WO2014071863A1 - 苯腈类化合物作为制备抗肿瘤药物的应用 - Google Patents

苯腈类化合物作为制备抗肿瘤药物的应用 Download PDF

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WO2014071863A1
WO2014071863A1 PCT/CN2013/086723 CN2013086723W WO2014071863A1 WO 2014071863 A1 WO2014071863 A1 WO 2014071863A1 CN 2013086723 W CN2013086723 W CN 2013086723W WO 2014071863 A1 WO2014071863 A1 WO 2014071863A1
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cancer
preparation
formula
antitumor drug
compound according
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刘长令
柴宝山
关爱莹
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中国中化股份有限公司
沈阳化工研究院有限公司
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    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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 invention belongs to the field of medicine and relates to the field of anti-tumor drugs. Specifically, it relates to the use of a benzonitrile compound as an antitumor drug.
  • Patent No. 3,331,735 reports that the compounds of the following formula have killing and nematicidal activity: (X is H, F, C1 or Br, at least one of which is not H);
  • An object of the present invention is to provide a use of a benzonitrile compound of the formula I as shown in the preparation of an antitumor drug.
  • a benzonitrile compound As a preparation of an antitumor drug, a benzonitrile compound has a compound structure as shown in Formula I:
  • Ri R 2 , R 3 and R 4 may be the same or different and are respectively selected from fluorine, chlorine, bromine or iodine.
  • benzonitrile-based compounds preferred compounds for use as antitumor drugs are:
  • Ri R 2 , R 3 and R 4 may be the same or different and are each selected from fluorine or chlorine.
  • benzonitrile compound as an antitumor agent application further preferred compound is: formula I Ri R 2, R 3, R4 is selected from chloro or fluoro simultaneously; or, R 2, R4 is selected from fluoro, R 3 is selected from From chlorine.
  • Ri R 2 , R 3 and R 4 are simultaneously selected from chlorine.
  • the compounds of the formula I according to the invention can be obtained commercially or by known methods, see in particular 485050, CN101092376, US20080019906, Journal of Medicinal Chemistry, 21(9)-913, 1978, etc.; or by the following route:
  • Ri is as previously described, and X is selected from the group consisting of chlorine, bromine or iodine.
  • the present invention includes a formulation which is prepared by dispersing a compound contained in the above formula I as an active ingredient, and a formulation thereof.
  • the preparation method is: dissolving the compound covered by the present invention into a water-soluble organic solvent, a nonionic surfactant, a water-soluble lipid, various cyclodextrin, a fatty acid, a fatty acid ester, a phospholipid or a combination thereof.
  • the preparation solution is prepared in a solvent; physiological saline is added to obtain 1-20% of carbohydrates.
  • the organic solvent includes polyethylene glycol (PEG), ethanol, propylene glycol or a combination solvent of these solvents.
  • the compounds and prodrugs covered by the formula I of the present invention are used for the preparation of a therapeutic, prophylactic or palliative antitumor drug or pharmaceutical preparation, and the pharmaceutically active ingredient is one or two or more benzonitrile compounds of the formula I . It is especially useful for treating or alleviating cancer caused by tumor cells in human tissues or organs.
  • the cancer referred to is colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, kidney cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer, rectal cancer. , nasopharyngeal carcinoma, glioma, osteosarcoma or gastric cancer.
  • the compound of the present invention can be used as an active ingredient of an antitumor drug, and can be used alone or in combination with other antitumor and antiviral drugs.
  • the combination therapy referred to in the present invention includes the use of at least one compound of the present invention and a reactive derivative thereof in combination with one or more other anti-tumor antiviral drugs to increase the overall therapeutic effect.
  • the amount of drug to be administered and the time of administration should be based on the most reasonable therapeutic effect achieved under different conditions.
  • the pharmaceutical agents encompassed include an effective amount of a compound of formula I.
  • effective dose herein is meant the amount of the compound required to produce a therapeutic effect in the subject being treated.
  • the effective dose or dose can be varied by an experienced person depending on the recommendations of the situation. For example, the type of tumor treated is different, and the drug usage is different; whether it is shared with other treatments such as other anti-tumor drugs or antiviral drugs, the dosage may change. Any formulation form that can be used can be made.
  • the compound encompassed by the formula I in the present invention is generally soluble in an organic solvent, a water-soluble solvent, and an organic solvent and a mixed solvent of a water-soluble solvent and water.
  • the water-soluble solvent is preferably an alcohol, polyethylene glycol, N-methyl-2-pyrrolidinone, hydrazine, hydrazine-dimethylacetamide, hydrazine, hydrazine-dimethylformamide, dimethyl sulfoxide, acetonitrile, and It is used together.
  • the alcohol is preferably methanol, ethanol, isopropanol, glycerol or ethylene glycol.
  • the compound of the present invention can be formulated into a preparation by mixing with a usual preparation carrier.
  • the compound is dissolved in a water-soluble organic solvent, an aprotic solvent, a water-soluble lipid, a cyclodextrin, a fatty acid, a phospholipid or a mixed solvent of these solvents to prepare a drug solution; and then adding physiological saline to obtain 1-20% A carbohydrate, such as an aqueous solution of glucose.
  • a water-soluble organic solvent such as an aprotic solvent
  • a water-soluble lipid such as an aqueous solution of glucose
  • the product drug prepared by using the compound of the above formula I as an active ingredient can be administered by oral or parenteral route, or can be administered by a drug pump in vivo and other methods, and the parenteral route referred to herein is given.
  • Medicine refers to subcutaneous, intramuscular, intravenous, intraarterial, atrial, intrasynovial, intrasternal, intrathecal, invasive Intra-injury, intracranial injection or instillation techniques.
  • the mixing eventually becomes the desired pharmaceutical dosage form.
  • It may be tablets, pills, capsules, granules, syrups, injections, lyophilized powders, emulsions, powders, lyophilized powders, dropping pills, milk suspensions, aqueous suspensions, aqueous solutions, colloids, colloidal solutions, sustained release Formulations, nanoformulations or other forms of dosage form for use in animals or clinics.
  • the compounds of the formula I of the present invention are useful for the treatment, prevention or alleviation of the preparation of cancer drugs for a certain tissue or organ.
  • the cancers mentioned include, but are not limited to, colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, kidney cancer, leukemia, prostate cancer, pancreatic cancer, bladder cancer. , rectal cancer, nasopharyngeal carcinoma, glioma, osteosarcoma or gastric cancer.
  • Human cancer cell lines used Bladder cancer T24, J82, prostate cancer LNCap, human lung cancer A549, H460, H520, human leukemia HL-60, and the like.
  • Example 1 Conventional use of human lung cancer A549, human leukemia HL-60, human bladder cancer cell T24, etc.
  • the inhibition rate of the test sample on the growth of each human cancer cell was determined by MTT method.
  • the cells were removed from the incubator, washed twice with PBS solution, digested with 0.25% trypsin solution, added to the medium to terminate digestion, centrifuged and pipetted to form a cell suspension, and counted under an inverted microscope.
  • the cells were prepared into a cell suspension at a concentration of 5 ⁇ 10 4 /ml, and 100 ⁇ l of the cells were added to each well of a 96-well plate, placed in 5% carbon dioxide, and incubated overnight at 37 ° C in humidified air, and the above dilution was added to a different concentration gradient.
  • the drug was tested for 48 h, and MTT was added. After 4 hours of reaction, the living cells were reduced to produce formazan by MTT tetrazolium, then DMSO was added to dissolve formazan, and the absorbance at 570 nm was measured on a 96-well plate reader.
  • Example 2 Growth inhibition rate of human bladder cancer cells ⁇ 24, J82, prostate cancer cells LNCap, lung cancer cells A549, H460, H520, about 1000 to 3000 cells were seeded by in vitro cell culture technique.
  • a cell culture medium capable of culturing the test tumor cell strain well known to those skilled in the art was added to each well, and cultured in a cell culture incubator (CO 2 5%, 370 ° C) for 24 hours. Then, the appropriate concentration of the reference drug and the test substance prepared above are added to the well, and it is noted that the volume of the addition solution does not exceed 0.5% of the total volume. The cells were allowed to continue to grow in the cell culture incubator. After one week, the cell culture medium was aspirated and washed once with cold 1 ml of PBS. Then, it was fixed with 1% formalin for 10 minutes at room temperature, and then washed once with cold 1 ml of PBS.
  • Control agent AZD6244 generic name Sel U m e tinib.
  • Inhibition rate remaining cells per concentration treated / cells remaining in the non-medicated control group X 100%

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Abstract

本发明公开了一种如通式（I）所示的苯腈类化合物作为制备抗肿瘤药物的应用，（I）式中各取代基的定义见说明书。通式（I）化合物具有很好的抗肿瘤活性，特别是对人肺癌 A549、人白血病 HL-60 等活性优异。

Description

苯腈类化合物作为制备抗肿瘤药物的应用 技术领域
本发明属于医药领域，涉及一种抗肿瘤药物领域。具体地涉及一种苯腈类化合物 作为抗肿瘤药物的应用。
背景技术
已有许多间苯二腈类化合物的制备与应用报道，专利 US3331735报道了如下通式 化合物具有杀 、 杀线虫活性：
Figure imgf000002_0001
(X为 H, F, C1或 Br， 其中至少一个不为 H);
当 X均选自 C1时， 即为农用杀菌 构如下:
Figure imgf000002_0002
然而， 现有技术中， 上述苯腈类化合物未见作为医药领域抗肿瘤药物的报道。
发明内容
本发明的目的在于提供一种结构如通式 I所示的苯腈类化合物在制备抗肿瘤药 物中的应用。
本发明的技术方案如下：
苯腈类化合物作为制备抗肿瘤药物的应用， 化合物结构如通式 I 所示：
Figure imgf000002_0003
式中：
Ri R2、 R3、 R4可相同或不同， 分别选自氟、 氯、 溴或碘。
上述苯腈类化合物中作为抗肿瘤药物应用时较优选的化合物为： 通式 I 中
Ri R2、 R3、 R4可相同或不同， 分别选自氟或氯。
上述苯腈类化合物中作为抗肿瘤药物应用时进一步优选的化合物为： 通式 I 中 Ri R2、 R3、 R4同时选自氯或氟； 或 、 R2、 R4选自氟， R3选自氯。
上述苯腈类化合物中作为抗肿瘤药物应用时最优选的化合物为： 通式 I中：
Ri R2、 R3、 R4同时选自氯。
本发明具有抗肿瘤活性的化合物通过表 1中列出的具体化合物来说明，但并不限 定本发明。
Figure imgf000003_0001
表 1
Figure imgf000003_0002
本发明的通式 I 化合物可以通过市售购得或通过已知方法制备， 具体参见 485050、 CN101092376、 US20080019906、 Journal of Medicinal Chemistry, 21(9) -913,1978等； 或通过如下路线制得：
Figure imgf000004_0001
式中： Ri如前所述， X选自氯、 溴或碘。
本发明包括以上述通式 I 所包含的化合物为活性成分配制成的制剂成分以及其 制剂组成的配制。制剂制备方法为： 将本发明所涵盖的化合物溶解到水溶性的有机溶 剂、 非离子性的表面活性剂、 水溶性的类脂、 各种环糊精、 脂肪酸、 脂肪酸酯、 磷脂 或其组合溶剂中而制得制剂溶液； 加入生理盐水获 1-20%的碳水化合物。所述有机溶 剂包括聚乙二醇 （PEG) , 乙醇， 丙二醇或这些溶剂的组合溶剂。
本发明所述通式 I 中所涵盖的化合物和前药用于制备治疗、 预防或缓解抗肿瘤 药物或药物制剂， 药物活性成分为一种或两种以上通式 I 所示的苯腈类化合物。 尤 其适用于治疗或缓解人体组织或器官肿瘤细胞引起的癌症。 所指癌症优选结肠癌、 肝癌、 淋巴瘤、 肺癌、 食管癌、 乳腺癌、 中枢神经系统肿瘤、 黑色素瘤、 卵巢癌、 宫颈癌、 肾癌、 白血病、 前列腺癌、 胰腺癌、 膀胱癌、 直肠癌、 鼻咽癌、 神经胶质 瘤、 骨肉瘤或胃癌等。
本发明化合物可用于抗肿瘤药物的活性成分， 可以单独使用， 也可以与其它抗 肿瘤、 抗病毒药物联合用药。 本发明所指的联合用药治疗过程中， 包括运用至少一 种本发明化合物以及其活性衍生物与其他一种或多种抗肿瘤抗病毒药物一起使用以 增加总体疗效。 联合用药时的药量和给药时间应根据不同的情况下所取得的最合理 治疗效果而定。
所涵盖的药剂配伍包括通式 I中的化合物的有效剂量。 此处的 "有效剂量"指的是 对于所治疗对象能产生治疗效果所需要该化合物的用量。 该有效剂量或剂量可以由 有经验者根据不同情况的建议而不同。 比如， 所治疗的肿瘤种类不同， 药物的用法 不同； 是否与其它的治疗方法如其他抗肿瘤药物或抗病毒药物共用等， 剂量均可发 生改变。 可以制成任何可使用的制剂剂型。
本发明中通式 I中涵盖的化合物一般易溶解到有机溶剂、 水溶性溶剂以及有机 溶剂和水溶性溶剂与水的混合溶剂中。 水溶性溶剂优选醇、 多聚乙二醇、 N-甲基 -2- 吡咯啉酮、 Ν,Ν-二甲基乙酰胺、 Ν,Ν-二甲基甲酰胺、 二甲亚砜、 乙腈以及其合用。 所述的醇优选甲醇， 乙醇， 异丙醇， 丙三醇或乙二醇。 本发明化合物可以与常用的 制剂载体混合而制成制剂。 化合物溶解到水溶性的有机溶剂、 非质子性溶剂、 水溶 性类脂、 环糊精、 脂肪酸、 磷脂中或这些溶剂的混合溶剂中而制得药物溶液； 再加 入生理盐水获 1-20%的碳水化合物， 如葡萄糖的水溶液。 由此而制得的制剂稳定并 用于动物和临床。
以上述通式 I中化合物为活性成分制备成的产品药物， 可以通过口服或非肠道 途径给药， 也可通过体内移植药物泵以及其他方法给药， 此处所指的非肠道途径给 药是指皮下皮内、 肌肉内、 静脉内、 动脉内、 心房内、 滑膜内、 胸骨内、 鞘内、 创 伤部位内、 颅内注射或滴注技术等。 由技术人员运用常规的方法配比， 混合最终成 为所需要的药物剂型。 可以是片剂、 丸剂、 胶囊、 冲剂、 糖浆、 注射液、 冻干粉针 剂型、 乳剂、 粉剂、 冻干粉、 滴丸、 乳悬液、 水悬溶液、 水溶液、 胶体、 胶体溶 液、 缓释制剂、 纳米制剂或以其他形式的剂型用于动物或临床。
本发明通式 I中的化合物用于治疗、 预防或缓解某一组织或器官的癌症药物的 制备。 所指癌症包括但不只限于结肠癌、 肝癌、 淋巴瘤、 肺癌、 食管癌、 乳腺癌、 中枢神经系统肿瘤、 黑色素瘤、 卵巢癌、 宫颈癌、 肾癌、 白血病、 前列腺癌、 胰腺 癌、 膀胱癌、 直肠癌、 鼻咽癌、 神经胶质瘤、 骨肉瘤或胃癌等。
具体实 式
以下具体实施例用来进一步说明本发明， 但本发明并非限于这些例子。
抗肿瘤活性测定
体外对肿瘤细胞抑制作用的检测实验如下：
所用人癌肿瘤细胞株： 膀胱癌 T24、 J82, 前列腺癌 LNCap, 人肺癌 A549、 H460、 H520, 人白血病 HL-60等。
实施例 1 : 对人肺癌 A549、 人白血病 HL-60、 人膀胱癌细胞 T24等采用常规
MTT法测定供试样品对各人癌细胞生长的抑制率。
将细胞从培养箱中取出， 用 PBS液清洗两次， 用 0.25%胰蛋白酶溶液消化， 加 入培养基终止消化， 离心后用吸管吹打使之形成细胞悬液， 并于倒置显微镜下进行 计数。 将细胞配制成浓度为 5xl04/ml的细胞悬液， 在 96孔板每孔加入细胞 100μ1， 放置于 5%二氧化碳， 37 °C湿化空气中培养过夜， 加入上述稀释成不同浓度梯度的 待测药物， 令其作用 48 h后， 加入 MTT， 经反应 4小时， 活细胞将 MTT tetrazolium 成分还原产生 formazan, 之后加入 DMSO以溶解 formazan, 最后以 96孔平板读数仪 上测量 570 nm的吸光值。
部分测试结果见表 2:
表 2对人癌细胞生长的抑制率
Figure imgf000005_0001
实施例 2: 对人膀胱癌细胞 Τ24、 J82, 前列腺癌细胞 LNCap, 肺癌细胞 A549、 H460、 H520的生长抑制率， 采用体外细胞培养技术， 将约 1000到 3000个细胞种入
24孔板中， 而后再每孔加入 1毫升本领域技术人员熟知的能够培养试验用肿瘤细胞 株的细胞培养液， 在细胞培养箱中 (CO2 5%,370°C )培养 24小时后， 再将适当浓度的 对照药和上述制备所得物质待测药加入孔中， 注意， 加入液的体积不超过总体积的 0.5%。 让细胞继续在细胞培养箱中生长， 一个星期后， 将细胞培养液吸出， 用冷的 1 毫升 PBS洗一次。 然后， 用 1%的福尔马林室温固定 10分钟， 再用冷的 1毫升 PBS 洗一次。 加入 0.1%的结晶紫染色 30分钟。 结晶紫回收再利用。 染好色的细胞用去离 子水慢慢冲洗， 室温晾干后， 保存。 按每个浓度处理的所剩细胞与无药处理的对照 组的所剩细胞计算细胞抑制率。 对照药剂 AZD6244, 通用名称 SelUmetinib。
抑制率 =每个浓度处理的所剩细胞 /无药处理的对照组的所剩细胞 X 100%
部分测试结果见表 3 : 表 3 对人癌细胞生长的抑制率
Figure imgf000006_0001
注： 1."/"代表未测。
2.膀胱癌 T24J、 82， 前列腺癌 LNCap, 人肺癌 A549、 H460、 H520所有菌株 基均为 RMPI-1640。

Claims

1、苯腈类化合物作为制备抗肿瘤药物的应用，其特征在于化合物结构如通式 I 所
Figure imgf000007_0001
式中：
Ri R2、 R3、 R4可相同或不同， 分别选自氟、 氯、 溴或碘。
2、 根据权利要求 1所述的苯腈类化合物作为制备抗肿瘤药物的应用， 其特征在 于： 所述的通式 I化合物中 、 R2、 R3、 R4可相同或不同， 分别选自氟或氯。
3、 根据权利要求 2所述的苯腈类化合物作为制备抗肿瘤药物的应用， 其特征在 于： 通式 I中： 、 R2、 R3、 R4同时选自氯或氟。
4、 根据权利要求 3所述的苯腈类化合物作为制备抗肿瘤药物的应用， 其特征在 于： 通式 I中： Ri、 R2、 R3、 R4同时选自氯。
5、 根据权利要求 2所述的苯腈类化合物作为制备抗肿瘤药物的应用， 其特征在 于： 通式 I中： R2、 R4选自氟， R3选自氯。
6、根据权利要求 1-5任意一项所述的苯腈类化合物作为制备抗肿瘤药物的应用， 其特征在于： 以通式 I 所示的苯腈类化合物为活性成分制备成口服或非肠道途径的 形式进行给药， 或通过体内移植药物泵的形式进行给药。
7、 根据权利要求 6所述的苯腈类化合物作为制备抗肿瘤药物的应用， 其特征在 于： 以通式 I 所示的苯腈类化合物为活性成分制备治疗、 预防或缓解肿瘤的药物， 药物剂型为片剂、 丸剂、 胶囊、 冲剂、 糖浆、 注射液或冻干粉针剂型。
8、 根据权利要求 7所述的苯腈类化合物作为制备抗肿瘤药物的应用， 其特征在 于： 药物活性成分为一种或两种以上通式 I所示的苯腈类化合物。
9、 根据权利要求 8所述的苯腈类化合物作为制备抗肿瘤药物的应用， 其特征在 于： 将其应用于制备治疗、 预防或缓解结肠癌、 肝癌、 淋巴瘤、 肺癌、 食管癌、 乳腺 癌、 中枢神经系统肿瘤、 黑色素瘤、 卵巢癌、 宫颈癌、 肾癌、 白血病、 前列腺癌、 胰 腺癌、 膀胱癌、 直肠癌、 鼻咽癌、 神经胶质瘤、 骨肉瘤或胃癌药物中。
10、 根据权利要求 9所述的苯腈类化合物作为制备抗肿瘤药物的应用， 其特征在 于： 将其应用于制备治疗、 预防或缓解肺癌或白血病药物中。
PCT/CN2013/086723 2012-11-09 2013-11-08 苯腈类化合物作为制备抗肿瘤药物的应用 WO2014071863A1 (zh)

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