CN110357863A - 一种三嗪双芳香环衍生物表皮生长因子抑制剂及其制备方法与用途 - Google Patents
一种三嗪双芳香环衍生物表皮生长因子抑制剂及其制备方法与用途 Download PDFInfo
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- CN110357863A CN110357863A CN201910796126.7A CN201910796126A CN110357863A CN 110357863 A CN110357863 A CN 110357863A CN 201910796126 A CN201910796126 A CN 201910796126A CN 110357863 A CN110357863 A CN 110357863A
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Abstract
本发明公开一种EGFR蛋白酪氨酸激酶的临床突变体的选择性抑制剂,及具有如式(I)的结构,是一类含有三嗪的双芳香环模板化合物,同时公开了该类化合物的制备方法和其作为EGFR蛋白酪氨酸激酶的临床突变体的选择性抑制剂的应用,尤其是对于T790M变异的表皮生长因子受体EGFR的抑制作用,和在治疗与表皮生长因子受体EGFR过度表达相关疾病如肾癌、肺癌、前列腺癌、胰腺癌、乳腺癌和胶质细胞瘤。
Description
技术领域
本发明涉及三嗪双芳香环衍生物。
背景技术
皮生长因子EGFR(epithelial growth factor receptor)是一个170kDa的跨膜糖蛋白受体酪氨酸激酶,由表皮生长因子激活,影响细胞的生长和分化。EGF或TGFα对EGFR的结合激活受体的酪氨酸激酶活力。EGFR羧基末端的酪氨酸残基Tyr1068、Tyr1148、和Tyr1173是EGF结合后发生的自动磷酸化的主要位点。一旦被激活,EGFR1068位和1173位磷酸化的酪氨酸残基就能介导Grb2对EGFR的结合。此外,1173位磷酸化的酪氨酸残基是SHC在EGFR上的主要结合位点。EGFR广泛分布在许多正常和恶性上皮细胞中,其过度表达和自我激活可能与许多肿瘤的发生发展有关。目前主要用于各种上皮源性恶性肿瘤包括头颈部鳞癌、肺癌、乳腺癌和膀胱癌等的研究。
蛋白酪氨酸激酶(protein tyrosine kinase,PTK)是一类催化ATP上γ-磷酸转移到蛋白酪氨酸残基上的激酶。许我生长因子受体蛋白包括表皮生长因子受体通过磷酸化而起作用,表皮生长因子受体EGFR酪氨酸激酶使表皮生长因子受体磷酸化。临床上,EGFR酪氨酸激酶抑制剂已被用于癌症的治疗,第一代可逆的EGFR酪氨酸激酶抑制剂吉非替尼和埃罗替尼。对身体里有这些特定的激活突变的病毒人表现出了显著的临床反应(50-80%)。然而,对于这些药物产生继发性而药突变的病人会几个月内遭受癌症的复发。第二代EGFR酪氨酸激酶抑制剂包括来那替尼,达克替尼,阿法替尼,这些药物的结构中都含有亲电的基团Michael受体。其中以阿法替尼为药物代表为例,烯丙酰胺结构对阿法替尼的抗肿瘤活性起着至关重要的作用,它作为Michael受体与EGFR上半胱氨酸残基(Cys797)的催化部位(新核的巯基)发生迈克尔加成反应,从而使激酶失活,不可逆地抑制酪氨酸激酶的活性,因而具有良好的耐受性。研究者们通过培养抑制剂与受体的晶体,从分子水平上完全证明了这些共价键的存在,并且发现了阿法替尼通过与HER2的Cys 805以及HER4的Cys 803作用进而强力抑制这些酶。在对野生型EGFR体外测试显示,阿法替尼在对野生型EGFR与L858R/T790M双突变型的抑制作用与吉非替尼、埃罗替尼以及拉帕替尼相比有着更好的效果。此外,阿法替尼对DER4的抑制作用高于拉帕替尼30倍。第三代EGFR酪氨酸激酶抑制剂奥希替尼对L858R/T790M/C797S三突变型的抑制作用也达到纳摩尔。以奥希替尼为先导,进一步开发出对突变型具有强抑制作用的EGFR酪氨酸激酶抑制剂,同时,研发高效、低毒的具有耐药性的抗肿瘤新药在当前药物研发领域中十分重要。
发明内容
本发明为了抑制T790M变异的EGFR酪氨酸激酶,设计了一系列抑制剂小分子,发现了对T790M变异EGFR具有高抑制活性的化合物,并且该化合物对癌细胞具有明显的抑制作用,该化合物为含有三嗪的双芳香环化合物和α,β-不饱和羧酸酰胺结构。该化合物可以对T790M/L858R变体EGFR实现高活性抑制,并可以抑制或杀死EGFRT790M变异的肿瘤细胞,同时对野生型EGFR具有很高的抑制活性作用。
本发明提供了式(I)所示三嗪双芳香环衍生物的化合物、或其立体异构体、或其药学上可接受的盐,该类化合物含有双芳香环和α,β-不饱和羧酸酰胺结构,其可作为一种不可逆EGFR抑制剂,
其中:A可选如下任一种
X1可以选N或者CR5;
R1可以选H,卤素,CN,NO2,CF3,CHF2,C1-C6烷基,C1-C6环烷基,C1-C6烯烷基,C1-C6炔烷基,C1-C6氧烷基,C1-C6胺烷基;
R2可以选H,C1-C6烷基,C1-C6环烷基,C1-C6烯烷基,C1-C6炔烷基,C1-C6氧烷基,C1-C6胺烷基,C1-C6烷羰基,C1-C6烯羰基;
R3可以选H,CN,NO2,CF3,CHF2,C1-C6烷基,C1-C6环烷基,C1-C6烯烷基,C1-C6炔烷基,C1-C6氧烷基,C1-C6胺烷基;
R4可以选H,卤素,CN,C1-C6烷基,C1-C6环烷基,C1-C6烯基,C1-C6炔基,C1-C6氧烷基,CF3,CHF2;
R5可以选H,C1-C6烷基,C1-C6环烷基,C1-C6烯基,C1-C6炔基,C1-C6烷氧基,C1-C6胺烷基;
优选择地,所述化合物包括具有如表1结构的化合物:
表1结构通式(I和II)的化合物包括编号601-608的一种
本发明还提供了上述EGFR蛋白酪氨酸激酶选择性抑制剂的一种制备方法,如图1所示。包括以下步骤:起始原料I-1经偶联反应得到中间体II-1,中间体II-1经过两步亲核取代得到通式(I)所示的化合物(如图1所示)。
图1通式I化合物的合成与制备
本发明还提供了前述的化合物、或基立体异构体、或其药学上可接受的盐在制备抗肿瘤药物、EFGR激酶抑制剂中的用途。
所述药物组合物为片剂、胶囊、颗粒剂、喷雾剂或者注射剂的形式。
所述药学上可接受的载体选自填充剂、崩解剂、粘合剂和润滑剂中的一种或多种。包括但不限于任何和全部的溶剂、分散介质、包衣、吸收延迟剂等,这样的介质和药剂用于药学活性物质在本领域的众所周知的。
本发明还提供了所述三嗪双芳香环表皮生长因子抑制剂及药学上可接受的盐作为蛋白酪氨酸激酶抑制剂的用途;
进一步地,所述蛋白酪氨酸激酶抑制剂为表皮生长因子受体抑制剂;
更优选地,所述表皮生长因子受体抑制剂为对T790M变异的表皮生长因子受体的抑制剂。
三嗪双芳香环表皮生长因子抑制剂及药学上可接受的盐或者其药物组合物在制备用于治疗表皮生长因子受体过度表达相关疾病的药物中的用途。
进一步地,所述肿瘤为肝癌、肺癌、前列腺癌、胰腺癌、乳腺癌和星形胶质母细胞瘤。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改,替换或变更。
以下通过实施形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解发本发明上述主题的范围仅于以下的实例。凡基于发明上述内容所实现的技术均属于本发明的范围。
具体实施方式
以下通过具体的实施例进一步说明本发明。
合成与制备通式I化合物起始原料I-1经偶联反应得到中间体II-1,中间体II-1经过两步亲核取代得到通式(I)所示的化合物。值得说明的是,通式(I)化合物包括但不限于下述列举的化合物。
实施例1:2-{1'-N,N-二甲胺基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(1”-甲基-1H-3”-吲哚)三嗪(化合物601)
2-氯-4-(1’-甲基-1H-3’-吲哚)三嗪的制备:
将2,4-二氯三嗪(0.60g,4mmol)溶于乙二醇二甲醚(20mL)中,于冰浴下搅拌,分批加入三氯化铁(0.77g,4.59mmol),之后于室温下搅拌反应15分钟。然后滴加N-甲基吲哚(0.68g,5.2mmol),之后加热到60℃搅拌反应24小时。停止反应,降至0℃,加入3.5mL甲醇和9mL水,然后再室温下搅拌反应3小时。析出大量固体,过滤,用甲醇洗涤滤饼,烘干得到黄色固体0.70g,收率:72%。LC/MS(ESI):m/z 245(M+H)+。
4-氟-2-甲氧基-5-硝基苯胺基酸叔丁酯的制备:
将4-氟-2-甲氧基-5-硝基苯胺(50g,0.269mol),Boc酸酐(58.62g,0.269mol)溶于乙腈(1L)中,升温到55℃反应7小时,减压旋蒸掉乙腈,加入乙酸乙酯(500mL)溶解,然后搅拌下滴加石油醚(100mL),析出固体,过滤,得到黄色固体61.5g,收率:81%
N-(2-二甲基氨基乙基)甘酸乙酯的制备:
将乙醛酸水合物(60g,0.652mol)溶于甲醇(500mL)中,在室温搅拌30分钟,然后冷却至0℃,滴加N,N-二甲基乙二胺(57g,0.646mol),搅拌30分钟后,加入10%Pd/C(8.2g),然后加甲醇(10mL)用氢气置换三次,在室温下搅拌反应24小时。停止反应,滤除钯炭,少量甲醇洗涤滤饼,滤液减压浓缩得到粗品N-(2-二甲基氨基乙基)甘酸。将所得粗品N-(2-二甲基氨基乙基)甘酸溶于乙醇(500mL),然后室温搅拌下加入浓硫酸(8mL),回流16小时,减压蒸掉乙醇,加入乙酸乙酯(500mL)溶解,然后加入250mL水,用15%NaOH溶液调到Ph为11,分层萃取,水层用乙酸乙酯(2*50mL)萃取,然后用饱和食盐水水洗,无水硫酸镁干燥,浓缩得到棕黄色油102.2g,收率:90%。LC/MS(ESI):m/z 175(M+H)+。
4-(N,N-二甲基-N’-乙酸乙酯乙二胺基)-2-甲氧基-5-硝基苯胺基酸叔丁酯的制备:
将4-氟-2-甲氧基-5-硝基苯胺基酸叔丁酯(40g,0.14mol)溶于DMAC(600mL)中,于室温下搅拌,加入N-(2-二甲基氨基乙基)甘酸乙酯(26.7g,12mmol)和DIPEA(23.4g,0.18mol),之后加热至60℃,搅拌反应6小时。经TLC检测反应完全。停止反应,冷却至室温,将反应液缓缓倒入搅拌着的冰水中,析出大量固体,抽滤,滤饼干燥,得到浅黄色固体54.2g,收率:88%。LC/MS(ESI):m/z 441(M+H)+。
1-(N,N-二甲氨基乙基)-3-氧代-4-boc胺基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉的制备
将4-(N,N-二甲基-N’-乙酸乙酯乙二胺基)-2-甲氧基-5-硝基苯胺基酸叔丁酯(44g,0.1mol)溶于甲醇(600mL)中,加入5%Pd/C(0.15g),用氢气置换三次,之后于40Psi氢气大气压下,搅拌反应3小时。经TLC检测反应完全。停止反应,滤除钯炭,少量甲醇洗涤滤饼,滤液减压浓缩经快速柱分离得到黄色固体24.4g,收率:67%。LC/MS(ESI):m/z 365(M+H)+。
1-(N,N-二甲氨基乙基)-3-氧代-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉的制备
将1-(N,N-二甲氨基乙基)-3-氧代-4-boc胺基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(21.6g,59.2mmol)溶于1,4-二氧六环(600mL),于室温下搅拌,加入4M HCL(160mL),搅拌反应10小时。经TLC检测反应完全。停止反应。用饱和Na2CO3溶液调pH 7~9,用二氯甲烷(500mL)萃取,干燥,减压浓缩得到黄色固体14.37g,收率:92%。LC/MS(ESI):m/z 265(M+H)+。
1-(N,N-二甲氨基乙基)-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉的制备:
将1-(N,N-二甲氨基乙基)-3-氧代-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(13.2g,50mmol)溶于THF(20mL)中,在0℃下搅拌,加入LiAlH4,随后在0℃下搅拌反应30分钟,然后加热至80℃,搅拌反应4小时。经TLC检测反应完全。停止反应。冷却至0℃,滴入水(0.5mL)淬灭反应,然后加入浓盐酸(6mL)和水(20mL),搅拌30分钟,析出固体,抽滤,滤饼干燥,所得粗品经快速柱分离得到棕黄色固体8.53g,收率:68%。LC/MS(ESI):m/z 251(M+H)+。
2-[4’-氟-5’-硝基-2’-甲氧基]苯胺基-4-(1”-甲基-1H-3”-吲哚)三嗪的制备:
将2-氯-4-(1-甲基-1H-3-吲哚)三嗪(244mg,1mmol)溶于20mL二氧六环中,于室温下搅拌加入1-(N,N-二甲氨基乙基)-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(275mg,1.1mmol)和对甲苯磺酸(215mg,1.1mmol),之后加热到85℃,搅拌反应7小时。LCMS检测反应完全。停止反应,冷却到室温,加入5mL水和40%NaOH调至pH=9。过滤,用甲醇洗涤滤饼,烘干得到黄色固体,431mg,收率:94%。LC/MS(ESI):m/z 459(M+H)+。
2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(1”-甲基-1H-3”-吲哚)三嗪(化合物601)的制备:
将2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-(1”-甲基-1H-3”-吲哚)三嗪(174mg,0.38mmol)和DIPEA(0.073mL,0.42mmol)溶于二氯甲烷(5mL)中,在0℃下搅拌,然后滴加丙烯酰氯(34.5mg,0.38mmol)溶于DCM(1mL)溶液,之后搅拌反应2小时。经TLC检测反应完全。停止反应,加入DCM(25mL),然后用50mL饱和NaHCO3水洗,水层用DCM(2*25mL)萃取,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体88mg,收率:45%。1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.89(s,1H),8.17(d,1H),7.59(d,1H),7.44(m,1H),7.33(m,1H),7.19(s,1H),7.12(s,1H),6.43-6.48(m,2H),6.09(m,1H),5.74(m,1H),3.74-3.86(m,10H),3.45(m,2H),2.50(m,2H),2.31(s,6H)。LC/MS(ESI):m/z513(M+H)+。
实施例2:2-{1'-N,N-二甲胺基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(1”-甲基-7”-氮杂-1H-3”-吲哚)三嗪(化合物602)的制备:
2-氯-4-(1’-甲基-7’-氮杂-1H-3’-吲哚)三嗪的制备:
将1-甲基-3-(4,4,5,5-四甲基-1,3,2-二氧硼烷-2-基)-1H-吡咯并[2,3-B]吡啶(0.74g,2.87mmol)和2,4-二氯三嗪(0.51g,3.44mmol)溶于乙二醇二甲醚(20mL)中,然后搅拌加入二氯二叔丁基-(4-二甲基氨基苯基)膦钯(II)(0.31g,0.19mmol),2M碳酸钠溶剂(3.2mL,6.3mmol).在氮气保护下,搅拌加热到80℃反应4小时。经TLC检测反应完全。停止反应,加水(1mL)稀释。乙酸乙酯(25mL)萃取2次,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体457mg,收率:65%。LC/MS(ESI):m/z 246(M+H)+。
2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-(1”-甲基-7”-氮杂-1H-3”-吲哚)三嗪的制备:
将2-氯-4-(1’-甲基-7’-氮杂-1H-3’-吲哚)三嗪(245mg,1mmol)溶于20mL二氧六环中,于室温下搅拌加入1-(N,N-二甲氨基乙基)-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(275mg,1.1mmol)和对甲苯磺酸(215mg,1.1mmol),之后加热到85℃,搅拌反应7小时。LCMS检测反应完全。停止反应,冷却到室温,加入5mL水和40%NaOH调至pH=9。过滤,用甲醇洗涤滤饼,烘干得到黄色固体,413mg,收率:90%。LC/MS(ESI):m/z 460(M+H)+。
2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(1”-甲基-7”-氮杂-1H-3”-吲哚)三嗪(化合物602)的制备:
将2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-(1”-甲基-7”-氮杂-1H-3”-吲哚)三嗪(349mg,0.76mmol)和DIPEA(0.146mL,0.84mmol)溶于二氯甲烷(10mL)中,在0℃下搅拌,然后滴加丙烯酰氯(69mg,0.76mmol)溶于DCM(2mL)溶液,之后搅拌反应2小时。经TLC检测反应完全。停止反应,加入DCM(50mL),然后用100mL饱和NaHCO3水洗,水层用DCM(2*50mL)萃取,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体211mg,收率:54%。1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.89(s,1H),8.51(m,1H),8.39(d,1H),7.12-7.17(m,2H),7.06(s,1H),6.43-6.48(m,2H),6.09(m,1H),5.74(m,1H),3.74-3.86(m,7H),3.59(s,3H),3.45(m,2H),2.50(m,2H),2.21(s,6H)。LC/MS(ESI):m/z 514(M+H)+。
实施例3:2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(3”-吡唑[1,5-a]吡啶)三嗪(化合物603)
2-氯-4-(1’-甲基-1H-3’-吲哚)三嗪的制备:
将吡唑并吡啶(1,5,-A)-3-硼酸酯(0.70g,2.87mmol)和2,4-二氯三嗪(0.51g,3.44mmol)溶于乙二醇二甲醚(20mL)中,然后搅拌加入二氯二叔丁基-(4-二甲基氨基苯基)膦钯(II)(0.13g,0.19mmol),2M碳酸钠溶剂(32mL,6.3mmol)。在氮气保护下,搅拌加热到80℃反应4小时。经TLC检测反应完全。停止反应,加水(2mL)稀释。乙酸乙酯(25mL)萃取2次,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体378mg,收率:57%。LC/MS(ESI):m/z 232(M+H)+。
2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-(3”-吡唑[1,5-a]吡啶)三嗪的制备:
将2-氯-4-(3’-吡唑[1,5-a]吡啶)三嗪(231mg,1mmol)溶于20mL二氧六环中,于室温下搅拌加入1-(N,N-二甲氨基乙基)-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(275mg,1.1mmol)和对甲苯磺酸(215mg,1.1mmol),之后加热到85℃,搅拌反应7小时。经TLC检测反应完全。停止反应,冷却到室温,加入5mL水和40%NaOH溶液调至pH=9。过滤,用甲醇洗涤滤饼,烘干得到黄色固体,369mg,收率:83%。LC/MS(ESI):m/z 446(M+H)+。
2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(3”-吡唑[1,5-a]吡啶)三嗪(化合物603)的制备:
将2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-(3”-吡唑[1,5-a]吡啶)三嗪(338mg,0.76mmol)和DIPEA(0.146mL,0.84mmol)溶于二氯甲烷(10mL)中,在0℃下搅拌,然后滴加丙烯酰氯(69mg,0.76mmol)溶于DCM(2mL)溶液,之后搅拌反应2小时。经TLC检测反应完全。停止反应,加入DCM(50mL),然后用100mL饱和NaHCO3水洗,水层用DCM(2*50mL)萃取,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体174mg,收率:46%。1H NMR(400MHz,DMSO-d6)δ9.56(s,1H),8.89(s,1H),8.42(d,1H),7.86(s,1H),7.13-7.42(m,3H),6.43-6.54(m,3H),6.09(m,1H),5.74(m,1H),3.74-3.86(m,7H),3.45(m,2H),2.50(m,2H),2.21(s,6H)。LC/MS(ESI):m/z 500(M+H)+。
实施例4:2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-[4”-(4”’-甲基哌嗪基)苯基]三嗪(化合物604)
2-氯-4-[4’-(4”-甲基哌嗪基)苯基]三嗪的制备:
在氮气保护下,将4-(4’-甲基哌嗪基)苯硼酸(0.63g,2.87mmol)和2,4-二氯喹唑啉(0.51g,3.44mmol)溶于乙二醇二甲醚(20mL)中,然后搅拌加入四(三苯基膦)钯(II)(0.13g,0.185mmol),2M碳酸钠溶剂(32mL,6.31mmol)。然后搅拌加热到80℃反应4小时。经TLC检测反应完全。停止反应,加水(2mL)稀释。乙酸乙酯(25mL)萃取2次,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体440mg,收率:53%。LC/MS(ESI):m/z 290(M+H)+。
2-{1'-N,N-二甲氨基乙基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-[4”-(4”’-甲基哌嗪基)苯基]三嗪的制备:
将2-氯-4-[4’-(4”-甲基哌嗪基)苯基]三嗪(289mg,1mmol)溶于100mL二氧六环中,于室温下搅拌加入1-(N,N-二甲氨基乙基)-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(275mg,1.1mmol)和对甲苯磺酸(0.21g,1.1mmol),之后加热到85℃,搅拌反应7小时。LCMS检测反应完全。停止反应,冷却到室温,加入10mL水和40%NaOH调至pH=9。过滤,用甲醇洗涤滤饼,烘干得到黄色固体,446mg,收率:89%。LC/MS(ESI):m/z 504(M+H)+。
2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-[4”-(4-甲基哌嗪基)苯基]三嗪(化合物604)的制备:
将2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-[4”-(4”’-甲基哌嗪基)苯基]三嗪(382mg,0.76mmol)和DIPEA(0.146mL,0.84mmol)溶于二氯甲烷(10mL)中,在0℃下搅拌,然后滴加丙烯酰氯(69mg,0.76mmol)溶于DCM(2mL)溶液,之后搅拌反应2小时。经TLC检测反应完全。停止反应,加入DCM(50mL),然后用100mL饱和NaHCO3水洗,水层用DCM(2*50mL)萃取,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体199mg,收率:47%。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.89(s,1H),7.87(d,2H),7.12(s,1H),6.92(d,2H),6.43-6.48(m,2H),6.09(m,1H),5.74(m,1H),3.74-3.86(m,7H),3.44-3.45(m,6H),2.50(m,2H),2.21-2.35(m,13H)。LC/MS(ESI):m/z 558(M+H)+。
实施例5:2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(1”-萘基)三嗪(化合物605)
2-氯-4-[1’-萘基]三嗪的制备:
将1-萘硼酸(0.49g,2.87mmol)和2,4-二氯三嗪(0.51g,3.44mmol)溶于乙二醇二甲醚(20mL)中,然后搅拌加入二氯二叔丁基-(4-二甲基氨基苯基)膦钯(II)(0.13g,0.185mmol),2M碳酸钠溶剂(32mL,6.31mmol)。然后搅拌加热到80℃反应5小时。经TLC检测反应完全。停止反应,加水(2mL)稀释。乙酸乙酯(25mL)萃取2次,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体443mg,收率:64%。LC/MS(ESI):m/z 242(M+H)+。
2-{1'-N,N-二甲氨基乙基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-[1”-萘基]三嗪的制备:
将2-氯-4-[4’-(4”-甲基哌嗪基)苯基]三嗪(241mg,1mmol)溶于20mL二氧六环中,于室温下搅拌加入1-(N,N-二甲氨基乙基)-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(275mg,1.1mmol)和对甲苯磺酸(0.21g,1.1mmol),之后加热到85℃,搅拌反应7小时。LCMS检测反应完全。停止反应,冷却到室温,加入10mL水和40%NaOH调至pH=9。过滤,用甲醇洗涤滤饼,烘干得到黄色固体,400mg,收率:88%。LC/MS(ESI):m/z 456(M+H)+。
2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(1”-萘基)三嗪(化合物605)的制备:
将2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-[4”-(4”’-甲基哌嗪基)苯基]三嗪(346mg,0.76mmol)和DIPEA(0.146mL,0.84mmol)溶于二氯甲烷(10mL)中,在0℃下搅拌,然后滴加丙烯酰氯(69mg,0.76mmol)溶于DCM(2mL)溶液,之后搅拌反应2小时。经TLC检测反应完全。停止反应,加入DCM(50mL),然后用100mL饱和NaHCO3水洗,水层用DCM(2*50mL)萃取,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体147mg,收率:38%。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.89-8.97(m,2H),8.01-8.25(m,4H),7.52-7.59(m,2H),7.12(s,1H),6.43-6.48(m,2H),6.09(m,1H),5.74(m,1H),3.74-3.86(m,7H),3.45(m,2H),2.50(m,2H),2.21(s,6H)。LC/MS(ESI):m/z 510(M+H)+。
实施例6:2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(4”-吗啉苯基)三嗪(化合物406)的制备:
2-氯-4-[4’-吗啉基苯基]三嗪的制备:
将4-吗啉基苯硼酸(0.59g,2.87mmol)和2,4-二氯三嗪(0.51g,3.44mmol)溶于乙二醇二甲醚(20mL)中,然后搅拌加入二氯二叔丁基-(4-二甲基氨基苯基)膦钯(II)(0.13g,0.185mmol),2M碳酸钠溶剂(32mL,6.31mmol)。然后搅拌加热到80℃反应5小时。经TLC检测反应完全。停止反应,加水(2mL)稀释。乙酸乙酯(25mL)萃取2次,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体491mg,收率:62%。LC/MS(ESI):m/z 277(M+H)+。
2-{1'-N,N-二甲氨基乙基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-[4”-吗啉基苯基]三嗪的制备:
将2-氯-4-[4’-(4”-甲基哌嗪基)苯基]三嗪(276mg,1mmol)溶于100mL二氧六环中,于室温下搅拌加入1-(N,N-二甲氨基乙基)-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(275mg,1.1mmol)和对甲苯磺酸(0.21g,1.1mmol),之后加热到85℃,搅拌反应7小时。LCMS检测反应完全。停止反应,冷却到室温,加入10mL水和40%NaOH调至pH=9。过滤,用甲醇洗涤滤饼,烘干得到黄色固体,363mg,收率:74%。LC/MS(ESI):m/z 491(M+H)+。
2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(4”-吗啉苯基)三嗪(化合物606)的制备:
将2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-[4”-(4”’-甲基哌嗪基)苯基]三嗪(372mg,0.76mmol)和DIPEA(0.146mL,0.84mmol)溶于二氯甲烷(10mL)中,在0℃下搅拌,然后滴加丙烯酰氯(69mg,0.76mmol)溶于DCM(2mL)溶液,之后搅拌反应2小时。经TLC检测反应完全。停止反应,加入DCM(50mL),然后用100mL饱和NaHCO3水洗,水层用DCM(2*50mL)萃取,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体178mg,收率:43%。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.89(s,1H),7.87(d,2H),7.12(s,1H),6.92(d,2H),6.43-6.48(m,2H),6.09(m,1H),5.74(m,1H),3.74-3.86(m,11H),3.45(m,2H),3.15(m,4H),2.50(m,2H),2.21(s,6H)。LC/MS(ESI):m/z 545(M+H)+。
实施例7:2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(2”-萘基)三嗪(化合物607)的制备:
2-氯-4-[2’-萘基]三嗪的制备:
将2-萘硼酸(0.49g,2.87mmol)和2,4-二氯三嗪(0.51g,3.44mmol)溶于乙二醇二甲醚(20mL)中,然后搅拌加入二氯二叔丁基-(4-二甲基氨基苯基)膦钯(II)(0.13g,0.185mmol),2M碳酸钠溶剂(32mL,6.31mmol)。然后搅拌加热到80℃反应5小时。经TLC检测反应完全。停止反应,加水(2mL)稀释。乙酸乙酯(25mL)萃取2次,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体318mg,收率:46%。LC/MS(ESI):m/z 242(M+H)+。
2-{1'-N,N-二甲胺基乙基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-[2”-萘基]三嗪的制备:
将2-氯-4-[4’-(4”-甲基哌嗪基)苯基]三嗪(241mg,1mmol)溶于20mL二氧六环中,于室温下搅拌加入1-(N,N-二甲氨基乙基)-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(275mg,1.1mmol)和对甲苯磺酸(0.21g,1.1mmol),之后加热到85℃,搅拌反应7小时。LCMS检测反应完全。停止反应,冷却到室温,加入10mL水和40%NaOH调至pH=9。过滤,用甲醇洗涤滤饼,烘干得到黄色固体,355mg,收率:78%。LC/MS(ESI):m/z 456(M+H)+。
2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-(2”-萘基)三嗪(化合物607)的制备:
将2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-[4”-(4”’-甲基哌嗪基)苯基]三嗪(346mg,0.76mmol)和DIPEA(0.146mL,0.84mmol)溶于二氯甲烷(10mL)中,在0℃下搅拌,然后滴加丙烯酰氯(69mg,0.76mmol)溶于DCM(2mL)溶液,之后搅拌反应2小时。经TLC检测反应完全。停止反应,加入DCM(50mL),然后用100mL饱和NaHCO3水洗,水层用DCM(2*50mL)萃取,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体186mg,收率:48%。1H NMR(400MHz,DMSO-d6)δ9.09(m,2H),8.89(s,1H),8.49(d,1H),8.03-8.16(m,3H),7.59-7.61(m,2H),7.12(s,1H),6.43-6.48(m,2H),6.09(m,1H),5.74(m,1H),3.74-3.86(m,7H),3.45(m,2H),2.50(m,2H),2.21(s,6H)。LC/MS(ESI):m/z 510(M+H)+。
实施例8:2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-[4”-(4”’-甲基哌嗪基)-2”-甲氧基苯基]三嗪(化合物608)的制备:
2-氯-4-[2’-甲氧基-4’-(4’-甲基哌嗪基)苯基]喹唑啉的制备:
在氮气保护下,将4-(4’-甲基哌嗪基)-2-甲氧基苯硼酸(0.72g,2.87mmol)和2,4-二氯喹唑啉(0.51g,3.44mmol)溶于乙二醇二甲醚(20mL)中,然后搅拌加入二氯二叔丁基-(4-二甲基氨基苯基)膦钯(II)(0.13g,1.85mmol),2M碳酸钠溶剂(32mL,6.31mmol)。然后搅拌加热到80℃反应5小时。经TLC检测反应完全。停止反应,加水(2mL)稀释。乙酸乙酯(25mL)萃取2次,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体439mg,收率:48%。LC/MS(ESI):m/z 320(M+H)+。
2-{1'-N,N-二甲氨基乙基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-[2”-甲氧基-4”-(4”’-甲基哌嗪基)苯基]三嗪的制备:
将2-氯-4-[4’-(4”-甲基哌嗪基)苯基]喹唑啉(0.32g,1mmol)溶于20mL二氧六环中,于室温下搅拌加入1-(N,N-二甲氨基乙基)-4-氨基-7-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉(275mg,1.1mmol)和对甲苯磺酸(0.21g,1.1mmol),之后加热到85℃,搅拌反应7小时。LCMS检测反应完全。停止反应,冷却到室温,加入10mL水和40%NaOH调至Ph=9。过滤,用甲醇洗涤滤饼,烘干得到黄色固体,490mg,收率:92%。LC/MS(ESI):m/z 534(M+H)+。
2-{1'-N,N-二甲氨基乙基-4'-丙烯酰胺基-7'-甲氧基-1’,2’,3’,4’-四氢-6'-喹喔啉}-4-[4”-(4”’-甲基哌嗪基)-2”-甲氧基苯基]三嗪(化合物608)的制备:
将2-[1'-N,N-二甲氨基乙基-7’-甲氧基-1’,2’,3’,4’-四氢-6’-喹喔啉]-4-[4”-(4”’-甲基哌嗪基)苯基]三嗪(405mg,0.76mmol)和DIPEA(0.146mL,0.84mmol)溶于二氯甲烷(10mL)中,在0℃下搅拌,然后滴加丙烯酰氯(69mg,0.76mmol)溶于DCM(2mL)溶液,之后搅拌反应2小时。经TLC检测反应完全。停止反应,加入DCM(50mL),然后用100mL饱和NaHCO3水洗,水层用DCM(2*50mL)萃取,无水MgSO4干燥,浓缩,粗产品通过快速柱分离得到黄色固体245mg,收率:55%。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.89(s,1H),7.59(d,1H),7.12(s,1H),6.48-6.59(m,4H),6.09(m,1H),5.74(m,1H),3.78-3.86(m,10H),3.43-3.45(m,6H),2.35-2.48(m,6H),2.21(s,9H)。LC/MS(ESI):m/z 588(M+H)+。
实施例9:EGFR激酶抑制活性及相关突变位点结合率的测定
对上述实施例1-8制得的化合物601-608,采用FRET技术来测定前述化合物对EGFR激酶抑制活性,该抑制活性采用IC50这一指标对表示,IC50即EGFR激酶的活性被抑制50%时的化合物的浓度。
同时采用TR-FRET技术对本发明化合物实施例1-8制得的化合物601-608的EGFR-T790M激酶活性抑制作用进行测定,也采用IC50这一指标对表示。采用Life technologies公司Z’-LYTETM Kinase Assay Kits(PV3193),并选用Tyrosine 4Peptide中的EGFR-T790M激酶解决方案进行活性测定试验。测定结果见表2
表2实施例化合物的EGFR抑制活性及EGFRT790M结合率测定
实施例10:本发明化合对癌细胞株的抑制活性测定(MTT法检测)
细胞株:人非小细胞肺癌腺癌细胞株NCI-H1975(EGFR-T790M高表达),人非小细胞肺细胞株A549(EFGR高表达)。
方法:将细胞株NCI-H1975和A549置于20%FBS(胎牛血清)(Gibco)+1640+1%双抗进行培养。然后取生长状态良好的NCI-H1975细胞,5000个/孔分别接种于96孔细胞板,置于37℃、含5%CO2的培养箱中孵出育24h使细胞贴壁完全。弃去旧培养液,每孔依次加入100μL含0.3、1、3、10、30、100、300、1000、3000和10000nmol/L待测化合物的培养液,溶剂对照组每孔加入100μL含0.1%DMSO的培养液,每组3复孔,72h后弃去旧的培养液,避光条件下每孔加入100μL含0.5mg·mL-1MTT的培养液,置于细胞培养箱中继续孵育4h,弃去上清,每孔加入100μLDMSO,振荡,用酶标仪在492nm波长下测定各孔吸光度值。根据各化合物不同浓度对备细胞生长的抑制率,经换算得到下表中的IC50(nM)。
表3化合物对肺癌细胞株作用
NCI-H1975 | A549 | |
样品编号 | IC<sub>50</sub>(nM) | IC<sub>50</sub>(nM) |
601 | 15 | 1.6 |
607 | 24 | 3.4 |
Claims (10)
1.一种具有结构通式(I)的三嗪双芳香环表皮生长因子抑制剂及药学上可接受的盐
其中:A可选如下任一种
X1可以选N或者CR5;
R1可以选H,卤素,CN,NO2,CF3,CHF2,C1-C6烷基,C1-C6环烷基,C1-C6烯烷基,C1-C6炔烷基,C1-C6氧烷基,C1-C6胺烷基;
R2可以选H,C1-C6烷基,C1-C6环烷基,C1-C6烯烷基,C1-C6炔烷基,C1-C6氧烷基,C1-C6胺烷基,C1-C6烷羰基,C1-C6烯羰基;
R3可以选H,CN,NO2,CF3,CHF2,C1-C6烷基,C1-C6环烷基,C1-C6烯烷基,C1-C6炔烷基,C1-C6氧烷基,C1-C6胺烷基;
R4可以选H,卤素,CN,C1-C6烷基,C1-C6环烷基,C1-C6烯基,C1-C6炔基,C1-C6氧烷基,CF3,CHF2;
R5可以选H,C1-C6烷基,C1-C6环烷基,C1-C6烯基,C1-C6炔基,C1-C6烷氧基,C1-C6胺烷基。
2.根据权利要求1所述的三嗪双芳香环双芳香环表皮生长因子抑制剂及药学上可接受的盐,其特征在于,所述结构通式(I)的化合物包括编号601-608的一种
。
3.一种制备权利要求1或者2所述的三嗪双芳香环表皮生长因子抑制剂及药学上可接受的盐的方法。其特征在于包括如下步骤:
(1)化合物I-1和I-2通过偶联反应得到化合物II-1:
其中:A可选如下任一种
X1可以选N或者CR5;
R4可以选H,卤素,CN,C1-C6烷基,C1-C6环烷基,C1-C6烯基,C1-C6炔基,C1-C6烷氧基,CF3,CHF2;
R5可以选H,C1-C6烷基,C1-C6环烷基,C1-C6烯基,C1-C6炔基,C1-C6烷氧基,C1-C6胺烷基;
(2)化合物II-1和II-2通过取代反应得到化合物III-1:
(3)化合物III-1和III-2通过亲核反应得到化合物I:
4.一种药物组合物,其特征在于,包含权利要求1或者2所述的三嗪双芳香环表皮生长因子抑制剂及药学上可接受的盐,以及药学上可接受的载体。
5.根据权利要求4所述的药物组合物,其特征在于,所述药物组合物为片剂、胶囊、颗粒剂、喷雾剂或者注射剂的形式。
6.根据权利要求4所述的药物组合物,其特征在于,所述药学上可接受的载体选自填充剂、崩解剂、粘合剂和润滑剂中的一种或多种。
7.权利要求1和或者2所述的三嗪双芳香环表皮生长因子抑制剂及药学上可接受的盐作为蛋白酪氨酸激酶抑制剂的用途。
8.根据权利要求7所述的用途,其特征在于:所述蛋白酪氨酸激酶抑制剂为表皮生长因子受体抑制剂。
9.权利要求1和或者2所述的三嗪双芳香环表皮生长因子抑制剂及药学上可接受的盐或者权利要求4至6中任一项所述的药物组合物在制备用于治疗表皮生长因子受体过度表达相关疾病的药物中的用途。
10.根据权利要求9所述的用途,其特征在于:所述表皮生长因子受体过度表达相关疾病选自肾癌、肺癌、前列腺癌、胰腺癌、乳腺癌和胶质细胞瘤中的一种或多种。
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