CN115246843A - 一类十四元稠环衍生物及其应用 - Google Patents
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- A—HUMAN NECESSITIES
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- C07F9/02—Phosphorus compounds
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- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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Abstract
本发明属于药物化学领域,涉及一类十四元稠环衍生物。具体涉及式I所示化合物及其药学上可接受的盐及其应用,
Description
技术领域
本发明属于药物化学领域,涉及一类十四元稠环衍生物。具体涉及这一类化合物及其药学上可接受的盐及其在制备预防、改善或治疗与间变性淋巴瘤激酶(ALK)和/或EML4-ALK融合蛋白和/或原癌基因蛋白酪氨酸激酶ROS(ROS1)介导的疾病中的应用。
背景技术
间变性淋巴瘤激酶(ALK)是受体酪氨酸激酶超家族的一个成员并且氨基酸序列水平和ROS1等成员密切相关。间变性淋巴瘤激酶在肿瘤学中有一个重要的作用,引起该激酶活化并使该激酶表达增加的全长ALK酶点突变已被证明导致神经母细胞瘤。此外ALK与其它蛋白质融合也被证明导致与癌症相关的激酶活化。在淋巴瘤中可以发现许多引起基因融合的此类ALK易位,如在间变性大细胞淋巴瘤中的核磷蛋白NPM-ALK融合;3-5%的非小细胞肺腺癌(NSCLC)中的EML4-ALK嵌合蛋白等。目前针对ALK突变的靶向药物有一代ALK靶向药克唑替尼(Crizotinib),二代ALK靶向药包括色瑞替尼(Ceritinib)、艾乐替尼(Alectinib)、布加替尼(brigatinib),以及三代ALK靶向药物劳拉替尼(Lorlatinib)。
前药(Prodrug)是指一类在体外无活性或活性较小,在体内经过一个活多个步骤的酶和/或化学种类的生物转化,释放出活性物质而产生药理作用的化合物,又称生物可逆性药物。前药是一种很有用的药物设计方法,广泛应用于多种药物分子的设计中。例如改造物理化学性质,更具体说是溶解度、主被动吸收性质活组织特异性分布等等。通常通过前药残基改善潜在活性组分的性质,且为达到最佳的作用曲线,而根据适应症、作用靶点、组份的性质和给药的途径等特性,设计合理的前药残基及释放机理是十分有必要的。
劳拉替尼(Lorlatinib),化学名为(10R)-7-氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈,化学式如下所示:
劳拉替尼是辉瑞研发的可以靶向和抑制ALK和ROS1的新一代ALK抑制剂。由于疗效显著(一项I/II期临床试验(B7461001)结果:ALK阳性初治缓解率90%,ALK阳性接受克里唑替尼治疗后缓解率69%),美国FDA已经授予其突破性疗法和“孤儿药”地位(用于预防、治疗、诊断罕见病的药品)。在2018年11月2日,批准上市用于治疗ALK阳性转移性非小细胞肺癌(NSCLC)患者。
发明内容
本发明提供一种具有十四元稠环的劳拉替尼衍生物,具有如下式I结构的化合物或其药学上可接受的盐:
其中:
R1、R2相同或者不同,选自H或-(CH2)n-X-R3,X选自-(CH2)m-、-O-、-OCO-、-OCONH-、-NH-、NR4-,n、m分别代表0-12的整数,R3、R4相同或不同,选自烷基、烯基、叔丁氧羰基、磺酰基、磷酰基,且R1、R2不同时为H。
优选的,所述的n、m分别代表0-6的整数,R3、R4相同或不同,选自C1-C6的烷基、C2-C6烯基、叔丁氧羰基、取代或非取代的烷基磺酰基、取代或非取代的苯磺酰基、磷酰基。
进一步优选的,n、m分别代表0-3的整数,R3、R4相同或不同,选自C1-C6的烷基、C2-C6烯基、叔丁氧羰基、被卤素和/或羟基取代或非取代的C1-C6的烷基磺酰基、被卤素、羟基、C1-C6的烷基中的一种或几种取代或非取代的苯磺酰基、磷酰基。
一些具体的优选方案,R3、R4相同或不同,选自甲基、乙基、丙基、异丙基、乙烯基、丙烯基、异丙烯基、叔丁氧羰基、被卤素和/或羟基取代或非取代的甲磺酰基、被卤素、羟基、甲基、乙基中的一种或几种取代或非取代的苯磺酰基、磷酰基。
本发明具体示例为:
化合物Ⅰ-1:(10R)-7-甲氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-2:(10R)-7-乙氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-3:(10R)-7-乙酸酯基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-4:(10R)-7-甲氧基乙基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-5:(10R)-7-乙基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-6:(10R)-7-氨基丙基(二甲基)氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-7:(10R)-7-氨基甲酸酯基甲基叔丁氧羰基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-8:(10R)-7-乙烯氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-9:(10R)-7-二乙基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-10:(10R)-7-二甲氧基甲基叔丁氧羰基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-11:(10R)-7-二氨甲酰氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-12:(10R)-7-二乙烯氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-13:(10R)-7-甲磺酸基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-14:(10R)-7-磷酸基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
化合物Ⅰ-15:(10R)-7-磷酸酯基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈。
本发明另一目的在于提供一种药物组合,包括治疗有效量的本发明所述化合物或其药学上可接受的盐,以及一种或多种药学上可接受的载体或赋形剂。
本发明另一目的在于提供所述化合物或其药学上可接受的盐及药物组合在制备用于治疗或改善间变性淋巴瘤激酶和/或EML4-ALK融合蛋白和/或原癌基因蛋白酪氨酸激酶介导的疾病的药物中的应用。
一个优选的方案,所述间变性淋巴瘤激酶(ALK)和/或EML4-ALK融合蛋白和/或原癌基因蛋白酪氨酸激酶ROS(ROS1)介导的疾病为癌症,选自非小细胞肺癌、鳞状细胞癌、慢性淋巴细胞白血病、神经母细胞瘤、前列腺癌、乳突状肾细胞癌、大肠直肠腺癌、神经母细胞瘤、间变性大细胞淋巴瘤、多发性骨髓瘤、急性骨髓性白血病、乳腺癌、实体癌和胃癌。
本发明优点:本发明设计得到的劳拉替尼(Lorlatinib)前药化合物在血浆中能迅速转化为原药劳拉替尼,与原药相比,具有更好的生物利用度,增强了药效。
具体实施方式
下面通过实施例进一步详述本发明,但本发明并不限于下述的实施例。
实施例1(10R)-7-甲氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备。
将化合物(10R)-7-氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈(100mg,0.246mmol)溶于20ml的二甲亚砜中,在冰浴中冷却至0℃,加入氢化钠继续搅拌3分钟后,缓慢滴加氯甲基甲基醚后,撤去冰浴,回温至室温后,继续搅拌4小时。加入水终止反应后,二氯甲烷萃取,无水硫酸钠干燥,过滤,浓缩。粗产品用乙酸乙酯:石油醚=1:10柱层析,得灰白色固体82mg,产率74%。
1HNMR(300MHz,CDCl3)δ:7.94(d,1H),7.41(dd,1H),7.29(dd,1H),7.01(m,1H),6.92(d,1H),6.79(t,1H),5.98(d,2H),5.66(m,1H),4.44(d,1H),4.36(d,1H),4.20(s,3H),4.05(s,3H),3.13(s,3H),1.80(d,3H);MS m/z:451.1[M+1]。
实施例2(10R)-7-乙氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为氯甲基乙基醚,得到标题化合物灰白固体82mg,产率72%。1HNMR(300MHz,CDCl3)δ:7.94(d,1H),7.41(dd,1H),7.31(dd,1H),7.01(m,1H),6.92(d,1H),6.79(t,1H),5.98(d,2H),5.66(m,1H),4.44(d,1H),4.36(d,1H),4.05(s,3H),3.50(s,2H),3.13(s,3H),1.80(d,3H),1.11(s,3H);MS m/z:465.1[M+1]。
实施例3(10R)-7-乙酸酯基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为氯甲基乙酸酯,得到标题化合物灰白固体89mg,产率76%。1HNMR(300MHz,CDCl3)δ:7.92(d,1H),7.40(m,1H),7.23(m,1H),7.04(m,1H),6.90(d,1H),6.80(t,1H),5.88(d,2H),5.55(m,1H),4.44(d,1H),4.36(d,1H),4.05(s,3H),3.13(s,3H),2.20(s,3H),1.80(d,3H);MS m/z:479.1[M+1]。
实施例4(10R)-7-甲氧基乙基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为氯乙基甲基醚,得到标题化合物灰白固体69mg,产率60%。1HNMR(300MHz,CDCl3)δ:7.94(d,1H),7.41(m,1H),7.21(m,1H),7.02(m,1H),6.91(d,1H),6.82(t,1H),5.76(d,2H),5.45(m,1H),4.43(d,1H),4.36(d,2H),4.05(s,3H),3.79(m,2H),3.65(m,2H),3.16(s,3H),1.80(d,3H);MS m/z:465.2[M+1]。
实施例5(10R)-7-乙基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为氯乙烷,得到标题化合物灰白固体90mg,产率84%。1HNMR(300MHz,CDCl3)δ:7.93(d,1H),7.42(m,1H),7.21(m,1H),7.05(m,1H),6.90(d,1H),6.83(t,1H),5.78(d,2H),5.48(m,1H),4.42(d,1H),4.36(d,2H),4.05(s,3H),3.48(m,2H),1.80(d,3H),1.15(t,3H);MS m/z:435.2[M+1]。
实施例6(10R)-7-氨基丙基(二甲基)氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为氯丙基N,N-二甲基氨基,得到标题化合物灰白固体54mg,产率45%。
1HNMR(300MHz,CDCl3)δ:7.94(d,1H),7.41(dd,1H),7.32(m,1H),7.01(m,1H),6.92(d,1H),6.79(t,1H),5.67(m,1H),4.44(d,1H),4.36(d,1H),4.05(s,3H),3.35(m,2H),3.13(s,3H),2.38(d,2H),2.15(s,6H),1.80(d,3H),1.72(d,2H);MS m/z:492.2[M+1]。
实施例7(10R)-7-氨基甲酸酯基甲基叔丁氧羰基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为叔丁氧羰基氨基甲酸酯基甲基氯,得到标题化合物灰白固体62mg,产率44%。1HNMR(300MHz,CDCl3)δ:8.12(s,1H),7.92(d,1H),7.40(s,1H),7.24(s,1H),7.02(s,1H),6.92(d,1H),6.80(t,1H),5.84(m,2H),5.68(m,1H),4.44(d,1H),4.36(d,1H),4.07(s,3H),3.13(s,3H),1.81(d,3H),1.38(s,9H);MS m/z:580.2[M+1]。
实施例8(10R)-7-乙烯氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为氯甲基乙烯醚,得到标题化合物灰白固体68mg,产率60%。1HNMR(300MHz,CDCl3)δ:7.98(d,1H),7.38(dd,1H),7.23(m,1H),7.01(m,1H),6.92(d,1H),6.79(t,1H),6.44(m,1H),5.70(m,3H),4.44(d,1H),4.36(m,3H),4.05(s,3H),3.13(s,3H),1.80(d,3H);MS m/z:463.1[M+1]。
实施例9(10R)-7-二乙基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为氯乙烷(三倍量),得到标题化合物灰白固体93mg,产率82%。1HNMR(300MHz,CDCl3)δ:7.93(d,1H),7.21(m,1H),7.05(m,1H),6.90(d,1H),6.83(t,1H),5.78(d,2H),5.48(m,1H),4.42(d,1H),4.36(d,2H),4.05(s,3H),3.48(m,4H),1.80(d,3H),1.15(t,6H);MS m/z:463.2[M+1]。
实施例10(10R)-7-二甲氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,氯甲基甲基醚(三倍量),得到标题化合物灰白固体99mg,产率81%。1HNMR(300MHz,CDCl3)δ:7.94(d,1H),7.41(dd,1H),7.01(m,1H),6.92(d,1H),6.79(t,1H),5.98(m,4H),5.66(m,1H),4.44(d,1H),4.36(d,1H),4.05(s,3H),3.50(s,2H),3.13(s,6H),1.80(d,3H),1.11(s,3H);MS m/z:495.1[M+1]。
实施例11(10R)-7-二氨甲酰氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为叔丁氧羰基氨基甲酸酯基甲基氯(三倍量),得到标题化合物灰白固体67mg,产率36%。1HNMR(300MHz,CDCl3)δ:8.12(s,1H),7.92(d,1H),7.24(s,1H),7.02(s,1H),6.92(d,1H),6.80(t,1H),5.84(m,4H),5.68(m,1H),4.44(d,1H),4.36(d,1H),4.07(s,3H),3.13(s,3H),1.81(d,3H),1.39(s,18H);MSm/z:753.2[M+1]。
实施例12(10R)-7-二乙烯氧基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
按照实施例1的方法和反应条件,将氯甲基甲基醚替换为氯甲基乙烯醚(三倍量),得到标题化合物灰白固体57mg,产率45%。1HNMR(300MHz,CDCl3)δ:7.98(d,1H),7.19(m,1H),7.01(m,1H),6.92(d,1H),6.79(t,1H),6.45(m,2H),5.71(m,5H),4.44(d,1H),4.36(m,5H),4.05(s,3H),3.13(s,3H),1.80(d,3H);MS m/z:518.1[M+1]。
实施例13(10R)-7-甲磺酸基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
将化合物(10R)-7-氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈(100mg,0.246mmol)溶于20ml的二氯甲烷中,在冰浴中冷却至0℃,加入1ml三乙胺继续搅拌3分钟后,缓慢滴加甲磺酰氯后,撤去冰浴,回温至室温后,继续搅拌4小时。加入水终止反应后,二氯甲烷萃取,无水硫酸钠干燥,过滤,浓缩。粗产品用乙酸乙酯:石油醚=1:10柱层析,得灰白色固体83mg,产率70%。1HNMR(300MHz,CDCl3)δ:7.93(d,1H),7.40(dd,1H),7.21(m,1H),7.00(m,1H),6.92(d,1H),5.66-5.70(m,1H),4.42(d,1H),4.37(d,1H),4.06(s,3H),3.12(s,3H),2.49(s,6H),1.78(d,3H);MS m/z:485.1[M+1]。
实施例14(10R)-7-磷酸基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈
按照实施例14的方法和反应条件,将甲磺酰氯替换为三氯氧磷,得到标题化合物灰白固体51mg,产率43%。1HNMR(300MHz,CDCl3)δ:7.93(d,1H),7.41(dd,1H),7.31(dd,1H),7.03(m,1H),6.92(d,1H),6.79(t,1H),5.72(m,1H),4.8(s,2H),4.44(d,1H),4.36(d,1H),4.05(s,3H),3.13(s,3H),1.80(d,3H);MS m/z:487.1[M+1]。
实施例15((10R)-7-磷酸酯基甲基氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈的制备
将化合物(10R)-7-氨基-12-氟-2,10,16-三甲基-15-氧叉-10,15,16,17-四氢-2H-8,4-(亚甲氧桥)吡唑[4,3-h][2,5,11]-苯并噁二氮杂环十四烯-3-腈(100mg,0.246mmol)和5ml甲醛的四氢呋喃溶液置于20ml的四氢呋喃中,室温下搅拌12h,在冰浴中冷却至0℃,缓慢滴加三氯氧磷后,撤去冰浴,回温至室温后,继续搅拌4小时。倒入冰中终止反应后,二氯甲烷萃取,无水硫酸钠干燥,过滤,浓缩。粗产品用甲基叔丁基醚和二氯甲烷重结晶,得白色固体23mg,产率31%。1HNMR(300MHz,CDCl3)δ:10.45(br,2H),7.93(d,1H),7.40(dd,1H),7.25(dd,1H),7.00(m,1H),6.90(d,1H),6.80(t,1H),6.01(d,2H),5.65-5.72(m,1H),4.41(d,1H),4.37(d,1H),4.06(s,3H),3.12(s,3H),1.82(d,3H);MS m/z:519.1[M+1]。
实施例16体外对不同肿瘤细胞增殖的抑制作用:
以人体白血病细胞K562、人肝癌细胞HepG2、人肺癌细胞A549、人肝癌细胞SMMC-7721、低分化胃癌细胞BGC-823为受试细胞株,用TMS法测试化合物的抗肿瘤活性。化合物劳拉替尼以及实施例1、2、9化合物用二甲亚砜溶解,用含0.1%二甲亚砜的培养液为空白对照。用四参数拟合计算半数抑制浓度(IC50),结果如下表1所示。
表1
实施例17前药化合物I-1~I-15体外稳定性试验
1.高效液相色谱测定条件
液相色谱仪:Waters 2489UV/Visible Detector,Waters 1525Binary HPLCPump;
色谱柱:Kromasil 100-5-C18,Dim:4.6x150mm,Part/Serial:M05CLA15/E121514;
流动相:A相:乙腈和B相:水,梯度洗脱;
流速:1mL/min柱温25℃;
检测波长254nm进样量10μL;
在流动相无干扰下,劳拉替尼保留时间约为13min。
2.样品制备
将目标化合物溶于DMSO溶剂中,浓度均按照浓度折算为劳拉替尼120mg/mL,取20μL该溶液加入1.18mL新鲜大鼠空白血浆中,37℃孵化得到样品。
3.样品预处理
在规定时间点每次精密吸取样品120μL,加入120μL乙腈,高速涡旋混合2min,10000r/min离心15min,取上清液,过13mm 0.45μm滤膜,即可测定。
4.原药劳拉替尼血浆稳定性试验
取20μL劳拉替尼的DMSO溶液(120mg/mL),加入1.18mL新鲜大鼠空白血浆中,37℃孵化,分别于不同时间点取样120μL,按前述方法样品预处理。用HPLC法测定,记录峰面积,计算药物浓度。结果如表2所示。
表2
时间/h | 1 | 3 | 6 | 24 |
血浆中劳拉替尼浓度(mg/mL) | 1.21 | 1.22 | 1.20 | 1.20 |
由表2中的数据表明,劳拉替尼在血浆中可以稳定存在。
5.化合物I-1~I-15的体外血浆转化实验
参照前述血浆稳定性试验操作,对化合物I-1~I-15进行了体外血浆转化实验,测试化合物I-1~I-15在不同时间点转化为劳拉替尼的转化率。结果如表3所示。
表3
以上数据表明,化合物I-1~I-15在血浆中均能迅速转化为原药劳拉替尼。
实施例18测定本发明化合物的药代动力学
取健康的SD雄性大鼠,体重200~220g,每天定时饲以大鼠标准配方颗粒饲料,实验前禁食12h,给药后4h恢复进食,实验前后和实验过程中均自由饮水。随机分组,每组4只,分别单剂量灌胃给予待测化合物。每组大鼠的给药剂量均按摩尔浓度折算为相当于劳拉替尼20mg/kg,分别于给药前(0h)和给药后0.0833、0.25、0.5、1、2、3、4、6、8、10、24h有眼底静脉丛取血约0.2~0.3ml,EDTA-k2抗凝,离心分离血浆,准确量取50uL内标溶液,用涡旋混合器告诉混匀3min,离心5min(4℃,14000rpm),收集上清液,转移100ul上清液至进样瓶,LC-MS/MS进样0.5ul检测,记录色谱图,记录每个时间点的血浆中的血药浓度,计算劳拉替尼及I-1~I-15的口服生物利用度。结果如下表4所示。
表4
化合物 | 口服生物利用度(AUC,μL·h) |
劳拉替尼 | 37.258 |
实施例1 | 48.327 |
实施例2 | 47.769 |
实施例3 | 45.321 |
实施例4 | 46.632 |
实施例5 | 41.342 |
实施例6 | 40.347 |
实施例7 | 39.126 |
实施例8 | 38.127 |
实施例9 | 42.316 |
实施例10 | 46.352 |
实施例11 | 41.671 |
实施例12 | 38.731 |
实施例13 | 42.045 |
实施例14 | 47.562 |
实施例15 | 41.127 |
体内外的药理学实验表明,通过本发明的设计方法得到的劳拉替尼前药化合物在血浆中,通过酶的作用可以有效转化为原药劳拉替尼,体内研究表明化合物具有良好的生物利用度,部分化合物优于劳拉替尼,具有进一步临床研究的潜力。
Claims (9)
2.根据权利要求1所述的式I化合物或其药学上可接受的盐,其特征在于n、m分别代表0-6的整数,R3、R4相同或不同,选自C1-C6的烷基、C2-C6烯基、叔丁氧羰基、取代或非取代的烷基磺酰基、取代或非取代的苯磺酰基、磷酰基。
3.根据权利要求1所述的式I化合物或其药学上可接受的盐,其特征在于n、m分别代表0-3的整数,R3、R4相同或不同,选自C1-C6的烷基、C2-C6烯基、叔丁氧羰基、被卤素和/或羟基取代或非取代的C1-C6的烷基磺酰基、被卤素、羟基、C1-C6的烷基中的一种或几种取代或非取代的苯磺酰基、磷酰基。
4.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于R3、R4相同或不同,选自甲基、乙基、丙基、异丙基、乙烯基、丙烯基、异丙烯基、叔丁氧羰基、被卤素和/或羟基取代或非取代的甲磺酰基、被卤素、羟基、甲基、乙基中的一种或几种取代或非取代的苯磺酰基、磷酰基。
6.一种药物组合,包括治疗有效量的权利要求1-5中任一项所述化合物或其药学上可接受的盐,以及一种或多种药学上可接受的载体或赋形剂。
7.根据权利要求1-5任一项所述化合物或其药学上可接受的盐、权利要求6所述的药物组合在制备用于治疗或改善间变性淋巴瘤激酶和/或EML4-ALK融合蛋白和/或原癌基因蛋白酪氨酸激酶介导的疾病的药物中的应用。
8.根据权利要求7所述的应用,其特征在于所述疾病为癌症。
9.根据权利要求8所述的应用,其特征在于所述癌症选自非小细胞肺癌、鳞状细胞癌、慢性淋巴细胞白血病、神经母细胞瘤、前列腺癌、乳突状肾细胞癌、大肠直肠腺癌、神经母细胞瘤、间变性大细胞淋巴瘤、多发性骨髓瘤、急性骨髓性白血病、乳腺癌和胃癌。
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