WO2015158244A1 - 一种异羟肟酸类化合物及其在制备抑制癌细胞增殖和/或治疗癌症的药物中的应用 - Google Patents

一种异羟肟酸类化合物及其在制备抑制癌细胞增殖和/或治疗癌症的药物中的应用 Download PDF

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WO2015158244A1
WO2015158244A1 PCT/CN2015/076519 CN2015076519W WO2015158244A1 WO 2015158244 A1 WO2015158244 A1 WO 2015158244A1 CN 2015076519 W CN2015076519 W CN 2015076519W WO 2015158244 A1 WO2015158244 A1 WO 2015158244A1
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human
hydroxamic acid
cancer cell
acid compound
cancer
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French (fr)
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袁其朋
邓炳华
谢瑞
武新颖
屈悦
杨明
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北京化工大学
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms

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  • the present invention relates to a class of hydroxamic acid compounds, processes for their preparation and uses.
  • Histone deacetylase HDAC
  • histone acetyltransferase HAT
  • Histone deacetylase HDAC
  • histone acetyltransferase HAT
  • the acetylation and deacetylation of histones is a way to regulate gene transcription.
  • the degree of acetylation of histones affects the expression of genes by affecting the structure of chromatin. Histone acetylation status is diverse, and specific gene sites perform histone acetylation in a site-specific manner.
  • Histone deacetylase and histone acetyltransferase jointly control the acetylation of histones in vivo. The situation is in dynamic balance. Histone acetyltransferase acts as a coactivator to regulate transcription, regulate cell cycle, and participate in DNA damage repair. Histone deacetylases are involved in chromosomal translocation, transcriptional regulation, gene silencing, cell cycle, cell differentiation and proliferation, and apoptosis.
  • Histone deacetylase inhibitors can increase acetylation of chromosomal specific histones by inhibiting histone deacetylase activity. In turn, the tumor suppressor gene is restored to expression, thereby inhibiting the growth of cancer cells.
  • Histone deacetylase inhibitors have certain tumor specificity, inhibiting both proliferating and resting mutant cells, but do not cause growth arrest or apoptosis in some normal cells.
  • Histone deacetylase inhibitors are a new class of high-efficiency, low-toxic anti-tumor drugs with great development potential, and have great research value.
  • SAHA histone deacetylase inhibitor
  • SAHA Vorinostat
  • the present invention provides a hydroxamic acid compound represented by the general formula (I), which has been experimentally proven to have a strong ability to inhibit proliferation against a variety of cancer cells, and has an excellent therapeutic effect on patients suffering from cancer.
  • Chinese Patent Application Publication No. CN103159646A discloses that a compound N-(2,5-dimethoxyphenyl)-N'-hydroxyoctanediamide has an inhibitory effect on proliferation of various cancer cells, but fails to reach The better result.
  • U.S. Patent No. 5,369,108 discloses a series of hydroxamic acid compounds which also have an inhibitory effect on the proliferation of cancer cells.
  • the present invention provides a series of novel hydroxamic acid-based compounds, and the hydroxamic acid compounds having excellent anti-cancer cell proliferation provided by the present invention have not been mentioned or disclosed in the above patents.
  • U.S. Patent (US 5,369,108) first describes the preparation of Volley using an acid chloride intermediate. Novo (SAHA) method, which not only produces low yields but also causes serious environmental pollution and produces a large amount of waste.
  • Chinese patent applications Publication Nos. CN102264694A and CN103159646A
  • J.Med.Chem. 2005, 48, 5047-5051 also report the preparation of SAHA, which utilizes the Carter condensing agent BOP or dicyclohexylcarbodiimide (DCC).
  • Other condensing agents and auxiliary agents such as N,N-diisopropylethylamine (DIEA) promote the synthesis of the intermediate (IV) in the first step.
  • DIEA N,N-diisopropylethylamine
  • condensing agents and adjuvants described herein are not only expensive, but also produce two molar equivalents of condensing agent and auxiliary by-product waste, resulting in serious environmental pollution. Moreover, their purification of the hydroxamic acid compound needs to be separated by a silica gel column, and in addition to a long time, silica gel and a large amount of eluent are wasted.
  • the present invention provides a novel process for the efficient synthesis of vorinostat (SAHA) using boric acid as a catalyst without waste other than water.
  • SAHA vorinostat
  • This reaction is not only highly atomic, but also a green and low carbon chemical reaction.
  • the present invention relates to the design and synthesis of a class of hydroxamic acids.
  • the present invention provides a hydroxamic acid compound which is more excellent in pharmacodynamic activity.
  • Another technical problem to be solved by the present invention is to provide a process for producing the above hydroxamic acid compound. The reason why the present invention can solve the above problems is achieved by the following technical solutions:
  • a hydroxamic acid compound characterized by the structure represented by the following formula (I):
  • A is selected from: hydrogen or hydroxyl
  • B is selected from the group consisting of: bromine, chlorine, fluorine or alkyl
  • C is selected from the group consisting of hydrogen, bromine, chlorine, fluorine, alkyl or alkoxy;
  • D is selected from the group consisting of hydrogen, chlorine, alkyl or fluoro substituted alkyl.
  • A, C, and D are not hydrogen at the same time; and B and C are not fluorine at the same time.
  • the hydroxamic acid compound of the present invention is selected from the following structures of the aromatic benzene ring group in the formula (I):
  • the salt formed by chemical reaction of the hydroxamic acid compound with an inorganic acid, an organic acid, an inorganic base or an organic base forms a hydrate or a solvate with water or a solvent.
  • the inorganic or organic acid is selected from the group consisting of hydrochloric acid and hydrobromine. Acid, hydroiodic acid, sulfuric acid, nitric acid, carbonic acid, phosphoric acid, perchloric acid, acetic acid, citric acid, oxalic acid, lactic acid, malic acid, salicylic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, substituted Benzenesulfonic acid, isonicotinic acid, oleic acid, citric acid, pantothenic acid, ascorbic acid, succinic acid, maleic acid, gentisic acid, fumaric acid, gluconic acid, uronic acid, gluconic acid, sucrose, formic acid, Benzoic acid, glutamic acid, pamoic acid or sorbic acid; the inorganic or organic base is selected from the group consisting of sodium hydroxide, potassium
  • the solvate refers to a covalent bond, a hydrogen bond, an ionic bond, a van der Waals force, a complexing force or inclusion of the hydroxamic acid compound and a chemically used solvent.
  • a stabilizing substance formed wherein the solvent is selected from the group consisting of methanol, ethanol, propanol, butanol, ethylene glycol, propylene glycol, polyethylene glycol or acetone.
  • the invention also discloses a method for preparing the hydroxamic acid of the formula (I) according to the invention, which is prepared by the following steps:
  • M is an alkali metal
  • R is methyl, ethyl, n-propyl, isopropyl, butyl or substituted butyl, pentyl or substituted pentyl
  • A, B, C, D A, B, C D is independently selected from the group consisting of hydrogen, hydroxy, methyl, methoxy, bromo, chloro, fluoro or fluoro substituted alkyl.
  • Step (1) reacting a compound of the formula (II) with a compound of the formula (III) in the presence of a hydrocarbon as a solvent under the catalysis of boric acid to prepare an amide product (IV), the reaction time is from 1 to 24 hours.
  • the temperature is from 20 ° C to 145 ° C.
  • Step (2) mixing NH 2 OH ⁇ HCl with an alkali metal salt of a metal hydroxide or an alcohol dissolved in an organic solvent, stirring at 20° C. to 60° C. for 0.5 to 3 hours, and adding the product IV of the step (1). Stirring is continued at 20 ° C to 60 ° C for 1 to 5 hours, separated, and purified to obtain the desired hydroxamic acid compound (I).
  • the molar ratio of the compound (II) to boric acid according to the present invention is 1 to 0.01 to 1.00, preferably 1 to 0.01 to 0.20.
  • the molar ratio of the compound (II) to the compound (III) in the reaction step (1) of the present invention is from 1 to 1.20, preferably from 1 to 1.03.
  • the hydrocarbon used as a solvent according to the present invention is pentane, hexane, heptane, octane, toluene, xylene, trimethylbenzene or a mixture thereof.
  • the solvent is heptane, toluene or xylene.
  • the ratio of the molar ratio of the alkali metal salt of NH 2 OH ⁇ HCl to the alkali metal hydroxide or alcohol of the present invention to the product (IV) of the step (1) is (19 to 3): (18 to 2): 1 .
  • the alkali metal hydroxide or alkali metal salt of the alcohol of the present invention is selected from the group consisting of lithium, sodium, potassium or cesium.
  • the metal salt of the alcohol of the present invention is sodium methoxide, sodium ethoxide or potassium t-butoxide, preferably It is sodium methoxide.
  • Step (1) Weigh 1.46 g (10 mmol) of 3-chloro-4-fluoroaniline, 1.88 g (10 mmol) of monomethyl suberic acid, and 0.31 g (5 mmol) of boric acid in a 100 ml three-neck round bottom flask, and add 30 ml of toluene. , nitrogen protection, magnetic stirring, oil bath heating to toluene reflux, the water generated in the reaction process is separated by a water separator, and the water separator is filled with toluene before the reaction, the reaction time is 12h, and the thin layer chromatography plate is used for tracking.
  • reaction solution was poured into 300 ml of petroleum ether under stirring, stirred for 0.5 h, and then vacuum-filtered with a sand core funnel to obtain a solid, and the solid was washed with water to remove the catalyst boric acid, and then washed with petroleum ether. The solid was dried and the solid was drained. The final solid was 1.57g, and the yield was 49.7%;
  • Step (2) Weigh 2.02g (36mmol) of KOH dissolved in 10ml of methanol, add 2.64g (38mmol) of NH 2 OH ⁇ HCl, mix and stir for 40h at 40 degrees Celsius, cool to room temperature, then add the first step reaction. The obtained product was 0.63 g (2 mmol), and the reaction was followed by a thin layer chromatography plate. After 0.5 h, the reaction solution was poured into 300 ml of ice water under magnetic stirring to precipitate a solid, which was filtered and washed twice with 20 ml of distilled water.
  • Step (1) Weigh 0.8g (3.33mmol) of 3-bromo-5-trifluoromethylaniline, 0.63g (3.33mmol) of monomethyl malonate, and 0.10g (1.67mmol) of boric acid in 100ml three rounds.
  • the bottom flask was added with 30 ml of toluene, protected with nitrogen, magnetically stirred, heated in an oil bath to reflux with toluene, and the water formed during the reaction was separated by a water separator.
  • the water separator was filled with toluene before the reaction, and the reaction time was 20 h.
  • the reaction was followed by a thin layer chromatography plate.
  • reaction solution was poured into 300 ml of petroleum ether under stirring, stirred for 0.5 h, and then vacuum-filtered with a sand core funnel to obtain a solid, and the solid was washed with water to remove the catalyst boric acid, and then washed with petroleum ether. The solid was dried and the solid was drained. The final solid was 1.11 g, and the yield was 81.2%;
  • Step (2) Weigh KOH 1.21g (21.6mmol) dissolved in 10ml of methanol, add 1.58g (22.8mmol) of NH 2 OH ⁇ HCl, mix and stir for 40h at 40 degrees Celsius, cool to room temperature, then add first The product obtained by the reaction was 0.50 g (1.2 mmol), and the reaction was followed by a thin layer chromatography plate. After 0.5 h, the reaction was completed. The reaction solution was poured into 300 ml of ice water under magnetic stirring to precipitate a solid, which was filtered and washed with 20 ml of distilled water.
  • the solid was twice, 10 ml each time, vacuum-dried, washed twice with 20 ml of diethyl ether, 10 ml each time, and then dried and then recrystallized from acetonitrile to obtain 0.21 g of B123 solid.
  • Human lung cancer cells (A549), human gastric cancer cells (MGC80-3), and human esophageal cancer cells (TE-1) were prepared in RPMI-1640 (HyClone) medium containing 10% fetal bovine serum with 0.25% trypsin. Passage after passage.
  • the inhibitory effect on human skin melanoma cells is superior to the positive control compound vorinostat (SAHA) (US Pat. No. 5,369,108). Especially B110 and B123, its inhibition effect is significantly better than voltino (SAHA).
  • SAHA positive control compound vorinostat
  • the hydroxamic acid compounds provided by the present invention are superior to the control compounds in inhibiting human skin melanoma cells (A375), human lung cancer cells (A549) and human gastric cancer cells (MGC80-3).
  • Vorinostat (SAHA) hydroxamic acid, the present invention particularly preferably B110, B116 and B123 and other three hydroxamic acid compounds for human esophageal cancer (TE-1) cancer cell administration experiments, the results are listed in Table III .

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Abstract

一种如通式(I)所示的异羟肟酸类化合物，及其在制备抑制癌细胞增殖和/或治疗癌症的药物中的应用。其中取代基A~D如说明书所定义。该异羟肟酸类化合物具有抑制癌细胞增殖的能力，尤其对抑制人皮肤黑色素瘤细胞(A375)，人肺癌细胞(A549)，人胃癌细胞(MGC80-3)，人食管癌细胞(TE-1)和人肝癌细胞(HepG2)具有优异的抑制癌细胞增殖的活性。

Description

一种异羟肟酸类化合物及其在制备抑制癌细胞增殖和/或治疗癌症的药物中的应用 技术领域
本发明涉及一类异羟肟酸类化合物及其制备方法和用途。
背景技术
组蛋白去乙酰化酶(histone deacetylase，HDAC)和组蛋白乙酰转移酶(histone acetyltransferase，HAT)为真核细胞中广泛存在的一类相互拮抗的蛋白酶，它们共同调控着组蛋白末端氨基酸残基的乙酰化，使之处于平衡状态。组蛋白的乙酰化和去乙酰化修饰为调控基因转录的一种方式，组蛋白的乙酰化程度通过影响染色质的结构进而影响基因的表达。组蛋白乙酰化状态呈多样性，特定基因部位以位点特异方式进行组蛋白的乙酰化。肿瘤的发生与核小体核心组蛋白氮端的赖氨酸残基的乙酰化和去乙酰化的失衡有密切关系，组蛋白去乙酰化酶和组蛋白乙酰转移酶共同控制着体内组蛋白的乙酰化处于动态平衡。组蛋白乙酰转移酶可作为辅激活因子调控转录，调节细胞周期，参与DNA损伤修复。组蛋白去乙酰化酶则和染色体易位、转录调控、基因沉默、细胞周期、细胞分化和增殖以及细胞凋亡相关。多项研究表明组蛋白乙酰转移酶和组蛋白去乙酰化酶平衡的紊乱会使基因表达失控，从而导致肿瘤的发生，研究组蛋白去乙酰化酶抑制剂对于探究肿瘤发生机制以及开发新型抗肿瘤药物具有重要意义。
在癌细胞中，组蛋白去乙酰化酶过量时会促进组蛋白的去乙酰化，进而使组蛋白与脱氧核糖核酸(deoxyribonucleic acid，DNA)之间的作用力增大，核小体由松弛变得紧密，最终抑制了特定基因的表达，尤其是某些抑癌基因。组蛋白去乙酰化酶抑制剂则可以通过抑制组蛋白去乙酰化酶的活性提高染色体特定组蛋白的乙酰化， 进而促进抑癌基因恢复表达，从而抑制癌细胞的生长。组蛋白去乙酰化酶抑制剂具有一定的肿瘤特异性，对增殖和静止的变异细胞均有抑制作用，而对一些正常细胞并不引起生长停滞或凋亡。组蛋白去乙酰化酶抑制剂是一类具有极大发展潜力的新型、高效、低毒的抗肿瘤药物，拥有巨大的研究价值。
组蛋白去乙酰化酶抑制剂中研究较为成功的代表是SAHA。
Figure PCTCN2015076519-appb-000001
伏立诺他(SAHA)是首个被美国FDA批准上市用于治疗转移性皮肤T细胞淋巴瘤的药物，但在近年的研究中发现SAHA仍存在生物利用度较差，抑制癌细胞增殖的选择性不强的缺陷。因此，探寻在结构上比SAHA更具有较高抗癌细胞增殖活性的异羟肟酸类化合物是该领域工作者重要的科研项目。如能成功，实对抗癌药物的开发具有深长和重要意义，同时带来了巨大的国民经济价值。
本发明提供了如通式(Ⅰ)所示的异羟肟酸类化合物，实验证明其对多种癌细胞均具有强大的抑制增殖的能力,对患有癌症的病人可有优良的治疗效果。中国专利申请(公开号CN103159646A)公开了一种化合物N-(2，5-二甲氧基苯基)-N’-羟基辛二酰胺对多种癌细胞具有抑制增殖的作用，然而未能达到较佳的效果。美国专利(US5369108)公开一系列的异羟肟酸类化合物，亦对癌细胞的增殖具有抑制作用。本发明提供了一系列的新型的异羟肟酸类化合物，本发明所提供的具有优良抗癌细胞增殖的异羟肟酸类化合物在上述专利中从未被提及或公开过。
美国专利(US5369108)首先描述了采用酰氯中间体制备伏立 诺他(SAHA)的方法，此方法不仅产率低同时带来严重的环境污染，产生大量废物。中国专利申请(公开号CN102264694A和CN103159646A)以及J.Med.Chem.2005,48,5047-5051也报道了SAHA的制备方法，它们均采用卡特缩合剂BOP或二环己基碳二亚胺(DCC)等其它缩合剂及N，N-二异丙基乙胺(DIEA)等辅助剂，促进第一步骤的中间体(IV)的合成。文中所述的缩合剂与辅助剂不但昂贵，同时反应后产生二摩尔当量的缩合剂及辅助剂之副产品废物，造成环境的严重污染。而且它们纯化异羟肟酸化合物需采用硅胶柱分离处理，除了时间较长外，还浪费了硅胶及大量的洗脱剂。
本发明提供了一种以硼酸为催化剂，除水之外并无废物产生的高效合成伏立诺他(SAHA)的新方法。此反应不但具有高度原子经济，同时也是绿色及低碳化学反应。
本发明中所引述的文献、著作、专利和专利申请公开书，其中全部或局部都明确地和独立地都在本专利申请书引用参考。
发明内容
本发明涉及一类异羟肟酸的设计与合成，为了克服现有技术的上述不足，本发明提供一种药效活性更优异的异羟肟酸类化合物。本发明解决的另一技术问题是提供上述异羟肟酸类化合物的制备方法。本发明之所以能够解决上述问题乃是通过以下技术方案给予实现：
一种异羟肟酸类化合物，其特征在于下列通式(I)所示的结构：
Figure PCTCN2015076519-appb-000002
Figure PCTCN2015076519-appb-000003
A选自：氢或羟基；
B选自：溴，氯，氟或烷基；
C选自：氢，溴，氯，氟，烷基或烷氧基；
D选自：氢，氯，烷基或氟取代烷基。
其中A，C，D不同时为氢；B和C不同时为氟。
作为一种优选方案，本发明的异羟肟酸类化合物选自下列在通式(Ⅰ)中的芳香苯环基的结构：
Figure PCTCN2015076519-appb-000004
作为一种优选方案，所述的异羟肟酸类化合物与无机酸、有机酸、无机碱或有机碱通过化学反应形成的盐，与水或溶剂形成水合物或溶剂合物。
作为一种最优选方案，所述的无机或有机酸选自：盐酸、氢溴 酸、氢碘酸、硫酸、硝酸、碳酸、磷酸、高氯酸、醋酸、柠檬酸、草酸、乳酸、苹果酸、水杨酸、酒石酸、甲磺酸、乙磺酸、苯磺酸、取代的苯磺酸、异烟酸、油酸、鞣酸、泛酸、抗坏血酸、丁二酸、马来酸、龙胆酸、富马酸、葡萄糖酸、糖醛酸、葡萄糖二酸、蔗糖酸、甲酸、苯甲酸、谷氨酸、双羟萘酸或山梨酸；所述的无机或有机碱选自：氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铁、氢氧化钙、氢氧化钡、氢氧化铝、氢氧化镁、氢氧化锌、氨水、氢氧化有机季铵盐、碳酸钠、碳酸锂、碳酸钙、碳酸钡、碳酸镁、碳酸化有机季铵盐、碳酸氢钠、碳酸氢钾、碳酸氢锂、碳酸氢钙、碳酸氢钡、碳酸氢镁、或碳酸氢化有机季铵盐。
作为一种最优选方案，所述的溶剂合物是指所述的异羟肟酸类化合物与化学上常用的溶剂以共价键、氢键、离子键、范德华力、络合力或包合形成的稳定物质，其中的溶剂选自：甲醇、乙醇、丙醇、丁醇、乙二醇、丙二醇、聚乙二醇或丙酮。
本发明还公开了一种制备本发明所述的异羟肟酸通式(I)化合物的方法，它是由下列步骤制备而得到的：
步骤(1):
Figure PCTCN2015076519-appb-000005
步骤(2):
中间体(IV)+NH2OH·HCl+M-OH(或M-OR”)
Figure PCTCN2015076519-appb-000006
其中M为碱金属；R为甲基，乙基，正丙基，异丙基，丁基或取代的丁基，戊基或取代的戊基；A，B，C，D A，B，C，D独立地选自氢，羟基，甲基，甲氧基，溴，氯，氟或氟取代烷基。
上述化合物(I)由下列步骤制备而成。
步骤(1)：在硼酸催化下，将通式(II)化合物与通式(III)化合物在碳氢化合物作溶剂情况下反应，从而制备酰胺产物(IV)，反应时间是1至24小时，温度为20℃至145℃。
步骤(2)：将NH2OH·HCl与溶于有机溶剂的金属氢氧化物或醇的碱金属盐混合，在20℃至60℃搅拌0.5至3小时，加入步骤(1)的产物Ⅳ后，在20℃至60℃下继续搅拌1至5小时，分离，纯化，从而获得所需的异羟肟酸类化合物(I)。
本发明所述的化合物(II)与硼酸的摩尔比为1比0.01～1.00，优选比为1比0.01～0.20.
本发明所述的化合物(II)与化合物(III)在反应步骤(1)的摩尔之比为1比1～1.20，优选比为1比1.03。
本发明所述的用作溶剂的碳氢化合物为戊烷、己烷、庚烷、辛烷、甲苯、二甲苯，三甲苯或它们的混和物。优选溶剂为庚烷、甲苯或二甲苯。
本发明所述的NH2OH·HCl与碱金属氢氧化物或者醇的碱金属盐与步骤(1)之产物(IV)的摩尔之比为(19～3):(18～2):1。
本发明所述的碱金属氢氧化物或者醇的碱金属盐选自：锂，钠，钾或铯。
本发明所述的醇的金属盐是甲醇钠，乙醇钠或叔丁醇钾，优选 者为甲醇钠。
下列化合物为本发明合成其中一部分的异羟肟酸：
表I本发明合成其中一部分的异羟肟酸
Figure PCTCN2015076519-appb-000007
Figure PCTCN2015076519-appb-000008
具体实施方式
通过以下的具体实施方式，对本发明的上述内容再作进一步的详细解释及展述，使本领域的普通技术人员能够更加容易地理解本发明，但不应该将此理解为本发明所述主题的范围仅限于以下的实例及限制本发明的任何或所有权利，更不应该背离本发明的精神。
异羟肟酸实施例1:
N-(3-氯-4-氟苯基)-N’-羟基辛二酰胺(异羟肟酸)(简称B115)的制备。
步骤(1)：称量3-氯-4-氟苯胺1.46g(10mmol)，辛二酸单甲酯1.88g(10mmol)，硼酸0.31g(5mmol)置于100ml三口圆底烧瓶，加入30ml甲苯，氮气保护，磁力搅拌，油浴加热至甲苯回流，用分水器分出反应过程中生成的水，反应前分水器中加满甲苯，反应时间为12h，期间用薄层层析板跟踪反应，展开剂为乙醚：石油醚＝1:1。反应完成后将反应液倒入搅拌中的300ml石油醚中，搅拌0.5h后，用砂芯漏斗抽真空过滤得固体，并用水对固体进行清洗以除去催化剂硼酸，抽干后再用石油醚清洗固体并将固体抽干。最终得固体1.57g,产率为：49.7％；
步骤(2)：称量KOH 2.02g(36mmol)溶解于10ml甲醇，加入NH2OH·HCl 2.64g(38mmol)，混匀后40摄氏度磁力搅拌0.5h，冷却到室温，再加入第一步反应得到的产物0.63g(2mmol)，期间用薄层层析板跟踪反应，0.5h后反应结束后将反应液倒入磁力搅拌中的300ml冰水中，析出固体，过滤，用20ml蒸馏水洗固体两次，每次10ml，真空抽干后用20ml乙醚洗两次，每次10ml，再抽干后用乙腈重结晶得B115固体0.25g，产率为：39.7％，MS(ES+)m/z： 317.1068(M+H)+，1HNMR(DMSO-d6,400MHz):δ＝10.33(s,1H),10.08(s,1H),8.65(s,1H),7.94(d,J＝7.0Hz,1H),7.46(m,1H),7.35(t,J＝9.1Hz,1H),2.30(t,J＝7.4Hz,2H),1.94(t,J＝7.3Hz,2H),1.53(m,4H),1.28(m,4H)。
异羟肟酸实施例2:
N-(3-溴-5-三氟甲基苯基)-Nˊ-羟基辛二酰胺(简称B123)的制备。
步骤(1)：称量3-溴-5-三氟甲基苯胺0.8g(3.33mmol)，辛二酸单甲酯0.63g(3.33mmol)，硼酸0.10g(1.67mmol)置于100ml三口圆底烧瓶，加入30ml甲苯，氮气保护，磁力搅拌，油浴加热至甲苯回流，用分水器分出反应过程中生成的水，反应前分水器中加满甲苯，反应时间为20h，期间用薄层层析板跟踪反应，展开剂为乙醚：石油醚＝1:1。反应完成后将反应液倒入搅拌中的300ml石油醚中，搅拌0.5h后，用砂芯漏斗抽真空过滤得固体，并用水对固体进行清洗以除去催化剂硼酸，抽干后再用石油醚清洗固体并将固体抽干。最终得固体1.11g,产率为：81.2％；
步骤(2)：称量KOH 1.21g(21.6mmol)溶解于10ml甲醇，加入NH2OH·HCl 1.58g(22.8mmol)，混匀后40摄氏度磁力搅拌0.5h，冷却到室温，再加入第一步反应得到的产物0.50g(1.2mmol)，期间用薄层层析板跟踪反应，0.5h后反应结束，将反应液倒入磁力搅拌中的300ml冰水中，析出固体，过滤，用20ml蒸馏水洗固体两次，每次10ml，真空抽干后用20ml乙醚洗两次，每次10ml，再抽干后用乙腈重结晶得B123固体0.21g，产率为：41.2％，MS(ES+)m/z：411.0527(M+H)+，1HNMR(DMSO-d6,400MHz):δ＝10.36(s,1H),10.33(s,1H),8.66(s,1H),8.13(s,1H),7.99(s,1H),7.60(s,1H),2.34(t,J＝7.3Hz,2H),1.95(t,J＝7.4Hz,2H),1.54(m,4H),1.29(m,4H)。
其它化合物制备方法与以上实例相似。
异羟肟酸B110:MS(ES+)m/z:334.0821(M+H)+；1HNMR(DMSO-d6,400MHz):δ＝10.33(s,1H),10.16(s,1H), 8.65(s,1H),8.00(s,1H),7.55(d,J＝8.8Hz,1H),7.48(d,J＝8.8Hz,1H),2.31(t,J＝7.4Hz,2H),1.94(t,J＝7.4Hz,2H),1.53(m,4H),1.28(m,4H)。
异羟肟酸B114:MS(ES+)m/z:334.0807(M+H)+；1HNMR(DMSO-d6,400MHz):δ＝10.33(s,1H),9.53(s,1H),8.65(s,1H),7.72(d,J＝8.8Hz,1H),7.66(s,1H),7.41(d,J＝8.8Hz,1H),2.37(t,J＝7.3Hz,2H),1.95(t,J＝7.4Hz,2H),1.54(m,4H),1.29(m,4H)。
异羟肟酸B115:MS(ES+)m/z:317.1068(M+H)+；1HNMR(DMSO-d6,400MHz):δ＝10.33(s,1H),10.08(s,1H),8.65(s,1H),7.94(d,J＝7.0Hz,1H),7.46(m,1H),7.35(t,J＝9.1Hz,1H),2.30(t,J＝7.4Hz,2H),1.94(t,J＝7.3Hz,2H),1.53(m,4H),1.28(m,4H)。
异羟肟酸B116:MS(ES+)m/z:361.0571，363.0548；1HNMR(DMSO-d6,400MHz):δ＝10.32(s,1H),10.20(s,1H),8.65(s,1H),7.77(d,J＝11.6Hz,1H),7.61(t,J＝8.5Hz,1H),7.28(d,J＝8.8Hz,1H),2.31(t,J＝7.4Hz,2H),1.94(t,J＝7.3Hz,2H),1.53(m,4H),1.28(m,4H)。
异羟肟酸B123:MS(ES+)m/z:412.0558(M+H)+；1HNMR(DMSO-d6,400MHz):δ＝10.36(s,1H),10.33(s,1H),8.66(s,1H),8.13(s,1H),7.99(s,1H),7.60(s,1H),2.34(t,J＝7.3Hz,2H),1.95(t,J＝7.4Hz,2H),1.54(m,4H),1.29(m,4H)。
实施例3：
(1)实验细胞系，选用五种癌细胞：人皮肤黑色素瘤细胞(A375)，人肺癌细胞(A549)，人胃癌细胞(MGC80-3)，人肝癌细胞(HepG2)或人食管癌细胞(TE-1)，其中人皮肤黑色素瘤细胞(A375)和人肝癌细胞(HepG2)在含10％胎牛血清的DMEM培养基中，用0.25％胰蛋白酶常规消化后传代。人肺癌细胞(A549)，人胃癌细胞(MGC80-3)，和人食管癌细胞(TE-1)在含10％胎牛血清的RPMI-1640(HyClone)培养基中，用0.25％胰蛋白酶常规消化后传代。
(2)将对数生长期的癌细胞消化成单个细胞后，以4×104个/ml 的密度接种于96孔板中，每孔加入0.1ml的细胞悬液，在含5％CO2的37℃培养箱中培养12小时，将本发明的异羟肟酸及对照药伏立诺他(SAHA)均作用于同一细胞，每个浓度设置3个复孔，待细胞贴壁后，加异羟肟酸或SAHA处理，针对癌细胞给不同浓度的药，48h后，各孔加入MTT溶液20μL孵育4小时后，弃培养基，每孔加入150μL DMSO，摇振均匀10分钟，使甲囋结晶充分溶解后，用酶标仪检测490nm处的吸光度值并计算IC50值。
表II：异羟肟酸对不同癌细胞的抑制度
Figure PCTCN2015076519-appb-000009
表II的结果表明：不同结构的异羟肟酸对不同癌细胞增殖的抑制能力不同。
(1)对于人皮肤黑色素瘤细胞：B110、B115、B116和B123的抑制作用优于阳性对照化合物伏立诺他(SAHA)(美国专利号5369108)。尤其是B110和B123，其抑制效果明显优于伏立诺他 (SAHA)。
(2)对于人肺癌细胞：B110、B115、B116和B123的抑制作用优于阳性对照化合物SAHA，同时如上述对人皮肤黑色素瘤细胞具有明显抑制效果的B110和B123,这类异羟肟酸对人肺癌细胞的抑制效果同样均明显优于对照化合物伏立诺他(SAHA)。
(3)对于胃癌细胞：对于人胃癌细胞MGC80-3，B110、B115、B116和B123的抑制作用优于阳性对照化合物SAHA，同时如上述对人皮肤黑色素瘤细胞和人肺癌细胞均具有明显抑制效果的B110和B123,对于人胃癌细胞MGC80-3的抑制效果也同样地均明显优于对照化合物伏立诺他(SAHA)。
根据表II的结果，本发明提供的异羟肟酸化合物中不乏对人皮肤黑色素瘤细胞(A375)，人肺癌细胞(A549)及人胃癌细胞(MGC80-3)的抑制作用均优于对照化合物伏立诺他(SAHA)的异羟肟酸，本发明特优选B110，B116和B123等三个异羟肟酸化合物做人食管癌(TE-1)的癌细胞给药实验，结果列于表III。
表III：异羟肟酸对人食管癌的癌细胞的抑制度
Figure PCTCN2015076519-appb-000010
表III结果表明，所选的三个异羟肟酸对食管癌TE-1的抑制作用皆优于阳性对照化合物伏立诺他(SAHA)。

Claims (10)

  1. 一种异羟肟酸类化合物，其特征在于下列通式(I)所示的结构：
    Figure PCTCN2015076519-appb-100001
    A选自：氢，氯，溴或羟基；
    B选自：溴，氯，氟或烷基；
    C选自：氢，溴，氯，氟，烷基或烷氧基；
    D选自：氢，氯，烷基或氟取代烷基。
    其中A，C，D不同时为氢；B和C不同时为氟
  2. 根据权利要求1所述的异羟肟酸类化合物，其特征在于，所述的异羟肟酸类化合物与无机酸、有机酸、无机碱或有机碱所形成的盐，与水或适合的溶剂形成水合物或溶剂合物及药学上可接受的载体和/或添加剂。
  3. 根据权利要求1所述的异羟肟酸类化合物，其特征在于，所述通式(I)中的芳香环基选自：
    Figure PCTCN2015076519-appb-100002
    Figure PCTCN2015076519-appb-100003
  4. 根据权利要求1或2所述的异羟肟酸类化合物，其特征在于，所述的异羟肟酸类化合物选自：
    Figure PCTCN2015076519-appb-100004
  5. 权利要求1至4中任意一项所述的异羟肟酸类化合物在制备抑制癌细胞增殖或治疗癌症的药物中的应用。
  6. 根据权利要求5所述的应用，其中癌细胞或癌症包括人黑色 素瘤细胞A375，人肺癌细胞A549，人胃癌细胞MGC80-3，人食管癌细胞TE-1，人大细胞肺癌细胞H460，人肝癌细胞HepG2,人乳腺癌细胞MCF-7，人胰腺癌细胞PANC-1，结肠癌，直肠癌，宫颈癌，卵巢癌。
  7. 根据权利要求6所述的应用，其中癌细胞或/和癌症是人恶性黑色素瘤细胞A375，人肺癌细胞A549，人胃癌细胞MGC80-3，人肝癌细胞HepG2或人食管癌细胞TE-1。
  8. 一种制备权利要求1所述的异羟肟酸类化合物(通式I)的方法：
    上述化合物(I)由下列步骤制备而成
    步骤(1):
    Figure PCTCN2015076519-appb-100005
    步骤(2):
    Figure PCTCN2015076519-appb-100006
    其中M为碱金属；R为甲基，乙基，正丙基，异丙基，丁基或取代的丁基，戊基或取代的戊基；A，B，C，D独立地选自氢，羟 基，甲基，甲氧基，溴，氯，氟或氟取代烷基；
    步骤(1)：在硼酸催化下，将通式(Ⅱ)化合物与通式(Ⅲ)化合物以碳氢化合物作溶剂进行反应，从而制备酰胺产物(Ⅳ)；其中化合物(Ⅱ)与硼酸的摩尔之比为1：(0.01～1.00)；其中所述的化合物(Ⅱ)与化合物(Ⅲ)的摩尔比为1：(1～1.2)；其中所述的碳氢化合物溶剂选自戊烷、己烷、庚烷、辛烷、甲苯、二甲苯、三甲苯或它们的混合物；反应时间是1至24小时，温度为20℃至145℃；
    步骤(2)：将NH2OH·HCl与溶于有机溶剂的碱金属氢氧化合物M-OH或醇的碱金属盐M-OR”混合，在20℃至60℃搅拌0.5至3小时，加入步骤(1)的产物(Ⅳ)后，在20℃至60℃下继续搅拌1至5小时，分离，纯化，获得所需的异羟肟酸类化合物(Ⅰ)；其中所述的NH2OH·HCl与金属氢氧化物与步骤(1)之产物(Ⅳ)的摩尔比为(19～3):(18～2):1。
  9. 根据权利要求8所述的方法，其中所述的碱金属氢氧化合物为氢氧化钠，氢氧化钾或氢氧化铯。
  10. 根据权利要求8所述的方法，其中所述的醇的碱金属盐为甲醇钠，乙醇钠或叔丁醇钾。
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