CN116570598B - 苯基哌嗪喹唑啉类化合物用于制备P-gp抑制剂药物中的应用 - Google Patents
苯基哌嗪喹唑啉类化合物用于制备P-gp抑制剂药物中的应用 Download PDFInfo
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- A61P35/02—Antineoplastic agents specific for leukemia
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Abstract
本发明涉及苯基哌嗪喹唑啉类化合物或其药学上可接受的盐或其药物组合物用于制备P‑gp抑制剂药物或用于制备逆转肿瘤多药耐药性药物中的应用,其中,所述苯基哌嗪喹唑啉类化合物具有式Ⅰ‑式Ⅲ任一所示结构,其中,R选自取代或未取代、有杂原子或无杂原子的直链、支链或环状的多至10个碳原子的烃基碳链,取代或未取代的单环芳基、杂芳基的任一种。苯基哌嗪喹唑啉类化合物可抑制P‑gp高表达的耐药细胞中抗肿瘤药物的排出,增加细胞中抗肿瘤药物的浓度,具有良好的逆转肿瘤多药耐药效果、毒性小、对肝药酶活性无显著性影响等优势。
Description
技术领域
本发明属于医药技术领域,具体涉及一种苯基哌嗪喹唑啉类化合物用于制备P-gp抑制剂药物及逆转肿瘤多药耐药性药物中的应用。
背景技术
肿瘤多药耐药(Multidrug Resistance,MDR)是指肿瘤细胞对一种抗肿瘤药物出现耐药时,又对其他多种结构及作用机制均不同的抗肿瘤药物产生了耐药性。在肿瘤耐药的多种机制中,P-糖蛋白(P-glyoprotein,P-gp)介导的肿瘤多药耐药是一种重要机制。P-gp是一种广谱转运蛋白,可转运广泛的治疗药物,包括抗癌药物(如长春花生物碱,蒽环霉素,表鬼臼毒素和紫杉烷类),HIV-蛋白酶抑制剂,镇痛药,抗组胺药,免疫抑制剂,强心苷,钙通道阻滞剂,钙调蛋白抑制剂,止吐药,抗蠕虫药,抗生素和类固醇等。P-gp在肿瘤细胞中过度表达,使得P-gp对细胞内的药物外排作用增强而导致肿瘤细胞产生抗肿瘤药物耐药性。P-gp是导致肿瘤多药耐药的主要原因之一,也是研发抗肿瘤多药耐药以实现抗肿瘤药物增效增敏的重要靶点。
维拉帕米(Verapamil,VRP)是第一代P-gp抑制剂,常用作P-gp抑制研究中的阳性对照药,但它需要较高剂量才能达到良好的MDR效果,而其高剂量对人体产生较大的毒副作用而限制其临床应用。以PSC833为代表的第二代P-gp抑制剂在临床阶段与抗肿瘤药物共同使用时易引发多种并发症,产生一些难以预测的不良后果而使得临床用药受限,例如,会与抗肿瘤药物对CYP3A4酶产生竞争作用,导致抗肿瘤药物的代谢受到抑制而产生严重的药代动力学问题,严重威胁患者健康,而限制其开发与应用。为了克服第二代P-gp抑制剂的局限性,利用组合化学和结构-活性关系发展了高特异性和低毒性的第三代P-gp抑制剂,但因临床试验中出现了不良毒性及其与化疗药物发生相互作用而未能推向市场。因此,研究开发低毒高效的抑制P-gp作用的肿瘤多药耐药逆转药物依然是抗肿瘤领域的研究重点。
发明内容
本发明的目的在于提供苯基哌嗪喹唑啉类化合物或其药学上可接受的盐或其药物组合物用于制备P-gp抑制剂药物中的应用,其中,所述苯基哌嗪喹唑啉类化合物具有式Ⅰ-式Ⅲ任一所示结构,
其中,R选自取代或未取代、有杂原子或无杂原子的直链、支链或环状的多至10个碳原子的烃基碳链,取代或未取代的单环芳基、杂芳基的任一种。
本发明的优选技术方案中,所述取代或未取代的单环芳基、杂芳基选自苯基、对甲基苯基、对硝基苯基、对氟苯基、对溴苯基、邻甲氧基苯基、苯磺酰基、对甲基苯磺酰基、对甲氧基苯磺酰基、间硝基苯磺酰基、苄基或间氯苄基中的任一种。
本发明优选的技术方案中,所述的苯基哌嗪喹唑啉类化合物选自QJJ-1至QJJ-28的任一结构,
本发明的优选技术方案中,所述的药学上可接受的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、硫酸盐、氨基酸盐、谷氨酸盐、精氨酸盐、乙酸盐、丙酸盐、苯磺酸盐、甲基苯磺酸盐、柠檬酸盐、乳酸盐、富马酸盐、酒石酸盐、琥珀酸盐的任一种或其组合。
本发明优选的技术方案中,所述P-gp抑制剂药物和抗肿瘤药物竞争性地结合P-gp,抑制抗肿瘤药物排出,逆转肿瘤多药耐药。
本发明优选的技术方案中,所述P-gp抑制剂药物与抗肿瘤药物同时给药或先后给药。
本发明优选的技术方案中,所述药物组合物含有苯基哌嗪喹唑啉类化合物或其药学上可接受的盐和药学上可接受的载体。
本发明优选的技术方案中,所述药物组合物含有苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、抗肿瘤药物和药学上可接受的载体。
本发明优选的技术方案中,所述抗肿瘤药物选自长春碱类药物、蒽环类药物、紫杉醇类药物、喜树碱类药物、鬼臼毒素类药物、铂类抗癌药物中的任一种或其组合。
本发明优选的技术方案中,所述抗肿瘤药物选自长春碱或其药学上可接受的盐、长春新碱或其药学上可接受的盐、长春地辛或其药学上可接受的盐、长春瑞滨或其药学上可接受的盐、阿霉素、柔红霉素、表阿霉素、吡喃阿霉素、阿克拉霉素、去甲氧柔红霉素、氨柔比星、紫杉醇、多西他赛、拓扑替康、喜树碱、羟基喜树碱、伊立替康、依托泊苷、替尼泊苷、顺铂、卡铂、奈达铂、洛铂、奥沙利铂中的任一种或其组合。
本发明优选的技术方案中,药物组合物中的苯基哌嗪喹唑啉类化合物与抗肿瘤药物的摩尔比为1:0.1-10,优选为1:0.25-5,更优选为1:0.5-2。
本发明的优选技术方案中,药物组合物中的苯基哌嗪喹唑啉类化合物与阿霉素的摩尔比为1:0.1-10,优选为1:0.25-5,更优选为1:0.5-2。
本发明的优选技术方案中,药物组合物中的QJJ1-QJJ5、QJJ12的任一种与阿霉素的摩尔比为1:0.1-10,优选为1:0.25-5,更优选为1:0.5-2。
本发明的优选技术方案中,药物组合物中的药学上可接受载体的用量或其种类根据组合物中有效成分的理化性质和含量、制剂类型、制剂的溶出及生物利用度等因素而定。
本发明优选的技术方案中,所述药物或药物组合物的给药方式选自口服给药、注射给药、黏膜给药、皮肤给药中的任一种。
本发明优选的技术方案中,所述药物组合物对耐药肿瘤细胞的MDR逆转倍数≥50倍,优选≥150倍,更优选≥300倍。
本发明优选的技术方案中,所述肿瘤选自肝癌、乳腺癌、肺癌、胃癌、结肠癌、***、卵巢癌、白血病、黑色素癌中的任一种或其组合。
本发明优选的技术方案中,本发明的药物组合物可为本领域熟知的各种剂型,并可采用本领域常规的制剂技术制备得到。适合于本发明的制剂选自口服制剂、注射剂、外用制剂、吸入制剂的任一种。
本发明优选的技术方案中,所述的口服制剂选自口服液体制剂、片剂、胶囊剂、颗粒剂、糖浆剂、散剂、露剂、混悬液、丸剂、滴丸、合剂、糊剂、乳剂、茶剂的任一种。
本发明优选的技术方案中,所述的外用制剂选自凝胶剂、膏剂、贴膏剂、霜剂、软膏剂、搽剂、洗剂、栓剂、涂抹剂、凝胶膏剂、软膏剂的任一种。
本发明优选的技术方案中,所述的吸入制剂选自气雾剂、干粉吸入剂、喷雾剂、鼻喷雾剂、吸入液体制剂的任一种。
本发明优选的技术方案中,所述的注射剂选自溶液型注射液、乳剂型注射液、混悬剂型注射液、注射用无菌粉末、大输液的任一种。
本发明所述的药学上可接受的载体为本领域熟知用于制备所需制剂的常用赋形剂或辅料,包括但不仅限于填充剂(又称稀释剂)、润滑剂(包括润滑剂、助流剂、抗粘着剂)、分散剂、润湿剂、粘合剂、崩解剂、pH调节剂、渗透压调节剂、致孔剂、增溶剂、抗氧剂、抑菌剂、止痛剂、助悬剂、乳化剂、助乳化剂、冻干保护剂、矫味剂、赋香剂、助溶剂、潜溶剂等。
粘合剂,例如糖浆、***胶、明胶、山梨醇、黄芪胶、纤维素或其衍生物、明胶浆、淀粉浆、聚乙烯吡咯烷酮、预胶化淀粉、羟丙基淀粉等,优选纤维素衍生物选自微晶纤维素、羧甲基纤维素钠、乙基纤维素、甲基纤维素、羟丙基纤维素、羟丙甲基纤维素的任一种或其组合。填充剂,例如乳糖、糖粉、糊精、淀粉或其衍生物、纤维素或其衍生物、无机钙盐、山梨醇、甘露醇等,优选无机钙盐选自氯化钙、硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等,优选纤维素衍生物选自微晶纤维素、羧甲基纤维素钠、乙基纤维素、甲基纤维素、羟丙基纤维素、羟丙甲基纤维素的任一种,优选淀粉衍生物选自淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、土豆淀粉、玉米淀粉的任一种或其组合。润滑剂,例如微粉硅胶、硬脂酸镁、滑石粉、胶态二氧化硅、氢氧化铝、硼酸、氢化植物油、聚乙二醇、十二烷基硫酸钠等。崩解剂,例如淀粉或其衍生物、交联聚乙烯吡咯烷酮、微晶纤维素、低取代羟丙基纤维素、交联羧甲基纤维素钠等,优选淀粉衍生物选自羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、土豆淀粉、玉米淀粉的任一种或其组合。润湿剂,例如十二烷基硫酸钠、聚山梨酯(吐温)、水或醇等。抗氧剂,例如亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、维生素C、维生素E、二丁基苯酸、丁基羟基茴香醚(BHA)、二丁羟基甲苯(BHT)、没食子酸丙酯(PG)、叔丁基对苯二酚(TBHQ)等。抑菌剂(杀菌剂),例如苯酚、甲酚、三氯叔丁醇、苯甲醇等。止痛剂,例如三氯叔丁醇、苯甲醇、利多卡因、普鲁卡因等。助悬剂,例如胶体微晶纤维素、羧甲基纤维素钠、乙基纤维素、甲基纤维素、羟丙基纤维素、羟丙甲基纤维素、糖浆、甘油、明胶、***胶、西黄蓍胶、海藻酸钠(钾)、果胶等。酸碱调节剂(pH调节剂),例如盐酸、枸橼酸、氢氧化钠(钾)、冰醋酸、酒石酸钠(钾)(钾)、柠檬酸钠(钾)、苹果酸钠(钾)、磷酸二氢钠(钾)、磷酸氢二钠(钾)等。渗透压调节剂,例如氯化钠(钾)、葡萄糖、甘油等。乳化剂,例如硬脂酸钠、硬脂酸钾、硬脂酸三乙醇胺、硬脂酸镁、硬脂酸钙、十二烷基硫酸钠、十二烷基苯磺酸钠、聚山梨酯(吐温)、司盘、卖泽、苄泽、聚乙烯醇、西黄蓍胶、***胶、普朗尼克F-68,卵磷酯、豆磷脂等。助乳化剂,例如正丁醇、乙二醇、乙醇、丙二醇、甘油、聚甘油酯等。冻干保护剂,例如蔗糖、乳糖、半乳糖、葡萄糖、海藻糖、甘露醇、山梨醇等。增溶剂,例如吐温-80、普朗尼克F-68、卖泽、苄泽、胆酸盐、去氧胆酸盐等。调味剂,例如蜂蜜、糖浆、胶浆剂、泡腾剂、香精、甜味剂等。潜溶剂,如甘油、丙二醇、聚乙二醇等。
本发明的优选技术方案中,将本发明的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐和/或抗肿瘤药物与药学上可接受的缓释制剂载体或控释制剂载体按照本领域熟知的缓释制剂或控释制剂的制备方法,如加入阻滞剂包衣或制成骨架型制剂将本发明的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐和/或抗肿瘤药物微囊化后,将其制成缓释制剂或控释制剂等。
本发明所述的缓释制剂载体或控释制剂载体包括但不仅限于油脂性掺入剂、亲水胶体、水不溶性、肠溶性、生物可降解性阻滞剂等,所述的油脂性掺入剂选自单硬脂酸甘油酯、氢化蓖麻油、矿油、聚硅氧烷或二甲基硅氧烷等;所述的亲水胶体选自甲基纤维素(MC)、羧甲基纤维素钠(CMC-Na)、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、聚乙烯吡咯烷酮(PVP)、***胶、西黄耆胶、卡波姆(卡波普)、聚乙烯醇(PVA)、果胶、海藻酸盐、壳聚糖、黄原胶、瓜尔胶、脚叉菜胶、明胶、琼脂、半乳甘露聚糖的任一种或其组合;所述的水不溶性阻滞剂选自乙基纤维素(EC)、醋酸纤维素(CA)、聚乙烯、聚丙烯、聚硅氧烷、乙烯醋酸乙烯共聚物(EVA)、聚甲基丙烯酸甲酯的任一种或其组合;所述肠溶性阻滞剂选自邻苯二甲酸醋酸纤维素(CAP)、邻苯二甲酸羟丙甲基纤维素(HPMCP)、邻苯二甲酸聚乙烯醇(PVAP)、醋酸羟丙甲基纤维素琥珀酸酯(HPMCAS)、丙烯酸树脂等;所述生物可降解性阻滞剂选自蜡质类、脂肪酸及其酯、脂肪醇等,如巴西棕榈蜡、硬脂酸、单硬脂酸甘油酯、硬脂醇、十六醇等。
本发明的另一目的在于提供苯基哌嗪喹唑啉类化合物或其药学上可接受的盐或其药物组合物用于制备肿瘤多药耐药逆转药物中的应用,其中,所述苯基哌嗪喹唑啉类化合物具有式Ⅰ-式Ⅲ任一所示结构,
其中,R选自取代或未取代、有杂原子或无杂原子的直链、支链或环状的多至10个碳原子的烃基碳链,取代或未取代的单环芳基、杂芳基的任一种。
本发明的优选技术方案中,所述取代或未取代的单环芳基、杂芳基选自苯基、对甲基苯基、对硝基苯基、对氟苯基、对溴苯基、邻甲氧基苯基、苯磺酰基、对甲基苯磺酰基、对甲氧基苯磺酰基、间硝基苯磺酰基、苄基或间氯苄基中的任一种。
本发明优选的技术方案中,所述的苯基哌嗪喹唑啉类化合物选自QJJ-1至QJJ-28的任一结构,
本发明的优选技术方案中,所述的药学上可接受的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、硫酸盐、氨基酸盐、谷氨酸盐、精氨酸盐、乙酸盐、丙酸盐、苯磺酸盐、甲基苯磺酸盐、柠檬酸盐、乳酸盐、富马酸盐、酒石酸盐、琥珀酸盐的任一种或其组合。
本发明优选的技术方案中,所述苯基哌嗪喹唑啉类化合物和抗肿瘤药物竞争性地结合P-gp,抑制抗肿瘤药物排出,逆转肿瘤多药耐药。
本发明优选的技术方案中,所述苯基哌嗪喹唑啉类化合物与抗肿瘤药物同时给药或先后给药。
本发明优选的技术方案中,所述药物组合物含有苯基哌嗪喹唑啉类化合物或其药学上可接受的盐和药学上可接受的载体。
本发明优选的技术方案中,所述药物组合物含有苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、抗肿瘤药物和药学上可接受的载体。
本发明优选的技术方案中,所述抗肿瘤药物选自长春碱类药物、蒽环类药物、紫杉醇类药物、喜树碱类药物、鬼臼毒素类药物、铂类抗癌药物中的任一种或其组合。
本发明优选的技术方案中,所述抗肿瘤药物选自长春碱或其药学上可接受的盐、长春新碱或其药学上可接受的盐、长春地辛或其药学上可接受的盐、长春瑞滨或其药学上可接受的盐、阿霉素、柔红霉素、表阿霉素、吡喃阿霉素、阿克拉霉素、去甲氧柔红霉素、氨柔比星、紫杉醇、多西他赛、拓扑替康、喜树碱、羟基喜树碱、伊立替康、依托泊苷、替尼泊苷、顺铂、卡铂、奈达铂、洛铂、奥沙利铂中的任一种或其组合。
本发明优选的技术方案中,药物组合物中的苯基哌嗪喹唑啉类化合物与抗肿瘤药物的摩尔比为1:0.1-10,优选为1:0.25-5,更优选为1:0.5-2。
本发明的优选技术方案中,药物组合物中的苯基哌嗪喹唑啉类化合物与阿霉素的摩尔比为1:0.1-10,优选为1:0.25-5,更优选为1:0.5-2。
本发明的优选技术方案中,药物组合物中的QJJ1-QJJ5、QJJ12的任一种与阿霉素的摩尔比为1:0.1-10,优选为1:0.25-5,更优选为1:0.5-2。
本发明的优选技术方案中,药物组合物中的药学上可接受载体的用量或其种类根据组合物中有效成分的理化性质和含量、制剂类型、制剂的溶出及生物利用度等因素而定。
本发明优选的技术方案中,所述药物或药物组合物的给药方式选自口服给药、注射给药、黏膜给药、皮肤给药中的任一种。
本发明优选的技术方案中,所述药物组合物对耐药肿瘤细胞的MDR逆转倍数≥50倍,优选≥150倍,更优选≥300倍。
本发明优选的技术方案中,所述肿瘤选自肝癌、乳腺癌、肺癌、胃癌、结肠癌、***、卵巢癌、白血病、黑色素癌中的任一种或其组合。
本发明优选的技术方案中,本发明的药物组合物可为本领域熟知的各种剂型,并可采用本领域常规的制剂技术制备得到。适合于本发明的制剂选自口服制剂、注射剂、外用制剂、吸入制剂的任一种。
本发明优选的技术方案中,所述的口服制剂选自口服液体制剂、片剂、胶囊剂、颗粒剂、糖浆剂、散剂、露剂、混悬液、丸剂、滴丸、合剂、糊剂、乳剂、茶剂的任一种。
本发明优选的技术方案中,所述的外用制剂选自凝胶剂、膏剂、贴膏剂、霜剂、软膏剂、搽剂、洗剂、栓剂、涂抹剂、凝胶膏剂、软膏剂的任一种。
本发明优选的技术方案中,所述的吸入制剂选自气雾剂、干粉吸入剂、喷雾剂、鼻喷雾剂、吸入液体制剂的任一种。
本发明优选的技术方案中,所述的注射剂选自溶液型注射液、乳剂型注射液、混悬剂型注射液、注射用无菌粉末、大输液的任一种。
本发明所述的药学上可接受的载体为本领域熟知用于制备所需制剂的常用赋形剂或辅料,包括但不仅限于填充剂(又称稀释剂)、润滑剂(包括润滑剂、助流剂、抗粘着剂)、分散剂、润湿剂、粘合剂、崩解剂、pH调节剂、渗透压调节剂、致孔剂、增溶剂、抗氧剂、抑菌剂、止痛剂、助悬剂、乳化剂、助乳化剂、冻干保护剂、矫味剂、赋香剂、助溶剂、潜溶剂等。
粘合剂,例如糖浆、***胶、明胶、山梨醇、黄芪胶、纤维素或其衍生物、明胶浆、淀粉浆、聚乙烯吡咯烷酮、预胶化淀粉、羟丙基淀粉等,优选纤维素衍生物选自微晶纤维素、羧甲基纤维素钠、乙基纤维素、甲基纤维素、羟丙基纤维素、羟丙甲基纤维素的任一种或其组合。填充剂,例如乳糖、糖粉、糊精、淀粉或其衍生物、纤维素或其衍生物、无机钙盐、山梨醇、甘露醇等,优选无机钙盐选自氯化钙、硫酸钙、磷酸钙、磷酸氢钙、沉降碳酸钙等,优选纤维素衍生物选自微晶纤维素、羧甲基纤维素钠、乙基纤维素、甲基纤维素、羟丙基纤维素、羟丙甲基纤维素的任一种,优选淀粉衍生物选自淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、土豆淀粉、玉米淀粉的任一种或其组合。润滑剂,例如微粉硅胶、硬脂酸镁、滑石粉、胶态二氧化硅、氢氧化铝、硼酸、氢化植物油、聚乙二醇、十二烷基硫酸钠等。崩解剂,例如淀粉或其衍生物、交联聚乙烯吡咯烷酮、微晶纤维素、低取代羟丙基纤维素、交联羧甲基纤维素钠等,优选淀粉衍生物选自羧甲基淀粉钠、淀粉乙醇酸钠、预胶化淀粉、改良淀粉、羟丙基淀粉、土豆淀粉、玉米淀粉的任一种或其组合。润湿剂,例如十二烷基硫酸钠、聚山梨酯(吐温)、水或醇等。抗氧剂,例如亚硫酸钠、亚硫酸氢钠、焦亚硫酸钠、硫代硫酸钠、维生素C、维生素E、二丁基苯酸、丁基羟基茴香醚(BHA)、二丁羟基甲苯(BHT)、没食子酸丙酯(PG)、叔丁基对苯二酚(TBHQ)等。抑菌剂(杀菌剂),例如苯酚、甲酚、三氯叔丁醇、苯甲醇等。止痛剂,例如三氯叔丁醇、苯甲醇、利多卡因、普鲁卡因等。助悬剂,例如胶体微晶纤维素、羧甲基纤维素钠、乙基纤维素、甲基纤维素、羟丙基纤维素、羟丙甲基纤维素、糖浆、甘油、明胶、***胶、西黄蓍胶、海藻酸钠(钾)、果胶等。酸碱调节剂(pH调节剂),例如盐酸、枸橼酸、氢氧化钠(钾)、冰醋酸、酒石酸钠(钾)(钾)、柠檬酸钠(钾)、苹果酸钠(钾)、磷酸二氢钠(钾)、磷酸氢二钠(钾)等。渗透压调节剂,例如氯化钠(钾)、葡萄糖、甘油等。乳化剂,例如硬脂酸钠、硬脂酸钾、硬脂酸三乙醇胺、硬脂酸镁、硬脂酸钙、十二烷基硫酸钠、十二烷基苯磺酸钠、聚山梨酯(吐温)、司盘、卖泽、苄泽、聚乙烯醇、西黄蓍胶、***胶、普朗尼克F-68,卵磷酯、豆磷脂等。助乳化剂,例如正丁醇、乙二醇、乙醇、丙二醇、甘油、聚甘油酯等。冻干保护剂,例如蔗糖、乳糖、半乳糖、葡萄糖、海藻糖、甘露醇、山梨醇等。增溶剂,例如吐温-80、普朗尼克F-68、卖泽、苄泽、胆酸盐、去氧胆酸盐等。调味剂,例如蜂蜜、糖浆、胶浆剂、泡腾剂、香精、甜味剂等。潜溶剂,如甘油、丙二醇、聚乙二醇等。
本发明的优选技术方案中,将本发明的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐和/或抗肿瘤药物与药学上可接受的缓释制剂载体或控释制剂载体按照本领域熟知的缓释制剂或控释制剂的制备方法,如加入阻滞剂包衣或制成骨架型制剂将本发明的苯基哌嗪喹唑啉类化合物或其药学上可接受的盐和/或抗肿瘤药物微囊化后,将其制成缓释制剂或控释制剂等。
本发明所述的缓释制剂载体或控释制剂载体包括但不仅限于油脂性掺入剂、亲水胶体、水不溶性、肠溶性、生物可降解性阻滞剂等,所述的油脂性掺入剂选自单硬脂酸甘油酯、氢化蓖麻油、矿油、聚硅氧烷或二甲基硅氧烷等;所述的亲水胶体选自甲基纤维素(MC)、羧甲基纤维素钠(CMC-Na)、羟乙基纤维素(HEC)、羟丙基纤维素(HPC)、羟丙基甲基纤维素(HPMC)、聚乙烯吡咯烷酮(PVP)、***胶、西黄耆胶、卡波姆(卡波普)、聚乙烯醇(PVA)、果胶、海藻酸盐、壳聚糖、黄原胶、瓜尔胶、脚叉菜胶、明胶、琼脂、半乳甘露聚糖的任一种或其组合;所述的水不溶性阻滞剂选自乙基纤维素(EC)、醋酸纤维素(CA)、聚乙烯、聚丙烯、聚硅氧烷、乙烯醋酸乙烯共聚物(EVA)、聚甲基丙烯酸甲酯的任一种或其组合;所述肠溶性阻滞剂选自邻苯二甲酸醋酸纤维素(CAP)、邻苯二甲酸羟丙甲基纤维素(HPMCP)、邻苯二甲酸聚乙烯醇(PVAP),醋酸羟丙甲基纤维素琥珀酸酯(HPMCAS)、丙烯酸树脂等;所述生物可降解性阻滞剂选自蜡质类、脂肪酸及其酯、脂肪醇等,如巴西棕榈蜡、硬脂酸、单硬脂酸甘油酯、硬脂醇、十六醇等。
除非另有说明,本发明涉及液体与液体之间的百分比时,所述的百分比为体积/体积百分比;本发明涉及液体与固体之间的百分比时,所述百分比为体积/重量百分比;本发明涉及固体与液体之间的百分比时,所述百分比为重量/体积百分比;其余为重量/重量百分比。
与现有技术相比,本发明具有下述有益的技术效果:本发明首次发现苯基哌嗪喹唑啉类化合物可通过与抗肿瘤药物竞争性地结合P-gp,激活P-gp ATPase活性,替代抗肿瘤药物被P-gp排出,最终抑制P-gp高表达的耐药细胞中抗肿瘤药物的排出,增加细胞中抗肿瘤药物的浓度,实现其逆转肿瘤多药耐药的作用,并具有良好的逆转肿瘤多药耐药效果、毒性小、对肝药酶活性无显著性影响等优势。
附图说明
图1实施例4中QJJ-1、QJJ-2、QJJ-3对CYP3A4酶活性的影响(UT为未处理组,KET为酮康唑组;***P<0.001相对于UT组);
图2实施例5中HepG-2、MCF-7、HepG-2/ADM和MCF-7/ADR细胞中P-gp表达水平;
图3实施例6中QJJ-1、QJJ-2、QJJ-3、QJJ-4和QJJ-5对HepG-2/ADM细胞(A)和MCF-7/ADR细胞(B)中DOX外排作用的影响(***p<0.001相对于DOX组;##p<0.01,###p<0.001相对于VRP组);
图4实施例7中QJJ-1、QJJ-2、QJJ-3、QJJ-4和QJJ-5对P-gp ATPase活性的影响(NT为未处理组;*P<0.05,***P<0.001相对于NT组)。
具体实施方式
以下参照实施例说明本发明,但本发明不局限于实施例。
试验用细胞:人肝癌细胞HepG-2、人乳腺癌细胞MCF-7、人肝癌耐药细胞株HepG-2/ADM、人乳腺癌耐药细胞株MCF-7/ADR、人心肌细胞AC16均为商购。
试验药物:阿霉素(DOX,购自浙江海正药业)、维拉帕米(VRP,购自美国MPBiomedicals公司)。
实验试剂配制:
(1)阿霉素(Doxorubicin,DOX)母液:将适量的DOX溶解于二甲基亚砜(DMSO)中,将其配制成浓度为200mM的DOX母液。
(2)维拉帕米(Verapamil,VRP)母液:将适量的VRP溶解于二甲基亚砜(DMSO)中,将其配制成浓度为100mM的VRP母液。
(3)苯基哌嗪喹唑啉类化合物母液:将适量的苯基哌嗪喹唑啉类化合物QJJ-1、QJJ-2、QJJ-3、QJJ-4、QJJ-5、QJJ-12溶解于二甲基亚砜(DMSO)中,将其配制成浓度为100mM的苯基哌嗪喹唑啉类化合物母液。
(4)1640培养液:向1640培养基(商购)中加入10%胎牛血清、1%双抗,配制1640培养液。
(5)酮康唑(Ketoconazole,KET)溶液:将适量酮康唑粉末溶解于乙腈中,将其配制成浓度为5mM的酮康唑溶液。
(6)荧光素检测试剂:将50mL Reconstitution Buffer with esterase与Luciferin Detection Reagent(lyophilized)粉末混合,配制成荧光素检测试剂。
实施例1 DOX对肿瘤细胞的生长抑制作用
采用MTT法测定DOX对肿瘤细胞的生长抑制活性。
(1)DOX含药培养液的配制:将200mM DOX母液用1640培养液分别稀释为梯度浓度的DOX含药培养液,200μM、100μM、80μM、40μM、20μM、10μM、5μM、2.5μM、1.25μM、0.625μM、0.3125μM、0.156μM、0.078μM、0.039μM,备用。
(2)实验分组:
①空白对照组:给予1640培养液。
②DOX组:HepG-2和MCF-7细胞的给药浓度为0.039μM-10μM的DOX;
HepG-2/ADM和MCF-7/ADR细胞的给药浓度为2.5μM-200μM的DOX。
(3)实验步骤
①取对数生长期、生长状态良好的细胞,细胞计数后,接种于96孔板,每孔100μL,HepG-2、MCF-7和MCF-7/ADR细胞数目分别为5×103个/孔,HepG-2/ADM细胞数目为8×103个/孔,边缘孔加入100μL PBS。将接种后的96孔板置于37℃、5% CO2、饱和湿度的培养箱中培养。
②细胞种板24h后,在显微镜下观察细胞贴壁情况,吸弃96孔板内旧培养液,DOX给药组加入100μL的DOX含药培养液,空白对照组加入100μL不含药的1640培养液,置于37℃、5% CO2、饱和湿度的培养箱中培养72h。
③MTT显色:在避光条件下,每孔加入20μL 5mg/mL MTT,边缘孔除外,置于37℃、5% CO2、饱和湿度的培养箱中培养4h。
④检测:吸弃96孔板内的液体,每孔加入150μL DMSO,振荡摇匀10min,用酶标仪测定570nm处的吸光度。
抑制率=(1-实验组OD值/空白对照组平均OD值)×100%
半数抑制浓度(IC50)通过GraphPad Prism拟合,当抑制率为50%时的药物浓度。
耐药细胞株的耐药倍数(The multidrug resistance ratio,MR)=IC50(耐药细胞株)/IC50(敏感细胞株),结果见表1。
HepG-2/ADM和MCF-7/ADR耐药细胞株对DOX的耐药倍数分别是231.08与191.74倍,对DOX具有高度耐药性。
表1阿霉素在四种肿瘤细胞中的IC50(Mean±SD,n=3)和耐药细胞株的耐药倍数
实施例2苯基哌嗪喹唑啉类化合物的细胞生长抑制作用研究
采用MTT法测定苯基哌嗪喹唑啉类化合物对细胞的生长抑制活性。
(1)实验分组:
①空白对照组:给予1640培养液。
②给药组:分别给予所需浓度的化合物QJJ-1、QJJ-2、QJJ-3、QJJ-4、QJJ-5和QJJ-12。
将化合物QJJ-1、QJJ-2、QJJ-4、QJJ-5和QJJ-12的100mM母液用1640培养基分别稀释为100μM、80μM、40μM、20μM、10μM、5μM、2.5μM、1.25μM,备用。
将化合物QJJ-3的100mM母液用1640培养基稀释为50μM、25μM、12.5μM、6.25μM、3.125μM、1.56μM、0.78μM、0.39μM,备用。
(2)实验步骤
取对数生长期的细胞(HepG-2、MCF-7、MCF-7/ADR、AC16)按照细胞数为每孔5×103个/100μL和HepG-2/ADM按照细胞数目为每孔8×103个/100μL,分别接种于96孔板后,再将其置于37℃、5% CO2、饱和湿度的培养箱中培养。
细胞种板24h后,观察细胞贴壁情况,吸弃96孔板内旧培养液,给药组加入100μL的含药1640培养基,空白对照组加入100μL不含药的1640培养基,将其置于37℃、5% CO2、饱和湿度的培养箱中培养72h。
在避光条件下,96孔板中每孔加入20μL 5mg/mL MTT,边缘孔除外,将其置于37℃、5% CO2、饱和湿度的培养箱中培养4h,吸弃96孔板内的液体,每孔加入150μL DMSO,振荡摇匀10min,用酶标仪测定570nm处的吸光度。利用检测得到的OD值,计算待测化合物对各细胞株的抑制率和IC50值。结果见表2。
实验结果表明,六种化合物对四种肿瘤细胞和人正常心肌细胞的毒性很低。
表2化合物的IC50(Mean±SD,n=3)
实施例3苯基哌嗪喹唑啉类化合物逆转肿瘤耐药活性研究
采用MTT法测定化合物的逆转肿瘤耐药活性。
(1)实验分组:
①空白对照组:给予1640培养液。
②DOX组:HepG-2和MCF-7细胞的给药浓度为0.039μM-10μM的DOX;HepG-2/ADM和MCF-7/ADR细胞的给药浓度为2.5μM-200μM的DOX。
③DOX+化合物联合给药组:
10μM组:给予DOX+化合物(QJJ-1、QJJ-2、QJJ-3、QJJ-4、QJJ-5、QJJ-12、VRP的任一种)的含药培养液,其中DOX的终浓度为10μM、5μM、2.5μM、1.25μM、0.625μM、0.3125μM、0.156μM、0.125μM、0.078μM、0.0125μM的不同浓度,化合物终浓度为10μM;
5μM组:给予DOX+化合物(QJJ-1、QJJ-2、QJJ-3、QJJ-4、QJJ-5、QJJ-12的任一种)的含药培养液,其中DOX的终浓度为10μM、5μM、2.5μM、1.25μM、0.625μM、0.3125μM、0.156μM、0.125μM、0.078μM、0.0125μM的不同浓度,化合物终浓度为5μM;
2.5μM组:给予DOX+化合物(QJJ-4、QJJ-5、QJJ-12的任一种)的含药培养液,其中DOX的终浓度为10μM、5μM、2.5μM、1.25μM、0.625μM、0.3125μM、0.156μM、0.125μM、0.078μM、0.0125μM的不同浓度,化合物终浓度为2.5μM;
(2)实验步骤
取对数生长期的细胞接种于96孔板,HepG-2、MCF-7、MCF-7/ADR细胞数目为每孔5×103个/100μL,HepG-2/ADM细胞数目为每孔8×103个/100μL,将其置于37℃、5% CO2、饱和湿度的培养箱中培养。
细胞给药、MTT显色、酶标仪检测、计算等实验操作同实施例1,测定待测化合物对两株耐药肿瘤细胞的MDR逆转作用,结果见表3、表4。
耐药逆转倍数(reversal fold,RF)=IC50(DOX组)/IC50(DOX+化合物联合给药组)
化合物QJJ-4和QJJ-5与DOX联用后,均能明显提高DOX对耐药肿瘤细胞的生长抑制,逆转肿瘤多药耐药,且在高浓度(10μM)和中浓度(5μM)均显现出比VRP更好的逆转效果。化合物QJJ-12在高浓度(10μM)时显现出比VRP更好的逆转效果。
化合物QJJ-1、QJJ-2和QJJ-3对HepG-2/ADM与MCF-7/ADR耐药肿瘤细胞的MDR逆转倍数可分别达53-145.95和194.52-322.5倍。
表3化合物与DOX联用抑制肿瘤细胞生长活性及MDR逆转效果(mean±SD)
表4化合物与DOX联用抑制肿瘤细胞生长活性及MDR逆转效果(mean±SD)
实施例4苯基哌嗪喹唑啉类化合物对肝药酶活性的影响
采用P450-GloTM CYP3A4试剂盒测定苯基哌嗪喹唑啉类化合物对代表性肝药酶CYP3A4酶活性的影响。结果见图1,苯基哌嗪喹唑啉类化合物对CYP3A4的活性无明显影响。
实施例5肿瘤细胞的P-gp表达水平
采用Western Blot法检测HepG-2、HepG-2/ADM、MCF-7和MCF-7/ADR细胞中P-gp蛋白表达情况。结果见图2。P-gp蛋白在敏感肿瘤细胞株HepG-2和MCF-7中低表达,而在耐药肿瘤细胞株HepG-2/ADM和MCF-7/ADR中高表达。
实施例6苯基哌嗪喹唑啉类化合物抑制耐药肿瘤细胞中抗肿瘤药物外排作用的研究
采用多功能酶标仪检测苯基哌嗪喹唑啉类化合物对耐药肿瘤细胞中抗肿瘤药物外排作用的影响。空白对照组(1640培养液)、DOX(10μM)组、DOX(10μM)+VRP(10μM)组、DOX(10μM)+QJJ-1(10μM)组、DOX(10μM)+QJJ-2(10μM)组、DOX(10μM)+QJJ-3(10μM)组、DOX(10μM)+QJJ-4(10μM)组、DOX(10μM)+QJJ-5(10μM)组。检测结果见图3,苯基哌嗪喹唑啉类化合物能显著抑制耐药肿瘤细胞对DOX的外排作用,且抑制作用强于VRP。
实施例7苯基哌嗪喹唑啉类化合物对P-gp ATPase活性的影响
采用Pgp-GloTM Assay System(Promrga)试剂盒检测苯基哌嗪喹唑啉类化合物对P-gp ATPase酶活性的影响。根据试剂盒的原理,化合物与P-gp ATPase相互作用导致ATPase发生抑制或活化,影响ATP的水解而使体系中ATP的量发生变化。剩余未被水解的ATP将作为荧光素酶产生的发光信号被检测出来,根据化学发光信号强度判断化合物对ATPase的影响。
如发生相互作用后,化学发光强度与不加化合物处理的基础P-gp ATPase(NT组)相比,发光强度减弱,则代表化合物(如VRP)与P-gp ATPase底物结合位点结合,活化ATPase使ATP发生水解导致一定量的消耗,即为P-gp ATPase底物型竞争性抑制剂。如发光强度增强,说明化合物(如Na3VO4)为P-gp ATPase抑制剂。结果见图4。苯基哌嗪喹唑啉类化合物均能显著激活P-gp ATPase酶活性,促进ATP的消耗,为P-gp ATPase的竞争性底物,替代抗肿瘤药物被耐药肿瘤细胞排出细胞,抑制耐药肿瘤细胞对抗肿瘤药物的外排作用。
以上对本发明具体实施方式的描述并不限制本发明,本领域技术人员可以根据本发明作出各种改变或变形,只要不脱离本发明的精神,均应属于本发明权利要求保护的范围。
Claims (21)
1.苯基哌嗪喹唑啉类化合物或其药学上可接受的盐或其药物组合物用于制备逆转肿瘤耐药性药物中的应用,其中,所述苯基哌嗪喹唑啉类化合物选自QJJ-1至QJJ-5、QJJ-7、QJJ-10、QJJ-11、QJJ-12的任一结构,肿瘤耐药药物为阿霉素,所述肿瘤为肝癌、乳腺癌;
; ;
。
2.如权利要求1所述的应用,所述的药学上可接受的盐选自盐酸盐、氢溴酸盐、氢碘酸盐、硝酸盐、碳酸盐、磷酸盐、磷酸氢盐、磷酸二氢盐、硫酸盐、氨基酸盐、乙酸盐、丙酸盐、苯磺酸盐、甲基苯磺酸盐、柠檬酸盐、乳酸盐、富马酸盐、酒石酸盐、琥珀酸盐的任一种或其组合。
3.如权利要求1所述的应用,所述药物组合物含有苯基哌嗪喹唑啉类化合物或其药学上可接受的盐和药学上可接受的载体。
4.如权利要求1所述的应用,所述药物组合物含有苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、阿霉素和药学上可接受的载体。
5.如权利要求4所述的应用,药物组合物中的苯基哌嗪喹唑啉类化合物与阿霉素的摩尔比为1:0.1-10。
6.如权利要求5所述的应用,药物组合物中的苯基哌嗪喹唑啉类化合物与阿霉素的摩尔比为1:0.25-5。
7.如权利要求6所述的应用,药物组合物中的苯基哌嗪喹唑啉类化合物与阿霉素的摩尔比为1:0.5-2。
8.如权利要求4所述的应用,药物组合物中的QJJ1-QJJ5、QJJ12的任一种与阿霉素的摩尔比为1:0.1-10。
9.如权利要求8所述的应用,药物组合物中的QJJ1-QJJ5、QJJ12的任一种与阿霉素的摩尔比为1:0.25-5。
10.如权利要求9所述的应用,药物组合物中的QJJ1-QJJ5、QJJ12的任一种与阿霉素的摩尔比为1:0.5-2。
11.如权利要求1所述的应用,所述药物组合物的给药方式选自口服给药、注射给药、黏膜给药、皮肤给药中的任一种。
12.如权利要求1所述的应用,所述药物组合物对耐药肿瘤细胞的MDR逆转倍数≥50倍。
13.如权利要求12所述的应用,所述药物组合物对耐药肿瘤细胞的MDR逆转倍数≥150倍。
14.如权利要求13所述的应用,所述药物组合物对耐药肿瘤细胞的MDR逆转倍数≥300倍。
15.如权利要求1所述的应用,所述药物组合物为本领域熟知的各种剂型,采用本领域常规的制剂技术制备得到,选自口服制剂、注射剂、外用制剂、吸入制剂的任一种。
16.如权利要求15所述的应用,所述的口服制剂选自片剂、胶囊剂、颗粒剂、散剂、露剂、丸剂、合剂、糊剂、茶剂的任一种。
17.如权利要求15所述的应用,所述的外用制剂选自凝胶剂、膏剂、霜剂、搽剂、洗剂、栓剂、涂抹剂的任一种。
18.如权利要求15所述的应用,所述的吸入制剂选自干粉吸入剂、吸入液体制剂的任一种。
19.如权利要求15所述的应用,所述的注射剂选自溶液型注射液、乳剂型注射液、混悬剂型注射液、注射用无菌粉末、大输液的任一种。
20.如权利要求4所述的应用,所述的药学上可接受的载体包括填充剂、润滑剂、分散剂、润湿剂、粘合剂、崩解剂、pH调节剂、渗透压调节剂、致孔剂、增稠剂、增溶剂、抗氧剂、抑菌剂、止痛剂、助悬剂、乳化剂、助乳化剂、冻干保护剂、矫味剂、赋香剂、助溶剂、潜溶剂中的任一种或其组合。
21.如权利要求1-20任一项所述的应用,将药物组合物与药学上可接受的缓释制剂载体或控释制剂载体制成缓释制剂或控制制剂。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104230913A (zh) * | 2013-06-06 | 2014-12-24 | 黄传满 | 哌嗪取代喹唑啉类化合物及其用途 |
CN114920704A (zh) * | 2019-07-26 | 2022-08-19 | 暨南大学 | 一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 |
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104230913A (zh) * | 2013-06-06 | 2014-12-24 | 黄传满 | 哌嗪取代喹唑啉类化合物及其用途 |
CN114920704A (zh) * | 2019-07-26 | 2022-08-19 | 暨南大学 | 一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 |
CN115108999A (zh) * | 2019-07-26 | 2022-09-27 | 暨南大学 | 一种苯基哌嗪喹唑啉类化合物或其药学上可接受的盐、制法与用途 |
Non-Patent Citations (5)
Title |
---|
Design, synthesis, and biological evaluation of quinazoline derivatives containing piperazine moieties as antitumor agents;Wen Li等;Journal of Chemical Research;第44卷(第9-10期);第536-542页 * |
Modulation of the function of human MDR1 P-glycoprotein by the antimalarial drug mefloquine;Riffkin, CD等;biochemical pharmacology;第52卷(第10期);第1545-1552页 * |
Tandutinib (MLN518) reverses multidrug resistance by inhibiting the efflux activity of the multidrug resistance protein 7 (ABCC10);Deng, W等;ONCOLOGY REPORTS;第29卷(第6期);第2479-2485页 * |
Tyrosine kinase inhibitors influence ABCG2 expression in EGFR-positive MDCK BCRPcells via the PI3K/Akt signaling pathway;Pick, A等;CHEMMEDCHEM;第7卷(第4期);第650-662页 * |
刘海彬等.6,7-二甲氧基-4-哌嗪喹唑啉缩氨基硫脲衍生物的合成及体外抗肿瘤活性研究.化学学报.2012,第0卷(第05期),第674-678页. * |
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