CN1674919A - Cgrp拮抗剂化合物在治疗牛皮癣中的应用 - Google Patents
Cgrp拮抗剂化合物在治疗牛皮癣中的应用 Download PDFInfo
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- CN1674919A CN1674919A CNA038194236A CN03819423A CN1674919A CN 1674919 A CN1674919 A CN 1674919A CN A038194236 A CNA038194236 A CN A038194236A CN 03819423 A CN03819423 A CN 03819423A CN 1674919 A CN1674919 A CN 1674919A
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Abstract
本发明提供了基于具有降血钙素-相关基因肽(CGRP)拮抗作用的化合物治疗、预防和/或改善牛皮癣的方法和组合物。本发明还公开了鉴定具有CGRP拮抗剂作用的化合物的方法,其中所述的化合物是治疗牛皮癣的合适候选化合物。
Description
发明领域
本发明涉及作为CGRP拮抗剂,或降低其活性具体用于治疗和或预防牛皮癣的组合物和化合物。
背景技术
牛皮癣是一种困扰大约2%人群的慢性皮肤失调症。该疾病与皮肤细胞的快速更新(超增殖)并伴随分化的损失使得皮肤表面形成银白色鳞片相关。另外,毛细血管变得扭曲和扩张以及出现炎症反应,使得皮肤变红。牛皮癣最通常出现在头皮、膝盖、肘、手和脚等处,但可影响皮肤的任意一部分。其病因未知,但被认为有遗传的原因,且被认为是一种T-细胞调节的自身免疫皮肤失调症。人们进行了许多努力来治疗该疾病,且已经尝试了一些抑制细胞***进行局部和全身性治疗牛皮癣的方法,并在短时间内对清洁皮肤产生了有限的成功。然而,这些治疗操作的原理至今仍不清楚。本领域所采用的治疗看起来有减轻病症的迹象。病斑可自发地消失或通过治疗而消失,但很有可能会复发。
本发明的目的是基于强烈地表明牛皮癣是一种神经***疾病以及神经肽降血钙素基因-相关的肽(CGRP)是所述疾病的主要介质的观察结果和新发现来提供治疗牛皮癣的方法。
CGRP是在中枢神经***和外周神经***二者的神经末端中储存和释放的37个氨基酸的多肽。通过免疫组织化学(诸如ELISA)和放射免疫测定的方法在支配心脏、外周的和大脑的血管和肾脏的神经中检测到CGRP。已表明CGRP通过与已在许多组织中鉴定的特异性细胞表面受体结合来调节生物反应。
CGRP同样也是一种非常重要的伤口愈合的神经肽(NP)且是在所述作用过程中释放的第一种NP。CGRP是一种非常强烈的血管扩张剂和迟发型超敏反应(DTH)的强烈抑制剂。已知CGRP在毛发生长的调节中起作用且可刺激角质细胞的增殖。
类胰蛋白酶是一种裂解CGRP并降低其活性的蛋白酶。CGRP 8-37是通过类胰蛋白酶特异性裂解CGRP产生的内生肽。CGRP 8-37是CGRP受体的高度亲合性拮抗剂。人们认为这些拮抗剂是身体下调节神经信号(负反馈调控)所使用的内生化合物。
患牛皮癣的乳突状皮肤中比健康的皮肤中具有更多的毛细血管弯曲。水平结节中的这些血管是von Zumbusch寻常性牛皮癣和脓疱性牛皮癣中病斑的完整组分。牛皮癣病斑乳突状皮肤中的毛细血管袢变得扩张且在表皮增生之前已检测到其形态上的弯曲。基于对扩大中的牛皮癣病斑进行的光显微镜研究,Pinkus和Mehthregan推断伴随乳突中炎性细胞和血清渗出的最***管舒张是牛皮癣中的激发作用(Pinkus,Mehthregan J.Invest.Dermatol 1966 Jan;46(1):109-16)。
一些研究了扩大中的1-mm牛皮癣病斑的研究者发现牛皮癣病斑边缘处的真皮乳突的增殖增大了。他们认为该增大是一种激发作用,尽管刺激物是未知的(参见,例如,Braun Falco和Cristophers,Arch.Dermatol.Forsch.1974;251(2):95-110)。Braverman等人根据寻常性牛皮癣中弯曲恢复正常的模式以及Zumbuch疾病中血管标记的模式发现了毛细血管袢如何扩大的机制。外乳突静脉边缘的内皮细胞扩张且如乳突扩张一样动脉部分变得较短。静脉部分变成网孔状(Braverman,LM.,Psoriasis 3rd ed.(pp.399-407),1998,ed.:Roenikg,H.H.;Maibach H.l.,Marcel Dekker Inc.,NY)。
毛发生长周期过程中的大鼠皮肤微脉管***出现类似的现象(Sholley和Cotran Am.J.Anat.1976年10月;147(2):243-54)。通过内皮细胞的增殖增加了活跃生长的毛囊(毛发生长初期阶段)周围的毛细血管网的大小。事实上,由毛细血管提供所有的内皮细胞。在人皮肤,无毛的(Braverman,I.M.如上文)以及刮光的(McLeod,W.A.;J.Invest.Dermatol.,1970,55(5),354-7),毛囊周围的毛细血管网具有静脉超微结构:桥接穿孔和分层基膜。当大鼠毛囊进入毛发生长中期,血管网络的大小部分地通过丧失以及部分地皱缩而大大地减小。
毛发的生长循环是一种众所周知的现象(参见例如,Hair Structureand LifeCycle,http://follicle.com)。毛发以重复循环的方式生长。一个循环可被分为三个阶段:毛发生长初期(生长阶段)、毛发生长中期(过渡阶段)以及毛发生长终止期(休止期)。
在任意时刻,大约所有毛发的85%处于毛发生长初期阶段。在毛发生长初期阶段的末端,毛发进入毛发生长中期阶段,其持续大约一或两周的时间。毛发生长终期阶段紧接着毛发生长中期阶段且通常持续大约5-6周。在任一时刻,大约所有毛发的10-15%处于此阶段。毛发相对地大部分处于此阶段的原因可能是因为在伤口愈合情况下准备进行角质细胞增殖。为进行此作用,普通的因子被用于调节早期伤口愈合以及调节毛发的生长周期。CGRP提供了此种作用。
假定当皮肤痊愈时,CGRP使毛囊进入增生期在表面产生干细胞角质细胞来参与表皮的角质细胞增殖。角质细胞来自外根鞘或或毛囊的乳突真皮。这些认为神经肽在调节毛发生长中起重要作用的事实被进一步地支持(参见,例如,J.Invest.Dermatol.Symp.Proc.1997;2(1),61-68)。
研究表明真皮乳突可能是斑形脱发(AA)的主要目标。这就是为什么CGRP是AA和牛皮癣中干细胞的共同作用物的原因。所有特异性亚型的牛皮癣角质细胞被认为来自位于毛囊中的干细胞。
如实施例4所描述的,已观察到牛皮癣常常在皮肤中呈现为具有六角形结构,也就是说,单独分离的以及以蜂窝模式相互连接的牛皮癣病斑表现为六角形。假定这些六角形可表示感官神经分布的神经学单元。这些可表明当牛皮癣病斑扩大时涉及一或多个神经部分或单元。在Herpes Zoster(病毒神经感染)病斑中有类似的分布和形状(参见实施例5)。这些进一步支持了牛皮癣的模式是疾病神经起源的指示的理论。
牛皮癣中的六-角(六角形的)形状病斑形成了身体产生部分的固定大小的大部分,如实施例4所示。皮肤中神经分布的精确结构从来没有被详细描述过,但六角形的形状在自然中如在蜂巢以及肝脏的门静脉***中是广泛地存在的。
牛皮癣病斑最常见的部位可通过牛皮癣的神经起源来解释。病斑的严格对称是常见的且病斑位于已知的或可能的神经重叠的区域,如例如肚脐、后背、暂时刮光的区域、肘以及膝。在头皮和骶骨区域是与皮肤的胚胎发育最接近的神经嵴非常可能的胚胎期部分。这进一步被通过缺少表层发育不全的表皮大部分往往位于右颞颥区域的头皮上和脊椎裂位于腰骶区域的事实所支持。头皮、腰骶区、肘和膝中牛皮癣的位置是尤其让人感兴趣的。对于具有四肢的动物而言,这些部分为末端的背面、前面以及突出部分。牛皮癣病斑常常在皮肤上重复地出现在相同的位置,即具有记忆效应。这些通常与单纯性疱疹感染(***皮肤中的病毒神经感染)中所观察到的相同。我查看了具有沿皮片分布的牛皮癣病斑(神经支配区域)的牛皮癣患者的临床病例。相同的模式在带状疱疹感染(病毒神经感染)中被观察到。
发明人已经观察到牛皮癣病斑可能分布在手的神经支配区域。皮肤中的个别角质细胞也具有六角形的形式。牛皮癣角质细胞高水平表达刺激皮肤中神经生长的NGF(神经生长因子)。(Acta Derm Venmarch,1998,84-86)关于感觉神经损伤后牛皮癣得以改善的报道是进一步支持神经在牛皮癣发病机理中的作用的临床证据(J.of theAm.Acad.Dermatol.28,3,488-489;Int.J.Dermatol.1990;9:418-20)。
一些其它的观察支持了下述本发明的论点,即牛皮癣是一种神经发生疾病,这些在现有技术中并没有清楚地显示。脑血管发生意外事故之后牛皮癣发展到对侧至偏瘫。(Int.J:Dermatol.3.(8):598-9 1993年8月)。麻风病患者具有破坏了的外周神经。同时也也注意到麻风病患者具有降低的牛皮癣发生率。神经损伤伴随CGRP增加。CGRP 8-37(一种CGRP拮抗剂,如下所述)阻断了其增加(Am.J.Physio.268(2pt2)H584-90 1995年2月)。已有报道在皮肤神经切断后牛皮癣斑块迅速得以缓解(Dewing,S.B.Arch Dernatol 104:220-221 1971)。
在通过荧光素血管造影术进行的研究中,在着色的兔中观察到视网膜色素上皮细胞。在远离髓状射线的地方看到六角形模式。该模式在周缘比接近电极的地方变得更大。血管造影术检测的与通过扫描电子显微术和荧光光学显微术检测的视网膜色素上皮细胞在大小和形状上非常地匹配。这些在视网膜感官神经支配中的模式类似于皮肤神经单元所描述的。皮肤中的六角形模式在周缘即四肢变得较大(lida等,Nippon Ganka Gakkai Zasshi 1991,95(5):421-7)。
牛皮癣中的CGRP和P物质(SP)以及在神经功能中可能的协同作用。
Farber等在1986年首先提出了神经肽在牛皮癣发病机理中的可能的作用(参见综述Raychaudhuri,P.,Farber,E.M.Psoriasis 3rd ed.(pp.383-391),1998,ed.:Roenikg,H.H.;Maibach H.L,Marcel DekkerInc.,NY)。研究人员致力于研究SP以及被提议用于治疗牛皮癣的某些SP拮抗剂,例如Somatostatin和Spantide(Farber等人/,同上文)。SP和CGRP通常位于皮肤中的相同神经中。SP和CGRP在伤口愈合中都具有活性,CGRP在早期阶段且SP在稍后的阶段具有活性。报道显示在牛皮癣皮肤中有高密度的SP和CGRP,参见例如,Jiang等,Int.J.Dermatol.1998,37,572-574。
P物质拮抗剂Spantide抑制急性以及迟发型皮肤过敏性(DTH)反应。这些可通过CGRP被调节,如众所周知用CGRP抑制DTH,因此SP可作为CGRP的调节因子(Wallengren J.Br.J.Dermatol,1991,124(4):324-8)。
P物质调节CGRP的血管舒张活性。动物实验揭示了此现象依赖于来自肥大细胞的蛋白酶。(Brain S.D.;Williams,T.J.″Substance Pregulates the vasodilator activity of CGRP″.Nature 1988 335(6185),73-5)。这些实验表明当神经肽被注入到人皮肤中时,SP将通过CGRP诱导的持久血管舒张转变为瞬变响应。随后的研究(J.Geronol.:Biol.Sciences1996,Vol.51A,no,B354-B361)利用“大鼠后脚中的水疱模型”证明SP终止对CGRP已存在的血管舒张应答的能力。所观察的结果不但证实了SP和CGRP在人皮肤中的联合给药可限制CGRP的血管舒张活性,而且通过SP对血管舒张活性作用产生的调节抑制作用是剂量-依赖的。这些可表明牛皮癣中SP的变化是主要的调节(次级)特性。
Haukkarinen等报道了(Haukkarinen等,Journal of Pathology,(1996)180,200-205)含有SP、CGRP和VIP的感觉神经和含有活性类胰蛋白酶和无活性糜蛋白酶的肥大细胞之间的接触值的研究。牛皮癣病斑中肥大细胞的SP和CGRP的接触值增加了,而VIP的接触值减少了。类胰蛋白酶有效地裂解CGRP和VIP但不裂解SP,而糜蛋白酶裂解SP。这些表明了牛皮癣中的调节机制增加了CGRP的裂解但不增加SP的裂解,即增加了活性的类胰蛋白酶来下调控CGRP,但活性糜蛋白酶没有增加。
我相信在牛皮癣中,降低类胰蛋白酶活性可能是增加CGRP活性的主要步骤。这些可能是因为在CGRP的下调节(负反馈)的特异性步骤缺失了,因为CGRP 8-37没有充分地产生。这些修饰的肽是CGRP受体的高度-亲合性拮抗剂,正如以上所讨论的。如果牛皮癣中的特异性类胰蛋白酶没有被正确地构建和失去功能,其可能对CPGRP活性产生根本的影响。类胰蛋白酶编码基因中的一些突变可能会造成这种结果。牛皮癣的不同严重程度可通过特异性类胰蛋白酶中的不同突变来进行解释。因此,如果是这些情况,牛皮癣可通过在一种酶***中的改变且可仅仅通过所述类胰蛋白酶中任意牛皮癣亚型的单个氨基酸的改变来解释。
特定的实验支持了这些假设,例如,已知吸烟增加了牛皮癣可能性,且吸烟也为人们所知引起肺中类胰蛋白酶的缺陷。然而,这些不改变本发明的效果,通过阻断CGRP,可治疗或预防牛皮癣。这些假说可通过从牛皮癣患者以及鉴定可能的基因缺陷的对照组筛选类胰蛋白酶(或编码类胰蛋白酶的基因)被很容易地验证。
一些其它的针对CGRP的因子是比SP更可能的牛皮癣介质。CGRP不诱导引起痒感但SP会引起痒感,且痒感是通常最不与牛皮癣有关联的症状;CGRP不与SP一样产生风团及潮红,以及SP对于传导疼痛和烧灼感是非常活跃的,二者均不是牛皮癣的正常症状。然而CGRP产生长期的红斑,其与牛皮癣有关,但SP不产生。
有斑点的牛皮癣通常参见下述的链球菌感染。一些链球菌可引起此疾病。这些细菌通常全部产生外毒素C,其是一种当注入皮肤中引起血管舒张的热毒素。过去这些被用于称为Dicks试验的链球菌感染的诊断试验。来自北京医科大学的实验工作表明产生内毒素的大鼠其血浆中的CGRP水平增加了(Tang等,生理学报1997 4月;49(2):160-6(医学文摘PMID:9812851))。CGRP由感觉神经元释放且感觉神经元中CGRPmRNA的转录和CGRP的合成在大鼠内因性中毒的进展过程中增加了。
反复注射来自葡萄球菌的内毒素引起免疫缺陷小鼠中的角质增生。牛皮癣在链球菌感染活跃时发病可因此通过CGRP的增加来解释。
所有上述事实和描述的实验强烈地表明CGRP是牛皮癣的关键介质,其随后启发本发明提供了通过利用特异性CGRP拮抗剂治疗牛皮癣的方法。
一些化合物已被发现选择性地抑制CGRP受体,诸如小分子的非-肽化合物,肽和抗体。此类活性CGRP拮抗剂被期望用于通过CGRP调节对各种疾病病症进行的治疗中。被建议用于此治疗的疾病包括头痛,尤其是偏头痛;NIDDM;神经性炎症;心血管失调;慢性炎症;疼痛;内毒素性休克;关节炎;过敏性鼻炎;变应性接触性皮炎;炎症性皮肤病以及哮喘。然而据我所知,没有人建议用于治疗牛皮癣的化合物。
现有技术中公开的被用作CGRP拮抗剂的化合物包括4-亚硫酰基苯甲酰胺化合物(WO 98/56779),3,4-二硝基苯甲酰胺化合物(WO 98/09630),一组修饰的氨基酸(WO 00/55154),以及benzamidazolinylpiperadine化合物(WO00/18764)。
抗CGRP的抗体也已有描述,以及CGRP无活性的衍生物,例如缺少8个N-末端的氨基酸不同于正常CGRP的CGRP 8-37。US5,935,586描述了利用治疗剂/化妆品组合物中拮抗剂治疗皮肤病,尤其是,苔藓病、痒疹、pruriginous toxidermas和急性瘙痒。US 5,932,215描述了治疗皮肤充血、红斑痤疮和离散性红斑的类似应用。
发明概述
本发明的假说表明肽(CGRP)相关的降血钙素基因的超表达引起牛皮癣的大部分病理现象如超增殖,T-细胞数目的增加,血流量增加以及病斑的局部化。
其还可以解释日光的治疗效果,以及链球菌感染对牛皮癣的消极影响。斑秃(AA)是一种功能性毛发疾病其中缺少CGRP似乎是一种致因。AA和牛皮癣之间的反比关系已被观察并在此处描述。CGRP可能是在两种疾病中的共同因子,如其涉及乳突细胞用于伤口愈合的应用以及通过那些途径可激活伤口愈合作用中的毛囊,众所周知牛皮癣是一种与早期伤口愈合作用相关联的疾病。此处描述的实验表明牛皮癣病斑的六角形结构强烈地暗示所述疾病与感官神经支配的神经单元相关。
总之,其是发明人阐述的一种新的假说并在此处支持牛皮癣是一种神经起源的疾病以及CGRP可能是所述疾病的关键介质。依照这种假说,所述CGRP的调节在牛皮癣中不能适当地发挥功能,从而,通过利用CGRP拮抗化合物调节CGRP是控制牛皮癣的一种方式。
本发明描述了一种通过调节体内特别是皮肤中CGRP的浓度来治疗和预防牛皮癣的新方法,例如通过利用CGRP拮抗剂。本发明被新的实验和此处描述的对牛皮癣为神经病学起源且其中CGRP为关键介质的解释所支持。
本发明是基于通过改变至少所述牛皮癣病斑的CGRP水平诸如通过阻断CGRP活性可以治疗和/或预防所述疾病的概念。
这些可能受给药CGRP拮抗剂化合物,或给药类胰蛋白酶或其它影响CGRP水平的化合物的影响。
具体描述
如所描述的,本发明涉及通过利用CGRP拮抗剂化合物治疗、改善或预防牛皮癣的方法。迄今为止尚没有人想象到利用CGRP拮抗剂来治疗牛皮癣。因此,本发明的特征为至少一种治疗牛皮癣的CGRP拮抗剂化合物的应用。
“CGRP拮抗剂”在上下文中表示无论有机的或-无机的能够降低活性CGRP水平的任意分子,例如,通过抑制受体结合CGRP的抑制或抑制影响神经纤维合成和/释放CGRP,或增加对活性CGRP的分解。因此类胰蛋白酶活性的多肽属于此类入此处所定义的能通过裂解所述肽影响CGRP的水平,以及稳定类胰蛋白酶的化合物,诸如肝素。如上所述,最近已经开发了许多满足这些原则的化合物且从而应用于本发明中。
在这里,治疗表示治愈或至少部分缓解所述疾病症状至少一段时间的治疗方式,改善疾病表示完全或部分缓解牛皮癣症状。
微量渗析是用于组织液取样的方法。其已应用于皮肤及其它组织中。
激光-Doppler流量测定是用于测定皮肤中局部面积血流量的技术。
在第一个方面,本发明提供了一种治疗受试者牛皮癣的方法,包括将治疗有效量的至少一种在药学可接受制剂中的CGRP拮抗剂化合物施用于所述受试者。治疗有效量将依赖特定的化合物进行选择,但典型地在大约0.00001%到5%的用于所述治疗的药物组合物总重量的范围内,优选地为大约0.0001%到2.5%的重量,诸如在0.001%到到1%的范围内。或在0.001%到0.1%重量的范围内。
合适的药用制剂可根据传统的药学方法依赖所选择的化合物以及给药的预定途径来配制,如以下进一步所讨论的。
本发明的方法包括全身性的和/或局部的治疗方法。因此,用于本发明的组合物可口服给药,鼻给药,直肠给药,肺部给药,口腔或通过皮下注射,静脉注射或肌内注射进行给药来达到未梢的病斑,或通过局部性给药组合物,诸如局部地,真皮的,皮内的,或皮下地,或通过真皮或诸如通过微量渗析进行皮下注射。然而,目前优选的实施方案包括局部给药。
从此处所述的可很容易地理解,本发明提供了一个相关的方面,CGRP拮抗剂化合物在治疗、改善或预防受试者牛皮癣的药物制备中的应用。此药物优选地为在这里公开的组合物。
然而,在另一个方面,本发明提供了通过使用诸如上述定义的CGRP拮抗剂化合物减少毛发生长的方法。此方面来自CGRP调节毛发生长周期的新理论,正如上面所讨论的。在本发明优选的实施方案中,这些方法包括将药物诸如乳膏剂、软膏剂、凝胶、糊剂,电离子透入疗法(iontopophoresis)***、液体或洗液局部或皮肤涂覆到需要减少毛发生长的区域。
本发明的局部制剂包括活性成分与一或多种药用载体和/或赋形剂化合物以及选择性地一或多种治疗活性成分。
适于局部给药的制剂通常可配制为用于涂覆的任意药物方式,这些包括液体或半液体制剂包括洗液、乳膏剂、糊剂、软膏剂、脂质体、凝胶剂、诸如iontopophoresis、悬浮液和乳浊液、包括油/水(w/o)、w/o、o/w/o、w/o/w乳浊液或微乳浊液。它们可通过混合磨碎的或粉未状的活性成分,单独或在溶液或水悬浮液中或不含水液体中,借助于合适的机械设备,与疏水性或亲水性基体混合来获得。所述基体可为碳氢化合物诸如硬的、软的或液体石蜡,甘油,蜡(例如蜂蜡、巴西棕榈蜡),金属皂,粘胶,天然来源的油诸如玉米、杏仁、蓖麻或橄榄油、矿物油、动物油(perhydroxysqualene);或脂肪酸诸如硬脂酸以及醇类诸如乙醇、异丙醇和丙二醇。所述制剂可包括任意合适的表面活性剂诸如阴离子的、阳离子的或非离子型表面活性剂诸如山梨聚糖酯或其聚氧乙烯衍生物。同时也包括悬浮剂诸如天然树胶、纤维素衍生物或无机材料诸如silicaceous硅石。所述制剂可另外包括本领域公知的吸收促进剂、稳定剂,例如蛋白质稳定剂。
用于本发明的已知的拮抗剂化合物包括4-亚硫酰基苯甲酰胺化合物诸如WO985677934中公开的,诸如在WO98/09630中公开的二硝基苯甲酰胺化合物,benzamidazolinyl piperadine化合物,诸如WO00/18764中公开的,CGRP衍生物,包括具有序列THRLAGLLSRSGGMVKSNFVPTNVGSKAF(SEQ ID NO:1)的CGRP 8-37,和抗-CGRP抗体。本领域所描述的Boehringer Ingelheim制备的令人感兴趣的化合物,一种非肽分子,命名为BIBN4096BS(参见Wu等,Biochem.Soc.Trans.2002,8月.30(4):468-473)。
化合物被确定具有CGRP拮抗剂的活性且从而为用于本发明的候选化合物包括:
(±)-4-[(2-氯苯基)亚硫酰基]-N-甲基-N-(2-甲基苯基)-3-硝基苯甲酰胺;
(+)-4-[(2-氯苯基)亚硫酰基]-N-甲基-N-(2-甲基苯基)-3-硝基苯甲酰胺;
(-)-4-[(2-氯苯基)亚硫酰基]-N-甲基-N-(2-甲基苯基)-3-硝基苯甲酰胺;
(±)-4-[(4-氯苯基)亚硫酰基]-N-甲基-N-(2-甲基苯基)-3-硝基苯甲酰胺;
(±)-N-甲基-N-(2-甲基苯基)-4-[(1-环氧-2-嘧啶基)亚硫酰基]-3-硝基苯甲酰胺;
(±)-N-甲基-N-(2-甲基苯基)-3-硝基-4-(2-噻唑基亚硫酰基)苯甲酰胺;
(±)-N-甲基-N-(2-甲基苯基)-4-[(5-甲基-1,3,4-噻重氮基-2基)亚硫酰基]-3-硝基苯甲酰胺;
N-[3-[(二乙基氨基)羰基]丙基]-N-(2-乙基苯基)-3-硝基-4-(2-噻唑基亚硫酰基)苯甲酰胺;
1-(4-氨基-3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]甲基磺酰基亚氨基甲基]-D-苯丙氨酰基)-4-(1-哌啶基)-哌啶;
1-(4-氨基-3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶;
1-(4-氨基-3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]苯基磺酰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶;
1-(3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(1-哌啶基)-哌啶;
1-(N2-[3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]甲基磺酰基亚氨基甲基]-D-酪氨酰基]-L-赖氨酰基]-4-(4-嘧啶基)-哌嗪;
1-(N2-[3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]苯基磺酰基亚氨基甲基]-D-酪氨酰基]-L-赖氨酰]-4-(4-嘧啶基)-哌嗪;
1-(4-氨基-3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶;
1-(4-溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基)-3,5-二甲基-D,L-苯丙氨酰基)-4-(1-哌啶基)-哌啶;
1-[3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(4-哌啶基)哌嗪;
1-(4-氨基-3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基)-4-(4-吡啶基)-哌嗪;
1-[3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)哌啶;
1-[3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(4-哌嗪基)哌啶;
1-[4-溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)哌啶;
1-[4-氨基-3,5-二溴-N-[[4-(1,3-二氢-4-苯基-2(2H)-氧代咪唑-1-基]-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(4-甲基-1-哌嗪基)哌啶;
1-[4-氨基-3,5-二溴-N-[[4-(2,3,4,5-四氢-2(1H)-氧代-1,3-苯并二氮基-3-基-)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(4-甲基-1-哌嗪基)哌啶;
1-[4-氨基-3,5-二溴-N-[[4-(2,4-二氢-5-苯基-3(3H)-氧代-1,2,4-***-2-基]-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-哌啶基)哌啶;
1-[4-氨基-3,5-二溴-N-[[4-(2,3,4,5-四氢-2(1H)-氧代-1,3-苯并二氮基-3-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-哌啶基)哌啶;
1-[3,5-二溴-N-[[4-(2,4-二氢-5-苯基-3(3H)-氧代-1,2,4-***-2-基]-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(1-哌啶基)哌啶;
1-[3,5-二溴-N-[[4-(2,3,4,5-四氢-2(1H)-氧代-1,3-苯并二氮基-3-基-)-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(1-哌啶基)哌啶;
1-[3,5-二溴-N-[[4-(2,4-二氢-5-苯基-3(3H)-氧代-1,2,4-***-2-基]-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)哌嗪;
1-[3,5-二溴-N-[[4-(2,3,4,5-四氢-2(1H)-氧代-1,3-苯并二氮基-3-基-)-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)哌嗪;
1-[4-氨基-3,5-二溴-N-[[4-(2,4-二氢-5-苯基-3(3H)-氧代-1,2,4-***-2-基]-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)哌嗪;
1-[4-氨基-3,5-二溴-N-[[4-(2,3,4,5-四氢-2(1H)-氧代-1,3-苯并二氮基-3-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-甲基-4-哌嗪基)哌嗪;
1-[3,5-二溴-N-[[4-(3,4-二氢-2(1-H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-4-甲基-D,L-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌啶;
1-[3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-4-甲基-D,L-苯丙氨酰基]-4-(1-哌啶基)-哌啶;
1-[3,5-二溴-N-[[4-(3,4-二氢-2(1H)-氧代喹唑啉-3-基)-1-哌啶基]氰基亚氨基甲基]-4-甲基-D,L-苯丙氨酰基]-4-(4-嘧啶基)-哌嗪;
1-[4-氨基-3,5-二溴-N-[[4-(1,3-二氢-2(2H)-氧代咪唑[4,5-c]喹唑啉-3-基]-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-哌啶基)-哌啶;
1-[4-氨基-3,5-二溴-N-[[4-(7-甲氧基-2,3,4,5-四氢-2(1H)-氧代-1,3-苯并二氮-3-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-哌啶基)哌啶;
1-[4-氨基-3,5-二溴-N-[[4-(5,7-二氢-6-氧代二苯并[d,f][1,3]-diazepin-5-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-哌啶基)哌啶;
1-[4-氨基-3,5-二溴-N-[[4-(7-甲氧基-2,3,4,5-四氢-2(1H)-氧代-1,3-苯并diazepin-3-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)哌嗪;
1-[4-氨基-3,5-二溴-N-[[4-(1,3-二氢-2(2H)-氧代咪唑[4,5-c]喹唑啉-3-基]-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)-哌嗪;
1-[4-氨基-3,5-二溴-N-[[4-(2,3,4,5-四氢-2(1H)-氧代-1,3-苯并diazepin-3-基)-1-哌啶基]磺酰基]-D-苯丙氨酰基]-4-(1-甲基-4-哌啶基)哌嗪;
1-[3,5-二溴-N-[[4-(7-甲氧基-2,3,4,5-四氢-2(1H)-氧代-1,3-苯并diazepin-3-基)-L-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(1-哌啶基)哌啶;
1-[3,5-二溴-N-[[4-(7-甲氧基-2,3,4,5-四氢-2(1H)-氧代-1,3-苯并diazepin-3-基)-L-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(1-甲基-4-哌啶基)哌嗪;
1-[3,5-二溴-N-[[4-(1,3-二氢-2(2H)-氧代咪唑并[4,5-c]喹唑啉-3-基]-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基)-4-(1-哌啶基)-哌啶;
1-[3,5-二溴-N-[[4-(1,3-二氢-2(2H)-氧代咪唑并[4,5-氧代喹唑啉-3-基]-1-哌啶基]氰基亚氨基甲基]-D-酪氨酰基]-4-(1-甲基-哌啶基)-哌嗪;
1-[4-氨基-3,5-二溴-N-[[4-(7-甲氧基-2,3,4,5-四氢-2(1H)-氧代-1,3-苯并diazepin-3-基)-1-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(4-甲基-1-哌嗪基)哌啶;
1-[4-氨基-3,5-二溴-N-[[4-(1,3-二氢-2(2H)-氧代咪唑并[4,5-氧代喹唑啉-3-基]-4-哌啶基]氰基亚氨基甲基]-D-苯丙氨酰基]-4-(4-甲基-1-哌嗪基)-哌啶;
以及其药用的盐。
进一步预期CGRP活性的间接抑制对本发明可能是有益的。这些包括辣椒素阻断剂capzaezine,如假定CGRP在辣椒素通过VANILLIN受体的作用之下。其它的这种间接抑制剂包括组胺H3-受体激动剂诸如IMETIT,其可以下调节CGRP。
在本发明有益的实施方案中,药物组合物包括CGRP拮抗剂化合物与治疗方式结合给药治疗牛皮癣,诸如利用本领域的标准方法进行UVB治疗。
在本发明另一个方面,提供了鉴定治疗牛皮癣的药物候选化合物的方法。所述方法包括步骤获得怀疑结合于CGRP受体的化合物;将诸如在大约0.1μM到1mM范围内的不同浓度的化合物添加到含有CGRP受体的样品中以及温育适当的时间;将标记的CGRP肽添加到温育的样品中(例如,放射性标记的,诸如用碘,但是也可使用其它的本领域公知的标记方法);测定含有不同浓度侯选化合物的所述样品中标记的CGRP肽与CGRP受体的结合;以及测定化合物与CGRP受体的结合亲合性;其中测定的与CGRP受体结合的化合物被确定为用于制备治疗牛皮癣的药物的候选化合物。本发明的实施方案具体描述在实施例10中。
在一个方法实施方案中,所述样品含有具有CGRP受体结合表面的活细胞。在特定的实施方案中所述样品含有细胞膜制剂。
附图说明
图1a&b:描述具有脱发和牛皮癣的患者头皮的照片。
图2a&b:患者腿上的牛皮癣模式。
图3:手指上的牛皮癣病斑。
图4:显示带状疱疹病斑的照片。
图5:皮肤损伤后形成的牛皮癣病斑。
图6:显示患者头皮上脱发模式的照片。
实施例
实施例1
案例研究:神经肽素感觉神经可能参与AA
R.Rossi等的最近研究(Rossi,R.等.Neuroreport,8,1135-1138 1997)表明AA患者具有降低的基本血流量。其进一步表明CGRP和SP(P物质)的水平而不是VIP(血管活性肠肽)在受AA影响的患者的头皮活体检查中是下降的。对刺激物的反应改变了,因此在斑形脱发头皮中观察到比对照头皮中对皮内CGRP更大和更长时间的血管舒张应答。作者的研究显示CGRP受体过敏性,取决于上述的神经肽存在量的降低。
实施例2
AA和牛皮癣患者的临床观察
对具有AA和牛皮癣的唐氏综合症患者进行的临床观察表明AA患者从一个耳朵到另一个通过其枕骨区域覆盖着一个区域。其整个头皮覆盖牛皮癣除了其具有AA的区域(参见图1a&b)。那些区域中的头皮在临床上是正常的。该患者在肘部具有牛皮癣且具有强烈的牛皮癣家史。
实验强烈地表明在两种疾病之间存在反比关系,其在此描述之前是不为人们所知的。结合AA区域的CGRP水平是降低的实施例1的结果,进一步支持了关于CGRP是牛皮癣中致病因素的主张。
实施例3
对用UVB治疗的牛皮癣患者进行的临床观察
按照标准的临床实践观察和回访接受UVB治疗的患者。我们注意到一些患者在预治疗后、在开始治疗后的第一天、在开始转好之前经历了牛皮癣的瞬时恶化。恶化被定义为存在的病斑突然发作或增加了尺寸大小或出现了新的病斑。
回访的95个患者中,有38人说它们遭遇了牛皮癣的恶化。21人产生了新的病斑,最普遍的持续1或2天。这些病斑通常被描述为小、薄的和充血斑点。17个病人出现已经存在的牛皮癣病斑的短时间恶化。这些症状典型地在预处理后24-48小时内出现。所有的患者,然而,受益于该治疗,即,在经过比较久的时间后牛皮癣全部得到了改善。
我假定在治疗的开始,增加的CGRP是对UV射线和热损伤的正常反应。这些已在大鼠的实验中被观察到(参见Gillardon等Neurosci.Lett.1991年四月1日;124(2):144-7)。因为刺激是进行中的,可以理解通过下调节CGRP增加防御机制和减少细胞更新对机体是有好处的。通过此方法,可减少突变和患皮肤癌的危险。因此,在治疗痊愈作用之前,UVB治疗开始期间皮肤中增加的CGRP水平增强了患者牛皮癣的症状。
实施例4
牛皮癣模式和部位的研究
我们已经仔细地研究了大量患者的牛皮癣病斑来分析病斑的模式。许多患者可以被观察到六角形纹样的模式,参见图2-3。这种模式之前没有被描述过。假定该模式是神经病学单元的表现。皮肤中神经分布的精确结构从来没有被详细描述过。
实施例5
带状疱疹模式
带状疱疹病斑的模式已被研究。我们注意到这种模式也显示出六角形纹样(图4)。带状疱疹,一种病毒神经感染,具有已知的神经病学联系,且在带状疱疹和牛皮癣二者中观察六角形纹样的事实支持了这种模式是神经病学单元的表现。
实施例6
皮肤损伤后牛皮癣病斑的形成
牛皮癣患者在其皮肤擦伤或损伤处产生了牛皮癣病斑。经常可观察到病斑处看起来皮肤已经损伤,此称为Koebner′s现象。我注意到病斑显示出精确的六角形纹样(参见图5)。因此可以断定“直线排列”病斑的位置是由皮肤损伤所引起的,精确的结构-模式包括半圆形或六角形,是疾病神经关联的强烈表现。在图5中可进一步观察到六角形的大小是相互关连的,诸如例如由六角形组成的宽泛排列其是由较小六角形单元的较小排列组成的。此增殖表明固定大小的神经单元在牛皮癣中是激活的。这些之前在现有技术中从来没有被提出过。
实施例7
斑形脱发模式的研究
附图6a和b的斑形脱发(AA)患者的头皮显示成非圆形的脱发点形成了类似六角形的形状。根据此处AA和牛皮癣之间关系的讨论,同样显示神经因子指示性模式的AA的显示进一步支持了关于牛皮癣是一种神经紊乱的观点。
实施例8
案例研究:斑形脱发的局部免疫治疗
奥雷基亚等(Orecchia,G.等,Dermatologica,1990,180,57-59)描述了用局部敏化剂SABDE(方形酸二丁基酯)治疗AA。接收治疗的患者在其获得毛发再生长的相同位置产生了牛皮癣。当治疗后疾病恶化时,疾病牛皮癣斑块上的毛发是最后脱落的,直到全身脱毛(Alopecia Universalis)。
如同详细说明中所讨论的,来自毛囊的激活的角质细胞作为补充细胞,CGRP可将休止期(毛发生长终期阶段)的毛发转变为活性阶段(毛发生长初期阶段)的。当身体暴露于非常少量的抗原时(如局部免疫治疗)CGRP被释放来终止发展中的迟发型超敏反应(DTH)的进程。我认为这就是为什么SABDE和DPCP在AA治疗中有效的原因。涉及CGRP作为DTH下调节因子和初期伤口愈合中的作用物能够将毛囊由毛发生长终期转变为毛发生长初期阶段的机制解释了为什么牛皮癣和AA之间具有反比关系,如实施例1中所证明的。
实施例9
治疗牛皮癣的洗液
通过局部给药来治疗和/或预防牛皮癣的洗液制备如下:由说明书中公开的化合物中或通过实施例的方法鉴定的化合物中选择合适的化合物。如下制备10%的洗液:将约0.1到0.5g的化合物溶于乙醇(6ml)中,以及将溶液与用矿物油、棉子油、异丙基棕榈酸酯和水与表面活性剂诸如山梨糖醇酐倍半油酸酯制备的水混油洗液混合。水混油洗液中的成分例如分别为10∶10∶5∶70∶5的重量比。
实施例10
拮抗化合物的筛选
筛选阻止CGRP受体与CGRP结合的化合物的方法描述在WO98/56779中。因此,该方法将鉴定对本发明可能有用的化合物。
简要地,所选择的测试化合物被测定[125I]CGRP(购自Amersham,Chicago,IL)的抑制。SK-N-MC细胞(American Type Culture Collection,Rockville,MD)被培养在含有胎牛血清(10%)的基本培养基(″MEM″)中。细胞在T-150三角瓶中或Costar multiwel平皿中培养并且保持在37℃、90%湿度带有5%CO2和95%空气的培养箱中。
细胞在5mM Tris-HCl pH 7.4,10mM Na-EDTA中搅匀且获得的匀浆物在4℃下48,000g离心20分钟。将颗粒重新悬浮在20 mLNa-HEPES pH 7.4,10mM MgCl中并再次离心。薄膜颗粒重悬浮在相同的缓冲液中并-70℃冷冻储存。通过利用BSA(牛血清蛋白)作为标准的Pierce BCA法测定蛋白质浓度。
20mM Na-HEPES pH7.4,10mM MgCl2,0,05%BSA和0.1mg/mL杆菌肽进行[125I]CGRP受体结合试验。膜(50μg/ml)与总体积为500μl的不同浓度(诸如约1μM和1mM范围内的浓度)的测试化合物和40μM[125I]CGRP一起在25℃温育60分钟。通过添加2ml冰冷的0.9%NaCl终止反应,然后通过预浸在0.5%聚乙烯亚胺(PEI)中的Skatron Filtermates快速过滤。滤纸用2ml冷的0.9%NaCl漂洗两次并通过γ测量器测定放射性。用常规的配体-结合分析和程序诸如LIGAND程序来分析结合数据。
实施例11
牛皮癣病斑周围边缘CGRP的测定
用激光Doppler血流测量法来测定牛皮癣病斑周围正常皮肤的血流量以确定牛皮癣病斑的活性边缘的位置。众所周知牛皮癣病斑生长有方向性,即具有生长或活性边缘。(参见,Cunliff等,J.nvest.Dermatol.1989,92(6):782-5)。测定两个牛皮癣病斑受试者的活性边缘和无活性(相对的)边缘的CGRP水平。最初的结果表明活性边缘与无活性的边缘相比其CGRP水平增加了。通过利用带有15kDa阻断探针的组织液样品微量透析设备进行该试验;活性的和无活性的边缘被抽样总共165分钟。在每次抽样中每个样品获得165μl的体积。用ELISA测定神经肽CGRP的浓度。组织液抽样后对取的皮肤部位进行组织活体检查。在活性边缘观到增加的血流量表明了通过增加乳突真皮中的毛细血管袢数目增加的微血管同样也扩张了。没有发现表皮细胞增生或T-细胞激活。
结果强烈地表明皮肤中CGRP水平浓度的增加是牛皮癣发展过程中的非常早期的活动。此支持了GCRP水平调节(即增强CGRP水平)的失败可能是牛皮癣病的致病因素。
序列表
<110>Sveinsson,Birkir
<120>CGRP拮抗剂化合物在治疗牛皮癣中的应用
<130>P5048 PC00
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<151>2002-08-12
<150>IS 6496
<151>2002-08-12
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Claims (14)
1.一种治疗、改善或预防受试者牛皮癣的方法,包括将治疗有效量的至少一种CGRP拮抗剂化合物以药用制剂形式施用于受试者。
2.根据权利要求1的方法,其中至少一种CGRP拮抗剂化合物选自:4-亚硫酰基苯甲酰胺化合物,3,4-二硝基苯甲酰胺化合物,benzamidazolinyl piperadine化合物,抗-CGRP抗体,包括肽CGRP 8-37的CGRP衍生物,类胰蛋白酶活性多肽,以及化合物BIBN4096BS,以及包括肝素的稳定类胰蛋白酶的化合物。
3.根据权利要求1的方法,其中CGRP拮抗剂化合物被局部给药,诸如表皮,真皮,皮内,或皮下,或通过真皮或皮下输注,诸如通过微量透析进行给药。
4.根据权利要求1的方法,其中CGRP拮抗剂化合物经口服、鼻、直肠、肺部、含服或通过皮下注射、静脉注射或肌内注射进行给药。
5.根据权利要求1的方法,其中的CGRP拮抗剂化合物经局部进行给药。
6.CGRP拮抗剂化合物在制备用于治疗、预防或改善受试者牛皮癣的药物中的应用。
7.根据权利要求6的应用,其中的化合物选自:4-亚硫酰基苯甲酰胺化合物,3,4-二硝基苯甲酰胺化合物,benzamidazolinyl piperadine化合物,抗-CGRP抗体,包括CGRP 8-37的CGRP衍生物,类胰蛋白酶,包括肝素的稳定类胰蛋白酶的化合物,以及化合物BIBN4096BS。
8.根据权利要求6的应用,其中的药物经局部给药。
9.一种治疗牛皮癣的药用组合物,含有至少一种活性CGRP拮抗剂物质以及至少一种药用赋形剂。
10.根据权利要求9的药物组合物,其中的组合物经局部、表皮、皮内、皮下、iontopophoretic给药或经诸如微量透析的输注进行给药。
11.根据权利要求10的药物组合物,其中的组合物经局部给药。
12.一种鉴定用于治疗牛皮癣的药物的候选化合物的方法,包括如下步骤:
(i)获得可能结合于CGRP受体的化合物;
(ii)将大约0.1μM到1mM范围内的不同浓度的化合物添加到含有CGRP受体的样品中并温育合适的时间;
(iii)添加标记的CGRP肽到温育样品中;
(iv)测定标记的CGRP肽与CGRP受体在具有不同浓度化合物的样品中的结合;以及
(v)测定化合物与CGRP受体的结合亲合性;
由此确定结合CGRP受体的化合物被鉴定为用于治疗牛皮癣的药物中的候选化合物。
13.根据权利要求11的方法,其中所述样品含有具有表面结合的CGRP受体的活细胞。
14.根据权利要求11的方法,其中所述样品含有细胞膜制剂。
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FR2732221B1 (fr) * | 1995-03-28 | 1997-04-25 | Oreal | Utilisation d'un antagoniste de cgrp pour traiter les rougeurs cutanees d'origine neurogene et composition obtenue |
FR2732220B1 (fr) | 1995-03-28 | 1997-04-25 | Oreal | Utilisation d'un antagoniste de cgrp pour traiter les lichens et les prurits et composition obtenue |
EP0737471A3 (fr) | 1995-04-10 | 2000-12-06 | L'oreal | Utilisation d'un sel d'une métal alcalino-terreux comme inhibiteur de TNF-alpha dans une composition unique et composition obtenue |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107586338A (zh) * | 2011-05-20 | 2018-01-16 | 奥尔德生物控股有限责任公司 | 抗cgrp组合物及其用途 |
CN107586338B (zh) * | 2011-05-20 | 2021-09-17 | H.伦德贝克公司 | 抗cgrp组合物及其用途 |
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