WO2021098319A1 - 6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其制备方法和医药用途 - Google Patents

6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其制备方法和医药用途 Download PDF

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WO2021098319A1
WO2021098319A1 PCT/CN2020/111184 CN2020111184W WO2021098319A1 WO 2021098319 A1 WO2021098319 A1 WO 2021098319A1 CN 2020111184 W CN2020111184 W CN 2020111184W WO 2021098319 A1 WO2021098319 A1 WO 2021098319A1
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benzylidene
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凌勇
缪捷飞
凌长春
刘昕
李洋阳
钱建强
孟迟
谢旭东
吴红梅
张逸蓉
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南通大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/687—Unsaturated compounds containing a keto groups being part of a ring containing halogen
    • C07C49/697—Unsaturated compounds containing a keto groups being part of a ring containing halogen containing six-membered aromatic rings
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/43—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C07C211/44—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring
    • C07C211/52—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton having amino groups bound to only one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

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  • the present invention relates to the field of medicine, in particular to a class of 6-benzylidene-2-arylethynyl cyclohexenone derivatives and pharmaceutically acceptable salts thereof, their preparation methods, and pharmaceutical combinations containing these derivatives And their medical uses, especially in the preparation of malignant tumor therapeutic drugs.
  • Tumors are the second leading cause of death in humans after cardiovascular diseases. Although there are a variety of anti-tumor drugs available in clinic, due to factors such as the complexity of tumor etiology, tumor resistance, and the toxic and side effects of anti-tumor drugs, the existing drugs still cannot meet the needs of treatment. Therefore, it is of great significance to find new anti-tumor drugs with high efficacy, strong targeting, and low side effects.
  • PL can selectively increase the level of ROS and other levels of oxidative stress in cancer cells, inhibit thioredoxin oxidoreductase (TrxR), and cause DNA damage and promote cancer cell apoptosis.
  • TrxR thioredoxin oxidoreductase
  • the designed compound not only improves the anti-tumor activity and target inhibition ability of the compound of the invention, but also can selectively inhibit the proliferation of tumor cells with less damage to normal cells. At the same time, it also enriches the diversity of the benzylidene cyclohexenone skeleton. .
  • the purpose of the present invention is to provide a novel 6-benzylidene-2-arylethynyl cyclohexenone derivative and its preparation method and medical use.
  • a 6-benzylidene-2-arylethynyl cyclohexenone derivative having the structure of the following general formula I:
  • R and R' are the same or different, each represents one or more substituents on the corresponding substituted benzene ring, selected from H, halogen group, hydroxyl, amino, nitro, alkyl, haloalkyl, alkoxy, haloalkane
  • substituents are the same or different.
  • R and R' are the same or different, and each represents one or more substituents on the corresponding substituted benzene ring, selected from H, halogen group, hydroxyl, amino, nitro, C1-C6 alkyl, C1-C6 One or more of the halogenated alkyl group, C1-C6 alkoxy group, C1-C6 halogenated alkoxy group, C1-C6 alkylamino group, when R or R'represents multiple substituents, the substituents are the same Or different.
  • R and R' are the same or different, and each represents one or more substituents on the corresponding substituted benzene ring, selected from H, F, Cl, Br, I, hydroxyl, amino, nitro, methyl, ethyl, Propyl, isopropyl, trifluoromethyl, pentafluoroethyl, trichloromethyl, tribromomethyl, methoxy, ethoxy, trifluoromethoxy, trichloromethoxy, tribromomethyl One or more of oxy group, methylamino group, ethylamino group and methylethylamino group.
  • R or R' represents multiple substituents, the substituents are the same or different.
  • R' represents one or more substituents on the benzene ring, selected from H, F, Cl, Br, and when R'represents multiple substituents, the substituents are the same or different.
  • R represents one or more substituents on the benzene ring, selected from one of H, a halogen group, a nitro group, a methyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, and a methylamino group.
  • R' represents a halogen group.
  • Another object of the present invention is to provide a method for preparing the derivative of 6-benzylidene-2-arylethynyl cyclohexenone of the general formula I of the present invention, which comprises the following steps:
  • R represents one or more substituents on the benzene ring, selected from one of H, a halogen group, a nitro group, a methyl group, a trifluoromethyl group, a methoxy group, a trifluoromethoxy group, and a methylamino group.
  • R' represents a halogen group.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the 6-benzylidene-2-arylethynyl cyclohexenone derivative of the present invention or a pharmaceutically acceptable salt thereof. Further, it may be composed of a therapeutically effective dose of the compound of general formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or adjuvant.
  • Another object of the present invention is to provide the 6-benzylidene-2-arylethynyl cyclohexenone derivative of the present invention or a pharmaceutically acceptable salt thereof in the preparation of thioredoxin oxidoreductase inhibitory drugs
  • the drug with thioredoxin oxidoreductase inhibitory activity is a drug for preventing and/or treating cancer.
  • the cancer is liver cancer, prostate cancer, colon cancer, gastric cancer or lung cancer.
  • the compounds of the present invention can be combined with other anti-tumor drugs such as alkylating agents (such as cyclophosphamide or cisplatin), antimetabolites (such as 5-fluorouracil or hydroxyurea), topoisomerase inhibitors (such as camptothecin), mitotic Inhibitors (such as paclitaxel or vinblastine), DNA inserters (such as doxorubicin) are used in combination, and can also be used in combination with radiotherapy.
  • alkylating agents such as cyclophosphamide or cisplatin
  • antimetabolites such as 5-fluorouracil or hydroxyurea
  • topoisomerase inhibitors such as camptothecin
  • mitotic Inhibitors such as paclitaxel or vinblastine
  • DNA inserters such as doxorubicin
  • the present invention uses the skeleton transition and splicing principle of the active structure on the basis of the active fragment ⁇ , ⁇ -unsaturated ketone to introduce an aryl acetylene group at a suitable position , Formed a new dominant backbone of cyclohexenone, designed and synthesized a series of new 6-benzylidene-2-arylethynyl cyclohexenone derivatives that can induce tumor cell ROS levels and target TrxR.
  • the compound of the present invention greatly enriches the structural diversity of piperamide analogs, and has the activity of significantly inhibiting multiple types of tumor cells, and at the same time, the inhibitory effect on normal cells is weak, indicating that the compound of the present invention has certain tumor selectivity. Furthermore, the compounds of the present invention can significantly inhibit the activity of TrxR targets and induce an increase in the level of ROS in tumor cells, thereby promoting the anti-tumor activity of the compounds of the present invention.
  • the target compound I 8 was obtained by reacting 4h instead of 4a with 2-fluorophenylacetylene, with a yield of 67%. MS(ESI)m/z:387[M+H] + .
  • Example 15 Study on the determination of tumor cell and normal cell proliferation inhibition rate of the compound of the present invention by MTT method
  • the MTT in vitro anti-tumor test was used to evaluate the anti-proliferation activity of the compounds of the present invention on four human cancer cell lines.
  • Piperamine (PL) was used as a positive control drug.
  • Human cancer cell lines human liver cancer cell HepG2, human lung cancer cell H1975, human gastric cancer cell HGC-27, human prostate cancer cell DU145, human normal cell: human gastric mucosal epithelial cell GES-1.
  • the experimental method is as follows: Take a bottle of cells in a good state of exponential growth, add 0.25% trypsin to digest, make the adherent cells fall off, and prepare a suspension containing 2 ⁇ 10 4 to 4 ⁇ 10 4 cells per milliliter.
  • the cell suspension was inoculated on a 96-well plate, 180 ⁇ L per well, and placed in a constant temperature CO 2 incubator for 24 hours.
  • Change the medium and add test compounds I 1 -I 14 (compounds are dissolved in DMSO and diluted with PBS, the concentration of test compound is 20 ⁇ M, 20 ⁇ L per well, and incubated for 72 hours.
  • MTT is added to a 96-well plate, 20 ⁇ L per well, and incubated Reaction in the box for 4 hours.
  • the compounds I 1 to I 14 of the present invention have simultaneously studied their proliferation inhibitory activity on normal gastric cells.
  • Experimental results show that the inhibitory activity of most of the compounds of the invention on normal gastric cells is significantly weaker than that on tumor cells. This shows that the compound of the present invention can selectively inhibit the growth of tumor cells at a certain concentration, while causing less damage to normal cells.
  • the ROS-Glo hydrogen peroxide test method measures ROS changes by directly detecting H 2 O 2 levels in cells.
  • the cells were seeded into a 96-well cell culture plate and cultured with the test drug (20 ⁇ M) for 24 hours.
  • the fluorescence is detected by BioTek Synergy HT multi-mode microplate reader.
  • I 4 to I 9 and I 11 to I 12 in the compounds of general formula I of the present invention are selected as representatives, and the ROS levels in tumor cells are tested at a concentration of 20 ⁇ M.
  • DCFH-DA was used as a fluorescent probe to determine the changes of ROS in human gastric cancer HGC27 cells after drug treatment. The changes in fluorescence intensity can quantitatively reflect the intracellular ROS levels.
  • the results showed that the compounds I 4 to I 9 and I 11 to I 12 of the present invention can significantly increase the expression level of ROS in HGC27 cells at 20 ⁇ M, which is 4.2 to 9.5 times that of the control group, and is better than the positive control drug PL (3.7 times that of the control group). ).
  • Table 3 The expression levels of ROS in tumor cells of the compounds I 4 ⁇ I 9 and I 11 ⁇ I 12 of the present invention at a concentration of 20 ⁇ M (take the ROS level of the control group as 1 unit)

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Abstract

本发明公开一类6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其药学上可接受的盐、制备方法、含有这些衍生物的药用组合物以及它们的医药用途，特别是在制备针对恶性肿瘤治疗药物中的应用。本发明化合物具有一定的肿瘤选择性，能够显著抑制肿瘤增殖，对正常细胞的抑制作用较弱。本发明化合物能够显著抑制TrxR靶点活性，诱导肿瘤细胞内ROS水平增加，从而促进本发明化合物的抗肿瘤活性。

Description

6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其制备方法和医药用途 技术领域
本发明涉及药物领域，具体涉及一类6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其药学上可接受的盐，它们的制备方法，含有这些衍生物的药用组合物以及它们的医药用途，特别是在制备针对恶性肿瘤治疗药物中的应用。
背景技术
肿瘤是仅次于心血管疾病的人类第二大致死病因。临床上虽有多种抗肿瘤药物可供使用，但由于肿瘤病因的复杂性、肿瘤的耐药性以及抗肿瘤药物的毒副作用等因素，现有药物仍然不能满足治疗的需要。因此，寻找药效高、靶向性强、毒副作用小的新型抗肿瘤药物具有重要意义。
荜茇酰胺(piperlongumine,PL)具有α,β-不饱和酮的天然产物，能够有效杀死各种转移性癌细胞、且较少损伤正常细胞。α,β-不饱和酮是天然产物以及合成小分子中的重要药效基团，它可以和肿瘤高表达的生物大分子的亲核基团(如半胱氨酸残基的巯基)相互作用，调节肿瘤细胞内增殖和转移多种信号通路发挥抗肿瘤作用。机制研究表明，PL可以选择性的增加癌细胞内的ROS水平和其他氧化应激方面的水平，抑制硫氧还蛋白氧化还原酶(TrxR)，从而造成癌细胞的DNA损伤和促进癌细胞凋亡。通过骨架跃迁优化PL结构，结合PL衍生物的构效关系，设计合成新型6-苄亚基-2-芳基乙炔基环己烯酮衍生物，提高该类化合物对恶性肿瘤细胞的抑制活性是开发新的抑制硫氧还蛋白氧化还原酶活性药物的研发思路。
发明内容
本发明为了进一步提高苄亚基环己烯酮衍生物的抗肿瘤活性和酶抑制活性，根据PL及其衍生物的构效关系，在活性α,β-不饱和酮基础上，在合适的位置引入芳基乙炔基团，形成全新的环己烯酮优势骨架，设计并合成了一系列具有诱导肿瘤细胞ROS水平和靶向TrxR的新型6-苄亚基-2-芳基乙炔基环己烯酮衍生物。所设计化合物不仅提高了发明化合物的抗肿瘤活性和靶标抑制能力，而且能够选择性地抑制肿瘤细胞增殖，而对正常细胞损伤较小，同时也丰富了苄亚基环己烯酮骨架的多样性。
本发明的目的在于提供一种新型6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其制备方法和医药用途。
本发明具体技术方案如下：
一种6-苄亚基-2-芳基乙炔基环己烯酮衍生物，具有下述通式I的结构:
Figure PCTCN2020111184-appb-000001
其中，R和R’相同或不同，各代表相应取代苯环上一个或多个取代基，选自H、卤素基团、羟基、氨基、硝基、烷基、卤代烷基、烷氧基、卤代烷氧基、烷胺基中的一种或几种，R或R’代表多个取代基时，各取代基相同或不同。
优选的，R和R’相同或不同，各代表相应取代苯环上一个或多个取代基，选自H、卤素基团、羟基、氨基、硝基、C1-C6的烷基、C1-C6的卤代烷基、C1-C6的烷氧基、C1-C6的卤代烷氧基、C1-C6的烷胺基中的一种或几种，R或R’代表多个取代基时，各取代基相同或不同。
优选的，R和R’相同或不同，各代表相应取代苯环上一个或多个取代基，选自H、F、Cl、Br、I、羟基、氨基、硝基、甲基、乙基、丙基、异丙基、三氟甲基、五氟乙基、三氯甲基、三溴甲基、甲氧基、乙氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基、甲胺基，乙胺基、甲乙胺基中的一种或几种，R或R’代表多个取代基时，各取代基相同或不同。优选的，R’代表苯环上一个或多个取代基，选自H、F、Cl、Br，R’代表多个取代基时，各取代基相同或不同。
优选的，R代表苯环上一个或多个取代基，选自H、卤素基团、硝基、甲基、三氟甲基、甲氧基、三氟甲氧基、甲胺基中的一种或几种；R’代表卤素基团。
上述结构通式I优选化合物代号及其对应的结构如表1所示：
表1通式Ⅰ部分化合物代号及其对应的结构
Figure PCTCN2020111184-appb-000002
Figure PCTCN2020111184-appb-000003
本发明的另一目的在于提供本发明通式I所述6-苄亚基-2-芳基乙炔基环己烯酮的衍生物的制备方法，包括如下步骤：
(1)由R取代的苯甲醛与环己烯-2-酮通过Adol缩合反应(优选在TiCl 4和PPh 3的催化下)得到化合物3，R代表苯环上一个或多个取代基，选自H、卤素基团、羟基、氨基、硝基、烷基、卤代烷基、烷氧基、卤代烷氧基、烷胺基中的一种或几种，R代表多个取代基时，各取代基相同或不同；
Figure PCTCN2020111184-appb-000004
(2)将化合物3与碘单质反应(优选CCl 4:Py＝1:1的混合溶剂中)得到化合物4；
Figure PCTCN2020111184-appb-000005
(3)将化合物4与R’取代苯乙炔通过Sonogashira偶联反应(优选在Pd(PPh 3) 4和N,N-二异丙基乙胺(DIPEA)存在下)得到6-苄亚基-2-芳基乙炔基环己烯酮衍生物，R’代表苯环上一个或多个取代基，选自H、卤素基团、羟基、氨基、硝基、烷基、卤代烷基、烷氧基、卤代 烷氧基、烷胺基中的一种或几种，R’代表多个取代基时，各取代基相同或不同；
Figure PCTCN2020111184-appb-000006
具体合成路线如下：
Figure PCTCN2020111184-appb-000007
优选的，R代表苯环上一个或多个取代基，选自H、卤素基团、硝基、甲基、三氟甲基、甲氧基、三氟甲氧基、甲胺基中的一种或几种；R’代表卤素基团。
本发明另一目的在于提供一种药物组合物，包含本发明所述的6-苄亚基-2-芳基乙炔基环己烯酮衍生物或其药学上可接受的盐。进一步的，可以由治疗上有效剂量的通式I化合物或其药学上可接受的盐与药学上可接受的载体或辅料的药物组成。
本发明另一目的在于提供本发明所述6-苄亚基-2-芳基乙炔基环己烯酮衍生物或其药学上可接受的盐在制备硫氧还蛋白氧化还原酶抑制活性的药物中的应用。所述具有硫氧还蛋白氧化还原酶抑制活性的药物为预防和/或治疗癌症的药物。所述癌症是肝癌、前列腺癌、结肠癌、胃癌或肺癌等。
本发明化合物可以单独或与一种或一种以上的药学上可接受的载体组合制成制剂以供给药。例如，溶剂、稀释剂等，可以用口服剂型给药，如片剂、胶囊、可分散粉末、颗粒剂等。本发明药物组合物的各种剂型可以按照药学领域中熟知的方法进行制备。这些药用制剂中可以含有与载体组合的例如0.05％～90％重量的活性成分，更常见约15％～60％之间重量的活性成分。本发明化合物剂量可以是0.005～5000mg/kg/天，也可根据疾病严重程度或剂型的不同使用剂量超出此剂量范围。
本发明化合物可以与其他抗肿瘤药物例如烷化剂(如环磷酰胺或顺铂)、抗代谢药(如5-氟尿嘧啶或羟基脲)、拓扑异构酶抑制剂(如喜树碱)、有丝分裂抑制剂(如紫杉醇或长春碱)、DNA插入剂(如阿霉素)联合应用，另外还可以与放射治疗联合应用。这些其他抗肿瘤药物或放射治疗可以与本发明化合物同时或在不同时间给予。这些联合治疗可以产生协同作用从而有助 于改善治疗效果。
本发明优点：
本发明根据天然产物荜茇酰胺及其衍生物的构效关系，在活性片段α,β-不饱和酮基础上，利用活性结构的骨架跃迁和拼合原理，在合适的位置引入芳基乙炔基团，形成全新的环己烯酮优势骨架，设计并合成了一系列具有诱导肿瘤细胞ROS水平和靶向TrxR的新型6-苄亚基-2-芳基乙炔基环己烯酮衍生物。本发明化合物极大地丰富了荜茇酰胺类似物的结构多样性，并具有显著抑制多类肿瘤细胞的活性，同时对正常细胞的抑制作用较弱，说明本发明化合物具有一定的肿瘤选择性。再者，本发明化合物具有显著抑制TrxR靶点活性，诱导肿瘤细胞内ROS水平增加，从而促进本发明化合物的抗肿瘤活性。
具体实施方式
为了进一步阐明本发明，下面给出一系列实施例，这些实施例完全是例证性的，它们仅用来对本发明具体描述，不应当理解为对本发明的限制。
实施例1(E)-6-苯亚乙烯基-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 1)的制备
(E)-6-苯亚乙烯基-环己-2-烯酮(3a)
将原料环己烯-2-酮(0.95g,10.0mmol)溶于15ml无水二氯甲烷中，再在-50℃条件下加入200mg TiCl 4和PPh 3(2.62g,10.0mmol)，15min后加入苯甲醛(2.12g,20.0mmol)，室温下反应过夜。反应完全后加入10％K 2CO 3溶液处理10min，收集有机层，真空浓缩，经柱层析纯化，得到1.69g固体3a，收率：79％。MS(ESI)m/z:185[M+H] +.
(E)-2-碘代-6-苯亚乙烯基-环己-2-烯酮(4a)
将化合物3a(0.37g,2.0mmol)溶于16ml CCl 4和吡啶1:1的混合溶液中，于室温下加入碘单质(1.01g,4.0mmol)，避光搅拌3h。反应完全后，加入80ml饱和NH 4Cl溶液，混合液用乙酸乙酯(3×40ml)萃取，有机层用饱和硫代硫酸钠洗涤后，再用无水MgSO 4干燥后浓缩，经柱层析纯化，得到固体产物4a 0.76g，收率：95％。MS(ESI)m/z:311[M+H] +.
(E)-6-苯亚乙烯基-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 1)
将化合物4a(0.62g,2mmol)和2-氟苯乙炔(0.72g，6mmol)溶于15ml无水1,4-二氧六环中，氮气氛下加入Pd(PPh 3) 4(0.23g,0.2mmol)，CuI(76.18mg,0.4mmol)和DIPEA(1.05ml，6mmol)，室温搅拌10min。反应完全后，加入80ml饱和NH 4Cl溶液，混合液用二氯甲烷(3×40ml)萃取，有机层用MgSO 4干燥后浓缩，经柱层析纯化，得到目标化合物I 1 0.52g，收率：60％。MS(ESI)m/z:303[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.48-7.53(m,2H,Ar-H,ArCH),7.35-7.43(m,6H,Ar-H),7.15-7.19(m,2H,Ar-H),6.43(m,1H,C＝CH),2.97(m,2H, CH 2),2.43(m,2H,CH 2)。
实施例2(E)-6-(4-氟苯亚乙烯基)-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 2)的制备
(E)-6-(4-氟苯亚乙烯基)-环己-2-烯酮(3b)
参照化合物3a的制备方法，将苯甲醛替换成4-氟苯甲醛，得到固体化合物3b，收率：75％。MS(ESI)m/z:203[M+H] +.
(E)-2-碘代-6-(4-氟苯亚乙烯基)-环己-2-烯酮(4b)
参照化合物4a的制备方法，得到固体化合物4b，收率：95％。MS(ESI)m/z:329[M+H] +.
(E)-6-(4-氟苯亚乙烯基)-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 2)
参照化合物I 1的制备方法，将4b替代4a与2-氟苯乙炔反应，得到目标化合物I 2，收率：65％。MS(ESI)m/z:321[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.69(d,J＝8.4Hz,2H,Ar-H),7.51-7.55(m,2H,ArCH),7.38-7.41(m,3H,Ar-H),7.14-7.16(m,2H,Ar-H),6.41(m,1H,C＝CH),2.95(m,2H,CH 2),2.42(m,2H,CH 2)。
实施例3(E)-6-(2-甲基-4-甲氧基-苯亚乙烯基)-2-((4-氟苯基)乙炔基)环己-2-烯酮(I 3)的制备
(E)-6-(2-甲基-4-甲氧基-苯亚乙烯基)-环己-2-烯酮(3c)
参照化合物3a的制备方法，将苯甲醛替换成2-甲基-4-甲氧基苯甲醛，得到固体化合物3c，收率：68％。MS(ESI)m/z:229[M+H] +.
(E)-2-碘代-6-(2-甲基-4-甲氧基-苯亚乙烯基)-环己-2-烯酮(4c)
参照化合物4a的制备方法，得到固体化合物4c，收率：95％。MS(ESI)m/z:355[M+H] +.
(E)-6-(2-甲基-4-甲氧基-苯亚乙烯基)-2-((4-氟苯基)乙炔基)环己-2-烯酮(I 3)
参照化合物I 1的制备方法，将4c替代4a与4-氟苯乙炔反应，得到目标化合物I 3，收率：62％。MS(ESI)m/z:347[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.55(s,1H,ArCH),7.46(d,J＝8.4Hz,2H,Ar-H),7.10-7.16(m,3H,Ar-H),6.73(m,1H,Ar-H),6.69(m,1H,Ar-H),6.30(m,1H,CH＝),3.78(s,3H,OCH 3),2.84(m,2H,CH 2),2.35(m,2H,CH 2),2.28(s,3H,Ar-CH 3).
实施例4(E)-6-(3-硝基-4-甲氧基苯亚乙烯基)-2-((2-氯苯基)乙炔基)-环己-2-烯酮(I 4)的制备(E)-6-(3-硝基-4-甲氧基苯亚乙烯基)-环己-2-烯酮(3d)
参照化合物3a的制备方法，将苯甲醛替换成3-硝基-4-甲氧基苯甲醛，得到固体化合物3d，收率：76％。MS(ESI)m/z:260[M+H] +.
(E)-2-碘代-6-(3-硝基-4-甲氧基苯亚乙烯基)-环己-2-烯酮(4d)
参照化合物4a的制备方法，得到固体化合物4d，收率：95％。MS(ESI)m/z:386[M+H] +.
(E)-6-(3-硝基-4-甲氧基苯亚乙烯基)-2-((2-氯苯基)乙炔基)-环己-2-烯酮(I 4)
参照化合物I 1的制备方法，将4d替代4a与2-氯苯乙炔反应，得到目标化合物I 4，收率： 58％。MS(ESI)m/z:394[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.78(d,J＝2.1Hz,1H,Ar-H),7.41-7.49(m,3H,Ar-H,ArCH),7.31-7.33(m,2H,Ar-H),7.25(m,1H,Ar-H),7.11(d,J＝8.7Hz,1H,Ar-H),6.36(m,1H,CH＝),3.89(s,3H,OCH 3),2.92(m,2H,CH 2),2.37(m,2H,CH 2)。
实施例5(E)-6-(3-甲氧基苯亚乙烯基)-2-((2-溴苯基)乙炔基)环己-2-烯酮(I 5)的制备
(E)-6-(3-甲氧基苯亚乙烯基)-环己-2-烯酮(3e)
参照化合物3a的制备方法，将苯甲醛替换成3-甲氧基苯甲醛，得到固体化合物3e，收率：70％。MS(ESI)m/z:215[M+H] +.
(E)-2-碘代-6-(3-甲氧基苯亚乙烯基)-环己-2-烯酮(4e)
参照化合物4a的制备方法，得到固体化合物4e，收率：95％。MS(ESI)m/z:341[M+H] +.
(E)-6-(3-甲氧基苯亚乙烯基)-2-((2-溴苯基)乙炔基)环己-2-烯酮(I 5)
参照化合物I 1的制备方法，将4e替代4a与2-溴苯乙炔反应，得到目标化合物I 5，收率：55％。MS(ESI)m/z:393[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.51(s,1H,ArCH),7.40-7.45(m,2H,Ar-H),7.33(m,1H,Ar-H),7.26(m,1H,Ar-H),7.13(m,1H,Ar-H),7.02(m,1H,Ar-H),6.81(m,1H,Ar-H),6.39(m,1H,CH＝C),3.77(s,3H,OCH 3),2.96(m,2H,CH 2),2.37(m,2H,CH 2)；
实施例6(E)-6-(3-三氟甲基苯亚乙烯基)-2-((2,4-二氟苯基)乙炔基)环己-2-烯酮(I 6)的制备
(E)-6-(3-三氟甲基苯亚乙烯基)-环己-2-烯酮(3f)
参照化合物3a的制备方法，将苯甲醛替换成3-三氟甲基苯甲醛，得到固体化合物3f，收率：72％。MS(ESI)m/z:253[M+H] +.
(E)-2-碘代-6-(3-三氟甲基苯亚乙烯基)-环己-2-烯酮(4f)
参照化合物4a的制备方法，得到固体化合物4f，收率：95％。MS(ESI)m/z:379[M+H] +.
(E)-6-(3-三氟甲基苯亚乙烯基)-2-((2,4-二氟苯基)乙炔基)环己-2-烯酮(I 6)
参照化合物I 1的制备方法，将4f替代4a与2,4-二氟苯乙炔反应，得到目标化合物I 6，收率：58％。MS(ESI)m/z:389[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.57(s,1H,CH＝),7.43-7.46(m,3H,Ar-H),7.19(d,J＝8.0Hz,2H,Ar-H),7.01(m,1H,Ar-H),6.71(s,1H,Ar-H),6.49(m,1H,C＝CH),3.00(m,2H,CH 2),2.45(m,2H,CH 2)。
实施例7(E)-6-(4-(二甲基氨基)苯亚乙烯基)-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 7)的制备
(E)-6-(4-(二甲基氨基)苯亚乙烯基)-环己-2-烯酮(3g)
参照化合物3a的制备方法，将苯甲醛替换成4-二甲氨基苯甲醛，得到固体化合物3g，收率：70％。MS(ESI)m/z:228[M+H] +.
(E)-2-碘代-6-(4-(二甲基氨基)苯亚乙烯基)-环己-2-烯酮(4g)
参照化合物4a的制备方法，得到固体化合物4g，收率：95％。MS(ESI)m/z:354[M+H] +.
(E)-6-(4-(二甲基氨基)苯亚乙烯基)-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 7)
参照化合物I 1的制备方法，将4g替代4a与2-氟苯乙炔反应，得到目标化合物I 7，收率：60％。MS(ESI)m/z:346[M+H] +.
实施例8(E)-6-(4-三氟甲氧基苯亚乙烯基)-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 8)的制备
(E)-6-(4-三氟甲氧基苯亚乙烯基)-环己-2-烯酮(3h)
参照化合物3a的制备方法，将苯甲醛替换成4-三氟甲氧基苯甲醛，得到固体化合物3h，收率：65％。MS(ESI)m/z:269[M+H] +.
(E)-2-碘代-6-(4-三氟甲氧基苯亚乙烯基)-环己-2-烯酮(4h)
参照化合物4a的制备方法，得到固体化合物4h，收率：95％。MS(ESI)m/z:395[M+H] +.
(E)-6-(4-三氟甲氧基苯亚乙烯基)-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 8)
参照化合物I 1的制备方法，将4h替代4a与2-氟苯乙炔反应，得到目标化合物I 8，收率：67％。MS(ESI)m/z:387[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.52-7.55(m,2H,Ar-H,CH＝),7.46(m,1H,Ar-H),7.37(m,1H,Ar-H),7.31(d,J＝8.0Hz,2H,Ar-H),7.15(d,J＝8.0Hz,2H,Ar-H),7.03(m,1H,Ar-H),6.43(m,1H,C＝CH),2.93-2.99(m,2H,CH 2),2.38-2.43(m,2H,CH 2)。
实施例9(E)-6-(4-三氟甲氧基苯亚乙烯基)-2-((2-氯苯基)乙炔基)环己-2-烯酮(I 9)的制备
参照化合物I 1的制备方法，将4h替代4a与2-氯苯乙炔反应，得到目标化合物I 9，收率：67％。MS(ESI)m/z:403[M+H] +. 1H NMR(400MHz,DMSO-d 6)δ7.57(s,1H,CH＝),7.47(m,1H,Ar-H),7.31-7.35(m,4H,Ar-H),7.16(d,J＝8.0Hz,2H,Ar-H),7.05(m,1H,Ar-H),6.48(m,1H,C＝CH),2.98(m,2H,CH 2),2.41(m,2H,CH 2)。
实施例10(E)-6-(3,4-二甲氧基苯亚乙烯基)-2-((4-氟苯基)乙炔基)环己-2-烯酮(I 10)的制备
(E)-6-(3,4-二甲氧基苯亚乙烯基)-环己-2-烯酮(3i)
参照化合物3a的制备方法，将苯甲醛替换成3,4-二甲氧基苯甲醛，得到固体化合物3i，收率：80％。MS(ESI)m/z:245[M+H] +.
(E)-2-碘代-6-(3,4-二甲氧基苯亚乙烯基)-环己-2-烯酮(4i)
参照化合物4a的制备方法，得到固体化合物4i，收率：95％。MS(ESI)m/z:371[M+H] +.
(E)-6-(3,4-二甲氧基苯亚乙烯基)-2-((4-氟苯基)乙炔基)环己-2-烯酮(I 10)
参照化合物I 1的制备方法，将4i替代4a与4-氟苯乙炔反应，得到目标化合物I 10，收率：62％。MS(ESI)m/z:363[M+H] +. 1HNMR(400MHz,DMSO-d 6)δ7.47-7.51(m,3H,Ar-H),7.27(m,1H,CH＝),7.16(d,J＝8.0Hz,2H,Ar-H),6.97(m,2H,Ar-H),6.43(m,1H,C＝CH),3.95(m, 3H,OCH 3),3.81(m,3H,OCH 3),3.01(m,2H,CH 2),2.39(m,2H,CH 2).
实施例11(E)-6-(3,4,5-三甲氧基苯亚乙烯基)-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 11)的制备(E)-6-(3,4,5-三甲氧基苯亚乙烯基)-环己-2-烯酮(3j)
参照化合物3a的制备方法，将苯甲醛替换成3,4,5-三甲氧基苯甲醛，得到固体化合物3j，收率：75％。MS(ESI)m/z:275[M+H] +.
(E)-2-碘代-6-(3,4,5-三甲氧基苯亚乙烯基)-环己-2-烯酮(4j)
参照化合物4a的制备方法，得到固体化合物4j，收率：95％。MS(ESI)m/z:401[M+H] +.
(E)-6-(3,4,5-三甲氧基苯亚乙烯基)-2-((2-氟苯基)乙炔基)环己-2-烯酮(I 11)
参照化合物I 1的制备方法，将4j替代4a与2-氟苯乙炔反应，得到目标化合物I 11，收率：60％。MS(ESI)m/z:393[M+H] +. 1H NMR(400MHz,CDCl 3)δ7.57(m,1H,Ar-H),7.47(d,J＝1.6Hz,1H,Ar-H),7.38(m,1H,CH＝),7.19(m,1H,Ar-H),7.07(m,1H,Ar-H),7.01(m,1H,CH＝C),6.54(m,2H,Ar-H),3.82(s,3H,OCH 3),3.81(s,6H,2×OCH 3),3.02(m,2H,CH 2),2.49(m,2H,CH 2)。
实施例12(E)-6-(3,4,5-三甲氧基苯亚乙烯基)-2-((4-氟苯基)乙炔基)环己-2-烯酮(I 12)的制备
参照化合物I 1的制备方法，将4j替代4a与4-氟苯乙炔反应，得到目标化合物I 12，收率：62％。MS(ESI)m/z:393[M+H] +. 1H NMR(400MHz,CDCl 3)δ7.48(m,2H,Ar-H),7.36(s,1H,CH＝C),7.00-7.08(m,3H,Ar-H,CH＝),6.58(s,2H,Ar-H),3.86(s,3H,OCH 3),3.85(s,6H,OCH 3),3.05(m,2H,CH 2),2.52(m,2H,CH 2)。
实施例13(E)-6-(3,4,5-三甲氧基苯亚乙烯基)-2-((2-溴苯基)乙炔基)环己-2-烯酮(I 13)的制备
参照化合物I 1的制备方法，将4j替代4a与2-溴苯乙炔反应，得到目标化合物I 13，收率：55％。MS(ESI)m/z:453[M+H] +. 1H NMR(400MHz,CDCl 3)δ7.59(s,1H,Ar-H),7.48(m,1H,Ar-H),7.40(m,1H,CH＝),7.23(m,1H,Ar-H),7.03(m,2H,Ar-H,CH＝C),6.57(s,2H,Ar-H),3.84(s,3H,OCH 3),3.82(s,6H,2×OCH 3),3.05(m,2H,CH 2),2.51(m,2H,CH 2)。
实施例14(E)-6-(3,4,5-三甲氧基苯亚乙烯基)-2-((2,4-二氟苯基)乙炔基)环己-2-烯酮(I 14)的制备
参照化合物I 1的制备方法，将4j替代4a与2,4-二氟苯乙炔反应，得到目标化合物I 14，收率：60％。MS(ESI)m/z:411[M+H] +.
实施例15采用MTT法对本发明化合物的肿瘤细胞和正常细胞增殖抑制率测定研究
采用MTT体外抗肿瘤试验评价了本发明化合物对4种人癌细胞株的抗增殖活性。采用荜茇明碱(PL)作为阳性对照药。人癌细胞株：人肝癌细胞HepG2、人肺癌细胞H1975、人胃癌细胞HGC-27、人前列腺癌细胞DU145，人正常细胞：人胃黏膜上皮细胞GES-1。
实验方法如下：取处于指数生长期状态良好的细胞一瓶，加入0.25％胰蛋白酶消化，使贴壁细胞脱落，制成每毫升含2×10 4～4×10 4个细胞的悬液。取细胞悬液接种于96孔板上，每孔180μL，置恒温CO 2培养箱中培养24小时。换液，加入受试化合物I 1-I 14(化合物用DMSO溶解后用PBS稀释，受试化合物浓度为20μM，每孔20μL，培养72小时。将MTT加入96孔板中，每孔20μL，培养箱中反应4小时。吸去上清液，加入DMSO，每孔150μL，平板摇床上振摇5分钟。用酶联免疫检测仪在波长为570nm处测定每孔的吸收度，计算细胞抑制率。药理实验结果如表2所示，结果显示本发明化合物Ⅰ 1-Ⅰ 14在20μmol/L的浓度下，对多个人源肿瘤细胞的增殖具有不同程度的抑制作用，大部分本发明化合物对多个癌细胞具有较强程度的抑制作用，且优于阳性对照药PL，尤其本发明化合物对前列腺癌细胞表现出更优的抑制作用，活性显著优于阳性对照药PL。
表2本发明化合物对部分人肿瘤细胞和正常细胞的抑制率％(20μM)
Figure PCTCN2020111184-appb-000008
ND:未检测。
此外，本发明化合物Ⅰ 1-Ⅰ 14同时研究了对胃正常细胞的增殖抑制活性。实验结果表明，大部分本发明化合物对胃正常细胞的抑制活性均明显弱于对肿瘤细胞的抑制活性。由此说明本发明化合物在一定浓度下能够选择性地抑制肿瘤细胞生长，而对正常细胞损伤较小。
实施例16本发明化合物对TrxR抑制活性研究
受试药物(10μM)对TrxR活性影响通过TrxR活性测试盒(BioVision,Milpitas,CA,USA)评估。受试细胞株HGC27在离心管中用1x buffer液溶解后冰浴20分钟，然后在10000×g 4℃下离心15分钟。上清液转移到新的离心管里，蛋白浓度通过Bio-Rad蛋白测试法计算。样品用buffer液稀释到2X工作浓度。参照试剂盒说明书进行加样和测试。读数前使用BioTek Synergy HT多模式酶标仪震荡后5分钟内每隔20秒在412nm波长下测定吸光度。
实验结果如表3所示，结果表明化合物Ⅰ 1-Ⅰ 14在10μM浓度下均对TrxR具有显著抑制活性，大部分化合物均显示出比阳性对照药PL更强或相当的抑制活性，提示本发明化合物Ⅰ 1-Ⅰ 14具有较好的TrxR抑制活性，与其显示出抗肿瘤活性相一致。
表3本发明化合物Ⅰ 1-Ⅰ 14体外TrxR抑制率％(10μM)
Figure PCTCN2020111184-appb-000009
ND:未检测。
实施例17细胞内ROS水平测定
ROS-Glo过氧化氢测试法(Promega,Southampton,UK)通过直接探测细胞里H 2O 2水平测量ROS改变。细胞接种到96孔细胞培养板里并用受试药物(20μM)培养24小时。每孔加入过氧化氢底物溶液且在恒温CO 2培养箱37℃孵育6小时。孵育结束后，每个孔加入ROS-Glo探测液室温下孵育20分钟。荧光通过BioTek Synergy HT多模式酶标仪探测。
选择本发明通式I化合物中I 4～I 9、I 11～I 12为代表，对其在20μM浓度下对肿瘤细胞内的ROS水平进行了测试。用DCFH-DA作为荧光探针测定了人胃癌HGC27细胞在加入药物处理后的ROS变化情况，从荧光强度的变化可定量反映细胞内的ROS水平。结果表明，本发明化合物I 4～I 9、I 11～I 12在20μM可以明显提升HGC27细胞中的ROS表达水平，是control组4.2～9.5倍，优于阳性对照药PL(control组的3.7倍)。
表3本发明化合物I 4～I 9、I 11～I 12在20μM浓度下对肿瘤细胞内ROS表达水平(以control组ROS水平为1个单位)
Figure PCTCN2020111184-appb-000010

Claims (9)

  1. 一种6-苄亚基-2-芳基乙炔基环己烯酮衍生物，具有下述通式I的结构:
    Figure PCTCN2020111184-appb-100001
    其中，R和R’相同或不同，各代表相应取代苯环上一个或多个取代基，选自H、卤素基团、羟基、氨基、硝基、C1-C6的烷基、C1-C6的卤代烷基、C1-C6的烷氧基、C1-C6的卤代烷氧基、C1-C6的烷胺基中的一种或几种，R或R’代表多个取代基时，各取代基相同或不同。
  2. 根据权利要求1所述的6-苄亚基-2-芳基乙炔基环己烯酮衍生物，其特征在于：
    其中，R和R’相同或不同，各代表相应取代苯环上一个或多个取代基，选自H、F、Cl、Br、I、羟基、氨基、硝基、甲基、乙基、丙基、异丙基、三氟甲基、五氟乙基、三氯甲基、三溴甲基、甲氧基、乙氧基、三氟甲氧基、三氯甲氧基、三溴甲氧基、甲胺基，乙胺基、甲乙胺基中的一种或几种，R或R’代表多个取代基时，各取代基相同或不同。
  3. 根据权利要求2所述的6-苄亚基-2-芳基乙炔基环己烯酮衍生物，其特征在于：
    R’代表苯环上一个或多个取代基，选自H、F、Cl、Br，R’代表多个取代基时，各取代基相同或不同。
  4. 根据权利要求3所述的6-苄亚基-2-芳基乙炔基环己烯酮衍生物，其特征在于：所述通式I的结构中的R和R’选自如下组合：
    R＝H，R’＝2’-F；
    或者R＝4-F，R’＝2’-F；
    或者R＝2-CH 3-4-OCH 3，R’＝4’-F；
    或者R＝3-NO 2-4-OCH 3，R’＝2’-Cl；
    或者R＝3-OCH 3，R’＝2’-Br；
    或者R＝3-CF 3，R’＝2’,4’-di-F；
    或者R＝4-N(CH 3) 2，R’＝2’-F；
    或者R＝4-OCF 3，R’＝2’-F；
    或者R＝4-OCF 3，R’＝2’-Cl；
    或者R＝3,4-di-OCH 3，R’＝4’-F；
    或者R＝3,4,5-tri-OCH 3，R’＝2’-F；
    或者R＝3,4,5-tri-OCH 3，R’＝4’-F；
    或者R＝3,4,5-tri-OCH 3，R’＝2’-Br；
    或者R＝3,4,5-tri-OCH 3，R’＝2’,4’-di-F。
  5. 根据权利要求1-4任一项所述的6-苄亚基-2-芳基乙炔基环己烯酮衍生物的制备方法，其特征在于：包括如下步骤：
    (1)由R取代的苯甲醛与环己烯-2-酮通过Adol缩合反应得到化合物3，R代表苯环上一个或多个取代基，选自H、卤素基团、羟基、氨基、硝基、C1-C6的烷基、C1-C6的卤代烷基、C1-C6的烷氧基、C1-C6的卤代烷氧基、C1-C6的烷胺基中的一种或几种，R代表多个取代基时，各取代基相同或不同；
    Figure PCTCN2020111184-appb-100002
    (2)将化合物3与碘单质反应得到化合物4；
    Figure PCTCN2020111184-appb-100003
    (3)将化合物4与R’取代苯乙炔通过Sonogashira偶联反应得到权利要求1-4任一项所述的6-苄亚基-2-芳基乙炔基环己烯酮衍生物，R’代表苯环上一个或多个取代基，选自H、卤素基团、羟基、氨基、硝基、C1-C6的烷基、C1-C6的卤代烷基、C1-C6的烷氧基、C1-C6的卤代烷氧基、C1-C6的烷胺基中的一种或几种，R’代表多个取代基时，各取代基相同或不同；
    Figure PCTCN2020111184-appb-100004
  6. 一种药物组合物，其特征在于包含权利要求1-4任一项所述的6-苄亚基-2-芳基乙炔基环己烯酮衍生物或其药学上可接受的盐。
  7. 根据权利要求1-4任一项所述6-苄亚基-2-芳基乙炔基环己烯酮衍生物或其药学上可接受的盐在制备硫氧还蛋白氧化还原酶抑制活性的药物中的应用。
  8. 根据权利要求7所述的应用，其特征在于所述具有硫氧还蛋白氧化还原酶抑制活性的药物为预防和/或治疗癌症的药物。
  9. 根据权利要求8所述的应用，其特征在于所述癌症是肝癌、前列腺癌、结肠癌、胃癌或肺癌。
PCT/CN2020/111184 2019-11-19 2020-08-26 6-苄亚基-2-芳基乙炔基环己烯酮衍生物及其制备方法和医药用途 WO2021098319A1 (zh)

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