CN117731658A - 一种乙脑病毒抑制剂 - Google Patents
一种乙脑病毒抑制剂 Download PDFInfo
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- CN117731658A CN117731658A CN202311651427.3A CN202311651427A CN117731658A CN 117731658 A CN117731658 A CN 117731658A CN 202311651427 A CN202311651427 A CN 202311651427A CN 117731658 A CN117731658 A CN 117731658A
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Abstract
本发明提供了一种流行性乙型脑炎病毒抑制剂的化合物及其制备方法和应用。该化合物具有显著地抗乙脑病毒活性,可用于乙脑病毒的检测、预防和治疗,为乙脑病毒的预防和治疗提供了新方法,具有非常重要的经济和社会意义。
Description
技术领域
本发明属于化学药物领域,具体涉及一种对流行性乙型脑炎病毒具有抑制活性的化合物,以及该该化合物在乙脑病毒感染方面的应用。
背景技术
流行性乙型脑炎又称日本乙型脑炎(Japanese encephalitis,JE),简称乙脑,是由流行性乙型脑炎病毒(Japanese encephalitis virus,JEV)引起的一种中枢神经系统的急性人畜共患传染病,被世界动物卫生组织(OIE)列为二类动物疫病,被我国卫生部列为乙类传染病。该传染病主要以三带缘库蚊(Culex tritaeniorhynchus)作为主要的传播媒介,患者主要表现为发烧、剧烈头痛、恶心、呕吐、嗜睡不醒等症状,重者可出现抽搐、昏迷,甚至出现呼吸衰竭而死亡。流行性乙型脑炎的爆发具有明显的季节性和一定的地理分布区,多发生于夏秋季节蚊类孳生的季节,属于自然疫源性虫媒传染病。
乙型脑炎病毒粒子为球形,二十面体对称,直径约35-40nm,分子量为4.2×106D。JEV基因组全长约11kb,由5′-UTR(Untranslated Region,UTR)、3′-UTR以及仅有的一个开放读码框(Open Reading Frame,ORF)共同组成一个开放式阅读框(ORF),编码大小为3432个多聚蛋白体。其中,E蛋白是JEV最重要的结构蛋白,也是目前研究最广泛和充分的蛋白。E蛋白分子量为53kDa,含有500个氨基酸残基,其对应的基因组也是相对保守的区域。
疫苗被认为是预防JE较为有效的途径之一。近年来,虽然随着各类JEV疫苗(主要为减毒活疫苗和灭活疫苗)的研究和广泛应用,JE患病率有所下降,但在疫苗普遍接种的国家中,也尚存在接种者体内特异性抗体逐年衰减这一难以规避的现象,局部地区仍有小范围流行或偶有散发病例报道。Pan等的研究指出,在JE广泛流行的区域内,不同年龄组血清中的JEV抗体阳性率程度与该年龄组JE发病率呈负相关。这提示目前正使用的疫苗的长效免疫效果仍有待改进,有望克服这一问题的新型疫苗亟待研发及推广,以进一步降低发病率,缓解公共卫生压力。
目前没有特异性治疗方法,对症退热治疗可以使用对乙酰氨基酚,因此,开发对乙脑病毒有效的治疗药物十分必要。
发明内容
本发明的目的,在于提供一种全新的具有抑制乙脑病毒的化合物或其立体异构体或可药用盐,所述化合物具有如下结构:
X选自氢或卤素;
R1选自羟基、卤素、羰基、羰氧基、烷基羰基、烷氧基、甲酰基、羧基、氨基或取代的氨基、叠氮基、任选被取代的4-7元环烷基、任选被取代的4-7元杂环烷基、任选被取代的4-7元芳香环基、任选被取代的4-7元杂芳香环基;
n为0、1、2或3;
R2选自卤素、羟基、羧基、氨基、叠氮基或氰基。
一个具体的实施方案中,本发明具有如下结构式所示化合物
X选自氢或卤素;
R3选自任选被取代的4-7元环烷基、任选被取代的4-7元杂环烷基、任选被取代的4-7元芳香环基、任选被取代的4-7元杂芳香环基;优选为吡啶基或苯基;
n为0、1或2;
R2选自叠氮基或氰基。
一个具体的实施方案中,本发明为具有如下结构式所示的化合物
X选自氢或卤素;
R3为吡啶基或苯基;
R2选自叠氮基或氰基。
具体地,本发明涉及具有如下结构的化合物或其立体异构体或可要用盐,:
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。
本发明公开内容的药物组合物可以通过口服、胃肠外或通过植入贮库进行给药。如再次使用的术语胃肠外包括皮下、皮内、静脉内、肌内、关节内、滑膜内、胸骨内、鞘内和损伤区注射或输液技术。
药物组合物可以以无菌可注射制剂的形式,例如,以无菌可注射含水或含油悬浮液的形式。可以根据本领域已知的技术使用合适的分散剂或润湿剂以及悬浮剂配置这种悬浮液。关于这些化合物的制备细节是本领域熟练技术人员已知的。
当口服给药时,本发明公开内容的药物组合物可以以任何口服可接受的剂型给药,所述剂型包括,但不限于,胶囊、片剂和含水混悬液和溶液。在口服运用片剂的情况中,通常使用的载体包括乳糖和玉米淀粉。还可以加入润滑剂如硬脂酸镁。对于以胶囊形式进行的口服给药,有用的载体/稀释剂包括乳糖、高和低分子量聚乙二醇和干玉米淀粉。当含水混悬液口服给药时,所述活性成分与乳化剂和混悬剂混合。如果需要的话,可以加入某些甜味剂和/或调味剂和/或着色剂。
用于上述组合物的其它适宜载体可以在标准药物教课书中找到,例如在“Remington’sPharmaceutical Sciences”,19th ed.,Mack Publishing Company,Easton,Penn.,1995中。本领域技术人员已知所述公开内容的关于药物组合物的适宜递送形式的设计和制备的更多细节。
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乙脑病毒类化合物。
在用于预防和/或治疗乙脑病毒时,本发明公开内容中的化合物的剂量水平典型地在约1至约500毫克每千克(mg/kg)体重每日,更具体地说,在约1至约50mg/kg体重每日。典型地,本发明公开内容中的药物组合物可以每天给药约1次-约3次,优选地是乙脑发生前或发生后服用一次。或者作为连续输液的形式给药,这样的给药可以作为慢性或急性疗法使用。可以与载体材料混合以制备单一剂型的活性成分的数量将随所治疗的宿主和具体的给药方式而改变。
另一方面,本发明涉及一种制品或药盒,包含容器和包装插页,其中所述容器中装有本发明所述的具有本发明所述结构的化合物或其异构体或可药用盐,或包含本发明所述结构化合物的组合物,所述包装插页上载有药物的使用说明书。在一个优选的实施方案中,该制品或药盒进一步包含一个或多个容器,该容器中装有一种或多种预防或治疗乙脑病毒感染的其它抗病毒药物。
术语定义:
除非另有定义,本文使用的所有技术和科学术语具有与本发明所属领域的普通技术人员通常理解的相同的含义。
术语“未取代的”,当其用于限定某个基团时,意思是,该限定的基团没有为氢原子之外的其它基团所取代,此时该某个基团具有按照本发明所属领域的普通技术人员通常理解的相同含义。例如,未取代的杂环基,是指杂环上的氢原子没有被任何其它基团所取代,比如呋喃、吡啶、二氢吡啶等。
术语“取代的”,当其用于限定某个基团时,意思是,其限定的基团上的某1个、2个、3个或更多个氢原子被取代基的取代,1个、2个、3个或更多个氢原子,可以是同一个碳(或氮)原子上的氢原子,也可以是不同碳(或氮)上的氢原子,此时该某个基团的含义应结合取代基来理解,本发明中,除非特别说明,当提及“取代的”,意指有其由限定的基团中的氢原子由选自下列中的某一个、2个、3个或更多个取代基所取代:
氰基、卤素、羟基、羧基、酯基、酰胺基、磺酰胺基、胺基、甲酰基、低级烷基、低级烃基、低级炔基、卤代低级烷基、羟基取代的低级烷基、环烷基、芳基、杂环基、芳基低级烷基、杂环基低级烷基、低级烷基氧基、卤代低级烷基氧基、低级烷基氧基低级烷基、低级烷基氧基低级烷基氧基、低级烷基羰基、低级烷基氧基羰基、低级烷基氨基、低级烷基羰基氨基、低级烷基氨基羰基、低级烷基磺酰基、低级烷基磺酰基氨基、羧基低级烷基氧基、芳基低级烷基氧基。
在涉及到具体命名时,取代基通常置于被取代的基团之前,如“羧基亚甲基氧基”指氧基被亚甲基取代,二而亚甲基又被羧基取代,其结构可表示为:
术语“立体异构体”是指由分子中原子在空间上排列方式不同产生的异构体,包括顺反异构体、对映异构体和构象异构体。所有立体异构体均属于本发明的范围,本发明的化合物可以为单独立体异构体或其它异构体的混合物,如外消旋体,或者所有其它立体异构体的混合物。
术语“盐”是指本发明化合物与酸形成的药学上可接受的盐,如可以是有机或无机盐,比如选自:盐酸、硫酸、磷酸、硝酸、富马酸、柠檬酸、马来酸、苯磺酸、磺酸、苹果酸、琥珀酸、乳酸、乙酸、丙二酸等。
术语“烃基”包括烷基或烃基(如烯基或炔基)。
烷基是指直连或支链或环状的饱和的由碳和氢构成的取代基,低级烷基是指由1-6个碳原子构成的烷基。烯基是指直连或支链或环状的不饱和的由碳和氢构成的取代基,低级烯基是指由1-6个碳原子构成的烯基;炔基是指直连或支链的不饱和的由碳和氢构成的取代基,低级炔基是指由1-6个碳原子构成的炔基。取代的烷基(或取代的烃基)是指烷基上的一个或一个以上的氢原子被其它基团如卤素、羟基、羧基、氰基、环烷基、芳基、杂芳基、氧代、杂环烷氧基等取代。
术语“环烷基”指饱和或不饱和单环烃基,一般包含3-20个碳原子,环烷基可以是单环,也可以是螺环、桥环、稠环或并环。
术语芳基不仅包含碳环芳基,也包含杂环芳基。碳环芳基指6-10元全碳环或多环芳香基团,包括苯基、萘基、联苯基等,碳环芳基也可以是取代或未被取代的。杂环芳基是指含有至少一个杂原子的杂芳香体系基团,包括单环杂环芳基或稠环杂环芳基,杂原子选自氧、硫或氮,包括但不限于呋喃、噻吩、吡咯、噻唑等,杂芳基可以是取代或未被取代的。
术语“杂环基”是指至少含有一个杂原子的环烷基饱和或不饱和单环烃基
具体实施方式
以下列举本发明化合物的一般制造方法,另外,萃取、纯化等只要进行通常有机化学的实验中进行处理即可。
本发明化合物的合成可以参考本领域中公知的步骤进行实施。
原料化合物可以使用市售的化合物、本说明书中记载的化合物、本说明书中引用的文献中记载的化合物,和其它公知化合物。
本发明化合物中,可以存在互变异构体,本发明含有这些化合物,包含其所有可能的异构体和它们的混合物。
当欲获得本发明化合物的盐时,对于本发明的化合物,可以制备成适合的盐的形式。
各缩写的意思
MsCl:甲基磺酰氯
Et3N:三乙胺
DCM:二氯甲烷
EtOAc:乙酸乙酯
NaCN:氰化钠
NaN3:叠氮化钠
18-crown-6:18-冠-6
DMSO:二甲基亚砜
Na2CO3:碳酸钠
1,4-dioxane:1,4-二氧六环
PdCl2(PPh3)2:双(三苯基膦)氯化钯
MeOH:甲醇
DMF:N,N-二甲基甲酰胺
HATU:2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯
DIPEA:N,N-二异丙基乙胺
实施例1:下式化合物的合成
化合物1的合成
500mL茄形瓶中3-(4-溴苯氧基)丙烷-1-醇(15.0g,64.9mmol)溶于120mL二氯甲烷,后加入三乙胺(7.2g,71.4mmol),冰浴降温至0℃,维持0℃滴加MsCl的二氯甲烷溶液(14.1g,68.1mmol in 30mL DCM),30min滴加完全,后自然升温至室温,反应过夜,加入水150mL淬灭反应,分液后有机相分别用水洗(100mL x 1),饱和食盐水洗(50mL x 1),无水硫酸钠干燥后减压浓缩,残余物正相柱层析分离,DCM/EtOAc体系洗脱,洗脱液减压浓缩得目标化合物(类白色固体,19.1g,95.1%)
ESI(310.0,312.0,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 7.40(d,2H),6.82(d,2H),4.42(t,2H),4.13(t,2H),3.22(s,3H),2.02(m,2H).
相似的操作过程应用于3-(4-溴-2-氟苯氧基)甲磺酸丙酯的合成,得类白色固体产物8.5g(96.3%)
ESI(327.0,329.0,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 7.40(m,1H),7.36(m,1H),6.78(m,1H),4.39(t,2H),4.12(t,2H),3.22(s,3H),2.11(m,2H).
100mL茄形瓶中加入3-(4-溴苯氧基)甲磺酸丙酯(3.4g,10.9mmol),DMSO(20mL),18-冠-6(0.3g)及NaCN(1.60g,32.6mmol),75℃下反应过夜,降温后倒入至200mL去离子水中,抽滤收集不溶物,后正相柱层析纯化,DCM/EtOAc洗脱,得类白色固体(1.68g,64.3%)。
ESI(240.0,242.0,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 7.38(d,2H),6.90(d,2H),4.11(t,2H),2.21(m,2H),1.98(m,2H).
相似的操作应用于
ESI(258.0,260.0,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 7.36(m,2H),6.78(m,1H),4.00(t,2H),1.96-2.10(m,4H).
100mL茄形瓶中加入3-(4-溴苯氧基)甲磺酸丙酯(4.1g,13.3mmol),DMSO(30mL),18-冠-6(0.4g)及NaN3(1.04g,16.0mmol),50℃下反应过夜,降温后倒入至300mL去离子水中,抽滤收集不溶物,100mL纯化水洗涤滤饼,后正相柱层析纯化,DCM/EtOAc洗脱,得类白色固体(2.67g,78.6%)。
ESI(256.0,258.0,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 7.38(d,2H),6.90(d,2H),4.11(t,2H),2.21(m,2H),1.98(m,2H).
相似的操作应用于
ESI(274.0,276.0,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 7.35(m,2H),6.84(m,1H),4.08(t,2H),1.75(m,2H),1.53(m,2H).
50mL茄形瓶中加入4-(4-溴苯氧基)丁腈(1.0g,4.2mmol)、(4-氨基噻吩-2-基)硼酸(655mg,4.6mmol)、碳酸钠(801mg,7.6mmol)二氧六环/水(20mL/1mL)及PdCl2(PPh3)2(295mg,0.42mmol),回流反应6h,后减压浓缩,残余物柱层析纯化,DCM/MeOH体系洗脱得淡黄色固体(470mg,43.4%)。
ESI(369.3,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 8.42(s,1H),7.55(d,2H),6.94(d,2H),6.27(s,1H),4.28(brs,2H),4.12(t,2H),2.12(m,2H),1.85(t,2H).
相似的操作应用于
ESI(277.1,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 8.40(s,1H),7.50(m,2H),7.24(m,1H),6.30(s,1H),4.57(brs,2H),4.03(t,2H),2.10(m,2H),1.88(t,2H).
ESI(275.2,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 8.40(s,1H),7.51(m,2H),7.24(m,1H),6.30(s,1H),4.57(brs,2H),4.03(t,2H),1.72(m,2H),1.47(t,2H).
ESI(293.2,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 8.25(s,1H),7.50(m,2H),7.28(m,1H),6.41(s,1H),4.77(brs,2H),4.14(t,2H),1.72(m,2H),1.48(t,2H).
25mL茄形瓶中加入4-(4-(4-氨基噻吩-2-基)苯氧基)丁腈(70mg,0.27mmol)、吡啶甲酸(37mg,0.30mmol)、HATU(114mg,0.30mmol)、DIPEA(42mg,0.32mmol)及无水DMF(5mL),N2保护下室温反应6h后减压浓缩,残余物Pre-TLC纯化,DCM/MeOH展板,得目标化合物(浅褐色固体,71mg,72.5%)
ESI(363.1,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 11.2(s,1H),8.72(d,1H),8.33(s,1H),8.37(s,1H),7.95(m,2H),7.76(d,2H),6.99(d,2H),6.33(s,1H),3.98(t,2H),2.12(m,2H),1.85(t,2H).
相似的操作,可用于合成如下结构化合物(化合物2至12):
化合物13的合成
25mL茄形瓶中加入4-(4-(4-氨基噻吩-2-基)苯氧基)丁腈(70mg,0.27mmol)、2-溴甲基吡啶氢溴酸盐(137mg,0.54mmol)、碳酸铯(264mg,0.81mmol)及无水DMF(5mL),N2保护下80℃反应8h后在DCM/水中分液,DCM反萃水相(15mL x 2),合并有机相,水洗涤(20mL x1),饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥后减压浓缩,残余物Pre-TLC纯化,DCM/MeOH展板,得目标化合物(浅棕色固体,78mg,42.3%)
ESI(350.1,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 8.62(d,1H),8.24(s,1H),7.84(m,1H),7.78(br s 1H),7.70(m,2H),7.23(m,2H),7.01(d,2H),6.37(m,1H),4.83(s,2H),4.24(t,2H),1.85-2.10(m,4H).
类似的方法,可以合成化合物14至24。
实施例4化合物33的合成
50mL茄形瓶中加入4-(4-溴苯氧基)丁腈(1.0g,4.2mmol)、(4-氨基咪唑-2-基)硼酸(579mg,4.6mmol)、碳酸钠(801mg,7.6mmol)二氧六环/水(20mL/1mL)及PdCl2(PPh3)2(295mg,0.42mmol),回流反应6h,后减压浓缩,残余物柱层析纯化,DCM/MeOH体系洗脱得淡黄色固体(420mg,41.4%)。
ESI(242.2,[M+H]+),1H-NMR(400MHz,CDCl3):δppm 12.52(br s,1H),7.87(d,2H),7.10(d,2H),7.03(s,1H),6.58(br s,2H),6.52(d,1H),4.11(t,2H),2.21(m,2H),1.87(m,2H).
25mL茄形瓶中加入4-(4-(4-氨基咪唑-2-基)苯氧基)丁腈(0.27mmol)、吡啶甲酸(37mg,0.30mmol)、HATU(114mg,0.30mmol)、DIPEA(42mg,0.32mmol)及无水DMF(5mL),N2保护下室温反应6h后减压浓缩,残余物Pre-TLC纯化,DCM/MeOH展板,得目标化合物(浅褐色固体,9.8mg,10.5%)
ESI(346.2,[M+H]+),1H-NMR(400 MHz,CDCl3):δppm 12.32(br s,1H),10.52(brs,1H),8.82(d,1H),8.35(d,1H),8.10(m,1H),7.97(m,1H),7.88(d,2H),7.03(d,2H),7.04(d,1H),6.48(d,1H),4.13(t,2H),2.06(m,2H),1.87(t,2H)。
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实施例5:化合物对乙脑病毒的抑制活性
所用试剂与材料:DMEM培养基、FBS、PBS、0.25%的胰蛋白酶,均为Thermo公司产品;DMSO、无水乙醇均为Sigma公司产品。
乙型脑炎毒株NJ-2008感染BHK细胞,试验步骤如下:
1、种植细胞:在96孔细胞培养板中接种BHK细胞,按8×103/孔接种,24小时后细胞长至单层(细胞覆盖孔底的面积约为80%),吸出培养基,接入NJ-2008细胞,37℃,含5%CO2培养箱培养1小时后,吸附完成后,弃上清液,用DMEM培养基洗去未吸附的病毒,加入用含5%胎牛血清的DMEM培养基稀释至指定浓度的各化合物,于37℃,5%CO2的培养箱中培养48小时,收集各个孔中的上清,再根据空斑试验检测病毒滴度。
空斑试验:采用BJK细胞进行空斑实验,即把BJK细胞接种于24孔板,24h后依次接种400uL含2%FBS培养基10倍稀释的NJ-2008上清液,稀释度为10-1至10-10,每个稀释度2个副孔,至于37℃,5%CO2培养箱培养吸附1h,然后加入600uL甲基纤维素覆盖液(含2%胎牛血清的DMEM),37℃,5%CO2培养箱培养,4-5天左右观察结果。
记录对病毒抑制情况,并计算EC50和EC90的浓度(结果见下表)。
化合物用DMSO溶解,按如下浓度梯度往下稀释,200μM、100μM、50μM、25μM、10μM、5μM、2.5μM、1μM。
当EC50或EC90介于10μM及以下时,活性计为A;EC50或EC90介于10~50μM时,活性计为B;当EC50或EC90介于50μM~100μM范围时,活性计为C,当EC50或EC90介于100μM~200μM范围时,活性计为D,当EC50或EC90介于大于200μM范围时,本实验认为未测出活性。结果见下表。
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Claims (4)
1.具有以下的式(I)所示的化合物或其立体异构体或可药用盐在具有预防或治疗流行性乙型脑炎病毒感染药物中的应用,
X选自氢或卤素;
R1选自羟基、卤素、羰基、羰氧基、烷基羰基、烷氧基、甲酰基、羧基、氨基或取代的氨基、叠氮基、任选被取代的4-7元环烷基、任选被取代的4-7元杂环烷基、任选被取代的4-7元芳香环基、任选被取代的4-7元杂芳香环基;
n为0、1、2或3;
R2选自卤素、羟基、羧基、氨基、叠氮基或氰基。
2.根据权利要求1所述的应用,其中所述化合物结构为
X选自氢或卤素;
R3选自任选被取代的4-7元环烷基、任选被取代的4-7元杂环烷基、任选被取代的4-7元芳香环基、任选被取代的4-7元杂芳香环基;优选为吡啶基或苯基;
n为0、1或2;
R2选自叠氮基或氰基。
3.根据权利要求2所述的应用,其中所述化合物结构为:
X选自氢或卤素;
R3为吡啶基或苯基;
R2选自叠氮基或氰基。
4.根据权利要求1-3中任意一权利要求所述的应用,其中所述化合物结构为:
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