CN1255422C - 核苷 - Google Patents

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CN1255422C
CN1255422C CNB998028851A CN99802885A CN1255422C CN 1255422 C CN1255422 C CN 1255422C CN B998028851 A CNB998028851 A CN B998028851A CN 99802885 A CN99802885 A CN 99802885A CN 1255422 C CN1255422 C CN 1255422C
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deoxidations
acid
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oxygen base
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CN1290268A (zh
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H·维林
周晓雄
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Medivir AB
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Abstract

其中R各自独立地为H或-CH3的式(I)化合物及其可药用盐具有优良的药理特征，并且具有抗HBV和HIV的抗病毒活性。

Description

核苷
                        技术领域
本发明涉及核苷类似物，例如包括逆病毒逆转录酶抑制剂和乙肝病毒(HBV)DNA聚合酶抑制剂在内的抗病毒核苷类似物。本发明提供了具有有价值药物参数的新化合物、其制备方法、含有所述化合物的药物组合物、以及使用这些化合物来抑制包括HBV和HIV在内的病毒性和肿瘤性疾病的方法。
                        背景技术
国际专利申请WO 88/00050公开了具有抗逆病毒和抗HBV活性的一系列3’-氟代核苷，包括化合物2’，3’-二去氧，3’-氟鸟嘌呤核苷(FLG)和3’-氟胸苷(FLT)。3’-氟胸苷作为抗HIV剂进行过临床试验，虽然其抗病毒活性和药物代谢动力学特性良好，但是其表现出很强毒性(Flexner等人，J Inf Dis 170(6)1394-403(1994))。前一化合物FLG在体外的活性很强，然而本发明者们已经发现，其生物利用率不好，约为4％，因此该化合物的体内使用被严重限制到腹膜内和皮下给药的动物模型。
US 4963662总的公开了一系列3’-氟代核苷和相应的三磷酸盐，并具体公开了FLT的5’-O-棕榈酰衍生物的制备，但是没有报道在生物利用率方面有任何改善。国际专利申请WO 9313778公开了在6-位被修饰的FLG衍生物，尤其是用正丙氧基、环丁氧基、环丙基氨基、哌啶基或吡咯烷基修饰的衍生物。国际专利申请WO 9314103公开了其中鸟嘌呤6-位上的氧被氨基、醚基、卤素或磺酸根替代的FLG衍生物。
本申请人尚未公开的国际专利申请PCT/SE 98/01467、TH 45550和TW 87113427描述了FLG的前药，其中包含接头结构和一个或两个脂肪族氨基酸。在这些未出版专利申请中描述的广义化合物当中，我们已经发现了特别合适的前药，其具有优良生物利用率，同时又产生性质相同的代谢降解产物。换句话说，该代谢副产物与身体所产生的具有有效调节和消除机制的化合物相同。
                        发明简述
本发明提供了式I化合物及其可药用盐：
Figure C9980288500041
其中：
R独立地为H或-CH3。
本发明还提供了包含式I化合物及其盐和可药用载体或稀释剂的药物组合物。另一方面，本发明提供了抑制HBV和逆病毒，例如HIV的方法，包括例如把有效量的式I化合物或其盐给予感染有逆病毒或HBV的个体，来将式I化合物或其盐与逆病毒或HBV接触。本发明还提供了式I化合物或其盐在治疗中的应用，例如在制备用于治疗逆病毒或HBV感染的药物中的应用。
在治疗由逆病毒例如HIV、或HBV引起的病症时，优选以每次50-1500mg、每天2次或3次，尤其是每次100-700mg、每天2次或3次的方式将式I化合物或其盐给药。希望获得0.01-100μg/ml、尤其是0.1-5μg/ml的活性代谢物血清水平。
优选的式I化合物包括：
5’-O-[(S，R)2，3-二(L-缬氨酰氧基)丙酰基]-2’，3’-二去氧-3’-氟鸟嘌呤核苷，
5’-O-[(S，R)2，3-二(L-异亮氨酰氧基)丙酰基]-2’，3’-二去氧-3’-氟鸟嘌呤核苷，最优选
5’-O-[(R)2，3-二(L-缬氨酰氧基)丙酰基]-2’，3’-二去氧-3’-氟鸟嘌呤核苷，
5’-O-[(R)2，3-二(L-异亮氨酰氧基)丙酰基]-2’，3’-二去氧-3’-氟鸟嘌呤核苷；
及其可药用盐。
本发明化合物可形成盐，所述盐构成了本发明的另一方面。式I化合物的适宜药用盐包括有机酸盐、尤其是羧酸盐，包括(但不限于)乙酸盐、三氟乙酸盐、乳酸盐、葡糖酸盐、柠檬酸盐、酒石酸盐、马来酸盐、苹果酸盐、泛酸盐、羟乙基磺酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、丁酸盐、双葡糖酸盐、环戊甲酸盐、葡庚糖酸盐、甘油磷酸盐、草酸盐、庚酸盐、己酸盐、富马酸盐、烟酸盐、棕榈酸盐、果胶酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、酒石酸盐、乳二糖酸盐、新戊酸盐、樟脑酸盐、十一烷酸盐和琥珀酸盐，有机磺酸盐，例如甲磺酸盐、乙磺酸盐、2-羟基乙磺酸盐、樟脑磺酸盐、2-萘磺酸盐、苯磺酸盐、对氯苯磺酸盐或对甲苯磺酸盐；和无机酸盐，例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、半硫酸盐、硫氰酸盐、过硫酸盐、磷酸盐和磺酸盐。式I化合物在有些情况下是以水合物形式分离出的。
保持逆病毒和HBV抑制剂的惯常使用法，将其与一种或多种其它抗病毒剂联合给药是有利的，对于HIV，所述其它抗病毒剂有例如AZT、ddI、ddC、d4T、3TC、H2G、阿巴卡韦(abacavir)、ABT 606、磷卡萘替(foscarnet)、羟基脲、里托纳韦(ritonavir)、英迪纳韦(indinavir)、沙喹纳韦(saquinavir)、奈韦拉平(nevirapine)、德拉韦里定(delaviridine)、MIV 150、依法韦瑞(efavirenz)、Vertex VX 478/安普瑞拉韦(amprenavir)或Agouron AG 1343等；对于HBV，所述其它抗病毒剂有例如拉米夫定(lamivudine)、干扰素、泛西洛维(famciclovir)、阿达弗韦(adefovir)、洛比可韦(lobucovir)、BMS 200475L-FMAU、FTC、DAPD、Nabi 3700001等。
所述其它抗病毒剂通常以能最大地反映各自治疗价值的彼此相关的剂量给药。所述其它抗病毒剂与式I化合物或其盐的摩尔比为100∶1-1∶100、尤其是25∶1-1∶25通常是适当的。其它抗病毒剂的给药通常与用于治疗疱疹感染的抗病毒核苷给药没多少共同性。
虽然活性剂可单独给药，但是优选将活性剂作为药物制剂的一部分给药。这种药物制剂包含上述活性剂和一种或多种可药用载体/赋形剂，并任选包含其它治疗组分。载体必须与制剂中的其它组分相配伍并对使用者无害。
制剂包括适于直肠给药、鼻内给药、局部给药(包括颊给药和舌下给药)、阴道给药或非胃肠道给药(包括皮下给药、肌内给药、静脉内给药和真皮内给药)的制剂，但是所述制剂优选为口服给药制剂。可将制剂制成便于给药的单位剂型，例如片剂和缓释胶囊，并且可通过制药领域内众所周知的方法制备。
所述方法包括将上述活性剂与载体混合的步骤。一般情况下，通过把活性剂与液态载体或极细固体载体或二者均匀且充分地混合在一起来制备制剂，然后如果需要的话将产物定形。本发明提供了制备药物组合物的方法，包括将式I化合物或其可药用盐与可药用载体或赋形剂混合在一起。如果药物制剂的制备涉及将药物赋形剂与盐形式的活性组分充分混合，则通常优选使用非碱性，即酸性或中性赋形剂。
可将本发明口服给药制剂制成分开的单元，例如分别含有预定量活性剂的胶囊、扁囊或片剂；粉剂或粒剂；活性剂在含水液体或非水液体中的溶液或悬浮剂；或水包油液态乳剂或油包水液态乳剂以及大丸剂等。
对于口服组合物(例如片剂和胶囊)，所谓适当载体例如包括如下的载体：常规赋形剂，例如粘合剂，例如糖浆、金合欢、明胶、山梨醇、西黄蓍胶、聚乙烯吡咯烷酮(聚维酮)、甲基纤维素、乙基纤维素、羧甲基纤维素钠、羟丙基甲基纤维素、蔗糖和淀粉；填充剂和载体，例如玉米淀粉、明胶、乳糖、蔗糖、微晶纤维素、高岭土、甘露糖醇、磷酸氢二钙、氯化钠、和藻酸；以及润滑剂，例如硬脂酸镁、硬脂酸钠和其它硬脂酸金属盐，甘油硬脂酸酯、硬脂酸、硅氧烷液体、滑石、蜡、油和胶态二氧化硅。还可加入矫味剂，例如薄荷、冬青油、樱桃矫味剂等。还可能需要加入着色剂以使剂型易于辨认。并可通过本领域众所周知的方法将片剂包衣。
可通过压片或模制，任选使用一种或多种辅助组分来制备片剂。可通过将任选与粘合剂、润滑剂、惰性稀释剂、防腐剂、表面活性剂或分散剂混合的、呈自由流动形式，例如粉末或颗粒形式的活性剂，在适当压片机中压片来制成压缩片。可通过将用惰性液态稀释剂润湿的粉状化合物的混合物在适当机器中模制来制备模制片。可任选将片剂包衣或刻痕，并且可将片剂配制成能缓慢或有控制地释放活性剂的片剂。
其它适于口服给药的制剂包括在有味基质、通常是蔗糖和金合欢或西黄蓍胶中包含活性剂的锭剂；在惰性基质，例如明胶和甘油中包含活性剂的软锭剂；以及在适当液态载体中包含活性剂的漱口剂。
另一方面，本发明提供了制备式I化合物的方法，包括用下式所示活化酸
Figure C9980288500071
其中PGR是用常规保护基例如Fmoc、BOC或CBz进行N-保护的上述R，将核苷FLG酰化，
Figure C9980288500072
在酰化反应中使用的活化衍生物可包括例如酰卤、酸酐、活化酸酯、或在偶合剂，例如二环己基碳化二亚胺存在下的酸。代表性活化酸衍生物包括酰氯、衍生自烷氧基羰基卤，例如异丁氧基羰基氯等的酸酐、N-羟基琥珀酰胺衍生的酯、N-羟基邻苯二甲酰亚胺衍生的酯、N-羟基-5-降冰片烯-2，3-二甲酰胺衍生的酯、2，4，5-三氯苯酚衍生的酯等。其它活化酸包括其中式RX中的X代表OR’部分，而其中R定义同上，并且R’是例如COCH3、COCH2CH3或COCF3，或者X是苯并三唑的酸衍生物。
可预先形成活化酸，或者通过使用试剂，例如二环己基碳化二亚胺(DCC)或O-(1H-苯并三唑-1-基)N，N，N’，N’-四甲基脲四氟硼酸盐(TBTU)在原位生成。当使用酰卤，例如酰氯时，可将叔胺催化剂，例如三乙胺、N，N’-二甲基苯胺、吡啶或二甲基氨基吡啶加到反应混合物中以结合释放的氢卤酸。
反应优选在非反应性溶剂，例如N，N-二甲基甲酰胺、四氢呋喃、二氧杂环己烷、乙腈、或卤代烃，例如二氯甲烷中进行。如果需要的话，可将任一上述叔胺催化剂用作溶剂，小心使其适当过量。反应温度通常可在0℃-60℃之间变化，但是优选为5℃-50℃。1-60小时后，通常基本上反应完全了。可通过采用适当溶剂系统的薄层色谱法(TLC)追踪反应过程。通常情况下，当通过TLC确定出反应完全时，将产物用有机溶剂萃取，并通过色谱法纯化，和/或从适当溶剂系统中重结晶。
可通过色谱法分离出在核苷碱上发生酰化所形成的副产物，但是可通过控制反应条件将这种错误酰化降至最小。这些控制的条件可例如通过加大反应物浓度或加入速度、尤其是加大酰化剂的浓度和加入速度，通过降低反应温度或通过选择溶剂来达到。可通过TLC追踪反应，以监测控制的条件。可用常规保护基将碱上的6-酮基和尤其是2-氨基保护起来预先阻止错误酰化。
2，3-二N-保护氨基酰基甘油酸中间体是这样制备的：用常规保护基，例如甲氧基苄基将甘油酸上的羧基保护，用适当N-保护氨基酸酯化，然后将甲氧基苄基选择性地脱去保护。
可按照在国际专利申请WO 94/29311中描述的方法，用2-氧杂-4-氮杂环烷-1，3-二酮将R2和R1(如果存在的话)氨基酸衍生物酯化成连接基团，该文献引入本发明以作参考。
                        发明详述
                        实施例1
2，3-二(N-CBz-L-缬氨酰氧基)丙酸(MSS-137)
a)2，3-二(N-CBZ-L-缬氨酰氧基)丙酸1，1-二甲基乙酯
将DCC(7.2g，35mmol)加到2，3-二羟基丙酸1，1-二甲基乙酯(2.43g，15mmol)、N-CBZ-L-缬氨酸(7.54g，30mmol)和DMAP(0.37g，3mmol)在150ml二氯甲烷内的溶液中，将该混合物在室温搅拌2天。将该混合物冷却至约5℃，滤出尿烷。把滤液蒸发，加入乙酸乙酯，将有机相用5％乙酸、5％碳酸氢钠和水洗涤2次。将有机相用硫酸钠干燥，过滤，并减压蒸发。通过硅胶柱色谱法分离产物。产率：8.2g＝86％
1H-NMR(DMSO d-6)0.87(m，12H)1.40(d，9H)2.12(m，1H)4.02-4.40(m，2H)5.04(d，4H)5.20(m，1H)7.36(m，10H)7.72(d，2H)
b)2，3-二(N-CBZ-L-缬氨酰氧基)丙酸
将三氟乙酸(25ml)加到2，3-二(N-CBZ-L-缬氨酰氧基)丙酸1，1-二甲基乙酯(7.2g，11.4mmol)在二氯甲烷(25ml)内的溶液中，把所得溶液在室温搅拌5小时。将溶液减压蒸发，并与甲苯共蒸发2次。通过硅胶柱色谱法分离产物。产率：5.9g＝90％
1H-NMR(DMSO-d6)0.92(m，12H)2.08(m，2H)3.92-4.17(m，2H)4.30-4.67(m，2H)5.04(s，4H)5.28(m，1H)7.32(m，10H)7.70(m，2H)
                        实施例2
2’，3’-二去氧-3’-氟-5’-O-[2，3-二(L-缬氨酰氧基)丙酰基]鸟嘌呤核苷
1)2’，3’-二去氧-3’-氟-5’-O-[2，3-二(N-CBZ-L-缬氨酰氧基)丙酰基]鸟嘌呤核苷(MSS-138)
将2’，3’-二去氧-3’-氟鸟嘌呤核苷(2.15g，8mmol)、2，3-二(N-CBZ-L-缬氨酰氧基)丙酸(6.2g，10.8mmol)、DMAP(244mg，2mmol)和HOBT(1.46g，10.8mmol)的混合物与DMF共蒸发2次，并减至约120ml。加入DCC(2.48g，12mmol)，将混合物在室温搅拌2天。将混合物过滤，并把溶液减压蒸发。加入150ml乙酸乙酯，将有机相用5％乙酸、5％碳酸氢钠和水洗涤2次。将有机相用硫酸钠干燥，并减压蒸发。通过硅胶柱色谱法分离产物。产率：2.25g＝35％
1H-NMR(DMSO d-6)0.88(m，12H)2，12(m，2H)2.50-3.00(m，2H)3.88-4.14(m，2H)4.22-4.62(m，6H)5.04(s，4H)5.30-5.61(m，2H)6.16(m，1H)6.50(s，2H)7.32(m，10H)7.70(m，2H)7.92(s，1H)
b)2’，3’-二去氧-3’-氟-5’-O-[2，3-二(L-缬氨酰氧基)丙酰基]鸟嘌呤核苷
将2’，3’-二去氧-3’-氟-5’-O-[2，3-二(N-CBZ-L-缬氨酰氧基)丙酰基]鸟嘌呤核苷(0.41g，0.5mmol)在乙酸乙酯(40ml)和乙酸(20ml)中的溶液，用钯碳(200mg)在室温于30p si氢化2小时.滤出催化剂，并用乙酸乙酯和乙酸洗涤。将溶液减压蒸发，把产物真空干燥，获得了二盐酸盐。产率：0.3g＝95％
1H-NMR(DMSO d-6and D2O)0.94(m，12H)2.18(m，2H)2.52-3.00(m，2H)3.88-4.09(m，2H)4.36-4.72(m，6H)5.42-5.72.
                            生物实施例1
                           药物代谢动力学
在被认为是可用于评价核苷类似物药物代谢动力学参数有用的大鼠模型中，证实了口服本发明前药可在体内释放FLG。将口服组合物在包含丙二醇的可药用载体中以相当于0.1mmol/kg的剂量对禁食大鼠(一式三份)给药。为了进行比较，对一组大鼠静脉内给予0.01mmol/kg的代谢物2’，3’-二去氧-3’-氟鸟嘌呤核苷。然后监测血清中代谢物的血清水平，其中血清是各动物个体在给药后以0.5小时至高达6小时时间间隔采集的(对于FLG是5分钟-6小时)。
以类似于Stahle等人1995，在“药物学生物医药分析杂志”(J.Pharm.Biomed.Anal.)13，369-376的方式，通过以254 nm UV检测器的HPLC分析代谢物。HPLC系统可以是以1.2％2-丙醇溶剂、并缓冲至pH 4.5的0.05M磷酸二氢铵缓冲液为基础，或者是以2％乙腈溶剂、并缓冲至pH 7.0的0.05M磷酸二氢钠缓冲液为基础。色谱柱可以是带有7μm C18保护柱、粒径为5μm的100×2.1mmBASC18柱，或者是Zorbax SB-CN C18 150×4.6mm.5μm柱。本发明化合物的蛋白结合与代谢物的蛋白结合一样小到可以忽略，因此可将血清样本通过Amicon或Microcon 30滤器超滤。将主峰部分进一步以柱色谱法纯化，以有助于FLG对低重量血清组分的分辨率。将静脉内(iv)水平乘以因子10，以获得与口服效值相比的AUC值。绝对口服生物利用率确定为0-∞AUCiv/0-∞AUC口服之间的比值。
实施例2化合物表现出的0-6小时的绝对生物利用率为68％、72％和64％，其产生的活性代谢物血浆水平在抗病毒抑制水平以上(如科学文献所报道的水平)。因此，相对于代谢物2’，3’-二去氧-3’-氟鸟嘌呤核苷，本发明化合物提供了显著增强的口服生物利用率。尤其是，本发明化合物以相对持续不变的方式释放到血液中，而不是产生中间峰。这意味着血液中可利用的有效量活性代谢物可长达若干小时，从而有助于每天给药一次。此外，缓释可避免更快释放速度条件下化合物出现的急性中毒问题。
                      制剂实施例1
                          片剂
将下述组分通过0.15mm筛网过筛，并干混合，
10g  5’-O-[(R)2，3-二(L-缬氨酰氧基)丙酰基]-2’，3’-二去氧-3’-
     氟鸟嘌呤核苷
40g  乳糖
49g  微晶纤维素
1g   硬脂酸镁
使用压片机将该混合物压制成每片含250mg活性组分的片剂。
                      制剂实施例2
                       肠溶包衣片
在片剂包衣器中用包含下述组分的溶液将制剂实施例1的片剂喷雾包衣，
120g 基纤维素
30g  丙二醇
10g  脱水山梨醇一油酸酯
加蒸馏水至1000ml
                      制剂实施例3
                        控释制剂
50g  5’-O-[(R)2，3-二(L-缬氨酰氧基)丙酰基]-2’，3’-二去氧-3’-
     氟鸟嘌呤核苷
12g  羟丙基甲基纤维素(Methocell K15)
4.5g 乳糖
将上述组分干混合，并用聚维酮的水糊状物制粒。加入硬脂酸镁(0.5g)，并将该混合物在压片机中压制成直径为13mm、每片含500mg活性剂的片剂。
                      制剂实施例4
                         软胶囊
250g  5’-O-[(S)2，3-二(L-缬氨酰氧基)丙酰基]-2’，3’-二去氧
      -3’-氟鸟嘌呤核苷
100g  卵磷脂
100g  花生油
将本发明化合物分散在卵磷脂和花生油中，并装入软明胶胶囊中。

Claims (8)

1.式I化合物及其可药用盐：
Figure C998028850002C1
其中：
R各自独立地为H或-CH3。
2.权利要求1的化合物，其中两个R都是氢。
3.权利要求2的化合物，其中所述化合物选自
5’-O-[2，3-二(L-缬氨酰氧基)丙酰基]-2’，3’-二去氧-3’-氟鸟嘌呤核苷；
和它的可药用盐。
4.权利要求2的化合物，其中所述化合物选自
5’-O-[(R)2，3-二(L-缬氨酰氧基)丙酰基]-2’，3’-二去氧-3’-氟鸟嘌呤核苷；
和它的可药用盐。
5.权利要求2的化合物，其中所述化合物是5’-O-[(R)2，3-二(L-缬氨酰氧基)丙酰基]-2’，3’-二去氧-3’-氟鸟嘌呤核苷。
6.抗HIV或抗HBV组合物，其中包含任一前述权利要求定义的化合物以及其可药用载体。
7.权利要求1-5任一项的化合物在制备用于治疗HIV或HBV的药物中的应用。
8.权利要求6的组合物在制备用于治疗HIV或HBV的药物中的应用。
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