CN112920202B - 一种帽依赖性蛋白酶抑制剂 - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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Abstract
本发明涉及一种具有帽依赖性核酸内切酶抑制活性的化合物,以及该该化合物在流感治疗方面的应用。
Description
技术领域
本发明属于化学药物领域,具体涉及一种具有帽依赖性核酸内切酶抑制活性的化合物,以及该该化合物在流感治疗方面的应用。
背景技术
流感病毒每年导致一种传染病,全世界有29万至65万人死亡,300万至500万人患有严重疾病。此外,由新出现的重组病毒引起的流行病可能对全球产生毁灭性的影响。因此,有必要继续努力改进疫苗和抗病毒药物作为对策。目前有两类抗病毒药物可供临床使用:神经氨酸酶抑制剂(NAIs:奥司他韦、扎那米韦、帕拉米韦)和M2离子通道抑制剂(金刚烷胺、金刚乙胺)。然而,目前流行的流感病毒在很大程度上对M2抑制剂s3具有耐药性。此外,NAIs的抗病毒能力相对较弱,这类药物的另一个担忧是耐药性的出现,就像2008年至2009年耐奥司他韦的H1N1流感流行季节一样。因此,流感病毒感染的治疗和预防需要更有效的抗病毒药物,具有新的作用机制。
流感病毒的异三聚体RNA依赖性RNA聚合酶(RdRp)由PA、PB1和PB2亚基组成。它负责在被感染细胞的细胞核中复制和转录分段的单链病毒RNA基因组(vRNA)。病毒mRNA的转录是通过一种独特的“抢帽”机制进行的。这涉及到通过将初生的封顶转录本与PB2子单元结合,然后在核苷酸处被PA子单元中的依赖于cap的内切酶(CEN)切割,从而实现对宿主RNA聚合酶的高劫持。由PB1 subunit1的RdRp功能产生的短的、带cap酶的寡聚物作为病毒mRNA转录的引物。病毒转录本在模板vRNA保守的富集区域被一种机制聚腺苷酸化,以在核输出后转化为功能蛋白。由于抢帽是病毒复制的必要条件,因此cap-binding、endonuclease和RdRp活性都是小分子抑制物的有吸引力的靶点,实际上有几种针对聚合酶的新化合物正在积极的临床开发中。2014年,一种RNA合成抑制剂Favipiravir(Avigan)在日本获得批准,尽管该适应症仅限于治疗对其他药物没有反应的新型流感病毒。Pimodivir(JNJ-63623872,VX-787)是一种PB2 cap-binding inhibitor,它单独与奥司他韦联合用于简单流感的病毒学疗效,但仅对A型流感病毒有效。因此,仍然需要继续努力发现和开发性能更好的流感药物。
发明内容
本发明的目的,在于提供一种全新的具有帽依赖性核酸内切酶抑制活性的化合物,所述化合物具有如下结构:
其中R1为氢、氘或形成前药的PR基;
R2各自独立地为氢、氘、卤素、羟基、烷基、卤代烷基、或烷氧基;
M为0~2的整数
X为CH2、O、S或N。
一个优选的实施方案是,本发明所述化合物或其药学上可接受的盐,其中R2优选为卤素,X为S。
具体地,本发明涉及具有如下结构的化合物:
其中所述R1为氢或形成前药的PR基。
PR基选自如下结构:
(1)-C(=O)-PR0、-C(=O)-L-PR0、-C(=O)-L-O-PR0、-C(=O)-L-O-L-PR0;
(2)-C(=O)-O-PR1、-C(=O)-O-L-PR1、-C(=O)-N-PR1;
(3)-C(PR2)2-O-PR3、-C(PR2)2-O-C(=O)-O-PR3
所述L为直链或直链状的亚烷基、或者直链或智利安装的亚希基;
所述PR0为氢或任选被取代基Q取代的烷基、任选被取代基Q取代的烯基、任选被取代基Q取代的碳环基、任选被取代基Q取代的杂环基、任选被取代基Q取代的烷基氨基、或任选被取代基Q取代的烷基硫基;
PR1、PR3各自独立地为氢、氘或被取代基Q取代的烷基、任选被取代基Q取代的碳环基、任选被取代基Q取代的杂环基、任选被取代基Q取代的碳环烷基、任选被取代基Q取代的杂环烷基、或任选被取代基Q取代的烷基甲硅烷基;
PR2为氢、氘或烷基;
取代基Q为氢、氘、氧代基、烷基、羟基烷基、氨基、烷基氨基、碳环基、杂环基、碳环烷基、烷基羰基、卤素、羟基、羰基、烷基羰基氨基、烷基羰基氨基烷基、烷基羰氧基、烷氧基羰基、烷氧基羰基烷基、烷氧基羰氧基、烷基氨基羰氧基、烷基氨基烷基、烷氧基、氰基、硝基、叠氮基、烷基磺酰基、三烷基甲硅烷基或磷酰基。
一个更为优选的实施方案是,所述R1为氢,所述的PR基为:
-C(=O)-CH3、-C(=O)-O-(CH2)2-O-CH3、-CH2-O-C(=O)-CH3、-CH2-O-C(=O)-O-CH3、
-CH2-O-C(=O)-O-CH2CH3、-CH(CH3)-O-C(=O)-O-CH3、
-CH2-O-C(=O)-CH(CH3)-NH-C(=O)-O-C(CH3)3、CH2C6H5。
具体地,本发明涉及如下结构的化合物:
其中所述R1为氢。
本发明还涉及由化合物1-21的前药,当其为前药时,R1的具体结构为
如化合物1的前药具有如下结构
本发明还涉及一种药物组合物,包含本发明所述化合物或其药学上可接受的盐,以及药学上可接受的载体。
本发明中,除包含本发明所述化合物或其药学上可接受的盐外,还可以包含有其它抗流感病毒类化合物,比如奥司他韦。
本发明的又一方面,涉及本发明所述化合物或其药学上可接受的盐在制备具有预防或治疗流感药物中的应用,以及包含本发明所述化合物的组合物在治疗流感方面的应用,组合物中,还可以包含其它抗流感病毒化合物,如奥司他韦。
具体实施例
实施例1中间体I-A结构合成
步骤A:1-((3-(苄氧基)-4-氧代-4H-吡喃-2-基)(羟基)甲基)环丙烷甲醛(化合物IA.1)
将3-(苄氧基)-4-氧代-4H-吡喃-2-甲醛(8g,30.4mmol)溶于400mL四氢呋喃中,在室温下加入吡咯烷(0.2mL,10mmol),冰醋酸(1.73mL,45mmol)和环丙基甲醛(3g,36.5mmol),搅拌2小时。把反应液直接旋干,过柱纯化得到产物(1.1g,产率:12%)。LCMSESI(+)m/z:301.1(M+1).
步骤B:4',5'-二羟基螺[环丙烷-1,3'-吡啶并[1,2-b]哒嗪]-6'(4'H)-酮嗪]-6'(4'H)-酮(化合物IA.2)
将化合物IA.1(1.1g,3.67mmol)溶于20mL的N,N-二甲基甲酰胺中,加入盐酸肼(2.5g,36.7mmol),升温至80度搅拌2小时。将反应液倒入100mL的水中,用60mL的乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,有机相用无水硫酸钠干燥。过滤、旋干,柱层析纯化得到产物(670mg,产率:62%)。LCMS ESI(+)m/z:297.1(M+1).
步骤C:5'-(苄氧基)-6'-氧代-4',6'-二氢螺[环丙烷-1,3'-吡啶并[1,2-b]哒嗪]-4'-基酯(化合物IA.3)
将化合物IA.2(670mg,2.26mmol),三乙胺(461mg,4.52mmol)和N,N-二甲基-4-氨基吡啶(83mg,0.68mmol)溶入10mL的四氢呋喃中,在0度下将含有醋酸酐(462mg,4.52mmol)的3mL四氢呋喃溶液缓慢滴入,然后在室温下搅拌1小时。反应液中加入10mL的水,用30mL的乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,有机相用无水硫酸钠干燥。过滤、旋干,过柱纯化得油状产物(800mg,产率:99%)。LCMS ESI(+)m/z:339.1(M+1).
步骤D:5'-(苄氧基)-6'-氧代-1',2',4',6'-四氢螺[环丙烷-1,3'-吡啶并[1,2-b]吡啶]-4'-基酯(化合物IA.4)
将化合物IA.3(800mg,3.2mmol)溶于20mL的四氢呋喃溶液中,在冰浴下分批加入硼氢化钠(171mg,5.3mmol),搅拌30分钟。用饱和的氯化铵溶液淬灭,用30mL的乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,有机相用无水硫酸钠干燥。过滤、旋干,纯化得产物(725mg,产率:90%)。LCMS ESI(+)m/z:341.1(M+1).
步骤E:4'-乙酰氧基-5'-(苄氧基)-6'-氧代-4',6'-二氢螺[环丙烷-1,3'-吡啶并[1,2-b]哒嗪]-1'1H)-羧酸叔丁酯(化合物IA.5)
将化合物IA.4(900mg,2.64mmol),三乙胺(342mg,5.3mmol)和N,N-二甲基-4氨基吡啶(28mg,0.23mmol)溶入10mL的四氢呋喃中,在0度下将含有二碳酸二叔丁酯(641mg,5.3mmol)的3mL四氢呋喃溶液缓慢滴入,然后在室温下搅拌1小时。反应液中加入20mL的水稀释,用30mL的乙酸乙酯萃取三次,合并有机相,用饱和食盐水洗涤,有机相用无水硫酸钠干燥。过滤、旋干,过柱纯化得到油状产物(1.1g,产率:95%)。LCMS ESI(+)m/z:441.1(M+1).
步骤F:(苄氧基)-4'-羟基-6'-氧代-4',6'-二氢螺[环丙烷-1,3'-吡啶并[1,2-b]哒嗪]-1'(21H)-羧酸叔丁酯(化合物IA.6)
将化合物IA.5(1.1g,2.50mmol)溶于20mL甲醇溶液中,加入碳酸钾(312mg,2.26mmol),在室温下搅拌1小时。反应完后减压浓缩,剩余物加水(30mmL)稀释,用40mL乙酸乙酯萃取两次,有机相用无水硫酸钠干燥。过滤、旋干,纯化得到产物(550mg,产率:55%)。LCMSESI(+)m/z:399.1(M+1).
步骤G:(苄氧基)-4',6'-二氧代-4',6'-二氢螺[环丙烷-1,3'-吡啶并[1,2-b]哒嗪]-1'(2'H)-甲酸乙酯(化合物IA.7)
将化合物IA.6(550mg,1.38mmol)溶于10mL二氯甲烷溶液中,冷却至0度,缓慢加入1.4g戴斯-马丁氧化剂,逐渐升至室温搅拌1小时。加入碳酸氢钠和硫代硫酸钠水溶液淬灭反应,用20mL二氯甲烷分三次萃取,合并有机相,用饱和食盐水洗涤三次,用无水硫酸钠干燥有机相。过滤、旋干,纯化得到产物(500mg,产率:91%)。LCMS ESI(+)m/z:397.1(M+1).
步骤H:5'-(苄氧基)-1',2'-二氢螺[环丙烷-1,3'-吡啶并[1,2-b]哒嗪]-4',6'-二酮(化合物IA.8)
将化合物IA.7(500mg,1.26mmol)溶于10mL二氯甲烷溶液中,冰浴下慢慢滴加3mL三氟乙酸,加完后升到室温搅拌30分钟。将反应液直接旋干得到产物(100mg,产率:27.1%)。LCMS ESI(+)m/z:297.1(M+1).
步骤I:将化合物38.8(50mg,0.09mmol)溶于3mL的N,N-二甲基甲酰胺溶液中,加入氯化锂(113mg,2.7mmol),加热至100度,搅拌30分钟。反应完后用油泵减压浓缩,剩余物溶于3mL的甲醇,过滤,滤液用反相制备,冻干后得到目标产物实施例IA(8mg,产率:20%)。
实施例2中间体I-B结构合成
步骤A:2-(溴甲基)-6-氟吡啶(化合物IB.1)
将化合物2-氟基-6-甲基吡啶(2g)溶解于30mL四氯化碳中,加入N-溴代丁二酰亚胺(3.18g,17.9mmol)和过氧化苯甲酰(118mg,0.5mmol),在氮气的保护下,85℃反应过夜。反应完毕后,将反应液用硅藻土过滤,滤饼用四氯化碳(15mLX2)洗,滤液依次用10%亚硫酸氢钠(20mLX2)和饱和食盐水(20mL)洗涤。无水硫酸钠干燥。过滤、旋干后得到目标产物(1.68g,产率:51.2%)。
步骤B:2-(((6-氟吡啶-2-基)甲基)硫基)苯甲酸甲酯(化合物IB.2)
冰浴下,将化合物IB.1(1.68g)溶于15mL N,N-二甲基甲酰胺中,然后加入碳酸钾(2.3g,16.6mmol)和2-巯基苯甲酸甲酯(1.68g,10.0mmol),继续在冰浴下搅拌1小时。通过TLC监测反应完全。加水(45mL)到反应液中,用乙酸乙酯(20mLX3)萃取,用饱和食盐水(30mL)洗涤,无水硫酸钠干燥。过滤,旋干,经硅胶柱纯化后得到产物(2.2g,产率:91.7%)。
步骤C:2-(((6-氟吡啶-2-基)甲基)硫代)苯甲酸(化合物IB.3)
将化合物IB.2(2.2g)溶于15mL四氢呋喃和5mL甲醇中,然后加入4mL氢氧化钠溶液(4M),在80℃下搅拌1小时。反应完后将反应液减压浓缩,剩余物加水(30mL)溶解,将反应液用盐酸调节pH=3,水相用乙酸乙酯(20mLX3)萃取。合并有机相,用无水硫酸钠干燥。过滤、旋干后得到目标产物(2g,产率:95.6%,白色固体)。
步骤D:2-氟苯并[6,7]硫杂七环[3,4-b]吡啶-5(11H)-酮(化合物IB.4)
将化合物IB.3(810mg)溶于10mLN,N-二甲基甲酰胺中。冰浴下,依次加入碳酸铯(1.63g,4.99mmol),溴化锂(724mg,8.33mmol)和碘甲烷(520mg,3.66mmol),反应混合物搅拌反应1小时。通过TLC监测反应完全,加水(30mL)稀释反应液,用乙酸乙酯(15mLX3)萃取。合并有机相,用无水硫酸钠干燥。过滤、旋干后用硅胶柱(石油醚:乙酸乙酯=5:1)纯化,得到目标产物(130mg,产率:15.2%,白色固体)。
步骤E:2-F-5,11-二氢苯并[6,7]硫杂七环[3,4-b]吡啶-5-醇(化合物IB.5)
冰浴条件下,将化合物66.6(130mg)溶于5mL四氢呋喃和1mL甲醇中,加入硼氢化钠(29mg,0.77mmol),零度下继续搅拌0.5小时。加入饱和的氯化铵溶液(2.5mL)淬灭反应,用乙酸乙酯(15mLX2)萃取,合并有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥。过滤、浓缩后得到产物(130mg,产率:99.2%,白色固体)。
实施例3化合物2的合成
将化合物IA.8(100mg)溶于8mL的1,2-二氯乙烷中,加入化合物IB.5(130mg,0.5mmol)和二氯乙酸(2滴),反应液在85℃下搅拌2小时。通过LCMS监测原料反应完全。用饱和碳酸氢钠溶液(5mL)淬灭反应,水相用二氯甲烷(15mL)萃取,无水硫酸钠干燥。过滤、旋干,剩余物用硅胶柱(二氯甲烷:甲醇=10:1)纯化后得到产物1.8(90mg,淡黄色油状,产率:50%)。LCMS ESI(+)m/z:251.1(M+1)
实施例4:体外细胞抑制试验
如下进行CPE抑制试验以评估测试化合物抑制帽依耐性核酸内切酶活性的效力。
将96孔组织培养板中的MDCK细胞与测试化合物和A型流感或B型流感病毒在低感染率下于37℃培养72小时,通过添加0.5%甲醛来固定培养板,然后用0.5%结晶紫染色,随后,用微盘分析仪(Multiskan Ascent,Thermo)测波长570nm的吸光值,相对于病毒对照组,测试化合物将病毒诱导的CPE降低50%所需的浓度,表示50%有效剂量(EC50)。
用CPE抑制试验评估化合物1-21,其中,对于A型流感病毒感染,化合物1、2和10的CE50值小于20nM,化合物19表现出大于100μM的抑制活性,而化合物20及21的活性介于10-50μM,其与化合物活性在100-1000nM之间。对于B型流感病毒感染,化合物1、2和10也同样表现出低于50nM的抑制活性,19、20和21的抑制活性同样也非常不理想。都大于10μM。
Claims (3)
1.具有以下式的化合物或其药学上可接受的盐:
其中所述R1为氢。
2.一种药物组合物,包含权利要求1所述化合物或其药学上可接受的盐,以及药学上可接受的载体。
3.权利要求1所述化合物或其药学上可接受的盐在制备具有预防或治疗流感药物中的应用。
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