WO2023123695A1 - 二氯乙酸偶联二苯乙烷类化合物、其制备方法和应用 - Google Patents

二氯乙酸偶联二苯乙烷类化合物、其制备方法和应用 Download PDF

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WO2023123695A1
WO2023123695A1 PCT/CN2022/081328 CN2022081328W WO2023123695A1 WO 2023123695 A1 WO2023123695 A1 WO 2023123695A1 CN 2022081328 W CN2022081328 W CN 2022081328W WO 2023123695 A1 WO2023123695 A1 WO 2023123695A1
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compound
coupled
diphenylethane
dichloroacetic acid
tumor
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French (fr)
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吴范宏
黄金文
薛康燕
聂辉
刘福力
唐慧
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上海华理生物医药股份有限公司
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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
    • C07C69/62—Halogen-containing esters
    • C07C69/63—Halogen-containing esters of saturated acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton

Definitions

  • the invention belongs to the technical field of drug synthesis, and in particular relates to a dichloroacetic acid coupled diphenylethane compound and a preparation method and application thereof.
  • cancer is still the second leading cause of death in the world. Due to the shortcomings of traditional cancer treatment methods, targeted tumor drugs have become a research hotspot. Targeted tumor drugs use a single compound to act on two or more different biological targets to enhance the efficacy of tumor suppression while achieving high selectivity and low toxicity. However, the efficacy levels of tumor-targeting drugs are uneven, and some of them have strong specificity but the efficacy of tumor inhibition needs to be improved. It is usually necessary to modify an existing anti-tumor drug in order to obtain a drug with better activity. It is a high-risk project that costs hundreds of millions of dollars, takes ten years as the research and development cycle, and faces various eliminations such as drug efficacy and approval.
  • German chemist Warburg discovered that even under aerobic conditions, cancer cells still tend to carry out the aerobic glycolysis pathway rather than the oxidative phosphorylation pathway carried out by normal cells. This special phenomenon is called “Warburg effect”.
  • PDK pyruvate dehydrogenase kinase
  • DCA dichloroacetic acid
  • Sodium dichloroacetate is a small molecule compound that has been used for many years to treat lactic acidosis.
  • DCA can act on the energy metabolism pathway of tumor cells by inhibiting PDK, promote oxidative phosphorylation of tumor cells, induce apoptosis, and inhibit tumor growth.
  • PDK inhibitors containing dichloroacetic acid structure such as: VER-246608, 2-Chloro-N-(2-methylphenyl)propanamide, Mitaplatin, etc.
  • VER-246608 2-Chloro-N-(2-methylphenyl)propanamide
  • Mitaplatin etc.
  • problems in the clinical application of DCA For example, the efficacy of DCA is not high in clinical trials, and some patients who use the drug will experience symptoms such as pain and numbness.
  • DCA-derived drug candidates with high antitumor activity and low toxicity.
  • the technical problem to be solved by the present invention is to provide a new compound with anti-tumor activity and its preparation method and application.
  • Diphenylethane compounds such as erianin are tubulin-targeted drugs with good antitumor activity.
  • Dichloroacetic acid compounds have the activity of PDK inhibitors, but their efficacy is not high in clinical trials, and some patients may also produce pain, numbness or toxic side effects.
  • the structure of dichloroacetic acid was modified to improve anti-tumor activity and reduce side effects while maintaining its targeting effect.
  • the present invention finds that based on diphenylethane compounds such as erianin combined with dichloroacetic acid in a certain way, it has good antitumor activity and low toxicity. Therefore, the present invention combines natural product diphenylethane compounds with energy-targeting drug sodium dichloroacetate in order to obtain anti-tumor active compounds with multiple targets.
  • the present invention provides a kind of dichloroacetic acid coupling diphenylethane compound, its structure is as general formula (I):
  • R 1 , R 2 and R 3 are independently selected from any of -OH, -OMe, and H, R 4 is selected from any of -OMe, -OEt, R 5 and R 6 are selected from chlorine atoms or fluorine atoms , m is 0 or 1, n can be selected from 1, 2, 3, 4, 6, 7, 8, 11 or 12.
  • R 4 is selected from -OMe or -OEt.
  • the present invention also provides a pharmaceutical composition, the active ingredient of which is the above-mentioned dichloroacetic acid-coupled diphenylethane compound.
  • the pharmaceutical composition consists of an effective dose of the above-mentioned dichloroacetic acid-coupled diphenylethane compound and a pharmaceutically acceptable carrier.
  • its pharmaceutical preparation is selected from but not limited to the following dosage forms: freeze-dried powder, powder, injection, liposome, emulsion, microcapsule, suspension or solution administered in the form of intravenous injection; granules administered in the form of oral administration , tablet, capsule, or syrup; or suppository.
  • the pharmaceutical composition is a drug for inhibiting tumor cell proliferation, growth or damage, and eliminating tumor cells.
  • the pharmaceutical composition is suitable for humans or animals.
  • the animal is selected from but not limited to monkey, rat, mouse, rabbit, cat, dog, cow, horse, sheep or pig.
  • the present invention also provides a method for preparing the above-mentioned dichloroacetic acid-coupled diphenylethane derivatives.
  • the synthesis route is as follows:
  • the present invention provides the application of the dichloroacetic acid-coupled diphenylethane compound in the preparation of antitumor drugs.
  • the various tumors mainly include: lung cancer, non-small cell lung cancer, liver cancer, pancreatic cancer, gastric cancer, bone cancer, esophageal cancer, breast cancer, prostate cancer, testicular cancer, colon cancer, ovarian cancer, bladder cancer, cervical cancer Carcinoma, melanoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, cystic carcinoma, medullary carcinoma, bronchial carcinoma, bone cell carcinoma , epithelial carcinoma, cholangiocarcinoma, choriocarcinoma, embryonal carcinoma, seminoma, Wilms carcinoma, glioma, astrocytoma, medulloblastoma
  • the present invention relates to the therapeutic use of the dichloroacetic acid-coupled diphenylethane compounds.
  • Said indications include tumors (cancers) or diseases caused by abnormal cell proliferation.
  • the antineoplastic drug targets tumors or neoplasms derived from one or more of gastric cancer cells, lung cancer cells, cervical cancer cells, colon cancer cells, breast cancer cells or liver cancer cells.
  • the anti-tumor drugs include drugs or agents that relieve or inhibit tumor cell proliferation.
  • adding the dichloroacetic acid-coupled diphenylethane compound into the culture environment of tumor cells cultured in vitro can control the number of tumor cells.
  • the concentration range of the dichloroacetic acid-coupled diphenylethane compound in the cell culture medium is 0.1-10 ⁇ M (mol/L).
  • the invention also provides a reagent for inhibiting cell proliferation, which contains the dichloroacetic acid-coupled diphenylethane compound.
  • the cells are tumor cells cultured in vitro.
  • Erianin the English name is 2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)ethyl]benzolol, referred to as Erianin, the CAS number is 95041-90-0, and the chemical formula is C 18 H 22 O 5 .
  • Erianin is extracted from the whole plant of the orchid plant Dendrobium. It is a Chinese herbal medicine monomer with anti-tumor effect. Although there is still some controversy about its anti-tumor effect, it has good proliferation inhibition for certain tumor cells. The effect has been confirmed.
  • Sorafenib is a new multi-targeted oral drug for the treatment of tumors, especially for the treatment of gastrointestinal stromal tumors and metastatic renal cells that do not respond to or cannot tolerate standard therapy, and can selectively target Receptors to certain proteins are thought to act as a molecular switch during tumor growth. It has obtained the "fast track” approval granted by the FDA for the above indications in the United States, and it has been used as a commonly used anti-tumor drug in clinical practice in my country.
  • the drug for treating tumor contains effective dosage of dichloroacetic acid-coupled diphenylethane compound or dichloroacetic acid-coupled diphenylethane compound and a pharmaceutically acceptable carrier.
  • LD is the English abbreviation of lethal dose, which refers to the minimum dose required for a substance that can cause the death of an organism.
  • lethal dose refers to the minimum dose required for a substance that can cause the death of an organism.
  • the overall mortality rate of experimental subjects is different, usually divided into half-lethal dose, absolute lethal dose, minimum lethal dose and maximum tolerated dose.
  • the IC 50 used in the present invention is the half-inhibitory concentration (or called the half-inhibition rate), which refers to the concentration of the inhibitor when the "reaction" is half-inhibited.
  • the half-inhibition rate refers to the concentration of the inhibitor when the "reaction" is half-inhibited.
  • anti-tumor it can be understood as the concentration of the drug used when the number of tumor cells is halved.
  • terapéuticaally effective amount refers to the amount of dichloroacetic acid-coupled diphenylethane compound that is non-toxic but sufficient to achieve desired biological, therapeutic and/or preventive results. dose. The result may be reduction and/or alleviation of signs, symptoms or causes of disease, or any other desired alteration of a biological system.
  • an "effective dose” for therapeutic use is that required to produce a clinically significant improvement in disease as disclosed herein by itself or comprising the dichloroacetic acid-coupled diphenyl ethane compounds herein.
  • the amount of the composition of ethanes The appropriate effective dosage in any individual case can be determined by one of ordinary skill in the art using routine experimentation. Therefore, the effective dose of the dichloroacetic acid-coupled diphenylethane compound used in the present invention refers to the amount that can achieve the desired oral administration of the dichloroacetic acid-coupled diphenylethane compound.
  • “Pharmaceutically acceptable” means that a substance is not biologically or otherwise undesirable, that is, the substance can be administered to an individual without causing undesired biological interaction with any ingredient in the composition.
  • treatment and its grammatical synonyms include effecting a therapeutic effect and/or a prophylactic effect.
  • therapeutic effect is meant alleviation or eradication of the underlying condition being treated.
  • Therapeutic effect is also achieved by the eradication or alleviation of one or more physical symptoms associated with the underlying condition, whereby improvement is observed in the patient despite the fact that the patient may still be afflicted by the underlying condition.
  • the methods of the invention may be performed on patients clinically diagnosed with tumors, or who report one or more physiological symptoms of these states despite the fact that such states may not have been diagnosed, or on these A patient is administered a composition of the invention.
  • the term "pharmaceutically acceptable carrier” refers to a carrier used for treatment, ie administration, including various excipients and diluents.
  • the term refers to pharmaceutical carriers which are not themselves essential active ingredients and which do not have undue adverse effects upon administration.
  • Suitable carriers are well known to those skilled in the art, and pharmaceutically acceptable carriers in medicaments may include liquids, such as water, saline, glycerin and Tween.
  • auxiliary substances in these carriers such as disintegrants, wetting agents, emulsifiers, pH buffering substances and the like.
  • the medicine for treating tumor provided by the invention can be prepared into various dosage forms according to different administration routes. These dosage forms can be administered in one of the following ways: orally, topically (skin patches, subcutaneous implants), parenterally, eg subcutaneously and intramuscularly, or by means of an explanted reservoir. Among them, oral administration is preferred when treating tumors.
  • a safe and effective amount of dichloroacetic acid-coupled diphenylethane compounds is administered to large Rats, wherein the safe and effective amount is usually at least about 80 mg/kg body weight for tumor treatment, and in most cases no more than 100 mg/kg body weight, the preferred dosage is about 40-80 mg/kg body weight; of course, specific
  • the dose is taken as an example for humans, and factors such as the age, body weight, natural health status, nutritional status, activity intensity of the compound, administration, metabolic rate and other factors of the patient should also be considered.
  • dichloroacetic acid-coupled diphenylethane compound Before administration, the dichloroacetic acid-coupled diphenylethane compound can be mixed with sodium carboxymethylcellulose, physiological saline or any other suitable solution known to those skilled in the art.
  • the dichloroacetic acid-coupled diphenylethane formulations can be administered as solid (lyophilized) or liquid formulations as desired.
  • the present invention combines sodium dichloroacetate, a representative drug of energy-targeted PDK (phosphatidylinositol-dependent kinase) inhibitor, with a diphenylethane compound with VEGFR2 targeting.
  • PDK phosphatidylinositol-dependent kinase
  • the two benzene rings are connected by a single bond, which can greatly improve the stability of the drug, and at the same time reduce the toxicity. Analysis and separation, the process yield is significantly improved, the loss of raw materials is greatly reduced, the unit synthesis process cost is also greatly reduced, the stability of the drug is improved, and it does not need to be stored in the dark, which brings great convenience to storage and practical application.
  • the ethoxydiphenylethane compound of the present invention has obvious antitumor activity on various tumor cells cultured in vitro, and can reach or even surpass the antitumor effect of erianin or sonafenib.
  • the invention discloses a dichloroacetic acid-coupled diphenylethane compound with the structure shown in the general formula (I), a preparation method and application thereof.
  • the dichloroacetic acid coupled diphenylethane compound of the present invention is coupled with dichloroacetic acid at the 4' position of the B aromatic ring of diphenylethane, and simultaneously the 3, 4, and 5 positions of its A ring are respectively replaced by methoxy Substituted by radical, hydroxyl or fluorine atom; the 3' position of its B ring is substituted by methoxy, ethoxy, trifluoromethyl, difluoromethyl, difluoroethyl; the 4' position of its B ring is replaced by two The chlorine atoms of chloroacetic acid are replaced by fluorine atoms or bromine atoms.
  • dichloroacetic acid and diphenylethane were combined with amino acids of different chain lengths to obtain compounds with better antitumor activity.
  • the synthesis method is the same as 7a, and 3-methoxy-4-benzyloxybenzyl chloride triphenyl phosphonium salt is replaced by 3-benzyloxy-4-ethoxybenzyl chloride triphenyl phosphonium salt to obtain 526 mg of yellow oil 7b , yield 78.88%.
  • the synthesis method is the same as 7a, and 3-methoxy-4-benzyloxybenzyl chloride triphenyl phosphonium salt is used instead of 3-benzyloxy 4-methoxy-benzyl chloride triphenyl phosphonium salt to obtain 565 mg of yellow oil 7c , yield 83.83%.
  • the synthesis method was the same as that of 7a, except that 3-benzyloxybenzylchlorotriphenylphosphonium salt was used instead of 3-benzyloxy4-methoxy-benzylchlorotriphenylphosphonium salt to obtain 506 mg of yellow oil 7d with a yield of 73.12%.
  • the synthesis method was the same as that of 7a, except that 3-benzyloxy-4-methoxy-benzyl chloride triphenylphosphonium salt was replaced by 4-benzyloxybenzyl chloride triphenylphosphonium salt to obtain 513 mg of yellow oil 7e with a yield of 74.10%.
  • the synthesis method was the same as that of 7a, except that 3,4,5-trimethoxybenzaldehyde was replaced by 3,5-dimethoxybenzaldehyde to obtain 557 mg of yellow oil 7f with a yield of 80.45%.
  • the synthesis method was the same as that of 7a, except that 3,4,5-trimethoxybenzaldehyde was replaced by 3,4-dimethoxybenzaldehyde, and 571 mg was used to obtain 7 g of yellow oil, with a yield of 82.47%.
  • the synthesis method was the same as that of 7a, except that 3,4,5-trimethoxybenzaldehyde was replaced by 3-methoxybenzaldehyde to obtain 684 mg of yellow oil 7h, with a yield of 95.80%.
  • the synthesis method was the same as that of 7a, except that 3,4,5-trimethoxybenzaldehyde was replaced by 3-methoxybenzaldehyde to obtain 659 mg of yellow oil 7i with a yield of 92.20%.
  • the synthesis method was the same as that of compound 8a, and alanine methyl ester hydrochloride was replaced by glycine methyl ester hydrochloride to obtain 294 mg of compound 8b with a yield of 78.34%.
  • the synthesis method was the same as that of compound 8a, and ⁇ -aminobutyric acid methyl ester hydrochloride was replaced with glycine methyl ester hydrochloride to obtain 182 mg of compound 8c with a yield of 50.48%.
  • the synthesis method was the same as that of compound 8a, but aminocaproic acid methyl ester hydrochloride was replaced by glycine methyl ester hydrochloride to obtain 227 mg of compound 8d with a yield of 67.54%.
  • Embodiment 15.CCK-8 method tests the antitumor activity of the compound on various tumor cells
  • Cells in logarithmic growth phase were used for experiments.
  • the cells were digested, counted, and made into a cell suspension of 1 ⁇ 10 5 cells/mL, inoculated in a 96-well plate (100 ⁇ L/well), and placed in a 5% CO 2 incubator at 37°C for 24 hours; each well Add the test substance containing the corresponding concentration, and set up negative control group and blank group at the same time, each group has 3 multiple wells; after placing the plate in the incubator for 72 hours, observe the cell morphology of each group under the microscope, and add 10 ⁇ L of CCK8 solution to each well , continue to incubate for 4 hours in the cell incubator, and measure the absorbance value at 450 nm.
  • IC 50 value for Hela was 0.5160 ⁇ M/mL, which was much different from the IC 50 value of erianin at 8.3 ⁇ M/mL, which indicated that compound 7a introduced dichloroacetic acid on the basis of erianin, which greatly improved the compound’s ability to treat Hela. Inhibitory activity of HeLa cells.
  • compound 7a is more selective to HepG2 liver cancer cell lines, and its IC 50 value for HepG2 cells is 0.0489 ⁇ M/mL, compared with the IC 50 value of erianin 0.0728 ⁇ M/mL, The activity was nearly doubled.
  • Compound 8d has better inhibitory activity than erianin on human gastric cancer SGC7901 cell line and human breast cancer MCF-7 cell line. Its IC 50 value on Hela cells was 0.2883 ⁇ M/mL, while the IC 50 value of erianin was 0.0728 ⁇ M/mL. The inhibitory effect of compound 8d on Hela cells was also significantly better than that of erianin.
  • dichloroacetic acid-coupled diphenylethane compound of the present invention has strong anti-tumor activity, which is significantly better than the positive control Erianin, and has a good application and development prospect.
  • ICR mice SPF grade mice were used in the experiment, and the experimental animals were fasted overnight before gavage.
  • 20 animals (body weight 19-22 g, half male and half female) were poisoned at a dose of 5000 mg/kg ⁇ bw, and randomly divided into groups according to body weight.
  • the highest dose of the drug under test was 5000mg/kg, given by intragastric administration once, observed once at 0.5h, 1h, 2h, 4h, and 24h respectively, and recorded the mortality rate, and then observed once a day, recorded the mortality rate, and lasted for 154 days.
  • Surviving mice were sacrificed one day later, and pathological anatomy was performed.
  • the human liver cancer cell HepG2 xenograft tumor model was established by inoculating the human liver cancer cell line HepG2 subcutaneously in the axilla of nude mice. HepG2 cells in the logarithmic growth phase were inoculated subcutaneously in the right armpit of 55 nude mice under sterile conditions. Use a vernier caliper to measure the diameter of the transplanted tumor.
  • mice in each group that is, the model group, 7a low-dose group (50mg/kg), 7a middle dose group (100mg/kg), 7a high dose group (150mg/kg), sorafenib group (50mg/kg).
  • Animals in the model group were intragastrically administered with the same volume of solvent, once a day; 7a low-dose group, 7a middle-dose group, and 7a high-dose group were administered by intragastric administration once a day at 50 mg/kg, 100 mg/kg, and 150 mg/kg, respectively.
  • tumor inhibition rate (%) (tumor weight of model group-tumor weight of administration group)/tumor weight of model group ⁇ 100%.
  • the above compounds can significantly inhibit the growth of transplanted tumors in tumor-bearing nude mice.
  • the tumors in the low-dose group can be observed to shrink; on the 9th day in the middle-dose group, the tumors can be observed There is a trend of shrinking; in the high-dose group on the 7th day, it can be observed that the tumor has a trend of shrinking significantly.
  • Sorafenib is a multi-targeted antitumor oral drug widely used clinically at present, and the tumor inhibition rate of the compound of the present invention is better than Sorafenib, and has better safety (LD50>5000mg/ kg).

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Abstract

本发明属于药物合成技术领域，尤其是涉及二氯乙酸偶联二苯乙烷类化合物及其制备方法和应用。本发明的二氯乙酸偶联二苯乙烷类化合物结构如通式(I)所示，其中R1、R2和R3分别选自但不限于-OH、-OMe、H中的任意一种，R4选自但不限于-OMe、-OEt中的任意一种，R5和R6选自氯原子或氟原子，m为0或者1，n选自1-8或者11-12中的正整数。本发明的二氯乙酸偶联二苯乙烷类化合物结构稳定、毒性低，制备工艺简便、收率高，并且不需要避光保存，对多种体外培养的肿瘤细胞均有明显的抗肿瘤活性，体内抗肿瘤效果显著。通式(I)为：

Description

二氯乙酸偶联二苯乙烷类化合物、其制备方法和应用 技术领域
本发明属于药物合成技术领域，尤其是涉及二氯乙酸偶联二苯乙烷类化合物及其制备方法和应用。
背景技术
根据世卫组织提供数据显示，癌症仍然是世界上第二大死亡原因，由于传统癌症治疗手段的缺陷，靶向肿瘤药物成为研究的热点。靶向肿瘤药物即使用单一化合物作用于两或多个不同的生物靶点，以达到增强抑制肿瘤的效力的同时，做到高选择性与低毒性的特点。但是，靶向肿瘤药物的药效层次不齐，有一些虽然特异性强但是抑制肿瘤的效力有待提高，而在现有某个抗肿瘤药物基础上进行修饰以期获得活性更佳的药物，这通常是花费数亿资金、以十年为研发周期、面临药效和审批等各种淘汰的高风险项目。
1956年，德国化学家Warburg发现，即使在有氧条件下，癌细胞依旧倾向于进行有氧糖酵解途径，而不是正常细胞所进行的氧化磷酸化途径。这种特殊现象被称为“Warburg效应”。经研究表明，丙酮酸脱氢酶激酶(PDK)是糖酵解所必需物质，因此抑制该酶将逆转Warburg效应，而二氯乙酸(DCA)正是一种PDK的抑制剂。二氯乙酸钠是一种小分子化合物，多年来一直用于治疗乳酸酸中毒。近年来研究发现，DCA通过抑制PDK，能作用于肿瘤细胞能量代谢途径，促进肿瘤细胞氧化磷酸化、诱导凋亡，抑制肿瘤生长。通过不断研究，现已有几种含二氯乙酸结构的PDK抑制剂，如：VER-246608、2-Chloro-N-(2-methylphenyl)propanamide、Mitaplatin等。然而DCA的临床应用存在一些问题，例如DCA的药效在临床实验中不高，某些使用该药的患者会出现疼痛、麻木等症状，目前在我国还没有DCA合法药物出售。因此需要寻找新的具有高抗肿瘤活性、低毒性DCA衍生候选药物化合物。
发明内容
本发明要解决的技术问题提供一种新的具有抗肿瘤活性的化合物及其制备方法和应用。
二苯乙烷类化合物，如毛兰素是微管蛋白靶向药物，有较好的抗肿瘤活性。二氯乙酸类化合物具有PDK抑制剂的活性，但是其药效在临床实验中并不高，对部分患者还会产生疼痛、麻木或者的毒副作用。本研究对二氯乙酸进行结构修改，在保持其靶向作用的前提下提高抗肿瘤活性和降低毒副作用。前期的研究尝试使用很多其他化合物基团(包括天然产物)对二氯乙酸及其衍生物进行修饰或者改造，但是结果都不太理想，包括化合物不稳定、半衰期太短、溶解性不佳、毒性太强、抗肿瘤活性较差、代谢时间过长、制备成本太高、工艺条件太苛刻等问题。本发明发现，基于二苯乙烷类化合物如毛兰素等通过一定的方式与二氯乙酸结合具有很好的抗肿瘤活性和低毒性。因此，本发明通过天然产物二苯乙烷类化合物与能量靶向药物二氯乙酸钠拼合，以期得到具有多靶点的抗肿瘤活性化合物。
本发明提供一种二氯乙酸偶联二苯乙烷类化合物，其结构如通式(I)：
Figure PCTCN2022081328-appb-000001
其中，
R 1、R 2和R 3独立的选自-OH、-OMe、H中任一种，R 4选自-OMe、-OEt中任一种，R 5、R 6选自氯原子或氟原子，m为0或者1，n可选自1、2、3、4、6、7、8、11或者12。
可选的，R 4选自-OMe或者-OEt。
本发明还提供了一种药物组合物，所述的药物组合物的活性成分是上述二氯乙酸偶联二苯乙烷类化合物。
可选的，所述的药物组合物由有效剂量的上述的二氯乙酸偶联二苯乙烷类化合物和药学上可接受的载体组成。
可选的，其药物制剂选自但不限于以下剂型：静脉注射形式给药的冻干粉剂、粉剂、注射剂、脂质体、乳剂、微囊、悬浮液或溶液；口服形式给药的颗粒剂、片剂、胶囊或糖浆；或是栓剂。
可选的，所述的药物组合物是抑制肿瘤细胞增殖、生长或者损伤、消除肿瘤细胞的药物。
可选的，所述的药物组合物适用于人或者动物。所述的动物选自但不限于猴、大鼠、小 鼠、兔、猫、狗、牛、马、羊或者猪。
另一方面，本发明还提供了一种上述二氯乙酸偶联二苯乙烷衍生物的制备方法，当R 1、R 2和R 3中一个以上为-OH时，其合成路线如下：
Figure PCTCN2022081328-appb-000002
具体步骤如下：
(1)当R 1、R 2和R 3中一个以上为-OH时，首先将
Figure PCTCN2022081328-appb-000003
中的羟基用苄氯保护，获得相应的苄基保护产物；
(2)将苄基保护产物和三苯基磷叶立德
Figure PCTCN2022081328-appb-000004
进行wittig反应，得到苄基保护的二苯乙烯化合物；
(3)将苄基保护的二苯乙烯类化合物还原并脱保护，得到相应的二苯乙烷化合物；
(4)当二氯乙酸与二苯乙烷直接偶联时，将
Figure PCTCN2022081328-appb-000005
与相应的二苯乙烷类化合物缩合，得到一系列二氯乙酸偶联二苯乙烷类化合物。
上述制备方法中，R 1、R 2和R 3均不为-OH时，省略用苄氯保护的步骤，直接与
Figure PCTCN2022081328-appb-000006
发生wittig反应。
在上述制备方法中，当二氯乙酸与二苯乙烷以不同链长的氨基酸结合时，包括以下步骤：
(1)将不同链长的氨基酸
Figure PCTCN2022081328-appb-000007
(n＝1、2、3、4、6、7、8、11、12)通过二氯亚砜，制备为相应的氨基酸甲酯盐酸盐
Figure PCTCN2022081328-appb-000008
(n＝1、2、3、4、6、7、8、11、12)；
(2)将不同链长的氨基酸甲酯盐酸盐与
Figure PCTCN2022081328-appb-000009
缩合，得到化合物
Figure PCTCN2022081328-appb-000010
(n＝1、2、3、4、6、7、8、11、12)；
(3)将化合物
Figure PCTCN2022081328-appb-000011
水解脱甲基保护，得到相应的酸
Figure PCTCN2022081328-appb-000012
(n＝1、2、3、4、6、7、8、11、12)；
(4)将
Figure PCTCN2022081328-appb-000013
(n＝1、2、3、4、6、7、8、11、12)与相应的二苯乙烷类化合物缩合，得到一系列二氯乙酸偶联二苯乙烷类化合物。
再一方面，本发明提供了所述的二氯乙酸偶联二苯乙烷类化合物在制备抗肿瘤药物中的应用。所述各种肿瘤主要包括有：肺癌、非小细胞肺癌、肝癌、胰腺癌、胃癌、骨癌、食道 癌、乳房癌、前列腺癌、睾丸癌、结肠癌、卵巢癌、膀胧癌、子宫颈癌、黑色素瘤、鳞状细胞癌、基底细胞癌、腺癌、汗腺癌、皮脂腺癌、乳头状癌、乳头状腺癌、囊性腺癌、囊性癌、髓状癌、支气管癌、骨细胞癌、上皮癌、胆管癌、绒毛膜癌、胚癌、精原细胞癌、维尔姆斯癌、胶质细胞癌、星形细胞瘤、成神经管细胞瘤、颅咽管瘤、室管膜瘤、松果体瘤、成血细胞瘤、声带神经瘤、脑膜瘤、成神经细胞瘤、成视神经细胞瘤、成视网膜细胞瘤、神经纤维瘤、纤维肉瘤、成纤维细胞瘤、纤维瘤、纤维腺瘤、纤维软骨瘤、纤维囊瘤、纤维粘液瘤、纤维骨瘤、纤维粘液肉瘤、纤维乳头状瘤、粘液肉瘤、粘液囊瘤、粘液软骨瘤、粘液软骨肉瘤、粘液软骨纤维肉瘤、粘液腺瘤、成粘液细胞瘤、脂肉瘤、脂肪瘤、脂肪腺瘤、成脂细胞瘤、脂肪软骨瘤、脂肪纤维瘤、脂肪血管瘤、粘液脂瘤、软骨肉瘤、软骨瘤、软骨肌瘤、脊索瘤、绒毛膜腺瘤、绒毛上皮瘤、成绒毛膜细胞瘤、骨肉瘤、成骨细胞瘤、骨软骨纤维瘤、骨软骨肉瘤、骨软骨瘤、骨囊瘤、骨牙质瘤、骨纤维瘤、骨纤维肉瘤、血管肉瘤、血管瘤、血管脂肪瘤、血管软骨瘤、成血管细胞瘤、血管角质瘤、血管神经胶质瘤、血管内皮瘤、血管纤维瘤、血管肌瘤、血管脂肪瘤、血管淋巴管瘤、血管脂肪平滑肌瘤、血管肌脂瘤、血管肌神经瘤、血管粘液瘤、血管网状内皮瘤、淋巴管肉瘤、淋巴肉芽瘤、淋巴管瘤、淋巴瘤、淋巴粘液瘤、淋巴肉瘤、淋巴管纤维瘤、淋巴细胞瘤、淋巴上皮瘤、成淋巴细胞瘤、内皮瘤、成内皮细胞瘤、滑膜瘤、滑膜肉瘤、间皮瘤、结缔组织瘤、尤因瘤、平滑肌瘤、平滑肌肉瘤、成平滑肌瘤、平滑肌纤维瘤、横纹肌瘤、横纹肌肉瘤、横纹肌粘液瘤、急性淋巴白血病、急性骨髓性白血病、慢性病细胞、红细胞增多症、淋巴瘤、多发性骨髓瘤。
本发明涉及所述二氯乙酸偶联二苯乙烷类化合物的治疗用途。所述的适应症包括肿瘤(癌症)或者由于细胞增殖异常导致的疾病。
可选的，所述的抗肿瘤药针对源自胃癌细胞、肺癌细胞、宫颈癌细胞、肠癌细胞、乳腺癌细胞或者肝癌细胞中的一种或者几种产生的肿瘤或者赘生物。
可选的，所述的抗肿瘤药物包括缓解或者抑制肿瘤细胞增殖的药物或者试剂。
可选的，所述的二氯乙酸偶联二苯乙烷类化合物加入体外培养的肿瘤细胞的培养环境中，可以控制肿瘤细胞的数量。
可选的，所述的二氯乙酸偶联二苯乙烷类化合物在细胞培养基中的浓度范围是0.1-10μM(摩尔/升)。
本发明还提供了一种抑制细胞增殖的试剂，含有所述的二氯乙酸偶联二苯乙烷类化合物。可选的，所述的细胞是体外培养的肿瘤细胞。
实验结果表明，本发明的二氯乙酸偶联二苯乙烷类化合物具有与毛兰素或者索拉非尼相当或者更好的抗肿瘤活性。
毛兰素，英文名为2-Methoxy-5-[2-(3,4,5-trimethoxyphenyl)ethyl]benzolol，简称为Erianin，CAS号为95041-90-0，化学式C 18H 22O 5。毛兰素提取自兰科植物石斛Dendrobium的全株，是一种具有抗肿瘤作用的中草药单体，虽然对于其抗肿瘤效果还有一定争议，但是其对于某些肿瘤细胞具有较好的增殖抑制效果已经得到证实。
索拉非尼是一种新型多靶向性的治疗肿瘤的口服药物，尤其可以用于治疗对标准疗法没有响应或不能耐受之胃肠道基质肿瘤和转移性肾细胞，能选择性地靶向某些蛋白的受体，被认为在肿瘤生长过程中起着一种分子开关的作用。它在美国已经获得了FDA授予的上述适应证的“快通道”审批，在我国已经作为临床上常用抗肿瘤药物。
本发明提供的治疗肿瘤药物中含有有效剂量的二氯乙酸偶联二苯乙烷类化合物或者二氯乙酸偶联二苯乙烷类化合物和药学上可接受的载体。
本发明中LD是lethal dose的英文缩写，指能使生物体死亡的物质所需的最少剂量。根据药物的不同用量，实验受试总体死亡率各不相同，通常可分半致死剂量、绝对致死剂量、最小致死剂量和最大耐受剂量等不同给药量。
本发明中使用的IC 50是半抑制浓度(或称半数抑制率)，是指“反应”被抑制一半时抑制剂的浓度。在抗肿瘤方面，可以理解为肿瘤细胞数量减半时所使用的药物的浓度。
本发明中使用的“治疗有效量”或“有效剂量”指的是无毒的但足以达到希望的生物学、治疗的和/或预防的结果的二氯乙酸偶联二苯乙烷类化合物的剂量。该结果可以是疾病的征兆、症状或诱因的减少和/或减轻，或者任何其他希望的生物系统的改变。例如，用于治疗用途的“有效剂量”是产生临床上疾病的显著改善所需的如这里所公开的二氯乙酸偶联二苯乙烷类化合物本身或包含这里的二氯乙酸偶联二苯乙烷类化合物的组合物的量。在任何个别情况中的合适的有效剂量可以由本领域普通技术人员使用常规的试验确定。因此，本发明中使用的二氯乙酸偶联二苯乙烷类化合物的有效剂量指能够达到希望的二氯乙酸偶联二苯乙烷类化合物口服使用的量。
“药学上可接受的”意思是一种物质在生物学上或其他方面不是不合需要的，即该物质可以施用于个体而不引起不希望的生物学效应或不以有害的方式与包含该物质的组合物中的任何成分发生相互作用。
术语“治疗”及其语法上的同义词包括实现治疗效果和/或预防效果。治疗效果意思是进 行治疗的基础病症的缓解或根除。治疗效果还通过一种或多种与基础病症相关的生理症状的根除或缓解而获得，从而在患者中观察到改善，尽管事实是患者可能仍受到基础病症的折磨。对于预防效果，可用于临床诊断为肿瘤的患者身上，或者尽管可能还没有诊断出这一状态，但报告有这些状态的一种或多种生理学症状的患者身上实行本发明的方法，或者对这些患者施用本发明的组合物。
如本文所用，术语“药学上可接受的载体”指用于治疗即给药的载体，包括各种赋形剂和稀释剂。该术语指这样一些药剂载体：它们本身并不是必要的活性成分，且施用后没有过分的副作用。合适的载体是指本领域普通技术人员所熟知的，在药物中药学上可接受的载体可包括液体，如水、盐水、甘油和吐温。另外，这些载体中还可能存在辅助性的物质，如崩解剂、润湿剂、乳化剂、pH缓冲物质等。
本发明提供的治疗肿瘤的药物可以根据不同给药途径而制备成各种剂型。这些剂型可以下面方式之一施用：口服、局部用药(皮肤贴剂、皮下埋植剂)、非肠道用药，如皮下和肌肉，或借助一种外植储器用药。其中治疗肿瘤时优选口服的给药方式。
在本发明中，本发明的二氯乙酸偶联二苯乙烷类化合物在用于治疗用途或者作为药物使用时，是将安全有效量的二氯乙酸偶联二苯乙烷类化合物施用于大鼠，其中该安全有效量治疗肿瘤时通常至少约80毫克/千克体重，而且在大多数情况下不超过100毫克/千克体重，较佳的剂量是约40-80毫克/千克体重；当然，具体剂量以人为例，还要考虑患者的年龄、体重、自然健康状况、营养状况、化合物活性强度、服用、代谢速率等因素，这些都是本领域技术人员技能范围之内的知识与技能，此不赘述。
在给药前，二氯乙酸偶联二苯乙烷类化合物可与羧甲基纤维素钠、生理盐水或为本领域的熟练人员所熟知的任何其他适合的溶液混合。二氯乙酸偶联二苯乙烷类化合物制剂可如需求的那样以固体(冷冻干燥)或液体制剂形式给药。
本发明将能量靶向PDK(磷脂酰肌醇依赖性激酶)抑制剂的代表药物二氯乙酸钠，与具有VEGFR2靶向的二苯乙烷类化合物进行拼合。本发明的乙氧基二苯乙烷类化合物中，两个苯环是通过单键连接能够极大的提高了药物的稳定性，同时能降低毒性，其制备工艺更加简便，不需要通过柱层析分离，工艺收率明显提高，原料损耗大大降低，单位合成工艺成本也大大降低，提高了药物的稳定性，不需要避光保存，使保存和实际应用中带来了很大方便。本发明的乙氧基二苯乙烷类化合物对多种体外培养的肿瘤细胞均有明显的抗肿瘤活性，能够达到 甚至超越毛兰素或者索那菲尼的抗肿瘤效果。
具体实例方式
本发明公开了一种结构如通式(I)所示的二氯乙酸偶联二苯乙烷类化合物及其制备方法和应用。本发明的二氯乙酸偶联二苯乙烷类化合物在二苯乙烷的B芳环的4’位与二氯乙酸偶联，同时将其A环的3、4、5位分别由甲氧基、羟基或氟原子取代；将其B环的3’位由甲氧基、乙氧基、三氟甲基、二氟甲基、二氟乙基取代；将其B环4’位上二氯乙酸的氯原子由氟原子或溴原子取代。另外，将二氯乙酸与二苯乙烷以不同链长的氨基酸结合，得到了抗肿瘤活性较好的化合物。
下面结合优选例进一步说明本发明的技术方案。
实施例1. 2-甲氧基-5-(3,4,5-三甲氧基苯乙基)苯基2,2-二氯乙酸酯(简称为7a)的制备
Figure PCTCN2022081328-appb-000014
在氮气保护下，在装有温度计并干燥过的100mL三口烧瓶中，加入3-苄氧基-4-甲氧基苄氯三苯基磷盐10g(19.05mmol),加入50mL的无水四氢呋喃，放入冰盐浴，待温度冷却到0℃后，缓慢加入叔丁醇钾3.22g(28.57mmol)，持续搅拌30min。然后在缓慢滴加3,4,5-三甲氧基苯甲醛的四氢呋喃溶液(10mL)，约20min滴加完毕，然后将反应装置自然缓慢升温至室温，继续反应4小时。关闭反应装置，旋蒸除去四氢呋喃，加入60mL水，100mL乙酸乙酯，萃取分出乙酸乙酯层，水层用乙酸乙酯60mL×2萃取；合并乙酸乙酯层，无水硫酸钠干燥。减压蒸馏去除溶剂得到黄色固体，经快速柱层析分离，得到5.89g顺反式产物。然后将其与钯碳混合，加入乙醇24mL，氢气置换三次，反应搅拌6h。用硅藻土抽滤钯碳，经快速纸层析分离，得到3.21g产物5a。取500mg毛兰素，加入干燥二氯甲烷8mL、三乙胺0.327mL后冰盐浴搅拌10min。然后缓慢滴加二氯乙酰氯0.166mL，继续反应1.5小时。反应完毕后加20mL水淬灭，二氯甲烷40mL，萃取分出有机相，水层用二氯甲烷20×2萃取。合并有机相，无水 硫酸钠干燥，减压蒸馏得到黄色油状物，经快速纸层析分离，得到586mg白色固体，产率为86.91％。
1H NMR(400MHz,CDCl 3)δ7.01(d,J＝8.3Hz,1H),6.93(s,1H),6.89(d,J＝8.4Hz,1H),6.33(s,2H),6.19(s,1H),3.81(d,J＝5.0Hz,12H),2.84(s,4H)； 13C NMR(101MHz,CDCl 3)δ162.68,153.15,149.04,138.93,137.10,136.35,134.54,127.77,121.99,112.72,105.53,77.33,64.09,60.92,56.19,56.12,38.26,36.98。
上述结果表明，该方法成功制备了2-甲氧基-5-(3,4,5-三甲氧基苯乙基)苯基2,2-二氯乙酸酯。
实施例2. 2-乙氧基-5-(3,4,5-三甲氧基苯乙基)苯基2,2-二氯乙酸酯(7b)的制备
Figure PCTCN2022081328-appb-000015
合成方法同7a，用3-苄氧基-4-乙氧基苄氯三苯基磷盐代替3-甲氧基-4-苄氧基苄氯三苯基磷盐，得到526mg黄色油状物7b，产率78.88％。
1H NMR(400MHz,CDCl 3)δ6.98(dd,J＝8.3,1.8Hz,1H),6.92(d,J＝1.8Hz,1H),6.88(d,J＝8.3Hz,1H),6.33(s,2H),6.19(s,1H),4.03(q,J＝7.0Hz,2H),3.82(d,J＝5.3Hz,9H),2.84(s,4H),1.37(t,J＝7.0Hz,3H)； 13C NMR(101MHz,CDCl 3)δ162.69,153.11,148.35,137.23,134.41,127.71,121.92,113.71,105.58,64.77,64.08,60.95,56.14,38.25,37.00。
实施例3. 2-甲氧基-4-(3,4,5-三甲氧基苯乙基)苯基2,2-二氯乙酸酯(7c)的制备
Figure PCTCN2022081328-appb-000016
合成方法同7a，用3-甲氧基-4-苄氧基苄氯三苯基磷盐代替3-苄氧基4-甲氧基-苄氯三苯基磷盐，得到565mg黄色油状物7c，产率83.83％。
1H NMR(400MHz,CDCl 3)δ7.07(d,J＝7.5Hz,1H),6.75(dd,J＝7.5,1.4Hz,1H),6.71(t,J＝1.2Hz,1H),6.47(s,2H),6.27(s,1H),3.89(s,2H),3.83(s,6H),,2.84(s,4H)； 13C NMR(101MHz,CDCl 3)δ165.17,153.21,153.19,150.72,150.72,150.67,150.66,141.99,141.97,141.94,141.92,136.80,136.75,136.71,136.31,135.64,135.59,122.06,122.04,122.02,122.00,121.98,121.26,121.20,121.18,121.15,113.50,113.48,113.46,113.44,113.41,105.94,105.92,105.89,105.87,105.84,63.17,60.79,56.12,56.05,37.64,37.62,37.61,37.59,37.55,37.02,36.99,36.96,36.94。
实施例4. 3-(3,4,5-三甲氧基苯乙基)苯基2,2-二氯乙酸酯(7d)的制备
Figure PCTCN2022081328-appb-000017
合成方法同7a，用3-苄氧基苄氯三苯基磷盐代替3-苄氧基4-甲氧基-苄氯三苯基磷盐，得到506mg黄色油状物7d，产率73.12％。
1H NMR(400MHz,CDCl 3)δ7.15(dt,J＝7.4,1.0Hz,1H),7.09–7.03(m,1H),6.48(d,J＝1.1Hz,1H),3.82(d,J＝2.7Hz,4H),2.89(m,2H)； 13C NMR(101MHz,CDCl 3)δ163.64,153.10,150.70,150.68,150.64,150.62,136.71,136.38,136.36,134.59,134.56,134.53,130.44,130.41,130.38,121.74,121.73,121.72,121.71,106.55,106.52,63.07,60.80,56.12,38.09,38.06,38.04,37.66,37.63,37.62,37.60。
实施例5. 4-(3,4,5-三甲氧基苯乙基)苯基2,2-二氯乙酸酯(7e)的制备
Figure PCTCN2022081328-appb-000018
合成方法同7a，用4-苄氧基苄氯三苯基磷盐代替3-苄氧基4-甲氧基-苄氯三苯基磷盐，得到513mg黄色油状物7e，产率74.10％。
1H NMR(400MHz,CDCl 3)δ7.15(dt,J＝7.4,1.0Hz,1H),7.09–7.03(m,1H),6.48(d,J＝1.0Hz,1H),3.82(d,J＝2.0Hz,4H),2.89(m,2H)； 13C NMR(101MHz,CDCl 3)δ163.64,153.11,153.09,150.70,150.68,150.64,150.62,136.76,136.71,136.66,136.37,134.56,130.45,130.42,130.40,130.39,130.37,121.77,121.76,121.75,121.74,121.71,121.70,121.69,121.68,106.59,106.56,106.54,106.51,106.49,63.07,60.80,56.12,38.09,38.07,38.06,38.03,37.65,37.63,37.60。
实施例6. 5-(3,5-二甲氧基苯乙基)-2-甲氧基苯基2,2-二氯乙酸酯(7f)的制备
Figure PCTCN2022081328-appb-000019
合成方法同7a，用3,5-二甲氧基苯甲醛代替3,4,5-三甲氧基苯甲醛，得到557mg黄色油状物7f，产率80.45％。
1H NMR(400MHz,CDCl 3)δ6.92(m,1H),6.38(m,1H),3.88(s,1H),3.77(s,2H),2.91(m,2H)； 13C NMR(101MHz,CDCl 3)δ163.83,160.88(dd,J＝2.7,1.4Hz),149.52(dd,J＝7.1,2.6Hz),143.73(ddd,J＝5.0,3.7,1.8Hz),141.13(dd,J＝7.2,1.0Hz),134.52(dt,J＝7.4,1.7Hz),123.20(dddt,J＝9.0,6.3,3.2,1.4Hz),120.37(ddd,J＝6.5,3.6,1.4Hz),112.56(tt,J＝7.4,2.5Hz),107.29(dt,J＝6.0,2.9Hz),98.06(td,J＝5.9,2.4Hz),63.17,56.00,55.31,37.41(ddd,J＝10.3,4.6,2.3Hz)。
实施例7. 5-(3,4-二甲氧基苯乙基)-2-甲氧基苯基2,2-二氯乙酸酯(7g)
Figure PCTCN2022081328-appb-000020
合成方法同7a，用3,4-二甲氧基苯甲醛代替3,4,5-三甲氧基苯甲醛，571mg得到黄色油状物7g，产率82.47％。
1H NMR(400MHz,CDCl 3)δ6.92(m,4H),6.81(m,4H),6.27(s,1H),3.88(s,3H),3.83(d,J＝1.3Hz,8H),2.85(d,J＝1.5Hz,5H)； 13C NMR(101MHz,CDCl 3)δ163.83,149.75,149.73,149.69,149.54,149.51,147.86,147.84,141.50,141.43,135.16,134.64,134.58,123.24,123.22,123.20,123.18,121.50,121.48,121.45,120.41,120.40,120.38,120.36,120.35,120.32,112.62,112.50,112.10,63.17,56.00,55.91,55.88,37.76,37.69,37.30。
实施例8. 2-甲氧基-5-(3-甲氧基苯乙基)苯基2,2-二氯乙酸酯(7h)的制备
Figure PCTCN2022081328-appb-000021
合成方法同7a，用3-甲氧基苯甲醛代替3,4,5-三甲氧基苯甲醛，得到684mg黄色油状物7h，产率95.80％。
1H NMR(400MHz,CDCl 3)δ7.23(m,1H),6.92(m,1H),6.90(m,2H),6.79(m,3H),6.27(s,1H),3.87(s,2H),3.78(s,2H),2.89(m,4H)； 13C NMR(101MHz,CDCl 3)δ163.86,159.73,159.68,159.66,149.67,149.65,143.39,143.37,143.36,143.35,143.34,141.97 134.64,134.62,134.58,129.43,129.40,129.36,129.35,129.34,123.66,123.58,120.48,120.47,120.39,115.09,115.06,115.04,115.02,114.98,114.46,114.34,113.97,113.83,112.53,112.49,112.48,112.45,63.17,56.00,36.78, 36.32。
实施例9. 2-甲氧基-5-(4-甲氧基苯乙基)苯基2,2-二氯乙酸酯(7i)的制备
Figure PCTCN2022081328-appb-000022
合成方法同7a，用3-甲氧基苯甲醛代替3,4,5-三甲氧基苯甲醛，得到659mg黄色油状物7i，产率92.20％。
1H NMR(400MHz,CDCl 3)δ7.23(m,1H),6.91(m,1H),6.89(m,2H)6.80(m,3H),6.28(s,1H),3.87(s,2H),3.79(s,2H),2.83(s,4H)； 13C NMR(101MHz,CDCl 3)δ163.86,158.96,158.88,149.65,149.59,141.97,141.96,134.64,134.45,130.84,130.78,,123.69,123.60,123.58,120.07,120.04,119.98,113.87,112.53,112.48,112.46,112.42,63.17,56.00,55.32,37.46,37.44,37.35,37.28,,37.21。
实施例10. 2-甲氧基-5-(3,4,5-三甲氧基苯乙基)苯基3-(2,2-二氯乙酰胺)乙酸酯(8a)的制备
Figure PCTCN2022081328-appb-000023
将甘氨酸甲酯盐酸盐3g(23.89mmol)，加入干燥二氯甲烷80mL与三乙胺8.3mL(59.74mmol)，冰盐浴搅拌15min。缓慢滴加二氯乙酰氯，继续反应搅拌1.5小时。反应完毕后加20mL水淬灭，二氯甲烷40mL，萃取分出有机相，水层用二氯甲烷20×2萃取。合并有机相，无水硫酸钠干燥，减压蒸馏得到黄色油状物，经快速纸层析分离，得到3.98g化合物11a。将3g(15mmol)化合物11a加入30mL甲醇：水＝4：1，再加入氢氧化锂 718mg(30mmol)，反应6小时。反应完毕后减压蒸馏去除溶剂，加40mL水，用2M盐酸调PH至3-4，再加入90mL乙酸乙酯，萃取分出有机相，水层用乙酸乙酯60×2萃取。合并有机相，无水硫酸钠干燥，减压蒸馏得到黄色油状物，经快速纸层析分离，得到1.6g化合物6a。将150mg(0.806mmol)化合物6a加入3ml干燥二氯甲烷，加入368mg(0.967mmol)HATU，冰盐浴搅拌10min后加入0.199mL(1.21mmol)DIPEA，搅拌反应15mim后加入257mg毛兰素，反应3小时后，滤去白色固体，经快速柱层析分离，得到254mg化合物8a，产率为64.79％。
1H NMR(400MHz,CDCl 3)δ7.00(d,J＝8.4Hz,1H),6.89(d,J＝8.6Hz,2H),6.34(s,2H),6.02(s,1H),4.39(d,J＝5.2Hz,2H),3.81(d,J＝4.5Hz,12H),2.84(s,4H)； 13C NMR(101MHz,CDCl 3)δ167.30,164.41,153.09,149.00,138.89,137.23,136.16,134.47,127.33,122.55,112.40,105.43,66.00,60.93,56.10,56.06,41.84,38.29,36.99。
实施例11. 2-甲氧基-5-(3,4,5-三甲氧基苯乙基)苯基3-(2,2-二氯乙酰胺)丙酸酯(8b)的制备
Figure PCTCN2022081328-appb-000024
合成方法同化合物8a，将丙氨酸甲酯盐酸盐替换甘氨酸甲酯盐酸盐，得到294mg化合物8b，产率为78.34％。
1H NMR(400MHz,CDCl 3)δ6.99(dd,J＝8.4,2.2Hz,1H),6.88(d,J＝8.4Hz,1H),6.84(d,J＝2.1Hz,1H),6.34(s,2H),6.01(s,1H),3.84–3.77(m,12H),3.69(q,J＝6.1Hz,2H),2.83(s,6H)； 13C NMR(101MHz,CDCl 3)δ170.16,164.42,153.06,149.05,139.18,137.30,136.13,134.40,126.99,122.75,112.35,105.55,66.49,60.86,56.07,38.20,36.93,36.03,33.45。
实施例12. 2-甲氧基-5-(3,4,5-三甲氧基苯乙基)苯基4-(2,2-二氯乙酰胺)丁酸酯(8c)的制备
Figure PCTCN2022081328-appb-000025
合成方法同化合物8a，将γ-氨基丁酸甲酯盐酸盐替换甘氨酸甲酯盐酸盐，得到182mg化合物8c，产率为50.48％。
1H NMR(400MHz,CDCl 3)δ7.46(t,J＝7.1Hz,1H),6.94–6.88(m,1H),6.92–6.83(m,2H),6.51(t,J＝0.9Hz,2H),6.28(s,1H),3.87(s,2H),3.82(d,J＝5.7Hz,9H),3.26(q,J＝7.2Hz,2H),2.87–2.79(m,4H),2.43(t,J＝7.1Hz,2H),1.78(p,J＝7.1Hz,2H)； 13C NMR(400MHz,CDCl 3)δ171.52,,168.36,153.29,149.60,140.73,136.79,134.51,134.48,123.48,123.41,120.76,112.50,105.89,60.75,56.13,40.17,36.63,32.44,32.41,24.90,24.81。
实施例13. 2-甲氧基-5-(3,4,5-三甲氧基苯乙基)苯基6-(2,2-二氯乙酰胺)己酸酯(8d)的制备
Figure PCTCN2022081328-appb-000026
合成方法同化合物8a，将氨基己酸甲酯盐酸盐替换甘氨酸甲酯盐酸盐，得到227mg化合物8d，产率为67.54％。
1H NMR(400MHz,CDCl 3)δ6.97(dd,J＝8.3,2.1Hz,1H),6.90–6.81(m,3H),6.35(s,2H),5.95(s,1H),3.83–3.78(m,12H),3.34(q,J＝6.7Hz,2H),2.83(s,4H),2.58(t,J＝7.3Hz,2H),1.78(p,J＝7.4Hz,2H),1.63(p,J＝7.2Hz,2H),1.47(tt,J＝9.6,5.9Hz,2H)； 13C NMR(101MHz,CDCl 3)δ171.76,164.31,153.05,149.32,139.51,137.46,134.32,126.74,122.86,112.35,105.43,66.61,60.93,56.08,56.05,40.19,38.31,37.02,33.79,28.74,26.10,24.51。
实施例14.对肿瘤细胞增殖的体外抑制活性
取对数生长期细胞进行实验。细胞经消化、计数、制成1×10 5个/mL的细胞悬液，接种于96孔板中(100μL/孔)，置于37℃，5％CO 2培养箱中培养24小时；每孔加入含相应浓度的受试物，同时设立阴性对照组及空白组，每组3复孔；将板置于培养箱中培养72h后，显微镜下观察各组细胞形态，每孔加入10μL的CCK8溶液，在细胞培养箱内继续孵育4小时，450nm下测定吸光值，并计算细胞增殖抑制率，P<0.05为有统计学意义。其结果如表1所示。
2.实验结果
实验表明，化合物7a与8d对HepG2细胞有着良好的抑制活性，其中，化合物7b的HepG2抑制率优于毛兰素。
表1：部分实施实例化合物对HepG2细胞株的体外活性评价
Figure PCTCN2022081328-appb-000027
其中， *P<0.05, **p<0.01。
实施例15.CCK-8法测试化合物对多种肿瘤细胞的抗肿瘤活性
1.试验方法
取对数生长期细胞进行实验。细胞经消化、计数、制成1×10 5个/mL的细胞悬液，接种于96孔板中(100μL/孔)，置于37℃，5％CO 2培养箱中培养24小时；每孔加入含相应浓度的受试物，同时设立阴性对照组及空白组，每组3复孔；将板置于培养箱中培养72h后，显微镜下观察各组细胞形态，每孔加入10μL的CCK8溶液，在细胞培养箱内继续孵育4小时，450nm下测定吸光值。实验取8个浓度梯度，测试其相应浓度的抑制率。数据应用GraphPad Prism 5.0统计软件，两组组间比较采用t-test检验，多组间比较采用One-way Anova(Dunnett)，P<0.05为有统计学意义，并计算IC 50值。其结果如表2所示。
2.实验结果
表2：部分实施实例化合物对多种肿瘤细胞株的体外活性评价
Figure PCTCN2022081328-appb-000028
以上体外培养肿瘤细胞的抗肿瘤活性评价的结果表明，二氯乙酸偶联二苯乙烷类化合物对人胃癌SGC7901细胞株、人肺腺癌A549细胞株、人宫颈癌Hela细胞株、人乳腺癌MCF-7细胞株、人肝癌HepG2细胞株、人结肠癌SW480细胞株等多种肿瘤细胞株有广泛的抑制活性。其对Hela的IC 50值为0.5160μM/mL，相较于毛兰素的IC 50值8.3μM/mL活性差距较大，说明化合物7a在毛兰素基础上引入二氯乙酸大大提高了化合物对Hela细胞的抑制活性。
从体外抗肿瘤比较而言，化合物7a对HepG2肝癌细胞株的更具选择性，其对HepG2细胞的IC 50值为0.0489μM/mL，相较于毛兰素的IC 50值0.0728μM/mL，活性提高了近一倍。
化合物8d对人胃癌SGC7901细胞株与人乳腺癌MCF-7细胞株具有较优于毛兰素的抑制活性。其对Hela细胞IC 50值为0.2883μM/mL，而毛兰素的IC 50值为0.0728μM/mL，化合物8d的Hela细胞的抑制效果同样明显优于毛兰素。
上述结果表明，本发明的二氯乙酸偶联二苯乙烷类化合物具有较强的抗肿瘤活性，显著优于阳性对照物毛兰素，具有较好的应用开发前景。
实施例16.小鼠单次灌胃给药的急毒性实验
1.实验方法
实验选用ICR小鼠(SPF级)，灌胃前，实验动物隔夜禁食。试验以5000mg/kg·bw剂量，染毒20只动物(体重19-22g，雌雄各半)，按体重随机分组。受试药物剂量最高为5000mg/kg，单次灌胃给药，0.5h、1h、2h、4h、24h分别观察一次，记录死亡率，以后每天观察一次，记录死亡率，持续154天，第15天处死未死亡小鼠，进行病理解剖。
2.实验结果
单次灌胃给药，高中低剂量口服给药都没有动物死亡(LD>5000mg/kg)，解剖未见明显的残留药液，小鼠解剖未见心、肺、脾、肾等脏器异常，受试药物安全性好。
实施例17.灌胃给药对荷瘤裸鼠移植瘤的抑瘤率实验
1.实验方法
人肝癌细胞HepG2异种移植瘤模型，由人肝癌细胞株HepG2接种于裸鼠腋下皮下而建立。取对数生长期的HepG2细胞，在无菌条件下，接种于55只裸小鼠右侧腋下皮下。用游标卡尺测量移植瘤直径，待肿瘤生长至100mm 3左右时挑选生长状态良好且肿瘤大小均一性好的荷瘤裸鼠48只，随机分成8组，每组6只，即模型组、7a低剂量组(50mg/kg)、7a中剂量组(100mg/kg)、7a高剂量组(150mg/kg)、索拉非尼组(50mg/kg)。模型组动物尾灌胃等容量溶媒，每天灌胃给药一次；7a低剂量组、7a中剂量组、7a高剂量组分别按照50mg/kg、100mg/kg、150mg/kg每天灌胃给药一次，共给药14次；索拉非尼组按照50mg/kg每天灌胃给药一次，共给药14次。使用测量瘤径的方法动态观察受试物抗肿瘤的效应。分别隔天测量肿瘤直径，测量肿瘤直径的同时称量裸鼠体重。第15天时处死小鼠，手术剥取瘤块称重，液氮罐保存肿瘤组织，计算抑瘤率(％)。抑瘤率(％)＝(模型组瘤重-给药组瘤重)/模型组瘤重×100％。
2.实验结果
按给药方案，上述化合物能明显抑制荷瘤裸鼠移植瘤的生长，给药后低剂量组第11天左右，可以观察到肿瘤有缩小的趋势；中剂量组第9天，可以观察到肿瘤有缩小的趋势；高剂量组第7天，可以观察到肿瘤有明显缩小的趋势。
表3.化合物7a对人肝癌细胞HepG2裸鼠移植瘤生长的抑制作用
Figure PCTCN2022081328-appb-000029
上述结果表明，本发明的化合物能够显著的抑制体内瘤体的增长并且肿瘤有缩小的趋势，随着化合物剂量的增加，瘤体缩小的速度增加。索拉非尼是一种目前临床上广泛使用的多靶向性的抗肿瘤口服药，本发明的化合物的抑瘤率优于索拉非尼，并具有更好的安全性(LD50>5000mg/kg)。
上述相关说明以及对实施例的描述是为便于该技术领域的普通技术人员能理解和应用本发明。熟悉本领域技术的人员显然可以容易地对这些内容做出各种修改，并把在此说明的一般原理应用到其他实施例中而不必经过创造性的劳动。因此，本发明不限于上述相关说明以及对实施例的描述，本领域的技术人员根据本发明的揭示，不脱离本发明范畴所做出的改进和修改都应该在本发明的保护范围之内。

Claims (15)

  1. 一种二氯乙酸偶联二苯乙烷类化合物，其特征在于，其结构如通式(I)所示：
    Figure PCTCN2022081328-appb-100001
    其中，
    R 1、R 2和R 3分别选自但不限于-OH、-OMe、H中的任意一种，
    R 4选自但不限于-OMe、-OEt中的任意一种，
    R 5和R 6选自氯原子或氟原子，
    m为0或者1，
    n选自1-8或者11-12中的正整数。
  2. 如权利要求1所述的二氯乙酸偶联二苯乙烷类化合物，其特征在于，所述的二氯乙酸偶联二苯乙烷类化合物选自：
    Figure PCTCN2022081328-appb-100002
    Figure PCTCN2022081328-appb-100003
    Figure PCTCN2022081328-appb-100004
    或者
    Figure PCTCN2022081328-appb-100005
  3. 一种药物组合物，其特征在于，所述的药物组合物的活性成分是权利要求1所述的二氯乙酸偶联二苯乙烷类化合物。
  4. 如权利要求3所述的药物组合物，其特征在于，所述的药物组合物由有效剂量的权利要求1所述的二氯乙酸偶联二苯乙烷类化合物和药学上可接受的载体组成。
  5. 如权利要求3所述的药物组合物，其特征在于，其药物制剂选自但不限于以下剂型：静脉注射形式给药的冻干粉剂、粉剂、注射剂、脂质体、乳剂、微囊、悬浮液或溶液；口服形式给药的颗粒剂、片剂、胶囊或糖浆；或是栓剂。
  6. 如权利要求3所述的药物组合物，其特征在于，所述的药物组合物是抑制肿瘤细胞增殖、生长或者损伤、消除肿瘤细胞的药物。
  7. 权利要求1所述的二氯乙酸偶联二苯乙烷类化合物的制备方法，其特征在于，当R 1、R 2和R 3中一个以上为-OH时，该制备方法包括以下步骤：
    (1)将
    Figure PCTCN2022081328-appb-100006
    中的羟基用苄氯保护，获得相应的苄基保护产物；
    (2)将苄基保护产物和三苯基磷叶立德
    Figure PCTCN2022081328-appb-100007
    进行wittig反应，得到苄基保护的二苯乙烯化合物；
    (3)将苄基保护的二苯乙烯类化合物还原并脱保护，得到相应的二苯乙烷化合物；
    (4)当m＝0时，将
    Figure PCTCN2022081328-appb-100008
    与相应的二苯乙烷类化合物缩合，得到二氯乙酸偶联二苯乙 烷类化合物或者二氯乙酸偶联二苯乙烯类化合物。
  8. 如权利要求7所述的制备方法，其特征在于，R 1、R 2和R 3均不为-OH时，省略用苄氯保护的步骤，直接与
    Figure PCTCN2022081328-appb-100009
    发生wittig反应。
  9. 如权利要求7所述的制备方法，其特征在于，当二氯乙酸与二苯乙烷与不同链长的氨基酸结合时，包括以下步骤：
    (1)将不同链长的氨基酸
    Figure PCTCN2022081328-appb-100010
    通过二氯亚砜，制备获得相应的氨基酸甲酯盐酸盐
    Figure PCTCN2022081328-appb-100011
    其中n＝1、2、3、4、6、7、8、11或者12；
    (2)将不同链长的氨基酸甲酯盐酸盐与
    Figure PCTCN2022081328-appb-100012
    缩合，得到化合物
    Figure PCTCN2022081328-appb-100013
    其中n＝1、2、3、4、6、7、8、11或者12；
    (3)将化合物
    Figure PCTCN2022081328-appb-100014
    水解脱甲基保护，得到相应的酸
    Figure PCTCN2022081328-appb-100015
    其中n＝1、2、3、4、6、7、8、11或者12；
    (4)将
    Figure PCTCN2022081328-appb-100016
    与相应的二苯乙烷类化合物缩合，得到相应的二氯乙酸偶联二苯乙烷类化合物(I)，其中n＝1、2、3、4、6、7、8、11或者12。
  10. 权利要求1所述的二氯乙酸偶联二苯乙烷类化合物的应用，其特征在于，所述的二氯乙酸偶联二苯乙烷类化合物在制备抗肿瘤药物中的应用。
  11. 如权利要求10所述的应用，其特征在于，所述的抗肿瘤药针对源自胃癌细胞、肺癌细胞、宫颈癌细胞、肠癌细胞、乳腺癌细胞或者肝癌细胞中的一种或者几种产生的肿瘤或者赘生物。
  12. 如权利要求10所述的应用，其特征在于，所述的抗肿瘤药物包括缓解或者抑制肿瘤细胞增殖的药物或者试剂。
  13. 如权利要求10所述的应用，其特征在于，所述的二氯乙酸偶联二苯乙烷类化合物在细胞培养基中的浓度范围是0.1-10μM。
  14. 一种抑制细胞增殖的试剂，其特征在于，所述的试剂含有权利要求1所述的二氯乙酸偶联二苯乙烷类化合物。
  15. 如权利要求14所述的抑制细胞增殖的试剂，其特征在于，所述的细胞是体外培养的肿瘤细胞。
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