CN1997367A - 预防和治疗过敏性炎症的组合物 - Google Patents
预防和治疗过敏性炎症的组合物 Download PDFInfo
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- CN1997367A CN1997367A CNA2005800226596A CN200580022659A CN1997367A CN 1997367 A CN1997367 A CN 1997367A CN A2005800226596 A CNA2005800226596 A CN A2005800226596A CN 200580022659 A CN200580022659 A CN 200580022659A CN 1997367 A CN1997367 A CN 1997367A
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- asthma
- benzamidine
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Abstract
本文中公开的是治疗和预防过敏性炎症的组合物,包括N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒或其药物学上可接受盐。该组合物对过敏性炎症表现出优良的医疗效果,其可以明显减少典型慢性炎症症状,例如支气管肺泡囊洗液中嗜酸性粒细胞水平的增加以及血液中总白细胞水平和嗜酸性粒细胞水平的增加、由于粘液细胞数量的增加导致的支气管上皮细胞的肥大或增生、肺泡壁肥大导致的肺泡表面积的降低、以及炎症细胞的浸润。
Description
技术领域
[0001]本发明一般地涉及预防和治疗过敏性炎症的组合物,并且更具体地涉及用于预防或治疗过敏性炎症的包含N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒或其药物学上可接受盐的组合物。
背景技术
[0002]由于与环境污染、应激、生活环境等相关的各种病理已增长,因此过敏性炎症也增长。过敏性炎症被归因于免疫系统的异常,其中鼻粘膜或支气管粘膜或者皮肤对于外部过敏原过敏。过敏反应的基本原因包括应激、渗血等,然而,主要原因是营养失衡。
[0003]取决于对外源过敏原发生免疫应答的部位,过敏性炎症表现为各种症状,包括过敏性鼻炎、哮喘、特应性皮炎等。另外,变应性结膜炎、变应性皮炎、接触性皮炎、荨麻疹等在过敏性炎症的范围之内。由于这些症状,尽管非常多样,但在基于对外部引入的物质过敏的病理上是共同的,所以对于所有症状,都可以开出过度免疫应答的抑制剂作为药方。
[0004]哮喘,过敏反应的代表,是在呼吸器官特别是肺和支气管中发生的慢性炎症。当哮喘病人服药或过度运动或吸入受污染和/或冷空气时,他们的呼吸器官尤其是上呼吸道器官应答性增加。该超应答性与气道中气流梗阻即气道梗阻或气管狭窄有关,但使用支气管扩张药可以容易地减轻。哮喘的共同特征中的对室内和/或室外过敏原的超应答性以及气道收缩已知是由肥大细胞和嗜酸性IgE介导(Beasley et al.,Am.Rev.Respir.Dis.,129,806-817,1989)。
[0005]哮喘伴随有主要在支气管和肺中的过敏性超应答性。具体而言,气道由于粘膜细胞增殖和支气管中的上皮结缔组织的炎症而被阻塞。同样,已知肺部显示出相似的组织学行为。尽管迄今尚未被消楚地揭示,据报道,哮喘的病理特征在于气道狭窄、水肿、粘液分泌、炎症细胞浸润等。在典型的外源性哮喘的机理中,当抗原被引入气道,B细胞与巨噬细胞和辅助性T细胞合作产生抗原特异性抗体IgE和IgG。这些抗原特异性抗体结合到肥大细胞和嗜碱性细胞表面的受体上,然后当再暴露于相同抗原时所述肥大细胞和嗜碱性细胞被活化,以释放多种细胞因子和过敏反应/炎症介质,包括组胺、前列腺素D2、缓慢反应物质(白三烯类C4、D4)等到细胞外。由于这些细胞因子和介质,当暴露于气源性致敏原时,哮喘病人表现出早期哮喘应答,该应答的特征在于持续数秒到数分钟的一段时间的快速气道收缩和在30至60分钟内从收缩表观恢复。然后,从肥大细胞分泌的介质和从巨噬细胞、肥大细胞和辅助性T细胞分泌的细胞因子使包括嗜酸性粒细胞在内的炎症细胞增殖并活化,从而表现出后期哮喘应答,其中支气管狭窄、粘液分泌和炎症细胞浸润在暴露于气源性致敏原后3至4小时开始,并在4至18小时后达到峰值(Robertson et al.,J.Allergy Clin.Immunol.,54,244-257,1974)。
[0006]目前可得的治疗哮喘的治疗剂包括β2-肾上腺素受体激动剂,其扩张气道平滑肌和有效抑制超应答性介质从肥大细胞的分泌;肾上腺皮质激素,其表现出免疫抑制效应;以及色甘酸二钠和奈多罗米钠(nedocromil sodium),已知两者既抑制早期哮喘应答又抑制后期哮喘应答。然而,β2-肾上腺素受体拮抗剂仅具有短期的治疗效果并且疾病会迅速复发。肾上腺素皮质激素具有断续的治疗效果,长期剂量后伴有严重的副作用。
[0007]近来,对花生四烯酸代谢物(包括前列腺素)、脂加氧酶和白细胞三烯类作用的阻断研究已经作为炎症和超应答性降低的途径而被引入。白三烯B4,在5-脂加氧酶途径中形成的花生四烯酸代谢物之一,涉及由组织浸润性和组织促凝固性多形有核白细胞分泌的组织退化性酶和活性化学剂的作用。
[0008]然而,如下文中所提到,因为除了白三烯B4外还有许多因子涉及到哮喘的发生并因此能够诱导各利体内应答,所以尽管某些化合物有效抑制白三烯B4,但不能期望这些化合物对哮喘的治疗具有效果。
[0009]例如,根据Lilly公司,U.S.A.进行的哮喘适应症的临床试验(Clint D.W.Brooks et al.,J. Med.Chem.1996 39(14),2629-2649),白三烯B4受体拮抗剂LY293111被报道在治疗哮喘中无效(Evans DJ,Thorax.1996 Dec;51(12):1178-84)。白三烯B4受体拮抗剂ONO-4057也被报道当与半胱氨酰白三烯受体拮抗剂Zafirlukast结合使用时对支气管哮喘具有医疗效果,但是当单独使用时对其的治疗无效(SakuradaT.et,al.,Eur J Pharmacol.1999 Apr 9:370(2):153-9)。因此,不能说白三烯B4受体拮抗剂对于包括哮喘的过敏性炎症的治疗有效。
[0010]同时,白三烯B4受体拮抗剂被用于多种疾病的治疗。例如,日本末审查专利公开第6-502164号公开了新的单环和双环芳基化合物,其通过选择性地抑制白三烯B4有效地治疗风湿性关节炎、痛风、牛皮癣以及炎性肠病。在日本特许公开第4-244023号中,ω-6不饱和脂肪酸例如二高γ-亚麻酸,被描述对心律不齐、急性心肌梗死具有医疗效果,其对白三烯B4的产生具有抑制活性。日本特许公开第1-190656号公开了新的白三烯B3二甲基酰胺(leukotriene B3 dimethyl amide),其作为抗炎症剂、抗风湿剂和痛风药物是有效的,具有对白三烯B4的拮抗活性。
[0011]由本发明人进行的对过敏性炎症广泛和深入的研究导致了本发明,发现了N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒和4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒,其已由本发明人开发成治疗骨质疏松的药剂(韩国专利公开号10-2003-8654),可以显著减少典型慢性炎症症状,例如支气管肺泡囊洗液中嗜酸性粒细胞水平的增加以及血液中总白细胞水平和嗜酸性粒细胞水平的增加、由于粘液产生细胞的增加导致的支气管上皮细胞的肥大或增生、肺泡壁肥大导致的肺泡表面积的降低、以及炎症细胞的浸润,对包括哮喘在内的过敏性炎症表现出优良的医疗效果。
发明内容
[0012]因此,紧记在现有技术中出现的上述问题,做出本发明,本发明的一个目标是提供预防和治疗过敏性炎症的组合物,包括 N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒、4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒或药物学上可接受盐。
[0013]本发明的另一个目标是提供使用该组合物治疗和预防过敏性炎症的方法。
附图说明
[0014]图1是光学显微照片,显示了用Masson氏三色染色的哮喘诱导肺组织的切片样本。
最佳实施方式
[0015]本发明涉及预防和治疗过敏性炎症的组合物,包括由下面的化学式1表示的苄脒化合物或其药学学上可接受盐。
化学式1
(其中,R是氢原子或羟基基团)
[0016]化学式1的苄脒化合物可以以本领域中已知的药物可接受盐的形式被使用。用药物学可接受的自由酸制备的酸加成盐是优选的。适合在本发明中使用的自由酸可以是无机酸或有机酸。无机酸的例子包括盐酸、溴酸、硫酸、磷酸等等,而有机酸的例子可以是柠檬酸、乙酸、乳酸、酒石酸、富马酸、蚁酸、丙酸、草酸、三氟乙酸、甲磺酸、苯磺酸、马来酸、苯甲酸、葡糖酸、乙醇酸、琥珀酸、4-吗啉代乙磺酸、樟脑磺酸、4-硝基苯磺酸、羟基-O-磺酸、4-甲苯磺酸、半乳糖醛酸、扑酸、谷氨酸和天冬氨酸。
[0017]化学式1的苄脒化合物可以根据已知的方法制备(Lee,Sung-Eun,Synthesis and Biological Activity of Natural Products and Designed NewHybrid Compounds for the Treatment of LTB4 Related Disease,BusanNational University,博士学位论文,1999年8月)。
[0018]如本文中所使用,术语“过敏性炎症”是指由各种致敏原导致的非特异性炎症疾病,例如过敏性鼻炎、哮喘、变应性结膜炎、变应性皮炎、特应性皮炎以及荨麻疹。
[0019]在本发明的具体实施方式中,化学式1的苄脒化合物被发现具有减少典型慢性炎症症状的巨大效果,所述症状例如支气管肺泡囊灌洗液中嗜酸性粒细胞水平的增加以及血液中总白细胞水平和嗜酸性粒细胞水平的增加、由于粘液细胞增加导致的支气管上皮细胞的肥大或增生、肺泡壁肥大导致的肺泡表而积的降低以及炎症细胞的浸润。
[0020]本发明的组合物可以进一步包括至少一种具有与化学式1的苄脒化合物或其药物学上可接受盐等价或相似的功能的有效成分。
[0021]本发明的组合物可以进一步包括一种或更多药物学上可接受的载体。适当的载体可以选自盐水、无菌水、Ringer’s溶液、缓冲盐溶液、葡萄糖溶液、麦芽糖糊精溶液、甘油、乙醇及其组合,并且如果必要的话,可以进一步补充其它通常的添加剂例如抗氧化剂、缓冲液、稳定剂(static agent)等。与稀释剂、分散剂、表而活性剂、粘结剂和润滑剂结合,本发明的组合物还可以被配制成可注射剂型例如水溶液、悬液、乳液等,药丸,胶囊,颗粒和片剂。而且,取决于成分或疾病的类型,可以使用本领域或已知的或在Remington′s PharmaceuticalScience((最新版),Mack Publishing Company,Easton PA)中公开的方法制备该制剂。
[0022]根据目的,本发明的组合物可以口服或胃肠外给药(例如静脉内、皮下、腹内或局部)。本发明的组合物的剂量根据体重、年龄、性别、健康状态、饮食、给药时间周期、给药途径、排泄速度、疾病严重程度等变化。当所有这些因素都被考虑时,化学式1的苄脒化合物以1天约10至1,000mg/kg的剂量给药一次或许多次,并且更优选1天约50至500mg/kg的剂量。
[0023]对于过敏性炎症的预防和治疗,本发明的组合物可以被单独使用或与外科手术、激素治疗、化疗和/或生物应答控制剂结合使用。
[0024]通过下面的实施例可以获得对本发明更好的理解,所述实施例被描述是为了举例说明,而不被解释成对本发明的限制。
实施例:用卵白蛋白诱导的哮喘小鼠模型中的治疗效应
[0025]测定化学式1的苄脒化合物在卵白蛋白诱导的哮喘小鼠模型中对过敏性炎症的疗效。从用卵白蛋白致敏开始,苄脒化合物被给药连续18天。致敏后15天实验动物被再暴露于卵白蛋白,然后在该次再暴露后3天被处死。观察肺重量、外周血和支气管肺泡囊洗液中的细胞成分以及肺组织病理学中的变化。
1.实验动物和饲养管理
[0026]使总共20只雌性C57BL/6小鼠(6周龄,BioGenomics,Korea)在被用于真实试验之前适应实验室环境6天。当以5只的密度被置于塑料笼中时,实验动物在受控温度(20至25℃)和湿度(30至35%)下在饲养室中饲养。在12小时的光暗周期下,小鼠被允许自由获得饲料和自来水。在用卵白蛋白在15只小鼠诱导哮喘的同时,5只小鼠被用作非治疗组。
2.样品的制备和给药
[0027]100mg和200mg N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒被完全溶解在5ml无菌蒸馏水中。从用卵白蛋白致敏当日起,溶液中的苄脒化合物以每kg体重100mg和200mg的剂量1天经口给药1次。对照组以相同的方式施用相同体积的无菌蒸馏水。
3.通过用卵白蛋白免疫和暴露于卵白蛋白诱导哮喘
[0028]使4ml生理盐水中200μg卵白蛋白(Grade V;Sigma,St.Louis,MO,USA)和180mg氢氧化铝(Al(OH)3,干粉凝胶;Aldrich,Milwaukee,USA)的溶液于4℃过夜,并施用于实验动物(200μl,腹腔注射)以致敏。对于非治疗组,仅含有氢氧化铝的盐水溶液被注射。致敏后15天,使用喷雾器在空气中喷散1.5%卵白蛋白溶液,随后使实验动物暴露于该喷雾10分钟,以在其中诱导哮喘。以相同的方式使非治疗组仅暴露于盐水。所有的实验动物在暴露后3天被处死。
4.体重和体重增加的变化
[0029]在给药后1、7、14、16和17天,测量所有实验动物的体重。为了减少由于饲料摄入引起的个体间差异,在重量测量前,所有实验动物在给药开始当日和处死日被禁食18小时或更长。为了使个体动物的体重变化的差异最小化,计算致敏时期、暴露后哮喘诱导以及整个实验期间的体重增加。
[0030]结果在下面的表1中给出。
表1:体重增加的变化
组别 | 致敏时期 | 暴露后哮喘诱导时期 | 整个实验期间 | |
正常 | 3.08±0.71 | 0.52±0.33 | 2.34±0.63 | |
对照 | 3.02±0.84 | 0.84±0.29 | 2.50±0.73 | |
化学式1的化合物 | 100 (mg/kg) | 3.50±0.51 | 0.34±0.34* | 2.68±0.52 |
200(mg/kg) | 3.08±0.71 | 0.36±0.59 | 2.90±0.40 |
*:与对照相比显著性(p<0.05)
[0031]如表1中可见,除了暴露后哮喘诱导时期,在全部实验时期没有观察到体重增加的显著变化,表明几乎没有可归因于实验物质的施用或实验动物间的个体差异的误差。而且,在暴露后哮喘诱导时期,对照组被观察到显著增加体重,而苄脒化合物给药组显示体重增加的显著降低。
5.肺重量的测量
[0032]在实验的最后一天,肺被从相邻器官中分离出。以克测量取出的肺的重量。为使由于个体动物中体重差异导致的误差最小化,使用下面的数学式1以体重百分比计算肺的相对重量。
式1
[0033]结果在下面的表2中给出。
表2:肺重量变化
组别 | 绝对重量(g) | 相对重量(%) | |
正常 | 0.112±0.004 | 0.63±0.021 | |
对照 | 0.138±0.004* | 0.750±0.015* | |
化学式1的化合物 | 100(mg/kg) | 0.128±0.007*,## | 0.697±0.030*,## |
200(mg/kg) | 0.125±0.008**,# | 0.682±0.030**,## |
※与正常组相比显著性(*:p<0.01,**:p<0.05),
与对照组相比显著性(#:p<0.01,##p<0.05)
[0034]如从表2显而易见,相比于正常组,对照组中哮喘诱导的肺绝对和相对重量显著增加(p<0.01),而相比于对照组,在苄脒化合物给药组中,它们呈剂量依赖模式的显著减小(p<0.01或p<0.05)。
[0035]因此,化学式1的苄脒化合物被发现可以预防由于哮喘导致的肺重量增加。
6.血液中白细胞的总计数和白细胞的比例计算
[0036]在实验的最后一日,所有的实验动物被用醚麻醉,并经受剖腹术,以暴露腹腔静脉,并从腹腔静脉取出1ml血。使用血球计数器,测量以×103/1mm3为单位的血液样品总白细胞数。在血液收集之后,立刻将血液样品涂布在玻片上,用甲醇固定并用Giemsa染色。然后,计算每200个白细胞的淋巴细胞、嗜酸性粒细胞、嗜中性粒细胞、单核细胞和嗜碱细胞的各自比例,在下面的表3中表示为百分比。
表3:血液中白细胞计数的变化
白细胞比例 | 正常 | 对照 | 苄脒化合物给药 | |
100mg/kg | 200mg/kg | |||
总白细胞 | 824±0.97 | 14.04±0.91* | 10.68±1.76**,## | 10.44±1.81**,## |
淋巴细胞(%) | 84.10±1.98 | 40.00±10.60* | 41.70±12.90* | 53.80±5.50*,# |
嗜酸性粒细胞(%) | 3.10±1.39 | 54.20±10.63* | 49.60±15.79* | 36.90±8.33*,# |
嗜中性粒细胞(%) | 9.20±2.00 | 3.80±1.10* | 4.90±2.90** | 5.20±2.00** |
单核细胞(%) | 3.20±0.30 | 2.00±1.20** | 3.70±1.60 | 4.40±1.70## |
嗜碱细胞(%) | 0.30±0.40 | 0.00±0.00 | 0.10±0.20 | 0.00±0.00 |
※与正常组相比显著性(*:p<0.01,**:p<0.05),
与对照组相比显著性(#:p<0.01,##:p<0.05)
[0037]由于哮喘诱导,如从表3的数据可以理解的,相比于正常组,在对照组中,血液中总白细胞的计数及其嗜酸性粒细胞比例增加,具有显著性(p<0.01),而相比于对照组,在苄脒化合物给药组中,它们都被剂量依赖地降低,具有显著性(p<0.01或p<0.05)。
[0038]因此,该结果显示化学式1的苄脒化合物显著抑制哮喘引起的炎症应答。
7.支气管肺泡囊洗液的细胞成分的比例计数
[0039]在实验的最后一天,检测支气管和肺泡分泌物的细胞学组成。对于该目的,在被用醚麻醉后,实验动物被手术,以打开颈区和胸腔。对颈静脉放血,随后进行气管插管术。通过管注射3ml磷酸缓冲盐2次,并且推拿胸腔30秒,以从肺获得细胞悬浮液。在3000rpm下离心该细胞悬浮液30分钟并重悬于DPBS中(Gibco BRL,NU,USA)。在细胞悬浮液被涂布于玻片后,用Giemsa对细胞进行染色。涂片中的全部细胞的总数以及嗜中性粒细胞、嗜酸性粒细胞、嗜碱细胞、巨噬细胞和上皮样细胞的各部分计数被测量,在下面的表4中给出。
表4:在支气管囊洗液中白细胞数的变化
白细胞比例 | 正常 | 对照 | 苄脒化合物给药 | |
100mg/kg | 200mg/kg | |||
淋巴细胞(%) | 59.90±9.32 | 38.40±12.30* | 56.90± 15.04 | 56.80±22.52 |
嗜酸性粒细胞(%) | 2.90±0.74 | 14.60±3.70* | 4.30±1.44# | 3.60±2.88# |
嗜中性粒细胞(%) | 8.80±0.91 | 16.20±4.72* | 17.50±8.06** | 13.90±9.85 |
单核细胞(%) | 3.80±0.76 | 2.90±2.82 | 3.10±3.73 | 3.50±2.57 |
嗜碱细胞(%) | 0.70±0.57 | 1.11±0.42 | 0.50±0.50 | 0.10±0.22# |
上皮样细胞(%) | 22.40±8.94 | 26.10±16.91 | 21.00±14.77 | 15.50±9.74 |
※与正常组相比显著性(*:p<0.01,**:p<0.05),
与对照组相比显著性(#:p<0.01,##:p<0.05)
[0040]根据哮喘诱导,如从表4可以看出,相比于正常组,在对照组中,支气管囊洗液中嗜酸性粒细胞的比例增加,具有显著性(p<0.01),但相比于对照组,在苄脒化合物给药组中,它们呈剂量依赖模式减少,具有显著性(p<0.01)。
[0041]因此,发现化学式1的苄脒化合物可以明显限制哮喘引导的炎症应答。
8.组织处理和组织病理学观察
[0042]在哮喘诱导后摘出的肺在10%中性福尔马林中被固定并嵌入石蜡中。石蜡包埋的组织以3至4μm的厚度被切片,用苏木素-伊红或Masson’s三色染色并通过光学显微镜观察。
[0043]结果在图1中给出。
[0044]根据哮喘诱导,如图1所示,相对于正常组,在对照组中,发现在初级细支气管和肺泡周围以及支气管上皮细胞周围的组织中具有增加的炎症细胞群,但相比于对照组,苄脒化合物给药组在组织中显示出呈剂量依赖模式的炎症细胞群减少。
[0045]使用分析图像处理系统(analysis image processing system)(SISGermany),从上面制备的肺组织样本检测肺泡面积(肺组织中肺泡腔的比例)、支气管和细支气管中的杯状细胞群、支气管和细支气管的壁厚。在表5中,肺泡面积被表示为百分比,支气管和细支气管中杯状细胞群被表示为每1,000个细胞的数量,支气管和细支气管的壁厚以μm表示。
表5:组织病理学的变化
正常 | 对照 | 苄脒化合物给药 | |||
100mg/kg | 200mg/kg | ||||
肺泡面积 | 76.18±4.68 | 26.80±2.79* | 55.53±4.26*,# | 61.62±6.93**,# | |
壁厚 | 支气管 | 25.44±3.79 | 124.34±47.80* | 60.92±8.53*,# | 40.69±5.37*,# |
细支气管 | 16.91±4.30 | 51.67±11.11* | 27.73±4.68*,## | 24.79±3.03*,# | |
杯状细胞数量 | 支气管 | 139.00±23.46 | 617.00±87.01* | 317.60±75.46*,# | 256.80±71.58*,# |
细支气管 | 17.60±4.88 | 94.40±26.89* | 53.80±11.73*,## | 42.80±10.69*,# |
※与正常组相比显著性(*:p<0.01,**:p<0.05),
与对照组相比显著性(#:p<0.01,##:p<0.05)
[0046]根据哮喘诱导,如从表5可以看出,相比于正常组,在对照组中,肺组织的肺泡面积减小,具有显著性(p<0.01),但相比于对照组,苄脒化合物给药组被发现具有呈剂量依赖模式增加的肺泡而积,具有显著性(p<0.0 1)。
[0047]当哮喘被诱导,相比于正常组,对照组中,肺支气管和细支气管的壁厚以及支气管和细支气管的杯状细胞数都增加,具有显著性(p<0.01),但相比于对照组,苄脒化合物给药组显示出呈剂量依赖模式的显著降低(p<0.01或p<0.05)。
[0048]结果,化学式1的苄脒化合物被鉴定为对由哮喘引起的炎症应答具有有效的抑制效果。
9.统计学
[0049]所有数字被表示为平均值±标准偏差,并借助SPSS(用于window的统计包程序)(Release 6.1.3.,SPSS Inc.,USA)使用Mann-WhitneyU-Wilcoxon Rank Sum 分析相对于正常或对照的差异的统计学显著性。
[0050]同样地,N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒的甲磺酸盐和盐酸盐,以及4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}-苄脒及其甲磺酸盐和盐酸盐被发现表现出与上面相同的治疗效果。
工业实用性
[0051]本发明的组合物可以显著减少典型慢性炎症症状,例如支气管肺泡囊洗液中嗜酸性粒细胞水平的增加以及血液中总白细胞水平和嗜酸性粒细胞水平的增加、由于粘液产生细胞的增加导致的支气管上皮细胞的肥大或增生、肺泡壁肥大导致的肺泡表面积的降低以及炎症细胞的浸润,从而对过敏性炎症表现出优良的医疗效果。
[0052]尽管本发明优选的实施方式被公开,用于说明的目的,但是本领域普通技术人员将理解,进行多种修饰、添加和取代而不背离如附随的权利要求所公开的本发明的范围和精神是可能的。
Claims (5)
1.用于预防和治疗过敏性炎症的药物组合物,包括由下面的化学式1表示的苄脒化合物或其药物学上可接受盐。
化学式1
(其中,R是氢或羟基)
2.权利要求1所述药物组合物,其中所述盐是甲磺酸盐或盐酸盐。
3.权利要求1所述药物组合物,其中所述过敏性炎症选自过敏性鼻炎、哮喘、变应性结膜炎、变应性皮炎、特应性皮炎、接触性皮盐以及荨麻疹。
4.权利要求3所述药物组合物,其中所述炎症是哮喘或过敏性鼻炎。
5.治疗或预防过敏性炎症的方法,其中由下面的化学式1所表示的苄脒化合物或其药物学上可接受盐被施用于过敏性炎症病人:
化学式1
(其中,R是氢或羟基)。
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KR20060017929A (ko) | 2004-08-04 | 2006-02-28 | 동화약품공업주식회사 | 티아졸 유도체가 치환된 신규한 벤즈아미딘 유도체, 그의제조방법 및 이를 유효성분으로 하는 약학 조성물 |
CN101652355B (zh) * | 2007-04-19 | 2012-11-07 | 同和药品株式会社 | N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒2乙磺酸盐、其制备方法和包含其的药物组合物 |
Family Cites Families (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5455274A (en) * | 1992-12-09 | 1995-10-03 | Ciba-Geigy Corporation | Hydroxyamidine derivatives |
DE4309285A1 (de) * | 1993-03-23 | 1994-09-29 | Boehringer Ingelheim Kg | Heterocyclen enthaltende Amidinderivate, ihre Herstellung und Verwendung |
WO1995032201A1 (en) * | 1994-05-25 | 1995-11-30 | G.D. Searle & Co. | Alkoxy-substituted dihydrobenzopyran-2-sulfonimides derivatives, their preparation and their use as leukotriene b4 antagonists |
DE4424714A1 (de) * | 1994-07-13 | 1996-01-18 | Boehringer Ingelheim Kg | Neue chemische Verbindung, ihre Herstellung und ihre Verwendung als Arnzneistoff |
TW332201B (en) * | 1995-04-06 | 1998-05-21 | Janssen Pharmaceutica Nv | 1,3-Dihydro-1-(phenylalkyl)-2H-imidazol-2-one derivatives |
DE19636689A1 (de) * | 1996-09-10 | 1998-03-12 | Boehringer Ingelheim Kg | Neue Benzamidinderivate |
JP3191943B2 (ja) * | 1997-02-04 | 2001-07-23 | ドン ワ ファーマシューティカル インダストリアル カンパニー リミテッド | 3−アミノ−1,2−ベンゾイソオキサゾール誘導体類とその製造方法及び用途 |
US6291531B1 (en) * | 1999-10-07 | 2001-09-18 | Boehringer Ingelheim Pharma Kg | LTB4 antagonist, processes for the preparation thereof and its use as a pharmaceutical composition |
KR100454767B1 (ko) * | 2001-07-19 | 2004-11-03 | 동화약품공업주식회사 | 4-[(4-티아졸릴)페녹시]알콕시-벤즈아미딘 유도체의골다공증 예방 및 치료제로서의 용도 |
US6921752B2 (en) * | 2002-03-26 | 2005-07-26 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Use of LTB4 antagonists in veterinary medicine |
KR20060017929A (ko) * | 2004-08-04 | 2006-02-28 | 동화약품공업주식회사 | 티아졸 유도체가 치환된 신규한 벤즈아미딘 유도체, 그의제조방법 및 이를 유효성분으로 하는 약학 조성물 |
BRPI0514386B8 (pt) * | 2004-11-23 | 2021-05-25 | Dong Wha Pharmaceutical Ind Co Ltd | bis (metanossulfonato) de n-hidróxi-4-{5-[4-(5-isopropil-2-metil-1,3-triazol-4-il)fenóxi]pentóxi}benzamidina, método para preparar os mesmos, suas composições farmacêuticas e formulações orais |
CN101652355B (zh) * | 2007-04-19 | 2012-11-07 | 同和药品株式会社 | N-羟基-4-{5-[4-(5-异丙基-2-甲基-1,3-噻唑-4-基)苯氧基]戊氧基}苄脒2乙磺酸盐、其制备方法和包含其的药物组合物 |
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- 2005-07-05 CN CN2005800226596A patent/CN1997367B/zh not_active Expired - Fee Related
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- 2005-07-05 AU AU2005260328A patent/AU2005260328B2/en not_active Ceased
- 2005-07-05 CA CA2572898A patent/CA2572898C/en not_active Expired - Fee Related
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- 2005-07-05 JP JP2007519133A patent/JP4657297B2/ja not_active Expired - Fee Related
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109387593A (zh) * | 2017-08-11 | 2019-02-26 | 上海市徐汇区中心医院 | 急性髓细胞白血病化疗敏感性测评试剂盒及其应用 |
CN109387593B (zh) * | 2017-08-11 | 2020-10-09 | 上海市徐汇区中心医院 | 急性髓细胞白血病化疗敏感性测评试剂盒及其应用 |
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CA2572898A1 (en) | 2006-01-12 |
WO2006004370A1 (en) | 2006-01-12 |
JP2008505069A (ja) | 2008-02-21 |
AU2005260328B2 (en) | 2009-10-01 |
KR20060049860A (ko) | 2006-05-19 |
CN1997367B (zh) | 2010-11-24 |
US20080200526A1 (en) | 2008-08-21 |
KR100682199B1 (ko) | 2007-02-12 |
HK1101674A1 (en) | 2007-10-26 |
BRPI0513046A (pt) | 2008-04-22 |
EP1773333A1 (en) | 2007-04-18 |
ZA200700113B (en) | 2007-09-26 |
CA2572898C (en) | 2010-04-20 |
JP4657297B2 (ja) | 2011-03-23 |
EP1773333A4 (en) | 2010-04-21 |
IL180526A (en) | 2010-11-30 |
AU2005260328A1 (en) | 2006-01-12 |
IL180526A0 (en) | 2008-03-20 |
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