WO2023070373A1 - 一类多环聚酮化合物在制备抗新型冠状病毒药物中的应用 - Google Patents

一类多环聚酮化合物在制备抗新型冠状病毒药物中的应用 Download PDF

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WO2023070373A1
WO2023070373A1 PCT/CN2021/126733 CN2021126733W WO2023070373A1 WO 2023070373 A1 WO2023070373 A1 WO 2023070373A1 CN 2021126733 W CN2021126733 W CN 2021126733W WO 2023070373 A1 WO2023070373 A1 WO 2023070373A1
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compound
cov
sars
alkyl
preparation
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叶文才
王英
胡利军
唐维
李药兰
张冬梅
范春林
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暨南大学
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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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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

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  • the present invention relates to a class of medicines for treating and preventing virus infection. More specifically, the present invention relates to the application of a class of polycyclic polyketide compounds in the preparation of anti-new coronavirus SARS-CoV-2 drugs.
  • SARS-CoV-2 The 2019 novel coronavirus (SARS-CoV-2) is an RNA virus with an envelope and a linear single-stranded positive strand genome, which mainly causes pneumonia and severe acute respiratory syndrome (COVID-19), which can be accompanied by renal failure and even die.
  • SARS-CoV-2 is mainly transmitted through respiratory droplets or direct contact with secretions, and there is also evidence that it can be transmitted through aerosol and fecal-oral routes. Its transmission speed is fast and wide, and it seriously threatens human health and life. Since the outbreak of the new coronavirus caused by SARS-CoV-2 in December 2019, it has spread rapidly around the world. At present, the cumulative number of confirmed infections has exceeded 15 million, and new infections and deaths are still rising.
  • the object of the present invention is to provide a class of polycyclic polyketide compounds with anti-new coronavirus SARS-CoV-2.
  • the results of activity tests show that this series of polyketides have inhibitory effect on the new coronavirus SARS-CoV-2 at the cellular level, can significantly reduce the virus's toxicity in cells, and inhibit the cytopathy induced by it in a concentration-dependent manner.
  • the polyketide compound has a different chemical structure type from remdesivir and chloroquine phosphate, and is expected to develop into a new class of anti-new coronavirus SARS-CoV-2 drugs.
  • the present invention provides a class of polyketide compounds having a structure represented by formula I or pharmaceutically acceptable salts thereof or stereoisomers or prodrug molecules thereof in the preparation of anti-new coronavirus drugs:
  • R 1 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl or aryl;
  • R 2 and R 3 are independently selected from a hydrogen atom or -C(O)R 6 ;
  • R 4 and R 5 are independently selected from a hydrogen atom, C 1 to C 6 alkyl, -C(O)R 6 or -S(O) m R 6 ;
  • R 6 is selected from a hydrogen atom, a substituted or unsubstituted C 1 -C 12 alkyl group, a substituted or unsubstituted C 3 -C 6 cycloalkyl group or a substituted or unsubstituted aryl group;
  • n 1 or 2;
  • the compound shown in the general formula I is characterized in that, the R 3 is a hydrogen atom, and the polyketide compound has the structural formula shown in the general formula II or Its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule:
  • R 1 , R 2 , R 4 and R 5 are as defined in claim 1.
  • the compound represented by the general formula III includes, but is not limited to:
  • said R 2 is a hydrogen atom
  • said polyketide compound has the structural formula shown in general formula III or its pharmaceutically acceptable salt or stereo Isomer or its prodrug molecule:
  • R 1 , R 3 , R 4 and R 5 are as defined in claim 1.
  • the compound represented by the general formula IV includes, but is not limited to:
  • the present invention relates to a pharmaceutical composition, which contains a therapeutically effective dose of polyketide compounds represented by general formulas I, II and III or pharmaceutically acceptable salts or stereoisomers or prodrug molecules thereof, and One or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention relates to the polyketide compound represented by general formula I, II and III containing therapeutically effective dosage, or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule or according to claim 6 Use of the pharmaceutical composition in the preparation of anti-new coronavirus SARS-CoV-2 drugs.
  • the present invention relates to the polyketide compound represented by general formula I, II and III containing therapeutically effective dosage, or its pharmaceutically acceptable salt or its stereoisomer or its prodrug molecule or according to claim 6
  • alkyl as used herein is meant to include both branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • the definition of “C 1 -C 6 " in “C 1 -C 6 alkyl” includes groups having 1, 2, 3, 4, 5 or 6 carbon atoms arranged in a linear or branched chain.
  • “C 1 -C 6 alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, pentyl, and hexyl.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl and the like.
  • alkoxy refers to a group with an -O-alkyl structure, such as -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 CH(CH 3 ) 2 , -OCH 2 CH 2 CH 2 CH 3 , -OCH(CH 3 ) 2 , etc.
  • aryl includes, but is not limited to: imidazolyl, triazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • Prodrug means a prodrug converted into the structure of the compound involved in the present application and the pharmaceutically acceptable salt thereof in vivo.
  • “Pharmaceutical composition” means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, and other components such as a physiologically/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • “Pharmaceutically acceptable salt” refers to the salt of the compound of the present invention, which is safe and effective when used in mammals, and has proper biological activity.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
  • the known starting materials of the present invention can be adopted or synthesized according to methods known in the art, or can be purchased from Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Bailingwei, Anaiji, Da Swiss Chemicals and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction process in the embodiment adopts thin-layer chromatography (TLC), and the developing agent used in reaction, the eluent system of the column chromatography that separation and purification compound adopts and the developing agent system of thin-layer chromatography include: A : Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: acetone, E: dichloromethane/acetone system, F: ethyl acetate/dichloromethane System, G: ethyl acetate/dichloromethane/n-hexane, H: ethyl acetate/dichloromethane/acetone, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and Alkaline or acidic reagents such as acetic acid for adjustment.
  • TLC thin-layer chromatography
  • acetic anhydride (30.6mg, 0.3mmol) and triethylamine (40.4mg, 0.4mmol) were added to a dichloromethane solution (2mL) containing compound 6 (44.2mg, 0.1mmol), and heated to reflux . After reacting overnight, the temperature was cooled to room temperature, and 1N aqueous HCl (3 mL) was added to quench the reaction, and extracted with dichloromethane three times (3 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography to obtain compound 20 (48.4 mg, yield 92%).
  • tert-butylacetyl chloride (16.1 mg, 0.12 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) were added to a solution of compound 6 (44.2 mg, 0.1 mmol) in dichloromethane (2 mL ). After reacting for 2 hours, the reaction was quenched by adding 1N aqueous HCl (3 mL), and extracted 3 times with dichloromethane (3 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography to obtain compound 22 (18.4 mg, yield 35%).
  • Benzoyl chloride (16.9 mg, 0.12 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) were added to a dichloromethane solution (2 mL) containing compound 6 (44.2 mg, 0.1 mmol) at room temperature. After reacting for 2 hours, the reaction was quenched by adding 1N aqueous HCl (3 mL), and extracted 3 times with dichloromethane (3 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography to obtain compound 23 (23.5 mg, yield 43%).
  • Phenylacetyl chloride (18.6 mg, 0.12 mmol) and 4-dimethylaminopyridine (24.4 mg, 0.2 mmol) were added to a solution of compound 6 (44.2 mg, 0.1 mmol) in dichloromethane (2 mL) at room temperature. After reacting for 2 hours, the reaction was quenched by adding 1N aqueous HCl (3 mL), and extracted 3 times with dichloromethane (3 mL ⁇ 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was separated and purified by silica gel column chromatography to obtain compound 25 (21.8 mg, yield 39%).
  • the SARS-CoV-2 virus strain was isolated by the Guangdong Provincial Center for Disease Control and Prevention (CDC) (see the GISAID database for the complete genome sequence data, sequence number: EPI_ISL_403934, strain number: BetaCoV/Guangdong/20SF014/2020); cell culture medium It is MEM medium containing 10% fetal bovine serum (FBS) and 1% penicillin-streptomycin (PS), and the cell maintenance solution is MEM medium containing 2% FBS and 1% PS. The cells were cultured at 37°C in a 5% CO 2 incubator, and passaged once every 2 to 3 days; SARS-CoV-2 was cultured in Vero-E6 cells and stored in a -80°C refrigerator for later use.
  • CDC Guangdong Provincial Center for Disease Control and Prevention
  • FBS, MEM, and PS were purchased from Life Technologies in the United States
  • Chloroquine diphosphate was purchased from Sigma-Aldrich in the United States
  • CCK-8 kit was purchased from Shanghai Biyuntian Biotechnology Co., Ltd.
  • virus fluorescence quantitative RT-PCR kit purchased from Guangzhou Daan Gene Technology Co., Ltd.
  • CPE virus-induced cytopathic disease
  • the CPE method was used to determine the inhibitory effect of the test compound on SARS-CoV-2-induced cytopathy.
  • the virus liquid was discarded, and 0.1 mL of a compound-containing cell maintenance solution was added to each well.
  • the cells were cultured in a 37°C, 5% CO 2 incubator, and the cytopathic changes (CPE) were observed in the P3 laboratory every 24 hours. 48 hours after virus infection, the CPE results in each well were recorded.
  • CPE cytopathic changes
  • CCK-8 kit was used to determine the cytotoxicity of the test compound.
  • the Vero-E6 cells were seeded in a 96-well cell culture plate, and the culture plate was placed in a 37°C, 5% CO2 incubator for culture. After 24 hours, the cell supernatant was discarded, and the compound diluted with the culture medium was added, and 6 replicate wells were set for each concentration, and a cell control group (no compound was added) was set at the same time. After continuing to culture for 48 hours, the cell viability was measured using CCK-8 kit, and the cytotoxicity of the compound was calculated.
  • IC 50 refers to the half inhibitory concentration (50% Inhibition Concentration), expressed by IC 50 ( ⁇ M):
  • CC 50 refers to the half cytotoxic concentration (50% Cytotoxic Concentration), represented by CC 50 ( ⁇ M);
  • c SI refers to the selectivity index (Selectivity Index), and its value is CC 50 /IC 50 .
  • test compound 13 was detected by fluorescent quantitative RT-PCR method.
  • Seed Vero-E6 cells in a 6-well cell culture plate and culture them in a 37°C, 5% CO2 incubator for 24 hours, discard the cell supernatant, add the cell maintenance solution containing compound 13, and add the maintenance solution at the same time Diluted virus solution (MOI 0.1), set 3 replicate wells in each group, and set up cell control group (without adding virus and compound 13), compound 13 control group (without adding virus), virus control group (without adding compound 13).
  • test compound 13 The inhibitory effect of test compound 13 on the expression level of SARS-CoV-2 nucleoprotein in cells was detected by immunofluorescence labeling method.
  • Compound 13 can significantly reduce the expression level of the nucleoprotein (green fluorescence in Figure 2) of SARS-CoV-2. After SARS-CoV-2 infected Vero-E6 cells, the expression level of viral nucleoprotein in the cells could be detected to be high, and the expression level of nucleoprotein was significantly reduced after compound 13 was added. When the compound concentration is 2 ⁇ M, the inhibition rate of SARS-CoV-2 nucleoprotein expression level is higher than 95%.

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Abstract

本发明公开了一类多环聚酮化合物在制备用于抗新型冠状病毒SARS-CoV-2药物中的应用。本发明发现的聚酮类化合物在细胞水平对新型冠状病毒SARS-CoV-2具抑制作用，能显著降低病毒在细胞中的毒价，抑制其诱导的细胞病变，且具有浓度依赖性。此外，该聚酮类化合物具有与瑞德西韦、磷酸氯喹不同的化学结构类型，有望发展成为一类新型的抗新型冠状病毒SARS-CoV-2药物。因此，此类化合物在治疗新型冠状病毒SARS-CoV-2感染所引起的相关疾病中具有良好的应用前景。

Description

一类多环聚酮化合物在制备抗新型冠状病毒药物中的应用 技术领域
本发明涉及一类用于治疗和预防病毒感染的药物。更具体而言，本发明涉及一类多环聚酮化合物在制备用于抗新型冠状病毒SARS-CoV-2药物中的应用。
背景技术
2019新型冠状病毒(SARS-CoV-2)是一种具有囊膜、基因组为线性单股正链的RNA病毒，主要导致肺炎和严重急性呼吸综合症(COVID-19)，可伴随肾衰竭，甚至死亡。SARS-CoV-2主要通过呼吸道飞沫或直接接触分泌物传播，也有证据表明可经气溶胶和粪-口途径传播，其传播速度快且范围广泛，严重威胁人类的健康和生命。自2019年12月由SARS-CoV-2引起的新型冠状病毒疫情爆发以来，在全球范围内迅速蔓延，目前累计确诊感染人数已超过1500万，且新增感染和死亡病例仍在不断上升。目前尚无针对SARS-CoV-2感染的预防性疫苗，多数疫苗仍处于临床研究阶段。此外，临床上也缺乏特效的抗SARS-CoV-2药物。临床报道的干扰素、克立芝及一些传统中药方剂对新型冠状病毒引起的肺炎具有治疗效果，但这些药物的抗病毒作用仍需进一步确证。文献报道，磷酸氯喹、瑞德西韦等具有抗新冠病毒SARS-CoV-2作用。目前，核苷类似物瑞德西韦是全球唯一一个获得批准的抗SARS-CoV-2药物，在体外和体内动物模型中均表现出了良好的抗SARS-CoV-2活性。然而，中国的临床试验研究结果显示，其对严重型COVID-19患者的治疗效果并不明显，WHO建议应继续对瑞德西韦的疗效进行全面评估。因此，研发治疗和预防新型冠状病毒SARS-CoV-2感染的抗病毒新药，对于降低COVID-19患者的重症率和死亡率、阻断疫情的蔓延和再度爆发均具有重要意义。
发明内容
本发明的目的在于提供一类具有抗新型冠状病毒SARS-CoV-2的多环聚酮类化合物。活性测试结果显示，该系列聚酮类化合物在细胞水平对新型冠状病毒SARS-CoV-2具抑制作用，能 显著降低病毒在细胞中的毒价，抑制其诱导的细胞病变，且具有浓度依赖性。此外，该聚酮类化合物具有与瑞德西韦、磷酸氯喹不同的化学结构类型，有望发展成为一类新型的抗新型冠状病毒SARS-CoV-2药物。
为了实现上述目的，本发明通过以下方案予以实现：
本发明提供一类具有式I所示结构的聚酮类化合物或其药学上可接受的盐或其立体异构体或其前药分子在制备抗新型冠状病毒药物中的应用：
Figure PCTCN2021126733-appb-000001
式中：
R 1选自C 1～C 6烷基、C 3～C 6环烷基或芳基；
R 2和R 3独立地选自氢原子或-C(O)R 6；
R 4和R 5独立地选自氢原子、C 1～C 6烷基、-C(O)R 6或-S(O) mR 6；
R 6选自氢原子、取代或未取代C 1～C 12烷基、取代或未取代C 3～C 6环烷基或者取代或未取代芳基；
m为1或2；
其中，各取代独立地指被选自下组的取代基取代：卤素、羟基、氨基、C 1～C 3烷基、C 1～C 3烷氧基、-NH(C 1～C 3烷基)、-N(C 1～C 3烷基)(C 1～C 3烷基)、-C(＝O)(C 1～C 3烷基)。
在本发明的一个优选的实施方案中，所述的通式I所示的化合物，其特征在于，所述R 3为氢原子，所述的聚酮类化合物具有通式II所示的结构式或其药学上可接受的盐或其立体异构体或其前药分子：
Figure PCTCN2021126733-appb-000002
其中：R 1、R 2、R 4和R 5如权利要求1中所定义。
在本发明的一个优选的实施方案中，所述的通式III所示的化合物包括，但不限于：
Figure PCTCN2021126733-appb-000003
在本发明的另一个优选的实施方案中，其特征在于，所述R 2为氢原子，所述的聚酮类化合物具有通式III所示的结构式或其药学上可接受的盐或其立体异构体或其前药分子：
Figure PCTCN2021126733-appb-000004
其中：R 1、R 3、R 4和R 5如权利要求1中所定义。
在本发明的一个优选的实施方案中，所述的通式IV所示的化合物包括，但不限于：
Figure PCTCN2021126733-appb-000005
Figure PCTCN2021126733-appb-000006
Figure PCTCN2021126733-appb-000007
Figure PCTCN2021126733-appb-000008
本发明涉及一种药物组合物，其含有治疗有效剂量的通式I、II和III所示的聚酮类化合物或其药学上可接受的盐或其立体异构体或其前药分子，以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明涉及含有治疗有效剂量的通式I、II和III所示的聚酮类化合物，或其药学上可接受的盐或其立体异构体或其前药分子或根据权利要求6所述的药物组合物在制备用于抗新型冠状病毒SARS-CoV-2药物中的用途。
本发明涉及含有治疗有效剂量的通式I、II和III所示的聚酮类化合物，或其药学上可接受的盐或其立体异构体或其前药分子或根据权利要求6所述的药物组合物在制备用于治疗新型冠状病毒SARS-CoV-2所引起的肺炎等疾病药物中的用途。
除非有相反陈述，在说明书和权利要求书中使用的术语具有下述含义。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C 1～C 6烷基”中“C 1～C 6”的定义包括以直链或支链排列的具有1、2、3、4、5或6个碳原子的基团。例如，“C 1～C 6烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基、己基。术语“环烷基”指具有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、环丁基、环戊基或环己基等。术语“烷氧基”指具有-O-烷基结构的基团，如-OCH 3、-OCH 2CH 3、-OCH 2CH 2CH 3、-OCH 2CH(CH 3) 2、-OCH 2CH 2CH 2CH 3、-OCH(CH 3) 2等。术语“芳基”包括但不限于：咪唑基、三唑基、吡唑基、呋喃基、噻吩基、噁唑基、异噁唑基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基。
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人 员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
“前药”表示在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药。
“药物组合物”表示含有一种或多种本文所述化合物或其生理学上/可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学/可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。
“可药用盐”是指本发明化合物的盐，这类盐用于哺乳动物体内时具有安全性和有效性，且具有应有的生物活性。
附图说明
图1化合物13对SARS-CoV-2核酸水平的抑制作用
图2化合物13对SARS-CoV-2核蛋白表达水平的抑制作用
具体实施方式
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-300、Bruker AVANCE-400、Bruker AVANCE-500或Bruker AVANCE-600核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)、氘代氯仿(CDCl 3)、氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。
MS的测定用FINNIGAN LCQAd(ESI)质谱仪(生产商:Thermo，型号：Finnigan LCQ advantage MAX)。
柱层析一般使用烟台黄海硅胶200～300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自Acros Organics、Aldrich Chemical Company、韶远化学科技(Accela ChemBio Inc)、百灵威、安耐吉、 达瑞化学品等公司。
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
实施例中无特殊说明，溶液是指水溶液。
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，分离纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：二氯甲烷/甲醇体系，B：正己烷/乙酸乙酯体系，C：石油醚/乙酸乙酯体系，D：丙酮，E：二氯甲烷/丙酮体系，F：乙酸乙酯/二氯甲烷体系，G：乙酸乙酯/二氯甲烷/正己烷，H：乙酸乙酯/二氯甲烷/丙酮，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
以下实施例制备得到的具体化合物均包括但不限于出现在前面表格所述1～25中。
实施例1
6,8-羟基-5-(3-甲基丁酰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(1)的制备
Figure PCTCN2021126733-appb-000009
第一步
室温下，将间苯三酚26a(2.5g,20mmol)溶于硝基甲烷溶液中，先后加入无水三氯化铝 (10.7g,80mmol)和异丁酰氯(2.3g,22mmol)，并升温至回流。反应12小时后，将反应液缓慢倒入冰水中，加入饱和酒石酸钾钠溶液(100mL)后剧烈搅拌。反应液用乙酸乙酯萃取3次(100mL×3)。将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物26c(3.6g,产率为85％)。
第二步
室温下，将化合物26c(2.1g,10mmol)溶于MeOH溶液(30mL)中，加入NaOMe的MeOH溶液(5mmol/mL,9mL,45mmol)。室温反应10min后，向反应体系中加入碘甲烷(3.1mL,50mmol)，升温至55℃反应15分钟，降温至0℃，用1N HCl酸化处理。乙酸乙酯萃取反应液三次(3×10mL)，将有机相合并，并用饱和NaCl溶液(5mL)洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到黄色油状化合物26d(2.4g,产率为91％)。
第三步
将化合物26d(2.4g,9.1mmol)溶于四氢呋喃溶液中，降至-78℃后，逐滴加入二异丙基氢化铝。反应2小时后，加入饱和酒石酸钾钠水溶液(100mL)淬灭反应。升至室温搅拌3小时后，反应液用乙酸乙酯萃取反应液3次(100mL×3)。将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物26e(2.0g,产率为89％)。
第四步
室温下，将化合物26c(1.0g,5mmol)溶于四氢呋喃中，加入到化合物26e(1.8g,7.5mmol)。反应4小时后，加入对甲苯磺酸一水合物(2.9g,15mmol)，并升温至回流。反应2小时后，降至室温，加入饱和碳酸氢钠水溶液(100mL)淬灭反应，反应液用乙酸乙酯萃取3次(100mL×3)。将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物1(896mg,产率为50％)。
1H NMR(500MHz,CDCl 3)δ13.29(s,1H),7.29(d,J＝7.2Hz,3H),7.24(d,J＝7.8Hz,2H), 7.16(t,J＝7.2Hz,1H),5.27(s,1H),3.95(h,J＝6.6Hz,1H),1.85(tt,J＝14.3,7.3Hz,2H),1.69–1.65(m,1H),1.63(s,3H),1.51(s,3H),1.35(s,3H),1.28(d,J＝6.7Hz,3H),1.12(s,3H),0.93(t,J＝7.5Hz,3H)； 13C NMR(125MHz,CDCl 3)δ212.1,204.1,199.0,167.7,164.3,160.5,153.1,114.8,106.3,105.4,100.2,56.2,53.4,47.4,46.9,25.5,25.1,24.9,24.8,24.6,24.4,23.5,23.2,23.0,22.7；HR-ESI-MS m/z 443.2432[M+H] +。
实施例2
6,8-二羟基-5-(2-二基丁酰基)-9-异丙基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(2)的制备
Figure PCTCN2021126733-appb-000010
室温下，将化合物27b(1.0g,5mmol)溶于四氢呋喃中，加入到化合物27a(1.8g,7.5mmol)。反应4小时后，加入对甲苯磺酸一水合物(2.9g,15mmol)，并升温至回流。反应2小时后，降至室温，加入饱和碳酸氢钠水溶液(100mL)淬灭反应，反应液用乙酸乙酯萃取3次(100mL×3)。将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物2(964mg,产率为45％)。
1H NMR(500MHz,CDCl 3)δ13.32(s,1H),6.29(s,1H),4.30(d,J＝3.5Hz,1H),3.90(dt,J＝13.7,6.8Hz,1H),1.94–1.85(m,1H),1.61(s,3H),1.44(s,3H),1.43(s,3H),1.38(s,3H),1.26(s,3H),1.25(s,3H),1.23(s,2H),0.82(d,J＝6.8Hz,3H),0.78(d,J＝6.8Hz,3H)； 13C NMR(125MHz,CDCl 3)δ212.0,209.1,198.1,167.8,164.9,159.6,153.6,112.2,104.0,103.7,100.7,56.3,47.4,39.8,34.9,31.7,29.8,25.3,25.1,24.9,24.3,21.0,19.0,18.9,17.8；HR-ESI-MS m/z 429.2279[M+H] +。
实施例3
6,8-二羟基-5-(2-甲基丁酰基)-9-苯基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(3)的制备
Figure PCTCN2021126733-appb-000011
室温下，将化合物27b(1.0g,5mmol)溶于四氢呋喃中，加入到化合物28a(2.0g,7.5mmol)。反应4小时后，加入对甲苯磺酸一水合物(2.9g,15mmol)，并升温至回流。反应2小时后，降至室温，加入饱和碳酸氢钠水溶液(100mL)淬灭反应，反应液用乙酸乙酯萃取3次(100mL×3)。将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物3(994mg,产率为43％)。
1H NMR(400MHz,CDCl 3)δ13.50(s,1H),6.31(s,1H),4.31(t,J＝5.5Hz,1H),3.19(dd,J＝17.0,7.2Hz,1H),2.94(dd,J＝17.1,5.9Hz,1H),2.34(dt,J＝13.0,6.5Hz,1H),1.63(s,3H),1.47(s,3H),1.42(s,4H),1.39(s,5H),1.00(dd,J＝11.2,6.6Hz,6H),0.90–0.75(m,6H)； 13C NMR(100MHz,CDCl 3)δ211.3,209.5,197.5,165.0,164.9,159.6,151.5,143.9,128.7,128.2,127.1,113.2,105.2,104.7,101.0,56.5,47.3,45.8,33.2,28.1,25.1,24.9,24.5,23.3,16.5,11.4；HR-ESI-MS m/z463.2112[M+H] +。
实施例4
6,8-二羟基-5-(2-甲基丁酰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(4)的制备
室温下，将化合物27b(1.0g,5mmol)溶于四氢呋喃中，加入到化合物26e(1.8g,7.5mmol)。反应4小时后，加入对甲苯磺酸一水合物(2.9g,15mmol)，并升温至回流。反应2小时后，降至室温，加入饱和碳酸氢钠水溶液(100mL)淬灭反应，反应液用乙酸乙酯萃取3次(100mL×3)。 将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物4(1.2g,产率为52％)。
1H NMR(600MHz,CDCl 3)δ13.21(s,1H),6.26(s,1H),4.31(t,J＝5.9Hz,1H),3.89(q,J＝6.6Hz,1H),1.76(dt,J＝13.8,6.6Hz,1H),1.60(s,3H),1.57(d,J＝7.0Hz,1H),1.51–1.47(m,1H),1.43(d,J＝1.0Hz,8H),1.39(s,3H),1.25(d,J＝6.7Hz,3H),0.87(ddd,J＝11.7,6.4,4.4Hz,12H)； 13C NMR(150MHz,CDCl 3)δ211.9,209.4,198.7,167.5,164.3,159.6,153.0,114.5,106.1,105.4,100.5,56.3,47.4,46.5,45.6,28.5,25.2,25.1,25.0,24.9,24.8,24.3,23.7,23.4,16.0,11.3；HR-ESI-MS m/z 443.2430[M+H] +。
实施例5
6,8-二羟基-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮中间体(26)的制备
室温下，将化合物26a(630mg,5mmol)溶于四氢呋喃中，加入到化合物26e(1.8g,7.5mmol)。反应4小时后，加入对甲苯磺酸一水合物(2.9g,15mmol)，并升温至回流。反应2小时后，降至室温，加入饱和碳酸氢钠水溶液(100mL)淬灭反应，反应液用乙酸乙酯萃取3次(100mL×3)。将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物26(896mg,产率为50％)。
1H NMR(600MHz,CD 3OD)δ6.17(d,J＝2.3Hz,1H),6.10(d,J＝2.3Hz,1H),4.18(t,J＝5.7Hz,1H),3.33(dt,J＝3.3,1.6Hz,1H),1.54(s,3H),1.49(m,2H),1.45(s,3H),1.39(m,1H),1.36(s,3H),1.34(s,3H),0.85(d,J＝6.5Hz,3H),0.81(d,J＝6.4Hz,3H)； 13C NMR(150MHz,CD 3OD)δ212.4,198.2,168.5,156.8,155.7,152.4,113.5,104.6,98.8,94.0,55.4,47.0,45.6,25.5,24.7,23.9,23.8,23.6,23.3,22.9,22.3；HR-ESI-MS m/z 359.1847[M+H] +。
实施例6
6,8-二羟基-9-环丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮中间体(29)的制备
Figure PCTCN2021126733-appb-000012
第一步
室温下，将间苯三酚26a(2.5g,20mmol)溶于硝基甲烷溶液中，先后加入无水三氯化铝(10.7g,80mmol)和环丁酰氯(2.6g,22mmol)，并升温至回流。反应12小时后，将反应液缓慢倒入冰水中，加入饱和酒石酸钾钠溶液(100mL)后剧烈搅拌。反应液用乙酸乙酯萃取3次(100mL×3)。将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物29c(3.4g,产率为83％)。
第二步
室温下，将化合物29c(2.1g,10mmol)溶于MeOH溶液(30mL)中，加入NaOMe的MeOH溶液(5mmol/mL,9mL,45mmol)。室温反应10分钟后，向反应体系中加入碘甲烷(3.1mL,50mmol)，升温至55℃反应15分钟，降温至0℃，用1N HCl酸化处理。乙酸乙酯萃取反应液三次(3×10mL)，将有机相合并，并用饱和NaCl溶液(5mL)洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到黄色固体化合物29d(2.4g,产率为90％)。
第三步
将化合物29d(2.4g,9.0mmol)溶于四氢呋喃溶液中，降至-78℃后，逐滴加入二异丙基氢化铝。反应2小时后，加入饱和酒石酸钾钠水溶液(100mL)淬灭反应。升至室温搅拌3小时后，反应液用乙酸乙酯萃取反应液3次(100mL×3)。将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物29e(1.9g,产率为85％)。
第四步
室温下，将化合物26a(630mg,5mmol)溶于四氢呋喃中，加入到化合物29e(1.8g,7.5mmol)。反应4小时后，加入对甲苯磺酸一水合物(2.9g,15mmol)，并升温至回流。反应2小时后，降至室温，加入饱和碳酸氢钠水溶液(100mL)淬灭反应，反应液用乙酸乙酯萃取3次(100mL×3)。将有机相合并，并用饱和NaCl溶液洗涤。无水硫酸钠干燥过滤后，有机相在减压条件下蒸干溶剂。所得粗产物经硅胶柱层析分离纯化得到化合物29(927mg,产率为52％)。
1H NMR(300MHz,CD 3OD)δ6.19(d,J＝2.2Hz,1H),6.12(d,J＝2.2Hz,1H),4.12(d,J＝5.7Hz,1H),2.59(dt,J＝9.0,6.8Hz,1H),1.65(m,5H),1.53(s,3H),1.42(s,3H),1.35(s,3H),1.31(s,3H)； 13C NMR(75MHz,CD 3OD)δ212.4,198.5,169.2,156.8,155.8,152.8,111.1,102.3,98.9,94.0,55.5,41.9,29.6,24.7,24.2,23.9,23.6,23.5,17.2；HR-ESI-MS m/z 357.1693[M+H] +。
实施例7
6,8-二羟基-7-(3-甲基丁酰基)-9-异丁基-2,2,4,4-二甲基-4,9-氢-1H-氧杂蒽-1,3(2H)-二酮(6)的制备
室温下，将四氯化钛(0.4mmol,1.0M in CH 2Cl 2)和3-甲基丁酰氯(0.11mmol)分别加入到化合物26(0.1mmol)的二氯甲烷的溶液中，并常温搅拌。反应24小时后，加入1N盐酸水溶液淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到相应产物6(15.5mg,产率为35％)。
1H NMR(500MHz,CDCl 3)δ13.05(s,1H),7.58(s,1H),6.13(s,1H),4.29(t,J＝5.3Hz,1H),3.01(m,2H),2.29(m,1H),1.73(s,3H),1.57(s,3H),1.45(s,3H),1.43(s,3H),1.42(m,3H),1.39(s,3H),1.01(s,3H),0.99(s,3H),0.89(d,J＝5.8Hz,3H),0.85(d,J＝5.6Hz,3H)； 13C NMR(125MHz,CDCl 3)δ212.2,206.5,197.9,167.1,162.6,158.5,155.6,114.2,107.6,106.6,94.8,56.1,53.2,47.2,45.9,25.2,25.1,24.7,24.6,24.6,24.2,23.5,23.2,22.8,22.8；HR-ESI-MS m/z 443.2432[M+H] +。
实施例8
6,8-二羟基-7-(3-甲基丁酰基)-9-苯基-2,2,4,4-四甲基4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(8)的制备
Figure PCTCN2021126733-appb-000013
室温下，将四氯化钛(0.4mmol,1.0M in CH 2Cl 2)和3-甲基丁酰氯(0.11mmol)分别加入到化合物30(0.1mmol)的二氯甲烷的溶液中，并常温搅拌。反应24小时后，加入1N盐酸水溶液淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到相应产物8(23.4mg,产率为53％)。
1H NMR(400MHz,CDCl 3)δ7.30–7.12(m,5H),6.23(s,1H),5.21(s,1H),2.91(qd,J＝15.9,6.6Hz,2H),2.22(dq,J＝13.2,6.9Hz,1H),1.59(s,3H),1.49(s,3H),1.33(s,3H),1.11(s,3H),0.93(d,J＝6.8Hz,3H),0.91(d,J＝6.8Hz,3H)； 13C NMR(100MHz,CDCl 3)δ211.8,206.4,197.5,165.3,162.8,159.6,154.4,143.9,128.5,128.3,126.9,113.2,108.1,105.3,95.0,56.5,53.2,47.3,33.4,25.1,24.9,24.7,24.6,23.3,22.9,22.9；HR-ESI-MS m/z 463.2121[M+H] +。
实施例9
6,8-二羟基-7-(2-甲基丁酰基)-9-异丙基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(10)的制备
Figure PCTCN2021126733-appb-000014
室温下，将四氯化钛(0.4mmol,1.0M in CH 2Cl 2)和2-甲基丁酰氯(0.11mmol)分别加入到化合物31(0.1mmol)的二氯甲烷的溶液中，并常温搅拌。反应24小时后，加入1N盐酸水溶液 淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到相应产物10(23.4mg,产率为45％)。
1H NMR(500MHz,CDCl 3)δ12.33(s,1H),7.96(s,1H),6.14(s,1H),4.32(d,J＝3.5Hz,1H),3.76(q,J＝6.7Hz,1H),1.98(td,J＝6.9,3.5Hz,1H),1.86(ddd,J＝13.5,7.4,6.1Hz,1H),1.58(s,3H),1.45(m,1H),1.43(s,3H),1.42(s,3H),1.37(s,3H),1.18(d,J＝6.7Hz,3H),0.93(t,J＝7.4Hz,3H),0.80(d,J＝6.9Hz,3H),0.78(d,J＝7.0Hz,3H)； 13C NMR(125MHz,CDCl 3)δ212.3,211.1,198.2,168.3,162.2,158.9,156.5,112.0,107.5,104.9,95.1,56.3,47.5,46.6,34.7,32.0,26.9,25.3,25.2,24.7,24.1,19.4,18.9,16.7,12.1；HR-ESI-MS m/z 429.2277[M+H] +。
实施例10
6,8-二羟基-7-乙酰基-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(11)的制备
室温下，将化合物26(44.2mg,0.1mmol)溶于冰醋酸(4mL)溶液中，分别加入醋酐(20.6μL,0.22mmol)和三氟化硼乙醚(13.6μL,0.105mmol)，并升温至100℃。反应3小时后，加入1N氢氧化钠水溶液(4mL)淬灭反应，并用乙酸乙酯萃取3次(8mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物在二氯甲烷和正己烷混合液重结晶得到化合物11(16.4mg,产率为41％)。
1H NMR(500MHz,CDCl 3)δ13.12(s,1H),7.73(s,1H),6.17(s,1H),4.30(t,J＝5.5Hz,1H),2.75(s,3H),1.58(s,3H),1.46(m,3H),1.46(s,3H),1.44(s,3H),1.40(s,3H),0.89(d,J＝6.0Hz,3H),0.86(d,J＝5.8Hz,3H)； 13C NMR(125MHz,CDCl 3)δ212.2,204.2,198.1,167.2,162.7,158.8,156.0,114.3,107.6,106.4,94.7,56.1,47.2,45.9,33.2,25.1,24.8,24.6,24.2,23.5,23.2；HR-ESI-MS m/z 401.1957[M+H] +。
实施例11
6,8-二羟基-7-丙酰基-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(12)的制备
室温下，将四氯化钛(0.4mmol,1.0M in CH 2Cl 2)和丙酰氯(0.11mmol)分别加入到化合物26(0.1mmol)的二氯甲烷的溶液中，并常温搅拌。反应24小时后，加1N盐酸水溶液淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到化合物12(17.8mg,产率为43％)。
1H NMR(500MHz,CD 3OD)δ6.16(s,1H),4.21(t,J＝5.2Hz,1H),3.16(q,J＝7.1Hz,2H),1.55(s,3H),1.46(s,3H),1.38(m,3H),1.37(s,3H),1.35(s,3H),1.17(t,J＝7.1Hz,3H),0.86(d,J＝5.8Hz,3H),0.81(d,J＝5.7Hz,3H)； 13C NMR(125MHz,CD 3OD)δ211.8,207.6,197.9,167.3,162.6,160.2,155.9,113.9,107.0,104.8,93.6,55.7,46.9,45.2,37.2,25.0,24.9,24.0,23.8,23.5,22.9,22.7,22.3,7.5；HR-ESI-MS m/z 415.2112[M+H] +。
实施例12
6,8-二羟基-7-(2-甲基丁酰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(13)的制备
室温下，将四氯化钛(0.4mmol,1.0M in CH 2Cl 2)和2-甲基丁酰氯(0.11mmol)分别加入到化合物26(0.1mmol)的二氯甲烷的溶液中，并常温搅拌。反应24小时后，加入1N盐酸水溶液淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到相应产物13(23.4mg,产率为53％)。
1H NMR(400MHz,CDCl 3)δ13.37(s,1H),8.03(s,1H),6.20(s,1H),4.29(d,J＝5.0Hz,1H),3.80(q,J＝6.6Hz,1H),1.87(dt,J＝13.5,6.5Hz,1H),1.56(s,3H),1.44(m,7H),1.42(s,3H),1.39(s,3H),1.17(d,J＝6.7Hz,3H),0.93(t,J＝7.4Hz,3H),0.86(d,J＝5.6Hz,3H),0.84(d,J＝5.4Hz,3H)； 13C NMR(100MHz,CDCl 3)δ212.3,211.4,198.8,167.8,163.1,158.6,155.7,114.4,107.4,106.6,95.0,56.2,47.4,46.5,46.0,26.9,25.4,25.3,24.9,24.8,24.4,23.7,23.3,16.7,12.1；HR-ESI-MS m/z 443.2438[M+H] +。
实施例13
6,8-二羟基-7-癸酰基-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(14)的制备
室温下，将四氯化钛(0.4mmol,1.0M in CH 2Cl 2)和癸酰氯(0.11mmol)分别加入到化合物26(0.1mmol)的二氯甲烷的溶液中，并常温搅拌。反应24小时后，加入1N盐酸水溶液淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到化合物14(20.0mg,产率为39％)。
1H NMR(300MHz,CDCl 3)δ13.56(s,1H),8.33(s,1H),6.26(s,1H),4.33(t,J＝5.1Hz,1H),3.16(t,J＝7.3Hz,2H),1.73(m,2H),1.59(s,3H),1.47(s,3H),1.45(s,3H),1.42(s,3H),1.40(m,15H),0.88(t,J＝4.9Hz,9H)； 13C NMR(75MHz,CDCl 3)δ212.1,207.4,198.9,168.0,162.9,158.9,155.7,114.3,107.5,106.2,94.74,56.1,47.3,45.9,44.6,31.9,29.6,29.5,29.5,29.3,25.1,24.8,24.7,24.6,24.3,23.6,23.2,22.7,14.1；HR-ESI-MS m/z 513.3210[M+H] +。
实施例14
6,8-二羟基-7-(3-甲基丁酰基)-9-环丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(17)的制备
室温下，将四氯化钛(0.4mmol,1.0M in CH 2Cl 2)和环丁酰氯(0.11mmol)分别加入到化合物29(0.1mmol)的二氯甲烷的溶液中。反应搅拌24小时后，加入1N盐酸水溶液淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到化合物17(18.0mg,产率为41％)。
1H NMR(500MHz,CDCl 3)δ11.74(s,1H),9.40(s,1H),6.23(s,1H),4.43(d,J＝5.5Hz,1H),3.05(m,2H),2.70(m,1H),2.32(m,1H),1.62(m,6H),1.59(s,3H),1.47(s,6H),1.42(s,3H),1.01(d,J＝3.5Hz,3H),1.00(d,J＝3.5Hz,3H)； 13C NMR(125MHz,CDCl 3)δ212.0,206.6,198.6,168.5,161.2,160.2,156.0,111.5,108.0,103.1,95.5,56.0,53.4,47.3,41.3,29.4,25.4,25.0,24.6,24.6,24.4,22.9,22.8,17.8；HR-ESI-MS m/z 441.2268[M+H] +。
实施例15
6,8-二羟基-7-(环丁基羰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(18)的制备
室温下，将四氯化钛(0.4mmol,1.0M in CH 2Cl 2)和环丁基酰氯(0.11mmol)分别加入到化合物26(0.1mmol)的二氯甲烷的溶液中，并常温搅拌。反应24小时后，加入1N盐酸水溶液淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到化合物18(18.9mg,产率为43％)。
1H NMR(300MHz,CDCl 3)δ13.50(s,1H),8.26(s,1H),6.20(s,1H),4.27(m,2H),2.34(m,4H),1.96(m,2H),1.58(s,3H),1.48(m,3H),1.46(s,3H),1.44(s,3H),1.41(s,3H),0.88(d,J＝4.5Hz,3H),0.86(s,3H)； 13C NMR(75MHz,CDCl 3)δ212.2,207.2,198.6,167.7,163.0,158.8,155.7,114.3,106.4,106.1,94.6,77.5,77.0,76.6,56.1,47.3,46.6,45.9,25.2,25.1,24.9,24.8,24.6,24.2,23.6,23.2,17.6；HR-ESI-MS m/z 441.2271[M+H] +。
实施例16
6,8-二乙酰氧基-7-(3-甲基丁酰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(20)的制备
室温下，将醋酸酐(30.6mg,0.3mmol)和三乙胺(40.4mg,0.4mmol)加入到含有化合物6(44.2mg,0.1mmol)的二氯甲烷溶液中(2mL)，并加热至回流。反应过夜后降温至常温，加入1N HCl水溶液(3mL)淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相用无水硫酸钠干燥、过滤、减压浓缩得到粗产物。粗产物经硅胶色谱柱分离纯化得到化合物20(48.4mg,产率为92％)。
1H NMR(300MHz,CDCl 3)δ6.92(s,1H),3.99(t,J＝6.0Hz,1H),2.60(dd,J＝6.7,4.6Hz,2H),2.29(s,3H),2.26(s,3H),2.19(dd,J＝13.2,6.5Hz,1H),1.52(s,3H),1.42(s,3H),1.35(s, 3H),1.34(m,3H),1.32(s,3H),0.94(s,3H),0.92(s,3H),0.89(d,J＝6.1Hz,3H),0.79(d,J＝6.1Hz,3H)； 13C NMR(75MHz,CDCl 3)δ211.6,199.7,197.2,168.4,168.1,167.4,152.0,146.5,145.4,125.1,118.7,112.9,109.0,56.0,52.6,47.2,47.1,26.3,24.8,24.5,24.4,24.2,24.1,23.2,22.8,22.5,22.5,21.0,20.7；HR-ESI-MS m/z 527.2637[M+H] +。
实施例17
6-甲磺酰氧基-8-羟基-7-(3-甲基丁酰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(20)的制备
室温下，将甲磺酰氯(13.7mg,0.12mmol)和4-二甲氨基吡啶(24.4mg,0.2mmol)加入到含有化合物6(44.2mg,0.1mmol)的二氯甲烷溶液中(2mL)。反应2小时后，加入1N HCl水溶液(3mL)淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到化合物20(42.1mg,产率为81％)。
1H NMR(300MHz,CDCl 3)δ13.27(s,1H),6.75(s,1H),4.35(d,J＝5.2Hz,1H),3.29(s,3H),2.97(m,2H),2.28(m,1H),1.56(s,3H),1.45(s,6H),1.41(m,3H),1.40(s,3H),1.37(s,3H),0.99(s,3H),0.96(s,3H),0.89(d,J＝5.3Hz,3H),0.84(d,J＝5.2Hz,3H)； 13C NMR(75MHz,CDCl 3)δ211.7,205.0,197.4,166.6,162.5,154.8,147.8,114.4,113.9,111.4,101.6,56.2,52.7,47.1,46.1,38.7,25.4,25.2,25.0,24.7,24.6,24.5,24.0,23.2,23.1,22.6,22.6；HR-ESI-MS m/z 521.2204[M+H] +。
实施例18
6-(2,2-二甲基丙酰氧基)-8-羟基-7-(3-甲基丁酰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(22)的制备
室温下，将叔丁基乙酰氯(16.1mg,0.12mmol)和4-二甲氨基吡啶(24.4mg,0.2mmol)加入到含有化合物6(44.2mg,0.1mmol)的二氯甲烷溶液中(2mL)。反应2小时后，加入1N HCl水 溶液(3mL)淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到化合物22(18.4mg,产率为35％)。
1H NMR(500MHz,CDCl 3)δ13.56(s,1H),6.22(s,1H),4.36(t,J＝4.9Hz,1H),2.81(d,J＝6.6Hz,2H),2.35(m,1H),1.56(s,3H),1.46(s,3H),1.44(s,9H),1.44(m,3H),1.42(s,3H),1.38(s,3H),0.99(d,J＝3.5Hz,3H),0.98(d,J＝3.7Hz,3H),0.90(d,J＝4.9Hz,3H),0.86(d,J＝4.9Hz,3H)； 13C NMR(125MHz,CDCl 3)δ212.0,204.5,197.4,176.9,166.6,162.5,154.9,151.5,113.9,112.8,111.9,102.2,56.2,52.3,47.1,45.9,39.5,27.2,25.5,25.2,24.7,24.7,24.4,24.2,24.2,23.3,23.2,22.7,22.7；HR-ESI-MS m/z 527.3001[M+H] +。
实施例19
6-苯甲酰氧基-8-羟基-7-(3-甲基丁酰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(23)的制备
室温下，将苯甲酰氯(16.9mg,0.12mmol)和4-二甲氨基吡啶(24.4mg,0.2mmol)加入到含有化合物6(44.2mg,0.1mmol)的二氯甲烷溶液中(2mL)。反应2小时后，加入1N HCl水溶液(3mL)淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相用无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到化合物23(23.5mg,产率为43％)。
1H NMR(500MHz,CDCl 3)δ13.54(s,1H),8.14(d,J＝7.8Hz,2H),7.64(d,J＝7.3Hz,1H),7.50(t,J＝7.6Hz,2H),6.42(s,1H),4.31(d,J＝5.4Hz,1H),2.70(d,J＝6.8Hz,2H),2.13(m,1H),1.47(s,3H),1.41(m,3H),1.37(s,3H),1.34(s,3H),1.31(s,3H),0.84(d,J＝5.2Hz,3H),0.80(d,J＝5.0Hz,3H),0.71(t,J＝5.8Hz,6H)； 13C NMR(125MHz,CDCl 3)δ212.0,204.7,197.5,166.7,164.7,162.8,155.0,150.6,134.5,130.3,129.0,128.6,114.0,113.2,111.5,103.0,56.2,52.7,47.2,46.1,25.5,25.2,24.7,24.6,24.42,24.3,23.3,23.2,22.5,22.4；HR-ESI-MS m/z 549.2687[M+H] +。
实施例20
6-三氟甲磺酰氧-8-羟基-7-(3-甲基丁酰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(24)的制备
室温下，将三氟甲磺酰氯(20.2mg,0.12mmol)和4-二甲氨基吡啶(24.4mg,0.2mmol)加入到含有化合物6(44.2mg,0.1mmol)的二氯甲烷溶液中(2mL)。反应2小时后，加入1N HCl水溶液(3mL)淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到化合物24(27.0mg,产率为47％)。
1H NMR(500MHz,CDCl 3)δ13.19(d,J＝15.9Hz,1H),6.61(d,J＝8.6Hz,1H),4.38(m,1H),2.93(m,2H),2.29(m,1H),1.59(s,3H),1.47(s,3H),1.45(m,3H),1.43(s,3H),1.39(d,J＝2.5Hz,3H),0.99(d,J＝2.5Hz,3H),0.97(s,3H),0.92(d,J＝5.0Hz,3H),0.85(d,J＝5.0Hz,3H)； 13C NMR(125MHz,CDCl 3)δ211.5,204.4,197.3,166.5,162.5,154.7,147.2,115.8,113.9,110.9,101.5,56.2,52.6,47.1,46.0,25.5,25.2,25.1,24.7,24.6,24.5,23.9,23.2,23.1,22.5,22.4；HR-ESI-MS m/z 575.1918[M+H] +。
实施例21
6-苯乙酰氧基-8-羟基-7-(3-甲基丁酰基)-9-异丁基-2,2,4,4-四甲基-4,9-二氢-1H-氧杂蒽-1,3(2H)-二酮(25)的制备
室温下，将苯乙酰氯(18.6mg,0.12mmol)和4-二甲氨基吡啶(24.4mg,0.2mmol)加入到化合物6(44.2mg,0.1mmol)的二氯甲烷溶液中(2mL)。反应2小时后，加入1N HCl水溶液(3mL)淬灭反应，并用二氯甲烷萃取3次(3mL×3)。有机相经无水硫酸钠干燥、过滤、减压浓缩得到粗产物。所得粗产物经硅胶色谱柱分离纯化得到化合物25(21.8mg,产率为39％)。
1H NMR(500MHz,CDCl 3)δ13.49(s,1H),7.40(m,5H),6.36(s,1H),4.35(t,J＝5.1Hz,1H),3.95(s,2H),2.71(d,J＝6.6Hz,2H),2.27(m,1H),1.56(s,3H),1.45(m,3H),1.44(s,3H),1.41(s,3H),1.38(s,3H),0.94(s,3H),0.93(s,3H),0.90(d,J＝5.1Hz,3H),0.85(d,J＝5.0Hz,3H)；HR-ESI-MS m/z 587.2843[M+H] +。
实施例22
聚酮类化合物体外抗SARS-CoV-2活性评价
材料：SARS-CoV-2病毒株为广东省疾病预防控制中心(CDC)分离(全基因组序列数据见GISAID数据库，序列号：EPI_ISL_403934，毒株编号：BetaCoV/Guangdong/20SF014/2020)；细胞培养液是含10％胎牛血清(FBS)和1％青霉素-链霉素(PS)的MEM培养基，细胞维持液是含2％FBS和1％PS的MEM培养基。细胞培养在37℃，5％CO 2培养箱中，2～3天进行传代1次；SARS-CoV-2培养在Vero-E6细胞中，保存于-80℃冰箱备用。FBS、MEM、PS均购自美国Life Technologies公司，磷酸氯喹(Chloroquine diphosphate)购自美国Sigma-Aldrich公司，CCK-8试剂盒购自上海碧云天生物技术有限公司，病毒荧光定量RT-PCR试剂盒购自广州达安基因科技有限公司。
1.聚酮类化合物对病毒诱导细胞病变(CPE)的抑制作用
实验方法：采用CPE法测定受试化合物对SARS-CoV-2诱导的细胞病变的抑制作用。将Vero-E6细胞接种在96孔细胞培养板中，放置在37℃，5％CO 2培养箱中培养24小时。随后，吸弃细胞上清液，加入用细胞维持液稀释后的化合物。同时加入用维持液稀释后的病毒液，病毒感染复数MOI＝0.1，每个浓度设置5个复孔，同时设置细胞对照组(不加入病毒和化合物)、化合物对照组(不加入病毒)、病毒对照组(不加入化合物)。随后，将细胞放置在37℃，5％CO 2培养箱中，待病毒吸附1小时后，弃病毒液，每孔加入0.1mL含化合物的细胞维持液。将细胞放置在37℃，5％CO 2培养箱中培养，每隔24小时，在P3实验室观察细胞病变(CPE)情况。在病毒感染48小时后，记录各孔中CPE结果。
实验结果：如表1所示，化合物1～25可不同程度地抑制SARS-CoV-2诱导的细胞病变，其中化合物13的活性最为显著，其半数抑制浓度IC 50值为0.70±0.03μM，其活性强于磷酸氯喹(1.50±0.15μM)。化合物13选择指数SI值(CC 50/IC 50)为48.69，与磷酸氯喹SI值66.67接近。
2.聚酮类化合物对Vero-E6细胞的毒性测试
实验方法：采用CCK-8试剂盒测定受试化合物的细胞毒性。将Vero-E6细胞接种在96孔细 胞培养板中，将培养板放置在37℃，5％CO 2培养箱中培养。24小时后，吸弃细胞上清液，加入用培养基稀释后的化合物，每个浓度设置6个复孔，同时设置细胞对照组(不加入化合物)。继续培养48小时后，采用CCK-8试剂盒测定细胞活力，并计算化合物的细胞毒性。
实验结果：如表1所示，化合物1～25对Vero-E6显示出了一定的细胞毒性，半数细胞毒性浓度CC 50值介于18.00～84.00μM之间。
表1.聚酮类化合物对SARS-CoV-2诱导的细胞病变的抑制作用及其细胞毒性
Figure PCTCN2021126733-appb-000015
a IC 50指半数抑制浓度(50％Inhibition Concentration)，用IC 50(μM)表示：
Figure PCTCN2021126733-appb-000016
b CC 50指半数细胞毒性浓度(50％Cytotoxic Concentration)，用CC 50(μM)表示；
c SI指选择性系数(Selectivity Index)，其值为CC 50/IC 50。
3.化合物13对病毒核酸的抑制作用
实验方法：采用荧光定量RT-PCR法检测受试化合物13对SARS-CoV-2的抑制作用。将Vero-E6细胞接种在6孔细胞培养板中，在37℃，5％CO 2培养箱中培养24小时后，弃细胞上清液，加入含有化合物13的细胞维持液，同时加入用维持液稀释后的病毒液(MOI＝0.1)，每组设置3个复孔，同时设置细胞对照组(不加入病毒和化合物13)、化合物13对照组(不加入病毒)、病毒对照组(不加入化合物13)。在37℃，5％CO 2培养箱中培养48小时，提取病毒RNA，通过荧光定量RT-PCR检测病毒核酸含量。
实验结果：如图1所示，化合物13可显著降低细胞中SARS-CoV-2的核酸水平，并具有浓度依赖性。当化合物13浓度为2μM时，对SARS-CoV-2核酸的抑制作用为97.5％。
4.化合物13对病毒核蛋白(Nucleoprotein)表达水平的抑制作用
实验方法：采用免疫荧光标记的方法检测受试化合物13对细胞中SARS-CoV-2核蛋白表达水平的抑制作用。将Vero-E6细胞接种在96孔板中，待细胞长满单层后，弃细胞上清液，加入病毒(MOI＝0.05)稀释液，同时加入不同浓度的化合物13。在37℃感染1小时后，弃病毒和化合物混合液，加入含不同化合物浓度的维持液。病毒感染24小时后，加入4％多聚甲醛溶液进行固定，用PBS清洗，依次加入病毒核蛋白一抗和Alexa488nm荧光二抗，并加入DAPI标记细胞核，应用Celigo扫板测定荧光强度，计算化合物对病毒感染的抑制率。
实验结果：如图2所示，化合物13可显著降低SARS-CoV-2的核蛋白(图2中绿色荧光)的表达水平。SARS-CoV-2感染Vero-E6细胞后，可检测到病毒核蛋白在细胞中的表达水平较高，加入化合物13后，核蛋白的表达水平显著降低。化合物浓度为2μM时对SARS-CoV-2核蛋白表达水平的抑制率高于95％。
最后有必要说明的是，以上对本发明的具体实施例进行了详细描述，但其只作为范例，本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言，任何对本发明进行的等同 修改和替代也都在本发明的范畴之中。因此，在不脱离本发明的精神和范围下所作的均等变换和修改，都应涵盖在本发明的范围内。

Claims (8)

  1. 具有式I所示结构的聚酮类化合物或其药学上可接受的盐或其立体异构体或其前药分子在制备抗新型冠状病毒药物中的应用：
    Figure PCTCN2021126733-appb-100001
    式中：
    R 1选自C 1～C 6烷基、C 3～C 6环烷基或芳基；
    R 2和R 3独立地选自氢原子或-C(O)R 6；
    R 4和R 5独立地选自氢原子、C 1～C 6烷基、-C(O)R 6或-S(O) mR 6；
    R 6选自氢原子、取代或未取代C 1～C 12烷基、取代或未取代C 3～C 6环烷基或者取代或未取代芳基；
    m为1或2；
    其中，各取代独立地指被选自下组的取代基取代：卤素、羟基、氨基、C 1～C 3烷基、C 1～C 3烷氧基、-NH(C 1～C 3烷基)、-N(C 1～C 3烷基)(C 1～C 3烷基)、-C(＝O)(C 1～C 3烷基)。
  2. 根据权利要求1所述的应用，其特征在于，所述R 3为氢原子，所述的聚酮类化合物具有通式II所示的结构式或其药学上可接受的盐或其立体异构体或其前药分子：
    Figure PCTCN2021126733-appb-100002
    其中：R 1、R 2、R 4和R 5如权利要求1中所定义。
  3. 根据权利要求2所述的应用，其特征在于，所述聚酮类化合物选自：
    Figure PCTCN2021126733-appb-100003
  4. 根据权利要求1所述的应用，其特征在于，所述R 2为氢原子，所述的聚酮类化合物具有通式III所示的结构式或其药学上可接受的盐或其立体异构体或其前药分子：
    Figure PCTCN2021126733-appb-100004
    其中：R 1、R 3、R 4和R 5如权利要求1中所定义。
  5. 根据权利要求4所述的应用，所述聚酮类化合物选自：
    Figure PCTCN2021126733-appb-100005
  6. 根据权利要求1～5中任一项所述的通式I、II、和III所示的聚酮类化合物，或其药学上可接受的盐或其立体异构体或其前药分子，以及一种或多种药学上可接受的载体、稀释剂或赋形剂所组成的药物组合物。
  7. 根据权利要求1～5中任一项所述的通式I、II、和III所示的聚酮类化合物，或其药学上可接受的盐或其立体异构体或其前药分子或根据权利要求6所述的药物组合物在制备用于抗新型冠状病毒SARS-CoV-2药物中的用途。
  8. 根据权利要求1～5中任一项所述的通式I、II、和III所示的聚酮类化合物，或其药学上可接受的盐或其立体异构体或其前药分子或根据权利要求6所述的药物组合物在制备用于治疗或预防新型冠状病毒SARS-CoV-2所引起的肺炎等疾病药物中的用途。
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