CN101443332A - 抗病毒嘧啶核苷衍生物 - Google Patents
抗病毒嘧啶核苷衍生物 Download PDFInfo
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- CN101443332A CN101443332A CNA2007800169982A CN200780016998A CN101443332A CN 101443332 A CN101443332 A CN 101443332A CN A2007800169982 A CNA2007800169982 A CN A2007800169982A CN 200780016998 A CN200780016998 A CN 200780016998A CN 101443332 A CN101443332 A CN 101443332A
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Abstract
本发明提供了用于治疗或预防例如由水痘带状疱疹病毒引起的水痘或带状疱疹的病毒感染的化合物或其药物可接受盐或水合物,所述化合物具有通式(II):其中X为O、S、NH或CH2,Y为O、S或NH,Z为O、S或CH2,R1为C1-6烷基,优选正烷基,例如正戊基或正己基,并且R2和R3中的一个为OH,且R3和R2中的另一个为中性非极性氨基酸部分。所述中性非极性氨基酸部分R2或R3可以为(IV):其中R4、R5、R6和R7各自独立地为H或C1-2烷基。在优选实施方案中,R2或R3中的一个为缬氨酸、白氨酸、异白氨酸或丙氨酸,尤其为缬氨酸。
Description
本发明涉及在预防和治疗例如由水痘带状疱疹病毒(VaricellaZoster virus)(VZV)引起的病毒感染中具有治疗用途的某些核苷类似物的酯衍生物。水痘带状疱疹病毒是水痘和带状疱疹的发病原因,其能够引起相当严重的人类疾病及痛苦。本发明还提供包含这样的酯衍生物的药物组合物,以及通过给予这样的衍生物来治疗或预防病毒感染的方法。
WO 01/83501 A1,其内容引入本文作为参考,描述了某些具有抗水痘带状疱疹病毒(VZV)的有效活性的核苷类似物,所述核苷类似物具有通式(I):
其中:
Ar为任选取代的芳族环系统,所述芳族环系统包含一个六元芳族环或两个稠合六元芳族环;
R8和R9各自独立地选自氢、烷基、环烷基、卤素、氨基、烷基氨基、二烷基氨基、硝基、氰基、烷氧基、芳氧基、硫醇、烷基硫醇、芳基硫醇、芳基;
Q选自O、S和CY2,其中Y可以相同或不同且选自H、烷基和卤素;
X选自O、NH、S、N-烷基、(CH2),其中m为1至10,和CY2,其中Y可以相同或不同且选自氢、烷基和卤素;
Z选自O、S、NH和N-烷基;
U”为H且U’选自H和CH2T,或U’与U”接合以形成包含Q的环部分,其中U’-U”一起分别选自CTH-CT’T”和CT’=CT’以提供选自如下的环部分:
其中T选自OH、H、卤素、O-烷基、O-酰基、O-芳基、CN、NH2和N3;
T’选自H和卤素,且其中存在一个以上可以相同或不同的T’;
T”选自H和卤素;且
W选自H、磷酸酯基及其药物可接受盐、衍生物或前药;
其限制条件为当T为OAc且T’和T”存在且为H时,Ar不为4-(2-苯并噁唑基)苯基。
下述化合物1和2为根据WO 01/83501A1尤其优选的化合物:
化合物1 化合物2
本发明的目的是提供用于治疗或预防病毒感染,尤其是由水痘带状疱疹病毒(VZV)导致或加重的病毒感染的新颖化合物。
本发明的另一目的是提供用于治疗这样的病毒感染的化合物,所述化合物具有改良的生物利用度。
本发明的另一目的是提供具有有利药物动力学特性的这样的化合物。
本发明的不同目的是提供制备这样的化合物的方法。
本发明的一方面因此提供通式(II)化合物或其药物可接受盐或水合物:
其中X为O、S、NH或CH2,
Y为O、S或NH,
Z为O、S或CH2,
R1为C1-6烷基,优选为正烷基,例如正戊基或正己基,且
R2和R3中的一个为OH,且R3和R2中的另一个为中性非极性氨基酸部分。
所述中性非极性氨基酸部分R2或R3优选为:
其中R4、R5、R6和R7各自独立地为H或C1-2烷基。
R6和R7优选均为H。
在某些实施方案中,R2或R3中的一个可以是缬氨酸、白氨酸、异白氨酸或丙氨酸。R2或R3优选为缬氨酸。
应当理解,本发明的缬氨酸酯可以是L-缬氨酸、D-缬氨酸或D,L-缬氨酸。
此外,X、Y和Z优选均为O。
本发明的尤其优选化合物为:
化合物3 化合物5
应当理解,化合物3和5分别为化合物1的3’-和5’-羟基的缬氨酸酯。
本发明的不同方面提供合成本发明化合物的方法,所述方法包括以受保护的中性非极性氨基酸来酯化式(III)化合物:
其中R1、X、Y和Z如上文定义。
所述氨基酸优选具有式(IV):
其中R4、R5、R6和R7如上文定义。
α-氨基在酯化反应期间受到适当保护。在某些实施方案中,其中R6和R7均为H,可以用3.9-芴甲氧羰基(Fmoc)保护基来保护所述氨基酸。其它适当保护基是已知的且可为本领域技术人员所用。
可以在Schotten-Baumen条件下引入Fmoc基。其例外地具有对酸的稳定性。该基团的裂解可以通过E1 β-消除机制而被碱催化(氨、哌啶、吗啉、DBU)。
优选在Mitsunobu条件1下进行酯化:
1Mitsunobu,Synthesis,January 1981:1-28
可以通过在THF中以HCl溶液处理酯(V)来制备氢氯酸盐。
优选地,R1为正戊基,X、Y和Z均为O,且R4和R5均为甲基。
已发现本发明的化合物及其氢氯酸盐例如化合物6(见下文)与WO 01/83501 A1的化合物1相比具有有利的药物动力学(PK)特性及改良的生物利用度。
化合物6
生物利用度通常是药物作为治疗剂的实际应用中的关键因素,并且显示出增强的PK和/或溶解度的化合物与具有较差PK特性的化合物相比通常具有改良的效能,即使其体外效能可能类似。这样的化合物,即已知的体外活性化合物的衍生物通常称为前药。新颖化合物5及其氢氯酸盐化合物6是两种这样的前药的实例。
如下文所述测试了化合物5和6的抗病毒活性并发现其有活性。此外,在小鼠模型中进行了化合物1与化合物5的药物动力学表现的对比研究以证实化合物5与化合物1相比的改良的生物利用度。
本发明的另一方面因此提供本发明化合物,其用于治疗方法中,尤其是病毒感染的预防或治疗方法中。在某些实施方案中,所述化合物可以被提供用于治疗或预防水痘带状疱疹病毒的感染。
本发明的另一方面提供本发明化合物用于制造供预防或治疗病毒感染,尤其是由水痘带状疱疹病毒导致的病毒感染例如水痘或带状疱疹的药物的用途。
本发明的另一方面提供预防或治疗病毒感染的方法,所述方法包括将有效量的本发明化合物给予需要该治疗的人类或非人类动物患者。
本发明的另一方面提供药物组合物,其包含本发明化合物和药物可接受赋形剂。本发明具体实施方案的药物能够通过口服、经肠或不经肠的途径来给予,包括静脉内、肌肉内、腹膜内、皮下、经皮、呼吸道(气雾剂)、直肠、阴道和局部(包括颊内及舌下)给予。
对于口服给药,本发明具体实施方案的化合物通常会以片剂或胶囊形式、作为散剂或颗粒、或作为水溶液或悬浮液提供。
用于口服使用的片剂可以包括与药物可接受赋形剂混合的该活性成分,所述赋形剂例如惰性稀释剂、崩解剂、粘合剂、润滑剂、甜味剂、调味剂、染色剂和防腐剂。适当的惰性稀释剂包括碳酸钠及碳酸钙、磷酸钠及磷酸钙,和乳糖,而玉米淀粉和藻酸是适当的崩解剂。粘合剂可以包括淀粉和明胶,而如果存在润滑剂,则会通常为硬脂酸镁、硬脂酸或滑石。如果需要,这样的片剂可以用诸如甘油单硬脂酸酯或甘油二硬脂酸酯的材料包衣以延迟胃肠道中的吸收。
用于口服使用的胶囊包括硬质明胶胶囊和软质明胶胶囊,在所述硬质明胶胶囊中活性成分与固体稀释剂混合,在所述软质明胶胶囊中活性成分与水或油如花生油、液态石蜡或橄榄油混合。
用于直肠给药的制剂可以呈现为具有包含例如可可脂或水杨酸酯的适当基质的栓剂。
适于阴道给药的制剂可以呈现为除活性成分之外含有本领域已知的适当载体的阴道栓剂、棉球、乳膏、凝胶、糊剂、泡沫或喷雾制剂。
对于肌肉内、腹膜内、皮下和静脉内使用,本发明具体实施方案的化合物通常会作为被缓冲至适当pH值和等渗性的无菌水溶液或悬浮液提供。适当的含水载体包括林格溶液(Ringer’s solution)和等渗氯化钠。本发明具体实施方案的水性悬浮液可以包括诸如纤维素衍生物、海藻酸钠、聚乙烯吡咯啶酮及黄耆胶的悬浮剂和诸如卵磷脂的湿润剂。用于水性悬浮液的适当防腐剂包括乙基和正丙基对羟基苯甲酸酯。
本发明具体实施方案的化合物能够作为脂质体制剂呈现。
通常,每千克患者体重每天的适当剂量会是0.001mg至300mg,优选每千克体重每天0.01mg至25mg,且最优选每千克体重每天0.05mg至10mg。期望的剂量优选呈现为全天以适当时间间隔给予两次、三次、四次、五次或六次或更多次子剂量。这样的子剂量可以作为单位剂型给予,例如,每单位剂型含有0.1mg至1500mg,优选0.2mg至1000mg,且最优选0.5mg至700mg的活性成分。
以下为参照附图的本发明的各种实施例,从所述实施例会明显看出本发明化合物的更多优点和效应。
在图中,仅有的图为化合物1(25mg/kg)或化合物5(31.25mg/kg,与25mg/kg化合物1等效)单次灌胃(oral gavage)给药后雌性小鼠体内平均值±SD血浆化合物1(以相对峰面积显示)的图表。
实验程序及生物学结果
化合物的制备
实例1
化合物5的制备;缬氨酸酯的形成
化合物1 化合物5
将化合物1(200mg,0.5mmol,如WO 01/83501 A1中的第15页实施例3所述制备)溶解于无水DMF(5mL)中,随后将结合聚合物的三苯膦[370mg,1.1mmol,(3mmol p/g树脂)]和偶氮二甲酸二叔丁酯(DBAD)(231mg,1.0mmol)添加至混合物中并搅拌20分钟。在30分钟的时间内逐滴添加DMF(5mL)中的Fmoc-Val-OH(340mg,1.0mmol)溶液。在氩气氛中于室温下搅拌反应混合物直至起始物质完全消失(过夜)。滤出树脂并用乙酸乙酯洗涤。将哌啶(1mL,10mmol)添加至该溶液中并搅拌10分钟。在加热不超过35℃、减压下除去溶剂并将残余物溶解于乙酸乙酯(20mL)中,用10% NaHCO3(3 x 20mL)和盐水(2 x 20mL)洗涤。通过柱层析法(梯度CH2Cl2:MeOH 100% 98%95% 90%)纯化最终残余物,得到137mg呈黄色固体的化合物5(产率55%)。
1H-NMR(CDCl3)δ:8.3(1H,s),7.55(2H,d),7.15(2H,d),6.6(1H,s),6.25(1H,t),4.45-4.30(4H,m),3.23(1H,d),2.80(1H,m),2.53(2H,t),2.12(1H,m),1.97(1H,m),1.60(2H,m),1.24(4H,m),0.90-0.78(9H,m)。
13C-NMR(CDCl3)δ:175.16,171.62,156.26,154.89,145.19,135.29,129.02,125.69,124.95,108.60,96.82,88.73,85.08,70.90,64.19,60.19,41.91,35.82,32.32,31.44,30.89,22.50,19.30,17.24,13.99。
实施例2
化合物6的制备;HCl盐的形成
化合物6
将300mg化合物5溶解于3mL THF中。于0℃在用力搅拌下添加2mL 1M HCl并搅拌混合物10分钟。在减压下将溶剂干燥以获得322mg(100%)黄色油,其通过添加醚被固化。
1H-NMR(d6-DMSO)δ:8.6(4H,bs),7.70(2H,d),7.30(2H,d),7.20(1H,s),6.22(1H,t),5.60(1H,bs),4.48(2H,m),4.30(1H,m),4.16(1H,m),3.98(1H,m),2.61(2H,t),2.44(1H,m),2.25(1H,m),2.18(1H,m),1.57(2H,m),1.32(4H,m),1.00-0.83(9H,m)。
13C-NMR(d6-DMSO)δ:171.13,168.88,153.97,153.70,144.18,137.94,129.04,125.77,124.58,107.22,98.75,87.71,84.13,69.73,65.26,57.35,40.18,34.88,30.88,30.39,29.38,21.91,18.26,17.55,13.90。
生物学及药物动力学研究
为证实化合物5的改良暴露图形(exposure profile),使用小鼠动物模型进行了若干实验。以下为代表性结果。
化合物1和化合物5的预备比较病毒学研究
该预备研究的目的在于比较接种有胸苷激酶缺损oka VZV病毒株的HEL细胞中化合物1与化合物5的抗病毒活性。抗病毒活性评估为与对照培养物相比在3至7天孵育期后1或5减少病毒斑形成的能力。显示两种化合物之间相当功效的抗病毒功效研究的初步结果如表4.2所示。
表1:比较在HEL细胞中的抗水痘带状疱疹病毒活性的化合物1和化合物5的初步结果
化合物 | VZV OKA中的EC50 |
1 | 0.007μM(2.8ng/mL) |
5 | 0.016μM(8.0ng/mL) |
注意:由于缬氨酸酯,化合物5的分子量约为化合物1的1.25倍。
总之,这些比较性预备体外研究的结果表明,化合物5与化合物1具有相当的体外抗病毒活性。
化合物5的非临床药物动力学研究
用化合物1和化合物5进行预备研究以比较在小鼠中口服给药后化合物1的相对生物利用度。两组雌性小鼠接受在0.5%羧甲基纤维素中调配成单次灌胃剂量的等摩尔剂量的化合物1(25mg/kg)或化合物5(31.25mg/kg;与25mg/kg化合物1等效)。将小鼠在给药后0.25小时至3小时的时间点相继处死(每时间点3只小鼠),提取血浆样本并使用未经确认的具有荧光检测的HPLC方法分析化合物1的浓度。结果以化合物1的相对峰面积表示,其假定在这些浓度范围内,峰面积与浓度成正比。
该研究的结果如附图所示。与接受化合物1的小鼠相比,接受化合物5的小鼠体内化合物1的血浆浓度高得多。应当注意,尽管这些数据不提供化合物1的绝对血浆浓度,但能够自峰面积估计化合物5使化合物1的口服生物利用度增加约8.4至10倍(例如,AUC增加约840%且Cmax增加约1000%)。
总之该资料支持以下假设:化合物5为化合物1的前药,并大大增加化合物1的口服生物利用度。
Claims (19)
3.如权利要求2所述的化合物,其中R6和R7均为H。
4.如权利要求1所述的化合物,其中R2或R3中的一个为缬氨酸、白氨酸、异白氨酸或丙氨酸。
5.如权利要求1或4所述的化合物,其中R2或R3为缬氨酸。
6.如权利要求5所述的化合物,其中所述缬氨酸为L-缬氨酸、D-缬氨酸或D,L-缬氨酸。
7.如前述权利要求中任一权利要求所述的化合物,其中X、Y和Z优选均为O。
11.如权利要求10所述的方法,其中所述氨基酸具有式(IV):
其中R4、R5、R6和R7如权利要求2定义。
12.如权利要求11所述的方法,其中R6和R7均为H,且在所述酯化反应期间所述α-氨基基团由3.9-芴甲氧羰基(Fmoc)保护基保护。
13.如权利要求10、11或12所述的方法,其中所述酯化在Mitsunobu条件下进行。
14.如权利要求10-13中任一权利要求所述的方法,其还包括用HCl溶液处理所述酯以形成氢氯酸盐。
15.如权利要求10-14中任一权利要求所述的方法,其中R1为正戊基或正己基,X、Y和Z均为O,且R4和R5均为甲基。
16.权利要求1-9中任一权利要求所述的化合物,其用于人体或动物体的治疗方法中。
17.权利要求1-9中任一权利要求所述的化合物在制造用于预防或治疗病毒感染的药物中的用途。
18.预防或治疗病毒感染的方法,所述方法包括向需要该治疗的人类或非人类动物患者给予有效剂量的权利要求1-9中任一权利要求所述的化合物。
20.药物组合物,其包含与药物可接受赋形剂组合的权利要求1-9中任一权利要求所述的化合物。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB0609178.9A GB0609178D0 (en) | 2006-05-09 | 2006-05-09 | Novel compounds |
GB0609178.9 | 2006-05-09 | ||
PCT/GB2007/001677 WO2007129083A1 (en) | 2006-05-09 | 2007-05-09 | Anti-viral pyrimidine nucleoside derivatives |
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EP (1) | EP2016081B1 (zh) |
JP (1) | JP5261374B2 (zh) |
KR (1) | KR101447522B1 (zh) |
CN (1) | CN101443332B (zh) |
AT (1) | ATE506367T1 (zh) |
AU (1) | AU2007246814B2 (zh) |
BR (1) | BRPI0711354A2 (zh) |
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CN102443032A (zh) * | 2010-10-09 | 2012-05-09 | 英希比泰克斯公司 | 制备抗病毒组合物的方法及其中间体的应用 |
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GB0009486D0 (en) * | 2000-04-17 | 2000-06-07 | Univ Cardiff | Chemical compounds |
GB2452556A (en) * | 2007-09-07 | 2009-03-11 | Univ Leuven Kath | Nucleoside analogues esterified at 3 and/or 5 positions by neutral non-polar amino acid, or oligopeptide thereof, for combating Varicella Zoster virus |
EP2625181B1 (en) | 2010-10-09 | 2016-07-13 | ContraVir Pharmaceuticals, Inc. | Method of preparation of antiviral compounds and useful intermediates thereof |
MD4110C1 (ro) * | 2010-10-21 | 2011-12-31 | Валериу РУДИК | Preparat antiherpetiс |
KR101875997B1 (ko) * | 2015-05-04 | 2018-07-06 | 엔 앤드 엔 파마세우티칼스 인크. | 엔-메탄노카르바티미딘을 이용한 대상포진의 치료방법 |
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JPS62255499A (ja) | 1986-04-28 | 1987-11-07 | Teijin Ltd | 螢光性ヌクレオシド又はヌクレオチド |
EP0346108A3 (en) | 1988-06-09 | 1991-04-24 | The Wellcome Foundation Limited | Anti-infective nucleosides |
YU43193A (sh) | 1992-06-22 | 1997-01-08 | Eli Lilly And Company | 2'-deoksi-2',2'-difluoro(4-supstituisani)pirimidinski nukleozidi antivirusnog i antikancerogenog dejstva i međuproizvodi |
GB9505025D0 (en) | 1995-03-13 | 1995-05-03 | Medical Res Council | Chemical compounds |
US6022876A (en) * | 1996-11-15 | 2000-02-08 | Yale University | L-β-dioxolane uridine analogs and methods for treating and preventing Epstein-Barr virus infections |
GB9708611D0 (en) | 1997-04-28 | 1997-06-18 | Univ Cardiff | Chemical compounds |
GB9716231D0 (en) | 1997-07-31 | 1997-10-08 | Amersham Int Ltd | Base analogues |
CA2379988C (en) | 1999-07-22 | 2010-10-19 | Newbiotics, Inc. | Enzyme catalyzed therapeutic activation |
AU6358900A (en) | 1999-07-22 | 2001-02-13 | Newbiotics, Inc. | Enzyme catalyzed anti-infective therapeutic agents |
CN1391486A (zh) | 1999-07-22 | 2003-01-15 | 新生物公司 | 治疗对治疗有抗性的肿瘤的方法 |
GB0009486D0 (en) * | 2000-04-17 | 2000-06-07 | Univ Cardiff | Chemical compounds |
GB0011203D0 (en) * | 2000-05-09 | 2000-06-28 | Univ Cardiff | Chemical compounds |
MY141594A (en) * | 2000-06-15 | 2010-05-14 | Novirio Pharmaceuticals Ltd | 3'-PRODRUGS OF 2'-DEOXY-ß-L-NUCLEOSIDES |
US6875751B2 (en) * | 2000-06-15 | 2005-04-05 | Idenix Pharmaceuticals, Inc. | 3′-prodrugs of 2′-deoxy-β-L-nucleosides |
WO2004002999A2 (en) * | 2002-06-28 | 2004-01-08 | Idenix (Cayman) Limited | Modified 2' and 3' -nucleoside produgs for treating flaviridae infections |
BRPI0408561A (pt) * | 2003-03-20 | 2006-03-21 | Microbiol Quimica Farmaceutica | métodos para manufatura de 2'-desoxi-59-l-nucleosìeos |
US20050137141A1 (en) | 2003-10-24 | 2005-06-23 | John Hilfinger | Prodrug composition |
WO2005121162A1 (en) | 2004-06-07 | 2005-12-22 | Anadys Pharmaceuticals, Inc. | 3-β-D-RIBOFURANOSYLTHIAZOLO[4,5-d]PYRIDIMINE NUCLEOSIDES AND USES THEREOF |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102443032A (zh) * | 2010-10-09 | 2012-05-09 | 英希比泰克斯公司 | 制备抗病毒组合物的方法及其中间体的应用 |
CN102443032B (zh) * | 2010-10-09 | 2015-07-22 | 英希比泰克斯公司 | 制备抗病毒组合物的方法及其中间体的应用 |
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