CN103232394A - 含吡唑类化合物、其制备方法和用途 - Google Patents
含吡唑类化合物、其制备方法和用途 Download PDFInfo
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- CN103232394A CN103232394A CN2013101923349A CN201310192334A CN103232394A CN 103232394 A CN103232394 A CN 103232394A CN 2013101923349 A CN2013101923349 A CN 2013101923349A CN 201310192334 A CN201310192334 A CN 201310192334A CN 103232394 A CN103232394 A CN 103232394A
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Abstract
本发明涉及抗癌相关的药物领域。具体而言，本发明涉及具有通式I的、有抗肿瘤性能的吡唑类衍生物及其制备方法、药物组合物及用途。
Description
技术领域
本发明涉及抗肿瘤相关的药物领域。具体而言，本发明涉及具有抗肿瘤作用的吡唑类衍生物及其制备方法，以及含有它们的药物组合物。
背景技术
癌症是威胁人类生命的首要疾病，据统计，每年全球癌症死亡总数达700万人，我国每年死于肿瘤的患者100多万人，并逐渐增加，已成为城市人口的第一位死因。目前在我国临床上传统的治疗癌症疾病的药物有很多，它们在临床上治疗效果也较明显，但是缺点在于：特异性低，选择性差，导致明显的毒副作用，容易产生严重的癌症多药耐药现象。
随着分子生物学的发展，当今抗癌症药物正从传统的细胞毒性药物，向针对机制的多环节作用的新型抗癌症药物发展，目前国内外关注的抗癌作用的新靶点中重要之一就是蛋白酪氨酸激酶(黄敏，丁健，抗肿瘤药物新靶点，《中国处方药》，2006，12(57)，10-15)。蛋白酪氨酸激酶目前有超过20个分属不同家族的受体和非受体酪氨酸激酶被作为靶标进行抗癌药物筛选，其抑制剂已经有几个上市，为了寻找活性更好的药物，近年来分子靶向抗癌药物治疗又提出另一个挑战性概念：多靶标酪氨酸激酶抑制(multiple targeted tyrosine kinase inhibition)的策略，是抗肿瘤的重要的方向。
本发明公开了一类含有吡唑结构的蛋白酪氨酸激酶抑制剂，可以用于制备抗肿瘤药物。
发明内容
本发明的一个目的是提供一种具有通式I的含有吡唑结构的蛋白酪氨酸激酶抑制剂。
本发明的另一个目的是提供制备具有通式I的化合物的方法。
本发明的再一个目的是提供含有通式I的化合物作为有效成分，以及一种或多种药学上可接受的载体、赋形剂或稀释剂的药用组合物，及其在抗肿瘤方面的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明具有通式I的化合物具有下述结构式：
其中，
R1和R2独立地选自H，C1-C5的烷基，苯基，被F、Cl、Br、I、CN、NO2、C1-C5的烷基取代的苯基；
n＝0-5。
优选以下通式I化合物，
其中，
R1和R2独立地选自H，C1-C3的烷基，苯基，被F、Cl、CN、NO2、C1-C3的烷基取代的苯基；
n＝1-3。
更优选的本发明具有通式I的化合物如下所示：
本发明所述通式I化合物通过以下步骤合成：
化合物A和化合物B在碱存在下在合适的溶剂中反应，可以得到化合物I。
其中所述碱选自三乙胺、二异丙基乙基胺、KOH、NaOH、碳酸钾、碳酸钠、乙醇钠、氢化钠，溶剂选自三氯甲烷、二氯甲烷、乙腈、DMF等。该反应可以使用碘盐作为催化剂，如KI和NaI等。
本发明所述式I化合物，可以与一种或多种药学上可接受的载体、赋形剂或稀释剂共同制成药物组合物。该药物组合物可以制成固体口服制剂、液体口服制剂、注射剂等剂型。所述固体及液体口服制剂包括：片剂、分散片、糖衣剂、颗粒剂、干粉剂、胶囊剂和溶液剂。所述的注射剂包括：小针、大输液、冻干粉针等。
本发明的组合物，所述的药学或食品学上可接受辅料选自：填充剂、崩解剂、润滑剂、助流剂、泡腾剂、矫味剂、防腐剂、包衣材料、或其它赋形剂。
本发明的组合物，所述的药学或食品学上可接受辅料。填充剂包括乳糖、蔗糖、糊精、淀粉、预胶化淀粉、甘露醇、山梨醇、磷酸氢钙、硫酸钙、碳酸钙、微晶纤维素的一种或几种的组合物；所述的粘合剂包括蔗糖、淀粉、聚维酮、羧甲基纤维素钠、羟丙甲纤维素、羟丙纤维素、甲基纤维素、聚乙二醇、药用乙醇、水的一种或几种的组合物；所述的崩解剂包括淀粉、交联聚微酮、交联羧甲基纤维素钠、低取代羟丙基纤维素、羧甲纤维素钠、泡腾崩解剂的一种或几种的组合物。
本发明所述通式I化合物具有针对癌症的抑制作用，可作为有效成分用于制备癌症方面的治疗药物。本发明所述通式I化合物的活性是通过体外抗肿瘤模型验证的。
本发明的通式I化合物在相当宽的剂量范围内是有效的。实际服用本发明通式I化合物的剂量可由医生根据有关的情况来决定。这些情况包括：被治疗者的身体状态、给药途径、年龄、体重、对药物的个体反应，症状的严重程度等。
具体实施方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1
1.66g(10mmol)化合物A-1和2.00g(10mmol)化合物B-1溶解到15mL干燥的MeCN中，再加入4.15g(30mmol)碳酸钾，而后在氮气气氛中加热回流过夜。反应混合物倾倒到冰水中，用50mL×3的二氯甲烷萃取，合并有机相用食盐水洗涤，无水硫酸钠干燥，在旋蒸仪上蒸去溶剂，得到I-1的粗品，柱层析纯化，得到I-1的纯品。MS，m/z＝286([M+H]+).
实施例2
1.66g(10mmol)化合物A-1和2.00g(10mmol)化合物B-1溶解到15mL干燥的DMF中，再加入4.15g(30mmol)碳酸钾和0.2g KI，而后在氮气气氛中120℃过夜。反应混合物倾倒到冰水中，用50mL×3的二氯甲烷萃取，合并有机相用食盐水洗涤，无水硫酸钠干燥，在旋蒸仪上蒸去溶剂，得到I-1的粗品，柱层析纯化，得到I-1的纯品。MS，m/z＝286([M+H]+).
实施例3-10
参照实施例1和2的操作，合成下表中具有式I的化合物。
实施例11
制备工艺：将活性成分和辅料预先粉碎过筛100目，称取主药加辅料乳糖、预胶化淀粉羧甲淀粉钠、和微晶纤维素充分混合，过60目筛三次，加入聚维酮溶液，混合，制软材，过20目筛，制湿颗粒，于50-60℃干燥后，加硬脂酸镁和滑石粉预先过筛，然后加入到上述的颗粒中充分混合后，测定中间体颗粒，压片。
实施例12
制备工艺：将活性成分加辅料乳糖、部分交联聚维酮、微晶纤维素、阿斯巴甜和橘子香精过筛充分混合均匀，加入2％羟丙甲纤维素溶液，混合，制软材，过24目筛，制湿颗粒，于50-60℃干燥后，20目筛整粒。将剩余交联聚维酮、硬脂酸镁和滑石粉过筛后，加入到上述的颗粒中充分混合后，测定中间体颗粒，压片。
实施例13
制备工艺：将主药与辅料分别过100目筛，充分混合，采用辊压机压饼，再用整粒剂过18目筛整粒，最后加入润滑剂硬脂酸镁，混合均匀压片。
实施例14
制备工艺：将活性成分粉碎过100目筛，加辅料甘露醇、山梨醇、甜菊甙和橙皮酊，充分混合，加入5％聚乙二醇6000溶液，混合，制软材，过18目筛，制湿颗粒，于50-60℃干燥后，18目筛整粒。将硬脂酸镁和滑石粉预先过筛，然后加入到上述的颗粒中充分混合后，测定中间体颗粒，压片。
实施例15
制备工艺：将主药与辅料分别过100目筛，充分混合，然后称取处方量辅料与主药充分混合。再加入粘合剂制软材，14目筛制粒，55℃干燥，12目筛整粒，测定袋重包装。
实施例16
制备工艺：取注射用水80ml，加主药、甘露醇、乳糖、泊洛沙姆搅拌使溶解后，加1mol/L的枸橼酸调节PH至7.0-9.0，补加水至100ml。加入0.5g活性炭，在30℃下搅拌20分钟，脱炭，采用微孔滤膜过滤除菌，滤液按每支1ml进行分装，预冻2小时后，冷冻下减压干燥12小时，至样品温度到室温后，再干燥5小时，制得白色疏松块状物，封口即得。
实施例17
制备工艺：取注射用水100ml，加主药、焦亚硫酸钠、碳酸氢钠搅拌使溶解后，加适量氢氧化钠调节PH为7.0-9.0，补加注射用水至200ml，加入2g活性炭，搅拌吸附30分钟，除炭、精滤、以每支2ml灌封、灭菌，即得。
实施例18
制备工艺：取注射用水2000ml，加主药、三羟甲基氨基甲烷、低分子右旋糖苷、EDTA-2Na搅拌使溶解后，用碳酸氢钠调节PH为7.0-9.0，加入10g活性炭，在20-50℃下搅拌吸附30分钟，除炭，补加水至5000ml，精滤、灌封每瓶50ml，灭菌，即得。
实施例19
(1)材料
细胞株：白血病HL-60细胞、胃腺癌SGC-7901细胞、乳腺癌MCF-7细胞、肺癌A-549细胞，均购自中国科学院上海细胞研究所。
试剂：MTT，Amresco分装；DMEM培养基，Gibco；小牛血清，兰州民海生物；胰蛋白酶，Amresco分装；氟尿嘧啶注射液，0.25g/10ml(支)，天津金耀氨基酸有限公司。
仪器：超净工作台，苏州净化设备厂；CO2培养箱，Thermo公司，型号：HERA Cell150；倒置显微镜，Carl Zeiss公司，型号：Axiovert 200；酶联免疫检测仪，TECAN公司，型号：Sunrise；离心机，Kerdro公司，型号：Heraeus。
(2)方法
细胞培养：肿瘤细胞接种在含10％小牛血清，100IU/ml青霉素G钠盐及100ug/ml硫酸链霉素的DMEM培养液中，置37℃、100％相对湿度、含5％CO2的培养箱中，传代3次后备用。
MTT法测定：取对数生长期的细胞，经0.25％胰蛋白酶消化后(悬浮细胞无须消化)，悬浮于含10％小牛血清的DMEM培养液中，用玻璃滴管轻轻吹打成单细胞悬液，显微镜下用血细胞记数板记数活细胞。96孔培养板每孔接种细胞悬液90μl(细胞浓度调整为6～8×104个/ml)，在37℃、100％相对湿度、含5％CO2、95％空气的培养箱培养24h后，每孔加5μl药液(终浓度为10μg/ml)。另外，每个浓度设阴性对照(等浓度DMSO)及空白本底(不加细胞)，各组均设6个复孔。再连续培养48h，然后每孔加入10μl5mg/ml的MTT溶液，继续培养4h后，仔细吸去上清液(悬浮细胞，需要先离心，再吸去上清)。每孔加入100μl DMSO，置微量振荡器震荡以使结晶完全溶解，酶标仪492nm单波长比色，测定OD值。以下述方法计算细胞生长抑制率作为评价指标。
抑制率(％)＝[1-(实验组OD均值-空白组OD均值)/(对照组OD均值-空白组OD均值)]×100％。
(3)结果
表1.样品对体外培养肿瘤细胞的抑制率(％)
(4)结论
从上述体外试验结果可以看出，本发明所述通式I化合物在10μg/ml浓度时体外作用48h后对这4种人类癌细胞均具有较强的抑制作用。
Claims (8)
1.具有通式I的化合物或其药学上可接受的盐：
其中，
R1和R2独立地选自H，C1-C5的烷基，苯基，被F、C1、Br、I、CN、NO2、C1-C5的烷基取代的苯基；
n＝0-5。
2.权利要求1所定义的具有通式I的化合物或其药学上可接受的盐，：
其中，
R1和R2独立地选自H，C1-C3的烷基，苯基，被F、Cl、CN、NO2、C1-C3的烷基取代的苯基；
n＝1-3。
3.权利要求1所定义的通式I化合物或其药学上可接受的盐，选自：
4.合成权利要求1-3所定义的通式I化合物的方法，包括以下步骤：
化合物A和化合物B在碱存在下在合适的溶剂中反应，可以得到化合物I；
其中所述碱选自三乙胺、二异丙基乙基胺、KOH、NaOH、碳酸钾、碳酸钠、乙醇钠、氢化钠，溶剂选自三氯甲烷、二氯甲烷、乙腈、DMF；当溶剂为DMF时，该反应使用碘盐作为催化剂，选自KI和NaI。
5.权利要求1-4所定义的通式I化合物在制备抗肿瘤药物方面的应用。
6.一种药物组合物，含有权利要求1-4之一的通式I化合物以及药学上可接受的辅料。
7.权利要求6所述的药物组合物，其中，所述的组合物为固体口服制剂、注射制剂。
8.根据权利要求7所述固体及液体口服制剂包括：分散片、肠溶片、咀嚼片、口崩片、胶囊、颗粒剂、口服溶液剂，所述注射制剂包括注射用水针、注射用粉针及小输液。
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