CN104902900A - 使用cbp/连环蛋白的抑制剂治疗病毒性和传染性疾病 - Google Patents
使用cbp/连环蛋白的抑制剂治疗病毒性和传染性疾病 Download PDFInfo
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Abstract
本公开一般地涉及α-螺旋模拟的结构并且特别地涉及是β-连环蛋白抑制剂的α-螺旋模拟的结构。本公开还涉及在治疗病毒性和传染性疾病中的应用,包括被HIV、HPV、HBV、HSV,和细菌感染,所述细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria),和包含这种α螺旋模拟的β-连环蛋白抑制剂的药物组合物。
Description
相关申请的交叉引用
本申请要求2012年10月19日提交的美国临时申请61/716,116;2013年1月3日提交的美国临时申请61/748,621;和2013年5月8日提交的美国临时申请61/820,995的优先权;其各自以它的整体通过引用并入本文。
公开背景
Wnt/β-连环蛋白信号转导由于它在人生物学的许多方面中的关键作用而逐渐成为先驱。该信号转导通路在胚胎形成、器官形成和保持组织和器官动态平衡中具有作用。然而,该通路的异常激活在许多病毒性和传染性疾病状态中也是明显的。
人类免疫缺陷病毒(HIV)是导致获得性免疫缺陷综合征(AIDS)的慢病毒属(逆转录病毒科的成员),所述获得性免疫缺陷综合征是其中免疫系统的进行性衰竭允许威胁生命的机会性感染和癌症发展的人类中的疾病状态。
人乳头瘤病毒(HPV)是能够传染人类的乳头瘤病毒科的病毒。如同所有乳头瘤病毒,HPVs仅在皮肤或粘膜的角化细胞中建立生产性感染。尽管大多数已知类型的HPV在大多数人中不产生症状,但一些类型可导致疣(瘊),尽管其他在少数情况下可导致宫颈、外阴、阴道、阴茎、口咽和肛门的癌症。
还称为人疱疹病毒1和2(HHV-1和-2)的单纯性疱疹病毒1和2 (HSV-1和HSV-2)是传染人类的疱疹病毒科(herpes virus family或Herpesviridae)的两个成员。HSV-1 (其产生大多数唇疱疹)和HSV-2 (其产生大多数生殖器疱疹)二者是普遍存在和接触传染的。它们可在感染的人产生和脱落病毒时传播。单纯性疱疹病毒感染的症状包括嘴、嘴唇或生殖器的皮肤或粘膜中的水疱。
结核病、MTB或TB (简称结核杆菌(tubercle bacillus))是常见的,并且在许多情况下是由许多分枝杆菌属(mycobacteria)菌株,通常结核分枝杆菌(Mycobacterium tuberculosis)导致的致命的、传染性疾病。结核病通常侵袭肺但还能影响身体的其他部分。它在具有活性TB感染的人咳嗽、打喷嚏,或者另外通过空气传播它们的唾液时通过空气传播。
引起细胞内感染的其他微生物包括单核细胞增多性李斯特菌(Listeria monocytogenes)(其导致李斯特菌病和败血症)和志贺氏菌属(Shigella)种(其导致痢疾)。这些细菌是食物传播疾病和新生儿/幼儿感染和死亡的重要原因。李斯特菌属(Listeria)是感染包括吞噬细胞如巨噬细胞的许多细胞型的致命食物传播病原体。单核细胞增多性李斯特菌(L. monocytogenes)杀死20%至30%的具有临床感染的个体,并且是新生儿脑膜炎的主要原因。志贺氏菌属(Shigella)种,特别是福氏志贺菌(S. flexneri)、索氏志贺菌(S. sonnei)和痢疾志贺菌(S. dysenteriae)感染胃肠道细胞并且导致严重的胃肠症状如腹泻和胃痉挛。志贺氏菌属(Shigella)感染是每年超过9千万例痢疾和超过100,000死亡的原因,主要在发展中国家的儿童中。
细胞内感染的细胞反应是自噬,一种细胞通过其包封和破坏外来和不期望的细胞内成分的过程。自噬从在细胞内核内体/自噬体中包封微生物开始。自噬体与包含分解酶的溶酶体融合以形成自噬溶酶体。在自噬溶酶体内部,酸性和溶解性环境杀死微生物。各种微生物如结核分枝杆菌和HIV通过下调或抑制自噬和保持细胞内感染避免该过程(Specter, Topics Antiviral Med. 19:6-10, 2011.)
Wnt信号转导与多重水平上的免疫反应有关。Wnt信号转导与T-细胞形成的调节有关,并且还调节自噬。例如,已经证实减少水平的β-连环蛋白上调自噬 (Nguyen等人,J. Cell. Mol. Med. 13:3687-3698, 2009)。因此,Wnt信号转导对反应于微生物感染发挥几种潜在作用。
Gattinoni等人(Nat Med. 15(7): 808–813, 2009)的研究显示Wnt信号转导在保持成熟记忆CD8+ T细胞中的干性中的关键作用。该研究的结果对通过靶向Wnt通路设计新接种策略和采用的免疫疗法具有重要意义。
Bulut等人(PLoS One 2011;6(11): e27243)的研究确定Wnt信号转导通路的激活和它对HPV-介导的宫颈癌的贡献之间的潜在联系。这些结果表明典型Wnt通路的激活可能代表HPV-感染的上皮细胞的恶性转化所需的继发性事件。因此,靶向典型Wnt通路可提供开发预防处于HPV感染风险中的群体的疾病进展和治疗晚期宫颈癌以及其他病毒性和传染性疾病的临床干预的基础。
公开简述
本公开提供了通过单独或结合另外的抗病毒或抗菌治疗给予β-连环蛋白信号转导抑制剂治疗传染性疾病的方法,包括被HIV、HPV、HBV、HSV,和细菌感染,所述细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)。本公开还提供α螺旋模拟的β-连环蛋白抑制剂化合物和包含β-连环蛋白的抑制剂的组合物。
附图简述
图1:在巨噬细胞中的HIV复制 (HIV p24抗原的ng/ml)显示随化合物C浓度增加的剂量反应(减少量的p24抗原)。
图2A-2B:1 μM和2 μM下的化合物A诱导自噬。(A-B),在存在或不存在化合物A (Cmpd A)或雷帕霉素(Rapa,自噬的阳性对照)情况下的细胞治疗显示增加量的LC3B II和减少量的LC3B I,相对于阴性对照(没有化合物A,没有雷帕霉素),自噬的指示物。在2 μM 化合物A下,以及雷帕霉素,LC3B II和LC3B I二者的水平相对于阴性对照显著降低。(B),在雷帕霉素和化合物A-治疗的细胞中死骨片1/p62 (SQSTM1)水平相对于阴性对照降低,表明增加的自噬。
图3A-3B:(A),饼图表明在存在或不存在β-连环蛋白抑制剂化合物C的情况下,在10-天孵育后分选Tscm (左图)或Tcm (右图)的指出的T细胞子集的比例。示出来自一个典型研究主体的结果。(B),在使用或不使用化合物C的10天孵育后保持它们的最初CCR7+ CD62L+ 表型的分选CD4 Tscm或CD4 Tcm的比例。示出来自n=3三个研究主体的累积数据。
公开详述
近来,开发非肽化合物,其模拟在生物活性蛋白质或肽中发现的回折的二级结构。例如,U.S. Pat. No. 5,440,013和公开的PCT申请Nos. WO94/03494、WO01/00210A1和WO01/16135A2各自公开构象约束的非肽化合物,其模拟回折的三维结构。此外,U.S. Pat. No. 5,929,237和它的部分继续申请U.S. Pat. No. 6,013,458公开了构象约束的化合物,其模拟生物活性肽和蛋白质的回折区域的二级机构。关于回折模拟,在WO2007/056513和WO2007/056593中已经公开了模拟生物活性肽和蛋白质的α-螺旋区域的二级结构的构象约束的化合物。
本公开提供了新化合物、药物组合物和治疗病毒性和传染性疾病的方法,包括被HIV、HPV、HBV、HSV,和细菌感染,所述细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)。发明人确定抑制β-连环蛋白信号转导是治疗这些疾病的有效方法。
本发明的α螺旋模拟的β-连环蛋白抑制剂的结构和化合物在WO 2010/044485、WO 2010/128685、WO 2009/148192和US 2011/0092459中公开,其各自以它的整体通过引用并入本文。现在,已经发现这些化合物可用于治疗病毒性和传染性疾病,包括HIV、HPV、HBV、HSV,和细菌,所述细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)。
本发明的α 螺旋模拟的β-连环蛋白抑制剂的优选结构具有下式(I):
其中:
A为-CHR7-,
其中
R7为任选取代的芳基烷基、任选取代的杂芳基烷基、任选取代的环烷基烷基或任选取代的杂环烷基烷基;
G为-NH-、-NR6-或-O-
其中
R6为低级烷基或低级烯基;
R1为-Ra-R10;
其中
Ra为任选取代的低级亚烷基,且
R10为任选取代的二环稠合芳基或任选取代的二环稠合杂芳基;
R2为–(CO)-NH-Rb-R20,
其中
Rb为键或任选取代的低级亚烷基;且
R20为任选取代的芳基或任选取代的杂芳基;且
R3为C1-4烷基。
这些化合物特别适用于预防和/或治疗病毒性和传染性疾病,包括HIV、HPV、HBV、HSV和结核病。
本发明的α 螺旋模拟的β-连环蛋白抑制剂的更优选结构具有上述式(I)中的下列取代基:
A为-CHR7-,
其中
R7为任选被羟基或C1-4烷基取代的芳基烷基;
G为-NH-、-NR6-或-O-
其中
R6为C1-4烷基或C1-4 烯基;
R1为-Ra-R10;
其中
Ra为C1-4 亚烷基,且
R10为二环稠合芳基或二环稠合杂芳基,任选被卤素或氨基取代;
R2为–(CO)-NH-Rb-R20,
其中
Rb为键或C1-4亚烷基;且
R20为芳基或杂芳基;且
R3为C1-4烷基。
这些化合物特别适用于预防和/或治疗病毒性和传染性疾病,包括HIV、HPV、HBV、HSV,和细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)。
本发明的最优选的α 螺旋模拟的β-连环蛋白抑制剂如下:
(6S,9S)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-8-(萘-1-基甲基)-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-2-烯丙基-N-苄基-6-(4-羟基苄基)-9-甲基-8-(萘-1-基甲基)-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基苄基)-9-甲基-8-(萘-1-基甲基)-4,7-二氧代六氢吡嗪并[2,1-c][1,2,4]噁二嗪-1(6H)-甲酰胺,
(6S,9S)-8-((2-氨基苯并[d]噻唑-4-基)甲基)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-2-烯丙基-N-苄基-6-(4-羟基苄基)-9-甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
4-(((6S,9S)-1-(苄基氨基甲酰基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基二氢磷酸酯,
4-(((6S,9S)-1-(苄基氨基甲酰基)-2,9-二甲基-8-(萘-1-基甲基)-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基二氢磷酸酯,
4-(((6S,9S)-1-(苄基氨基甲酰基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基磷酸钠,
4-(((6S,9S)-1-(苄基氨基甲酰基)-2,9-二甲基-4,7-二氧代-8-(萘-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基磷酸钠,
(6S,9S)-2-烯丙基-6-(4-羟基苄基)-9-甲基-4,7-二氧代-N-((R)-1-苯基乙基)-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-2-烯丙基-6-(4-羟基苄基)-9-甲基-4,7-二氧代-N-((S)-1-苯基乙基)-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基-2,6-二甲基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-8-(苯并[b]噻吩-3-基甲基)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-8-(苯并[c][1,2,5]噻二唑-4-基甲基)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基苄基)-8-(异喹啉-5-基甲基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-8-((5-氯噻吩并[3,2-b]吡啶-3-基)甲基)-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹喔啉-5-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,和
(6S,9S)-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)-N-(噻吩-2-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺。
这些化合物特别适用于预防和/或治疗病毒性和传染性疾病,包括HIV、HPV、HBV、HSV和细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)。
在最优选的实施方案中,所述化合物为:
4-(((6S,9S,9aS)-1-(苄基氨基甲酰基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基二氢磷酸酯 (化合物A),或
(6S,9S,9aS)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺 (化合物C)。
这些化合物特别适用于预防和/或治疗病毒性和传染性疾病,包括HIV、HPV、HBV、HSV和细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)。
尽管不期望受束缚,但这些化合物在治疗这些疾病状态中的有效性部分基于这些化合物通过抑制环AMP反应-元件结合蛋白(CBP)阻滞TCF4/β-连环蛋白转录通路的能力,由此改变wnt通路信号转导,发现其改善结果。
“β-连环蛋白抑制剂”是可降低或阻止β-连环蛋白活动的物质。β-连环蛋白活动包括易位至核、结合TCF (T细胞因子)转录因子和共激活TCF靶标基因的TCF转录因子-诱导的转录。“β-连环蛋白抑制剂”还可干扰CBP和β-连环蛋白的相互作用。因此,β-连环蛋白抑制剂抑制或降低CBP/β-连环蛋白信号转导和CBP/β-连环蛋白信号转导通路的活动,包括减少一种或多种下游信号转导事件。
本文公开了用于治疗病毒性和传染性疾病的α 螺旋模拟的β-连环蛋白抑制剂化合物,包括HIV、HPV、HBV、HSV和细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)。
传染性疾病是由微生物如病毒或细菌的侵袭引起的疾病。通过本发明的化合物和方法可治疗的传染性疾病的实例如下。
人类免疫缺陷病毒(HIV)导致获得性免疫缺陷综合征(AIDS),所述获得性免疫缺陷综合征是导致免疫系统的进行性衰竭并允许机会性感染和癌症在免疫受损的主体中生长的疾病状态。
丙型肝炎是由丙型肝炎病毒(HBV)引起的肝的传染性炎性疾病。感染常无症状,但慢性感染可导致肝瘢痕并最终导致肝硬化,其通常在许多年后变明显。在一些情况下,具有肝硬化的那些继续发展肝功能衰竭、肝癌或威胁生命的食管和胃静脉曲张。
人乳头瘤病毒(HPV)是感染皮肤或粘膜的角化细胞的乳头瘤病毒。一些类型可导致生殖器疣(瘊),而其他可导致宫颈、外阴、阴道、阴茎、口咽和肛门的癌症。HPV感染是宫颈非典型增生的流行原因,一种如果不治疗可发展为宫颈癌的癌前疾病状态。
还称为人疱疹病毒1和2 (HHV-1和-2)的单纯性疱疹病毒1和2 (HSV-1和HSV-2)是疱疹病毒科的两个成员。HSV-1 (其产生大多数唇疱疹)和HSV-2 (其产生大多数生殖器疱疹)二者是普遍存在和接触传染的。它们可在感染的人产生和脱落病毒时传播。单纯性疱疹病毒感染的症状包括嘴、嘴唇或生殖器的皮肤或粘膜中的水疱。
结核病、MTB或TB (简称结核杆菌(tubercle bacillus))是常见的,并且在许多情况下是由许多分枝杆菌属(mycobacteria)菌株,通常结核分枝杆菌(Mycobacterium tuberculosis)导致的致命的、传染性疾病。结核病通常侵袭肺但还能影响身体的其他部分。它在具有活性TB感染的人咳嗽、打喷嚏,或者另外通过空气传播它们的唾液时通过空气传播。
李斯特菌属(Listeria)是感染包括吞噬细胞如巨噬细胞的许多细胞型的致命食物传播病原体。单核细胞增多性李斯特菌(L. monocytogenes)杀死20%至30%的具有临床感染的个体,并且是新生儿脑膜炎的主要原因。志贺氏菌属(Shigella)种,特别是福氏志贺菌(S. flexneri)、索氏志贺菌(S. sonnei)和痢疾志贺菌(S. dysenteriae)感染胃肠道细胞并且导致严重的胃肠症状如腹泻和胃痉挛。志贺氏菌属(Shigella)感染是每年超过9千万例痢疾和超过100,000死亡的原因,主要在发展中国家的儿童中。
可通过本发明的β-连环蛋白抑制剂治疗的其他传染性疾病包括由流产布鲁氏菌(Brucella abortus)、沙眼衣原体(Chlamydia trachomatis)、嗜肺军团菌(Legionella pneumophila)、牙龈卟啉单胞菌(Porphyromonas gingivalis)、沙门氏菌属(Salmonellaspecies)、金黄色葡萄球菌(Staphylococcus aureus)、化脓链球菌(Streptococcus pyogenes)、柯萨奇病毒(Coxsackievirus)、巨细胞病毒(Cytomegalovirus)、登革病毒(Dengue virus)、甲型流感病毒(Influenza A virus)、脊髓灰质炎病毒(Poliovirus)、呼吸道合胞体病毒(Respiratory syncytial virus)和水痘带状疱疹病毒(Varicella zoster virus)引起的感染。
如本文使用的,“治疗”是指试图改变受治疗的个体或细胞的疾病进程的临床干预,并且可在临床病理学过程中进行。治疗的治疗效果包括但不限于,预防疾病复发、缓解症状、减少疾病的任何直接或间接病理学结果、降低疾病发展的速度、改善或减轻疾病状态和缓解或改善预后。
如本文使用的,术语“治疗有效量”和“有效量”可交换地用于是指足以导致预防病毒性和传染性疾病的发展或发病的本发明组合物的量,包括HIV、HPV、HBV、HSV,和细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria),或其一种或多种症状,以增强或改进另一治疗的效果,和/或以减轻这种疾病的一种或多种症状。
可以足以减轻、改善、稳定、逆转或减慢疾病的发展,或另外减小疾病的病理学结果,或减少疾病的症状的一个或多个剂量将治疗有效量给予患者。改善或减少不必是永久的,但可达至少一小时、至少一天或至少一周或更多的时间段。有效量通常由医生基于个例决定并且在本领域技术人员的技术范围内。当确定合适剂量以达到有效量时,通常考虑几个因素。这些因素包括患者的年龄、性别和体重、受治疗的疾病状态、疾病状态的严重程度以及给药途径、剂型和方案以及期望结果。
如本文使用的,术语“主体”和“患者”可交换地使用并且是指动物,优选为哺乳动物如非灵长类(例如,牛、猪、马、猫、狗、大鼠等)和灵长类(例如,猴和人),且最优选为人。
本文描述的α 螺旋模拟的β-连环蛋白抑制剂用于预防或治疗疾病。具体地,本公开提供了治疗处于病毒性感染风险中(或易患病毒性感染)的主体的预防和治疗方法二者。因此,本方法提供了通过给予需要其的主体有效量的α 螺旋模拟的β-连环蛋白抑制剂预防和/或治疗主体中的病毒性和传染性疾病,包括HIV、HPV、HBV、HSV,和细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)。例如,给予主体α 螺旋模拟的β-连环蛋白抑制剂以努力改善病毒性感染的一个或多个症状。
Wnt/β连环蛋白的抑制有可能改变细胞使得它们变为不太理想的病毒宿主。因此,本发明的β-连环蛋白抑制剂可与在处置改变的宿主细胞中变得更有效的抗病毒化合物结合给予。
因此,本发明包括其中以联合疗法给予化合物的方法。即,化合物可与用于治疗病毒性或细菌性感染的其他试剂组合,但分别使用。在这些组合方法中,化合物通常以1-100 mg/kg体重每天的每日剂量组合其他试剂给予。其他试剂通常以治疗使用的量给予。然而,具体给药方案由医生使用合理的医疗判断确定。
适用于涉及与本文公开的抑制化合物的抗病毒联合疗法的组合物和方法的化合物的一些实例包括但不限于下列:抗病毒剂如阿昔洛韦及其前药伐昔洛韦;更昔洛韦及其前药缬更昔洛韦;膦甲酸钠;溴呋啶;西多福韦;阿德福韦;拉米夫定;波普瑞韦;恩替卡韦;生殖器疣局部治疗如咪喹莫特、普达非洛或冷冻手术;聚乙二醇干扰素;逆转录酶抑制剂;蛋白酶抑制剂;HIV整合酶链转移抑制剂;HIV融合和进入抑制剂;和组蛋白去乙酰化酶复合物(HDAC)抑制剂。HDAC抑制剂包括但不限于羟肟酸(或异羟肟酸)如曲古抑菌素、伏立诺他 (SAHA)、abexinostat (PCI-24781)、贝利司他 (PXD101)、LAQ824和帕比司他 (LBH589);PCI-34051;环状四肽如trapoxin B;缩酚肽如罗咪酯肽;苯甲酰胺如恩替诺特(MS-275)、CI994和mocetinostat (MGCD0103);亲电酮;脂肪酸化合物如苯基丁酸盐和丙戊酸;烟酰胺和NAD衍生物如二氢香豆素、苯并香豆素(naphthopyranone)和2-羟基萘甲醛(2-hydroxynaphaldehyde)。
用于细菌性感染如被分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)感染的与本文公开的抑制化合物的联合疗法包括但不限于下列:异烟肼、利福平、利福喷汀、乙胺丁醇和吡嗪酰胺。
传染性疾病,包括HIV、HPV、HBV、HSV和细菌包括分枝杆菌属(Mycobacterium)、志贺氏菌属(Shigella)和李斯特菌属(Listeria)的治疗是指给予本文描述的化合物或组合以治疗患有这种传染性疾病的主体。传染性疾病的治疗的一种结果是减少疾病的症状。传染性疾病的治疗的另一结果是减少免疫细胞的炎症和浸润。传染性疾病的治疗的另一结果是减少微生物浸润至宿主细胞或组织。传染性疾病的治疗的另一结果是减少引起感染的微生物的传播。
可将本文描述的α 螺旋模拟的β-连环蛋白抑制剂并入药物组合物用于单独或组合给予主体用于治疗或预防本文描述的病症。这类组合物通常包括活性剂和药物可接受的载体。如本文使用的,术语“药物可接受的载体”包括与药物给药相容的盐水、溶剂、分散介质、包衣、抗菌剂和抗真菌剂、等渗和吸收延迟剂等。还可将补充活性化合物并入组合物中。
任何合适的给药途径可用于提供哺乳动物,特别是人有效剂量的本文描述的化合物。例如,可使用口服、直肠、局部、肠胃外、眼、肺、鼻给药等。剂型包括片剂、锭剂、分散剂、悬浮剂、溶液剂、胶囊剂、乳膏剂、软膏剂、气雾剂等。
使用的活性成分的有效剂量可依赖使用的特定化合物、给药方式、受治疗的疾病状态和受治疗的疾病状态的严重程度而变化。这种剂量可由本领域技术人员容易地确定。
当治疗或控制传染性疾病,包括HIV、HPV、HBV、HSV和结核病时,通常,当以约0.01毫克至约100毫克每千克的动物体重的每日剂量给予本文描述的化合物,优选以单一每日剂量或以分开剂量每天给予两至六次,或者以缓释形式给予本文描述的化合物时获得满意的结果。对于大多数大型哺乳动物,总每日剂量为约1.0毫克至约1000毫克。在70 kg成人的情况下,总每日剂量通常为约1毫克至约500毫克。对于特别有效的化合物,成人的剂量可低至0.1 mg。在一些情况下,每日剂量可高达1克。剂量方案可在该范围内调整或甚至在该范围之外以提供最佳治疗反应。
通常使用片剂或胶囊剂进行口服给药。片剂和胶囊剂中的剂量的实例为0.1 mg、0.25 mg、0.5 mg、1 mg、2 mg、5 mg、10 mg、15 mg、20 mg、25 mg、30 mg、40 mg、50 mg、100 mg、200 mg、250 mg、300 mg、400 mg、500 mg和750 mg。其他口服形式也可具有相同或类似剂量。
本文还描述了包含本文描述的化合物和药物可接受的载体的药物组合物。本文描述的药物组合物包含本文描述的化合物或药物可接受的盐作为活性成分以及药物可接受的载体和任选其他治疗成分。药物组合物还可包含前药,或其药物可接受的盐,如果给予前药。
组合物可适于口服、直肠、局部、肠胃外(包括皮下、肌内和静脉内)、眼(眼睛)、肺(鼻或颊吸入)或鼻给药,尽管在任何给定情况下最合适的途径依赖受治疗的疾病状态的性质和严重程度和活性成分的性质。可方便地以单位剂型形式提供它们并且通过任何制药学领域熟知的方法制备。
在实际使用中,根据常规药物混合技术可将本文描述的化合物作为活性成分混合在与药物载体的紧密混合物中。载体可采取多种形式,依赖给药所需的制剂形式,例如,口服给药或肠胃外给药(包括静脉内)。在制备作为口服剂型的组合物中,可使用任何常见药物介质,在口服液体制剂如悬浮剂、酏剂和溶液剂的情况下诸如例如,水、乙二醇、油、醇、调味剂、防腐剂、着色剂等;或在口服固体制剂如,粉末剂、硬和软胶囊剂以及片剂的情况下载体如淀粉、糖、微晶纤维素、稀释剂、造粒剂、润滑剂、粘结剂、崩解剂等,其中固体口服制剂优于液体制剂。
由于它们容易给药,片剂和胶囊剂代表最有利的口服单位剂型,在该情况下使用固体药物载体。如果需要,可通过标准水性或非水性技术将片剂包衣。这类组合物和制剂应包含至少0.1%的活性化合物。当然,这些组合物中的活性化合物的百分比可变化并且可方便地为单位重量的约2%至约60%。在这类治疗有用的组合物中的活性化合物的量使得获得有效剂量。还可鼻内给予活性化合物,例如,作为滴液剂或喷雾剂。
片剂、丸剂、胶囊剂等还可包含粘结剂如黄芪胶、阿拉伯树胶、玉米淀粉或明胶;赋形剂如磷酸氢钙;崩解剂如玉米淀粉、土豆淀粉、海藻酸;润滑剂如硬脂酸镁;和甜味剂如蔗糖、乳糖或糖精。当单位剂型为胶囊剂时,它可包含除了上述类型的材料之外的液体载体如脂肪油。
各种其他材料可以包衣形式存在或者改变剂量单位的物理形式。例如,可使用虫胶、糖或二者将片剂包衣。糖浆剂或酏剂除了活性成分之外可包含蔗糖作为甜味剂,对羟基苯甲酸甲酯和对羟基苯甲酸丙酯作为防腐剂,染料和调味剂如樱桃或橙子调味剂。
还可肠胃外给予本文描述的化合物。可在与表面活性剂或表面活性剂的混合物适当混合的水中制备这些活性化合物的溶液剂或悬浮剂,所述表面活性剂如羟丙基纤维素、聚山梨醇酯80和中链和长链脂肪酸的甘油单酯和甘油二酯。还可在甘油、液体聚乙二醇及其混合物(于油中)制备分散剂。在一般的储存和使用条件下,这些制剂包含防腐剂以防止微生物生长。
适于可注射使用的药物形式包括无菌水溶液剂或分散剂和无菌粉末,其用于临时制备无菌可注射溶液剂或分散剂。在所有情况下,形式必须是无菌的并且必须流动达到容易可注射性存在的程度。它在制备和储存条件下必须是稳定的并且必须防止微生物如细菌和真菌的污染作用。载体可为溶剂或分散介质,包含例如,水、乙醇、多元醇 (例如,丙三醇、丙二醇和液体聚乙二醇)、其合适的混合物和植物油。
实施例
本研究的实施例的方法如下。
细胞分选和流式细胞仪-根据标准方案,使用靶向CD4、CD3、CD45RA、CCR7、CD62L、CD122、CD95的单克隆抗体染色PBMC。在20分钟后,使用FACS Aria细胞分选仪(BD Biosciences)以70磅每平方英寸在特别指定的生物安全柜(Baker Hood)中将CCR7+ CD45RA+ 天真CD4 T细胞、CCR7+ CD45RA-中枢记忆CD4 T细胞 (CD4 Tcm)、CCR7- CD45RA- CD4 T细胞、CCR7- CD45RA+ 终末分化CD4 T细胞 (CD4 Ttd)和CCR7+ CD45RA+ CD62L+ CD95+ CD122+ T记忆干细胞CD4 T细胞 (CD4 Tscm)活分选。为了表型表征,另外使用CCR5或CXCR4抗体,或Annexin V将细胞染色,并在LSRII流式细胞仪(BD Biosciences)上获取。使用FlowJo软件(Treestar)分析数据。
评价细胞相关HIV-1 DNA – 如前面描述的将分离的CD4 T细胞消化(Nat Med 15, 893-900 (2009))以提取细胞裂解物。发明人使用前面描述的引物和探针扩增总HIV-1 DNA (Methods 47, 254-260 (2009))。作为标准曲线,发明人扩增慢性感染的293T细胞的连续稀释液(由Dr. Bushman, University of Pennsylvania友情提供)。相对于前面使用相同标准定量的CCR5基因拷贝数计算前病毒HIV-1 DNA拷贝数。
分析细胞相关的未剪接HIV-1 RNA - 使用前述方案通过半巢式实时PCR定量分选CD4 T细胞中的细胞相关的未剪接HIV-1 RNA (J Infect Dis 206, 1443-1452 (2012))。以每微克总RNA的HIV-1 RNA拷贝数的形式计算结果。一起处理来自所有患者的样品以避免组间可变性。
体外感染试验 – 在补充有10% FCS和50 U/ml的rhIL-2的RPMI培养基中培养来自没有预先体外激活的HIV-1阴性供体的未选择的PBMC。总共10 × 106 PBMCs被GFP-编码的VSV-G-假型病毒(MOI=0.01)或GFP-编码的R5-向性病毒株(Ba-L, MOI=0.07,由Dr. Littman, New York University友情提供)感染。然后,使用PBS将细胞洗涤两次并在96圆底孔板中以106细胞/ml培养5天。在第5天,使用表面抗体将细胞染色以识别单个CD4 T细胞子集,洗涤并在LSRII流式细胞仪装置上分析。
分析HIV-1复制产物 - 如前面描述的,从细胞裂解物用引物MH531和MH532和探针LRT-P扩增HIV-1晚期逆转录(HIV-1 late reverse transcripts)。使用巢式PCR检测整合HIV-1 DNA,其中Alu-1/Alu-2引物和HIV-1 LTR引物 L-M667用于第一轮PCR且LTR引物AA55M,λ T引物和MH603探针用于第二轮定量PCR。使用已建立方案扩增HIV-1 2-LTR DNA。看家基因CCR5的扩增用于定量输入细胞数。来自HIV-1–感染细胞系293T的细胞裂解物的DNA的 连续稀释液(由F. Bushman, University of Pennsylvania, Philadelphia, PA, USA提供)用于参照目的。
病毒生长试验 – 如前面描述的并进行一些修改进行病毒生长试验(Viral outgrowth assay)(Methods Mol Biol 304, 3-15 (2005))。在圆底96-孔板中以10,000细胞/孔 (Tscm)或20,000细胞/孔 (Tcm and Tem)接种分选的CD4+ T细胞群。随后,使用PHA (2 mg/ml)、rh IL-2 (100单位/ml)和来自HIV-阴性健康供体的辐射的同种异体PBMCs刺激细胞。在培养的第3天并再次在培养的第7天和第14天将来自HIV-阴性供体的CD8-去除、PHA-刺激的PBMC加入至各个孔。每七天使培养基去除33%的细胞悬浮液并使用包含新鲜rh IL-2(100U/ml)的培养基补充。在14-21天后,将来自各个孔的细胞上清液收获并且通过用TZM-bl细胞孵育上清液估算包含传染性HIV-1的孔的数量,其为包含在HIV-1 LTR控制下的萤火虫荧光素酶的整合报告基因的受纳HeLa细胞克隆,允许感染的敏感和精确检测。通过发光定量荧光素酶活性,并且其与在初始接种体中存在的感染病毒颗粒数成正比。
病毒测序 - 来自分选T细胞群和血浆的细胞裂解物用于包括V3区域的HIV-1信封测序。对于血浆样品,在蛋白酶K消化和RNA分离(通过酸性异硫氰酸胍进行)之前,将来自各个时间点的中值6 mL血浆在170.000 g下超速离心30 min。使用外部引物 envA/LA17 (PLoS Pathog 7, e1001303 (2011))一式三份地进行一步RT-PCR反应(Superscript III, Invitrogen)。合并的PCR产物用作模板以通过巢式PCR用内部引物 LA12和LA13产生单扩增子。将扩增产物插入TOPO克隆载体并且用于转化感受态细菌。通过过夜培养扩增单个细菌菌落,并连接提取的DNA并在ABI 3100 PRISM自动测序仪上通过T7或T3引物直接测序,而不进行预先PCR-基扩增。jModeltest v0.1.1用于推断最佳系统模型以解释序列比对发展(alignment sequence evolution)。
体外培养试验 – 通过细胞分选分离选择的CD4 T细胞子集,在37℃下使用2 μM CFSE标记细胞7 min,并在存在或不存在化合物C,(6S,9S,9aS)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺 (Prism Biolabs)下使用rhIL-15 (25 ng/ml;Peprotech)孵育10 d。此后,将细胞收获并通过流式细胞仪表型表征。
统计学 - 以平均值和SD形式或使用盒形-虚线图(表明中值、四分位差和最小值和最大值)总结数据。计算Pearson相关系数以分析相关性。通过2-尾学生t检验,Mann-Whitney U检验或配对Wilcoxon秩和检测标定数据之间的差的统计学显著性。
实施例1:化合物
C以剂量依赖方式抑制HIV
对于这些实验,从HIV血清反应阴性供体中分离外周血单核细胞 (PBMCs)并使用前述方法分化为巨噬细胞时间为7-10天 (J Biol Chem 286: 18890-18902 (2011);PLoS Pathogens 8(5):e1002689 pp 1-13 (2012);PLoS Pathogens 8(11):e1003017 (2012))。使用化合物C将巨噬细胞预处理24小时,其为β-连环蛋白抑制剂(6S,9S,9aS)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺。使用在增加的浓度下的化合物C处理巨噬细胞并通过检测释放进入培养基上清液的HIV p24抗原监测生产性感染10天。如图1所示,化合物C以剂量依赖方式抑制HIV复制。
结论:在100 pM至2 μM的浓度下化合物C以剂量依赖方式抑制HIV。
实施例2:
1和2 μM下的化合物A诱导自噬.
在允许性感染期间,HIV下调自噬。雷帕霉素(mTOR的抑制剂)和1α,25-二羟基胆钙化醇(1,25D3)(维生素D3的激素活性形式)通过巨自噬(自噬)在人巨噬细胞中发挥抗-Mtb和抗-HIV活性。自噬的标志是吞噬大量细胞质和胞质细胞器如线粒体和内质网的双膜自噬体。自噬体最终与溶酶体融合,由此产生能够降解内含物的单膜自噬溶酶体,其然后能被细胞再利用。自噬已被认为是对抗一些细菌、病毒和其他病原体的有效先天免疫机制(有时称为异体自噬)。
微管相关蛋白质1A/1B-轻链3(LC3)是在哺乳动物组织和培养的细胞中广泛分布的可溶蛋白质(在Methods Mol. Biol. 445, 77-88 (2008)中评论)。在自噬期间,自噬体吞噬细胞质组分,包括胞质蛋白质和细胞器。伴随地,LC3 (LC3-I)的胞质形式与磷脂酰乙醇胺结合以形成LC3-磷脂酰乙醇胺共轭物 (LC3-II),其被募集至自噬体膜。自噬体与溶酶体融合以形成自噬溶酶体,并且自噬体内的组分被溶酶体水解酶降解。同时,降解自噬溶酶体腔中的LC3-II。因此,自噬体标记LC3-II的溶酶体周转(turnover)反映饥饿诱导的自噬活动,并且通过免疫印迹法或免疫荧光法检测LC3是自噬和自噬相关过程,包括自噬细胞死亡的指示物。
图2显示为了评价化合物A,其为β-连环蛋白抑制剂4-(((6S,9S,9aS)-1-(苄基氨基甲酰基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基二氢磷酸酯是否诱导微管相关蛋白质1A/1B-轻链3B (LC3B,自噬的指示物)而进行的实验。为了这些研究,将巨噬细胞暴露于雷帕霉素 100 nM (自噬潮(autophagic flux)的已知诱导物),提取蛋白质并进行免疫印迹法。
在自噬期间,LC3B (LC3B-I)形成LC3B-磷脂酰乙醇胺共轭物 (LC3B-II),将其募集至自噬体膜。当有自噬潮时,存在导致转化LC3B-II的LC3B-I的脂化。因此,在自噬潮期间,与LC3B-I相比,LC3B-II的相对量增加。
如图2A-2B所示,相对于阴性/未处理的对照,LC3B-II与LC3B-I的比例增加,表示增加的自噬。
此外,发明人考虑自噬潮的另一标记(死骨片1(sequestosome 1),还称为SQSTIM1或p62)。在活性自噬期间,SQSTIM1降解 (减少)。如图2B所示,SQSTIM1随1和2 μM下的β-连环蛋白抑制剂以及雷帕霉素对照减少。
重要地,在研究的β-连环蛋白抑制剂浓度下,迄今,没有观察到细胞毒性。
结论:1和2 μM下的化合物A诱导自噬,因此可提高对HIV和Mtb感染的免疫力。
实施例3:使用β
-连环蛋白抑制剂靶向HIV储存库细胞
潜伏感染的CD4 T细胞代表HIV-1的转录沉默储存库和储存染色体整合的病毒DNA (harbor chromosomally integrated viral DNA),其在激活和抗逆转录病毒治疗停止后能够恢复HIV-1复制(Science 278, 1295-1300 (1997);Nature Medicine 5, 512-517 (1999))。这些细胞主要由具有缓慢自发衰老速率的长寿命记忆T细胞组成,表明HIV-1开发促进病毒持久性的细胞免疫记忆的生理学机制 (Nat Med 15, 893-900 (2009))。最近,在一些动物物种中发现具有干细胞特征的小比例T细胞。这些称为“T记忆干细胞” (Tscm)的细胞似乎代表记忆T细胞的最初发展阶段。功能上,Tscm超过所有已知替代T细胞子集的增殖能力,并且可分化为大量中枢记忆 (Tcm)、效应记忆(Tem)和终末分化T (Ttd)细胞。
为了评价β-连环蛋白抑制剂对CD4 T细胞发展的影响,使用化合物C,其为β-连环蛋白抑制剂(6S,9S,9aS)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺孵育分选的Tscm和Tcm。化合物C为化合物A的活性代谢物。发明人观察到与对照实验相比,化合物C大幅度促进Tscm的分化,并且在较小程度上,促进Tcm分化为更成熟的CCR7- CD62L-阴性CD4 T细胞群 (图3A-3B)。
结论:通过本文公开的β-连环蛋白抑制剂治疗HIV-感染的细胞促进HIV-1感染的Tscm分化为具有减少的体内持久性的更成熟、短寿命的T细胞。这能减少HIV-感染的细胞的储存,因此导致根除病毒。
Claims (16)
1.用于治疗病毒性和传染性疾病的α螺旋模拟β-连环蛋白抑制剂化合物,其具有下式(I):
其中:
A为-CHR7-,
其中R7为氢、任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的芳基烷基、任选取代的杂芳基烷基、任选取代的环烷基烷基、任选取代的杂环烷基烷基、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基或任选取代的杂环烷基;
G为-NH-、-NR6-、-O-、-CHR6-或-C(R6)2-,
其中R6独立地选自任选取代的烷基、任选取代的烯基和任选取代的炔基;
R1为任选取代的芳基烷基、任选取代的杂芳基烷基、任选取代的环烷基烷基或任选取代的杂环烷基烷基;
R2为–W21-W22-Rb-R20,
其中W21为–(CO)-或–(SO2)-;W22为键、-O-、-NH-或任选取代的低级亚烷基;Rb为键或任选取代的低级亚烷基;且R20为任选取代的烷基、任选取代的烯基、任选取代的炔基、任选取代的芳基、任选取代的杂芳基、任选取代的环烷基或任选取代的杂环烷基;且
R3为任选取代的烷基、任选取代的烯基或任选取代的炔基,
或其药物可接受的盐。
2.如权利要求1所述的化合物,其选自:
(6S,9S)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-8-(萘-1-基甲基)-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-2-烯丙基-N-苄基-6-(4-羟基苄基)-9-甲基-8-(萘-1-基甲基)-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基苄基)-9-甲基-8-(萘-1-基甲基)-4,7-二氧代六氢吡嗪并[2,1-c][1,2,4]噁二嗪-1(6H)-甲酰胺,
(6S,9S)-8-((2-氨基苯并[d]噻唑-4-基)甲基)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-2-烯丙基-N-苄基-6-(4-羟基苄基)-9-甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
4-(((6S,9S)-1-(苄基氨基甲酰基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基二氢磷酸酯,
4-(((6S,9S)-1-(苄基氨基甲酰基)-2,9-二甲基-8-(萘-1-基甲基)-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基二氢磷酸酯,
4-(((6S,9S)-1-(苄基氨基甲酰基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基磷酸钠,
4-(((6S,9S)-1-(苄基氨基甲酰基)-2,9-二甲基-4,7-二氧代-8-(萘-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基磷酸钠,
(6S,9S)-2-烯丙基-6-(4-羟基苄基)-9-甲基-4,7-二氧代-N-((R)-1-苯基乙基)-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-2-烯丙基-6-(4-羟基苄基)-9-甲基-4,7-二氧代-N-((S)-1-苯基乙基)-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基-2,6-二甲基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-8-(苯并[b]噻吩-3-基甲基)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-8-(苯并[c][1,2,5]噻二唑-4-基甲基)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基苄基)-8-(异喹啉-5-基甲基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-8-((5-氯噻吩并[3,2-b]吡啶-3-基)甲基)-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,
(6S,9S)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹喔啉-5-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺,和
(6S,9S)-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)-N-(噻吩-2-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺。
3.如权利要求1所述的化合物,其选自:
4-(((6S,9S,9aS)-1-(苄基氨基甲酰基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基) 八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-6-基)甲基)苯基二氢磷酸酯,和
(6S,9S,9aS)-N-苄基-6-(4-羟基苄基)-2,9-二甲基-4,7-二氧代-8-(喹啉-8-基甲基)八氢-1H-吡嗪并[2,1-c][1,2,4]三嗪-1-甲酰胺。
4.包含权利要求1、2或3所述的化合物的药物组合物。
5.治疗传染性疾病的方法,其包括给予需要其的患者有效量的权利要求1、2或3所述的化合物。
6.如权利要求5所述的方法,其中所述传染性疾病为人类免疫缺陷病毒(HIV)感染。
7.如权利要求5所述的方法,其中所述传染性疾病为丙型肝炎病毒(HBV)感染。
8.如权利要求5所述的方法,其中所述传染性疾病为结核病(TB)。
9.如权利要求5所述的方法,其中所述传染性疾病为单纯性疱疹病毒1 (HSV-1)感染。
10.如权利要求5所述的方法,其中所述传染性疾病为单纯性疱疹病毒2 (HSV-2)感染。
11.如权利要求5所述的方法,其中所述传染性疾病为人乳头瘤病毒(HPV)感染。
12.如权利要求11所述的方法,其中所述方法治疗或预防宫颈非典型增生。
13.如权利要求11所述的方法,其中所述方法治疗或预防生殖器疣。
14.如权利要求5所述的方法,其中所述传染性疾病为被志贺氏菌属(Shigella)或李斯特菌属(Listeria)种感染。
15.如权利要求5所述的方法,其还包括给予一种或多种抗病毒剂,其选自阿昔洛韦、伐昔洛韦、更昔洛韦、缬更昔洛韦、膦甲酸钠、溴呋啶、西多福韦、阿德福韦、拉米夫定、波普瑞韦、恩替卡韦、咪喹莫特、普达非洛、聚乙二醇干扰素、逆转录酶抑制剂、蛋白酶抑制剂、HIV整合酶链转移抑制剂、HIV融合或HIV进入抑制剂;和组蛋白去乙酰化酶复合物(HDAC)抑制剂。
16.如权利要求15所述的方法,其中一种或多种抗病毒剂之一是HDAC抑制剂,其选自羟肟酸、曲古抑菌素、伏立诺他、abexinostat、贝利司他、LAQ824、帕比司他、PCI-34051、环状四肽、trapoxin B、缩酚肽、罗咪酯肽、苯甲酰胺、恩替诺特、CI994、mocetinostat (MGCD0103)、亲电酮;脂肪酸化合物、苯基丁酸盐、丙戊酸、烟酰胺、二氢香豆素、苯并香豆素和2-羟基萘甲醛。
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