CN112608331A - 中间体及其在合成sting蛋白激动剂化合物中的应用 - Google Patents
中间体及其在合成sting蛋白激动剂化合物中的应用 Download PDFInfo
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Abstract
本公开提供一种化合物,以及其制备方法及作物STING蛋白激动剂化合物中间体的应用。
Description
本申请为分案申请,其母案的中国专利申请申请号为201980005220.4,母案申请日为2019年08月22日。
本申请要求以下专利申请的优先权:(1)发明名称为“一种高活性STING蛋白激动剂”于2018年8月29日提交到中国专利局的中国专利申请201810996231.0的优先权,和(2)发明名称为“一种高活性STING蛋白激动剂”于2018年11月23日提交到中国专利局的中国专利申请201811407028.1的优先权,其内容均通过引用以整体并入本文。
技术领域
本发明涉及一种杂环化合物,具体地涉及一种高活性的STING蛋白激动剂及其用途。
背景技术
免疫治疗的阳性反应通常依赖于肿瘤细胞与肿瘤微环境(TME)内免疫调节的相互作用。在这些相互作用下,肿瘤微环境在抑制或增强免疫应答中发挥着重要的作用。认识免疫治疗与TME间的相互作用不仅是剖析作用机制的关键,也为改善目前免疫治疗的疗效提供了新的方法。细胞因子是可以调节免疫应答的一大类蛋白质,可以直接激活免疫效应细胞或刺激肿瘤基质细胞,以致为淋巴细胞的募集产生的趋化因子和粘附分子。这些功能表明根据不同的肿瘤微环境,针对细胞因子也可以是肿瘤免疫治疗的一种有效途径。
STING(干扰素基因刺激蛋白)是目前肿瘤免疫治疗领域药物研发中最新最热的免疫治疗靶点。干扰素基因刺激蛋白是一种跨膜蛋白,通常在152-173位区域交接形成二聚体并处于自我抑制状态。当受到部分配体的刺激后分子构型发生变化并被激活,招募细胞质中的TANK结合激酶1,介导TBK1对IRF3的磷酸化,导致干扰素-β和其它多种细胞素的形成。IFNβ的产生是STING活化的标志。肿瘤微环境天然免疫的信号传导是肿瘤特异性T细胞的激活和肿瘤浸润性淋巴细胞浸润的关键步骤。其中I型IFN对肿瘤激活的T细胞活化起着关键作用。这样,STING不仅诱导I型干扰素基因的表达,在天然免疫信号通路中起着重要作用;STING激动剂能激活包括树突状细胞等免疫刺激细胞,改变肿瘤微环境并诱导了肿瘤特异性T细胞的产生。在鼠科动物实验中,一种黄酮类血管破坏剂DMXAA通过激活鼠源STING蛋白,诱导IFN-β和其它天然细胞素的产生,并有效地抑制多种实体肿瘤的生长。但是该药在一个人体非小细胞临床实验中和标准化疗联合使用未能观察到明显疗效。后来实验证实,尽管人源和鼠源STING蛋白的相似度高达81%,前者基因编码379个氨基酸,后者基因编码378个氨基酸,但DMXAA却无法激活人源STING蛋白。环二核苷酸是到目前为止发现的唯一一类既能直接激活鼠源又能激活人源STING蛋白的STING激动剂。直接把CDN注射到B16黑色素瘤、CT26直肠癌、和4T1乳腺癌肿块,不仅导致明显的抑制作用直至肿瘤消失,同时也诱导系统的持久性抗原特异性T细胞免疫,造成动物其它部位未注射药物的肿瘤生长也受到抑制。MLRR-S2CDA引起多种实体肿瘤微环境的改变,激活有效的肿瘤引发的CD8+T细胞和持久的疗效。近年来大量的研究报道表明STING通路能有效地启动机体的天然免疫系统,是至今为数不多的、经多方验证能诱导产生细胞因子干扰素的信号传导通路,该通路在天然免疫中至关重要。淋巴细胞充分浸润到肿瘤组织是免疫治疗成功的关键。该作用靶点通路的激活也促进肿瘤微环境中效应T细胞的浸染及应答,因此该靶点逐渐成为是抗肿瘤治疗尤其是免疫治疗研究的重要靶标。在多个小鼠接种模型中对多种难治症、转移性实体肿瘤有效,不仅直接注射的肿瘤消失,其它部位生长的肿瘤生长也受到明显抑制,甚至还可以预防肿瘤的发生。
发明内容
本发明提供了一种中间体化合物,其具有如下结构:
除此之外,本发明还提供了一种上述中间体的化合物的制备方法,其特征在于包括以下步骤:
除此之外,本发明还提供了一种上述化合物作为中间体在制备STING蛋白激动剂化合物中的应用。
具体实施例
当未包括制备途径时,相关中间体是市售的(例如来自Sigma Aldrich,Alfa)。
通用过程
使用市售试剂而不需进一步纯化。室温是指20-27℃。1H-NMR谱在Bruker仪器上于500MHz记录。化学位移值以百万分率表示,即δ值。以下简写用于NMR信号的多重性:s=单峰,brs=宽峰,d=二重峰,t=三重峰,m=多重峰。耦合常数以J值列出,以Hz测量。NMR和质谱结果根据背景峰校正。色谱是指使用100筛目硅胶进行并在氮气压力(快速色谱)条件下完成的柱色谱。用于监测反应的TLC指使用特定流动相和来自Merck的硅胶F254作为固定相进行的TLC。
实施例1
化合物1由以下步骤制备:
第一步:将N-叔丁氧羰基-N’-苄氧羰基-L-鸟氨酸1a(25g,68mmol),三乙胺(11.5mL,81.9mmol)溶于四氢呋喃(100mL)中,在冰浴条件下滴加氯甲酸异丁酯(10mL,79mmol),冰浴下搅拌半小时,依次加入硼氢化钠(7.8g,205mmol),水(3mL,缓慢滴加),继续在冰浴下搅拌2小时。LCMS监测反应结束,加水(150mL)淬灭,用乙酸乙酯萃取水相(150mL*3),合并有机相,无水硫酸钠干燥,过滤,浓缩得到化合物1b(20g),无色油状液体,产率83%。ESI-MS(m/z):353.6[M+H]+;1HNMR(500MHz,DMSO-d6)δppm7.39-7.25(m,5H),7.19(t,J=5.2Hz,1H),6.43(d,J=8.3Hz,1H),4.98(s,2H),4.53(t,J=5.4Hz,1H),3.30-3.07(m,2H),2.94(dd,J=12.4,6.4Hz,2H),1.57-1.39(m,2H),1.35(s,9H),1.23-1.12(m,2H)。
第二步:将化合物1b(20g,56mmol)溶于二氯甲烷(200mL)中,加入氯化氢-1,4二氧六环溶液(4N,70mL,280mmol),室温搅拌过夜。LCMS监测反应结束,反应液浓缩得到化合物1c(13g),无色油状液体,产率93%。ESI-MS(m/z):253.6[M+H]+。
第三步:将3-氟-4-羟基苯甲腈1d(13.7g,100mmol)溶于浓硫酸(200mL)中,冰浴下滴加硝酸(50mL),反应混合物在冰浴下搅拌三小时,LCMS监测反应结束,将反应混合物缓慢倒入冰水中,用乙酸乙酯取水相(300mL*3),合并有机相,无水硫酸钠干燥,过滤,浓缩得到化合物1e(15g),棕色固体,产率82%。1H NMR(500MHz,DMSO-d6)δppm 8.29(s,1H),8.12(d,J=10.4Hz,1H)。
第四步:将化合物1e(15g,82mmol)溶于二氯甲烷(100mL)中,冰浴下滴加草酰氯(13.7mL,163mmol),反应混合物在冰浴下搅拌30分钟后升至80℃搅拌两小时。LCMS监测反应结束,将反应混合物倒入冰水中,用乙酸乙酯取水相(250mL*3),合并有机相,无水硫酸钠干燥,过滤,浓缩得到化合物1f(11.3g),黄色固体,产率69%。1H NMR(500MHz,DMSO-d6)δppm 8.62(s,1H),8.50(dd,J=8.8,1.6Hz,1H)。
第五步:取化合物1f(5g,25mmol)溶于N,N-二甲基甲酰胺(20mL)中,依次加入化合物1c(13g,51mmol)和碳酸钾(6.9g,50mmol)。反应混合物在60℃下搅拌过夜。LCMS监测反应结束,加水(100mL),用乙酸乙酯萃取水相(150mL*3),有机相合并后通过硅胶柱层析分离得到化合物1g(6.1g),黄色油状液体,产率57%。ESI-MS(m/z):417.6[M+H]+。
第六步:将化合物1g(6g,14mmol)溶于N,N-二甲基甲酰胺(15mL)中,加入碳酸铯(9.2g,28mmol)。反应混合物在60℃下搅拌2小时,LCMS监测反应结束,加水(100mL),用乙酸乙酯萃取水相(150mL*3),有机相合并后通过硅胶柱层析分离得到化合物1h(4.7g),黄色固体,产率82%。ESI-MS(m/z):397.7[M+H]+;1H NMR(500MHz,DMSO-d6)δppm 8.88(s,1H),8.12(s,1H),7.38(s,1H),7.36-7.19(m,6H),4.97(s,2H),4.10(dd,J=23.9,10.9Hz,2H),3.72(s,1H),3.01(s,2H),1.67-1.52(m,4H)。
第七步:将化合物1h(4.7g,11.8mmol)溶于甲醇(100mL)中,加入氨水(20mL)。再取连二亚硫酸钠(10g,57mmol)溶于20mL水中,室温下缓慢加入反应液后,继续室温搅拌半小时。LCMS监测反应结束,向反应混合物中加水(200mL),用乙酸乙酯萃取水相(200mL*3),有机相合并后,无水硫酸钠干燥,过滤,浓缩得到化合物1i(3.8g),淡黄色固体,产率87%。ESI-MS(m/z):367.7[M+H]+;1H NMR(500MHz,DMSO-d6)δppm 7.42-7.23(m,6H),6.45(dd,J=11.9,1.8Hz,2H),5.45(d,J=1.6Hz,1H),5.01(s,2H),4.99(s,2H),4.07(dd,J=10.5,2.5Hz,1H),3.71(dd,J=10.5,6.3Hz,1H),3.34(dd,J=5.9,2.8Hz,1H),3.01(dd,J=12.2,6.2Hz,2H),1.63-1.29(m,4H)。
第八步:将化合物1i(3.8g,10mmol)溶于甲醇(60mL)中,加入溴化氰(5.4g,51mmol),60℃下搅拌过夜。LCMS监测反应结束后,浓缩反应液,加入乙酸乙酯(150mL)和饱和碳酸钠水溶液(150mL),分层萃取,水相继续用乙酸乙酯(100mL)萃取两次,合并有机相,无水硫酸钠干燥,过滤,浓缩得到化合物1j(3.5g),淡黄色固体,产率86%。ESI-MS(m/z):392.6[M+H]+。
第九步:将化合物1j(3.5g,9mmol)于N,N-二甲基甲酰胺(20mL)中,加入氢氧化钠(1g,25mmol),冰浴下缓慢滴加30%双氧水(12mL),升至室温搅拌半小时,LCMS监测反应结束,向反应混合物中加水(100mL),用乙酸乙酯萃取水相(150mL*3),有机相合并后,无水硫酸钠干燥,过滤,浓缩得到化合物1k(2.8g),黄色固体,产率76%。ESI-MS(m/z):410.5[M+H]+。
第十步:将1-乙基-3-甲基吡唑-5-羧酸(1.6g,10.3mmol)溶于N,N-二甲基甲酰胺(8mL)中,依次加入HATU(3.9g,10.3mmol),HOBt(700mg,5.2mmol)和三乙胺(2.8mL,20mmol),反应混合物在室温下搅拌半小时。再加入化合物1k(2.8g,6.8mmol),混合物升至60℃下搅拌5小时。LCMS监测反应结束,向反应混合物中加水(40mL),用乙酸乙酯萃取水相(100mL*3),有机相合并后通过硅胶柱层析分离得到化合物1l(2.6g),白色固体,产率70%。ESI-MS(m/z):546.4[M+H]+;1HNMR(500MHz,DMSO-d6)δ12.71(s,1H),7.90(s,1H),7.57(s,1H),7.34-7.21(m,8H),6.62(s,1H),4.95(s,2H),4.66-4.53(m,4H),4.23(d,J=9.5Hz,1H),3.08-2.96(m,2H),2.15(s,3H),1.81-1.72(m,2H),1.62-1.52(m,2H),1.34(t,J=7.1Hz,3H)。
第十一步:将化合物1l(2.5g,4.6mmol)加入氢溴酸-醋酸溶液(50mL)中,室温搅拌半小时,LCMS监测反应结束,加入乙醚(50mL),过滤,再用乙醚(30mL*3)洗滤饼后,将滤饼干燥得到化合物1m(1.8g),白色固体,产率96%。白色固体,ESI-MS(m/z):412.6[M+H]+。
第十二步:取化合物1m(100mg,0.24mmol)溶于N,N-二甲基甲酰胺(2mL)中,依次加入化合物1n(144mg,0.5mmol),碳酸铯(160mg,0.5mmol)。反应混合物在70℃下过夜搅拌,LCMS监测反应结束后,向反应混合物中加水(20mL),用乙酸乙酯萃取水相(30mL*3),有机相合并后通过硅胶柱层析分离得到化合物1o(80mg),白色固体,产率50%。ESI-MS(m/z):664.6[M+H]+。
第十三步:将化合物1o(80mg,0.12mmol)溶于甲醇(10mL)中,加入氨水(4mL)。再取连二亚硫酸钠(105mg,0.6mmol)溶于水(1.5mL)中,室温下缓慢加入反应液后,继续搅拌半小时。LCMS监测反应结束,加水(25mL),用乙酸乙酯萃取水相(25mL*3),有机相合并后,无水硫酸钠干燥,过滤,浓缩得到化合物1p(41mg),白色固体,产率54%。ESI-MS(m/z):634.6[M+H]+。
第十四步:将化合物1p(41mg,0.06mmol)溶于甲醇(5mL)中,加入溴化氰(35mg,0.33mmol),60℃下搅拌过夜。LCMS监测反应结束后,浓缩反应液,加入乙酸乙酯(30mL),室温下搅拌半小时,过滤,滤饼用乙酸乙酯洗三次(30mL*3)后,干燥得到化合物1q(26mg),淡黄色固体,产率62%。ESI-MS(m/z):659.5[M+H]+。
第十五步:将1-乙基-3-甲基-吡唑-5-羧酸(10mg,0.06mmol)溶于N,N-二甲基甲酰胺(0.5mL)中,依次加入HATU(23mg,0.06mmol),HOBt(4mg,0.03mmol)和三乙胺(20mg,0.2mmol),反应混合物在室温下搅拌半小时。再加入化合物1q(26mg,0.04mmol),混合物升至60℃下搅拌3小时。LCMS监测反应结束,反应液用反相制备色谱提纯得到化合物1(10mg),白色固体,产率32%。ESI-MS(m/z):795.6[M+H]+;1HNMR(500MHz,DMSO-d6)δppm12.80(s,2H),7.95(d,J=30.3Hz,2H),7.61(d,J=28.0Hz,2H),7.32(d,J=14.5Hz,4H),6.52(d,J=42.9Hz,2H),4.85-4.04(m,12H),3.15(s,3H),2.11(s,3H),2.07(s,3H),2.04-1.80(m,7H),1.33-1.26(m,6H)。
实施例5
化合物5由以下步骤制备:
第一步:将化合物1m(200mg,0.45mmol)溶于N,N-二甲基甲酰胺(4mL)中,依次加入化合物5a(155mg,0.67mmol)和碳酸铯(326mg,1.00mmol)。反应混合物在70℃下搅拌过夜,LC-MS监测反应结束后,向反应混合物中加入水(100mL),水相用乙酸乙酯萃取(100mL*3),有机相合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,残留物通过硅胶柱层析分离得到化合物5b(130mg),白色固体,产率48%。ESI-MS(m/z):606.7[M+H]+。
第二步:将化合物5b(130mg,0.21mmol)溶于甲醇(8mL)中,加入氨水(2mL)。再取连二亚硫酸钠(190mg,1.10mmol)溶于水(2mL)中,室温下缓慢加入反应液后,继续搅拌半小时。LC-MS监测反应结束,加水(30mL),水相用乙酸乙酯萃取(50mL*3),有机相合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩得到化合物5c(70mg),白色固体,产率57%。ESI-MS(m/z):576.6[M+H]+。
第三步:将化合物5c(70mg,0.12mmol)溶于N,N-二甲基甲酰胺(2mL)中,加入5d(0.4N的1,4-二氧六环溶液,0.3mL,0.12mmol),室温搅拌0.5小时。加入N,N'-二环己基碳二亚胺(40mg,0.19mmol),反应混合物在80℃下搅拌过夜,LC-MS监测反应结束后,反应液用反相制备色谱提纯得到化合物5(22mg),白色固体,产率25%。ESI-MS(m/z):736.4[M+H]+;1HNMR(500MHz,DMSO-d6)δ12.69(br s,1H),7.97(s,1H),7.90(s,1H),7.66(s,1H),7.59(s,1H),7.37(s,1H),7.33(s,2H),7.28(s,1H),6.54(s.1H),6.52(s,1H),4.73(br s,1H),4.66-4.52(m,5H),4.46-4.36(m,1H),4.36-4.22(m,2H),3.88(s,3H),2.13-2.07(m,6H),2.03-1.96(m,2H),1.95-1.87(m,2H),1.34-1.26(m,6H)。
实施例6
化合物6由以下步骤制备:
第一步:取化合物1m(200mg,0.45mmol)溶于N,N-二甲基甲酰胺(4mL)中,依次加入化合物6a(260mg,0.67mmol),碳酸铯(326mg,1.00mmol)。反应混合物在70℃下搅拌过夜,LC-MS监测反应结束后,向反应混合物中加水(100mL),水相用乙酸乙酯萃取(100mL*3),有机相合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,残留物通过硅胶柱层析分离得到化合物6b(150mg),白色固体,产率52%。ESI-MS(m/z):650.6[M+H]+。
第二步:将化合物6b(150mg,0.23mmol)溶于甲醇(10mL)中,加入氨水(3mL)。再取连二亚硫酸钠(200mg,1.15mmol)溶于2mL水中,室温下缓慢加入反应液后,继续搅拌0.5小时。LC-MS监测反应结束,反应体系中加水(30mL),水相用乙酸乙酯萃取(50mL*3),有机相合并,用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩得到化合物6c(120mg),白色固体。ESI-MS(m/z):620.6[M+H]+。产物未进行进一步纯化,直接用于下一步反应。
第三步:将化合物6c(60mg,由第二步反应得到)溶于N,N-二甲基甲酰胺(2mL)中,加入5d(0.4N的1,4-二氧六环溶液,0.25mL,0.1mmol),室温搅拌半小时。加入N,N'-二环己基碳二亚胺(40mg,0.19mmol),反应混合物在80℃下过夜搅拌,LC-MS监测反应结束后,反应液用反相制备色谱HPLC纯化得到化合物6(20mg),白色固体,产率27%。ESI-MS(m/z):781.6[M+H]+;
1H NMR(500MHz,DMSO-d6)δ12.71(br s,2H),7.96(s,1H),7.89(s,1H),7.65(s,1H),7.59(s,1H),7.37(s,1H),7.33(s,1H),7.30-7.25(m,2H),6.55(s,1H),6.49(s,1H),4.75(br s,1H),4.65-4.48(m,5H),4.45-4.36(m,1H),4.35-4.28(m,1H),4.28-4.12(m,3H),3.49(t,J=6.2Hz,2H),2.10(s,3H),2.08(s,3H),2.04-1.97(m,2H),1.96-1.88(m,2H),1.82-1.74(m,2H),1.33-1.26(m,6H)。
STING激动剂生物学筛选和结果
试验例1:化合物对STING野生型(WT)和HAQ亚型激动能力的检测(方法1)
STING-232H质粒购买自Origene(RC208418),并在此质粒基础上构建STING野生型质粒以及STING HAQ型(HAQ型氨基酸突变为R71H、G230A、和R293Q)表达质粒。使用表达STING变体(野生型和HAQ型)的质粒转染HEK-BlueTM ISG-KO-STING(Invivogen,cat#hkb-kostg)细胞来检测化合物对STING的激活作用(参见WO2017/175147A1)。GFP质粒(VT2069)购买自优宝生物。具体操作如下:第一天以每孔1ng的质粒(WT,HAQ,GFP)分别在96孔板中转染HEK-BlueTM ISG-KO-STING细胞,每孔细胞数量为0.8×105细胞,并控制每孔lipofectamine 2000(Invitrogen,cat#11668-027)量为0.1μl。转染24h后更换培养基并加入合适浓度的测试化合物,控制DMSO浓度为0.5%。孵育24h后取上清,采用Great EscAPeSEAP chemiluminescence KIT(Clontech,cat#631738)进行SEAP检测。剩余细胞采用CellTiter-Glo Luminescent Cell Viability Assay(Promega,cat#G7573)检测细胞活性。SEAP检测和CellTiter-Glo Luminescent Cell Viability Assay检测都依据试剂盒操作说明进行。数据采用化合物的刺激信号与0.5%DMSO的信号的比值描述。
试验例2:化合物对STING野生型(WT)和HAQ亚型激动能力的检测(方法2)
STING-232H质粒购买自Origene(RC208418),并在此质粒基础上构建STING野生型质粒以及STING HAQ型(HAQ型氨基酸突变为R71H、G230A、和R293Q)表达质粒。使用表达STING变体(野生型和HAQ型)的质粒转染HEK-BlueTM ISG-KO-STING(Invivogen,cat#hkb-kostg)细胞来检测化合物对STING的激活作用(参见WO2017/175147A1)。GFP质粒(VT2069)购买自优宝生物。具体操作如下:第一天以每孔WT(0.0625ng),HAQ(1ng),GFP(0.0625ng和1ng)的质粒分别在96孔板中转染HEK-BlueTM ISG-KO-STING细胞,每孔细胞数量为0.8×105细胞,并控制每孔lipofectamine 2000(Invitrogen,cat#11668-027)量为0.1μl。转染24h后更换培养基并加入合适浓度的测试化合物,控制DMSO浓度为0.5%。孵育24h后取上清,采用Great EscAPe SEAP chemiluminescence KIT(Clontech,cat#631738)进行SEAP检测。剩余细胞采用CellTiter-Glo Luminescent Cell Viability Assay(Promega,cat#G7573)检测细胞活性。SEAP检测和CellTiter-Glo Luminescent Cell Viability Assay检测都依据试剂盒操作说明进行。数据采用化合物的刺激信号与0.5%DMSO的信号的比值描述。
试验例3:化合物刺激THP1细胞释放IFNβ
本实验通过检测化合物刺激THP1细胞产生IFNβ的能力来评估其激活STING的能力。THP1细胞购买自中科院细胞所(Cat#TCHu 57)。根据化合物的溶解度设置起始浓度,并以3倍稀释设置8个浓度点,用培养基稀释成2×工作液,DMSO浓度0.2%。取对数生长期的THP1细胞用培养基稀释成2×106cells/ml,每孔加入50ul细胞悬液后再加50ul稀释好的化合物,使得DMSO浓度为0.1%。充分混匀后放入37℃,5%CO2的细胞培养箱中孵育24h收集上清。用human IFNβELISA KIT(R&D,DY814-05)检测上清中的IFNβ。最终的数据用GraphPadPrism或者XLfit进行曲线拟合并计算EC50。
化合物 | hIFNβELISA(EC50,μM) |
1 | 2.1 |
5 | 3.7 |
6 | 4.8 |
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