CN111698988B - 包含酰腙衍生物的抗炎组合物 - Google Patents
包含酰腙衍生物的抗炎组合物 Download PDFInfo
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- CN111698988B CN111698988B CN201980010952.2A CN201980010952A CN111698988B CN 111698988 B CN111698988 B CN 111698988B CN 201980010952 A CN201980010952 A CN 201980010952A CN 111698988 B CN111698988 B CN 111698988B
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Abstract
本发明涉及用于预防、改善或治疗炎症性疾病的组合物，包含酰腙衍生物化合物、其立体异构体或其药学上可接受的盐作为有效成分。本发明的酰腙衍生物化合物、其立体异构体或其药学上可接受的盐可通过有效地抑制炎症细胞因子及炎症性信号传导途径来有效地改善皮肤炎等的炎症性疾病的症状。由此，本发明的组合物可有效地用于预防、改善或治疗炎症性疾病。
Description
技术领域
本发明涉及用于预防、改善或治疗炎症性疾病的组合物，包含由化学式1表示的化合物、其立体异构体或其药学上可接受的盐作为有效成分。
背景技术
特应性皮肤炎为一种在现代人当中频繁发生且在医学上还未确定其原因的慢性皮肤病。通常，特应性皮肤炎被认为是因人类免疫系统的失衡而引起的疾病。近年来，由于在国内外从儿童到成人广泛发生特应性皮肤炎，因此，需要开发对特应性皮肤炎有效的治疗剂。
目前，类固醇类的特应性皮肤炎抑制剂被用作治疗剂。然而，由于缺乏能够准确地诊断特应性皮肤炎的病因的诊断法和基于其诊断法的准确的定制治疗法，因此，已知其在表现出暂时性缓解效果而不是特应性皮肤炎的根本性解决方法的同时具有产生耐性的副作用。由此，迫切需要开发一种在免疫学治疗及抗炎功效方面卓越且几乎没有副作用而能够长期使用的药剂。
另一方面，在韩国公开专利公报第10-2014-0032916号中公开了N-亚甲基萘[2，1-b]呋喃-2-碳酰肼衍生物具有显著抑制细胞有丝分裂并有效地作用于表现出多药耐药性的癌细胞。并且，在韩国公开专利公报第10-2017-0098170号中公开了改善稳定性及溶解度并对癌细胞增殖表现出抑制效果的吲哚衍生物化合物。虽然上述多个文献公开了酰腙(Acylhydrazone)衍生物化合物可有效地用于抑制一部分癌细胞增殖，但是完全没有公开对炎症性疾病的抑制效果。
发明内容
技术问题
本发明人为了开发有效的炎症性疾病的预防及治疗剂而进行研究的结果，确认酰腙衍生物化合物在炎症诱发的动物模型及细胞株模型中表现出优秀的抗炎效果而可用作炎症性疾病的预防或治疗剂，从而完成了本发明。
解决问题的方案
为了实现上述目的，本发明的一实施方式提供用于预防或治疗炎症性疾病的药学组合物，包含酰腙衍生物化合物、其立体异构体或其药学上可接受的盐作为有效成分。
本发明的再一实施方式提供用于预防或改善炎症性疾病的食品组合物，包含上述化合物或其立体异构体作为有效成分。
本发明的另一实施方式提供用于预防或改善皮肤炎的化妆品组合物，包含上述化合物或其立体异构体作为有效成分。
本发明的又一实施方式提供上述药学组合物的用途，用于预防或治疗炎症性疾病。
本发明的还有一实施方式提供上述药学组合物的用途，用于制备炎症性疾病的预防或治疗用药剂。
本发明的还有一实施方式提供用于预防或治疗炎症性疾病的方法，包括处理上述药学组合物的步骤。
本发明的还有一实施方式提供上述化妆品组合物的用途，用于预防或改善皮肤炎。
本发明的还有一实施方式提供上述化妆品组合物的用途，用于制备皮肤炎的预防或改善用化妆品。
本发明的还有一实施方式提供用于预防或改善皮肤炎的方法，包括处理上述化妆品组合物的步骤。
发明的效果
本发明的酰腙衍生物化合物、其立体异构体或其药学上可接受的盐可通过有效地抑制炎症细胞因子及炎症性信号传导途径来有效地改善皮肤炎等的炎症性疾病的症状。由此，本发明的组合物可有效地用于预防、改善或治疗炎症性疾病。
附图说明
图1为利用背部诱发皮肤炎的小鼠用肉眼确认酰腙衍生物化合物的皮肤炎抑制效果的图。
图2a为示出在利用酰腙衍生物化合物或环孢菌素A(Cyclosporine A)对背部诱发皮肤炎的小鼠进行处理之后皮肤组织中白细胞介素-4(IL-4)的表达量的图。
图2b为示出在利用酰腙衍生物化合物或环孢菌素A对背部诱发皮肤炎的小鼠进行处理之后皮肤组织中白细胞介素-13(IL-13)的表达量的图。
图2c为示出在利用酰腙衍生物化合物或环孢菌素A对背部诱发皮肤炎的小鼠进行处理之后皮肤组织中白细胞介素-2(IL-2)的表达量的图。
图3a为示出形成表皮的基底层、棘层、颗粒层及角质层和各个层的表达标记的图。
图3b为示出在利用酰腙衍生物化合物或环孢菌素A对背部诱发皮肤炎的小鼠进行治理之后皮肤组织中角蛋白14(Keratin 14)的表达量的图。
图3c为示出在利用酰腙衍生物化合物或环孢菌素A对背部诱发皮肤炎的小鼠进行处理之后皮肤组织中角蛋白1(Keratin 1)的表达量的图。
图3d为示出在利用酰腙衍生物化合物或环孢菌素A对背部诱发皮肤炎的小鼠进行处理之后皮肤组织中丝蛋白基因(Filaggrin gene)的表达量的图。
图4为利用耳朵诱发皮肤炎的小鼠用肉眼确认酰腙衍生物化合物的皮肤炎抑制效果的图。
图5为在利用酰腙衍生物化合物或环孢菌素A对耳朵诱发皮肤炎的小鼠进行处理之后利用苏木精及曙红对皮肤组织进行染色的照片。
图6a为示出在利用酰腙衍生物化合物或环孢菌素A对耳朵诱发皮肤炎的小鼠进行处理之后皮肤组织中白细胞介素-4的表达量的图。
图6b为示出在利用酰腙衍生物化合物或环孢菌素A对耳朵诱发皮肤炎的小鼠进行处理之后皮肤组织中白细胞介素-13的表达量的图。
图6c为示出在利用酰腙衍生物化合物或环孢菌素A对耳朵诱发皮肤炎的小鼠进行处理之后皮肤组织中白细胞介素-2的表达量的图。
图7为在利用酰腙衍生物化合物或环孢菌素A对耳朵诱发皮肤炎的小鼠进行处理之后测量皮肤组织中免疫细胞数量的图。
图8a为示出在利用酰腙衍生物化合物或环孢菌素A对耳朵诱发皮肤炎的小鼠进行处理之后皮肤组织中角蛋白14的表达量的图。
图8b为示出在利用酰腙衍生物化合物或环孢菌素A对耳朵诱发皮肤炎的小鼠进行处理之后皮肤组织中角蛋白1的表达量的图。
图9为利用免疫细胞株确认酰腙衍生物化合物的炎症性信号传导途径的抑制效果的图。
具体实施方式
以下，将具体说明本发明。另一方面，在本发明中所公开的每个说明及实施方式也可应用于其他说明及实施方式。即，在本发明中所公开的各种要素的所有组合均属于本发明的范围内。并且，不应认为本发明的范围由下述具体的说明限制。
本发明提供用于预防或治疗炎症性疾病的药学组合物，包含由下述化学式1表示的酰腙衍生物化合物、其立体异构体或其药学上可接受的盐作为有效成分：
化学式1：
在上述化学式中，R1为C1-C4烷基或-(CH2)m(C＝O)OR2，R2为C1-C4烷基，m为0、1、2或3。具体地，上述R1可以为甲基、乙基、丙基或丁基。并且，当m为0时，R1可以为-(C＝O)OR2，当m为1时，R1可以为-(CH2)(C＝O)OR2，当m为2时，R1可以为-(CH2)2(C＝O)OR2，当m为3时，R1可以为-(CH2)3(C＝O)OR2。并且，R2可以为甲基、乙基、丙基或丁基。
根据本发明的一实施方式，在由上述化学式1表示的化合物中，R1可以为甲基。根据本发明的再一实施方式，在由上述化学式1表示的化合物中，R2可以为甲基或乙基。
在本发明的一实施方式中，由上述化学式1表示的化合物可以为下述化学式2的化合物：
化学式2：
由上述化学式2表示的化合物称为乙基(2-甲基-3-(E)-{[(萘[2,1-b]呋喃-2-基羰基)肼基]甲基}-1H-吲哚-1-基)乙酸酯，在本说明书中简称为WCI-1004。
在本发明的一实施方式中，由上述化学式1表示的化合物可以为下述化学式3的化合物：
化学式3：
由上述化学式3表示的化合物称为(E)-N'-(1，2-二甲基-1H-吲哚-3-基)亚甲基)萘[2,1-b]呋喃-2-碳酰肼，在本说明书中简称为WCI-1015。
在本发明的一实施方式中，由上述化学式1表示的化合物可以为下述化学式4的化合物：
化学式4：
由上述化学式4表示的化合物称为甲基(E)-2-(2-甲基-3-((2-(萘[2,1-b]呋喃-2-羰基)肼基)甲基)-1H-吲哚-1-基)乙酸酯，在本说明书中简称为WCI-1031。
在本发明中，由上述化学式1表示的化合物可通过例如韩国公开专利公报第10-2017-0098170中所公开的方法来制备，但不限于此。
在本发明中，药学上可接受的盐是指医药行业中常用的盐。例如，存在由钙、钾、钠及镁等制备的无机离子盐，由盐酸、硝酸、磷酸、溴酸、碘酸、高氯酸及硫酸等制备的无机酸盐，由乙酸、三氟乙酸、柠檬酸、马来酸、琥珀酸、草酸、苯甲酸、酒石酸、富马酸、扁桃酸、丙酸、柠檬酸、乳酸、乙醇酸、葡萄糖酸、半乳糖醛酸、谷氨酸、戊二酸、葡糖醛酸、天冬氨酸、抗坏血酸、碳氢酸、香草酸及氢碘酸等制备的有机酸盐，由甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸及萘磺酸等制备的磺酸盐，由甘氨酸、精氨酸及赖氨酸等制备的氨基酸盐及由三甲胺、三乙胺、氨、吡啶及甲基吡啶等制备的胺盐等，但是，在本发明中所指的盐的类型并不局限于所列举的这些盐。
本发明的由化学式1表示的化合物可包含一个以上的不对称碳。由此，可作为外消旋体、外消旋混合物、单一对映异构体、非对映异构体混合物及每个非对映异构体存在。这些异构体，例如由化学式1表示的化合物可通过柱色谱法或高效液相色谱法等的分割来分离。或者，可使用已知构型的光学纯的起始物质和/或试剂立体特异性地合成由化学式1表示的每个化合物的立体异构体。
由本发明的上述化学式1表示的酰腙衍生物化合物、其立体异构体，或其药学上可接受的盐可有效地用于预防或治疗炎症性疾病。
本申请中所使用的术语“炎症性疾病”是指以疼痛(因有害物质的生成及神经刺激引起的疼痛)、发热(因血管舒张引起的热)、发红(因血管舒张及血流增加引起的潮红)、肿胀(因过度流入或限制流出流体而引起的肿瘤)及功能丧失(可以为部分或完全、暂时性或永久性的功能丧失)征兆中的一种以上为特征的状态。可使用本发明的化学式1的化合物的炎症性疾病的非限制性示例包括皮肤炎、过敏、牛皮鲜、湿疹、瘙痒症(prurtis)、皮肤瘙痒、荨麻疹、特发性慢性荨麻疹、硬皮病，鼻息肉、鼻炎、慢性鼻窦炎、鼻充血、鼻痒、哮喘、慢性阻塞性肺疾病、类风湿性关节炎、结膜炎、角膜结膜炎、眼炎、干眼症、心力衰竭、心律不齐、动脉粥样硬化、多发性硬化症、炎症性肠疾病、炎症性疼痛、神经性疼痛、骨关节炎疼痛及甲状腺自身免疫性疾病，但不限于此。
在本发明的一实施方式中，炎症性疾病可以为皮肤炎。在本发明中，上述皮肤炎包括特应性皮肤炎、接触性皮肤炎、过敏性皮肤炎、痤疮、湿疹、酒渣鼻、牛皮鲜、油性皮肤及接触性传染性脓疱病，但不限于此。
在本发明的一实施方式中，皮肤炎可以为特应性皮肤炎。在本发明中，术语特应性皮肤炎是指炎症性、复发性、非传染性及瘙痒性慢性皮肤障碍，通常与其他特应性障碍如过敏性鼻炎及哮喘有关。本发明的术语特应性皮肤炎还包括从发生的场所或其外观或诱发其的压力要素来命名的特定形态的特应性皮肤炎。特应性皮肤炎表现出干燥的湿疹性皮肤、丘疹、严重瘙痒等症状，特应性患者的病灶样品中确认到表皮增生(epidermalhyperplasia)、表皮增殖及淋巴细胞及肥大细胞的积聚。通常，特应性皮肤炎患者患有严重的瘙痒，通过其诱发皮肤病灶的炎症而进一步加剧瘙痒并进一步恶化临床症状。
在本发明的实施例中，由于由化学式1表示的化合物在皮肤炎诱发的动物模型中抑制皮肤红斑及皮肤干燥症状(图1及图4)，有效地抑制炎症细胞因子的表达和表皮增生症状(图2a至图2c、图3a至3d、图6a至图6c、图8a及8b)，并且在免疫细胞株中有效地抑制炎症性信号传导途径(图9)，因此，已证实，其可有效地用作包括皮肤炎在内的炎症性疾病的治疗剂。
在本发明中，术语“炎症细胞因子”是指诱发体内发生的炎症反应的细胞因子，其在本发明所属技术领域中作为普通含义来使用。例如，白细胞介素-2、白细胞介素-4及白细胞介素-13等可用作诱发皮肤炎的炎症细胞因子。
上述药学组合物还可包含表现出抗炎活性的一种以上有效成分。
上述药学组合物还可包含药剂学上可接收的添加剂。在此情况下，药剂学上可接收的添加剂可使用淀粉、糊化淀粉、微晶纤维素、乳糖、聚维酮、胶体二氧化硅、磷酸氢钙、乳糖、甘露醇、麦芽糖、阿拉伯胶、预糊化淀粉、玉米淀粉、粉状纤维素，羟丙基纤维素、欧巴代、淀粉乙醇酸钠、巴西棕榈蜡、合成硅酸铝、硬脂酸、硬脂酸镁、硬脂酸铝、硬脂酸钙、白糖、葡萄糖、山梨糖醇及滑石粉等。相对于上述组合物，优选地，本发明的药剂学上可接收的添加剂包含0.1重量份至90重量份，但不限于此。
在实际临床给药的情况下，上述药学组合物可通过口服及非口服的各种剂型来给药。在制剂化的情况下，可使用通常使用的填充剂、增量剂、结合剂、湿润剂、崩解剂、表面活性剂等的稀释剂或赋形剂来配制。用于口服给药的固体制剂可包括片剂、丸剂、散剂、颗粒剂及胶囊剂等。这些固体制剂可通过在天名精提取物中混合至少一种诸如淀粉、碳酸钙(Calcium carbonate)、蔗糖(Sucrose)、乳糖(Lactose)或明胶等的赋形剂来配制。并且，除了单纯的赋形剂之外，也可使用润滑剂，例如，硬脂酸镁滑石粉等。悬浮剂、内用药剂、乳剂及糖浆剂等属于用于口服的液相制剂，除了作为通常使用的单纯稀释剂的水及液体石蜡之外，还可包括诸如湿润剂、甜味剂、芳香剂及保鲜剂等的各种赋形剂。用于非口服给药的制剂可包括无菌水溶液、非水性溶剂、悬浮剂、乳剂、冻干制剂及栓剂。作为非水性溶剂及悬浮溶剂，可使用丙二醇(Propylene glycol)、聚乙二醇、诸如橄榄油等的植物油及诸如油酸乙酯之类的可注射的酯类等。作为栓剂的基剂，可使用合成脂肪酸酯(witepsol)、聚乙二醇、吐温(tween)61、可可脂、月桂酸酯及甘油明胶等。
上述药学组合物可根据所需方法进行口服给药或非口服给药。在非口服给药的情况下，可选择经皮给药、皮肤外用、腹腔内注射、直肠内注射、皮下注射、静脉注射、肌肉内注射或胸部内注射的注入方式，例如，可进行经皮给药。根据患者的体重、年龄、性别、健康状态、饮食、给药时间、给药方法、排泄率及疾病的重症度等，给药量有多种范围。
上述药学组合物以药剂学有效量给药。在本发明中，“药剂学有效量”是指以能够应用于医学治疗的合理的受益/风险比例足以治疗疾病的量。上述有效量可根据患者的疾病类型、重症度、药物的活性、对药物的敏感度、给药时间、给药途径及排出比例、治疗时间，包括同时所使用的药物的因素及在其他医学领域众所周知的因素来确定。
本发明的组合物可作为单独的治疗剂进行给药或联合其他治疗剂来进行给药，可与现有的治疗剂依次或同时给药，可单次或多次给药。考虑上述多个因素，重要的是能够以最小限度的量获得最大效果而又没有副作用。这可由本领域所属技术人员容易地确定。
具体地，本发明化合物的有效量可根据患者的年龄、性别及体重而变化。通常，每天、每隔一天或一周1次至5次或每天1次至5次，每1kg体重可给药0.1mg至100mg，优选地，每1kg体重可给药0.5mg至10mg。但是，由于可根据给药途径、重症度、性别、体重及年龄等而增加或减少给药量，因此，上述给药量不以任何方法限制本发明的范围。
由于本发明的由化学式1表示的化合物在诱发皮肤炎的小鼠模型中表现出优秀的炎症抑制活性，因此，包含这些作为有效成分的组合物可有效地用作用于预防或改善炎症的食品组合物。
通常，上述食品组合物还可进一步包含其他食品组合物、保健功能食品或饮料中的添加剂等。
例如，上述食品组合物可含有诸如白糖、结晶果糖、葡萄糖、D-山梨糖醇、甘露醇、异麦芽低聚糖、甜菊苷、阿斯巴甜、乙酰磺胺酸钾及三氯蔗糖等的甜味剂、诸如无水柠檬酸、DL-苹果酸、琥珀酸及其盐等的酸味剂、诸如苯甲酸及其衍生物等的保鲜剂、诸如各种营养剂、维生素、矿物质(电解质)、合成调味剂及天然调味剂等的调味剂、诸如着色剂及促进剂(奶酪及巧克力等)、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶质增稠剂、pH调节剂、稳定剂、防腐剂、甘油、乙醇及用于碳酸饮料的碳酸化剂等。并且，上述多个食品组合物可含有用于制备天然果汁及蔬菜饮料的果肉。在每100重量份的本发明的食品组合物中，可使用比例约为20重量份以下的范围内的这些添加剂。
在上述食品组合物为饮料的情况下，还可包含饮料中通常所包含的香味剂或天然碳水化合物。上述天然碳水化合物可以为诸如葡萄糖及果糖等的单糖、诸如麦芽糖及蔗糖等的二塘、诸如糊精及环糊精等的多糖或诸如木糖醇、山梨糖醇及赤藓糖醇等的糖醇。并且，作为上述香味剂，可以为诸如索马甜、甜叶菊提取物(莱鲍迪甙A及甘草酸苷等)的天然香味剂或诸如糖精、阿斯巴甜等的合成香味剂。在上述食品组合物为饮料的情况下，每100ml的组合物中通常可包含约1g至20g的天然碳水化合物，优选地，可包含约5g至12g的天然碳水化合物。
上述食品组合物可通过制备成粉末、颗粒、片剂、胶囊或饮料的形态来用作食品类、饮料、口香糖、维生素复合剂及健康辅助食品类。
并且，本发明的由化学式1表示的化合物在诱发皮肤炎的小鼠模型中表现出优秀的炎症抑制活性，因此，包含这些作为有效成分的组合物也可有效地用作用于预防或改善皮肤炎的化妆品组合物。
上述化妆品组合物可制备成本领域中通常制备的任何剂型。例如，可制成溶液、悬浮液、乳化液、糊剂、凝胶、霜、乳液、粉、肥皂、含表面活性剂的洁面剂、油、粉状粉底、乳化液粉底、蜡粉底及喷雾剂等，但不限于此。更详细地，可制备成柔性化妆水、营养化妆水、营养霜、按摩霜、精油、眼霜、洗面奶、卸妆泡沫、卸妆水、面膜、喷雾剂或粉末剂型。
在上述化妆品组合物的剂型为糊剂、霜或凝胶的情况下，作为载体成分可利用动物油、植物油、蜡、石蜡、淀粉、胺黄树胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、二氧化硅、滑石粉或氧化锌等。
在上述化妆品组合物的剂型为粉或喷雾剂的情况下，作为载体成分可利用乳糖、滑石粉、二氧化硅、氢氧化铝、硅酸钙或聚酰胺粉末，尤其，在上述化妆品组合物的剂型为喷雾剂的情况下，可进一步包含诸如氯氟烃、丙烷/丁烷或二甲醚等的推进剂。
在上述化妆品组合物的剂型为溶液或乳化液的情况下，作为载体成分利用溶剂、增溶剂或乳化剂，例如，包含水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1，3-丁二醇油、甘油脂肪族酯、聚乙二醇或脱水山梨糖醇的脂肪酸酯。
在上述化妆品组合物的剂型为悬浮液的情况下，作为载体成分可利用诸如水、乙醇或丙二醇等的液态稀释剂、诸如乙氧基异硬脂醇、聚氧乙烯山梨醇酯及聚氧乙烯山梨糖醇酐酯等的悬浮剂、微晶纤维素、甲基氢氧化铝、膨润土、琼脂或胺黄树胶等。
在上述化妆品组合物的剂型为含表面活性剂的洁面剂的情况下，作为载体成分可利用脂肪醇硫酸盐、脂肪醇醚硫酸盐、磺基琥珀酸单酯、羟乙基磺酸盐、咪唑啉衍生物、甲基牛磺酸盐、肌氨酸盐、脂肪酸酰胺醚硫酸盐、烷基酰胺甜菜碱、脂肪醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、羊毛脂衍生物或乙氧基化甘油脂肪酸酯等。
本发明的再一实施方式提供上述药学组合物的用途，用于预防或治疗炎症性疾病。
本发明的另一实施方式提供上述药学组合物的用途，用于制备炎症性疾病的预防或治疗用药剂。
本发明的又一实施方式提供用于预防或治疗炎症性疾病的方法，包括处理上述药学组合物的步骤。
本发明的还有一实施方式提供上述化妆品组合物的用途，用于预防或改善皮肤炎。
本发明的还有一实施方式提供上述化妆品组合物的用途，用于制备皮肤炎的预防或改善用化妆品。
本发明的还有一实施方式提供用于预防或改善皮肤炎的方法，包括处理上述化妆品组合物的步骤。
本发明的实施方式
以下，将通过实施例更详细地说明本发明。但是，这些制备例及实施例仅用于示例性说明本发明，而本发明的范围并不局限于这些实施例。
I.利用背部诱发皮肤炎的小鼠确认酰腙衍生物化合物的皮肤炎抑制效果
实施例1.用肉眼确认酰腙衍生物化合物的皮肤炎抑制效果
为了证明酰腙衍生物化合物的抗炎效果，做出利用噁唑酮诱导的皮肤炎模型小鼠。具体地，在将150μl的5％噁唑酮(4-ethoxymethylene-2-phenyl-2-oxazolin-5-one)涂敷在6周龄HR-1(无毛(Hairless))小鼠的背部皮肤之后，通过将150μl的稀释成0.1％的相同化合物每周涂敷3次，共涂敷11次来诱导皮肤炎症反应。接着，将150μl的酰腙衍生物化合物分别以500nM的浓度每周涂敷5次，共涂敷19次。为了比较并验证化合物的功效，使用抗炎效果广为人知的环孢菌素(Cyclosporine)A作为比较物质，在实验中还反映了仅用作为溶剂的乙醇进行处理的阴性对照组及仅用噁唑酮进行处理的阳性对照组。每个实验组的小鼠数量保持在10只以上，共重复实验了两次。
其结果，在仅用噁唑酮进行处理的阳性对照组中，观察到红色斑点的形态和干燥状态的皮肤，确认了典型的皮肤炎症反应被诱导。相反，在用作为酰腙衍生物化合物的WCI-1004、WCI-1015及WCI-1031化合物或环孢菌素A进行处理的实验组中，观察到与利用作为溶剂的乙醇进行处理的阴性对照组非常类似的皮肤状态。由此，确认了酰腙衍生物化合物有效地抑制皮肤炎症反应(图1)。
实施例2.确认酰腙衍生物化合物的炎症细胞因子表达抑制效果
与诸如特应性皮肤炎等的皮肤炎发病最有关联的炎症细胞因子被熟知为主要从Th2 T细胞分泌的白细胞介素-4及白细胞介素-13等。为了进一步确认酰腙衍生物化合物对由噁唑酮诱发皮肤炎的小鼠的抗炎效果，以炎症组织为对象，对作为与皮肤炎发病有最深关联的细胞因子的白细胞介素-4及白细胞介素-13和在Th2 T细胞中分泌的白细胞介素-2的mRNA水平进行了定量。
具体地，从实施例1中制备的诱发皮肤炎的小鼠中采集皮肤组织并利用组织破碎机进行了粉碎。将粉碎的组织粉末溶解在Trizol试剂(西格玛公司)，并利用RNeasy minikit(凯杰公司)提取了RNA。在利用ImProm-IITM反转录试剂盒(ImProm-IITM ReberseTranscription kit)(普洛麦格公司(Promega))将提取的RNA反转录为cDNA之后，使用CFX96TM实时聚合酶链式反应检测系统(伯乐公司)来通过定量聚合酶链式反应(quantitative PCR)方法测量了存在于皮肤组织的细胞因子的水平。
其结果，在仅用噁唑酮进行处理的阳性对照组中，上述炎症细胞因子的水平显著增加。相反，在用环孢菌素、WCI-1004、WCI-1015或WCI-1031化合物进行处理的实验组的皮肤组织中，确认上述炎症细胞因子的表达水平显著降低。尤其，用WCI-1004、WCI-1015或WCI-1031化合物进行处理的实验组的皮肤组织中的炎症细胞因子表达水平低于用环孢菌素进行处理的实验组的皮肤组织。由此，确认了酰腙衍生物化合物的炎症细胞因子抑制效果比环孢菌素更优秀(图2a至图2c)。
实施例3.确认酰腙衍生物化合物的表皮增生抑制效果
在诱发皮肤炎的情况下，将诱发诸如皮肤厚度变厚的表皮增生(epidermalhyperplasia)等的病例症状。为了确认酰腙化合物是否在利用噁唑酮诱发炎症反应的皮肤中可缓解皮肤炎症状并保持皮肤稳态，通过与实施例2相同的方法，即，在从皮肤组织提取核糖核酸(RNA)之后，通过利用定量聚合酶链式反应方法测量角蛋白14(Keratin 14)、角蛋白1(Keratin 1)及丝蛋白基因(Filaggrin gene)的mRNA表达水平来进行了调查。
其结果，单独用噁唑酮进行处理而诱发皮肤炎的小鼠中表现出皮肤基底层的角蛋白14、皮肤上层的角蛋白1及皮肤最上层的丝蛋白基因的表达水平全部增加的表皮增生(epidermal hyperplasia)症状(图3a)。相反，在用环孢菌素、WCI-1004、WCI-1015或WCI-1031化合物进行处理的实验组的皮肤组织中，确认了上述因子的表达水平全部恢复至正常水平而治愈了表皮增生症状(图3b至图3d)。
由此，确认了酰腙衍生物化合物的优秀的炎症抑制效果及皮肤再生效果。
II.利用耳朵诱发皮肤炎的小鼠确认酰腙衍生物化合物的皮肤炎抑制效果
实施例4.肉眼确认酰腙衍生物化合物的皮肤炎抑制效果
为了证明酰腙衍生物化合物的抗炎效果，做出利用噁唑酮诱导的皮肤炎模型小鼠。具体地，通过将150μl的3％浓度噁唑酮涂敷在6周龄小鼠的腹部皮肤来诱导免疫反应，通过将20μl的稀释成0.5％的相同化合物每隔一天涂敷在小鼠的耳朵，共涂敷5次来诱导炎症反应。接着，在利用涂敷30分钟后，将20μl的酰腙衍生物化合物分别以500nM的浓度涂敷共5次。
为了比较并验证化合物的功效，使用抗炎效果广为人知的环孢菌素A作为比较物质。并且，在实验中还反映了仅用作为溶剂的乙醇进行处理的阴性对照组及仅用噁唑酮进行处理的阳性对照组。每个实验组的小鼠数量保持在10只以上，共重复实验了两次。
其结果，与仅用作为溶剂的乙醇进行涂敷的耳朵相比，单独用噁唑酮进行涂敷的阳性对照组的耳朵表现出发红，确认了炎症反应良好地被诱导。相反，在用作为酰腙衍生物化合物的WCI-1004、WCI-1015及WCI-1031化合物和环孢菌素进行处理的动物组中，观察到与用乙醇进行处理的阴性对照组非常类似的皮肤状态。由此，确认了酰腙衍生物化合物有效地抑制皮肤炎症反应(图4)。
实施例5.通过组织病理学分析确认酰腙衍生物化合物的皮肤炎抑制效果
为了在完成涂敷实验之后对皮肤进行病理学观察，采集每个小鼠的耳朵皮肤组织并用苏木精-曙红(Hematoxylin and Eosin)进行了染色。
其结果，通常若诱发皮肤炎则表现出称为表皮增生(epidermal hyperplasia)的病理学现象，与仅用乙醇进行涂敷的阴性对照组的耳朵皮肤组织相比，从单独用噁唑酮进行涂敷的阳性对照组采集的耳朵皮肤组织的整体厚度增加约2倍，上皮的厚度增加约3倍。相反，在从用WCI-1004、WCI-1015、WCI-1031化合物或环孢菌素进行处理的实验组采集的耳朵皮肤组织中确认了整个皮肤及上皮的厚度减小，这与阴性对照组非常类似。由此，确认了酰腙衍生物化合物有效地抑制皮肤炎症反应(图5)。
实施例6.确认酰腙衍生物化合物的炎症细胞因子表达抑制效果
与诸如特应性皮肤炎等的皮肤炎发病最有关联的炎症细胞因子被熟知为主要从Th2 T细胞分泌的白细胞介素-4及白细胞介素-13等。为了进一步确认酰腙衍生物化合物对由在实施例4的噁唑酮诱发皮肤炎的小鼠的抗炎效果，通过采集耳朵皮肤组织来对白细胞介素-4及白细胞介素-13和在Th2 T细胞中分泌的白细胞介素-2的信使核糖核酸(mRNA)水平进行了定量。
具体地，从在实施例4中制备的诱发皮肤炎的小鼠采集耳朵皮肤组织并利用组织破碎机进行粉碎。将粉碎的组织粉末溶解在Trizol试剂(西格玛公司(Sigma))，并利用RNeasy mini kit(凯杰公司)提取了核糖核酸。在利用ImProm-IITM反转录试剂盒(普洛麦格公司)将提取的核糖核酸反转录为cDNA之后，使用CFX96TM实时聚合酶链式反应检测系统(CFX96TM Real-Time PCR Detection System)(伯乐公司(Bio-Rad))并通过定量聚合酶链式反应(qPCR)方法测量了存在于皮肤组织的细胞因子的水平。
其结果，与仅用乙醇进行涂敷的阴性对照组的耳朵皮肤组织相比，单独用噁唑酮进行涂敷的阳性对照组的耳朵皮肤组织的组织中的白细胞介素-4、白细胞介素-13及白细胞介素-2的表达量增加。相反，确认了用WCI-1004、WCI-1015、WCI-1031化合物或环孢菌素进行处理的实验组的耳朵皮肤组织中的细胞因子表达量显著减少至上述阳性对照组的细胞因子表达量水平的50％(图6a至图6c)。
实施例7.确认酰腙衍生物化合物的炎症性免疫细胞数量减少效果
若诱发皮肤炎，则通常观察到整个皮肤中的炎症性免疫细胞数量增加的病理学现象。为了进一步确认酰腙衍生物化合物在由实施例4的噁唑酮诱导皮肤炎的小鼠中的抗炎效果，通过采集耳朵皮肤组织来测量了炎症性免疫细胞数量。
其结果，与仅用乙醇进行涂敷的阴性对照组的皮肤组织相比，单独用噁唑酮进行涂敷的阳性对照组的耳朵皮肤组织的炎症性免疫细胞数量增加了约3倍。相反，在用WCI-1004、WCI-1015、WCI-1031化合物或环孢菌素进行处理的实验组的耳朵皮肤组织中观察到与阴性对照组的水平类似的炎症性免疫细胞数量。由此，确认了酰腙衍生物化合物减少了炎症性免疫细胞数量(图7)。
实施例8.确认酰腙衍生物化合物的表皮增生抑制效果
在诱发皮肤炎的情况下，将诱发诸如皮肤厚度变厚的表皮增生(epidermalhyperplasia)等的病例症状。为了在利用噁唑酮诱发炎症反应的皮肤中确认酰腙化合物可缓解皮肤炎症状并保持皮肤稳态，通过与实施例6相同的方法，即，在从皮肤组织提取RNA之后，通过利用定量聚合酶链式反应方法测量角蛋白14、角蛋白1的信使核糖核酸表达水平来进行了调查。
其结果，单独用噁唑酮进行涂敷的阳性对照组的耳朵皮肤组织表现出角蛋白14及角蛋白1的表达水平全部增加的表皮增生症状。相反，在用WCI-1004、WCI-1015、WCI-1031化合物或环孢菌素进行处理的实验组的耳朵皮肤组织中的角蛋白14及角蛋白1的表达水平恢复而治愈了表皮增生症状。由此，确认了酰腙衍生物化合物的优秀的炎症抑制效果、皮肤再生及稳态保持效果(图8a及图8b)。
实施例9.利用免疫细胞株确认酰腙衍生物化合物的炎症性信号传导途径抑制效果
为了进一步确认酰腙衍生物化合物参与炎症抑制效果的药理作用机理(mechanism of action)，在培养作为小鼠来源巨噬细胞免疫细胞株的原始细胞株之后，观察了本发明的化合物对参与炎症细胞因子生产的活化B细胞核因子k轻链增强剂(NF-κB，nuclear factor kappa-light-chain-enhancer of activated B cells)信号传导途径的影响。活化B细胞核因子k轻链增强剂信号传导途径在参与炎症反应中起到重要作用，尤其，已知，若诱导p65(RelA)的磷酸化，则磷酸化的p65移动到免疫细胞的核并诱导引起炎症反应的细胞因子的表达。
具体地，在达尔伯克改良伊格尔培养基(包含10％的牛胎血清)培养规定量(在6-孔板的情况下，5×105至10×105个/孔)的原始细胞之后，同时用WCI-1004、WCI-1015及WCI-1031化合物和诱发活化B细胞核因子k轻链增强剂信号传导过程的因子(肿瘤坏死因子-α或脂多糖等)处理了12小时至24小时。通过在RIPA裂解提取缓冲液(RIPA Lysis andExtraction Buffer)(赛默飞公司(Thermofisher))中添加蛋白质水解抑制剂及去磷酸化抑制剂来从原始细胞中提取了蛋白质。蛋白免疫印迹(Western bloting)过程使用了本发明所属技术领域中通常使用的方法，对磷酸化的p65使用了细胞信号技术(Cell SignalingTechnology)公司的特异性抗体产品。
其结果，在用WCI-1004、WCI-1015或WCI-1031化合物对巨噬细胞免疫细胞株进行处理的情况下，确认了通过参与炎症细胞因子的生产的活化B细胞核因子k轻链增强剂信号途径来有效地抑制已知诱导免疫反应的p65(RelA)的磷酸化(图9)。
由此，确认了酰腙衍生物化合物有效地阻隔与炎症反应相关的活化B细胞核因子k轻链增强剂信号途径。
Claims (15)
1.包含由下述化学式1表示的化合物的组合物在制备用于预防或治疗炎症性疾病的药物中的用途，所述炎症性疾病选自由皮肤炎、牛皮癣、湿疹、瘙痒症、荨麻疹和硬皮病组成的组，
化学式1：
在所述化学式1中，R1为C1-C4烷基或-(CH2)m(C＝O)OR2，R2为C1-C4烷基，m为0、1、2或3。
2.根据权利要求1所述的用途，其特征在于，R1为甲基，并且R2为甲基或乙基。
3.根据权利要求1所述的用途，其特征在于，由所述化学式1表示的化合物选自下述化学式中的一种：
4.根据权利要求1所述的用途，其特征在于，所述炎症性疾病为皮肤炎。
5.根据权利要求4所述的用途，其特征在于，所述皮肤炎为特应性皮肤炎、接触性皮肤炎或过敏性皮肤炎。
6.根据权利要求1所述的用途，其特征在于，所述组合物抑制炎症细胞因子的表达。
7.根据权利要求6所述的用途，其特征在于，所述细胞因子包括白细胞介素-2、白细胞介素-4或白细胞介素-13。
8.根据权利要求1所述的用途，其特征在于，所述组合物抑制皮肤红斑或皮肤干燥症状。
9.根据权利要求1所述的用途，其特征在于，所述组合物抑制表皮增生。
10.根据权利要求1所述的用途，其特征在于，所述组合物通过经皮给药或口服给药。
11.根据权利要求1所述的用途，其特征在于，所述瘙痒症为皮肤瘙痒。
12.根据权利要求1所述的用途，其特征在于，所述荨麻疹为特发性慢性荨麻疹。
13.包含由下述化学式1表示的化合物的组合物在制备用于缓解皮肤红斑或皮肤干燥症状的化妆品中的用途，
化学式1：
在所述化学式1中，R1为C1-C4烷基或-(CH2)m(C＝O)OR2，R2为C1-C4烷基，m为0、1、2或3。
14.根据权利要求13所述的用途，其特征在于，R1为甲基，并且R2为甲基或乙基。
15.根据权利要求13所述的用途，其特征在于，由所述化学式1表示的化合物选自下述化学式中的一种：
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