CN104829596B - 吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途 - Google Patents
吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途 Download PDFInfo
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- CN104829596B CN104829596B CN201410046278.2A CN201410046278A CN104829596B CN 104829596 B CN104829596 B CN 104829596B CN 201410046278 A CN201410046278 A CN 201410046278A CN 104829596 B CN104829596 B CN 104829596B
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Abstract
本发明涉及一种吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途,所述吡咯取代吲哚酮类衍生物具有如下通式(I)所示结构。本发明还涉及所述吡咯取代吲哚酮类衍生物在治疗受体酪氨酸激酶介导的疾病中的用途,以及含有此类结构化合物的用于治疗肿瘤等相关疾病的药物组合物。
Description
技术领域
本发明涉及一种吡咯取代吲哚酮类衍生物或其药学上可接受的盐、其制备方法、包含该衍生物的组合物、及其用途,更具体而言,本发明涉及多靶点酪氨酸激酶抑制剂吡咯取代吲哚酮类衍生物,以及其药物组合物和医药用途。
背景技术
癌症是当今社会对人们的健康威胁最大的疾病。目前为止市场上大量使用的抗癌药物仍然是上世纪发现的一些细胞毒药物。这些细胞毒药物在治疗肿瘤的过程中大量杀死正常细胞给病人带来难以忍受的副作用,并且随着这类药物的大量使用耐药性正成为另一个难以克服的问题。
肿瘤血管抑制是上世纪末发展的用于治疗肿瘤的新方法。它的研究基础是基于Folkman提出的肿瘤的存活、生长和转移依赖大量新生血管的观点(Folkman.J.et.al.N.Engl.J.Med.,1971,285,1182-1186.)。大量的临床发现肿瘤组织含有数量众多的新生血管,肿瘤细胞的生长和转移需要大量的血管提供足够的氧气和营养。抑制肿瘤细胞血管的生长即可“饿死”肿瘤细胞,同时正常细胞周围的新生血管很少,新生血管抑制对正常细胞的影响很小,这使得血管抑制类抗肿瘤药物具有高效、安全、低毒等特点。
血管抑制可分为直接抑制和间接抑制两类,直接抑制作用是作用于血管的内皮细胞,抑制血管的生成、扩展和对肿瘤细胞的营养支持,目前使用的主要方法为细胞毒药物的节律化治疗,节律化的治疗虽然可以减轻细胞毒药物的副作用但仍然难以改变药物对人体的伤害。间接抑制作用通过抑制血管生成过程中所需要的血管生成因子来抑制血管的新生(Cao,Y.et.al.Int.J.Biochem.Cell Biol.,2001,33,357-369.)。血管新生的过程包括:血管内皮细胞在激活因子的作用下激活;内皮细胞分泌蛋白酶降解基底膜;内皮细胞的迁移和增殖;新毛细血管官腔的形成;募集周细胞,以稳定新生成 的毛细管的外围结构。生理条件下存在两类作用于血管生成的因子,分别是血管生成抑制因子和促血管生成因子。血管生成抑制因子按照作用的特异性不同可分为两大类。一类是特异性作用于内皮细胞的血管生成抑制因子,包括血管生成抑制素和内皮细胞生成抑制素等。另一类是非特异性作用于内皮细胞的血管生成抑制因子,包括细胞因子,组织金属蛋白酶抑制剂,丝氨酸蛋白酶抑制剂与抑癌基因产物等。促血管生成因子包括表皮生长因子(EGF)、内皮细胞生长因子(VEGF)、血小板衍生生长因子(PDGF)和成纤维细胞生长因子(FGF)等(Hanks,S.K.,et.al.FASEB,1995,9,576-696)。在不同类型的肿瘤中可见不同促血管生成因子的高表达,如上皮细胞肿瘤中常见EGF的高表达,胶质瘤中常见PDGF的高表达。目前针对肿瘤新生血管路径开发抗癌药物的策略主要是增加血管生成抑制因子和减少促血管生成因子,其中抑制促血管新生因子的高表达特别是作用于VEGF/VEGFR信号通路是当前研究的主流。
VEGF是人体内的一种糖蛋白,在血管的生成过程中发挥重要的作用。人类的VEGF家族包括VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGF-E和PLGF。VEGF能选择性的作用于VEGFR(VEGF受体),VEGFR是一类酪氨酸激酶跨膜蛋白,VEGF与VEGFR结合后使VEGFR的构象发生改变,并导致受体的二聚化,同时使胞内的酪氨酸位点发生磷酸化并激活下游的转导通路(Joukov,V.,et.al.EMBO J.,1996,15,290-298.)。大量的研究表明,VEGF/VEGFR信号转导通路是细胞内最重要的促血管生成和转移通路,通过抑制此通路可以抑制内皮细胞的生长和转移,从而抑制肿瘤的生长。目前已有多个药物成功上市,同时还有超过三十个在临床研究阶段。比较重要的是重组人源化VEGF单克隆抗体-贝伐单抗(商品名Avastin),贝伐单抗是第一个成功上市的抗肿瘤血管生成药物,其能够特异性的与VEGF-A结合从而阻断VEGF/VEGFR通路。此药物在上市初期取得了非常大的成功,但随着使用时间的延长,耐药性的问题渐渐显露出来。进一步的研究发现,特异性的抑制VEGF-A的作用会使细胞释放出大量其他的促血管生成因子,如PLGF和FGF等,这种现象被称为血管生成救援反应。为了解决耐药性的问题,发展多靶点的抑制剂是一条可行的策略。
舒尼替尼(sunitinib)就是这类多靶点的抗癌药物。舒尼替尼是辉瑞公司开发的作用于多靶点酪氨酸激酶的抑制剂,它可以有效的抑制VEGFR-1、VEGFR-2、VEGFR-3、PDGFR-β、c-Kit、FLT-3等受体酪氨酸激酶,通过抑制这些蛋白阻断癌变 细胞中多种促血管生成因子的表达,达到抑制新生血管生成,“饿死”癌细胞的目的(Abrams,T.J.et.al.Mol.CancerTher.,2003,2,1011-1021.)。另外,对存在c-Kit、FLT-3突变的肿瘤细胞也有特异性的直接抑制作用。舒尼替尼于2006年被FDA批准上市,主要用于胃肠道间质瘤和肾细胞癌的治疗,是首个被同时批准用于两类适应症的抗癌药物。舒尼替尼虽然抗肿瘤药效明显,但在临床使用的患者上仍然表现出乏力、骨髓抑制及发热等副作用,而且其组织蓄积性强,不能连续服用,临床采用连续服用4周后停用两周的方案。而研究发现,肿瘤新生血管形成作用可在停药期间恢复。因此,有必要通过化学结构的改变以降低毒副作用、优化成药性,寻找到更为安全有效的理想药物。
发明内容
本发明的目的是提供一种高效低毒副作用的多靶点受体酪氨酸激酶抑制剂。
本发明的又一目的是提供一类具有抑制肿瘤生长的吡咯取代吲哚酮类衍生物。
本发明的再一目的是提供包含上述吡咯取代吲哚酮类衍生物的药物组合物。
本发明的再一目的是提供上述吡咯取代吲哚酮类衍生物和包含该衍生物的药物组合物的用途。
本发明提供一种具有如下通式(I)所示结构的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐:
其中:
m选自0、1、2;
n选自1、2、3;
R选自氢、C1-C6直链或支链烷基、C3-C7环烷基、用C1-C6直链或支链烷基取代 的甲酰基、C3-C7环烷基甲酰基、叔丁基氧羰基、取代的氨基甲酰基、或者5-7元环状氨基甲酰基。
在上述吡咯取代的吲哚酮类衍生物中,R优选选自氢、C1-C3直链或支链烷基、C4-C6环烷基、用C1-C3直链或支链烷基取代的甲酰基、C3-C6环烷基甲酰基、叔丁基氧羰基、N,N-二甲基甲酰基、N,N-二乙基甲酰基、N,N-二丙基甲酰基、、吡咯烷-1-甲酰基、或者哌啶-1-甲酰基。
在上述吡咯取代的吲哚酮类衍生物中,R更优选选自氢、甲基、叔丁基氧羰基、N,N-二甲基甲酰基、或者吡咯烷-1-甲酰基。
本发明中,所述具有通式(I)所示结构的吡咯取代的吲哚酮类衍生物优选选自下列化合物1-15:
在本发明的第二方面,还提供了一种制备本发明的吡咯取代的吲哚酮类衍生物的方法,所述方法包括以下步骤:
(a)使结构式I所示的3,5-二甲基-2-吡咯甲醛与硝酸钾浓硫酸发生硝化反应生成结构式II所示的化合物:
具体而言,取结构式I所示的3,5-二甲基-2-吡咯甲醛溶于浓硫酸,降温至零下10℃左右,再加入硝酸钾,保温反应。反应结束后,加入冷水中剧烈搅拌后过滤得到化合物II,重结晶得纯品。
(b)使结构式II所示的3,5-二甲基-4-硝基-2-吡咯甲醛与结构式III所示的5-氟吲哚啉酮在吡咯烷的催化作用下发生缩合反应生成结构式IV所示的化合物:
具体而言,将结构式II所示的3,5-二甲基-4-硝基-2-吡咯甲醛加入乙醇中,升温到50℃,再加入结构式III所示的5-氟吲哚啉酮,保温反应。反应结束后,过滤得到化合物IV的纯品。
(c)使结构式IV所示的化合物与锌粉发生还原反应生成结构式V所示的化合物:
具体而言,取结构式IV所示的化合物溶于四氢呋喃,水和甲醇的混合溶液中,升温至50℃,加入饱和氯化铵和锌粉,保温反应。反应结束后,蒸干溶剂用乙酸乙酯,萃取得到化合物V的纯品。
(d)使结构式V所示的化合物与相应的酸VI发生缩合反应生成结构式VII所 示的化合物:
具体而言,取结构式V所示的化合物溶于四氢呋喃中,于室温下加入碱(DIPEA、DMAP、吡啶等)和缩合剂(EDCI、DCC等)进行保温反应。反应结束后,蒸干溶剂,得到结构式VII所示的化合物粗品,水洗,用溶剂(乙酸乙酯、甲醇等)淋洗,得到纯品化合物VII。
根据本发明,本发明提供包含治疗有效剂量的一种或多种通式(I)的吡咯取代吲哚啉酮类衍生物或其药学上可接受的盐的药物组合物,该组合物可以进一步包括药学上的常规辅料,例如赋形剂、甜味剂等。
本发明的吡咯取代吲哚啉酮类衍生物或其药学上可接受的盐,具有抑制酪氨酸激酶的活性,可用于制备用于治疗酪氨酸激酶表达异常引起的肿瘤的药物。即,本发明的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐可以用于治疗酪氨酸激酶介导的肿瘤及抑制相关肿瘤细胞生长,包括向病人给予治疗有效量的吡咯取代吲哚啉酮类衍生物或其药学上可接受的盐,同时可以用于制备用于治疗酪氨酸激酶介导的肿瘤及抑制相关肿瘤细胞生长的药物。
有益效果
本发明制备的吡咯取代吲哚啉酮衍生物或其药学上可接受的盐对多种酪氨酸激酶具有抑制作用,整体动物试验表明,该类化合物具有抑制肿瘤生长之功效。特别是本发明的吡咯取代吲哚啉酮衍生物或其药学上可接受的盐的毒副作用很低。该类化合物可用于治疗多种肿瘤类疾病。本发明化合物合成简单,易于制备,且合成原料丰富。
具体实施方式
下面结合具体实施例对本发明作进一步阐述,但本发明不局限于此。
下述制备例中,1H-NMR用Varian Mercury AMX300,400,500型仪器测定。MS用VGZAB-HS或VG-7070型以及Esquire 3000 plus-01005测定。所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得。除另有说明外,所有反应均是在氩气保护下进行并用TLC跟踪,后处理时均经饱和食盐水洗和无水硫酸镁干燥过程。产品的纯化除另有说明外均使用硅胶的柱色谱法,所使用的硅胶为200-300目,GF254为青岛海洋化工厂或烟台缘博硅胶公司生产。
制备例1:化合物1的制备
将原料3,5-二甲基-2-吡咯甲醛I(5g,40mmol)溶于60mL浓硫酸中,然后将体系温度降到-10℃,在此温度下分批缓慢加入硝酸钾(4.35g,42mmol),于2h左右加完。在此过程中温度保持在-10℃,加完后在此温度下继续搅拌2h左右,TLC检测反应完全后,将此溶液加入1L冰水中,并用1L乙酸乙酯分两次萃取,有机层用饱和食盐水洗,无水硫酸钠干燥,过滤后减压蒸干有机溶剂得到7g粗品,将此粗品加入10-20mL乙酸乙酯中,剧烈搅拌后过滤得到目标化合物II纯品5g。
取化合物II(1.68g,10mmol)和化合物III(1.8g,12mmol)加入50mL无水乙醇中,在室温下加入四氢吡咯(850mg,12mmol)。加完后,体系颜色变黄,升高温度到50℃,并在此温度下继续反应2h。反应结束后直接对体系进行过滤,滤饼用少量乙醇和乙酸乙酯洗涤,得到目标化合物IV纯品2.7g。1HNMR(400 MHz,DMSO-d6)δ11.14(s,1H),7.88(dd,J=9.2,2.4Hz,1H),7.82(s,1H),7.05-6.97(m,1H),6.88(dd,J=8.5,4.5Hz,1H),2.64(s,3H),2.58(s,3H)。
取化合物IV(900mg,3mmol)于500mL两口瓶中,然后分别向其中加入200mL四氢呋喃、100mL甲醇、60mL水、60mL饱和氯化铵溶液。加完后升温到50℃,接着在搅拌下加入锌粉(1.8g,30mmol),加完锌粉后在此条件下继续反应2h,此过程中体系变澄清后又变浑浊。变浑浊后,LC-MS检测反应完全结束。反应完全后,将溶液蒸干,加入饱和碳酸钠溶液将体系调至碱性并用2L乙酸乙酯分两次萃取。乙酸乙酯层用饱和食盐水洗,无水硫酸钠干燥,过滤后减压蒸干有机溶剂得到目标化合物V(800mg)。
取化合物V(270mg,1mmol)溶于四氢呋喃(20mL)中,于室温下加入Boc保护的4-哌啶甲酸(270mg,1.2mmol),EDCI(220mg,1.1mmol),DIPEA(260mg,2mmol)及催化量的DMAP。加完后,于室温继续反应8h左右,TLC检测反应结束。反应结束后,蒸干四氢呋喃溶液,加入大量乙酸乙酯和水分层并过滤得到目标化合物粗品。粗品用甲醇淋洗后得到纯品1。1H NMR(400MHz,DMSO-d6)δ13.59(s,1H),10.83(s,1H),9.12(s,1H),7.71(dd,J=9.5,2.6Hz,1H),7.66(s,1H),6.93-6.86(m,1H),6.86-6.81(m,1H),3.99-3.95(m,2H),3.10-2.94(m,1H),2.79-2.75(m,2H),2.17(s,3H),2.15(s,3H),1.82-1.78(m,2H),1.55-1.45(m,2H),1.41(s,9H)。
制备例2:化合物2的制备
取化合物1(480mg,1mmol)加入10mL四氢呋喃中,于室温下加入10mL三氟乙酸,接着将温度升到50℃继续反应2h左右,LC-MS检测反应完全。反应结束后,蒸干大部分溶液,余下用饱和碳酸钠溶液中和过滤得到产物粗品。粗品经乙酸乙酯和甲醇淋洗得到纯品2。1HNMR(400MHz,DMSO-d6)δ13.60(s,1H),10.85(s,1H),9.26(s,1H),7.71(dd,J=9.5,2.4Hz,1H),7.67(s,1H),6.94-6.86(m,1H),6.87-6.83(m,1H),3.34(d,J=12.3Hz,2H),3.06-2.89(m,2H),2.74-2.59(m,1H),2.18(s,3H),2.16(s,3H),2.05-1.94(m,2H),1.89-1.74(m,2H)。
制备例3:化合物3的制备
取化合物2(383mg,1mmol)加入到20mL四氢呋喃中,于室温下加入DIPEA(260mg,2mmol)和二甲胺基甲酰氯(214mg,2mmol),加完后继续反应12h左右,TLC检测反应几乎完全。反应结束后,蒸干溶剂用20mL乙酸乙酯和10mL甲醇淋洗固体得到目标化合物纯品3。1HNMR(400MHz,DMSO-d6)δ13.58(s,1H),10.82(s,1H),9.10(s,1H),7.70(dd,J=9.5,2.5Hz,1H),7.66(s,1H),6.95-6.86(m,1H),6.85-6.77(m,1H),3.87-3.70(m,1H),3.63-3.54(m,2H),2.86-2.58(m,8H),2.18(s,3H),2.15(s,3H),1.85-1.76(m,2H),1.71-1.55(m,2H)。
制备例4:化合物4的制备
实验操作如方法1的合成,用Boc保护的脯氨酸取代Boc保护的哌啶甲酸得到目标化合物4。1H NMR(400MHz,DMSO)δ13.59(s,0.6H),13.58(s,0.4H),10.84(s, 1H),9.20(s,0.6H),9.13(s,0.4H),7.70(dd,J=9.5,2.5Hz,1H),7.66(d,J=3.0Hz,1H),6.89(dd,J=12.5,5.5Hz,1H),6.83(dd,J=8.4,4.7Hz,1H),4.38–4.15(m,1H),3.52–3.41(m,1H),3.35–3.28(m,1H),2.35–2.22(m,1H),2.21(s,2H),2.18(s,3H),2.16(s,1H),1.98–1.79(m,3H),1.43(s,3H),1.39(s,6H)(Boc取代基不能自由旋转产生异构)。
制备例5:化合物5的制备
取化合物2(383mg,1mmol)加入到20mL四氢呋喃和甲醇的混合溶剂中(1:1),于室温下加入甲醛水溶液(500mg,5mmol)和氰基硼氢化钠(120mg,2mmol),加完后继续反应12h,TLC检测反应进程,反应结束后蒸干溶剂,柱层析得到目标化合物5。1H NMR(400MHz,DMSO-d6)δ13.58(s,1H),10.83(s,1H),9.05(s,1H),7.70(dd,J=9.5,2.4Hz,1H),7.66(s,1H),6.93-6.86(m,1H),6.85-6.80(m,1H),2.87-2.77(m,2H),2.36-2.21(m,1H),2.17(s,3H),2.16(s,3H),2.15(s,3H),1.94-1.59(m,6H)。
制备例6:化合物6的制备
化合物6的合成方法同2。用4取代1得到目标化合物6。1H NMR(400MHz,DMSO-d6)δ13.60(s,1H),10.83(s,1H),9.23(s,1H),7.71(dd,J=9.3,2.4Hz,1H),7.67(s,1H),6.93-6.87(m,1H),6.83(dd,J=8.4,4.6Hz,1H),3.70(dd,J=8.7,5.5Hz,1H),2.91(t,J=6.6Hz,1H),2.18(s,2H),2.16(s,2H),2.10-1.98(m,1H),1.85-1.74(m,1H),1.72-1.63(m,2H)。
制备例7:化合物7的制备
化合物7的合成方法同1。用Boc保护的2-哌啶甲酸取代Boc保护的4-哌啶甲酸得到目标化合物7。1H NMR(400MHz,DMSO-d6)δ13.60(s,1H),10.84(s,1H),9.16(s,1H),7.71(dd,J=9.5,2.5Hz,1H),7.67(s,1H),6.94-6.87(m,1H),6.85-6.81(m,1H),4.79-4.63(m,1H),3.87-3.75(m,1H),3.30-3.09(m,1H),2.19(s,3H),2.17(s,3H),1.81-1.59(m,3H),1.41(s,9H),1.44-1.22(m,3H)。
制备例8:化合物8的制备
化合物8的合成方法同3。用4取代2得到目标化合物8。1H NMR(400MHz,DMSO-d6)δ13.59(s,1H),10.84(s,1H),8.99(s,2H),7.74-7.68(m,1H),7.66(s,1H),6.93-6.86(m,1H),6.83(dd,J=8.4,4.6Hz,1H),4.39(t,J=7.4Hz,1H),3.60-3.44(m,1H),3.43-3.37(m,1H),2.80(s,6H),2.28-2.20(m,1H),2.16(s,3H),2.14(s,3H),1.97-1.88(m,1H),1.87-1.70(m,2H)。
制备例9:化合物9的制备
化合物8的合成方法同3。用4取代2得到目标化合物9。1H NMR(400MHz,DMSO-d6)δ13.59(s,1H),10.83(s,1H),8.97(s,1H),7.70(dd,J=9.6,2.5Hz,1H),7.66(s,1H),6.92-6.86(m,1H),6.84-6.81(m,1H),3.30-3.25(m,1H),2.99(d,J=13.2Hz,1H),2.60(t,J=11.3Hz,1H),2.18(s,2H),2.16(s,2H),1.91-1.73(m,2H),1.56-1.33(m,4H)。
制备例10:化合物10的制备
化合物8的合成方法同3。用4取代2得到目标化合物10。1H NMR(400MHz,DMSO-d6)δ13.59(s,1H),10.83(s,1H),9.20(s,1H),7.71(dd,J=9.4,2.5Hz,1H),7.67(s,1H),6.89(dd,J=13.8,6.7Hz,1H),6.86-6.82(m,1H),4.13-4.02(m,1H),3.89(d,J=13.1Hz,1H),2.94-2.72(m,2H),2.48-2.41(m,1H),2.18(s,3H),2.16(s,3H),2.01-1.94(m,1H),1.73-1.57(m,2H),1.42(s,9H),1.39-1.24(m,1H)。
制备例11:化合物11的制备
取化合物2(383mg,1mmol)加入到20mL四氢呋喃中,于室温下加入DIPEA(260mg,2mmol)和对硝基氯甲酸苯酯(240mg,1.2mmol),加完后继续反应12h左右,TLC检测反应几乎完全。反应结束后,加入四氢吡咯(142mg,2mmol)和过量的DIPEA(260mg,2mmol),加完后继续反应12h以上,TLC检测反应。反应结束后蒸干溶剂用20mL乙酸乙酯和10mL甲醇淋洗固体得到目标化合物纯品11。 1H NMR(400MHz,DMSO-d6)δ13.58(s,1H),10.82(s,1H),9.09(s,1H),7.70(dd,J=9.4,2.5Hz,1H),7.66(s,1H),6.93-6.86(m,1H),6.83(dd,J=8.5,4.6Hz,1H),3.70(d,J=13.5Hz,2H),3.27(t,J=6.4Hz,4H),2.73(t,J=11.6Hz,1H),2.18(s,3H),2.15(s,3H),1.86-1.71(m,6H),1.67-1.54(m,2H)。
制备例12:化合物12的制备
化合物12的合成方法同2。用10取代1得到目标化合物12。1H NMR(400MHz,DMSO-d6)δ13.59(s,1H),10.90(s,1H),9.17(s,0H),7.69(dd,J=9.4,2.4Hz,1H),7.65(s,1H),6.94-6.82(m,2H),3.67-3.52(m,2H),3.15-2.56(m,3H),2.45(d,J=10.0Hz,2H),2.17(s,3H),2.15(s,3H),1.89(d,J=9.2Hz,1H),1.61(d,J=10.4Hz,2H),1.42(s,1H)。
制备例13:化合物13的制备
化合物13的合成方法同3。用12取代2得到目标化合物13。1H NMR(400MHz, DMSO-d6)δ13.59(s,1H),10.83(s,1H),9.18(s,1H),7.71(dd,J=9.4,2.4Hz,1H),7.66(s,1H),6.89(dd,J=9.2,2.4Hz,1H),6.86-6.80(m,1H),3.72-3.59(m,1H),3.51(d,J=13.2Hz,1H),2.90-2.81(m,1H),2.78-2.68(m,7H),2.64-2.55(m,1H),2.18(s,3H),2.15(s,3H),1.97(d,J=14.9Hz,1H),1.73-1.57(m,2H),1.53-1.38(m,1H)。
制备例14:化合物14的制备
化合物14的合成方法同11。用12取代2得到目标化合物14。1H NMR(400MHz,DMSO-d6)δ13.59(s,1H),10.83(s,1H),9.18(s,1H),7.71(dd,J=9.4,2.5Hz,1H),7.66(s,1H),6.93-6.86(m,1H),6.83(dd,J=8.4,4.8Hz,1H),3.75(d,J=12.7Hz,1H),3.61(d,J=12.4Hz,1H),3.28(s,4H),2.90-2.81(m,1H),2.73(t,J=11.4Hz,1H),2.60-2.50(m,1H),2.06-1.91(m,1H),1.76(s,4H),1.74-1.59(m,2H),1.55-1.39(m,1H)。
制备例15:化合物15的制备
此步的合成方法同化合物6的合成,用D型的N-Bn脯氨酸替代L型的N-Bn脯氨酸得到目标化合物。1H NMR(400MHz,DMSO)δ13.60(s,1H),10.83(s,1H),9.23(s,1H),7.71(dd,J=9.3,2.4Hz,1H),7.67(s,1H),6.93–6.87(m,1H),6.83(dd,J=8.4,4.6Hz,1H),3.70(dd,J=8.7,5.5Hz,1H),2.91(t,J=6.6Hz,1H),2.18(s,2H),2.16(s,2H),2.10–1.98(m,1H),1.85–1.74(m,1H),1.72–1.63(m,2H)。
制备例16:化合物6盐酸盐的制备
取饱和的乙醇氯化氢溶液0.5mL,将其用无水乙醇稀释十倍后,加入化合物6(368mg,1mmol),搅拌5~10分钟后,将反应液减压浓缩,用少量甲醇洗涤可得到化合物6盐酸盐。
所有其它化合物的盐酸盐,均可以用此方法将相应的化合物与稀盐酸乙醇液反应进行制备。
以上吡咯取代的吲哚酮类衍生物的制备例作参考,其它的此类衍生物也可以参照上述方法制得。
另外,申请人通过与上述类似方法或其他本领域的公知方法,合成了以下比较化合物1-3。
比较化合物1
比较化合物1与化合物2相同,区别在于最右侧的哌啶基以N原子与羰基相连
比较化合物2
比较化合物2与化合物6相同,区别在于最右侧的吡咯烷基以N原子与羰基相连。
比较化合物3
比较化合物3与化合物2相同,区别在于最右侧的哌啶基通过亚甲基与羰基相连。
实施例
下面结合具体实施例对本发明作进一步阐述,但这些实施例不应解释为限制本发明。
试验实施例1:KDR酪氨酸激酶体外生化活性测定
采用HTRF(homogeneous time-resolved fluorescence)方法测定化合物对KDR(VEGF受体)酪氨酸激酶体外抑制活性。将激酶缓冲液、受试化合物或舒尼替尼、底物和ATP溶液的混合物加至10μL终体积至384孔板,室温孵育适当时间;每孔加入10μL SA-XL665和TK抗体,室温孵育1h,采用Synergy2读数。
结果显示:在0.1μM、1μM浓度,上述实施例化合物对KDR均具有显著抑制活性。化合物3、6、8、9、11、13等活性与舒尼替尼相当。
表1实施例化合物对KDR的体外抑制活性
IC50(nM) | |
2 | 290 |
3 | 78 |
5 | 141 |
6 | 83 |
8 | 66 |
9 | 89 |
11 | 74 |
12 | 142 |
13 | 77 |
14 | 143 |
15 | 65 |
舒尼替尼 | 62 |
Staurosporine | 8.14 |
Staurosporine(星形孢菌素):阳性对照化合物
试验实施例2:对HUVEC的细胞毒作用及VEGF诱导的HUVEC细胞体外增殖活性测定
VEGF诱导的人脐静脉内皮细胞系(HUVEC)增殖抑制活性检测:将人脐静脉内皮细胞(HUVEC)培养于含10%FBS,18u/mL肝素和30μg/mL ECGS的F-12K中,实验选取4-8代的HUVEC。用胰酶消化细胞,重悬于培液中(1×105/mL),每孔100μL加于96孔板中,贴壁过夜。更换含5%FBS的F-12K培液,培养24h。加 入受试化合物或舒尼替尼或对照的5%FBS-F-12K培养液,孵育30min。加入终浓度为30ng/mL VEGF165或溶媒(DMSO)的0.1%FBS-F-12K培养液,诱导培养72h。吸去培养液,每孔加入120μL MTS检测液,37℃孵育,读取OD490。以5%FBS-F-12K培养液处理组为阴性对照,从VEGF165刺激组OD值中减去阴性对照组OD值,得到VEGF刺激生长值,计算抑制率,用GraphPad Prism软件制作量效曲线并计算半数效应浓度(EC50)。
细胞毒性检测:上述HUVEC细胞培养于含10%胎牛血清(FBS)、100U/ml青霉素、100μg/mL链霉素、30ug/mL ECGS、18u/mL肝素的F-12K培养基中,胰酶消化处于对数生长期的HUVEC,用含有5%的FBS F-12K完全培养基调整细胞密度至需要的浓度,接种细胞150μL于96孔板中,3000/孔,24小时后加入含有5%FBS完全培养基稀释的4倍浓度受试化合物50μL,以同样体积的DMSO稀释液的作为对照。细胞继续培养72h后每孔加入20μL MTS、1μl PMS。1-2小时后检测OD490,以OD650值作为参考。用GraphPad Prism软件制作量效曲线并计算半数细胞毒性浓度(CC50)。计算受试化合物对人脐静脉内皮细胞(HUVEC)的治疗指数(Therapeutic Index,TI),TI=CC50/EC50。
结果显示:上述实施例化合物均可显著抑制VEGF刺激的HUVEC细胞增殖,但活性弱于舒尼替尼。不过,部分化合物(化合物2,3,5,6,8,11,13,14,15)对HUVEC的细胞毒作用显著低于舒尼替尼。化合物2,3,5,6,8,11,14,15的治疗指数(TI)约为舒尼替尼的2-3倍,显示出更大的治疗窗。
在比较化合物1和2中,由于最右侧的含氮杂环基团以杂原子与羰基相连,其治疗指数(TI)与舒尼替尼大致相当,明显低于本发明的化合物。在比较化合物3中,由于最右侧的含氮杂环基团通过亚甲基与羰基相连,其治疗指数(TI)也与舒尼替尼大致相当,明显低于本发明的化合物
表2.部分化合物对HUVEC的细胞毒作用、VEGF诱导的体外增殖活性及治疗指数
化合物 | EC50(nM) | CC50(nM) | TI=CC50/EC50 |
2 | 16.15 | >20000 | >1238 |
3 | 13.74 | >20000 | >1456 |
5 | 18.43 | >20000 | >1085 |
6 | 13.35 | 17566.77 | 1316 |
8 | 11.35 | >20000 | >1762 |
11 | 13.93 | >20000 | >1436 |
14 | 13.04 | >20000 | >1534 |
15 | 14.21 | 17732.12 | 1247 |
舒尼替尼 | 7.73 | 4144.09 | 536 |
比较化合物1 | 13.23 | 5689.26 | 430 |
比较化合物2 | 12.31 | 6982.25 | 567 |
比较化合物3 | 14.64 | 8054.61 | 550 |
试验实施例3:抑制人源MV-4-11肿瘤细胞株增殖活性测定
人源急性白血病细胞MV-4-11是Flt-3突变细胞株。采用MTS方法测定化合物对MV-4-11的体外抗增殖活性:胰酶消化处于生长对数期的细胞,计数,取适量细胞重悬于培液中,每孔150μL加于96孔板中,过夜培养后。每孔加入50μL4倍梯度稀释的受试化合物或对照的培养液,培养72h。吸干培养液,每孔加入120μL MTS检测液(100μL新鲜培养基和20μL MTS溶液),37℃孵育,读取OD490值。采用Graphpad Prism5软件分析处理数据,求得IC50。
结果显示:上述实施例化合物1-15对MV-4-11均显示显著抗增殖活性,部分化合物活性与舒尼替尼相当或更强(见下表)。FLT-3(FMS样酪氨酸激酶3)是一种III型受体酪氨酸激酶,广泛存在于系统、免疫系统和神经系统中。FLT-3基因突变以及过度表达将会导致肿瘤的发生。化合物1-15对MV-4-11特异性的抗增殖活性也提示实施例化合物与舒尼替尼相似,为FLT-3抑制剂。
表3.部分化合物对人源MV-4-11细胞株体外增殖的抑制作用
化合物 | IC50(nM) | 最大抑制率(%) |
2 | 4.70 | 92.6 |
3 | 10.67 | 92.1 |
5 | 1.68 | 95.0 |
6 | 11.58 | 92.4 |
9 | 5.34 | 94.3 |
12 | 7.87 | 93.1 |
13 | 6.41 | 90.2 |
15 | 12.34 | 92.5 |
舒尼替尼 | 3.94 | 94.4 |
试验实施例4:体内对MV-4-11裸鼠移植瘤的抑制作用
MV-4-11细胞体外培养扩增,收取对数生长期的细胞,重悬于无血清EMEM培养液中,用注射器将细胞悬液注入雄性Balb/c裸小鼠前右肢腋窝皮下。定期观察动物及移植瘤生长情况;待瘤体积生长至约100-300mm3左右时,选取肿瘤大小适中的动物随机分组,每组6只。分别给予空白溶媒(0.5%CMC)或上述实施例化合物6或舒尼替尼的混悬液,灌胃给药,剂量为80mg/kg,每天一次,给药周期3周;给药期间,监测瘤径、动物体重,观察动物生活状态;给药3周后结束试验,CO2处死并解剖动物。
肿瘤体积(tumor volume,TV)的计算公式为:TV=1/2×a×b2,其中,a表示肿瘤长径;b表示肿瘤短径。
结果显示:灌胃21天,溶剂对照组肿瘤增长至起始体积的近6倍,而化合物6治疗组移植肿瘤完全消失,而且化合物6对动物体重没有显著影响。舒尼替尼虽然也显示出明显抗肿瘤效果,大多数动物肿瘤消失,但动物体重显著下降,毒性明显。
表4.化合物6对MV-4-11裸鼠移植瘤的抑制作用
**:P<0.01,与溶剂对照比较
从MV-4-11裸鼠移植瘤实验结果中可以发现,本发明中的化合物6对MV-4-11移植瘤具有很好的抑制作用,80mg/kg剂量可使肿瘤完全消失,而对体重的影响较小,舒尼替尼则使动物体重明显下降,毒性明显。结果显示该系列化合物具有与舒尼替尼相当的抗肿瘤效果,但毒性更小,治疗窗更大,具有更好的开发价值。
Claims (9)
1.具有如下通式(I)所示结构的吡咯取代的吲哚酮类衍生物、化合物4、化合物6、化合物7、化合物8、化合物9、或化合物15或其药学上可接受的盐:
其中:
m选自0、1、2;
n选自1、2、3;
R选自氢、C1-C6直链或支链烷基、C3-C7环烷基、用C1-C6直链或支链烷基取代的甲酰基、C3-C7环烷基甲酰基、叔丁基氧羰基、取代的氨基甲酰基、或者5-7元环状氨基甲酰基,其中所述取代的氨基甲酰基选自N,N-二甲基甲酰基、N,N-二乙基甲酰基、N,N-二丙基甲酰基、吡咯烷-1-甲酰基、或者哌啶-1-甲酰基;
2.如权利要求1所述的吡咯取代的吲哚酮类衍生物,其中R选自氢、C1-C3直链或支链烷基、C4-C6环烷基、用C1-C3直链或支链烷基取代的甲酰基、C3-C6环烷基甲酰基、叔丁基氧羰基、N,N-二甲基甲酰基、N,N-二乙基甲酰基、N,N-二丙基甲酰基、吡咯烷-1-甲酰基、或者哌啶-1-甲酰基。
3.如权利要求1所述的吡咯取代的吲哚酮类衍生物,其中R选自氢、甲基、叔丁基氧羰基、N,N-二甲基甲酰基、或者吡咯烷-1-甲酰基。
4.如权利要求1所述的吡咯取代的吲哚酮类衍生物,其中所述具有通式(I)所示结构的吡咯取代的吲哚酮类衍生物选自以下化合物1-3、5、10~14:
5.一种药物组合物,其包含治疗有效剂量的一种或多种根据权利要求1~4中任一项所述的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐;和可选的辅料。
6.根据权利要求1~4中任一项所述的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐或根据权利要求5所述的药物组合物在制备酪氨酸激酶抑制剂中的用途。
7.根据权利要求1~4中任一项所述的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐或根据权利要求5所述的药物组合物在用于治疗和/或预防哺乳动物中与受体酪氨酸激酶相关疾病的药物中的用途。
8.根据权利要求1~4中任一项所述的吡咯取代的吲哚酮类衍生物或其药学上可接受的盐或根据权利要求5所述的药物组合物在用于治疗或辅助治疗和/或预防哺乳动物由受体酪氨酸激酶介导的肿瘤或由受体酪氨酸激酶驱动的肿瘤细胞增殖和迁移的药物中的用途。
9.根据权利要求7或8所述的用途,其中,所述哺乳动物为人类。
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CN201410046278.2A CN104829596B (zh) | 2014-02-10 | 2014-02-10 | 吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途 |
MX2016010272A MX369473B (es) | 2014-02-10 | 2015-02-04 | Derivado de indolona sustituido por pirrol, método de preparación del mismo, composición que comprende el mismo y uso del mismo. |
SG11201606545SA SG11201606545SA (en) | 2014-02-10 | 2015-02-04 | Pyrrole-substituted indolone derivative, preparation method therefor, composition comprising the same and use thereof |
JP2016552314A JP6211205B2 (ja) | 2014-02-10 | 2015-02-04 | ピロール置換インドロン系誘導体、その製造方法、該誘導体を含む組成物、及びその使用 |
PT15746066T PT3106459T (pt) | 2014-02-10 | 2015-02-04 | Derivado da indolona substituído com pirrole, seu método de preparação, composição que compreende o mesmo e sua utilização |
AU2015215335A AU2015215335B2 (en) | 2014-02-10 | 2015-02-04 | Pyrrole-substituted indolone derivative, preparation method therefor, composition comprising same and use thereof |
KR1020167024807A KR101805693B1 (ko) | 2014-02-10 | 2015-02-04 | 피롤 치환된 인돌론 유도체, 이의 제조방법, 이를 함유하는 조성물 및 이의 용도 |
RU2016136351A RU2650682C2 (ru) | 2014-02-10 | 2015-02-04 | Пирролзамещенное производное индолона, способ его получения, включающая его композиция и применение |
BR112016018371-1A BR112016018371B1 (pt) | 2014-02-10 | 2015-02-04 | Derivados de indolona substituídos com pirrol, composição os compreendendo e uso dos mesmos |
MYPI2016702887A MY176521A (en) | 2014-02-10 | 2015-02-04 | Pyrrole-substituted indolone derivative, preparation method therefor, composition comprising the same and use thereof |
EP15746066.8A EP3106459B1 (en) | 2014-02-10 | 2015-02-04 | Pyrrole-substituted indolone derivative, preparation method therefor, composition comprising same and use thereof |
CA2939012A CA2939012C (en) | 2014-02-10 | 2015-02-04 | Pyrrole-substituted indolone derivative, preparation method therefor, composition comprising the same and use thereof |
ES15746066.8T ES2687418T3 (es) | 2014-02-10 | 2015-02-04 | Derivado de indolona sustituido con pirrol, método para su preparación, composición que comprende el mismo y su uso |
US15/117,400 US9556154B2 (en) | 2014-02-10 | 2015-02-04 | Pyrrole-substituted indolone derivative, preparation method therefor, composition comprising same and use thereof |
PL15746066T PL3106459T3 (pl) | 2014-02-10 | 2015-02-04 | Podstawiona pirolem pochodna indolonu, sposób jej wytwarzania, zawierająca ją kompozycja i jej zastosowanie |
PCT/CN2015/072230 WO2015117551A1 (zh) | 2014-02-10 | 2015-02-04 | 吡咯取代吲哚酮类衍生物、其制备方法、包含该衍生物的组合物、及其用途 |
SA516371644A SA516371644B1 (ar) | 2014-02-10 | 2016-08-09 | مشتق إندولون به استبدال ببيرول وطريقة تحضيره والتركيبات المشتملة عليه واستخدامه |
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US10462491B2 (en) | 2015-11-02 | 2019-10-29 | Dolby Laboratories Licensing Corporation | Layered representation and delivery of high dynamic range video |
CN108727341B (zh) * | 2017-04-13 | 2021-02-19 | 勤浩医药(苏州)有限公司 | 一种吡咯取代吲哚酮类衍生物或其药学上可接受的盐、及它们的制备方法和用途 |
CN108191835A (zh) * | 2018-01-09 | 2018-06-22 | 中国药科大学 | 一类新型的含吡咯环和吲哚啉结构rip1激酶抑制剂及其用途 |
RS65150B1 (sr) * | 2018-09-19 | 2024-02-29 | Suzhou Genhouse Pharmaceutical Co Ltd | Pirol-supstituisan derivat indolona ili njegova farmaceutski prihvatljiva so i postupak njihove pripreme i njihova primena |
CN109232580A (zh) * | 2018-11-14 | 2019-01-18 | 南阳师范学院 | 一种1H-吡咯并[1,2-a]吲哚-2(3-H)-酮的合成方法 |
CN112321568B (zh) * | 2020-09-22 | 2023-02-17 | 南京中医药大学 | 4-甲基吡咯取代的吲哚酮衍生物、其制备方法及其医药用途 |
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DE122008000002I1 (de) * | 2000-02-15 | 2008-04-17 | Sugen Inc | Pyrrol substituierte indolin-2-on protein kinase inhibitoren |
US6677368B2 (en) * | 2000-12-20 | 2004-01-13 | Sugen, Inc. | 4-aryl substituted indolinones |
US6797725B2 (en) * | 2001-04-09 | 2004-09-28 | Sugen, Inc. | Prodrugs of a 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
WO2003031438A1 (en) * | 2001-10-10 | 2003-04-17 | Sugen, Inc. | 3-[4-(substituted heterocyclyl)-pyrrol-2-ylmethylidene]-2-indolinone derivatives as kinase inhibitors |
CA2466807A1 (en) * | 2001-11-21 | 2003-06-05 | Sugen, Inc. | Pharmaceutical formulations comprising indolinone derivatives |
HN2003000272A (es) * | 2002-09-10 | 2008-07-29 | Pharmacia Italia Spa | Formulaciones que comprenden un compuesto de indolinona |
CN101007801A (zh) * | 2006-01-27 | 2007-08-01 | 上海恒瑞医药有限公司 | 吡咯取代的2-二氢吲哚酮衍生物、其制法与医药上的用途 |
CA2662902C (en) * | 2006-09-15 | 2015-11-24 | Xcovery, Inc. | Kinase inhibitor compounds |
EP2229359B1 (en) * | 2007-12-03 | 2017-11-29 | Boehringer Ingelheim International GmbH | Process for the manufacture of an indolinone derivative |
US8829039B2 (en) * | 2008-05-23 | 2014-09-09 | Shanghai Institute Of Pharmaceutical Industry | Dihydroindolinone derivatives |
CN102276584A (zh) * | 2010-06-08 | 2011-12-14 | 齐鲁制药有限公司 | 吡咯取代的2-二氢吲哚酮衍生物、其制备方法及用途 |
CN103130744B (zh) | 2012-08-28 | 2014-10-15 | 沈阳药科大学 | 一种硒唑甲酸类化合物及其制备方法和用途 |
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MX369473B (es) | 2019-11-08 |
MX2016010272A (es) | 2017-02-06 |
KR20160117605A (ko) | 2016-10-10 |
SA516371644B1 (ar) | 2019-08-29 |
KR101805693B1 (ko) | 2017-12-06 |
SG11201606545SA (en) | 2016-09-29 |
RU2016136351A3 (zh) | 2018-03-15 |
RU2016136351A (ru) | 2018-03-15 |
CA2939012C (en) | 2018-11-06 |
ES2687418T3 (es) | 2018-10-25 |
PT3106459T (pt) | 2018-10-18 |
MY176521A (en) | 2020-08-13 |
AU2015215335A1 (en) | 2016-09-01 |
PL3106459T3 (pl) | 2018-11-30 |
BR112016018371B1 (pt) | 2022-06-14 |
US20160347740A1 (en) | 2016-12-01 |
WO2015117551A1 (zh) | 2015-08-13 |
CA2939012A1 (en) | 2015-08-13 |
JP6211205B2 (ja) | 2017-10-11 |
AU2015215335B2 (en) | 2017-07-27 |
BR112016018371A2 (pt) | 2017-10-17 |
EP3106459A4 (en) | 2017-07-12 |
US9556154B2 (en) | 2017-01-31 |
EP3106459B1 (en) | 2018-07-04 |
CN104829596A (zh) | 2015-08-12 |
EP3106459A1 (en) | 2016-12-21 |
RU2650682C2 (ru) | 2018-04-17 |
JP2017505803A (ja) | 2017-02-23 |
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