2 ml of acetic anhydride at 40 ° C, stir for 7.5 hours, then use silica gel column chromatography to separate, wash Removing agent: dichloromethane-ethyl acetate 9:2 (volume ratio) to obtain 0.75 g of the product.

Elemental analysis, C ₁₉ H ₂₀ ClNO ₄ S:

Calculated C, 57.94; H, 5.12; C1, 9.00; N, 3.56;

Found C, 57.76; H, 5.13; C1, 9.09; N, 3.43.

EI-MS (m/z): 393.1 (M ⁺ ).

The obtained oil was dissolved in 5.5 times the amount of acetone (mass/volume ratio, g/ml), and an equimolar amount of methanesulfonic acid was added dropwise at 5°C-10°C under stirring to obtain its methanesulfonate.

Example 3: α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-fluorophenylacetic acid methyl ester (compound 3)

α-[2-Oxo- _2,4,5,6,7,7a -hexahydrothieno[3,2-c]pyridin-5-yl]-o-fluorophenylacetic acid methyl ester (II c) 1.6 g, dissolved in 50 ml of dichloromethane, under the protection of high-purity nitrogen, add 0.9 g of 4-dimethylaminopyridine, add 2 ml of acetic anhydride at 10 ° C, stir for 7 hours, then use silica gel column chromatography to separate and elute Reagent: dichloromethane-ethyl acetate 9:2 (volume ratio) to obtain 0.81 g of the product.

HNMR spectrum:

¹ HNMRδppm 2.14(s, 3H), 2.64(t, 2H), 2.75(t, 2H), 3.47(dd, 2H), 3.61(s, 3H), 4.79(s, 1H), 6.15(s, 1H) , 7.15(m, 2H), 7.28(m, 1H), 7.56(m, 1H).

Elemental analysis, C ₁₈ H ₁₈ FNO ₄ S:

Calculated C, 59.49; H, 4.99; F, 5.23; N, 3.85;

Found C, 59.35; H, 5.00; F, 5.16; N, 3.72.

EI-MS (m/z): 363.1 (M ⁺ ).

Resolution: Dissolve the obtained oil in 6 times the amount of acetone (mass/volume ratio, g/ml), heat up under stirring, add 0.5 mole of (+)-camphorsulfonic acid at 40°C-45°C, and continue stirring After 3.5 hours, it was placed at 25°C-30°C to precipitate crystals. Filter to obtain two parts of crystalline solid and filtrate, which are processed separately.

Stir the above crystalline solid with equimolar sodium bicarbonate and 9 times the amount of isopropanol at 45°C-50°C for 2.5 hours, filter to remove insoluble matter. The solvent was evaporated from the filtrate under reduced pressure to obtain an oil. The oil was dissolved in ethyl acetate, and under stirring, equimolar concentrated sulfuric acid was added dropwise at 5°C-10°C, and after the addition was completed, stirring was continued at room temperature for 12 hours to obtain a white solid, namely (+)-α-( 4,5,6,7-Tetrahydrothieno[3,2-c]pyridin-5-yl)-o-fluorophenylacetic acid methyl ester sulfate. [α] ²⁵ _D = +59.1 (c = 1, methanol).

The above filtrate is separated and purified by chiral column to obtain (-)-α-(4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-fluorobenzene methyl acetate.

Example 4: α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-ethyl o-fluorophenylacetate (Compound 4)

According to the method provided in Example 3, α-[2-oxo-2,4,5,6,7,7a- _{hexahydrothieno} [3,2-c]pyridin-5-yl]-o-fluoro Methyl phenylacetate (II c) was replaced by α-[2-oxo- _2,4,5,6,7,7a -hexahydrothieno[3,2-c]pyridin-5-yl]-o Ethyl fluorophenylacetate (II d) is sufficient.

Elemental analysis, C ₁₉ H ₂₀ FNO ₄ S:

Calculated C, 60.46; H, 5.34; F, 5.03; N, 3.71;

Found C, 60.35; H, 5.21; F, 5.16; N, 3.72.

EI-MS (m/z): 377.1 (M ⁺ ).

Example 5: α-(2-propionyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-phenylacetic acid methyl ester (compound 5)

According to the method provided in Example 1, α-[2-oxo-2,4,5,6,7,7a- _{hexahydrothieno} [3,2-c]pyridin-5-yl]-o-chloro Methyl phenylacetate (IIa) was replaced by α-[2-oxo- _2,4,5,6,7,7a -hexahydrothieno[3,2-c]pyridin-5-yl]-benzene For methyl acetate (II e), acetic anhydride can be replaced with propionic anhydride.

Elemental analysis, C ₁₉ H ₂₁ NO ₄ S:

Calculated C, 63.49; H, 5.89; N, 3.90;

Found C, 63.45; H, 5.80; N, 3.82.

EI-MS (m/z): 359.1 (M ⁺ ).

Example 6: ethyl α-(2-isobutyryloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-phenylacetate (compound 5)

According to the method provided in Example 2, α-[2-oxo-2,4,5,6,7,7a- _{hexahydrothieno} [3,2-c]pyridin-5-yl]-o-chloro Ethyl phenylacetate (II b) was replaced by α-[2-oxo- _2,4,5,6,7,7a -hexahydrothieno[3,2-c]pyridin-5-yl]-benzene Ethyl acetate (II f), acetic anhydride can be replaced with isobutyric anhydride.

Elemental analysis, C ₂₁ H ₂₅ NO ₄ S:

Calculated C, 65.09; H, 6.50; N, 3.61;

Found C, 65.15; H, 6.42; N, 3.71.

EI-MS (m/z): 387.2 (M ⁺ ).

Effect Example 1: Rat Arteriovenous Bypass Thrombosis Model Test

Positive control drug: compound A, namely clopidogrel.

Healthy fasting male SD rats (provided by the Experimental Animal Center of the Second Military Medical University, certificate number: SCXK (Shanghai) 2002-0006), weighing 220 g to 300 g, were randomly divided into groups. There were 8 rats in each group, and a blank control group, a positive control group and a test compound group were set up. They were administered by gavage respectively, the dose was 30 mg/kg, and the administration volume was 0.8 ml/100 g, and the blank control group was given an equivalent amount of 1.0% sodium carboxymethyl cellulose. Two hours after administration, the rat was anesthetized with pentobarbital sodium 40 mg/kg, fixed in the supine position, and the left jugular vein and right carotid artery were separated. An external shunt was connected to two blood vessels through a 10cm long polyethylene tube (inner diameter 1.5mm). In the middle of the polyethylene tubing was attached another 3 cm roughened nylon cord for thrombus formation. Record the time from releasing the blood flow, maintain the extracorporeal circulation for 15 minutes, then remove the shunt, and weigh the nylon thread containing the thrombus as soon as possible (the weight of the nylon thread itself has been measured before the test begins), and the wet weight of the thrombus (mg) is obtained. ). The thrombus was placed in a vacuum oven at room temperature for 8 hours, and its dry weight (mg) was obtained.

Effect on experimental thrombus in rats (X±SD, n=8)

testing sample Thrombus wet weight (mg) Thrombus dry weight (mg) Blank group Compound A Compound 1 Compound 2 31.3±7.9 14.8±5.5 ^*** 12.9±5.0 ^*** 13.3±4.9 ^*** 10.1±2.25.6±1.2 ^*** 4.9±1.2 ^*** 5.0±1.3 ^*** Compound 3 Compound 4 Compound 5 Compound 6 12.6±4.6 ^*** 13.1±5.1 ^*** 13.6±4.7 ^*** 14.0±5.0 ^*** 4.7±1.2 ^*** 4.9±1.1 ^*** 5.0±1.0 ^*** 5.1±1.1 ^***

^*** P<0.001.

Effect embodiment 2: toxicity test

Acute toxicity test is the oldest toxicity test method, which has been used in drug evaluation for a long time and is an important content of new drug safety evaluation. The guiding principles for preclinical research of new drugs generally stipulate that animals are observed continuously for 7-14 days after administration, and the distribution of animal toxicity and dead animals is recorded.

Samples: Compound 1, Compound 2, Compound 3, Compound 4, Compound 5, Compound 6 and the control drug Compound A (clopidogrel), the content of which is 99.7%.

Experimental animals: Kunming mice, clean grade, four weeks old, half male and half male, body weight 20g±2g, provided by the Experimental Animal Center of Second Military Medical University, certificate number: SCXK (Shanghai) 2002-0006.

Laboratory conditions: temperature ℃ 22±2 ℃, relative temperature 50%-70%.

After the pre-test, carry out the test as follows.

Method: Take 60 mice and randomly divide them into 6 groups according to body weight, 10 in each group, half male and half male. With 6000mg/kg as the highest dose, according to the ratio of 1:0.7, 16000.0mg/kg, 4200.0mg/kg, 2940.0mg/kg, 2058mg/kg, 1440.6mg/kg were given to the mice of the 6 groups by intragastric administration. , 1008.4mg/kg, test compound is formulated into different concentrations with 1% CMCNa, administration volume 0.2ml/10g, fasting before administration can not help but water for 12 hours, fasting within 3 hours after administration, feeding observation for 14 days, Toxic reactions and death conditions of mice were recorded, and the median lethal dose (LD ₅₀ ) was calculated by the modified Cole's method.

After taking the medicine, she had reduced activity, followed by mania, general convulsions, raised tail, belly sticking to the ground, and imbalance, followed by symptoms such as salivation, bloodshot eyes, tearing, and diarrhea. She died of dyspnea without obvious struggle before death. The test animals that have endured the drug generally recover their desire to eat and drink 6h to 10h after administration, and their coat and activities gradually return to normal.

Necropsy pathological changes: Partial necropsy of the dead animals showed that the coat was dry and hairy, and the lips, limbs, and tail were bruised; the liver had scattered needle-like bleeding points; , and even the entire small intestine congestion, bleeding, intestinal wall edema; emphysema, full of needle-like bleeding points.

Compound 2, Compound 3, Compound 4, Compound 5, Compound 6 and Compound A were subjected to acute toxicity tests in the same manner as above.

test results

compound _LD50 (mg/kg) Compound 1 3840 Compound 2 3790 Compound 3 3880 Compound 4 3670 Compound 5 3780 Compound 6 3750 Compound A 3100

Conclusion: The LD ₅₀ of the six compounds are all greater than 3000 mg/kg; and the toxicity is lower than compound A.

Application Example 1: Tablet

Prescription: 50 grams of Compound 1, 110 grams of lactose, 15 grams of PEG-4000, 6 grams of magnesium stearate, 12 grams of starch, 16 grams of croscarmellose sodium, 6 grams of calcium carbonate, appropriate amount of distilled water, made 1000 piece.

Prepare tablets according to conventional methods in the art.

Application Example 2: Capsules

Prescription: 25 grams of compound 3, 58 grams of starch, 38 grams of lactose, 15 grams of sucrose, 29 grams of microcrystalline cellulose, an appropriate amount of 10% polyvinylpyrrolidone ethanol solution, 2 grams of magnesium stearate, made into 1000 capsules.

Prepare capsules according to conventional methods in the art.

Claims (12)

1. A thiophene derivative, characterized in that: as the structural compound shown in (I) formula or its pharmaceutically acceptable salt, optical isomer, Wherein, R ₁ is: C ₁ -C ₃ alkyl; R ₂ is: hydrogen, chlorine, fluorine; R ₃ is: C ₁ -C ₄ alkyl. 2. The thiophene derivative or its pharmaceutically acceptable salt, optical isomer as claimed in claim 1, characterized in that: the thiophene derivative compound is: α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-chlorophenylacetic acid methyl ester, α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-chlorophenylacetic acid ethyl ester, α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-fluorophenylacetic acid methyl ester, α-(2-Acetoxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-o-fluorophenylacetic acid ethyl ester, α-(2-propionyloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl)-phenylacetic acid methyl ester or α-[2-Isobutyryloxy-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-5-yl]-phenylacetic acid ethyl ester. 3. Thiophene derivative compound or its pharmaceutically acceptable salt as claimed in claim 1-2, is characterized in that: described pharmaceutically acceptable salt is the compound shown in (I) formula and inorganic acid or organic acid salt formed. 4. Thiophene derivative compound or pharmaceutically acceptable salt thereof as claimed in claim 3, is characterized in that: described inorganic acid is hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, and organic acid is acetic acid, oxalic acid, propane Diacid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. 5. The application of thiophene derivatives in medicine, characterized in that: the medicinal compound containing the thiophene derivative compound described in any one of claims 1-3 or its pharmaceutically acceptable salts and optical isomers in a therapeutically effective amount combination. 6. The application of thiophene derivatives in medicine as claimed in claim 5, characterized in that: said pharmaceutical composition includes various solid and liquid oral preparations. 7. The preparation method of the thiophene derivative compound or its pharmaceutically acceptable salt and optical isomer according to claims 1-3, characterized in that: In an organic solvent, in the presence of a basic catalyst, the compound of the general formula (II) reacts with the compound of the general formula (III) to prepare the compound shown in the formula (IV);

In an organic solvent, in the presence of a basic catalyst, the compound of general formula (IV) reacts with different acid anhydrides (R ₁ CO-O-COR ₁ ) to prepare the compound shown in formula (I);

The compound represented by the formula (I) reacts with an inorganic acid or an organic acid in an organic solvent to form a salt. The compound represented by formula (I) is resolved into optical isomers by an acidic resolving agent. In the above structural formula, R ₁ , R ₂ , and R ₃ are as defined in claim 1. 8. The preparation method of thiophene derivative compound or its pharmaceutically acceptable salt, optical isomer as claimed in claim 7, it is characterized in that: described basic catalyst is organic base triethylamine, 4-dimethyl One or both of the aminopyridines. 9. The preparation method of thiophene derivative compound or its pharmaceutically acceptable salt and optical isomer according to claim 7, characterized in that: the reaction temperature is 10°C-40°C. 10. The preparation method of thiophene derivative compound or its pharmaceutically acceptable salt, optical isomer as claimed in claim 7, it is characterized in that: described organic solvent is dichloromethane, trichloromethane, dimethyl A type of formamide. 11. the compound shown in (I) formula as described in any one in claim 1-3 or its pharmaceutically acceptable salt, optical isomer, it is characterized in that: in the preparation treatment thrombotic disease medicine application. 12. The application of the thiophene derivative compound or its pharmaceutically acceptable salts and optical isomers in the medicine for treating thrombotic diseases as claimed in claim 11, characterized in that: the medicine for treating thrombotic diseases refers to the In the preparation of drugs for the treatment of myocardial infarction, angina pectoris, reocclusion and restenosis after angioplasty or aortocoronary bypass, stroke, transient ischemic attack, peripheral arterial occlusive disease, pulmonary embolism or deep vein thrombosis application.