WO2014082581A1 - α-(3,5-二甲氧基苯亚甲基)-α'-烃基亚甲基环酮及其制备方法 - Google Patents

α-(3,5-二甲氧基苯亚甲基)-α'-烃基亚甲基环酮及其制备方法 Download PDF

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WO2014082581A1
WO2014082581A1 PCT/CN2013/088012 CN2013088012W WO2014082581A1 WO 2014082581 A1 WO2014082581 A1 WO 2014082581A1 CN 2013088012 W CN2013088012 W CN 2013088012W WO 2014082581 A1 WO2014082581 A1 WO 2014082581A1
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arh
alkyl
dimethoxybenzylidene
cyclohexanone
hydrocarbylmethylenecycloketone
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PCT/CN2013/088012
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English (en)
French (fr)
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敖桂珍
聂继华
李环球
莫凌萱
陈蕾
宋恒
陈韶华
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无锡药兴医药科技有限公司
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Priority to JP2015544340A priority Critical patent/JP2016501869A/ja
Priority to EP13858613.6A priority patent/EP2927208A4/en
Publication of WO2014082581A1 publication Critical patent/WO2014082581A1/zh
Priority to US14/723,785 priority patent/US9409845B2/en

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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
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • 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
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/24—Sulfones; Sulfoxides having sulfone or sulfoxide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C—CHEMISTRY; METALLURGY
    • 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
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to the field of anti-tumor drugs, and more particularly to an ⁇ -(3,5-dimethoxybenzylidene)- ⁇ ' hydrocarbyl methylene cyclic ketone and a process for the preparation thereof.
  • neoplasm Malignant neoplasm has become one of the major diseases that are increasingly common and seriously threaten human life and quality of life. Tumor disease has risen to become the world's second "killer” after cardiovascular disease, but the current cancer lesions The mechanism of action and metastasis and the effect of drugs on cancer cells is still unclear. Now the treatment of tumors is still largely based on the chemotherapy of anti-tumor drugs, but chemical drugs have large side effects and multi-drug resistance. Etc. Epidermal growth factor receptor (EGFR) inhibits the tumor cells, increases the lethality of tumor cells, and reduces adverse effects on normal tissue cells. Such drugs are non-cytotoxic, Sexuality, regulation and cell stability, toxicity and clinical manifestations have a large area with the currently used cytotoxic drugs, and have a more f effect with conventional chemotherapy and radiotherapy.
  • EGFR Epidermal growth factor receptor
  • Resveratrol is a natural polyphenolic compound, mainly derived from the rhizome extract of Polygonum cuspidatum, which has a variety of biological effects, including neuroprotection, cardiovascular protection, anti-inflammatory and anti-tumor effects. Especially for the inhibition of liver cancer, gastric cancer, leukemia, cervical cancer, esophageal cancer, etc. has important clinical value. Resveratrol exhibits an inhibitory effect in the initiation, promotion and development of cancer, making it useful in the field of cancer chemoprevention and treatment. Curcumin is an important active ingredient extracted from the rhizome of turmeric and turmeric of the genus Zingiberaceae. It has strong pharmacological activity and wide indications.
  • curcumin has anti-inflammatory, anti-tumor, anti-angiogenesis, anti-mutation, anti-bacterial, and viral. , a variety of pharmacological effects such as antioxidants and neuroprotection.
  • the anti-tumor effect of curcumin includes inhibition of in vitro growth and induction of apoptosis of various tumor cells and inhibition of tumorigenesis in vivo, but curcumin has low activity in vivo, less absorption in vivo, rapid metabolism and bioavailability. Low degree, which greatly limits its application.
  • the main technical problem to be solved by the present invention is to provide an ⁇ -(3,5-dimethyl oxalylmethyl)- ⁇ '-hydrocarbyl methylene cyclic ketone and an antibacterial method thereof. effect.
  • a technical solution adopted by the present invention is: Providing an ⁇ -(3,5-dimethyl benzene benzoic acid)
  • the structural formula of the aryl group is , including hydrogen > hydroxy, halogen, tt, methylsulfonyl> alkoxy having from 1 to 4 carbons, alkyl, haloalkyl or alkyl tt, including hydrogen, hydroxy, halogen, methanesulfonyl, containing 1 - 4 carbon alkane groups, alkyl groups,
  • Alkyl, haloalkyl or alkyl R 4 includes hydrogen.
  • the invention provides a preparation method of ⁇ -(3,5-dimethoxybenzylidene)- ⁇ '-hydrocarbylmethylenecycloketone, which comprises the steps of: azeotropic dehydration of a cyclic ketone and morpholine to obtain an enamine Condensation reaction of an enamine with 3,5-dimethoxybenzaldehyde to obtain a ⁇ - ⁇ -(3,5-dioxyphenylhydrazinyl)-cycloketone, ⁇ - ⁇ - ( 3,5- Dioxybenzylidene)-cycloketone is condensed with alkyl formaldehyde or aryl formaldehyde under acidic or subductive conditions to give ⁇ - (3,5-dimethoxybenzylidene)- ⁇ '-hydrocarbyl Methylcycloketone.
  • the cyclic ketone comprises cyclohexanone or cyclopentanone.
  • An antitumor agent comprising the ex-(3,5-dimethoxybenzylidene)- ⁇ '-hydrocarbylfluorenylene ring according to claim 1 and a pharmaceutically acceptable carrier.
  • An anti-tumor drug comprising the medically acceptable salt of ⁇ -(3,5-dimethoxybenzylidene)- ⁇ '-hydrocarbylmethylenecycloketone according to claim 1 and a pharmaceutically acceptable Acceptable carrier.
  • the ⁇ -(3,5-dimethoxylomethylene)- ⁇ '-hydrocarbylmethylenecycloketone comprises 0% by weight of the antitumor drug. , 05-90%.
  • the ⁇ -(3,5-dimethoxylomethylene)- ⁇ '-hydrocarbylmethylenecycloketone comprises 15% by weight of the antitumor drug. -60%.
  • the carrier comprises a solution, a diluent, a tablet, a capsule, a dispersed powder or a granule.
  • the beneficial effects of the present invention are: ⁇ (3,5 dimethoxybenzylidene)- ⁇ '-hydrocarbyl methylene cyclic ketone of the present invention and a process for producing the same, the ⁇ (3,5 dimethoxy group) Benzamethylene)- ⁇ '-hydrocarbylmethylenecycloketone is a combination of the structure of the natural anti-tumor active ingredient resveratrol and curcumin, and the result is a more active anti-tumor drug, and Epidermal growth factor receptor has good ⁇ making discourse DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
  • ⁇ -(3,5-dimeth benzamethylene
  • R is an aryl group or an alkyl group
  • ⁇ ' represents a compound in the formula ⁇ -(3,5-dimethoxybenzylidene)- ⁇ '-hydrocarbylmethylenecycloketone.
  • the 6-position substitution when the starting material is cyclohexanone, the ⁇ -position of the compound in the formula a-(3,5-dimethoxybenzylidene)- ⁇ '-hydrocarbylcyclodecyl ketone .
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Example E- 2- (3,5- dioxy harmless Methyl)-cyclohexanone and 3-chlorobenzaldehyde are used as raw materials, and the preparation process is as follows.
  • Compound (2E, 6E)-2-(3,5-dimethoxybenzylidene)-6- ( 3-chlorobenzylidene)cyclohexanone has a melting point of 107.5 108.4 °C, hydrogen i !
  • Example 1 Taking E-2 (3,5-dioxybenzylidene)-cyclohexanone and 2-fluorobenzaldehyde as raw materials, the preparation process is as shown in Example 1.
  • the melting point of the compound (2E, 6E)-2-(3,5-dimethoxybenzylidene)-6-(2-fluorobenzylidene)cyclohexanone is 83 0 to 83.61, and the hydrogen spectrum is H.
  • Example 6 Prepared by using E- 2-(3,5-dioxybenzylidene)-cyclohexanone and 3-bromobenzaldehyde as starting materials. See the example compound (2E, 6E)- 2- (3,5). - dimethyl-l-phenylenemethylene) -6-(3-bromo-methylene)cyclohexanone has a melting point of 1 11.9.
  • Example 7 E- 2-(3,5-dioxybenzylidene)-cyclohexanone and 4-bromobenzaldehyde were used as raw materials.
  • the compound (2E, 6E)-2-(3,5-dimethoxybenzylidene) 6-(4-bromobenzylidene)cyclohexanone has a melting point of 126.4 to 128,6 ⁇ , hydrogen language !
  • Example 8 E- 2 (3,5-dioxybenzylidene)-cyclohexanone and 4-fluorobenzaldehyde were used as raw materials.
  • Example 1 Compound (2E, 6E) -2- (3,5- dimethoxyphenyl methylene) -6- (4-fluorobenzylidene) m.p.
  • Example 9 E- 2-(3,5-dioxybenzylidene)-cyclohexanone and 4-chlorobenzaldehyde were used as raw materials.
  • Example 10 Taking E- 2-(3,5-dioxybenzylidene)-cyclohexanone and cyclohexylfurfural as raw materials, the preparation process is as shown in Example 1.
  • the compound (2E, 6E)-2-(3,5-dimethoxylomethylene)-6-(cyclohexylmethylene)cyclohexanone has a melting point of 94.
  • Example 11 E- 2-(3,5-dioxybenzylidene)-cyclohexanone and 3-methoxybenzaldehyde were used as starting materials.
  • Example 12 300 mg, i.22 mmoi of E-2 (3,5 dioxabenzylidene) cyclohexanone and 168 mg of 1.22 mmoi of 3,4-dihydroxybenzaldehyde were added to 10 mL of ethanol, and added. 203 ⁇ L, 2.43 ⁇ > ⁇ concentrated hydrochloric acid, stirred at room temperature for 30 min, added with 50 mL of water and 20 mL of x 3 ethyl acetate. After drying anhydrous sodium sulfate, the solvent was evaporated, using petroleum ether and ethyl acetate.
  • Example 13 E- 2-(3,5-dioxybenzylidene)-cyclohexanone and 2-methoxybenzaldehyde were used as raw materials. For the preparation process, see Example-1.
  • the compound (2E, 6E)-2-(3,5-dimethoxybenzylidene)-6-(2-methoxybenzylidene)cyclohexanone has a melting point of 90.8 to 91.2 V.
  • Example 14 E- 2-(3,5-dioxylomethylene)-cyclohexanone and 4-hydroxybenzaldehyde were used as raw materials, and the preparation process was as described in Example 12.
  • Example 16 Starting from E- 2-(3,5-dioxybenzylidene)-cyclohexanone and 3-hydroxy-4-methoxybenzaldehyde, the preparation process is shown in Example 12.
  • Example 17 E- 2 (3,5-dioxybenzylidene)-cyclohexanone and 4-methoxybenzaldehyde were used as raw materials.
  • the melting point of the compound (2E, 6E)-2-(3,5-dimethoxybenzyl)-6-(4-methoxybenzylidene)cyclohexanone is 97.7-98.
  • Example 18 E- 2-(3,5-dioxybenzylidene)-cyclohexanone and 3,5-dimethoxybenzaldehyde are used as raw materials.
  • Example 19 E- 2-(3,5-dioxylomethylene)-cyclohexanone and 4-methylsulfonyl stinyl formaldehyde were used as raw materials.
  • the melting point of the compound (2E, 6E)-2-(3,5-dimethoxybenzyl)-6-(4-methylsulfonylbenzylidene)cyclohexanone is 162.0 163.5 V
  • Embodiment 20 is a diagrammatic representation of Embodiment 20.
  • Example 22 Using E- 2-(3,5-dioxylbendyl)-cyclopentanone and 3-chlorobenzaldehyde as raw materials, the preparation process was the same as in Example 1 to obtain (2E, 5E)-2. - (3,5-Dimethoxybenzylidene)-5-(3-chlorobenzylidene)cyclopentanone.
  • Example 25 Using E- 2-(3,5-dioxyphenylene)-cyclopentanone and 2-bromobenzaldehyde as raw materials, the preparation process is the same as in the first embodiment to obtain (2E, 5E)-2. - (3,5-Dimethoxybenzylidene)-5-(2-bromobenzyl)cyclopentanone. Melting point is 159.0 ⁇ 160.3, hydrogen spectrum !
  • Example Twenty-six E- 2-(3,5-dioxyphenylene)-cyclopentanone and 3-bromobenzaldehyde were used as raw materials, and the preparation process was the same as in Example 1 to obtain (2E, 5E)-2. - (3,5-Dimethoxybenzylidene)-5-(3-bromobenzethylene)cyclopentan.
  • the melting point is MU MZ.
  • Example 27 Using E- 2-(3,5-dioxylbendyl)-cyclopentanone and 4-bromobenzaldehyde as raw materials, the preparation process was the same as in Example 1 to obtain (2E, 5E)-2.
  • Example 29 Using E- 2-(3,5-dioxyphenylene)-cyclopentanone and 4-chlorobenzaldehyde as raw materials, the preparation process is the same as in the first embodiment to obtain (2E, 5E)-2. - (3,5-Dimethoxybenzylidene 5-(4-chlorobenzylidene)cyclopentanone.
  • Example 30 Using E- 2-(3,5-dioxyphenyl)-cyclopentanone and cyclohexylbenzaldehyde as raw materials, the preparation process was the same as in Example 1 to obtain (2E, 5E)-2-(3 , 5-dimethoxy benzylidene) -5-(cyclohexylbenzylidene)cyclopenta S.
  • Example 31 E- 2-(3,5-dioxyphenylene)-cyclopentanone and 3-methoxybenzaldehyde were used as raw materials, and the preparation process was the same as in Example 1 (2E, 5E). - 2-(3,5-Dimethoxybenzylidene)-5-(3-methoxylomethylene)cyclopentanone.
  • Example thirty-two E- 2-(3,5-dioxyphenylene)-cyclopentanone and 3,4-dihydroxybenzene. Formaldehyde were used as raw materials, and the preparation process was the same as in Example 12 (2E). , 5E)-2-(3,5-Dimethoxybenzylidene)-5-(3,4-dihydroxylomethylene)cyclopentanone. HR-MS: Calcd. For C 21 :H 20 () 5 M : 353.1384, Found: 352.1385.
  • Embodiment 34 pimoj 'i6g[- [ge: +[H+M] 3 ⁇ 4 i- : ⁇ I ): Si ⁇ 3 ⁇ 4H ' ⁇ ) ⁇ '9 ⁇ '£L 9Z 99 'LPL'lOl '8'80 ⁇ 8S U ' ⁇ 8 '83 ⁇ '968' ⁇ : ⁇ ' ⁇ ' ⁇ '£91' £ 'Z VSil ' ⁇ ' ⁇ c£'8£i ⁇ 36 ⁇ 9 ⁇ 3 ⁇ 4£0'191 ' ⁇ 3 ⁇ 4 ⁇ ⁇ 96 ⁇ :( «i( )g : ( XD 'zfflAi00t?) WN ⁇ : ⁇ ⁇ (3 ⁇ 4[) ⁇ - ⁇ ' « ()n: ⁇ 90 ⁇ £ '( :)() ' ⁇ 9 ⁇ ) ⁇ ''£'( :)() 'HE ')98' ⁇ : '(1-PV ⁇ - ⁇ 's
  • Example 39 The preparation process was carried out in the same manner as in Example 1 using E- 2-(3,5-dimethyl-based strepinyl.)-cyclopentanone and 4-methylsulfonyl stinyl (2E, 5E).
  • Example 40 Using E-2 (3,5-dioxyphenylene)-cyclopentanone and 3,5-di-tert-butyl-4-hydroxybenzaldehyde as raw materials, the preparation process is the same as in the twelfth embodiment. (2E, 5E)-2-(3,5-dimethylhydrazinobenzylidene)-5-(3,5-di-tert-butyl-4-hydroxylomethylene)cyclopentanone.
  • the test compound was dissolved in dimethyl sulfoxide and then diluted to the corresponding concentration in DMEM medium, wherein the final concentration of dimethyl amide was less than 0.01%.
  • the tumor cells in the exponential growth phase were trypsinized, counted, and the number of cells was adjusted to 1 ⁇ 0 5 cells in the culture medium, and inoculated into a 96-well plate at 200 ⁇ , and cultured for 2 hours.
  • the experiment was divided into negative control group, blank control group and experimental group. Each group had 3 re-openings.
  • the negative control group only added cells, no drugs.
  • the blank control group only added dimethyl sulfoxide solution, and the experimental group was in each well.
  • the other compounds have strong anti-proliferative effect on cutaneous melanoma A16-F 10 tumor cell forest In curcumin.
  • (2E, 6E)- 2- (3,5-dimethyl azinobenzyl)-6-(3,4-dihydroxy Benzamethylene)cyclohexanone has the highest anti-tumor activity and has an IC 50 value of ⁇ 1 ⁇ . All compounds have a good affinity for the epidermal growth factor receptor EGFR.
  • an anti-tumor drug comprising ⁇ -(3,5-dimethoxybenzylidene)- (!'-hydrocarbylmethylenecycloketone or a medically acceptable salt thereof and a pharmaceutically acceptable carrier
  • the compound or a medically acceptable salt thereof may be administered in a divided form, either alone or in combination with one or more acceptable carrier carriers, for example, using a solvent, a diluent, or the like, or an oral dosage form such as a tablet. , capsules, dispersible powders, granules, etc.
  • the various forms of the pharmaceutical compositions of the invention may be prepared according to methods well known in the art of pharmacy.
  • the compound comprises 0.05-90% by weight of the anti-tumor drug.
  • the anti-tumor drug is 15-60% by weight of the anti-tumor drug, and may be administered according to 0.005-5000 mg/kg/day, or may be administered beyond the dose range according to the severity of the disease or the dosage form.
  • Curcumin derivatives can also be combined with other anti-tumor drugs, such as alkylation, antimetabolites, topoisomerase inhibition, and mitotic enzyme inhibitors > DNA insertion. Combination therapy can produce synergy to help Improve treatment
  • the tumor includes a human cancer cell line Hep G2 liver cancer cell line and human skin melanoma ⁇ -F10 cell ⁇ .

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Abstract

本发明公开了一种α-(3,5-二甲氧基苯亚甲基)-α'-烃基亚甲基环酮，结构为(I)或(II)。其中R为芳基或烷基，制备方法为：将环酮和吗啡啉混合共沸脱水得到烯胺，将烯胺与3,5-二甲氧基苯甲醛发生缩合反应，再在酸性或碱性条件下与烷基甲醛或芳基甲醛缩合得到产物，还包括α-(3,5-二甲氧基苯亚甲基)-α'-烃基亚甲基环酮或其医学上能接受的盐和药学上能接受的载体的抗肿瘤药物。通过上述方式，本发明提供的α-(3,5-二甲氧基苯亚甲基)-α'-烃基亚甲基环酮及其制备方法，所述化合物是对天然产物抗肺瘤活性成分白藜芦醇和姜黄素的结构进行拼合以及修饰，获得了活性更高的抗肿瘤药物，对表皮生长因子受体具有良好的抑制作用。

Description

«~(3，5~二甲氧基苯亚曱基) - α' -烃基亚甲基环酮及其制备方法
技术领域 本发明涉及抗胂瘤药物领域， 特别是涉及一种 α- (3,5-二甲氧基苯亚甲基) -α'烃基亚甲基 环酮及其制备方法。
背景技术
恶性胂瘤已成为日益常见且严重威胁人类生命和生活质量的主要疾病之一， 胂瘤病已上 升为仅次于心血管病的世界第 2位 "杀手，'， 但目前对癌细胞的病变和转移以及药物对癌细胞 的作用机理仍不清晰。 现在肺瘤的治疗很大程度上仍是以抗胂瘤药物的化学治疗为主， 但化 学药物存在毒副作用大、 产生多药耐药性等问题。 表皮生长因子受体（EGFR )抑制 作用于 相关的肿瘤细胞上， 能够提高对肿瘤细胞的杀伤力， 并减少对正常组织细胞的不良作用等。 此类药物具有非细胞毒性、 耙向性、 调节作用和细胞稳定性作用， 毒性和临床表现与现在常 用的细胞毒类药物有很大区^ , 与常规化疗、 放疗合用有更 f的效果。
白藜芦醇是一种天然多酚类化合物， 主要来源于蓼科植物虎杖的根茎提取物， 具有多种 生物学作用， 包括神经保护作用、 心血管保护作用 抗炎及抗肺瘤作用等， 尤其对肝癌、 胃 癌、 白血病、 宫颈癌、 食管癌等的抑制作用具有重要的临床价值。 白藜芦醇在癌症的始发、 促进及发展阶段表现出的抑制作用， 使其应用在癌症化学预防和治疗领域。 姜黄素是从姜科姜黄属植物姜黄、 莪术等的根茎中提取的一种重要活性成分， 药理活性 强且适应症广， 具有抗炎、 抗胂瘤、 抗血管生成、 抗突变、 抗菌、 病毒、 抗氧化和神经保护 等多种药理作用。 姜黄素的抗胂瘤作用包括对多种肿瘤细胞的体外生长抑制和诱导凋亡以及 在体内抑制胂瘤发生的能力， 但姜黄素在体内的活性偏低 体内吸收少、 代谢过快和生物利 用度低， 极大的限制了它的应用。
发明内容 本发明主要解决的技术问题是提供一种 α- (3,5-二甲氣基笨亚甲基) -α'-烃基亚甲基环酮及 其 备方法， 该化合物具有抗胂瘤作用。 为解决上述技术问题， 本发明采用的一个技术方案是： 提供一种 α-(3,5-二甲氣基苯亚甲
Figure imgf000004_0001
在本发明一个较佳实施例中， 所述芳基的结构式为
Figure imgf000004_0002
， 其中 包括氢 > 羟基、 卤素、 tt、 甲砜基 > 含 1-4个碳的烷氧基、 烷基、 卤代烷基或烷基 tt, 包括氢、 羟基、 卤素、 、 甲砜基、 含 1-4个碳的烷氣基、 烷基、 |¾代烷基或烷基 包括氢、 羟基、 卤素、 -#1¾、 甲砜基、 含 1-4个碳的烷氣基.。 烷基、 卤代烷基或烷基 R4包括氢.。 羟基、 卤素 > 甲飒基、 含 1-4个碳的烷氧基、 烷基 卤代烷基或烷基氨基； 所述烷基为含 1-8 个碳的烷基。 提供一种 α-(3,5-二甲氧基苯亚甲基) -α'-烃基亚甲基环酮的制备方法, 包括步骤为： 将环 酮和吗啡啉混合共沸脱水得到烯胺， 将烯胺与 3,5-二甲氧基苯甲醛发生缩合反应得到 Ε- α- ( 3,5-二氧基苯亚曱基) -环酮， 将 Ε-α- ( 3，5-二氧基苯亚甲基) -环酮在酸性或减性条件下与 烷基甲醛或芳基甲醛缩合得到 α— (3,5-二甲氧基苯亚甲基) -α'-烃基亚甲基环酮。 在本发明一个较佳实施例中， 所述环酮包括环己酮或环戊酮。 一种抗肿瘤药物， 包括权利要求 1所述的 ex- (3,5-二甲氧基苯亚甲基) -α'-烃基亚曱基环酮 和药学上能接受的载体。
一种抗胂瘤药物， 包括权利要求 1 所述的 α- (3,5-二甲氧基苯亚甲基) -α'-烃基亚甲基环酮 的医学上能接受的盐和药学上能接受的载体。 在本发明一个较佳实施例中， 所述 α- (3,5-二甲氧基笨亚甲基) -α'-烃基亚甲基环酮占所述 抗胂瘤药物的重量百分比为 0,05-90%。
在本发明一个较佳实拖例中， 所述 α- (3,5-二甲氧基笨亚甲基) -α'-烃基亚甲基环酮占所述 抗肿瘤药物的重量百分比为 15-60%。
在本.发明一个较佳实施例中， 所述载体包括溶 、 稀释剂、 片剂、 胶嚢、 分散粉末或颗 粒剂。 本发明的有益效果是： 本发明的 α (3,5二曱氧基苯亚甲基) -α'-烃基亚甲基环酮及其制备 方法， 所述 α (3,5二甲氧基苯亚甲基) -α'-烃基亚甲基环酮是对天然产物抗胂瘤活性成分白藜 芦醇和姜黄素的结构进行拼合以及修饰， 结果获得了活性更高的抗肿瘤药物， 且对表皮生长 因子受体具有良好的抻制作用„ 具体实施方式 下面对本发明的较佳实施例进行详细阐述, 以使本发明的优点和特征能更易于被本领域 技术人员理解， 从而对本发明的保护范围做出更为清楚明确的界定。 一种 α- (3,5-二甲氧基笨亚甲基） -α'-烃基亚甲基环酮， 结构通式为
Figure imgf000005_0001
其中 R 为芳基或烷基， 当原料为环 己酮时， 通式 α- (3,5-二甲氧基苯亚甲基)- α'-烃基亚甲基环酮中 α'代表化合物的 6位取代， 当 原料为环己酮时， 通式 a- (3,5-二甲氧基苯亚甲基) -α'-烃基亚曱基环酮中 α'代表化合物的 5位 取 。
实施例一:
(】）将 10.79g、 O.llmoi的环己酮和】 0.4g、 0.12mol的吗啉加至 20mL笨中， 装上分水器， 回流共沸直至无水生成为止，减压蒸去苯和吗 ，得到浠胺。将 6.54g、 0.043mol的烯胺和 5.40g、 0.033moi的 3,5-二曱 |基苯曱醛加至 20mL苯中， 装上分水器， 回流共沸，直至无水生成为止， 共 8h, 冷却至室温， 搅拌下緩慢加入 6mol/Lik酸， 室温下搅捽 2h, 分出苯层， 水层用笨层 萃取， 合并笨层， 无水硫酸钠千燥， 减压蒸去溶剂， 用石油醚和乙醇重结晶得黄色针状晶体 E 2-( 3,5-二氧基苯亚甲基)-环己酮，收率 74%,熔点为 55.0〜56.6€。氢谱1 H NMR: δ： 7.4 l(s, 1H, =CH), 6.53(d, 2H, J=2.0Hz, ArH), 6.45(t, 1H, J=2.0Hz, ArH), 3.80(s, 6H, OCH3), 2.84(dt, 2H, J=i.9, 6.5Hz, CH2), 2.54(t, 2H, j=6.6Hz, C¾), 1.90(m, 2H， C¾)， 1.78(m， 2H, C¾)。
( 2 ) 将 300mg、 1.22mmoi的 E- 2- ( 3,5-二氧基笨 甲基) -环己酮和 129mg > 124 μ L、 1.22mmol的苯甲醛加入到 lOmL 10%的 NaOH乙醇溶液中， 室温搅拌 30min后反应完毕， 加入 50mL水和 20mL x 3 乙酸乙酯萃取， 无水硫酸納干燥后蒸去溶剂， 用石油醚和乙酸乙酯体积 比为 15:1透行柱层析， 得到 355mg淡黄色针状结晶 (2E, 6E)- 2- (3,5-二甲氧基苯亚甲基) - 6-笨亚 甲基环己酮，产率 87,2%，熔点为 90,2~91,0 „氢谱3 H- NMR(400MHz， CDC13): δ： 7.59~7.60(m, 3H, =CH, ArH), 7.52(s, 1H， =CH)， 7.45(i, 2H, 7.2Hz, ArH), 7.37'、7.40(m, IH, ArH), 6.75(s， 2H, ArH), 6.5 lis, 1H， ArH), 3.83(s, 6H, OC ), 3. i i(s， 4H, - C¾); 碳谱 13C- NMR(400MHz, CDC13): δ=196.375， 160.962, 137.885, 137.707， 137.423, 135.940, 134.021, 133.964, 130.955, 129.595, 128.954, 108.879, 101.799, 55.557， 26.690, 26.658： HR-MS: Calcd. For C21H20()3[M十 Hf: 321 ,1485, Found: 321,1475。 实施例 以 E- 2- (3,5-二氧基笨亚甲基)-环己酮和 3-氯苯甲醛为原料， 制备过程参见实施倒一。化合 物 (2E,6E)- 2- (3，5-二甲氧基苯亚甲基) -6- (3-氯苯甲亚基)环己酮的熔点为 107.5 108.4 °C , 氢 i !H-NMR(400MHz, CDC ): δ： 7.72(s, IH, =CH), 7.70(s, IH, =CH), 7.43(s, IH, ArH), 7.33(m, 3H, Arl:I), 6.6 lid 2H， J=2.1Hz, ArH), 6.47(t, I H, J:::2.1Hz, ArH), 3.82(s, 6H, ()CI¾), 2.92(m, 4:H, CH2), 1.81(qumt, 2e, j:::6.5Hz, CH2)。碳谱 i3C- NMR(40(》MHz, CDC13): 6: 190.257, 160.841， 137.985, 137,876, 137.577, 137,541, 136.631, 135,558, 134.564, 130.172, 129.936, 128.795, 108.625, 101.106， 55.707, 28.762, 28.684, 23.117. HR-MS: Calcd. For C22H21CK¾ [M+H]+: 369.1252, Found: 369 J 257。 实施例三： 以 E- 2- (3,5-二氧基苯亚甲基)-环己酮和 2-氯笨甲醛为原料， 制备过程参见实施例一。化合 物 (2E， 6E)- 2- (3,5-二甲氧基苯 甲基)- 6- (2-氯苯亚甲基)环己酮的熔点为 104.CM 04,71： , 氢谱 〗H- NMR (400MHz, CDC13): δ： 7.88(s， IH, =CH), 7.74(s, IH, =CH)， 7.44(m， IH, ArH), 7.33(m, IH, ArH), 7.28(m, 2H， ArH), 6.6 l(d, 2H, J=2.0Hz, ArH), 6.47(t, IH, J=2.1Hz, ArH), 3.82(s, 6H, OCH3), 2.94(t, 2H, J= 5.6Hz, C¾), 2.76(t, 2H, J=5.5Hz， CH2)， 1.77(quint， 2H, J=6.2Hz, CH2). i 3C NMR (400MHz, CDC13): δ: 190.280, 160.837, 138.169, 137.948, 137.752, 136.739, 135.260, 134.694， 133.913, 130.818, 130.009, 129.827, 126.555， 108.627, 101.090, 55.706, 28.983, 28.483, 23.363.HR- MS: Caicd. For C22H21CK:》3 [M+H]+: 369.1252, Found: 369.1251。 实施例四：
以 E- 2 (3,5-二氧基苯亚甲基)-环己酮和 2-氟苯曱醛为原料， 制备过程参见实施例一。化合 物 (2E, 6E)- 2- (3,5-二甲氧基苯亚甲基) -6- (2-氟苯亚甲基)环己酮的熔点为 83 0〜83.61 , 氢谱 〗H- NMR (400MHz, CDCL): δ 7.82(s, IH, =CH), 7.72(s， IH, =CH), 7.30~7.39(m, 2H， ArH), 7.16(t, IH, J=7.5Hz, ArH), 7.1 l(t, IH, J=9.3Hz, ArH), 6.60(d, 2H， j=2.1Hz, ArH), 6.47(t, IH, J=2.0Hz, ArH), 3.82(s, 6H, OCH3)， 2.94(t, 2H, J=5.4Hz, C¾), 2.80(t, 2H, J=5.8Hz, C ), 1.78(quint, 2H, J=6.5Hz, C ). 13C-NMR(400MHz, CDC13): δ: 190.173, 160.836, 138.570, 137.967, 137.597， 136.772, 131.009, 130.670, 130.589, 129.727, 124.009, 116.154, 115.937, 108.617， 101.088, 55.715, 28.953, 28.749， 23.246. HI - S: Calcd. For C22H21F()3 [M+Hf: 353.1547, Found: 353.1549。 实施例五： 以 E- 2 (3,5-二氧基苯亚甲基)-环己酮和 2-溴苯曱醛为原料， 制备过程参见实施例一。化合 物 (2E, 6E)-2-(3,5-二甲氧基苯亚甲基) -6-(2-溴苯亚甲基)环己酮的熔点为 111.7-112.5€, 氢谱 - NMR (400MHz, CDCI3): δ： 7.82(s, 1H, <Ή), 7.74(s, IH, -CH), 7.63(d, IH, J-7,9Hz, ArH), 7.30(m, 2H, ArH), 7.20(i, 1H， J= 8.0Hz, ArH), 6.60(d, 2H, J=1.9Hz, ArH), 6.47(t, IH, J=1.9Hz, ArH), 3,82(s, 6H, -OC¾), 2.93(t 2H， J=5.6Hz, - CH2)， 2,74( 2H, J=5.3Hz, - CH2), 1.77(quint, 2H, J=6.5Hz, - C¾). i3C- NMR(400MHz， CDC ): δ: 190.273, 160,844， 137.958, 137,894， 137.796, 136.730, 136.559, 136.196, 133.208, 130.848, 129.961, 127.178, 125.408, 108.638, 101.102, 55.720, 28.996， 28.381, 23.362. HR-MS: Calcd. For C22H2jBr03 [M+H]+: 413.0747, Found: 413.0765。 实施例六： 以 E- 2- (3，5-二氧基苯亚甲基)-环己酮和 3-溴苯甲醛为原料， 制备.过程参见实施例 化合 物 (2E, 6E)- 2- (3,5-二甲氣基笨亚甲基) -6- (3-溴笨亚甲基)环己酮的熔点为 1 11.9. 1 12.7 , 氢谱 NMR_(400MHz, CDC13): δ： 7,72(s, I H, -CH), 7 69(s, I H, -CH), 7.59(s, IH, ArH), 7 46(d, IH, J=7.7Hz, ArH), 7.36(d, IH, J=7.6Hz, ArH), 7.28(t, IH, J=7.9Hz, ArH), 6.60(s, 2H, ArH), 6.47(s, IH, ArH), 3.82(s, 6H, OCH3), 2.9 l(m, 4H, CH2), L79(quint, 2H， J=6.3Hz， C¾). i3C-NMR(400MHz, CDC13): δ: 190.151， 160.825, 138.269, 137.846， 137.558, 136.593, 135,402, 133.047, 131.667, 130.167, 129.157, 122.721 , 108.617, 101.105, 55.676, 28.728, 28.622, 23.097. HR-MS: Calcd. For C22H21Br03 [M+H]+: 413.0747, Found: 413.0747.
实施例七： 以 E- 2- (3,5-二氧基苯亚甲基)-环己酮和 4-溴苯甲醛为原料， 制备过程参见实施例一。 化合 物 (2E, 6E)- 2- (3,5-二甲氧基苯亚曱基) 6- (4-溴苯亚甲基)环己酮的熔点为 126.4〜128,6 Ό， 氢语 ! H-NMR(400MHz, CDC13): δ： 7.7 l(s, IH, =CH), 7.70(s, IH, =CH), 7.53(d, 2H, J=8.3Hz， ArH), 7 32(d, 2H, J-83Hz, ArH), 6.60(d, 2H, J- 1.8Hz, ArH), 6„47(s, I H, ArH), 3.82(s, 6H, OCH3), 2.93(i, 2H, j:::5.4Hz, CH2), 2.88(t, 2H, j:::5.4Hz, CH2), 1.79(quini, 2:H, J=6.4Hz, CH2). i3C-NMR(40()MHz, CDCb): δ: 〗90.323, 160.845, 137.912, 137.454, 136.967， 136.685, 1 35.922, 135.069, 132.1 15, 131 ,905, 123 , 159, 108,617, 101 ,084, 55/71 8, 28.755, 23.137. HR-MS: Calcd. For C22H2iBri¾ [Μ-ί-Η]+: 413.0747, Found: 413.0761.
实施例八： 以 E- 2 (3,5-二氧基苯亚甲基)-环己酮和 4-氟苯曱醛为原料， 制备过程参见实施例一。化合 物 (2E, 6E)-2-(3,5-二甲氧基苯亚甲基) -6-(4-氟苯亚甲基)环己酮的熔点为 Ϊ07.2~108.3 , 氢谱 ¾H-NMR(400MHz, CDC13): δ (ppm): 7,73(s, IH, =CH), 7.70(s, IH, =CH), 7.44(d, 2H, J=8.6Hz, ArH), 7.08(d， 2H, J=8.5Hz, ArH), 6.59(d, 2H, j=1 .7Hz, ArH), 6.45(s, I H, ArH), 3.80(s, 6H, OCH3), 2.86〜2.93(m， 4H, CH2), 1.78(ijiunt, 2H, J=6.1Hz, CH2), i3C-NMR(400MHz, CDC13): 5(ppm): 1 90.421 , 160.876, 1 37.996, 137.260, 136.801 , 136.156, 132.622, 132.540, 132.375, 115.923, 1 15.709, 108.616, 101.072, 55.708， 28.765, 28.702, 23.196. HR-MS: Calcd. For C22H21F03 [M+H]+: 353. 1547， Found: 353.1575.
实施例九： 以 E- 2- (3,5-二氧基苯亚甲基)-环己酮和 4-氯苯甲醛为原料， 制备过程参见实施例一。化合 物 (2E, 6E)- 2-(3，5-二甲氧基苯亚甲基) - 6- (4氯苯亚甲基)环己酮的熔点为 124.4~124.8 'C , 氢谱 1H- MR(400MHz, CDC13): δ (ppm): 7.72(s, I H, ==CH), 7.71(s, I H, = Ή), 7.38(m, 4:H, ArH), 6.60(d, 2H， j-2, l Hz, ArH), 6,47(t, I H, J-2, lHz, ArH), 3.82(s, 6H, OCH3), 2.93(t, 2H, J-5.6Hz, CH2), 2.87(t, 2H, J-5.5Hz, CH2), 1.79(quint, 2H, J-6.5Hz, CH2). i3C-NMR(400 Hz, CDCI3): δ(ρρΐϋ): 190.341 , 160,852, 137.923, 137.417, 136,847， 136.702, 135.900, 134,816， 134.636, 131.895, 128.949, 108.613, 101.074, 55.713, 28.752, 23.144. HR-MS: Calcd. For C22H2iC103 [M+H] ; : 369, 1252, Found: 369 1269,
实施例十： 以 E- 2- (3，5-二氧基苯亚甲基)-环己酮和环己基曱醛为原料， 制备过程参见实施例一。 化合 物 (2E, 6E)- 2- (3,5-二甲氧基笨亚甲基) -6- (环己基亚甲基)环己酮的熔点为 94.( 95.1 'C , 氢谱 NMR_(400MHz, CDC13): δ (ppm): 7,64(s, IH, -CH), 6.73 (d, IH, J 9.8Hz, ArH), 6.60(d, 2H, J=1.9Hz, ArH), 6.45(s, IH, ArH), 3.81(s, 6H, OCH3)， 2.86(t 2H, J=5.6Hz, CH2), 2.60(†, 2H, J=5.5Hz， CH2)， 2.29(m, IH, CH), 1.74-1.77(m, 4H， CH2)， L67(m, 2H, CH2), 1.14~ .35(m, 6H, CH2). i C-NMR(400MHz, CDC13): 6(ppm): 190.633, 160.785, 146.497, 138,165， 137.117, 136.557, 134.262, 108.505, 100.872, 55.694, 37.558, 32.046， 28.853, 2.6.466, 26.180, 25.941, 23.040. HR-MS: Calcd. For C22H2803 [M+H]+: 341.2111, Found: 341.2111.
实施例十一： 以 E- 2- (3,5-二氧基苯亚甲基)-环己酮和 3-甲氧基苯甲醛为原料， 制备过程参见实施例 -一。 化合物 (2E, 6E)- 2- (3,5-二甲氧基苯亚曱基) -6- (3-甲氧基苯亚甲基)环己酮的熔点为 92.0〜92.6 °C , 氩旙〗H-NMR(400MHz， CDC¾): δ (ppm): 7.76(s， IH, =CH), 7.71(s, IH, =CH)， 7.32(t, IH, J-7„9Hz, ArH), 7.06(d, IH, J-7.7Hz, ArH), 7.00(s, IH, ArH), 6.90(d, IH, J-8.2Hz, ArH), 6,60(d, 2H, J==1.6Hz, Arl:I), 6.50(s, I H, ArH), 3.84(s, 3H, CH3)， 3.82(s, 6H, OCH3), 2.9(){t, 4H, J==5.2Hz, ( )， 1.80(qumt, 2H， J==6.4Hz, CH2). 13C-NMR: 5(ppm): 】90.429, 160.792, 】59.652, 137.955, 137,471, 137.107, 136,832, 136.619, 129,600, 123.085, 116.005, 114,455, 108.548, 100,994, 55,630, 55,507, 28,755, 28,728, 23,156, HR-MS: Calcd. For C23『:i24 [M+H]+: 365,1747, Found: 365,1747.
实施例十二 将 300mg、 i.22mmoi的 E- 2 (3,5二氣基苯亚甲基)环己酮和 168mg、 1.22mmoi的 3，4-二羟 基苯甲醛加入到 10mL乙醇中 ,加入 203 μ L、 2.43ηπικ>ί的浓盐酸，室温搅捽 30min,加入 50mL 水和 20mL x 3乙酸乙酯萃取，无水疏酸钠千燥后蒸去溶剂，用石油醚和乙酸乙酯体积比为 15:1 进行柱层析， 得到 320mg淡黄色针状结晶 (2E, 6E) 2-(3,5-二甲氧基苯亚甲基) - 6- (3,4 -二羟基苯 甲基.)环己酮，产率 78.7%,熔点为】57.6〜158.7°C。氢谱 5H- NMR: δ： 7.79(s, 1H,：:: CH), 7.7 lis, IH, -CH), 7.19(s, IH, ArH), 7.04(d, IH, J=8 3Hz, ArH), 6.93(d, IH, J-8.2Hz, ArH), 6.60(s, 2H, ArH), 6.47(d, IH, 6Hz， ArH), 3,82(d, 6H, J-1.6Hz, OCH3), 2 90(m, 4H, CH2), 1.79(qiimt, 2H, J:::5.7Hz, (¾);碳谱 13C- NMR: δ- 189.808, 160.872, 147.521 , 145.617, 137.848, 137.753， 137.630, 135.768, 133.608, 127.474， 12.4.263, 118,335， 116.360, 108.601, 101.240, 55.840, 28.557, 28,367， 22.934。 HR-MS: Calcd. For C22H2205 [M+H]+: 367.1540, Found: 367.1541。
实施例十三： 以 E- 2- (3,5-二氧基苯亚甲基)-环己酮和 2-甲氧基苯甲醛为原料， 制备过程参见实施例 -一。 化合物 (2E, 6E)- 2- (3,5-二甲氧基苯亚曱基) -6- (2-甲氧基苯亚甲基)环己酮的熔点为 90.8〜91.2 V. , 氢谱1 H- NMR(400MHz, CDC13): δ (ppm): 7.99(s, IH, =CH), 7.7 l(s, IH, =CH), 7.33(m, 2H, ArH), 6 97(t, IH, J-7.4Hz, ArH), 6.92(d, IH, J-8.2Hz, ArH), 6,60(d, 2H, J-2,0Hz, ArH), 6.46(t, IH, j=2.0Hz, ArH), 3.87(s, 31:1, OCH3), 3.82(s， 6H， OC ), 2.92(i, 2H, J==5.7Hz, ( :)， 2.84(t， 2H, J==5.5Hz, CH2), 1.77(quini, 2H， J::=6.2Hz, CH2). 13C- MR S(ppm): 190.502, 160.769, 158.596, 138.117, 137.105, 136.911, 136.417， 132.909, 130.533, 130.388, 125.110， 120.152, 110.817, 108.510, 100.880, 55.686, 55.611, 28.956, 28.735, 23.421, HR-MS: Calcd. For C23H2404[M+H]; : 365.1747, Found: 365.1750.
实施例十四： 以 E- 2- (3,5-二氧基笨亚甲基)-环己酮和 4-羟基苯甲醛为原料, 制备过程参见实拖例十二。 化合物 (2E，6E)- 2- (3,5-二甲氧基苯亚甲基) -6- (4-羟基笨亚甲基)环己酮的熔点为 155.0~155.6 , 氢谱 - NMR(400MHz, CDC1.,): 6 (ppm): 7.76(s, IH, =CH), 7.72(s, IH, =CH), 7.39(A 2H, J-8.3Hz, ArH), 6.90(d, 2H， j:::8.4Hz, ArH), 6.59(s, 2H, ArH), 6.46(s, IH, ArH), 6.27(s, I H, OH), 3.81 (s, 6H, OCH3)， 2.90(m, 41:1, CH2), 1.79(m, 21:1, CH2). 13C-NMI : δ (ppm): 191.373， 160.838, 157.381 , 138,314, 138.045, 137.259， 137.102, 134,065, 133.039, 128,507, 115.982, 108.648, 101.149, 55.748, 28.860, 28.718, 23.219. HR-MS: Caicd. For C22H2204 [M+H]+: 351 ,1591, Found: 351.1590.
实施例十五：
以 E- 2- (3,5-二氧基苯亚曱基)-环己酮和 4-二甲氨基苯甲醛为原料， 制备过程参见实施例 一。 化合物 (2E, 6E)-2-(3,5-二甲氧基苯亚甲基 )-6-(4-二甲氨基苯亚甲基）环己酮的熔点为 109.6-11031： , 氢谱1 H- NM:R(400MHz, CDC13): δ (ppm): 7.78(s, IH, -CH), 7.70(s, IH, -CH), 7.46(d, 2H, J=8.8Hz, ArH), 6,72(d, 2H, J=8.8Hz, ArH), 6.60(A 2H， J=2.0Hz, ArH), 6.44(s, IH, ArH), 3.81(s, 6H, OCH3)， 3,03(s, 6H， NCH3), 2.95(t, 2H, J=6.3Hz, CH2), 2.90(t 2H， J=5,6Hz), 1.80(quint 2H, J=6.2Hz, CH2). 13C-NM : S(ppm): 190.267, 160.794, 150.851, 138.751， 138.411, 137.439, 135.885, 133.004, 131.900， 124.155, 111.895, 108.468， 100.776， 55.675, 40.389, 29.099, 28.733, 23.333. HR-MS: Calcd. For C24H27N03[M+H]+: 378.2064, Found: 378.2060.
实施例十六： 以 E- 2- (3,5-二氧基苯亚甲基)-环己酮和 3-羟基- 4-甲氧基笨甲醛为原料，制备过程参见实施 例十二。化合物 (2E, 6E)- 2- (3,5-二甲氧基苯亚曱基) -6- (3-羟基 4-甲氧基苯亚甲基)环己酮的熔点 为 131.2~131.6€ ,氢谱' Ή- NMR(400MHz， CDCI3): 7.72(s, 1H， =CH), 7.69(s， IH, =CH)， 7.01(d, I H, j:::8.2Hz, ArH), 6.97(s, IH, ArH), 6.93(d, I H, j:::8.2Hz, ArH), 6.58(d, 2H, j:::1.5Hz, ArH), 6.43(s， I H, ArH), 5.86(s， I H, OH), 3.90(s， 3H， OCH3), 3.79(s, 6H, OCH3), 2.87(m, 4H, CH2), 1.77(qumt, 211 j:::6.2Hz, Cl¾). f 3C- NMR: 5 ppm): 190.406, 160.764， 146.897， 146.642, 138.046, 137,833, 136.960, 136.735, 134.218, 128,600, 124.835, 114.805, 113,616, 108.524, 100,915, 56,175, 55,635, 28,827, 28,664, 23,182, HR-MS: Calcd. For C23¾4〕5[M+H]+: 381 ,1697, Found: 381 ,1692.
实施例十七： 以 E- 2 (3,5-二氧基苯亚甲基)-环己酮和 4-甲氧基苯甲醛为原料， 制备过程参见实施例一。 化合物 (2E, 6E)- 2- (3,5-二甲氧基苯 甲基) -6- (4-甲氧基苯亚甲基)环己酮的熔点为 97.7-98. ϊ ， 氢谱1 Η- NM:R(400MHz, CDC13): δ (ppm): 7.77(s, IH, =€H), 7.71(s, IH,：:: CH), 7.46(d, 2H, J=8.7Hz, ArH), 6,94(d， 2H, J=8,7Hz， ArH), 6.60(d, 2H， J=1.9Hz, ArH), 6.46(s, IH, ArH), 3.85(s, 3H, C¾)， 3.82(s, 6H, OC ), 2.92(t, 4H, J=5.9Hz, CH2), 1.80 (quint, 2H, J=6.4Hz, C ). 〗3C NMR: 6(ppni): 190.280, 160.745, 160.225, 138.045， 137.273, 136.970， 136.560， 134,257, 1 32.562, 128.771 , 114.127, 1 08.460, 100.849, 55.573, 28.774, 28.657, 23.150. H -MS: Calcd. For C23H2404[M+H]÷: 365. 1747， Found: 365.1747.
实施例十八： 以 E- 2- (3,5-二氧基苯亚甲基)-环己酮和 3,5-二甲氧基苯甲醛为原料， 备过程参见实施例 - . 化合物 (2E, 6E)-2，6-二 (3，5-二甲氧基苯亚甲基)环己酮的熔点为 135.7-136.5 °C , 氢 i 1H- MR(400MHz, CDCi3): δ (ppm): 7.7 lis, 2H,：:: CH)， 6.60(d, 4H, J=2.1Hz， ArH:)， 6.46(i, 2H， J-2.1Hz, Aril), 3.82(s, 12H, OC )， 2,92(i, 4H, J-5.5Hz, CH2), 1.78(qiimt, 2H, J-6.6Hz, CH2). 13C-N R δ dipm): 190.525, 160.833, 137.995, 137.243， 136.866, 108.592, 】01 ,041 , 55 ,702, 28.813, 23.181. HR-MS: Calcd. For C24H2605[M+H]+: 395.1853, Found: 395.1869.
实施例十九： 以 E- 2- (3,5-二氧基笨亚甲基)-环己酮和 4-甲砜基笨甲醛为原料， 制备过程参见实施例一。 化合物 (2E， 6E)- 2- (3,5-二甲氧基苯 甲基)- 6- (4-甲砜基苯亚甲基)环己酮的熔点为 162.0 163.5 V , 氢谱 NMR(400MHz, CDC13): δ (ppm): 7,79(d， 2H, J=8.2Hz, ArH), 7.76(s, 1H, =CH), 7.73{s, 1H, =:CH), 7.61(ii 2H, J=8.2Hz， ArH), 6.61 (s, 2H, ArH), 6.48(s, 1 H, ArH), 3.82(s, 6H, OCH3), 3.09(s， 3H, S02CH3)， 2.95(t, 2H, J=5.1Hz, CH2)， 2.89(t, 2H, J=5.3Hz， CH2)， 1 .80(quint, 2H， J=5.6Hz,CH2). i 3C- NMR: 6(ppm): 189.744, 160.713, 141.522, 139.929, 139.108, 137.843, 137.523, 136.255, 134.311 , 130.899, 〗27.501 , 108.540, 101 .071 , 55.543， 44.536, 28.541 , 28.499， 22.860. HR-MS: Ca!cd. For C23H24()5S[M+H]4 : 413.1417， Found: 41 3.1396.
实施例二十：
以 E- 2- (3，5-二氧基苯亚甲基)-环己酮和 3,5-二叔丁基- 4羟基苯甲醛为原料， 制备过程参见 实施例十二„化合物 (2E， 6E)- 2- (3,5-二曱氣基苯亚甲基) 6- (3,5-二叔丁基- 4-羟基苯亚甲基)环己 酮的熔点为 148.2-149.9 X： , 氢镨1關 MR(400MHz， CDCI3): δ (ppm): 7.79(s, 1H, =CH)， 7.70(s, 1H, =€H)， 7,37(s, 2H， ArH), 6.60(s, 2H, ArH), 6.45(s, 1H, ArH), 5.48(s, 1H, OH), 3,82(s, 6H, OCH3), 2.903(ni, 4H, CH2), 1.80(quint, 2H, J=5.8Hz, CH2), 1.46(s, 18H, CH3), i3C- NMR δ (ppm): 190.493, 160.829, 155.078, 139.015, 138.272, 137.232, 136.481， 136.151 , 133.471 , 128.514, 127.638, 108.539, 100.878, 55.704， 34.704， 30.539, 28.925, 2.8.785, 23.435. HR MS: Calcd. For C30¾8O4[M十 ΗΓ: 463.2843, Found: 463.2829.
实施例二十一：
(】 ) 以环戊酮和吗啡为原料， 制备过程同实施例一步骤（ 1 )得到黄色针状晶体 E- 2- (3,5- 二氧基苯亚基)—环戊酮， 收率 62.0%, 熔点为 98 ~ 99 X 氢旙 1H-NMR(400MHz， CDCI3): δ： 7.3 l(t, 1H, j=5.2Hz, =CH), 6.68(d， 2H, J=2.0Hz, ArH), 6.49(t， I H, J=2.0Hz, ArH), 3.82.(s， 6H, OCH3), 2.98(td, 2H, j=2.5, 7.2Hz, C¾), 2.4 l (t, 2H, J=7.9Hz， CH2),2.03(qumt, 2H, j=7.6Hz, C )。
( 2 ) 以 E- 2- (3，5-二氣基笨亚基)-环戊酮和苯甲醛为原料， 制备过程同实施倒一步驟 ( 2 ) 得到 (2E, 5E)- 2- (3,5二甲氧基苯亚甲基) 5-苯亚甲基环戊酮。 熔点为 135.1 136.3€ , 氢谱 5e-N R(400MHz, CDC13): δ: 7.59〜7.60(m, 3H， ：:: CH， ArH), 7.52(s， IH, == Ή), 7.45(t， 2:H, J-7„2Hz, ArH), 7,37~7.40(t, IH, J-7.12Hz, ArH), 6.75(s, 2H, ArH), 6.5 l (s, IH, ArH), 3.83(s, 6H, OCH3), 3,1 l(s, 4H， CH2). °C-NMR(400MHz, CDCi3) : 6(ppm): 196.375, 160,962, 137.885, 137.707, 137.423, 135.940， 134.021, 133,964, 130.955, 129.595， 128.954, 108.879, 101.799, 55,557， 26.690, 26.658. HR-MS: Calcd. For C21H20O3[M+H]; : 321,1485, Found: 321.1475,
实施例二十二： 以 E- 2- (3，5-二氧基笨亚基)-环戊酮和 3-氯苯甲醛为原料， 制备过程同实施例一得到 (2E, 5E)- 2- (3,5-二甲氧基笨亚甲基) -5- (3-氯苯亚甲基）环戊酮。 熔点为 145.8 147.6 X： , 氢谱 ¾H-NMR(400MHz, CDCh): 6 (ppm): 7.90(s, IH, =CH)， 7.56-7.58(m, IH, ArH), 7.53(s, IH, =CH), 7.45〜7.47(m, IH, ArH), 7.29~7.32(m, 2H， ArH), 6.74(d， IH, ArH), 6.73(d, IH, ArH),6.51(s, IH, ArH), 3.83(s, 6H, OCH3), 3.00-3.10(m, 4H, CH2). 13C-NMR (400MHz, CDC13): 6(ppm): 196.050, 161 ,048, 139.710, 137,664, 136.288, 〗34,494, 134.061, 130.403, 130.333, 130.290, 129.769, 126.898， 108.956, 101 .960, 55.654, 26.900， 26.564. HR-MS: Calcd. For C2iH19Ci()3[M十 Hf: 355.1095， Found: 355.1089.
实施例二十三： 以 E- 2- (3,5-二氧基苯亚基)-环戊酮和 2-氯苯甲醛为原料， 制备过程同实施例一得到 (2E, 5E)- 2-(3，5-二曱氧基苯亚甲基) 5- (2-氯苯亚曱基）环戊酮„ 熔点为 162.4〜162.9 ， 氢谱 1H- MR(400MHz, (::ί)(¾): δ (ppm): 7.91(s, I H, ==CH), 7.57(d, I H, j:::6.7Hz, ArH), 7.53{s, 】H, =CH), 7.46(d, IH, J=7.6Hz, ArH), 7.30-7.32 (m, 2H, ArH), 6.74(s, 2H, ArH), 6.5 l(s, IH, ArH), 3.83(s, 6H， OCH3), 3.01-3, 11 (m, 4H, CH2). 13C-NM (400MHz, CDC13): 6(ppm): 196.121, 161,080, 139.751, 137.709, 136.326, 134.542, 134.119, 130.431， 130.377, 130.320, 129.863, 126.914, 108.987, 101.982, 55.705, 26.956, 26.613. HR-MS: Calcd. For C21Hj 9Ci03[M+H]+: 355.1095, Found: 355,1086,
实施例二十四： 以 E- 2- (3,5-二氧基笨亚基)-环戊酮和 2-氟笨甲醛为原料， 制备过程同实施例一得到 (2E, 5E)- 2- (3,5-二甲氧基苯亚甲基) -5- (2-氟苯 甲基）环戊酮。 熔点为 133.6〜134.9 I , 氢谱 iH-NMR(400MHz, CDC13): δ (ppm): 7.8 lis, IH, =CH), 7.59(d, IH, J=6.7Hz, ArH), 7.53(s, IH, =CH), 7.46(d, IH, J:::8.3Hz, ArH), 7.2 lit, IH, J==7.6Hz, ArH), 7.14(t, IH, J:::8.9Hz, ArH), 6.75(s, 21:1, ArH), 6.51(s, I H, ArH), 3.84(s, 61:1, ()(: ), 3.03-3.13(m, 4:H, C ). 13C-丽 R(400MHz, CDCI3) : 5(ppm): 】96.092, 161.058, 139.295, 137.732, 134.418, 131.338, 131.253, 130.338, 125.553, 125.497, 124.386, 116.273, 116.054, 108.975, 101.954, 55.672, 26.801, 26,723, HR-MS: Calcd. For C2i F()3[M+H] : 339.1391, Found: 339.1386.
实施例二十五： 以 E- 2-(3，5-二氧基苯亚基)-环戊酮和 2-溴苯甲醛为原料， 制备过程同实施例一得到 (2E, 5E)- 2- (3,5-二甲氧基笨亚甲基) -5- (2-溴苯 甲基）环戊酮。 熔点为 159.0〜160.3 , 氢谱 !H-NMR(400MHz, CDC!?): δ (ppm): 7.81(s IH, =CH), 7.59(t, IH, J=7.7Hz, ArH), 7.53(s, IH,:: CH)， 7.34 7J9(m, I H, ArH), 7.2 I H, J:::7.6Hz, ArH), 7.14(t, IH, J=9.6Hz ArH), 6.75(s, 2H ArH), 6.5 l(s, IH, ArH), 3.84(s, 6H, ()(〕 ), 3.04-3.13(m, 41:1, CH2). i3C- MR(400MHz, CDC13): 6(ppm); 196.063, 161.071, 139.772, 137/720, 137.691, 135.811 134.545, 133.653, 132,434, 130.562, 130.394, 127.520, 126.720, 108.976, 101.979, 55.703, 26.957, 26.473. HR- MS: Calcd. For C21H19Br()3[M ΗΓ: 399.0590, Found: 399.0584.
实施例二十六： 以 E- 2- (3,5-二氧基苯亚基)-环戊酮和 3-溴苯甲醛为原料， 制备过程同实施例一得到 (2E, 5E)- 2- (3,5-二甲氧基笨亚甲基) -5- (3-溴笨亚甲基）环戊綱。 熔点为 MU MZ. C 氢谱 1H-NMR(400MHz, CDCh): δ (Ppm):7.73(s, IH, -CH), 7.50~7„53(m, 4H, ArH, -CH), 7.32(t, IH, J=7.7Hz, ArH), 6.75(s, 2H ArH), 6,52(s, IH, ArH), 3.84(s 6H, OCH3)， 3.11~-3.13(m, 4H CH2). 3C NMR(400MHz CDC13): δ (ppm): 196.237 161.097, 138.830, 138.117, 137.668, 137.584, 134.639, 133.345, 132.418, 132.305, 130.519, 129.558, 123.137； 109.041, 102.069, 55.700, 26.755, 26.693. HR- MS: Calcd. For C21Hj9Br03[M+H]+: 399.0590, Found: 399.0573.
实施例二十七： 以 E- 2- (3,5-二氧基笨亚基)-环戊酮和 4-溴苯甲醛为原料， 制备过程同实施例一得到（2E, 5E)- 2- (3 5-二甲氧基苯亚甲基) 5-(4-溴苯亚甲基）环戊酮 a 熔点为 182.0,483.3€， 氢谱 iH-NMR(400MHz, CDCl,): δ (ppm): 7.57(d, 2H j=8.4Hz, ArH), 7.52(s, 2H, =CH), 7.45(d, 2H, J-8.4Hz, ArH), 6.74(s, 2H, ArH), 6.51 (s, IH, ArH), 3.84(s, 6H, ()(¾), 3.04-3.14 m, 4H, CH2). L'C-NMI (400Mez, CDCi3): δ (ppm): 】96.373, 161.116, 138.169, 137.733, 134.952 134.503, 132.803, 132,335, 132.318, 124,064, 109.053, 102.019, 55.736, 26.775. HR- MS: Calcd. For C2jHi9Br03[M+H]+: 399.0590, Found: 399.0588.
实施例二十八：
以 E- 2- (3,5-二氧基苄亚基)-环戊酮和 4-氟苯甲醛为原料， 制备过程同实施例一得到 (2E, 6E)- 2- (3,5-二甲氧基笨亚甲基) -5- (4-氟苯 甲基）环戊酮。 熔点为 147.7 149.4 , 氢谱 NMR(400MHz, CDC13): δ (ppm): 7.54 - 7.59(m, 3H, ArH, =CH), 7.50(s, IH, =CH), 7. ll( 2H, J=8.5Hz ArH), 6.73(s, IH, ArH), 6.72(s, 1H ArH), 6.49(s, IH, ArH), 3.82(s, 6H, OCH3), 3.04~3.13(m, 4H, CH2). i C-NMR(400MHz, CDC13)： δ (ppm): 196.527, 161.144, 137.899, 137.826, 137.095, 134.343, 133.063, 133.004, 132.921, 116.395, 1 16.178, 109.054, 108.786, 101.988, 55.756 26.821, 26.696. HR- MS: Calcd. For C2i:Hi9F()3[M HTf: 339.1391, Found: 339.1377.
实施例二十九： 以 E- 2- (3,5-二氧基苯亚基)-环戊酮和 4-氯苯甲醛为原料， 制备过程同实施例一得到 (2E, 5E)- 2- (3,5-二甲氧基苯亚甲基 5- (4氯苯亚甲基）环戊酮。 熔点为 178.5 179.2 , 氢谱 5e-N R(400MHz, CDCI3): δ (ppm): 7.52(m 4H, ArH, ===CH), 7.41 (d, 2H, j:::8.4Hz, ArH), 6.75(s, IH, ArH), 6.74(s, IH, ArH), 6.5 l(s, IH, ArH), 3 84(s, 6H, OC¾), 3 05 3.14(m, 4H, CH2). 13C-NMR(400MHz, CDC13): δ (ppm): 196.362, 161.115, 137.996, 137.749, 135.650, 134.542, 134.454， 132.750, 132.135, 129.352, 109.048, 102.006, 55.734, 26.790, 26.753. HR- MS: Calcd. For C21H19CK¾[M+H]+: 355.1095, Found: 355.1081.
实施例三十： 以 E- 2- (3,5-二氧基苯 基)-环戊酮和环己基苯甲醛为原料， 制备过程同实施例一得到 (2E, 5E)-2-(3，5-二甲氧基笨亚甲基) -5- (环己基苯亚甲基)环戊 S同。 熔点为 110.5~111.7€, 氢谱 1H- MR(400MHz, (::ί)(¾): δ (ppm): 7.42(s, I H, ==CH), 6.71 (s, 211 ArH), 6.61 (d, I H, J==9.8Hz, -CH), 6,49(s, IH, ArH), 3 82(s, 6H, OCH3), 3.00(td, 2H, J-2,5Hz, 7.9Hz, CH2), 2.72(td, 2H, J-2.7Hz, 7.7Hz, CH2), 2.19~2.32(m, 】H, CH), 1.74~1.78(m, 2H, CH2), l,67~1.70(m, 2H, CH2), l 14~1.36(m， 6H, CH2). 13C-N R(400MHz, CDC13): S(ppm): 196.187, 161.015, 143.279, 138.995， 137.883, 136.536, 133.450, 108,844， 101.709, 55.649, 39,179， 31.873, 26.409, 26,122, 25.812, 2.3.816. H -MS: Calcd. For C2iH2603[M+H] ;: 327,1955, Foimd: 327.1953.
实施例三十一： 以 E- 2- (3,5-二氧基苯亚基)-环戊酮和 3-甲氧基苯甲醛为原料， 制备过程同实施例一得到 (2E, 5E)- 2- (3,5-二甲氧基苯亚甲基) -5- (3-甲氧基笨亚甲基)环戊酮。 熔点为 125.0~126.2X：, 氢 谱1 H NMR(400MHz， CDC13): δ (ppm): 7.56(s, IH, =CH), 7.52(s, IH, =€H)， 7,36(t, IH, J=7.8Hz, ArH), 7.20(d, IH, J=7.7Hz, ArH), 7.12(s, IH, ArH), 6.94(dd， IH, J=1.8Hz， 8.3Hz, ArH), 6.75(s, 1H， ArH), 6.75(s, IH, ArH), 6.5 l(s, IH, ArH), 3.85(s， 3H, OCH3), 3.83(s， 6H, OCH3), 3.11(s, 4H, CH2). i C-NMR(400MHz, CDC13): 6(ppm): 196.505, 161.073, 159.964, 137.969, 137.809, 137.769, 137.358, 134.151， 134.101 , 129.992， 123.588, 116.266， 115.380, 108.979, 101.927, 55.690, 55.570, 26.798. H -MS: Calcd. For C22H2204[M+H] : 351.1591, Found: 351.1578.
实施例三十二： 以 E- 2- (3，5-二氧基苯亚基)-环戊酮和 3,4-二羟基苯.甲醛为原料， 制备过程同实施例十二得 到 (2E, 5E)-2-(3，5-二甲氧基苯亚甲基 )-5-(3，4-二羟基笨亚甲基)环戊酮。 HR-MS: Calcd. For C21:H20()5 M : 353.1384, Found: 352.1385.
实施例三十三： 以 E- 2 (3,5二氧基苯亚基)-环戊酮和 2甲氧基苯甲醛为原料， 制备过程同实施例一得到 (2E, 5E)- 2- (3，5-二甲氧基笨亚甲基) -5- (2-甲氧基笨亚甲基)环戊酮。 熔点为 170.4~171.7 , 氢 谱1 H- NMR(400MHz, CDC{3): δ (ppm): 8,02(s, IH, -CH), 7 54(d, IH, J-7„7Hz, ArH), 7,5 l(s, IH, =CH), 7.36(t, IH, J=8,2Hz, ArH), 7.0 l(t, IH, J=7.5Hz, ArH), 6.94(d， IH, J=8.3Hz， ArH), 6.74(d, 2H， J=1.7Hz， ArH), 6.50(s, IH, ArH), 3.89(s, 3H, OC )， 3.83(s, 6H， OCH,), 3,01〜3.10(m, 4H, CH2).〗¾ NMR(400MHz, CDC13): S(ppm): 196,487， 161.040, 159.242， 138.334, 137.959, 137.425, 133.648, 131.189, 130.069, 128.700, 125.097, 120.556, 111.096, 108.877, 101.777, 55.796, 55.673, 26.988, 26.863. HR-MS: Calcd. For C22H2204[M+H]+: 351.1591, Found: 351.1575.
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ZT0880/C10ZN3/X3d I8S丽 OZ OAV 到 (2E, 5E)-2，5-二 (3,5-二甲氧基苯亚甲基）环戊酮。 熔点为 159.6-160.4 "C , 氢谱 5e-N R(400M Hz, CDC13): δ (ppm): 7.5 l (s, 2H, :::CH), 6.74(s, 4H， ArH), 6.5 l (s, 2H, ArH), 3.83(s. 12H， OCH3), 3„10(s, 4H， CH2). 13C-NMR(400MHz, CDCi3): δ (ppm): 196.455, 161 ,066, 137.925, 137.787, 134.181， 108.976, 101.947, 55.679, 26.785. HR- MS: Calcd. For C23H2405[M十 H]+: 381.1697, Found: 381 , 1683,
实施例三十九： 以 E- 2- (3，5-二氣基笨亚基.) -环戊酮和 4-甲砜基笨甲醛为原料， 制备过程同实施例一得到 (2E, 5E)-2-(3，5-二甲氧基笨亚甲基 )-5-(4-甲飒基苯亚甲基）环戊酮„ 氢谱1 H- NMR(400MHz， CDCI3): δ (ppm): 8.08(d, 2H, J=8.3Hz, ArH), 7.75(d, 2H, J=8.4Hz, ArH), 7,58(s, IH, =CH), 7.56(s, I H, ==CH), 6.75(d, 2H, J===2.0Hz, ArH ), 6.53{t, I H, J==2.0Hz, ArH), 3.84(s, 6H, ()CH3)， 3.14.、-3.16(m， 4H, CH2), 3.09(s, 3H, CH3S02). 13C-NMR.(400MHz, CDCi3): S(ppm): 161.186, 141.402, 141 .069, 140,606, 137.534, 137.265, 135.393, 131.394, 131 .334, 128.090, 109.184, 102.235, 55.780, 44,805, 26,886, 26.791. HR- MS: Calcd, For C22H3205S[M+H] : 399.1261 , Found: 399, 1262,
实施例四十： 以 E- 2 (3,5-二氧基苯亚基)-环戊酮和 3,5二叔丁基- 4-羟基苯甲醛为原料， 制备过程同实施 例十二得到 (2E, 5E)-2-(3,5-二甲氡基笨亚甲基) - 5- (3，5-二叔丁基- 4-羟基笨亚甲基)环戊酮。熔点 为 216,9-218.3 °C , 氢谱 - NMR(400MHz, CDC13): δ (ppm):7,59(s, I H, -CH), 7.49(s, 3H, Ή, ArH), 6.75(s, 2H, ArH), 6.50(s, IH, ArH), 5.58(s, IH, OH), 3.83(s, 6H, OCH3), 3, l l(s, 4H, CH2), 1.48(s, 18H, C¾). 13C-NM (400MHz, CDCl,): 6 (ppm): 196.462, 161.050, 155.857, 138.537, 138.063, 136.625, 135.877, 134.254, 133.317； 128.802, 127.601， 108.841 , 101.840， 55.664, 34.687, 30.464, 26.910, 26.830. HR- MS: Calcd. For C29H30O4[M+HT: 449.2686, Found: 449.2686.
对肿瘤细胞增殖的影响: 采用四甲基氮唑蓝比色法 (MTT)评价 α - ( 3,5-二甲氧基笨亚甲 基；)- α '-烃基亚甲基环酮对人肝癌 Hep G2胂瘤细胞株和人皮肤黑色素瘤 A16- F10细胞株的抗 增殖活性。 实验过程为：肿瘤细胞在含 10%胎牛血清、 iOOU'mL— )青霉素和 lOOU.ffiL 链霉素的 DMEM 培养液中,在培养箱中于 37 、 5%C02和饱和湿度条件下培养。受试化合物用二甲亚砜溶解， 然后用 DMEM培养基稀释成相应浓度， 其中二甲亚我的终浓度小于 0.01%。 取 于指数生长期的胂瘤细胞，胰蛋白酶消化，计数，用培养液调整细胞数目至 1 X〗05个 细胞 mL, 接种到 96孔板， 每孔 200 μ ί, 培养〗 2h加药。 实验分阴性对照組, 空白对照组和 实验组， 每组均设 3个复孔, 阴性对照组只加细胞， 不加药， 空白对照组只加二甲亚砜溶液, 实验组于每孔中加 11 μ L含不同浓度被测样品的溶液， 使得药物终浓度分別为 40.0、 20.0 , 10.0、 5.0、 1.0和 0.1 y g/mL。 于 37 "C、 5%C02培养箱中继续培养 48h, 轻轻吸掉培养液， 每 孔加入 200 μ L 0.5mg mL的 MTT液, 继续培养 6h, 将 MTT培养液吸掉，每.孔加入 150 L二甲 亚飒振荡溶解 lOmin,用酶标仪测定各礼光吸收度 OD值，测定波长 570nm和参考波长 630 nm, 实验重复三次， 其中细胞抑制率（％)：::： (阴性对照组 01〕值一受试物组 01)值） / (阴性对照组 OD值一空白对照组 OD值） χ 100%, 结果见表 1和表 2。 化合物对 EGFR抑制作用的测定：根据时间分辨荧光检测技术检测 EGFR激酶活性来评份 自动磷酸化水平. 受试物溶解在 100% DMSO中， 用 25mM HEPES ( pH=7.4 )稀释到所需的 浓度.， 每孔加 ΙΟ μ 受试物和 ΙΟ μ ί含 · 5 ng EGFR用 100 mM HEPES按 1 :80稀释的重组酶室 温培养 lO mi 然后加入 10 μ ΐ. 的含 20 mM HEPES、 2 mM Mii(::l2、 100 μ M Na3V04、 和 1 mM DTT緩冲液和 20 μ ί的 0.1 mM ATP-50 mM MgCl2培养 1 h。 每块板的阳性纽加 ATP- MgCl2酶， 阴性对照组不加 ATP- MgCl2酶， 培养 lh后吸尽液体， 每孔用緩冲液清洗三次。 将 75 μ L含 400 Tig铕标记的抗磷酸.化酪氨酸抗体加到孔中培养 lh, 洗涤， 加入增强溶液， 激 发波 340nm和发射波 615 Victor 2型时间分辨荧光仪检测荧光强度， 其中化合物自动磷酸 化的抑制率为： 自动磷酸化的抑制率 =100%-|：(阴性对照) 性对照-阴性对照)] , 结果见表 1。
表】化合物对肿瘤細胞的抗增殖作用和对 EGFR的抑制作用
抗增殖
化合物 R ICso [μΜ]
Hep G2 A16-F10
(2E, 6E)- 2- (3,5-二甲氧基苯亚曱
Ph 4,74 2.45 .68 基)— 6-苯亚甲基》己酮
(2E, 6E)- 2- (3，5-二甲氧基笨亚甲
3-ClP 6.11 5 o j 7 2,27 基)- 6- (3-氯苯甲亚基)环己酮 ； r、
(2E, 6E)- 2- (3,5-二甲氧基苯亚甲
2 ClPh 5,67 3.23 1.54 基)- 6- (2-氯苯亚甲基)环己酮
(2E, 6E)- 2- (3,5-二甲氧基笨亚甲
2~FPh 7.53 5.64 2.17 基)- 6- (2-氟苯亚甲基)环己酮
(2E, 6E)- 2- (3,5-二甲氧基苯亚甲
2-BrPh 32.20 12.42 8.08 基) -6-(2-溴苯亚甲基)环己酮
(2E, 6E)- 2-(3，5-二甲氧基苯亚甲
3- BrPh 16.67 6.85 基)— 6- (3-溴苯亚甲基)环己酮
(2E, 6E)- 2- (3,5二甲氧基苯亚甲
4-BrPh 29.16 2.27 7.12 基)— 6— (4-溴笨亚甲基)环己酮
(2E, 6E)- 2- (3,5-二甲氧基苯亚曱
4-FPh 12.09 7.63 5.69 基)— 6— (4-氟笨亚甲基)环己酮
(2E, 6E)- 2- (3，5-二甲氧基笨亚甲
4-ClP 25,48 8。4 15.32 基)— 6- (4-氯苯亚甲基)环己酮
(2E, 6E)- 2- (3,5-二甲氧基苯亚甲
c-C6Hu 17.17 12.21 •7
基)- 6- (环己基亚甲基)环己酮
(2E, 6E)- 2- (3,5-二甲氧基笨亚甲
3- CH3OPI1 17.24 9.72 6.13 基) 6- (3-甲氧基苯亚甲基)环己 (IE, 6E)- 2- (3,5-二甲氧基苯亚甲
基)— 6— (3,4-二羟基苯亚甲基)环己 3,4-diHOP 1 ,01 0.71 0.43
同
(2E, 6E)- 2- (3,5-二甲氧基笨亚甲
基) 6- (2-甲氧基苯亚甲基)环己 2- CH3OPh > 200 20.89
β同
(2Ε, 6Ε)- 2- (3,5二甲氧基苯亚甲
4-HOPh 10.47 3.28 4.66 基 .)—6— (4—羟基苯亚甲基)环己酮
(2Ε, 6Ε)- 2- (3,5-二甲氧基苯亚甲
基)„6— (4—二甲 苯亚甲基)环 4-(CH3)2NPli 11.76 5.84 3.98
己 S同
(2Ε, 6Ε)- 2-(3，5-二甲氧基苯亚甲
3-HO-4- 基)— 6— (3羟基- 4-甲氧基苯亚曱 11.05 7.04 5.37
C¾OPh
基)环己酮
(2Ε, 6Ε)- 2-二 (3，5-二甲氧基苯亚
4- CH3OPh 58.07 32.65 18.67 甲基)环己酮 Λ
(2Ε, 6Ε)- 2,6- (3，5-二甲氧基笨亚 O
O ！
3,5-di
甲基 )—6— (3,5-二甲氧基笨亚甲基） 8.56 4.71 2.08
CH3OPh
环己酮
(2Ε, 6Ε)- 2-(3，5-二甲氧基苯亚甲
基 )—6— (4—甲飒基苯亚甲基)环己 4- CH3SO2PI1 6.68 3.58 】.96
β同
(2Ε, 6Ε)- 2- (3,5二甲氧基苯亚甲
3,5- (C )3C- 4
基)- 6- (3,5-二叔丁基- 4-羟基苯亚 11 ,1 1 7.69 4.81
- HOPh
甲基)环己酮
姜黄素 26.99 18.65 8.65 厄洛 .'替/ ( erioiinib ) 0.12 0:2 0.03 表 1的药理实验结杲表明， 大部分化合物对人类肝癌 HepG2聍瘤细胞株和皮肤黑色素瘤 A16-F10细胞株的增殖具有很强抑制活性。 除化合物 (2E, 6E)- 2- (3,5-二甲氧基苯 甲基)- 6- (2- 溴苯亚甲基）环己酮、 (2E, 6E)- 2-(3,5-二甲氧基苯亚甲基) - 6- (4-溴苯亚甲基）环己酮、 (2E, 6E)-2-(3,5-二甲氧基苯亚甲基) -6-(2-甲氧基苯亚甲基)环己酮、 (2E, 6E)-2-(3,5-二甲氣基苯亚甲 基)— 6— (4-甲氧基苯 甲基.)环己酮外， 其余^^合物对 HepG2钟瘤细胞株抗增殖作用明显强于姜 黄素。 除 (2E, 6E) 2-(3,5-二甲氧基苯亚甲基) - 6- (2-甲氧基苯亚甲基)环己酮、 (2E, 6E)- 2- (3,5-二 曱氣基苯亚甲基)— 6- (4-甲氧基苯亚甲基)环己酮外， 其余化合物对皮肤黑色素瘤 A16- F 10 肿瘤 細胞林的抗增殖作用明显强于姜黄素。 其中 (2E, 6E)- 2- (3,5-二甲氣基笨亚甲基) -6- (3,4-二羟基 苯亚甲基)环己酮的抗胂瘤活性最大， 其 IC50值为 < 1μΜ。 所有化合物对表皮生长因子受体 EGFR具有良好的押制作用。
表 2化合物对 HepG2胂瘤细胞的抗增殖作用
Figure imgf000018_0001
表 2的药理实验结果表明， 5个化合物对 HepG2胂瘤细胞抹具有抗增殖作用， 其中 (2E, 5E)- 2- (3,5-二甲氧基苯 甲基) -5-苯亚甲基环戊酮、 （2E, 5E)- 2- (3,5-二甲氧基苯亚甲基)—5- (3,4- 二羟基苯亚甲基)环戊酮的活性明显强于姜黄素。
比较表 1和表 2的实验结果， 发现在同样的取代基 R情况下， α - ( 3,5-二曱氣基苯亚甲 基）-《 '-烃基亚甲基环己酮对 HepG2肿瘤细胞株抗增殖作用大于 α - ( 3,5-二甲氧基笨亚甲基 ) - ex '-烃基亚甲基环戊酮。
提供一种抗胂瘤药物， 包括 α - ( 3,5二甲氧基苯亚甲基） - (！'-烃基亚甲基环酮或其医学 上能接受的盐和药学上能接受的载体。 所述化合物或其医学上能接受的盐可以单独或与一种 以上可接受的载体纽合剂制成制剖给药， 例如采用溶剂、 稀释剂等， 也可以口服剂型给药， 如片剂、 胶嚢、 可分散粉末、 颗粒剖等。 本发明药物组合物的各种 型可以按照药学领域中 熟知的方法进行制备。 所述化合物占所述抗胂瘤药物的重量百分比为 0.05-90%, 更,优选占所 述抗肿瘤药物的重量百分比为 15-60%, 可以按照 0.005~5000mg/kg/天给药 , 也可根据疾病严 重程度或剂型的不同超出此剂量范围给药， 所述姜黄素衍生物还可以与其他抗胂瘤药物， 如烷化 . 抗代谢药、 拓朴异构酶抑制齐 'ϊ . 有丝分裂酶抑制剂 > DNA插入 联合应用， 联合治疗可以产生协同作用从而以有助于改善治 疗效果， 其中肿瘤包括人类癌细胞株 Hep G2肝癌细胞株和人皮肤黑色素瘤 Α - F10细胞祙。 以上所述仅为本发明的实施例， 并非因此限制本发明的专利范围， 凡是利用本发明说明 书内容所作的等效结构或等效流程变换， 或直接或间接运用在其他相关的技术领域， 均同理 包括在本发明的专利保护范围内。

Claims

权 利 要 求 书
一种 α- (3,5-二甲氧基苯 甲基) -α'-烃基亚甲基环酮， 其特征在于， 结构为：
Figure imgf000020_0001
其中 R为芳 ,基或烷基, s
2、 裉据权利要 i所述的 α- (3，5-二甲氧基苯亚甲基) - α'烃基亚甲基环酮， 其特征在于,
所述芳基的结构式为
Figure imgf000020_0002
, 其中 包括氢、 羟基、 卤素、 氨基、 甲颯基、 含】— 4个碳 的烷氧基> 坑基、 鹵代烷基或坑基 -fUt, 包括氢、 羟基、 卤素 > 氨基、 甲砜基、 含 1 -4个 碳的烷氧基、 烷基、 卤代烷基或烷基 JUt、 包括氢、 羟基、 卤素、 氨基、 甲砜基、 含 个碳的烷氧基、 烷基、 卤代烷基或烷基 -tt, 包括氢、 羟基、 卤素、 氨基、 甲颯基、 含 1-4 个碳的烷氧基 > 坑基、 鹵代烷基或坑基氨基； 所述烷基为含 1-8个碳的坑基。
3、 根据权利要求 i所述的 α- (3,5-二甲氧基苯亚甲基) -α'-烃基亚甲基环酮的制备方法， 其 特征在于， 包括步 为： 将环酮和吗啡啉混合共沸脱水得到烯胺， 将烯胺与 3,5-二甲氧基苯 甲醛发生缩合反应得到 Ε-α~ ( 3,5-二氧基笨亚甲基） -环酮， 将 Ε-α- ( 3,5-二氧基苯亚甲基） - 环酮在酸性或碱性条件下与烷基甲 或芳基甲醛缩合得到 α (3,5二曱氧基苯亚甲基) - α'-烃基 亚甲基环酮。
4、 根据权利要求 3所述的制备方法， 其特征在于， 所述》酮包括》己酮或》戊酮。
5、 一种抗肿瘤药物， 其特征在于， 包括权利要求 i所述的 α-(3,5-二甲氧基苯亚甲基) -α'- 烃基亚甲基环酮和药学上能接受的载体。
6、 一种抗肿瘤药物， 其特征在于， 包括; k刮要求 1所述的 α (3,5-二甲！ ^苯亚曱基) α'- 烃基亚甲基环酮的医学上能接受的盐和药学上能接受的载体。
Ί、 根据权利要求 5所述的抗肿瘤药物， 其特征在于， 所述 α- (3，5-二甲氧基苯亚甲基) - α'- 烃基亚甲基环酮占所述抗肿瘤药物的重量百分比为 0.05-90%.
8、 权利要求 7所述的抗肿瘤药物， 其特征在于， α- (3,5-二甲氣基笨亚甲基) -α'-烃基 亚甲基环酮占所述抗肿瘤药物的重量百分比为 15-60%。
9、 裉据; k刮要求 5或 6所述的抗胂瘤药物， 其特征在于， 所述载体包括溶剂、 稀释剂、 片剂、 胶.嚢.。 分散粉末或颗粒剂。
10、 根据权利要求 1或 2所述的化合物， 用于制备表皮生长因子受体抑制 药物。
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