CN1370181A - 局部使用的新的二肽基肽酶iv效应物 - Google Patents
局部使用的新的二肽基肽酶iv效应物 Download PDFInfo
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- CN1370181A CN1370181A CN00811936A CN00811936A CN1370181A CN 1370181 A CN1370181 A CN 1370181A CN 00811936 A CN00811936 A CN 00811936A CN 00811936 A CN00811936 A CN 00811936A CN 1370181 A CN1370181 A CN 1370181A
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Abstract
本发明涉及通式(I)的化合物,其中A是侧链中具有至少一个官能团的氨基酸;而B是与A的侧链中的官能团共价结合的化合物,即,除由至多6个甘氨酸单体组成的甘氨酸均聚物之外的链长为至多20个氨基酸的寡肽或摩尔质量为至多20000g/mol的聚乙二醇;C是与A酰胺键合的噻唑烷、吡咯烷、氰基吡咯烷、羟脯氨酸、脱氢脯氨酸或哌啶基。这些化合物可用于局部影响二肽基肽酶IV的活性。
Description
本发明涉及新的二肽基肽酶IV效应物。这些效应物可用于靶向影响限于局部的病理生理和生理过程(炎症、趋化性、自身免疫疾病、伤口愈合),其中通过效应物(特别是底物、假底物、抑制剂、抗体、结合蛋白、结合拮抗剂、结合激动剂)影响二肽基肽酶IV和具有相似或相同活性的酶和具有相关一级结构的蛋白质(例如FAP,成纤维细胞激活蛋白(Fibroblast Activation Protein)(Levy等,1999))的酶活性和结合活性。
除了在最终导致蛋白质破坏成氨基酸的非特异性蛋白水解中涉及的蛋白酶之外,调节蛋白酶是已知的,它们参与内源肽活性物质的官能作用(激活、失活、修饰)(Kirschke等,1995)(Krusslich和Wimmer,1987)。特别是在免疫学研究和神经肽研究中,已发现许多所谓的转化酶、信号肽酶或脑啡肽酶(Gomez等,1998)(Ansorge等,1991)。
因为在许多肽类激素中经常存在氨基酸脯氨酸和因为那些肽类的相关结构性质,所以讨论脯氨酸特异性肽酶类似于信号肽酶的功能(Yaron和Naider,1993);(Vanhoof等,1995)。由于其特定结构,那些肽中的脯氨酸确定了那些肽的构象和稳定性,使之免遭非特异性蛋白酶的破坏(Kessler,1982)。相反,对于目前的活性物质研究来说,以高特异性、结构修饰方式作用于含脯氨酸序列(特别是HIV蛋白酶、亲环蛋白)的酶是有吸引力的目标。尤其是,对于在脯氨酸之后裂解的肽酶脯氨酰内肽酶(PEP)和二肽基肽酶IV(DP IV)来说,有可能得出结论:在天然肽底物的生物学活性的修饰及其被那些酶选择性裂解之间可能存在关联。因此认为在免疫应答期间,PEP参与的学习和记忆过程,信号传输涉及DP IV(Ishiura等,1989);(Hegen等,1990)。
在血流和几乎所有器官中均发现DP IV活性和类DP IV活性(例如,溶酶体DP II的底物特异性几乎等同于DP IV的),当生物学活性肽序列含有与N-末端氨基酸相邻的脯氨酸或丙氨酸残基时,该活性在血流和几乎所有器官中高度特异性地从该生物学活性肽的N-末端裂解二肽。因此认为在体内调节多肽的生物学活性中涉及该酶(Vanhoof等,1995)。
最近已证明一系列趋化因子(特别是RANTES、SDF-1α、MDC、eotaxin)是DP IV的底物,通过DP IV调节它们的功能(Proost等,1998;Proost等,1998;Proost等,1999);(Shioda等,1998)。由于其趋化作用,趋化因子基本上在局部免疫过程如自身免疫过程、炎症和伤口愈合的调节中被涉及(Nelson和Krensky,1998)。在最近的工作中,我们已能证明生物学活性肽在P1-位置上具有丝氨酸或苏氨酸(胰高血糖素、VIP、PACAP),而且还是DP IV的底物。
在皮肤中的神经元、免疫和血管活性过程的调节中涉及一系列生物学活性DP IV底物(特别是物质P、促生长素抑制素、VIP、PACAP)(Scholzen等,1998);(Wallengren,1997)。因此,在调节胃肠道、免疫和神经活性肽的活性方面,二肽基肽酶IV代表重要的调控中心,因此它是令人感兴趣的治疗靶(Augustyns等,1999)。然而,信号级联的精确细节尚未得到充分阐明。
已更详细地了解DP IV在血糖调节中的作用。由于有限的蛋白水解,肠降血糖素GIP1-4和GLP7-37失活。通过延长肠降血糖素的活性和增加胰岛素的释放,血浆DP IV活性的抑制导致血糖水平正常化(Demuth等,1996;Pauly等,1999;Pauly等,1996)。
DP IV在免疫系统中的作用尚未得到充分阐明。它是T淋巴细胞的激活标志和腺苷脱氨酶的受体。在细胞培养物中和体内使用DPIV抑制剂具有免疫抑制作用(Ansorge等,1995;Reinhold等,1997;Kubota等,1992)。使用抗CD26的单克隆抗体,已获得对细胞内信号级联(Ca2+流入、激酶活化)的激活作用,有时与酶的酶活性无关(Hegen等,1993;Kameoka等,1995;Tanaka等,1993;Khne等,1995)。
衍生于物质P的N-末端序列的赖氨酰-脯氨酰类似物显示促进伤口愈合的作用,这归因于与物质P类似的结构。相反,全身使用不可逆的DP IV抑制剂导致抑制伤口愈合(Buntrock等,1998;Kohl等,1991;Kohl等,1989)。
除了将DP IV抑制剂用于使血糖正常化之外,至今DP IV抑制剂还被全身使用以治疗动物模型的关节炎。
在关节炎患者和动物关节炎模型中,已观察到DP IV活性的降低(Küllertz和Boigk,1986(Fujita等,1992))。尤其是,由于口服或皮下给予全身作用的DP IV抑制剂,在动物模型中实现了抑制烷基二胺诱导的关节炎(Tanaka等,1997;Tanaka等,1998)。
使用DP IV抑制剂,还获得了对其它自身免疫疾病的作用。例如,由于DP IV抑制,可能实现抑制髓磷脂碱性蛋白特异性T细胞克隆的增殖(Reinhold等,1998)。
在各种皮肤病(银屑病、扁平苔癣)和致癌的皮肤病中,可能证明在角质形成细胞和成纤维细胞中DP IV活性增加(Novelli等,1996)(Raynaud等,1992)。成纤维细胞激活蛋白与DP IV密切相关,其与DP IV有约50%序列同源性,其可能与Pineiro-Sanchez等,1997所描述的seprase相同,成纤维细胞激活蛋白也通过失活的上皮癌成纤细胞以更高程度表达并愈合伤口(Niedermeyer等,1998)。
由于蛋白在人体中的广泛分布和涉及DP IV、DP IV活性和DPIV相关蛋白的各种机理,用DP IV抑制剂进行的全身治疗(肠内或非胃肠给药)可能导致一系列不期望的副作用。例如,DP IV抑制剂的非胃肠或肠内给药将以调节或去调节的方式干扰葡萄糖代谢。
现已可能证明酶二肽基肽酶IV的侧链修饰的底物可被酶识别并以与未修饰的底物相同的方式被裂解(DEMUTH,H.-U.,HEINS,J.,1995)。
例如,现已可能表明磷酸化二肽-(B)-对硝基酰苯胺[KASPARI,A.等,1996]是DP IV、DP IV抑制剂的底物,例如Glu(Gly)-Thia或Lys(Z-NO2)-Thia[REINHOLD,D.等,1998]被完全转运。
本发明要解决的问题在于制备可靶向影响限于局部的病理生理和生理过程的化合物。本发明的问题特别在于得到DP IV或DP IV类似物活性的限于局部的抑制,其目的是对局部活性肽激素活性的调节进行靶向干扰。
通过提供通式
的化合物解决本发明的问题:其中A是侧链中具有至少一个官能团的氨基酸,B是与A的侧链中的至少一个官能团共价结合的化合物,即- 链长为至多20个氨基酸的寡肽,除了由至多6个甘氨酸单体组成的甘氨酸均聚物之外,或- 摩尔质量为至多20000g/mol的聚乙二醇,C是与A酰胺键合的噻唑烷、吡咯烷、氰基吡咯烷、羟脯氨酸、脱氢脯氨酸或哌啶基。
根据本发明,特别地提供至少一种药物组合物,其包含
至少一种通式
的化合物和至少一种适用于作用部位的常规辅剂,其中A是氨基酸,优选为α-氨基酸,特别是侧链中具有至少一个官能团的天然α-氨基酸,优选是苏氨酸、酪氨酸、丝氨酸、精氨酸、赖氨酸、天冬氨酸、谷氨酸或半胱氨酸,B是与A的侧链中的至少一个官能团共价结合的化合物,即链长为至多20个氨基酸的寡肽,摩尔质量为至多20000g/mol的聚乙二醇,具有8至50个碳原子的任选地取代的有机胺、酰胺、醇、酸或芳族化合物,C是与A酰胺键合的噻唑烷、吡咯烷、氰基吡咯烷、羟脯氨酸、脱氢脯氨酸或哌啶基。
而且,这种化合物或药物组合物用于局部影响,特别是降低二肽基肽酶IV或类似酶的活性。
说明书和权利要求书中的术语“烷基”可以指C1-50烷基,优选是C6-30烷基,特别是C8-12烷基;例如,烷基可以是甲基、乙基、丙基、异丙基或丁基;
术语“烷”,例如术语“烷氧基”中的“烷”,以及术语“烷酰基”中的术语“烷”均定义为“烷基”。
芳族化合物优选是取代的或任选地未取代的苯基、苄基、萘基、联苯基或蒽基,它们优选具有至少8个碳原子;
术语“链烯基”可以指C2-10链烯基,优选为C2-6链烯基,它们在任何期望位置具有双键并可以是取代的或未取代的;
术语“炔基”可以指C2-10炔基,优选为C2-6炔基,它们在任何期望位置具有三键并可以是取代的或未取代的;
术语“取代的”或取代物可以指任何期望的被一个或多个,优选一个或两个烷基、链烯基、炔基、单或多价酰基、烷酰基、烷氧烷酰基或烷氧烷基取代;因此前述取代物可以具有一个或多个(但优选零个)作为侧基的烷基、链烯基、炔基、单或多价酰基、烷酰基、烷氧烷酰基或烷氧烷基;
各自具有8至50个碳原子,优选10至20个碳原子的有机胺、酰胺、醇或酸可以具有如下分子式:(烷基)2N-或烷基-NH-,-CO-N(烷基)2或-CO-NH(烷基),-烷基-OH或-烷基-COOH。
尽管有延长的侧链官能团,但本发明的化合物仍然可以与酶二肽基肽酶IV和类似酶的活性中心结合,但不再被肽转运蛋白Pep T1活性转运。所得的降低的或大大限制的本发明化合物的可转运性,以理想的方式,导致DP IV和类似酶的局部抑制。
本发明的化合物或根据本发明所使用的化合物可以分别以外消旋体的形式或纯的光学异构体化合物的形式,相对于A优选以L-苏型或L-别型(L-allo)的形式存在或使用[此处是否不应读成A?]。
因此,通过局部给予特异性DP IV抑制剂以局部干扰肽的调节,由于仅仅发生限于局部的DP IV活性抑制,所以有可能避免由肠内或非胃肠给予DP IV抑制剂所引起的全身副作用。因为避免了化合物的快速全身分布,所以在很大程度上不影响全身调节过程或在其它组织中的调节过程。
通过延长/扩展侧链修饰,例如多于七个碳原子,从而根据本发明有可能获得可转运性的显著降低(表1)。表1的实施例清楚地表明,随着侧链空间大小的增加,物质的可转运性降低。通过侧链的空间和立体扩展,例如大于单取代的苯基、羟胺基或氨基酸残基的原子基团大小,根据本发明有可能修饰或抑制靶物质的可转运性。
因此,可能以有差别的方式影响活体中的DP IV活性。
因此,一方面,通过本发明,可能实现抑制剂在所治疗的组织中的有效作用,另一方面,通过限于局部,也就是说局部给予DP IV抑制剂,可能在很大程度上避免抑制剂的全身作用。因此,有可能有效地影响局部的生理和病理生理过程(炎症、银屑病、关节炎、自身免疫疾病、变态反应),且几乎没有副作用。
本发明得到下述事实的支持:· 肠内或非胃肠,也就是说口服和静脉内或皮下给予的DP IV抑
制剂全身分布,并抑制全身的DP IV及类似活性。· 但是,在调节局部信号级联(趋化性、炎症、神经传递)中涉及
一系列DP IV的生物学活性肽底物。· 本发明的侧链修饰的DP IV抑制剂令人惊奇地显示高的抑制能
力,但几乎不或根本不被吸收和转运,因此不导致显著的全身作
用。
因此本发明提供新的DP IV抑制剂和在体内应用DP IV抑制剂的新方法。这种抑制剂可以通过化学修饰和/或配方而与使用类型相适应。例如,通过在侧链上的体积大的亲水性取代基使全身分布困难或防止全身分布。
可以在药物和化妆品制剂中给予该抑制剂。
局部使用包括通过以下方式局部使用抑制剂:用软膏、乳膏或化妆品直接施用到待治疗的组织(例如皮肤、伤口、肿瘤)上,和用含效应物的药贴、敷料等的间接施用,以滴剂、喷雾剂或吸入剂等的形式间接施用在身体的部分(嘴、鼻、耳、眼睛、肺)上,直接注射入待治疗的组织或注射到待治疗的组织附近,以及植入含效应物的材料。局部使用进一步包括口服或肛门给予非吸收或不易吸收的二肽基肽酶IV或类DP IV序列的效应物,其目的是选择性影响胃肠DP IV。
根据本发明,特别地使用的化合物是其中链长为3至15,特别是4至10个氨基酸的寡肽,和/或摩尔质量至少为250g/mol,优选至少为1500g/mol至15000g/mol的聚乙二醇,和/或具有至少12个碳原子且优选至多30个碳原子的任选地取代的有机胺、酰胺、醇、酸或芳族化合物。而且,本发明公开了药物和化妆品组合物,其包含至少一种本发明的化合物,任选地与本领域的常规载体或辅剂组合。
本发明的化合物或药物或化妆品组合物可用于局部影响二肽基肽酶IV或类似酶的活性,特别是用于预防或治疗皮肤病或粘膜病、自身免疫疾病和炎症如银屑病、变态反应、关节炎、肿瘤或自身免疫疾病。
该化合物和药物或化妆品组合物可以软膏、乳膏、化妆品、药贴、敷料、滴剂、喷雾剂、吸入剂、植入物或注射溶液的形式配方并使用。
本发明所使用的辅剂是本领域已知的。
因此,本发明涉及二肽基肽酶IV和类DP IV酶活性和类DP IV蛋白的效应物的局部使用。局部使用可以局部修饰前述高度特异性的酶的活性,所述酶在生物学活性肽(特别是趋化因子、物质P、VIP、PHM、PACAP、生长因子)的失活和活化关键性地被涉及。
因此,在局部免疫过程中的靶向干扰是可能的,有效的和靶向治疗与其相关的病理生理和生理过程(银屑病、牙周炎、关节炎、变态反应、炎症)也是可能的。本发明使简单地和高局部浓度地使用抑制剂成为可能。
作为相应效应物的低全身负荷的结果,避免了对肠降血糖素系统或全身免疫应答的影响。
实施例实施例1:侧链修饰的谷氨酰噻唑烷作为不易转运的DP IV抑制剂的作用
合成具有结构H-Glu(X)-Thia的侧链修饰的谷氨酰噻唑烷,其中将各种链长的聚乙二醇或甘氨酸寡聚体用作X(参见描述合成的方法A)。研究那些衍生物的结合特性及它们被肽转运蛋白PepT1的可转运性,并测定相对于DP IV的Ki值(表1)。
令人惊奇地发现,侧链修饰仅轻微程度地改变与化合物的结合特性。相反,该抑制剂被肽转运蛋白转运的能力通过侧链修饰得到显著地降低。
所述DP IV抑制剂因此特别适于在体内实现DP IV的限于局部的抑制。表1:所选择的DP IV抑制剂的可转运性和抑制常数
1使3H-D-Phe-Ala(80mM)与表达PepT1的P.pastoris细胞的结合抑制至50%的化合物有效浓度(EC50值)2X.leavis的表达PepT1卵母细胞的转运特性-通过两个电极电压钳方法,I=转运所产生的内部电流3实施例的化合物对纯化的肾DP IV的竞争性抑制的抑制常数4不可检测实施例2:口服给予DP IV抑制剂对血清DP IV活性的影响
化合物氨基酸噻唑烷 | EC50(mM)1 | Imax(nA)2 | Ki(mol/l)3 |
H-Ile-ThiaH-Glu-Thia | 0.981.1 | 25±835±13 | 1.3e-7±11.1%6.1e-7±11.4% |
侧链修饰的谷氨酰噻唑烷 | |||
H-Gly(NHOH)-ThiaH-Glu(Gly3)-ThiaH-Glu(Gly5)-ThiaH-Glu(PEG)-Thia | 3.188.54>10>10 | 42±11n.d.4n.d.4n.d.4 | 1.7e-6±8.6%1.92e-7±8.4%9.93e-8±11.4%3.11e-6±9.8% |
研究在健康Wistar大鼠中,口服给予侧链修饰的DP IV抑制剂(5μM/300mg大鼠)后和口服给予未修饰的抑制剂相比,血浆DP IV的抑制(全身作用)。
尽管抑制剂具有与DP IV近似相等的Ki值(表1),但总的来说,新的侧链修饰的抑制剂对血浆DP IV的抑制慢得多且程度较低。这意味着在肠内更不易吸收或根本不吸收抑制剂。特别地,在Glu(Gly)5-Thia的情况下,没有可检测到的口服给予活性成分的全身作用。
因此,那些抑制剂可以用作合成新的且不产生全身作用的可局部给予的DP IV抑制剂的基本结构。实施例3:合成侧链修饰的DP IV抑制剂3.1合成Boc-Glu-Thia
根据方法B(方法参见3.4节)的Boc-Glu(OMe)-OH与Thia*HCl的反应,根据方法G的Boc-Glu(OMe)-Thia的水解。表2 Boc-Glu-Thia的分析数据
1薄层色谱系统A:氯仿/甲醇90∶10系统B:苯/丙酮/乙酸25∶10∶0.5系统C:正丁醇/EA/乙酸/水1∶1∶1∶12HPLC分离条件柱子:Nucleosil C-18,7μ250mm×21mm洗脱剂:恒溶剂洗脱,40%ACN/水/0.1%TFA流速:6ml/分λ=220nm3.2侧链修饰的Boc-谷氨酰噻唑烷
化合物 | 实验式Mr合成方法收率 | MS[M+H]+TLC:Rf/系统m.p. | [α]20D浓度溶剂 | 元素分析(计算/实际)% | HPLCRt[min]/系统 |
Boc-Glu-Thia | C13H22N2O5S318.38B+G62% | 319.50.52/A10.42/B1115-118℃ | -3.1c=1甲醇 | C:49.04/48.89H:6.96/6.82N:8.80/8.59 | 13.93/A2 |
通过引入各种大小的游离基,在γ-羧酸官能团处修饰Boc-Glu-Thia。游离基通过它们的氨基形成结合于γ-羧酸官能团的酰胺而偶联,取决于自由基的不同而使用各种偶联方法。
使用所述方法,使下述氨基成分连接于Boc-Glu-Thia:
氨基成分 | 偶联方法(参见3.4节) | 收率 |
聚乙二醇胺(Mr≈8000) | C | 93% |
H-Gly-Gly-Gly-OH | D+E | 49% |
H-Gly-Gly-Gly-Gly-Gly-OH | D+E | 86% |
在2情况下,反应产物的纯化不同于合成的一般描述。Boc-Glu(Gly5)-Thia
搅拌过夜,产物从混合物中沉淀出;随后过滤之并用0.1N HCl和大量水洗涤。接着在真空下用P4O10干燥之。Boc-Glu(PEG)-Thia
与一般过程相反,将用于合成的起始物质溶于500倍过量的DMF中。反应完成后,在真空下完全除去DMF,并将残余物溶于大量甲醇中。在倾入醚后形成上层,产物与未反应的PEG一起沉淀出。在凝胶过滤柱(Pharmazia,Sephadex G-25,90μm,260mm-100mm)上,通过制备HPLC分离进行精细纯化。
分离条件:洗脱剂:水;流速:5ml/min;λ=220nm表3:侧链修饰的Boc-谷氨酰噻唑烷的合成数据
2HPLC分离条件柱子:Nucleosil C-18,7μ,250mm×21mm洗脱剂:无梯度,40%ACN/水/0.1%TFA流速:6ml/minλ=220nm3.3.侧链修饰的谷氨酰噻唑烷
化合物 | 实验式Mr收率 | MS[M+H]+TLC/Rf/系统m.p. | [α]20D浓度溶剂 | 元素分析(计算/实际)% | HPLCRt[min]/系统 |
Boc-Glu(Gly3)-Thia | C19H31N5O8S489.5449% | 490.5 | C:46.62H:6.38N:14.31 | ||
Boc-Glu(Gly5)-Thia | C23H37N7O10S603.6486% | 604.50.09/C202℃开始分解 | n.dm. | C:45.76/45.60H:6.18/6.11N:16.24/16.56 | 11.93/A2 |
Boc-Glu(PEG)-Thia | 93% | ≈8000(质量集中)52-53℃ | n.dm. | n.dm. | n.dm. |
使用方法F将N-末端Boc保护基从表3所列的化合物裂解下来。通过制备HPLC分离纯化用Gly衍生物修饰的物质,该物质以三氟乙酸盐的形式存在。以与Boc保护的前体相同的方式,在凝胶过滤柱上纯化H-Glu(PEG)-Thia。表4:侧链修饰的谷氨酰噻唑烷的合成数据
3 HPLC分离条件柱子:Nucleosil C-18,7μ,250mm×21mm洗脱剂:ACN/水/0.1%TFA梯度:30分钟内20%ACN→90%ACN流速:6ml/minλ=220nmn.dm.-未检测或不可检测3.4一般合成步骤方法A:使用CFIBE作为活化剂,通过混合酸酐方法进行的肽键连接
化合物 | 实验式Mr收率 | MS[M+H]+TLC/Rf/系统m.p. | [α]20D浓度溶剂 | 元素分析(计算/实际)% | HPLCRt[min]/系统 |
H-Glu(Gly3)-Thia*TFA | C16H24N5O8SF3503.4594% | 503.450.32/C91-94℃ | =4.1c=1甲醇 | C:38.17/37.56H:4.80/4.78N:13.91/13.43 | 7.84/C3 |
H-Glu(Gly5)-Thia*TFA | C20H30N7O10SF3617.5598% | 617.550.25/C105-107℃ | n.dm. | C:38.90/38.82H:4.90/4.79N:15.88/15.39 | 8.22/C3 |
H-Glu(PEG)-Thia*HCl | 92% | ≈8000(质量集中) | n.dm. | n.dm. | n.dm. |
将10mmol N-端保护的氨基酸或肽溶于20ml无水THF中。将溶液冷却到-15℃±2℃。在各例中在搅拌下逐步加入10mmolN-MM和10mmol氯甲酸异丁酯,严格遵守所述的温度范围。约6分钟后,加入10mmol氨基成分。当氨基成分是盐时,接着向反应混合物中进一步加入10mmol N-MM。然后将反应混合物在冷态下搅拌2小时并在室温下搅拌过夜。
使用旋转蒸发仪浓缩反应混合物,在EA中收集,用5%KH2SO4溶液、饱和NaHCO3溶液和饱和NaCl溶液洗涤,并用Na2SO4干燥。真空除去溶剂之后,在EA/戊烷中重结晶该化合物。方法B:使用新戊酰氯作为活化剂,通过混合酸酐方法进行的肽键连接
将10mmol N-端保护的氨基酸或肽溶于20ml无水THF中。将溶液冷却到0℃。在各例中,在搅拌下逐步加入10mmolN-MM和10mmol新戊酰氯,严格遵守所述的温度范围。约6分钟后,将混合物冷却到-15℃,一达到更低的温度后,就加入10mmol氨基成分。当氨基成分是盐时,接着向反应混合物中进一步加入10mmol N-MM。然后将反应混合物在冷态下搅拌2小时并在室温下搅拌过夜。
按方法A进行进一步的操作。方法C:使用TBTU作为活化剂进行的肽键连接
将10mmol N-端保护的氨基酸或肽和10mmol C-端保护的氨基酸成分溶于20ml无水THF中。将溶液冷却到0℃。在各例中在搅拌下逐步加入10mmol DIPEA和10mmol TBTU,将反应混合物在0℃下搅拌1小时接着在室温下搅拌过夜。在真空下完全除去DMF并按方法A所述对产品进行操作。方法D:合成活性酯(N-羟基琥珀酰亚胺酯)
将10mmol N-端保护的氨基酸或肽和10mmol N-羟基琥珀酰亚胺溶于20ml无水THF中。将溶液冷却到0℃,并在搅拌下加入10mmol二环己基碳二酰亚胺。将反应混合物在0℃下进一步搅拌2小时接着在室温下搅拌过夜。过滤所得到的N,N′-二环己基脲,在真空下除去溶剂并从EA/戊烷中重结晶残留的产物。方法E:使用N-羟基琥珀酰亚胺酯进行的酰胺键连接
将10mmol C-端未保护的氨基成分引入到NaHCO3溶液(20mmol溶于20ml水中)中。室温下,在搅拌下缓慢地逐滴加入溶于10ml二噁烷的10mmol N-端保护的N-羟基琥珀酰亚胺酯。继续搅拌反应混合物过夜并在真空下除去溶剂。
按方法A进行进一步的操作。方法F:Boc保护基的裂解
向1mmol Boc-保护的氨基酸吡咯酰胺(pyrrolidide)、噻唑酰胺(thiazolidide)或肽中加入3ml 1.1N HCl/冰醋酸(方法F1)或3ml 1.1N HCl/二噁烷(方法F2)或3ml 50%溶于DCM的TFA(方法F3)。通过TLC监控室温下的裂解。反应完成后(约2小时),使用无水乙醚以盐酸盐的形式沉淀出化合物,抽滤分离该化合物并在真空下用P4O10干燥之。使用甲醇/醚重结晶或再沉淀该产物。方法G:水解
将1mmol肽甲酯溶于10ml丙酮和11ml 0.1M NaOH溶液中并在室温下搅拌。通过TLC监控水解进程。反应完成后,真空下除去丙酮。使用浓KH2SO4溶液酸化残留的水溶液,直到pH达到2-3。接着用EA提取产物数次;用饱和NaCl溶液洗涤合并的乙酸乙酯部分并用Na2SO4干燥之,真空下除去溶剂。用EA/戊烷进行结晶。
图1:
显示每300g大鼠(n=2)口服给予5μmol抑制剂后,血浆DPIV活性的百分抑制随时间的进程。
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Claims (27)
2.权利要求1的化合物,其特征在于A是α-氨基酸。
3.前述权利要求之一的化合物,其特征在于A是天然α-氨基酸。
4.前述权利要求之一的化合物,其特征在于氨基酸是苏氨酸、酪氨酸、丝氨酸、精氨酸、赖氨酸、天冬氨酸、谷氨酸或半胱氨酸。
5.前述权利要求之一的化合物,其特征在于寡肽的链长为3至15个氨基酸。
6.前述权利要求之一的化合物,其特征在于寡肽是均聚物、共聚物或嵌段共聚物。
7.前述权利要求之一的化合物,其特征在于聚乙二醇的摩尔质量至少为250g/mol。
8.前述权利要求之一的化合物,其特征在于C是噻唑烷、吡咯烷、氰基吡咯烷基。
9.药物组合物,其包含前述权利要求之一的化合物,任选地与本领域的常规载体或辅剂组合。
10.化妆品组合物,其包含权利要求1至8之一的化合物,任选地与本领域的常规载体或辅剂组合。
11.至少一种前述权利要求之一的化合物或药物或化妆品组合物用于局部影响二肽基肽酶IV或类似酶的活性的用途。
12.至少一种权利要求1至10之一的化合物或药物或化妆品组合物用于预防或治疗皮肤病或粘膜病、自身免疫疾病和炎症的用途。
13.至少一种权利要求1至10之一的化合物或药物或化妆品组合物用于预防或治疗炎症、银屑病、变态反应、关节炎、肿瘤或自身免疫疾病的用途。
14.软膏、乳膏、化妆品、药贴、敷料、滴剂、喷雾剂、吸入剂、植入物或注射溶液形式的至少一种权利要求1至10之一的化合物或药物或化妆品组合物的用途。
16.权利要求15的药物组合物,其特征在于A是α-氨基酸。
17.权利要求15或16的药物组合物,其特征在于A是天然α-氨基酸。
18.权利要求15至17之一的药物组合物,其特征在于氨基酸是苏氨酸、酪氨酸、丝氨酸、精氨酸、赖氨酸、天冬氨酸、谷氨酸或半胱氨酸。
19.权利要求15至18之一的药物组合物,其特征在于寡肽的链长为3至15个氨基酸。
20.权利要求15至19之一的药物组合物,其特征在于寡肽是均聚物、共聚物或嵌段共聚物。
21.权利要求15至20之一的药物组合物,其特征在于聚乙二醇的摩尔质量至少为250g/mol。
22.权利要求15至21之一的药物组合物,其特征在于C是噻唑烷、吡咯烷或氰基吡咯烷基。
23.权利要求15至22之一的药物组合物,其特征在于其以软膏、乳膏、化妆品、药贴、敷料、滴剂、喷雾剂、吸入剂、植入物或注射溶液的形式使用。
24.权利要求15至23之一的药物组合物,其特征在于其与本领域的常规载体组合使用。
25.权利要求15至24之一的药物组合物用于局部影响二肽基肽酶IV或类似酶的活性的用途。
26.权利要求15至24之一的药物组合物用于预防或治疗皮肤病或粘膜病、自身免疫疾病和炎症的用途。
27.权利要求15至24之一的药物组合物用于预防或治疗炎症、银屑病、牙周炎、变态反应、关节炎、肿瘤或自身免疫疾病的用途。
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DE19940130.6 | 1999-08-24 | ||
DE19940130A DE19940130A1 (de) | 1999-08-24 | 1999-08-24 | Neue Effektoren der Dipeptidyl Peptidase IV zur topischen Anwendung |
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EP (2) | EP1206485B1 (zh) |
JP (1) | JP2003519099A (zh) |
KR (1) | KR20020040787A (zh) |
CN (1) | CN1370181A (zh) |
AT (1) | ATE357455T1 (zh) |
AU (1) | AU769404B2 (zh) |
BR (1) | BR0013577A (zh) |
CA (1) | CA2379875A1 (zh) |
DE (2) | DE19940130A1 (zh) |
ES (1) | ES2282130T3 (zh) |
IL (1) | IL148170A0 (zh) |
MX (1) | MXPA02001800A (zh) |
NO (1) | NO20020858D0 (zh) |
NZ (1) | NZ528770A (zh) |
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1999
- 1999-08-24 DE DE19940130A patent/DE19940130A1/de not_active Withdrawn
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2000
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- 2000-08-20 JP JP2001518409A patent/JP2003519099A/ja not_active Withdrawn
- 2000-08-20 CA CA002379875A patent/CA2379875A1/en not_active Abandoned
- 2000-08-20 EP EP00953186A patent/EP1206485B1/de not_active Expired - Lifetime
- 2000-08-20 ES ES00953186T patent/ES2282130T3/es not_active Expired - Lifetime
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- 2000-08-20 EP EP07104464A patent/EP1792910A2/de not_active Withdrawn
- 2000-08-20 KR KR1020027002338A patent/KR20020040787A/ko not_active Application Discontinuation
- 2000-08-20 PT PT00953186T patent/PT1206485E/pt unknown
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- 2002-02-22 US US10/082,001 patent/US6949515B2/en not_active Expired - Fee Related
- 2002-02-22 NO NO20020858A patent/NO20020858D0/no not_active Application Discontinuation
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008119208A1 (fr) * | 2007-04-03 | 2008-10-09 | Beijing Molecule Science And Technology Co., Ltd. | Dérivés de thiomorpholine substitués en n en tant qu'inhibiteurs de la dipeptidyl peptidase iv et leurs utilisations pharmaceutiques |
CN101279955B (zh) * | 2007-04-03 | 2012-11-28 | 北京摩力克科技有限公司 | 作为二肽肽激酶-iv抑制剂的n-取代硫吗啉衍生物及其医药用途 |
CN110607336A (zh) * | 2019-10-17 | 2019-12-24 | 江南大学 | 酶催化制备半胱氨酸寡肽及其膜敷料的制备方法 |
CN110607336B (zh) * | 2019-10-17 | 2024-01-26 | 江南大学 | 酶催化制备半胱氨酸寡肽及其膜敷料的制备方法 |
Also Published As
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US6949515B2 (en) | 2005-09-27 |
CA2379875A1 (en) | 2001-03-01 |
WO2001014318A3 (de) | 2001-11-01 |
US20030092630A2 (en) | 2003-05-15 |
EP1792910A2 (de) | 2007-06-06 |
ATE357455T1 (de) | 2007-04-15 |
KR20020040787A (ko) | 2002-05-30 |
US20020165164A1 (en) | 2002-11-07 |
NO20020858L (no) | 2002-02-22 |
DE50014187D1 (de) | 2007-05-03 |
MXPA02001800A (es) | 2003-09-25 |
DE19940130A1 (de) | 2001-03-01 |
US20050209159A1 (en) | 2005-09-22 |
BR0013577A (pt) | 2002-04-30 |
EP1206485A2 (de) | 2002-05-22 |
PT1206485E (pt) | 2007-05-31 |
US7335645B2 (en) | 2008-02-26 |
NZ528770A (en) | 2005-02-25 |
WO2001014318A2 (de) | 2001-03-01 |
ZA200200794B (en) | 2003-03-26 |
ES2282130T3 (es) | 2007-10-16 |
NO20020858D0 (no) | 2002-02-22 |
JP2003519099A (ja) | 2003-06-17 |
AU769404B2 (en) | 2004-01-29 |
AU6572100A (en) | 2001-03-19 |
IL148170A0 (en) | 2002-09-12 |
EP1206485B1 (de) | 2007-03-21 |
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