CN115322120A - 一类小分子化合物及在制备治疗dhodh介导疾病药物中的用途 - Google Patents
一类小分子化合物及在制备治疗dhodh介导疾病药物中的用途 Download PDFInfo
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Abstract
本发明属于医药领域,特别涉及一类小分子化合物及其在制备治疗DHODH介导的疾病药物中的用途。本发明涉及的一类具有新型骨架的小分子化合物,结构如式I所示;该类化合物具有良好的DHODH酶活抑制活性,可用于治疗DHODH介导的各类疾病,包括但不限于抗肿瘤、自身免疫性疾病及抗病毒感染等多种疾病。
Description
技术领域:
本发明属于医药技术领域,特别涉及一类小分子化合物及在制备治疗DHODH介导疾病药物中的用途。
背景技术:
二氢乳清酸脱氢酶(dihydroorotate dehydrogenase,DHODH)位于线粒体内膜,为细胞嘧啶核苷酸从头合成通路的限速酶。研究表明,DHODH是治疗肿瘤、自身免疫性疾病及病毒感染等多种疾病的有效靶点。
DHODH在多种癌症中过表达,包括急性髓系白血病、淋巴瘤、多发性骨髓瘤、结直肠癌、肺癌、乳腺癌、宫颈癌、胶质母细胞瘤干细胞等,抑制DHODH酶活,可有效的抑制肿瘤细胞增殖。近年来,DHODH被视为极具潜力的抗肿瘤靶点。目前,已有多个DHODH抑制剂(Brequinar、ASLAN003、PCT299、BAY2402234、AG-636和JNJ-74856665)进入临床研究阶段。
抑制DHODH可以降低激活的免疫细胞数量,从而实现免疫抑制的效果;目前,DHODH抑制剂来福米特(Leflunomide)及其代谢物特立氟胺(Teriflunomide)获批上市,用于类风湿关节炎的治疗;抑制剂Vidofludimus用于自身免疫性疾病的治疗处于临床Ⅱ期研究阶段。
研究表明,DHODH抑制剂可抑制细胞内病毒的RNA合成,进而展现出良好的病毒抑制活性。2020年Brequinar和特立氟胺用于新冠病毒感染的治疗进入临床研究阶段。
发明内容:
本发明所解决的技术问题是提供了一类新型小分子化合物,结构如式I所示:
其中R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
R3至R5为H、F、Cl、Br、I、甲基。
R6为甲基,卤素取代的甲基,乙基,卤素取代的乙基,丙基,卤素取代的丙基,环丙基,卤素取代的环丙基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
优选的化合物R6为甲基,乙基,环丙基。
其中R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
R3至R5为H、F、Cl、Br、I、甲基。
进一步的R6为甲基,其结构如式Ⅱ所示:
R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
R3至R5为H、F、Cl、Br、I、甲基。
进一步的优选化合物R3至R5为F、Cl、Br。
其中R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
进一步优选的化合物,R3为F,R4和R5为H,结构如式Ⅲ所示:
其中R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
进一步的优选化合物R1为甲基、乙基、异丙基、(S)-三氟异丙基。
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基。所述的卤素取代为F、Cl、Br、I的单取代或多取代。
进一步的,上述优选化合物的结构式为:
本发明提供了该类分子的合成方法:
制备方法,合成路线如下:
(a)原料1在80%的氨水溶液中高温高压的条件氨化获得中间体2;
(b)中间体2在叔丁醇钾的作用下获得中间体3;
(c)中间体3在KOH水溶液中高温水解获得中间体4;
(d)中间体4通过Fmoc氨基保护获得中间体5;
(e)中间体5通过与草酰氯反应获得酰氯中间体6;
(f)中间体6与各类胺缩合反应获得酰胺中间体7;
(g)中间体7在哌啶作用下脱Fmoc保护获得中间体8;
(h)中间体8通过酰胺缩合获得中间体9;
(i)中间体9在NaOH水溶液中水解获得终产物IV。
本发明所述的一类新型小分子化合物包含其任一原子的同位素取代。
本发明所述的一类新型小分子化合物包含其药学可接受的盐。
本发明上述新型小分子包含其各式药物组合物,即药学上可以接受的辅助性成分组合。
本发明提供了上述的一类新型小分子化合物在制备治疗DHODH介导的疾病药物中的用途。
附图说明:
图1、优选化合物13t和13u体内抗肿瘤活性。
具体实施方式
以下结合实施例对本发明作进一步的阐述。实施例仅用于说明本发明,而不是以任何方式限制本发明。
表1.新型小分子化合物结构
实施例一:代表性中间体2的制备
量取2,4,5-三氟苯腈1(2.0g,12.7mmol)加入20mL含量为25-28%氨水,在高压反应釜中130℃搅拌6h;冷却至室温,析出大量白色固体,过滤并用纯水清洗3次,干燥后获得中间体2粗品(1.9g,97.1%),未进一步纯化用于下一步反应。
实施例二:代表性中间体3的制备
将异丙醇(1.2g,19.5mmol,3.0equiv)溶解于20mL无水的四氢呋喃(THF),随后加入叔丁醇钾(t-BuOK,2.2g,19.5mmol,3.0equiv),搅拌10分钟后加入中间体2粗品(1.0g,6.5mmol,1.0equiv),反应液搅拌回流,TLC监测反应完全后冷却至室温,乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析分离获得白色固体3(950mg,75.2%)。
1H NMR(400MHz,DMSO)δ7.32(d,J=11.2Hz,1H),6.46(d,J=7.5Hz,1H),6.18(s,2H),4.64–4.42(m,1H),1.28(d,J=6.0Hz,6H)。
实施例三:代表性中间体4的制备
中间体3(800mg,4.1mmol)加入15mL 3M的KOH水溶液中,反应液在100℃搅拌20h,冷却至室温,用盐酸稀溶液中和反应液并调为酸性(pH=5),乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析分离获得白色固体4(785mg,90.0%)。
1H NMR(400MHz,DMSO)δ11.65(s,1H),7.35(d,J=12.3Hz,1H),6.43(d,J=7.7Hz,1H),5.92(s,2H),4.50–4.37(m,1H),1.27(d,J=6.0Hz,6H)。
实施例四:代表性中间体5的制备
将中间体4(750mg,3.5mmol,1.0equiv)和碳酸氢钠固体(887mg,10.6mmol,3.0equiv)分别加入15mL无水的四氢呋喃中,随后室温逐滴加入氯甲酸-9-芴基甲酯(1.3g,5.3mmol,1.5equiv)的四氢呋喃溶液,滴加完成后在60℃搅拌12h,冷却至室温,乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析分离获得白色固体5(1.1g,72.1%)。
1H NMR(400MHz,DMSO)δ12.56(s,1H),9.87(s,1H),7.91(d,J=7.5Hz,2H),7.80(d,J=7.4Hz,2H),7.59(d,J=6.7Hz,1H),7.48(d,J=11.3Hz,1H),7.44(t,J=7.4Hz,2H),7.35(t,J=7.4Hz,2H),4.51–4.42(m,3H),4.31(t,J=7.1Hz,1H),1.26(d,J=6.0Hz,6H)。
实施例五:代表性中间体7的制备
将中间体5(1g,2.3mmol,1.0equiv)溶于15mL无水的二氯甲烷,加入3滴催化量的N,N-二甲基甲酰胺(DMF),在搅拌条件下逐滴加入草酰氯溶液(1.5g,11.5mmol,5.0equiv),室温搅拌4h,后直接旋干反应液,获得酰氯中间体6未纯化直接用于下一步反应;将中间体6溶于10mL无水二氯甲烷中,加入2-氯-6-氟苯胺(500mg,3.5mmol,1.5equiv)的二氯甲烷溶液和无水三乙胺(696mg,6.9mmol,3.0equiv),室温反应8h,旋干后柱层析分离获得白色固体7(1.0g,79.0%)。
1H NMR(400MHz,DMSO)δ9.99(s,1H),9.70(s,1H),7.92(d,J=7.5Hz,2H),7.81(d,J=7.4Hz,2H),7.75(d,J=6.9Hz,1H),7.65(d,J=11.4Hz,1H),7.40(m,7H),4.72(m 1H),4.46(d,J=7.2Hz,2H),4.33(t,J=7.1Hz,1H),1.39(d,J=6.0Hz,6H)。
实施例六:代表性中间体8的制备
将中间体7(900mg,1.6mmol)溶于10mL N,N-二甲基甲酰胺(DMF)中,随后加入3mL哌啶,室温搅拌5h,乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析分离获得白色固体8(401mg,74.3%)。
1H NMR(400MHz,DMSO)δ9.52(s,1H),7.52(d,J=12.5Hz,1H),7.42(d,J=7.6Hz,1H),7.34(m,2H),6.56(d,J=7.4Hz,1H),5.99(s,2H),4.70(m,1H),1.40(d,J=6.0Hz,6H)。
实施例七:代表性化合物13i的制备
将中间体8(350mg,1.0mmol,1.0equiv)和无水三乙胺and(311mg,3.1mmol,3.0equiv)溶于10mL二氯甲烷中,随后加入5-甲基异恶唑-4-甲酰氯(190mg,1.5mmol,1.0equiv)的二氯甲烷溶液,室温搅拌5h,旋干得中间体9粗品,未进一步纯化直接用于下一步反应;将粗品中间体9溶于pH=12的异丙醇(70%)/H2O(30%)中,室温搅拌2h,使用稀盐酸水溶液中和并调为酸性,乙酸乙酯萃取,无水硫酸钠干燥,浓缩后柱层析分离获得白色固体13i(287mg,64.1%)。
1H NMR(400MHz,DMSO)δ12.62(s,1H),9.66(s,1H),8.55(d,J=6.6Hz,1H),7.62(d,J=12.1Hz,1H),7.44(d,J=7.4Hz,1H),7.41–7.30(m,2H),4.73(m,1H),2.04(s,3H),1.42(d,J=6.0Hz,6H)。
13C NMR(100MHz,DMSO)δ189.36,167.28,162.51,158.50(d,J=250.8Hz),152.89,145.80(d,J=235.9Hz),134.09(d,J=12.2Hz),131.91(d,J=3.1Hz),128.91(d,J=9.1Hz),125.60(d,J=3.2Hz),124.61,124.25(d,J=15.9Hz),116.32(d,J=21.8Hz),115.55(d,J=20.8Hz),113.17(d,J=5.4Hz),105.86(d,J=1.7Hz),77.86,73.09,27.48,22.14(2C)。
HRMS(ESI)m/z:472.0832[M+Na+]。
化合物13a-h,13j-y制备根据上述的化合物13i的制备方法进行。
化合物13a
1H NMR(400MHz,DMSO)δ12.29(s,1H),10.37(s,1H),8.51(d,J=6.6Hz,1H),8.46(t,J=8.1Hz,1H),7.76(d,J=12.2Hz,1H),7.34(m,1H),7.22(t,J=7.5Hz,1H),7.16–7.10(m,1H),4.80(m,1H),2.09(s,3H),1.44(d,J=6.0Hz,6H)。
13C NMR(100MHz,DMSO)δ188.24,166.68,162.15(d,J=1.3Hz),152.63,152.60(d,J=240.8Hz),146.31(d,J=236.9Hz),133.61(d,J=12.7Hz),127.09(d,J=10.1Hz),125.24(d,J=3.2Hz),124.65(d,J=7.7Hz),123.28,121.88,116.58(d,J=22.2Hz),115.53(d,J=18.9Hz),114.09(d,J=6.4Hz),106.41,79.28,73.36,26.56,22.02(2C)。
HRMS(ESI)m/z:428.0664[M+Na+]。
化合物13b
1H NMR(400MHz,DMSO)δ12.42(s,1H),10.18(s,1H),8.55(d,J=6.6Hz,1H),8.38(dd,J=8.3,0.9Hz,1H),7.76(d,J=12.3Hz,1H),7.55(dd,J=8.0,1.2Hz,1H),7.38(t,J=7.3Hz,1H),7.16(td,J=7.9,1.4Hz,1H),4.80(m,1H),2.07(s,3H),1.44(d,J=6.1Hz,6H)。
13C NMR(100MHz,DMSO)δ187.76,166.44,162.31,152.77,146.40(d,J=236.6Hz),135.43,133.39(d,J=12.6Hz),129.75,128.20,125.59,123.43,123.36,122.76,116.82(d,J=22.2Hz),114.50(d,J=5.9Hz),106.67,79.87,73.61,26.19,22.29(2C)。
HRMS(ESI)m/z:454.0946[M+Na+]。
化合物13c
1H NMR(400MHz,DMSO)δ12.33(s,1H),10.04(s,1H),8.52(d,J=6.6Hz,1H),8.23(dd,J=8.2,0.9Hz,1H),7.75(d,J=12.3Hz,1H),7.70(dd,J=8.0,1.2Hz,1H),7.41(t,J=7.3Hz,1H),7.11(td,J=8.0,1.5Hz,1H),4.79(m,1H),2.09(s,3H),1.46(d,J=6.1Hz,6H)。
13C NMR(100MHz,DMSO)δ187.02,166.05,162.28,152.75,146.57(d,J=236.8Hz),136.55,133.01,132.90(d,J=12.5Hz),128.61,126.36,124.50,121.98,116.89(d,J=22.4Hz),115.05(d,J=5.8Hz),114.70,107.07,80.77,73.73,25.62,22.33(2C)。
HRMS(ESI)m/z:498.0439[M+Na+]。
化合物13d
1H NMR(400MHz,DMSO)δ12.58(s,1H),10.24(s,1H),8.51(d,J=6.7Hz,1H),7.74(d,J=11.9Hz,1H),7.58(d,J=11.9Hz,1H),7.37(m,2H),6.92(td,J=8.4,2.5Hz,1H),4.65(m,1H),2.04(s,3H),1.42(d,J=6.0Hz,6H)。
13C NMR(100MHz,DMSO)δ189.35,167.27,163.13,162.71(d,J=239.8Hz),152.45,145.88(d,J=235.8Hz),140.88(d,J=11.1Hz),133.67(d,J=12.2Hz),131.01(d,J=9.5Hz),124.66,116.03(d,J=21.9Hz),115.66(d,J=2.3Hz),114.82(d,J=5.6Hz),110.44(d,J=21.1Hz),106.72(d,J=26.5Hz),106.15(d,J=2.0Hz),77.82,73.22,27.49,22.23(2C)。
HRMS(ESI)m/z:438.1242[M+Na+]。
化合物13e
1H NMR(400MHz,DMSO)δ12.11(s,1H),10.14(s,1H),8.38(d,J=6.6Hz,1H),7.71(dd,J=9.0,5.0Hz,2H),7.60(d,J=11.8Hz,1H),7.20(t,J=8.9Hz,2H),4.66(m,1H),2.10(s,3H),1.41(d,J=6.0Hz,6H)。
13C NMR(100MHz,DMSO)δ186.96,166.10,162.66,158.67(d,J=240.1Hz),152.10,146.78(d,J=237.0Hz),135.57(d,J=2.6Hz),131.54(d,J=12.5Hz),121.71,121.63,117.63(d,J=5.4Hz),116.42,116.20,116.06,115.84,107.91,80.82,73.22,25.34,22.21(2C)。
HRMS(ESI)m/z:438.1239[M+Na+]。
化合物13f
1H NMR(400MHz,DMSO)δ11.94(s,1H),10.38(s,1H),8.48(d,J=7.6Hz,1H),8.42(d,J=6.5Hz,1H),7.79(d,J=12.3Hz,1H),7.09(m,2H),6.96(t,J=8.3Hz,1H),4.80(m,1H),3.92(s,3H),2.14(s,3H),1.45(d,J=6.0Hz,6H)。
13C NMR(100MHz,DMSO)δ187.03,166.06,161.78,152.43,148.52,146.61(d,J=236.6Hz),132.56(d,J=12.4Hz),128.17,124.20,122.07,121.01,120.25,116.83(d,J=22.2Hz),115.66(d,J=5.6Hz),111.20,107.10,80.69,73.31,56.05,25.64,22.11(2C)。
HRMS(ESI)m/z:428.1617[M+H+]。
化合物13g
1H NMR(400MHz,DMSO)δ11.91(s,1H),10.14(s,1H),8.33(d,J=6.5Hz,1H),7.62(d,J=11.8Hz,1H),7.43(s,1H),7.26(t,J=8.1Hz,1H),7.16(d,J=8.0Hz,1H),6.69(dd,J=8.1,2.1Hz,1H),4.67(m,1H),3.76(s,3H),2.13(s,3H),1.42(d,J=6.0Hz,6H)。
13C NMR(100MHz,DMSO)δ187.62,166.42,162.67,160.12,152.18,146.58(d,J=236.4Hz),140.30,132.13(d,J=11.8Hz),130.22,122.46,116.87(d,J=4.5Hz),116.28(d,J=22.1Hz),112.14,109.48,107.45,105.73,80.00,73.26,55.48,25.93,22.23(2C)。
HRMS(ESI)m/z:428.1625[M+Na+]。
化合物13h
1H NMR(400MHz,DMSO)δ12.03(s,1H),10.21(s,1H),8.35(d,J=6.5Hz,1H),8.07(dd,J=6.8,2.3Hz,1H),7.64–7.50(m,2H),7.41(t,J=9.1Hz,1H),4.63(m,1H),2.11(s,3H),1.40(d,J=6.0Hz,6H)。
13C NMR(100MHz,DMSO)δ188.28,166.74,163.20,153.73(d,J=242.8Hz),152.31,146.25(d,J=236.4Hz),136.45(d,J=2.9Hz),132.70(d,J=12.0Hz),123.26,121.32,120.31(d,J=6.8Hz),119.72(d,J=18.4Hz),117.54(d,J=21.9Hz),116.20,116.06(d,J=16.6Hz),107.01,79.18,73.19,26.51,22.19(2C)。
HRMS(ESI)m/z:472.0852[M+Na+]。
化合物13i
1H NMR(400MHz,DMSO)δ11.88(s,1H),9.62(s,1H),8.36(d,J=6.0Hz,1H),7.62(d,J=11.7Hz,1H),7.38(m,1H),7.20(t,J=8.1Hz,2H),4.70(m,1H),2.15(s,3H),1.40(d,J=5.8Hz,6H)。
13C NMR(101MHz,DMSO)δ187.75,166.46,162.76,158.05(dd,J=248.6,5.3Hz,2C),152.66,146.40(d,J=236.6Hz),132.80(d,J=11.8Hz),128.30(t,J=9.8Hz),122.69,116.42(d,J=22.2Hz),115.22(d,J=5.0Hz)115.00(t,J=17.2Hz),112.28(d,J=22.8Hz),112.27(d,J=13.5Hz),107.28,79.85,73.44,26.11,22.04(2C)。
HRMS(ESI)m/z:456.1126[M+Na+]。
化合物13j
1H NMR(400MHz,DMSO)δ12.62(s,1H),9.64(s,1H),8.56(d,J=6.6Hz,1H),7.63(d,J=12.1Hz,1H),7.58(d,J=7.7Hz,1H),7.40–7.28(m,2H),4.96–4.65(m,1H),2.04(s,3H),1.43(d,J=6.0Hz,6H)。
13C NMR(100MHz,DMSO)δ189.40,167.30,162.40,158.43(d,J=251.8Hz),152.93,145.77(d,J=235.7Hz),134.16(d,J=12.2Hz),129.56(d,J=8.9Hz),128.62(d,J=3.2Hz),125.69(d,J=15.5Hz),124.65,122.47(d,J=2.1Hz),116.34(d,J=22.2Hz),116.10(d,J=21.0Hz),112.97(d,J=5.6Hz),105.74(d,J=2.0Hz),77.81,73.03,27.52,22.18(2C)。
HRMS(ESI)m/z:516.0345[M+Na+]。
化合物13k
1H NMR(400MHz,DMSO)δ12.61(s,1H),9.74(s,1H),8.55(d,J=6.6Hz,1H),7.59(m,3H),7.37(t,J=8.1Hz,1H),4.74(m,1H),2.05(s,3H),1.42(d,J=6.0Hz,6H)。
13C NMR(100MHz,DMSO)δ189.38,167.29,162.55,152.88,145.75(d,J=235.6Hz),134.00(d,J=12.2Hz),133.76(2C),133.57,129.40,128.93(2C),124.67,116.28(d,J=22.0Hz),113.42(d,J=5.7Hz),105.85(d,J=2.1Hz),77.81,73.04,27.52,22.18(2C)。
HRMS(ESI)m/z:488.0555[M+Na+]。
化合物13m
1H NMR(400MHz,DMSO)δ12.11(s,1H),9.60(s,1H),8.40(d,J=6.4Hz,1H),7.63(d,J=11.9Hz,1H),7.48–7.33(m,1H),7.18(t,J=8.1Hz,2H),3.92(s,3H),2.11(s,3H)。
13C NMR(100MHz,DMSO)δ186.89,165.96,162.87,158.60(dd,J=248.4,5.1Hz,2C),154.66,146.42(d,J=236.1Hz),132.46(d,J=12.2Hz),128.62(t,J=9.5Hz),121.82,116.72(d,J=21.9Hz),115.46(t,J=16.7Hz),114.28(d,J=4.8Hz),112.18(d,J=22.9Hz),112.17(d,J=13.0Hz),80.91,56.85,25.47。
HRMS(ESI)m/z:406.1005[M+H+]。
化合物13n
1H NMR(400MHz,DMSO)δ12.21(s,1H),9.69(s,1H),8.43(d,J=6.4Hz,1H),7.63(d,J=11.9Hz,1H),7.47–7.27(m,3H),3.94(s,3H),2.10(s,3H)。
13C NMR(100MHz,DMSO)δ187.21,166.13,161.38(d,J=248.0Hz),157.66,154.71,146.37(d,J=236.1Hz),133.07(d,J=2.8Hz),132.69(d,J=12.0Hz),129.16(d,J=9.2Hz),125.57(d,J=3.1Hz),124.71(d,J=16.1Hz),122.16,116.67(d,J=22.3Hz),115.37(d,J=21.0Hz),114.04(d,J=4.9Hz),104.82,80.53,56.94,25.74。
HRMS(ESI)m/z:444.0539[M+Na+]。
化合物13o
1H NMR(400MHz,DMSO)δ12.16(s,1H),9.69(s,1H),8.42(d,J=6.4Hz,1H),7.64(d,J=11.9Hz,1H),7.57(d,J=7.3Hz,1H),7.38–7.29(m,2H),3.95(s,3H),2.11(s,3H)。
13C NMR(101MHz,DMSO)δ187.13,166.09,162.50,158.76(d,J=251.0Hz),154.71,146.41(d,J=236.2Hz),132.62(d,J=12.7Hz),129.75(d,J=8.8Hz),128.58(d,J=3.2Hz),126.12(d,J=15.6Hz),123.63(d,J=1.7Hz),122.07,116.67(d,J=22.2Hz),115.95(d,J=21.0Hz),114.14(d,J=5.3Hz),104.90,80.62,56.98,25.67。
HRMS(ESI)m/z:488.0025[M+Na+]。
化合物13p
1H NMR(400MHz,DMSO)δ12.23(s,1H),9.59(s,1H),8.42(d,J=6.5Hz,1H),7.59(d,J=11.8Hz,1H),7.38(m,1H),7.19(t,J=8.1Hz,2H),4.21(q,6.9Hz,2H),2.09(s,3H),1.43(t,J=6.9Hz,3H)。
13C NMR(100MHz,DMSO)δ187.14,166.11,162.82,158.20(dd,J=248.7,5.3Hz,2C),153.62,146.43(d,J=236.6Hz),132.42(d,J=13.0Hz),128.40(t,J=9.7Hz),122.05,116.51(d,J=22.2Hz),115.12(t,J=16.8Hz),114.81(d,J=6.5Hz),112.25(d,J=13.4Hz),112.25(d,J=23.0Hz),105.89,80.59,65.65,25.65,14.77。
HRMS(ESI)m/z:420.1163[M+H+]。
化合物13q
1H NMR(400MHz,DMSO)δ12.34(s,1H),9.67(s,1H),8.46(d,J=6.5Hz,1H),7.61(d,J=11.9Hz,1H),7.37(m,3H),4.22(q,J=6.9Hz,2H),2.08(s,3H),1.44(t,J=6.9Hz,3H)。
13C NMR(100MHz,DMSO)δ187.18,166.12,162.54,158.62(d,J=250.7Hz),153.71,146.43(d,J=236.4Hz),132.54(d,J=12.2Hz),132.29(d,J=3.0Hz),129.04(d,J=9.1Hz),125.60(d,J=3.2Hz),124.31(d,J=16.0Hz),122.07,116.57(d,J=22.3Hz),115.49(d,J=20.8Hz),114.53(d,J=5.2Hz),105.81,80.57,65.71,25.67,14.91。
HRMS(ESI)m/z:436.0868[M+H+]。
化合物13r
1H NMR(400MHz,DMSO)δ12.39(s,1H),9.65(s,1H),8.47(d,J=6.6Hz,1H),7.63(d,J=12.0Hz,1H),7.57(d,J=7.8Hz,1H),7.39–7.28(m,2H),4.23(q,J=6.9Hz,2H),2.07(s,3H),1.46(t,J=6.9Hz,3H)。
13C NMR(100MHz,DMSO)δ187.39,166.22,162.44,158.52(d,J=251.8Hz),153.77,146.36(d,J=236.2Hz),132.72(d,J=12.2Hz),129.68(d,J=8.8Hz),128.62(d,J=3.2Hz),125.75(d,J=15.5Hz),122.85(d,J=2.0Hz),122.31,116.56(d,J=22.2Hz),116.05(d,J=21.0Hz),114.23(d,J=5.8Hz),105.67,80.32,65.73,25.85,14.98。
HRMS(ESI)m/z:480.0370[M+H+]。
化合物13s
1H NMR(400MHz,DMSO)δ12.31(s,1H),9.76(s,1H),8.45(d,J=6.4Hz,1H),7.58(m,3H),7.37(t,J=8.1Hz,1H),4.23(q,J=6.9Hz,2H),2.08(s,3H),1.44(t,J=6.9Hz,3H)。
13C NMR(100MHz,DMSO)δ187.24,166.17,162.57,153.67,146.44(d,J=236.6Hz),133.96(2C),133.65,132.40(d,J=12.1Hz),129.48,128.90(2C),122.10,116.52(d,J=22.3Hz),114.91(d,J=5.0Hz),105.91,80.50,65.68,25.69,14.94。
HRMS(ESI)m/z:452.0574[M+H+]。
化合物13t
1H NMR(400MHz,DMSO)δ12.63(s,1H),9.46(s,1H),8.57(d,J=6.4Hz,1H),7.49(d,J=11.5Hz,1H),7.45–7.32(m,1H),7.19(t,J=8.1Hz,2H),5.11(m,1H),2.04(s,3H),1.50(d,J=6.4Hz,3H)。
13C NMR(100MHz,DMSO)δ189.46,167.25,163.19,158.26(dd,J=249.0,5.0Hz,2C),151.13,146.68(d,J=237.9Hz),133.38(d,J=12.3Hz),128.63(t,J=9.5Hz),124.61,116.26(d,J=5.0Hz),125.04(q,J=280.0Hz),115.99(d,J=22.2Hz),114.80(t,J=17.0Hz),112.31(d,J=23.0Hz),112.31(d,J=13.2Hz),107.66,77.75,74.31(q,J=30.8Hz),27.50,13.89。
HRMS(ESI)m/z:510.0862[M+Na+]。
化合物13u
1H NMR(400MHz,DMSO)δ12.64(s,1H),9.51(s,1H),8.59(d,J=6.4Hz,1H),7.52(d,J=11.5Hz,1H),7.46–7.30(m,3H),5.16(m,1H),2.06(s,3H),1.52(d,J=6.4Hz,3H)。
13C NMR(100MHz,DMSO)δ189.46,167.24,163.04,158.77(d,J=250.5Hz),151.17,146.61(d,J=237.9Hz),133.44(d,J=12.1Hz),132.74(d,J=2.7Hz),129.37(d,J=9.7Hz),125.73(d,J=3.1Hz),125.06(q,J=279.7Hz),124.60,123.98(d,J=16.1Hz),116.03(d,J=22.0Hz),115.88,115.52(d,J=20.8Hz),107.47,77.75,74.07(q,J=31.3Hz),27.51,13.96。
HRMS(ESI)m/z:526.0568[M+Na+]。
化合物13v
1H NMR(400MHz,DMSO)δ12.64(s,1H),9.50(s,1H),8.59(d,J=6.5Hz,1H),7.58(d,J=7.4Hz,1H),7.54(d,J=11.5Hz,1H),7.41–7.30(m,2H),5.16(m,1H),2.05(s,3H),1.52(d,J=6.4Hz,3H)。
13C NMR(100MHz,DMSO)δ189.46,167.24,162.97,158.71(d,J=251.4Hz),151.22(d,J=1.3Hz),146.61(d,J=237.9Hz),133.45(d,J=12.1Hz),130.04(d,J=8.9Hz),128.76(d,J=3.3Hz),125.41(d,J=15.7Hz),124.91(q,J=280.1Hz),124.60,123.33(d,J=1.5Hz),116.16(d,J=7.3Hz),115.96(d,J=6.1Hz),115.89(d,J=2.6Hz),107.60,77.76,74.11(q,J=30.9Hz),27.51,13.99。
HRMS(ESI)m/z:570.0066[M+Na+]。
化合物13w
1H NMR(400MHz,DMSO)δ12.63(s,1H),9.67(s,1H),8.58(d,J=6.5Hz,1H),7.58(d,J=8.1Hz,2H),7.51(d,J=11.4Hz,1H),7.39(t,J=8.1Hz,1H),5.15(m,1H),2.05(s,3H),1.51(d,J=6.4Hz,3H)。
13C NMR(100MHz,DMSO)δ189.44,167.23,163.07,151.14(d,J=1.3Hz),146.53(d,J=237.8Hz),134.18(2C),133.34,133.23,129.79,128.99(2C),125.09(q,J=279.9Hz),124.61,116.18(d,J=5.6Hz),115.95(d,J=22.0Hz),107.54,77.76,73.93(q,J=31.3Hz),27.50,13.98。
HRMS(ESI)m/z:542.0272[M+Na+]。
化合物13x
1H NMR(400MHz,DMSO)δ12.63(s,1H),9.69(s,1H),8.58(d,J=6.5Hz,1H),7.72(dd,J=8.1,1.0Hz,1H),7.61(dd,J=8.1,1.0Hz,1H),7.52(d,J=11.4Hz,1H),7.31(t,J=8.1Hz,1H),5.15(m,1H),2.04(s,3H),1.51(d,J=6.4Hz,3H)。
13C NMR(100MHz,DMSO)δ189.43,167.23,162.99,151.18(d,J=1.2Hz),146.52(d,J=237.8Hz),134.60,134.15,133.27(d,J=12.3Hz),132.10,130.30,129.61,125.11(q,J=280.1Hz),124.82,124.61,116.22(d,J=5.9Hz),115.96(d,J=22.1Hz),107.70,77.76,73.96(q,J=31.2Hz),27.51,14.02。
HRMS(ESI)m/z:585.9763[M+Na+]。
化合物13y
1H NMR(400MHz,DMSO)δ12.63(s,1H),9.72(s,1H),8.58(d,J=6.5Hz,1H),7.76(d,J=8.1Hz,2H),7.55(d,J=11.5Hz,1H),7.23(t,J=8.1Hz,1H),5.16(m,1H),2.05(s,3H),1.51(d,J=6.4Hz,3H)。
13C NMR(100MHz,DMSO)δ189.43,167.22,162.89(d,J=1.2Hz),151.24,146.51(d,J=237.8Hz),135.92,133.27(d,J=12.2Hz),132.74(2C),130.79,125.13(q,J=280.3Hz),124.74(2C),124.61,116.21(d,J=5.8Hz),115.99(d,J=22.1Hz),107.83,77.76,73.98(q,J=30.4Hz),27.50,14.06。
HRMS(ESI)m/z:629.9256[M+Na+]。
实施例八:化合物的体外酶活性测定
实验方法:
96孔板中先后加入DHODH蛋白(50mmol),辅酶Q(100μmol)及DCIP(120μmol);后加入待测小分子(0.001~10μM)或空白DMSO,置于室温孵育5min,然后每孔加入1μL底物DHO(终浓度:500μmol)。运用酶标仪测定600nm处吸光值,每30s读取一次,持续6min。用软件GraphPad Prism5.0计算化合物的IC50值,该实验以ASLAN003为阳性对照,每次实验至少设置3个复孔。
表2.本发明化合物的体外酶水平抑制结果
注:ND表示未测定
实施例九:化合物的体外肿瘤细胞增殖抑制活性测定
实验方法:
将相应细胞(2-10×103个/孔)接种于96孔板中,孵育24h,加入含浓度梯度化合物的培养基,每个浓度梯度设置3个复孔,并同时设置DMSO溶剂对照和空白对照组,37℃孵育96h,后加入浓度为5mg/mL的MTT试剂20μL,再培养2~4h后,再加入50μL酸化的SDS并孵育过夜,用酶标仪测定其在570nM的吸光度。用软件GraphPad Prism5.0计算化合物的IC50值,该实验以ASLAN003为阳性对照。
采用以上方法,对本发明部分优选化合物进行测试,淋巴瘤细胞Raji,人正常肝细胞L02进行增殖抑制活性测试,结果见表3。
表3.优选化合物体外抗肿瘤活性
注:选择性指数SI=IC50(L02)/IC50(Raji)。
进而对活性优良的化合物13t和13u进一步测试在其他肿瘤细胞株上的抑制活性,结果如表4。
表4.优选化合物13t和13u体外抗肿瘤活性
实施例十:优选化合物在Raji细胞异种移植瘤模型中的活性测定
实验动物:NOD/SCID小鼠,6-8周龄,体重18-22g,每组10只。细胞株:人源淋巴瘤细胞Raji。
测试化合物:13u,13t;ASLAN003(ASL)为阳性对照。
实验方法:
雌性NOD/SCID小鼠皮下注射Raji细胞(1×107个/只)。当肿瘤体积均达到100mm3时,随机分组。分别口服给药13t(5%EtOH+95%H2O)、13u(5%EtOH+95%H2O)和ASLAN003(5%DMSO+95%PEG300),每日剂量为40mg/kg,连续给药治疗25天,每2天测量体重和肿瘤体积。实验结束时,对肿瘤进行解剖并称重。
Claims (10)
1.一类新型小分子化合物,其特征在于结构如式I所示:
R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基,所述的卤素取代为F、Cl、Br、I的单取代或多取代;
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基,所述的卤素取代为F、Cl、Br、I的单取代或多取代;
R3,R4,R5独立的为H、F、Cl、Br、I、甲基;
R6为甲基,卤素取代的甲基,乙基,卤素取代的乙基,丙基,卤素取代的丙基,环丙基,卤素取代的环丙基,所述的卤素取代为F、Cl、Br、I的单取代或多取代。
2.根据权利要求1中式I所示小分子化合物,其特征在于其中R6为甲基,乙基,环丙基;
R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基,所述的卤素取代为F、Cl、Br、I的单取代或多取代;
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基,所述的卤素取代为F、Cl、Br、I的单取代或多取代;
R3,R4,R5独立的为H、F、Cl、Br、I、甲基;
最优的,R6为甲基,其结构如式Ⅱ所示:
R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基,所述的卤素取代为F、Cl、Br、I的单取代或多取代;
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基,所述的卤素取代为F、Cl、Br、I的单取代或多取代;
R3,R4,R5独立的为H、F、Cl、Br、I、甲基。
3.根据权利要求2中式II所示化合物,其特征在于优选的R3至R5独立的为F、Cl、Br;
R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基,所述的卤素取代为F、Cl、Br、I的单取代或多取代;
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基,所述的卤素取代为F、Cl、Br、I的单取代或多取代;
最优的,R3为F,R4和R5为H,结构如式Ⅲ所示:
R1为甲基、乙基、丙基、丁基、异丙基、叔丁基、三氟甲基、三氟乙基、(S)-三氟异丙基、(R)-三氟异丙基、六氟-2-丙基、C3-C6环烷基、卤素取代的C3-C6环烷基,所述的卤素取代为F、Cl、Br、I的单取代或多取代;
R7至R26独立的为H、F、Cl、Br、I、C1-C4烷基、卤素取代的C1-C4烷基、C1-C4烷氧基、卤素取代的C1-C4烷氧基、C1-C4烷硫基、卤素取代的C1-C4烷硫基,所述的卤素取代为F、Cl、Br、I的单取代或多取代。
6.权利要求1-5中所述的一类新型小分子化合物的任一原子的同位素取代。
7.权利要求1-6中所述的一类新型小分子化合物药学可接受的盐。
8.药物组合物,由权利要求1-7中所述的一类新型小分子化合物添加药学上可以接受的辅助性成分制备而成。
9.权利要求1-8中所述的一类新型小分子化合物在制备治疗DHODH介导的疾病药物中的用途。
10.权利要求9中所述的DHODH介导的疾病选自肿瘤、自身免疫性疾病和病毒感染。
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CN103965133A (zh) * | 2013-01-31 | 2014-08-06 | 华东理工大学 | 一种具有dhodh抑制活性的含n、s杂环化合物及其制备和用途 |
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