CN106146408A - 2,5,6位取代嘧啶酮衍生物的制备方法及其作为抗乙肝病毒药物的应用 - Google Patents
2,5,6位取代嘧啶酮衍生物的制备方法及其作为抗乙肝病毒药物的应用 Download PDFInfo
- Publication number
- CN106146408A CN106146408A CN201510183688.6A CN201510183688A CN106146408A CN 106146408 A CN106146408 A CN 106146408A CN 201510183688 A CN201510183688 A CN 201510183688A CN 106146408 A CN106146408 A CN 106146408A
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- CN
- China
- Prior art keywords
- dimethoxybenzyl
- pyrimidin
- benzo
- triazol
- methyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- -1 pyrimidines ketone Chemical class 0.000 title claims abstract description 228
- 239000003814 drug Substances 0.000 title abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 241000700605 Viruses Species 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 8
- 125000005605 benzo group Chemical group 0.000 claims description 69
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- DNCYBUMDUBHIJZ-UHFFFAOYSA-N 1h-pyrimidin-6-one Chemical compound O=C1C=CN=CN1 DNCYBUMDUBHIJZ-UHFFFAOYSA-N 0.000 claims description 4
- VOLRSQPSJGXRNJ-UHFFFAOYSA-N 4-nitrobenzyl bromide Chemical compound [O-][N+](=O)C1=CC=C(CBr)C=C1 VOLRSQPSJGXRNJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052740 iodine Inorganic materials 0.000 claims description 4
- ZLDPFYGASPHXNT-UHFFFAOYSA-N 4-[(3,4-dimethoxyphenyl)methyl]-5-iodo-2-[(4-iodophenyl)methylsulfanyl]-1H-pyrimidin-6-one Chemical compound COc1ccc(Cc2nc(SCc3ccc(I)cc3)[nH]c(=O)c2I)cc1OC ZLDPFYGASPHXNT-UHFFFAOYSA-N 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- OQCMAEVCNADXCL-UHFFFAOYSA-N 2-[2-(4-bromophenoxy)ethylsulfanyl]-4-[(3,4-dimethoxyphenyl)methyl]-5-iodo-1H-pyrimidin-6-one Chemical compound COc1ccc(Cc2nc(SCCOc3ccc(Br)cc3)[nH]c(=O)c2I)cc1OC OQCMAEVCNADXCL-UHFFFAOYSA-N 0.000 claims description 2
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- BSYPBZARJJBENH-UHFFFAOYSA-N 4-[(3,4-dimethoxyphenyl)methyl]-5-iodo-2-[(2-nitrophenyl)methylsulfanyl]-1H-pyrimidin-6-one Chemical compound COc1ccc(Cc2nc(SCc3ccccc3[N+]([O-])=O)[nH]c(=O)c2I)cc1OC BSYPBZARJJBENH-UHFFFAOYSA-N 0.000 claims description 2
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Abstract
本发明公开了一类新的2,5,6位取代嘧啶酮衍生物,即式(I)化合物,其具有良好的抗HBV病毒活性,各个基团的定义详见说明书。此外,本发明还公开了该衍生物的制备方法以及含有该衍生物的药物组合物以及所述2,5,6位取代嘧啶酮衍生物和包含所述2,5,6位取代嘧啶酮衍生物的药物组合物作为抗HBV药物的应用。
Description
技术领域
本领域涉及药物化学领域,更具体地说,涉及一种新的2,5,6位取代嘧啶酮衍生物及其制备方法及其作为抗乙肝病毒药物的应用。
背景技术
乙型肝炎病毒(hepatitis B virus,HBV)感染所导致的急、慢性疾病,已经对全世界人民的健康造成了很大的影响。它广泛流行于世界各国,据WHO统计,全球有约20亿人曾感染过HBV,其中3.6亿人为慢性乙肝,每年死于慢性乙型肝炎相关疾病的患者达100万。调查结果显示,我国有7~8亿人感染过HBV,人群乙肝病毒表面抗原(HBsAg)的携带率为10.34%,估计约有1.3亿人为HBV携带者,且年新增乙肝感染者约200万人。其中慢性乙肝患者约有2000~3000万,每年死于慢性乙肝相关疾病的人数达30万。据乙肝年报告的发病率数据仍显示有显著上升趋势。乙型肝炎不仅严重影响现代人的身体健康,而且给社会、家庭带来了沉重的经济负担,是全世界医学界共同关注的重要课题。
目前,被批准上市用于治疗乙肝的药物主要有两类:免疫调节制剂和核苷类逆转录酶抑制剂。其中,前者包括α-干扰素和长效干扰素;后者包括拉米夫定、替比夫定、恩替卡韦、阿德福韦酯、替诺夫韦、克来夫定与恩曲他滨。
IFN是机体感染病毒时,宿主细胞通过抗病毒应答产生的一组结构类似、功能相近的低分子糖蛋白,是抗病毒感染最重要的一种细胞因子。主要分为α、β和γ三型,其中IFN-α和β具有直接抗病毒作用。干扰素-α2b最早由美国的Schering-Plough公司研制成功并于1992年经FDA批准上市用于治疗病毒性肝炎,其主要作用是通过诱导宿主细胞产生特异性抗病毒因子,提高T细胞活性,同时抑制负性调节因子的分泌,诱导B细胞成熟,增加I类白细胞组织兼容性抗原的表达,达到辅助淋巴细胞清除病毒感染的肝细胞的作用。近年来还发现,干扰素有抗肝细胞纤维化的作用。目前,干扰素在抗HBV治疗存在的主要问题是适用人群有限,可抑制病毒复制但无法清除病毒,其毒副作用也是普遍存在的。最常见的是发热及流感样综合征,患者体重减轻、脱发、情绪激动,骨髓抑制致血细胞、血小板减少,轻度贫血,偶可发生神经系统损伤,影响内分泌系统功能,亦有产生干扰素抗体者。
核苷类逆转录酶抑制剂是目前治疗乙肝的主要药物,其能够通过和HBV病毒的天然底物 dNTP竞争HBV病毒的结合位点,从而达到抑制HBV活性而发挥抗病毒作用。虽然核苷类抗HBV药物的疗效显著,但由于用药周期长、毒副反应大、易产生耐药性等缺点限制了其在临床上的应用,因此,研发具有高效低毒,新型的HBV药物是科学家面前的一个十分迫切和重要的课题。
目前被批准用于抗HBV的7种核苷类药物都具有抗HIV活性。其中拉米夫定、替诺福韦、恩曲他滨已被FDA批准用于HIV治疗,而阿德福韦酯、恩替卡韦、替比夫定、克来夫定都有关于抗HIV活性的报导。HBV聚合酶与HIV逆转录酶具有同源性。因此人们会对一些具有良好抗HIV活性的药物进行抗HBV活性筛选。Lee等人将非核苷类抗HIV-1试剂2,5-吡啶二羧酸类衍生物用于抗HBV的研究,并发现其具有良好活性。
S-DABO类化合物是抗HIV-1转录酶抑制剂,其具有结构多样、高效低毒等特性。但是没有人关注过他的HBV活性。因而我们设计合成了具有抗HBV活性的2,5,6位取代嘧啶酮衍生物,并探究其作用机制,对于发展新型非核苷类抗HBV药物,特别是对抗临床常用药物耐药的药物,具有特别重要的意义。
发明内容
本发明人经研究而制备了一系列2,5,6位取代嘧啶酮衍生物,这些化合物具有抗HBV活性。
本发明的目的是提供新的2,5,6位取代嘧啶酮衍生物。
本发明的另一个目的是提供上述衍生物的制备方法。
本发明的第三个目的是提供上述衍生物的应用。
本发明的第四个目的是提供含有上述衍生物的药物组合物及其应用。
本发明是通过如下技术方案而实施:
一方面,本发明提供了新的2,5,6位取代嘧啶酮衍生物,即式(I)化合物,或其药学上可接受的溶剂化物:
其中,
R1为3,4-二甲氧基苯基,苯并[d]三氮唑-1-基;
R2为4-硝基溴苄,4-氰基溴苄,4-碘溴苄,4-三氟甲基溴苄,3,5-二甲氧基溴苄, 2-硝基溴苄,3-氯溴苄,2-(4-硝基苯氧基)乙基,2-(4-甲基苯氧基)乙基,2-(4-溴苯氧基)乙基,环庚基,环己-2-烯-1-基;
R3为H,卤素(如Cl、Br、I),N(CH3)2,CH(CH3)2
第二方面,本发明还提供了上述2,5,6位取代嘧啶酮衍生物的制备方法,其包括如下步骤:
上述各化合物中的取代基R1、R2与R3定义与本发明所提供的上述化合物中所定义的相同。
第三方面,本发明提供了上述2,5,6位取代嘧啶酮衍生物作为抗HBV药物的应用。本发明的式(I)化合物对HBV DNA以及HBeAg具有明显的抑制活性。
第四方面,本发明还提供了包含上述新的2,5,6位取代嘧啶酮衍生物的药物组合物及其药学上可接受的溶剂化物作为抗HBV药物的应用。在该药物组合物中含有效成分(式(I)化合物)的适合范围从1.0毫克到500毫克每单位(片、胶囊或注射液);在这些药物组合物里,通常有效成分的总质量占所有成分总质量的0.5%-95%。有效成分可以通过口服以固体剂型的形式,如胶囊,片剂,粉剂,或者以液体剂型形式,如糖浆,混悬液,也可以采用注射灭菌的液体剂型。
本发明提供以下药物剂型:
片剂
大量的片剂可以通过传统的制备方法制备,单位剂量如下:100mg本发明式(I)化合 物,0.2mg滑石粉,5mg硬脂酸镁,275mg微晶纤维素,11mg淀粉,98.8mg乳糖。采用适当的包衣提高可口性或者达到缓释作用。
胶囊剂
大量的单位胶囊制备通过填充标准两块硬胶囊,每块含有100mg粉末本发明式(I)的化合物,175mg乳糖,24mg滑石粉,6mg硬脂酸镁。
注射剂
通过肠外给药的药物注射剂通过如下制备:搅拌1.5%(质量)的本发明式(I)化合物和10%(体积)的丙二醇及水,得到的溶液加入氯化钠配成等渗液并灭菌。
本发明的药物组合物可单独给药也可与其它抗病毒药物联合用药。被治疗动物包括哺乳动物、爬行动物、甲壳动物、两栖类、鱼类、家禽类。主要范围为哺乳动物特别是人。
另外需要指出,本发明化合物的使用剂量和使用方法取决于诸多因素,包括患者的年龄、体重、性别、自然健康状况、化合物的活性强度、服用时间、代谢速度、病症的严重程度,具体剂量和使用方法由主治医师根据患者的具体病情判断。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。如无特殊说明,下述实施例中“减压旋干溶剂”一般指“水泵减压条件下用旋转蒸发仪蒸干溶剂。
实施例1
化合物3a:3,4-二甲氧基苯乙酰乙酸乙酯
将8g处理过的Zn粉分散在干燥的25mLTHF中,滴加溴乙酸乙酯引发反应,回流40min后将354mg(2.0mmol)3,5-二甲氧基苯乙腈固体加入反应瓶中,0.5mL(4.4mmol)溴乙酸乙酯溶解在3mL THF中滴入反应液中,继续加热回流1h。待反应冷却,加入10mL THF稀释,用20mL 50%K2CO3猝灭反应,常温下继续搅拌1h,抽滤掉Zn粉,所得滤液分层,水层用10mL×2次THF萃取,合并有机相,加入2N盐酸溶液30mL,继续室温搅拌2h,减压蒸去THF并用CH2Cl2萃取水层,用饱和NaHCO3溶液洗3次,Na2SO4干燥除水,减压蒸馏得化合物3a的粗品,直接用于下一步反应。
实施例2
化合物3b:(苯并[d]三唑-1-基)乙酰乙酸乙酯
将0.5mol的丙二酸二乙酯的钾盐置于800mL无水乙睛中,依次加入0.595mol的无水MgCl2,0.717mol Et3N,室温搅拌2个小时,得到反应液A。将0.25mol的2-(苯并[d]三唑-1-基)乙酸和0.275mol的N,N-羰基二咪唑置于300mL乙睛中反应15分钟,得到反应液B。将反应液B倒入反应液A中,室温搅拌12h后回流2h,TLC跟踪至反应完全。冰浴条件下滴加13%HCl 150mL,滴完搅拌10min,分层将有机层溶剂蒸干,再加入150mL乙酸乙醋。有机相分别用饱和NaHCO3与饱和NaCl溶液洗涤3次,无水MgSO4干燥,减压蒸馏得化合物3b的粗品,直接用于下一步反应。
实施例3
化合物4a:6-(3,5-二甲氧基苄基)-2-硫代-2,3-二氢嘧啶-4(1H)-酮
将6.5g Na切成小块加入到285mL乙醇溶液中,搅拌使其完全溶解,再加入14.72g硫脲,微热搅拌20min,加入19.46g(0.07mol)3,4-二甲氧基苯乙酰乙酸乙酯(3a),回流6h,溶液呈橙黄色,TLC检测反应完全,蒸干乙醇,用少量水再溶解,用2N盐酸调pH至3左右,析出大量黄白色固体,用乙醇重结晶,得白色产物。
实施例4
化合物4b:6-(苯并[d]三氮唑-1-基)甲基-2-硫代-2,3-二氢嘧啶-4(1H)-酮
化合物4b的制备方法与化合物4a相同。
通式I化合物的制备
化合物5a2-5a13,5b1-5b8均按照合成化合物5a1的操作方法制备,化合物6a2-6a13,6b1-6b8均按照合成化合物6a的操作方法制备。
实施例5
化合物5a1:6-(3,4-二甲氧基苄基)-2-(4-硝基苄硫基)嘧啶-4(3H)-酮
将77mg(0.36mmol)对硝基溴苄,100mg(0.36mmol),6-(3,4-二甲氧基苄基)-2-硫代-2,3-二氢嘧啶-4(1H)-酮以及99mg(0.72mmol)K2CO3加入到2mL的DMF中,常温搅拌10min后60V电压加热,3h后TLC检测反应完全,加入少量水,用2N盐酸溶液调pH至酸性,用20mL乙酸乙酯萃取反应液3次,合并有机相,饱和NaCl溶液洗涤3次,无水Na2SO4干燥除水,最后柱色谱分离,得到白色固体85mg。
Yield:63%.mp:203-204℃.1H NMR(400MHz,CDCl3)δ:3.779(s,2H,ArCH2),3831(s,3H,OCH3),3.884(s,3H,OCH3),4.414(s,2H,SCH2),6.024(s,1H,5-H),6.730-6.822(m,3H,ArH),7.392(m,2H,ArH),8.052(m,2H,ArH),13.315(s,1H,NH);13C NMR(100MHz,CDCl3)δ:33.514,43.455,55.960,108.620,111.359,112.693,121.589,123.634,129.954,144.572,147.191,148.205,149.140,159.371,165.728,168.296;MS(ESI):m/z,412.42[M-H]-.
实施例6
化合物5a2:6-(3,4-二甲氧基苄基)-2-(4-氰基苄硫基)嘧啶-4(3H)-酮
Yield:53%.mp:208-209℃.1H NMR(400MHz,DMSO):3.702(s,3H,OCH3),3.727(s,2H,ArCH2),3.737(s,3H,OCH3),4.737(s,2H,SCH2),6.048(s,1H,5-H),6.756-6.840(m,3H,ArH),7.446-7.466(d,2H,o-ArH,J=8Hz),7.641-7.661(d,2H,m-ArH,J=8Hz),12.538(s,1H,NH);13CNMR(100MHz,DMSO)δ:33.292,42.744,55.941,55.989,110.235,112.415,113.700,119.196,121.768,130.384,132.566,148.049,149.138;MS(ESI):m/z,392.23[M-H]-.
实施例7
化合物5a3:6-(3,4-二甲氧基苄基)-2-(2-(4-硝基苯氧基)乙硫基)-4(3H)-酮
Yield:46%.mp:206-208℃,1H NMR(400MHz,DMSO)δ:3.496-3.527(t,2H,SCH2),3.667(s,3H,OCH3),3691(s,2H,ArCH2),3.703(s,3H,OCH3),4.261-4.293(t,2H,OCH2),5.988(s,1H,5-H),6.780(m,2H,ArH),6.882(s,1H,ArH),7.106-7.128(d,2H,o-ArH,J=8.8Hz),8.171-8.194(d,2H,m-ArH,J=9.2Hz),12.573(s,1H,NH);13C NMR(100MHz,DMSO)δ:28.879,42.749,55.860,67.289,112.229,113.554,115.467,121.598,126.312,30.611,141.461,147.972,149.060,163.819,170.789;MS(ESI):m/z,392.23[M-H]-.
实施例8
化合物5a4:6-(3,4-二甲氧基苄基)-2-(4-碘苄硫基)嘧啶-4(3H)-酮
Yield:47%.mp:180-181℃.1H NMR(400MHz,DMSO)δ:3.713(s,3H,OCH3),3.727(s,2H,ArCH2),3.750(s,3H,OCH3),4.293(s,2H,SCH2),6.003(s,1H,5-H),6.719-6.969(m,3H,ArH),7.049-7.070(d,2H,o-ArH,J=8.4Hz),7.537-7.558(d,2H,m-ArH,J=8.4Hz),12.544(s,1H,NH); 13C NMR(100MHz,DMSO)δ:32.611,42.268,55.486,93.032,111.847,113.150,121.278,130.170,131.277,136.978,137.969,147.508,148.599;MS(ESI):m/z,493.19[M-H]-.
实施例9
化合物5a5:6-(3,4-二甲氧基苄基)-2-(4-三氟甲基苄硫基)嘧啶-4(3H)-酮
Yield:50%.mp:172-174℃.1H NMR(400MHz,CDCl3)δ:3.806(s,2H,ArCH2),3.847(s,3H,OCH3),3.886(s,3H,OCH3),4.419(s,2H,SCH2),6.034(s,1H,5-H),6.761-6.813(m,3H,ArH),7.363-7.382(d,2H,o-ArH,J=7.6Hz),7.475-7.494(d,2H,m-ArH,J=7.6Hz);13C NMR(100MHz,CDCl3)δ:33.869,43.402,55.906,108.386,111.357,112.616,121.621,125.426,129.464,140.944,148.152,149.123,159.883,165.676,168.230;MS(ESI):m/z,435.38[M-H]-.
实施例10
化合物5a6:6-(3,4-二甲氧基苄基)-2-(3,5-二甲氧基苄硫基)嘧啶-4(3H)-酮
Yield:48%.mp:162-163℃.1H NMR(400MHz,CDCl3)δ:3.762(s,6H,OCH3),3.791(s,2H,ArCH2),3.849(s,3H,OCH3),3.880(s,3H,OCH3),4.372(s,2H,SCH2),5.965(s,1H,5-H),6.364(s,1H,p-ArH),6.515(s,2H,ArH),6.773-6.814(d,3H,ArH),13.253(s,1H,NH);13C NMR(100MHz, CDCl3)δ:34.936,43.634,55.324,55.829,55.939,99.626,107.158,108.252,108.290,111.351,112.522,121.598,129.365,138.493,148.027,149.036,160.378,160.845,168.512;MS(ESI):m/z,427.41[M-H]-.
实施例11
化合物5a7:6-(3,4-二甲氧基苄基)-2-(2-(4-甲基苯氧基)乙硫基)嘧啶-4(3H)-酮
Yield:51%.mp:200℃.1H NMR(400MHz,DMSO)δ:2.219(s,3H,PhCH3),3.440-3.472(t,2H,SCH2),3.673-3.692(d,8H,OCH3;ArCH2),4.062-4.094(t,2H,OCH2),5.963(s,1H,5-H),6.769-6.820(m,4H,ArH),6.889(s,1H,ArH),7.062-7.082(d,2H,m-ArH,J=8Hz),12.620(s,1H,NH);13C NMR(100MHz,DMSO)δ:20.522,29.255,55.835,66.213,112.164,113.481,114.708,121.613,129.912,130.316,147.935,149.000,156.408;MS(ESI):m/z,303.23[M-H]-.
实施例12
化合物5a8:6-(3,4-二甲氧基苄基)-2-(2-(4-溴苯氧基)乙硫基)嘧啶-4(3H)-酮
Yield:47%.mp:208-209℃.1H NMR(400MHz,DMSO)δ:3.491-3.522(t,2H,SCH2),3.666(s,3H,OCH3),3.688(s,2H,ArCH2),3.701(s,3H,OCH3),4.260-4.291(t,2H,OCH2),5.982(s,1H,5-H),6.750-6800(m,2H,ArH),6.882(s,1H,ArH),7.112-7.132(d,2H,o-ArH,J=8Hz),8.174-8.194(d,2H,m-ArH,J=8Hz),12.717(s,1H,NH);13C NMR(100MHz,DMSO)δ:28.859,42.655,55.866,67.299,112.207,113.530,115.473,121.587,126.324,130.623,132.299,141.446,147.947,149.040,163.824;MS(ESI):m/z,477.51[M-H]-.
实施例13
化合物5a9:6-(3,4-二甲氧基苄基)-2-(环庚基硫基)嘧啶-4(3H)-酮
Yield:26%.mp:261-263℃.1H NMR(400MHz,DMSO)δ:1.235-1.975(m,12H,SCHCH12),3.664(s,2H,SCH2),3.717(s,3H,OCH3),3.730(s,3H,OCH3),3.878(m,1H,SCH),5.922(s,1H,5-H),6.784-6.978(m,3H,ArH),12.362(s,1H,NH);13C NMR(100MHz,DMSO)δ:22.310,25.491,27.597,33.117,34.012,42.425,44.920,55.401,55.506,103.365,111.636,113.119,121.215,130.292,147.516,148.569,156.262,161.042;MS(ESI):m/z,373.45[M-H]-.
实施例14
化合物5a10:6-(3,4-二甲氧基苄基)-2-(环己-2-烯-1-基硫基)嘧啶-4(3H)-酮
Yield:44%.mp:159-160℃.1H NMR(400MHz,CDCl3)δ:1.689-2.056(m,6H,CH2),3.743(s,2H,ArCH2),3.865(s,3H,OCH3),3.875(s,3H,OCH3),4.624(s,1H,CH),5.717-5.893(m,2H,CH),5.983(s,1H,5-H),6.778-6.810(m,3H,ArH),13.068(s,1H,NH);13C NMR(100MHz,CDCl3)δ:19.592,24.796,28.994,41.658,43.654,55.833,55.978,107.886,111.345,112.643,121.587,125.411,129.672,131.897,147.978,148.975,160.783,165.690,168.443;MS(ESI):m/z,357.38[M-H]-.
实施例15
化合物5a11:6-(3,4-二甲氧基苄基)-2-(2-硝基苄硫基)嘧啶-4(3H)-酮
Yield:57%.mp:160-161℃.1H NMR(400MHz,CDCl3)δ:3.799(s,2H,ArCH2),3852(s,3H,OCH3),3.892(s,3H,OCH3),4.737(s,2H,SCH2),6.048(s,1H,5-H),6.756-6.840(m,3H,ArH),7.321-7.407(m,3H,ArH),8.041-8.034(d,1H,ArH),13.084(s,1H,NH);13C NMR(100MHz,CDCl3)δ:31.362,43.462,55.909,55.988,108.514,111.378,112.465,121.723,125.123,128.686,129.629,132.520,133.373,133.493,148.008,149.098,160.137,165.538,167.953;MS(ESI):m/z,412.42[M-H]-.
实施例16
化合物5a12:6-(3,4-二甲氧基苄基)-2-(3-氯苄硫基)嘧啶-4(3H)-酮
Yield:66%.mp:161-162℃.1H NMR(400MHz,CDCl3)δ:3.081(s,2H,ArCH2),3850(s,3H,OCH3),3.889(s,3H,OCH3),4.361(s,2H,SCH2),6.004(s,1H,5-H),6.757-6.848(m,3H,ArH),7.147-7239(m,3H,ArH),7.358(s,1H,ArH),13.021(s,1H,NH);13C NMR(100MHz,CDCl3)δ:33.933,43.539,55.859,55.956,108.415,111.376,112.501,121.638,127.287,127.759,129.329,129.748,134.203,138.735,148.058,149.067,159.082,165.551,168.350;MS(ESI):m/z,401.34[M-H]-.
实施例17
化合物5a13:6-(3,4-二甲氧基苄基)-2-(3-甲氧基苄硫基)嘧啶-4(3H)-酮
Yield:54%.mp:181℃.1H NMR(400MHz,CDCl3)δ:3.784(s,3H,OCH3),3.797(s,2H,ArCH2),3848(s,3H,OCH3),3.887(s,3H,OCH3),4.399(s,2H,SCH2),5.962(s,1H,5-H),6.773-6.899(m,6H,ArH),7.155-7.194(m,1H,ArH),13.049(s,1H,NH);13C NMR(100MHz,CDCl3)δ:34.592,43.573,55.206,55.837,55.953,108.227,11.344,112.518,113.137,114.727,121.627,129.558,137.872,148.025,149.041,159.683,160.356,165.569,168.361;MS(ESI):m/z,397.50[M-H]-.
实施例18
化合物5b1:6-(苯并[d]三氮唑-1-基)甲基-2-(4-硝基苄硫基)嘧啶-4(3H)-酮
Yield:45%.mp:223-224℃.1H NMR(400MHz,DMSO)δ:4.178(s,2H,ArCH2),5.871(s,2H,SCH2),6.159(s,1H,5-H),7.214-7.235(d,2H,o-ArH,J=8.4Hz),7.372-7.409(t,1H,ArH),7.506-7.543(t,1H,ArH),7.29-7.850(d,1H,ArH),7.827-7.847(d,2H,m-ArH,J=8Hz),8.042-8.063(d,1H,ArH);13C NMR(100MHz,DMSO)δ:32.743,55.346,111.250,119.612.123.666,124.527,128.016,130.222,133.901,145.640,146.382,146.808;MS(ESI):m/z,393.18[M-H]-.
实施例19
化合物5b2:6-(苯并[d]三氮唑-1-基)甲基-2-(4-氰基苄硫基)嘧啶-4(3H)-酮
Yield:36%.mp:221-222℃.1H NMR(400MHz,DMSO)δ:4.121(s,2H,ArCH2),5.868(s,2H,SCH2),6.148(s,1H,5-H),7.146-7.186(d,2H,o-ArH,J=8Hz),7.383-7.421(t,1H,ArH),7.514-7.559(m,3H,ArH),7.834-7.855(d,1H,ArH),8.068-8.-8.089(d,1H,ArH),12.757(s,1H,NH);13C NMR(100MHz,DMSO)δ:33.058,51.547,110.232,111.257,119.137,119.668,124.537,128.018,130.024,132.495,133.921,144.149,145.644;MS(ESI):m/z,373.19[M-H]-.
实施例20
化合物5b3:6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-硝基苯氧基)乙硫基)嘧啶-4(3H)-酮
Yield:44%.mp:217-218℃.1H NMR(400MHz,DMSO)δ:3.155(t,2H,ArCH2),3.805(t,2H,OCH2),5.863(s,2H,SCH2),6.101(s,1H,5-H),6.962-6.984(d,2H,o-ArH,J=8.8Hz),7.375-7.413(t,1H,ArH),7.536-7.575(t,1H,ArH),7.877-7.898(d,1H,ArH),8.035-8.056(d,1H,ArH),8.203-8.225(d,2H,m-ArH,J=8.8Hz),12.851(s,1H,NH);13C NMR(100MHz,DMSO)δ:29.020,51.381,66.740,111.384,115.386,119.618,124.495,126.335,128.002,134.073,141.462,145.518,163.657;MS(ESI):m/z,423.23[M-H]-.
实施例21
化合物5b4:6-(苯并[d]三氮唑-1-基)甲基-2-(4-碘苄硫基)嘧啶-4(3H)-酮
Yield:36%.mp:202-204℃.1H NMR(400MHz,DMSO)δ:3.990(s,2H,ArCH2),5.867(s,2H,SCH2),6.124(s,1H,5-H),6.747-6.766(d,2H,o-ArH,J=7.6Hz),7.436-7.549(m,4H,ArH),7.859-7.880(d,1H,ArH),8.077-8.-8.098(d,1H,ArH),12.822(s,1H,NH);13C NMR(100MHz,DMSO)δ:32.957,51.601,93.520,111.347,119.635,124.543,128.013,131.439,133.955,137.389,145.657,170.797;MS(ESI):m/z,474.34[M-H]-.
实施例22
化合物5b5:6-(苯并[d]三氮唑-1-基)甲基-2-(4-三氟苄基硫基)嘧啶-4(3H)-酮
Yield:43%.mp:178-180℃.1H NMR(400MHz,DMSO)δ:4.133(s,2H,ArCH2),5.880(s,2H,SCH2),6.162(s,1H,5-H),7.159-7.179(d,2H,o-ArH,J=8Hz),7.421-7.550(m,4H,ArH), 7.850-7.871(d,1H,ArH),8.056-8.078(d,1H,ArH),12.817(s,1H,NH);13C NMR(100MHz,DMSO)δ:32.835,51.590,111.296,119.621,124.521,125.402,125.437,127.994,133.936,145.669,170.786;MS(ESI):m/z,416.27[M-H]-.
实施例23
化合物5b6:6-(苯并[d]三氮唑-1-基)甲基-2-(3,5-二甲氧基苄硫基)嘧啶-4(3H)-酮
Yield:9%.mp:111-112℃.1H NMR(400MHz,DMSO)δ:3.774(s,6H,OCH3),4.186(s,2H,ArCH2),5.682(s,2H,SCH2),5.742(s,1H,5-H),6.368(s,1H,ArH),6.428(s,2H,ArH),7.325-7.363(t,1H,ArH),7.488-7.524(t,1H,ArH),7.810-7.831(d,1H,ArH),7.990-8.011(d,1H,ArH),13.113(s,1H,NH);13C NMR(100MHz,DMSO)δ:35.136,51.930,55.366,99.722,107.136,107.431,109.423,120.256,124.198,127.878,137.591,146.079,160.914,161.499,162.266,164.671;MS(ESI):m/z,408.30[M-H]-.
实施例24
化合物5b7:6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-甲基苯氧基)乙硫基)嘧啶-4(3H)-酮
Yield:37%.mp:176℃.1H NMR(400 MHz,DMSO)δ:2.227(s,3H,PhCH3),3.106(t,2H,SCH2),3.608(t,2H,OCH2),5.847(s,2H,ArCH2),6.072(s,1H,5-H),6.628-6.648(d,2H,o-ArH,J=8Hz),7.061-7.081(d,2H,m-ArH,J=8Hz),7.403-7.440(t,1H,ArH),7.541-7.579(t,1H,ArH),7.875-7.896(d,1H,ArH),8.066-8.-8.086(d,1H,ArH),12.795(s,1H,NH);13C NMR(100MHz,DMSOδ:20.515,29.718,51.429,111.414,114.635,119.612,124.482,127.612,129.914,130.261,134.107,145.579,156.310;MS(ESI):m/z,392.23[M-H]-.
实施例25
化合物5b8:6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-溴苯氧基)乙硫基)嘧啶-4(3H)-酮
Yield:36%.mp:182-183℃.1H NMR(400MHz,DMSO)δ:3.094-3.123(t,2H,ArCH2),3.617-3.645(t,2H,OCH2),5.854(s,2H,SCH2),6.079(s,1H,5-H),6.718-6.740(d,2H,o-ArH,J=8.8Hz),7.437-7.578(m,4H,ArH),7.875-7.896(d,1H,ArH),8.061-8.082(d,1H,ArH),12.840(s,1H,NH);13C NMR(100MHz,DMSO)δ:29.360,51.399,111.415,112.657,117.071,119.622,124.051,128.000,132.598,134.077,145.543,157.691;MS(ESI):m/z,458.20[M-H]-.
实施例26
化合物6a1:6-(3,4-二甲氧基苄基)-2-(4-硝基苄硫基)-5-碘代嘧啶-4(3H)-酮
将70mg(0.169mmol)6-(3,4-二甲氧基苄基)-2-(4-碘苄硫基)嘧啶-4(3H)-酮(5a1),42mg(0.186mmol)NIS加入到1mL的DMF中,冰浴搅拌过夜,加冰水使产物析出,抽滤,得白色固体52mg。
Yield:57%.mp:264-266℃.1H NMR(400MHz,DMSO)δ:3682(s,3H,OCH3),3.709(s,3H,OCH3),4.031(s,2H,ArCH2),4.410(s,2H,SCH2),6.707-6.727(d,1H,ArH),6.826-6.846(d,1H,ArH),6.938(s,1H,ArH),7.420-7.441(d,2H,o-ArH,J=8.4Hz),7.984-8.005(d,2H,m-ArH,J=8.4Hz),12.964(s,1H,NH);13C NMR(100MHz,DMSO)δ:33.076,46.167,55.871,112.232,113.565,121.286,123.712,130.181,130.749,146.690,146.828,148.103,149.029;HRMS(ESI):m/z,calcd.for C20H17N3O5SI[M-H]-:537.9934,found537.9938.
实施例27
化合物6a2:6-(3,4-二甲氧基苄基)-2-(4-氰基苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:47%.mp:241-242℃.1H NMR(400MHz,DMSO)δ:3.688(s,3H,OCH3),3.723(s,3H,OCH3),4.028(s,2H,ArCH2),4.381(s,2H,SCH2),6.709-6.729(d,1H,ArH),6.842-6.863(d.1H,ArH),6.937-6.941(d,1H,ArH),7.367-7.388(d,2H,o-ArH,J=8.4Hz),7.604-7.624(d,2H,m-ArH,J=8Hz),13.024(s,1H,NH);13C NMR(100MHz,DMSO)δ:33.429,55.913,55.980,110.277,112.402,113.627,119.167,121.338,130.114,130.256,132.550,144.295,148.141,149.067;HRMS(ESI):m/z,calcd.for C21H17N3O3SI[M-H]-:518.0035,found518.0034.
实施例28
化合物6a3:6-(3,4-二甲氧基苄基)-2-(2-(4-硝基苯氧基)乙硫基)-5-碘代嘧啶-4(3H)-酮
Yield:40%.mp:210-212℃.1H NMR(400MHz,DMSO)δ:3.457-3.489(t,2H,SCH2),3.649(s,3H,OCH3),3.697(s,3H,OCH3),3.998(s,2H,ArCH2),4.176-4.208(t,2H,OCH2),6.746-6.793(m,2H,ArH),6.903-6.931(m,2H,ArH),7.050-7.073(d,2H,o-ArH,J=9.2Hz),8.151-8.174(d,2H,m-ArH,J=9.2Hz),13.053(s,1H,NH);13C NMR(100MHz,DMSO)δ:29.985,46.148,55.632,67.083,112.180,113.364,115.407,121.181,126.293,130.120,141.459,148.048,148.975,163.755,179.849;MS(ESI):m/z,568.26[M-H]-.
实施例29
化合物6a4:6-(3,4-二甲氧基苄基)-2-(4-碘苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:42%.mp:207-208℃.1H NMR(400MHz,DMSO)δ:3.702(s,3H,OCH3),3.743(s,3H,OCH3),4.046(s,2H,ArCH2),4.271(s,2H,SCH2),6.736-6.761(m,1H,ArH),6.865-6.885(d,1H,ArH),6.955-7.006(m,3H,ArH),7.511-7.531(d,2H,ArH,J=8Hz),13.008(s,1H,NH);13CNMR(100MHz,DMSO)δ:33.300,56.019,93.593,112.416,113.598,121.352,130.120,131.659,137.481,138.139,148.136,149.063;MS(ESI):m/z,619.28[M-H]-.
实施例30
化合物6a5:6-(3,4-二甲氧基苄基)-2-(4-三氟甲基苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:43%.mp:233-234℃.1H NMR(400MHz,DMSO)δ:3.683(s,3H,OCH3),3.704(s,3H,OCH3),4.055(s,2H,ArCH2),4.389(s,2H,SCH2),6.741-6.962(m,3H,ArH),7.376-7.396(d,2H,o-ArH,J=8Hz),7.492-7.512(d,2H,m-ArH,J=8Hz),13.057(s,1H,NH);13C NMR(100MHz,DMSO);δ:33.135,46.202,55.834,112.270,113.540,121.319,125.473,125.510,130.215,143.361,148.112,149.044;MS(ESI):m/z,561.38[M-H]-.
实施例31
化合物6a6:6-(3,4-二甲氧基苄基)-2-(3,5-二甲氧基苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:43%.mp:163-164℃.1H NMR(400MHz,DMSO)δ:3.686-3.718(m,12H,OCH3),4.032-4.057(d,2H,ArCH2),4.316-4.474(s,2H,SCH2),6.396(s,1H,ArH),6.499-6.534(m,2H,ArH),6.826-6.993(d,3H,ArH),13.021(s,1H,NH);13C NMR(100MHz,DMSO)δ:34.371,55.587,55.966,82.252,99.552,107.379,112.379,113.429,121.231,129.931,139.800,148.148,149.035,159.441,160.920,161.073;MS(ESI):m/z,553.61[M-H]-.
实施例32
化合物6a7:6-(3,4-二甲氧基苄基)-2-(2-(4-甲基苯氧基)乙硫基)-5碘代嘧啶-4(3H)-酮
Yield:57%.mp:187-188℃.1H NMR(400MHz,DMSO)δ:2.215(s,3H,PhCH3),3.414-3.446(t,2H,SCH2),3.663(s,3H,OCH3),3.692(s,3H,OCH3),3.993(t,4H,OCH2;ArCH2),6.745-6.786(m,4H,ArH),7.066-7.086(d,1H,ArH),7.046-7.066(d,2H,m-ArH,J=8Hz),13.054(s,1H,NH);13C NMR(100MHz,DMSO)δ:20.026,29.150,55.350,55.542,111.692,112.833,114.185,120.764,129.451,129.808,147.570,148.451,155.877;MS(ESI):m/z,537.61[M-H]-.
实施例33
化合物6a8:6-(3,4-二甲氧基苄基)-2-(2-(4-溴苯氧基)乙硫基)-5-碘代嘧啶-4(3H)-酮
Yield:66%.mp:210-212℃.1H NMR(400MHz,DMSO)δ:3.457-3.489(t,2H,SCH2),3.647(s,3H,OCH3),3.697(s,3H,OCH3),3.996(s,2H,ArCH2),4.176-4.208(t,2H,OCH2),6.764(s,2H,ArH),6.929(s,1H,ArH),7.044-7.063(d,2H,o-ArH,J=7.6Hz),8.147-8.167(d,2H,m-ArH,J=8Hz),13.050(s,1H,NH);13C NMR(100MHz,DMSO)δ:29.230,46.182,55.834,67.073,112.165,113.355,115.390,121.181,126.280,130.105,141.452,148.049,148.975,163.746;MS(ESI):m/z,603.41[M-H]-.
实施例34
化合物6a9:6-(3,4-二甲氧基苄基)-2-(环庚基硫基)-5-碘代嘧啶-4(3H)-酮
Yield:32%.mp:223-224℃.1H NMR(400MHz,CDCl3)δ:1.274-1.855(m,12H,SCHCH12),3.700(m,1H,SCH),3.841(s,3H,OCH3),3.873(s,3H,OCH3),4.326(s,2H,SCH2),6.764-7.256(m,3H,ArH),11.752(s,1H,NH);13C NMR(100MHz,CDC13)δ:25.774,28.099,34.598,46.808,51.629,55.992,56.132,89.652,113.311,118.737,123.176,133.625,148.325,149.223,160.633,161.785,167.893;HRMS(ESI):m/z,calcd.for C20H24N2O3SI[M-H]-:499.0552,found499.0564.
实施例35
化合物6a10:6-(3,4-二甲氧基苄基)-2-(环己-2-烯-1-基硫基)-5-碘代嘧啶-4(3H)-酮
Yield:38%.mp:194-195℃.1H NMR(400MHz,CDCl3)δ:1.671-2.067(m,6H,CH2),3.875(s,6H,OCH3),4.062-4.117(m,2H,ArCH2),4.522(s,1H,CH),5.712-5.902(m,2H,CH),6.801-6.951(m,3H,ArH),11.965(s,1H,NH);13C NMR(100MHz,CDCl3)δ:19.597,24.794,28.989,42.397,46.662,55.936,84.792,111.150,112.661,121.534,125.076,129.703,132.379,147.996,148.799,160.241,162.075,168.874;MS(ESI):m/z,483.13[M-H]-.
实施例36
化合物6a11:6-(3,4-二甲氧基苄基)-2-(2-硝基苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:34%.mp:194-195℃.1H NMR(400MHz,DMSO)δ:3.716(s,3H,OCH3),3.726(s,3H, OCH3),4.073(s,2H,ArCH2),4.609(s,2H,SCH2),6.813-6.988(m,3H,ArH),7.222-7.240(d,1H,ArH),7.435-7.527(m,2H,ArH),8.023-8.043(d,1H,ArH),13.039(s,1H,NH);13C NMR(100MHz,DMSO)δ:30.654,45.709,55.415,55.512,111.926,113.049,120.962,124.944,129.020,129.765,132.123,133.125,147.661,147.740,148.638;MS(ESI):m/z,538.17[M-H]-.
实施例37
化合物6a12:6-(3,4-二甲氧基苄基)-2-(3-氯苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:67%.mp:175-176℃.1H NMR(400MHz,CDCl3)δ:3.841(s,3H,OCH3),3.869(s,3H,OCH3),4.148(s,2H,ArCH2),4.318(s,2H,SCH2),6.797-6.927(m,3H,ArH),7.079-7283(m,4H,ArH),12.563(s,1H,NH);13C NMR(100MHz,CDCl3)δ:34.172,46.681,55.899,55.963,85.585,111.280,112.537,121.415,127.138,127.853,129.068,129.807,134.302,138.540,148.063,148.887,159.415,162.374,168.914;HRMS(ESI):m/z,calcd.for C20H17N2O3SClI[M-H]-:526.9693,found526.9697.
实施例38
化合物6a13:6-(3,4-二甲氧基苄基)-2-(3-甲氧基苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:53%.mp:169-170℃.1H NMR(400MHz,CDCl3)δ:3.777(s,3H,OCH3),3.836(s,3H,OCH3),3.869(s,3H,OCH3),4.148(s,2H,SCH2),4.371(s,2H,ArCH2),6.789-6.956(m,6H,ArH),7.169(t,1H,ArH),12.347(s,1H,NH);13C NMR(100MHz,CDCl3)δ:35.022,46.656,55.222,55.833,55.894,85.309,111.229,112.522,113.143,114.682,121.345,121.430,129.650,137.622,148.039,148.867,159.753,159.952,162.283,168.894;MS(ESI):m/z,523.43[M-H]-.
实施例39
化合物6b1:6-(苯并[d]三氮唑-1-基)甲基-2-(4-硝基苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:49%.mp:238-239℃.1H NMR(400MHz,DMSO)δ:3.763(s,2H,ArCH2),6.014(s,2H,SCH2),6.927-6.947(d,2H,o-ArH,J=8Hz),7.302-7.339(t,1H,ArH),7.471-7.509(t,1H,ArH),7.791-7.182(d,1H,ArH),7.872-7.897(d,2H,ArH),7.954-7.975(d,1H,ArH),13.276(s,1H,ArH); 13C NMR(100MHz,DMSO)δ:32.395,55.430,111.365,119.506,123.634,124.316,127.915,129.816,134.399,145.498,145.605,146.817;MS(ESI):m/z,519.24[M-H]-.
实施例40
化合物6b2:6-(苯并[d]三氮唑-1-基)甲基-2-(4-氰基苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:33%.mp:186-187℃.1H NMR(400MHz,DMSO)δ:3.686(s,2H,ArCH2),6.008(s,2H,SCH2),6.858-6.878(d,2H,o-ArH,J=8Hz),7.322-7.360(t,1H,ArH),7.496-7.515(m,3H,ArH),7.794-7.815(d,1H,ArH),7.976-8.-7.997(d,1H,ArH),13.247(s,1H,NH),13C NMR(100MHz,DMSO)δ:32.697,55.405,110.269,111.376,119.099,119.534,124.341,127.929,129.614,132.481,134.341,143.446,145.501;MS(ESI):m/z,499.14[M-H]-.
实施例41
化合物6b3:6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-硝基苯氧基)乙硫基)-5-碘代嘧啶-4(3H)-酮
Yield:38%.mp:236-237℃.1H NMR(400MHz,DMSO)δ:2.670(t,2H,ArCH2),3.617-3.645(t,2H,OCH2),5.959(s,2H,SCH2),6.870-6.892(d,2H,o-ArH,J=8.8Hz),7.383(t,1H,ArH),7.551(t,1H,ArH),7.842-7.863(d,1H,ArH),8.029-8.050(d,1H,ArH),8.192-8.214(d,2H,m-ArH,J=8.8Hz),13.219(s,1H,NH);13C NMR(100MHz,DMSO)δ:29.097,55.303,111.526,115.306,119.565,124.332,126.298,127.890,134.573,141.041,145.443,163.628;HRMS(ESI):m/z,calcd.for C19H14N6O4SI[M-H]-:548.9842,found548.9845.
实施例42
化合物6b4:6-(苯并[d]三氮唑-1-基)甲基-2-(4-碘苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:37%.mp:205-206℃.1H NMR(400MHz,DMSO)δ:3.523(s,2H,ArCH2),6.020(s,2H,SCH2),6.468-6.488(d,2H,o-ArH,J=8Hz),7.398-7.547(m,4H,ArH),7.282-7.849(d,1H,ArH),8.011-8.032(d,1H,ArH),13.210(s,1H,NH);13C NMR(100MHz,DMSO)δ:32.171,54.939,93.157,110.999,119.042,123.877,127.430,130.576,133.996,136.879,145.038,160.905;MS(ESI):m/z,600.27[M-H]-.
实施例43
化合物6b5:6-(苯并[d]三氮唑-1-基)甲基-2-(4-三氟苄基硫基)-5-碘代嘧啶-4(3H)-酮
Yield:42%.mp:231-233℃.1H NMR(400MHz,DMSO)δ:3.689(s,2H,ArCH2),6.031(s,2H,SCH2),6.872-6.892(d,2H,o-ArH,J=8Hz),7.383-7.524(m,4H,ArH),7.824-7.845(d,1H,ArH),7.981-8.002(d,1H,ArH),13.289(s,1H,NH);13C NMR(100MHz,DMSO)δ:32.001,53.935,110.941,119.009,123.843,124.903,124.940,127.414,128.970,133.963,142.011,145.027;MS(ESI):m/z,542.20[M-H]-.
实施例44
化合物6b6:6-(苯并[d]三氮唑-1-基)甲基-2-(3,5-二甲氧基苄硫基)-5-碘代嘧啶-4(3H)-酮
Yield:48%.mp:243-244℃.1H NMR(400MHz,DMSO)δ:3.394(s,2H,ArCH2),3.684(s,6H,OCH3),5.999(s,2H,SCH2),6.090(s,2H,ArH),6.323(s,1H,ArH),7.325-7.363(t,1H,ArH),7.488-7.524(t,1H,ArH),7.810-7.831(d,1H,ArH),7.990-8.011(d,1H,ArH),13.113(s,1H,NH); 13C NMR(100MHz,DMSO)δ:34.073,51.586,55.622,99.672,107.223,111.360,119.667,124.494,127.954,133.955,145.626,160.861;HRMS(ESI):m/z,calcd.for C20H17N5O3SI[M-H]-:534.0097.found534.0099.
实施例45
化合物6b7:6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-甲基苯氧基)乙硫基)-5-碘代嘧啶-4(3H)-酮
Yield:40%.mp:199-200℃.1H NMR(400MHz,DMSO)δ:2.226(s,3H,PhCH3),2.605(t,2H,SCH2),3.121(t,2H,OCH2),5.984(s,2H,ArCH2),6.518-6.537(d,2H,o-ArH,J=7.6Hz),7.050-7.069(d,2H,m-ArH,J=7.6Hz),7.403-7.439(t,H,ArH),7.545-7.582(t,1H,ArH),7.857-7.877(d,1H,ArH),8.069-8.089(d,1H,ArH),13.091(s,1H,NH);13C NMR(100MHz,DMSO)δ:20.519,29.928,55.214,111.533,114.531,119.569,124.353,127.916,130.218,134.660,145.507,156.232;MS(ESI):m/z,518.30[M-H]-.
实施例46
化合物6b8:6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-溴苯氧基)乙硫基)-5-碘代嘧啶-4(3H)-酮
Yield:33%.mp:308℃.1H NMR(400MHz,DMSO)δ:2.619(t,2H,ArCH2),3.151(t,2H,OCH2),5.989(s,2H,SCH2),6.602-6.623(d,2H,o-ArH,J=8.4Hz),7.395-7.450(m,3H,ArH),7.545-7.583(t,1H,ArH),7.851-7.872(d,1H,ArH),8.059-8.080(s,1H,ArH),13.201(s,1H,NH); 13C NMR(100MHz,DMSO)δ:29.598,55.192,111.493,112.671,116.999,119.591,124.369,127945,132.553,134.628,145.487,157.623;MS(ESI):m/z,584.17[M-H]-.
实施例47
体外抗HBV活性测定实验
一、实验材料
1.1HepAD38细胞
HepAD38细胞系是人肝细胞肿瘤细胞系,其HBV DNA产量比Hep2.2.15细胞高11倍,所需培养时间只有Hep2.2.15细胞的一半,适用于抗HBV药物筛选。
1.2试剂
DMEM培养液,胎牛血清,胰蛋白酶,二甲基亚砜(DMSO).
1.3主要仪器
二氧化碳培养箱,细胞培养瓶,24孔细胞培养板,倒置显微镜,低温高速离心,电子分析天平,生物安全柜,酶联仪
二、实验方法
细胞上清中HBV DNA含量实验
化合物用含DMSO的培养液配制成各浓度药液,分别加入24孔培养板中,每孔0.5mL,每浓度3孔。24小时后换入含药培养基,2天后换入相同的含药培养基,24h后收集细胞上清。收集到的细胞上清在100℃下煮沸10min,12000rpm离心10min。最后用荧光定量PCR检测细胞培养上清中HBV DNA的表达量,通过GraphPad Prism分析得抑制率以及EC50。
细胞毒性实验
将细胞铺至96孔板,24h后药物样品母液,用HepAD38细胞培养基配置成200μM、100μM、50μM共3个浓度,加入到96孔板细胞培养板,每浓度6孔,用含有0.4%DMSO的培养基作为对照组。每2天换同浓度药液并设无药细胞对照组,共培养7天。用MTT法 检测细胞存活率。
三、实验结果
a10μM浓度下的抑制率;b数据是至少两次实验的平均值
表一化合物对HepAD38细胞培养上清DNA的抑制率
a半最大效应浓度;b引起50%细胞死亡的浓度;c治疗指数,CC50/EC50.
表二化合物EC50与CC50值
四、结果分析
分析实验结果,可以看出2,5,6位取代嘧啶酮衍生物具有良好的抗乙肝病毒活性,且其毒性较低,具有较高的治疗指数,是一类新的非核苷类乙肝病毒抑制剂。
Claims (4)
1.一种2,5,6位取代嘧啶酮嘧啶酮衍生物,如式(I),或其药学上可接受的溶剂化物:
其中,
R1为3,4-二甲氧基苯基,苯并[d]三氮唑-1-基;
R2为4-硝基溴苄,4-氰基溴苄,4-碘溴苄,4-三氟甲基溴苄,3,5-二甲氧基溴苄,2-硝基溴苄,3-氯溴苄,2-(4-硝基苯氧基)乙基,2-(4-甲基苯氧基)乙基,2-(4-溴苯氧基)乙基,环庚基,环己-2-烯-1-基;
R3为H,卤素(如Cl、Br、I),N(CH3)2,CH(CH3)2
所保护的化合物名称为:
6-(3,4-二甲氧基苄基)-2-(4-硝基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-氰基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-硝基苯氧基)乙硫基)-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-碘苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-三氟甲基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3,5-二甲氧基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-甲基苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-溴苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(环庚基硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(环己-2-烯-1-基硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-硝基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3-氯苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3-甲氧基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-硝基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-氰基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-硝基苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-碘苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-三氟苄基硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(3,5-二甲氧基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-甲基苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-溴苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-硝基苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-氰基苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-硝基苯氧基)乙硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-碘苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-三氟甲基苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3,5-二甲氧基苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-甲基苯氧基)乙硫基)-5碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-溴苯氧基)乙硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(环庚基硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(环己-2-烯-1-基硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-硝基苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3-氯苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3-甲氧基苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-硝基苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-氰基苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-nitrophenoxy)ethylthio)-5-碘代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-碘苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-三氟苄基硫基)-5-碘代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(3,5-二甲氧基苄硫基)-5-碘代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-甲基苯氧基)乙硫基)-5-碘代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-溴苯氧基)乙硫基)-5-碘代嘧啶-4(3H)-酮。
6-(3,4-二甲氧基苄基)-2-(4-硝基苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-氰基苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-硝基苯氧基)乙硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-碘苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-三氟甲基苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3,5-二甲氧基苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-甲基苯氧基)乙硫基)-5溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-溴苯氧基)乙硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(环庚基硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(环己-2-烯-1-基硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-硝基苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3-氯苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3-甲氧基苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-硝基苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-氰基苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-nitrophenoxy)ethylthio)-5-溴代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-碘苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-三氟苄基硫基)-5-溴代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(3,5-二甲氧基苄硫基)-5-溴代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-甲基苯氧基)乙硫基)-5-溴代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-溴苯氧基)乙硫基)-5-溴代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-硝基苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-氰基苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-硝基苯氧基)乙硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-碘苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(4-三氟甲基苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3,5-二甲氧基苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-甲基苯氧基)乙硫基)-5氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-(4-溴苯氧基)乙硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(环庚基硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(环己-2-烯-1-基硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(2-硝基苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3-氯苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-2-(3-甲氧基苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-硝基苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-氰基苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-nitrophenoxy)ethylthio)-5-氯代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-碘苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(4-三氟苄基硫基)-5-氯代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(3,5-二甲氧基苄硫基)-5-氯代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-甲基苯氧基)乙硫基)-5-氯代嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-2-(2-(4-溴苯氧基)乙硫基)-5-氯代嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(4-硝基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(4-氰基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(2-(4-硝基苯氧基)乙硫基)-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(4-碘苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(4-三氟甲基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(3,5-二甲氧基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(2-(4-甲基苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(2-(4-溴苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(环庚基硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(环己-2-烯-1-基硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(2-硝基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(3-氯苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-异丙基-2-(3-甲氧基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-异丙基-2-(4-硝基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-异丙基-2-(4-氰基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-异丙基-2-(2-(4-硝基苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-异丙基-2-(4-碘苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-异丙基-2-(4-三氟苄基硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-异丙基-2-(3,5-二甲氧基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-异丙基-2-(2-(4-甲基苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-异丙基-2-(2-(4-溴苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(4-硝基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(4-氰基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(2-(4-硝基苯氧基)乙硫基)-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(4-碘苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(4-三氟甲基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(3,5-二甲氧基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(2-(4-甲基苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(2-(4-溴苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(环庚基硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(环己-2-烯-1-基硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(2-硝基苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(3-氯苄硫基)嘧啶-4(3H)-酮;
6-(3,4-二甲氧基苄基)-5-二甲胺基-2-(3-甲氧基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-二甲胺基-2-(4-硝基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-二甲胺基-2-(4-氰基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-二甲胺基-2-(2-(4-硝基苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-二甲胺基-2-(4-碘苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-二甲胺基-2-(4-三氟苄基硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-二甲胺基-2-(3,5-二甲氧基苄硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-二甲胺基-2-(2-(4-甲基苯氧基)乙硫基)嘧啶-4(3H)-酮;
6-(苯并[d]三氮唑-1-基)甲基-5-二甲胺基-2-(2-(4-溴苯氧基)乙硫基)嘧啶-4(3H)-酮。
2.权利要求1中任一项所述的2,5,6位取代嘧啶酮嘧啶酮衍生物的制备方法,其包括如下步骤:
这里,在上述各化合物中的取代基R1、R2与R3定义如权利要求1中所述衍生物中化合物式(I)所定义的。
3.包含权利要求1中任一项所述的2,5,6位取代嘧啶酮嘧啶酮衍生物的药物组合物。
4.权利要求1中任一项所述2,5,6位取代嘧啶酮嘧啶酮衍生物作为抗HBV药物的应用。
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Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101597263A (zh) * | 2008-06-05 | 2009-12-09 | 首都医科大学 | 新型s-dabo类hiv-1逆转录酶抑制剂的制备及其用途 |
CN103864699A (zh) * | 2012-12-11 | 2014-06-18 | 北京大学 | 具有抗HBV病毒且兼具抗HIV和HCV病毒作用的新一类非核苷S-DABOs嘧啶酮衍生物的制备和应用 |
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Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101597263A (zh) * | 2008-06-05 | 2009-12-09 | 首都医科大学 | 新型s-dabo类hiv-1逆转录酶抑制剂的制备及其用途 |
CN103864699A (zh) * | 2012-12-11 | 2014-06-18 | 北京大学 | 具有抗HBV病毒且兼具抗HIV和HCV病毒作用的新一类非核苷S-DABOs嘧啶酮衍生物的制备和应用 |
Non-Patent Citations (3)
Title |
---|
HUA QIN ET AL.,: "Synthesis and biological evaluation of novel C5 halogen-functionalized S-DABO as potent HIV-1 non-nucleoside reverse transcriptase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
VINEY LATHER ET AL.,: "Topological models for the prediction of anti-HIV activity of dihydro (alkylthio) (naphthylmethyl) oxopyrimidines", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
张继明等: "HIV耐药性研究对HBV耐药性研究的借鉴", 《肝脏》 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109956865A (zh) * | 2017-12-22 | 2019-07-02 | 浙江瑞博制药有限公司 | 一种西格列汀中间体的制备方法 |
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