CN1192687A - 低聚糖化合物的细菌抑制 - Google Patents
低聚糖化合物的细菌抑制 Download PDFInfo
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- CN1192687A CN1192687A CN96196047A CN96196047A CN1192687A CN 1192687 A CN1192687 A CN 1192687A CN 96196047 A CN96196047 A CN 96196047A CN 96196047 A CN96196047 A CN 96196047A CN 1192687 A CN1192687 A CN 1192687A
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Abstract
本发明涉及通过给予粘合抑制有效量的式Ⅰ化合物,治疗选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和其混合物的细菌引起的呼吸道感染的方法。
Description
本发明背景
本发明的范围
本发明涉及使用低聚糖以及含相同成分的药用组合物治疗由选自肺炎双球菌(Streptococcus pneumoniae)、流感嗜血杆菌(Haemophilusinfluenza)、副流感嗜血杆菌(Haemophilus parainfluenza)、洋葱假单胞菌[Burkholderia(Pseudomonas)cepacia]和其混合物的细菌引起的细菌感染的方法。
背景讨论
肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌是与如肺炎、细菌性支气管炎、结膜炎、窦炎和中耳炎等呼吸道疾病有关的致病菌。在上述每种疾病中，所述的细菌都可移生到鼻咽，结膜、肺、支气管或耳道等健康组织中，使众多人染病。所述的细菌粘连在细胞表面的细菌特菌异受体部位。
为了减缓细菌移生，常规治疗是依靠抗生素的用药。可是，抗生素治疗常受到产生抗生素耐药菌的影响(和最终产生用已知的抗生素无法治疗的“超级细菌”)。美国微生物学会在1995年5月发表的一篇报告中指出越来越多的传染性病菌正变成用抗生素可不治疗的，在公共卫生危机发生之前必须采取措施扭转这种趋势。
研究人员已对致病菌与组织受体粘连的互相作用进行了研究，并已证明特定的碳水化合物序列化合物能抑制细菌的粘连。
Krivan等人在美国专利5386027中报道了用含有在中间或含在末端的GalNAcβ1-4 Galβ1-4-Glc序列的化合物粘合抑制与呼吸道感染有关的特异“机会致病菌”。所报道的粘合抑制的特异肺致病菌是绿脓杆菌、流感嗜血杆菌、金葡球菌、肺炎双球菌、肺炎杆菌和大肠杆菌。该文献假定神经节苷脂GM1大量的存在于人的肺部组织中和假定肺致病菌需要至少一个未被唾液酰基(Sialyl)取代的末端或中间的GalNAcβ1-4Gal。
Andersson等人在J.Exp.Med.[(1983)，v.158，p.559-570，]中报道关于肺炎双球菌粘合抑制研究并确定二糖Glc NAcβ1-3Galβ作为特异的糖共轭物(glycoconjugate)受体。该文献报道化合物3即Neu Acα2-3Galβ1-4-Glc NAcβ1-3 Galβ1-4-Glc-Cer无粘合抑制作用(564页，表IV下的首句)。
Rosenstein等人在Infection and Immunity[(1992)，Vol.60，no.12，5078-5084]中报道从囊性纤维变性患者中分离出的绿脓杆菌M35和大肠杆菌C600对于各种低聚糖结构的粘合特异性。指出Galβ1-4-GlcNAcβ1-3 Galβ1-4-Glc具有高粘合活性，而Neu Acα2-6 Galβ1-4-GlcNAcβ1-3 Galβ1-4-Glc却无活性。
Ramphal等人在Infection和Immunity[(1991)Vol.59，no.2，p.700-704]中报道绿脓杆菌对1型(Galβ1-3-Glc NAc)和2型(Galβ1-4-GlcNAc)二糖的粘合抑制研究。在直接粘连测定中，Neu Acα2-6 Galβ1-4-Glc NAcβ1-3 Galβ1-4-Glc无活性。
Ginsburg等人在美国专利5225330中报道了使用特定的碳水化合物受体序列化合物吸收微生物的诊断方法。该文献指出肺炎支原体(表I，11列)的粘合抑制中，Sialylparagoboside无活性，但是报道了N-glycolylsialoparagloboside的大肠杆菌的抑制作用。
Feizi等人在Biochemistry(1994，33，6342-6349)中报道Neu Acα2-6 Galβ1-4-Glc NAcβ1-3 Galβ1-4-Glc没有被免疫球蛋白E-粘合蛋白粘合或仅微弱的粘合，而Neu Accα2-3 Galβ1-3-Glc NAcβ1-3-Galβ1-4-Glc却被该蛋白紧紧粘合。
Magnani等人在WO 92/18610中，报道于体内和体外抑制恶性细胞对内皮细胞的粘合中应用了唾液酰-Lea(Neu5Acα2-3-Galβ1-3[Fucα1-4]GlcNAc)和唾液酰-Lex(Neu5Acα2-3-Galβ1-4[Fucα1-3]GlcNAc)。
Andersson等人在J.ofInfectious Diseases[(1986)，Vol，153，no，2，232-237)中报道了人乳成份可抑制肺炎双球菌和流感嗜血杆菌对人咽或颊的上皮细胞的粘合。
因此，寻找治疗选自肺炎双球菌，流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和其混合物的细菌的细菌感染的新方法，该法具有产生抗生素耐药菌的较低可能性。在该研究中，抗粘连化合物是潜在有用的候选物。
本发明概述
因此，本发明目的之一是提供通过给予粘合抑制有效量的式I化合物，抑制选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和其混合物的细菌移生的新方法，其中
R1是H，(β-1)GalNAc-，SO3B(其中B是H或阳离子)或式II唾液酸；
其中
R6、R7、R8和R10各自独立为H、C1-6酰基、乳酰基、C1-6烷基、硫酸酯、磷酸酯、脱水、式II的唾液酸、(α-1)Fuc、(β-1)Glc或(β-1)Gal；
R9是NH-C1-6酰基、乙醇酰胺基、氨基或羟基；和
A是H或阳离子；
R2是H或(α-1)Fuc-；
R3和R4各自独立为OH或NHAc；
R5是H、SO3B(其中B是H或阳离子)或同上述定义的式II的唾液酸；和
Y是化学键或是连接基团；
Z是H或多价载体(support)；
m是0或1；和
p是1-1000的整数。
本发明的第二目的是提供抑制选自诊断患有肺炎病人中的肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和混合物的细菌的细菌移生的方法。
本发明另一目的是提供抑制选自诊断患有细菌性支气管炎病人中的肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和混合物的细菌的细菌移生的方法。
本发明另一目的是提供抑制选自诊断患有中耳炎病人中的肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和混合物的细菌的细菌移生的方法。
本发明另一目的是提供含有式I化合物的新的药用组合物。
其中
R1是H，(β-1)GalNAc-，SO3B(其中B是H或阳离子)或式II的唾液酸；
其中
R6、R7、R8和R10各自独立为H、C1-6酰基、乳酰基、C1-6烷基、硫酸酯、磷酸酯、脱水、式II的唾液酸、(α-1)Fuc、(β-1)Glc或(β-1)Gal；
R9是NH-C1-6酰基、乙醇酰胺基、氨基或羟基；和
A是H或阳离子；
R2是H或(α-1)Fuc-；
R3和R4各自独立为OH或NHAc；
R5是H、SO3B(其中B是H或阳离子)或同上述定义的式II的唾液酸；和
Y是化学键或是连接基团；
Z是H或多价载体(support)；
m是0或1；和
p是1-1000的整数；
其中当R5是H时，R1不是H和当R1是唾液酸时，R2不是(α-)Fuc。
在优选的实施例中，式I的化合物具有下述的结构式：
其中
Y是化学键或连接基团；
Z是H或多价载体；和
p是1-1000的整数。
通过本发明者的发现即借助式I化合物抑制选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和其混合物的细菌移生来使本发明这些和其它的目的成为可能的。优选实施例的详细论述
本文中使用下列缩写“Gal”为半乳糖；“Glc”为葡萄糖、“GlcNac”为N-乙酰葡萄糖胺；“GalNAc”为N-乙酰半乳糖胺；“Fuc”为岩藻糖；“NAN或NeuAc”为N-乙酰神经氨酸。
特定的低聚糖化合物包括NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-Galβ1-4-GlcNAc，NeuAcα2-6-Galβ1-4-[Fucα1-3]GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-[Fucα1-3]GlcNAc，GalNAcβ1-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，GalNAcβ1-3-Galβ1-4-GlcNAc，GalNAcβ1-3-Galβ1-4-Glc，NeuAcα2-3-Galβ1-4-GlcNAc，NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-6-Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-GlcNAc，NcuAcα2-6-[GalNAcβ1-3]Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-GlcNAc，GalNAcβ1-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc和GalNAcβ1-3-Galβ1-4-GlcNAc.]
除化合物Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc之外，低聚糖化合物的优选基团为上述定义的基团。
所述的每一化合物也可以以一价(即，p＝1)或以多价形式(即，p＝2-1000)，用或不用连接基团Y来实施给药。此外，所述的连接基团Y可直接键合Z(其中Z是H或是多价载体)。
本发明的低聚糖可使用任何已知方法获得，包括(1)酶催化，使用美国专利5180674中介绍的方法之一，(2)合成，使用经典有机化学方法，(3)通过天然的低聚糖、糖脂，或糖肽的降解或(4)从如人乳天然来源中分离。Kuhn，R.和Gauche A.[Chem Ber.，95，513(1962)]和Dorland等人[Eur.J.Bioch，87，323(1978)]报道了LSTc的分离。
例如，乳糖经酶催化可制备化合物NeuAcα2-6 Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc。因此，乳糖与β半乳糖甙β1-3N-乙酰葡糖氨基转移酶和UDP-GlcNAc、βN-乙酰葡糖氨基甙β1-4半乳糖基转移酶和UDP-Gal及β半乳糖甙α2-3唾液酰基转移酶和CMP-NeuAc在适当条件下反应以影响所述三个糖基从糖核苷酸到合适的受体分子的转移。
基团R1和R5可以是基团SO3B，其中B可以是H或是阳离子。因此，所述的式I化合物包括硫酸酯取代基及其盐。合适的阳离子包括碱金属、碱土金属或铵。可使用任何已知适合药用的阳离子，包括常用的无毒性盐的阳离子，包括金属盐例如碱金属盐(如钠盐、钾盐等)或碱土金属盐(如钙盐、镁盐等)、铵盐。有机碱盐(如三甲胺盐、三乙胺盐、吡啶盐、甲基吡啶盐、二环己胺盐、N，N’-二苄基乙二胺盐等)、有机酸盐(如甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、甲苯磺酸盐等)、无机酸盐(如氢氯化物、氢溴化物、硫酸盐、磷酸盐等)、氨基酸盐(如精氨酸盐、天冬氨酸盐、谷氨酸盐等)以及诸如此类盐。
所述的式I化合物也可以是相应的氮杂糖，其中用氮置换吡喃环上一个或多个氧以形成哌啶环体系。
用对本技术领域的普通技术人员熟知的常规的方法可制备相应于式I的氮杂糖，例如经典的有机化学技术或使用适当的氮杂糖化物作受体底物的酶催化法。通过相应葡萄糖转移酶将氮杂糖核苷酸转移成天然糖。从天然资源中可分离出氮杂葡萄糖，再经半乳糖转移酶的作用，在像UDP-gal半乳糖给予体的存在下，将其转化成氮杂乳糖。
所述的式I化合物也可以是相应的硫糖，其中用硫置换吡喃环上的一个或多个氧形成四氢噻喃环体系。
用对本技术领域的普通技术人员熟知的常规方法可制备相应于式I的硫糖，如经典的有机化学技术或使用适当的硫糖化物作受体底物的酶催化法。因常规经典有机化学技术将相应一糖化物制备成一硫糖化物。
所述的式II化合物是唾液酸，即与神经氨酸有关的9位碳被羧化的糖类化合物。当A是H时，所述的羧酸以游离酸形式存在，当A是阳离子时，所述羧酸为盐。
合适的阳离子包括碱金属，碱土金属或铵。可以使用任何已知可作为药用的适当阳离子，包括常用的无毒性盐的阳离子，有像碱金属盐(如钠盐、钾盐等)或碱土金属盐(如钙盐、镁盐等)的金属盐、铵盐、有机碱盐(如三甲胺盐、三乙胺盐、吡啶盐、甲基吡啶盐、二环己基胺盐、N，N’-二苄基乙二胺盐等)、有机酸盐(如甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐、甲苯磺酸盐等)、无机酸盐(如氢氯化物、氢溴化物、硫酸盐、磷酸盐等)、氨基酸盐(如精氨酸盐、天冬氨酸盐、谷氨酸盐等)以及诸如此类盐。
优选所述的式II化合物选自N-乙酰-神经氨酸、N-乙醇酰-神经氨酸、氧代-脱氧-nonulosonic acid、9-0-乙酰N-乙酰-神经氨酸、9-0-乙酰N-乙醇酰-神经氨酸、9-0-乙酰-氧代-脱氧-nonulosonic、7-0-乙酰-N-乙酰-神经氨酸、7-0-乙酰-N-乙醇酰-神经氨酸、4-0-乙酰-N-乙酰-神经氨酸、4-0-乙酰-N-乙醇酰-神经氨酸、7，9-二-0-乙酰-N-乙酰-神经氨酸、8，9-二-0-乙酰-N-乙酰-神经氨酸、7，9-二-0-乙酰-N-乙醇酰-神经氨酸、8，9-二-0-乙酰-N-乙醇酰-神经氨酸、4，9-二-0-乙酰-N-乙酰-神经氨酸、7，8，9-三-0-乙酰-N-乙酰-神经氨酸、7，8，9-三-0-乙酰-N-乙醇酰-神经氨酸、9-0-乳酰-N-乙酰-神经氨酸、9-0-乳酰-N-乙醇酰-神经氨酸、4-0-乙酰-9-0-乳酰-N-乙酰-神经氨酸、4-0-乙酰-9-0-乳酰N-乙醇酰-神经氨酸、8-0-甲基-N-乙酰-神经氨酸、8-0-甲基-N-乙醇酰-神经氨酸、8-0-甲基-9-0-乙酰-N-乙醇酰-神经氨酸、8-0-甲基-7，9-二-0-乙酰-N-乙醇酰-神经氨酸、8-0-硫代-N-乙醇酰-神经氨酸、8-0-偶磷-N-乙酰-神经氨酸、2，3-二脱氢2，6脱水-N-乙酰-神经氨酸、9-0-乙酰-2，3-二脱氢2，6脱水-N-乙酰-神经氨酸、9-0-乳酰-2，3-二脱氢2，6脱水-N-乙酰神经氨酸、2，3-二脱氢2，6脱水-N-乙醇酰-神经氨酸、9-0-乙酰-2，3二脱氢2，6脱水-N-乙醇酰-神经氨酸、9-0-乳酰-2，3-脱氢2，6脱水-N-乙醇酰-神经氨酸、8-0-甲基-2，3二脱氢2，6脱水-N-乙醇酰-神经氨酸、2，7脱水-N-乙酰-神经氨酸、2，7脱水-N-乙醇酰-神经氨酸、8-0-甲基-2，7脱水-N-乙醇酰-神经氨酸、4，8脱水-N-乙酰-神经氨酸及其盐。更优选所述的式II唾液酸是N-乙酰-神经氨酸或N-乙醇酰-神经氨酸、在A.Varki Glycobiology[Vz，(1992)P25-40]中介绍了这些唾液酸。据此，该文献描述唾液酸的来源以及酶催化合成式I低聚糖所必需的适当唾液酰转移酶。
当用唾液酸取代式II化合物时，所述的R7位为优选取代。
所述的连接基团Y是能连接式I化合物的低聚糖部分与基团Z的任何基团。合适的连接基团包括糖化物、低聚糖、肽、蛋白质、C2-20烷基、氧化烯链基或不降低式I化合物的低聚糖部分粘合抑制活性的任何其它基团。此外，所述的连接基团也可以是化学键，其中式I化合物的低聚糖部分直接连接基团Z。
可提供低聚糖作为根据式I的多价分子(即，p＝2-1000)。在该实施例中，使用已知的技术将所述的低聚糖部分连接到多价载体上，以使制备其中一个以上的低聚糖单个分子通过基团Y用共价键连接于所述的多价载体的共轭体(conjugate)。多价载体应是足够长的以提供由2-1000(即，p＝2-1000的整数)之间，优选2-100，更优选2-50的连接于多价载体的低聚糖部分的分子留下的多价分子。
合适的多价载体是在连接基团的末端上具有多个连接部位的化合物，(该连接基团不连接还原性末端糖化物)或是在葡萄糖C1配糖的氧或N-乙酰葡萄糖胺残基上具有多个连接部位的化合物。实例包括(但不仅限于此)多元醇、多糖、聚赖氨酸、抗生物素蛋白、聚丙烯酰胺、葡聚糖、类脂、类脂乳状液、脂质体、dendrimer、人血清白蛋白、牛血清白蛋白或环糊精。
用连接基团Y连接还原性末端糖化物(即，Glc或GlcNAc)和将连接基团Y连接多价载体的所需的化学方法是众所周知的连接化学领域的方法。例如，还原性末端糖化物和Y之间的键可以通过使还原性末端糖化物C1上的醛或羧酸或经氧化反应引入到还原性末端糖化物上的醛或羧酸基与所述Y基团反应形成的，从而形成合适的键，如-NH-、-N(R’)-，其中R’是C1-20烷基。羟基烷基胺、酰胺、酯、硫酯、硫酰胺。
通过以吡喃糖形式的C1羟基与酰化剂和卤代分子反应在还原性末端糖化物和Y之间形成所述的键，接着与亲核试剂反应形成合适的键，例如-NH-、-N(R’)-，其中R’是C1-20烷基、-S-和-O-。Stowell等人在Advance in Carbohydrate Chemistry andBiochemistry[37(1980)P225+]中介绍了该类型的连接化学方法。
通过还原性末端糖化物的游离异头碳，可以将低聚糖部分直接连接(即Y是化学键)于多价载体上。另一方面，通过Smith等人在Complex Carbohydrates Part C，Methods in Enzymology[Volume L，Edby V1 Ginsburg(1978)，P169-171]中介绍的苯乙胺-异硫氰酸盐衍生物可以连接还原性末端糖化物。优选所述的式I低聚糖在水中保持可溶性。然而将式I低聚糖以适合的载体中的悬浮液形式给药也是可能的。
通过对需用药的患者给予粘合抑制有效剂量的式I低聚糖可完成抑制细菌移生的方法。用药方法取决于输送低聚糖所要求的部位。例如治疗呼吸道感染，优选以气雾剂形式，将低聚糖给药于鼻咽、肺或支气管。治疗中耳炎，优选以滴剂方式将低聚糖给药于鼻咽。治疗结膜炎，优选以像滴眼剂或眼药膏剂方式将低聚糖给药于结膜组织。
适当的组合物可以采取溶液剂、悬浮剂或适合感染部位给药(尤其是肺、支气管、鼻咽或中耳)的任何可接受用药的方式。也可以以气雾干粉末方式将低聚糖给药于肺部和支气管。
药用组合物通常是根据用药途径，使用标准组成方式，以选取适当载体的混合物形式用药。
在技术上加入惯用的任何稀释剂制备溶液剂或悬浮剂。例如，合适的稀释剂包括水〔抑菌的、无菌和/或无热原〕、乙醇、丙二醇、聚氧化乙烯、山梨糖醇和山梨糖醇酐酯。可将氯化钠、葡萄糖或甘油以适当的数量掺入该液体制剂中，以制备等渗溶液。
所述的式I低聚糖也可以与对选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和其混合物的细菌有抗菌活性的抗生素联合用药。抗生素的合适类型的实例有氨基糖甙类、amphenicols类、利福霉素类、像碳青霉烯类、头孢菌素类、头霉素类、单菌霉素类、氧头孢烯和青霉素类的β-内酰胺类、lincosamides、大环内酯类、多肽类、四环素类。2，4-二氨基嘧啶类、硝基呋喃类、喹诺酮类、氨苯磺胺类、砜类、β-内酰胺酶抑制剂和像多烯类的抗真菌类抗生素。合适的抗生素化合物的特定实例包括(但不仅限于此)：甲硝哒唑、四环素、铋、红霉素、氨苯磺胺、青霉素、头孢菌素、羟氨苄青霉素、环丝氨酸、磷霉素、万古霉素、杆菌肽、多粘菌素类、丝裂霉素、新生霉素、放线菌素、利福霉素、氯洁霉素、林可霉素、异烟肼、氟胞嘧啶、氯霉素、嘌呤霉素、褐霉酸、灰黄霉素、对氨基水杨酸、三甲氧苄二氨嘧啶、亚胺硫霉素。合适的抗生素也包括默克索引第十一版所收载的抗生素化合物，尤其是列在THER-9、THER-10和THER-13页上的，其全部内容在此结合到本发明中作为参考。与本发明低聚糖联合使用的抗生素用量大约与其已知的治疗用药量相同。因此通过常规试验可确定抗生素的有效剂量。
所述治疗的组合物也可以进一步包含常用的助溶剂，缓冲剂、解痛剂、技术防腐剂，和可任选着色剂、香味剂、调味剂、甜味剂以及在技术已知的其它可作药用的活性试剂。
所述的药用组合物的优选组成方式是提供等渗溶液。该组合物的pH优选在6-8，优选为6.8-7.7，更优选为生理pH。
一般讲，合适的患者是人类。然而本方法也适用于动物的治疗，包括(但不仅限于此)像猪类、牛类、马类、绵羊、山羊、狗类、猫类、啮齿动物和非人的灵长目动物。
根据本发明的优选实施例，含有低聚糖的药用组合物以气雾剂给药于所需要治疗的患者，以抑制粘合或消除来自病人的喉、结膜、肺或支气管道的选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌和其混合物细菌的移生。
对于气雾剂给药而言，优选以良好的分散形式与表面活性剂和抛射剂一道提供式I低聚糖化合物。所述的式I低聚糖的一般用量大约是0.5-30％(重量)，优选为1-10％(重量)。所述的表面活性剂应是无毒并优选溶于抛射剂中。该表面活性剂的代表性试剂是含有6-22个碳原子的脂肪酸(如己酸、辛酸、十二酸、十六酸、十八酸、亚油酸、亚麻酸、olesteric和油酸)与脂族多元醇或它的环酐(例如像乙二醇、甘油、赤藓醇、阿糖醇、甘露醇、山梨糖醇、由山梨糖醇衍生的己糖醇酐)形成的酯或部分酯化物，和这些酯化物的聚氧化乙烯和聚氧化丙烯衍生物。可以使用像混合的或天然甘油酯的混合酯。所述的表面活性剂占组合物的约0.1-约20％(重量)，优选为约0.25-约5％。
组合物的配物一般是抛射剂。液态的抛射剂一般在常态下为气体，在压力下凝聚成液态。合适的液态抛射剂一般是含多至5个碳原子的较低级烷烃如丁烷和丙烷；和优选像R-11的氟化的或氟氯化的烷烃。也可以使用上述的混合物。在制备气雾剂中，配有适当气阀的容器充有包含分散的化合物和表面活性剂的适当抛射剂。将该组分保持在高压下直到经阀门的作用而释放。
就作为气雾剂给药而言，通过对于药物传递领域的普通技术人员熟知的常用的方法，制备该气雾剂。
当以单价形式的气雾剂给药治疗呼吸道感染时，组成的组合物提供的粘液膜中浓度为0.0001-20mg/ml，优选0.01-10mg/ml。
当作为多价分子用药治疗呼吸道感染时，用含有式I低聚糖的药用组合物的气雾剂给药以达到粘液膜中浓度为0.00001-2mg/ml，优选0.001-1mg/ml。
根据本发明的另一实施例，经鼻咽对需要治疗病人的耳部给予含低聚糖的药用组合物，以便抑制粘合，或消除来自病人中耳的选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和其混合物的细菌的移生。需要治疗的患者一般诊断为中耳炎。
该给药模式就是对感染部位给予粘合抑制有效剂量的式I低聚糖。最一般的方式为将含有式I的低聚糖的滴鼻剂或喷雾剂经鼻咽对耳部给药。式I低聚糖也可以以口腔洗液的形式给药，其中所述的低聚糖通过嗽口和反复洗嗽的作用对感染部位用药。
当对耳部用药时，合适的方式是用无毒可药用的稀释剂或溶剂制备成液体溶液剂或悬浮剂，例如像在1，3-丁二醇中的溶液剂。可使用作为载体和溶剂的是水、Ringer’s溶液和氯化钠等渗溶液。此外，通常使用无菌非挥发油作为溶剂或悬浮介质。为此，可使用任何温和的非挥发性油，包括合成的单或双甘油酯。此外，在可注射的制剂中可较好地使用像油酸的脂肪酸。
当以单价形式对耳部给药治疗中耳炎时，所组成的组合物在感染部位提供的浓度为0.0001-20mg/ml，优选0.01-10mg/ml。
当以多价分子用药治疗中耳炎时，所组成的组合物在感染部位提供的浓度为0.00001-2mg/ml，优选0.001-1mg/ml。
根据本发明的另一实施例，对需要治疗的病人眼部给予含低聚糖的药用组合物，以抑制粘合或消除来自病人眼部的选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋菌假单胞菌和其混合物的细菌的移生。需要治疗的患者一般诊断为结膜炎。
当对眼部用药时，合适的形式是用无毒可药用的稀释剂或溶剂制备成的液体溶液剂或悬浮液剂，例如像眼用盐溶液。
当以单价形式对眼部用药治疗结膜炎时，所组成的组合物在感染部位提供的浓度为0.0001-20mg/ml，优选0.01-10mg/ml。
当以多价分子的用药治疗结膜炎时，所组成的组合物在感染部位提供的浓度为0.00001-2mg/ml，优选0.001-1mg/ml。
通过至少一日一次给药达到上述剂量，优选一日两次，更优选一日三次和最优选一日四次给药。
本发明也可用于在需要的患者身上预防肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌的细菌感染。尽管在所有对细菌感染无症状的病人身上防止细菌感染一般是合乎需要的，然而有特定的人群，对其而言，细菌感染结果能产生不可接受的细菌感染的风险。特别对于儿童、老年人或免疫受损的人的细菌感染结果尤其严重。因此，可以将式I低聚糖以足够预防细菌感染的剂量给药于需要预防选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌的细菌感染的病人。
为预防呼吸道的细菌感染，一般以单价形式给予式I低聚糖以提供粘液膜中的浓度为0.0001-20mg/ml，优选0.01-10mg/ml。至少一日一次，优选一日两次用药，以达到预防剂量。
当为预防呼吸道感染，以多价分子用药时，给予含有式I低聚糖的气雾剂药用组合物，以达到粘液膜中浓度为0.00001-2mg/ml，优选0.001-1mg/ml。
当为预防中耳炎，经鼻咽对耳部给药时，以单价形式组成的组合物提供在耳膜中的浓度为0.0001-20mg/ml，优选0.01-10mg/ml。
当为预防中耳炎，以多价分子形式经鼻咽对耳部给药时，包括式I低聚糖的治疗中耳炎的用药在耳膜中的浓度达0.00001-2mg/ml，优选0.001-1mg/ml。
用于抑制细菌感染的本发明药用组合物的组成基本上如上所述。式I低聚糖的量将根据用药的方式而变化，基于将粘合抑制的有效量传递到感染部位所必需的用量。总而言之，所述药物含低聚糖的浓度在单价形式时为约0.01-2000mg/ml，优选1-1000mg/ml，而在多价形式时为约0.001-200mg/ml，优选0.1-100mg/ml。
本发明的其它特征将在下面描述实施例过程中表现出来，对发明给予说明且并不限于其实施例。
在全部实施例中使用下列缩写：LSTc：NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcLNnT：Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcLSTd (3′LSTc)：NeuAcα2-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcGalNAcβ1-3 LNnT：GalNAcβ1-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc
HSA：人血清白蛋白实施例1NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc的合成
使乳糖与UDP-N-乙酰葡萄糖胺和β-半乳糖甙β1-3N-乙酰葡萄糖胺基转移酶(在37℃，在0.1M HEPS缓冲水溶液中从猪血清提取而得)接触。然后，使所得三糖产物与UDP-Gal和β-N-乙酰葡萄糖氨基甙β1-4半乳糖基转移酶(在37℃，在0.1M HEPS缓冲水溶液中从牛奶中分离而得)接触。然后，使所得的四糖产物与CMP-NAN和β-半乳糖甙α2-6唾液酰基转移酶(在37℃，在0.1M HEPES缓冲水溶液中从鼠肝分离而得)接触。用常规方法分离得到的目的五糖产品。实施例2
使用类似Rostand，K，和Esko，[(1993)J.Biol.Chem.268pp24053-3，]研究对CHO细胞放射性同性素标记绿脓杆菌的粘合方法的类似方法，试验低聚糖化合物的粘合抑制作用。对在此所述的研究而言，是在含有3H-赖氨酸的赖氨酸缺乏tryptic大豆液体培养基中培养标记肺炎双球菌(菌株R-6、P70和其它临床呼吸道分离菌株)。用来自大肠杆菌的赖氨酸脱羧酶预处理tryptic大豆液体培养基则得到赖氨酸缺乏型的该液体培养基，培养所述细菌4-5小时，此时培养物成指数增长。收集并在补充0.2％低内毒素的牛血清白蛋白Leibovitz L-15培养基中冲洗所述细菌。将该菌稀释至约3×108/ml，然后与L-15-BSA或与待试验的各种化合物以1∶1混合。将该细菌混合物置摇瓶机上轻微摇动进行室温培养。10-15分钟后，将细菌混合物的样品转移到96-穴的聚苯乙烯平板中的融合单层的培养上皮细胞表面上。最常用的细胞是Chang结膜的Wong-Kilbourne衍生物。也使用人鼻咽细胞系Detroit 562，和人肺细胞系A549。在室温轻摇下用所述细胞培养细菌30分钟。用含有0.2％的牛血清白蛋白的PBS洗去未粘合的细菌。往各穴中加入闪烁体溶液，和将该平板置于微片闪烁计数器中测定粘合细菌的数量。
用相同方法进行流感嗜血杆菌对上皮细胞粘连操作，其改动之处为：所述的细菌在赖氨酸缺乏的嗜血杆菌试验培养基上培养过夜。在近107/ml的浓度下用所述细胞培养细菌60分钟。
IC50(mM)LSTc
LSTc-HSA3
Det-562和FaDu：鼻咽癌CaLu-3和A4591：肺癌10lung：鼠气管初级上皮HUVEC2：人脐静脉内皮细胞1用IL1α激活细胞2用TNFα或凝血酶激活细胞3LSTc粘合人血清白蛋白主链；低聚糖：prot的摩尔比＝20∶1。给定低聚糖的摩尔浓度。抑制肺炎双球菌对呼吸道上皮细胞的粘连
| 细菌 | Det-562 | FaDu | CaLu-3 | 1°lung | A549 | HUVEC | CHANG |
| 肺炎双球菌 | 5.4 | 4.0 | 4.4 | 0.4 | 0.1 | 0.1 | 1.5 |
| 洋葱假单胞菌 | 1 |
| 细菌 | Det-562 | FaDu | CaLu-3 | 1°lung | A549 | HUVEC |
| 肺炎双球菌 | 0.10 | 0.0004 | ||||
| 流感嗜血杆菌 | 0.03 |
IC50(mM)
[均值(SD)]
单价
多价4
1. Detroit-562和FaDu：人鼻咽癌GaLu-3和A549：人肺癌HUVEC：人脐静脉内皮细胞(初级)鼠气管上皮单层(初级)Chang：人结膜癌2.用IL1α激活3.用TNFα或凝血酶激活4.人血清白蛋白主链：低聚糖：port的摩尔比＝20∶1。给定低聚糖的摩尔浓度。实施例3LSTc和LNnT的体内试验兔子将肺炎双球菌株AII与低聚糖混合，并用气管滴注法给予新西兰白兔，用Saukkonen等人(1991，J.Exp.Med，173：1143-9)所介绍的方法在指示时间计数肺洗出菌落数。在粘连抑制剂低聚糖的存在下兔肺的肺炎双球菌的移生
| 细胞系1 | |||||||
| Det-562 | FaDu | CaLu-3 | 1°1ung | A5492 | HUVEC3 | Chang | |
| LNnT | 7.0 | ＞16.0 | 0.095(0.005) | 0.052(0.022) | 8.0 | ||
| LSTc | 4.0 | 4.5 | 4.4 | 0.25 | 0.069(0.032) | 0.069(0.035) | 1.4 |
| LSTd(3′LSTc) | 0.095(0.005) | 0.090 | 0.6 | ||||
| GalNAcβ1-3LNnT | 0.080 | 0.075 | |||||
| GalNAcβ1-3Galβ1-4Glc | 0.085 | 0.070 | ＞6.0 | ||||
| 细胞系1 | ||||||
| Det-562 | FaDu | CaLu-3 | 1°lung | A5492 | HUVEC3 | |
| LNnT | ＞0.500 | 0.100 | 0.030(0.020) | |||
| LSTc | 0.125 | 0.160 | 0.110 | 0.250 | 0.021(0.006) | 0.023(0.012) |
| GalNAcβ1-3Gal-HSA | 0.500 | 0.020 | 0.100 | 0.0004 | 0.100 | 0.087(0.018) |
| CFU* | ||||
| 试验条件 | LSTc(100μM) | LNnT(100μM) | 对照(盐) | |
| 1 | 接种物：5×105细菌；气管内的；24小时灌洗 | 1.4×1059.1×103＇ | 8.7×1024.7×103＇ | 7.5×1067.1×105＇ |
| 4日灌洗 | ＜10，＜10 | ＜10，＜10 | 1.6×1044.5×103＇ | |
| 2 | 接种物：5×105细菌气管内的4日灌洗 | 0，0 | 0，0 | 1.6×1044.5×103＇ |
| 3 | 接种物：5×107细菌**气管内的；24小时灌洗 | 0，0 | 0，0 | 3.1×1052.2×104＇ |
| 4 | 接种物：105细菌；气管内的；24小时灌洗 | 1.1×1031.4×103 | 1.4×1051.4×105＇ | |
*在第四天洗肺和将洗液定量涂在血琼脂上以便计数每毫升洗液中的细菌菌落。2只兔为一组。
**给予该高的接种物的盐水对照动物病得非常严重，肺部具有大量移生菌。一只兔子患菌血症(104CFU/ml血)。经低聚糖治疗的动物在整个试验中均为健康。实施例4用使粘连逆转的低聚糖治疗兔肺炎双球菌的预移生
用气管滴注法将肺炎双球菌株AII给予新西兰白兔。24小时所有兔子生病并伴有肺炎症状。24小时后，通过气管内给予低聚糖(LNnT)或对照物(盐水)。再过24小时后，按实施例3所述计数洗肺菌落数。
在48小时，LNnT处理的兔子是健康的，反之盐水处理的对照兔子生病伴有肺出血、充血。实施例5鼠将新生Sprague-Dawley鼠鼻内接种20μl盐水中的106肺炎双球菌株SIII。在指示时间灌洗鼻腔，经连续稀释，涂于血琼脂上，测定菌落数。在粘连抑制剂低聚糖的存在下鼠鼻咽的肺炎双球菌的移生
*在指示时间，灌洗鼻腔并测定每毫升洗液中的CFU数目。实施例6
| CFU | ||
| 试验条件 | LNnT(100μM) | 对照(盐水) |
| 接种物：105细菌低聚糖处理24小时后和细菌滴注48小时后气管内灌洗 | 0，0 | 5.4×103，4.8×103 |
| CFU* | ||||
| 试验条件 | LSTc-HSA(100μM) | LNnT-HSA(100μM) | 对照(盐水) | |
| 1 | 接种物：106细菌；鼻内的；4只鼠/组；3小时洗鼻 | 4.1(±1.0)×104 | 3.5(±0.4)×104 | 8.8(±0.8)×106 |
| 7日洗鼻 | 3±1 | 6±1 | 268±62 | |
| 2 | 接种物：106细菌；鼻内的；8只鼠/组；5.5小时灌洗 | 4.1(±0.8)×104 | 3.7(±0.9)×104 | 8.3(±0.8)×104 |
使用实施例2中介绍的试验方法，用不同的低聚物化合物试验四株细菌的粘连抑制。抑制其它致病菌对呼吸道上皮细胞的粘连
IC50(mM)
[均值(SD)]
*试验的最高浓度为10-15mM的单价低聚糖和0.2-0.25mM的多价低聚糖，给定其碳水化合物的摩尔浓度。实施例7
| 细菌 | 流感嗜血杆菌(菌株46519) | 流感嗜血杆菌(菌株39689) | 副流感嗜血杆菌(菌株44241) | 洋葱假单胞菌 |
| 细胞 | Chang | Chang | DET-562 | Calu3 |
| LNnT | ＞14.0 | ＞14.0 | 5.6 | |
| LSTc | ＞10.0 | 1 | ||
| calNAcβ1-3LNnT | 7.8(2.9) | ＞10.0 | ||
| GalNAcβ1-3Galβ1-4Glc | 4.2(5.3) | 10.6(7.7) | ||
| LNnT-HSA | ＞0.2 | ＞0.2 | 0.10 | |
| LSTc-HSA | ＞0.2 | 0.03 | ||
| GalNAcβ1-3Gal-BSA | 0.25 |
将含有500mg的NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc、100ml无菌水和10ml的丙二醇的10ml等渗药用组合物以气雾剂形式给药于诊断患有肺炎的病人。一日治疗三次，每隔8小时给药一次直至细菌感染已消除为止。实施例8
将含有1000mg的NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc和100ml的1，3-丁二醇的5滴药用组合物以滴鼻剂或鼻喷雾剂形式给药于诊断患中耳炎病人的鼻咽中。一日治疗两次，每12小时给药一次，直至已消除细菌感染为止。实施例9
将含有800mg的NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc和100ml的等渗盐溶液的5滴滴眼溶液以滴眼剂的形式给药于诊断患有结膜炎的病人眼中。一日治疗4次，每隔6小时给药一次，直至已消除细菌感染为止。实施例10
将含有500mg的GalNAcβ1-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc、100ml的无菌水和100ml丙二醇的10ml的等渗药用组合物以气雾剂形式给药于诊断患有肺炎的病人。一日治疗三次，每隔8小时给药一次，直至已消除细菌感染为止。实施例11
将含有500mg的NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc、100ml的无菌水和10ml丙二醇的10ml的等渗药用组合物以气雾剂形式给药于诊断患有肺炎的病人。一日治疗三次，每隔8小时给药一次，直至已消除细菌感染为止。实施例12
将含有200mg的NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc-HSA(20∶1的低聚糖：prot的比例)、100ml的无菌水和10ml的丙二醇的10ml的等渗药用组合物以气雾剂形式给药于诊断患有肺炎的病人。一日治疗三次，每隔12小时给药一次，直至已消除细菌感染为止。
显然，按照上述的技术有可能对本发明做修改和改动。因此，在附带的权利要求范畴之内，除在此特别描述的方法之外实施本发明是可以理解的。
Claims (11)
1.通过给予粘合抑制有效量的式I化合物，抑制选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和其混合物的细菌移生的方法，
其中
R1是H，(β-1)GalNAc-，SO3B(其中B是H或阳离子)，或式II的唾液酸；
其中
R6、R7、R8和R10各自独立为H、C1-6酰基、乳酰基、C1-6烷基、硫酸酯、磷酸酯、脱水、式II的唾液酸、(α-1)Fuc、(β-1)Glc或(β-1)Gal；
R9是NH-C1-6酰基、乙醇酰胺基、氨基或羟基；和
A是H或阳离子；
R2是H或(α-1)Fuc-；
R3和R4各自独立为OH或NHAc；
R5是H、SO3B(其中B是H或阳离子)或同上述定义的式II的唾液酸；和
Y是化学键或是连接基团；
Z是H或多价载体；
m是0或1；和
p是1-1000的整数。
2.权利要求1的方法，其中所述的患者受选自肺炎双球菌、流感嗜血杆菌、副流感嗜血杆菌、洋葱假单胞菌和其混合物的细菌感染。
3.权利要求2的方法，其中所述的患者患有支气管炎。
4.权利要求2的方法，其中所述的患者患有肺炎。
5.权利要求1的方法，其中所述的患者患有中耳炎。
6.权利要求1的方法，其中所述的式I化合物选自NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-Galβ1-4-GlcNAc，NeuAcα2-6-Galβ1-4-[Fucα1-3]GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-[Fucα1-3]GlcNAc，GalNAcβ1-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，GalNAcβ1-3-Galβ1-4-GlcNAc，GalNAcβ1-3-Galβ1-4-Glc，NeuAcα2-3-Galβ1-4-GlcNAc，NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-6-Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-GlcNAc，GalNAcβ1-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，GalNAcβ1-3-Galβ1-4-GlcNAc，和其混合物。
7.权利要求1的方法，其中所述的式I化合物具有下式：
其中
Y是化学键或是连接基团；
Z是H或多价载体；和
p是1-1000的整数。
8.权利要求7的方法，其中Y是化学键，Z是H和p是1。
9.通过给予粘合抑制有效量的式I化合物，抑制选自肺炎双球菌、流感嗜血杆菌，副流感嗜血杆菌、洋葱假单胞菌和其混合物的细菌移生的药用组合物，其中
R1是H，(β-1)GalNAc-，SO3B(其中B是H或阳离子)，或式II唾液酸；
其中
R6、R7、R8和R10各自独立为H、C1-6酰基、乳酰基、C1-6烷基、硫酸酯、磷酸酯、脱水、式II的唾液酸、(α-1)Fuc、(β-1)Glc或(β-1)Gal；
R9是NH-C1-6酰基、乙醇酰胺基、氨基或羟基；和
A是H或阳离子；
R2是H或(α-1)Fuc-；
R3和R4各自独立为OH或NHAc；
R5是H、SO3B(其中B是H或阳离子)或同上述定义的式II的唾液酸；和
Y是化学键或连接基团；
Z是H或多价载体；
m是0或1；和
p是1-1000的整数。
其中当R5是H时，R1不是H和当R1是唾液酸时，R2不是(α-)Fuc。
10.权利要求9的组合物，其中所述的式I化合物选自NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-Glc，NeuAcα2-6-Galβ1-4-GlcNAc，NeuAcα2-6-Galβ1-4-[Fucα1-3]GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-[Fucα1-3]GlcNAc，GalNAcβ1-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-Glc，GalNAcβ1-3-Galβ1-4-GlcNAc，GalNAcβ1-3-Galβ1-4-Glc，NeuAcα2-3-Galβ1-4-GlcNAc，NeuAcα2-6-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-6-Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，NeuAcα2-6-[GalNAcβ1-3]Galβ1-4-[Fucα1-3]GlcNAcβ1-3-Galβ1-4-GlcNAc，GalNAcβ1-3-Galβ1-4-GlcNAcβ1-3-Galβ1-4-GlcNAc，GalNAcβ1-3-Galβ1-4-GlcNAc，和其混合物。
11.权利要求9的药用组合物，其中所述的组合物是像气雾剂的合适给药形式。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/488,053 US5736533A (en) | 1995-06-07 | 1995-06-07 | Bacterial inhibition with an oligosaccharide compound |
| US08/488,053 | 1995-06-07 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1192687A true CN1192687A (zh) | 1998-09-09 |
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ID=23938149
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN96196047A Pending CN1192687A (zh) | 1995-06-07 | 1996-06-03 | 低聚糖化合物的细菌抑制 |
Country Status (11)
| Country | Link |
|---|---|
| US (2) | US5736533A (zh) |
| EP (1) | EP0839042A4 (zh) |
| JP (1) | JPH11507043A (zh) |
| KR (1) | KR19990022658A (zh) |
| CN (1) | CN1192687A (zh) |
| AU (1) | AU710078B2 (zh) |
| CA (1) | CA2224102A1 (zh) |
| HU (1) | HUP9901150A3 (zh) |
| IL (1) | IL122406A0 (zh) |
| NZ (1) | NZ308961A (zh) |
| WO (1) | WO1996040169A1 (zh) |
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| CN109414447A (zh) * | 2016-06-24 | 2019-03-01 | 格礼卡姆股份公司 | 包括hmo的组合物、其制备和用于预防和/或治疗病毒和/或细菌感染的用途 |
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-
1995
- 1995-06-07 US US08/488,053 patent/US5736533A/en not_active Expired - Fee Related
-
1996
- 1996-06-03 HU HU9901150A patent/HUP9901150A3/hu unknown
- 1996-06-03 IL IL12240696A patent/IL122406A0/xx not_active IP Right Cessation
- 1996-06-03 NZ NZ308961A patent/NZ308961A/en unknown
- 1996-06-03 WO PCT/US1996/008333 patent/WO1996040169A1/en not_active Application Discontinuation
- 1996-06-03 CA CA002224102A patent/CA2224102A1/en not_active Abandoned
- 1996-06-03 EP EP96920613A patent/EP0839042A4/en not_active Withdrawn
- 1996-06-03 KR KR1019970710021A patent/KR19990022658A/ko not_active Application Discontinuation
- 1996-06-03 AU AU58865/96A patent/AU710078B2/en not_active Ceased
- 1996-06-03 JP JP9500967A patent/JPH11507043A/ja active Pending
- 1996-06-03 CN CN96196047A patent/CN1192687A/zh active Pending
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1998
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109414447A (zh) * | 2016-06-24 | 2019-03-01 | 格礼卡姆股份公司 | 包括hmo的组合物、其制备和用于预防和/或治疗病毒和/或细菌感染的用途 |
Also Published As
| Publication number | Publication date |
|---|---|
| AU710078B2 (en) | 1999-09-16 |
| WO1996040169A1 (en) | 1996-12-19 |
| MX9709503A (es) | 1998-10-31 |
| US5736533A (en) | 1998-04-07 |
| EP0839042A1 (en) | 1998-05-06 |
| KR19990022658A (ko) | 1999-03-25 |
| HUP9901150A2 (hu) | 1999-08-30 |
| NZ308961A (en) | 1999-10-28 |
| IL122406A0 (en) | 1998-06-15 |
| EP0839042A4 (en) | 1999-04-07 |
| JPH11507043A (ja) | 1999-06-22 |
| US6001819A (en) | 1999-12-14 |
| CA2224102A1 (en) | 1996-12-19 |
| HUP9901150A3 (en) | 2001-11-28 |
| AU5886596A (en) | 1996-12-30 |
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