CN1301158A - 用于治疗人类获得性免疫缺陷病毒和其它病毒感染的组合物 - Google Patents
用于治疗人类获得性免疫缺陷病毒和其它病毒感染的组合物 Download PDFInfo
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- CN1301158A CN1301158A CN99806363A CN99806363A CN1301158A CN 1301158 A CN1301158 A CN 1301158A CN 99806363 A CN99806363 A CN 99806363A CN 99806363 A CN99806363 A CN 99806363A CN 1301158 A CN1301158 A CN 1301158A
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- benzimidazole
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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Abstract
可用于有效治疗病毒感染(特别是HIV)的药物组合物,该组合物包括约250—6000mg的式I所示苯并咪唑衍生物或其药学上可接受的有机或无机加成盐,其中,X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基;n为小于4的正整数;Y为氢、氯、硝基、氧氯、甲基或乙基;R为氢或1—8个碳原子的烷基;R2为4—噻唑基。较佳的化合物为噻苯达唑。本发明中发现上述化合物单独使用或与其它抗病毒剂合用可用于抑制HIV和治疗HIV感染。这些组合物可防止HIV病毒复制,防止对噻苯达唑治疗有耐药性病毒株的建立,防止或延缓HIV病毒感染细胞及延缓病毒在受处理细胞中的再现。这些组合物对于肝炎和诸如疱疹、流感和鼻病毒之类病毒也有效。
Description
发明的领域
本发明为治疗病毒感染(特别是HIV)的方法。药物组合物包含一种或几种苯并咪唑衍生物，特别是噻唑苯并咪唑化合物。
发明的背景
HIV和其它病毒感染是死亡的一个主要原因。HIV是攻击机体免疫系统的病毒在体内复制的一种疾病。HIV病毒不易破坏，也没有使宿主细胞避而不复制病毒的好机制。
一些药物证明能治疗毁坏性疾病，包括齐多夫定(AZT,RetrovirTM)、2,3’-双脱氧肌苷(二脱氧肌苷，ddI.VidexTM)、双脱氧胸苷(d4T,ZeritTM)、2’,3’-双脱氧胞苷(双脱氧胞苷ddC,HividTM)、奈韦拉平(ViramuneTM)、拉未夫定(EpivirTM,3TC)、蛋白酶抑制剂、沙奎那韦(InviraseTM、FortovaseTM)、利托那韦(NorvirTM)、萘非那韦(ViraceptTM)、efavienz(SustivaTM)、abacavir(ZiagenTM)、安泼那韦(AgeneraseTM)、茚地那韦(CrixivanTM)、更昔洛韦、AzDU、地拉夫定(RescriptorTM)、红细胞生成素、集落刺激因子(G-CSF和GM-CSF)、非核苷抑制剂和核苷抑制剂。见M.I.Johnston&D.F.Hoth,Science,260(5112),1286-1293(1993)和D.D.Richman,Science,272(5270),1886-1888(1996)。有人试验了一种AIDS疫苗(Salk’s疫苗)，发现从CD8得到的几种蛋白质趋化因子起HIV抑制剂作用。除了上述合成核苷类似物、蛋白质和抗体外，发现一些植物和得自植物的物质具有体外抗HIV活性。但是，HIV病毒是不易破坏的，也没有使宿主细胞避而不复制病毒的好机制。
因此，医学专业人员继续研究能预防HIV感染、处理HIV载体以防止其向full-blown deadly AIDS发展、及治疗AIDS患者的药物。因此，极希望得到靶向HIV病毒、抑制病毒复制的物质。
单纯疱疹是另一类难治愈的病毒感染。Ⅰ型和Ⅱ型单纯疱疹病毒(HSV)是通常感染人的持续存在的病毒。Ⅰ型HSV引起口部“单纯疱症”(并存唇疱疹)，Ⅱ型HSV引起生殖器疱疹，在世界很多地方成为主要的性病。生殖器疱疹目前尚无完全满意的治疗方法。此外，HSV还可引起脑炎，一种威胁生命的脑部感染(The Merck Manual,Holvey,Ed.,1972；whitley，单纯疱疹病毒，Virology，第2版，Raven出版社(1990))。HSV引起的一种最严重的疾病是树枝状角膜炎，这是一种产生角膜分支状损伤的眼部感染，此种损伤又可导致永久性瘢痕和失明。眼部HSV感染是失明的主要原因。
肝炎是人体肝脏的疾病。它被证明系肝脏炎症，通常由病毒感染、有时由毒性物质引起。肝炎可发展成肝硬化、肝癌，最终死亡。已知一些病毒(如肝炎A、B、C、D、E和G)引起各种类型的肝炎。其中，乙型肝炎病毒和丙型肝炎病毒是最严重的。乙型肝炎病毒是DNA病毒，病毒体大小为42nm。丙型肝炎病毒的病毒体大小为30-60nm。见D.S.Chen,J.Formos.Med.Assoc.,95(1),6-12(1996)。
丙型肝炎感染人数是HIV感染人数的4-5倍。丙型肝炎难以治疗，估计全世界有500百万人感染此病(约为感染HIV的人数的15倍)。目前尚无有效的免疫法可用，丙型肝炎只能通过其它预防性措施加以控制，如改善卫生和环境卫生条件和阻断传播途径。目前，慢性丙型肝炎唯一可接受的治疗是干扰素，须进行至少6个月的治疗，及利巴韦林，它可抑制病毒在受感染细胞中的复制，还可改善某些人的肝功能。但是，用干扰素合用或不合用利巴韦林的长期疗效有限，反应率仅约25％。乙型肝炎病毒感染导致广谱肝损伤。而且，慢性乙型肝炎感染与随后发展的肝细胞癌相关联，这是已知主要的死亡原因。目前乙型肝炎病毒感染的预防是治疗上有效的乙肝疫苗。但是，疫苗对治疗已感染者(如携带者和患者)无效。很多药物被用于治疗乙型肝炎，但除了干扰素外无一被证明有效。
用干扰素治疗乙型肝炎病毒和丙型肝炎病毒成功率有限，其经常伴有不良副作用，如疲劳、发热、寒战、头痛、肌痛、关节痛、轻度脱发、精神病作用及其伴有的疾病、自身免疫现象及其伴有的疾病，及甲状腺功能不良。由于干扰素治疗疗效有限及频发不良反应，因此需要更有效的治疗这些病毒感染的有效方案。
Lovert(Diss.Abstr.Int.(Sci.)(1979),39(11)第5315-5316页公开了使用噻苯达唑治疗癌症。Edlind等(Chemical Abstr.(1994),121.175012x)、Brown等(J.Am.chem.Soc.(1961),83,pg1764-1765)和Aur(J.Pediatr.(1971),78(1),pg.129-131)公开了使用噻苯达唑治疗蠕虫感染。Wagner等(U.s.3,370,957)公开了噻苯达唑抗真菌组合物。
迄今未见使用噻苯达唑治疗病毒感染的公开或提示。但是,由于所述治疗病毒感染的很多弊端，不断地需要新的和改进的治疗病毒感染的方法。
发明的概要
要求保护的是治疗动物(特别是温血动物和人)的药物组合物，包括药物载体和有效量的式Ⅰ抗病毒化合物：其中：
X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；
n为小于4的正整数；
Y为氢、氯、硝基、氧氯、甲基或乙基；
R为氢或1-8个碳原子的烷基；
R2为4-噻唑基。
较佳的苯并咪唑5位或7位上有氯(Cl-)或氧氯(ClO-)取代(苯环桥碳的间位)，苯环的其余取代基是氢。
较佳的化合物是如下式Ⅲ化合物其中R3为氢或1-8个碳原子的烷基或其与有机或无机酸的药学上可接受的无毒酸加成盐。最佳的化合物为2-(4-噻唑基)苯并咪唑。
组合物还可用于治疗HIV和其它病毒感染。药物可每天给药或每周1-4次。
本发明中发现，上述化合物对于HIV的抑制和HIV感染的治疗有用。本发明还提供治疗HIV感染的方法，包括对感染HIV的宿主给予药学上或治疗上有效的或可接受量的上述化合物，特别是R为4-噻唑基的化合物。
更具体地，本发明提供一种抗病毒组合物，包括药物载体和此处定义的苯并咪唑衍生物，以及治疗病毒感染的方法。这些组合物可防止病毒复制，建立患者抗病毒能力，预防或延缓病毒对细胞的感染，预防病毒形成对抗病毒剂治疗的耐药性，延长受感染细胞的生命期和/或延缓病毒在受治疗细胞中的再现。
本发明提供治疗诸如HIV、疱疹、肝炎、流感和/或鼻病毒等病毒感染的组合物和方法，抗病毒组合物单用和/或其它治疗法合用。
发明的详细描述
A．定义：
本文所用的“药学上可接受的”成分是适用于人和/或动物、无过度不良反应(如毒性、刺激性和变态反应)的物质，相应于合理的利益/风险比。
本文所用的术语“治疗有效量”指足以产生所需要的治疗反应而无无过度不良反应(如毒性、刺激性和变态反应)的一种组分的量，相应于按本发明方法使用时合理的利益/风险比。具体的“治疗有效量”通常因诸如受治疗的特定病情、患者的身体状况、受治疗的哺乳动物的类型、疗程、同期治疗(若有的话)的性质、采用的具体制剂和所用化合物的结构等的不同而不同。治疗有效量通常被认为是安全有效的量。
本文所用的“药物加成盐”或“药学上可接受的盐”是抗病毒化合物与有机或无机酸的盐。这些较佳的酸加成盐为氯化物、溴化物、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲酸盐、酒石酸盐、马来酸盐、苹果酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐，以及本领域普通技术人员知道的那些盐。
本文所用的“药物载体”是将抗病毒剂传送给动物或人的药学上可接受的溶剂、悬浮剂或赋形剂。载体可以是液体或固体的，按意欲给药的途径加以选择。
本发明的抗病毒化合物是苯并咪唑和/或其盐。苯并咪唑在下面作详细描述。较佳的抗病毒化合物是Merk出售的名为“噻苯达唑”的产品。
本文所用的“病毒”包括感染动物或哺乳动物包括人的病毒。病毒包括HIV、流感、脊髓灰质炎病毒、肝炎、疱疹、鼻病毒和本领域普通技术人员已知的那些病毒。
本文所用的“附加治疗”指需要该药治疗的患者在用苯并咪唑衍生物的同时给以治疗该病的其它药物。此附加治疗可以是序贯治疗，患者先用一种药物治疗，然后在一定的时间内给以其它药物，或可以是伴随治疗，两种药物基本上同时给药。
B．抗病毒组合物
本发明的抗病毒苯并咪唑化合物是是式(Ⅰ)或式(Ⅱ)所示化合物。较佳的化合物为2-(4-噻唑基)苯并咪唑或其药学上可接受的无毒酸加成盐。合适的酸加成盐是选自氯化物、溴化物、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲酸盐、酒石酸盐、马来酸盐、苹果酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐，以及本领域普通技术人员知道的那些有机或无机酸加成盐。
本发明还提供苯并咪唑化合物的前体药物。“前体药物”被认为是具有一个或一个以上官能团或共价结合于其上的载体的式Ⅰ、Ⅱ或Ⅲ所示化合物，其官能团或载体从式Ⅰ、Ⅱ或Ⅲ所示化合物上除去即形成各自的化合物。苯并咪唑化合物的前体药物的制备系用一个或一个以上掩蔽团修饰化合物中存在的一个或一个以上官能团，通过常规的体内、体外处理方式掩蔽团断开，或形成母体化合物。前体药物包括这样的化合物，其中羟基、胺或巯基结合于任何基团，它们分别断裂形成游离羟基、氨基或巯基。前体药物的例子包括(但不限于)苯并咪唑衍生物中醇和胺官能团的乙酸盐、甲酸盐或苯甲酸衍生物；苯并咪唑衍生物中醇和酚官能团的磷酸酯、二甲基甘氨酸酯、氨基烷基苯基酯、氨基烷基酯和羧基烷基酯；以及本领域普通技术人员已知的那些。
苯并咪唑衍生物的药学上可接受的盐包括例如从无毒无机或有机酸形成的苯并咪唑化合物的常规无毒盐或季铵盐。例如，这样的常规无毒盐包括得自无机酸(如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等)的盐和得自有机酸(如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、双羟萘酸、马来酸、羟基马来酸、苯基乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酸基苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙二磺酸、草酸、羟乙磺酸等)的盐。
本发明的药学上可接受的盐系用常规化学方法从含碱性或酸性基团的苯并咪唑衍生物进行合成的。一般来说，这样的盐是通过游离酸或碱形式的这些化合物与化学计量量的合适的碱或酸在水或有机溶剂中或在二者的混合物中进行反应而制得；一般来说，以非水性介质如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈为佳。合适的盐列于Remington’s Pharmaceuticla Sciences,第17版，Mack出版公司，Easton,Pa.,1985,第1418页，其揭示内容合并于此作为参考。本文所引用的所有参考文献揭示的内容均完整地合并于此作为参考。
苯并咪唑衍生物以有机合成领域普通技术人员熟知的很多方法加以制备。用下述方法及合成有机化学领域已知的合成方法或本领域普通技术人员理解的它们的变体对苯并咪唑衍生物进行合成。较佳的方法包括(但不限于)下述方法。这些化合物按1973年授予Adams等的美国专利3,738,995进行制备。噻唑基衍生物胺Brown等，J.Am.Chem.Soc.,83,1764(1961)和Grenda等，J.Org.Chem.,30,259(1965)中描述的方法加以制备。上面所引的每篇参考文献的揭示的内容均合并于此作为参考。
C．剂量和剂量给药形式
抗病毒化合物的鉴定、药物载体和投药化合物的量根据哺乳动物的种类和体重及受治疗的病毒或病毒感染而有大的变化。给药剂量随已知的因素而有大的变化，这些因素如特定抗病毒化合物的药物动力学特征及给药方式和途径；年龄、性别、代谢速率、吸收效率、接受治疗者的健康状况和体重；症状的性质和程度；所施用的合并治疗种类；用式Ⅰ、Ⅱ或Ⅱ化合物治疗的频率；及所需的治疗效应。
苯并咪唑较佳为微粉化的或粉状的，这样更容易被机体分散和溶解。碾磨或粉磨药物的方法是本领域熟知的。例如，使用锤碎或类似的磨碎器械。较佳的颗粒大小为小于约100μ，更佳为小于50μ。
适合于内服的剂型(组合物)每单位包含1.0mg-5000mg活性成分。这些药物组合物中，活性成分的量通常约为组合物总量的0.5-95重量％。根据患者的体重，剂量可按每天或每周一次或几次进行给药。可能需要多剂单位以达到治疗有效量。例如，如果剂型为1000mg，患者体重为40kg，一粒药丸可为该患者提供每公斤25mg的剂量。对于80公斤的患者来说，它提供的剂量仅仅为12.5mg/kg。
本发明的抗病毒化合物在剂量约为500mg/kg、2500mg/kg、3500mg/kg、4000mg/kg、5000mg/kg和6000mg/kg时，在小鼠体内显示抗病毒和抗癌效应。一般来说，小鼠的有效剂量约为人预期有效剂量的12倍。作为一般指导，对于人，低至约30mg/kg体重和高达约10000mg/kg体重的剂量适合于作为治疗有效量。较佳为使用约250-5000mg/kg体重。其他较佳的剂量范围为100mg/kg至约3000mg/kg体重。但是，约2-400mg/kg体重也适合于治疗某些病毒感染。
静脉给药在恒速输入时最佳给药量可为约1-1000mg/kg。苯并咪唑衍生物可每天给药一次，或一天总量分为2、3或4次给药。苯并咪唑衍生物可每天给药一次或几次，或每周一次至三次。
给予本发明的抗病毒化合物(活性成分)通过各种方式使活性成分与哺乳动物或动物机体的药物作用部位接触来抑制病毒生长或病毒感染。它们作为单独的治疗剂或与其它治疗剂合用以常规方法给药，这些方法在联合用药中可加以应用。
剂量单位可包括单一化合物或与其它化合物、其它病毒抑制化合物或其它抗病毒化合物的混合物。苯并咪唑可以口服剂型给药，如片剂、胶囊、丸剂、粉剂、颗粒、酏剂、酊剂、悬浮液、糖浆和乳剂。苯并咪唑衍生物还可经静脉(快速浓注或输注)、腹腔内、皮下或肌内给药，均使用药剂领域普通技术人员熟知的剂型。
此处详细描述的化合物构成活性成分并典型地与合适的药物稀释剂、填充剂、赋形剂或载体(此处统称药学上可接受的载体或载体物质)混合，这些物质根据制备给药的方式加以选择，且符合常规的药学实践。剂量单位可为适合于口服、直肠给药、局部给药、静脉注射或非经胃肠道给药的液体形式。
苯并咪唑衍生物可单独给药，但一般与药学上可接受的载体混合。该载体可以是固体或液体，载体的类型一般根据使用的给药形式加以选择。
片剂可包含合适的粘合剂、润滑剂、崩解剂、着色剂、调味剂、致流动剂和熔化剂。例如，在口服用片剂或胶囊剂型中，活性成分可与口服无毒的药学上可接受的惰性载体(如乳糖、明胶、琼脂、淀粉、蔗糖、葡萄糖、甲基纤维素、硬脂酸镁、磷酸二钙、硫酸钙、甘露醇、山梨醇等)混合。
合适的粘合剂包括淀粉、明胶、天然糖(如葡萄糖或β-乳糖)、玉米甜味剂、天然和合成树胶，如阿拉伯胶、黄耆胶或藻酸钠、羧甲基纤维素、聚乙二醇、蜡等。这些剂型中所用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括(但不限于)淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。
苯并咪唑衍生物还可以脂质体给药系统的形式给药，如小单层囊泡、大单层囊泡和多层囊泡。脂质体可从各种磷脂形成，如胆固醇、硬脂酰胺或磷脂酰胆碱。
苯并咪唑还可与作为可靶向药物载体的可溶性聚合物偶联。这样的聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟基丙基甲基丙烯酰胺-苯酚、聚羟基乙基天冬酰胺酚或棕榈酰残基取代的聚环氧乙烯-多熔素。本发明的化合物还可偶联于用来达到药物控释的一类生物可降解聚合物，例如，聚乳酸、聚乙醇酸、聚乳酸和聚乙醇酸的共聚物、聚ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二氢吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲嵌段共聚物。
活性成分可以固体剂型(如胶囊、片剂和粉剂)或液体剂型(如酏剂、糖浆和悬浮液)口服给药。还可以灭菌液体剂型非经胃肠道给药。
明胶胶囊可包含活性成分和粉状载体，如乳糖、淀粉、纤维素衍生物、硬脂酸镁、硬脂酸等。类似的稀释剂可用来制备压制片。片剂和胶囊均可制成即时释放产品或缓释产品，以提供数小时持续释放药物。压制片可以包糖衣或包膜以遮蔽任何令人不快的味道及保护片剂不受大气影响，或包肠衣使其在胃肠道中选择性崩解。
为了以液体剂型口服给药，将口服药物成分与任何口服、无毒、药学上可接受的惰性载体(如乙醇、甘油、水等)混合。合适的液体剂型的例子包括在水、药学上可接受的脂肪和油、醇包括酯或其它有机溶剂中的溶液或悬浮液、乳剂、糖浆或酏剂、悬浮液、溶液和/或从非泡腾颗粒重建的悬浮液及从泡腾颗粒重建的泡腾制剂。这样的液体剂型可包括例如合适的溶剂、防腐剂、乳化剂、悬浮剂、稀释剂、甜味剂、增稠剂和熔化剂。
口服给药用的液体剂型可包含着色剂和调味剂以提高患者的接受度。一般来说，水、合适的油、盐水、含水右旋糖(葡萄糖)和相应的糖溶液和乙二醇(如丙二醇或聚乙二醇)是非经胃肠道溶液的合适载体。
非经胃肠道给药用溶液较佳为包含活性成分的水溶性盐、合适的稳定剂，如果需要，还有缓冲物质。抗氧化剂，诸如亚硫酸氢钠、亚硫酸钠或抗坏血酸，单独或合用，是合适的稳定剂。还使用柠檬酸及其盐和EDTA钠。此外，非经胃肠道溶液可包含防腐剂，如苯扎氯铵、羟苯甲酯或羟苯丙酯、及三氯叔丁醇。合适的药物载体在Mack出版公司出版的本领域标准参考书Remington’s Pharmaceutical Sciences中有描述。
苯并咪唑衍生物还可通过使用合适的鼻内赋形剂以鼻内形式给药，或用本领域普通技术人员熟知的透皮贴片形式通过透皮途径给药。以透皮给药系统的形式给药，在整个剂量治疗方案中所给剂量一般是持续的而不是间断的。
非胃肠道和静脉内形式还可包括矿物质和使其与所选择的注射类型或释药系统相配伍的其它物质。
本发明化合物给药用的有用药物剂型阐述如下：
胶囊
通过填充标准两半硬胶囊，每个100-500mg粉状活性成分、5-150mg乳糖、5-50mg纤维素和6mg硬脂酸镁，制备大量单位胶囊。
软明胶胶囊
制备活性成分在可食用油(如豆油、棉籽油或橄榄油)中的混合物，借助正排量泵注入明胶中，形成含100-500mg活性成分的软明胶胶囊。将胶囊洗涤和干燥。
片剂
用常规方法制备大量片剂，使剂量单位为100-500mg活性成分、0.2mg胶态二氧化硅、5mg硬脂酸镁、50-275mg微晶纤维素、11mg淀粉和98.8mg乳糖。施加合适的包衣以提高可口性或延缓吸收。
可注射的溶液
将1.5重量％活性成分在10体积％丙二醇和水中进行搅拌，制备适合于注射给药的非胃肠道组合物。将溶液用氯化钠配成等渗，灭菌、
悬浮液
制备口服给药用水性悬浮液，使每5ml含100mg细分的活性成分、200mg羧甲基纤维素钠、5mg苯甲酸钠、1.0g山梨醇溶液(U.S.P.)和0.025ml香草醛。
本发明还包括例如用于治疗HIV感染的药盒，包括含有含治疗有效量苯并咪唑衍生物的药物组合物的一个或一个以上容器。如果需要，这样的药盒还可包括一种或一种以上不同的常规药盒成分，例如，带有一种或几种药学上可接受的载体的容器，另外的容器等，如会容易地被本领域技术人员明白的那些容器。药盒中还可包括印刷的指南，作为插入物或标签，指明给药成分的量、给药指导和/或将各成分混合的指导。
应当理解，虽然在本发明的实践中特定物质和条件是重要的，但并不排除非特定物质和条件，只要它们不阻碍本发明的利益被认识。
D．辅助治疗
单一治疗中可使用一种或一种以上苯并咪唑。一种或一种以上苯并咪唑衍生物可与其它抗病毒剂或增强剂合用。增强剂为影响机体对抗病毒剂的反应的物质。在HIV，用AZT、TC-3或蛋白酶抑制剂进行辅助治疗一般是有效的。对于肝炎，可用阿昔洛韦、泛昔洛韦或valacyclovir，利巴韦林、干扰素或利巴韦林和干扰素或β-球蛋白合用作为辅助治疗。对于疱疹，可用α-干扰素。
在本发明的一些实施方案中，噻苯达唑与一种或一种以上其他抗炎药、抗病毒药、抗真菌药、杀阿米巴药、杀毛滴虫剂、镇痛药、抗肿瘤药、抗高血压药、抗菌剂和/或类固醇药物合用以治疗病毒感染。在本发明的一些优选实施方案中，噻苯达唑与一种或几种以下物质合用来治疗病毒感染。这些物质是：β-内酰胺抗生素、四环素、氯霉素、新霉素、短杆菌肽、杆菌肽、磺胺类、硝呋醛、萘啶酸、可的松、氯化可的松、倍他米松、地塞米松、氟可龙、泼尼松龙、曲安奈德、吲哚美辛、舒林酸、阿昔洛韦、金刚烷胺、金刚乙胺、重组可溶性CD4(rsCD4)、抗受体抗体(对于鼻病毒)、奈韦拉平、cidofovir(VistideTM)磷酰基甲酸三钠(FoscarnetTM)、泛昔洛韦、贲昔洛韦、伐昔洛韦(缬阿昔洛韦)(valacyclovir)，核酸/复制抑制剂、干扰素、齐多夫定(AZT,RetrovirTM)、2,3’-双脱氧肌苷(二脱氧肌苷，ddI.VidexTM)、双脱氧胸苷(d4T,ZeritTM)、2’,3’-双脱氧胞苷(双脱氧胞苷ddC,HividTM)、奈韦拉平(ViramuneTM)、拉米夫定(EpivirTM,3TC)、蛋白酶抑制剂、沙奎那韦(InviraseTM、FortovaseTM)、利托那韦(NorvirTM)、萘非那韦(ViraceptTM)、efavienz(SustivaTM),abacavir(ZiagenTM)、安泼那韦(AgeneraseTM)、茚地那韦(CrixivanTM)、更昔洛韦、AzDU、地拉夫定(RescriptorTM)、利福平、clathiromycin、红细胞生成素、集落刺激因子(G-CSF and GM-CSF)、非核苷逆转录酶抑制剂、核苷抑制剂、阿霉素、氟尿嘧啶、甲氨喋呤、天冬酰胺酶及其组合。
当噻苯达唑与其它治疗剂合用时，噻苯达唑与其它治疗剂的比例在需要时可根据所需要的治疗效果、观察到的合并用药副作用或医药领域普通技术人员知道的其它方面的考虑加以改变。一般来说，噻苯达唑与其它治疗剂的比例可从约0.5％∶99.5％wt至约99.5％∶0.5％wt。
当噻苯达唑在其它治疗剂之前或之后给药来治疗病毒感染时，噻苯达唑与其它治疗剂各自的剂量和给药方案可改变。辅助治疗可相继进行，即先用一种药物治疗再用第二种药物治疗，或相随进行，即两种或两种以上药物基本上同时给药。相继治疗可以在第一种治疗完成后和第二种治疗开始前有有关合理的时间。同时用两种药物进行的治疗可在同一天的剂量中或在分开的剂量中。例如，第1天用一种药物，第2天用另一种药物。确切的方案取决于接受治疗的疾病、感染的严重程度和对治疗的反应。
例如，噻苯达唑的完全剂量方案可在其它治疗剂的完全剂量方案前或后执行，或可实施对噻苯达唑和其它治疗剂剂量的改变。作为进一步的实施例，噻苯达唑可与其它治疗剂相随给药。
E．治疗方法
治疗方法可以是在待治疗的特定病毒类型的治疗上有效的任何合适方法。治疗可通过口服、直肠、局部、非胃肠道或静脉途径给药等。施用有效量的方法也因受治疗的病毒或病毒感染而异。据信，通过静脉、皮下或肌内施用非胃肠道治疗苯并咪唑化合物，配以适当的载体、另外的一种或几种病毒抑制化合物或稀释剂以利于施药将是对温血动物投用这些化合物的较佳方法。
治疗病毒感染的方法也可通过口服、直肠、局部、非胃肠道或静脉给药。实际时间和剂量取决于受治疗的病毒和所需要的血液浓度。
下面的实施例是阐述性的，并非意味着对本发明的限制。下面的实施例阐述了噻苯达唑，2-(4-噻唑基)-1H-苯并咪唑，对HIV的效应和苯并咪唑类衍生物对很多病毒的效应。
噻苯达唑在抑制慢性感染细胞中HIV病毒产生上总的来说是有效的。细胞外病毒计数有效地趋向零或不可检出的水平。噻苯达唑在治疗有效浓度即使降低感染细胞的增殖速度也不杀死慢性感染细胞。噻苯达唑并不影响未感染细胞CD4的表达。在有效浓度，噻苯达唑减慢但不改变感染或非感染细胞的正常细胞RNA或蛋白质合成。噻苯达唑在大量慢性感染细胞类型中有效(该效应不出现细胞类型特异性)。
噻苯达唑对各种HIV病毒株有效(非病毒株特异性，虽然观察到某些株的差异；SK-1＞IIIB＞RF)。在所采用的试验条件下，噻苯达唑对SIV无论体外或体内似乎均无效。
给药20个月后，在设计促进病毒株耐药性发生的试验中未发生病毒株对噻苯达唑的耐药性。在为存在HIV药物而采用的试验中，6个月或不到6个月中发生耐药性，而对蛋白酶抑制剂的耐药株在约3-4个月中即产生。
噻苯达唑对急性感染细胞中存在的HIV药物AZT、3TC、ddC或蛋白酶抑制剂(沙奎那韦和茚地那韦)的活性无不良影响，这些存在的药物也无一干扰噻苯达唑在慢性感染细胞中的效应。
噻苯达唑对蛋白酶抑制剂耐药性病毒也有效。
噻苯达唑在治疗停止后4-80天赋予短暂的抑制HIV病毒产生作用。
这些研究的结果详细总结于下：
实施例1
HIV试验
HIV病毒复制试验
在慢性感染HIV病毒细胞中测试噻苯达唑。这些细胞群具有完整的HIV基因组拷贝，以相当高的水平组成性产生HIV(得自Frederick研究中心的CEM-SK1、U937-SK1 H9-SK1)，或被隐性感染而仅在用佛波醇酯、肿瘤坏死因子或IL6(U1和ACH2)刺激后才产生。用式Ⅱ化合物处理时，所有受试细胞株中病毒产生均减少，这些化合物不刺激隐性感染细胞中病毒的产生。当定量测定上清液逆转录酶活性、上清液p24及细胞内p24时，观察到病毒产生的减少，表明该化合物在细胞内蛋白质合成前的复制步骤抑制病毒产生。
从感染细胞产生的病毒粒子的感染性的定量测定证明感染病毒粒子数目的减少与上清液RT或p24的减少平行，表明化合物减少病毒产生量但不改变病毒粒子的质。在对靶细胞无毒的浓度观察到慢性感染细胞产生病毒的作用受抑制。噻苯达唑在大于1-10μg/ml的浓度抑制病毒产生。
对慢性感染细胞的毒性与对未感染细胞所观察到的相似。通过胸苷(DNA)、尿苷(RNA)和亮氨酸(蛋白质)掺入细胞大分子的评估进行噻苯达唑对慢性感染细胞的评估。如预期的那样，细胞大分子合成的抑制平行于两种化合物的毒性，而在见于抑制慢性感染细胞病毒产生的无毒低浓度并不出现。
用这些化合物对慢性感染细胞进行28天处理后，在未感染和慢性感染细胞中似乎化合物对靶细胞的毒性相似。该化合物并不优先杀死HIV感染的细胞。对于噻苯达唑来说，病毒产生水平的降低是稳定的，在大于10μg/ml的浓度观察到。
这些结果提示，噻苯达唑可快速降低慢性感染HIV-1的细胞群产生病毒的水平，随着接触该化合物的时间延长，抗病毒效应得以维持。病毒产生的减少出现在对宿主细胞基本无毒、对细胞DNA、RNA和蛋白质合成基本无作用的浓度。
病毒耐药性试验
将慢性感染HIV细胞在噻苯哒唑存在下进行培养，第一个月1μg/ml，第二个月5μg/m1，第三个月l0μg/ml，第四个月20和40μg/ml，第五和第六个月80μg/ml。每个月末，对细胞进行病毒产生评估，以未用这些化合物处理的慢性感染细胞作对照。在这六个月处理的每个月，均未见抗病毒效应的改变，毒性也保持不变，噻苯达唑保持对HIV的活性，经耐药性病毒或细胞适应性的选择，病毒对噻苯达唑的耐药性并不迅速达到，从而防止化合物产生毒性。以40和80μg/ml噻苯达唑处理的培养物完全保持了对病毒产生的抑制。
以前处理过的慢性感染细胞中病毒产生的再现
将用式Ⅱ化合物长期处理的慢性感染细胞洗去化合物，进行培养，以测定病毒产生是否恢复及何时恢复。在这些试验中使用经处理导致病毒产生总体上消除的培养物。这些培养物包括在20、40和80μg/ml噻苯达唑存在下经培养的慢性感染细胞。在低浓度(20μg/ml和4μg/ml)各化合物存在下的培养细胞中病毒产生在4天内恢复。在40μg/ml噻苯达唑浓度中培养的细胞中约12天病毒产生恢复。对于高浓度噻苯达唑中培养的细胞，病毒产生在约70天时首次观察到。
噻苯达唑处理细胞的易感性
将用噻苯达唑长期预处理的细胞洗去化合物用作靶细胞群。将细胞分成3群，标以第1、2或3组。第1组用该化合物处理24小时(与长期处理期所用的浓度相同)，洗去化合物，在感染病毒和新鲜化合物存在下进行培养。第2组处理24小时，洗去化合物，仅在感染病毒存在下进行培养。第3组预处理和感染期均仅在新鲜培养基中培养(无病毒或化合物)。不管培养条件如何，这些细胞群的病毒产生均相同。这些结果表明，长期处理的慢性感染细胞并不过分感染HIV。
另外的慢性HIV研究
慢性HIV-1感染细胞U1来自前单核细胞株U937的急性感染。慢性HIV-l感染细胞ACH-2来自T细胞株A3.01的急性HIV-1感染。
将这些细胞在佛波醇酯、PMA的存在下在培养基中进行培养。PMA引起细胞(U1和ACH-2两者)失活和不分裂。它还引起U-1细胞分化。这导致PMA处理培养物中的细胞少于单纯培养基的培养物。这些细胞用受试化合物进行处理时测定细胞生存力。
两种细胞株均组成性地产生小量HIV-1。p-24 ELISA显示ACH-2细胞株比U1细胞产生更多的HIV-1。当两种细胞株在PMA存在下进行培养时，用p-24抗原ELISA测得产生的HIV-1量增加。此外，测定了每个显微镜视野建立阳性HIV mRNA表达细胞的数目。从这些数字可进行比较，因为每种药物浓度有同样的细胞数粘附在玻片上(约10×106个细胞/ml)。
这些细胞用试验样品进行处理。噻苯达唑60μg/ml抑制HIV单核细胞复制为74％，而T细胞HIV复制增加26％。以干扰素为阳性对照，它抑制HIV单核细胞复制达80％。AZT在此模型上未显示活性。
2-(甲氧基羰基氨基)苯并咪唑抑制HIV单核细胞复制9％，而T细胞HIV复制增加44％。阳性对照为干扰素，它抑制HIV单核细胞复制达80％，而抑制T细胞HIV复制达60％。
急件HIV试验
在HIV体外急性模型，2-(4-噻唑基)-1H-苯并咪唑(60μg/ml)抑制病毒复制98％，AZT(1μg/ml)抑制病毒复制98％。
治疗指数(TI)，即药物的毒性剂量与药物有效剂量之比，2-(4-噻唑基)-1H-苯并咪唑为2.8，AZT为12,500。
实施例2疱疹
在剂量为200mg/kg的2-(4-噻唑基)-1H-苯并咪唑体内疱疹筛选试验中，10％小鼠存活，平均死亡天数为10.4天；100mg/kg剂量时，50％小鼠生存，平均死亡天数为9.2天。阳性对照为阿昔洛韦，(75mg/kg)，60％小鼠存活，平均死亡天数为17.2天。
在体外疱疹模型上对2-(4-噻唑基)-1H-苯并咪唑进行试验，未见活性。
实施例3流感
在体外流感模型上对2-(4-噻唑基)-1H-苯并咪唑进行试验，未见活性。
在体内流感模型上，以200mg/kg剂量试验了2-(4-噻唑基)-1H-苯并咪唑，67％小鼠存活，平均死亡天数为8天；100mg/kg剂量时，62％存活，平均死亡天数为8.7天。阳性对照为金刚烷胺(75mg/kg)，100％小鼠存活21天。
实施例4鼻病毒
在体外鼻病毒模型上试验了2-(4-噻唑基)-1H-苯并咪唑，与A-36683进行对比。治疗指数(TI)，即药物的毒性剂量与药物有效剂量之比，2-(4-噻唑基)-1H-苯并咪唑为1-2，而A-36683为1000-3200。
Claims (19)
1．治疗病毒感染有效的药物组合物，包括药物载体和治疗有效量的式Ⅰ所示苯并咪唑或其药学上可接受的盐：
其中，X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、氧氯、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基。
2．如权利要求1所述的药物组合物，包括药学上可接受的载体和约25-6000mg的式Ⅱ所示苯并咪唑或其药学上可接受的有机或无机酸加成盐
其中，R为氢或1-8个碳原子的烷基；R2为4-噻唑基。
3．如权利要求2所述的药物组合物，其中所述苯并咪唑为2-(4-噻唑基)苯并咪唑，其量为约250-5000mg。
4．如权利要求2所述的药物组合物，其中所述药学上可接受的盐为选自氯化物、溴化物、硫酸盐、硝酸盐、磷酸盐、磺酸盐、甲酸盐、酒石酸盐、马来酸盐、苹果酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐的有机或无机酸加成盐及其混合物。
5．在病毒感染上抑制病毒复制有效的药物组合物，包括药物载体和治疗有效量的式Ⅰ所示苯并咪唑或其药学上可接受的盐：其中，X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、氧氯、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基。
6．如权利要求5所述的组合物，包括约25-5000mg的式Ⅱ所示苯并咪唑或其药学上可接受的盐
其中，R为氢或1-8个碳原子的烷基；R2为4-噻唑基。
8．如权利要求7所述的组合物，其中所述苯并咪唑为2-(4-噻唑基)苯并咪唑或其药学上可接受的盐，所述组合物包含约100-6000mg所述的苯并咪唑。
9．有效防止对病毒感染处理耐药性病毒株的发展的药物组合物，包括药物载体和治疗有效量的式Ⅰ所示苯并咪唑或其药学上可接受的盐：
其中，X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、氧氯、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基。
9．如权利要求8所述的组合物，包括药学上可接受的载体和约25-5000mg所述苯并咪唑。
10．一种有效治疗对蛋白酶抑制剂处理有耐药性的病毒感染的药物组合物，包括药物载体和治疗有效量的式Ⅰ所示苯并咪唑或其药学上可接受的盐：
其中，X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、氧氯、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基。
11．在具有病毒感染的细胞中有效降低RNA和蛋白质合成速率的药物组合物，包括药物载体和治疗有效量的式Ⅰ所示苯并咪唑或其药学上可接受的盐：
其中，X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、氧氯、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基。
12．有效延长具有病毒感染的哺乳动物寿命的药物组合物，包括药物载体和治疗有效量的式Ⅰ所示苯并咪唑或其药学上可接受的盐：
其中，X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、氧氯、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基。
13．如权利要求1、2、3、4、5、6、7、8、9、10、11和12之一所述的组合物，进一步包括辅助治疗剂。
14．如权利要求13所述组合物，其中所述辅助治疗剂是抗病毒剂。
15．如权利要求13所述组合物，其中所述辅助治疗剂包括选自以下组的一种治疗剂：阿昔洛韦、金刚烷胺、金刚乙胺、重组可溶性CD4(rsCD4)、抗受体抗体、奈韦拉平、cidofovir、磷酰基甲酸三钠、泛昔洛韦、贲昔洛韦、伐昔洛韦、核酸/复制抑制剂、干扰素、齐多夫定(AZT)、2,3’-双脱氧肌苷(ddI)、双脱氧胸苷(d4T)、2’,3’-双脱氧胞苷(双脱氧胞苷ddC)、奈韦拉平、拉米夫定(3TC)、蛋白酶抑制剂、沙奎那韦、利托那韦、萘非那韦、efavienz,abacavir、安泼那韦、茚地那韦、更昔洛韦、AzDU、地拉夫定、利福平、clathiromycin、红细胞生成素、集落刺激因子、非核苷逆转录酶抑制剂和核苷抑制剂。
16．如权利要求1、2、3、4、5、6、7、8、9、10、11、12、13、14和15之一所述的组合物，其中病毒感染是由HIV、流感、肝炎和鼻病毒中一种或一种以上引起的。
17．如权利要求1、2、3、4、5、6、7、8、9、10、11、12、13、14、15和16之一所述的组合物，其中所述组合物是选自溶液剂、乳剂、悬浮液和从非泡腾或泡腾制剂重建的悬浮液的水性液体剂型。
18．如权利要求1、2、3、4、5、6、7、8、9、10、11、12、13、14、15和16之一所述的组合物，其中所述组合物是包括选自乳糖、蔗糖、明胶和琼脂的载体的固体剂型。
19．在具有病毒感染的细胞中降低RNA或蛋白质合成速率的方法，其特征在于用有效量的式Ⅰ所示苯并咪唑或其盐处理细胞
其中，X为氢、卤素、少于7个碳原子的烷基或少于7个碳原子的烷氧基；n为小于4的正整数；Y为氢、氯、硝基、氧氯、甲基或乙基；R为氢或1-8个碳原子的烷基；R2为4-噻唑基。
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- 1999-05-19 TR TR2000/03383T patent/TR200003383T2/xx unknown
- 1999-05-19 KR KR1020007012938A patent/KR20010043709A/ko not_active Application Discontinuation
- 1999-05-19 PE PE1999000422A patent/PE20000550A1/es not_active Application Discontinuation
- 1999-05-19 WO PCT/US1999/011059 patent/WO1999059585A1/en not_active Application Discontinuation
- 1999-05-19 SK SK1744-2000A patent/SK17442000A3/sk unknown
- 1999-05-19 JP JP2000549250A patent/JP2002515432A/ja not_active Withdrawn
- 1999-05-19 HU HU0103319A patent/HUP0103319A2/hu unknown
- 1999-05-19 IL IL13900299A patent/IL139002A0/xx unknown
- 1999-05-19 EP EP99923219A patent/EP1079831A1/en not_active Withdrawn
- 1999-05-19 CA CA002329877A patent/CA2329877A1/en not_active Abandoned
- 1999-05-19 AR ARP990102384A patent/AR019305A1/es unknown
- 1999-05-19 CO CO99030834A patent/CO5050303A1/es unknown
- 1999-05-19 ID IDW20002656A patent/ID27457A/id unknown
- 1999-05-19 PL PL99344223A patent/PL344223A1/xx unknown
- 1999-05-19 BR BR9911043-1A patent/BR9911043A/pt not_active IP Right Cessation
- 1999-05-19 CN CN99806363A patent/CN1301158A/zh active Pending
- 1999-05-19 AU AU40042/99A patent/AU4004299A/en not_active Abandoned
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2000
- 2000-11-17 NO NO20005839A patent/NO20005839L/no not_active Application Discontinuation
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110099916A (zh) * | 2016-10-21 | 2019-08-06 | 米歇尔伊德恩实验室 | 衍生自塞内加尔莲花戟的治疗组合物 |
| CN111491633A (zh) * | 2017-12-05 | 2020-08-04 | 爱尔兰詹森科学公司 | 用组合产品治疗rsv |
| CN115721606A (zh) * | 2021-08-27 | 2023-03-03 | 博美利克斯技术公司 | 胶束、其制备方法以及包含其的药物组合物 |
| US11998530B2 (en) | 2021-08-27 | 2024-06-04 | Biometrix Technology Inc. | Micelle comprising benzimidazole-carbohydrate conjugate compound, preparation method thereof and use thereof as anticancer agent or antiviral agent comprising the same |
Also Published As
| Publication number | Publication date |
|---|---|
| PL344223A1 (en) | 2001-10-08 |
| JP2002515432A (ja) | 2002-05-28 |
| AU4004299A (en) | 1999-12-06 |
| NO20005839L (no) | 2001-01-16 |
| AR019305A1 (es) | 2002-02-13 |
| US6245789B1 (en) | 2001-06-12 |
| SK17442000A3 (sk) | 2001-08-06 |
| CO5050303A1 (es) | 2001-06-27 |
| IL139002A0 (en) | 2001-11-25 |
| EP1079831A1 (en) | 2001-03-07 |
| CA2329877A1 (en) | 1999-11-25 |
| HUP0103319A2 (hu) | 2002-05-29 |
| WO1999059585A1 (en) | 1999-11-25 |
| BR9911043A (pt) | 2001-02-13 |
| NO20005839D0 (no) | 2000-11-17 |
| TR200003383T2 (tr) | 2001-03-21 |
| ID27457A (id) | 2001-04-12 |
| KR20010043709A (ko) | 2001-05-25 |
| PE20000550A1 (es) | 2000-06-29 |
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