WO2018171004A1 - 一类治疗血栓相关性疾病的化合物、制备方法及其药物用途 - Google Patents

一类治疗血栓相关性疾病的化合物、制备方法及其药物用途 Download PDF

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WO2018171004A1
WO2018171004A1 PCT/CN2017/082633 CN2017082633W WO2018171004A1 WO 2018171004 A1 WO2018171004 A1 WO 2018171004A1 CN 2017082633 W CN2017082633 W CN 2017082633W WO 2018171004 A1 WO2018171004 A1 WO 2018171004A1
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compound
salt
pharmaceutically acceptable
acceptable salt
group
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PCT/CN2017/082633
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何广卫
储昭兴
许勤龙
李家明
徐云根
叶文峰
魏萍
朱启华
莫佳佳
赵炎
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合肥医工医药有限公司
合肥恩瑞特药业有限公司
南京医工医药技术有限公司
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Publication of WO2018171004A1 publication Critical patent/WO2018171004A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • C07F9/65616—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

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  • the present invention relates to the field of medical technology, and in particular to a compound for treating a thrombosis-related disease or a salt thereof, and a method for preparing the compound or a salt thereof, and a pharmaceutical use of the compound or a salt thereof.
  • a compound for treating a thrombosis-related disease or a salt thereof and a method for preparing the compound or a salt thereof, and a pharmaceutical use of the compound or a salt thereof.
  • medicinal chemistry In the field of medicinal chemistry.
  • thrombosis-related diseases Heart, brain, and pulmonary circulation diseases such as myocardial infarction, stroke, and pulmonary embolism caused by thrombosis can be collectively referred to as thrombosis-related diseases.
  • the incidence of such diseases is high among various diseases, and there is an increasing trend in recent years. It threatens the health of human beings and becomes the focus and hotspot of medical research and new drug development.
  • thrombolytic drugs drugs for the prevention and treatment of thrombosis-related diseases
  • anticoagulants drugs for the prevention and treatment of thrombosis-related diseases
  • thrombolytic therapy is mainly used for the treatment of acute ischemic cerebral infarction, but most patients are admitted to hospital.
  • the timing of thrombolysis has been missed or limited to various conditions without thrombolysis, and the thrombolytic drugs are prone to allergies, cryopreservation and other shortcomings, which make the clinical application of such drugs very limited; anticoagulant drugs have exact curative effect.
  • the effect is limited to venous thrombosis, and the risk of bleeding is large, and the application is not as extensive as anti-platelet aggregation drugs.
  • the anti-platelet aggregation drug for arterial thrombosis is the most commonly used drug, and the representative drugs include cyclooxygenase inhibitor aspirin, P 2 Y 12 receptor inhibitor clopidogrel, ticagrelor, etc., P 2 Y 12 receptor.
  • Inhibitors have become the main drug in clinical application, but some patients in clinical practice still have problems such as insufficient efficacy or bleeding risk [See Zhang Xia, Ke Yongsheng: Progress in clinical research of new P 2 Y 12 receptor inhibitor ticagrelor [ J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2014, 19(4): 459-465]. Therefore, there is still a strong demand for new anti-platelet aggregation drugs in the clinic.
  • Chinese Patent Application Publication No. CN105481861A discloses ticagrelor derivatives, wherein the following compounds A, B and C are specifically disclosed.
  • CN105481861A also discloses the anti-platelet aggregation effect of the compounds A, B, C and ticagrelor. The results show that the compound B has an anti-platelet aggregation effect, but does not exhibit superior water solubility, and can only be administered orally.
  • the compound of the formula I according to the invention or a pharmaceutically acceptable salt thereof has the best anti-platelet aggregation effect of the compound B disclosed by ticagrelor or CN105481861A. Higher biological activity and unexpected results.
  • the present invention provides a compound of the following formula I or a pharmaceutically acceptable salt thereof
  • R 1 and R 2 are each independently selected from H or an alkyl group of 1 to 6 carbon atoms, preferably, the alkyl group is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a pentyl group, wherein, when the formula I is a free compound, a compound wherein R 1 and R 2 are both H is excluded.
  • it is a sodium salt, a potassium salt, a calcium salt, a magnesium salt, an arginine salt, a lysine salt, a histidine salt, an ornithine salt, an ethylenediamine salt, an ethanolamine salt, Diethanolamine salt, triethanolamine salt or meglumine salt.
  • the compound described above or a pharmaceutically acceptable salt thereof which is a compound of the formula TM-1, Compound TM-2, Compound TM-3, Compound TM-4 or TM-5:
  • Another object of the present invention is also a pharmaceutical composition characterized by comprising a therapeutically effective amount of the above-mentioned compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a therapeutically effective amount is, for example, a dose of from 5 mg to 2000 mg.
  • composition of the present invention described above can be applied to a patient by a suitable administration form, for example, it can be administered orally, parenterally, rectally, or transdermally.
  • a suitable administration form for example, it can be administered orally, parenterally, rectally, or transdermally.
  • Form or transtracheal administration form preferably, wherein:
  • the oral administration form is, for example, selected from the group consisting of a tablet, a capsule, a granule, a syrup, an oral solution, Powder, dispersible tablet, fast disintegrating tablet, instant tablet, sustained release tablet, controlled release tablet, pill, dry suspension, oral film, etc.;
  • the parenteral administration form for example, selected from the group consisting of an injection solution, a lyophilized powder, a solution or a suspension;
  • the rectal administration form is selected from the group consisting of a suppository and an enema;
  • the transdermal absorption administration form is selected from the group consisting of a cream and a transdermal patch.
  • the transtracheal administration form is selected from the group consisting of a solution, a suspension, a dry powder, a sol, an aerosol, and the like.
  • the thromboembolic diseases associated with platelet aggregation described above include, but are not limited to, unstable angina; myocardial infarction; atherosclerosis and thrombosis or embolic stroke caused by it, transient ischemia, Coronary angioplasty, peripheral vascular disease; thrombotic complications caused by vascular grafting and surgery; thrombocytopenic thrombocytopenic purpura; venous occlusive disease; vascular injury secondary to thrombosis or inflammatory diseases such as vasculitis, Arthritis, glomerulonephritis, migraine, Raynaud's syndrome, etc.; thrombosis-related complications such as asthma, adult respiratory distress syndrome, antiphospholipid syndrome, etc.
  • R 1 and R 2 are as defined above;
  • the method comprises the steps of:
  • the starting material and phosphorus oxychloride are dissolved in an organic solvent, and an inorganic base or an organic base is added to obtain a compound 1 after the reaction;
  • the compound 1 and the acid are dissolved in an organic solvent to obtain a compound 2 after the reaction;
  • Compound 2 and an alcohol compound are dissolved in an organic solvent or water or a mixed solvent thereof, and reacted with an acidic catalyst, a basic catalyst or a catalyst to obtain a compound of the present invention or A pharmaceutically acceptable salt.
  • the method comprises the steps of:
  • the starting material and phosphorus oxychloride are dissolved in an organic solvent (for example selected from triethyl phosphate, dichloromethane or tetrahydrofuran, chloroform, 1,4-dioxane), and an inorganic base or an organic base is added (for example) Selected from N,N-diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide), cooling to 0-5 ° C, stirring, reaction 3 ⁇ 6h, directly added water, extraction with an organic solvent (ethyl acetate, dichloromethane, chloroform, 1,4-dioxane, tetrahydrofuran), drying, and recovering the organic solvent under reduced pressure to obtain compound 1;
  • an organic solvent for example selected from triethyl phosphate, dichloromethane or tetrahydrofuran, chloroform, 1,4-diox
  • Compound 1 and an acid are dissolved in an organic solvent (for example, selected from the group consisting of methanol, ethanol, acetone, ethyl acetate, dichloromethane, chloroform, 1,4-dioxane, In tetrahydrofuran), maintaining at 15 to 20 ° C, stirring, reacting for 6 to 12 hours, recovering the organic solvent under reduced pressure to obtain compound 2;
  • an organic solvent for example, selected from the group consisting of methanol, ethanol, acetone, ethyl acetate, dichloromethane, chloroform, 1,4-dioxane, In tetrahydrofuran
  • Compound 2 and an inorganic base for example selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide
  • an organic base for example selected from basic amino acids such as lysine, arginine, histidine, Ornithine, B Diamine, ethanolamine, diethanolamine, triethanolamine or meglumine
  • an organic solvent for example, selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, etc.
  • water or a mixed solvent thereof for example, selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, etc.
  • water or a mixed solvent thereof for example, selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, acetone, etc.
  • water or a mixed solvent thereof for example, selected from the group consisting of methanol, ethanol, isopropanol
  • test methods are generally carried out according to conventional conditions or conditions recommended by the manufacturer; the raw materials and reagents are all commercially available.
  • the above reaction solution was slowly dropped into 20 ml of methanol, reacted at 0 to 5 ° C for 1 h, and heated to 10 to 15 ° C to continue the reaction for 1 h.
  • 30 ml of water was added to the above reaction droplets, and the temperature was controlled at 5 to 15 ° C. After the dropwise addition was completed, the temperature was raised to 25 to 30 ° C for 1 hour.
  • the solubility of the compounds B, C in the compound TM-1, the compound TM-2, the compound TM-3, the compound TM-4, the compound TM-5 and the ticagrelor, CN105481861A in water is as described in the above table, and the compound of the present invention is relative to The solubility of compounds B and C in ticagrelor and CN105481861A in water is significantly improved.
  • the stability data of the compound C in the compound TM-1, the compound TM-2, the compound TM-3, the compound TM-4, the TM-5 and the CN105481861A are as shown in the above table, and the compound of the present invention is more stable than the compound C in CN105481861A. improve.
  • Healthy male Sprague-Dawley rats weighing 210-250 g were randomly divided into blank group, ticagrelor group, compound B, TM-1, TM-2, TM-3, TM-4, TM-5 group.
  • 10 rats in the drug-administered group were dosed at 5 mg/kg, 0.5% sodium carboxymethylcellulose (CMC-Na) was suspended or dissolved, and administered by single gavage.
  • the blank group was given a corresponding volume of 0.5% CMC- Na. Blood was collected 2 hours after administration, and anticoagulated with 3.8% sodium citrate. Do not prepare platelet-rich plasma (PRP) and platelet-poor plasma (PPP).
  • PRP platelet-rich plasma
  • PPPP platelet-poor plasma
  • Inhibition rate (%) (maximum aggregation rate of blank group - maximum aggregation rate of administration group) / maximum aggregation rate of blank group ⁇ 100%.
  • Healthy male Sprague-Dawley rats weighing 180-220 g were randomly divided into blank group, ticagrelor group, compound B, TM-1, TM-2, TM-3, TM-4, TM-5 group.
  • Ten rats in the administration group were dosed at 5 mg/kg, and 0.5% sodium carboxymethylcellulose (CMC-Na) was suspended or dissolved.
  • the blank group was given a corresponding volume of 0.5% CMC-Na.

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Abstract

本发明提供了一类通式I的具有抗血小板聚集活性的化合物及其药学上可接受的盐、制备方法和药物组合物与应用。本发明的化合物及其药学上可接受的盐以及药物组合物可用于预防或者治疗血栓栓塞性相关性疾病，具有很强的抗血小板聚集活性和抑制血栓的作用，其中R1、R2如说明书所述定义。

Description

一类治疗血栓相关性疾病的化合物、制备方法及其药物用途 技术领域
本发明涉及医药技术领域，具体涉及一类治疗血栓相关性疾病的化合物或其盐以及制备这类化合物或其盐的方法以及这类化合物或其盐的药物用途。属于药物化学领域。
背景技术
由血栓引起的心肌梗塞、中风、肺栓塞等心、脑、肺循环疾患，可统称为血栓相关性疾病，该类疾病发病率高居各种疾病前列，且近年来还有渐增之势，已严重威胁人类的生命健康，成为医学研究和新药开发的重点和热点。
目前临床上预防和治疗血栓相关性疾病的药物主要有溶血栓药、抗凝血药和抗血小板聚集药，溶栓治疗主要用于治疗急性缺血性脑梗死的方法，但是由于大多数患者入院时已错过溶栓时机或限于各种条件而未能溶栓，以及溶栓药易致过敏、低温保存等自身缺点明显，使该类药物临床应用受到很大限制；抗凝血药物疗效确切，但作用仅局限于静脉血栓，加之出血风险较大，应用不及抗血小板聚集药广泛。而针对动脉血栓的抗血小板聚集药为最常用的药物，代表药物有环氧合酶抑制剂阿司匹林、P2Y12受体抑制剂氯吡格雷、替格瑞洛等，P2Y12受体抑制剂已成为目前临床应用的主要药物，但临床上部分患者还是存在疗效不足或有出血风险等问题[参见章霞、柯永胜：新型P2Y12受体抑制剂替格瑞洛临床研究进展[J].中国临床药理学和治疗学,2014,19(4):459-465]。因此，临床对新型抗血小板聚集药物仍有强烈需求。
中国专利申请公布文件CN105481861A公开了替格瑞洛衍生物，其中还具体公开了下列化合物A、化合物B和化合物C，
Figure PCTCN2017082633-appb-000001
CN105481861A还公开了化合物A、B、C和替格瑞洛的抗血小板凝聚效果，结果显示了化合物B具有抗血小板凝聚效果，但未显示出更优的水溶性，仅能口服给药。
提供一类抗血小板活性更强，且水溶性好、临床顺应性好，可通过多种方式给药的抗血小板聚集药物，更能满足多种血栓栓塞疾病临床需求。
发明内容
本发明在现有技术的基础上，令人意外地发现，本发明的通式I化合物或其药学上可接受盐，比替格瑞洛或者CN105481861A公开的抗血小板凝聚效果最好的化合物B具有更高生物活性，取得意想不到效果。
本发明技术方案如下：
本发明提供了下列通式I的化合物或其药学上可接受的盐
Figure PCTCN2017082633-appb-000002
其中，R1、R2各自独立选自H或1～6碳原子的烷基，优选地，所述的烷基为甲基、乙基、丙基、异丙基、丁基、戊基、已基；其中，当通式I为游离体化合物时，排除R1、R2同时为H的化合物。
上述所述的化合物或其药学上可接受的盐，其为通式I化合物的无机盐或有机碱盐。优选地，其为通式I化合物的钠盐、钾盐、钙盐、镁盐、精氨酸盐、赖氨酸盐、组氨酸盐、鸟氨酸盐、乙二胺盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐或葡甲铵盐。
更优选地，上述所述的化合物或其药学上可接受的盐，其为下式化合物 TM-1、化合物TM-2、化合物TM-3、化合物TM-4或者TM-5：
Figure PCTCN2017082633-appb-000003
本发明另一目的还提供一种药物组合物，其特征在于含有治疗有效量的上述所述的化合物或其药学可接受盐以及药物可接受的载体。优选地，其中所述的治疗有效量，例如剂量5mg至2000mg。
本发明上述所述的药物组合物，其可以通过合适的给药形式应用于患者，例如可以为口服给药形式、非胃肠道给药形式、经直肠给药形式、经透皮吸收给药形式或者经气道给药形式；优选地，其中：
所述的口服给药形式，例如选自片剂、胶囊剂、颗粒剂、糖浆剂、口服液、 粉剂、分散片、速崩片、速溶片、缓释片、控释片、丸剂、干混悬剂、口腔膜剂等；
所述的经非胃肠道给药形式，例如选自注射液、冻干粉针、溶液剂或混悬剂；
所述的经直肠给药形式选自栓剂、灌肠液；
所述的经透皮吸收给药形式选自乳膏剂、透皮贴剂
所述的经气道给药形式选自溶液剂、混悬剂、干粉剂、溶胶剂、气雾剂等。
作为本发明另一发明目的，提供了上述所述化合物或其药学上可接受盐或者上述所述的药物组合物制备用于预防或者治疗血小板聚集相关的血栓栓塞性疾病的药物的应用。
优选地，上述所述的血小板聚集相关的血栓栓塞性疾病，其包括但不限于：不稳定性心绞痛；心肌梗塞；动脉粥样硬化及其引起的血栓或栓塞性中风、短暂的局部缺血、冠状动脉成形术、外周血管疾病；血管移植及外科手术引起的血栓性并发症；血栓形成的血小板减少性紫癜；静脉闭塞性疾病；血管损伤继发血栓形成或炎症性疾病，如脉管炎、关节炎、肾小球肾炎、偏头痛、雷诺氏综合征等；血栓形成相关并发症，如哮喘、成人呼吸窘迫综合症、抗磷脂综合症等。
作为本发明又一发明目的，还提供了制备上述所述化合物或其药学上可接受盐的方法，其反应路线如下：
Figure PCTCN2017082633-appb-000004
其中，R1、R2如上所述定义；
优选地，所述方法包括如下步骤：
(1)化合物1的制备
将起始原料和三氯氧磷溶于有机溶剂中，加入无机碱或有机碱，反应后得到化合物1；
(2)化合物2的制备
将化合物1和酸溶于有机溶剂中，反应后得到化合物2；
(3)本发明化合物或其药学上可接受盐的制备
将化合物2和无机碱或有机碱溶于有机溶剂或水或它们的混合溶剂中，反应后得到本发明化合物或其药学上可接受盐；或者
化合物2和醇类化合物(甲醇、乙醇、异丙醇、丁醇)溶解于有机溶剂或水或它们的混合溶剂中，在酸性催化剂、碱性催化剂或无催化剂下反应后得到本发明化合物或其药学上可接受盐。
优选地，所述方法包括如下步骤：
(1)化合物1的制备
将起始原料和三氯氧磷溶于有机溶剂(例如选自磷酸三乙酯、二氯甲烷或四氢呋喃、三氯甲烷、1,4二氧六环)中，加入无机碱或有机碱(例如选自N,N-二异丙基乙胺、碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁)，降温至0～5℃，搅拌，反应3～6h，直接加水，有机溶剂(乙酸乙酯、二氯甲烷、三氯甲烷、1,4二氧六环、四氢呋喃)萃取，干燥，减压回收有机溶剂后得到化合物1；
(2)化合物2的制备
将化合物1和酸(例如选自盐酸、硫酸、路易斯酸)溶于有机溶剂(例如选自甲醇、乙醇、丙酮、乙酸乙酯、二氯甲烷、三氯甲烷、1,4二氧六环、四氢呋喃)中，保持15～20℃，搅拌，反应6～12h，减压回收有机溶剂后得到化合物2；
(3)本发明化合物或其药学上可接受盐的制备
将化合物2和无机碱(例如选自氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁)或有机碱(例如选自碱性氨基酸，如赖氨酸、精氨酸、组胺酸、鸟氨酸、乙 二胺、乙醇胺、二乙醇胺、三乙醇胺或者葡甲胺)溶于有机溶剂(例如选自甲醇、乙醇、异丙醇、正丁醇、丙酮等)或水或它们的混合溶剂中，保持15～20℃，搅拌，反应1～3h，经减压回收溶剂，或经过滤分离得到本发明式I化合物(化合物TM)或其药学上可接受盐；或者化合物2和醇类化合物(甲醇、乙醇、异丙醇、丁醇)溶解于有机溶剂或水或它们的混合溶剂中，在酸性催化剂(盐酸、硫酸、)、碱性催化剂(氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、赖氨酸、精氨酸、组胺酸、鸟氨酸、乙二胺、乙醇胺、二乙醇胺、三乙醇胺或者葡甲胺)或无催化剂下，保持室温或回流反应2～24h，经减压回收溶剂，或经过滤分离得到化合物TM或其药学上可接受盐。
具体实施例
为了使本发明所解决的技术问题、技术方案及有益效果更加清楚明白，以下结合具体实施例，对本发明作进一步的说明。下述实施例中，除非另有说明，所述的试验方法通常按照常规条件或制造厂商建议的条件实施；所述的原料、试剂均通过市售购买获得。
实施例1化合物TM-1的合成
1.1化合物1的合成
Figure PCTCN2017082633-appb-000005
氮气保护下，反应瓶中加入起始原料(5.01g,8.90mmol)，DIPEA(11.4g,88.9mmol)，THF 50mL，5℃搅拌至澄清。缓慢滴加新蒸POCl3(13.6g,88.9mmol)，约15min滴毕，反应3h。TLC[CH2Cl2:CH3OH＝4:1]检测反应基本完全，加入水100mL搅拌均相。乙酸乙酯100mL萃取三次，饱和食盐水50mL洗涤。收集有机层，无水硫酸钠干燥。蒸除有机溶剂，得黄色固体化合物1粗品5.69g，收率99.4％。1H NMR(400MHz,CDCl3)δ(ppm):7.04～6.93(m,3H,ArH),5.83～5.45(m,1H),5.03(s,1H),4.73(s,1H),4.15～3.87(m,2H),3.51-3.38(m,2H),2.99(s,3H),2.50(s,2H),2.12-2.04(m,1H),1.63(s,2H),1.47(s,4H),1.28-1.24(m,4H), 0.94～0.78(m,SCH2CH2CH3,3H)；ESI-Mass for C26H33F2N6O7PS m/z(M+H)+:643.2。
1.2化合物2的合成
Figure PCTCN2017082633-appb-000006
反应瓶中加入化合物1(5.69g,8.85mmol)，甲醇50mL，25℃下搅拌澄清。缓慢滴加3N盐酸30mL，约15min滴毕，反应6h。加入水50mL，乙酸乙酯150mL萃取三次。收集有机层，蒸除溶剂得白色粉末化合物2粗品5.3g，收率98.9％。1H NMR(400MHz,CD3OH)δ(ppm):7.14-7.04(m,2H,PhH),6.98(s,1H,PhH),5.01(q,J＝8.8Hz,1H,HOCH),4.66(q,J＝12.0Hz,1H,CHOH),4.08(q,J＝8.0Hz,1H,CHN),3.94-3.90(m,2H,POCH2CH2O),3.89-3.85(m,1H,OCH),3.68(t,J＝12.0Hz,2H,POCH2CH2O),3.03-2.94(m,2H,SCH2),2.87-2.77(m,1H,NHCH),2.71-2.63(m,1H,PhCH),2.15-2.09(m,1H,OCH2CH),2.08-2.04(m,1H,OCH2CH),1.68-1.46(m,1H,SCH2CH),1.41-1.36(m,1H,SCH2CH),1.30-1.25(m,1H,NHCHCH),1.23-1.14(m,1H,NHCHCH),0.94(t,J＝4.0Hz,3H,SCH2CH2CH3)；ESI-Mass forC23H29F2N6O7PS:m/z(M+H)+:603.2。
1.3化合物TM-1的合成
Figure PCTCN2017082633-appb-000007
反应瓶中加入化合物2(5.30g,8.80mmol)，甲醇40mL搅拌溶解。氢氧化钠(0.70g,17.6mmol)水溶液10mL，5℃混合搅拌1h。减压回收溶剂，粗品 乙醇/水体系重结晶，得淡黄色粉末2.08g，收率36.6％。1H NMR(400MHz,D2O)δ(ppm):7.15(dd,J＝16.0Hz,J＝4.0Hz,1H,PhH),7.06(t,J＝4.0Hz,1H,PhH),6.95(s,1H,PhH),5.26～5.16(m,1H,HOCH),4.91(t,J＝4.0Hz,1H,CHOH),4.58(s,1H,CHN),4.33(s,1H,)4.23～4.14(m,1H,POCH2CH2O),(m,1H,OCH),4.02～4.01(m,2H,POCH2CH2O),3.12～3.04(m,2H,SCH2),2.95-2.89(m,2H,NHCH),2.71-2.63(m,1H,PhCH),2.30-2.09(s,1H,OCH2CH),2.16(s,1H,OCH2CH),1.64～1.59(m,2H,SCH2CH2),1.57-1.51(m,1H,NHCHCH),1.47-1.42(m,1H,NHCHCH),0.93(t,J＝4.0Hz,3H,SCH2CH2CH3).ESI-Mass for C23H27F2 N6Na2O7PS:m/z(M-2Na+H)-:601.2,(M-Na)-:623.1。
实施例2化合物TM-2的合成
Figure PCTCN2017082633-appb-000008
反应瓶中加入化合物2(1.000g,1.66mmol)，甲醇2mL搅拌溶解。赖氨酸(0.485g,3.32mmol)水溶液1mL，25℃混合搅拌1h。减压回收溶剂，粗品乙醇/水体系重结晶，得黄色固体粉末0.57g，收率45.9％。ESI-Mass for C23H29F2N6O7PS·C6H14N2O2m/z(M-H)-:747.2。
实施例3化合物TM-3的合成
Figure PCTCN2017082633-appb-000009
反应瓶中加入化合物2(1.000g,1.66mmol)，水8mL搅拌溶解。精氨酸(0.289g,1.66mmol)水溶液2mL，25℃混合搅拌1h。搅拌后减压回收溶剂，直至完全蒸除溶剂，得白色固体粉末1.13g，收率87.4％。ESI-Mass for C23H29F2N6O7PS·C6H14N4O2m/z(M-H)-:775.3。
实施例4化合物TM-4的合成
Figure PCTCN2017082633-appb-000010
反应瓶中加入化合物2(100mg,0.166mmol)，水8mL搅拌溶解。葡甲胺葡甲胺(65.0mg,0.332mmol)水溶液2mL，25℃混合搅拌1h。搅拌后减压回收溶剂，直至完全蒸除溶剂，得白色固体粉末101mg，收率62.1％。ESI-Mass for C23H29F2N6O7PS m/z(M+CH3OH-H)-:828.85.
实施例5化合物TM-5的合成
Figure PCTCN2017082633-appb-000011
氮气保护下，反应瓶中依次加入异亚丙基替格瑞洛(1.00g,1.78mmol)，N,N-二异丙基乙胺(2.30g,17.8mmol)和四氢呋喃10mL，5℃搅拌至澄清，降温至-5℃～0℃。上述反应液中滴加三氯氧磷(2.72g,17.7mmol)的5ml四氢呋喃溶液，控制反应液温度0～5℃，10min滴加完毕，控温0～5℃反应2h。
氮气保护下，将上述反应液缓慢滴入20ml甲醇中，0～5℃反应1h，升温至10～15℃继续反应1h。向上述反应液滴加30ml水，控温5～15℃，滴加完毕， 升温至25～30℃反应1h。60ml乙酸乙酯分两次萃取，合并有机相，依次用30ml水和30ml饱和食盐水洗涤有机相，得到的有机相再用1g无水硫酸钠干燥1h，抽滤，滤液进行减压蒸馏，得到白色固体1.01g，收率90.11％。1H NMR(400MHz,CDCl3)δ(ppm):7.13-7.06(m,2H,ArH),7.00(s,1H,NH),6.91(s,1H,ArH),5.00-4.94(m,1H),4.65-4.62(m,1H),4.31-4.29(m,1H),4.24-4.11(m,2H),4.04-4.00(m,1H),3.80-3.75(m,8H,OCH3,OCH2),3.12-2.91(m,4H,SCH2,OCH2),2.47-2.40(m,1H),2.16-2.12(m,1H),1.69-1.64(m,2H),1.45-1.35(m,2H),0.97(t,J＝4.0Hz,3H,SCH2CH2CH3).ESI-Mass forC25H33F2N6O7PSm/z(M+H)+:631.1917.
试验例1：溶解度及稳定性
结果见表1和表2。
表1本发明中典型化合物的溶解度相关数据
Figure PCTCN2017082633-appb-000012
化合物TM-1、化合物TM-2、化合物TM-3、化合物TM-4、化合物TM-5及替格瑞洛、CN105481861A中的化合物B、C在水中溶解度如上表所述，本发明化合物相对于替格瑞洛及CN105481861A中的化合物B、C在水中的溶解度显著提升。
表2本发明化合物的稳定性数据
Figure PCTCN2017082633-appb-000013
Figure PCTCN2017082633-appb-000014
化合物TM-1、化合物TM-2、化合物TM-3、化合物TM-4、TM-5及CN105481861A中的化合物C稳定性数据如上表所示，本发明化合物相对于CN105481861A中的化合物C稳定性明显提高。
试验例2：生物活性评价
1.大鼠体内血小板聚集抑制实验
取健康雄性SD大鼠，体重210-250g，随机分为空白组、替格瑞洛组、化合物B、TM-1、TM-2、TM-3、TM-4、TM-5组，每组10只，给药组大鼠剂量均为5mg/kg，0.5％羧甲基纤维素钠(CMC-Na)混悬或溶解，均单次灌胃给药，空白组给予相应体积0.5％CMC-Na。给药后2h采血，用3.8％枸橼酸钠抗凝，分 别制备富血小板血浆(PRP)和贫血小板血浆(PPP)。取PPP，在LBY-NJ4型4通道血小板聚集仪测定ADP(10uL)诱导的血小板最大聚集率，计算抑制率(％)。抑制率(％)＝(空白组最大聚集率－给药组最大聚集率)/空白组最大聚集率×100％。
结果见表2。由结果可知，与空白组相比，各给药组均具有极显著的抗血小板聚集效果(P<0.01)；与替格瑞洛比较，化合物B及TM-1～TM-5均能显著抑制血小板聚集(P<0.05，P<0.01)；与化合物B比较，化合物TM-1～TM-5能不同程度抑制血小板聚集(P<0.05，P<0.01)，且抑制率均在50％以上。表明发明的化合物抗ADP诱导的大鼠血小板聚集作用优于替格瑞洛及化合物B。
表2.对ADP诱导的血小板聚集的影响(Mean±SD，n＝10)
Figure PCTCN2017082633-appb-000015
注：＊P<0.05，＊＊P<0.01vs空白组；△P<0.05，△△P<0.01vs替格瑞洛；#P<0.05，##P<0.01vs
化合物B
2.大鼠颈动-静脉旁丝线上血栓实验
取健康雄性SD大鼠，体重180-220g，随机分为空白组、替格瑞洛组、化合物B、TM-1、TM-2、TM-3、TM-4、TM-5组，每组10只，给药组大鼠剂量均为5mg/kg，0.5％羧甲基纤维素钠(CMC-Na)混悬或溶解。单次灌胃给药，空白组给予相应体积的0.5％CMC-Na。
参照文献方法造模，给药后1h，用3％水合氯醛腹腔麻醉，仰卧固定分离右颈总动脉及左颈外静脉。取内径为1.5mm，长10cm的聚乙烯管，内置一根长6cm的丝线(预先称重)，以肝素生理盐水溶液(50U/ml)充满聚乙烯管。将聚乙烯管的一端插入左颈外静脉后，注入肝素(50U/kg)，另一端插入右颈总动脉。开放血流15min后中断血流并迅速取出丝线称重，总重减去原丝线重即为血栓湿重，放入烘箱70℃烘干，称取丝线重量减去原丝线重即为血栓干重，并计算抑制率[血栓湿重抑制率(％)＝(空白组血栓湿重－给药组血栓湿重)/空白组血栓湿重×100％；血栓干重抑制率(％)＝(空白组血栓干重－给药组血干湿重)/空白组血栓干重 ×100％]。
结果见表3。由结果可知，与空白组相比，各给药组均能显著降低血栓湿重和干重(P<0.01)；与替格瑞洛比较，化合物B及TM-1～TM-5均能显著降低血栓湿重和干重(P<0.05，P<0.01)；与化合物B比较，化合物TM-1～TM5能不同程度降低血栓湿重和干重(P<0.05，P<0.01)，提示所发明的化合物抑制血栓形成作用强于替格瑞洛及化合物B。
表3.对大鼠动静脉旁路血栓干湿重的影响(Mean±SD，n＝10)
Figure PCTCN2017082633-appb-000016
注：＊P<0.05，＊＊P<0.01vs空白组；△P<0.05，△△P<0.01vs替格瑞洛；#P<0.05，##P<0.01vs
化合物B

Claims (10)

  1. 通式I的化合物或其药学上可接受的盐
    Figure PCTCN2017082633-appb-100001
    其中，R1、R2各自独立选自H或1～6碳原子的烷基，当通式I为游离体化合物时，排除R1、R2同时为H的化合物。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于其为通式I化合物的无机盐或有机碱盐。
  3. 根据权利要求2所述的化合物或其药学上可接受的盐，其中所述的盐选自钠盐、钾盐、钙盐、镁盐、精氨酸盐、赖氨酸盐、组氨酸盐、鸟氨酸盐、乙二胺盐、乙醇胺盐、二乙醇胺盐、三乙醇胺盐或葡甲铵盐。
  4. 根据权利要求1－3所述的化合物或其药学上可接受的盐，其为下式化合物TM-1、化合物TM-2、化合物TM-3、化合物TM-4或者化合物TM-5：
    Figure PCTCN2017082633-appb-100002
    Figure PCTCN2017082633-appb-100003
  5. 药物组合物，其特征在于含有治疗有效量的权利要求1－4所述的化合物或其药学可接受盐以及药物可接受的载体。
  6. 根据权利要求5所述的药物组合物，其中所述的治疗有效量为5mg至2000mg。
  7. 根据权利要求5－6所述的药物组合物，其为口服给药形式、经非胃肠道给药形式、经直肠给药形式、经透皮吸收给药形式或者经气道给药形式；优选地，其中：
    所述的口服给药形式选自片剂、胶囊剂、颗粒剂、糖浆剂、口服液、粉剂、分散片、速崩片、速溶片、缓释片、控释片、丸剂、干混悬剂、口腔膜剂；
    所述的经非胃肠道给药形式，例如选自注射液、冻干粉针、溶液剂或混悬剂；
    所述的经直肠给药形式选自栓剂、灌肠液；
    所述的经透皮吸收给药形式选自乳膏剂、透皮贴剂；
    所述的经气道给药形式选自溶液剂、混悬剂、干粉剂、溶胶剂、气雾剂等。
  8. 权利要求1-4所述化合物或其药学上可接受盐或者权利要求5-7所述的药物组合物制备用于预防或者治疗血小板聚集相关的血栓栓塞性疾病的药物的应用；
  9. 权利要求8中所述的血小板聚集相关的血栓栓塞性疾病包括但不限于：不稳 定性心绞痛；心肌梗塞；动脉粥样硬化及其引起的血栓或栓塞性中风、短暂的局部缺血、冠状动脉成形术、外周血管疾病；血管移植及外科手术引起的血栓性并发症；血栓形成的血小板减少性紫癜；静脉闭塞性疾病；血管损伤继发血栓形成或炎症性疾病，如脉管炎、关节炎、肾小球肾炎、偏头痛、雷诺氏综合征等；血栓形成相关并发症，如哮喘、成人呼吸窘迫综合症、抗磷脂综合症等。
  10. 制备权利要求1-4所述化合物或其药学上可接受盐的方法，其反应路线如下：
    Figure PCTCN2017082633-appb-100004
    其中，R1、R2如权利要求1所述定义；
    优选地，所述方法包括如下步骤：
    (1)化合物1的制备
    将起始原料和三氯氧磷溶于有机溶剂中，加入无机碱或有机碱，反应后得到化合物1；
    (2)化合物2的制备
    将化合物1和酸溶于有机溶剂中，反应后得到化合物2；
    (3)权利要求1化合物或其药学上可接受盐的制备
    将化合物2和无机碱或有机碱溶于有机溶剂或水或它们的混合溶剂中，反应后得到权利要求1化合物或其药学上可接受盐；或者
    化合物2和醇类化合物(例如甲醇、乙醇、异丙醇、丁醇)溶解于有机溶剂 或水或它们的混合溶剂中，在酸性催化剂、碱性催化剂或无催化剂下反应后得到权利要求1化合物或其药学上可接受盐。
    优选地，所述方法包括如下步骤：
    (1)化合物1的制备
    将起始原料和三氯氧磷溶于有机溶剂(例如选自磷酸三乙酯、二氯甲烷或四氢呋喃、三氯甲烷、1,4二氧六环)中，加入无机碱或有机碱(例如选自N,N-二异丙基乙胺、碳酸钾、碳酸钠、碳酸铯、氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁)，降温至0～5℃，搅拌，反应3～6h，直接加水，有机溶剂(例如乙酸乙酯、二氯甲烷、三氯甲烷、1,4二氧六环、四氢呋喃)萃取，干燥，减压回收有机溶剂后得到化合物1；
    (2)化合物2的制备
    将化合物1和酸(例如选自盐酸、硫酸、路易斯酸)溶于有机溶剂(例如选自甲醇、乙醇、丙酮、乙酸乙酯、二氯甲烷、三氯甲烷、1,4二氧六环、四氢呋喃)中，保持15～20℃，搅拌，反应6～12h，减压回收有机溶剂后得到化合物2；
    (3)权利要求1化合物或其药学上可接受盐的制备
    将化合物2和无机碱(例如选自氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁)或有机碱(例如选自碱性氨基酸，如赖氨酸、精氨酸、组胺酸、鸟氨酸、乙二胺、乙醇胺、二乙醇胺、三乙醇胺或者葡甲胺)溶于有机溶剂(例如选自甲醇、乙醇、异丙醇、正丁醇、丙酮等)或水或它们的混合溶剂中，保持15～20℃，搅拌，反应1～3h，经减压回收溶剂，或经过滤分离得到权利要求1化合物或其药学上可接受盐；或者化合物2和醇类化合物(例如甲醇、乙醇、异丙醇或丁醇)溶解于有机溶剂或水或它们的混合溶剂中，在酸性催化剂(例如盐酸或硫酸)、碱性催化剂(例如氢氧化钠、氢氧化钾、氢氧化钙、氢氧化镁、赖氨酸、精氨酸、组胺酸、鸟氨酸、乙二胺、乙醇胺、二乙醇胺、三乙醇胺或者葡甲胺)或无催化剂下，保持室温或回流反应2～24h，经减压回收溶剂，或经过滤分离得到权利要求1化合物或其药学上可接受盐。
PCT/CN2017/082633 2017-03-18 2017-04-28 一类治疗血栓相关性疾病的化合物、制备方法及其药物用途 WO2018171004A1 (zh)

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