CN112225723B - 一种吲哚类衍生物、制备方法及应用 - Google Patents
一种吲哚类衍生物、制备方法及应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一种吲哚类衍生物、制备方法及应用,属于化学医药技术领域。
背景技术
Aurora-A是Aurora蛋白激酶家族成员,是一类在细胞增殖过程中起重要作用的丝氨酸/苏氨酸激酶,参与细胞有丝分裂的很多过程,包括细胞G2/M转换、有丝分裂纺锤体的装配、染色单体分离和细胞质分裂等过程,对细胞有丝分裂过程起重要的调控作用。Aurora-A的异常表达会导致细胞中心体扩增、基因组的非整倍性和染色体不稳定性。由于Aurora-A在很多类型肿瘤中异常表达,所以Aurora-A是治疗有关肿瘤的潜在靶点。
以Aurora-A激酶为靶点进行抗肿瘤药物研究越来越受到人们重视,Aurora-A激酶在有丝分裂中才被表达和激活,它们对于非增殖的细胞无效,而在人体中大多数正常细胞的增殖速度不快,因此Aurora-A激酶抑制剂属于靶向抗肿瘤药物。
因此,发现一种结构新颖、活性高的Aurora-A激酶抑制剂具有重要意义。
发明内容
本发明针对现有技术存在的不足,提供了一种吲哚类衍生物、制备方法及应用,该吲哚类衍生物通过抑制Aurora-A激酶的活性达到治疗肿瘤的目的,具体技术方案如下:
一种吲哚类衍生物或其药学上可接受的盐,所述吲哚类衍生物具有如式Ι所示的结构:
其中,R1选自取代或不取代的苯基、取代或不取代的芳杂环基、取代或不取代的五元环、取代或不取代的六元环,或者,R1和与其相邻的氮原子一起形成五元杂环基或六元杂环基;
当所述R1选自取代或不取代的五元环时,所述五元环含有的杂原子最多为2个;
当所述R1选自取代或不取代的六元环时,所述六元环含有的杂原子最多为2个。
作为上述技术方案的改进,所述吲哚类衍生物选自下述式1-式24中的任一化合物,结构式如下:
式1
式2
式3
式4
式5
式6
式7
式8
式9
式10
式11
式12
式13
式14
式15
式16
式17
式18
式19
式20
式21
式22
式23
式24。
所述吲哚类衍生物或其药学上可接受的盐的制备方法,包括如下步骤:
步骤1)、式II所示化合物与式III所示化合物在碱和缩合剂的作用下于反应溶剂中进行反应,得到式IV所示化合物;所述反应温度为20-80℃;所述碱包括三乙胺(别名Et3N)、二异丙基乙胺(别名DIEA)、N-甲基吗啉、4-二甲氨基吡啶中的至少一种;所述缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(别名HATU)、O-苯并三氮唑-四甲基脲六氟磷酸盐、二环己基碳二亚胺、双(2-氧代-3-恶唑烷基)次磷酰氯中的至少一种;所述反应溶剂为甲苯、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺(别名DMF)、二甲基亚砜中的至少一种。
步骤2)、式IV所示化合物在酸作用下于反应溶剂中进行反应,得到式V所示化合物;所述反应温度为20-60℃;所述酸为三氟乙酸和盐酸(别名HCl)中的至少一种;所述反应溶剂为乙酸乙酯(别名EtOAc)、二氯甲烷、甲苯和乙腈中的至少一种。
步骤3)、式V所示化合物和式VI所示化合物在碱和缩合剂作用下于反应溶剂中进行反应,得到式I所示化合物。所述反应温度为20-60℃;所述碱为三乙胺、二异丙基乙胺、N-甲基吗啉中的至少一种;所述反应溶剂为N,N-二甲基甲酰胺、二氯甲烷(别名DCM)、甲苯、四氢呋喃、乙腈中的至少一种。
所述的吲哚类衍生物或其药学上可接受的盐作为Aurora-A激酶抑制剂在制备治疗或预防肿瘤的药物中的应用。
作为上述技术方案的改进,所述肿瘤选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、肾癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、软骨肉瘤、肌肉瘤、纤维肉瘤中的任一种。
本发明的有益效果:
1)、本发明所述吲哚类衍生物或其药学上可接受的盐能够通过抑制Aurora-A激酶活性达到治疗肿瘤目的,在用作治疗或预防肿瘤药物的研究领域具有重要的意义和极大的研究价值。本发明的一个目的,合成一种新的Aurora-A激酶抑制剂,其包括向需要此种治疗或预防的患者给予治疗有效量的一种或者多种本发明化合物或其药用盐、立体异构体或互变异构体。
2)、本发明所述吲哚类衍生物的合成方法,合成反应过程中副产物少,收率高,具有极大的应用价值。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
定义
“药学上可接受的盐”是指那些保留母体化合物的生物有效性及特性的盐。该盐包括:酸加成盐,其是通过母体化合物的游离碱与无机酸或与有机酸的反应而获得的;所述无机酸诸如盐酸、氢溴酸、氢碘酸、硝酸、磷酸、硫酸及高氯酸等;所述有机酸诸如乙酸、草酸、(D)或(L)苹果酸、马来酸、甲烷磺酸、乙烷磺酸、对甲苯磺酸、水杨酸、酒石酸、苯磺酸(苯磺酸盐)、苯甲酸、樟脑磺酸、柠檬酸、富马酸、葡萄糖酸、谷氨酸、羟乙磺酸、乳酸、马来酸、扁桃酸、黏液酸、双羟萘酸、泛酸、琥珀酸、酒石酸或丙二酸等;优选为盐酸或(L)-苹果酸;或者当母体化合物中存在的酸质子被置换为金属离子或与有机碱配位时,形成盐,所述金属离子例如碱金属离子、碱土金属离子或铝离子;所述有机碱诸如乙醇胺、二乙醇胺、三乙醇胺、缓血酸胺、N-甲基葡糖胺及类似物。
“苯基”是指以苯环为官能团的基团。“取代”是指分子中的1个、2个或多个氢原子被其它不同的原子或分子所替换,包括该分子中同位原子或异位原子上的1个、2个或多个取代。“芳杂环基”是指以“芳杂环”为官能团的基团,“芳杂环”即“芳香杂环”,是具有平种结构特点的杂环,其环中原子构成一个环闭的共轭体系,分子呈平面型,此平面上下两侧有环状的离域电子云,共轭体系中的P电子数都符合休克尔规则。例如吡啶、呋喃环、噻唑环、嘧啶环等等。“杂环”是指环中含碳原子和一个或多个杂原子的饱和、不饱和或芳族的环基。含有5个成环的原子即为“五元环”,含有6个成环的原子即为“六元环”。“五元环”中含有一个或多个杂原子即为“五元杂环”,“六元环”中含有一个或多个杂原子即为“六元杂环”。
本发明的化合物可具有一个或多个不对称中心;该化合物因此可以个别(R)-立体异构体或(S)-立体异构体形式制备或以其混合物形式制备。除非另有说明,否则本说明书及权利要求中的特定化合物的描述或名称意欲包括个别对映异构体与其外消旋混合物或其它混合物。用于测定立体化学构型及分离立体异构体的方法在本领域中是熟知的(参见"Advanced Organic Chemistry"的第4章中的论述,第4版,J. March,John Wiley及Sons,New York,1992)。因此,本发明亦涵盖具有抑制VEGFR活性的任何立体异构形式、其相应对映异构体(d-异构体及l-异构体或(+)异构体及(-)异构体)及其非对映异构体及其混合物且不限于任一种立体异构形式。
实施例1
如式1所示的化合物:4-(3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲基)苯甲酰胺的制备方法,反应式如下:
第一步:
将化合物1a(27.6g,100.0mmol)、化合物1b(12.8g,100.0mmol)、二异丙基乙胺(DIEA,25.8g,200.0mmol)、HATU(45.6g,120.0mmol)溶于DMF(200mL)中,室温搅拌反应12小时,TLC监测反应,反应完毕后降至室温,加入水200mL淬灭反应,加入乙酸乙酯(300mL×2)提取,合并有机层,干燥、浓缩、柱层析分离得到28.5g类白色固体(化合物1c),收率为73.8%。
第二步:
将化合物1c(28.0g,72.5mmol)溶于乙酸乙酯(EtOAc,100mL)中,室温下加入氯化氢乙酸乙酯溶液(50mL),室温搅拌反应4小时,过程逐渐析出固体,过滤,干燥得到23.8g白色固体(化合物1d),收率为91.7%。
第三步:
将化合物1d(358mg,1.0mmol)、化合物1e(136mg,1.0mmol)、三乙胺(Et3N,303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(DCM,300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到246mg类白色固体(化合物1),收率为54.9%,ESI(+) m/z=449.2。
实施例2
如式2所示的化合物:4-(3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲基)-N,N-二甲基苯甲酰胺的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物2a(164mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到312mg类白色固体(化合物2),收率为65.4%,ESI(+) m/z=478.2。
实施例3
如式3所示的化合物:4-(3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲基)苯磺酰胺的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物3a(172mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到226mg类白色固体(化合物3),收率为46.7%,ESI(+) m/z=485.2。
实施例4
如式4所示的化合物:1-(4-乙酰苯基)-3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物4a(135mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到268mg类白色固体(化合物4),收率为59.9%,ESI(+) m/z=448.2。
实施例5
如式5所示的化合物:N-(4-(3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲基)苯基)乙酰胺的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物5a(150mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到282mg类白色固体(化合物5),收率为61.0%,ESI(+) m/z=463.2。
实施例6
如式6所示的化合物:N-(4-(3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲基)苯基)甲基磺酰胺的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物6a(186mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到305mg类白色固体(化合物6),收率为61.2%,ESI(+) m/z=499.2。
实施例7
如式7所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(4-甲氧基苯基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物7a(123mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到228mg类白色固体(化合物7),收率为52.4%,ESI(+) m/z=436.2。
实施例8
如式8所示的化合物:4-(3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲基)吡啶-2-甲酰胺的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物8a(137mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到247mg类白色固体(化合物8),收率为55.1%,ESI(+) m/z=449.2。
实施例9
如式9所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(4-氟苯基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物9a(150mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到244mg类白色固体(化合物9),收率为57.7%,ESI(+) m/z=424.2。
实施例10
如式10所示的化合物:1-(4-氯苯基)-3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物10a(127mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到266mg类白色固体(化合物10),收率为60.5%,ESI(+) m/z=440.2。
实施例11
如式11所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(4-氟-3-甲氧基苯基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物11a(141mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到238mg类白色固体(化合物11),收率为52.5%,ESI(+) m/z=454.2。
实施例12
如式12所示的化合物:1-(2,4-二氟苯基)-3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物12a(129mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到245mg类白色固体(化合物12),收率为55.6%,ESI(+) m/z=442.2。
实施例13
如式13所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(6-氟吡啶-3-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物13a(112mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到219mg类白色固体(化合物13),收率为51.7%,ESI(+) m/z=425.2。
实施例14
如式14所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(嘧啶-5-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物14a(95mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到223mg类白色固体(化合物14),收率为54.8%,ESI(+) m/z=408.2。
实施例15
如式15所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(2-甲氧基吡啶-4-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物15a(124mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到255mg类白色固体(化合物15),收率为58.5%,ESI(+) m/z=437.2。
实施例16
如式16所示的化合物:1-(苯并[d][1,3]二氧戊烷-5-基)-3-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物16a(137mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到288mg类白色固体(化合物16),收率为64.1%,ESI(+) m/z=450.2。
实施例17
如式17所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(1-甲基哌啶-4-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物17a(114mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到258mg类白色固体(化合物17),收率为60.6%,ESI(+) m/z=427.2。
实施例18
如式18所示的化合物:N-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)吗啉-4-甲酰胺的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物18a(87mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到280mg类白色固体(化合物18),收率为70.0%,ESI(+) m/z=400.2。
实施例19
如式19所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(1-乙酰基哌啶-4-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物19a(142mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到265mg类白色固体(化合物19),收率为58.4%,ESI(+) m/z=455.2。
实施例20
如式20所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(4-氧代环己基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物20a(113mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到301mg类白色固体(化合物20),收率为70.8%,ESI(+) m/z=426.2。
实施例21
如式21所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(1-甲基吡咯烷-3-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物21a(100mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到275mg类白色固体(化合物21),收率为66.7%,ESI(+) m/z=413.2。
实施例22
如式22所示的化合物:N-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-氧代吡咯烷-1-甲酰胺的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物22a(85mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到295mg类白色固体(化合物22),收率为74.3%,ESI(+) m/z=398.2。
实施例23
如式23所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(3-氧代环戊基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物23a(99mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到322mg类白色固体(化合物23),收率为78.3%,ESI(+) m/z=412.2。
实施例24
如式24所示的化合物:1-(2-(3-(二甲基氨基)哌啶-1-羰基)-1H-吲哚-4-基)-3-(四氢-2H-吡喃-4-基)脲的制备方法,反应式如下:
将化合物1d(358mg,1.0mmol)、化合物24a(101mg,1.0mmol)、三乙胺(303mg,3.0mmol)、CDI(162mg,1.0mmol)溶于二氯甲烷(300mL)中,室温搅拌反应过夜,TLC监测反应,反应完毕后,直接浓缩,柱层析分离得到302mg类白色固体(化合物24),收率为73.1%,ESI(+) m/z=414.2。
实施例25
Aurora-A激酶体外活性测试的实验方法如下:
在96孔板中先后加入10μL反应溶液、10μL Aurora-A激酶、10μL底物、10μL待测化合物溶液、10μL LATP溶液,混匀后孵育30分钟;然后在每个孔板中加入10μL激酶反应终止液,接着在每个孔板中加入10μL磷酸-组蛋白H3抗体,在25℃孵育60分钟后加入100μLLHRP-抗体螯合剂溶液,在25℃孵育60分钟,继而加入100μL TMB底物于25℃孵育10分钟,最后在每个孔板中加入100μL ELISA终止液,用酶联免疫检测仪记录450nm的读数,以不加药物的溶剂作为空白对照,通过计算得到IC50,具体数据如下表所示:
A<50 nM,50 nM≤B≤500 nM,500nM<C;
实施例 | IC<sub>50</sub>(Aurora-A) | 实施例 | IC<sub>50</sub>(Aurora-A) |
化合物1 | A | 化合物13 | A |
化合物2 | A | 化合物14 | C |
化合物3 | B | 化合物15 | A |
化合物4 | B | 化合物16 | B |
化合物5 | A | 化合物17 | A |
化合物6 | C | 化合物18 | C |
化合物7 | A | 化合物19 | C |
化合物8 | B | 化合物20 | B |
化合物9 | B | 化合物21 | B |
化合物10 | C | 化合物22 | B |
化合物11 | C | 化合物23 | A |
化合物12 | A | 化合物24 | C |
在上述实施例中,化合物1是指如式1所示化合物,化合物1a是指如式1a所示化合物,以此类推。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (7)
3.根据权利要求2所述的吲哚类衍生物或其药学上可接受的盐的制备方法,其特征在于,在步骤1)中,反应温度为20-80℃,
所述碱包括三乙胺、二异丙基乙胺、N-甲基吗啉、4-二甲氨基吡啶中的至少一种;
所述缩合剂为1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、O-苯并三氮唑-四甲基脲六氟磷酸盐、二环己基碳二亚胺、双(2-氧代-3-恶唑烷基)次磷酰氯中的至少一种;
所述反应溶剂为甲苯、四氢呋喃、二氯甲烷、N,N-二甲基甲酰胺、二甲基亚砜中的至少一种。
4.根据权利要求2所述的吲哚类衍生物或其药学上可接受的盐的制备方法,其特征在于,在步骤2)中,反应温度为20-60℃,
所述酸为三氟乙酸和盐酸中的至少一种,
所述反应溶剂为乙酸乙酯、二氯甲烷、甲苯和乙腈中的至少一种。
5.根据权利要求2所述的吲哚类衍生物或其药学上可接受的盐的制备方法,其特征在于,在步骤3)中,反应温度为20-60℃,
所述碱为三乙胺、二异丙基乙胺、N-甲基吗啉中的至少一种,
所述缩合剂为N,N'-羰基二咪唑、碳酰氯、双(三氯甲基)碳酸酯中的至少一种,
所述反应溶剂为N,N-二甲基甲酰胺、二氯甲烷、甲苯、四氢呋喃、乙腈中的至少一种。
6.根据权利要求1所述的吲哚类衍生物或其药学上可接受的盐在制备治疗或预防肿瘤的药物中的应用。
7.根据权利要求6所述的吲哚类衍生物或其药学上可接受的盐在制备治疗或预防肿瘤的药物中的应用,其特征在于,所述肿瘤选自皮肤癌、膀胱癌、卵巢癌、乳腺癌、胃癌、前列腺癌、结肠癌、肺癌、骨癌、脑癌、直肠癌、食管癌、舌癌、肾癌、宫颈癌、子宫体癌、子宫内膜癌、睾丸癌、泌尿癌、黑素癌、星型细胞癌、脑膜瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、急性淋巴性白血病、慢性淋巴性白血病、急性骨髓性白血病、慢性粒细胞白血病、成人T细胞白血病淋巴瘤、肝细胞癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、精原细胞瘤、软骨肉瘤、肌肉瘤、纤维肉瘤中的任一种。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005116035A1 (en) * | 2004-05-27 | 2005-12-08 | Pfizer Products Inc. | Pyrrolopyrimidine derivatives useful in cancer treatment |
CN101160316A (zh) * | 2004-07-16 | 2008-04-09 | 苏内西斯医药公司 | 适合用作aurora激酶抑制剂的噻吩并嘧啶 |
CN101365701A (zh) * | 2005-11-18 | 2009-02-11 | 布里斯托尔-迈尔斯.斯奎布公司 | 吡咯并三嗪激酶抑制剂 |
CN101389324A (zh) * | 2005-12-23 | 2009-03-18 | 史密丝克莱恩比彻姆公司 | Aurora激酶的氮杂吲哚抑制剂 |
CN101857588A (zh) * | 2010-06-08 | 2010-10-13 | 东南大学 | 4-芳香胺基喹唑啉类衍生物及其用途 |
WO2011067145A1 (en) * | 2009-12-04 | 2011-06-09 | Nerviano Medical Sciences S.R.L. | Tricyclopyrazole derivatives |
CN103458970A (zh) * | 2011-03-07 | 2013-12-18 | 泰莱托恩基金会 | Tfeb磷酸化抑制剂及其应用 |
-
2020
- 2020-12-16 CN CN202011481178.4A patent/CN112225723B/zh active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005116035A1 (en) * | 2004-05-27 | 2005-12-08 | Pfizer Products Inc. | Pyrrolopyrimidine derivatives useful in cancer treatment |
CN101160316A (zh) * | 2004-07-16 | 2008-04-09 | 苏内西斯医药公司 | 适合用作aurora激酶抑制剂的噻吩并嘧啶 |
CN101365701A (zh) * | 2005-11-18 | 2009-02-11 | 布里斯托尔-迈尔斯.斯奎布公司 | 吡咯并三嗪激酶抑制剂 |
CN101389324A (zh) * | 2005-12-23 | 2009-03-18 | 史密丝克莱恩比彻姆公司 | Aurora激酶的氮杂吲哚抑制剂 |
WO2011067145A1 (en) * | 2009-12-04 | 2011-06-09 | Nerviano Medical Sciences S.R.L. | Tricyclopyrazole derivatives |
CN101857588A (zh) * | 2010-06-08 | 2010-10-13 | 东南大学 | 4-芳香胺基喹唑啉类衍生物及其用途 |
CN103458970A (zh) * | 2011-03-07 | 2013-12-18 | 泰莱托恩基金会 | Tfeb磷酸化抑制剂及其应用 |
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