CN105294795A - 新型核苷氨基磷酸酯衍生物及其应用 - Google Patents
新型核苷氨基磷酸酯衍生物及其应用 Download PDFInfo
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- CN105294795A CN105294795A CN201510799993.8A CN201510799993A CN105294795A CN 105294795 A CN105294795 A CN 105294795A CN 201510799993 A CN201510799993 A CN 201510799993A CN 105294795 A CN105294795 A CN 105294795A
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Abstract
本发明公开了一类新型核苷氨基磷酸酯衍生物及其应用，其为式I所示的化合物或其药学可接受的酸式盐、溶剂化物或水合物，其中，R1为C1～4烷基或氘代C1～4烷基；R2为任意取代的苯基或萘基，其取代基选自氘、C1～4烷基、C1～4烷氧基；且R1和R2中至少含有一个氘取代基；R3为氨基酸酰基或多肽酰基。本发明的化合物可应用于治疗哺乳动物病毒性感染，尤其是丙型肝炎病毒感染方面。
Description
技术领域
本发明属于药物化学技术领域，具体涉及一种新型的核苷氨基磷酸酯衍生物、药学可接受的酸式盐、溶剂化物或水合物，它们的制备方法、药物组合物及它们在制备用于哺乳动物感染性疾病、预防或治疗丙型肝炎、肝硬化、肝癌的药物中的用途。
背景技术
丙型肝炎病毒(HCV)感染是世界范围内的健康问题，临床表现多样，轻至炎症，重至肝硬化、肝癌。全世界有超过2亿的受感染个体，每年至少有3至4百万人被感染。一旦被感染后，大约20％的人能清除该病毒，但是剩余的人可能在他们的余生中携带HCV。10％至20％的慢性感染个体最终发展成肝脏破坏性的硬化或癌症。当前用于HCV感染的治疗药物有重组干扰素、单独或与核苷类似物利巴韦林相结合的疗法，以及吉拉德上市的sofosbuvir。尽管存在这些现有技术，但生物利用度高，肝脏选择性好，药效高的HCV感染治疗药物仍是临床的迫切需求。
发明内容
本发明的目的是提供一类新型的具有抗丙肝活性的核苷氨基磷酸酯衍生物、药学可接受的酸式盐、溶剂化物或水合物。
本发明的另一目的是提供一种含有上述核苷氨基磷酸酯衍生物、药学可接受的酸式盐、溶剂化物或水合物的药物组合物。
本发明的第三个目的是提供一种上述核苷氨基磷酸酯衍生物、药学可接受的酸式盐、溶剂化物或水合物作为抗哺乳动物病毒性感染药物或用于预防或治疗丙型肝炎、肝硬化、肝癌等疾病中的用途。
本发明的目的可以通过以下措施达到：
一种核苷氨基磷酸酯衍生物，如通式I的化合物或其药学可接受的酸式盐、溶剂化物或水合物：
其中，
R1为C1～4烷基或氘代C1～4烷基；
R2为任意取代的苯基或萘基，其取代基选自氘、C1～4烷基、C1～4烷氧基；
且R1和R2中至少含有一个氘取代基；
R3为氨基酸酰基或多肽酰基。
在一种优选方案中，R1为甲基、乙基、丙基、异丙基、氘代甲基、氘代乙基或氘代异丙基。
在一种更优选的方案中，R1为-CH3、-CH2CH3、-CH(CH3)2、-CD3(又称氘代甲基-d3)、-CD2CD3(又称氘代乙基-d5)、-CH(CD3)2(又称氘代异丙基-d6)或-CD(CD3)2(又称氘代异丙基-d7)。
在一种优选方案中，R2为苯基或氘代苯基。
在一种更优选的方案中，R2为-C6H5或-C6D5(又称氘代苯基-d5)。
本发明的式I化合物中，R1和R2中至少含有一个氘取代基，是指R1和R2选用的各基团中至少有一个为含氘基团，它可以为R1为含氘基团而R2不为含氘基团，还可以为R2为含氘基团而R1不为含氘基团，还可以为R1和R2均为含氘基团。
在一种优选方案中，R3为天然氨基酸酰基、非天然氨基酸酰基或二肽酰基。
在一种更优选的方案中，R3为天然氨基酸酰基。
在一种更优选的方案中，R3为甘氨酰基、丙氨酰基、缬氨酰基、亮氨酰基、异亮氨酰基、苯丙氨酰基、色氨酰基、酪胺酰基、天冬氨酰基、天冬酰胺酰基、谷氨酰基、谷氨酰胺酰基、赖氨酰基、甲硫氨酰基、丝氨酰基、苏氨酰基、半胱氨酰基、脯氨酰基、组胺酰基或精氨酰基。
在一种更优选的方案中，R1为-CD3、-CD2CD3、-CH(CH3)2、-CH(CD3)2或-CD(CD3)2，R2为-C6H5或-C6D5，R3为甘氨酰基、丙氨酰基、缬氨酰基、亮氨酰基、异亮氨酰基、苯丙氨酰基、色氨酰基、酪胺酰基、天冬氨酰基、天冬酰胺酰基、谷氨酰基、谷氨酰胺酰基、赖氨酰基、甲硫氨酰基、丝氨酰基、苏氨酰基、半胱氨酰基、脯氨酰基、组胺酰基或精氨酰基。
在本发明的特别优选实施方案中，本发明的化合物或其药学可接受的酸式盐、溶剂化物或水合物，其中化合物选自：
在本发明的实施方案中，本发明提供的所述衍生物包括式I化合物的对映异构体和外消旋体。
在本发明的实施方案中，本发明所述的衍生物包括式I化合物或其药学上可接受的酸式盐，包括但不限于化合物与下列酸形成的盐：盐酸、氢溴酸、硫酸、硝酸、柠檬酸、酒石酸、磷酸、乳酸、乙酸、马来酸、富马酸、苹果酸、杏仁酸、甲磺酸、苯磺酸、对甲苯磺酸、草酸或琥珀酸。
本发明中的“C1～4烷基”是指含有1、2、3或4个碳原子的直链或支链饱和烃基，包括但不限于甲基、乙基、正丙基、异丙基、正丁基等。
本发明中的“氘”是氢(H)的同位素，也被称为重氢，元素符号一般为D。
本发明中的“氘代”是指基团中的氢(H)被氘(D)所取代，它包括单取代或两个或两个以上的多取代。例如本发明中的“氘代异丙基”是指一个或多个氢(H)被氘(D)所取代的异丙基，例如-CH(CD3)2、-CH(CD3)(CH3)、-CH(CD3)2或-CD(CD3)2等。
本发明中的“任意取代”是指具有取代基或不具有取代基。
本发明中的“C1～4烷氧基”是指含有1、2、3或4个碳原子的直链或支链的烷基取代的氧基，即“C1～4烷基-O-”。
本发明中的“氨基酸酰基”是指氨基酸(NH2-R-C(＝O)-OH)中的羧基缺少-OH所形成的基团(NH2-R-C(＝O)-)。这里所指的氨基酸包括20种天然氨基酸，也包括各种非天然氨基酸，例如：丙氨酸(Ala)、缬氨酸(Val)、亮氨酸(Leu)、异亮氨酸(Ile)、脯氨酸(Pro)、苯丙氨酸(Phe)、色氨酸(Trp)、蛋氨酸(Met)、甘氨酸(Gly)、丝氨酸(Ser)、苏氨酸(Thr)、半胱氨酸(Cys)、酪氨酸(Tyr)、天冬酰胺(Asn)、谷氨酰胺(Gln)、天冬氨酸(Asp)、谷氨酸(Glu)、赖氨酸(Lys)、精氨酸(Arg)、组氨酸(His)等。
本发明中的“多肽酰基”是指多肽中的羧基(-C(＝O)-OH)缺少-OH所形成的基团，这里的多肽包括由2个、3个或4个以上氨基酸通过肽键所形成的小分子化合物，优选为二肽，包括但不限于甘谷二肽、甘酪二肽、丙谷二肽、丙组二肽等。
第二方面，本发明提供了上述核苷氨基磷酸酯衍生物式I化合物或其药学上可接受酸式盐、溶剂化物或水合物的制备方法，包括下列步骤：
式II化合物与式III化合物在缩合剂条件下或式II化合物与式IV化合物反应，再脱除氨基保护基得到式I化合物
其中，式II化合物、式III化合物和式IV化合物中的R1、R2、R3如式I化合物中所定义，缩合剂可以为羰基二咪唑(CDI)、N,N'-二异丙基碳二亚胺(DIC)、N,N'-二环己基碳二亚胺(DCC)、N-(3-二甲氨基丙基)-N'-乙基碳二亚胺盐酸盐(EDC·HCl)、O-(7-氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)，Cbz基团为保护氨基的苄氧羰基保护基。
作为一种优选的实施方案，本发明提供了上述核苷氨基磷酸酯衍生物式I化合物或其药学上可接受的酸式盐、溶剂化物或水合物的制备方法，所述方法包括将式II化合物或其盐溶于有机溶剂中，冷却下分批加入碱，然后与式IV化合物反应，再用催化氢化脱除Cbz保护基，得到式I化合物；或者将式III化合物与缩合剂反应，加入碱，再与式II化合物或其盐的有机溶剂反应，再用催化氢化脱除Cbz保护基，得到式I化合物，如果有必要可以通过常规方法例如重结晶、柱层析等进一步纯化。这里，所述的碱可以是无机碱或有机碱，可选自碳酸钠、碳酸钾、碳酸氢钠、碳酸氢钾、三乙胺、或N,N-二异丙基乙胺等。式I化合物与酸的有机溶剂溶液或水溶液按照比例成盐得到式I化合物的酸式盐。
特别的，对于本发明中例如MJ10807、MJ10808、MJ10810、MJ10811、MJ10813、MJ10814、MJ10815、MJ10816、MJ10817、MJ10818、MJ10819、MJ10820等R3基团中具有额外易反应官能团的化合物，加入相应的侧链保护，侧链保护可以是苄氧羰基、苄基等，并在缩合反应后加入脱保护步骤。
第三方面，本发明还提供了包含治疗有效量的前述各核苷氨基磷酸酯衍生物式I化合物、或其药学上接受的酸式盐、溶剂化物或者水合物的药物组合物，该药物组合物可以还包含可药用载体或稀释剂，该药物组合物还可以其他活性成分，以形成联合用药的组合物或是具有协同增效的组合物。该药物组合物可通过静脉注射给药、通过注射入组织给药、腹膜内给药、口服给药或鼻腔内给药。该药物组合物可具有选自溶液、分散体、悬浮液、粉末、胶囊、片剂、丸剂、延时释放胶囊、延时释放片剂和延时释放丸剂的形式。该药物组合物的给药剂量为5-5000mg/日。
第四方面，本发明提供了上述核苷氨基磷酸酯衍生物如式I化合物、或其药学上接受的酸式盐、溶剂化物或者水合物可用于制备预防或治疗哺乳动物病毒感染药物，特别是用于制备预防或治疗哺乳动物丙型肝炎、肝硬化或肝癌药物中。本发明中的哺乳动物包括但不限于人、虎、狼、鼠、鹿、貂、猴、貘、树懒、斑马、狗、兔、狐、熊、象、豹子、麝牛、狮子、小熊猫、猪、羚羊、驯鹿、考拉、犀牛、猞猁、穿山甲、长颈鹿、熊猫、食蚁兽、猩猩、海牛、水獭、灵猫、海豚、海象、鸭嘴兽、刺猬、北极狐、北极熊、袋鼠、犰狳、河马、海豹、鲸、鼬等。
与现有技术相比，本发明的新型的核苷氨基磷酸酯衍生物具有显著的抗HCV活性，其抗HCV活性的关键指标肝脏活性代谢物的浓度甚至明显高于sofosbuvir。
附图说明
图1SD大鼠灌胃给予20mg/kg的本发明化合物及sofosbuvir后肝脏活性代谢物GS-461203的浓度(ng/g)。
具体实施方式
以下通过实施例来示例性说明本发明的实施方案，对于本领域的普通技术人员而言，在本发明的教导下，根据现有技术，对本发明实施方案进行的改进，仍属于本发明的保护范围内。
实施例中使用的化合物原料的来源是：所有的试剂及起始原料为商购所得，式II化合物参考J.Org.Chem.2011,76,8311-8319的方法合成。
核磁共振氢谱数据是由BrukerAV‐300核磁共振波谱仪采集并处理。
实施例1MJ10803的合成
(1)中间体M811的合成
将起始原料4‐硝基苯二氯磷酸(S1,25.6g,0.1mol)用150ml无水处理的二氯甲烷溶解，降温至‐60℃，搅拌下缓慢滴加氘代苯酚‐d5(9.9g,0.1mol)和三乙胺(15ml,0.11mol)的45ml无水二氯甲烷溶液，滴加完毕，自然升温至‐5℃，反应3h。将丙氨酸异丙酯盐酸盐(16.8g,0.11mol)加入至反应液中，0℃下搅拌30min，滴加三乙胺(28.6ml,0.21mol)，5℃下反应3h，过滤不溶物，浓缩反应液，得油状物，硅胶柱层析得白色固体M811和M811D的混合物13.7g，混合物收率33.6％。
混合物用50ml二异丙醚溶解，搅拌降温至5℃，搅拌保温22h，进一步降温至‐10℃，搅拌降温44h，过滤，滤饼40℃减压干燥至恒重，得白色固体。
白色固体用40ml二异丙醚重结晶，缓慢降温至白色固体产生，进一步缓慢降温至‐10℃，保温16h，过滤，滤饼干燥，得白色固体8.1g，中间体M811，收率20.3％。MS(m/z)：414.2[M+1]+。
(2)中间体M812的合成
在反应瓶中加入核苷(S2,260mg,1mmol)，用6ml干燥四氢呋喃(THF)溶解，冰浴下，氮气保护，滴加1M的叔丁基氯化镁的四氢呋喃溶液2.5ml(2.5mmol)，加完，室温搅拌30min。中间体M811(537mg,1.3mmol)用6ml四氢呋喃溶解，滴加至反应液中，室温反应24h。冰浴下，用10ml饱和氯化铵淬灭反应，乙酸乙酯萃取，饱和碳酸氢钠溶液洗涤，无水硫酸钠干燥，浓缩，硅胶色谱柱分离，纯化得到目标化合物，中间体M812(135mg)，收率25.4％。MS(m/z)：535.3[M+1]+。
(3)中间体M813的合成
将Cbz‐Val‐OH(S3,251mg,1mmol)用2mlN,N‐二甲基甲酰胺(DMF)溶解，降温至‐5℃，搅拌下加入DIC(63.1mg,0.5mmol)，室温下反应30min，继续降温至‐5℃，依次加入中间体M812(267mg,0.5mmol)的2mlDMF溶液，三乙胺(60.7mg,0.6mmol)，催化量4‐二甲氨基吡啶(DMAP)，室温反应4h，反应结束倒入10ml水中，用10ml乙酸乙酯萃取3遍，合并有机层，无水硫酸钠干燥，旋干溶剂，得黄色固体，用硅胶柱层析分离，得到类白色粉末(中间体M813,205mg，收率53.4％。MS(m/z)：768.3[M+1]+。
(4)MJ10803的合成
将中间体M813(383mg,0.5mmol)用3ml甲醇溶解，加入5％Pd/C360mg，氢气下反应20min，反应结束后，过滤掉Pd/C，滤液旋干溶剂，用硅胶柱层析分离，得到白色粉末(MJ10803)153mg，收率48.3％。MS(m/z)：634.3[M+1]+；1H-NMR(DMSO-d6)δ：0.88-1.36(m,18H),1.86-1.93(m,1H),3.22-3.26(m,1H),3.76-3.83(m,2H),4.00-4.06(m,1H),4.21-4.31(m,2H),4.81-4.89(m,1H),5.33-5.51(m,1H),5.64-5.66(m,2H),6.03-6.11(m,2H),7.71-7.72(m,1H),7.96(s,1H)。
实施例2MJ10823的合成
(1)中间体M821的合成
丙氨酸氘代异丙酯盐酸盐‐d6由丙氨酸在氘代异丙醇‐d6中，用酸催化反应制得。
将起始原料4‐硝基苯二氯磷酸(S1,25.6g,0.1mol)用150ml无水处理的二氯甲烷溶解，降温至‐60℃，搅拌下缓慢滴加氘代苯酚‐d5(9.9g,0.1mol)和三乙胺(15ml,0.11mol)的45ml无水二氯甲烷溶液，滴加完毕，自然升温至‐5℃，反应3h。将丙氨酸氘代异丙酯盐酸盐‐d6(17.4g,0.11mol)加入至反应液中，0℃下搅拌30min，滴加三乙胺(28.6ml,0.21mol)，5℃下反应3h，过滤不溶物，浓缩反应液，得油状物，硅胶柱层析得白色固体M821和M821D的混合物12.9g，混合物收率30.8％。
混合物用50ml二异丙醚溶解，搅拌降温至5℃，搅拌保温22h，进一步降温至‐10℃，搅拌降温44h，过滤，滤饼40℃减压干燥至恒重，得白色固体。
白色固体用40ml二异丙醚重结晶，缓慢降温至白色固体产生，进一步缓慢降温至‐10℃，保温16h，过滤，滤饼干燥，得白色固体7.6g，中间体M821，收率18.1％。MS(m/z)：420.2[M+1]+。
(2)中间体M822的合成
以中间体M821为原料，同实施例1中间体M812的方法，制得目标化合物。MS(m/z)：541.3[M+1]+。
(3)中间体M823的合成
以中间体M822为原料，同实施例1中间体M813的方法，制得目标化合物。MS(m/z)：774.3[M+1]+。
(4)MJ10823的合成
以中间体M823为原料，同实施例1中MJ10803的方法，制得目标化合物。MS(m/z)：640.3[M+1]+；1H-NMR(DMSO-d6)δ：0.86-1.28(m,12H),1.83-1.90(m,1H),3.21-3.24(m,1H),3.77-3.82(m,2H),3.98-4.05(m,1H),4.23-4.28(m,2H),4.62(s,1H),5.32-5.52(m,1H),5.62-5.65(m,2H),6.01-6.09(m,2H),7.69-7.73(m,1H),7.93(s,1H)。
实施例3MJ10863的合成
以丙氨酸氘代异丙酯盐酸盐‐d7为原料，同实施例2中的方法，制得目标化合物。MS(m/z)：641.3[M+1]+。
丙氨酸氘代异丙酯盐酸盐‐d7由丙氨酸在氘代异丙醇‐d8中，用酸催化反应制得。
实施例4MJ10843的合成
以丙氨酸氘代异丙酯盐酸盐‐d6、苯酚为原料，同实施例1中的方法，制得目标化合物。MS(m/z)：635.3[M+1]+；1H-NMR(DMSO-d6)δ：0.89-1.29(m,12H),1.85-1.93(m,1H),3.23-3.25(m,1H),3.78-3.83(m,2H),4.00-4.08(m,1H),4.19-4.30(m,2H),4.58(s,1H),5.31-5.50(m,1H),5.63-5.68(m,2H),6.01-6.11(m,2H),7.15-7.21(m,3H),7.34-7.41(m,2H),7.69-7.73(m,1H),7.99(s,1H)。
丙氨酸氘代异丙酯盐酸盐‐d6由丙氨酸在氘代异丙醇‐d6中，用酸催化反应制得。
实施例5MJ10883的合成
以丙氨酸氘代异丙酯盐酸盐‐d7、苯酚为原料，同实施例1中的方法，制得目标化合物。MS(m/z)：636.3[M+1]+。
丙氨酸氘代异丙酯盐酸盐‐d7由丙氨酸在氘代异丙醇‐d8中，用酸催化反应制得。
实施例6其他化合物的合成
下表中化合物的合成同实施例1MJ10803,其不同之处在于采用不同的起始原料,不同对应的中间体,并且与不同的氨基酸进行缩合反应，脱保护，得目标产物。
实施例7大鼠灌胃给予测试化合物后肝脏中GS‐461203的含量测定
GS-461203是抗丙肝药索非布韦(sofosbuvir)在体内形成的活性代谢产物，它通过NS5B聚合酶可掺入至丙肝病毒的RNA中，发挥抗病毒作用。给药后肝脏中GS-461203的含量可以反映该化合物抗丙肝病毒作用的强弱。
108只SD大鼠，平均分成6组，以20mg/kg的剂量分别灌胃给予sofosbuvir、和专利化合物的供试液，并分别于给药后0.5、1、2、4、8、24小时时,通过吸入二氧化碳处死动物(3只/每时刻/组)，肝脏灌注冰浴生理盐水后摘取肝脏样本适量，立即放入-80℃环境下。
大鼠肝脏样本加冰浴70％甲醇水溶液(含EDTA等)，匀浆，离心，取上清液适量，挥干，以含0.1％甲酸的乙腈水溶液溶解，即为供试品溶液。
以LC/MS/MS法测定其中GS-461203的含量，并计算肝脏暴露量(AUC)，结果见表1。
表1大鼠灌胃给药后肝脏中GS-461203的暴露量(AUC)
| 化合物 | sofosbuvir | MJ10803 | MJ10823 | MJ10843 | MJ10863 | MJ10883 |
| 剂量(mg/kg) | 20 | 20 | 20 | 20 | 20 | 20 |
| AUC0-t(μg.h/g) | 15.4 | 30.4 | 28.7 | 31.2 | 33.8 | 30.8 |
专利化合物肝脏GS-461203AUC高于sofosbuvir，其中MJ10803组、MJ10823组、MJ10843组、MJ10863组和MJ10883组显著高于sofosbuvir组。
实施例8溶解度测定
Sofosbuvir在酸性和碱性条件下都无法成盐，中性水溶液中几乎不溶解，而专利化合物可以与酸成盐，增加其在水中的溶解度，在制剂上提供便利。
专利化合物盐酸盐的制备：将专利化合物的游离碱基用乙酸乙酯溶解，滴加氯化氢乙酸乙酯溶液，搅拌10min，加入石油醚，析出沉淀，沉淀用石油醚洗涤3遍，减压除去溶剂，得产品的盐酸盐。
参考标准溶液的配制：分别将sofosbuvir、专利化合物的盐酸盐，用甲醇溶解，配成0.5mg/ml的溶液。
将待测样品用水溶解，至底部有沉淀析出，过滤，以紫外分光光度法测定吸光系数，计算样品浓度，试验显示专利化合物的溶解度大于15mg/ml，MJ10803、MJ10823、MJ10843、MJ10863和MJ10883的结果见表2。
表2发明化合物溶解度
| 化合物 | sofosbuvir | MJ10803盐酸盐 | MJ10823盐酸盐 |
| 溶解度 | <2mg/ml | >15mg/ml | >15mg/ml |
| 化合物 | MJ10843盐酸盐 | MJ10863盐酸盐 | MJ10883盐酸盐 |
| 溶解度 | >15mg/ml | >15mg/ml | >15mg/ml |
Claims (10)
1.式I所示的化合物或其药学可接受的酸式盐、溶剂化物或水合物：
其中，
R1为C1～4烷基或氘代C1～4烷基；
R2为任意取代的苯基或萘基，其取代基选自氘、C1～4烷基、C1～4烷氧基；
且R1和R2中至少含有一个氘取代基；
R3为氨基酸酰基或多肽酰基。
2.根据权利要求1所述的化合物或其药学可接受的酸式盐、溶剂化物或水合物，其中，R1为甲基、乙基、丙基、异丙基、氘代甲基、氘代乙基或氘代异丙基，R2为苯基或氘代苯基，并且R1和R2中至少含有一个氘取代基。
3.根据权利要求2所述的化合物或其药学可接受的酸式盐、溶剂化物或水合物，其中，R1为-CH3、-CH2CH3、-CH(CH3)2、-CD3、-CD2CD3、-CH(CD3)2或-CD(CD3)2，R2为-C6H5或-C6D5，并且R1和R2中至少含有一个氘取代基。
4.根据权利要求1所述的化合物或其药学可接受的酸式盐、溶剂化物或水合物，其中，R3为天然氨基酸酰基、非天然氨基酸酰基或二肽酰基。
5.根据权利要求4所述的化合物或其药学可接受的酸式盐、溶剂化物或水合物，其中，R3为甘氨酰基、丙氨酰基、缬氨酰基、亮氨酰基、异亮氨酰基、苯丙氨酰基、色氨酰基、酪胺酰基、天冬氨酰基、天冬酰胺酰基、谷氨酰基、谷氨酰胺酰基、赖氨酰基、甲硫氨酰基、丝氨酰基、苏氨酰基、半胱氨酰基、脯氨酰基、组胺酰基或精氨酰基。
6.根据权利要求1所述的化合物或其药学可接受的酸式盐、溶剂化物或水合物，其中，R1为-CD3、-CD2CD3、-CH(CH3)2、-CH(CD3)2或-CD(CD3)2，R2为-C6H5或-C6D5，R3为甘氨酰基、丙氨酰基、缬氨酰基、亮氨酰基、异亮氨酰基、苯丙氨酰基、色氨酰基、酪胺酰基、天冬氨酰基、天冬酰胺酰基、谷氨酰基、谷氨酰胺酰基、赖氨酰基、甲硫氨酰基、丝氨酰基、苏氨酰基、半胱氨酰基、脯氨酰基、组胺酰基或精氨酰基。
7.根据权利要求1所述的化合物或其药学可接受的酸式盐、溶剂化物或水合物，其中，化合物选自：
8.一种药物组合物，其包含权利要求1～7中任一项所述的化合物或其药学可接受的酸式盐、溶剂合物或水合物。
9.权利要求1～7中任一项所述的化合物或其药学可接受的酸式盐、溶剂合物或水合物在制备预防或治疗哺乳动物病毒感染药物中的用途。
10.权利要求1～7中任一项所述的化合物或其药学可接受的酸式盐、溶剂合物或水合物在制备预防或治疗哺乳动物丙型肝炎、肝硬化或肝癌药物中的用途。
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| WO2017101785A1 (zh) * | 2015-12-15 | 2017-06-22 | 杭州和正医药有限公司 | 一种化合物、其制备方法、药物组合物及其用途 |
| CN106967141A (zh) * | 2016-05-16 | 2017-07-21 | 赵蕾 | 核苷氨基磷酸酯化合物及其医药组合物和用途 |
| CN108218940A (zh) * | 2016-12-13 | 2018-06-29 | 南京圣和药业股份有限公司 | 核苷氨基磷酸酯类化合物、其制备方法及用途 |
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| WO2017053834A1 (en) * | 2015-09-25 | 2017-03-30 | Board Of Regents Of The University Of Nebraska | Mibg analogs and uses thereof |
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| CN101918425A (zh) * | 2007-03-30 | 2010-12-15 | 法莫赛特股份有限公司 | 核苷氨基磷酸酯前药 |
| WO2013092481A1 (en) * | 2011-12-20 | 2013-06-27 | F. Hoffmann-La Roche Ag | 2',4'-difluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication |
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| CN101918425A (zh) * | 2007-03-30 | 2010-12-15 | 法莫赛特股份有限公司 | 核苷氨基磷酸酯前药 |
| WO2013092481A1 (en) * | 2011-12-20 | 2013-06-27 | F. Hoffmann-La Roche Ag | 2',4'-difluoro-2'-methyl substituted nucleoside derivatives as inhibitors of hcv rna replication |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017101785A1 (zh) * | 2015-12-15 | 2017-06-22 | 杭州和正医药有限公司 | 一种化合物、其制备方法、药物组合物及其用途 |
| CN106967141A (zh) * | 2016-05-16 | 2017-07-21 | 赵蕾 | 核苷氨基磷酸酯化合物及其医药组合物和用途 |
| CN106967141B (zh) * | 2016-05-16 | 2020-08-11 | 南京甘宁生物科技有限公司 | 核苷氨基磷酸酯化合物及其医药组合物和用途 |
| CN108218940A (zh) * | 2016-12-13 | 2018-06-29 | 南京圣和药业股份有限公司 | 核苷氨基磷酸酯类化合物、其制备方法及用途 |
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