WO2023274203A1 - 一种含氮多环类芳香化合物及其制备方法和应用 - Google Patents

一种含氮多环类芳香化合物及其制备方法和应用 Download PDF

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WO2023274203A1
WO2023274203A1 PCT/CN2022/101788 CN2022101788W WO2023274203A1 WO 2023274203 A1 WO2023274203 A1 WO 2023274203A1 CN 2022101788 W CN2022101788 W CN 2022101788W WO 2023274203 A1 WO2023274203 A1 WO 2023274203A1
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compound
nitrogen
polycyclic aromatic
methyl
containing polycyclic
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PCT/CN2022/101788
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French (fr)
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朱华结
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河北科技大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present application relates to the field of medicine, in particular to a nitrogen-containing polycyclic aromatic compound and its preparation method and application.
  • Malignant tumors are abnormalities in structure, function and metabolism that lead to abnormal proliferation of local tissues caused by malignant changes of cells.
  • the current methods of treating malignant tumors are mainly surgical treatment and radio/chemotherapy.
  • tumor diseases and patients suitable for surgical treatment and radio/chemotherapy are limited by many factors, especially for patients with advanced tumors, there is no effective treatment and mitigation means, so screening and developing new Active or potential therapeutic agents have been the goal of efforts.
  • cisplatin is a non-specific drug for cells. Studies have shown that cisplatin can bind to DNA and cause cross-linking, thereby destroying the function of DNA and inhibiting cellular DNA replication. In clinical application, cisplatin has a broad anti-tumor spectrum, and is used for head and neck squamous cell carcinoma, ovarian cancer, germ cell carcinoma, seminoma, lung cancer, thyroid cancer, lymphosarcoma and reticulocyte sarcoma, etc., big data Statistically good tumor treatment effect is currently considered to be one of the most effective broad-spectrum anti-tumor drugs in clinical treatment, but it also shows serious side effects in clinical practice.
  • cisplatin can cause renal tubular cell death and renal tissue damage through mechanisms such as oxidative stress, DNA damage, and inflammatory response, thereby reducing glomerular filtration rate and significantly reducing renal excretion, resulting in a large amount of cisplatin accumulation in the kidney. Cause severe kidney failure. Cisplatin can also damage cochlear hair cells, causing hearing loss, leading to deafness or tinnitus.
  • the problem of drug resistance in use has always been a problem that needs to be faced and solved. The development of corresponding upgraded drugs and alternative drugs is always full of expectations for both drug developers and patients.
  • the application provides a nitrogen-containing polycyclic aromatic compound, its preparation method and application.
  • the nitrogen-containing polycyclic aromatic compound provided by the application has excellent broad-spectrum anti-tumor activity and low toxicity, and can be used as a lead compound for the development of new anti-tumor compounds.
  • R 1 and R 9 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, benzyloxy, and halogen;
  • R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , and R 13 are each independently selected from H, C 1-6 alkyl, -COOR x ; R x is selected from C 1-6 alkyl;
  • R 6 and R 14 are independently selected from H or C 1-6 alkyl groups
  • R 7 and R 8 are each independently selected from H or C 1-6 alkyl groups.
  • a C 1-6 alkyl group refers to a straight-chain or branched-chain alkyl group with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl , n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, etc.;
  • C 1-6 alkyl refers to a straight group with 1-6 carbon atoms
  • Alkyl or branched chain alkyl for example can be methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentoxy, Isopentyloxy, neopentyloxy, n-hexyloxy, etc.
  • the pharmaceutically acceptable salt refers to a salt formed by a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base and the compound, which retains the biological activity.
  • the specific product of the pharmaceutically acceptable salt can be determined by conventional means in accordance with the well-known knowledge in the field of pharmaceutical research and preparation. Exemplarily:
  • the organic acid can be selected from the organic acids capable of forming salts commonly used in the pharmaceutical field, such as formic acid, acetic acid, propionic acid, trifluoroacetic acid, oxalic acid, benzoic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, Tartaric acid, malic acid, lactic acid, salicylic acid, etc.
  • the inorganic acid can be selected from those commonly used in the pharmaceutical field that can form salts, such as hydrochloric acid, sulfuric acid, phosphoric acid, and the like.
  • the organic base can be selected from those commonly used in the pharmaceutical field that can form salts, such as pyridine, imidazole, pyrazine, indole, purine, aniline, and the like.
  • the inorganic base can be selected from the inorganic bases commonly used in the pharmaceutical field capable of forming salts, such as alkali metal hydrides, alkali metal hydroxides, alkali metal alkoxides, potassium carbonate, sodium carbonate, lithium carbonate, potassium bicarbonate, Sodium bicarbonate, etc.
  • the alkali metal hydride can be sodium hydride and/or potassium hydride
  • the hydroxide of alkali metal can be sodium hydroxide, potassium hydroxide, lithium hydroxide etc.
  • the alkoxide of alkali metal can be sodium methylate, sodium ethylate , potassium tert-butoxide, sodium tert-butoxide, etc.
  • C 1-6 alkyl groups are selected from C 1-3 alkyl groups, such as methyl, ethyl, propyl, isopropyl, etc.
  • C 1-6 alkoxy groups are selected from C 1-3 3 alkoxy groups, such as methoxy, ethoxy, propoxy, isopropoxy and the like.
  • R 1 and R 9 are each independently selected from one of H, methyl, ethyl, ethoxy, benzyloxy, and chlorine;
  • R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 are each independently selected from one of H, methyl, ethyl, and -COOMe;
  • R 6 and R 14 are each independently selected from H, methyl or ethyl
  • R 7 and R 8 are each independently selected from H, methyl or ethyl.
  • R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13 are all selected from H;
  • R 2 , R 3 , R 12 , R 13 are all selected from H, and R 4 , R 5 , R 10 , R 11 are all selected from methyl or ethyl;
  • R 2 , R 3 , R 12 , R 13 are all selected from methyl, and R 4 , R 5 , R 10 , R 11 are all selected from H;
  • R 2 , R 3 , R 12 and R 13 are all selected from H, R 4 and R 5 are respectively selected from H and -COOMe, R 10 and R 11 are respectively selected from H and -COOMe.
  • both R 7 and R 8 are selected from H or methyl
  • R 7 is selected from methyl, R 8 is selected from H;
  • R 7 is selected from ethyl
  • R 8 is selected from methyl
  • both R 1 and R 9 are selected from one of H, methyl, ethyl, ethoxy, benzyloxy, and chlorine;
  • both R 6 and R 14 are selected from H, methyl or ethyl.
  • both R 1 and R 9 are located at the position numbered 5 of the indole ring atom where they are located.
  • the nitrogen-containing polycyclic aromatic compounds of the present application can be compounds numbered 1-22:
  • the small molecular compound with the structure of formula I exhibited excellent broad-spectrum anti-tumor activity, especially for cervical cancer cells HELA, breast cancer cells MCF-7, MDA-MB-231, melanoma cells A375, Lung cancer cell A549 and bone marrow cancer cell SP2/0 all showed an inhibitory rate comparable to cisplatin, and it can be seen from its toxicity test on 293T normal cells and acute toxicity test in mice that the small molecular compound with the structure of formula I The toxicity of cisplatin is much lower than that of cisplatin. Therefore, the compound represented by formula 1 can be used as a lead compound for the research of novel low-toxicity and high-efficiency broad-spectrum antitumor drugs.
  • the present application also provides the preparation method of the aforementioned nitrogen-containing polycyclic aromatic compound, comprising the following steps:
  • the reactants in the above process can be purchased commercially, or can be obtained by self-synthesis by known means, such as referring to Journal of Medicinal Chemistry (2010), 53(14), 5155-5164, CN104529865B and other documents.
  • the appropriate excess of the reactant formula 3 compound can be controlled.
  • the molar ratio of the formula 1 compound, the formula 2 compound and the formula 3 compound can be controlled. 1:1: (1 ⁇ 1.4).
  • the preparation process takes the reactant formula 1 compound and the formula 2 compound to participate in the reaction as much as possible to generate the target product as the end point. According to the situation of the reactant and the corresponding reaction conditions, it can basically be determined by proper exploration or by means of conventional means. The specific operation Among them, for example, by means of TLC, HPLC, NMR, etc., it can be judged that the reaction is completed if the reaction raw material compound of formula 1 and the compound of formula 2 in the reaction system disappear substantially.
  • the preparation conditions of the compound of formula I are relatively mild, and the product can be obtained by carrying out the above reaction at a temperature of -20-60°C.
  • chlorinated solvents can be dichloromethane, chloroform, etc.
  • the alcoholic solvent can be methanol, ethanol, etc.
  • the etheric solvent can be tetrahydrofuran.
  • the inventors found that when the solvent is selected from dichloromethane, the compound represented by formula I can be prepared by the reaction with a higher yield.
  • the reaction process is completed under the action of an acid catalyst, and the selection of the specific acid catalyst and reaction conditions is a routine method for those in the industry who have basic knowledge of the synthesis of relevant organic compounds.
  • the acid catalyst can be selected from acid catalysts commonly used in PS reactions, including but not limited to trifluoroacetic acid, glacial acetic acid, hydrochloric acid, p-toluenesulfonic acid, and the like.
  • the present application also provides a pharmaceutical composition, which comprises the above-mentioned nitrogen-containing polycyclic aromatic compound.
  • the pharmaceutical composition of the present application refers to the compound represented by formula 1 as the active ingredient, plus pharmaceutically acceptable pharmaceutical excipients or carriers.
  • the pharmaceutical composition of the present application can be prepared into various formulations, such as oral formulations, injection formulations, suppositories, etc., by conventional methods in the art.
  • Preparations suitable for oral administration include solid preparations, solutions, suspensions or emulsions, etc., and solid preparations may specifically be tablets, granules, capsules, powders, etc.
  • excipients those conventionally used in the pharmaceutical field can be used.
  • examples of usable pharmaceutical excipients include excipients (e.g. carbohydrate derivatives such as lactose, sucrose, dextrose, mannitol and sorbitol; starch derivatives such as corn starch, potato starch, dextrin and carboxymethyl starch; cellulose Derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium; gum arabic; dextran; silicate derivatives such as magnesium aluminum metasilicate; Phosphate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.), binders (such as gelatin, polyvinylpyrrolidone and polyethylene glycol), disintegrants (such as cellulose derivatives such as carboxymethylcellulose sodium, polyvinylpyrrolidone), lubricants (e.g.
  • talc calcium stearate, magnesium stearate, spermaceti, boric acid, sodium benzoate, leucine), stabilizers (methylparaben, paraben Propyl esters, etc.), flavoring agents (such as commonly used sweeteners, sour agents, and spices, etc.), diluents, and solvents for injections (such as water, ethanol, and glycerin, etc.).
  • the nitrogen-containing polycyclic aromatic compounds provided by the application have excellent broad-spectrum anti-tumor activity, therefore, the application also provides the above-mentioned nitrogen-containing polycyclic aromatic compounds and their pharmaceutically acceptable salts as active ingredients in the preparation Use in antineoplastic drugs.
  • the present application also provides a method for preventing and/or treating tumors, the method comprising: administering to the patient a drug containing the aforementioned nitrogen-containing polycyclic aromatic compounds and pharmaceutically acceptable salts thereof as active components .
  • Treatment in this application refers to reversing, alleviating one or more symptoms of the above-mentioned diseases or patients suffering from the above-mentioned diseases, inhibiting the progress of the above-mentioned diseases or one or more symptoms of patients suffering from the above-mentioned diseases, or preventing the above-mentioned diseases or diseases One or more symptoms of the patient.
  • the patients described in this application include all members of the animal kingdom, including but not limited to mammals and humans, and the mammals can be mice, rats, cats, monkeys, dogs, horses, pigs, etc.
  • the patient of the present application is a human.
  • the dosage can be based on the route of administration, the patient's age, body weight, condition or the type of disease to be treated and vary in severity.
  • the nitrogen-containing polycyclic compound provided by this application is a small molecular compound with novel structure, which exhibits excellent broad-spectrum anti-tumor activity, especially for cervical cancer cells HELA, breast cancer cells MCF-7 and MDA-MB-231 , melanoma cell A375, lung cancer cell A549, and bone marrow cancer cell SP2/0 all showed inhibition rates comparable to cisplatin. And it can be seen from the toxicity test on 293T normal cells and the acute toxicity test on mice that the toxicity of the small molecular compound with the structure of formula I is much lower than that of cisplatin. Therefore, the compound represented by formula I can be used as a lead compound for the research of novel low-toxicity and high-efficiency broad-spectrum antitumor drugs.
  • CCK-8 method was used to determine the inhibitory rate of drugs on A375, A549, MDA-MB-231, SP2/0 and cells
  • the experimental drug was compound 14 synthesized by the aforementioned method, and the positive control drug was cisplatin.
  • CCK8 kit was purchased from TargetMol China; Annexin V-FITC/PI double staining cell apoptosis detection kit was purchased from seven biotech company.
  • the multifunctional microplate reader FLUOstar Omega was purchased from BMG LABTECH, Germany;
  • Flow cytometer Flow Cytometer was purchased from BD Company, USA.
  • the drug is prepared by preparing cisplatin and compound 14 respectively into mother solutions, which are sequentially added to tumor cell lines in good logarithmic growth phase from low to high (0.5 ⁇ M to 100 ⁇ M), and the cell survival rate is detected by the CCK-8 method. See Table 1 for the IC 50 values of 14 and cisplatin on A375, A549, MDA-MB-231, and SP2/0 four tumor cells.
  • the drug to be tested used in the determination of human normal cell line 293T is compound 1 to compound 22 of the present application.
  • the experimental results showed that the inhibitory IC 50 value of cisplatin on 293T normal cells was 17.29, while the inhibitory IC 50 values of the experimental drugs Compound 1-Compound 22 of the present application on 293T normal cells were all greater than 40 ⁇ M. The inhibitory IC 50 value can reach 133.63 ⁇ M. It can be seen that the cytotoxicity of the compound of the present application to normal cell 293T is far less than that of cisplatin.
  • test drug used to measure the inhibition rate of cancer cell HELA is compound 15 and compound 20 of the present application
  • test drug used to measure the inhibition rate of cancer cell MCF-7 is compound 15 of the present application. See Table 2 for the data of the inhibitory IC 50 values of the above-mentioned drugs to be tested and cisplatin on HELA and MCF-7 tumor cells.
  • the inhibitory activity of the compounds of the present application to HELA and MCF-7 is slightly worse than that of cisplatin, but the inhibitory IC50 value of the two to HELA and MCF-7 is on an order of magnitude, and the activity Little difference.
  • Binding Buffer Add 100 ⁇ L of Binding Buffer to resuspend the cells, except for the single-stained control and blank control, add 5 ⁇ L of FITC and 5 ⁇ L of PI to each tube, mix gently, and incubate at room temperature in the dark for 15 minutes, add 400 ⁇ L of Binding Buffer to each well before testing on the machine, and mix well On-board testing.
  • Blank control drug-induced apoptotic cells—without adding fluorescent reagents (adjust the scattered light voltage to determine the FSC SSC of the population).
  • Negative control normal cells (without drug treatment) plus all the fluorescent staining reagents of the experiment (at the lower left corner, determine the voltage of the two fluorescent channels).
  • mice Take 12 KM mice weighing 18-22g, aged 4-6 weeks, and feed them adaptively for 7 days. All animals and mice can eat freely and have sufficient fresh drinking water.
  • the feeding environment conforms to the SPF experimental animal-grade environment Facilities standard.
  • the KM mice were randomly divided into 6 groups, and the solution (vehicle DMSO) was injected intraperitoneally respectively, with an injection volume of 20mL/kg, wherein the first group to the fourth group were injected with the solution of compound 14, and the dosage was 20, 40, 60, 80mg/kg, the fifth group is a positive control group injected with cisplatin solution, the cisplatin dose (calculated with cisplatin as the active ingredient dose) is 20mg/kg, the sixth group is a negative control group, only injected vehicle. The behavioral changes and death within 14 days after administration of the animals were observed.
  • the animals in the experimental group injected with 20mg/kg compound 14 have no abnormalities, and the weight gain of the animals is not significantly different from that of the normal control group; Reduced fur erection, listlessness, and 1 animal died on the 6th day; in the experimental group injected with 40mg/kg compound 14, the weight gain of the animals slowed down after administration compared with the negative control group, and the behavior and spirit of the animals were normal. No death was seen during this period; in the experimental group injected with 60 mg/kg compound 14, one animal died on the 6th day, and in the experimental group injected with 80 mg/kg compound 14, 2 animals died on the second day after administration. Therefore, it can be inferred that the lethal dose of compound 14 is about 60 mg/kg, and the lethal dose of cisplatin is about 20 mg/kg.

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Abstract

一种含氮多环类芳香化合物及其制备方法和应用。含氮多环类芳香化合物具有式I的结构，该化合物具有优异的广谱抗肿瘤活性，对宫颈癌细胞、乳腺癌细胞、黑色素瘤细胞、肺癌细胞、骨髓癌细胞均表现出与顺铂相当的抑制活性，且相比于顺铂具有更低的毒性，可作为先导化合物用于抗肿瘤的开发。

Description

一种含氮多环类芳香化合物及其制备方法和应用
本申请要求于2021年6月28日提交中国专利局、申请号为202110721322.5、申请名称为“一种含氮多环类芳香化合物及其制备方法和应用”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本申请涉及医药领域，尤其涉及一种含氮多环类芳香化合物及其制备方法和应用。
背景技术
恶性肿瘤是细胞恶性变化导致局部组织发生异常增生，在结构、功能及代谢方面存在的异常。目前治疗恶性肿瘤的方法主要是手术治疗、放/化治疗。至少基于现阶段的认知，适于手术治疗和放/化治疗的肿瘤疾病和病患受到很多因素的限制，特别是对肿瘤晚期病患尚无有效的治疗和缓解手段，所以筛选和开发新的或潜在的治疗用药一直是努力的目标。
以顺铂为例，顺铂是一种细胞非特异性药物，研究显示，顺铂能够与DNA结合，引起交叉联结，从而破坏DNA的功能，并抑制细胞DNA复制。临床应用中，顺铂抗瘤谱较广，被用于头颈部鳞癌、卵巢癌、胚胞性癌、精原性细胞瘤、肺癌、甲状腺癌、淋巴肉瘤及网状细胞肉瘤等，大数据统计表现良好的肿瘤治疗效果，是目前临床治疗上被认为最有效的广谱抗肿瘤药物之一，但其临床也表现出严重毒副作用。例如，顺铂可通过氧化应激、DNA损伤及炎症反应等机制导致肾小管细胞死亡，肾组织损伤，从而使肾小球滤过率下降，肾脏排泄显著减少，导致其在肾脏中大量蓄积，引起严重的肾脏衰竭。顺铂也会损伤耳蜗毛细胞，造成听力丧失，导致耳聋或耳鸣。另一方面，在用药物的耐药性问题，一直是需要面对和解决的课题，相应的升级药和替代药开发，无论对于药物研发者还是病患，始终满怀期待。
因此，开发新的广谱抗肿瘤药物具有重要的意义。
发明内容
本申请提供一种含氮多环类芳香化合物及其制备方法和应用。本申请提供的含氮多环类芳香化合物具有优异的广谱抗肿瘤活性，且表现出较低的毒性，可作为先导化合物用于新型抗肿瘤的开发。
本申请提供一种含氮多环类芳香化合物及其药学上可接受的盐，该化合物具有式I所示的结构：
Figure PCTCN2022101788-appb-000001
其中，R 1、R 9各自独立地选自H、C 1～6的烷基、C 1～6的烷氧基、苄氧基、卤素；
R 2、R 3、R 4、R 5、R 10、R 11、R 12、R 13各自独立地选自H、C 1～6的烷基、-COOR x；R x选自C 1～6烷基；
R 6、R 14各自独立地选自H或C 1～6的烷基；
R 7、R 8各自独立地选自H或C 1～6的烷基。
本申请中，C 1～6的烷基指的是碳原子个数为1～6个的直链烷基或支链烷基，例如可以是甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基等；C 1～6的烷基指的是碳原子个数为1～6个的直链烷基或支链烷基，例如可以是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、正戊氧基、异戊氧基、新戊氧基、正己氧基等。
根据本申请的含氮多环类芳香化合物，其中，药学上可接受的盐指的是由适宜的非毒性有机酸、无机酸、有机碱或无机碱与化合物形成的盐，其保留有化合物的生物活性。该药用盐的具体产物可以按照药物研究和制备领域的公知性知识，经常规手段摸索而确定。示例性地：
有机酸可选自制药领域通常使用的能够成盐的有机酸，如甲酸、乙酸、丙酸、三氟乙酸、草酸、苯甲酸、对甲苯磺酸、马来酸、富马酸、柠檬酸、酒石酸、苹果酸、乳酸、水杨酸等。
无机酸可选自制药领域通常使用的能够成盐的无机酸，如盐酸、硫酸、磷酸等。
有机碱可选自制药领域通常使用的能够成盐的有机碱，如吡啶、咪唑、吡嗪、吲哚、嘌呤、苯胺等。
无机碱可选自制药领域通常使用的能够成盐的无机碱，例如碱金属氢化物、碱金属的氢氧化合物、碱金属的烷氧化物、碳酸钾、碳酸钠、碳酸锂、碳酸氢钾、碳酸氢钠等。其中，碱金属氢化物可以是氢化钠和/或氢化钾，碱金属的氢氧化物可以是氢氧化钠、氢氧化钾、氢氧化锂等，碱金属的烷氧化物可以是甲醇钠、乙醇钠、叔丁醇钾、叔丁醇钠等。
进一步的，C 1～6的烷基选自为C 1～3的烷基，例如，甲基、乙基、丙基、异丙基等；C 1～6的烷氧基选自C 1～3的烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基等。
在一种具体的实施方式中，R 1、R 9各自独立地选自H、甲基、乙基、乙氧基、苄氧基、氯中的一种；
和/或，R 2、R 3、R 4、R 5、R 10、R 11、R 12、R 13各自独立地选自H、甲基、乙基、-COOMe中的一种；
和/或，R 6、R 14各自独立地选自H、甲基或乙基；
和/或，R 7、R 8各自独立地选自H、甲基或乙基。
在一种具体的实施方式中，R 2、R 3、R 4、R 5、R 10、R 11、R 12、R 13均选自H；
或，R 2、R 3、R 12、R 13均选自H，R 4、R 5、R 10、R 11均选自甲基或乙基；
或，R 2、R 3、R 12、R 13均选自甲基，R 4、R 5、R 10、R 11均选自H；
或，R 2、R 3、R 12、R 13均选自H，R 4、R 5分别选自H和-COOMe，R 10、R 11分别选自H和-COOMe。
在一种具体的实施方式中，R 7、R 8均选自H或甲基；
或，R 7选自甲基、R 8选自H；
或，R 7选自乙基、R 8选自甲基。
在一种具体的实施方式中，R 1、R 9均选自H、甲基、乙基、乙氧基、苄氧基、氯中的一种；
和/或，R 6、R 14均选自H、甲基或乙基。
在有机化学领域的公知常识中，吲哚环的原子编号如下：
Figure PCTCN2022101788-appb-000002
优选地，R 1、R 9均位于其所在的吲哚环原子标号为5的位置。
作为非限定性实例，本申请的含氮多环类芳香化合物可以为编号为1～22的化合物：
Figure PCTCN2022101788-appb-000003
Figure PCTCN2022101788-appb-000004
Figure PCTCN2022101788-appb-000005
发明人研究发现，具有式I结构的小分子化合物，表现出优异的广谱抗肿瘤活性，尤其是对宫颈癌细胞HELA，乳腺癌细胞MCF-7、MDA-MB-231，黑色素瘤细胞A375，肺癌细胞A549，骨髓癌细胞SP2/0均表现出与顺铂相当的抑制率，且从其对293T正常细胞的毒性实验、以及小鼠急性毒性实验中可看出，式I结构的小分子化合物的毒性远低于顺铂的毒性。因此，式1所示的化合物可作为先导化合物用于新型低毒高效的广谱抗肿瘤药物的研究。
本申请还提供前述含氮多环类芳香化合物的制备方法，包括如下步骤：
Figure PCTCN2022101788-appb-000006
使式1化合物、式2化合物与式3化合物在酸催化剂作用下进行反应，得到式I所示的化合物。
上述过程的反应物均可商购，或通过公知的手段，如参考Journal of Medicinal Chemistry(2010),53(14),5155-5164、CN104529865B等文献自行合成得到。
在具体的反应过程中，为确保反应进行到底而得到目标产物，可控制反应物式3化合物适当过量，综合考量下，例如可控制式1化合物、式2化合物与式3化合物的摩尔比基本为1：1：(1～1.4)。
该制备过程以反应物式1化合物和式2化合物尽可能全部参与反应而生成目标产物作为终点，根据反应物的情况以及相应的反应条件，通过适当摸索或借助常规手段基本就能够确定，具体操作中，例如借助TLC、HPLC、NMR等，显示反应体系中的反应原料式1化合物和式2化合物基本消失可判定反应完成。
式I化合物的制备条件较为温和，使上述反应在-20～60℃温度下进行反应即可得到产物。
上述反应在溶剂体系中，氯代溶剂、醇类溶剂、醚类溶剂均可使反应顺利进行。示例行的，氯代溶剂可以是二氯甲烷、三氯甲烷等，醇类溶剂可以是甲醇、乙醇等，醚类溶剂可以是四氢呋喃。
发明人在对溶剂进行筛选后发现，当溶剂选自二氯甲烷时，能够使反应以较高的产率制备得到式I所示的化合物。
如前述的制备方法，反应过程在酸催化剂作用下完成，具体的酸催化剂以及反应条件选择，对于具备相关有机化合物合成基础知识的业内人士，均属于常规手段。
例如，酸催化剂可选自PS反应中常规使用的酸催化剂，包括但不限于三氟乙酸、冰醋酸、盐酸、对甲苯磺酸等。
本申请还提供一种药物组合物，该药物组合物包括如上所述的含氮多环类芳香化合物。本申请的药物组合物是指以式1所示的化合物为活性成分，再加以药学上可接受的药用辅料或载体。
本申请的药物组合物可以通过本领域的常规方法制备成各种制剂型式，例如口服制剂、注射制剂、栓剂等。适合于口服的制剂包括固体制剂、溶液剂、混悬剂或乳剂等，固体制剂具体可以是片剂、颗粒剂、胶囊剂、散剂等。栓剂例如适用于肠胃外施用的药物制剂注射制剂例如可以是肌肉注射剂或静脉滴注制剂等，根据需要也可以制成粉针或冻干粉针。
药物辅料可使用在制药领域中常规使用的物质。可用的药物辅料的例子包括赋形剂(例如糖类衍生物诸如乳糖、蔗糖、葡萄糖、甘露糖醇和山梨糖醇；淀粉衍生物诸如玉米淀粉、土豆淀粉、糊精和羧甲基淀粉；纤维素衍生物如结晶纤维素、羟丙基纤维素、羧甲基纤维素、羧甲基纤维素钙、羧甲基纤维素钠；阿拉伯胶；右旋糖酐；硅酸盐衍生物如偏硅酸镁铝；磷酸盐衍生物如碳酸钙；硫酸盐衍生物如硫酸钙等)、粘合剂(例如明胶、聚乙烯吡咯烷酮和聚乙二醇)、崩解剂(例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮)、润滑剂(例如滑石、硬脂酸钙、硬脂酸镁、鲸蜡、硼酸、苯甲酸钠、亮氨酸)、稳定剂(对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等)、矫味剂(例如常用的甜味剂、酸味剂和香料等)、稀释剂和注射液用溶剂(例如水、乙醇和甘油等)。
如前述，本申请提供的含氮多环类芳香化合物具有优异的广谱抗肿瘤活性，因此，本申请还提供如上所述的含氮多环类芳香化合物及其药用盐作为活性成分在制备抗肿瘤药物中的用途。
药效学研究显示，式I所示的化合物及其药用盐对宫颈癌细胞、乳腺癌细胞、黑色素瘤细胞、肺癌细胞、骨髓癌细胞均表现出与顺铂相当的抑制活性。
本申请还提供一种预防和/或治疗肿瘤的方法，所述方法包括：给患者施用以如前所述的含氮多环类芳香化合物及其药学上可接受的盐为活性组分的药物。
本申请中治疗指的是逆转、减轻上述病症或者患有上述疾病的患者的一个或多个症状，抑制上述疾病或者患有上述疾病的患者的一个或多个症状的进展或者 防止上述疾病或者疾病患者的一个或多个症状。
本申请所述的患者包括动物界的所有成员，包括但不限于哺乳动物和人，哺乳动物可以是小鼠、大鼠、猫、猴子、狗、马、猪等。优选地，本申请的患者是人。
本申请的式1所示的化合物及其可药用盐在用于预防和/或治疗肿瘤时，其给药剂量可根据给药途径、患者的年龄、体重、状况或者待治疗疾病的类型以及严重性而变化。
通过药效学实验可以预期到，采用本申请的含氮多环类芳香化合物及其药学上可接受的盐为活性组分的药物对宫颈癌、乳腺癌、黑色素瘤、肺癌、骨髓癌等恶性肿瘤都具有良好的药效。
本申请至少具有以下有益效果：
本申请提供的含氮多环类化合物是一种结构新颖的小分子化合物，表现出优异的广谱抗肿瘤活性，尤其是对宫颈癌细胞HELA，乳腺癌细胞MCF-7及MDA-MB-231，黑色素瘤细胞A375，肺癌细胞A549，骨髓癌细胞SP2/0均表现出与顺铂相当的抑制率。且从其对293T正常细胞的毒性实验、以及小鼠急性毒性实验中可看出，式I结构的小分子化合物的毒性远低于顺铂的毒性。因此，式I所示的化合物可作为先导化合物用于新型低毒高效的广谱抗肿瘤药物的研究。
具体实施方式
下文将结合具体实施例对本申请做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本申请，而不应被解释为对本申请保护范围的限制。凡基于本申请上述内容所实现的技术均涵盖在本申请旨在保护的范围内。
化合物1的合成
Figure PCTCN2022101788-appb-000007
合成步骤包括：将色胺(化合物a)(1mmol)溶于二氯甲烷中，并加入乙二醛(化合物b)(0.55mmol，0.55equiv.)、
Figure PCTCN2022101788-appb-000008
分子筛和三氟乙酸(5-10％mol)，在-5～5℃下反应，待TLC检测到色胺基本消失后，反应结束，过滤除去
Figure PCTCN2022101788-appb-000009
分子筛，浓缩滤液，对浓缩后的滤液进行柱层析分离(二氯甲烷：甲醇＝(30～50):1)，得到化合物1(102mg，收率为60％)。
化合物1的表征如下：
1H NMR(600MHz,CDCl3)δ10.08(s,1H),7.22(t,J＝8.0Hz,3H),7.07(d,J＝7.4Hz,1H),7.03(dd,J＝14.8,7.4Hz,3H),6.92(t,J＝7.4Hz,1H),6.73(t,J＝7.4Hz,1H),6.53(d,J＝7.8Hz,1H),5.03(s,1H),4.19(s,1H),4.12(d,J＝3.7Hz,1H),3.22(d,J＝4.8Hz,1H),3.09(dd,J＝18.1,7.4Hz,1H),3.02–2.96(m,1H),2.90(d,J＝7.3Hz,2H),2.70(d,J＝10.8Hz,1H),2.48(s,1H),2.16(dt,J＝13.7,6.7Hz,1H).
13C NMR(151MHz,CDCl3)δ150.89,136.82,129.77,129.14,127.04,123.44,121.94,119.72,119.53,118.13,111.88,111.29,109.65,87.86,71.42,63.56,57.32,48.17,43.50,38.92,21.71.
HRMS-ESI m/z calcd for C 22H 22N 4[M+H] +343.1923,found 343.1920.
参考化合物1的合成步骤制备得到化合物2～化合物22。
Figure PCTCN2022101788-appb-000010
化合物2的表征如下：
1H NMR(600MHz,CDCl 3)δ7.46(d,J＝8.1Hz,1H),7.23(m,2H),7.19(m,2H),7.10–7.04(m,1H),6.80(t,J＝7.3Hz,1H),6.49(d,J＝7.9Hz,1H),4.72(s,1H),4.31(d,J＝6.8Hz,1H),3.70(m,3H),3.54(m,1H),3.24(s,1H),3.21–3.15(m,1H),3.06–3.01(m,1H),2.96(s,3H),2.83(m,1H),2.62–2.55(m,1H),2.23(m,1H),1.76–1.67(m,1H),1.62–1.56(m,1H),1.48–1.41(m,1H).
13C NMR(151MHz,CDCl 3)δ147.01,137.64,137.55,132.32,127.13,126.66,122.55,120.49,118.87,118.22,118.02,109.47,108.97,106.76,96.29,65.58,62.00,58.86,48.54,44.94,37.10,36.64,29.37,22.70.
HRMS-ESI m/z calcd for C 24H 26N 4[M+H] +371.2236,found 371.2230.
Figure PCTCN2022101788-appb-000011
化合物3的表征如下：
1H NMR(600MHz,CDCl 3)δ7.49(d,J＝8.4Hz,1H),7.29(d,J＝8.0Hz,1H),7.24(d,J＝7.2Hz,1H),7.20–7.15(m,2H),7.10–7.07(m,1H),6.77(t,J＝7.3Hz,1H),6.49(d,J＝7.8Hz,1H),4.89(s,1H),4.31(m,1H),3.53–3.49(m,1H),3.40–3.36(m,1H),3.33–3.27(m,2H),3.03(m,2H),2.84(m,1H),2.64–2.58(m,1H),2.31(s,2H),2.20–2.15(m,2H),1.64–1.58(m,2H),1.30(d,J＝7.1Hz,3H),1.20(dd,J＝ 7.1,3.5Hz,3H).
13C NMR(151MHz,CDCl 3)δ136.28,132.60,132.46,128.25,122.56,118.97,118.24,116.82,109.37,106.30,97.13,68.31,65.73,44.87,43.14,39.15,29.67,22.87,15.50,12.42.
HRMS-ESI m/z calcd for C 26H 30N 4[M+H] +399.2549,found 399.2547.
Figure PCTCN2022101788-appb-000012
化合物4的表征如下：
1H NMR(400MHz,CDCl 3)δ10.00(s,1H),7.19(d,J＝8.7Hz,1H),6.89(m,1H),6.78(m,2H),6.72(m,1H),6.58(d,J＝8.5Hz,1H),5.14(s,1H),4.31(s,2H),3.83(s,3H),3.77(s,3H),3.28(m,1H),3.18(m,1H),3.00(m,3H),2.77(m,1H),2.64(m,1H),2.33(m,1H).
13C NMR(150MHz,CDCl 3)δ154.19,151.50,144.79,135.69,135.36,131.07,128.99,114.41,112.82,112.79,112.21,109.63,109.61,100.48,88.43,70.14,63.83,57.23,55.89,48.73,41.05,37.34,22.05.
HRMS-ESI m/z calcd for C 24H 26N 4O 2[M+H] +403.2134,found 403.2129.
Figure PCTCN2022101788-appb-000013
1H NMR(600MHz,CDCl 3)δ7.15(d,J＝8.8Hz,1H),6.93(d,J＝2.3Hz,1H),6.84(m,2H),6.73(dd,J＝8.4,2.5Hz,1H),6.42(d,J＝8.5Hz,1H),4.60(s,1H),3.85(s,3H),3.79(s,3H),3.67(s,3H),3.50(m,1H),3.26(m,1H),3.13(m,1H),3.02(m,1H),2.95(m,1H),2.93(s,3H),2.77(m,1H),2.53(m,1H),2.11(m,1H),1.45(m,2H).
13C NMR(151MHz,CDCl 3)δ153.88,153.39,147.72,137.89,132.98,129.92,126.79,116.27,113.71,111.38,110.44,109.84,107.91,100.35,87.70,72.43,62.93,58.56,56.03,49.03,44.55,37.93,22.96.
HRMS-ESI m/z calcd for C 26H 30N 4O 2[M+H] +431.2447,found 431.2440.
Figure PCTCN2022101788-appb-000014
化合物6的表征如下：
1H NMR(600MHz,CDCl 3)δ9.42(s,1H),7.22(s,1H),7.14(d,J＝8.2Hz,1H),6.95(s,1H),6.90(t,J＝8.1Hz,2H),6.52(d,J＝7.9Hz,1H),5.00(s,1H),4.24(d,J＝3.7Hz,1H),4.01(d,J＝4.5Hz,1H),3.26(m,1H),3.06–2.90(m,4H),2.73(m,1H),2.42(s,3H),2.38(m,1H),2.29(s,3H),2.12–2.07(m,1H).
13C NMR(151MHz,CDCl 3)δ148.54,135.20,130.20,129.52,129.25,128.71,127.39,124.07,123.52,117.93,111.56,110.91,109.70,88.13,71.60,63.77,57.61,48.47,43.63,39.18,29.84,21.70,21.61,20.95.
HRMS-ESI m/z calcd for C 24H 26N 4[M+H] +371.2236,found 371.2230.
Figure PCTCN2022101788-appb-000015
化合物7的表征如下：
1H NMR(600MHz,CDCl 3)δ7.14(d,J＝8.8Hz,1H),6.91(d,J＝2.1Hz,2H),6.86(m,1H),6.78(m,1H),6.45(d,J＝8.5Hz,1H),4.67(s,1H),4.34(s,1H),3.84(s,3H),3.80(s,3H),3.69(s,3H),3.51(d,1H),3.02(m,1H),2.92(s,3H),2.79(m,1H),2.31(m,2H).
13C NMR(151MHz,CDCl 3)δ153.27,135.67,130.05,128.86,128.70,128.09,126.83,126.63,123.40,118.59,118.38,109.36,109.16,100.15,91.68,66.86,63.93,58.33,43.97,43.65,43.08,39.78,38.25,32.60,21.61,20.88.
HRMS-ESI m/z calcd for C 26H 30N 4[M+H] +399.2549,found 399.2541.
Figure PCTCN2022101788-appb-000016
化合物8的表征如下：
1H NMR(600MHz,CDCl 3)δ7.42(m,1H),7.25(d,J＝7.4Hz,1H),7.17(s,1H),7.10(t,J＝7.6Hz,1H),7.02(m,2H),6.80(t,J＝7.4Hz,1H),6.61(d,J＝7.8Hz,1H),4.51(s,1H),4.32(d,J＝3.6Hz,1H),3.97(m,1H),2.82(d,J＝14.7Hz,1H),2.64(d, J＝14.7Hz,1H),2.50(d,J＝14.0Hz,1H),2.04(d,J＝14.0Hz,1H),1.54(s,3H),1.53(s,3H),1.26(s,3H)1.25(s,3H).
13C NMR(151MHz,CDCl 3)δ151.04,137.31,130.16,128.88,127.16,123.86,121.87,119.35,119.17,117.85,111.91,111.35,109.38,87.10,72.75,64.50,64.34,55.90,52.58,38.22,29.83,29.21,28.42,27.29,22.08.
HRMS-ESI m/z calcd for C 26H 30N 4[M+H] +399.2549,found 399.2543.
Figure PCTCN2022101788-appb-000017
化合物9的表征如下：
1H NMR(600MHz,CDCl 3)δ7.64(d,J＝7.9Hz,1H),7.32(d,J＝7.8Hz,1H),7.29(d,J＝7.8Hz,1H),7.12(m,2H),7.05(t,J＝7.2Hz,1H),6.76(t,J＝7.4Hz,1H),6.63(d,J＝7.8Hz,1H),5.21(s,1H),4.44(s,1H),4.10(d,J＝2.8Hz,1H),3.06(m,3H),2.84(m,2H),1.47(s,3H×2),1.26(s,3H×2).
13C NMR(151MHz,CDCl 3)δ151.56,137.54,129.82,128.51,126.91,126.02,124.01,122.25,120.14,119.46),119.28,118.51,112.59,109.91,80.52,71.00,69.09,57.73,51.73,51.19,50.96,40.89,34.86,30.34,24.70,23.40.
MS-ESI m/z calcd for C 26H 30N 4[M+Na] +399.2549,found 399.2543.
Figure PCTCN2022101788-appb-000018
化合物10的表征如下：
1H NMR(600MHz,CDCl 3)δ10.07(s,1H),7.57(d,J＝8.0Hz,1H),7.36(dd,J＝7.7,4.3Hz,2H),7.13(dd,J＝14.2,7.0Hz,2H),7.03(t,J＝7.5Hz,1H),6.78(t,J＝7.4Hz,1H),6.64(d,J＝7.7Hz,1H),4.83(s,1H),4.09(s,1H),2.97(d,J＝11.6Hz,1H),2.85(d,J＝11.6Hz,2H),2.28(m,1H),2.03(m,1H),1.94(m,2H),1.85(m,2H),1.73(m,3H),1.50(m,1H),1.00(t,J＝7.1Hz,3H),0.91(t,J＝7.5Hz,3H),0.69(t,J＝7.4Hz,3H),0.56(t,J＝7.5Hz,3H).
13C NMR(151MHz,CDCl 3)δ151.56,137.54,129.82,128.51,126.91,126.02,124.01,122.25,120.14,119.46,119.28,118.51,112.59,109.91,80.52,71.00,69.09,57.73,51.19,50.96,40.89,34.86,30.34,24.70,23.40,10.42,9.03, 8.24,7.78.
HRMS-ESI m/z calcd for C 30H 38N 4[M+H] +455.3175,found 455.3169.
Figure PCTCN2022101788-appb-000019
化合物11的表征如下：
1H NMR(600MHz,CDCl 3)δ7.68(d,J＝8.0Hz,1H),7.32(d,J＝7.4Hz,1H),7.25(s,1H),7.19(m,3H),7.07(t,J＝7.4Hz,1H),6.73(t,J＝7.4Hz,1H),6.49(d,J＝7.9Hz,1H),4.76(s,1H),4.32(d,J＝2.0Hz,1H),4.11(d,J＝2.9Hz,1H),3.69(s,3H),3.10(d,J＝9.8Hz,1H),3.06–3.01(m,3H),3.00(s,3H),2.83(d,J＝11.0Hz,1H),1.52(s,3H×2),1.47(s,3H×2).
13C NMR(151MHz,CDCl 3)δ154.35,137.76,129.29,126.48,125.20,121.55,120.36,120.03,119.02,117.45,109.56,107.01,89.30,70.10,60.96,59.35,58.91,44.40,36.01,34.23,30.89,29.59),27.03,26.02,22.31.
HRMS-ESI m/z calcd for C 28H 34N 4[M+H] +427.2862,found 427.2859.
Figure PCTCN2022101788-appb-000020
化合物12的表征如下：
1H NMR(600MHz,CDCl 3)δ9.31(s,1H),7.46(d,J＝7.8Hz,1H),7.35(d,J＝8.0Hz,1H),7.14–7.05(m,4H),6.78(t,J＝7.5Hz,1H),6.62(d,J＝7.8Hz,1H),5.01(s,1H),3.48(s,1H),3.34–3.28(m,2H),3.12(m,1H),3.01–2.94(m,1H),2.69(d,J＝7.8Hz,1H),2.64(m,1H),2.14(m,1H),2.04(m,1H),1.52(s,3H),1.28(s,3H).
13C NMR(151MHz,CDCl 3)δ150.36,136.73,128.65,127.05,125.10,121.81,119.26,118.94,118.18,111.67,110.35,85.89,65.75,65.60,45.16,40.51,39.33,29.69,22.38,19.52.
HRMS-ESI m/z calcd for C 24H 26N 4[M+H] +371.2236,found 371.2230.
Figure PCTCN2022101788-appb-000021
化合物13的表征如下：
1H NMR(600MHz,CDCl 3)δ7.43(d,J＝1.7Hz,1H),7.25(s,1H),7.09(dd,J＝8.6,1.8Hz,1H),7.04(dd,J＝8.3,2.0Hz,1H),7.01(d,J＝1.8Hz,1H),6.57(d,J＝8.3Hz,1H),4.88(s,1H),3.31(m,2H),3.16(m,1H),3.00(m,1H),2.60(m,2H),2.00(m,1H),1.85(m,1H),1.39(s,3H),1.35(s,3H).
13C NMR(151MHz,CDCl 3)δ148.90,134.94,134.11,128.30,128.20,125.15,125.00,123.67,121.89,117.76,112.42,111.39,107.87,85.16,65.84,65.49,63.85,50.99,46.42,42.07,39.55,29.85,23.94,22.16,17.91.
HRMS-ESI m/z calcd for C 24H 24Cl 2N 4[M+H] +439.1456,found 439.1450.
Figure PCTCN2022101788-appb-000022
化合物14的表征如下：
1H NMR(600MHz,CDCl 3)δ9.21(s,1H),7.27(d,J＝7.2Hz,1H),6.98(s,1H),6.83(m,1H),6.70(m,2H),6.65(m,1H),4.84(s,1H),3.89(s,3H),3.79(s,3H),3.41(dd,J＝13.9,6.5Hz,1H),3.33(m,1H),3.15(m,1H),3.7(m,1H),2.65(dd,J＝15.6,5.2Hz,1H),2.51(m,1H),1.96(m,1H),1.81(m,1H),1.40(s,3H),1.35(s,3H).
13C NMR(600MHz,CDCl 3)δ153.93,144.31,140.63,135.15,131.60,127.62,112.74,112.22,111.93,111.68,111.25,107.45,100.49,84.69 76.28,66.00,65.15,56.14,46.85,42.35,39.76,24.71,23.14,17.37.
HRMS-ESI m/z calcd for C 26H 30N 4O 2[M+H] +431.2447,found 431.2476.
Figure PCTCN2022101788-appb-000023
化合物15的表征如下：
1H NMR(600MHz,CD 3OD)δ7.25(m,2H),7.08(s,1H),6.94(m,2H),6.49(d,J＝7.9Hz,1H),5.16(s,1H),3.37-3.25(m,6H),3.05-2.98(m,1H),2.72(dd,J＝14.8,3.6Hz,1H),2.58-2.49(m,1H),2.40(s,3H),2.28(s,3H),1.73(s,3H),1.22(s,3H).
13C NMR(151MHz,CD 3OD)δ150.72,136.86,136.24,130.85,129.38,129.11,128.54,128.51,126.57,124.59,118.88,112.16,111.79,110.95,88.83,79.19,67.48,67.03,45.01,40.07,39.22,23.21,21.59,20.96,19.79,17.40.
HRMS-ESI m/z calcd for C 26H 30N 4[M+H] +399.2549,found 399.2544.
Figure PCTCN2022101788-appb-000024
化合物16的表征如下：
1H NMR(600MHz,CDCl 3)δ9.44(s,1H),7.50(d,J＝7.8Hz,1H),7.38(d,J＝8.0Hz,1H),7.16(t,J＝7.2Hz,1H),7.09(m,3H),6.81(t,J＝7.3Hz,1H),6.72(d,J＝7.6Hz,1H),4.58(s,1H),4.53(s,1H),3.92(s,1H),3.38(dd,J＝14.4,6.1Hz,1H),3.24(m,1H),3.10–3.03(m,2H),2.64(dd,J＝15.9,5.3Hz,1H),2.12–2.05(m,1H),1.92–1.87(m,1H),1.66(m,1H),1.51(s,3H).
13C NMR(151MHz,CDCl 3)δ149.01,137.68,136.93,136.76,127.90,127.28,122.38,121.51,120.04,119.13,118.16,111.34,107.74,82.43,80.14,62.57,61.81,48.45,41.53,39.40,29.73,16.11.
HRMS-ESI m/z calcd for C 23H 24N 4[M+H] +357.2079,found 357.2075.
Figure PCTCN2022101788-appb-000025
化合物17的表征如下：
1H NMR(600MHz,CDCl 3+CD 3OD(～5/1))δ7.43(d,J＝7.8Hz,1H),7.38(d,J＝8.1Hz,1H),7.10(m,3H),7.03(m,1H),6.72(t,J＝7.5Hz,1H),6.56(d,J＝7.9Hz,1H),5.13(s,1H),3.45(m,1H),3.12(m,1H),2.93(m,1H),2.81(m,1H),2.54(m,1H),2.28(m,1H),1.72(s,2H),1.60(m,2H),1.19(s,3H),0.68(t,J＝7.3Hz,3H).
13C NMR(151MHz,CDCl 3+CD 3OD(～5/1))δ150.83,137.22,129.62,126.67,126.39,125.13,122.70,119.53,118.78,118.19,112.09,109.96,87.44,79.47,65.80,63.57,44.20,37.74,30.25,29.72,21.93,17.74,11.14.
HRMS-ESI m/z calcd for C 25H 28N 4[M+H] +385.2392,found 385.2387.
Figure PCTCN2022101788-appb-000026
化合物18的表征如下：
1H NMR(600MHz,CDCl 3)δ9.55(s,1H),7.43(d,J＝1.7Hz,1H),7.25(s,1H),7.09(dd,J＝8.6,1.8Hz,1H),7.04(dd,J＝8.3,2.0Hz,1H),7.01(d,J＝1.8Hz,1H),6.57(d,J＝8.3Hz,1H),4.88(s,1H),3.31(dt,J＝15.8,5.7Hz,2H),3.16(dt,J＝11.6,7.2Hz,1H),3.00(ddd,J＝16.1,10.8,7.6Hz,1H),2.64(dd,J＝15.7,3.9Hz,1H),2.60–2.56(m,1H),2.05–1.96(m,2H),1.85(dt,J＝13.5,6.9Hz,1H),1.39(s,3H),1.35(s,3H).
13C NMR(151MHz,CDCl 3)δ148.90,134.94,134.11,128.30,128.20,125.15,125.00,123.67,121.89,117.76,112.42,111.39,107.87,85.16,65.84,65.49,50.99,46.42,42.07,39.55,23.94,17.91.
HRMS-ESI m/z calcd for C 23H 22Cl 2N 4[M+H] +425.1300,found 425.1289.
Figure PCTCN2022101788-appb-000027
化合物19的表征如下：
1H NMR(600MHz,CDCl 3)δ7.28(d,J＝8.7Hz,1H),6.94(m,2H),6.80(dd,J＝8.7,2.4Hz,1H),6.68(m,2H),4.71(s,1H),4.08(s,1H),3.85(s,3H),3.77(s,3H),3.37(dd,J＝13.9,6.2Hz,1H),3.14(m,2H),3.03(m,1H),2.62(dd,J＝15.6,4.9Hz,1H),2.37(m,1H),2.00(m,2H),1.52(s,3H).
13C NMR(151MHz,CDCl 3)δ154.95,154.12,142.94,136.72,131.99,127.49,113.93,112.45,112.40,111.79,109.54,108.84,100.54,84.45,77.77,63.02,62.80,56.19,56.12,47.63,39.83,39.29,28.20,17.47.
HRMS-ESI m/z calcd for C 25H 28N 4O 2[M+H] +417.2291,found 417.2287.
Figure PCTCN2022101788-appb-000028
化合物20的表征如下：
1H NMR(600MHz,CDCl 3)δ7.25(m,2H),7.00(s,1H),6.96(d,J＝8.7Hz,1H),6.90(d,J＝7.8Hz,1H),6.60(d,J＝7.9Hz,1H),4.70(s,1H),4.02(s,1H),3.33(m,1H),3.20(m,1H),3.12(m,1H),3.00(m,1H),2.62(dd,J＝15.7,4.9Hz,1H),2.43(s,3H),2.35(m,1H),2.27(s,3H),1.99(m,1H),1.93(m,1H),1.47(s,3H).
13C NMR(151MHz,CDCl 3)δ146.95,136.60,135.12,129.62,128.90,128.57,127.40,123.58,123.34,117.98,111.35,111.18,108.39,84.23,78.27,62.73,47.82,40.43,39.36,27.86,21.59,21.05,17.66.
HRMS-ESI m/z calcd for C 25H 28N 4[M+H] +385.2392,found 385.2387.
Figure PCTCN2022101788-appb-000029
化合物21的表征如下：
1H NMR(600MHz,CDCl 3)δ9.75(s,1H),7.24(s,1H),6.91(d,J＝2.0Hz,1H),6.79(dd,J＝8.7,2.3Hz,1H),6.65(dd,J＝8.5,.3Hz,1H),6.59(d,J＝2.2Hz,1H),6.5(d,J＝8.5Hz,1H),5.15(s,1H),4.49(dd,J＝11.6,7.2Hz,1H),4.15(dd,J＝11.8,5.0Hz,1H),4.06(m,2H),3.94(m,2H),3.83(s,3H),3.47(s,3H),3.31(dd,J＝15.7,11.9Hz,1H),2.87(dd,J＝15.8,5.0Hz,1H),2.22(dd,J＝12.9,7.1Hz,1H),1.42(t,J＝7.0Hz,3H),1.37(t,J＝7.0Hz,3H),1.25(s,3H),1.21(s,3H).
13C NMR(151MHz,CDCl 3)δ174.25,173.69,153.13,152.32,144.54,139.94,132.60,131.65,127.06,113.84,112.29,112.26,111.98,110.00,105.42,101.20,81.72,75.28,67.98,65.31,64.50,64.21,61.75,52.25,52.05,42.99,29.67,24.26,22.05,20.26,15.11,15.02.
HRMS-ESI m/z calcd for C 32H 39N 4O 6[M+H] +575.2870,found 574.2791.
Figure PCTCN2022101788-appb-000030
化合物22的表征如下：
1H NMR(600MHz,CDCl 3)δ9.72(s,1H),7.40(d,J＝7.4Hz,2H),7.31(m,6H),7.24(t,J＝6.7Hz,2H),7.18(m,2H),6.93(s,1H),6.80(dd,J＝8.7,2.0Hz,1H),6.67 (dd,J＝8.5,2.1Hz,1H),6.54(d,J＝1.8Hz,1H),6.43(d,J＝8.5Hz,1H),5.07(s,1H),5.02(s,2H),4.90(q,J＝11.5Hz,2H),4.36(dd,J＝11.6,7.2Hz,1H),4.08(dd,J＝11.8,4.9Hz,1H),3.76(s,3H),3.40(s,3H),3.24(m,1H),2.79(m,1H),2.12(m,1H),1.37(s,4H),1.30(m,1H),1.10(s,3H).
13C NMR(151MHz,CDCl 3)δ173.18,153.65,137.97,137.24,133.00,129.88,128.82,128.72,128.60,128.12,127.81,127.76,127.62,127.48,127.14,126.51,113.75,113.33,112.82,102.07,83.27,71.46,71.15,52.61,39.07,33.43,32.07,26.92,26.12,22.82,14.22,11.04.
HRMS-ESI m/z calcd for C 42H 43N 4O 6[M+H] +699.3183,found:699.3190.
二、生物活性评价
1)、抗肿瘤活性实验
1、CCK-8法测定药物对A375、A549、MDA-MB-231、SP2/0、细胞的抑制率
a、细胞和药物
细胞株：人源黑色素瘤A375(中国科学院药物研究所提供)，人源肺癌细胞A549，人源三阴乳腺癌MDA-MB-231，小鼠骨髓瘤SP2/0；
实验药物为前述方法合成的化合物14，阳性对照药为顺铂。
b、试剂
CCK8试剂盒，购自TargetMol中国；Annexin V-FITC/PI双染细胞凋亡检测试剂盒，购自seven biotech公司。
c、仪器
多功能酶标仪FLUOstar Omega，购自德国BMG LABTECH公司；
流式细胞仪Flow Cytometer，购自美国BD公司。
d、实验方法
取对数生长期状态良好的细胞，用胰酶消化后，加入配制好的培养基制备成细胞混悬液，调整细胞密度为5×10 4个细胞/mL，将消化好的细胞接种于96孔板中，每孔加入100μL的细胞悬液，在37℃，5％CO 2的细胞培养箱中孵育过夜，细胞贴壁生长后，分别设置空白对照组和不同浓度梯度的待测化合物组，每组设置5个平行复孔，每孔加入药物150μL继续培养48h后，每孔分别加入10μL的CCK8溶液，震荡混匀后放入培养箱继续培养1.5h，用多功能酶联免疫检测仪测定光密度值(OD)，设置波长为450nm，实验重复三次，并根据公式：细胞存活率＝(实验组－空白对照组/对照组)×100％，计算并统计各组不同药物浓度的细胞存活率，并使用GraphPad Prism软件计算结果。
所述药物是将顺铂和化合物14分别配制成母液，从低到高(0.5μM～100μM)依次加入处于对数生长期状态良好的肿瘤细胞株，用CCK-8方法检测细胞存活率，化合物14和顺铂对A375、A549、MDA-MB-231、SP2/0四种肿瘤细胞的抑制的IC 50值见表1。
表1
Figure PCTCN2022101788-appb-000031
从表1的数据中可看出，化合物14对A375、MDA-MB-231、A549、SP2/0、HELA、MCF-7细胞的抑制的IC 50值均与顺铂相当，由此可见，化合物14表现出了与顺铂相当的广谱抗肿瘤活性。
2、MTT法测定药物对HELA、MCF-7及人体正常细胞293T的细胞抑制率
取对数生长期的两株癌细胞HELA和MCF-7以及人体正常细胞株293T，用细胞计数板对细胞进行计数，然后将细胞悬液浓度调至105个/mL，将细胞接种到96孔板上，每孔加入100μL，细胞悬液均匀后放入到CO 2培养箱中培养，待细胞均匀生长铺满培养皿底后加入待试药物，设DMEM培养液为阴性对照组(待试药物完全溶于培养液，未用DMSO溶解)，顺铂为阳性对照组，每孔加入100μL，每个浓度设4个平行，培养48h后加入10μL MTT再培养4h，弃去上清液，加入分析纯的二甲基亚砜100μL，置于摇床上摇匀，待溶液完全均匀后用酶标仪在波长490nm处测其吸光度值。重复实验2次。
其中，测定人体正常细胞株293T所使用的待试药物为本申请的化合物1～化合物22。
实验结果表明：顺铂对293T正常细胞的抑制IC 50值为17.29，而本申请的实验药物化合物1～化合物22对293T正常细胞的抑制IC 50值均大于40μM，其中，化合物15对293T正常细胞的抑制IC 50值能够达到133.63μM。由此可见，本申请的化合物对正常细胞293T的细胞毒性远小于顺铂。
其中，测定对癌细胞HELA抑制率所使用的待试药物为本申请的化合物15和化合物20，测定对癌细胞MCF-7抑制率所使用的待试药物为本申请的化合物15。上述待试药物及顺铂对HELA、MCF-7两种肿瘤细胞抑制IC 50值的数据见表2。
表2
  抑制HELA的IC 50值(μM) 抑制MCF-7的IC 50值(μM)
化合物15 23.56 29.78
化合物20 40.13 -
顺铂 13.15 14.18
从表2的数据中可以看出，本申请的化合物对HELA、MCF-7的抑制活性稍差于顺铂，但两者的对HELA和MCF-7的抑制IC 50值在一个数量级上，活性差异不大。
2)、流式检测细胞凋亡
取对数生长期状态良好的细胞，用胰酶消化后，加入配制好的培养基制备成细胞混悬液，调整细胞密度为5×10 4个细胞/mL，将消化好的细胞接种于6孔板中，每孔加入2mL的细胞悬液，在37℃，5％CO 2的细胞培养箱中孵育过夜，细胞贴壁生长后，分别设置空白对照组和不同浓度梯度的待测实验药物组，每孔加入药物2mL继续培养48h后，用不含EDTA的胰酶消化并收集细胞，细胞凋亡的检测需调整细胞密度为1×10 6个/ml，放入5mL离心管中，1000rmp离心5min，用PBS洗涤三次。加入100μL的Binding Buffer重悬细胞，除单染对照和空白对照，每管加入5μLFITC和5μLPI，轻轻混匀，室温避光孵育15min，上机检测前每孔加入400μL的Binding Buffer，混匀后上机检测。
空白对照：经药物诱导的凋亡细胞—不加荧光试剂(调整散射光电压，确定群体的FSC SSC)。
阴性对照：正常细胞(不经药物处理)加该实验的所有荧光染色试剂(左下角位置，确定两荧光通道的电压)。
单染对照：FITC和PI各做一管，调补偿阳性对照：经药物诱导的凋亡细胞或加热诱导的凋亡细胞加该实验所有的荧光试剂(确认试剂、仪器及操作没有问题)。
检测结果如表3所示。
表3
Figure PCTCN2022101788-appb-000032
Figure PCTCN2022101788-appb-000033
从表3的数据中可以看出，化合物14均能诱导A375、MDA-MB-231、A549、SP2/0细胞的早期凋亡和晚期凋亡，且随着药物浓度的增大，细胞的凋亡率越高，尤其对小鼠骨髓瘤细胞表现出更强的凋亡作用，在药物浓度为30μM时对SP2/0细胞早期和晚期总的凋亡率达到97％。
3)小鼠毒性实验
取体重18～22g的KM种小鼠12只，4-6周龄，适应性饲养7天，全部动物小鼠可自由取食，并有充足的新鲜饮用水，饲养环境符合SPF实验动物级环境设施标准。
将KM种小鼠随机分成6组，分别腹腔注射溶液(溶媒DMSO)，注射容积20mL/kg，其中第一组至第四组注射化合物14的溶液，给药剂量分别为20、40、60、80mg/kg，第五组为阳性对照组注射顺铂溶液，顺铂剂量(以顺铂为有效成分进行剂量的计算)是20mg/kg，第六组为阴性对照组，仅注射溶媒。观察动物给药后的行为变化及14日内的死亡情况。
通过观察可发现：注射20mg/kg化合物14的实验组的动物未见异常，动物体重增长与正常对照组无显著区别；注射20mg/kg组小鼠体重给药后3天体重明显减轻，动物活动减少，皮毛竖立，精神萎靡，第6天有1只动物死亡；注射40mg/kg化合物14的实验组，在给药后动物体重增长与阴性对照组比较减慢，动物行为活动及精神正常，观察期间未见死亡；注射60mg/kg化合物14的实验组，第6天有1只动物死亡，注射80mg/kg化合物14的实验组，动物有2只在给药后第2天全部死亡。由此可以推测化合物14的致死剂量在60mg/kg左右，顺铂的致死剂量在20mg/kg左右。
以上，对本申请的实施方式进行了说明。但是，本申请不限定于上述实施方式。凡在本申请的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。

Claims (18)

  1. 一种含氮多环类芳香化合物及其药学上可接受的盐，所述化合物具有式I所示的结构：
    Figure PCTCN2022101788-appb-100001
    其中，R 1、R 9各自独立地选自H、C 1～6的烷基、C 1～6的烷氧基、苄氧基、卤素；
    R 2、R 3、R 4、R 5、R 10、R 11、R 12、R 13各自独立地选自H、C 1～6的烷基、-COOR x；R x选自C 1～6烷基；
    R 6、R 14各自独立地选自H或C 1～6的烷基；
    R 7、R 8各自独立地选自H或C 1～6的烷基。
  2. 根据权利要求1所述的含氮多环类芳香化合物及其药学上可接受的盐，其中，C 1～6的烷基选自C 1～3的烷基、C 1～6的烷氧基选自C 1～3的烷氧基。
  3. 根据权利要求2所述的含氮多环类芳香化合物及其药学上可接受的盐，其中，R 1、R 9各自独立地选自H、甲基、乙基、乙氧基、苄氧基、氯中的一种；
    和/或，R 2、R 3、R 4、R 5、R 10、R 11、R 12、R 13各自独立地选自H、甲基、乙基、-COOMe中的一种；
    和/或，R 6、R 14各自独立地选自H、甲基或乙基；
    和/或，R 7、R 8各自独立地选自H、甲基或乙基。
  4. 根据权利要求3所述的含氮多环类芳香化合物及其药学上可接受的盐，其中，R 2、R 3、R 4、R 5、R 10、R 11、R 12、R 13均选自H；
    或，R 2、R 3、R 12、R 13均选自H，R 4、R 5、R 10、R 11均选自甲基或乙基；
    或，R 2、R 3、R 12、R 13均选自甲基，R 4、R 5、R 10、R 11均选自H；
    或，R 2、R 3、R 12、R 13均选自H，R 4、R 5分别选自H和-COOMe，R 10、R 11分别选自H和-COOMe。
  5. 根据权利要求3或4所述的含氮多环类芳香化合物及其药学上可接受的盐，其中，R 7、R 8均选自H或甲基；
    或，R 7选自甲基、R 8选自H；
    或，R 7选自乙基、R 8选自甲基。
  6. 根据权利要求3-5任一项所述的含氮多环类芳香化合物及其药学上可接受的盐，其中，R 1、R 9均选自H、甲基、乙基、乙氧基、苄氧基、氯中的一种；
    和/或，R 6、R 14均选自H、甲基或乙基。
  7. 根据权利要求1-6任一项所述的含氮多环类芳香化合物及其药学上可接受的盐，其中，R 1、R 9均位于其所在吲哚环的5号位。
  8. 权利要求1-7任一项所述的含氮多环类芳香化合物的制备方法，包括以下步骤：
    Figure PCTCN2022101788-appb-100002
    使式1化合物、式2化合物与式3化合物在酸催化剂作用下进行反应，得到式I所示的化合物。
  9. 根据权利要求8所述的制备方法，其中，式1化合物、式2化合物的摩尔比为1：1：(1～1.4)。
  10. 根据权利要求8或9所述的制备方法，其中，所述反应的温度为-20～60℃。
  11. 根据权利要求8-10任一项所述的制备方法，其中，所述反应的体系中还包括溶剂，所述溶剂选自氯代溶剂、醇类溶剂、醚类溶剂中的至少一种。
  12. 根据权利要求8-11任一项所述的制备方法，其中，所述酸催化剂选自冰醋酸、三氟乙酸、盐酸、对甲苯磺酸中的至少一种。
  13. 一种药物组合物，包括权利要求1-7任一项所述的含氮多环类芳香化合物和药剂学上可接受的药物辅料。
  14. 根据权利要求13所述的药物组合物，其中，所述药物组合物的剂型包括口服制剂、注射制剂或栓剂中的至少一种。
  15. 权利要求1-7任一项所述的含氮多环类芳香化合物在制备抗肿瘤药物中的用途。
  16. 根据权利要求15所述的用途，其中，所述抗肿瘤药物包括抗宫颈癌、抗乳腺癌、抗黑色素瘤、抗肺癌或抗骨髓癌的药物。
  17. 一种预防和/或治疗肿瘤的方法，其中，所述方法包括：给患者施用以权利要求1-7任一项所述的含氮多环类芳香化合物及其药学上可接受的盐为活性组分的药物。
  18. 根据权利要求17所述的方法，其中，所述肿瘤包括宫颈癌、乳腺癌、黑色素瘤、肺癌、骨髓癌中的至少一种。
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