CN102406644A - 芳基脲衍生物用于制备治疗移植排斥药物的新用途 - Google Patents
芳基脲衍生物用于制备治疗移植排斥药物的新用途 Download PDFInfo
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Abstract
本发明公开了一种芳基脲衍生物用于制备治疗移植排斥药物的新用途，所述芳基脲衍生物为1-(3-(三氟甲基)-4-氯-苯基)-3-(3-(6-(1-甲基-4-吡唑基)-4-嘧啶氧基)-苯基)脲，本发明化合物能够明显减轻机体对移植器官的排斥反应，改善移植器官功能，可以用于制备防治器官移植免疫排斥反应的药物，特别是用于制备防治肾移植、肝移植或心脏移植手术后免疫排斥反应的药物。
Description
技术领域
本发明涉及芳基脲衍生物在制备免疫抑制药物中的应用，特别是在制备用于防治器官移植排斥反应的免疫抑制药物中的应用。
背景技术
近30年来，随着移植器官排斥反应的免疫生物学的研究进展，特别是抗免疫排斥反应药物在临床上的使用，使器官移植的数量、种类和成功率都得到显著提高。目前，最常用的抗免疫排斥反应药物是环抱菌素(CsA)，CsA实际上是一种免疫抑制剂，它是通过抑制体内的免疫排斥反应，改善移植器官的功能和延长存活时间。但是，CsA引起的依赖剂量的肝细胞毒性和肾中毒等的毒副作用，以及昂贵的价格，使CsA的使用受到限制。
目前，已经发现将近30种免疫抑制剂，其中部分已经在临床上用于治疗器官移植患者免疫排斥反应。试验发现，这些新发展的药物，也具有与CsA类似的问题。因此，寻找效果好、毒副作用小和用药成本更低的可用于抗免疫排斥反应的新药物，是当前一个重要研究课题。
发明内容
本发明的目的是提供式I化合物在制备免疫抑制药物中的应用；特别是在制备用于防治器官移植排斥反应的免疫抑制药物中的应用。
WO2007076473在2007年公开了式I化合物：
并提到了该化合物用作raf激酶抑制剂的用途。式I化合物的中文命名为：1-(3-(三氟甲基)-4-氯-苯基)-3-(3-(6-(1-甲基-4-吡唑基)-4-嘧啶氧基)-苯基)脲。
本发明人惊奇地发现，式I化合物在治疗移植排斥方面有意料不到的优秀的效果。
本发明的实验证明，式I化合物具有显著的免疫抑制作用。动物模型试验进一步证明，式I化合物能够明显减轻机体对移植器官的排斥反应，改善移植器官功能，延长移植器官人或其它哺乳动物的存活期。
本发明的试脸表明，本发明化合物可以用于制备防治器官移植免疫排斥反应的免疫抑制药物，特别是用于制备防治肾移植、肝移植或心脏移植手术后免疫排斥反应的药物。
对于肾移植来说，急性排斥反应发生在肾移植术一周以后，表现为病人发热、尿量减少、高血压、移植肾压痛、血肌酐升高。慢性排斥反应：一般发生在肾移植的六个月以后，最早可发生在三个月以后。表现为移植肾功能逐渐地降低、有蛋白尿或血尿、高血压等，病情缓慢进展，最终导致移植肾功能的丧失。
本发明化合物可用于器官移植后的急性和慢性移植排斥反应，特别可用于肝移植或肾移植后的急性和慢性移植排斥反应。
本发明化合物还可以与其它具有免疫抑制功能的药物联合应用治疗器官移植排斥反应。
式I化合物优选的以静脉输注和口服方式给药，优选以片剂或胶囊形式给药。其他给药途径也是可行的，例如通过植入物、肠胃外给药(除静脉给药外，如腹膜内和皮下注射)、直肠给药、鼻内给药、阴道内给药和经皮给药。
可按照给药途径对剂量方案进行调整。例如，口服给药剂量常常高出静脉给药剂量10倍。
式I化合物可作为唯一的活性治疗剂给药或作为含有多于一个抗移植排斥剂的治疗方案中的一部分进行给药。利用协同作用的治疗剂常常要求对每种特定药物剂量减少，从而增加了特定试剂的安全范围。
含有本发明的活性化合物的口服制剂可包括任何传统的口服形式，包括片剂、胶囊、颊形式、含片、锭剂和口服液体、悬浮液或溶液。胶囊可含有活性化合物与惰性填料和/或稀释剂知药学可接受的淀粉(如玉米、土豆或木薯淀粉)、糖类、人工增甜剂、粉末状纤维素如结晶和微晶纤维素、面粉、明胶、树胶等的混合物.有用的片剂可通过传统的压制、湿制粗法或干制拉法并利用药学可接受的稀释剂、粘合剂、润滑剂、崩解剂、表面改性剂(包括表面活性剂)、悬浮剂或稳定剂，包括但并不局限于硬脂酸镁、硬脂酸、滑石、十二烷基硫酸钠、微晶纤维素、羧甲基纤维素钙、聚乙烯吡咯烷酮、明胶、海藻酸、阿拉伯胶、黄原胶、柠檬酸钠、复合硅酸盐、碳酸钙、甘氨酸、糊精、蔗糖、山梨醇、磷酸氢钙、硫酸钙、乳糖、高岭土、甘露醇、氯化钠、滑石、干淀粉和粉末状糖类。优选的表面改性剂包括非离子型和阴离子型表面改性剂。表面改性剂的代表性示例包括但并不局限于泊洛沙姆188、洁尔灭、硬脂酸钙、十六醇十八醇混合物、脱水山梨醇酯、胶体二氧化硅、磷酸盐、十二烷基硫酸钠、硅酸铝镁和三乙醇胺.此处的口服制可利用标准的延迟或控制释放制剂来改变活性化合物的吸收。口服制剂也包括给予包含在含有所需的适当增溶剂或乳化剂的水或果汁中的活性成分。
本发明的化合物也可通过肠胃外或腹膜内给药。可在适于与表面活性剂如羟丙基纤维素混合的水中制备作为游离碱或药学可接受盐的这些化合物的溶液或悬浮液。也可在甘油、液体聚乙二醇及其与油的混合物中制备分散体。在普通贮存和应用条件下，这些制剂含有防腐剂以防止微生物生长。
适于注射应用的药物形式包括无菌水溶液或分散体以及用于临时制备无菌注射液和分散体的无菌粉末。在所有情况下，这些形式必需是无菌的从而保存易于注射的能力。其在制备和贮存条件下必需是稳定的，并且贮存在可防止微生物如细菌和真菌污染的条件下。载体可为含有如水、乙醇、多元醇(如甘油、丙二醇和液体聚乙二醇)、它们合适的混合物及植物油的溶别或分散介质。对于本发明公开的内容的目的来讲，经皮给药应理解为通过体表和包括上皮和粘膜组织在内的身体通道进行的所有给药。这样的给药可通过利用本发明的化合物或其药学可接受的盐以洗剂、霜剂、泡沫、贴剂、悬浮液、溶液和栓剂(直肠和阴道)形式进行。
通过以下实施例进一步证明本发明化合物抗移植排斥的作用。
具体实施方式
实施例1：树突状细胞的体外培养和本发明式I化合物对其表面分子表达的作用
静脉抽取健康成人外周血50ml/人，EDTA-K3抗凝，用Ficoll-Hypaque分离PBMC，以完全的RPMI1640悬浮细胞，调整细胞浓度为2×106/ml，加入24孔培养板中，每孔0.5ml，37℃，5％CO2孵箱培养2h，使其中的单核细胞贴壁，用温热的无血清的RPMI1640液轻轻洗培养板以去除非贴壁细胞，即获得贴壁的单核细胞，在培养板中加入含rhGM-CSF 1000IU/ml、rh-IL-4800IU/ml的AIM-V培养基，置于37℃5％CO2孵箱中，隔天半量更换培养液。在培养的第3及第5天，每孔加入LPS(1μg/ml)，将其分为两组，分别为式I化合物作用组和未作用组，在培养的第7天，在式I化合物作用组中加入100μg/ml的式I化合物，共培养10天。
收集悬浮的细胞，该悬浮细胞即为树突状细胞，流式检测HLA-DR、CD80、CD83、CD86、CD11c、CD3、CD14的表达情况。结果发现，施用式I化合物后，健康人树突状细胞表达的CD80、CD86、CD83的阳性率均明显下调，与刺激前后相比差异均有显著性(P＜0.01)，具体比较结果见表1。
表1.健康人树突状细胞经式I化合物作用前后DC表面分子表达的比较
*表示有统计学意义(P＜0.01)
树突细胞(dendritic cell，DC)是目前已知的唯一能激活幼稚T细胞的抗原递呈细胞，能调节T淋巴细胞，B淋巴细胞的功能，处于启动、调控并维持特异性免疫应答的中心环节。
通过对健康人外周血树突细胞(DC)的分离及培养，并探讨DC在体外转化过程中式I化合物的作用，发现式I化合物可参与对DC成熟及免疫刺激能力的调节，式I化合物的刺激可抑制人DC的分化及成熟，从而抑制免疫应答，达到免疫耐受。
式I化合物刺激组的DC表型与未刺激组相比，CD80、CD83、CD86的表达显著降低，CD14的表达显著升高。CD83是DC成熟的重要标志，在DC行使功能中具有重要作用，病毒感染能下调CD83的表达，从而抑制机体产生的抗病毒免疫反应；CD14则是单核细胞的特异性分子标记，其表达量高提示DC转化欠佳；CD80/CD86为DC表面的免疫共刺激分子，其表达的降低可影响DC的抗原递呈的功能。结果表明，在式I化合物的作用下，健康人外周血单核细胞向DC转化过程中DC表型和成熟均低于未刺激组。
实施例2：
清洁级健康雄性Wistar大鼠作为供者，体重190-220g，清洁级健康雄性SD大鼠作为受者，体重200-250g，根据前人研究(陶然.肝移植动物模型//郑树森.肝脏移植.北京：人民卫生出版社.2001：140-143)，利用改良双套管法建立大鼠原位肝移植模型。
将肝移植大鼠模型随机分为5组，每组6只，其中3组分别给予式I化合物2.0、10.0和50.0mg/kg/d，另外2组分别给予CsA(10.0mg/kg/d)和生理盐水(0.5ml/d)作为对照，均为腹腔途径给药。观察各组大鼠的存活时间，结果见表2。
表2肝移植大鼠存活时间比较
比较发现，式I化合物10.0和50.0mg/kg/d组的存活时间明显长于生理盐水对照组(P＜0.01)，式I化合物具有明显的抗移植排斥反应的作用，并且，式I化合物50.0mg/kg/d组的存活时间与CsA对照组相比，式I化合物50.0mg/kg/d组略优于CsA对照组。
Claims (6)
1.式I化合物用于制备治疗移植排斥的药物的用途。
2.根据权利要求1所述的用途，其中，所述移植排斥为急性移植排斥。
3.根据权利要求1所述的用途，其中，所述移植排斥为慢性移植排斥。
4.根据权利要求1所述的用途，其中，所述移植排斥为肝移植排斥。
5.根据权利要求1所述的用途，其中，所述移植排斥为肾移植排斥。
6.根据权利要求1所述的用途，其中，所述移植排斥为心脏移植排斥。
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| EP3313530A4 (en) * | 2015-06-26 | 2019-02-20 | Dana Farber Cancer Institute, Inc. | 4,6-PYRIMIDINYLENE DERIVATIVES AND USE THEREOF |
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