CN1190424C - 含喹啉的α-酮酰胺半胱氨酸和丝氨酸蛋白酶抑制剂 - Google Patents
含喹啉的α-酮酰胺半胱氨酸和丝氨酸蛋白酶抑制剂 Download PDFInfo
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- CN1190424C CN1190424C CNB988099152A CN98809915A CN1190424C CN 1190424 C CN1190424 C CN 1190424C CN B988099152 A CNB988099152 A CN B988099152A CN 98809915 A CN98809915 A CN 98809915A CN 1190424 C CN1190424 C CN 1190424C
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- 150000002993 phenylalanine derivatives Chemical class 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
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- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
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- 125000004076 pyridyl group Chemical group 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
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- QQWYQAQQADNEIC-RVDMUPIBSA-N tert-butyl [(z)-[cyano(phenyl)methylidene]amino] carbonate Chemical compound CC(C)(C)OC(=O)O\N=C(/C#N)C1=CC=CC=C1 QQWYQAQQADNEIC-RVDMUPIBSA-N 0.000 description 1
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Abstract
本发明公开了含喹啉的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60/061,267,申请日为1997.10.7)和名称为“含喹啉的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。
技术领域
本申请涉及含喹啉的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。
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,包括人在内,一般通过包括半胱氨酸或丝氨酸蛋白酶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蛋白酶,它们普遍存在于哺乳动物组织内。已经确认了两种主要的钙蛋白酶-钙蛋白酶I和钙蛋白酶II。在许多组织中,钙蛋白酶II为主要形式,而病理状况下的神经组织中钙蛋白酶I为主要形式。半胱氨酸蛋白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、急性中枢神经系统损伤、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还与神经细胞的编程性细胞死亡有关,这涉及各种神经退化性疾病,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是一种对细小核糖核酸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,裂解血纤蛋白原生成血纤蛋白并激活凝血因子VIII,凝血酶涉及血栓静脉炎、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。胰弹性蛋白酶涉及胰腺炎。胃促胰酶是一种在合成血管紧张素中起重要作用的酶,涉及高血压、心肌分裂和冠状心脏病。组织蛋白酶G与异常结缔组织退化有关,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,能够在研究和临床药物两方面促进发展。本发明的目的即在于此,以及其它重要的结果。
发明内容
本发明涉及所选的含喹啉的α-酮酰胺半胱氨酸和丝氨酸蛋白酶抑制剂,用通式I表示:
其中:
X是CH、N、或CQ1,条件是当X为CQ1时,Q或Q1至少一个为H;
R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)nNH-L,所述烷基、芳烷基、杂烷基和杂芳基烷基任选地被一个或多个J基团取代;
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、S(=O)2R2和N-硝基亚氨基;
R2选自低级烷基和具有约6-约14个碳原子的芳基;
R1选自H、卤素、氰基、硝基、磺酸、羟基,烷基、烷氧基、羟甲基、烷氧基甲基、芳烷基、羧基、烷氧羰基、烷羰氧基、卤代烷基、N(RR3)和酰基;
R3同R;Q选自H、低级烷基、环烷基、羟基、烷氧基、卤素、具有约7-约15个碳原子的芳烷基、具有约8-约16个碳原子的芳基链烯基、具有约8-约16个碳原子的芳炔基、具有约6-约14个碳原子的芳基、具有约5-约14个环原子的杂芳基、具有约5-约14个环原子的杂烷基、具有约3-约10个碳原子的环烷基、S-R、S(=O)R、S(=O)2R、N(RR3)和NHS(=O)2R,所述芳烷基、芳基链烯基、芳炔基、芳基、杂芳基、杂烷基任选地被一个或多个J基团取代;
Q1同Q;
Z为COCONH-R7;
R7选自基团K、-A-N(R8)-G、-O-A-N(R8)-G、-A-SO2N(R8)(R9)和-O-A-SO2N(R8)(R9);
K选自烷基、链烯基、炔基、环烷基、杂烷基、杂芳基、芳基、芳烷基、杂环烷基、烷氧基、烷氧基烷基、芳基烷氧基、和N(RR3),所述K基团任选地被一个或多个J基团取代;
A是任选地被一个或多个J基团取代的低级亚烷基;
R8选自H和低级烷基;
R9选自H、烷基、芳基和杂环基,所述烷基、芳基和杂环基任选地被一个或多个J基团取代;
G选自C(=O)芳基、C(=O)杂芳基、C(=O)杂烷基、烷基羰基、C(=S)NH(芳基)、C(=O)NH(芳基)、C(=O)NH(环烷基)、CO2(芳基)、C(=O)烷基、CO2(烷基)、CO2(芳烷基)、烷基磺酰基、链烯基磺酰基、芳基磺酰基、杂芳基磺酰基、具有R或S构型的天然氨基酸侧链、保护基团和SO2N(RR3),所述G基团任选地被一个或多个J基团取代;
J选自H、卤素、氰基、硝基、羟基,烷基、烷氧基、芳基、芳烷基、烷氧羰基、烷羰氧基、链烯基羰氧基、卤代烷基、氨基烷基、卤代烷氧基、SO2N(RR3)、SO2NH(芳基)、SO2NH(杂芳基)、NHC(=O)NH(芳基)、NH(C=O)NH(杂芳基)、NHSO2(芳基)、NHC(=O)烷基、NHC(=O)芳基、NHC(=O)杂芳基、N(RR3)和NH=C(NH2)2,其中N(RR3)中的R和R3基团不再被J进一步取代;
n是2-6的整数;
或者该化合物药学上可接受的盐;
其条件是:R7为K时,Q选自任选取代的芳基链烯基和任选取代的芳基炔基;以及
进一步的条件是:当K是烷基,Q是任选取代的芳基炔基时,X不是CH。
在式I化合物的优选实施方案中,X是CH。在式I化合物的更优选的实施方案中,R选自具有2-4个碳原子的烷基和芳烷基,并特别优选苄基。
在式I化合物的优选实施方案中,R1是H或烷氧基,并优选H。
在式I化合物的优选实施方案中,Q选自芳基炔基、芳基和卤素,并且优选苯炔基。
在式I化合物的更优选的实施方案中,A选自(CH2)n和(CH2)vCH2-J,其中n为2或3,v是1-6的整数,当A是(CH2)vCH2-J时,v优选为2或3。
在式I化合物的优选实施方案中,K选自烷基、羟基烷基、卤代烷基、炔基、杂环烷基、芳烷基和杂烷基。
在式I化合物的更优选的实施方案中,G选自取代或未取代的C(=O)芳基、C(=O)杂芳基、芳基磺酰基和杂芳基磺酰基,G优选选自未取代的芳基磺酰基、取代的芳基磺酰基、未取代的杂芳基磺酰基和取代的杂芳基磺酰基。
在式I化合物的优选实施方案中,X是CH;Z是COCONH-K;R1是H;及R选自具有2-4个碳原子的烷基和芳烷基,并特别优选苄基。
在式I化合物的特别优选的实施方案中,X是CH;Z是COCONH-K;R1是H;R选自具有2-4个碳原子的烷基和芳烷基,并特别优选苄基;以及Q是芳基炔基,并且优选苯乙炔基。
在式I化合物的特别优选的实施方案中,Q、X、R1、R和Z选自下面表2-5所列的取代基。式I化合物的特别优选的实施方案列在下面表2-5中。
由于本发明的含喹啉的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。
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方面表现出相似性质的天然和合成化合物。该化合物还可用于改进在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、丝氨酸蛋白酶与某些具体疾病的关系已知的条件下,本发明化合物可用于减轻、缓解、降低和/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,提供了抑制丝氨酸蛋白酶或半胱氨酸蛋白酶的方法,包括以有效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)。
制备本发明含喹啉的α-酮酰胺抑制剂的方法也公开了。对本领域技术人员而言,一旦具备了该公开内容,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。
具体实施方式
在此公开所选择的含喹啉α-酮酰胺半胱氨酸蛋白酶和丝氨酸蛋白酶抑制剂,用下式I表示:
其中:
X是CH、N、或CQ1,条件是当X为CQ1时,Q或Q1至少一个为H;
R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)nNH-L,所述烷基、芳烷基、杂烷基和杂芳基烷基任选地被一个或多个J基团取代;
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、S(=O)2R2和N-硝基亚氨基;
R2选自低级烷基和具有约6-约14个碳原子的芳基;
R1选自H、卤素、氰基、硝基、磺酸、羟基,烷基、烷氧基、羟甲基、烷氧基甲基、芳烷基、羧基、烷氧羰基、烷羰氧基、卤代烷基、N(RR3)和酰基;
R3同R;
Q选自H、低级烷基、环烷基、羟基、烷氧基、卤素、具有约7-约15个碳原子的芳烷基、具有约8-约16个碳原子的芳基链烯基、具有约8-约16个碳原子的芳炔基、具有约6-约14个碳原子的芳基、具有约5-约14个环原子的杂芳基、具有约5-约14个环原子的杂烷基、具有约3-约10个碳原子的环烷基、S-R、S(=O)R、S(=O)2R、N(RR3)和NHS(=O)2R,所述芳烷基、芳基链烯基、芳炔基、芳基、杂芳基、杂烷基、任选地被一个或多个J基团取代;
Q1同Q;
Z为COCONH-R7;
R7选自基团K、-A-N(R8)-G、-O-A-N(R8)-G、-A-SO2N(R8)(R9)和-O-A-SO2N(R8)(R9);
K选自烷基、链烯基、炔基、环烷基、杂烷基、杂芳基、芳基、芳烷基、杂环烷基、烷氧基、烷氧基烷基、芳基烷氧基、和N(RR3),所述K基团任选地被一个或多个J基团取代;
A是任选地被一个或多个J基团取代的低级亚烷基;
R8选自H和低级烷基;
R9选自H、烷基、芳基和杂环基,所述烷基、芳基和杂环基任选地被一个或多个J基团取代;
G选自C(=O)芳基、C(=O)杂芳基、C(=O)杂烷基、烷基羰基、C(=S)NH(芳基)、C(=O)NH(芳基)、C(=O)NH(环烷基)、CO2(芳基)、C(=O)烷基、CO2(烷基)、CO2(芳烷基)、烷基磺酰基、链烯基磺酰基、芳基磺酰基、杂芳基磺酰基、具有R或S构型的天然氨基酸侧链、保护基团和SO2N(RR3),所述G基团任选地被一个或多个J基团取代;
J选自H、卤素、氰基、硝基、羟基,烷基、烷氧基、芳基、芳烷基、烷氧羰基、烷羰氧基、链烯基羰氧基、卤代烷基、氨基烷基、卤代烷氧基、SO2N(RR3)、SO2NH(芳基)、SO2NH(杂芳基)、NHC(=O)NH(芳基)、NH(C=O)NH(杂芳基)、NHSO2(芳基)、NHC(=O)烷基、NHC(=O)芳基、NHC(=O)杂芳基、N(RR3)和NH=C(NH2)2,其中N(RR3)中的R和R3基团不再被J进一步取代;
n是2-6的整数;或者该化合物药学上可接受的盐;
其条件是:R7为K时,Q选自任选取代的芳基链烯基和任选取代的芳基炔基;以及
进一步的条件是:当K是烷基,Q是任选取代的芳基炔基时,X不是CH。
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在取代基R连接的碳上具有L-构型,但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。
本文所用的术语“喹啉”指“喹啉”或“喹啉N-氧化物”结构。
在式I化合物中,一个取代基的键表示为与连接两个环原子的键相交,是指该取代基可以和环上的任一原子键接。
本文所用的术语“烷基”包括直链、支链和环状烃基,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、辛基、环丙基、甲基环戊基、环己基和金刚烷基,优选的烷基具有1-约10个碳原子,更优选具有1-约6个碳原子(即“低级烷基”)。“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。“酰基”(即“烷羰基”)是烷基羰基。“芳基”是指芳香环化合物,包括但不限于苯基、甲苯基、萘基、蒽基、菲基、芘基、联苯基和二甲苯基,优选的芳基包括苯基和萘基。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“是通过氧连接的烷基,烷氧基的举例包括甲氧基(-OCH3)和亚乙基(-OCH2CH3)。通常地,术语“氧基”作为后缀时指通过氧原子连接,因此,烷氧羰基是含有烷氧基取代基的羰基,即通式-C(=O)-O-R基团,其中R是烷基。术语“烷氧基烷基”表示烷氧基连接烷基。术语“芳氧基”表示通过氧原子连接的芳基。术语“芳基烷氧基”表示通过氧原子连接的芳烷基。
本文所用的术语“链烯基”包括至少具有一个碳-碳双键的直链或支链的烃链,链烯基举例包括乙烯基和丙烯基,芳基链烯基是带有一个或多个芳基的链烯基。所用的术语“炔基”包括至少具有一个碳-碳叁键的直链或支链的烃链,炔基举例包括乙炔基和丙炔基,芳基炔基是带有一个或多个芳基的炔基。
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”,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、噻唑基、四唑基、喹啉基、异喹啉基、苯并咪唑基、联吡啶基、苯二甲酰亚氨基和苯并四噻唑基。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”表示芳环内含有一个或多个杂原子的芳基。术语“杂芳基烷基”表示通过一个烷基连接的杂芳基。术语“杂烷基”表示杂环上含有至少一个饱和碳原子的杂环基,杂烷基举例包括哌啶、二氢吡啶、四氢异喹啉基和ε-己内酰胺基团。
本文所用的术语“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-构型的通式为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.,1975,73-75页。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1
CH3- HS-CH2-
HO-CH2- HO2C-CH(NH2)-CH2-S-S-CH2-
C6H5-CH2- CH3-CH2-
HO-C6H5-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-
(CH3)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已知的化学功能基团,它们可以选择性地附加到官能度上,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,这些基团存在于化合物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。
应用到本发明化合物的其它保护基包括那些带有能取代到氨基上的酰基、芳酰基、烷基、烷基磺酰基、芳烷基磺酰基或芳基磺酰基的基团。其它可用的保护基包括烷基醚,例如,丝氨酸甲基醚。
本发明公开的化合物能用于抑制半胱氨酸蛋白酶和丝氨酸蛋白酶。本文所用的术语“抑制”或“抑制作用”是指对酶的活性具有反效应。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本文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的例子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形成的盐。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,尤其是从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;或者制成其它适合这些给药方式的剂型以及本领域技术人员所熟知的其它药剂形式。
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药物科学”(Mack出版公司,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、氢化萘及类似物。尤其是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赋形剂。其它对这些活性化合物可能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;或者是可以含有如聚氧乙烯-9-月桂基醚、甘氨胆酸盐和脱氧胆酸盐的水溶液或以滴鼻剂形式给药的油溶液,或者在鼻内使用的凝胶。非肠道给药制剂也可以包括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阴道给药的柠檬酸。用于透皮膜片的制剂优选亲油性乳剂。
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障碍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依据许多因素而变化,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,典型的剂量范围是每天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。这些剂型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,例如疾病或功能障碍的种类或程度、具体患者的整体健康状况、所选化合物的相对的生物效能、化合物赋形剂的组成以及给药途径。
本文所用的术语“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,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,例如让患有蛋白酶异常和/或畸形活性疾病或功能障碍的病人服入本发明化合物,也落在术语“接触”所确定的范围。
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内容的限定。
实施例
实施例1-158:
表2-5所示的化合物采用下面的“一般方法”所示的条件进行制备,酶抑制活性(IC50)按照实施例159和160的描述进行测定。
在所有实施例中,除非另外指出,R1均为H。
一般方法:
采用硅胶涂层板(MK6F 60A,尺寸1×3英寸,层厚250μm,Whatman Inc.)完成薄层色谱;采用硅胶涂层板(尺寸20×20英寸,层厚1000微米,Analtech)完成制备性薄层色谱;采用Merck硅胶,40-63μm,230-400目完成制备性柱色谱;1H NMR谱使用四甲基硅烷作为内标,在300MHZ于GE QE300 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。
按照下面一般方法A、B、C或C的其中之一制备化合物。
一般方法A
4a R4=tBOC,R5=H,R=CH2Ph
4b R4=H.HCl,R5=CH3,R=CH2Ph
4c R4=tBOC,R5=H,R=C4H9
4d R4=H.HCl,R5=CH3,R=C4H9
4e R4=tBOC,R5=H,R=C3H7
4f R4=H.HCl,R5=CH3,R=C3H7
化合物2的制备
将式1化合物(20g,0.106mol)和氯氧化亚磷(50mL,0.54mol)混合物持续回流3小时,冷却后,将反应混合物缓慢倒入冰水中,有白色沉淀生成,滤出沉淀,用冷水充分洗涤,重新溶解于乙酸乙酯(300mL)中,溶液用无水硫酸钠干燥,过滤并除去溶剂得到14.78g化合物2,该化合物使用时不需要进一步提纯。
化合物2:黄褐色固体;1H-NMR(DMSO-d6)δ8.60(d,1H),8.00(d,1H),7.90(s,1H),7.80(t,1H),7.70(t,1H);MS m/e 208和210(M+H具有氯同位素)。
化合物3的制备
将化合物2(20g,0.0966mol)、苯乙炔(13.02g,14mL,0.127mol)、(PPh3)PdCl2(1.40g,0.00193mol)、CuI(0.42g,0.00386mol)、三乙胺(19.66g,27mL,0.192mol)和无水DMSO(150mL)组成的混合物在60-70℃加热3小时,冷却后,将反应混合物缓慢倒入冰水(300mL)中,水溶液用2 N盐酸酸化,并用二氯甲烷萃取(3×700mL),有机层用盐水(1×250mL)洗涤,干燥(无水硫酸钠)和浓缩,所得残留物在二氯甲烷-己烷中重结晶,得到23.8g化合物3。
化合物3:白色固体;1H-NMR(DMSO-d6)δ8.60(d,1H),8.10(d,1H),8.05(s,1H),7.85(t,1H),7.70(m,3H),7.45(m,3H);MS m/e274(M+H)。
化合物4a的制备
化合物4a,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。
化合物4b的制备
往冷至-10℃的化合物4a(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,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4b,直接用于下一步合成。MS m/e 210(M+H)。
化合物5(R=苄基)的制备
往冷至0℃的化合物3(0.88g,0.0032mol)在无水DMF(10mL)的溶液中,加入N-甲基吗啉(0.98g,0.0096mol),随后加入1-HOBt(0.43g,0.0032mol)和BOP(1.70g,0.0039mol),将混合物搅拌15分钟,并加入化合物4b(0.95g,0.0039mol),撤去冷浴,混合物搅拌4小时,倒入冰水(40mL)中,萃取至乙酸乙酯(3×40mL),有机层用2%柠檬酸溶液(2×40mL)、2%碳酸氢钠溶液(2×40mL)、盐水(1×50mL)洗涤,无水硫酸钠干燥,减压蒸去溶剂,所得粗产物用闪蒸塔色谱提纯(洗脱剂:40%乙酸乙酯的环己烷),得到1.10g化合物5。
化合物5(非对映异构体混合物):白色固体;1H-NMR(CDCl3)δ8.10(d,1H),7.80-7.20(2组多重峰,14H),6.40(2组双重峰,1H),5.00(m,1H),4.60和4.30(2组三重峰,1H),3.85和3.75(2个单峰,3H),3.50和3.35(2组双重峰,1H),3.10和3.00(2组二倍双重峰,2H),MS m/e465(M+H)。
化合物6(R=苄基)的制备
往冷至0℃的化合物5(4.33g,9.33mmol)在1∶1无水二氯甲烷和无水乙腈(60mL)的溶液中,缓慢加入Dess-Martin全碘烷试剂(periodinane agent)(7.90g,18.66mmol),撤去冷浴,混合物再搅拌2小时,然后将混合物用二氯甲烷(50mL)稀释并用10%硫代硫酸钠溶液(5×50mL)、饱和碳酸氢钠溶液(2×50mL)和盐水(1×50mL)洗涤,干燥(无水硫酸钠)并减压除去溶剂,所得残留物用闪蒸塔色谱提纯(洗脱剂:1∶1乙酸乙酯-环己烷),得到3.3g化合物6。
化合物6:白色固体;1H-NMR(CDCl3)δ8.20-7.20(m,15H),6.65(d,1H),5,80(q,1H),3.95(s,3H),3.50(dd,1H),3.20(dd,1H);MSm/e 463(M+H)。
化合物7(R=苄基)的制备
室温下,将化合物6(1.20g,2.60mmol)、1N NaOH(6.5mL)和MeOH(15mL)的混合物搅拌1.5小时,TLC(50%乙酸乙酯的二氯甲烷)显示化合物6全部消失,反应混合物在旋转蒸发器(rotavapor)上浓缩,并重新溶解于水(25mL)中,水层用乙醚(2×15mL)洗涤并用1N盐酸酸化,然后用乙酸乙酯(3×50mL)萃取水层,合并后的乙酸乙酯层用盐水(1×20mL)洗涤,干燥(MgSO4)并在旋转蒸发器上浓缩,得到1.17g化合物7。
化合物7:部分1H-NMR(CDCl3)显示位于δ3.95的COOCH3峰消失;MS m/e 449(M+H)。
化合物8的制备
例如按照合成化合物5所述,在NMM/HOBt/BOP/DMF存在下,通过将化合物7与胺偶合制备化合物8。将粗产物的二氯甲烷溶液或乙酸乙酯溶液通过Sep-Pak_Vac 6cc(1g)硅胶柱(Waters Corporation,Milford,MA)进行提纯,并先后用二氯甲烷、二氯甲烷和乙酸乙酯的混合物洗脱。
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。
一般方法B
在一般方法B中,按照合成化合物7所述的相同方法,将一般方法A得到的式5化合物水解为式9化合物;然后按照合成化合物5所述,将式9化合物与胺(NMM/HOBt/BOP/DMF)偶合制得α-羟基酰胺(化合物10);式10化合物经Dess-Martin氧化生成本发明的酮酰胺(化合物8),该化合物即可使用或用有机溶剂重结晶。
一般方法C
在一般方法C中,按照合成化合物5所述,首先将化合物4a(一般方法A)与胺(NMM/HOBt/BOP/DMF)偶合生成化合物11;在常规条件下(4 N HCl的二噁烷溶液,室温下)进行tBoc-脱保护,生成铵盐化合物12;按照合成化合物5所述,化合物12与化合物3(NMM/HOBt/BOP/DMF)偶合得到化合物10。
化合物10经Dess-Martin氧化生成化合物8。
一般方法D
在一般方法D中,将一般方法C得到的化合物11氧化生成化合物13,将其进行tBoc-脱保护,生成化合物14;将化合物3与化合物14偶合制备本发明的酮酰胺(化合物8)。
应当注意到,尽管一般方法A、B、C和D只显示了2-苯乙炔基喹啉(3)作为本发明喹啉成分的情况,但它们对所有其它喹啉-4-羧酸也是适用的。类似地,用Leu、Nle(4c)、Nva(4e)衍生的,或者由任何α-羟基-β-氨基酸延伸的不同羟基酸替换化合物4a(苯丙氨酸衍生物),这些方法也是适用的。
中间产物的制备
化合物15和16的制备
将化合物3(1.00g,3.66mmol)溶解于DMF(14mL),搅拌溶液并在大气压下使用10%Pd-C(170mg)氢化50小时(23和29小时后再加入10%Pd-C(共计230mg)),过滤后,在40℃真空蒸去溶剂,残留物溶解于二氯甲烷,溶液用水和盐水各洗涤两次,然后用无水MgSO4干燥,蒸发溶剂得到化合物15和16的混合粗产物(700mg)橙褐色半固体,用甲醇重结晶提纯化合物15,由所得母液通过制备性TLC(洗脱剂:CH2Cl2-MeOH-HOAC,94∶5∶1)提纯化合物16。
化合物15:MS m/e 276(M+H)。
化合物16:1H-NMR(DMSO-d6)δ8.64(d,1H),8.08(d,1H),7.92(s,1H),7.82(t,1H),7.70(t,1H),7.38(m,5H),3.30(t,2H),3.16(t,2H);MS m/e 278(M+H)。
一般方法E所示是合成含有磺酰氨端基部分的胺的代表性例子。
一般方法E
化合物18的制备
往1,2-乙二胺(化合物17,10.80g,12.00mL,0.18mol)的THF(30mL)溶液中,在4小时内缓慢加入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,残留物溶于水(150mL)中,水层用固体柠檬酸一水合物酸化(pH~5-6),用乙醚(3×50mL)洗涤,然后用6N NaOH溶液(在0℃)处理至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)并浓缩,生成7.23g单保护二胺,化合物18。化合物18:半固体;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19的制备
将冷的(0-5℃)化合物18(0.321g,0.002mol)的二氯甲烷(5mL)溶液,连续用三乙胺(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正戊烷洗涤数次,得到0.60g磺酰胺衍生物,化合物19。化合物19:白色固体;熔点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20的制备
将化合物19(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铵盐,化合物20。
化合物20: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)。
一般方法F所示是合成含有磺酰氨端基部分的烷氧基胺的代表性例子。
一般方法F
化合物23的制备
往苯基异羟肟酸(化合物21,5.00g,0.0365mol)的DMF(50mL)溶液中,缓慢加入甲醇钠(2.50g,0.044mol),反应混合物搅拌10分钟,加入N-(2-溴乙基)邻苯二甲酰亚氨(化合物22,9.00g,0.0333mol),反应混合物搅拌过夜,在旋转蒸发器上浓缩,在二氯甲烷(200mL)和0.1N NaOH(200mL)之间进行分配,分离出有机层,用水(2×30mL)洗涤,干燥(MgSO4)和浓缩至小体积,与乙醇一起研磨生成4.30g化合物23,使用时不需要进一步纯化;MS m/e 311(M+H)。
化合物24的制备
将化合物23(1.00g,0.0032mol)、肼(1mL)和95%乙醇的混合物保持回流6小时,冷却后,将反应混合物过滤,滤液浓缩得到0.575g化合物24,直接用于下一步合成;MS m/e 181(M+H)。
化合物25的制备
按照合成化合物19所述的相同方法(一般方法E),由化合物24制备化合物25;粗产物用闪蒸塔色谱提纯(洗脱剂:20%乙酸乙酯的二氯甲烷),得到0.75g化合物25;MS m/e 321(M+H)。
化合物26的制备
将化合物25(0.60g,1.87mol)和6N HCl(20mL)的混合物保持回流3小时,冷至室温并过滤,滤液真空浓缩过夜,生成铵盐,化合物26;MS m/e 217(M+H)。
化合物27的制备
2-苯基喹唑啉-4-羧酸(化合物27)按照Giardina等人,J.Med.Chem.1997,40,1794-1807所述的一般方法进行制备,该物质可以代替化合物3而应用到一般方法A中。
根据一般方法A制备实施例11化合物
17:浅黄色固体,1H-NMR(CDCl3)δ8.10(d,1H),7.95(d,1H),7.75(t,1H),7.70-7.10(系列多重峰,13H),6.55(d,1H),5.90(m,1H),3.65-3.10(系列多重峰,6H),3.40(s,3H);MS m/e 506(M+H)。
根据一般方法B制备实施例96化合物
105:浅黄色固体,1H-NMR(CDCl3)δ 8.10(d,1H),7.95(d,1H7.80-7.10(系列多重峰,19H),6.55(d,1H),5.90(m,1H),5.10(t,1H3.50(m,3H),3.20(m,3H);MS m/e 631(M+H)。
根据一般方法C制备实施例144化合物
159:浅黄色固体,1H-NMR(DMSO-d6)δ9.35(d,1H),8.90(t,1H),8.50(d,1H),8.10(t,1H),8.00-7.70(m,7H),7.55(t,2H),7.40-7.10(m,6H),5.50(m,1H),3.30(m,2H),3.00(q,3H),2.75(m,1H);MS m/e648和650(M+H,含有氯的不同同位素),670和672(M+Na,含有氯的不同同位素)。
实施例159
半胱氨酸蛋白酶活性的抑制作用
要评定其抑制活性,先制备每个被测化合物在100%无水DMSO中的储液(40倍浓缩)并以5μl将各个抑制剂样品等分到96-孔培养板的三个一组的每个孔中。按照Meyer等人(Biochem.J.1996,314:511-519)所述的方法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,1mMEDTA,1mM EGTA和5mM β-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以及含有5μlDMSO但不包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溶于测定缓冲液中的50mM CaCl2加入到培养板的所有孔中。底物的水解每5分钟测定一次,共测定30分钟。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型钙蛋白酶的抑制活性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是无限抑制剂浓度下的百分抑制率。
结果列于表2-5。
测定对另一种半胱氨酸蛋白酶-组织蛋白酶B(Calbiochem,cat#219364)的抑制活性时,测定方式与上述方式基本同上,只是稀释组织蛋白酶B使用不同的测定缓冲液,其组成为50mM的乙酸钠(pH6.0)/1mM EDTA/1mM二硫苏糖醇,底物是0.1mM Cbz-Phe-Arg-AMC(Bachem,cat#I-1160)。另外,因为该酶是具有组成活性的,所以改变试剂加入的顺序。将抑制剂加入培养板后,将酶制品稀释为测定缓冲液的约2倍浓缩储液,每个孔中加入100μl,当将100μl底物加入在测定缓冲液中的2倍浓缩储液后,即开始测定。底物水解的测定采用Fluoriskan II型仪器(ex=390nm,em=460nm),结果列于表6中。
实施例160
丝氨酸蛋白酶的抑制活性
测定对丝氨酸蛋白酶α-糜蛋白酶(Sigma Chem.Co.Cat.#c-3142)的抑制活性时,按照实施例159的方案进行,只是稀释酶所用的测定缓冲液的组成是50mM Hepse(pH7.5)/0.5M NaCl,并且底物的最后浓度是0.03mM Succ-Ala-Ala-Pro-Phe-AMC(Bachem,Inc.Cat.#I-1465)。此外,由于α-糜蛋白酶不是钙敏感酶而且是具有组成活性的,因此在96孔培养板加入抑制剂储液后,先加入100μl测定缓冲液稀释的酶的2倍浓缩储液,再将100μl底物加入在测定缓冲液中的2倍浓缩储液,反应即开始。底物的水解每5分钟测定一次,测定30分钟,采用Fluoriskan II型仪器(ex=390nm,em=460nm),结果列于表6中。
表2
Q=苯乙炔基
X=CH
R=CH2C6H5
Z=COCONH-R7
实施例 | R7 | 钙蛋白酶IIC50nM** | 合成方法 | 质谱MH+ |
1 | CH2C≡CH | (91%) | A | 486 |
2 | CH2CF3 | (98%) | A | 530 |
3 | CH2C=CH2 | 210 | A | 488 |
4 | CH2环丙烷 | (100%) | A | 502 |
5 | CH2CH2CN | (95%) | A | 501 |
6 | CH2CH2环己烯-1-基 | (89%) | A | 556 |
7 | CH2CH(OCH3)2 | 110 | A | 536 |
8 | CH2CH2CH2OCH2CH2OCH3 | 570 | A | 564 |
9 | CH2CH2OCH2CH2OCH2CH2OC6H13 | 230 | A | 664 |
10 | CH2CH2OCH2CH2OH | 630 | A | 536 |
11 | CH2CH2OCH3 | 480 | A | 506 |
12 | CH2CH2CH2OH | (94%) | A | 506 |
13 | (CH2)4OH | (100%) | A | 520 |
14 | (CH2)5OH | (98%) | A | 534 |
15 | 金刚烷基 | (41%) | A | 582 |
16 | 环丙烷 | (100%) | A | 488 |
17 | (1-苄基)哌啶-4-基 | 638 | A | 621 |
18 | (2-甲基环己基) | (76%) | A | 544 |
19 | (4-甲基环己基) | (91%) | A | 544 |
20 | (3-甲基环己基) | (94%) | A | 544 |
21 | 4-哌啶-1-CO2Et | (100%) | A | 603 |
22 | ε-己内酰胺 | 78 | A | 559 |
23 | CH(苄基)CH2OH | (75%) | A | 582 |
24 | CH(CH2OCH3)CH(OH)Ph | (21%) | A | 582 |
25 | CH(CH2OH)(CH2)4NHC(NH苄氧羰基)=N苄氧羰基 | (42%) | A | 805 |
26 | CH(CH3)-1-萘基 | (31%) | A | 602 |
27 | CH(CH3)Ph | 510 | A | 552 |
28 | 环己-2-醇 | (61%) | A | 546 |
29 | [反式]环己-4-醇 | 296 | A | 546 |
30 | 环己基 | (85%) | A | 530 |
31 | 环戊烷-1-CH2OH | (27%) | A | 546 |
32 | 四氢萘-1-基 | (31%) | A | 578 |
33 | 胡椒-5-基 | 388 | A | 582 |
34 | (CH2)4Ph | 227 | A | 580 |
35 | 苯并二噁烷-6-基 | (71%) | A | 582 |
36 | CH2Ph | 79* | B | 538 |
37 | CH2(3,4-二甲氧基-苯基) | (95%) | A | 598 |
38 | CH2(3,5-二甲氧基-苯基) | (92%) | A | 598 |
39 | CH2(4-NH2SO2-Ph) | 184 | A | 617 |
40 | CH2C6H4-3-NO2 | (95%) | A | 583 |
41 | CH2CH2(3,4-二甲氧基-苯基) | (88%) | A | 612 |
42 | CH2CH2(4-NH2SO2-Ph) | 69 | A | 631 |
43 | CH2CH2Ph | 390 | A | 552 |
44 | CH2CHPh2 | (85%) | A | 628 |
45 | CH2-吡啶-2-基 | 210 | A | 540 |
46 | CH2-吡啶-3-基 | (91%) | A | 540 |
47 | CH2-吡啶-4-基 | (98%) | A | 540 |
48 | CH2CH2-2-甲基-5-硝基咪唑 | (95%) | A | 601 |
49 | CH2CH2-5-甲氧基-吲哚-3-基 | 160 | A | 621 |
50 | CH2CH2CH2-咪唑-1-基 | (84%) | A | 556 |
51 | CH2CH2CH2-吗啉-4-基 | 424 | A | 575 |
52 | CH2CH2CH2-吡咯烷-2-酮 | 366 | A | 573 |
53 | CH2CH2-邻苯二甲酰亚氨 | 226 | A | 621 |
54 | CH2四氢呋喃-2-基 | (84%) | A | 532 |
55 | 1,2-二氢化茚-2-基 | (60%) | A | 564 |
56 | CH2CH2NHCO(4-氟苯基) | 146 | A | 613 |
57 | CH2CH2NHCO(4-甲氧基苯基) | (71%) | A | 625 |
58 | CH2CH2NHCO-2-呋喃基 | 98 | A | 585 |
59 | CH2CH2NHCO-吗啉 | 248 | A | 604 |
60 | CH2CH2NHCOCH3 | 140 | A | 533 |
61 | CH2CH2NHCONH(4-溴苯基) | (94%) | A | 689 |
62 | CH2CH2NHCONH(4-甲氧基苯基) | 190 | A | 640 |
63 | CH2CH2NHCONH-金刚烷-1-基 | 257 | A | 668 |
64 | CH2CH2NHCONHPh | 67 | A | 610 |
65 | CH2CH2NHCOPh | (100%) | A | 595 |
66 | CH2CH2NHCSNH(4-甲氧基苯基) | 113 | A | 656 |
67 | CH2CH2NHCSNH(4-硝基苯基) | 93 | A | 671 |
68 | CH2CH2NHSO2-(2-硝基苯基) | 260 | A | 676 |
69 | CH2CH2NHSO2-(4-氟苯基) | 47 | A | 649 |
70 | CH2CH2NHSO2-(1-甲基咪唑-4-基) | 137 | A | 635 |
71 | CH2CH2NHSO2-(2,1,3-噻二唑-4-基) | 89 | A | 689 |
72 | CH2CH2NHSO2-(2,5-二氯苯基) | (96%) | A | 699 |
73 | CH2CH2NHSO2-(2-甲氧羰基噻吩-3-基) | 220 | A | 695 |
74 | CH2CH2NHSO2-(2-氰基-苯基) | 132 | A | 656 |
75 | CH2CH2NHSO2-(3,4-二氯苯基) | 100 | A | 699 |
76 | CH2CH2NHSO2-(3,5-二甲基异噁唑-4-基) | (98%) | A | 650 |
77 | CH2CH2NHSOx-(3-氰基-苯基) | 77 | A | 656 |
78 | CH2CH2NHSO2-(3-硝基苯基) | (88%) | A | 676 |
79 | CH2CH2NHSO2-(4-乙酰氨基苯基) | 43 | A | 688 |
80 | CH2CH2NHSO2-(4-三氟甲氧基苯基) | 200 | A | 694 |
81 | CH2CH2NHSO2-(4-甲氧基苯基) | 62 | A | 661 |
82 | CH2CH2NHSO2-(4-氰基苯基) | 70 | A | 656 |
83 | CH2CH2NHSO2-(4-氨基苯基) | 70 | A | 646 |
84 | CH2CH2NHSO2-(4-硝基苯基) | 26 | B | 676 |
85 | CH2CH2NHSO2-(5-(苯甲酰基NHCH2)噻吩-2-基) | 48 | A | 770 |
86 | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 31 | A | 712 |
87 | CH2CH2NHSO2-(吡啶-3-基) | 56* | C | 632 |
88 | CH2CH2NHSO2-萘-2-基 | 41 | A | 681 |
89 | CH2CH2NHSO2-喹啉-8-基 | 130 | A | 682 |
90 | CH2CH2NHSO2-噻吩-2-基 | 76 | A | 637 |
91 | CH2CH2NHSO2CH=CH-Ph | 42 | A | 657 |
92 | CH2CH2NHSO2CH2Ph | 94 | A | 645 |
93 | CH2CH2NHSO2CH3 | 180 | A | 569 |
94 | CH2CH2NHSO2NMe2 | 141 | A | 598 |
95 | CH2CH2NHSO2Ph | 43 | A | 631 |
96 | CH2CH2NHSO2Ph | 29* | B | 631 |
97 | (CH2)3NH苄氧羰基 | (100%) | A | 605 |
98 | (CH2)3NHCONHPh | 126 | A | 624 |
99 | (CH2)3NHSO2CH3 | 130 | A | 583 |
100 | (CH2)3NHSO2Ph | 55 | A | 645 |
101 | (CH2)6NHSO2-(5-氯化萘-1-基) | (84%) | A | 771 |
102 | OCH3 | 82 | A | 538 |
103 | OCH2CH3 | 65 | A | 492 |
104 | Obn | 60 | A | 554 |
105 | OCH2CH2NHSO2Ph | 128 | A | 647 |
106 | (CH2)4CH(COOCH3)NH苄氧羰基 | (97%) | A | 691 |
107 | CH2CH2CO2叔丁基 | (93%) | A | 576 |
108 | CH2CH2NH-L-Pro-SO2Ph | (94%) | A | 728 |
109 | CH(苄基)COOCH3 | 655 | A | 610 |
110 | NMe2 | (43%) | A | 491 |
111 | CH2CH2O-COC(=CH2)CH3 | (95%) | A | 560 |
表3
Q=苯乙炔基
X=CH
Z=COCONH-R7
实施例 | R7 | R | 钙蛋白酶IIC50nM** | 合成方法 | 质谱MH+ |
112 | CH2CH2OCH3 | 异丁基 | (95%) | B | 472 |
113 | CH2CH(OCH3)2 | 异丁基 | (92%) | A | 502 |
114 | CH2CH2OCH2CH2OH | 异丁基 | (93%) | A | 502 |
115 | CH2CH2NHCO2CH2Ph | 异丁基 | (100%) | B | 591 |
116 | CH2CH2NHCONHPh | 异丁基 | (89%) | A | 576 |
117 | CH2CH2NHSO2Ph | 异丁基 | (82%) | A | 597 |
118 | CH2CH2NHSO2(3,4-二氯苯基) | 异丁基 | 120 | B | 666 |
119 | (CH2)3NHSO2Ph | 异丁基 | (80%) | A | 611 |
120 | CH2CH2OCH3 | 乙基 | (92%) | A | 444 |
121 | CH2CH(OCH3)2 | 乙基 | (94%) | A | 474 |
122 | CH2CH2NHSO2Ph | 乙基 | (89%) | A | 569 |
123 | CH2CH2NHSO2(3,4-二氯苯基) | 乙基 | 58 | A | 637 |
124 | (CH2)3NHSO2Ph | 乙基 | 80 | A | 583 |
125 | CH2CH2NHCONHPh | 乙基 | (32%) | A | 548 |
126 | CH2CH2NHSO2(3,4-二氯苯基) | 丁基 | 39 | A | 665 |
127 | CH2CH2NHSO2(4-硝基苯基) | 丁基 | 29 | A | 642 |
128 | CH2CH2NHSO2(3,4-二氯苯基) | 丙基 | 187 | A | 651 |
129 | CH2CH2NHSO2(4-硝基苯基) | 丙基 | 27 | A | 628 |
表4
X=CH
R=CH2C6H5
Z=COCONH-R7
实施例 | Q | R7 | 钙蛋白酶IIC50nM** | 合成方法 | 质谱MH+ |
130 | PhCH=CH | 丁基 | 105 | D | 506 |
131 | H | CH2CH2NHSO2Ph | (97%)* | C | 531 |
132 | H(N-氧化物) | CH2CH2NHSO2Ph | (96%) | D | 547 |
133 | HO | CH2CH2NHSO2Ph | (95%) | D | 547 |
134 | CH3O | CH2CH2NHSO2Ph | (17%) | D | 434 |
135 | 哌啶-1-基 | CH2CH2NHSO2Ph | (91%) | D | 624 |
136 | 吡啶-3-基 | CH2CH2NHSO2Ph | (99%) | D | 608 |
137 | PhCH2C2 | CH2CH2NHSO2Ph | 116 | D | 635 |
138 | Cl | CH2CH2NHSO2Ph | 28* | C | 565 |
139 | Cl | CH2CH(CH3)NHSO2Ph[S] | 59 | C | 579 |
140 | Cl | CH2CH(CH3)NHSO2Ph[R] | 155 | C | 579 |
141 | Cl | CH2CH2NHSO2(吡啶-3-基) | 87* | C | 566 |
142 | CH3 | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 24* | C | 628 |
143 | 2-CH3 *** | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 35* | C | 658 |
144 | Cl | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 14 | C | 648 |
145 | 环丙基 | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 71 | C | 654 |
146 | 噻吩-2-基 | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 85 | C | 696 |
147 | Cl | CH2CH2SO2NHPh | 81 | C | 565 |
148 | Cl | CH2CH2SO2NH(4-氟苯基) | 75 | C | 583 |
表2-4脚注:
* 单一对映体
**(钙蛋白酶I在10,000nM的百分抑制率)
***R1是6-甲氧基
表5
Z=COCONH-R7
实施例 | Q | X | R | R7 | 钙蛋白酶1IC50nM** | 合成方法 | 质谱MH+ |
149 | Cl | CH | 正丁基 | CH2CH2NHSO2(4-硝基苯基) | 23 | B | 576 |
150 | Cl | CH | 正丙基 | CH2CH2NHSO2(4-硝基苯基) | (78%) | B | 562 |
151 | Cl | CH | 正丁基 | CH2CH2NHSO2(3,4-二氯苯基) | 217 | B | 599 |
152 | Cl | CH | 正丙基 | CH2CH2NHSO2(3,4-二氯苯基) | 325 | B | 585 |
153 | Ph | N | 苄基 | CH2CH2NHSO2Ph | (95%) | C | 608 |
154 | Ph | N | 苄基 | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 83 | C | 691 |
155 | Cl | CH | 正丁基 | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 31 | B | 614 |
156 | Cl | CH | 正丙基 | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 43 | B | 600 |
157 | Cl | CH | CH3OCH2 | CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基] | 61 | B | 603 |
158 | Cl | CH | CH3OCH2 | CH2CH2NHSO2Ph | (94%) | B | 519 |
**(钙蛋白酶I在10000nM的百分抑制率)
表6:对组织蛋白酶B和α-糜蛋白酶的抑制作用
实施例化合物 | 组织蛋白酶BIC50(nM) | 糜蛋白酶IC50(nM) |
100 | 360 | 36 |
96 | 375 | 66 |
103 | 435 | 380 |
104 | 330 | 1160 |
84 | 348 | 14 |
86 | 1030 | 475 |
在本专利文件中所提及的专利、申请和印刷出版物均全部引作参考。
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,所有这些变化都将落在本发明的范围内。
Claims (20)
1.具有式I的化合物或其可药用盐:
其中:
X是CH或CQ1,条件是当X为CQ1时,Q或Q1至少一个为H;
R选自H、具有1-6个碳原子的烷基、具有7-15个碳原子的芳烷基、烷氧基烷基;
R1选自H、卤素、羟基,烷基、烷氧基、羟甲基、烷氧基甲基和卤代烷基;
R3同R;Q选自H、具有1-6个碳原子的低级烷基、环烷基、羟基、烷氧基、卤素、具有7-15个碳原子的芳烷基、具有8-16个碳原子的芳基链烯基、具有8-16个碳原子的芳炔基、具有6-14个碳原子的芳基、具有5-14个环原子的杂芳基、具有5-14个环原子的杂烷基、具有3-10个碳原子的环烷基、S-R、S(=O)R、S(=O)2R、N(RR3)和NHS(=O)2R;
Q1同Q;
Z为COCONH-R7;
R7选自基团K、-A-N(R8)-G、-O-A-N(R8)-G、-A-SO2N(R8)(R9)和-O-A-SO2N(R8)(R9);
K选自烷基、链烯基、炔基、环烷基、杂烷基、杂芳基、芳基、芳烷基、杂环烷基、烷氧基、烷氧基烷基、芳基烷氧基和N(RR3),所述K基团被一个或多个J基团取代或未被取代;
A是被一个或多个J基团取代或未被取代的具有1-6个碳原子的低级亚烷基;
R8选自H和具有1-6个碳原子的低级烷基;
R9选自H、烷基、芳基和杂环基,所述烷基、芳基和杂环基被一个或多个J基团取代或未被取代;
G选自C(=O)芳基、C(=O)杂芳基、C(=O)杂烷基、烷基羰基、C(=S)NH(芳基)、C(=O)NH(芳基)、C(=O)NH(环烷基)、CO2(芳基)、C(=O)烷基、CO2(烷基)、CO2(芳烷基)、烷基磺酰基、链烯基磺酰基、芳基磺酰基、杂芳基磺酰基、具有R或S构型的天然氨基酸侧链、保护基团和SO2N(RR3),所述G基团被一个或多个J基团取代或未被取代;
J选自H、卤素、氰基、硝基、羟基,烷基、烷氧基、芳基、芳烷基、烷氧羰基、烷羰氧基、链烯基羰氧基、卤代烷基、氨基烷基、卤代烷氧基、SO2N(RR3)、SO2NH(芳基)、SO2NH(杂芳基)、NHC(=O)NH(芳基)、NH(C=O)NH(杂芳基)、NHSO2(芳基)、NHC(=O)烷基、NHC(=O)芳基、NHC(=O)杂芳基、N(RR3)和NH=C(NH2)2,其中SO2N(RR3)中的R和R3不再被J进一步取代;
其条件是:R7为K时,Q选自芳基链烯基和芳基炔基;以及
进一步的条件是:当K是烷基,Q是芳基炔基时,X不是CH。
2.权利要求1的化合物或其可药用盐,其中X是CH。
3.权利要求1的化合物或其可药用盐,其中R选自具有2-4个碳原子的烷基和芳烷基。
4.权利要求3的化合物或其可药用盐,其中R是苄基。
5.权利要求1的化合物或其可药用盐,其中R1是H或烷氧基。
6.权利要求5的化合物或其可药用盐,其中R1是H。
7.权利要求1的化合物或其可药用盐,其中Q选自具有8-16个碳原子的芳炔基、具有6-14个碳原子的芳基和卤素。
8.权利要求7的化合物或其可药用盐,其中Q是苯炔基。
9.权利要求1的化合物或其可药用盐,其中A选自(CH2)n和(CH2)vCH2-J,其中n是2或3,v是1-6的整数。
10.权利要求9的化合物或其可药用盐,其中A是(CH2)vCH2-J,其中v是2或3。
11.权利要求1的化合物或其可药用盐,其中K选自烷基、羟基烷基、卤代烷基、炔基、杂环烷基、芳烷基和杂烷基。
12.权利要求1的化合物或其可药用盐,其中G选自C(=O)芳基、C(=O)杂芳基、芳基磺酰基和杂芳基磺酰基,所述G基团被一个或多个J基团取代或未被取代。
13.权利要求12的化合物或其可药用盐,其中G选自未取代的芳基磺酰基、被一个或多个J基团取代的芳基磺酰基、未取代的杂芳基磺酰基和被一个或多个J基团取代的杂芳基磺酰基。
14.权利要求1的化合物或其可药用盐,其中X是CH,Z是COCONH-K,R1是H,R选自具有2-4碳原子的烷基和芳烷基。
15.权利要求14的化合物或其可药用盐,其中R是苄基。
16.权利要求1的化合物或其可药用盐,其中X是CH,Z是COCONH-K,R1是H,R选自具有2-4碳原子的烷基和芳烷基,Q是芳炔基。
17.权利要求16的化合物或其可药用盐,其中R是苄基。
18.权利要求16的化合物或其可药用盐,其中Q是苯乙炔基。
19.权利要求1的化合物或其可药用盐,其选自下表2-5所述的化合物1-158和其可药用盐:
表2
Q=苯乙炔基
X=CH
R=CH2C6H5
Z=COCONH-R7
R1=H
R7
1
CH2C=CH
2
CH2CF3
3
CH2C=CH2
4
CH2环丙烷
5
CH2CH2CN
6
CH2CH2环己烯-1-基
7
CH2CH(OCH3)2
8 CH2CH2CH2OCH2CH2OCH3
9
CH2CH2OCH2CH2OCH2CH2OC6H13
10
CH2CH2OCH2CH2OH
11
CH2CH2OCH3
12
CH2CH2CH2OH
13
(CH2)4OH
14
(CH2)5OH
15
金刚烷基
16
环丙烷
17
(1-苄基)哌啶-4-基
18
(2-甲基环己基)
19
(4-甲基环己基)
20
(3-甲基环己基)
21
4-哌啶-1-CO2Et
22
ε-己内酰胺
23
CH(苄基)CH2OH
24
CH(CH2OCH3)CH(OH)Ph
25
CH(CH2OH)(CH2)4NHC(NH苄氧羰基)=N苄氧羰基
26
CH(CH3)-1-萘基
27
CH(CH3)Ph
28
环己-2-醇
29
[反式]环己-4-醇
30
环己基
31
环戊烷-1-CH2OH
32
四氢萘-1-基
33
胡椒-5-基
34
(CH2)4Ph
35
苯并二噁烷-6-基
36
CH2Ph
37
CH2(3,4-二甲氧基-苯基)
38
CH2(3,5-二甲氧基-苯基)
39
CH2(4-NH2SO2-Ph)
40
CH2C6H4-3-NO2
41
CH2CH2(3,4-二甲氧基-苯基)
42
CH2CH2(4-NH2SO2-Ph)
43
CH2CH2Ph
44
CH2CHPh2
45
CH2-吡啶-2-基
46
CH2-吡啶-3-基
47
CH2-吡啶-4-基
48
CH2CH2-2-甲基-5-硝基咪唑
49
CH2CH2-5-甲氧基-吲哚-3-基
50
CH2CH2CH2-咪唑-1-基
51
CH2CH2CH2-吗啉-4-基
52
CH2CH2CH2-吡咯烷-2-酮
53
CH2CH2-邻苯二甲酰亚氨
54
CH2四氢呋喃-2-基
55
1,2-二氢化茚-2-基
56
CH2CH2NHCO(4-氟苯基)
57
CH2CH2NHCO(4-甲氧基苯基)
58
CH2CH2NHCO-2-呋喃基
59
CH2CH2NHCO-吗啉
60
CH2CH2NHCOCH3
61
CH2CH2NHCONH(4-溴苯基)
62
CH2CH2NHCONH(4-甲氧基苯基)
63
CH2CH2NHCONH-金刚烷-1-基
64
CH2CH2NHCONHPh
65
CH2CH2NHCOPh
66
CH2CH2NHCSNH(4-甲氧基苯基)
67
CH2CH2NHCSNH(4-硝基苯基)
68
CH2CH2NHsO2-(2-硝基苯基)
69
CH2CH2NHSO2-(4-氟苯基)
70
CH2CH2NHSO2-(1-甲基咪唑-4-基)
71
CH2CH2NHSO2-(2,1,3-噻二唑-4-基)
72
CH2CH2NHSO2-(2,5-二氯苯基)
73
CH2CH2NHSO2-(2-甲氧羰基噻吩-3-基)
74
CH2CH2NHSO2-(2-氰基-苯基)
75
CH2CH2NHSO2-(3,4-二氯苯基)
76
CH2CH2NHSO2-(3,5-二甲基异噁唑-4-基)
77
CH2CH2NHSO2-(3-氰基-苯基)
78
CH2CH2NHSO2-(3-硝基苯基)
79
CH2CH2NHSO2-(4-乙酰氨基苯基)
80
CH2CH2NHSO2-(4-三氟甲氧基苯基)
81
CH2CH2NHSO2-(4-甲氧基苯基)
82
CH2CH2NHSO2-(4-氰基苯基)
83
CH2CH2NHSO2-(4-氨基苯基)
84
CH2CH2NHSO2-(4-硝基苯基)
85
CH2CH2NHSO2-(5-(苯甲酰基NHCH2)噻吩-2-基)
86
CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基]
87
CH2CH2NHSO2-(吡啶-3-基)
88
CH2CH2NHSO2-萘-2-基
89
CH2CH2NHSO2-喹啉-8-基
90
CH2CH2NHSO2-噻吩-2-基
91
CH2CH2NHSO2CH=CH-Ph
92
CH2CH2NHSO2CH2Ph
93
CH2CH2NHSO2CH3
94
CH2CH2NHSO2NMe2
95
CH2CH2NHSO2Ph
96
CH2CH2NHSO2Ph
97
(CH2)3NH苄氧羰基
98
(CH2)3NHCONHPh
99
(CH2)3NHSO2CH3
100
(CH2)3NHSO2Ph
101
(CH2)6NHSO2-(5-氯化萘-1-基)
102
OCH3
103
OCH2CH3
104
Obn
105
OCH2CH2NHSO2Ph
106 (CH2)4CH(COOCH3)NH苄氧羰基
107
CH2CH2CO2叔丁基
108
CH2CH2NH-L-Pro-SO2Ph
109
CH(苄基)COOCH3
110
NMe2
111
CH2CH2O-COC(=CH2)CH3
表3
Q=苯乙炔基
X=CH
Z=COCONH-R7
R1=H
R7
R
112
CH2CH2OCH3
异丁基
113
CH2CH(OCH3)2
异丁基
114
CH2CH2OCH2CH2OH
异丁基
115
CH2CH2NHCO2CH2Ph
异丁基
116
CH2CH2NHCONHPh
异丁基
117
CH2CH2NHSO2Ph
异丁基
118
CH2CH2NHSO2(3,4-二氯苯基)
异丁基
119
(CH2)3NHSO2Ph
异丁基
120
CH2CH2OCH3
乙基
121
CH2CH(OCH3)2
乙基
122
CH2CH2NHSO2Ph
乙基
123
CH2CH2NHSO2(3,4-二氯苯基)
乙基
124
(CH2)3NHSO2Ph
乙基
125
CH2CH2NHCONHPh
乙基
126
CH2CH2NHsO2(3,4-二氯苯基)
丁基
127
CH2CH2NHSO2(4-硝基苯基)
丁基
128
CH2CH2NHSO2(3,4-二氯苯基)
丙基
129
CH2CH2NHSO2(4-硝基苯基)
丙基
表4
X=CH
R=CH2C6H5
Z=COCONH-R7
R1=H
Q
R7
130
PhCH=CH
丁基
131
H
CH2CH2NHSO2Ph
132
H(N-氧化物)
CH2CH2NHSO2Ph
133
HO
CH2CH2NHSO2Ph
134
CH3O
CH2CH2NHSO2Ph
135
哌啶-1-基
CH2CH2NHSO2Ph
136
吡啶-3-基
CH2CH2NHSO2Ph
137
PhCH2C2
CH2CH2NHSO2Ph
138
Cl
CH2CH2NHSO2Ph
139
Cl
CH2cH(CH3)NHSO2Ph[S]
140
Cl
CH2CH(CH3)NHSO2Ph[R]
141
Cl
CH2CH2NHSO2(吡啶-3-基)
142
CH3
CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基]
143
2-CH3 ***
CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基]
144
Cl
CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基]
145
环丙基
CH2cH2NHSO2[5-(2-吡啶基)噻吩-2-基]
146
噻吩-2-基
CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基]
147
Cl
CH2CH2SO2NHPh
148
Cl
CH2CH2SO2NH(4-氟苯基)
*** R1是6-甲氧基
表5
Z=COCONH-R7
R1=H
Q
X
R
R7
149
Cl
CH
正丁基
CH2CH2NHSO2(4-硝基苯基)
150
Cl
CH
正丙基
CH2CH2NHSO2(4-硝基苯基)
151
Cl
CH
正丁基
CH2CH2NHSO2(3,4-二氯苯基)
152
Cl
CH
正丙基
CH2CH2NHSO2(3,4-二氯苯基)
155
Cl
CH
正丁基
CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基]
156
Cl
CH
正丙基
CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基]
157 Cl CH CH3OCH2 CH2CH2NHSO2[5-(2-吡啶基)噻吩-2-基]
158
Cl
CH
CH3OCH2
CH2CH2NHSO2Ph
20.抑制丝氨酸蛋白酶或半胱氨酸蛋白酶的组合物,包括权利要求1的化合物和药学上可接受的载体。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US6126797P | 1997-10-07 | 1997-10-07 | |
US60/061,267 | 1997-10-07 | ||
US09/167,193 US6083944A (en) | 1997-10-07 | 1998-10-06 | Quinoline-containing α-ketoamide cysteine and serine protease inhibitors |
US09/167,193 | 1998-10-06 |
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CN1274283A CN1274283A (zh) | 2000-11-22 |
CN1190424C true CN1190424C (zh) | 2005-02-23 |
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CNB988099152A Expired - Fee Related CN1190424C (zh) | 1997-10-07 | 1998-10-07 | 含喹啉的α-酮酰胺半胱氨酸和丝氨酸蛋白酶抑制剂 |
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US (1) | US6083944A (zh) |
EP (1) | EP1032393B1 (zh) |
JP (1) | JP2001518506A (zh) |
KR (1) | KR100647177B1 (zh) |
CN (1) | CN1190424C (zh) |
AT (1) | ATE335485T1 (zh) |
AU (1) | AU749099B2 (zh) |
CA (1) | CA2304204C (zh) |
DE (1) | DE69835532T2 (zh) |
ES (1) | ES2270532T3 (zh) |
HK (1) | HK1029936A1 (zh) |
NZ (1) | NZ504024A (zh) |
WO (1) | WO1999017775A1 (zh) |
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US6150378A (en) * | 1997-10-07 | 2000-11-21 | Cephalon, Inc. | Peptidyl-containing α-ketoamide cysteine and serine protease inhibitors |
CA2328440C (en) * | 1998-04-20 | 2010-06-15 | Basf Aktiengesellschaft | Heterocyclically substituted amides used as calpain inhibitors |
ATE274512T1 (de) * | 1999-02-12 | 2004-09-15 | Smithkline Beecham Plc | Phenylharnstoffe und phenylthioharnstoffe als orexinrezeptorantagonisten |
US7282512B2 (en) | 2002-01-17 | 2007-10-16 | Smithkline Beecham Corporation | Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors |
AU2003209297A1 (en) * | 2002-01-18 | 2003-09-02 | Massachusetts Eye And Ear Infirmary | Methods and compositions for preserving the viability of photoreceptor cells |
MXPA04010523A (es) | 2002-04-25 | 2005-06-08 | Ono Pharmaceutical Co | Compuestos derivados de dicetohidrazina y medicamentos que los contienen como ingrediente activo. |
AU2004288800A1 (en) * | 2003-11-10 | 2005-05-26 | Wyeth | Methods and compositions for selectin inhibition |
CA2554999A1 (en) * | 2004-02-04 | 2005-08-25 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
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 |
WO2007019427A2 (en) * | 2005-08-08 | 2007-02-15 | Massachusetts Eye & Ear Infirmary | Methods and compositions for preserving the viability of photoreceptor cells |
BRPI0721298A2 (pt) * | 2006-12-29 | 2014-03-25 | Abbott Gmbh & Co Kg | Composto de carboxamida e seus usos como inibidores de calpaína |
TWI453019B (zh) * | 2007-12-28 | 2014-09-21 | Abbvie Deutschland | 甲醯胺化合物 |
TWI519530B (zh) | 2009-02-20 | 2016-02-01 | 艾伯維德國有限及兩合公司 | 羰醯胺化合物及其作為鈣蛋白酶(calpain)抑制劑之用途 |
US8236798B2 (en) | 2009-05-07 | 2012-08-07 | Abbott Gmbh & Co. Kg | Carboxamide compounds and their use as calpain inhibitors |
US8598211B2 (en) | 2009-12-22 | 2013-12-03 | Abbvie Inc. | Carboxamide compounds and their use as calpain inhibitors IV |
US9051304B2 (en) | 2009-12-22 | 2015-06-09 | AbbVie Deutschland GmbH & Co. KG | Carboxamide compounds and their use as calpain inhibitors V |
CN103501784A (zh) | 2010-12-09 | 2014-01-08 | Abbvie德国有限责任两合公司 | 甲酰胺化合物及它们作为钙蛋白酶抑制剂v的用途 |
US9150545B2 (en) | 2012-04-03 | 2015-10-06 | AbbVie Deutschland GmbH & Co. KG | Carboxamide compounds and their use as calpain inhibitors V |
EP3426674A4 (en) | 2016-03-09 | 2019-08-14 | Blade Therapeutics, Inc. | CYCLIC KETO AMID COMPOUNDS AS CALPAIN MODULATORS AND METHOD FOR THE PRODUCTION AND USE THEREOF |
EP3481835A4 (en) | 2016-07-05 | 2020-02-26 | Blade Therapeutics, Inc. | CALPAIN MODULATORS AND THEIR THERAPEUTIC USES |
MX2019003425A (es) | 2016-09-28 | 2019-08-16 | Blade Therapeutics Inc | Moduladores de calpainas y usos terapeuticos de los mismos. |
BR112020019560A2 (pt) * | 2018-03-28 | 2021-01-05 | Blade Therapeutics, Inc. | Moduladores de calpaína e usos terapêuticos dos mesmos |
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US5034376A (en) * | 1986-10-31 | 1991-07-23 | Pfizer Inc. | Nor-statine and nor-cyclostatine polypeptides |
EP0423358A4 (en) * | 1989-04-15 | 1992-05-06 | Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai | Postostatin and related compound thereof, or their salts |
US5340825A (en) * | 1990-08-31 | 1994-08-23 | Warner-Lambert Company | Pro drugs for CCK antagonists |
US5444042A (en) * | 1990-12-28 | 1995-08-22 | Cortex Pharmaceuticals | Method of treatment of neurodegeneration with calpain inhibitors |
WO1992012140A1 (en) * | 1990-12-28 | 1992-07-23 | Georgia Tech Research Corporation | Peptides ketoamides, ketoacids, and ketoesters |
US5650508A (en) * | 1991-12-27 | 1997-07-22 | Georgia Tech Research Corporation | Peptide ketoamides |
EP0846694A1 (en) * | 1992-01-23 | 1998-06-10 | Toray Industries, Inc. | Morphinan derivative and its pharmaceutical applications |
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 |
ATE273959T1 (de) * | 1994-05-27 | 2004-09-15 | Glaxosmithkline Spa | Chinolinderivate als tachykinin nk3 rezeptor antagonisten |
US5614649A (en) * | 1994-11-14 | 1997-03-25 | Cephalon, Inc. | Multicatalytic protease inhibitors |
JPH08208462A (ja) * | 1994-11-24 | 1996-08-13 | Takeda Chem Ind Ltd | カテプシンl阻害剤 |
EP0832066B1 (en) * | 1995-06-06 | 2001-09-12 | Pfizer Inc. | Substituted n-(indole-2-carbonyl-) amides and derivatives as glycogen phosphorylase inhibitors |
EP1491533A3 (en) * | 1997-03-14 | 2005-01-19 | Cephalon, Inc. | Quinoline-and naphthalenecarboxamides, pharmaceutical compositions thereof and their use as calpain inhibitors |
-
1998
- 1998-10-06 US US09/167,193 patent/US6083944A/en not_active Expired - Fee Related
- 1998-10-07 WO PCT/US1998/021054 patent/WO1999017775A1/en active IP Right Grant
- 1998-10-07 DE DE69835532T patent/DE69835532T2/de not_active Expired - Lifetime
- 1998-10-07 CA CA2304204A patent/CA2304204C/en not_active Expired - Fee Related
- 1998-10-07 ES ES98952109T patent/ES2270532T3/es not_active Expired - Lifetime
- 1998-10-07 NZ NZ504024A patent/NZ504024A/xx unknown
- 1998-10-07 AT AT98952109T patent/ATE335485T1/de not_active IP Right Cessation
- 1998-10-07 EP EP98952109A patent/EP1032393B1/en not_active Expired - Lifetime
- 1998-10-07 JP JP2000514646A patent/JP2001518506A/ja not_active Ceased
- 1998-10-07 CN CNB988099152A patent/CN1190424C/zh not_active Expired - Fee Related
- 1998-10-07 AU AU97882/98A patent/AU749099B2/en not_active Ceased
- 1998-10-07 KR KR1020007003685A patent/KR100647177B1/ko not_active IP Right Cessation
-
2001
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Also Published As
Publication number | Publication date |
---|---|
EP1032393A4 (en) | 2002-06-12 |
ES2270532T3 (es) | 2007-04-01 |
ATE335485T1 (de) | 2006-09-15 |
EP1032393A1 (en) | 2000-09-06 |
DE69835532T2 (de) | 2007-02-15 |
AU9788298A (en) | 1999-04-27 |
WO1999017775A1 (en) | 1999-04-15 |
EP1032393B1 (en) | 2006-08-09 |
JP2001518506A (ja) | 2001-10-16 |
KR100647177B1 (ko) | 2006-11-17 |
DE69835532D1 (de) | 2006-09-21 |
NZ504024A (en) | 2002-09-27 |
KR20010024432A (ko) | 2001-03-26 |
CA2304204C (en) | 2010-05-18 |
US6083944A (en) | 2000-07-04 |
CA2304204A1 (en) | 1999-04-15 |
AU749099B2 (en) | 2002-06-20 |
HK1029936A1 (en) | 2001-04-20 |
CN1274283A (zh) | 2000-11-22 |
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