WO2021073038A1 - 一种邻羟基苯甲酸聚二醇酯类化合物及其合成制备方法和医药用途 - Google Patents

一种邻羟基苯甲酸聚二醇酯类化合物及其合成制备方法和医药用途 Download PDF

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WO2021073038A1
WO2021073038A1 PCT/CN2020/080340 CN2020080340W WO2021073038A1 WO 2021073038 A1 WO2021073038 A1 WO 2021073038A1 CN 2020080340 W CN2020080340 W CN 2020080340W WO 2021073038 A1 WO2021073038 A1 WO 2021073038A1
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compound
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polyglycol
acetoxybenzoyl
hydroxybenzoic acid
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PCT/CN2020/080340
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聂丹
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新乡海盈生物科技有限责任公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
    • C07C69/80—Phthalic acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

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  • the invention relates to a polyglycol ortho-hydroxybenzoic acid compound and a preparation method thereof, and also relates to the use of the compound in anticoagulation, belonging to the fields of medicine synthesis and medicine and health.
  • Cardiovascular and cerebrovascular diseases have become the number one killer of human health.
  • Thrombotic diseases mainly include myocardial infarction, pulmonary embolism, atrial fibrillation, cerebral infarction, etc., especially myocardial infarction and stroke, which are mainly caused by embolism, are still the main causes of death in cardiovascular and cerebrovascular diseases.
  • more than 2.6 million people die from cardiovascular and cerebrovascular diseases each year, and 75% of the surviving patients are disabled, of which more than 40% are severely disabled.
  • Aspirin was marketed in 1898 and has been used for a century. It has strong antipyretic and analgesic effects and is widely used in anti-inflammatory and anti-rheumatic treatments; small doses of aspirin can be used to prevent the onset of cardiovascular and cerebrovascular diseases and transient ischemic diseases , Inhibit the aggregation of platelets and prevent the formation of blood clots. Therefore, it is clinically recommended that patients with heart and cerebrovascular diseases take a small dose of aspirin to prevent thrombosis and thus prevent cardiovascular and cerebrovascular events.
  • aspirin examples include: a compound gualou-aspirin gastrointestinal pill capsule and its preparation method and application (2017); an arginine aspirin tablet and its preparation method (2017); a kind of aspirin resistance Sex monitoring method; the method of combining prednisone and aspirin and the preparation of a combination drug for the treatment of antinuclear antibody-positive infertility, etc., but the derivatives involved are not the same as this application, and the compounds in this category are new compounds.
  • the purpose of the present invention is to provide a polyglycol ortho-hydroxybenzoate compound.
  • the polyglycol ortho-hydroxybenzoate compound of the present invention has a significant anticoagulant effect and is dose-dependent, which is better than The same dose of aspirin has anticoagulant effect.
  • the synthesis route of the invention is simple, can effectively save synthesis time and reduce costs, has simple operation, is easy to implement, and is suitable for industrial production.
  • the present invention provides a polyglycol phthalate compound having a structure represented by formula I or formula II,
  • n 1-20
  • R is H, -C 1-20 alkyl and 2-acetoxybenzoyl.
  • the compound of the present invention is preferably a compound of the structure shown in formula I
  • n 1-20
  • R is H, -C 1-20 alkyl and 2-acetoxybenzoyl.
  • the compound of the present invention is more preferably a compound of the following structure
  • R is H, -C 1-20 alkyl and 2-acetoxybenzoyl.
  • the compound of the present invention is most preferably a compound of the following structure
  • the present invention further provides a preparation method of the preferred compound of the present invention, and its synthetic route is as follows:
  • reaction time in step (1) is 1-4 hours, preferably 1.5 hours.
  • Pyridine is the catalyst.
  • aspirinyl chloride: ethylene glycol diethyl ether (v:v) 10:1 to 1:1, preferably 5:1.
  • dichloromethane: ethyl acetate in step (3) 100:1 to 100:50 (v:v), preferably 15:1.
  • the present invention further provides the application of the compound of the present invention in the preparation of drugs with prolonged blood coagulation effect, which is the so-called anticoagulant effect.
  • the present invention further provides a pharmaceutical composition containing the compound of the present invention.
  • the pharmaceutical composition is selected from any pharmaceutically acceptable preparation form. Such as selected from tablets, capsules, granules, powders, oral liquids, injections.
  • the preparation of the formulations adopts conventional methods in the prior art.
  • the present invention aims to develop a preparation method of ortho-hydroxybenzoic acid polyglycol ester compound.
  • the research results can effectively develop new compound types. And it produces a wide range of social benefits, and it can be foreseen that its economic benefits are huge and its application prospects are broad.
  • the experimental route of the present invention is feasible and reasonable.
  • the total yield of the polyglycol phthalate compound obtained is up to 42%, and the purity is up to over 99%.
  • the present invention has the following main advantages.
  • the present invention has better fat solubility, can better penetrate the blood-brain barrier, reduces the dosage of drugs, and has better tolerance;
  • the compound of the present invention is neutral and has no Gastric mucosal irritation reduces potential gastrointestinal reactions; it is more stable to acid and alkali, which is conducive to drug stability and transportation.
  • the method of the present invention has reasonable process design, practicability, low cost, less use of toxic and harmful reagents, no pollution to the environment, and is suitable for large-scale industrial production.
  • Figure 1 shows the synthetic route of polyglycol phthalate compounds
  • Figure 2 is a hydrogen spectrum of the structure identification of polyglycol phthalate compounds
  • Figure 3 is a carbon spectrum of the structure identification of polyglycol o-hydroxybenzoic acid ester compounds
  • the carbon spectrum gives 13 carbon signals, of which ⁇ 169.8 and 164.6 are the carbon signals of the ester carbonyl group, ⁇ 150.7, 133.9, 132.0, 126.0, 123.8, and 123.2 are the carbon signals on the benzene ring, and ⁇ 68.3, 66.7, 64.4 are the carbon signals on the benzene ring.
  • Oxygen-carbon signal, ⁇ 21.0 and 15.1 are carbon signals.
  • Test drug Polyglycol phthalate compound (ie the compound prepared in Example 1 of the present invention), aspirin (Bayer Pharmaceuticals)
  • mice were administered by gavage, the gavage volume was 0.1ml/10g, and the gavage was performed once a day for 7 days. All animals eat and drink freely, and weigh every three days. After intragastric administration on the seventh day, blood was taken from the intraocular canthus of the mouse to measure the clotting time; the serum was separated, and the levels of thromboxane A2 (TXA2) and prostacyclin (PGI2) in the serum were determined using an ELISA kit for further evaluation Anticoagulant effect of polyglycol phthalate compounds.
  • TXA2 thromboxane A2
  • PKI2 prostacyclin
  • SPF male Kunming mice were purchased, all animals were quarantined, and the adaptation period was observed for 3 days, and the body weight was measured once during the animal reception and quarantine period. According to the animal's weight gain, general physical signs, and activities during the adaptation period, qualified animals enter the formal experiment.
  • SPF male mice of Kunming species were weighed and randomly divided into 6 groups, namely the normal control group (gave the same volume of olive oil), aspirin low-dose group (7mg/kg/d), aspirin High-dose group (40mg/kg/d), low-dose group, middle-dose group and high-dose group (7mg/kg/d, 16mg/kg/d, 40mg/kg/d ), 15 per group.
  • mice The gastric volume of mice was 100ml/kg, and the gastric administration was once a day for 7 days.
  • the aspirin group uses physiological saline as the solvent, and the test substance group uses olive oil as the solvent. All mice eat and water freely.
  • venous blood was taken from the intraocular canthus to measure the clotting time; the serum was separated, and the levels of TXA2 and PGI2 in the serum were determined to calculate TXA2/PGI2.
  • general clinical observation was performed once a day. Observe the appearance, spirit and activity of the mice after administration. If an animal is dead or dying, understand the cause of death in time, record the number of deaths and make up for it afterwards. (See Table 1)
  • mice in each group were given 200mg/kg aphrodin anesthetized, blood was taken from the intraocular canthus, the first two drops were discarded, and two drops were placed on a clean glass slide , Use a clean fine needle to pick up once every 15s, and take the blood droplets in the glass slide as the standard, that is, the process of soluble fibrinogen in the blood becoming insoluble fibrin, and record the flow of blood The liquid state becomes a jelly clot process that cannot flow, and the average clotting time of two drops of blood is recorded.
  • TXA2 and PGI2 levels in blood 30 minutes after the animal was administered on the seventh day, blood was taken from the intraocular canthus, and TXA2 and PGI2 levels in the blood were detected by an ELISA kit to calculate TXA2/PGI2.
  • the measurement data uses the paired t test method, the count data uses the non-parametric test method, and the grade data uses the NPar Tests Mann-Whitney test.
  • the data of each administration group and the control group of the same period are respectively tested for significance, *P ⁇ 0.05 and ** P ⁇ 0.01 means significant difference and very significant difference; P>0.05 means no significant difference.
  • mice in each group were anesthetized with 200mg/kg avertin, venous blood was taken from the intraocular canthus and dropped on a glass slide.
  • the clotting time was determined according to the appearance time of fibrin.
  • the prolonged clotting time is positively correlated with the strength of the anticoagulant effect of the drug.
  • Table 2 and Figure 4 Compared with the normal control group, the low-dose aspirin group significantly prolonged the coagulation time of mice (P ⁇ 0.05), which was consistent with the clinical anticoagulant effect of aspirin, indicating that the anticoagulant in this experiment
  • the efficacy evaluation system has good stability.
  • the low-dose, middle-dose and high-dose groups of polyglycol phthalate compounds can significantly prolong the coagulation time of mice (P ⁇ 0.01), and the coagulation time is obvious compared with the same dose of aspirin group extend. It shows that polyglycol phthalate compounds have significant anticoagulant effect.
  • the TXA2/PGI2 level of the low-dose aspirin group has no significant change (P>0.05), indicating that the low-dose aspirin group has no platelet agglutination effect;
  • the level of TXA2/PGI2 was significantly higher (P ⁇ 0.01), indicating that the high-dose aspirin group has a significant effect on promoting platelet aggregation;
  • the low-dose, middle-dose and high-dose groups of polyglycol phthalate compounds were compared with normal groups.
  • TXA2/PGI2 levels had no significant effect (P>0.05). It shows that polyglycol phthalate compounds have no significant effect on promoting platelet aggregation.
  • a high dose of aspirin can promote platelet formation, which is not conducive to its antithrombotic effect, and the present invention has no such shortcomings.

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Abstract

本发明公开了一种邻羟基苯甲酸聚二醇酯类化合物及其合成制备方法和医药用途，所述的邻羟基苯甲酸聚二醇酯类化合物具有式I或式II所示的结构；所述化合物具有延长凝血时间作用显著，适用于血栓形成性疾病的预防和治疗，且具有安全性好、用药简单方便、原料成本低廉易得、便于运输与保存的优点，(I), (II) 其中，n＝1-20，R选自：H，-C1-20烷基和2-乙酰氧基苯甲酰基。

Description

一种邻羟基苯甲酸聚二醇酯类化合物及其合成制备方法和医药用途 技术领域
本发明涉及一种邻羟基苯甲酸聚二醇酯类化合物及其制备方法，还涉及该化合物在抗凝血中的用途，属于药物合成和医药卫生领域。
背景技术
心脑血管疾病已成为人类健康的头号杀手，全球每年因脑卒中、心肌梗死、冠心病、动脉粥样硬化等死亡人数达1200万人。血栓性疾病主要包括心肌梗死、肺栓塞、心房颤动、脑梗死等，尤其是以栓塞为主要诱因的心肌梗死和脑卒中仍然是心脑血管疾病主要的死亡原因。中国每年死于心脑血管疾病的人数达到260万人以上，存活的患者75％致残，其中40％以上重残。随着近年来我国居民的心血管疾病患病率的不断上升，抗血栓药物市场需求不断增加。据统计，2016年我国抗血栓药物市场规模达275.1亿元，较2015年增长7.76％。
阿司匹林于1898年上市，已应用百年，具有较强的解热镇痛作用，广泛用于抗炎、抗风湿治疗；小剂量的阿司匹林可用于预防心脑血管疾病和短暂性缺血性疾病的发作，抑制血小板的聚集，预防血管内血栓形成。因此，在临床上建议心、脑血管患者服用小剂量的阿司匹林，防止血栓形成从而达到预防心脑血管事件发生。然而，随着阿司匹林临床应用研究的不断深入，大量临床研究和长期随访发现，长期口服阿司匹林治疗后，仍有部分心、脑血管疾病患者发生血栓栓塞事件，加大治疗剂量，不仅未能达到治疗及预防目的，而且不良反应增加，出现“阿司匹林抵抗”现象。因此，临床上阿司匹林作为抗血栓治疗药物的应用仍存在不足，为此本发明经过设计及筛选，对阿司匹林进行改构，并成功制备阿司匹林衍生物-邻羟基苯甲酸聚二醇酯类化合物。
目前关于阿司匹林专利包括：一种复方瓜蒌-阿司匹林胃肠溶微丸胶囊及其制备方法和应用(2017)；一种精氨酸阿司匹林片及其制备方法(2017)；一种阿司匹林的耐药性监测方法；强的松与阿司匹林联合用药的方法及其在制备治疗抗核抗体阳性不孕联合药等等，但所涉及衍生物与本申请均不相同，且本类化合物为新化合物。
发明内容
本发明的目的在于提供一种邻羟基苯甲酸聚二醇酯类化合物，本发明的邻羟基苯甲酸 聚二醇酯类化合物具有显著的抗凝血作用，且具有剂量依赖性，此作用优于同等剂量阿司匹林抗凝血作用。本发明合成路线简单，可有效的节省合成时间及降低成本，操作简单，易于实施，适用于工业生产。
为此，本发明提供一种具有式I或式II所示的结构的邻羟基苯甲酸聚二醇酯类化合物，
Figure PCTCN2020080340-appb-000001
其中，n＝1-20,R为H，-C 1-20烷基和2-乙酰氧基苯甲酰基。
本发明所述的化合物，优选为式I所示结构的化合物
Figure PCTCN2020080340-appb-000002
其中，n＝1-20,R为H，-C 1-20烷基和2-乙酰氧基苯甲酰基。
本发明所述的化合物，更优选为以下结构的化合物
Figure PCTCN2020080340-appb-000003
其中，R为H，-C 1-20烷基和2-乙酰氧基苯甲酰基。
本发明所述的化合物，最优选为以下结构的化合物
Figure PCTCN2020080340-appb-000004
化学名：2-乙酰氧基苯甲酸1,2-二羟基乙酯，分子式：C 13H 16O 5，分子量：252。
本发明进一步提供本发明所述的优选的化合物的制备方法，其合成路线如下：
Figure PCTCN2020080340-appb-000005
其制备方法，步骤如下：
(1)阿司匹林酰氯的合成：在干燥的圆底烧瓶中，依次加入乙酰水杨酸，二氯亚砜，吡啶，进行反应，然后蒸除过量二氯亚砜，加入二氯甲烷，密闭备用；
(2)邻羟基苯甲酸聚二醇酯的合成：在圆底儿烧瓶中依次加入乙二醇醚，三乙胺，反应的产物；
(3)产物的分离：以二氯甲烷：乙酸乙酯＝15:1为流动相进行硅胶柱层析分离；
其中，步骤(1)中所述反应的时间为1-4个小时，优选1.5个小时。氯化亚砜过量1-10倍(摩尔量)。吡啶为催化剂。其中，步骤(2)中的阿司匹林酰氯：乙二醇二乙醚(v：v)＝10:1～1:1，优选5:1。其中，步骤(3)中的二氯甲烷：乙酸乙酯＝100：1～100：50(v：v)，优选15：1。
本发明进一步提供本发明所述的化合物在制备具有延长血液凝固作用的药物中的应用，即所谓的抗凝血作用。
本发明进一步提供含有本发明所述的化合物的药物组合物。所述的药物组合物，选自任何一种可药用的制剂形式。如选自片剂，胶囊剂、颗粒剂，粉剂，口服液，注射剂。所述制剂的制备均采用现有技术中的常规方式。
本发明旨在开发一种邻羟基苯甲酸聚二醇酯类化合物制备方法。研究成果能有效地为开发新的化合物类型。且产生广泛的社会效益，而且可以预见其经济效益巨大，应用前景广阔。
本发明实验路线可行且合理。得到邻羟基苯甲酸聚二醇酯类化合物总收率最高可达42％，纯度最高可达99％以上。本发明与阿司匹林相比主要具有优点如下，本发明具有更好的脂溶性能够更好的透过血脑屏障，降低用药剂量，具有更好的耐受性；其次本发明化合物呈中性，无胃粘膜刺激性，减少潜在的胃肠道反应；对酸碱更加稳定，有利于药品稳定性有利于运输。此外，本发明的方法工艺设计合理，切实可行，成本较低，有毒有害试剂使用较少，不对环境造成污染，适用于大量工业生产。
附图说明
图1为邻羟基苯甲酸聚二醇酯类化合物的合成路线；
图2为邻羟基苯甲酸聚二醇酯类化合物结构鉴定氢谱图；
图3为邻羟基苯甲酸聚二醇酯类化合物结构鉴定碳谱图；
图4邻羟基苯甲酸聚二醇酯类化合物对小鼠凝血时间的影响；
数据以均值±标准差表示， *P<0.05vs.正常对照组， **P<0.01vs.正常对照组。
图5邻羟基苯甲酸聚二醇酯类化合物对小鼠血清TXA2/PGI2水平的影响；
数据以均值±标准差表示， *P<0.05vs.正常对照组， **P<0.01vs.正常对照组。
具体实施方法
下面结合具体实施例来进一步描述本发明，本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
实施例1邻羟基苯甲酸聚二醇酯类化合物的合成
在干燥的50mL圆底烧瓶中，依次加入乙酰水杨酸1.2g，二氯亚砜2mL，吡啶一滴，在70℃条件下反应1.5h蒸除过量二氯亚砜后加入10mL二氯甲烷，密闭备用。其中以2％氢氧化钠为尾气接收液。在50ml圆底儿烧瓶中依次加入乙二醇乙醚200μL，三乙胺300μL，二氯甲烷5mL，后滴入上述二氯甲烷阿司匹林酰氯溶液10mL，室温反应1h后，以二氯甲烷：乙酸乙酯＝15:1为流动相进行硅胶柱层析分离。得淡黄色油状物0.27g，产率为51.9％。产物为2-乙酰氧基苯甲酸1,2-二羟基乙酯。
实施例2邻羟基苯甲酸聚二醇酯类化合物的合成
在干燥的500mL圆底烧瓶中，依次加入乙酰水杨酸20g，二氯亚砜34mL，吡啶一滴，在70℃条件下反应1.5h蒸除过量二氯亚砜后加入40mL二氯甲烷，密闭备用。其中以2％氢氧化钠为尾气接收液。在250mL圆底儿烧瓶中依次加入乙二醇乙醚3.4mL，三乙胺5mL，二氯甲烷80mL，后滴入上述二氯甲烷阿司匹林酰氯溶液40mL，室温反应1h后，以二氯甲烷：乙酸乙酯＝15:1为流动相进行硅胶柱层析分离。得淡黄色油状物5.2037g，产率为59.9％。产物为2-乙酰氧基苯甲酸1,2-二羟基乙酯。
实施例3阿司匹林丙二醇单乙酯的合成
在干燥的50mL圆底烧瓶中，依次加入乙酰水杨酸1g，二氯亚砜2mL，吡啶一滴，在70℃条件下反应1.5h蒸除过量二氯亚砜后加入10mL二氯甲烷，密闭备用。其中以2％氢氧化钠为尾气接收液。在50ml圆底儿烧瓶中依次加入丙二醇乙醚230μL，三乙胺300μL，二氯甲烷5mL，后滴入上述二氯甲烷阿司匹林酰氯溶液10mL，室温反应1h后，以二氯甲烷：乙酸乙酯＝15:1为流动相进行硅胶柱层析分离。得淡黄色油状物0.3g， 产率为53％。产物为2-乙酰氧基苯甲酸1,2-二羟基乙酯。
实施例4邻羟基苯甲酸聚二醇酯类化合物结构鉴定
邻羟基苯甲酸聚二醇酯类化合物淡黄色油状物， 1H-NMR(600MHz,DMSO-d 6)中δ8.06(1H,dd,J＝7.8,1.8Hz)、7.56(1H,t,J＝7.8,1.8Hz)、7.32(1H,td,J＝7.6,1.3Hz)、7.10(1H,dd,J＝8.1,1.3Hz)为苯环上邻位及间位偶合质子信号，4.42(2H,t)、3.73(2H,t)、3.56(2H,q,J＝7.0Hz)为三个亚甲基质子信号,2.37(3H,s)、1.23(3H,t,J＝7.0Hz)为甲基质子信号。碳谱给出13个碳信号，其中δ169.8、164.6为酯羰基碳信号，δ150.7、133.9、132.0、126.0、123.8、123.2为苯环上碳信号，δ68.3、66.7、64.4为连氧碳信号，δ21.0、15.1为碳信号。
综合上述信息确定该化合物结构如下图所示。
Figure PCTCN2020080340-appb-000006
实施例5本发明产品的功效性试验1
1、实验材料
实验动物：SPF级别雄性昆明种小鼠(20-25g)90只。
受试药物：邻羟基苯甲酸聚二醇酯类化合物(即本发明实施例1制备的化合物)、阿司匹林(拜尔制药公司)
2、实验原理
通过对小鼠灌胃给药，灌胃体积为0.1ml/10g，每日灌胃一次，持续给药7天。所有动物自由进食和饮水，每三天称量体重。第七天灌胃结束后，采取小鼠眼内眦取血方法，测量其凝血时间；分离血清，利用ELISA试剂盒测定血清中血栓素A2(TXA2)与前列环素(PGI2)水平，进一步评价邻羟基苯甲酸聚二醇酯类化合物的抗凝血作用。
3、实验方法
3.1动物分组
购买SPF级别雄性昆明小鼠90只，对全部动物进行检疫，并进行适应期观察3天，在动物接收和检疫期间各进行一次体重测量。根据适应期动物体重增长、一般体征、活动等情况，合格的动物进入正式实验。将适应性喂养后的SPF级别的昆明种雄性小鼠称重，随机分为6组，即正常对照组(灌胃给予同等体积橄榄油)、阿司匹林低剂量组(7mg/kg/d)、阿司匹林高剂量组(40mg/kg/d)、邻羟基苯甲酸聚二醇酯类化合物低剂量组、中剂量组 和高剂量组(7mg/kg/d、16mg/kg/d、40mg/kg/d)，每组15只。
3.2实验步骤
小鼠灌胃体积为100ml/kg，每日灌胃一次，持续7天。阿司匹林组以生理盐水为溶剂，受试物组以橄榄油为溶剂。所有小鼠自由进食、水。第七天灌胃结束30分钟后，眼内眦取静脉血，测量其凝血时间；分离血清，测定血清中TXA2与PGI2水平，计算TXA2/PGI2。实验过程中每天进行一次一般临床观察。观察小鼠给药后的外观、精神及活动情况。若有动物死亡或濒死，及时了解死因，记录死亡数并补入后补。(见表1)
表1.各组动物给药及饮食情况
Figure PCTCN2020080340-appb-000007
3.3主要检测指标
(1)称量体重，每隔三天称一次体重。
(2)凝血时间测定：各组小鼠第七天给药30分钟后，给予200mg/kg阿弗丁麻醉，眼内眦取血，前两滴弃去，滴两滴于干净的载玻片上，用干净的细针每15s挑一次，以载玻片中的血滴可被拉起丝为标准，即血液中的可溶性纤维蛋白原变成不可溶的纤维蛋白的过程，记录血液从流动的液体状态变成不能流动的胶冻状凝块过程，记录两滴血的平均凝血时间。
(3)血中TXA2、PGI2水平测定：动物第七天给药30分钟后，眼内眦取血，ELISA试剂盒检测血中TXA2、PGI2水平，计算TXA2/PGI2。
4、实验数据与结果
4.1数据处理
计量资料用成对t检验方法，计数资料采用非参数检验法，等级资料用NPar Tests Mann-Whitney检验，各给药组数据与同期对照组数据分别进行显著性检验，*P<0.05和**P<0.01分别表示差异显著和差异非常显著；P>0.05表示无显著性差异。
4.2实验结果
4.2.1凝血时间统计
各组小鼠给予200mg/kg阿弗丁麻醉后，眼内眦取静脉血，并滴于载玻片上，根据纤维蛋白出现时间，判定凝血时间。凝血时间延长与药物的抗凝血作用强度呈正相关。结果如表2和图4所示，阿司匹林低剂量组与正常对照组相比显著延长小鼠凝血时间(P<0.05)，与阿司匹林临床抗凝血治疗效果相一致，表明本实验抗凝血药效学评价系统具有较好的稳定性。邻羟基苯甲酸聚二醇酯类化合物低剂量、中剂量及高剂量组与正常对照组相比均能显著延长小鼠凝血时间(P<0.01)，与同等剂量阿司匹林组相比，凝血时间明显延长。表明邻羟基苯甲酸聚二醇酯类化合物具有显著的抗凝血作用。
表2.凝血时间测定功能评价
Figure PCTCN2020080340-appb-000008
注：数据以均值±标准差表示，*P<0.05vs.正常对照组，**P<0.01vs.正常对照组。
4.2.2血栓素A2/前列环素(TXA2/PGI2)水平
将所取的血液样本离心，留取血浆，使用血栓素A2酶联免疫吸附测定试剂盒与前列环素酶联免疫吸附测定试剂盒检测血浆中的血栓素A2与前列环素水平，并计算两者比值评价药物的抗凝血功能，比值越低，说明该药物的抗凝功能越强。结果如表3和图5所示，阿司匹林低剂量组与正常对照组相比TXA2/PGI2水平无显著变化(P>0.05)，表明阿司匹林低剂量组无促血小板凝集作用；阿司匹林高剂量组与正常对照组相比TXA2/PGI2水平显 著增高(P<0.01)，表明阿司匹林高剂量组具有显著的促血小板凝集作用；邻羟基苯甲酸聚二醇酯类化合物低剂量、中剂量及高剂量组与正常对照组相比TXA2/PGI2水平均无显著影响(P>0.05)。表明邻羟基苯甲酸聚二醇酯类化合物无显著的促进血小板凝集作用。实验表明阿司匹林高剂量能够促进血小板形成，不利于其抗血栓作用，而本发明无此缺点。
表3.抗血小板聚集功能评价
Figure PCTCN2020080340-appb-000009
注：数据以均值±标准差表示， *P<0.05vs.正常对照组， **P<0.01vs.正常对照组。

Claims (10)

  1. 具有式I或式II所示的结构的邻羟基苯甲酸聚二醇酯类化合物，
    Figure PCTCN2020080340-appb-100001
    其中，n＝1-20,R为H，-C 1-20烷基和2-乙酰氧基苯甲酰基。
  2. 如权利要求1所述的化合物，为式I所示结构的化合物
    Figure PCTCN2020080340-appb-100002
    其中，n＝1-20,R为H，-C 1-20烷基和2-乙酰氧基苯甲酰基。
  3. 如权利要求2所述的化合物，为以下结构的化合物
    Figure PCTCN2020080340-appb-100003
    其中，R为H，-C 1-20烷基和2-乙酰氧基苯甲酰基。
  4. 如权利要求3所述的化合物，为以下结构的化合物
    Figure PCTCN2020080340-appb-100004
  5. 权利要求3所述的化合物制备方法，其特征在于，合成路线如下：
    Figure PCTCN2020080340-appb-100005
  6. 如权利要求5所述的制备方法，步骤如下：
    (1)阿司匹林酰氯的合成：在干燥的圆底烧瓶中，依次加入乙酰水杨酸，二氯亚砜， 吡啶，进行反应，然后蒸除过量二氯亚砜，加入二氯甲烷，密闭备用；
    (2)邻羟基苯甲酸聚二醇酯的合成：在圆底儿烧瓶中依次加入乙二醇醚，三乙胺，反应的产物；
    (3)产物的分离：以二氯甲烷：乙酸乙酯＝15:1为流动相进行硅胶柱层析分离；
    其中，步骤(1)中所述反应的时间为1-4个小时，氯化亚砜加入量为乙酰水杨酸的1-10倍；吡啶为催化剂；其中，步骤(2)阿司匹林酰氯：乙二醇二乙醚(v：v)＝10:1～1:1。
  7. 权利要求1所述的化合物在制备具有延长血液凝固作用的药物中的应用。
  8. 含有权利要求1所述的化合物的药物组合物。
  9. 如权利要求8所述的药物组合物，选自任何一种可药用的制剂形式。
  10. 如权利要求9所述的药物组合物，其特征在于，选自片剂，胶囊剂、颗粒剂，粉剂，口服液，注射剂。
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