TECHNICAL FIELD

The present invention belongs to the field of medical technology. Specifically, the present invention relates to a class of compounds having an anti-platelet aggregation effect, a preparation method and use thereof, as well as a pharmaceutical composition containing the compound. More specifically, the present invention relates to a thienopyridine derivative containing an unsaturated aliphatic olefinic bond, a preparation method and use thereof, as well as a pharmaceutical composition. The present invention also relates to a crystalline form of the compound, a preparation method and use of the crystalline form, and a pharmaceutical composition comprising the crystalline form.

BACKGROUND ART

Clopidogrel is an oral ADP receptor antagonist jointly developed by two pharmaceutical companies, Sanofi and Bristol-Myers Squibb, which has been approved for marketing. It is developed on the basis of certain structural modifications to the early-developed antiplatelet agent, ticlopidine, and is currently used as a first-line antithrombotic agent clinically. However, it has been confirmed in many years of clinical use that clopidogrel has great defects. As a prodrug, clopidogrel needs to be subjected to two steps of metabolism in vivo by the P450 enzyme system in the liver, and metabolized into an active metabolite to take effect. As there are differences in the expression of related enzymes in different individuals, especially CYP2C19, on which the metabolism of the first step depends, has gene polymorphism, leading to large individual differences between clinical treatment effects of clopidogrel, and it is prone to make the phenomenon of “clopidogrel resistance” happen, which would further lead to somewhat harmful cardiovascular events.

Prasugrel was jointly developed by Daiichi Sankyo (Japan) and Eli Lilly (US), which is an ADP receptor antagonist antiplatelet agent developed on the basis of clopidogrel. In comparison with clopidogrel, prasugrel takes effect more rapidly and has greater activity, with less difference in response to the drug between patients. However, prasugrel also has great defects. It has a greater and even fatal hemorrhagic risk, and also has adverse effects such as hepatotoxicity thrombocytopenia, and neutropenia.

At the same time, thienopyridine compounds reported in the existing literatures also have the problem of instability. By way of example, clopidogrel free base is an oil, which has many disadvantages such as being unstable and difficult to be made into oral preparations. Other thienopyridine compounds reported in some literatures have similar disadvantages that the compounds are present as oils and need to form salts with strong acids such as hydrochloric acid and sulfuric acid, and the product is unstable and prone to degradation. These disadvantages make these compounds have poor druggability, or be prone to have problems during production, sale, storage, and use.

So far, no research has shown that there is a compound which can solve both the problem of clopidogrel resistance and the problem of severe hemorrhagic side effect and potential hepatotoxicity of prasugrel, and can also solve the problem of poor stability.

Therefore, there is an urgent clinical need to develop ADP receptor antagonist antiplatelet agents with clear therapeutic effect, no metabolic resistance, higher safety and better stability.

DESCRIPTION OF THE INVENTION

The technical problem to be solved by the present invention is to overcome the above-mentioned disadvantages and develop an ADP receptor antagonist antiplatelet agent with clear therapeutic effect, no resistance, as well as higher safety and stability.

It is an object of the present invention to provide a thienopyridine ester derivative containing an unsaturated aliphatic olefinic bond, a method for preparing the thienopyridine ester derivative containing an unsaturated aliphatic olefinic bond, use of the thienopyridine ester derivative containing an unsaturated aliphatic olefinic bond, and a pharmaceutical composition comprising the thienopyridine ester derivative containing an unsaturated aliphatic olefinic bond.

It is another object of the present invention to provide a crystalline form of the thienopyridine ester derivative containing an unsaturated aliphatic olefinic bond, a method for preparing the crystalline form, a pharmaceutical composition comprising the crystalline form, and use of the crystalline form.

It is yet another object of the present invention to provide a method for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation.

The object of the present invention is achieved by the following technical solutions:

In one aspect, the present invention provides a compound having a structure of formula (I):



wherein R is methyl, ethyl, propyl, vinyl or propenyl.

The compound having the structure of formula (I) of the present invention is preferably selected from the following compounds:I-1: methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate

I-2: methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate

I-3: methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H-yl)-acetate

I-4: methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate

I-5: methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate



The compound having the structure of formula (I) of the present invention is more preferably selected from the following compounds:I-1: methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate; andI-2: methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate.

In another aspect, the present invention provides a method for preparing the compound having the structure of formula (I) of the present invention, the method comprises the steps of:

reacting a compound having a structure of formula (II) with a corresponding acid, acyl chloride or acid anhydride in the presence of a base to prepare the compound having the structure of formula (I):


wherein R is methyl, ethyl, propyl, vinyl or propenyl;

preferably, in the method for preparing the compound having the structure of formula (I) of the present invention, the base is triethylamine or N,N-diisopropylethylamine, and/or the reaction is carried out in the presence of a solvent such as dichloromethane.

preferably, the compound having the structure of formula (II) is prepared by reacting a compound having a structure of formula (III) with a compound having a structure of formula (IV) in the presence of a base:



preferably, in the reaction for preparing the compound having the structure of formula (II) from the compound having the structure of formula (III) and the compound having the structure of formula (IV), said base is potassium carbonate, said reaction is carried out in the presence of a solvent such as acetonitrile, and/or said reaction is carried out at a temperature of 20-40° C.

In some embodiments, the solvent used in the preparation method of the present invention may be a solvent which is inert under the reaction conditions, including, but not limited to, ethers, such as tetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether etc.; halogenated hydrocarbons, such as 1,2-dichloroethane, dichloromethane, chloroform, carbon tetrachloride etc.; alcohols, such as methanol, ethanol, isopropanol, tert-butanol etc.; hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexane etc.; and other solvents, such as dimethyl sulfoxide, dimethylformamide, acetonitrile, pyridine, water, hexamethylphosphoric triamide etc. The solvent may also be a mixture of the above solvents.

In certain embodiments of the present invention, in the method for preparing the compound having the structure of formula (I) of the present invention and in the reaction for preparing the compound having the structure of formula (II) from the compound having the structure of formula (I) and the compound having the structure of formula (IV), the reaction can be carried out under different pressures, such as a reduced pressure, a normal pressure or an increased pressure, preferably under a normal pressure.

In certain embodiments of the present invention, in the method for preparing the compound having the structure of formula (I) of the present invention and in the reaction for preparing the compound having the structure of formula (II) from the compound having the structure of formula (I) and the compound having the structure of formula (IV), the reaction is generally carried out at a temperature of −78° C. to a reflux temperature, preferably in a range of 0° C. to a reflux temperature.

In yet another aspect, the present invention provides use of the compound having the structure of formula (I) of the present invention in the manufacture of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

In another aspect, the present invention provides a method for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, the method comprises administering to a subject in need thereof a therapeutically effective amount of the compound having the structure of formula (I) of the present invention, the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

In yet another aspect, the present invention provides a pharmaceutical composition comprising the compound having the structure of formula (I) of the present invention and a pharmaceutically acceptable carrier or excipient.

In certain embodiments of the present invention, the pharmaceutical composition is a solid oral preparation, a liquid oral preparation, or an injection. Preferably, the solid oral preparation is a tablet, a capsule or a granule; the liquid oral preparation is a syrup or an oral solution; and/or the injection is a liquid injection, a powder for injection or a small-volume infusion solution.

In another aspect, the present invention also provides a crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1), a preparation method and use thereof, as well as a pharmaceutical composition comprising the crystalline form A.

The crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1) has an X-ray powder diffraction pattern having diffraction peaks at 5.31, 16.13, 20.24 and 21.58 expressed by 2θ degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1) has an X-ray powder diffraction pattern having diffraction peaks at 5.31, 10.70, 12.43, 16.13, 17.47, 20.24, 21.58, 25.83 and 27.09 expressed by 2θ degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1) has an X-ray powder diffraction pattern having a diffraction angle (2θ) and interplanar spacing (d value) as shown in Table 1, with the 2θ angle measurement error being ±0.2.

TABLE 1Diffraction angle and interplanar spacing results ofX-ray powder diffraction pattern of crystalline form2θ (±0.2°)d (Å)5.3116.6310.708.2612.437.1216.135.4917.475.0720.244.3821.584.1125.833.4527.093.29

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1) has an X-ray powder diffraction pattern substantially as shown inFIG. 1.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1) has a DSC-TGA pattern substantially as shown inFIG. 2.

The crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1) of the present invention has good appearance stability and reproducibility between batches, which exists as a white or off-white solid and is stable as crystalline form A during continuous preparation of multiple batches.

The crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1) of the present invention has a good stability, and the crystalline form remains stable under high temperature, high humidity, and light conditions.

The present invention also provides a method for preparing the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1), comprising the steps of:

dissolving the compound of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1) in an organic solvent, heating to obtain a clear solution, precipitating a crystal by stirring and cooling, collecting the crystal by filtration, and drying to obtain the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1), wherein the organic solvent is one or more selected from the group consisting of methanol, ethanol, propanol, isopropanol, toluene, ethyl acetate, acetone, acetonitrile and methyl tert-butyl ether.

Preferably, in the method of the present invention for preparing the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1), the step of heating comprises heating to a reflux temperature; and/or the step of precipitating a crystal by cooling comprises cooling to a temperature of 10-30° C.

The present invention also provides use of the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5 (4H)-yl)-acetate (I-1) in the manufacture of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a method for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, the method comprises administering to a subject in need thereof a therapeutically effective amount of the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1), and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a pharmaceutical composition comprising the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-butenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-1) and a pharmaceutically acceptable carrier or excipient.

In certain embodiments of the present invention, the pharmaceutical composition is a solid oral preparation, a liquid oral preparation, or an injection; preferably, the solid oral preparation is a tablet, a capsule or a granule; the liquid oral preparation is a syrup or an oral solution; and/or the injection is a liquid injection, a powder for injection or a small-volume infusion solution.

In another aspect, the present invention also provides a crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2), a preparation method and use thereof, as well as a pharmaceutical composition comprising the crystalline form A.

The crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has an X-ray powder diffraction pattern having diffraction peaks at 5.52, 16.73, 19.43 and 22.38 expressed by 2θ degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has an X-ray powder diffraction pattern having diffraction peaks at 5.52, 11.10, 12.30, 16.73, 18.86, 19.43, 22.38, 23.40 and 23.80 expressed by 2θ degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has an X-ray powder diffraction pattern having a diffraction angle (2θ) and interplanar spacing (d value) as shown in Table 2, with the 2θ angle measurement error being ±0.2.

TABLE 2Diffraction angle and interplanar spacing results ofX-ray powder diffraction pattern of crystalline form2θ (±0.2°)d (Å)5.5216.0111.107.9612.307.1916.735.3018.864.7019.434.5622.383.9723.403.8023.803.74

Preferably, the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has an X-ray powder diffraction pattern substantially as shown inFIG. 3.

Preferably, the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has a DSC-TGA pattern substantially as shown inFIG. 4.

The present invention also provides a method for preparing the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2), comprising the steps of:

dissolving the compound of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) in an organic solvent, heating to obtain a clear solution, precipitating a crystal by stirring and cooling, collecting the crystal by filtration, and drying to obtain the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2), wherein the organic solvent is one or more selected from the group consisting of methanol, ethanol, ethyl acetate, acetonitrile and methyl tert-butyl ether.

Preferably, in the method of the present invention for preparing the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2), the step of heating comprises heating to a reflux temperature; and/or the step of precipitating a crystal by cooling comprises cooling to a temperature of 10-30° C.

The present invention also provides use of the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) in the manufacture of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a method for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, the method comprises administering to a subject in need thereof a therapeutically effective amount of the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2), and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a pharmaceutical composition comprising the crystalline form A of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) and a pharmaceutically acceptable carrier or excipient.

In certain embodiments of the present invention, the pharmaceutical composition is a solid oral preparation, a liquid oral preparation, or an injection; preferably, the solid oral preparation is a tablet, a capsule or a granule; the liquid oral preparation is a syrup or an oral solution; and/or the injection is a liquid injection, a powder for injection or a small-volume infusion solution.

In yet another aspect, the present invention also provides a crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2), a preparation method and use thereof, as well as a pharmaceutical composition comprising the crystalline form B.

The crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has an X-ray powder diffraction pattern having diffraction peaks at 4.31, 8.66, 13.01, 17.42 and 19.52 expressed by 2θ degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has an X-ray powder diffraction pattern having diffraction peaks at 4.31, 8.66, 10.29, 10.94, 13.01, 17.42, 19.52, 23.17, 24.22 and 24.92 expressed by 20 degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has an X-ray powder diffraction pattern having a diffraction angle (2θ) and interplanar spacing (d value) as shown in Table 3, with the 2θ angle measurement error being ±0.2.

TABLE 3Diffraction angle and interplanar spacing results ofX-ray powder diffraction pattern of crystalline form2θ (±0.2°)d (Å)4.3120.508.6610.2010.298.5910.948.0813.016.8017.425.0919.524.5423.173.8424.223.6724.923.57

Preferably, the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has an X-ray powder diffraction pattern substantially as shown inFIG. 5.

Preferably, the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) has a DSC-TGA pattern substantially as shown inFIG. 6.

The present invention also provides a method for preparing the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2), comprising the steps of: dissolving the compound of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) in acetic acid, heating to obtain a clear solution, precipitating a crystal by cooling, collecting the crystal by filtration, and drying to obtain the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2).

Preferably, in the method of the present invention for preparing the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2), the step of heating comprises heating to a temperature of 60° C. to a reflux temperature; and/or the step of precipitating a crystal by cooling comprises cooling to a temperature of 20-30° C.

The present invention also provides use of the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) in the manufacture of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a method for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, the method comprises administering to a subject in need thereof a therapeutically effective amount of the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2), and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a pharmaceutical composition comprising the crystalline form B of methyl (S)-2-(2-chlorophenyl)-2-(2-((2E,4E)-2,4-hexadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-2) and a pharmaceutically acceptable carrier or excipient.

In certain embodiments of the present invention, the pharmaceutical composition is a solid oral preparation, a liquid oral preparation, or an injection; preferably, the solid oral preparation is a tablet, a capsule or a granule; the liquid oral preparation is a syrup or an oral solution; and/or the injection is a liquid injection, a powder for injection or a small-volume infusion solution.

In another aspect, the present invention also provides a crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3), a preparation method and use thereof, as well as a pharmaceutical composition comprising the crystalline form A.

The crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3) has an X-ray powder diffraction pattern having diffraction peaks at 5.71, 11.49, 17.28, 19.57 and 23.14 expressed by 2θ degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3) has an X-ray powder diffraction pattern having diffraction peaks at 5.71, 11.49, 12.43, 15.95, 16.56, 17.28, 19.57, 23.14, 23.66, 24.98 and 26.09 expressed by 20 degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3) has an X-ray powder diffraction pattern having a diffraction angle (2θ) and interplanar spacing (d value) as shown in Table 4, with the 2θ angle measurement error being ±0.2.

TABLE 4Diffraction angle and interplanar spacing results ofX-ray powder diffraction pattern of crystalline form2θ (±0.2°)d (Å)5.7115.4611.497.7012.437.1215.955.5516.565.3517.285.1319.574.5323.143.8423.663.7624.983.5626.093.41

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3) has an X-ray powder diffraction pattern substantially as shown inFIG. 7.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3) has a DSC-TGA pattern substantially as shown inFIG. 8.

The present invention also provides a method for preparing the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3), comprising the steps of: dissolving the compound of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3) in methanol, heating to obtain a clear solution, precipitating a crystal by stirring and cooling, collecting the crystal by filtration, and drying to obtain the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3).

Preferably, in the method of the present invention for preparing the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3), the step of heating comprises heating to a reflux temperature; and/or the step of precipitating a crystal by cooling comprises cooling to a temperature of 10-30° C.

The present invention also provides use of the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3) in the manufacture of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a method for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, the method comprises administering to a subject in need thereof a therapeutically effective amount of the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3), and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a pharmaceutical composition comprising the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2,4-pentadienoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-3) and a pharmaceutically acceptable carrier or excipient.

In certain embodiments of the present invention, the pharmaceutical composition is a solid oral preparation, a liquid oral preparation, or an injection; preferably, the solid oral preparation is a tablet, a capsule or a granule; the liquid oral preparation is a syrup or an oral solution; and/or the injection is a liquid injection, a powder for injection or a small-volume infusion solution.

In yet another aspect, the present invention also provides a crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4), a preparation method and use thereof, as well as a pharmaceutical composition comprising the crystalline form A.

The crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4) has an X-ray powder diffraction pattern having diffraction peaks at 5.32, 16.09, 18.28, 20.68 and 21.51 expressed by 2θ degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4) has an X-ray powder diffraction pattern having diffraction peaks at 5.32, 10.68, 12.98, 14.57, 16.09, 17.64, 18.28, 19.83, 20.68 and 21.51 expressed by 2θ degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4) has an X-ray powder diffraction pattern having a diffraction angle (2θ) and interplanar spacing (d value) as shown in Table 5, with the 2θ angle measurement error being ±0.2.

TABLE 5Diffraction angle and interplanar spacing results ofX-ray powder diffraction pattern of crystalline form2θ (±0.2°)d (Å)5.3216.6010.688.2812.986.8114.576.0716.095.5017.645.0218.284.8519.834.4720.684.2921.514.13

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4) has an X-ray powder diffraction pattern substantially as shown inFIG. 9.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4) has a DSC-TGA pattern substantially as shown inFIG. 10.

The present invention also provides a method for preparing the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4), comprising the steps of:

dissolving the compound of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4) in an organic solvent, heating to obtain a clear solution, precipitating a crystal by stirring and cooling, collecting the crystal by filtration, and drying to obtain the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4), wherein the organic solvent is one or more selected from the group consisting of methanol, ethanol, toluene, ethyl acetate, acetone, acetonitrile and methyl tert-butyl ether.

Preferably, in the method of the present invention for preparing the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4), the step of heating comprises heating to a reflux temperature; and/or the step of precipitating a crystal by cooling comprises cooling to a temperature of 10-30° C.

The present invention also provides use of the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-(4H)-yl)-acetate (I-4) in the manufacture of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a method for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, the method comprises administering to a subject in need thereof a therapeutically effective amount of the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4), and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a pharmaceutical composition comprising the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-pentenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-4) and a pharmaceutically acceptable carrier or excipient.

In certain embodiments of the present invention, the pharmaceutical composition is a solid oral preparation, a liquid oral preparation, or an injection; preferably, the solid oral preparation is a tablet, a capsule or a granule; the liquid oral preparation is a syrup or an oral solution; and/or the injection is a liquid injection, a powder for injection or a small-volume infusion solution.

In another aspect, the present invention also provides a crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5), a preparation method and use thereof, as well as a pharmaceutical composition comprising the crystalline form A.

The crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5) has an X-ray powder diffraction pattern having diffraction peaks at 5.58, 16.84, 19.46, 22.50 and 23.47 expressed by 2θ degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5) has an X-ray powder diffraction pattern having diffraction peaks at 5.58, 11.19, 12.21, 15.64, 16.84, 19.00, 19.46, 20.09, 22.50, 23.47, 23.99 and 25.81 expressed by 20 degree using Cu-Ka radiation, with a 2θ angle measurement error being ±0.2.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5) has an X-ray powder diffraction pattern having a diffraction angle (2θ) and interplanar spacing (d value) as shown in Table 6, with the 2θ angle measurement error being ±0.2.

TABLE 6Diffraction angle and interplanar spacing results ofX-ray powder diffraction pattern of crystalline form2θ (±0.2°)d (Å)5.5815.8311.197.9012.217.2415.645.6616.845.2619.004.6719.464.5620.094.4222.503.9523.473.7923.993.7125.813.45

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5) has an X-ray powder diffraction pattern substantially as shown inFIG. 11.

Preferably, the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5) has a DSC-TGA pattern substantially as shown inFIG. 12.

The present invention also provides a method for preparing the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5), comprising the steps of: dissolving the compound of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5) in an organic solvent, heating to obtain a clear solution, precipitating a crystal by stirring and cooling, collecting the crystal by filtration, and drying to obtain the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5), wherein the organic solvent is one or more selected from the group consisting of methanol, ethanol, acetone, acetonitrile and methyl tert-butyl ether.

Preferably, in the method of the present invention for preparing the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5), the step of heating comprises heating to a reflux temperature; and/or the step of precipitating a crystal by cooling comprises cooling to a temperature of 10-30° C.

The present invention also provides use of the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-(4H)-yl)-acetate (I-5) in the manufacture of a medicament for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a method for preventing and/or treating cardiovascular and cerebrovascular diseases caused by platelet aggregation, the method comprises administering to a subject in need thereof a therapeutically effective amount of the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5), and the cardiovascular and cerebrovascular diseases are, for example, coronary artery syndrome, myocardial infarction, myocardial ischemia, and the like.

The present invention also provides a pharmaceutical composition comprising the crystalline form A of methyl (S,E)-2-(2-chlorophenyl)-2-(2-(2-hexenoyloxy)-6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)-acetate (I-5) and a pharmaceutically acceptable carrier or excipient.

In certain embodiments of the present invention, the pharmaceutical composition is a solid oral preparation, a liquid oral preparation, or an injection; preferably, the solid oral preparation is a tablet, a capsule or a granule; the liquid oral preparation is a syrup or an oral solution; and/or the injection is a liquid injection, a powder for injection or a small-volume infusion solution.

The compound having the structure of formula (I) and the crystalline form of each compound of the present invention are effective in a relatively wide dosage range. For example, the daily dosage is in the range of 1 to 1000 mg/person, and it can be administered in one or several times. The actual dosage should be determined by a physician based on relevant conditions, including the physical condition of the subject being treated, the route of administration, age and weight of the patient, individual response to the drug, and the severity of the symptoms, and the like.

The inventors of the present application have surprisingly found that, the pharmacodynamic studies show that the compounds having the structures of formula (I) provided by the present invention have a significant inhibitory effect on platelet aggregation, and the therapeutic effect is better than clopidogrel; the pharmacokinetic studies show that the compounds having the structures of formula (I) of the present invention can be rapidly and effectively converted into pharmacologically active metabolites to exert their inhibitory effect on platelet aggregation, and will not cause resistance resulted from gene polymorphism of related enzymes of population; the safety evaluation shows that the compounds of the formula (I) of the present invention have high safety; the pharmaceutical research shows that the compounds having the structures of formula (I) of the present invention are easy to be prepared and exist in a solid form; and the stability study shows that the compounds having the structures of formula (I) of the present invention have good stability, which facilitates the formulation, storage and use of agents.

At the same time, the inventors of the present application also surprisingly found that the compounds having the structures of formula (I) of the present invention exist in a solid form, while compounds having structures similar to the compounds having the structures of formula (I) of the present invention, which only have minor changes in the unsaturated aliphatic olefinic bond, such as Example compounds D-1, D-2, D-3, D-4, D-5, D-6 and D-7, are oils and are difficult to form salts, which are extremely adverse to drugability.

The results of various studies show that the compounds having the structures of formula (I) of the present invention obviously have unexpected effects compared with those disclosed in the prior arts. The compounds having the structures of formula (I) of the present invention exist in a solid form, which not only can solve the problem of clopidogrel resistance, but also can solve the problem of severe hemorrhagic side effect and poor safety of some drugs, as well as the problem of poor stability of existing compounds. It can be developed into an ADP receptor antagonist antiplatelet agent with clear therapeutic effects, no resistance and better stability.

Each crystalline form of the compounds having the structures of formula (I) of the present invention also have the above-mentioned effects in pharmacodynamics, pharmacokinetics, safety and stability.

