CN115160279B - 苯并吡喃酮类化合物、药物组合物和应用 - Google Patents
苯并吡喃酮类化合物、药物组合物和应用 Download PDFInfo
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- CN115160279B CN115160279B CN202210890525.1A CN202210890525A CN115160279B CN 115160279 B CN115160279 B CN 115160279B CN 202210890525 A CN202210890525 A CN 202210890525A CN 115160279 B CN115160279 B CN 115160279B
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Abstract
本发明公开了一种苯并吡喃酮类化合物、药物组合物和应用,该化合物结构如式I,还包含其药学上可接受的盐。该类化合物及其药物组合物可有效抑制cGAs活性,抑制活性最优低于5μM浓度水平。其制备的为cGAS抑制剂药物,应用广泛,可用于治疗自身免疫性疾病、炎症性疾病或神经变性病症,在分子水平和细胞水平均可以发挥药效,并且该类化合物制备方法适用性广,简便易行。
Description
技术领域
本发明涉及一种苯并吡喃酮类化合物、药物组合物和应用,尤其涉及一种可制备为cGAS抑制剂药物的苯并吡喃酮类化合物、药物组合物和应用。
背景技术
存在于胞质中的DNA对动物细胞来说是一种重要的损伤相关分子模式(DAMPs),它可以被先天免疫受体识别并触发细胞内信号级联。dsDNA由受损的线粒体、垂死的细胞、DNA损伤、基因组不稳定性、细菌、DNA病毒和逆转录病毒引发。
环状GMP-AMP合成酶(cGAS)是一种胞质双链DNA感受器(dsDNA),作为一种模式识别受体,cGAS通过感知内源性或外源性的dsDNA而产生免疫应答反应。细胞质内的dsDNA与cGAS结合后,使cGAS激活,激活的cGAS通过发生构象的变化打开催化核苷酸结合口袋,然后,ATP和GTP进入其中,cGAS催化它们生成cGAMP,cGAMP作为第二信使对干扰素刺激物(STING)具有高亲和力,cGAMP与STING的结合促进STING易位到高尔基体并发生磷酸化而激活,激活的STING通过募集和激活TANK结合激酶1(TBK1)以磷酸化干扰素调节因子3(IRF3),激活的IRF3进入细胞核并触发I型干扰素(IFN-1)的产生,导致IFN刺激基因的表达。STING还可以招募IκB激酶(IKK),进而催化核因子κB(NF-κB)抑制剂IκBa的磷酸化。IκBa磷酸化加速NF-κB的核易位,以促进其它炎症细胞因子的转录。IFN-1和许多其他促炎细胞因子,最终激活先天免疫反应和T细胞反应,以消除病原体感染和组织损伤,但在某些情况下,细胞内异常积聚的dsDNA会持续性的异常激活cGAS而导致机体产生过多的I型干扰素和促炎细胞因子从而导致机体免疫系统异常或导致一些无菌性炎症。
目前,研究表明多种自身免疫性疾病和炎症性疾病以及某些神经性病变与cGAS的异常激活有关,包括系统性红斑狼疮、冻疮性狼疮、Aicardi-Goutieres综合征、类风湿性关节炎、心肌炎、急性胰腺炎、酒精性脂肪肝、非酒精性脂肪肝、老年性黄斑病变、亨廷顿疾病、渐冻症等,在这些疾病中致病的直接原因为cGAS在机体内的异常高表达或胞内dsDNA过量积累,因此,cGAS是治疗自身免疫性疾病和炎症性疾病的有效靶点。现有的cGAS抑制剂尚存在一些缺陷,比如现在报道的cGAS抑制剂抑制效力不足,大多都处于微摩尔水平;对人源与鼠源的cGAS抑制效力相差较大;基于这些原因目前尚无处于临床阶段的cGAS抑制剂。
发明内容
发明目的:针对现有化合物体外活性不足、体内药效不佳等问题,本发明旨在提供一种可有效抑制cGAS的苯并吡喃酮类化合物、药物组合物和应用。
技术方案:作为本发明涉及的第一方面,本发明的一种苯并吡喃酮类化合物具有式I的结构,所述化合物包含其药学上可接受的盐:
其中:
R1为Me、i-Pr或n=2-4;
Ra、Rb为Me、Et或或者Ra、Rb与相连的氮原子形成/>
R2为H、p=3、4;
Rc、Rd为H、Et或/>或者Rc、Rd与相连的氮原子形成
R3为H或
R4为H、CH3、Cl、CF3、NO2或6-7元含氮杂环,包含邻位、间位或对位取代。
黄酮是一类含苯并吡喃酮结构的化合物,在植物中分布广泛。黄酮类化合物具有多种生物活性,其中包括抗炎和免疫调节的作用。此本发明发现黄酮类化合物对cGAS具有抑制作用,在此基础上对黄酮类化合物进行结构衍生化得到一系列黄酮类化合物的衍生物,它们都对cGAS具有良好的抑制作用。
优选,上述结构中:
Ra、Rb为Et或或者Ra、Rb与相连的氮原子形成/>
R2为H;
R4为H、临位取代的Cl、对位取代的CF3、对位取代的NO2、对位取代的的或对位取代的/>
优选,上述结构中:
R1为Me、i-Pr或
R4为H、临位取代的Cl、对位取代的的或对位取代的/>
更有选,上述化合物选自以下任一化合物:
上述化合物的药学上可接受的盐为上述化合物与酸或碱形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、丙二酸、异丁酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、扁桃酸或杏仁酸,所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱。
作为本发明涉及的第二方面,上述化合物与药学上可接受的载体形成药物组合物,制成常见的药用制剂,如片剂、胶囊、糖浆、悬浮剂或注射剂,制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第三方面,上述化合物及其药物组合物可制备为cGAS抑制剂药物。
作为本发明涉及的第四方面,与上述化合物具有类似结构的一种苯并吡喃酮类化合物也可以制备为cGAS抑制剂药物,具体地这种苯并吡喃酮类化合物选自以下任一化合物:
上cGAS抑制剂述药物为治疗自身免疫性疾病、炎症性疾病或神经变性病症的药物,可具体治疗系统性红斑狼疮、家族性冻疮狼疮、Aicardi-Goutieres综合征、类风湿性关节炎、酒精性脂肪肝、非酒精性脂肪肝、老年性黄斑病变、亨廷顿症或渐冻症。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)该类化合物及其药物组合物可有效抑制cGAs活性,抑制IC50值均达到低于30μM浓度水平,最优低于5μM;
(2)该类化合物及其药物组合物应用广泛,可制备为cGAS抑制剂药物,用于治疗自身免疫性疾病、炎症性疾病或神经变性病症;所述药物在分子水平和细胞水平均可以发挥药效;
(3)化合物制备方法适用性广泛,简便易行。
附图说明
图1为化合物对IL-6mRNA表达水平的影响结果;
图2为化合物对IL-1βmRNA表达水平的影响结果。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1:L1-1的合成
第一步:I-2的制备
将131g(1.44mol)氢氧化四甲铵溶于1200mL水中,搅拌下加入60g(0.24mol)白杨素,25℃下搅拌10min,加入20g过二硫酸钾,每隔30min加入20g过二硫酸钾,至至两当量,维持25℃继续反应3h。用KH2PO4调节至pH=6-7,乙酸乙酯萃取,除去未反应的原料,正丁醇萃取(400mL×3),合并正丁醇层,无水硫酸钠干燥。抽滤,减压蒸除溶剂,得40g橙黄色固体,收率40.15%。
第二步:I-4的制备
将8.46g(0.2mol)化合物I-2溶于80mL DMF中,搅拌下加入5.52g(0.4mol)K2CO3和3.42g(0.3mol)溴苄,40℃反应4h,TLC监控至原料消失,抽滤,滤液(I-3)搅拌下加入6M HCl至pH=2,室温搅拌过夜。析出大量橙黄色固体,加入160mL水,抽滤,干燥得6g黄色固体,收率80.76%。
第三步:I-5的制备
将5g(13.8mmol)化合物I-4溶于250mL乙腈中,搅拌下加入2.9g(3mmol)K2CO3及2.8g(15.2mmol)1,2-二溴乙烷,回流反应4h,TLC至原料消失。趁热抽滤,滤液浓缩,乙酸乙酯和石油醚混合溶剂重结晶,得4.5g黄色固体,收率70.34%。[M+H]+calcd for 467.0489,MS found 467.0486.
第四步:I-6的制备
将0.5g(1.1mmol)I-5、1g(过量)二甲胺盐酸盐、0.6g(4.4mmol)K2CO3、25mL乙腈依次加入100mL单颈瓶中,回流反应10h,TLC至原料消失,停止反应。趁热抽滤,滤饼四氢呋喃洗涤,滤液浓缩,柱层析(乙酸乙酯:甲醇=10:1),得0.3g黄色固体(LW-201),收率63.8%。[M+H]+calcd for 432.1805,MS found 432.1805;1H-NMR(300MHz,DMSO-d6):δ=12.69(s,1H,5-OH),8.10(m,2H,J=1.95Hz,Ph-H),7.62(m,5H,J=3.63Hz,Ph-H),7.42(m,3H,J=1.95Hz,Ph-H),7.06(s,1H,Ar-H),6.76(s,1H,Ar-H),5.32(s,2H,ArOCH2),4.37(t,2H,J=4.59Hz,ArOCH 2 CH2),3.51(t,2H,J=4.59Hz,N-CH2),2.77(s,6H,2×N-CH3).
第五步:L1-1的制备
将150mg化合物I-5溶于15mL THF中,搅拌下加入15mg 10%的Pd/C,通入氢气,室温反应10h,TLC至原料消失。停止反应,抽滤除去Pd/C,滤液减压蒸除溶剂,乙醚打浆,得65mg黄色固体,收率60.32%。[M+H]+calcd for 342.1336,MS found 342.133;1H-NMR(300MHz,DMSO-d6):δ=12.48(s,1H,5-OH),8.08(m,2H,J=5.55Hz,Ph-H),7.61(m,3H,J=5.55Hz,Ph-H),6.67(s,1H,Ar-H),6.14(s,1H,Ar-H),4.40(t,2H,J=5.67Hz,O-CH2),2.82(t,2H,J=5.67Hz,N-CH2),2.41(s,6H,2×N-CH3).
采用与实施例1相似的操作,制得下列化合物:
[M+H]+calcd for 402.1547,MS found 402.1544;1H-NMR(300MHz,CDCl3):δ=12.49(s,1H,5-OH),7.91(m,2H,J=2.52Hz,Ph-H),7.60(m,3H,J=2.52Hz,Ph-H),6.65(s,1H,Ar-H),6.34(s,1H,Ar-H),4.27(t,2H,J=4.5Hz,Ar-O-CH2),3.91(t,4H,J=4.92Hz,2×CH2 -OH),2.95(br,6H,3×N-CH2).
[M+H]+calcd for 397.1758,MS found 397.1759;1H-NMR(300MHz,CDCl3):δ=12.38(s,1H,5-OH),7.97(m,2H,J=2.52Hz,Ph-H),7.54(m,3H,J=2.52Hz,Ph-H),6.66(s,1H,Ar-H),6.37(s,1H,Ar-H),4.27(t,2H,J=4.5Hz,Ar-O-CH2),3.39~2.40(br,10H,5×N-CH2 ),2.38(s,3H,N-CH3).
[M+H]+calcd for 356.1492,MS found 356.15;1H-NMR(300MHz,DMSO-d6):δ=12.54(s,1H,5-OH),8.05(m,2H,J=3.54Hz,Ph-H),7.61(m,3H,J=3.54Hz,Ph-H),6.93(s,1H,Ar-H),6.22(s,1H,Ar-H),4.07(t,2H,J=5.37Hz,O-CH2),3.19(t,2H,J=6.57Hz,N-CH2),2.72(s,6H,2×N-CH3),2.11(m,2H,J=6.57Hz,O-CH2-CH2 ).
[M+H]+calcd for 384.1805,MS found 384.181;1H-NMR(300MHz,DMSO-d6):δ12.34(s,1H,5-OH),7.83(m,2H,J=3.54Hz,Ph-H),7.56(m,3H,J=3.54Hz,Ph-H),6.61(s,1H,Ar-H),6.49(s,1H,Ar-H),4.26(t,2H,J=5.37Hz,O-CH2),3.37(t,2H,J=6.57Hz,N-CH2),3.25(q,4H,J=7.14Hz,2×N-CH2 -CH3),2.35(m,2H,J=6.57Hz,O-CH2-CH2 ),1.39(t,2H,J=7.14Hz,N-CH2-CH3 ).
[M+H]+calcd for 416.1709,MS found 416.1708;1H-NMR(300MHz,DMSO-d6):δ=12.30(s,1H,5-OH),7.82(m,2H,J=5.31Hz,Ph-H),7.38(m,3H,J=5.31Hz,Ph-H),6.54(s,1H,Ar-H),6.21(s,1H,Ar-H),4.15(t,2H,J=6.00Hz,O-CH2),3.04(b,6H,3×N-CH2 ),2.09(b,2H,N-CH2-CH2 ).
[M+H]+calcd for 382.1649,MS found 382.1654;1H-NMR(300MHz,CDCl3):δ=12.52(s,1H,5-OH),8.01(m,2H,J=7.95Hz,Ph-H),7.58(m,3H,J=7.95Hz,Ph-H),6.75(s,1H,Ar-H),5.86(s,1H,Ar-H),4.04(t,2H,J=6.3Hz,O-CH2),3.10(b,6H,3×N-CH2),1.76(br,6H,N-CH2-CH2 -CH2 ).
[M+H]+calcd for 398.1594,MS found 398.1598;H-NMR(300MHz,CDCl3):δ=12.4(s,1H,5-OH),7.91(m,2H,J=1.59Hz,Ph-H),7.56(m,3H,J=1.59Hz,Ph-H),6.63(s,1H,Ar-H),6.36(s,1H,Ar-H),4.15(t,2H,J=4.83Hz,O-CH2),3.85(t,2H,J=4.65Hz,2×O-CH2),2.74(q,6H,J=5.7Hz,3×N-CH2 ),2.08(m,2H,J=4.83Hz,O-CH2-CH2 ).
[M+H]+calcd for 370.1649,MS found 370.1652;1H-NMR(300MHz,DMSO-d6):δ=12.52(s,1H,5-OH),8.08(m,2H,J=1.59Hz,Ph-H),7.63(m,3H,J=1.59Hz,Ph-H),7.00(s,1H,Ar-H),6.34(s,1H,Ar-H),4.04(t,2H,J=4.83Hz,O-CH2),3.09(t,2H,J=4.65Hz,N-CH2),2.72(s,6H,3×N-CH3 ),1.81(m,2H,J=4.83Hz,O-CH2-CH2 ).
[M+H]+calcd for 398.1962,MS found 398.1959;H-NMR(300MHz,DMSO-d6):δ=12.52(s,1H,5-OH),8.08(m,2H,J=6.06Hz,Ph-H),7.63(m,3H,J=6.06Hz,Ph-H),7.00(s,1H,Ar-H),6.32(s,1H,Ar-H),4.06(t,2H,J=4.83Hz,O-CH2),3.09(t,6H,J=6.45Hz,3×N-CH2),1.82(br,4H,O-CH2-CH2 -CH2 ),1.16(t,6H,J=7.11Hz,2×N-CH2-CH3 ).
[M+H]+calcd for 396.1805,MS found 396.1812;1H-NMR(300MHz,DMSO-d6):δ=12.50(s,1H,5-OH),8.05(br,2H,Ph-H),7.60(br,3H,Ph-H),6.87(s,1H,Ar-H),6.11(s,1H,Ar-H),4.07(br,2H,ArOCH2),2.97(br,6H,3×N-CH2),1.85(br,8H,2×CH2 -CH2 ).
[M+H]+calcd for 412.1754,MS found 412.1755;1H-NMR(300MHz,CDCl3):δ=12.35(s,1H,5-OH),7.92(m,2H,J=6.06Hz,Ph-H),7.54(m,3H,J=6.06Hz,Ph-H),6.65(s,1H,Ar-H),6.36(s,1H,Ar-H),4.24(t,2H,J=4.83Hz,O-CH2),3.85(t,4H,J=6.45Hz,2×O-CH2),2.98(br,2H,N-CH2 ),2.59(br,4H,2×N-CH2),1.85(br,4H,O-CH2-CH2 -CH2 ).
[M+H]+calcd for 515.254,MS found 515.2545;1HNMR(300MHz,CDCl3):δ=12.35(s,1H,5-OH),7.92(m,2H,J=4.26Hz,Ph-H),7.54(m,3H,J=4.26Hz,Ph-H),6.65(s,1H,Ar-H),6.36(s,1H,Ar-H),4.24(t,2H,J=4.83Hz,O-CH2),2.75(t,2H,J=6.45Hz,N-CH2),2.61(br,4H,2×N-CH2 ),2.39(s,3H,N-CH3),1.85(br,4H,O-CH2-CH2 -CH2 ).
实施例2:L2-1的合成
第一步:将100g(0.8mol)焦性没食子酸,1000mL丙酮加入2000mL三颈瓶中,搅拌,依次加入26.7g(0.16mol)KI、220g(0.16mol)K2CO3和265mL(2.4mol)溴化苄,加热回流48h。TLC检测(石油醚:乙酸乙酯=10:1)原料消失。滤除碳酸钾,滤饼用二氯甲烷(100mL×4)洗涤,滤液浓缩至干,得到红褐色油状物。加入甲醇:乙醇(4:1/V:V)1000mL混合溶液,搅拌析出白色固体,抽滤,50mL×4甲醇洗涤,红外灯下干燥,得白色固体275g,收率87.5%。[M+H]+calcd for 397.1804,MS found 397.1872;1H-NMR(300MHz,CDCl3):δ=7.27~7.3(m,15H,Ar-H),6.92(t,1H,J=8.4Hz,Ar-H),6.64(d,2H,J=8.4Hz,Ar-H),5.1(s,4H,-OCH2Ph),5.07(s,2H,-OCH2Ph).
第二步:将1,2,3-三苄氧基苯60g(0.126mol)溶于100mL乙酸中,搅拌,加热至40℃使其完全溶解。缓慢滴加3mL硝酸,搅拌4h,滤除白色固体。滤液加入10mL硝酸,搅拌4h,过滤,合并滤饼得到粗品40g,无需纯化直接投入下一步。
第三步:将上步30g 2,6-二苄氧基对苯醌,260mL乙酸乙酯加入1000mL三颈瓶中,搅拌,分批加入过量的保险粉饱和水溶液,剧烈搅拌40min,过滤,分离有机层,有机层用100mL×2稀盐酸洗涤,100mL×2饱和食盐水洗涤,有机层无水硫酸钠干燥,过滤,滤液浓缩至干得黄色粗品,200mL甲醇重结晶,滤除硝化物杂质,滤液浓缩至干,100mL甲苯重结晶去除产品中的硫以及硫化物,得到灰白色片状晶体14g,两步总收率34%。[M+H]+calcd for323.1283,MS found 323.1367,m.p.115~117℃;1H-NMR(300MHz,CDCl3):δ=7.26~7.43(m,10H,Ar-H),6.15(s,2H,Ar-H),5.16(s,1H,Ar-OH),5.10(s,4H,-OCH2Ph),4.36(s,1H,Ar-OH).
第四步:将27g(0.084mol)2,6-二苄氧基对苯酚溶于214mL乙醇中,搅拌,加入20mL硫酸二甲酯,缓慢滴加28%氢氧化钠溶液,调节pH 8~9。室温搅拌2h,TLC检测(石油醚:乙酸乙酯=3:1)原料反应消失。过滤,滤饼水洗涤至中性,红外灯下干燥,得到白色固体25.1g,收率85.5%。[M+H]+calcd for 351.1596,MS found 351.1643;1H-NMR(300MHz,CDCl3):δ=7.26~7.46(m,10H,Ar-H),6.19(s,2H,Ar-H),5.12(s,4H,-OCH2Ph),3.84(s,3H,-OCH3),3.68(s,3H,-OCH3).
第五步:将10g(0.029mol)化合物II-4,70mL甲醇和0.43g 10%的Pd/C加入250mL的单颈瓶中。通入氢气8h,TLC检测(石油醚:乙酸乙酯=4:1)原料消失。滤除Pd/C,滤液浓缩干得褐色油状物4.86g,收率99%。[M+H]+calcd for 171.0657,MS found 171.0864;无需纯化,直接用于下步反应。
第六步:将4.63g(0.028mol)对甲基肉桂酰氯,4.66g(0.027mol)2,6-二甲氧基间苯二酚,20mL无水乙醚溶液加入100mL三颈瓶中。搅拌20min,向反应瓶中加入9.2mL BF3-Et2O溶液,40℃搅拌1.5h,TLC检测(乙酸乙酯:甲醇=1:0.1)原料消失。过滤,滤饼用10mL×3甲醇洗涤,红外灯下干燥,得到砖红色固体3.8g,收率43.9%。[M+H]+calcd for315.1232,MS found 315.1312.m.p.225℃~226℃;1H-NMR(300MHz,DMSO-d6):δ=8.17(d,1H,J=15.3Hz,-CH=CH-CO),8.02(d,1H,J=15.3Hz,-CH=CH-CO),7.78(d,2H,J=7.5Hz,Ar-H),7.34(d,2H,J=7.5Hz,Ar-H),6.21(s,1H,Ar-H),3.98(s,3H,-OCH3),3.70(s,3H,-OCH3),2.39(s,3H,-CH3).
第七步:将3.76g(0.016mol)化合物II-7溶于12mL无水DMSO中,搅拌,加热至100℃使得固体完全溶解,加入2颗碘(催化量)。提高温度至140℃搅拌5h,TLC检测(石油醚:乙酸乙酯:甲醇)=2:1:0.1)原料消失,冷却,放置冰箱数小时待析出黄色固体后,抽滤,滤饼用5mL×3甲醇洗涤,红外灯下干燥,得到黄色固体1.41g,收率37.7%。[M+H]+calcd for313.1076,MS found 313.1053;m.p.282℃~285℃;1H-NMR(300MHz,DMSO-d6):δ10.55(s,1H,7-ArOH),7.91(d,2H,J=8.1Hz,Ar-H),7.39(d,2H,J=8.1Hz,Ar-H),6.69(s,1H,Ar-H),6.47(s,1H,-C=CH),3.85(s,3H,-OCH3),3.77(s,3H,-OCH3),2.40(s,3H,Ar-CH3).
第八步:将2.1g(6.73mmol)化合物(17),105mL无水乙腈加入250mL三颈瓶中,冰水浴降温至0℃,加入5.37g(0.040mol)碾碎的无水三氯化铝,搅拌,升温回流8h,TLC检测(石油醚:乙酸乙酯:甲醇)=2:1:0.1)原料消失,冷却,加入60mL(4mol/L)盐酸,用200mL×2二氯甲烷萃取,有机层水洗涤至中性,分离有机层,无水硫酸钠干燥。柱层析分离得到黄色固体1.05g,收率51.2%。[M+H]+calcd for 299.0919,MS found 299.0916;1H-NMR(300MHz,CDCl3):δ=12.54(s,1H,5-OH),10.78(s,1H,7-OH),7.96(d,2H,J=8.1Hz,Ar-H),7.42(d,2H,J=8.1Hz,Ar-H),6.94(s,1H,Ar-H),6.30(s,1H,-C=CH),3.85(s,3H,-OCH3),2.41(s,3H,-CH3).
采用与实施例2相似的操作,制得下列化合物:
[M-H]-calcd for 317.0217,MS found 317.0229;1H-NMR(300MHz,DMSO-d6):δ=12.45(s,1H,5-OH),10.83(s,1H,7-Ar-OH),8.08(d,2H,J=8.7Hz,Ar-H),7.68(d,2H,J=8.7Hz,Ar-H),7.03(s,1H,Ar-H),6.32(s,1H,-C=CH),3.85(s,3H,-OCH3).
[M+H]+calcd for 351.0480,MS found 351.0462;1H-NMR(300MHz,DMSO-d6):δ11.39(s,1H,5-Ar-OH),8.37(d,2H,J=8.07Hz,Ar-H),8.04(d,2H,J=8.07Hz,Ar-H),7.39(s,1H,Ar-H),6.37(s,1H,-C=CH),3.86(s,3H,-OCH3).
[M-H]-calcd for 328.0457,MS found 328.0468;1H-NMR(300MHz,DMSO-d6):δ=8.42(d,2H,J=8.7Hz,Ar-H),8.32(d,2H,J=8.7Hz,Ar-H),7.19(s,1H,Ar-H),6.35(s,1H,-C=CH),3.87(s,3H,-OCH3).
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[M-H]-calcd for 317.0217,MS found 317.0200;1H-NMR(300MHz,DMSO-d6):δ=12.38(s,1H,5-ArOH),10.88(s,1H,7-Ar-OH),7.7(dd,1H,J1=1.62Hz,J2=8.4Ar-H),7.56-7.69(m,3H,Ar-H),6.59(s,1H,Ar-H),6.35(s,1H,-C=CH),3.75(s,3H,-OCH3).
实施例3:L3-1的合成
第一步:在500mL三颈瓶中加入间苯三酚(63g,0.5mol)和300mL无水乙醚,室温搅拌溶解,再依次加入无水ZnCl2(13.4g,0.1mol)和无水乙腈(50g,1.25mol),0℃下通入干燥的HCl气体反应40h,TLC检测(V石油醚:V乙酸乙酯=1:2)反应完全,静止待反应液温度升至室温,抽滤,滤饼烘干至恒重后溶于200mL水中,加热回流6h,析出大量固体,冷却至室温,抽滤,烘干,得白色固体60g,收率71%。
第二步:在500mL三颈瓶中加入中间体III-2(33.6g,0.2mol)和350mL无水丙酮,室温搅拌溶解,再加入63.48g K2CO3(0.46mol),室温条件下滴加硫酸二甲酯(39.78mL,0.42mol),1h左右滴加完毕,45℃继续反应4h,TLC检测(V石油醚:V乙酸乙酯=3:1)反应完全,静止冷却至室温,抽滤,滤液倒入5倍体积的水中,用1M HCl调pH=3-4,析出大量固体。抽滤,干燥得白色固体32.5g,收率83%。
第三步:在500mL三颈瓶中加入中间体III-3(16.36g,84mmol)和250mL乙醇,室温搅拌溶解,再加入11.39g对氟苯甲醛(92mmol),冰浴条件下滴加7%KOH水溶液150mL(0.21mol),滴加过程中保持温度小于5℃。1h左右滴加完毕,40℃继续反应10h,TLC检测(V石油醚:V乙酸乙酯=6:1)反应完全,静止冷却至室温,反应液倒入10倍体积的水中,用6M HCl调pH=3-4,析出大量固体。抽滤,烘干,得黄色固体21.33g,收率84.6%。
第四步:在250mL三颈瓶中加入中间体III-4(17.33g,57mmol)和43mL无水DMSO,升温至60℃,搅拌溶解,再加入催化量的I2(0.36g,1.4mmol),升温至130℃继续反应5h,TLC检测(V石油醚:V乙酸乙酯=3:1)反应完全,反应液趁热倒入10倍体积的饱和硫代硫酸钠水溶液中,析出大量固体。抽滤,烘干,得淡黄色固体16.3g,收率95%。
第五步:在1L茄形瓶中加入中间体III-5(21.36g,71mmol)和48%的氢溴酸300mL,回流反应60h,TLC检测(V石油醚:V乙酸乙酯=2:1)反应完全,静止冷却至室温,反应液倒入10倍体积的冰水中,析出大量固体。抽滤,滤饼用水多次洗涤至pH呈中性,干燥得粗品20.9g,聚酰胺柱层析(V石油醚:V乙酸乙酯=2:1)得淡黄色固体16.2g,收率83%。
第六步:在1L茄形瓶中加入中间体III-6(18g,71mmol)、氢氧化四甲铵(71.89g,40mmol)和450mL水,室温搅拌溶解,再每隔20min分8次加入过硫酸钾(35.7g,130mmol),加入过程中保持温度低于30℃,室温继续反应3h,TLC检测(V石油醚:V乙酸乙酯=2:1)反应完全,抽滤,滤液用磷酸二氢钾(约30g)调pH=6-7,析出固体,再每隔5min分3次加入45g氯化钠,室温搅拌过夜。抽滤,滤饼用20mL甲醇洗涤,烘干,得土黄色固体17g,收率60.8%。
第七、八步:在100mL三颈瓶中加入中间体III-7(10g,22.7mmol)和80mL DMF,室温搅拌溶解,再加入6.26g K2CO3(45.4mmol),室温条件下滴加烯丙基溴(4.12g,34.05mmol),5min左右滴加完毕,50℃继续反应8h,TLC检测(V二氯甲烷:V甲醇=10:1)反应完全,静止冷却至室温,抽滤,滤饼用20mL甲醇洗涤,滤液用6M HCl调pH=1-2,室温搅拌过夜,析出固体。抽滤,滤饼用10mL甲醇洗涤,烘干,得黄色固体(III-9)6.0g,收率77%。1HNMR(300MHz,DMSO-d6):δ=12.69(s,1H,5-OH),9.23(s,1H,8-OH),7.92(d,2H,J=9.00Hz,Ar-H),7.12(d,2H,J=9.00Hz,Ar-H),6.93(s,1H,CHCO),6.79(s,1H,Ar-H),5.90(m,1H,-CH=CH2),5.43(m,2H,-CH=CH2),5.34(s,2H,OCH2-Ar).
第九步:在100mL三颈瓶中加入中间体III-9(1g,3mmol)和10mL DMF,室温搅拌溶解,再加入0.84g K2CO3(6mmol)和0.34g溴代异丙烷(3.6mmol),80℃反应5h,TLC检测(V石油醚:V乙酸乙酯=2:1)反应完全,反应液趁热倒入10倍体积的冰水中,析出固体,静止2h,抽滤,烘干,粗品用正己烷和甲醇混合溶剂重结晶,得黄色固体680mg,收率62.3%。1HNMR(300MHz,DMSO-d6):δ=12.89(s,1H,5-OH),7.88(d,2H,J=9.00Hz,Ar-H),7.21(d,2H,J=9.00Hz,Ar-H),6.94(s,1H,CHCO),6.80(s,1H,Ar-H),5.90(m,1H,-CH=CH2),5.43(m,2H,-CH=CH 2),5.33(s,2H,OCH2-Ar),4.45(m,1H,CH(CH3)2),1.29(d,6H,J=6.00Hz,CH(CH 3)2).
第十步:在10mL耐压瓶中加入中间体19(500mg,1.35mmol)和5mL DMF,室温搅拌溶解,升温至240℃反应30min(微波反应Power:300W),TLC检测(V石油醚:V乙酸乙酯=2:1)反应完全,反应液倒入10mL冰水中,静止3h,析出固体,抽滤,滤饼烘干的黄色固体400mg,收率80%.1HNMR(300MHz,DMSO-d6):δ=12.90(s,1H,5-OH),10.59(s,1H,7-OH),7.89(d,2H,J=9.00Hz,Ar-H),7.21(d,2H,J=9.00Hz,Ar-H),6.94(s,1H,CHCO),5.90(m,1H,-CH=CH2),5.43(m,2H,-CH=CH 2),4.45(m,1H,CH(CH3)2),3.31(d,J=5.70Hz,2H,-CH 2CH=CH2),1.29(d,6H,J=6.00Hz,CH(CH 3)2).
第十一步:在100mL三颈瓶中加入中间体20(100mg,0.27mmol)和8mL无水DMSO,升温至60℃,搅拌溶解,再在N2保护下依次加入116mg哌嗪(3.5mmol)和70mg DIEA(0.54mmol),80℃反应24h,TLC检测(V石油醚:V乙酸乙酯=2:1)反应完全,反应液趁热倒入10mL饱和食盐水中,静止3h,抽滤,滤饼用10mL水洗涤,烘干得粗品120mg,粗品用甲醇和二氯甲烷的混合溶剂重结晶,得黄色固体66mg,收率56%。m.p.214~220℃.[M+H]+calcdfor437.2032,MSfound 437.2204.1HNMR(300MHz,DMSO-d6):δ=13.0(s,1H,5-OH),10.59(s,1H,7-OH),7.86(d,2H,J=9.00Hz,Ar-H),7.05(d,2H,J=9.00Hz,Ar-H),6.75(s,1H,CHCO),5.87(m,1H,-CH=CH2),4.93(m,2H,-CH=CH 2),4.40(m,1H,CH(CH3)2),3.62(s,4H,N(CH 2CH2)2NH),3.28(d,J=5.70Hz,2H,-CH 2CH=CH2),2.83(s,4H,N(CH2CH 2)2NH),1.31(d,6H,J=6.00Hz,CH(CH 3)2).
采用与实施例3相似的操作,制得下列化合物:
[M+H]+calcd for 451.2188,MS found 451.2263.1HNMR(300MHz,DMSO-d6):δ=13.1(s,1H,5-OH),10.59(s,1H,7-OH),7.86(d,2H,J=9.00Hz,Ar-H),6.89(d,2H,J=9.00Hz,Ar-H),6.72(s,1H,CHCO),5.90(m,1H,-CH=CH2),4.95(m,2H,-CH=CH 2),4.42(m,1H,CH(CH3)2),3.62(s,4H,Ar-N(CH 2)2),3.31(d,J=5.70Hz,2H,-CH 2CH=CH2),2.93(s,2H,NHCH 2),2.70(s,2H,NHCH 2),1.80(m,2H,NCH2CH 2CH2NH),1.31(d,6H,J=6.00Hz,CH(CH 3)2).
[M+H]+calcd for 451.2188,MS found 451.2263.1HNMR(300MHz,DMSO-d6):δ=13.1(s,1H,5-OH),10.59(s,1H,7-OH),7.90(d,2H,J=9.00Hz,Ar-H),6.89(d,2H,J=9.00Hz,Ar-H),6.80(s,1H,CHCO),5.91(m,1H,-CH=CH2),4.96(m,2H,-CH=CH 2),4.40(m,1H,CH(CH3)2),3.35(s,4H,N(CH 2CH2)2NH),3.31(d,J=5.70Hz,2H,-CH 2CH=CH2),2.48(s,4H,N(CH2CH 2)2NH),2.25(s,3H,NCH3),1.32(d,6H,J=6.00Hz,CH(CH 3)2).
实施例4:L4-1的合成
第一步:氮气保护下,将汉黄芩素(IV-1)0.4g(1.4mmol)和无水丙酮10mL加至25mL反应瓶中,搅拌溶解后加入碳酸钾0.21g(1.54mmol),1,4-二溴丁烷0.20mL(1.69mmol)。加热回流,TLC检测原料消失后过滤除去无机盐,减压蒸除溶剂和过量的1,4-二溴丁烷,得粗品,经柱层析分离得黄色固体0.59g,收率77%。1H-NMR(300MHz,CDCl3),δ=2.09(4H,m,-OCH2-CH2-CH2 -CH2Br),3.53(2H,m,J=12.3Hz,-CH2 Br),3.93(3H,s,-OCH3),4.15(2H,t,J=6.0Hz,-OCH2 ),6.41(1H,s,Ar-H),6.68(1H,s,-CH=),7.56(3H,m,Ar-H),7.94(2H,m,Ar-H),12.54(1H,s,-OH).
第二步:氮气保护下,将化合物IV-2 500mg(1.2mmol)和无水乙腈50mL加至100mL反应瓶中,搅拌溶解后加入二乙胺0.44g(6mmol)。加热回流,TLC检测原料消失后,减压蒸除溶剂及过量的胺,得粗品,经柱层析分离得黄色固体0.39g,收率79%。[M+H]+calcd for421.2124,MS found 421.2156.1H-NMR(300MHz,CDCl3),δ=12.55(1H,s,-OH),7.97(2H,m,Ar-H),7.93(3H,m,Ar-H),6.68(1H,s,-CH=),6.43(1H,s,Ar-H),4.14(2H,t,J=12.9Hz,-OCH2-CH2),3.93(3H,s,8-OCH3),2.58(6H,m,3-N-CH2),1.91(2H,m,-CH2 -CH2OAr),1.88(2H,m,-CH2 -CH2-N),1.06(6H,m,2-CH3).
采用与实施例4相似的操作,制得下列化合物:
[M+H]+calcd for 444.2022,MS found 444.2082.1H-NMR(300MHz,CDCl3),δ=12.55(1H,s,5-OH),7.96(2H,m,Ar-H),7.56(3H,m,Ar-H),6.68(1H,s,-CH=),6.43(1H,s,Ar-H),4.14(2H,t,J=12.9Hz,7-OCH2 -CH2),3.94(3H,s,8-OCH3),3.66(4H,t,J=10.5Hz,2-CH2 OH),2.72(6H,m,3-N-CH2),1.94(2H,m,-CH2 -CH2-O-Ar),1.73(2H,m,-CH2 -CH2-N).
[M+H]+calcd for 426.1917,MS found 426.2001.1H-NMR(300MHz,CDCl3),δ=12.53(1H,s,5-OH),7.96(2H,m,Ar-H),7.56(3H,m,Ar-H),6.68(1H,s,-CH=),6.45(1H,s,Ar-H),4.19(2H,t,J=12.9Hz,7-OCH2 -CH2),3.93(3H,s,8-OCH3),3.73(4H,m,2-OCH2 ),2.54(6H,m,3-N-CH2),1.76(2H,m,-CH2 -CH2OAr),1.57(2H,m,-CH2 -CH2-N).
[M+H]+calcd for 444.2022,MS found 444.2109.1H-NMR(300MHz,CDCl3),δ=12.55(1H,s,5-OH),7.97(2H,m,Ar-H),7.93(3H,m,Ar-H),7.34(5H,m,Ar-H),6.68(1H,s,-CH=),6.43(1H,s,Ar-H),4.14(2H,t,J=12.6Hz,-OCH2 -CH2),3.93(3H,s,-OCH3),3.83(2H,s,Ar-CH2 ),2.72(2H,m,CH2 -NH),1.90(2H,m,-CH2 -CH2OAr),1.73(2H,m,-CH2 -CH2-NH).
[M+H]+calcd for 462.1917,MS found 426.1973.1H-NMR(300MHz,CDCl3),δ=12.55(1H,s,-OH),7.97(2H,m,Ar-H),7.56(3H,m,Ar-H),6.83(2H,m,Ar-H),6.68(3H,m,2-Ar-H,1-CH=),6.41(1H,s,Ar-H),4.17(2H,t,J=12.0Hz,7-OCH2 -CH2),3.93(3H,s,8-OCH3),3.75(3H,s,CH3 -OAr),3.22(2H,m,-CH2 -NH),2.05(2H,m,-CH2 -CH2OAr),1.91(2H,m,-CH2 -CH2-N).
[M+H]+calcd for 410.1967,MS found 410.1121.1H-NMR(300MHz,CDCl3),δ=12.55(1H,s,5-OH),7.97(2H,m,Ar-H),7.56(3H,m,Ar-H),6.68(1H,s,-CH=),6.45(1H,s,Ar-H),4.17(2H,t,J=12.9Hz,7-OCH2 -CH2),3.93(3H,s,8-OCH3),2.58(6H,m,3-N-CH2),1.82(4H,m,2-CH2 ),1.57(2H,m,-CH2 -CH2-N).
[M+H]+calcd for 424.2124,MS found 424.2278.1H-NMR(300MHz,CDCl3),δ=12.55(1H,s,5-OH),7.97(2H,m,Ar-H),7.56(3H,m,Ar-H),6.68(1H,s,-CH=),6.45(1H,s,Ar-H),4.17(2H,t,J=12.3Hz,7-OCH2 -CH2),3.93(3H,s,8-OCH3),2.45(6H,m,3-N-CH2),2.10(2H,m,-CH2 -CH2OAr),1.46(6H,m,3-CH2),1.38(2H,m,-CH2 -CH2-N).
[M+H]+calcd for 439.2233,MS found 439.2431.1H-NMR(300MHz,CDCl3),δ:=12.53(1H,s,5-OH),7.96(2H,m,Ar-H),7.56(3H,m,Ar-H),6.68(1H,s,-CH=),6.43(1H,s,Ar-H),4.13(2H,t,J=12.9Hz,7-OCH2 -CH2),3.93(3H,s,8-OCH3),2.47(10H,m,5-CH2 ),2.30(3H,s,N-CH3),1.90(2H,m,-CH2 -CH2OAr),1.70(2H,m,-CH2 -CH2-N).
[M+H]+calcd for 432.1811,MS found 432.1893.1H-NMR(300MHz,CDCl3),δ=12.55(1H,s,5-OH),7.97(2H,m,Ar-H),7.93(3H,m,Ar-H),7.34(5H,m,Ar-H),6.68(1H,s,-CH=),6.43(1H,s,Ar-H),4.14(2H,t,J=12.6Hz,-OCH2 -CH2),3.93(3H,s,-OCH3),3.83(2H,s,Ar-CH2 ),2.72(2H,m,CH2 -NH),1.90(2H,m,-CH2 -CH2OAr),1.73(2H,m,-CH2 -CH2-NH).
实施例5:化合物对人源cGAS的生物化学活性研究
1、全长人源cGAS的表达及纯化
将对应于全长h-cGAS(1-522)的序列插入到修饰的pRSFDuet-1载体中,使得ULP1切割位点将cGAS与(His6)-SUMO标签分开。随后通过测序确定该序列。SUMO标记的蛋白在大肠杆菌中表达。细菌在37℃培养至OD600为0.8时,将培养温度降至18℃,加入终浓度为0.3mMIPTG诱导过夜。细菌在4℃离心,在Ni A buffer(500mM NaCl、20mM咪唑、50mM Tris-HCl,pH7.5)中超声破碎。细胞裂解物在离心机中以20000rpm离心1h。离心后,将上清液装入HisTrap FF柱,并用Ni Abuffer洗涤。然后,用Ni B buffer(500mM NaCl、2500mM咪唑、50mMTris-HCl,PH 7.5)洗脱目的蛋白。在含有300mM NaCl、1mM DTT、20mM Tris-HCl、pH 7.5的缓冲液中,用ULP1切割并去除His6-SUMO标签。透析后,使用HisTrap FF色谱柱将标签去除。包含流动相的cGAS蛋白在肝素柱上进一步分离纯化,然后用分子筛柱缓冲液(300mM NaCl和1mM DTT,20mM Tris-HCl,pH 7.5)在16/60G200 Superdex柱上凝胶过滤,得到目的蛋白。
构建体序列:氨基酸1-522,人cGAS,
MQPWHGKAMQRASEAGATAPKASARNARGAPMDPTESPAAPEAALPKAGKFGPARKSGSRQKKSAPDTQERPPVRATGARAKKAPQRAQDTQPSDATSAPGAEGLEPPAAREPALSRAGSCRQRGARCSTKPRPPPGPWDVPSPGLPVSAPILVRRDAAPGASKLRAVLEKLKLSRDDISTAAGMVKGVVDHLLLRLKCDSAFRGVGLLNTGSYYEHVKISAPNEFDVMFKLEVPRIQLEEYSNTRAYYFVKFKRNPKENPLSQFLEGEILSASKMLSKFRKIIKEEINDIKDTDVIMKRKRGGSPAVTLLISEKISVDITLALESKSSWPASTQEGLRIQNWLSAKVRKQLRLKPFYLVPKHAKEGNGFQEETWRLSFSHIEKEILNNHGKSKTCCENKEEKCCRKDCLKLMKYLLEQLKERFKDKKHLDKFSSYHVKTAFFHVCTQNPQDSQWDRKDLGLCFDNCVTYFLQCLRTEKLENYFIPEFNLFSSNLIDKRSKEFLTKQIEYERNNEFPVFDEF。
2、化合物对h-cGAS抑制作用的生物活性测试
化合物对cGAS的酶活测试方法是基于焦磷酸酶的一种欧联测定方法。最终测试浓度为20mM Tris,pH 7.5,5mM MgCl2,0.01%Tween-20,1mM ATP,0.3mM GTP,5μg/mL HT-DNA,h-cGAS 150nM。
所有的化合溶解在DMSO中,在浓度为10mM。然后再用DMSO将化合物稀释到200μM,之后将2μL的DMSO稀释液加入到8μL的reaction buffer中,涡旋混匀。10μL的酶储备液(600nM)加入到96孔板中。之后加入10μL化合物稀释液,室温下于摇床上孵育5min。孵育之后加入10μL PPase(200nM)、5μL ATP+GTP混合物(8mM ATP、2.4mM GTP),最后加入5μL HT-DNA(40μg/mL)启动反应,37℃反应90min。之后,加入40μL EDTA溶液(50mM)淬灭反应,再加入20μL孔雀绿检测试剂,置于摇床上25min后检测620nm处吸光度。以未加HT-DNA的作为阴性对照,加入DMSO而非化合物的作为阳性对照。
Inhibition%=1-(Abs样品-Abs阴性对照)/(Abs阳性对照-Abs阴性对照)
实验结果如下表1所示。
表1.化合物对h-cGAS的抑制作用(IC50)
由表1可见,本发明的化合物对cGAS均有抑制活性,且达到微摩尔水平。活性较为突出的化合物有L1-6以及L2-5。
3、化合物对软骨细胞炎症相关指标的生物活性评价
将提取的软骨大鼠细胞,12孔板每孔5×105细胞,用抑制剂孵育1h后,使用TNF-α与OM联合给药建立软骨细胞炎症模型,4h后收集细胞,用TRIzol提取RNA,并用Nano-Drop2000分光光度计定量,使用Trans-SCRIPT First-Strand cDNA合成SuperMix试剂盒进行逆转录。随后,使用Applied Biosystems(Thermo Fisher Scientific,Waltham,USA)用SYBRGreen扩增反转录产物,引物序列如下表所示,检测IL-6、IL-1βmRNA表达水平,以未使用TNF-α和OM刺激的作为空白对照,以加入DMSO而不含抑制剂的作为模型对照,将所得数据导入Graphpad prism 7.0进行分析,分析结果如图1、图2所示。
Gene | (sequence5’-3’)forward | reverse |
IL-6 | ACTCACCTCTTCAGAACGAATTG | CCATCTTTGGAAGGTTCAGGTTG |
IL-1β | TTGACGGACCCCAAAAGATG | CAGCTTCTCCACAGCCACAA |
由图1、图2可见,本发明的部分化合物对大鼠的软骨炎症模型的炎症因子的产生有明显的抑制作用。尤其是对cGAS抑制活性较好的化合物L1-6与L2-5,可将IL-6与IL-1β的产生减少3倍左右,这说明L1-6与L2-5可以通过抑制cGAS的作用进而抑制炎症因子的产生,同时也说明这些分子在应用于炎症性疾病中具有一定潜力。
Claims (9)
1.一种苯并吡喃酮类化合物,其特征在于,具有式I的结构,所述化合物包含其药学上可接受的盐:
其中:
R1为n=2-4;
Ra、Rb为
R2为H;
R3为H;
R4为H。
2.根据权利要求1所述的化合物,其特征在于,所述结构中:
R1为
R4为H。
3.根据权利要求1所述的化合物,其特征在于,选自以下任一化合物:
4.根据权利要求1~3任一所述的化合物,其特征在于,所述药学上可接受的盐为所述化合物与酸或碱形成的盐,所述酸为盐酸、氢溴酸、硫酸、磷酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、苹果酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸或杏仁酸,所述碱为含有碱性金属阳离子、碱土金属阳离子或铵阳离子盐的无机碱。
5.一种药物组合物,其特征在于,所述药物组合物包含权利要求1~4任一所述的化合物以及药学上可接受的载体。
6.一种权利要求1~4任一所述的化合物或者权利要求5所述的药物组合物在制备cGAS抑制剂药物中的应用。
7.一种苯并吡喃酮类化合物在制备cGAS抑制剂药物中的应用,其特征在于,所述化合物选自以下任一化合物:
8.根据权利要求6或7所述的应用,其特征在于,所述药物为治疗自身免疫性疾病、炎症性疾病或神经变性病症的药物。
9.根据权利要8所述的应用,其特征在于,所述疾病为系统性红斑狼疮、家族性冻疮狼疮、Aicardi-Goutieres综合征、类风湿性关节炎、酒精性脂肪肝、非酒精性脂肪肝、老年性黄斑病变、亨廷顿症或渐冻症。
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