CN113501808A - 一种新型亚磺酰基苯胺基的嘧啶衍生物及其在制备抗肿瘤药物中的应用 - Google Patents
一种新型亚磺酰基苯胺基的嘧啶衍生物及其在制备抗肿瘤药物中的应用 Download PDFInfo
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- CN113501808A CN113501808A CN202110625173.2A CN202110625173A CN113501808A CN 113501808 A CN113501808 A CN 113501808A CN 202110625173 A CN202110625173 A CN 202110625173A CN 113501808 A CN113501808 A CN 113501808A
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- Prior art keywords
- pyrimidine derivative
- sulfinyl
- alk
- carbon atoms
- anilino
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Abstract
Description
技术领域
本发明涉及药物领域,特别涉及一种新型亚磺酰基苯胺基的嘧啶衍生物及其在制备抗肿瘤药物中的应用。
背景技术
间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)是一种高度保守的受体型酪氨酸激酶。研究表明,ALK的异常表达如基因突变、重排,扩增与多种人类恶性肿瘤(如神经母细胞瘤,非小细胞肺癌等)密切相关。在非小细胞肺癌中,大约5%左右的患者伴有ALK与棘皮动物微管结合蛋白4(Echinoderm micro tubuleassociated protein-like 4,EML4)的基因融合突变,激活ALK及其下游的多种信号转导通路,促进细胞的快速增殖与分化,最终导致肿瘤的发生。因此ALK抑制剂也是近年来抗肿瘤药物研发的热点之一。2011年,全球第一个治疗ALK依赖的非小细胞肺癌药物的克唑替尼(crizotinib)上市。接着,对ALK激酶专属性和亲和力更强的第二代ALK抑制剂色瑞替尼(ceritinib),布加替尼(brigatinib)等也陆续上市。尽管这些药物在挽救病人生命的过程中起到了重要作用,但是长期使用之后由于多种原因不可避免的产生耐药。
表皮细胞生长因子受体(epidermal growth factor receptor,EGFR)酪氨酸激酶是受体酪氨酸激酶中的一类。EGFR广泛分布于除血管组织之外的上皮细胞膜中。正常细胞中,EGFR酪氨酸激酶受其配体调节,发挥着调控正常细胞的生长、增殖等功能。当该通路的调控基因出现突变或者扩增时,可使得其介导的下游通路异常激活,从而诱发多种癌症。靶向EGFR酪氨酸激酶也是抗肿瘤药物研发重要手段之一。迄今为止,第一到第三代EGFR抑制剂,如吉非替尼,阿法替尼和奥西替尼(Osimertinib,AZD9291)也先后上市,对EGFR基因敏感突变的非小细胞肺癌患者,或对第一代EGFR抑制剂产生耐药的患者,具有很好的疗效。尽管这些新型靶向药物(如奥西替尼)对非小细胞肺癌患者的疗效令人鼓舞,但是肿瘤细胞具有极强的筛选能力,仍然有可能在对第三代EGFR抑制剂适应后,产生新的耐药性。另外,EGFR激活已被证明是使用小分子ALK抑制剂如克唑替尼,艾乐替尼和塞瑞替尼后产生的一种代偿性耐药机制。同时,在临床实践中,随着检测技术发展,陆续发现同时伴有EGFR突变和ALK重排(简称为“双突变”)的癌症患者。Lee等报道韩国肺腺癌EGFR和ALK双突变发生率为0.9%。Yang等连续检测中国NSCLC患者977例,共发现EGFR和ALK双突变患者13例,双突变发生率为1.3%。
2017年,文献(European Journal of Medicinal Chemistry 2017,136,497-510)报道了结构特征为含有磺酰基苯胺基嘧啶衍生物的双靶点(EGFR和ALK)抗肿瘤药物设计合成及活性研究。其优选化合物具有优良的肿瘤细胞抑制活性,但生物利用度不高(24%),有待于进一步优化。专利WO2017/101803A也报道了含有磺酰基苯胺基嘧啶衍生物的研究,也存在类似的情况。因此,寻找活性好,副作用少的抗肿瘤化合物,进行成药性研究,是亟待解决的问题。
发明内容
为了克服上述现有技术的不足和缺陷,本发明提供了一种新型亚磺酰基苯胺基的嘧啶衍生物。
本发明同时提供所述新型亚磺酰基苯胺基的嘧啶衍生物在制备抗肿瘤药物中的应用。
本发明为实现上述目的,本发明所采用的技术方案为:
一种新型亚磺酰基苯胺基的嘧啶衍生物,其结构式为式I:
式I中,R1为含有1个到4个碳原子烷基;R2,R3和R4分别为卤素原子,含碳数1-4的链状烷基,环烷基及含碳数为1-4的烷氧基;R5为含有1个到4个碳原子的烷基;R6为氢、甲基或丙烯酰胺基;R7为哌啶基、哌嗪基或N,N,N-三甲基乙二氨基,其中,哌啶基、哌嗪基中与氮原子连接的氢可被含碳数为1-3的直链烷基取代。
作为一种优选的技术方案,R1为含有1个到4个碳原子直链烷基,且直链烷基上的氢原子可被1个到4个碳原子烷基取代。
作为一种优选的技术方案,当R1上的氢原子被1个到4个碳原子烷基取代时,碳原子上连接氢或氢的同位素氘。
作为一种优选的技术方案,卤素原子为氟或氯。
作为一种优选的技术方案,R1为-CD(CD3)2、环丙烷基、环丙甲基、异丙基、乙基、-CD2CD3;R2,R3和R4分别为卤素原子,含碳数1-2的链状烷基;R5为甲基、乙基或异丙基;R7为哌啶基、N-甲基哌啶基或N,N,N-三甲基乙二氨基。
本发明同时保护一种ALK抑制剂,包含所述亚磺酰基苯胺基的嘧啶衍生物。
此外,本发明还保护一种ALK和EGFR双靶点抑制剂,包含所述亚磺酰基苯胺基的嘧啶衍生物。
进一步地,R6为氢或者甲基等烷基时,式I为含有亚磺酰基苯胺基嘧啶衍生物ALK抑制剂。R6是丙烯酰胺基时,式I为含有亚磺酰基苯胺基嘧啶衍生物ALK和EGFR双靶点抑制剂,也可以作为ALK抑制剂。
上述新型含有亚磺酰基苯胺基嘧啶衍生物,R6为氢或者甲基等烷基,R7为哌啶基的ALK抑制剂合成路线和方法,以代表性目标物A-1的合成为例,说明如下:
合成路线中,起始原料2-氨基苯硫酚与溴乙烷反应得硫醚中间体M-1,再与双氧水反应生产具有亚砜结构的中间体M-2,后者与2,4,5-三氯嘧啶反应得到关键中间体M-3。另一方面,2-异丙氧基-4-氯-5-甲基硝基苯与4-吡啶硼酸在催化剂存在下偶联得到中间体M-4,后者与碘甲烷反应生成M-5。M-5经硼氢化钠还原,再经钯碳或二氧化铂催化氢化还原,得关键中间体M-7。M-7与关键中间体M-3在酸催化下反应得目标化合物A-1。化合物A-1经手性分离(AD-H柱;流动相:异丙醇/正己烷,40/60;流速:0.5mL/min.),得到具有光学活性的两个对映异构体A-1a(保留时间:8.38分)和A-1b(保留时间:10.85分)。
上述新型含有亚磺酰基苯胺基嘧啶衍生物,R6是丙烯酰胺基,R7为哌嗪基,高哌嗪基或N,N,N-三甲基乙二氨基等的ALK/EGFR双靶点抑制剂合成方法,以代表性目标物B-1的合成为例,说明如下:
合成路线中,2-氨基-5-氟-苯乙基硫醚与双氧水反应得到具有亚砜结构的中间体M-9。后者在氢化钠的作用下,与2,4,5-三氯嘧啶反应得到中间体M-10。商品化的2-甲氧基-4-氟-5-硝基苯胺与中间体M-10在酸存在反应得到M-11。M-11硝基邻位的氟原子被三甲基乙二胺取代的中间体M-12,后者经氯化亚锡还原硝基,再与丙烯酰氯反应得到目标化合物B-1。该系列其它目标化合物的合成步骤和方法,与目标化合物B-1的合成类似。化合物B-1经手性分离(AD-H手性柱;流动相:异丙醇/正己烷,40/60;流速:0.5mL/min.),得到具有光学活性的两个对映异构体(-)B-1a(保留时间:24.6分)和(+)B-1b(保留时间:27.0分)。化合物B-1的手性分离也可以用其它手性柱,如Y352546进行分离。
所述新型含有手性亚砜基团的苯胺基嘧啶衍生物,其对肿瘤细胞、特别是对ALK异常表达如基因突变、重排,扩增的人类恶性肿瘤,及EGFR基因T7900M突变的非小细胞肺癌细胞有优异的抑制增殖效果,显著优于文献报道的含硫酰基的基团的嘧啶衍生物。
本发明还提供上述新型手性亚砜基团的苯胺基嘧啶衍生物(新型亚磺酰基苯胺基的嘧啶衍生物)的药学上可接受的盐,即新型手性亚砜基团的嘧啶衍生物和药学上可接受的阴离子,如氯离子,甲磺酸根离子等形成相应的盐类,采用公知的成盐方法制备得到。
上述新型手性亚砜基团的苯胺基嘧啶衍生物在制备抗肿瘤药物中的应用,是以这类化合物为活性成分,有效地治疗肿瘤。
上述新型手性亚砜基团的苯胺基嘧啶衍生物以药用的溶剂化物的形式使用,所述溶剂化物优选水合物。
本发明还提供一种用于治疗肿瘤的药物组合物,其中含有治疗有效量的上述新型手性亚砜基团的苯胺基嘧啶衍生物和药学上可接受的辅助剂。所述药物组合物可以制成注射剂、片剂、胶囊剂、丸剂、悬浮剂或乳剂的形式使用;其给药途径可为口服、经皮、静脉或肌肉注射。
与现有技术相比,本发明的有益效果是:
(1)本发明中含有亚砜基团的苯胺基嘧啶衍生物,通过细胞水平上的抗肿瘤活性实验(L858R/T790M突变基因的非小细胞肺癌H1975肿瘤细胞,ALK高表达的BaF3细胞)证明,与现有ALK抑制剂及EGFR/ALK双靶点参照物相比,有更加良好的抗肿瘤活性。
(2)通过人肝微粒体实验证明,本发明中含有亚砜基团的苯胺基嘧啶衍生物与文献中含有异丙硫酰基的苯胺基嘧啶衍生物相比,稳定性有较大幅度的提高。
附图说明
图1为化合物B3a(P1)和B3b(P2)的裸鼠移植瘤抗肿瘤实验(以L858R/T790M突变的非小细胞肺癌H1975肿瘤细胞建模)结果。图1中A图为试验期间各组裸鼠肿瘤体积的变化情况;B图用柱状图表示了各组裸鼠肿瘤体积在给药后的变化情况;C图为试验结束后各组裸鼠肿瘤的重量及抑瘤率;D图表示试验期间各组裸鼠的重量变化情况。
图2为体内抗肿瘤实验图。
具体实施方式
下面对本发明的具体实施方式作进一步说明。在此需要说明的是,对于这些实施方式的说明用于帮助理解本发明,但并不构成对本发明的限定。此外,下面所描述的本发明各个实施方式中所涉及的技术特征只要彼此之间未构成冲突就可以相互组合。
实施例1:化合物A-1的合成。
(1)中间体M-1的合成
2-氨基苯硫酚(10mmol,1.25g)溶于甲醇20ml,依次加入氢氧化钾固体(20mmol,5.6g),溴乙烷(12mmol,1.3g)常温搅拌过夜。TLC点板确定反应完毕后,旋干除去甲醇,加入二氯甲烷30ml,水15ml,萃取两次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩后得粗产品中间体-1,直接投下一步使用。1H NMR(400MHz,Chloroform-d)δ7.41(dd,J=7.6,1.3Hz,1H),7.14(td,J=8.0,1.5Hz,1H),6.80–6.62(m,2H),4.37(s,2H),2.79(q,J=7.3Hz,2H),1.26(t,J=7.3Hz,3H).
(2)中间体M-2的合成
中间体M-1(10mmol,1.53g)溶于5ml冰醋酸中,冰浴下缓慢滴加30%的过氧化氢溶液(1.25g,11mmol),冰浴搅拌30分钟后,室温下反应4~5小时后,TLC点板确定反应完毕。将3.5g氢氧化钠溶于碎冰后加入反应体系,搅拌5分钟。混合物用二氯甲烷30ml萃取两次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥。减压除去溶剂,硅胶柱层析纯化,石油醚:乙酸乙酯=8:1到2:1进行洗脱,浓缩后得淡黄色油状物1.56g。产率:92%。1H NMR(400MHz,DMSO-d6)δ7.27(d,J=7.9Hz,1H),7.20(t,J=7.8Hz,1H),6.71(dd,J=18.1,8.1Hz,2H),5.63(s,2H),2.94(tq,J=13.2,6.6Hz,2H),1.06(t,J=7.6Hz,3H).
(3)中间体M-3的合成
将上一步反应得到的中间体2-(乙基)亚磺酰基苯胺(10mmol,1.7g)溶于的干燥DMF(30mL),冰浴下加入60wt%氢化钠(25mmol,1g,2.5eq),搅拌15分钟。缓慢滴加入2,4,5-三氯嘧啶(20mmol,3.62g)的干燥DMF(10mL)溶液,1小时内滴完,撤去冰浴常温反应过夜。TLC检测反应完毕,慢慢加入水30mL淬灭反应,乙酸乙酯萃取3次,每次30ml,合并有机相,水洗,饱和食盐水洗涤,无水硫酸钠干燥,浓缩得粗产物,硅胶柱层析纯化(石油醚:乙酸乙酯=10:1到4:1),得淡黄色固体产物1.92g。产率:61%。1H NMR(400MHz,Chloroform-d)δ11.03(s,1H),8.62(d,J=8.5Hz,1H),8.25(d,J=1.3Hz,1H),7.58(t,J=7.9Hz,1H),7.31(dd,J=7.7,1.7Hz,1H),7.19(t,J=7.5Hz,1H),3.29–2.81(m,2H),1.27(td,J=7.6,1.2Hz,3H).
(4)中间体M-4的合成
在含有1-氯-5-氟-2-甲基-4-硝基苯(20mmol,3.78g)的异丙醇溶液(25ml)中,加入碳酸铯(30mmol,9.77g),加热回流10小时。TLC检测反应完毕,减压浓缩除去溶剂,残余物加入二氯甲烷(30ml)和水(20ml)萃取,合并萃取2次的有机相,饱和食盐水洗涤,无水硫酸钠干燥。除去溶剂得到橙色固体产物3.8g。产率:83%.1H NMR(400MHz,Chloroform-d)δ7.72(d,J=7.5Hz,1H),7.09(d,J=7.9Hz,1H),4.63(dt,J=13.8,6.1Hz,1H),2.36(d,J=7.9Hz,3H),1.41(t,J=7.0Hz,6H).
(5)中间体M-5的合成
将上一步产物1-氯-5-异丙氧基-2-甲基-4-硝基苯(10mmol,2.29g)溶于30ml1,4-二氧六环中,依次加入碳酸钾固体(25mmol,3.46g),双三苯基膦二氯化钯(210.6mg,0.3mmol),4-吡啶硼酸(12mmol,1.48g),水10ml。反应在氮气保护下回流反应8小时,TLC检测反应完毕后,减压浓缩除去溶剂。残余物加入水15ml,二氯甲烷40ml萃取,合并3次的萃取液,饱和食盐水洗涤,无水硫酸钠干燥。减压除去溶剂,粗产物硅胶柱层析纯化(石油醚:乙酸乙酯:二氯甲烷/8:2:1)洗脱,得黄色固体2.55g。产率:93%。1H NMR(400MHz,Chloroform-d)δ8.61(d,J=6.1Hz,2H),7.27(d,J=6.1Hz,2H),6.68(d,J=18.5Hz,2H),4.53(p,J=6.0Hz,1H),2.21(s,3H),1.38(d,J=6.1Hz,6H).
(6)中间体M-6的合成
将上一步产物2-异丙氧基-4-吡啶基-5-甲基硝基苯(10mmol,2.72g),溶于15ml乙腈中,加入碘甲烷(15mmol,2.15g),50℃反应3小时,TLC确定反应完毕后,减压除去溶剂后粗产物直接进行下一步反应。粗产物溶于甲醇20ml,冰浴下分批每次少量的加入硼氢化钠(40mmol,1.51g),搅拌反应半小时,室温下继续反应2小时。在反应体系中加入饱和氯化铵淬灭反应,减压除去溶剂,残余物加入二氯甲烷30ml,水30ml萃取。合并3次萃取液,饱和食盐水洗涤,无水硫酸钠干燥。减压除去溶剂,粗产物柱层析纯化(二氯甲烷:甲醇=50:1到20:1得淡黄色油状产物2.1g。产率:72%.1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),6.81(s,1H),5.60(s,1H),4.59(dq,J=12.1,6.2Hz,1H),3.10(q,J=2.8Hz,2H),2.66(t,J=5.6Hz,2H),2.41(d,J=16.5Hz,4H),2.24(s,3H),1.64(s,1H),1.36(d,J=6.0Hz,6H).
(7)中间体M-7的合成
上一步产物(5mmol,1.45g)溶于甲醇5ml中,加入10%钯炭(150mg),于反应釜压力为45psi,50℃条件下氢化反应24小时。降至室温,硅藻土抽滤除去钯炭,无水乙醇10ml润洗抽滤硅藻土两次,抽滤液旋干,硅胶柱层析纯化得无色油状物。1H NMR(400MHz,Chloroform-d)δ6.73(s,1H),6.53(s,1H),4.44(p,J=6.1Hz,1H),3.62(s,2H),2.98(d,J=11.5Hz,2H),2.60(p,J=8.1,7.6Hz,1H),2.34(s,3H),2.21(s,3H),2.07(dd,J=15.0,11.2Hz,2H),1.83–1.64(m,4H),1.33(d,J=6.1Hz,6H).
(8)目标物A-1的合成
取中间体-7(1mmol,262mg)溶于异丙醇10ml中,加入中间体M-3(2mmol,630mg),三氟乙酸(2mmol),加热回流反应8小时。TLC检测反应完毕。浓缩除去异丙醇,10%氢氧化钠溶液调pH至10,二氯甲烷(30ml)萃取三次。合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,残余物硅胶柱层析纯化(乙酸乙酯:石油醚=1:2到3:1)得到淡黄色固体。1H NMR(400MHz,Chloroform-d)δ9.98(s,1H),8.53–8.35(m,1H),8.00(d,J=37.2Hz,2H),7.57–7.36(m,2H),7.32(d,J=7.6Hz,1H),7.09(t,J=7.5Hz,1H),6.72(s,1H),4.50(dq,J=12.1,6.0Hz,1H),3.26(d,J=9.9Hz,2H),3.17–2.93(m,2H),2.74–2.58(m,1H),2.45(s,3H),2.34(t,J=12.2Hz,2H),2.08(s,3H),1.91(d,J=12.0Hz,2H),1.73(t,J=12.9Hz,2H),1.29(d,J=6.0Hz,6H),1.17(t,J=7.5Hz,3H).
实施例2:目标产物A-2的合成
(1)中间体M-8的合成
将中间体-4(1-氯-5异丙氧基-2-甲基-4-硝基苯,10mmol,2.29g)溶于30ml1,4-二氧六环,依次加入碳酸钾固体(25mmol,3.46g),双三苯基膦二氯化钯(210.6mg,0.3mmol),1-Boc-(11mmol,3.4g),水10ml。氮气保护下回流反应8小时。TLC检测反应完毕后,减压除去溶剂,残余物用二氯甲烷40ml,水15ml萃取3次,合并萃取液,饱和食盐水洗涤,无水硫酸钠干燥。减压除去溶剂。残余物硅胶柱层析纯化(石油醚:乙酸乙酯:二氯甲烷=8:2:1)得白色固体3.1g。产率;82%。1H NMR(400MHz,Chloroform-d)δ7.61(s,1H),6.79(s,1H),5.62(s,1H),4.62(p,J=6.1Hz,1H),4.07(s,2H),3.64(t,J=5.6Hz,2H),2.33(s,2H),2.24(s,3H),1.51(s,9H),1.38(d,J=6.1Hz,6H).
(2)目标产物A-2的合成
中间体M-8(5mmol,1.88g)溶于甲醇(5ml)中,加入10%钯炭(190mg),在反应釜内压力为45psi,50℃条件下氢化反应24小时。降至室温,硅藻土抽滤除去钯炭,无水乙醇10ml润洗抽滤硅藻土两次,抽滤液旋干,硅胶柱层析纯化得无色油状物。
取上述无色油状产物(1mmol,350mg)溶于异丙醇10ml,加入中间体M-3(2mmol,630mg),三氟乙酸(2mmol),加热回流反应8小时,TLC检测,反应完毕浓缩除去异丙醇,二氯甲烷30ml萃取。萃取液经无水硫酸钠干燥。减压浓缩,硅胶柱层析纯化(乙酸乙酯:石油醚=1:2到3:1)得到淡黄色固体。1H NMR(400MHz,Chloroform-d)δ10.06(s,1H),8.54(d,J=8.3Hz,1H),8.08(d,J=36.3Hz,2H),7.57–7.33(m,3H),7.16(t,J=7.5Hz,1H),6.80(s,1H),4.54(p,J=6.0Hz,1H),3.13(ddd,J=43.9,12.9,7.4Hz,4H),2.77(ddt,J=11.2,6.0,2.9Hz,3H),2.18(s,3H),1.75(d,J=9.4Hz,5H),1.36(d,J=6.1Hz,6H),1.26(t,J=7.5Hz,3H).
本系列其它目标化合物的合成与于实施例1和实施例2类似。其中,中间体M-1的氘代物,邻-氨基苯基氘代乙基硫醚,由对-甲基苯磺酸氘代乙酯与氨基硫酚反应得到。A系列化合物的结构式和谱图数据列于表1中。
表1含有手性亚砜结构的ALK抑制剂的合成
ALK/EGFR双靶点抑制剂的合成步骤以化合物B-1的合成为例进行说明。实施例3:ALK/EGFR双靶点抑制剂B-1的合成
(1)中间体M-9的合成
在50mL圆底烧瓶中,加入2-氨基-5-氟苯乙基硫醚(10mmol,1.76g),冰醋酸(6mL),30%H2O2(12mmol,1.36g)。反应混合物在0℃下搅拌3小时,TLC检测原料后,用1M的氢氧化钠溶液淬灭反应,乙酸乙酯提取3次。合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,除去溶剂,剩残余物经硅胶柱层析得中间体M-9.油状液体,87%产率。1H NMR(400MHz,CDCl3)δ7.05–6.89(m,2H),6.72–6.53(m,1H),4.74(s,2H),3.40–2.94(m,2H),1.22(t,J=7.5Hz,3H).。Ms(M+1),192。
(2)中间体M-10的合成
在含有中间体M-9(5mmol,0.96g,5mmol)的DMF溶液(12mL)中,加入氢化钠(10mmol,0.4g,60%)。0℃下搅拌30分钟,慢慢滴加2,4,5-三氯嘧啶(7.5mmol,1.37g)的DMF溶液10mL。反应体系升至室温搅拌12小时后,倒入适量冰水。乙酸乙酯提取3次。合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,减压浓缩,粗产物经硅胶柱层析得中间体M-10.无色固体。产率:60%。1H NMR(400MHz,CDCl3)δ10.68(s,1H),8.57(dd,J=9.3,4.7Hz,1H),8.24(s,1H),7.33–7.27(m,1H),7.07(dd,J=7.2,3.0Hz,1H),3.33–2.89(m,2H),1.29(t,J=7.5Hz,3H)。
(2)中间体M-11的合成
在含有中间体M-10(1mmol,332mg)及4-氟-2-甲氧基-5-硝基苯胺(1.1mmol,205mg)的正丁醇(12mL)溶液中,滴加浓盐酸(3mmol,0.248mL)。80℃搅拌反应6小时,冷至室温,浓缩经硅胶柱层析纯化得中间体M-11,淡黄色固体。产率,65%。1H NMR(400MHz,CDCl3)δ11.59(s,1H),10.58(s,1H),8.59(d,J=7.7Hz,1H),8.17(dd,J=9.0,4.5Hz,1H),7.94(s,1H),7.22–7.05(m,2H),6.82(d,J=11.9Hz,1H),4.06(s,3H),3.13(d,J=11.0Hz,2H),1.32(t,J=7.3Hz,3H)。
(3)中间体M-12的合成
在含有中间体M-11(1mmol,483mg)的二氧六环溶液中,加入N,N-二异丙基-N-乙基胺(3mmol,388mg),及N,N.N-三甲基乙二胺(1.5mmol,153mg)。反应在100℃搅拌2小时,TLC检测反应。反应结束后浓缩,残余物经硅胶柱纯化(CH2Cl2/MeOH,40:1)得中间体M-11.红色固体。产率:72%。1H NMR(400MHz,CDCl3)δ9.62(s,1H),8.63(s,1H),8.25(dd,J=9.1,4.7Hz,1H),8.12(s,1H),7.30(s,1H),7.25–7.12(m,2H),6.64(s,1H),3.94(s,3H),3.31–3.18(m,2H),3.17–2.98(m,2H),2.85(s,3H),2.53(dd,J=7.7,6.4Hz,2H),2.25(s,6H),1.25(t,J=7.5Hz,3H).
(5)目标产物B-1的合成
在含有中间体M-12(1mmol,566mg)的二氯甲烷(8mL)/甲醇(8mL)的混合液中,加入二水二氯化锡(10mmol,2.11g),搅拌下滴加浓盐酸(2.1mL)。反应混合物在50℃下搅拌5小时,氨水调pH至5后再用碳酸钠调pH至7。硅藻土过滤,滤液浓缩干燥后直接进行下一步反应。
将上一步的粗产物溶于无水二氯甲烷(10mL),加入N,N-二异丙基-N-乙基胺。0℃,氮气保护下加入丙烯酰氯(1.1mmol,100mg)。30分钟后,加入饱和碳酸氢钠溶液淬灭反应,二氯甲烷提取,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥。减压浓缩后残余物经经硅胶柱纯化(CH2Cl2/MeOH,30:1)得目标产物B-1.无色固体。产率:60%。1H NMR(400MHz,CDCl3)δ10.05(s,1H),9.50(s,1H),9.13(s,1H),8.34(dd,J=9.1,4.8Hz,1H),8.14(s,1H),7.29(s,1H),7.11–6.97(m,2H),6.75(s,1H),6.26(s,2H),5.72–5.54(m,1H),3.84(s,3H),3.23–3.02(m,2H),2.87(s,2H),2.69(s,3H),2.29(s,8H),1.28(t,J=7.5Hz,3H).13C NMR(125MHz,CDCl3)δ163.19,159.38,157.71,155.76,155.29,145.42,136.65,135.80,132.22,130.70,126.93,126.09,118.74,118.51,113.72,113.47,105.91,104.58,57.34,56.09,47.66,45.38,43.56,7.52.HRMS(ESI)m/z):[M+H]+calculated for C27H33N7O3FSCl,590.2111;found,590.2124.Purity:99.9%(by HPLC).
消旋体化合物B-1经手性HPLC(手性柱:Y352546,流动相:正己烷(0.1%二乙胺):乙醇=75:25,V/V)分离得两个对映异构体B-1a和B-1b。本系列其它目标物的合成步骤和方法,和目标化合物B-1类似,其结构和谱图如表2所示。
表2含有手性亚砜结构的ALK/EGFR双靶点抑制剂的合成
抗肿瘤活性测试例:含有手性亚砜基团的嘧啶衍生物的抗肿瘤活性
对于本发明的新型含有手性亚砜基团嘧啶衍生物的抗肿瘤细胞活性测试,我们选择EGFR高表达的非小细胞肺癌细胞H1975和细胞Pc9及ALK高表达的H2228,BaF3细胞进行了MTT法抗肿瘤细胞增殖活性的评估。具体操作步骤如下:将肿瘤细胞按一定的细胞量接种在96孔培养板内,细胞密度为5*103~1*104个/孔,在37℃,二氧化碳浓度为5%的培养箱中过夜后,加入待测化合物样品。培养72小时后,加入MTT继续4小时,加入DMSO溶解,震摇,然后在酶标仪(570nm)下进行检测。上述化合物对非小细胞肺癌细胞H2228(ALK),H1975和Pc9等细胞的半数抑制浓度IC50值如表3所示。
表3.ALK抑制剂的体外抗肿瘤测试
*化合物A-1a和化合物A-1b由化合物A1经HPLC手性分离得到(AD-H柱,流动相:异丙醇/正己烷,40/60,流速:0.5mL/min);A-1a(保留时间:9.72分钟);A-1b(保留时间:12.45分钟)。化合物A-2a,A-2b等的分离条件与A-1a和A-1b相似。
表4.EGFR/ALK目标化合物的体外抗肿瘤测试(IC50μM)
*化合物7c为文献中最优化合物(European Journal of MedicinalChemistry2017,136,497-510)。
化合物B系列的手性异构体由其消旋体经手性分离得到。例如,化合物B-3经手性分离(AD-H手性柱;流动相:异丙醇/正己烷,40/60;流速:0.5mL/min.),得到具有光学活性的两个对映异构体(-)B-3a(保留时间:24.6分)和(+)B-3b(保留时间:27.0分)。其它化合物的手性分离情况类似。
抗肿瘤活性测试例:化合物的肝微粒体稳定性试验
对第二轮筛选的化合物进行了人肝微粒体的稳定性实验,结果说明,化合物的分子结构对稳定性影响很大。其中,含氘原子或含氟原子的化合物B1,B2等乙基或氘代烷基与亚硫酰基相联的化合物表现出良好的肝微粒体稳定性。
表5部分目标化合物的肝微粒体稳定性试验
化合物名称 | T<sub>1/2</sub> | CL(μL/min/mg) |
Verapamil | 28.0 | 123.7 |
化合物B1 | 223.3 | 15.5 |
化合物B2 | 161.8 | 21.4 |
化合物B4 | 125.2 | 27.7 |
化合物B5 | 50.5 | 68.7 |
化合物B6 | 26.3 | 131.9 |
化合物B7 | 32.3 | 107.2 |
化合物B8 | 49.1 | 70.5 |
化合物B9 | 31.9 | 108.7 |
化合物B10 | 37.7 | 92.0 |
化合物B11 | 52.0 | 66.7 |
体内抗肿瘤实验的研究测试例
实验动物BALB/c裸鼠(5周龄,18-20g),雄性SPF级,购于北京维通利华实验动物技术有限公司。取培养至3-5代的对数期生长的EGFR双突变高表达的H1975细胞,经胰酶消化后用不含血清的培养基配制成1.0×107个/ml浓度的细胞悬液。用注射器在右侧皮下注射H1975细胞悬液,细胞接种体积为0.1ml/只。待成瘤后,用游标卡尺测量移植瘤直径,肿瘤长至1000mm3,脱颈处死小鼠,剥离出肿瘤组织块,将肿瘤块剪成大小均一,约4-6mm3的组织块,皮下接种于裸小鼠右肢偏腋窝处,将动物按体重和肿瘤体积随机分为阴性对照组和给药组,给药组分为4组,B3经手性分离得到两个对映异构体B3a和B3b(下图中用(-)-P1和(+)-P2代表)按20mg/kg给药各一组,B3a的给药量为40mg/kg一组,另一组用美国FDA批准治疗非小细胞肺癌第三代靶向药物奥西替尼为阳性对照。在肿瘤体积达到200mm3左右,灌胃给药,持续给药一周。阴性对照组给等量生理盐水。给药时用游标卡尺测量肿瘤组织的长径和短径,记录小鼠体重。
观察指标:肿瘤体积TV=1/2×a×b2(其中a、b分别表示长、宽)
TGI=(TW阴性对照-TW治疗组)/TW阴性对照×100%,TW值为平均瘤重。体内抗肿瘤实验结果如图2所示。
结果显示两个对映异构体B3a和B3b,有较好的抗肿瘤效果,给药量为20mg/kg时,给药后1-2天就有明显肿瘤生长抑制效果,肿瘤体积没有增长,且呈明显下降趋势。用药7天后肿瘤完全得到抑制,手性化合物B1a【(-)-P1】,的抑瘤率达到90%以上。其对映异构体B3b【(+)P2】的抑瘤率达到95%以上,与B3a的40mg/kg给药量效果相当。在整个给药过程中,各组小鼠的体重无明显变化,小鼠的行为无异常。
按照同样的方法,我们用ALK高表达的H2228肿瘤细胞建模,进行化合物B3a和B3b的裸鼠体内抗肿瘤实验。结果显示,化合物B3a和B3b在给药后都可以使肿瘤体积下降,肿瘤抑制率TGI分别为75.3%和85.9%。在整个给药过程中,各组小鼠的体重无明显变化,小鼠的行为也无异常。
以上对本发明的实施方式作了详细说明,但本发明不限于所描述的实施方式。对于本领域的技术人员而言,在不脱离本发明原理和精神的情况下,对这些实施方式进行多种变化、修改、替换和变型,仍落入本发明的保护范围内。
Claims (10)
2.根据权利要求1所述新型亚磺酰基苯胺基的嘧啶衍生物,其特征在于,R1为含有1个到4个碳原子直链烷基,且直链烷基上的氢原子可被1个到4个碳原子烷基取代。
3.根据权利要求2所述新型亚磺酰基苯胺基的嘧啶衍生物,其特征在于,当R1上的氢原子被1个到4个碳原子烷基取代时,碳原子上连接氢或氢的同位素氘。
4.根据权利要求1所述新型亚磺酰基苯胺基的嘧啶衍生物,其特征在于,卤素原子为氟或氯。
5.根据权利要求1所述新型亚磺酰基苯胺基的嘧啶衍生物,其特征在于,R1为-CD(CD3)2、环丙烷基、环丙甲基、异丙基、乙基、-CD2CD3;R2,R3和R4分别为卤素原子,含碳数1-2的链状烷基;R5为甲基、乙基或异丙基;R7为哌啶基、N-甲基哌啶基或N,N,N-三甲基乙二氨基。
6.一种ALK抑制剂,其特征在于,包含权利要求1所述亚磺酰基苯胺基的嘧啶衍生物。
7.一种ALK和EGFR双靶点抑制剂,其特征在于,包含权利要求1所述亚磺酰基苯胺基的嘧啶衍生物。
8.根据权利要求7所述ALK和EGFR双靶点抑制剂,其特征在于,R6是丙烯酰胺基时,包含权利要求1所述亚磺酰基苯胺基的嘧啶衍生物制备成ALK和EGFR双靶点抑制剂。
9.权利要求1所述亚磺酰基苯胺基的嘧啶衍生物在制备抗癌药物中的应用。
10.根据权利要求9所述的应用,其特征在于,是在制备抗肺腺癌、肺癌药物中的应用。
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