WO2019007015A1 - 硫醚酸结构的化合物在制备抗血小板聚集药物中的应用 - Google Patents

硫醚酸结构的化合物在制备抗血小板聚集药物中的应用 Download PDF

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WO2019007015A1
WO2019007015A1 PCT/CN2018/000238 CN2018000238W WO2019007015A1 WO 2019007015 A1 WO2019007015 A1 WO 2019007015A1 CN 2018000238 W CN2018000238 W CN 2018000238W WO 2019007015 A1 WO2019007015 A1 WO 2019007015A1
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compound
acid structure
use according
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范克
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北京北朋科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles

Definitions

  • the present invention belongs to the field of pharmacy, and in particular, the present invention relates to the use of a compound having a thioether acid structure for the preparation of a medicament for the treatment or prevention of cardiovascular and cerebrovascular diseases caused by platelet aggregation.
  • Clopidogrel and prasugrel are a prodrug, which needs to be metabolized into active products in the body after cyclization, and its effective active group is fluorenyl-butenoic acid structure.
  • active sulfhydryl groups Many small molecular polar compounds containing naked thiol groups have certain pharmacological effects against platelet aggregation, such as acetylcysteine, tiopronin and captopril, but these small molecular compounds are not useful.
  • Stefans are widely used in the treatment of respiratory diseases, especially polysaccharides. Most of their molecular structures contain thioether structures and rarely contain naked sulfhydryl groups. We searched for related literature on stanbo compounds and platelets. It was found that only one compound of erdosteine was reported to interact with platelets. The two articles were published by the same author Arica in the same journal Human&Experimental Toxicology on the function of erdosteine on blood system. The effect, but their test results turned out to be the pharmacological effect of erdosteine to increase the number of platelets and promote hemostasis, which has aroused our interest.
  • the anti-platelet aggregation function of erdosteine is due to the active metabolite of erdosteine in the body, which is the structure of thioglycolic acid after hydrolysis and ring opening, in order to further verify the anti-platelet aggregation of erdosteine.
  • the pharmacological effects we directly used rat plasma for in vitro tests, found that erdosteine without hydrolysis and ring opening also has a better pharmacological effect of reducing platelet aggregation, which is presumed to be able to act as a pharmacological agent to reduce platelet aggregation.
  • the group should be a thioether acetate structure, so we applied diacetate thioether (thiodiacetic acid) to the antiplatelet aggregation test, and the anti-platelet effect was actually three times the effect of the same dose of aspirin! This is very amazing.
  • the reactive group should be a thioether acetic acid or thioether propionic acid structure, so we will be able to obtain compounds containing thioether acetic acid or thioether propionic acid structures such as carboxymethacetin, formoterol, mestam, erdo Stein, Mojistein, ritastatin, clergyan, nesostatan, mitridan, ixastatin, taurestatin, temmetan, samistat, omo Systematic pharmacodynamics in anti-platelet aggregation with stann, darsacetam, carbamastat, danostatan, guaiastin, estristin and thiodiacetic acid, and the same dose of aspirin Screening, the experimental results are that these compounds have better anti-platelet aggregation pharmacological effects compared with the same concentration of aspirin, especially thiodiacetic acid has better pharmacological effects against platelet aggregation. That is,
  • PRP Platelet-rich plasma
  • PPP was used as a substrate and PRP was measured. Add 170 ⁇ L of PPP and 30 ⁇ L of water to the test channel, press the PPP key for substrate measurement, and add 170 ⁇ L of LPRP and 20 ⁇ L of test drug (final concentration of 100 ⁇ g/ml) to another test cup. Add one magnetic bead. The test cup was incubated in a pre-warming channel at 37 ° C for 3 min. After the end, the test cup was moved into the test channel, and the start button was used for measurement. The inducer AA 10 ⁇ L (final concentration was 1 mM) was added, and the platelets were recorded for 5 min according to Born turbidimetry. The maximum aggregation rate and calculate its inhibition rate.
  • Aggregation inhibition rate (control group aggregation rate - test group aggregation rate) / control group aggregation rate ⁇ 100%.
  • 42 SD rats weighing 210-230 g were randomly divided into 7 groups, namely, negative control group (0.9% normal saline, 5 ml/kg), erdosteine group (50 mg/kg), and Mojistan group. (50 mg/kg), ritostan group (50 mg/kg), nesostatin group (sodium salt, 50 mg/kg), omometastat group (50 mg/kg), positive control group (clopidogrel, 50mg/kg). All were administered by intragastric administration, and the administration volume was 5 ml/kg. Once a day, it was administered for three consecutive days.
  • Adjust the platelet aggregation instrument add 200 ⁇ L of the adjusted sample to the plastic test cup, add a magnetic bead, and incubate the test cup in a 37 ° C pre-warming channel for 3 min. After the end, transfer the test cup into the test channel and add the inducer ADP. 3 ⁇ L (final concentration: 45 ⁇ M) was measured, and the maximum aggregation rate of platelets was recorded within 5 min. The inhibition rate was calculated by comparison with the results of the negative control group, and the platelet aggregation inhibition rate of each group was calculated. The results were as follows:
  • the above materials were mixed, passed through a 60 mesh sieve, and compressed by a tableting machine to prepare tablets each having a tablet weight of 200 mg.
  • the tablet can be coated as needed.
  • the above materials were mixed, passed through a 60 mesh sieve, and filled into hollow hard capsules to prepare capsules each having a grain weight of 200 mg.
  • thiodiacetic acid 50 mg of thiodiacetic acid, 120 mg of lactose, 29 mg of microcrystalline cellulose, and 1 mg of magnesium stearate were mixed, sieved, and tableted to prepare a tablet of 200 mg.
  • statin 50 mg of this statin, 80 mg of lactose, 69 mg of microcrystalline cellulose, and 1 mg of magnesium stearate were mixed, sieved, and tableted to prepare a tablet of 200 mg.
  • ritastatin 50 mg of ritastatin, 80 mg of lactose, 69 mg of microcrystalline cellulose, and 1 mg of magnesium stearate were mixed, sieved, and tableted to prepare a tablet of 200 mg.
  • nesostatan sodium 50 mg of nesostatan sodium, 80 mg of lactose, 69 mg of microcrystalline cellulose, and 1 mg of magnesium stearate were mixed and sieved, and then placed in a capsule to prepare a capsule of 200 mg.
  • ixestam 50 mg of ixestam, 80 mg of lactose, 69 mg of microcrystalline cellulose, and 1 mg of magnesium stearate were mixed and sieved, and then placed in a capsule to prepare a capsule of 200 mg.
  • samistatin 25 mg of samistatin, 105 mg of lactose, 69 mg of microcrystalline cellulose, and 1 mg of magnesium stearate were mixed, sieved, and tableted to prepare a tablet of 200 mg.
  • danostatan 50 mg of danostatan, 80 mg of lactose, 69 mg of microcrystalline cellulose, and 1 mg of magnesium stearate were mixed, sieved, and tableted to prepare a tablet of 200 mg.
  • guaiacrit 25 mg of guaiacrit, 105 mg of lactose, 69 mg of microcrystalline cellulose, and 1 mg of magnesium stearate were mixed and sieved to prepare a tablet of 200 mg.

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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

本发明提供了硫醚酸结构的化合物在制备用于治疗或预防由血小板聚集引起的心脑血管疾病的药物中的应用。其中包含有羧甲司坦、福多司坦、厄多司坦、莫吉司坦、来托司坦、普瑞司坦、奈索司坦、米地司坦、伊沙司坦、牛磺司坦、替美司坦、沙米司坦、奥莫司坦、达西司坦、卡他司坦、达诺司坦、愈创司坦、本司坦、和硫代二乙酸。

Description

硫醚酸结构的化合物在制备抗血小板聚集药物中的应用 技术领域
本发明属于药学领域，具体而言，本发明涉及硫醚酸结构的化合物在制备用于治疗或预防由血小板聚集引起的心脑血管疾病的药物中的应用。
背景技术
随着我国人口老龄化程度日益加剧，由血栓性问题引起的心脑血管疾病不断上升，常表现为心肌梗死、中风、缺血性脑梗死、静脉血栓栓塞等，全球每年死于该类疾病的人数接近世界总死亡人数的四分之一，因此抗血栓类药物的开发成为全球各大制药公司竞相开发的热点，代表性的药品有阿司匹林和氯吡格雷，其中氯吡格雷在2015年在国内市场的销售金额达92亿元，此药品已经连续几年排在全国各种药品口服用药的第一名位置。但是以阿司匹林和氯吡格雷为代表的药品不良反应过多，以引起消化道出血和脑出血为主要不良反应，更不幸的是氯吡格雷抗血小板作用并不能使所有患者受益，部分患者对氯吡格雷的心血管的保护作用存在氯吡格雷抵抗，对于阿司匹林也同样有部分患者会产生阿司匹林抵抗。因此市场上需要更多全新结构的化学药品来改善现有品种的不足。
氯吡格雷和普拉格雷为一个前体药，需要在体内经过开环氧化后代谢成活性产物起药理作用，其有效活性基团为巯基丁烯酸结构，我们从活性的巯基着手分析发现，很多含有裸露巯基的分子量较小的小分子极性化合物，有一定的抗血小板聚集的药理作用，如乙酰半胱氨酸、硫普罗宁和卡托普利等，但这些小分子化合物并没有用于抗血小板聚集疾病的治疗，推测其原因可能是，其裸露的巯基和蛋白分子结合能力过强，不良反应过大，出血率过高，这些分子不单单是能抗血小板聚集有时还能够达到溶栓的药理作用，而这对于长期用药的患者是极其不利的，会引起出血率的风险大大增加，抗血小板聚集药物的开发方向是在保证药效的同时如何最大限度的降低出血率，而这些含有裸露巯基的小分子极性化合物显然是不适合长期用药的。我们在此基础之上，期望寻找含有硫醚结构的小分子极性化合物来尝试用于抗凝药物的开发，考虑到硫醚结构的化合物和蛋白的结合能力弱远远达不到巯基的活性的，推测可能的结果可能是没有抗凝的药理作用，我们检索了相关文献没有查到硫醚结构的小分子极性化合物用于抗血小板聚集的文献报道。我们也只是随意做个尝试，但是试验结果，远远超过我们的预料。发现多个含有硫醚酸结构的小分子极性化合物有很好的抗凝药理作用。
发明内容
司坦类化合物被广泛应用于呼吸疾病的治疗，特别是多痰的治疗，其分子结构中大 多含有硫醚结构，并极少含有裸露的巯基，我们检索有关司坦类化合物和血小板的相关文献，发现只有一个厄多司坦(erdosteine)的化合物被报道和血小板相互作用的两篇文献，这两篇文献由同一作者Arica发表在同一期刊Human&Experimental Toxicology上的有关厄多司坦对血液系统功能的影响，但是他们的试验结果竟然是厄多司坦有提升血小板数量并促进止血的药理作用，这引起了我们的兴趣，他们的实验方法是将体重在180-200g的大鼠28只随机分成4组，空白组给于生理盐水，另外三组按高中低三个剂量分别给予厄多司坦3mg/kg/day、10mg/kg/day、30mg/kg/day，连续给药三天后，取血，测定血小板数量，结果是中剂量组血小板数量比空白组稍高，低剂量和高剂量组的血小板数量远高于中剂量组(P＜0.05)，并且低剂量组和高剂量组的血小板数量基本相同。也就是说厄多司坦到底是有促进止血作用还是有抗凝血的作用是模糊不清的。
我们从厄多司坦着手，用于化痰时其在体内的活性代谢物为水解开环后的巯基丁酸结构，和氯吡格雷在体内的活性代谢物巯基丁烯酸结构有点接近，我们在重复Arica的实验中，并没有能够重复出他们的实验过程和实验结果，相反的是在我们的实验过程中得出厄多司坦有一定的抗血小板聚集的实验结论。于是我们推测厄多司坦抗血小板聚集的功能是由厄多司坦在体内的活性代谢物为水解开环后的巯基丁酸结构在起作用，为了深入验证厄多司坦在抗血小板聚集中的药理作用，我们直接用大鼠血浆进行体外测试，发现没有经过水解开环的厄多司坦也有较好的降低血小板聚集的药理作用，由此推测其能起降低血小板聚集的药理作用的活性基团应该是硫醚乙酸结构，于是我们将二乙酸硫醚(硫代二乙酸)应用于抗血小板聚集试验，结果其抗血小板的药效作用竟然是同等剂量的阿司匹林的三倍的作用效果！这是非常神奇的。我们再把同时具有硫醚乙酸结构和硫醚丙酸结构的羧甲司坦应用于抗血小板聚集试验，结果其抗血小板的药效作用等同于阿司匹林，只能推测起降低血小板聚集的药理作用的活性基团应该是硫醚乙酸或者硫醚丙酸结构，于是我们将能够得到的含有硫醚乙酸或者硫醚丙酸结构的化合物如羧甲司坦、福多司坦、美司坦、厄多司坦、莫吉司坦、来托司坦、普瑞司坦、奈索司坦、米地司坦、伊沙司坦、牛磺司坦、替美司坦、沙米司坦、奥莫司坦、达西司坦、卡他司坦、达诺司坦、愈创司坦、本司坦和硫代二乙酸等，和同等剂量的阿司匹林做了在抗血小板聚集方面的系统药效学筛选，实验结果是这几个化合物和同浓度的阿司匹林对比有较好的抗血小板聚集的药理作用，特别是硫代二乙酸具有更好的抗血小板聚集的药理作用。就是说具有硫醚脂肪酸结构的小分子极化合物在治疗由血小板聚集引起的疾病方面有很好的治疗效果。
具体实施方式
药效学试验1：
A、血小板的制备：大鼠经10％水合氯醛4ml/kg麻醉，腹主动脉取血，3.2％枸橼酸钠抗凝(血液与抗凝剂体积比为9∶1)，1200rpm离心10min，分离富血小板血浆(PRP)；3500rpm离心10min，分离贫血小板血浆(PPP)。
B、聚集率的测定：用PPP作为基底，PRP进行测定。在塑料测试杯中加入170μL PPP和30μL水放入测试通道，按PPP键进行基底测量；在另一测试杯中加入170μLPRP和20μL待测药物(终浓度为100μg/ml)，加一粒磁珠，将测试杯放入37℃预温通道中温育3min，结束后将测试杯移入测试通道，按开始键进行测定，加入诱导剂AA10μL(终浓度为1mM)，按Born比浊法记录5min内血小板最大聚集率，并计算其抑制率。
C、数据处理：
聚集抑制率＝(对照组聚集率-试验组聚集率)/对照组聚集率×100％。
D、实验结果如下：
硫醚酸结构的化合物对血小板聚集的抑制作用一
试验化合物 给药浓度(μg/ml) 抑制率(％)
阿司匹林 100 17.58
羧甲司坦 100 16.73
福多司坦 100 24.58
盐酸美司坦 100 63.43
硫代二乙酸 100 47.59
乙酰半胱氨酸 100 40.61
普瑞司坦 100 17.12
米地司坦 100 39.77
伊沙司坦 100 32.36
达西司坦 100 26.84
达诺司坦 100 34.72
卡他司坦 100 41.43
本司坦 100 15.28
替美司坦 100 36.93
沙米司坦 100 23.36
愈创司坦 100 17.33
牛磺司坦 100 16.47
备注：盐酸美司坦IC60＝93.56(μg/ml)
药效学试验2：
将体重在210-230克的SD大鼠42只，随机分成7组，即阴性对照组(0.9％生理盐水，5ml/kg)、厄多司坦组(50mg/kg)、莫吉司坦组(50mg/kg)、来托司坦组(50mg/kg)、奈索司坦组(钠盐，50mg/kg)、奥莫司坦组(50mg/kg)、阳性对照组(氯吡格雷，50mg/kg)。均采用灌胃给药，给药体积均为5ml/kg。一天1次，连续三天给药。最后一次给药2小时后经10％水合氯醛4ml/kg麻醉，腹主动脉取血，3.2％枸橼酸钠抗凝(血液与抗凝剂体积比为9∶1)，1200rpm离心10min，分离富血小板血浆(PRP)；3500rpm离心15min，分离贫血小板血浆(PPP)。用血小板计数仪测定PRP中的血小板数后，通过PPP调整PRP的血小板数至250×10 9个/L左右。调节血小板聚集仪，在塑料测试杯中加入200μL调节好的样品，加一粒磁珠，将测试杯放入37℃预温通道中温育3min，结束后将测试杯移入测试通道，加入诱导剂ADP 3μL(终浓度为45μM)，进行测定，记录5min内血小板最大聚集率，通过和阴性对照组的结果比较，计算其抑制率，计算出每组的血小板聚集抑制率，结果如下：
硫醚酸结构的化合物对血小板聚集的抑制作用二
Figure PCTCN2018000238-appb-000001
实施例1
羧甲司坦  750mg
乳糖  1000mg
微晶纤维素  240mg
硬脂酸镁  10mg
将上述物料混合后、过60目筛、通过压片机压片，制成每片片重为200mg的片剂。根据需要可以对此片剂进行包衣。
实施例2
羧甲司坦  500mg
乳糖  1200mg
微晶纤维素  290mg
硬脂酸镁  10mg
将上述物料混合后、过60目筛，装入空心的硬胶囊中，制成每粒粒重为200mg的胶囊剂。
实施例3
将50mg的硫代二乙酸、120mg乳糖、29mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例4
将50mg的福多司坦、100mg乳糖、49mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例5
将50mg的本司坦、80mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例6
将50mg的厄多司坦、80mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例7
将50mg的莫吉司坦、80mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例8
将50mg的来托司坦、80mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例9
将50mg的普瑞司坦、80mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例10
将50mg的奈索司坦钠、80mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后装入到胶囊中，制成200mg的胶囊剂。
实施例11
将20mg的米地司坦、105mg乳糖、74mg微晶纤维素、1mg硬脂酸镁，混合过筛后装入到 胶囊中，制成粒重200mg的胶囊剂
实施例12
将50mg的伊沙司坦、80mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后装入到胶囊中，制成200mg的胶囊剂。
实施例13
将50mg的牛磺司坦、90mg乳糖、59mg微晶纤维素、1mg硬脂酸镁，混合过筛后装入到胶囊中，制成200mg的胶囊剂。
实施例14
将25mg的替美司坦、100mg乳糖、74mg微晶纤维素、1mg硬脂酸镁，混合过筛后装入到胶囊中，制成200mg的胶囊剂。
实施例15
将25mg的沙米司坦、105mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例16
将25mg的奥莫司坦、105mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例17
将25mg的达西司坦、105mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例18
将25mg的卡他司坦、105mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例19
将50mg的达诺司坦、80mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。
实施例20
将25mg的愈创司坦、105mg乳糖、69mg微晶纤维素、1mg硬脂酸镁，混合过筛后压片制成200mg的片剂。

Claims (20)

  1. 硫醚酸结构的化合物在制备用于治疗或预防由血小板聚集引起的心脑血管疾病的药物中的应用。
  2. 根据权利要求1所述的应用，其特征在于：所述的硫醚酸结构的化合物选自：羧甲司坦、福多司坦、厄多司坦、莫吉司坦、来托司坦、普瑞司坦、奈索司坦、米地司坦、伊沙司坦、牛磺司坦、替美司坦、沙米司坦、奥莫司坦、达西司坦、卡他司坦、达诺司坦、愈创司坦、本司坦和硫代二乙酸。
  3. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为羧甲司坦，或其药学上可接受的盐。
  4. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为福多司坦，或其药学上可接受的盐。
  5. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为莫吉司坦，或其药学上可接受的盐。
  6. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为来托司坦，或其药学上可接受的盐。
  7. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为普瑞司坦，或其药学上可接受的盐。
  8. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为奈索司坦，或其药学上可接受的盐。
  9. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为米地司坦，或其药学上可接受的盐。
  10. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为伊沙司坦，或其药学上可接受的盐。
  11. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为牛磺司坦，或其药学上可接受的盐。
  12. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为替美司坦，或其药学上可接受的盐。
  13. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为沙米司坦，或其药学上可接受的盐。
  14. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为奥莫司坦，或其药学上可接受的盐。
  15. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为达西司坦，或其药学上可接受的盐。
  16. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为卡他司坦，或其药学上可接受的盐。
  17. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为达诺司坦，或其药学上可接受的盐。
  18. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为愈创司坦，或药学上可接受的盐。
  19. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为本司坦，或其药学上可接受的盐。
  20. 根据权利要求2所述的应用，其特征在于：所述的硫醚酸结构的化合物为硫代二乙酸，或其药学上可接受的盐。
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