CN1227491A - 用尿苷三磷酸及相关化合物治疗窦炎的方法 - Google Patents

用尿苷三磷酸及相关化合物治疗窦炎的方法 Download PDF

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CN1227491A
CN1227491A CN97197135A CN97197135A CN1227491A CN 1227491 A CN1227491 A CN 1227491A CN 97197135 A CN97197135 A CN 97197135A CN 97197135 A CN97197135 A CN 97197135A CN 1227491 A CN1227491 A CN 1227491A
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K·雅各布斯
J·赖德奥特
B·耶克萨
W·彭德格斯特
S·西迪基
D·J·德鲁茨
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Abstract

本发明是一种用选自UTP、ATP、CTP或它们的衍生物的核苷磷酸或用腺苷或尿苷的二核苷四磷酸来治疗窦炎的方法。

Description

用尿苷三磷酸及相关化合物治疗窦炎的方法
技术领域
本发明涉及一种通过施用某些尿苷三磷酸、腺苷三磷酸或胞苷三磷酸来消除或防止来自患者窦道的滞留的粘液样分泌物积聚的方法。
发明背景
窦炎是一种通常与上呼吸道感染有关的鼻窦炎症。窦炎是美国最常见的影响着估计为3千1百万人的卫生保健方面的疾病。(A.Moss和V.Parsons,NationalCenter for Health Statistics,1986:66-7.DHHS Publication No.(PHS)86-1588(1985))。其他较少见的原因包括变态反应、空气污染、潜水、在水下游泳和鼻结构缺陷(鼻隔异常)和牙科治疗的并发症。窦炎常见的并发症是由于紧靠着窦部和耳咽管而产生的相关中耳感染(中耳炎)。(M.Revonta和A.Blokmanis,Can.Fam.Physician 40,1969-72,1975-76(1994))。此外，大多数原发性纤毛运动障碍症患者会遇到慢性或周期性窦炎。
随着窦炎的发展，来自窦部的粘液集聚在窦道内。粘液的这种堵塞促成了该病症常见的头痛、疼痛、发热和呼吸困难。常见的症状是头痛、前额和面部窦区域触痛或不适、流鼻涕、体温微升和全身不适。
目前，通用的窦炎治疗包括用于防治感染的抗生素、缓解充血的抗组胺药/减充血药(通常是喷鼻剂或滴鼻剂)或生理盐水喷鼻剂、粘液溶解剂，吸入蒸气，在窦区域施加温压，使用缓解不适的止痛药和消炎药。(D.Kennedy,Otolaryngol.Head Neck Surg.103,845-46(1990))。此外，应减少或避免暴露于环境刺激物(如污染、烟尘和灰尘)。若窦炎变成慢性，则可考虑用外科手术扩大窦道和导液。
另一个处于窦炎发病危险的患者人群是插入了鼻腔导气管的患者。(J.Reuler,West.J.Med.163(1),40-8(1995))。鼻腔导气管刺激鼻咽通气道的衬层，由于紧靠窦部，鼻咽通气道中存在大量的微生物，可导致严重的窦炎。目前的治疗方法仍与前述方法相似，包括使用抗生素和止痛药、施加温压、外科方法导液，但还需要除去鼻腔导气管和通过气管切开术(或者，在较少的情况下，通过口咽通道)重新插管。该类窦炎的症状是严重不适和窦区域触痛、来自鼻窦气道的排泄增加、发热和潜在性的其他更严重的感染和并发症。
如美国专利No.5,292,498所述，尿苷三磷酸(UTP)和腺苷三磷酸(ATP)已被证明可影响人通气道上皮细胞的离子输送活性。具体地说，UTP和ATP诱导囊肿性纤维化患者的肺上皮细胞中氯化物和水的分泌，帮助作为该病特征的高粘度状态的通气道表面粘液的液化和促进其输送。此外还发现，UTP和ATP刺激肺上皮细胞中纤毛的拍动(beat)频率，此外，还促进囊肿性纤维化患者、肺炎患者或正常人的肺分泌出来的粘液的输送。(R.Boucher等，Adenosine andAdenine Nucleotides:Fron Molecular Biology to Integrative Physiology,p.525-32,标题为“尿苷三磷酸在肺中的机制和治疗作用”，L.Belardinelli等编，AlunmwerAcademic Publishers出版，波士顿，1995)；(L.Gheber等，J.Membrane Biol.147,83-93,(1995))。法国一生物技术公司(SYNTHELABO FRANCE实验室)已开发出一种用尿苷三磷酸(ATP)作为活性化合物治疗鼻腔粘液状流体充塞的方法，该方法的商标名称是rhinATPTM。名称为rhinATPTM的该技术是以美国专利No.5,420,116的名义取得特许的(申请人意将该专利及在该专利中引用的其他所有专利文献和出版物所公开的内容并入此处供参考)。他们的治疗方法包括以喷鼻剂或滴鼻剂的形式对鼻腔施用ATP。
本申请人已发现，在流体阻塞部位施用UTP及其相关化合物和其他核苷磷酸〔如P1,P4-二(尿苷-5′)四磷酸(U2P4)、腺苷5′-三磷酸(ATP)、胞苷5′-三磷酸(CTP)、1,N6-亚乙烯基腺苷5′-三磷酸、1-氧化-腺苷5′-三磷酸、3,N4-亚乙烯基胞苷5′-三磷酸或P1,P4-二(腺苷-5′)四磷酸(A2P4)〕可更容易地清除窦炎患者阻滞的粘液状流体。UTP和U2P4是本发明的较佳实例。在症状首次出现不久即施用UTP或U2P4，可避免窦部全面阻塞及由此产生的症状。
发明概要
本发明公开了一种需要这种治疗的患者的窦炎治疗方法。该方法包括对患者施用有效量的式Ⅰ的化合物或其药用盐以使粘液状分泌物水合并刺激窦道腔上皮细胞中纤毛的拍动频率：
                            式Ⅰ
Figure A9719713500061
式中：
X1、X2和X3各独立地是O-或S-。较佳地，X2和X3是O-。
R1是O、亚氨基、亚甲基或二卤代亚甲基(如二氯亚甲基、二氟亚甲基)。较佳地，R1是是氧或二氟亚甲基。
R2是H或Br。较佳地，R2是H。尤其优选的式Ⅰ化合物是尿苷5′-三磷酸(UTP)和尿苷5′-O-(3-硫代三磷酸)〔UTPγS〕。
除了式Ⅰ之外，式Ⅱ即P1,P4-二(尿苷-5′)四磷酸〔U2P4〕也是本发明的较佳实例。式Ⅱ的另一个化合物是P1,P4-二(腺苷-5′)四磷酸〔A2P4〕。本发明的方法也可包括施用式Ⅲ化合物(腺苷5′-三磷酸〔ATP〕或1,N6-亚乙烯基腺苷5′-三磷酸或1-氧化-腺苷5′-三磷酸)或式Ⅳ化合物(胞苷5′-三磷酸〔CTP〕或3,N4-亚乙烯基胞苷5′-三磷酸)。
                               式Ⅱ
Figure A9719713500071
式中：
B是尿嘧啶或腺嘌呤，其连接方式如式Ⅰ和Ⅲ中所示。
                              式Ⅲ式中：
R1、X1、X2和X3的定义如式Ⅰ中所示。
R3和R4是H，而R2不存在，N-1与C-6之间有一个双键(腺嘌呤)，或者
R3、R4和R2一起为-CH=CH-，与N-6与C-6之间的双键一起形成一个从N-6到N-1的环(1,N6-亚乙烯基腺苷)。                           式Ⅳ
Figure A9719713500081
式中：
R1、X1、X2和X3的定义如式Ⅰ中所示。
R5和R6是H，而R7不存在，N-3和C-4之间有一个双键(胞苷)，或者
R5、R6和R7一起为-CH=CH-，与N-4与C-4之间的双键一起形成一个从N-3到N-4的环(3,N4-亚乙烯基胞苷)。
本发明的第二方面是含有有效量的式Ⅰ、Ⅱ、Ⅲ或Ⅳ的化合物的药物制剂，该制剂可在需要这种治疗的患者体内使粘液状分泌物水合并刺激窦道腔上皮细胞中纤毛的拍动频率。
本发明的第三方面是用此处公开的活性化合物来生产这样一种药物，该药物能治疗性地使粘液状分泌物水合并刺激需要这种治疗的患者窦道腔上皮细胞中纤毛的拍动频率。
具体实施方式的描述
本发明的方法可用来使阻滞的粘液状分泌物水合并刺激需要这种治疗的患者窦部中纤毛的拍动频率。本发明通过以下三个途径改善了粘液纤毛的清除率：(1)提高腔上皮细胞表面的纤毛拍动频率；(2)增加杯状细胞的粘蛋白分泌，(3)增加了腔上皮细胞的氯离子分泌，其结果是，向周边纤毛液体层中增加水的分泌。此外，体外数据提示，UTP增加了来自Ⅱ型aveolar细胞的表面活性剂磷脂的生成和分泌。(L.Gobran等，Am.J.Physiol.267,L625-L633(1994))。由杯状细胞分泌的粘蛋白在纤毛上面形成一个层，捕捉包括病毒和细胞在内的外来颗粒；粘蛋白层由纤毛的波状运动给药；纤毛周围的周边纤毛液体层的水合可促进纤毛运动。
本发明主要涉及病人的治疗，但也可用于兽医目的，用来治疗其他哺乳类动物，如狗和猫。
上述式Ⅰ化合物的例子包括：(a)尿苷5′-三磷酸(UTP)；(b)尿苷5′-O-(3-硫代三磷酸)(UTPγS)；和(c)5-溴-尿苷5′-三磷酸(5-BrUTP)。这些化合物是已知的，或可用已知的方法或对于该领域技术人员是显而易见的改进的方法制得。通常可参见N.Cusack和S.Hourani,Annals N.Y.Acad.Sci.,603,172-81，标题为“细胞外ATP的生物作用”。例如，UTP可用Kenner等在J.Chem.Soc.1954,2288中描述的方法或Hall和Khorana在J.Am.Chem.Soc.76,5056(1954)中描述的方法来制得。参见Merck Index,Monograph No.9795(第11版，1989)。UTPγS可用S.Goody和F.Eckstein在J.Am.Chem.Soc.93,6252(1971)中描述的方法制得。
为简便起见，此处式Ⅰ-Ⅳ举例说明了天然存在的D-构型的活性化合物，但本发明也包括L-构型的化合物，以及D-和L-构型的化合物的混合物，除非另有说明。优选天然存在的D-构型。
式Ⅱ化合物的例子包括(P1,P4-二(腺苷-5′)四磷酸(A2P4)或P1,P4-二(尿苷-5′)四磷酸(U2P4))。这些化合物可根据已知的方法或P.Zamecnik等在Proc.Natl.Acad.Sci.USA 89,838-42(1981)和K.Ng和L.E.Orgel在NucleicAcids Res.15(8),3572-80(1987)中描述的改进方法制得。U2P4可用与C.Vallejo等在Biochem.Biophys.Acta 438,304-09(1976)中描述的类似的方法制得。
上述式Ⅲ化合物的例子包括(a)腺苷5′-三磷酸(ATP)和(b)1,N6-亚乙烯基腺苷5′-三磷酸。上述式Ⅳ化合物的例子包括(a)胞苷5′-三磷酸和(b)3,N4-亚乙烯基胞苷5′-三磷酸。这些化合物可根据已知的方法或对于本领域技术人员是显而易见的改进方法来制得。例如，核苷的磷酸化可用标准方法进行，这些方法例如可参见D.Hoard和D.Ott,J.Am.Chem.Soc.87,1785-1788(1965)；M.Yoshikawa等，Tetrahedron Lett.5065-68(1967)和Bull.Chem.Soc.(Jpn)42,3505-08(1969)；J.Moffatt和H.Khorana,J.Am.Chem.Soc.,83,649-59(1961)；和B.Fisher等，J.Med.Chem.36,3937-46(1993)和其中的参考文献。胞苷和腺苷的亚乙烯基衍生物可用已知的方法制得，这些方法例如可参见N.Kotchetkov等，Tetrahedron Lett.1993(1971)；J.Barrio等，Biochem.Biophys.Res.Commun.46,597(1972)；J.Secrist等，Biochemistry 11,3499(1972)；J.Bierndt等，Nucleic Acids Res.5,789(1978)；K.Koyasuga-Mikado等，Chem.Pharm.Bull.(Tokyo)28,932(1980)。具有α-、β-和γ-硫代亚磷酸基团的衍生物可用下列文献中所述的方法或对这些方法加以改进而制得：J.Ludwig和F.Eckstein,J.Org.Chem.54,631-35(1989)；R.Goody和F.Eckstein,Biochemmistry 15,1685(1976)；F.Eckstein和R.Goody,J.Am.Chem.Soc.,93,6252(1971)。
R1为CCl2和CF2的式Ⅰ、Ⅲ或Ⅳ化合物可用类似于G.Blackburn等在J.Chem.Soc.Perkin Trans.I.1119-25(1984)中所述的方法进行制备。R1为CH2的式Ⅰ、Ⅱ、Ⅲ化合物可用类似于T.Myers等在J.Am.Chem.Soc.85,3292-95(1963)中所述的方法进行制备。
此外，UTP、ATP、CTP、A2P4、3,N4-亚乙烯基胞苷三磷酸、1,N6-亚乙烯基腺苷5′-三磷酸、1-氧化腺苷5′-三磷酸、ATPγS、ATPβS、ATPαS、AMPPCH2P、AMPPNHP、N4-亚乙烯基胞苷和1,N6-亚乙烯基腺苷市场上有售，例如可从Sigma Chemical公司(PO Box 14058,St.Louis,MO63178)购得。
式Ⅰ-Ⅳ的活性化合物可直接或以其药用盐的形式〔如碱金属盐(如钠盐、钾盐)、碱土金属盐或铵盐和四烷基铵盐(N+X4,X是C1-4)。药用盐保留了母体化合物的所需生物活性，且不会产生不良的毒理作用。
此处公开的化合物可通过各种合适的方式施用于肺、窦、耳或眼，但较好的施用方法是，施用含活性化合物的液/液悬浮液(患者吸入的可适于呼吸的颗粒的喷鼻剂、或液体配方的滴鼻剂、液体配方的滴眼剂)。用来制备喷鼻剂或鼻用粉剂、滴鼻剂、滴眼剂的活性化合物的液体药学组合物可用本领域技术人员已知的技术将活性化合物与合适的载体(如无菌无热原的水或无菌盐水)混合而制得。
使粘液状分泌物水合和刺激鼻窦中纤毛拍动频率的活性化合物的剂量根据患者状态而定，但其有效量一般足以达到患者窦道上的活性化合物浓度，即约10-7至10-1摩尔/升(例如，UTP为0.00001-52mg/ml)，较好的约为10-6至10-1摩尔/升(例如，UTP为0.001-50mg/L)。
根据施用的活性化合物的具体配方的溶解度，可将促进流体排出的日服用剂量分成一或数个单位剂量施用。较好的是，日服药方案为不多于每日4次。
另一种向患者窦部施用活性化合物以促进流体/分泌物排出的方式可包括采用各种口服形式，可以是将活性化合物的液体悬浮液灌入患者口中或让患者吞服药丸。
又一种向窦部施用有效量的活性化合物的方式包括将雾化的活性化合物施用于呼吸道，以使活性化合物进入鼻咽和肺并直接或通过全身吸收和循环而到达窦部。活性化合物可以各种形式气雾化，例如(但不限于)干粉吸入剂、剂量经计量的吸入剂、或液/液悬浮液。以干粉形式给药时，UTP可单独配制，或与稀释剂或载体(如糖，即乳糖、蔗糖、海藻糖、甘露糖)或其他合乎要求的用于肺或通气道给药的赋形剂一起配制。干粉可用喷雾干燥、制粉、冷冻干燥等本领域已知的方法得到。
另外的将活性化合物施用于窦部的方式包括采用各种局部施用的形式，可以是将乳膏或凝胶施用于鼻、眼或外耳并随后渗入患者窦道。
另一种向窦部施用活性化合物的方式包括采用注射形式，将活性化合物从鼻或面部窦区域直接注射至窦道中。
还有一种向窦部施用活性化合物的方式包括采用栓剂的形式，以使治疗有效量的化合物通过全身吸收和循环到达窦部。
再有一种施用活性化合物的方式包括在外科手术过程中滴注活性化合物的凝胶、乳膏、粉末、泡沫、结晶或液体悬浮液，以使治疗有效量的活性化合物到达窦部。
本发明的较佳实例……UTP和U2P4及式Ⅰ至式Ⅳ的其他化合物在与其他药剂或方法合用以治疗窦炎时也具有治疗益处，所述的其他药剂的例子包括(但不限于)抗生素；抗病毒剂；抗组胺药/减充血药；吸入蒸气；粘液溶解剂；非类固醇类消炎剂；类固醇类化合物；在面部窦区域施加温压。
进行了体内测试以说明兔子窦部纤毛拍动频率的增加，从而显示本发明所述的化合物在消除或防止阻滞的粘液状分泌物在窦道积聚方面的效用。该测试是T.Ganbo、K.Hisamatsu、K.Kikushima、M.Nakajima、H.Inoue和Y.Murakami在“Effects of Platelet Activating Factor on Mucociliary Clearance of the EustachianTube”,Ann.Otol.Rhinol.Laryngol.,Vol.105,p.140-145(1996)中所述方法的改进方法。
对两只体重各为2-3kg的成年新西兰白兔肌注赛拉嗪(5mg/kg)和氯胺酮(40mg/kg)，使它们麻醉。手术切除头两侧的上颌窦。立即从窦组织中取得窦粘膜试样并在RPMI 1640溶液中置于有凹坑的显微镜玻片上。然后将该玻片置于装有光电倍增管的显微镜上。将光电倍增管的输出信号通过模拟-数字板输入到微机中。鉴别出具有最快速纤毛拍动频率的组织区域并将该区域置于显微镜视场的中心。启动数据采集30秒种(基线)并在施用受试化合物后立即重复。调整数字化的输出信号并用快速富里叶转换程序在频率区进行分析。将与上述程序的最大功率相伴的频率确定为最佳频率并进行记录。配方Ⅱ的产物(8.3和82.5mg/ml)将纤毛拍动频率从基线值的12.0±1.1拍/分增加至18.3±1.3拍/分(平均值±标准偏)和18.0±0.45拍/分。
在下面的实施例中对本发明作更详细的说明。该实施例是对本发明的举例说明而不是对本发明的限定。
                    实验例1
                   急性窦炎的治疗
将尿苷5′-三磷酸(UTP)或P1,P4-二(尿苷-5′)四磷酸(U2P4)施用于诊断为急性窦炎的患者。施用的UTP是滴鼻剂或喷鼻剂，一日2-3次，在窦炎急性发作期间共施用3-5日。UTP的浓度在10-7至10-1摩尔/升(例如，UTP为0.001-50mg/ml)。施用UTP的治疗在窦炎预诊结果出来后即开始，而不必在抗生素治疗后才开始。各患者的治疗时间为1个星期(或在症状持续期间)。
UTP在促进阻塞的窦部流体排出方面的效用通过症状陈述的减少及物理检查结果进行测定。
UTP的安全性用生活征的标准安全指标进行测定，这些生活征包括心率、呼吸频率、血压、心电图和实验室血液试验(如血的化学组成和全血计数)以及观察到/报告的任何不良反应。
此处描述的本发明的方法和化合物提供了一种引导被窦炎折磨的患者体内的粘液状分泌物从通道排出的方法。该方法包括对患者窦部施用有效量的尿苷三磷酸〔如尿苷5′-三磷酸(UTP)、U2P4或UTP的任何类似物〕，使粘液状分泌物水合或刺激窦部中纤毛的拍动频率。
上面对本发明作了全面地描述，本领域的普通技术人员会明白，在不脱离附具的权利要求书的实质或范围的情况下，可对本发明作许多变化和改进。

Claims (16)

1．一种治疗需要这种治疗的患者的窦炎的方法，该方法包括对患者施用在药用载体中的有效量的式Ⅰ、Ⅱ、Ⅲ或Ⅳ的化合物或其药用盐，刺激流体从窦部排出：
                      式Ⅰ
Figure A9719713500021
式中：
X1、X2和X3各独立地选自OH或SH；
R1选自O、亚氨基、亚甲基和二卤代亚甲基；
R2选自H和Br；
                        式Ⅱ
Figure A9719713500022
式中：
B是尿嘧啶或腺嘌呤，其连接方式如式Ⅰ和Ⅲ中所示；
                        式Ⅲ
Figure A9719713500023
式中：
R1、X1、X2和X3的定义如式Ⅰ中所示，
R3和R4是H，而R2不存在，N-1与C-6之间有一个双键(腺嘌呤)，或者
R3和R4是H，而R2是O,N-1与C-6之间有一个双键(1-氧化-腺嘌呤)，或者
R3、R4和R2一起为-CH-CH-，与N-6与C-6之间的双键一起形成一个从N-6到N-1的环(1,N6-亚乙烯基腺苷)；
                         式Ⅳ
Figure A9719713500031
式中：
R1、X1、X2和X3的定义如式Ⅰ中所示，
R5和R6是H，而R7不存在，N-3和C-4之间有一个双键(胞苷)，或者
R5、R6和R7一起为-CH-CH-，与N-4与C-4之间的双键一起形成一个从N-3到N-4的环(3,N4-亚乙烯基胞苷)。
2．如权利要求1所述的方法，其中，所述化合物通过施用液/液悬浮液而给药的，以使治疗有效量的该化合物直接或通过全身吸收和循环而接触患者窦部；所述液/液悬浮液包括施用于眼的该化合物的滴眼剂、或施用于患者鼻咽通气道的该化合物的滴鼻剂、粉剂或喷雾剂。
3．如权利要求1所述的方法，其中，所述化合物是通过将该化合物以口服形式施用于患者而进行给药的，以使治疗有效量的该化合物通过全身吸收和循环而接触患者窦部。
4．如权利要求1所述的方法，其中，所述化合物是通过将该化合物以雾化的气溶胶悬浮液或溶液的形式施用于患者的鼻咽通气道而给药的，以使治疗有效量的该化合物直接或通过全身吸收和循环而接触患者窦部。
5．如权利要求1所述的方法，其中，所述化合物是通过将局部施用剂型的该化合物经过患者的鼻、眼、外耳或鼻咽通气道施用于窦部而给药的，以使治疗有效量的该化合物直接或通过全身吸收和循环而接触患者窦部。
6．如权利要求1所述的方法，其中，所述化合物是通过将该化合物以注射的形式施用于患者而给药的，以使治疗有效量的该化合物通过全身吸收和循环而接触患者窦部。
7．如权利要求1所述的方法，其中，所述化合物是通过将该化合物以栓剂的形式施用于患者而给药的，以使治疗有效量的该化合物通过全身吸收和循环而接触患者窦部。
8．如权利要求1所述的方法，其中，所述化合物是通过在外科手术过程中滴注活性化合物的凝胶、乳膏、粉末、泡沫、结晶或液体悬浮液而给药的，以使治疗有效量的该化合物直接或通过全身吸收和循环而接触患者窦部。
9．如权利要求1所述的方法，其中，施用有效量的所述化合物，使该化合物在患者窦部表面的浓度达到约10-7至10-1摩尔/升。
10．如权利要求1所述的方法，其中，X2和X3是OH。
11．如权利要求1所述的方法，其中，R1是氧。
12．如权利要求1所述的方法，其中，R2是H。
13．如权利要求1所述的方法，其中，式Ⅰ化合物选自尿苷5′-三磷酸、尿苷5′-O-(3-硫代三磷酸)、5-溴-尿苷5′-三磷酸和它们的药用盐。
14．如权利要求1所述的方法，其中，式Ⅱ化合物选自P1,P4-二(尿苷-5′)四磷酸(U2P4)和P1,P4-二(腺苷-5′)四磷酸(A2P4)及它们的药用盐。
15．如权利要求1所述的方法，其中，式Ⅲ化合物选自腺苷5′-三磷酸、1,N6-亚乙烯基腺苷5′-三磷酸、1-氧化-腺苷5′-三磷酸及它们的药用盐。
16．如权利要求1所述的方法，其中，式Ⅳ化合物选自胞苷5′-三磷酸(CTP)、3,N4-亚乙烯基胞苷5′-三磷酸及它们的药用盐。
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WO1998003177A1 (en) 1998-01-29
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EP0939637A1 (en) 1999-09-08
US5981506A (en) 1999-11-09
AU4408997A (en) 1998-02-10
US5958897A (en) 1999-09-28
CA2259552A1 (en) 1998-01-29
US5789391A (en) 1998-08-04
US5972904A (en) 1999-10-26
NZ333983A (en) 2000-09-29
EP0939637A4 (en) 2001-09-26
KR20000067852A (ko) 2000-11-25

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