CN101056627B - 间质性膀胱炎治疗剂 - Google Patents
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Abstract
Description
技术领域
本发明涉及用于治疗间质性膀胱炎的试剂。具体而言,本发明涉及用于治疗间质性膀胱炎的试剂,该试剂包括苯氧基乙酸衍生物,或其药理学可接受的盐或其水合物或溶剂合物。
背景技术
间质性膀胱炎为膀胱的病症,其伴随尿急、尿频以及腹部和会阴区疼痛,但不伴随感染和具体的病理发现。在膀胱炎中间质性膀胱炎导致非常严重的症状,该症状显示整个膀胱壁的炎症,其不仅扩展到粘膜而且扩展到肌肉层。关于其病因,已有人提出膀胱粘膜屏障功能的损坏,感觉神经、C纤维向粘膜一侧的延伸,与在C纤维附近的肥大细胞有关,等(参见非专利文献1)。
作为用于治疗间质性膀胱炎的试剂,通常采用三环抗抑郁剂、抗组胺剂、类固醇、甲苯磺酸舒普拉司特、木聚硫钠(Pentosan PolysulfateSodium)、Ca拮抗剂等的口服给药,肝素、透明质酸、二甲亚砜(DMSO)、辣椒素、树脂毒素(resiniferatoxin)等的膀胱内灌注治疗等。
其中,据估计辣椒素和仙人掌毒素的功能机制为C纤维,即辣椒素敏感性感觉神经的脱敏作用,并且已经有人报道具有毒蕈碱M3受体-选择性结合活性的1-苯基-1,2,3,4-四氢异喹啉-2-羧酸喹核碱-3’-基酯具有辣椒素敏感性感觉神经抑制作用(参见专利文献1)。
顺便提及,已有报道由通式(I)表示的苯氧基乙酸衍生物或其药理学可接受的盐或其水合物或溶剂合物具有选择性β3-肾上腺素受体刺激活性,并因此用作如下疾病用的预防或治疗剂:由肥胖症、高血糖症或肠道运动过速导致的疾病和由尿频、尿失禁、抑郁症、胆石或胆管运动过速导致的疾病(参见专利文献2)。然而,关于苯氧基乙酸衍生物和辣椒素敏感性感觉神经抑制活性之间的关系尚没有报道或提议。
通式1
其中R1表示羟基或低级烷氧基。
非专利文献1:由Medical Review,2004,第12卷,第1期发表的Hainyo Shogai Practice(Urinary Disturbance Practice)
专利文献1:国际申请WO 03/006019
专利文献2:国际申请WO 00/02846
发明内容
要解决的技术问题
本发明的目的在于提供用于治疗间质性膀胱炎的试剂。
技术方案
考虑到上述问题,本发明的发明人进行了广泛的研究并发现由上述通式(I)表示的苯氧基乙酸衍生物具有抑制辣椒素敏感性感觉神经的活性并因此对于间质性膀胱炎显著有效,从而完成了本发明。
即,本发明的主旨在于用于治疗间质性膀胱炎的试剂,其包含由通式(I)表示的苯氧基乙酸衍生物或其药理学可接受的盐或其水合物或溶剂合物,以及辣椒素敏感性感觉神经抑制剂。
有益效果
由于由通式(I)表示的苯氧基乙酸衍生物或其药理学可接受的盐或其水合物或溶剂合物具有选择性β3-肾上腺素受体刺激活性和辣椒素敏感性感觉神经的抑制活性,因此它可以用于治疗间质性膀胱炎,特别是伴随疼痛的间质性膀胱炎。
附图说明
图1为显示化合物1对抑制辣椒素敏感性感觉神经的作用的图。纵坐标表示Evans蓝颜料的量(ng/mg·膀胱湿重),并且横坐标表示化合物1的浓度(log[化合物1](mol/l))。标记##表示p<0.05(对照组),和**示p<0.05(溶剂组)。
图2为显示托特罗定对抑制辣椒素敏感性感觉神经的作用的图。纵坐标表示Evans蓝颜料的量(ng/mg·膀胱湿重),并且横坐标表示托特罗定的浓度(log[托特罗定](mol/l))。标记##表示p<0.05(对照组)。
最佳实施方式
在通式(I)中,所述低级烷氧基指具有1至6个碳原子,优选1至3个碳原子的直链或支链烷氧基。
通式(I)的苯氧基乙酸衍生物可通过专利文献2中描述的方法制备,并且作为所述苯氧基乙酸衍生物,(-)-2-[4-[2-[[(1S,2R)-2-羟基-2-(4-羟基-苯基)-1-甲基乙基]氨基]乙基]-2,5-二甲基苯氧基]-乙酸乙酯是理想的。
作为苯氧基乙酸衍生物的药理学可接受的盐,可以提及例如,与钠、钾、钙等无机碱的盐;以及与吗啉、哌啶等有机胺的盐。
本发明的用于治疗间质性膀胱炎的试剂可通过将由通式(I)表示的苯氧基乙酸衍生物或其药理学可接受的盐或其水合物或溶剂合物与常规使用的药物载体混合而制备。
所述药物载体可响应于每种剂型通过任选组合它们而使用,并且它们的例子包括乳糖等填充剂;硬脂酸镁等润滑剂;羧甲基纤维素等崩解剂;羟丙基甲基纤维素等粘合剂;聚乙二醇等表面活性剂;碳酸氢钠等起泡剂;环糊精等增溶剂;柠檬酸等酸味剂;乙二胺四乙酸钠盐等稳定剂;磷酸盐等pH调节剂等。
关于本发明的用于治疗间质性膀胱炎的试剂的剂型,可以提及例如,粉末、颗粒、fine subtilaes、干糖浆、片剂、胶囊等口服给药制剂;注射剂、粘合剂制剂、栓剂等非肠道给药制剂等,其中口服给药制剂是理想的。
以如下方式制备上述药物制剂是理想的,所述方式为每个成年人每天以口服给药制剂给药1至1000mg,特别是0.01至100mg范围内的由通式(I)表示的苯氧基乙酸衍生物,或其药理学可接受的盐或其水合物或溶剂合物,一天一次或将每天剂量分成数剂。
本发明的用于治疗间质性膀胱炎的试剂还可包含间质性膀胱炎的其它药物,优选具有不同功能机制的间质性膀胱炎药物。作为具有不同功能机制的间质性膀胱炎用药物,可例举的有上述三环抗抑郁剂、抗组胺剂、类固醇、甲苯磺酸舒普拉司特、木聚硫钠、Ca拮抗剂、肝素、透明质酸等。
实施例
基于实施例在下文中进一步详细描述本发明,但本发明不限于这些内容。
测试实施例1
利用聚乙烯管PE 50对已经通过腹膜内给药0.15ml 20%聚氨酯麻醉的雌性Balb/c小鼠(Japan SLC)进行气管插管。将聚乙烯管PE 10通过尿道插入膀胱,并通过该管注射(-)-2-[4-[2-[[(1S,2R)-2-羟基-2-(4-羟苯基)-1-甲基乙基]氨基]乙基]-2,5-二甲基苯氧基]-乙酸乙酯(下文中被称为“化合物1”)的盐酸盐,该盐酸盐已经溶解于生理盐水和2当量氢氧化钠中至浓度为10μM,并用生理盐水进一步稀释成多个浓度。从注射起1小时后,将溶解于包含0.1%DMSO和0.1%吐温80的生理盐水中的Evans蓝(30mg/kg)和辣椒素(0.3mg/kg)的溶液(10ml/kg)通过尾静脉给药。给药后精确地5分钟,通过颈椎错位处死动物以提取膀胱。从所提取的膀胱除去尿和血后,测量膀胱的湿重,并将该提取的膀胱放到事先在其中已经分配了150μl部分甲酰胺的96孔微量培养板的每个孔中。在将所述膀胱在甲酰胺中浸渍过夜后,通过在620nm波长处测量100μl上清液的吸光度而确定在所述膀胱组织中的颜料。另外,计算每1mg膀胱湿重的Evans蓝颜料的量。关于这一点,其中将生理盐水注射到膀胱中并对其给药不包含辣椒素的Evans蓝溶液的小鼠用作正常对照。
结果在图1中示为平均值±标准偏差。在正常对照组和辣椒素刺激组之间的组间显著性差异通过student t-检验检查。在化合物1给药组和非给药组之间的组间显著性差异通过差异的一维分析和随后的Dunnett多组间比较进行检查。p<0.05的值被认为是显著性的。
在对照组和溶剂组之间,Evans蓝颜料的量在溶剂组中显著性高(p<0.01)。另外,化合物1浓度依赖性地降低Evans蓝颜料的量。具体地,Evans蓝颜料的量在1μM给药组中显著降低(p<0.01====,这与对照组的水平相同。
测试实施例2
以如在实施例1中相同的方式确定在膀胱组织中的颜料,除了用托特罗定替代化合物1和用Hartman氏溶液替代生理盐水和2当量氢氧化钠。关于这一点,其中将Hartman氏溶液注射到膀胱中并对其给药不包含辣椒素的Evans蓝溶液的小鼠用作正常对照。
在对照组和溶剂组之间,Evans蓝颜料的量在溶剂组中显著性高(p<0.01)。Evans蓝颜料的量在托特罗定给药组和溶剂组之间没有发现显著不同。
具有选择性β3-肾上腺素受体刺激作用的化合物1显著抑制辣椒素敏感性感觉神经,但具有毒蕈碱受体拮抗作用的托特罗定不抑制辣椒素敏感性感觉神经。
工业实用性
由于由通式(I)表示的苯氧基乙酸衍生物或其药理学可接受的盐或其水合物或溶剂合物具有选择性β3-肾上腺素受体刺激作用和显著的对辣椒素敏感性感觉神经的抑制作用,因此它可以用作如下疾病的预防或治疗剂:伴随疼痛的间质性膀胱炎和膀胱过度活动症,涉及辣椒素敏感性感觉神经的其它疾病(例如,急性或慢性和全身性或局部性疼痛和发炎),和肠易激综合征(IBS)等。
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PCT/JP2005/020499 WO2006051797A1 (ja) | 2004-11-10 | 2005-11-09 | 間質性膀胱炎の治療薬 |
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Shigeru Itabashi et al..Evidence that an atypical β-adrenoceptor mediates theprejunctional inhibition of non-adrenergic non-cholinergiccontraction in guinea-pig bronchi.European Journal of Pharmacology218.1992,218187-190. * |
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CN101056627A (zh) | 2007-10-17 |
EP1810673A4 (en) | 2009-11-11 |
TWI356699B (en) | 2012-01-21 |
US7446128B2 (en) | 2008-11-04 |
EP1810673A1 (en) | 2007-07-25 |
KR20070084500A (ko) | 2007-08-24 |
JP4928272B2 (ja) | 2012-05-09 |
TW200621226A (en) | 2006-07-01 |
CA2586459A1 (en) | 2006-05-18 |
AR051665A1 (es) | 2007-01-31 |
US20060100275A1 (en) | 2006-05-11 |
WO2006051797A1 (ja) | 2006-05-18 |
JPWO2006051797A1 (ja) | 2008-05-29 |
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