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CN104402785A - Novel bisamides derivative and preparation method and application thereof - Google Patents

Novel bisamides derivative and preparation method and application thereof Download PDF

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CN104402785A
CN104402785A CN201410519816.5A CN201410519816A CN104402785A CN 104402785 A CN104402785 A CN 104402785A CN 201410519816 A CN201410519816 A CN 201410519816A CN 104402785 A CN104402785 A CN 104402785A
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alkyl
halo
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acetyl
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李正名
陈有为
刘艾林
李玉新
王宝雷
潘里
万莹莹
刘敬波
陈伟
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Nankai University
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Nankai University
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Abstract

The invention relates to a novel bisamides derivative and a preparation method and an application thereof. A general formula of the novel bisamides derivative is shown as follows, and each group is shown in patent claims. The novel bisamides derivative has good antineoplastic activity, such as lung cancer, liver cancer and intestinal cancer. partial compound has higher in-vitro inhibition rate on three cancer cell bacterial strains than a control sample 5-fluorouracil, partial compound has in-vitro inhibition rate on lung adenocarcinoma (A549), liver cancer(Bel7402) and intestinal cancer (HCT-8) three cancer cell bacterial strains as high as more than 85%, and most compound has in-vitro inhibition rate on liver cancer (Bel7402) cell bacterial strain as high as more than 80%. The novel bisamides derivative can possibly be an antitumor drug.

Description

新型双酰胺衍生物及其制备和应用Novel bisamide derivatives and their preparation and application

技术领域technical field

本发明涉及新化合物的制备方法和应用，具体是新型双酰胺类衍生物的制备方法与作为制备抗肿瘤药物的应用。The invention relates to a preparation method and application of a new compound, in particular to a preparation method of a novel bisamide derivative and its application as an antitumor drug.

背景技术Background technique

肿瘤是人类面临的一个全球性难题，这类致命的疾病所引发的死亡率排在导致人类死亡病因的首位。目前化学药物治疗在解决恶性肿瘤问题中占有非常重要的地位。比如直接作用于DNA的药物：氮甲(formylmerphalan)、环磷酰胺(cyclophophamide)、卡莫司汀(carmusrtin)、喜树碱及其衍生物等；抗代谢抗肿瘤的药物：5-氟尿嘧啶(5-fluorouracil)、盐酸阿糖胞苷(cytarabine hydrochloride)等；抗有丝分裂的药物和基于肿瘤信号转导机制的药物等等。科学工作者们一直致力于发现高效新型的抗肿瘤药物。在现有技术中，如本发明所示结构新颖的双酰胺类衍生物的制备及其抗肿瘤活性的应用尚未见报道。Tumor is a global problem faced by human beings, and the death rate caused by this fatal disease ranks first in the cause of human death. Chemotherapy plays a very important role in solving the problem of malignant tumors. For example, drugs that directly act on DNA: formylmerphalan, cyclophophamide, carmustine, camptothecin and its derivatives, etc.; anti-metabolism and anti-tumor drugs: 5-fluorouracil (5 -fluorouracil), cytarabine hydrochloride, etc.; anti-mitotic drugs and drugs based on tumor signal transduction mechanisms, etc. Scientists have been devoting themselves to discovering new and efficient anti-tumor drugs. In the prior art, there are no reports on the preparation of bisamide derivatives with novel structure and their anti-tumor activity as shown in the present invention.

发明内容Contents of the invention

本发明的目的在于提供一种式I所示的新型双酰胺类衍生物的合成方法及其在制备抑制肿瘤细胞活性方面药物的应用。The object of the present invention is to provide a method for synthesizing novel bisamide derivatives represented by formula I and its application in the preparation of drugs for inhibiting tumor cell activity.

本发明提供的双酰胺衍生物具有如下通式：Bisamide derivatives provided by the present invention have the following general formula:

式中：X是C或者N。In the formula: X is C or N.

R1是H、卤素、氰基、硝基、氨基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6酰基、卤代C1-C6酰基、C1-C6烷基酰氨基、卤代C1-C6烷基酰氨基、C1-C6烷基氨基、卤代C1-C6烷基氨基、C1-C6烷硫基、卤代C1-C6烷硫基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、氯代苯基、苯氧基、卤代苯氧基、苯磺酰基、卤代苯磺酰基。R 1 is H, halogen, cyano, nitro, amino, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkane Oxygen, C 1 -C 6 acyl, halogenated C 1 -C 6 acyl, C 1 -C 6 alkylamido, halogenated C 1 -C 6 alkylamido, C 1 -C 6 alkylamino, Halogenated C 1 -C 6 alkylamino, C 1 -C 6 alkylthio, halogenated C 1 -C 6 alkylthio, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 - C 6 cycloalkyl, phenyl, chlorophenyl, phenoxy, halophenoxy, benzenesulfonyl, halobenzenesulfonyl.

R2是C1-C6烷基、卤代C1-C6烷基、C1-C6烷硫基、卤代C1-C6烷硫基、C2-C6烯氧基、卤代C2-C6烯氧基、C2-C6炔氧基、卤代C2-C6炔氧基、C2-C6烷酰氧基或卤代C2-C6烷酰氧基、C1-C6烷基羰基、C1-C6烷氧基C1-C6烷基、卤代C1-C6烷氧基C1-C6烷基、C1-C6烷硫基C1-C6烷基、或 R 2 is C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkylthio, halogenated C 1 -C 6 alkylthio, C 2 -C 6 alkenyloxy, Halogenated C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, Halogenated C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyloxy or halogenated C 2 -C 6 alkanoyl Oxygen, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkylthio C 1 -C 6 alkyl, or

m是0，1或2；n是0或1。m is 0, 1 or 2; n is 0 or 1.

R3是H、氰基、硝基，硫氰基、羟基、胍基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C1-C6烷基酰基、卤代C1-C6烷基酰基、氨基烷基酰基、氨基硫代羰基、卤代乙酰氨基硫代羰基。R 3 is H, cyano, nitro, thiocyano, hydroxyl, guanidino, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 1 -C 6 alkyl acyl, halogenated C 1 -C 6 alkyl acyl, aminoalkyl acyl, aminothiocarbonyl, haloacetamidothiocarbonyl.

R4是H、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基；R 4 is H, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy;

R5是H、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基；R 5 is H, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy;

R6是H、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基；R7是H、C1-C6烷基。R 6 is H, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy; R 7 is H, C 1 -C 6 alkyl.

R7是H、氰基、硝基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基；R7是H、C1-C6烷基。R 7 is H, cyano, nitro, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy; R 7 is H, C 1 -C 6 alkyl.

R8是H、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C2-C6环烷基。R 8 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 cycloalkyl.

R9是H、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C2-C6环烷基。R 9 is H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 cycloalkyl.

R10是卤代乙酰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C2-C6烯基、苯基、苯氧基、苄基、苯甲酰胺、苯氨基、5或6元杂环芳环基、萘基或芳族的8，9或10元稠合的杂双环体系，每个环或则环系任选的被1-5个各自独立的取代基所取代，这些取代基各自独立自卤素、氰基、硝基、C1-C6烷基酰基、卤代C1-C6烷基酰基、C1-C6烷基、卤代C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷氧基、C2-C6烯基、卤代C2-C6烯基、烷基硫基、卤代烷基硫基、烷基砜基、卤代烷基砜基，C1-C6烷氧基羰基、卤代C1-C6烷氧基羰基、C1-C6烷基氨基羰基、卤代C1-C6烷基氨基羰基，C1-C6烷基磺酰基、卤代C1-C6烷基磺酰基。R 10 is haloacetyl, C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkoxy , C 2 -C 6 -alkenyl, phenyl, phenoxy, benzyl, benzamide, phenylamino, 5- or 6-membered heterocyclic aromatic ring, naphthyl or aromatic 8-, 9- or 10-membered fused heterobicyclic ring systems, Each ring or ring system is optionally substituted by 1-5 independent substituents, each of which is independently selected from halogen, cyano, nitro, C 1 -C 6 alkanoyl, halogenated C 1 -C 6 alkyl acyl, C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkoxy, C 2 -C 6 Alkenyl, halogenated C 2 -C 6 alkenyl, alkylthio, halogenated alkylthio, alkylsulfone, halogenated alkylsulfone, C 1 -C 6 alkoxycarbonyl, halogenated C 1 -C 6 Alkoxycarbonyl, C 1 -C 6 alkylaminocarbonyl, halogenated C 1 -C 6 alkylaminocarbonyl, C 1 -C 6 alkylsulfonyl, halogenated C 1 -C 6 alkylsulfonyl.

在上述化合物的定义中，所用术语不论单独使用还是用在复合词中，代表如下取代基：In the definitions of the compounds above, the terms used, whether used alone or in compound words, represent the following substituents:

卤素为氟、氯、溴或碘；烷基为直链或支链烷基；卤代烷基为直链或支链烷基，在这些烷基上的氢原子可以部分或全部被卤原子取代；烯基为有2-6个碳原子的直链或支链并可在任何位置上存在有双键；炔基为有2-6个碳原子的直链或支链并可在任何位置上存在有三键；五元或六元杂环中杂原子为N，O和S。Halogen is fluorine, chlorine, bromine or iodine; alkyl is straight chain or branched chain alkyl; haloalkyl is straight chain or branched chain alkyl, and the hydrogen atoms on these alkyl groups can be partially or completely replaced by halogen atoms; The base is a straight chain or branched chain with 2-6 carbon atoms and double bonds can exist at any position; the alkynyl group is a straight chain or branched chain with 2-6 carbon atoms and there can be triple bonds at any position. bond; the heteroatoms in the five-membered or six-membered heterocycle are N, O and S.

可选地，X是C或者N。Optionally, X is C or N.

R1是H、卤素、氰基、硝基、氨基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、正己基、环己基、一氯甲基、一氯乙基、二氯乙基、溴甲基，氟甲基、二氟甲基、三氟甲基、七氟异丙基、甲氧基、氯甲氧基、氟甲氧基、三氟甲氧基、三氯甲氧基、乙氧基、氟乙氧基、氯乙氧基、丙氧基、乙酰基、一氯乙酰基、二氯乙酰基、三氯乙酰基、溴乙酰基、甲酰胺基、乙酰氨基、氯乙酰氨基，氟乙酰氨基、甲硫基、氯甲硫基、氟甲硫基、甲磺酰基、卤代甲磺酰基。 R is H, halogen, cyano, nitro, amino, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, iso Pentyl, n-hexyl, cyclohexyl, monochloromethyl, monochloroethyl, dichloroethyl, bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, heptafluoroisopropyl, methoxy chloromethoxy, fluoromethoxy, trifluoromethoxy, trichloromethoxy, ethoxy, fluoroethoxy, chloroethoxy, propoxy, acetyl, monochloroacetyl, Dichloroacetyl, trichloroacetyl, bromoacetyl, formamido, acetylamino, chloroacetylamino, fluoroacetylamino, methylthio, chloromethylthio, fluoromethylthio, methylsulfonyl, halomethyl Sulfonyl.

R2是C1-C6烷基、卤代C1-C6烷基、C1-C6烷硫基、卤代C1-C6烷硫基、C2-C6烯氧基、卤代C2-C6烯氧基、C2-C6炔氧基、卤代C2-C6炔氧基、C2-C6烷酰氧基或卤代C2-C6烷酰氧基、C1-C6烷基羰基、C1-C6烷氧基C1-C6烷基、卤代C1-C6烷氧基C1-C6烷基、C1-C6烷硫基C1-C6烷基、或 R 2 is C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, C 1 -C 6 alkylthio, halogenated C 1 -C 6 alkylthio, C 2 -C 6 alkenyloxy, Halogenated C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, Halogenated C 2 -C 6 alkynyloxy, C 2 -C 6 alkanoyloxy or halogenated C 2 -C 6 alkanoyl Oxygen, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxy C 1 -C 6 alkyl, halogenated C 1 -C 6 alkoxy C 1 -C 6 alkyl, C 1 -C 6 alkylthio C 1 -C 6 alkyl, or

m是0，1或2；n是0或1。m is 0, 1 or 2; n is 0 or 1.

R3是H、氰基、硝基，硫氰基、羟基、胍基、三氟乙酰基、三氟乙酰氨基乙酰基、氨基硫代羰基。 R3 is H, cyano, nitro, thiocyano, hydroxy, guanidino, trifluoroacetyl, trifluoroacetylaminoacetyl, aminothiocarbonyl.

R4、R5、R6、R7是H、氰基、硝基、甲基、乙基、正丙基、异丙基、一氯甲基、一氯乙基、二氯乙基、溴甲基，氟甲基、二氟甲基、三氟甲基、甲氧基、氯甲氧基、氟甲氧基、三氟甲氧基、三氯甲氧基、乙氧基、氟乙氧基、氯乙氧基。R 4 , R 5 , R 6 , R 7 are H, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, monochloromethyl, monochloroethyl, dichloroethyl, bromine Methyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, chloromethoxy, fluoromethoxy, trifluoromethoxy, trichloromethoxy, ethoxy, fluoroethoxy base, chloroethoxy.

R8、R9是H、甲基。R 8 and R 9 are H or methyl.

R10是卤代乙酰基、甲基、乙基、正丙基、异丙基、一氯甲基、一氯乙基、二氯乙基、溴甲基，氟甲基、二氟甲基、三氟甲基、甲氧基、氯甲氧基、氟甲氧基、三氟甲氧基、三氯甲氧基、乙氧基、氟乙氧基、氯乙氧基、氯乙烯基、苯基、苯氧基、苄基、苯甲酰胺、苯氨基、5或6元杂环芳环基、萘基或芳族的8，9或10元稠合的杂双环体系，每个环或则环系任选的被1-5个各自独立的取代基所取代，这些取代基各自独立自卤素、氰基、硝基、甲基、乙基、正丙基、异丙基、一氯甲基、一氯乙基、二氯乙基、溴甲基，氟甲基、二氟甲基、三氟甲基、五氟乙基、七氟异丙基、甲氧基、氯甲氧基、氟甲氧基、三氟甲氧基、三氯甲氧基、乙氧基、氟乙氧基、氯乙氧基、氯乙烯基、甲硫基、氯甲硫基、甲砜基、氯甲砜基，乙酰基、一氯乙酰基、二氯乙酰基、三氯乙酰基、溴乙酰基、甲氨基羰基、氯甲氨基羰基、甲氧基羰基、氯甲氧基羰基、甲酰胺基，氯甲酰胺基、甲酰氧基、氯甲酰氧基、甲磺酰基，氯甲磺酰基。 R is haloacetyl, methyl, ethyl, n-propyl, isopropyl, monochloromethyl, monochloroethyl, dichloroethyl, bromomethyl, fluoromethyl, difluoromethyl, Trifluoromethyl, methoxy, chloromethoxy, fluoromethoxy, trifluoromethoxy, trichloromethoxy, ethoxy, fluoroethoxy, chloroethoxy, chlorovinyl, benzene Base, phenoxy, benzyl, benzamide, phenylamino, 5 or 6 membered heterocyclic aromatic ring group, naphthyl or aromatic 8, 9 or 10 membered fused heterobicyclic ring system, each ring or The ring system is optionally substituted with 1-5 substituents independently selected from halogen, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, monochloromethyl , monochloroethyl, dichloroethyl, bromomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, heptafluoroisopropyl, methoxy, chloromethoxy, fluorine Methoxy, trifluoromethoxy, trichloromethoxy, ethoxy, fluoroethoxy, chloroethoxy, chlorovinyl, methylthio, chloromethylthio, methylsulfonyl, methylsulfone chloride Acetyl, monochloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, methylaminocarbonyl, chloromethylaminocarbonyl, methoxycarbonyl, chloromethoxycarbonyl, formamido, chloromethyl Amide, formyloxy, chloroformyloxy, methylsulfonyl, chloromethylsulfonyl.

更优选，X是C和N。More preferably, X is C and N.

R1是H、卤素、CN、NO2、NH2、乙酰氨基、一氯乙酰氨基、二氯乙酰氨基。R 1 is H, halogen, CN, NO 2 , NH 2 , acetamido, monochloroacetamido, dichloroacetamido.

R2是C1-C6烷基、卤代C1-C6烷基、或R3是氰基、三氟乙酰基、氨基乙酰基、三氟乙酰氨基乙酰基、乙酰氨基乙酰基。R 2 is C 1 -C 6 alkyl, halogenated C 1 -C 6 alkyl, or R 3 is cyano, trifluoroacetyl, aminoacetyl, trifluoroacetylaminoacetyl, acetamidoacetyl.

R8、R9是H、甲基。R 8 and R 9 are H or methyl.

R10是取代苯基，环被1-5个各自独立的取代基所取代，这些取代基各自独立自卤素、氰基、硝基、甲基、乙基、正丙基、异丙基、一氯乙基、甲氧基、氯甲氧基、乙氧基、氟乙氧基、一氯乙酰基、二氯乙酰基、三氯乙酰基、溴乙酰基、甲氨基羰基、氯甲氨基羰基、甲氧基羰基、氯甲氧基羰基。R 10 is a substituted phenyl group, the ring is substituted by 1-5 independent substituents, and these substituents are independently selected from halogen, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, one Chloroethyl, methoxy, chloromethoxy, ethoxy, fluoroethoxy, monochloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl, methylaminocarbonyl, chloromethylaminocarbonyl, Methoxycarbonyl, chloromethoxycarbonyl.

本发明提供的双酰胺衍生物制备方法包括的步骤：The steps that the bisamide derivative preparation method provided by the invention comprises:

双酰胺衍生物(I)合成方法一：Bisamide derivative (I) synthetic method one:

通式II化合物与通式III化合物，摩尔比1∶1，溶于有机溶剂中，然后加入有机碱，在室温下反应0.5-48小时，然后加入适量酸酸化制得化合物IV，直接下一步加入有机溶剂，然后加入有机碱和甲基磺酰氯，甲基磺酰氯和化合物IV的摩尔比为1∶1，在温度10℃以下反应0.5-3小时，制得化合物V，将一当量的化合物VI加入到上一个反应体系中，然后加入适量有机碱，在温度为-10℃到沸点下反应0.5-48小时制得目标化合物VII；化合物VII在冰浴条件下溶于含有机碱的有机溶剂中，然后加入化合物VIII，在0℃至室温条件下反应3-24h得到目标化合物I，；反应式中各基团如权利要求1所示。The compound of the general formula II and the compound of the general formula III, the molar ratio is 1:1, dissolved in an organic solvent, then adding an organic base, reacting at room temperature for 0.5-48 hours, and then adding an appropriate amount of acid to acidify to obtain compound IV, which is directly added in the next step Organic solvent, then add organic base and methanesulfonyl chloride, the molar ratio of methanesulfonyl chloride and compound IV is 1:1, and react at a temperature below 10°C for 0.5-3 hours to obtain compound V, and one equivalent of compound VI Add to the previous reaction system, then add an appropriate amount of organic base, and react at a temperature of -10°C to boiling point for 0.5-48 hours to obtain the target compound VII; compound VII is dissolved in an organic solvent containing an organic base under ice-bath conditions , and then add compound VIII, react at 0°C to room temperature for 3-24h to obtain the target compound I; each group in the reaction formula is as shown in claim 1.

所述的有机溶剂选自二氯甲烷、氯仿、四氯化碳、苯、甲苯、二甲苯、正己烷、环己烷、乙酸乙酯、四氢呋喃、1，4-二氧六环、N，N-二甲基甲酰胺或二甲基亚砜。Described organic solvent is selected from dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, n-hexane, cyclohexane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, N,N - dimethylformamide or dimethylsulfoxide.

所述的酸选自：甲基磺酸、苯磺酸、对甲基苯磺酸、乙酸、磷酸酯，或盐酸、硫酸或磷酸；The acid is selected from: methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, phosphoric acid ester, or hydrochloric acid, sulfuric acid or phosphoric acid;

所述的碱选自有机碱：三乙胺、吡啶、1，8-二氮杂-双环(5，4，0)十一碳-7-烯或N，N-二甲基苯胺；The base is selected from organic bases: triethylamine, pyridine, 1,8-diaza-bicyclo(5,4,0)undec-7-ene or N,N-dimethylaniline;

双酰胺衍生物(I)合成方法二：Bisamide derivative (I) synthetic method two:

通式II化合物与通式VI化合物，摩尔比为1∶1，溶于乙酸中，在沸点下反应0.5-12小时制得目标化合物IX；通式IX化合物和通式III化合物，摩尔比为1∶1，溶于有机溶剂中，然后加入适量的酸或碱，在温度为-10℃到沸点下反应0.5-48小时制得化合物X。化合物X在冰浴条件下溶于含有机碱的有机溶剂中，然后加入化合物XI，在0℃至室温条件下反应3-24h得到目标化合物I；反应式中各基团如权利要求1所示；R2除外，R2为C1-C5直连烷基或卤代烷基。The compound of general formula II and the compound of general formula VI, the molar ratio is 1: 1, is dissolved in acetic acid, reacts at the boiling point for 0.5-12 hours to obtain target compound IX; The compound of general formula IX and the compound of general formula III, the molar ratio is 1 : 1, dissolved in an organic solvent, then adding an appropriate amount of acid or base, and reacting at a temperature ranging from -10°C to boiling point for 0.5-48 hours to obtain compound X. Compound X is dissolved in an organic solvent containing an organic base under ice bath conditions, then compound XI is added, and reacted at 0°C to room temperature for 3-24h to obtain the target compound I; each group in the reaction formula is as shown in claim 1 ; Except for R 2 , R 2 is C 1 -C 5 straight-connected alkyl or haloalkyl.

所述的有机溶剂选自二氯甲烷、氯仿、四氯化碳、苯、甲苯、二甲苯、正己烷、环己烷、乙酸乙酯、四氢呋喃、1，4-二氧六环、N，N-二甲基甲酰胺或二甲基亚砜。Described organic solvent is selected from dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, xylene, n-hexane, cyclohexane, ethyl acetate, tetrahydrofuran, 1,4-dioxane, N,N - dimethylformamide or dimethylsulfoxide.

所述的酸选自：甲基磺酸、苯磺酸、对甲基苯磺酸、乙酸、磷酸酯，或盐酸、硫酸或磷酸。The acid is selected from: methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, phosphoric acid ester, or hydrochloric acid, sulfuric acid or phosphoric acid.

所述的碱选自有机碱：三乙胺、吡啶、1，8-二氮杂-双环(5，4，0)十一碳-7-烯或N，N-二甲基苯胺；或无机碱：氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、甲醇钠、叔丁醇钠或叔丁醇钾；The base is selected from organic bases: triethylamine, pyridine, 1,8-diaza-bicyclo(5,4,0)undec-7-ene or N,N-dimethylaniline; or inorganic Alkali: sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, sodium tert-butoxide or potassium tert-butoxide;

本发明还包括通式I化合物药学上可接受的盐。The present invention also includes pharmaceutically acceptable salts of the compounds of general formula I.

本发明还提供一种药物组合物，至少包含一种药学上可接受的载体和式I化合物或其溶剂化物。The present invention also provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a compound of formula I or a solvate thereof.

本发明还提供式I化合物或其溶剂化物药物组合物在制备抗肿瘤(例如：人肺癌细胞，人肝细胞性肝癌细胞，回盲肠癌细胞)药物方面的应用。特别是在制备治疗实体瘤药物方面的应用，药物的剂型包括注射剂、口服可接受的制剂、局部用药制剂、喷雾剂或者滴剂。The present invention also provides the application of the compound of formula I or its solvate pharmaceutical composition in the preparation of anti-tumor (for example: human lung cancer cells, human hepatocellular liver cancer cells, ileocecal cancer cells) drugs. Especially for the application in the preparation of medicines for treating solid tumors, the dosage forms of medicines include injections, orally acceptable preparations, topical preparations, sprays or drops.

本发明的双酰胺类衍生物，具有很好的抗肿瘤活性。特别是通过对人肺腺癌(A549)、肝癌(Bel7402)和肠癌(HCT-8)三种癌细胞菌株体外抑制试验，证实本发明的双酰胺衍生物具有很好的抗肿瘤活性，部分化合物对三种癌细胞菌株的体外抑制率均高于对照样5-氟尿嘧啶，部分化合物对对肺腺癌(A549)、肝癌(Bel7402)和肠癌(HCT-8)三种癌细胞菌株的体外抑制率高于85％，大部分化合物肝癌(Bel7402)细胞菌株的体外抑制率高于80％。The bisamide derivatives of the present invention have good antitumor activity. Especially through in vitro inhibition tests on three cancer cell strains of human lung adenocarcinoma (A549), liver cancer (Bel7402) and intestinal cancer (HCT-8), it is confirmed that the bisamide derivatives of the present invention have good antitumor activity, and some The in vitro inhibitory rates of the compounds on the three cancer cell strains were higher than those of the control 5-fluorouracil. Some compounds were effective against the three cancer cell strains of lung adenocarcinoma (A549), liver cancer (Bel7402) and intestinal cancer (HCT-8) in vitro. The inhibition rate is higher than 85%, and the in vitro inhibition rate of most compounds on liver cancer (Bel7402) cell strains is higher than 80%.

本发明的新型苯双酰胺衍生物对肿瘤细胞具有显著的细胞毒活性，有望成为抗肿瘤药物。The novel phenylenediamide derivatives of the present invention have significant cytotoxic activity on tumor cells, and are expected to become antitumor drugs.

具体实施方式Detailed ways

以下结合实施例来进一步说明本发明，其目的是能更好的理解本发明的内容乃体现本发明的实质性特点，因此所举之例不应视为对本发明保护范围的限制。The present invention is further described below in conjunction with embodiment, and its purpose is that content of the present invention can be better understood and embodies substantive characteristics of the present invention, so the example given should not be considered as limiting the protection scope of the present invention.

实施例中未注明具体条件的实验方法，通常按照常规条件以及手册中所述的条件，或按照制造厂商所建议的条件；所用的设备、材料、试剂等，如无特殊说明，均可从商业途径得到。For the experimental methods that do not indicate specific conditions in the examples, usually follow the conventional conditions and the conditions described in the manual, or according to the conditions suggested by the manufacturer; used equipment, materials, reagents, etc., if there are no special instructions, can be obtained from obtained commercially.

实施例1Example 1

N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-甲基-1-(1-硫甲基)-2-丙基)邻苯二甲酰胺(衍生物01)的合成：N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-methyl-1-(1-thiomethyl)-2- Synthesis of propyl)phthalamide (derivative 01):

步骤A：制备2-碘-6-羧基-N-(1，1-二甲基-2-甲硫基乙基)苯甲酰胺Step A: Preparation of 2-iodo-6-carboxy-N-(1,1-dimethyl-2-methylthioethyl)benzamide

3-碘代邻苯二甲酸酐(2.74g)、1-甲硫基-2-甲基-2-氨基丙烷(1.19g)和三乙胺(1.00g)混合溶于适量二氯甲烷中。反应混合物搅拌反应12h，后处理得黄色固体2-碘-6-羧基-N-(1，1-二甲基-2-甲硫基乙基)苯甲酰胺。收率75％，m.p.127-128℃。3-Iodophthalic anhydride (2.74g), 1-methylthio-2-methyl-2-aminopropane (1.19g) and triethylamine (1.00g) were mixed and dissolved in an appropriate amount of dichloromethane. The reaction mixture was stirred and reacted for 12 h, and worked up to obtain 2-iodo-6-carboxy-N-(1,1-dimethyl-2-methylthioethyl)benzamide as a yellow solid. Yield 75%, m.p. 127-128°C.

步骤B：制备N-乙酰基-2-甲基苯胺.Step B: Preparation of N-acetyl-2-methylaniline.

2-甲基苯胺(5.1g)、三乙胺(10.1g)和乙酰氯(3.9g)溶于适量二氯甲烷中，室温下搅拌2h。后处理得到N-乙酰基-2-甲基苯胺.Yield 95％，m.p.108-109℃。2-Methylaniline (5.1g), triethylamine (10.1g) and acetyl chloride (3.9g) were dissolved in an appropriate amount of dichloromethane, and stirred at room temperature for 2h. Workup gives N-acetyl-2-methylaniline. Yield 95%, m.p.108-109°C.

步骤C：制备N-(5-(2，2-二氯乙酰基)-2-甲基苯基)乙酰胺Step C: Preparation of N-(5-(2,2-dichloroacetyl)-2-methylphenyl)acetamide

N-乙酰基-2-甲基苯胺(2.98g)、乙酰氯(3.12g)、三氯化铝(8.54g)溶于1，2-二氯乙烷。混合物加热搅拌24小时。后处理得到浅黄色固体。产率78％，m.p.157-158℃。N-acetyl-2-methylaniline (2.98g), acetyl chloride (3.12g), aluminum chloride (8.54g) were dissolved in 1,2-dichloroethane. The mixture was stirred with heating for 24 hours. Workup gave light yellow solid. Yield 78%, m.p. 157-158°C.

步骤D：制备2-甲基-5-二氯乙酰基苯胺Step D: Preparation of 2-methyl-5-dichloroacetylaniline

N-(5-(2，2-二氯乙酰基)-2-甲基苯基)乙酰胺(1.1g)和的稀盐酸溶于甲醇，加热到回流反应8h。当后处理得到黄色固体2-甲基-5-二氯乙酰基苯胺。产率95％，m.p.70-71℃。N-(5-(2,2-dichloroacetyl)-2-methylphenyl)acetamide (1.1g) and dilute hydrochloric acid were dissolved in methanol, heated to reflux for 8h. Workup gave 2-methyl-5-dichloroacetylaniline as a yellow solid. Yield 95%, m.p. 70-71°C.

步骤E：制备N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-甲基-1-(1-硫甲基)-2-丙基)邻苯二甲酰胺Step E: Preparation of N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-methyl-1-(1-thiomethyl) )-2-propyl)phthalamide

2-碘-6-羧基-N-(1，1-二甲基-2-甲硫基乙基)苯甲酰胺(1.97g)、三乙胺(0.50g)溶于二氯甲烷溶液，保持温度5℃以下滴加溶有甲磺酰氯(0.57g)的二氯甲烷溶液，反应混合物在冰浴中搅拌反应完全，然后缓慢滴加溶有2-甲基-5-二氯乙酰基苯胺(1.09g)的二氯甲烷溶液，室温搅拌反应，后处理得白色固体搅拌-(4-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-甲基-1-(1硫甲基)丙烷-2-基)邻苯二甲酰胺。2-iodo-6-carboxy-N-(1,1-dimethyl-2-methylthioethyl)benzamide (1.97g) and triethylamine (0.50g) were dissolved in dichloromethane solution, keeping Temperature below 5 ℃, dropwise add the dichloromethane solution that dissolves methanesulfonyl chloride (0.57g), the reaction mixture is stirred in an ice bath to complete the reaction, then slowly add dropwise the solution of 2-methyl-5-dichloroacetylaniline ( 1.09g) in dichloromethane solution, stirred at room temperature for reaction, after treatment to obtain a white solid stirring -(4-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -( 2-Methyl-1-(1thiomethyl)propan-2-yl)phthalamide.

实施例二：Embodiment two:

N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-甲基-1-(1-甲磺酰基)-2-丙基)邻苯二甲酰胺(衍生物02)的合成：N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-methyl-1-(1-methylsulfonyl)-2- Synthesis of propyl)phthalamide (derivative 02):

将N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-甲基-1-(1-硫甲基)-2-丙基)邻苯二甲酰胺(0.30g)、间氯过氧苯甲酸(0.17g)溶于四氢呋喃中，室温下搅拌，后处理得到白色终产物N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-甲基-1-(1-甲磺酰基)-2-丙基)邻苯二甲酰胺。N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-methyl-1-(1-thiomethyl)-2 -Propyl)phthalamide (0.30g) and m-chloroperoxybenzoic acid (0.17g) were dissolved in tetrahydrofuran, stirred at room temperature, and post-treated to obtain the white final product N 1 -(5-(2,2- Dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-methyl-1-(1-methylsulfonyl)-2-propyl)phthalamide.

实施例三：Embodiment three:

N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-甲基-1-(1-(N-氨基羰基硫代羰基)甲硫基)-2-丙基)邻苯二甲酰胺(衍生物03)的合成：N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-methyl-1-(1-(N-aminocarbonylthio Synthesis of carbonyl)methylthio)-2-propyl)phthalamide (derivative 03):

冰浴下，将N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-甲基-1-(1-硫甲基)-2-丙基)邻苯二甲酰胺(0.30g)，醋酸碘代苯(0.134g)，氰氨(0.1g，1.5mmol)溶于四氢呋喃中，升温至室温搅拌，后处理得白色固体N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-甲基-1-(1-(N-氨基羰基硫代羰基)甲硫基)-2-丙基)邻苯二甲酰胺。Under ice bath, add N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-methyl-1-(1-thiomethyl Base)-2-propyl)phthalamide (0.30g), iodobenzene acetate (0.134g), and cyanamide (0.1g, 1.5mmol) were dissolved in tetrahydrofuran, heated to room temperature and stirred, and post-treated to obtain a white Solid N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-methyl-1-(1-(N-aminocarbonylthio Carbonyl)methylthio)-2-propyl)phthalamide.

实施例四：Embodiment four:

N1-(4-氰基苯基)-3-碘-N2-(2-甲基-1-(1-甲硫基)-2-丙基)邻苯二甲酰胺(化合物35)N 1 -(4-cyanophenyl)-3-iodo-N 2 -(2-methyl-1-(1-methylthio)-2-propyl)phthalamide (compound 35)

步骤A：制备4-硝基苯腈Step A: Preparation of 4-nitrobenzonitrile

4-硝基苯甲醛(7.56g)，300mL氨水和碘单质(13.9g)溶于四氢呋喃，室温下搅拌，后处理得到白色固体4-硝基苯腈，收率75％，m.p.115-116℃。4-Nitrobenzaldehyde (7.56g), 300mL of ammonia and iodine (13.9g) were dissolved in tetrahydrofuran, stirred at room temperature, and post-treated to obtain 4-nitrobenzonitrile as a white solid with a yield of 75%, m.p.115-116°C .

步骤B：制备4-氰基苯胺Step B: Preparation of 4-cyanoaniline

4-硝基苯腈(2.16g)和0.216g钯碳溶于甲醇，再通入氢气，室温下搅拌。后处理得到浅黄色固体4-氰基苯胺，产率85％，m.p.75-76℃。4-Nitrobenzonitrile (2.16 g) and 0.216 g of palladium carbon were dissolved in methanol, and hydrogen gas was introduced, and stirred at room temperature. Workup gave 4-cyanoaniline as a pale yellow solid in 85% yield, m.p.75-76°C.

步骤C：制备N1-(4-氰基苯基)-3-碘-N2-(2-甲基-1-(1-甲硫基)-2-丙基)邻苯二甲酰胺Step C: Preparation of N 1 -(4-cyanophenyl)-3-iodo-N 2 -(2-methyl-1-(1-methylthio)-2-propyl)phthalamide

2-碘-6-羧基-N-(1，1-二甲基-2-甲硫基乙基)苯甲酰胺(1.97g)、三乙胺(0.50g)溶于二氯甲烷溶液，保持温度5℃以下滴加溶有甲磺酰氯(0.57g)，反应完全后加入4-氰基苯胺(0.59g)，室温搅拌后处理得白色固体N1-(4-氰基苯基)-3-碘-N2-(2-甲基-1-(1-甲硫基)-2-丙基)邻苯二甲酰胺。2-iodo-6-carboxy-N-(1,1-dimethyl-2-methylthioethyl)benzamide (1.97g) and triethylamine (0.50g) were dissolved in dichloromethane solution, keeping Add methanesulfonyl chloride (0.57g) dropwise at a temperature below 5°C, add 4-cyanoaniline (0.59g) after the reaction is complete, and stir at room temperature to obtain a white solid N 1 -(4-cyanophenyl)-3 -iodo-N 2 -(2-methyl-1-(1-methylthio)-2-propyl)phthalamide.

实施例五：N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-氯乙基)邻苯二甲酰胺(衍生物421)Example 5: N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-chloroethyl)phthalamide (derivative object 421)

步骤A：制备2-碘-6-羧基-N-(2-氯乙基)苯甲酰胺Step A: Preparation of 2-iodo-6-carboxy-N-(2-chloroethyl)benzamide

3-碘代邻苯二甲酸酐(2.74g)、2-氯乙胺盐酸盐(1.39g)和三乙胺(2.40g，24mmol)溶于二氯甲烷溶液，混合物搅拌反应12h，后处理得到白色固体2-碘-6-羧基-N-(2-氯乙基)苯甲酰胺，收率76％。3-iodophthalic anhydride (2.74g), 2-chloroethylamine hydrochloride (1.39g) and triethylamine (2.40g, 24mmol) were dissolved in dichloromethane solution, the mixture was stirred for 12h, and post-treated The white solid 2-iodo-6-carboxy-N-(2-chloroethyl)benzamide was obtained in a yield of 76%.

步骤B：制备N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-氯乙基)邻苯二甲酰胺Step B: Preparation of N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-chloroethyl)phthalamide

2-碘-6-羧基N-(1，1-二甲基-2-甲硫基乙基)苯甲酰胺(1.97g)、三乙胺(0.50g)溶于二氯甲烷溶液，保持温度5℃以下滴加溶有甲磺酰氯(0.57g)，混合物在冰浴中反应完全，然后加入2-甲基-5-二氯乙酰基苯胺(1.09g)，室温搅拌反应，后处理得白色固体N1-(5-(2，2-二氯乙酰基)-2-甲基苯基)-3-碘-N2-(2-氯乙基)邻苯二甲酰胺。2-iodo-6-carboxy N-(1,1-dimethyl-2-methylthioethyl)benzamide (1.97g) and triethylamine (0.50g) were dissolved in dichloromethane solution and kept at temperature Below 5°C, add methanesulfonyl chloride (0.57g) dropwise, and the mixture reacts completely in an ice bath, then add 2-methyl-5-dichloroacetylaniline (1.09g), stir at room temperature, and after treatment, a white Solid N 1 -(5-(2,2-dichloroacetyl)-2-methylphenyl)-3-iodo-N 2 -(2-chloroethyl)phthalamide.

现将根据实施例1～5的制备方法而采用不同的原料制备的该类衍生物01～508，列入表1a～1c，部分衍生物1H NMR(Bruker AV400 spectrometer using tetramethylsilane as the internalstandard)数据列入表2。The derivatives 01-508 prepared by using different raw materials according to the preparation methods of Examples 1-5 are now listed in Tables 1a-1c, and some derivatives 1 H NMR (Bruker AV400 spectrometer using tetramethylsilane as the internal standard) data Included in Table 2.

本发明的部分化合物结构式如下：The structural formula of some compounds of the present invention is as follows:

表1aTable 1a

表1bTable 1b

表1cTable 1c

表2Table 2

实施例六：本发明提供的邻苯二甲酰胺类衍生物的抗肿瘤活性Embodiment 6: Antitumor activity of phthalamide derivatives provided by the present invention

1)抗肿瘤活性实验原理1) Experimental principle of anti-tumor activity

四氮唑[MTT，3-(4，5-dimethylthiazol-2-yl)-2，5-diphenyl-tetrazolium bromide]是一种能接受氢原子的染料。活细胞线粒体中与NADP相关的脱氢酶在细胞内可将黄色的MTT转化成不溶性的蓝紫色的formazon，而死细胞则无此功能。用DMSO溶解formazon后，在一定波长下用酶标仪测定光密度值，既可定量测出细胞的存活率。Tetrazolium [MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide] is a dye that can accept hydrogen atoms. The dehydrogenase associated with NADP in the mitochondria of living cells can convert yellow MTT into insoluble blue-purple formazon in cells, while dead cells have no such function. After dissolving formazon with DMSO, measure the optical density value with a microplate reader at a certain wavelength, which can quantitatively measure the survival rate of cells.

2)抗肿瘤活性实验方法2) Anti-tumor activity test method

A实验材料：A549(人肺癌细胞)，BEL-7402(人肝细胞性肝癌细胞)，HCT-8(回盲肠癌细胞)，5-Fu(5-氟尿嘧啶)，1640培养基(A549、HCT-8)，MEM培养基(BEL7402)，胎牛血清，噻唑蓝(MTT)，二甲基亚砜(DMSO)，生理盐水，96孔细胞培养板(Costar)，水套式CO2细胞培养箱(Sanyo，日本)，M5微孔读板机(MD，美国)。A Experimental materials: A549 (human lung cancer cells), BEL-7402 (human hepatocellular carcinoma cells), HCT-8 (ileocecal cancer cells), 5-Fu (5-fluorouracil), 1640 medium (A549, HCT- 8), MEM medium (BEL7402), fetal bovine serum, thiazolium blue (MTT), dimethyl sulfoxide (DMSO), physiological saline, 96-well cell culture plate (Costar), water-jacketed CO 2 cell incubator ( Sanyo, Japan), M5 microplate reader (MD, USA).

B：试验步骤B: Test procedure

a.选用对数生长期的贴壁A549(人肺癌细胞)，BEL-7402(人肝细胞性肝癌细胞)，HCT-8(回盲肠癌细胞)三种肿瘤细胞(中国医学科学院药物研究所国家药物筛选中心细胞库提供)，分别用胰酶消化后，用10％小牛血清的RPMI1640培养液配成15000个/ml的细胞悬液，接种在96孔培养板中，每孔接种190μl，37℃，5％CO2培养24h。a. Three kinds of tumor cells, A549 (human lung cancer cells), BEL-7402 (human hepatocellular carcinoma cells), and HCT-8 (ileocecal cancer cells), in the logarithmic growth phase (National Institute of Materia Medica, Chinese Academy of Medical Sciences) were selected. Drug Screening Center Cell Bank), digested with trypsin respectively, prepared 15000 cells/ml cell suspension with 10% calf serum RPMI1640 culture medium, inoculated in 96-well culture plate, inoculated 190 μl per well, 37 Cultivate at 5% CO 2 for 24h.

b.实验组加样品10μl，每孔终体积为200μl，用1640培养液补足。37℃，5％CO2培养3d。b. Add 10 μl of sample to the experimental group, the final volume of each well is 200 μl, and make up with 1640 culture medium. Culture at 37°C, 5% CO 2 for 3 days.

c.弃上清液，每孔加入100μl新鲜配制的0.5mg/ml MTT的无血清培养液，37℃继续培养4h。小心弃上清，并加入150μl DMSO溶解MTT formazon沉淀，用微型振荡器混匀，在酶标仪上测定波长544nm处的光密度值。c. Discard the supernatant, add 100 μl freshly prepared 0.5 mg/ml MTT serum-free culture medium to each well, and continue to incubate at 37°C for 4 hours. Discard the supernatant carefully, and add 150 μl DMSO to dissolve the MTT formazon precipitate, mix with a micro-oscillator, and measure the optical density value at a wavelength of 544 nm on a microplate reader.

3)抗肿瘤活性实验方法3) Anti-tumor activity test method

a.细胞抑制率计算a. Calculation of cell inhibition rate

肿瘤细胞生长抑制率(％)＝(OD对照-OD实验)/(OD对照-OD空白)X 100％Tumor cell growth inhibition rate (%)=(OD control-OD experiment)/(OD control-OD blank) X 100%

阳性评价标准：抑制率大于50％。Positive evaluation criteria: inhibition rate greater than 50%.

b.IC50值计算b. Calculation of IC 50 value

式样浓度对数值与细胞抑制率线性回归，利用软件(GWBASIC软件)计算试样针对细胞的半数抑制浓度IC50值。The logarithmic value of the sample concentration and the cell inhibition rate were linearly regressed, and the IC 50 value of the half inhibitory concentration of the sample against the cells was calculated by software (GWBASIC software).

通过体外细胞毒试验，得到如下结果：Through the in vitro cytotoxicity test, the following results were obtained:

表3部分化合物在5μg/mL的浓度下的细胞抑制率Cell inhibition rate of some compounds in table 3 at a concentration of 5 μg/mL

表中抑制率等级：A级为＞50％，B级为50％～20％，C级为＜20％。Inhibition rate grades in the table: grade A is >50%, grade B is 50%-20%, grade C is <20%.

部分化合物活性超过对照药5-氟尿嘧啶(5-fu)举例如下表5：Some compounds are more active than the reference drug 5-fluorouracil (5-fu). Examples are shown in Table 5 below:

表4化合物01和02对BEL-7402，HCT-8和A549的IC50值Table 4 IC 50 values of compounds 01 and 02 against BEL-7402, HCT-8 and A549

从表3可以看出本发明的大部分双酰胺类衍生物在测试浓度下对A549(人肺癌细胞)，BEL-7402(人肝细胞性肝癌细胞)，HCT-8(回盲肠癌细胞)三种肿瘤细胞有非常好的抑制效果，大部分衍生物的抑制率都超过对照样5-fu(5-氟尿嘧啶)，从表4可以看出已测试的化合物01和化合物02的部分IC50值均小于对照样5-fu(5-氟尿嘧啶)。因此，本发明的新型双酰胺衍生物具有很好的抗肿瘤活性。As can be seen from Table 3, most of the bisamides derivatives of the present invention are to A549 (human lung cancer cells), BEL-7402 (human hepatocellular carcinoma cells), HCT-8 (ileocecal cancer cells) three This tumor cell has a very good inhibitory effect, and the inhibition rate of most of the derivatives is higher than that of the control sample 5-fu (5-fluorouracil). It can be seen from Table 4 that the partial IC 50 values of the tested compound 01 and compound 02 are all Less than the control sample 5-fu (5-fluorouracil). Therefore, the novel bisamide derivatives of the present invention have good antitumor activity.

Claims (10)

1. a class bisamide derivatives (I), is characterized in that having following structural formula:
In formula: X is C or N;
R 1h, halogen, cyano group, nitro, amino, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group, C 1-C 6acyl group, halo C 1-C 6acyl group, C 1-C 6alkyl amido, halo C 1-C 6alkyl amido, C 1-C 6alkylamino, halo C 1-C 6alkylamino, C 1-C 6alkylthio, halo C 1-C 6alkylthio, C 2-C 6thiazolinyl, C 2-C 6alkynyl, C 3-C 6cycloalkyl, phenyl, chlorophenyl, phenoxy group, halogenated phenoxy, benzenesulfonyl, halobenzenelsulfonyl;
R 2c 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkylthio, halo C 1-C 6alkylthio, C 2-C 6alkene oxygen base, halo C 2-C 6alkene oxygen base, C 2-C 6alkynyloxy group, halo C 2-C 6alkynyloxy group, C 2-C 6alkanoyloxy or halo C 2-C 6alkanoyloxy, C 1-C 6alkyl-carbonyl, C 1-C 6alkoxy C 1-C 6alkyl, halo C 1-C 6alkoxy C 1-C 6alkyl, C 1-C 6alkylthio C 1-C 6alkyl or
M is 0,1 or 2;
N is 0 or 1;
R 3h, cyano group, nitro, thiocyanogen, hydroxyl, guanidine radicals, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group, C 1-C 6alkyl acyl, halo C 1-C 6alkyl acyl, aminoalkyl group acyl group, aminothiocarbonyl, haloacetamido thiocarbonyl;
R 4h, cyano group, nitro, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group;
R 5h, cyano group, nitro, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group;
R 6h, cyano group, nitro, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group; R 7h, C 1-C 6alkyl;
R 7h, cyano group, nitro, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group;
R 8h, C 1-C 6alkyl, C 2-C 6alkenyl, C 2-C 6alkynyl, C 2-C 6cycloalkyl;
R 9h, C 1-C 6alkyl, C 2-C 6alkenyl, C 2-C 6alkynyl, C 2-C 6cycloalkyl;
R 10haloacetyl, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group, C 2-C 6thiazolinyl, phenyl, phenoxy group, benzyl, benzamide, phenylamino, 5 or 6 yuan of heterocycle aromatic ring yls, naphthyl or aromatics 8,9 or 10 yuan of assorted bicyclic systems condensed, each ring or ring system optional by 1-5 separately independently substituting group replace, these substituting groups separately independence from halogen, cyano group, nitro, C 1-C 6alkyl acyl, halo C 1-C 6alkyl acyl, C 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkoxyl group, halo C 1-C 6alkoxyl group, C 2-C 6thiazolinyl, halo C 2-C 6thiazolinyl, alkyl sulfenyl, haloalkylthio, alkyl sulfuryl, haloalkyl sulfuryl, C 1-C 6alkoxy carbonyl, halo C 1-C 6alkoxy carbonyl, C 1-C 6alkyl amino-carbonyl, halo C 1-C 6alkyl amino-carbonyl, C 1-C 6alkyl sulphonyl, halo C 1-C 6alkyl sulphonyl,
In the definition of above-claimed cpd, no matter term used is used alone or is used in compound word, represent following substituting group:
Halogen is fluorine, chlorine, bromine or iodine;
Alkyl is straight or branched alkyl;
Haloalkyl is straight or branched alkyl, and the hydrogen atom on these alkyl can partly or entirely be replaced by halogen atom;
Thiazolinyl is have the straight or branched of 2-6 carbon atom and can have double bond on any position;
Alkynyl is have the straight or branched of 2-6 carbon atom and can have triple bond on any position;
In five yuan or hexa-member heterocycle, heteroatoms is N, O and S.
2. bisamide derivatives according to claim 1, is characterized in that:
X is C or N;
R 1h, halogen, cyano group, nitro, amino, methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl, isopentyl, n-hexyl, cyclohexyl, chloromethyl, one chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, seven fluorine sec.-propyls, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy, propoxy-, ethanoyl, one chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide, formamido-, kharophen, chloro acetylamino, acetyl fluoride is amino, methylthio group, chloromethane sulfenyl, fluorine methylthio group, methylsulfonyl, halo methylsulfonyl,
R 2c 1-C 6alkyl, halo C 1-C 6alkyl, C 1-C 6alkylthio, halo C 1-C 6alkylthio, C 2-C 6alkene oxygen base, halo C 2-C 6alkene oxygen base, C 2-C 6alkynyloxy group, halo C 2-C 6alkynyloxy group, C 2-C 6alkanoyloxy or halo C 2-C 6alkanoyloxy, C 1-C 6alkyl-carbonyl, C 1-C 6alkoxy C 1-C 6alkyl, halo C 1-C 6alkoxy C 1-C 6alkyl, C 1-C 6alkylthio C 1-C 6alkyl or
M is 0,1 or 2;
N is 0 or 1;
R 3h, cyano group, nitro, thiocyanogen, hydroxyl, guanidine radicals, trifluoroacetyl group, trifluoroacetamido ethanoyl, aminothiocarbonyl;
R 4, R 5, R 6, R 7h, cyano group, nitro, methyl, ethyl, n-propyl, sec.-propyl, chloromethyl, a chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy;
R 8, R 9h, methyl;
R 10it is haloacetyl, methyl, ethyl, n-propyl, sec.-propyl, chloromethyl, one chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy, chlorovinyl, phenyl, phenoxy group, benzyl, benzamide, phenylamino, 5 or 6 yuan of heterocycle aromatic ring yls, 8,9 or 10 yuan of assorted bicyclic systems condensed of naphthyl or aromatics, or each ring ring system optional by 1-5 separately independently substituting group replace, these substituting groups separately independence from halogen, cyano group, nitro, methyl, ethyl, n-propyl, sec.-propyl, chloromethyl, one chloroethyl, Dichloroethyl, brooethyl, methyl fluoride, difluoromethyl, trifluoromethyl, pentafluoroethyl group, seven fluorine sec.-propyls, methoxyl group, chlorine methoxyl group, fluorine methoxyl group, trifluoromethoxy, trichloromethoxy, oxyethyl group, fluorine oxyethyl group, chloroethoxy, chlorovinyl, methylthio group, chloromethane sulfenyl, methylsulfonyl, chloromethane sulfuryl, ethanoyl, one chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide, amino-carbonyl, chloromethane aminocarboxyl, methoxycarbonyl, chloromethVloxvcarbonyl, formamido-, chloroformyl amido, methanoyl, chloromethane acyloxy, methylsulfonyl, chloromethanesulfonyl.
3. bisamide derivatives according to claim 1, is characterized in that:
X is C and N
R 1h, halogen, CN, NO 2, NH 2, kharophen, a chloro acetylamino, dichloro acetamino;
R 2c 1-C 6alkyl, halo C 1-C 6alkyl or r 3cyano group, trifluoroacetyl group, glycyl, trifluoroacetamido ethanoyl, kharophen ethanoyl;
R 8, R 9h, methyl;
R 10it is substituted-phenyl; ring by 1-5 separately independently substituting group replace, these substituting groups separately independence from halogen, cyano group, nitro, methyl, ethyl, n-propyl, sec.-propyl, a chloroethyl, methoxyl group, chlorine methoxyl group, oxyethyl group, fluorine oxyethyl group, a chloracetyl, dichloro-acetyl, tribromo-acetyl base, acetyl bromide, amino-carbonyl, chloromethane aminocarboxyl, methoxycarbonyl, chloromethVloxvcarbonyl.
4. bisamide derivatives according to claim 1, is characterized in that they are compounds of following synthesis:
Compound 1:N 1-(5-chloracetyl-2-aminomethyl phenyl) the iodo-N of-3- 2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 2:N 1-(5-dichloro-acetyl-2-aminomethyl phenyl) the iodo-N of-3- 2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 3:N 1-(5-dichloro-acetyl-2-aminomethyl phenyl)-3-nitro-N 2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 4:N 1-(5-dichloro-acetyl-2-aminomethyl phenyl)-3-nitro-N 2-(2-methyl isophthalic acid-(methylsulfonyl)-2-propyl group) phthalic diamide;
Compound 5:N 1-(5-dichloro-acetyl-2-aminomethyl phenyl)-N 2the adjacent pyridine diformamide of-(2-methyl isophthalic acid-(methylthio group)-2-propyl group);
Compound 6:N 1-(5-dichloro-acetyl-2-aminomethyl phenyl)-N 2the adjacent pyridine diformamide of-(2-methyl isophthalic acid-(methylsulfonyl)-2-propyl group);
Compound 7:N 1-(5-dichloro-acetyl-2,6-3,5-dimethylphenyl) the iodo-N of-3- 2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 8:N 1-(5-dichloro-acetyl-2,6-3,5-dimethylphenyl) the iodo-N of-3- 2-(2-methyl isophthalic acid-(methylsulfonyl)-2-propyl group) phthalic diamide;
Compound 9:N 1-(4-dichloro-acetyl phenyl) the iodo-N of-3- 2-(2-methyl isophthalic acid-(methylthio group)-2-propyl group) phthalic diamide;
Compound 10:N 1-(4-dichloro-acetyl phenyl) the iodo-N of-3- 2-(2-methyl isophthalic acid-(methylsulfonyl)-2-propyl group) phthalic diamide;
Compound 11:N 1-(5-dichloro-acetyl-2-aminomethyl phenyl) the iodo-N of-3- 2-(2-chloroethyl) phthalic diamide;
Compound 12:N 1-(5-dichloro-acetyl-2-aminomethyl phenyl)-3-nitro-N 2-(2-chloroethyl) phthalic diamide.
5. the preparation method of bisamide derivatives according to claim 1, is characterized in that comprising following step:
Bisamide derivatives (I) synthetic method one:
Compounds of formula II and compound of formula III, mol ratio 1: 1, be dissolved in organic solvent, then organic bases is added, at room temperature react 0.5-48 hour, then add appropriate amount of acid acidifying and obtain compound IV, directly next step adds organic solvent, then organic bases and Methanesulfonyl chloride is added, the mol ratio of Methanesulfonyl chloride and compound IV is 1: 1, at temperature less than 10 DEG C reaction 0.5-3 hour, obtained compound V, the compound vI of monovalent is joined in a upper reaction system, then appropriate organic bases is added, 0.5-48 hour obtained target compound VII is reacted under temperature is for-10 DEG C to boiling point, compound VI I is dissolved in the organic solvent containing organic bases under condition of ice bath, then adds compound VI II, reacts 3-24h and obtain target compound I under 0 DEG C to room temperature condition, in reaction formula, each group is as shown in claim 1.
Bisamide derivatives (I) synthetic method two:
Compounds of formula II and compound of formula VI, mol ratio is 1: 1, is dissolved in acetic acid, reacts 0.5 at the boiling point -12 hours obtained target compound IX; Formula IX compound and compound of formula III, mol ratio is 1: 1, is dissolved in organic solvent, then adds appropriate acid or alkali, under temperature is for-10 DEG C to boiling point, react 0.5-48 hour obtained compounds X.Compounds X is dissolved in the organic solvent containing organic bases under condition of ice bath, then adds compounds X I, reacts 3-24h and obtain target compound I under 0 DEG C to room temperature condition; In reaction formula, each group is as shown in claim 1; R 2except, R 2for C 1-C 5direct-connected alkyl or haloalkyl; Described organic solvent is selected from methylene dichloride, chloroform, tetracol phenixin, benzene,toluene,xylene, normal hexane, hexanaphthene, ethyl acetate, tetrahydrofuran (THF), Isosorbide-5-Nitrae-dioxane, DMF or dimethyl sulfoxide (DMSO); Described acid is selected from: methylsulphonic acid, Phenylsulfonic acid, p-methyl benzenesulfonic acid, acetic acid, phosphoric acid ester, or hydrochloric acid, sulfuric acid or phosphoric acid.
6. preparation method according to claim 5, is characterized in that described alkali is selected from organic bases: triethylamine, pyridine, 1,8-diaza-dicyclo (5,4,0) 11 carbon-7-alkene or DMA; Or mineral alkali: sodium hydroxide, potassium hydroxide, sodium carbonate, salt of wormwood, sodium methylate, sodium tert-butoxide or potassium tert.-butoxide; Described oxygenant is potassium permanganate, m-CPBA, NaClO 2, NaIO 4/ RuO 2, H 2o 2or ozone.
7. the arbitrary described bisamide derivatives of claim 1-4 and new intermediate thereof are preparing the application in antitumor drug.
8. their mixture of the arbitrary described bisamide derivatives of claim 1-4 or its pharmacy acceptable salt or its positional isomers, steric isomer, optical isomer, cis-trans-isomer or any ratio is preparing the application in antitumor drug, comprise lung cancer, liver cancer or intestinal cancer.
9. a pharmaceutical composition, comprises the pharmaceutically acceptable carrier of at least one and formula I or its solvate as defined in claim 1.
10. pharmaceutical composition according to claim 9 is preparing the application in antitumor drug.
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CN109574892A (en) * 2018-11-29 2019-04-05 常州沃腾化工科技有限公司 Microchannel plate should prepare the iodo- N-(1,1- dimethyl -2-methylmercaptoethyl of 3-) method of phthalamic acid

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Application publication date: 20150311