CN1163235C - 抗病毒的线性聚合物 - Google Patents
抗病毒的线性聚合物 Download PDFInfo
- Publication number
- CN1163235C CN1163235C CNB971964378A CN97196437A CN1163235C CN 1163235 C CN1163235 C CN 1163235C CN B971964378 A CNB971964378 A CN B971964378A CN 97196437 A CN97196437 A CN 97196437A CN 1163235 C CN1163235 C CN 1163235C
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- chemical compound
- virus
- lysine
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Abstract
一种抗病毒化合物,它包含有多个侧链基团的线性非糖类聚合物,其中至少有一个侧链基团具有键合或连接到其上的含有阴离子或阳离子的部分。
Description
发明领域
本发明涉及抗病毒剂,特别是涉及多离子、尤其是多阴离子的线性聚合物,已发现它们具有显著的抗病毒活性,特别是能抗人免疫缺陷病毒(HIV),呼吸道合胞病毒(RSV),人流感病毒A和B,乙型肝炎病毒(HBV)和其它有包膜病毒。
发明背景
在进行抗HIV的筛选时已经确认某些磺化多糖具有抗病毒活性,但是这些化合物相当不稳定,因此要得到有效的抗病毒作用就需要服用大量的这些化合物。另外,这些化合物中有许多,包括诸如肝素和葡聚糖硫酸酯等是强有力的抗凝剂,由于这种活性使得它们特别不适合在临床中用作抗病毒剂。
国际专利申请No.PCT/AU95/00350(WO 95/34595)公开了一类抗病毒化合物,它包含树状聚合物(dendrimer)如具有多个端基的聚酰氨基胺(polyamidoamine)或聚赖氨酸树状聚合物,其中至少有一个端基具有键合或连接到其上的含有阴离子或阳离子的部分,特别是含有磺酸、含有羧酸、或含有三甲基铵的部分。
本发明提供了一组新的基于具有线性“骨架”的特定类型的多离子聚合物的抗病毒剂,其具有确实的抗HIV1和HIV2,RSV,HBV和人流感病毒A和B的抗病毒活性。这些化合物非常适合用作抗病毒剂来预防和治疗人类疾病。
发明概述
按照本发明,它提供了一种抗病毒化合物,其包含具有多个侧链基团的线性非糖类聚合物,其中至少有一个侧链基团具有键合或连接其上的含有阴离子或阳离子的部分。
本发明特别优选的抗病毒化合物是在其侧链基团上连接有含磺酸的部分、含羧酸的部分、含磷酸或膦酸的部分、含硼酸的部分、含神经氨酸或唾液酸的部分或含有在其4位或其它位置上有修饰的神经氨酸或唾液酸的部分的线性聚合物。
本发明化合物在本文中被称为多离子聚合物,在整个说明书中使用的该术语,其含义不仅包括这些聚合物本身,而且还包括它们的药学上或兽医可接受的盐,例如碱金属或碱土金属盐如钠、钾或钙盐。
发明详述
按照本发明优选的多离子聚合物是通式I的线性聚合物:
其中:
R是形成线性聚合物骨架的非糖类单体单元;
X是可选的单体单元R的侧链基团上的连接基;和
A是含有阴离子的部分。
因此,依照本发明,优选的线性聚合物是由阴离子部分(A)可选地通过连接基(X)轭合到线性非糖类聚合物骨架(由大量单体单元R组成)上而形成的多阴离子物质。所得多阴离子线性聚合物具有重复单元的分子量范围分布,由此得到所期望的分子量分布的中值。所期望的是,分子量分布的中值范围是1,000-1,000,000,优选为10,000-600,000。
单体单元优选为胺或酰胺部分,更优选为氨基酸部分。特别优选的单体单元是赖氨酸部分。从Sigma化学公司可购得具有不同分子量范围的聚-L-赖氨酸。
阴离子部分A可直接或经各种官能连接基X而连接到线性聚合物骨架上的活性侧链基团上,官能连接基X例如是但不限于:酯、酰胺、醚、硫醚、胺、脲、硫脲、甲氨酸酯和碳酸酯。
可选的连接基X也可作为聚合物和阴离子部分A之间的间隔基,并可由烷基链(可选为取代的或分支的),烷氧基、多烷氧基、烷硫基或多烷硫基链(可选为取代的),或链烯基、多链烯基、炔基或多炔基链(可选为取代的)组成。合适的间隔基链包括式-(CH2)n-Z-(CH2)n-基团,其中Z是-CH2-,-CH=CH-,-C≡C-,-O-或-S-,而n是1-15的整数。
按照本发明,线性聚合物骨架上至少有一个、并优选有相当数量的活性侧链基团具有共价键合其上的含有阴离子或阳离子的部分。该聚合物骨架的侧链末端可以是氨基或其它官能活性基团如OH、SH等,它们随后可与阴离子或阳离子部分反应。若聚合物骨架的侧链基团为胺基,则含有阴离子或阳离子的部分可以通过各种官能基包括酰胺和硫脲键而连接到聚合物骨架上。优选的可键合或连接到聚合物骨架的侧链基团上的含有阴离子或阳离子的部分包括含有磺酸的部分,含有羧酸的部分(包括含有神经氨酸和唾液酸的部分以及含有经修饰的神经氨酸和唾液酸的部分),含有硼酸的部分,含有磷酸和膦酸的部分(包括含有酯化磷酸和膦酸的部分)以及含有三甲基铵的部分。
合适的可键合或连接到线性聚合物的氨基或其它侧链基团上的含有阴离子或阳离子的部分包括诸如以下基团(其中n为0或正整数,特别是n为0或1-20的整数):
-NH(CH2)nSO3 - -(CH2)nSO3 - -Ar(SO3 -)n
-CH2CH(SO3 -)COOH -CH(SO3 -)CH2COOH -ArX(CH2)nSO3 - X=O,S,NH
-ArXP(=O)(OR)2 X=O,CH2,CHF,CF2 R=烷基,芳基,H,Na
-ArXP(=O)(OR1)(NR2R3) X=O,CH2,CHF,CF2 R1=烷基,芳基,H,Na
R2、R3=烷基,芳基
-Ar[P(=O)(OR)2]n R=烷基,芳基,H,Na n=1-3
-Ar[B(OH)2]n n=1-3 -Ar[COOH]n n=1-3
按照本发明,除了上述基团外,各种含有神经氨酸或唾液酸的部分或含有已修饰的神经氨酸或唾液酸的部分也可键合或连接到侧链基团上。这些部分包括神经氨酸的各种N-和O-取代的衍生物,特别是N-和O-酰基衍生物如N-乙酰基,O-乙酰基和N-乙醇酰基衍生物,以及其中神经氨酸基团被修饰,特别是通过在4-位被氨基、酰胺基、氰基、叠氮基或胍基取代而修饰的部分。
本发明的多离子聚合物可以用本领域技术人员熟知的标准化学方法制备。在下文的实施例部分中以举例方式描述了合适的方法。
如前所述,已发现本发明的多离子聚合物显示出显著的抗病毒活性,特别是抗有包膜病毒的活性。因此,这些多离子聚合物可用于预防和治疗病毒感染,例如HIV1和HIV2以及其它有包膜病毒感染,包括DNA病毒如乙型肝炎病毒和RNA病毒包括黄病毒如丙型肝炎病毒、牛病毒性腹泻病毒和日本脑炎病毒(JEV)。本发明的多离子聚合物也可用于对人流感病毒A和B,鼻病毒,冠状病毒,人副流感病毒,呼吸道合胞病毒(RSV),水痘带状疱疹病毒(VZV),人巨细胞病毒(CMV),EB病毒(EBV),人乳头瘤病毒(HPV),腺病毒,1型和2型单纯疱疹病毒(HSV),麻疹病毒和水泡性口炎病毒(VSV)的预防和治疗中。
因此,另一方面本发明提供了用于人或非人类动物的预防性或治疗性抗病毒治疗的药物或兽医组合物,它包含上文中已大致描述的多离子聚合物,以及至少一种药学上或兽医可接受的载体或稀释剂。
这种组合物的配制是本领域技术人员所熟知的。合适的药学上可接受的载体和/或稀释剂包括所有任意的常规溶剂,分散介质,填充剂,固体载体,水溶液,涂层,抗细菌和抗真菌剂,等渗剂和吸收延迟剂等。药物活性物质中这些介质和试剂的使用是本领域中熟知的,这在诸如Remington药物科学,第18版,Mack出版公司,宾西法尼亚,美国中进行了描述。除了与活性成分不相容的任何常规介质或试剂以外,其它均可考虑用于本发明的药物组合物中。也可在该组合物中加入辅助活性成分。
为了易于给药和使剂量均匀,尤为有利的是以剂量单位形式配制组合物。本文中所用的剂量单位形式是指适合作为单位剂量而用于要进行治疗的病人的物理分散单元;每个单元含有计算好能产生预期治疗效果的预定量的活性成分和所需的药物载体和/或稀释剂。本发明的新的剂量单位形式的规格取决并直接依赖于:(a)活性成分的特有性能和要达到的特定治疗效果,和(b)用于特定治疗的这类活性成分的配制领域中的固有限制。
在另一方面,本发明提供了预防性或治疗性治疗人或非人类动物中病毒感染的方法,它包含给所述人或动物施用如上文中已大致描述的预防性或治疗性抗病毒有效量的多离子聚合物。
另一方面,本发明提供了如上文中大致描述的预防性或治疗性抗病毒有效量的多离子聚合物在人或非人类动物中病毒感染的预防或治疗中,或在用于预防或治疗人或非人类动物中病毒感染的药剂的制备中的应用。
可使用各种给药途径。当然,所选择的特定方式将依据要治疗的特定病情和治疗效力所需的剂量而定。一般来说,本发明的方法可利用医学上可接受的任何给药方式,也就是说能达到本发明活性成分的治疗浓度而不会导致临床上不可接受的副作用的任何方式来实施。这样的给药方式包括口服、直肠、局部、鼻、吸入、经皮或胃肠外(例如皮下、肌内和静脉内)途径。用于口服给药的制剂包括诸如胶囊、片剂、锭剂等分散单元。其它途径包括直接鞘内给药到脊柱液中,利用诸如本领域普通技术人员熟知的各种导管和气囊血管成形术设备直接加入和实质内注射到靶向区域。
该组合物可方便地以单位剂量形式存在并可用制药领域中熟知的任何方法制备。这样的方法包括将活性成分加入到构成一种或多种辅助成分的载体中的步骤。一般说来,通过将活性成分均匀而紧密地掺入到液体载体、精细分离的固体载体、或二者中,然后如果需要,将该产物成形,即可制得该组合物。
适于口服给药的本发明组合物可以作为在脂质体中或作为含水液体或不含水流体中的悬液如糖浆、酏剂、或乳剂中的分散单元如胶囊、扁囊剂、片剂或锭剂存在,每个单元含有预定量的活性成分。
适于胃肠外给药的组合物方便地包含活性成分的无菌含水制剂,其优选与接受者的血液等渗。该含水制剂可以按照已知方法,利用那些合适的分散或湿润剂和悬浮剂来配制。无菌注射制剂也可以是在无毒的胃肠外可接受的稀释剂或溶剂中的无菌注射溶液或悬液,例如在聚乙二醇中的溶液。可以应用的可接受的赋形剂和溶剂是水、Ringer’s溶液和等渗氯化钠溶液。另外,通常将无菌固定油类用作溶剂或悬浮介质。出于这一目的,可应用任何温和固定油包括合成的单甘油酯或甘油二酯。另外,注射用制剂中可应用脂肪酸如油酸。
该活性化合物也可配制成用于将活性成分由鼻内或吸入给药的递送系统,例如含有活性成分的精细分散的气雾喷剂。
其它递送系统可包括缓释系统。优选的缓释系统是可使本发明活性成分以缓释的小丸或胶囊形式释放的那些系统。许多类型的缓释系统均可使用。这些包括但不限于:(a)浸蚀系统,其中活性成分包含在基质中,和(b)扩散系统,其中活性成分以可控速率通过聚合物渗透。另外,也可使用基于泵的硬件释放系统,它们中的某些可适于植入。
活性成分以预防或治疗有效量给药。预防或治疗有效量是指至少部分达到预期效果、或延迟所治疗的特定疾病的发作、或抑制其发展、或完全终止其发作或发展所需的量。当然,这样的量将依据所治疗的特定疾病、该疾病的严重程度和患者个体状况包括年龄、体质、身材大小、重量和并行的治疗等而定。这些因素是本领域普通技术人员熟知的,并可仅仅根据例行试验确定。一般优选使用最大剂量,也就是说,根据合理的医学鉴定判断出的最高安全剂量。不过,本领域普通技术人员将理解,出于医学原因、心理原因或实际上任何其它原因,可以较低的剂量或容许的剂量给药。
一般说来,活性成分的日口服剂量将是约0.01mg/kg/天到1000mg/kg/天。一开始可给予小剂量(0.01-1mg),接着增加剂量到最多约1000mg/kg/天。如果这样的剂量不足以使患者产生反应,甚至可以使用更高的剂量(或者可以通过不同的更局限的递送途径使用有效的更高剂量)直到患者的容限。也可考虑每天多次给药来达到化合物的适当系统浓度。
按照本发明的活性成分也可以兽用组合物的形式存在,例如,它可用该领域中的常规方法制备。这样的兽用组合物的实例包括适于以下给药途径的那些:
(a)口腔给药,外用,例如兽用顿服药(例如含水或不含水的溶液或悬液);片剂或大药团;用于与饲料混合的粉末、颗粒或小丸;用于舌头的糊剂;
(b)胃肠外给药例如通过皮下、肌内或静脉内注射,如作为无菌溶液或悬液;或(合适时)通过乳房内注射给药,此时悬液或溶液经乳头直接导入到乳房中;
(c)局部应用,例如作为皮肤用的霜剂,软膏或喷雾剂;或
(d)阴道内给药,例如作为阴道栓剂,霜剂或泡沫。
除非在上下文中另有要求,否则在整个说明书以及后面的权利要求书中,词语“包含”应理解为包括所宣称的整数或整数组,但并不表示不包括任何其它整数或整数组。
从以下实施例中将明显看出本发明的其它特征,这些实施例是为了阐述而不是限制本发明的。
实施例1
以4-磺苯基硫脲钠结尾的聚赖氨酸的制备
A.将固体4-磺苯基异硫氰酸钠一水合物(2.55g;10mmol)加入聚-L-赖氨酸(15-30K)(Sigma化学公司)(1.0g)在水(20ml)和N,N-二甲基-N-烯丙胺缓冲液(pH9.5;15ml)的混合物中的溶液中。当茚三酮试验为阴性时,将所得混合物在氮气下于53℃加热3小时。将冷却后的混合物过滤,浓缩滤液得到灰色固体残余物。将该固体残余物再溶于水并通过Amberlite IR 120(Na)柱,然后浓缩。粗产物通过凝胶过滤法(交联葡聚糖LH20;水)纯化并冷冻干燥得到以4-磺苯基硫脲钠结尾的聚-L-赖氨酸BRI2995,为白色松散固体(1.25g)。
B.类似地制备分子量为1-4K BRI2994、为4-15K BRI2967、为150-300K BRI2996的以4-磺苯基硫脲钠结尾的聚赖氨酸。
实施例2
以3,6-二磺萘基硫脲钠结尾的聚赖氨酸的制备
将固体3,6-二磺萘基异硫氰酸钠(200mg;0.51mmol)加入聚-L-赖氨酸(15-30K)(50mg)在水(2ml)和N,N-二甲基-N-烯丙胺缓冲液(pH9.5;2ml)的混合物中的溶液中。当茚三酮试验为阴性时,将所得混合物在氮气下于53℃加热3小时。将冷却后的混合物过滤,浓缩滤液得到棕色固体残余物。将该固体残余物再溶于水并通过Amberlite IR120(Na)柱,然后浓缩。粗产物通过凝胶过滤(交联葡聚糖LH20;水)纯化并冷冻干燥得到以3,6-二磺萘基硫脲钠结尾的聚-L-赖氨酸BRI6047,为白色松散固体(87mg)。
实施例3
聚-L-赖氨酰[(8-辛酰氨基)-5-乙酰氨基-3,5-二脱氧-2-硫-D-甘油基-α-D-半乳糖基-2-那鲁诺吡喃糖苷酸(nonulopyranosidoic acid)]n BRI6150的制备
聚-L-赖氨酸--------------(NHCO[CH2]7-)-X
用下述方法制备[(8-辛酸N-羟基琥珀酰亚胺酯)5-乙酰氨基-4,7,8,9-四-O-乙酰基-3,5-二脱氧-2-硫-D-甘油基-α-D-半乳糖基-2-nonulopyranosid]甲酯。向5-乙酰氨基-4,7,8,9-四-O-乙酰基-2-S-乙酰基-3,5-二脱氧-2-硫-D-甘油基-α-D-半乳糖基-2-nonulopyranosonate-甲酯(methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2-S-acetyl-3,5-dideoxy-2-thio-D-glycero-α-D-galacto-2-nonulopyranosonate)(A.Hasegawa,J.Nakamura和M.Kiso,糖类化学杂志,5(1),11-19,1986)(100mg)的无水二甲基甲酰胺溶液(1ml)中加入8-溴辛酸(41mg)和二乙胺(280mg),该溶液在20℃搅拌17小时。真空除去溶剂,残余物在乙酸乙酯和冰冷的5%盐酸之间分配。有机层用水洗涤,用硫酸钠干燥,并蒸发得到残余物(130mg)。将其溶于乙酸乙酯(5ml)中并加入N-羟基琥珀酰亚胺(26mg)和二环己基碳二亚胺(46mg)。该混合物在20℃搅拌17小时,然后滤除白色沉淀。将滤液浓缩并用闪蒸硅胶色谱法纯化,用乙酸乙酯洗脱。将含有产物的洗脱部分合并,蒸发得到白色泡沫97mg。71%
向聚-L-赖氨酸.HBr MW 150-300Kd(22mg)的无水二甲亚砜溶液(1ml)中加入二异丙基乙胺(15mg)和[(8-辛酸N-羟基琥珀酰亚胺酯)5-乙酰氨基-4,7,8,9-四-O-乙酰基-3,5-二脱氧-2-硫-D-甘油基-α-D-半乳糖基-2-nonulopyranosid]甲酯(90mg)。该混合物在氩气下于20℃搅拌60小时,然后真空除去溶剂。将残余物溶于新鲜配制的于甲醇中的0.5M甲醇钠溶液(4ml),将该混合物在氩气下于20℃搅拌48小时。蒸除溶剂,将残余物溶于水(1.5ml)并搅拌24小时。该溶液用交联葡聚糖LH20进行尺寸排阻色谱,用水洗脱。冷冻干燥后得到产物聚-L-赖氨酰[(8-辛酰氨基)-5-乙酰氨基-3,5-二脱氧-2-硫-D-甘油基-α-D-半乳糖基-2-那鲁诺吡喃糖苷酸]n,为白色粉末49mg。94%。
实施例4
以3,5-二羧苯基硫脲钠结尾的聚赖氨酸的制备
将聚-L-赖氨酸氢溴化物(4-15K)(Sigma化学公司)(50mg)的水溶液(2ml)加入3,5-二羧苯基异硫氰酸钠(305mg)的水溶液(3ml)中,用含水碳酸氢钠将所得溶液的pH调节到9。然后将所得溶液在氮气下于53℃加热4小时。冷却该溶液并过滤,浓缩滤液得到米色固体残余物。粗产物经凝胶过滤(交联葡聚糖LH20;水)纯化并冷冻干燥得到以3,5-二羧苯基硫脲钠结尾的聚-L-赖氨酸,为白色松散固体(71mg)。
实施例5
以4-(膦酰基甲基)苯基硫脲钠结尾的聚赖氨酸的制备
将固体4-(膦酰基甲基)苯基异硫氰酸盐(231mg;1.0mmol)加入聚-L-赖氨酸氢溴化物(30-70K)(Sigma化学公司)(50mg)在吡啶/水的1∶1混合物中的溶液中。用1M碳酸钠将该混合物的pH调节到9.5,将该溶液在氮气下于53℃加热过夜。冷却该混合物并过滤,浓缩滤液得到棕色固体残余物。粗产物经凝胶过滤(交联葡聚糖LH20;水)纯化得到棕色固体(82mg)。
实施例6
以1-膦酰基-氧苯基-4-硫脲结尾的聚-L-赖氨酸的制备
向在53℃加热并搅拌的聚-L-赖氨酸氢溴化物(50mg,Sigma P2636,30-70千道尔顿)的水溶液(10ml)中加入4-膦酰基-氧苯基异硫氰酸盐(153mg),并用1M碳酸钠溶液将该混合物的pH调节到9.5-10。该混合物在53℃加热并搅拌5小时,然后过滤。澄清溶液经交联葡聚糖LH20凝胶过滤纯化,用水洗脱。洗脱液冷冻干燥得到白色泡沫产物。77mg。94%。
实施例7
以苯甲酰氨基-4-硼酸结尾的聚-L-赖氨酸的制备
在惰性气氛下,向聚-L-赖氨酸氢溴化物(50mg,Sigma P2636,30-70千道尔顿)的DMSO溶液(10ml)中加入4-羧苯基硼酸N-羟基琥珀酰亚胺酯(90mg)和1M碳酸钠溶液(2ml),该混合物在20℃搅拌60小时。真空除去溶剂,将残余物溶于水(5ml)并过滤。澄清溶液经交联葡聚糖LH20凝胶过滤纯化,用水洗脱。冷冻干燥洗脱液得到白色泡沫产物。50mg。90%。
实施例8
抗病毒活性测试
表1-4分别显示了本发明的多离子线性聚合物抗HIV1、人和鼠CMV、HSV 1和2以及人流感A病毒的活性的测试结果。表5显示了实施例1中化合物抗宽范围病毒的抗病毒活性。表6和7分别显示了实施例2和3中化合物抗RSV、MV和流感病毒的抗病毒活性。
利用标准测试方案,抗病毒活性测定为使至少50%测试中使用的细胞免受病毒影响的测试化合物的有效剂量(EC50)。另外,因为需要测试化合物对细胞是安全的,因此测定细胞的细胞毒性(CC50),其为杀死50%未感染细胞的测试化合物的浓度。总的抗病毒活性可表示为选择性指数(SI),即CC50/EC50。
表1BRI线性聚合物的抗HIV活性
化合物 | 病毒株 | 浓度 | EC50 | CC50 | 抗病毒指数-SI | 结构 |
BRI6047 | HIV 1 IIIB | μM | 0.002 | >3.44 | >1720 | 聚-l-赖氨酸(15-30K)萘基二磺酸钠 |
BRI2967 | HIV 1 IIIB | μM | 0.014 | >20.8 | >1480 | 聚-l-赖氨酸(4-15K)苯基磺酸钠 |
BRI2994 | HIV 1 IIIB | μM | 0.60 | >62.5 | >1040 | 聚-l-赖氨酸(1-4K)苯基磺酸钠 |
BRI2995 | HIV 1 IIIB | μM | 0.005 | >5.7 | >1140 | 聚-l-赖氨酸(15-30K)苯基磺酸钠 |
BRI2996 | HIV 1 IIIB | μM | 0.007 | >0.8 | >114 | 聚-d-赖氨酸(150-300K)苯基磺酸钠 |
标准 | ||||||
AZT | HIV 1 IIIB | μg/ml | 0.0001 | 1.17 | 15,775 | |
DS5000葡聚糖硫酸酯 | HIV 1 IIIB | μg/ml | 0.0263 | >250 | >9,497 |
表2在细胞培养物中的抗巨细胞病毒(Davis株)活性
化合物 | EC50μg/ml | CC50μg/ml | 丙氧鸟苷CC50μg/ml | 所用细胞 |
BRI 2995 | ||||
HCMV CPE抑制 | 2.7 | >100 | 0.1 | HFF |
HCMV噬斑减少 | 9.1 | >100 | 0.2 | HFF |
MCMV噬斑减少 | 17.7 | 100 | 0.5 | MEF |
HCMV=人巨细胞病毒;MCMV=鼠(小鼠)巨细胞病毒。
测试采用人胚肺细胞(HEL);人包皮成纤维细胞(HFF);小鼠胚胎成纤维细胞(MEF)。
EC50 CPE=将病毒对细胞的致细胞病变效应降低50%的抑制性浓度。
CC50=使HEL细胞生长减少50%所需的细胞毒性浓度。
表3在细胞培养物中的抗单纯疱疹病毒1和2的活性
BRI 2995 | EC50μg/ml | CC50μg/ml | 丙氧鸟苷CC50μg/ml | |
HSV-1 CPE抑制 | 0.88 | >100 | 0.06 | HFF |
HSV-1 噬斑减少 | 25.9 | >100 | 0.3 | HFF |
HSV-2 CPE抑制 | 1.4 | >100 | 0.2 | HFF |
HSV-2 噬斑减少 | 13.6 | >100 | 0.6 | HFF |
HSV-1=人单纯疱疹病毒-1(粘膜疱疹)。
HSV-2=人单纯疱疹病毒-2(生殖器疱疹)。
测试采用人包皮成纤维细胞(HFF)。
EC50 CPE=将病毒对细胞的致细胞病变效应降低50%的抑制性浓度。
EC50噬斑减少=将病毒噬斑减少50%的抑制性浓度。
CC50=使细胞生长减少50%所需的细胞毒性浓度。
表4
BRI 6150
聚-L-赖氨酸(平均590KO(NHCO[CH2]7-)-X
抗流感A病毒两个株系的活性
化合物 | EC50μg/ml,Tokyo株 | EC50μg/ml,G70C株 |
BRI 6150 | 0.03 | 0.04 |
表5Poly-L-Lysine(NHCSNHPhSO3Na)x26-K-53K
BRI 2995ARB 95-336 | CPE-抑制EC50(CC50)μg/ml | 病毒计数或噬斑减少EC50(CC50)μg/ml | CPE-抑制EC50 (CC50)μg/mlSI | 病毒计数EC50 (CC50)μg/mlSI |
病毒;株系 | ||||
病毒唑 | ||||
RSV;Long | 10(>1000) >100 | 10(100) 10 | 10(560) 56 | 200(200) 1 |
0.3(30) 100 | >0.1(30) >300 | 7(90) 13 | 1(40) 40 | |
RSV;A2 | 0.5(55) 110 | 0.1(>100) >1000 | 13 (400) 31 | 2(>1000) >500 |
丙氧鸟苷 | ||||
CMV;Davis | 2.7(>100) >37 | 9.1(>100) >11 | 0.1 | 0.2 |
MCMV | 17.7(>100) >5.7 | 0.6 | ||
无环鸟苷 | ||||
VZV | 93.3(>100) >1.1 | 0.5 | ||
HSV-1 | 0.88(>100) >125 | >100(>100) 0 | 0.06 | 0.3 |
HSV-2 | 1.4(>100) >71 | >100(>100) 0 | 0.2 | 0.6 |
对照药物(?) | ||||
Flu A:H1N1 | 2.0(538) 269 | 2.4(261) 109 | 6.1(>100) >16 | 5.6 (>100) >18 |
Flu B | 6.5(501) 77 | 6.5(171) 28 | 3.3(100) >30 | 6.2 (>100) >16 |
浓度 μM | 叠氮胸苷 | |||
HIV-1;IIIB | 0.15(>250) >1,680 | 0.00037(4.38)11,840 | ||
HIV-2;ROD | 2.32 (>250) >108 |
病毒:RSV=呼吸道合胞病毒;
HSV=单纯疱疹病毒(1型=粘膜疱疹;2型=生殖器疱疹);
CMV=巨细胞病毒;
VZV=水痘带状疱疹病毒;
MCMV=鼠巨细胞病毒;
FluA=流感A病毒;
FluB =流感B病毒;
HIV-1 & 2=1型和2型人免疫缺陷病毒。
术语:CPE=病毒对感染细胞的致细胞病变效应或当测定细胞毒性
(CC50)时单纯化合物对细胞的作用。
表6Poly-L-lysine CONH.CH2CH2NHCSNH[Naphth-3,6-(SO3Na)2]
(37K-75K)
BR/6047ARB-96-222 | CPE-抑制EC50(CC50)μg/mlSI | PR=噬斑减少NR=中性红细胞计数EC50(CC50)μg/mlSI | CPE-抑制EC50(CC50)μg/mlSI | PR=噬斑减少NR=中性红细胞计数EC50(CC50)μg/mlSI |
病毒;株系 | 对照药物 | |||
病毒唑 | ||||
RSV;A2 | 1(110) 110 | NR<1.0(100) >100 | 7(90) 13 | NR1.0(40) 40 |
RSV;A2 | 病毒产生EC50(CC50) | EC90μMSI=CC50/EC90 | 病毒产生EC50 CC50 | EC90SI=CC50/EC90 |
RSV;A2 | 1.0(34) | 3.0 11 | 6.0(71) | 6.0 12 |
MV | 18(55) 3 | 25(118) 5 | ||
对照药物(?) | ||||
FluA;H1N1 | <1.0(599)>599 | NR<1.0(178) >178 | 5.6(>100) >18 | 5.0(>100) >20 |
FluA;H1N1 | 15(>100) >6.7 | NR14(100) 7.1 | 7.6(>100) >16 | NR5.8(>100) >13 |
FluA;H1N1 | 3.8(>100) 26 | NR12(>100) >8.3 | 5.0(>100) >20 | NR5.4(>100) >18 |
FluA;H1N1 | 3.2(>100)>57 | NR7.2(>100) >14 | 2.2(>100) >45 | NR2.8(>100) >36 |
FluA;H1N1 | 病毒产生EC50(CC50) | EC90SI=CC50EC90 | 病毒产生EC50CC50 | EC90SI=CC50/EC90 |
0.53(140) | 0.8 175 | 4.7 (24) | 3.0 8 | |
FluB | 13(487) 37 | NR19(267) 14 | 4.3(100) >23 | 5.5(>100) >18 |
FluB | 病毒产生EC50(CC50) | EC90SI=CC50/EC90 | 病毒产生EC50CC50 | EC90SI=CC50EC90 |
2.2(140) | 49 2.8 | 1.7 (24) | 1.5 16 |
表7聚-L-赖氨酸-{NH.CO.(CH2)7S-[2-5-乙酰基-神经氨酸]}x(590k)
BR/6150ARB-96-227 | CPE-抑制EC50(CC50)μg/mlSI | CPE-抑制EC50(CC50)μg/mlSI | CPE-抑制EC50(CC50)μg/mlSI | CPE-抑制EC50(CC50)μg/mlSI |
病毒;株 | 对照药物 | |||
病毒唑 | ||||
RSV;A2 | <1.0(>1000)>1000 | 13.0(400) 31 | ||
RSV;A2 | <1.0(>1000)>1000 | 2.0(>1000)>500 | ||
FluB | <1(>720)>720 | NR<1>1000 >1000 | NR1.8(>100) >56 | |
RSV;A2 | 病毒产生EC50(CC50) | EC90SI=CC50/EC90 | 病毒产生EC50(CC50) | EC90SI=CC50/EC90 |
3.0(>1000) | 2.0 >500 | 6.0 (71) | 6.0 12 |
Claims (18)
1.一种抗病毒的线性、非糖类聚合物,其中具有多个侧链基团,所述侧链基团中至少有一个具有键合或连接到其上的含有阴离子或阳离子的部分。
2.按照权利要求1的化合物,它包含通式I的线性聚合物:
其中:
R是形成线性聚合物骨架的非糖类单体单元;
X是可选的单体单元R的侧链基团上的连接基;和
A是含有阴离子的部分。
3.按照权利要求2的化合物,其中所述线性聚合物的分子量分布的中值范围是1,000-1,000,000。
4.按照权利要求3的化合物,其中所述分子量分布的中值范围是10,000-600,000。
5.按照权利要求2的化合物,其中所述单体单元R是胺或酰胺部分。
6.按照权利要求5的化合物,其中所述单体单元R是氨基酸。
7.按照权利要求6的化合物,其中所述单体单元R是赖氨酸。
8.按照权利要求2的化合物,其中所述连接基X,当存在时,是选自下列成员的官能连接基:酯,酰胺,醚,硫醚,胺,脲,硫脲,甲氨酸酯和碳酸酯。
9.按照权利要求2的化合物,其中所述连接基X,当存在时,是选自下列成员的间隔基:可选地被取代或分支的烷基链;可选地被取代的烷氧基、多烷氧基、烷硫基或多烷硫基链;可选地被取代的链烯基、多链烯基、炔基或多炔基链;以及式-(CH2)n-Z-(CH2)n-基团,其中Z是-CH2-,-CH=CH-,-C≡C-,-O-或-S-,而n是1-15的整数。
10.按照权利要求1-9中任一项所述的化合物,其中所述含有阴离子或阳离子的部分通过酰胺或硫脲键而键合到所述线性聚合物的活性官能侧链基团上。
11.按照权利要求10所述的化合物,其中所述含有阴离子或阳离子的部分通过酰胺或硫脲键而键合到所述线性聚合物的胺、巯基或羟基侧链基团上。
12.按照权利要求1-9中任一项所述的化合物,其中所述含有阴离子的部分选自下列成员:含有磺酸的部分,含有羧酸的部分,含有硼酸的部分,以及含有磷酸和膦酸的部分。
13.按照权利要求12所述的化合物,其中所述含有阴离子的部分选自下列成员:包括含有经修饰和未经修饰的神经氨酸和唾液酸的部分,以及含有酯化磷酸和膦酸的部分。
14.按照权利要求1-9中任一项所述的化合物,其中键合到氨基或其它活性官能侧链基团上的部分选自下列基团,其中n为0或正整数:-NH(CH2)nSO3 - -(CH2)nSO3 - -Ar(SO3 -)n-CH2CH(SO3 -)COOH -CH(SO3 -)CH2COOH -ArX(CH2)nSO3 - X=O,S,NH-(CH2)nNMe3 -Ar(NMe3)n -Ar(CH2NMe3)n
-ArXP(=O)(OR)2 X=O,CH2,CHF,CF2 R=烷基,芳基,H,Na
-ArXP(=O)(OR1)(NR2R3) X=O,CH2,CHF,CF2 R1=烷基,芳基,H,Na
R2、R3=烷基,芳基
-Ar[P(=O)(OR)2]n R=烷基,芳基,H,Na n=1-3
-Ar[B(OH)2]n n=1-3 -Ar[COOH]n n=1-3
15.按照权利要求1或2的化合物,它选自下列成员:
i.以4-磺苯基硫脲结尾的聚-L-赖氨酸;
ii.以3,6-二磺萘基硫脲结尾的聚-L-赖氨酸;
iii.以(8-辛酰氨基)-5-乙酰氨基-3,5-二脱氧-2-硫-D-甘油基-α-D-半乳糖基-2-那鲁诺吡喃糖苷酸结尾的聚-L-赖氨酸;
iv.以3,5-二羧苯基硫脲结尾的聚-L-赖氨酸;
v.以4-(膦酰基甲基)苯基硫脲结尾的聚-L-赖氨酸;
vi.以1-膦酰基氧苯基-4-硫脲结尾的聚-L-赖氨酸;和
vii.以苯甲酰氨基-4-硼酸结尾的聚-L-赖氨酸。
16.用于人或非人类动物的预防性或治疗性抗病毒治疗的药用或兽用组合物,它包含权利要求1-15中任一项的化合物,以及至少一种药学上或兽医可接受的载体或稀释剂。
17.权利要求1-15中任一项的化合物在制备可用于对人或非人类动物进行预防性或治疗性抗病毒治疗的药物中的用途。
18.按照权利要求17的用途,其中所述抗病毒治疗是对以下病毒感染的治疗:HIV-1或HIV-2,乙型或丙型肝炎病毒,牛病毒性腹泻病毒,日本脑炎病毒,人流感病毒A和B,鼻病毒,冠状病毒,人副流感病毒,呼吸道合胞病毒,水痘带状疱疹病毒,人巨细胞病毒,EB病毒,人乳头瘤病毒,腺病毒,1型和2型单纯疱疹病毒,麻疹病毒或水泡性口炎病毒。
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AUPO1043A AUPO104396A0 (en) | 1996-07-17 | 1996-07-17 | Antiviral linear polymers |
AUPO1043 | 1996-07-17 |
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US (1) | US6740635B2 (zh) |
EP (1) | EP0928306A4 (zh) |
JP (1) | JP2000516971A (zh) |
KR (1) | KR100589022B1 (zh) |
CN (1) | CN1163235C (zh) |
AU (2) | AUPO104396A0 (zh) |
BR (1) | BR9710376A (zh) |
CA (1) | CA2262863A1 (zh) |
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HUP9904009A3 (en) | 1996-11-14 | 2001-07-30 | Biota Scient Man Pty Ltd Melbo | Method and novel compounds for use therein |
FR2781485B1 (fr) | 1998-07-21 | 2003-08-08 | Denis Barritault | Polymeres biocompatibles leur procede de preparation et les compositions les contenant |
AUPP913999A0 (en) | 1999-03-12 | 1999-04-01 | Biota Scientific Management Pty Ltd | Novel chemical compounds and their use |
AUPR001000A0 (en) | 2000-09-08 | 2000-10-05 | Biota Scientific Management Pty Ltd | Novel chemical compounds and their use |
US20040220139A1 (en) * | 2003-04-29 | 2004-11-04 | Sceusa Nicholas A. | Inhibiting viral infections |
DE102005056592A1 (de) * | 2005-11-25 | 2007-05-31 | Basf Ag | Herstellung und Verwendung von hochfunktionellen, hoch-oder hyperverzweigten Polylysinen |
JP2011136977A (ja) * | 2009-06-16 | 2011-07-14 | Sekisui Chem Co Ltd | Rnaウイルス感染阻止塗料用組成物、rnaウイルス感染阻止塗料及びrnaウイルス感染阻止製品 |
JP2011020993A (ja) | 2009-06-16 | 2011-02-03 | Sekisui Chem Co Ltd | Rnaウイルス感染阻止成形用組成物及びrnaウイルス感染阻止成形品 |
EP2568289A3 (en) | 2011-09-12 | 2013-04-03 | International AIDS Vaccine Initiative | Immunoselection of recombinant vesicular stomatitis virus expressing hiv-1 proteins by broadly neutralizing antibodies |
EP2586461A1 (en) | 2011-10-27 | 2013-05-01 | Christopher L. Parks | Viral particles derived from an enveloped virus |
KR101547787B1 (ko) * | 2012-03-27 | 2015-08-26 | 세키스이가가쿠 고교가부시키가이샤 | 섬유 가공용 인플루엔자 바이러스 감염 저지제, 이것을 사용한 섬유 제품 및 그의 제조 방법 |
US9347065B2 (en) | 2012-03-29 | 2016-05-24 | International Aids Vaccine Initiative | Methods to improve vector expression and genetic stability |
CA2899424A1 (en) | 2013-02-19 | 2014-08-28 | Johnson & Johnson Consumer Companies, Inc. | Methods and compositions for improving appearance and formation of scar tissue |
CA2955406A1 (en) | 2014-07-29 | 2016-02-04 | Uniwersytet Jagiellonski | Anionically modified polyallylamine derivative, use of anionically modified polyallylamine derivative as medicine, particularly for propylaxis and treatment of infections of respiratory tract caused by human metapneumovirus (hmpv), human rhinoviruses (hrv), and infection by influenza virus type a (iav) and pharmaceutical composition comprising the... |
AU2021204697B1 (en) * | 2020-04-15 | 2021-11-11 | Starpharma Pty Ltd | Method of prophylaxis of coronavirus and/or respiratory syncytial virus infection |
GB202007701D0 (en) | 2020-05-22 | 2020-07-08 | Univ Manchester | Antiviral polymers |
CN114053394B (zh) * | 2020-07-30 | 2024-06-21 | 广州朗圣药业有限公司 | 新型化合物在制备预防和/或治疗冠状病毒感染的药物中的应用 |
TWI836258B (zh) * | 2020-08-21 | 2024-03-21 | 澳大利亞商星法馬私人有限公司 | 預防冠狀病毒及/或呼吸道融合病毒感染的方法 |
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HU187669B (en) * | 1982-03-31 | 1986-02-28 | Richter Gedeon Vegyeszet | Process for producing new copolymeres and salts |
JPS632901A (ja) * | 1986-06-24 | 1988-01-07 | Chisso Corp | 植物ウイルス病防除剤 |
NL8900442A (nl) * | 1989-02-22 | 1990-09-17 | Stichting Rega V Z W | Gesulfateerde vinylpolymeren in geneesmiddelen voor het behandelen van retrovirus-infecties. |
JP2909500B2 (ja) * | 1989-03-23 | 1999-06-23 | ベルレックス、ラボラトリーズ、レンコーポレイテッド | 水溶性抗高脂質血症剤として有用な官能化側鎖を有するポリアミド |
FR2669535A1 (fr) * | 1990-11-26 | 1992-05-29 | Medgenix Group Sa | Utilisation a titre de medicament de macromolecules polysulfonees. |
US5869457A (en) | 1991-03-11 | 1999-02-09 | Rijksuniversiteit Te Groningen | Modified proteins and their use for controlling viral infections |
ES2149537T3 (es) * | 1992-01-14 | 2000-11-01 | Hisamitsu Pharmaceutical Co | Resina intercambiadora de aniones no reticulados y composicion farmaceutica que contiene la misma. |
AUPM623994A0 (en) * | 1994-06-15 | 1994-07-07 | Biomolecular Research Institute Limited | Antiviral dendrimers |
FR2727117A1 (fr) | 1994-11-18 | 1996-05-24 | Geffard Michel | Utilisation de conjugues de la polylysine pour la preparation de medicaments utiles dans le traitement des maladies neurodegeneratives et des affections degeneratives a caractere autoimmun |
US6034129A (en) | 1996-06-24 | 2000-03-07 | Geltex Pharmaceuticals, Inc. | Ionic polymers as anti-infective agents |
US6007803A (en) | 1997-09-19 | 1999-12-28 | Geltex Pharmaceuticals, Inc. | Ionic polymers as toxin binding agents |
US6060235A (en) | 1997-09-19 | 2000-05-09 | Geltex Pharmaceuticals, Inc. | Antiviral polymers comprising acid functional groups and hydrophobic groups |
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1996
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- 1997-07-17 JP JP10506371A patent/JP2000516971A/ja active Pending
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CN1225653A (zh) | 1999-08-11 |
EP0928306A4 (en) | 2003-04-16 |
AU3330197A (en) | 1998-02-10 |
KR20000067865A (ko) | 2000-11-25 |
US20020025919A1 (en) | 2002-02-28 |
NZ333541A (en) | 2000-09-29 |
US6740635B2 (en) | 2004-05-25 |
BR9710376A (pt) | 1999-08-17 |
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WO1998003572A1 (en) | 1998-01-29 |
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