CN114181161B - (2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物及其制备方法与应用 - Google Patents
(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物及其制备方法与应用 Download PDFInfo
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- CN114181161B CN114181161B CN202111628318.0A CN202111628318A CN114181161B CN 114181161 B CN114181161 B CN 114181161B CN 202111628318 A CN202111628318 A CN 202111628318A CN 114181161 B CN114181161 B CN 114181161B
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- pyrimidin
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- A—HUMAN NECESSITIES
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Abstract
本发明属于有机化合物合成及医药应用技术领域,公开了一种(2‑((取代氧基)苯基)氨基)嘧啶‑4‑基)氨基苯甲酰衍生物及其制备方法与应用。该(2‑((取代氧基)苯基)氨基)嘧啶‑4‑基)氨基苯甲酰衍生物的结构如通式I、II所示其中,R1选自C1‑6直链或支链烷基酯基;R2选自含或不含卤素\氮\氧\硫原子的C1‑6直链或支链烷基、芳基;R3选自氢、氰基、卤素、三氟甲基、甲基、甲氧基;R4取自羟胺酰基。该类化合物具有一定的BTK/FLT3双重抑制活性和抗肿瘤活性。
Description
技术领域
本发明属于有机化合物合成及医药应用技术领域,尤其涉及一种(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物及其制备方法与应用。
背景技术
布鲁顿酪氨酸激酶(Bruton’s tyrosine kinase,BTK)是B细胞受体(B cellreceptor,BCR)和Fc受体(Fc receptor,FcR)信号通路的关键节点。BCR和FcR分别在B细胞和髓样细胞(巨噬细胞、单核细胞和肥大细胞等)的表面表达。BTK通过BCR和FcR信号通路调控B细胞和髓样细胞的存活与生物学功能,是治疗各种涉及B细胞和/或巨噬细胞异常疾病的重要靶标(参见:Drug discovery today 2014;19(8):1200-1204和Mol cancer.2018;17(1):57)。FMS样酪氨酸激酶3(Fms-like tyrosine kinase 3,FLT3)属于Ⅲ型受体酪氨酸激酶,主要表达于CD34+造血干细胞和未成熟造血祖细胞表面,在造血干细胞和DC祖细胞的发育过程中发挥着重要作用(参见:Physiological reviews 2019;99(3):1433-1466)。FLT3是治疗血液***恶性肿瘤和自体免疫疾病的重要靶标。临床前及临床研究表明,双重抑制BTK和FLT3具有协同作用(参见:Blood 2019;134(Supplement_1):5477-5477),因此设计合成结构新颖、具有成药性的新型BTK/FLT3双靶点药物,对于治疗血液***恶性肿瘤及自体免疫疾病来说具有重要意义。
发明内容
有鉴于此,本发明的目的在于提供一种(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物及其制备方法与应用,其具有BTK/FLT3双重抑制活性且具有抗肿瘤作用。该类化合物生物活性优良,同时提升了化合物的分子多样性和新颖性。
为了实现上述目的,本公开了以下技术方案:
在本发明的第一方面,本发明提供了一种化合物或其药学上可接受的盐,该化合物为具有通式I和II所示结构的(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物:
其中,R1选自C1-6直链或支链烷基酯基;R2选自含或不含卤素\氮\氧\硫原子的C1-6直链或支链烷基、芳基;R3选自氢、氰基、卤素、三氟甲基、甲基、甲氧基;R4取自羟胺酰基。
优选地,所述R1、R4的取代位置为C-2位、C-3位、C-4位;
优选地,R1选自-COOMe;R2选自甲氧基乙基、苯基;R3选自氟;R4取自-CONHOH;
优选地,上述化合物中,
具有通式I所示结构的化合物选自以下任一化合物:
2-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯(I-1)
2-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯(I-2)
3-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯(I-3)
3-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯(I-4)
4-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯(I-5)
4-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯(I-6)
具有通式II所示结构的化合物选自以下任一化合物:
2-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺(II-1)
2-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺(II-2)
3-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺(II-3)
3-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺(II-4)
4-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺(II-5)
4-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺(II-6)
上述化合物名称后的括号中为其相应的代号,为叙述方便和表达简洁,上述括号中的代号在本说明书以下内容中将被直接应用。
本发明所述的化合物可以游离形式或进一步以盐的形式存在,目的是为了提高水溶性,增加生物利用度。
本发明所述的“药学上可接受的盐”是指常规的无毒性的盐,主要包括本申请化合物的碱性氨基所形成的盐。这些盐是本领域熟练技术人员熟知的,熟练的技术人员可以制备本领域知识所提供的任何药学上可接受的盐。此外,熟练技术人员还可以根据溶解度、稳定性、容易制剂等因素取某种盐而舍去另一种盐。这些盐的测定和最优化在熟练技术人员的经验范围内。
本发明还提供了通式I、II所示结构化合物的制备方法,所述制备方法包括进行如下反应路线:
其中,R1选自C1-6直链或支链烷基酯基;R2选自含或不含卤素\氮\氧\硫原子的C1-6直链或支链烷基、芳基;R3选自氢、氰基、卤素、三氟甲基、甲基、甲氧基;R4取自羟胺酰基。
试剂及条件:(a)不同氨基苯甲酸甲酯,N,N-二异丙基乙胺(DIPEA),异丙醇,85℃,4h;(b)取代苯胺,三氟乙酸,正丁醇,110℃,12h;(c)氢氧化钾,盐酸羟胺,无水甲醇,0℃~r.t.,2h。
具体步骤如下:
(i)将起始化合物1和氨基苯甲酸甲酯溶于异丙醇中,加入DIPEA,85℃反应4小时。TLC检测,反应完全,冷却至室温,有大量固体析出,过滤,滤饼用乙酸乙酯重结晶,得中间体2。
(ii)将中间体2溶于正丁醇中,加入取代苯胺,再向溶液中滴加三氟乙酸,110℃反应12h。TLC检测,反应完全,冷却至室温,减压蒸除溶剂,硅胶柱层析,得化合物I,即通式I所示结构的(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物。
(iii)利用氢氧化钾和盐酸羟胺及无水甲醇制备NH2OK溶液。将化合物I溶于NH2OK溶液中,室温反应2h。TLC检测,反应完全,减压蒸除溶剂,加水,用稀盐酸调pH值至6-7,有固体析出,过滤,滤饼用甲醇或乙酸乙酯重结晶,得通式II所示结构的(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物。
本发明的室温为20℃-30℃。
本发明还提供了一种药物组合物,其含有上述化合物或其药学上可接受的盐。
上述药物组合物,可以选自以下任意方式施与:口服、喷雾吸入、直肠给药、鼻腔给药、***给药、局部给药、非肠道给药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内或颅内注射或输入,或借助一种外植的储器用药,其中优选口服、肌注、腹膜内或静脉内用药方式。
本发明还提供了一种药物制剂,其包含上述化合物或其药学上可接受的盐或含有上述化合物或其药学上可接受的盐的组合物和药学上可接受的辅料和/或载体。
本发明化合物或含有它的药物组合物可以单位剂量形式给药。给药剂型可以是液体剂型、固体剂型。液体剂型可以是真溶液类、胶体类、微粒剂型、乳剂剂型、混旋剂剂型。其他剂型例如片剂、胶囊、滴丸、气雾剂、丸剂、粉剂、溶液剂、混悬剂、乳剂、颗粒剂、栓剂、冻干粉针剂、包合物、填埋剂、贴剂、擦剂等。
本发明的药物组合物或药物制剂中还可以含有常用的载体,这里所述可药用载体包括但不局限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血清蛋白,缓冲物质如磷酸盐,甘油,山梨酯,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态氧化硅,三硅酸镁,聚乙烯吡咯烷酮,纤维素物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,蜂蜡,羊毛酯等。载体在药物组合物中的含量可以是1重量%-98重量%,通常大约占到80重量%。为方便起见,局部麻醉剂,防腐剂,缓冲剂等可直接溶于载体中。
口服片剂和胶囊可以含有赋形剂如粘合剂,如糖浆,***胶,山梨醇,黄芪胶,或聚乙烯吡咯烷酮,填充剂,如乳糖,蔗糖,玉米淀粉,磷酸钙,山梨醇,氨基乙酸,润滑剂,如硬脂酸镁,滑石,聚乙二醇,硅土,崩解剂,如马铃薯淀粉,或可接受的增润剂,如月桂醇钠硫酸盐。片剂可以用制药学上公知的方法包衣。
口服液可以制成水和油的悬浮液,溶液,乳浊液,糖浆,也可以制成干品,用前补充水或其它合适的媒质。这种液体制剂可以包含常规的添加剂,如悬浮剂,山梨醇,纤维素甲醚,葡萄糖糖浆,凝胶,羟乙基纤维素,羧甲基纤维素,硬脂酸铝凝胶,氢化的食用油脂,乳化剂,如卵磷脂,山梨聚糖单油酸盐,***树胶;或非水载体(可能包含可食用油),如杏仁油,油脂如甘油,乙二醇,或乙醇;防腐剂,如对羟基苯甲酸甲酯或丙酯,山梨酸。如需要可添加调味剂或着色剂。
栓剂可包含常规的栓剂基质,如可可黄油或其它甘油酯。
对于胃肠外投药,液态剂型通常由化合物和一种消毒的载体制成。载体首选水。依照所选载体和药物浓度的不同,化合物既可溶于载体中也可制成悬浮溶液,在制成注射用溶液时先将化合物溶于水中,过滤消毒后装入封口瓶或安瓿中。
必须认识到,通式I、II化合物的最佳给药剂量和间隔是由化合物性质和诸如给药的形式、路径和部位以及所治疗的特定哺乳动物等外部条件决定的,而这一最佳给药剂量可用常规的技术确定。同时也必须认识到,最佳的疗程,即同时I、II化合物在额定的时间内每日的剂量,可用本领域内公知的方法确定。
本发明还提供了一种药物组合物,包含上述化合物或其药学上可接受的盐。
本发明还提供了一种药物试剂,包括有效成分和药学上可接受的辅料和/或载体,所述有效成分包含上述化合物或其药学上可接受的盐。
本发明还提供了一种抑制剂,所述抑制剂为BTK抑制剂、FLT3抑制剂和BTK/FLT3双重抑制剂中的一种,所述抑制剂包含上述的化合物或其药学上可接受的盐作为活性成分。
优选的,所述抑制剂为BTK/FLT3双重抑制剂,所述抑制剂包含2-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺或其药学上可接受的盐作为活性成分。
本发明还提供了一种化合物在制备抗肿瘤药物中的应用,所述化合物为上述的化合物或其药学上可接受的盐
进一步的,所述肿瘤为淋巴瘤和白血病。
与现有技术相比,本发明提供了具有全新结构骨架的BTK/FLT3双靶点抑制剂,代表性化合物对BTK和FLT3具有强效双重抑制活性IC50值在低纳摩尔水平(IC50<200nM),其对血液***恶性肿瘤细胞的抗增殖活性与上市药物伊鲁提尼和索拉菲尼相当。本发明为全新抗肿瘤药物的研发提供了新方案。
以下实验例仅用于说明本发明的技术效果,但所述的实验例不用于限制本发明。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。以下实验例仅用于说明本发明的技术效果,但所述的实验例不用于限制本发明。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1:中间体2的制备
将原料2,4-二氯-5-氟嘧啶(12mmol,1.2eq)、氨基苯甲酸甲酯(10mmol,1.0eq)和DIPEA(10mmol,1.0eq)溶于20mL异丙醇中,85℃加热反应4小时。反应毕,反应液冷却至室温,有大量固体析出,过滤,滤饼用乙酸乙酯重结晶,得中间体2。
实施例2:目标化合物I的制备
将中间体2(1mmol,1eq)溶于30mL正丁醇中,加入不同取代苯胺(1.1mmol,1.1eq),再向溶液中滴加5滴三氟乙酸,110℃加热反应12h。反应毕,反应液冷却至室温,减压蒸除溶剂,硅胶柱层析(二氯甲烷/甲醇=200:1-20:1),得目标化合物I。
I-1:2-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯
1H NMR(400MHz,DMSO-d6)δ10.93(d,J=2.3Hz,1H),9.22(s,1H),8.91(d,J=8.5Hz,1H),8.20(d,J=3.2Hz,1H),8.03(dd,J=8.0,1.6Hz,1H),7.63(dt,J=8.0,1.6Hz,1H),7.53(d,J=9.0Hz,2H),7.16(dt,J=8.0,1.2Hz,1H),6.92–6.86(m,2H),4.09–4.03(m,2H),3.90(s,3H),3.68–3.63(m,2H),3.32(s,3H).13C NMR(101MHz,DMSO-d6)δ168.76,156.23,154.01,149.33(d,J=11.2Hz),142.43,141.70,141.56(d,J=17Hz),141.21(d,J=244Hz),134.84,134.21,131.33,122.30,121.64,120.97,115.59,114.72,70.98,67.51,58.64,53.08.HRMS(ESI)m/z calcd for C21H22FN4O4[M+H]+413.1620,found 413.1621.
I-2:2-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯
1H NMR(400MHz,DMSO-d6)δ10.93(d,J=2.2Hz,1H),9.43(s,1H),8.89(d,J=8.5Hz,1H),8.24(d,J=3.2Hz,1H),8.03(dd,J=8.0,1.6Hz,1H),7.68(d,J=9.0Hz,2H),7.65–7.58(m,1H),7.40–7.33(m,2H),7.21–7.13(m,1H),7.13–7.05(m,1H),7.03–6.94(m,4H),3.90(s,3H).13C NMR(101MHz,DMSO-d6)δ168.73,158.35,155.94(d,J=2.7Hz),150.68,149.43(d,J=9.7Hz),142.65,141.57,141.35,140.20,137.18,134.78,131.33,130.37,123.08,122.43,121.40,121.11,120.06,117.85,115.83,53.09.HRMS(ESI)m/zcalcd for C24H20FN4O3[M+H]+431.1514,found 431.1516.
I-3:3-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯
1H NMR(400MHz,DMSO-d6)δ9.54(s,1H),9.06(s,1H),8.21(t,J=1.7Hz,1H),8.18(d,J=8.3Hz,1H),8.11(d,J=3.6Hz,1H),7.66(d,J=7.8Hz,1H),7.54–7.42(m,3H),6.78(d,J=9.0Hz,2H),4.02(dd,J=5.4,3.8Hz,2H),3.83(s,3H),3.67–3.61(m,2H),3.31(s,3H).13C NMR(101MHz,DMSO-d6)δ166.65,156.18(d,J=2.7Hz),153.62,149.90(d,J=10.8Hz),141.61(d,J=19.7Hz),140.74(d,J=245Hz),139.85,134.41,130.41,129.39,126.25,123.97,122.39,121.09,114.54,70.96,67.41,58.62,52.59.HRMS(ESI)m/z calcdfor C21H22FN4O4[M+H]+413.1620,found 413.1620.
I-4:3-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯
1H NMR(400MHz,DMSO-d6)δ9.60(s,1H),9.29(s,1H),8.22(t,J=1.8Hz,1H),8.18-8.14(t,J=6.8Hz,2H),7.69–7.61(m,3H),7.47(t,J=7.9Hz,1H),7.38–7.31(m,2H),7.08(t,J=7.4Hz,1H),6.97–6.91(m,2H),6.88(d,J=9.0Hz,2H),3.79(s,3H).13C NMR(101MHz,DMSO-d6)δ166.59,158.32,155.94(d,J=2.9Hz),150.34,150.00(d,J=10.9Hz),141.58(d,J=19.6Hz),140.80(d,J=245Hz),139.74,137.35,130.37(d,J=6.9Hz),129.42,126.48,124.12,123.04,122.60,120.84,119.91,117.84,52.58.HRMS(ESI)m/z calcd forC24H20FN4O3[M+H]+431.1514,found 431.1516.
I-5:4-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯
1H NMR(400MHz,DMSO-d6)δ9.67(s,1H),9.13(s,1H),8.15(d,J=3.6Hz,1H),8.01(d,J=8.8Hz,2H),7.88(d,J=8.9Hz,2H),7.52(d,J=9.0Hz,2H),6.87(d,J=9.0Hz,2H),4.08–4.03(m,2H),3.84(s,3H),3.68–3.63(m,2H),3.32(s,3H).13C NMR(101MHz,DMSO-d6)δ166.39,155.99(d,J=2.6Hz),154.07,149.66(d,J=10.7Hz),144.22,141.29(d,J=20.3Hz),140.82(d,J=246Hz),134.06,130.30,123.63,121.88,120.26,114.72,70.94,67.49,58.62,52.36.HRMS(ESI)m/z calcd for C21H22FN4O4[M+H]+413.1620,found413.1621.
I-6:4-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯
1H NMR(400MHz,DMSO-d6)δ9.99(s,1H),9.59(s,1H),8.24(d,J=4.0Hz,1H),7.98(d,J=8.8Hz,2H),7.89(d,J=8.8Hz,2H),7.61(d,J=8.9Hz,2H),7.43–7.34(m,2H),7.11(t,J=7.4Hz,1H),7.04–6.95(m,4H),3.83(s,3H).13C NMR(101MHz,DMSO-d6)δ166.25,157.88,154.14,152.12,150.84(d,J=11.0Hz),143.24,140.48(d,J=247Hz),137.37(d,J=15.5Hz),135.43,130.46,130.25,124.69,123.43,123.14,121.19,119.85,118.22,52.45.HRMS(ESI)m/z calcd for C24H20FN4O3[M+H]+431.1514,found 431.1516.
实施例3:目标化合物II的制备
将KOH(28.55g,509mmol)和NH2OH·HCI(23.84g,343mmol)分别溶于70mL和120mL无水甲醇中,得到溶液A和溶液B。冰浴条件下,将A溶液滴加至B溶液中,有白色固体析出,继续反应1小时,过滤沉淀,得到NH2OK溶液。将化合物I(0.50mmol)溶于10mL NH2OK溶液中,室温搅拌2h。反应毕,减压蒸除溶剂,加入20mL水,用1M HCl调pH值至6-7,有固体析出,过滤,滤饼用甲醇/乙酸乙酯重结晶,得目标化合物II。
II-1:2-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.56(s,1H),11.22(s,1H),9.37(s,1H),9.16(s,1H),8.77(d,J=8.4Hz,1H),8.14(d,J=3.3Hz,1H),7.62(d,J=7.9Hz,1H),7.57–7.48(m,3H),7.11(t,J=7.5Hz,1H),6.91–6.85(m,2H),4.07–4.04(m,2H),3.67–3.63(m,2H),3.31(s,3H).13C NMR(101MHz,DMSO-d6)δ166.43,156.24(d,J=2.9Hz),153.89,149.34(d,J=9.9Hz),141.20(d,J=20.6Hz),141.17(d,J=244Hz),139.75,134.33,132.24,128.03,122.24,121.63,121.48,121.27,118.87,114.69,70.98,67.49,58.64.HRMS(ESI)m/zcalcd for C20H21FN5O4[M+H]+414.1572,found 414.1568.
II-2:2-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.57(s,1H),11.25(s,1H),9.38(s,1H),9.37(s,1H),8.77(d,J=8.3Hz,1H),8.18(d,J=3.2Hz,1H),7.69(d,J=9.0Hz,2H),7.63(d,J=7.8Hz,1H),7.49(t,J=7.9Hz,1H),7.39–7.34(m,2H),7.13–7.06(m,2H),7.01–6.94(m,4H).13CNMR(101MHz,DMSO-d6)δ166.37,158.38,155.99(d,J=3.2Hz),150.58,149.43(d,J=10.0Hz),141.40(d,J=245Hz),141.10(d,J=19.9Hz),139.64,137.31,132.18,130.36,128.06,123.05,122.37,121.38,121.30,120.07,119.06,117.82.HRMS(ESI)m/z calcdfor C23H19FN5O3[M+H]+432.1466,found 432.1464.
II-3:3-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),9.45(s,1H),9.07(s,1H),9.03(s,1H),8.09(d,J=3.6Hz,1H),7.98(s,1H),7.96(d,1H),7.50(d,J=9.0Hz,2H),7.45–7.37(m,2H),6.80(d,J=9.0Hz,2H),4.03(t,J=4.4Hz,2H),3.62(t,J=4.4Hz,2H),3.31(s,3H).13CNMR(101MHz,DMSO-d6)δ164.79,156.18(d,J=2.7Hz),153.63,150.10(d,J=10.8Hz),141.98,141.33(d,J=19.2Hz),139.50(d,J=8.2Hz),134.40,133.84,128.97,124.60,121.86,121.00,114.64,70.98,67.40,58.62.HRMS(ESI)m/z calcd for C20H21FN5O4[M+H]+414.1572,found 414.1567.
II-4:3-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.19(s,1H),9.51(s,1H),9.26(s,1H),9.06(s,1H),8.13(d,J=3.6Hz,1H),8.01(d,J=7.5Hz,1H),7.97(s,1H),7.65(d,J=8.8Hz,2H),7.46–7.29(m,4H),7.06(t,J=7.4Hz,1H),6.94-6.89(m,4H).13C NMR(101MHz,DMSO-d6)δ164.67,158.44,155.98(d,J=2.9Hz),150.19,150.18(d,J=10Hz),141.33(d,J=18.8Hz),141.01(d,J=246Hz),139.44,137.47,133.85,130.33,128.97,124.74,122.94,121.91,121.01,120.79,120.15,117.69.HRMS(ESI)m/z calcd for C23H19FN5O3[M+H]+432.1466,found432.1465.
II-5:4-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),9.52(s,1H),9.11(s,1H),8.98(s,1H),8.12(d,J=3.7Hz,1H),7.92(d,J=8.7Hz,2H),7.71(d,J=8.8Hz,2H),7.53(d,J=9.0Hz,2H),6.87(d,J=9.1Hz,2H),4.08–4.02(m,2H),3.68–3.63(m,2H),3.31(s,3H).13C NMR(101MHz,DMSO-d6)δ164.39,156.22(d,J=2.8Hz),153.80,149.69(d,J=10.5Hz),142.35,141.56(d,J=19.7Hz),140.85(d,J=245Hz),134.41,127.80,127.00,121.32,120.31,114.69,70.97,67.48,58.63.HRMS(ESI)m/z calcd for C20H21FN5O4[M+H]+414.1572,found414.1569.
II-6:4-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺
1H NMR(400MHz,DMSO-d6)δ11.15(s,1H),9.57(s,1H),9.33(s,1H),8.98(s,1H),8.16(d,J=3.6Hz,1H),7.93(d,J=8.7Hz,2H),7.74–7.66(m,4H),7.39–7.34(m,2H),7.08(t,J=7.4Hz,1H),7.00–6.93(m,4H).13C NMR(101MHz,DMSO-d6)δ164.35,158.36,155.99(d,J=2.8Hz),150.46,149.77(d,J=10.6Hz),142.23,141.48(d,J=19.3Hz),141.07(d,J=246Hz),137.37,130.38,127.80,127.15,123.03,121.16,120.42,120.08,117.77.HRMS(ESI)m/z calcd for C23H19FN5O3[M+H]+432.1466,found 432.1465.
实验例:化合物对BTK和FLT3抑制活性测试、对肿瘤细胞的抗增殖活性测试
1)化合物对BTK、FLT3激酶抑制活性实验:
实验材料和仪器:本实验由英国公司Eurofins Pharma协助完成。
实验方法:将所有测试的化合物使用DMSO配制成最终测试浓度50倍的工作液。首先将化合物工作液作为第一组分加入到测试孔中,然后加入激酶buffer稀释的BTK或FLT3激酶溶液。Mg/ATP的加入,激酶反应被引发。随后,室温下孵育40分钟,加入0.5%的磷酸溶液终止反应。取10μL反应液点到P30滤纸垫上,使用0.425%磷酸洗涤4次,每次洗涤4分钟,然后用甲醇洗涤一次,随后进行干燥和闪烁计数。
试验中设定了化合物测试组(C),阳性对照组(P)和空白对照组(B)。阳性对照组中不加测试化合物,使用DMSO代替(最终浓度2%),其他组分与测试组相同(残留激酶活性100%);空白对照组中使用星形孢菌素(staurosporine)代替测试化合物,消除激酶活性并建立基线(残留激酶活性0%)。
使用Gragphad Prism6.0软件,以浓度对数为横坐标,抑制率为中坐标,拟合曲线,计算IC50值。目标化合物对BTK、FLT3激酶抑制活性测定实验结果见表1。
表1.目标化合物对BTK和FLT3激酶抑制活性
A:抑制率>60%;B:60%>抑制率>40%;C:抑制率<40%
表1实验数据表明,大部分化合物对BTK和FLT3具有较强的抑制活性(1μM浓度下激酶抑制率>60%)。其中,化合物II-1表现出强效双重抑制作用。
2)化合物对肿瘤细胞的生长抑制活性实验:
实验材料和仪器:Jeko-1和RAW264.7细胞株、RPMI-1640培养基、胎牛血清、PBS缓冲液、青霉素纳(10000units/mL)-硫酸链霉素(10mg/mL)、CCK-8试剂盒、倒置光学显微镜、细胞培养箱、超净工作台、台式离心机、酶标仪、超低温冰箱。
实验方法:
取对数生长期肿瘤细胞接种于96孔培养板中,细胞数为1×104/孔,加入不同浓度所测化合物的细胞培养液,同时设立阳性对照组和DMSO空白对照组,调整DMSO浓度≤1‰。每个浓度设3个复孔,加毕,置37℃,5%CO2恒温培养箱中孵育72h。随后每孔加入20μL CCK-8溶液,培养板置于37℃,5%CO2恒温培养箱中继续孵育1-4h,用酶标仪测定其在450nm波长下的吸光度值,所得数值与阴性DMSO对照组进行归一化处理,应用Prism 6.0软件计算IC50值
表2.目标化合物对Jeko-1和RAW264.7细胞生长抑制作用
IC50:半数抑制浓度
A:IC50<2μM;B:2μM<IC50<20μM;C:20μM<IC50
表2实验数据表明,大部分化合物对Jeko-1细胞具有显著的抗增殖活性,IC50值与阳性对照药伊鲁替尼相当甚至更低,大部分化合物对RAW264.7细胞具有中等强度的抗增殖活性。
以上所述仅为本公开的优选实施例而已,并不用于限制本公开,对于本领域的技术人员来说,本公开可以有各种更改和变化。凡在本公开的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本公开的保护范围之内。
Claims (9)
1.一种化合物或其药学上可接受的盐,所述化合物为通式I或通式II所示结构的(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物:
,
其中,R1为-COOMe;R2选自含或不含卤素\氮\氧\硫原子的C1-6直链或支链烷基;或R2为苯基;R3选自氢、氰基、卤素、三氟甲基、甲基、甲氧基;R4取自羟胺酰基。
2.如权利要求1所述的化合物,其特征是,R1、R4的取代位置为C-2位、C-3位、C-4位;R2选自甲氧基乙基、苯基;R3选自氟;R4取自-CONHOH。
3.如权利要求2所述的化合物,其特征在于,通式I所示结构的化合物选自下列任一化合物:
2-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯;
2-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯;
3-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯;
3-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯;
4-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯;
4-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)苯甲酸甲酯;
通式II所示结构的化合物选自下列任一化合物:
2-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺;
2-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺;
3-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺;
3-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺;
4-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺;
4-((5-氟-2-((4-苯氧基苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺。
4.权利要求1所述的化合物的制备方法,其特征在于,以化合物1和氨基苯甲酸酯为起始原料通过以下反应路线制备通式I和通式II所示结构的(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物:
,
其中,R1选自C1-6直链或支链烷基酯基;R2选自含或不含卤素\氮\氧\硫原子的C1-6直链或支链烷基;或R2为苯基;R3选自氢、氰基、卤素、三氟甲基、甲基、甲氧基;R4取自羟胺酰基;
所述制备方法包括以下步骤:
S1.将化合物1和氨基苯甲酸甲酯溶于异丙醇中,加入DIPEA,85℃反应,TLC检测反应完全后,冷却至室温,有大量固体析出,过滤,滤饼用乙酸乙酯重结晶,得中间体2;
S2.将中间体2溶于正丁醇中,加入取代苯胺,再向溶液中滴加三氟乙酸,110℃反应,TLC检测反应完全后,冷却至室温,减压蒸除溶剂,硅胶柱层析,得通式I所示结构的(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物;
S3.将通式I所示结构的2,4,5-三取代嘧啶衍生物溶于NH2OK溶液中,室温反应,TLC检测反应完全,减压蒸除溶剂,加水,用稀盐酸调pH值至6-7,有固体析出,过滤,滤饼用甲醇或乙酸乙酯重结晶,得通式II所示结构的(2-((取代氧基)苯基)氨基)嘧啶-4-基)氨基苯甲酰衍生物。
5.一种药物组合物,包含权利要求1~3任一项所述的化合物或其药学上可接受的盐。
6.一种药物制剂,其特征在于,包括有效成分和药学上可接受的辅料和/或载体,所述有效成分包含权利要求1~3任一项所述化合物或其药学上可接受的盐。
7. 一种抑制剂,其特征在于,所述抑制剂为BTK抑制剂、FLT3抑制剂和BTK/ FLT3双重抑制剂中的一种,所述抑制剂包含权利要求1~3任一项所述的化合物或其药学上可接受的盐作为活性成分。
8.根据权利要求7所述的抑制剂,其特征在于,所述抑制剂为BTK/ FLT3双重抑制剂,所述抑制剂包含2-((5-氟-2-((4-(2-甲氧基乙氧基)苯基)氨基)嘧啶-4-基)氨基)-N-羟基苯甲酰胺或其药学上可接受的盐作为活性成分。
9.一种化合物在制备抗肿瘤的药物中的应用,所述化合物为权利要求1~3任一项所述的化合物或其药学上可接受的盐,所述肿瘤为淋巴瘤或白血病。
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