CN1324250A - 治疗或预防病毒感染及其所致疾病的方法 - Google Patents
治疗或预防病毒感染及其所致疾病的方法 Download PDFInfo
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- CN1324250A CN1324250A CN99812583A CN99812583A CN1324250A CN 1324250 A CN1324250 A CN 1324250A CN 99812583 A CN99812583 A CN 99812583A CN 99812583 A CN99812583 A CN 99812583A CN 1324250 A CN1324250 A CN 1324250A
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Abstract
治疗和预防病毒感染及其所致疾病的方法。
Description
发明领域
本发明涉及治疗或预防病毒感染及其所致疾病、特别是由黄病毒科病毒引起的病毒感染及其所致疾病的方法。
发明背景
黄病毒科由三个属和通常未指定到具体属的7种病毒组成。肝炎病毒属包括丙型肝炎病毒(HCV)。病毒例如GB病毒-A和类似于GB病毒-A的介质、GB病毒-B和GBV-C或G型肝炎病毒虽然目前没有正式归类为肝炎病毒属,但是它们与HCV紧密相关,并代表着黄病毒科当中未指定到属的成员。还属于黄病毒科的有瘟病毒属,包括牛病毒性腹泻病毒(BVDV)、边界病病毒和经典的猪热病毒,和黄病毒属,包括例如登革热病毒、黄热病病毒、日本脑炎病毒、和蜱传脑炎病毒。
黄病毒科病毒在人和动物群体中引起严重疾病。HCV是全球人类肝炎的主要病因。世界健康组织估计,目前在全世界范围内有一亿七千万人感染有该病毒。大多数感染变得持久,并且约60%感染者发展成慢性肝病。慢性HCV感染可导致发展成肝硬化、肝细胞癌和肝衰竭。
在美国是使用干扰素或者联合使用干扰素与利巴韦林来治疗HCV引起的肝炎。在某些患者中这些治疗改善了血清酶反应。余下的患者对这些治疗没有反应。就对于这些治疗有反应的患者而言,仅在小部分患者中观察到了持续的临床改善;大多数患者在停止治疗后复发。因此,治疗慢性丙肝的有效性是不定的,并且其治愈比例很低。此外,治疗经常伴有严重的副作用。
驯养家畜的瘟病毒感染在全球范围内引起了严重的经济损失。瘟病毒引起多种临床表现,包括流产、形成畸形、呼吸困难、慢性消耗病、免疫系统机能障碍、和易感染其它病毒和细菌。一些BVDV菌株引起急性致死性疾病。BVDV还在胎儿中建立了持久感染。当出生后,这些持久感染(PI)的动物一生都保持病毒感染并成为连续的病毒贮主。PI动物经常死于致命的粘膜性疾病。
黄病毒是人的重要病原体,并且也在全球范围内流行。至少有38种导致人类疾病的黄病毒,包括登革热病毒、黄热病病毒和日本脑炎病毒。黄病毒引起多种急性发热性疾病、脑炎和出血性疾病。
目前没有任何治疗或预防黄病毒感染的抗病毒药物。
很明显,需要治疗和预防由黄病毒科病毒引起的感染和疾病的新手段。
至于诊断、控制、预防和治疗病毒感染及其所致疾病的途径,经常期望鉴定出可在这些途径中利用的病毒特异性功能。特别是,病毒编码多肽的酶活性是相当有用的。这些病毒特异性组分经常是病毒复制所必需的,并且可以作为抗病毒药物开发策略的合适的靶目标物。
在许多RNA病毒生命周期中起关键作用的其中一种这样的靶目标物是病毒编码的依赖于RNA的RNA聚合酶(RdRp)蛋白。至于黄病毒科病毒,对于肝炎病毒和瘟病毒该蛋白称为NS5B,对于黄病毒该蛋白称为NS5(统称为NS5)。RdRp蛋白是病毒复制酶复合物的关键组分,该复合物使得病毒能够复制其RNA基因组并生成后代病毒。RNA病毒的RdRp是开发抗病毒药物的有吸引力的靶目标物。
发明简述
本发明提供了在感染病毒的活宿主中治疗病毒感染以及由该感染所引起的疾病的方法,包括给所述宿主施用治疗有效量的式Ⅰ化合物或其前体、以及它们的异构体和可药用盐:其中X代表选自S、O、或NRa的部分,Ra是氢或具有1-5个碳原子的烷基;
R1代表基团,其选自:未取代或取代的杂环基、未取代或取代的二环部分、未取代或取代的苯基(C6H5)、未取代或取代的联苯基(C6H5-C5H4)、其中n是1-5的整数的未取代或取代的ω-苯基链烯基(C6H5(CH=CH)n)例如2-苯基乙烯基、其中p是1-5的整数的未取代或取代的ω-苯基链炔基(C6H5(C≡C)p)、或具有1-5个碳原子的未取代或取代的直链或支链烷基,所述杂环基选自呋喃、噻吩、噁唑、噁二唑、吡啶、嘧啶、吡唑、三唑、哒嗪、1,3-氧硫杂环戊烷、噻唑、噻二唑、嘧唑、吡咯、四唑和三嗪,所述二环部分选自苯并呋喃、异苯并呋喃、苯并噻吩、异苯并噻吩、苯并噁唑、苯并吡咯、异吲哚、苯并吡唑、喹啉、异喹啉、1,2-苯并二嗪、1,3-苯并二嗪、1,2,3-苯并三唑、苯并噻唑、苯并嘧唑、1,2,3-苯并三嗪、和1,2,4-苯并三嗪,所述杂环基和二环部分上的取代基选自具有1-5个碳原子的烷基、卤素、烷氧基、羟基、硝基、或未取代或取代的苯基;
R2和R3独立地代表氢、未取代或取代的苯基、或-(CH2)qCOOH,其中q是1-5的整数,并且R2和R3当中至少有一个是氢;
苯基上的取代基、联苯基上的取代基、ω-苯基链烯基上的取代基、和ω-苯基链炔基上的取代基是至少一个选自下述基团的取代基:卤素、硝基、羧基、羟基、具有1-5个碳原子的烷基、三氟甲基、烷氧基、酰氧基(acylocy)、氰基、氨基、烷基氨基、二烷基氨基、磺酰氨基、氨基甲酰基、烷氧羰基、硫羟基、烷硫基、烷基亚磺酰基、和烷基磺酰基;所述烷基上的取代基是至少一个选自下述基团的取代基:羧基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、硫羟基或烷硫基。
在上述式Ⅰ化合物中,杂环基、二环部分、苯基、联苯基等上的取代基还可以是全卤代烷基、二卤代烷基、一卤代烷基,并且杂环基和二环部分还可以被硫羟基、烷硫基、烷基亚磺酰基或烷基磺酰基取代。
上述化合物还可用于在易感染的宿主中预防病毒感染以及由该感染所引起的疾病,包括给所述宿主施用预防有效量的上述化合物或其前体。
发明详述
在本发明方法中使用的化合物可依据下述一般合成方案(除了别的方法以外)由已知原料方便地制得。
下面举例说明可用于实施本发明的具体抗病毒化合物的制备。
在实施上述一般合成方案的过程中,将适当的醛与巴比土酸或2-硫代巴比土酸在二甲基甲酰胺(DMF)与乙酸的混合物中于80℃反应或者在DMF与盐酸的混合物中于室温反应。或者,可使用在乙醇中的哌啶作为反应介质来进行该反应。醛原料或例如可通过还原转化成醛的酸是从不同商业渠道(例如Sigma,St.Louis,MO)获得的。
用于实施本发明的其它化合物可通过在上述反应方案中替换适当原料而以类似方式制得。
体外试验已经证实了本发明化合物作为抗病毒剂的有用性。抗病毒活性是通过在关于RNA合成的酶学分析中测定化合物抗病毒RdRp的抑制活性而确定的。
上述式Ⅰ化合物的所有可能异构体都在本发明范围内。这些异构体的代表性实例包括但不限于顺式和反式异构体。
本文所用术语“烷基”是指具有1-5个碳原子的脂族烃基。同样,组合使用以命名取代基例如烷氧基、烷基氨基等的术语“烷基”或其任意变型也是指具有1-5个碳原子的脂族烃基。
本文所用术语“氨基甲酰基”是指式-C(=O)-NR″R所示基团或取代基,其中R″和R代表氢或烷基。
本文所用术语“磺酰氨基”是指式-SO2NR″R或-NR″-SO2R所示基团,其中R″和R定义同上。
特别适用于实施本发明的是包括异构形式在内的式Ⅱ化合物、及其异构体和可药用盐:其中Y和Z可以是氢、卤素、硝基、羧基、羟基、烷氧基、具有1-5个碳原子的烷基、三氟甲基、三氟甲氧基、酰氧基、氰基、磺酰氨基、氨基甲酰基、烷氧羰基、硫羟基、烷硫基、烷基亚磺酰基、烷基磺酰基、氨基、烷基氨基或二烷基氨基,W可以是-O-、-S-、或-N(Rb)-,Rb是氢或具有1-5个碳原子的烷基,X定义同上。
上述式Ⅰ和Ⅱ化合物及其可药用盐显现出抗病毒活性。本发明方法能特别有效地抗黄病毒科病毒,并可用于在活宿主中治疗和/或预防由这些病毒引起的感染和疾病。
上述化合物或其前体(例如前药)及其可药用盐还可用于与补充活性剂联合使用来在活宿主中治疗和预防病毒感染和疾病,所述补充活性剂包括但不限于干扰素、利巴韦林、蛋白酶抑制剂、免疫球蛋白、免疫调节剂、保肝剂、抗炎剂、抗生素、抗病毒剂、抗感染剂等。
本发明化合物还可用于在细胞、组织或器官培养物以及其它体外应用中防止或消除病毒感染。例如,将本发明化合物作为补充物加到细胞或组织生长培养基和细胞或组织培养组分中可防止先前没有感染病毒的培养物被病毒感染或污染。上述化合物还可用于从被病毒感染或污染的培养物或其它生物材料(例如血液)中消除病毒,其中是在本领域技术人员确定的各种处理条件下处理适当时间来消除病毒。
某些用于本发明方法的化合物例如具有碱性取代基的化合物可与各种无机酸和有机酸、包括但不限于盐酸或乙酸形成适用的盐,具有酸性官能团的化合物可与无机碱或有机碱形成盐,所述碱包括但不限于碱金属氢氧化物、碱土金属氢氧化物、哌啶、氢氧化铵、三乙胺等。
式Ⅰ和Ⅱ化合物的可药用盐是依据下述本领域技术人员熟知的方法制得的。
在本发明方法中使用的抗病毒药物组合物包含一种或多种上述式Ⅰ或Ⅱ化合物作为活性组分,并任选包含至少一种补充活性剂,和可药用载体或辅助剂。
本发明组合物可制成多种给药剂型,包括片剂、小胶囊、丸剂或糖衣丸剂,或者可填充在适当容器例如胶囊中,或者对于悬浮剂可填充在瓶中。本文所说的“可药用载体”包括适于特定所需剂型的任意和所有溶剂、稀释剂、或其它液体载体、分散或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。Remington's Pharmaceutical Science,第15版,E.W.Martin(Mack Publishing Co.,Easton,PA,1975)中公开了用于配制药物组合物的各种载体和制备药物组合物的已知技术。除非常规载体与实施本发明所用的抗病毒化合物不配伍、例如产生不良生物作用或者以有害方式与药物组合物中的任意其它组分相互作用,否则其应用包括在本发明范围内。
在本发明药物组合物中,按包括载体和/或补充活性剂(若有的话)在内的组合物的总重量计,活性组分的含量可以为至少0.5%重量,通常不超过90%重量。活性剂的比例优选为占组合物重量的2-50%。
可使用适于肠内或非胃肠道给药给药的药物有机或无机固体或液体载体来配制组合物。明胶、乳糖、淀粉、硬脂酸镁、滑石、植物和动物脂肪和油、树胶、聚亚烷基二醇、或其它已知药物载体或赋形剂可全部适于用作载体或赋形剂。
可以以能有效地减轻病毒感染性的任意剂量和任意给药途径施用上述化合物。因此,本文所说的“减轻病毒感染性的有效量”是指对于病毒感染能提供预期治疗的无毒但是足够量的抗病毒剂。所需准确量随着治疗个体的不同而变化,并取决于具体患者的种类、年龄、和身体一般状况、感染的严重程度、具体抗病毒剂及其给药方式等。
为了便于给药和使剂量一致,优选将本发明抗病毒化合物配制在单位剂型中。本文所说的“单位剂型”是指适用于欲治疗患者的抗病毒剂的物理不连续剂型。每一单位剂型应当含有经计算能产生预期疗效的量的活性物质,可仅含有活性物质,或者含有活性物质和所选的可药用载体。一般以含有约0.1mg-约500mg、优选约1mg-约100mg抗病毒剂(按组合物重量计)的单位剂型施用抗病毒化合物。
本发明所述的抗病毒化合物可以以其自身的形式给药,或者以能衍生出该活性剂的前体例如前药的形式给药。前药是本发明所述化合物的衍生物,它在体内通过化学或代谢过程转化成活性化合物而产生药理作用。前药包括但不限于具有羧基或羟基官能团的上述式Ⅰ或Ⅱ化合物的酯。这种酯可由单纯的或官能化的脂族醇或羧酸制得。这种前药可依据药物化学和药物制剂学领域中众所周知的方法制得。
根据欲治疗感染的性质和严重程度,本发明抗病毒化合物可经口服给药,经直肠给药,经非胃肠道给药例如通过肌内注射、皮下注射、静脉内注射等给药,经脑池内给药,经阴道内给药,经腹膜内给药,经局部给药例如以粉剂、软膏剂、滴剂等剂型局部给药,或吸入给药例如通过气雾剂等吸入给药。根据给药途径,本发明化合物可以以约0.001-约120mg/kg个体体重/天、优选约0.01-约30mg/kg个体体重/天的剂量水平给药,每天给药一次或多次,以获得预期疗效。
例如,对于口服给药,合适的剂量大约为30mg/kg体重/天,而对于静脉内给药,剂量一般为大约10mg/kg体重/天。
这些抗病毒化合物一般每天给药1-4次以施以上述日剂量。然而,本发明化合物和组合物的准确给药方案必须取决于各治疗宿主的需要、给药治疗的类型和医疗专门医师的判断。本文所用术语“宿主”既包括人又包括动物。
鉴于在本发明方法中使用的化合物所产生的对病毒RNA合成的抑制作用,可以预计这些化合物不仅能用于病毒感染的治疗性治疗,还能用于预防病毒感染。无论是治疗还是预防病毒感染,剂量可基本上相同。
提供下述实施例来更详细地描述本发明。以优选方式实施本发明的这些实施例只是举例说明,并不是对本发明的限制。
下述实施例举例说明了在本发明方法中使用的化合物的化学合成。
实施例15-(2,4-二羟基苯基亚甲基)-2-硫代二氢嘧啶-4,6-二酮
向0.144g(1mmol)4,6-二羟基-2-巯基嘧啶和2ml乙酸在2ml DMF内的溶液中加入2,4-二羟基苯甲醛(1mmol)在2ml DMF中的溶液。将该悬浮液在氮气氛下于80℃加热16小时。冷却至室温,将该反应混合物倒入水中,通过过滤收集沉淀。用水洗涤该粗产物,将固体在甲醇中煮沸1分钟。过滤,获得了2.6mg产物。
实施例25-(5-(2-三氟甲基苯基)呋喃-2-基亚甲基)-2-硫代二氢嘧啶-4,6-二酮
将0.242g(1mmol)5-(2-三氟甲基苯基)呋喃甲醛、0.144g(1mmol)4,6-二羟基-2-巯基嘧啶和1滴哌啶在6ml乙醇中的悬浮液在搅拌下于80℃加热4小时。冷却,将该橙色悬浮液倒入50ml水中,并超声处理10分钟。将橙色溶剂过滤并干燥,获得了0.204g产物,为橙色粉末。
实施例35-(5-溴噻吩-2-基亚甲基)-2-硫代二羟基嘧啶-4,6-二酮
按照与实施例1相同的方法,将0.144g(1mmol)4,6-二羟基-2-巯基嘧啶、和0.207g(1mmol)5-溴噻吩甲醛在2ml冰醋酸与4ml DMF的溶液中于80℃加热12小时。冷却至室温,将该反应混合物倒入水中,通过过滤收集沉淀。用水洗涤粗产物,将所得固体在甲醇中煮沸1分钟。过滤,获得了92mg产物,为橙色固体。
实施例45-(5-(5-[3,4-二氯苯基]呋喃-2-基亚甲基)嘧啶-2,4,6-三酮
a)在-78℃、氩气氛下,向6.03g(0.0273mol)5-溴-2-呋喃甲醛二甲缩醛在75mg无水THF内的溶液中加入12ml(1.1当量)25M正丁基锂。10分钟后,用8.88g(1当量)氯化三丁基锡终止该黄色溶液的反应,将该反应混合物缓慢地升至室温。用水提取该溶液后,用无水硫酸钠干燥有机层,除去溶剂,获得了11.3g 5-三丁基锡-2-呋喃甲醛二甲缩醛,为微红色油状物。
b)向2.38g(10.5 mmol)1-溴-3,4-二氯苯和5.0g(11.6mmol)上述步骤a)产物在25ml无水四氢呋喃内的溶液中加入356mg氯化钯(Ⅱ)二(三苯基磷),将该溶液在氩气氛下加热回流。该溶液缓慢地转变成深棕色,在回流温度下加热12小时。冷却至室温后,用乙醚稀释该溶液,并用水萃取再次。用乙醚提取水层,合并有机层,干燥并用木炭脱色。除去溶剂,把残余物溶于乙酸乙酯中,将该溶液过硅胶柱。将该溶液浓缩至干,把残余物溶于95%己烷和5%乙酸乙酯的溶液中,并过硅胶HPLC柱。收集各级分,将通过TLC证实含有纯产物的级分合并,并用乙酸乙酯/己烷的混合物重结晶,获得了245mg 5-(3,4-二氯苯基)呋喃-2-基甲醛。
c)向100mg(0.4l5mmol)在上述步骤b)中制得的呋喃甲醛和56mg(0.436mmol)巴比土酸在10ml乙醇内的溶液中加入2滴哌啶,将该溶液加热回流。开始形成橙色固体。将该混合物在回流状态下保持5分钟,然后冷却至室温。将该混合物倒入水中,收集固体,用水和己烷洗涤并干燥。干燥后,获得了330mg本标题化合物。
实施例5
抑制病毒RNA复制
病毒聚合酶及其相关蛋白抑制剂的发现通常需要评价大量化学化合物或化学化合物的混合物。因此,需要能作大量筛选的聚合酶活性分析-换句话说高吞吐量分析。有多种本领域技术人员众所周知的能高效率地筛选大量样本的分析方法。参见,例如Cole,JL,Meth Enzymology,275:310-328(1996)。任何一种这些分析都可适于病毒RdRp活性分析。
测定黄病毒科病毒的病毒RdRp活性的一种方法在体外RdRp分析中使用了重组NS5蛋白。例如,Behrens等人,EMBO J.,15:12-22(1996)和Lohmann等人,J.Virol.,71:8416-8428(1997)中描述了HCV NS5B RdRp的杆状病毒表达、纯化和酶活性。PCT/US96/15571[WO/97/12033]和Yuan等人[Biochem BiophysRes Comm,232:231-235(1997)]中公开了HCV NS5B RdRp蛋白的细菌表达、纯化和酶活性。在另一实例中,通常属于本申请所拥有的Collett的PCT/US99/07404公开了包含功能HCV NS5B序列的组合物,及其在鉴定用于治疗肝炎病毒感染的化合物中的应用。如上述关于HCV RdRp的实例所述,已经纯化了细菌表达的登革热黄病毒NS5蛋白,并且其表现出RdRp活性[Tan等人,Virology,216:317-325(1996)],该活性与从重组杆状病毒感染细胞纯化的瘟病毒BVDV的NS5B蛋白所具有的活性相同[Zhong等人,J.Virol.,72:9365-9369(1998)]。
例如,可通过使用基本上依据Collett的PCT/US99/07404制得的NS5蛋白来在体外RdRp分析中测定候筛选抗病毒化合物的抑制活性。将纯化的NS5蛋白在标准RdRp反应混合物中培养。该反应混合物通常由缓冲剂、盐、阳离子、还原剂等以及三磷酸核苷和RNA模板引物组成。为了与各NS5蛋白的特定反应相适应,可能需要对这种反应混合物中的各组分作出改动。这种改动是本领域技术人员众所周知的。用该分析评价了如实施例1-4与表1和2所示的代表性式Ⅰ化合物的抗病毒活性。测试化合物的抑制活性以IC50值表示。IC50值代表RdRp活性被抑制50%时化合物的浓度。用至少一种黄病毒科病毒进行的抑制RdRp活性的分析结果显示,测试化合物的IC50值为约0.1μM-约30μM。
需要低浓度测试化合物来达到对HCV RdRp活性的50%抑制意味着本发明方法能有效地抑制黄病毒科病毒复制中依赖于病毒RdRp酶的RNA合成。
虽然已经描述、并且依据一些优选的实施方案举例说明了本发明,但是其它实施方案对于本领域技术人员来说是显而易见的。因此,本发明并不限于这些所描述和举例说明的特定实施方案,而是能够在不背离本发明实质的情况下作出修饰和改变,本发明全部范围由本申请权利要求书确定。
R
Claims (14)
1.在感染至少一种黄病毒科病毒的活宿主中治疗所述感染以及由该感染所引起的疾病的方法,所述方法包括给所述宿主施用治疗有效量的式Ⅰ化合物或其前体、以及它们的异构体和可药用盐:其中X代表选自S、O、或N(Ra)的部分,Ra是氢或具有1-5个碳原子的烷基;
R1代表基团,其选自:未取代或取代的杂环基、未取代或取代的二环部分、未取代或取代的苯基(C6H5)、未取代或取代的联苯基(C6H5-C5H4)、其中n是1-5的整数的未取代或取代的ω-苯基链烯基(C6H5(CH=CH)n)、其中p是1-5的整数的未取代或取代的ω-苯基链炔基(C6H5(C≡C)p)、或具有1-5个碳原子的未取代或取代的直链或支链烷基,所述杂环基选自呋喃、噻吩、噁唑、噁二唑、吡啶、嘧啶、吡唑、三唑、哒嗪、1,3-氧硫杂环戊烷、噻唑、噻二唑、嘧唑、吡咯、四唑和三嗪,所述二环部分选自苯并呋喃、异苯并呋喃、苯并噻吩、异苯并噻吩、苯并噁唑、苯并吡咯、异吲哚、苯并吡唑、喹啉、异喹啉、1,2-苯并二嗪、1,3-苯并二嗪、1,2,3-苯并三唑、苯并噻唑、苯并嘧唑、1,2,3-苯并三嗪、和1,2,4-苯并三嗪,所述杂环基和二环部分上的取代基选自具有1-5个碳原子的烷基、卤素、烷氧基、羟基、硝基、全卤代烷基、二卤代烷基、一卤代烷基、硫羟基、烷硫基、烷基亚磺酰基、烷基磺酰基、或未取代或取代的苯基;
R2和R3独立地代表氢、未取代或取代的苯基、或-(CH2)qCOOH,其中q是1-5的整数,并且R2和R3当中至少有一个是氢;
苯基上的取代基、联苯基上的取代基、ω-苯基链烯基上的取代基、和ω-苯基链炔基上的取代基是至少一个选自下述基团的取代基:卤素、硝基、羧基、羟基、具有1-5个碳原子的烷基、全卤代烷基、二卤代烷基、一卤代烷基、烷氧基、酰氧基(acylocy)、氰基、氨基、烷基氨基、二烷基氨基、磺酰氨基、氨基甲酰基、烷氧羰基、硫羟基、烷硫基、烷基亚磺酰基、和烷基磺酰基;所述烷基上的取代基是至少一个选自下述基团的取代基:羧基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、硫羟基或烷硫基。
2.权利要求1的方法,其中所述化合物是以含有约0.001-约120mg所述化合物/kg患者体重/天的单位剂量施用的。
3.权利要求2的方法,其中所述单位剂量包含可药用载体。
4.权利要求3的方法,其中所述化合物的前体是以前药形式施用的。
5.权利要求1的方法,其中所述化合物或所述化合物的前体是与至少一种选自干扰素、利巴韦林、蛋白酶抑制剂、免疫球蛋白、免疫调节剂、保肝剂、抗炎剂、抗生素、抗病毒剂、或抗感染剂的补充活性剂联合施用的。
6.权利要求5的方法,其中所述化合物或所述化合物的前体与所述至少一种补充活性剂是同时施用的。
7.权利要求1的方法,其中所述给药途径选自口服给药、直肠给药、非胃肠道给药、脑池内给药、阴道内给药、腹膜内给药、局部给药或吸入给药。
8.在易感染的活宿主中预防由至少一种黄病毒科病毒引起的感染以及由该感染所引起的疾病的方法,所述方法包括给所述宿主施用预防有效量的式Ⅰ化合物或其前体、以及它们的异构体和可药用盐:其中X代表选自S、O、或N(Ra)的部分,Ra是氢或具有1-5个碳原子的烷基;
R1代表基团,其选自:未取代或取代的杂环基、未取代或取代的二环部分、未取代或取代的苯基(C6H5)、未取代或取代的联苯基(C6H5-C5H4)、其中n是1-5的整数的未取代或取代的ω-苯基链烯基(C6H5(CH=CH)n)、其中p是1-5的整数的未取代或取代的ω-苯基链炔基(C6H5(C≡C)p)、或具有1-5个碳原子的未取代或取代的直链或支链烷基,所述杂环基选自呋喃、噻吩、噁唑、噁二唑、吡啶、嘧啶、吡唑、三唑、哒嗪、1,3-氧硫杂环戊烷、噻唑、噻二唑、嘧唑、吡咯、四唑和三嗪,所述二环部分选自苯并呋喃、异苯并呋喃、苯并噻吩、异苯并噻吩、苯并噁唑、苯并吡咯、异吲哚、苯并吡唑、喹啉、异喹啉、1,2-苯并二嗪、1,3-苯并二嗪、1,2,3-苯并三唑、苯并噻唑、苯并嘧唑、1,2,3-苯并三嗪、和1,2,4-苯并三嗪,所述杂环基和二环部分上的取代基选自具有1-5个碳原子的烷基、卤素、烷氧基、羟基、硝基、全卤代烷基、二卤代烷基、一卤代烷基、硫羟基、烷硫基、烷基亚磺酰基、烷基磺酰基、或未取代或取代的苯基;
R2和R3独立地代表氢、未取代或取代的苯基、或-(CH2)qCOOH,其中n是1-5的整数,并且R2和R3当中至少有一个是氢;
苯基上的取代基、联苯基上的取代基、ω-苯基链烯基上的取代基、和ω-苯基链炔基上的取代基是至少一个选自下述基团的取代基:卤素、硝基、羧基、羟基、具有1-5个碳原子的烷基、全卤代烷基、二卤代烷基、一卤代烷基、烷氧基、酰氧基(acylocy)、氰基、氨基、烷基氨基、二烷基氨基、磺酰氨基、氨基甲酰基、烷氧羰基、硫羟基、烷硫基、烷基亚磺酰基、和烷基磺酰基;所述烷基上的取代基是至少一个选自下述基团的取代基:羧基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、硫羟基或烷硫基。
9.权利要求8的方法,其中所述化合物是以含有约0.001-约120mg所述化合物/kg患者体重/天的单位剂量施用的。
10.权利要求9的方法,其中所述单位剂量包含可药用载体。
11.权利要求8的方法,其中所述化合物的前体是以前药形式施用的。
12.权利要求8的方法,其中所述化合物或所述化合物的前体是与至少一种选自干扰素、利巴韦林、蛋白酶抑制剂、免疫球蛋白、免疫调节剂、保肝剂、抗炎剂、抗生素、抗病毒剂、或抗感染剂的补充活性剂联合施用的。
13.权利要求12的方法,其中所述化合物或所述化合物的前体与所述至少一种补充活性剂是同时施用的。
14.权利要求8的方法,其中所述给药途径选自口服给药、直肠给药、非胃肠道给药、脑池内给药、阴道内给药、腹膜内给药、局部给药或吸入给药。
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JP (1) | JP2002524423A (zh) |
KR (1) | KR20010074949A (zh) |
CN (1) | CN1324250A (zh) |
AU (1) | AU751201B2 (zh) |
BR (1) | BR9913406A (zh) |
CA (1) | CA2343522A1 (zh) |
MX (1) | MXPA01002253A (zh) |
WO (1) | WO2000013708A1 (zh) |
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CN103509009A (zh) * | 2012-06-21 | 2014-01-15 | 中国科学院上海药物研究所 | 2-取代-5-苯基呋喃类化合物、其制备方法、药物组合物及其用途 |
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BR112015017414A2 (pt) | 2013-01-23 | 2017-07-11 | Hoffmann La Roche | derivados de triazol antivirais |
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RU2534613C2 (ru) | 2013-03-22 | 2014-11-27 | Александр Васильевич Иващенко | Алкил 2-{ [(2r,3s,5r)-5-(4-амино-2-оксо-2н-пиримидин-1-ил)- -гидрокси-тетрагидро-фуран-2-илметокси]-фенокси-фосфориламино} -пропионаты, нуклеозидные ингибиторы рнк-полимеразы hcv ns5b, способы их получения и применения |
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US6387365B1 (en) * | 1995-05-19 | 2002-05-14 | Schering Corporation | Combination therapy for chronic hepatitis C infection |
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1999
- 1999-09-03 MX MXPA01002253A patent/MXPA01002253A/es unknown
- 1999-09-03 CA CA002343522A patent/CA2343522A1/en not_active Abandoned
- 1999-09-03 KR KR1020017002817A patent/KR20010074949A/ko not_active Application Discontinuation
- 1999-09-03 WO PCT/US1999/020402 patent/WO2000013708A1/en not_active Application Discontinuation
- 1999-09-03 EP EP99948133A patent/EP1109580A4/en not_active Withdrawn
- 1999-09-03 AU AU61370/99A patent/AU751201B2/en not_active Ceased
- 1999-09-03 US US09/389,265 patent/US6440985B1/en not_active Expired - Fee Related
- 1999-09-03 JP JP2000568514A patent/JP2002524423A/ja not_active Withdrawn
- 1999-09-03 CN CN99812583A patent/CN1324250A/zh active Pending
- 1999-09-03 BR BR9913406-3A patent/BR9913406A/pt not_active Application Discontinuation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103509009A (zh) * | 2012-06-21 | 2014-01-15 | 中国科学院上海药物研究所 | 2-取代-5-苯基呋喃类化合物、其制备方法、药物组合物及其用途 |
Also Published As
Publication number | Publication date |
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KR20010074949A (ko) | 2001-08-09 |
BR9913406A (pt) | 2002-01-29 |
EP1109580A4 (en) | 2004-05-26 |
JP2002524423A (ja) | 2002-08-06 |
MXPA01002253A (es) | 2003-06-04 |
AU6137099A (en) | 2000-03-27 |
CA2343522A1 (en) | 2000-03-16 |
US6440985B1 (en) | 2002-08-27 |
WO2000013708A1 (en) | 2000-03-16 |
AU751201B2 (en) | 2002-08-08 |
EP1109580A1 (en) | 2001-06-27 |
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