CN1091595C - 一种化合物在制备治疗消化不良症药物中的用途 - Google Patents

一种化合物在制备治疗消化不良症药物中的用途 Download PDF

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CN1091595C
CN1091595C CN96196137A CN96196137A CN1091595C CN 1091595 C CN1091595 C CN 1091595C CN 96196137 A CN96196137 A CN 96196137A CN 96196137 A CN96196137 A CN 96196137A CN 1091595 C CN1091595 C CN 1091595C
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L·芬德里克斯
A·佩特尔森
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Abstract

利用血管紧张肽II型1受体拮抗药预防和治疗消化不良症的方法和含有这种化合物的药物制剂。

Description

一种化合物在制备治疗消化不良症药物中的用途
发明领域
本发明涉及利用血管紧张肽II型1受体拮抗药预防和/或治疗消化不良症，及对消化不良症有作用的药物制剂的制备。
发明背景
本发明发现了在本技术领域已知的血管紧张肽II型1受体拮抗药的新医药用途。有关这些化合物对消化不良症的药理学和/或治疗性质未见任何报导或被公知。
本发明血管紧张肽II型1受体拮抗药为通式I
Figure C9619613700061
其中A分别为：
Figure C9619613700062
Figure C9619613700071
Figure C9619613700081
上述化合物可以外消旋体或基本上纯的旋光异构体使用；可以中性或盐的形式使用，优选生理上可用的盐，如钠盐，钾盐，铵盐，钙盐或镁盐。上述化合物也可以水解性酯的形式使用。
通式I的化合物，其中A为I∶1分子部分，普通命名为losartan，出自于欧洲专利EP253310。
通式I的化合物，其中A为I∶5分子部分，普通命名为CandesartanCilexetil，其密码为TCV-116，出自于欧洲专利EP-459136。
通式I的化合物，其中A为I∶9分子部分，普通命名为irbesartan。
通式I的化合物，其中A为I∶13分子部分，普通命名为Candesartan，出自于欧洲专利EP 459136。
肠胃***功能紊乱很普遍，它是由于大量医疗会诊的结果。每年约有30％的西方人经历了从温和消化不良到严重疼痛等消化不良症。这种症状可能是由某个器官发病所致(如消化器官溃疡)，或者更普通的是其病因未知(即正如通过各种诊断程序证明的上部肠道的器官病理学缺乏)。在临床治疗中，后者的并发症通常称为“非溃疡性消化不良”，“功能性消化不良”，“非器官性消化不良”等。病因未知的消化不良的治疗包括各种药理学原理(即胃酸的中和，用药物影响肠壁的蠕动等)，有些方法产生的作用尚未确定，有时甚至产生严重的负作用。
溃疡性消化不良可通过服用抗酸药或胃酸分泌抑制剂来治疗。非粘膜病理的类溃疡性消化不良症也可用相同方法治疗。这类消化不良症亚群(与酸有关的消化不良)被限定为与服用中和剂，或者用质子泵抑制剂或组胺2型受体拮抗药抑制胃酸分泌有关的症状。但前者持效时间短，每天需多次服用中和剂。后者的缺点是药价昂贵，和由于抗酸药的胃内条件增加肠道和/或***感染的危险性对内脏生理学有很大刺激。其它用于治疗消化不良症的药用物质是促运动药(如西沙必利)或抗胆碱能化合物，但它们一般都有变化无常的效果和较大的负作用。可以说目前用于治疗消化不良症的大多数药物都有严重的缺点。
干扰血管紧张肽原酶-血管紧张肽体系(RAS)的化合物是本技术领域熟知的并用于治疗心血管疾病，尤其是治疗动脉性高血压和心脏病。原则上，通过抑制血管紧张肽原酶或阻滞作用点的受体可干扰RAS。现在有了血管紧张肽原酶拮抗药，血管紧张肽转化酶抑制剂(ACE)和血管紧张肽II受体(AII)受体拮抗药。除能治疗心血管疾病外，本发明要求的某些化合物还对未特别指出的“肠胃功能紊乱”有疗效。
发明的公开
至今还不清楚上部胃肠道与酸有关的疾病的确切病理。但前提是***酸接近表层的粘膜细胞。正常条件下不会出现这种情况，因为粘液和碳酸氢盐溶液不停地流动，使得在粘膜表面形成一个中性层。不同管理机理的复杂网络调节着这个重要的酸中和过程。
本发明叙述一种治疗消化不良症的新方法。它是用药物干扰RAS，调节胃十二指肠粘膜表面的中和能力。
血管紧张肽原酶-血管紧张肽体系(RAS)：
已知RAS与交感神经***降低胃十二指肠的酸中和能力有关。上面已很清楚地介绍了可用于干扰RAS的几种不同方法。
令人惊讶的是已发现血管紧张肽II型受体拮抗药能药物性阻滞具有专一性的AII型l受体，逆转AII对提高胃十二指肠中和能力的抑制作用。因此，在血管紧张肽II型l受体存在时，增加原生质AII的浓度，将加强表面中和能力，进而必将消除***酸诱发消化不良症的前提。
本发明发现服用专一性AII型1受体阻滞剂，通过提高胃十二指肠粘膜的酸中和能力，有益于治疗消化不良症。
因此，本发明涉及一种治疗消化不良的新方法，它是用上述通式为I的已知化合物采药物性干扰血管紧张肽原酶-血管紧张肽体系。
本发明惊奇地发现通式为I的化合物，
Figure C9619613700101
或其生理学上可用的盐和/或其立体化学异构体可有效预防和/或治疗消化不良症。通式I中A分别为：
Figure C9619613700111
Figure C9619613700121
因已通过静脉途径在动物身上证实了对胃十二指肠酸中和能力的作用，有理由相信这种作用是全身性的，与所采取的给药方式无关，其它给药途径如直肠或口服给药也有作用。
在预防和/或治疗消化不良症时，给予通式I化合物的剂量由多种因素如病人的病情严重程度及其状态决定。每天口服、直肠及静脉给药的剂量范围为1至500毫克不等。
本发明的最佳方式是用其中A为I∶1(Losartan)或1∶5(TCV-116)的通式I化合物。
科学试验
为研究胃十二指肠酸中和能力，在被麻醉的老鼠身上做如下实验。给未经前处理的老鼠静脉注射AII，其酸中和能力有少许下降。而用AII受体阻滞剂Losartan预处理过的老鼠，给它注射相同剂量AII，发现其酸中和能力有所提高。表1给被麻醉的老鼠静脉注射AII前和后，其十二指肠粘膜的酸中和能力。
             未经前处理的老鼠           用Losartan前处理过的老鼠
              (μEq/h×cm)                    (μEq/h×cm)
原始            12±1，5                        13±1，2
注射AII         10±3                           22±2，3*
数据以±SEM方式给出，n＝6+6。有效数据差别用星号标出(学生t-试验，不成对样品)。给未经前处理的老鼠静脉注射AII，其酸中和能力降低了。用血管紧张肽II受体阻滞剂Losartan前处理过的老鼠，注射相同剂量AII，其十二指肠粘膜的酸中和能力显著提高。药物制剂
可以采用常规药剂形式。优选注射液形式，但也可采用其它制剂形式，如口服液、悬浮液、片剂或胶囊。可选择的用药途径有舌下片剂或溶液，直肠液，悬浮液或rectiols。
药物制剂含有1至500毫克活性组分，优选是10至250毫克。

Claims (8)

1.通式为1的化合物，或其生理学上可用的盐和/或其立体化学异构体在制成治疗消化不良症药剂方面的用途，
其中A分别为：
Figure C9619613700041
2.权利要求1的用途，其中通式I化合物中A为I∶1。
3.权利要求1的用途，其中通式I化合物中A为I∶5。
4.用于预防和/或治疗消化不良症的药物制剂，其活性组分为权利要求1的化合物。
5.权利要求4的药物制剂为剂量单元形式。
6.权利要求4的药物制剂包括活性组分及适于药用的载体。
7.权利要求4或6的药物制剂含有作为活性组分的其中A为I∶1的通式为I的化合物。
8.权利要求4或6的药物制剂含有作为活性组分的其中A为I∶5的通式为I的化合物。
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CA2225175A1 (en) 1997-01-03
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MX9710002A (es) 1998-07-31
SE9502219D0 (sv) 1995-06-19
EP0840607B1 (en) 2002-03-27
NO975922L (no) 1997-12-16
DE69620186D1 (de) 2002-05-02
CZ289400B6 (cs) 2002-01-16
HK1010152A1 (en) 1999-06-17
EE9700366A (et) 1998-06-15
DE69620186T2 (de) 2002-10-31
ATE214925T1 (de) 2002-04-15
WO1997000070A1 (en) 1997-01-03
KR19990023021A (ko) 1999-03-25
US6096772A (en) 2000-08-01
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AU1184097A (en) 1997-01-15
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CN1192681A (zh) 1998-09-09
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