WO2014067379A1 - Deuterated dimethyl amine parthenolide, preparation method and use thereof in drug preparation - Google Patents

Deuterated dimethyl amine parthenolide, preparation method and use thereof in drug preparation Download PDF

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WO2014067379A1
WO2014067379A1 PCT/CN2013/084601 CN2013084601W WO2014067379A1 WO 2014067379 A1 WO2014067379 A1 WO 2014067379A1 CN 2013084601 W CN2013084601 W CN 2013084601W WO 2014067379 A1 WO2014067379 A1 WO 2014067379A1
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acid
cancer
compound
formula
preparation
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Chinese (zh)
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陈悦
张泉
龙菁
王盼盼
邱传将
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天津尚德药缘科技有限公司
南开大学
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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

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  • the present invention is in the field of pharmaceutical technology, and in particular, the present invention relates to deuterated diterpene dianophoprin lactone, a process for its preparation and use in the preparation of a medicament.
  • the tumor is extremely human tt.
  • Anti-tumor research is a challenging and significant field in the field of life sciences. .
  • the past treatment methods focused on the eradication and killing of cancer cells.
  • the anti-tumor drugs commonly used in clinical practice are mainly fine drugs, such anticancer drugs have poor selectivity, strong side effects, and easy to produce drug resistance. Disadvantages are typical double-sided edge drugs, and it is difficult to eradicate cancer.
  • Many cancers have a higher recurrence rate. The high recurrence rate of malignant tumors has been a difficult problem for doctors in the midst of tumors.
  • Parthenolide is a compound extracted from the white chrysanthemum that was 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 her cancer caused by UV rays. In this study, it was found that parthenolide can inhibit the activation of the transcription factor F- ⁇ , and its activity may be mainly due to the Michael addition reaction with the parthenolide on the Cys38 of the P65/NF-KB subunit.
  • 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 a lot of attention.
  • the present invention is to provide a compound of the following formula (I), and any one of HX and hydrazine
  • the pharmaceutically acceptable salt thereof is a compound of the formula (II) and a formula ( ⁇ )
  • suitable solvents are lower aliphatic alcohols such as decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, and chloroform, dichlorodecane, benzene, toluene, tetrahydrofuran, dioxane Hexacyclic, 1,2-dioxaethane, pyridine, tetrachloromethane, diethyl ether, tert-butyl decyl ether, and/or a combination solvent of two or more of them; the base is low fc 3 ⁇ 43 ⁇ 4JM, such as Triterpenoid _», triethyl _», tripropyl _», tributylamine, and pyridine, 2-, 3-, and 4-mercaptopyridine, 2-, 3-, and 4-dimercaptopyridine, And salty, such as lithium carbonate, carbonic acid clock, sodium carbonate
  • cancer is acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, ⁇ Cancer, retinoblastoma, childhood hepatoblastoma, liver cancer, melanoma, squamous cell carcinoma, colorectal cancer, colon cancer, glioma, digestive neoplasm, nasopharyngeal carcinoma, glioma, stomach cancer, lung Adenocarcinoma, esophagus, lung cancer. .
  • a pharmaceutical composition for treating rheumatoid arthritis comprising at least one of said compounds as an active ingredient, and a pharmaceutically acceptable carrier or other compound for treating rheumatoid arthritis.
  • a pharmaceutical composition for treating cancer comprising at least one of said compound as an active ingredient, and a pharmaceutically acceptable carrier or other compound for treating cancer, wherein the cancer is preferably acute myeloid leukemia, Chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, mt ⁇ ⁇ Tumor, childhood hepatoblastoma, liver cancer, melanoma, ⁇ cancer, colorectal cancer, colon cancer, glioma, digestive neoplasm, nasopharyngeal carcinoma, glioma, gastric cancer, lung adenocarcinoma, esophageal cancer, Lung cancer.
  • the present invention is to provide a compound of the following formula (I), and any of the compounds of HX and
  • the pharmaceutically acceptable salt thereof is a compound of the formula (II) and a formula ( ⁇ )
  • the object of the present invention is to provide a method for preparing the formula (I), and the method of purifying the parthenolide and hydrazine in a suitable solvent, at a suitable temperature, and at a suitable time.
  • Chemical ⁇ 7, ⁇ 1 ⁇ 2 is:
  • suitable solvents are lower aliphatic alcohols such as decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, and chloroform, dichlorodecane, benzene, toluene, tetrahydrofuran, dioxane Hexacyclic, 1,2-dioxaethane, pyridine, tetrachloromethane, diethyl ether, tert-butyl decyl ether, and/or a combination solvent of two or more of them; the base is low fc 3 ⁇ 43 ⁇ 4JM, such as Triterpenoid _», triethyl _», tripropyl _», tributylamine, and pyridine, 2-, 3-, and 4-mercaptopyridine, 2-, 3-, and 4-dimercaptopyridine, And salty, such as lithium carbonate, carbonic acid clock, sodium carbonate
  • Middle cancer for acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, ⁇ Cancer, retinoblastoma, childhood hepatoblastoma, liver cancer, melanoma, squamous cell carcinoma, colorectal cancer, colon cancer, glioma, digestive neoplasm, nasopharyngeal carcinoma, glioma, stomach cancer, lung Adenocarcinoma, esophageal cancer, and cancer.
  • a pharmaceutical composition for treating rheumatoid arthritis comprising at least one of said compounds as an active ingredient, and a pharmaceutically acceptable carrier or other compound for treating rheumatoid arthritis.
  • a pharmaceutical composition for treating cancer comprising at least one of said compound as an active ingredient, and a pharmaceutically acceptable carrier or other compound for treating cancer, wherein the cancer is preferably acute myeloid leukemia, Chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, pancreatic cancer, reticulum Tumor, childhood hepatoblastoma, liver cancer, melanoma, ⁇ cancer, colorectal cancer, colon cancer, glioma, digestive neoplasm, nasopharyngeal carcinoma, glioma, gastric cancer, lung adenocarcinoma, esophageal cancer , lung cancer.
  • the cancer is preferably acute myeloid leukemia, Chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer
  • the compound 1-50 obtained by the method of the present invention was subjected to model preparation, drug grouping, and preparation of rat synovial cell culture supernatant according to the method provided in the literature [3].
  • test compounds were examined by the method provided in [3].
  • the effect of test compounds on the secretion of IL-1 ⁇ by synoviocytes was examined by the method provided in [8].
  • test compounds (I), (II) and (III) at the dose of 30 mg/kg.2d compared with the normal control and sodium chloride group are as follows:
  • HL-60, K562, MCF-7, CNE-1, CNE-2, SW620, A549, HepG-2, Ec9706, SGC7901, C6, SW1116, A498, ASPC-1, HT-29, HeLa, GL15, B16F1 , T24, SKOV3, SW579, PC-3 respectively represent acute leukemia cell line, chronic leukemia fine ⁇ Zhu, breast cancer fine ⁇ Zhu, human high score 4 ⁇ nasopharyngeal carcinoma fine ⁇ Zhu, human ⁇ 4 4 nasopharyngeal carcinoma ⁇ Zhu, cancer Zhu, lung cancer Zhu, liver cancer Zhu, esophageal cancer Zhu, gastric cancer Zhu, glioma fine capsule, colon cancer packet, kidney cancer packet, pancreatic cancer packet, Colon cancer cell line, cervical cancer cell line, human glioblastoma cell line, melanoma cell line, bladder cancer, fine, Zhu,
  • the compound (I), (II), (III) prepared in the examples and the excipient were added in a ratio of 5:1 by weight to a granule, and granulated and tableted to obtain a tablet.
  • the compounds (I), (II), and (III) prepared in the examples were added to the excipients in a ratio of 5:1 by weight to form a J-crossing agent.

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  • Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention relates to a deuterated dimethyl amine parthenolide as represented by formula (I), preparation method and uses thereof in drug preparation, in particular to the uses thereof in the preparation of drugs for treating cancers and rheumatoid arthritis.

Description

氘^ ^甲絲小白菊内酯， 其制备方法和在制备药物中的用途 技术领域  氘^^甲丝白白菊内, its preparation method and use in the preparation of medicine
本发明属于药物技术领域， 具体地说， 本发明涉及氘代二曱差安小白菊内 酯， 其制备方法和在制备药物中的用途。  The present invention is in the field of pharmaceutical technology, and in particular, the present invention relates to deuterated diterpene dianophoprin lactone, a process for its preparation and use in the preparation of a medicament.
背景技术  Background technique
肿瘤极^ ^着人类 tt, 我国 癌症患者约 200万人， 每年新发 160 万例， 这是一个不小的群体， 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 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^^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。  The tumor is extremely human tt. There are about 2 million cancer patients in China, and 1.6 million new cases are issued each year. This is a big group. Anti-tumor research is a challenging and significant field in the field of life sciences. . The past treatment methods focused on the eradication and killing of cancer cells. At present, the anti-tumor drugs commonly used in clinical practice are mainly fine drugs, such anticancer drugs have poor selectivity, strong side effects, and easy to produce drug resistance. Disadvantages are typical double-sided edge drugs, and it is difficult to eradicate cancer. Many cancers have a higher recurrence rate. The high recurrence rate of malignant tumors has been a difficult problem for doctors in the midst of tumors. More and more studies have confirmed that there are a few tumor stem cells in the tumor. They are usually in the Tweman cycle state, 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.
倍半萜内酯类化^小白菊内酯（Parthenolide )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***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 她癌。 对其作用才 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 与小白菊内酯发生了 Michael加成反应， 由于 NF-κΒ是调控肿瘤^ 1、 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 ^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 ¾^们的广泛关注。 Sesquiterpene lactones Parthenolide is a compound extracted from the white chrysanthemum that was 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 her cancer caused by UV rays. In this study, it was found that parthenolide can inhibit the activation of the transcription factor F-κΒ, and its activity may be mainly due to the Michael addition reaction with the parthenolide on the Cys38 of the P65/NF-KB subunit. Because NF-κΒ is an important gene that regulates tumor 1, metastasis, and drug resistance, Inhibition of F-κΒ activation may increase the sensitivity of the tumor to apoptosis induced by the tumor suppressor. Recently, Dr. Jordan, CT and colleagues at the University of Rochester Medical School in New York found that 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 a lot of attention.
目前未见关于式（I )化合物， 其制备方法和在制备药物中的用途的报道。  There are currently no reports on the compounds of formula (I), their preparation and their use in the preparation of medicaments.
发明内容  Summary of the invention
本发明在于提 ^-种如下式（I )的化合物，及其与 HX、 Ζ其中任意一种  The present invention is to provide a compound of the following formula (I), and any one of HX and hydrazine
Figure imgf000003_0001
Figure imgf000003_0001
其中 ΗΧ为氢氟酸、 盐酸、 氢溴酸、 氢 酸、 硫酸、 硝酸、 磷酸、 碳酸， 硼酸、 ***、 礫钼酸、 亚磷酸、 亚硫酸、 种檬酸、 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 J^ 、 i-^ 、 2-^ 、 酒石酸、 丙二酸、丁二酸、 富马酸、 乙醇酸、 石 J事酸、 甘氨酸、 Li^酸、 磺酸、 烟酸、 曱基吡啶酸、 异烟 酸、 二氯乙酸、 苯曱酸或取代苯曱酸的任意一种； Z为氟、 氯、 溴、 碘、 对曱 酯基、 曱磺酸酯基、 酯基或三氟曱基磺酸酯基的任意一种； 为 烃基、 环 羟扉^ ¾、 婦基、 tt、 芳基、 环基、 芳棘^ »、 芳基燁基、 芳基; ¾、 又代曱基、 烷 «JM« ^芳 的任意 一种。  Among them, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydrogen acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, selenous acid, sulphur molybdate, 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 acid, valeric acid, oleic acid, lauric acid, 曱J^, i-^, 2 -^, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic acid, sulphuric acid, glycine, Li acid, sulfonic acid, nicotinic acid, mercaptopicolinic acid, isonicotinic acid, dichloroacetic acid, Any one of benzoic acid or substituted benzoic acid; Z is any one of fluorine, chlorine, bromine, iodine, p-nonyl ester, sulfonate, ester or trifluorosulfonate; Any one of a hydrocarbon group, a cyclic oxindole, a cyclyl group, a tt, an aryl group, a cyclic group, an aromatic thorn group, an aryl fluorenyl group, an aryl group, a 3⁄4, a substituted fluorenyl group, and an alkane «JM« ^ aryl group .
其药学上可接受的盐为式（ II )化^和式（ ΠΙ )化^ The pharmaceutically acceptable salt thereof is a compound of the formula (II) and a formula (ΠΙ)
Figure imgf000004_0001
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0002
小白菊内酯 (1)。  Parthenolide (1).
上述方法中， 适当的溶剂为低级脂肪醇， 如曱醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 叔丁醇， 和氯仿， 二氯曱烷， 苯， 曱苯， 四氢呋喃， 二氧六环， 1,2- 二曱 乙烷， 吡啶， 四氯^ ^炭， ***， 叔丁基曱基醚， 和 /或其中两种或多种 溶剂的组合溶剂； 碱为低 fc ¾¾JM , 如三曱 _»、 三乙 _»、 三丙 _»、 三丁基胺， 和吡啶， 2-, 3-, 和 4-曱基吡啶， 2-, 3-, 和 4-二曱 基吡啶， 和无 才 W咸，如碳酸锂、碳酸钟、碳酸钠、碳酸铯、碳酸钙、碳酸镁；适当的温度为—20 °C 到 130 °C; 适当时间为 30 中到 24小时。  In the above method, suitable solvents are lower aliphatic alcohols such as decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, and chloroform, dichlorodecane, benzene, toluene, tetrahydrofuran, dioxane Hexacyclic, 1,2-dioxaethane, pyridine, tetrachloromethane, diethyl ether, tert-butyl decyl ether, and/or a combination solvent of two or more of them; the base is low fc 3⁄43⁄4JM, such as Triterpenoid _», triethyl _», tripropyl _», tributylamine, and pyridine, 2-, 3-, and 4-mercaptopyridine, 2-, 3-, and 4-dimercaptopyridine, And salty, such as lithium carbonate, carbonic acid clock, sodium carbonate, barium carbonate, calcium carbonate, magnesium carbonate; suitable temperature is -20 ° C to 130 ° C; suitable time is 30 to 24 hours.
一种制备式 ( I )化合物的盐的方法， 式（ I )化合物与 HX或 Ζ反应得式 (IV)和（V) ^^7, 具体 式为： A method for preparing a salt of a compound of the formula (I), wherein the compound of the formula (I) is reacted with HX or hydrazine to give the formula (IV) and (V) ^^7, the specific formula is:
Figure imgf000005_0001
所述化^在制备治疗类风湿性关节炎药物或辅助药物中的用途。
Figure imgf000005_0001
The use of the compound in the preparation of a medicament for treating rheumatoid arthritis or an auxiliary drug.
所述化合物化合物在制备治疗癌症药物或辅助治疗癌症药物中的用途。 其 中癌症^ 为急性髓系白血病、 慢性髓系白血病、 慢性淋巴白血病、 肾癌、 皮 肤癌、 乳腺癌、 子***、 卵巢癌、 膀胱癌、 脑肿瘤、 ***癌、 头颈鳞癌、 喉癌、 ^癌、 视网膜母细胞瘤、 儿童肝母细胞瘤、 肝癌、 黑色素瘤、 曱状腺 癌、 大肠癌、 结肠癌、 胶质瘤、 消化 中瘤、 鼻咽癌、 脑胶质瘤、 胃癌、 肺腺 癌、 食管 、 肺癌。 。  Use of the compound of the compound for the preparation of a medicament for treating cancer or for adjuvant treatment of cancer. Among them, cancer is acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, ^Cancer, retinoblastoma, childhood hepatoblastoma, liver cancer, melanoma, squamous cell carcinoma, colorectal cancer, colon cancer, glioma, digestive neoplasm, nasopharyngeal carcinoma, glioma, stomach cancer, lung Adenocarcinoma, esophagus, lung cancer. .
一种治疗类风湿性关节炎的药物组^ , 所述药物组^含有作为活性成 分的至少一种所述化^化合物以及药学上可接受的载体或其他治疗类风湿性 关节炎的化合物。  A pharmaceutical composition for treating rheumatoid arthritis, comprising at least one of said compounds as an active ingredient, and a pharmaceutically acceptable carrier or other compound for treating rheumatoid arthritis.
一种治疗癌症的药物组合物， 所述药物组^含有作为活性成分的至少一 种所述化^化合物以及药学上可接受的载体或其他治疗癌症的化合物， 其中 癌症优选为急性髓系白血病、 慢性髓系白血病、 慢性淋巴白血病、 肾癌、 皮肤 癌、 乳腺癌、 子***、 卵巢癌、 膀胱癌、 脑肿瘤、 ***癌、 头颈鳞癌、 喉 癌、 mt ^ 视网月莫母细包瘤、 儿童肝母细胞瘤、 肝癌、 黑色素瘤、 曱^^癌、 大肠癌、 结肠癌、 胶质瘤、 消化 中瘤、 鼻咽癌、 脑胶质瘤、 胃癌、 肺腺癌、 食管癌、 肺癌。 实施方式 A pharmaceutical composition for treating cancer, comprising at least one of said compound as an active ingredient, and a pharmaceutically acceptable carrier or other compound for treating cancer, wherein the cancer is preferably acute myeloid leukemia, Chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, mt ^ 视网月莫母细包Tumor, childhood hepatoblastoma, liver cancer, melanoma, 曱^^ cancer, colorectal cancer, colon cancer, glioma, digestive neoplasm, nasopharyngeal carcinoma, glioma, gastric cancer, lung adenocarcinoma, esophageal cancer, Lung cancer. Implementation
本发明在于提 ^-种如下式（I )的化合物，及其与 HX、 Ζ其中任意  The present invention is to provide a compound of the following formula (I), and any of the compounds of HX and
Figure imgf000006_0001
其中 ΗΧ为氢氟酸、 盐酸、 氢溴酸、 氢 酸、 硫酸、 硝酸、 酸、 碳酸, 硼酸、 ***、 礫钼酸、 亚磷酸、 亚硫酸、 种檬酸、 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 J^ 、 i-^ 、 2-^ 、 酒石酸、 丙二酸、丁二酸、 富马酸、 乙醇酸、 石 J事酸、 甘氨酸、 Li^酸、 磺酸、 烟酸、 曱基吡啶酸、 异烟 酸、 二氯乙酸、 苯曱酸或取代苯曱酸的任意一种； Z为氟、 氯、 溴、 碘、 对曱 酯基、 曱磺酸酯基、 酯基或三氟曱基磺酸酯基任意一种； ¾为烃 基、 环 羟棘^ »、 婦基、 芳基、 环基、 芳棘^ »、 芳 斜基、 芳基 JJF又代曱基、 烷 «JM««芳 ^ ¾任意一种。
Figure imgf000006_0001
Among them, hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydrogen acid, sulfuric acid, nitric acid, acid, carbonic acid, boric acid, selenous acid, sulphur molybdate, 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 acid, valeric acid, oleic acid, lauric acid, 曱J^, i-^, 2 -^, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic acid, sulphuric acid, glycine, Li acid, sulfonic acid, nicotinic acid, mercaptopicolinic acid, isonicotinic acid, dichloroacetic acid, Any one of benzoic acid or substituted benzoic acid; Z is any one of fluorine, chlorine, bromine, iodine, p-nonyl ester, sulfonate, ester or trifluorosulfonate; 3⁄4 It is any one of a hydrocarbon group, a cyclic hydroxyxanthene group, a thiol group, an aryl group, a cyclic group, an aromatic thorn group, an aryl group, an aryl group JJF, a fluorenyl group, and an alkane «JM«« 芳^3⁄4.
其药学上可接受的盐为式（ II )化^和式（ ΠΙ )化^  The pharmaceutically acceptable salt thereof is a compound of the formula (II) and a formula (ΠΙ)
Figure imgf000006_0002
Figure imgf000006_0002
( II ) ( ΠΙ ) 。  (II) ( ΠΙ ).
本发明的目的 于提供一种制备式（I )化^的方法， 小白菊内酯与氘 曱 在适当溶剂， ^适当的温度^牛下， ^^适当时间后， 纯化得式 (I)化^ 7, ^ ½式为: The object of the present invention is to provide a method for preparing the formula (I), and the method of purifying the parthenolide and hydrazine in a suitable solvent, at a suitable temperature, and at a suitable time. (I) Chemical ^ 7, ^ 1⁄2 is:
Figure imgf000007_0001
Figure imgf000007_0001
小白菊内酯 (1)。  Parthenolide (1).
上述方法中， 适当的溶剂为低级脂肪醇， 如曱醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 叔丁醇， 和氯仿， 二氯曱烷， 苯， 曱苯， 四氢呋喃， 二氧六环， 1,2- 二曱 乙烷， 吡啶， 四氯^ ^炭， ***， 叔丁基曱基醚， 和 /或其中两种或多种 溶剂的组合溶剂； 碱为低 fc ¾¾JM , 如三曱 _»、 三乙 _»、 三丙 _»、 三丁基胺， 和吡啶， 2-, 3-, 和 4-曱基吡啶， 2-, 3-, 和 4-二曱 基吡啶， 和无 才 W咸，如碳酸锂、碳酸钟、碳酸钠、碳酸铯、碳酸钙、碳酸镁；适当的温度为—20 °C 到 130 °C; 适当时间为 30 中到 24小时。  In the above method, suitable solvents are lower aliphatic alcohols such as decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, and chloroform, dichlorodecane, benzene, toluene, tetrahydrofuran, dioxane Hexacyclic, 1,2-dioxaethane, pyridine, tetrachloromethane, diethyl ether, tert-butyl decyl ether, and/or a combination solvent of two or more of them; the base is low fc 3⁄43⁄4JM, such as Triterpenoid _», triethyl _», tripropyl _», tributylamine, and pyridine, 2-, 3-, and 4-mercaptopyridine, 2-, 3-, and 4-dimercaptopyridine, And salty, such as lithium carbonate, carbonic acid clock, sodium carbonate, barium carbonate, calcium carbonate, magnesium carbonate; suitable temperature is -20 ° C to 130 ° C; suitable time is 30 to 24 hours.
一种制备式 ( I )化合物的盐的方法， 式（ I )化合物与 HX或 Ζ反应得式 (IV)和（V) ^^7, 具体 式为：  A method for preparing a salt of a compound of the formula (I), wherein a compound of the formula (I) is reacted with HX or hydrazine to give formula (IV) and (V) ^^7, the specific formula is:
Figure imgf000007_0002
Figure imgf000007_0002
所述化^在制备治疗类风湿性关节炎药物或辅助药物中的用途。  The use of the compound in the preparation of a medicament for treating rheumatoid arthritis or an auxiliary drug.
所述化合物化合物在制备治疗癌症药物或辅助治疗癌症药物中的用途。 其 中癌症^ 为急性髓系白血病、 慢性髓系白血病、 慢性淋巴白血病、 肾癌、 皮 肤癌、 乳腺癌、 子***、 卵巢癌、 膀胱癌、 脑肿瘤、 ***癌、 头颈鳞癌、 喉癌、 ^癌、 视网膜母细胞瘤、 儿童肝母细胞瘤、 肝癌、 黑色素瘤、 曱状腺 癌、 大肠癌、 结肠癌、 胶质瘤、 消化 中瘤、 鼻咽癌、 脑胶质瘤、 胃癌、 肺腺 癌、 食管癌、 申癌。 Use of the compound of the compound for the preparation of a medicament for treating cancer or for adjuvant treatment of cancer. Its Middle cancer ^ for acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, ^Cancer, retinoblastoma, childhood hepatoblastoma, liver cancer, melanoma, squamous cell carcinoma, colorectal cancer, colon cancer, glioma, digestive neoplasm, nasopharyngeal carcinoma, glioma, stomach cancer, lung Adenocarcinoma, esophageal cancer, and cancer.
一种治疗类风湿性关节炎的药物组^ , 所述药物组^含有作为活性成 分的至少一种所述化^化合物以及药学上可接受的载体或其他治疗类风湿性 关节炎的化合物。  A pharmaceutical composition for treating rheumatoid arthritis, comprising at least one of said compounds as an active ingredient, and a pharmaceutically acceptable carrier or other compound for treating rheumatoid arthritis.
一种治疗癌症的药物组合物， 所述药物组^含有作为活性成分的至少一 种所述化^化合物以及药学上可接受的载体或其他治疗癌症的化合物， 其中 癌症优选为急性髓系白血病、 慢性髓系白血病、 慢性淋巴白血病、 肾癌、 皮肤 癌、 乳腺癌、 子***、 卵巢癌、 膀胱癌、 脑肿瘤、 ***癌、 头颈鳞癌、 喉 癌、 胰腺癌、 视网月莫母细包瘤、 儿童肝母细胞瘤、 肝癌、 黑色素瘤、 曱^^癌、 大肠癌、 结肠癌、 胶质瘤、 消化 中瘤、 鼻咽癌、 脑胶质瘤、 胃癌、 肺腺癌、 食管癌、 肺癌。  A pharmaceutical composition for treating cancer, comprising at least one of said compound as an active ingredient, and a pharmaceutically acceptable carrier or other compound for treating cancer, wherein the cancer is preferably acute myeloid leukemia, Chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, pancreatic cancer, reticulum Tumor, childhood hepatoblastoma, liver cancer, melanoma, 曱^^ cancer, colorectal cancer, colon cancer, glioma, digestive neoplasm, nasopharyngeal carcinoma, glioma, gastric cancer, lung adenocarcinoma, esophageal cancer , lung cancer.
为了理解本发明， 下面以实施例进一步说明本发明， 但不限制本发明。 实施例 1: 式（I ) ^^的制备  In order to understand the present invention, the present invention will be further illustrated by the following examples without restricting the invention. Example 1: Preparation of Formula (I) ^^
Figure imgf000008_0001
取小白菊内酯（298 mg ) , 氘^ ^曱胺（1.47 g), 溶于 40 M1二氯曱烷， 加 入 4.97 g碳酸钟， 40 °0½ 18小时， 过滤， 减压^ ll, 石 交柱层析纯^ 到 化^ 7 (I ) (323 mg)。 ^勿 ( I ) : Ή MR (400 MHz, CDC13) δ 5.16 (br d, J= 11.9 Hz, IH), 3.79 (t, J= 9.1 Hz, IH), 2.73-2.66(m, 2H), 2.57 (d, J= 13.3 Hz, IH), 2.41 - 2.27 (m, IH), 2.28 - 2.16 (m, 8H), 2.16 - 1.96 (m, 4H), 1.65 (s, 3H), 1.63 - 1.54 (m, IH), 1.25 (s, 3H), 1.23-1.12 (m, IH); 13C NMR (100 MHz, CDC13) δ 176.6, 134.7, 125.0, 82.1, 66.5, 61.5, 57.7, 57.6, 47.7, 46.2, 41.1, 36.6, 29.9, 24.1, 17.2, 17.0. 实施例 2: 式（ II ) ^^的制备
Figure imgf000009_0001
Figure imgf000008_0001
Take parthenol (298 mg), 氘^^ guanamine (1.47 g), dissolve in 40 M1 dichlorodecane, add 4.97 g of carbonic acid clock, 40 °01⁄2 18 hours, filter, decompression ^ ll, stone cross column Analysis of pure ^ to chemical ^ 7 (I ) (323 mg). ^Do not (I): Ή MR (400 MHz, CDC1 3 ) δ 5.16 (br d, J = 11.9 Hz, IH), 3.79 (t, J = 9.1 Hz, IH), 2.73-2.66 (m, 2H), 2.57 (d, J= 13.3 Hz, IH), 2.41 - 2.27 (m, IH), 2.28 - 2.16 (m, 8H), 2.16 - 1.96 (m, 4H), 1.65 (s, 3H), 1.63 - 1.54 ( m, IH), 1.25 (s, 3H), 1.23-1.12 (m, IH); 13 C NMR (100 MHz, CDC1 3 ) δ 176.6, 134.7, 125.0, 82.1, 66.5, 61.5, 57.7, 57.6, 47.7, 46.2, 41.1, 36.6, 29.9, 24.1, 17.2, 17.0. Example 2: Preparation of formula (II) ^^
Figure imgf000009_0001
将 323 mg ( I )溶于 15 Ml***， ifT HCl气体，搅拌 10 , 離^ i宿得^ ( II ) (325 mg)。  323 mg ( I ) was dissolved in 15 Ml of diethyl ether, ifT HCl gas, and stirred for 10 minutes to obtain ^ ( II ) (325 mg).
化^ 7 ( II ) : ¾ NMR (400 MHz, D20) δ 5.24 (br d, J= 12.4 Hz, IH), 4.31 (t, J= 9.2 Hz, IH), 3.62(d, J= 13.6 Hz, IH), 3.42(d, J= 13.6 Hz, IH), 3.10(d, J= 9.2 Hz, IH), 2.97(s, 6H), 2.49 - 2.41(m, IH), 2.40 - 2.23 (m, 2H), 2.22 - 2.13(m, 2H), 2.11 - 2.04(m, 2H), 1.95 - 1.82 (m, IH), 1.71 (s, 3H), 1.34 (s, 3H), 1.27- 1.16 (m, 1H)。 实施例 3: 式（III) ^^的制备
Figure imgf000009_0002
^ 7 ( II ) : 3⁄4 NMR (400 MHz, D 2 0) δ 5.24 (br d, J = 12.4 Hz, IH), 4.31 (t, J = 9.2 Hz, IH), 3.62 (d, J = 13.6) Hz, IH), 3.42 (d, J = 13.6 Hz, IH), 3.10 (d, J = 9.2 Hz, IH), 2.97 (s, 6H), 2.49 - 2.41 (m, IH), 2.40 - 2.23 (m , 2H), 2.22 - 2.13(m, 2H), 2.11 - 2.04(m, 2H), 1.95 - 1.82 (m, IH), 1.71 (s, 3H), 1.34 (s, 3H), 1.27- 1.16 (m , 1H). Example 3: Preparation of formula (III) ^^
Figure imgf000009_0002
( I ) ( III ) 将 323 mg ^^物 ( I )溶于 10 Ml曱醇， 加入 127 mg富马酸， 搅拌 10分 钟， 减压 ^勿 (III) (450mg)。 ( I ) ( III ) 323 mg of the compound (I) was dissolved in 10 Ml of decyl alcohol, 127 mg of fumaric acid was added, and the mixture was stirred for 10 minutes, and the pressure was reduced to (III) (450 mg).
化^ 7 (III)： ¾ MR (400 MHz, D20) δ 6.68(s, 2H), 5.25 (br d, J= 12.4 Hz, 1H), 4.32 (t,J=9.2 Hz, 1H), 3.62(d,J= 13.6 Hz, 1H), 3.43(d,J= 13.6 Hz, 1H), 3.10(d J= 9.2 Hz, 1H), 2.98(s, 6H), 2.53 - 2.40(m, 1H), 2.39 - 2.24 (m, 2H), 2.21 - 2.1 l(m, 2H), 2.10-2.01(m,2H), 1.94-1.83(m, 1H), 1.71 (s, 3H), 1.35 (s, 3H), 1.28- 1.17 (m, 1H); 13C MR(100 MHz, D20) δ 177.4, 171.4, 135.7, 134.7, 124.9, 83.3, 66.6, 64.8, 55.6, 47.0, 45.1, 41.9, 39.9, 35.5, 28.2, 23.5, 16.1,15.9. 实施例 4: 化合物（I)、 （Π)、 （ΠΙ)的抗类风湿性关节炎活性测试 ^ 7 (III): 3⁄4 MR (400 MHz, D 2 0) δ 6.68(s, 2H), 5.25 (br d, J= 12.4 Hz, 1H), 4.32 (t, J=9.2 Hz, 1H), 3.62 (d, J = 13.6 Hz, 1H), 3.43 (d, J = 13.6 Hz, 1H), 3.10 (d J = 9.2 Hz, 1H), 2.98 (s, 6H), 2.53 - 2.40 (m, 1H) , 2.39 - 2.24 (m, 2H), 2.21 - 2.1 l(m, 2H), 2.10-2.01(m, 2H), 1.94-1.83(m, 1H), 1.71 (s, 3H), 1.35 (s, 3H) ), 1.28- 1.17 (m, 1H); 13 C MR (100 MHz, D 2 0) δ 177.4, 171.4, 135.7, 134.7, 124.9, 83.3, 66.6, 64.8, 55.6, 47.0, 45.1, 41.9, 39.9, 35.5 , 28.2, 23.5, 16.1, 15.9. Example 4: Anti-rheumatoid resistance test of compounds (I), (Π), (ΠΙ)
在类风湿性关节炎药物领域， 有很多文献报道药物成分对滑膜细胞 分泌 TNF-α, PGE2和 IL-Ιβ的影响， 用动物实验的数据来考察药物治疗 RA的效果。 这些文献有： [1] 鞠大宏， 贾红伟， 吴皓等， 鹿瓜多肽注射 液对 C II诱导的免疫性关节炎大鼠血清 TNF-α, IL-6以及 C II抗体活性的 影响， 中国中医基石出医学杂志， 2003,9 ( 11 ): 17。 [2] 何金华， 梁清华， 张花生等， 痹肿消汤对实验性关节炎大鼠血浆 TNF-α的影响， 湖南医科 大学学报， 2002, 27 (5): 524. [3] 黄清春， 张声鹏， 徐秋英， 复方丹参 对 II型胶原蛋白诱导大鼠模型滑膜细胞分泌及肿瘤坏死因子的影响， 现 代康复， 2001, 5 ( 10): 54-55。 [4]郑治刚, 细胞因子及其检测方法和临 床意义， 陝西医学检验， 2001, 16 (2): 59。 [5]周军， 方素萍， 齐云等， 葛根汤对佐剂性关节炎大鼠关节液炎症介质的影响， 中国实验方剂学杂 志， 2001, 7 (3 ): 29。 [6]马骥， 卢秉久， 朱晓明等， 痛痹颗粒治疗类风 湿性关节炎的药效学研究， 中医药学刊， 2001, 19 (6): 734。 [7]朱江， 谢文利， 晋玉璋等， 栀子对类风湿性关节炎大鼠血清 IL-Ιβ和 TNF-α的 影响， 中成药， 2005, 27 (7): 801。 [8]黄清春， 张声鹏， 黄伟毅等， 复 方丹参注射液对 CIA大鼠滑膜细胞 IL-ipmRNA表达的影响， 安徽中医 学院学报， 2002, 21 ( 5 ): 39-41。 In the field of rheumatoid arthritis drugs, there are many reports on the effects of pharmaceutical ingredients on the secretion of TNF-α, PGE2 and IL-Ιβ by synovial cells. The data of animal experiments were used to investigate the effect of drugs on RA. These documents are: [1] Yan Dahong, Jia Hongwei, Wu Wei, et al. Effects of Lugua polypeptide injection on serum TNF-α, IL-6 and C II antibody activity in rats with C II induced immune arthritis, Chinese traditional medicine cornerstone Medical Journal, 2003, 9 (11): 17. [2] He Jinhua, Liang Qinghua, Zhang Pean, etc. Effect of Qizhongxiao Decoction on plasma TNF-α in experimental arthritis rats, Journal of Hunan Medical University, 2002, 27 (5): 524. [3] Huang Qingchun Zhang Shengpeng, Xu Qiuying, Effect of Compound Danshen on the secretion of synoviocytes and tumor necrosis factor in rat model induced by type II collagen, Modern Rehabilitation, 2001, 5 (10): 54-55. [4] Zheng Zhigang, Cytokine and its detection methods and clinical significance, Shaanxi Medical Laboratory, 2001, 16 (2): 59. [5] Zhou Jun, Fang Suping, Qi Yun et al. Effects of Gegen Decoction on inflammatory mediators of joint fluid in rats with adjuvant arthritis, Chinese Journal of Experimental Traditional Chinese Medicine, 2001, 7 (3 ): 29. [6] Ma Wei, Lu Bingjiu, Zhu Xiaoming et al. Pharmacodynamic study of Tongzhi Granules in the treatment of rheumatoid arthritis, Journal of Traditional Chinese Medicine, 2001, 19 (6): 734. [7] Zhu Jiang, Xie Wenli, Jin Yuxi, et al. Effects of medlar on serum IL-Ιβ and TNF-α in rats with rheumatoid arthritis, Chinese patent medicine, 2005, 27 (7): 801. [8] Huang Qingchun, Zhang Shengpeng, Huang Weiyi, etc. Effect of Fangdanshen Injection on IL-ipmRNA expression in synovial cells of CIA rats, Journal of Anhui University of Traditional Chinese Medicine, 2002, 21 ( 5 ): 39-41.
取本发明方法获得的化合物 1-50, 按文献 [3]提供的方法进行模型制 备、 药物分组、 大鼠滑膜细胞培养基上清的制备。  The compound 1-50 obtained by the method of the present invention was subjected to model preparation, drug grouping, and preparation of rat synovial cell culture supernatant according to the method provided in the literature [3].
按文献 [3]提供的方法考察测试化合物对滑膜细胞分泌 TNF-α, PGE2 的影响。按文献 [8]提供的方法考察测试化合物对滑膜细胞分泌 IL-1 β的 影响。  The effects of test compounds on the secretion of TNF-α and PGE2 by synovial cells were examined by the method provided in [3]. The effect of test compounds on the secretion of IL-1 β by synoviocytes was examined by the method provided in [8].
测试化合物（ I ) 、 （ II ) 、 ( III )在剂量 30 mg/kg.2d下与正常对照、 氯化 钠组的实验数据如下：  The experimental data of test compounds (I), (II) and (III) at the dose of 30 mg/kg.2d compared with the normal control and sodium chloride group are as follows:
滑膜细 ^^养上清中 TNF-α的含量（ X土 s, ng/mL )  The content of TNF-α in the synovial membrane (X soil s, ng/mL)
Figure imgf000011_0001
(I) 15.34士 1.86
Figure imgf000011_0001
(I) 15.34 ± 1.86
( II ) 18.66士 0.88  (II) 18.66 士0.88
( III ) 23.66士 1.65 本发明以大鼠为人类 RA动物模型，采用滑膜细^^^咅养的方法，观察了 (I)、 （ II )、 (III)对滑膜细胞分泌 TNF-α, PGE2和 IL-Ιβ的影 响， 结果表明， 化合物 （I)、 （Π)、 （ΠΙ)在大剂量组、 小剂量组均能 显著下调 TNF-a, PGE2和 IL-Ιβ的含量， 从而达到减轻致骨和软骨的破 坏恢复关节活动功能， 发挥治疗 RA效果。  (III) 23.66±1.65 In the present invention, rats were used as human RA animal models, and the secretion of TNF-α by synovial cells was observed by means of synovial membranes (I), (II) and (III). The effects of PGE2 and IL-Ιβ showed that the compounds (I), (Π) and (ΠΙ) could significantly down-regulate the contents of TNF-a, PGE2 and IL-Ιβ in the high-dose group and the low-dose group. Reduce the damage of bone and cartilage and restore joint function, and play a role in the treatment of RA.
实施例 3: 化合物抑制癌症的活性测试 Example 3: Activity test of compounds inhibiting cancer
将各种癌细胞配成 2x105Μ1细胞悬液，加入 24 圆底细^^养板内，分 别加入 (I)、 （ II )、 （III) , ^-测试浓度 5孔， 置 37°C、 5%C02 ^^湿度 牛下培养 18小时，用 M T法在醇联检测仪 570 nm波长测得^度 (A)值， 计算出本发明^^对测试癌细胞的抑制作用。 Various cancer cells were prepared into 2x10 5 Μ1 cell suspension, added to the 24 round bottom fine ^^ plate, respectively (I), (II), (III), ^- test concentration 5 holes, set at 37 ° C, The 5% C0 2 ^^ humidity was cultured for 18 hours under the bovine, and the degree (A) value was measured by the MT method at a wavelength of 570 nm of the alcohol detector to calculate the inhibitory effect of the present invention on the test cancer cells.
表 1 ( I )、 （ II )、 (III)对各种癌细胞的抑制活性 ( IC5。, μΜ ) Table 1 (I), (II), (III) Inhibitory activity against various cancer cells (IC 5 , μΜ )
Figure imgf000012_0001
C6 8.9 15.9 17.1
Figure imgf000012_0001
C6 8.9 15.9 17.1
SW1116 12.4 21.5 22.7  SW1116 12.4 21.5 22.7
A498 12.5 15.3 19.3  A498 12.5 15.3 19.3
ASPC-1 13.9 19.1 22.4  ASPC-1 13.9 19.1 22.4
HT-29 10.8 19.8 19.8  HT-29 10.8 19.8 19.8
HeLa 11.4 17.3 19.7  HeLa 11.4 17.3 19.7
GL15 12.6 14.3 21.5  GL15 12.6 14.3 21.5
B16F1 9.4 17.2 25.2  B16F1 9.4 17.2 25.2
T24 12.2 19.6 24.9  T24 12.2 19.6 24.9
SKOV3 15.9 19.4 30.4  SKOV3 15.9 19.4 30.4
SW579 17.3 22.5 28.4  SW579 17.3 22.5 28.4
PC-3 12.0 18.4 27.5  PC-3 12.0 18.4 27.5
其中 HL-60、 K562、 MCF-7、 CNE-1、 CNE-2、 SW620、 A549、 HepG-2, Ec9706、 SGC7901、 C6、 SW1116、 A498、 ASPC-1、 HT-29, HeLa, GL15、 B16F1、 T24、 SKOV3、 SW579、 PC-3 分别表示急性白血病细胞株、 慢性白血 病细 ^朱、 乳腺癌细 ^朱、 人高分 4匕鼻咽癌细 ^朱、 人氐分 4匕鼻咽癌细 ^朱、 癌细 朱、 肺癌细 朱、 肝癌细 朱、 食管癌细 朱、 胃癌细 朱、 脑胶 质瘤细包株、 结肠癌细包株、 肾癌细包株、 胰腺癌细包株、 结肠癌细包株、 子 ***细胞株、 人胶质母细胞瘤细胞株、 黑素瘤细胞株、 膀胱癌细 ^朱、 卵巢 癌细 ^朱、 曱 Ψ ^癌细 朱、 ***癌细 ^朱。  Among them HL-60, K562, MCF-7, CNE-1, CNE-2, SW620, A549, HepG-2, Ec9706, SGC7901, C6, SW1116, A498, ASPC-1, HT-29, HeLa, GL15, B16F1 , T24, SKOV3, SW579, PC-3 respectively represent acute leukemia cell line, chronic leukemia fine ^ Zhu, breast cancer fine ^ Zhu, human high score 4 匕 nasopharyngeal carcinoma fine ^ Zhu, human 氐 4 4 nasopharyngeal carcinoma ^Zhu, cancer Zhu, lung cancer Zhu, liver cancer Zhu, esophageal cancer Zhu, gastric cancer Zhu, glioma fine capsule, colon cancer packet, kidney cancer packet, pancreatic cancer packet, Colon cancer cell line, cervical cancer cell line, human glioblastoma cell line, melanoma cell line, bladder cancer, fine, Zhu, ovarian cancer, fine, Zhu, 曱Ψ, cancer, Zhu, prostate cancer, fine^ Zhu.
活性测试结 明， 筛选的^^对受试细^^示出较强的抑制活性， 而且 对正常细 50 μΜ时， 均^ 现出明显的杀伤作用。 实施例 4: 注射液  The activity test showed that the screened ^^ showed a strong inhibitory activity on the test, and it showed obvious killing effect on the normal fine 50 μΜ. Example 4: Injection
实施例制备的^^物（ I ) 、 （ II ) 、 （ ΠΙ )用少量的 DMSO溶解后， 按常 注射用水， 精滤， 灌封灭菌制成注射液。 实施例 5: 片剂 The compound (I), (II), and (ΠΙ) prepared in the examples were dissolved in a small amount of DMSO, and then injected into water, finely filtered, and potted to prepare an injection. Example 5: Tablet
实施例制备的化^ (I) 、 （ II ) 、 (III)与赋形剂按照重量比为 5:1 的 比例加 武形剂， 制粒压片， 得片剂。  The compound (I), (II), (III) prepared in the examples and the excipient were added in a ratio of 5:1 by weight to a granule, and granulated and tableted to obtain a tablet.
实施例 6: 胶嚢 Example 6: Plastic bottles
实施例制备的化^ (I) 、 （ II ) 、 (III)与赋形剂按照重量比为 5:1 的 比例加 武形剂， 制成 J交嚢。  The compounds (I), (II), and (III) prepared in the examples were added to the excipients in a ratio of 5:1 by weight to form a J-crossing agent.
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变原料、 工艺^牛等环节来实 ii^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 ϋ显而易见的， 麵皮视为包括在本发明的范围之内。  The compounds, uses and methods of the invention have been described by way of specific examples. Those skilled in the art can appropriately change the raw materials, the process, and the like by referring to the contents of the present invention, and the related changes are not deviated from the content of the present invention. All similar substitutions and modifications are known to the prior art. It will be apparent to those skilled in the art that the dough is considered to be included within the scope of the present invention.

Claims

权 利 要 求 书 Claims
1、 一种如下式（I )的化合物， 及其与 HX、 Ζ其中任意一种形成在药学 A compound of the following formula (I), which is formed in pharmacy with any of HX and hydrazine
Figure imgf000015_0001
Figure imgf000015_0001
2、 根据权利要求 1所述的化合物， 其中 ΗΧ为氢氟酸、 盐酸、 氢溴酸、 氢 碘酸、 硫酸、 硝酸、 磷酸、 碳酸， 硼酸、 ***、 礫钼酸、 亚磷酸、 亚硫酸、 种檬酸、 马来酸、 1 苹果酸、 L-苹果酸、 DL-苹果酸、 L-乳酸、 D-乳酸、 DL-乳 酸、草酸、 曱石 、 戊酸、 油酸、 月桂酸、对曱 黄酸、 1-^ 、 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、 月 酸、 磺酸、 烟酸、 曱基吡啶酸、 异烟酸、 二氯乙酸、 苯曱酸或耳又代苯曱酸的任意一 种； Z为氟、 氯、 溴、 碘、 对曱 黄酸酯基、 曱磺酸酯基、 ^黄酸酯 ^三氟 曱基磺酸酯基的任意一种； ¾为烃基、 环 羟 UM¾¾、 婦基、 絲、 芳基、 杂环基、 芳_¾ 又^»、 芳基婦基、 芳基 tt、 « 又代曱基、 烷 取^ M芳 ^ ¾的任意一种。  2. The compound according to claim 1, wherein the hydrazine is hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, boric acid, selenous acid, schmomolybdic acid, phosphorous acid, sub- Sulfuric acid, citric acid, maleic acid, 1 malic acid, L-malic acid, DL-malic acid, L-lactic acid, D-lactic acid, DL-lactic acid, oxalic acid, vermiculite, valeric acid, oleic acid, lauric acid, For ruthenic acid, 1-^, 2-^xanthic acid, citric acid, tartaric acid, malonic acid, succinic acid, fumaric acid, glycolic acid, thionic acid, glycine, niacin, sulfonic acid, nicotinic acid, Any one of pyrithione, isonicotinic acid, dichloroacetic acid, benzoic acid or benzoic acid; Z is fluorine, chlorine, bromine, iodine, p-xanthate, sulfonate Any one of the yellow esters of trifluorosulfonyl sulfonate; 3⁄4 is a hydrocarbon group, a cyclic hydroxy group, a sulfonyl group, a aryl group, a aryl group, a heterocyclic group, a aryl group, an aryl group, an aryl group , aryl tt, « again thiol, alkane ^ M fang ^ 3⁄4 of any one.
3、 根据权利要求 1所述的^^物， 其药学上可接受的盐为式（ II )化合物 和式（ III )化合物 3. The compound according to claim 1, wherein the pharmaceutically acceptable salt is a compound of the formula (II) and a compound of the formula (III)
Figure imgf000016_0001
Figure imgf000016_0001
Figure imgf000016_0002
Figure imgf000016_0002
小白菊内酯 (1)。  Parthenolide (1).
5、根据权利要求 4所述的制备式（I) 的方法中，适当的溶剂为 ^^及 脂肪醇， 如曱醇、 乙醇、 丙醇、 异丙醇、 正丁醇、 叔丁醇， 和氯仿， 二氯曱烷， 苯， 曱苯， 四氢呋喃， 二氧六环， 1,2-二曱氧基乙烷， 吡啶， 四氯化碳， ***， 叔丁基曱基醚，和 /或其中两种或多种溶剂的组合溶剂；碱为^ fc tt又代胜， 如三曱基胺、三乙基胺、三丙基胺、三丁基胺，和吡啶， 2-, 3-, 和 4-曱基吡啶, 2—, 3-, 和 4-二曱 吡啶， 和无才 咸， 如碳酸锂、 碳酸钟、 碳酸钠、 碳酸铯、 碳酸钙、碳酸镁；适当的温度为 -20 °〇到 130 °C;适当时间为 30 中到 24小时。  5. The process for the preparation of the formula (I) according to claim 4, wherein a suitable solvent is a fatty alcohol such as decyl alcohol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, and Chloroform, dichlorodecane, benzene, toluene, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, pyridine, carbon tetrachloride, diethyl ether, tert-butyl decyl ether, and/or a combination solvent of two or more solvents; the base is ^fc tt again, such as tridecylamine, triethylamine, tripropylamine, tributylamine, and pyridine, 2-, 3-, and 4-mercaptopyridine, 2-, 3-, and 4-dipyridinium, and salt-free, such as lithium carbonate, carbonic acid, sodium carbonate, barium carbonate, calcium carbonate, magnesium carbonate; suitable temperature is -20 ° 〇 to 130 °C; appropriate time is 30 to 24 hours.
6、 一种制备式 (I)化合物的盐的方法， 式（I)化合物与 HX或 Ζ反应 得式（IV)和（ V )化合物， 具体反应式为： 6. A process for the preparation of a salt of a compound of formula (I), wherein a compound of formula (I) is reacted with HX or hydrazine to give compounds of formula (IV) and (V), the specific reaction formula being:
Figure imgf000017_0001
Figure imgf000017_0001
7、权利要求 1至 3任一权利要求的^^在制备治疗类风湿性关节炎药物 或辅助药物中的用途。 Use of any of claims 1 to 3 for the preparation of a medicament for treating rheumatoid arthritis or an auxiliary medicament.
8、 权利要求 1至 3任一权利要求的化^在制备治疗癌症药物或辅助治疗 癌症药物中的用途。 其中癌症^ 为急性髓系白血病、 慢性髓系白血病、 慢性 淋巴白血病、 肾癌、 皮肤癌、 乳腺癌、 子***、 卵巢癌、 膀胱癌、 脑肿瘤、 ***癌、 头颈鳞癌、 喉癌、 ^ ^癌、 视网膜母细胞瘤、 儿童肝母细胞瘤、 肝 癌、 黑色素瘤、 曱状腺癌、 大肠癌、 结肠癌、 胶质瘤、 消化 il中瘤、 鼻咽癌、 脑胶质瘤、 胃癌、 肺腺癌、 食管癌、 肺癌。  A use according to any one of claims 1 to 3 for the preparation of a medicament for treating cancer or for adjuvant treatment of cancer. Among them, cancer is acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, ^ ^CANCER, retinoblastoma, childhood hepatoblastoma, liver cancer, melanoma, squamous cell carcinoma, colorectal cancer, colon cancer, glioma, digestive il tumor, nasopharyngeal carcinoma, glioma, gastric cancer , lung adenocarcinoma, esophageal cancer, lung cancer.
9、一种治疗类风湿性关节炎的药物组^ , 所述药物组^含有作为活性 成分的至少一种权利要求 1至 3任一权利要求的化合物以及药学上可接受的载 体或其他治疗类风湿性关节炎的化合物。  A pharmaceutical composition for treating rheumatoid arthritis, comprising at least one compound according to any one of claims 1 to 3 as an active ingredient, and a pharmaceutically acceptable carrier or other therapeutic class A compound of rheumatoid arthritis.
10、 一种治疗癌症的药物组^ , 所述药物组^含有作为活性成分的至 少一种权利要求 1至 3 权利要求的化合物以及药学上可接受的载体或其他 治疗癌症的化^ , 其中癌症优选为急性髓系白血病、 慢性髓系白血病、 慢性 淋巴白血病、 肾癌、 皮肤癌、 乳腺癌、 子***、 卵巢癌、 膀胱癌、 脑肿瘤、 ***癌、 头颈鳞癌、 喉癌、 ^ ^癌、 视网膜母细胞瘤、 儿童肝母细胞瘤、 肝 癌、 黑色素瘤、 曱状腺癌、 大肠癌、 结肠癌、 胶质瘤、 消化 il中瘤、 鼻咽癌、 脑胶质瘤、 胃癌、 肺腺癌、 食管癌、 肺癌。  A pharmaceutical composition for treating cancer, comprising at least one compound according to Claims 1 to 3 as an active ingredient, and a pharmaceutically acceptable carrier or other cancer treatment, wherein the cancer Preferred for acute myeloid leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, kidney cancer, skin cancer, breast cancer, cervical cancer, ovarian cancer, bladder cancer, brain tumor, prostate cancer, head and neck squamous cell carcinoma, laryngeal cancer, ^ ^ Cancer, retinoblastoma, childhood hepatoblastoma, liver cancer, melanoma, squamous cell carcinoma, colorectal cancer, colon cancer, glioma, digestive il tumor, nasopharyngeal carcinoma, glioma, stomach cancer, lung Adenocarcinoma, esophageal cancer, lung cancer.
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