CN110590768B - 杂环化合物、其组合物及其作为抗流感病毒药物的应用 - Google Patents
杂环化合物、其组合物及其作为抗流感病毒药物的应用 Download PDFInfo
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- CN110590768B CN110590768B CN201810605064.2A CN201810605064A CN110590768B CN 110590768 B CN110590768 B CN 110590768B CN 201810605064 A CN201810605064 A CN 201810605064A CN 110590768 B CN110590768 B CN 110590768B
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Classifications
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
本发明提供了涉及式(I)所示的一类杂环化合物或其药学可接受的盐及其制备方法和在制备治疗或预防流感病毒的药物中的应用。作为新型的病毒聚合酶抑制剂,这些化合物能抑制A型流感病毒RNA的转录和合成,与已有病毒聚合酶抑制剂相比,本发明化合物具有显著更优的活性,更好的水溶解性且结构更简单。
Description
技术领域
本发明属于医药化学领域,尤其涉及一类杂环化合物、杂环化合物盐及其制备方法和作为治疗和预防流感病毒的药物的应用。
背景技术
流感是一种能致命的传染性疾病,有很高的发病率和死亡率。每年有5-20%的人群感染流感病毒,并引起呼吸或心脏等其他并发症,在世界范围内每年导致数十万人死亡,流感大流行时可能导致数百万人死亡,20世纪的流感大爆发曾致数千万人死亡。这些流行的流感都是在动物身上流感病毒发生突变,从动物物种传播到人类引起的。
流感病毒属于正粘病毒科(orthomyxoviridae)家族的反义RNA病毒,包括5个种属:A型病毒、B型病毒、C型病毒、Isavirus和Thogoto病毒。A型病毒是一种从禽类向人类传播的病毒,有很高的致病率,并大规模流行,造成严重的后果。根据A型流感的不同血清型,分为不同的流感病毒。例如H1N1引起1918年的西班牙流感,H2N2引起1957年的亚洲流感,H3N2引起1968年的香港流感,H5N1为2007年-2008年的流感类型。其他还有H1N2,H7N7,H9N2,H7N2,H7N3,H10N7等。
A型流感病毒颗粒大小为80-120nm。其基因组并非单一片段的核酸,而是8个片段的反义RNA。A型流感的8个基因组编码11种蛋白质:血凝素(HA),神经氨酸酶(NA),核蛋白(NP),M1,M2,NS1,NS2,PA,PB1,PB1-F2和PB2。HA和NA是病毒颗粒外的大分子蛋白。HA是介导病毒结合靶细胞和病毒基因组进入靶细胞的凝集素,NA参与子代病毒的释放,因此这些蛋白都可以作为开发流感抑制剂的靶向蛋白。
治疗流感的方法是疫苗或抗病毒药物。由于每个季节的疫苗是当年的主要菌株,所以对感染主要菌株以外的病人或者老年人疗效很弱。另外流感病毒突变很快,疫苗需要每年更新。如果流感大流行,能否生产足够多的疫苗或开发正确的疫苗都是一种很大的挑战。
现在标准的抗病毒药物是神经氨酸酶抑制剂,例如奥塞米韦(Oseltamivir)和扎那米韦(Zanamivir)。这些药物可以用于治疗A型流感和B型流感感染的病人,但是神经氨酸酶抑制剂必须在感染的48小时内治疗,对重症的病人可能没有临床效果。另外流感病毒突变性强,已有报道H5N1流感病毒对神经氨酸酶抑制剂产生耐药性。这类抗流感药物的作用是阻止病毒在人体细胞之间扩散,药物本身并没有阻止病毒增殖的功效。因此需要开发全新的机理以及高效低毒并且突变门槛高的抗流感药物,以满足临床和潜在流感爆发的需要。
流感病毒的聚合酶包含三个亚基:PB1,PB2和PA,这三个亚基负责8个RNA片段的复制和转录。这三个亚基都是药物开发的靶标。在合成病毒mRNA时,病毒聚合酶通过“cap-snatching”机理利用宿主的前-mRNA作为转录的引物,在PB2亚基中就包含这种机理的区域,用于结合m-RNA前体的m7GTP。针对这个区域的PB2抑制剂是一类全新机理的抗流感病毒化合物,有巨大的临床应用价值。
现有的PB2抑制剂对A型流感病毒有效,并且高效抑制已知临床的血清型病毒,例如H1N1和H5N1等。PB2抑制剂能高效的抑制病毒RNA的转录和合成,而神经氨酸酶抑制剂对RNA的合成没有作用。另外神经氨酸酶抑制剂对低病毒感染的人群有效,而PB2抑制剂对所有的MIO都有保护作用,预示PB2抑制剂对重症患者也会有很好的保护作用。和神经氨酸酶抑制剂只在48小时内有效不同,PB2抑制剂在120小时仍然有效。特别是PB2抑制剂和神经氨酸酶抑制剂联合用药,极大的提高临床效果和延长感染病毒的后可以治疗的时间。PB2抑制剂和PA内切酶抑制剂联合用药,动物模型显示疗效优于单个药物的作用。将来PB2抑制剂和神经氨酸酶以及PA内切酶抑制剂等联合用药,可以预期能加快患者的康复和提高临床病人的生存率。
现有技术中,虽然已有一些PB2抑制剂的文献报道,但是它们的结构较为复杂,水溶性较差,活性也还需要进一步提高。开发新型的PB2抑制剂,替代或联合现有的神经氨酸酶抑制剂以及其他抗流感药物是临床迫切的需求。
发明内容
本发明所要解决的技术问题是提供一类新型杂环化合物,该类化合物是新型PB2抑制剂,具有显著更强效的抑制流感病毒的体外活性,并具有更优秀的药代动力学特性。
为解决以上技术问题,本发明采取如下技术方案:
本发明描述的具有式(I)所示的杂环化合物或其异构体、可药用盐、溶剂化物或结晶。在本发明所述的一些实施实例中,也提供了具有式(I)所代表结构的异构体和其他化学保护形式,例如包括化学水解或生物降解为酸的前药形式,酯和其他前体药物。本发明提供的杂环化合物,具有式(I)结构,
其中,
R1选自F或Cl;
R2选自C1~C8的烃基、C3~C6的环烃基、取代的C1~C8的烃基、取代的C3~C6的环烃基,其中取代烃基、取代环烃基中的取代基独立为选自氟、氯、C1~C8的烃基以及C1~C8的烃氧基中的一个或多个基团;
R3选自氢、C1~C8的烃基羰基氧C1~C4的烃基-、C1~C8的烃基氧羰基氧C1~C4的烃基-;
Z选自N或CH。
根据本发明的一个优选方面,式(I)中,R2选自C1~C8的烷基、C3~C6的环烷基、取代的C1~C8的烷基、取代的C3~C6的环烷基,其中取代烷基、取代环烷基中的取代基独立为选自氟、氯、C1~C8的烷基以及C1~C8的烷氧基中的一个或多个。更优选地,式(I)中,R2选自C1~C6的烷基、C3~C6的环烷基、取代的C1~C6的烷基、取代的C3~C6的环烷基,其中取代烷基、取代环烷基中的取代基独立为选自氟、氯、C1~C3的烷基以及C1~C3的烷氧基中的一个或多个。
根据本发明的一些具体优选方案,式(I)中,R2选自甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、环己基、氟代甲基、氟代乙基、氟代正丙基、氟代异丙基、氟代环丙基、氟代环丁基、氟代环戊基、氟代环己基、氯代甲基、氯代乙基、氯代正丙基、氯代异丙基、氯代环丙基、氯代环丁基、氯代环戊基、氯代环己基、甲氧基取代的甲基、甲氧基取代的乙基、甲氧基取代的环丙基、甲氧基取代环丁基、乙氧基取代的甲基、乙氧基取代的乙基、乙氧基取代的环丙基、乙氧基取代环丁基。
根据本发明,在构成化合物的其他基团相同时,如将上述的R2基团用其他可能的基团例如与嘧啶环形成并环结构的噻吩环等来替代,将导致化合物的水溶性显著降低、不稳定的代谢以及多数情况下化合物活性的降低。
根据本发明的又一优选方面,式(I)中,R3选自氢、C1~C8的烷基羰基氧C1~C4的烷基-、C1~C8的烷氧基羰基氧C1~C4的烷基-。更优选地,式(I)中,R3选自氢、C1~C4的烷基羰基氧C1~C2的烷基-、C1~C4的烷氧基羰基氧C1~C2的烷基-。
根据本发明的一些具体优选方案,R3选自氢、甲基羰基氧甲基-、甲基羰基氧1-乙基-、乙基羰基氧甲基-、异丙基羰基氧甲基-、叔丁基羰基氧甲基-、甲氧基羰基氧甲基-、甲氧基羰基氧1-乙基-、乙氧基羰基氧甲基-、异丙氧基羰基氧甲基-、正丁氧基羰基氧甲基-、异丙基氧基羰基氧1-乙基-。
在根据本发明的一些实施方式中,式(I)中R1为Cl;R2选自甲基或环丙基;R3选自H、C1~C8的烷基羰基氧C1~C4的烷基-、C1~C8的烷氧基羰基氧C1~C4的烷基-;Z选自N或CH。
在根据本发明的又一些实施方式中,式(I)中R1为F;R2选自甲基或环丙基;R3选自H、C1~C8的烷基羰基氧C1~C4的烷基-、C1~C8的烷氧基羰基氧C1~C4的烷基-;Z选自N或CH。
在根据本发明的还一些实施方式中,式(I)中R1是F;R2是甲基;R3是H;Z选自CH或N。
在根据本发明的另一些实施方式中,式(I)中R1是F;R2是环丙基;R3是H;Z选自CH或N。
根据本发明的一个优选方面,式(I)中,Z为N。
根据本发明,典型的通式(I)所示的杂环化合物为如下式(I-1)、式(I-2)、式(I-3)、式(I-4)、式(I-5)、式(I-6)、式(I-7)、式(I-8)、式(I-9)、式(I-10)、式(I-11)、式(I-12)、式(I-13)、式(I-14)、式(I-15)、式(I-16)、式(I-17)、式(I-18)、式(I-19)、式(I-20)、式(I-21)、式(I-22)、式(I-23)、式(I-24)、式(I-25)、式(I-26)、式(I-27)、式(I-28)、式(I-29)、式(I-30)、式(I-31)、式(I-32)、式(I-33)、式(I-34)、式(I-35)、式(I-36)、式(I-37)、式(I-38)、式(I-39)、式(I-40)所示的化合物。
本发明还提供了本发明通式(I)所示的杂环化合物的制备方法,所述制备方法包括:
(1)使化合物A与化合物B在过渡金属催化剂存在下发生偶联反应,得到化合物C,化合物A、B、C中所涉及的R1、R2、R3、Z的定义同前,化合物A、C中的P代表氨基保护基;。
(2)使化合物C进行碱性水解和脱去氨基保护基得到式(I)所示的杂环化合物。
上述步骤(1)中,过渡金属催化剂具体可以是例如钯催化剂。经典的钯催化剂有Pd(PPh3)4(Ph=phenyl),Pd(PPh3)2Cl2,Pd(dppf)2Cl2(dppf=1,1’-Bis(diphenylphosphino)-ferrocene),Pd(acac)2(acac=acetylacetonate),PdCl2(PCy3)2(PCy=cyclohexyl),Pd2(dba)3(dba=dibenzylideneacetone)等,这些钯催化剂优选与磷试剂联合用于偶合反应。
上述的氨基保护基可以是本领域已知的那些,没有特别限制,具体例如对甲苯磺酰基,2-(三甲基硅基)乙氧基甲基,四氢吡喃基或三苯甲基等。
根据本发明的一些实施方案,式A、C、(I)中,Z为CH,P为对甲苯磺酰基,步骤(2)的一个示例性实施过程如下:在无机碱存在下碱性水解,先后脱去对甲苯磺酰基和乙酯得到目标物。
根据本发明的另一些实施方案,式A、C、(I)中,Z为N,P为四氢吡喃基或三苯甲基,步骤(2)的一个示例性实施过程如下:用三氟乙酸(TFA)脱去四氢吡喃基或三苯甲基,然后在无机碱存在下进行碱性水解。
上述的无机碱没有特别限制,例如可以是氢氧化锂,氢氧化钠或氢氧化钾等。
本发明还提供一类抗流感的前药,具有式(II)结构,
其中,R1、R2、Z的定义同前,R4选自C1~C8的烷基羰基-或C1~C8的烷氧基羰基-。前药的设计能改善化合物的理化性质,增进吸收,提高化合物的生物利用度,并减少了可能的临床剂量。前药具体可以是例如下面的化合物:
本发明的一类杂环化合物及其盐显示强效抑制流感病毒的活性,比现有临床上同类化合物的活性高4-10倍左右,并具有优秀的药代动力学特性,有很强的成药性。甲基和环丙基等疏水性取代基团的引入能有效地增强与PB2亚基疏水腔的相互作用,提高化合物的活性;同时能屏蔽嘧啶环,阻断P450氧化酶氧化嘧啶杂环的位点,降低化合物代谢的不稳定性。这些高活性的化合物或前药将和神经氨酸酶抑制剂、PA核酸内切酶抑制剂或其他抗流感药物联合用药,在临床上提供预防或快速治愈流感病毒感染的药物。
本发明还进一步提供包含本发明提供的一类杂环化合物、其异构体、其药物可接受的盐或其溶剂化物的药物组合物。在一些实施实例中,该组合物还包括药物可接受的载体。在一些实施例中,所述药物组合物还包含一种或多种治疗剂,所述治疗剂选自神经氨酸酶抑制剂、PA核酸内切酶抑制剂或其他抗流感药物。
本发明提供了所述的杂环化合物或其异构体、可药用盐、水合物、溶剂化物、结晶或含有所述杂环化合物的药物组合物在制备治疗或预防流感病毒的药物中的应用。
优选地,本发明提供了所述的杂环化合物或其异构体、可药用盐、水合物、溶剂化物、结晶或含有所述杂环化合物的药物组合物在制备PB2抑制剂等抗流感药物中的应用。
本发明同时还提供所述药物组合物在制备用于治疗或预防流感病毒感染药物中的应用以及采用所述药物组合物治疗或预防流感病毒感染患者疾病的方法。
根据本发明的药物组合物,其中本发明化合物优选以治疗有效量存在。
上述药物组合物中药学上可接受的载体,可以是例如药学上可接受的稀释剂、赋型剂、填充剂、粘合剂、崩解剂、吸收促进剂、表面活性剂、润滑剂、香味剂、甜味剂等。
以本发明化合物为活性成分制备的药物可以是片剂、粉剂、胶囊、粒剂、口服液以及注射制剂等多种形式。药物组合物的剂型优选为片剂、胶囊或针剂。
上述各种剂型的药物均可以按药学领域的常规方法制备。
本发明还提供本发明化合物在制备预防或治疗病毒感染疾病中的用途,优选其中病毒感染疾病为流感病毒感染。
跟本发明的一个具体方面,本发明的药物组合物组成可以由下配比构成:
由于以上技术方案的实施,本发明与现有技术相比存在如下优势:
本发明提供了一类新型的杂环化合物,该类杂环化合物和现有广泛应用的神经氨酸酶抑制剂比较有巨大的优势,这些化合物表现为强效的A型流感病毒抑制剂,有效的抑制病毒RNA的复制和合成。这些化合物对重症患者和流感感染120小时的病人仍有强效的保护作用,而神经氨酸酶抑制剂只在48小时内有效,且对流感严重感染的病人无效。这类杂环化合物有强效的PB2抑制活性,具有优异的药代动力学特性,有很强的成药性。
进一步地,根据本发明化合物,其嘧啶环结构的氮原子邻位的氢原子被甲基、环丙基等基团取代,与采用其他取代基例如噻吩环等相比,这些取代基将更好地阻断P450的氧化,降低化合物的代谢不稳定性,有利于提高药物的生物利用度和降低临床药物的剂量。
更进一步地,根据共晶的结构分析,嘧啶环结构上R2取代的位置是一个疏水性的空腔,新产生的疏水性作用降低化合物的结合能,所以化合物的抑制活性有很大的提高。
本发明的化合物单独或和神经氨酸酶抑制剂、PA核酸内切酶抑制剂或其他抗流感药物联合用药,用于治疗临床的流感病人或用于预防大流感的贮备药物。
进一步地,本发明的杂环化合物结构简单,可以较低的成本制备得到。
具体实施方式
术语定义
除非另外定义,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“异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。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例如外消旋体,或者所有其它立体异构体的混合。
术语“盐”是指本发明所述的化合物与酸形成的药学上可接受的盐,所述的酸可以是有机酸或无机酸,具体可选自:磷酸、硫酸、盐酸、氢溴酸、柠檬酸、马来酸、丙二酸、扁桃酸、琥珀酸、富马酸、醋酸、乳酸、硝酸、磺酸、对甲苯磺酸、苹果酸、甲烷磺酸或其类似物。
术语“溶剂化物”是指通过与溶剂分子配位形成固态或液态的配合物的本发明化合物的形式。水合物是溶剂化物的特殊形式,其中与水发生配位。在本发明范围内,溶剂化物优选是水合物。
术语“结晶”是指本发明所述的化合物形成的各种固体形态,包括晶型、无定形。
术语“烃基”是指直链、支链或环状的饱和或不饱和主要由碳和氢构成的取代基。优选1-20个碳原子,更优选1-12个碳原子。术语“烷基”是指直链、支链的饱和烃基。烷基具体包括甲基、乙基、正丙基、异丙基、环丙基、正丁基、异丁基、叔丁基、环丁基、正戊基、异戊基、新戊基、环己基、正己基、异己基、2,2,-甲基丁基和2,3-二甲基丁基、16-烷基、18-烷基。术语“C1-20烷基”是指含有1-20个碳原子的直链、支链饱和烃基。取代烷基指被取代基取代的烷基。当烷基被取代时,取代基可以在任何可使用的连接点上取代,取代基可以是单取代或多取代。取代基独立的选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、氘、卤素、硫醇、羟基、硝基、羧基、酯基、氰基,环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、氧代,在命名时取代基通常置于烷基之前。
术语“环烷基”指饱和和/或部分不饱和单环或多环环烃基。单环可包括3-10个碳原子。单环环烷烃基的非限制实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基等。多环环烷基包括螺环、稠环和桥环的环烷基。环烷基包括无取代基和含有取代基。取代基选自一个或多个取代基团,包括但不仅限于以下基团,独立的选自烷基、环烷基、烷氧基、卤素、羧基、酯基、氨基、酰胺基、羟基、氰基、硝基、芳基、杂芳基。
术语“卤素”是指氟、氯、溴、碘,优选为氟、氯、溴。
术语“卤代烷基”是指至少被一个卤素原子取代的烷基。
以下实施例可以使本专业技术人员更全面地理解本发明,但不以任何方式限制本发明。所有化合物的结构均经1H NMR或MS所确定。
实施例中用到的化合物名称缩写如下:
DCM:二氯甲烷;EtOAc:乙酸乙酯;THF:四氢呋喃;DME:乙二醇二甲醚;1,4-Dioxane:1,4-二氧六环;Pd2(dba)3:三(二亚苄基丙酮)二钯;Xantphos:4,5-双二苯基膦-9,9-二甲基氧杂葸;tBuONa:叔丁醇钠;TsCl:对甲苯磺酰氯;DIPEA:二异丙基乙胺;Pd(dppf)Cl2:[1,1'-双(二苯基膦基)二茂铁]二氯化钯;mCPBA:间氯过氧苯甲酸;X-phos:2-二环己基磷-2,4,6-三异丙基联苯。
以下实施例中的化合物Int-1、化合物Int-2的制备方法如下。
制备(1S,2S,3S,4R)-3-氨基二环[2.2.2]辛-5-烯-2-羧酸乙酯三氟乙酸盐(化合
物Int-1)
化合物2的制备:
马来酸酐(10g,0.1mol)溶解于氯仿(100mL)中,冰浴至0℃,向反应液中滴加1,3-环己二烯(11.2mL,0.11mol),滴加完毕,缓慢升至室温,避光的情况下搅拌过夜。反应液浓缩,加入甲醇(70mL),加热至50℃,搅拌10min,冰浴至0℃,搅拌30min,过滤,干燥,得到白色固体即化合物2(14g,71%)。1H NMR(400MHz,CDCl3):δ6.31-6.32(m,2H),3.21-3.22(m,2H),3.14-3.16(m,2H),1.60-1.64(m,2H),1.59-1.60(m,2H).13C NMR(100MHz,CDCl3)δ:172.9,133.1,44.6,31.6,22.8.
化合物3的制备:
化合物2(24.6g,138.0mmol)和奎宁(49.2g,151.6mmol)悬浮在无水甲苯(92mL)中,反应液冷却至-16℃,滴加无水乙醇(52.4mL,898.6mmol),在-20℃下反应20h,过滤,滤饼用少量的冷却甲苯洗涤,室温下干燥,得到白色固体化合物3(57g,75%)。
化合物4的制备:
化合物3(5.77g,10.5mmol)悬浮到甲苯(29mL),冰浴下加入6N盐酸(3.9mL),升至室温,低于25℃,搅拌至固体全部变为液体,时间为1小时左右,静置分层,分出有机相,水相用甲苯(10mLx2)洗涤,合并有机相,加入无水硫酸钠(6g),密闭下,在低于5℃的冰箱中搅拌8-12小时,反应液经过装有无水硫酸钠的漏斗过滤,少量甲苯洗涤,得到的甲苯溶液冷至-20℃,缓慢滴加叔戊醇钾(1.7M,8mL),强力搅拌,滴加完毕,在-20℃搅拌30-40分钟,加入乙酸(0.3mL),接着加入2N盐酸(8.1mL),在5℃左右搅拌30分钟,静置,分出水相,有机相用缓冲溶液(2mL x3)洗涤(缓冲溶液的制备为7.9g磷酸二氢钠和1.3g磷酸氢二钠和143mL纯净水),蒸去甲苯,得到油状的液体,加入庚烷(2mL),在40℃搅拌30分钟,放到0℃的冰箱过夜,得到的结晶用少量的庚烷洗涤,得到1.5g无色结晶(64%)。
1H NMR(400MHz,CDCl3):δ11.74(brs,1H),6.37(t,J=7.2Hz,1H),6.22(t,J=7.2Hz,1H),4.14-4.22(m,2H),3.20(dd,J=2.4Hz,J=5.6Hz,1H),3.05-3.07(m,1H),2.95-2.97(m,1H),2.83-2.85(m,1H),1.61-1.67(m,1H),1.45-1.52(m,1H),1.30-1.34(m,1H),1.25(t,J=7.2Hz,3H),1.09-1.17(m,1H).13C NMR(100MHz,CDCl3):δ180.4,173.7,134.6,132.5,60.9,45.8,45.1,32.5,32.3,24.3,20.2,14.2.
化合物5的制备:
三乙胺(5.8mL,41.6mmol)缓慢的加到化合物4(4.3g,19.1mmol)的甲苯(50mL)溶液中,接着升温至95℃,滴加DPPA(diphenyl phosphoryl azide)(4.1mL,19.0mmol),在96℃反应1小时,加入叔丁醇(3.6mL,38.2mmol),在96℃的条件下反应过夜,冷至室温,加入Boc2O(4.1g,19.0mmol),搅拌过夜,倒入饱和的碳酸氢钠溶液,乙酸乙酯萃取,饱和食盐水洗涤,浓缩,柱层析纯化得到1.1g化合物5。
化合物Int-1的制备:
向冰浴的化合物5(2g,6.7mmol)的二氯甲烷(10mL)溶液中滴加三氟乙酸(5mL),5分钟滴加完毕,在冰浴下继续搅拌30分钟,TLC显示原料基本消耗完全,减压蒸去二氯甲烷和三氟乙酸,加入***(5mL),搅拌,减压蒸去***,得到的固体用***洗涤两次,得到白色的固体即化合物Int-1,1.5g,78%。
1H NMR(400MHz,DMSO-d6):δ7.95(brs,3H),6.50(t,J=7.2Hz,1H),6.17(t,J=7.2Hz,1H),4.09-4.19(m,2H,3.66(m,1H),2.87-32.89(m,1H),2.80-2.81(m,1H),2.30(m,1H),1.48-1.53(m,1H),1.20-1.35(m,5H),1.02-1.09(m,1H).13C NMR(100MHz,DMSO-d6):δ172.1,136.2,130.4,61.2,51.4,48.8,33.0,32.9,22.7,19.5,14.4.
制备5-氟-3-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-1-甲苯磺酰基-
1H-吡咯并[2,3-b]吡啶(化合物Int-2)
化合物7的制备:N-溴代丁二酰亚胺(NBS,5.29g,29.7mmol)加入到化合物6(4.50g,33mmol)的二氯甲烷(100mL)溶液中并于室温下反应19小时,反应结束后加入饱和的亚硫酸氢钠溶液(200mL),分液,有机层用20%的氢氧化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液真空浓缩得到粗品4.62g。
化合物8的制备:化合物7(4.40g,20.4mmol)溶于30mL干燥的DMF中,加入钠氢(1.30g,32.6mol)并搅拌30分钟。然后加入对甲苯磺酰氯(5.78g,30.6mmol)并反应4小时。反应结束后倒入到冰水混合物中,析出固体,过滤,滤饼用石油醚洗涤,粗品用乙酸乙酯重结晶得到3.10g化合物8。收率:42.1%。
化合物int-2的制备:化合物8(1.50g,4.05mmol),双联频哪醇硼酸酯(3.089g,12.16mmol),Pd(dppf)Cl2(0.296g,0.41mmol)和乙酸钾(1.193g,12.16mmol)加入到25mL1,4-二氧六环中,氮气鼓泡除去体系中的氧气,混合物加热回流19小时,旋干,粗品溶于乙酸乙酯(150mL),用硅胶垫过柱,产品用甲基叔丁基醚(4.5mL)和石油醚(15mL)重结晶得0.605g产物。收率:35.9%。
下面结合具体实施例,对本发明做进一步的说明:
实施例1:制备(2S,3S)-3-((5-氟-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-6-甲基嘧啶-4-基)氨基)二环[2.2.2]辛-5-烯-2-羧酸(I-1)
化合物1b的制备:
甲基溴化镁(27mL,0.027mol,1M四氢呋喃溶液)加入三口瓶,冷却至0℃,加入化合物1a(2.990g,0.018mol)的四氢呋喃溶液(10mL),滴完10-15℃下搅拌1h;冷却至0℃,依次滴加入三乙胺(2.5mL,0.018mol)和I2(4.960g,0.018mol)的THF溶液(60mL),加料完毕保持此温度搅拌1h,然后室温搅拌过夜。加入亚硫酸氢钠溶液洗涤,乙酸乙酯(150mL)萃取3次,合并乙酸乙酯层,依次用水(200mL)和饱和食盐水(200mL)洗涤,无水硫酸钠干燥后浓缩,粗产品用硅胶柱层析(PE/EA=100/5)纯化得浅黄色油状物1.010g,即化合物1b。
化合物1c的制备:
化合物1b(0.130g,0.718mmol),化合物Int-1(0.204g,0.718mmol)和DIPEA(0.401g,2.730mmol)依次加入至四氢呋喃(30mL)和无水乙醇(2mL)中,加热至回流搅拌12h。加水淬灭,乙酸乙酯(30mL)萃取2次,合并乙酸乙酯层,饱和食盐水(30mL)洗涤,无水硫酸钠干燥后减压浓缩干,硅胶柱层析(PE/EA=20/1至10/1)纯化得淡黄色油状物0.115g,即化合物1c。
化合物1d的制备:
化合物1c(0.115g,0.338mmol)、化合物Int-2(0.311g,0.745mmol)和碳酸钠(0.110g,1.02mmol)加入至100mL单口瓶中,氮气置换三次,加入Pd2(dba)3(0.016g,0.016mmol)和X-phos(0.040g,0.085mmol),氮气置换三次,加入2-甲基四氢呋喃(5mL)和水(1mL),再次用氮气置换三次后加热至回流反应7h。冷却至室温,粗品直接拌硅胶柱层析(PE:EA=15:1)纯化得淡黄色固体0.199g,即化合物1d。
1HNMR(400MHz,CDCl3)δ:8.63(dd,1H,J1=2.8Hz,J2=8.4Hz),8.59(s,1H),8.32(d,1H,J=2.0Hz),8.15(d,2H,J=8.4Hz),7.31(s,1H),6.61(t,1H,J1=7.2Hz,J2=7.6Hz),6.32(t,1H,J1=6.8Hz,J2=7.6Hz),4.89-4.80(m,2H),4.32-4.17(m,2H),2.99-2.96(m,1H),2.93-2.90(m,1H),2.41(d,3H,J=2.8Hz),2.40(s,3H),2.25-2.23(m,1H),1.91-1.85(m,1H),1.73-1.72(m,1H),1.57-1.46(m,1H),1.38-1.33(m,1H),1.26-1.15(m,4H).
化合物I-1的制备:
化合物1d(0.190g,0.320mmol)溶于甲醇(2ml)和二氧六环(2mL),加入氢氧化锂的水溶液(0.055g,1.280mmol,2mL水),加料完毕后,加热至回流反应3h。减压浓缩干,加入乙酸乙酯(20mL)和水(20mL)溶解,1N盐酸调节pH=6,乙酸乙酯(20mL)萃取3次,合并乙酸乙酯层,饱和食盐水洗涤,硫酸钠干燥后减压浓缩,粗品硅胶柱层析(PE/EA=5:1)得到淡黄色固体0.065g,即化合物I-1。
1HNMR(400MHz,CDCl3)δ:11.68(s,1H),8.71(dd,1H,J1=2.4Hz,J2=8.8Hz),8.58(d,1H,J=2.0Hz),8.01(t,1H,J1=2.0Hz,J2=7.2Hz),6.71(t,1H,J1=7.2Hz,J2=7.2Hz),6.44(t,1H,J1=6.4Hz,J2=8.0Hz),5.31(m,1H),4.90(m,1H),3.15-3.13(m,1H),2.85(m,1H),2.42(d,1H,J=4.8Hz),2.35(m,1H),1.91-1.76(m,2H),1.50-1.42(m,1H),1.24-1.18(m,4H).
LC/MS m/z:412.1(M+H).
实施例2:制备(2S,3S)-3-(6-环丙基-5-氟-2-(5-氟-1H-吡咯并[2,3-b]吡啶-3-基)-嘧啶-4-基)氨基)二环[2.2.2]辛-5-烯-2-羧酸(I-7)
化合物7b的制备:
环丙基溴化镁(27mL,27.000mmol,1M四氢呋喃溶液)加入三口瓶,冷却至0℃,加入化合物1a(2.980g,17.850mmol)的四氢呋喃溶液(20mL),滴完10-15℃搅拌1h,冷却至0℃,依次滴加入三乙胺(2.5mL,17.850mmol)和I2(4.960g,17.850mmol)的THF溶液(60mL),加料完毕后保持此温度搅拌1h,后室温搅拌过夜。加入亚硫酸氢钠溶液洗涤,乙酸乙酯(150mL)萃取3次,合并乙酸乙酯层,饱和食盐水(200mL)洗涤,无水硫酸钠干燥后减压浓缩干,硅胶柱层析(PE/EA=100/5)纯化得浅黄色固体2.310g,即化合物7b。
化合物7c的制备:
化合物7b(0.082g,0.396mmol)、Int-1(0.115g,0.396mmol)和DIPEA(0.194g,1.505mmol)依次加入至四氢呋喃(15mL)和无水乙醇(1mL)中,加热至回流搅拌6h,TLC检测反应结束。按上述的投料量和操作再投一批,第二批反应结束后将两批反应液合并,加水淬灭,乙酸乙酯(30mL)萃取2次,合并乙酸乙酯层,饱和食盐水(30mL)洗涤,无水硫酸钠干燥后减压浓缩干,硅胶柱层析(PE/EA=100/5)纯化得淡黄色固体0.154g,即化合物7c。
化合物7d的制备:
化合物7c(0.154g,0.421mmol)、int-2(0.386g,0.926mmol)和碳酸钠(0.134g,1.260mmol)加入至100mL单口瓶中,氮气置换三次后加入Pd2(dba)3(0.019g,0.021mmol)和X-phos(0.050g,0.105mmol),氮气置换三次;加入2-甲基四氢呋喃(5mL)和水(1mL),再次用氮气置换三次后加热至回流反应7h。冷却至室温,粗品直接拌硅胶柱层析(PE:EA=10:1)纯化得固体0.250g,即化合物7d。
1HNMR(400MHz,CDCl3)δ:8.54(s,1H),8.46(dd,1H,J1=2.8Hz,J2=9.2Hz),8.31(d,1H,J=2.0Hz),8.14(d,2H,J=8.4Hz),7.32(s,1H),6.59(t,1H,J1=8.0Hz,J2=7.2Hz),6.33(t,1H,J1=6.8Hz,J2=7.6Hz),4.87-4.78(m,2H),4.37-4.14(m,2H),2.98-2.95(m,1H),2.92-2.90(m,1H),2.39(s,3H),2.26-2.22(m,2H),1.92-1.86(m,1H),1.72-1.66(m,1H),1.46-1.39(m,1H),1.30-1.26(m,1H),1.24-1.18(m,5H),1.08-1.05(m,2H).
化合物I-7的制备:
化合物7d(0.240g,0.387mmol)溶于甲醇(2mL)和二氧六环(2mL),加入氢氧化锂的水溶液(0.068g,1.548mmol,2mL水),加料完毕后,加热至回流反应3h。减压浓缩干,加入乙酸乙酯(20mL)和水(20mL)溶解,1N盐酸调节pH=6,乙酸乙酯(20mL)萃取3次,合并乙酸乙酯层,饱和食盐水洗涤,硫酸钠干燥后减压浓缩干,粗品薄层层析(DCM:MeOH=15:1)纯化得淡黄色固体0.067g,即化合物I-7。
1HNMR(400MHz,CDCl3)δ:11.68(s,1H),8.58(d,1H,J=2.4Hz),8.46(dd,1H,J1=2.8Hz,J2=9.2Hz),7.99(t,1H,J=2.4Hz),6.69(t,1H,J1=4.0Hz,J2=7.2Hz),6.44(t,1H,J1=6.4Hz,J2=7.2Hz),5.29(d,1H,J=9.6Hz),4.87(d,1H,J=9.2Hz),3.15-3.12(m,1H),2.87-2.85(m,1H),2.35-2.34(m,1H),2.28-2.25(m,1H),1.88-1.76(m,2H),1.50-1.43(m,1H),1.32-1.22(m,4H),1.08-1.06(m,2H).
LC/MS m/z:438.0(M+H).
实施例3:体外生物活性研究和细胞毒性研究
待测化合物:本发明化合物I-1、本发明化合物I-7以及对照化合物VX-787(Pimodivir)。体外生物活性研究的试验方法:将MDCK细胞以2,000细胞每孔的密度种入384孔细胞培养板中,随后置于37℃,5%CO2培养箱中培养过夜。第二天化合物稀释后分别加入到细胞孔内(3倍倍比稀释,8个测试浓度点),流感病毒A/PR/8/34(H1N1)株随后以每孔2*TCID90加入细胞培养孔中,培养基中DMSO终浓度为0.5%。细胞板置于37℃,5%CO2培养箱中培养5天。培养5天后使用细胞活力检测试剂盒CCK8检测细胞活性。原始数据用GraphPadPrism软件对化合物的抑制率和细胞毒性进行非线性拟合分析,得到EC50值(结果参见表1)。
细胞毒性研究的研究方法:化合物的细胞毒性测定和抗病毒活性测定平行进行,除了不加病毒,其它的实验条件和抗病毒活性实验一致。培养5天后使用细胞活力检测试剂盒CCK8检测细胞活性。原始数据用于化合物细胞毒性(CC50)计算(结果参见表1)。
表1.化合物对于流感病毒A/PR/8/34(H1N1)的抑制活性以及毒性
结论:化合物I-1和I-7具有优秀的抑制H1N1的活性,EC50低于1nM,并且具有很低的细胞毒性。
本发明的其他化合物与化合物I-1和I-7具有基本相同的结构,可以预期他们具有与化合物I-1和I-7相当的优异活性。
此外,本发明的化合物,其与现有的PB2抑制剂相比,还具有结构简单、溶解性好、生物利用度高、代谢稳定等优势。
以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以对本发明进行若干改进和修饰,这些改进和修饰也落入本发明权利要求的保护范围内。
Claims (5)
3.含有如权利要求1或2所述的杂环化合物或其可药用盐的药物组合物,其特征在于,所述药物组合物为抗病毒药物组合物,其中还选择性地包含一种或多种治疗剂,所述治疗剂选自以下组成的群:神经氨酸酶抑制剂、核苷类药物、PB2抑制剂、PB1抑制剂或M2抑制剂。
4.权利要求1或2所述的杂环化合物或其可药用盐或权利要求3中的药物组合物在制备预防和/或治疗病毒感染性疾病的药物中的应用。
5.根据权利要求4所述的应用,所述病毒感染性疾病是流感A型或流感B型引起的感染性疾病。
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