WO2011131103A1 - 含笑内酯衍生物，其药物组合物及其制备方法和用途 - Google Patents

含笑内酯衍生物，其药物组合物及其制备方法和用途 Download PDF

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Publication number
WO2011131103A1
WO2011131103A1 PCT/CN2011/072782 CN2011072782W WO2011131103A1 WO 2011131103 A1 WO2011131103 A1 WO 2011131103A1 CN 2011072782 W CN2011072782 W CN 2011072782W WO 2011131103 A1 WO2011131103 A1 WO 2011131103A1
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Prior art keywords
cancer
acid
aryl
lactone
group
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PCT/CN2011/072782
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English (en)
French (fr)
Inventor
陈悦
张泉
卢亚欣
翟佳黛
丁亚辉
龙菁
范洪霞
张浩亮
王淼
马维维
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Accendatech Co Ltd
Nankai University
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Accendatech Co Ltd
Nankai University
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Priority claimed from CN 201010153701 external-priority patent/CN102234259B/zh
Priority claimed from CN2010105107261A external-priority patent/CN101978959B/zh
Priority to KR1020127027257A priority Critical patent/KR101421140B1/ko
Priority to DK11771556.5T priority patent/DK2562172T3/en
Priority to EP11771556.5A priority patent/EP2562172B1/en
Priority to JP2013505317A priority patent/JP5801873B2/ja
Application filed by Accendatech Co Ltd, Nankai University filed Critical Accendatech Co Ltd
Priority to RU2012144434/04A priority patent/RU2537319C2/ru
Priority to ES11771556.5T priority patent/ES2575681T3/es
Priority to CN2011800201363A priority patent/CN103038225A/zh
Priority to CA2819408A priority patent/CA2819408C/en
Publication of WO2011131103A1 publication Critical patent/WO2011131103A1/zh
Priority to US13/642,516 priority patent/US9255078B2/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/10—Spiro-condensed systems

Definitions

  • Lactone derivative, drug group thereof, preparation method and use thereof Lactone derivative, drug group thereof, preparation method and use thereof
  • the present invention relates to the field of pharmaceutical technology, and in particular to a pharmaceutical composition for treating cancer or adjuvant treatment of tumors containing a lactone derivative or a salt thereof as an active ingredient, a preparation method thereof, and a drug ⁇ And the group should not be used in the preparation of anticancer or adjuvant anticancer drugs.
  • BACKGROUND OF THE INVENTION Cancer is extremely human. There are about 2 million cancer patients in China, and 1.6 million new cases are issued each year. This is a big anti-tumor research, which is an extremely challenging and significant field in the field of combat. In the past, the treatment methods focused on the eradication and killing of cancer cells.
  • the anticancer drugs commonly used in clinical practice are mainly fine drugs, and such anticancer drugs have poor selectivity, strong side effects, and easy to produce drug resistance. It is a typical double-sided blade drug, and it is difficult to eradicate cancer. Many cancers have a higher recurrence rate. The high recurrence rate of malignant tumors has been a problem for the tumor doctors. More and more studies have confirmed that there are a few tumor stem cells in the tumor. They are usually in the Tweman cycle, have low sensitivity to chemotherapy drugs, and are the source of tumor recurrence. Therefore, the discovery of cancer stem cells brings new targets to cancer treatment, and drug research for cancer stem cells provides a possibility to completely cure cancer.
  • the sesquiterpene lactone compound ParthenoMe is a compound extracted from the white chrysanthemum, which is originally used to treat skin infections, rheumatism and migraine. Recent studies have shown that parthenolide can inhibit the growth of cancer cells such as prostate cancer, breast cancer, gastric cancer, leukemia, kidney cancer, lung cancer, colon adenocarcinoma, and medulloblastoma, in the white chrysanthemum Ester can also treat cancer caused by ultraviolet rays.
  • cancer cells such as prostate cancer, breast cancer, gastric cancer, leukemia, kidney cancer, lung cancer, colon adenocarcinoma, and medulloblastoma
  • parthenolide can inhibit the activation of the transcription factor F- ⁇ , its activity may be mainly derived from the P65 NF-KB subunit Cys38 on the sulfhydryl group and the parthenolide Michael addition Response, since NF- ⁇ is an important gene regulating tumor invasion, metastasis, and drug resistance, inhibition of F- ⁇ activation may increase the sensitivity of tumors to apoptosis induced by tumor suppressor.
  • parthenolide can specifically eliminate stem cells that cause acute and chronic myeloid leukemia without damaging normal stem cells, which may be fundamentally To curb the recurrence of leukemia, the unique mechanism of action of parthenolide has attracted extensive attention.
  • Lactonic acid lactone is also a sesquiterpene lactone ⁇ , which is a sesquiterpene lactone in the guaiac wood pit. It has been reported in the literature [J. Nat. Prod. 1993, 56, 90-98; Bioorg Med. Chem. Lett. 2003, 11, 1503-1510], in the present invention, it has been found that a derivative containing a lactone or a salt thereof has a use for treating cancer.
  • the present invention provides a lactone-containing derivative, an effective amount of a pharmaceutical composition of the formula (I) containing a lactone derivative or a salt thereof and a pharmaceutically acceptable carrier for treating cancer or with other anticancer drugs
  • a composition, a process for the preparation thereof, and a use of the formula (I) containing a lactone derivative or a salt thereof, or a pharmaceutical composition thereof for the preparation of a medicament for treating cancer In order to achieve the above object of the present invention, the present invention provides the following technical solutions:
  • the present invention provides a lactone-containing lactone derivative of the following formula (I) or a salt thereof
  • R 5 R6 wherein R 5 and may be the same or different, R 5 and respectively are hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, An aryl group, an alkylaryl group, an arylalkyl group, an arylalkenyl group, an arylalkynyl group or a heterocyclic group;
  • R 2 R 3 is a double bond
  • R 2 is a substituted C 1-8 hydrocarbon group, which is taken as a ring; a hetero atom ring aryl or heterocyclic aryl group, an acid moiety or -R 7 Rs and its pharmaceutically active form with an inorganic or organic acid Acceptable salts include quaternary ammonium salts formed with hydrazine.
  • the substituent is preferably a carboxylic acid fragment or a -NR 7 R 8 substituted fluorenylene group.
  • R 7 and may be the same or different, respectively hydrogen, alkyl, cycloalkyl, hydroxy-substituted alkyl, aryl, silk, aryl, aryl, arylaryl, aryl, trifluoro Sulfhydryl, poly W 3 ⁇ 43 ⁇ 4, nitrile group, nitrile fluorenyl group, tt, ⁇ 3 ⁇ 4 ⁇ , sulfo tt, sulfonamide aryl; or R 7 , Rg and N atoms form a cyclic structure, a 3-9 membered ring,
  • the cyclic structure may be substituted by one or more substituents; the substituent is selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, arylalkenyl , arylalkynyl or heterocyclic; R 7 and is hydrogen, ⁇
  • Z is fluorine, chlorine, bromine, iodine, p-xanthate, sulfonate, orthotrifluoride;
  • R 9 is; 3 ⁇ 4, ring; 3 ⁇ 4, hydroxy and 3 ⁇ 4, Glycosyl, tt, aryl, heterocyclic, aryl, 3 ⁇ 4, aryl aryl, aryl tt, «also thiol, alkane « and ⁇ 3 ⁇ 4 aryloxy Substituted alkyl; inorganic or organic acid is hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydrogenic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, selenous acid, phosphoric acid, phosphorous acid, sulfurous acid, citric acid , maleic acid, D-malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-lactic acid, oxalic acid, sulfonic
  • X is oxygen or R 10 N, of which. Is hydrogen, cycloalkyl, aryl, alkynyl, aryl, alkylaryl, arylalkyl, arylalkenyl, arylalkynyl or heterocyclic;
  • Y is a single bond, oxygen, R U N, Ri 2 R B C, wherein R u is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, alkylaryl, arylalkyl, aryl Alkenyl, arylalkynyl or heterocyclic; R 12 and Ro are the same or different, respectively hydrogen, fluorine, chlorine, bromine, iodine, 3 ⁇ 4, ring; 3 ⁇ 4, hydroxy 1 and ⁇ , base, , silk, aryl, cyclic group, aromatic _3 ⁇ 4 and ⁇ tt, aryl aryl, aryl
  • R 2 is a -R 7 R 8 substituted anthracene segment-substituted fluorenylene group, wherein R 7 and may be the same or different, respectively hydrogen, alkyl, cycloalkyl, hydroxy-substituted alkyl, olefin Alkyl, alkynyl, aryl, aryl, aryl, aryl, aryl, tt, heterocyclyl, trifluoromethyl, poly M 3 ⁇ 4tt, nitrile, nitrile fluorenyl, tt, ⁇ 3 ⁇ 4 ⁇ , Sulfon tt, sulfoaryl$ ⁇ ; or R 7 , R 8 and N atoms form a cyclic structure, the ring is a 3-9 membered ring, and the cyclic structure may be substituted by one or more substituents selected from hydrogen, Alkyl, cycloalkyl, alkenyl, alkynyl,
  • the present invention also provides a method for preparing the caprolactone derivative of the above formula (I) or a salt thereof, the preparation method comprising the steps of: using caprolactone as a raw material, adding a catalyst, adding a catalyst, passing through The original saccharide reaction of the corresponding group or structure is prepared.
  • the formula (I) of the present invention contains a lactone lactone derivative or a salt thereof, which is represented by the following formula ( ⁇ ),
  • the present invention provides a method for preparing a formula ( ⁇ ) containing a lactone lactone.
  • the method comprises the following steps: the starting material is a lactone and a decylamine, and the reaction is prepared to obtain a formula ( ⁇ ) Lactones.
  • the present invention provides a process for preparing a formula (m) containing a lactone derivative, which comprises the following steps: a lactone and a propionyl chloride, the catalyst is triethylamine, and the solvent is dichlorodecane. , a lactone-containing lactone derivative of the formula (m) is prepared.
  • the present invention provides a process for the preparation of a derivative of the formula (IV) containing a lactone, the method comprising the steps of: the starting material is a lactone and m-chloroperoxybenzoic acid, and the solvent is dichlorodecane. , J1 ⁇ 2 is prepared to obtain a lactone-containing lactone derivative of the formula (IV).
  • the present invention provides a process for preparing a salt of the formula (V) containing a lactone derivative-biochemical, the method comprising the steps of: the starting material is a formula ( ⁇ ) containing a lactone derivative dissolved in dichloromethane In the hydrochloric acid, the pH is adjusted to 4 to 5, and the aqueous solution is lyophilized to obtain a lactone-containing lactone derivative of the formula (V).
  • the present invention also provides the use of the lactone-containing lactone derivative of the above formula (I) or a salt thereof for treating cancer, wherein the cancer is leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, Intestinal cancer, kidney cancer, oral cancer, Hejie Jinlinba cancer, pancreatic cancer, colorectal cancer, cervical cancer, non-Hodgkin's cancer, glioma, melanoma, bladder cancer, ovarian cancer , squamous adenocarcinoma or Kaposi's sarcoma.
  • the cancer is leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, Intestinal cancer, kidney cancer, oral cancer, Hejie Jinlinba cancer, pancreatic cancer, colorectal cancer, cervical cancer, non-Ho
  • the present invention also provides the above-described caprolactone derivative of the formula (I) or a salt thereof for use as adjunctive therapy for cancer, wherein the cancer is leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, cancer, lung cancer, liver cancer, esophagus Cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, pancreatic cancer, colorectal cancer, cervical cancer, non-Hodgkin, cancer, glioma, melanoma, bladder Cancer, ovarian cancer, sputum cancer or Kaposi's sarcoma.
  • the cancer is leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, cancer, lung cancer, liver cancer, esophagus Cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, pancreatic cancer, colorectal cancer, cervical cancer, non-Hodgkin, cancer, glioma, melanoma
  • the present invention is also a use of a formula (I) containing a lactone lactone derivative or a salt thereof for the preparation of a medicament for treating cancer, wherein the cancer is leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, colorectal cancer , lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, He Jiejin lymphoma, »cancer, colorectal cancer, cervical cancer, non-Hodgkin, cancer, glioma , melanoma, bladder cancer, ovarian cancer, squamous adenocarcinoma or Kaposi's sarcoma.
  • the cancer is leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, colorectal cancer , lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, He Jiejin lymphoma, »cancer, colorec
  • the present invention is also a use of a formula (I) containing a lactone lactone derivative or a salt thereof for the preparation of a medicament for treating cancer, wherein the cancer is leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, large intestine Cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, ⁇ cancer, colorectal cancer, cervical cancer, non-Hodgkin, cancer, nerve Glioma, melanoma, bladder cancer, ovarian cancer, sputum cancer or Kaposi's sarcoma.
  • the cancer is leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, large intestine Cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, ⁇ cancer, colorectal cancer, cervical cancer, non-Hodgkin,
  • the present invention also provides a pharmaceutical composition for treating cancer comprising an effective amount of a lactone-containing lactone derivative of the formula (I) or a salt thereof and a pharmaceutically acceptable carrier or other anticancer drug
  • a pharmaceutical composition for treating cancer comprising an effective amount of a lactone-containing lactone derivative of the formula (I) or a salt thereof and a pharmaceutically acceptable carrier or other anticancer drug
  • the present invention also provides the use of the above formula (n), (m), (IV), (V) in the above-described lactone-containing lactone derivative or a salt thereof for treating cancer, wherein the cancer is leukemia, breast cancer, prostate cancer, Nasopharyngeal carcinoma, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, He Jiejinlinba cancer, pancreatic cancer, colorectal cancer, cervical cancer, non-Jie Jinlin Bar, glioma, melanoma, bladder cancer, ova
  • the present invention also provides the above-mentioned formula ( ⁇ ), ( ⁇ ), (IV), (VH ⁇ in the lactone-containing lactone derivative or a salt thereof, wherein the cancer is leukemia, breast cancer, Prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, pancreatic cancer, colorectal cancer, cervical cancer, non-health Jerkinba cancer, neuroma, melanoma, bladder cancer, ovarian cancer, ⁇ cancer or Kaposi's sarcoma.
  • the cancer is leukemia, breast cancer, Prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, pancreatic cancer, colorectal cancer, cervical cancer, non-health Jerkinb
  • the present invention also provides a use of a compound of the formula (n), (m), (IV), (V) in a lactone-containing lactone derivative or a salt thereof for the preparation of a medicament for treating cancer, wherein the cancer is leukemia , breast cancer, prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, pancreatic cancer, colorectal cancer, child neck Cancer, non-Hodgkin's cancer, neuroma, melanoma, bladder cancer, ovarian cancer, ⁇ cancer or Kaposi's sarcoma.
  • the cancer is leukemia , breast cancer, prostate cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, pancreatic cancer, colorec
  • the present invention also provides a use of the formula (n), (m), (IV), (v ⁇ in the preparation of a lactone derivative or a salt thereof, in the preparation of an auxiliary drug for treating cancer, wherein the cancer For leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, pancreatic cancer, colorectal cancer, sub-officer Cervical cancer, non-Hodgkin's lymphoma, neuroma, melanoma, bladder cancer, ovarian cancer, ⁇ 3 ⁇ 4 cancer or Kaposi's sarcoma.
  • the cancer For leukemia, breast cancer, prostate cancer, nasopharyngeal carcinoma, cancer, lung cancer, liver cancer, esophageal cancer, gastric cancer, intestinal cancer, kidney cancer, oral cancer, Hodgkinba cancer, pancreatic cancer, colorectal cancer
  • the present invention also provides a pharmaceutical composition for treating cancer, which comprises an effective amount of a formula (n), (m), (IV), (V) and a salt thereof.
  • a pharmaceutically acceptable carrier or a combination with other anti-cancer drugs is included in the composition for treating cancer.
  • the compound of the present invention when used as a medicament, it can be used as it is, or it can be used in the form of a pharmaceutical composition.
  • the pharmaceutical composition contains from 0.1 to 99%, preferably from 0.5 to 90%, of the present invention, the remainder being pharmaceutically acceptable, pharmaceutically acceptable carriers and/or excipients which are non-toxic and inert to the animal or Used in combination with other anti-cancer drugs.
  • the group of the present invention can be prepared into an injection, a tablet, a capsule, and the like.
  • the pharmaceutically acceptable carrier or excipient is one or more solid, semi-solid and liquid diluents, ⁇ and pharmaceutical preparations.
  • the pharmaceutical composition of the present invention is used in the form of a unit weight.
  • the medicament of the present invention can be administered in both injection and oral administration, such as intravenous injection and intramuscular injection, and the oral dosage form can be a tablet and a capsule.
  • Lactide-containing lactone derivative of the present invention or a salt thereof exhibits a good effect in treating cancer, and exhibits a remarkable killing effect on normal cells.
  • HL-60, K562, MCF-7, CNE-1, CNE-2, SW620, A549, HepG-2, Ec9706, SGC7901, SW1116, A498, ASPC-1, HT-29, HeLa, GL15, B16F1, T24 , SKOV3, SW579, PC-3 respectively represent acute leukemia, Zhu, chronic leukemia, fine breast, breast cancer, Zhu, human well-differentiated nasopharyngeal carcinoma, Zhu, human poorly differentiated nasopharyngeal carcinoma, Zhu, colorectal cancer, Zhu, Yueshi Carcinoma cell, liver cancer packet, esophageal cancer packet, gastric cancer packet, colon cancer packet, kidney cancer cell line, pancreatic cancer, ⁇ Zhu, colon cancer, and cervical cancer
  • Example 14 The compound II, III, IV, and V prepared in Example 14 were dissolved in a small amount of DMSO, and then injection water was prepared by conventional addition, water injection, and potting to prepare an injection.
  • Example 14 The compound II, III, IV, V prepared in Example 14 and the excipient were added in a ratio of 5:1 by weight to a granule, and granulated to obtain a tablet.
  • Example 14 The compound II, III, IV, V prepared in Example 14 and the excipient were prepared in a ratio of 5:1 by weight.

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Description

说
含笑内酯衍生物， 其药物组^^及其制备方法和用途
¾ 页域 本发明属于药物技术领域， 具体地说， 涉及含笑内酯衍生物或其盐， 以其 为有效成分的治疗癌症或辅助治疗肿瘤的药物组合物， 其制备方法， 以及该药 物^^和组 勿在制备抗癌或辅助抗癌药物中的应用。 背景技术 肿瘤极 着人类 我国 癌症患者约 200万人， 每年新发 160 万例， 这是一个不小的 抗肿瘤研究是当今生 ^斗学领域极具挑战性且意 义重大的领域。 过去的治疗方法侧重于对癌细胞的铲除和杀伤， 目前， 临床上 常用的抗肿瘤药物主要是细 ^类药物， 这类抗癌药具有选择性差、 毒副作用 强、 易产生耐药性等缺点， 是典型的双面刃药物， 而且难以根除癌症， 不少癌 症的复发比例较高。 恶性肿瘤的高复发率一直是困 4 中瘤医生的难题， 越来越 多的研究证实肿瘤细^ ^中存在少数能使 广增的肿瘤干细胞。 它们通常 处于†曼周期状态， 对化疗药物敏感性低， ^中瘤复发的才 源。 因此肿瘤干细胞 的发现给肿瘤治疗带来新的靶标， 针对肿瘤干细胞的药物研究为彻底治愈癌症 提供可能。
近年来，从天然产物中寻找抗癌活性化^已经成为抗癌药物的开发热点， 前 20年间，全世界推出的药物小分子新化学实体中，有 61 %可追溯到天然产物。 天然产物在某些治疗领域出现率非常高： 78 %的抗菌^ ^和 74 %的抗肿瘤化 勿都是天然产物， 或从某个天然产物衍生而来， 实践证明， 天然产物在抗癌 药物发现中的独特作用重新引起高度重视。 传统治疗肿瘤的化疗药物均存在耐 药问题， 尤其^中瘤干细胞更不敏感。 抗癌中药博大 高效^ ^， 从中有 可能筛选出高效杀伤肿瘤干细胞， 从而治疗恶性肿瘤的药物。
倍半萜内酯类化合物小白菊内酯（ParthenoMe )是从小白菊中提取的化合 物， 最初 来治疗皮肤感染、 风湿病以及偏头痛。 近期研究表明， 小白菊内 酯可抑制前列腺癌、 乳腺癌、 胃癌、 白血病癌、 肾癌、 肺癌、 结肠腺癌、 成神 经管细胞瘤等癌细胞的生长， 在动物才莫型上小白菊内酯还能治疗紫外线引起的 夫癌。 对其作用^ ί里研究发现， 小白菊内酯能抑制转录因子 F-κΒ的激活， 其活性可能主要来源于 P65 NF-KB亚基的 Cys38上的巯基与小白菊内酯发生了 Michael加成反应， 由于 NF-κΒ是调控肿瘤侵袭、 转移、 药物抗性的重要基因， 抑制 F-κΒ的激活有可能提高肿瘤对于抑瘤剂所引起的细胞凋亡的敏感性。 最 近， 纽约罗切斯特大学医学院的 Jordan, C. T.博士及其同事发现小白菊内酯能 够在基本不损伤正常干细胞的情况下， 针对性地消灭引发急性和慢性骨髓性白 血病的干细胞， 从而有可能根本上遏制白血病复发， 小白菊内酯这一独特的作 用机制， 已引^们的广泛关注。
含笑内酯也属于倍半萜内酯类^ ^勿，为愈创木坑型倍半萜内酯类化^ , 已经有文献报道 [J. Nat. Prod. 1993, 56, 90-98; Bioorg. Med. Chem. Lett. 2003, 11, 1503-1510],本发明在已有发现的^出上，发现了含笑内酯的衍生物或其盐具有 治疗癌症的用途。 发明内容 本发明提供了一种含笑内酯的衍生物， 含有效量的式（ I )含笑内酯衍生 物或其盐及可药用载体的治疗癌症的药物组合物或与其他抗癌药物的组合物， 其制备方法， 以及式 ( I )含笑内酯衍生物或其盐， 或其药物组^ ^在制备治 疗癌症药物中的应用。 为了实现本发明的上述目的， 本发明提供如下的技术方案:
本发明提供了如下式（I )的含笑内酯衍生物^ ^或其盐
Figure imgf000005_0001
其中 为11、 ~0(0) 或" C(0) R5R6, 其中为 R5和 可以相同或不同， 、 R5和 分别为氢、 烷基、 环烷基、 烯基、 炔基、 芳基、 烷基芳基、 芳基烷 基、 芳基烯基、 芳基炔基或杂环基；
R2=R3为双键， 或者
为 H, R2为取代的 C1-8烃基， 其中取 为环; 杂原子环 芳基 或杂环芳基， 酸片段或 - R7Rs及其与无机酸或有机酸形成的在药学上可接 受的盐， 包括与 Ζ形成的季铵盐。取代基优选为 基酸片段或 -NR7R8取代的亚 曱基。
其中 R7和 可以相同或不同， 分别为氢、 烷基、 环烷基、 羟基取代烷基、 婦基、 絲、 芳基、 芳基、 芳基 芳基婦基、 芳基 环基、 三 氟曱基、 多 W ¾¾、 腈基、 腈基曱基、 tt、 曱¾^、 磺 tt、 磺酰 胺 芳^ tt; 或者 R7、 Rg和 N原子形成环状结构， 为 3-9元环， 环状结 构上可以被一个或多个取代 又代； 取代基选自氢、 烷基、 环烷基、 烯基、 炔 基、 芳基、 烷基芳基、 芳基烷基、 芳基烯基、 芳基炔基或杂环基； R7和 为氢、 ^^子数为 1-8的; 环; ¾。
Z为氟、 氯、 溴、 碘、 对曱 黄酸酯基、 曱^ S炱酯基、 黄酸酯 ^三氟曱 基石 酯基； R9为; ¾、 环; ¾、 羟 又^ ¾、 婦基、 tt、 芳基、 杂环基、 芳 又^ ¾、 芳基婦基、 芳基 tt、 « 又代曱基、 烷 « 又^ ¾Μ芳氧 取代烷基； 无机酸或有机酸为氢氟酸、 盐酸、 氢溴酸、 氢典酸、 硫酸、 硝酸、 磷酸、 碳酸， 硼酸、 亚硒酸、 磷相酸、 亚磷酸、 亚硫酸、 柠檬酸、 马来酸、 D- 苹果酸、 L-苹果酸、 DL-苹果酸、 L-乳酸、 D-乳酸、 DL-乳酸、 草酸、 曱磺酸、 戊酸、 油酸、 月桂酸、 对曱 _S^;M、 酞酸、 酒石酸、 丙 二酸、 丁二酸、 富马酸、 乙醇酸、 硫醇酸、 甘氨酸、 交、 磺酸、 烟酸、 曱 基吡啶酸、 异烟酸、 苯曱酸或耳又 ^苯曱酸。
X为氧或 R10N, 其中 。为氢、 环烷基、 婦基、 炔基、 芳基、 烷基 芳基、 芳基烷基、 芳基烯基、 芳基炔基或杂环基；
Y为单键、 氧、 RUN、 Ri2 RBC, 其中 Ru为氢、 烷基、 环烷基、 烯基， 炔 基、 芳基、 烷基芳基、 芳基烷基、 芳基烯基、 芳基炔基或杂环基； R12和 Ro 以相同或不同， 分别为氢、 氟、 氯、 溴、 碘、 ；¾、 环; ¾、 羟 1 又^^ 基、 婦基、 絲、 芳基、 环基、 芳_¾ 又^ tt、 芳麟基、 芳基
取代曱基、 烷 « 又^ ¾ ^芳 &。
其中 为11、 Y为^!建和 R2=R3为双键不同时存在。
优选地， 其中 R2为 - R7R8取代的亚曱 炱片段取代的亚曱基， 其中 R7和 可以相同或不同， 分别为氢、 烷基、 环烷基、 羟基取代烷基、 烯基、 炔 基、 芳基、 芳基、 芳基 、 芳基婦基、 芳基 tt、 杂环基、 三氟曱基、 多 M ¾tt、 腈基、 腈基曱基、 tt、 曱¾^、 磺 tt、 磺 芳 $ ^; 或者 R7、 R8和 N原子形成环状结构， 环 为 3-9元环， 环状结构上可 以被一个或多个取代 又代， 取代基选自氢、 烷基、 环烷基、 烯基、 炔基、 芳基、 烷基芳基、 芳基烷基、 芳基烯基、 芳基炔基或杂环基。 其中 R7和 为氢、 千数为 1-8的; 环; ¾。
本发明还提供了上述式 ( I )的含笑内酯衍生物或其盐的制备方法， 制备方 法包括如下步骤： 以含笑内酯为原料， 在有积容剂中， 加入催化剂， 通过与带 有相应基团或结构的原利 质反应制备得到。 irn^ 本发明的式（I)含笑内酯衍生物^ ^或其盐为如下式（Π)、 式
(m)、 式（IV)、 式（V)
)。
Figure imgf000007_0001
^K 本发明提供了一种制备式（π)含笑内酯衍生物^ ^的方法， 该 方法包 ^舌如下步 原料为含笑内酯与二曱基胺，反应制备得到式（Π)的含笑 内酯 ^汙生物。
^ 本发明提供了一种制备式（m)含笑内酯衍生物^ ^的方法， 该 方法包 4舌如下步 原料为含笑内酯和丙酰氯， 催化剂为三乙胺， 溶剂为二氯 曱烷， 制备得到式（m)的含笑内酯衍生物。
具体地， 本发明提供了一种制备式 (IV)含笑内酯衍生物化^ ^的方法， 该方法包括如下步骤： 原料为含笑内酯和间氯过氧苯曱酸， 溶剂为二氯曱烷， J½制备得到式（IV)的含笑内酯衍生物。
^K本发明提供了一种制备式（ V )含笑内酯衍-生物^ ^物的盐的方法， 该方法包括如下步骤： 原料为式（π)含笑内酯衍生物溶于二氯曱烷中， 盐酸调 节 pH至 4~5, 将水溶液冻干即得式（V)的含笑内酯衍生物。 本发明还提供了上述式（I )的含笑内酯衍生物化^或其盐治疗癌症用途， 其中癌症为白血病、 乳腺癌、 前列腺癌、 鼻咽癌、 癌、 肺癌、 肝癌、 食道 癌、 胃癌、 肠道癌、 肾癌、 口腔癌、 何杰金林巴癌、 胰腺癌、 直肠结肠癌、 子 官颈癌、 非何杰金林巴癌、 神经胶质瘤、 黑瘤、 膀胱癌、 卵巢癌、 曱状腺癌或 卡波西肉瘤。
本发明还还提供了上述式 ( I )的含笑内酯衍生物^ ^或其盐作为辅助治 疗癌症用途， 其中癌症为白血病、 乳腺癌、 前列腺癌、 鼻咽癌、 癌、 肺癌、 肝癌、 食道癌、 胃癌、 肠道癌、 肾癌、 口腔癌、 何杰金林巴癌、 胰腺癌、 直肠 结肠癌、 子官颈癌、 非何杰金林巴癌、 神经胶质瘤、 黑瘤、 膀胱癌、 卵巢癌、 曱 ^癌或卡波西肉瘤。
本发明还才是供了一种式 ( I )的含笑内酯衍生物化^或其盐在制备治疗癌 症的药物中的用途， 其中癌症为白血病、 乳腺癌、 前列腺癌、 鼻咽癌、 大肠癌、 肺癌、 肝癌、 食道癌、 胃癌、 肠道癌、 肾癌、 口腔癌、 何杰金淋巴癌、 »癌、 直肠结肠癌、 子官颈癌、 非何杰金林巴癌、 神经胶质瘤、 黑瘤、 膀胱癌、 卵巢 癌、 曱状腺癌或卡波西肉瘤。
本发明还才是供了一种式 ( I )的含笑内酯衍生物化^或其盐在制备治疗癌 症的辅助药物中的用途， 其中癌症为白血病、 乳腺癌、 前列腺癌、 鼻咽癌、 大 肠癌、 肺癌、 肝癌、 食道癌、 胃癌、 肠道癌、 肾癌、 口腔癌、 何杰金林巴癌、 ^^癌、 直肠结肠癌、 子官颈癌、 非何杰金林巴癌、 神经胶质瘤、 黑瘤、 膀胱 癌、 卵巢癌、 曱^^癌或卡波西肉瘤。
本发明还提供了一种用于治疗癌症的药物组^ ,其中含有有效量的式（ I ) 的含笑内酯衍生物^ ^或其盐和药学上可接受的载体或与其他抗癌药物的组 本发明还提供了上述含笑内酯衍生物^ ^或其盐中的式（n ) 、 ( m ) 、 ( IV ) 、 （V )化^治疗癌症用途， 其中癌症为白血病、 乳腺癌、 前列腺癌、 鼻咽癌、 大肠癌、 肺癌、 肝癌、 食道癌、 胃癌、 肠道癌、 肾癌、 口腔癌、 何杰 金林巴癌、 胰腺癌、 直肠结肠癌、 子官颈癌、 非何杰金林巴癌、 神经胶质瘤、 黑瘤、 膀胱癌、 卵巢癌、 曱状腺癌或卡波西肉瘤。
本发明还还提供了上述含笑内酯衍生物^ ^或其盐中的式（Π)、 （ΠΙ)、 (IV)、 （VH^勿作为辅助治疗癌症用途， 其中癌症为白血病、 乳腺癌、 前 列腺癌、 鼻咽癌、 大肠癌、 肺癌、 肝癌、 食道癌、 胃癌、 肠道癌、 肾癌、 口腔 癌、 何杰金林巴癌、 胰腺癌、 直肠结肠癌、 子官颈癌、 非何杰金林巴癌、 神经 瘤、 黑瘤、 膀胱癌、 卵巢癌、 曱^^癌或卡波西肉瘤。
本发明还提供了一种含笑内酯衍生物^ ^或其盐中的式（n)、 (m)、 (IV)、 （V)化合物在制备治疗癌症的药物中的用途， 其中癌症为白血病、 乳 腺癌、 前列腺癌、 鼻咽癌、 大肠癌、 肺癌、 肝癌、 食道癌、 胃癌、 肠道癌、 肾 癌、 口腔癌、 何杰金林巴癌、 胰腺癌、 直肠结肠癌、 子官颈癌、 非何杰金林巴 癌、 神经 瘤、 黑瘤、 膀胱癌、 卵巢癌、 曱^^癌或卡波西肉瘤。
本发明还提供了一种含笑内酯衍生物^ ^或其盐中的式（n)、 (m)、 (IV)、 （νΗ^·勿在制备治疗癌症的辅助药物中的用途，其中癌症为白血病、 乳腺癌、 前列腺癌、 鼻咽癌、 癌、 肺癌、 肝癌、 食道癌、 胃癌、 肠道癌、 肾癌、 口腔癌、 何杰金林巴癌、 胰腺癌、 直肠结肠癌、 子官颈癌、 非何杰金淋 巴癌、 神经 瘤、 黑瘤、 膀胱癌、 卵巢癌、 曱 ^¾癌或卡波西肉瘤。
本发明还提供了一种用于治疗癌症的药物组合物， 其中含有有效量的含笑 内酯衍生物或其盐中的式（n)、 （m)、 (IV)、 (V)化^和药学上可接 受的载体或与其他抗癌药物的组合物。
本发明化合物用作药物时， 可以直 吏用， 或者以药物组合物的形式使用。 该药物组合物含有 0.1— 99%,优选为 0.5— 90%的本发明^^物，其余为药物学 上可接受的， 对 动物无毒和惰性的可药用载体和 /或赋形剂或与其他抗癌药 物联合用药。 本发明的组^可以制备成注射液、 片剂和胶嚢等。 所述的药用载体或赋形剂是一种或多种固体、 半固体和液体稀释剂、 ^ 以及药物制品辅剂。 将本发明的药物组合物以单位体重服用量的形式使用。 本 发明的药物可经注射和口服两种形式给药， 注射如静脉注射和肌肉注射， 口服 的剂型可以是片剂和胶嚢剂。
本发明的含笑内酯衍生物或其盐在治疗癌症方面显示出较好的效果， 而且 对正常细胞^ 现出明显的杀伤作用。
* 实 式 为了理解本发明， 下面以实施例进一步说明本发明， 但不意于限制本发明 的保护范围。
实施例 1:
11PH，13-二曱基氨基含笑内酯（化合物 II ) (结构式如下式（ II ) )的制备
Figure imgf000010_0001
含笑内酯（106 mg, 0.40 mmol ) , 三乙胺 (2.0mL ) , 曱醇（30 mL )加到 lOO mL的圓底烧瓶中， 加热回流 3小时， 减压浓缩， 石 交柱层析（石油醚： 乙 酸乙酯:三乙胺 =50 : 50 : 0.5 ) , 得白色固体 107.4 mg, 收率： 86%。
式： C17H27N03
量： 293
性状： 白色无定型 4分末
谱图数据：
¾ NMR (CDC13, 400 MHz) δ 3.76 (t, J = 10.0 Hz, 1H), 2.96 (s, 1H), 2.49-2.67 (m, 3H), 2.28-2.34(m, IH), 2.30-2.34 (m, 2H), 2.18 (s,6H), 2.09 (br s, 2H), 1.96(d, J =11.2, IH) , 1.67-1.73(m, 2H), 1.60(s, 3H) 1.22(br s, 3H),1.18(br s, 2H); 13C NMR (CDC13, 100 MHz) δ 177.0, 131.8, 131.3, 84.0, 80.2, 58.3, 58.1, 50.9, 46.0, 44.6, 38.4, 35.3, 30.0, 27.2, 23.7, 22.8。
实施例 2
4-丙酰基含笑内酯（化合物 III ) (结构式如下式（III ) )的制备
Figure imgf000011_0001
含笑内酯（106mg, 0.40 mmol ) , 三乙胺 (2.0mL ) , 丙酰氯 ( 0.2 mL ) 、 5 mL二氯曱;^口入到 20 mL的圓底烧瓶中， 室温搅拌^ 1 24 h,减压 硅 月交柱层析（石油醚： 乙酸乙酯 = 90: 10 ) , 得白色固体 87 mg, 收率： 72%。 制备得到的 4-丙酰基含笑内酯的结构数据：
式： C18H24N04
量： 304
性状： 白色无定型 4分末
谱图数据：
¾ NMR (CDC13, 400 MHz) δ 6.14 (s, IH), 5.42 (s, IH), 3.74 (t, J = 10.0 Hz , J = 10.0 Hz, IH), 1.80-2.74 (m, 12H), 1.67 (s, 3H), 1.50 (s, 3H), 1.07 (t, J = 4.0 Hz, 3H); 13C NMR (CDC13, 100 MHz) δ 173.8, 170.1, 139.5, 131.5, 130.4, 118.6, 88.4, 83.0, 56.6, 50.1, 36.5, 34.9, 30.4, 28.7, 25.9, 24.1, 18.8, 9.1。
实施例 3
1，10-环氧含笑内酯（化合物 IV ) (结构式如下式（IV ) )的合成方法：
Figure imgf000012_0001
含笑内酯（106 mg, 0.40 mmol ) , 间氯: ¾苯曱酸 ( 0.45 mmol ) 、 5 mL 二氯曱;^口入到 20 mL的圓底烧瓶中， 室温搅拌反应 6 h, 减压浓 ill, Πί 层析（石油醚： 乙酸乙酯 = 80: 20 ) , 得白色固体 96 mg, 收率： 91%。 制备 得到的 1,10-环氧含笑内酯的结构数据：
式： C15H20NO4
量： 264
性状： 白色无定型 4分末
谱图数据：
¾ NMR (CDC13, 400 MHz) δ 6.13 (d, J = 3.2 Hz, 1H), 5.44 (d, J = 2.8 Hz, 1H), 3.73 (t, J = 10.4 Hz, 1H), 1.30-2.46 (m, 11H), 1.29 (s, 3H), 1.28 (s, 3H); 13C NMR (CDC13, 100 MHz) δ 168.7, 137.8, 118.6, 79.2, 77.3, 74.2, 66.7, 52.6, 48.4, 37.1, 33.8, 29.0, 24.6, 22.5, 21.3。
实施例 4
11PH，13-二曱基氨基含笑内酯盐酸盐（化合物 V ) (结构式如下式（ V ) ) ) 的合成方法
Figure imgf000012_0002
含笑内酯二曱 Ufe (293 mg, 1 mmol )溶于二氯曱烷（2 mL )中， 室温搅 拌， 然后滴加盐酸溶液， 至 pH值 4~5, 二氯曱烷萃取（2 X 10 mL) , 将水层 冻干得白色固体， 收率： 82%。 制备得到的 11βΗ,13-二曱基 含笑内酯盐酸 盐的结构 I史据：
式： C17H28C1N03
量： 328.5
性状： 白色无定型 4分末
谱图数据：
[a]D 2°= -42.0 (c = 10, H20); IRCcm"1): 3334.25, 2927.18, 2856.17, 1767.94,
1467.25, 992.801, 967.371, 874.796, 831.311, 719.915, 669.783, 626.854, 504.324; ^NMR (D20, 400 MHz) δ 4.14 (t , / = 10.3 Hz, 1H), 3.51 (q,/ = 12.6 Hz, 1H), 3.40 (dd,/= 13.3, 2.9 Hz, 1H), 3.18-3.04 (m, 1H), 2.96 (d , J = 10.6 Hz, 6H), 2.67 (d,J= 10.2 Hz, 1H), 2.37 (dd,/= 16.2, 8.1 Hz, 1H), 2.27-2.05 (m, 4H), 1.87 (d,J= 12.9 Hz, 1H), 1.73 (dd,/= 19.5, 11.7 Hz, 2H), 1.66 (s, 3H), 1.46-1.31 (m, 2H), 1.26 (s, 3H); 13C NMR (CDC13, 100 MHz) δ 178.4, 132.6, 131.4, 85.1, 80.7, 56.9, 55.6, 49.9, 45.1, 42.3, 41.5, 39.2, 34.4, 29.5,25.9, 23.2,21.4.
实施例 5: 含笑内酯衍生物的药理作用
将各种癌细胞配成 2xl05/mL细胞悬液，加入 圓底细 咅养板内，分 别加入含笑内酯及期汙生物， 测试浓度 5孔， 置 37°C、 5%C02^^湿度 ^牛下培养 18小时， 用 MTT法在酶联检测仪 570匪波长测得吸光度 (A)值， 计算出本发明化^对测试癌细胞的抑制作用。
表 1 含笑内酯及期汙生物对各种癌细胞的抑制活性 ( IC50, μΜ )
细胞系 化 勿 III 化 勿 V
HL-60 2.4 4.5 5.8 11.5
Κ562 4.2 6.7 9.7 21.4 MCF-7 4.6 3.4 8.9 26.8
C E-1 11.2 5.9 6.7 22.5
C E-2 16.5 12.4 5.6 16.9
SW620 5.8 5.6 3.8 13.5
A549 7.2 7.7 5.7 18.1
HepG-2 4.5 15.4 7.4 27.9
Ec9706 9.2 7.6 6.6 15.7
SGC7901 14.6 14.7 13.4 24.9
SW1116 11.5 21.5 11.7 31.2
A498 12.4 5.3 4.3 16.3
ASPC-1 3.9 15.1 26.4 33.6
HT-29 4.8 9.8 9.8 19.2
HeLa 9.4 17.3 9.7 33.4
GL15 12.6 14.3 21.5 25.8
B16F1 3.4 13.2 5.2 18.6
T24 14.2 13.6 7.9 22.5
SKOV3 5.9 9.4 10.4 15.4
SW579 17.3 22.5 12.4 32.6
PC-3 8.7 11.4 17.2 23.5
其中 HL-60、 K562、 MCF-7, CNE-1、 CNE-2, SW620、 A549、 HepG-2, Ec9706、 SGC7901 , SW1116、 A498、 ASPC-1、 HT-29, HeLa, GL15、 B16F1、 T24、 SKOV3、 SW579、 PC-3分别表示急性白血病细 朱、 慢性白血病细 朱、 乳腺 癌细 朱、 人高分化鼻咽癌细 朱、 人低分化鼻咽癌细 朱、 大肠癌细 朱、 月市癌细包株、 肝癌细包株、 食管癌细包株、 胃癌细包株、 结肠癌细包株、 肾癌 细胞株、 胰 ^癌细^ ^朱、 结肠癌细包株、 子宫颈癌细包株、 人 母细胞瘤细 胞株、 黑素瘤细胞株、 膀胱癌细 朱、 卵巢癌细胞株、 曱状腺癌细胞株、 前列 腺癌细 朱。 活性测试结絲明， 筛选的化^ ^对受试细胞显示出较强的抑制活性， 而 JJ^ 正常细 50 μΜ时， 均^ 现出明显的杀伤作用。
实施例 6: 注射液
实施例 14中制备的化^ II、 III、 IV、 V用少量的 DMSO溶解后， 按 常规加注射用水， 精滤， 灌封灭菌制成注射液。
实施例 7: 片剂
实施例 14中制备的化合物 II、 III、 IV、 V与赋形剂按照重量比为 5:1的 比例加 U武形剂， 制粒压片， 得片剂。
实施例 8: 胶嚢
实施例 14中制备的化合物 II、 III、 IV、 V与赋形剂按照重量比为 5:1的 比例力口 U武形剂， 制^交嚢。
本发明的化合物、 用途和方法已经通过具体的实施例进行了描述。 本领域 技术人员可以借鉴本发明的内容适当改 料、 工艺 牛等环节来实 目应的 其它目的， 其相关改变都没有脱离本发明的内容， 所有类似的替换和改动对于 本领域技术人员来 ^显而易见的， 都被视为包括在本发明的范围之内。

Claims

权 利 要 求 书
1、 一种如下式（I )的化合物或其盐，
Figure imgf000016_0001
其中 为11、 ~0(0) 或" C(0) R5R6, 其中为 R5和 可以相同或不同， 、 R5和 分别为氢、 烷基、 环烷基、 烯基、 炔基、 芳基、 烷基芳基、 芳基烷 基、 芳基烯基、 芳基炔基或杂环基；
R2=R3为双键， 或者
为 H, R2为取代的 C1-8烃基， 其中取 为环; 杂原子环 芳基 或杂环芳基， 酸片段或 - R7R8及其与无机酸或有机酸形成的在药学上可接 受的盐， 包括与 R9Z形成的季铵盐。
其中 R7和 可以相同或不同， 分别为氢、 烷基、 环烷基、 羟基取代烷基、 婦基、 絲、 芳基、 芳基、 芳基 芳基婦基、 芳基 环基、 三 氟曱基、 多 W ¾¾、 腈基、 腈基曱基、 tt、 曱¾^、 磺 tt、 磺酰 胺絲芳 R7、 和 N原子形成环状结构， 环优选为 3-9元环， 环状结构 上可以被一个或多个取代 又代， 包括氢、 烷基、 环烷基、 烯基、 炔基、 芳 基、 烷基芳基、 芳基烷基、 芳基烯基、 芳基炔基或杂环基； Z为氟、 氯、 溴、碘、对曱^ M酯基、 曱磺酸酯基、 黄酸酯 ^三氟曱基^ M酯基； R9为 环 羟脉^ tt、 婦基、 芳基、 扭、基、 芳 1 又^ tt、 芳基婦基、 芳基絲、 又代曱基、 烷 « 又^ ¾Μ芳 又^ 无机 酸或有机酸为氢氟酸、 盐酸、 氢溴酸、 氢?典酸、 硫酸、 硝酸、 磷酸、 碳酸， 硼 酸、 亚踊酸、 磷相酸、 亚磷酸、 亚硫酸、 柠檬酸、 马来酸、 D-苹果酸、 L-苹果 酸、 DL-苹果酸、 L-乳酸、 D-乳酸、 DL-乳酸、 草酸、 曱蹟酸、 戊酸、 油酸、 月 桂酸、 对曱基^黄酸、 1-^黄酸、 2-^黄酸、 酞酸、 酒石酸、 丙二酸、 丁二酸、 富马酸、 乙醇酸、 硫醇酸、 甘氨酸、 交、 磺酸、 烟酸、 曱基吡啶酸、 异烟 酸、 笨曱酸或耳又 ^笨曱酸；
X为氧或 R10N, 其中 R1()为氢、 环烷基、 婦基、 炔基、 芳基、 烷基 芳基、 芳基烷基、 芳基烯基、 芳基炔基或杂环基；
Y为单键、 氧、 RUN、 Ri2 RBC, 其中 Ru为氢、 烷基、 环烷基、 烯基， 炔 基、 芳基、 烷基芳基、 芳基烷基、 芳基烯基、 芳基炔基或杂环基； R12和 R13可以相同或不同， 分别为氢、 氟、 氯、 溴、 碘、 ；¾、 环; ¾、 羟 1 又^¾ 基、 婦基、 絲、 芳基、 环基、 芳_¾ 又^ tt、 芳麟基、 芳基
取代曱基、 烷 « 又^ ¾ ^芳
其中 为11、 Y为^!建和 R2=R3为双键不同时存在。
2、根据权利要求 1所述的^^物或其盐，其中 R# 为 - R7Rs取代的亚曱 MAiJ交片段取代的亚曱基， 其中 R7和 R8可以相同或不同， 分别为氢、 ' 、 环; ¾、 羟脉^ ¾、 婦基、 芳基、 芳基、 芳基 芳基婦基、 芳基絲、 杂环基、 三氟曱基、 多 又^ tt、 腈基、 腈基曱基、 tt、 曱酰基、 基、 ^M ^^MM ; 或者 R7、 和 N原子形成环状结构， 环 优选为 3 - 9元环， 环状结构上可以被一个或多个取 又代， 取^ 自氢、 烷基、 环烷基、 婦基、 炔基、 芳基、 烷基芳基、 芳基烷基、 芳基婦基、 芳 基炔基或杂环基。 其中 R7和 优选为氢、 ^^子数为 1-8的; 环烷基。
3、根据权利要求 1所述的^^物或其盐， 本发明的式（I )含笑内酯衍生物 或其盐优选为式（π )、 式（m )、 式（IV )、 式（V )化合物
Figure imgf000018_0001
4、 一种制备式（Π)化 勿的方法， 该方法包 4舌如下步 原料为含笑内 酯与二曱 J½制备得到式（Π)的含笑内酯衍生物
(II) 。
Figure imgf000018_0002
5、 一种制备式（m) ^^勿的方法， 该方法包 4舌如下步 原料为含笑内 酯和丙酰氯， 催化剂为三乙胺， 溶剂为二氯曱烷， ^制备得到式（m)的含 笑内酯衍生物
Figure imgf000018_0003
6、一种制备式（IV )含笑内酯衍生物^ ^的方法，该方法包 4舌如下步 -骤: 原料为含笑内酯和间氯过氧苯曱酸， 溶剂为二氯曱烷， 反应制备得到式（IV ) 的含笑内酯衍生物
Figure imgf000019_0001
7、 一种制备式（V )含笑内酯衍生物的盐方法， 该方法包 4舌如下步 原 料为式（II )含笑内酯衍生物溶于二氯曱烷中， 盐酸调节 pH至 4 ~ 5, 将水溶液 冻干即得式（V )的含笑内酯衍生物
Figure imgf000019_0002
8、 权利要求 1-3 项所述的含笑内酯衍生物或其盐在制备治疗癌症的药 物中的用途， 其中癌症为白血病、 乳腺癌、 前列腺癌、 鼻咽癌、 癌、 肺癌、 肝癌、 食道癌、 胃癌、 肠道癌、 肾癌、 口腔癌、 何杰金林巴癌、 胰腺癌、 直肠 结肠癌、 子官颈癌、 非何杰金林巴癌、 神经胶质瘤、 黑瘤、 膀胱癌、 卵巢癌、 曱 ^癌或卡波西肉瘤。
9、 权利要求 1-3 项所述的含笑内酯或其盐在制备治疗癌症的辅助药物 中的用途， 其中癌症为白血病、 乳腺癌、 前列腺癌、 鼻咽癌、 大肠癌、 肺癌、 肝癌、 食道癌、 胃癌、 肠道癌、 肾癌、 口腔癌、 何杰金林巴癌、 胰腺癌、 直肠 结肠癌、 子官颈癌、 非何杰金林巴癌、 神经胶质瘤、 黑瘤、 膀胱癌、 卵巢癌、 曱 ^癌或卡波西肉瘤。
10、一种用于治疗癌症的药物组^ ,其中含有有效量的权利要求 1-3任一 项所述的含笑内酯衍生物或其盐和药学上可接受的载体或其他抗癌药物。
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CN103724307A (zh) * 2012-10-12 2014-04-16 天津尚德药缘科技有限公司 含笑内酯二甲基胺富马酸盐的晶型及制备方法
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US12048682B2 (en) 2018-04-13 2024-07-30 The University Of Chicago Combination of micheliolide derivatives or nanoparticles with ionizing radiation and checkpoint inhibitors for cancer therapy
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US12319666B2 (en) 2020-03-26 2025-06-03 Accendatech Co. Ltd. Hydrate of dimethylaminomicheliolide fumarate and preparation method therefor and use thereof
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CA2819408A1 (en) 2011-10-27
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PT2562172E (pt) 2016-06-07
DK2562172T3 (en) 2016-06-20
EP2562172A4 (en) 2013-10-02
PL2562172T3 (pl) 2016-09-30
CN103038225A (zh) 2013-04-10
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US20130109749A1 (en) 2013-05-02
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