CN1346344A - 取代的2-氨基苯甲酰胺天冬氨酸特异性半胱氨酸蛋白酶抑制剂及其应用 - Google Patents
取代的2-氨基苯甲酰胺天冬氨酸特异性半胱氨酸蛋白酶抑制剂及其应用 Download PDFInfo
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Abstract
本发明涉及用通式(I)表示的新的2-氨基苯甲酰胺,其中R1-R3、X和A-D如本文定义。本发明还涉及发现了式(I)化合物是有效的天冬氨酸特异性半胱氨酸蛋白酶和编程性细胞死亡抑制剂。因此,本发明的抑制剂可阻止或阻断各种临床症状中的细胞死亡,在这些症状中,细胞、组织或整个器官可能会发生损失。
Description
发明的背景技术
发明领域
本发明涉及药物化学。具体地说,本发明涉及作为天冬氨酸特异性半胱氨酸蛋白酶抑制剂的取代的2-氨基苯甲酰胺和类似物。本发明还涉及这些2-氨基苯甲酰胺和类似物在减少或治疗类编程细胞死亡和/或减少白细胞介素1-β的生成中的应用。
背景技术的描述
有机体通过各种已知的方法如调节细胞死亡、程序化细胞死亡或编程性细胞死亡来消除不必要的细胞。这些细胞死亡的发生是动物体发育以及组织内环境稳定和成熟的正常方面(Glucksmann,A.,Biol.Rev.Cambridge Philos.Soc.26:59-86(1951);Glucksmann,A.,Archivesde Biologie 76:419-437(1965);Ellis等人,Dev.112:591-603(1991);Vaux等人,Cell 76:777-779(1994))。编程性细胞死亡可调节细胞的数目,促进形态发生,除去有害的或其它的异常细胞,以及消除已经完成其功能的细胞。另外,编程性细胞死亡是对各种生理应激反应如缺氧或缺血的响应(PCT申请公开WO96/20721)。
有一些能够体现调节细胞死亡的细胞所共有的形态变化,包括原生质和膜核出疱、细胞皱缩(核质和细胞质的皱缩)、细胞器的再定位和压紧、染色质皱缩和生成凋亡小体(含有细胞内物质的膜附着颗粒)(Orrenius,S.,J Internal Medicine,237:529-536(1995))。
通过细胞自杀的内源性机制可实现编程性细胞死亡(Wyllie,A.H.,inCell Death in Biology and Pathology,Bowen和Lockshin编辑,Chapmanand Hall(1981),pp.9-34)。由内部或外部的信号造成细胞可激活细胞自身编码的自杀程序。通过小心调节遗传程序的激活执行自杀程序(Wylie等人,Int.Rev.Cyt.68:251(1980);Ellis等人,Ann.Rev.CellBio.7:663(1991))。凋亡细胞和细胞体通常会在溶解之前被邻近的细胞和巨噬细胞识别和清除。尽管有大量的细胞需要清除,但是由于有此清除机制,因此不会引起炎症(Orrenius,S.,J.Internal Medicine,237:529-536(1995))。
哺乳动物白细胞介素-1β(IL-1β)在各种病理过程,包括慢性或急性炎症和自身免疫疾病中起着重要的作用(Oppenheim,J.H.等人Immunology Today,7,45-56(1986))。IL-1β是作为前体细胞多肽(前-IL-1β)被合成的,它不能与IL-1β受体结合,并且是非生物活性的(Mosley等人,J.Biol.Chem.,262:2941-2944(1987))。通过抑制IL-1β前体向成熟的IL-1β转化,可以抑制白细胞介素-1的活性。白细胞介素-1β转化酶(ICE)是负责活化白细胞介素-1B(IL-1β)的蛋白酶(Thornberry,N.A.,等人,Nature 356:768(1992);Yuan,J.,等人,Cell 75:641(1993))。ICE是特定底物的半胱氨酸蛋白酶,它可分裂非活性的白细胞介素-1前体以产生成熟的IL-1。ICE和CPP32的编码基因是哺乳动物ICE/Ced-3基因族的成员,其至少包括了十二种成员:ICE,CPP32/Yama/Apopain,mICE2,ICE4,ICH1,TX/ICH-2,MCH2,MCH3,MCH4,FLICE/MACH/MCH5,ICE-LAP6和ICErel III。此类半胱氨酸蛋白酶的蛋白分解活性,其活性位点(半胱氨酸残基)对ICE-介导的编程性细胞死亡是必需的,在调节细胞死亡时看来是重要的(Miura等人,Cell 75:653-660(1993))。此基因家族最近被命名为天冬氨酸特异性半胱氨酸蛋白酶(Caspase)(Alnernri,E.S.等人,Cel1,87,171(1996),和Thomberry,N.A.等人,J.Biol.Chem.,272,17907-17911(1997)),并可按照其已知的功能分成三组。表1列出了这些已知的天冬氨酸特异性半胱氨酸蛋白酶。
表1
酶* |
组I:炎症调节剂 |
天冬氨酸特异性半胱氨酸蛋白酶-1(ICE) |
天冬氨酸特异性半胱氨酸蛋白酶-4(ICErel-II,TX,ICH-2) |
天冬氨酸特异性半胱氨酸蛋白酶-5(ICErel-III,TY) |
组II:编程性细胞死亡作用剂 |
天冬氨酸特异性半胱氨酸蛋白酶-2(ICH-1,mNEDD2) |
天冬氨酸特异性半胱氨酸蛋白酶-3(apopain,CPP-32,YAMA) |
天冬氨酸特异性半胱氨酸蛋白酶-7(Mch-3,ICE-LAP3,CMH-1) |
组III:编程性细胞死亡活化剂 |
天冬氨酸特异性半胱氨酸蛋白酶-6(Mch2) |
天冬氨酸特异性半胱氨酸蛋白酶-8(MACH,FLICH,Mch5) |
天冬氨酸特异性半胱氨酸蛋白酶-9(ICE-LAP6,Mch6) |
天冬氨酸特异性半胱氨酸蛋白酶-10 |
IL-1也是在大范围内调节生物响应的细胞因子,这些生物响应包括炎症、感染性休克、创伤治愈、血细胞生成和某些白血病的发育(Dinarello,C.A.,Blood,77:1627-1652(1991);diGiovine等人,Immunology Today,11:l3(1990))。
许多有效的天冬氨酸特异性半胱氨酸蛋白酶抑制剂在天冬氨酸特异性半胱氨酸蛋白酶肽底物结构的基础上被合成出来。但是,与它们在体外的有效性相反,还没有抑制剂在所有编程性细胞死亡的细胞模型中有良好的效力(1C50<1μM)的报道(Thornberry,N.A.Chem.Biol.5:R97-103(1998))。因此,对在所有编程性细胞死亡的细胞模型中是有效的,和在编程性细胞死亡的动物模型中是具有活性的细胞死亡抑制剂仍然有需求。这些抑制剂可作为治疗剂以治疗需要调节细胞死亡和IL-1细胞因子活性发挥作用的疾病。
WO 93/05071公开了具有下式结构的肽ICE抑制剂:
Z-Q2-Asp-Q1其中Z是N-端基的保护基团;Q2是0-4氨基酸,因此Q2-Asp序列相对于至少是蛋白序列Ala-Tyr-Val-His-Asp;Q1含有负电性的离去基团。
WO 96/03982公开了具有下式结构的天冬氨酸类似物作为ICE抑制剂:其中R2是H或烷基;R3是离去基团如卤素;R1是杂芳基-CO或氨基酸残基。
U.S.P5,585,357公开了下式结构的肽酮类化合物作为ICE抑制剂:其中n是0-2;每个AA各自独立地是L-缬氨酸或L-丙氨酸;R1选自N-苄氧羰基和其它基团;R8,R9,R10各自独立地是氢、低级烷基和其它基团。
Thornberry等人(Biochemisiry,33,3934-3940,1994)报道了使ICE不可逆失活的肽酰氧基甲基酮:其中Ar是COPh-2,6-(CF3)2,COPh-2,6-(CH3)2,Ph-F5和其它基团。
Mjalli等人(Bioorg.Med.Chem.Lett.,4,1965-1968,1994)报道了下述有效的可逆ICE抑制剂活化酮的制备:其中X是NH(CH2)2,OCO(CH2)2,S(CH2)3和其它基团。
Dolle等人(J.Med.Chem.,37,3863-3866,1994)报道了ICE的不可逆抑制剂α-((1-苯基-3-(三氟甲基)-吡唑-5-基)氧基)甲基酮,如:
Mjalli等人(Bioorg.Med Chem.Lett.,5,1405-1408,1995)报道了N-酰基-天冬氨酸酮的ICE抑制作用:其中XR2是NH(CH2)2Ph,OCO(CH2)2环己基和其它基团。
Mjalli等人(Bioorg.Med.Chem.Lett.,5,1409-1414,1995)报道了如下述的N-酰基-天冬氨酰基芳氧基甲基酮的ICE抑制作用:
发明的综述本发明涉及下述式I、II和III化合物:其中
R1是任意取代的烷基或氢;
R3是N-保护基团;
R2是氢或任意取代的烷基;
A是CR6或氮;
B是CR7或氮;
C是CR8或氮;
D是CR9或氮;
条件是A,B,C或D中不能有两个以上是氮;并且R6-R9各自独立地是氢、卤素、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、氰基、C1-C6酰氨基、羟基、C1-C6酰氧基、C1-C6烷氧基、烷硫基、或羧基;或
R6和R7,或R7和R8,或R9和R10之一与它们所连接的碳原子一起形成碳环或杂环;
E是CR14、氮、氧或硫;
F是CR15、氮、氧或硫;
G是CR16、氮、氧或硫;
条件是E,F,G中只有一个是氮、氧或硫;其中R14-R16各自独立地是氢、卤素、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、氰基、C1-C6酰氨基、羟基、C1-C6酰氧基、C1-C6烷氧基、烷硫基、或羧基;或
R14和R15,或R15和R16之一与它们所连接的碳原子一起形成碳环或杂环;
Q表示任意取代的饱和或部分饱和的碳环或杂环;
X是1-4氨基酸的肽或是键;和
Y是1-4氨基酸的肽或是键。
本发明涉及到发现:用式I、II和III表示的化合物是天冬氨酸特异性半胱氨酸蛋白酶抑制剂。本发明还涉及用本发明化合物缓解、预防和治疗以编程性细胞死亡为产生因素或结果的疾病。本发明的应用实例包括保护由局部缺血和整体缺血的神经系统;治疗神经变性疾病,如阿尔茨海默氏病、亨廷顿病、蛋白质致病颗粒疾病、帕金森病、多发性硬化症、肌萎缩性侧索硬化、共济失调、毛细管扩张和脊髓延髓萎缩;治疗心脏疾病,包括心肌梗塞、充血性心力衰竭和心肌病;治疗肾病;治疗自身免疫疾病,包括红斑狼疮、风湿性关节炎、I型糖尿病、Sjgren综合症和血管球性肾炎;治疗多囊的肾病和贫血症/红细胞生成;治疗免疫系统疾病,包括AIDS和SCIDS;治疗或缓解动物的败血症或多器官坏死症;缓解或预防在移植中的细胞、组织和器官损伤;缓解或预防工业生物技术中的细胞系死亡;缓解或预防脱发(头发损失);缓解皮细胞的提前死亡;治疗或缓解急性胰腺炎中的编程性细胞死亡;治疗或预防牛皮癣或发炎肠病的炎症反应;和治疗或缓解烧伤后器官的编程性细胞死亡。
本发明提供了药物组合物,该组合物含有减少动物体编程性细胞死亡有效量的式I、II和III化合物。
本发明还提供了哺乳动物器官或组织的保存或储存溶液,或哺乳动物或酵母细胞的生长介质,为了减少所述器官、组织或细胞中的编程性细胞死亡,所述的溶液或介质中含有有效量的式I、II和III化合物。
本发明还涉及在化疗和放疗期间应用天冬氨酸特异性半胱氨酸蛋白酶抑制剂治疗、缓解或预防非癌细胞死亡,以及用于治疗和缓解癌症化疗和放疗的副作用。
具体地说,本发明涉及治疗、缓解或预防下述疾病的方法:口腔粘膜炎、胃肠道粘膜炎、膀胱粘膜炎、腮腺炎、骨髓细胞死亡、皮肤细胞死亡以及由于动物癌症进行的化疗或放疗引起的脱发,该方法包括给需要进行这种治疗的动物施用有效量天冬氨酸特异性半胱氨酸蛋白酶抑制剂。
发明的详细说明
R1是任意取代的烷基或氢;
R3是N-保护基团,包括叔丁氧羰基、乙酰基和苄氧羰基;
R2是氢或任意取代的烷基;
A是CR6或氮;
B是CR7或氮;
C是CR8或氮;
D是CR9或氮;条件是A,B,C或D中不能有两个以上是氮;并且R6-R9各自独立地是氢、卤素、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、氰基、C1-C6酰氨基、羟基、C1-C6酰氧基、C1-C6烷氧基、烷硫基、或羧基;或
R6和R7,或R7和R8,或R9和R10之一与它们所连接的碳原子一起形成碳环或杂环;
E是CR14、氮、氧或硫;
F是CR15、氮、氧或硫;
G是CR16、氮、氧或硫;条件是E,F,G中只有一个是氮、氧或硫;其中R14-R16各自独立地是氢、卤素、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、氰基、C1-C6酰氨基、羟基、C1-C6酰氧基、C1-C6烷氧基、烷硫基、或羧基;或
R14和R15,或R15和R16之一与它们所连接的碳原子一起形成碳环或杂环;
Q表示任意取代的饱和或部分饱和的碳环或杂环;
X是1-4氨基酸的肽或是键;和
Y是1-4氨基酸的肽或是键;当X或Y是一个氨基酸时它可以是诸如下述的20个常见氨基酸中的任意一个:Ala,Val,Leu,Ile,Pro,Phe,Trp,Met,Gly,Ser,Thr,Cys,Tyr,Asp,Asn,GIu,Asn,Lys,Arg和His。当X是肽时,它可以是Asp-Glu,Asp-Ala,Asp-Phe,Val-Glu,Leu-Glu,Thr-Glu,Ile-Glu,Tyr-Glu,Trp-Glu.当Y是肽时,它可以是Glu-His,Glu-Ile,Glu-Thr,Glu-Val,Glu-Phe,Thr-His,Val-His,Ala-His和Glu-Pro。
就R1而言,优选的烷基是C1-6烷基基团,例如甲基、乙基、丙基、异丙基、异丁基、戊基和己基基团;以及取代的C1-6烷基基团例如是CH2OCH3和CH2OCOCH3(AM)。
本发明涉及到发现用式I、II和III表示的化合物是天冬氨酸特异性半胱氨酸蛋白酶抑制剂。在各种出现细胞、组织或整个器官损失的临床治疗条件和工业应用中,这些抑制剂可减慢或阻断细胞死亡。因此,本发明还涉及治疗、预防和缓解编程性细胞死亡起作用的症状的方法。这些症状在下文将更完全的进行描述。
本发明的方法包括给需要这种治疗的动物施用能有效抑制编程性细胞死亡有效量的本发明的抑制剂,或其药用盐或其前药。
可用作天冬氨酸特异性半胱氨酸蛋白酶抑制剂的式I、II和III化合物的优选实施方案是用下式IV化合物或其药用盐或其前药作为天冬氨酸特异性半胱氨酸蛋白酶抑制剂:其中R1R2-、R6-R9和X如前文关于式I的定义。
由R6和R7,或R7和R8,或R8和R9一起形成的桥是-OCH2O-,-OCF2O-,-(CH2)3-,-(CH2)4-,-OCH2CH2O-,-CH2N(R13)CH2-,-CH2CH2N(R13)CH2-,-CH2N(R13)CH2CH2-和-CH=CH-CH=CH-;其中R13是氢、烷基或环烷基。
R10是氢、C1-C6烷氧基、C1-C6烷基、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C6-C10芳基(C1-C6)烷基、苄氧基、取代的苄氧基、或NR11R12,其中R11和R12各自独立地是氢、C1-C6烷基、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C6-C10芳基(C1-C6)烷基,或R11和R12结合形成杂环系统包括吡咯烷、哌啶、哌嗪或吗啉。
优选的R1是H,Me,Et,t-Bu或AM。优选的R2是氟甲基、酰氧基甲基、芳基酰氧基甲基和氨基甲基。优选的R10是苄氧基和取代的苄氧基。优选的X是1-2氨基酸的肽或键。
具有式I-IV结构的优选天冬氨酸特异性半胱氨酸蛋白酶抑制剂的实例包括但不限于下述化合物:2-(Z-氨基)苯甲酰基-Asp-fmk,2-(Z-氨基)-3-甲基苯甲酰基-Asp-fmk,2-(Z-氨基)-3,5-二甲基苯甲酰基-Asp-fmk,2-(Z-氨基)-4-氯苯甲酰基-Asp-fmk,2-(Z-氨基)-5-氯苯甲酰基-Asp-fmk,2-(Z-氨基)-5-氟苯甲酰基-Asp-fmk,2-(Z-氨基)-6-氟苯甲酰基-Asp-fmk,顺式-2-(Z-氨基)-环己烷羧基-Asp-fmk,2-(Z-氨基)-5-甲基苯甲酰基-Asp-fmk,2-(Z-氨基)-6-甲基苯甲酰基-Asp-fmk,2-(Z-氨基)-6-氯苯甲酰基-Asp-fmk,2-(Z-氨基)-3-甲氧基苯甲酰基-Asp-fmk,3-(Z-氨基)噻吩-2-羧基-Asp-fmk,3-(甲氧羰基氨基)噻吩-2-羧基-Asp-fmk,顺式-2-(Z-氨基)-环戊烷羧基-Asp-fmk,反式-2-(Z-氨基)-环戊烷羧基-Asp-fmk,2-(Z-氨基)苯甲酰基-Asp-DCB-甲基酮,甲氧羰基-Val-(2-氨基苯甲酰基)-Asp-fmk,Z-Glu-(2-氨基苯甲酰基)-Asp-fmk,和Z-Val-(2-氨基苯甲酰基)-Asp-fmk,其中Z是苄氧羰基,fmk是氟代甲基酮和DCB是2,6-二氯苯甲酰氧基。
所用的芳基基团是C6-14芳基,特别是C6-10芳基。具体的C6-14芳基基团包括苯基、萘基、菲基、蒽基、茚基、薁基、联苯基、亚联苯基和芴基基团。
所用的环烷基基团是C3-8环烷基。具体的环烷基基团包括环丙基、环丁基、环戊基、环己基和环庚基。
所用的饱和或部分饱和的碳环基团是如上文定义的环烷基基团,以及环烯基基团,如环戊烯基、环庚烯基和环辛烯基。
所用的卤素基团包括氟、氯、溴和碘。
所用的烷基基团包括直链或支链的C1-10烷基基团,更优选C1-6烷基基团。具体的C1-10烷基基团包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、3-戊基、己基和辛基基团。还包括在本发明化合物的苯环的两个相邻位置上取代的1,3-亚丙基基团。
所用的芳烷基基团包括被上述任一C6-14芳基取代的C1-10烷基基团,所用的基团包括苄基、苯乙基和萘甲基。
所用的卤代烷基基团包括被一个或多个氟、氯、溴或碘原子取代的C1-10烷基基团,例如氟甲基、二氟甲基、三氟甲基、五氟乙基、1,2-二氟乙基、氯甲基、氯氟甲基和三氯甲基基团。
所用的烷氧基基团包括被一个上文定义的C1-10烷基取代的氧。
所用的烷硫基基团包括被一个上文定义的C1-10烷基取代的硫,并且还包括这些烷硫基基团的亚砜和砜。
所用的酰氨基基团是与氨基氮相连接的任意C1-6酰基(烷酰基),例如乙酰氨基、丙酰胺基、丁酰胺基、戊酰胺基、己酰胺基,以及芳基取代的C2-6取代的酰基。
所用的酰氧基基团是与氧基(-O-)相连接的任意C1-6酰基(烷酰基),例如甲酰氧基、乙酰氧基、丙酰氧基、丁酰氧基、戊酰氧基、己酰氧基等。
所用的芳酰氧基,包括被上述酰氧基基团所取代的上述芳基基团,例如2,6-二氯苯甲酰氧基、2,6-二氟苯甲酰氧基和2,6-二-(三氟甲基)-苯甲酰氧基基团。
所用的氨基基团包括-NH2、-NHR11和-NR11R12,其中的R11和R12是上述C1-10烷基或环烷基基团。
所用的饱和或部分饱和的杂环基基团包括四氢呋喃基、吡喃基、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、咪唑啉基、吲哚基、异吲哚基、奎宁环基、吗啉基、异苯并二氢吡喃基、苯并二氢吡喃基、吡唑烷基、吡唑啉基、季酮酸酰基(tetronoyl)和tetramoyl基团。
所用的杂芳基基团包括任一下述基团:噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、苯并吡喃基、呫吨基、吩黄嘌呤基(phenoxanthiinyl)、2H-吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、中氮茚基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、2,3-二氮杂萘基(phthalzinyl)、1,5-二氮杂萘基、quinozalinyl、噌啉基、喋啶基、咔唑基、β-咔啉基、菲啶基、吖啶基(acrindinyl)、响啶基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异噁唑基、呋咱基、吩噁嗪基、1,4-二氢喹噁啉基-2,3-二酮、7-氨基异香豆素、吡啶并[1,2-a]嘧啶-4-酮、1,2-苯并异噁唑-3-基、苯并咪唑基、2-羟吲哚基和2-氧代苯并咪唑基。在环上含有氮原子的杂芳基中,该氮原子可以是N-氧化物形式,例如吡啶N-氧化物、吡嗪N-氧化物、嘧啶N-氧化物等。
可选择的取代基包括一个或多个烷基;卤素;卤代烷基;环烷基;由一个或多个低级烷基、卤素、卤代烷基或杂芳基选择性取代的芳基;由一个或多个低级烷基、卤素、卤代烷基或杂芳基选择性取代的芳氧基;芳烷基;由一个或多个低级烷基、卤代烷基和芳基选择性取代的杂芳基;由一个或多个低级烷基、卤代烷基或杂芳基选择性取代的杂芳氧基;烷氧基;烷硫基;芳硫基;氨基;酰氧基;由一个或多个低级烷基、卤代烷基和芳基选择性取代的芳酰氧基;由一个或多个低级烷基、卤素或卤代烷基选择性取代的二苯基氧膦基氧基;由一个或多个低级烷基、卤代烷基和芳基选择性取代的杂环基;由一个或多个低级烷基、卤代烷基和芳基选择性取代的杂环烷氧基;由一个或多个低级烷基、卤代烷基和芳基选择性取代的部分不饱和的杂环烷基;或由一个或多个低级烷基、卤代烷基和芳基选择性取代的部分不饱和的杂环烷基氧基。可在R2上出现的这些选择性取代基的具体例子包括但不限于:在2,4和5位置上由低级烷基选择性取代的3-吡唑基氧基;3-(1-苯基-3-三氟甲基)吡唑基氧基;2,6-二(三氟甲基)苯甲酰氧基;2,6-二甲基苯甲酰氧基;五氟苯氧基;2,6-二氯苯甲酰氧基;2-(3-(2-咪唑基)萘基)氧基;二苯基氧膦基氧基;季酮酸酰基;和tetramoyloxy基团。
本发明的某些化合物可以包括光学异构体的立体异构体存在。本发明包括所有的立体异构体,和这些异构体的外消旋混合物以及可按照本领域普遍专业技术人员熟知的那些方法分离的各种单个对映体。
药用可接受加成盐的例子包括无机酸和有机酸加成盐,如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐;以及无机和有机碱加成盐,例如氢氧化钠和三(羟甲基)氨基甲烷(TRIS,tromethane)。
前药的实例包括式I-IV化合物,其中的R1是烷基或取代的烷基如CH2OCH3和CH2OCOCH3(AM酯)。
本发明还涉及治疗动物患有对天冬氨酸特异性半胱氨酸蛋白酶抑制作用发生反应的疾病的方法,应用与本发明方法的化合物的优选实施方案是前述定义的式I-IV化合物。
本发明的化合物可用本领域熟练技术人员已知的方法制备。具体地,式I-IV化合物可用流程1所例举的方法制备。中间体1可按照Revesz等人所述的方法制备(Tetrahedron Lett.,35,9693-9696,1994)。1和N-保护的2-氨基苯甲酸偶合得到酰胺2,其中的N-保护的2-氨基苯甲酸是可以买到的,或者可由能够买到的2-氨基苯甲酸如2-Z-氨基苯甲酸制备。按照Revesz等人所述的方法(Tetrahedron Lett.,35,9693-9696,1994)用Dess-Martin试剂氧化2,可得到3。使酯进行酸催化裂解可得到游离酸4。
流程1
本发明一个重要的方面是发现了式I-IV化合物是天冬氨酸特异性半胱氨酸蛋白酶抑制剂。因此,在发生细胞、组织或整个器官损失的各种临床症状中,这些抑制剂可以减慢或阻断细胞死亡。
本发明的细胞死亡抑制剂在神经系统(脑、脊髓和外周神经系统)发生缺血和兴奋中毒的各种症状时用于减少或防止细胞死亡,这些症状包括但不限于由于脑中风引起的病灶缺血和因为心脏停搏引起的整体缺血,以及脊髓损伤(Emery等人,J.Neurosurgery,89:911-920(1998))。一种特别的应用是用于治疗高危分娩时胎儿出生期间或水淹时发生的缺氧的影响。细胞死亡抑制剂也可以用于减少或防止由于外伤(如头部外伤)、病毒感染或辐射引起的神经细胞死亡(例如癌症放疗引起的副作用)引起的神经系统细胞死亡。细胞死亡抑制剂可用于减少或防止神经变性性疾范围内的细胞死亡,这些疾病包括但不限于阿尔茨海默氏病(Mattson等人,Brain Res.807:167-176(1998)),亨廷顿病、帕金森病、多发性硬化症、肌萎缩侧索硬化和脊髓延髓萎缩。本发明细胞死亡抑制剂在体内的神经保护作用可用大鼠短暂病灶脑缺血模型进行试验(Xue等人,Stroke,21:166(1990))。细胞死亡抑制剂也可以用于治疗或缓解急性细菌性脑膜炎中的细胞死亡。
本发明的细胞死亡抑制剂可用减少或防止任何可能引起心肌死亡的症状中的细胞死亡(Black等人,J.Mol.Cel.Card.,30:733-742(1998)和Maulik等人,Free Radic.Biol.Med.,24:869-875(1998))。这些包括由心肌缺血和再灌注引起的心肌梗塞,充血性心力衰竭和心肌病。一种特别的应用是预防或减少在心脏的某些病毒感染中出现的心肌细胞死亡。
本发明细胞死亡抑制剂的体内活性可用Rodriguez等人(Rodriguez等人,J.Exp.Med.,184:2067-2072(1996))所述的“小鼠肝脏编程性细胞死亡”模型进行试验。在此模型中,小鼠经静脉内(IV)用能在肝脏或其他器官中引起广泛编程性细胞死亡,从而可导致无显著特点的器官衰竭和死亡的抗Fas抗体处理。此模型用于间接地测试本发明细胞死亡抑制剂的系统生物利用率,以及它们在体内的抗编程性细胞死亡性能。因此,本发明的细胞死亡抑制剂可用于减少或防止肝细胞的编程性细胞死亡(Jones等人,Hepatology,27:1632-42(1998)),例如在败血时(Jaeschke等人,J.Immunol.,160:3480-3486(1998))和遗传性1型酪氨酸血症(HT1)时(Kubo等人,Proy.Nati.Acad.Sci.USA,95:9552-9557(1998))。本发明的细胞死亡抑制剂还可以用于治疗肝炎(Suzuki,Proc.Soc.Exp.Biol.Med.,217:450-454(1998));在治疗或缓解急性胰腺炎(pancreatitus)中的编程性细胞死亡;以及治疗或缓解烧伤后的器官编程性细胞死亡。
本发明细胞死亡抑制剂可用于减少或防止视黄醛神经元的细胞死亡(Kermer等人,J.Neurosci.,18:4656-4662(1998)和Miller等人,Am.J.Vet. Res.59..149-152(1998)),这种情况可能发生在会提高眼压的疾病(如青光眼)或与老化有关的视黄醛疾病(如与年龄有关的斑疹变形)。该抑制剂可用于治疗视黄醛的遗传退化性疾病如色素性视网膜炎。
本发明细胞死亡抑制剂还可以用于减少或防止肾脏的细胞死亡。这包括肾淀粉样变性(Hiraoka等人,Nippon Jinzo Gakkai Shi,40:276-83(1998)),急性肾衰竭(Lieberthal等人,Semin Nephrol.,18:505-518(1998)),由环孢霉素A引起的鼠的管状上皮细胞死亡(Ortiz等人,KidneyInternational Supp.68:S25-S29(1998))和HIV-诱导的肾病(Conaldi等人,J.Clin.Invest.102:2041-2049(1998))。
本发明细胞死亡抑制剂还可以用于减少或防止由于慢性酒精摄入引起的颊粘膜细胞死亡。(Slomiany等人,Biochem.Mol.Biol.Int.,45:1199-1209(1998))。
本发明细胞死亡抑制剂还可以用于减少或防止植物的细胞死亡(Richberg等人,Curr.Opin.Plant Biol.,1:480-485(1998)),例如由病原体引起的植物细胞死亡(Pozo等人,Curr.Biol.,8:1129-1132(1998)和Greenberg等人,Cell,77:551-563(1994))。
本发明细胞死亡抑制剂还可以用于减少或防止由于辐射和紫外光照射引起的细胞死亡(Sheikh等人,Oncogene,17“本发明细胞死亡抑制剂还可以用于减少或防止肾脏的细胞死亡。17:2555-2563(1998))。
本发明细胞死亡抑制剂还可以用于减少或防止骨髓增生异常综合征(MDS)中骨髓细胞的编程性细胞死亡(Mundle等人,Am.J.Hematol.,60:3647(1999))。
本发明细胞死亡抑制剂还可以用于减少或防止免疫细胞的早熟死亡,特别是用于治疗免疫缺陷疾病如获得性免疫缺陷综合征(AIDS)和有关的疾病,重度复合性免疫缺陷综合症(SCIDS)和有关的疾病。本发明细胞死亡抑制剂还可以用于治疗辐射引起的免疫抑制。
人体器官和组织移植是器官衰竭的常用治疗方法。但是,在器官移植过程中,供体的器官或组织处于细胞死亡的危险之中,因为在移植到宿主之前缺少正常的血液供应。这种缺血状态可通过将细胞死亡抑制剂灌注到供体的器官或组织来进行处理,或者在器官/组织贮存介质中直接加入细胞死亡抑制剂。本发明细胞死亡抑制剂还可以在器官移植后用于保护其不受再灌注和/或宿主免疫细胞的影响,以减少或防止供体器官或组织的细胞死亡,所述的再灌注和/或宿主免疫细胞的影响可能通过触发编程性细胞死亡而杀死靶标。细胞死亡抑制剂的细胞保护作用可用于人或动物体外受精过程中防止精子或卵子死亡。这些抑制剂可用于采集过程中,也可以包含于贮存介质之中。
为满足工业或医药应用,哺乳动物细胞系、昆虫细胞和酵母细胞通常被用于生产大量的重组蛋白(例如抗体、酶或激素)。这些细胞系中某些细胞的寿命受生长条件、受到限制的重组分子的性质(有些是有毒的)和其它未知的因素的限制。通过在生长介质中加入浓度范围为1-100μM的这种细胞死亡抑制剂可延长工业用细胞系的寿命。
控制头发生长或损失的因素大多数是未知的。但是,有证据表明头发毛囊的退化(称之为退化期)至少部分是由于编程性细胞死亡。因此,可以理解的是,本发明的细胞死亡抑制剂可用于治疗由于各种症状造成的头发损失,这些症状包括但不限于男性脱发、放疗或化疗引起的脱发,以及由于情绪紧张引起的脱发。这些也证明了编程性细胞死亡在头发颜色损失中起作用。因此,可以理解的是,本发明的细胞死亡抑制剂可用于治疗或预防头发过早变灰的情况。
在暴露于大量的辐射、热或化学品之后会造成皮肤上皮细胞的死亡。可以理解的是,本发明的细胞死亡抑制剂可用于治疗、缓解或预防这种类型的皮肤损伤。在一种具体的应用中,细胞死亡抑制剂可以作为局部使用剂型如乳膏的一部分应用,以治疗急性的过度接触阳光,和防止皮肤起水疱和脱皮。
最近Goldberg等人(Nature Genetics,13:442-449(1996))报道了亨廷顿病(HD)基因产生的一种蛋白质huntingtin可由CPP32分裂,但不能由ICE分裂。基于HD的突变体是CAG三核苷酸在其HD基因的5’端扩展。超过36次复制的三核苷酸扩展体与HD的临床表现有关。CAG扩展刺激由CPP32造成的huntingtin分裂,这些与CPP32在HD的编程性细胞死亡中的作用有关。本发明化合物具有CPP32抑制活性,可用于阻断CPP32诱导的编程性细胞死亡,因此可用于预防和治疗HD和以三核苷酸复制体的扩展为特征的其它疾病如强直性肌营养不良、脆性X精神阻滞、脊髓延髓肌萎缩、I型脊髓小脑性共济失调(spinocerebellar atoxia type I)和Dentato-Rubro苍白球萎缩(pallidoluysian atrophy)。
本发明还涉及治疗、缓解或预防动物的口腔粘膜炎、胃肠道粘膜炎、膀胱粘膜炎、腮腺炎、骨髓细胞死亡、皮肤细胞死亡或癌症化疗或放射治疗引起的头发损失的方法,该方法包括给需要进行这种治疗的动物施用有效量的天冬氨酸特异性半胱氨酸蛋白酶抑制剂。
当动物用化疗和/或放疗治疗以杀死癌细胞时,不希望有的副作用是快速分裂的非癌细胞的编程性细胞死亡。这些非癌细胞包括胃肠道、皮肤、头发和骨髓细胞。按照本发明,将天冬氨酸特异性半胱氨酸蛋白酶抑制剂施用于这些非癌细胞以防止这些细胞的编程性细胞死亡。在一具体实施方案中,天冬氨酸特异性半胱氨酸蛋白酶抑制剂是局部施用的,如施用于胃肠道、口腔、皮肤或头皮,以防止胃肠道、皮肤或头发细胞的编程性细胞死亡,但是可使癌细胞死亡。因此,在一个实施例中,有可能在用化疗或放疗治疗脑癌时通过局部施用天冬氨酸特异性半胱氨酸蛋白酶抑制剂保护外部皮肤、头发细胞、胃肠道和骨髓。在口腔粘膜炎的情况下,天冬氨酸特异性半胱氨酸蛋白酶抑制剂可以例如漱口液或口腔洗涤液的形式,胶体的形式,或在口腔内缓慢释放的锭剂的形式施用以防止化疗剂或放疗引起的天冬氨酸特异性半胱氨酸蛋白酶的活化和细胞的编程性细胞死亡。在胃肠道粘膜炎的情况下,天冬氨酸特异性半胱氨酸蛋白酶抑制剂可以不会系统吸收的形式,或敷于胃肠道表面的形式,或是栓剂剂型施用,以治疗胃肠道粘膜炎。在腮腺炎的情况下,天冬氨酸特异性半胱氨酸蛋白酶抑制剂可作为灌肠剂或栓剂的一部分给药。在膀胱粘膜炎的情况下,天冬氨酸特异性半胱氨酸蛋白酶抑制剂可通过膀胱导管施用。在用于防止放疗或化疗引起的脱发时天冬氨酸特异性半胱氨酸蛋白酶抑制剂可以诸如头发洗液、发胶、洗发香波或头发护理剂的形式施用于头皮。重要的是,天冬氨酸特异性半胱氨酸蛋白酶抑制剂可在使用化疗剂或射线之前施用,以防止化疗剂和射线对正常皮肤造成损害的效果。
本发明的细胞死亡抑制剂还可用于治疗或预防牛皮癣或炎性肠疾病中的炎性反应。
在本发明保护范围之内的药物组合物包括所有其中含有达到所述目的有效量的本发明化合物的组合物。当个体的需要发生变化时,所确定的每一组分有效量最佳范围在本领域已知的范围之内。具体地说,给哺乳动物如人施用的口服剂量为相对于所治疗的、患有编程性细胞死亡引起的疾病的哺乳动物体重每天0.0025-50mg/kg,或是其等量的药用盐,其中所述的疾病例如是神经元细胞死亡、心脏疾病、视网膜疾病、多囊性肾疾病、免疫系统疾病和脓毒病。在治疗或预防上述疾病时,优选的口服剂量是0.01mg/kg左右至10mg/kg左右。对于肌内注射来说,所用剂量一般是口服剂量的大约一半。例如,为治疗或预防神经元细胞死亡,适宜的肌内注射剂量可以是大约0.0025到大约25mg/kg,而比较优选的是大约0.01到大约5mg/kg。
单位口服剂量可包含从大约0.01到大约50mg/kg,而比较优选的是大约0.1到大约10g/kg化合物。单位剂量可一天内一次或多次以一片或几片服用,每片包含有该化合物或其溶剂化物从大约0.01到大约10,而通常是从大约0.25到大约50mg。
在局部用制剂中,该化合物可以每克载体大约0.01到100mg的浓度存在。在一个优选的实施方案中,该化合物以约0.07-1.0mg/ml的浓度存在,比较优选的是大约0.1-0.5mg/ml,最优选的是大约0.4mg/ml。
本发明化合物除了作为初加工化学品给予外,还可作为药用制剂的一部分给予,该药用制剂包含有适宜的药用载体,后者含有能增助将该化合物加工成药用制剂的赋形剂和辅助剂。这些制剂中特别优选的是那些可口服或局部用的制剂,可服用的优选剂型如片剂、糖衣药丸、缓释菱形剂和胶囊、洗口水和漱口水、凝胶、液体悬浮液、染发剂、发胶、洗发水和可直肠使用的制剂,如栓剂,以及由注射用、局部用或口服用适宜的溶液,包含从大约0.01-99%,优选从大约0.25-75%的活性化合物和赋形剂。
本发明化合物的非毒性药用盐也包括在本发明的范围内。酸加成盐是通过混合本发明特定的细胞死亡抑制剂溶液和非毒性药用可接受的酸,如盐酸、富马酸、马来酸、琥珀酸、乙酸、柠檬酸、酒石酸、碳酸、磷酸、草酸等的溶液制备的。碱加成盐是通过混合本发明特定的细胞死亡抑制剂溶液和非毒性药用可接受的碱,如氢氧化钠、氢氧化钾、胆碱氢氧化物、碳酸钠、Tris等的溶液制备的。
本发明的药用组合物可给予能感受到本发明化合物有效作用的任何动物。这些动物中最重要的是哺乳动物,例如,人类,虽然本发明并不试图有这样的限制。
天冬氨酸特异性半胱氨酸蛋白酶抑制剂和其药用组合物可以达其目的的任何方式给予。例如,可通过肠胃外的、皮下的、静脉的、肌内的、腹膜内的、经皮肤的、口腔的、鞘膜内的、颅内的、鼻内的或局部用方式给予。另外,或同时,可由口服的方式给予。服用的剂量取决于接受者的年龄、健康状况和体重,同时实施治疗的种类,若有的话,还取决于治疗的频率和所希望产生作用的性质。一般地,天冬氨酸特异性半胱氨酸蛋白酶抑制剂局部用于要保护以防编程性细胞死亡并分别防化疗剂的组织。例如,顺铂通过静脉注射给予,以治疗脑癌、肺癌、乳腺癌、肝癌、肾癌、胰腺癌、卵巢癌、前列腺癌,天冬氨酸特异性半胱氨酸蛋白酶抑制剂局部给予,以治疗、缓解或预防口腔或胃肠道内编程性细胞死亡,如漱口水用来治疗口腔粘膜炎;IV注射水溶液用来治疗骨髓细胞死亡;适宜于涂敷胃肠表面的口服制剂或适宜治疗包括直肠炎在内的胃肠粘膜炎的灌肠剂或栓剂。天冬氨酸特异性半胱氨酸蛋白酶抑制剂也可通过膀胱导管使用,以治疗、缓解或预防膀胱炎。另外,或同时,天冬氨酸特异性半胱氨酸蛋白酶抑制剂可局部用于皮肤和/或头皮,以治疗、缓解或预防头发和皮肤细胞的编程性细胞死亡。在另一个实施方案中,化疗剂或放疗可局部应用,以治疗局部癌症,如脑癌、肺癌、乳腺癌、肝癌、肾癌、胰腺癌、卵巢癌、前列腺癌,天冬氨酸特异性半胱氨酸蛋白酶抑制剂可系统地通过静脉注射给予,以治疗、缓解或预防胃肠道细胞、口腔上皮细胞、骨髓细胞、皮细胞和头发细胞的编程性细胞死亡。例如,在脑癌治疗中的口腔粘膜炎的情况下,可使用不穿透血-脑屏障的天冬氨酸特异性半胱氨酸蛋白酶抑制剂,例如,系统地静脉注射后由辐射治疗脑瘤。这可保护口腔粘膜免受放射的有害影响,而天冬氨酸特异性半胱氨酸蛋白酶抑制剂不能保护辐射对脑瘤的疗效。重要的是,天冬氨酸特异性半胱氨酸蛋白酶抑制剂可在放疗前使用,这样就可预防辐射对正常口腔粘膜细胞的有害影响。
本发明的药用制剂按照已有的方法制造,例如,通过普通的混合、成粒、糖衣药丸制造、溶解或冻干工艺。口服用的药用制剂可通过使活性化合物与固体赋形剂结合而制备,优选磨碎所得到的混合物,并把该混合物加工成颗粒,如果希望或有必要的话,加入适当的辅助剂后,就得到片剂或糖衣药丸芯。
具体地说,适宜的赋形剂是一些填充剂,例如糖类,如乳糖或蔗糖、甘露糖醇或山梨糖醇、纤维素制剂和/或磷酸钙,如磷酸三钙或磷酸氢钙,以及粘合剂,例如使用玉米淀粉、小麦淀粉、稻米淀粉、土豆淀粉的淀粉糊、明胶、黄蓍胶、甲基纤维素、羟基丙基甲基纤维素、羧基甲基纤维素钠和/或聚乙烯吡咯烷酮。如果希望的话,还可加入崩解剂,如上述淀粉和羧基甲基淀粉、交联聚乙烯吡咯烷酮、琼脂、褐藻酸或其盐,如褐藻酸钠。辅助剂优先是流量控制剂和润滑剂,如硅、滑石、硬脂酸或其盐,如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。糖衣药丸芯用适宜的糖衣包封,如果希望的话,应当是耐胃液的。为此目的,可使用浓缩的糖类溶液,优选包含阿拉伯树胶、滑石、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、挥发性漆溶液和适宜的有机溶剂或溶剂混合物。为了制备耐胃液的糖衣,可使用适宜的纤维素制剂,如乙酰基纤维邻苯二甲酸酯或羟基丙基甲基-纤维素邻苯二甲酸酯。可将染料或颜料加入到片剂或糖衣药丸糖衣中,例如,为区别或表征活性化合物结合的剂型。
可以口服用的其他药用制剂包括由明胶构成的推入配合胶囊,以及由明胶和一种增塑剂如甘油或山梨糖醇构成的软密封胶囊。推入配合胶囊可以粒状形式包含活性化合物,其颗粒可混合有填充剂如乳糖、粘合剂如淀粉和/或润滑剂如滑石或硬脂酸镁,而优选稳定剂。在软性胶囊中,活性化合物优选溶解或悬浮在适宜的液体中,如脂肪油或液体石蜡。此外,可加入稳定剂。
可直肠使用的可能的药用制剂包括栓剂,由一种或多种活性化合物和一种栓剂基的结合而构成。适宜的栓剂基质如天然或合成的甘油三酯或石蜡烃。其次,使用由活性化合物与一种基质结合而构成的明胶直肠胶囊也是可能的。可能的基质包括液体甘油三酯、聚乙二醇或石蜡烃。
适宜的肠胃外使用的制剂包括水溶形式的活性化合物的水溶液,例如,水溶盐和碱溶液。此外,可使用作为适宜的油性注射悬浮液的活性化合物的悬浮液。适宜的亲脂性溶剂或载体包括脂肪油,如芝麻油,或合成脂肪酸酯,如油酸乙酯或甘油三酯,或聚乙二醇-400(该化合物在PEG-400中是可溶的)。水溶性注射悬浮液可包含增加悬浮液粘度的物质,如羧基甲基纤维素钠、山梨糖醇和/或葡聚糖。该悬浮液还优选包含稳定剂。
按照本发明的一个方面,本发明化合物以局部用制剂和肠胃外制剂使用,并用来治疗皮肤损伤,如暴露高水平的射线包括紫外线、热或化学品引起的那些皮肤损伤。
对皮肤有治疗作用的一种或多种另外的物质也可加入到这种组合物中。该组合物还可包含一种或多种能够增加皮肤中环状-AMP水平的化合物。适宜的化合物包括大约0.1-1%的腺核苷或核酸水解产物,和大约0.5-5%的罂粟碱,两者均以该组合物的重量计。大约0.1-2%的β-肾上腺素能兴奋剂如异丙基肾上腺素,或大约0.1-1%的环状-AMP,也都是适宜的,也都是以该组合物的重量计算的。可以加入到本发明组合物中的其他类型适宜的活性组分,包括对皮肤具有有益作用的已知的任意化合物。这些化合物包括视黄酸如维生素A,加入量以重量计大约是0.003-0.3%,和色满醇,如维生素E或它的衍生物,加入量以重量计大约是0.1-1.0%,两者均以该组合物的重量为基础计算。另外,抗炎剂和角膜形成剂也可以加入到整容用的组合物中。典型的抗炎剂是皮质甾类如氢化可的松或其乙酸酯,加入量以重量计大约是0.25-5%,或皮质甾类如地塞米松,,加入量以重量计大约是0.025-0.5%,两者均以该组合物的重量为基础计算。典型的角膜形成剂是煤焦油,加入量大约是0.1-20%,或蒽林,加入量大约是0.05-2%,两者均以该组合物的重量为基础计算。本发明的局部用组合物,通过选择适宜的载体,优选配制成油剂、乳脂、洗液、软膏等。适宜的载体包括植物油或矿物油、白凡士林(白软石蜡)、支链的脂或油、动物脂或高分子量醇(大于C12)。优选的载体是那些活性组分在其中可溶的载体。如果希望的话,还可包括乳化剂、稳定剂、致湿剂和抗氧化剂以及提供颜色或香味的药剂。另外,在这些局部用制剂中,还可使用经皮肤穿透的增强剂。这些增强剂的例子可在美国专利Nos.3,989,816和4,444,762中找到。
乳脂优选由矿物油、自乳化蜂蜡和水的混合物配制,在该混合物中掺和有在少量油如杏仁油中溶解的活性组分。这种乳脂的典型例子包含大约40分的水、大约20分的蜂蜡、大约40分的矿物油和大约1分的杏仁油。
软膏通过使在植物油如杏仁油中的活性组分溶液同热的软石蜡混合,并使该混合物冷却而配制。这种软膏的典型例子包含以重量计的大约30%的杏仁油和70%的白软石蜡。
洗液通常通过将活性组分溶解在适宜的高分子量醇如丙二醇或聚乙二醇中来制备。
此外,这些组合物可包含其他药剂、增长剂、伤口密封剂、载体等,这对本领域专业技术人员是已知或显而易见的。本发明组合物提供给已遭受皮肤损伤如烧伤的温血动物,如人类,其量应足以比宿主不予处理使治愈过程更快。这种应用的有效量,取决于接受治疗的病人皮肤损伤的严重程度和总体健康状况。长期的维持量以需要而调整。对兽医应用来说,依需要可给予较高的剂量。
在治疗遭受头发增长减少的动物的情况,本发明组合物给予的量应足以增加头发的生长速度。这种应用的有效量,取决于接受治疗的病人头发增长减少的程度和总体健康状况。长期的维持量以需要而调整。对兽医应用来说,依需要可给予较高的剂量。
当这些化合物被用于植物的时候,通过喷雾可用于植物的叶和/或茎和/或花。这些化合物可以微粒的形式喷洒,或溶解或悬浮于某种适用的载体中喷洒,如水或油-水乳化液。这些化合物还可与植物的生长土壤结合。在这种应用中,化合物被植物的根所吸收。
在一个优选的实施方案中,天冬氨酸特异性半胱氨酸蛋白酶抑制剂被配制成漱口剂,用来治疗、减缓或预防口腔粘膜炎。这种漱口剂是还可包含醇、甘油、合成甜味剂和表面活性剂、增香剂和着色剂的天冬氨酸特异性半胱氨酸蛋白酶抑制剂的水溶液。它们还可包含抗感染的药剂,如双辛氢啶和十六烷基氯化吡啶嗡。这种漱口剂还可包含局部麻醉剂(如苯坐卡因、可卡因、盐酸达克罗宁、利多卡因、盐酸丙美卡因或teracainehydrochloride),用来减轻放疗或化疗带来的疼痛。漱口剂可以是酸性或碱性的pH。参阅Remington’s Pharmaceutical Sciences,A.R.Gennaro(ed),Marck Publishing Company,pp.1046,1526和1965(1990)。
在另一个优选的实施方案中,天冬氨酸特异性半胱氨酸蛋白酶抑制剂被配制成能够涂敷胃肠表面的口服制剂,用来治疗、减缓或预防胃肠粘膜炎。胃肠粘膜炎的例子包括食管炎、胃炎和肠炎。这种制剂可包含胃的抗酸剂,如碳酸铝、氢氧化铝凝胶、亚硝酸铋、碱式水杨酸铋、碳酸钙、二羟基铝碳酸钠、水合铝酸镁、碳酸镁、氢氧化镁、氧化镁、碳酸氢钠、铋奶、二羟基铝氨基乙酸盐、磷酸镁、聚三硅酸镁和它们的混合物。其他添加剂包括但不限于H2-受体拮抗剂、助消化剂、止吐剂、吸附剂和混杂剂。参阅Remington’s Pharmaceutical Sciences,A.R.Gennaro(ed),Marck Publishing Company,pp.774-778(1990)。
化疗剂如顺铂和放疗常常引起病人早期和后期开始的呕吐。因而,在一个具体实施方案中,止吐剂与天冬氨酸特异性半胱氨酸蛋白酶抑制剂一起共服,以避免呕吐,并保持天冬氨酸特异性半胱氨酸蛋白酶抑制剂与胃肠道的接触。这种止吐剂的例子包含但不限于阻塞多巴胺能呕吐受体的化合物,如胃复安和三甲氧苯甲酰胺、大麻素。胃复安可在化疗/放疗/天冬氨酸特异性半胱氨酸蛋白酶抑制剂以前或期间口服,以防止早期的呕吐反应,以后则按照美国专利Nos.5,760,086和4,536,386提供的方法经鼻服用,以防止后期开始的呕吐。在化疗/放疗后的时间里,天冬氨酸特异性半胱氨酸蛋白酶抑制剂和止吐剂可共服,以治疗、减缓或防止胃肠粘膜炎。
在另一个实施方案中,天冬氨酸特异性半胱氨酸蛋白酶抑制剂可配制成IV注射溶液,用于治疗、减缓或防止骨髓细胞死亡。
该组合物可给予已进行了化疗或放疗并引起非癌细胞死亡的温血动物,如人类服用,比较优选的方法是在用化疗或放疗治疗前或治疗期间服用。
下面的实施例说明但并不限制本发明的方法和组合物。其他在临床上经常遇到的和对本领域专业技术人员是明显的各种条件和参数的适宜性改进和适应性变化,都属于本发明的精神和范围。
实施例1
2-(Z-氨基)苯甲酰基-Asp-fmk
步骤A.2-Z-氨基苯甲酸.在0℃将氯甲酸苄基酯(0.6mL,4.2mmol)加入到2-氨基苯甲酸(0.30g,4.2mmol)的吡啶(2mL)溶液中。而后,使该混合物在室温下搅拌1小时,用EtOAc(50mL)稀释,用2N HCl、水和盐水洗涤,Na2SO4干燥,真空浓缩。该粗产品用4∶1的正己烷/EtOAc洗涤两次,真空干燥,得到标题化合物,为白色固体(270mg,1.0mmol,45%)。
1H NMR(DMSO-d3):δ11.49(brs,1H),8.22(d,J=7.5,1H),7.95(d,J=7.5,1H),7.51(t,J=7.5,1H),7.39-7.32(m,5H),7.05(d,J=7.5,1H),5.15(s,2H).
步骤B.5氟3-[2-Z-氨基苯甲酰基氨基]-4-羟基戊酸叔丁基酯. 将在THF(10mL)中的2-氨基苯甲酸(90mg,0.33mmol)、1-(3-二甲基氨基丙基)-3-乙基碳二亚胺氢氯化物(EDCl,61mg,0.40mmol)、1-羟基苯并三唑水合物(HOBT,73mg,0.38mmol),二甲基氨基吡啶(DMAP,22mg,0.18mmol)和3-氨基-5-氟-4-羟基戊酸叔丁酯(79mg,0.38mmol)的混合物在室温下搅拌20小时,用1∶1的正己烷/EtOAc(75mL)稀释,用水、2N HCl、水、2N NaOH和盐水洗涤,Na2SO4干燥,真空浓缩。残留物用色谱法纯化(3∶2正己烷/EtOAc),得到标题化合物,为黄色收湿性固体(52mg,0.11mmol,33%)。
步骤C.2-(Z-氨基)苯甲酰基-Asp(Obu-t)-fmk. 将全碘发(periodinane)(0.41g,0.97mmol)和5氟-3-[2-Z-氨基苯甲酰基氨基]-4-羟基戊酸叔丁基酯(52mg,0.11mmol)在二氯甲烷(15mL)中的混合物回流20小时,冷却到室温,加入25mL含有1.0g Na2S2O3的饱和碳酸氢钠水溶液。将所得到的混合物搅拌2小时,用1∶1的正己烷/EtOAc(75mL)稀释,用水和盐水洗涤,Na2SO4干燥,真空浓缩。残留物用色谱法纯化(3∶2正己烷/EtOAc),得到标题化合物,为黄色收湿性固体(45mg,0.10mmol,91%)。
1H NMR(CDCl3):δ10.48(s,1H),8.42(d,J=8.7,
1H),7.51-7.33(m,7H),7.07(m,1H),5.30-4.98(m,1H),5.21(s,2H),3.11-
2.83(m,2H),1.44(s,9H).
步骤D.2-(Z-氨基)苯甲酰基-Asp-fmk.向在5mL CH2Cl2中2-(Z-氨基)苯甲酰基-Asp(Obu-t)-fmk(45mg,0.10mmol)的溶液加入1mL TFA.将所得到的溶液在室温下搅拌1小时,用EtOAc(75mL)稀释,用水、Na2HPO4洗涤到pH5,而后用盐水洗涤,Na2SO4干燥,真空浓缩,得到标题化合物,为白色固体(15mg,0.037mmol,38%)。
1H NMR(DMSO-d6):δ10.63(s,1H),9.08(s,1H),8.14(d,J=7.8,1H),7.76(d,J=7.8,1H),7.54(t,J=7.8,1H),7.41-7.35(m,5H),7.15(t,J=7.8,1H),5.16(s,2H),5.26-4.95(m,2H),4.83(m,1H),3.00-2.64(m,2H).
实施例2
2-(Z-氨基)-6-甲基苯甲酰基-Asp-fmk
标题化合物如实施例1描述的四个步骤由2-(氨基)-6-甲基苯甲酸制备。
1H NMR(DMSO-d6):δ 8.85(s,1H),8.68(s,1H),7.49-7.01(m,8H),5.12(s,2H),4.82(m,1H),5.26-4.95(m,2H),3.00-2.64(m.2H),2.26(s,3H).
实施例3
2-(Z-氨基)-5-甲基苯甲酰基-Asp-fmk
标题化合物如实施例1描述的四个步骤由2-(氨基)-5-甲基苯甲酸制备。
1H NMR(DMSO-d6):δ10.48(s,1H),9.10(d,J=9,1H),8.00(d,J=8.7,1H),7.89(s,1H),7.58(s,1H),7.41-7.34(m,5H),5.14(s,2H),4.83(m,1H),5.39-4.41(m,2H),2.94-2.80(m.2H),2.30(s,3H).
实施例4
2-(Z-氨基)-3-甲基苯甲酰基-Asp-fmk
标题化合物如实施例1描述的四个步骤由2-(氨基)-3-甲基苯甲酸制备。
1H NMR(DMSO-d6):δ9.05(s,1H),8.73(s,1H),7.38-7.20(m,8H),5.08(s,2H),4.72(m,1H),5.32(bs,2H),2.81-2.66(m.2H),2.21(s,3H).
实施例5
2-(Z-氨基)-3-甲氧基苯甲酰基-Asp-fmk
标题化合物如实施例1描述的四个步骤由2-(氨基)-3-甲氧基苯甲酸制备。
1H NMR(DMSO-d6):δ8.73(bs,1H),8.64(bs,1H),7.57-7.06(m,9H),5.06(s,2H),4.72(bs,1H),5.26-4.97(m,2H),3.78(s,3H),2.78-2.66(m.2H).
实施例6
2-(Z-氨基)-5-氟苯甲酰基-Asp-fmk 标题化合物如实施例1描述的四个步骤由2-(氨基)-5-氟苯甲酸制备。
1H NMR(DMSO-d6):δ10.40(bs,1H),
9.13(bs,1H),8.07(q,J=5.1,1H),7.61(d,J=6.6,1H),7.46-7.33(m,6H),
5.15(s,2H),4.81(bs,1H),2.84-2.72(m.2H).
实施例7
顺式2-(Z-氨基)环己羧基-Asp-fmk
标题化合物如实施例1描述的四个步骤由顺式2-氨基环己羧酸制备。
1H NMR(DMSO-d6):δ8.28(bs,1H),7.39-7.09(m,5H),4.98(s,2H),4.52-4.45(m,1H),3.99(bs,1H),2.62-2.53(m,4H),1.77-1.23(m,8H).
实施例8
2-(Z-氨基)-3,5-二甲基苯甲酰基-Asp-fmk
标题化合物如实施例1描述的四个步骤由2-氨基-3,5-二甲基苯甲酸制备。
1H NMR(DMSO-d6):δ8.05(s,1H),7.42-7.17(m,8H),5.15(s,2H),5.19-5.03(m,2H),4.87(m,1H),2.30(s,3H),2.26(s,3H).
实施例9
2-(Z-氨基)-5-氯苯甲酰基-Asp-fmk
标题化合物如实施例1描述的四个步骤由2-氨基5-氯苯甲酸制备。
1H NMR(DMSO-d6):δ10.56(s,1H),9.19(s,1H),8.15(d,J=9.0,1H),7.84(s,1H),7.61(d,J=9.0,1H),7.41-7.37(m,5H),5.16(s,2H),4.81(m,1H),5.41-4.80(m,2H),2.84-2.73(m,2H).
实施例10
2-(Z-氨基)-6-氯苯甲酰基-Asp-fmk标题化合物如实施例1描述的四个步骤由2-氨基-6-氯苯甲酸制备。
1H NMR(DMSO-d6):δ9.17(d,J=4.2,1H),8.95(s,1H),7.74-7.24(m,8H),5.50-5.21(m,2H),5.15(s,2H),4.85-4.78(m,1H),2.98-2.65(m,2H).
实施例11
2-(Z-氨基)-4-氯苯甲酰基-Asp-fmk
标题化合物如实施例1描述的四个步骤由2-氨基-3,5-二甲基苯甲酸制备。
1H NMR(DMSO-d6):δ10.84(s,1H),9.19(s,1H),8.24(s,1H),7.81(d,J=8.4,1H),7.42-7.24(m,6H),5.18(s,2H),5.25-5.20(m,2H),4.82(m,1H),2.94-2.63(m,2H).
实施例12
3-(Z-氨基)噻酚-2-羧基-Asp-fmk
步骤A.3-(Z-氨基)噻酚-2-羧酸.将3-氨基噻酚-2-羧酸甲酯(0.2g,1.27mmol)在2N NaOH(10mL)中的混合物在90℃加热15分钟,而后冷却到0℃。向所得到的溶液加入氯甲酸苄基酯(1.5mL,10.5mmol)。而后使该混合物在室温下搅拌1小时,用3∶1的正己烷∶乙酸乙酯(2×15mL)洗涤。水相用2N HCl酸化到pH~1-2,用乙酸乙酯(3×15mL)萃取,水和盐水洗涤,Na2SO4干燥,真空浓缩。得到标题化合物,为白色固体(70mg)。
而后该标题化合物如实施例1描述的三个步骤(B-D)制备。
1H NMR(DMSO-d6):δ10.43(s,1H),8.74(s,1H),7.81(d,
J=5.4,1H),7.73(d,J=5.4,1H),7.44-7.35(m,5H),5.18(s,2H),5.32-5.04
(m,2H),4.79(m,1H),2.88-2.67(m,2H).
实施例13
3-(甲氧基羧基氨基)噻酚-2-羧基-Asp-fmk
标题化合物如实施例12描述的四个步骤由3-氨基噻酚-2-羧酸甲酯和氯甲酸甲酯制备。1H NMR(DMSO-d6):δ10.34(s,1H),8.70(s,1H),7.79(d,J=5.7,1H),7.72(d,J=5.7,1H),5.31-4.80(m,3H),3.70(s,3H),2.96-2.73(m,2H).
实施例14
顺式2-(Z-氨基)环戊烷羧基-Asp-fmk
标题化合物如实施例1描述的四个步骤由顺式2-氨基环戊烷羧酸制备。
1H NMR(DMSO-d6):δ8.35(s,1H),7.34-7.28(m,5H),7.09(m,1H),5.13-4.50(m,5H),4.11(m,1H),2.81(m,1H),2.73-2.51(m,2H),1.91-1.40(m,6H).
实施例15
反式2-(Z-氨基)环己烷羧基-Asp-fmk
标题化合物如实施例1描述的四个步骤由反式2-氨基环己烷羧酸制备。
1H NMR(DMSO-d6):δ12.48(s,1H),8.26-8.15(m,1H),7.38-7.17(m,5H),5.18-4.47(m,5H),2.67-2.50(m,2H),2.19(m,1H),1.83-1.06(m,10H).
实施例16
Z-Glu-(2-氨基苯甲酰基)-Asp-fmk
步骤A.Z-Glu(Obu-t)2-氨基苯甲酸.在-45℃向Z-Glu(Obu-t)OH(272mg,0.81mmol)在THF(5mL)中的溶液加入N-甲基吗啉(110μL,1.1mmol),随后加入氯甲酸异丁酯(105μL,0.81mmol)。该混合物在-45℃下搅拌30分钟,加入在THF(5mL)中的邻氨基苯甲酸(127mg,0.93mmol)溶液,接着加入更多的N-甲基吗啉(220μL,1.82mmol)。使所得到的混合物搅拌过夜,用冷却浴使其慢慢地加热到室温。在用EtOAc(100mL)稀释后,该混合物用2N HCl、水、饱和NaHCO3、水、2NHCl、水和盐水洗涤,Na2SO4干燥,真空浓缩。得到高收湿性白色固体产品(330mg,0.72mmol,89%)。
1HNMR(DMSO-d6):δ11.79(s,1H),8.59(d,J=8.6,1H),8.00(t,J=6.0,1H),7.60(t,J=8.6,1H),7.39-7.31(m,5H),7.17(t,J=7.8,1H),5.16-4.99(m,2H),4.08(m,1H),2.33(m,2H),2.08-1.75(m,2H),1.38(s,9H).步骤B.5氟3-[Z-Glu(Obu-t)-2-(氨基苯甲酰基)氨基]-4-羟基]戊酸叔丁基酯.将在THF(6mL)中的Z-Glu(Obu-t)2-氨基苯甲酸(330mg,0.72mmol)、EDCl(129mg,0.67mmol)、HOBT(104mg,0.68mmol)、DMAP(46mg,0.38mmol)和3-氨基-5-氟-4-羟基戊酸叔丁基酯(136mg,O.66mmol)的混合物在室温下搅拌20小时。用1∶1的正己烷/EtOAc(75mL)稀释后,该混合物用水、2N HCl、水、2N NaOH和盐水洗涤,Na2SO4干燥,真空浓缩。残留物用色谱法纯化(先3∶1后3∶2正己烷/EtOAc),得到标题化合物,为白色固体(45mg,0.068mmol,10%)。
步骤C.Z-Glu(OBu-t)-[2-氨基苯甲酰基]-Asp(Obu-t)-fmk.标题化合物按实施例1步骤C描述的类似方法合成,产率58%。
步骤D.Z-Glu[2-氨基苯甲酰基]-Asp-fmk.标题化合物按实施例1步骤D描述的类似方法合成,产率14%。
1H NMR(DMSO-d6):δ11.46(s,1H),9.18(s,1H),8.57-7.20(m,6H),5.36-4.84(m,5H),4.04(brs,1H),2.95-1.81(m,6H).
实施例17
Z-Val-(2-氨基苯甲酰基)-Asp-Fmk
标题化合物按实施例16步骤描述的方法由Val合成14%。
1H NMR(DMSO-d6):δ11.34-11.25(m,1H),9.17-7.17(m,11H),5.42-4.30(m,5H),3.95-3.75(m,1H),2.95-2.57(m,2H),1.92(m,1H),0.91-0.84(m,6H).
实施例18
2-(Z-氨基)苯甲酰基-Asp-DCB-甲基酮
步骤A.Z-Asp(Obu-t)-DCB-甲基酮.向Z-(OBu-t)-溴代甲基酮(500mg,1.24mmol)在DMF(10mL)中的溶液加入氟化钾(320mg,5.50mmol)和二氯苯甲酸(348mg,1.82mmol)。使该混合物在室温下搅拌12小时,而后用25ml乙酸乙酯稀释,用NH4Cl水溶液和盐水洗涤,Na2SO4干燥,真空浓缩。得到标题化合物,为白色固体(0.78g,2.62mmol,69%)。
1H NMR(CDCl3):7.34(m,8H),5.96(d,J=8.7,1H),5.21(d,J=6.6,2H),5.16(s,2H),4.70(m,1H),2.88(m,2H),1.27(s,9H).
步骤B.Asp(Obu-t)-DCB-甲基酮-HCl.向Z-Asp(OBu-t)-DCB-甲基酮(572mg,1.14mmol)在乙醇(15mL)中的溶液加入Pd/C(50mg)和6NHCl(0.2ml)。使该混合物在室温、H2气氛(1atm)下搅拌12小时,而后过滤浓缩。得到标题化合物,为浅白色固体(416mg,1.04mmol,90%)。
1H NMR(CDCl3):7.27(m,3H),5.28(m,2H),4.94(m,1H),3.27(m,2H),1.42(s,9H).
步骤C. 2-(Z-氨基)苯甲酰基-Asp(Obu-t)-DCB-甲基酮.在-45℃向2-(Z-氨基)苯甲酸(140mg,0.52mmol)在THF(5mL)中的溶液加入N-甲基吗啉(65μL,0.59mmol),随后加入氯甲酸-2-甲基丙酯(70μL,0.54mmol)。30分钟后,将Asp(Obu-t)-DCB-甲基酮-HCl在THF(5mL)中的溶液加入到上述溶液中。使所得到的混合物进一步搅拌过夜,用冷却浴使其慢慢地加热到室温。用1∶1的正己烷/EtOAc(100mL)稀释,用水、2N HaOH和盐水洗涤,Na2SO4干燥,真空浓缩。残留物用色谱法纯化(3∶1正己烷/EtOAc),得到标题化合物,为白色固体(365mg,0.05mmol,19%)。
1H NMR(CDCl3):10.90(s,1H),8.49(d,J=7.5,1H),7.87(dd,J=8.1,1.8,1H),7.56-7.32(m,9H),7.08(t,J=6.9,1H),5.23(s,2H),5.28(m,1H),4.90(d,J=1.8,2H).3.16-2.91(m,1H),1.43(m,9H).
步骤D.2-(Z-氨基)苯甲酰基-Asp-DCB-甲基酮.使2-(z-氨基)苯甲酰基-Asp(OBu-t)-DCB-甲基酮(35mg)和TFA(1mL)在二氯甲烷(3mL)的溶液在室温下搅拌2小时。该混合物用EtOAc(70mL)稀释,饱和Na2HPO4洗涤到pH~5,而后用水、盐水洗涤,Na2SO4干燥,真空浓缩,得到标题化合物,为白色固体(10mg,0.016mmol,33%)。
1H NMR(CDCl3):10.94(s,1H),8.49(d,J=8.4,1H),7.87(dd,J=8.1,1.5,1H),7.53(m,1H),7.45-7.33(m,8H),7.07(m,1H),5.22(s,2H),5.10-5.07(m,1H),4.90(m,2H),3.11(dd,J=8.4,19.0,1H),2.95(dd,J=1.8,19.0,1H)).
实施例19
甲氧基羧基-Val-(2-氨基苯甲酰基)-Asp-fmk
步骤A.5氟-3-(2-氨基苯甲酰基氨基)-4-羟基戊酸叔丁基酯.HCl.5氟-3-(2-氨基苯甲酰基氨基)-4-羟基戊酸叔丁基酯(80mg,0.174mmol)、Pd/C(23mg)和6N HCl(0.087mL)在乙醇(5mL)中的混合物在氢气氛、室温下搅拌2小时。使该混合物过滤,蒸发溶剂,得到标题产品。在下一步使用,无需纯化。
步骤B.5氟-3-(甲氧基羧基-Val-2-氨基苯甲酰基氨基)-4-羟基戊酸叔丁基酯。在-45℃向甲氧基羰基-Val-OH(31mg,0.17mmol)在THF(5mL)中的溶液加入N-甲基吗啉(38μL,0.34mmol),随后加入氯甲酸异丁基酯(45μL,0.034mmol)。该混合物在-45℃搅拌30分钟,加入5氟-3-(2-氨基苯甲酰基氨基)-4-羟基戊酸叔丁基酯。加入HCl在THF(5ml)中的溶液,接着加入更多的N-甲基吗啉(50μL,0.45mmol)。使所得到的混合物搅拌过夜,用冷却浴使其慢慢地加热到室温。用乙酸乙酯(50mL)稀释后,该混合物用水和盐水洗涤,Na2SO4干燥,真空浓缩。残留物用色谱法纯化(3∶2正己烷∶乙酸乙酯),得到标题化合物,为白色收湿性固体(20mg,0.041mol,24%)。
1H NMR(CDCl3):δ11.36-11.24(m,1H),8.54(d,J=8.7,1H),7.55-7.05(m,4H),5.40(m,1H),4.89-3.85(m,6H),3.71(d,J=1.8,3H),2.84-2.61(m,2H),2.29(m,1H),1.46-1.44(m,9H),1.05-0.98(m,6H).
步骤C,D.甲氧基羧基-Val-(2-氨基苯甲酰基)-Asp-fmk.标题化合物按实施例1步骤C和D描述的类似方法合成。
1H NMR(DMSO-d6):δ12.52(s,1H),11.27(d,J=6.0,1H),9.18(m,1H),7.88-7.54(m,4H),7.20(t,J=7.5,1H),5.39-4.44(m,3H),3.83(m,1H),3.57(d,J=2.4,3H),2.96-2.65(m,2H),2.18(m,1H),0.92(t,J=6.3,6H).
实施例20
酶活性
2-(Z-氨基)苯甲酰基-Asp-fmk作为天冬氨酸特异性半胱氨酸蛋白酶-3的抑制剂的活性,通过酶的荧光测定进行测定。利用附着在荧光离去基因上的合成肽底物测定酶活性。合成底物由酶的断裂导致在荧光分光光度计上或荧光微量滴定板阅读器上可阅读的荧光讯号。
在酶测定中测试了12个试验化合物的浓度,从30pM到10μM。酶的反应是在2ngr天冬氨酸特异性半胱氨酸蛋白酶3(购自PharMimgen,Becton分公司,San Diego,CA)、各种浓度的试验化合物、10μM天冬氨酸特异性半胱氨酸蛋白酶3底物Ac-DEVA-AMC(购自Quality
Controlled Biochemicals,Inc.Hopkinton,MA)和天冬氨酸特异性半胱氨酸蛋白酶缓冲液(20mMPIPES,100mMNaCl,10mM DTT,1mM EDTA,0.1%CHAPS和10%蔗糖,pH7.2)存在下进行的,总体积为100μL。酶的反应是在96孔板中进行的,在37℃孵化30分钟。而后该板由荧光板阅读器(EG&G WALLAG 1420-002)利用刺激过滤器在355nm/发射过滤器在460nm阅读。所得数据由GraphPrism软件进行分析,得到0.2μM的IC50值。
到此我们对本发明已进行了充分的描述,本领域普遍专业技术人员将认识到,同类型的产品是可在很宽和相当范围的条件、配方和其他参数下实施,而不影响本发明的范围或其任意的实施方案。这里所引用的所有专利、专利申请和出版物都全部纳入以供整体参考。
Claims (65)
R1是任意取代的烷基或氢;
R3是N-保护基团;
R2是氢或任意取代的烷基;
Q表示任意取代的饱和或部分饱和的碳环或杂环;
X是1-4氨基酸的肽或是键;和
Y是1-4氨基酸的肽或是键;
A是CR6或氮;
B是CR7或氮;
C是CR8或氮;
D是CR9或氮;
条件是A,B,C或D中不能有两个以上是氮;和R6-R9各自独立地是氢、卤素、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、氰基、C1-C6酰氨基、羟基、C1-C6酰氧基、C1-C6烷氧基、烷硫基、或羧基;或
R6和R7,或R7和R8,或R8和R9之一与它们所连接的碳原子一起形成碳环或杂环;
E是CR14、氮、氧或硫;
F是CR15、氮、氧或硫;
G是CR16、氮、氧或硫;
条件是E,F,G中只有一个是氮、氧或硫;其中R14-R16各自独立地是氢、卤素、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、氰基、C1-C6酰氨基、羟基、C1-C6酰氧基、C1-C6烷氧基、烷硫基、或羧基;或
R14和R15,或R15和R16之一与它们所连接的碳原子一起形成碳环或杂环。
2、按照权利要求1的化合物,其中的R3是叔丁氧羰基、乙酰基和苄氧羰基;
3、按照权利要求1的化合物,其中的R1是H、Me、Et或乙酰氧基甲基。
4、按照权利要求1的化合物,其中的R2是氢、氟甲基、酰氧基甲基、芳基酰氧基甲基或氨基甲基。
5、按照权利要求1的化合物,其中的X是键。
6、按照权利要求1的化合物,其中的A、B、C和D是CH。
7、按照权利要求1的化合物,其中的A是氮,和B、C和D是CH。
8、按照权利要求1的化合物,其中的G是硫,和E和F是CH。
9、按照权利要求1的化合物,其中的Q是环己基或环戊基。
其中R2是氢或任意取代的烷基,其中的取代基是卤素、羟基、烷氧基、芳氧基、烷硫基、芳硫基、氨基、酰氧基或芳基酰氧基;R6-R9各自独立地是氢、卤素、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C1-C6烷基、C2-C6链烯基、C2-C6炔基、C6-C10芳基(C1-C6)烷基、C6-C10芳基(C2-C6)链烯基、C6-C10芳基(C2-C6)炔基、C1-C6羟基烷基、硝基、氨基、氰基、C1-C6酰氨基、羟基、C1-C6酰氧基、C1-C6烷氧基、烷硫基、或羧基;或
R6和R7,或R7和R8,或R8和R9之一与它们所连接的碳原子一起形成碳环或杂环,选自下述基团:-OCH2O-,-OCF2O-,-(CH2)3-,-(CH2)4-,-OCH2CH2O-,-CH2N(R13)CH2-,-CH2CH2N(R13)CH2-,-CH2N(R13)CH2CH2-和-CH=CH-CH=CH-;其中R13是氢、烷基或环烷基;
R10是氢、C1-C6烷氧基、C1-C6烷基、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C6-C10芳基(C1-C6)烷基、苄氧基、取代的苄氧基、或NR11R12,其中R11和R12各自独立地是氢、C1-C6烷基、C1-C6卤代烷基、C6-C10芳基、C4-C7环烷基、C6-C10芳基(C1-C6)烷基,或R11和R12结合形成选自吡咯烷、哌啶、哌嗪或吗啉的杂环系统。
11、按照权利要求10的化合物,其中的R2是氢、氟甲基、酰氧基甲基、芳基酰氧基甲基和氨基甲基。
12、按照权利要求10的化合物,其中的R10是苄氧基。
13、按照权利要求10的化合物,其中的R1是H,Me或乙酰氧基甲基。
14、按照权利要求10的化合物,其中的X是1-2氨基酸的肽或键。
15、按照权利要求1的化合物,其中所述的化合物选自下述化合物:
2-(Z-氨基)苯甲酰基-Asp-fmk,
2-(Z-氨基)-3-甲基苯甲酰基-Asp-fmk,
2-(Z-氨基)-3,5-二甲基苯甲酰基-Asp-fmk,
2-(Z-氨基)-4-氯苯甲酰基-Asp-fmk,
2-(Z-氨基)-5-氯苯甲酰基-Asp-fmk,
2-(Z-氨基)-5-氟苯甲酰基-Asp-fmk,
2-(Z-氨基)-6-氟苯甲酰基-Asp-fmk,
顺式-2-(Z-氨基)-环己烷羧基-Asp-fmk,
2-(Z-氨基)-5-甲基苯甲酰基-Asp-fmk,
2-(Z-氨基)-6-甲基苯甲酰基-Asp-fmk,
2-(Z-氨基)-6-氯苯甲酰基-Asp-fmk,
2-(Z-氨基)-3-甲氧基苯甲酰基-Asp-fmk,
3-(Z-氨基)噻吩-2-羧基-Asp-fmk,
3-(甲氧羰基氨基)噻吩-2-羧基-Asp-fmk,
顺式-2-(Z-氨基)-环戊烷羧基-Asp-fmk,
反式-2-(Z-氨基)-环戊烷羧基-Asp-fmk,
2-(Z-氨基)苯甲酰基-Asp-DCB-甲基酮,
甲氧羰基-Val-(2-氨基苯甲酰基)-Asp-fmk,
Z-Glu-(2-氨基苯甲酰基)-Asp-fmk,和
Z-Val-(2-氨基苯甲酰基)-Asp-fmk。
16、药物组合物,该组合物含有权利要求1的化合物,以及药用载体。
17、抑制细胞或组织死亡的方法,该方法包括使所述的细胞或组织与有效量的权利要求1化合物接触。
18、治疗或缓解动物的中枢或外周神经系统、视黄醛神经元、心肌或免疫系统细胞中细胞死亡的方法,该方法包括给需要进行这种治疗或缓解的动物施用有效量的权利要求1化合物。
19、权利要求18的方法,其中所述的细胞死亡是指中枢或外周神经系统的细胞死亡,并且细胞死亡是由于下述原因之一:
(a)选自下述的缺血和兴奋中毒症状:由脑中风引起的局部缺血和由心脏停搏引起的整体缺血;
(b)外伤性损伤;
(c)病毒感染;
(d)辐射引起的神经细胞死亡;
(e)选自下述的神经变性疾病:阿尔茨海默氏病、帕金森病、蛋白质致病颗粒疾病、多发性硬化症、肌萎缩性侧索硬化和脊髓延髓萎缩;
(f)脊髓损伤;或
(g)急性细菌性脑膜炎。
20、权利要求18的方法,其中所述的细胞死亡是指中枢或外周神经系统的细胞死亡,并且细胞死亡是由于三核苷酸的扩大重复了特定的基因。
21、权利要求18的方法,其中所述的细胞死亡是由于亨廷顿病。
22、权利要求18的方法,其中所述的细胞死亡是指心肌组织的细胞死亡,并且是由于心肌梗塞、充血性心力衰竭、心肌病或心脏的病毒感染。
23、权利要求18的方法,其中所述的细胞死亡是指视黄醛神经元的细胞死亡,并且是由于眼球内压力增加、与年龄有关的斑疹变性或视网膜色素变性。
24、权利要求18的方法,其中所述的细胞死亡是指免疫系统中的细胞死亡,并且是由于选自下述的免疫缺陷疾病:获得性免疫缺陷综合症、重度复合性免疫缺陷综合症和辐射引起的免疫抑制。
25、权利要求18的方法,其中所述的细胞死亡是由于选自红斑狼疮、风湿性关节炎和I型糖尿病的自身免疫疾病。
26、权利要求18的方法,其中所述的细胞死亡是由于I型糖尿病。
27、治疗或预防动物疾病的方法,所述的疾病是指多囊的肾病、肾淀粉样变性、急性肾衰竭、环孢霉素A诱导的管状上皮细胞死亡、缺氧引起的肾近端小管坏死、HIV诱导的动物肾病或贫血症/红细胞生成,该方法包括给需要进行这种治疗的动物施用有效量的权利要求1化合物。
28、保护哺乳动物器官或组织不发生由于缺乏正常的血液供应而造成细胞死亡的方法,该方法包括使所述的器官或组织与有效量的权利要求1化合物接触。
29、权利要求28的方法,其中所述的器官或组织在移植给哺乳动物之前置于储存介质中。
30、权利要求28的方法,其中所述的接触包括将所述的化合物输注给器官或组织,或者将所述的器官或组织浸浴在含有所述化合物的储存介质中。
31、在移植给宿主之后减少或防止供体的器官或组织细胞由于再灌注损伤或宿主免疫细胞的作用造成的细胞死亡的方法,该方法包括给需要这种治疗的宿主施用有效量的权利要求1化合物。
32、为了减少或防止用于体外受精过程的哺乳动物的精子或卵子死亡的方法,该方法包括使所述的精子或卵子与有效量的权利要求1化合物接触。
33、延长哺乳动物或酵母细胞系寿命的方法,该方法包括使所述的细胞系与有效量的权利要求1化合物接触。
34、权利要求33的方法,其中所述的接触包括在细胞生长介质中含有所述的化合物。
35、治疗或减少哺乳动物脱发或使头发过早变灰的方法,该方法包括使需要这种治疗的头发或毛囊与有效量的权利要求1化合物接触。
36、权利要求35的方法,其中是治疗脱发,所述的脱发是由于男性脱发、放疗、化疗或情绪紧张。
37、治疗或减少哺乳动物由于和大量的辐射、热或化学品接触造成皮肤损伤的方法,该方法包括将权利要求1化合物应用于需要这种治疗的哺乳动物。
38、权利要求37的方法,其中所述的化合物以乳膏的形式使用。
39、权利要求37的方法,其中所述的皮肤损伤是由于急性的过度接触阳光,以及其中所述的治疗可减少皮肤起水疱和脱皮。
40、治疗或缓解动物败血病或多种器官衰竭的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
41、治疗或缓解动物肝炎的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
42、治疗或缓解动物I型遗传性酪氨酸血症的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
43、治疗或缓解动物慢性酒精摄入引起的口腔粘膜细胞死亡的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
44、治疗或缓解植物或鲜花的细胞死亡的方法,该方法包括给需要这种治疗的植物或鲜花的细胞施用有效量的权利要求1化合物。
45、治疗或缓解由于辐射或紫外线照射引起的动物细胞死亡的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
46、治疗或缓解髓发育不良综合征(MDS)中骨髓细胞的编程性细胞死亡的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
47、治疗或缓解急性胰腺炎中细胞的编程性细胞死亡的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
48、治疗或预防牛皮癣或炎性肠疾病中炎性反应的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
49、治疗或缓解烫伤后器官的编程性细胞死亡的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
50、治疗或缓解肠缺血再灌输后小肠组织损伤的方法,该方法包括给需要这种治疗的动物施用有效量的权利要求1化合物。
51、治疗、缓解或预防动物的口腔粘膜炎、胃肠道粘膜炎、膀胱粘膜炎、腮腺炎、骨髓细胞死亡、皮肤细胞死亡或癌症化疗或放射治疗引起的头发损失的方法,该方法包括给需要进行这种治疗的动物施用有效量的权利要求1化合物。
52、权利要求51的方法,其中所述的化合物是以局部或口服给药。
53、权利要求52的方法,其中所述的化合物以漱口剂的一部分给药用于治疗、缓解或预防口腔粘膜炎。
54、权利要求52的方法,其中所述的化合物是以缓慢释放的口含锭剂的一部分给药。
55、权利要求52的方法,其中所述的化合物以栓剂的一部分给药。
56、权利要求52的方法,其中所述的化合物以胶体的一部分制剂。
57、权利要求52的方法,其中所述的化合物通过膀胱导尿管给药以治疗、缓解或预防膀胱粘膜炎。
58、权利要求52的方法,其中所述的化合物以灌肠剂的一部分给药以治疗、缓解或预防动物的腮腺炎。
59、权利要求52的方法,其中所述的化合物通过口服制剂给药,该制剂能够涂覆于胃肠表面以治疗、缓解或预防动物的胃肠道粘膜炎。
60、权利要求59的方法,其中的胃肠道粘膜炎是食道粘膜炎、胃粘膜炎或肠粘膜炎。
61、权利要求51的方法,其中所述的化合物静脉注射以治疗、缓解或预防骨髓细胞死亡。
62、权利要求51的方法,其中所述的化合物以药物组合物的一部分给药,该药物组合物含有药用载体。
63、权利要求51的方法,其中所述的化合物是在所述的动物的癌症化疗或放疗之后给药。
64、权利要求51的方法,其中所述的化合物是在所述的动物的癌症化疗或放疗期间给药。
65、权利要求51的方法,其中所述的化合物是在所述的动物的癌症化疗或放疗之前给药。
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EP (1) | EP1165490B1 (zh) |
JP (1) | JP2002539183A (zh) |
KR (1) | KR20010110667A (zh) |
CN (1) | CN1346344A (zh) |
AT (1) | ATE336480T1 (zh) |
AU (1) | AU3876600A (zh) |
CA (1) | CA2367340A1 (zh) |
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- 2000-03-15 JP JP2000605545A patent/JP2002539183A/ja not_active Withdrawn
- 2000-03-15 CN CN00805049A patent/CN1346344A/zh active Pending
- 2000-03-15 AU AU38766/00A patent/AU3876600A/en not_active Abandoned
- 2000-03-15 KR KR1020017011734A patent/KR20010110667A/ko not_active Application Discontinuation
- 2000-03-15 DE DE60030097T patent/DE60030097T2/de not_active Expired - Fee Related
- 2000-03-15 EP EP00917859A patent/EP1165490B1/en not_active Expired - Lifetime
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101919833A (zh) * | 2010-07-16 | 2010-12-22 | 暨南大学 | 一种芳香类化合物作为制备Caspase 3抑制剂的用途 |
CN106317161A (zh) * | 2015-06-29 | 2017-01-11 | 深圳翰宇药业股份有限公司 | 一种氟甲基酮肽系列化合物的制备方法 |
CN106317161B (zh) * | 2015-06-29 | 2020-05-15 | 深圳翰宇药业股份有限公司 | 一种氟甲基酮肽系列化合物的制备方法 |
CN108355134A (zh) * | 2017-01-26 | 2018-08-03 | 上海交通大学 | 胱氨酸蛋白酶抑制剂在制备治疗或预防紫外光诱导的皮肤损伤药物中的应用 |
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WO2000055114A1 (en) | 2000-09-21 |
DE60030097T2 (de) | 2007-03-08 |
DE60030097D1 (de) | 2006-09-28 |
ATE336480T1 (de) | 2006-09-15 |
US6620782B1 (en) | 2003-09-16 |
AU3876600A (en) | 2000-10-04 |
KR20010110667A (ko) | 2001-12-13 |
EP1165490B1 (en) | 2006-08-16 |
CA2367340A1 (en) | 2000-09-21 |
EP1165490A4 (en) | 2002-09-18 |
US20030181388A1 (en) | 2003-09-25 |
EP1165490A1 (en) | 2002-01-02 |
JP2002539183A (ja) | 2002-11-19 |
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