Sofalcone derivatives and their pharmaceutical use

Abstract

A series of sofalcone derivatives are provided. [Solution] The present invention provides a series of sofalcone derivatives, which are compounds having the structure of formula (I), for example, and have platelet aggregation inhibitory and antithrombotic effects. The sofalcone derivatives of the present invention are TxA2 receptor antagonists, and have the effect of inhibiting platelet aggregation without easily affecting hemostatic function. The present invention also provides a method for preparing the sofalcone derivatives, and a method for using the sofalcone derivatives in the prevention or treatment of thrombotic diseases or in the inhibition of platelet aggregation. JPEG2026001671000013.jpg5577

Description

[Technical Field]

[0001] The present invention relates to a series of sofalcone derivatives, which have platelet aggregation inhibitory and antithrombotic effects. The present invention also relates to a method of using these sofalcone derivatives for the treatment of thrombotic diseases or for inhibiting platelet aggregation. [Background technology]

[0002] Thromboxane A2 (TxA2) is the major metabolite of arachidonic acid (AA) in platelets. When platelets are activated, AA is released from the phospholipids of the cell membrane into the cytoplasm, where it is further converted to prostaglandin (PG) G2 / H2 by cyclooxygenase (COX), and then to TxA2 by TxA2 synthase. TxA2 can be released extracellularly from platelet cells and acts on thromboxane A2 receptors on the platelet membrane, inducing platelet activation and aggregation. Therefore, TxA2 is an important mechanism for enhancing platelet activation. Aspirin inhibits COX, thereby reducing TxA2 synthesis in platelets, and thus exhibiting an antiplatelet effect. However, aspirin can also inhibit prostaglandin synthesis in other cells, for example, by inhibiting the synthesis of prostaglandin I2 (PGI2) in vascular endothelial cells and prostaglandin E2 (PGE2) in gastric cells. Inhibition of PGI2 may counteract the antiplatelet effect of aspirin, and inhibition of PGE2 may be related to the induction of peptic ulcers by aspirin. Therefore, the development of drugs that can antagonize the TxA2 receptor or selectively inhibit TxA2 synthase may be superior to aspirin-based antiplatelet therapy.

[0003] Currently, there are two TxA2 receptor antagonists used clinically: seratrodast and ramatroban. However, these are only used to treat asthma or allergic rhinitis, and their use in antiplatelet therapy is not yet approved. Picotamide has two effects: as an antagonist of both TxA2 synthase and TxA2 receptors, but its efficacy is relatively low. Therefore, it is not yet widely used in clinical antiplatelet therapy. Consequently, the development of novel TxA2 receptor antagonists is of urgent importance.

[0004] Sofalcone belongs to the chalcone group of compounds and is a derivative obtained by artificial synthesis and modification of sophoradin, a component of sophora subprostrata. Sophora subprostrata is a commonly used herbal medicine, traditionally used for clearing heat, detoxifying, and relieving throat swelling. Modern research has discovered that sophora subprostrata has anti-ulcer properties, and its active ingredient has been identified as sophoradin. Taisho Pharmaceutical Co., Ltd. in Japan developed sofalcone through artificial synthesis and chemical modification based on the chemical structure of sophoradin, and marketed it as an anti-ulcer drug in 1984. Based on its safety and efficacy, it was approved as an over-the-counter drug in Japan in 1999. Previous studies have shown that the mechanism of solfalcon's anti-ulcer effect and its activity in inhibiting 15-hydroxy-prostaglandin dehydrogenase (15-PGDH) are related to an increase in PGE2 content in gastric tissue. In addition, two human metabolites of solfalcon also possess anti-ulcer effects. Beyond its anti-ulcer effects, when solfalcon is used in combination with rabeprazole, amoxicillin, and clarithromycin, it can enhance the suppression of Helicobacter pylori infection in gastric tissue, achieving an anti-gastritis effect. Recent studies have also shown that solfalcon can not only suppress inflammatory responses between macrophages and adipocytes but also reduce the differentiation of pre-adipocytes into adipocytes, indicating its potential use in diseases such as obesity and metabolic syndrome. However, there have been no studies on solfalcone in cardiovascular disease, particularly studies on its antiplatelet effects. [Overview of the project] [Problems that the invention aims to solve]

[0005] The present invention proves that sofalcone has antiplatelet activity and its mechanism is a TXA2 antagonist. The present invention further modifies based on the chemical structure of sofalcone, synthesizes a series of novel chemical derivatives, and measures their antiplatelet aggregation activities. Furthermore, structure-activity relationship is used to optimize the pharmacophore.

Means for Solving the Problems

[0006] The sofalcone derivatives disclosed by the present invention can very well and effectively inhibit platelet aggregation induced by the TXA2 receptor agonist U46619 or collagen. It also shows an antithrombotic effect in animal experiments and furthermore does not affect the hemostatic function. Therefore, the sofalcone derivatives disclosed by the present invention can be used as novel platelet inhibitors with high efficacy and low side effects.

[0007] The term "a" or "one" used herein is for describing the elements and components of the present invention. This term is only used to provide the basic concept of the present invention. In addition, the description should be understood to include one or at least one. Furthermore, unless otherwise clearly indicated in the context, singular terms include pluralities and plural terms include singulars. When used in combination with the term "comprising" in the claims, the term "a" or "one" can represent one or more.

[0008] The term "or" used herein can refer to "and / or".

[0009] The present invention provides a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0010]

Chemical formula

[0011] In the formula, R 1is None, H, phenyl group (phenyl, Ph), thiophenyl group, furanyl group, pyridinyl group, bromothiophenyl group, thiazolyl group, or a phenyl group substituted with X, where X is H, halogen, NO2, NH2, NHAc, O-Ac, O-geranyl group, C 1-6 alkyl group, O-C 1-10 alkyl group, OH, OBn, aminothio group, O-isoprenyl group, O-halobenzyl group, O-C 1-6 alkyloxybenzyl group (O-C 1-6 alkyloxybenzyl), O-C 1-6 alkyl-CO-phenyl group, or O-C 1-6 alkyl-COO-C 1-6 alkyl group; R 2 is None, H, OH, halogen, O-geranyl group, O-isoprenyl group, O-C 1-10 alkyl group, O-Ac, OBn, O-halobenzyl group, O-C 1-6 alkyloxybenzyl group, phenyl-O-isoprenyl group, O-C 1-6 alkyl-CO-phenyl group, or O-C 1-6 alkyl-COO-C 1-6 alkyl group; R 3 is OH or O-C 1-6 alkyl group; n is from 1 to 7.

[0012] In a specific embodiment, the halogen includes fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and astatine (At). In a preferred specific embodiment, the halogen is fluorine or chlorine.

[0013] In another specific embodiment, the C 1-6 alkyl group is C 1-3Contains alkyl groups.

[0014] In a specific example, the OC 1-10 The alkyl group is the OC 1-8 Contains an alkyl group. In preferred specific examples, the OC 1-8 The alkyl group is the OC 1-6 Contains an alkyl group. In a more preferred specific example, the OC 1-6 The alkyl group is the OC 1-3 Contains alkyl groups.

[0015] In another specific embodiment, the OC 1-6 Alkyloxybenzyl group is OC 1-3 Contains an alkyloxybenzyl group.

[0016] In a specific example, the OC 1-6 The alkyl-CO-phenyl group is OC 1-3 Contains alkyl-CO-phenyl groups.

[0017] In another specific embodiment, the OC 1-6 Alkyl-COO-C 1-6 Alkyl groups are OC 1-3 Alkyl-COO-C 1-3 Contains alkyl groups.

[0018] In specific examples, n is 1 to 5.

[0019] In a specific example, the R 1 is phenyl-4-fluoro, the R 2 H, R 3 OH is , and n is 5.

[0020] In a specific example, the R 1 is a phenyl-4-O-isoprenyl group, and the R 2 is an O-isoprenyl group, the R 3 OH is , and n is 3 to 7. In a preferred specific embodiment, R1 is a phenyl-4-O-isoprenyl group, the R 2 is an O-isoprenyl group, the R 3 OH is present, and n is 3.

[0021] The present invention provides a composition comprising a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0022] The present invention also provides a method for using a composition for preparing an antiplatelet aggregation agent. The composition comprises a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0023] The present invention further provides a method of using a composition for preparing a preventive or therapeutic agent for diseases associated with platelet aggregation. The composition comprises a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0024] The present invention further provides a method for preventing or treating thrombosis disease, comprising administering to an individual suffering from thrombosis a composition containing a compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof.

[0025] The present invention also provides compounds having the structure of formula (II) or pharmaceutically acceptable salts thereof.

[0026] [ka]

[0027] In the formula, R 1 is a phenyl group, or a phenyl group substituted with Y, where Y is a halogen, OH, O-isoprenyl, or OC 1-6 It is an alkyl group; R 2 is H, OH, O-isoprenyl group, or OC 1-6 It is an alkyl group; R 3 OH, OC1-6 It is an alkyl group; n is between 1 and 7.

[0028] In specific examples, the halogen is fluorine.

[0029] In another specific embodiment, n is 1 to 5.

[0030] The present invention provides a composition comprising a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof.

[0031] The present invention also provides a method for using a composition for preparing an antiplatelet aggregation agent. The composition comprises a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof.

[0032] The present invention further provides a method of using a composition for preparing a preventive or therapeutic agent for diseases associated with platelet aggregation. The composition comprises a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof.

[0033] The present invention further provides a method for preventing or treating thrombotic diseases, comprising administering to an individual suffering from a thrombotic disease a composition containing a compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof.

[0034] As used in this text, the term "medically acceptable salt" refers to derivative compounds obtained by modifying a compound with an acid or alkali and its salt. However, the type of salt is not limited as long as it is physiologically acceptable for use.

[0035] In this text, the term “prevention” means suppressing or preventing the symptoms of a particular disease, disorder, symptom, or side effect. In this text, the term “treatment” means alleviating or eliminating a disease, illness, or one or more symptoms associated with such disease, illness, or condition; or including alleviating or eradicating the cause of the disease, illness, or symptom itself.

[0036] In this text, the term "individual" may refer to mammals, preferably humans.

[0037] In the present invention, compounds having the structure of formula (I) or formula (II) have an antiplatelet aggregation effect. Furthermore, compounds having the structure of formula (I) or formula (II) can suppress platelet aggregation activity. Therefore, the compounds of the present invention, or their derivatives or pharmaceutically acceptable salts thereof, can be used to suppress platelet aggregation and have antithrombotic activity but do not have a bleeding tendency. Accordingly, the present invention provides an antiplatelet agent comprising a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0038] In some embodiments, the present invention provides a method for inhibiting platelet aggregation, comprising administering to an individual in need a composition comprising a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. More further, the present invention provides a method for preventing or treating a disease associated with platelet aggregation, comprising administering to an individual suffering from a disease associated with platelet aggregation a compound comprising a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0039] Thrombotic disorders arise in response to injury or other signals that cause platelets to accumulate at the site of injury. The compounds having the structure of formula (I) or formula (II) provided by the present invention can inhibit platelet aggregation and are therefore applicable to the preparation of therapeutic or prophylactic agents for various platelet aggregation-related diseases or thrombotic disorders. As used herein, the term “thrombotic disorder” refers to a disease in which a thrombus is formed or present in a blood vessel, causing or inducing ischemia or infarction of tissue supplied by the blood vessel. In specific examples, the platelet aggregation-related disease or thrombotic disorder includes arterial cardiovascular thrombotic disorders, venous cardiovascular thrombotic disorders, or thrombotic disorders in the cardiac chambers or peripheral circulation. In preferred specific embodiments, the disease or thrombotic disorder associated with the platelet aggregation activity includes unstable angina, acute coronary syndrome, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, thrombophlebitis, arterial embolism, kidney embolism, pulmonary embolism, or thrombotic disorders resulting from medical implants, devices, or processes that expose blood to artificial surfaces that promote thrombosis.

[0040] The compounds of the present invention can be administered in oral dosage forms such as tablets, capsules (including sustained-release and time-release compounds, respectively), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of the present invention can also be administered intravenously (bolus or perfusion), intraperitoneally, subcutaneously, or intramuscularly. Accordingly, the present invention uses dosage forms well known to those skilled in the art. The compounds of the present invention can be administered alone, but are generally administered with a pharmaceutical carrier selected based on a generally selected route of administration and standard pharmaceutical practice.

[0041] In addition, the compounds of the present invention can also be used to inhibit platelet aggregation in blood and blood products outside the body. For example, they may be stored or processed from living organisms (e.g., for diagnostic or research purposes).

[0042] In the present invention, the compounds having the structure of formula (I) or formula (II) can not only act as antagonists of the TxA2 receptor, but can also reduce the synthesis of TxA2. At the same time, the compounds having the structure of formula (I) or formula (II) can also suppress the enzymatic activity of COX1 and COX2. Therefore, the compounds having the structure of formula (I) or formula (II) can inhibit platelet activation and aggregation, and are also antithrombotic. In addition, the compounds having the structure of formula (I) or formula (II) do not affect the normal hemostatic function in the body of the individual. Therefore, the present invention provides a method for suppressing platelet activation and aggregation in an individual without inducing bleeding, and includes administering to the individual a composition containing a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. The present invention further provides a method for suppressing thrombus formation in an individual without inducing bleeding, and includes administering to the individual a composition containing a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. In this invention, compared to a normal individual, the individual has a relatively high risk of thrombus formation or is in a relatively dangerous state.

[0043] In summary, the present invention designs and synthesizes a series of novel compounds based on the chemical structure of sofalcone, which possess antiplatelet and antithrombotic effects and do not affect hemostatic function in animal studies. Therefore, the compounds of the present invention can be used as novel antiplatelet drugs or in antiplatelet therapy. [Brief explanation of the drawing]

[0044] [Figure 1] Figure 1 shows the synthesis method for sofalcone derivatives. [Figure 2] Figure 2 shows the synthesis method for sofalcone derivatives. MeI: iodomethane. [Figure 3] Figure 3 shows the synthesis method for the solfalkone derivative. [Figure 4] Figure 4 shows the synthesis method for sofalcone derivatives. DCM: Dichloromethane. KI: Potassium iodide. DMF: Dimethylformamide. [Figure 5] Figure 5 shows that sofalcone and its derivatives can competitively antagonize platelet aggregation induced by U46619. Figure 5A shows that sofalcone (SFC) can competitively antagonize platelet aggregation induced by U46619. Figure 5B shows that sofalcone derivative 3 can competitively antagonize platelet aggregation induced by U46619. Figure 5C shows that sofalcone derivative 30 can competitively antagonize platelet aggregation induced by U46619. Human platelet suspensions were pretreated with dimethyl sulfoxide (DMSO) or sofalcone (SFC) (Figure 5A), sofalcone derivative 3 (Figure 5B), or sofalcone derivative 30 (Figure 5C), and then platelet aggregation was stimulated by adding U46619 at different concentrations (0.1-10 μM). Data are shown as mean ± standard error of the mean (n=5). [Figure 6] Figure 6 shows the effects of sofalcone and its derivatives on arachidonic acid (AA)-induced TxB2 and PGE2 production. Figure 6A shows the effects of sofalcone (SFC) and its derivatives on arachidonic acid-induced TxB2 production. Figure 6B shows the effects of sofalcone and its derivatives on arachidonic acid-induced PGE2 production. Human platelet suspension was pretreated with dimethyl sulfoxide (DMSO) or sofalcone (SFC), sofalcone derivative 3, or sofalcone derivative 30, and then arachidonic acid (100 μM) was added to stimulate the production of arachidonic acid metabolites TxB2 and PGE2. Data are shown as mean ± standard error of the mean (n≧5). Compared to the control group, *P<0.05, **P<0.01, and ***P<0.001. ASA: Aspirin. [Figure 7]Figure 7 shows that sofalcone and its derivatives have anti-arterial thrombotic effects. Figure 7A shows that sofalcone (SFC) has anti-arterial thrombotic effects. Figure 7B shows that sofalcone derivative 17 has anti-arterial thrombotic effects. Mice were orally administered sofalcone (SFC, once daily for a total of 4 times), derivative 17, or aspirin (ASA) (single dose). Then, thrombosis was induced in the carotid arteries of the mice with ferric chloride solution, and the time required for the thrombus to occlude the carotid artery (occlusion time) was measured using an ultrasound imaging system. Data are shown as mean ± standard error of the mean (n≧6). Compared to the control group, *P<0.05 and ***P<0.001. [Figure 8] Figure 8 shows that sofalcone and its derivatives do not affect normal hemostatic function. Figure 8A shows that sofalcone (SFC) does not affect normal hemostatic function. Figure 8B shows that sofalcone derivative 17 does not affect normal hemostatic function. Mice were orally administered sofalcone (SFC, once daily for a total of 4 times), derivative 17, or aspirin (ASA) (single dose). After that, the tails were amputated and the bleeding time of the mice was measured. Data are shown as mean ± standard error of the mean (n≧6). Compared to the control group, ***P<0.001. ns: No significant difference. [Modes for carrying out the invention]

[0045] The following examples are not limiting and merely illustrate various aspects and features of the present invention.

[0046] Materials and methods 1. Preparation and analysis of solfalkone and its derivatives Any of the compounds disclosed herein can be produced by methods commonly used in the relevant field or by methods shown in the examples of the present invention. The preparation methods for the solfalkone and its derivatives of the present invention are shown in Figures 1 to 4.

[0047] Figures 1 to 4 show typical synthesis methods for sofalcone derivatives.

[0048] In the method for preparing the compounds shown in Figure 1, the present invention will be illustrated by the preparation processes of compounds 02, 39, 50, 51, and 61.

[0049] Preparation of Compound 02 The starting material S7 (0.83 g, 3 mmol) is placed in a reaction flask, ethanol (EtOH) is used as the solvent, and the mixture is stirred with a stirring bar. 50% KOH is slowly added dropwise, and the mixture is allowed to stand for 10 minutes. Then, 4-fluorobenzaldehyde (0.37 g, 3 mmol), which has been previously dissolved in ethanol, is added dropwise to the reaction flask, and the mixture is stirred at room temperature for 12-16 hours. Thin-layer chromatography (TLC) can be used to determine that the reaction is complete, and the precipitation of solid suspended matter can be confirmed. The solvent is removed using a vacuum concentrate, 200 mL of water is added, and the mixture is further acidified with 6N hydrochloric acid (HCl) to a pH of 4. The crude product is then extracted with ethyl acetate (EA). The mixture is then purified by column chromatography, and EA:n-hexane (hex) = 1:1 is used as the eluent. Recrystallization with ethanol yields compound O2.

[0050] 1 H NMR(400MHz,CDCl3)δ7.67-7.72(d,J=16Hz,1H,Ar-H),7.67-7.65(dd,J=8Hz, 1H,Ar-H),7.61-7.57(m,1H,Ar-H),7.54(s,1H),7.48-7.44(m,1H,Ar-H),7.38 -7.32(m,1H,Ar-H),7.19-7.08(m,1H,Ar-H),7.04-7.01(m,1H),6.97(s,1H), 6.95(s,1H),4.08(m,4H),2.15(m,2H),1.71(m,2H),1.56(m,2H),1.27(m,2H).

[0051] Preparation of compound 39 Compound 02 (1.12 g, 3 mmol) is placed in a reaction flask, ethanol is used as the solvent, and the mixture is stirred with a stirring bar. 3 ml of concentrated hydrochloric acid is slowly added dropwise, and the reaction is carried out under reflux for 2 hours, followed by TLC measurement. After determining that the reaction is complete, the solvent is removed using a vacuum concentrate, and 200 mL of water is added. The crude product is extracted with EA. Subsequently, the compound 39 can be obtained by purifying it using EA:n-hexane (hex) = 1:1 as the eluent by column chromatography.

[0052] 1 H NMR(400MHz,CDCl3)δ7.67-7.72(d,J=16Hz,1H,Ar-H),7.67-7.65(dd,J=8Hz,1H, Ar-H),7.61-7.57(m,1H,Ar-H),7.54(s,1H),7.48-7.42(m,1H,Ar-H),7.35-7.32 (m,1H,Ar-H),7.19-7.06(m,1H,Ar-H),7.04-7.01(m,1H),6.97(s,1H),6.95(s,1 H),4.08(m,4H),2.13(m,2H),1.79(m,2H),1.54(m,2H),1.26(m,2H),1.22(m,3H).

[0053] Preparation of compound 50 Compound 02 (1.12 g, 3 mmol) is placed in a reaction flask, and a palladium-carbon catalyst Pd / C (0.11 g, 1 mmol) is added. The reaction flask is suctioned to create a vacuum, methanol (MeOH) is used as the solvent, and then hydrogen gas is injected, and the reaction is carried out at room temperature for 1 to 3 hours. After determining that the reaction is complete by TLC measurement, the mixture is filtered under reduced pressure using a Celite-packed filter, and then the solvent is removed using a vacuum concentrate. Subsequently, the mixture is purified by column chromatography using EA:n-hexane (hex) = 1:5 as the eluent to obtain compound 50.

[0054] 1H NMR(400MHz,CDCl3)δ7.73(d,J=16Hz,1H,Ar-H),7.64(dd,J=8Hz,1H,Ar-H),7.61-7.56(m,1H,Ar-H),7.52(s,1H),7.48-7.43(m ,1H,Ar-H),7.37-7.32(m,1H,Ar-H),7.18-6.95(m,3H,Ar-H),4.05(m,4H),2.19(m,2H),1.81(m,2H),1.56(m,2H),1.46(m,2H).

[0055] Preparation of compound 51 The starting material S7 (0.83 g, 3 mmol) is placed in a reaction flask, ethanol is used as the solvent, and the mixture is stirred with a stirring bar. 50% potassium hydroxide (KOH) is slowly added dropwise, and the mixture is allowed to stand for 10 minutes. Then, thiophene-2-carboxaldehyde (0.34 g, 3 mmol), which has been previously dissolved in ethanol, is added dropwise to the reaction flask, and the mixture is stirred at room temperature for 12-16 hours. After determining that the reaction is complete by TLC measurement, the precipitation of solid suspended matter can be confirmed. The solvent is removed using a vacuum concentrate, 200 mL of water is added, and the mixture is further acidified with 6N HCl to a pH of 4. The crude product is then extracted with ethyl acetate (EA). After purification by column chromatography, EA:n-hexane (hex) = 1:1 is used as the eluent. Recrystallization with ethanol yields compound 51.

[0056] 1 H NMR(400MHz,CDCl3)δ7.78-7.75(d,J=12Hz,1H,Ar-H),7.67-7.63(dd,J=16Hz,1H,Ar-H),7.46-7.42(m,1H,Ar-H),7.30(s,1H),7.26-7.28(d,1H,Ar- H),7.07-7.04(m,1H,Ar-H),7.02(t,1H,Ar-H),6.96-6.74(d,J=8.1H,Ar- H),4.056(m,2H),1.81-1.82(m,2H),1.63-1.61(m,2H),1.53-1.51(m,2H).

[0057] Preparation of compound 61 Compound 51 (1.12 g, 3 mmol) is placed in a reaction flask, ethanol is used as the solvent, and the mixture is stirred with a stirring bar. 3 ml of concentrated hydrochloric acid is slowly added dropwise, and the mixture is heated under reflux for 2 hours. After determining that the reaction is complete by TLC measurement, the solvent is removed using a vacuum concentrate, and 200 mL of water is added. The crude product is extracted with EA. Subsequently, the compound 61 can be obtained by purifying it using EA:n-hexane (hex) = 1:1 as the eluent by column chromatography.

[0058] 1 H NMR(400MHz,CDCl3)δ7.78-7.75(d,J=16Hz,1H,Ar-H),7.67-7.65(dd,J=8Hz,1H, Ar-H),7.74-7.41(m,1H,Ar-H),7.37-7.36(d,J=16Hz,1H,Ar-H),7.32(s,1H),7. 28(s,1H),7.06-7.05(m,1H),7.02-6.98(m,1H),6.95-6.93(d,J=Hz,1H),4.01-4 .02(m,4H),2.1-2.17(m,2H),1.86-1.79(m,2H),1.65-1.47(m,4H),1.22(m,3H).

[0059] In the method for preparing the compounds shown in Figure 2, the present invention will be illustrated by the preparation processes of compounds 74 and 76.

[0060] Preparation of Compound 74 Process 1: Place the starting material S13 (0.92 g, 3 mmol) in a reaction flask, add ethanol as the solvent, and stir with a stirring bar. Slowly add 50% KOH dropwise and let stand for 10 minutes. Then, add S14 (0.57 g, 3 mmol), which has been previously dissolved in ethanol, dropwise to the reaction flask and stir at room temperature for 12-16 hours. After determining that the reaction is complete by TLC measurement, the precipitation of solid suspended matter can be confirmed. Remove the solvent using a vacuum concentrate and add 200 mL of water. Further acidify with 6N HCl to a pH of 4, and then extract the crude product with ethyl acetate (EA). Subsequently, purify by column chromatography, and use EA:n-hexane (hex) = 1:1 as the eluent. Recrystallize with ethanol to obtain the compound solfalkone.

[0061] Process 2: Place 1.4 g of solfalkone (3 mmol) in a reaction flask, add methanol as the solvent, and stir with a stirring bar. Then slowly add 3 ml of concentrated hydrochloric acid dropwise and heat under reflux for 1-2 hours. After confirming complete reaction with a TLC strip, remove the solvent using a vacuum concentrator, add 200 ml of water, and extract the crude product with EA. Subsequently, purify by column chromatography to obtain compound 69.

[0062] Process 3: Compound 69 (0.98 g, 3 mmol) is placed in a reaction flask, and palladium-carbon catalyst Pd / C (0.11 g, 1 mmol) is added. The reaction flask is suctioned to create a vacuum, methanol is added as the solvent, and then hydrogen gas is injected, and the mixture is reacted at room temperature for 1 to 3 hours. After determining that the reaction is complete by TLC measurement, the mixture is filtered under reduced pressure through a Celite-packed filter, and then the solvent is removed using a vacuum concentrate. The mixture is then purified by column chromatography to obtain compound 72.

[0063] Process 4: Compound 72 (0.99 g, 3 mmol) and potassium carbonate (2.1 g, 15 mmol) are placed in a reaction flask, acetone is used as the solvent, and the mixture is stirred with a stirring bar. Then, isoprenyl bromide (1.88 g, 12 mmol) is slowly added dropwise, and the mixture is reacted at room temperature for 12-16 hours. After determining that the reaction is complete by TLC measurement, the solvent is removed using a vacuum concentrator, 200 mL of water is added, and the mixture is neutralized with 6N HCl to a pH of 7. The crude product is extracted with EA. Then, the compound is purified using EA:n-hexane (hex) = 1:5 as the eluent to obtain compound 74.

[0064] 1 H NMR(400MHz,CDCl3)δ7.83-7.81(d,J=8Hz,1H,Ar-H),7.16-7.14(d,J=8Hz,2H,Ar-H),6.84-6.82(d,J=8Hz,2H,Ar-H),6.58-6.56(d,1H,Ar-H), 5.51-5.44(m,2H),4.66(s,2H),4.54-4.46(dd,J=32Hz,4H),3.73(s,3H ),3.36-3.43(t,2H),2.96(t,3H),1.81-1.78(m,6H),1.75-1.73(m,6H).

[0065] Preparation of compound 76 Compound 74 (1.4 g, 3 mmol) is placed in a reaction flask, methanol is added as the solvent, and the mixture is stirred with a stirring bar. 50% KOH is slowly added dropwise, and the mixture is reacted at room temperature for 1-2 hours. After confirming complete reaction using a TLC strip, the solvent is removed using a vacuum concentrator, and 200 mL of water is added. The mixture is then acidified with 6N HCl to pH=4, and the crude product is extracted with EA. Subsequently, the compound 76 can be obtained by purifying it using EA:n-hexane (hex) = 1:5 as the eluent by column chromatography.

[0066] 1H NMR(400MHz,CDCl3)δ7.72-7.70(d,J=8Hz,1H,Ar-H),7.12-7.11(d,J=4Hz,2H,Ar-H),6.84-6.82(d,J=16Hz,2H,Ar -H),6.59-6.44(m,2H,Ar-H),5.48-5.44(m,2H),4.69-4.46(m,6H),3.21(s,2H),2.96(s,2H),1.80-1.73(m,12H).

[0067] In the method for preparing the compound shown in Figure 3, the present invention will be illustrated by the preparation process of compound 98.

[0068] Preparation of compound 98 The starting material S1 (1.23 g, 4 mmol) is placed in a reaction flask, ethanol is used as the solvent, and the mixture is stirred with a stirring bar. 50% KOH is slowly added dropwise, and the mixture is allowed to stand for 10 minutes. Then, terephthalaldehyde (0.27 g, 2 mmol), which has been previously dissolved in ethanol, is added dropwise to the reaction flask, and the mixture is stirred at room temperature for 12-16 hours. After determining that the reaction is complete by TLC measurement, the precipitation of solid suspended matter can be confirmed. The solvent is removed using a vacuum concentrate, 200 mL of water is added, and the mixture is further acidified with 6N HCl to a pH of 4. The crude product is extracted with ethyl acetate (EA). Subsequently, the compound is purified by column chromatography using EA:n-hexane (hex) = 1:1 as the eluent. Recrystallization with ethanol yields compound 98.

[0069] 1 H NMR(400MHz,DMSO)δ8.11-8.08(d,J=12Hz,4H,Ar-H),7.81(s,4H,Ar-H),6.67-6.49(m,2H) ,5.45-5.42(m,2H),4.87(m,4H),4.62-4.61(d,J=4,4H),1.75-1.73(m,12H),2.96(s,2H).

[0070] In the method for preparing the compounds shown in Figure 4, the present invention will be illustrated by the preparation processes of compounds 83 and 84.

[0071] Preparation of compound 83 Compound 69 (0.98 g, 3 mmol) and potassium carbonate (2.1 g, 15 mmol) are placed in a reaction flask, acetone is used as the solvent, and ethyl 2-bromoacetate (1.00 g, 6 mmol) is slowly added dropwise. The mixture is reacted at room temperature for 12-16 hours. After determining that the reaction is complete by TLC measurement, the solvent is removed using a vacuum concentrator, 200 mL of water is added, and the mixture is neutralized with 6N HCl to a pH of 7. The crude product is extracted with EA. Subsequently, the compound 83 can be obtained by purification using EA:n-hexane (hex) = 1:5 as the eluent by column chromatography.

[0072] 1 H NMR(400MHz,DMSO)δ7.72-7.59(m,6H,Ar-H),7.00-6.98(d,J=8Hz,2H,Ar-H),6.71-6.7 0(m,1H,Ar-H),5.01(s,2H),4.89-4.85(d,J=16Hz,4H),3.72(s,3H),1.25-1.20(m,6H).

[0073] Preparation of compound 84 Compound 83 (1.5 g, 3 mmol) is placed in a reaction flask, acetone is used as the solvent, and the mixture is stirred with a stirring bar. 50% KOH is slowly added dropwise, and the mixture is reacted at room temperature for 1-2 hours. After confirming complete reaction using a TLC strip, the solvent is removed using a vacuum concentrator, and 200 mL of water is added. The mixture is then acidified with 6N HCl to pH=4, and the crude product is extracted with EA. Subsequently, the compound 84 can be obtained by purifying the compound using EA:n-hexane (hex) = 1:1 as the eluent by column chromatography.

[0074] 1H NMR(400MHz,DMSO)δ7.89-7.85(d,J=16Hz,1H,Ar-H),7.75-7.23(d,J=8Hz,1H,Ar-H),7.68-7.62(t,2H,Ar-H),7.58(s,1H,Ar-H),6 .96-6.94(d,J=8Hz,1H,Ar-H),6.70-6.69(d,J=4Hz,6H,Ar-H),6.65-6.63(dd,J=8Hz,1H),4.90(s,2H),4.79-7.75(d,J=16Hz,4H).

[0075] 2. Preparation of human platelet suspension A blood sample is collected from a healthy donor, and an acid-citrate-dextrose (ACD) solution is used as an anticoagulant. Platelets are obtained from the blood sample by centrifugation, washed to remove any remaining plasma, and a platelet suspension is prepared.

[0076] 3. Measurement of platelet aggregation reaction This experiment uses a platelet aggregation analyzer (Chrono-Log Co., Havertown, PA, USA) for measurement. The measurement compound is added to a platelet suspension and reacted for 3 minutes at 37°C with stirring (1200 rpm). Subsequently, platelet stimulant U46619 or collagen is added to induce platelet aggregation, and the measurement time is 5 minutes. Regarding the principle of platelet aggregation measurement, when platelets aggregate in response to a stimulant, the light transmittance of the platelet suspension increases. By calculating the change in light transmittance of the platelet suspension before and after stimulation, the platelet aggregation rate can be obtained.

[0077] 4. Measurement of TxB2 and PGE2 content in platelets The compound to be measured is added to a platelet suspension and reacted for 3 minutes at 37°C with stirring (1200 rpm). Subsequently, arachidonic acid (AA) (100 μM) is added and reacted for 4 minutes, and finally, EDTA (5 mM) is added to stop the reaction. The above sample is centrifuged at 4°C and 13,000 rpm for 1 minute, and the supernatant is collected. The concentrations of TxB2 and PGE2 in the supernatant are measured using enzyme immunoassay kits (TxB2 ELISA kit and PGE2 ELISA kit; Cayman Chemical Company), respectively.

[0078] 5. Measurement of COX1 and COX2 enzyme activity COX1 and COX2 enzyme activity is analyzed using a human COX inhibitor screening kit (Cayman Chemical Company). The compound to be measured is allowed to stand with human recombinant COX1 or COX2 enzyme and heme at 37°C for 15 minutes, then AA (10 μM) is added and the mixture is reacted for 2 minutes. Subsequently, stannous chloride is added to reduce the product of the above COX reaction, PGH2, to PGF2α. Finally, the PGF2α content in the sample is measured by enzyme immunoassay, and the inhibition rate is calculated.

[0079] 6. Iron chloride-induced carotid artery thrombosis test in mice This study evaluates the antithrombotic effect of the compound being tested by utilizing the fact that ferric chloride induces vascular damage and even thrombosis. The compound is administered orally to BALB / c mice approximately 6-8 weeks old. Subsequently, the mice are anesthetized with isoflurane, and the right carotid artery is surgically exposed. Filter paper (2x4mm) containing 8.5% ferric chloride is then used to test the compound. 2The filter paper is attached to the right carotid artery for 3 minutes. After removing the filter paper, any remaining ferric chloride is wiped away with a cotton ball moistened with saline solution, and the blood flow in the right carotid artery is measured using an ultrasound imaging system (VEVO 2100 system; VisualSonics) combined with a Doppler flow probe (MS400, 18-38MHz). Vascular occlusion is determined by the cessation of blood flow for 1 minute. If blood flow does not stop after 30 minutes, it is considered the endpoint of the experiment.

[0080] 7. Bleeding test in mice This invention evaluates the effect of a target compound on normal hemostasis by using a method that involves excising the tail end of a mouse to induce bleeding. The target compound is administered orally to BALB / c mice approximately 6-8 weeks old. The mice are then anesthetized with isoflurane, and a 2mm portion of the tail end is excised. The mouse tail is immersed in 37°C saline solution, and the bleeding time is observed. Bleeding time is defined as the time required from tail excision until bleeding completely stops. If bleeding does not stop after 15 minutes, it is considered the experimental endpoint.

[0081] 8.Statistical analysis The experimental results of this invention are expressed as mean ± standard error of the mean. Statistical significance is calculated using one-way analysis of variance (ANOVA) in GraphPad Prism software. A p-value < 0.05 is considered statistically significant.

[0082] result 1. Antiplatelet aggregation effect of solfolcone derivatives This invention divides the solfolcone derivatives prepared in Figures 1 to 4 into two types. (A) The first type of compound has the compound of formula (I).

[0083] [ka]

[0084] The compounds having formula (I) include derivatives 1-48, 51-71, 77-99, and 101-114. (B) The second compound has a compound of formula (II).

[0085] [ka]

[0086] The compounds having formula (II) include derivatives 49, 50, 72-76, 100, 115, and 116.

[0087] Table 1 shows that sofalcone (SFC) derivatives can effectively suppress platelet aggregation induced by the TxA2 agonist U46619 or collagen, and that their efficacy is superior to that of the clinically administered drugs aspirin and seratrodast.

[0088] [Table 1]

[0089] JPEG0007886041000006.jpg208167

[0090] JPEG0007886041000007.jpg210166

[0091] JPEG0007886041000008.jpg211170

[0092] JPEG0007886041000009.jpg212169

[0093] 2. Sofalcone and its derivatives competitively antagonize platelet aggregation induced by U46619. Figures 5A to 5C show that sofalcone and its derivatives 3 and 30 can suppress platelet aggregation induced by U46619 (100 μM) in human platelet suspension. Human platelet suspension was pretreated with dimethyl sulfoxide (DMSO), sofalcone (20 μM and 50 μM), and sofalcone derivatives 3 or 30 (both 0.2 μM and 0.5 μM), and then platelet aggregation was stimulated by adding different concentrations of U46619 (0.1 to 10 μM). In the presence of sofalcone and its derivatives, the U46619 concentration-platelet aggregation reaction curve shifts parallel to the right, but the maximum value of platelet aggregation is not significantly affected. Based on these results, it can be seen that sofalcone and its derivatives 3 or 30 can competitively antagonize the TxA2 receptor.

[0094] 3. Effects of sofalcone and its derivatives on AA metabolites of human platelets Figures 6A and 6B show the effects of sofalcone and its derivatives 3 and 30 on the production of TxB2 (a stable metabolite of TxA2) and PGE2 induced by arachidonic acid (AA) (100 μM) in human platelet suspension. Sofalcone and its derivative 30 do not inhibit the production of platelet TxB2 and PGE2. However, derivative 3 is similar to aspirin and can inhibit the production of both TxB2 and PGE2. Based on these results, it can be seen that derivative 3 not only has TxA2 receptor antagonistic activity but can also reduce TxA2 synthesis.

[0095] 4. Effects of sofalcone derivatives on human recombinant COX1 and COX2 Table 2 shows that derivative 3 can inhibit the enzyme activity of human recombinant COX1 and COX2 in a dose-dependent manner, and has a favorable inhibitory effect on COX1. Based on these results, it can be seen that derivative 3 reduces platelet TxA2 synthesis by inhibiting COX1.

[0096] [Table 2]

[0097] 5. Antithrombotic effects of solfalkone and its derivatives in animal models Figures 7A and 7B show that mice were administered orally with sofalcone (50 mg / kg daily for a total of 4 days) or derivative 17 (potassium salt of derivative 30) (single dose of 10 or 25 mg / kg). In a FeCl3-induced carotid thrombosis model, the carotid occlusion time was clearly prolonged, demonstrating its antithrombotic effect in vivo. By comparison, aspirin (ASA) (25 mg / kg) also prolonged the carotid occlusion time.

[0098] 6. Effects of sofalcone and its derivatives on bleeding time in animal models Figures 8A and 8B show that administering sofalcone (50 mg / kg daily for a total of 4 days) or its derivative 17 (potassium salt of 17) (single dose of 10 or 25 mg / kg) via enteral tube to mice did not affect the bleeding time at the amputated tail of the mice, demonstrating that it did not suppress normal hemostatic function. In comparison, aspirin (ASA) (25 mg / kg) clearly prolonged the bleeding time at the amputated tail of mice.

[0099] This invention is appropriately described as being able to be implemented under important conditions or limitations not specifically disclosed herein. The terms used herein are not limiting. There is no difference between expressions and descriptions using these terms and any other equivalents, but it should be recognized that the rights within this invention are modifiable. Accordingly, although examples and other circumstances of the invention have been described herein, the disclosures herein can be modified and altered by those skilled in the art, and such modifications and alterations will be deemed to be within the scope of the rights of this invention.

Claims

1. A compound having the structure of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 In the formula, n is between 2 and 7, and R １ is a phenyl group, thiophenyl group, furanyl group, pyridinyl group, bromothiophenyl group, thiazolyl group, or a phenyl group substituted with X, and X is H, halogen, NO ２ NH ２ NHAc, O-Ac, O-geranyl group, O-C １－１０ Alkyl group, OH, OBn, O-isoprenyl group, O-halobenzyl group, O-C １－６ Alkyloxybenzyl group, O-C １－６ Alkyl-CO-phenyl group, or O-C １－６ Alkyl-COO-C １－６ It is an alkyl group, R ２ is H, OH, halogen, O - geranyl group, O - isoprenyl group, O - C １－１０ alkyl group, O - Ac, OBn, O - halobenzyl group, O - C １－６ alkyloxybenzyl group, phenyl - O - isoprenyl group, O - C １－６ alkyl - CO - phenyl group, or O - C １－６ alkyl - COO - C １－６ alkyl group, and R ３ is OH or O-C １－６ Is it an alkyl group? Alternatively, n is 5, The aforementioned R １ is 2-(3-aminothiophenyl), the R ２ H and the R ３ Is it an OH group, or The aforementioned R １ is 2-(4-methyl-2-amino-thiophenyl), the R ２ H and the R ３ Is it an OH group? Alternatively, n is 1, The aforementioned R １ Ph-OMe, the R ２ OMe, and the R ３ Is it OET? The aforementioned R ２ is an O-isoprenyl group, the R ３ is OH, and the R １ is Ph-fluoro, Ph-Chloro, Ph-NO ２ Or is it Ph-NHAc? The aforementioned R １ is Ph-fluoro, the R ２ H and the R ３ Is it an OH group? The aforementioned R １ Ph, the R ２ is fluoro, and the R ３ Is it an OH group? The aforementioned R １ is Ph-fluoro, the R ２ is fluoro, and the R ３ Is it an OH group? The aforementioned R １ is Ph-fluoro, the R ２ is OH, and the R ３ Is it OET? The aforementioned R １ Ph-chloro, the R ２ is OH, and the R ３ Is it OET? The aforementioned R １ Ph-NO ２ , the R ２ is OH, and the R ３ Is it OET? The aforementioned R １ Ph-NH ２ , the R ２ H and the R ３ Is it OET? The aforementioned R １ is pyridinyl, the R ２ H and the R ３ Is it an OH group? The aforementioned R １ Ph-OAc, the R ２ is OAc, and the R ３ Is it OMe? The aforementioned R １ Ph-OCH ２ COPh, the R ２ ga OCH ２ COPh, and the R ３ Is it OMe? The aforementioned R １ Ph-OBn, the R ２ OBn, and the R ３ Is it OMe or OH? The aforementioned R １ is Ph-O-Fluorobenzyl, the R ２ is O-Fluorobenzyl, and the R ３ Is it OMe? The aforementioned R １ is Ph-O-Methoxylbenzyl, the R ２ is O-Methoxylbenzyl, and the R ３ Is it OMe? The aforementioned R １ is Ph-O-Fluorobenzyl, the R ２ is O-Fluorobenzyl, and the R ３ Is it an OH group? The aforementioned R １ Ph-O(CH ２ ) ３ CH ３ , the R ２ O(CH ２ ) ３ CH ３ , and the R ３ Is it OMe or OH? The aforementioned R １ is Ph - O(CH ２ ) ５ CH ３ , the aforementioned R ２ is O(CH ２ ) ５ CH ３ , and the aforementioned R ３ is OMe or OH, or The above R １ is Ph-O(CH ２ ) ７ CH ３ , the above R ２ is O(CH ２ ) ７ CH ３ , and the above R ３ is OMe or OH, or, The aforementioned R １ Ph-O(CH ２ ) ９ CH ３ , the R ２ O(CH ２ ) ９ CH ３ , and the R ３ is OMe or OH. A compound or a pharmaceutically acceptable salt thereof.

2. The aforementioned R １ is phenyl-4-fluoro, the R ２ H, the aforementioned R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is OH and n is 5.

3. The aforementioned R １ is a phenyl-4-O-isoprenyl group, the R ２ is an O-isoprenyl group, the R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is OH and n is 3 to 7.

4. The aforementioned R １ is a phenyl-4-O-isoprenyl group, the R ２ is an O-isoprenyl group, the R ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is OH and n is 3.

5. A method of using a composition for preparing an antithrombotic agent, wherein the composition comprises a compound or a pharmaceutically acceptable salt thereof, The compound has the structure of formula (I), 【Chemistry 2】 In the formula, R １ is a phenyl group, thiophenyl group, furanyl group, pyridinyl group, bromothiophenyl group, thiazolyl group, or a phenyl group substituted with X, and X is H, halogen, NO ２ NH ２ NHAc, O-Ac, O-geranyl group, C １－６ Alkyl alkyl group, O-C １－１０ Alkyl group, OH, OBn, O-isoprenyl group, O-halobenzyl group, O-C １－６ Alkyloxybenzyl group, O-C １－６ Alkyl-CO-phenyl group, or O-C １－６ Alkyl-COO-C １－６ It is an alkyl group, R ２ H, OH, halogen, O-geranyl group, O-isoprenyl group, O-C １－１０ Alkyl group, O-Ac, OBn, O-halobenzyl group, O-C １－６ Alkyloxybenzyl group, phenyl-O-isoprenyl group, O-C １－６ Alkyl-CO-phenyl group, or O-C １－６ Alkyl-COO-C １－６ It is an alkyl group, R ３ is OH or O-C １－６ It is an alkyl group, Instructions for use, where n is between 1 and 7.

6. A method of using a composition for preparing a drug for the prevention or treatment of thrombotic disease, wherein the composition comprises a compound or a pharmaceutically acceptable salt thereof. The compound has the structure of formula (I), 【Transformation 3】 R １ is a phenyl group, thiophenyl group, furanyl group, pyridinyl group, bromothiophenyl group, thiazolyl group, or a phenyl group substituted with X, and X is H, halogen, NO ２ NH ２ NHAc, O-Ac, O-geranyl group, C １－６ Alkyl alkyl group, O-C １－１０ Alkyl group, OH, OBn, O-isoprenyl group, O-halobenzyl group, O-C １－６ Alkyloxybenzyl group, O-C １－６ Alkyl-CO-phenyl group, or O-C １－６ Alkyl-COO-C １－６ It is an alkyl group, R ２ H, OH, halogen, O-geranyl group, O-isoprenyl group, O-C １－１０ Alkyl group, O-Ac, OBn, O-halobenzyl group, O-C １－６ Alkyloxybenzyl group, phenyl-O-isoprenyl group, O-C １－６ Alkyl-CO-phenyl group, or O-C １－６ Alkyl-COO-C １－６ It is an alkyl group, R ３ is OH or O-C １－６ It is an alkyl group, Instructions for use, where n is between 1 and 7.

7. The method of use according to claim 6, wherein the thrombotic disease includes unstable angina, acute coronary syndrome, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral artery occlusive disease, venous thromboembolism, thrombophlebitis, arterial embolism, renal embolism, pulmonary embolism, or a thrombotic disease resulting from a medical implant, device, or process that exposes blood to an artificial surface that promotes thrombosis.

8. A compound having the structure of formula (II) or a pharmaceutically acceptable salt thereof, 【Chemistry 4】 In the formula, R １ is a phenyl group, or a phenyl group substituted with Y, where Y is a halogen, OH, O-isoprenyl group, or O-C １－６ It is an alkyl group; R ２ is an H, OH, O-isoprenyl group, or O-C １－６ It is an alkyl group; R ３ OH, O-C １－６ It is an alkyl group; A compound or a pharmaceutically acceptable salt thereof, wherein n is between 3 and 7.

9. A method of using a composition for preparing an antithrombotic agent, wherein the composition comprises a compound or a pharmaceutically acceptable salt thereof. The aforementioned compound has the structure of formula (II), 【Transformation 5】 In the formula, R １ is a phenyl group, or a phenyl group substituted with Y, and Y is a halogen, OH, O-isoprenyl group, or O-C １－６ It is an alkyl group, R ２ is an H, OH, O-isoprenyl group, or O-C １－６ It is an alkyl group, R ３ OH, O-C １－６ It is an alkyl group, Instructions for use, where n is between 1 and 7.

10. A method of using a composition for preparing a drug for the prevention or treatment of thrombotic disease, wherein the composition comprises a compound or a pharmaceutically acceptable salt thereof. The aforementioned compound has the structure of formula (II), 【Transformation 6】 In the formula, R １ is a phenyl group, or a phenyl group substituted with Y, and Y is a halogen, OH, O-isoprenyl group, or O-C １－６ It is an alkyl group, R ２ is an H, OH, O-isoprenyl group, or O-C １－６ It is an alkyl group, R ３ OH, O-C １－６ It is an alkyl group, Instructions for use, where n is between 1 and 7.

11. The method of use according to claim 10, wherein the thrombotic disease includes unstable angina, acute coronary syndrome, myocardial infarction, transient ischemic attack, stroke, atherosclerosis, peripheral artery occlusive disease, venous thromboembolism, thrombophlebitis, arterial embolism, renal embolism, pulmonary embolism, or a thrombotic disease resulting from a medical implant, device, or process that exposes blood to an artificial surface that promotes thrombosis.

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