CN105311033B - 抗病毒治疗 - Google Patents
抗病毒治疗 Download PDFInfo
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- CN105311033B CN105311033B CN201510619148.8A CN201510619148A CN105311033B CN 105311033 B CN105311033 B CN 105311033B CN 201510619148 A CN201510619148 A CN 201510619148A CN 105311033 B CN105311033 B CN 105311033B
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Abstract
抗病毒治疗。本发明涉及化合物的联用药，其包含HIV整合酶抑制剂及其它治疗剂。这种联用药可有效用于抑制HIV复制、预防和/或治疗HIV感染和用于治疗AIDS和/或ARC。
Description
本申请是申请日为2011年1月24日的发明名称为“抗病毒治疗”的PCT/US2011/022219号发明专利申请的分案申请，原申请进入中国国家阶段获得的国家申请号为201180015114.8.
本发明的背景.
人类免疫缺陷性病毒(“HIV”)是获得性免疫缺陷综合征(爱滋病,“AIDS”)的病原体，这种疾病的特征为：破坏免疫系统，尤其是破坏CD4+ T细胞，同时伴随有对机会感染的敏感性，而它的前身AIDS相关的综合症(“ARC”)是一种以下列症状为特征的综合症：例如，持久性的全身淋巴结病、发热和体重减轻。HIV是逆转录病毒；它的RNA至DNA的转化是通过酶(逆转录酶)的作用完成的。抑制逆转录酶的功能的化合物可以抑制HIV在受感染细胞中的复制。这种化合物可有效用于预防或治疗人的HIV感染。
除了CD4之外，HIV为进入到靶细胞需要辅助受体。趋化因子受体和CD4一起起到HIV的辅助受体的作用。趋化因子受体CXCR4和CCR5已经被确定为HIV-1的主要辅助受体。CCR5起到嗜巨噬细胞(macrophage-tropic)HIV融合并进入到宿主细胞中的主要辅助受体作用。人们认为这些趋化因子受体在HIV感染的建立和扩散方面起到主要的作用。因此，人们认为CCR5拮抗剂用作抗HIV的活性治疗剂。
正如在一些其它逆转录病毒的情况下那样，HIV编码蛋白酶的生产，该蛋白酶使前体多肽在形成感染性病毒体所必需的过程中实现翻译后断裂。这些基因产物包括pol，其编码病毒体RNA依赖性的DNA聚合酶(逆转录酶)、核酸内切酶、HIV蛋白酶和gag(其编码病毒体的核心蛋白)。
抗病毒药物设计的一个焦点是产生能够通过干扰病毒多蛋白前体的加工来抑制感染性病毒体形成的化合物。这些前体蛋白的加工需要病毒编码的、对复制必不可少的蛋白酶的作用。人们使用肽基抑制剂证明了HIV蛋白酶抑制作用的抗病毒潜力。
在人T细胞中，HIV复制所需要的步骤是通过病毒编码的整合酶使前病毒的DNA插入到宿主细胞基因组中。人们认为，整合是在下述过程中通过整合酶介导的,该过程涉及稳定核蛋白与病毒DNA序列的复合物的组装，两个核苷酸从线型前病毒DNA的3'端断裂，以及该前病毒DNA的凹进的3'OH端在宿主靶向位点所产生的交错切口处共价连接。所产生的缝隙的修复合成可以通过细胞酶完成。HIV整合酶的抑制剂可以有效用于治疗AIDS和抑制病毒复制。
在HIV感染和相关病症的治疗过程中，给予治疗化合物的联用药(combinations)可以导致抗病毒活性增强、毒性降低、延迟耐药性的进展和提高药物效果。在单一剂量单位中给予的联用药可以导致患者依从性提高，同时降低药片负荷，并使给药计划简化。然而，不是所有的化合物都适合于以联用形式给药。影响联用药的可行性的因素包括：化合物的化学不稳定性，剂量单位的大小，拮抗潜力或仅仅具有联用化合物的加和活性和获得合适制剂的困难度。
因此还需要发现适合在治疗HIV感染的联用药和合适药物组合物中使用的治疗剂。由于某些HIV整合酶抑制剂的高效能和药物动力学特性，它们作为联合治疗中的组成部分是很有吸引力的。
附图的简要说明
图1∶式(I)化合物GSK1349572A与阿巴卡韦(ABC)的联用药对HIV-1IIIB的抑制。
图2∶式(I)化合物GSK1349572A与依法韦恩茨(EFV)的联用药对HIV-1IIIB的抑制。
图3∶式(I)化合物GSK1349572A与洛匹那韦(LPV)的联用药对HIV-1IIIB的抑制。
本发明概述
本发明涉及化合物的联用药，其包含HIV整合酶抑制剂及其它治疗剂。这种联用药可有效用于抑制HIV复制、预防和/或治疗HIV感染和用于治疗AIDS和/或ARC。本发明的特征还在于含有HIV整合酶抑制剂的药物组合物。
本发明的详细说明
本发明涉及联用药，其包含下列式(I)、(II)或(III)的化合物∶
(I)
(II)
(III)
或其可药用盐，和一或多种选自下列的治疗剂：核苷酸逆转录酶抑制剂，核苷逆转录酶抑制剂(NRTIs)，非核苷逆转录酶抑制剂(NNRTIs)，蛋白酶抑制剂，CCR5拮抗剂，CXCR4拮抗剂，融合抑制剂，成熟抑制剂和整合酶抑制剂。
本发明涉及治疗HIV感染、AIDS和AIDS相关病症的方法，该方法给予患者式(I)、(II)或(III)的化合物和一或多种选自下列的治疗剂：核苷酸逆转录酶抑制剂，核苷逆转录酶抑制剂(NRTIs)，非核苷逆转录酶抑制剂(NNRTIs)，蛋白酶抑制剂，CCR5拮抗剂，CXCR4拮抗剂，融合抑制剂，成熟抑制剂和整合酶抑制剂。
式(I)的化合物还称为GSK1349572。 式(I)化合物的化学名称是(4R,12as)-N-[2,4-氟苯基)甲基]-3,4,6,8,12,12a-六氢-7-羟基-4-甲基-6,8-二氧代-2H-吡啶并[1',2':4,5]吡嗪并[2,1-b][1,3]噁嗪-9-甲酰胺。
式(II)化合物的化学名称是(3S,11aR)-N-[(2,4-二氟苯基)甲基]-2,3,5,7,11,11a-六氢-6-羟基-3-甲基-5,7-二氧代-噁唑并[3,2-a]吡啶并[1,2-d]吡嗪-8-甲酰胺。
式(III)化合物的化学名称是(4aS,13aR)-N-[2,4-二氟苯基)甲基]-10-羟基-9,11-二氧代-2,3,4a,5,9,11,13,13a-八氢-1H-吡啶并[1,2-a]吡咯并[1',2':3,4，]咪唑并[1,2-d]吡嗪-8-甲酰胺。
术语“可药用载体或助剂”是指可以与本发明化合物一起给予患者的载体或助剂，其不会破坏本发明化合物的药理学活性，并且当以足够递送治疗数量的抗病毒剂的剂量给予时，其是无毒的。
本文使用的术语“治疗”是指患者具体病症的症状减轻，或与具体病症有关的可确定的量度的改善，并且可以包括抑制无症状患者的症状复发，例如，具有潜在病毒感染的患者。治疗可以包括预防，这是指预防患者的疾病或病症，或防止这种疾病或病症的症状出现。本文使用的术语“患者”是指哺乳动物，包括人。
本文使用的术语“患者”是指病人、动物或生物样品。
按照本发明化合物的可药用盐包括衍生自可药用无机和有机酸和碱的那些盐。合适的酸的例子包括盐酸，氢溴酸，硫酸，硝酸，高氯酸，富马酸，马来酸，磷酸，乙二醇酸，乳酸，水杨酸，琥珀酸，对甲苯磺酸，酒石酸，乙酸，柠檬酸，甲磺酸，乙磺酸，甲酸，苯甲酸，丙二酸，萘-2-磺酸和苯磺酸。其它酸，例如草酸，尽管本身不是可药用的，但可以在得到本发明化合物和其可药用酸加成盐的过程中用作中间体的盐的制备中使用。衍生自合适的碱的盐包括碱金属(例如钠)、碱土金属(例如镁)、铵、NW4 +(其中W是C1-4烷基)及其它胺盐。优选的盐是钠盐。
本发明化合物的盐可以利用本领域技术人员已知的方法来制备。例如，在合适的溶剂中，用合适的碱或酸处理本发明的化合物，可以得到相应的盐。
本发明涉及治疗或预防人的病毒感染的方法，例如HIV感染，该方法包括：给予人治疗有效量的式(I)、(II)或(III)的化合物或其可药用盐与一或多种选自下列的治疗剂的联用药：核苷酸逆转录酶抑制剂，核苷逆转录酶抑制剂(NRTIs)，非核苷逆转录酶抑制剂(NNRTIs)，蛋白酶抑制剂，CCR5拮抗剂，CXCR4拮抗剂，融合抑制剂，成熟抑制剂和整合酶抑制剂。可以同时或顺序给予联用药。
式(I)、(II)和(III)的化合物尤其适合于治疗或预防HIV感染和有关的病症。本文谈到的治疗可以延伸至预防以及确定感染、症状和相关的临床病症的治疗，例如AIDS相关症(ARC)、卡波济氏肉瘤和AIDS痴呆。
联合治疗包括：给予本发明的化合物或其可药用盐和另一种药学活性剂。活性组分和药学活性剂可以在相同或不同的药物组合物中同时(即并行)给予，或以任何次序顺序给予。为了获得目标联合治疗效果，可以选择活性组分和药学活性剂的数量和给药的相对时间。
这种治疗剂的例子包括但不局限于：有效治疗病毒感染或相关病症的药剂。在这些药剂之中有核苷酸逆转录酶抑制剂，无环核苷膦酸酯，例如(S)-1-(3-羟基-2-膦酰基-甲氧基丙基)胞嘧啶(HPMPC)，[[[2-(6-氨基-9H-嘌呤-9-基)乙氧基]甲基]氧亚膦基(phosphinylidene)]二(氧甲撑)-2,2-二甲基丙酸(bis-POM PMEA，阿德福韦酯)，阿德福韦，[[(1R)-2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基]膦酸(泰诺福韦)，泰诺福韦二吡呋酯富马酸盐和(R)-[[2-(6-氨基-9H-嘌呤-9-基)-1-甲基乙氧基]甲基]膦酸双(异丙氧羰基氧基甲基)酯(bis-POC-PMPA)；核苷逆转录酶抑制剂，例如3'-叠氮基-3'-脱氧胸苷(AZT，叠氮胸苷)，2',3'-双脱氧胞苷(ddC，扎西他滨)，2',3'-二脱氧腺苷，2',3'-去羟肌苷(ddI，去羟肌苷)，2',3'-双脱氧胸苷(d4T，双脱氧胸苷)，(-)-顺式-1-(2-羟甲基)-1,3-氧硫杂环戊烷-5-基)-胞嘧啶(拉米夫定)，顺式-1-(2-(羟甲基)-1,3-氧杂硫杂环戊烷-5-基)-5-氟胞嘧啶(FTC，恩曲他滨(emtricitabine))，(-)-顺式-4-[2-氨基-6-(环丙氨基)-9H-嘌呤-9-基]-2-环戊烯-1-甲醇(阿巴卡韦)，福齐夫定替酯(fozivudine tidoxil)，阿洛夫定，氨多索韦(amdoxovir)，艾夫他滨(elvucitabine)，阿立他滨(apricitabine)和festinavir(OBP-601)；蛋白酶抑制剂，例如茚地那韦，利托那韦，奈非那韦，安普那韦，沙奎那维，佛萨普那韦，洛匹那韦，阿扎那韦(atazanavir)，替拉那韦(tipranavir)，达芦那韦(darunavir)，贝卡那韦(brecanavir)，帕利那韦(palinavir)，拉西那韦(lasinavir)，TMC-310911，DG-17，PPL-100和SPl-256；非核苷逆转录酶抑制剂(NNRTIs)，例如内维拉平，地拉韦啶，依法韦恩茨，GSK2248761(IDX-12899)，来司韦林(lersivirine)(UK-453,061)，利匹韦林(rilpivirine)(TMC-278)，依曲韦林(etravirine)，洛韦胺(loviride)，immunocal，奥替普拉(oltipraz)，卡普韦林(capravirine)和RDEA-806；整合酶抑制剂，例如雷特格韦(raltegravir)，埃替拉韦(elvitegravir)和JTK-656；CCR5和/或CXCR4拮抗剂，例如，马拉维若(maraviroc)，vicriviroc(Sch-D)，TBR-652(TAK-779)，TAK-449，PRO-140，GSK706769和SCH-532706；融合抑制剂，例如恩夫韦地(T-20)，T-1249，PRO-542，ibalizumab(TNX-355)，BMS-378806(BMS-806)，BMS-488043，KD-247，5-螺旋抑制剂和HIV连接抑制剂；和成熟抑制剂，例如，贝韦立马(bevirimat)(PA-344和PA-457)。
本发明的特征在于联用药，其包含式(I)的化合物
(I)
或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征还在于联用药，其包含式(I)的化合物或其可药用盐和一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨或洛匹那韦。本发明的特征在于联用药，其包含式(I)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(I)的化合物或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(I)的化合物或其可药用盐与一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于HIV感染的治疗方法，包括：给予患者式(I)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于药物组合物，其包含式(I)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶拉米夫定，阿巴卡韦，依法韦恩茨，泰诺福韦，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征在于药物组合物，其包含式(I)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于药物组合物，其包含式(I)的化合物或其可药用盐和阿巴卡韦以及此种情况下可药用的载体。
本发明的特征在于联用药，其包含式(II)的化合物
(II)
或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征还在于联用药，其包含式(II)的化合物或其可药用盐和一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于联用药，其包含式(II)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(II)的化合物或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(II)的化合物或其可药用盐与一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于HIV感染的治疗方法，包括：给予患者式(II)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于药物组合物，其包含式(II)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶拉米夫定，阿巴卡韦，依法韦恩茨，泰诺福韦，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦阿扎那韦(atazanavir)。
本发明的特征在于药物组合物，其包含式(II)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于药物组合物，其包含式(II)的化合物或其可药用盐和阿巴卡韦以及此种情况下可药用的载体。
本发明的特征在于联用药，其包含式(III)的化合物
(III)
或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征还在于联用药，其包含式(III)的化合物或其可药用盐和一或多种选自下列的治疗剂：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征还在于联用药，其包含式(III)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(III)的化合物或其可药用盐和一或多种选自下列的治疗剂：拉米夫定，阿巴卡韦，泰诺福韦，依法韦恩茨，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦(atazanavir)。
本发明的特征在于HIV感染的治疗方法，包括：给予患者式(III)的化合物或其可药用盐与一或多种选自下列的治疗剂的联用药：阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于HIV感染的治疗方法，包括：给予患者式(III)的化合物或其可药用盐和阿巴卡韦。
本发明的特征在于药物组合物，其包含式(III)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶拉米夫定，阿巴卡韦，依法韦恩茨，泰诺福韦，GSK2248761，来司韦林(lersivirine)，洛匹那韦，佛萨普那韦和阿扎那韦阿扎那韦(atazanavir)。
本发明的特征在于药物组合物，其包含式(III)的化合物或其可药用盐和一或多种选自下列的治疗剂以及此种情况下可药用的载体∶阿巴卡韦、依法韦恩茨和洛匹那韦。本发明的特征在于药物组合物，其包含式(III)的化合物或其可药用盐和阿巴卡韦以及此种情况下可药用的载体。
本发明的特征在于上述的联用药、治疗方法和药物组合物，其中式(I)、(II)或(III)化合物的可药用盐是钠盐。
本发明的特征在于上述联用药、治疗方法和药物组合物，其中一或多种治疗剂是所述治疗剂的可药用盐，例如，阿巴卡韦半硫酸盐，佛萨普那韦钙，硫酸阿扎那韦(atazanavir)，硫酸泰诺福韦二吡呋酯，vicriviroc马来酸盐或贝韦立马(bevirimat)二甲葡胺。
本发明的特征在于上述治疗方法，其中患者是人。
本发明的特征在于上述联用药、治疗方法和药物组合物，其中顺序给予联用药。
本发明的特征在于上述联用药、治疗方法和药物组合物，其中同时或并行给予联用药。
式(I)、(II)和(III)的化合物可以利用WO 2006/116764、U.S. 61/193,634(WO2010/068253)或61/193,636(WO2010/068262)(本文以引证的方式将它们结合到本文中)公开的方法来制备。
阿巴卡韦可以利用公开在下列中的方法来制备：美国专利US5,034,394；5,089,500；6,294,540；5,641,889；5,840,990；5,919,941；5,808,147；6,392,085；6,448,403；5,917,041；6,087,501；5,917,042；6,555,687；6,552,193；6,870,053；6,294,540；6,340,587；或6,646,125。
拉米夫定可以利用公开在下列中的方法来制备：美国专利US5,047,407；7,119,202；5,905,082；5,696,254；5,663,320；5,693,787；6,051,709；或6,329,522。
泰诺福韦可以利用美国专利US5,922,695、5,935,946、5,977,089、6,043,230、6,069,249来制备。
依法韦恩茨可以利用公开在下列中的方法来制备：美国专利US5,519.021；5,663,169；5,811,423；6,555,133；6,639,071；或6,939,964。
GSK2248761可以利用公开在美国专利US7,534,809中的方法来制备。
来司韦林(Lersivirine)可以利用公开在美国专利US7,109,228中的方法来制备。
洛匹那韦可以利用公开在美国专利US5,914,332中的方法来制备。
佛萨普那韦可以利用公开在美国专利US6,436,989、6,514,953或6,281,367中的方法来制备。
阿扎那韦(atazanavir)可以利用公开在美国专利US5,849,911或6,087,383中的方法来制备。
联用药的治疗剂可以按照公开的方法或利用本领域技术人员已知的任何方法来制备。
在本发明的一个方面，可以将式(I)、(II)或(III)的化合物或其可药用盐与一或多种治疗剂一起配制为组合物。该组合物可以是药物组合物，其包含式(I)、(II)或(III)的化合物、一或多种治疗剂和可药用载体、助剂或赋形剂。在一个实施方案中，该组合物包含有效治疗或预防生物样品或病人中的病毒感染(例如HIV感染)数量的本发明的联用药。在另一个实施方案中，可以将本发明的联用药和其药物组合物进行配制，用于给予病人，例如，口服给药，其中该药物组合物包含有效抑制病毒复制或治疗或预防病毒感染或疾病或病症(例如HIV感染)数量的本发明的联用药和可药用载体、助剂或赋形剂。
本发明的特征在于用于医学治疗的按照本发明的联用药，例如，用于治疗或预防病毒感染，例如HIV感染和相关病症。按照本发明的化合物尤其可用于治疗AIDS和相关的临床病症，例如AIDS相关综合症(ARC)，渐进性的全身化淋巴结病(PGL)，卡波济氏肉瘤，血小板减少性紫癜，AIDS相关的神经病症，例如AIDS痴呆综合症、多发性脑硬化或热带轻瘫（paraperesis），抗HIV抗体阳性和HIV-阳性病症，包括无症状患者中的这种病症。
按照另一个方面，本发明提供了治疗或预防受感染患者(例如，哺乳动物，包括人)中的病毒感染的症状或影响的方法，该方法包括：给予所述患者药学有效量的按照本发明的联用药。按照本发明的一个方面，病毒感染是逆转录病毒感染，尤其是HIV感染。
本发明进一步包括按照本发明的联用药在制备药物中的用途，该药物用于同时(并行)或顺序给予被治疗病毒感染的患者，尤其是HIV感染。
本发明进一步提供了治疗患者(例如，哺乳动物，包括人)的临床病症的方法，其中临床病症包括上文讨论的那些病症，该方法包括：用药学有效量的按照本发明的化合物治疗所述患者。本发明还包括治疗或预防任何上述疾病或病症的方法。
本发明的化合物可以与已知能够抑制或降低化合物代谢的药剂(例如利托那韦)一起给予。相应地，本发明的特征在于治疗或预防上文所描述疾病的方法，该方法给予本发明化合物与代谢抑制剂的联用药。这种联用药可以同时或顺序给予。
通常，对于每个上述病症，合适的剂量在每千克接受者(例如人)体重每天0.01至250 mg范围内、在每千克体重每天0.1至100 mg范围内、在每千克体重每天1至30 mg范围内、在每千克体重每天0.5至20 mg范围内。除非另有陈述，否则，活性组分的所有重量以式(I)、(II)或(III)的母体化合物及其它治疗剂的形式来计算。对于其盐，重量可以按比例提高。目标剂量可以以每天以合适的间隔时间给予的一个、两个、三个、四个、五个、六个或更多个子剂量形式提供。在某些情况下，目标剂量可以隔天给予。可以用单位剂型给予这些子剂量，例如，每个单位剂型含有1至2000 mg、5至500 mg、10至400 mg、20至300 mg每种活性组分。
可以给予联用药，获得每个活性组分的峰值血浆浓度。
尽管可以单独给予活性组分，但优选以药物组合物形式提供。本发明的组合物包含上述活性组分以及一或多种其可接受的载体和一或多种其它治疗剂。每个载体在与组合物的其它组分相容的意义上必须是可接受的，并且对患者无害。
药物组合物包括适合于口服、直肠、鼻部、局部(包括透皮、口腔和舌下)、阴道或肠胃外(包括皮下、肌内、静脉内、皮内和眼内)给药的那些药物组合物。组合物可以方便地存在于单位剂型中，并且可以用药学领域任何众所周知的方法来制备。这种方法代表本发明的进一步特征，并且包括下列步骤：使活性组分与构成一或多种助剂成分的载体结合。通常，如下制备组合物：使活性组分与液体载体或细碎的固体载体或两者均匀和密切地结合，而后，如有必要，使产品成型。
本发明进一步包括上文所定义的药物组合物，其中以组件的试剂盒形式相互分离地提供本发明的化合物或其可药用衍生物和另一种治疗剂。
适合于透皮给药的组合物可以以离散贴片形式提供，这种贴片适合于保持与接受者的表皮长时间地密切接触。这种贴片合适地含有活性化合物：1)在任选缓冲的水溶液中，或2)溶解和/或分散在粘附剂中，或3)分散在聚合物中。活性化合物的合适浓度大约为1%至25%，优选大约3%至15%。作为一种具体可能性，利用通常在Pharmaceutical Research 3(6)，318(1986)中所描述的电迁移或离子电渗方法，活性化合物可以从贴片中输送。
适合于口服给药的本发明药物组合物可以以下列形式提供：离散单位形式，例如胶囊剂、小胶囊、扁囊剂或片剂，其中每个优选含有预定数量的活性组分；粉剂或颗粒剂形式；在水或非水液体中的溶液剂或混悬剂形式；或水包油型液体乳剂或油包水型液体乳剂形式。活性组分还可以以丸剂(bolus)、膏剂或糊剂形式提供。
片剂可以通过压制或模制来制备，任选与一或多种助剂成分一起压制或模制。压制片可以如下制备：在合适的机械中，压制自由流动形式的(例如粉末或颗粒)活性组分,任选与粘合剂(例如，聚维酮，明胶，羟基丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如，淀粉乙醇酸钠，交联聚维酮，交联羧甲基纤维素钠)、表面活性剂或分散剂混合。模制片可以如下制备：在合适的机械中，将用惰性液体稀释剂湿润的粉末化合物混合物模制。可以任选将片剂包衣或刻痕，并且可以使用例如变化比例的羟基丙基甲基纤维素配制，以便使其中的活性组分缓慢或控制释放，从而提供目标释放特性。片剂可以任选拥有肠溶衣，以便在胃以外的肠管部分中释放。
适合于口腔局部给药的药物组合物包括：含有活性组分(在调味基质中，通常是蔗糖和阿拉伯胶或黄芪胶)的糖锭；包含活性组分(在惰性基质中，例如明胶和丙三醇，或蔗糖和阿拉伯胶)的软锭剂；和包含活性组分(在合适的液体载体中)的漱口药。
适合于阴道给药的药物组合物可以以阴道栓、塞、乳膏剂、凝胶剂、糊剂、泡沫体或喷雾剂形式提供。除了活性组分之外，药物组合物还可以含有本领域已知的合适载体。
直肠给药的药物组合物可以以含有合适载体(包括，例如，可可脂或水杨酸酯或本领域通常使用其它物质)的栓剂形式提供。栓剂可以方便地如下形成：将活性联用药与软化或熔融载体混合，而后在模具中冷却并成型。
适合于肠胃外给药的药物组合物包括水和非水等渗无菌注射溶液剂，其可以含有抗氧化剂、缓冲剂、抑菌剂和能够使该药物组合物与目标接受者的血液等渗的溶质；和水和非水的无菌混悬剂，其可以包含悬浮剂和增稠剂；和脂质体或其它微粒系统，可以对其进行设计，使化合物靶向血液组分或一个或多个器官。药物组合物可以提供于单位剂量或多剂量密封容器中，例如，安瓿和小瓶，并且可以保存在冷冻干燥(冻干)条件下，只需要在临近使用之前加入无菌的液体载体即可，例如注射用水。可以用先前所描述种类的无菌粉剂、颗粒剂和片剂来制备临时注射溶液剂和混悬剂。
单位剂量药物组合物包括含有上文列举的活性组分的日剂量或日子剂量或其合适部分的那些药物组合物。
本发明的药物组合物可以以患者包装形式提供，在单个包装(例如，泡罩包装)中含有一个或多个疗程的药物组合物。可以理解，借助于单个患者包装或每个组合物的患者包装来给予本发明的联用药是本发明的另外的特征。
应该理解，根据所述药物组合物的类型，除了上面具体提及的组分之外，本发明的药物组合物还可以包含本领域的其它常规药剂，例如，适合于口服给药的那些药物组合物可以进一步包含例如甜味剂、增稠剂和调味剂。
实施例
实施例1∶生物活性
试验
方法
借助于基于四唑盐的比色方法，在人T细胞白血病毒(HTLV-1)转变的细胞系MT-4中，测定抗病毒HIV活性。将试验化合物的等分样品在深孔主试验板的纵向上(vertically)稀释于培养基(RPMI 1640，10% vol./vol.胎牛血清(FBS)和10(μg/mL庆大霉素)中，浓度比最终试验浓度大约高40倍。 以1:2或1:3.16的比例进行系列稀释。将HIV抑制剂在主试验板的横向上(horizontally)加以稀释，浓度还是比最终试验浓度大约高40倍。使用自动的96孔移液系统(RapidPlate-96，Zymark Corp.)，将纵向稀释和横向稀释的化合物的少量等分样品在子板中混合。 将棋盘式稀释物进行排列，以便在存在和不存在每个浓度的HIV抑制剂条件下试验每个浓度的试验化合物。对于每个联用药，一式三份地进行抗HIV活性试验，或进行更多的试验。采集指数(Exponentially)生长的MT-4细胞，并在Jouan离心机(ModelCR 4 12)中、在1,000 rpm下离心10分钟。将细胞球粒重新悬浮在新的培养基(RPMI 1640，20% vol./vol. FBS，20% vol./vol. IL-2和10 μg/mL庆大霉素)中，密度为1.25 x 106个细胞/mL。 通过加入稀释的HIV-1(菌株IIIB)，使细胞等分样品感染，得到每1 x 104个细胞73 pfU的病毒多重性感染(MOI)。用培养基稀释类似的细胞等分样品，提供模拟感染(mock-infected)对照物。在37℃，在含有湿润的5% CO2氛围的组织培养箱中，使细胞感染进行1小时。培养1小时之后，将病毒/细胞悬液加入到含有预先稀释的化合物的板的每个孔中。然后将板放入含有湿润的5% CO2的组织培养箱中，保持5天。在培养期的最后，将40μLCellTiter 96 MTS试剂(Promega No. G3581)加入到培养板的每个孔中。 将板在37℃下培养2至3小时，使其显色。使用微板吸光度读数器(Tecan No. 20-300)在492 nM测定吸光度O.D.。
使用的病毒
HIV-1菌株IIIB，野生型实验室菌株，病毒滴度=6.896 E4 TCID50/mL。
数据分析
虽然一些试验形式理论上可能失去拮抗作用(由于联合细胞毒性)，但本文所描述的方法不应该失去拮抗效应。在MT-4细胞试验中的读出数据使用MTS(基于四唑盐的染色剂)，其中该试剂的吸光度(O.D.)变化用于估计处理后的总的细胞数目。 由于两种影响，最终的MT-4细胞数目可能减少。首先，当在感染之后5天期间HIV杀死75%以上的MT-4细胞时，可能出现HIV引起的细胞毒性。其次，可能出现化合物引起的细胞毒性，在这种的情况下，化合物直接杀死MT-4细胞，或在感染或未感染的细胞中妨碍细胞生长(停滞)5天。在这些情况中的任何一种情况下，与抗HIV-1化合物保护的受感染细胞相比较，或相对于未经处理的和未感染的对照细胞，O.D.降低。 由于抗HIV活性的细胞毒性效果和拮抗作用两者导致O.D.降低，我们不应该由于联合细胞毒性而忽视(miss)拮抗效应，但可能低估协同作用的联用药。
在试验过程中，可以如下评价联合细胞毒性：将含有未感染的MT-4细胞(源自于含有最高浓度试验化合物或比较化合物的试验板)的孔与含有HIV-1感染的MT-4细胞(在相应的最高联用药浓度下)的孔进行比较。对于这些数值中的每个数值，每个试验板有一个孔，并由此每个联用药试验中至少有3个孔。虽然它们不包括正式的联合细胞毒性分析，但联用药中的化合物与单独化合物的比例可以提供在检验浓度范围内化合物联合细胞毒性的度量。
利用Selleseth，D.W.等人，(2003) Antimicrobial Agents and Chemotherapy47:1468-71所描述的方法，分析每对化合物联用药的相互作用。协同作用和拮抗作用定义为自剂量加合值的偏离值，剂量加和值发生在当两种药物如同它们是相同的药物一样相互作用时。自加和值的平均偏离值在-0.1至-0.2范围内表示弱协同作用，接近-0.5的数值表示强协同的相互作用。反之，0.1至0.2的正值表示在治疗之间存在弱的拮抗作用。
结果
发现式(I)的化合物与雷特格韦(raltegravir)、阿德福韦和马拉维若(maraviroc)具有加和效果，并且不受利巴韦林的存在的影响。发现式(I)的化合物与双脱氧胸苷(stavudine,司他夫定)、阿巴卡韦、依法韦恩茨、内维拉平、洛匹那韦、安普那韦、恩夫韦地具有协同作用。
Claims (13)
1.联用药，其包含式(I)的化合物
或其可药用盐与利匹韦林(rilpivirine)或其可药用盐。
2.按照权利要求1的联用药，其中式(I)化合物的可药用盐是钠盐。
3.按照权利要求1或2的联用药，其中利匹韦林的可药用盐是盐酸盐。
4.按照权利要求1-3的任一项的联用药，其用于医学治疗。
5.按照权利要求1-3的任一项的联用药，其用于治疗HIV感染。
6.按照权利要求1-3的任一项的联用药，其用于预防HIV感染。
7.药物组合物，其包含按照权利要求1-3中任一项的联用药以及其可药用载体。
8.按照权利要求1-3的任一项的联用药，其中同时给予该联用药。
9.按照权利要求1-3的任一项的联用药，其中顺序给予该联用药。
10.按照权利要求1-3的任一项的联用药在制备用于治疗或预防HIV感染的药物中的用途。
11.按照权利要求10的用途，其中式(I)化合物和利匹韦林同时给予。
12.按照权利要求10的用途，其中式(I)化合物和利匹韦林顺序给予。
13.一种患者包装，其包括按照权利要求1-3的任一项的联用药。
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