CN1956720B - 治疗hiv感染的联合药物 - Google Patents
治疗hiv感染的联合药物 Download PDFInfo
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- CN1956720B CN1956720B CN2005800160669A CN200580016066A CN1956720B CN 1956720 B CN1956720 B CN 1956720B CN 2005800160669 A CN2005800160669 A CN 2005800160669A CN 200580016066 A CN200580016066 A CN 200580016066A CN 1956720 B CN1956720 B CN 1956720B
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Abstract
本发明包括使用化合物1结合治疗AIDS或HIV感染患者的其它药物的药物组合物和方法。
Description
相关申请的相互参考
本发明要求2004年3月24日提交的美国临时申请USSN60/555,767的权益。
发明背景
HIV-1(人类免疫缺陷病毒-1)感染依然是主要的医疗问题,到2002年年底全世界估计有4200万人受到感染。HIV和AIDS(获得性免疫缺陷综合症)的病例数量快速增加。2002年,据报道有大约500万人受到新的感染,3100万人死于AIDS。目前治疗HIV的可用药物包括10种核苷逆转录酶(RT)抑制剂或经批准的单丸组合物:齐多夫定或AZT(或)、去羟肌苷或DDI(或)、司他夫定或D4T(or)、拉米夫定或3TC(或)、扎西他滨或DDC(或)、琥珀酸阿巴卡韦(或)、替诺福韦双异丙氧基甲酰氧基甲酯延胡索酸盐(或)、恩曲他滨(或)、(含有3TC和AZT)、(含有阿巴卡韦、3TC和AZT);3种非核苷逆转录酶抑制剂:奈韦拉平(或)、地拉韦啶(或)和依法韦仑(或),8种拟肽蛋白酶抑制剂或经批准的制剂:沙奎那韦(或或)、茚地那韦(或)、利托那韦(或)、奈非那韦(或)、安普那韦(或)、阿扎那韦(Reyataz R)、福沙那韦(或Lexiva)、(含有洛匹那韦和利托那韦)和1种融合抑制剂恩夫韦地(或T-20或)。
假如单独使用,每一种这些药物只能短暂抑制病毒复制。然而,当联合使用时,这些药物对病毒血症和疾病进程具有显著的作用。
事实上,最近已经证明由于广泛应用联合治疗,AIDS患者中的死亡率显著降低。尽管有这些给人印象深刻的结果,30-50%的患者最终对联合药物治疗无效。不充足的药物效力、非顺应性、受限制的组织穿透力和在某些细胞型中药物特定的局限性(例如在静息细胞中大多数核苷类似物都不能被磷酸化)可引起不完全抑制敏感病毒。此外,当存在最佳以下药物浓度时,HIV-1的高复制率和快速转化以及频繁的突变整合导致了耐药变异体的出现,并引起治疗失败(Larder andKemp;Gulick;Kuritzkes;Morris-Jones et al;Schinazi et al;Vacca andCondra;Flexner;Berkhout and Ren et al;(Ref. 6-14))。因此,继续需要治疗HIV感染的新化合物和方法。
1-苯甲酰基-4-[2-[4-甲氧基-7-(3-甲基-1H-1,2,4-三唑-1-基)-1H-吡咯并[2,3-c]吡啶-3-基]-1,2-二氧代乙基]-哌嗪(化合物1)是HIV-1吸附抑制剂,其证明对多种HIV-1的实验室和临床病毒株都具有有效的抗病毒活性(参见2003年11月6日公开的美国专利申请20030207910)。
化合物1
化合物1通过选择性防止外部的病毒包膜蛋白gp120吸附到它的细胞受体CD4而起作用。gp120结合CD4是病毒进入的第一步,其不同于后来与趋化因子受体(CCR5或CXCR4)的相互作用或病毒-细胞融合事件。通过抑制这种相互作用,化合物1阻断了病毒进入细胞。
发明描述
本发明包括治疗HIV感染和AIDS的药物组合物和方法。
本发明的一方面是治疗人类患者中的HIV感染的方法,包括给予治疗有效量的1-苯甲酰基-4-[2-[4-甲氧基-7-(3-甲基-1H-1,2,4-三唑-1-基)-1H-吡咯并[2,3-c]吡啶-3-基]-1,2-二氧代乙基]-哌嗪(化合物1)或其药物可接受的盐或溶剂合物,和治疗有效量的至少一种其它治疗AIDS或HIV感染的药物,所述治疗AIDS或HIV感染的其它药物选自核苷HIV逆转录酶抑制剂、非核苷HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、HIV融合抑制剂、HIV吸附抑制剂、CCR5抑制剂、CXCR4抑制剂、HIV出芽或成熟抑制剂和HIV整合酶抑制剂。
本发明的另一方面是其中所述药物为核苷HIV逆转录酶抑制剂的方法。
本发明的另一方面是其中所述核苷HIV逆转录酶抑制剂选自阿巴卡韦、去羟肌苷、恩曲他滨、拉米夫定、司他夫定、替诺福韦、扎西他滨和齐多夫定或其药物可接受的盐或溶剂合物的方法。
本发明的另一方面是其中所述药物为非核苷HIV逆转录酶抑制剂的方法。
本发明的另一方面是其中所述非核苷HIV逆转录酶抑制剂选自地拉韦啶、依法韦仑和奈韦拉平或其药物可接受的盐或溶剂合物的方法。
本发明的另一方面是其中所述药物为HIV蛋白酶抑制剂的方法。
本发明的另一方面是其中所述HIV蛋白酶抑制剂选自安普那韦、阿扎那韦、茚地那韦、洛匹那韦、奈非那韦、利托那韦、沙奎那韦和福沙那韦或其药物可接受的盐或溶剂合物的方法。
本发明的另一方面是其中所述药物为HIV融合抑制剂的方法。
本发明的另一方面是其中所述HIV融合抑制剂为恩夫韦地或T-1249或其药物可接受的盐或溶剂合物的方法。
本发明的另一方面是其中所述药物为HIV吸附抑制剂的方法。
本发明的另一方面是其中所述药物为CCR5抑制剂的方法。
本发明的另一方面是其中所述CCR5抑制剂选自Sch-C、Sch-D、TAK-220、PRO-140和UK-427,857或其药物可接受的盐或溶剂合物的方法。
本发明的另一方面是其中所述药物为CXCR4抑制剂的方法。
本发明的另一方面是其中所述CXCR4抑制剂为AMD-3100或其药物可接受的盐或溶剂合物的方法。
本发明的另一方面是其中所述药物为HIV出芽或成熟抑制剂的方法。
本发明的另一方面是其中所述出芽或成熟抑制剂为PA-457或其药物可接受的盐或溶剂合物的方法。
本发明的另一方面是其中所述药物为HIV整合酶抑制剂的方法。
本发明的另一方面是其中所述HIV整合酶抑制剂为3-[(4-氟苄基)甲氧基氨基甲酰基]-2-羟基丙烯酸或2-(2,2)-二甲基-5-氧代-[1,3]-二氧戊环-4-亚基)-N-(4-氟苄基)-N-甲氧基乙酰胺或其药物可接受的盐或溶剂合物的方法。
本发明的另一方面是包含治疗有效量的1-苯甲酰基-4-[2-[4-甲氧基-7-(3-甲基-1H-1,2,4-三唑-1-基)-1H-吡咯并[2,3-c]吡啶-3-基]-1,2-二氧代乙基]-哌嗪或其药物可接受的盐或溶剂合物、至少一种治疗AIDS或HIV感染的药物和药物可接受载体的药物组合物,所述治疗AIDS或HIV感染的药物选自核苷HIV逆转录酶抑制剂、非核苷HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、HIV融合抑制剂、HIV吸附抑制剂、CCR5抑制剂、CXCR4抑制剂、HIV出芽或成熟抑制剂和HIV整合酶抑制剂。
本发明的另一方面是其中所述药物为核苷HIV逆转录酶抑制剂的组合物。
本发明的另一方面是其中所述核苷HIV逆转录酶抑制剂选自阿巴卡韦、去羟肌苷、恩曲他滨、拉米夫定、司他夫定、替诺福韦、扎西他滨和齐多夫定或其药物可接受的盐或溶剂合物的组合物。
本发明的另一方面是其中所述药物为非核苷HIV逆转录酶抑制剂的组合物。
本发明的另一方面是其中所述非核苷HIV逆转录酶抑制剂选自地拉韦啶、依法韦仑和奈韦拉平或其药物可接受的盐或溶剂合物的组合物。
本发明的另一方面是其中所述药物为HIV蛋白酶抑制剂的组合物。
本发明的另一方面是其中所述HIV蛋白酶抑制剂选自安普那韦、阿扎那韦、茚地那韦、洛匹那韦、奈非那韦、利托那韦、沙奎那韦和福沙那韦或其药物可接受的盐或溶剂合物的组合物。
本发明的另一方面是其中所述药物为HIV融合抑制剂的组合物。
本发明的另一方面是其中所述HIV融合抑制剂为恩夫韦地或T-1249或其药物可接受的盐或溶剂合物的组合物。
本发明的另一方面是其中所述药物为HIV吸附抑制剂的组合物。
本发明的另一方面是其中所述药物为CCR5抑制剂的组合物。
本发明的另一方面是其中所述CCR5抑制剂选自Sch-C、Sch-D、TAK-220、PRO-140和UK-427,857或其药物可接受的盐或溶剂合物的组合物。
本发明的另一方面是其中所述药物为CXCR4抑制剂的组合物。
本发明的另一方面是其中所述CXCR4抑制剂为AMD-3100或其药物可接受的盐或溶剂合物的组合物。
本发明的另一方面是其中所述药物为HIV出芽或成熟抑制剂的组合物。
本发明的另一方面是其中所述出芽或成熟抑制剂为PA-457或其药物可接受的盐或溶剂合物的组合物。
本发明的另一方面是其中所述药物为HIV整合酶抑制剂的组合物。
本发明的另一方面是其中所述HIV整合酶抑制剂为3-[(4-氟苄基)甲氧基氨基甲酰基]-2-羟基丙烯酸或2-(2,2)-二甲基-5-氧代-[1,3]-二氧戊环-4-亚基)-N-(4-氟苄基)-N-甲氧基乙酰胺或其药物可接受的盐或溶剂合物的组合物。
“组合”、“共同给予”、“同时”和类似涉及给予化合物1和至少一种抗HIV药物的术语是指,该组分是联合抗逆转录病毒疗法或高活性抗逆转录病毒疗法(HAART)的一部分,为AIDS和HIV感染领域的从业人员所理解。
“治疗有效量”是指提供有意义的患者利益所需的药物量,为AIDS和HIV感染领域的从业人员所理解。一般而言,治疗目的是抑制病毒量、恢复和保护免疫功能、提高生活质量和降低与HIV有关的发病率和死亡率。
“患者”是指感染HIV病毒并适合治疗的人,为AIDS和HIV感染领域的从业人员所理解。
“治疗”、“疗法”、“给药方案”、“HIV感染”、“ARC”、“AIDS”和相关术语按AIDS和HIV感染领域从业人员的理解使用。
本发明包括所有化合物1的药物可接受的盐形式。药物可接受的盐是以下的盐,其中反荷离子不会显著促进化合物生理学活性或毒性,本身作为药理学等价物发挥功能。在许多情况中,盐具有的物理性质,例如溶解度或结晶度,使得它们适合于配制。可依据普通有机技术应用市售试剂制备所述盐。合适的阴离子盐形式包括乙酸盐、醋硬脂酸盐、苯磺酸盐、溴化物、氯化物、柠檬酸盐、延胡索酸盐、葡糖醛酸盐、氢溴酸盐、氢氯酸盐、氢碘酸盐、碘化物、乳酸盐、马来酸盐、甲磺酸盐、硝酸盐、双羟萘酸盐、磷酸盐、琥珀酸盐、硫酸盐、酒石酸盐、苯甲酸盐和昔萘酸盐(xinofoate)。
本发明也包括所有化合物1的溶剂合物形式,特别是水合物。溶剂合物不会显著促进化合物的生理学活性或毒性,本身作为药理学等价物发挥功能。溶剂合物可以化学计量的量形成,或可从外来溶剂或两者的组合产生。溶剂合物的一种是水合物。一些水合形式包括一水合物、半水合物和二水合物。
生物学方法
当化合物1与各种其它抗病毒药物联合使用时,化合物1显示具有协同或相加-协同的抗HIV病毒活性,如下所述。
病毒和细胞系。T-细胞系、MT-2和PM-1通过AIDS研究和参考试剂计划NIAID获得,分别由D.Richman博士和R.Gallo博士惠赠。在添加了10%胎牛血清、2mM L-谷氨酰胺的RPMI 1640培养基中培养这两种细胞系,并每周传代培养2次。HIV-1的LAI株获自FredHutchinson Cancer Research Center,BaI株来自NIH。扩增这两种病毒原种,并使用病毒感染测定在MT-2细胞(LAI)和PM-1细胞(BaI)中进行滴度测定。
化学药品。使用公开的或已知的反应合成化合物1、阿扎那韦、去羟肌苷、司他夫定、依法韦仑、恩夫韦地(T-20)、T-1249、AMD-3100、Sch-C、Sch-D和UK-427,857。使用公开或普通的技术从处方药的市售制剂中抽提并纯化安普那韦、茚地那韦、奈非那韦、奈韦拉平、洛匹那韦、拉米夫定、利托那韦、替诺福韦、沙奎那韦、地拉韦啶和阿巴卡韦。经测定替诺福韦为双异丙氧基甲酰氧基甲酯延胡索酸盐。扎西他滨获自国立卫生研究院(National Institutes of Health)。齐多夫定购自Sigma,恩曲他滨来自Moravek Biochemicals。3-[(4-氟苄基)甲氧基氨基甲酰基]-2-羟基丙烯酸(化合物2)和2-(2,2)-二甲基-5-氧代-[1,3]-二氧戊环-4-亚基)-N-(4-氟苄基)-N-甲氧基乙酰胺(化合物3)描述于美国专利第6,777,440号。抗HIV药物的纯度大于95%,除了AMD-3100(>90%)、Sch-D(80%)和UK-427,857(>90%)外。
药物敏感性和细胞毒性测定。对于药物的敏感性测定,使用HIV-1LAI在0.005 MOI下感染MT-2细胞(或使用HIV-1Bal感染PM-1细胞),接种在含有系列稀释受试化合物的96孔微量滴定板中(0.1 x 106个细胞/ml)。使用两种药物1∶1、1∶2.5和2.5∶1的比率设定药物组合,并在预多重实验(prior multiple experiments)中测定各药物的EC50值。各药物比率由3倍系列稀释的列组成,并进行4个重复。微量滴定板在37℃/5%CO2下培养。将感染HIV-1 LAI的MT-2细胞培养5天。在感染后的第五天,从各个孔中收集20μl,并通过逆转录酶(RT)测定进行定量,或在包含非核苷逆转录酶抑制剂的样品中通过MTS测定定量。将用HIV-1 Bal感染并用于研究与CCR5抑制剂组合的PM-1细胞培养6天。在感染后第6天,从各个孔中收集20μl,20倍和50倍稀释,并通过p24测定定量。使用未受感染的细胞进行细胞毒性测定,使其暴露在相同的药物组合下,并培养6天。通过MTS测定确定细胞的成活率。通过使用中位数效应方程(median effect equation)的指数形式如下所述计算EC50,计算CC50值。
药物组合效果分析。对于CI值的测定,将药物以固定比率稀释,分析多种比率。将药物的系列稀释度跨越接近各化合物EC50值的浓度范围,如此可比较相等的抗病毒活性。使用中位数效应方程,评估各单独药物和每一组合的浓度效应曲线。使用非线性回归途径(ProcNlin)在PC SAS 8.01版上拟合该方程(SAS Institute Inc.,SAS Version8.01,Cary,NC:SAS Institute Inc.,1990)。
使用中位数效应方程Fa=1/[1+(ED50/药物浓度)m],从单个药物实验中确定各药物的EC50值。在这个方程中,Fa代表受侵袭的部分,代表病毒量的部分已经被消去。例如,0.75的Fa表明相对于无药物对照,病毒复制已被抑制75%。ED50是预期降低病毒50%量的药物浓度,m是反映浓度-效应曲线斜率的参数。
为了评估不同药物组合治疗的抗病毒效果,依照Chou和Rideout计算组合指数(CI)。组合指数如下计算:
CI=[D]1/[Dm]1+[D]2/[Dm]2
在这个方程中,[Dm]1和[Dm]2是药物单独产生特定水平效果的浓度,而[D]1和[D]2是产生相同水平效果的组合中的药物浓度。
理论上,假如CI等于1意味相加,假如CI小于1为协同作用,假如CI大于1为拮抗作用。然而,药物组合研究的广泛实验表明,存在解释CI的过程中必须考虑的内在实验室变量。在最佳情况下,给定数据中的误差,我们可构建含有CI可能值的范围。在此报告中,这些范围报告在紧靠着CI各个点估计值的括号中。例如,当我们报道“0.53(0.46,0.60)”的CI,这表示我们的最佳估计CI值为0.53,但由于数据中的误差,对于CI从0.46至0.60中的值也是合理的。这个范围,0.46-0.60,完全落入了1.0以下,因此CI所有可能的值都小于1.0。因此,我们可推断对此情况而言是协同作用。假如这个范围完全超过1,则我们推断为拮抗作用。假如这个范围包括1.0,我们推断为为相加作用。
在进行下面的组合实验中,在各个研究过程中,都测定了化合物1和各个比对化合物的EC50,用于随后的数据分析。这个测定值与我们先前公开的数据一致,并在表1显示。
表1用于两种药物组合研究的化合物的抗HIV活性
化合物1与核苷逆转录酶抑制剂的两种药物组合。在接近各化合物EC50值的浓度范围内将核苷逆转录酶抑制剂与化合物1组合,如此可比较相等的抗病毒活性。使用SAS Proc NLIN计算所有的估计值和两参数对数(a two-parameter logistic)。数据显示在表2中,为不同摩尔比例逆转录酶抑制剂的组合指数和渐进置信区(参见材料和方法)。核苷逆转录酶抑制剂与化合物1组合显示出协同至相加-协同的抗病毒作用。没有发现显著的抗HIV活性的拮抗作用。如通过MTS还原测定法测定,任何药物组合在最高受试浓度时都没有碰到增强的毒性作用。
表2.使用化合物1与核苷逆转录酶抑制剂的两种药物组合
a化合物1与比对化合物的比例
b渐进置信区的下限大于1表示拮抗作用,上限小于1表示协同作用,区间内包含1的值表示相加。95%置信区显示在括号内,代表数据中的变化尺度。
化合物1与非核苷逆转录酶抑制剂的两种药物组合。表3中的结果表明化合物1与依法韦仑和地拉韦啶的组合效应是协同作用,而与奈韦拉平的组合效应是相加-协同。任何药物组合在最高受试浓度下没有发现任何增加的毒性作用。
表3.使用化合物1和非核苷逆转录酶抑制剂的两种药物组合
a化合物1与比对化合物的比例
b渐进置信区的下限大于1表示拮抗作用,上限小于1表示协同作用,区间内包含1的值表示相加。95%置信区显示在括号内,代表数据中的变化尺度。
包含化合物1和HIV蛋白酶抑制剂的两种药物组合。一般而言,蛋白酶抑制剂与化合物1的组合是协同至相加-协同。在这些联合抗病毒测定的任一项中,在最高受试浓度下都没有发现任何增加的毒性作用。得自这两种药物组合研究的结果概括于表4中。
表4.使用化合物1和蛋白酶抑制剂的两种药物组合
a化合物1与比对化合物的比例
b渐进置信区的下限大于1表示拮抗作用,上限小于1表示协同作用,区间内包含1的值表示相加。95%置信区显示在括号内,代表数据中的变化尺度。
化合物1和进入抑制剂两种药物组合。表5中的结果表明化合物1与AMD-3100的组合在50%和75%抑制水平上具有强烈的协同作用,在90%趋向于相加作用。因此,它被归为中等协同。在组合药物的最高浓度没有发现任何显著的毒性作用。
表5.使用化合物1和进入抑制剂两种药物组合的抗HIV活性
a化合物1与比对化合物的比例
b渐进置信区的下限大于1表示拮抗作用,上限小于1表示协同作用,区间内包含1的值表示相加。95%置信区显示在括号内,代表数据中的变化尺度。
化合物1与HIV整合酶抑制剂两种药物组合。表6中的结果表明化合物1和化合物2的组合为中等协同。在组合药物的最高浓度没有发现显著的毒性作用。
表6.使用化合物1和化合物2两种药物组合的抗HIV活性
a化合物1与比对化合物的比例
b渐进置信区的下限大于1表示拮抗作用,上限小于1表示协同作用,区间内包含1的值表示相加。95%置信区显示在括号内,代表数据中的变化尺度。
HIV吸附是HIV复制中必需的步骤,化合物1抑制HIV吸附,可用于治疗HIV感染和随后的病理学疾病如AIDS和ARC。如上所示,化合物1与多种其它药物联合使用是有效的,可在HAAART和其它新的复合组合物和疗法中特别有益。
化合物1通常作为药物组合物给予,组合物的活性成分可单独由化合物1组成,或化合物1与至少一种用于治疗AIDS或HIV感染的其它药物。该组合物通常使用药物可接受的载体或媒介物制成,并可含有常规的赋形剂。可使用普通的制剂技术制备该组合物。本发明包括所有的常规剂型。优选固体和液体组合物。一些固体形式包括粉剂、片剂、胶囊剂和锭剂。片剂包括咀嚼片、缓冲片和缓释片。胶囊包括肠溶衣和缓释胶囊。粉剂用于口服使用和重建在溶液中。粉剂包括低压冻干和速溶粉剂。在固体组合物中,化合物1和任何抗逆转录病毒的药物以剂量单位范围存在。一般而言,化合物1的剂量单位范围为1-1000mg/单位。一些剂量实例为1mg、10mg、100mg、250mg、500mg和1000mg。一般而言,其它抗逆转录病毒药物存在的单位剂量范围与临床上使用的那类药物相似。典型地其为0.25-1000mg/单位。
液体包括水溶液剂、糖浆剂、酏剂、乳剂和混悬剂。在液体组合物中,化合物1和任何抗逆转录病毒的药物以剂量单位范围存在。一般而言,化合物1的剂量单位范围为1-100mg/单位。一些剂量的实例为1mg/mL、10mg/mL、25mg/mL、50mg/mL和100mg/mL。一般而言,其它抗逆转录病毒药物存在的单位剂量范围与临床上使用的那类药物相似。典型地其为1-100mg/单位。
本发明包括所有常规的给药方式;优选口服和胃肠外(肌内注射、静脉注射、皮下注射)方式。一般而言,给药方案与其它临床使用的抗逆转录病毒药物相似。典型地,化合物1的每日剂量为每天1-100mg/kg体重。一般而言,多数化合物要求口服,少数为胃肠外方式。然而,由医生使用合理的医学判断确定具体的给药方案。
本发明也包括在联合治疗中给予化合物1的方法。即,化合物1可与其它用于治疗AIDS和HIV感染的药物联合使用,但分开给予。这些药物的某些包括HIV吸附抑制剂、CCR5抑制剂、CXCR4抑制剂、HIV细胞融合抑制剂、HIV整合酶抑制剂、HIV核苷逆转录酶抑制剂、HIV非核苷逆转录酶抑制剂、HIV蛋白酶抑制剂、出芽和成熟抑制剂、免疫调节剂和抗感染药物。在这些组合方法中,化合物1通常以每天1-100mg/kg体重的每日剂量与其它药物联合给予。其它药物一般以治疗使用量给予。然而,由医生使用合理的医学判断确定具体的给药方案。
表7罗列了一些适合于本发明的用于治疗AIDS和HIV感染的药物。但本发明并不限于这些药物。
表7.抗病毒药
药物名 | 生产商 | 适应症 |
097(非核苷逆转录酶抑制剂) | Hoechst/Bayer | HIV感染、AIDS、ARC |
安普那韦141 W94GW 141(蛋白酶抑制剂) | Glaxo Wellcome | HIV感染、AIDS、ARC |
阿巴卡韦(1592U89)GW 1592(核苷逆转录酶抑制剂) | Glaxo Wellcome | HIV感染、AIDS、ARC |
乙酰马喃 | Carrington Labs(Irving,TX) | ARC |
阿昔洛韦 | Burroughs Wellcome | HIV感染、AIDS、ARC,与AZT合用 |
AD-439 | Tanox Biosystems | HIV感染、AIDS、ARC |
AD-519 | Tanox Biosystems | HIV感染、AIDS、ARC |
阿德福韦二匹伏酯AL-721 | Gilead SciencesEthigen(Los Angeles,CA) | HIV感染、ARC、PGL HIV阳性、AIDS |
HIVα-干扰素与利托那韦合用 | Glaxo Wellcome | 皮肤多发性出血性肉瘤 |
安沙霉素LM 427 | Adria Laboratories(Dublin,OH)Erbamont(Stamford,CT) | ARC |
中和pH不稳定的α变体干扰素的抗体 | Advanced BiotherapyConcepts(Rockville,MD) | AIDS、ARC |
药物名 | 生产商 | 适应症 |
AR177 | Aronex Pharm | HIV感染,AIDS,ARC |
β-氟代-ddA | Nat'l Cancer Institute | AIDS有关的疾病 |
BMS-232623(CGP-73547)(蛋白酶抑制剂) | Bristol-Myers Squibb/Novartis | HIV感染、AIDS、ARC |
BMS-234475(CGP-61755)(蛋白酶抑制剂) | Bristol-Myers Squibb/Novartis | HIV感染、AIDS、ARC |
CI-1012 | Warner-Lambert | HIV-1感染 |
西多福韦 | Gilead Science | CMV视网膜炎、疱疹、乳头瘤病毒 |
硫酸凝胶多糖 | AJI Pharma USA | HIV感染 |
巨细胞病毒免疫珠蛋白 | MedImmune | CMV视网膜炎 |
赛美维 | Syntex | 视力压迫 |
更昔洛韦 | CMV外周、CMV视网膜炎 | |
Delaviridine(逆转录酶抑制剂) | Pharmacia-Upj ohn | HIV感染、AIDS、ARC |
硫酸葡聚糖 | Ueno Fine Chem.Ind.Ltd.(Osaka,Japan) | AIDS、ARC、HIV阳性无症状 |
ddC双脱氧胞苷 | Hoffman-La Roche | HIV感染、AIDS、ARC |
ddI双脱氧肌苷 | Bristol-Myers Squibb | HIV感染、AIDS、ARC;与AZT/d4T合用 |
DMP-450(蛋白酶抑制剂) | AVID(Camden,NJ) | HIV感染,AIDS,ARC |
依法韦仑(DMP 266)(-)6-氯-4-(S)-环丙基乙基-4(S)-三氟-甲基-1,4-二氢-2H-3,1-苯并噁嗪-2-酮,STOCRINE(非核苷逆转录酶抑制剂) | DuPont Merck | HIV感染、AIDS、ARC |
EL10泛西洛韦 | Elan Corp,PLC(Gainesville,GA)Smith Kline | HIV感染带状疱疹、单纯性疱疹 |
FTC(逆转录酶抑制剂) | Emory University | HIV感染、AIDS、ARC |
GS 840(逆转录酶抑制剂) | Gilead | HIV感染、AIDS、ARC |
HBY097(非核苷逆转录酶抑制剂) | Hoechst MarionRoussel | HIV感染、AIDS、ARC |
金丝桃素 | VIMRx Pharm. | HIV感染、AIDS、ARC |
重组人β干扰素 | Triton Biosciences(Almeda,CA) | AIDS、皮肤多发性出血性肉瘤、ARC |
α-n3干扰素 | Interferon Sciences | ARC、AIDS |
免疫调节剂
药物名 | 生产商 | 适应症 |
IMREG-2 | Imreg(New Orleans,LA) | AIDS、皮肤多发性出血性肉瘤、ARC、PGL |
Imuthiol DiethylDithio Carbamate | Merieux Institute | AIDS、ARC |
α-2干扰素 | Schering Plough | 皮肤多发性出血性肉瘤,与AZT合用,AIDS |
甲硫脑啡肽 | TNI Pharmaceutical(Chicago,IL) | AIDS、ARC |
MTP-PE胞壁酰三肽粒细胞集落刺激因子 | Ciba-Geigy Corp.Amgen | 皮肤多发性出血性肉瘤,AIDS,与AZT合用 |
Remune | Immune ResponseCorp. | 免疫疗法 |
rCD4重组可溶性人CD4 | Genentech | AIDS、ARC |
rCD4-IgG混合物 | AIDS、ARC | |
重组可溶性人CD4 | Biogen | AIDS、ARC |
α2a干扰素 | Hoffman-La Rochein combination w/AZT | 皮肤多发性出血性肉瘤、AIDS、ARC |
SK&F106528可溶性T4 | Smith Kline | HIV感染 |
胸腺喷丁肿瘤坏死因子,TNF | ImmunobiologyResearch Institute(Annandale,NJ)Genentech | HIV感染ARC,与γ干扰素合用 |
抗感染药
药物名 | 生产商 | 适应症 |
克林霉素与伯氨喹 | Pharmacia Upjohn | PCP |
氟康唑 | Pfizer | 隐球菌性脑膜炎,念珠菌病 |
制霉菌素锭剂 | Squibb Corp. | 预防口腔念珠菌 |
盐酸依氟鸟氨酸依氟鸟氨酸 | Merrell Dow | PCP |
依西酸喷他脒(IM & IV) | LyphoMed(Rosemont,IL) | PCP治疗 |
甲氧苄啶 | 抗菌剂 | |
甲氧苄啶/磺胺 | 抗菌剂 | |
吡曲克辛 | Burroughs Wellcome | PCP治疗 |
依西酸喷他脒吸入剂 | Fisons Corporation | PCP预防 |
乙酰螺旋霉素 | Rhone-Poulencdiarrhea | Cryptosporidial |
伊曲康唑-R51211 | Janssen-Pharm. | 组织胞浆菌病;隐球菌性脑膜炎 |
曲美沙特柔红霉素 | Warner-LambertNeXstar,Sequus | PCP皮肤多发性出血性肉瘤 |
重组人促红细胞生成素重组人生长因子 | Ortho Pharm.Corp.Serono | 严重贫血,与AZT治疗合用与AIDS有关的消瘦、恶病质 |
醋酸甲地孕酮 | Bristol-Myers Squibb | 厌食症的治疗,伴有AIDS |
睾酮 | Alza,Smith Kline | 与AIDS有关的消瘦 |
总肠内营养物 | Norwich EatonPharmaceuticals | 与AIDS有关的腹泻和吸收不良 |
Claims (30)
1.治疗有效量的1-苯甲酰基-4-[2-[4-甲氧基-7-(3-甲基-1H-1,2,4-三唑-1-基)-1H-吡咯并[2,3-c]吡啶-3-基]-1,2-二氧代乙基]-哌嗪或其药物可接受的盐,和治疗有效量的至少一种用于治疗AIDS或HIV感染的其它药物在制备药物中的用途,所述药物用于治疗人类患者中HIV感染,所述治疗AIDS或HIV感染的其它药物选自核苷HIV逆转录酶抑制剂、非核苷HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、HIV融合抑制剂、CCR5抑制剂、CXCR4抑制剂和HIV整合酶抑制剂。
2.权利要求1的用途,其中所述药物为核苷HIV逆转录酶抑制剂。
3.权利要求2的用途,其中所述核苷HIV逆转录酶抑制剂选自阿巴卡韦、去羟肌苷、恩曲他滨、拉米夫定、司他夫定、替诺福韦、扎西他滨和齐多夫定,或其药物可接受的盐。
4.权利要求1的用途,其中所述药物为非核苷HIV逆转录酶抑制剂。
5.权利要求4的用途,其中所述非核苷HIV逆转录酶抑制剂选自地拉韦啶、依法韦仑和奈韦拉平,或其药物可接受的盐。
6.权利要求1的用途,其中所述药物为HIV蛋白酶抑制剂。
7.权利要求6的用途,其中所述HIV蛋白酶抑制剂选自安普那韦、阿扎那韦、茚地那韦、洛匹那韦、奈非那韦、利托那韦、沙奎那韦和福沙那韦,或其药物可接受的盐。
8.权利要求1的用途,其中所述药物为HIV融合抑制剂。
9.权利要求8的用途,其中所述HIV融合抑制剂为恩夫韦地或T-1249,或其药物可接受的盐。
10.权利要求1的用途,其中所述药物为CCR5抑制剂。
11.权利要求10的用途,其中所述CCR5抑制剂选自Sch-C、Sch-D、TAK-220、PRO-140和UK-427,857,或其药物可接受的盐。
12.权利要求1的用途,其中所述药物为CXCR4抑制剂。
13.权利要求12的用途,其中所述CXCR4抑制剂为AMD-3100,或其药物可接受的盐。
14.权利要求1的用途,其中所述药物为HIV整合酶抑制剂。
15.权利要求14的用途,其中所述HIV整合酶抑制剂为3-[(4-氟苄基)甲氧基氨基甲酰基]-2-羟基丙烯酸或2-(2,2)-二甲基-5-氧代-[1,3]-二氧戊环-4-亚基)-N-(4-氟苄基)-N-甲氧基乙酰胺,或其药物可接受的盐。
16.一种药物组合物,所述药物组合物包含治疗有效量的1-苯甲酰基-4-[2-[4-甲氧基-7-(3-甲基-1H-1,2,4-三唑-1-基)-1H-吡咯并[2,3-c]吡啶-3-基]-1,2-二氧代乙基]-哌嗪或其药物可接受的盐、至少一种用于治疗AIDS或HIV感染的其它药物和药物可接受载体,所述治疗AIDS或HIV感染的其它药物选自核苷HIV逆转录酶抑制剂、非核苷HIV逆转录酶抑制剂、HIV蛋白酶抑制剂、HIV融合抑制剂、CCR5抑制剂、CXCR4抑制剂和HIV整合酶抑制剂。
17.权利要求16的组合物,其中所述药物为核苷HIV逆转录酶抑制剂。
18.权利要求17的组合物,其中所述核苷HIV逆转录酶抑制剂选自阿巴卡韦、去羟肌苷、恩曲他滨、拉米夫定、司他夫定、替诺福韦、扎西他滨和齐多夫定,或其药物可接受的盐。
19.权利要求16的组合物,其中所述药物为非核苷HIV逆转录酶抑制剂。
20.权利要求19的组合物,其中所述非核苷HIV逆转录酶抑制剂选自地拉韦啶、依法韦仑和奈韦拉平,或其药物可接受的盐。
21.权利要求16的组合物,其中所述药物为HIV蛋白酶抑制剂。
22.权利要求21的组合物,其中所述HIV蛋白酶抑制剂选自安普那韦、阿扎那韦、茚地那韦、洛匹那韦、奈非那韦、利托那韦、沙奎那韦和福沙那韦,或其药物可接受的盐。
23.权利要求16的组合物,其中所述药物为HIV融合抑制剂。
24.权利要求23的组合物,其中所述HIV融合抑制剂为恩夫韦地或T-1249,或其药物可接受的盐。
25.权利要求16的组合物,其中所述药物为CCR5抑制剂。
26.权利要求25的组合物,其中所述CCR5抑制剂选自Sch-C、Sch-D、TAK-220、PRO-140和UK-427,857,或其药物可接受的盐。
27.权利要求16的组合物,其中所述药物为CXCR4抑制剂。
28.权利要求27的组合物,其中所述CXCR4抑制剂为AMD-3100,或其药物可接受的盐。
29.权利要求16的组合物,其中所述药物为HIV整合酶抑制剂。
30.权利要求29的组合物,其中所述HIV整合酶抑制剂为3-[(4-氟苄基)甲氧基氨基甲酰基]-2-羟基丙烯酸或2-(2,2)-二甲基-5-氧代-[1,3]-二氧戊环-4-亚基)-N-(4-氟苄基)-N-甲氧基乙酰胺,或其药物可接受的盐。
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