CN1282241A - 局部麻醉剂抗血管性头痛的新用途 - Google Patents
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Abstract
本发明公开式(Ⅰ)化合物或其药物上可接受的盐用于制造一种血管性头痛病症、尤其偏头痛治疗用药剂的新用途,其中R1代表C3-5烷基,R2与R3独立地代表C1-3烷基。
Description
发明领域
本发明涉及〔(3-烷氧基苯氧基)乙基〕二烷基胺衍生物的一种新用途。更具体地说,本发明涉及〔(3-烷氧基苯氧基)乙基〕二烷基胺衍生物作为一种血管性头痛治疗用药剂、尤其作为一种偏头痛治疗药剂的用途。
背景和先有技术
偏头痛是一种在受折磨个体中显示出治疗反应谱的疾病。有些患病者是幸运的,其疗法可以是非处方药治疗,或甚至利用行为改变、针刺、和催眠作为顿挫头痛的手段的非药物养生法。卧床休息、使房间变暗、和利用放置到颞动脉及其分支上的冰袋,可以改变发作。睡眠在结束发作方面也有有益的效果。然而,大多数患者将需要处方药来缓解偏头痛。最需要治疗的症状是头痛和胃肠症状。在较小的程度上,畏光和预感成为治疗的理由;后者也可能是十分紊乱的而且需要治疗,尽管其持续时间相当短暂。急性偏头痛期间,由于胃肠蠕动减少,药剂经口吸收并不是最好的。发作越严重,吸收减少程度越大。此外,恶心和频繁呕吐的存在将妨碍药理性药剂的经口给药。
在20世纪大部分时间内,麦角生物碱已经成为有效疗法的基石。但仍有很多患者对麦角类药物没有反应。它们发现反应是不完全的,所遇到的副作用是频繁的和紊乱的,而且禁忌妨碍它们用于很多偏头痛患者。
偏头痛的确切发病机理仍不清楚。已经提出了很多理论,但无一能解释所有临床特征或解释近年来证实的所有病理生理方面。人们的认识一直在血管理论(Wolff,1963年)与神经原理论(Sicuteri,1986年)之间摆动,以及短暂末梢血液移动(Hannington等人,1981年)。然而,近年来,已经出现一种普遍共识:在偏头痛中,血管部分和神经部分两者都有关,而且很可能相互关联(Lance等人,1983年;Welch,1987年:Olesen,1991年)。
最近的流行病学数据表明,成年妇女中的17.6%和成年男人中的5.7%患偏头痛(Stewart等人,1992年)。疾病控制中心(1991年)最近报告,近十年来,偏头痛的流行已经增加60%。此外,偏头痛被显著漏诊,患偏头痛的成年妇女中只有40%、成年男人中只有30%被诊断为患者(Lipton等人,1992年)。还有,这个未诊断偏头痛患者群体中的80%经历着无能(Stewart等人,1992年),多数人为其它医学症状寻求定期医疗护理。
偏头痛也被漏治。只有约40%妇女和30%男人利用处方药(Celentano等人,1992年)。然而,这些患者中多数中断了处方药疗法而依靠非处方药疗法。
目前用于治疗偏头痛及其它形式的血管性头痛的最常见药物,除其它外,有2,2,3-三甲基丁烷类、麦角胺、阿司匹林、和NSAIDS。
刚才提到的药物的一个主要问题是,它们往往有60分钟至多达4小时的药效开始时间,这在偏头痛等血管性头痛病症的治疗中是一个缺点。此外,这些药物往往呈适合于经口给药的形式,从而往往给患者带来问题,因为患有偏头痛或其它形式的血管性头痛病症的患者中间恶心和呕吐是常见的。
《头痛》(Headache,1995;35:pp 83-84)报告了一项用喷雾瓶经鼻内给药的利多卡因(4%)研究。这项研究的结果显示,该研究中的患者只有27%经历轻度缓解,且该研宄中的患者无一经历优异缓解。
WO 98/38998公开了左旋布比卡因和罗哌卡因在偏头痛治疗中的用途。然而,这些局部麻醉剂在结构上区别于按照本发明使用的局部麻醉剂。
为了达到使患有血管性头痛的患者感到满意的头痛缓解,用来治疗血管性头痛病症的药物较好应能迅速起作用,而且也应具有尽可能少的副作用。
因此,本发明要解决的课题是为血管性头痛病症、尤其偏头痛找到一种新的治疗途径。本发明要解决的又一个课题是找到一种能向患有血管性头痛病症的患者提供迅速起作用、即迅速缓解疼痛以及缓解与血管性头痛病症并发的其它症状的新治疗途径。
发明概要
R1代表C3-5烷基,和
R2与R3独立地代表C1-3烷基。
本发明的一个进一步方面是以上式Ⅰ化合物用于制造一种偏头痛治疗用药剂的用途。
本发明的又一个进一步方面是血管性头痛病症、尤其偏头痛的一种治疗方法,包含向患有所述血管性头痛病症的对象给药一有效量的一种含有式Ⅰ化合物作为活性剂的药剂。
熟悉本门技术的人员将知道属于血管性头痛定义之下的各种头痛病症种类。然而,可以给出下列扼要解释。
“血管性头痛”这一术语旨在包括任何一种血管性头痛,尤其偏头痛、簇状头痛、创伤后头痛、紧张性头痛、肌肉性头痛和由于血管疾病引起的头痛。
“偏头痛”这一术语应当按照《偏头痛国际分类法》(头痛分类委员会,1988年)来解释。然而,所规定的血管性头痛病症不要视为以任何方式对本发明的限制。
“簇状头痛”最典型地定义为在通常持续2周至3个月的时期内的发作、并间隔至少14天但通常若干个月的缓解的暂时簇状发作-这种类型的簇状头痛也称为“阵发性簇状头痛”。“慢性簇状头痛”的特征在于在一年以上时间内不存在至少14天的缓解(《疼痛教科书》第3版第504页,1994年)。
“创伤后头痛”是作为某种头部创伤的结果而引起的头痛(《疼痛教科书》第3版第504页,1994年)。
“紧张性头痛”和“肌肉性头痛”属于以前描述为“肌肉收缩”、“精神性的”、“应力”或“基本的”的头痛群(《疼痛教科书》第3版第502页,1994年)。
按照以上式Ⅰ的化合物也可以较好地用于鼻区外科。
“迅速起作用”这一术语系指治疗效果或预防效果较好能在给药时间起15分钟内达到。
患有偏头痛等血管性头痛症状的患者往往感觉到头痛发作正在逼近。按照本发明,当一位患者开始感到血管性头痛病症的发作就要折磨他或她时,这位患者就可以服用、较好经鼻内服用某一剂量的式(Ⅰ)化合物。由于式Ⅰ的活性剂能迅速起作用,因而正在逼近的头痛的发作就会在它发展成一种疼痛的血管性头痛病症之前被阻止。
按照本发明的用途也涵盖式Ⅰ化合物作为急救药给药。这意味着式Ⅰ化合物的使用对于充分发展的偏头痛等血管性头痛病症的治疗也是有效的。
因此,本发明的意图不仅涵盖血管性头痛病症的治疗性处理,而且也涵盖血管性头痛病症的预防性处理。
包含以上式Ⅰ化合物作为活性剂的药剂可以以进一步包含药物上可接受的载体、稀释剂或辅药的医药配方形式给药。
按照以上式Ⅰ的化合物可以经鼻或经静脉内给药。较好,该药剂是以喷雾剂形式经鼻给药。“喷雾剂”这一术语将是熟悉本门技术的人员所熟知的,但包括一种诸如为增加与鼻粘膜的接触面积而分布的溶液。呈滴剂和散剂形式的药剂的给药是一种更加有用的替***法。
以上式Ⅰ的活性剂的剂量将因所用配方而异,也因要治疗的血管性头痛病症的严重性而异。较好的剂量是0.01~200mg活性剂/kg体重、更好的是0.1~2mg活性剂/kg体重。若式Ⅰ化合物用于预防性处理,则适用类似的范围。
按照本发明用作活性剂的较好化合物,是选自下列任何一种的式Ⅰ化合物:
异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
二异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
二乙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
异丙基·甲基·〔2-(3-正丁氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正丁氧基苯氧基)乙基〕胺;
二异丙基·〔2-(3-正丁氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正戊氧基苯氧基)乙基〕胺;和
二异丙基·〔2-(3-正戊氧基苯氧基)乙基〕胺。
按照本发明使用的、特别好的式Ⅰ化合物是:
(ⅱ)乙基·异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺,即式Ⅲ化合物
生物学评估
有人提出涉及血管舒张和血浆蛋白外渗的脑组织内部神经原性炎症是头痛发病的一种机理(Michael A.Moscowitz,《神经病学》43,(增刊3),1993年6月)。
Ⅰ.为了确定以上式Ⅰ化合物抑制神经原性炎症的能力,使用了以下试验模型。
考察了异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺对大鼠后爪神经原性炎症的效果。
动物准备
6只雄性Sprague Dawley大鼠(260-290g)用氧化亚氮/氧混合物(2/3-1/3)中的2%异氟甲氧氟烷麻醉,在***气管导管后进行人工通风。给颈静脉插导管,经静脉内注射0.06mg/kg泮库溴铵(Pavulon)而使这些动物瘫痪。在整个实验期期间,监测异氟甲氧氟烷、O2、N2O和最后一次呼吸进出肺部的CO2(3.5~4.5%)。核心温度用家用电热毯***保持在38±0.5℃。
把这些动物准备得能进行双腿坐骨神经的电刺激(3mA,2ms,2Hz,5min)。在刺激前10分钟,在连接刺激电极的坐骨神经末梢上,施用10~20μl异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺(2%)凝胶配方(批号TARO-83-2)或需要时施用载体(批号106-10-2)。然后,在电极近端切断这些神经,在刺激前2分钟经静脉内给药伊文思蓝染料(10mg/ml,kg)。
神经原性炎症评价
在刺激结束后5分钟,利用以下表1中所示的4分法,评定受坐骨神经支配的后爪皮肤区域中伊文思蓝定域外渗等级,从而评价神经原性炎症。在初步实验中,核查了该载体不能阻止神经原性炎症的发展。
表 1
分值 | 伊文思蓝外渗 |
0 | 皮肤上无蓝色斑点证据 |
1 | 坐骨神经支配面积的<25%染成蓝色 |
2 | 坐骨神经支配面积的25~75%染成蓝色 |
3 | 坐骨神经支配面积的>75%染成蓝色 |
实验方案
在以下进行的试验中使用如下凝胶配方。
成分 | 数量[mg/g] |
异丙基·甲基·[2-(3-正丙氧基苯氧基)乙基]胺 | 20 |
羟丙基甲基纤维素4000cps | 20 |
盐酸2M | 44 |
氢氧化钠2M,调至pH4.0~5.5 | 适量 |
水,纯化到1.00g | 适量 |
该凝胶是通过将异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺与盐酸混合、然后添加该水的大部分来制备的。将混合物搅拌,直至异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺全部溶解。将pH调至约4,添加剩余的水。得到的溶液加热到70℃,然后边剧烈搅拌边添加羟丙基甲基纤维素。最后,该胶冻边搅拌边冷却,测定pH,必要时将其调至4.0~5.5。
3只大鼠在一侧坐骨神经上得到如上所述的2%凝胶配方,而在另一侧得到载体。两侧坐骨神经同时用同一种恒电流刺激器刺激。用载体处理的一侧得到异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺(2%)凝胶配方凝胶和刺激程序,而另一侧要么没有处理要么没有刺激,然后用来作为假冒对照(没有神经原性炎症)。如同以下表2中所示,在坐骨神经上局部施用的异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺(2%),阻止了如伊文思蓝外渗所评价的大鼠中神经原性炎症的发展。
表 2
处理 | 分值 | 1 | 2 | 3 | |
异丙基·甲基·[2-(3-正丙氧基苯氧基)乙基]胺(n=6) | 5 | 1 | |||
载体(n=3) | |||||
假冒(n=3) | 3 |
Ⅱ.临床模型
对按照4分口述评定尺度(VRS)(分别为无、轻度、中度和重度)有中度到重度疼痛的偏头痛患者给药一种上述式Ⅰ化合物。给药途径是两种不同类型的经鼻给药:一种是前方施用,另一种是鼻背施用。每一种给药类型都有各自的无效对照剂对照。按照目视类比尺度(VAS)记录患者的底线VAS分值。
每位患者在10分钟时间内每2分钟每个鼻孔喷一次药。因此,每位患者得到上述式Ⅰ化合物的总共10次喷药(每个鼻孔喷5次)。
在第一波给药(每个鼻孔喷1次)之后,每5分钟记录一次患者满意程度,直至2小时。按照4分VRS和VAS尺度记录偏头痛疼痛情况,初次给药后2小时前每15分钟记录1次,然后在24小时前每小时记录1次。按照与VRS和VAS相同的时间表,记录恶心、呕吐、畏光、畏声等其它症状。
在整个处理期中,以及在研究药物给药后的跟踪访问时,监测有害事件。
Claims (13)
2.按照权利要求1的用途,其中,血管性头痛病症是偏头痛、簇状头痛、创伤后头痛、紧张性头痛、肌肉性头痛和由于血管疾病引起的头痛中任何一种。
3.按照权利要求2的用途,其中,血管性头痛病症是偏头痛。
4.按照以上权利要求中任何一项的用途,其中,该活性剂是选自下列任何一种的式Ⅰ化合物:
异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
二异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
二乙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
异丙基·甲基·〔2-(3-正丁氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正丁氧基苯氧基)乙基〕胺;
二异丙基·〔2-(3-正丁氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正戊氧基苯氧基)乙基〕胺;和
二异丙基·〔2-(3-正戊氧基苯氧基)乙基〕胺。
5.按照权利要求4的用途,其中,该活性剂选自下列的任何一种:
异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;和
二异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺。
6.按照以上权利要求中任何一项的用途,其中,该用途适合于经鼻内给药。
7.按照以上权利要求中任何一项的用途,其中,该用途适合于经静脉内给药。
8.血管性头痛病症的治疗方法,包含对患有所述血管性头痛病症的患者给药一有效量的通式Ⅰ化合物或其药物上可接受的盐式中
R1代表C3-5烷基;和
R2与R3独立地代表C1-3烷基。
9.按照权利要求8的方法,其中,血管性头痛病症是偏头痛。
10.按照权利要求8或9的方法,其中,该活性剂选自下列任何一种:
异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
二异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
二乙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
异丙基·甲基·〔2-(3-正丁氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正丁氧基苯氧基)乙基〕胺
二异丙基·〔2-(3-正丁氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正戊氧基苯氧基)乙基〕胺;和
二异丙基·〔2-(3-正戊氧基苯氧基)乙基〕胺。
11.按照权利要求10的方法,其中,该活性剂选自下列任何一种:
异丙基·甲基·〔2-(3-正丙氧基苯氧基)乙基〕胺;
乙基·异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺;和
二异丙基·〔2-(3-正丙氧基苯氧基)乙基〕胺。
13.权利要求12的药物组合物,其中,血管性头痛病症是偏头痛。
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CN108473560A (zh) * | 2015-09-24 | 2018-08-31 | 泰瓦制药国际有限公司 | 预防、治疗和减轻(持续性)创伤后头痛 |
US11028160B2 (en) | 2016-09-23 | 2021-06-08 | Teva Pharmaceuticals International Gmbh | Treating refractory migraine |
US11555064B2 (en) | 2014-03-21 | 2023-01-17 | Teva Pharmaceuticals International Gmbh | Treating headache comprising administering an antibody to calcitonin gene-related peptide |
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US7799337B2 (en) | 1997-07-21 | 2010-09-21 | Levin Bruce H | Method for directed intranasal administration of a composition |
US6491940B1 (en) | 1999-01-27 | 2002-12-10 | Bruce H. Levin | Apparatus for administering composition for inhibiting cerebral neurovascular disorders and muscular headaches |
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US11555064B2 (en) | 2014-03-21 | 2023-01-17 | Teva Pharmaceuticals International Gmbh | Treating headache comprising administering an antibody to calcitonin gene-related peptide |
CN108473560A (zh) * | 2015-09-24 | 2018-08-31 | 泰瓦制药国际有限公司 | 预防、治疗和减轻(持续性)创伤后头痛 |
US11028160B2 (en) | 2016-09-23 | 2021-06-08 | Teva Pharmaceuticals International Gmbh | Treating refractory migraine |
US11028161B2 (en) | 2016-09-23 | 2021-06-08 | Teva Pharmaceuticals International Gmbh | Treating refractory migraine |
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HUP0100599A3 (en) | 2002-04-29 |
ID26703A (id) | 2001-02-01 |
SE9704770D0 (sv) | 1997-12-19 |
CA2314452A1 (en) | 1999-07-01 |
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NO20003138D0 (no) | 2000-06-16 |
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EE200000394A (et) | 2001-12-17 |
WO1999032103A1 (en) | 1999-07-01 |
JP2001526217A (ja) | 2001-12-18 |
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