WO2015018182A1 - Phenylacetic acid derivative and antitumor use thereof - Google Patents

Phenylacetic acid derivative and antitumor use thereof Download PDF

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Publication number
WO2015018182A1
WO2015018182A1 PCT/CN2014/000750 CN2014000750W WO2015018182A1 WO 2015018182 A1 WO2015018182 A1 WO 2015018182A1 CN 2014000750 W CN2014000750 W CN 2014000750W WO 2015018182 A1 WO2015018182 A1 WO 2015018182A1
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acid
methyl ester
cancer
linear
dihydroxyphenylacetic
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PCT/CN2014/000750
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French (fr)
Chinese (zh)
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李梢
张小虎
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北京京朋汇药业研究发展有限公司
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Publication of WO2015018182A1 publication Critical patent/WO2015018182A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/734—Ethers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • 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
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/42—Unsaturated compounds containing hydroxy or O-metal groups
    • C07C59/52—Unsaturated compounds containing hydroxy or O-metal groups a hydroxy or O-metal group being bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/732—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids of unsaturated hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention belongs to the field of pharmacy, and specifically relates to phenylacetic acid derivatives and their use in the preparation of antitumor drugs. Background technique
  • the tumor is the body's normal regulation of its growth at the genetic level under the action of various carcinogenic factors, resulting in the clonal abnormal proliferation of new organisms, which appear as a mass.
  • Tumor cells differ from normal cells in terms of external morphology, metabolism, and function, and exhibit persistent proliferation. According to valid statistics, tumors are the first of three major factors that threaten the health of human life around the world, so the development of anti-tumor drugs has been a hot topic.
  • Cytotoxic drugs including drugs that destroy DNA structure and function (such as cyclophosphamide, irinotecan), Drugs that affect nucleic acid biosynthesis (such as 5-fluorouracil, cytarabine, amidoxime);
  • drugs that affect hormone balance including anti-estrogen drugs (such as toremifene), antiandrogens Drugs (such as bicalutamide) and aromatase inhibitors (such as letrozole);
  • other and auxiliary drugs including immune function regulators (such as interleukins, interferons), biological response modifiers (such as Ero Actinidin, gefitinib), cell differentiation inducers (such as retinoic acid, arsenic acid), antifolate preparations (Libitai), monoclonal antibodies (such as Avastin) and adjuvant analgesia,
  • cytotoxic drugs generally cause moderate to severe digestive system reactions (such as malignant vomiting, stomatitis), myelosuppression (such as leukopenia, thrombocytopenia) and organ toxicity (such as Neurotoxicity, liver and kidney toxicity), hormone balance interference drugs can cause mild to moderate gastrointestinal reactions, reproductive system damage and even depressive symptoms in patients, most regulators and inducers can also cause different degrees of skin reactions and Liver and kidney dysfunction.
  • irinotecan Hydrochloride is commonly used in adult metastatic large intestines.
  • Alimta is the first anti-pleural mesothelioma drug, which can cause bone marrow suppression in patients, including neutropenia, thrombocytopenia, anemia or various types of cytopenia, liver and kidney dysfunction are hanged (Zheng Hang Et al.
  • Bevacizumab (Avast in) is a monoclonal antibody to vascular endothelial growth factor VEGF by binding to VEGF And prevent it from binding to receptors on the surface of endothelial cells, reducing microvascular production and inhibiting the progression of metastatic lesions, but its side effects are obvious, including gastrointestinal perforation, wound dehiscence syndrome, Bleeding, hypertensive crisis, nephrotic syndrome, and congestive heart failure (Eric 0. Gamboa et al. Clinical Colorectal Cancer, 9(1), 2010. ; A Mailliez et al. British Journal of Cancer, 103, 2010.; Sanjaykumar Hapani et al. Oncology, 79, 2010. )
  • R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of a hydroxyl group, a halogen, a d-C 5 linear or branched fluorenyl group, a C 2 -C 5 linear or branched unsaturated hydrocarbon group,
  • the two adjacent substituents of or Z, or R 2 , R 3 , R 4 and R 5 together with the carbon atom to which they are attached form a ternary or higher substituted or unsubstituted carbocyclic ring, or a substituted or Unsubstituted oxygen-containing heterocycle;
  • ⁇ selected from c "c 5 linear or branched alkyl, allyl, propargyl, dibutyl, decylallyl, alkynyl, methyl alkyne, substituted or unsubstituted phenyl Or a substituted or unsubstituted benzyl group;
  • X is selected from 0 or NH; -
  • R 6 is selected from the group consisting of hydrogen, C" ( 5 linear or branched saturated alkyl groups,
  • R 8 is selected from hydrogen, hydroxy, nitro, d-C 5 straight or branched saturated alkyl, or ( ⁇ -C 5 straight or branched alkyl
  • R 9 , R 10 , Rn , R 12 and R 13 are each independently selected from hydroxy, halo, C "C 5 straight or branched fluorenyl, C 2 - C 5 straight or branched unsaturated hydrocarbon, or / ⁇ 5 , or R, R lfl , Rn .
  • the two adjacent substituents of Rn and R 13 together with the carbon atom to which they are attached form a ternary or higher substituted or unsubstituted carbocyclic ring, or substituted Or an unsubstituted oxygen-containing heterocyclic ring;
  • R is selected from d-C 5 straight or branched alkyl
  • R 3 is hydroxy or ⁇ ( ⁇ R15 ; more preferred, 13 is hydroxy, and R 2 or R 4 is hydroxy or ⁇ .
  • R 2 , R 3 , R 4 and R 5 together with the carbon atom to which they are attached form a five- or six-membered or unsubstituted oxygenate.
  • Heterocyclic; uncyclized in Ri, R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, ⁇ , halo, d-C 5 straight or branched saturated alkyl, c 2 - c 5 a linear or branched unsaturated hydrocarbon group, or ⁇ . Rl5 .
  • R 3 and R 4 , or R 4 and R 5 together with the carbon atom to which they are attached form a five- or six-membered substituted or unsubstituted oxygen-containing heterocyclic ring containing two oxygen atoms;
  • R 3 and R 4 together with the carbon atom to which they are attached form a substituted or unsubstituted
  • R 8 is hydrogen or a hydroxyl group.
  • R 9 , R 10 , Ru, R 12 and R 13 are each independently selected from hydrogen, hydroxy, c "c 5 straight or branched alkyl, c 2 - c 5 straight or A branched unsaturated hydrocarbon group, or ⁇ 0 ⁇ R15 . More preferably, and 1 is a hydroxyl group.
  • the dC 5 linear or branched fluorenyl group of the present invention is preferably selected from the group consisting of decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl.
  • the C 2 -C 5 linear or branched unsaturated hydrocarbon group preferably from ethyl hydrazino, allyl, 1-propenyl, isopropenyl, allyl, allyl, 3-pentenyl, acetylene ⁇ , propargyl, 2-propynyl, alkynyl, alkynyl.
  • the compounds of the invention are preferably selected from:
  • the compound of the present invention is more preferably a compound of the following:
  • the invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt, polymorph, enantiomer or racemate thereof, in the manufacture of an anti-tumor drug.
  • the tumor is a solid tumor.
  • the tumor is selected from the group consisting of lung cancer, breast cancer, cervical cancer, rhabdomyosarcoma, nasopharyngeal carcinoma, pancreatic cancer, laryngeal cancer, skin cancer, liver cancer, neuroblastoma, nephroblastoma, intestinal cancer, One or more of gastric cancer and adrenocortical tumors.
  • the tumor is selected from one or more of the group consisting of lung cancer, breast cancer, cervical cancer, nephroblastoma, nasopharyngeal carcinoma, laryngeal cancer, neuroblastoma, intestinal cancer, and gastric cancer.
  • the compounds of the present invention produce an anti-tumor effect by inhibiting tumor cell proliferation, migration, and/or inducing tumor cell apoptosis.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-described compound of the present invention or a pharmaceutically acceptable salt, polymorph, enantiomer or racemate thereof.
  • the pharmaceutical composition is any one of clinically acceptable dosage forms, including gastrointestinal administration preparations and parenteral administration preparations;
  • the gastrointestinal administration preparation is selected from the group consisting of a powder, a tablet, a granule, a capsule, a dropping pill, an emulsion or a suspension;
  • the parenteral administration preparation is selected from the group consisting of an injection, an inhalation, a spray, an aerosol, a suppository, a perfusion, a patch or an ointment.
  • halogen as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom or a ruthenium atom; preferably a chlorine atom and a bromine atom.
  • the intake amount or amount of the compound of the present invention varies depending on the purity of the compound, the strength of action, the safety, the age of the subject, and the body weight. As a preventive or therapeutic tumor, it is usually 5 mg to 2 g per day for an adult, more preferably 10 mg to lg once or several times a day.
  • Figure 1 Results of the MTT experiment of Example 23; wherein, Figures 1-1 to 1-14 show DO, T83, D80, T73, T33, D23, T21, C52, D76, C17, C67, DO-1, DO, respectively. - 2, D0-3 survival rate of swollen cell A549 at different concentrations.
  • Figure 2 Effect of each compound on the migration ability of tumor cell A549 in Example 25, where Control is a blank control.
  • Figure 3 Effect of each compound on the migration ability of tumor cell A204 in Example 25, where Control is a blank control.
  • Figure 4 Effect of each compound on the migration ability of tumor cell line G401 in Example 25, where Control is a blank control.
  • Figure 5 Effect of each compound on the migration ability of tumor pericytes CT26 in Example 25, where Control is a blank control.
  • Figure 6 Effect of each compound on the migration ability of tumor cell A549 in Example 26, where Control is a blank control.
  • Figure 7 Effect of each compound on the migration ability of tumor cell G401 in Example 26, where Control is a blank control.
  • Figure 8 Effect of each compound on the migration ability of tumor cells HEP-2 in Example 26, where Control is a blank control.
  • Figure 9 Effect of each compound on apoptosis of tumor cell A549 in Example 27, where Control is a blank control.
  • Figure 10 Effect of each compound on apoptosis of tumor cell G401 in Example 27, where Control is a blank control.
  • Figure 11 Effect of each compound on apoptosis of tumor cell A549 in Example 28, with Cont rol as a blank control.
  • Figure 12 Effect of each compound on apoptosis of tumor cell G401 in Example 28, in which Cont rol was a blank control.
  • Figure 13 Effect of each compound on apoptosis of tumor fines HEP-2 in Example 28, where Control is a blank control.
  • LC-MSD Trap High Performance Liquid Chromatography-Ion Trap
  • DAD Diode Array Detector
  • detection wavelengths 214 nM and 254 nM
  • ESI source ion trap mass spectrometry
  • 3,4-Dihydroxyphenylacetic acid (DO, 3.0 g, 17.9 mraol) was dissolved in 25 mL of ethanol, and a catalytic amount of concentrated acid was added under stirring, and the mixture was heated under reflux for 12 hours.
  • 3-methoxy-4-hydroxy-benzaldehyde (10.0 g, 65.8 mmol) was dissolved in 150 mL of acetonitrile, and a catalytic amount of potassium and TMSCN (9.8 g, 98.6 mmol) was added under stirring. Stir at room temperature for 12 hours.
  • Step 7-1 prepared T73-2 (10 g, 55.9 let ol) was dissolved in methanol (15 mL), and 6.7 g of sodium hydroxide (168 mmol) and 75 mL of water were added with stirring. After stirring for 8 hours at room temperature, the pH was adjusted to 3 with a 1N aqueous solution of hydrochloric acid, and extracted with ethyl acetate (30 mL, 3). Synthesis of 65% X 7-3 product T73:
  • T83 3-decyloxy-4-hydroxyphenylacetate
  • the 3-methoxy-4-hydroxyphenylacetic acid (3.0 g, 16.4 ⁇ ol) prepared in Example ⁇ was dissolved in 100 mL of methanol, and a catalytic amount of concentrated sulfuric acid was added under stirring, and the mixture was heated under reflux for 12 hours. After cooling to room temperature, the reaction liquid was concentrated on a rotary evaporator, and the obtained oil was diluted to 150 mL of ethyl acetate solution, with a saturated NaHC0 3 solution (50 mL * 2 ) and saturated brine (50 mL).
  • Example 14 3-methoxy-4-allyl Methyl oxyphenylacetate (105), 3-methoxy-4-hydroxy-5-allylphenyl decanoate (107), 3-methoxy-4-hydroxy-5-propylphenylacetate Ester (110), 3, 4-dihydroxy-5-propylphenylacetate (111) and 3,4-dihydroxy-5-propylphenylacetic acid (112)
  • the C17-2 (600 mg, 1.37 mmol) prepared in Step 20-1 was dissolved in 3 mL of tetrahydrofuran and 3 mL of 2N aqueous sodium hydroxide and stirred at room temperature for 8 hr. The solvent was removed and 10 mL of water was added, and washed with 5 mL of ethyl acetate. The aqueous phase was adjusted to pH 2 with hydrochloric acid and extracted three times with 10 mL of ethyl acetate. The organic phase was dried and concentrated to give a white solid C17-4 (400 mg, 84% X
  • the C17-6 (20 mg, 0.03 yol) prepared in the step 20-2 was dissolved in 5 mL of ethyl acetate, and 2 mg of palladium carbon was added thereto, and the mixture was replaced with hydrogen three times, and stirred at 40 °C for 4 hours. Filtration with celite, EtOAc (EtOAc:EtOAc:EtOAc)
  • Triazole blue (3-(4,5-dimercaptothiazol-2)-2,5-diphenyltetrazolium bromide, MTT) experiment, test compound (dose gradient 10 mg/mK) 1 mg/mK 100 ⁇ g/m 10 M g/mK lg/ml, 100 ng/ml) treated lung cancer A549 cells, nasopharyngeal carcinoma CNE-2Z cells, nephroblastoma G401 cells and laryngeal carcinoma HEP-2 cells for 24 hours, MTT staining for 4 hours, two The methyl sulfoxide (DMS0) was dissolved, and the absorbance value was measured at 570 nm. Using the compound gradient as the abscissa, the cell survival rate as the ordinate, plotting the standard curve, and calculating the half-inhibition rate IC 5 . .
  • 065-1 46 ⁇ g/ml 21 ⁇ g/ml 22 ⁇ g/ml 71 ⁇ g/ml 17 ⁇ g/ml
  • Apoptosis flow assay was used to test compounds 065-1, 065-2, 067, 069, 070, 071, 072, 073, 077, 079, 099, 100, 102, 109, 111 and 122 (10 ⁇ ⁇ , this dose is a safe dose) to treat lung cancer ⁇ 549, nephroblastoma G401 and laryngeal carcinoma HEP-2 cells for 24 hours, then centrifuge the cells (1500 rpm, 5 min) and resuspend in PBS for 2 times. After staining with Annexin-V FITC and PI for 15 min, flow cytometry was used to detect apoptosis. The ratio of cells, the percentage of cells with early apoptosis and late apoptosis, and the total apoptosis were positive for DO, and a blank control group was also established.

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Abstract

Provided is a compound according to formula I and uses thereof in the preparation of antitumor medications, wherein each substituent group R1, R2, R3, R4, R5, R6 and X are defined as in the Description.

Description

苯乙酸衍生物及其抗肿瘤用途 相关申请的交叉引用  Phenylacetic acid derivatives and their antitumor use cross-reference to related applications
本申请要求 2013年 8月 5 日递交的中国专利申请号为 201310337414.9 的专利申请的权益， 在此将其全部内容引入作为参考。 技术领域  This application claims the benefit of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of the entire disclosure of Technical field
本发明属于药学领域， 具体涉及苯乙酸衍生物及其在制备抗肿瘤药物中 的用途。 背景技术  The present invention belongs to the field of pharmacy, and specifically relates to phenylacetic acid derivatives and their use in the preparation of antitumor drugs. Background technique
肿瘤是机体在各种致癌因素作用下， 细胞在基因水平上失去对其生长的 正常调控， 导致其克隆性异常增生而形成的新生物， 表现为肿块。 肿瘤细胞 在外部形态、 代谢和功能方面不同于正常细胞， 多呈现持续性增殖。 据有效 数据统计， 肿瘤是目前威胁全世界人类生命健康的三大因素之首， 所以抗肿 瘤药物的研发一直是热点。  The tumor is the body's normal regulation of its growth at the genetic level under the action of various carcinogenic factors, resulting in the clonal abnormal proliferation of new organisms, which appear as a mass. Tumor cells differ from normal cells in terms of external morphology, metabolism, and function, and exhibit persistent proliferation. According to valid statistics, tumors are the first of three major factors that threaten the health of human life around the world, so the development of anti-tumor drugs has been a hot topic.
根据抗肿瘤药物的传统分类和研究进展，可将常用的抗肿瘤药物分为以 下几大类： 一、 细胞毒药物， 包括破坏 DNA结构和功能的药物 （如环磷酰 胺、 伊立替康）、 影响核酸生物合成的药物 （如 5-氟尿嘧啶、 阿糖胞苷、 曱 氨喋呤）等；二、影响激素平衡的药物， 包括抗雌激素类药物（如托瑞米芬）、 抗雄激素类药物（如比卡鲁胺）和芳香化酶抑制剂 （如来曲唑）等； 三、 其 它及辅助药物， 包括机体免疫功能调节剂 （如白介素、 干扰素）、 生物反应 调节剂 （如埃罗替尼、 吉非替尼）、 细胞分化诱导剂 （如维曱酸、 亚砷酸）、 抗叶酸制剂 （力比泰）、 单克隆抗体（如阿瓦斯汀）和辅助镇痛、 止吐、 白 细胞升高等药物。 但是， 以上药物或多或少存在着副作用， 像细胞毒药物一 般会引发患者的中重度消化系统反应（如恶性呕吐、 口腔炎）、骨髓抑制（如 白细胞减少、 血小板减少）和器官毒性（如神经毒性、 肝肾毒性）， 激素平 衡干扰药物则会引起患者的轻中度胃肠道反应、生殖系统损伤甚至精神抑郁 症状， 多数调节剂和诱导剂等也会引发患者不同程度的皮肤反应和肝肾功能 损害。 例如伊立替康 ( I r inotecan Hydrochlor ide ) 常用于成人转移性大肠 癌的治疗，效果比较显著，但是用药后， 20%的患者出现胃肠道不良反应—— 严重腹泻， 78.7%的患者均出现过中性粒细胞减少症， 9%的患者出现短暂严 重的急性胆碱能综合征（Bret Wallace等. Science, 330, 2010.； 孙祎等. 中国药房， 18(35)， 2007.； 吴育红等. 安徽医药， 14(10), 2010. ); 力比 泰 ( Pemetrexed disodium, Alimta )是首个抗胸膜间皮瘤药物， 它可以引 起患者的骨髓抑制， 包括中性粒细胞减少、 血小板减少、 贫血或各类血细胞 减少， 肝、 肾功能不全者忌用 （郑航等. 肿瘤防治研究， 34(4)， 2007.； 王 剑英等. 中外健康文摘， 12， 2011. ); 阿瓦斯汀（Bevacizumab, Avast in) 是血管内皮生长因子 VEGF的单克隆抗体，通过结合 VEGF并防止其与内皮细 胞表面的受体结合， 减少了微血管的生成并抑制了转移病灶进展， 但是它的 副作用很明显， 包括胃肠穿孔、 伤口开裂综合症、 出血、 高血压危象、 肾病 综合征和充血性心力衰竭等 ( Eric 0. Gamboa 等. Clinical Colorectal Cancer, 9(1)， 2010. ; A Mailliez等. British Journal of Cancer, 103, 2010.； Sanjaykumar Hapani等. Oncology, 79, 2010. )„ According to the traditional classification and research progress of anti-tumor drugs, commonly used anti-tumor drugs can be divided into the following categories: 1. Cytotoxic drugs, including drugs that destroy DNA structure and function (such as cyclophosphamide, irinotecan), Drugs that affect nucleic acid biosynthesis (such as 5-fluorouracil, cytarabine, amidoxime); Second, drugs that affect hormone balance, including anti-estrogen drugs (such as toremifene), antiandrogens Drugs (such as bicalutamide) and aromatase inhibitors (such as letrozole); Third, other and auxiliary drugs, including immune function regulators (such as interleukins, interferons), biological response modifiers (such as Ero Actinidin, gefitinib), cell differentiation inducers (such as retinoic acid, arsenic acid), antifolate preparations (Libitai), monoclonal antibodies (such as Avastin) and adjuvant analgesia, antiemetic, white blood cell Higher drugs. However, the above drugs have more or less side effects, such as cytotoxic drugs generally cause moderate to severe digestive system reactions (such as malignant vomiting, stomatitis), myelosuppression (such as leukopenia, thrombocytopenia) and organ toxicity (such as Neurotoxicity, liver and kidney toxicity), hormone balance interference drugs can cause mild to moderate gastrointestinal reactions, reproductive system damage and even depressive symptoms in patients, most regulators and inducers can also cause different degrees of skin reactions and Liver and kidney dysfunction. For example, irinotecan Hydrochloride is commonly used in adult metastatic large intestines. The treatment of cancer is more effective, but after administration, 20% of patients have gastrointestinal adverse reactions - severe diarrhea, 78.7% of patients have had neutropenia, and 9% of patients have transient acute Cholinergic syndrome (Bret Wallace et al. Science, 330, 2010.; Sun Wei et al. Chinese Pharmacy, 18(35), 2007.; Wu Yuhong et al. Anhui Medicine, 14(10), 2010.); Pemetrexed Disodium, Alimta is the first anti-pleural mesothelioma drug, which can cause bone marrow suppression in patients, including neutropenia, thrombocytopenia, anemia or various types of cytopenia, liver and kidney dysfunction are hanged (Zheng Hang Et al. Cancer Research, 34(4), 2007.; Wang Jianying et al. Chinese and Foreign Health Digest, 12, 2011. ); Bevacizumab (Avast in) is a monoclonal antibody to vascular endothelial growth factor VEGF by binding to VEGF And prevent it from binding to receptors on the surface of endothelial cells, reducing microvascular production and inhibiting the progression of metastatic lesions, but its side effects are obvious, including gastrointestinal perforation, wound dehiscence syndrome, Bleeding, hypertensive crisis, nephrotic syndrome, and congestive heart failure (Eric 0. Gamboa et al. Clinical Colorectal Cancer, 9(1), 2010. ; A Mailliez et al. British Journal of Cancer, 103, 2010.; Sanjaykumar Hapani et al. Oncology, 79, 2010. )„
因此， 开发新的抗肿瘤有效化合物仍然是目前肿瘤药物研究的一个关键 问题。 发明内容  Therefore, the development of new anti-tumor effective compounds remains a key issue in current oncology drug research. Summary of the invention
本发明的目的在于提供一种新的苯乙酸衍生物。该类化合物能够有效地 抑制多种肿瘤， 可用于临床上多种肿瘤的预防和 /或治疗。  It is an object of the present invention to provide a novel phenylacetic acid derivative. These compounds are effective in inhibiting a variety of tumors and can be used for the prevention and/or treatment of various tumors in the clinic.
用于实现本发明上述目的的技术方案如下：  The technical solution for achieving the above object of the present invention is as follows:
一种式 I所示化合物，  a compound of formula I,
Figure imgf000004_0001
其中， 、 R2、 R3、 R4和 R5各自独立地选自 、 羟基、 卤素、 d- C5直链 或支链垸基、 C2-C5直链或支链不饱和烃基、 或 、Z ，或 、 R2、 R3、 R4和 R5中相邻的两个取代基与它们相连的碳原子一起形成三元以上的取代的或 未取代的碳环、 或者取代的或未取代的含氧杂环； 其中 ^选自 c「c5直链或支链烷基、 烯丙基、 炔丙基、 稀丁基、 曱基烯丙基、 炔丁基、 甲基炔丁基、 取代或未取代的苯基、 或取代或未取代的苄基；
Figure imgf000004_0001
Wherein, R 2 , R 3 , R 4 and R 5 are each independently selected from the group consisting of a hydroxyl group, a halogen, a d-C 5 linear or branched fluorenyl group, a C 2 -C 5 linear or branched unsaturated hydrocarbon group, The two adjacent substituents of or Z, or R 2 , R 3 , R 4 and R 5 together with the carbon atom to which they are attached form a ternary or higher substituted or unsubstituted carbocyclic ring, or a substituted or Unsubstituted oxygen-containing heterocycle; ^ selected from c "c 5 linear or branched alkyl, allyl, propargyl, dibutyl, decylallyl, alkynyl, methyl alkyne, substituted or unsubstituted phenyl Or a substituted or unsubstituted benzyl group;
X选自 0或 NH; -  X is selected from 0 or NH; -
R6选自氢、 C「 ( 5直链或支链饱和烷基、
Figure imgf000005_0001
R 6 is selected from the group consisting of hydrogen, C" ( 5 linear or branched saturated alkyl groups,
Figure imgf000005_0001
Figure imgf000005_0002
其中
Figure imgf000005_0002
among them
R8选自氢、 羟基、 硝基、 d- C5直链或支链饱和烷基、 或（^- C5直链或支 链烷基 R 8 is selected from hydrogen, hydroxy, nitro, d-C 5 straight or branched saturated alkyl, or (^-C 5 straight or branched alkyl
R9、 R10, Rn 、 R12和 R13各自独立地选 ^、 羟基、 鹵素、 C「C5直链或支 链垸基、 C2- C5直链或支链不饱和烃基、 或 。/^5，或 R,、 Rlfl、 Rn . Rn和 R13 中相邻的两个取代基与它们相连的碳原子一起形成三元以上的取代的或未 取代的碳环、 或者取代的或未取代的含氧杂环； R 9 , R 10 , Rn , R 12 and R 13 are each independently selected from hydroxy, halo, C "C 5 straight or branched fluorenyl, C 2 - C 5 straight or branched unsaturated hydrocarbon, or /^ 5 , or R, R lfl , Rn . The two adjacent substituents of Rn and R 13 together with the carbon atom to which they are attached form a ternary or higher substituted or unsubstituted carbocyclic ring, or substituted Or an unsubstituted oxygen-containing heterocyclic ring;
R 选自 d- C5直链或支链烷基； R is selected from d-C 5 straight or branched alkyl;
条件是 3和 都是羟基， X是 0, 1 6是氢时， iU、 R2和 R5不能同时为氢。 一种优选 ό 结构类型， R3是羟基或 \(^R15; 更优逸的， 1 3是羟基， R2 或 R4是羟基或^^^^ 。 The condition is that both 3 and are hydroxyl groups, X is 0, and when 16 is hydrogen, iU, R 2 and R 5 cannot be hydrogen at the same time. A preferred ό structure type, R 3 is hydroxy or \(^ R15 ; more preferred, 13 is hydroxy, and R 2 or R 4 is hydroxy or ^^^^.
还有一种优选的结构类型， ^、 R2、 R3、 R4和 R5中相邻的两个取代基与它 们相连的碳原子一起形成五元或六元取代的或未取代的含氧杂环； Ri、 R2、 R3、 R4和 R5中未成环的各自独立地选自氢、 ^基、 卤素、 d- C5直链或支链饱 和烷基、 c2- c5直链或支链不饱和烃基、 或 \。 Rl5。 There is also a preferred type of structure in which two adjacent substituents of ^, R 2 , R 3 , R 4 and R 5 together with the carbon atom to which they are attached form a five- or six-membered or unsubstituted oxygenate. Heterocyclic; uncyclized in Ri, R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, ^, halo, d-C 5 straight or branched saturated alkyl, c 2 - c 5 a linear or branched unsaturated hydrocarbon group, or \. Rl5 .
更优选的， R3和 R4、或 R4和 R5与它们相连的碳原子一起形成五元或六元 含两个氧原子的取代或未取代的含氧杂环； More preferably, R 3 and R 4 , or R 4 and R 5 together with the carbon atom to which they are attached form a five- or six-membered substituted or unsubstituted oxygen-containing heterocyclic ring containing two oxygen atoms;
进一步优选 R3和 R4与它们相连的碳原子一起形成取代或未取代的 It is further preferred that R 3 and R 4 together with the carbon atom to which they are attached form a substituted or unsubstituted
[ 1 , 3] -二氧戊环。  [ 1 , 3] - Dioxolane.
上述碳环、含氧杂环、 l , 3] -二氧戊环的取代基选自羟基、 卤素、羰基、 c「c5直链或支链烷基、 或^\0 ("15。 本发明所述的化合物， 优选 R8为氢或羟基。 The carbon ring, oxygen-containing heterocyclic, l, 3] - dioxolane substituted group selected from hydroxy, halogen, carbonyl, C "c 5 linear or branched alkyl, or ^ \ 0 (" 15. In the compound of the present invention, it is preferred that R 8 is hydrogen or a hydroxyl group.
本发明所述的化合物， 优选 R9、 R10, Ru、 R12和 R13各自独立^选自氢、 羟基、 c「c5直链或支链烷基、 c2- c5直链或支链不饱和烃基、 或 \0^R15。 更 优选的， 。和 1^为羟基。 The compound of the present invention, preferably R 9 , R 10 , Ru, R 12 and R 13 are each independently selected from hydrogen, hydroxy, c "c 5 straight or branched alkyl, c 2 - c 5 straight or A branched unsaturated hydrocarbon group, or \ 0 ^ R15 . More preferably, and 1 is a hydroxyl group.
本发明所述 d-C5直链或支链垸基， 优选自曱基、 乙基、 正丙基、 异丙 基、 正丁基、 异丁基、 仲丁基、 叔丁基、 戊基。 The dC 5 linear or branched fluorenyl group of the present invention is preferably selected from the group consisting of decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl.
所述 C2-C5直链或支链不饱和烃基， 优选自乙浠基、 烯丙基、 1-丙烯基、 异丙烯基、 烯丁基、 烯戊基、 3-戊烯基、 乙炔 ^、 炔丙基、 2-丙炔基、 炔丁 基、 炔戊基。 The C 2 -C 5 linear or branched unsaturated hydrocarbon group, preferably from ethyl hydrazino, allyl, 1-propenyl, isopropenyl, allyl, allyl, 3-pentenyl, acetylene ^, propargyl, 2-propynyl, alkynyl, alkynyl.
本发明所述化合物优选自：  The compounds of the invention are preferably selected from:
3-曱氧基 -4, 5-二羟基苯乙酸（ 065-1 )，  3-decyloxy-4,5-dihydroxyphenylacetic acid (065-1),
3 -曱氧基 -4， 5-二羟基苯乙酸甲酯 （ 070 )，  3-methoxy-methyl 4,5-dihydroxyphenylacetate ( 070 ),
3, 4， 5 -三羟基苯乙酸 ( 065-2 ),  3, 4, 5 - trihydroxyphenylacetic acid ( 065-2 ),
3， 4， 5 -三羟基苯乙酸曱酯（ 069 )，  3, 4, 5-trihydroxyphenylacetate (069),
3 -苯甲氧基- 4， 5 -二羟基苯乙酸甲酯（077 ), 3-benzyloxy- 4,5-dihydroxyphenylacetic acid methyl ester (0 77 ),
3- ( 2'-甲基丙氧基） -4， 5-二羟基苯乙酸（ 079 )，  3-( 2'-methylpropoxy) -4,5-dihydroxyphenylacetic acid ( 079 ),
3-曱氧基 -4-烯丙氧基苯乙酸曱酯 （105 )，  3-decyloxy-4-allyloxyphenylacetic acid decyl ester (105),
3 -曱氧基- 4-羟基- 5-烯丙基苯乙酸曱酯（107 ),  3-methoxy- 4-hydroxy-5-allylphenylacetate (107),
3 -曱氧基- 4-羟基- 5-丙基苯乙酸甲酯（110 ),  3-methoxy-4-hydroxy-5-propylphenylacetate (110),
3, 4-二羟基 -5-丙基苯乙酸甲酯 （111 )，  Methyl 3, 4-dihydroxy-5-propylphenylacetate (111),
3， 4-二羟基 -5-丙基苯乙酸（ 112 )，  3, 4-dihydroxy-5-propylphenylacetic acid (112),
3 -氯 -4-羟基- 5-甲氧基苯乙酸曱酯（100 ),  3-chloro-4-hydroxy-5-methoxyphenylacetate (100),
3-氯- 4， 5-二羟基苯乙酸（ 067 )，  3-chloro-4,5-dihydroxyphenylacetic acid ( 067 ),
3 -氯 -4, 5-二羟基苯乙酸曱酯 （ 072 )，  3-chloro-4,5-dihydroxyphenylacetate (072),
3-溴- 4-羟基- 5-甲氧基苯乙酸甲酯（ 099 ),  Methyl 3-bromo-4-hydroxy-5-methoxyphenylacetate (099),
3 -溴- 4, 5-二羟基苯乙酸（ 073 )，  3-Bromo-4,5-dihydroxyphenylacetic acid ( 073 ),
3-溴 -4， 5-二羟基苯乙酸曱酯 （ 071 ),  3-bromo-4,5-dihydroxyphenylacetate ( 071 ),
2, 3, 6-三氯 -4， 5-二羟基苯乙酸曱酯 ( 102 )，  2,3,6-trichloro- 4,5-dihydroxyphenylacetate ( 102 ),
2, 3， 6-三氯- 4, 5-二羟基苯乙酸 ( 109 ), 3, 4-二羟基苯乙酸乙酯 (删）， 2, 3, 6-trichloro-4, 5-dihydroxyphenylacetic acid (109), Ethyl 3, 4-dihydroxyphenylacetate (deleted),
3, 4-亚甲二氧基苯乙酸（D76 ),  3, 4-methylenedioxyphenylacetic acid (D76),
3, 4-亚甲二氧基苯乙酸曱酯（D ),  3, 4-Methylenedioxyphenylacetate oxime (D),
3-曱氧基 -4羟基苯乙酸（T73 )，  3-decyloxy-4-hydroxyphenylacetic acid (T73),
3, 4-二羟基苯乙酸（3'，4'-二羟基）苯乙酯 （C17 )，  3, 4-dihydroxyphenylacetic acid (3',4'-dihydroxy)phenylethyl ester (C17),
N- ( 3', 4'-二羟基 )苯乙基- ( 3， 4-二羟基）苯乙酸胺（ C52 ), N-(3',4'-dihydroxy)phenethyl-(3,4-dihydroxy)phenylacetic acid amine (C52),
N-2-羟基苯乙基- ( 3， 4-二羟基） -苯乙酸胺（ C67 )， N-2-hydroxyphenethyl-(3,4-dihydroxy)-phenylacetic acid amine (C67),
3, 4-二羟基苯乙酸曱氧基曱醇酯（T33 ),  3, 4-dihydroxyphenylacetic acid decyl sterol ester (T33),
3-甲氧基 -4羟基苯乙酸曱酯（T83 ),  3-methoxy-4-hydroxyphenylacetate (T83),
2-氧代苯并 [1， 3]二氧戊环- 5-乙酸（T21 )，  2-oxobenzo[1,3]dioxolan-5-acetic acid (T21),
3-羟基- 4-甲氧基苯乙酸曱酯（DO- 2 )，  3-hydroxy-4-methoxyphenylacetate (DO-2),
3, 4-二羟基苯乙酸乙氧基曱醇酯（DO- 3 )， 3, 4-dihydroxyphenylacetic acid ethoxylated sterol ester (DO-3),
2-乙氧基 -7-异丙氧基苯并 [1， 3]二氧戊环 -5-乙酸甲酯（ 076 )， 2 -乙氧基- 7-羟基苯并 [1, 3]二氧戊环- 5-乙酸甲酯 （ 074 )，Methyl 2-ethoxy-7-isopropoxybenzo[1,3]dioxolan-5-acetate ( 076 ), 2-ethoxy-7-hydroxybenzo[1,3] Oxypentan-5-methyl acetate (07 4 ),
2-乙氧基 - 7-苄氧基苯并 [1, 3]二氧戊环- 5-乙酸甲酯 （075 )。 本发明所述化合物， 更优选如下化合物： 2 - ethoxy - 7 - benzyloxy-benzo [1, 3] dioxolan---5-- acid methyl ester (075). The compound of the present invention is more preferably a compound of the following:
3, 4, 5-三羟基苯乙酸曱酯 ( 069 )  3,4,5-trihydroxyphenylacetate ( 069 )
3-甲氧基 -4， 5-二羟基苯乙酸曱酯（ 070 ),  3-methoxy-4,5-dihydroxyphenylacetate (070),
3- ( 2'-甲基丙氧基） -4， 5-二羟基苯乙酸（ 079 ),  3-( 2'-methylpropoxy) -4,5-dihydroxyphenylacetic acid ( 079 ),
2, 3， 6-三氯 -4， 5-二羟基苯乙酸曱酯（102) 2, 3, 6-trichloro- 4, 5-dihydroxyphenylacetate (102)
3， 4-二羟基 -5-丙基苯乙酸曱酯 (111) , 3, 4-dihydroxy-5-propylphenylacetate (111),
2, 3， 6-三氯- 4， 5-二羟基苯乙酸 （109) ,  2, 3, 6-trichloro-4, 5-dihydroxyphenylacetic acid (109),
N- 2-羟基苯乙基- ( 3, 4-二羟基） -苯乙酸胺 (C67) ,  N- 2-hydroxyphenethyl-(3,4-dihydroxy)-phenylacetic acid amine (C67),
3, 4-二羟基苯乙酸曱氧基甲醇酯 （T33) , 3, 4-dihydroxyphenylacetic acid methoxyoxymethanol ester (T33),
3， 4-亚曱二氧基苯乙酸曱酯（D23 ), 3, 4-decylene dioxyphenylacetate oxime ester (D23),
3-甲氧基 -4， 5-二羟基苯乙酸（ 065-1 ), 3-methoxy-4, 5-dihydroxyphenylacetic acid (065-1),
3, 4, 5-三羟基苯乙酸（065-2) ,  3, 4, 5-trihydroxyphenylacetic acid (065-2),
3, 4， 5-三羟基苯乙酸甲酯 (071)， 3， 4-二羟基苯乙酸乙酯（D80) , Methyl 3,4,5-trihydroxyphenylacetate (071), Ethyl 3, 4-dihydroxyphenylacetate (D80),
3, 4-二羟基苯乙酸（ 3'， 4'-二羟基 )苯乙酯（ C17 )，  3, 4-dihydroxyphenylacetic acid (3',4'-dihydroxy)phenylethyl ester (C17),
3, 4-二羟基苯乙酸乙氧基曱醇酯（D0-3)。  3, 4-Dihydroxyphenylacetic acid ethoxylated sterol ester (D0-3).
本发明还提供本发明所述化合物或其药学上可以接受的盐、 多晶形体、 对映体或外消旋体在制备抗肿瘤的药物中的用途。  The invention also provides the use of a compound of the invention, or a pharmaceutically acceptable salt, polymorph, enantiomer or racemate thereof, in the manufacture of an anti-tumor drug.
优选的， 所述肿瘤为实体瘤。  Preferably, the tumor is a solid tumor.
更优选的， 所述肿瘤选自肺癌、 乳腺癌、 宫颈癌、横紋肌肉瘤、 鼻咽癌、 胰腺癌、 喉癌、 皮肤癌、 肝癌、 神经母细胞瘤、 腎母细胞瘤、 肠癌、 胃癌和 肾上腺皮质瘤中的一种或多种。  More preferably, the tumor is selected from the group consisting of lung cancer, breast cancer, cervical cancer, rhabdomyosarcoma, nasopharyngeal carcinoma, pancreatic cancer, laryngeal cancer, skin cancer, liver cancer, neuroblastoma, nephroblastoma, intestinal cancer, One or more of gastric cancer and adrenocortical tumors.
最优选的， 所述肿瘤选自肺癌、 乳腺癌、 宫颈癌、 肾母细胞瘤、鼻咽癌、 喉癌、 神经母细胞瘤、 肠癌和胃癌中的一种或多种。  Most preferably, the tumor is selected from one or more of the group consisting of lung cancer, breast cancer, cervical cancer, nephroblastoma, nasopharyngeal carcinoma, laryngeal cancer, neuroblastoma, intestinal cancer, and gastric cancer.
本发明所述化合物通过抑制肿瘤细胞增殖、 迁移， 和 /或诱导肿瘤细胞 凋亡而产生抗肿瘤作用。  The compounds of the present invention produce an anti-tumor effect by inhibiting tumor cell proliferation, migration, and/or inducing tumor cell apoptosis.
本发明还提供一种药物组合物， 其中包括上述的本发明所述化合物或其 药学上可以接受的盐、 多晶形体、 对映体或外消旋体。  The present invention also provides a pharmaceutical composition comprising the above-described compound of the present invention or a pharmaceutically acceptable salt, polymorph, enantiomer or racemate thereof.
所述药物组合物为临床上可接受的任一剂型 ， 包括经胃肠道给药制剂 和非经胃肠道给药制剂；  The pharmaceutical composition is any one of clinically acceptable dosage forms, including gastrointestinal administration preparations and parenteral administration preparations;
优选的， 所述经胃肠道给药制剂任选自散剂、 片剂、 颗粒剂、 胶嚢剂、 滴丸、 乳剂或混悬剂；  Preferably, the gastrointestinal administration preparation is selected from the group consisting of a powder, a tablet, a granule, a capsule, a dropping pill, an emulsion or a suspension;
优选的， 所述非经胃肠道给药制剂任选自注射剂、 吸入剂、 喷雾剂、 气 雾剂、 栓剂、 灌注剂、 贴剂或软膏剂。  Preferably, the parenteral administration preparation is selected from the group consisting of an injection, an inhalation, a spray, an aerosol, a suppository, a perfusion, a patch or an ointment.
本发明所述 "卤素"， 是指氟原子、 氯原子、 溴原子、 碓原子； 优选氯 原子和溴原子。  The "halogen" as used in the present invention means a fluorine atom, a chlorine atom, a bromine atom or a ruthenium atom; preferably a chlorine atom and a bromine atom.
本发明所述化合物的摄入量或给予量， 根据化合物的纯度、 作用强度、 安全性、 服用对象的年龄、 体重等不同而不同。 作为预防或治疗肿瘤用， 通 常为成人每天 5mg-2g， 更优选的每天一次或数次摄入 10mg- lg。  The intake amount or amount of the compound of the present invention varies depending on the purity of the compound, the strength of action, the safety, the age of the subject, and the body weight. As a preventive or therapeutic tumor, it is usually 5 mg to 2 g per day for an adult, more preferably 10 mg to lg once or several times a day.
体外活性和作用机理研究表明， 本发明所述苯乙酸类衍生物具有一定的 抗肿瘤作用。  Studies on in vitro activity and mechanism of action indicate that the phenylacetic acid derivatives of the present invention have a certain antitumor effect.
( 1 )采用 MTT法检测本发明所述化合物对多种肿瘤细胞增殖的抑制作用。 实验发现， 多种化合物对肺癌细胞 A549、 肾母细胞瘤细胞 G401、 鼻咽癌细 胞 CNE2Z、喉癌细胞 HEP2、 等多种肿瘤细胞都有明显抑制作用， 尤其是 3， 4- 二羟基苯乙酸乙酯（D80)、 3，4-二羟基苯乙酸（3'，4'-二羟基）苯乙酯（C17)、 3, 4- 羟基苯乙酸甲氧基甲醇酯（ T33 )、 3, 4-亚曱二氧基苯乙酸甲酯（ D23 )、 N- 2-羟基苯乙基-（ 3， 4-二羟基） -苯乙酸胺（C67 )、 3, 4-二羟基苯乙酸乙氧 基甲醇酯（DO- 3)、 3-甲氧基 - 4,5-二羟基苯乙酸（ 065- 1 )、 3， 4， 5-三羟基苯 乙酸（ 065-2 )、 3,4,5-三羟基苯乙酸甲酯（ 069 )、 3-(2' -曱基丙氧基）-4,5- 二羟基苯乙酸（ 079 )、 3, 4-二羟基 -5-丙基苯乙酸曱酯 （ 111 )。 (1) The inhibitory effect of the compound of the present invention on proliferation of various tumor cells was examined by MTT assay. The experiment found that a variety of compounds have significant inhibitory effects on lung cancer cell A549, nephroblastoma cell G401, nasopharyngeal carcinoma cell CNE2Z, laryngeal carcinoma cell HEP2, and other tumor cells, especially 3, 4- Ethyl dihydroxy phenylacetate (D80), 3,4-dihydroxyphenylacetic acid (3',4'-dihydroxy)phenylethyl ester (C17), 3, 4-hydroxyphenylacetic acid methoxymethanol ester (T33) , 3, 4-indenylene dioxyphenylacetate methyl ester ( D23 ), N- 2-hydroxyphenethyl-( 3, 4-dihydroxy) -phenylacetic acid amine (C67 ), 3, 4-dihydroxybenzene Ethoxymethanol acetate (DO-3), 3-methoxy-4,5-dihydroxyphenylacetic acid (065-1), 3,4,5-trihydroxyphenylacetic acid (065-2), 3, Methyl 4,5-trihydroxyphenylacetate ( 069 ), 3-(2'-mercaptopropoxy)-4,5-dihydroxyphenylacetic acid ( 079 ), 3, 4-dihydroxy-5-propyl Ethyl phenylacetate (111).
(2)采用细胞迁移检测（Transwell ) 实验， 用所述化合物（选用安全剂量 ΙΟμΜ)处理多种肿瘤细胞并用结晶紫对细胞进行染色， 检测细胞迁移的个 数， 发现 3，4-二羟基苯乙酸乙酯 （D80)、 3, 4-二羟基苯乙酸甲氧基曱醇酯 (T33)、 Ν- 2-羟基苯乙基-（3,4-二羟基） -苯乙酸胺（C67)、 N- ( 3', 4'-二羟 基）苯乙基- ( 3， 4-二羟基）苯乙酸胺（C52)、 3,4-二羟基苯乙酸乙氧基曱 醇酯（DO- 3)、 3-甲氧基 -4， 5-二羟基苯乙酸（ 065- 1 )、 3,4,5-三羟基苯乙酸 ( 065-2 )、 3， 4-二羟基- 5-丙基苯乙酸曱酯（111)、 2 -氡代苯并 [1， 3]二氧戊 环- 5-乙酸 (T21)、 3， 4， 5-三羟基苯乙酸甲酯（ 069 )、 2， 3， 6-三氯- 4, 5-二羟 基苯乙酸曱酯（102)等化合物对肿瘤细胞的迁移具有一定抑制作用。  (2) Using the cell migration assay (Transwell) experiment, the tumor cells were stained with the compound (using a safe dose of ΙΟμΜ) and stained with crystal violet to detect the number of cell migration, and 3,4-dihydroxybenzene was found. Ethyl acetate (D80), 3, 4-dihydroxyphenylacetic acid methoxysterol ester (T33), bis-2-hydroxyphenethyl-(3,4-dihydroxy)-phenylacetic acid amine (C67), N-(3',4'-dihydroxy)phenethyl-(3,4-dihydroxy)phenylacetic acid amine (C52), 3,4-dihydroxyphenylacetic acid ethoxylated sterol ester (DO-3) , 3-methoxy-4,5-dihydroxyphenylacetic acid (065-1), 3,4,5-trihydroxyphenylacetic acid (065-2), 3,4-dihydroxy-5-propylphenylacetic acid Oxime ester (111), 2-deuterobenzo[1,3]dioxolan-5-acetic acid (T21), methyl 3,4,5-trihydroxyphenylacetate (069), 2, 3, 6 Compounds such as trichloro-4, 5-dihydroxyphenylacetate (102) have a certain inhibitory effect on the migration of tumor cells.
( 3)采用流式细胞技术检测细胞凋亡实验， 用所述化合物 （选用安全剂量 ΙΟμΜ)处理多种肿瘤细胞并用 Annexin V- FITC和 PI对细胞进行染色， 计 算凋亡细胞的比例，发现 3，4-二羟基苯乙酸乙酯（080)、 3, 4-二羟基苯乙酸 曱氧基曱醇酯（T33)、 3,4-二羟基苯乙酸（3',4'-二羟基）苯乙酯（C17)、 3,4- 二羟基苯乙酸乙氧基甲醇酯（ DO- 3 )、 甲 4, 5-二羟基苯乙酸（ 065-1 )、 3, 4, 5-三羟基苯乙酸 ( 065-2 )、 3, 4， 5-三羟基苯乙酸甲酯 ( 069 )、 N- ( 3'， 4'- 二羟基）苯乙基- ( 3， 4-二羟基）苯乙酸胺 (C52)等化合物对肿瘤细胞的凋 亡具有一定促进作用。  (3) Flow cytometry was used to detect apoptosis. The tumor cells were treated with the compound (safe dose ΙΟμΜ) and stained with Annexin V- FITC and PI to calculate the proportion of apoptotic cells. , 4-dihydroxyphenylacetate (080), 3, 4-dihydroxyphenylacetic acid decyl sterol ester (T33), 3,4-dihydroxyphenylacetic acid (3',4'-dihydroxy)benzene Ethyl ester (C17), 3,4-dihydroxyphenylacetic acid ethoxymethanol (DO-3), methyl 4,5-dihydroxyphenylacetic acid (065-1), 3,4, 5-trihydroxyphenylacetic acid (065-2), 3,4,5-trihydroxyphenylacetic acid methyl ester (069), N-(3',4'-dihydroxy)phenethyl-(3,4-dihydroxy)phenylacetic acid amine ( Compounds such as C52) have a certain promoting effect on the apoptosis of tumor cells.
上述实验说明所述化合物可能通过抑制细胞增殖和迁移， 以及诱导细胞 凋亡而发挥广谱的抗肿瘤作用。 附图说明  The above experiments demonstrate that the compounds may exert a broad spectrum of anti-tumor effects by inhibiting cell proliferation and migration, as well as inducing apoptosis. DRAWINGS
下面结合附图对本发明做进一步说明。  The invention will be further described below in conjunction with the accompanying drawings.
图 1: 实施例 23 的 MTT 实验结果； 其中， 图 1-1 至 1-14分别显示 DO, T83, D80, T73, T33, D23, T21, C52, D76, C17, C67, DO-1, DO- 2, D0-3不同浓度下 肿瘸细胞 A549的存活率。 图 2:实施例 25中，各化合物对肿瘤细胞 A549迁移能力的影响，其中 Control 为空白对照。 Figure 1: Results of the MTT experiment of Example 23; wherein, Figures 1-1 to 1-14 show DO, T83, D80, T73, T33, D23, T21, C52, D76, C17, C67, DO-1, DO, respectively. - 2, D0-3 survival rate of swollen cell A549 at different concentrations. Figure 2: Effect of each compound on the migration ability of tumor cell A549 in Example 25, where Control is a blank control.
图 3:实施例 25中，各化合物对肿瘤细胞 A204迁移能力的影响，其中 Control 为空白对照。 Figure 3: Effect of each compound on the migration ability of tumor cell A204 in Example 25, where Control is a blank control.
图 4:实施例 25中，各化合物对肿瘤细月包 G401迁移能力的影响，其中 Control 为空白对照。 Figure 4: Effect of each compound on the migration ability of tumor cell line G401 in Example 25, where Control is a blank control.
图 5:实施例 25中，各化合物对肿瘤细月包 CT26迁移能力的影响，其中 Control 为空白对照。 Figure 5: Effect of each compound on the migration ability of tumor pericytes CT26 in Example 25, where Control is a blank control.
图 6:实施例 26中，各化合物对肿瘤细胞 A549迁移能力的影响，其中 Control 为空白对照。 Figure 6: Effect of each compound on the migration ability of tumor cell A549 in Example 26, where Control is a blank control.
图 7:实施例 26中，各化合物对肿瘤细胞 G401迁移能力的影响，其中 Control 为空白对照。 Figure 7: Effect of each compound on the migration ability of tumor cell G401 in Example 26, where Control is a blank control.
图 8:实施例 26中，各化合物对肿瘤细胞 HEP- 2迁移能力的影响，其中 Control 为空白对照。 Figure 8: Effect of each compound on the migration ability of tumor cells HEP-2 in Example 26, where Control is a blank control.
图 9: 实施例 27中， 各化合物对肿瘤细胞 A549凋亡的影响， 其中 Control 为空白对照。 Figure 9: Effect of each compound on apoptosis of tumor cell A549 in Example 27, where Control is a blank control.
图 10: 实施例 27中， 各化合物对肿瘤细胞 G401凋亡的影响， 其中 Control 为空白对照。 Figure 10: Effect of each compound on apoptosis of tumor cell G401 in Example 27, where Control is a blank control.
图 11: 实施例 28中， 各化合物对肿瘤细胞 A549凋亡的影响， 其中 Cont rol 为空白对照。 Figure 11: Effect of each compound on apoptosis of tumor cell A549 in Example 28, with Cont rol as a blank control.
图 12: 实施例 28中， 各化合物对肿瘤细胞 G401凋亡的影响， 其中 Cont rol 为空白对照。 Figure 12: Effect of each compound on apoptosis of tumor cell G401 in Example 28, in which Cont rol was a blank control.
图 13: 实施例 28中，各化合物对肿瘤细包 HEP- 2凋亡的影响，其中 Control 为空白对照。 具体实施方式 Figure 13: Effect of each compound on apoptosis of tumor fines HEP-2 in Example 28, where Control is a blank control. detailed description
以下参照具体的实施例来说明本发明。 本领域技术人员能够理解， 这些 实施例仅用于说明本发明， 其不以任何方式限制本发明的范围。  The invention is described below with reference to specific embodiments. Those skilled in the art can understand that the examples are only intended to illustrate the invention, and are not intended to limit the scope of the invention in any way.
下述实施例中所述实验方法， 如无特殊说明， 均为常规方法； 所述试剂 和材料， 如无特殊说明， 均可从商业途径获得； 所用溶剂和药品均为分析纯 或化学純； 溶剂在使用前均经过重新蒸馏； 无水溶剂均按照标准方法或文献 方法进行处理。 柱层析硅胶（100- 200 目）和薄层层析硅胶（GF254)为青岛海洋化工厂和 烟台化工厂产品； 如未特别说明， 均采用石油醚（60- 90 °C)/乙酸乙酯（v/v) 作为洗脱剂； 显色剂用碘或磷钼酸的乙醇溶液； 所有萃取溶剂未经说明均用 无水 Na2S04干燥。 The experimental methods described in the following examples are all conventional methods unless otherwise specified; the reagents and materials are commercially available unless otherwise specified; the solvents and pharmaceuticals used are of analytical or chemical purity; The solvent is re-distilled before use; the anhydrous solvent is treated according to standard methods or literature methods. Column chromatography silica gel (100-200 mesh) and thin layer chromatography silica gel (GF254) are products of Qingdao Ocean Chemical Plant and Yantai Chemical Plant; unless otherwise specified, petroleum ether (60- 90 °C)/ethyl acetate is used. (v/v) as an eluent; the developer was treated with iodine or a solution of phosphomolybdic acid in ethanol; all extraction solvents were dried over anhydrous Na 2 SO 4 unless otherwise stated.
'H-NMR用 Bruck-400型核磁共振仪记录， TMS为内标。  'H-NMR was recorded with a Bruck-400 nuclear magnetic resonance apparatus, and TMS was an internal standard.
LC-MS 用美国 Agilent 公司 1100型高效液相色谱-离子阱质 i普联用仪 (LC- MSD Trap)记录， 二极管阵列检测器（DAD) , 检测波长 214 nM和 254 nM， 离子阱质谱 (ESI源）。  LC-MS was recorded with Agilent's Model 1100 High Performance Liquid Chromatography-Ion Trap (LC-MSD Trap), Diode Array Detector (DAD), detection wavelengths of 214 nM and 254 nM, ion trap mass spectrometry ( ESI source).
HPLC柱为 Agela Durashell C18 ( 4.6 x 50 mm, 3.5 μπι); 流动相为 0.1% NH4HC03水溶液：乙腈（5分钟内从 5: 95到 95: 5)；流速为 1.8 mL/min。 实施例 -羟基- 4-曱氧基苯乙酸曱酯（DO- 2)的合成  The HPLC column was Agela Durashell C18 (4.6 x 50 mm, 3.5 μπι); the mobile phase was 0.1% aqueous NH4HCO3: acetonitrile (5:95 to 95:5 in 5 minutes); the flow rate was 1.8 mL/min. EXAMPLES - Synthesis of hydroxy 4-indolyl phenylacetate (DO-2)
Figure imgf000011_0001
Figure imgf000011_0001
3-羟基- 4-甲氧基-苯乙酸 (DO-1, 2.5 g, 13.7 mmol)溶于 50mL甲醇中， 在搅拌条件下加入 0.2 mL的浓^ ·酸， 加热回流 3小时。 冷却至室温， 反应 液在旋转蒸发仪上浓缩， 得到的油状物稀释到 100 mL的乙酸乙酯溶液中， 有机相用饱和食盐水（50 mL*2 ) 洗， 无水 υ酸钠干燥过滤后， 旋转浓缩除 去溶剂， 溶质经柱层析精制 （流动相为石油醚： 乙酸乙酯 = 3: 1 )得无色油 状物 D0-2 (2.1 g, 79%)。  3-Hydroxy-4-methoxy-phenylacetic acid (DO-1, 2.5 g, 13.7 mmol) was dissolved in 50 mL of methanol, and 0.2 mL of concentrated acid was added under stirring, and the mixture was refluxed for 3 hours. After cooling to room temperature, the reaction solution was concentrated on a rotary evaporator, and the obtained oil was diluted to 100 mL of ethyl acetate. The organic phase was washed with saturated brine (50 mL*2) and dried over anhydrous sodium sulfate. The solvent was removed by rotary EtOAc (EtOAc:EtOAc:EtOAc)
1H-NMR (400 MHz, CDC13) δ 6.80 (s， 1Η), 6.75—6.68 (m, 2H) , 5.561H-NMR (400 MHz, CDC1 3 ) δ 6.80 (s, 1Η), 6.75—6.68 (m, 2H), 5.56
(s, 1H), 3.81 (s, 3H) , 3.62 (s, 3H) , 3.31 (s， 3H)。 实施例 2 3,4-二羟基苯乙酸乙氧基甲酯 （DO- 3) 的合成
Figure imgf000011_0002
(s, 1H), 3.81 (s, 3H), 3.62 (s, 3H), 3.31 (s, 3H). Example 2 Synthesis of 3,4-dihydroxyphenylacetic acid ethoxymethyl ester (DO-3)
Figure imgf000011_0002
DO DO-3  DO DO-3
3， 4-二羟基苯乙酸（DO, 5.0 g, 30.0 mmol )和三乙胺 （ 9. lg， 90.0 mmol )溶于 30 mL二氯曱垸中， 在零度条件下滴加 1.84g 氯曱乙醚（ 30.0 讓 ol )， 将反应液在室温 搅拌过夜。 反应液分别用 0. IN HC1溶液 （15 mL) 和 NaHC03溶液（15 mL ) 洗， 有才; ^目用无水石克酸钠干燥过滤后， 旋转浓缩除 去溶剂， 溶盾经柱层析精制 （流动相为石油醚 ： 乙酸乙酯 = 2 : 1)得无 色油状物 DO- 3 (2.0 g, 29.5% )。 ,3, 4-Dihydroxyphenylacetic acid (DO, 5.0 g, 30.0 mmol) and triethylamine ( 9. lg, 90.0 mmol) were dissolved in 30 mL of dichloropurine, and 1.84 g of chlorohydrazine ether was added dropwise at zero. ( 30.0 Let ol) and stir the reaction at room temperature overnight. The reaction solution was washed with 0. IN HC1 solution (15 mL) and NaHC0 3 solution (15 mL), and the product was dried. After drying and filtering with anhydrous sodium sulfate, the solvent was removed by rotary concentration, and the solution was purified by column chromatography. (The mobile phase was petroleum ether: ethyl acetate = 2:1) to give a colorless oil, DO-3 (2.0 g, 29.5%). ,
― NMR (400 MHz, CDC13) δ 6.72 (d, /= 2.0 Hz, 1H), 6.69 (s， 1H), 6.62 (m, 1H), 5.65 (br s， 1H), 5.45 (br s, 1H)， 5.24 (s， 2H) , 3.60 (q, / =6.4 Hz, 2H), 3.48 (s, 2H) , 1.14 (t, / =6.4 Hz, H)。 实施例 3 3, 4-二羟基苯乙酸乙酯 （D80) 的合成
Figure imgf000012_0001
― NMR (400 MHz, CDC1 3 ) δ 6.72 (d, /= 2.0 Hz, 1H), 6.69 (s, 1H), 6.62 (m, 1H), 5.65 (br s, 1H), 5.45 (br s, 1H ), 5.24 (s, 2H), 3.60 (q, / =6.4 Hz, 2H), 3.48 (s, 2H), 1.14 (t, / =6.4 Hz, H). Example 3 Synthesis of 3,4-Dihydroxyphenylacetate (D80)
Figure imgf000012_0001
DO D80  DO D80
3, 4-二羟基苯乙酸（DO, 3.0 g， 17.9 mraol )溶于 25mL 乙醇中， 在搅 拌条件下加入催化量的浓疏酸， 加热回流 12 小时。 冷却至室温， 反应液在 旋转蒸发仪上浓缩， 得到的油状物稀释到 50mL的乙酸乙酯溶液中， 有机相 用飽和 NaHC03溶液（25 mL*2 )和饱和食盐水（25 mL)洗， 无水^ ^酸钠干燥 过滤后， 旋转浓缩除去溶剂， 溶盾经柱层析精制 （流动相为石油醚 ： 乙酸 乙酯 = 10 ： 1)得无色油状物 D80 (1.1 g， 88.5%)。 3,4-Dihydroxyphenylacetic acid (DO, 3.0 g, 17.9 mraol) was dissolved in 25 mL of ethanol, and a catalytic amount of concentrated acid was added under stirring, and the mixture was heated under reflux for 12 hours. Cooled to room temperature, the reaction solution was concentrated on a rotary evaporator, the resulting oil was diluted into 50mL of ethyl acetate, the organic phase was washed with saturated NaHC0 3 solution (25 mL * 2) and saturated brine (25 mL) wash, After drying and drying with anhydrous sodium sulfate, the solvent was evaporated and concentrated, and then evaporated, and then purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1) to give colorless oil D80 (1.1 g, 88.5%) .
Ή-NMR (300 MHz, DMSO-rf^) δ 8.86 (s， 1Η) , 8.77 (s， 1H)， 6.66-6.63 (m， 2H), 6.47 (dd, /= 8.1, 2.1 Hz, 1H)， 4.08—3.99 (m， 2H), 3.42 ( s， 2H) ， 1.20—1.14 (m, 3H)。 -亚甲二氧 （D23) 的合成
Figure imgf000012_0002
Ή-NMR (300 MHz, DMSO-rf^) δ 8.86 (s, 1 Η), 8.77 (s, 1H), 6.66-6.63 (m, 2H), 6.47 (dd, /= 8.1, 2.1 Hz, 1H), 4.08—3.99 (m, 2H), 3.42 ( s, 2H) , 1.20—1.14 (m, 3H). - Synthesis of MDMA (D23)
Figure imgf000012_0002
4-1 中间体 D23- 1的合成： 4-1 Synthesis of intermediate D23-1:
3， 4-二羟基苯乙酸（DO, 10.0g, 59.5 mmol )溶于 125mL曱醇中， 在搅 拌条件下加入催^ i量的浓石充酸， 加热回流 12 小时。 冷却至室温， 反应液在 旋转蒸发仪上浓缩， 得到的油状物稀释到 150 mL的乙酸乙酯溶液中， 有机 相用饱和 NaHC03溶液 ( 50 mL*2 )和饱和食盐水（ 50 mL ) 洗， 无水硫酸钠干 燥过滤后， 除去溶剂， 溶质经柱层析精制 （流动相为石油醚 ： 乙酸乙酯 = 10 : 1 )得无色油状物 D23—2 (10.8 g, 100%)。 3, 4-Dihydroxyphenylacetic acid (DO, 10.0 g, 59.5 mmol) was dissolved in 125 mL of decyl alcohol, and a concentrated amount of concentrated stone was added to the acid under stirring, and the mixture was heated under reflux for 12 hours. Cool to room temperature, concentrate the reaction on a rotary evaporator, dilute the oil to 150 mL of ethyl acetate, organic The phase was washed with saturated NaHC0 3 solution (50 mL*2) and saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, and the solvent was removed. The solute was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10 : 1 ) A colorless oil D23-2 (10.8 g, 100%).
4-2 D23的合成： 4-2 Synthesis of D23:
步骤 4-1得到的 D23-1 (4.4 g, 23 mmol)溶于 60 mL DMF中， 16.8 g 氟化铯（ 111 mmol )和 lOmL分别加入到上述溶液中。 将反应液加入至回流 3 小时后， 将反应液冷却到室温， 加入 200 mL二氯甲烷， 有机相用饱和食盐 水洗（ 10GmL*2 ),无水充酸钠干燥过滤后，旋去溶剂，溶质经柱层析精制（流 动相为石油醚 ： 二氯曱烷 = 10 ： 1 )得无色油状物 D23 ( 1.9g, 41%)。  D23-1 (4.4 g, 23 mmol) obtained in Step 4-1 was dissolved in 60 mL of DMF, and 16.8 g of cesium fluoride (111 mmol) and 10 mL were respectively added to the above solution. After the reaction solution was added to reflux for 3 hours, the reaction solution was cooled to room temperature, 200 mL of dichloromethane was added, and the organic phase was washed with saturated brine (10GmL*2), dried over anhydrous sodium sulfate, and then evaporated, solvent, solute Purification by column chromatography (mobile phase: petroleum ether: methylene chloride = 10:1)
!H-NMR (300 MHz, DMSCU δ 6.91-6.83 (m， 2H)， 6.71 (d， /= 8.1 Hz, 1H)， 5.99 (s, 2H), 3.60 (s, 3H) , 3.58 (s, 2H)。 -二甲氧基苯乙酸 (D76)的合成
Figure imgf000013_0001
 ! H-NMR (300 MHz, DMSCU δ 6.91-6.83 (m, 2H), 6.71 (d, / = 8.1 Hz, 1H), 5.99 (s, 2H), 3.60 (s, 3H), 3.58 (s, 2H Synthesis of -dimethoxyphenylacetic acid (D76)
Figure imgf000013_0001
D23 D76  D23 D76
按照实施例 4的方法制备的 D23 ( 3 g, 15.5 mmol )溶于甲醇（ 15 mL ), 在搅拌的情况下加入 0.6 g氢氧化锂（ 23.2 隱 ol )和 0.5mL的水， 上述溶 液在室温下搅拌 5个小时， 浓缩除去溶剂， 加入 75mL的水， 用 1N的盐酸水 溶液调解 PH值等于 3， 用乙酸乙酯 （30 mL * 3)萃取， 有机相用无水硫酸 钠干燥过滤后， 浓缩得到白色化合物 D76 (2.2 g， 80%)。  D23 (3 g, 15.5 mmol) prepared according to the method of Example 4 was dissolved in methanol (15 mL), and 0.6 g of lithium hydroxide ( 23.2 sec ol ) and 0.5 mL of water were added while stirring, and the above solution was at room temperature. The mixture was stirred for 5 hours, and the solvent was evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated, evaporated. The white compound D76 (2.2 g, 80%) was obtained.
'H-NMR (300 MHz, CDC13) δ 6.79-6.78 (m, 2H)， 6.72 (d, /= 6.9 Hz, 1H), 5.96 (s， 2H), 4.78 (br s, 1H), 3.57 (s， 2H)。 'H-NMR (300 MHz, CDC1 3 ) δ 6.79-6.78 (m, 2H), 6.72 (d, /= 6.9 Hz, 1H), 5.96 (s, 2H), 4.78 (br s, 1H), 3.57 ( s, 2H).
Figure imgf000013_0002
Figure imgf000013_0002
DO · T33  DO · T33
3， 4-二羟基苯乙酸（DO, 3.0 g, 17.9 mmol )和三乙胺 （ 2.7 g， 26.7 腿 ol )溶于 40 mL二氯曱烷中，在零度条件下滴加 2.5 g 曱氧基曱基溴（ 19.8 mmol ), 将反应液在室温下搅拌过夜。 反应液浓缩加 150 mL乙酸乙酯， 分别 用 1 N HC1溶液 （100 mL)和饱和食盐水溶液（50 mL) 洗， 有机相用无水石克 酸钠干燥过滤后, 除去溶剂， 溶质经柱层析精制 （流动相为石油醚 ： 乙酸 : 乙酯 - 5 ： 1)得无色油状物 Τ33 ( 500 mg, 13%)。 3, 4-Dihydroxyphenylacetic acid (DO, 3.0 g, 17.9 mmol) and triethylamine (2.7 g, 26.7 leg ol) were dissolved in 40 mL of dichloromethane, and 2.5 g of decyloxy group was added dropwise at zero temperature. The solution was stirred at room temperature overnight. The reaction solution was concentrated and 150 mL of ethyl acetate was added and washed with 1 N HCl solution (100 mL) and brine (50 mL). After drying and filtration with sodium sulfate, the solvent was removed, and the solute was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate : ethyl acetate : 5:1) to afford colorless oil Τ33 (500 mg, 13%).
XH-NMR (300 MHz, SO- d6) δ 8.87 (br s， 1H) , 8.80 (br s， 1H), 6.75-6.64 (m, 2H) , 6.50 (dd, /= 8.1, 1.8 Hz, 1H), 5.16 (s, 2H) , 3.49 (s, 2H), 3.31 (s， 3H). 实施例 7 3-曱氧基 -4-羟基苯乙酸（T73) 的合成 X H-NMR (300 MHz, SO-d6) δ 8.87 (br s, 1H) , 8.80 (br s, 1H), 6.75-6.64 (m, 2H) , 6.50 (dd, /= 8.1, 1.8 Hz, 1H ), 5.16 (s, 2H), 3.49 (s, 2H), 3.31 (s, 3H). Example 7 Synthesis of 3-decyloxy-4-hydroxyphenylacetic acid (T73)
Figure imgf000014_0001
Figure imgf000014_0001
T73  T73
7-1 中间体 T73- 2的合成： 7-1 Intermediate Synthesis of T73-2:
3-甲氧基 -4-羟基-苯甲醛（10.0 g, 65.8 mmol )溶于 150 mL乙腈中， 在搅拌的条件下加入催化量的換化钾和 TMSCN (9.8 g, 98.6 mmol ), 反应液 在室温下搅拌 12小时。 将溶剂浓缩在旋转蒸发仪上， 粗产品用 150 mL乙酸 乙酯稀释， 用饱和 NaHC03水溶液（50 mL)和饱和食盐水（50 mL) 洗， 无水 硫酸钠干燥过滤后， 除去溶剂， 溶质经柱层析精制 （流动相为石油醚 ： 乙 酸乙酯 = 10 ： 1)得无色油状物 T73-2 (10.5 g， 89%)。 3-methoxy-4-hydroxy-benzaldehyde (10.0 g, 65.8 mmol) was dissolved in 150 mL of acetonitrile, and a catalytic amount of potassium and TMSCN (9.8 g, 98.6 mmol) was added under stirring. Stir at room temperature for 12 hours. After the solvent was concentrated on a rotary evaporator, the crude product was diluted with 150 mL of ethyl acetate, and saturated brine (50 mL) and washed with saturated NaHC0 3 solution (50 mL), dried over anhydrous sodium sulfate by filtration, the solvent was removed, solute Purification by column chromatography (mobile phase: petroleum ether: ethyl acetate = 10:1)
7-2 中间体 T73- 3的合成： 7-2 Intermediate Synthesis of T73-3:
步骤 7-1制备的 T73- 2 (10 g, 55.9讓 ol )溶于曱醇（15 mL)， 在搅拌 的情况下加入 6.7 g氢氧化钠 （ 168 mmol )和 75 mL的水， 上述溶液在室温 下搅拌 8个小时， 用 1N的盐酸水溶液调解 PH值等于 3， 用乙酸乙酯（ 30 mL * 3)萃取，有机相用无水硫酸钠干燥过滤后， 浓缩得到 Τ73-3Π.1 g, 65% X 7-3 产物 T73的合成：  Step 7-1 prepared T73-2 (10 g, 55.9 let ol) was dissolved in methanol (15 mL), and 6.7 g of sodium hydroxide (168 mmol) and 75 mL of water were added with stirring. After stirring for 8 hours at room temperature, the pH was adjusted to 3 with a 1N aqueous solution of hydrochloric acid, and extracted with ethyl acetate (30 mL, 3). Synthesis of 65% X 7-3 product T73:
步骤 7-2制备的 T73- 3 ( 5 g, 25 隱 ol )溶于乙醇 （ 100 mL ), 加入 10% 的 Pd/C ( 500 mg)和 lmL的浓盐酸， 用氢气置换 2次， 反应液在室温下搅拌 6小时， 过滤掉催化剂， 滤液蒸干得到 T73 (7.1 g， 65%)。 'H-NMR (300 MHz, CDC13) δ 6.86 (d， /= 3.9 Hz, 1H)， 6.79-6.74 m: 2H), 5.57 (br s, 2H) , 3.88 (s, 3H)， 3.57 (s， 2H)。 实施例 8 3-曱氧基 -4羟基苯乙酸曱酯（T83) 的合成
Figure imgf000015_0001
Step 7-2 prepared T73- 3 (5 g, 25 sec ol) dissolved in ethanol (100 mL), added 10% Pd/C (500 mg) and 1 mL of concentrated hydrochloric acid, and replaced with hydrogen twice, the reaction solution After stirring at room temperature for 6 hours, the catalyst was filtered off, and the filtrate was evaporated to dryness to give <RTIgt; 'H-NMR (300 MHz, CDC1 3 ) δ 6.86 (d, /= 3.9 Hz, 1H), 6.79-6.74 m : 2H), 5.57 (br s, 2H) , 3.88 (s, 3H), 3.57 (s , 2H). Example 8 Synthesis of 3-decyloxy-4-hydroxyphenylacetate (T83)
Figure imgf000015_0001
Τ73 Τ83  Τ73 Τ83
实施例 Ί制备的 3-曱氧基 -4羟基苯乙酸（ 3.0 g， 16.4誦 ol )溶于 100 mL曱醇中， 在搅拌条件下加入催化量的浓硫酸， 加热回流 12小时。 冷却至 室温， 反应液在旋转蒸发仪上浓缩， 得到的油状物稀释到 150 mL的乙酸乙 酯溶液中， 有 «目用饱和 NaHC03溶液（50 mL * 2 )和饱和食盐水（50 mL ) 洗， 无水硫酸钠干燥过滤后， 除去溶剂， 溶质经柱层析精制 （流动相为石油 醚 ： 乙酸乙酯 = 20 ： 1 )得无色油状物 T83 ( 2.9 g, 90% The 3-methoxy-4-hydroxyphenylacetic acid (3.0 g, 16.4 诵ol) prepared in Example 溶于 was dissolved in 100 mL of methanol, and a catalytic amount of concentrated sulfuric acid was added under stirring, and the mixture was heated under reflux for 12 hours. After cooling to room temperature, the reaction liquid was concentrated on a rotary evaporator, and the obtained oil was diluted to 150 mL of ethyl acetate solution, with a saturated NaHC0 3 solution (50 mL * 2 ) and saturated brine (50 mL). After washing and drying with anhydrous sodium sulfate, the solvent was removed, and the solvent was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 20:1) to give colorless oil T83 (2.9 g, 90%)
'H-NMR (300 MHz, DMSO-^ δ 8.86 (s， 1H)， 6.81 (d， /= 1.8 Hz, 1H), 6.71-6.61 (m, 2H) , 3.74 (s， 3H) , 3.60 (s, 3H)， 3.54 (s， 2H)。 实施例 9 3-甲氧基 -4， 5-二羟基苯乙酸（ 065-1 )和 3， 4， 5-三羟基苯乙 酸 -2 ) 的合成：
Figure imgf000015_0002
'H-NMR (300 MHz, DMSO-^ δ 8.86 (s, 1H), 6.81 (d, /= 1.8 Hz, 1H), 6.71-6.61 (m, 2H), 3.74 (s, 3H), 3.60 (s , 3H), 3.54 (s, 2H). Example 9 Synthesis of 3-methoxy-4,5-dihydroxyphenylacetic acid (065-1) and 3,4,5-trihydroxyphenylacetic acid-2):
Figure imgf000015_0002
3, 4， 5-三曱氧基苯乙酸（ SM， 1 g， 4.4醒 ol )溶于 1.6 mL乙酸和 3.3 mL 48%氢溴酸溶液中， 混合物加热回流 16小时， 冷却后加入 5 mL水， 用乙酸 乙酯 （15 mL * 3)萃取， 有机相用 5 mL水洗， 有机相用无水疏酸钠干燥、 浓缩， 溶质经柱层析精制 （流动相为二氯甲烷： 曱醇 = 20: 1到 10 ： 1 ) 得褐色固体 065—1 ( 220 mg, 25%)和 065-2 ( 240 mg, 30%)； 3, 4, 5-trimethoxyphenoxyacetic acid (SM, 1 g, 4.4 awake ol) was dissolved in 1.6 mL of acetic acid and 3.3 mL of 48% hydrobromic acid solution. The mixture was heated to reflux for 16 hours. After cooling, 5 mL of water was added. Extracted with ethyl acetate (15 mL * 3), the organic phase was washed with 5 mL of water, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the solute was purified by column chromatography (mobile phase: dichloromethane: decyl alcohol = 20 : 1 to 10 : 1 ) brown solids 065-1 (220 mg, 25%) and 065-2 (240 mg, 30%);
065-1 XH NMR (400 MHz, OUS0-d6) δ 12.25 (br s, 1H) , 8.88 (s, 1H)， 8.10 (s, 1H), 6.32 (s, 2H)， 3.71 (s， 3H) , 3.33 (s, 2H) 。 065-1 X H NMR (400 MHz, OUS0-d6) δ 12.25 (br s, 1H) , 8.88 (s, 1H), 8.10 (s, 1H), 6.32 (s, 2H), 3.71 (s, 3H) , 3.33 (s, 2H).
065-2 ^丽 R (400 MHz, d S0-d6) δ 12.21 (br s， 1H), 8.74 (s， 2H) , 065-2 ^丽 R (400 MHz, d S0-d6) δ 12.21 (br s, 1H), 8.74 (s, 2H) ,
7.95 (br s, 1H)， 6.16 (s, 2H) , 3.24 (s， 2H)。 实施例 10 3-甲氧基 -4, 5-二羟基苯乙酸甲酯（ 070 ) 的合成：
Figure imgf000016_0001
7.95 (br s, 1H), 6.16 (s, 2H), 3.24 (s, 2H). Example 10 Synthesis of methyl 3-methoxy-4,5-dihydroxyphenylacetate (070):
Figure imgf000016_0001
065-1 070 实施例 9得到的 065-1 ( 300 mg, 1.5謹 ol )溶于 5 mL曱醇中， 在搅拌 条件下加入催化量的浓硫酸, 加热回流 3小时。 冷却至室温， 反应液在旋转 蒸发仪上浓缩， 得到的油状物稀释到 15mL的乙酸乙酯溶液中， 有机相用饱 和食盐水（5 mL) 洗， 无水 ¾酸 #1干燥过滤后， 除去溶剂， 溶质经柱层析精 制 （流动相为二氯甲垸： 甲醇 =50 ： 1)得无色油状物 070 ( 280 mg， 87% X 065-1 070 Example 065-1 (300 mg, 1.5 mM ol) was dissolved in 5 mL of methanol, and a catalytic amount of concentrated sulfuric acid was added under stirring, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, the reaction mixture was concentrated on a rotary evaporator, and the obtained oil was diluted to 15 mL of ethyl acetate. The organic phase was washed with saturated brine (5 mL), dried and filtered and evaporated. The solvent and the solute were purified by column chromatography (mobile phase: methylene chloride:methanol = 50:1) to give colorless oil 070 (280 mg, 87% X
!H NMR (400 MHz, CDC13) δ 6.52 (s， 1H), 6.41 (s， 1H)， 5.36 (s, 2H), 3.87 (s， 3H), 3.70 (s, 3H) , 3.51 ( s, 2H )„ 实施例 11 3 4, 5-三羟基苯乙酸甲酯. ( 069 ) 的合成:
Figure imgf000016_0002
 ! H NMR (400 MHz, CDC1 3) δ 6.52 (s, 1H), 6.41 (s, 1H), 5.36 (s, 2H), 3.87 (s, 3H), 3.70 (s, 3H), 3.51 (s, 2H) „ Example 11 Synthesis of 3 4,5-trihydroxyphenylacetic acid methyl ester. ( 069 ):
Figure imgf000016_0002
065-2 069  065-2 069
实施例 9制备的 065-2 ( 2.5 g, 13.6 随 ol )溶于 50 mL曱醇中， 在搅 拌条件下加入催化量的浓硫酸， 加热回流 5小时。 冷却至室温， 反应液在旋 转蒸发仪上浓缩， 得到的油状物稀释到 100 mL的乙酸乙酯溶液中， 有机相 用饱和食盐水（40 mL) 洗， 无水疏酸钠干燥过滤后， 除去溶剂， 溶质经柱 层析精制（流动相为二氯曱烷：甲醇 =50 ： 1)得白色固体 069( 2.4 g， 89%)。  The 065-2 (2.5 g, 13.6 with ol) prepared in Example 9 was dissolved in 50 mL of methanol, and a catalytic amount of concentrated sulfuric acid was added under stirring, and the mixture was heated under reflux for 5 hours. After cooling to room temperature, the reaction solution was concentrated on a rotary evaporator, and the obtained oil was diluted to 100 mL of ethyl acetate. The organic phase was washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate. The solvent and the solute were purified by column chromatography (mobile phase: methylene chloride:methanol = 50:1) to afford white solid 069 ( 2.4 g, 89%).
!H NMR (400 MHz, CDC13) δ 6.43 (s， 2H) , 5.12 (s， 2H) , 3.70 (s， 3H), 3.47 (s， 2H) 。 实施例 12 2-乙氧基 -7-羟基苯并 [1,3]二氧戊环- 5-乙酸甲酯（074)、 2- 乙氧基 -7-苄氧基苯并 [1， 3]二氧戊环- 5-乙酸曱酯（075)、 3-苯曱氧基- 4,5- 二羟基苯乙酸甲酯（ 077 ) 的合成： 、
Figure imgf000017_0001
 ! H NMR (400 MHz, CDC1 3) δ 6.43 (s, 2H), 5.12 (s, 2H), 3.70 (s, 3H), 3.47 (s, 2H). Example 12 2-Ethoxy-7-hydroxybenzo[1,3]dioxolan-5-acetic acid methyl ester (074), 2-ethoxy-7-benzyloxybenzo[1,3 Synthesis of dioxolane-5-acetate (075), 3-benzoquinoxy-4,5-dihydroxyphenylacetate (077): ,
Figure imgf000017_0001
069 ( 2.0 g, 10.1 ramol )溶于 60 mL 曱苯， 在搅拌的情况下加入原乙 酸三乙酯 （2.99 g， 20.2 mmol )和催化量的 amberlyst 15E ( 200 mg )， 混 合溶液加分水器加热回流 16 小时， 冷却过滤， 滤液在旋转蒸发仪上浓缩得 到浅黄色油状物 074 ( 2.5 g， 100% X  069 ( 2.0 g, 10.1 ramol ) dissolved in 60 mL of toluene, adding triethyl orthoacetate (2.99 g, 20.2 mmol) and catalytic amount of amberlyst 15E (200 mg) with stirring, mixed solution and water separator Heat to reflux for 16 hours, cooled and filtered, and the filtrate was concentrated on a rotary evaporator to afford pale yellow oil 074 ( 2.5 g, 100% X
074 ( 0.51 g, 2.0 睡 ol )溶于 5 mL丙酮中， 在搅拌的情况下加入溴苄 ( 342 mg, 2.0 mmol )和碳酸钾 ( 276 mg, 2.0 mmol ), 混合溶液加热回流 074 (0.51 g, 2.0 ounce ol) was dissolved in 5 mL of acetone, and bromobenzyl (342 mg, 2.0 mmol) and potassium carbonate (276 mg, 2.0 mmol) were added with stirring.
24小时。 冷却至室温， 浓缩得到的油状物稀释到 50 mL的乙酸乙酯溶液中， 有 目用饱和食盐水（20 mL * 2) 洗， 无水 A酸钠干燥过滤后， 除去溶剂， 溶质经柱层析精制（流动相为石油醚： 乙酸乙酯 - 5: 1 )得无色油状物 075 (210 mg, 30%)。 24 hours. After cooling to room temperature, the oil obtained by concentration was diluted into 50 mL of ethyl acetate solution, and the mixture was washed with saturated brine (20 mL * 2), dried over anhydrous sodium sulfate, filtered, and solvent was removed. Refining (mobile phase: petroleum ether: ethyl acetate - 5:1) afforded 075 (210 mg, 30%).
075 ( 70 mg, 0.2 mmol )溶于 2 mL 2 N盐酸甲醇中， 混合物在室温下 搅拌 3小时， 浓缩得到的油状物稀幹到 10 mL的乙酸乙酯溶液中， 有机相用 饱和食盐水（5 mL * 2) 洗， 无水 酸钠干燥过滤后， 除去溶剂， 溶质经柱 层析精制（流动相为二氯甲烷：曱醇 = 50: 1 )得无色油状物 077( 30 mg, 51% );  075 (70 mg, 0.2 mmol) was dissolved in 2 mL of 2N MeOH (MeOH). The mixture was stirred at room temperature for 3 hr. The concentrated oil was evaporated to 10 mL of ethyl acetate. 5 mL * 2) Washing, drying with anhydrous sodium chloride, removing the solvent, solute was purified by column chromatography (mobile phase: methylene chloride: decyl alcohol = 50:1) to give colorless oil 077 (30 mg, 51 % );
'Η NMR (400 MHz, CDC13) δ 7.40 (m, 5H)， 6.54 (s， 1H)， 6.50 ( s, 1H), 5.53 (br s, 2H)， 5.06 (s, 2H) , 3.68 (s， 3H) , 3.49 (s， 2H)。 实施例 13 2-乙氧基 -7-异丙氧基苯并 [1, 3]二氧戊环- 5-乙酸曱酯 ( 0 - ( 2'-甲基丙氧基） -4, 5-二羟基苯乙酸（ 079 ) 的合成： 'Η NMR (400 MHz, CDC1 3 ) δ 7.40 (m, 5H), 6.54 (s, 1H), 6.50 ( s, 1H), 5.53 (br s, 2H), 5.06 (s, 2H) , 3.68 (s , 3H), 3.49 (s, 2H). Example 13 2-Ethoxy-7-isopropoxybenzo[1,3]dioxolane-5-acetic acid decyl ester (0 - (2'-methylpropoxy)-4, 5- Synthesis of dihydroxyphenylacetic acid ( 079 ):
Figure imgf000017_0002
Figure imgf000017_0002
实施例 12制备的 074 ( 0.51 g, 2.0 誦 ol )溶于 5 mL丙酮中， 在搅拌 的情况下加入异丁基溴 （ 548 mg, 4.0腿 ol )、 催化量的四丁基碘化铵 ( 73 mg)和碳酸钾（ 552 mg， 4.0 mmol ), 混合溶液加热回流 24小时。 冷却至室 温，' 浓缩得到的油状物稀释到 50mL的乙酸乙酯溶液中， 有机相用饱和食盐 水（2GmL*2)洗，无水^ ^酸钠干燥过滤后， 除去溶剂， 溶质经柱层析精制（流 动相为石油醚： 乙酸乙酯 = 5 ： 1)得无色油状物 076 ( 110 mg, 18%)。 The 074 (0.51 g, 2.0 诵ol) prepared in Example 12 was dissolved in 5 mL of acetone, and isobutyl bromide (548 mg, 4.0 leg ol) was added with stirring, and a catalytic amount of tetrabutylammonium iodide ( 73 (mg) and potassium carbonate (552 mg, 4.0 mmol), and the mixed solution was heated to reflux for 24 hours. After cooling to room temperature, the oil obtained by concentration was diluted into 50 mL of ethyl acetate solution, and the organic phase was washed with saturated brine (2GmL*2), dried over anhydrous sodium sulfate and filtered, solvent was removed, and the solvent was passed through the column. The oil was purified (mobile phase: petroleum ether: ethyl acetate = 5:1) toield 076 (110 mg, 18%).
076 ( 110 mg, 0.35 mmol ), 在搅拌条件下加入 3 mL 6 N HC1溶液， 回 流 3 小时， 冷却至室温， 用二氯曱烷 ( 10 mL * 2)萃取， 有机相用饱和食 盐水（5mL * 2) 洗， 无水硫酸钠干燥过滤后， 旋去溶剂， 溶质经柱层析精 制 （流动相为二氯曱烷： 曱醇 = 20 ： 1)得白色固体 079 ( 51 mg, 57% X 079 :H NMR (400 MHz, DMSO-dS) δ 12.12 (br s， 1H) , 8.81 (s， 1H) , 7.88 (s， 1H)， 6.31 (s, 1H), 6.29 (s， 1H)， 3.65 (d, /= 6.4 Hz, 1H), 3.31 (s， 2H)， 2.00 (m, 1H), 0.95 (d, / = 6.4 Hz, 6H ) . 实施例 14 3-甲氧基 -4-烯丙氧基苯乙酸甲酯（105)、 3-甲氧基 -4-羟基 - 5-烯丙基苯乙酸曱酯（107)、 3-甲氧基 -4-羟基- 5-丙基苯乙酸甲酯（110)、 3， 4-二羟基 -5-丙基苯乙酸曱酯（ 111 )和 3， 4-二羟基 -5-丙基苯乙酸（ 112 ) 的 076 (110 mg, 0.35 mmol), 3 mL of 6 N HCl solution was added under stirring, refluxed for 3 hours, cooled to room temperature, extracted with dichloromethane (10 mL * 2), and brine (5 mL) * 2) Washed, dried over anhydrous sodium sulfate and filtered. The solvent was evaporated, and the solvent was purified by column chromatography (mobile phase: methylene chloride: decyl alcohol = 20:1) to give white solid 079 (51 mg, 57% X 079 : H NMR (400 MHz, DMSO-dS) δ 12.12 (br s, 1H) , 8.81 (s, 1H), 7.88 (s, 1H), 6.31 (s, 1H), 6.29 (s, 1H), 3.65 (d, /= 6.4 Hz, 1H), 3.31 (s, 2H), 2.00 (m, 1H), 0.95 (d, / = 6.4 Hz, 6H). Example 14 3-methoxy-4-allyl Methyl oxyphenylacetate (105), 3-methoxy-4-hydroxy-5-allylphenyl decanoate (107), 3-methoxy-4-hydroxy-5-propylphenylacetate Ester (110), 3, 4-dihydroxy-5-propylphenylacetate (111) and 3,4-dihydroxy-5-propylphenylacetic acid (112)
Figure imgf000018_0001
Figure imgf000018_0001
111 112  111 112
实施例 8制备的 3-甲氧基 -4-羟基苯乙酸曱酯（T83, 500 mg, 2.5 mmol ) 溶于丙酮 （5 mL), 加入碳酸钾 ( 704 mg, 5.1 mmol )和烯丙基溴（ 370 mg, 3.1 mmol I 混合物加热回流 5小时， 然后冷却到常温， 水（10 mL)力口入， 用乙酸乙酯（10 mL * 3)萃取， 有机相用 5 mL7j洗，'有机相用无水石直酸钠 干燥、 浓缩， 残留物经柱层析精制 （流动相为石油醚： 乙酸乙酯 = 5: 1 ) 得无色液体 105 ( 500 mg， 83%)。 v The methoxy 3-methoxy-4-hydroxyphenylacetate (T83, 500 mg, 2.5 mmol) prepared in Example 8 was dissolved in acetone (5 mL), and potassium carbonate (704 mg, 5.1 mmol) and allyl bromide were added. ( 370 mg, 3.1 mmol I mixture was heated to reflux for 5 hours, then cooled to normal temperature, water (10 mL) was forced in, It was extracted with ethyl acetate (10 mL * 3), and the organic phase was washed with 5 mL of 7j. The organic phase was dried over anhydrous sodium sulphate and concentrated. The residue was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 5: 1) A colorless liquid 105 (500 mg, 83%). v
!H NMR (400 MHz, CDC13) δ 6.85-6.75 (m, 3H) , 6.11-6.02 (m， 1H), 5.39 (d, /= 17.2 Hz, 1H), 5.27 (d, /= 10.8 Hz, 1H)， 4.60 (d, / = 4.4 Hz, 2H), 3.87 (s， 3H)， 3.69 (s, 3H) , 3.56 (s， 2H)。 ! H NMR (400 MHz, CDC1 3) δ 6.85-6.75 (m, 3H), 6.11-6.02 (m, 1H), 5.39 (d, / = 17.2 Hz, 1H), 5.27 (d, / = 10.8 Hz, 1H), 4.60 (d, / = 4.4 Hz, 2H), 3.87 (s, 3H), 3.69 (s, 3H), 3.56 (s, 2H).
105 ( 500 mg, 2, 1 mmol )溶于 N-曱基吡咯烷酮（ 2 mL ), 在 200 °C下 反应 5小时， 然后冷却到常温， 用 10 mL乙酸乙酯稀释， 10 mL水洗三次。 有机相用无水硫酸钠千燥、 浓缩， 残留物经柱层析精制 （流动相为石油醚： 乙酸乙酯 = 4 ： 1)得淡黄色油状液体 107 ( 400 mg, 80%)。  105 (500 mg, 2, 1 mmol) was dissolved in N-decylpyrrolidone (2 mL), reacted at 200 ° C for 5 hours, then cooled to room temperature, diluted with 10 mL of ethyl acetate and washed three times with 10 mL of water. The organic phase was dried over anhydrous sodium sulfate (MgSO4).
lR NMR (400 MHz, CDC13) δ 6.69 (s, 1H), 6.65 (s，lH), 6.03-5.97 (m, 1H), 5.63 (s，lH)， 5.11-5.03 (m, 2H) , 3.88 (s, 3H) , 3.69 (s, 3H) , 3.53 (s， 2H) , 3.39 (d, J = 6.0 Hz, 2H)。 lR NMR (400 MHz, CDC1 3 ) δ 6.69 (s, 1H), 6.65 (s, lH), 6.03-5.97 (m, 1H), 5.63 (s, lH), 5.11-5.03 (m, 2H), 3.88 (s, 3H), 3.69 (s, 3H), 3.53 (s, 2H), 3.39 (d, J = 6.0 Hz, 2H).
107 ( 400 mg, 1.7 mmol )溶于乙酸乙酯 （ 4 mL ), 加入 5% Pd/C催化剂 (40 mg), 在 1大气压的氢气气氛下反应 10小时， 抽滤， 滤液用 10 mL乙 酸乙酯稀释， 5mL水洗一次。 有机相用无水^ ^酸钠干燥、 浓缩， 残留物经柱 层析精制（流动相为石油醚： 乙酸乙酯 =4 ： 1)得淡黄色油状液体 110( 300 mg, 75%)。  107 (400 mg, 1.7 mmol) was dissolved in ethyl acetate (4 mL), 5% Pd/C catalyst (40 mg) was added, and reacted under a hydrogen atmosphere of 1 atm for 10 hours, suction filtered, and the filtrate was taken with 10 mL of ethyl acetate The ester was diluted and washed once with 5 mL of water. The organic phase was dried over anhydrous EtOAc (EtOAc)EtOAc.
110 ( 300 mg, 1.3 mmol )溶于二氯曱烷（4 mL )， 冰水浴下加入 3 N三 溴化硼的二氯甲烷溶液（lmL)， 然后在常温反应 2小时， 水（lOmL)加入， 用乙酸乙酯（ 10 mL * 3)萃取， 有机相用 5 mL水洗， 有机相用无水石克酸钠 干燥、 浓缩， 残留物经柱层析精制 （流动相为石油醚： 乙酸乙酯 = 4 : 1 ) 得白色固体 111 ( 200 mg, 71%)。  110 (300 mg, 1.3 mmol) was dissolved in dichloromethane (4 mL), and a solution of 3 N boron tribromide in dichloromethane (1 mL) was added in ice water, then reacted at room temperature for 2 hours, and water (10 mL) was added. It was extracted with ethyl acetate (10 mL * 3), the organic phase was washed with 5 mL of water, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 4 : 1 ) White solid 111 (200 mg, 71%).
!H NMR (400 MHz, CDC13) δ 6.63 (s, 1H)， 6.57 (s， 1H), 6.06 (br s， 1H), 5.33 (br s, 1H)， 3.70 (s, 3H) , 3.49 (s, 2H) , 2.55 (t, 7= 6.8 Hz, 2H) , 1.66-1.58 (m， 2H ) , 0.96 (t, / = 7.2 Hz, 3H)。 ! H NMR (400 MHz, CDC1 3) δ 6.63 (s, 1H), 6.57 (s, 1H), 6.06 (br s, 1H), 5.33 (br s, 1H), 3.70 (s, 3H), 3.49 ( s, 2H), 2.55 (t, 7 = 6.8 Hz, 2H), 1.66-1.58 (m, 2H), 0.96 (t, / = 7.2 Hz, 3H).
111 ( 100 mg, 0.45 mmol )和 6 N 盐酸（ 3 mL )在搅拌下加热回流 2 小时， 冷却后用乙酸乙酯 （10 mL * 3)萃取， 有机相用 5 mL水洗， 有机相 用无水硫酸钠干燥、 浓缩， 残留物经柱层析精制 （流动相为石油醚： 乙酸乙 酯 = 1 ： 1)得白色固体 112 (24 mg, 25%)。  111 (100 mg, 0.45 mmol) and 6 N hydrochloric acid (3 mL) were heated under reflux with stirring for 2 hrs, cooled and extracted with ethyl acetate (10 mL * 3). The organic phase was washed with 5 mL of water. The residue was purified by EtOAcqqqqqqqqq
Ή NMR (400 MHz, CDC13) δ 12.12 (br s, 1H), 9.12 (s, 1H) , 7.95 (s, 1H), 6.53 (s, 1H), 6.39 (s, 1H), 3.33 (s， 2H) , 2.50—2.42 (m, 2H) , 1.52— 1.48 (m, 2H ) , 0.88 (t, / = 7.2 Hz, 3H)。 实施例 15 3-氯- 4-羟基- 5-甲氧基苯乙酸甲酯（ 100 )和 3-氯 -4, 5 -二 NMR NMR (400 MHz, CDC1 3 ) δ 12.12 (br s, 1H), 9.12 (s, 1H), 7.95 (s, 1H), 6.53 (s, 1H), 6.39 (s, 1H), 3.33 (s, 2H) , 2.50—2.42 (m, 2H), 1.52— 1.48 (m, 2H ) , 0.88 (t, / = 7.2 Hz, 3H). Example 15 Methyl 3-chloro-4-hydroxy-5-methoxyphenylacetate (100) and 3-chloro-4,5-di
Figure imgf000020_0001
Figure imgf000020_0001
T83 100 067 实施例 8制备的 3-曱氧基 -4-羟基苯乙酸曱酯（T83， 400 mg, 2. Ommol ) 溶于四氢呋喃 （5 mL)， 搅拌下按次序加入 N-氯代丁二酰亚胺（ 300 mg, 2.2 ramol )和氢化钠 ( 160 mg, 5.3 mmol, 80%分散于矿物油）， 常温反应 16 小 时， 水（10 mL)加入， 用乙酸乙酯 （10 mL * 3)萃取， 有机相用 5 mL水 洗， 有机相用无水^ <酸钠干燥、 浓缩， 残留物经柱层析精制 （流动相为石油 醚： 乙酸乙酯 = 4 : 1 )得淡黄色液体 100 ( 327 mg, 71%)。  T83 100 067 3-methoxy-4-hydroxyphenylacetate oxime ester (T83, 400 mg, 2. Ommol) prepared in Example 8 was dissolved in tetrahydrofuran (5 mL), and N-chlorobutane was added in order with stirring. Imid (300 mg, 2.2 ramol) and sodium hydride (160 mg, 5.3 mmol, 80% dispersed in mineral oil), reacted at room temperature for 16 hours, water (10 mL) was added with ethyl acetate (10 mL * 3) The organic phase was washed with 5 mL of water, the organic phase was dried over anhydrous sodium sulfate, and the residue was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 4:1). 327 mg, 71%).
NMR (400 MHz, CDC13) δ 6.87 (s， lH)， 6.72 (s, lH)， 5.84 (br s， 1H), 3.90 (s， 3H), 3.70 (s, 3H) , 3.52 (s, 2H)。 NMR (400 MHz, CDC1 3 ) δ 6.87 (s, lH), 6.72 (s, lH), 5.84 (br s, 1H), 3.90 (s, 3H), 3.70 (s, 3H) , 3.52 (s, 2H) ).
100 ( 100 mg, 0.43 mmol )溶于 0.26 mL乙酸和 0.33 mL 48%氢溴酸溶 液中， 混合物力 p热回流 16小时， 冷却后加入 2 mL水， 用乙酸乙酯（ 5 mL * 3)萃取， 有机相用 2 mL水洗， 有机相用无水硫酸钠干燥、 浓缩， 溶 经柱 层析精制（流动相为二氯曱烷：曱醇 =20 ： 1 )得褐色固体 067( 57 mg， 57%);  100 (100 mg, 0.43 mmol) was dissolved in 0.26 mL of acetic acid and 0.33 mL of 48% hydrobromic acid solution. The mixture was heated to reflux for 16 hours. After cooling, 2 mL of water was added and extracted with ethyl acetate (5 mL * 3) The organic phase was washed with 2 mL of water, the organic phase was dried over anhydrous sodium sulfate and evaporated, and then purified by column chromatography (mobile phase: methylene chloride: decyl alcohol = 20:1) to give brown solid 067 ( 57 mg, 57 %);
'Η NMR (400 MHz, DMSO-^ δ 12.21 (br s, 1H), 9.87 (s, 1H)， 8.97 (s， 1H), 6.66 (s， 1H), 6.64 (s， 1H)， 3.37 (s, 2H) 。 实施例 16 3-氯 -4 5-二羟基苯乙酸曱酯（ 072 ) 的合成:
Figure imgf000020_0002
'Η NMR (400 MHz, DMSO-^ δ 12.21 (br s, 1H), 9.87 (s, 1H), 8.97 (s, 1H), 6.66 (s, 1H), 6.64 (s, 1H), 3.37 (s , 2H). Example 16 Synthesis of 3-chloro-4 5-dihydroxyphenylacetic acid decyl ester ( 072 ):
Figure imgf000020_0002
100 072 实施例 15制备的化合物 100 ( 80 mg, 0.35 腿 ol )溶于 5 ml二氯曱烷 中， 在零摄氏度搅拌条件下加入 1 mL 3N 三溴化硼的二氯曱烷溶液， 室温下 搅拌 3小时， 反应液在零摄氏度下加水淬灭， 用二氯曱烷（ 5 mL * 2 )萃取， 有机相用饱和食盐水（4 mL * 2) 洗， 无水硫酸钠干燥过滤后， 除去溶剂， 溶质经柱层析精制 （流动相为二氯曱烷： 甲醇 - 50 ： 1)得白色固体 072 (50 mg, 66%)。 100 072 Compound 100 prepared in Example 15 (80 mg, 0.35 leg ol) was dissolved in 5 ml of dichloromethane, and 1 mL of 3N boron tribromide in dichloromethane was added at 0 ° C under stirring. After stirring for 3 hours, the reaction solution was quenched with water at 0 ° C and extracted with dichloromethane (5 mL * 2 ). The organic phase was washed with saturated brine (4 mL * 2), dried over anhydrous sodium sulfate and filtered and evaporated. The solvent was purified by column chromatography (mobile phase: methylene chloride:methanol - 50:1) (50 mg, 66%).
丽 R (400 MHz, CDC13) δ 6.82 (s, 1H) , 6.72 (s, 1H)， 5.42 (s， 1H)， 5. 0 (s, 1H)， 3.70 (s， 3H) , 3.47 (s， 2H)。 实施例 17 3-溴 -4_羟基 -5-甲氧基苯乙酸甲酯（ 099 )、 3-溴- 4， 5-二羟 基苯乙酸 酯 （ 071 )和 3-溴- 4， 5-二羟基苯乙酸（ 073 ) 的合成： R (400 MHz, CDC1 3 ) δ 6.82 (s, 1H) , 6.72 (s, 1H), 5.42 (s, 1H), 5. 0 (s, 1H), 3.70 (s, 3H) , 3.47 (s , 2H). Example 17 Methyl 3-bromo-4-hydroxy-5-methoxyphenylacetate (099), 3-bromo-4, 5-dihydroxyphenylacetate (071) and 3-bromo-4, 5- Synthesis of dihydroxyphenylacetic acid ( 073 ):
Figure imgf000021_0001
Figure imgf000021_0001
071 073 实施例 8制备的 3-甲氧基 -4-羟基苯乙酸曱酯 （T83， 1.6 g, 8.2 蘭 ol ) 溶于 11 mL丙酮和 22 mL水中， 按次序加入溴化钠 （ 3.4 g, 32.8 mmol )和 Oxone (5.0 g， 16.4 mmol )。 在室温下反应 30分钟， 20 mL水加入， 用乙 酸乙酯 （10 mL * 2)萃取， 有机相用饱和食盐水（10 mL * 2) 洗， 无水硫 酸钠干燥过滤后， 除去溶剂， 溶质经柱层析精制 （流动相为石油醚： 乙酸乙 酯 = 4 ： 1)得淡黄色固体 099 ( 700 mg, 31%)。  071 073 3-methoxy-4-hydroxyphenylacetate oxime ester prepared in Example 8 (T83, 1.6 g, 8.2 lan ol) was dissolved in 11 mL of acetone and 22 mL of water, and sodium bromide (3.4 g, 32.8 mmol) and Oxone (5.0 g, 16.4 mmol). The reaction was carried out for 30 minutes at room temperature, 20 mL of water was added, and extracted with ethyl acetate (10 mL * 2). The organic phase was washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate and filtered and evaporated Purification by column chromatography (mobile phase: petroleum ether: ethyl acetate = 4:1)
XH NMR (400 MHz, CDC13) δ 7.01 (s, 1H)， 6.76 (s, 1H)， 5.90 (s， 1H)， 3.90 (s， 3H), 3.70 (s， 3H) , 3.53 ( s, 2H )。 X H NMR (400 MHz, CDC1 3 ) δ 7.01 (s, 1H), 6.76 (s, 1H), 5.90 (s, 1H), 3.90 (s, 3H), 3.70 (s, 3H) , 3.53 ( s, 2H).
化合物 099 ( 200 mg, 0.73 mmol )溶于 10 mL二氯曱烷中， 在零摄氏度 搅拌条件下加入 2mL 3N 三溴化硼的二氯曱烷溶液， 室温下搅拌 3小时， 反 应液在零摄氏度下加水淬灭， 用二氯甲烷（10 mL * 2)萃取， 有机相用饱 和食盐水（10 mL * 2) 洗， 无水 酸钠干燥过滤后， 除去溶剂， 溶质经柱 层析精制（流动相为二氯曱烷：曱醇 =50 ： 1)得白色固体 071( 130 mg， 68% X :H NMR (400 MHz, CDC13) δ 6.94 (s, 1H), 6.81 (s， 1H) , 5.10 (br s， 2H), 3.70 (s， 3H), 3.49 (s, 2H)。 化合物 071 ( 65 mg, 0.25 mmol )"J在搅拌条件下加入 2 mL 6 N HC1溶 液， 回流 3 小时， 冷却至室温， 用二氯曱烷（10 mL * 2)萃取， 有机相用 饱和食盐水（5 mL * 2) 洗， 无水 υ酸钠干燥过滤后， 旋去溶剂， 溶盾经柱 层析精制（流动相为二氯甲烷：甲醇 =20 ： 1)得白色固体 073( 35 mg， 57%)。 Compound 099 (200 mg, 0.73 mmol) was dissolved in 10 mL of dichloromethane, and 2 mL of 3N boron tribromide in dichloromethane was added under stirring at 0 ° C., stirred at room temperature for 3 hours, and the reaction solution was at zero degrees Celsius. It was quenched with water and extracted with dichloromethane (10 mL * 2). The organic phase was washed with saturated brine (10 mL * 2), dried over anhydrous sodium sulfate and filtered, and solvent was removed. The phase is methylene chloride: decyl alcohol = 50: 1) White solid 071 (130 mg, 68% X:H NMR (400 MHz, CDC1 3 ) δ 6.94 (s, 1H), 6.81 (s, 1H), 5.10 (br s, 2H), 3.70 (s, 3H), 3.49 (s, 2H). Compound 071 ( 65 mg, 0.25 mmol ) "J was added to 2 mL of 6 N HCl solution under stirring, refluxed for 3 hours, cooled to room temperature, extracted with dichloromethane (10 mL * 2), and brine. (5 mL * 2) After washing and drying with anhydrous sodium citrate, the solvent was evaporated, and the solvent was purified by column chromatography (mobile phase: methylene chloride:methanol = 20:1) to give white solid 073 (35 mg, 57%).
JH NMR (400 MHz, DMSO-^ δ 12.21 (br s， 1H), 9.74 (s， 1H)， 8.99 (s， 1H), 6.80 (s， 1H), 6.67 (s， 1H), 3.38 (s, 2H) 。 实施例 18 2, 3,6-三氯 -4, 5-二羟基苯乙酸曱酯（102)和 2, 3， 6-三氯 -4, 5 - J H NMR (400 MHz, DMSO-^ δ 12.21 (br s, 1H), 9.74 (s, 1H), 8.99 (s, 1H), 6.80 (s, 1H), 6.67 (s, 1H), 3.38 (s , 2H). Example 18 2,3,6-trichloro-4,5-dihydroxyphenylacetic acid decyl ester (102) and 2,3,6-trichloro-4,5-
Figure imgf000022_0001
Figure imgf000022_0001
102 109  102 109
3, 4-二羟基苯乙酸（D0， 840 rag, 5.0 mmol )溶于 10 mL醋酸中， 加 入磺酰氯（ 3.8 g， 25 mmol )， 混合物在室温下反应 48小时， 然后减压旋去 溶剂， 得粗产物 1.5 g。 粗产物溶于曱醇 20 mL， 常温下加入 0.2 mL浓；琉酸， 然后加热回流 3小时， 冷却到室温， 除去溶剂， 经柱层析精制（流动相为石 油醚： 乙酸乙酯 = 4 : 1)得白色固体 102 ( 400 mg, 28%)。  3, 4-Dihydroxyphenylacetic acid (D0, 840 rag, 5.0 mmol) was dissolved in 10 mL of acetic acid, sulfonyl chloride (3.8 g, 25 mmol) was added, and the mixture was reacted at room temperature for 48 hours, then the solvent was evaporated under reduced pressure. The crude product was obtained in 1.5 g. The crude product was dissolved in 20 mL of decyl alcohol, and 0.2 mL of concentrated; citric acid was added at room temperature, then heated under reflux for 3 hours, cooled to room temperature, solvent was removed, and purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 4: 1) A white solid 102 (400 mg, 28%).
JH NMR (400 MHz, CDC13) δ 5.95 (s, 1H) , 5.77 (s, 1H)， 3.99 (s, 2H) , 3.74 (s, 3H)。 J H NMR (400 MHz, CDC1 3 ) δ 5.95 (s, 1H), 5.77 (s, 1H), 3.99 (s, 2H), 3.74 (s, 3H).
化合物 102 ( 100 mg, 0.37 mmol ), 在搅拌条件下加入 2 mL 6 N HC1 溶液， 回流 3 小时， 冷却至室温， 用二氯曱烷（10 mL * 2)萃取， 有枳 4目 用饱和食盐水（5 mL * 2) 洗， 无水硫酸钠干燥过滤后， 除去溶剂， 溶质经 柱层析精制（流动相为石油醚： 乙酸乙酯 =1 ： 1 )得白色固体 109 ( 25 mg， 25%)。  Compound 102 (100 mg, 0.37 mmol), 2 mL of 6 N HCl solution was added under stirring, refluxed for 3 hours, cooled to room temperature, extracted with dichloromethane (10 mL * 2), with 4 mL of saturated salt After washing with water (5 mL * 2), dried over anhydrous sodium sulfate and filtered, solvent was removed, and the solvent was purified by column chromatography (mobile phase: petroleum ether: ethyl acetate = 1 : 1 ) to give a white solid 109 (25 mg, 25 %).
!H NMR (400 MHz, DMS0-i/d) δ 12.51 (br s, 1H), 10.10 (s， 1H) , 9.91 (s, 1H), 3.82 (s， 2H)。 19 N- -羟基苯乙基- ( 3, 4-二羟基 ) -苯乙酸胺 ( C67 )的合成:
Figure imgf000023_0001
 ! H NMR (400 MHz, DMS0 -i / d) δ 12.51 (br s, 1H), 10.10 (s, 1H), 9.91 (s, 1H), 3.82 (s, 2H). Synthesis of 19 N--hydroxyphenethyl-(3,4-dihydroxy)-phenylacetic acid amine (C67):
Figure imgf000023_0001
DO C67-1 C67  DO C67-1 C67
3, 4-二羟基苯乙酸（DO, 168 mg, 1.0 mmol ) 和 C67- 1 ( 164 mg , 1.2 mmol )溶于 2 mL的 DMF中 , 向此溶液中分别加入 160 mg的 HOBt ( 1.2 mmol )、 230 mg的 EDCI ( 1.2 mmol ), 混合溶液在常温下搅拌 16个小时。 加 入 10 mL的乙酸乙酯进行稀释， 分别用 5 mL 1 N的盐酸水溶液和 5 mL的 饱和食盐水洗， 有机相干燥浓缩， 过硅胶柱纯化（石油醚： 乙酸乙酯 =2: 3) 得到无色油状物 ( 230 mg, 80%)。  3,4-Dihydroxyphenylacetic acid (DO, 168 mg, 1.0 mmol) and C67- 1 (164 mg, 1.2 mmol) were dissolved in 2 mL of DMF, and 160 mg of HOBt (1.2 mmol) was added to the solution. 230 mg of EDCI (1.2 mmol), and the mixed solution was stirred at room temperature for 16 hours. After adding 10 mL of ethyl acetate, the mixture was diluted with 5 mL of 1 N aqueous hydrochloric acid and 5 mL of saturated brine, and the organic phase was dried and concentrated and purified by silica gel column ( petroleum ether: ethyl acetate = 2: 3) Color oil (230 mg, 80%).
NMR (400 MHz, DMSO-^ δ 8.78 (s, 1H), 8.69 (s， 1H) , 7.88 (s， 1H), 7.33 - 7.23 (m , 5H) , 6.66 (s， 1H) , 6.61 (d， /= 8.0 Hz, 1H) , 6.45 (d, 7= 8.0 Hz, 1H)， 5.46 (d, /= 4.0 Hz, 1H)， 4.56 (br s， 1H) , 3.26— 3.21 (m, 3H), 3.11 - 3.08 (m， 1H). 实施例 20 3, 4-二羟基苯乙酸（ 3'， 4'-二羟基 )苯乙酯（C17)的合成:
Figure imgf000023_0002
NMR (400 MHz, DMSO-^ δ 8.78 (s, 1H), 8.69 (s, 1H), 7.88 (s, 1H), 7.33 - 7.23 (m, 5H), 6.66 (s, 1H), 6.61 (d, /= 8.0 Hz, 1H), 6.45 (d, 7= 8.0 Hz, 1H), 5.46 (d, /= 4.0 Hz, 1H), 4.56 (br s, 1H), 3.26— 3.21 (m, 3H), 3.11 - 3.08 (m, 1H). Example 20 Synthesis of 3,4-dihydroxyphenylacetic acid (3',4'-dihydroxy)phenylethyl ester (C17):
Figure imgf000023_0002
DO C17-2 C17-3  DO C17-2 C17-3
OBn NaOH, THF, 8h Bn° OH SOCI2,rfx, 4h BnOOBn NaOH, THF, 8h Bn ° OH SOCI 2 , rfx, 4h BnO
Figure imgf000023_0003
Figure imgf000023_0003
C17-2 C17-4 C17-5
Figure imgf000023_0004
C17-2 C17-4 C17-5
Figure imgf000023_0004
20-1 中间体 C17- 2的合成：  20-1 Synthesis of intermediate C17-2:
3, 4-二羟基苯乙酸 ( DO, 3.0 g， 17.9 mmol )和 6.4 mL溴苄 ( 53.6 mmol ) 溶于 40 mL的 DMF中， 向此溶液中加入 7.4 g碳酸钾 ( 17.9 mmol ), 在 40 度下搅拌 12小时。 加入 200 mL的乙酸乙酯将此溶液稀释， 用 100 mL的饱 和食盐水洗三次，有机相干燥浓缩，过硅胶柱纯化（石油醚：乙酸乙酯 = 10: 1 ) 得到白色固体 C17-2 (7 g， 89% X 20-2 中间体 C17- 3的合成： 3, 4-Dihydroxyphenylacetic acid (DO, 3.0 g, 17.9 mmol) and 6.4 mL of benzyl bromide (53.6 mmol) were dissolved in 40 mL of DMF. To this solution was added 7.4 g of potassium carbonate ( 17.9 mmol ) at 40 Stir for 12 hours. The solution was diluted with 200 mL of ethyl acetate, washed three times with 100 mL of brine, and then evaporated to dryness. Synthesis of g, 89% X 20-2 Intermediate C17-3:
步骤 20-1制备的 C17- 2 ( 600 mg, 1.37 讓 ol )溶于 10 mL的干燥四氢 呋喃中， 在零度下加入 104.5 mg氢化铝锂（2.75 mmol ), 此溶液在室温下 搅拌 2小时。 加入十水硫酸钠淬灭并加入 20 mL乙酸乙酯稀释过滤， 滤液浓 缩过硅胶柱纯化（石油醚： 乙酸乙酯 =4: 1)得到白色固体 C17-3 ( 400 mg, 87%)。  The C17-2 (600 mg, 1.37 let ol) prepared in Step 20-1 was dissolved in 10 mL of dry tetrahydrofuran, and then 104.5 mg of lithium aluminum hydride (2.75 mmol) was added at 0 °, and the solution was stirred at room temperature for 2 hours. The mixture was quenched with EtOAc EtOAc (EtOAc)EtOAc.
XH NMR (400 MHz, CDC13) δ 7.46 - 7.30 (ra, 10H), 6.88 (d, /= 8.4 Hz, 1H), 6.82 (s， 1H)， 6.73 (d, 7 = 8.4 Hz, 1H)， 5.16 (s， 2H), 5.14 (s, 2H), 3.78 (s， 2H), 2.75 (t, 7 = 6.4 Hz, 2H) . 20- 3 中间体 C17- 4的合成： X H NMR (400 MHz, CDC1 3 ) δ 7.46 - 7.30 (ra, 10H), 6.88 (d, /= 8.4 Hz, 1H), 6.82 (s, 1H), 6.73 (d, 7 = 8.4 Hz, 1H) , 5.16 (s, 2H), 5.14 (s, 2H), 3.78 (s, 2H), 2.75 (t, 7 = 6.4 Hz, 2H) . 20- 3 Synthesis of intermediate C17-4:
步骤 20-1制备的 C17-2 ( 600 mg, 1.37 mmol )溶于 3 mL四氢呋喃和 3 mL 2 N的氢氧化钠的水溶液中， 室温搅拌 8小时。 除去溶剂加入 10 mL水， 用 5 mL乙酸乙酯洗， 水相用盐酸调 PH到 2, 用 10 mL乙酸乙酯萃取三次。 有机相干燥浓缩得到白色固体 C17-4 ( 400 mg, 84% X  The C17-2 (600 mg, 1.37 mmol) prepared in Step 20-1 was dissolved in 3 mL of tetrahydrofuran and 3 mL of 2N aqueous sodium hydroxide and stirred at room temperature for 8 hr. The solvent was removed and 10 mL of water was added, and washed with 5 mL of ethyl acetate. The aqueous phase was adjusted to pH 2 with hydrochloric acid and extracted three times with 10 mL of ethyl acetate. The organic phase was dried and concentrated to give a white solid C17-4 (400 mg, 84% X
丽 R (400 MHz, CDC 13) δ 7.46 - 7.30 (m， 10Η), 6.90 - 6.88 (m， 2H) ,Li R (400 MHz, CDC 1 3 ) δ 7.46 - 7.30 (m, 10Η), 6.90 - 6.88 (m, 2H) ,
6.79 (d, / = 8.0 Hz, 1H), 5.14 (s, 4H) , 3.55 (s, 2H) . 6.79 (d, / = 8.0 Hz, 1H), 5.14 (s, 4H), 3.55 (s, 2H).
20-4 中间体 C17-5的合成： 20-4 Intermediate Synthesis of C17-5:
步骤 20- 3制备的 C17- 4 (63mg, 0.18醒 ol )溶于 1 mL的二氯亚石风中， 加热回流 4小时。 将反应液浓缩得到油状物 C17- 5 ( 66 mg, 0.18 mmol ) 直接用于下一步反应。  The C17-4 (63 mg, 0.18 awake ol) prepared in Step 20-3 was dissolved in 1 mL of chlorite and heated to reflux for 4 hours. The reaction mixture was concentrated to give EtOAc (EtOAc m.
20-5 中间体 C17- 6的合成： 20-5 Synthesis of intermediate C17-6:
步骤 20- 2制备的 C17-3 ( 50 mg, 0.15 mmol )和 18.2 mg三乙胺（ 0.18 mmol )溶于 2mL的二氯甲烷中，在零度下滴加步骤 20-2制备的 C17- 5( 66 mg, 0.18 mmol ), 此反应液在室温下搅拌 3小时， 反应液分别用 2 mL 1 N的盐 酸和 2 mL 1 N的氢氧化钠水溶液洗， 有机相干燥浓缩， 过硅胶柱纯化（石 油醚： 乙酸乙酯 = 10: 10得到白色固体 C17-6 (80 mg, 80%)。 The C17-3 (50 mg, 0.15 mmol) and 18.2 mg of triethylamine (0.18 mmol) prepared in the step 20-2 were dissolved in 2 mL of dichloromethane, and the C17-5 prepared in the step 20-2 was added dropwise at zero degree ( 66 mg, 0.18 mmol), the reaction mixture was stirred at room temperature for 3 hours, and the reaction mixture was washed with 2 mL of 1 N hydrochloric acid and 2 mL of 1 N aqueous sodium hydroxide solution, and the organic phase was dried and concentrated and purified by silica gel column Oleic ether: ethyl acetate = 10: 10 gave white solid C17-6 (80 mg, 80%).
:H NMR (400 MHz, CDC13) δ 7.43-7.31 (m, 2 OH), 6,86 — 6.83 (m, 3H), 6.77 (s， 1H), 6.73 (d, /= 8.4 Hz, 1H), 6.64 (d, /= 8.4 Hz, 1H) , 5.14 (s, 8H)， 4.20 (t, / = 6.4 Hz, 2H), 3.45 (s, 2H) , 2.78 (t, J = 6.4 Hz, 2H). : H NMR (400 MHz, CDC1 3 ) δ 7.43-7.31 (m, 2 OH), 6,86 — 6.83 (m, 3H), 6.77 (s, 1H), 6.73 (d, /= 8.4 Hz, 1H) , 6.64 (d, /= 8.4 Hz, 1H), 5.14 (s, 8H), 4.20 (t, / = 6.4 Hz, 2H), 3.45 (s, 2H), 2.78 (t, J = 6.4 Hz, 2H) .
20-6 产物 C17的合成： 20-6 Synthesis of product C17:
步骤 20-2制备的 C17-6 ( 20 mg, 0.03顏 ol )溶于 5mL乙酸乙酯中， 加 入 2 mg钯碳， 用氢气置换三次， 在 40度下搅拌 4小时。 用硅藻土过滤， 滤 液浓缩过硅胶柱纯化（石油醚： 乙酸乙酯 = 1: 1)得到油状物 C17 (48 mg, 88% λ  The C17-6 (20 mg, 0.03 yol) prepared in the step 20-2 was dissolved in 5 mL of ethyl acetate, and 2 mg of palladium carbon was added thereto, and the mixture was replaced with hydrogen three times, and stirred at 40 °C for 4 hours. Filtration with celite, EtOAc (EtOAc:EtOAc:EtOAc)
:H NMR (400 MHz, MS -d ) δ 8.86 (s, 1H), 8.78 (s， 2H)， 8.59 (s， 1H) , 6.64— 6.57 (m, 4H) , 6.47 - 6.42 (m, 2H)， 4.10 (t, /= 6.4 Hz, 2H) , 3.41 (s, 2H)， 2.67 (t, / = 6.4 Hz， 2H). 实施例 21 N- ( 3',4'-二羟基）苯乙基- ( 3， 4-二羟基）苯乙酸胺（C52) : H NMR (400 MHz, MS -d ) δ 8.86 (s, 1H), 8.78 (s, 2H), 8.59 (s, 1H) , 6.64 - 6.57 (m, 4H) , 6.47 - 6.42 (m, 2H) , 4.10 (t, /= 6.4 Hz, 2H), 3.41 (s, 2H), 2.67 (t, / = 6.4 Hz, 2H). Example 21 N-(3',4'-dihydroxy)phenethyl - (3,4-dihydroxy)phenylacetic acid amine (C52)
Figure imgf000025_0001
Figure imgf000025_0001
DO C52-1 C52 3，4-二羟基苯乙酸（00， 2.0 g, 11.9 mmol)和多巴胺盐酸盐（2.7 g， 14.3 mmol)溶于干燥的 DMF (12 mL) , 搅拌下加入 EDCI (2.74 g, 14.3 mmol)和 DIPEA (1.84 g, 14.3 mmol). 常温下搅拌 16小时， 然后用乙酸乙酯（100 mL) 稀释， 用 15 mL 1 N 的稀盐酸洗涤， 再用 15 mL饱和食盐水洗 3次， 无水硫 酸钠干燥， 过滤浓缩， 经柱层析纯化（流动相为二氯曱烷：曱醇 = 25 ： 1)得 到化合物 C52 (1.0 g , 27%) , 为一白色固体。  DO C52-1 C52 3,4-Dihydroxyphenylacetic acid (00, 2.0 g, 11.9 mmol) and dopamine hydrochloride (2.7 g, 14.3 mmol) dissolved in dry DMF (12 mL), EDCI (2.74) g, 14.3 mmol) and DIPEA (1.84 g, 14.3 mmol). Stir at room temperature for 16 hours, then dilute with ethyl acetate (100 mL), wash with 15 mL of 1 N diluted hydrochloric acid, and wash with 15 mL of brine. The organic layer was dried over anhydrous sodium sulfate (MgSO4).
JH NMR (400 MHz, OUSQ-d6) δ 8.79 (s, 1H), 8.75 (s, 1H), 8.67 (s， 1H), 8.65 (s， 1H)， 7.91 (s， 1H) , 6.64 (d, / = 8.0 Hz, 1H) , 6.62 ( s, 1H), 6.61 (s, 1H), 6.56 (s, 1H), 6.45 (d, / = 8.0 Hz, 1H), 6.40 (d, /= 8, 0 Hz, 1H), 3.17 (s， 2H) , 3.18—3.11 (m, 2H) , 2.51-2.40 (m, 2H)。 -氧代苯 [1, 3]二氧戊环- 5-乙酸 (T21)的合成: J H NMR (400 MHz, OUSQ-d6) δ 8.79 (s, 1H), 8.75 (s, 1H), 8.67 (s, 1H), 8.65 (s, 1H), 7.91 (s, 1H), 6.64 (d , / = 8.0 Hz, 1H), 6.62 ( s, 1H), 6.61 (s, 1H), 6.56 (s, 1H), 6.45 (d, / = 8.0 Hz, 1H), 6.40 (d, /= 8, 0 Hz, 1H), 3.17 (s, 2H), 3.18—3.11 (m, 2H), 2.51-2.40 (m, 2H). Synthesis of oxobenzene [1,3]dioxolane-5-acetic acid (T21):
Figure imgf000026_0001
Figure imgf000026_0001
T21  T21
DO  DO
3， 4-二羟基苯乙酸（D0， 2.0 g, 11.9 醒。1)和 Ν,Ν'-琥珀酰亚胺基碳酸 酯（3.1 g, 12.1 mmol) 溶于千燥的二氯曱烷（100 mL) , 搅拌下加入三乙胺 (1.44 g， 14.3 mmol)0 常温下搅拌 16小时， 然后分别用 15 mLl 的稀盐 酸和 15 mL饱和食盐水洗涤， 无水^ <酸钠干燥， 过滤浓缩， 经硅胶柱层析纯 化（流动相为石油醚：乙酸乙酯 =1: 1)得到化合物 T21 (0.8 g , 34%) , 为一白 色固体。 3, 4-dihydroxyphenylacetic acid (D0, 2.0 g, 11.9 awake.1) and hydrazine, Ν'-succinimidyl carbonate (3.1 g, 12.1 mmol) dissolved in dry dichloromethane (100 mL), was added with stirring triethylamine (1.44 g, under stirring 14.3 mmol) 0 at room temperature for 16 hours and then were washed with 15 mLl dilute hydrochloric acid and 15 mL of saturated brine, dried over anhydrous ^ <sodium sulfate, filtered and concentrated Purification by silica gel column chromatography (EtOAc:EtOAc:EtOAc:
!H NMR (400 MHz, DMSO-^ δ 12.43 (br s， 1H), 7.42-7.40 (m, 2H)， 7.17 (d, / = 8.0 Hz, 1H)， 3.66 (s, 2H)。 实施例 23 对肿瘤细胞增殖的影响 （ I ) ! H NMR (400 MHz, DMSO- ^ δ 12.43 (br s, 1H), 7.42-7.40 (m, 2H), 7.17 (d, / = 8.0 Hz, 1H), 3.66 (s, 2H). Example 23 Effect on tumor cell proliferation (I)
实验方案： 采用噻唑蓝（3- (4， 5-二甲基噻唑- 2)- 2， 5-二苯基四氮唑 溴盐， MTT) 实验， 3， 4-二羟基苯甲酸（DO) 为对照， 选取前述代表性苯乙 酸类衍生物 D80、 C17、 T33、 D23、 C67等（剂量梯度为 10 mg/ral、 1 mg/m 100 μ g/ίΆl, 10 Mg/mK 1 μ g/ml, 100 ng/ml )分别处理肿瘤细胞 24小时， 之后 MTT染色 4小时， 之后二曱基亚砜（DMS0)溶解， 酶标仪 570 nm下测 吸光光度值。 计算细胞存活率。  Experimental protocol: using thiazolyl blue (3-(4,5-dimethylthiazole-2)-2,5-diphenyltetrazolium bromide, MTT) experiment, 3,4-dihydroxybenzoic acid (DO) For the control, the above representative phenylacetic acid derivatives D80, C17, T33, D23, C67, etc. were selected (dose gradient 10 mg/ral, 1 mg/m 100 μg/ίΆl, 10 Mg/mK 1 μg/ml). , 100 ng/ml ), the tumor cells were treated for 24 hours respectively, and then stained with MTT for 4 hours, after which the dimethyl sulfoxide (DMS0) was dissolved, and the absorbance value was measured at 570 nm. Cell viability was calculated.
实验结果： D0、 D80、 C17、 T33、 D23、 C67和 DO- 3对肺癌 Α549细胞增 殖具有一定抑制作用， 而且呈剂量依赖关系。 且这些化合物 100 ug/ml剂量 作用组中， A549细胞存活率均在 80%以上，提示化合物 D80、 C17、 T33、 D23、 C67和 DO- 3具备一定的安全性，可以用于抗肿瘤基础研究和临床验证。具体 结果见图 1。 实施例 24 对肿瘤细胞和正常细胞增殖的影响 （ II )  Experimental results: D0, D80, C17, T33, D23, C67 and DO-3 have a certain inhibitory effect on the proliferation of lung cancer Α549 cells in a dose-dependent manner. In the 100 ug/ml dose group, the survival rate of A549 cells was above 80%, suggesting that compounds D80, C17, T33, D23, C67 and DO-3 have certain safety and can be used for basic anti-tumor research. And clinical validation. The specific results are shown in Figure 1. Example 24 Effect on proliferation of tumor cells and normal cells (II)
实验方案： 采用噻唑蓝 （3- (4， 5-二曱基噻唑 -2)- 2, 5-二苯基四氮唑 溴盐， MTT)实验，待测化合物（剂量梯度为 10 mg/mK 1 mg/mK 100 μ g/m 10 M g/mK l g/ml、 100 ng/ml )分别处理肺癌 A549细胞、 鼻咽癌 CNE- 2Z 细胞、 肾母细胞瘤 G401细胞和喉癌 HEP-2细胞 24小时， MTT染色 4小时， 二甲基亚砜（DMS0 )溶解， 酶标仪 570 nm下测吸光光度值。 以化合物梯度 为横坐标， 细胞存活率为纵坐标， 绘制标准曲线， 并计算半数抑制率 IC5。。 Experimental protocol: Triazole blue (3-(4,5-dimercaptothiazol-2)-2,5-diphenyltetrazolium bromide, MTT) experiment, test compound (dose gradient 10 mg/mK) 1 mg/mK 100 μg/m 10 M g/mK lg/ml, 100 ng/ml) treated lung cancer A549 cells, nasopharyngeal carcinoma CNE-2Z cells, nephroblastoma G401 cells and laryngeal carcinoma HEP-2 cells for 24 hours, MTT staining for 4 hours, two The methyl sulfoxide (DMS0) was dissolved, and the absorbance value was measured at 570 nm. Using the compound gradient as the abscissa, the cell survival rate as the ordinate, plotting the standard curve, and calculating the half-inhibition rate IC 5 . .
实险结果： 待测化合物中， 065-1、 065-2、 069、 079和 111对这些肿瘤 细胞增殖的抑制作用显著， 其中 065-2和 069对 293细胞增殖的抑制作用要 小于对肿瘤细胞的抑制作用，提示 065-2和 069对肿瘤细胞的作用具有一定 的选择性。 具体结果见表 1。  Risk results: Among the tested compounds, 065-1, 065-2, 069, 079 and 111 have significant inhibitory effects on the proliferation of these tumor cells, and 065-2 and 069 inhibit the proliferation of 293 cells less than tumor cells. The inhibition, suggesting that 065-2 and 069 have a certain selectivity for tumor cells. The specific results are shown in Table 1.
表 1 对 5种细胞增殖的影响 （ IC5。 ) Table 1 Effect on proliferation of five kinds of cells (IC 5 . )
A549细胞 CNE-2Z细胞 G401细胞 HEP-2细胞 293细胞 A549 cells CNE-2Z cells G401 cells HEP-2 cells 293 cells
DO 42 g/ml 35 μ g/ml 27 μ g/ml 56 μ g/ml 370 μ g/ml DO 42 g/ml 35 μg/ml 27 μg/ml 56 μg/ml 370 μg/ml
065-1 46 μ g/ml 21 μ g/ml 22 μ g/ml 71 μ g/ml 17 μ g/ml 065-1 46 μ g/ml 21 μg/ml 22 μg/ml 71 μg/ml 17 μg/ml
065-2 39 g/ml 24 μ g/ml 1 μ g/ml 50 μ g/ml 192 μ g/ral 065-2 39 g/ml 24 μg/ml 1 μg/ml 50 μg/ml 192 μ g/ral
067 69 μ g/ml 149 μ g/ml 105 μ g/ml 243 g/ml 450 μ g/ml067 69 μg/ml 149 μg/ml 105 μg/ml 243 g/ml 450 μg/ml
069 37 μ g/ml 55 μ g/ml 11 μ g/ml 66 μ g/ml 131 μ g/ml069 37 μg/ml 55 μg/ml 11 μg/ml 66 μg/ml 131 μg/ml
099 350 μ g/ml 543 μ g/ml 152 μ g/ml 718 μ g/ml 780 μ g/ml099 350 μg/ml 543 μg/ml 152 μg/ml 718 μg/ml 780 μg/ml
100 163 μ g/ml 327 μ g/ml 119 μ g/ml 460 μ g/ml 1092 μ g/ml100 163 μ g/ml 327 μg/ml 119 μg/ml 460 μg/ml 1092 μg/ml
070 55 μ g/ml 36 μ g/ml 38 μ g/ml 6 μ g/ml 8. 5 μ g/ml070 55 μg/ml 36 μg/ml 38 μg/ml 6 μg/ml 8. 5 μg/ml
071 368 μ g/ml 418 g/ml 420 μ g/ml 749 μ g/ral 943 μ g/ral071 368 μ g/ml 418 g/ml 420 μg/ml 749 μ g/ral 943 μ g/ral
072 641 μ g/ml 579 μ g/ml 587 μ g/ml 1030 μ g/ml 862 μ g/ml072 641 μ g/ml 579 μ g/ml 587 μ g/ml 1030 μ g/ml 862 μ g/ml
073 555 μ g/ml 434 μ g/ml 395 μ g/ml 822 μ g/ml 397 μ g/ml073 555 μ g/ml 434 μg/ml 395 μg/ml 822 μg/ml 397 μg/ml
077 74 μ g/ml 56 μ g/ral 69 μ g/ml 108 μ g/ml 47 μ g/ml 077 74 μg/ml 56 μg/ral 69 μg/ml 108 μg/ml 47 μg/ml
079 44 μ g/ml 57 μ g/ml 46 μ g/ml 52 μ g/ml 11 μ g/ml  079 44 μg/ml 57 μg/ml 46 μg/ml 52 μg/ml 11 μg/ml
102 290 μ g/ml 394 μ g/ml 222 μ g/ml 371 μ g/ml 210 μ g/ml 102 290 μg/ml 394 μg/ml 222 μg/ml 371 μg/ml 210 μg/ml
109 52 μ g/ml 62 μ g/ml 51 μ g/ml 47 μ g/ml 24 μ g/ml 109 52 μg/ml 62 μg/ml 51 μg/ml 47 μg/ml 24 μg/ml
111 33 μ g/ml 41 g/ml 30 μ g/ml 51 μ g/ml 29 μ g/ml  111 33 μg/ml 41 g/ml 30 μg/ml 51 μg/ml 29 μg/ml
122 78 μ g/ml 106 μ g/ml 114 μ g/ral 194 μ g/ral 19 μ g/ml 实施例 25 对肿瘤细胞迁移的影响 （ I )  122 78 μg/ml 106 μg/ml 114 μg/ral 194 μg/ral 19 μg/ml Example 25 Effect on tumor cell migration ( I )
实验方案： 采用细胞迁移检测 （Transwe l l ) 实验， Ι Ο μ Μ待测化合物 、 D80、 T73、 T33、 D23、 T21、 C52、 D76、 C17、 C67、 DO- 1、 DO- 2、 DO- 3 分别处理肺癌 A549细胞、 肌肉瘤 A204细胞、 肾母细胞瘤 G401细胞和结肠 癌 CT26细胞 24小时， 经过无水冰曱醇固定、 结晶紫染色和拍照， 检测细胞 迁移的个数。 以 DO为阳性对照， 同时设空白对照组。 Experimental protocol: Cell migration assay (Transwe ll) experiment, Ι Ο μ Μ test compound, D80, T73, T33, D23, T21, C52, D76, C17, C67, DO-1, DO-2, DO-3 Lung cancer A549 cells, mytioma A204 cells, nephroblastoma G401 cells and colon cancer CT26 cells were treated for 24 hours respectively, and subjected to anhydrous hazelnitol fixation, crystal violet staining and photographing to detect the number of cell migration. The DO was used as a positive control, and a blank control group was also set.
实验结果：化合物 D80、 T33、 T21、 C52、 C67和 DO- 3可以显著抑制 A549、 A204、 G401 和 CT26细胞的迁移， 作用强于 D0。 具体见图 2-图 5。 实施例 26 对肿瘤细胞迁移的影响 （ I I )  Experimental results: Compounds D80, T33, T21, C52, C67 and DO-3 significantly inhibited the migration of A549, A204, G401 and CT26 cells, which was stronger than D0. See Figure 2-5 for details. Example 26 Effect on Tumor Cell Migration (I I )
实验方案： 采用细胞迁移检测 （Transwel l ) 实验， 10 μ Μ待测化合物 065—1、 065—2、 067、 069、 070、 071、 072、 073、 077、 079、 099、 100、 102、 109、 111和 122分别处理肺癌 Α549、 胃癌 G401和喉癌 HEP- 2细月包 24小时， 经过无水冰曱醇固定、 结晶紫染色和拍照， 检测细胞迁移的个数。 以 DO为 阳性对照， 同时设空白对照组。  Experimental protocol: Cell migration assay (Transwell l) experiment, 10 μ Μ test compound 065—1, 065—2, 067, 069, 070, 071, 072, 073, 077, 079, 099, 100, 102, 109 , 111 and 122 were treated with lung cancer Α549, gastric cancer G401 and laryngeal carcinoma HEP-2 for 24 hours respectively, and were subjected to anhydrous hazelnitol fixation, crystal violet staining and photographing to detect the number of cell migration. The DO was used as a positive control and a blank control group was also set.
实验结果: 化合物 065-1、 065-2、 069、 102和 111可以显著抑制 A549、 G401和 HEP2细胞的迁移。 具体见图 6-图 8。 实施例 27 对肿瘤细胞凋亡的影响 （I )  Experimental results: Compounds 065-1, 065-2, 069, 102 and 111 significantly inhibited the migration of A549, G401 and HEP2 cells. See Figure 6-8 for details. Example 27 Effect on Tumor Cell Apoptosis (I)
实睑方案： 待测化合物 T83、 D80、 T73、 T33、 D23、 Τ21、 C52、 D76、 C17、 C67、 DO- 1、 DO- 2、 DO- 3 ( 10 μ Μ, 该剂量为安全剂量）处理肺癌 A549细胞 和腎母细胞瘤 G401细胞 24小时， 之后进行 Annexin V-FITC和 PI双染， 采 用流式细胞检测技术对凋亡细胞进行识别， 并计算出凋亡细胞数目。 以 DO 为阳性对照， 同时设空白对照组。  Practical solution: The compounds to be tested T83, D80, T73, T33, D23, Τ21, C52, D76, C17, C67, DO-1, DO-2, DO-3 (10 μ Μ, the dose is a safe dose) Lung cancer A549 cells and nephroblastoma G401 cells were treated for 24 hours, followed by Annexin V-FITC and PI double staining. Apoptotic cells were identified by flow cytometry and the number of apoptotic cells was calculated. The DO was used as a positive control, and a blank control group was also set.
实验结果： 化合物 T83、 D80、 T73、 T33、 D23、 Τ21、 C52、 D76、 C17、 C67和 DO- 3对 A549和 G401细胞凋亡（包括早期凋亡和晚期凋亡）都具有一 定促进作用 ,表现在凋亡细胞在所有细胞中的比例增大。其中 D80、 T33、 C17、 C52和 DO- 3促凋亡作用强于 D0。 具体结果见图 9-图 10。 实施例 28 对肿瘤细胞凋亡的影响 （I I )  Experimental results: Compounds T83, D80, T73, T33, D23, Τ21, C52, D76, C17, C67 and DO-3 have a certain promoting effect on apoptosis of A549 and G401 cells, including early apoptosis and late apoptosis. It is manifested in an increase in the proportion of apoptotic cells in all cells. Among them, D80, T33, C17, C52 and DO-3 promoted apoptosis more strongly than D0. The specific results are shown in Figure 9-10. Example 28 Effect on Tumor Cell Apoptosis (I I )
实验方案：采用细胞凋亡流式检测实验，待测化合物 065-1、 065-2、 067、 069、 070、 071、 072、 073、 077、 079、 099、 100、 102、 109、 111和 122 ( 10 μ Μ,该剂量为安全剂量）分别处理肺癌 Α549、腎母细胞瘤 G401和喉癌 HEP- 2 细胞 24小时， 之后离心收集细胞（ 1500 rpm, 5 min ), PBS重悬离心 2次， 之后用 Annexin- V FITC和 PI分别染色 15 min, 流式细胞分析仪检测凋亡细 胞的 分比， 早期凋亡和晚期凋亡的细胞百分比之和及凋亡总 以 DO为 阳性对照， 同时设空白对照组。 Experimental protocol: Apoptosis flow assay was used to test compounds 065-1, 065-2, 067, 069, 070, 071, 072, 073, 077, 079, 099, 100, 102, 109, 111 and 122 (10 μ Μ, this dose is a safe dose) to treat lung cancer Α549, nephroblastoma G401 and laryngeal carcinoma HEP-2 cells for 24 hours, then centrifuge the cells (1500 rpm, 5 min) and resuspend in PBS for 2 times. After staining with Annexin-V FITC and PI for 15 min, flow cytometry was used to detect apoptosis. The ratio of cells, the percentage of cells with early apoptosis and late apoptosis, and the total apoptosis were positive for DO, and a blank control group was also established.
实验结果： 化合物 065-1、 065-2和 069对 A549、 G401和 HEP2细胞的 凋亡具有显著的促进作用，且这 3种化合物的作用要显著强于 D0。具体结果 见图 11-图 13。 总之。 本发明提供了一种新的苯乙酸衍生物， 其具有抗肿瘤活性， 能够 促进肿瘤细胞凋亡、 抑制肿瘤细胞的迁移， 可以开发出新的抗肿瘤药物， 为 临床肿瘤治疗提供新的选择。 以上对本发明具体实施方式的描述并不限制本发明， 本领域技术人员可 以根据本发明作出各种改变或变形， 只要不脱离本发明的精神， 均应属于本 发明所附权利要求的范围。  Experimental results: Compounds 065-1, 065-2 and 069 significantly promoted the apoptosis of A549, G401 and HEP2 cells, and the effects of these three compounds were significantly stronger than D0. The specific results are shown in Figure 11 - Figure 13. In short. The present invention provides a novel phenylacetic acid derivative which has antitumor activity, can promote tumor cell apoptosis, inhibit tumor cell migration, and can develop a new antitumor drug, and provides a new choice for clinical tumor treatment. The above description of the specific embodiments of the present invention is not intended to limit the invention, and various modifications and changes may be made by those skilled in the art without departing from the spirit and scope of the invention.

Claims

权 利 要 求 Rights request
1、 式 I所示的化合物， 1. The compound represented by formula I,
Figure imgf000030_0001
其中， 、 R2、 R3、 R4和 R5各自独立地选自夢、 羟基、 卤素、 d- C5直链 或支链烷基、 C2- C5直链或支链不饱和烃基、 或 \0 Rl5，或 、 R2、 R3、 R4和 R5中相邻的两个取代基与它们相连的碳原子一起形成三元以上的取代的或 未取代的碳环、 或者取代的或未取代的含氧杂环； 其中 R15选自 C!-Cs直链或 支链烷基、 烯丙基、 炔丙基、 烯丁基、 甲基烯丙基、 炔丁基、 甲基炔丁基、 取代或未取代的苯基、 或取代或未取代的苄基；
Figure imgf000030_0001
Among them, R 2 , R 3 , R 4 and R 5 are each independently selected from dream, hydroxyl, halogen, d-C 5 linear or branched alkyl group, C 2 - C 5 linear or branched unsaturated hydrocarbon group , or \ 0 Rl5 , or, R 2 , R 3 , R 4 and R 5 The two adjacent substituents together with the carbon atoms to which they are connected form a three-membered or more substituted or unsubstituted carbocyclic ring, or substituted or unsubstituted oxygen-containing heterocyclic ring; wherein R 15 is selected from C!-Cs linear or branched chain alkyl, allyl, propargyl, alkenyl, methylallyl, alkynyl butyl, methyl Alkynyl butyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;
X选自 0或 NH; X is selected from 0 or NH;
R6选自氢、 C「 C5直链或支链烷基、
Figure imgf000030_0002
其中 R 6 is selected from hydrogen, C "C 5 linear or branched alkyl,
Figure imgf000030_0002
in
118选自氢、 羟基、 硝基、 C广 C5直链或支链烷基、 或 - C5直链或支链烷 基氧基， 11 8 is selected from hydrogen, hydroxyl, nitro, C -C5 linear or branched alkyl group, or -C5 linear or branched alkyloxy group,
R9、 Rio, Rn 、 R12和 R13各自独立地选自 、 羟基、 卤素、 CrC5直链或支 链烷基、 C2- C5直链或支链不饱和烃基、 或 \。ZR15，或 R9、 RL。、 RLL、 R12和 R13 中相邻的两个取代基与它们相连的碳原子一起形成三元以上的取代的或未 取代的碳环、 或者取代的或未取代的含氧杂环； R 9 , Rio, Rn , R 12 and R 13 are each independently selected from, hydroxyl, halogen, CrC 5 linear or branched alkyl, C 2 -C 5 linear or branched unsaturated hydrocarbon group, or \. Z R15 , or R 9 , RL . , RLL , the two adjacent substituents in R 12 and R 13 together with the carbon atoms to which they are connected form a substituted or unsubstituted carbocyclic ring with three or more members, or a substituted or unsubstituted oxygen-containing heterocyclic ring;
R14选自 - C5直链或支链烷基； R 14 is selected from - C 5 linear or branched alkyl;
条件是 R3和 R4都是羟基， X是 0, R6是氢时， ^、 R2和 R5不能同时为氢。 The condition is that R 3 and R 4 are both hydroxyl groups, X is 0, and R 6 is hydrogen, R 2 and R 5 cannot be hydrogen at the same time.
2、 根据权利要求 1所述的化合^ 其特征在于： R3是羟基或^ \。/Rl5; 优选的， 113是羟基， R2或 R4是羟基或 ^\。/Rl5。 3、 根据权利要求 1所述的化合物， 其特征在于： E 、 R2、 R3、 R 。 R5中 相邻的两个取代基与它们相连的碳原子一起形成五元或六元取代的或未取 代的含氧杂环； R!、 R2、 R3、 R4和 R5中未成环的各自独立地选自氨、/ έ基、 卤 2. The compound according to claim 1, characterized in that: R3 is hydroxyl or R3. /Rl5 ; Preferably, 11 3 is hydroxyl, R 2 or R 4 is hydroxyl or ^\. /Rl5 . 3. The compound according to claim 1, characterized in that: E, R2 , R3 , R. The two adjacent substituents in R 5 together with the carbon atoms to which they are connected form a five- or six-membered substituted or unsubstituted oxygen-containing heterocycle; R!, R 2 , R 3 , R 4 and R 5 do not form Rings are each independently selected from hydrogen, /έ group, halogen
Ri5 素、 d- c5直链或支链饱和烷基、 c2- c5直链或支链不饱和烃基、 或^\0^ ； 优选的， 1 3和 、或 R4和 115与它们相连的碳原子一起形成五元或六元含 两个氧原子的取代或未取代的含氧杂环； Ri5 element, d- c5 linear or branched chain saturated alkyl group, c2 - c5 linear or branched chain unsaturated hydrocarbon group, or ^\ 0 ^; preferably, 1 3 and, or R 4 and 11 5 and Their connected carbon atoms together form a five- or six-membered substituted or unsubstituted oxygen-containing heterocycle containing two oxygen atoms;
更优选地， R3和 R4与它们相连的碳原子一起形成取代或未取代的 [1, More preferably, R 3 and R 4 together with the carbon atom to which they are attached form a substituted or unsubstituted [1,
3] - 二氧戊环。 3] - Dioxolane.
4、 根据权利要求 1至 3中任一项所述的化合物， 其特征在于： 所述碳 环、 含氧杂环、 [ ， 3] -二氧戊环的取代基选自羟基、 卤素、 羰基、 C「C5直链 或支链垸基、 或, \。 Rl5。 4. The compound according to any one of claims 1 to 3, characterized in that: the substituents of the carbocyclic ring, oxygen-containing heterocycle, [, 3]-dioxolane are selected from the group consisting of hydroxyl, halogen, and carbonyl. , C "C 5 straight chain or branched chain alkyl group, or, \. Rl5 .
5、 根据权利要求 1至 4中任一所述的化合物， 其特征在于： R8为氢或 羟基。 5. The compound according to any one of claims 1 to 4, characterized in that: R 8 is hydrogen or hydroxyl.
6、根据权利要求 1至 5中任一所述的化合物，其特征在于： R9、 R 。、 Ru、 R12和 R 各自独立也选自氢、 羟基、 C「C5直链或支链烷基、 C2- C5直链或支链 不饱和烃基、 或 ^\0^ ； . 6. The compound according to any one of claims 1 to 5, characterized in that: R 9 , R . , Ru, R 12 and R are each independently selected from hydrogen, hydroxyl, C C 5 linear or branched alkyl group, C 2 -C 5 linear or branched unsaturated hydrocarbon group, or ^\ 0 ^; .
优选的， 。和 Ru为羟基。 Preferably, . and Ru is hydroxyl.
7、 根据权利要求 1至 6中任一所述的化合物， 其特征在于： 所述 C「C5 直链或支链烷基选自曱基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 仲丁 基、 叔丁基、 戊基； 7. The compound according to any one of claims 1 to 6, characterized in that: the C[ C5 linear or branched alkyl group is selected from the group consisting of methyl group, ethyl group, n-propyl group, isopropyl group, and n-propyl group. Butyl, isobutyl, sec-butyl, tert-butyl, pentyl;
所述 C2-C5直链或支链不饱和烃基选自乙烯基、 烯丙基、 1-丙烯基、 异 丙烯基、 浠丁基、 烯戊基、 3-戊烯基、 乙炔基、 炔丙基、 2-丙炔基、 炔丁基、 炔戊基。 The C 2 -C 5 linear or branched unsaturated hydrocarbon group is selected from vinyl, allyl, 1-propenyl, isopropenyl, butyl, alkenyl, 3-pentenyl, ethynyl, Propargyl, 2-propynyl, butynyl, pentyl.
8、 根据权利要求 1所述的化合物， 其特征在于： 所述化合物选自： 3-曱氧基 -4， 5-二羟基苯乙酸， 8. The compound according to claim 1, characterized in that: the compound is selected from: 3-methoxy-4, 5-dihydroxyphenylacetic acid,
3-曱氧基 - 4， 5-二羟基苯乙酸曱酯， 3-Methoxy-4,5-dihydroxyphenylacetic acid methyl ester,
3， 4, 5-三羟基苯乙酸， 3, 4, 5-Trihydroxyphenylacetic acid,
3, 4, 5-三羟基苯乙酸甲酯， 3, 4, 5-Trihydroxyphenylacetic acid methyl ester,
3-苯曱氧基- 4, 5-二羟基苯乙酸曱酯， 3-Phenylmethoxy-4,5-dihydroxyphenylacetic acid methyl ester,
3- ( 2'-曱基丙氧基） -4， 5-二羟基苯乙酸， 3-甲氧基- 4-烯丙氧基苯乙酸甲酯， 3-(2'-methylpropoxy)-4,5-dihydroxyphenylacetic acid, Methyl 3-methoxy-4-allyloxyphenylacetate,
3-甲氧基- 4-羟基- 5-烯丙基苯乙酸甲酯， 3-Methoxy-4-hydroxy-5-allylphenylacetate methyl ester,
3-曱氧基- 4-羟基- 5-丙基苯乙酸甲酯， 3-Methoxy-4-hydroxy-5-propylphenylacetic acid methyl ester,
3， 4-二羟基 -5-丙基苯乙酸曱酯， 3. 4-Dihydroxy-5-propylphenylacetic acid methyl ester,
3, 4-二羟基 -5-丙基苯乙酸， 3, 4-dihydroxy-5-propylphenylacetic acid,
3-氯- 4-羟基- 5-曱氧基苯乙酸甲酯， 3-Chloro-4-hydroxy-5-methoxyphenylacetic acid methyl ester,
3-氯- 4, 5-二羟基苯乙酸， 3-Chloro-4,5-dihydroxyphenylacetic acid,
3-氯- 4， 5-二羟基苯乙酸曱酯， 3-Chloro-4,5-dihydroxyphenylacetic acid methyl ester,
3-溴- 4-羟基- 5-曱氧基苯乙酸甲酯， 3-Bromo-4-hydroxy-5-methoxyphenylacetic acid methyl ester,
3 -溴- 4， 5-二羟基苯乙酸， 3-bromo-4,5-dihydroxyphenylacetic acid,
3-溴 -4， 5-二羟基苯乙酸曱酯， 3-Bromo-4,5-dihydroxyphenylacetic acid methyl ester,
2, 3, 6-三氯- 4， 5-二羟基苯乙酸曱酯， 2, 3, 6-trichloro-4, 5-dihydroxyphenylacetic acid methyl ester,
2， 3， 6 -三氯 -4， 5-二羟基苯乙酸， 2,3,6-trichloro-4,5-dihydroxyphenylacetic acid,
3， 4-二羟基苯乙酸乙酯， 3. 4-Dihydroxyphenylacetic acid ethyl ester,
3， 4-亚甲二氧基苯乙酸， 3, 4-methylenedioxyphenylacetic acid,
3, 4-亚甲二氧基苯乙酸甲酯， 3, 4-Methylenedioxyphenylacetic acid methyl ester,
3-甲氧基 -4羟基苯乙酸， 3-Methoxy-4hydroxyphenylacetic acid,
3， 4-二羟基苯乙酸（3'，4'-二羟基）苯乙酯， 3, 4-Dihydroxyphenylacetic acid (3', 4'-dihydroxy) phenethyl ester,
N- ( 3', 4'-二羟基）苯乙基- ( 3, 4-二羟基）苯乙酸胺， N-(3', 4'-dihydroxy)phenylethyl-(3, 4-dihydroxy)phenylacetic acid amine,
N - 2-羟基苯乙基- ( 3, 4-二羟基） -苯乙酸胺， N-2-Hydroxyphenylethyl-(3,4-dihydroxy)-phenylacetic acid amine,
3, 4-二羟基苯乙酸曱氧基甲醇酯， 3, 4-dihydroxyphenylacetic acid methoxymethanol ester,
3-曱氧基 -4羟基苯乙酸曱酯， 3-Methoxy-4hydroxyphenylacetic acid methyl ester,
2-氧代苯并 [1, 3]二氧戊环- 5-乙酸， 2-Oxobenzo[1, 3]dioxolane-5-acetic acid,
3-羟基- 4-曱氧基苯乙酸曱酯， Methyl 3-hydroxy-4-methoxyphenylacetate,
3, 4-二羟基苯乙酸乙氧基曱醇酯， 3, 4-Dihydroxyphenylacetic acid ethoxymethanol ester,
2-乙氧基- 7-异丙氧基苯并 [ 1， 3]二氧戊环- 5-乙酸曱酯, 2-乙氧基- 7-羟基苯并 [ 1， 3]二氧戊环- 5-乙酸曱酯， 2-乙氧基 -7-苄氧基苯并 [1, 3]二氧戊环 -5-乙酸曱酯； 优选的， 所述化合物选自： 2-Ethoxy-7-isopropoxybenzo[1,3]dioxolane-5-methylacetate, 2-ethoxy-7-hydroxybenzo[1,3]dioxolane - Methyl 5-acetate, 2-ethoxy-7-benzyloxybenzo[1, 3]dioxolane-5-methyl acetate; Preferably, the compound is selected from:
3, 4, 5-三羟基苯乙酸曱酯， 3, 4, 5-Trihydroxyphenylacetic acid methyl ester,
3-曱氧基 -4, 5-二羟基苯乙酸曱酯， 3-Methoxy-4,5-dihydroxyphenylacetic acid methyl ester,
3- ( 2'-曱基丙氧基） -4, 5-二羟基苯乙酸， 3-(2'-methylpropoxy)-4,5-dihydroxyphenylacetic acid,
2， 3, 6-三氯 -4, 5-二羟基苯乙酸甲酯， 2,3,6-Trichloro-4,5-dihydroxyphenylacetic acid methyl ester,
3， 4-二羟基 -5-丙基苯乙酸曱酯， 3. 4-Dihydroxy-5-propylphenylacetic acid methyl ester,
2, 3， 6-三氯- 4， 5 -二羟基苯乙酸， 2, 3, 6-trichloro-4, 5-dihydroxyphenylacetic acid,
N-2-羟基苯乙基- ( 3, 4-二羟基） -苯乙酸胺， N-2-Hydroxyphenylethyl-(3,4-dihydroxy)-phenylacetic acid amine,
3, 4-二羟基苯乙酸曱氧基曱醇酯， 3, 4-dihydroxyphenylacetic acid methoxymethol ester,
3, 4-亚曱二氧基苯乙酸曱酯， 3,4-Methylmethanedioxyphenylacetate,
3 -曱氧基- 4， 5-二羟基苯乙酸， 3-methoxy-4,5-dihydroxyphenylacetic acid,
3, 4, 5-三羟基苯乙酸， 3, 4, 5-trihydroxyphenylacetic acid,
3， 4， 5-三羟基苯乙酸曱酯， 3, 4, 5-Trihydroxyphenylacetic acid methyl ester,
3, 4-二羟基革乙酸乙酯， 3, 4-Dihydroxyethylpyraacetate,
3， 4-二羟基苯乙酸（3'，4'-二羟基）苯乙酯， 3, 4-Dihydroxyphenylacetic acid (3', 4'-dihydroxy) phenethyl ester,
3, 4-二羟基苯乙酸乙氧基曱醇酯。 3, 4-Dihydroxyphenylacetic acid ethoxymethanol ester.
9、 权利要求 1至 8任一项所述的化合物或其药学上可以接受的盐、 多 晶形体、 对映体或外消旋体在制备抗肿瘤的药物中的用途； 9. Use of the compound according to any one of claims 1 to 8 or its pharmaceutically acceptable salt, polymorph, enantiomer or racemate in the preparation of anti-tumor drugs;
优选的， 所述肿瘤为实体瘤； Preferably, the tumor is a solid tumor;
更优选的， 所述肿瘤选自肺癌、 乳腺癌、 宫颈癌、横纹肌肉瘤、 鼻咽癌、 胰腺癌、 喉癌、 皮肤癌、 肝癌、 神经母细胞瘤、 腎母细胞瘤、 肠癌、 胃癌和 ' 上腺皮质瘤中的一种或多种； More preferably, the tumor is selected from the group consisting of lung cancer, breast cancer, cervical cancer, rhabdomyosarcoma, nasopharyngeal cancer, pancreatic cancer, laryngeal cancer, skin cancer, liver cancer, neuroblastoma, nephroblastoma, intestinal cancer, gastric cancer, and ' One or more types of adrenocortical tumors;
最优选的， 所述肿瘤选自肺癌、 乳腺癌、 宫颈癌、 肾母细胞瘤、鼻咽癌、 喉癌、 神经母细胞瘤、 肠癌和胃癌中的一种或多种。 Most preferably, the tumor is selected from one or more of lung cancer, breast cancer, cervical cancer, nephroblastoma, nasopharyngeal cancer, laryngeal cancer, neuroblastoma, intestinal cancer and gastric cancer.
10、 根据权利要求 9所述的用途， 其特征在于： 所述化合物通过抑制肿 瘤细胞增殖、 迁移， 和 /或诱导肿瘤细胞凋亡而产生抗肿瘤作用。 10. The use according to claim 9, characterized in that: the compound produces anti-tumor effects by inhibiting tumor cell proliferation and migration, and/or inducing tumor cell apoptosis.
11、 一种药物组合物， 包括权利要求 1至 8中任一项所述的化合物或其 药学上可以接受的盐、 多晶形体、 对映体或外消旋体。 11. A pharmaceutical composition comprising the compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt, polymorph, enantiomer or racemate thereof.
12、 根据权利要求 11所述的药物组合物， 其特征在于： 所述药物组合 物为临床上可接受的任一剂型， 包括经胃肠道给药制剂和非经胃肠道给药制 剂； 12. The pharmaceutical composition according to claim 11, characterized in that: the pharmaceutical combination The drug is in any clinically acceptable dosage form, including preparations for gastrointestinal administration and preparations for parenteral administration;
优选的， 所述经胃肠道给药制剂任选自散剂、 片剂、 颗粒剂、 胶嚢剂、 滴丸、 乳剂或混悬剂； Preferably, the preparation for gastrointestinal administration is selected from powders, tablets, granules, capsules, dropping pills, emulsions or suspensions;
优选的， 所述非经胃肠道给药制剂任选自注射剂、 吸入剂、 喷雾剂、 气 雾剂、 栓剂、 灌注剂、 贴剂或软膏剂。 Preferably, the parenteral preparation is selected from injections, inhalants, sprays, aerosols, suppositories, infusions, patches or ointments.
PCT/CN2014/000750 2013-08-05 2014-08-05 Phenylacetic acid derivative and antitumor use thereof WO2015018182A1 (en)

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