CN1255132A - 1,3-氧硒戊环核苷的合成及抗人类免疫缺陷病毒和抗乙肝病毒活性 - Google Patents
1,3-氧硒戊环核苷的合成及抗人类免疫缺陷病毒和抗乙肝病毒活性 Download PDFInfo
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- CN1255132A CN1255132A CN98804934A CN98804934A CN1255132A CN 1255132 A CN1255132 A CN 1255132A CN 98804934 A CN98804934 A CN 98804934A CN 98804934 A CN98804934 A CN 98804934A CN 1255132 A CN1255132 A CN 1255132A
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Abstract
公开了一种治疗人或其它宿主动物中HIV感染、HBV感染或异常细胞增生的方法和组合物,包括:给药有效量在任选可药用载体中的1,3-氧硒戊环(oxaselenolane)核苷或其可药用盐。
Description
发明背景
美国国家变应性和感染性疾病研究院(National Institute ofAllergy and Infectious Disease)和退伍军人事务部(the Departmentof veterans Affairs)部分地资助本发明的研究,本发明源于这两个单位的美国公共健康服务研究(U.S.Public Health ServiceResearch)基金资助,美国政府对本发明享有专利权。
本发明属于合成核苷领域,具体讲涉及1,3-氧硒戊环(oxaselenolane)核苷及其药学用途、组合物和制备方法。
1981年,获得性免疫缺陷综合症(AIDS)被认为是一种严重危害人类免疫系统的疾病,该疾病几乎全部导致死亡。1983年,AIDS的病因确定为人类免疫缺陷病毒(HIV)。
1985年,据报道,合成核苷3′-叠氮-3′-脱氧胸苷(AZT)抑制人免疫缺陷病毒的复制。此后,许多其它合成核苷,包括2′,3′-二去氧肌苷(DDI)、2′,3′-二去氧胞苷(DDC)、2′,3′-二去氧-2′,3′-二脱氢胸苷(D4T)和(1S,4R)-4-[2-氨基-6-环丙基-氨基)-9H-嘌呤-9-基]-2-环戊烯-1-甲醇琥珀酸酯(“159U89”),已经证明能有效地抗HIV。通常地,在细胞激酶对5′-三磷酸酯的细胞磷酸化作用后,这些合成核苷掺入到生长的病毒DNA链中,由于没有3′-羟基基团,导致链终止。它们还能抑制病毒反转录酶或DNA聚合酶。
各种合成核苷成功地抑制体内或体外HIV的复制使许多研究人员设计和测试3′-位置碳原子被杂原子取代后的核苷。Norbeck等,公开了(±)-1-[(2β,4β)-2-(羟甲基)-4-二氧戊环基]胸苷(称为(±)-二氧戊环-T)显示一定的抗HIV活性(对ATH8细胞的EC50为20μM),并且在200μM的浓度时对未感染的对照细胞没有毒性。四面体通讯(TetrahedronLetters),30(46),6246,(1989)。转让给BioChem Pharm,Inc的欧洲0337713号专利申请公开和转让给该公司的US5041449公开了显示抗病毒活性的外消旋2-取代-4-取代-1,3-二氧戊环。已公开的PCT申请PCT/US91/09124和PCT/US93/08044公开了应用纯β-D-1,3-二氧戊环核苷来治疗HBV感染。PCT公开了β-D-1,3-二氧戊环核苷用于治疗HBV感染。
PCT/US95/11464公开了(-)-(2S,4S)-1-(2-羟基甲基)-1,3-二氧戊环-4-基)胞嘧啶用于治疗肿瘤和其它异常细胞增生。
BioChem Pharm,Inc的美国5047407号专利和该公司的欧洲0382526号专利申请公开公开了许多外消旋2-取代-5-取代-1,3-二氧戊环核苷具有抗病毒活性,并且特别报道了2-羟甲基-5-(胞嘧啶-1-基)-1,3-氧硫戊环(以下称之为BCH-189)的外消旋混合物具有与AZT大致相同的抗HIV活性,但毒性较AZT低。在Liotta等的美国5539116号专利中,称为3TC的BCH-189的(-)对映异构体如今已在美国上市用于治疗人的HIV。
已经公开顺-2-羟甲基-5-(5-氟胞嘧啶-1-基)-1,3-氧硫戊环(下面称之为“FTC”)具有强抗HIV活性。Schinazi等,“顺-5-氟-1-[2-(羟甲基)-1,3-氧硫戊环-5-基]胞嘧啶的外消旋体和对映异构体对人免疫缺陷病毒的选择性抑制”,抗微生物试剂和化疗(Antimicrobial Agentsand Chemotherapy),1992年11月,2423-2431页。还可参见美国5,210,085号专利、美国5,204,466号专利、WO91/11186以及WO92/14743。
另一种对人类造成严重健康问题的病毒是乙肝病毒(以下称“HBV”)。作为人癌症的引发因素,HBV仅次于烟草。HBV的致癌机理尚不清楚。有假说认为它可能直接引发肿瘤的生长,或者通过与感染相关的慢性炎症、肝硬化以及细胞再生间接引发肿瘤的生长。
经过2-6个月宿主未察觉的潜伏期后,HBV感染能够导致急性肝炎和肝损伤,从而引起异常的疼痛、黄疸和某些酶的血浆浓度升高。HBV能够引起暴发性肝炎,它是一种迅速发展的经常致死性疾病,其中肝脏的大部分受到损害。
病人患急性肝炎后一般会恢复。然而,对于有些病人,病毒抗原在血中长时间或无限期保持高浓度,从而引起慢性感染。慢性感染可以造成慢性持续性肝炎。在发展中国家,感染慢性持续性乙肝病毒的病人是非常普遍的。截止1991年中期,仅在亚洲就有约2.25亿慢性HBV携带者,在全球几乎有3亿携带者。慢性持续性肝炎可以造成疲劳、肝硬化和肝细胞癌(一种原发性肝癌)。
在西方工业化国家,HBV感染的高危人群包括那些与HBV携带者或它们的血样品接触的人。HBV的流行病学特征与获得性免疫缺陷综合症非常相似,从而可以解释为什么在患有AIDS或AIDS相关综合征的病人中常常发生HBV感染。然而HBV比HIV传染性更强。
FTC和3TC均显示抗HBV活性。参见Fumran等,“顺-5-氟-1-[2-(羟甲基)-1,3-氧硫戊环-5-基]-胞嘧啶的(-)和(+)对映异构体的抗乙肝病毒活性、细胞毒性和合成代谢特征”,抗微生物剂和化疗(Antimicrobial Agents and Chemotherapy),1992年12月,2686-2692页;和Cheng等,生物化学杂志(Journal of BiologicalChemistry),267(20)卷,13938-13942(1992)。
已经开发了人血清来源的疫苗用于使患者免受HBV感染,而且最近疫苗已经通过基因工程产生,并在目前得到广泛应用。但不幸的是,疫苗不能治疗那些已经感染HBV的病人。应用一种基因工程蛋白α-干扰素的每日治疗也显示了一定的治疗前景,但这种治疗只对约1/3的治疗病人是成功的,而且,干扰素不能口服。
由于1,3-二氧戊环和1,3-氧硫戊环核苷类已经显示了有价值的抗病毒和抗癌活性,为了寻找有生物价值的核苷,合成其电子等排体类化合物1,3-氧硒戊环核苷引起了人们的兴趣。虽然它们的结构与3′-杂原子被取代的核苷相似,但由于合成氧硒戊环结构的难度,合成1,3-氧硒戊环核苷还是较困难的。正因如此,未见1,3-氧硒戊环核苷的报道。
由于这样一个事实即获得性免疫缺陷综合症、AIDS相关综合症和乙肝病毒已在世界范围内流行并使感染病人非常悲惨,因此非常需要提供有效的治疗这些疾病的新制剂。
因此,本发明的一个目的是提供一种治疗感染HIV的病人的方法和组合物。
本发明的另一个目的是提供一种治疗感染HBV的病人或其它宿主动物的方法和组合物。
本发明的另一个目的是提供一种合成1,3-氧硒戊环核苷的方法。
本发明还有一个目的是提供1,3-氧硒戊环核苷和包括1,3-氧硒戊环核苷的药物组合物。
发明概述
本发明公开一种治疗HIV或HBV感染的病人及其它宿主动物的方法和组合物,包括施用有效量的在任选可药用载体中的1,3-氧硒戊环核苷或其可药用盐。
在一个实施方案中,1,3-氧硒戊环核苷具有下列通式:
其中B是嘌呤或嘧啶碱基,R为氢、酰基或磷酸酯,包括单磷酸酯、二磷酸酯或三磷酸酯。在另一个实施方案中,1,3-氧硒戊环核苷是以亲脂性或亲水性前药的形式提供,这将在下面详细描述。在另一个供选择的实施方案中,分子中的硒原子被氧化。优选的1,3-氧硒戊环核苷在不高于约5微摩尔的浓度下在体外试验中就能显示抗HIV或抗HBV活性,最优选的1,3-氧硒戊环核苷在约1微摩尔或更低的浓度就能在体外试验中显示这些活性,这些物质例如在本申请中详细描述的物质。治疗HIV和HBV时,在体外试验中显示IC50毒性例如此处记载的高于50微摩尔、和更优选地约100微摩尔或更高的1,3-氧硒戊环核苷也是优选的。
1,3-氧硒戊环核苷优选为分离的对映异构体β-L-核苷或β-D-核苷。在一个实施方案中,核苷是基本上纯的β-L-或β-D-核苷,即基本上不存在相应的β-D-或β-L-核苷。
优选的化合物是2-羟甲基-4-(N-5′-胞嘧啶-1’-基)-1,3-氧硒戊环和2-羟甲基-4-(N-5′-氟胞嘧啶-1’-基)-1,3-氧硒戊环。已经发现这些核苷的分离的(-)-β-L-异构体比它们的β-D-对映体更有效。然而,这些化合物的(+)对映体对CEM细胞没有毒性。
在另一个实施方案中,活性化合物或者其衍生物或盐可以与其它抗病毒剂如在第IV部分更详细描述的其它抗HIV或抗HBV剂联合给药或交替给药。通常地,在交替给药治疗期间,有效剂量的每种药剂顺序给药、而在联合给药治疗中,有效剂量的两种或更多试剂一起给药。给药的剂量依据药物的吸收、失效和排泄速率以及本领域技术人员已知的其它因素而定。应该注意的是:由于所需治疗疾病的严重程度不同,给药的剂量值也可以相应变化。还需要理解的是:对于任何一个具体的病人,根据个体需要以及根据给药人员或监督给药人员的职业判断,应该随时调整具体的用药方法和方案。
这些化合物还可以用于治疗马传染性贫血病毒(EIAV)、猫免疫缺陷病毒和猴免疫缺陷病毒(Wang,S.,Montelaro,R.,Schinazi,R.R.,Jagerski,B.和Mellors,J.W.:核苷和非核苷类逆转录酶抑制剂(NNRTI)的抗马传染性贫血病毒(EIAV)活性。第一届全国人类逆转录病毒和相关感染会议(First National Conference on HumanRetroviruses and Related Infections),华盛顿,DC,1993年12月12-16日;Sellon D.C.,马传染性贫血,Vet.Clin.North Am.EquinePrac.美国,9:321-336,1993;Philpott,M.S.,Ebner,J.P.,Hoover,E.A.,应用定量聚合酶链反应评价9-(2-膦酰基甲氧乙基)腺嘌呤对猫免疫缺陷病毒的治疗,Vet.Immunol.Immunopathol.35:155166,1992)。
附图简述
图1表示本发明实施例1中描述的1,3-氧硒戊环核苷的一种制备方法。
图2表示本发明实施例3中描述的β-D和β-L-1,3-氧硒戊环核苷的一种制备方法。
图3表示[2-(1’R,2’S,5’R)-薄荷基-(5-酮-1,3-氧硒戊环)]-L-羧酸酯的x-射线晶体结构图。
图4表示(+)-β-Se-ddC、(-)-β-Se-ddc、(+)-β-Se-FddC和(-)-β-Se-Fddc对映体的结构。
发明详述
此处所用的术语“分离的对映异构体”指含有至少约95-100%或更优选地,大于97%的核苷单一对映异构体的核苷组分
术语“基本上纯净形式”是指一种对映异构体的核苷组分,它包括另一种对映体的量不高于5%重量比、更优选不高于2%重量比和最优选不高于1%重量比。
术语“嘌呤或嘧啶碱基”包括但不限于N6-alyl嘌呤、N6-乙酰嘌呤、N6-苄基嘌呤、N6-卤代嘌呤、N6-乙烯基嘌呤、N6-炔基嘌呤、N6-酰基嘌呤、N6-羟烷基嘌呤、N6-硫烷基嘌呤、N2-烷基嘌呤、N4-烷基嘧啶、N4-酰基嘧啶、N4-苄基嘌呤、N4-卤代嘧啶、N4-乙烯基嘧啶、N4-炔基嘧啶、N4-酰基嘧啶、N4-羟烷基嘧啶、N6-硫烷基嘧啶、胸腺嘧啶、胞嘧啶、6-氮杂嘧啶包括6-氮杂胞嘧啶、2-和/或4-巯基嘧啶、尿嘧啶、C5-烷基嘧啶、C5-苄基嘧啶、C5-卤代嘧啶、C5-乙烯基嘧啶、C5-炔基嘧啶、C5-酰基嘧啶、C5-羟烷基嘌呤、C5-酰氨基嘧啶、C5-氰基嘧啶、C5-硝基嘧啶、C5-氨基嘧啶,N2-烷基嘌呤、N2-烷基-6-硫代嘌呤、5-氮杂胞嘧啶基、5-氮杂脲嘧啶基、三唑并嘧啶基(trazolopyridinyl)、咪唑并嘧啶基、吡咯并嘧啶基,和吡唑并嘧啶基。需要时可以保护碱中的氧和氮官能团。合适的保护基团是本领域技术人员所熟知的,包括三甲基甲硅烷基、二甲基己基甲硅烷基、叔丁基二薄荷基甲硅烷基,和叔丁基二苯基甲硅烷基、三苯甲基、烷基、酰基如乙酰基和丙酰基,甲磺酰基和对甲苯磺酰基。优选的碱包括胞嘧啶、5-氟胞嘧啶、尿嘧啶、胸腺嘧啶、腺嘌呤、鸟嘌呤、黄嘌呤、2,6-氨基嘌呤、6-氨基嘌呤和6-氯嘌呤。
此处所用的术语烷基,除特别说明外,是指饱和的,直链、支链或环状的,伯、仲或叔的烃基,典型地是C1-C18,具体包括甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、环戊基、异戊基、新戊基、己基、异己基、环己基、环己基甲基、3-甲基戊基、2,2-二甲基丁基,和2,3-二甲基丁基。烷基可以任选地被一个或多个基团取代,这些取代基团选自:羟基、氨基、烷基氨基、芳氨基、烷氧基、芳氧基、硝基、氰基、磺酸、磺酸酯、磷酸、磷酸酯或膦酸酯,根据需要可以对其进行保护或不保护,这些是本领域熟练技术人员已知的,例如如Greene等在“有机合成的保护性基团(Protective Groups in OrganicSynthesis)”.John wiley and Sons,第二版,1991年中所教导的,该文在此引入作为参考。
此处所用的术语低级烷基,除非特别说明,指饱和的直链或支链C1-C4烷基。
在此所用的“保护的”是指为防止进一步反应或为其它目的加入到氧、氮或磷原子上的基团(但另有说明除外)。大量的氧和氮保护基团是有机合成领域技术人员已知的。
此处所用的术语芳基,除非特别说明,是指苯基或联苯基、或萘基,优选苯基。芳基可以任选地被一个或多个基团取代,这些基团选自:羟基、卤素、烷基、烯基、炔基、烷芳基、芳烷基、氨基、烷基氨基、烷氧基、芳氧基、硝基、氰基、磺酸、磺酸酯、磷酸、磷酸酯或膦酸酯,根据需要可以为未保护或保护形式,而这种保护是本领域熟练技术人员所已知的,例如见Greene等,“有机合成中的保护基(ProtectiveGroups in Organic Synthesis)”.John wiley and Sons,第二版,1991年中所教导。
术语烷芳基或烷基芳基是指带有芳基取代基的烷基。
术语芳烷基或芳基烷基是指带有烷基取代基的芳基。
此处所用的术语卤素包括氯、溴、碘和氟。
术语酰基是指式-C(O)R′基团,其中的R′为烷基、芳基、烷芳基、芳烷基、杂芳基、烷氧基烷基包括甲氧基甲基;芳烷基包括苄基;芳氧基烷基例如苯氧甲基;芳基包括被卤素、C1-C4烷基或C1-C4烷氧基任意取代的苯基,或为氨基酸残基。
此处所用的术语“离去基团”是那些能从分子中裂解但在正常状况下与该分子相连的基团。
术语氨基酸包括天然或合成氨基酸,包括但不限于丙氨酰、缬氨酰基、亮氨酰基、异亮氨酰基、脯氨酰基、苯丙氨酰基、色氨酰基、蛋氨酰基、甘氨酰基、丝氨酰基、苏氨酰基、半胱氨酰基、酪氨酰基、天冬氨酰基、谷氨酰胺基、天冬氨酰基、glutaroyl、赖氨酰基、精氨酰基和组氨酰基。
此处所用的术语杂芳基或杂芳香基是指芳香环中包括至少一个硫、氧或氮的芳香基团。非限制性的例子为呋喃基、吡啶基、嘧啶基、噻吩基、异噻唑基、咪唑基、四唑基、吡嗪基、苯并呋喃基、苯并噻吩基、喹啉基、异喹啉基、苯并噻吩基、异苯并呋喃基、吡唑基、吲哚基、异吲哚基、苯并咪唑基、嘌呤基,咔唑基、噁唑基、噻唑基、异噻唑基、1,2,4-噻二唑基、异噁唑基、吡咯基、喹唑啉基、哒嗪基、吡嗪基、邻二氮萘基、2,3-二氮杂萘基、喹喔啉基、黄嘌呤基、次黄嘌呤基和蝶啶基。杂环碱基的氧和氮官能团根据需要可以进行保护。合适的保护基团是本领域技术人员熟知的,它们包括:三甲基甲硅烷基、二甲己基甲硅烷基、叔丁基二甲基甲硅烷基和叔丁基二苯基甲硅烷基、三苯甲基和取代的三苯甲基,烷基、酰基例如乙酰基和丙酰基,甲磺酰基、和对甲苯磺酰基。
术语亲脂性前药是指这样的1,3-氧硒戊环核苷,其在5′-羟基位置含有可以裂解的共价取代基因而使该核苷的亲脂性比具有5′-羟基的母体核苷更强些。
术语亲水性前药是指这样的1,3-氧硒核苷其在5′-羟基位置含有可以裂解的共价取代基因而使该核苷的亲水性比具有5′-羟基的母体核苷更强些。
此处公开的本发明是治疗人或其它宿主动物中HIV或HBV感染以及以类似方式复制的其它病毒感染的方法和组合物,包括给药有效量在任选可药用载体中的1,3-氧硒戊环核苷、其可药用衍生物包括带有5′-离去基团的1,3-氧硒核苷包括酰化了的或磷酸酯化的衍生物或其可药用盐。关于本发明的化合物,或者它们本身具有抗病毒活性如抗HIV-1、抗HIV-2和抗HBV或抗类似免疫缺陷病毒(抗-SIV)活性;或者它们经代谢形成具有抗病毒活性的化合物。
本发明中,这些公开的化合物或其可药用衍生物或盐或含有这些化合物的可药用制剂可用于治疗HIV感染或其它相关病症如AIDS相关综合症(ARC)、持续性弥散淋巴结病(PGL)、AIDS相关性神经学疾病、抗HIV抗体阳性和HIV阳性疾病、卡波济氏肉瘤、血小板减少症和机会感染。另外,这些化合物或制剂可以预防性地用于防止或阻止抗HIV抗体或HIV抗原阳性或者感染HIV的病人的临床疾病的发展。
该化合物或者其可药用衍生物或盐,或者含有该化合物或者其衍生物或盐的制剂,也可用于预防和治疗HBV感染和其它相关性疾病例如抗HBV抗体阳性和HBV阳性疾病、HBV引起的慢性肝炎、肝硬化、急性肝炎、暴发性肝炎、慢性持续性肝炎和疲劳。这些化合物或制剂可预防性地用于防止或阻止那些抗HBV抗体阳性或HBV抗原阳性或接触HBV的个体的临床疾病进展。
该化合物可以与合适的酯化剂如酰卤或酸酐反应转变成可药用酯。该化合物或其可药用衍生物可以通过常规方式如用合适的碱处理转变成其可药用盐。该化合物的酯或盐可以例如通过水解转变成母体化合物。
总之,本发明包括如下特征:
(a)上面概括的1,3-氧硒戊环核苷、其可药用衍生物和盐;
(b)用于医疗目的例如治疗或预防HIV或HBV感染的1,3-氧硒戊环核苷、其可药用衍生物和盐;
(c)应用1,3-氧硒戊环核苷、其可药用衍生物或盐制备治疗HIV和HBV感染的药物;
(d)含有1,3-氧硒戊环核苷、其可药用衍生物或盐和可药用载体或稀释剂的药物制剂;
(e)制备1,3-氧硒戊环的方法;和
(f)通过与其它抗病毒剂联合给药或交替给药,应用1,3-氧硒戊环核苷治疗病毒感染。
I.活性化合物和其生理上可接受的衍生物和盐
此处公开的活性化合物是外消旋形式或分开的对映体形式的1,3-氧硒戊环核苷。
给药的活性化合物可以是给药至接受者能够直接或间接提供该母体化合物或者它本身显示活性的任何一种衍生物。非限制性的例子是可药用盐(或者称为“生理学上可接受的盐”)和该活性化合物的5′和N4嘧啶或N6嘌呤被酰化或烷基化的衍生物(或者称为“生理活性衍生物”)。在一个实施方案中,酰化基团为羧酸酯,其中酯基的非羰基部分选自直链、支链或环状的烷基或低级烷基,烷氧基烷基包括甲氧基甲基,芳烷基包括苄基,芳氧基烷基例如苯氧甲基、芳基包括任选由卤素、C1-C4烷基或C1-C4烷氧基取代的苯基;磺酸酯例如烷基或芳烷基磺酰基如甲磺酰基,磷酸酯包括但不限于单、双或三磷酸酯,三苯甲基或单甲氧基三苯甲基、取代的苄基、三烷基甲硅烷基(例如二甲基-5-丁基甲硅烷基)或二苯基甲基甲硅烷基。酯中的芳基任选地含有苯基。
对活性化合物的修饰,特别是在N4嘧啶基或N6嘌呤和5′-O位置的修饰可以影响该活性物质的生物利用度和代谢速率,从而控制该活性物质的转运。另外,这些修饰可以影响该化合物的抗病毒活性,在某些情况下增加母体化合物的活性。根据此处描述的方法或本领域熟练技术人员熟知的其它方法制备该衍生物并测试其抗病毒活性可以很容易地评价上述结论。
核苷前药
为了增加核苷的活性、生物利用度、稳定性或改变其它性质,此处描述的任何一种核苷均可以作为核苷前药给药。许多核苷前药配体是已知的。通常地,核苷的烷基化、酰基化或其它磷酸单酯、双酯或三酯的亲脂性修饰会增加该核苷的稳定性。能够替换磷酸酯部分的一个或多个氢原子的取代基团的例子是烷基、芳基、甾族化合物、包括糖的碳水化合物、1,2-二乙酰甘油和醇类。许多这些物质记载在R.Jones和N.Bischofberger,抗病毒研究(Antiviral Research),27(1995)1-17。所有这些前药可以与公开的核苷联合用药以达到预期效果。
在一个实施方案中,1,3-氧硒戊环核苷以5-羟基亲脂性前药形式提供。多篇非限制性美国专利中公开了合适的与核苷共价结合优选与核苷5-OH位置共价结合的亲脂性取代基或亲脂性制剂,这些美国专利包括:美国专利号5,419,794(1992年9月22日;Yatvin等);5,194,654(1993年3月16日,Hostetler等);5,223,263(1993年6月29日,Hostetler等);5,256,641(1993年10月26日,Yatvin等);5,411,947(1995年5月2日,Hostetler等);5,463,092(1995年10月31日,Hostetler等);5,543,389(1996年8月6日,Yatvin等);5,543,390(1996年8月6日,Yatvin等);5,543,391(1996年8月6日,Yatvin等);和5,554,728(1996年9月10日,Basava等),所有这些文献在此引入作为参考。
一些外国专利申请也公开了可以与本发明中1,3-氧硒戊环核苷结合的亲脂性取代基或亲脂性制剂,这些包括WO89/02733,WO90/00555,WO91/16920,WO91/18914,WO93/00910,WO94/26273,WO/15132,EP0350287,EP93917054.4,和WO91/19721。
1,3-氧硒戊环核苷衍生物的其它非限制性实施例是含有下列出版物中公开的取代基的衍生物。这些1,3-氧硒戊环核苷衍生物可以用于本文记载的指示剂或者作为抗病毒剂包括抗HIV或抗HBV试剂。Ho,D.H.W.(1973)1β-D-阿拉伯呋喃基胞嘧啶激酶和脱氨基酶在人或小鼠组织中的分布。癌症研究(Cancer Res).33,2816-2820;Holy,A.(1993)等极性亚磷修饰的核苷类似物。In:De Clerq(编),抗病毒药物设计进展(Advances in Antiviral Drug Design),第1卷,JAI出版社,179-231页;Hong,C.I.Nechaev,A.,和West,C.R.(1979a),可的松和氢化可的松的1β-3-阿拉伯呋喃基胞嘧啶结合物的合成和抗肿瘤活性.,生物化学和生物物理学研究通讯(Biochem.Biophys.Rs.Commun.)88,1223-1229;Hong,C.I.,Nechaev,A.,Kirisits,A.J.Buchheit,D.J.和West,C.R.(1980)强效抗肿瘤试剂的核苷结合物。3.皮质类固醇和精选的亲脂性醇类的1-(β-D-阿拉伯呋喃)胞嘧啶结合物的合成和抗肿瘤活性,药物化学杂志(J.Med.Chem).28,171-177;Hostetler,K.Y.,Stuhmiller,L.M.,Lenting,H.B.M.van den Bosch,H.和Richman,D.D.(1990)叠氮基胞嘧啶和其它抗病毒核苷的磷脂类似物的合成和抗反转录病毒活性,生物化学杂志(J.Biol.Chem.)266,11714-11717;Hostetler,K.Y.,Korba,B.,Sridhar,C.,Gerdener,M.(1994a)乙肝感染的细胞和小鼠增强型肝摄取中的磷脂酰基-二脱氧胞嘧啶的抗病毒活性,抗病毒研究。(Antiviral Res.)24,59-67;Hostertler,K.Y.,Richman,D.D.,Sridhar,C.N.Felgner,P.L.,Felgner,J.,Ricci,J.,Gerdener,M.F.Selleseth,D.W.和Ellis,M.N.(1994b)磷脂酰叠氮胸腺嘧啶和磷脂酰-ddc:鼠淋巴组织摄取和在人免疫缺陷病毒感染细胞和rauscher白血病病毒感染小鼠中抗病毒活性的评价,抗微生物试剂化疗(Antimicrobial Agents Chemother.)38,2792-2797;Hunston,R.N.,Jones,A.A.McGuigan,C.,Walker,R.T.,Balzarini,J.,和De Clercq,E.(1984)一些衍生自2’-脱氧-5-氟尿嘧啶的环磷酸三酯的合成和生物特性,药物化学杂志(J.Med Chem.)27,440-444;Ji,Y.H.,Moog,C.,Schmitt,G.,Bischoff,P.和Luu,B.(1990);用作强效抗肿瘤剂的7β-羟基胆甾醇和嘧啶核苷的单磷酸双酯:合成和抗肿瘤活性的初步评价,药物化学杂志(J.Med.Chem)33.2264-2270;Jones,A.S.,McGuigan,C.,Walter,R.T.,Balzarini,J.和DeClercq,E.(1984)一些核苷环氨基磷酸酯的合成、性质和生物活性。J.Chem.Soc,Perkin Trans,I,1471-1474;Juodka,B.A.和Smart,J.(1974)一种(P→N)氨基酸ditribonucleoside的合成,Coll.Czech.Chem.Comm.39,363-968;Kataoka,S.,Imai,J.,Yamaji,N.,Kato,M.,Saito,M.,Kawada,T.和Imai,S.(1989)AlkylactedcMP衍生物;选择性合成和生物活性。Nucleic Acids Res.Sym.Ser.,21,1-2;Kataoka,S.,Uchida,R.和Yamaji,N.(1991)3′,5′-环磷酸腺苷(cAMP)的苄基和甲基三酯的简易合成,杂环(Heterocycles)32,1351-1356;Kinchington,D.,Harvey,J.J.,O’connor,T.J..Jones.B.C.N.M.,Devine,K.G.,Taylor-Robinson,D.,Jeffries,D.J.和McGuigan,C.(1992)抗HIV和ULV的齐多呋定氨基磷酸酯和二氨基磷酸酯衍生物的体外抗病毒活性比较。抗病毒化学。化疗(Antiviral Chem.Chemother.),3,107-112;Kodama,K.,Morozumi,M.,Saitoh,K.I.,Kuninaka,H.,Yoshino,H.和Saneyoshi,M.(1989)1-β-D-阿拉伯呋喃基胞嘧啶-5 ′-十八烷基磷酸酯的抗肿瘤活性和药理学;1-β-D-阿拉伯呋喃基胞嘧啶的口服活性衍生物。日本癌症研究杂志(Jpn.J.Cancer Res.)80,679-685;Korty,M.和Engels,J.(1979)腺嘌呤和鸟嘌呤3′,5′-磷酸和苄基酯对豚鼠心室心肌层的作用,Naunyn-Schmiedeberg′s Arch.Pharmacol.310,103-111;Kumar,A.,Goe,P.L.,Jones,A.S.Walker,R.T.Balzarini,J.和DeClercq,E.(1990)一些环氨基磷酸核苷衍生物的合成和生物学评价,药物化学杂志(J.Med.Chem.)33,2368-2375;LeBec,C.,和Huynh-dinh,T.(1991)作为抗肿瘤前药的5-氟尿嘧啶和阿拉伯胞嘧啶的亲脂性磷酸三酯衍生物的合成,四面体通讯(Tetrahedron Lett)32,6553-6556;Lichtenstein,J.,Barner,H.D.和Cohen S.S.(1960)大肠杆菌的外源性核苷的代谢,生物化学杂志(J.Biol.Chem.)235,457-465;Lucthy,J.,.Von Daeniken,A.,Friederich,J.Manthey,B.,Zweifel,J.,Schlatter,C.和Benn,M.H.(1981)三种天然氰基表硫代烷烃(cyanoepithioalkanes)的合成和毒理学特性。Mitt.Geg.Lebensmittelunters.Hyg.72,131-133(美国化学文摘,95,127093);McGuigan,C.TOllerfield.S.M.和Riley.P.A.(1989)抗病毒药物Ara的一些磷酸三酯衍生物的合成和生物学评价,核酸研究(Nucleic Acids Res.)17,6065-6075;McGuigan,C.,Devine,K.G.,O′Connor,T.J.,Galpin,S.A.,Jeffries,D.J.和Kinchington,D.(1990a)一些作为抗HIV化合物的3′-叠氮-3′-脱氧胸腺嘧啶(AZT)的新氨基磷酸酯衍生物的合成和评价,抗病毒化学化疗,1,107-113;McGuigan,C.,O′Connor,T.J.,Nicholls,S.R.Nickson,C.和Kinchington,D(1990b)一些新的AZT和ddCyd取代二烷基磷酸酯衍生物的合成及抗HIV活性,抗病毒化学化疗(AntiviralChem.Chemother.),1,355-360;McGuigan,C.,Nicholls,S.R.,O′Connor,T.J.,和Kinchington(1990c)一些用作强效抗AIDS药物的3′-位修饰核苷的新二烷基磷酸酯衍生物的合成,抗病毒化学化疗(Antiviral Chem.Chemother)1,25-33;McGuigan,C.,Devine,K.G.,O′Connor,T.J.,和Kinchington,D.(1991)3′-叠氮-3′-脱氧胸腺嘧啶(AZT)的卤烷基氨基磷酸酯衍生物的合成和抗HIV活性;三氯乙基甲氧丙氨酸基化合物的强活性,抗病毒研究(Antiviral Res).15,255-263;McGuigan,C.,Pathirana,R.N.,Mahmood,N.,Devine,K.G.和Hay,A.J.(1992)对抗AZT作用细胞系具有抗HIV1活性的AZT的芳基磷酸酯衍生物,抗病毒研究(Antiviral Res.)17,311-321;McGuigan,C.,Pathirana,R.N.,Choi,S.M.,Kinchington,D.和O′Connor,T.;J.(1993a)用作HIV抑制剂的AZT的氨基磷酸酯衍生物;对羧基末端的研究。抗病毒化学化疗(Antiviral Chem.Chemother.)4,97-101;McGuigan,C.,Pathirana,R.N.,Balzarini,J.和De Clercq,E.;(1993b)AZT的芳基磷酸酯衍生物对生物活性AZT核苷的细胞内传递,药物化学杂志(J.Med.Chem.)36,1048-1052。
抗HIV剂AZT的磷酸氢烷基酯衍生物可能比其母体核苷类似物毒性更低些。抗病毒化学.化疗.(Antiviral Chem.Chemother..).5,271-277;Meyer,R.B.,Jr.;,Shuman,.D.A.和Robins,R.K.1973嘌呤核苷3′,5′-环氨基磷酸酯的合成,四面体通讯(Tetrahedron Lett.)269-272;Nagyvary,J.Gohil,R.N.,Kirchner,C.R.和Stevens,J.D.(1973)环AMP中性酯的研究,生物化学与生物物理学研究通讯(Biochem.Biophys.Res.Commun)55,1072-1077;Namane,A.Goyette,C.,Fillion,M.P.,Fillion,G.和Huynh-Dinh,T.(1992)应用葡基磷酸三酯前药增加AZT的脑释放,药物化学杂志(J.Med.Chem.)35,3939-3044;Nargeot,J.Nerbonne,J.M.Engels,J.和Leser,H.A.(1983)Natl.Acad.Sci.U.S.A.80,2395-2399;Nelson,K.A.,Bentrude,W.G.,Stser,W.N.和Hutchinson.J.P.(1987)核苷环状3′,5′-单磷酸酯的磷酸酯环的椅式-扭曲式(chair-twist)平衡问题,胸腺嘧啶苯基环3′,5′-单磷酸酯非对映体的1HNMR和x-射线晶体学研究,美国化学会志(J.Am.Chem.Soc.109,4058-4064);Nerbonne,J.M.,Richard,S.,Nargeot,J.和Lester,H.A.(1984)新的可光敏化的环核苷产生细胞内环AMP和环GMP浓度猛烈增高,自然(Nature)301,74-76;Neumann,J.M.,Herve,M.,Debouzy,J.C.,Guerra,F.I.,Gouyette,C.,Dupraz,B.和Huynh-Dinh,T.(1989)合成胸腺嘧啶的匍基磷酸酯并通过基NMR研究跨膜转运,美国化学会志(J.Am.Chem.Soc).111,4270-4277;Ohno,R.,Tatsumi,N.,Hirano,M.,Imai,K.Mizoguchi,H.,Nakamura,T.,Kosaka,M.,Takatuski,K.,Yamaya,T.,Toyama,K.,Yoshida,T.,Masaoka,T.,Hashimoto,S.,Ohshima,T.,Kimura,I.,Yamasa,K.和Kimura,J.(1991)口服1-β-D-阿拉伯呋喃胞嘧啶-5′-十八烷基磷酸酯治疗脊髓障碍性痉挛(myslodyspastic)综合症的治疗,肿瘤学(Oncology)48,451-455。Palomino,E.,Kessle,D.和Horwitz.J.P.(1989)二氢吡啶载体系统用于2′,3′-二脱氧核苷在脑中的缓释,药物化学杂志(J.Med.Chem.)32,622-625;Perkins,R.M.,Barney,S.,Wittrock,R.,Clark,P.H.,Levin,R.Lambert,D.M.,Petteway,S.R.,Serafinowska,H.T.,Bailey,S.M.,Jackson,S.,Harnden,M.R.,Ashton,R.,Sutton,D.,Harvey,J.J.和Brown,A.G.(1993)BRL47923及其口服前药SB298657A的抗小鼠rauscher鼠白血病病毒感染活性.抗病毒研究(Antiviral Res),20(增刊I),84;Pinatadosi,C.,Marasco,C.J.,Jr.,Morris-Natschke,S.L.,Meyer,K.L.,Gumus,F.,Surles,J.R.,Ishaq,K.S.,Kucera,L.S.Iyer,N.,Wallen,C.A.,Piantadosi,S.和Modest,E.J.(1991)新的醚脂核苷结合物的合成和抗HIV-1活性评价,药物化学杂志(J.Med.Chem)34,1408-1414;Pompon.A.,Lefebvre,I.,Imbach,J.L.,Kahn,S.和Farquhar,D.(1994)细胞提取物和组织培养基中叠氮胸腺嘧啶-5′-单磷酸酯的单和双(新戊酰氧甲基)酯的降解途径;联机ISRP-洗涤′HPLC技术的应用,抗病毒化学化疗。5,91-98;Postemark,T.(1974)环AMP和环GMP。药理学年度综述(Anu.Rev.Pharmacol).14,23-33;Prisbe,E.J.,Martin,J.C.M.,McGee,D.P.C.,Barker,M.F.,Smee,D.F.Duke,A.E.,Matthews,T.R.和Verheyden,J.C.M.,McGee,D.P.C.,Barker,M.F.,Smee,D.F.Duke,A.E.,Matthews,T.R.和Verheyden,J.P.J.(1986)9-[(1,3-二羟基-2-丙氧基)甲基]鸟嘌呤的磷酸酯和膦酸酯衍生物的合成和抗疱疹病毒活性,药物化学杂志(J.Med.Chem)29,671-675;Pucch,F.,Gosselin,G.,Lefebvre,I.,Pompon,A.,Aubertin,A.M.Dirn,A.和Imbach,J.L.(1993)核苷单磷酸酯经还原酶介导的活化过程的细胞内传递,抗病毒研究(AntiviralRes).22,155-174;Pugaeva,V.P.,Kochkeva,S.I.,Mashbits,F.D.和Eizengart,R.S.(1969),工业大气中乙烯硫化物的毒理学评价和健康标准等级评价,Gig,Trf.Prof.Zabol.13,47-48(美国化学文摘72,212);Robins,R.K.(1984)作为反转录病毒和肿瘤抑制剂的核苷类似物的可能性,药理学研究(Pham.Res)11-18;Rosowsky,A.,Kim.S.H.,Ross和J.Wick,M.M.(1982)用作前药的亲脂性的1-β-D-阿拉伯呋喃基胞嘧啶及其N4-酰基和2,2′-脱水-3′O-酰基衍生物的5′-(烷基磷酸酯),J.Med.Chem.25,171-178;Ross,W.(1961)葡萄糖预处理后行人对载有碱性侧链的芳香性氮芥的敏感性增加。生物制药(Biochem.Pharm)8,235-240;Ryu,E.K.,Ross,R.J.,Matsushita,T.,
MacCoss,M.,Hong,C.I.和West,C.R.(1982)。磷脂-核苷结合物3.1-β-D-阿拉伯呋喃胞嘧啶5′二磷酸酯[-],2-二酰基甘油的合成和初步生物学评价,药物化学杂志(J.Med.Chem)25,1322-1329;Saffhill,R.和Hume,W.J.(1986)不同来源血清中5-碘脱氧尿嘧啶和5-溴脱氧尿嘧啶的降解以及用这些化合物结合到DNA的结果,Chem.Biol.Interact.57,347-355,Saneyoshi,M.,Morozumi,M.,Kodama,K.,
Machida.,Kuninaka,A.和Yoshino,H.(1980)合成核苷和核苷XVI。1-β-D-阿拉伯呋喃胞嘧啶5′-烷基或芳基磷酸酯的合成和生物学评价,化学药理学学报(Chem.Pharm.Bull)28,2915-2923;Sastry,J.K.,Nehete,P.N.,Khan,S.,Nowak,B.J.,Plunkett,W.,
Arlinghaus,R.B.和Farquhar,D.(1992)膜渗透性二脱氧尿嘧啶5′-单磷酸酯类似物抑制人免疫缺陷病毒。分子药理学(Mol.Pharmacol.)41,441-445;Shaw,J.P.,Jones,R.J.Arimilli,M.N.,Louie,M.S.,Lee,W.A.和Cundy,K.C.(1994)雄性Sprague-Dawley鼠中PMEA前药的PMEA口服生物利用度,第9次AAPS年会。SanDiego,CA(文摘)。Shuto,S.,Ueda,S.,Imamura,S.,Fukukuawa,K.Matsuda,A.和Ueda,T.(1987)通过酶促两相反应简易一步合成5′-磷脂酰核苷。四面体通讯(Tetrahedron Lett),28,199-202;Shuto,S.,Itoh,H.,Ueda,S.,Imamura,S.,Kukukawa,K.,Tsujino,M.Matsuda,A.和Ueda,T.(1988)5′-(3-sn-磷脂酰基)核苷的简易酶促合成,化学药理学学报(Chem.Pharm.Bull.)36,209-217。一个优选的磷酸酯前药基团是S-酰基-2-硫乙基,也称之为“SATE”。
II活性化合物的制备
迄今为止,由于合成1,3-氧硒戊环的环结构有难度,1,3-氧硒戊环核苷因而没有生产。本文在此提供一种生产该环的方法。图1显示该方法的一个实施方案。本文还提供生产分离的β-D(即2S,5R)和β-L 1,3-氧硒戊环(即2R,5S)核苷的方法。图2表示该方法的一个实施例。图1还提供下列实施例中所用化合物的编号方式。
实施例1 1,3-氧硒戊环的制备
应用Kirby的方法制备硒代氰酸酯得到非常高的产率。第一步,在乙醇中,溴代乙酸乙酯(BrCH2CO2Et)与硒代氰酸钾反应生成硒代氰酸酯2。
为了合成内酯5,开始曾经试图用NaBH4还原硒代氰酸酯2,然后用NaOH水解得到的酯生成硒醇乙酸,该物质可用于氧硒戊环系统5的结构。然而,在用HCl酸化至pH2期间,硒醇乙酸发生降解。据报道,硒醇在空气中容易被氧气氧化成稳定的二聚体,该二聚体能用H3PO2又还原成硒醇。已经发现,把双(硒代乙酸)还原成硒醇以及环化反应可以在一个反应罐中进行,无需分离中间产物。因此,1和KSeCN在乙醇中回流1小时,然后在0℃下用NaBH4还原20-30分钟可得到二聚体3。与最近报道的联硒化物制备方法相比,本方法反应条件温和、产率高并且容易后处理。通过3与乙酸水溶液(50%)回流24小时,然后用H3PO2还原成硒醇乙酸,进而再在氮气保护下,并在H3PO2存在下就地与2-苄氧基乙醛缩合,得到33%产率的内酯5。还原内酯5时,发现较之酯,DIBAL-H在THF中能够选择性地还原内酯,而它在甲苯中没有观测到选择性。因此,在THF中用DIBAL-H还原5,然后就地用乙酸酐乙酰化得到乙酸糖酯7,无需纯化,在SnCl4或TMSOTf存在下,缩合乙酸酯7与甲硅烷基化的碱得到没有分离的8a和8b的α-和β-异构体混合物。在甲醇中用甲胺或氨除去8a和8b中的保护性基团苯甲酰基得到α/β-混合物核苷形式的终产物核苷。依次在甲醇/乙醚和甲醇中重复重结晶该α/β-混合物得到α-胞嘧啶核苷,而母液应用HPLC分离(C18柱,20%的甲醇水溶液)得到β-胞嘧啶核苷(9a)。该α/β-混合物用硅胶色谱分离得到β和α-5-氟胞嘧啶核苷。应用元素分析、1H和13CNMR确证了合成的硒杂戊环核苷的结构。在2D-NOESY实验中,观察到β-异构体9b的2′-H和5′-H之间存在相关性,而在α-异构体10b中发现没有这种相关性,根据这个实验确定了其立体化学归属。同时,由于杂环碱基的去屏蔽作用,与10a和10b相比,9a和9b中的2H化学位移在高场,这也可以支持所述立体化学归属。
立体化学
由于该核苷中1,3-氧硒戊环的1′和4′碳原子是手性碳原子,它们的非氢取代基(分别为吡啶或嘌呤碱基和CHOR基团)相对于糖环系统可以是顺式(同面)或反式(异面)。因此这四种光学异构体代表下列四种构型(糖基定位在水平面,并且氧原子在后面):顺式(两个基团都“向上”,相当于天然核苷的构型)、顺式(两个基团都“向下”,非天然构型)、反式(C2′取代基“向上”,C4′取代基“向下”)和反式(C2′取代基“向下”,C4′取代基“向上”)。“D-核苷”是天然构型的顺式核苷,“L-核苷”是非天然构型的顺式核苷。
通过两种方式可得到1,3-氧硒戊环核苷的对映异构体:如实施例2中所述手性层析核苷;和分级结晶1,3-氧硒戊环的L-薄荷醇非对映体,继之在路易丝酸存在下将已拆分的1,3-氧硒戊环核苷与所需的碱基进行缩合。
实施例2 通过手性色谱拆分2-羟甲基-4-(n-5′-胞嘧啶-1′-基)-1,3-氧硒戊环和2-羟甲基-4-(n-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环的β-D和β-L对映异构体
通过手性色谱拆分2-羟甲基-4-(N-5′-胞嘧啶-1′-基)-1,3-氧硒戊环和2-羟甲基-4-(N-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环。把化合物(外消旋,约2mg)溶于最少量(约400μl)的甲醇(HPLC级)中。拆分所用条件如下:Waters HPLC系统;柱:Chiralpak AS 4.6×250mm;流动相:2-丙醇,流速:0.80毫升/分钟;检测器:UV-260nm;喷射气体:氦气;喷射速度:25毫升/分钟/溶剂罐;注射量:每次20μl溶液;保留时间:(-)-(2S,5R)-β-L-2′,3′-二脱氧-3′-硒杂-胞嘧啶核苷,5.50分钟;(+)-(2R,5S)-β-D-2′,3′-二脱氧-3′-硒杂-胞嘧啶核苷,6.92分钟;(-)-(2S,5R)-β-L-2′,3′-二脱氧-5-氟-3′-硒杂-胞嘧啶核苷,5.97分钟;(+)-(2R,5S)-β-D-2′,3′-二脱氧-5-氟-3′-硒杂-胞嘧啶核苷,9.62分钟。拆分后化合物的光学纯度大于95%ee。
实施例3 通过转变成非对映异构体再通过分级结晶法分离非对映异构体来拆分1,3-氧硒戊环中间的β-D和β-L对映异构体
(-)-L-薄荷醇羧基醛((-)-L-Mentholcarboxyal.)。把p-TsOH(5g)加入到(-)-L-薄荷醇(30g,0.2mol)和gluoxylic acid(36.8g,0.4mol)的甲苯(1000ml)混合物中,该反应混合物在100℃下搅拌3小时。反应完成后,用Et3N中和p-TsOH(5g)并蒸发至干。残余物用氯仿(500ml)溶解,水洗涤(3×500ml),收集有机层,干燥(Na2SO4),蒸发。得到的油状物用石油醚重结晶得到白色晶体(-)-L-薄荷醇羧基醛20g(50%):mp82℃;1HNMR(CHCl3)δ9.40(s,1H,CHO),4.78(dt,J=4.45,11Hz,1H,1-H),0.75-2.03(m,19H);13CNMR(CHCl3)δ184.41,170.22,87.13,46.79,40.40,34.00,31.42,26.11,23.28,21.94,20.68,16.15。分析计算C12H20O3:C,67.89;H,9.50;实测值:C,67.65;H,9.67。M/S m/e 212.3(M+)。[2-(1′R,2′S,5′R)-基-(5-酮-1,3-氧硒戊环)]-L-羧酸酯(11)和[2-(1′R,2′S,5′R)-基-(5-酮-1,3-氧硒戊环)]-D-羧酸酯。
把(SeCH2COOH)2(4.15g,15mmol)加入到(-)-L-薄荷醇羧基醛(6.4g,30mmol)的甲苯(100ml)溶液中,在氩气保护和搅拌状态下,反应混合物缓缓加热到100℃。以1小时的时间滴加次磷酸(50%水溶液,2.7ml)。在氩气保护和剧烈搅拌下将反应混合物再回流1小时。然后,反应混合物蒸发至20ml,用EtOAc(250ml)稀释,水洗涤(3×500ml)。收集有机层,干燥(Na2SO4),蒸发。残余物用硅胶柱色谱纯化,用EtOAc-Hex(1∶10,V/V)作为洗脱剂,得到固体11共3.9g(77.6%)。混合物在室温下用己烷重结晶得到无色细针状晶体11:mp106.5℃;[α]25 D=59.86°(c0.5,CHCl3);1HNMR(CHCl3)δ5.83(s,1H,2′-H),4.77(dt,J=4.45,12Hz,1H,1-H),3.97(d,J=15.34Hz,1H,4′-Hb),3.67(dt,J=15.35Hz,4J=21.17Hz,1H,4′-Ha),0.75-2.03(m,19H);13CNMR(CHCl3)δ173.97,168.67,76.88,63.84,47.07,40.46,34.02,31.38,26.07,23.23,22.65,21.93,20.71,16.11。元素分析C14H22O4Se:计算值:C,50.45;H,6.65;实测值:C,50.65;H,6.62 MS m/e 333(M+)。母液在-5℃下结晶;[α]25 D=-111.71°(c 0.5,CHCl3);1HNMR(CHCl3)δ5.83(s,1H,2′-H),4.78(dt,J=4.45,12Hz,1H,1-H),3.95(d,J=15.41Hz,1H,4′-Ha),3.68(dt,J=15.45Hz,4J=19.35Hz,1H,4′-Ha),0.75-2.03(m,19H);13CNMR(CHCl3)δ173.98,168.63,76.15,63.76,46.95,39.88,34.01,31.32,26.22,23.24,22.98,21.94,20.74,16.14。元素分析C14H22O4Se:计算值:C,50.45;H,6.65;实测值:C,50.47;H,6.63 MS m/e 333(M+)。1-β-L-(2′-羟甲基-1,3′-氧硒戊环-5′-基)-5-氟胞嘧啶(15)和1-α-L-(2′-羟甲基-1’,3′-氧硒戊环-5′-基)-5-氟胞嘧啶(16)
在氩气保护、搅拌状态和10℃的温度下,以1小时的时间把内酯11(1g,3.33mmol)的5mlTHF溶液加入到三叔丁基氢化铝锂溶液(6mmol,6ml 1M的THF溶液)。然后在-5-0℃下缓缓加入乙酸酐(2g,20mmol)。反应混合物再搅拌1小时,用乙酸乙酯(100ml)稀释,水洗(3×100ml),干燥(Na2SO4),浓缩至干,得到粗品5′-乙酸酯13。乙酸糖酯13溶于CH2Cl2(5ml),缓缓加入到甲硅烷基化的5-氟胞嘧啶中(其中5-氟胞嘧啶制备方法如下:在氩气保护下,搅拌5-氟胞嘧啶(0.34g,2.63mmol)、2,4,6-三甲基吡啶(0.8ml,6.61mmol)和三氟甲磺酸叔丁基二甲基甲硅烷基酯(1.32g,5.08mmol)的混合物1小时即得)。把碘化三甲基甲硅烷(0.35g,1.75mmol)加入到上面得到的反应混合物中,室温搅拌18小时,用CHCl3(100ml)稀释,倒入到Na2S2O3水溶液(100ml)中,用水洗涤,干燥(Na2SO4),浓缩至干。残余物用硅胶闪柱色谱纯化,CHCl3作洗脱剂,得到固体粗品13(0.15g,11.2%)。1HNMR(CDCl3)δ8.35(d,J=6.3Hz,1H,6-H),7.55,7.53(2×brs,2H,NH2),6.45(m,1-h,5′-H),6.14(m,1H,2′-H),4.79(m,1H,1-H),3.66(m,2H,6′-Hab)。化合物14(0.15g,0.33mmol)的THF(10ml)溶液在室温和氩气保护下1小时,反应混合物再搅拌1小时,加入甲醇(5ml)终止反应,得到的混合物用硅胶短柱色谱纯化,洗脱剂为乙酸乙酯-己烷-甲醇(1∶1∶1,V/V,100ml)。洗脱液浓缩至干,得到的固体用硅胶柱纯化,用氯仿-乙醇(20∶1,V/V)作洗脱剂,得到类白色固体β-L-(15)和α-L-核苷(16)的混合物0.033g(34%)。该混合物用硅胶柱再分离,洗脱剂为四种溶剂的混合物:乙酸乙酯-己烷-氯仿-乙醇(5∶5∶2∶1,V/V)。
1-β-L-(2′-羟甲基-1,3′-氧硒戊环-5′-基)-5-氟胞嘧啶(15)
白色固体(0.01g,10.2%);mp186-189℃(MeOH);[α]25 D=-55.69(c0.35,MeOH);UV(H2O))λmax280.0nm(ε10646,pH2),280.0nm(ε7764,pH11);1HNMR(DMSO-d6)δ8.07(d,J=7.1Hz,1H,6-H),7.92,7.67(2×brs,2H,NH2,D2O可交换),6.06(t,J=2.96Hz,1-H,5′-H),5.42(t,J=4.82Hz,1H,2′-H),5.34(t,J=5.68Hz,1H,OH,D2O可交换),3.81(m,1H,6′-Ha),3.68(m,1H,6′-Hb),3.39(dd,J=4.84Hz,1H,4′-Hb),3.08(dd,J=8.11Hz,1H,4′-Ha);13CNMR(DMSO-d6)δ157.7(C=O),153.3(4-C),137.6(6-C),135.2(5-C),88.3(5′-C),78.2(2′-C),64.0(6′-C),28.9(4′-C);元素分析C8H10O3N3FSe:计算值:C,32.67,H3.43,N,14.29;实测值:C,32.62;H,3.51,N,14.41;M/S m/e 295(M+)。
1-α-L-(2′-羟甲基)-1′,3′-氧硒戊环-5′-基)-5-氟胞嘧啶(16)
白色固体(0.013g,13.2%);mp193-195℃(MeOH);[α]25 D=+84.20°(c0.26,MeOH);UV(H2O)λmax279.5nm(ε7638,pH7),287.5nm(ε9015,pH2);281.0nm(ε6929,PH11);1HNMR(DMSO-d6)δ7.91(d,J=7.1Hz,1H,6-H),7.88,7.63(2×brs,2H,NH2,D2O可交换),6.35(t,J=4.95Hz,1H,5′-H),5.63(dd,J=4.83Hz,1H,2′-H),5.28(t,J=5.67Hz,1H,OH,D2O可交换),3.70(m,1H,6′-Ha),3.53(m,1H,6′-Hb),3.47(dd,J=4.82Hz,1H,4′-Ha),3.24(dd,J=7.88Hz,1H,4′-Hb),13CNMR(DMSO-d6)δ157.8(C=O),153.2(4-C),137.3(6-C),134.9(5-C),88.6(5′-C),80.9(2′-C),65.5(6′-C),29.4(4′-C);元素分析C8H10O3N3FSe:计算值:C,32.67,H,3.43,N,14.29;实测值:C,32.59;H,3.49,N,14.20;M/S m/e 295(M+)。核苷8和9的合成以同样的方式从内酯3(1g,3,33mmol)完成,得到1-β-D-(2′-羟甲基)-1’,3′-氧硒戊环-5′-基)-5-氟胞嘧啶8。白色固体(0.007g,8.5%);mp 186-189℃(MeOH);[α]25 D=+56.21°(c0.33,MeOH);UV(H2O)λmax280.0nm(ε8576,pH7),289.0nm(ε10456,pH2),280.0nm(ε7795,pH11):1HNMR(DMSO-d6)δ8.07(d,J=7.1Hz,1H,6-H),7.92,7.67(2×brs,2H,NH2,D2O可交换),6.06(5,J=2.96Hz,1-H,5′-H),5.42(5,J=4.82Hz,1-H,2′-H),5.34(5,J=5.68Hz,1H,OH,D2O可交换),3.81(m,1H,6′-Ha),3.68(m,1H,6′-Hb),3.39(dd,J=4.84Hz,1H,4′-Hb),3.08(dd,J=8.11,1H,4′-Ha);13CNMR(DMSO-d6)δ157.7(C=O),153.3(4-C),137.6(6-C),135.2(5-C),88.3(5′-C),78.2(2′-C),64.0(6′-C),28.9(4′-C);元素分析C8H10O3N3FSe计算值:C,32.67;H,3.43,N14.29;实测值:C,32.57;H,3.39;N14.35;M/S m/e295(M+)。
1-α-D-(2′-羟甲基-1′,3′-氧硒戊环-5′-基)-5-氟胞嘧啶9。
白色固体(0.01g,10%);mp 193-195℃(MeOH);[α]25 D=-85.49°(c0.31,MeOH);UV(H2O)λmax279.5nm(ε7644,pH7),287.5nm(ε9067,pH2),281.0nm(ε6983,pH11):1HNMR(DMSO-d6)δ7.91(d,J=7.1Hz,1H,6-H),7.88,7.63(2×brs,SH,NH2,D2O可交换),6.35(5,J=4.95Hz,1-H,5′-H),5.63(dd,J=4.83Hz,1H,2′-H),5.28(5,J=5.67Hz,1H,OH,D2O可交换),3.70(m,1H,6′-Ha),13CNMR(DMSO-d6)δ157.8(C=O),153.2(4-C),137.3(6-C),134.9(5-C),88.6(5′-C),80.9(2′-C),65.5(6′-C),29.4(4′-C);元素分析C8H10O3N3FSe:计算值:C,32.67;H,3.43,N14.29;实测值:C,32.67;H,3.48;N14.47;M/S m/e295(M+)。
表1提供了(+)-β-Se-FddC,(-)-β-Se-FddC,(+)-α-Se-FddC,(-)-α-Se-FddC和(-)-β-Se-ddC的分离结果图,并将它们的保留时间和吸收波长与(-)-β-FTC和(+)-β-FTC进行了比较。
表1 分离结果
化合物 | 保留时间(min) | 吸收波长,nm | 旋光度(度) | 纯度 |
(-)-β-Se-FddC | 4.8 | 247.3,285.1 | -103.2(c0.5,MeOH) | 100 |
(+)-β-Se-FddC | 7.7 | 247.3,285.1 | +96.8(c).5,MeOH) | 100 |
(-)-α-Se-FddC | 4.8 | 247.3,285.1 | ND | 100 |
(+)-α-Se-FddC | 6.6 | 247.3,285.1 | ND | 90 |
(-)-β-FTC | 4.7 | 242.6,285.1 | --- | -- |
(+)-β-FTC | 6.9 | 242.6,285.1 | --- | -- |
(-)-β-Se-ddC | 9.5 | 242.6,270.9 | -72.4(cl,DMSO) | 100 |
(+)-β-Se-ddC | 11.9 | 242.6,270.9 | +56.4(cl,DMSO) | 96 |
(-)-α-Se-ddC | ND | 242.6,270.9 | -46.7(cl,DMSO) | 100 |
(+)-α-Se-ddC | ND | 242.6,270.9 | +26.1(cl,DMSO) | 94 |
表2提供了在ChiralPak AS上分离的化合物的拆分和分离因子。分离因子定义为第二个洗脱出的异构体保留时间和死时间之差与首先洗脱出来的异构体的保留时间和死时间之差的比值。拆分因子定义为(+)和(-)异构体保留时间之差与两个吸收峰之间谱带宽度的比值的两倍。表2 在ChiralPak AS.上的分离对比。色谱条件:流动相为2-丙醇;注射100μg样品的10μl甲醇溶液;紫外检测波长为254nm,流速单位是ml/min。
化合物 分离因子αa 拆分因子Rs b
外消旋α-Se-FddC 2.34 1.91
外消旋β-Se-FddC 3.14 3.28
外消旋β-FTC 2.84 2.87a分离因子=(第二个洗脱出的异构体的保留时间-死时间)/(第一个洗脱异构体的保留时间-死时间)b拆分因子=2×[(+)和(-)异构体的保留时间之差]/(两峰的谱带宽度)。表3给出不同溶剂比例和流速对外消旋β-Se-ddC的手性拆分的影响。表3 不同溶剂比例和流速对外消旋β-Se-ddC的手性拆分的影响
乙醇-己烷比例 | 流速(ml/min) | 拆分R3 | 第一个洗脱峰面积(uV*sec×107) | 第一个峰保留时间 |
100∶0 | 0.8 | 1.25 | 1.25 | 4.65 |
50∶50 | 0.8 | 1.48 | 1.13 | 6.06 |
40∶60 | 0.8 | 1.76 | 1.11 | 7.21 |
30∶70 | 0.8 | 2.05 | 1.08 | 9.71 |
30∶70 | 1.0 | 1.98 | 0.88 | 7.83 |
30∶70 | 1.4 | 1.90 | 0.64 | 5.59 |
20∶80 | 1.4 | 2.12 | 0.61 | 9.78 |
40∶60 | 0.6 | 1.75 | 1.46 | 9.53 |
活性核苷的单、二和三磷酸酯衍生物可以按照已公开的方法制备。单磷酸酯可以按照Imai等.,有机化学杂志(J.Org.Chem)34(6),1547-1550(1969年6月)所描述的方法制备。二磷酸酯可按照Davisson等,有机化学杂志(J.Org.Chem)52(9),1794-1801(1987)中描述的方法制备。三磷酸酯可按照Hoard等,美国化学会志(J.Am.Chem.Soc)87(8),1785-1788(1965)中记载的方法制备。
III.联合给药和交替给药治疗
已经认识到:用抗病毒剂长期治疗后,会出现抗药性变型HIV和HBV。产生抗药性的典型原因是用于病毒生命周期的酶编码基因突变所造成的,对于HIV,最典型的这些酶是反转录酶、蛋白酶或DNA多聚酶;对于HBV是DNA多聚酶。近来,已经发现:抗HIV感染药物和能引起与该主要药物不同类型突变的另一种甚至可能包括第三种抗病毒化合物联合用药或交替用药,可以延长、增强或恢复该抗HIV感染药物的作用。或者,通过这种联合用药或交替用药治疗,可以改变药物的药代动力学、生物分布或药物的其它参数。通常地,联合用药治疗比交替用药治疗典型地更优选些,因为前者对病毒同时产生多重作用。
在一个实施方案中,第二种治疗HIV的抗病毒剂可以是反转录酶抑制剂(“RTI”),它可以是合成核苷(“NRTI”)或非核苷化合物(“NNRTI”)。在一个可选择的方案中,对于HIV的情况,第二种(或第三种)抗病毒剂可以是蛋白酶抑制剂。在另一个方案中,第二种(或第三种)化合物可以是焦磷酸酯类似物或融合蛋白结合抑制剂(fusing bindinginhibitor)。Schinazi等“与抗药性有关的反转录病毒基因突变”国际抗病毒报道(International Antiviral News),1(14)卷,国际医学出版社(International Medical Press)编撰了许多抗病毒化合物的体内和体外抗药性数据表。
对于治疗HBV,联合或交替用药治疗优选的化合物包括FTC((-)对映异构体或消旋体)、L-FMAU、干扰素、β-D-二氧戊环-鸟嘌呤(DXG)、β-D-二氧戊环-2,6-二氨基嘌呤(DAPD)、和β-d-二氧戊环-6-氯嘌呤(ACP)、泛西洛维、喷西洛维、BMS-200475、bisbornPMEA(adefovir、dipivoxil)、lobucavir、甘西洛维和利巴韦林。
对于治疗HIV,在此公开的可用来与这些化合物联合或交替给药治疗的抗病毒剂的优选实例包括2-羟甲基-5-(5-氟尿嘧啶-1-基)-1,3-氧硫戊环(FTC);2-羟甲基-5-(胞嘧啶-1-基)-1,3-氧硒戊环(3TC)的(-)对映异构体、长波佛、无环鸟苷、干扰素、AZT、DDI、DDC、D4T、CS-92(3′-叠氮-2′,3-二脱氧-5-甲基-胞嘧啶核苷)、和β-D-二氧戊环核苷如β-D-二氧戊环鸟嘌呤(DXG)、β-D-二氧戊环-6-氯嘌呤(ACP)、和MKC-442(6-苄基-1-(乙氧甲基)-5-异丙基尿嘧啶)。
优选的蛋白酶抑制剂包括crixova(Merck)、nelfinavir(Agouron)、ritonavir(Abbot)、saquinavir(Roche)和DMP-450(Dupont Merck)。
可以与上面任何一种1,3-氧硒戊环核苷联合或交替给药的化合物的非限制性实施例包括:(1S,4R)-4-[2-氨基-6-环丙基-氨基]-9H-嘌呤-9-基]-2-环戊烯-1-甲醇琥珀酸酯(“1592”,一种长波佛类似物;GlaxoWellcome);3TC:(-)-β-L-2′,3′-二脱氧-3′-硫代胞啶(GlaxoWellcome);a-APAR18893:a-硝基-苯氨基-苯乙酰胺;A-77003;C2对称碱基化蛋白酶抑制剂(Abbott);A-75925:C2-对称碱基化蛋白酶抑制剂(Abott);AAP-BHAP:双杂芳基哌嗪类似物(Upjohn);ABT-538:C2对称碱基化蛋白酶抑制剂(Abbott);Azddu:3′-叠氮-2′,3′-二脱氧尿嘧啶核苷;AZT:3′-叠氮-3′-脱氧胸腺嘧啶核苷(Glaxo Wellcome);AZT-p-ddI:3′-叠氮-3′-脱氧胸腺嘧啶-(5,5′)-2′,3′-二脱氧次黄嘌呤核甙酸(Ivax);BHAP:双杂芳基哌嗪;BILA1906:N-{1S-{{{3-[2S-{(1,1-二甲基乙基)氨基}羰基}-4R-]3-吡啶甲基)硫基]-1-哌啶基]-2R-羟基-1S-(苯甲基)-丙基]氨基]羰基]-2-甲基丙基}2-喹啉甲酰胺(BioMega/Boehringer-Ingelheim);BILA 2185:N-(1,1-二甲基乙基)-1-[2S-[[2-2,6-二甲基苯氧基)-1-氧代乙基]氨基]2-R-羟基-4-苯基丁基]4R-吡啶硫基-2-哌啶甲酰胺(Bio Mega/Boehringer-Ingelheim);BM+51.0836:噻噻并异二氢酮吲哚衍生物;BMS186,318:氨基二醇衍生物HIV-1蛋白酶抑制剂(Bristo-Myers-Squibb);d4API:9-[2,5-二氢-5-(膦酰基甲氧基)-2-呋喃]腺嘌呤(Gilead);d4C:2′,3′-二脱氢-2′,3′-二脱氧胞啶;d4T:2′,3′-二脱氢-3′-脱氧胸腺啶(Bristol-Myers-Squibb);ddC:2′,3′-二脱氧胞啶(Roche);ddI:2′,3′-二脱氧肌苷(Bristol-Myers-Squibb);DMP-266:1 1,4-二氢-2H-3,1-苯并噁嗪-2-酮;DMP-450:{[4R-(4-a,5-a,6-b,7-b)]-六氢-5,6-双(羟基)-1,3-双(3-氨基)苯基]甲基)-4,7-双(苯甲基)-2H-1,3-二氮杂卓-2-酮}-双甲磺酸酯(Avid);DXG:(-)-β-D二氧六环-鸟嘌呤核苷(Triangle);EBU-dM:5-乙基-1-乙氧甲基-6-(3,5-二甲基苄基)尿嘧啶;E-EBU:5-乙基-1-乙氧甲基-6-苄基尿嘧啶;DS:硫酸葡聚糖酯;E-EPSeU:1-(乙氧基甲基)-(6-苯硒基)-5-乙基尿嘧啶;E-EPU:1-(乙氧甲基)-(6-苯硫基)-5-乙基尿嘧啶FTC:β-2′,3′-二脱氧基-5-氟-3′-硫代胞啶(Triangle);HBY097:S-4-异丙氧羰基-6-甲氧基-3-(甲硫基-甲基)-3,4-二氢喹喔啉-2(1H)-硫酮;HEPT:1-[2-羟乙氧基)甲基]6-(苯硫基)胸腺嘧啶;HIV-1:1型人免疫缺陷病毒;JM2763:1,1′-(1,3-丙烷二基)-双-1,4,8,11-四氮杂环十四烷(Johnson Matthey);JM3100:1,1′-[1,4-亚苯基双-(亚甲基)-双-1,4,8,11-四氮杂环十四烷(JohnsonMatthey);KNI-272:含有(2S,3S)-3-氨基-2-羟基-4-苯基丁酸的三肽;L-697,593;5-乙基-6-甲基-3-(2-苯二酰亚氨基-乙基)吡啶-2(1H)-酮;L-735,524:羟基-氨基戊烷酰胺HIV-1蛋白酶抑制剂(Merk);L-697,661:3-{[(-4,7-二氯-1,3-苯并噁唑-2-基)-甲基]氨基}5-乙基-6-甲基吡啶-2(1H)-酮;L-FDDC:(O)-β-L-5-氟-2′,3′-二脱氧胞啶;L-FDOC:(-)-β-L-5-氟-二氧戊环胞嘧啶;MKC-442:6-苄基-1-乙氧甲基-5-异丙基尿嘧啶(I-EBU:Triangle/Mitsubishi);Nevirapine:11-环丙基-5,11-二氢-4-甲基-6H-联吡啶并[3,2-b:2′,3′-e]-二氮杂卓-6-酮(Boehringer-Ingelheim);NSC648400:1-苄氧甲基-5-乙基-6-(α-吡啶硫基)尿嘧啶(E-BPTU);P9941:[2-吡啶乙酰基-IlePheAla-y(CHOH)2](Dupont Merck);PFA:膦酰基甲酸酯(foscarnet;Astra);PMEA:9-(2-膦酰甲氧乙基)腺嘌呤(Gilead);PMPA:(R)-9-(2-膦酰甲氧丙基)腺嘌呤(Gilead);Ro 31-8959:羟乙基胺衍生物HIV-1蛋白酶抑制剂(Roche);RPI-312:肽类蛋白酶抑制剂,1-[(3s)-3-(n-α-苄氧羰基)-1-天门东酰胺基)-氨基-2-羟基-4-苯基丁酰基]-n-叔丁基-1-脯氨酸酰胺;2760:6-氯-3,3-二甲基-4-(异丙氧羰基)-3,4-二氢-喹喔啉-2(1H)硫酮;SC-52151:羟乙基脲电子等排物蛋白酶抑制剂(Searle);SC-55389A:羟乙基-脲电子等排物蛋白酶抑制剂(Searle);TIBOR82150:(+)-(5S)-4,5,6,7-四氢-5-甲基-6-(3-甲基-2-丁烯基)咪唑并[4,5,1-jk][1,4]-苯并二氮杂-2(1H)-硫酮(Janssen);TIBO 82913:(+)-(5S)-4,5,6,7-四氢-9-氯-5-甲基-6-(3-甲基-2-丁烯基)咪唑-[4,5,1jk]-[1,4]苯并二氮杂单-2(1H)-硫酮(Janssen);TSAO-m3T:[2′,5′-双-O-(叔丁基二甲基甲硅烷基)-3′-螺-5′-(4′-氨基-1′,2-氧硫杂环戊烯-2′,2′-二氧化物)]-b-D-呋喃戊糖基-N3-甲基胸腺嘧啶;U90152:1-[3-[1-甲基乙基)-氨基]-2-吡啶基]-4-[[5-[(甲磺酰基)-氨基]-1H-吲哚-2-基]羰基]哌嗪;UC:硫代羧酰基苯胺衍生物(Uniroyal);UC-781=N-[4-氯-3-(3-甲基-2-丁烯氧基)苯基]-2-甲基-3-呋喃硫代甲酰胺;UC-82=N-[4-氯-3-(3-甲基-2-丁烯氧基)苯基]-2-甲基-3-噻吩硫代甲酰胺;VB11,328:羟乙基磺酰胺蛋白酶抑制剂(Vertex);VS-478:羟乙基磺酰胺蛋白酶抑制剂(Vertex);XM323:环脲蛋白酶抑制剂(Dupont Merck)。
IV 1,3-氧硒戊环核苷抑制HIV和HBV复制的能力
通过多种实验技术可以测定核苷抑制HIV的能力。此处所用的技术(下面将作详细描述)测定在植物血球凝集素(PHA)刺激的、感染HIV-1(LAV系)的人外周血单核(PBM)细胞中抑制病毒复制的能力。通过测定病毒编码的反转录酶来确定所产生的病毒量。产生酶的量与产生病毒的量成正比。
实施例4 1,3-氧硒戊环核苷的抗HIV-活性。
本实施例测试2-羟甲基-4-(N-5′-胞嘧啶-1′-基)-1,3-氧硒戊环和2-羟甲基-4-(N-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环的抗HIV活性。
来自乙肝和HIV-1血清反应阴性的健康供体的、植物血球凝集素刺激的三天龄PBM细胞(106细胞/ml)以每毫升50%组织培养感染剂量(TICD50)的约100倍浓度感染HIV-1(LAV株),再把该感染后的细胞在有或没有各种浓度抗病毒化合物的存在下培养。
感染约1小时后。把该含有被测试化合物(两倍于培养基中的最终浓度)或不含有该化合物的培养基加入到烧瓶(5ml;最终体积10ml)中。用AZT作阳性对照。
这些细胞与病毒接触(经反转录酶检测浓度约2×105dpm/ml),然后置于CO2培养箱中。HIV-1(LAV株)来自乔治亚州亚特兰大疾病控制中心(the Center for Disease Control)。PBM细胞的培养方法、病毒的收集方法和反转录酶活性的测定方法按照McDougal等,(免疫方法学杂志(J.Immun.Meth.)76.171-183,1985)和Spira等(J.Clin.Meth.25.97-99,1987)描述的方法进行,但培养基中不含有两性霉素B(参见Schinazi等.,抗微生物剂化疗(Antimicrob.AgentsChemother.)32.1784-1787(1988);同前述杂志,34:1061-1067(1990))。
在第6天时,该细胞及上清液转移到15ml试管中,以900g离心约10分钟。移走5毫升上清液,以40,000rpm的速度离心30分钟(Beckman 70.1Ti转轴)使病毒浓缩。加工该溶解的病毒团用于反转录酶含量测定。结果以dpm/ml样品上清液表示。少量上清液(1ml)的病毒也可在溶解和测定反转录病毒含量之前离心浓缩。
半数有效(EC50)浓度通过半数有效方法测定(抗微生物试剂化疗(Antimicrob.Agents Chemother.)30,491-498(1986))。简单地说,从反转录酶测定确定的病毒抑制百分比对化合物微摩尔浓度作图。EC50就是病毒生长抑制为50%时的化合物浓度。
在有和没有药物的存在下,促细胞分裂剂刺激的未感染人PBM细胞(3.8×105细胞/毫升)在与上面抗病毒检测所用的相似条件下培养。6天后用血细胞计数器和台盼蓝排除法(参见Schinazi等,抗微生物试剂和化疗(Antimicrobial Agents and Chemotherapy),22(3),499(1982)对细胞计数,IC50为抑制50%正常细胞生长时的化合物浓度。
表4提供了2-羟甲基-4-(N-5′-胞嘧啶-1′-基)-1,3-氧硒戊环和2-羟甲基-4-(N-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环的EC50值(在PBM细胞中抑制50%病毒复制的核苷浓度,估计有10%误差系数)和IC50值(促细胞分裂剂刺激的未感染PBM细胞、CEM细胞和Vero细胞被抑制50%时核苷的浓度)。
表4氧硒戊环核苷的抗HIV活性
碱基 | 在PBM细胞中的抗HIV活性(EC50μM) | PMB CEM Vero毒性(IC50μM) |
胞嘧啶5-氟胞嘧啶 | 0.880.07 | >100 >100 >100>100 >100 >100 |
表5提供了外消旋β-Se-ddC、其(+)和(-)异构体以及外消旋β-Se-FddC、其(+)和(-)异构体的纯度百分比、EC50值(μM)、EC90值(μM)和IC50值表5 氧硒戊环胞嘧啶核苷的外消旋物和对映异构体的抗HIV活性以及细胞毒性
化合物 | 对映异构体 | %纯度 | EC50μM | EC90μM | IC50PBM |
β-Se-ddCβ-Se-ddCβ-Se-ddCβ-Se-FddCβ-Se-FddCβ-Se-FddC | ±-+±-+ | 50≈100≈ 9650≈100≈100 | 2.690.883.395.550.2141.9 | 2095.4267716.411.05164 | >100>100>100>100>100>100 |
在反转录基因密码子184处显示突变的HIV感染的PBM细胞中,也测定了外消旋β-Se-ddC、其(+)和(-)异构体以及外消旋β-Se-FddC、其(+)和(-)异构体的抗HIV活性。表6提供了实验结果,表中显示,外消旋和(-)-β-Se-FddC对突变病毒显示显著的活性。
表6 氧硒戊环核苷的抗克隆M184HIV-1作用
注:FI(倍数增加)EC50=克隆病毒的EC50数据/xxBRU的EC50数据
化合物 | 对映异构体 | %纯度 | 病毒 | EC50μM | EC90μM | FIEC50 | FIEC90 |
β-Se-ddCβ-Se-ddCβ-Se-ddCβ-Se-FddCβ-Se-FddCβ-Se-FddC | ±-+±-+ | 50≈100≈ 9650≈100≈ 96 | xxBRUxxBRUxxBRUM184VM184VM184V | 1.840.118.62108>50>50 | 6.900.9535.1337>50>50 | ---59>455>6 | ---49>53>1 |
实施例5 1,3-氧硒戊环核苷的抗HBV活性
活性化合物在2.2.15细胞培养物(用肝炎病毒转化的HepG2细胞)中抑制病毒生长的能力可通过下面描述的方法进行评价。
已经记载了该培养基系统中抗病毒作用的测定和HBV DNA分析的概述和描述(Korba和Milman,1991,抗病毒研究(AntiviralRes.,)15:217)。在两个独立的传代细胞中进行抗病毒评价,在所有培养盘的所有孔中以相同的浓度和在相同的时间内接种。
由于细胞内和细胞外HBV DNA浓度的固有变化,对于未处理细胞中的HBV DNA形式,只有大于其平均浓度3.5倍(对于HBV毒粒DNA)或3.0倍(对于HBV-DNA复制中间体)的降低才认为在统计学上是显著的(P<0.05)。每个细胞内DNA标本(在这些实验中每个细胞保持恒定)的整合HBV DNA含量可以用来计算细胞内HBV DNA形式的浓度,因此确保同样含量的细胞内DNA在独立的样品中进行比较。
在未处理细胞中,细胞外HBV毒粒DNA值的典型范围是50-150pg/ml培养基(平均约76pg/ml)。未处理细胞中,细胞内HBV DNA复制中间体范围是50-100μg/pg细胞DNA(平均约74pg/μg细胞DNA)。通常地,由于经过抗病毒化合物处理,细胞内HBV DNA含量的降低比HBV毒粒DNA含量的降低较不明显些,并且发生得更慢些(Korba和milman,1991,抗病毒研究,15:217)。
对这些实验的杂交分析方式导致约10pg细胞内HBV DNA至2-3基因组复制物/细胞和1.0pg/ml细胞外HBV DNA至3×105病毒颗粒/ml当量值。
由于细胞生存的一般作用,可以进行毒性分析来测试是否有任何观测到的抗病毒作用。一种可行的方法是测定中性红染料的摄取量,这是在许多病毒宿主系统包括HSV和HIV系统中细胞生存力的一种标准的和广泛应用的检测方法。在96孔平底组织培养盘中进行毒性分析。通过与下面记载的抗病毒检测相同的方案,应用测试化合物培养并处理用于毒性分析的细胞。每个化合物测试4种浓度。每种浓度在三种相同的培养基中测试(“A”、“B”和“C”孔)。通过中性红色染料的摄取来确定毒性的相对程度。内部染料在510nm的吸收峰(Asin)用于定量分析。得到的值以9个独立的未处理细胞培养基(维持在与测试化合物同一个96孔培养盘)的平均Asin百分比形式提供。
实施例6应用1,3-氧硒戊环核苷治疗异常细胞增生
此处记载的一些1,3-氧硒戊环核苷可用来治疗包括肿瘤和癌的异常细胞增生。根据下面的方法,通过在CEM细胞或其它肿瘤或增生细胞系中测定化合物可以容易地检测抗增生活性的程度。CEM细胞是人淋巴瘤细胞(可以从ATCC、Rockville、MD得到的T-成淋巴细胞增多症细胞系)。化合物对CEM的毒性提供了关于化合物抗肿瘤活性有用的信息。毒性以IC50(微摩尔)方式测量。IC50是指在培养基中抑制肿瘤细胞50%增长时的测试化合物浓度。IC50越低,化合物的抗肿瘤活性越强。通常地,如果1,3-氧硒核苷在CEM或其它非灭活肿瘤细胞系中的毒性小于10微摩尔、更优选地小于5微摩尔和最优选地小于1微摩尔,则它显示抗肿瘤活性并可以用于治疗异常细胞增生。
药物溶液,包括作为阳性对照的放线菌酮,以最终浓度的2倍一式三份置于50μl的培养基中,在37℃温度下使之在5%CO2培养箱中平衡。在50μl培养基中加入Log相细胞使最终浓度达到2.5×103(CEM和SK-MEL-28)、5×103(MNAN,MDA-MB-435s,SKMES-1,DU-145,Lncap),或1×104(PC-3,MCF-7)细胞/孔,然后在5%CO2的空气和37℃的温度下培养3天(DU-145,PC-3,MNAN)、4天(MCF-7、SK-MEL-28、CEM)或5天(SK-MES-1、MDA-MB-435s、LNCaP)。对照孔包括单独的培养基(空白)和加上不含药物的培养基的细胞。在生长期之后,在每个孔中加入15μl细胞滴度的96套检测染料溶液(Promega,Madison,WI),该培养盘在5%CO2培养箱中37℃温度下培养8小时。在每个孔中加入Promega细胞滴度96套终止检测的溶液,并在培养箱中培养4-8小时。应用Biotek Biokinetics盘记录器(plate read,Biotek,Winooski,VT)读取只含培养基的孔在570nm的吸收值使其作为空白。计算出相对于未处理对照组的平均抑制生长百分比。计算出IC50、IC90、斜率和r值,计算方法参见Chou和Talaly.Chou T-C,Talalay P.量效关系的定量分析:多重药物或酶抑制剂的联合作用,Adv Enzyme Regul.1984:22:27-55。
IV药物组合物的制备
对于患有此处记载的任何一种疾病包括HIV感染、HBV感染或异常细胞增生的病人,可以通过对该病人施用在任选可药用载体或稀释剂中的有效量的1,3-氧硒核苷来进行治疗。该活性物质可以以液体或固体形式通过任何给药途径如口服、肠胃外给药、静脉注射、真皮内给药、皮下给药或局部给药。
可药用载体或稀释剂中含有足够量的活性化合物,从而对病人施用治疗有效量的化合物以抑制体内病毒复制特别是HIV和HBV复制,并且对治疗病人没有引起严重的毒性作用。“抑制量”是指活性成分的量足以产生例如通过此处记载的抑制检测方法可以检测出的抑制作用。
对于上面所提到的条件,化合物的优选剂量范围约1-50mg/kg体重/天,优选1-20mg/kg体重/天,更通常地为0.1-约100mg/kg受药者体重/天。根据要给用的母体核苷的重量,可以算出可药用衍生物的有效剂量范围。如果衍生物本身显示活性,通过上面应用衍生物的重量或本领域熟练技术人员已知的其它方式可以估计出有效量。
该化合物可合适地通过单位形式或任何其它合适剂型给药,包括但不限于每单位剂型中含有7-3000mg、优选70-1400mg活性成分。50-1000mg的口服剂量通常是合适的。
理想地,给药活性成分使活性化合物的血浆浓度峰值达到约0.2-70pM,优选约1.0-10μM。该目的是可以达到的,例如通过静脉注射0.1至5%活性成分溶液,任选生理盐水溶液或者以活性成分的药团形式给药。
药物组合物中,活性化合物的浓度依据药物的吸收、失活和排泄速率以及本领域技术人员已知的其它因素而定。应该注意:由于所需治疗疾病的严重程度不同,剂量值也可以相应变化。还应该明白:对于任何具体的受治疗者,根据个体需要以及给药人员或监督给药人员的职业判断,应该随时调整给药方案;此处提出的浓度范围仅仅是举例性的,它并不能限制所要求保护的组合物的范围和实行。活性成分可以一次给药或者分成许多更小剂量以不同的间隔时间给药。
该活性化合物的优选给药方式是口服。口服组合物通常包括惰性稀释剂或可食用载体。它们可包覆在明胶胶囊中或者压制成片剂。为了口服治疗给药的目的,活性化合物应该加入到赋形剂中然后用于制片剂、锭剂或胶囊。还可含有可药用的粘合剂和/或辅料物质作为组合物的一部分。
所述片剂、丸剂、胶囊和锭剂等可含有任何一种下列成分或类似性质的化合物:粘合剂如微晶纤维素、黄芪胶或明胶;赋形剂如淀粉或乳糖;崩解剂如海藻酸、Primogel或玉米淀粉;润滑剂如硬脂酸镁或Sterotes;助流剂如胶体二氧化硅;甜味剂如蔗糖和糖精;或矫味剂如薄荷、水杨酸甲酯或柑橘调味料(orange flavoring)。当单位剂型是胶囊时,除了上述类型物质外,它还可包括液体载体如脂肪油。另外,单位剂型还可含有能改变剂量单位物理形态的其它各种物质,例如糖、虫胶或其它可肠溶剂的包衣物。
该化合物可以作为酏剂、悬浮剂、糖浆剂、糯米纸囊剂或口香糖等的组份给药。除活性成分外,糖浆剂还可以含有用作甜味剂的蔗糖和某些防腐剂、染料和着色剂和调味品。
该化合物或者其可药用衍生物或盐还可与不削弱其预期作用的其它活性成分混合,或者与能增补其预期作用的物质混合,例如抗生素、抗真菌剂、抗炎症试剂、蛋白酶抑制剂或其它如上所详述的核苷或非核苷抗病毒剂。用于非肠道、真皮内、皮下或局部给药的溶液或悬浮液可以包括下列成分:无菌稀释剂如注射用水、生理盐水、不挥发油、聚乙二醇、甘油、丙二醇或其它合成溶剂,抗菌剂如苄醇或对羟基苯甲酯;抗氧化剂例如抗坏血酸或亚硫酸氢钠;络合剂如乙二胺四乙酸;缓冲剂如乙酸盐、柠檬酸盐或磷酸盐;还有用来调节紧张性的物质如氯化钠或葡萄糖。非肠道给药制剂可装入安瓿、一次性注射器或者玻璃或塑料制的多剂量小瓶中。
如果静脉注射给药,优选的载体是生理盐水或磷酸缓冲的盐水(PBS)。
在优选的实施方案中,活性化合物结合载体一起制备,所述载体可保护化合物免受体内迅速消除,如控释制剂包括植入剂和微胶囊给药系统。可以应用能生物降解的和生物相容的聚合物如乙烯乙酸乙烯酯、聚酐类、聚羟基乙酸、胶原、聚原酸酯和聚乳酸。这些制剂的制备方法对本领域技术人员来说是明显的。这些物质还可购自Alza公司。
脂质体悬浮液(包括以病毒抗原单克隆抗体感染的细胞为靶向物的脂质体)作为可药用载体也是优选的。这可按照本领域技术人员已知的方法制备,例如美国4,522,811号专利(该文件全文在此引入作为参考)所记载的方法。例如,脂质体制剂制备方法如下:把合适的脂类(如硬脂酰磷脂酰乙醇胺、硬脂酰磷脂酰胆硷、二十烷酰基磷脂酰胆碱和胆甾醇)溶解在无机溶剂中,然后蒸发,在容器表面留下干燥的脂类薄层膜;然后把活性化合物或者其单磷酸酯、二磷酸酯和/或三磷酸酯衍生物的水溶液加入到该容器中;然后,用手旋转容器使脂类物质离开容器侧边并分散脂类聚合体,因此形成脂质体悬浮液。
根据优选实施方案描述了本发明。根据本发明前面的详细描述可以对本发明作出各种改进和修饰,这对本领域熟练技术人员来说是显而易见的。也就是说,所有这些改进和修饰包括在本发明的范围内。
Claims (57)
2、如权利要求1所述的1,3-氧硒戊环核苷,其中B是嘧啶碱基。
3、如权利要求1所述的1,3-氧硒戊环核苷,其中B是嘌呤碱基。
4、如权利要求2或3所述的1,3-氧硒戊环核苷,其中R是氢。
5、如权利要求2或3所述的1,3-氧硒戊环核苷,其中R是酰基。
6、如权利要求2或3所述的1,3-氧硒戊环核苷,其中R是单磷酸酯。
7、如权利要求2或3所述的1,3-氧硒戊环核苷,其中R是二磷酸酯。
8、如权利要求2或3所述的1,3-氧硒戊环核苷,其中R是三磷酸酯。
9、如权利要求2或3所述的1,3-氧硒戊环核苷,其中R是稳定的磷酸酯。
10、如权利要求3所述的1,3-氧硒戊环核苷,其中R是脂醚。
11、如权利要求1所述的1,3-氧硒戊环核苷,其中B是胞嘧啶。
12、如权利要求1所述的1,3-氧硒戊环核苷,其中B是5-氟胞嘧啶。
13、如权利要求1所述的1,3-氧硒戊环核苷,其中B是鸟嘌呤。
14、权利要求1所述的1,3-氧硒戊环核苷,所述核苷为2-羟甲基-4-(N-5′-胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
15、权利要求1所述的1,3-氧硒戊环核苷,所述核苷为2-羟甲基-4-(N-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
16、权利要求1所述的1,3-氧硒戊环核苷,所述核苷为分离的对映异构体(-)-β-L-2-羟甲基-4-(N-5′-胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
17、权利要求1所述的1,3-氧硒戊环核苷,所述核苷为分离的对映异构体(-)-β-L-2-羟甲基-4-(N-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
18、治疗人或其它宿主动物的HIV或HBV感染的药物组合物,该组合物含有有效量的权利要求1所述的1,3-氧硒戊环核苷和可药用载体。
19、治疗人或其它宿主动物的HIV或HBV感染的药物组合物,该组合物含有有效量的权利要求2所述的1,3-氧硒戊环核苷和可药用载体。
20、治疗人或其它宿主动物的HIV或HBV感染的药物组合物,该组合物含有有效量的权利要求3所述的1,3-氧硒戊环核苷和可药用载体。
21、治疗人或其它宿主动物的HIV或HBV感染的药物组合物,该组合物含有有效量的权利要求4-17中任一项权利要求所述的1,3-氧硒戊环核苷和可药用载体。
23、如权利要求22所述的治疗HIV的方法,其中B是嘧啶碱基。
24、如权利要求22所述的治疗HIV的方法,其中B是嘌呤碱基。
25、如权利要求22所述的治疗HIV的方法,其中R是氢。
26、如权利要求22所述的治疗HIV的方法,其中R是酰基。
27、如权利要求22所述的治疗HIV的方法,其中R是单磷酸酯。
28、如权利要求22所述的治疗HIV的方法,其中R是二磷酸酯。
29、如权利要求22所述的治疗HIV的方法,其中R是三磷酸酯。
30、一种如权利要求22所述的治疗HIV的方法,其中R是氢。
31、一种如权利要求22所述的治疗HIV的方法,其中R是酰基。
32、一种如权利要求22所述的治疗HIV的方法,其中R是单磷酸酯。
33、一种如权利要求23所述的治疗HIV的方法,其中R是二磷酸酯(ditriphosphate)。
34、一种如权利要求24所述的治疗HIV的方法,其中R是三磷酸酯。
35、一种如权利要求25所述的治疗HIV的方法,其中所述的1,3-氧硒戊环核苷为2-羟甲基-4-(N-5′-胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
36、一种如权利要求26所述的治疗HIV的方法,其中所述的1,3-氧硒戊环核苷为2-羟甲基-4-(N-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
37、一种如权利要求27所述的治疗HIV的方法,其中所述的1,3-氧硒戊环核苷为分离的对映异构体(-)-β-L-2-羟甲基-4-(N-5′-胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
38、一种如权利要求28所述的治疗HIV的方法,其中所述的1,3-氧硒戊环核苷为分离的对映异构体(-)-β-L-2-羟甲基-4-(N-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
40、一种如权利要求39所述的治疗HBV的方法,其中B是嘧啶碱基。
41、一种如权利要求39所述的治疗HBV的方法,其中B是嘌呤碱基。
42、一种如权利要求39所述的治疗HBV的方法,其中R是氢。
43、一种如权利要求39所述的治疗HBV的方法,其中R是酰基。
44、一种如权利要求39所述的治疗HBV的方法,其中R是单磷酸酯。
58、一种如权利要求39所述的治疗HBV的方法,其中R是二磷酸酯(ditriphosphate)。
45、一种如权利要求39所述的治疗HBV的方法,其中R是三磷酸酯。
46、一种如权利要求39所述的治疗HBV的方法,其中R是氢。
47、一种如权利要求39所述的治疗HBV的方法,其中R是酰基。
48、一种如权利要求39所述的治疗HBV的方法,其中R是单磷酸酯。
49、一种如权利要求39所述的治疗HBV的方法,其中R是二磷酸酯。
50、一种如权利要求39所述的治疗HBV的方法,其中R是三磷酸酯。
51、一种如权利要求39所述的治疗HBV的方法,其中所述的1,3-氧硒戊环核苷为2-羟甲基-4-(N-5′-胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
52、一种如权利要求39所述的治疗HBV的方法,其中所述的1,3-氧硒戊环核苷为2-羟甲基-4-(N-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
53、一种如权利要求39所述的治疗HBV的方法,其中所述的1,3-氧硒戊环核苷为分离的对映异构体(-)-β-L-2-羟甲基-4-(N-5′-胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
54、一种如权利要求39所述的治疗HBV的方法,其中所述的1,3-氧硒戊环核苷为分离的对映异构体(-)-β-L-2-羟甲基-4-(N-5′-氟胞嘧啶-1′-基)-1,3-氧硒戊环或其可药用盐。
55、权利要求1所述的1,3-氧硒戊环核苷及其可药用的衍生物和盐在制备治疗HIV或HBV感染的药物中的应用。
56、权利要求1所述的1,3-氧硒戊环核苷及其可药用的衍生物和盐与其它抗病毒剂联合或交替给药用于治疗病毒感染。
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL142910A0 (en) * | 1998-11-02 | 2002-04-21 | Triangle Pharmaceuticals Inc | Combination therapy to treat hepatitis b virus |
NO20001903L (no) | 1999-04-14 | 2000-10-16 | Dow Chemical Co | Polyuretan-filmer fremstilt fra polyuretan-dispersjoner |
NO20001904L (no) | 1999-04-14 | 2000-10-16 | Dow Chemical Co | Polyuretanfilmer fremstilt ved elektrolytisk utfelling fra polyuretandispersjoner |
MY164523A (en) | 2000-05-23 | 2017-12-29 | Univ Degli Studi Cagliari | Methods and compositions for treating hepatitis c virus |
EA200601591A1 (ru) | 2000-05-26 | 2007-02-27 | Айденикс (Кайман) Лимитед | Применение рибонуклеозидных соединений для лечения флавивирусных и пестивирусных инфекций |
AU2002335489B2 (en) | 2001-03-01 | 2008-06-05 | Abbott Laboratories | Polymorphic and other crystalline forms of cis-FTC |
US7608600B2 (en) | 2002-06-28 | 2009-10-27 | Idenix Pharmaceuticals, Inc. | Modified 2′ and 3′-nucleoside prodrugs for treating Flaviviridae infections |
US20070026090A1 (en) * | 2003-09-05 | 2007-02-01 | Oren Tirosh | Treatment and prevention of inflammatory disease and mitochondrial dysfunction with high dose selenium |
EP2374434B1 (en) | 2006-09-06 | 2016-03-02 | Cook Medical Technologies LLC | Stents with connectors and stabilizing biodegradable elements |
MX2012011222A (es) | 2010-04-01 | 2013-01-18 | Centre Nat Rech Scient | Compuestos y composiciones farmaceuticas para el tratamiento de infecciones virales. |
KR101021294B1 (ko) * | 2010-10-11 | 2011-03-11 | 공주대학교 산학협력단 | 신규한 셀레닐 메틸 우라실 화합물 및 이를 이용한 방사선 치료 증진제 및 의약 조성물 |
US9243025B2 (en) | 2011-03-31 | 2016-01-26 | Idenix Pharmaceuticals, Llc | Compounds and pharmaceutical compositions for the treatment of viral infections |
EP2755985B1 (en) | 2011-09-12 | 2017-11-01 | Idenix Pharmaceuticals LLC | Compounds and pharmaceutical compositions for the treatment of viral infections |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5223263A (en) * | 1988-07-07 | 1993-06-29 | Vical, Inc. | Liponucleotide-containing liposomes |
US4947966A (en) * | 1986-09-30 | 1990-08-14 | Zahnradfabrik Friedrichshafen Ag | Vehicle gearbox with incorporated brake |
NZ228645A (en) * | 1988-04-11 | 1991-09-25 | Iaf Biochem Int | 1,3-dioxolane derivatives substituted in the 5th position by a purine or pyrimidine radical; treatment of viral infections |
US5466806A (en) * | 1989-02-08 | 1995-11-14 | Biochem Pharma Inc. | Processes for preparing substituted 1,3-oxathiolanes with antiviral properties |
US5047407A (en) * | 1989-02-08 | 1991-09-10 | Iaf Biochem International, Inc. | 2-substituted-5-substituted-1,3-oxathiolanes with antiviral properties |
US5041449A (en) * | 1988-04-11 | 1991-08-20 | Iaf Biochem International, Inc. | 4-(nucleoside base)-substituted-1,3-dioxolanes useful for treatment of retroviral infections |
US5194654A (en) * | 1989-11-22 | 1993-03-16 | Vical, Inc. | Lipid derivatives of phosphonoacids for liposomal incorporation and method of use |
US5463092A (en) * | 1989-11-22 | 1995-10-31 | Vestar, Inc. | Lipid derivatives of phosphonacids for liposomal incorporation and method of use |
JP2567536B2 (ja) * | 1989-12-20 | 1996-12-25 | バイオテック オーストラリア プロプライアタリィ リミティド | Paiー2の変異体 |
US6346627B1 (en) * | 1990-02-01 | 2002-02-12 | Emory University | Intermediates in the synthesis of 1,3-oxathiolane nucleoside enantiomers |
US6642245B1 (en) * | 1990-02-01 | 2003-11-04 | Emory University | Antiviral activity and resolution of 2-hydroxymethyl-5-(5-fluorocytosin-1-yl)-1,3-oxathiolane |
US5204466A (en) * | 1990-02-01 | 1993-04-20 | Emory University | Method and compositions for the synthesis of bch-189 and related compounds |
US5700937A (en) * | 1990-02-01 | 1997-12-23 | Emory University | Method for the synthesis, compositions and use of 2'-deoxy-5-fluoro-3'-thiacytidine and related compounds |
US5256641A (en) * | 1990-11-01 | 1993-10-26 | State Of Oregon | Covalent polar lipid-peptide conjugates for immunological targeting |
US5149794A (en) * | 1990-11-01 | 1992-09-22 | State Of Oregon | Covalent lipid-drug conjugates for drug targeting |
US5543389A (en) * | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education On Behalf Of The Oregon Health Sciences University, A Non Profit Organization | Covalent polar lipid-peptide conjugates for use in salves |
US5543390A (en) * | 1990-11-01 | 1996-08-06 | State Of Oregon, Acting By And Through The Oregon State Board Of Higher Education, Acting For And On Behalf Of The Oregon Health Sciences University | Covalent microparticle-drug conjugates for biological targeting |
US5179104A (en) * | 1990-12-05 | 1993-01-12 | University Of Georgia Research Foundation, Inc. | Process for the preparation of enantiomerically pure β-D-(-)-dioxolane-nucleosides |
WO1992010496A1 (en) * | 1990-12-05 | 1992-06-25 | University Of Georgia Research Foundation, Inc. | ENANTIOMERICALLY PURE β-L-(-)-1,3-OXATHIOLANE NUCLEOSIDES |
US5925643A (en) * | 1990-12-05 | 1999-07-20 | Emory University | Enantiomerically pure β-D-dioxolane-nucleosides |
NZ241625A (en) * | 1991-02-22 | 1996-03-26 | Univ Emory | 1,3-oxathiolane derivatives, anti-viral compositions containing such and method of resolving racemic mixture of enantiomers |
GB9104740D0 (en) * | 1991-03-06 | 1991-04-17 | Wellcome Found | Antiviral nucleoside combination |
ATE219366T1 (de) * | 1991-03-06 | 2002-07-15 | Univ Emory | Verwendung von 5-fluoro-2'-deoxy-3'-thiacytidin zur behandlung von hepatitis b |
WO1992018517A1 (en) * | 1991-04-17 | 1992-10-29 | Yale University | Method of treating or preventing hepatitis b virus |
GB9110874D0 (en) * | 1991-05-20 | 1991-07-10 | Iaf Biochem Int | Medicaments |
US5554728A (en) * | 1991-07-23 | 1996-09-10 | Nexstar Pharmaceuticals, Inc. | Lipid conjugates of therapeutic peptides and protease inhibitors |
GB9116601D0 (en) * | 1991-08-01 | 1991-09-18 | Iaf Biochem Int | 1,3-oxathiolane nucleoside analogues |
-
1998
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- 1998-03-19 US US09/044,558 patent/US6071922A/en not_active Expired - Fee Related
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- 1998-03-19 DE DE69823984T patent/DE69823984T2/de not_active Expired - Lifetime
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- 1998-03-19 EA EA199900843A patent/EA001920B1/ru not_active IP Right Cessation
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105039489A (zh) * | 2004-02-03 | 2015-11-11 | 埃莫里大学 | 制备1,3-二氧戊环核苷的方法 |
CN107614025A (zh) * | 2014-11-03 | 2018-01-19 | 尼古拉·弗拉基米罗维奇·鲍文 | 抗菌表面处理 |
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AU739240B2 (en) | 2001-10-04 |
DE69823984T2 (de) | 2005-05-12 |
AU6866598A (en) | 1998-10-12 |
US6590107B1 (en) | 2003-07-08 |
US6071922A (en) | 2000-06-06 |
EA199900843A1 (ru) | 2000-04-24 |
ES2221164T3 (es) | 2004-12-16 |
EA005097B1 (ru) | 2004-10-28 |
EA200100494A1 (ru) | 2001-10-22 |
CA2287370A1 (en) | 1998-09-24 |
ATE267198T1 (de) | 2004-06-15 |
CN1196701C (zh) | 2005-04-13 |
EA200100494A3 (ru) | 2002-02-28 |
EP0970078B1 (en) | 2004-05-19 |
CA2287370C (en) | 2010-02-09 |
US6197777B1 (en) | 2001-03-06 |
EP0970078A1 (en) | 2000-01-12 |
WO1998041522A1 (en) | 1998-09-24 |
DE69823984D1 (de) | 2004-06-24 |
EA001920B1 (ru) | 2001-10-22 |
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