WO2020244253A1 - 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 - Google Patents

一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 Download PDF

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WO2020244253A1
WO2020244253A1 PCT/CN2020/076031 CN2020076031W WO2020244253A1 WO 2020244253 A1 WO2020244253 A1 WO 2020244253A1 CN 2020076031 W CN2020076031 W CN 2020076031W WO 2020244253 A1 WO2020244253 A1 WO 2020244253A1
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alkyl
substituted
phenyl
hydrogen
alkoxy
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闫道广
钟文彬
徐梦阳
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暨南大学
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    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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    • 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
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    • 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
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    • C07D471/12—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 three hetero rings
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Definitions

  • the present invention relates to the technical field of anti-tumor medicine, and more specifically, to the application of a class of small molecule compounds or pharmaceutically acceptable salts thereof in the preparation of anti-tumor metastasis drugs.
  • Tumor is one of the most common and serious diseases that endanger human health in the world today, and its incidence is second only to cardiovascular diseases.
  • Tumor metastasis refers to the whole process of malignant tumor cells detached from their original site, transported in the body through various channels (such as blood, lymph, etc.), to reach other distant tissues to continue to proliferate and grow to form a secondary tumor.
  • Invasion and metastasis are one of the most important characteristics that distinguish malignant tumors from benign tumors. It is estimated that 90% of the deaths of cancer patients are due to cancer cell metastasis. Therefore, studying how to inhibit and/or prevent the metastasis of tumor cells is an important direction for the development of anti-tumor drugs.
  • liver cancer Hepatocellular cancer, HCC
  • HCC Hepatocellular cancer
  • liver cancer cells Whether in long-term cell culture or in animal models, liver cancer cells have a strong ability to migrate and infiltrate, making common treatment methods such as resection, radiotherapy, and chemotherapy ineffective. As a result, patients with liver cancer have a poor prognosis and a high recurrence rate.
  • the purpose of the present invention is to provide the application of a class of small molecule compounds or pharmaceutically acceptable salts thereof in the preparation of anti-tumor metastasis drugs.
  • the compound of the present invention can significantly inhibit the invasion, migration and horizontal movement ability of tumor cells in vitro; and has low cytotoxicity, high safety to normal cells, and has good drug-making properties, and can be prepared as anti-tumor drugs and/or anti-tumor drugs Metastatic drugs are used to prevent and treat tumor cell metastasis in patients with advanced malignant tumors.
  • Another object of the present invention is to provide a pharmaceutical composition prepared from the small molecule compound or a pharmaceutically acceptable salt thereof.
  • X, Y, Z are independently C, N, O or S;
  • R 1 is hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl Group, amino group, substituted amino group, phenyl ester group, Or glycoside; wherein R 4 is C 3-9 cycloalkyl or Wherein R 6 is hydrogen, halogen, hydroxyl, nitro, C 1-4 alkyl, C 1-4 substituted alkyl or C 1-4 alkoxy, n is an integer from 0 to 4; R 5 is hydroxyl, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or phenyl;
  • R 2 is hydrogen, hydroxy, nitro, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl or Wherein R 7 is C 1-4 alkyl, C 1-4 substituted alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 3 is hydrogen, hydroxy, nitro, carbonyl, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy, phenyl, Or glycoside; wherein R 8 and R 9 are independently hydrogen, hydroxyl, nitro, halogen, C 1-4 alkyl, C 1-4 alkoxy; n is an integer of 0-4;
  • the substituents in the C 1-4 substituted alkyl group, C 1-6 substituted alkyl group, substituted phenyl group, substituted benzyl group, and substituted amino group are halogen, hydroxy, phenyl, C 1-4 alkyl, C 1 -4 alkoxy or C 3-6 cycloalkyl.
  • the X, Y, and Z are C or N independently.
  • R 1 is hydrogen, hydroxy, C 1-6 alkyl, C 1-6 substituted alkyl, phenyl, substituted phenyl, benzyl, amino, substituted amino, phenyl ester, Or glycoside; wherein R 4 is C 3-9 cycloalkyl or Wherein R 6 is hydrogen, halogen, hydroxyl or nitro, n is an integer from 0 to 4; R 5 is C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy or C 3- 6 cycloalkyl;
  • R 1 is hydroxyl, C 1-4 alkyl or Wherein n is an integer from 0 to 4, and R 6 is hydrogen, halogen, hydroxy, nitro, C 1-4 alkyl or C 1-4 alkoxy;
  • R 2 is hydrogen
  • R 3 is hydrogen, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy or glycoside;
  • R 1 is hydroxyl, C 1-4 alkyl or Wherein n is an integer of 0-4, and R 6 is hydrogen, halogen, hydroxyl, nitro, C 1-4 alkyl or -COOCH 3 ;
  • R 2 is hydrogen;
  • R 3 is hydrogen or C 1-6 substituted alkyl; the substituents in C 1-6 substituted alkyl are halogen, hydroxy, and phenyl;
  • R 1 is hydroxy or C 1-4 alkyl
  • R 2 is hydrogen
  • R 3 is hydrogen or glycoside.
  • R 1 is hydrogen, hydroxy, methyl, ethyl, propyl, isopropyl, acetate, ethylcyclopentane, phenyl, substituted phenyl, Benzyl, amine, Or glycoside; where R 4 is
  • the substituent in the substituted phenyl group is one or more of fluorine, chlorine, bromine, nitro, hydroxyl, methyl, ethyl, methoxy or ethoxy.
  • the small molecule compound is one of the following structures:
  • the pharmaceutically acceptable salt is prepared by reacting the small molecule compound with an acid or a base.
  • the acid is hydrochloric acid, sulfuric acid or hydrobromic acid
  • the base is sodium hydroxide, calcium hydroxide or potassium hydroxide.
  • the anti-tumor metastasis is anti-metastasis of one or more of liver cancer, breast cancer, lung cancer, gastric cancer, cervical cancer, ovarian cancer, esophageal cancer, colorectal cancer, nasopharyngeal cancer, brain cancer or bone cancer.
  • the present invention also protects a pharmaceutical composition prepared from the small molecule compound or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprising a therapeutically effective amount of the small molecule compound represented by formula (I) and/or its pharmaceutically acceptable salt Acceptable salt:
  • X, Y, Z are independently C, N, O or S;
  • R 1 is hydrogen, hydroxyl, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl, benzyl, substituted benzyl Group, amino group, substituted amino group, phenyl ester group, Or glycoside; wherein R 4 is C 3-9 cycloalkyl or Wherein R 6 is hydrogen, halogen, hydroxyl, nitro, C 1-4 alkyl, C 1-4 substituted alkyl or C 1-4 alkoxy, n is an integer from 0 to 4; R 5 is hydroxyl, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl or phenyl;
  • R 2 is hydrogen, hydroxy, nitro, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, phenyl, substituted phenyl or Wherein R 7 is C 1-4 alkyl, C 1-4 substituted alkyl, C 1-4 alkoxy or C 3-6 cycloalkyl;
  • R 3 is hydrogen, hydroxy, nitro, carbonyl, C 1-6 alkyl, C 1-6 substituted alkyl, C 1-6 alkoxy, phenyl, Or glycoside; wherein R 8 and R 9 are independently hydrogen, hydroxyl, nitro, halogen, C 1-4 alkyl, C 1-4 alkoxy; n is an integer of 0-4;
  • the substituents in the C 1-4 substituted alkyl group, C 1-6 substituted alkyl group, substituted phenyl group, substituted benzyl group, and substituted amino group are halogen, hydroxy, phenyl, C 1-4 alkyl, C 1 -4 alkoxy or C 3-6 cycloalkyl.
  • the pharmaceutical composition can be prepared into injections, emulsions, tablets, powders, granules, ointments, liposomes or oral liquids.
  • the present invention has the following beneficial effects:
  • the small molecule compound of the present invention or a pharmaceutically acceptable salt thereof can significantly inhibit the invasion, migration and horizontal movement ability of tumor cells in vitro; and has low cytotoxicity, high safety to normal cells, and is a good medicine Features, can be prepared into anti-tumor drugs and/or anti-tumor metastasis drugs for application to prevent and treat tumor cell metastasis in patients with advanced malignant tumors;
  • the small molecule compound or its pharmaceutically acceptable salt has a simple structure, is easy to synthesize, can be prepared in large-scale industrial production, and is easy to popularize and apply.
  • Figure 1 shows the effects of compound 1 at different concentrations on HepG2 cell migration.
  • Figure 2 shows the effect of different concentrations of Compound 2 on HepG2 cell migration.
  • Figure 3 shows the effect of compound 3 at different concentrations on the migration of HepG2 cells.
  • Figure 4 shows the effect of compound 4 at different concentrations on HepG2 cell migration.
  • Figure 5 shows the effect of compound 5 at different concentrations on the migration of HepG2 cells.
  • Figure 6 shows the effects of compound 7 at different concentrations on HepG2 cell migration.
  • Figure 7 shows the effect of compound 8 at different concentrations on HepG2 cell migration.
  • Figure 8 shows the effect of compound 11 at different concentrations on the migration of HepG2 cells.
  • Figure 9 shows the effect of compound 28 at different concentrations on the migration of HepG2 cells.
  • Figure 10 shows the effects of compound 32 at different concentrations on HepG2 cell migration.
  • Figure 11 shows the effect of compound 33 at different concentrations on HepG2 cell migration.
  • Figure 12 shows the effect of different concentrations of Compound 1 on the migration of HepG2 cells measured by a scratch experiment.
  • Figure 13 shows the effect of different concentrations of compound 32 on the migration of HepG2 cells measured by a scratch experiment.
  • Figure 14 shows the effect of compound 33 at different concentrations on the migration of HepG2 cells measured by a scratch experiment.
  • test methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used, unless otherwise specified, are commercially available reagents and materials.
  • the virtual screening compound library is a compound database prepared by the laboratory.
  • the compound library is processed as follows: remove ions and complex water molecules, add charge, protonate, and produce three-dimensional conformation. These processes are all completed in the drug design software package Discovery Studio 3.0.
  • the protonation is carried out under the condition of pH 6.5-8.5.
  • the prepared small molecule library is used for virtual screening.
  • Example 1 The compound screened in Example 1 was used for further screening to test the cytotoxicity of the compound.
  • the specific process is as follows:
  • HepG2 cells are cultured in vitro, using DMEM medium containing 10% fetal bovine serum, and routinely maintained and subcultured at 37°C and 5% carbon dioxide concentration.
  • Drug intervention Plate HepG2 cells on a 96-well plate with 1 ⁇ 10 3 cells per well; the next day, treat the cells with different concentration gradients of small molecule compounds, and set up 3 parallel multiple wells for each concentration.
  • Test method After 72 hours, use CCK-8 kit to detect cytotoxicity.
  • the cytotoxicity of different compounds at different concentrations was calculated. Use the relative value as the ordinate and the drug concentration as the abscissa to draw a graph of the effect of each compound on the cell growth rate, and calculate the drug concentration (CC 50 ) when each drug causes 50% cell death to evaluate the cytotoxicity of each compound.
  • Example 3 The compound inhibits the migration ability of HepG2 cells
  • Example 2 The compound screened in Example 2 was used as the test object to test its ability to inhibit HepG2 cell migration.
  • the specific process of the experiment is as follows:
  • HepG2 cells are cultured in vitro, using high-sugar DMEM medium containing 10% fetal bovine serum, 100U/mL penicillin, 100 ⁇ g/mL streptomycin, and routine maintenance culture at 37°C and 5% carbon dioxide concentration. And pass down.
  • Transwell migration experiment cells were digested with trypsin and centrifuged to collect 2 ⁇ 10 6 cells; cells were washed once with 1mL PBS buffer and centrifuged to collect cells; 1mL serum-free medium was added to resuspend cells; complete medium was used to configure different concentrations After taking 0.6mL of the various compounds into a 24-well plate, put them into the cell culture chamber. Add 0.1 mL of the resuspended cells to the upper chamber of the small chamber and place them in a 37°C, 5% CO 2 environment for culture.
  • the cell was taken out, washed with PBS, and air-dried; after fixing the cells with 4% PFA for 20 minutes, the cell was cleaned with PBS and air-dried; stained with 1% crystal violet/2% (v/v) methanol for 30 min, then stained with PBS Clean and air dry and take pictures. Repeat 3 independent experiments.
  • Transwell migration experiment takes pictures, each sample randomly selects 10 fields of view to take pictures (magnification: 100 ⁇ ; scale: 200 ⁇ m). Use image pro plus 6.0 to count the number of cells in each field of view. The effective concentration of each compound to inhibit 50% cancer cell migration was calculated to evaluate the effect of each compound.
  • test results of compounds 1 to 33 are shown in Table 1, and the test results of some compounds are shown in Figures 1 to 11.
  • Figures 1 to 11 are compounds 1, 2, 3, 4, 5, 7, 8, 11, 28 , 32, 33 experiment test results;
  • Figures 12-14 are compound 1, 32, 33 scratch test results obtained.
  • most of the compounds provided in the above examples have low or even no toxicity to cells, and can inhibit HepG2 cell migration well, and can be prepared as anti-tumor drugs and/or anti-tumor metastasis drugs for application. Prevention and treatment of tumor cell metastasis in patients with advanced malignant tumors.

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Abstract

本发明公开了一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用。所述化合物的结构如式(Ⅰ)所示；所述小分子化合物或其药学上可接受的盐，在体外可显著抑制肿瘤细胞的侵袭、迁移和水平运动能力；且细胞毒性较小，对正常细胞安全性高，具有很好的成药特性，可制备成为抗肿瘤药物和/或抗肿瘤转移药物进行应用，用于防治中晚期恶性肿瘤病人的肿瘤细胞的转移；同时，所述小分子化合物或其药学上可接受的盐的结构简单、易于合成，可大规模工业化生产制备，易于推广应用。

Description

一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 技术领域
本发明涉及抗肿瘤医药技术领域，更具体地，涉及一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用。
背景技术
肿瘤是当今世界危及人类健康的一种最常见、最严重的疾病，其发病率仅次于心血管疾病。肿瘤转移是指恶性肿瘤细胞脱离其原发部位，在体内通过各种途径(如血液、淋巴等)的转运，到达远端其它组织继续增殖生长，形成继发肿瘤的全过程。侵袭与转移是恶性肿瘤区别于良性肿瘤的最主要的特征之一。据估计，90％肿瘤病人的死亡是源于癌细胞转移。因此，研究如何抑制和/或预防肿瘤细胞的转移是抗肿瘤药物研发的重要方向。
以原发性肝癌(Hepatocellular carcinoma，HCC)为例，虽然目前对于诊断和治疗肝癌的技术手段有了很大的提高，最主要的手段还是手术切除，但是只有大约20％～30％的肝癌患者能够在其患病的早期阶段被诊断出来，进而有机会采取最有效的治疗手段。不同阶段的肝癌患者对于同一种治疗手段的预后情况大大不同，如同样是手术切除治疗，中晚期肝癌患者即使采取手术治疗手段，复发的几率很大。因为术后残留的肝癌细胞会转移到其它组织，最常见的是肺转移，通过浸润到其它组织的细胞群中，引发了更加严重的癌症，加大了治疗的难度。无论在长期的细胞培养中还是动物模型体内，肝癌细胞都有很强的迁移和侵润能力，使得普通的治疗手段，如切除手术、放疗、化疗等效果不明显。从而使肝癌患者治疗预后差，复发率高。
因此，寻找抑制肿瘤细胞转移，是治疗肿瘤的一项重要的手段，新型抗肿瘤转移药物的发现对挽救恶性肿瘤患者的生命具有至关重要的临床意义和社会价值。
发明内容
本发明的目的在于提供一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用。本发明化合物在体外可显著抑制肿瘤细胞的侵袭、迁移和水平运动能力；且细胞毒性较小，对正常细胞安全性高，具有很好的成药特性，可制备成为抗肿瘤药物和/或抗肿瘤转移药物进行应用，用于防治中晚期恶性肿瘤病人的肿瘤细胞的 转移本发明的另一目的在于提供由所述小分子化合物或其药学上可接受的盐制备的药物组合物。
本发明的上述目的是通过以下方案予以实现的：
一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，所述化合物的结构如式(Ⅰ)所示：
Figure PCTCN2020076031-appb-000001
其中所述X、Y、Z分别独立地为C、N、O或S；
R 1为氢、羟基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基、苯基、取代苯基、苄基、取代苄基、胺基、取代胺基、苯酯基、
Figure PCTCN2020076031-appb-000002
或糖苷；其中R 4为C 3-9环烷基或
Figure PCTCN2020076031-appb-000003
其中R 6为氢、卤素、羟基、硝基、C 1-4烷基、C 1-4取代烷基或C 1-4烷氧基，n为0～4的整数；R 5为羟基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基或苯基；
R 2为氢、羟基、硝基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基、苯基、取代苯基或
Figure PCTCN2020076031-appb-000004
其中R 7为C 1-4烷基、C 1-4取代烷基、C 1-4烷氧基或C 3-6环烷基；
R 3为氢、羟基、硝基、羰基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、苯基、
Figure PCTCN2020076031-appb-000005
或糖苷；其中R 8和R 9分别独立地为氢、羟基、硝基、卤素、C 1-4烷基、C 1-4烷氧基；n为0～4的整数；
所述C 1-4取代烷基、C 1-6取代烷基、取代苯基、取代苄基、取代胺基中的取代基为卤素、羟基、苯基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基。
优选地，所述X、Y、Z分别独立地为C或N。
优选地，当X、Y和Z均为N时，化合物的结构如式(Ⅱ)所示：
Figure PCTCN2020076031-appb-000006
R 1为氢、羟基、C 1-6烷基、C 1-6取代烷基、苯基、取代苯基、苄基、胺基、取代胺基、苯酯基、
Figure PCTCN2020076031-appb-000007
或糖苷；其中R 4为C 3-9环烷基或
Figure PCTCN2020076031-appb-000008
其中R 6为氢、卤素、羟基或硝基，n为0～4的整数；R 5为C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基或C 3-6环烷基；
当Y为N，X和Z均为C时，化合物的结构如式(Ⅲ)所示：
Figure PCTCN2020076031-appb-000009
R 1为羟基、C 1-4烷基或
Figure PCTCN2020076031-appb-000010
其中n为0～4的整数，R 6为氢、卤素、羟基、硝基、C 1-4烷基或C 1-4烷氧基；
R 2为氢；R 3为氢、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基或糖苷；
当Y为C，X和Z均为N时，化合物的结构如式(Ⅳ)所示：
Figure PCTCN2020076031-appb-000011
R 1为羟基、C 1-4烷基或
Figure PCTCN2020076031-appb-000012
其中n为0～4的整数，R 6为氢、卤素、羟基、硝基、C 1-4烷基或-COOCH 3；
R 2为氢；R 3为氢或C 1-6取代烷基；C 1-6取代烷基中的取代基为卤素、羟基、苯基；
当X为C，Y和Z均为N时，化合物的结构如式(Ⅴ)所示：
Figure PCTCN2020076031-appb-000013
R 1为羟基或C 1-4烷基；R 2为氢；R 3为氢或糖苷。
优选地，当X、Y和Z均为N时，R 1为氢、羟基、甲基、乙基、丙基、异丙基、乙酸基、乙基环戊烷、苯基、取代苯基、苄基、胺基、
Figure PCTCN2020076031-appb-000014
Figure PCTCN2020076031-appb-000015
或糖苷；其中R 4为
Figure PCTCN2020076031-appb-000016
Figure PCTCN2020076031-appb-000017
取代苯基中的取代基为氟、氯、溴、硝基、羟基、甲基、乙基、甲氧基或乙氧基中的一个或多个。
优选地，所述小分子化合物为以下结构中的一种：
Figure PCTCN2020076031-appb-000018
Figure PCTCN2020076031-appb-000019
优选地，所述其药学上可接受的盐是由所述小分子化合物与酸或者碱反应制备得到。
更优选地，所述酸为盐酸、硫酸或氢溴酸；所述碱为氢氧化钠、氢氧化钙或氢氧化钾。
优选地，所述抗肿瘤转移为抗肝癌、乳腺癌、肺癌、胃癌、宫颈癌、卵巢癌、食管癌、大肠癌、鼻咽癌、脑癌或骨癌中的一种或多种的转移。
本发明同时还保护由所述小分子化合物或其药学上可接受的盐制备的药物组合 物，所述药物组合物包含治疗有效量的式(Ⅰ)所示小分子化合物和/或其药学上可接受的盐：
Figure PCTCN2020076031-appb-000020
其中所述X、Y、Z分别独立地为C、N、O或S；
R 1为氢、羟基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基、苯基、取代苯基、苄基、取代苄基、胺基、取代胺基、苯酯基、
Figure PCTCN2020076031-appb-000021
或糖苷；其中R 4为C 3-9环烷基或
Figure PCTCN2020076031-appb-000022
其中R 6为氢、卤素、羟基、硝基、C 1-4烷基、C 1-4取代烷基或C 1-4烷氧基，n为0～4的整数；R 5为羟基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基或苯基；
R 2为氢、羟基、硝基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基、苯基、取代苯基或
Figure PCTCN2020076031-appb-000023
其中R 7为C 1-4烷基、C 1-4取代烷基、C 1-4烷氧基或C 3-6环烷基；
R 3为氢、羟基、硝基、羰基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、苯基、
Figure PCTCN2020076031-appb-000024
或糖苷；其中R 8和R 9分别独立地为氢、羟基、硝基、卤素、C 1-4烷基、C 1-4烷氧基；n为0～4的整数；
所述C 1-4取代烷基、C 1-6取代烷基、取代苯基、取代苄基、取代胺基中的取代基为卤素、羟基、苯基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基。
哟选地，所述药物组合物可制备成为注射剂、乳剂、片剂、散剂、颗粒剂、软膏、脂质体或口服液。
与现有技术相比，本发明具有以下有益效果：
本发明所述小分子化合物或其药学上可接受的盐，在体外可显著抑制肿瘤细胞的侵袭、迁移和水平运动能力；且细胞毒性较小，对正常细胞安全性高，具有很好的成药特性，可制备成为抗肿瘤药物和/或抗肿瘤转移药物进行应用，用于防治中晚期恶性 肿瘤病人的肿瘤细胞的转移；
同时，所述小分子化合物或其药学上可接受的盐的结构简单、易于合成，可大规模工业化生产制备，易于推广应用。
附图说明
图1为不同浓度的化合物1对HepG2细胞迁移的影响。
图2为不同浓度的化合物2对HepG2细胞迁移的影响。
图3为不同浓度的化合物3对HepG2细胞迁移的影响。
图4为不同浓度的化合物4对HepG2细胞迁移的影响。
图5为不同浓度的化合物5对HepG2细胞迁移的影响。
图6为不同浓度的化合物7对HepG2细胞迁移的影响。
图7为不同浓度的化合物8对HepG2细胞迁移的影响。
图8为不同浓度的化合物11对HepG2细胞迁移的影响。
图9为不同浓度的化合物28对HepG2细胞迁移的影响。
图10为不同浓度的化合物32对HepG2细胞迁移的影响。
图11为不同浓度的化合物33对HepG2细胞迁移的影响。
图12为通过划痕实验测定不同浓度的化合物1对HepG2细胞迁移的影响。
图13为通过划痕实验测定不同浓度的化合物32对HepG2细胞迁移的影响。
图14为通过划痕实验测定不同浓度的化合物33对HepG2细胞迁移的影响。
具体实施方式
下面结合具体实施例对本发明做出进一步地详细阐述，所述实施例只用于解释本发明，并非用于限定本发明的范围。下述实施例中所使用的试验方法如无特殊说明，均为常规方法；所使用的材料、试剂等，如无特殊说明，为可从商业途径得到的试剂和材料。
实施例1
化合物的筛选，步骤如下：
1、化合物库预处理：虚拟筛选化合物库为实验室自备化合物数据库。化合物库作如下处理：去除离子及络合水分子、加电荷、质子化、产生三维构象。这些流程均在药物设计软件包Discovery Studio 3.0中完成。其中质子化在pH 6.5-8.5条件下进行。准备好的小分子库用于虚拟筛选。
2.以基于虎眼万年青皂甙(OSW-1)的结构进行相似度匹配的数据库搜寻，找出结构类似的化合物。
筛选得到的化合物结构如表1所示。
表1 化合物结构
Figure PCTCN2020076031-appb-000025
Figure PCTCN2020076031-appb-000026
Figure PCTCN2020076031-appb-000027
实施例2 化合物细胞毒性测定
以实施例1筛选的化合物进行进一步的筛选，测试化合物的细胞毒性，具体过程如下：
1.细胞培养：体外培养HepG2细胞，使用含有10％胎牛血清的DMEM培养基，在37℃，5％二氧化碳浓度条件下进行常规维持培养和传代。
2.药物干预：将HepG2细胞铺板至96孔板，每孔1×10 3细胞；次日，分别使用不同浓度梯度的小分子化合物处理细胞，每个浓度设3个平行复孔。
3.测试方法：72小时后，用CCK-8试剂盒检测细胞毒性。
按照10％的比例，每100uL培养基中加入10uL CCK-8，并于37℃进行孵育2小时后，用酶标仪检测吸收光值(OD450)。
相对于对照组的吸光值，分别计算出不同化合物在不同浓度的作用下的细胞毒性。以相对值为纵坐标，药物浓度为横坐标绘制各化合物对细胞生长率作用的曲线图，并 计算各药物使50％细胞死亡时的药物浓度(CC 50)以评价各化合物的细胞毒性。
每种化合物的每个浓度至少进行3次重复实验。
实施例3 化合物抑制HepG2细胞迁移能力
以实施例2筛选的化合物为测试对象，测试其抑制HepG2细胞迁移的能力，实验具体过程如下：
1.细胞培养：体外培养HepG2细胞，使用含有10％胎牛血清，100U/mL青霉素，100μg/mL链霉素的高糖DMEM培养基，在37℃，5％二氧化碳浓度条件下进行常规维持培养和传代。
2.Transwell迁移实验：用胰酶消化细胞后离心收集2×10 6细胞；用1mL PBS缓冲液洗涤细胞一次，离心收集细胞；加入1mL无血清培养基重悬细胞；用完全培养基配置不同浓度的各种化合物，取0.6mL至24孔板后，放入细胞培养小室。取0.1mL重悬的细胞加入小室上室，置于37℃，5％CO 2的环境中培养。24小时后取出小室，用PBS清洗干净，风干；用4％PFA固定细胞20min后，用PBS将小室清洗干净，风干；取1％结晶紫/2％(v/v)甲醇染色30min，用PBS清洗干净，风干后拍照。重复3次独立实验。
4.结果处理：Transwell迁移实验拍照，每个样品随机选取10个视野拍照(放大倍数：100×；标尺：200μm)。用image pro plus 6.0对每个视野的细胞数进行统计。计算各化合物的抑制50％癌症细胞迁移的起效浓度，以评价各化合物的作用。
划痕实验具体过程如下：
(1)先用marker笔在6孔板背后，用直尺比着，均匀得划横线，大约每隔0.5～1cm一道，横穿过孔。每孔至少穿过5条线；
(2)每孔中加入约5x10 5个细胞，掌握为过夜培养贴壁；
(3)第二天用枪头比着直尺，尽量垂至于背后的横线划痕；
(4)用PBS洗细胞3次，去处划下的细胞，加入无血清培养基；
(5)放入37度5％CO 2培养箱，培养。按0，48，72小时拍照取样。
每种化合物的每个浓度至少进行3次重复实验。
实施例2和3的测试结果如表2所示。
表2 化合物的细胞毒性和抑制HepG2细胞迁移试验结果
Figure PCTCN2020076031-appb-000028
Figure PCTCN2020076031-appb-000029
化合物1～33的测试结果如表1所示，部分化合物的测试结果如图1～11所示，图1～11分别是化合物1、2、3、4、5、7、8、11、28、32、33实验的测试结果；图12～14分别是化合物1、32、33划痕实验得到测试结果。
从表1中可知，实施例提供的大部分化合物的细胞毒性较低，甚至部分化合物对于细胞没有任何的毒性；同时大部分化合物对HepG2细胞具有较好的抑制转移作用，其中尤其是化合物1、32、33，没有或较低的细胞毒性，而对于HepG2细胞表现出优异的抑制转移作用，且在纳摩尔浓度条件下就能起效，化合物1、32、33的划痕实验也验证了这个结论。
综上，上述实施例提供的大部分化合物对于细胞的毒性较低，甚至没有毒性，同时能够很好的抑制HepG2细胞迁移，可制备成为抗肿瘤药物和/或抗肿瘤转移药物进行应用，用于防治中晚期恶性肿瘤病人的肿瘤细胞的转移。
最后所应当说明的是，以上实施例仅用以说明本发明的技术方案而非对本发明保护范围的限制，对于本领域的普通技术人员来说，在上述说明及思路的基础上还可以做出其它不同形式的变化或变动，这里无需也无法对所有的实施方式予以穷举。凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明权利要求的保护范围之内。

Claims (9)

  1. 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，所述化合物的结构如式(Ⅰ)所示：
    Figure PCTCN2020076031-appb-100001
    其中所述X、Y、Z分别独立地为C、N、O或S；
    R 1为氢、羟基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基、苯基、取代苯基、苄基、取代苄基、胺基、取代胺基、苯酯基、
    Figure PCTCN2020076031-appb-100002
    或糖苷；其中R 4为C 3-9环
    Figure PCTCN2020076031-appb-100003
    其中R 6为氢、卤素、羟基、硝基、C 1-4烷基、C 1-4取代烷基或C 1-4烷氧基，n为0～4的整数；R 5为羟基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基或苯基；
    R 2为氢、羟基、硝基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基、苯基、取代苯基或
    Figure PCTCN2020076031-appb-100004
    其中R 7为C 1-4烷基、C 1-4取代烷基、C 1-4烷氧基或C 3-6环烷基；
    R 3为氢、羟基、硝基、羰基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、苯基、
    Figure PCTCN2020076031-appb-100005
    或糖苷；其中R 8和R 9分别独立地为氢、羟基、硝基、卤素、C 1-4烷基、C 1-4烷氧基；n为0～4的整数；
    所述C 1-4取代烷基、C 1-6取代烷基、取代苯基、取代苄基、取代胺基中的取代基为卤素、羟基、苯基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基。
  2. 根据权利要求1所述小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，所述X、Y、Z分别独立地为C或N。
  3. 根据权利要求2所述小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，当X、Y和Z均为N时，化合物的结构如式(Ⅱ)所示：
    Figure PCTCN2020076031-appb-100006
    R 1为氢、羟基、C 1-6烷基、C 1-6取代烷基、苯基、取代苯基、苄基、胺基、取代胺基、苯酯基、
    Figure PCTCN2020076031-appb-100007
    或糖苷；其中R 4为C 3-9环烷基或
    Figure PCTCN2020076031-appb-100008
    其中R 6为氢、卤素、羟基或硝基，n为0～4的整数；R 5为C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基或C 3-6环烷基；
    当Y为N，X和Z均为C时，化合物的结构如式(Ⅲ)所示：
    Figure PCTCN2020076031-appb-100009
    R 1为羟基、C 1-4烷基或
    Figure PCTCN2020076031-appb-100010
    其中n为0～4的整数，R 6为氢、卤素、羟基、硝基、C 1-4烷基或C 1-4烷氧基；
    R 2为氢；R 3为氢、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基或糖苷；
    当Y为C，X和Z均为N时，化合物的结构如式(Ⅳ)所示：
    Figure PCTCN2020076031-appb-100011
    R 1为羟基、C 1-4烷基或
    Figure PCTCN2020076031-appb-100012
    其中n为0～4的整数，R 6为氢、卤素、羟基、硝基、C 1-4烷基或-COOCH 3；
    R 2为氢；R 3为氢或C 1-6取代烷基；C 1-6取代烷基中的取代基为卤素、羟基、苯基；
    当X为C，Y和Z均为N时，化合物的结构如式(Ⅴ)所示：
    Figure PCTCN2020076031-appb-100013
    R 1为羟基或C 1-4烷基；R 2为氢；R 3为氢或糖苷。
  4. 根据权利要求3所述小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，当X、Y和Z均为N时，R 1为氢、羟基、甲基、乙基、丙基、异丙基、乙酸基、乙基环戊烷、苯基、取代苯基、苄基、胺基、
    Figure PCTCN2020076031-appb-100014
    Figure PCTCN2020076031-appb-100015
    或糖苷；其中R 4为
    Figure PCTCN2020076031-appb-100016
    Figure PCTCN2020076031-appb-100017
    取代苯基中的取代基为氟、氯、溴、硝基、羟基、甲基、乙基、甲氧基或乙氧基中的一个或多个。
  5. 根据权利要求3所述小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，所述小分子化合物为以下结构中的一种：
    Figure PCTCN2020076031-appb-100018
    Figure PCTCN2020076031-appb-100019
  6. 根据权利要求3所述小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，所述其药学上可接受的盐是由所述小分子化合物与酸或者碱反应制备得到。
  7. 根据权利要求3所述小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用，其特征在于，所述抗肿瘤转移为抗肝癌、乳腺癌、肺癌、胃癌、宫颈癌、卵巢癌、食管癌、大肠癌、鼻咽癌、脑癌或骨癌中的一种或多种的转移。
  8. 一种药物组合物，其特征在于，所述药物组合物包含治疗有效量的式(Ⅰ)所示小分子化合物和/或其药学上可接受的盐：
    Figure PCTCN2020076031-appb-100020
    其中所述X、Y、Z分别独立地为C、N、O或S；
    R 1为氢、羟基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基、苯基、取代 苯基、苄基、取代苄基、胺基、取代胺基、苯酯基、
    Figure PCTCN2020076031-appb-100021
    或糖苷；其中R 4为C 3-9环烷基或
    Figure PCTCN2020076031-appb-100022
    其中R 6为氢、卤素、羟基、硝基、C 1-4烷基、C 1-4取代烷基或C 1-4烷氧基，n为0～4的整数；R 5为羟基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基或苯基；
    R 2为氢、羟基、硝基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、C 3-6环烷基、苯基、取代苯基或
    Figure PCTCN2020076031-appb-100023
    其中R 7为C 1-4烷基、C 1-4取代烷基、C 1-4烷氧基或C 3-6环烷基；
    R 3为氢、羟基、硝基、羰基、C 1-6烷基、C 1-6取代烷基、C 1-6烷氧基、苯基、
    Figure PCTCN2020076031-appb-100024
    或糖苷；其中R 8和R 9分别独立地为氢、羟基、硝基、卤素、C 1-4烷基、C 1-4烷氧基；n为0～4的整数；
    所述C 1-4取代烷基、C 1-6取代烷基、取代苯基、取代苄基、取代胺基中的取代基为卤素、羟基、苯基、C 1-4烷基、C 1-4烷氧基或C 3-6环烷基。
  9. 根据权利要求8所述药物组合物，其特征在于，所述药物组合物可制备成为注射剂、乳剂、片剂、散剂、颗粒剂、软膏、脂质体或口服液。
PCT/CN2020/076031 2019-06-06 2020-02-20 一类小分子化合物或其药学上可接受的盐在制备抗肿瘤转移药物中的应用 WO2020244253A1 (zh)

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