CN104788369B - 双吡啶基苯氧基脂肪酰胺衍生物及其医药用途 - Google Patents
双吡啶基苯氧基脂肪酰胺衍生物及其医药用途 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了双吡啶基苯氧基脂肪酰胺衍生物及其医药用途，其化学结构式如式I或Ⅱ所示：式中R1、R2选自：氢、C1～C2烷基；X1选自：氢、C1～C2烷基、氟、氯、溴或碘；X2选自：三氟甲基、氟、氯、溴或碘；X3、X4选自：氢、C1～C2烷基或硝基；X5选自：氰基或乙氨基。本发明还涉及含有上述化合物的药物组合物及双吡啶基苯氧基脂肪酰胺衍生物在制备制备抗流感病毒神经氨酸酶抑制剂中的应用。
Description
技术领域
本发明涉及一种化合物，具体涉及一种双吡啶基苯氧基脂肪酰胺衍生物及其医药用途。
背景技术
4-芳氧基苯氧基烷酸衍生物在抗癌药物的研究中也有大量报道[InvestigationalNew Drugs，1999，16:287–296；Investigational New Drugs，1998，16:129–139；药学学报，2005，40(9):814-819]，其中XK469(2-(4-(7-氯喹喔啉-2-基氧基)苯氧基)丙酸)是美国杜邦公司正在进行Ⅰ期临床研究的一新型抗肿瘤药物，XK469具有很广的抗瘤谱，副作用小，对多种实体瘤模型有效，如结肠癌Colon38和乳腺癌等[J Med Chem，2001，44(11):1758-76]。2-苯氧基烷酰胺应用的中国发明专利如下：(1)2-[4-(苯并噁唑-2-基氧基)苯氧基]烷酰胺及其应用，CN103086995A，2013.5.8公开；(2)2-(4-芳氧基苯氧基)烷酰胺及其应用，CN103086921A，2013.5.8公开；(3)2-[4-(喹喔啉-2-基氧基)苯氧基]烷酰胺及其应用，CN103086985A，2013.5.8公开；(4)具有生物活性的N-氧基稠杂氧苯氧羧酸酰胺类化合物及其制备方法，2013.1.31申请，CN201310038398.3；(5)N-(芳基烷基)芳氧苯氧羧酸酰胺类化合物及其制备方法与应用，2013.7.2申请，CN201310274623.3；(6)N-(芳基烷氧基)芳氧苯氧羧酸酰胺类化合物及其制备方法与应用，2013.7.2申请，CN201310273568.6。
禽流感病毒(avian influenza virus，AIV)属于甲型流感病毒，可以分为16个H(H1-H16)亚型和9个N(N1-N9)亚型，在甲型流感病毒众多亚型中，H5和H7为高致病性禽流感病毒。至今发现能直接感染人的禽流感病毒亚型有H5N1、H7N2、H7N3、H7N7、H9N2、H10N7、H7N9以及2013年12月在我国江西发现了新禽流感H10N9亚型。这些亚型的症状表现各不一样，主要可以表现为呼吸道症状、结膜炎，甚至死亡。其中高致病性H5N1亚型和2013年3月在人体上首次发现的新禽流感H7N9亚型尤为引人关注。
1997年，在香港首次发现能直接感染人类的H5N1亚型。截止到2014年7月，全球共报告了人感染高致病性H5N1禽流感667例，其中死亡了393例。病例分布于16个国家，其中，我国发现了45例，死亡30例。大多数人感染H5N1禽流感病例为年轻人和儿童。2009爆发的H1N1流感病毒，导致了全球性的高速传播，对全球健康构成了严重的威胁。截止到2014年12月世界卫生组织(World Health Organization，WHO)公布的H1N1流感确诊131万多人，死亡14000多人。2013年3月，我国首次发现人感染H7N9禽流感病例，为全球首次发现的新禽流感病毒亚型。截止2015年1月25日，世界卫生组织公布的H7N9禽流感确诊494人，死亡221人。
双吡啶基苯氧基脂肪酰胺衍生物对神经氨酸酶抑制活性没有报道。
发明内容
本发明的目的是针对以上问题，提供一种化合物，其能够用于制备抗流感病毒药物。
为解决上述技术问题，本发明所采用的技术方案是：一种双吡啶基苯氧基脂肪酰胺衍生物，其化学结构式如式I或Ⅱ所示：
式中R1、R2选自：氢、C1～C2烷基；X1选自：氢、C1～C2烷基、氟、氯、溴或碘；X2选自：三氟甲基、氟、氯、溴或碘；X3、X4选自：氢、C1～C2烷基或硝基；X5选自：氰基或乙氨基。
优选的方案中，具体的化合物结构式为：
本发明还涉及一种药物组合物，其中含有上述双吡啶基苯氧基脂肪酰胺衍生物及药学上可接受的载体。
本发明还涉及所述的双吡啶基苯氧基脂肪酰胺衍生物在制备抗流感病毒药物中的应用。
进一步地，本发明涉及所述的双吡啶基苯氧基脂肪酰胺衍生物在制备抗流感病毒神经氨酸酶抑制剂中的应用。
本发明涉及的双吡啶基苯氧基脂肪酰胺衍生物的合成原料易得，制备方法简单，易于工业化生产。为双吡啶基苯氧基脂肪酰胺衍生物开拓了一个新的药物应用方向。
具体实施方式
下面结合具体实施，进一步阐明本发明。这些实施例应理解为仅用于说明本发明而不是用于限制本发明的保护范围。在阅读了本发明记载的内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等效变化和修饰同样落入本发明权利要求书所限定的范围。
实施例1：
N-(6-乙氨基-3-硝基吡啶-2-基)-2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰胺的制备
2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰氯3.3mmol、二氯甲烷40mL，2-氨基-6-乙氨基-3-硝基吡啶3.3mmol和催化量的4-二甲基氨基吡啶，搅拌10min，滴入三乙胺10mmol，回流8h，反应液倒入150ml冰水中，二氯甲烷萃取，无水硫酸钠干燥，脱溶，柱层析得到N-(6-乙氨基-3-硝基吡啶-2-基)-2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰胺收率30.0％；1H NMR(300MHz，CDCl3)δ：1.30(t，J＝6.6Hz，3H，CH3)，1.72(d，J＝6.6Hz，3H，CH3)，4.09～4.16(m，2H，CH2)，4.76～4.85(m，1H，CH)，6.14(d，J＝9.3Hz，1H，吡啶环-H)，6.96(d，J＝9.3Hz，1H，吡啶环-H)，7.07～7.15(m，4H，苯环-H)，7.48～7.52(m，1H，吡啶环-H)，7.86(d，J＝2.1Hz，1H，吡啶环-H)，8.32(br.s，1H，NH)，12.17(s，1H，NH)；LC-MS，m/z：476.0[M+H]+。
实施例2：
N-乙基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰胺的制备
2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰氯3.3mmol、1,2-二氯乙烷40mL，2-氰基-6-乙氨基-3-硝基吡啶3.3mmol和催化量的4-二甲基氨基吡啶，搅拌10min，滴入三乙胺10mmol，回流8h，反应液倒入150ml冰水中，二氯甲烷萃取，无水硫酸钠干燥，脱溶，柱层析得到N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰胺，收率25.3％，m.p.102.3～103.1℃；1H NMR(300MHz，CDCl3)δ：1.29(t，J＝7.2Hz，3H，CH3)，1.68(d，J＝6.6Hz，3H，CH3)，4.09(q，J＝7.2Hz，2H，CH2)，5.33(q，J＝6.6Hz，1H，CH)，6.74(d，J＝9.0Hz，2H，苯环-H)，7.01(d，J＝9.0Hz，2H，苯环-H)，7.47(dd，J1＝9.0，J2＝2.1Hz，1H，吡啶环-H)，7.80(d，J＝9.3Hz，1H，吡啶环-H)，7.88(d，J＝2.1Hz，1H，吡啶环-H)，8.49(d，J＝9.3Hz，1H，吡啶环-H)；LC-MS，m/z：486.0[M+H]+。
实施例3：
N-甲基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基-3-氯吡啶-2-氧基)苯氧基]丙酰胺的制备
2-[4-(5-三氟甲基-3-氯吡啶-2-氧基)苯氧基]丙酰氯3.3mmol、1,2-二氯乙烷40mL，2-氰基-6-甲氨基-3-硝基吡啶3.3mmol和催化量的4-二甲基氨基吡啶，搅拌10min，滴入三乙胺10mmol，回流7h，反应液倒入150ml冰水中，二氯甲烷萃取，无水硫酸钠干燥，脱溶，柱层析得到N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基-3-氯吡啶-2-氧基)苯氧基]丙酰胺，收率29.8％，黄色粘稠液体；1H NMR(300MHz，CDCl3)δ：1.71(d，J＝6.6Hz，3H，CH3)，3.63(s，3H，CH3)，5.38(q，J＝6.6Hz，1H，CH)，6.83(d，J＝9.0Hz，2H，苯环-H)，7.05(d，J＝9.0Hz，2H，苯环-H)，7.96(s，1H，吡啶环-H)，8.09(d，J＝9.3Hz，1H，吡啶环-H)，8.27(s，1H，吡啶环-H)，8.51(d，J＝9.3Hz，1H，吡啶环-H)；LC-MS，m/z：521.8[M+H]+。
实施例4：
N-甲基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰胺的制备
2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰氯3.3mmol、1,2-二氯乙烷40mL，2-氰基-6-甲氨基-3-硝基吡啶3.3mmol和催化量的4-二甲基氨基吡啶，搅拌10min，滴入三乙胺10mmol，回流8h，反应液倒入150ml冰水中，二氯甲烷萃取，无水硫酸钠干燥，脱溶，柱层析得到N-甲基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰胺，收率26.4％；1H NMR(300MHz，CDCl3)δ：1.71(d，J＝6.6Hz，3H，CH3)，3.63(s，3H，CH3)，5.37(q，J＝6.6Hz，1H，CH)，6.84(d，J＝9.0Hz，2H，苯环-H)，6.98(d，J＝8.7Hz，1H，吡啶环-H)，7.04(d，J＝9.0Hz，2H，苯环-H)，7.88(dd，J1＝8.7，J2＝2.4Hz，1H，吡啶环-H)，8.10(d，J＝9.0Hz，1H，吡啶环-H)，8.43(d，J＝2.4Hz，1H，吡啶环-H)，8.52(d，J＝9.0Hz，1H，吡啶环-H)；LC-MS，m/z：487.9[M+H]+。
实施例5：
N-乙基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰胺的制备
2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰氯3.3mmol、1,2-二氯乙烷40mL，2-氰基-6-乙氨基-3-硝基吡啶3.3mmol和催化量的4-二甲基氨基吡啶，搅拌10min，滴入三乙胺10mmol，回流8h，反应液倒入150ml冰水中，二氯甲烷萃取，无水硫酸钠干燥，脱溶，柱层析得到N-乙基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰胺，收率21.1％；1H NMR(300MHz，CDCl3)δ：1.27(t，J＝7.2Hz，3H，CH3)，1.68(d，J＝6.6Hz，3H，CH3)，4.06～4.14(m，2H，CH2)，5.34(q，J＝6.6Hz，1H，CH)，6.75(d，J＝9.0Hz，2H，苯环-H)，6.98～7.04(m，3H，苯环-H，吡啶环-H)，7.81(d，J＝9.0Hz，1H，吡啶环-H)，7.89(d，J＝8.4Hz，1H，吡啶环-H)，8.44(s，1H，吡啶环-H)，8.50(d，J＝9.0Hz，1H，吡啶环-H)；LC-MS，m/z：502.0[M+H]+。
实施例6：
双吡啶基苯氧基脂肪酰胺衍生物的抗流感病毒神经氨酸酶活性
按专利方法[ZL200910043678,2010.8.18授权]测定。
1.实验原理
化合物MUNANA是神经氨酸酶的特异性底物，在神经氨酸酶作用下产生的代谢产物在360nm照射激发下，可以产生450nm荧光，荧光强度的变化可以灵敏地反应神经氨酸酶活性。酶都来自A/PR/8/34(H1N1)病毒毒株。
2.实验方法
在酶反应体系中，一定浓度样品与流感病毒神NA悬浮于反应缓冲液中(pH6.5)，加入荧光底物MUNANA启动反应体系，37℃孵育40分钟后，加反应终止液终止反应。在激发波长360nm和发射波长为450nm的参数条件下，测定荧光强度值。反应体系的荧光强度可以反映酶的活性。根据荧光强度的减少量可以计算化合物对NA的抑制率。
3.检测样品：双吡啶基苯氧基脂肪酰胺衍生物：
式中R1、R2选自：氢、C1～C2烷基；X1选自：氢、C1～C2烷基、氟、氯、溴或碘；X2选自：三氟甲基、氟、氯、溴或碘；X3、X4选自：氢、C1～C2烷基或硝基；X5选自：氰基或乙氨基。
4.活性结果
优选化合物在反应系统中检测浓度40.0μg/mL时对神经氨酸酶的抑制活性结果如表1所示：
| 双吡啶基苯氧基脂肪酰胺衍生物 | 抑制率/％ |
| N-(6-乙氨基-3-硝基吡啶-2-基)-2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰胺 | 16.25 |
| N-乙基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰胺 | 13.91 |
| N-甲基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基-3-氯吡啶-2-氧基)苯氧基]丙酰胺 | 13.64 |
| N-甲基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰胺 | 22.52 |
| N-乙基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰胺 | 18.71 |
表1
活性测试结果表明，双吡啶基苯氧基脂肪酰胺衍生物对流感病毒神经氨酸酶具有抑制活性，可用于制备抗流感病毒神经氨酸酶抑制剂。
Claims (2)
1.化学结构式I所示的双吡啶基苯氧基脂肪酰胺衍生物在制备抗流感病毒神经氨酸酶抑制剂中的应用：
Ⅰ式中R1选自：甲基；R2选自：氢、C1～C2烷基；X1选自：氢、氟或氯；X2选自：三氟甲基或氯；X3选自：氢或硝基；X4选自：氢或硝基；X5选自：氰基或乙氨基。
2.权利要求1所述的应用，其中式Ⅰ所示的双吡啶基苯氧基脂肪酰胺衍生物选自N-(6-乙氨基-3-硝基吡啶-2-基)-2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰胺、N-乙基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(3-氟-5-氯吡啶-2-氧基)苯氧基]丙酰胺、N-甲基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基-3-氯吡啶-2-氧基)苯氧基]丙酰胺、N-甲基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰胺或N-乙基-N-(6-氰基-5-硝基吡啶-2-基)-2-[4-(5-三氟甲基吡啶-2-氧基)苯氧基]丙酰胺。
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| WO2010108187A2 (en) * | 2009-03-20 | 2010-09-23 | Brandeis University | Compounds and methods for treating mammalian gastrointestinal microbial infections |
| CN102584690A (zh) * | 2012-01-19 | 2012-07-18 | 上海长恒生物医药科技有限公司 | 吡啶-2-酮类化合物，其制备方法以及所述吡啶-2-酮类化合物的应用 |
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| WO2010108187A2 (en) * | 2009-03-20 | 2010-09-23 | Brandeis University | Compounds and methods for treating mammalian gastrointestinal microbial infections |
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