CN115677665B - 含联苯类衍生物及其医药用途 - Google Patents
含联苯类衍生物及其医药用途 Download PDFInfo
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- CN115677665B CN115677665B CN202110843500.1A CN202110843500A CN115677665B CN 115677665 B CN115677665 B CN 115677665B CN 202110843500 A CN202110843500 A CN 202110843500A CN 115677665 B CN115677665 B CN 115677665B
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Abstract
本发明涉及药物化学领域,公开了一类具有PD‑1/PD‑L1抑制活性的联苯类衍生物及其医药应用。本发明还公开了含有所述具有PD‑1/PD‑L1抑制活性的联苯类衍生物或其药学上可接受的盐、药学上可接受的载体的组合物,及其在制备PD‑1/PD‑L1抑制剂中的应用,可用于治疗与免疫检查点PD‑1/PD‑L1相关的多种癌症或肿瘤,适用性广。
Description
技术领域
本发明属于药物化学领域,具体涉及一类含有联苯结构的衍生物,以及这些化合物在制备***的药物中的用途。
背景技术
近几年来肿瘤免疫疗法已成为肿瘤治疗领域的焦点,与直接针对肿瘤细胞的传统治疗手段不同,肿瘤免疫疗法是利用人体自身免疫***对肿瘤细胞进行杀伤。免疫检查点通路的活化会抑制T细胞的激活,防止人体免疫***的过度激活,维持正常机体的免疫耐受,避免自身免疫疾病的发生。肿瘤细胞会表达过量的负性免疫检查点蛋白,与淋巴细胞结合后,过度激活免疫检查点通路从而导致肿瘤免疫逃逸的发生。在这些免疫检查点当中,PD-1/PD-L1的过度激活对于肿瘤的发展起着至关重要的作用。当使用阻断剂阻断PD-1/PD-L1相互作用,可以使免疫细胞重新识别并杀死肿瘤细胞,从而达到***的目的。目前PD-1/PD-L1单克隆抗体在临床上已经取得了优异的成果,在黑色素瘤、结肠癌、非小细胞肺癌等肿瘤治疗中展示出较好的疗效(Clinical and Translational Oncology,2019,21:702–712;The Oncologist,2019,24(Suppl 1):S31-S41;Human Vaccines&Immunotherapeutics,2014,10(11):3111-6;Journal of Medicinal Chemistry,2020,63,(22):13825–13850)。
近年来,已有多种PD-1/PD-L1单抗药物被批准上市,并且这些单抗药物在多种肿瘤的临床治疗中取得了突破性进展。许多肿瘤患者的生存期显著延长,并且部分患者得到完全缓解。虽然单抗药物的临床效果显著,但由于其半衰期较长,并且与靶点结合时间过久,可能会导致严重的免疫相关不良反应。单抗药物的生产工艺复杂,价格昂贵且不便于储存运输,普通患者只能望“药”兴叹。与单克隆抗体相比,小分子药物具有价格低廉、可口服给药、可跨越生物屏障、便于运输和储存、良好的膜通透性和非免疫原性等优势。目前还没有PD-1/PD-L1小分子抑制剂上市,因而开发PD-1/PD-L1蛋白-蛋白相互作用的抑制剂具有重大的现实意义和潜在的应用前景。
发明内容
发明目的:针对上述现有技术,本发明提供了具有PD-1/PD-L1抑制活性的联苯类衍生物,其制备方法以及作为PD-1/PD-L1蛋白-蛋白相互作用抑制剂的制药应用。
技术方案:本发明公开了一种如通式(I)所示的联苯类衍生物或其药学上可接受的盐:
其中:
X、Y和Z各自分别代表:N或CH;
A代表取代的苯基或芳杂环基,所述芳杂环基是含有1~3个O、N或S原子的五元或六元芳香环,所述的取代基是H、F、Cl、Br、CN、NH2、OH、CF3、OCF3、C1~C4的烷基或C1-C4的烷氧基;
m=0、1或2;n=0、1或2;
R1和R2各自分别代表NR6R7、OR7或取代的含有1~2个O或N原子的四元、五元或六元杂环烷基
R6代表氢或C1~C3的烷基;
R7代表取代的C1~C6的烷基,所述的取代基为OH、NH2、COOH、CONH2、COOCH3、COOCH2CH3、C1~C4的烷氧基,可以是单取代或多取代;
所述取代的含有1~2个O或N原子的四元、五元或六元杂环烷基为取代的四氢吡咯-1-基、取代的哌啶-1-基、取代的吗啉-1-基、取代的哌嗪-1-基或取代的氮杂环丁烷-1-基,其中所述的取代基为OH、NH2、COOH、CONH2、COOCH3、COOCH2CH3、CF3、OCF3、C1~C4的烷氧基、C1~C4的烷基,可以是单取代或多取代;
R3和R4各自分别代表H、F、Cl、Br、CN、CF3、C1~C3的烷基或环丙基;
R5代表H、F、Cl、Br、CN、CF3、OCH3、OCH2CH3、OCF3、C1~C4的烷基或环丙基。
当m=1,A为1,4-二取代的1,2,3-三氮唑环时,本发明的化合物优选如下通式(II):
其中:X、Y、Z、R1、R2、R3、R4、R5和n的定义同前。
n优选0或1。
X优选N或CH。
Y和Z优选CH。
R1和R2各自优选OH、其中R8代表CH3、CH2CH3、CH2CH2OH、甲酰基、乙酰基、环丙基等;R9和R10各自分别代表H、OH、COOH、CH2COOH、CH2NH2、CH2OH、CH2CH2OH、F、Cl、Br、CH3、CH2CH3、环丙基等;R11代表OH、NH2、NHCH3、NHCH2CH3、CH3、OCH3、OCH2CH3;R12代表CONH2、NHCOCH3、OH、CH2OH、CH2CH2OH、COOH、CH2COOH等;R13代表H、CH3、CH2CH3、CH2OH、CH2CH2OH等;R14和R15各自分别代表H、COOH、NH2、F、Cl、Br、CH3、CH2CH3、CH2OH、CH2CH2OH、CONH2、环丙基等;W代表CH2、O、NH、N-CH3、N-CH2CH3、N-CH2CH2OH、N-COCH3等;p代表0或1。
R3和R4各自优选F、Cl或CH3。
R5优选H、F、CH3或OCH3。
其中:
X更优选N。
R1和R2更优选-OH、-NHCH2CONH2、-NHCH2CH2OH、
R3和R4更优选CH3。
R5更优选OCH3。
上述化合物的药学上可接受的盐为通式(I)或(II)化合物的酸加成盐,其中用于成盐的酸为:氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
本发明通式(I)的化合物可用下列方法制备:
当X代表N或CH;Y和Z代表CH;A代表1,4-二取代的1,2,3-三氮唑环;m=1;n=0或1时,化合物(I)可用下列方法制备:
其中:X、n、R1、R2、R3、R4和R5的定义同前。
由化合物III与化合物IV经suzuki反应制备化合物V,所用溶剂选自甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙二醇二甲醚、乙二醇单甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂,优选1,4-二氧六环和水的混合溶剂;所用碱选自乙醇钠、乙酸钾、氢氧化钠、氢氧化钾、碳酸钾、碳酸氢钠、碳酸氢钾、碳酸钠或磷酸三钾,优选碳酸钾;所用催化剂选自Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2或NiCl2(dppf),优选Pd(PPh3)4;反应温度选自50~120℃,优选60~100℃。
由化合物V先与硫酸成盐后,再与亚硝酸钠反应得到重氮盐,最后与联硼酸频哪醇酯反应制备化合物VI,所用溶剂选自甲醇、乙醇、四氢呋喃、1,4-二氧六环、乙二醇二甲醚、乙腈、水或上述溶剂组成的混合溶剂,优选甲醇和水的混合溶剂。
由化合物VI与化合物VII经suzuki反应制备化合物VIII,所用溶剂选自甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙二醇二甲醚、乙二醇单甲醚、1,4-二氧六环、四氢呋喃、甲醇、乙醇、乙腈、丙酮、水或任意两种溶剂组成的混合溶剂,优选1,4-二氧六环和水;所用碱选自乙醇钠、乙酸钾、氢氧化钠、氢氧化钾、碳酸钾、碳酸氢钠、碳酸氢钾、磷酸三钾、碳酸钠或三乙胺,优选碳酸钾;所用催化剂是Pd(PPh3)4、Pd(dppf)Cl2、Pd(PPh3)2Cl2、Pd(OAc)2或NiCl2(dppf),优选Pd(PPh3)4。反应温度选自50~120℃,优选60~100℃。
由化合物VIII与相应的胺经还原胺化反应制备目标化合物II,所用溶剂选自二氯甲烷、二氯乙烷、三氯甲烷、四氯化碳、四氢呋喃、甲醇、甲苯、乙醇、乙腈、N,N-二甲基甲酰胺或上述任意两种或三种溶剂组成的混合溶剂,优选二氯甲烷或二氯甲烷和甲醇的混合溶剂;还原剂选自硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠,优选三乙酰氧基硼氢化钠;反应温度选自0~80℃,优选25~40℃。
本发明所述的通式(I)化合物(包括手性异构体)及其水合物、溶剂合物或结晶在制备PD-1/PD-L1抑制剂类药物中的应用也在本发明的保护范围内。
进一步地,其中的PD-1/PD-L1抑制剂可用于制备治疗非小细胞肺癌、结肠癌、黑色素瘤等癌症的药物。
药理实验显示,在均相时间分辨荧光实验(HTRF)中,本发明的联苯类衍生物可以对PD-1/PD-L1的相互作用产生良好的抑制作用。在表面等离子共振实验中,本发明的联苯类衍生物对人PD-L1具有很好的亲和力。本发明的联苯类衍生物不但可以很好地抑制PD-1/PD-L1的结合,还能促进T细胞活力的恢复,促进免疫因子INF-γ的分泌,因而可以用于肿瘤的免疫治疗。本发明的联苯类衍生物活性优异,因而开发PD-1/PD-L1的联苯类抑制剂具有重大的现实意义和潜在的应用前景。
有益效果:与现有技术相比,本发明具有如下显著优点:(1)提供的新型联苯类衍生物可以显著抑制PD-1/PD-L1的相互作用,尤其重要的是,可以显著地阻断PD-L1对CD3+T细胞的抑制作用,具有促进T细胞分泌免疫因子INF-γ的效应。在肿瘤细胞和T细胞共孵育的实验中,该联苯化合物对INF-γ表达促进效应高于阳性药BMS-202,因而具有增强T细胞抗肿瘤的功效;因此,本发明联苯类衍生物可以作为免疫检查点PD-1/PD-L1抑制剂用于制备肿瘤免疫治疗的药物。(2)本发明的联苯类衍生物的合成路线设计巧妙、简便易行,原料便宜易得,合成工艺安全、环保,易于规模化生产。(3)本发明化合物作为活性成分的药物可用于治疗与免疫检查点PD-1/PD-L1相关的多种癌症或肿瘤,适用性广。
附图说明
图1是肿瘤细胞和T细胞共培养中的INF-γ表达实验。
具体实施方式
下面结合具体实施例对本发明作出详细说明。
实施例1
N,N'-(((((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(2-甲氧基吡啶-6,3-二基))双(亚甲基))双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂二基))双(乙烷-2,1-二基))二乙酰胺(II-1:n=1,X=N,R1=R2=-NHCH2CH2NHCOCH3,R3=R4=CH3,R5=OCH3)
2,2'-二甲基-[1,1'-联苯]-3,3'-二胺(V)的合成
将3-溴-2-甲基苯胺(III)(10.00g,53.8mmol)和化合物IV(12.50g,53.8mmol)溶于二氧六环(150mL)中,将碳酸钾(20.83g,150.6mmol)的水(15mL)溶液滴加至反应液中,氮气保护,加入Pd(PPh3)4(1.55g,1.35mmol),升温至80℃反应12小时,TLC(石油醚:乙酸乙酯=8:1)监测原料反应完全,停止加热,冷至室温。抽滤除去不溶物,滤液加水(100mL)稀释,乙酸乙酯(120mL×3)萃取,饱和氯化钠溶液洗涤(100mL×3),无水硫酸钠干燥。抽滤,滤液减压蒸除溶剂得粗品,经柱层析(石油醚100%~石油醚:乙酸乙酯=15:1)纯化得黄色固体粉末8.58g,收率75.2%。m.p.134~136℃。1H NMR(400MHz,Chloroform-d)δ7.07(t,J=7.7Hz,2H,ArH),6.72(d,J=7.9Hz,2H,ArH),6.63(d,J=7.6Hz,2H,ArH),3.37(br,4H,NH2),1.90(s,6H,CH3)。
2,2'-(2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(4,4,5,5-四甲基-1,3,2-二氧杂硼烷)(VI)的合成
将化合物V(4.00g,18.9mmol)溶于甲醇(40mL)中,依次加入HCl溶液(37.7mL,3mol/L)和水(20mL),室温搅拌30分钟。降温至0℃,缓慢滴加亚硝酸钠水溶液(18.86mL,2.2mol/L),滴毕继续保温搅拌30分钟后,将双联频哪醇硼酸酯(19.20g,75.6mmol)溶于甲醇(40mL)中,然后缓慢滴加至反应液中,滴毕后恢复至室温搅拌2小时,TLC监测(石油醚:乙酸乙酯=30:1)原料反应完全。加入二氯甲烷(50mL)稀释后,分液,水相再用二氯甲烷(50mL×2)萃取,合并二氯甲烷层,用饱和氯化钠溶液洗涤(50mL×3),无水硫酸镁干燥。抽滤,滤液减压蒸除溶剂得粗品,经柱层析(石油醚:乙酸乙酯=250:1)纯化得白色固体粉末3.54g,收率42.9%。m.p.167-168℃。1H NMR(300MHz,Chloroform-d)δ7.77(dd,J=7.3,1.7Hz,2H,ArH),7.23(t,J=7.4Hz,2H,ArH),7.15(dd,J=7.5,1.7Hz,2H,ArH),2.23(s,6H,ArCH3),1.38(s,24H,CH3)。
1-((6-氯-2-甲氧基吡啶-3-基)甲基)-1H-1,2,3-三氮唑-4-甲醛(VII-1)的合成
6-氯-2-甲氧基吡啶-3-甲醛(2)的合成
将6-氯-2-甲氧基吡啶(2.00g,13.9mmol)溶于无水THF(10mL)中,氮气保护。降温至-10℃下,缓慢注入异丙基氯化镁(6.95mL,6.95mmol,1.00mol/L)。滴毕,-10℃下反应30分钟。继续在-10℃下注入正丁基锂(6.67mL,16.7mmol,2.50mol/L)。滴毕,继续在此温度下搅拌2小时后,滴加无水DMF(2.21mL,27.8mmol)。滴毕,继续搅拌1.5小时。TLC监测原料反应完全,升至室温。将反应液缓慢加入至由乙酸(5.00g)、浓盐酸(2.00g)、异丙醇(20.00mL)和水(20.00mL)组成的混合液中,淬灭反应后升温至50℃反应2小时。冷至室温,蒸除有机溶剂滤液冷却后析出固体,抽滤得黄色固体,经真空干燥得1.58g化合物2,收率66.1%。m.p.62-64℃。1H NMR(300MHz,DMSO-d6)δ10.18(s,1H,CHO),8.13(d,J=7.9Hz,1H,ArH),7.28(d,J=7.9,1H,ArH),4.02(s,3H,OCH3).
(6-氯-2-甲氧基)-3-吡啶甲醇(3)的合成
将化合物2(2.20g,12.8mmol)溶于无水四氢呋喃(8.00mL)和无水甲醇(3.00mL)中。降温至0℃下,缓慢分批加入硼氢化钠(0.59g,15.4mmol)。加毕,撤去冰浴,放置室温搅拌30min。TLC(石油醚:乙酸乙酯=8:1)监测原料反应完全,停止反应,加水淬灭反应。减压蒸除有机溶剂,残余物用乙酸乙酯(10mL×3)萃取,合并有机相,用饱和氯化钠溶液(20mL×3)洗涤,无水硫酸钠干燥。抽滤除去无水硫酸钠,蒸除溶剂得粗品,经柱层析分离得白色固体粉末1.64g,收率73.7%。m.p.58-61℃。1H NMR(300MHz,Chloroform-d)δ7.56(d,J=7.5,1H,ArH),6.92(d,J=7.6Hz,1H,ArH),4.63(s,2H,CH2),4.00(s,3H,OCH3)。
6-氯-3-(氯甲基)-2-甲氧基吡啶盐酸盐(4)的合成
将化合物3(11.80g,68.0mmol)溶于二氯甲烷(70mL)中,缓慢滴加亚硫酰氯(6.01mL,81.6mmol),反应液从浑浊到澄清透明,室温搅拌过夜。TLC(石油醚:乙酸乙酯=8:1)监测原料反应完全,向反应液中加入甲苯(20mL),减压蒸除溶剂,冷却后得淡绿色晶体15.34g,收率98.8%。m.p.62-64℃。MS(ESI):m/z[M+H]+.Calcd for C7H8Cl2NO:191.9;Found:192.0。
3-(叠氮甲基)-6-氯-2-甲氧基吡啶(5)的合成
将化合物4(15.34g,79.9mmol)和DIPEA(15.49g,119.9mmol)加入DMF(150mL)中,室温搅拌1小时。加入CsF(14.57g,95.9mmol)和TMSN3(12.6mL,95.9mmol),升温至80℃反应5小时。TLC(石油醚:乙酸乙酯=30:1)监测原料反应完全。停止加热,冷至室温。将反应液倒入冰水(300mL)中,乙酸乙酯萃取(150mL×3),合并有机层,用饱和氯化钠洗涤(100mL×3),无水硫酸钠干燥。抽滤除去无水硫酸钠,蒸除溶剂得粗品,经柱层析分离得无色透明油状液体13.06g,收率82.3%。MS(ESI):m/z[M+H]+Calcd for C7H8ClN4O:199.0;Found:199.1。
6-氯-3-((4-(二乙氧基甲基)-1H-1,2,3-三氮唑-1基)甲基)-2-甲氧基吡啶(6)的合成
将化合物5(12.50g,62.9mmol)和丙醛二乙基乙缩醛(9.67g,75.5mmol)溶于乙腈(72mL)和水(24mL)中,加入CuI(0.60g,3.16mmol)。升温至30℃反应12小时。TLC(石油醚:乙酸乙酯=4:1)监测原料反应完全,停止加热,冷至室温。倒入冰水(50mL)中,用乙酸乙酯萃取(100mL×2),合并有机层,用饱和氯化钠水溶液洗涤(100mL×2),无水硫酸钠干燥。抽滤除去不溶物,蒸除溶剂得无色透明油状液体15.53g,该中间体不经提纯直接用于下一步反应。
1-((6-氯-2-甲氧基吡啶-3-基)甲基)-1H-1,2,3-三氮唑-4-甲醛(ⅥI-1)的合成
将化合物6(15.00g,45.9mmol)溶于二氯甲烷(50mL)中,缓慢滴加三氟乙酸(6.82mL,91.8mmol)。滴毕,室温反应1小时。TLC(石油醚:乙酸乙酯=2:1)监测反应完全。用2N NaOH溶液调节pH至碱性,用二氯甲烷萃取(50mL×3),合并有机层,用饱和NaCl溶液洗涤(50mL×2),无水硫酸钠干燥。抽滤除去无水硫酸钠,蒸除溶剂得粗品,经柱层析纯化得白色固体粉末11.14g,收率96.1%。m.p.128-130℃。1H NMR(300MHz,Chloroform-d)δ10.20(s,1H,CHO),8.22(s,1H,ArH),7.61(d,J=7.7Hz,1H,ArH),7.03(d,J=7.7Hz,1H,ArH),5.60(s,2H,CH2),4.09(s,3H,OCH3).
1,1'-(((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(2-甲氧基吡啶-6,3-二基))双(亚甲基))双(1H-1,2,3-三氮唑-4-甲醛)(VIII-1)的合成
将化合物ⅥI-1(1.42g,3.27mmol)、化合物ⅤI(2.06g,8.17mmol)、Pd(PPh3)4(0.38g,0.33mmol)、K2CO3(1.27g,9.17mmol)的水(2mL)溶液和二氧六环(20mL)依次加入茄形瓶中,氮气保护,升温至80℃搅拌反应12小时。TLC(石油醚:乙酸乙酯=2:1)监测原料反应完全,停止加热,冷至室温。抽滤除去不溶物,用乙酸乙酯(50mL×3)萃取,合并有机层,用饱和氯化钠溶液(50mL×2)洗涤,无水硫酸钠干燥。抽滤除去不溶物,减压蒸除溶剂得粗品,经柱层析(石油醚:乙酸乙酯=4:1~1.5:1)纯化得白色固体粉末1.56g,收率77.6%。m.p.179-181℃。1H NMR(400MHz,DMSO-d6)δ10.05(s,2H,CHO),8.96(s,2H,ArH),7.70(d,J=7.6Hz,2H,ArH),7.45(dd,J=7.7,1.5Hz,2H,ArH),7.38(t,J=7.6Hz,2H,ArH),7.24–7.21(m,4H,ArH),5.72(s,4H,CH2),3.92(s,6H,OCH3),2.05(s,6H,CH3).
N,N'-(((((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(2-甲氧基吡啶-6,3-二基))双(亚甲基))双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂二基))双(乙烷-2,1-二基))二乙酰胺(II-1)的合成
将化合物VIII-1(0.20g,0.33mmol)、N-乙酰基乙二胺(0.10g,0.98mmol)和乙酸(2滴)溶于二氯甲烷(5mL)和甲醇(2mL)中,室温搅拌反应1小时。降温至0℃,将NaBH(OAc)3(0.28g,1.32mmol)分批加入反应液中,室温搅拌4小时。TLC(二氯甲烷:甲醇=10:1)监测原料反应完全,用饱和碳酸氢钠水溶液调节pH至7,用二氯甲烷(10mL×3)萃取,合并有机层,用饱和氯化钠溶液洗涤(10mL×2),无水硫酸钠干燥。抽滤除去不溶物,减压蒸除溶剂得粗品,经硅胶柱层析纯化得黄色固体粉末0.09g,收率34.2%。m.p.86-88℃。1H NMR(300MHz,DMSO-d6)δ8.02(s,2H,ArH),7.83(s,2H,2CONH),7.54(d,J=7.6Hz,2H,ArH),7.46(dd,J=7.7,1.7Hz,2H,ArH),7.39(t,J=7.5Hz,2H,ArH),7.22(td,J=7.4,2.6Hz,4H,ArH),5.60(s,4H,2ArCH2),3.95(s,6H,2OCH3),3.78(s,4H,ArCH 2NH),3.14(q,J=6.4Hz,4H,2CH2NHCH 2),2.59(t,J=6.5Hz,4H,2CONHCH 2),2.07(s,6H,2ArCH3),1.80(s,6H,2COCH3).HRMS(ESI):m/z[M+H]+Calcd for C42H51N12O4:787.4156;Found:787.4149。
实施例2
2,2'-((((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(2-甲氧基吡啶-6,3-二基))双(亚甲基))双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂二基))双(乙烷-1-醇)(II-2:n=1,X=N,R1=R2=-NHCH2CH2OH,R3=R4=CH3,R5=OCH3)的合成
以化合物ⅦI-1(0.20g,0.33mmol)和乙醇胺(0.06g,0.98mmol)为原料,操作同化合物II-1,得黄色固体粉末0.08g,收率34.9%。m.p.112-114℃。1H NMR(300MHz,DMSO-d6)δ8.10(d,J=7.9Hz,2H,ArH),7.55(t,J=7.2Hz,2H,ArH),7.45(d,J=7.6Hz,2H,ArH),7.38-7.28(m,2H,ArH),7.25–7.09(m,4H,ArH),5.65–5.48(m,4H,ArCH2),4.05(s,6H,OCH3),3.90(s,4H,2NHCH 2Ar),2.54–2.49(m,4H,CH2CH 2OH),2.76–2.66(m,4H,CH 2CH2OH),2.03(s,6H,2ArCH3).HRMS(ESI):m/z[M+H]+Calcd for C38H45N10O4:705.3625;Found:705.3615。
实施例3
2,2'-((((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(2-甲氧基吡啶-6,3-二基))双(亚甲基))双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂二基))二乙酰胺(II-3:n=1,X=N,R1=R2=-NHCH2CONH2,R3=R4=CH3,R5=OCH3)
以化合物ⅦI-1(0.20g,0.33mmol)和甘氨酰胺盐酸盐(0.15g,1.32mmol)为原料,操作同化合物II-1的合成,得黄色固体粉末0.11g,收率46.3%。m.p.86-88℃。1H NMR(300MHz,DMSO-d6)δ8.08(s,2H,ArH),7.56(d,J=7.5Hz,2H,ArH),7.47(dd,J=7.7,1.7Hz,2H,ArH),7.40(t,J=7.6Hz,2H,ArH),7.34(br,2H,CONH2),7.30–7.18(m,4H,ArH),7.09(s,2H,CONH2),5.61(s,4H,2ArCH2),3.97(s,6H,2OCH3),3.77(s,4H,2ArCH 2NH),3.10(s,4H,2COCH2),2.65(s,2H,2NH),2.08(s,6H,2ArCH3)。HRMS(ESI):m/z[M+H]+Calcd forC38H43N12O4:731.3530;Found:731.3528。
实施例4
5,5'-(((((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(2-甲氧基吡啶-6,3-二基))双(亚甲基))双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂二基))双(亚甲基))双(吡咯烷-2-酮)(II-4:n=1,X=N,R1=R2为(吡咯烷-2-酮-5-基)甲胺基,R3=R4=CH3,R5=-OCH3)
以化合物ⅦI-1(0.20g,0.33mmol)和5-氨甲基-2-吡咯烷酮(0.15g,1.32mmol)为原料,操作同化合物II-1的合成,得黄色固体粉末0.12g,收率45.5%。m.p.111-114℃。1HNMR(300MHz,Chloroform-d)δ7.60(s,2H,ArH),7.51(d,J=7.5Hz,2H,ArH),7.44–7.38(m,2H,ArH),7.32(t,J=7.6Hz,2H,ArH),7.24–7.19(m,2H,ArH),7.05(d,J=7.5Hz,2H,ArH),6.32(br,2H,NHCO),5.54(s,4H,ArCH2N),4.03(s,6H,OCH3),3.94(s,4H,ArCH 2NH),3.80-3.69(m,2H,2CH),2.86(dd,J=12.0,4.0Hz,2H,NHCH 2),2.61(dd,J=12.0,8.5Hz,2H,NHCH 2),2.33(t,J=8.0Hz,4H,NHCH 2CH),2.25-2.17(m,2H,CH2),2.17-2.12(m,2H,CH2),2.11(s,6H,ArCH3),2.08-2.00(m,2H,CH2),1.80-1.69(m,2H,CH2).HRMS(ESI):m/z[M+Na]+Calcd for C44H50N12O4Na:833.3976;Found:833.3993。
实施例5
2,2',2”,2”'-((((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(2-甲氧基吡啶-6,3-二基))双(亚甲基))双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂三基))四(乙烷-1-醇)(II-5:n=1,X=N,R1=R2=-N(CH2CH2OH)2,R3=R4=CH3,R5=OCH3)的合成
以化合物ⅦI-1(0.20g,0.33mmol)和二乙醇胺(0.13mL,0.98mmol)为原料,操作同化合物II-1的合成,得黄色固体粉末0.11g,收率42.6%。m.p.90-92℃。1H NMR(300MHz,DMSO-d6)δ8.09(s,2H,ArH),7.51(d,J=7.5Hz,2H,ArH),7.46(dd,J=7.7,1.6Hz,2H,ArH),7.38(t,J=7.5Hz,2H,ArH),7.22(td,J=7.5,2.4Hz,4H,ArH),5.60(s,4H,ArCH2),4.43(s,4H,4OH),3.94(s,6H,2OCH3),3.79(s,4H,2NHCH 2),3.39(s,4H,2CH2CH 2OH),3.19(d,J=4.3Hz,4H,2CH 2CH2OH),2.06(s,6H,2ArCH3)。HRMS(ESI):m/z[M+H]+Calcd for C42H53N10O6:793.4150;Found:793.4152。
实施例6
((((2,2'-二甲基-[1,1'-联苯]-3,3'-二基)双(2-甲氧基吡啶-6,3-二基))双(亚甲基))双(1H-1,2,3-三氮唑-1,4-二基))二甲醇(II-6:n=1,X=N,R1=R2=-OH,R3=R4=CH3,R5=OCH3)的合成
将化合物ⅦI-1(0.20g,0.33mmol)溶于甲醇(2mL)中,降温至0℃。将NaBH4(19mg,0.51mmol)加入到反应液中,搅拌30分钟。TLC监测原料反应完全,加入水淬灭过量的硼氢化钠。减压蒸除甲醇,残留物加二氯甲烷(20mL)稀释,分液,二氯甲烷层用饱和氯化钠溶液(5mL×3)和水(5mL×3)洗涤,无水硫酸钠干燥。抽滤除去不溶物,减压蒸除溶剂得粗品,经柱层析得黄色固体粉末0.17g,收率84.5%。m.p.144-146℃。1H NMR(400MHz,DMSO-d6)δ8.03(s,2H,ArH),7.53(d,J=7.6Hz,2H,ArH),7.43(d,J=7.6Hz,2H,ArH),7.36(t,J=7.5Hz,2H,ArH),7.20(dd,J=11.1,6.9Hz,4H,ArH),5.58(s,4H,ArCH2N),5.21(t,J=5.7Hz,2H,OH),4.53(d,J=5.6Hz,4H,CH2),3.93(s,6H,OCH3),2.04(s,6H,ArCH3)。HRMS(ESI):m/z[M+H]+Calcd for C34H35N8O4:619.2781;Found:619.2777。
实施例7
N,N'-(((((3,3”'-二甲氧基-2',2”-二甲基-[1,1':3',1”:3”,1”'-四苯基]-4,4”'-二基)双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂二基))双(乙烷-2,1-二基))二乙酰胺(II-7:n=0,X=CH,R1=R2=-NHCH2CH2NHCOCH3,R3=R4=CH3,R5=OCH3)的合成
1-(4-溴-2-甲氧基苯基)-1H-1,2,3-三氮唑-4-甲醛(VII-2)的合成
4-溴-2-甲氧基苯胺(8)的合成
将邻甲氧基苯胺7(20.00g,162.4mmol)溶于乙腈(100mL)中。降温至0℃下,将N-溴代琥珀酰亚胺(33.8g,195.0mmol)缓慢分批加入反应液中。加毕,室温反应过夜。TLC(石油醚:乙酸乙酯=15:1)监测原料反应完全,加水稀释,用乙酸乙酯萃取(100mL×3),合并有机层,用饱和氯化钠洗涤(100mL×2),无水硫酸钠干燥。抽滤除去无水硫酸钠,减压蒸除溶剂得粗品,经柱层析(石油醚:乙酸乙酯=100:1~60:1)纯化得红褐色固体19.82g。收率60.4%。m.p.60-61℃。1H NMR(300MHz,Chloroform-d)δ6.95-6.88(m,2H,ArH),6.63(dt,J=8.4,1.1Hz,1H,ArH),3.89(s,3H,OCH3),3.81(s,2H,NH2)。
1-叠氮基-4-溴-2-甲氧基苯(9)的合成
将化合物8(6.47g,32.0mmol)溶于乙腈中,缓慢滴加亚硝酸特丁酯(3.96g,38.4mmol)。滴毕后,降温至0℃,缓慢滴加叠氮基三甲基硅烷(4.42g,38.4mmol),滴毕后,室温反应2小时。TLC(石油醚:乙酸乙酯=30:1)监测反应完全。蒸干溶剂,残留物用二氯甲烷溶解,柱层析纯化得淡褐色透明油状液体3.66g。收率50.1%。1H NMR(300MHz,Chloroform-d)δ7.13(dd,J=8.4,1.6Hz,1H,ArH),7.08(d,J=1.5Hz,1H,ArH),6.93(d,J=8.3,1H,ArH),3.94(s,3H,OCH3)。
1-(4-溴-2-甲氧基苯基)-4-(二乙氧基甲基)-1H-1,2,3-三氮唑(10)的合成
将化合物9(3.88g,17.0mmol)溶于乙腈(21mL)和水(7mL)中,缓慢滴加炔丙醛二乙基乙缩醛(2.61g,20.4mmol)。加入CuI(0.16g,0.85mmol),升温至30℃反应24小时。TLC(石油醚:乙酸乙酯=4:1)监测反应完全,停止加热,冷至室温。将反应液倒入冰水(30mL)中,用乙酸乙酯萃取(20mL×2),饱和氯化钠水溶液洗涤(20mL×2),合并有机层,无水硫酸镁干燥。抽滤除去不溶物,蒸除溶剂得黄色油状液体5.57g,该反应产物不经提纯直接用于下一步反应。
1-(4-溴-2-甲氧基苯基)-1H-1,2,3-三氮唑-4-甲醛(VII-2)的合成
将化合物10(5.57g,15.6mmol)溶于二氯甲烷中(20mL),室温下缓慢滴加三氟乙酸(2.32mL,31.2mmol)。滴毕,室温反应1小时。TLC监测(石油醚:乙酸乙酯=4:1)反应完全,用2N NaOH调节pH至8,二氯甲烷(30mL×2)萃取至无荧光,合并有机层,用饱和NaCl溶液洗涤(20mL×2),无水硫酸镁干燥。抽滤除去无水硫酸镁,蒸除溶剂得粗品,经柱层析(石油醚:乙酸乙酯=8:1)纯化得白色固体粉末4.18g,收率94.8%。m.p.137-138℃。1H NMR(300MHz,DMSO-d6)δ10.13(s,1H,CHO),9.26(s,1H,ArH),7.69(d,J=8.4Hz,1H,ArH),7.63(d,J=2.1Hz,1H,ArH),7.42(dd,J=8.4,2.0Hz,1H,ArH),3.92(s,3H,OCH3)。
1,1'-(3,3”'-二甲氧基-2',2”-二甲基-[1,1':3',1”:3”,1”'-四苯基]-4,4”-二基)双(1H-1,2,3-三氮唑-4-甲醛)(VIII-2)的合成
将化合物VI(0.20g,0.46mmol)、化合物VII-2(0.32g,1.15mmol)和K3PO4(0.10g,0.46mm)的水(0.5mL)溶液溶于四氢呋喃中,氮气保护下加入Pd(dppf)Cl2(34mg,0.046mmol),升温至65℃反应12小时。TLC(石油醚:乙酸乙酯=2:1)原料反应完全,停止加热,冷至室温。抽滤除去不溶物,减压蒸除溶剂得粗品,经柱层析(石油醚:乙酸乙酯=5:1~3:1)纯化得黄色固体粉末0.23g,收率85.4%。m.p.108-110℃。1H NMR(400MHz,Chloroform-d)δ10.28(s,2H,CHO),8.80(s,2H,ArH),7.96(d,J=8.1Hz,2H,ArH),7.37(d,J=7.4Hz,2H,ArH),7.33(d,J=1.6Hz,2H,ArH),7.18(dd,J=8.1,1.7Hz,2H,ArH),7.14(d,J=1.7Hz,2H,ArH),3.98(s,6H,OCH3),2.06(s,6H,ArCH3)。
N,N'-(((((3,3”'-二甲氧基-2',2”-二甲基-[1,1':3',1”:3”,1”'-四苯基]-4,4”'-二基)双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂二基))双(乙烷-2,1-二基))二乙酰胺(II-7)的合成
以化合物VIII-2(0.20g,0.34mmol)和N-乙酰基乙二胺(0.14g,1.37mmol)为原料,操作同化合物II-1,得黄色固体粉末0.08g,收率30.9%。m.p.82-84℃。1H NMR(300MHz,DMSO-d6)δ8.39(s,2H,ArH),7.89(s,2H,CONH),7.71(d,J=8.1Hz,2H,ArH),7.46-7.32(m,6H,ArH),7.26(dd,J=7.2,1.9Hz,2H,ArH),7.18(dd,J=8.1,1.7Hz,2H,ArH),3.94(s,6H,OCH3),3.92(s,4H,ArCH2),3.26-3.19(m,6H,ArHCH2NHCH 2),2.70(t,J=6.6Hz,4H,CONHCH 2),2.06(s,6H,ArCH3),1.83(s,6H,COCH3).HRMS(ESI):m/z[M+H]+Calcd for C42H49N10O4:757.3938;Found:757.3940。
实施例8
2,2'-((((3,3”'-二甲氧基-2',2”-二甲基-[1,1':3',1”:3”,1”'-四苯基]-4,4”'-二基)双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂二基))双(乙烷-1-醇)(II-8:n=0,X=CH,R1=R2=-NHCH2CH2OH,R3=R4=CH3,R5=OCH3)
以化合物VIII-2(0.20g,0.34mmol)和乙醇胺(81μL,1.37mmol)为原料,操作同化合物II-1,得黄色固体粉末0.10g,收率43.3%。m.p.96-98℃。1H NMR(300MHz,DMSO-d6)δ8.38(s,2H,ArH),7.69(d,J=8.1Hz,2H,ArH),7.43–7.30(m,6H,ArH),7.23(dd,J=7.1,2.1Hz,2H,ArH),7.16(dd,J=8.1,1.8Hz,2H,ArH),3.92(s,10H,OCH3/ArCH 2NH),3.52(t,J=5.6Hz,4H,2CH 2OH),2.71(t,J=5.7Hz,4H,2NHCH 2CH2),2.03(s,6H,2ArCH3)。HRMS(ESI):m/z[M+H]+Calcd for C38H43N8O4:675.3407;Found:675.3414。
实施例9
2,2'-((((3,3”'-二甲氧基-2',2”-二甲基-[1,1':3',1”:3”,1”'-四苯基]-4,4”'-二基)双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂二基))双(3-羟基丙酸)(II-9::n=0,X=CH,R1=R2=-NHCH(CH2OH)COOH,R3=R4=CH3,R5=OCH3)
以化合物VIII-2(0.20g,0.34mmol)和丝氨酸甲酯盐酸盐(0.21g,1.37mmol)为原料,操作同化合物II-1,得淡绿色粘稠液体0.10g。将所得淡绿色液体(0.10g,0.13mmol)溶于甲醇(1mL)和四氢呋喃(1mL)中,滴加氢氧化锂(30mg,1.27mmol)水(0.5mL)溶液,室温搅拌过夜。TLC(二氯甲烷:甲醇=15:1)监测原料反应完全,减压蒸除有机溶剂,用0.1M HCl调节pH至6左右,大量固体析出,抽滤得灰色固体50mg,收率19.2%。m.p.>250℃。1H NMR(300MHz,DMSO-d6)δ8.43(s,2H,ArH),7.69(d,J=8.1Hz,2H,ArH),7.37(q,J=7.3,6.4Hz,4H,ArH),7.32(s,2H,ArH),7.23(d,J=7.4Hz,2H,ArH),7.15(d,J=8.3Hz,2H,ArH),4.09(d,J=13.8Hz,2H,CH 2OH),3.99(d,J=14.2Hz,2H,CH 2OH),3.92(s,6H,OCH3),3.62(d,J=5.5Hz,4H,NHCH 2),3.19(d,J=5.5Hz,2H,CH),2.01(s,6H,ArCH3)。
实施例10
((3,3”'-二甲氧基-2',2”-二甲基-[1,1':3',1”:3”,1”'-四苯基]-4,4”'-二基)双(1H-1,2,3-三氮唑-1,4-二基))二甲醇(II-10:n=0,X=CH,R1=R2=-OH,R3=R4=CH3,R5=OCH3)
将化合物VIII-2(0.20g,0.34mmol)溶于甲醇(5mL)中,降温至0℃。将NaBH4(19mg,0.51mmol)加入到反应液中,搅拌30分钟。TLC监测原料反应完全,加入水淬灭过量的硼氢化钠。减压蒸除甲醇,残余物加二氯甲烷(10mL)稀释,用饱和氯化钠溶液(5mL×3)和水(5mL×3)洗涤,无水硫酸钠干燥。抽滤除去不溶物,减压蒸除溶剂得粗品,经柱层析纯化得黄色固体粉末0.13g,收率64.6%。m.p.130-132℃。1H NMR(300MHz,DMSO-d6)δ8.38(s,2H,ArH),7.71(d,J=8.1Hz,2H,ArH),7.42–7.36(m,4H,ArH),7.34(d,J=1.7Hz,2H,ArH),7.27(dd,J=7.1,2.0Hz,2H,ArH),7.19(dd,J=8.1,1.7Hz,2H,ArH),5.34(t,J=5.6Hz,2H,2OH),4.65(d,J=5.4Hz,4H,2ArCH2),3.94(s,6H,2OCH3),2.07(s,6H,2ArCH3)。HRMS(ESI):m/z[M+H]+Calcd for C34H33N6O4:589.2563;Found:589.2543。
实施例11
1,1'-(((3,3”'-二甲氧基-2',2”-二甲基-[1,1':3',1”:3”,1”'-四苯基]-4,4”'-二基)双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(哌啶-2-羧酰胺)(II-11:n=0,X=CH,R1=R2为2-胺甲酰基哌啶-1-基,R3=R4=CH3,R5=OCH3)的合成
以化合物VIII-2(0.20g,0.34mmol)和2-哌啶甲酰胺(0.12g,1.03mmol)为原料,操作同化合物II-1,得白色固体粉末0.05g,收率18.1%。m.p.146-148℃。1H NMR(300MHz,DMSO-d6)δ8.41(s,2H,ArH),7.73(d,J=8.1Hz,2H,ArH),7.42(d,J=7.2Hz,2H,ArH),7.38(dd,J=7.7,1.9Hz,2H,ArH),7.34(d,J=1.7Hz,2H,ArH),7.31(s,2H,CONH2),7.26(dd,J=7.1,1.9Hz,2H,ArH),7.19(dd,J=8.0,1.7Hz,2H,ArH),7.14(s,2H,CONH2),3.94(s,6H,2OCH3),3.87(d,J=14.1Hz,2H,ArCH2),3.57(d,J=14.2Hz,2H,ArCH2),3.35(s,2H,2CH),2.95(d,J=11.2Hz,2H,1/2Piperidine-CH2),2.78–2.70(m,2H,Piperidine-CH2),2.13(d,J=11.4Hz,2H,1/2Piperidine-CH2),2.06(s,6H,ArCH3),1.78(d,J=12.3Hz,2H,1/2Piperidine-CH2),1.68(d,J=12.7Hz,2H,1/2Piperidine-CH2),1.57(s,2H,1/2Piperidine-CH2),1.51–1.39(m,2H,1/2Piperidine-CH2),1.23(d,J=14.3Hz,2H,1/2Piperidine-CH2).HRMS(ESI):m/z[M+H]+Calcd for C46H53N10O4:809.4251;Found:809.4263。
实施例12
2,2',2”,2”'-((((3,3”'-二甲氧基-2',2”-二甲基-[1,1':3',1”:3”,1”'-四苯基]-4,4”'-二基)双(1H-1,2,3-三氮唑-1,4-二基))双(亚甲基))双(氮杂三基))四(乙烷-1-醇)(II-12:n=0,X=CH,R1=R2=-N(CH2CH2OH),R3=R4=CH3,R5=OCH3)的合成
以化合物VIII-2(0.20g,0.34mmol)和二乙醇胺(0.13mL,1.37mmol)为原料,操作同化合物II-1,得黄绿色固体0.08g,收率30.7%。m.p.92-94℃。1H NMR(400MHz,DMSO-d6)δ8.38(s,2H,ArH),7.70(d,J=8.0Hz,2H,ArH),7.40(t,J=7.4Hz,2H,ArH),7.36(dd,J=7.7,1.9Hz,2H,ArH),7.31(d,J=1.9Hz,2H,ArH),7.24(dd,J=7.3,1.8Hz,2H,ArH),7.16(dd,J=8.1,1.8Hz,2H,ArH),4.40(s,4H,OH),3.92(s,6H,OCH3),3.87(s,4H,2ArCH2),3.50(t,J=6.1Hz,8H,4CH 2OH),2.59(t,J=6.3Hz,8H,4NCH 2CH2),2.04(s,6H,2ArCH3).HRMS(ESI):m/z[M+H]+Calcd for C42H51N8O6:763.3932;Found:763.3936。
实施例13
本发明部分化合物的药理学实验及结果如下:
1.对PD-1/PD-L1的抑制活性评价
实验目的:使用PD-1/PD-L1 binding assas kit检测试剂盒(CISBIO公司),检测式(I)化合物抑制剂PD-1/PD-L1相互作用的活性。
实验原理:HTRF(均相时间分辨荧光,Homogeneous Time-ResolvedFluorescence)是一种用来检测纯液相体系中待测物的技术。其主要利用两种荧光基团的能量转移,这两种荧光基团分为能量供体铕(Eu+)和能量受体。当供体被外来激发(例如闪光灯或激光),若与受体在足够近的距离之内,可以将能量共振转移到受体上,受体被激发出特定的波长。利用HTRF技术,该测定法能够以高通量形式对化合物和抗体阻滞剂进行简单、快速的表征。通过使用标记有Eu+(铕)(HTRF能量供体)的抗Tag1和标记有XL665(HTRF能量受体)的抗Tag2,可以检测PD-L1与PD-1之间的相互作用。使用Tag1和Tag2分别标记PD-L1蛋白和PD-1蛋白,Eu+和XL665通过抗体分别结合到PD-L1和PD-1形成复合物。当PD-L1和PD-1相互靠近结合时,Eu+被外来激光激发后会触发朝向XL665的荧光共振能量转移,后者又在665nm处特异性发射。该特定信号与PD1/PD-L1相互作用的程度成正比。因此,阻止PD-1/PD-L1相互作用的化合物或抗体将导致HTRF信号降低。
实验材料:试剂盒购买自CISBIO公司的PD-1/PD-L1 binding assay kits;96孔板:购买CISBIO公司。
测试仪器:Perkin Elmer,型号:EnVision。
受试化合物:式(II)中的化合物。使用DMSO溶解,diluent buffer稀释;DMSO浓度不超过0.5%。
实验过程:使用PD1/PD-L1 binding assay kits。设置阴性组、阳性组和给药组,每组2个复孔。阳性对照组,向96孔板中加入2μL diluent;按照说明书稀释后的4uL PD-L1和4uL PD-1;阴性对照组,向96孔板中加入6μL diluent和4μL PD-L1;给药组将2μL受试(I)式化合物(或者阳性化合物BMS-202)、4μLPD-L1和4μL PD-1依次加入到96孔板中。使用封板膜封板,1000rpm离心1分钟,室温孵育15分钟。而后将Buffer稀释后的Anti-Tag-Eu3+和Anti-tag-XL665等体积混合均匀,然后每孔中加入10μL混合液,封板1000rpm离心1分钟,室温孵育2小时。移除封板膜,使用EnVision读取数据665nm和615nm的荧光强度,并计算ratio=Signal 665nm/Signal 620nm*104。使用Graphpad计算化合物的IC50。本实验选用BMS公司的WO2015034820专利中的BMS-202为阳性药,活性数据参见表1。
A表示0.50-10nM;B表示10.01-100nM;C表示100.01nM~1μM。
表1.化合物在蛋白水平对hPD-1/hPD-L1的阻断作用
实验结果表明,本发明的化合物具有显著的PD-1/PD-L1蛋白-蛋白相互作用的抑制活性。
2.阻断PD-L1抑制T细胞分泌INF-γ表达作用的实验
实验原理:Hep3B-OS8-hPDL1细胞(上海睿智化学研究有限公司)表面稳定表达hPD-L1蛋白;CD3+T细胞(上海睿智化学研究有限公司)表面表达PD-1;当两株细胞被共培养的时候,Hep3B-OS8-hPDL1细胞表面的hPD-L1会与蛋白CD3+T细胞表面PD-1蛋白相互作用,从而抑制CD3+T细胞的激活、增殖、免疫因子INF-γ的表达。当化合物阻断PD-1/PD-L1相互作用的时候,将解除对CD3+T细胞的抑制,从而促进INF-γ的表达。
实验过程:用EDTA抗凝管盛放全血,密度梯度离心法分离PBMC。用EasySepTMHuman T Cell Isolation Kit从PBMC中进一步分离得到CD3+T细胞,并用RPMI-1640完全培养液重悬细胞调整浓度为5×105/mL。用10μg/mL丝裂霉素处理Hep3B-OS8-hPDL1细胞在37℃中孵育1.5h,PBS洗涤4次,RPMI-1640完全培养液重悬细胞调整浓度为5×105/mL。将Hep3B-OS8-hPDL1(50μL/well)和T细胞(100μL/well)加入到96孔圆底微孔板中。用RPMI-1640完全培养液配制4×Keytruda(50μL/well),4×待测化合物(50μL/well),将配制好的化合物以及Keytruda加入到对应的孔中(Keytruda的终浓度为5μg/mL),总体积为200μL。每个药物设置3个浓度梯度,双复孔,Keytruda和BMS-202为阳性对照组。37℃,5%CO2培养箱中孵育72小时。350×g离心5分钟后收150μL上清,ELISA检测IFN-γ分泌情况。GrapdPadPrism6进行数据处理。
结果如图1所示,实验结果明显可以看出,化合物II-3可以通过阻断PD-1/PD-L1相互作用,从而解除对CD3+T细胞的抑制作用,促进INF-γ的表达。化合物II-1、II-3和II-7剂量依赖性的促进INF-γ的表达,并且显著高于BMS-202,并且略低于Keytruda(5μg/mL)的效果,因而具有增强T细胞抗肿瘤的功效;因此,本发明联苯类化合物可以作为免疫检查点PD-1/PD-L1抑制剂而用于制备肿瘤免疫治疗的药物。
Claims (5)
1.通式II所示的化合物或其药学上可接受的盐:
;
II
其中n代表0或1,X代表N或CH,Y和Z代表CH;
R3和R4各自分别代表F、Cl或CH3;
R5代表H、F、CH3或OCH3;
R1和R2各自代表、/>、/>、/>、、/>和/>。
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,其中R3和R4分别代表CH3,R5代表OCH3。
3.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,药学上可接受的盐为通式I化合物与下列酸形成的酸加成盐:氯化氢、溴化氢、硫酸、碳酸、草酸、柠檬酸、琥珀酸、酒石酸、磷酸、乳酸、丙酮酸、乙酸、马来酸、甲磺酸、苯磺酸、对甲苯磺酸或阿魏酸。
4.一种药物组合物,其特征在于,包含权利要求1~3中任一项所述的化合物或其药学上可接受的盐及药学上可接受的载体。
5.权利要求1~3中任一项的化合物或其药学上可接受的盐、权利要求4所述的药物组合物在制备PD-1/PD-L1抑制剂类抗肿瘤药物中的用途。
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