CN1117560C - 反流抑制剂 - Google Patents
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Abstract
本发明涉及使用GABAB受体激动剂抑制一过性食管下括约肌松弛,和治疗胃食管反流疾病。
Description
技术领域
本发明涉及使用GABAB受体激动剂抑制一过性食管下括约肌松弛;治疗胃食管反流疾病;和/或治疗婴儿反胃。
技术背景
反流
在一些人中,食管下括约肌(LES)较其他人更经常易于松弛。结果,在此时由于机械屏障暂时丧失,胃内液体能够进入食管,这一情况下文称为“反流”。
胃食管反流疾病(GERD)是最普遍的上消化道疾病。目前治疗目的在于减少胃酸分泌,或通过增强食管清除力、食管下括约肌张力和胃排空,减少食管的酸接触。反流的主要机理已被认为取决于低张力的食管下括约肌。然而,最近的研究(如Holloway和Dent(1990)Gastroenterol.Clin.N.Amer.19,517-535)已显示绝大部分反流情况发生于一过性的食管下括约肌松弛(TLESR)时,即并非由吞咽触发的松弛。也已显示在患有GERD的病人中胃酸分泌通常是正常的。
因此,需要能减少TLESR的发生并且从而防止反流的化合物。理想地,该化合物应具有约12小时的作用时间,因为绝大部分反流发生在白天和饭后。
WO87/04077和US5,036,057公开了包含局部麻醉的、适合抑制食管下括约肌松弛的药用组合物。
GABAB受体激动剂
GABA(4-氨基丁酸)是在中枢和周围神经系统中的一种内源性神经递质。GABA受体传统上被分为GABAA和GABAB受体亚型。GABAB受体(参见kerr,D.I.B.和Ong,J.(1995)Pharmac.Ther.67卷,187-246页)属于G-蛋白偶联受体的超家族。GABAB受体激动剂被描述为用于CNS疾病,如在脊柱强直中的肌肉松弛,心血管疾病,哮喘,肠运动功能紊乱如过敏性肠综合征的治疗,以及为prokinetic和止咳剂。GABAB受体激动剂也被公开用于呕吐的治疗(WO96/11680)。
其它GABAB受体激动剂或部分的激动剂被公开在EP0356128、EP0181833、EP0399949、EP0463969和FR2,722,192中。GABAB调节剂的化学方面的综述参见Froestl,W.和Mickel,S.J.在:GABAReceptors,271-296页(Eds,S.J.Enna和N.G.Bowery,Humana PressInc.,Totowa,NJ,U.S.A.1997)。
在本领域中已知通过使用被克隆的受体基因转染的细胞能够改善药物筛选。较传统的筛选,此类被转染的细胞可以提供几个好处,最重要的大概就是选择性。转染细胞的其它好处是它们允许评估药物对克隆的人类受体的活性。GABAB受体最近已被克隆的事实(Kaupmann等,Nature386(6622),239-246,20 March 1997)为开发作用于GABAB受体的更特效的药物提供了机会。所述论文公开了得自大鼠的称作GABABR1a和GABABR1b的两种受体亚型,但是很显然几种其它的亚型能被分离到。
本发明的发现
令人惊奇地发现GABAB受体激动剂能被用于抑制一过性食管下括约肌松弛,并且因此能用于治疗胃食管反流性疾病。
因此,本发明提供使用GABAB受体激动剂来制造一种抑制一过性食管下括约肌松弛(TLESR),或者更确切的说,治疗胃食管反流性疾病的药剂。对于这一发明的目的,术语“激动剂”应被理解为包括完全激动剂和部分激动剂两者,由此“部分激动剂”应被理解为能够部分地,而不是全部地,激活GABAB受体的化合物。
所述TLESR的抑制也暗示着所述化合物能被用于婴儿反胃的治疗。婴儿反胃的有效治疗将是治疗由反流的胃内容物的吸入引起的肺部疾病,以及治疗由摄入营养的过度丢失引起的生长不良的一种重要方法。
在本发明的优选形式中,所述GABAB受体激动剂是一个被取代的氨基丙酸衍生物,其酸性端(acidic head)为羧基、膦酸基(phosphinic group)、亚酸膦基(phosphonous group)或亚磺酸基(sulfinic group)。
对GABAB受体具有激动的或部分激动的亲和力并且按照本发明能被使用的化合物的实例是:
4-氨基丁酸(GABA),
4-氨基-3-(4-氯代苯基)丁酸(巴氯芬),
4-氨基-3-苯丁酸,
4-氨基-3-羟基丁酸,
4-氨基-3-(4-氯代苯基)-3-羟基苯基丁酸,
4-氨基-3-(噻吩-2-基)丁酸,
4-氨基-3-(5-氯代噻吩-2-基)丁酸,
4-氨基-3-(5-溴代噻吩-2-基)丁酸,
4-氨基-3-(5-甲基噻吩-2-基)丁酸,
4-氨基-3-(2-咪唑基)丁酸,
4-胍基-3-(4-氯代苯基)丁酸,
3-氨基-2-(4-氯代苯基)-1-硝基丙烷,
(3-氨基丙基)亚膦酸,
(4-氨基丁-2-基)亚膦酸,
(3-氨基-2-甲基丙基)亚膦酸,
(3-氨基丁基)亚膦酸,
(3-氨基-2-(4-氯代苯基)丙基)亚膦酸,
(3-氨基-2-(4-氯代苯基)-2-羟基丙基)亚膦酸,
(3-氨基-2-(4-氟代苯基)丙基)亚膦酸,
(3-氨基-2-苯基丙基)亚膦酸,
(3-氨基-2-羟基丙基)亚膦酸,
(E)-(3-氨基丙烯-1-基)亚膦酸,
(3-氨基-2-环己基丙基)亚膦酸,
(3-氨基-2-苄基丙基)亚膦酸,
[3-氨基-2-(4-甲基苯基)丙基]亚膦酸,
[3-氨基-2-(4-三氟甲基苯基)丙基]亚膦酸,
[3-氨基-2-(4-甲氧基苯基)丙基]亚膦酸,
[3-氨基-2-(4-氯代苯基)-2-羟基丙基]亚膦酸,
(3-氨基丙基)甲基膦酸,
(3-氨基-2-羟基丙基)甲基膦酸,
(3-氨基丙基)(二氟甲基)膦酸,
(4-氨基丁-2-基)甲基膦酸,
(3-氨基-1-羟丙基)甲基膦酸,
(3-氨基-2-羟丙基)(二氟甲基)膦酸,
(E)-(3-氨基丙烯-1-基)甲基膦酸,
(3-氨基-2-氧代丙基)甲基膦酸,
(3-氨基丙基)羟甲基膦酸,
(5-氨基戊-3-基)甲基膦酸,
(4-氨基-1,1,1-三氟丁-2-基)甲基膦酸,
(3-氨基-2-(4-氯代苯基)丙基)亚磺酸,
3-氨基丙基亚磺酸。
优选地,对GABAB受体具有激动的或部分激动的亲和力的所述化合物是下例化合物中的任何-个:
4-氨基-3-(4-氯代苯基)丁酸(巴氯芬),
(3-氨基丙基)甲基膦酸,
(3-氨基-2-羟基丙基)甲基膦酸,
4-氨基丁酸(GABA),
(3-氨基-2-(4-氯代苯基)丙基)亚磺酸,
(3-氨基丙基)(二氟甲基)膦酸,
(3-氨基-2-氧代丙基)甲基膦酸,
4-氨基-3-(5-氯代噻吩-2-基)丁酸,
(3-氨基丙基)亚膦酸,
对所述目的的GABAB配位体的药学上可接受的盐的使用也包括在本发明中。绝大部分已知的GABAB配位体,例如巴氯吩、(3-氨基丙基)甲基膦酸和(3-氨基-2-(S)-羟基丙基)甲基膦酸,是两性的并且可以以内盐的形式出现。它们也能够形成酸加成盐和与碱形成的盐。这种盐是特别的药学上可接受的酸加成盐,和药学上可接受的用碱形成的盐。用于形成这种盐的合适的酸包括,例如,无机酸如盐酸、氢溴酸、硫酸或磷酸,或有机酸如有机磺酸和有机羧酸。GABAB配位体和碱的盐是,例如,碱金属盐,如钠盐或钾盐,或碱土金属盐,如钙盐或镁盐,以及铵盐,如那些含有氨或有机胺的盐。
对所述目的的GABAB配位体的旋光异构体的使用也包括在本发明中。许多已知的GABAB配位体,例如巴氯吩和(3-氨基-2-(S)-羟丙基)甲基膦酸,是因不对称碳原子的存在而产生的手性化合物。根据不对称的原子的存在,GABAB配位体可以是异构体混合物的形式,特别是外消旋物,或是纯异构体的形式,特别是对映体。
在另一方面,本发明提供了抑制一过性食管下括约肌松弛的方法,其包含给予需要这种治疗的哺乳动物(包括人类)有效剂量的如上述定义的GABAB受体激动剂。
本发明也提供用于抑制一过性食管下括约肌松弛的药用组合物。更确切地说,所述药用组合物对胃食管反流疾病的治疗和/或婴儿反胃的治疗是有用的。在所述药用组合物中的活性成分可以是如上述定义的GABAB受体激动剂中的任何一种。
日剂量
作为一种TLESR抑制剂和一种反流抑制剂的使用,GABAB受体激动剂可以以适合于已知GABAB受体激动剂对其是有用的其它疾病的剂量使用。所述活性物质通常的日剂量在一个较宽的范围内变化并且依据多种因素而定,例如每个病人的个体需要和给药途径。一般来说,药物剂量是在每天每公斤体重1μg至100mg的范围内,优选每天每公斤体重10μg至10mg。
药用制剂
为了临床使用,本发明的化合物被配制成口服、直肠、胃肠外或其它给药方式的药用制剂。该药用制剂含有与一种或多种药学上可接受的成分结合的本发明的化合物。载体可以是固体、半固体或液体稀释剂,或胶囊。这些药物制剂是本发明的进一步的目的。通常活性化合物的量是制剂重量的0.1-95%之间,优选在胃肠外使用的制剂中占0.2-20%(重量)和优选在口服给予的制剂中占1-50%(重量)。
在以剂量单位形式口服给予的含有本发明的化合物药用制剂的制备中,所选择的化合物可以与固体、粉末成分,如乳糖、蔗糖、山梨醇、甘露醇、淀粉、支链淀粉、纤维素衍生物、明胶或其它合适的成分,以及与崩解剂和润滑剂如硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠和聚乙二醇蜡混合。然后将混合物制作成颗粒或压成药片。
软明胶胶囊可以用装有活性化合物或本发明的化合物、植物油、脂肪或其它合适的用于软明胶胶囊的溶媒的混合物的胶囊来制备。硬明胶胶囊可以装有活性化合物的颗粒。硬明胶胶囊也可以装有与固体粉末成分如乳糖、蔗糖、山梨醇、甘露醇、马铃薯淀粉、谷物淀粉、支链淀粉、纤维素衍生物或明胶组合的活性化合物。
直肠给药的剂量单位可以被制备成(I)含有与中性脂肪碱混合的活性物质的栓剂形式;(II)含有与植物油、石蜡油或其它用于明胶直肠胶囊的合适的媒介混合的活性物质的明胶直肠胶囊形式;(III)预制的微量灌肠剂(ready-made micro enema)的形式;或(IV)干燥的微量灌肠剂的剂型,在临给药前置于合适的溶剂中复制。
口服给予的液体制剂可以以糖浆或混悬剂的形式制备,如含有0.2%-20%(重量)的活性成分的溶液或混悬液,其余成分由糖或糖醇和乙醇、水、甘油、丙二醇及聚乙二醇的混合物组成。需要时,这种液体制剂还可以含有着色剂、调味剂、甜味剂和羧甲基纤维素或其它增稠剂。口服给予的液体制剂可以以干粉的形式制备,在临使用前用合适的溶剂复制而成。
胃肠外给药的溶液可以被制备成本发明的化合物在药学上可接受的溶剂中的溶液的形式,优选占重量0.1%-10%的浓度。这些溶液也可以含有稳定剂成分和/或缓冲剂成分并且以安瓿或小瓶的形式分配成单位剂量。胃肠外给药的溶液也可以被制成干燥制剂,临用前用合适的溶剂复制而成。
化合物对TLESR活性的筛选
本发明进一步包括细胞的使用,该细胞由编码GABAB受体的核苷酸序列转染,用于筛选目的,以鉴定一过性食管下括约肌松弛的抑制剂。所述GABAB受体可以是GABAB受体亚型基因的任何一种,如GABABR1a和GABABR1b或迄今尚未克隆出的GABAB受体亚型。所述核苷酸序列可由任何物种得到,但优选从哺乳动物和最优选从人类获得。
因此,本发明进一步提供一种方法,用于一过性食管下括约肌松弛抑制剂的化合物的筛选,包括编码GABAB受体的核苷酸序列的使用。这一方法优选的形式包括步骤(a)用编码GABAB受体的核苷酸序列转染培养的细胞,以便GABAB受体在细胞的表面表达;(b)使受试化合物与所述细胞接触;和(c)测定该受试化合物是否结合到GABAB受体上,和/或激活GABAB受体。所述GABAB受体可以是,如GABABR1a或GABABR1b。
实施例
材料和方法
选用两种性别(5只雄性,3只雌性)重量在20-30kg的成年Labrador retriever狗。施行颈段食管造口术以便插管。在恢复期以后,狗被用于对照实验直到获得一个稳定的和可靠的对照反应。在对它们给予GABAB受体激动剂以前,狗被用于其它实验,但它们总是被允许一个至少2天的洗出(wash-out)期,在这段时间内不给予药物。每只狗的每个第四次实验均是一个对照实验,以确保结果的稳定性和可重复性。
实验大约在上午8时开始,此时动物已禁食约17小时。狗被放置在以前已习惯的巴甫洛夫台(Pavlov stand)中。一根细的末端开口的硅胶管通过食管造口被逆行引导进入咽部以记录吞咽。该导管用约每分钟2ml的空气灌注。一个多腔的装置被放在适当的位置以便记录近端胃、LES和远端食管的四个位置中的压力。该装置配备有6cm长的套管以可靠地测量LES压力。胃和LES腔道用每分钟0.45ml的除气蒸馏水灌注,而食管腔道以每分钟0.1ml(灌注)。使用一个低顺应性的气水压泵(low-compliancepneumohydraulic pump)以取得最理想的灌注条件。管腔内的压力用外部的压力传感器测量。使用Lab Windows/CVI软件(3.1版)放大并获得信号。压力刻度定在0和100mmHg,同时多腔装置放在稍低于压力传感器的水平。狗被放在适当的位置以使平均胃内压力约为0mmHg。一个锑pH-电极口向放置3cm到LES的上缘,并且如上所述获得该信号。使用Lab Windows软件分析获得的信号。
基线测量至少进行10分钟,然后用2分钟静脉给予溶媒(0.9%NaCl;0.5ml/kg)或GABAB受体激动剂。在给药完成后10分钟,以每分钟100ml(30ml/kg)的速率经多腔装置注入营养素。在营养素给予前10分钟开始持续静脉输注给予GABA;在某些例子中在给营养素前30分钟胃内给予R.S-巴氯芬。营养素含有10%蛋白胨(w/v)、5%内脂(Intralipid)(v/v)和5%D-葡萄糖(w/v)并且用HCl酸化至pH3.0。灌注以后立即以每分钟40ml吹入空气以构成从营养素灌注起始开始的总共90分钟的时间。然后对狗拔除插管同时进行基线测量以确保没有漂移发生。
TLESR由下列标准确定;LES和胃内压力差小于2mmHg、延续时间大于0.5秒和松弛不是由原发的蠕动(即由咽的信号)触发。压力下降的速率大于每秒钟10mHg。绝大部分(但不是全部)TLESR也能通过在食管造口特异的响声(即嗳气)被听觉觉察出。计算前45分钟时间和整个实验(90分钟)的TLESR的总数。与个体的对照数据相关的GABAB受体激动剂的作用被表示(n≥5)。每种激动剂至少在两只不同的狗中测试。
结果和讨论
TLESR实际上在禁食状态下从未发生,但总是发生于营养素灌注和空气吹入以后。TLESR的发生率在狗之间变化显著,但在个体内的变化则不大。
GABAB受体激动剂剂量依赖地减少TLESR的发生率。在45分钟的抑制大于整个实验期(90分钟)计算的抑制。由于胃的扩张是TLESR的主要刺激,当抑制化合物被给予时,45分钟值显然是最恰当的测量:TLESR的减少导致气体引起的胃扩张增强,并因此导致一个新的域值。这一混淆作用在实验的开始几乎不明显(见下面)。
GABAB受体激动剂对TLESR的抑制作用除了高剂量的R,S-巴氯芬引起一些镇静作用(在给药后大约一小时消失)以外,尚未记录到有行为的副作用。在对照实验中,当营养素灌注/空气吹入时胃内压力从0增加到约4mmHg。给予几乎完全抑制TLESR的剂量的GABAB受体激动剂伴有较大的胃内压力增加(10-13mmHg)。在实验结束时这种高胃内压力偶尔产生呕吐。它们是因为当TLESR被消除时,狗不能从胃内排出气体而发生。
结果(表1)显示在液体饮食后接着吹入空气,GABAB受体激动剂抑制TLESR的发生。该作用不是继发于镇静或催眠作用。结论是在胃食管反流疾病的治疗中,对GABAB受体具有亲和力的化合物可能是有用的治疗剂。
表1
在狗中各种GABAB受体激动剂对TLESR的作用(均数±标准误)。除非另外说明否则所有化合物均是静脉给予。
化合物 | 剂量(mg/kg) | 45分钟对照% | 90分钟对照% |
R,S-巴氯芬 | 0.3 | 47±6 | 66±8 |
1.5 | 11±6 | 43±19 | |
R,S-巴氯芬(胃内给予) | 1.5 | 12±6 | 54±12 |
R-巴氯芬 | 0.3 | 36±10 | 40±11 |
S-巴氯芬 | 1.5 | 76±10 | 92±10 |
(3-氨基丙基)甲基膦酸 | 0.003 | 57±12 | 76±5 |
0.01 | 32±8 | 39±7 | |
0.03 | 25±4 | 50±17 | |
0.1 | 5±5 | 33±9 | |
(3-氨基-2(S)-羟丙基)甲基膦酸 | 0.03 | 53±7 | 65±10 |
0.3 | 0±0 | 38±6 | |
GABA | 1.81 | 62±2 | 61±3 |
5.41 | 57±6 | 54±10 |
1静脉输注给予超过100分钟,即营养素和空气刺激以前10分钟和刺激期间。
Claims (13)
1.GABAB受体激动剂,或所述GABAB受体激动剂的药学上可接受的盐或旋光异构体在生产抑制一过性食管下括约肌松弛的药物中的用途。
2.权利要求1的用途,以治疗胃食管反流疾病。
3.权利要求1的用途,以治疗婴儿反胃。
4.权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是一个被取代的氨基丙酸衍生物,其酸性端为羧基、膦酸基、亚膦酸基或亚磺酸基。
5.根据权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是4-氨基-3-(4-氯代苯基)丁酸。
6.根据权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是(3-氨基丙基)甲基膦酸。
7.根据权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是(3-氨基-2-羟基丙基)甲基膦酸。
8.根据权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是4-氨基丁酸。
9.根据权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是(3-氨基-2-(4-氯代苯基)丙基)亚磺酸。
10.根据权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是(3-氨基丙基)(二氟甲基)膦酸。
11.根据权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是(3-氨基-2-氧代丙基)甲基膦酸。
12.根据权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是4-氨基-3-(5-氯代噻吩-2-基)丁酸。
13.根据权利要求1到3中任何一项的用途,其中所述GABAB受体激动剂是(3-氨基丙基)亚膦酸。
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