阅读说明：本技术 一种新型par-1抑制剂及其制备方法和在预防和/或治疗血栓性疾病中的用途 (Novel PAR-1 inhibitor, preparation method thereof and application thereof in preventing and/or treating thrombotic diseases ) 是由 董旭 于康 娄红祥 孙斌 于 2019-09-29 设计创作，主要内容包括：本发明属于血液抗凝固技术领域,具体涉及一种新型PAR-1抑制剂及其制备方法和在预防和/或治疗血栓性疾病中的用途。所述的新型PAR-1抑制剂,结构式为：<Image he="593" wi="319" file="DDA0002220955120000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>采用市售天然产物香紫苏内酯为原料,经四步反应制得。所述PAR-1抑制剂,母核与沃拉帕沙高度相似,作用靶点明确、结构新颖、活性高,其IC<Sub>50</Sub>值能够达到纳摩尔级别,安全性高,制备成本低廉、易于工业化批量生产,在作为治疗血栓性疾病的候选药物中具有很好的应用前景。(The invention belongs to the technical field of blood anticoagulation, and particularly relates to a novel PAR-1 inhibitor, a preparation method thereof and application thereof in preventing and/or treating thrombotic diseases. The novel PAR-1 inhibitor is characterized in that,the structural formula is as follows: the natural product sclareolide sold in the market is adopted as a raw material and is prepared by four-step reaction. The PAR-1 inhibitor has a mother nucleus highly similar to that of Vorapaxar, definite action target, novel structure, high activity and IC 50 The value can reach nanomolar level, the safety is high, the preparation cost is low, the industrial batch production is easy, and the application prospect in serving as a candidate drug for treating thrombotic diseases is good.)

1. A novel PAR-1 inhibitor characterized by: the structural formula is shown as the formula (I):

2. a process for the preparation of a novel PAR-1 inhibitor according to claim 1, characterized in that: the method comprises the following steps:

1) the sclareolide is used as an initial raw material, and hydroxyl is introduced at a carbonyl alpha-position through oxidation to prepare a compound shown in a formula (II);

2) LiAlH is used as carbonyl in the compound shown in the formula (II)₄Reducing to obtain a compound shown as a formula (III);

3) by NaIO₄Carrying out oxidative cracking on an o-diol structure in the compound shown in the formula (III) to prepare a compound shown in a formula (IV);

4) carrying out Wittig reaction on a compound shown as a formula (IV) and a compound shown as a formula (V) under the action of n-butyllithium to obtain a compound shown as a formula (I);

3. use of a novel PAR-1 inhibitor according to claim 1 characterized by: adding one or more of pharmaceutically acceptable pharmaceutical adjuvants, carriers, excipients or diluents to obtain a pharmaceutical composition for preventing and/or treating thrombotic diseases.

4. The use of a novel PAR-1 inhibitor according to claim 3 wherein: the thrombotic diseases include thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, heart failure, acute infarction, glomerulonephritis or peripheral vascular diseases.

5. The use of a novel PAR-1 inhibitor according to claim 3 wherein: the dosage form of the pharmaceutical composition is solid or liquid oral preparation and injection.

6. The use of a novel PAR-1 inhibitor according to claim 3 wherein: the medicine composition is tablet, dispersible tablet, enteric coated tablet, chewable tablet, orally disintegrating tablet, capsule, sugar coated preparation, granule, dry powder, oral solution, small water injection for injection, freeze dried powder for injection, large transfusion or small transfusion.

Technical Field

The invention belongs to the technical field of blood anticoagulation, and particularly relates to a novel PAR-1 inhibitor, a preparation method thereof and application thereof in preventing and/or treating thrombotic diseases.

Background

According to the Chinese cardiovascular disease report 2017 published by the national cardiovascular disease center at the day ago, the method comprises the following steps: about 2.9 hundred million Chinese patients with cardiovascular and cerebrovascular diseases (including coronary heart disease, cerebral apoplexy, heart failure, hypertension and the like) have a rapid growth trend. The death caused by cardiovascular and cerebrovascular diseases is the first cause of the total death among urban and rural residents, and is higher than that caused by tumors and other diseases. It is worth noting that the incidence of thrombotic diseases caused by vascular embolism (such as cerebral thrombosis, cerebral infarction, myocardial infarction, heart failure, cardiogenic shock, coronary heart disease, atherosclerosis and the like caused by thrombotic diseases) in cardiovascular and cerebrovascular diseases is increasing year by year and shows a trend of youthfulness, and the diseases have long course of disease, high cost, high lethality and high recurrence rate, and are now important public health problems in China.

At present, the demand of medicines for preventing and treating thrombotic diseases is great at home and abroad. Relevant survey data indicates: antithrombotic drugs have a huge market in China. Antithrombotic drugs can be classified into antiplatelet drugs (such as clopidogrel, ticagrelor and the like), anticoagulant drugs (such as rivaroxaban, low molecular heparin calcium and the like) and thrombolytic drugs (such as alteplase, urokinase and the like) according to the action mechanism, wherein the sale and use scale of the antiplatelet drugs occupies the market of the antithrombotic drugs in the Banqiangjiang mountains. However, most of the traditional antiplatelet drugs resist the formation of thrombus by inhibiting TXA2 or ADP, which easily influences the normal hemostatic function of human body while blocking the pathological thrombus formation process, thereby increasing the probability and risk of bleeding of patients.

This situation is expected to be improved and solved with the market introduction of PAR-1(Protease-activated receptor-1) inhibitory drugs. The medicine can block platelet aggregation and pathological thrombus enlargement mediated by thrombin by inhibiting PAR-1, and can not influence the normal protective hemostasis process of a human body in which TXA2 and ADP participate, so that the occurrence of bleeding in the treatment process of a patient is reduced. By far the first and only one antiplatelet drug developed and marketed based on PAR-1, voraxar Sulfate (trade name zontivty), a novel antiplatelet drug developed by the american default sato corporation. The drug was approved for marketing in the united states and canada in 5 months and 2016 and 11 months, respectively, in 2014 and 2016, respectively, and was primarily used in patients with a history of heart attacks and patients with arterial embolization of the lower extremities, and could further reduce the risk of heart attacks and strokes. Although the Vorapaxar has good anticoagulant activity, the Vorapax has the defects of complex structure, long synthetic route and high preparation cost; in addition, some people still have some bleeding side effects in the long-term use process, but due to the long half-life period (10 days), no proper medicine can resist and relieve the bleeding symptoms when the side effects occur, and the clinical application and market performance of the medicine are adversely affected.

Chinese patent CN 105732595a discloses a PAR-1 inhibitor based on terpene derivatives, a preparation method thereof and use thereof in treating thrombotic diseases, wherein the structural formula of the compound is as follows:

wherein the content of the first and second substances,represents a single bond or a double bond; r¹And R²All represent respectively: hydrogen atom, halogen atom, hydroxyl group, (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy or (C)₁-C₄) A hydroxyalkyl group;

or R¹And R²Together form a double bond;

or R¹And R²Together form a spiro or hetero spiro ring having 3 to 7 atoms;

R³represents a hydrogen atom, a hydroxyl group, or (C)₁-C₄) Alkyl, (C)₁-C₄) Hydroxyalkyl or (C)₁-C₄) An alkoxy group;

or R³represents-C (O) R⁶、-C(O)OR⁶or-C (O) NR⁶R⁷Wherein R is⁶、R⁷Independently selected from hydrogen atom or (C)₁-C₆) An alkyl group; r⁴Represents a hydroxyl group, (C)₁-C₄) Hydroxyalkyl or (C)₁-C₄) An alkoxy group;

or R⁴Represents an oxygen atom and forms a double bond with the carbon atom to which it is attached, i.e. a ketocarbonyl group;

R⁵represents a halogen atom, a trifluoromethoxy group or a trifluoromethyl group.

However, from the biological activity data of the compounds disclosed in the patent of invention, there are the following problems: the compound has low activity and IC₅₀Values only reach micromolar levels.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: overcomes the defects of the prior art, provides a novel PAR-1 inhibitor, the mother nucleus is highly similar to the Volaparsa, the inhibitor has definite action target, novel structure, high activity and IC₅₀The value can reach nanomolar level, and the safety is high; the invention also provides a preparation method and application thereof in preventing and/or treating thrombotic diseases, and has low preparation cost and good application prospect.

The structural formula of the novel PAR-1 inhibitor is shown as the formula (I):

the preparation method of the novel PAR-1 inhibitor comprises the following steps:

1) the sclareolide is used as an initial raw material, and hydroxyl is introduced at a carbonyl alpha-position through oxidation to prepare a compound shown in a formula (II);

2) LiAlH is used as carbonyl in the compound shown in the formula (II)₄Reducing to obtain a compound shown as a formula (III);

3) by NaIO₄Carrying out oxidative cracking on an o-diol structure in the compound shown in the formula (III) to prepare a compound shown in a formula (IV);

4) carrying out Wittig reaction on a compound shown as a formula (IV) and a compound shown as a formula (V) under the action of n-butyllithium to obtain a compound shown as a formula (I);

wherein: the above steps of preparing the compound represented by the formula (IV) from sclareolide as a starting material through the steps 1) to 3) are well known in the art.

The application of the novel PAR-1 inhibitor is to add one or more of pharmaceutically acceptable pharmaceutic adjuvants, carriers, excipients or diluents to prepare a pharmaceutical composition for preventing and/or treating thrombotic diseases.

Wherein:

the thrombotic diseases include thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, heart failure, acute infarction, glomerulonephritis or peripheral vascular diseases.

Preferably, the dosage form of the pharmaceutical composition is solid or liquid oral preparation and injection.

More preferably, the pharmaceutical composition is a tablet, a dispersible tablet, an enteric-coated tablet, a chewable tablet, an orally disintegrating tablet, a capsule, a sugar-coated agent, a granule, a dry powder, an oral solution, a small water injection for injection, a freeze-dried powder injection for injection, a large infusion solution or a small infusion solution.

The novel PAR-1 inhibitors may also be used in combination with at least one other cardiovascular disease agent during the course of therapy. Wherein said other cardiovascular disease agents are useful for the treatment of thrombosis related diseases including thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, myocardial infarction, glomerulonephritis, thrombotic stroke, thromboembolic stroke, peripheral vascular disease, other cardiovascular diseases and other diseases in which thrombin and its receptors play a pathological role.

The invention has the following beneficial effects:

(1) the PAR-1 inhibitor has a mother nucleus which is highly similar to Wolaparin, clear action target, novel structure, high activity and IC₅₀The value can reach nanomolar level, the safety is high, the preparation cost is low, the industrial batch production is easy, and the application prospect in serving as a candidate drug for treating thrombotic diseases is good.

(2) The starting material used in the synthetic process route of the compound is commercially available active natural material sclareolide. The reagents and materials used in the reaction route are common commercial products, and the generation and transformation of the chiral center of the compound are not involved in the synthesis process. Therefore, the synthesis route can prepare the target product from the starting material rapidly and efficiently through four-step reaction on the premise of ensuring that the chiral center conformation is not changed, has good economy and is suitable for large-scale industrial batch production.

Drawings

FIG. 1 is a graph of novel PAR-1 inhibitors according to the invention¹H NMR(400MHz,CDCl₃)；

FIG. 2 is a graph of novel PAR-1 inhibitors of the present invention¹³C NMR(100MHz,CDCl₃)。

Detailed Description

The present invention is further illustrated by, but is not limited to, the following examples.