CN1274288A - 含肽的α-酮酰胺半胱氨酸和丝氨酸蛋白酶抑制剂 - Google Patents
含肽的α-酮酰胺半胱氨酸和丝氨酸蛋白酶抑制剂 Download PDFInfo
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- CN1274288A CN1274288A CN98809921A CN98809921A CN1274288A CN 1274288 A CN1274288 A CN 1274288A CN 98809921 A CN98809921 A CN 98809921A CN 98809921 A CN98809921 A CN 98809921A CN 1274288 A CN1274288 A CN 1274288A
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- alkyl
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- heteroaryl
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Abstract
本发明公开了含肽的α-酮酰胺半胱氨酸蛋白酶和丝氨酸蛋白酶抑制剂,制备这些化合物的方法以及其应用方法。
Description
相关申请的引用
本申请要求美国临时申请(申请序号为60/061,309,申请日为1997.10.7)和名称为“含肽的α-酮酰胺半胱氨酸和丝氨酸蛋白酶抑制剂”的美国申请(申请日为1998.10.6)的利益,因此,它们的公开内容在此全部引用。
发明领域
本申请涉及含肽的α-酮酰胺半胱氨酸和丝氨酸蛋白酶抑制剂,制备这些化合物的方法及其使用方法。
发明背景技术
已经确认在人体组织中有许多半胱氨酸和丝氨酸蛋白酶,“蛋白酶”是将蛋白降解为更小组分(肽)的酶。术语“半胱氨酸蛋白酶”和“丝氨酸蛋白酶”是指以其中存在在催化过程中起关键作用的半胱氨酸或丝氨酸残基为显著特征的蛋白酶。哺乳动物,包括人,一般通过包括半胱氨酸或丝氨酸蛋白酶在内的各种各样的酶降解和加工蛋白。但是,在高浓度或非正常激活条件下,半胱氨酸或丝氨酸蛋白酶可以引起病理学过程。
例如,钙-激活的中性蛋白酶(“钙蛋白酶类”)包括一族细胞内半胱氨酸酶,它们普遍存在于在哺乳动物组织内。已经确认有两种主要的钙蛋白酶-钙蛋白酶I和钙蛋白酶II。钙蛋白酶II在许多组织中为主要存在形式,而钙蛋白酶I则被认为是在病理状况下的神经组织中主要存在形式。半胱氨酸酶类的钙蛋白酶族涉及许多疾病和功能失调,包括神经退化、中风、阿尔茨海默症、肌萎缩、运动神经损伤、急性中枢神经***损伤、肌营养不良、骨吸收、血小板聚集、白内障和炎症。钙蛋白酶I涉及兴奋性氨基酸引起的神经中毒疾病,包括局部缺血、低血糖、亨廷顿疾病、和癫痫。溶酶体半胱氨酸蛋白酶组织蛋白酶B与以下疾病有关:关节炎、炎症、心肌梗塞、肿瘤转移和肌营养不良。其它溶酶体半胱氨酸蛋白酶包括组织蛋白酶类C、H、L和S。白介素-1β转化酶(“ICE”)是一种催化白介素-1β生成的半胱氨酸蛋白酶,白介素-1β是一种涉及以下疾病的免疫调节蛋白:炎症、糖尿病、脓毒性休克、类风湿关节炎和阿尔茨海默疾病。ICE还与涉及各种神经退化性疾病的编程性细胞死亡有关,这些疾病包括帕金森疾病、局部缺血、肌萎缩性侧索硬化(ALS)。
半胱氨酸蛋白酶也可由各种病原体生产,一种半胱氨酸蛋白酶-梭菌蛋白酶是由梭状芽胞杆菌(histolyticum菌)生产的,其它蛋白酶由Cruzi锥虫、疟疾寄生物疟疾疟原虫和文氏疟原虫以及链球菌生产。甲肝病毒蛋白酶HAV C3是一种对细小RNA病毒结构蛋白和结构酶的合成至关重要的半胱氨酸蛋白酶。
与退化性疾病有关的丝氨酸蛋白酶举例包括凝血酶、人白细胞弹性蛋白酶、胰弹性蛋白酶、胃促胰酶和组织蛋白酶G。具体地说,凝血酶是在血液凝固级联中产生的,裂解血纤蛋白原成血纤蛋白并激活凝血因子VIII,凝血酶与下列疾病有关:血栓静脉炎、血栓形成和哮喘;人白细胞弹性蛋白酶与组织退化疾病有关;如类风湿关节炎、骨关节炎、动脉粥样硬化、支气管炎、囊纤维化和肺气肿;胰弹性蛋白酶与胰腺炎有关;胃促胰酶是一种在合成血管紧张素中起重要作用的酶,与高血压、心肌***和冠状心脏病有关;组织蛋白酶G与异常***退化有关,尤其是在肺部。
根据已知的半胱氨酸和丝氨酸蛋白酶与各种衰弱性疾病的关系,抑制这些酶的化合物是有用的,并能够促进在研究和临床药物两方面的发展。本发明的目的即在于此,以及其它重要的结果。
发明概要
Q具有结构式G-B-(CHR4)v,其中R4独立地是H或具有1-4个碳原子的烷基;
v是0、1或2;
B选自C(=O)、OC(=O)、S(=O)m、CH2、键、NR5C(=O)、S(=O)m-A-C(=O)和C(=O)-A-C(=O),其中,R5是H或低级烷基;
m是0、1或2;
A是低级亚烷基或亚环烷基,且任选地被一个或多个卤原子、芳基或杂芳基取代;
M为碳原子;
G选自H、保护基团、低级烷基、低级链烯基、具有约6-约14个碳原子的芳基、具有约5-约14个环原子的杂环基、具有约5-约14个环原子的杂环烷基、具有约7-约15个碳原子的芳烷基、杂芳基烷基、芳基杂烷基(其中芳基部分可以不稠合或与该杂烷基环稠合),所述烷基、芳基、杂环基、杂环烷基、芳基烷基、杂芳烷基和芳基杂烷基任选地被一个或多个J基团取代;
J选自卤素、氰基、硝基、低级烷基、环烷基、杂环烷基、杂烷基、卤代烷基、芳氧基烷基、烷硫基、烷基磺酰基、芳基、杂芳基、芳烷基、芳基烷氧基、芳基磺酰基、杂芳基磺酰基、烷氧羰基、烷氧基烷基、酰基、烷氧基、羟基、羧基、羟基烷基、氨基、烷基氨基、氨基烷基,所述氨基或所述烷基氨基或氨基烷基中的‘氨基’任选地被一个酰基、烷氧基或者被1-3个芳基、低级烷基、环烷基或烷氧基烷基所取代;所述芳基、杂芳基、杂环烷基和杂烷基可进一步任选地被一个J基团取代;
每个Aaa独立地是任选地含有一个或多个保护基团的氨基酸;
n是0、1、2或3;
R1和R2独立地选自H、具有1-约6个碳原子的烷基、具有约7-约15个碳原子的芳烷基、环上含有约5-约14个环原子的杂烷基、杂芳环上含有约5-约14个环原子的杂芳基烷基、烷氧基烷基、具有R或S构型的天然氨基酸侧链和(CH2)pNH-L,所述烷基、芳烷基、杂烷基、杂芳基烷基和烷氧基烷基任选地被一个或多个J基团取代;
p是0、1、2或3;
L选自具有2-约7个碳原子的烷氧羰基、其中芳基烷氧基含有约7-约15个碳原子的芳基烷氧羰基和S(=O)2R6;
R6选自低级烷基和具有约6-约14个碳原子的芳基;
R3选自H、具有1-约6个碳原子的烷基、具有约7-约15个碳原子的芳烷基、环上含有约5-约14个环原子的杂烷基、杂芳环上含有约5-约14个环原子的杂芳基烷基、烷氧基烷基、具有R或S构型的天然氨基酸侧链、(CH2)pNH-L、C(=O)R7、S(=O)2R7和保护基团,当其与R1连接的碳原子结合时,表示一个具有2-5个碳原子的亚烷基,该亚烷基任选地被选自下面的基团所取代:芳基、叠氮基、CN、已保护的氨基和OSO2-芳基;所述烷基、芳烷基、杂烷基、杂芳基烷基和烷氧基烷基任选地被一个或多个J基团取代;
R7选自:具有约6-约14个碳原子的芳基、具有约5-约14个环原子的杂芳基、具有约7-约15个碳原子的芳烷基、具有1-约10个碳原子的烷基,所述芳基、杂芳基、芳烷基和烷基任选地被一个或多个J基团、具有2-约7个碳原子的杂烷基、具有1-约10个碳原子的烷氧基和任选地被一个或多个烷基取代的氨基取代;
q是0或1;
X是单键或-O-;
A1同A;
D为稠合的芳基或杂芳基;
R11选自烷氧基、芳氧基和NHR12;
R12选自H、烷基、芳基和杂芳基,所述烷基、芳基和杂芳基任选地被一个或多个J基团所取代;
Y选自基团SO2R8、C(=O)NHR9、C(=S)NHR9、C(=NCN)R11、C(=NC(=O)NHR10)R11和CO2R8;
R8选自烷基、烷氧基、芳基和杂环基,所述烷基、烷氧基、芳基和杂环基任选地被一个或多个J基团所取代;
R9选自H、烷基、芳基、和杂芳基,所述烷基、芳基和杂芳基任选地被一个或多个J基团所取代;
或者R9烷基可以与A1亚烷基连接形成一个含氮的5-或6-元杂环;
R10选自H和低级烷基;
或者在基团SO2N(R8)(R10)中,R8和R10可以一起与它们所连接的N原子连接形成一个含氮的5-或6-元杂环;
或者在A1是亚烷基、K是N(R10)Y(其中R10是烷基)的条件下,所述R10可以与所述亚烷基A1连接形成一个含氮的5-或6-元杂环;或者上述化合物的可药用盐。
在式I化合物的优选实施方案中,n和v均为0,q为1,B是键,以及G是H。在式I化合物的更优选的实施方案中,R1是天然氨基酸侧链;在式I化合物进一步优选的实施方案中,R3为-S(=O)2R7。
在式I化合物的优选实施方案中,R2是苄基或烷氧基烷基,更优选的实施方案为,X是单键,以及Y是SO2R8;优选A1是-CH2-CH2-、-CH2-CH(CH3)-或-(CH3)CH-CH2-。
在式I化合物的更优选的实施方案中,R1是丝氨酸侧链,它任选地被苄基封端。优选地,丝氨酸侧链所连接的碳原子,即式I中表示的“M”为D-构型碳原子。
在式I化合物的优选实施方案中,R2是苄基,R7为甲基,R8为取代的苯基、未取代的苯基、取代的杂芳基或未取代的杂芳基;在特别优选的实施方案中,R8为芳基、被氨基取代的芳基、被杂环基甲基取代的芳基、杂芳基、被杂芳基取代的烷基,或被烷硫基、卤代烷基、烷基、苯磺酰基、卤素、氨基苯基、氨基或二烷基氨基烷基所取代的杂芳基。
在式I化合物进一步优选的实施方案中,n、v或q均为0,B是(C=O),以及G是苯基或低级烷基,所述苯基或低级烷基任选地被一个或多个J基团所取代。
在式I化合物的更优选的实施方案中,n、v均为0,q是1,R1是D-或L-构型的氨基酸侧链,R3为-S(=O)2R7,G是H,B是单键,R2是苄基或烷氧基烷基,X是单键,以及Y是SO2R8。
在其它优选实施方案中,A1是CH2CH2、CH2CH(CH3)或(CH3)CHCH2。在更优选的实施方案中,R1是D-构型的丝氨酸侧链且其羟基被苄基所覆盖,R2是苄基,R7为甲基,R8是取代的或未取代的苯基或者是取代的或未取代的杂芳基。
更优选的是表2、3、4和5中所列化合物的R1-R4、B、G、Aaa、X、A1、Y、n、q和v所示的取代基,特别优选的是化合物9、13、17、22和29-151所示的取代基。
式I化合物特别优选的实施方案如下面的表2、3、4和5所示,并特别优选化合物9、13、17、22和29-151。
由于本发明的含肽的α-酮酰胺能抑制半胱氨酸蛋白酶和丝氨酸蛋白酶,它们可以用于研究和治疗两方面。
在研究场合,具有确定属性的优选化合物可用于筛选那些在抑制蛋白酶活性方面表现出相似性质的天然和合成的化合物。该化合物还可用于改进在特定细胞模式和生物学条件下测定对特定蛋白酶抑制作用的体外和体内模型。
在治疗应用中,在半胱氨酸蛋白酶与某些具体疾病之间、丝氨酸蛋白酶与某些具体疾病之间的关系已知的情况下,本发明化合物可用于减轻、缓解、减少和/或预防那些与半胱氨酸蛋白酶和/或丝氨酸蛋白酶的异常和/或畸形活跃有关的疾病。
在优选的实施方案中,提供了含有本发明化合物和药学上可接受的载体的抑制丝氨酸蛋白酶或半胱氨酸蛋白酶的组合物。在另一个优选的实施方案中,提供抑制丝氨酸蛋白酶或半胱氨酸蛋白酶的方法,包括以抑制量的本发明化合物接触蛋白酶(选自丝氨酸蛋白酶和半胱氨酸蛋白酶)。
制备本发明含肽的α-酮酰胺抑制剂的方法也公开了。对本领域技术人员而言,一旦了解了本文公开的内容,其它可用的方法是显而易见的。本发明化合物的这些和其它特征在下面进行更详细的描述。发明详述
Q具有结构式G-B-(CHR4)v,其中R4独立地是H或具有1-4个碳原子的烷基;
v是0、1或2;
B选自C(=O)、OC(=O)、S(=O)m、CH2、单键、NR5C(=O)、S(=O)m-A-C(=O)和C(=O)-A-C(=O),其中,R5是H或低级烷基
m是0、1或2;
A是低级亚烷基或亚环烷基,且任选地被一个或多个卤原子、芳基或杂芳基取代;
M为碳原子;
G选自H、保护基团、低级烷基、低级链烯基、具有约6-约14个碳原子的芳基、具有约5-约14个环原子的杂环基、具有约5-约14个环原子的杂环烷基、具有约7-约15个碳原子的芳烷基、杂芳基烷基、芳基杂烷基(其中芳基部分可以不稠合或与该杂烷基环稠合),所述烷基、芳基、杂环基、杂环烷基、芳基烷基、杂芳烷基和芳基杂烷基任选地被一个或多个J基团取代;
J选自卤素、氰基、硝基、低级烷基、环烷基、杂环烷基、杂烷基、卤代烷基、芳氧基烷基、烷硫基、烷基磺酰基、芳基、杂芳基、芳烷基、芳基烷氧基、芳基磺酰基、杂芳基磺酰基、烷氧羰基、烷氧基烷基、酰基、烷氧基、羟基、羧基、羟基烷基、氨基、烷基氨基、氨基烷基,所述氨基或所述烷基氨基或氨基烷基中的‘氨基’任选地被一个酰基、烷氧基或者被1-3个芳基、低级烷基、环烷基或烷氧基烷基所取代;所述芳基、杂芳基、杂环烷基和杂烷基可进一步任选地被J基团取代;
每个Aaa独立地是任选地含有一个或多个保护基团的氨基酸;
n是0、1、2或3;
R1和R2独立地选自H、具有1-约6个碳原子的烷基、具有约7-约15个碳原子的芳烷基、环上含有约5-约14个环原子的杂烷基、杂芳环上含有约5-约14个环原子的杂芳基烷基、烷氧基烷基、具有R或S构型的天然氨基酸侧链和(CH2)pNH-L,所述烷基、芳烷基、杂烷基、杂芳基烷基和烷氧基烷基任选地被一个或多个J基团取代;
p是0、1、2或3;
L选自具有2-约7个碳原子的烷氧羰基、其中芳基烷氧基含有约7-约15个碳原子的芳基烷氧羰基和S(=O)2R6;
R6选自低级烷基和具有约6-约14个碳原子的芳基;
R3选自H、具有1-约6个碳原子的烷基、具有约7-约15个碳原子的芳烷基、环上含有约5-约14个环原子的杂烷基、杂芳环上含有约5-约14个环原子的杂芳基烷基、烷氧基烷基、具有R或S构型的天然氨基酸侧链、(CH2)pNH-L、C(=O)R7、S(=O)2R7和保护基团,当其与R1连接的碳原子结合时,表示一个具有2-5个碳原子的亚烷基,该亚烷基任选地被选自下面的基团所取代:芳基、叠氮基、CN、已保护的氨基和OSO2-芳基;所述烷基、芳烷基、杂烷基、杂芳基烷基和烷氧基烷基任选地被一个或多个J基团取代;
R7选自:具有约6-约14个碳原子的芳基、具有约5-约14个环原子的杂芳基、具有约7-约15个碳原子的芳烷基、具有1-约10个碳原子的烷基,所述芳基、杂芳基、芳烷基和烷基任选地被一个或多个J基团、具有2-约7个碳原子的杂烷基、具有1-约10个碳原子的烷氧基和任选地被一个或多个烷基取代的氨基取代;
q是0或1;
X是单键或-O-;
A1同A;
K选自基团N(R10)Y、
和SO2N(R8)(R10);
D为稠合的芳基或杂芳基;
R11选自烷氧基、芳氧基和NHR12;
R12选自H、烷基、芳基和杂芳基,所述烷基、芳基和杂芳基任选地被一个或多个J基团所取代;
Y选自基团SO2R8、C(=O)NHR9、C(=S)NHR9、C(=NCN)R11、C(=NC(=O)NHR10)R11和CO2R8;
R8选自烷基、烷氧基、芳基和杂环基,所述烷基、烷氧基、芳基和杂环基任选地被一个或多个J基团所取代;
R9选自H、烷基、芳基、和杂芳基,所述烷基、芳基和杂芳基任选地被一个或多个J基团所取代;
或者R9烷基可以与A1亚烷基连接形成一个含氮的5-或6-元杂环;
R10选自H和低级烷基;
或者在基团SO2N(R8)(R10)中,R8和R10可以一起与它们所连接的N原子连接形成一个含氮的5-或6-元杂环;
或者在A1是亚烷基、K是N(R10)Y(其中R10是烷基)的条件下,所述R10可以与亚烷基A1连接形成一个含氮的5-或6-元杂环;或者上述化合物的可药用盐。
应当承认,式I化合物可以存在各种不同的立体异构体形式,本发明的优选化合物具有的Aaa基团都是L-构型氨基酸,然而它们的外消旋体和独立对映异构体及其混合物都是本发明的组成部分。
式I化合物中表示为“M”的碳原子可以存在D-或L-构型,在优选实施方案中,M是具有D-构型的碳原子。
所用的术语“烷基”包括直链和支链烃基,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、1-乙基戊基、己基和辛基。“环烷基”是指环状的烷基,如环丙基、甲基环戊基和环己基。优选的烷基具有1-约10个碳原子,最优选具有1-约6个碳原子的“低级烷基”。“亚烷基”是具有两个连接点的烷基,即无终端的烷基;“低级亚烷基”是具有1-约6个碳原子的支链和非支链亚烷基,如亚乙基(-CH2CH2-)、亚丙基、亚丁基、亚己基、1-甲基亚乙基、2-甲基亚乙基和2-甲基亚丙基。“亚环烷基”是环状的亚烷基。“酰基”是烷基羰基。“芳基”是指芳香环化合物,优选包括但不限于苯基、甲苯基、萘基、蒽基、菲基和芘基;含有两个以键连接的芳环的环系也包括在“芳基”的定义中,如联苯基;优选的芳基包括苯基和萘基。
所用的术语“碳环”是指环部分仅由碳原子组成的环基团。术语“卤素”是指F、Cl、Br和I原子。术语“芳基烷基”(或“芳烷基”)是指带有芳基的烷基,如苄基。所用的”烷氧基“是通过氧原子连接的烷基,烷氧基的举例包括甲氧基(-OCH3)和乙氧基(-OCH2CH3)。一般地,术语“氧基”作为后缀时表示通过氧原子连接,因此,烷氧羰基是含有烷氧基取代基的羰基,即通式为-C(=O)-O-R的基团,其中R是烷基。术语“烷氧基烷基”是指连接烷氧基的烷基。术语“芳氧基”表示通过氧原子连接的芳基。术语“芳基烷氧基”是指通过氧原子连接的芳烷基。
术语“杂环”、“杂环基”和“杂环的”是指环部分至少含有一个杂原子(如O、N或S)的环基团,杂环基包括“杂芳基”和“杂烷基”。术语“杂芳基”表示芳环内含有一个或多个杂原子(如O、N或S)的芳基;含有两个以键连接芳环的环系(其中至少一个环含有杂原子)也包括在“杂芳基”的定义中;优选的“杂芳基”包括吡啶基、嘧啶基、吡咯基、呋喃基、噻吩基、咪唑基、***基、四唑基、喹啉基、异喹啉基、苯并咪唑基、噻唑基、联吡啶基、吡啶基噻吩基、嘧啶基噻吩基、苯并咪唑基、异噁唑基噻吩基、吡唑基噻吩基、苯二甲酰亚氨基和苯并噻唑基。术语“杂环烷基”表示通过一个低级烷基连接的杂环。术语“杂芳基烷基”表示通过一个烷基连接的杂芳基。所用的术语“杂烷基”表示杂环上至少含有一个饱和碳原子的杂环基,杂烷基举例包括哌啶、二氢吡啶、四氢异喹啉基。所用术语“芳基杂烷基”表示通过芳基连接的“杂烷基”,芳基杂烷基的一个优选例子是二苯并-γ-吡喃基。
所用的术语“氨基酸”表示同时含有氨基和羧基的的分子,所用的术语“L-氨基酸”表示在α-碳上具有L-构型的α-氨基酸,即具有L-构型和通式为CH(COOH)(NH2)-(侧链)的羧酸。类似地,术语“D-氨基酸”表示在α-碳上具有D-构型的和通式为CH(COOH)(NH2)-(侧链)的羧酸。L-氨基酸的侧链包括天然存在或非天然存在的部分,非天然存在的(即“非天然的”)氨基酸侧链是例如在氨基酸模拟物中,替换天然氨基酸侧链所用的部分,参见Lehninger,“生物化学”(Biochemistry),第2版,Worth Publishers Inc.,1975,pp73-75。具有代表性的氨基酸侧链是赖氨酸侧链,-(CH2)4NH2。其它有代表性的α-氨基酸侧链如下面的表1所示。
表1CH3- HS-CH2-HO-CH2- HO2C-CH(NH2)-CH2-S-S-CH2-C6H5-CH2- CH3-CH2-HO-C6H4-CH2- CH3-S-CH2-CH2-CH3-CH2-S-CH2-CH2-HO-CH2-CH2-CH3-CH(OH)-HO2C-CH2-NHC(=O)-CH2-
HO2C-CH2-CH2-NH2C(=O)-CH2-CH2-(CH3)2-CH-(CH2)2-CH-CH2-CH3-CH2-CH2-H2N-CH2-CH2-CH2-H2N-C(=NH)-NH-CH2-CH2-CH2-H2N-C(=O)-NH-CH2-CH2-CH2-CH3-CH2-CH(CH3)-CH3-CH2-CH2-CH2-H2N-CH2-CH2-CH2-CH2-
式I化合物中的官能团可以包括保护基团,保护基团本身被认为是一类化学官能团,它们可以选择性地连接到官能度上,如羟基、氨基、硫基和羧基。保护基团是可以随时从官能度脱去的基团,这些基团在化合物中使得官能度在化合物露置的反应条件下保持惰性。本发明可以采用各种不同的保护基团,这些保护基团的例子是苄氧羰基(Cbz,Z)、甲苯磺酰基、叔丁氧羰基、甲基酯和苄基醚基团,本发明的其它优选的保护基团可以参见Greene,T.W.和Wuts,P.G.M.的“有机合成中的保护基”(Protective Groups in Organic Synthesis),第2版,Wiley & Sons,1991;在此全部内容引作参考。
应用到本发明化合物的其它保护基团包括那些带有能取代到化合物氨基上的酰基、芳酰基、烷基、烷基磺酰基、芳烷基磺酰基或芳基磺酰基。其它有用的保护基团包括烷基醚,例如,丝氨酸甲基醚。
本发明公开的化合物用于抑制半胱氨酸蛋白酶和丝氨酸蛋白酶。所用的术语“抑制”或“抑制作用”是指对酶的活性具有负效应。抑制量是本发明化合物有效抑制半胱氨酸蛋白酶和/或丝氨酸蛋白酶的用量。
半胱氨酸蛋白酶和丝氨酸蛋白酶抑制剂的药学上可接受的盐同样落在所公开的化合物范围内。所用的术语“药学上可接受的盐”是指无机酸加成盐,如盐酸盐、硫酸盐和磷酸盐,或者有机酸加成盐,如乙酸盐、马来酸盐、富马酸盐、酒石酸盐和柠檬酸盐。药学上可接受的金属盐是碱金属盐(如钠盐和钾盐)、碱土金属盐(如镁盐和钙盐)、铝盐和锌盐。药学上可接受的有机胺加成盐的例子是与吗啉和哌啶所成的盐。药学上可接受的氨基酸加成盐的例子是与赖氨酸、甘氨酸和苯丙氨酸所形成的盐。
所提供的化合物可以与药学上可接受的无毒的赋形剂和载体混合制成药物组合物,如上所述,这些药物组合物可以制成用于非肠道给药的形式,尤其是溶液和悬浮液的形式;或者口服给药形式,尤其是片剂或胶囊;或者鼻内给药形式,尤其是粉剂、滴鼻剂或气雾剂;或者透皮给药形式,如通过透皮膜片;或者制成对本领域技术人员来说是显而易见的这些或其它的适宜的药剂形式。
该组合物可以方便地以单位剂量形式给药,并按照制药领域已知的任何方法进行制备,如“Remington′s Pharmaceutical Sciences”(MackPub.Co.,Easton,PA,1980)中所述。非肠道给药的制剂可以含有常用作赋形剂的蒸馏水或生理盐水、聚二醇如聚乙二醇、油和植物源、氢化萘及其类似物。具体地,具有生物相容性的可生物降解的环二酯聚合物、环二酯/二醇酯共聚物或聚氧乙烯-聚氧丙烯共聚物可用作控制活性化合物释放的有用的赋形剂。其它对这些活性化合物特别有用的非肠道释药体系包括乙烯-乙酸乙烯酯共聚物颗粒、渗透泵、可植入浸剂、环糊精和脂质体。吸入给药制剂可含有赋形剂,如乳糖;或者可以是以滴鼻剂形式给药的含有如聚氧乙烯-9-月桂基醚、甘氨胆酸盐和脱氧胆酸盐的水溶液或油溶液;或者在鼻内使用的凝胶。非肠道给药制剂也可以含有适于口腔给药的甘氨胆酸盐、适于直肠给药的水杨酸酯或适于***给药的柠檬酸。用于透皮膜片的制剂优选是亲油性乳剂。
本发明的物质在药物中可以单独用作活性成分,或者可以与其它有利于抑制疾病状态或功能失调状态下的半胱氨酸和丝氨酸蛋白酶的活性组分结合使用。
所述化合物在治疗组合物中的浓度随许多因素变化,包括所给药物的剂量、所用化合物的化学性质(例如疏水性)和给药途径。一般情况下,本发明的化合物可以按有效抑制量,以含有0.1-10%w/v化合物的生理缓冲水溶液进行非肠道给药,一般剂量范围是每天1μg/kg体重-约1g/kg体重;优选剂量范围为每天0.01mg/kg体重-约100mg/kg体重。这些制剂一般能提供本发明化合物的抑制剂量,但优选的给药剂量可能依赖于各种不同的因素,例如疾病或功能失调的类型或程度、具体患者的整体健康状况、所选化合物的相应的生物效能、化合物赋形剂的配制以及给药途径。
所用的术语“接触”意思是直接或间接引起至少两部分相互发生实质性关联,因此接触包括物理作用,如将几个部分一起置于同一个容器中,或者给药于患者。因此,例如让患有与蛋白酶异常/畸形活跃有关的疾病或功能失调的病人服入本发明化合物,也落在术语“接触”所对应的范围。
本发明将通过下述用来说明的实施例得到进一步的阐明,这些实施例不是,也不应解释为对所公开范围的限定。实施例一般方法:
在硅胶涂层板(MK6F 60A,尺寸1×3英寸,层厚250μm,WhatmanInc.)上进行薄层色谱;在硅胶涂层板(尺寸20×20英寸,层厚1000微米,Analtech)上进行制备性薄层色谱;采用Merck硅胶,40-63μm,230-400目,进行制备性柱色谱;1H NMR谱使用四甲基硅烷作为内标,在300MHZ于GE QE Plus谱仪上记录。电喷雾(electrospray)质谱在VG平台II型仪器(Fisons Instrument)上进行记录。
该化合物,以及本文使用的相关羟基酸均按照Harbeson等人,J.Med.Chem.1994,37,2918-2929所述的一般方法进行合成,它的全部内容引作参考。化合物2的制备
往冷的(-10℃)化合物1(4.30g,0.015mol)的无水甲醇(50mL)溶液中,缓慢加入亚硫酰氯(3.2mL),0.5小时后,撤去冷浴,混合物再搅拌16小时并进行浓缩,得到残留物,将残留物与乙酸乙酯(30mL)一起研磨得到白色固体,过滤分离出固体并干燥,得到3.50g化合物2,直接用于下一步合成。Ms m/e 210(M+H)。化合物3的制备
该化合物的制备如一般方法E所示。化合物4的制备
往冷至0℃的化合物1(1.00g,0.0034mol)的无水DMF(20mL)的溶液中,加入NMM(1.40g,0.014mmol),随后加入1-HOBt(0.54g,0.0040mmol)和BOP(1.80g,0.0040mmol),将混合物搅拌15分钟,并加入化合物3(0.75g,0.0032mmol),撤去冷浴,混合物搅拌4小时,倒入冰水(200mL)中,萃取至乙酸乙酯(3×100mL),有机层用2%柠檬酸溶液(2×50mL)、2%碳酸氢钠溶液(2×50mL)、盐水(1×50mL)洗涤,用无水硫酸钠干燥,减压蒸去溶剂,所得粗固体产物用n-戊烷洗涤数次,得到1.30g化合物4。
化合物4:白色固体(非对映异构体混合物);1H-NMR(DMSO-d6)δ7.90和7.65(2组三重峰,1H),7.75(d,2H),7.55(q,2H),7.15(m,6H),6.55和5.80(2组二重峰,1H),3.90(m,2H),3.30(d,1H),3.10(m,2H),2.75(m,2H),2.50(m,3H),1.20(s,9H),MS m/e 478(M+H),500(M+Na)。化合物5的制备
往化合物4(0.40g,0.84mmol)的1,4-二噁烷(15mL)溶液中,加入4N HCl的二噁烷溶液(15mL),反应混合物于室温下搅拌2小时,然后进行减压浓缩,得到的残留物用乙酸乙酯洗涤数次,真空干燥,得到0.30g化合物5;1H-NMR(DMSO-d6)显示位于δ1.20ppm无tBoc峰;MS m/e 378(M+H);该物质直接用于下一步合成。化合物7的制备:
在0℃的D-Ser(Bn)(化合物6,1.00g,5mmol)和1N NaOH(10mL,10mmol)的混合物中,缓慢加入甲磺酰氯(0.80g,7.69mmol),0.5小时后,撤去冷浴,反应混合物搅拌过夜,并用2N盐酸酸化(pH~2-3),然后用乙酸乙酯(3×50mL)萃取水层,合并后的有机层用水(1×20mL)和盐水(1×20mL)洗涤,MgSO4干燥,蒸去溶剂,得到的残留物重新溶解于二氯乙烷(10mL),加入环己烷生成白色固体,过滤并干燥得到1.02g化合物7。化合物8的制备
按照上述制备化合物4的方法制备该化合物,以NMM/HOBt/BOP作为偶合剂,将化合物7与化合物5偶合。在有些相关的实施例中,EDCI/HOBt被用作偶合剂。化合物9的制备
往冷至0℃的化合物8(0.31g,0.49mmol)的无水二氯甲烷(10mL)的溶液中,加入Dess-Martin全碘烷试剂(periodinane agent)(0.425g,1.00mmol),撤去冷浴,混合物再搅拌1小时,然后将混合物用二氯甲烷(10mL)稀释,并用10%硫代硫酸钠溶液(5×5mL)、饱和碳酸氢钠溶液(2×5mL)和盐水(1×5mL)洗涤,无水硫酸钠干燥,并减压除去溶剂,所得残留物用n-戊烷(10mL)洗涤并真空干燥,得到0.178g化合物9。1H-NMR谱显示发生了少量的差向异构。
化合物9:白色固体;1H-NMR(DMSO-d6)δ8.75(t,1H),8.60和8.50(两个双重峰,1H),7.75(d,2H),7.65-7.00(系列多重峰,15H),5.25(宽峰m,1H),4.45和4.235(两个单峰,2H),4.15(m,1H),3.35-2.60(系列多重峰,8H),3.35和3.25(两个单峰,3H),MS m/e631(M+H),653(M+Na)。实施例2按照一般方法B制备化合物13一般方法B
在一般方法B中,将如上述方法制备的化合物4,用Dess-Martin全碘烷试剂(periodinane agent)进行氧化,生成的化合物10进行tBoc-脱保护(2N HCl的二噁烷溶液),生成铵盐化合物11,将化合物11与N-苯磺酰基-(L)-Pro(化合物12)偶合(NMM/HOBt/BOP)制得化合物13。提纯是将粗产物的二氯甲烷溶液通过Sep-PakVac 6cc(1g)硅胶柱(Waters Corporation,Milford,MA)并先后用二氯甲烷、二氯甲烷和乙酸乙酯的不同混合物洗脱。Harbeson等人(J.Med.Chem.1994,37,2918-2929)报道了酮酰胺的硅胶色谱对P1手性中心的差向异构化作用。
化合物13:白色固体;1H-NMR(CDCl3)δ7.90-7.00(系列多重峰,18H),5.40和5.30(两个多重峰,1H),4.10(m,1H),3.50-3.00(m,8H),1.90-1.40(m,4H)。MS m/e 613(M+H),635(M+Na)。实施例3按照一般方法C制备化合物17
在一般方法C中,先将化合物2与L-Cbz-Leu偶合(NMM/HOBt/BOP)生成化合物14;将其水解(NaOH水溶液)得到化合物15;再将化合物15与化合物3偶合(NMM/HOBt/BOP)得到化合物16;化合物16经Dess-Martin氧化生成化合物17。
一般方法C化合物17:白色固体;1H-NMR(CDCl3)δ7.85(d,2H),7.60-7.00(系列多重峰,15H),6.60(d,1H),5.40(m,1H),5.20(q,1H),5.10(s,2H),4.10(宽峰,1H),3.50-3.30(系列多重峰,6H),1.65-1.30(m,3H),0.90(d,6H),MS m/e 623(M+H),645(M+Na)。实施例4按照一般方法D制备化合物22
在一般方法D中,将化合物7与化合物2偶合(NMM/HOBt/BOP)生成化合物18;化合物18经Dess-Martin氧化生成化合物19;化合物19水解(LiOH,甲醇-水)得到化合物20;化合物20与化合物21偶合(NMM/HOBt/BOP)得到化合物22;化合物22用硅胶色谱提纯。化合物22:白色固体;MS m/e 646(M+H),668(M+Na)。
一般方法E所示是制备含有磺酰氨端基的胺(化合物3)的代表性举例。
一般方法E化合物24的制备
往1,2-乙二胺(化合物23,10.80g,12.00mL,0.18mol)的THF(30mL)溶液中,在4小时时间内缓慢加入BOC-ON(22.10g,0.09mol)的THF(70mL)溶液,反应混合物搅拌过夜,在旋转蒸发器上浓缩,残留物加入水(150mL)中,水层用固体柠檬酸一水合物酸化(pH~5-6),用***(3×50mL)洗涤,然后用6N NaOH溶液在0℃处理使其呈碱性(pH~12-13),碱性溶液用乙酸乙酯(3×100mL)萃取,合并后的乙酸乙酯层进行干燥(MgSO4)和浓缩,生成7.23g单保护二胺,化合物24。化合物24:粘稠液体;1H-NMR(CDCl3)δ5.00(宽峰,1H),3.20(宽峰q,2H),2.80(t,2H),1.45(s,9H),1.25(宽峰,2H)。化合物25的制备
将冷的(0-5℃)化合物24(0.321g,0.002mol)的二氯甲烷(5mL)溶液,依次用三乙胺(0.243g,0.33mL,0.0024mol)和苯磺酰氯(0.423g,0.30mL,0.0024mol)处理,撤去冰浴,混合物再搅拌0.5小时,依次用水(2×5mL)、冷的(0-5℃)0.5N HCl(1×5mL)、2%NaHCO3溶液(1×5mL)和盐水(1×5mL)洗涤,将溶液干燥(MgSO4),蒸去溶剂得到的残留物用n-戊烷洗涤数次,得到0.60g磺酰胺衍生物,化合物25。化合物25:白色固体;溶点92-95℃;Rf(TLC,5%甲醇的二氯甲烷溶液)0.55;1H-NMR(CDCl3)δ7.85(d,2H),7.55(m,3H),5.30(宽峰d,1H),4.85(宽峰,1H),3.25(宽峰q,2H),3.10(宽峰q,2H),1.40(s,9H)。化合物3的制备
将化合物25(0.560g,0.0019mol)的1,4-二噁烷(4mL)溶液,用4N HCl的二噁烷溶液(4mL)处理,混合物于室温下搅拌1小时,在旋转蒸发器上浓缩,残留物用乙酸乙酯洗涤数次,真空干燥,得到0.40g化合物3。化合物3:白色固体;熔点178-180℃;1H-NMR(DMSO-d6)δ8.20-8.00(宽峰t,4H),7.80(d,2H),7.60(m,3H),2.95(宽峰q,2H),2.80(宽峰,2H)。实施例6化合物28的制备
一般方法F所示是制备含有联芳基磺酰氨端基的中间产物胺(化合物28)的代表性举例。
一般方法F
化合物26(0.50g,1当量,按照上述制备化合物25的一般方法,由化合物24和5-溴噻吩-2-磺酰氯制得)、二甲氧基乙烷(10mL)、2M Na2CO3(5当量)、苯基硼酸(1.40当量)和Pd(PPh3)4(0.04当量)的混合物于135℃加热2.5小时。反应混合物在旋转蒸发器上浓缩,将残留物加入(20mL)水中,水层以柠檬酸酸化并用二氯甲烷(3×20mL)萃取,合并的有机层用水(1×10mL)和盐水(1×10mL)洗涤,干燥(MgSO4)并浓缩至小体积,残留物与己烷一起研磨生成固体,过滤分离并真空干燥得到0.37g化合物27;1H-NMR(CDCl3)δ7.60-7.20(系列多重峰,7H),5.35(宽峰,1H),4.85(宽峰,1H),3.30(m,2H),3.20(m,2H),1.40(s,9H)。该反应方法的一般描述参见Miyaura等人,Chem.Rev.1995,95,2457-2483。
按照制备化合物3所述的方法,将化合物27转化为化合物28。实施例7按照一般方法G制备氨基乙磺酰胺中间产物
一般方法G所示是氨基乙磺酰胺中间产物的代表性的制备方法。
将按照已知方法(R.Winterbottom等人,J.Amer.Chem.Soc.,1947,69,1393-1401)制备的氨基乙磺酸的邻苯二甲酰亚胺,在回流的苯中,用五氯化磷将其转化为磺酰氯,在吡啶存在下与苯胺反应,形成相应的磺酰胺,再与肼一起回流脱去邻苯二甲酰亚氨保护基团,将所得的氨基乙磺酰胺以其盐酸盐形式分离出来。实施例8
按照表2和表3中所指出的一般方法,并使用适当的原料,合成表中的化合物29-50。实施例9半胱氨酸蛋白酶活性的抑制作用
为了评定其抑制活性,先制备每个待测化合物在100%无水DMSO中的储液(40倍浓缩)并将5μl的各个抑制剂预制剂等分到96-孔培养板的三个一组的每个孔中。按照Meyer等人所述的方法(Biochem.J.1996,314:511-519,在此其全部内容引作参考)制备重组人钙蛋白酶I,将其稀释到测定缓冲液中(即,50mM三羟甲基氨基甲烷缓冲液(Tris),50mM NaCl,1mM EDTA,1mM EGTA和5mMβ-巯基乙醇,pH7.5,包括0.2mM Succ-Leu-Tyr-MNA)。以175μl等分到含有各抑制剂储液的孔中和含有5μl DMSO但不含化合物的空白对比孔中。开始反应时,除了用于调整背景基线的三个孔外,将20μl 50mM CaCl2的测定缓冲液中加入到培养板的所有孔中。每5分钟测定一次底物的水解,共测定30分钟。在抑制剂不存在的条件下,底物水解在15分钟内是线性的。
对I型钙蛋白酶的抑制作用是按底物在抑制剂存在下相对于没有抑制剂存在的水解速率的下降百分比计算的。抑制速率和对比样速率的比较在底物水解的线性区间进行。在测试化合物5-7种不同的浓度下根据底物水解速率的下降百分比确定抑制剂的IC50(达到50%抑制率时的浓度),所得结果以百分抑制率对抑制剂浓度的对数作图,应用GraphPad Prism程序(GraphPad Software Inc.,San Diego,CA.)将数据带入下面所示的四参数方程,计算出IC50:
y=d+[(a-d)/(1+(x/c)b)]。
参数a、b、c和d定义如下:a是没有抑制剂条件下的百分抑制率,b是斜率,c是IC50,d是抑制剂无限浓度下的百分抑制率。
结果列于下面表2、3、4和5。
表2
Ser(Bn)13 PhSO2-L- Bn Ph (78%) B 613
Ser(Bn)29 Ms-D- Bn
14 A 714
Ser(Bn)30 PhSO2-L- Bn Ph (97%) B 663
Ser(Bn)34 Ms-D- Bn
25 A 786
Ser(Bn) (M+2)-35 Ms-D- Bn CH3 91 A 569
Ser(Bn)38* Ms-D- CH2OMe Ph (100%) A 585
Ser(Bn) 717
79Br,
81Br40 Ms-D- Bn
63 D 722
Ser(Bn)41 Ms-D- Bn
(88%) D 699
Ser(Bn) **42 Ms-D- Bn
14 C 712(M)+
Ser(Bn) (M+2)45 Ms-D- Bn
64 D 688
Ser(Bn)
*2∶1的非对映异构体 **百分抑制率@10μM
注:表2“W”栏中,Ser、Pro、Phe分别表示丝氨酸、脯氨酸、苯丙氨酸,Ms、PhSO2、Cbz分别表示氨基酸的氨基连接的甲磺酰基、苯磺酰基、苄氧羰基,(Bn)表示相应的氨基酸上的羟基形成醚时的苄基;“R2”一栏中的“Bn”表示苄基,“Me”表示甲基。
表3
支链型α-酮酰胺的抑制活性实施例 D 钙蛋白酶 制备方法 MS(M+1)编号 IC50 nM47
26 A 64548
43 A 64549
32 A 646(M+2)50 CH2CH2N(CH3)SO2Ph (100%) C 645
**
表4所列化合物按照上述一般方法A-G进行制备。
表4
α-酮酰胺的抑制活性
实施例编号 | W | R | 钙蛋白酶IC50 nM | MS(M+I) |
51 | Ms-D-Ser(苄基) | CH2CH2NHSO2(3-(2-NH2-噻吩-4-基)Ph) | 29 | 729 |
52 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-甲酰基苯基)-噻吩-2-基) | 5 | 741 |
53 | Ms-D-Ser(苄基) | CH2CH2NHC(=N-CN)OPh | 15 | 635 |
54 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(Me2NCH2)苯基)-噻吩-2-基) | 12 | 770 |
55 | Ms-D-Ser(苄基) | 3-苄氧羰基氨基-环己基(3-Boc-NH-环己基) | 42 | 645 |
56 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(吗啉代基-CH2)苯基)-噻吩-2-基) | 18 | 812 |
57 | Ms-D-Ser(苄基) | CH2CH2NHSO2(4-(吗啉代基-CH2)苯基) | 18 | 730 |
58 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(N-甲基哌嗪基-CH2)苯基)-噻吩-2-基) | 21 | 825 |
59 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(HOCH2)苯基)-噻吩-2-基)(2非对映异构体) | 35 | 765(M+Na) |
60 | Ms-D-Ser(苄基) | CH2CH2SO2NHPh | 47 | 631 |
61 | Ms-D-Ser(苄基) | CH2CH2SO2NH(4-CF3Ph) | 32 | 699 |
62 | Ms-D-Ser(苄基) | (CH2)3SO2NHPh | 18 | 645 |
63 | Ms-D-Ser(苄基) | (CH2)3SO2NH(4-CF3Ph) | 23 | 713 |
64 | Ms-D-Ser(苄基) | 6-酮哌啶-3-基 | (33)* | 545 |
65 | Ms-D-Ser(苄基) | CH2CH2N(Me)SO2(5-(3-甲酰基苯基)-噻吩-2-基) | 19 | 755 |
66 | Ms-D-Thr(苄基) | CH2CH2NHSO2(5-(吡啶-2-基)-噻吩-2-基) | 12 | 728 |
67 | Ms-D-Ser(苄基) | N(Me)SO2(5-(异噁唑-3-基)-噻吩-2-基) | 21 | 718 |
68 | Ms-(D,L)-Phenylgly | CH2CH2NHSO2(5-(吡啶-2-基)-噻吩-2-基) | 21 | 670 |
69 | Ms-(D,L)-Phenylgly | CH2CH2NHSO2Ph | 80 | 587 |
70 | Ms-D-Thr(苄基) | CH2CH2NHSO2(5-(3-(吗啉代基-CH2)苯基)-噻吩-2-基)(非对映异构体混合物) | 23 | 826 |
71 | Ms-D-Phe | CH2CH2NHSO2(5-(吡啶-2-基)-噻吩-2-基) | 18 | 684 |
72 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-氟苯基)-噻吩-2-基)(非对映异构体混合物) | 18 | 731 |
73 | Ms-D-Ser(苄基) | (CH2)3SO2NHOCH3 | 87 | 597(M-1) |
74 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-硝基苯基)-噻吩-2-基)(非对映异构体混合物) | 15 | 758 |
75 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-甲基苯基)-噻吩-2-基)(非对映异构体混合物) | 36 | 727 |
76 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(AcNH)苯基)-噻吩-2-基)(非对映异构体混合物) | 11 | 792(M+Na) |
77 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-乙酰基苯基)-噻吩-2-基)(非对映异构体混合物) | 10 | 777(M+Na) |
78 | Ms-D-Ser(苄基) | 1-(4-吗啉代基甲基)苯磺酰基)哌啶-4-基(非对映异构体混合物) | 48 | 770 |
79 | Ms-D-Ser(苄基) | CH2CH2NHSO2((4-(乙酰基苯基)哌嗪-1-基)CH2Ph)(非对映异构体混合物) | 11 | 847 |
80 | Ms-D-Ser(苄基) | (CH2)3SO2NH-(吗啉-4-基) | 169 | 652(M-1) |
81 | Ms-D-Ser(苄基) | (CH2)3SO2-(吗啉-4-基) | 124 | 639 |
82 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(4-甲氧基苯基)-噻吩-2-基)(非对映异构体混合物) | 13 | 765(M+Na) |
83 | Ms-D-Ser(苄基) | CH2CH2CH2-(邻磺酰苯甲酰亚胺基) | 48 | 657 |
84 | Ms-D-Ser(苄基) | CH2CH2NHSO2((4-(苄基)哌嗪-1-基)CH2Ph) | 23 | 819 |
85 | Ms-D-Ser(苄基) | CH2CH2NHSO2((4-(乙酰基)哌嗪-1-基)CH2Ph) | 14 | 771 |
86 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-N,N-二甲基氨基-萘-1-基) | 49 | 724 |
87 | Ms-D-Ser(苄基) | CH2CH2NHSO2(苯并噻吩-2-基) | 23 | 687 |
88 | Cbz-Leu-Leu | CH2CH2NHSO2(5-(吡啶-2-基)-噻吩-2-基) | 33 | 819 |
89 | Ms-D-Ser(苄基) | CH2CH2NHSO2((4-吡啶-2-基)哌嗪-1-基)CH2Ph)(非对映异构体混合物) | 21 | 806 |
90 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(4-甲酰基苯基)-噻吩-2-基) | 17 | 741 |
91 | Ms-D-Ser(苄基) | CH2CH2NHSO2(4-(2-(甲氧基甲基)吡咯烷基CH2)Ph) | 19 | 758 |
92 | Ms-D-Ser(苄基) | (CH2)5NHSO2(5-(吡啶-2-基)-噻吩-2-基)(非对映异构体混合物) | 12 | 756 |
93 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(2-(吗啉代基-CH2)苯基)-噻吩-2-基) | 40 | 812 |
94 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(4-(吗啉代基-CH2)苯基)-噻吩-2-基) | 22 | 812 |
95 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(哌啶基-CH2)苯基)-噻吩-2-基) | 30 | 810 |
96 | Ms-D-Ser(苄基) | CH2CH2NHSO2(2-乙酰氨基-4-甲基-噻唑-5-基) | 23 | 709 |
97 | Ms-D-Ser(苄基) | CH2CH2NHSO2(1-苯磺酰基-哌啶-4-基) | 32 | 671 |
98 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(2-甲酰基苯基)-噻吩-2-基) | 24 | 741 |
99 | Ms-D-Ser(苄基) | CH2CH2NHSO2((CH3O)CH3NCH2Ph)(非对映异构体混合物) | 21 | 704 |
100 | Ms-D-Ser(苄基) | CH2CH2NHSO2(4-(4-乙基哌嗪-1-基)CH2)Ph)(非对映异构体混合物) | 21 | 756 |
101 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(N,N-二乙基氨基甲基)苯基)-噻吩-2-基) | 22 | 798 |
102 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(环己基-N-甲基氨基甲基)苯基)-噻吩-2-基) | 36 | 838 |
103 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(吡咯烷基甲基)苯基)-噻吩-2-基) | 24 | 796 |
104 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-氰基苯基)-噻吩-2-基) | 10 | 738 |
105 | Ms-D-Ser(苄基) | CH2CH2NHSO2(4-(4-乙酰氨基苯氧基)CH2Ph) | 14 | 816(M+Na) |
106 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(氮杂环丁烷基甲基)苯基)-噻吩-2-基) | 44 | 782 |
107 | Ms-D-Ser(苄基) | 1-(5-(吡啶-2-基)噻吩-2-基-SO2)哌啶-4-基(非对映异构体混合物) | 23 | 754 |
108 | Ms-D-Ser(苄基) | CONHCH2CH2NHSO2(5-(3-(N-乙基-N-甲基氨甲基)苯基)-噻吩-2-基) | 10 | 784 |
109 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(二(2-甲氧基乙基)氨基甲基)苯基)-噻吩-2-基) | 22 | 858 |
110 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-氰基苯基)-噻吩-2-基)(非对映异构体混合物) | 11 | 738 |
111 | Ms-D-Ser(苄基) | CH2CH2NHSO2(4-(3-吡咯啉-1-基)CH2Ph)(非对映异构体混合物) | 73 | 712 |
112 | Ms-D-Ser(苄基) | CH2CH2NHSO2((4-(CH3SO2)-哌嗪-1-基)CH2Ph) | 37 | 807 |
113 | Ms-D-Ser(苄基) | CH2CH2NHSO2((4-(嘧啶-2-基)-哌嗪-1-基)CH2Ph | 24 | 807 |
114 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(硫吗啉代基甲基)苯基)-噻吩-2-基) | 33 | 828 |
115 | Ms-D-Ser(苄基) | CH2CH2NHSO2(5-(3-(4-酮哌啶基甲基)苯基)-噻吩-2-基) | 16 | 824 |
116 | Ms-L-Ser(苄基) | CH2CH2NHSO2Ph | 100 | 631 |
*百分抑制率@0.1μM
注:表4“W”栏中,Ser、Thr、Phenylgly、Phe、Leu分别表示丝氨酸、苏氨酸、苯基甘氨酸、苯丙氨酸、亮氨酸,Ms、Cbz分别表示氨基酸的氨基连接的甲磺酰基、苄氧羰基。
表5
本领域技术人员可以理解,对本发明的优选实施方案可以进行的诸多变化和修改而不背离本发明的精神,所有这些变化都落在本发明的范围内。
在本专利文件中所提及的专利、申请和印刷出版物全部内容均引作参考。
Claims (26)
1.具有式I的化合物或其可药用盐:其中:
Q具有式G-B-(CHR4)v,其中R4独立地是H或具有1-4个碳原子的烷基;
v是0、1或2;
B选自C(=O)、OC(=O)、S(=O)m、CH2、键、NR5C(=O)、S(=O)m-A-C(=O)和C(=O)-A-C(=O),其中,R5是H或低级烷基;
m是0、1或2;
A是低级亚烷基或亚环烷基,且任选地被一个或多个卤原子、芳基或杂芳基取代;
M为碳原子;
G选自H、保护基团、低级烷基、低级链烯基、具有约6-约14个碳原子的芳基、具有约5-约14个环原子的杂环基、具有约5-约14个环原子的杂环烷基、具有约7-约15个碳原子的芳烷基、杂芳基烷基和芳基杂烷基,其中所述芳基杂烷基中的芳基部分可以不稠合或与该杂烷基环稠合,所述烷基、芳基、杂环基、杂环烷基、芳基烷基、杂芳烷基和芳基杂烷基任选地被一个或多个J基团取代;
J选自卤素、氰基、硝基、低级烷基、环烷基、杂环烷基、杂烷基、卤代烷基、芳氧基烷基、烷硫基、烷基磺酰基、芳基、杂芳基、芳烷基、芳基烷氧基、芳基磺酰基、杂芳基磺酰基、烷氧羰基、烷氧基烷基、酰基、烷氧基、羟基、羧基、羟基烷基、氨基、烷基氨基和氨基烷基,所述氨基或所述烷基氨基或氨基烷基中的‘氨基’任选地被酰基、烷氧基或者被1-3个芳基、低级烷基、环烷基或烷氧基烷基所取代;所述芳基、杂芳基、杂环烷基和杂烷基可进一步任选地被一个J基团取代;
每个Aaa独立地是任选地含有一个或多个保护基团的氨基酸;
n是0、1、2或3;
R1和R2独立地选自H、具有1-约6个碳原子的烷基、具有约7-约15个碳原子的芳烷基、环上含有约5-约14个环原子的杂烷基、杂芳环上含有约5-约14个环原子的杂芳基烷基、烷氧基烷基、具有R或S构型的天然氨基酸侧链和(CH2)pNH-L,所述烷基、芳烷基、杂烷基、杂芳基烷基和烷氧基烷基任选地被一个或多个J基团取代;
p是0、1、2或3;
L选自具有2-约7个碳原子的烷氧羰基、其中芳基烷氧基含有约7-约15个碳原子的芳基烷氧羰基和S(=O)2R6;
R6选自低级烷基和具有约6-约14个碳原子的芳基;
R3选自H、具有1-约6个碳原子的烷基、具有约7-约15个碳原子的芳烷基、环上含有约5-约14个环原子的杂烷基、杂芳环上含有约5-约14个环原子的杂芳基烷基、烷氧基烷基、具有R或S构型的天然氨基酸侧链、(CH2)pNH-L、C(=O)R7、S(=O)2R7和保护基团,当与R1连接的碳原子结合时,R3表示一个具有2-5个碳原子的亚烷基,该亚烷基任选地被选自下面的基团所取代:芳基、叠氮基、CN、被保护的氨基和OSO2-芳基;所述烷基、芳烷基、杂烷基、杂芳基烷基和烷氧基烷基任选地被一个或多个J基团取代;
R7选自:具有约6-约14个碳原子的芳基、具有约5-约14个环原子的杂芳基、具有约7-约15个碳原子的芳烷基、具有1-约10个碳原子的烷基,所述芳基、杂芳基、芳烷基和烷基任选地被一个或多个J基团、具有2-约7个碳原子的杂烷基、具有1-约10个碳原子的烷氧基和任选地被一个或多个烷基取代的氨基取代;
q是0或1;
Z选自基团C(=O)C(=O)NH-X-A1-K和
X是单键或-O-;
A1同A;
D为稠合的芳基或杂芳基;
R11选自烷氧基、芳氧基和NHR12;
R12选自H、烷基、芳基和杂芳基,所述烷基、芳基和杂芳基任选地被一个或多个J基团所取代;
Y选自基团SO2R8、C(=O)NHR9、C(=S)NHR9、C(=NCN)R11、C(=NC(=O)NHR10)R11和CO2R8;
R8选自烷基、烷氧基、芳基和杂环基,所述烷基、烷氧基、芳基和杂环基任选地被一个或多个J基团所取代;
R9选自H、烷基、芳基和杂芳基,所述烷基、芳基或杂芳基任选地被一个或多个J基团所取代;
或者R9烷基可以与A1亚烷基连接形成一个含氮的5-或6-元杂环;
R10选自H和低级烷基;
或者在基团SO2N(R8)(R10)中,R8和R10可以一起与它们所连接的N原子连接形成一个含氮的5-或6-元杂环;
或者在A1是亚烷基,K是N(R10)Y,其中的R10是烷基的条件下,所述R10可以与所述亚烷基A1连接形成一个含氮的5-或6-元杂环。
2.权利要求1的化合物,其中n和v均为0,q是1,B是键,以及G为H。
3.权利要求1的化合物,其中R1是天然氨基酸的侧链。
4.权利要求1的化合物,其中R3是-S(=O)2R7。
5.权利要求1的化合物,其中R2是苄基或烷氧基烷基。
6.权利要求1的化合物,其中X是键,Y是SO2R8。
7.权利要求1的化合物,其中A1是-CH2-CH2-、-CH2-CH(CH3)-或-(CH3)CH-CH2-。
8.权利要求1的化合物,其中R1是丝氨酸侧链,该侧链任选地被苄基所封端。
9.权利要求8的化合物,其中M为D-构型的碳原子。
10.权利要求1的化合物,其中R2是苄基,R7为甲基,R8为取代的苯基、未取代的苯基、取代的杂芳基或未取代的杂芳基。
11.权利要求1的化合物,其中,R8为芳基、氨基取代的芳基、被杂环基甲基取代的芳基、杂芳基、被杂芳基取代的烷基,或被烷硫基、卤代烷基、烷基、苯磺酰基、卤素、氨基苯基、氨基或二烷基氨基烷基所取代的杂芳基。
12.权利要求1的化合物,其中n、v均为0,q是1,R1是D-或L-构型氨基酸的侧链,R3为-S(=O)2R7,G是H,B是键,R2是苄基或烷氧基烷基,X是键,以及Y是SO2R8。
13.权利要求1的化合物,其中A1是CH2CH2、CH2CH(CH3)或(CH3)CHCH2。
14.权利要求1的化合物,其中R1是D-构型的丝氨酸侧链且其羟基被苄基所封端,R2是苄基,R7为甲基,R8是取代的或未取代的苯基或者是取代的或未取代的杂芳基。
15.权利要求1的化合物,其中R1-R4、B、G、Aaa、X、A1、Y、n、q和v按照表2和3中所列的进行选择。
16.权利要求1的化合物,其中R1-R4、B、G、Aaa、X、A1、Y、n、q和v各自独立地选自表2和3所示的取代基。
17.具有下面结构式的权利要求1的化合物其中:
W、R2和R各自独立地选自表2所示的取代基。
18.权利要求17的化合物,其中W、R2和R按照表2中所列的进行选择。
20.具有下面结构式的权利要求1的化合物:其中:W和R各自独立地选自表4所示的取代基。
21.权利要求20的化合物,其中W和R按照表4中所列的进行选择。
22.具有下面结构式的权利要求1的化合物:其中:Q和R各自独立地选自表5所示的取代基。
23.权利要求22的化合物,其中Q和R按照表5中所列的进行选择。
24.权利要求1的化合物,其中n、v或q均为0,B是(C=O),以及G是苯基或低级烷基,所述苯基或低级烷基任选地被一个或多个J基团所取代。
25.抑制丝氨酸蛋白酶或半胱氨酸蛋白酶的组合物,包含权利要求1的化合物和可药用载体。
26.抑制丝氨酸蛋白酶或半胱氨酸蛋白酶的方法,包括将抑制量的权利要求1的化合物与选自丝氨酸蛋白酶和半胱氨酸蛋白酶的蛋白酶相接触。
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US (5) | US6150378A (zh) |
EP (1) | EP1021199A4 (zh) |
JP (1) | JP4443037B2 (zh) |
KR (1) | KR100544542B1 (zh) |
CN (1) | CN1207056C (zh) |
AU (1) | AU749555B2 (zh) |
CA (1) | CA2304116A1 (zh) |
NZ (1) | NZ503550A (zh) |
WO (1) | WO1999017790A1 (zh) |
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ATE244216T1 (de) * | 1996-12-11 | 2003-07-15 | Abbott Gmbh & Co Kg | Ketobenzamide als calpain-inhibitoren |
US6150378A (en) * | 1997-10-07 | 2000-11-21 | Cephalon, Inc. | Peptidyl-containing α-ketoamide cysteine and serine protease inhibitors |
US6686335B1 (en) * | 1998-09-22 | 2004-02-03 | Cephalon, Inc. | Hydroxamate-containing cysteine and serine protease inhibitors |
WO2001036604A2 (en) | 1999-11-18 | 2001-05-25 | Corvas International, Inc. | Nucleic acids encoding endotheliases, endotheliases and uses thereof |
WO2001040262A1 (en) * | 1999-12-03 | 2001-06-07 | Bristol-Myers Squibb Pharma Company | Alpha-ketoamide inhibitors of hepatitis c virus ns3 protease |
US7700341B2 (en) | 2000-02-03 | 2010-04-20 | Dendreon Corporation | Nucleic acid molecules encoding transmembrane serine proteases, the encoded proteins and methods based thereon |
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US6506901B2 (en) * | 2000-07-17 | 2003-01-14 | Wyeth | Substituted 2-(S)-hydroxy-3-(piperidin-4-yl-methylamino)-propyl ethers and substituted 2-aryl-2-(R)-hydroxy-1-(piperidin-4-yl-methyl)-ethylamine β-3 adrenergic receptor agonists |
US6465501B2 (en) | 2000-07-17 | 2002-10-15 | Wyeth | Azolidines as β3 adrenergic receptor agonists |
US6498170B2 (en) | 2000-07-17 | 2002-12-24 | Wyeth | Cyclamine sulfonamides as β-3 adrenergic receptor agonists |
US6410734B1 (en) * | 2000-07-17 | 2002-06-25 | Wyeth | 2-substituted thiazolidinones as beta-3 adrenergic receptor agonists |
US6537994B2 (en) | 2000-07-17 | 2003-03-25 | Wyeth | Heterocyclic β3 adrenergic receptor agonists |
US6525202B2 (en) * | 2000-07-17 | 2003-02-25 | Wyeth | Cyclic amine phenyl beta-3 adrenergic receptor agonists |
WO2002048097A1 (en) * | 2000-12-12 | 2002-06-20 | Corvas International, Inc. | Compounds, compositions and methods for treatment of parasitic infections |
HUP0303652A2 (hu) | 2000-12-20 | 2004-03-01 | Bristol-Myers Squibb Company | Ciklikus származékok, mint kemokin receptor aktivitás modulátorai és ezeket tartalmazó gyógyszerkészítmények |
AU2002241724A1 (en) | 2000-12-20 | 2002-07-01 | Bristol-Myers Squibb Company | Diamines as modulators of chemokine receptor activity |
WO2003062192A1 (en) | 2002-01-17 | 2003-07-31 | Smithkline Beecham Corporation | Cycloalkyl ketoamides derivatives useful as cathepsin k inhibitors |
JP2005516054A (ja) * | 2002-01-29 | 2005-06-02 | ワイス | コネキシンヘミチャンネルを調節する組成物及びその方法 |
JP4205381B2 (ja) * | 2002-07-30 | 2009-01-07 | 横浜ゴム株式会社 | タイヤ/ホイール組立体 |
JP2004058858A (ja) * | 2002-07-30 | 2004-02-26 | Yokohama Rubber Co Ltd:The | タイヤ/ホイール組立体 |
JP4758641B2 (ja) * | 2003-12-12 | 2011-08-31 | 千寿製薬株式会社 | α−ケトアミド誘導体、その製造方法、及びその用途 |
DE602004023873D1 (de) * | 2003-12-12 | 2009-12-10 | Senju Pharma Co | Verwendung davon |
WO2006102423A1 (en) * | 2005-03-21 | 2006-09-28 | Celera Genomics | Alpha ketoamide compounds as cysteine protease inhibitors |
WO2006124494A1 (en) * | 2005-05-13 | 2006-11-23 | Virginia Tech Intellectual Properties, Inc. | TRANSITION-STATE INHIBITORS OF PIN1, α-KETOAMIDE-CONTAINING PEPTIDOMIMETICS, AND SYNTHESES THEREOF |
US8518885B2 (en) * | 2008-02-06 | 2013-08-27 | Georgia Tech Research Corporation | Heterocyclic peptide ketoamides |
WO2010070615A1 (en) * | 2008-12-19 | 2010-06-24 | Medivir Uk Ltd | Cysteine protease inhibitors |
US10590084B2 (en) | 2016-03-09 | 2020-03-17 | Blade Therapeutics, Inc. | Cyclic keto-amide compounds as calpain modulators and methods of production and use thereof |
AU2017292646A1 (en) | 2016-07-05 | 2019-02-07 | Blade Therapeutics, Inc. | Calpain modulators and therapeutic uses thereof |
PE20191153A1 (es) | 2016-09-28 | 2019-09-05 | Blade Therapeutics Inc | Moduladores de calpainas y usos terapeuticos de los mismos |
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US5034376A (en) * | 1986-10-31 | 1991-07-23 | Pfizer Inc. | Nor-statine and nor-cyclostatine polypeptides |
US5162500A (en) * | 1989-04-15 | 1992-11-10 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Poststatin and related compounds or salts thereof |
US5340825A (en) * | 1990-08-31 | 1994-08-23 | Warner-Lambert Company | Pro drugs for CCK antagonists |
WO1992012140A1 (en) * | 1990-12-28 | 1992-07-23 | Georgia Tech Research Corporation | Peptides ketoamides, ketoacids, and ketoesters |
US5444042A (en) * | 1990-12-28 | 1995-08-22 | Cortex Pharmaceuticals | Method of treatment of neurodegeneration with calpain inhibitors |
US5650508A (en) * | 1991-12-27 | 1997-07-22 | Georgia Tech Research Corporation | Peptide ketoamides |
US5514694A (en) * | 1992-09-21 | 1996-05-07 | Georgia Tech Research Corp | Peptidyl ketoamides |
US5434265A (en) * | 1992-12-22 | 1995-07-18 | Eli Lilly And Company | Inhibitors of HIV protease |
US5563127A (en) * | 1993-03-24 | 1996-10-08 | The Dupont Merck Pharmaceutical Company | Boronic acid and ester inhibitors of thrombin |
US5658885A (en) * | 1993-04-27 | 1997-08-19 | The Dupont Merck Pharmaceutical Company | Amidino and guanidino substituted boronic acid inhibitors of trypsin-like enzymes |
US5541290A (en) * | 1993-06-24 | 1996-07-30 | Harbeson; Scott L. | Optically pure calpain inhibitor compounds |
DE4331134A1 (de) * | 1993-09-14 | 1995-03-16 | Bayer Ag | Neue antiviral wirksame Pseudopeptide |
US5614649A (en) * | 1994-11-14 | 1997-03-25 | Cephalon, Inc. | Multicatalytic protease inhibitors |
EP0793673A1 (en) * | 1994-11-24 | 1997-09-10 | Takeda Chemical Industries, Ltd. | Alpha-ketoamide derivatives as cathepsin l inhibitor |
CN1067081C (zh) | 1994-11-24 | 2001-06-13 | 三菱化学株式会社 | Mk7634物质,其制备方法及含mk7634的驱虫剂 |
AP9600817A0 (en) * | 1995-06-06 | 1996-07-31 | Pfizer | Novel cryatal form of anhydrous 7-( [1A,5A,6A]-6-amino3-3-azabicyclo [3.1.0.] hex-3-yl) -6-fluro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt. |
US5763576A (en) * | 1995-10-06 | 1998-06-09 | Georgia Tech Research Corp. | Tetrapeptide α-ketoamides |
CA2271116A1 (en) * | 1996-11-13 | 1998-05-22 | Gregory J. Wells | Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors |
US5952328A (en) * | 1997-11-12 | 1999-09-14 | Cephalon, Inc. | Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors |
ATE244216T1 (de) * | 1996-12-11 | 2003-07-15 | Abbott Gmbh & Co Kg | Ketobenzamide als calpain-inhibitoren |
US6083944A (en) * | 1997-10-07 | 2000-07-04 | Cephalon, Inc. | Quinoline-containing α-ketoamide cysteine and serine protease inhibitors |
US6096778A (en) * | 1997-10-07 | 2000-08-01 | Cephalon, Inc. | α-ketoamide multicatalytic protease inhibitors |
US6150378A (en) * | 1997-10-07 | 2000-11-21 | Cephalon, Inc. | Peptidyl-containing α-ketoamide cysteine and serine protease inhibitors |
-
1998
- 1998-10-06 US US09/166,808 patent/US6150378A/en not_active Expired - Fee Related
- 1998-10-07 KR KR1020007003686A patent/KR100544542B1/ko not_active IP Right Cessation
- 1998-10-07 EP EP98953275A patent/EP1021199A4/en not_active Withdrawn
- 1998-10-07 WO PCT/US1998/021055 patent/WO1999017790A1/en active IP Right Grant
- 1998-10-07 AU AU10686/99A patent/AU749555B2/en not_active Ceased
- 1998-10-07 CN CNB988099217A patent/CN1207056C/zh not_active Expired - Fee Related
- 1998-10-07 JP JP2000514661A patent/JP4443037B2/ja not_active Expired - Fee Related
- 1998-10-07 CA CA002304116A patent/CA2304116A1/en not_active Abandoned
- 1998-10-07 NZ NZ503550A patent/NZ503550A/en unknown
-
2000
- 2000-03-16 US US09/527,540 patent/US6288231B1/en not_active Expired - Fee Related
-
2001
- 2001-06-12 US US09/879,336 patent/US6703368B2/en not_active Expired - Fee Related
-
2003
- 2003-10-14 US US10/685,923 patent/US7001907B2/en not_active Expired - Fee Related
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2005
- 2005-11-15 US US11/273,850 patent/US20060069037A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
WO1999017790A1 (en) | 1999-04-15 |
CA2304116A1 (en) | 1999-04-15 |
US20020055616A1 (en) | 2002-05-09 |
CN1207056C (zh) | 2005-06-22 |
US6288231B1 (en) | 2001-09-11 |
US6150378A (en) | 2000-11-21 |
EP1021199A4 (en) | 2003-08-20 |
AU749555B2 (en) | 2002-06-27 |
JP2001518513A (ja) | 2001-10-16 |
EP1021199A1 (en) | 2000-07-26 |
KR100544542B1 (ko) | 2006-01-24 |
KR20010030945A (ko) | 2001-04-16 |
AU1068699A (en) | 1999-04-27 |
US20040102609A1 (en) | 2004-05-27 |
JP4443037B2 (ja) | 2010-03-31 |
US20060069037A1 (en) | 2006-03-30 |
US6703368B2 (en) | 2004-03-09 |
NZ503550A (en) | 2002-02-01 |
US7001907B2 (en) | 2006-02-21 |
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