WO2022063016A1 - 氘代的二氢二苯并硫杂卓化合物以及包含该化合物的药物组合物 - Google Patents

氘代的二氢二苯并硫杂卓化合物以及包含该化合物的药物组合物 Download PDF

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WO2022063016A1
WO2022063016A1 PCT/CN2021/118711 CN2021118711W WO2022063016A1 WO 2022063016 A1 WO2022063016 A1 WO 2022063016A1 CN 2021118711 W CN2021118711 W CN 2021118711W WO 2022063016 A1 WO2022063016 A1 WO 2022063016A1
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compound
deuterium
prodrug
deuterated
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张海龙
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长沙晶易医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the present invention relates to the field of medicine, in particular to a deuterated dihydrodibenzothiazepine compound represented by formula I, a prodrug thereof, a composition comprising the compound, and an application for treating influenza.
  • the shape and volume of deuterium in the drug molecule are basically the same as that of hydrogen. If the hydrogen in the drug molecule is selectively replaced by deuterium, the deuterated drug will generally retain the original biological activity and selectivity. At the same time, studies have shown that the combination of carbon-deuterium bonds is more stable than carbon-hydrogen bonds, which can directly affect the absorption, distribution, metabolism and excretion of certain drugs, thereby improving the efficacy, safety and tolerance of drugs. Therefore, if a specific carbon-hydrogen bond in the drug molecule is decomposed into the corresponding carbon-deuterium bond, the decomposition process will be delayed, so that the deuterated drug will act in the body for a longer time and the effect will be better.
  • Sorafenib and its deuterated compounds the pharmacokinetic characteristics of the deuterated compounds in rats are better than those of the original drug Sorafenib: longer half-life, larger area under the drug-time curve, and apparent However, the clearance rate is reduced, so the action time is longer and more effective; venlafaxine and its deuterated compounds, the first phase clinical trial shows that its metabolism rate is half of that of venlafaxine, so its time in the body is longer than that of venlafaxine. Lafaxine is longer and the effect is more pronounced. This all proves to a certain extent the superiority of deuterated products in the treatment of diseases.
  • Influenza influenza or flu is an acute respiratory infectious disease caused by influenza virus infection, and has become a viral infectious disease with the highest fatality rate.
  • Influenza virus is divided into three types: A, B, and C (also A, B, C) according to the different antigenic properties of the protein and matrix protein.
  • Influenza A virus has the widest host range and strong pathogenicity. It can cause large-scale influenza outbreaks in the world and is the most harmful to humans; Influenza B virus has low pathogenicity and mainly causes local outbreaks; Influenza C virus only infects immunity The low-income population is less likely to cause epidemics and the harm is relatively small.
  • influenza-related morbidity and mortality has increased in high-risk groups such as the elderly, pregnant women, and immunocompromised populations, with a recent study indicating that there are approximately 650,000 cases of influenza-related respiratory infections in dead fish annually worldwide. disease. Therefore, effective influenza treatment is critical.
  • anti-influenza drugs covering different mechanisms of action, but with the wide application of anti-influenza drugs, the problem of drug resistance is becoming more and more serious, and new influenza viruses with higher lethality may be produced. And cause a global pandemic, so it is expected to develop an anti-influenza drug with a new mechanism.
  • the dihydrodibenzothiazepine compound represented by the formula (I) is a new type of anti-influenza virus compound, which is achieved by inhibiting the cap-dependent nucleic acid PA endonuclease to block the process of viral genes in the initial stage of transcription. Treatment of acute uncomplicated influenza.
  • the main reason for limiting the application scope of drugs lies in the advantages and disadvantages of the absorption, distribution, metabolism and/or excretion of drugs. Rapid metabolism will lead to the metabolism of drugs from the body before they form active metabolites or play a therapeutic role. Cleared, so that the drug can not play a better role.
  • the deuterated dihydrodibenzothiazepine compound provided by the present invention is such a compound.
  • the purpose of the present invention is to provide a new class of deuterated compounds with anti-influenza virus activity and better pharmacodynamic properties, prodrugs thereof, and compositions containing the compounds.
  • a deuterated dihydrodibenzothiazepine compound represented by formula I or its tautomer, stereoisomer, prodrug, crystal form, pharmacy
  • R is deuterium or the following deuterium (D) group forming a prodrug
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 are each independently hydrogen or deuterium, or all of them are deuterium;
  • R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 , R 20 are each independently hydrogen or deuterium, or all of them are deuterium;
  • R 21 , R 22 , R 23 , R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 are each independently hydrogen or deuterium, or all of them are deuterium;
  • R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 are each independently hydrogen or deuterium, or all of them are deuterium;
  • R 41 , R 42 , R 43 , R 44 , R 45 are each independently hydrogen or deuterium, or all of them are deuterium;
  • the second aspect of the present invention provides a pharmaceutical composition, which contains a pharmaceutically acceptable carrier and the compound described in the first aspect of the present invention, or a tautomer, stereoisomer, pro- Drugs, crystal forms, pharmaceutically acceptable salts, hydrates or solvates.
  • deuterated refers to the substitution of one or more hydrogens in a compound or group by deuterated substitution; deuterated substitution may be mono-, di-, poly- or full-substitution.
  • deuterated substitution may be mono-, di-, poly- or full-substitution.
  • one or more deuterated and “one or more deuterated” are used interchangeably.
  • non-deuterated compound refers to a compound whose deuterium atom ratio is not higher than the natural deuterium isotope content (0.015%).
  • the term "pharmaceutically acceptable salt” means, within the scope of sound medical judgment, suitable for contact with human and lower animal tissues without undue toxicity, irritation, allergy, etc., and is compatible with Those salts with a reasonable benefit/hazard ratio.
  • Pharmaceutically acceptable salts are well known in the art.
  • crystal form refers to the different arrangements of chemical drug molecules, generally manifested as the existing form of the drug substance in the solid state.
  • the deuterated dihydrodibenzothiazepine compound of the present invention has a series of advantages compared to the former compound:
  • the compound of the present invention has excellent inhibitory activity on cap-dependent PA endonuclease polymerization
  • the drug concentration of the compound in the animal body can be increased, so as to improve the drug efficacy.
  • the inventors of the present invention unexpectedly found that the deuterated dihydrodibenzothiazepines and prodrugs of the present invention and their pharmaceutically acceptable salts have significantly better properties than non-deuterated compounds. Because of its pharmacokinetic and pharmacodynamic properties, it is more suitable for anti-influenza virus, and more suitable for preparing medicines for treating influenza and related diseases.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • the dosage form is not particularly limited.
  • Solid dosage forms for oral administration include but are not limited to tablets, pills, dry suspensions, granules, powders and capsules, and liquid dosage forms for oral administration include but are not limited to pharmaceutically acceptable emulsions, solutions , suspension, syrup or tincture.
  • Embodiment 1 the preparation of deuterated dihydrodibenzothiazepine
  • the fragment A compound can be prepared by the following reaction scheme 2:
  • the fragment B compound can be prepared by the following reaction scheme 3:
  • the fragment A compound can be prepared by the above reaction scheme 2
  • the fragment B compound can be prepared by the above reaction scheme 3.
  • the fragment A compound can be prepared by the above reaction scheme 2
  • the fragment B compound can be prepared by the above reaction scheme 3.
  • the fragment A compound can be prepared by the above reaction scheme 2
  • the fragment B compound can be prepared by the above reaction scheme 3.
  • the fragment A compound can be prepared by the above reaction scheme 2
  • the fragment B compound can be prepared by the above reaction scheme 3.
  • DBU is a sterically hindered amidine, basic
  • DMA Dimethylacetamide (Dimethylacetamide, DMAC or DMA), the full name is N,N-dimethylacetamide.
  • the chemical bed is dried to obtain dry particles of suitable particle size; colloidal silicon dioxide, talc, sucralose, essence and dry particles are added and mixed with a two-dimensional mixer to obtain a dry suspension.
  • the compound of the present invention hydrated lactose, croscarmellose sodium, polyvinylpyrrolidone, crystalline cellulose, sodium stearyl fumarate, hydroxypropyl dextrose and titanium oxide are mixed.
  • the mixture is granulated and dried to obtain granules of suitable size.
  • Talc is then added to the granules and mixed, and the mixture is compressed into tablets.
  • the compound of the present invention (10 mg) and lactose were passed through a 60 mesh screen.
  • the cornstarch was passed through a 120 mesh sieve. Mix them with a V-blender.
  • To the mixture was added an aqueous HPC-L solution (low viscosity hydroxypropyl cellulose), and then the mixture was kneaded, granulated (extrusion granulation hole diameter 0.5-1 mm), and dried.
  • the obtained dried granules were passed through a vibrating screen (12/60 mesh) to obtain granules.
  • the compound of the present invention (15 mg) and lactose were passed through a 60 mesh screen.
  • the cornstarch was passed through a 120 mesh sieve. Mix them with a V-blender.
  • Aqueous HPC-L low viscosity hydroxypropyl cellulose
  • the obtained dry granules were granulated and filled into size 4 hard gelatin capsules in a 150 mg capacity.
  • mice 8 mature mice, 7-8 weeks old, weighing about 30g, were divided into 2 groups, 4 mice in each group, and were given a single oral dose of 1mg/kg
  • Control group dihydrodibenzothiazepine compound
  • Test group deuterated dihydrodibenzothiazepine compounds, and their pharmacokinetic differences were compared.
  • Centrifuge to separate plasma within 1 hour after blood sample collection (centrifugation conditions: 5000 rpm, 5 min, 4 °C), use a pipette to aspirate 100 microliters of supernatant into a clean plastic centrifuge tube, mark the name and time of the compound and stored at -80°C for later use.
  • LC-MS was used to analyze and detect the samples, and the concentration-time data obtained were analyzed and calculated with DAS3.0 pharmacokinetic software to obtain the main absorption kinetic parameter T 1/2 ( h), AUC (0-t) (ng eq h/mL), AUC (0- ⁇ ) (ng eq h/mL), etc.

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  • Health & Medical Sciences (AREA)
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Abstract

本发明涉及氘代的二氢二苯并硫杂卓化合物，其互变异构体、立体异构体、前药、药学上可接受的盐、水合物或溶剂化物，以及包含该化合物的药物组合物和相关用途。本发明化合物及组合物具有帽依赖性核酸内切酶抑制活性和改进的药代动力学性质。

Description

氘代的二氢二苯并硫杂卓化合物以及包含该化合物的药物组合物 技术领域
本发明涉及医药学领域，具体涉及一种式Ⅰ所示的氘代的二氢二苯并硫杂卓化合物及其前药、包含该化合物的组合物以及作为治疗流行性感冒的应用。
背景技术
氘在药物分子中的形状和体积与氢基本上相同，如果药物分子的中氢被选择性的替换为氘，氘代药物一般还会保留原来的生物活性和选择性。同时有研究证明，碳氘键的结合比碳氢键更加稳定，可直接影响某些药物的吸收、分布、代谢和排泄等属性，从而提高药物的疗效、安全性和耐受性。因此如果药物分子中被分解的某个特定的碳氢键被氘代为相应的碳氘键后，将会延缓其分解过程，使氘代药物在身体内作用的时间更长，效果更优。如：索拉菲尼及其氘代化合物，氘代化合物在大鼠中的药代动力学特征更优于原药物索拉菲尼：半衰期更长，药时曲线下面积更大，而表观清除率却减少，因而作用时间更长，更加有效；文拉法辛及其氘代化合物，一期临床实验表明，其代谢速度是文拉法辛的一半，因而其在体内存在的时间比文拉法辛更长，疗效更加明显。这都在一定程度上证明了氘代产物在治疗疾病方面的优越性。
流行性感冒简称流感(influenza或flu)是由流行性感冒病毒的感染引起的急性呼吸道传染病，已经成为致死率最高的病毒性传染疾病。流感病毒根据该蛋白和基质蛋白抗原特性的不同，分为甲、乙、丙(也成A、B、C)三种类型。A型流感病毒宿主范围最广，致病力强，能引起全球大范围流感爆发，对人类危害最大；B型流感病毒致病能力较低，主要引起局部爆发；C型流感病毒仅感染免疫力低下的人群，较少引起流行，危害相对较小。
近年来，与流感相关的发病率和死亡率的风险在老年人、孕妇和免疫功能受损等高危人群中增加，最近一项研究表明，全世界每年约有65万例死鱼流感相关的呼吸道疾病。因此，有效的流感治疗是至关重要的。目前抗流行性感冒的药物很多，涵盖不同的作用机制，但随着抗流感药物的广泛应用，耐药性的问题越来越严重，有可能会产生致死性更高的新型流行性感冒病毒，并引起全球大流行，因此期望开发新机理的抗流行性感冒药。
技术问题
式(Ⅰ)所示二氢二苯并硫杂卓化合物就是一种新型抗抗流感病毒的化合物，它是通过抑制cap依赖的核酸PA内切酶阻断病毒基因在转录起始阶段的过程来治疗急性单纯性流行性感冒。但是，我们已知限制药物应用范围的主要原因在于药物的吸收、分布、代谢和(或) 排泄等性质的优劣，快速代谢会导致药物尚未形成活性代谢物或者未发挥治疗作用便从体内代谢清除，从而不能使药物发挥更好的效用。
因此，本领域仍需开发具有抑制cap依赖的核酸PA内切酶活性且药代动力学更优的化合物，本发明提供的氘代二氢二苯并硫杂卓化合物就是这样的化合物。
技术解决方案
本发明的目的就是提供一类新型的具有抗流感病毒活性和更好药效学性能的氘代化合物及其前药及包含该化合物的组合物。
在本发明的第一方面，提供了一种式Ⅰ所示的氘代的二氢二苯并硫杂卓化合物、或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化物：
Figure PCTCN2021118711-appb-000001
式中：
R为氘或形成前药的以下氘(D)代基团
Figure PCTCN2021118711-appb-000002
Figure PCTCN2021118711-appb-000003
R 1，R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9各自独立的为氢或氘，或者全部为氘；
R 10、R 11、R 12、R 13、R 14、R 15、R1 6、R 17、R 18、R 19，R 20各自独立的为氢或氘，或者全部为氘；
R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31各自独立的为氢或氘，或者全部为氘；
R 32、R 33、R 34、R 35、R 36、R 37，R 38、R 39、R 40各自独立的为氢或氘，或者全部为氘；
R 41、R 42、R 43、R 44、R 45各自独立的为氢或氘，或者全部为氘；
附加条件是：上述化合物至少含有一个氘原子。
本发明的第二个方面，提供了一种药物组合物，它含有药学上可接受的载体和本发明第一方面中所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化物。
定义
本文中，如无特别说明，“氘代”指化合物或基团中的一个或多个氢被氘代所取代；氘代可以是一取代、二取代、多取代或全取代。术语“一个或多个氘代的”与“一次或多次氘代”可互换使用。
本文中，如无特别说明，“非氘代的化合物”是指氘原子比例不高于天然氘同位素含量 (0.015％)的化合物。
如本文所述，术语“药学上可接受的盐”是指，在可靠的医学判断范围内，适合与人和低等动物的组织接触而没有过度毒性、刺激性、变态反应等等，并且与合理的益处/危险比例相称的那些盐。药学上可接受的盐在本领域是众所周知的。
如本文所述，术语“晶型”是指，化学药物分子的不同排列方式，一般表现为药物原料在固体状态下的存在形式。
有益效果
与现有技术相比，本发明的氘代二氢二苯并硫杂卓化合物相比于原化合物来说，具有一系列优点：
(1)本发明化合物对cap依赖的核算PA内切酶聚有优异的抑制性；
(2)通过氘代这一技术改变生物体中的代谢，使药物的代谢变得困难，这可以延长药物的半衰期，形成长效制剂；
(3)氘代后，由于同位素效应，能够提高化合物在动物体内的药物浓度，以提高药物疗效。
本发明的实施方式
本发明人经过研究，意外地发现，本发明的氘代的二氢二苯并硫杂卓及前药及其药学上可接受的盐与未经氘代的化合物相比，具有明显更优异的药物动力学和药效学性能，因此更适合抗流感病毒，进而更适用制备治疗流行性感冒以及相关疾病的药物。
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用本发明化合物时或药物组合物时，剂型没有特别限制。用于口服给药的固体剂型包括但不限于片剂、丸剂、干混悬剂、颗粒剂、散剂和胶囊剂，用于口服给药的液体剂型包括但不限于药学上可接受的乳液、溶液、混悬液、糖浆或酊剂。
以下通过实施例形式的具体实施方式，对本发明的上述内容再做进一步的详细说课。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1：氘代二氢二苯并硫杂卓的制备
根据式(Ⅰ)，当R为形成前药的全氘代的式a时，可得到式(Ⅱ)化合物，其可以通过反应路线1进行制备：
Figure PCTCN2021118711-appb-000004
反应路线1
Figure PCTCN2021118711-appb-000005
式中，片段A化合物可以通过以下反应路线2进行制备：
反应路线2
Figure PCTCN2021118711-appb-000006
式中，片段B化合物可以通过以下反应路线3进行制备：
反应路线3
Figure PCTCN2021118711-appb-000007
根据式(Ⅰ)，当R为形成前药的全氘代的式b时，可得到式(Ⅲ)化合物，其可以通过反应路线4进行制备：
Figure PCTCN2021118711-appb-000008
反应路线4：
Figure PCTCN2021118711-appb-000009
式中，片段A化合物可以通过上述反应路线2进行制备，片段B化合物可以通过上述反应路线3进行制备。
根据式(Ⅰ)，当R为形成前药的全氘代的式c时，可得到式(Ⅳ)化合物，其可以通过反应路线5进行制备：
Figure PCTCN2021118711-appb-000010
反应路线5：
Figure PCTCN2021118711-appb-000011
式中，片段A化合物可以通过上述反应路线2进行制备，片段B化合物可以通过上述反应路线3进行制备。
根据式(Ⅰ)，当R为形成前药的全氘代的式d时，可得到式(Ⅴ)化合物，其可以 通过反应路线6进行制备：
Figure PCTCN2021118711-appb-000012
反应路线6：
Figure PCTCN2021118711-appb-000013
式中，片段A化合物可以通过上述反应路线2进行制备，片段B化合物可以通过上述反应路线3进行制备。
根据式(Ⅰ)，当R为形成前药的全氘代的式e时，可得到式(Ⅵ)化合物，其可以通过反应路线7进行制备：
Figure PCTCN2021118711-appb-000014
反应路线7：
Figure PCTCN2021118711-appb-000015
式中，片段A化合物可以通过上述反应路线2进行制备，片段B化合物可以通过上述反应路线3进行制备。
以上反应路线中缩写定义：
DMSO：二甲基亚砜(Dimethyl sulfoxide)
TsOH：对甲苯磺酸
THF：四氢呋喃(Tetrahydrofuran)
DBU：是一个有位阻的脒类，具碱性
EA：乙酸乙酯(ethyl acetate)
DMA：二甲基乙酰胺(Dimethylacetamide，DMAC或DMA)，全称为N,N-二甲基乙酰胺。
实施例2：干混悬剂
将本发明化合物和甘露醇、麦芽糖、氯化钠、羟丙甲基纤维素采用湿法制粒机预混，用纯化水配制聚维酮粘合剂，加入预混物中进行制粒；用流化床进行干燥，得到合适粒径的干颗粒；加入胶态二氧化硅、滑石粉、三氯蔗糖、香精和干颗粒采用二维混合机进行总混得干混悬剂。
实施例3：片剂
混合本发明化合物、水合乳糖、交联羧甲基纤维素钠、聚乙烯吡咯烷酮、结晶纤维素、硬脂富马酸钠、羟丙基葡萄糖和氧化钛。将混合物制粒并干燥以得到合适大小的颗粒。然后将滑石粉添加到颗粒中混合，并将混合物压制成片剂。
实施例4：颗粒剂
将本发明化合物(10mg)和乳糖通过60目筛。玉米淀粉通过120目筛。将它们用V型搅拌器混合。向该混合物中加入HPC-L水溶液(低粘度羟丙基纤维素)，然后将混合物捏合，制粒(挤出造粒孔径0.5-1mm)，并干燥。将获得的干燥的颗粒通过振动筛(12/60目)以获得颗粒。
实施例5：胶囊剂
将本发明化合物(15mg)和乳糖通过60目筛。玉米淀粉通过120目筛。将它们用V型搅拌器混合。向其中加入水性HPC-L(低粘度羟丙基纤维素)，然后将混合物捏合，制粒(挤出造粒孔径0.5-1mm)，并干燥。将获得的干燥颗粒整粒，并将按照150mg装量装入4号硬明胶胶囊中。
实施例6：小鼠中的药代动力学评价
以式(Ⅱ)所示氘代二氢二苯并硫杂卓和未氘代的二氢二苯并硫杂卓为例。
Figure PCTCN2021118711-appb-000016
8只成熟小鼠，7-8周龄，体重约30g，分成2组，每组4只，单次口服给予1mg/kg剂量的(a)对照组：二氢二苯并硫杂卓化合物或(b)试验组：氘代的二氢二苯并硫杂卓化合物，比较其药代动力学差异。
每只动物每次用异氟烷麻醉后通过眼眶取血约0.10ml血液，EDTAK 2抗凝，采集时间点为：15min、30min、1h、2h、4h、6h、8h和24h。在最后一个时间点血样采集完成之后， 大鼠乙醚麻醉后处死。
血样采集后1小时之内离心分离血浆(离心条件：5000转/分钟，5min，4℃)，用移液器吸出100微升上清液至洁净的塑料离心管中，标明化合物的名称和时间点，于-80℃中保存备用。所有时间点采集完成后，采用LC-MS分析检测样品，所得浓度-时间数据，用DAS3.0药代动力学软件进行分析计算，得到小鼠给予化合物后主要吸收动力学参数T 1/2(h)、AUC (0-t)(ng eq·h/mL)、AUC (0-∞)(ng eq·h/mL)等。
结果如下：
化合物 二氢二苯并硫杂卓 氘代二氢二苯并硫杂卓
T 1/2(h) 6.31±3.22 9.04±4.12
AUC (0-t)(ng eq·h/mL) 132±13 189±21
AUC (0-∞)(ng eq·h/mL) 141±34 196±41
注：平均值±标准偏差
结果显示，氘代二氢二苯并硫杂卓化合物比二氢二苯并硫杂卓化合物的半衰期T 1/2延长了2.7小时，药时曲线下AUC (0-∞)(ng eq·h/mL)增加了43％。显示出本发明的氘代二氢二苯并硫杂卓化合物具有良好的药代动力学性质。

Claims (10)

  1. 一种式(Ⅰ)所示的氘代二氢二苯并硫杂卓化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化物：
    Figure PCTCN2021118711-appb-100001
    式中：
    R为氘或形成前药的以下氘(D)代基团
    Figure PCTCN2021118711-appb-100002
    Figure PCTCN2021118711-appb-100003
    R 1，R 2、R 3、R 4、R 5、R 6、R 7、R 8、R 9各自独立的为氢或氘；
    R 10、R 11、R 12、R 13、R 14、R 15、R1 6、R 17、R 18、R 19，R 20各自独立的为氢或氘；
    R 21、R 22、R 23、R 24、R 25、R 26、R 27、R 28、R 29、R 30、R 31各自独立的为氢或氘；
    R 32、R 33、R 34、R 35、R 36、R 37，R 38、R 39、R 40各自独立的为氢或氘；
    R 41、R 42、R 43、R 44、R 45各自独立的为氢或氘；
    附加条件是：上述化合物至少含有一个氘原子。
  2. 根据权利要求1所述化合物，其中，R为氘或形成前药的以下全氘(D)代基团
    Figure PCTCN2021118711-appb-100004
  3. 根据权利要求1所述化合物，其中，R为氘或形成前药的以下全氘(D)代基团
    Figure PCTCN2021118711-appb-100005
  4. 根据权利要求1所述化合物，其中，R为氘或形成前药的以下全氘(D)代基团
    Figure PCTCN2021118711-appb-100006
  5. 根据权利要求1所述化合物，其中，R为氘或形成前药的以下全氘(D)代基团
    Figure PCTCN2021118711-appb-100007
  6. 根据权利要求1所述化合物，其中，R为氘或形成前药的以下全氘(D)代基团
    Figure PCTCN2021118711-appb-100008
  7. 一种药物组合物，其含有药学上可接受的载体及权利要求1-6中任一项所述的化合物，或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化物。
  8. 根据权利要求1-6中任一项所述的化合物或其互变异构体、立体异构体、前药、晶型、药学上可接受的盐、水合物或溶剂化物，或权利要求7所述的药物组合物在用于制备治疗或预防与由具有cap依赖性核酸内切酶的病毒引起的疾病的药物中的用途。
  9. 根据权利要求8所述的用途，其中，由具有cap依赖性核酸内切酶的病毒引起的疾病选自甲型流感、乙型流感或丙型流感。
  10. 根据权利要求1所述式(Ⅰ)所示的氘代二氢二苯并硫杂卓化合物的制备方法，当所述式(Ⅰ)所示R为形成前药的全氘代的所述式a)时，可通过片段A化合物与片段B化合物进行制备，可得到式(Ⅱ)化合物，
    Figure PCTCN2021118711-appb-100009
    1)所述片段A化合物通过如下路线制备，
    Figure PCTCN2021118711-appb-100010
    2)所述片段B化合物通过如下路线制备，
    Figure PCTCN2021118711-appb-100011
    其特征在于：该方法的反应路线如下，
    Figure PCTCN2021118711-appb-100012
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