CN105636975B - 抗炎三肽 - Google Patents
抗炎三肽 Download PDFInfo
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- CN105636975B CN105636975B CN201480052003.8A CN201480052003A CN105636975B CN 105636975 B CN105636975 B CN 105636975B CN 201480052003 A CN201480052003 A CN 201480052003A CN 105636975 B CN105636975 B CN 105636975B
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Abstract
本发明涉及通式(1)所示的三肽化合物及其作为药物的用途，尤其是作为抗炎药物的用途。
Description
技术领域
本发明涉及三肽化合物及其作为药物的用途，尤其是其作为抗炎药物的用途。
背景技术
在医学上炎症的治疗非常重要。然而，现有的治疗方法不充分或者有问题。短暂的炎症是保护哺乳动物免受入侵的病原体侵害的有益机制。然而，由先天性免疫反应或者适应性免疫反应引起的失控性炎症可能导致组织的损伤和疼痛，并且这种失控性炎症是许多疾病的根本原因，这些疾病包括哮喘，也包括其它的过敏性、感染性、自身免疫性、退化性和特发性疾病。现有的治疗方法通常表现出较低的、延迟性的或者仅仅暂时性的效力，不良的副反应和/或缺乏选择性。
鉴于大量的炎症类型以及与炎症有关的疾病，以及现有药物的缺点，非常需要新的活性药剂以有效治疗这些疾病及其症状，而不会产生免疫抑制不良反应。
WO88/00833公开了三肽赖氨酸-脯氨酸-缬氨酸(Lys-Pro-Val)在制备治疗炎症的药剂中的用途。
WO02/064131描述了像赖氨酸-脯氨酸-苏氨酸(Lys-Pro-Thr)这样的炎症抑制化合物。
WO02/094856涉及甘氨酸-L-脯氨酸-L-谷氨酸(GPE)的类似物和肽模拟物。
WO03/002593公开了二肽基肽酶IV(DPP IV)抑制剂。
WO2007/080194公开了三肽基肽酶II(tripeptidyl peptidase II)(TPP II)抑制剂在增强γ放射癌症治疗的疗效中的用途。
WO2007/088099公开了三肽基肽酶II抑制剂在治疗缺血和神经退化中的用途。
WO2009/000296描述了三肽基肽酶II抑制剂在治疗自身免疫性、炎性疾病以及治疗移植排斥反应中的应用。
WO2009/000297公开了三肽基肽酶II抑制剂结合化学疗法在治疗癌症中的用途。
W02012/102832描述了甘氨酸-L-2甲基脯氨酸-L-谷氨酸在治疗孤独症谱系障碍(autism spectrum disorders)中的用途。
发明内容
本发明的目的在于提供可以作为药物活性化合物(尤其是用于抗炎的药物活性化合物)的新颖化合物。本发明的另一目的在于提供在对患者既安全又可靠的同时还具有增强的稳定性和改善的生物药效率的化合物。
本发明的目的是通过提供如下通式(I)所示的三肽化合物(在下文中也称为“化合物”)或其溶剂合物或水合物，或其药学上可接受的盐实现的：
其中，
AA1选自α-氨基酸、Nα-甲基氨基酸和Nα，Nα-二甲基氨基酸；和
AA2选自α-氨基异丁酸(Aib)、叔丁基甘氨酸、α-氨基异丁酸酰胺、叔丁基甘氨酰胺、Nα-甲基氨基酸和Nα-甲基氨基酸酰胺。
出乎意料地发现本发明的所述新颖化合物可以有效地作为药物(尤其是用于治疗炎性疾病的药物)中的药物活性化合物，与现有技术所知的化合物相比，本发明的所述新颖化合物同时具有增强的稳定性和改善的生物药效率。此外，其不会显示出毒性，没有不良的副作用。并且对于患者是安全的。
在本发明中，术语“酰胺”包括：-C(O)NH2，-C(O)NHR和-C(O)NR2，其中R是C1-C6烷基。优选地，术语酰胺表示-C(O)NH2。
进一步地，在本发明中，术语C1-C6烷基包括：甲基、乙基、正丙基、异丙基、正丁基、异丁基、正戊基、异戊基、正己基和异己基。C6-C10芳基包括任何芳香性的C6-C10环。优选地，所述C6-C10芳基是苯基。优选地，卤素包括：Cl，Br和I。
此外，在本发明中，定义如下：
1-Nal 1-萘基丙氨酸
2-Nal 2-萘基丙氨酸
Abu α-氨基丁酸
Aib α-氨基异丁酸
Ala 丙氨酸
Arg 精氨酸
Asn 天冬酰胺
Asp 天冬氨酸
Cha 环己基丙氨酸
Cit 瓜氨酸
Cys 半胱氨酸
Dab α，γ-二氨基丁酸
Dap α，β-二氨基丙酸
Gly 甘氨酸
His 组氨酸
Hle 高亮氨酸
Homophe 高苯丙氨酸
Ile 异亮氨酸
Leu 亮氨酸
Lys 赖氨酸
Met 甲硫氨酸
Nle 正亮氨酸
Nva 正缬氨酸
Orn 鸟氨酸
Phe 苯基丙氨酸
Phg 苯基甘氨酸
Pro 脯氨酸
Sar 肌氨酸
Ser 丝氨酸
t-butyl-Gly 叔丁基甘氨酸
Tic 1，2，3，4-四氢异喹啉-3-羧酸
Thr 苏氨酸
Trp 色氨酸
Tyr 酪氨酸
Val 缬氨酸
在本发明中，如上述通式(1)所示的三肽化合物是优选的，其中，
(1)AA1选自选自α-氨基酸、Nα-甲基氨基酸和Nα，Nα-二甲基氨基酸；AA2选自α-氨基异丁酸、叔丁基甘氨酸、α-氨基异丁酸酰胺和叔丁基甘氨酰胺；
或者可选择的，其中
(2)AA1选自选自α-氨基酸、Nα-甲基氨基酸和Nα，Nα-二甲基氨基酸；AA2选自Nα-甲基氨基酸和Nα-甲基氨基酸酰胺。
在本发明，通式(2)所示的三肽化合物(在下文中也称为“化合物”)更为优选：
其中AA1选自选自α-氨基酸、Nα-甲基氨基酸和Nα，Nα-二甲基氨基酸；
AA2选自Nα-甲基氨基酸和Nα-甲基氨基酸酰胺。
这些化合物提供了进一步提高的疗效(尤其是在治疗炎性疾病中)，增强的稳定性和生物药效率。
根据本发明进一步优选的实施例，在通式(1)和/或通式(2)所示的三肽化合物中，分别地，AA1是Nα，Nα-二甲基氨基酸，AA2是Nα-甲基氨基酸。
在本发明中，优选地，在AA1的定义中的Nα-甲基氨基酸和Nα，Nα-二甲基氨基酸选自下列物质构成的组：Nα-甲基-1-萘基丙氨酸，Nα，Nα-二甲基-1-萘基丙氨酸，Nα-甲基-2-萘基丙氨酸，Nα，Nα-二甲基-2-萘基丙氨酸，Nα-甲基-α-氨基丁酸，Nα，Nα-二甲基-α-氨基丁酸，Nα-甲基-丙氨酸，Nα，Nα-二甲基-丙氨酸，Nα-甲基-精氨酸，Nα，Nα-二甲基-精氨酸，Nα-甲基-天冬酰胺，Nα，Nα-二甲基-天冬酰胺，Nα-甲基-环己基丙氨酸，Nα，Nα-二甲基-环己基丙氨酸，Nα-甲基-瓜氨酸，Nα，Nα-二甲基-瓜氨酸，Nα-甲基-半胱氨酸，Nα，Nα-二甲基-半胱氨酸，Nα-甲基-α，γ-二氨基丁酸，Nα，Nα-二甲基-α，γ-二氨基丁酸，Nα-甲基-α，β-二氨基丙酸，Nα，Nα-二甲基-α，β-二氨基丙酸，肌氨酸，Nα，Nα-二甲基-甘氨酸，Nα-甲基-组氨酸，Nα，Nα-二甲基-组氨酸，Nα-甲基-高亮氨酸，Nα，Nα-二甲基-高亮氨酸，Nα-甲基-高苯丙氨酸，Nα，Nα-二甲基-高苯丙氨酸，Nα-甲基-异亮氨酸，Nα，Nα-二甲基-异亮氨酸，Nα-甲基-亮氨酸，Nα，Nα-二甲基-亮氨酸，Nα-甲基-赖氨酸，Nα，Nα-二甲基-赖氨酸，Nα-甲基-甲硫氨酸，Nα，Nα-二甲基-甲硫氨酸，Nα-甲基-正亮氨酸，Nα，Nα-二甲基-正亮氨酸，Nα-甲基-正缬氨酸，Nα，Nα-二甲基-正缬氨酸，Nα-甲基-鸟氨酸，Nα，Nα-二甲基-鸟氨酸，Nα-甲基-苯基丙氨酸，Nα，Nα-二甲基-苯基丙氨酸，Nα-甲基-苯基甘氨酸，Nα，Nα-二甲基-苯基甘氨酸，Nα-甲基-丝氨酸，Nα，Nα-二甲基-丝氨酸，Nα-甲基-叔丁基-甘氨酸，Nα，Nα-二甲基-叔丁基-甘氨酸，Nα-甲基-1，2，3，4-四氢异喹啉-3-羧酸，Nα-甲基-苏氨酸，Nα，Nα-二甲基-苏氨酸，Nα-甲基-色氨酸，Nα，Nα-二甲基-色氨酸，Nα-甲基-酪氨酸，Nα，Nα-二甲基-酪氨酸，Nα-甲基-缬氨酸，Nα，Nα-二甲基-缬氨酸，Nα-甲基-2-噻吩基丙氨酸，Nα，Nα-二甲基-2-噻吩基丙氨酸，Nα-甲基-3-苯并噻吩基丙氨酸，Nα，Nα-二甲基-3-苯并噻吩基丙氨酸，Nα-甲基-2-吡啶基丙氨酸，Nα，Nα-二甲基-2-吡啶基丙氨酸，Nα-甲基-3-吡啶基丙氨酸和Nα，Nα-二甲基-3-吡啶基丙氨酸。苯基丙氨酸可以被一个或多个选自由下列基团构成的组中的取代基取代：-NH2，-NH(C1-C6烷基)，-N(C1-C6烷基)2，-CH2NH2，-CH2NH(C1-C6烷基)，-CH2N(C1-C6烷基)2，OH，卤素，-CN，CF3，-NHC(O)CH3，-C(O)CH3，-OC1-C6烷基，-C(O)NH2和-C1-C6烷基。
在本发明中，优选地，在AA2的定义中的Nα-氨基酸和Nα-氨基酸酰胺选自由下列物质构成的组：Nα-甲基-α-氨基丁酸-OH，Nα-甲基-丙氨酸-OH，肌氨酸-OH，Nα-甲基-高亮氨酸-OH，Nα-甲基-异亮氨酸-OH，Nα-甲基-亮氨酸-OH，Nα-甲基-正亮氨酸-OH，Nα-甲基-正缬氨酸-OH，Nα-甲基-丝氨酸-OH，Nα-甲基-叔丁基-甘氨酸-OH，Nα-甲基-苏氨酸-OH，Nα-甲基-缬氨酸-OH，Nα-甲基-α-氨基丁酸-NH2，Nα-甲基-丙氨酸-NH2，肌氨酸-NH2，Nα-甲基-高亮氨酸-NH2，Nα-甲基-异亮氨酸-NH2，Nα-甲基-亮氨酸-NH2，Nα-甲基-正亮氨酸-NH2，Nα-甲基-正缬氨酸-NH2，Nα-甲基-丝氨酸-NH2，Nα-甲基-叔丁基-甘氨酸-NH2，Nα-甲基-苏氨酸-NH2和Nα-甲基-缬氨酸-NH2。
在本发明中，α-氨基酸包括所有在临近羧基的α-位上有氨基的氨基酸。在本发明中，优选地，在AA1的定义中，所述α-氨基酸选自由下列物质构成的组：1-萘基丙氨酸，2-萘基丙氨酸，α-氨基丁酸，丙氨酸，精氨酸，天冬酰胺，环己基丙氨酸，瓜氨酸，半胱氨酸，α，γ-二氨基丁酸，α，β-二氨基丙酸，甘氨酸，组氨酸，高亮氨酸，高苯丙氨酸，异亮氨酸，亮氨酸，赖氨酸，甲硫氨酸，正亮氨酸，正缬氨酸，鸟氨酸，苯基丙氨酸，苯基甘氨酸，丝氨酸，叔丁基-甘氨酸，1，2，3，4-四氢异喹啉-3-羧酸，苏氨酸，色氨酸，酪氨酸，缬氨酸，2-噻吩基丙氨酸，3-苯并噻吩基丙氨酸，2-吡啶基丙氨酸和3-吡啶基丙氨酸。苯基丙氨酸可以被一个或多个选自由下列基团构成的组中的取代基取代：-NH2，-NH(C1-C6烷基)，-N(C1-C6烷基)2，-CH2NH2，-CH2NH(C1-C6烷基)，-CH2N(C1-C6烷基)2，OH，卤素，-CN，CF3，-NHC(O)CH3，-C(O)CH3，-OC1-C6烷基，-C(O)NH2和-C1-C6烷基。更优选地，AA1选自赖氨酸，鸟氨酸，正亮氨酸和苯基丙氨酸。
在本发明中，优选的三肽化合物是这样的：在通式(1)中，其中AA1选自赖氨酸，鸟氨酸，正亮氨酸，苯基丙氨酸，Nα-甲基苯基丙氨酸，Nα，Nα-二甲基-正亮氨酸和Nα，Nα-二甲基-苯基丙氨酸；AA2选自α-氨基异丁酸，叔丁基甘氨酸和α-氨基异丁酸酰胺。
在本发明中，最优选的三肽化合物选自下列物质，或其溶剂合物或水合物，或其药学上可接受的盐构成的组：H-(L)-赖氨酸-(D)-脯氨酸-α-氨基异丁酸-OH，H-(L)-赖氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-OH，H-(L)-赖氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，H-(L)-赖氨酸-(L)-脯氨酸-(L)-叔丁基甘氨酸-OH，Nα，Nα-二甲基-(L)-赖氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-OH，H-(L)-赖氨酸-(L)-脯氨酸-α-氨基异丁酸-NH2，H-(L)-鸟氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，H-(L)-正亮氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，H-(L)-苯基丙氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，Nα，Nα-二甲基-(L)-赖氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-NH2，Nα，Nα-二甲基-(L)-赖氨酸-(D)-脯氨酸-Nα-甲基-(L)-缬氨酸-OH，Nα，Nα-二甲基-(L)-正亮氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-OH，Nα-甲基-(D)-苯基丙氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，H-(D)-苯基丙氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，Nα，Nα-二甲基-(L)-苯基丙氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，Nα，Nα-二甲基-(L)-正亮氨酸-(L)-脯氨酸-α-氨基异丁酸-OH或者Nα，Nα-二甲基-(L)-苯基丙氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-OH。
此外，在本发明中，本发明所述化合物可以以其酸或者碱的形式使用，或者以其盐的形式使用(尤其是生理上可接受的盐)，或者以其溶剂合物的形式使用(尤其是其水合物)。
药学上可接受的盐可以是加碱盐。所述加碱盐包括本发明所述的化合物与无机碱(例如：碱金属氢氧化物、碱土金属氢氧化物)或者有机碱(例如：一乙醇胺、二乙醇胺或者三乙醇胺)构成的盐，
方便地，可以进一步使用加酸盐，尤其是与无机酸(例如，盐酸、硫酸或者磷酸)构成的盐，或者与合适的有机羧酸或者磺酸构成的盐，或者与氨基酸组成的盐
本发明所述的化合物的药学上可接受的盐选自，例如，包括如下物质的组：氯化物、溴化物、碘化物、盐酸盐、氢溴酸盐、磺酸盐、甲磺酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、硝酸盐、甲酸盐、乙酸盐、丙酸盐、乳酸盐、柠檬酸盐、戊二酸盐、顺丁烯二酸盐、丙二酸盐、苹果酸盐、琥珀酸盐、酒石酸盐、草酸盐、富马酸盐、苯甲酸盐、对甲苯磺酸盐和/或氨基酸(优选蛋白氨基酸)的盐。
在本发明中，所述的化合物适于作为药物。这些药物能够具有止痛、退热、止痒、抗炎和/或者抗痉挛的作用。在本发明中，优选地，所述化合物和包含所述化合物的药物可以用在疾病的治疗性和/或预防性治疗方法中，所述疾病选自包含下列疾病的组：急慢性疾病、急慢性疼痛、瘙痒、低钠血症、水肿、肠梗阻、咳嗽和青光眼。进一步地，可以根据本发明治疗的疾病是多发性硬化(multiple sclerosis)、帕金森氏病和阿尔茨海默病。
在优选的实施例中，本发明所述的化合物尤其可用于炎性疾病的治疗性和/或预防性处理，诊断和/或治疗。
本发明还提供了本发明所述化合物在制备用于治疗性和/或预防性治疗炎性疾病的药剂中的用途。
在本发明中，疼痛相关的疾病尤其指那些由于炎症反应引起疼痛的疾病(也称之为炎性疼痛相关疾病和炎性疼痛)。
此外，在本发明中，炎性疾病选自包括下列疾病的组：心血管炎症，神经炎症，骨骼炎症，皮肤炎症，肌肉炎症，胃肠道炎症，眼部炎症，耳炎，由昆虫咬伤引起的炎症和由伤口愈合引起的炎症；动脉粥样硬化，缺血，再狭窄和血管炎；哮喘，干燥综合征，肺部炎症，慢性气道炎症和慢性阻塞性肺病(COPD)，过敏，银屑病、银屑病关节炎，湿疹，硬皮病、特应性皮炎和系统性红斑狼疮，关节炎，滑膜炎，骨髓炎，类风湿性关节炎，骨关节炎和强直性关节炎；败血症和败血性休克，糖尿病，葡萄糖不耐症，胰岛素抗药性和肥胖，结肠炎，溃疡性结肠炎，节段性肠炎，炎性肠病和肠易激综合征，以及由肿瘤增殖、肿瘤转移或者移植排斥反应(移植物抗宿主疾病；GvHD)而引起的炎性疾病和炎性状态。
尤其地，炎性疾病选自包括下列疾病的组：胃肠道炎性疾病，尤其是炎性肠病，例如，克罗恩病和/或溃疡性结肠炎，具有胆囊炎症的急性或者慢性炎症病变，炎性假息肉，深层囊性结肠炎，肠壁囊样积气，胰腺炎，阑尾炎，动脉硬化引起的心血管炎症，缺血，再狭窄和/或血管炎，脓毒症，败血症，过敏，哮喘，干燥综合征，肺部炎症，慢性气道炎症，慢性阻塞性肺病(COPD)，肿瘤增殖，肿瘤转移，移植排斥，关节炎性疾病，例如，类风湿性关节炎，外阴阴道炎和/或脑部、皮肤、毛囊、泌尿生殖道的炎性疾病和眼睛的炎性疾病，鼻窦炎，腱鞘炎、黏液囊炎，肌腱炎，肱骨外上髁炎，粘粘性囊炎、骨髓炎，骨关节炎，眼部炎症，耳炎和/或自身免疫性炎症，银屑病，银屑病关节炎，接触性皮炎，特应性湿疹，斑秃，硬皮病和其它纤维化疾病，系统性红斑狼疮，荨麻疹，扁平苔藓，淋巴瘤和/或过敏性疾病或者特征为肥大细胞参与的疾病。
瘙痒(发痒)，尤其是皮痒型瘙痒，是皮肤疾病的常见症状，通常作为一种疼痛刺激而感受。痒的感觉引起抓挠患处的渴望。抓挠而损伤的皮肤进一步为感染性病原体提供了良好的培养基，且皮肤抓破区域的炎症并不少见。此外，发痒和瘙痒本身可能引起炎症反应。瘙痒的皮肤和毛发疾病选自包含下列疾病的组：瘙痒，银屑病，银屑病关节炎，接触性皮炎，特应性湿疹，斑秃，硬皮病和其它纤维化疾病，系统性红斑狼疮，荨麻疹，扁平苔藓，淋巴瘤和/或过敏性疾病或者特征为肥大细胞参与的疾病。
在本发明意义上的疾病也包括其它疾病，例如，低钠血症，水肿，肠梗塞，咳嗽，青光眼，多发性硬化症，帕金森氏症和阿尔茨海默病。
通过本发明所述化合物进行治疗的涉及疾病的器官尤指所谓的屏障器官，也就是胃肠道，皮肤，肺，泌尿生殖道，大脑，耳鼻和咽喉道，牙齿，骨头，肝和毛发。本发明最优选的实施例涉及屏障器官疾病的治疗。
胃肠道疾病选自包含下列疾病的组：肠道易激综合症，胃部病变，胃肠道溃疡，胃肠粘膜的外源性和内源性损伤，胃肠道故障，腺瘤(尤其是在肠内)，和/或幼年性息肉。
肺部疾病(呼吸道疾病)包括：肺部炎性疾病，阻塞性肺病(例如：慢性阻塞性肺病(COPD))，限制性肺病，呼吸道感染(例如：上呼吸道感染，下呼吸道感染)，恶性肿瘤和良性肿瘤，胸腔疾病，肺血管疾病，和新生儿疾病。
泌尿生殖道疾病包括镇痛药肾病，膀胱癌，膀胱膨出(膀胱下垂)，终末期肾脏疾病(ESRD)，肾小球肾炎，肾小球硬化症，肺出血肾炎综合征，血尿(在尿内有血)，溶血性尿毒综合征，免疫球蛋白A(IgA)肾病，阳痿/勃起功能障碍，间质性膀胱炎，肾肿瘤，肾结石，肾移植，男不孕症，肾病综合征，神经源性膀胱，阴茎硬结症和多囊肾疾病。
进一步地，可以用本发明所述药物治疗的疾病在US 2011/0212882 A1中有说明，其通过引用的方式并入本文。
优选地，所述三肽和包含所述三肽的药剂可以用于皮肤炎性疾病，胃肠道炎性疾病，血管炎性疾病，自身免疫性炎症，过敏反应和/或移植排斥的治疗和/或预防。
众所周知，通常多肽类甚至更小的二肽(例如：肌肽)，显示出固有的不稳定性(Goebel，ASB等人，Dermal Peptide Delivery Using Enhancer Molecules andColloidal Carrier Systems-Part I：Carnosine，Skin Pharmacology &Physiology(2012)，25，281-287)。此外，H-赖氨酸-脯氨酸-缬氨酸-OH(KPV)在赖氨酸-脯氨酸二酮哌嗪形式下非常不稳定且容易降解。本发明所述化合物的进一步的优势源自以下事实：在水溶液中和组织匀浆中，所述化合物不会降解或降解度降低。
与H-赖氨酸-(D)-脯氨酸-苏氨酸-OH(K(D)PT相比，本发明所述化合物的另一优势是：亲水性降低。因此，所述化合物显示出改善的生物屏障渗透性。此外，本发明的所述化合物对于患者安全可靠。尤其是，没有观测到毒性。因此，本发明的所述化合物显示出改进的安全特性。
本发明所述的化合物或者包含所述化合物的组合物/药剂可以全身给药或者局部给药。优选地，本发明所述的化合物或者组合物/药剂是局部给药，尤其是以乳膏、油膏、膏药或酊剂的形式局部给药。
在本发明的上下文中，术语“预防性治疗”如其自身含义，尤其意味着本发明所述化合物可以在疾病症状出现前或者疾病风险存在前进行给药。
本发明所述的化合物可以根据传统的方法给药，例如：口服给药，经过皮肤给药，鼻内给药，粘膜给药，肺给药，肠给药，颊给药，直肠给药，尿道内给药，耳给药，通过吸入给药，通过注射给药(例如：静脉注射)，肠道外给药，腹腔内给药，皮内给药，皮下给药和/或者肌内给药和/或者局部给药(例如，在身体的疼痛区域给药)。口服给药是最优选的。
本发明所述的化合物尤其可用于通过如下方式制备药剂：与至少一种载体物质或者辅助物质一起被加工成的合适的剂型，例如，注射剂、滴剂、果汁、糖浆、喷雾、悬浊液、油膏、乳膏、洗液、凝胶、乳液、气雾剂形式，或者多颗粒形式，例如，小丸或者颗粒形式。
具有缓释的药物剂型(缓释制剂)对于本发明所述化合物的口服给药更为优选。具有缓释剂型的例子有：缓释骨架片，多层药片(例如：多层药片的涂层可以加工成抗胃酸的，例如，基于虫胶的涂层)，缓释胶囊或者使用了可生物降解聚合物(例如：多乳酸聚合物)的剂型。
传统的生理上可接受的药物辅助物质可以用于制备所述药剂，优选地，所述药物辅助物质选自包含下列物质的组：载体物质、填充剂、溶剂、稀释剂、润湿剂、乳化剂、染料、防腐剂、崩解剂、润滑剂、影响渗透压的盐、缓冲物质、香味剂和/或粘接剂。
在本发明中，所述通式(1)和通式(2)的化合物可以使用本领域技术人员所知的常规的固相肽合成的方法制备。在下面的实施例部分进行了更为详细的说明。
可选地，本发明所述通式(1)和通式(2)的化合物也可以在溶液中制备。
附图说明
图1是显示了初始人类T细胞中促炎性细胞因子的基因表达分析的图表。细胞用PMA/离子霉素刺激，并分别用PBS，α-MSH，K(D)PT和实施例3、8和9处理，浓度为10-9M。数值被标准化为β-肌动蛋白，显示了相对于PBS-刺激的细胞中基因表达的数值。
图2是显示了人类角质细胞(HaCaT)中促炎性因子的基因表达分析的图表。细胞用PMA/离子霉素刺激并用PBS，α-MSH，K(D)PT和实施例3、8和9处理，浓度为10-9M。数值被标准化为β-肌动蛋白，显示了相对于PBS-刺激的细胞中基因表达的数值。
图3是显示了初始小鼠T细胞中促炎性细胞因子的基因表达分析的图表。细胞用PMA/离子霉素刺激并用PBS，α-MSH，K(D)PT和实施例3、8和9处理，浓度为10-9M。数值被标准化为β-肌动蛋白，显示了相对于PBS-刺激的细胞中基因表达的数值。
图4是显示了初始人类T细胞中促炎性细胞因子的基因表达分析的图表。细胞用PMA/离子霉素刺激并分别用PBS，α-MSH，K(D)PT，霉酚酸酯(MMF)，地塞米松和实施例5、7、12和13处理，浓度为10-9M。数值被标准化为β-肌动蛋白，显示了相对于PBS-刺激的细胞中基因表达的数值。
图5是显示了人类角质细胞中(HaCaT)中促炎性细胞因子的基因表达分析的图表。细胞用PMA/离子霉素刺激并分别用PBS，α-MSH，K(D)PT，霉酚酸酯(MMF)，地塞米松和实施例5、7、12和13处理，浓度为10-9M。数值被标准化为β-肌动蛋白，显示了相对于PBS-刺激的细胞中基因表达的数值。
图6是显示了在初始小鼠T细胞中促炎性细胞因子的基因表达分析的图表。细胞用PMA/离子霉素刺激并分别用PBS，α-MSH，K(D)PT，霉酚酸酯(MMF)，地塞米松和实施例5、7、12和13治疗，浓度为10-9M。数值被标准化为β-肌动蛋白，显示了相对于PBS-刺激的细胞中基因表达的数值。
具体实施方式
下面描述了本发明的详细的实施例。其中，各种试剂符号和缩略词的含义如下：
Boc 叔丁氧基羰基
BTC 二(三氯甲基)碳酸酯
DIC N，N′-二异丙基碳二亚胺
DIPEA 乙基-二异丙基胺
DMF N，N-二甲基甲酰胺
DMSO 二甲基亚砜
eq. 当量
ESI-MS 电喷雾质谱
Fmoc 9H-芴-9-基甲氧基羰基
h 小时
HATU 2-(1H-7-氮杂苯并三唑-1-基)-1，1，3，3-四甲基脲六氟磷酸甲胺
HOBt 1-羟基苯并三氮唑
HOAc 醋酸
HPLC 高效液相色谱
m/z 质荷比
min 分钟
MeCN 乙腈
MeOH 甲醇
MW 分子量
RT 室温
T 温度
tBu 叔丁基
TFA 三氟乙酸
TIS 三异丙基硅烷
tR(min) 高效液相色谱保留时间
分析方法
高效液相色谱(HPLC)
分析型HPLC是在由Dr.Maisch(D-Ammerbuch)制造的含有分析柱Reprospher C18-DE(5μm，50x4.6mm)的Abimed(D-Langenfeld)Gilson HPLC(样品在水中浓度为1mg/mL)上进行的。梯度为水/0.1％三氟乙酸(v/v)(洗脱液A)和乙腈/0.1％三氟乙酸(v/v)(洗脱液B)，流速为1mL/min(10分钟法)。
产品的纯度根据在λ＝214nm测定的峰面积分析。
电喷雾质谱(ESI-MS)
电喷雾质谱分析在Waters-Micromass(D-Eschborn)ZQ质谱仪上进行。
多肽的合成，一般步骤
装载树脂
所有的肽都是通过固相多肽合成法制备的，利用Fmoc/tBu-策略，使用ClTCP(氯代-(2-氯)三苯甲基聚苯乙烯树脂H100 33，Rapp Polymere，蒂宾根，德国)。在Rink-amide聚苯乙烯树脂(H100 33，Rapp)上合成多肽酰胺。
ClTCP树脂(容量1.48mmol/g)用DMF平衡10分钟，并用DMF进行洗脱。将1当量的Fmoc-氨基酸(相对于装载的树脂)和4当量的DIPEA的DMF溶液加入所述树脂，并震荡120分钟。滤出树脂并用DMF洗脱。用含10当量甲醇和5当量DIPEA的DMF覆盖树脂，并用DMF，DCM和乙醚洗脱。
使用含30％哌啶的DMF将Rink树脂(容量0.67mmol/g)脱保护(2×15分钟)。在用DMF洗脱后，加入3当量Fmoc-氨基酸、3当量TBTU和6当量DIPEA的DMF溶液。震荡所述溶液180分钟。滤出树脂并用DMF，DCM和乙醚洗脱。反应的完成程度通过茚三酮检测法检测。
在装载树脂后，装填密度通过紫外吸收法检测。检测到脱离的Fmoc-二苯富烯(dibenzofulven)物质的吸收度在292nm。所有Fmoc-氨基酸的树脂装载量为0.5mmol/g，除了N-甲基氨基酸，N-甲基苏氨酸(叔丁基)，叔丁基甘氨酸和N-甲基缬氨酸，其导致了约0.4mmol/g的替换。
偶联步骤
向树脂中加入含30％哌啶的DMF溶液，并将所得混合物孵育5分钟。滤出树脂，重复该步骤15分钟。滤出树脂并用DMF洗脱。
将Fmoc-氨基酸(3当量)用于DMF中的HOBt(3当量)溶解。向树脂中加入含有DIPEA(6当量)的偶联试剂DIC(3当量)或者TBTU(3当量)以及Fmoc-氨基酸。
在经过180分钟(DIC)或者120分钟(TBTU)的偶联后，滤出偶联试剂，并用DMF，DCM和乙醚洗脱树脂。
在N-甲基氨基酸后偶联Fmoc-氨基酸
用净(dry)THF清洗树脂，并用在净THF中的DIPEA(14当量)孵育1-2分钟。滤出树脂。将Fmoc-氨基酸(3.5当量)溶解在于净THF中的BTC溶液(68mM)中。加入2，4，6-三甲基吡啶(10当量)，并向树脂中加入所得悬浊液。在180分钟后，滤出树脂并用DCM，THF和DMF洗脱。偶联反应的完成度通过四氯苯醌实验进行检查。
Me2-氨基酸的N-端偶联：
将Me2-氨基酸(3当量)以及HOBt(3当量)，HATU(3当量)和DIPEA(6当量)溶解在DMF中。向树脂中加入所得溶液并摇动2小时。滤出树脂并用DMF，DCM和乙醚洗脱。
脱离
在3小时内，肽从树脂和用三氟乙酸/TIS/水(92.5/5/2.5)脱保护的侧链上脱离。溶剂在真空下蒸发。所得油状物用乙醚处理从而沉淀出来，用乙醚清洗2次。通过超声将肽溶解在叔丁基醇/水(80/20)中，并进行冻干。
所有的Fmoc-氨基酸，标准的侧链保护剂：叔丁基(苏氨酸)和叔丁氧羰基(赖氨酸，鸟氨酸，α，γ-二氨基丁酸)
Nα，Nα-二甲基氨基酸可以用Garcia-Lopez，MT et al.，Archiv der Pharmazie(1989)，322，145-152中所述方法合成。
本发明所获得的化合物如下表1和表2所示。
表1：
表2：
生物实验
A.在蛋白质水平和基因表达水平检测细胞因子分泌
分别从健康受试者的外周血和未经任何处理的(naive)C57BL/6小鼠的次级淋巴组织分离出初始T细胞。所得细胞分别用佛波醇-12-十四酸酯-13-乙酸酯(PMA)/离子霉素和γ干扰素(IFN-γ)刺激48小时，以活化所得细胞。所得到的活化细胞释放出促炎性细胞因子。平行地，也分别用PMA/离子霉素和IFN-γ活化人类(HaCaT)角质细胞系。已知分别用PMA/离子霉素和IFN-γ处理将导致促炎性细胞因子IL-1，IL-2，IL-6，IL-17，IFN-γ或TNF-α的释放增加。同时，抗炎性IL-10的释放被抑制。在分别加入PMA/离子霉素和IFN-γ后两天，测定了上清液中诱导分泌的IL-1，从而证实细胞被激活。此后，用不同剂量(10-7M，10-9M和10-11M)的三肽、PBS(阴性对照)以及α-促黑激素(α-MSH)，K(D)PT、霉酚酸酯(MMF)和地塞米松(分别作为阳性对照)处理所述细胞。在刺激后48小时和72小时测定三肽的抗炎性。基于FACS分析的13-plex系统用于显示上清液中促炎性细胞因子分泌减少。IL-1，IL-2，IL-6，IL-12p70 IL-17，IFN-γ和TNF-α的数据被认为相关度最高。因此，优选地，所述三肽的抗炎性的分析是基于由这些分析所获得的结果。此外，通过mRNA的制备和随后的RT-qPCR分析证实这些结果。使用这些方法，确定了诸如IL-6，IL-17，IFN-γ和TNF-α等促炎性标记物的基因表达。
在第一个实验中，可以看出，与阳性对照K(D)PT相比，实施例3、8和9尤其显示出更强的抗炎效果的特性。这些实施例不但可以减少被活化的初始小鼠T细胞和初始人类T细胞中促炎性细胞因子的分泌，而且可以更有效地减少人类角质细胞中促炎性细胞因子的分泌。上述所有三肽抑制了所分析的促炎性细胞因子(IL-1，IL-2，IL-6，IL-17，IFN-γ或者TNF-α)中至少三种的分泌，比阳性对照K(D)PT的抑制程度更大。另外，在角质细胞中观测到了抗炎性细胞因子IL-10的分泌诱导(表3-5)。用实施例1和2处理导致角质细胞中促炎性细胞因子的分泌减少。
对于实施例3、8和9，通过测定上清液的细胞因子数据所得到的结果在基因表达水平得到了证实。RT-qPCR实验显示了实施例3和8的免疫调节活性，与作为阳性对照的K(D)PT具有可比性。用所述化合物刺激后，IL-6，IL-17，IFN-γ和TNF-α的mRNA表达在人类T细胞和小鼠T细胞中减少。此外，用实施例3、8和9处理与HaCaT角质细胞中促炎性细胞因子的基因表达的减少相关(图1-3)。
在第二个实验中，可以看出，实施例12可以减少所有三种细胞模型中促炎性细胞因子的表达。其活性与K(D)PT的活性具有可比性。用实施例6和13处理导致了人类T细胞和人类角质细胞中促炎性细胞因子的表达下降。对于实施例5和7，免疫性调节作用可见于人类T细胞和小鼠T细胞(表6-8)。
促炎性标记物(诸如IL-6，IL-17，IFN-γ和TNF-α)的编码基因的表达如前所述进行测定。实验结果显示了，用实施例13刺激导致所有被刺激的细胞中促炎性标记物的表达降低(图4-6)。
在第三个实验中，小鼠T细胞和人类T细胞以及HaCaT细胞用PMA/离子霉素进行刺激，并用实施例14，15，16和17以10-7M，10-9M和10-11M进行处理。使用Luminex技术测定上清液中细胞因子(T细胞中的IFN-γ，IL-17和IL-10以及HaCat的IFN-γ)浓度。测定了Il-1β，IL-6和TNF-α编码基因的表达。在所有的细胞类型和所有测试的浓度中，用实施例14，15，16和17处理导致促炎性细胞因子Il-1β，IL-6和TNF-α在mRNA水平的表达降低。此外，上清液中促炎性细胞因子IFN-γ和IL-17的浓度降低，而抗炎性细胞因子IL-10的浓度增加。而且，对所测试的所有浓度都能观测到该结果。
本发明所选择的实施例的抗炎和免疫调节作用与常规的免疫抑制剂进行了对比。因此，用MMF或者地塞米松刺激分别用PMA/离子霉素和IFN-γ活化的细胞。接着，在蛋白质水平和基因水平分析促炎性细胞因子的分泌(表9和图4-6)。令人惊讶发现：相比于所观测到的MMF的免疫调节活性，实施例13显示出更高的免疫调节活性。
对于生物实验，选择不同起源的两种人类细胞系，以对所获得的结果进行转化(translation)。HaCaT细胞属于用于科学研究的永生性人类角质细胞系的细胞类型。其在研究中的应用允许使用模型表征人类角质细胞，该模型是可重复的并且代表了人类上皮细胞系。相比之下，人类T淋巴细胞(T细胞)是一类淋巴细胞(自身是白细胞的一种类型)，其在细胞介导的炎症/免疫中扮演着核心角色。
B.小鼠的血管炎模型
C57BL/6小鼠接受了LPS皮内注射。在第二天，通过皮内注射TNF-α诱导血管炎。此外，注射偶氮蓝(Evan’s blue)。在注射TNF-γ后24小时，小鼠被挠伤。测定耳部厚度，并通过计算出血点评估血管炎程度。在耳部组织的偶氮蓝含量作为血管渗透性的标记物。通过组织学、FACS和RT-qRCR分析耳朵。
用实施例13(皮下)处理导致耳部厚度降低，并且出血点数量降低。在组织学上，可以观测到炎性渗透减少。
C.小鼠内咪喹莫特-诱导的银屑病
通过局部每天施用咪喹莫特8天诱导Balb/c小鼠的银屑病。用测试物治疗动物(局部或全身)。在第九天，用临床计分系统表征皮肤表型(0＝正常小鼠皮肤；1＝轻微变红；2＝红疹；3＝红疹，肿胀；4＝红疹，肿胀，鳞片；5＝红疹，肿胀，鳞片，(血性)损伤)。在组织结构上分析皮肤。通过流式细胞术和RT-qPCR分析淋巴结。受损皮肤的mRNA表达通过RT-qPCR分析。血清中细胞因子的浓度使用Luminex技术进行评估。
相对于空白对照，用实施例13(静脉注射)治疗导致表皮突(rete ridge)的尺寸减小。临床得分降低。在损伤皮肤中IL-17，IFN-γ，IL-23，IL-36和IL-22的mRNA表达降低。在接受过治疗的小鼠血清内TNF-α和IL-17的浓度降低。
用实施例14，15，16和17(静脉注射)治疗导致临床得分降低，且表皮厚度降低。在接受过治疗的小鼠的血清内TNF-α和IL-17的浓度降低。在受损皮肤内，IFN-γ和IL-36的mRNA表达相对于空白对照降低。
D.小鼠内硫酸葡聚糖(DSS)诱导的结肠炎
用含2.5％的硫酸葡聚糖(DSS)的饮用水处理C57BL/6小鼠7天，诱导结肠炎。用检测物检测小鼠。每天检测体重。在第八天，小鼠被挠伤。进行潜血(haemocult)实验。测定结肠的尺寸。使用H&E染色剂(H&E stains)计分系统测定结肠炎。用RT-qPCT分析结肠样品中的mRNA表达。
与空白对照相比，用实施例13(腹腔注射)治疗导致体重减少量降低。结肠尺寸部分正常化。在组织学上观测到疾病改善。与空白对照相比，观测到LY-6G，MPO，IFN-γ，IL-6和TNF-α的mRNA表达降低。
E.皮肤渗透研究
用离体的人类皮肤进行皮肤渗透研究。组织样品术后用生理盐水清洗，去除皮下脂肪层。钻取活组织(直径20mm，3.14cm2)，并在-20℃下保存。在渗透研究开始时，解冻全厚(full thickness)皮肤样品并用棉签弄干。渗透研究是在Franz扩散池中进行。含有所述三肽化合物的乳膏基质被施用于皮肤并分布均匀。皮肤样品被放置在预先温度调至32℃的扩散池上。分别在30，100和300分钟后，用棉签去除残留的组分。在从扩散池去除后，取3块钻取的活组织(直径6mm)。制备水平切面，从中提取出三肽化合物。用HPLC-MS分析所有提取物和受体介质中的肽含量。
F.溶液稳定性
将含有0.02％叠氮化钠的三肽化合物水溶液(c肽＝160μg/ml)(1500μL)及不含有叠氮化钠的三肽化合物的水溶液(1500μL)分别在32℃和8℃进行孵育。在0，30，100，300和1000分钟取样。将100μL样品用1900μL含内标(internal standard)的甲醇稀释，并用HPLC-MS进行分析。所有的分析重复三次。
对于实施例3，8和9，甚至在1000分钟后，没有观测到降解。
G.在人类皮肤匀浆中的稳定性
人类皮肤样品(耳部皮肤，脐区皮肤和青少年包皮)被混合在一起，冷冻在液氮中，搅匀。所得到的人类皮肤匀浆被分批(50-70mg)转移到蛋白质LoBind试管(2mL)中，并在-32℃下保存至使用。在稳定测试开始时，解冻人类皮肤匀浆。加入含有0.02％叠氮化钠或者不含叠氮化钠的三肽化合物水溶液(1500μL)(c肽＝160μg/mL)，所得混合物在32℃下孵育。在0，30，100，300和1000分钟取样。100μL样品用含有内标的1900μL甲醇稀释，并用HPLC-MS进行分析。所有的分析重复三次。
对于实施例8，分别在30分钟和100分钟后，测试溶液仍含有94-95％的起始浓度。在300分钟后进行观测，降至77-80％，在1000分钟后进行观测，分别降至40％(没有叠氮化物)和47％(含有叠氮化钠)。
在300分钟后，溶液中实施例9的量分别减少至58％(没有叠氮化物)和63％(含有叠氮化钠)。
对于实施例3没有观测到降解。在所有时间点所有样品含有80-90％的起始浓度。
药物组合物实施例
实施例3的组合物：
实施例8的组合物
实施例3的组合物：
作为本发明化合物口服组合物的具体实施例，将21mg实施例3与足够精细的乳糖一起配制，总量为580～590mg，填充0号硬质明胶胶囊。
实施例9的组合物：
作为本发明化合物口服组合物的另一个具体实施例，将17mg实施例9与足够精细的乳糖一起配制，总量为580-590mg，填充0号硬质明胶胶囊。
Claims (8)
1.一种如以下通式(1)所示的三肽化合物，或其溶剂合物或水合物，或其药学上可接受的盐：
其中，
AA1选自赖氨酸、鸟氨酸、正亮氨酸、苯基丙氨酸、Nα-甲基苯基丙氨酸、Nα,Nα-二甲基-正亮氨酸、Nα,Nα-二甲基-苯基丙氨酸和Nα,Nα-二甲基-赖氨酸；以及，
AA2选自α-氨基异丁酸、叔丁基甘氨酸、α-氨基异丁酸酰胺、Nα-甲基-苏氨酸-OH、Nα-甲基-苏氨酸-NH2和Nα-甲基-缬氨酸-OH。
2.根据权利要求1所述的三肽化合物，其中，在通式(1)中：
AA1选自赖氨酸，鸟氨酸，正亮氨酸，苯基丙氨酸，Nα-甲基苯基丙氨酸，Nα,Nα-二甲基-正亮氨酸和Nα,Nα-二甲基-苯基丙氨酸；
AA2选自α-氨基异丁酸，叔丁基甘氨酸和α-氨基异丁酸酰胺。
3.根据权利要求1所述的三肽化合物，选自由下列物质，或其溶剂合物或水合物，或其药学上可接受的盐构成的组：
H-(L)-赖氨酸-(D)-脯氨酸-α-氨基异丁酸-OH，H-(L)-赖氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-OH，H-(L)-赖氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，H-(L)-赖氨酸-(L)-脯氨酸-(L)-叔丁基甘氨酸-OH，Nα,Nα-二甲基-(L)-赖氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-OH，H-(L)-赖氨酸-(L)-脯氨酸-α-氨基异丁酸-NH2，H-(L)-鸟氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，H-(L)-正亮氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，H-(L)-苯基丙氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，Nα,Nα-二甲基-(L)-赖氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-NH2，Nα,Nα-二甲基-(L)-赖氨酸-(D)-脯氨酸-Nα-甲基-(L)-缬氨酸-OH，Nα,Nα-二甲基-(L)-正亮氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-OH，Nα-甲基-(D)-苯基丙氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，H-(D)-苯基丙氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，Nα,Nα-二甲基-(L)-苯基丙氨酸-(L)-脯氨酸-α-氨基异丁酸-OH，Nα,Nα-二甲基-(L)-正亮氨酸-(L)-脯氨酸-α-氨基异丁酸-OH或者Nα,Nα-二甲基-(L)-苯基丙氨酸-(D)-脯氨酸-Nα-甲基-(L)-苏氨酸-OH。
4.前述权利要求中任一项所述的三肽化合物在制备药物中的用途。
5.根据权利要求4所述的三肽化合物在制备药物中的用途，所述三肽化合物用于疾病的治疗性和/或预防性治疗，所述疾病选自包含下列疾病的组：急慢性炎性疾病、急慢性疼痛、瘙痒、低钠血症、水肿、肠梗阻、咳嗽和青光眼。
6.根据权利要求5所述的三肽化合物在制备药物中的用途，其中，所述炎性疾病选自包括下列疾病的组：心血管炎症，神经炎症，骨骼炎症，皮肤炎症，肌肉炎症，胃肠道炎症，眼部炎症，耳炎，由昆虫咬伤引起的炎症和由伤口愈合引起的炎症；动脉粥样硬化，缺血，再狭窄和血管炎；哮喘，干燥综合征，肺部炎症，慢性气道炎症和慢性阻塞性肺病(COPD)，过敏，银屑病，银屑病关节炎，湿疹，硬皮病、特应性皮炎和系统性红斑狼疮，关节炎，滑膜炎，骨髓炎，类风湿性关节炎，骨关节炎和强直性关节炎；败血症和败血性休克，糖尿病，葡萄糖不耐症，胰岛素抗药性和肥胖，结肠炎，溃疡性结肠炎，节段性肠炎，炎性肠病和肠易激综合征，以及由于肿瘤增殖、肿瘤转移或者移植排斥反应而引起的炎性疾病和炎性状态。
7.根据权利要求5或6所述的三肽化合物在制备药物中的用途，其中所述炎性疾病选自包括下列疾病的组：胃肠道炎性疾病，尤其是炎性肠病，例如，克罗恩病和/或溃疡性结肠炎，具有胆囊炎症的急性或者慢性炎症病变，炎性假息肉，深层囊性结肠炎，肠壁囊样积气，胰腺炎，阑尾炎，动脉硬化引起的心血管炎症，缺血，再狭窄和/或血管炎，脓毒症，败血症，过敏，哮喘，干燥综合征，肺部炎症，慢性气道炎症，慢性阻塞性肺病(COPD)，肿瘤增殖，肿瘤转移，移植排斥，关节炎性疾病，例如，类风湿性关节炎，外阴阴道炎和/或脑部、皮肤、毛囊、泌尿生殖道的炎性疾病和眼睛的炎性疾病，鼻窦炎，腱鞘炎、黏液囊炎，肌腱炎，肱骨外上髁炎，粘粘性囊炎、骨髓炎，骨关节炎，眼部炎症，耳炎和/或自身免疫性炎症，银屑病，银屑病关节炎，接触性皮炎，特应性湿疹，斑秃，硬皮病和其它纤维化疾病，系统性红斑狼疮，荨麻疹，扁平苔藓，淋巴瘤和/或过敏性疾病或者特征为肥大细胞参与的疾病。
8.一种药剂，所述药剂包括至少一种如权利要求1～3任一项所述的三肽化合物，或其溶剂合物或水合物，或其药学上可接受的盐。
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