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CN1160347A - 吲哚衍生物在治疗皮肤病、外周神经病、关节炎、头痛、口面疼痛、过敏或慢性导气管阻塞病、青光眼及眼部炎症中的应用 - Google Patents

吲哚衍生物在治疗皮肤病、外周神经病、关节炎、头痛、口面疼痛、过敏或慢性导气管阻塞病、青光眼及眼部炎症中的应用 Download PDF

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CN1160347A
CN1160347A CN95195603A CN95195603A CN1160347A CN 1160347 A CN1160347 A CN 1160347A CN 95195603 A CN95195603 A CN 95195603A CN 95195603 A CN95195603 A CN 95195603A CN 1160347 A CN1160347 A CN 1160347A
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P·古帕塔
J·拉许尔特
S·琼斯
S·F·罗伯森
G·M·R·塞缪尔斯
A·B·威尔森
M·J·威思
K·L·蒙克豪斯
G·C·兰特
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Pfizer Research and Development Co NV SA
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Abstract

本发明提供了其中的R1和R2各自独立地代表氢或C1-C6烷基的式I化合物或其可药用的盐在制造用于治疗下列疾病的药物中的应用：皮肤病；外周神经病；关节炎；胃肠道或泌尿生殖器病；与物质或其戒除有关的头痛；紧张性头痛；儿科偏头痛；外伤后家族性自主神经机能异常头痛；口面疼痛；过敏性或慢性导气管阻塞病；青光眼或眼部疾病；或预防偏头痛。

Description

吲哚衍生物在治疗皮肤病、 外周神经病、关节炎、头痛、 口面疼痛、过敏或慢性导气管 阻塞病、青光眼及眼部炎症中的应用
本发明涉及某些吲哚衍生物在治疗或预防医学病症中的新用途。
国际专利申请WO92/06973公开了一系列吲哚衍生物，它们是有效的5-羟色胺(5-HT)激动剂。这些化合物可用于治疗由于血清素激活的神经传递作用不足而造成的疾病，包括高血压、抑郁、焦虑、饮食紊乱、肥胖、滥用药物、集束性头痛、偏头痛、疼痛和慢性阵发性偏头痛，以及与血管疾病有关的头痛。WO92/06973涉及的化合物包括(R)-5-(甲氨基磺酰甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚(实施例5A，称作CP-122,288)和(R)-5-(甲氨基磺酰甲基)-3-(吡咯烷-2-基甲基)-1H-吲哚(实施例6A，称作CP-122,638)。
已知CP-122,288和CP-122,638具有对抗硬脑脊膜中神经原性炎症的效力〔W.S.Lee和M.A.Moskowitz，Brain Research(脑研究)，626(1993)，303-305〕。
现已发现，式I化合物及其可药用的盐可用于许多病症
Figure A9519560300041
其中R1和R2独立地代表H或C1-C6烷基。
上述的病症包括：
(a)皮肤病，例如牛皮癣；湿疹，特应性湿疹性皮炎；瘙痒(也称作顽固性痒病)，包括与肝硬变、癌症和血液渗析有关的瘙痒；灼伤；烫伤；晒伤；昆虫咬伤；荨麻疹；汗腺异常；大疱状类天疱疮；光照性皮肤病；皮肤水疱；成人痤疮；水痘；以及皮炎性疱疹；
(b)外周神经病，包括带状疱疹后神经痛；糖尿病性神经病，例如外周多神经病和神经根病；灼性神经痛和反射交感神经营养不良；乳房切除术后神经痛；手术后神经痛和疼痛；外阴前庭炎；幻肢痛；丘脑综合症(中枢性中风后疼痛)；颞下颌关节综合症；跖骨痛(Morton神经痛)；以及由椎间盘脱出或腕管及跗骨管综合症造成的神经压迫引起的神经痛；
(c)关节炎，包括骨关节炎和类风湿性关节炎；全身性红斑狼疮；纤维性肌痛；类风湿性脊椎炎；腱炎；
(d)胃肠道和泌尿生殖器疾病，包括膀胱炎；胃食管回流；胃炎；欲望节制；肠炎；过敏性肠综合症；这些化合物在调节胃肠道活动性方面也有效；
(e)与物质或其戒除(例如停止服药)有关的头痛；紧张性头痛；儿科偏头痛；偏头痛的预防；以及外伤后家族性自主神经机能异常头痛；
(f)口面疼痛，包括牙疼和起源于牙的疼痛；耳疼；TMJ疼痛(颞下颌关节痛)；窦道痛；面部肌肉痛；非关节炎和非肌肉骨骼性颈痛；口腔溃疡；美尼尔症；以及非典型的面部神经痛；
(g)过敏性和慢性导气管阻塞病，包括鼻炎；结膜炎；支气管水肿；支气管哮喘；神经病性肺水肿(成人呼吸道疾病综合症)；过敏症；以及血管水肿；
(h)青光眼(也称作眼内压迫)和眼部炎症。
因此，本发明的一个方面涉及以上定义的式I化合物或其可药用盐在制造用于任何一种上述病症的药物中的应用。
本发明的另一方面涉及一种药物制剂，其中含有如上定义的式I化合物或其可药用盐以及与之混合的一种可药用的辅剂、稀释剂或载体，其特征在于，它适合施用于皮肤。如下所述，可以使用常规方法制备这种局部用制剂。这种制剂可以是适合施用于皮肤，而将其它用药途径排除在外。
本发明的又一方面涉及在任何一种上述病症中的使用方法，它包括对需要这种治疗的患者施用治疗有效数量的如上定义的式I化合物或其可药用的盐。
如上定义的式I化合物可以以旋光异构体的形式存在。本发明包括所有的旋光异构体及其混合物。但是，优选如式IA所示的、具有(R)型立体化学结构的式I化合物。
Figure A9519560300061
R1和R2可以代表烷基，它们可以是直链、环状或支链的。但是，优选R1和R2各自代表甲基。式I化合物包括CP-122,288、CP-122,638和(R)-5-(氨基磺酰甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-引哚。
式I化合物在防止或减轻上述病症方面的作用是出乎意料的。这些病症中有一些可以用辣椒素〔(E)-N-〔(4-羟基-3-甲氧苯基)甲基〕-8-甲基-6-壬烯酰胺〕来治疗，已知它能通过降低神经元中的神经肽含量拮抗神经原性炎症。但是，辣椒素的作用模式与式I化合物完全不同。在对患者施药时，辣椒素选择性地活化主要的感觉传入神经，造成称作“SP”(P物质)和“CGRP”(降钙素基因相关肽)的引起炎症的物质的释放。辣椒素的继续作用造成主要感觉传入神经中神经肽减少，于是这些神经丧失了促使组织发炎的能力。因此，辣椒素的最初作用一般是增强发痒和与神经原性炎症有关的其它作用。相反，上述的式I化合物通过对位于感觉神经末端处的抑制性受体的激活作用立即抑制炎症。由于功能上的这一差别，式I化合物的作用不能由已知的辣椒素的作用来预料；另外，式I化合物没有在施用辣椒素时由于最初的发炎而引起的不良作用。
式I化合物的可药用的盐包括无毒的酸加成盐，也即含有可药用的阴离子的盐。具体的盐在WO 92/06973中有叙述，该专利申请还介绍了制备上述化合物及供施用于患者的含有该化合物的制剂的方法。但是，至少对口服而言，优选使用富马酸盐。
上述的式I化合物及其盐可以用一种或多种可药用的载体以常规方式配制。因此，活性化合物可以配制成用于局部、口服、经颊、鼻内、非肠道(例如静脉内、肌肉内或皮下)或直肠给药，或者是适合吸入或吹入的形式。在上述的专利申请WO 92/06973中叙述了配制方法。
为治疗上述病症而对患者施用的化合物的日剂量将由医师对任何指定的患者来确定，但一般来说，口服、非肠道或经颊用药的单位剂量通常为0.1-200mg活性组分，对于体重70kg的成年人每天可以服用例如1-4次。在气溶胶制剂中，每份计量好的剂量或“喷出量”可以含20μg至1000μg化合物，总日剂量为100μg至10mg。但是，已经发现，化合物CP-122,288和CP-122,638及(R)-5-(氨磺酰甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚在小几个数量级的剂量下仍有效。于是，对于这些化合物用于局部、口服、经颊、鼻内、非肠道(例如静脉内、肌肉内或皮下)、直肠、吸入或吹入给药的典型的单位剂量是1ng-200mg，对于气溶胶制剂则剂量相应减小。
以下试验说明了试验化合物对于上述大多数病症的效力。
(i)本发明化合物在抑制炎症方面的作用可以用Escott和Brain的方法〔Br.J.Pharmacol.(英国药理学杂志)，1993，110，772-776〕证实，在该方法中测定大鼠在隐静脉神经刺激后的后爪水肿。试验化合物以不同的剂量静脉内给药，结果记录成在受刺激与未受刺激的后爪中血浆外渗物之比。发现化合物CP122,288在用药量低至2×10-14mol/kg时即有显著作用〔Kajekar，Br.J.Pharmacol)英国药理学杂志(1995，115，1-2〕。
(ii)本发明化合物在抑制血管舒张方面的作用可以用Kajekar等的方法〔Br.J.Pharmacol(英国药理学杂志)，1995，115，8P〕证实，在该方法中测定大鼠后爪在隐静脉神经刺激后的血管舒张。试验化合物以不同的剂量静脉给药，结果记录成皮肤血液流动增加的变化。发现CP-122,288在低至2×10-12mol/kg的剂量下仍有显著作用。
本发明用以下实施例示例说明实施例1局部用含水乳膏制剂
             组分     量(g)
  (R)-5-(甲氨基磺酰甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚富马酸盐     0.001g
  含水乳膏BP     999.999g
1kg含水乳膏BP中含乳化软膏(300g)、苯氧基乙醇(10g)和纯化水(690g)。1kg乳化软膏中含乳化蜡(300g)、白凡士林(500g)和液体石蜡(200g)。
实施例2
局部用油质乳膏制剂
             组分     量(g)
   (R)-5-(甲氨基磺酰甲基)-3-(N-甲基吡咯烷-2-基甲基)-1H-吲哚富马酸盐     0.001g
   油质乳膏BP    999.999g
1kg油质乳膏BP中含羊毛脂醇软膏(500g)、苯氧基乙醇(10g)、干燥的硫酸镁(5g)和纯化水(485g)。1kg羊毛脂醇软膏中含羊毛脂醇(60g)、硬石蜡(240g)、白凡士林(100g)和液体石蜡(600g)。

Claims (14)

1、式I化合物或其可药用的盐在制造用于治疗皮肤病的药物中的应用其中R1和R2各自独立地代表氢或C1-C6烷基。
2、权利要求1定义的式I化合物或其可药用的盐在制造用于治疗外周神经病的药物中的应用。
3、权利要求1定义的式I化合物或其可药用的盐在制造用于治疗关节炎的药物中的应用。
4、权利要求1定义的式I化合物或其可药用的盐在制造用于治疗胃肠道或泌尿生殖器疾病的药物中的应用。
5、权利要求1定义的式I化合物或其可药用的盐在制造药物方面的应用，该药物用于治疗与物质或其戒除有关的头痛、紧张性头痛、儿科偏头痛、外伤后家族性自主神经机能异常头痛，或预防偏头痛。
6、权利要求1定义的式I化合物或其可药用的盐在制造用于治疗口面疼痛的药物中的应用。
7、权利要求1定义的式I化合物或其可药用的盐在制造用于治疗过敏性或慢性导气管阻塞病的药物中的应用。
8、权利要求1定义的式I化合物或其可药用的盐在制造用于治疗青光眼或眼部炎症的药物中的应用。
9、权利要求1至8中任一项中的应用，其中R1和R2均代表甲基。
10、上述任何一项权利要求中的应用，其中的式I化合物是富马酸盐的形式。
11、权利要求1中的应用，其中的药物是用于治疗瘙痒。
12、上述任何一项权利要求中的应用，其中式I化合物具有式IA所示的(R)型立体化学结构
Figure A9519560300031
13、一种药物制剂，其中含有权利要求1中定义的一种式I化合物或其可药用的盐，以及与之混合的一种可药用的辅剂、稀释剂或载体，该制剂的特征在于，它适合施用于皮肤上。
14、一种治疗以下疾病的方法：
(a)皮肤病；
(b)外周神经病；
(c)关节炎；
(d)胃肠道或泌尿生殖器病；
(e)与物质或其戒除有关的头痛；紧张性头痛；儿科偏头痛；外伤后家族性自主神经机能异常头痛；或预防偏头痛；
(f)口面疼痛；
(g)过敏性或慢性导气管阻塞病；或
(h)青光眼或眼部炎症；该方法包括向需要这种治疗或预防的患者施用治疗有效量的权利要求1定义的式I化合物或其可药用的盐。
CN95195603A 1994-10-12 1995-10-05 吲哚衍生物在治疗皮肤病、外周神经病、关节炎、头痛、口面疼痛、过敏或慢性导气管阻塞病、青光眼及眼部炎症中的应用 Pending CN1160347A (zh)

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