CN113277994A - 噻唑类化合物及其制备方法和用途 - Google Patents
噻唑类化合物及其制备方法和用途 Download PDFInfo
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- CN113277994A CN113277994A CN202110550766.7A CN202110550766A CN113277994A CN 113277994 A CN113277994 A CN 113277994A CN 202110550766 A CN202110550766 A CN 202110550766A CN 113277994 A CN113277994 A CN 113277994A
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Abstract
本发明涉及噻唑类化合物及其制备方法和用途,属于药物化学领域。其具有如下结构通式,
Description
技术领域
本发明涉及一种新型酰胺类化合物及其前药、药学上可接受的盐和它们的药物组合物、以及它们的制备方法和用途,尤其涉及噻唑类化合物及其制备方法和用途,属于药物化学领域。
背景技术
病毒性感染一直是人类健康的一大挑战。慢性乙型肝炎病毒(HBV)感染是在全球范围内导致严重肝脏疾病的常见原因。中国每年新发乙肝病毒感染人数高达100万以上,总感染人数达9000万。根据世界卫生组织(WHO)估计,全球有大约2.57亿HBV感染患者。每年约超过65万人死于HBV感染相关终末期肝病,包括肝功能衰竭、肝硬化和肝细胞癌(HCC)。目前,疫苗、核苷(NA)或核苷酸(NUC)类药物能够有效地降低新感染率,而且对于坚持长期病毒抑制疗法的HBV患者来说,能够延缓肝病的进展。乙肝表面抗原(HBsAg)阴转与肝脏功能改善、组织病理改善以及长期预后改善相关,是目前国内外最新慢性乙肝防治指南推荐的理想治疗目标,即乙型肝炎的功能性治愈或称为临床治愈的目标。然而直接抗病毒药物(DAA)[如核苷(酸)类似物(NA)]或免疫调节剂[如聚乙二醇化干扰素α(PEG-IFN)]单独使用实现临床治愈的作用有限。理论上,NA和PEG-IFN针对HBV发挥不同的抗病毒作用,合理联用能够产生协同和互补的效应,但仍然治愈率很低。目前一些具有新的作用机理的药物开始进入临床试验,如免疫检查点抑制剂(抗PD-1或抗CTLA-4疗法),衣壳组装抑制剂(AT-130,NVR-3778,JNJ6379等),RNAi疗法(JNJ3989或ARO-HBV)和细胞凋亡蛋白抑制剂(IAP,Inhibitors of Apoptosis Proteins)抑制剂(如APG-1387)等(Fanning et al.,NatureReviews Drug Discovery volume 18,pages827–844(2019))。但这些都不能实现乙肝功能性治愈的目标。因此需要发现更有效的乙肝治疗药物,提高其功能性治愈率。
COVID-19自2019年底在全球爆发到2021年3月17日止,全球感染人数已达到1.17亿,死亡人数超过260万,还没有明显结束象征。虽然有几款疫苗已经授予紧急使用权,但还没有有效药物正式批准上市。急需发现疗效确切的治疗药物,解决目前COVID-19引起的健康危机。
肺结核病虽然得到控制,但是,每年仍然引起超过150病人死亡。仍然需要疗效更好的治疗药物。
脂肪肝的发病率不断升高,伴随着由其引起肝纤维化发病率上升,但是没有有效的药物治疗。因此,急需发现有效治疗药物。
1976年勒马克实验室(Remark Laboratories)发现硝唑尼特(Nitazoxanide,化合物1),最初用于绦虫感染的治疗。在墨西哥首次作为抗寄生虫药物上市,英文商品名:Daxon和Colufase;后陆续在澳大利亚、新西兰等国上市,商品名CryptazTM;美国于2002年11月批准硝唑尼特作为由隐孢子虫、蓝氏贾第鞭毛虫引起的儿童腹泻的治疗药物上市,商品名Aliana。
近年来的研究发现,硝唑尼特具有广谱抗病毒作用(J.Genetic Engineering andBiotechology 2020,18,1),能有效抑制包括乙肝病毒(HBV),丙肝病毒(HCV),艾滋病病毒(HIV)和新冠状病毒(COVID-19),流感病毒(Influenza A/B)等病毒的复制。化合物1对乙肝病毒的多种蛋白,包括HBsAg,HBeAg,HBcAg,HBV R.I.,HBV RNA,cccDNA和HBV的变异株都有显著的抑制作用(Antiviral Res.2008,77,56)。硝唑尼特能有效杀死多药耐药革兰氏阴性菌(CID 2013,56,1685),显著抑制新冠病毒(J.Infect.Dev.Ctries.2020,14,982),治疗呼吸道感染也有效(DOI:10.1093/cid/ciz100),能有效抑制流感病毒(Antimicrob.AgentsChemother.2015,59,1061),具有广谱抗病毒包括抗HIV活性(J.GeneticEngineer.Biotech.2020,18,35),对肺结核有效(J.Med.Chem.2009,52,5789),对治疗脂肪肝炎引起的纤维化有效(US Pat.2018/0092885A1),对多种癌症也有效(MutationResearch/Fundamental and Molecular Mechanisms of Mutagenesis,Volume 768,October 2014,Pages 16-21)。中国专利CN201610329100.8还披露了化合物1用于阿兹海默症和帕金森病的用途。
硝唑尼特及其代谢活性药物替唑尼特(Tizoxanide,化合物2)水溶性很差,口服只有31.5%吸收,66.2%从大便排出(Int.J.Clin.Pharmacol.Ther.2000,38,387)。这对于治疗胃肠道疾病是可行的。但是,用于系统性治疗病毒感染,药物必须被有效吸收才能发挥药物作用。制备带有碱性基团的前药可以成盐,提高其水溶性,可能改善其生物利用度。Stachulski等报道,氨基酸酯盐酸盐(RM5061)的生物利用度从化合物1的2.8%提高到20%,(Eur.J.Med.Chem.2017,126,154)。
据报道,化合物1的活性成分极易被糖甙化生成没有生物活性的化合物5(TZG,Tizoxanide Glucuronide),血浆中的药物浓度有时难以达到有效治疗浓度。化合物2的任何形式的前药都不能改变其羟基被糖甙而失去生物活性的特性。
据文献报道,2-甲基取代化合物(2-Me-2)抑制丙肝病毒的活性明显低于化合物1,EC90降低了8倍(J.Med.Chem.2011,54,8670)。2-甲基取代化合物(2-Me-2)抗乙肝病毒的活性也明显降低,EC50降低了4倍(J.Med.Chem.2011,54,4119)。
发明内容
本发明的目标之一是提供一种生物活性更强的新型噻唑类化合物,能显著减少活性成分的糖甙化,显著提高药物暴露量。
发明人研究发现,RM5061并不能有效提高药物的暴露量。发明人设想将化合物1或2的邻位的H由不同的取代基取代,以阻止其羟基的糖甙化,有效地提高药物的暴露量。发明人惊奇地发现邻位被异丙基(I-1a-8)和乙基(I-1a-12)取代后抗乙肝表面抗原的活性反而提高了,I-1a-8和I-1a-12的EC50分别是化合物2的9.5和2.7倍。化合物I-1a-12在大鼠灌胃后药物暴露量是化合物2的12.5倍。
在此基础上,本发明提供一种式X所示的化合物或其前药,或它们药学上可接受的盐:
其中A和B独立地选自环烷基或取得的环烷基、杂环基或取代杂环基、芳香环基或杂芳香环基;Y选自C=O、C=NH、SO、SO2。
本发明进一步提供一种式Xa:
其中A和B如上所述。
可选地,A和B独立地选自下表所列基团:
其中,Ra、Rb、Rc、Rd和Re各自独立地选自:氢、烷基或取代烷基,烯基或取代烯基,炔基或取代炔基,环烷基或取代环烷基,杂环基或取代杂环基,芳基或取代芳基,烷氧基或取代烷氧基,卤素,氰基,硝基,羟基,-OCOR',-OCOOR',-OCONHR',氨基,-NHCOR',-NHCOOR',-NHCONHR',改性烷基,或氨基酸酯基
任选地,Ra和Rb、Rb和Rc、Rc和Rd、Rd和Re可以形成3-7元饱和或不饱和环;
酰胺的等效物可能有类似的生物活性。因此,本发明包括酰胺等效物:
其中,Ra-Rd和B如上述定义。
本发明进一步提供化合物I:
其中:
X选自NO2、Cl、Br;
R1选自,但不限于:烷基或取代烷基,烯基或取代烯基,炔基或取代炔基,环烷基或取代环烷基,杂环基或取代杂环基,芳基或取代芳基,烷氧基或取代烷氧基,卤素,氰基,硝基,羟基,-OCOR’,-OCOOR’,-OCONHR’,氨基,-NHCOR’,-NHCOOR’,-NHCONHR’,改性烷基,氨基酸酯基
R2、R3、R4各自独立地,但不限于选自:氢、烷基或取代烷基,烯基或取代烯基,炔基或取代炔基,环烷基或取代环烷基,杂环基或取代杂环基,芳基或取代芳基,烷氧基或取代烷氧基,卤素,氰基,硝基,羟基,-OCOR',-OCOOR',-OCONHR',氨基,-NHCOR',-NHCOOR',-NHCONHR',改性烷基,氨基酸酯基
任选地,R1、R2为烷基时,所述烷基上任意一个或多个氢被氘替代;
任选地,R1和R2,或者R2和R3,或者R3和R4形成3-7元饱和或不饱和环;
R选自氢、-COR',-COOR',-CONHR',氨基,-NHCOR',-NHCOOR',
各个R'相互独立地选自,但不限于:氢、烷基或取代烷基,烯基或取代烯基,炔基或取代炔基,环烷基或取代环烷基,杂环基或取代杂环基,芳基或取代芳基;
所述取代烷基、取代烯基、取代炔基、取代环烷基、取代芳基、和取代杂环基中的取代基各自独立地选自,但不限于:1-3个卤素,氰基,氨基,硝基,羟基,烷基,烷氧基,改性烷基,氨基酸酯基;
所述氨基酸酯基包括消旋的和光学纯的氨基酸基及其药学上可接受的盐,
所述“卤素”选自:F、Cl、Br或I;
所述“烷基”、“烷氧基”中的“烷基”为C1-12直链或支链烷基,可选为C1-8直链或支链烷基,可选为C1-5直链或支链烷基;可选为:甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、或正戊基;
所述“环烷基”为C3-8单环或双环环烷基;
所述“烯基”为C2-C6的烯基;
所述“炔基”为C2-C6的炔基;
所述“杂环基”为环上含有1个、2个或3个选自N、O、S的杂原子的3-10元非芳香杂环;
所述“芳基”为6-10元芳基;可选为苯基或萘基;
所述“改性烷基”为烷基的任意碳原子以及,如果存在,其上的氢原子一起,被选自-O-、-CO-、-NH2、-OH、卤素、-CN、-NO2中的一种或几种基团置换所得的基团;
所述式I化合物不为以下化合物3和4:
可选地,
R1选自,但不限于:烷基,卤素,氰基,硝基,或卤代烷氧基;
R2选自,但不限于:氢,烷基,或烷氧基;
R3选自,但不限于:氢,羟基,烷氧基,卤素,氨基,或-NHCOR';
R4选自,但不限于:氢,羟基,烷氧基,-NHCOR',或氨基;
可选地,
各个R'和R”各自独立地选自,但不限于:氢、甲基、乙基、正丙基、异丙基、正丁基、异丁基、苄基、仲丁基、正戊基、环丙基,环丁基,环戊基、环己基、苄基、苯基和取代苯基。
可选地,式I化合物或其前药,或它们药学上可接受的盐,所述的式I化合物选自下列化合物I-1:
其中:R1、R2、R3、R4和R的定义如上所述。
可选地,所述的式I化合物或其前药,或它们药学上可接受的盐,所述的式I化合物选自化合物I-1a或I-1b:
化合物I-1a和I-1b中:R1、R2、R3和R4的定义如上所述。
化合物I-1a和I-1b中优选:
R1选自,但不限于:烷基,卤素,氰基,硝基,卤代烷基或卤代烷氧基;
R2选自,但不限于:氢,烷基,或烷氧基;
R3选自,但不限于:氢,羟基,烷氧基,卤素,氨基,或-NHCOR';
R4选自,但不限于:氢,羟基,烷氧基,-NHCOR',或氨基;
可选地,
R1选自:甲基,乙基,异丙基,F,Br,氰基,硝基,或三氟甲基;
R2选自:氢,甲基,或甲氧基;
R3选自:氢,羟基,甲氧基,Br,氨基,或-NHAc;
R4选自:氢,羟基,甲氧基,-NHAc,或氨基。
其中,化合物I-1a、I-1b分别选自下述化合物I-1a-2~I-1a-39、以及I-1b-2~I-1b-39:
更优选如下化合物:R1选自:甲基,乙基,异丙基;
R2选自:氢,甲基;
R3选自:氢;
R4选自:氢。
可选地,所述药学上可接受的盐包括式I化合物的阴离子盐或阳离子盐;
可选地,所述药学上可接受的盐包括式I化合物的金属盐和铵盐;所述金属包括Na、K、Mg、Ca、Li、或Zn;
可选地,所述药学上可接受的盐包括式I化合物与无机酸或者有机酸形成的盐;
可选地,所述无机酸包括盐酸、氢溴酸、氢碘酸、硫酸、硝酸、磷酸、或碳酸;
可选地,所述有机酸包括甲酸、抗坏血酸、乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、柠檬酸、枸橼酸、酒石酸、葡萄糖酸、酒石氢酸、葡萄糖醒酸、碳酸、苦味酸、甲磺酸、乙磺酸、对甲苯磺酸、苯甲酸、苯磺酸、对溴苯磺酸、谷氨酸、水杨酸、或双羟萘酸;
可选地,所述药学上可接受的盐为式I化合物的盐酸盐;
可选地,所述药学上可接受的盐为在式I化合物的R基团处与酚羟基形成的金属盐,所述金属选自,但不限于,NH4、Na、K、Mg、Ca、Li、或Zn。
本发明另一方面,提供一种上述式I化合物或其前药,或它们药学上可接受的盐的制备方法,包括将化合物II-1与化合物II-2反应得到式I化合物的步骤;
其中,R、R1、R2、R3、R4和X的定义如权利要求1中所述。
本发明另一方面,提供一种药物组合物,包含式I化合物或其前药,或它们药学上可接受的盐中的一种或多种,以及药学上可接受的载体;
可选地,所述药物组合物的剂型包括口服的固体制剂、或液体制剂;
可选地,所述固体制剂包括片剂、粉剂、颗粒剂、或胶囊剂;
可选地,所述液体制剂包括水或生理盐水或油的悬浮剂、或糖浆。
可选地,所述药物组合物还包括除式I化合物或其前药,或它们药学上可接受的盐以外的活性化合物。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或上述的药物组合物在制备预防或治疗病毒感染的药物中的用途。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或其药物组合物在制备预防或治疗乙型肝炎的药物中的用途。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或者上述的药物组合物在制备预防或治疗冠状病毒感染的药物中的用途;
可选地,所述冠状病毒包括COVID-19、HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV和MERS-CoV。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或者上述的药物组合物在制备预防或治疗病毒性感冒的药物中的用途。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或者上述的药物组合物在制备预防或治疗肺结核病或多重耐药的肺结核病的药物中的用途。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或者上述的药物组合物在制备抑制细菌和耐药细菌药物中的用途。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或者上述的药物组合物在制备杀灭隐孢子虫、肠贾第鞭毛虫、或肠寄生虫的药物中的用途;
可选地,所述肠寄生虫包括贝氏孢子虫、阿米巴原虫、人蛔虫、钩虫、毛首鞭虫、牛肉绦虫、短膜壳绦虫或肝片吸虫。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或者上述的药物组合物在制备预防或治疗肝纤维化的药物中的用途。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或者所述的药物组合物在制备治疗阿兹海默症和帕金森病药物中的用途。
本发明另一方面,提供一种上述的式I化合物或其前药,或它们药学上可接受的盐,或者上述的药物组合物与其它制剂联用,作为预防或治疗疾病药物中的用途。
本发明任何化合物的氘代物都落在本发明范围内。
本发明有益技术效果:
一方面,化合物I或其前药或它们药学上可接受的盐能够显著提高生物活性。
另一方面,化合物I或其前药或它们药学上可接受的盐能有效地减少被糖甙化而失去生物活性,或显著提高有效药物的暴露量,扩大了临床应用。
具体实施方式
以下对本发明的具体实施方式进行详细的说明。应当理解的是,此处所描述的具体实施方式仅用于示例性地对本发明进行说明,并不用于限制本发明。以下百分含量没有特别说明,均为质量百分含量。
实施例1化合物的制备
1、制备I-1a-2
在干燥的圆底烧瓶中加入化合物1a(3.0g,17.8mmol),然后加入冰乙酸(40mL),0℃下依次缓慢滴加乙酸酐(6.8mL,71.4mmol,4.0eq)和浓硫酸(1.46mL,26.8mmol,1.5eq),移至室温反应过夜。加水,用乙酸乙酯萃取,水相用EA萃取一次,合并有机相,有机相用无水硫酸钠干燥,浓缩,真空抽干得到白色固体,直接用于下一步,产率80%。化合物1b 1H NMR(400MHz,CDCl3)δ7.67(d,J=7.9Hz,1H),7.30(t,J=8.0Hz,1H),7.22(d,J=8.2Hz,1H),3.89(s,3H),2.39(s,3H);m/z(ES+)(M+Na)+=233.1。
在干燥的圆底烧瓶中加入化合物1b(3.01g,14.3mmol),然后加入乙醚(30mL),加入吡啶(1.16mL,14.3mmol,1.0eq)和二氯亚砜(1.25mL,17.2mmol,1.2eq),室温反应一小时。过滤,除去溶剂,剩余物直接用于下步反应。将所得酰氯溶于DMF(40mL),加入2-氨基-5-硝基噻唑(2.08g,14.3mmol,1.0eq)和三乙胺(12mL,85.9mmol,6.0eq),60℃下反应三个小时,低温下用1M HCl淬灭,乙酸乙酯萃取,有机溶液用1M HCl洗掉未完全反应的2-氨基-5-硝基噻唑,然后先后用饱和碳酸氢钠,水和饱和食盐水洗各一次,无水硫酸钠干燥,浓缩,用石油醚:乙酸乙酯=4:1重结晶得到黄色固体I-1a-2(123mg)。化合物I-1a-2 1HNMR(400MHz,DMSO)δ:13.60(br s,1H),8.71(s,1H),7.43-7.37(m,3H),3.84(s,3H),2.25(s,3H);m/z(ES+)(M+Na)+=360.1.
2、采用制备化合物I-1a-2的方法制备得到下列化合物:
化合物1:1H NMR(400MHz,DMSO)δ13.60(br s,1H),8.70(s,1H),7.67(d,J=7.7Hz,1H),7.59(d,J=7.6Hz,1H),7.36(t,J=7.7Hz,1H),2.28(s,3H),2.21(s,3H);m/z(ES+)(M+Na)+=344.0。
化合物I-1a-3:1H NMR(400MHz,DMSO)δ13.90(br s,1H),8.74(s,1H),8.37(dd,J=6.7,8.3Hz,1H),8.21(dd,J=6.3,7.8Hz,1H),7.73(t,J=8.0Hz,1H),2.32(s,3H);m/z(ES+)(M-H)-=351.0。
化合物I-1a-4:1H NMR(400MHz,DMSO)δ13.80(br s,1H),8.71(s,1H),8.00(d,J=8.0Hz,1H),7.88(d,J=7.7Hz,1H),7.42(t,J=8.0Hz,1H),2.32(s,3H);m/z(ES+)(M-H)-=385.9。
化合物I-1a-5:1H NMR(400MHz,DMSO)δ13.78(br s,1H),8.73(s,1H),7.72-7.67(m,2H),7.54-7.48(m,1H),2.33(s,3H);19F NMR(400MHz,CDCl3)δ-128.53;m/z(ES+)(M-H)-=324.0。
化合物I-1a-6:1H NMR(400MHz,DMSO)δ13.83(br s,1H),8.73(s,1H),7.91(dd,J=6.4,7.8Hz,1H),7.85-7.82(m,1H),7.60(t,J=8.0Hz,1H),2.32(s,3H);19FNMR(400MHz,CDCl3)δ-57.07;m/z(ES+)(M-H)-=390.0。
化合物I-1a-7:1H NMR(400MHz,DMSO)δ13.90(br s,1H),8.74(s,1H),8.24-8.21(m,2H),7.69(t,J=7.8Hz,1H),2.38(s,3H);m/z(ES+)(M-H)-=331.0。
化合物I-1a-8:1H NMR(400MHz,DMSO)δ13.60(br s,1H),8.71(s,1H),7.69-7.66(m,2H),7.43(t,J=7.8Hz,1H),2.28(s,3H),1.19(s,3H),1.17(s,3H);m/z(ES+)(M-H)+=348.1。
化合物I-1a-9:1H NMR(400MHz,DMSO)δ13.53(br s,1H),8.70(s,1H),7.61(d,J=7.9Hz,1H),7.26(d,J=8.0Hz,1H),2.35(s,3H),2.29(s,3H),2.09(s,3H);m/z(ES+)(M+Na)+=358.0。
化合物I-1a-10:1H NMR(400MHz,DMSO)δ13.68(br s,1H),8.71(s,1H),7.90(d,J=2.2Hz,1H),7.84(d,J=1.8Hz,1H),2.28(s,3H),2.20(s,3H);m/z(ES+)(M-H)-=399.9。
化合物I-1a-11:1H NMR(400MHz,DMSO)δ13.48(br s,1H),8.70(s,1H),7.69(d,J=8.8Hz,1H),7.14(d,J=8.9Hz,1H),3.93(s,3H),3.73(s,3H),2.30(s,3H);m/z(ES+)(M+Na)+=390.1。
化合物I-1a-12:1H NMR(400MHz,DMSO)δ13.62(br s,1H),8.71(s,1H),7.68(d,J=7.6Hz,1H),7.61(d,J=7.6Hz,1H),7.40(t,J=7.7Hz,1H),2.58(dd,J=7.6,15.2Hz,2H),2.28(s,3H),1.15(t,J=7.5Hz,3H);m/z(ES+)(M-H)-=334.1。
实施例2抗病毒活性测试
1、试验目的:本实验的目的是评价化合物的体外抗HBV活性。应用HepG2.2.15细胞评价受试化合物的体外抗乙肝病毒活性。通过实时荧光定量PCR(qPCR)方法检测HepG2.2.15细胞上清中的HBV DNA的含量,ELISA检测HBsAg的含量测定化合物的抗HBV活性,同时CellTiter-Glo检测受试化合物对HepG2.2.15细胞活力影响。实验中采用LAM作为参考化合物,监控实验质量。活性化合物再应用人原代肝细胞(PHH)验证受试化合物体外抗HBV的药效。
2、材料
本发明受试化合物和对照化合物:
受试化合物由河南美泰宝生物制药有限公司提供,用100%DMSO配制成20mM的母液。
对照化合物:拉米夫定(LAM),由药明康德提供,用100%DMSO配制成20mM的母液。
3、细胞株
HepG2.2.15细胞由药明康德提供。
4、试剂和耗材:
本实验使用的主要试剂包括DNA提取试剂盒(Qiagen,货号51162),HBsAg ELISA试剂盒(货号:Antu-CL 0310),FastStart Universal Probe Master(Roche,货号04914058001),CellTiter-Glo检测试剂(Promega,货号G7573),96孔板(Costar 3599)和96well V型板(Axygen WIPP02280)。
5、仪器:
本实验使用的主要仪器包括荧光qPCR仪(Applied Biosystems,型号QuantStudio(TM)6Flex System),酶标仪(BioTek,型号Synergy 2)。
6、试验方法
6.1细胞铺板和化合物处理
第0天,将HepG2.2.15细胞以每孔60,000个细胞的密度接种到96孔板中,在37℃、体积百分含量5%CO2培养过夜。第1天加入含不同浓度本发明化合物的新鲜培养液,第4天起每天更换含不同浓度化合物的新鲜培养液,DMSO终浓度为0.5%。抗HBV活性测试化合物最终测试浓度(μM)为:100、33.3、11.1、3.70、1.23、0.41、0.14。
6.2、样品收集与检测
抗病毒活性测试:第7天,收集细胞上清,应用DNA提取试剂盒(Qiagen-51162)提取上清中的DNA,qPCR定量样品中的HBV DNA。qPCR反应体系见表3。HBV质粒DNA作为标准品,10倍系列稀释,标准品范围从1.0×107copies/μl至10copies/μl。PCR反应程序为:95℃10分钟,然后进入循环模式,95℃15秒,随后60℃,1分钟,共40个循环。依据标准曲线和各样品的Ct值计算样品中的HBV DNA含量。
参照安图生物HBsAg ELISA kit说明书,应用酶标仪检测HBsAg的含量。
6.3数据处理及统计分析
HBV DNA抑制率%=(DMSO对照组中的HBV DNA含量-样品中的HBV DNA含量)/DMSO对照组中的HBV DNA含量×100%
HBsAg抑制率(%)=(1-样品的HBsAg值/DMSO对照组HBsAg值)×100%
使用GraphPad Prism软件log(agonist)vs.response-Variable slope(fourparameters)分析方法处理数据得到EC50。
6.4结果和结论
受试化合物和对照化合物LAM对细胞培养上清中HBsAg、HBV DNA的抑制结果见下表1:
表1、化合物抗HBV活性(EC50)
对照化合物LAM在HepG2.2.15细胞中抑制HBV DNA的EC50值为0.11uM,符合预期结果。受试化合物中,化合物I-1a-8、I-1a-9和I-1a-12三个化合物具有与化合物1相当的抑制HBV DNA的活性,但是,它们抑制HBsAg的活性是化合物1的2.5到9.5倍。因为现有临床核苷类乙肝药物,如恩替卡韦和富马酸丙酚替诺福韦(TAF)都能够非常有效地抑制HBV DNA,但是,还没有有效抑制HBsAg的药物上市。所以,I-1a-8、I-1a-9和I-1a-12及其类似物的发现有十分重要意义。
实施例3、动物药代动力学试验
化合物以乙酸酯前药形式给药,在体内被酯酶水解释放出活性化合物,如化合物1转化为化合物2,以及化合物I-1a-12转化为化合物I-1b-12。
单次灌胃给予雄性SD大鼠受试化合物后,测定它们的代谢物在雄性SD大鼠体内的药代动力学性质。3只雄性SD大鼠单次灌胃给药。所有动物于给药后0.083h(5分钟)、0.167h(10分钟)、0.25h(15分钟)、0.5h(30分钟)、1h、2h、4h、8h和12h采集血浆样品。应用LC-MS/MS方法测定血浆样本中代谢产物(活性成分)的浓度。
1、给药
给药当天称量SD大鼠实际体重并计算给药体积。本试验中给药时雄性SD大鼠体重范围为230.65-259.01克。所有SD大鼠单次灌胃给药。
2、样品收集与制备
从试验动物颈静脉采集血液样本约0.2mL/动物/时间点,记录实际采血时间,给药后1小时以内的点在±1分钟范围内,其它时间在理论时间5%以内为可接受偏离范围。
血样采集以后,立即转移至贴有标签的含K2-EDTA(0.85-1.15mg)的商品化样品管中(江苏康健医疗用品有限公司),随后离心处理(3200g,4℃,10分钟)后取血浆。将血浆转移至预冷的离心管中,加入5倍体积含6种内标的ACN沉淀,如100μL血浆样品+500μL的含6种内标的ACN。沉淀后离心(4℃,12000rpm,10分钟)取上清(离心得血浆后20分钟内完成),在干冰中速冻,随后储存在-60℃或更低的超低温冰箱中,直到进行LC-MS/MS分析。
3、分析方法
化合物2和I-1b-12的血浆浓度使用LC-MS/MS方法进行测定。
4、药代动力学数据分析
使用WinNonlin Version 6.3(Pharsight,Mountain View,CA)药动学软件,以非房室模型对化合物2和I-1b-12的血浆药物浓度数据进行处理。使用线性对数梯形法计算相关药代动力学参数。
表2、化合物1的药代动力学参数
表2结果表明,雄性SD大鼠单次灌胃给予30mg/kg的化合物1后,化合物2的达峰浓度(Cmax)为19498±3831nmol/L,达峰时间(Tmax)出现在给药0.111±0.0485h。AUC0-last为8778±4722nmol·h/L。
表3、化合物I-1a-12的药代动力学参数
表3结果表明,雄性SD大鼠单次灌胃给予32.74mg/kg的I-1a-12后,I-1b-12的达峰浓度(Cmax)为46329±5890nmol/L,达峰时间(Tmax)出现在给药后0.500h。AUC0-last为109758±6007nmol·h/L。
表2和表3的药代动力学参数比较可见,化合物2的半衰期(1.3h)和I-1b-12的(1.22h)相当;化合物I-1b-12的Cmax(46329)是化合物2的(19498)2.4倍;化合物I-1b-12的AUC0-last(109758)是化合物2的(8778)的12.5倍。
根据抑制乙肝表面抗原(HBsAg)的活性和药代动力学的研究结果,上述实施例化合物不但抗病毒活性显著提高(提高2.5-10倍),而且有效药物的暴露量也有了巨大的提升(提升>10倍)。
Claims (10)
3.根据权利要求2所述的噻唑类化合物或其前药,或它们药学上可接受的盐,其特征在于,
R1选自:甲基,乙基,异丙基,F,Br,氰基,硝基,或三氟甲基;
R2选自:氢,甲基,或甲氧基;
R3选自:氢,羟基,甲氧基,Br,氨基,或-NHAc;
R4选自:氢,羟基,甲氧基,-NHAc,或氨基。
5.根据权利要求3所述的噻唑类化合物或其前药,或它们药学上可接受的盐,其特征在于,R1选自:甲基,乙基,异丙基;
R2选自:氢,甲基;
R3选自:氢;
R4选自:氢。
6.根据权利要求5所述的噻唑类化合物或其前药,或它们药学上可接受的盐,其特征在于,选自如下化合物:
。
7.根据权利要求1-6任一项所述的噻唑类化合物或其前药,或它们药学上可接受的盐的药物用途,其特征在于,
将其作为活性成分用于制备预防或治疗病毒感染药物。
8.如权利要求7噻唑类化合物或其前药,或它们药学上可接受的盐的药物用途,其特征在于,将其作为活性成分用于制备预防或治疗乙型肝炎药物;
将其作为活性成分用于制备预防或治疗冠状病毒感染药物;将其作为活性成分用于制备预防或治疗病毒性感冒药物;将其作为活性成分用于预防或治疗肺结核病或多重耐药肺结核病药物;将其作为活性成分用于制备抑制细菌和耐药细菌药物;将其作为活性成分用于制备杀灭隐孢子虫、肠贾第鞭毛虫、或肠寄生虫药物;将其作为活性成分制备预防或治疗肝纤维化药物;将其作为活性成分制备治疗阿兹海默症或帕金森病药物。
9.如权利要求8噻唑类化合物或其前药,或它们药学上可接受的盐的药物用途,其特征在于,
所述冠状病毒包括COVID-19、HCoV-229E、HCoV-OC43、HCoV-NL63、HCoV-HKU1、SARS-CoV或MERS-CoV;
所述肠寄生虫包括贝氏孢子虫、阿米巴原虫、人蛔虫、钩虫、毛首鞭虫、牛肉绦虫、短膜壳绦虫或肝片吸虫。
10.如权利要求7-9其中之一所述的噻唑类化合物或其前药,或它们药学上可接受的盐的药物用途,其特征在于,与药学上可接受的载体制成片剂、粉剂、颗粒剂、胶囊剂、悬浮剂或糖浆制剂或液体制剂。
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