WO2021169861A1 - 核苷类化合物在治疗冠状病毒感染性疾病中的用途 - Google Patents

核苷类化合物在治疗冠状病毒感染性疾病中的用途 Download PDF

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WO2021169861A1
WO2021169861A1 PCT/CN2021/077010 CN2021077010W WO2021169861A1 WO 2021169861 A1 WO2021169861 A1 WO 2021169861A1 CN 2021077010 W CN2021077010 W CN 2021077010W WO 2021169861 A1 WO2021169861 A1 WO 2021169861A1
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acid
alkyl
formula
coronavirus
infectious diseases
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PCT/CN2021/077010
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English (en)
French (fr)
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常俊标
杜锦发
蒋建东
李玉环
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河南真实生物科技有限公司
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Priority to BR112022017209A priority Critical patent/BR112022017209A2/pt
Priority to EP21760199.6A priority patent/EP4112050A4/en
Priority to US17/905,142 priority patent/US20230277576A1/en
Priority to MA57574A priority patent/MA57574A1/fr
Priority to JP2022551819A priority patent/JP2023516628A/ja
Priority to KR1020227030688A priority patent/KR20220146496A/ko
Application filed by 河南真实生物科技有限公司 filed Critical 河南真实生物科技有限公司
Priority to IL295840A priority patent/IL295840A/en
Priority to MX2022010248A priority patent/MX2022010248A/es
Priority to CA3167927A priority patent/CA3167927A1/en
Priority to AU2021228008A priority patent/AU2021228008A1/en
Publication of WO2021169861A1 publication Critical patent/WO2021169861A1/zh
Priority to ZA2022/10636A priority patent/ZA202210636B/en

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • 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
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A61K31/7072—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid

Definitions

  • the invention relates to a new antiviral use of nucleoside compounds.
  • Coronavirus is a kind of positive single-stranded RNA virus with envelope. It is widely spread among humans, other mammals and birds, and can cause diseases such as respiratory tract, intestinal tract, liver and nervous system. There are currently seven CoV known to cause human diseases, of which four CoV-229E, -OC43, -NL63 and -HKU1 are prevalent in the population and usually cause common cold symptoms. The other three SARS-CoV, MERS-CoV, and the new coronavirus (2019-nCoV, or COVID-19) all have serious hazards such as rapid onset, strong infectivity, and high fatality rate. Therefore, the rapid development of direct antiviral drugs to treat the new coronavirus infection is very urgent.
  • Compound 1 as an anti-AIDS drug has completed phase II clinical trials and has good safety.
  • the inventors determined the in vitro antiviral activity of compound 1 in MRC-5 cells infected with the new coronavirus. The results show that compound 1 has only weak inhibitory activity against the new coronavirus (EC 50 is 25 ⁇ M).
  • this article provides the use of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention or treatment of coronavirus infectious diseases.
  • this article provides a A method for preventing or treating coronavirus infectious diseases, comprising administering a therapeutically or preventively effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof,
  • R 1 is an OR 1 group that can be metabolized in the body to release a hydroxyl group, or any group that forms an O-phosphate group;
  • OR 1 is preferably an ester group, and R 1 is preferably H, R 5 -CO-, or
  • Ar is phenyl and substituted phenyl, naphthyl and substituted naphthyl, and the substituent is selected from C 1-6 alkyl, F, Cl, Br, I, CN, N 3 , OH, NH 2 , OR 5 , NHR 5 ;
  • R 2 is selected from: H, azido, C 1 -C 6 alkyl (e.g. methyl, ethyl), C 1 -C 6 alkoxy (e.g. methoxy, ethoxy), C 2 -C 6 alkynyl group (e.g. ethynyl), C 2 -C 6 alkenyl (e.g. vinyl), halo-C 1 -C 6 alkyl (e.g. 2-chloroethyl, 2-fluoroethyl, trifluoroethyl) ;
  • C 1 -C 6 alkyl e.g. methyl, ethyl
  • C 1 -C 6 alkoxy e.g. methoxy, ethoxy
  • C 2 -C 6 alkynyl group e.g. ethynyl
  • C 2 -C 6 alkenyl e.g. vinyl
  • halo-C 1 -C 6 alkyl
  • R 4 is selected from H, OH, halogen (such as F), C 1 -C 6 alkyl (such as methyl, ethyl), C 1 -C 6 alkoxy (such as methoxy, ethoxy);
  • B is selected from:
  • X 3 is selected from H, F, -OH and -NH 2 ;
  • Y is selected from CH and N;
  • Z is H, -OH or F
  • R 5 is selected from H, C 1 -C 6 alkyl (e.g. methyl, ethyl, propyl, isopropyl), C 2 -C 6 alkynyl (e.g. ethynyl), C 2 -C 6 alkenyl ( Such as vinyl), halogenated C 1 -C 6 alkyl (e.g. 2-chloroethyl, 2-fluoroethyl, trifluoroethyl), optionally C 1-6 alkyl, C 1-6 alkoxy Group, CN, N 3 , OH, NH 2 , halogen (e.g.
  • F, Cl, Br, I substituted phenyl, optionally C 1-6 alkyl, C 1-6 alkoxy, CN, N 3 , OH, NH 2 , halogen (for example, F, Cl, Br, I) substituted naphthyl.
  • the pharmaceutically acceptable salts of the compound of formula (I) include, but are not limited to, for example, the salt formed by the compound of formula (I) with the following acids: hydrochloric acid, hydrobromic acid, sulfamic acid, sulfuric acid, phosphoric acid, nitric acid, formic acid, acetic acid , Propionic acid, oxalic acid, glycolic acid, malonic acid, benzoic acid, lactic acid, gluconic acid, citric acid, tartaric acid, succinic acid, fumaric acid, maleic acid, mandelic acid, malic acid, methanesulfonic acid, ethanesulfonic acid Acid, isethionic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, camphorsulfonic acid, ascorbic acid palmitic acid, salicylic acid, sulfos
  • the compound of formula (I) can be purchased through commercial channels or prepared by known methods.
  • Coronavirus infectious diseases in this article refer to diseases caused by infection of coronaviruses of the family Coronavirus, including diseases caused by infection of humans or other animals.
  • diseases caused by human coronaviruses infecting humans including but not limited to CoV-229E, -OC43, -NL63, -HKU1, SARS-CoV, MERS-CoV, and new coronavirus (2019-nCoV, or COVID-19) ) Diseases caused by infection.
  • the effective amount of the compound of formula (I) for the treatment and prevention of coronavirus infectious diseases can be determined by those skilled in the art based on the information provided herein.
  • the dosage for adults can be 1-500 mg/day, optionally 1-50 mg/day, optionally 1-20 mg/day; optionally, 1-10 mg/day, and optionally 5 mg/day. It can be administered in a single dose or in multiple doses.
  • the mode of administration can be oral or parenteral administration. It can be an immediate-release dosage form, a sustained-release dosage form, or a controlled-release dosage form.
  • the specific dosage form can be various conventional dosage forms in this field.
  • oral preparations include tablets, hard or soft capsules, aqueous or oily suspensions, granules, emulsions, syrups, or elixirs.
  • injections include injections, powder injections, and the like.
  • Virus strain 2019-nCoV (COVID-19);
  • Test drug Azivudine phosphate amine prodrug (CL-236)
  • Reagents DMEM medium (Gibco), fetal bovine serum (Gibco), double antibodies, pancreatin, MTT (Amresco), etc.;
  • Kit QIAamp viral RNA mini kit (52906, Qiagen), One Step TB Green PrimeScript PLUS RT-PCR Kit (Perfect Real Time) (RR096A TaKaRa)
  • MTT The MTT method was used to detect the toxicity of azivudine phosphate amine prodrug CL-236 to Huh 7 cells.
  • MTT is called 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide, which is a yellow dye.
  • MTT colorimetry is a method to detect cell survival and growth.
  • the detection principle is that the succinate dehydrogenase in the mitochondria of living cells can reduce the exogenous MTT to water-insoluble blue-purple crystal formazan (Formazan) and deposit it in the cells, while dead cells have no such function.
  • 10% SDS (dissolved in 0.01mol/L HCl solution) can dissolve formazan in cells, and measure its light absorption value at 570nm with a multifunctional microplate reader, which can indirectly reflect the number of living cells. Within a certain range of cell numbers, the amount of MTT crystal formation is proportional to the number of cells.
  • the survival rate of the cells under the drug concentration can be calculated, and thus the half poisoning concentration (CC 50 ) of the drug can be calculated.
  • the antiviral activity was determined on the Huh 7 cell model, and each experiment was set up with 3 multiple holes, which were repeated 3 times in total.
  • qRT-PCR real-time RT-PCR
  • the primer is RBD-qF1: 5’-CAATGGTTTAACAGGCACAGG-3’;
  • RBD-qR1 5'-CTCAAGTGTCTGTGGATCACG-3'.
  • the total volume of the reaction system is 20 ⁇ L: 10 ⁇ L 2X One Step TB Green RT-PCR Buffer 4, 1.2 ⁇ L TaKaRa Ex Taq HS Mix, 0.4 ⁇ L PrimeScript PLUS RTase Mix, RBD-qF1 and RBD-qR1 0.8 ⁇ L, 0.4 ⁇ L ROX Reference Dye (50X), 2 ⁇ L viral RNA, 4.4 ⁇ L RNase Free dH2O.
  • the reaction parameters were: reverse transcription at 42°C for 5 minutes, pre-denaturation at 95°C for 10 seconds, PCR 40 cycles including denaturation at 95°C for 10 seconds, annealing and extension at 60°C for 30 seconds.
  • Inhibition rate (%) 1-the number of viral RNA copies of the experimental group/the number of viral RNA copies of the drug-free group ⁇ 100%.
  • TI therapeutic index
  • Azivudine Compound 1
  • Klitsch control group Twenty patients who were diagnosed with new coronavirus infection through nucleic acid reagent testing were selected and divided into Azivudine (Compound 1) group and Klitsch control group, with 10 cases in each group.
  • Treatment plan for Azivudine group take 5 mg per day (oral, 5 tablets, 1 mg per tablet); treatment plan for Kelizhi control group: Kelizhi (oral, 2 tablets/day, 250 mg/tablet) + Abi Dole tablets (200mg/time orally, 3 times/day) + interferon (5 million U, inhalation twice a day). Measure nucleic acid changes, body temperature changes, and observe various symptoms.
  • Azivudine cannot be effectively activated by phosphorylation, so the phosphate amine prodrug (CL-236) of Azivudine was used to indirectly measure its anti-coronavirus activity. Because it is known in the trial of using Azvudine to treat AIDS that Azvudine can be effectively activated in the human body, in human clinical trials, Azivudine is used directly instead of Azvudine phosphate. Amine prodrugs for the treatment of new coronavirus pneumonia.

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Abstract

式(I)所示的化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，所述式(I)化合物用于治疗新冠状病毒肺炎病人，在病毒核酸试验转阴率、转阴疗程、治愈出院时间都显示明显优势。

Description

核苷类化合物在治疗冠状病毒感染性疾病中的用途 技术领域
本发明涉及核苷类化合物新的抗病毒用途。
背景技术
冠状病毒(Coronavirus,CoV)是一类有包膜的正向单链RNA病毒，在人类、其他哺乳动物和鸟类中广泛传播，并可导致呼吸道、肠道、肝脏和神经系统等疾病。目前已知有七种CoV可导致人类疾病，其中四种CoV-229E、-OC43、-NL63和-HKU1在人群中流行，并通常引起普通感冒症状。而其他三种SARS-CoV、MERS-CoV和新冠状病毒(2019-nCoV，或称COVID-19)都具有发病快、传染性强和致死率高的严重危害性。因此，快速研发直接抗病毒药物，治疗新冠状病毒感染，十分迫切。
发明内容
化合物1作为抗艾滋病药物已经完成II期临床试验，安全性良好。
Figure PCTCN2021077010-appb-000001
发明人在新冠状病毒感染的MRC-5细胞内，测定了化合物1的体外抗病毒活性。结果表明，化合物1只有微弱的抑制新冠状病毒的活性(EC 50为25μM)。
然而，发明人直接用式(1)化合物进行研究性临床试验，惊奇地发现，较对照性常规治疗，用式(1)化合物治疗新冠状病毒肺炎病人，在病毒核酸试验转阴率、转阴疗程、治愈出院时间都显示明显优势。发明人认为，化合物1没有显示明显抑制病毒作用，可能与其在体外中不能有效地磷酸酯化有关。
鉴于此，本文中一方面，提供式(I)所示的化合物、或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，另一方面，本文中提供一种预防或治疗冠状病毒感染性疾病的方法，包括向有此需要的患者给予治疗或预防有效量的式(I)化合物或其药学上可接受的盐，
其中式(I)结构式如下：
Figure PCTCN2021077010-appb-000002
式(I)中，
R 1为OR 1基团可以在体内代谢释放出羟基，或者形成O-磷酸基的任何基团；OR 1优选为酯基，R 1优选为H、R 5-CO-、或
Figure PCTCN2021077010-appb-000003
其中Ar是苯基和取代苯基，萘基和取代萘基，所述取代基选自C 1-6烷基、F、Cl、Br、I、CN、N 3、OH、NH 2、OR 5、NHR 5；
R 2选自:H、叠氮基、C 1-C 6烷基(例如甲基、乙基)、C 1-C 6烷氧基(例如甲氧基、乙氧基)、C 2-C 6炔基(例如乙炔基)、C 2-C 6烯基(例如乙烯基)、卤代C 1-C 6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)；
R 3选自H、任选被取代的R-CO-、任选被取代的R-O(C＝O)-、和任选被取代的RNH-CO-，其中R选自C 1-C 6烷基(例如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基等)；其中，取代基选自C 1-C 6烷基、卤素(如F、Cl)、CN、N 3、和OR 5。
R 4选自H、OH、卤素(例如F)、C 1-C 6烷基(例如甲基，乙基)、C 1-C 6烷氧基(例如甲氧基，乙氧基)；
B选自：
Figure PCTCN2021077010-appb-000004
其中，X 1选自-OH、-NH 2、R 5CONH-、R 5COO-、R 5O(C＝O)NH-；
X 2选自-OH、-SH、-NH 2、R 5COO-、R 5COS-、R 5CONH 2-、R 5O(C＝O)NH-；
X 3选自H、F、-OH和-NH 2；
Y选自CH和N；
Z为H、-OH或F；
R 5选自H、C 1-C 6烷基(例如甲基、乙基、丙基、异丙基)、C 2-C 6炔基(例如乙炔基)、C 2-C 6烯基(例如乙烯基)、卤代C 1-C 6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)、任选被C 1-6烷基、C 1-6烷氧基、CN、N 3、OH、NH 2、卤素(例如F、Cl、Br、I)取代的苯基、任选被C 1-6烷基、C 1-6烷氧基、CN、N 3、OH、NH 2、卤素(例如F、Cl、Br、I)取代的萘基。
优先如下化合物或其药学上可接受的盐：
Figure PCTCN2021077010-appb-000005
Figure PCTCN2021077010-appb-000006
式(I)化合物的药学上可接受的盐包括，但不限于，例如式(I)化合物与以下酸形成的盐：盐酸、氢溴酸、氨基磺酸、硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、草酸、乙醇酸、丙二酸、苯甲酸、乳酸、葡糖酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、杏仁酸、苹果酸、甲磺酸、乙磺酸、羟乙基磺酸、苯磺酸、对甲苯磺酸、萘磺酸、萘二磺酸、樟脑磺酸、抗坏血酸棕榈酸、水杨酸、磺基水杨酸、2-羟基-3-萘甲酸、邻苯二甲酸、赖氨酸、精氨酸、谷氨酸、甘氨酸、丝氨酸、苏氨酸、丙氨酸、异亮氨酸、亮氨酸等。
式(I)化合物可通过商业渠道购买或者已知的方法制得。
本文中冠状病毒感染性疾病，是由冠状病毒科病毒感染所引发的疾病，包括感染人或其他动物所引起的疾病。特别是人冠状病毒感染人类所引发的疾病，包括但不限于CoV-229E、-OC43、-NL63、-HKU1、SARS-CoV、MERS-CoV和新冠状病毒(2019-nCoV，或称COVID-19)感染引起的疾病。
式(I)化合物的治疗和预防冠状病毒感染性疾病的有效量可由本领域技术人员根据本文提供的信息确定。例如，成年人用量可以为1-500mg/天，可选为1-50mg/天，可选为1-20mg/天；可选为1-10mg/天，可选为5mg/天。可以单次或分多次给药。
给药方式可以为口服或者胃肠外给药。可以是速释剂型，也可以是缓释剂型、控释剂型。具体剂型可是本领域的各种常规剂型。例如，口服制剂可以列举片剂、硬或软胶囊剂、水性或油性混悬剂、颗粒剂、乳剂、糖浆剂或酏剂等。注射剂可以列举注射液、粉针剂等。
具体实施方式
以下对本发明的具体实施方式进行详细说明。应当理解的是，此处所描述的具体实施方式仅用于示例性地对本发明进行说明，并不用于限制本发明。
试验例1.阿兹夫定磷酸酯胺前药CL-236抗新冠病毒活性测试
(一)实验材料与试剂
1.细胞系：Huh 7细胞，本实验室保存；
2.病毒株：2019-nCoV(COVID-19)；
3.测试药物：阿兹夫定磷酸酯胺前药(CL-236)
4.阳性对照药物：瑞德西韦；
5.试剂：DMEM培养基(Gibco)，胎牛血清(Gibco)，双抗，胰酶，MTT(Amresco)等；
6.试剂盒：QIAamp viral RNA mini kit(52906，Qiagen)，One Step TB Green PrimeScript PLUS RT-PCR Kit(Perfect Real Time)(RR096A TaKaRa)
7.耗材：细胞培养板，96孔酶标板等；
8.仪器：多功能酶标仪，StepOnePlus荧光定量PCR仪，二氧化碳培养箱等。
(二)实验步骤
1.阿兹夫定磷酸酯胺前药CL-236对细胞毒性测定
利用MTT法检测阿兹夫定磷酸酯胺前药CL-236对Huh 7细胞的毒性。MTT全称为3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-di-phenytetrazoliumromide，是一种黄颜色的染料。MTT比色法，是一种检测细胞存活和生长的方法。其检测原理为活细胞线粒体中的琥珀酸脱氢酶能使外源性MTT还原为水不溶性的蓝紫色结晶甲瓒(Formazan)并沉积在细胞中，而死细胞无此功能。10％SDS(溶于0.01mol/L HCl溶液中)能溶解细胞中的甲瓒，用多功能酶标仪在570nm波长处测定其光吸收值，可间接反映活细胞数量。在一定细胞数范围内，MTT结晶形成的量与细胞数成正比。通过检测不同干扰素浓度下570nm波长处光吸收值，即可计算该药物浓度下细胞的存活率，从而计算该药物的半数中毒浓度(CC 50)。
提前一天接种Huh 7细胞于96孔板中，每孔1×10 4个(注意96孔板最边缘的孔勿用作实验孔，加PBS防止其他孔培养基挥发)；观察细胞状态，达到约50％时，将阿兹夫定磷酸酯胺前药CL-236用含2％FBS的DMEM培养基进行2倍比稀释后，以100μL/孔加至细胞板中，每种浓度设6个重复；同时设置对照组(不含药物组)和空白组(不含细胞组)，置于37℃，5％CO 2的培养箱中培养；于加药后48h，每孔加入25μL MTT溶液(5mg/mL)，继续培养4h后，每孔加入125μL 10％SDS(溶于0.01mol/L HCl溶液中)，轻轻吹打，放置2h，使结晶物充分溶解，以空白组调零，测定OD570，按以下公式计算：存活率(％)＝加药组OD570/对照组OD570×100％。同时计算药物的半数中毒浓度(CC50)。
2.阿兹夫定磷酸酯胺前药CL-236对2019-nCoV(COVID-19)病毒的抑制效果评价
在Huh 7细胞模型上进行抗病毒活性测定，每次试验均设3复孔，共重复3次。
1)于24孔细胞培养板每孔中接种5×10 4个Huh 7细胞，在37℃，5％CO 2培养条件下，待汇合度达到60％时，按照感染复数MOI为0.005，分别向每孔中加入200μL用含2％FBS的DMEM培养基稀释后的2019-nCoV(COVID-19)病毒液，37℃、5％CO 2培养箱中吸附1h后，弃病毒液，将阳性对照药物和阿兹夫定磷酸酯胺前药CL-236用含2％FBS的DMEM培养基从最大无毒浓度开始进行2倍比稀释，以500μL/孔加至细胞板中，同时设置对照组(不含药物组)，于感染后48h收集上清病毒液。
2)利用real-time RT-PCR(qRT-PCR)对收集的病毒进行RNA定量：
收集的上清病毒液分别取140μL，按照QIAamp viral RNA mini kit试剂盒说 明书进行RNA提取。用One Step TB Green PrimeScript PLUS RT-PCR Kit(Perfect Real Time)试剂盒进行qRT-PCR检测，
引物为RBD-qF1:5’-CAATGGTTTAACAGGCACAGG-3’；
RBD-qR1:5’-CTCAAGTGTCTGTGGATCACG-3’。
反应体系总体积为20μL：10μL 2X One Step TB Green RT-PCR Buffer 4，1.2μL TaKaRa Ex Taq HS Mix，0.4μL PrimeScript PLUS RTase Mix，RBD-qF1和RBD-qR1各0.8μL，0.4μL ROX Reference Dye(50X)，2μL病毒RNA，4.4μL RNase Free dH2O。反应参数为：反转录42℃5min，预变性95℃10s，PCR 40个循环包括变性95℃10s，退火和延伸60℃30s。
3)计算每种浓度下的药物抑制率。抑制率(％)＝1-实验组病毒RNA拷贝数/不含药物组病毒RNA拷贝数×100％。同时计算药物的半数有效浓度(EC 50)和治疗指数(TI)＝半数中毒浓度(CC 50)/半数有效浓度(EC 50)。
(三)实验结果计算
表1.阿兹夫定磷酸酯胺前药CL-236抑制新冠病毒(COVID-19)活性
Figure PCTCN2021077010-appb-000007
试验例2
临床试验验证化合物1用于治疗新冠状病毒(COVID-19)肺炎的有效性和安全性。
选择20例通过核酸试剂测定确诊新冠状病毒感染的患者，分为阿兹夫定(化合物1)组和克力芝对照组，每组10例。阿兹夫定组治疗方案：每天服用5毫克(口服，5片，每片1毫克)；克力芝对照组治疗方案：克力芝(口服，2片/日，250mg/片)+阿比多尔片(口服200mg/次，3次/日)+干扰素(500万U，每日两次雾化吸入)。测定核酸变化，体温变化，观察各种症状。
结果如下表所示。
Figure PCTCN2021077010-appb-000008
临床试验结果表明，10例新冠状病毒感染患者中，阿兹夫定组全部患者核酸检测转阴，其中7例第8天内出院。
上述临床试验结果表明，化合物1治疗新冠病毒肺炎在病人核酸转阴率、转阴疗程、治愈率和治愈疗程几个指标都显示显著临床治疗优势。
其中一例使用克力芝支持治疗20多天仍不能转阴的病人，采用化合物1治疗后3天转阴。治疗中，没有发现任何药物有关的毒副作用。
在体外测试系统，阿兹夫定不能有效地被磷酸酯化活化，所以用阿兹夫定的 磷酸酯胺前药(CL-236)间接测定其抗新冠病毒的活性。因为，在用阿兹夫定治疗艾滋病的试验中知道，阿兹夫定在人体内可以有效地被活化，所以在人体临床试验中，直接使用阿兹夫定，而不是阿兹夫定磷酸酯胺前药，治疗新冠病毒性肺炎。

Claims (10)

  1. 式(I)所示的化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，
    Figure PCTCN2021077010-appb-100001
    式(I)中，
    R 1为H、R 5-CO-、或
    Figure PCTCN2021077010-appb-100002
    其中Ar为苯基、取代苯基、萘基或取代萘基，其中取代基选自C 1-6烷基、F、Cl、Br、I、CN、N 3、OH、NH 2、OR 5、NHR 5；
    R 2为:H、叠氮基、C 1-C 6烷基(例如甲基、乙基)、C 1-C 6烷氧基(如甲氧基、乙氧基)、C 2-C 6炔基(例如乙炔基)、C 2-C 6烯基(例如乙烯基)、或者卤代C 1-C 6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)；
    R 3为H、任选被取代的R-CO-、任选被取代的R-O(C＝O)-、或任选被取代的RNH-CO-，其中R为C 1-C 6烷基(例如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基等)，其中，取代基选自C 1-C 6烷基、卤素(如F、Cl)、CN、N 3、和OR 5；
    R 4为H、OH、卤素(例如F)、C 1-C 6烷基(例如甲基，乙基)、或C 1-C 6烷氧基(例如甲氧基，乙氧基)；
    B选自：
    Figure PCTCN2021077010-appb-100003
    其中，X 1为-OH、-NH 2、R 5CONH-、R 5COO-或R 5O(C＝O)NH-；
    X 2为OH、SH、NH 2、R 5COO-、R 5COS-、R 5CONH 2-、或R 5O(C＝O)NH-；
    X 3为H、F、OH或NH 2；
    Y为CH或N；
    Z为H、OH或F；
    R 5选自H、C 1-C 6烷基(例如甲基、乙基、丙基、异丙基)、C 2-C 6炔基(例如乙炔基)、C 2-C 6烯基(例如乙烯基)、卤代C 1-C 6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)、任选被C 1-6烷基、C 1-6烷氧基、CN、N 3、OH、NH 2、卤素(例如F、Cl、Br、I)取代的苯基、任选被C 1-6烷基、C 1-6烷氧基、CN、N 3、OH、NH 2、卤素(例如F、Cl、Br、I)取代的萘基。
  2. 根据权利要求1所述的式(I)所示化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，其中式(I)所示化合物为下列化合物：
    Figure PCTCN2021077010-appb-100004
    Figure PCTCN2021077010-appb-100005
    或者
    Figure PCTCN2021077010-appb-100006
  3. 根据权利要求1或2所述的式(I)所示化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，其中式(I)化合物的药学上可接受的盐包括式(I)化合物与以下酸形成的盐：盐酸、氢溴酸、氨基磺酸、硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、草酸、乙醇酸、丙二酸、苯甲酸、乳酸、葡糖酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、杏仁酸、苹果酸、甲磺酸、乙磺酸、羟乙基磺酸、苯磺酸、对甲苯磺酸、萘磺酸、萘二磺酸、樟脑磺酸、抗坏血酸棕榈酸、水杨酸、磺基水杨酸、2-羟基-3-萘甲酸、邻苯二甲酸、赖氨酸、精氨酸、谷氨酸、甘氨酸、丝氨酸、苏氨酸、丙氨酸、异亮氨酸或亮氨酸。
  4. 根据权利要求1-3任一项所述的式(I)所示化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，其中所述冠状病毒感染性疾病是由冠状病毒科病毒感染所引发的疾病，包括感染人或其他动物所引起 的疾病，尤其是人冠状病毒感染人类所引发的疾病，例如，CoV-229E、-OC43、-NL63、-HKU1、SARS-CoV、MERS-CoV或COVID-19感染引起的疾病。
  5. 根据权利要求1-3任一项所述的式(I)所示化合物或其药学上可接受的盐在制备预防或治疗冠状病毒感染性疾病的药物中的用途，其中所述药物剂型为速释剂型、缓释剂型、或控释剂型，例如片剂、硬、软胶囊剂、水性或油性混悬剂、颗粒剂、乳剂、糖浆剂、酏剂、注射液、或粉针剂。
  6. 一种预防或治疗冠状病毒感染性疾病的方法，包括向有此需要的患者给予治疗或预防有效量的式(I)化合物或其药学上可接受的盐，
    Figure PCTCN2021077010-appb-100007
    式(I)中，
    R 1为H、R 5-CO-、或
    Figure PCTCN2021077010-appb-100008
    其中Ar为苯基、取代苯基、萘基或取代萘基，其中取代基选自C 1-6烷基、F、Cl、Br、I、CN、N 3、OH、NH 2、OR 5、NHR 5；
    R 2为:H、叠氮基、C 1-C 6烷基(例如甲基、乙基)、C 1-C 6烷氧基(如甲氧基、乙氧基)、C 2-C 6炔基(例如乙炔基)、C 2-C 6烯基(例如乙烯基)、或者卤代C 1-C 6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)；
    R 3为H、任选被取代的R-CO-、任选被取代的R-O(C＝O)-、或任选被取代的RNH-CO-，其中R为C 1-C 6烷基(例如甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基等)，其中，取代基选自C 1-C 6烷基、卤素(如F、Cl)、CN、N 3、和OR 5；
    R 4为H、OH、卤素(例如F)、C 1-C 6烷基(例如甲基，乙基)、或C 1-C 6烷氧基(例如甲氧基，乙氧基)；
    B选自：
    Figure PCTCN2021077010-appb-100009
    其中，X 1为-OH、-NH 2、R 5CONH-、R 5COO-或R 5O(C＝O)NH-；
    X 2为OH、SH、NH 2、R 5COO-、R 5COS-、R 5CONH 2-、或R 5O(C＝O)NH-；
    X 3为H、F、OH或NH 2；
    Y为CH或N；
    Z为H、OH或F；
    R 5选自H、C 1-C 6烷基(例如甲基、乙基、丙基、异丙基)、C 2-C 6炔基(例如乙炔基)、C 2-C 6烯基(例如乙烯基)、卤代C 1-C 6烷基(例如2-氯乙基、2-氟乙基、三氟乙基)、任选被C 1-6烷基、C 1-6烷氧基、CN、N 3、OH、NH 2、卤素(例如F、Cl、Br、I)取代的苯基、任选被C 1-6烷基、C 1-6烷氧基、CN、N 3、OH、NH 2、卤素(例如F、Cl、Br、I)取代的萘基。
  7. 根据权利要求6所述的预防或治疗冠状病毒感染性疾病的方法，其中式(I)所示化合物为下列化合物：
    Figure PCTCN2021077010-appb-100010
    Figure PCTCN2021077010-appb-100011
    或者
    Figure PCTCN2021077010-appb-100012
  8. 根据权利要求6或7所述的预防或治疗冠状病毒感染性疾病的方法，其中式(I)化合物的药学上可接受的盐包括式(I)化合物与以下酸形成的盐：盐 酸、氢溴酸、氨基磺酸、硫酸、磷酸、硝酸、甲酸、乙酸、丙酸、草酸、乙醇酸、丙二酸、苯甲酸、乳酸、葡糖酸、柠檬酸、酒石酸、琥珀酸、富马酸、马来酸、杏仁酸、苹果酸、甲磺酸、乙磺酸、羟乙基磺酸、苯磺酸、对甲苯磺酸、萘磺酸、萘二磺酸、樟脑磺酸、抗坏血酸棕榈酸、水杨酸、磺基水杨酸、2-羟基-3-萘甲酸、邻苯二甲酸、赖氨酸、精氨酸、谷氨酸、甘氨酸、丝氨酸、苏氨酸、丙氨酸、异亮氨酸或亮氨酸。
  9. 根据权利要求6-8任一项所述的预防或治疗冠状病毒感染性疾病的方法，其中所述冠状病毒感染性疾病是由冠状病毒科病毒感染所引发的疾病，包括感染人或其他动物所引起的疾病，尤其是人冠状病毒感染人类所引发的疾病，例如，CoV-229E、-OC43、-NL63、-HKU1、SARS-CoV、MERS-CoV或COVID-19感染引起的疾病。
  10. 根据权利要求6-8任一项所述的预防或治疗冠状病毒感染性疾病的方法，其中所述药物剂型为速释剂型、缓释剂型、或控释剂型，例如片剂、硬、软胶囊剂、水性或油性混悬剂、颗粒剂、乳剂、糖浆剂、酏剂、注射液、或粉针剂。
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