CN112358481B - 长效恩替卡韦前药及其制备方法和应用 - Google Patents
长效恩替卡韦前药及其制备方法和应用 Download PDFInfo
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- CN112358481B CN112358481B CN202011240821.4A CN202011240821A CN112358481B CN 112358481 B CN112358481 B CN 112358481B CN 202011240821 A CN202011240821 A CN 202011240821A CN 112358481 B CN112358481 B CN 112358481B
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- entecavir
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Abstract
本发明涉及一种长效恩替卡韦前药及其制备方法和应用。该恩替卡韦前药具有式Ⅰ所示的结构，该化合物在体内能缓慢、持续、稳定地释放并转化为恩替卡韦原药，达到长效的目的。
在式I中，R1、R2和R3的定义如说明书所述。
Description
技术领域
本发明涉及药物化学领域，特别是涉及长效恩替卡韦前药及其制备方法和应用。
背景技术
恩替卡韦是一种用于治疗乙肝病毒(HBV)感染的新一代鸟嘌呤核苷类似物，主要用于病毒复制活跃、血清谷丙转氨酶(ALT)持续升高或肝脏组织学显示有活动性病变的慢性成人乙型肝炎的治疗。恩替卡韦与原有的核苷类似物比较具有抗病毒作用强、起效快、副作用小、临床耐药率低的优点，恩替卡韦能够强效抑制HBV，并且具有高耐药基因屏障。在乙肝治疗中，恩替卡韦作为一线抗病毒药物，是目前降病毒最快最强、变异几率最低的核苷类似物。恩替卡韦与食物同时服用会导致吸收延迟，Cmax降低44－46％，药时曲线下面积(AUC)降低18－20％。因此，本品需空腹服用(餐前或餐后至少2小时)，这也给患者带来了一定的不便。
我国是被世界公认的“乙肝大国”。在我国，慢性乙型肝炎病毒感染的人数约有1.3亿，其中3000万人患有慢性乙肝。根据最新的数据显示，我国每年因肝病死亡的人数接近50万，给社会造成损失高达1000亿元。
乙肝是一种慢性疾病，需要长期用药以控制感染者体内的病毒水平。目前在临床上，成人和16岁以上青少年感染者口服恩替卡韦需每天一次，每次0.5mg，根据病情，疗程可达6个月以上。为了提高患者服药的依从性，减少服药次数，降低病人少服、漏服的几率，更好地控制病人体内的病毒量，长效恩替卡韦有一定的市场需求。目前报道的研究方向主要集中在改善恩替卡韦的肝靶向性和提高生物利用度，尚无恩替卡韦长效制剂的上市，甚至在药化领域尚没有以长效为目的对恩替卡韦进行改造的报道。因此，本发明可填补这一空白。
发明内容
本发明通过对恩替卡韦的结构进行改造，制备出具有长效属性的前体药物。此类药物具有水难溶性特点，在体内可缓慢、持续、稳定地释放并转化为恩替卡韦。
本发明采取以下技术方案：
一方面，本发明提供一种恩替卡韦前药或其药学上可接受的盐或立体异构体，所述恩替卡韦前药的结构式如式I所示，
其中，
R1选自氢和C(O)XY，X选自O、NH、(CH2)m和化学键，Y选自C7-C30的支链或直链的饱和或不饱和烷基、C7-C30的取代烷基和甾体类脂肪链；
R2选自氢和C(O)XY，X选自O、NH、(CH2)m和化学键，Y选自C9-C30的支链或直链的饱和或不饱和烷基、C9-C30的取代烷基和甾体类脂肪链；
R3选自氢和C(O)XY，X选自O和NH，Y选自C10-C30的支链或直链的饱和或不饱和烷基以及C10-C30的取代烷基；
所述取代烷基任选地被选自：氧、氮、硫、卤素、胺基、酰胺基(NHCOR或CONHR)、羰基、酯基、环烷基、芳基和芳杂环的取代基取代；
其中，m为1-6的整数，R为C1-C26的支链或直链的饱和或不饱和烷基。
在其中一些实施方案中，R1选自氢和C(O)XY，X选自O、(CH2)m和化学键，Y选自C9-C29的支链或直链的饱和或不饱和烷基、C9-C29的取代烷基和胆烷类脂肪链；
R2选自氢和C(O)XY，X选自O、(CH2)m和化学键，Y选自C11-C29的支链或直链的饱和或不饱和烷基、C11-C29的取代烷基和胆烷类脂肪链；
R3选自氢和C(O)XY，X选自O和NH，Y选自C10-C28的支链或直链的饱和或不饱和烷基以及C10-C28的取代烷基；
所述取代烷基任选地被选自：氧、氮、硫、氯、氟、胺基、酰胺基(NHCOR或CONHR)、羰基、酯基、环烷基、芳基和芳杂环的取代基取代；
其中，m为1-6的整数，R为C1-C26的支链或直链的饱和或不饱和烷基。
在其中一些实施方案中，R1选自氢和C(O)XY，X选自O、(CH2)m和化学键，Y选自C9-C27的支链或直链的饱和或不饱和烷基、C9-C27的取代烷基和胆烷类脂肪链；
R2选自氢和C(O)XY，X选自O、(CH2)m和化学键，Y选自C13-C21的支链或直链的饱和或不饱和烷基、C13-C21的取代烷基和胆烷类脂肪链；
R3选自氢和C(O)XY，X选自O和NH，Y选自C11-C19的支链或直链的饱和或不饱和烷基以及C11-C19的取代烷基；
所述取代烷基任选地被选自：氧、氮、硫、氟、氯、胺基、NHCOR、CONHR、羰基、酯基、环烷基、芳基和芳杂环的取代基取代；
其中，m为1-6的整数，R为C1-C26的支链或直链的饱和或不饱和烷基。
在其中一些实施方案中，当R1为C(O)XY时，R2和R3均为氢，当R2为C(O)XY时，R1和R3均为氢，当R3为C(O)XY时，R1和R2均为氢；
在其中一些实施方案中，R1为C(O)XY，X为O或化学键，Y为C11-C25的支链或直链的饱和或不饱和烷基，R2和R3均为氢。
在其中一些实施方案中，R1为CH3-(CH2)n-CONH-(CH2)m-CO，其中，n为6至22的整数，m为1至6的整数，R2和R3均为氢；
优选地，R1为CH3-(CH2)n-CONH-(CH2)m-CO，其中，n为10至20的整数，m为1至3的整数，R2和R3均为氢。
在其中一些实施方案中，R1为C(O)XY，X为化学键，Y选自以下胆烷类脂肪链：
在其中一些实施方案中，R1为芳基取代的烷基，优选为萘基取代的烷基，更优选为萘基-C1-C3烷基。
在其中一些实施方案中，R2或R3独立地为C(O)XY，X为化学键，Y为C13-C19的支链或直链的饱和或不饱和烷基，且R2和R3中有一个为氢，R1为氢；
在其中一些实施方案中，R3为C(O)XY，X为O；
在其中一些实施方案中，式I所示的化合物选自如下结构之一：
另一方面，本发明提供一种制备上述恩替卡韦前药的方法，该方法是采用恩替卡韦或保护的恩替卡韦与有机酸在缩合剂的作用下或恩替卡韦或保护的恩替卡韦与酰氯以有机碱为辅酸剂的条件下来制备。
其中，有机酸选自前述的R1和R2相对应酸的部分。
其中，缩合剂选自EDCI，DCC，DIC，CDI，PyBOP，PyBrOP，HATU，HCTU，DEPBT，EEDQ，氯甲酸乙酯，氯甲酸异丙酯，氯甲酸异丁酯等。
其中，有机碱选自三乙胺，二异丙基乙基胺，吡啶，N-甲基吗啉，DBU等。
又一方面，本发明提供包含前述式I化合物(恩替卡韦前药)或者其药学上可接受的盐或立体异构体以及药学上可接受的载体或赋形剂的药物组合物；优选地，所述药物组合物为溶液型注射液、混悬型注射液、注射用无菌粉末。
在某些具体的实施方案中，上述药物组合物，以低溶解度的恩替卡韦前药为活性成分，配合悬浮溶剂和药学上可接受的辅料制成可供肌内注射或皮下注射的混悬液体，在体内形成一个药物贮库，前药从贮库中缓慢释放，在体内酶解成原药进而发挥疗效，达到了发挥长效治疗的目的。
再一方面，本发明还提供前述式I化合物(恩替卡韦前药)或者其药学上可接受的盐或立体异构体在制备用于预防和/或治疗乙肝的药物中的应用。优选地，所述药物为长效药物。
与现有技术相比，本发明具有以下有益效果：
本发明的恩替卡韦前药，其溶解度低，能够通过制成注射剂给药后，在体内形成一个药物贮库，延长了药物在体内的释放速度，达到了发挥长效治疗的目的。
附图的简要说明
图1为比格犬给药恩替卡韦-5’-二十二酸酯后恩替卡韦的血药浓度变化；以及
图2为比格犬给药恩替卡韦-5’-熊去氧胆酸酯后恩替卡韦的血药浓度变化。
具体实施方式
以下实施例对本发明做进一步的描述，但该实施例并非用于限制本发明的保护范围。
实施例1恩替卡韦-5’-棕榈酸酯的制备
于50mL单口瓶中，将690mg棕榈酸加入5mL氯化亚砜中，升温至78℃，搅拌反应1～2小时，反应完毕，减压浓缩至干，加DCM 5mL继续减压浓缩，用油泵抽真空1小时，制得酰氯待用。将恩替卡韦500mg加至10mL吡啶中，加催化量DMAP。降温至0℃，将制得酰氯滴加至反应瓶中。搅拌反应半小时后，升温至室温，搅拌反应过夜。
反应完毕加水和二氯甲烷萃取，饱和碳酸氢钠洗涤，饱和氯化钠洗涤。有机相用无水硫酸钠干燥，减压浓缩至干，柱层析：二氯甲烷：甲醇(体积比20：1～10:1)梯度洗脱，收集10：1的洗脱部分，得化合物1恩替卡韦-5’-棕榈酸酯105mg，产率11.29％。
1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),7.65(s,1H),6.47(s,2H),5.44–5.33(m,1H),5.14(s,1H),5.10(d,J＝2.8Hz,2H),4.63(s,1H),4.18(m,3H),2.74(s,1H),2.32(m,3H),2.15–2.03(m,1H),1.59–1.45(m,2H),1.21(s,24H),0.84(t,J＝6.8Hz,3H).
实施例2恩替卡韦-5’-硬脂酸酯的制备
参照实施例1的方法，用硬脂酸代替棕榈酸反应，反应产物经分离纯化得到化合物2恩替卡韦-5’-硬脂酸酯，产率25.50％。
1H NMR(400MHz,DMSO-d6)δ10.65(s,1H),7.66(s,1H),6.47(s,2H),5.43–5.33(m,1H),5.15(s,1H),5.10(d,J＝3.2Hz,1H),4.62(s,1H),4.18(m,3H),2.74(s,1H),2.36–2.24(m,3H),2.13–2.04(m,1H),1.58–1.49(m,2H),1.23(s,28H),0.84(t,J＝6.8Hz,3H).
实施例3恩替卡韦-5’-花生酸酯的制备
参照实施例1的方法，用花生酸代替棕榈酸反应，反应产物经分离纯化得到化合物3恩替卡韦-5’-花生酸酯，产率29.10％。
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),7.66(s,1H),6.40(s,2H),5.38(m,1H),5.15(s,1H),5.08(d,J＝3.2Hz,1H),4.62(s,1H),4.18(m,3H),2.73(s,1H),2.34–2.25(m,3H),2.15–2.01(m,1H),1.63–1.46(m,2H),1.23(s,32H),0.85(t,J＝6.8Hz,3H).
实施例4恩替卡韦-5’-二十二酸酯的制备
参照实施例1的方法，用二十二酸代替棕榈酸反应，反应产物经分离纯化得到化合物4恩替卡韦-5’-二十二酸酯，产率30.50％。
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),7.66(s,1H),6.41(s,2H),5.38(t,J＝8.9Hz,1H),5.15(s,1H),5.08(d,J＝3.2Hz,1H),4.62(s,1H),4.18(m,3H),2.70(d,J＝23.4Hz,1H),2.38–2.25(m,3H),2.15–2.00(m,1H),1.59–1.45(m,2H),1.22(s,36H),0.85(t,J＝6.7Hz,3H).
实施例5恩替卡韦-5’-熊去氧胆酸酯的制备
于250mL单口反应瓶中，将710mg去氧熊胆酸、500mg恩替卡韦、350mg EDCI、0.3mLDIPEA、催化量的DMAP溶于90mL DMF，搅拌反应18h。TLC检测，有一半反应完，继续搅拌至基本不再反应。
加1mL甲醇淬灭反应1h，反应完毕，加水和DCM萃取，有固体析出，固体可溶于甲醇，收集固体。TLC检测固体、有机相和水相，产品基本都在固体相。将固体相蒸干后，柱层析，二氯甲烷：甲醇(体积比10：1～7:1)，梯度洗脱，收集7:1部分。得化合物5恩替卡韦-5’-熊去氧胆酸酯300mg，产率25.53％。
1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.66(s,1H),6.41(s,2H),5.37(t,J＝9.1Hz,1H),5.15(s,1H),5.07(d,J＝3.2Hz,1H),4.61(s,1H),4.43(d,J＝4.6Hz,1H),4.17(m,3H),3.86(d,J＝6.8Hz,1H),3.31–3.23(m,2H),2.73(s,1H),2.42–2.20(m,3H),2.12–2.03(m,1H),1.92(d,J＝11.6Hz,1H),1.88–1.77(m,1H),1.77–1.59(m,4H),1.47–1.34(m,18H),0.89(d,J＝6.5Hz,4H),0.86(s,3H),0.60(s,3H).
实施例6恩替卡韦-5’-油酸酯的制备
参照实施例1的方法，用油酸代替棕榈酸反应，反应产物经分离纯化得到化合物6恩替卡韦-5’-油酸酯，产率21.98％。
1H NMR(400MHz,DMSO-d6)δ10.86(s,1H),7.64(s,1H),6.70(s,2H),5.44–5.24(m,3H),5.23–5.09(m,2H),4.60(t,J＝2.3Hz,1H),4.25–4.09(m,3H),2.71(s,1H),2.38–2.22(m,3H),2.08(m,1H),1.98(m,4H),1.51(m,2H),1.38–1.11(m,20H),0.84(t,J＝6.9Hz,3H).
实施例7恩替卡韦-5’-萘乙酸酯的制备
参照实施例1的方法，用萘乙酸代替棕榈酸反应，反应产物经分离纯化得到化合物7恩替卡韦-5’-萘乙酸酯，产率18.85％。
1H NMR(400MHz,DMSO-d6)δ10.81(br,1H),7.94(dt,J＝6.7,2.4Hz,2H),7.85(dd,J＝6.3,3.3Hz,1H),7.56(s,1H),7.52(dt,J＝6.5,3.6Hz,2H),7.48–7.42(m,2H),6.65(s,2H),5.33(t,J＝9.3Hz,1H),5.17(d,J＝3.2Hz,1H),5.00(t,J＝2.4Hz,1H),4.50(t,J＝2.5Hz,1H),4.28–4.13(m,4H),4.10(s,1H),2.80–2.69(m,1H),2.14(td,J＝12.0,11.4,4.9Hz,1H),2.06–1.90(m,1H).
实施例8恩替卡韦-5’-棕榈酰甘氨酸酯的制备
50mL单口瓶中加入甘氨酸甲酯盐酸盐(0.73g)、棕榈酸(1g)、DCC(1.21g)、DMAP(95mg)，加入20mL THF和DIPEA(1.51g)，室温搅拌过夜。过滤，滤液旋干，加DCM溶解，依次用水、稀盐酸、饱和碳酸氢钠、饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，甲醇重结晶得0.35g棕榈酰甘氨酸甲酯。
将上述0.35g棕榈酰甘氨酸甲酯溶于10mL THF中，将50mg氢氧化锂一水合物溶于5mL水，滴加至反应液中，室温搅拌3h，停止反应。加稀盐酸调pH至1-2，析出固体，过滤，干燥得棕榈酰甘氨酸。
50mL单口瓶中加入恩替卡韦88mg、棕榈酰甘氨酸100mg，加10mL DMF溶解，加EDCI(612mg)、HOBT(431mg)、TEA(0.44mL)，室温搅拌过夜。旋干，加DCM溶解，依次用稀盐酸、饱和碳酸氢钠、饱和食盐水洗，无水硫酸钠干燥，过滤，旋干，过柱得化合物8恩替卡韦-5’-棕榈酰甘氨酸酯43mg，产率23.63％。
1H NMR(400MHz,DMSO-d6)δ10.66(s,1H),7.65(s,1H),6.47(s,2H),5.44–5.33(m,1H),5.19–5.05(m,2H),4.63(s,1H),4.18(dt,J＝6.5,4.0Hz,3H),3.61(s,2H),3.08(d,J＝7.3Hz,1H),2.74(s,1H),2.32(t,J＝7.3Hz,3H),2.15–2.03(m,1H),1.59–1.45(m,2H),1.21(d,J＝10.2Hz,28H),0.84(s,3H).
实施例9恩替卡韦-3’-棕榈酸酯的制备
将1g恩替卡韦溶于10mL吡啶中，加1.4g(2.4eq)的TBSCl，搅拌反应2h，TLC检测原料基本消失，生产两个点。加甲醇终止反应，加水和DCM萃取，有机相用饱和碳酸氢钠，饱和氯化钠洗，溶液用无水硫酸钠干燥。减压浓缩至干，过柱，得到0.8g化合物9。
于50mL单口瓶中，将167mg棕榈酸加1mL氯化亚砜中，升温至78℃，搅拌反应1～2小时，反应完毕，减压浓缩至干，加DCM 5mL继续减压浓缩，用油泵抽真空1小时，制得酰氯待用。将200mg化合物9加至10mL吡啶中，加催化量DMAP。降温至0℃，将制得酰氯滴加至反应瓶中。搅拌反应半小时后，升温至室温，搅拌反应过夜。后处理反应完毕加水和二氯甲烷萃取，饱和碳酸氢钠洗，饱和氯化钠洗。有机相用无水硫酸钠干燥，减压浓缩至干，得350mg化合物10。
将350mg化合物10溶于5mL DCM中,加266mg三乙胺三氟化氢，室温搅拌过夜。依次用水、饱和碳酸氢钠、饱和食盐水洗，有机相用无水硫酸钠干燥后，过滤浓缩至干，柱层析，二氯甲烷：甲醇(体积比30:1～10：1)，收集10：1的洗脱部分，浓缩，得化合物11恩替卡韦-3’-棕榈酸酯130mg，总产率28.00％。
1H NMR(500MHz,DMSO-d6)δ10.61(s,1H),7.70(s,1H),6.43(s,2H),5.25–5.26(m,2H),5.16(s,1H),5.00(t,J＝5.0Hz,1H),4.61(s,1H),3.62(t,J＝5.7Hz,2H),2.67(s,1H),2.50(m,1H),2.28(t,J＝7.3Hz,2H),2.19(m,1H),1.58–1.46(m,2H),1.22(d,J＝13.2Hz,24H),0.84(t,J＝6.9Hz,3H).
实施例10恩替卡韦-3’-硬脂酸酯的制备
参照实施例9的方法，用硬脂酸代替棕榈酸反应，反应产物经分离纯化得到化合物13恩替卡韦-3’-硬脂酸酯，总产率22.44％。
1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.70(s,1H),6.42(s,2H),5.27(m,2H),5.16(s,1H),4.99(t,J＝4.9Hz,1H),4.61(s,1H),3.62(t,J＝5.2Hz,2H),2.67(s,1H),2.50(m,1H),2.29(d,J＝7.0Hz,2H),2.19(m,1H),1.52(s,2H),1.22(s,28H),0.84(t,J＝6.3Hz,3H).
实施例11恩替卡韦-2-氨基甲酸十二烷基酯的制备
于50mL单口瓶中，加恩替卡韦400mg，加吡啶10mL，加0.67mL TMSCl，搅拌反应3h，TLC检测，基本反应完全，加氯甲酸十二烷基酯0.6mL，搅拌反应过夜，反应完毕。
加甲醇淬灭反应，升温至45℃搅拌反应1h，反应完毕，加二氯甲烷和水萃取，有机相分别用饱和碳酸氢钠，饱和氯化钠洗萃取，有机相用无水硫酸钠干燥，浓缩至干，柱层析，二氯甲烷：甲醇(体积比8:1～5:1)梯度洗脱，收集5：1的洗脱部分，浓缩，得化合物14恩替卡韦-2-氨基甲酸十二烷基酯200mg，产率18.41％。
1H NMR(500MHz,DMSO-d6)δ11.35(br,1H),7.93(s,1H),5.44(t,J＝8.9Hz,1H),5.10(s,1H),4.93(s,1H),4.86(s,1H),4.53(s,1H),4.26(s,1H),4.15(t,J＝6.3Hz,2H),3.54(s,2H),2.54(s,1H),2.31(m,1H),2.12–2.04(m,1H),1.61(t,J＝6.7Hz,2H),1.32(d,J＝6.5Hz,2H),1.23(s,18H),0.84(t,J＝6.7Hz,3H).
实施例12恩替卡韦-5’-碳酸十二烷酯的制备
25mL二颈反应瓶中，加入恩替卡韦100mg，氮气保护，室温条件下，注入吡啶6mL，滴加氯甲酸十二烷基酯107.6mg(溶于2mL二氯甲烷中)(1.2当量)，室温搅拌过夜，反应液旋干至无吡啶，加入二氯甲烷10mL，异丙醇2mL，饱和碳酸氢钠5mL搅拌5分钟，分出有机相，用饱和氯化钠5mL洗涤，无水硫酸钠干燥，TLC制备，得白色固体15.4mg。收率：8.72％。
1H NMR(400MHz,DMSO-d6)δ10.65(br,1H),7.65(s,1H),6.47(s,2H),5.43–5.33(m,1H),5.16(s,1H),5.12(d,J＝2.8Hz,1H),4.62(s,1H),4.30–4.19(m,2H),4.16(s,1H),4.09(t,J＝6.8Hz,2H),2.77(s,1H),2.31(ddd,J＝12.6,10.5,4.7Hz,1H),2.13–2.03(m,1H),1.59(p,J＝6.8Hz,2H),1.25(m,18H),0.85(t,J＝6.8Hz,3H).
实施例13恩替卡韦-5’-二十六酸酯的制备
参照实施例1的方法，用二十六酸代替棕榈酸反应，反应产物经分离纯化得到化合物16恩替卡韦-5’-二十六酸酯，产率21.33％。
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),7.66(s,1H),6.40(s,2H),5.38(t,J＝8.9Hz,1H),5.14(s,1H),5.08(d,J＝3.2Hz,1H),4.62(s,1H),4.18(m,3H),2.73(d,J＝23.4Hz,1H),2.34–2.26(m,3H),2.10–2.05(m,1H),1.55–1.51(m,2H),1.22(s,44H),0.85(t,J＝6.7Hz,3H).
实施例14恩替卡韦-5’-三十酸酯的制备
参照实施例1的方法，用二十六酸代替棕榈酸反应，反应产物经分离纯化得到化合物17恩替卡韦-5’-三十酸酯，产率16.59％。
1H NMR(400MHz,DMSO-d6)δ10.58(s,1H),7.65(s,1H),6.40(s,2H),5.37(t,J＝8.9Hz,1H),5.14(s,1H),5.08(d,J＝3.2Hz,1H),4.61(s,1H),4.18(m,3H),2.73(s,1H),2.34–2.26(m,3H),2.10–2.04(m,1H),1.54–1.51(m,2H),1.22(s,52H),0.85(t,J＝6.7Hz,3H).
实施例15恩替卡韦-5’-鹅去氧胆酸酯的制备
参照实施例5的方法，用鹅去氧胆酸代替熊去氧胆酸反应，反应产物经分离纯化得到化合物18恩替卡韦-5’-鹅去氧胆酸酯，总产率20.09％。
1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.66(s,1H),6.41(s,2H),5.37(t,J＝9.1Hz,1H),5.15(s,1H),5.07(d,J＝3.2Hz,1H),4.61(s,1H),4.43(d,J＝4.6Hz,1H),4.17(m,3H),3.86(d,J＝6.8Hz,1H),3.31–3.23(m,2H),2.73(s,1H),2.42–2.20(m,3H),2.12–2.03(m,1H),1.92(d,J＝11.6Hz,1H),1.88–1.77(m,1H),1.77–1.59(m,4H),1.47–1.34(m,18H),0.89(d,J＝6.5Hz,4H),0.86(s,3H),0.60(s,3H).
实施例16恩替卡韦-5’-猪去氧胆酸酯的制备
参照实施例5的方法，用猪去氧胆酸代替熊去氧胆酸反应，反应产物经分离纯化得到化合物19恩替卡韦-5’-猪去氧胆酸酯，总产率23.50％。
1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.66(s,1H),6.41(s,2H),5.37(t,J＝9.1Hz,1H),5.15(s,1H),5.07(d,J＝3.2Hz,1H),4.61(s,1H),4.23(d,J＝4.6Hz,1H),4.17(m,3H),3.66(d,J＝6.8Hz,1H),3.31–3.23(m,2H),2.73(s,1H),2.42–2.20(m,3H),2.12–2.03(m,1H),1.92(d,J＝11.6Hz,1H),1.88–1.77(m,1H),1.77–1.59(m,4H),1.47–1.34(m,18H),0.89(d,J＝6.5Hz,4H),0.86(s,3H),0.60(s,3H).
实施例17恩替卡韦-5’-去氧胆酸酯的制备
参照实施例5的方法，用去氧胆酸代替熊去氧胆酸反应，反应产物经分离纯化得到化合物20恩替卡韦-5’-去氧胆酸酯，总产率17.95％。
1H NMR(500MHz,DMSO-d6)δ10.59(s,1H),7.66(s,1H),6.41(s,2H),5.37(t,J＝9.1Hz,1H),5.15(s,1H),5.07(d,J＝3.2Hz,1H),4.61(s,1H),4.37(d,J＝4.6Hz,1H),4.17(m,3H),3.80(d,J＝6.8Hz,1H),3.31–3.23(m,2H),2.73(s,1H),2.42–2.20(m,3H),2.12–2.03(m,1H),1.92(d,J＝11.6Hz,1H),1.88–1.77(m,1H),1.77–1.59(m,4H),1.57–1.34(m,18H),0.89(d,J＝6.5Hz,4H),0.86(s,3H),0.68(s,3H).
实施例18恩替卡韦-5’-二十二酸酯和恩替卡韦-5’-熊去氧胆酸酯体内药代试验
本试验采用普通级雄性比格犬2只，给药前禁食12h，饮水自由。将恩替卡韦-5’-二十二酸酯(由实施例4制备)和恩替卡韦-5’-熊去氧胆酸酯(由实施例5制备)制备成混悬溶液，分别按0.508mg/kg和0.552mg/kg的给药剂量肌肉注射。给药前及给药后1h,2h,4h,8h,12h,24h,48h,96h,144h,192h，240h，288h，360h，比格犬经前肢静脉采全血约1.0mL，置肝素化离心管中，6000rpm离心10min，分离血浆，-80℃保存待测。
血浆样品处理：取20μL甲醇-水(V:V,1:1)，20μL内标(芹菜素2μg/mL)，加入100μL血浆样品，涡旋混合，加入200μL甲醇，涡旋混合，14,000g离心力离心30min，取上清液10μL进样分析。结果见表1、表2及图1和图2。
表1.比格犬肌肉注射恩替卡韦-5’-二十二酸酯(0.508mg/kg)后恩替卡韦的血药浓度
表2.比格犬肌肉注射恩替卡韦-5’-熊去氧胆酸酯(0.552mg/kg)后恩替卡韦的血药浓度
试验结论：恩替卡韦-5’-二十二酸酯注射用混悬剂和恩替卡韦-5’-熊去氧胆酸酯注射用混悬剂在比格犬肌肉注射后能持续、平稳地释放，从而达到长效的目的。
Claims (9)
1.式I所示的化合物或其药学上可接受的盐：
其中，R1为CH3-(CH2)n-CONH-(CH2)m-CO，其中，n为6至22的整数，m为1至6的整数，R2和R3均为氢。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其特征在于，R1为CH3-(CH2)n-CONH-(CH2)m-CO，其中，n为10至20的整数，m为1至3的整数，R2和R3均为氢。
3.根据权利要求1或2所述的化合物或其药学上可接受的盐，其特征在于，式I所示的化合物选自如下结构：
4.式I所示的化合物或其药学上可接受的盐：
其中，R1为C(O)XY，X为化学键，Y选自C7-C30的支链或直链的饱和或不饱和烷基；R2和R3均为氢，
其中，所述化合物不为[(1R，3S，5S)-3-(2-氨基-6-氧代-1H-嘌呤-9(6H)-基)-5-羟基-2-亚甲基环戊基]辛酸甲酯、[(1R，3S，5S)-3-(2-氨基-6-氧代-1H-嘌呤-9(6H)-基)-5-羟基-2-亚甲基环戊基]癸酸甲酯、[(1R，3S，5S)-3-(2-氨基-6-氧代-1H-嘌呤-9(6H)-基)-5-羟基-2-亚甲基环戊基]十二酸甲酯、[(1R，3S，5S)-3-(2-氨基-6-氧代-1H-嘌呤-9(6H)-基)-5-羟基-2-亚甲基环戊基]十四酸甲酯、[(1R，3S，5S)-3-(2-氨基-6-氧代-1H-嘌呤-9(6H)-基)-5-羟基-2-亚甲基环戊基]十六酸甲酯或[(1R，3S，5S)-3-(2-氨基-6-氧代-1H-嘌呤-9(6H)-基)-5-羟基-2-亚甲基环戊基]十八酸甲酯。
5.根据权利要求4所述的化合物或其药学上可接受的盐，其特征在于，Y选自C9-C29的支链或直链的饱和或不饱和烷基。
6.根据权利要求4或5所述的化合物或其药学上可接受的盐，其特征在于，Y选自C9-C27的支链或直链的饱和或不饱和烷基。
7.包含如权利要求1至6中任一项所述的化合物或者其药学上可接受的盐以及药学上可接受的载体或赋形剂的药物组合物。
8.根据权利要求7所述的药物组合物，其特征在于，所述药物组合物为溶液型注射液、混悬型注射液、注射用无菌粉末。
9.根据权利要求1至6中任一项所述的化合物或者其药学上可接受的盐和/或权利要求7或8所述的药物组合物在制备用于预防和/或治疗乙肝的药物中的应用。
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