CN114929726A - 新肽及其在炎症治疗中的用途 - Google Patents
新肽及其在炎症治疗中的用途 Download PDFInfo
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- CN114929726A CN114929726A CN202080083112.1A CN202080083112A CN114929726A CN 114929726 A CN114929726 A CN 114929726A CN 202080083112 A CN202080083112 A CN 202080083112A CN 114929726 A CN114929726 A CN 114929726A
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Abstract
一种化合物,所述化合物包含氨基酸序列:W‑Lys‑X1‑Ser‑U‑X2‑Y‑G其中W、X1、U、X2和Y和G具有说明书中给出的含义,以及所述肽化合物的区域异构体、立体异构体以及药学上或化妆品可接受的盐。所述化合物特别可用于治疗以炎症为特征的病症,包括伤口;烧伤;和粘膜障碍,诸如肛门直肠疾病、炎性肠病、妇科疾病和牙科疾病。
Description
技术领域
本发明涉及新肽、此类肽在人类医学中的用途、以及包含所述肽的药物组合物。特别地,本发明涉及这些肽和组合物在治疗例如炎症中的用途。
背景技术
炎症典型地表征为对例如微生物、某些抗原、受损害的细胞或物理和/或化学因子的入侵的局部组织反应。炎症反应通常是一种保护机制,所述保护机制用于破坏、稀释或隔离有害剂和受损伤的组织,以及用于引发组织愈合。
炎症可能是由物理创伤、感染、一些慢性疾病(例如,银屑病和自身免疫疾病,诸如类风湿性关节炎)和/或对外部刺激的化学和/或生理反应(例如,作为过敏反应的一部分)导致的。可能涉及一系列复杂事件,其中炎性介质增加局部血管的血流量和扩张,导致发红和发热、体液渗出,通常导致局部肿胀、白细胞迁移到发炎区域中以及疼痛。
许多病症/障碍以异常的、组织损害性的炎症为特征和/或由其引起。此类病症典型地以激活免疫防御机制为特征,导致对宿主的危害大于益处的作用,并且通常与不同程度的组织发红或充血、肿胀、体温过高、疼痛、瘙痒、细胞死亡、组织破坏、细胞增殖和/或功能丧失相关。例子包括炎性肠病、类风湿性关节炎、多发性硬化症、银屑病、肾小球肾炎和移植排斥。
典型地,一系列复杂事件会导致炎性变化,诸如通过局部血管扩张导致的血流量增加,从而导致发红和发热、白细胞和血浆的外渗,通常导致局部肿胀、感觉神经的激活(导致一些组织疼痛)和功能丧失。这些炎性变化是由一连串细胞事件和生化事件触发的,所述事件涉及像嗜中性粒细胞、单核细胞、巨噬细胞和淋巴细胞的细胞,以及诸如血管活性胺、细胞因子、补体因子和活性氧类的炎症介质。
此外,炎症在伤口愈合过程中起关键作用。因此,伤口和烧伤可以归类为与炎症相关的病症。本领域的传统观念是抗炎药不应被直接应用于开放性伤口,因为这将不利于伤口愈合的进展。
纤维化是由发炎或受损害组织中及周围的纤维结缔组织(细胞外基质(ECM)的组分,诸如胶原蛋白和纤连蛋白)的过度积聚所定义的。尽管胶原蛋白沉积通常是伤口愈合的可逆部分,但如果组织损伤很严重,或者伤口愈合反应本身变得失调,胶原蛋白沉积通常会演变为逐渐不可逆的纤维化反应。此外,已知纤维化是许多慢性炎性疾病以及终末期肝病、肾病、特发性肺纤维化(IPF)和心力衰竭的发病和死亡的主要原因。它也是许多慢性自身免疫疾病的病理特征,诸如硬皮病、类风湿性关节炎、克罗恩病、溃疡性结肠炎、骨髓纤维化和系统性红斑狼疮。纤维化也可影响许多进行性肌病、转移和移植物排斥的发病机理。
贻贝粘附蛋白(MAP)(也称为贻贝(Mytilus edulis)足丝蛋白(mefp))是由海洋贝类物种(诸如贻贝(Mytilus edulis)、厚壳贻贝(Mytilus coruscus)和翡翠贻贝(Pernaviridis))分泌的蛋白质。已从贻贝产生十一种已鉴定的独立粘附蛋白亚型,包括胶原蛋白pre-COL-P、pre-COL-D和pre-COL-NG;贻贝足丝基质蛋白PTMP(近端丝基质蛋白)和DTMP(远端丝基质蛋白);和mfp蛋白mfp-2(有时称为“mefp-2”,下文可互换使用)、mfp-3/mefp-3、mfp-4/mefp-4、mfp-5/mefp-5、mfp-6/mefp-6以及最优选的mfp-1/mefp-1(参见,例如Zhu等人,Advances in Marine Science,32,560(2014)和Gao等人,Journal of AnhuiAgr.Sci.,39,19860(2011))。
mefp-1的重要部分由70至90个串联的以下十肽重复组成:Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:1;参见Waite,Int.J.Adhesion and Adhesives,7,9(1987))。此十肽序列可以作为天然存在的MAP的低分子量衍生物被分离,或者可以例如如Yamamoto在J.Chem.Soc.,Perkin Trans.1,613(1987)中所述合成。还参见Dalsin等人,J.Am.Chem.Soc.,125,4253(2003)。
还公开了十肽的类似物,尤其是Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:2)。参见,例如,US 5,616,311和WO 96/39128。
显然需要可以用于治疗炎症和以炎症为特征的病症的新的和/或改进的医药。
发明内容
根据本发明的第一方面,提供了一种(分离的)肽化合物,其具有以下氨基酸序列:
W-Lys-X1-Ser-U-X2-Y-G(SEQ ID No:3)
其中:
W代表1或2氨基酸序列,其中所述氨基酸选自以下的组的一种或多种:Lys、Ala和DOPA,所述序列任选地被3,4-二氢肉桂酸(HCA)残基N-封端;
X1代表Pro、Hyp或diHyp;
U代表Tyr或DOPA;
X2代表Ser、Pro、Hyp或diHyp;
Y代表1至5(例如1至4)氨基酸序列,其中所述氨基酸选自以下的组的一种或多个种:Lys、Ala、Pro、Hyp、diHyp、Thr、DOPA和Tyr;并且
G可能不存在(在这种情况下,Y是C末端氨基酸),或G可以代表DOPA或多巴胺(或更恰当地,“多巴胺片段”),
以及所述肽化合物的区域异构体、立体异构体、以及药学上或化妆品可接受的盐,
所述化合物、区域异构体、立体异构体和盐在下文中统称为“本发明化合物”。
如本文所用,术语“多巴胺”和“多巴胺片段”是指式I的结构片段,
其中,波浪线代表与Y附接的点。
可提及的本发明化合物包括这些化合物,其中:
W代表1或2氨基酸序列,其中所述氨基酸选自以下的组的一种或多种:Lys、Ala和DOPA;
X1代表Pro;
X2代表Ser、Pro或Hyp;并且
Y代表1至5(例如1至4)氨基酸序列,其中所述氨基酸选自以下的组的一种或多种:Lys、Ala、Pro、Hyp、Thr、DOPA和Tyr。
可提及的本发明的特定化合物是其中G不存在(即具有以下氨基酸序列)的那些:
W-Lys-X1-Ser-U-X2-Y(SEQ ID No:4),
其中W代表HCA、HCA-Ala-、HCA-Lys、HCA-Lys-Ala,更优选地DOPA-Lys-或DOPA-Lys-Ala-或尤其DOPA或DOPA-Ala-;并且
X1、U、X2和Y是如上文所定义的,
以及其区域异构体、立体异构体、以及药学上或化妆品可接受的盐。
本发明的优选化合物包括这些化合物,其中:
X1代表Hyp或更优选地Pro;
X2代表Pro或更优选地Hyp;
W代表HCA、HCA-Ala-,优选地Ala或Lys-Ala-或更优选地DOPA或DOPA-Ala-;和/或
Y代表5、优选地3或更优选地4氨基酸序列,其中所述氨基酸选自以下的组的一种或多种:Lys、Ala、Hyp、Thr、DOPA和Tyr。
更优选地,本发明化合物还包括这些化合物,其中Y代表选自以下的组的4氨基酸序列:-Pro-Y1-Y2-Lys-,或更优选地-Hyp-Y1-Y2-Lys-和-Thr-Y1-Y2-Lys-,其中Y1和Y2各自独立地选自以下的组:Pro或更优选地Ala、Hyp、Thr、DOPA和Tyr。
当Y代表4氨基酸序列时,本发明的优选化合物包括其中由Y定义的氨基酸序列选自以下的组的那些:
-Pro-Thr-DOPA-Lys-;
-Pro-Thr-Tyr-Lys-;
-Thr-Tyr-Pro-Lys-;和
-Thr-DOPA-Pro-Lys-;并且更优选地,
-Hyp-Thr-Tyr-Lys-;
-Hyp-Thr-DOPA-Lys-;
-Hyp-Thr-Ala-Lys-;
-Thr-Tyr-Hyp-Lys-;
-Thr-DOPA-Hyp-Lys-;和
-Thr-Ala-Hyp-Lys-。
当Y代表2氨基酸序列时,本发明的优选化合物包括其中由Y定义的氨基酸序列选自以下的组的那些:-Hyp-Thr-、-Thr-Tyr-和-Thr-DOPA-。
可提及的本发明的其他化合物包括这些化合物,其中由Y定义的氨基酸序列选自-Thr-Tyr-Lys-、-Tyr-Pro-Lys-、-DOPA-Pro-Lys-、-Hyp-Thr-Tyr-、-Hyp-Thr-Tyr-Hyp-Lys-,并且更优选地以下的组:-Thr-Tyr-Hyp-Lys-DOPA-和-Hyp-Thr-DOPA-。
可提及的本发明化合物包括这些化合物,其中:
U代表Tyr;并且
W代表DOPA或DOPA-Ala-。
在这方面,可提及的本发明的其他化合物包括具有以下氨基酸序列的那些:
DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:5);
DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:6);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:7);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:8);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:9);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:10);
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:11);
HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:12)。
可提及的本发明化合物包括这些化合物,其中
U代表Tyr;并且
W代表HCA或HCA-Ala-。
在这方面,可提及的本发明的其他化合物包括具有以下氨基酸序列的那些:
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:13);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:14);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:15);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:16);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:17);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:18);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:19);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:20);
HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:21);
HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:22);和
HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:23)。
可提及的本发明化合物包括这些化合物,其中
U代表Tyr;并且
W代表Lys-Ala-。
在这方面,可提及的本发明的其他化合物包括具有以下氨基酸序列的那些:
Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID No:24);
Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr(SEQ ID No:25);
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID No:26);
Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-Tyr(SEQ ID No:27)。
可以从上文列表中提及的本发明的具体化合物包括具有以下氨基酸序列的那些:
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID No:26),并且更优选地,
DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:5);
DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:6);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:7);和
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:8)。
可提及的本发明化合物包括这些化合物,其中:
U代表DOPA;并且
W代表DOPA或DOPA-Ala-。
在这方面,可提及的本发明的其他化合物包括具有以下氨基酸序列的那些:
DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:28);
DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:29);
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:30);
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:31);和
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:32)。
可提及的本发明化合物包括这些化合物,其中
W代表Ala。
在这方面,可提及的本发明的其他化合物包括具有以下氨基酸序列的那些:
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:33);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:34);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:35);和
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:36)。
根据本发明的进一步的方面,提供了一种(分离的)肽化合物,其具有以下氨基酸序列:
W-Lys-Pro-Ser-U-X2-Y-G(SEQ ID No:37),
其中:
G代表DOPA,或更优选地“多巴胺片段”;并且
W、U、X2和Y是如上文所定义的,
以及其区域异构体、立体异构体、以及药学上或化妆品可接受的盐。
可提及的本发明化合物包括这些化合物,其中:
W代表Ala或Lys-Ala-;和/或
G代表DOPA或多巴胺。
在这方面,可提及的本发明的其他化合物包括具有以下氨基酸序列的那些:
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA(SEQ ID No:38);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-多巴胺(SEQ ID No:39);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-多巴胺(SEQ ID No:40);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA(SEQ ID No:41);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID No:42);
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-DOPA(SEQ ID No:43);
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID No:44);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-多巴胺(SEQ ID No:45);
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-多巴胺(SEQ ID No:46);
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-多巴胺(SEQ ID No:47);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID No:48);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-DOPA(SEQ ID No:49);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID No:50);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-多巴胺(SEQ ID No:51);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-多巴胺(SEQ ID No:52);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-多巴胺(SEQ ID No:53);
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID No:54);
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-多巴胺(SEQ ID No:55);
Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID No:56);
Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA(SEQ ID No:57);
Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-多巴胺(SEQ ID No:58);和
Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA(SEQ ID No:59)。
可以从上文列表中提及的本发明的具体化合物包括具有以下氨基酸序列的那些:
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA(SEQ ID No:38);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-多巴胺(SEQ ID No:39);
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID No:54);和
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-多巴胺(SEQ ID No:55)。
此外,可提及的本发明化合物包括其中X2代表Hyp或特别是Pro的那些。
对于本发明的此类化合物,Y可以代表4氨基酸序列,其选自以下的组:-Pro-Y1-Y2-Lys-、-Hyp-Y1-Y2-Lys-和-Thr-Y1-Y2-Lys-,其中Y1和Y2各自独立地选自以下的组:Pro、Ala、Hyp、Thr、DOPA和Tyr。
当Y代表式-Hyp-Y1-Y2-Lys-或-Thr-Y1-Y2-Lys-的4氨基酸序列时,Y1和Y2是如上文所定义的或Y1和/或Y2可以代表Pro,使得由Y定义的氨基酸序列选自以下的组:-Thr-Tyr-Pro-Lys-和-Thr-DOPA-Pro-Lys-。
当Y代表式-Pro-Y1-Y2-Lys-的4氨基酸序列时,本发明的优选化合物包括其中由Y定义的氨基酸序列选自以下的组-的那些:-Pro-Thr-DOPA-Lys-和-Pro-Thr-Tyr-Lys。
在所有此类化合物中:
W优选地代表Ala;
X1优选地代表Pro;和/或
G优选地不存在。
在这方面,可提及的本发明的其他化合物包括具有以下氨基酸序列的那些:
Ala-Lys-Pro-Ser-Tyr-Pro-Pro-Thr-DOPA-Lys(SEQ ID No:60);
Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-Tyr-Lys(SEQ ID No:61);
Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-DOPA-Lys(SEQ ID No:62);
Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys(SEQ ID No:63);
Ala-Lys-Pro-Ser-Tyr-Pro-Thr-DOPA-Pro-Lys(SEQ ID No:64);
Ala-Lys-Pro-Ser-DOPA-Pro-Thr-Tyr-Pro-Lys(SEQ ID No:65);
Ala-Lys-Pro-Ser-DOPA-Pro-Thr-DOPA-Pro-Lys(SEQ ID No:66);
Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys(SEQ ID No:67);
Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-DOPA-Lys(SEQ ID No:68);
Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-Tyr-Lys(SEQ ID No:69);
Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-DOPA-Lys(SEQ ID No:70);
Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys(SEQ ID No:71);
Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-DOPA-Lys(SEQ ID No:72);
Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-Tyr-Lys(SEQ ID No:73);和
Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-DOPA-Lys(SEQ ID No:74)。
如本文所用,Pro代表脯氨酸,Ala代表丙氨酸,Ser代表丝氨酸,Tyr代表酪氨酸,Hyp代表羟基脯氨酸(包括3-羟基脯氨酸(3Hyp)和4-羟基脯氨酸(4Hyp)),diHyp代表二羟基脯氨酸(包括3,4-二羟基脯氨酸(3,4diHyp)、3,5-二羟基脯氨酸(3,5diHyp)和4,5-二羟基脯氨酸(4,5diHyp)),Thr代表苏氨酸,Lys代表赖氨酸,Ala代表丙氨酸,并且DOPA代表3,4-二羟基苯丙氨酸。3,4-二氢肉桂酸(HCA)残基基本上是DOPA残基,但是相对于与N-末端氨基酸(Lys或Ala)附接的羧酸,在2-或α-碳位置上没有-NH2基团。
本发明化合物,无论是呈盐的形式还是其他形式,包括在肽的氨基酸(例如,diHyp、Hyp和Tyr部分)内的区域异构体,以及此类区域异构体的混合物。例如,Tyr的定义内不仅包括酪氨酸(4-羟基苯丙氨酸),而且还包括2-和3-羟基苯丙氨酸。Hyp的定义内包括4-羟基脯氨酸(4Hyp)、3-羟基脯氨酸(3Hyp)和5-羟基脯氨酸(5Hyp)。更优选的是,Hyp残基为4-羟基脯氨酸。类似地,diHyp的定义内包括3,4-二羟基脯氨酸(3,4diHyp)、3,5-二羟基脯氨酸(3,5diHyp)和4,5-二羟基脯氨酸(4,5diHyp)。更优选的是,diHyp残基为3,4-二羟基脯氨酸(3,4diHyp)。
另外,除了本发明化合物中的氨基酸的标准中心碳原子(通常但非排他性地呈L-构型)之外,序列中的某些氨基酸还包含另外的手性碳原子。所有此类立体异构体及其混合物(包括外消旋混合物)包括在本发明的范围内。就此而言,Hyp的定义内包括反式-4-羟基-L-脯氨酸、顺式-4-羟基-L-脯氨酸、反式-3-羟基-L-脯氨酸、顺式-3-羟基-L-脯氨酸、反式-5-羟基-L-脯氨酸和顺式-5-羟基-L-脯氨酸,但是我们优选的是,用于本发明化合物的Hyp是4-羟基-L-脯氨酸。类似地,可以将相应的定义应用于diHyp,其中两个羟基也可以相对于彼此为顺式或反式。无论如何,本发明化合物的单独对映异构体都包括在本发明的范围内。
本发明化合物可以呈盐的形式。可提及的盐包括药学上可接受的和/或化妆品可接受的盐,诸如药学上和/或化妆品上可接受的酸加成盐和碱加成盐。此类盐可以通过常规手段形成,例如通过以下方式形成:使本发明化合物与一或多当量的适当的酸或碱任选地在溶剂中或在盐不溶的介质中反应,接着使用标准技术(例如,在真空中,通过冷冻干燥或通过过滤)除去所述溶剂或所述介质。盐也可以通过以下方式制备:将呈盐形式的本发明化合物的反离子与另一种反离子交换,例如使用合适的离子交换树脂。
优选的盐包括例如乙酸盐、盐酸盐、硫酸氢盐、马来酸盐、甲磺酸盐、甲苯磺酸盐、碱土金属盐(诸如钙和镁盐)或碱金属盐(诸如钠和钾盐)。最优选地,本发明化合物可以呈乙酸盐的形式。
本发明化合物可以通过常规技术,例如通过标准氨基酸偶联技术,使用标准偶联剂和溶剂来制备,例如如下文所述。本发明化合物可以使用适当的试剂和反应条件由可用的起始材料来合成。在这方面,技术人员尤其可以参考“Comprehensive OrganicSynthesis”,B.M.Trost和I.Fleming,Pergamon Press,1991。可使用的其他参考文献包括“Heterocyclic Chemistry”,J.A.Joule,K.Mills和G.F.Smith,第3版,由Chapman&Hall出版;“Compre hensive Heterocyclic Chemistry II”,A.R.Katritzky,C.W.Rees和E.F.V.Scriven,Pergamon Press,1996以及“Science of Synthesis”,第9-17卷(Hetarenes and Related Ring Systems),Georg Thieme Verlag,2006。
本发明化合物可以从其反应混合物中分离出,并且如果需要,可以使用如本领域技术人员已知的常规技术进行纯化。因此,如本文所述的用于制备本发明化合物的方法可以包括分离并且任选地纯化本发明化合物(作为最终步骤)。
本领域技术人员应意识到,在上文和下文所述方法中,可能需要通过保护基团来保护中间体化合物的官能团。官能团的保护和脱保护可以在反应之前或之后进行。
可以根据本领域技术人员熟知的和如下文所述的技术来应用和除去保护基团。例如,可以使用标准脱保护技术将本文所述的受保护的化合物/中间体化学地转化为未受保护的化合物。所涉及的化学类型将决定保护基团的需要和类型以及完成合成的顺序。保护基团的使用完整地描述于“Protective Groups in Organic Synthesis”,第5版,T.W.Greene&P.G.M.Wutz,Wiley-In terscience(2014),将其内容通过引用并入本文。
本发明化合物可用作人类和动物医药。因此,尽管它们也可以用作化妆品和/或用作医疗装置的一部分,但是它们被指示作为药物(和/或在兽医科学中)。
本发明化合物本身可以具有药理活性,但是可以存在或可以制备本发明化合物的某些药学上可接受的(例如,“受保护的”)衍生物,所述衍生物可不具有此类活性,但是所述衍生物可以被施用并且之后被代谢或化学地转化以形成本发明化合物。此类化合物(其可具有某种药理活性,条件是这种活性明显低于其代谢/转化所得的活性化合物的活性)因此可以被描述为本发明化合物的“前药”。
如本文所用,对前药的提及将包括在施用后预定时间内以实验上可检测的量形成本发明化合物的化合物。本发明化合物的所有前药都包括在本发明的范围内。
本发明化合物特别可用于治疗炎症。
术语“炎症的治疗”包括对身体的任何器官(包括软组织、关节、神经、血管系统、内脏器官,尤其是粘膜表面,特别是皮肤)中的炎症(无论何种原因)的治疗,并且还包括所有此类炎性障碍或病症、和/或以炎症(例如,作为症状)为特征的障碍或病症。
炎性障碍和/或病症可以(并且典型地)以免疫防御机制的激活为特征,所述激活产生对宿主的危害大于益处的作用。此类病症通常与不同程度的组织发红或充血、肿胀、水肿、体温过高、疼痛(包括隐痛(aching))、体液渗出、瘙痒(瘙痒症)、细胞死亡和组织破坏、细胞增殖和/或功能丧失。
可提及的炎性病症包括动脉炎、糖尿病、代谢综合征、玫瑰痤疮、哮喘和过敏、强直性脊柱炎、慢性阻塞性肺病、痛风性关节炎、炎性肠病(诸如克罗恩病和溃疡性结肠炎)、多发性硬化症、骨关节炎、胰腺炎、前列腺炎、银屑病性关节炎、类风湿性关节炎、肌腱炎、粘液囊炎、干燥综合征、系统性红斑狼疮、葡萄膜炎、荨麻疹、血管炎、肥大细胞增多症、糖尿病性血管并发症、偏头痛、动脉粥样硬化和相关的心血管障碍。可提及的以炎症为特征的疾病状态是慢性阻塞性肺病(COPD)。可提及的另外的以炎症为特征的疾病状态是炎性肠病,包括克罗恩病以及尤其是溃疡性结肠炎。可提及的以炎症为特征的其他疾病状态是妇科疾病,诸如子宫颈炎、阴道炎(vaginitis)(例如辐射阴道炎)和鞘炎(colpitis)。影响胃肠道的疾病,诸如胃溃疡病(例如胃炎、胃溃疡、胃癌和其他胃粘膜疾病)以及胃食管反流病(GERD)、便秘、和胃炎;与癌症和感染(例如病毒感染,诸如普通感冒或流感)相关的炎症。
可更尤其提及的炎性病症包括皮肤或粘膜(包括口腔、鼻、眼、阴道、子宫颈和/或肛门直肠粘膜、更特别是口腔或鼻粘膜)的炎症,诸如由感染(诸如病毒和/或细菌感染)引起的炎症,或过敏性/特应性病症(诸如鼻炎(例如,过敏性鼻炎)、咽炎、牙周炎、牙龈炎、干眼症、结膜炎(例如,过敏性结膜炎)、皮炎、荨麻疹(风团)和食物过敏);和其他炎性病症,诸如疱疹、药疹、多形性日光疹、晒伤、皮肤癌的早期表现(红斑样皮肤病变)、病理性脱发(包括皮肤移植后)、化学性皮疹、银屑病、多形性红斑、毛囊炎、湿疹和外耳炎。可提及的疾病状态是多形性日光疹。
更特别地,化合物可用于治疗以炎症为特征和/或与炎症相关的某些病症。此类病症可以包括伤口(包括擦伤(划痕)、切口(包括手术切口)、撕裂、穿刺、撕脱、瘀伤和结疤)和烧伤(包括在烧伤后由外科手术(诸如皮肤移植)引起的炎症)和其他病症(诸如痔疮)。伤口可以是急性的或慢性的,和/或可以由如本文所定义的一种或多种炎性障碍引起。
皮肤或粘膜的伤口可由对膜表面的内部或外部物理损伤引起,或者可由潜在的生理障碍引起(即,是其症状)。
物理(例如,“开放性”)伤口可由以下引起:锋利的物体(割口、切口、穿刺)或钝的物体/机械力(撕裂、擦伤、撕脱)、物理打击(瘀伤)、热或化学物(烧伤和水疱)、紫外光(晒伤)、寒冷(冻疮或冻伤)。伤口可以是浅表的(仅对表皮和/或真皮的损害),或者可以是全层伤口(在表皮和/或真皮下方的损害)。在严重的情况下,可能损害皮下和/或粘膜下组织,诸如肌肉、骨、关节、甚至内脏器官。
本发明化合物可用于缓解与炎症和/或伤口相关的疼痛(包括隐痛)。特别地,本发明化合物可用于缓解操作性疼痛和/或非操作性疼痛。技术人员应理解,术语“操作性疼痛”(即,手术疼痛)是指与出于医疗保健目的而进行的医学研究和治疗相关的急性疼痛。术语“非操作性”是指与炎症和/或受伤相关的一般性疼痛(例如,与牙溃疡、烧伤和/或疤痕相关的疼痛),并且不是特定医学干预的结果。
本发明化合物不仅可用于治疗与伤口本身和愈合过程相关的炎症、疼痛(包括隐痛)和/或瘙痒症(瘙痒),而且还可预防体液从伤口渗出、感染风险以及预防由炎症和/或伤口愈合过程引起的生理反应(诸如结疤和黑色素沉着)。
结疤是炎症和/或伤口愈合的结果,并且是作为这种炎症/愈合的结果的纤维组织形成的通用术语。
本发明化合物还可用于抑制黑色素沉着的产生,所述黑色素沉着的产生可能是或可能不是由炎症和/或伤口愈合引起的。本发明化合物还可用于抑制与黑色素沉着相关的障碍,诸如黄褐斑、雀斑、黑变病、面颊皮疹和其他色素沉着症,伴有黑素瘤的皮肤癌,以及由暴露于阳光引起的色素沉着症或皮肤疾病(像痤疮)。
伤口也可作为(例如,炎性)疾病或障碍的结果而发生。此类伤口可以包括皮肤和粘膜的水疱和/或溃疡。它们是通常长期持续且难以治疗的常见病症。皮肤组织可能经常被损害,去除,液化,感染和/或坏死。溃疡可能对健康导致继发性结果(特别是如果它们受感染的话),难以治愈并且治疗昂贵。它们还可能给患者造成显著的心理压力和经济损失,从而影响总体幸福感和生活品质。
在替代方案中,其中发现本发明化合物特别有用的炎性皮肤病症或疾病包括银屑病、痤疮、湿疹和皮炎,尤其是过敏性皮炎/特应性皮炎,以及在如以例如鼻炎(尤其是过敏性鼻炎)、痔疮、慢性阻塞性肺病和溃疡性结肠炎为特征的粘膜炎症的治疗中。
银屑病是一种慢性炎性皮肤疾病,具有复发的趋势(一些患者在其整个一生中都无法治愈)。银屑病的临床表现主要包括红斑和鳞屑。它可以在全身发生,但更常见地在头皮和四肢上被观察到。
痤疮是一种滤泡性(毛囊皮脂腺单位)慢性炎性皮肤疾病,其发生与像皮脂分泌过多、毛囊皮脂腺导管阻塞(包括封闭性粉刺和开放性粉刺)、细菌感染和炎性反应的主要因素密切相关,其倾向于在青年时期发生,以在面部的多形性皮肤病变为特征。因此,术语痤疮包括普通痤疮和玫瑰痤疮(即,酒渣鼻)。
湿疹是由多种内部和外部因素引起的具有强烈瘙痒的皮肤炎性反应。它具有三个阶段:急性、亚急性和慢性。在急性阶段,有渗出物产生的趋势,而慢性阶段包括浸润和肥大。皮肤病变通常瘙痒并且容易复发。
皮炎是一种常见的皮肤疾病,以粗糙、发红、瘙痒、湿疹和干燥为特征。如果不迅速治疗,由皮炎引起的小块、顽固性溃疡和色素斑可能发展为基底细胞癌、鳞状细胞癌和恶性黑色素瘤。皮炎可能是由各种内部和外部感染或非感染因素引起的,所述因素包括物质(接触性皮炎)或过敏(过敏性/特应性皮炎)。还包括脂溢性皮炎(脂溢性湿疹)和所有形式的类固醇依赖性皮炎(包括光敏感性皮脂溢疹、口周皮炎、玫瑰痤疮样皮炎、类固醇-玫瑰痤疮、类固醇诱导的玫瑰痤疮、医源性玫瑰痤疮(iatrosacea)、类似玫瑰痤疮的类固醇性皮炎、外用皮质类固醇诱导的玫瑰痤疮样皮炎、更特别是面部皮质类固醇成瘾性皮炎(FCAD)或面部皮质类固醇依赖性皮炎(FCDD),如以在长期用(包括不受控制的使用、滥用或误用)外用皮质类固醇治疗后在面部区域的潮红、红斑、毛细血管扩张、萎缩、丘疹和/或脓疱为特征;参见例如,Xiao等人,J.Dermatol.,2015,42,697-702和Lu等人,Clin.Exp.Dermatol.,2009,35,618-621。
鼻炎是在鼻内部的粘膜的刺激和炎症。鼻炎的常见症状包括鼻塞、流鼻涕、打喷嚏和后鼻滴涕。最常见的一种鼻炎是由过敏原引起的过敏性鼻炎,所述过敏原是诸如花粉、灰尘、霉菌或某些动物的皮肤屑。已出人意料地发现,即使当本发明化合物经鼻(即,向鼻粘膜)施用时,用本发明化合物治疗的患有过敏性鼻炎的患者也会经历眼部瘙痒的缓解。
痔疮是由在直肠和肛门内部或周围存在的痔疮血管的炎症引起的肿胀。症状包括大便通过后出血(即,受伤),痔疮脱垂,粘液排出以及在肛门区域中的瘙痒、痛、发红和肿胀。痔疮被认为是腹部压力升高的结果,例如作为便秘或腹泻的结果。
慢性阻塞性肺病(COPD)是一组导致呼吸困难的肺病症的名称,所述肺病症包括肺气肿(对肺泡的损害)和慢性支气管炎(长期的气道炎症)。当肺发炎、受损害和变窄时,发生COPD。对肺的损害通常是不可逆的并且导致进出肺的空气流动的伤害。COPD的症状包括呼吸急促、排痰性咳嗽、频繁的胸部感染和持续喘息。所述疾病的最常见原因是吸烟,但其他风险因素包括高水平的空气污染和职业性暴露于粉尘、化学物和烟雾。
本发明化合物可在减轻由包括本文一般和具体提及的那些在内的各种病症引起的红斑、发红和肿胀、水肿、水疱和大疱性类天疱疮方面具有积极作用,并且可抑制皮下组织液的渗出,并且抑制由此类炎性病症引起的瘙痒和疼痛。
可提及的其他炎性病症包括:
(a)粘膜炎症,诸如口腔粘膜炎、口疮性溃疡、中耳炎、喉炎、气管炎、食管炎、胃炎、肠炎和小肠结肠炎(包括细菌性痢疾、慢性阿米巴痢疾、血吸虫病、非特异性溃疡性结肠炎和局限性肠炎)、子宫颈炎和子宫颈内膜炎、子宫内膜炎、由吸入损伤等引起的炎症以及与影响粘膜表面(诸如在口腔、鼻咽、耳、喉咙、气管、胃肠道、子宫颈等中的那些)的癌症和感染(例如,病毒感染,诸如普通感冒或流感)相关的粘膜炎症。
(b)与例如骨折、骨和关节的化脓性感染相关的骨科炎症、由风湿性骨病引起的炎症以及化脓性骨髓炎(急性、慢性、局部、硬化、创伤后)、化脓性关节炎;骨肿瘤(骨瘤、骨样骨瘤、软骨瘤)、骨囊肿、破骨细胞瘤、原发性骨肉瘤(bone sarcoma)(骨肉瘤(osteosarcoma)、软骨肉瘤、骨纤维肉瘤、尤因肉瘤、非霍奇金淋巴瘤、骨髓瘤、脊索瘤)、转移性骨肿瘤、骨肿瘤样病变(骨囊肿、动脉瘤样骨囊肿、嗜酸性肉芽肿、纤维异常增生);和风湿性关节炎。
(c)神经炎症,诸如周围性多发性神经炎、面部神经炎、周围性神经炎、皮下神经炎、尺神经炎、肋间神经炎等。
(d)皮下和粘膜下软组织炎症,诸如肌炎、韧带炎、肌腱炎、脂膜炎、囊炎、淋巴结炎、腹股沟淋巴腺炎、扁桃体炎、滑膜炎、筋膜炎以及由肌肉、韧带、筋膜、肌腱、滑膜、脂肪、关节囊和淋巴组织的损伤、挫伤或撕裂引起的软组织炎症。
(e)血管炎症,诸如过敏性白细胞破碎性血管炎、过敏性皮肤血管炎、结节性多动脉炎、血栓性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液组成异常的血管炎、和风湿性血管炎、以及与由过敏性白细胞破碎性血管炎、结节性多动脉炎、血栓性血管炎、肉芽肿性血管炎、淋巴细胞性血管炎、血液组成异常的血管炎、和风湿性血管炎引起的血管癌相关的血管炎症。
(f)内脏器官(诸如心脏、胃、肠、肺、肝、脾、肾、胰腺、膀胱、卵巢和前列腺)的炎症,包括但不限于心包炎、心肌炎、心内膜炎、肺炎、肝炎、脾炎、肾炎、胰腺炎、膀胱炎、卵巢炎、前列腺炎和胃部溃疡的治疗。
(g)眼和周围区域的炎症,诸如结膜炎、角膜炎(例如,急性上皮角膜炎、钱币状角膜炎、间质性角膜炎、盘状角膜炎、神经营养性角膜炎、粘斑性角膜炎、单纯疱疹角膜炎、带状疱疹角膜炎、细菌性角膜炎、真菌性角膜炎、棘阿米巴性角膜炎、盘尾丝虫性角膜炎(onchocercal keratitis)、浅层点状角膜炎、溃疡性角膜炎、暴露性角膜炎、光性角膜炎和隐形眼镜急性红眼)、视神经炎等。
(h)牙龈和口腔的炎症,诸如牙周炎、牙龈炎、牙溃疡等。
(i)与风湿病相关的炎症、诸如风湿性血管炎、类风湿性关节炎、风湿性骨病、强直性脊柱炎、滑囊炎、克罗恩病、痛风、传染性关节炎、幼年特发性关节炎、骨关节炎、骨质疏松症、风湿性多肌痛、多肌炎、银屑病性关节炎、硬皮病、干燥综合征、脊柱关节病、系统性红斑狼疮、肌腱炎等。
本发明化合物还可以用于治疗消化系统的某些特定疾病,诸如胃食管反流病(GERD),其特征可以在于嘴里有酸味、反胃、胃灼热、吞咽疼痛和/或咽喉痛、流涎增加(心灼热)、恶心、胸痛和咳嗽。GERD可能引起食管损伤,包括反流性食管炎(即,食管上皮炎症,其可能在胃和食管的交界处或周围引起溃疡)、食管狭窄(即,由反流诱导的炎症引起的食管持续狭窄)、巴雷特食管(即,肠化生(即,远端食管的上皮细胞从鳞状到肠柱状上皮的变化))和/或食管腺癌(一种癌症形式))。
本发明化合物还可以用于治疗呼吸系统的某些特定疾病,诸如肺囊性纤维化、普通型间质性肺炎、过敏性肺炎、石棉肺、肺气肿、肺源性心脏病、肺栓塞等。可提及的特定疾病状态是特发性肺纤维化(IPF)。
IPF是一种弥漫性且致命性的肺间质疾病,其病理特征包括肺泡上皮损害、肺成纤维细胞的大量增殖、细胞外基质的过度沉积,最终导致不可逆的肺组织损害。在所述疾病的后期,患有IPF的受试者经历呼吸衰竭和死亡。已发现,本发明化合物可用于治疗IPF和/或减轻与所述疾病相关的症状。
本发明化合物还特别可用于治疗以下肺部和/或纤维化病症(无论是否在本文中另外提及):肺纤维化、肾纤维化、肝纤维化、矽肺、急性支气管炎、慢性支气管炎、气管支气管炎、支气管性哮喘、哮喘持续状态、支气管扩张、上呼吸道感染(包括普通感冒和流感)、过敏性气道炎症、细菌性肺炎、病毒性肺炎、支原体肺炎、立克次体肺炎(reckettsia)、放射性肺炎、肺炎球菌(包括葡萄球菌、链球菌和革兰氏阴性杆菌)肺炎、肺念珠菌病(包括曲霉菌病、毛霉菌病、组织胞浆菌病、放线菌病和诺卡氏菌病)、肺真菌病、隐球菌病、肺脓肿、过敏性肺炎、外源性过敏性肺泡炎、肺嗜酸性粒细胞增多症(包括吕弗琉综合征(Leoffer’ssyndrome)和嗜酸性细胞增多症)、阻塞性肺气肿、肺水肿、肺结核、呼吸性碱中毒/酸中毒、急性肺损伤、间质性肺病、脓胸、肺纤维瘤和肺心病。
本发明化合物有用的特定粘膜障碍和疾病包括例如肛门直肠疾病,诸如腹泻、痔疮、脓肿、瘘、裂、肛门瘙痒、肛窦炎、疣和直肠脱垂;炎性肠病,包括克罗恩病、特别是溃疡性结肠炎;妇科疾病,诸如子宫颈炎、阴道炎、骨盆疼痛和障碍;以及牙科疾病,诸如牙周炎。
通过增加SOD(超氧化物歧化酶)的产生并且降低脂质氧化,本发明化合物可以进一步具有抗氧化作用。因此可以认为本发明化合物具有抗氧化特性。
本发明化合物还可以具有退热特性,所述退热特性允许治疗发烧和/或减轻其症状;例如,通过降低受试者的体温,这导致发烧降低。因此,本发明化合物和包含它们的配制品可以被认为是退热药。
根据本发明的另外方面,提供了一种治疗炎症、炎性障碍、和/或以炎症(例如,作为症状)为特征的障碍/病症的方法,所述方法包括向需要这种治疗的患者施用本发明化合物或其盐。
为避免疑义,在本发明的上下文中,术语“治疗”、“疗法”和“治疗方法”包括对有需要的患者进行的治疗性或姑息性治疗以及对易患炎症和/或炎性障碍的患者进行的预防性治疗和/或诊断。
本发明化合物可以进一步具有抗病毒特性,如与任何病毒感染或疾病的任何症状(诸如疼痛和/或炎症)的治疗相反,所述抗病毒特性允许在本质上治疗病毒感染,即,通过干扰病毒在宿主内的复制来治疗病毒感染或病毒性疾病。此类抗病毒特性还可允许预防此类感染或疾病的发作、保护宿主细胞免受(例如,进一步)病毒感染、预防或停止病毒感染或疾病的传播(在单个宿主内,或从一个宿主到新宿主)、或预防病毒在宿主中潜伏后的重新激活。
根据本发明的另外方面,提供了一种治疗病毒感染的方法,所述方法包括向需要这种治疗的患者施用本发明化合物或其盐。
可提及的病毒感染包括由以下科的病毒引起的那些:腺病毒科(例如,腺病毒)、乳头瘤病毒科(例如,人乳头瘤病毒)、多瘤病毒科(例如,BK病毒;JC病毒)、疱疹病毒科(例如,1型单纯疱疹;2型单纯疱疹;水痘带状疱疹病毒;EB病毒(Epstein-Barr virus);人巨细胞病毒;人疱疹病毒,8型)、痘病毒科(例如,天花)、嗜肝病毒科(例如,乙型肝炎病毒)、细小病毒科(例如,细小病毒B19)、星状病毒科(例如,人星状病毒)、杯状病毒科(例如,诺如病毒;诺沃克病毒)、小RNA病毒科(例如,柯萨奇病毒、甲型肝炎病毒;脊髓灰质炎病毒;鼻病毒)、冠状病毒科(例如,严重急性呼吸综合征病毒)、黄病毒科(例如,丙型肝炎病毒;黄热病毒;登革热病毒;西尼罗河病毒;蜱传脑炎病毒)、逆转录病毒科(例如,人免疫缺陷型病毒;HIV)、披膜病毒科(例如,风疹病毒)、沙粒病毒科(例如,拉沙病毒)、布尼亚病毒科(例如,汉坦病毒(hantavirus);克里米亚-刚果出血热病毒;汉坦病毒(Hantaan virus))、丝状病毒科(例如,埃博拉病毒;马尔堡病毒;拉文病毒(Ravn virus))、正粘病毒科(例如,流感病毒,包括甲型流感病毒(例如,H1N1和H3N2病毒)、乙型流感病毒或丙型流感病毒)、副粘病毒科(例如,麻疹病毒;腮腺炎病毒;副流感病毒、呼吸道合胞病毒)、弹状病毒科(例如,狂犬病病毒)、肝炎病毒科(例如,戊型肝炎病毒)、呼肠孤病毒科(例如,轮状病毒;环状病毒;科蜱病毒(coltivirus);版纳病毒)以及未分配到科的病毒(诸如丁型肝炎病毒)。
可更特别提及的病毒包括1型单纯疱疹和2型单纯疱疹病毒、人乳头瘤病毒、流感病毒和副流感病毒。
本发明化合物可以进一步具有抗细菌和/或细菌抑制特性,如与任何细菌感染或疾病的任何症状(诸如疼痛和/或炎症)的治疗相反,所述特性可允许在本质上治疗细菌感染,即,通过干扰细菌在宿主中的生长或增殖来治疗细菌感染或细菌性疾病。因此,本发明化合物可以被认为是杀细菌剂和/或优选细菌抑制剂。
此类抗细菌特性还可允许预防这种感染或疾病的发作、保护宿主细胞免受(例如,进一步)细菌感染、预防或停止细菌感染或疾病的传播(在单个宿主内、或从一个宿主到新宿主)、或预防细菌在宿主中潜伏后的重新激活。
根据本发明的另外方面,提供了一种治疗细菌感染的方法,所述方法包括向需要这种治疗的患者施用本发明化合物或其盐。
如本文所公开的,本发明化合物可以进一步具有抗癌特性,如与癌症的任何症状(诸如疼痛和/或炎症)的治疗相反,所述抗癌特性可允许在本质上治疗癌症,即,通过干扰癌症来治疗癌症。此类抗癌特性还可以包括预防这种疾病的发作,例如通过治疗炎症并且从而预防这种发作。
根据本发明的另一方面,提供了一种治疗癌症的方法,所述方法包括向需要这种治疗的患者施用本发明化合物或其盐。
可提及的特定癌症包括由口腔粘膜炎、鼻炎、中耳炎、结膜炎、咽炎、喉炎、气管炎、食管炎、胃炎、小肠结肠炎、子宫颈炎、子宫内膜炎、红斑样皮肤病变等引起的口腔癌、鼻咽癌、中耳癌、结膜癌、喉癌、气管癌、食管癌、胃癌、肠癌、子宫颈癌、子宫内膜癌、皮肤癌等。可提及的特定皮肤癌是基底细胞癌。
“患者”包括爬虫类患者、鸟类患者以及优选哺乳动物(特别是人类)患者。
根据本发明,将本发明化合物优选地局部或全身施用,例如口服、静脉内或动脉内(包括通过血管内和其他血管周围装置/剂型(例如,支架))、肌内、皮肤、皮下、经粘膜(例如,舌下或经颊)、直肠、阴道内、皮内、透皮、经鼻、经肺(例如,气管或支气管),优选地外用,或通过任何其他肠胃外途径,以包含一种或多种化合物的药物制剂的形式,以一种或多种药学上可接受的剂型。
当待治疗的病症是鼻炎或由气道的病毒感染(例如上呼吸道感染,诸如普通感冒和流感)引起的炎症时,通过吸入(例如,经鼻)施用是特别有用的。
当待治疗的病症是COPD或IPF时,经肺施用是特别有用的。外用施用形式可以通过产生包含本发明化合物的喷雾剂来增强,例如通过使用粉末气雾剂或借助水雾使用适当的雾化技术或设备(诸如喷雾器)来增强。
当待治疗的病症是痔疮或溃疡性结肠炎时,肛门直肠施用是特别有用的,其使用适当的递送手段,诸如待注射的泡沫溶液或栓剂。
还可以借助本领域技术人员已知的标准延迟或延长释放包衣技术,通过肠胃外、特别是通过经口递送来实现至下胃肠道的施用。特别地,可以靶向上肠或下肠的不同部分。例如,也可以通过最初经口或肠胃外施用的靶向结肠的药物递送装置来实现结肠施用。
在替代方案中,可以将本发明化合物通过直接全身肠胃外施用来施用。这样的施用在治疗患者的一种或多种内脏器官的炎性和/或纤维化障碍或病症的方法中可以是有用的。
可提及的内脏器官包括胃、肠、胰腺、肝、脾、膀胱、血管系统、卵巢、前列腺,优选心脏和肾,并且更优选肺。
可提及的内脏器官的纤维化病症包括急性和/或严重内部纤维化病症,其特征在于发炎或受损害组织中及周围的纤维结缔组织(如上所述)的过度积聚。因此,本发明的配制品可用于治疗或预防纤维发生(如上所述)以及可与之相关的发病和死亡。因此,可以用本发明的配制品治疗的内脏器官的(例如急性和/或严重)纤维化病症包括肝、肾、肺、心血管系统(包括心脏和血管系统)、胰腺、脾、中枢神经系统(神经纤维化)、骨髓纤维化、眼睛、阴道、子宫颈等的纤维化。
内脏器官的炎性病症包括任何严重病症(即需要强化医学治疗的病症)或任何可发展为严重病症的病症,并且其中某种炎症组分明显(因为可以可检测到的炎症为特征),并且另外其中发病是明显的(或预期的)和/或威胁生命的。
可提及的炎性病症包括内脏器官的一种或多种急性障碍或病症(即需要立即进行医疗干预的一种或多种病症或可发展为需要立即进行医疗干预的病症的一种或多种病症),其特征在于一种或多种内脏器官(包括上文提及的器官中的任一种)中的炎症(例如,作为症状),诸如急性内部损害。通过治疗此类急性炎性障碍,本发明的配制品可以预防或阻止与此类病症相关的症状(急性或慢性)的发展,并且还可以阻止与此类病症相关的发病和/或死亡的进展。
因此可提及的急性炎性病症包括诸如腹膜炎、胰腺炎、结肠炎、直肠炎、胃炎、十二指肠炎、咽炎、GERD、牙周炎和口腔炎等病症。可提及的特定急性炎性病症包括对一种或多种内脏器官(包括上文提及的那些中的任一种)的急性损伤,例如急性肺损伤、吸入损伤(诸如烧伤)、急性呼吸窘迫综合征(ARDS)、严重急性呼吸综合征(SARS)、和多器官炎症、损伤和/或衰竭。
此类病症可由内部或外部创伤(例如损伤或烧伤)引起,或由例如病毒、细菌或真菌的感染引起。
例如,直肠炎(其包括嗜酸性、淋病性和/或溃疡性直肠炎)可能是由炎性肠病、感染、辐射(例如,对于癌症)、药物(诸如抗生素)、外科手术或过敏性病症(诸如食物不耐受)引起的。
例如,多器官炎症、损伤和/或衰竭可由广泛性和/或创伤性外部损伤(包括创伤性和/或广泛性外部烧伤)引起。创伤性外部烧伤应理解为包括二度烧伤,更特别地包括三度烧伤和四度烧伤。广泛性外部烧伤应理解为包括累及患者身体面积的至少约10%,例如至少约15%,包括至少约20%的烧伤。外部(和内部)烧伤可由暴露于热、化学物等引起。
急性炎性和/或纤维化病症也可由败血症或败血性休克引起,所述败血症或败血性休克可由病毒、细菌或真菌感染引起。此外,急性肺损伤、ARDS、以及特别是SARS可由病毒引起,诸如冠状病毒,包括新型SARS冠状病毒2型(SARS-CoV-2)。
因此,此外,一种或多种前述(例如,急性)炎性病症可(确实在某些情况下可能会)导致某种形式的内部组织损害和/或相关内部组织的功能障碍。因此,相关组织包括(例如粘膜)组织,诸如呼吸道上皮。这种组织损害也可造成上文提及的一种或多种纤维化病症。例如,已知在许多情况下,由新型冠状病毒SARS-CoV-2(2019年冠状病毒疾病或COVID-19)引起的SARS疾病会导致纤维化,其由多种因素(包括炎症)中的一种或多种引起。
在这方面,本发明化合物及其盐在治疗相关的炎性和/或纤维化病症中特别有用,因为此类病症通常以一种或多种合并症为特征。通过“以合并症为特征”的病症,我们认为所讨论的主要病症同时导致包括(并且确实优选)上文所述的那些病症在内的一种或多种其他医学病症(或由其引起),所述病症可相互影响和/或以某种方式彼此重叠。
因此,提供了:
·治疗患者的一种或多种内脏器官的至少一种炎性和/或纤维化障碍或病症的方法,所述方法包括将本发明化合物或其药学上可接受的盐直接全身肠胃外施用需要这种治疗的患者;
·治疗患者的一种或多种内脏器官的两种或更多种炎性和/或纤维化障碍或病症的方法,所述方法包括将本发明化合物或其药学上可接受的盐直接全身肠胃外施用需要这种治疗的患者;以及
·降低与患者的一种或多种内脏器官的一种或多种炎性和/或纤维化障碍或病症相关或可能相关的发病和/或死亡的发生率的方法,所述方法包括将本发明化合物或其药学上可接受的盐直接全身肠胃外施用需要这种治疗的患者。
当将本发明化合物/其盐直接和肠胃外施用时,可以将它们静脉内、动脉内、血管内、血管周围、肌内、皮肤和/或皮下施用,例如通过直接注射或通过任何其他肠胃外途径、以本发明化合物或其盐以药学上可接受的剂型形式施用。
因此,用于这种施用的药学上可接受的配制品可以包含与药学上可接受的佐剂、稀释剂或载体混合的本发明化合物,可以适当考虑直接肠胃外施用的预期途径和标准药学实践来选择所述药学上可接受的佐剂、稀释剂或载体。此类药学上可接受的载体可以是对活性化合物呈化学惰性的,并且在使用条件下可以无有害副作用或毒性。此类药学上可接受的载体还可以赋予本发明化合物的立即释放或调节释放。
因此,用于注射的配制品可以呈诸如悬浮液和/或更优选溶液的水性配制品(例如,(任选)缓冲的水性配制品(例如溶液),诸如含生理盐水的配制品(例如溶液)、含磷酸盐的配制品(例如溶液)、含乙酸盐的配制品(例如溶液)或含硼酸盐的配制品(例如溶液)、或可以在使用之前用诸如水性媒介物的媒介物重构的冻干粉末(例如注射剂))的形式。
用于注射的配制品可以包括本领域技术人员已知的其他合适的赋形剂,例如溶剂(例如水)、助溶剂、增溶剂(例如环糊精)、润湿剂、助悬剂、乳化剂、增稠剂、螯合剂、抗氧化剂、还原剂、抗微生物防腐剂、填充剂和/或保护剂。
用于注射的配制品被优选用如本文所述的缓冲液和/或pH调节剂通过标准技术缓冲至生理学上可接受的pH值(例如,pH在约4.5与约9.5之间,例如约6与约9之间,诸如约6.5与约8.5之间),和/或可以进一步包含张力调节剂(诸如氯化钠)。
尽管本发明化合物的上述优选递送方式包括以适合应用于皮肤和/或适当的粘膜表面的适当的(例如,药学上可接受的和外用可接受的)媒介物和/或可商购的配制品外用至炎症部位(例如,粘膜(包括口腔粘膜和/或鼻粘膜、肺、肛门直肠区域和/或结肠),或更优选皮肤),但还可以包括口服、静脉内、皮肤或皮下、经鼻、肌内、腹膜内或经肺递送。
通过注射施用对于将呈悬浮液的溶液形式的本发明化合物施用例如真皮(例如皮内注射)、关节腔或眼部中是特别有用的。
通过皮内注射(例如,皮内)施用对于将呈溶液或悬浮液形式(例如,真皮填充剂)的本发明化合物施用真皮中是特别有用的。这特别可用作如上文所述的用于黑色素沉着疗法的施用手段,或用于本发明化合物在治疗例如皱纹中的用途。
通过注射施用对于填充(例如鼻腔的外科手术部位、肛瘘、在牙龈与牙根或鼻窦之间的空间)特别有用。
本发明化合物通常将以一种或多种例如与(例如,药学上可接受的)佐剂、稀释剂或载体混合的药物配制品的形式施用,所述形式可以适当考虑预期的施用途径(例如,外用至相关粘膜(包括肺)或优选皮肤)和标准药用或其他(例如化妆)实践来选择。此类药学上可接受的载体可以是对活性化合物呈化学惰性的,并且在使用条件下可以无有害副作用或毒性。此类药学上可接受的载体还可以赋予本发明化合物的立即释放或调节释放。
合适的药物配制品可以是可商购的,或者在其他方面根据文献中描述的技术来制备,所述文献是例如Remington The Science and Practice of Pharmacy,第22版,Pharmaceutical Press(2012)和Martindale-The Complete Drug Reference,第38版,Pharmaceutical Press(2014)及其中提及的文件,将所有所述文件的相关公开内容通过引用特此并入。在其他方面,技术人员可以使用常规技术非创造性地实现包含本发明化合物的合适配制品的制备。
本发明化合物可以呈诸如乳液、悬浮液和/或溶液的水性配制品(例如,(任选)缓冲的水性配制品(例如,溶液),诸如含生理盐水的配制品(例如,溶液)、含磷酸盐的配制品(例如,溶液)、含乙酸盐的配制品(例如,溶液)或含硼酸盐的配制品(例如,溶液))或冻干粉末的形式。
可以将本发明化合物进一步和/或在替代方案中与适当的赋形剂组合以制备:
·凝胶配制品(对于所述凝胶配制品,合适的凝胶基质材料包括纤维素衍生物、卡波姆和海藻酸盐、西黄蓍胶、明胶、果胶、角叉菜胶、结冷胶、淀粉、黄原胶、阳离子瓜尔胶、琼脂、非纤维素多糖、糖类(诸如葡萄糖)、甘油、丙二醇、乙烯基聚合物、丙烯酸树脂、聚乙烯醇、羧乙烯基聚合物、特别是透明质酸);
·洗剂(对于所述洗剂,合适的基质材料包括纤维素衍生物、甘油、非纤维素多糖、不同分子量的聚乙二醇和丙二醇);
·糊剂或软膏(对于所述糊剂或软膏,合适的糊剂基质材料包括甘油、凡士林、石蜡、不同分子量的聚乙二醇等);
·乳膏或泡沫(对于所述乳膏或泡沫,合适的赋形剂(例如,发泡剂)包括羟丙基甲基纤维素、明胶、不同分子量的聚乙二醇、十二烷基硫酸钠、脂肪醇聚氧乙烯醚磺酸钠、玉米麸质粉和丙烯酰胺);
·粉末气雾剂(对于所述粉末气雾剂,合适的赋形剂包括甘露醇、甘氨酸、糊精、右旋糖、蔗糖、乳糖、山梨糖醇和聚山梨醇酯,例如干粉吸入剂);和/或
·用于口服使用或用于吸入的液体,例如水(气雾剂)喷雾剂(对于所述液体,合适的赋形剂包括粘度调节剂,诸如透明质酸、糖类(诸如葡萄糖和乳糖)、乳化剂、缓冲剂、醇、水、防腐剂、甜味剂、调味剂等);和/或
·可注射溶液或悬浮液(所述可注射溶液或悬浮液可以是水性的或其他形式的,并且对于所述可注射溶液或悬浮液,合适的赋形剂包括溶剂和共溶剂、增溶剂、润湿剂、悬浮剂、乳化剂、增稠剂、螯合剂、抗氧化剂、还原剂、抗微生物防腐剂、缓冲剂和/或pH调节剂、填充剂、保护剂和张力调节剂),可提及的特定可注射溶液或悬浮液包括真皮填充剂(即,可注射填充剂或软组织填充剂),特别地当本发明化合物与透明质酸组合时。
适当时,此类配制品还可以包含保湿剂,诸如丙三醇、甘油、聚乙二醇、海藻糖、丙三醇、矿脂、石蜡油、硅油、透明质酸及其盐(例如,钠盐和钾盐)、辛酸(octanoic/caprylic)甘油三酯等;和/或抗氧化剂,诸如维生素和谷胱甘肽;和/或pH调节剂,诸如酸、碱和pH缓冲液。此外,可以包括表面活性剂/乳化剂,诸如十六烷醇(鲸蜡醇)、脂肪酸(例如,硬脂酸)、十二烷基硫酸钠(月桂基硫酸钠)、脱水山梨糖醇酯(例如,脱水山梨糖醇硬脂酸酯、脱水山梨糖醇油酸酯等)、单酰基甘油酯(诸如单硬脂酸甘油酯)聚乙氧基化醇、聚乙烯醇、多元醇酯、聚氧乙烯烷基醚(例如,聚氧乙烯脱水山梨糖醇单油酸酯)、聚氧乙烯蓖麻油衍生物、乙氧基化脂肪酸酯、聚氧甘油酯、月桂基二甲基氧化胺、胆汁盐(例如,脱氧胆酸钠、胆酸钠)、脂质(例如,脂肪酸、甘油脂质、甘油磷脂、鞘脂、固醇、异戊烯醇(prenol)、糖脂(saccharolipid)、聚酮化合物)、磷脂、N,N-二甲基十二烷基胺-N-氧化物、十六烷基三甲基溴化铵、泊洛沙姆、卵磷脂、固醇(例如,胆固醇)、糖酯、聚山梨醇酯等;防腐剂,诸如苯氧基乙醇、乙基己基甘油等;以及增稠剂,诸如丙烯酰基二甲基牛磺酸酯/VP共聚物。具体地,特别是在乳膏配制品中,可以包括硬脂酸、单硬脂酸甘油酯、十六烷醇、脱水山梨糖醇硬脂酸酯、鲸蜡醇、辛酸/癸酸甘油酯等。
本发明化合物以及包含它们的(例如,药物)配制品(例如,如上所述的水溶液、凝胶、乳膏、软膏、洗剂、泡沫、糊剂和/或干粉)可以进一步与适当的基质材料组合以制备用于应用在生物表面(诸如皮肤或粘膜表面)上的敷料或治疗性贴剂。因此,可以使用此类配制品浸渍基质材料,诸如纱布、无纺布或丝质纸。可替代地,治疗性贴剂可以是例如创可贴、面膜、眼膜、手膜、脚膜等。
凡士林可用于将此类敷料应用于伤口,但我们还已发现,可以将基于PEG(例如,PEG 400)的软膏与基质材料组合以制备敷料,而无需使用凡士林。
本发明化合物还可以与固体支持物(诸如鼻敷料(例如,用于阻止鼻出血)、真皮支架(例如,用于伤口愈合)或人造骨(例如,在骨移植/植入的情况下)组合使用。
本发明化合物可以通过悬浮液、干粉或溶液的方式吸入施用。合适的吸入装置包括加压计量剂量吸入器(pMDI)(所述加压计量剂量吸入器可以是手动致动的或呼吸致动的,并且可以用或不用标准间隔器装置来进行使用)、干粉吸入器(DPI)(所述干粉吸入器可以是单剂量的、多剂量的和动力辅助的)以及软雾吸入器(SMI)或喷雾器(其中以比使用pMDI递送的喷雾剂慢的速度递送在细雾中的气雾剂药物)。
在pMDI中,本发明化合物可以作为分布在推进剂(例如,与赋形剂一起的HFA,所述赋形剂诸如甘露醇、乳糖、山梨糖醇等)中的微粒化颗粒的加压悬浮液或作为乙醇溶液被施用以便每次致动递送一个或多个在约20μL与约100μL之间的计量剂量。可以通过手动(例如,按压)或通过吸入(呼吸致动)来进行致动,其中涉及由弹簧驱动的流量触发系统。
在DPI中,本发明化合物可以以在胶囊内的微粉化药物颗粒(尺寸在约1μm与约5μm之间)(单独地或与较大粒度的无活性赋形剂(例如,甘露醇)共混)的形式施用,所述胶囊可以预装载或手动装载到装置中。从DPI吸入可以解聚药物颗粒并且将其在气道内分散。
在SMI中,本发明化合物可以作为溶液储存在装载到装置中的盒内。弹簧可以将剂量释放到微型泵中,使得当按钮被按压时释放所述剂量,从而释放出药物溶液的喷射流。
也可以使用各种喷雾器施用呈气雾化溶液的细雾的形式的本发明化合物。喷雾器可以包括呼吸增强型喷射喷雾器(在其中,在压缩机的辅助下,气流通过喷射移动,使药物溶液气雾化);呼吸致动型喷射喷雾器(在其中,在患者吸入后,在压缩机的辅助下,气流通过管移动,使药物溶液气雾化);超声喷雾器(在其中,压电晶体振动,通过加热引起气雾化,引起雾化);振动式网孔喷雾器(在其中,压电晶体使网孔板振动,引起气雾化以给出非常细小的液滴,而在雾化期间溶液的温度没有明显变化)。
根据本发明的另外方面,提供了一种用于制备如本文所定义的药物组合物/配制品的方法,所述方法包括使如上文所定义的本发明化合物与如上文所定义的一种或多种药学上可接受的赋形剂关联。
本发明化合物也可以在治疗中与一种或多种生长因子组合,所述生长因子选自血小板型生长因子(包括血小板源性生长因子,PDGF)、骨肉瘤源性生长因子(ODGF)、表皮生长因子(EGF)、转化生长因子(TGFα和TGFβ)、成纤维细胞生长因子(αFGF、βFGF)、胰岛素样生长因子(IGF-I、IGF-II)、神经生长因子(NGF)、白细胞介素型生长因子(IL-1、IL-1、IL-3)、红细胞生成素(EPO)和集落刺激因子(CSF)。
根据本发明的另外方面,提供了一种(例如,药物)组合物,其包含本发明化合物和一种或多种药学上可接受的赋形剂,诸如佐剂、稀释剂或载体。优选的配制品适合于局部应用于例如粘膜(包括口腔粘膜和/或鼻粘膜、肺、肛门直肠区域和/或结肠)或更优选地皮肤,并且因此包含外用可接受的佐剂、稀释剂或载体。
因此,进一步提供了适合于、适于和/或包装并且呈现用于外用施用(例如,至粘膜,包括口腔粘膜和/或鼻粘膜、肺、肛门直肠区域和/或结肠,或优选至皮肤)的包含本发明化合物的药物组合物,以及此类配制品在通过将所述配制品直接外用施用(例如,至粘膜,包括口腔粘膜和/或鼻粘膜、肺、肛门直肠区域和/或结肠,或优选至皮肤)的方式治疗包含炎症的障碍、炎性障碍和/或以炎症(例如,作为症状)为特征的病症中的用途。
关于本发明的这个方面,为避免疑义,包含本发明化合物的外用配制品可用于本文所述的任何和所有病症,包括(如上文提及、定义或描述的)在任何和所有炎性障碍的治疗中和/或在任何和所有的以炎症为特征的障碍的治疗中治疗炎症。类似地,可提及的包含本发明化合物的外用配制品包括本文提及、定义或描述的那些中的任何和全部。将本文相关公开内容的任何和全部通过引用与本发明的这个方面结合特此并入。
包含本发明化合物的外用(例如,基于液体或基于(例如,水性)溶液的配制品可以特别用于伤口恢复,并且可以减轻与伤口本身和伤口愈合过程相关的疼痛(包括隐痛)以及特别是瘙痒症/瘙痒。包含本发明化合物的此类外用配制品可以特别用于预防和/或抑制体液从伤口渗出,特别是在急性炎症阶段期间,例如在遭受烧伤或伤口后的最初48小时期间。这预防感染和其他生理反应的风险。包含本发明化合物的此类外用配制品还可以特别用于预防和/或抑制结疤和黑色素沉着(见上),无论是否与伤口或其他方面相关。
本发明化合物的施用可以是连续的或间歇的。施用方式还可以通过施用的时机和频率来确定,但是在炎症的治疗性治疗的情况下还取决于病症的严重程度。
取决于障碍和待治疗的患者以及施用途径,可以以不同的治疗有效剂量向有此需要的患者施用本发明化合物。
类似地,配制品中本发明化合物的量将取决于病症的严重程度以及待治疗的患者,但是可以由技术人员确定。
在任何情况下,医疗从业者或其他技术人员将能够常规确定实际剂量,所述实际剂量将是最适合于个体患者的,这取决于病症的严重程度和施用途径。本文提及的剂量是平均情况的例示;当然可存在较高或较低的剂量范围是理所当然的并且它们在本发明的范围内的个别情况。
剂量可以在每天一次与四次之间(例如,三次)施用。
在所有情况下以游离(非盐)化合物计算,本发明化合物在水溶液产品中的适当浓度可以为约0.01(例如,约0.1)至约15.0mg/mL。
在所有情况下以游离(非盐)化合物计算,本发明化合物的适当外用剂量在约0.05μg至约50μg/cm2处理面积,诸如约0.1μg(例如,约0.5μg)至约20μg/cm2处理面积,包括约1μg至约10μg/cm2处理面积,诸如约5μg/cm2处理面积的范围内。
用于经鼻施用(例如通过吸入)的本发明化合物的适当剂量在约0.01μg至约2000mg的范围内,例如在约0.1μg至约500mg之间、或在1μg至约100mg之间。可提及的用于经鼻施用的特定剂量包括在约10μg至约1mg之间,特别是约0.1mg(即,约100μg)的剂量。已经发现在与鼻通道和粘膜的炎症相关的病症(诸如鼻炎(例如,过敏性鼻炎))和/或与鼻窦炎外科手术相关的病症的治疗中,每天经鼻施用约0.1mg本发明化合物是特别有效的。
用于经肺施用(例如通过吸入)的本发明化合物的适当剂量在约0.01μg至约2000mg的范围内,例如在约0.1μg至约500mg之间、或在1μg至约100mg之间。可提及的用于经肺施用的特定剂量包括在约10μg至约10mg之间,特别是约0.6mg(即,60μg)至6mg的剂量(例如,用于治疗COPD或IPF)。
我们优选的是,包含本发明化合物的配制品的pH值在约1.0至约9.0的范围内(例如,约3.0至约8.0)。
在任何情况下,在本发明的上下文中,施用哺乳动物、特别是人的剂量应足以在合理的时间范围内在哺乳动物中产生治疗反应(如上文所述)。本领域技术人员应认识到,确切剂量和组成以及最适当的递送方案的选择也将尤其受以下影响:配制品的药理特性,所治疗病症的性质和严重程度,和接受者的身体状况和精神敏锐度,以及待治疗的患者的年龄、状况、体重、性别和反应,和疾病的阶段/严重程度,以及患者之间的遗传差异。
本发明化合物可用作人类和/或动物医药。
在本文所述用途和方法中,本发明化合物还可与可用于治疗炎症和/或炎性障碍的一种或多种药物活性成分(其他抗炎剂)组合。
因此,此类患者也可能正在(和/或可能已经)接受基于施用一种或多种此类其他已知的药物活性成分的疗法,我们将所述疗法意指为在用本发明化合物治疗之前、之外和/或之后接受处方剂量的一种或多种本文提及的活性成分。
可以使用的其他抗炎剂的非限制性例子还包括用于治疗风湿性疾病和/或关节炎的抗炎剂(诸如克他服宁(cataflam)、倍他米松、萘普生、环孢菌素、软骨素、塞来昔布、依托度酸、甲氯芬那酸盐、双水杨酸酯、甲基强的松龙和吡罗昔康);用于治疗骨关节炎的抗炎剂(诸如舒林酸、美洛昔康、非诺洛芬、依托昔布和萘丁美酮);用于治疗炎症及其症状(例如发烧、疼痛、瘙痒和/或肿胀)的抗炎剂(诸如甲灭酸、吲哚美辛、阿司匹林、酮咯酸、氟米龙、氯替泼诺、氢化可的松、氟米龙、溴芬酸、醋酸泼尼松龙、吲哚美辛和布洛芬);用于治疗过敏及其症状的抗炎剂(诸如苯吡胺、苯海拉明、萘甲唑啉、安他唑啉、泼尼松龙、洛度沙胺、吡嘧司特、羟甲唑啉、酮替芬、萘甲唑啉、吐根碱富马酸酯(emestine fumarate)、奥洛他定、氮卓斯汀、曲尼司特、左卡巴斯汀、可的松、麻黄素、西替利嗪、左西替利嗪、伪麻黄碱(pseudophedrine)、非索非那定、特非那定、氯雷他定和alexis);用于治疗呼吸系统疾病(包括哮喘和/或COPD)的抗炎剂(诸如布地奈德、环索奈德、奈多罗米、地塞米松、氨溴索和普鲁司特);用于治疗皮肤疾病的抗炎剂(诸如莫米松、曲安奈德、地奈德、磺胺醋酰、他克莫司、尿囊素和曲安奈德);用于治疗肥大细胞增多症的抗炎剂(诸如色甘酸);用于治疗痛风的抗炎剂(诸如双氯芬酸和非布索坦);用于治疗结膜炎的抗炎剂(诸如羟苄唑、普拉洛芬和硫酸锌);用于治疗眼部疾病的抗炎剂(例如右旋糖酐70、甲状腺素/碘塞洛宁、和眼氨肽(ocular extractive)),上述任何已知或可商购获得的药学上可接受的盐,以及上述任何化合物和/或盐的组合。
可提及的抗炎药包括内源性(和/或外源性)基于脂质的促消退、抗炎性分子或介质,诸如脂氧素、消退素和保护素。可提及的促炎剂包括前列腺素(例如拉坦前列素、前列环素E1和前列环素E2)和白三烯(例如白三烯B4)。
特别地可在炎症的治疗中与本发明化合物组合使用的其他抗炎剂包括可用于治疗炎症和/或以炎症作为其症状之一为特征的疾病(包括上文所述的那些)的治疗剂。取决于待治疗的病症,此类抗炎剂可以包括NSAID(例如阿司匹林)、氨基水杨酸盐(aminosalysate)(例如5-氨基水杨酸(美沙拉嗪))、白三烯受体拮抗剂(例如孟鲁司特、普鲁司特和扎鲁司特)、皮质类固醇、止痛剂和某些酶(诸如胰蛋白酶),例如如下文所述。本发明化合物也可以与白三烯(例如半胱氨酰白三烯和白三烯B4)组合。
可与本发明化合物组合的其他优选药剂包括LTB4(用于治疗伤口和烧伤)、NSAID(例如阿司匹林)或孟鲁司特(通常用于治疗炎症)和胰蛋白酶(用于治疗与例如病毒感染相关的粘膜炎症)。
本发明化合物还可以与其他治疗剂组合,所述其他治疗剂在被施用时已知会产生作为副作用的炎症。
本发明化合物还可以与干细胞(例如全能性(全能)干细胞、多能干细胞(诸如胚胎或诱导性多能干细胞)、多能性干细胞(诸如间充质干细胞)、寡能干细胞(诸如造血干细胞)或单能干细胞(诸如肌肉干细胞))组合。
其他已知的药学活性(例如抗炎)成分也可以以多种方式与本发明化合物组合施用。
例如,本发明化合物可以与其他药物活性成分(或“治疗剂”)“组合”用于在相同(例如药物)配制品中一起施用或在不同(例如,药物)配制品中单独(同时或顺序地)施用。
因此,此类组合产品提供用于本发明化合物与其他治疗剂的联合施用,并且因此可以呈现为单独的配制品,其中这些配制品中的至少一种包含本发明化合物并且至少一种包含(或其他)治疗剂,或者可以呈现(即,配制)为组合制剂(即,呈现为包括本发明化合物和(或其他)治疗剂的单一配制品)。
因此,进一步提供了:
(1)一种(例如药物)配制品,其包含本发明化合物;另一种抗炎剂或已知产生作为副作用的炎症的药剂;以及药学上可接受的赋形剂(例如,佐剂、稀释剂或载体),所述配制品在下文中被称为“组合制剂”;和
(2)一种试剂盒,其包含以下组分:
(A)包含与药学上可接受的非活性赋形剂(例如,佐剂、稀释剂或载体)混合的本发明化合物的药物配制品;和
(B)包含与药学上可接受的佐剂、稀释剂或载体混合的另一种抗炎剂或已知产生作为副作用的炎症的药剂的药物配制品,
所述组分(A)和(B)各自以适合于与彼此联合施用的形式提供。
在本发明的进一步方面,提供了一种用于制备如上文所定义的组合制剂(1)的方法,所述方法包括使本发明化合物、其他抗炎剂或已知产生作为副作用的炎症的药剂、和至少一种(例如,药学上可接受的)赋形剂关联。
在本发明的另外方面,提供了一种用于制备如上文所定义的试剂盒(2)的方法,所述方法包括使组分(A)和(B)关联。如本文所用,对关联的提及将意指使两种组分适合于和彼此联合施用。
因此,关于通过使两种组分彼此“关联”的如上文所定义的用于制备试剂盒的方法,我们包括,所述试剂盒的两种组分可以:
(i)作为单独的配制品(即,彼此独立)来提供,所述单独的配制品随后被放在一起以用于在组合疗法中彼此联合使用;或者
(ii)一起包装并且呈现为“组合包”的单独组分以用于在组合疗法中彼此联合使用。
因此,进一步提供了试剂盒,其包含:
(I)如本文所定义的组分(A)和(B)之一;以及
(II)将所述组分与所述两种组分中的另一种联合使用的说明。
为了提供重复剂量,本文所述试剂盒可以包括多于一种包含适当量/剂量的本发明化合物的配制品,和/或多于一种包含适当量/剂量的其他抗炎剂的配制品。如果存在多于一种包含一定量/剂量的任一种活性化合物的配制品,则此类配制品在任一种化合物的量、一种或多种化学组合物和/或一种或多种物理形式的方面可以相同或者可以不同。
关于如本文所述试剂盒,我们将“与……联合施用”意指为,在相关病症的治疗过程中顺序地、分开地和/或同时地施用包含本发明化合物和其他抗炎剂的相应配制品。
因此,关于根据本发明的组合产品,术语“与……联合施用”包括,组合产品的两种组分(本发明化合物和其他抗炎剂)被一起或在时间上足够接近地施用(任选重复地),以使患者在相关病症的治疗过程中能够受到有益作用,所述有益作用大于在如果在相同治疗过程中在不存在另一种组分的情况下单独施用(任选重复地)包含本发明化合物的配制品或包含另一种药剂的配制品的情况。对组合是否提供关于具体病症以及在其治疗过程中的更大有益作用的确定将取决于待治疗或预防的病症,但是可以由技术人员常规地实现。
此外,在根据本发明的试剂盒的上下文中,术语“与……联合”包括,两种组分中的一种或另一种可以在施用另一种组分之前、之后和/或与其同时被施用(任选地重复地)。当在此上下文中使用时,术语“同时施用”和“与……同时施用”包括,单独量/剂量的本发明的相关化合物和其他抗炎剂在彼此的48小时(例如,24小时)内被施用。
无论在本文何处(例如,在诸如本发明化合物和/或活性成分的浓度和/或剂量、分子量或pH的量的上下文中)使用词语“约”时,应意识到,此类变量是近似的并且因此可以相对于本文指定的数字变化±10%,例如±5%、优选地±2%(例如,±1%)。在这方面,术语“约10%”意指例如关于数字10的±10%,即,在9%与11%之间。
本发明化合物具有以下优点:它们可用于以炎症为特征的多种病症,无论所述病症是如上文所述的器官炎性疾病本身还是与炎症相关的或以炎症为特征的(例如,伤口或烧伤),和/或用于外科手术和/或化妆品应用。
本文所述的化合物、用途和方法还可以具有以下优点:在上文提及的病症的治疗中,相比于在现有技术中已知的类似化合物或方法(治疗),它们可以对于医师和/或患者而言更方便,更有效,毒性更低,具有更广泛的活性范围,更有效力,产生更少副作用,或者它/它们可具有其他有用的药理特性,无论用于治疗炎症、炎性障碍或以炎症作为症状为特征的障碍(包括伤口)还是在其他方面都如此。
通过以下实施例说明但绝非限制本发明,其中图1示出了直肠和肛门组织中的伊文思蓝含量,表明了测试化合物的血管渗透性。
实施例
实施例1
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:7)
将Fmoc-Lys(Boc)-Wang树脂(9.15g,41301,GL Biochem,中国上海)装载到玻璃反应柱中。
将二氯甲烷(DCM,200mL;Shandong Jinling Chemical Industry Co.Ltd.,中国山东)添加到柱中并且允许将树脂浸泡约半小时。然后通过真空过滤除去DCM。
将树脂用N,N-二甲基甲酰胺(DMF,200mL;Shandong Shitaifeng FertilizerIndustry Co Ltd,中国山东)洗涤3次。
将在DMF中的20%哌啶溶液(200mL;Shandong Shitaifeng Fertilizer IndustryCo Ltd,中国山东)作为脱保护溶液添加并且反应20分钟。然后通过真空过滤除去溶液并且将在柱中的树脂用DMF洗涤六次。
将Fmoc-4-Hyp(tBu)-OH(3.68g;21303,GL Biochem,中国上海)和2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基四氟硼酸铵(TBTU,2.89g;00705,GL Biochem,中国上海)添加到树脂中。将DMF(150mL)添加到反应柱中,接着添加N,N-二异丙基乙胺(DIPEA,2.33g;SuzhouHighfine Biotech Co.Ltd,中国江苏)。反应30分钟后,用很少树脂进行Kaiser测试,溶液的黄色以及无色凝胶指示反应完成。通过真空过滤除去溶剂。
重复以上偶联步骤以偶联相同量(按摩尔计)的剩余氨基酸:Fmoc-Tyr(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-4-Hyp(tBu)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Pro-OH、Fmoc-Lys(Boc)-OH、Fmoc-Ala-OH和Fm oc-DOPA(缩丙酮)-OH。
在单独的程序中,在将Fmoc-DOPA(缩丙酮)-OH偶联到树脂上之后,进行脱保护步骤以去除Dopa上的Fmoc保护。将树脂用DMF洗涤3次(每次200mL)。将在DMF中的20%哌啶溶液(200mL)作为脱保护溶液添加并且反应20分钟。然后,将树脂用以下溶剂各洗涤三次:DMF(每次200mL)、DCM(每次200mL)和甲醇(每次200mL;Xilong Scientific Co.,Ltd.,中国广东)。将树脂在真空下干燥约2小时。
添加130.0mL(即,10mL/克干燥树脂)裂解液以浸没与树脂结合的含肽化合物,所述裂解液由95%三氟乙酸(TFA)、2.5%水和2.5%三异丙基硅烷(Tis)组成。裂解约2小时后,通过过滤除去固体支持物并且在减压下收集滤液。将滤液用1300mL(即10mL/ml滤液)乙醚(Xilong Scientific Co.,Ltd.,中国广东)沉淀,并且通过过滤收集沉淀物。真空干燥沉淀物约2小时,产生4.53g粗标题化合物。
将粗产物首先在纯水中作为1mg/mL样品进行分析,并使用Shimadzu LCMS-8050系统进行检测。分析柱为安捷伦ZORBAX Eclipse SB-C18(4.6×250mm,5μm柱;检测:在220nm处的UV;溶剂A:在MeCN中的0.1%TFA,溶剂B:在水中的0.1%TFA,线性梯度为50分钟内从5%到90%的溶剂A浓度;流速1.0mL/min;样品体积:10μL)。
目标峰在9.719分钟时被洗脱,并且具有预期的分子量,纯度为79.363%。
MS:m/z 1362.4
然后将4.5g粗产物溶解于50mL纯水中,并使用LC3000半制备设备进行纯化。制备柱模型是双C18模型(Hanbon Sci.&Tech.Co.,Ltd.,中国江苏)(50*250mm,柱;检测:在220nm处的UV)。从LCMS检测步骤计算出适当的洗脱梯度(溶剂A:在MeCN中的0.1%TFA,溶剂B:在水中的0.1%TFA,线性梯度为在30分钟内5%到20%的溶剂A浓度;流速60.0mL/min)。收集级分并且使用Shimadzu LC-20HPLC系统(柱如上文,不同之处在于线性梯度为在25分钟内从5%-30%的溶剂A浓度)进行分析。
然后将纯度为98%的级分混合在一起,以进行阴离子交换步骤。这是使用LC3000半制备设备(制备柱型号:Dubhe-C18模型(如上文))实现的。将级分用纯水稀释一次并且直接装载至柱,在此之后以60mL/min的流速将柱用在纯水中的0.37%乙酸铵洗涤约20分钟然后用纯水洗涤另外的20分钟,然后用以下梯度洗脱(溶剂A:在MeCN中的0.1%HAc,溶剂B:在水中的0.1%HAc,线性梯度为在30分钟内从5%到20%的溶剂A浓度;流速60.0mL/min)。收集级分并且使用Shimadzu LC-20HPLC系统(柱和条件如上文)进行分析。将纯度为98%的级分混合并且冷冻干燥以给出3.23g纯化的标题化合物。
实施例2
其他肽I的合成
使用与上文实施例1中所述的程序基本相同的程序合成以下肽,不同之处在于在相关肽偶联序列中适当地使用适当的氨基酸:
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:33);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:34);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:36);
DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:6);
DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:29);
DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:5);
DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:28);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:9);
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:30);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:8);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:10);和
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:32)。
这些肽合成的粗品产率和纯度、保留时间、MS值和最终产率示出于下表1中。
表1
SEQ ID No. | 粗品量 | 粗品纯度 | 保留时间 | MS | 最终量 |
33 | 4.59g | 77.392% | 9.395 | 1183.3 | 2.87g |
34 | 4.38g | 79.176% | 9.957 | 1199.5 | 2.94g |
36 | 4.94g | 75.843% | 9.764 | 1215.2 | 2.97g |
6 | 4.63g | 76.125% | 9.356 | 1199.3 | 2.89g |
29 | 4.75g | 74.934% | 9.798 | 1215.1 | 2.96g |
5 | 4.86g | 78.312% | 9.456 | 1199.4 | 2.85g |
28 | 4.95g | 77.121% | 9.334 | 1215.5 | 2.99g |
9 | 5.14g | 79.853% | 9.562 | 1378.3 | 3.13g |
30 | 5.23g | 75.123% | 9.556 | 1395.6 | 3.22g |
8 | 5.15g | 77.944% | 9.662 | 1362.5 | 3.08g |
10 | 5.17g | 77.865% | 9.635 | 1378.4 | 3.11g |
32 | 5.29g | 76.947% | 9.593 | 1395.6 | 3.26g |
实施例3
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID No:54)
使用与上文实施例1中所述的方法基本相同的方法制备标题化合物,不同之处在于在肽合成的最开始时,使用Fmoc-Dopa(缩丙酮)-Wang树脂(9.72g,USUN Pharma.中国江阴),而不是Fmoc-Lys(Boc)-Wang树脂。从Dopa作为第一氨基酸合成此肽,然后在与上文实施例1中所述的相同方法中将Fmoc-Thr(tBu)-OH、Fmoc-4-Hyp(tBu)-OH、Fmoc-4-Hyp(tBu)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Pro-OH、Fmoc-Lys(Boc)-OH、Fmoc-Ala-OH和Fmoc-Lys(Boc)-OH偶联。
MS:m/z 1199.3
重复基本上相同的方法给出另一批粗标题化合物(产量5.22g)。分析显示目标峰在10.012分钟时被洗脱,具有预期分子量(MS:m/z 1199.3)。纯度为79.832%。
然后将5.2g粗产物如上文实施例1所述纯化,冷冻干燥后给出3.3g纯标题化合物。
实施例4
其他肽II的合成
使用与上文实施例3中所述的程序基本相同的程序合成以下肽,不同之处在于在相关肽偶联序列中适当地使用适当的氨基酸:
Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA(SEQ ID No:57);
Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID No:56);
Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA(SEQ ID No:59);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA(SEQ ID No:38);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID No:48);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID No:50);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA(SEQ ID No:41);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID No:42);和
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID No:44)。
这些肽合成的粗品产率和纯度、保留时间、MS值和最终产率示出于下表2中。
表2
SEQ ID No. | 粗品量 | 粗品纯度 | 保留时间 | MS | 最终量 |
57 | 5.19g | 77.392% | 10.195 | 1215.3 | 3.26g |
56 | 5.08g | 79.176% | 10.057 | 1215.5 | 3.34g |
59 | 4.94g | 75.843% | 10.164 | 1231.3 | 3.17g |
38 | 5.23g | 76.125% | 10.156 | 1362.5 | 3.19g |
48 | 5.05g | 74.934% | 10.198 | 1378.3 | 3.26g |
50 | 5.22g | 78.867% | 10.037 | 1394.2 | 3.38g |
41 | 5.12g | 79.393% | 10.129 | 1362.3 | 3.33g |
42 | 4.04g | 78.938% | 10.321 | 1378.2 | 3.39g |
44 | 5.13g | 77.876% | 10.235 | 1394.4 | 3.41g |
实施例5
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:17)
使用与上文实施例1中所述的方法基本相同的方法制备标题化合物,不同之处在于此处使用的最后一个氨基酸是3,4-二羟基氢肉桂酸(1.64g,Macklin,中国上海),而不是实施例1中所用的Fmoc-DOPA(缩丙酮)-OH。在将3,4-二羟基氢肉桂酸偶联到树脂上之后,可以用DMF、DCM和甲醇直接洗涤树脂,而没有实施例1中的脱保护步骤。其他程序与实施例1完全相同,以得到4.89g的粗标题化合物。
MS:m/z 1347.8
分析显示目标峰在9.667分钟时被洗脱,具有预期分子量(MS:m/z 1347.8)。纯度为77.957%。
然后将4.8g粗产物如上文实施例1所述纯化,冷冻干燥后给出3.4g纯标题化合物。
实施例6
其他肽III的合成
使用与上文实施例5中所述的程序基本相同的程序合成以下肽,不同之处在于在相关肽偶联序列中适当地使用适当的氨基酸:
HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:15);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:18);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:19);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:20);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:21);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:22);
HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:25);
HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:26);和
HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:27)。
这些肽合成的粗品产率和纯度、保留时间、MS值和最终产率示出于下表3中。
表3
SEQ ID No. | 粗品量 | 粗品纯度 | 保留时间 | MS | 最终量 |
15 | 4.59g | 77.392% | 9.395 | 1184.3 | 3.47g |
18 | 4.38g | 79.176% | 9.957 | 1363.6 | 3.34g |
19 | 4.94g | 75.843% | 9.764 | 1379.7 | 3.57g |
20 | 4.63g | 76.125% | 9.356 | 1347.3 | 3.39g |
21 | 4.85g | 74.934% | 9.798 | 1363.5 | 3.46g |
22 | 4.72g | 76.237% | 9.798 | 1379.8 | 3.48g |
25 | 4.69g | 78.958% | 9.798 | 1184.4 | 3.23g |
26 | 4.93g | 75.303% | 9.798 | 1200.3 | 3.67g |
27 | 4.88g | 79.058% | 9.798 | 1200.2 | 3.63g |
实施例7
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-多巴胺(SEQ ID No:39)
使用如上文实施例1中所述的几乎相同的方法,用Fmoc-Lys(Boc)-Wang树脂从Lys作为第一氨基酸合成标题化合物,以如上文实施例1所述的相同方法,将Fmoc-4-Hyp(tBu)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmo c-4-Hyp(tBu)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Ser(tBu)-OH、Fmoc-Pro-OH、Fmoc-Lys(Boc)-OH和Boc-Ala-OH偶联。
在将Boc-Ala-OH偶联到树脂上后,将树脂用以下溶剂各洗涤三次:DMF(每次200mL)、DCM(每次200mL)和甲醇(每次200mL)。然后将树脂通过真空干燥约2小时。
添加120.0mL(即,10mL/克干燥树脂)裂解液以浸没与树脂结合的含肽化合物,所述裂解液由在DCM中的2%三氟乙酸(TFA)构成。裂解约2小时后,通过过滤除去固体支持物并且在减压下收集滤液。然后在减压下将滤液通过旋转蒸馏浓缩。去除所有溶剂后,向烧瓶中添加DMF(100mL)以溶解固体,向反应溶液中添加多巴胺盐酸盐(1.71g,Aladdin,中国上海)、TBTU(2.89g)和DIPEA(2.33g)。反应30分钟后,反应完成。通过添加1200mL(即10mL/ml的最终溶液)饱和柠檬酸(Aladdin,中国上海)水溶液进行最终溶液的沉淀,并且通过过滤收集沉淀物。然后向沉淀物中添加120mL(即10mL/克固体)裂解液以溶解含肽固体,所述裂解液包含95%三氟乙酸(TFA)、2.5%水和2.5%三异丙基硅烷(Tis)。在裂解过程中,侧链被脱保护。裂解约2小时后,将溶液用1200mL(即10mL/ml滤液)乙醚沉淀,并且通过过滤收集沉淀物。将沉淀物通过真空干燥约2小时。最终,得到4.28g粗标题化合物。
MS:m/z 1318.5
分析显示目标峰在10.509分钟时被洗脱,具有预期分子量(MS:m/z1318.2)。纯度为70.476%。
然后将4.2g粗产物如上文实施例1所述纯化,冷冻干燥后给出2.8g纯标题化合物。
实施例8
其他肽IV的合成
使用与上文实施例7中所述的程序基本相同的程序合成以下肽,不同之处在于在相关肽偶联序列中适当地使用适当的氨基酸:
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-多巴胺(SEQ ID No:40);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-多巴胺(SEQ ID No:45);
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-多巴胺(SEQ ID No:47);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-多巴胺(SEQ ID No:51);和
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-多巴胺(SEQ ID No:53);
这些肽合成的粗品产率和纯度、保留时间、MS值和最终产率示出于下表4中。
表4
SEQ ID No. | 粗品量 | 粗品纯度 | 保留时间 | MS | 最终量 |
40 | 4.29g | 70.392% | 10.393 | 1318.5 | 2.55g |
45 | 4.31g | 69.173% | 10.953 | 1334.4 | 2.34g |
47 | 4.23g | 70.822% | 10.106 | 1350.6 | 2.67g |
51 | 4.33g | 68.948% | 10.354 | 1334.5 | 2.66g |
53 | 4.19g | 69.532% | 10.739 | 1350.5 | 2.36g |
实施例9
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-多巴胺(SEQ ID No:55)和Lys-Ala-
Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-多巴胺(SEQ ID No:58)
使用Thr作为第一氨基酸与Fmoc-Thr(tBu)-Wang树脂,并且在适当的肽偶联序列中使用适当的氨基酸,使用与上文实施例7中所述基本相同的方法合成标题化合物。
MS(SEQ ID No:20):m/z是1155.3(SEQ ID No:55)
MS(SEQ ID No:26):m/z是1171.3(SEQ ID No:58)
实施例10
Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID No:12)、Lys-Ala-Lys-
Hyp-Ser-DOPA-Hyp-Hyp-Thr-Tyr(SEQ ID No:16)、Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-
Thr-Tyr(SEQ ID No:13)和Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID No:14)
使用Tyr作为第一氨基酸与Fmoc-Tyr(tBu)-Wang树脂,并且在适当的肽偶联序列中使用适当的氨基酸,使用与上文实施例1中所述基本相同的方法合成标题化合物。
MS(SEQ ID No:12):m/z是1199.3(SEQ ID No:12)
MS(SEQ ID No:26):m/z是1215.3(SEQ ID No:16)
MS(SEQ ID No:20):m/z是1199.3(SEQ ID No:13)
MS(SEQ ID No:26):m/z是1183.3(SEQ ID No:14)
实施例11
用于制备肽凝胶配制品的通用方法
通过将适当量的分离的肽化合物与甲基纤维素(2.5%)、丙二醇(11%)、甘油(11%)混合来制备包含上述肽化合物(例如,SEQ ID No:7、39、33、34、15、58、50、22、18、32等)的各种凝胶。通过添加乙酸(pH调节剂;0至0.5g)将pH调节至5.5。所有赋形剂均获得自Sinopharm Chemical Reagent Co.Ltd。凝胶由注射用水制成。
实施例12
小鼠耳肿胀模型
由Changzhou Cvens Experimental Animal Co.Ltd.提供35只6-8周龄并且平均体重为18-25g的健康雄性BALB/c小鼠,并且将其圈养并且护理约1周,然后进行实验。圈养温度为约25℃至27℃,其中湿度为74%,12小时周期的光照与黑暗交替,并且自由获取食物和水。将小鼠随机分为7组,如下表5所述,其中每组5只小鼠。
表5
组 | 药物浓度 |
模型 | / |
Dex乳膏 | 10μg/g |
SEQ ID No:58 | 0.5mg/g |
SEQ ID No:50 | 0.5mg/g |
SEQ ID No:22 | 0.5mg/g |
SEQ ID No:18 | 0.5mg/g |
SEQ ID No:32 | 0.5mg/g |
将醋酸地塞米松乳膏(Dex乳膏;5mg/10g(这意味着在10g乳膏中含有5mg Dex),Fuyuan Pharmaceutical Co.Ltd.,中国安徽)用作阳性对照。
每只小鼠的左耳用作自体对照。用上述化合物以规定浓度处理每只小鼠的右耳。
将约0.1g各种凝胶和Dex乳膏应用于每组小鼠的右耳(内部和外部)。将空白凝胶基质应用于模型组的耳朵。1小时后,将20μL二甲苯(Shanghai Aladdin Bio-ChemTechnology Co.,Ltd.)应用于每只小鼠的同一只耳朵。
在应用二甲苯后40分钟,将小鼠通过颈脱位法处死。切下左耳和右耳。使用直径为8mm的EMS皮活检袋从两耳的相同部位取下一片耳。记录重量,并且根据以下公式以百分比计算肿胀率:
(右耳重量-左耳重量)/左耳重量×100
结果在下表6中示出。
表6
模型 | DEX | 15 | 58 | 50 | 22 | 18 | |
肿胀率 | 89% | 38% | 63% | 43% | 54% | 40% | 57% |
SD | 0.17 | 0.18 | 0.14 | 0.21 | 0.09 | 0.17 | 0.15 |
结果显示,所有肽均可消除由炎症引起的水肿。肽化合物SEQ ID No 58och 22的抗炎效果比测试的其他肽化合物强。
实施例13
巴豆油诱导的大鼠肛门肿胀模型
通过将一份蒸馏水、四份吡啶(Nanjing Chemical Reagent Co.,Ltd.)、五份醚(China Pharmaceutical Group Chemical Reagents Co.,Ltd)和十份6%巴豆油(Shanghai Yuanye Biotechnology Co.,Ltd.)醚溶液混合来制备巴豆油混合物。
由Changzhou Cvens Experimental Animal Co.Ltd.(中国江苏省常州)提供平均体重为180-220g的6-8周龄SD大鼠。在进行任何实验之前,将大鼠在标准条件下(在恒定温度或22℃±2℃下,12小时周期的光照与黑暗交替)圈养并且饲喂标准小鼠饮食与水持续约一周。
如下表7所示,将80只大鼠(40只雄性和40只雌性)随机分为8组,每组10只大鼠。
如上文实施例3中所述制备醋酸地塞米松乳膏。
表7
通过异氟烷(China Pharmaceutical Group Chemical Reagents Co.,Ltd.)吸入来麻醉大鼠。用75%的酒精棉球对肛门周围的皮肤消毒。然后,将0.16mL巴豆油混合物缓慢地滴在棉签上,并且插入大鼠肛门中0.5cm。
抬起大鼠以保持头部向上(将所述位置保持10秒钟),然后取出棉签,并且将巴豆油混合物均匀地应用于周围的皮肤上。向假性组施用相同的体积,但代替地是橄榄油。
建模后一小时,根据表7治疗每组大鼠。阳性对照药物是醋酸地塞米松乳膏(Fuyuan Pharmaceutical Co.Ltd.,中国安徽)。如实施例11所述制备每种化合物的凝胶。连续三天每天一次施用药物。
用1mL注射器(去除针头)抽取200μL相应药物。将注射器插入肛管,并且将约160mL相应测试物质推入肛管内约1.5cm。将剩余的相应测试物质应用于肛门附近的周围皮肤。将肛门周围的皮肤紧紧保持1分钟以防止药物排出。
在第四天的早晨,将1%伊文思蓝(EB)注射到尾静脉中。30分钟后,将大鼠通过颈脱位法处死。
将大鼠以仰卧位放置在解剖板上,并且打开其腹部。将直肠肛门组织(长度为15mm)分离并且称重,并且使用1mL甲酰胺萃取组织中存在的EB染料。
将所有样品转移到55℃水浴或加热块中。孵育24小时,从组织中萃取EB。将甲酰胺/EB混合物离心,以使任何剩余的组织碎片沉淀。在610nm处测量吸光度,使用500μL甲酰胺作为空白。
使用外渗的EB量(以ng为单位)/mg组织计算直肠和肛门组织中EB的含量,以评估血管渗透性。结果在图1中示出,并且显示所有化合物均可以减轻由巴豆油应用引起的炎性肿胀,如通过在不同处理中EB含量的变化所指示的。EB浓度降低指示血管通透性。
Claims (31)
1.一种化合物,所述化合物包含氨基酸序列:
W-Lys-X1-Ser-U-X2-Y-G
其中:
W代表1或2氨基酸序列,其中所述氨基酸选自以下的组的一种或多种:Lys、Ala和DOPA,所述序列任选地被3,4-二氢肉桂酸(HCA)残基N-封端;
X1代表Pro、Hyp或diHyp;
U代表Tyr或DOPA;
X2代表Ser、Pro、Hyp或diHyp;
Y代表1至5氨基酸序列,其中所述氨基酸选自以下的组的一种或多种:Lys、Ala、Pro、Hyp、diHyp、Thr、DOPA和Tyr;并且
G不存在或代表DOPA或多巴胺,
以及所述化合物的区域异构体、立体异构体、以及药学上或化妆品可接受的盐。
2.根据权利要求1所述的化合物,其中G不存在。
3.根据权利要求1或2所述的化合物,其中X1代表Pro。
4.根据前述权利要求中任一项所述的化合物,其中X2代表Hyp。
5.根据前述权利要求中任一项所述的化合物,其中W选自HCA、HCA-Ala-、Ala、DOPA、Lys-Ala-和DOPA-Ala-的组。
6.根据前述权利要求中任一项所述的化合物,其中Y代表4氨基酸序列,其中所述氨基酸选自以下的组的一种或多种:Lys、Ala、Hyp、Thr、DOPA和Tyr。
7.根据权利要求6所述的化合物,其中Y代表4氨基酸序列,其中所述氨基酸选自-Pro-Y1-Y2-Lys-、-Hyp-Y1-Y2-Lys-和-Thr-Y1-Y2-Lys-的组,其中Y1和Y2各自独立地选自Ala、Hyp、Pro、Thr、DOPA和Tyr的组。
8.根据权利要求6或7所述的化合物,其中由Y定义的氨基酸序列选自-Hyp-Thr-Tyr-Lys-、-Hyp-Thr-DOPA-Lys-、-Hyp-Thr-Ala-Lys-、-Thr-Tyr-Hyp-Lys-、-Thr-DOPA-Hyp-Lys-和-Thr-Ala-Hyp-Lys-的组。
9.根据权利要求1至6中任一项所述的化合物,其中由Y定义的氨基酸序列选自-Hyp-Thr-、-Thr-Tyr-、-Thr-DOPA-、-Hyp-Thr-Tyr-、-Hyp-Thr-Tyr-Hyp-Lys-、-Thr-Tyr-Hyp-Lys-DOPA-和-Hyp-Thr-DOPA-的组。
10.根据前述权利要求中任一项所述的化合物,其中所述化合物具有以下氨基酸序列:
DOPA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:5);
DOPA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:6);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:7);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:8);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:9);
DOPA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:10);
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:11);
Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID No:12);
Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr(SEQ ID No:13);
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr(SEQ ID No:14);
HCA-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:15);
Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-Tyr(SEQ ID No:16);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:17);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:18);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:19);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:20);
HCA-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:21);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:22);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:23);
HCA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:24);
HCA-Lys-Pro-Ser-Tyr-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:25);
HCA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:26);
HCA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:27);
DOPA-Lys-Pro-Ser-DOPA-Hyp-Thr-Ala-Hyp-Lys(SEQ ID No:28);
DOPA-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Ala-Lys(SEQ ID No:29);
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:30);
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys(SEQ ID No:31);
DOPA-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys(SEQ ID No:32);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:33);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:34);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys(SEQ ID No:35);或
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys(SEQ ID No:36)。
11.根据权利要求1所述的化合物,其中G代表DOPA和/或多巴胺。
12.根据权利要求1或权利要求11所述的化合物,其中W代表Ala或Lys-Ala。
13.根据权利要求12所述的化合物,其中所述化合物具有以下氨基酸序列:
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-DOPA(SEQ ID No:38);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-Tyr-Hyp-Lys-多巴胺(SEQ ID No:39);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-多巴胺(SEQ ID No:40);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-Tyr-Lys-DOPA(SEQ ID No:41);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID No:42);
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-DOPA(SEQ ID No:43);
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-DOPA(SEQ ID No:44);
Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA-Lys-多巴胺(SEQ ID No:45);
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-Tyr-Lys-多巴胺(SEQ ID No:46);
Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA-Lys-多巴胺(SEQ ID No:47);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID No:48);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-DOPA(SEQ ID No:49);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-DOPA(SEQ ID No:50);
Ala-Lys-Pro-Ser-Tyr-Hyp-Thr-DOPA-Hyp-Lys-多巴胺(SEQ ID No:51);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-Tyr-Hyp-Lys-多巴胺(SEQ ID No:52);
Ala-Lys-Pro-Ser-DOPA-Hyp-Thr-DOPA-Hyp-Lys-多巴胺(SEQ ID No:53);
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID No:54);
Lys-Ala-Lys-Pro-Ser-Tyr-Hyp-Hyp-Thr-多巴胺(SEQ ID No:55);
Lys-Ala-Lys-Hyp-Ser-Tyr-Hyp-Hyp-Thr-DOPA(SEQ ID No:56);
Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-DOPA(SEQ ID No:57);
Lys-Ala-Lys-Pro-Ser-DOPA-Hyp-Hyp-Thr-多巴胺(SEQ ID No:58);或
Lys-Ala-Lys-Hyp-Ser-DOPA-Hyp-Hyp-Thr-DOPA(SEQ ID No:59)。
14.根据前述权利要求中任一项所述的化合物,其中:
W代表Ala;
X1代表Pro;
X2代表Pro;
Y选自-Thr-Tyr-Pro-Lys-和-Thr-DOPA-Pro-Lys-、-Pro-Thr-DOPA-Lys-、-Pro-Thr-Tyr-Lys-、-Thr-Tyr-Lys-、-Tyr-Pro-Lys-和-DOPA-Pro-Lys-的组;和/或
G不存在。
15.根据权利要求14所述的化合物,其中所述化合物具有以下氨基酸序列:
Ala-Lys-Pro-Ser-Tyr-Pro-Pro-Thr-DOPA-Lys(SEQ ID No:60);
Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-Tyr-Lys(SEQ ID No:61);
Ala-Lys-Pro-Ser-DOPA-Pro-Pro-Thr-DOPA-Lys(SEQ ID No:62);
Ala-Lys-Pro-Ser-Tyr-Pro-Thr-Tyr-Pro-Lys(SEQ ID No:63);
Ala-Lys-Pro-Ser-Tyr-Pro-Thr-DOPA-Pro-Lys(SEQ ID No:64);
Ala-Lys-Pro-Ser-DOPA-Pro-Thr-Tyr-Pro-Lys(SEQ ID No:65);
Ala-Lys-Pro-Ser-DOPA-Pro-Thr-DOPA-Pro-Lys(SEQ ID No:66);
Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-Tyr-Lys(SEQ ID No:67);
Ala-Lys-Pro-Ser-Tyr-Pro-Hyp-Thr-DOPA-Lys(SEQ ID No:68);
Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-Tyr-Lys(SEQ ID No:69);
Ala-Lys-Pro-Ser-DOPA-Pro-Hyp-Thr-DOPA-Lys(SEQ ID No:70);
Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-Tyr-Lys(SEQ ID No:71);
Ala-Lys-Pro-Ser-Tyr-Hyp-Pro-Thr-DOPA-Lys(SEQ ID No:72);
Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-Tyr-Lys(SEQ ID No:73);或
Ala-Lys-Pro-Ser-DOPA-Hyp-Pro-Thr-DOPA-Lys(SEQ ID No:74)。
16.根据前述权利要求中任一项所述的化合物,其用于人类或动物医药。
17.根据权利要求1至15中任一项所述的化合物,其用作药物。
18.一种药物配制品,所述药物配制品包含根据权利要求1至15中任一项所述的化合物和药学上或化妆品可接受的佐剂、稀释剂或载体。
19.根据权利要求18所述的药物配制品,所述药物配制品适合于、适于和/或包装并且呈现用于外用施用,其中所述药学上或化妆品可接受的佐剂、稀释剂或载体是外用佐剂、稀释剂或载体。
20.根据权利要求18或19所述的药物配制品,所述药物配制品呈凝胶、喷雾剂、乳膏、软膏或干粉的形式。
21.根据权利要求18至20中任一项所述的药物配制品,所述药物配制品还包含另一种抗炎剂,或已知产生作为副作用的炎症的药剂。
22.一种试剂盒,所述试剂盒包括以下组分:
(A)根据权利要求18至20中任一项所述的药物配制品;以及
(B)包含与药学上可接受的佐剂、稀释剂或载体混合的另一种抗炎剂或已知产生作为副作用的炎症的药剂的药物配制品,
所述组分(A)和(B)各自以适合于与彼此联合施用的形式提供。
23.根据权利要求1至15中任一项所述的化合物、根据权利要求18至21中任一项所述的配制品、或根据权利要求22所述的试剂盒,其用于治疗炎症、炎性障碍、和/或以炎症为特征的障碍。
24.根据权利要求1至15中任一项所述的化合物、根据权利要求18至21中任一项所述的配制品、或根据权利要求22所述的试剂盒用于制造治疗炎症、炎性障碍、和/或以炎症为特征的障碍的药剂的用途。
25.一种治疗炎症、炎性障碍、和/或以炎症为特征的障碍的方法,所述方法包括向需要这种治疗的患者施用根据权利要求1至15中任一项所述的化合物、根据权利要求18至21中任一项所述的配制品、或根据权利要求22所述的试剂盒。
26.根据权利要求23所述的用于所述用途的化合物、配制品或试剂盒,根据权利要求24所述的用途,或根据权利要求25所述的方法,其中所述以炎症为特征的障碍是伤口或烧伤或导致伤口或烧伤。
27.根据权利要求26所述的用于所述用途的化合物、配制品或试剂盒,用途或方法,其中导致伤口的所述障碍是痔疮或溃疡性结肠炎。
28.根据权利要求16至27中任一项所述的用于所述用途的化合物、配制品或试剂盒,用途或方法(视情况而定),其中将所述一种或多种化合物或其盐以外用配制品的形式外用施用。
29.根据权利要求28所述的用于所述用途的化合物、配制品或试剂盒,用途或方法,其中通过向皮肤直接外用施用的方式来治疗相关病症。
30.根据权利要求28所述的用于所述用途的化合物、配制品或试剂盒,用途或方法,其中通过向粘膜表面直接外用施用的方式来治疗相关病症。
31.根据权利要求16至30中任一项所述的用于所述用途的化合物、配制品或试剂盒,用途或方法(视情况而定),其中将所述一种或多种化合物通过口服、静脉内、皮肤或皮下、经鼻、肌内、腹膜内、经肺或经肛门直肠递送来施用。
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