CN113905766A - 可编程的聚合药物 - Google Patents
可编程的聚合药物 Download PDFInfo
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- CN113905766A CN113905766A CN202080040307.8A CN202080040307A CN113905766A CN 113905766 A CN113905766 A CN 113905766A CN 202080040307 A CN202080040307 A CN 202080040307A CN 113905766 A CN113905766 A CN 113905766A
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Abstract
Description
背景
领域
本公开内容的实施方案一般涉及具有间隔基团的二聚体和多聚体生物活性化合物,以及它们的制备方法和在各种治疗方法中的用途。
相关技术的描述
与例如化学疗法不同,靶向药物缀合物将药物递送至靶细胞,几乎没有或没有脱靶活性。通常,靶向药物缀合物包含与生物活性负载或药物连接的靶向分子。通过将独特的靶向能力与生物活性药物的治疗有效性相结合,缀合物可以将药物仅递送至预期靶标并最大限度地减少潜在的副作用。
抗体-药物缀合物(ADC)是一类具有特殊意义的靶向药物缀合物,例如用于癌症治疗。用于癌症治疗的ADC将单克隆抗体的靶向特性与细胞毒性剂的杀癌能力相结合,以提供具有几个优于其它化疗剂的优点的治疗剂。但是,与ADC结构的复杂性相关的挑战,特别是抗体和药物之间的化学连接基(linker),已经给新的且有效的治疗剂的开发带来了重大困难。尽管第一种ADC于2001年获得批准,但下一种ADC获得批准花了将近十年的时间。截至目前,只有 和在全球上市(仅在中国获批)。
因此,本领域需要具有高治疗指数的有效靶向药物缀合物。本公开内容满足了这种需要并提供了进一步的相关优点。
简要概述
简而言之,本公开内容的实施方案一般涉及可用于在体内递送生物活性部分的化合物。具体例子包括靶向药物缀合物,其任选地包含能够选择性递送至靶标(诸如肿瘤细胞)的荧光和/或有色染料。还描述了用于制备此类分子的方法和试剂以及其用于向有此需要的患者提供治疗性处理的用途。
本文公开的化合物的实施方案包括一个或多个生物活性部分,其通过连接基(例如,“La”和/或“Lb”)共价地连接至共同主链。另外,本文描述的某些实施方案提供了具有在相同化合物内的多个生物活性部分的化合物,且可以进一步任选地包括靶向部分。所述生物部分可以是相同的或不同的,因此允许通过施用单一化合物进行单一药剂或组合治疗。
在一个实施方案中,提供了具有以下结构(I)的化合物或其立体异构体、互变异构体或盐:
其中R1、R2、R3、R4、R5、La、Lb、L1、L2、L3、M、m和n如本文中定义。结构(I)的化合物可用于多种应用,包括用作各种治疗方法的治疗剂。
在另一个实施方案中提供了组合物,其包含结构(I)的化合物和药学上可接受的载体。
在另一个实施方案中,提供了治疗疾病的方法,所述方法包括给有此需要的受试者施用治疗有效量的结构(I)的化合物或包含结构(I)的化合物的组合物,其中每个M独立地是有效地治疗疾病的生物活性部分。
在参考下述详细描述后会明白本公开内容的这些和其它方面。
详细描述
在以下描述中,阐述了某些具体细节以提供对本公开内容的各种实施方案的透彻理解。但是,本领域技术人员会理解,可以在没有这些细节的情况下实践本公开内容。
除非上下文另外要求,否则贯穿本说明书和权利要求,词语“包含(comprise)”及其变体,诸如,“包含(comprises)”和“包含(comprising)”,应当以开放的包容性含义进行解释,即“包括、但不限于”。
在本说明书中对“一个实施方案(one embodiment)”或“实施方案(anembodiment)”的提及是指,结合该实施方案描述的特定特征、结构或特性被包括在本公开内容的至少一个实施方案中。因此,贯穿本说明书在不同地方出现的短语“在一个实施方案中”或“在实施方案中”不一定都指代相同的实施方案。此外,可以在一个或多个实施方案中以任意合适的方式组合所述特定特征、结构或特性。
“氨基”表示-NH2基团。
“羧基”表示-CO2H基团。
“氰基”表示-CN基团。
“甲酰基”表示-C(=O)H基团。
“羟”或“羟基”表示-OH基团。
“亚氨基”表示=NH基团。
“硝基”表示-NO2基团。
“氧代”表示=O基团。
“巯基”、“硫醇”或“硫基(thio)”表示-SH基团。
“硫代(thioxo)”表示=S基团。
“烷基”表示仅由碳和氢原子组成的直链或支链烃链基团,不含有不饱和,具有1-12个碳原子(C1-C12烷基)、1-8个碳原子(C1-C8烷基)或1-6个碳原子(C1-C6烷基),且其通过单键连接至分子的其余部分,例如,甲基、乙基、正丙基、1-甲基乙基(异丙基)、正丁基、正戊基、1,1-二甲基乙基(叔丁基)、3-甲基己基、2-甲基己基等。除非在说明书中另外具体地说明,否则烷基任选地被取代。
“亚烷基”或“亚烷基链”表示将分子的其余部分连接至残基基团的直链或支链二价烃链,其仅由碳和氢组成,不含有不饱和,且具有1-12个碳原子,例如,亚甲基、亚乙基、亚丙基、亚正丁基、亚乙烯基、亚丙烯基、亚正丁烯基、亚丙炔基、亚正丁炔基等。亚烷基链通过单键连接至分子的其余部分并且通过单键连接至残基基团。亚烷基链与分子的其余部分和与残基基团的连接点可以是通过该链内的一个碳或任何两个碳。除非在说明书中另外具体地说明,否则亚烷基任选地被取代。
“亚烯基”或“亚烯基链”表示将分子的其余部分连接至残基基团的直链或支链二价烃链,其仅由碳和氢组成,含有至少一个碳-碳双键且具有2-12个碳原子,例如,亚乙烯基、丙亚烯基、亚正丁烯基等。亚烯基链通过单键连接至分子的其余部分和通过双键或单键连接至残基基团。亚烯基链与分子的其余部分和与残基基团的连接点可以是通过该链内的一个碳或任何两个碳。除非在说明书中另外具体地说明,否则亚烯基任选地被取代。
“亚炔基”或“亚炔基链”表示将分子的其余部分连接至残基基团的直链或支链二价烃链,其仅由碳和氢组成,含有至少一个碳-碳三键且具有2-12个碳原子,例如,亚乙烯基、丙亚烯基、亚正丁烯基等。亚炔基链通过单键连接至分子的其余部分和通过双键或单键连接至残基基团。亚炔基链与分子的其余部分和与残基基团的连接点可以是通过该链内的一个碳或任何两个碳。除非在说明书中另外具体地说明,否则亚炔基任选地被取代。
“烷基醚”表示如上定义的任何烷基,其中至少一个碳-碳键被碳-氧-碳键替换。碳-氧-碳键可以是在末端(如在烷氧基中)上,或碳氧键可以是在内部(即,C-O-C)。烷基醚包括至少一个碳-氧-碳键,但是可以包括超过一个。例如,聚乙二醇(PEG)被包括在烷基醚的含义内。除非在说明书中另外具体地说明,否则烷基醚基团任选地被取代。例如,在某些实施方案中,烷基醚被醇或-OP(=Ra)(Rb)Rc取代,其中Ra、Rb和Rc中的每个如关于结构(I)的化合物所定义。
“烷氧基”表示式-ORa的基团,其中Ra是含有1-12个碳原子的如上定义的烷基。除非在说明书中另外具体地说明,否则烷氧基任选地被取代。
“烷氧基烷基醚”表示式-ORaRb的基团,其中Ra是含有1-12个碳原子的如上定义的亚烷基,且Rb是如本文中定义的烷基醚基团。除非在说明书中另外具体地说明,否则烷氧基烷基醚基团任选地被取代,例如被醇或-OP(=Ra)(Rb)Rc取代,其中Ra、Rb和Rc中的每个如关于结构(I)的化合物所定义。
“杂烷基”表示如上定义的烷基,其包含在烷基内或在烷基末端处的至少一个杂原子(例如,Si、N、O、P或S)。在某些实施方案中,所述杂原子是在烷基内(即,杂烷基包含至少一个碳-[杂原子]x-碳键,其中x是1、2或3)。在其它实施方案中,所述杂原子是在烷基末端且因而用于将烷基连接至分子的其余部分(例如,M1-H-A),其中M1是分子的一部分,H是杂原子且A是烷基)。除非在说明书中另外具体地说明,否则杂烷基任选地被取代。示例性的杂烷基包括环氧乙烷(例如,聚环氧乙烷),任选地包括磷-氧键,诸如磷酸二酯键。
“杂烷氧基”表示式-ORa的基团,其中Ra是含有1-12个碳原子的如上定义的杂烷基。除非在说明书中另外具体地说明,否则杂烷氧基任选地被取代。
“亚杂烷基”表示如上定义的亚烷基,其包含在亚烷基链内或在亚烷基链的末端处的至少一个杂原子(例如,Si、N、O、P或S)。在某些实施方案中,所述杂原子是在亚烷基链内(即,亚杂烷基包含至少一个碳-[杂原子]-碳键,其中x是1、2或3)。在其它实施方案中,所述杂原子是在亚烷基的末端且因而用于将亚烷基连接至分子的其余部分(例如,M1-H-A-M2,其中M1和M2是分子的部分,H是杂原子且A是亚烷基)。除非在说明书中另外具体地说明,否则亚杂烷基任选地被取代。示例性的亚杂烷基包括环氧乙烷(例如,聚环氧乙烷)和下面解释的“C”、“HEG”和“PEG 1K”连接基团:
以上C-连接基、HEG连接基和/或PEG 1K连接基的多聚体被包括在亚杂烷基连接基的不同实施方案中。在PEG 1K连接基的某些实施方案中,n的范围为19-25,例如n是19、20、21、22、23、24或25。多聚体可以包含,例如,以下结构:
其中x是0或大于0的整数,例如,x范围为0-100(例如,1、2、3、4、5、6、7、8、9或10)。
“亚杂烯基”是包含至少一个碳-碳双键的如上定义的亚杂烷基。除非在说明书中另外具体地说明,否则亚杂烯基任选地被取代。
“亚杂炔基”是包含至少一个碳-碳三键的亚杂烷基。除非在说明书中另外具体地说明,否则亚杂炔基任选地被取代。
关于“杂原子连接基”的“杂原子”表示由一个或多个杂原子组成的连接基基团。示例性的杂原子连接基包括选自Si、O、N、P和S的单个原子和多个杂原子,例如连接基,其具有式-P(O-)(=O)O-或-OP(O-)(=O)O-和多聚体及其组合。
“磷酸酯”表示-OP(=O)(Ra)Rb基团,其中Ra是OH、O-或ORc;且Rb是OH、O-、ORc,硫代磷酸酯(thiophosphate)基团或其它磷酸酯基团,其中Rc是抗衡离子(例如,Na+等)。
“磷酰烷基(Phosphoalkyl)”表示-OP(=O)(Ra)Rb基团,其中Ra是OH、O-或ORc;且Rb是-O烷基,其中Rc是抗衡离子(例如,Na+等)。除非在说明书中另外具体地说明,否则磷酰烷基任选地被取代。例如,在某些实施方案中,磷酰烷基中的-O烷基部分任选地被羟基、氨基、巯基、磷酸酯、硫代磷酸酯、磷酰烷基、硫代磷酰烷基、磷酰烷基醚、硫代磷酰烷基醚或-OP(=Ra)(Rb)Rc中的一个或多个取代,其中Ra、Rb和Rc中的每个如关于结构(I)的化合物所定义。
“磷酰烷基醚”表示-OP(=O)(Ra)Rb基团,其中Ra是OH、O-或ORc;且Rb是-O烷基醚,其中Rc是抗衡离子(例如,Na+等)。除非在说明书中另外具体地说明,否则磷酰烷基醚基团任选地被取代。例如,在某些实施方案中,磷酰烷基醚基团中的-O烷基醚部分任选地被羟基、氨基、巯基、磷酸酯、硫代磷酸酯、磷酰烷基、硫代磷酰烷基、磷酰烷基醚、硫代磷酰烷基醚或-OP(=Ra)(Rb)Rc中的一个或多个取代,其中Ra、Rb和Rc中的每个如关于结构(I)的化合物所定义。
“硫代磷酸酯”表示-OP(=Ra)(Rb)Rc基团,其中Ra是O或S,Rb是OH、O-、S-、ORd或SRd;且Rc是OH、SH、O-、S-、ORd、SRd、磷酸酯基团或其它硫代磷酸酯基团,其中Rd是抗衡离子(例如,Na+等)且条件是:i)Ra是S;ii)Rb是S-或SRd;iii)Rc是SH、S-或SRd;或iv)i)、ii)和/或iii)的组合。
“硫代磷酰烷基”表示-OP(=Ra)(Rb)Rc基团,其中Ra是O或S,Rb是OH、O-、S-、ORd或SRd;且Rc是-O烷基,其中Rd是抗衡离子(例如,Na+等)且条件是:i)Ra是S;ii)Rb是S-或SRd;或iii)Ra是S且Rb是S-或SRd。除非在说明书中另外具体地说明,否则硫代磷酰烷基任选地被取代。例如,在某些实施方案中,硫代磷酰烷基中的-O烷基部分任选地被羟基、氨基、巯基、磷酸酯、硫代磷酸酯、磷酰烷基、硫代磷酰烷基、磷酰烷基醚、硫代磷酰烷基醚或-OP(=Ra)(Rb)Rc中的一个或多个取代,其中Ra、Rb和Rc中的每个如关于结构(I)的化合物所定义。
“硫代磷酰烷基醚”表示-OP(=Ra)(Rb)Rc基团,其中Ra是O或S,Rb是OH、O-、S-、ORd或SRd;且Rc是-O烷基醚,其中Rd是抗衡离子(例如,Na+等)且条件是:i)Ra是S;ii)Rb是S-或SRd;或iii)Ra是S且Rb是S-或SRd。除非在说明书中另外具体地说明,否则硫代磷酰烷基醚基团任选地被取代。例如,在某些实施方案中,硫代磷酰烷基中的-O烷基醚部分任选地被羟基、氨基、巯基、磷酸酯、硫代磷酸酯、磷酰烷基、硫代磷酰烷基、磷酰烷基醚、硫代磷酰烷基醚或-OP(=Ra)(Rb)Rc中的一个或多个取代,其中Ra、Rb和Rc中的每个如关于结构(I)的化合物所定义。
“碳环”表示包含3-18个碳原子的稳定的3-18元芳族或非芳族环。除非在说明书中另外具体地说明,否则碳环可以是单环、二环、三环或四环环系,其可以包括稠合或桥环系,且可以是部分地或完全地饱和的。非芳族碳环基残基包括环烷基,而芳族碳环基残基包括芳基。除非在说明书中另外具体地说明,否则碳环基团任选地被取代。
“环烷基”表示稳定的非芳族单环或多环碳环,其可以包括稠合或桥环系,具有3-15个碳原子,优选地具有3-10个碳原子,且其是饱和的或不饱和的并通过单键连接至分子的其余部分。单环环烷基包括,例如,环丙基、环丁基、环戊基、环己基、环庚基和环辛基。多环环烷基包括,例如,金刚烷基、降冰片基(norbornyl)、十氢萘基、7,7-二甲基-二环-[2.2.1]庚烷基等。除非在说明书中另外具体地说明,否则环烷基任选地被取代。
“芳基”表示包含至少一个碳环芳族环的环系。在某些实施方案中,芳基包含6-18个碳原子。芳基环可以是单环、二环、三环或四环环系,其可以包括稠合或桥环系。芳基包括、但不限于从醋蒽烯、苊烯、醋菲烯(acephenanthrylene)、蒽、薁、苯、荧蒽、芴、不对称引达省(indacene)、对称引达省、茚满、茚、萘、非那烯、菲、七曜烯(pleiadene)、芘和苯并菲衍生出的芳基。除非在说明书中另外具体地说明,否则芳基任选地被取代。
“杂环”表示包含1-12个碳原子和1-6个选自氮、氧和硫的杂原子的稳定的3-18元芳族或非芳族环。除非在说明书中另外具体地说明,否则杂环可以是单环、二环、三环或四环环系,其可以包括稠合或桥环系;且杂环中的氮、碳或硫原子可以任选地被氧化;氮原子可以任选地被季铵化;且杂环可以是部分地或完全地饱和的。芳族杂环的例子在下面列出在杂芳基的定义中(即,杂芳基是杂环的子集)。非芳族杂环的例子包括、但不限于二氧杂环戊烷基、噻吩基[1,3]二硫杂环己基、十氢异喹啉基、咪唑啉基、咪唑烷基、异噻唑烷基、异噁唑烷基、吗啉基、八氢吲哚基、八氢异吲哚基、2-氧代哌嗪基、2-氧代哌啶基、2-氧代吡咯烷基、噁唑烷基、哌啶基、哌嗪基、4-哌啶酮基、吡咯烷基、吡唑烷基、吡唑并嘧啶基、奎宁环基、噻唑烷基、四氢呋喃基、三氧杂环己烷基、三硫杂环己烷基、三嗪烷基、四氢吡喃基、硫代吗啉基、硫吗啉基、1-氧代-硫吗啉基和1,1-二氧代-硫吗啉基。除非在说明书中另外具体地说明,否则杂环基团任选地被取代。
“杂芳基”表示包含1-13个碳原子、1-6个选自氮、氧和硫的杂原子和至少1个芳族环的5-14元环系。为了本公开内容的某些实施方案的目的,杂芳基残基可以是单环、二环、三环或四环环系,其可以包括稠合或桥环系;且杂芳基残基中的氮、碳或硫原子可以任选地被氧化;氮原子可以任选地被季铵化。例子包括、但不限于氮杂环庚三烯基、吖啶基、苯并咪唑基、苯并噻唑基、苯并吲哚基、苯并间二氧杂环戊烯基、苯并呋喃基、苯并噁唑基、苯并噻唑基、苯并噻二唑基、苯并[b][1,4]二氧杂环庚二烯基(dioxepinyl)、1,4-苯并二氧杂环己烷基、苯并萘并呋喃基、苯并噁唑基、苯并间二氧杂环戊烯基、苯并二氧杂环己烯基、苯并吡喃基、苯并吡喃酮基、苯并呋喃基、苯并呋喃酮基、苯并噻吩基(苯并噻吩基)、苯并三唑基、苯并[4,6]咪唑并[1,2-a]吡啶基、苯并噁唑啉酮基、苯并咪唑亚硫酰基、咔唑基、噌啉基、二苯并呋喃基、二苯并噻吩基、呋喃基、呋喃酮基、异噻唑基、咪唑基、吲唑基、吲哚基、吲唑基、异吲哚基、吲哚啉基、异吲哚啉基、异喹啉基、吲嗪基、异噁唑基、萘啶基、噁二唑基、2-氧代氮杂环庚三烯基、噁唑基、氧杂环丙基、1-氧化(oxido)吡啶基、1-氧化嘧啶基、1-氧化吡嗪基、1-氧化哒嗪基、1-苯基-1H-吡咯基、吩嗪基、吩噻嗪基、吩噁嗪基、酞嗪基、喋啶基、喋啶酮基、嘌呤基、吡咯基、吡唑基、吡啶基、吡啶酮基、吡嗪基、嘧啶基、嘧啶酮基(pryrimidinonyl)、哒嗪基、吡咯基、吡啶并[2,3-d]嘧啶酮基、喹唑啉基、喹唑啉酮基、喹喔啉基、喹喔啉酮基、喹啉基、异喹啉基、四氢喹啉基、噻唑基、噻二唑基、噻吩并[3,2-d]嘧啶-4-酮基、噻吩并[2,3-d]嘧啶-4-酮基、三唑基、四唑基、三嗪基和噻吩基(即噻吩基)。除非在说明书中另外具体地说明,否则杂芳基任选地被取代。
“稠合”表示包含至少2个环的环系,其中所述2个环共享至少一个共同环原子,例如2个共同环原子。当稠合环是杂环基环或杂芳基环时,共同环原子可以是碳或氮。稠合环包括二环、三环、四环等。
本文使用的术语“取代”是指:以上基团(例如,烷基、亚烷基、亚烯基、亚炔基、亚杂烷基、亚杂烯基、亚杂炔基、烷氧基、烷基醚、烷氧基烷基醚、杂烷基、杂烷氧基、磷酰烷基、磷酰烷基醚、硫代磷酰烷基、硫代磷酰烷基醚、碳环、环烷基、芳基、杂环的和/或杂芳基)中的任一个,其中至少一个氢原子(例如,1、2、3个或所有氢原子)被与非氢原子的键替代,所述非氢原子是诸如,但不限于卤素原子诸如F、Cl、Br和I;基团诸如羟基、烷氧基和酯基中的氧原子;基团诸如硫醇基团、硫代烷基基团、砜基团、磺酰基基团和亚砜基团中的硫原子;基团诸如胺、酰胺、烷基胺、二烷基胺、芳基胺、烷基芳基胺、二芳基胺、N-氧化物、酰亚胺和烯胺中的氮原子;基团诸如三烷基甲硅烷基、二烷基芳基甲硅烷基、烷基二芳基甲硅烷基和三芳基甲硅烷基中的硅原子;以及各种其它基团中的其它杂原子。“取代”也是指以上基团中的任一个,其中一个或多个氢原子被与杂原子的高阶键(例如,双键或三键)替代,所述杂原子是诸如氧代基团、羰基基团、羧基基团和酯基团中的氧;以及基团诸如亚胺、肟、腙和腈中的氮。例如,“取代”包括上述基团中的任一个,其中一个或多个氢原子被-NRgRh、-NRgC(=O)Rh、-NRgC(=O)NRgRh、-NRgC(=O)ORh、-NRgSO2Rh、-OC(=O)NRgRh、-ORg、-SRg、-SORg、-SO2Rg、-OSO2Rg、-SO2ORg、=NSO2Rg和-SO2NRgRh替代。“取代”也是指上述基团中的任一个,其中一个或多个氢原子被-C(=O)Rg、-C(=O)ORg、-C(=O)NRgRh、-CH2SO2Rg、-CH2SO2NRgRh替代。在前述内容中,Rg和Rh是相同的或不同的,且独立地是氢、烷基、烷氧基、烷基氨基、硫代烷基、芳基、芳烷基、环烷基、环烷基烷基、卤代烷基、杂环基、N-杂环基、杂环基烷基、杂芳基、N-杂芳基和/或杂芳基烷基。“取代”进一步是指上述基团中的任一个,其中一个或多个氢原子被与以下基团的键替代:氨基、氰基、羟基、亚氨基、硝基、氧代、硫代、卤素、烷基、烷氧基、烷基氨基、硫代烷基、芳基、芳烷基、环烷基、环烷基烷基、卤代烷基、杂环基、N-杂环基、杂环基烷基、杂芳基、N-杂芳基和/或杂芳基烷基。在某些实施方案中,所述任选取代基是-OP(=Ra)(Rb)Rc,其中Ra、Rb和Rc中的每个如关于结构(I)的化合物所定义。另外,前述取代基中的每个也可以任选地被以上取代基中的一个或多个取代。
“缀合”或“生物缀合”表示在两个分子之间形成稳定共价键的化学策略。当分子之一是生物分子(例如,抗体)时,通常使用术语“生物缀合”。从这样的策略产生的产物或化合物是缀合物,是缀合的,或语法上等效的短语。
“荧光的”表示能够吸收特定频率的光并发射不同频率的光的分子。荧光是本领域普通技术人员众所周知的。
“有色的”表示吸收在有色光谱(即红色、黄色、蓝色等)内的光的分子。
“连接基”表示至少一个原子的连续链,诸如碳、氧、氮、硫、磷及其组合,其将分子的一部分连接到同一分子的另一部分或连接到不同的分子、部分或固体载体(例如,微粒)。连接基可以经由共价键或其它方式连接分子,例如离子键或氢键相互作用。
术语“生物分子”表示多种生物学材料中的任一种,包括核酸、碳水化合物、氨基酸、多肽、糖蛋白、激素、适配体及其混合物。更具体地,该术语意图包括、但不限于,RNA、DNA、寡核苷酸、修饰的或衍生化的核苷酸、酶、受体、朊病毒、受体配体(包括激素)、抗体、抗原和毒素、以及细菌、病毒、血细胞和组织细胞。在本公开内容的某些实施方案中,如在本文中进一步描述的,通过使生物分子与具有反应基团(其能够经由任何可利用的原子或官能团(诸如在生物分子上的氨基、羟基、羧基或巯基)将生物分子连接至化合物)的化合物接触,制备示例性的缀合物(例如,具有与其连接的生物分子的结构(I)的化合物)。
“反应基团”是能够与第二反应基团(例如,“互补反应基团”)反应以形成一个或多个共价键的部分,例如通过置换、氧化、还原、加成或环加成反应。示例性的反应基团提供在表1中,并且包括例如亲核体、亲电体、二烯、亲二烯体、醛、肟、腙、炔烃、胺、叠氮化物、酰基叠氮化物、酰基卤化物、腈、硝酮、巯基、二硫化物、磺酰卤、异硫氰酸酯、亚氨酸酯、活化酯、酮、α,β-不饱和羰基、烯烃、马来酰亚胺、α-卤代酰胺、环氧化物、氮丙啶、四嗪、四唑、膦、生物素、硫杂丙环等。
“固体载体”表示本领域已知的用于分子的固相载体的任何固体基质,例如“微粒”表示可用于附着到本公开内容的化合物的许多小颗粒中的任何一种,包括、但不限于玻璃珠、磁珠、聚合物珠、非聚合物珠等。在某些实施方案中,微粒包含聚苯乙烯珠。
“固体载体残基”表示当分子从固体载体裂解时保持与分子连接的官能团。固体载体残基是本领域已知的,并且可以基于固体载体的结构和与其连接分子的基团容易地推导出。
“靶向部分”是选择性地结合或缔合特定靶标(诸如肿瘤细胞抗原)的部分。“选择性地”结合或缔合意指,相对于其它靶标,靶向部分优先缔合或结合期望的靶标。例如,在某些实施方案中,选择性结合是指靶向部分或包含它的缀合物,其与期望的靶标的缔合或结合是相对于其它靶标的至少10倍或至少100倍。在某些实施方案中,本文公开的化合物包括与靶向部分的连接,目的是选择性地使化合物与期望的靶标(诸如肿瘤细胞抗原)结合或缔合,从而允许生物活性部分的靶向递送。示例性的靶向部分包括、但不限于抗体、抗原、核酸序列、酶、蛋白、细胞表面受体拮抗剂或细胞表面受体激动剂等。在某些实施方案中,靶向部分是这样的部分(诸如抗体):其选择性地结合或缔合在细胞上或细胞中的靶特征,例如在细胞膜或其它细胞结构上的靶特征,从而允许将生物活性部分递送至或递送进入感兴趣的细胞。在某些实施方案中,选择性地结合或缔合期望的生物靶标的小分子也被考虑作为靶向部分。本领域技术人员将理解将在各种实施方案中有用的其它生物靶标和相应的靶向部分。
“生理学上可裂解的连接基”表示在生物体或细胞系统的体内或体外环境存在的情况下,可以以规定的方式分裂或分离的分子连接,从而产生两个或更多个分离的分子。通常,诱导这种裂解或断裂事件的生理条件可以包括约20-40℃范围的温度、约1atm(101kPa或14.7psi)的大气压、约6-8的pH、约1-20mM的葡萄糖浓度、大气氧浓度和地球重力。在某些实施方案中,生理条件包括酶促条件(即,酶促裂解)。键裂解或断裂可以是均裂的或异裂的。
本文中公开的实施方案也意在涵盖所有通过用具有不同原子质量或质量数的原子替换一个或多个原子进行同位素标记的结构(I)的化合物。可以掺入公开的化合物中的同位素的例子包括氢、碳、氮、氧、磷、氟、氯和碘的同位素,分别诸如2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、36Cl、123I和125I。
通过本领域技术人员已知的常规技术,或通过类似于下文描述的那些的方法和以下实施例中的方法,使用适当的同位素标记的试剂代替以前使用的未标记的试剂,通常可以制备同位素标记的结构(I)的化合物。
“稳定的化合物”和“稳定的结构”意在指示这样的化合物:其足够稳固以承受(survive)从反应混合物中分离至有用程度的纯度并配制到有效的治疗剂中。
“任选的”或“任选地”是指,随后描述的事件或情况可能发生也可能不发生,并且该描述包括所述事件或情况发生的实例和不发生的实例。例如,“任选地取代的烷基”是指,所述烷基可以被取代或可以不被取代,并且该描述包括被取代的烷基和没有取代的烷基。
“盐”包括酸和碱加成盐。
“酸加成盐”表示与无机酸(诸如,但不限于,盐酸、氢溴酸、硫酸、硝酸、磷酸等)和有机酸(诸如,但不限于,乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、天冬氨酸、苯磺酸、苯甲酸、4-乙酰氨基苯甲酸、樟脑酸、樟脑-10-磺酸、癸酸、己酸、辛酸、碳酸、肉桂酸、柠檬酸、环己烷氨基磺酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、葡糖酸、葡糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、羟乙酸、马尿酸、异丁酸、乳酸、乳糖酸、月桂酸、马来酸、苹果酸、丙二酸、扁桃酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、油酸、乳清酸、草酸、棕榈酸、扑酸、丙酸、焦谷氨酸、丙酮酸、水杨酸、4-氨基水杨酸、癸二酸、硬脂酸、琥珀酸、酒石酸、硫氰酸、对甲苯磺酸、三氟乙酸、十一烯酸等)形成的那些盐。
“碱加成盐”表示通过向游离酸中加入无机碱或有机碱而制备的那些盐。衍生自无机碱的盐包括、但不限于钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等。衍生自有机碱的盐包括、但不限于以下的盐:伯胺、仲胺和叔胺、被取代的胺(包括天然存在的被取代的胺)、环胺和碱性离子交换树脂,诸如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、二乙醇胺、乙醇胺、地阿诺、2-二甲基氨基乙醇、2-二乙基氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴明(hydrabamine)、胆碱、甜菜碱、苯乙苄胺、二苄基乙二胺、乙二胺、葡糖胺、甲基还原葡糖胺、可可碱、三乙醇胺、氨丁三醇、嘌呤、哌嗪、哌啶、N-乙基哌啶、多胺树脂等。特别优选的有机碱是异丙胺、二乙胺、乙醇胺、三甲胺、二环己胺、胆碱和咖啡因。
结晶可以产生本文所述化合物的溶剂化物。本公开内容的实施方案包括所描述的化合物的所有溶剂化物。本文中使用的术语“溶剂化物”表示包含本公开内容的化合物的一个或多个分子与一个或多个溶剂分子的聚集体。溶剂可以是水,在这种情况下,溶剂化物可以是水合物。可替换地,溶剂可以是有机溶剂。因此,本公开内容的化合物可以作为水合物存在,包括一水合物、二水合物、半水合物、倍半水合物、三水合物、四水合物等,以及相应的溶剂化形式。本公开内容的化合物可以是真正的溶剂化物,而在其它情况下,本公开内容的化合物可以仅保留外来水或另一种溶剂或者是水加一些外来溶剂的混合物。
本公开内容的化合物(例如,结构I的化合物)或其盐、互变异构体或溶剂化物的实施方案可以含有一个或多个立构中心,并且因此可以产生对映异构体、非对映异构体和对于氨基酸在绝对立体化学方面可以定义为(R)-或(S)-、或定义为(D)-或(L)-的其它立体异构形式。本公开内容的实施方案意图包括所有这样的可能的异构体,以及它们的外消旋的和光学纯的形式。使用手性合成子或手性试剂可以制备光学活性的(+)和(-)、(R)-和(S)-、或(D)-和(L)-异构体,或使用常规技术(例如,色谱法和分步结晶)可以拆分光学活性的(+)和(-)、(R)-和(S)-、或(D)-和(L)-异构体。用于制备/分离各对映异构体的常规技术包括从合适的光学纯的前体手性合成,或使用例如手性高压液相色谱法(HPLC)拆分外消旋体(或盐或衍生物的外消旋体)。当本文所述化合物含有烯属双键或产生几何不对称的其它特征时,且除非另有说明,否则意指所述化合物包括E和Z几何异构体。同样,也意在包括所有互变异构形式。
“立体异构体”表示由通过相同键键合的相同原子构成但具有不可互换的不同的三维结构的化合物。本公开内容涵盖各种立体异构体及其混合物,且包括“对映异构体”,其表示两种立体异构体,它们的分子是彼此的不可重叠的镜像。
“互变异构体”表示质子从分子的一个原子转移到同一分子的另一个原子。本公开内容包括任何所述化合物的互变异构体。本领域普通技术人员可容易地推导出化合物的各种互变异构形式。
本文使用的化学命名方案和结构简图是I.U.P.A.C.命名法系统的改进形式,使用ACD/Name 9.07版软件程序和/或ChemDraw Ultra 11.0版软件命名程序(CambridgeSoft)。也使用本领域普通技术人员熟悉的通用名称。
如上面所指出的,在本公开内容的一个实施方案中,提供了化合物,其包含在一个或多个生物活性部分和任选靶向部分之间的共价连接基。在其它实施方案中,提供了化合物,其可用作合成中间体用于制备包含一个或多个生物活性部分和任选靶向部分的化合物。一般而言,本公开内容的实施方案涉及具有侧基(pendant)生物活性部分的聚合物。生物活性部分通过连接部分连接到聚合物。在另一方面,连接基提供生物活性部分和靶向部分之间的连接,所述靶向部分的作用是增加生物活性部分在期望靶标处的积累。也就是说,由于在预期靶标处的积累,生物活性可能增加,而脱靶效应会降低,从而最大限度地减少治疗剂的潜在副作用(例如,细胞毒性)。
在其它实施方案中,提供了具有以下结构(I)的化合物或其立体异构体、药学上可接受的盐或互变异构体:
其中:
M在每次出现时独立地是生物活性部分或其片段、生物活性部分的前药或其片段、荧光染料、成像剂或放射性同位素结合位点,条件是M的至少一次出现不是荧光染料;
L1和L2在每次出现时独立地是任选的亚烷基、亚烯基、亚炔基、亚杂烷基、亚杂烯基、亚杂炔基或杂原子连接基;
L3在每次出现时独立地是亚烷基、亚烯基、亚炔基、亚杂烷基、亚杂烯基或亚杂炔基连接基;
R1在每次出现时独立地是H、烷基或烷氧基;
R2和R3各自独立地是H、OH、SH、烷基、烷氧基、烷基醚、杂烷基、-OP(=Ra)(Rb)Rc、Q或其保护形式或L';
R4在每次出现时独立地是O-、S-、OZ、SZ或N(R6)2,其中Z是阳离子且每个R6独立地是H或烷基;
R5在每次出现时独立地是氧代、硫代或不存在;
Ra是O或S;
Rb是OH、SH、O-、S-、ORd或SRd;
Rc是OH、SH、O-、S-、ORd、OL'、SRd、烷基、烷氧基、杂烷基、杂烷氧基、烷基醚、烷氧基烷基醚、磷酸酯、硫代磷酸酯、磷酰烷基、硫代磷酰烷基、磷酰烷基醚或硫代磷酰烷基醚;
Rd是抗衡离子;
Q在每次出现时独立地是包含反应基团的部分或其保护形式,其能够与靶向部分上的互补反应基团Q′形成共价键;
L'在每次出现时独立地是包含与Q的共价键的连接基、靶向部分、包含与靶向部分的共价键的连接基、包含与固体载体的共价键的连接基、包含与固体载体残基的共价键的连接基、包含与核苷的共价键的连接基或包含与结构(I)的另一种化合物的共价键的连接基;
m在每次出现时独立地是0或更大的整数;且
n是1或更大的整数。
在其它实施方案中,提供了具有以下结构(I)的化合物或其立体异构体、药学上可接受的盐或互变异构体:
其中:
M在每次出现时独立地是生物活性部分或其片段、生物活性部分的前药或其片段、荧光染料、成像剂或放射性同位素结合位点,条件是M的至少一次出现不是荧光染料;
L1和L2在每次出现时独立地是任选的亚烷基、亚烯基、亚炔基或杂原子连接基;
L3在每次出现时独立地是亚烷基、亚烯基、亚炔基、亚杂烷基、亚杂烯基或亚杂炔基连接基;
R1在每次出现时独立地是H、烷基或烷氧基;
R2和R3各自独立地是H、OH、SH、烷基、烷氧基、烷基醚、杂烷基、-OP(=Ra)(Rb)Rc、Q或其保护形式或L';
R4在每次出现时独立地是O-、S-、OZ、SZ或N(R6)2,其中Z是阳离子且每个R6独立地是H或烷基;
R5在每次出现时独立地是氧代、硫代或不存在;
Ra是O或S;
Rb是OH、SH、O-、S-、ORd或SRd;
Rc是OH、SH、O-、S-、ORd、OL'、SRd、烷基、烷氧基、杂烷基、杂烷氧基、烷基醚、烷氧基烷基醚、磷酸酯、硫代磷酸酯、磷酰烷基、硫代磷酰烷基、磷酰烷基醚或硫代磷酰烷基醚;
Rd是抗衡离子;
Q在每次出现时独立地是包含反应基团的部分或其保护形式,其能够与靶向部分上的互补反应基团Q′形成共价键;
L'在每次出现时独立地是包含与Q的共价键的连接基、靶向部分、包含与靶向部分的共价键的连接基、包含与固体载体的共价键的连接基、包含与固体载体残基的共价键的连接基、包含与核苷的共价键的连接基或包含与结构(I)的另一种化合物的共价键的连接基;
m在每次出现时独立地是0或更大的整数;且
n是1或更大的整数。
连接基La和/或Lb可以用作M部分与化合物的其余部分的连接点。例如,在某些实施方案中,制备了结构(I)的化合物的合成前体,并且使用本领域已知的任何数量的简便方法,例如称为“点击化学”的方法,将M部分连接到合成前体。为此目的,任何快速且基本上不可逆的反应都可用于将M连接到合成前体以形成结构(I)的化合物。示例性反应包括铜催化的叠氮化物和炔烃的反应以形成三唑(Huisgen 1,3-偶极环加成),二烯和亲二烯体的反应(Diels-Alder),应变促进的炔烃-硝酮环加成,应变的烯烃与叠氮化物、四嗪或四唑的反应,烯烃和叠氮化物[3+2]环加成,烯烃和四嗪逆需求Diels-Alder,烯烃和四唑光反应和各种置换反应,诸如通过亲电子原子上的亲核攻击对离去基团的置换。示例性的置换反应包括胺与以下物质的反应:活化酯;N-羟基琥珀酰亚胺酯;异氰酸酯;异硫氰酸酯等。在某些实施方案中,形成La和/或Lb的反应可以在水性环境中进行。
因此,在某些实施方案中,La和/或Lb在每次出现时是包含能够通过两个互补反应基团的反应形成的官能团的连接基,例如为前述“点击”反应之一的产物的官能团。在不同的实施方案中,对于La和/或Lb的至少一次出现,官能团可以通过醛、肟、腙、炔烃、胺、叠氮化物、酰基叠氮化物、酰基卤化物、腈、硝酮、巯基、二硫化物、磺酰卤、异硫氰酸酯、亚氨酸酯、活化酯(例如,N-羟基琥珀酰亚胺酯)、酮、α,β-不饱和羰基、烯烃、马来酰亚胺、α-卤代酰胺、环氧化物、氮丙啶、四嗪、四唑、膦、生物素或硫杂丙环官能团与互补反应基团的反应(例如,胺与N-羟基琥珀酰亚胺酯或异硫氰酸酯的反应)形成。
在其它实施方案中,对于La和/或Lb的至少一次出现,官能团可以通过炔烃和叠氮化物的反应形成。在其它实施方案中,对于La和/或Lb的至少一次出现,官能团可以通过胺(例如,伯胺)和N-羟基琥珀酰亚胺酯或异硫氰酸酯的反应形成。
在更多实施方案中,对于La和/或Lb的至少一次出现,官能团包含烯烃、酯、酰胺、硫代酸酯、二硫化物、碳环、杂环或杂芳基基团。在更多实施方案中,对于La和/或Lb的至少一次出现,官能团包含烯烃、酯、酰胺、硫代酸酯、硫脲、二硫化物、碳环、杂环或杂芳基基团。在其它实施方案中,官能团包含酰胺或硫脲。在某些更具体的实施方案中,对于La和/或Lb的至少一次出现,La和/或Lb是包含三唑基官能团的连接基。而在其它实施方案中,对于La和/或Lb的至少一次出现,La和/或Lb是包含酰胺或硫脲官能团的连接基。
一些实施方案提供了能够在适当的条件(例如,生理条件)下被裂解的La。在某些实施方案中,La的至少一次出现存在。在某些更具体的实施方案中,La的至少一次出现包含酰胺键、酯键、磷酸二酯键、二硫键、双键、三键、醚键、腙、氨基酸序列、酮、二醇、氰基、硝基或其组合。
在某些实施方案中,La包含被分选酶识别的氨基酸序列。在某些实施方案中,所述氨基酸序列是Leu-Pro-X-Thr-Gly,其中X是任意氨基酸残基。在一些其它的实施方案中,La的至少一次出现是包含3个或更多个碳的连接基。在某些其它实施方案中,La的至少一次出现是包含至少一个氮的连接基。在某些实施方案中,La的至少一次出现包含以下结构之一:
在某些实施方案中,La的每次出现包含酰胺键、酯键、磷酸二酯键、二硫键、双键、三键、醚键、腙、氨基酸序列、酮、二醇、氰基、硝基或其组合。
在某些实施方案中,La的每次出现是包含3个或更多个碳的连接基。在某些实施方案中,La的每次出现是包含至少一个氮的连接基。在一些其它的实施方案中,La的每次出现包含以下结构之一:
在某些实施方案中,La的至少一次出现包含以下结构:
在某些实施方案中,La的至少一次出现包含一个或多个氨基酸残基。在某些实施方案中,所述氨基酸残基是缬氨酸。在某些更具体的实施方案中,La的至少一次出现包含以下结构之一:
在结构(I)的某些实施方案中,La包含以下结构之一:
在某些更具体的实施方案中,La的至少一次出现包含以下结构:
在某些更具体的实施方案中,La的至少一次出现包含以下结构之一:
在某些实施方案中,La的每次出现包含以下结构:
在某些实施方案中,La的每次出现包含一个或多个氨基酸残基。在某些实施方案中,所述氨基酸残基是缬氨酸。在某些具体实施方案中,La的每次出现包含以下结构之一:
在某些更具体的实施方案中,La的至少一次出现包含以下结构:
在某些实施方案中,La的至少一次出现具有以下结构:
在某些实施方案中,La的至少一次出现具有以下结构之一:
在某些实施方案中,La的至少一次出现具有以下结构:
在某些实施方案中,Lb的至少一次出现存在(且包含在生理条件下不可裂解的连接基)。在某些具体实施方案中,Lb的至少一次出现包含硫醚键。在某些具体实施方案中,Lb的至少一次出现包含以下结构:
在某些实施方案中,Lb的至少一次出现包含以下结构之一:
在某些实施方案中,Lb的每次出现包含在生理条件下不可裂解的连接基。在某些实施方案中,Lb的每次出现包含硫醚键。在某些实施方案中,Lb的每次出现包含以下结构:
在某些实施方案中,Lb的每次出现包含以下结构之一:
因此,在某些实施方案中,La或Lb包含酰胺键、酯键、二硫键、腙、磷酸三酯、二酯、β-葡糖苷酸、双键、三键、醚键、酮、二醇、氰基、硝基或其组合。
在某些实施方案中,La或Lb一起包含叔丁基氧基羰基、对甲氧基苄基、二烷基或二芳基二烷氧基硅烷、原酸酯、缩醛、β-硫代丙酸酯、缩酮、氨基磷酸酯、腙、乙烯基醚、亚胺、乌头酰基(aconityl)、三苯甲基、聚缩酮、双芳基腙、重氮苯、vivinal二醇、焦磷酸二酯或缬氨酸瓜氨酸。
在某些实施方案中,La在每次出现时独立地是在pH 6-8可裂解的连接基。例如,在某些实施方案中,L是在pH 6.0、6.1、6.2、6.3、6.4、6.5、6.6、6.7、6.8、6.9、7.0、7.1、7.2、7.3、7.4、7.5、7.6、7.7、7.8、7.9或8.0可裂解的连接基。
在某些实施方案中,La在每次出现时独立地是在20℃至40℃、25℃至35℃、30℃至35℃、30℃至37℃、35℃至37℃、35℃至40℃、32℃至38℃的温度可裂解的连接基。在某些实施方案中,L在每次出现时独立地是在约20℃、约21℃、约22℃、约23℃、约24℃、约25℃、约26℃、约27℃、约28℃、约29℃、约30℃、约31℃、约32℃、约33℃、约34℃、约35℃、约36℃、约37℃、约38℃、约39℃或约40℃的温度可裂解的连接基。
在某些实施方案中,La在每次出现时独立地是通过酶可裂解的连接基。例如,在某些实施方案中,所述酶是水解酶、氧化还原酶或裂解酶。在某些实施方案中,所述酶是EC4.1(例如,EC 4.1.1、EC 4.1.2、EC 4.1.3或EC 4.1.99)、EC 4.2、EC 4.3、EC4.4、EC 4.5、EC4.6或EC 4.99酶。
在某些实施方案中,La包含以下结构之一:
其中:
R是H、甲基、乙基、异丙基、叔丁基或苯基;
X是O或CH2;且
n是大于0的整数。
在其它实施方案中,对于Lb的至少一次出现,Lb-M具有以下结构:
其中L1a和L1b各自独立地是任选的连接基。
在不同的实施方案中,对于Lb的至少一次出现,Lb-M具有以下结构:
其中L1a和L1b各自独立地是任选的连接基。
在前述的不同的实施方案中,L1a或L1b或二者对于一次或多次出现而言不存在。在其它实施方案中,L1a或L1b或二者对于一次或多次出现而言存在。
在某些实施方案中,L1a和L1b当存在时各自独立地是亚烷基或亚杂烷基。例如,在某些实施方案中,L1a和L1b当存在时独立地包含以下结构之一:
在某些其它有关的实施方案中,Lb包含以下结构之一:
在某些实施方案中,La和/或Lb的至少一次出现包含以下结构之一:
其中
a、b和c各自独立地是1-6范围内的整数。
在某些实施方案中,La和/或Lb的每次出现具有以下结构之一:
其中:
a、b和c各自独立地是1-6范围内的整数。
在某些实施方案中,La和/或Lb的至少一次出现具有以下结构之一:
在某些更具体的实施方案中,所述化合物具有以下结构(IA):
其中:
x1和x2各自独立地是0-10的整数;且
x3和x4在每次出现时独立地是0-10的整数。
在结构(IA)的化合物的某些实施方案中,x1和x2各自独立地是0-3的整数且x3和x4在每次出现时独立地是0-3的整数。在一些其它的实施方案中,x1是1或0且x2是1或0。在更具体的实施方案中,x1是0且x2是1。在某些实施方案中,x1是1且x2是0。
在更多实施方案中,对于m的至少一次出现,L3是C1-C6亚烷基。在某些实施方案中,对于m的每次出现,L3是C1-C6亚烷基。
在某些更具体的实施方案中,所述化合物具有以下结构(IB):
其中:
x1和x2各自独立地是0-6的整数;
x3和x4在每次出现时独立地是0-6的整数;且
y是2-4的整数。
在结构(IB)的化合物的某些实施方案中,y的至少一次出现是2。在某些实施方案中,y在每次出现时是2。在某些实施方案中,x1、x2、x3或x4的至少一次出现是1且y在每次出现时是2。
在结构(I)的任何化合物的其它实施方案中,R4在每次出现时独立地是OH、O-或ORd。应当理解,“ORd”和“SRd”意图表示与阳离子有关的O-和S-。例如,磷酸酯基团的二钠盐可以表示为:
其中Rd是钠(Na+)。
在结构(I)的任何化合物的其它实施方案中,R5在每次出现时是氧代。
在任何前述化合物的某些不同的实施方案中,R1在每次出现时是H。
在其它各种实施方案中,R2和R3各自独立地是OH或-OP(=Ra)(Rb)Rc。在某些不同的实施方案中,R2或R3是OH或-OP(=Ra)(Rb)Rc,且R2或R3中的另一个是Q或包含与Q的共价键的连接基(例如,亚烷基或亚杂烷基)。
在结构(I)的任何前述化合物的更多不同实施方案中,R2和R3各自独立地是-OP(=Ra)(Rb)Rc。在这些实施方案中的一些中,Rc是OL'。在某些更具体的实施方案中,L'是靶向部分或与靶向部分的连接基。在有关的实施方案中,L'是与靶向部分的连接基,所述连接基包含环氧烷烃或磷酸二酯部分或其组合。
在其它实施方案中,R2和R3各自独立地是-OP(=Ra)(Rb)OL',且L'是与以下物质的亚烷基或亚杂烷基连接基:Q,靶向部分,分析物(例如,分析物分子),固体载体,固体载体残基,核苷或结构(I)的其它化合物。
连接基L'可以是适合用于将Q、靶向部分、分析物(例如,分析物分子)、固体载体、固体载体残基、核苷或结构(I)的其它化合物连接至结构(I)的化合物的任何连接基。有利地,某些实施方案包括选择的L'部分用于增加或优化化合物的水溶性的用途。在某些实施方案中,L'是亚杂烷基部分。在一些其它的某些实施方案中,L'包含环氧烷烃或磷酸二酯部分或其组合。在一些其它的某些实施方案中,L'包含环氧乙烷。在某些实施方案中,L'包含二硫化物。
在某些实施方案中,L'具有以下结构:
其中:
m”和n”独立地是1-10的整数;
Re是H、电子对或抗衡离子;
L”是靶向部分或与靶向部分的连接。
在某些实施方案中,m”是4-10的整数,例如4、6或10。在其它实施方案中,n”是3-6的整数,例如3、4、5或6。
在某些实施方案中,所述靶向部分是抗体、细胞表面受体激动剂、细胞表面受体拮抗剂等。在有关的实施方案中,所述抗体、细胞表面受体激动剂、细胞表面受体拮抗剂等是表皮生长因子受体(EGFR)抑制剂、肝细胞生长因子受体(HGFR)抑制剂、胰岛素-样生长因子受体(IGFR)抑制剂、叶酸(folate)或MET抑制剂。在某些实施方案中,所述抗体、细胞表面受体激动剂、细胞表面受体拮抗剂等是酪氨酸激酶抑制剂(例如,吉非替尼、厄洛替尼)、拉帕替尼、凡他尼布、奈拉替尼、奥希替尼、Tovantinib(ARQ197)、克唑替尼、卡博替尼、酪氨酸磷酸化抑制剂(例如,AG538、AG1024)、吡咯并(2,3-d)-嘧啶衍生物(例如,NVP-AEW541)、单克隆抗体(例如,芬妥木单抗、西妥昔单抗、帕木单抗、奈昔木单抗、加尼妥单抗、西妥木单抗、Dalotuzumab、罗妥木单抗、奥那妥组单抗、K1、拉贝珠单抗、米拉珠单抗、洛沃妥珠单抗、Inotuzumab)、BMS-777607、PF-02341066、PF-04217903、AMG-458、MK-2461、JNJ-38877605、GSK 1363089(foretinib)、XL880、XL 184、ARQ197、E7050或INCB28060。
在某些实施方案中,所述抗体是阿昔单抗、阿达木单抗、阿仑珠单抗、阿利西尤单抗(Alirocumab)、阿维巴坦(Avibactam)、巴利昔单抗、贝那利珠单抗、贝洛托舒单抗(Bezlotoxumab)、兰妥莫单抗(Blinatumomab)、布罗达单抗(Brodalumab)、布洛舒单抗、卡那奴单抗、卡拉西单抗、培化舍珠单抗(Certolizumab pegol)、达克珠单抗、地舒单抗、度匹鲁单抗、依库珠单抗、艾美赛珠单抗、厄瑞努单抗、依洛尤单抗、瑞玛奈珠单抗(Fremanezumab)、伽奈珠单抗(Galcanezumab)、戈利木单抗(Golimumab)、古塞库单抗(Guselkumab)、伊巴珠单抗(Ibalizumab)、艾达赛珠单抗(Idarucizumab)、英夫利昔单抗、Itolizumab、Ixekizumab、拉那利尤单抗(Lanadelumab)、洛吉维单抗(Lokivetmab)、美泊珠单抗(Mepolizumab)、那他珠单抗、奥托萨昔单抗(Obiltoxaximab)、奥瑞珠单抗(Ocrelizumab)、奥马佐单抗、帕利珠单抗、雷珠单抗(Ranibizumab)、瑞希巴库单抗(Raxibacumab)、瑞利珠单抗(Reslizumab)、Rmab、罗维珠单抗(Rovelizumab)、芦利珠单抗(Ruplizumab)、Sarilumab、苏金单抗(Secukinumab)、替曲吉珠单抗(Tildrakizumab)、Thiomab、托珠单抗(Tocilizumab)、乌司奴单抗(Ustekinumab)或维多珠单抗(Vedolizumab)。在某些更具体的实施方案中,所述抗体是阿利鲁单抗(Abrilumab)、阿克托舒单抗(Actoxumab)、阿杜那单抗(Aducanumab)、Afasevikumab、阿非莫单抗(Afelimomab)、阿尼鲁单抗(Anifrolumab)、安芦珠单抗(Anrukinzumab)(IMA-638)、阿塞珠单抗、阿托木单抗(Atorolimumab)、巴匹珠单抗(Bapineuzumab)、BCD-100、柏替木单抗(Bertilimumab)、贝索单抗(Besilesomab)、比西单抗(Biciromab)、比玛卢单抗(Bimagrumab)、比美吉珠单抗(Bimekizumab)、泊特埃单抗(Birtamimab)、布来鲁单抗(Bleselumab)、布索组单抗(Blosozumab)、伯考赛珠单抗(Bococizumab)、Brazikumab、布雷奴单抗(Briakinumab)、布洛赛珠单抗(Brolucizumab)、卡芦单抗(Carlumab)、卡罗妥昔单抗(Carotuximab)、西利珠单抗(Cedelizumab)、克拉扎珠单抗(Clazakizumab)、克立昔单抗(Clenoliximab)、康赛珠单抗(Concizumab)、考韦昔单抗(Cosfroviximab)、CR6261、Crenezumab、立赞利珠单抗(Crizanlizumab)、克罗特度单抗(Crotedumab)、德帕妥昔组单抗(Depatuxizumab)、莫福汀(mafodotin)、地洛妥单抗生物素(Derlotuximab biotin)、迪扎米珠单抗(Dezamizumab)、地利伏单抗、多玛洛珠单抗(Domagrozumab)、度司妥单抗(Dusigitumab)、依美昔单抗(Ecromeximab)、埃巴单抗(Edobacomab)、依法珠单抗(Efalizumab)、依芬古单抗(Efungumab)、埃迪鲁单抗(Eldelumab)、依来努单抗(Elezanumab)、依诺凯组单抗(Enokizumab)、Eptinezumab、厄利珠单抗(Erlizumab)、Etrolizumab、依维苏单抗(Evinacumab)、艾韦单抗(Exbivirumab)、Fanolesomab、法拉莫单抗(Faralimomab)、Faricimab、法司努单抗(Fasinumab)、泛维珠单抗(Felvizumab)、非扎奴单抗(Fezakinumab)、法兰妥单抗(Flanvotumab)、夫来库单抗(Fletikumab)、伏妥珠单抗(Flotetuzumab)、芳妥珠单抗(Fontolizumab)、福拉韦单抗(Foravirumab)、弗洛西单抗(Frovocimab)、福拉奴单抗(Fulranumab)、更汀芦单抗(Gantenerumab)、加维莫单抗(Gavilimomab)、吉伏组单抗(Gevokizumab)、瑾司鲁单抗(Gimsilumab)、戈利昔单抗(Gomiliximab)、Gosuranemab、伊利尤单抗(Ianalumab)、Inclacumab、伊诺莫单抗(Inolimomab)、Iomab-B、凯利昔单抗(Keliximab)、Lampalizumab、兰洛珠单抗(Landogrozumab)、拉韦昔单抗(Larcaviximab)、来金珠单抗(Lebrikizumab)、Lenvervimab、乐德木单抗(Lerdelimumab)、来利珠单抗(Letolizumab)、利韦单抗(Libivirumab)、利格利珠单抗(Ligelizumab)、洛迪赛珠单抗(Lodelcizumab)、培戈-鲁利珠单抗(Lulizumab pegol)、马塔西单抗(Marstacimab)、玛弗利木单抗(Mavrilimumab)、美替木单抗(Metelimumab)、米吉珠单抗(Mirikizumab)、莫维珠单抗(Motavizumab)、莫罗单抗CD3(Muromonab CD3)、奈巴库单抗(Nebacumab)、奈莫利珠单抗(Nemolizumab)、NEOD001、尼塞韦单抗(Nirsevimab)、奥度莫单抗(Odulimomab)、奥仑达利珠单抗(Olendalizumab)、奥洛组单抗(Olokizumab)、OMS721、奥匹努单抗(Opicinumab)、奥替苏单抗(Orticumab)、奥昔珠单抗(Otelixizumab)、Otilimab、奥塞芦单抗(Oxelumab)、奥扎奈珠单抗(Ozanezumab)、奥利组单抗(Ozoralizumab)、帕昔单抗(Pagibaximab)、帕诺库单抗(Panobacumab)、帕考珠单抗(Pascolizumab)、帕利珠单抗(Pateclizumab)、PDR001、珀雷吉珠单抗(Perakizumab)、培克珠单抗(Pexelizumab)、普拉鲁单抗(Placulumab)、洛扎利珠单抗(Plozalizumab)、泊奈组单抗(Ponezumab)、Porgaviximab、Prasinezumab、普立昔单抗(Priliximab)、PRO 140、奎利珠单抗(Quilizumab)、雷韦单抗(Rafivirumab)、雷泮赛珠单抗(Ralpancizumab)、Ranevetmab、Ravagalimab、雷夫利珠单抗(Ravulizumab)、瑞法奈珠单抗(Refanezumab)、瑞加韦单抗(Regavirumab)、瑞拉利单抗(Relatlimab)、利努苏单抗(Rinucumab)、Risankizumab、罗来度单抗(Roledumab)、洛莫索珠单抗(Romosozumab)、罗利珠单抗(Rontalizumab)、SA237、萨特利珠单抗(Satralizumab)、司韦单抗(Sevirumab)、SHP647、西法木单抗(Sifalimumab)、辛妥珠单抗(Simtuzumab)、西利珠单抗(Siplizumab)、Sirukumab、苏兰珠单抗(Solanezumab)、Sonepcizumab、Spartalizumab、司他芦单抗(Stamulumab)、硫索单抗(Sulesomab)、舒他伏单抗(Suptavumab)、舒利单抗(Sutimlimab)、舒维组单抗(Suvizumab)、苏托舒单抗(Suvratoxumab)、他度珠单抗(Tadocizumab)、他利珠单抗(Talizumab)、坦妥维单抗(Tamtuvetmab)、他尼珠单抗(Tanezumab)、替非珠单抗(Tefibazumab)、阿替莫单抗(Telimomab aritox)、替奈昔单抗(Teneliximab)、替利珠单抗(Teplizumab)、替妥木单抗(Teprotumumab)、特折鲁单抗(Tezepelumab)、替布利珠单抗(Tibulizumab)、托利珠单抗(Toralizumab)、曲罗芦单抗(Tralokinumab)、曲戈卢单抗(Trevogrumab)、妥韦单抗(Tuvirumab)、乌洛鲁单抗(Ulocuplumab)、乌珠单抗(Urtoxazumab)、伐利苏单抗(Varisacumab)、维帕莫单抗(Vepalimomab)、维森库单抗(Vesencumab)、维西珠单抗(Visilizumab)、沃巴利珠单抗(Vobarilizumab)或阿佐莫单抗(Zolimomab aritox)。在某些更具体的实施方案中,所述单克隆抗体是曲妥珠单抗、吉妥珠单抗(gemtuzumab)、brentuximab、沃瑟妥珠单抗(vorsetuzumab)、洛沃妥珠单抗(lorvotuzumab)、cantuzumab、bivatuzumabor inotuzumab或伐达妥昔单抗(vadastuximab)。
在某些实施方案中,所述抗体、细胞表面受体激动剂、细胞表面受体拮抗剂等靶向EGFR(例如,EGFRvIII)、HER 2、叶酸受体、CD19、CD20、CD22、CD27L、CD30、CD33、CD37、CD56、CD66e、CD70、CD74、CD79b、CA6、CD138、CA 6、间皮素、连接素4、STEAP1、MUC16、MaPi2b、GCC、Trop-2、AGS-5、ENPP3、碳酸酐酶IX、GPNMB、PDMA。
在某些其它实施方案中,所述抗体、细胞表面受体激动剂、细胞表面受体拮抗剂等靶向1-40-β-淀粉样蛋白;活化的F9,F10;ACVR2B;淀粉样蛋白;Ang-2;血管生成素3;炭疽毒素,保护性抗原;AOC3(VAP-1);炭疽芽孢杆菌炭疽;BAFF;β-淀粉样蛋白;C1s;C5;降钙素;降钙素基因相关肽α;家犬(Canis lupus familiaris)IL31;CCL11(嗜酸性粒细胞趋化因子-1);CCR2;CCR5;CD11;CD18;CD125;CD147(basigin);CD15;CD154(CD40L);CD19;CD2;CD20;CD23(IgE受体);CD25(IL-2受体的α链);CD28;CD3;CD4;CD40;CD41(整联蛋白α-IIb);CD45;CD5;CD52;CD6;CEA相关抗原;CFD;CGRP;难辨梭状芽胞杆菌;凝集因子A;补体C5a;CSF2;CXCR4(CD184);巨细胞病毒;达比加群(dabigatran);埃博拉病毒糖蛋白;EGFR;内皮联蛋白;内毒素;大肠杆菌;呼吸道合胞病毒的F蛋白;FGF 23;纤维蛋白II,β链;GCGR;GD3神经节苷脂;GDF-8;GMCSF;生长分化因子8;血凝素;乙型肝炎表面抗原;组蛋白复合物;HIV-1;HNGF;Hsp90;人β-淀粉样蛋白;人TNF;IgE;IGF-1受体(CD221);IGHE;甲型流感血凝素;整联蛋白受体和亚基;干扰素受体;白介素受体(各种);ITGB2(CD18);激肽释放酶;LAG3;LFA-1(CD11a);LINGO-1;脂磷壁酸;LOXL2;L-选择蛋白(CD62L);LTA;MASP-2;MCP-1;粘膜地址素细胞粘附分子;髓磷脂-相关的糖蛋白;肌生成抑制蛋白;NACP;NCA-90(粒细胞抗原);调节神经细胞凋亡的蛋白酶1;NGF;NOGO-A;NRP1;OX-40;oxLDL;PCSK9;PD-1;PDCD1,CD279;血小板-衍生的生长因子受体β;铜绿假单胞菌;狂犬病毒糖蛋白;RANKL;呼吸道合胞病毒;RGMA;RHD;猕猴因子;RSVFR;硬骨素(sclerostin);选择蛋白P;SOST;鞘氨醇-1-磷酸;金黄色葡萄球菌α毒素;tau蛋白;TFPI;TGFβ1;TGFβ2;TNF-α;TRAP;TSLP;TYRP1(糖蛋白75);VEGF-A;VWF;扎伊尔埃博拉病毒糖蛋白。
在某些具体实施方案中,所述靶向部分是抗体或抗体片段。在某些更具体的实施方案中,所述抗体或抗体片段是单克隆抗体(mAb)、抗原结合片段(Fab/Fab')、单结构域抗体(sdAb)、双特异性抗体(BsAb)、双特异性的t-细胞衔接物(engager)(BiTE)、单链可变片段(ScFv)、双亲和性重新靶向抗体(DART)、重链可变结构域(VH)、微抗体(minibody)、双抗体或AbdurinsTM(衍生自IgG)。
在一些其它的实施方案中,所述靶向部分是蛋白。例如,在某些实施方案中,所述靶向部分是白蛋白、干扰素、centyrin或趋化性受体配体。
在一些其它的实施方案中,L”是亚烷基或亚杂烷基部分。在一些其它的某些实施方案中,L”包含环氧烷烃、磷酸二酯部分、巯基、二硫化物或马来酰亚胺部分或其组合。
在结构(I)的任何前述化合物的其它更具体的实施方案中,R2或R3具有以下结构之一:
根据类似于本领域已知的用于制备寡核苷酸的那些的固相合成方法,可以制备结构(I)的化合物的某些实施方案。因此,在某些实施方案中,L'是与固体载体、固体载体残基或核苷的连接。包含活化的脱氧胸苷(dT)基团的固体载体(例如,多聚体和非多聚体)是容易得到的,且在某些实施方案中,可以用作用于制备结构(I)的化合物的起始原料。因此,在某些实施方案中,R2或R3具有以下结构:
本领域技术人员会理解,包括上述dT基团仅仅是为了易于合成和经济效率,而不是必需的。可以使用其它固体载体并且会导致在L'上存在不同的核苷或固体载体残基,或者可以在合成后除去或修饰核苷或固体载体残基。
在某些实施方案中,R2或R3包含以下结构之一:
在某些实施方案中,R2或R3包含以下结构之一:
在某些实施方案中,R3包含以下结构之一:
在某些实施方案中,R3包含以下结构之一:
m和n的值是可以基于期望的溶解度、渗透作用或治疗应用进行选择的变量。在其它实施方案中,n在每次出现时独立地是1-5的整数,例如1、2、3、4或5。通过选择n的不同值,也可以调节溶解度、渗透或保留。在某些实施方案中,n是1-100的整数。在其它实施方案中,n是1-10的整数。在某些实施方案中,n是1。在某些实施方案中,n是2。在某些实施方案中,n是3。在某些实施方案中,n是4。在某些实施方案中,n是5。在某些实施方案中,n是6。在某些实施方案中,n是7。在某些实施方案中,n是8。在某些实施方案中,n是9。在某些实施方案中,n是10。在某些实施方案中,n是1-10的整数。
在某些实施方案中,m是1-10的整数。在更具体的实施方案中,m的至少一次出现是1-5的整数。在某些实施方案中,m的每次出现是1-15的整数。在某些实施方案中,m的每次出现是1-10的整数。在更多实施方案中,m的每次出现是1-5的整数。
在其它实施方案中,Q在每次出现时独立地是包含反应基团的部分,其能够与分析物分子或固体载体形成共价键。在其它实施方案中,Q在每次出现时独立地是包含反应基团的部分,其能够与互补反应基团Q′形成共价键。例如,在某些实施方案中,Q′存在于结构(I)的另一种化合物上(例如,在R2或R3位置),且Q和Q′包含互补反应基团,使得结构(I)的化合物和结构(I)的其它化合物的反应产生共价地结合的结构(I)的化合物的二聚体。还可以以类似的方式制备结构(I)的多聚体化合物,并且所述多聚体化合物被包括在本公开内容的实施方案的范围内。
Q基团的类型和Q基团与结构(I)的化合物的其余部分的连接性不受限制,前提条件是,Q包含具有用于形成期望的键的适当反应性的部分。
在某些实施方案中,Q是在水性条件下不易水解但具有足够反应性以与分析物分子或固体载体上的相应基团(例如,胺、叠氮化物或炔烃)形成键的部分。
结构(I)的化合物的某些实施方案包含在生物缀合领域中常用的Q基团。例如,在某些实施方案中,Q包含亲核的反应基团,亲电的反应基团或环加成反应基团。在某些更具体的实施方案中,Q包含巯基、二硫化物、活化酯、异硫氰酸酯、叠氮化物、炔烃、烯烃、二烯、亲二烯体、酰卤、磺酰卤、膦、α-卤代酰胺、生物素、氨基或马来酰亚胺官能团。在某些实施方案中,所述活化酯是N-琥珀酰亚胺酯、亚氨酸酯或多氟苯基酯。在其它实施方案中,所述炔烃是烷基叠氮化物或酰叠氮。
Q基团可以方便地以受保护的形式提供以增加储存稳定性或其它期望的性能,然后在适当的时间除去保护基以与例如靶向部分或分析物偶联。因此,Q基团包括反应基团的“保护形式”,包括在上面和下表1中描述的任何反应基团。Q的“保护形式”表示这样的部分:其在预定反应条件下相对于Q具有较低反应性,但其在优选不降解结构(I)的化合物的其它部分或不与它们反应的条件下可转化为Q。根据特定的Q和期望的最终用途和储存条件,本领域技术人员可以推导出Q的适当保护形式。例如,当Q是SH时,Q的保护形式包括二硫化物,使用公知的技术和试剂可以将其还原以显示SH部分。
在下表I中提供了示例性Q部分。
表1.示例性Q部分
应当指出,在某些实施方案中,其中Q是SH,所述SH部分将倾向于与另一个巯基(例如在结构(I)的另一种化合物上)形成二硫键。因此,一些实施方案包括结构(I)的化合物,其为二硫化物二聚体形式,二硫键衍生自SH Q基团。
在某些实施方案的范围内还包括结构(I)的化合物,其中R2和R3中的一个或两个包含与结构(I)的另一种化合物的连接。例如,其中R2和R3中的一个或两个是-OP(=Ra)(Rb)Rc,且Rc是OL',且L'是包含与结构(I)的另一种化合物的共价键的连接基。这样的化合物可以如下制备:制备结构(I)的第一化合物,其具有例如约10个“M”部分(即,n=9)并具有用于与结构(I)的第二化合物上的互补Q'基团反应的合适“Q”。以此方式,可以制备具有任意数量的“M”部分(例如100个或更多)的结构(I)的化合物,而无需依次偶联每个单体。这样的结构(I)的化合物的示例性实施方案具有以下结构(I')
其中:
R1、R2、R3、R4、R5、La、Lb、L1、L2、L3、M、m和n的每次出现独立地如关于结构(I)的化合物所定义;
L”是包含由Q部分(例如,如表1中)与相应Q'部分反应产生的官能团的连接基;且
α是大于1的整数,例如1-100,或1-10。
结构(I')的其它化合物可由本领域普通技术人员推导,例如通过二聚化或聚合本文提供的结构(I)的化合物。
在其它实施方案中,Q部分被方便地掩蔽(例如,保护)为二硫化物部分,其随后可被还原以提供用于结合期望的靶向部分的活化Q部分。例如,Q部分可以被掩蔽为具有以下结构的二硫化物:
其中R是任选地被取代的烷基。例如,在某些实施方案中,Q被提供为具有以下结构的二硫化物部分:
其中n'是1-10的整数,例如6。
在一些其它的实施方案中,R2或R3之一是OH或-OP(=Ra)(Rb)Rc,且R2或R3中的另一个是包含与靶向部分的共价键的连接基或包含与固体载体的共价键的连接基。例如,在某些实施方案中,所述靶向部分是抗体、细胞表面受体激动剂、细胞表面受体拮抗剂等。在更不同的实施方案中,所述固体载体是多聚体珠或非多聚体珠。靶向部分可以针对任何数目的战略靶标(strategic target)。例如,生物靶标可以是细胞表面受体诸如肿瘤细胞抗原。肿瘤细胞抗原包括肿瘤特异性抗原和肿瘤相关抗原,例如EGFR、HER 2、叶酸受体、CD20、CD33、肿瘤胚胎抗原(oncofetal antigen)(例如,甲胎蛋白、癌胚抗原(carcinoembryonicantigen)、未成熟的层粘连蛋白受体、TAG-72)、CA-125、MUC-1、上皮肿瘤抗原、酪氨酸酶、黑素瘤-相关的抗原(MAGE)以及RAS或p53的异常产物。肿瘤细胞抗原还可以包括被表征为肿瘤胚胎、肿瘤病毒(例如,HPV E6、E7)、过表达/积累(例如,BING-4、钙活化的氯通道2、9D7、Ep-CAM、EphA3、HER2、端粒酶、间皮素、SAP-1、存活蛋白)、癌症-tetis(例如,BAGE家族、CAGE家族、GAGE家族、MAGE家族、SAGE家族、XAGE家族)、谱系限制性的、突变的、翻译后改变的、个体基因型的、CT9或CT10(例如,NY-ESO-1/LAGE-1、PRAME)的抗原。
在某些实施方案中,M在每次出现时独立地是NSAID、激酶抑制剂、蒽环类抗生素和EGFR抑制剂或烷化剂。在某些实施方案中,所述生物活性部分是抗癌药物。在某些具体实施方案中,M在每次出现时独立地是抗癌药物,且靶向部分是对肿瘤细胞抗原特异性的抗体。
本文中使用的抗癌药物包括衍生物。也就是说,抗癌药物已被修饰或衍生化,使得该药物可缀合或连接至另一分子(例如,以包括Q部分)。例如,美坦生是抗癌药物,而美坦生类化合物(maytansinoid)是抗癌药物衍生物。
在某些实施方案中,所述抗癌药物是表皮生长因子受体(EGFR)抑制剂、磷脂酰肌醇激酶(PI3K)抑制剂、胰岛素-样生长因子受体(IGF1R)抑制剂、Janus激酶(JAK)抑制剂、Met激酶抑制剂、SRC家族激酶抑制剂、促分裂原活化蛋白激酶(MEK)抑制剂、调节细胞外信号的激酶(ERK)抑制剂、拓扑异构酶抑制剂(诸如伊立替康或诸如依托泊苷或诸如多柔比星)、紫杉烷(诸如抗微管剂,包括紫杉醇和多西他赛)、抗代谢剂(诸如5-FU或诸如吉西他滨)、烷化剂(诸如顺铂或诸如环磷酰胺)或紫杉烷。
可以被修饰并掺入本公开内容的化合物的实施方案中的抗癌药物包括,例如,澳瑞他汀F(auristatin F);澳瑞他汀E;美坦生;卡奇霉素(calicheamicin);紫杉醇;多柔比星;念珠藻素;厄洛替尼;CC-1065;卡折来新;SJG-136;DSB-120;阿法替尼(afatinib);易瑞沙(Iressa);甲氨蝶呤;DNA甲基化剂(例如,丙卡巴肼、替莫唑胺、达卡巴嗪、N-甲基-N-硝基脲、N-甲基-N'-硝基-N-硝基鸟嘌呤等)。
抗癌药物的其它非限制性例子包括(甲磺酸伊马替尼)、 (硼替佐米)、康士得(比卡鲁胺)、(吉非替尼)和阿霉素、烷化剂诸如塞替派和环磷酰胺磺酸烷基酯诸如白消安、英丙舒凡和哌泊舒凡;氮丙啶类诸如苯佐替派、卡波醌、美妥替派和乌瑞替派;乙烯亚胺类和甲基三聚氰胺类,包括六甲蜜胺、曲他胺、三亚乙基磷酰胺、三亚乙基硫代磷酰胺和三羟甲基密胺;氮芥诸如苯丁酸氮芥、萘氮芥、氯磷酰胺、雌莫司汀、异环磷酰胺、氮芥、盐酸氧化氮芥、美法仑、新氮芥、苯芥胆甾醇、泼尼莫司汀、曲磷胺、尿嘧啶氮芥;亚硝基脲类诸如卡莫司汀、氯脲菌素、福莫司汀、洛莫司汀、尼莫司汀、雷莫司汀;抗生素诸如阿克拉霉素、放线菌素、安曲霉素(authramycin)、偶氮丝氨酸、博来霉素、放线菌素C、卡奇霉素、carabicin、洋红霉素、嗜癌霉素、色霉素、更生霉素、柔红霉素、地托比星、6-重氮基-5-氧代-L-正亮氨酸、多柔比星、表柔比星、依索比星、伊达比星、麻西罗霉素、丝裂霉素、麦考酚酸、诺拉霉素、橄榄霉素、培洛霉素、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素、罗多比星、链黑霉素、链佐星、杀结核菌素、乌苯美司、净司他丁、佐柔比星;抗代谢药诸如甲氨蝶呤和5-氟尿嘧啶(5-FU);叶酸类似物诸如二甲叶酸、甲氨蝶呤、蝶罗呤、三甲曲沙;嘌呤类似物诸如氟达拉滨、6-巯嘌呤、硫咪嘌呤、硫鸟嘌呤;嘧啶类似物诸如安西他滨、阿扎胞苷、6-氮杂尿苷、卡莫氟、阿糖胞苷、二脱氧尿苷、去氧氟尿苷、依诺他滨、氟尿苷、雄激素类诸如卡普睾酮、屈他雄酮丙酸盐、环硫雄醇、美雄烷、睾内酯;抗肾上腺类诸如氨鲁米特,米托坦,曲洛司坦;叶酸补充剂诸如亚叶酸(frolinicacid);醋葡醛内酯;丙醛氧基磷酰胺糖苷;氨基酮戊酸;安吖啶;bestrabucil;比生群;依达曲沙(edatraxate);地磷酰胺(defofamine);秋水仙胺;地吖醌;elfomithine;依利醋铵;依托格鲁;硝酸镓;羟基脲;香菇多糖;氯尼达明;米托胍腙;米托蒽醌;莫哌达醇;尼曲吖啶;喷司他丁;蛋氨氮芥;吡柔比星;鬼臼酸;2-乙基酰肼;丙卡巴肼;PSK.RTM.;雷佐生;西佐喃;锗螺胺;替奴佐酸;三亚胺醌;2,2',2”-三氯三乙胺;尿烷(urethan);长春地辛;达卡巴嗪;甘露莫司汀;二溴甘露醇;二溴卫矛醇;哌泊溴烷;gacytosine;阿糖胞苷(“Ara-C”);环磷酰胺;塞替派;紫杉烷,例如紫杉醇(泰素TM,Bristol-Myers Squibb Oncology,Princeton,N.J.)和多西他赛(泰索帝TM,Rhone-Poulenc Rorer,Antony,法国);视黄酸;埃斯波霉素或卡培他滨。还包括作为合适抗癌药物的是用于调节或抑制对肿瘤的激素作用的抗激素剂,诸如抗雌激素类,包括例如他莫昔芬、(诺瓦得士TM)、雷洛昔芬、抑制芳香酶的4(5)-咪唑、4-羟基他莫昔芬、曲沃昔芬、雷洛昔芬、LY 117018、奥那司酮和托瑞米芬(法乐通);和抗雄激素类诸如氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林;苯丁酸氮芥;吉西他滨;6-硫鸟嘌呤;巯嘌呤;甲氨蝶呤;铂类似物诸如顺铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;丝裂霉素C;米托蒽醌;长春新碱;长春瑞滨;诺维本;诺肖林;替尼泊苷;道诺霉素;氨基蝶呤;希罗达;伊班膦酸盐;喜树碱-11(CPT-11);拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(DMFO)、倍癌霉素A和培美曲塞(力比泰)。
在需要时,本公开内容的化合物或组合物的实施方案可以与常用处方抗癌药物组合使用,所述处方抗癌药物是诸如 ABVD、AVICINE、阿巴伏单抗、吖啶羧酰胺、阿德木单抗、17-N-烯丙基氨基-17-脱甲氧基格尔德霉素、Alpharadin、阿伏西地、3-氨基吡啶-2-甲醛缩氨基硫脲、氨萘非特、蒽二酮、抗-CD22免疫毒素、抗赘生物剂、抗致瘤草药、阿帕齐醌、阿替莫德、硫唑嘌呤、贝洛替康、苯达莫司汀、BIBW2992、比立考达、溴他利星、苔藓抑素、丁硫氨酸亚砜亚胺、CBV(化学疗法)、花萼海绵诱癌素、细胞周期非特异性的抗赘生物剂(antineoplastic agent)、二氯乙酸、圆皮海绵内酯、依沙芦星、依诺他滨、埃博霉素、艾立布林、依维莫司、依沙替康、依昔舒林、弥罗松酚、呋咯地辛、磷雌酚、ICE化学疗法方案、IT-101、伊美克、咪喹莫特、吲哚并咔唑、伊罗夫文、拉尼喹达、拉罗他赛、来那度胺、硫蒽酮、勒托替康、马磷酰胺、米托唑胺、萘福昔定、奈达铂、奥拉帕尼、奥他赛、PAC-1、万寿果、匹克生琼、蛋白酶体抑制剂、蝴蝶霉素、瑞喹莫德、卢比替康、SN-38、Salinosporamide A、沙帕他滨、Stanford V、苦马豆素、他拉泊芬、他立喹达、替加氟-尿嘧啶、Temodar、替司他赛、四硝酸三铂、三(2-氯乙基)胺、曲沙他滨、尿嘧啶氮芥、Vadimezan、长春氟宁、ZD6126或佐舒喹达。
M是基于期望的治疗和/或光学特性来选择,例如基于治疗特定疾病或病症(例如,癌症)或产生特定颜色和/或荧光发射波长。在某些实施方案中,M在每次出现时是相同的;但是,重要的是,注意到,每次出现的M不必是相同的M,且某些实施方案包括其中M在每次出现时都不相同的化合物。例如,在某些实施方案中,每个M不是相同的并选择不同的M部分以具有不同的治疗性能(例如,细胞毒性和抗炎)。在某些实施方案中,每个M不是相同的并选择不同的M部分以具有相同或相似的治疗性能(例如,细胞毒性)。
因此,在某些实施方案中,M的至少一次出现是抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂、激酶抑制剂、蒽环类抗生素和EGFR抑制剂或烷化剂。在某些实施方案中,M的至少一次出现是抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂或烷化剂。在某些具体实施方案中,M在每次出现时独立地是抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂、激酶抑制剂、蒽环类抗生素和EGFR抑制剂或烷化剂。在某些具体实施方案中,M在每次出现时独立地是抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂或烷化剂。
在某些实施方案中,M的至少一次出现选自:澳瑞他汀F、单甲基澳瑞他汀F、单甲基澳瑞他汀E、paciltaxol、SN-38、卡奇霉素、安曲霉素、abbeymycin、chicamycin、DC-81、mazethramycin、新茴霉素A、新茴霉素B、porothramycin prothracarcin、西班米星、西伯里亚霉素、托马霉素、DM1细胞毒(mertansine)、emtansine、伊立替康、喜树碱、托泊替康、silatecan、科西特康(cositecan)、依沙替康、勒托替康、吉马替康、贝洛替康和卢比替康。在某些实施方案中,M的至少一次出现具有以下结构之一:
在某些实施方案中,M的每次出现具有以下结构之一:
在某些实施方案中,每个M独立地选自以下的:
在某些实施方案中,M的至少一次出现是抗赘生物剂(例如,澳瑞他汀F、单甲基澳瑞他汀F、单甲基澳瑞他汀E、paciltaxol、SN-38)、烯二炔抗肿瘤抗生素(例如,卡奇霉素或更具体地卡奇霉素γ1)、烷化剂(例如,PBD或吡咯并(pyrollo)苯并二氮杂环庚三烯类)、美坦生类化合物类(例如,DM1细胞毒、emtansine)拓扑异构酶抑制剂(例如,SN38、伊立替康、喜树碱、托泊替康、silatecan、科西特康、依沙替康、勒托替康、吉马替康、贝洛替康、卢比替康)。
在某些实施方案中,M的每次出现是抗赘生物剂(例如,澳瑞他汀F、单甲基澳瑞他汀F、单甲基澳瑞他汀E、paciltaxol、SN-38)、烯二炔抗肿瘤抗生素(例如,卡奇霉素或更具体地卡奇霉素γ1)、烷化剂(例如,PBD或吡咯并苯并二氮杂环庚三烯类)、美坦生类化合物类(例如,DM1细胞毒、emtansine)拓扑异构酶抑制剂(例如,SN38、伊立替康、喜树碱、托泊替康、silatecan、科西特康、依沙替康、勒托替康、吉马替康、贝洛替康、卢比替康)。
在某些实施方案中,La-M具有以下结构:
在某些实施方案中,Lb-M具有以下结构之一:
在前述任一项的更多实施方案中,M是相同的。在其它实施方案中,每个M是不同的。在更多实施方案中,一个或多个M相同且一个或多个M不同。
在某些实施方案中,M的所选出现不相同并且选择不同的M部分以具有用于荧光共振能量转移(FRET)方法的吸收和/或发射。例如,在这样的实施方案中,选择不同的M部分使得在一个波长的辐射的吸收通过FRET机制引起在不同波长的辐射的发射。本领域普通技术人员可以基于期望的最终用途适当地选择示例性的M部分。用于FRET方法的示例性M部分包括荧光素和5-TAMRA(5-羧基四甲基罗丹明、琥珀酰亚胺基酯)染料。
M可以从M上的任何位置(即,原子)被连接到分子的其余部分。本领域技术人员将认识到将M连接到分子的其余部分的方法。示例性方法包括本文所述的“点击”反应。
在某些实施方案中,M是荧光的或有色的部分。可以使用任何荧光的和/或有色的部分,例如可以使用本领域已知的并且通常用于比色、UV和/或荧光测定的那些。可用于本公开内容的不同实施方案的M部分的例子包括、但不限于:呫吨衍生物(例如,荧光素、罗丹明、Oregon绿、曙红或德克萨斯红);花青衍生物(例如,花青、吲哚羰花青、氧杂羰花青、硫杂羰花青或部花青);方酸菁(Squaraine)衍生物和环取代的方酸菁,包括Seta、SeTau和Square染料;萘衍生物(例如,丹磺酰基和prodan衍生物);香豆素衍生物;噁二唑衍生物(例如,吡啶基噁唑、硝基苯并噁二唑或苯并噁二唑);蒽衍生物(例如,蒽醌,包括DRAQ5、DRAQ7和CyTRAK Orange);芘衍生物诸如级联蓝(cascade blue);噁嗪衍生物(例如,尼罗红、尼罗蓝、甲酚紫、噁嗪170);吖啶衍生物(例如,二氨基吖啶、吖啶橙、吖啶黄);芳基次甲基衍生物:金胺、结晶紫、孔雀石绿;和四吡咯衍生物(例如,卟吩、酞菁或胆红素)。其它示例性的M部分包括:花青染料、黄原酸酯/盐(xanthate)染料(例如,Hex、Vic、Nedd、Joe或Tet);Yakima黄;Redmond红;tamra;德克萨斯红和alexa 染料。
在前述任一种的其它实施方案中,M包含3个或更多个芳基或杂芳基环或其组合,例如4个或更多个芳基或杂芳基环或其组合、或甚至5个或更多个芳基或杂芳基环或其组合。在某些实施方案中,M包含6个芳基或杂芳基环或其组合。在其它实施方案中,所述环是稠合的。例如在某些实施方案中,M包含3个或更多个稠合环、4个或更多个稠合环、5个或更多个稠合环、或甚至6个或更多个稠合环。
在某些实施方案中,M是环状的。例如,在某些实施方案中,M是碳环的。在其它实施方案中,M是杂环的。在前述的其它实施方案中,M在每次出现时独立地包含芳基部分。在这些实施方案中的一些中,所述芳基部分是多环的。在其它更具体实例中,所述芳基部分是稠合的多环的芳基部分,例如其可以包含至少3个、至少4个或甚至超过4个芳基环。
在任何前述化合物的其它实施方案中,M包含至少一个杂原子。例如,在某些实施方案中,所述杂原子是氮、氧或硫。
在前述任一种的更多实施方案中,M包含至少一个取代基。例如,在某些实施方案中,所述取代基是氟、氯、溴、碘、氨基、烷基氨基、芳基氨基、羟基、巯基、烷氧基、芳氧基、苯基、芳基、甲基、乙基、丙基、丁基、异丙基、叔丁基、羧基、磺酸酯、酰胺或甲酰基。
在前述的某些甚至更具体的实施方案中,M是二甲基氨基均二苯乙烯、喹吖啶酮、氟苯基-二甲基-BODIPY、his-氟苯基-BODIPY、吖啶、三萘嵌二苯(terrylene)、六联苯、卟啉、苯并芘、(氟苯基-二甲基-二氟硼杂-二氮杂-引达省)苯基、(双-氟苯基-二氟硼杂-二氮杂-引达省)苯基、四联苯、双-苯并噻唑、三-苯并噻唑、双-萘基、双-蒽基、方酸菁、squarylium、9,10-乙炔基蒽或三萘基部分。在其它实施方案中,M是对三联苯、苝、偶氮苯、吩嗪、菲咯啉、吖啶、thioxanthrene、红荧烯、蒄、花青、苝酰亚胺或苝酰胺或其衍生物。在更多的实施方案中,M是香豆素染料、试卤灵染料、二吡咯亚甲基二氟化硼染料、钌联吡啶染料、能量转移染料、噻唑橙染料、聚甲炔或N-芳基-1,8-萘二甲酰亚胺染料。
在某些实施方案中,M是芘、苝、苝单酰亚胺或6-FAM或其衍生物。在一些其它的实施方案中,M具有以下结构之一:
尽管以上以阴离子形式(CO2 -)描述了包含羧酸基团的M部分,但本领域技术人员会理解,这将根据pH而变化,并且在不同的实施方案中包括质子化形式(CO2H)。
在某些具体实施方案中,所述化合物是选自表2的化合物。根据实施例中所述的规程制备表2中的化合物,并可以通过质谱法确认它们的身份。
表2.结构I的示例性化合物
除非另外指出,否则如表2和在整个申请中所用,M具有为结构(I)的化合物提供的定义。在某些实施方案中,M是F、F'、F”、N'、I'、D'、D”或AF。F、F′和F″分别表示具有以下结构的荧光素部分:
“N'”表示以下结构:
“I'”表示以下结构:
“D'”表示以下结构:
“D””表示以下结构:
“dT”表示以下结构:
其中:
R是H或直连键。
“AF”表示以下结构:
因此,在某些实施方案中,M的至少一次出现具有以下结构之一:
在某些更具体的实施方案中,M的每次出现具有以下结构:
在某些实施方案中,治疗包括减轻或缓解疼痛或炎症。在某些实施方案中,治疗包括疼痛控制或疼痛管理。在某些具体实施方案中,M的至少一次出现具有以下结构之一:
在某些更具体的实施方案中,M的每次出现具有以下结构之一:
一些实施方案包括缀合至靶向部分(诸如抗体)的任何前述化合物,包括在表2中提供的具体化合物。在某些实施方案中,一种结构(I)的化合物缀合至抗体。在某些实施方案中,1-2种结构(I)的化合物缀合至抗体。在某些实施方案中,2种结构(I)的化合物缀合至抗体。在某些实施方案中,3种结构(I)的化合物缀合至抗体。在某些实施方案中,4种结构(I)的化合物缀合至抗体。在某些实施方案中,5种结构(I)的化合物缀合至抗体。在某些实施方案中,不超过5种结构(I)的化合物缀合至抗体。
在不同的实施方案中,反应性聚合物可以用于制备结构(I)的化合物。在某些实施方案中,这些反应性聚合物是合成中间体,其包含可用于与互补部分反应以在M和反应性聚合物之间形成共价键的部分,所述反应经由任意数目的合成方法(例如上述“点击”反应),从而形成结构(I)的化合物。因此,在不同的实施方案中,使用具有以下结构(II)的反应性聚合物或其立体异构体、盐或互变异构体形成结构(I)的化合物:
其中:
G在每次出现时独立地是包含反应基团的部分,或其受保护的类似物,其能够与互补反应基团形成共价键;
La在每次出现时独立地是任选的生理学上可裂解的连接基且Lb在每次出现时独立地是任选的生理学上不可裂解的连接基,前提条件是,La和Lb一起的至少一次出现包含超过4个碳;
L1和L2在每次出现时独立地是任选的亚烷基、亚烯基、亚炔基、亚杂烷基、亚杂烯基、亚杂炔基或杂原子连接基;
L3在每次出现时独立地是亚烷基、亚烯基、亚炔基、亚杂烷基、亚杂烯基或亚杂炔基连接基;
R1在每次出现时独立地是H、烷基或烷氧基;
R2和R3各自独立地是H、OH、SH、烷基、烷氧基、烷基醚、杂烷基、-OP(=Ra)(Rb)Rc、Q或其保护形式或L';
R4在每次出现时独立地是O-、S-、OZ、SZ或N(R6)2,其中Z是阳离子且每个R6独立地是H或烷基;
R5在每次出现时独立地是氧代、硫代或不存在;
Ra是O或S;
Rb是OH、SH、O-、S-、ORd或SRd;
Rc是OH、SH、O-、S-、ORd、OL'、SRd、烷基、烷氧基、杂烷基、杂烷氧基、烷基醚、烷氧基烷基醚、磷酸酯、硫代磷酸酯、磷酰烷基、硫代磷酰烷基、磷酰烷基醚或硫代磷酰烷基醚;
Rd是抗衡离子;
Q在每次出现时独立地是包含反应基团的部分或其保护形式,其能够与靶向部分上的互补反应基团Q′形成共价键;
L'在每次出现时独立地是包含与Q的共价键的连接基、靶向部分、包含与靶向部分的共价键的连接基、包含与固体载体的共价键的连接基、包含与固体载体残基的共价键的连接基、包含与核苷的共价键的连接基或包含与结构(I)的另一种化合物的共价键的连接基;
m在每次出现时独立地是0或更大的整数;且
n是1或更大的整数。
在某些实施方案中,G的一次出现包含荧光染料部分。
在某些实施方案中,所述反应性聚合物选自下面表3。
表3.结构(II)的示例性反应聚合物
某些实施方案涉及治疗上有效的荧光化合物,条件是,M的至少一次出现不是荧光染料且M的至少一次出现是荧光染料。治疗上有效的荧光化合物包括包含至少一种生物活性部分或其片段或生物活性部分的前药或其片段的化合物,其在用光诸如紫外光激发后发出荧光信号。
本文公开的化合物的实施方案的“可调性的”,意味着通过任何前述化合物中变量的适当选择,本领域技术人员可以获得具有期望的和/或预定的摩尔荧光(摩尔亮度)的化合物。化合物的某些实施方案的“可调性”允许用户容易地获得具有用于特定测定的期望荧光和/或颜色的化合物。尽管所有变量可能对本文中公开的化合物的某些实施方案的摩尔荧光具有影响,但是认为M、L3、m和n的适当选择在公开的化合物的实施方案的摩尔荧光中起重要作用。因此,在一个实施方案中,提供了用于获得具有期望的摩尔荧光的化合物的方法,该方法包括选择具有已知荧光的M部分,制备包含M部分的结构(I)的化合物,和为L3、m和n选择合适的变量以达到期望的摩尔荧光。
为了便于说明,包含磷部分(例如,磷酸酯等)的各种化合物以阴离子状态(例如,-OPO(OH)O-、-OPO3 2-)描述。本领域技术人员将容易理解,电荷取决于pH,并且不带电荷的(例如,质子化的或盐,诸如钠或其它阳离子)形式也被包括在本公开内容的实施方案的范围内。
在不同的其它实施方案中提供了包含任何前述化合物和一种或多种靶向部分(例如,抗体、细胞表面受体激动剂、细胞表面受体拮抗剂等)的组合物。在某些实施方案中,提供了这样的组合物在用于治疗疾病的方法中的用途,所述方法包括给有此需要的受试者施用治疗有效量的结构(I)的化合物或包含结构(I)的化合物的组合物,其中每个M独立地是有效地用于治疗疾病的生物活性部分。
药物组合物
一个实施方案提供了组合物,其包含根据本文公开的实施方案中的任一个的化合物和药学上可接受的载体。
另一个实施方案提供了包含多个缀合物的组合物,所述缀合物包含经由单个连接共价地结合至2个或多个生物活性部分的抗体(例如,结构(I)的化合物),其中所述多个缀合物具有至少90%结构均一性。在更具体的实施方案中,所述多个缀合物具有至少95%结构均一性。在有关的实施方案中,所述多个缀合物具有大于99%结构均一性。在某些实施方案中,所述单个连接是与聚合物主链的连接,所述聚合物主链包含与其共价地结合的2个或多个生物活性部分。在前述实施方案中的某些中,所述一个或多个缀合物包含结构(I)的化合物。
在某些实施方案中,每个缀合物独立地是结构(I)的化合物,其中R2和R3之一是-OP(=Ra)(Rb)OL'或L',且L'是抗体或包含与抗体的共价键的连接基。
其它实施方案涉及药物组合物。药物组合物包含任意一种(或多种)结构(I)的化合物和药学上可接受的载体。在某些实施方案中,将所述药物组合物被配制用于口服施用。在其它实施方案中,将所述药物组合物配制用于注射。在更多的实施方案中,所述药物组合物包含结构(I)的化合物和额外治疗剂(例如,抗癌剂)。下文描述了这样的治疗剂的非限制性例子。
合适的施用途径包括、但不限于口服、静脉内、直肠、气雾剂、胃肠外、眼、肺、透粘膜、透皮、阴道、耳、鼻和局部施用。另外,仅作为示例,胃肠外递送包括肌肉内、皮下、静脉内、髓内注射、以及鞘内、直接心室内、腹膜内、淋巴内和鼻内注射。
在某些实施方案中,以局部而非全身方式施用结构(I)的化合物,例如经由将化合物直接注射到器官中,通常在贮库制剂或持续释放制剂中。在具体实施方案中,通过植入(例如皮下地或肌肉内地)或通过肌肉内注射施用长效制剂。此外,在其它实施方案中,在靶向药物递送系统中,例如在用器官特异性抗体包被的脂质体中,递送所述药物。在这样的实施方案中,脂质体靶向器官并被器官选择性地吸收。在其它实施方案中,以快速释放制剂的形式、以延长释放制剂的形式、或以中间释放制剂的形式提供结构(I)的化合物。在其它实施方案中,局部地施用结构(I)的化合物。
结构(I)的化合物在宽剂量范围内是有效的。例如,在成人的治疗中,0.01-1000mg、0.5-100mg、1-50mg/天和5-40mg/天的剂量是在某些实施方案中使用的剂量的实例。一个示例性的剂量是10-30mg/天。确切的剂量将取决于施用途径、施用化合物的形式、要治疗的受试者、要治疗的受试者的体重以及主治医师的偏好和经验。
在某些实施方案中,以单剂量施用结构(I)的化合物。通常,这样的施用将是通过注射,例如,静脉内注射,以便快速引入药剂。但是,其它途径也可酌情使用。单剂量的结构(I)的化合物也可用于治疗急性病症。
在某些实施方案中,以多剂量施用结构(I)的化合物。在某些实施方案中,给药是每天约一次、两次、三次、四次、五次、六次或超过六次。在其它实施方案中,给药是约每月一次、每两周一次、每周一次或每隔一天一次。在另一个实施方案中,将结构(I)的化合物和另一种药剂一起施用约每天一次至约每天六次。在另一个实施方案中,结构(I)的化合物和药剂的施用持续小于约7天。在另一个实施方案中,施用持续超过约6、10、14、28天、两个月、六个月或一年。在某些情况下,只要需要就可以实现并维持连续给药。
只要需要,结构(I)的化合物的施用可以持续。在某些实施方案中,将结构(I)的化合物施用超过1、2、3、4、5、6、7、14或28天。在某些实施方案中,将结构(I)的化合物施用小于28、14、7、6、5、4、3、2或1天。在某些实施方案中,将结构(I)的化合物在持续的基础上长期施用,例如用于治疗慢性效应。
在某些实施方案中,以剂量施用结构(I)的化合物。本领域中已知,由于化合物药代动力学的受试者间可变性,给药方案的个体化对于最佳治疗是必要的。考虑到本发明的公开内容,可以通过常规的实验发现用于本公开内容的化合物的给药。
在某些实施方案中,将结构(I)的化合物配制成药物组合物。在具体实施方案中,使用一种或多种生理上可接受的载体,包括促进活性化合物加工成可药用制剂的赋形剂和助剂,以常规方式配制药物组合物。适当的制剂取决于选择的施用途径。任何药学上可接受的技术、载体和赋形剂都适用于配制本文所述的药物组合物:Remington:The Science andPractice of Pharmacy,第十九版(Easton,Pa.:Mack Publishing Company,1995);Hoover,John E.,Remington’s Pharmaceutical Sciences,Mack Publishing Co.,Easton,Pennsylvania1975;Liberman,H.A.and Lachman,L.,编,Pharmaceutical DosageForms,Marcel Decker,New York,N.Y.,1980;和Pharmaceutical Dosage Forms and DrugDelivery Systems,第七版(Lippincott Williams&Wilkins1999)。
本文提供了药物组合物,其包含结构(I)的化合物和药学上可接受的稀释剂、赋形剂或载体。在某些实施方案中,所描述的化合物作为药物组合物施用,其中将结构(I)的化合物与其它活性成分混合,如在组合疗法中。本文涵盖在以下组合疗法部分和贯穿本公开内容中阐述的活性物质的所有组合。在具体实施方案中,药物组合物包括一种或多种结构(I)的化合物。
本文中使用的药物组合物表示结构(I)的化合物与其它化学组分诸如载体、稳定剂、稀释剂、分散剂、助悬剂、增稠剂和/或赋形剂的混合物。在某些实施方案中,药物组合物促进化合物施用于生物体。在实施本文提供的治疗方法或用途的某些实施方案中,将治疗有效量的本文提供的结构(I)的化合物在药物组合物中施用于患有待治疗的疾病、障碍或医学病症的哺乳动物。在具体实施方案中,所述哺乳动物是人。在某些实施方案中,治疗有效量根据疾病的严重程度、受试者的年龄和相对健康状况、所用化合物的效能和其它因素而变化。结构(I)的化合物单独使用,或与一种或多种治疗剂(作为混合物的组分)组合使用。
在一个实施方案中,将一种或多种结构(I)的化合物配制在水性溶液中。在具体实施方案中,所述水性溶液选自,仅作为示例,生理上相容的缓冲液,诸如汉克氏溶液、林格氏溶液或生理盐水缓冲液。在其它实施方案中,将一种或多种结构(I)的化合物配制用于透粘膜施用。在具体实施方案中,透粘膜制剂包括适合要渗透的屏障的穿透剂(penetrant)。在其中本文所述化合物被配制用于其它胃肠外注射的其它实施方案中,适当的制剂包括水性或非水性溶液。在具体实施方案中,这样的溶液包括生理上相容的缓冲剂和/或赋形剂。
在另一个实施方案中,本文描述的化合物被配制用于口服施用。通过将活性化合物与例如药学上可接受的载体或赋形剂组合来配制本文所述的化合物。在不同的实施方案中,将本文所述化合物配制成口服剂型,其包括,仅作为示例,片剂、粉剂、丸剂、糖衣丸、胶囊剂、液体、凝胶、糖浆剂、酏剂、浆、混悬剂等。
在某些实施方案中,如下获得用于口服使用的药物制品:将一种或多种固体赋形剂与一种或多种本文所述的化合物混合,任选地研磨所得混合物,并在加入合适的助剂(如果需要)后加工颗粒混合物,以获得片剂或糖衣丸芯。合适的赋形剂具体地是,填充剂诸如糖,包括乳糖、蔗糖、甘露醇或山梨醇;纤维素制品,诸如:例如,玉米淀粉、小麦淀粉、米淀粉、马铃薯淀粉、明胶、黄芪树胶、甲基纤维素、微晶纤维素、羟丙基甲基纤维素、羧甲纤维素钠;或其它,诸如:聚乙烯吡咯烷酮(PVP或聚维酮)或磷酸钙。在具体实施方案中,任选地加入崩解剂。崩解剂包括、仅作为示例,交联的交联羧甲纤维素钠、聚乙烯吡咯烷酮、琼脂或海藻酸或其盐诸如海藻酸钠。
在一个实施方案中,给剂型(诸如糖衣丸芯和片剂)提供一个或多个合适的包衣。在具体实施方案中,将浓缩的糖溶液用于包衣剂型。糖溶液任选地含有另外组分,诸如仅作为示例,阿拉伯树胶、滑石粉、聚乙烯吡咯烷酮、卡波普凝胶、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。染料和/或颜料也任选地被添加到包衣中以用于识别目的。另外,染料和/或颜料任选地用于表征活性化合物剂量的不同组合。
在某些实施方案中,将治疗有效量的至少一种本文所述化合物配制成其它口服剂型。口服剂型包括由明胶制成的推入-配合式胶囊剂以及由明胶和塑化剂(诸如甘油或山梨醇)制成的软密封胶囊剂。在具体实施方案中,推入-配合式胶囊剂含有与一种或多种填充剂混合的活性成分。填充剂包括,仅作为示例,乳糖、粘合剂诸如淀粉和/或润滑剂诸如滑石或硬脂酸镁和任选的稳定剂。在其它实施方案中,软胶囊剂含有溶解或悬浮在合适液体中的一种或多种活性化合物。合适的液体包括,仅作为示例,一种或多种脂肪油、液状石蜡或液体聚乙二醇。另外,任选地添加稳定剂。
在其它实施方案中,将治疗有效量的至少一种本文所述化合物配制用于含服或舌下施用。适合用于含服或舌下施用的制剂包括,仅作为示例,片剂、锭剂或凝胶。在其它实施方案中,将本文所述化合物配制用于胃肠外注射,包括适合用于快速推注或连续输注的制剂。在具体实施方案中,注射用制剂存在于单位剂型(例如,在安瓿中)或多次剂量容器中。防腐剂任选地添加到注射制剂中。在其它实施方案中,将药物组合物配制成适合用于胃肠外注射的形式,如在油性或水性媒介物中的无菌悬浮液、溶液或乳液。胃肠外注射制剂任选地含有配制剂,诸如悬浮剂、稳定剂和/或分散剂。在具体实施方案中,用于胃肠外施用的药物制剂包括水溶性形式的活性化合物的水性溶液。在另外的实施方案中,将活性化合物(例如,结构(I)的化合物)的悬浮液制备为适当的油性注射悬浮液。用于本文所述的药物组合物的合适的亲脂溶剂或媒介物包括,仅作为示例,脂肪油诸如芝麻油或合成的脂肪酸酯,诸如油酸乙酯或甘油三酯或脂质体。在某些具体实施方案中,水性注射悬浮液含有增加悬浮液的粘度的物质,诸如羧甲基纤维素钠、山梨醇或葡聚糖。任选地,悬浮液含有合适的稳定剂或增加化合物的溶解度以允许制备高浓缩溶液的试剂。可替换地,在其它实施方案中,活性成分为粉末形式,用于在使用前用合适的媒介物(例如,无菌的无热原的水)配制。
在其它实施方案中,局部地施用结构(I)的化合物。将本文所述化合物配制成多种局部施用的组合物,诸如溶液、悬浮液、洗剂、凝胶、糊剂、药棒、香膏、乳膏剂或软膏剂。这样的药物组合物任选地含有增溶剂、稳定剂、张度增强剂、缓冲液和防腐剂。
在其它实施方案中,将结构(I)的化合物配制用于透皮施用。在具体实施方案中,透皮制剂采用透皮递送装置和透皮递送贴剂,并且可以是亲脂性乳液或缓冲的水性溶液,溶解和/或分散在聚合物或粘合剂中。在不同的实施方案中,此类贴剂被构造用于药学试剂的连续、脉动(pulsatile)或按需递送。在另外的实施方案中,借助于离子电渗疗法贴剂等完成结构(I)的化合物的透皮递送。在某些实施方案中,透皮贴剂提供结构(I)的化合物的受控递送。在具体实施方案中,通过使用速率控制膜或通过将化合物捕获在聚合物基质或凝胶内来减慢吸收速率。在可替代的实施方案中,吸收增强剂用于增加吸收。吸收增强剂或载体包括帮助透过皮肤的可吸收的药学上可接受的溶剂。例如,在一个实施方案中,透皮装置是绷带的形式,其包含背衬构件、含有任选地具有载体的化合物的蓄池、任选的速率控制屏障(以在延长的时间段将化合物以受控和预定的速率递送至宿主的皮肤)和将装置固定到皮肤上的工具。
在其它实施方案中,将结构(I)的化合物配制用于通过吸入施用。适合通过吸入施用的各种形式包括、但不限于气雾剂、雾剂(mist)或粉剂。使用合适的推进剂(例如,二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、二氧化碳或其它合适的气体),从加压包或喷雾器以气雾剂喷雾呈现形式方便地递送结构(I)的任何化合物的药物组合物。在具体实施方案中,通过提供阀门以递送定量的量来确定加压气雾剂的剂量单元。在某些实施方案中,诸如,仅作为示例,用于吸入器或吹入器中的明胶的胶囊剂和药筒被配制为含有化合物和合适的粉末基质(诸如乳糖或淀粉)的粉末混合物。
在其它实施方案中,将结构(I)的化合物配制成直肠组合物诸如灌肠剂、直肠凝胶、直肠泡沫、直肠气雾剂、栓剂、冻胶状栓剂或滞留型灌肠剂,其含有常规栓剂基质诸如可可脂或其它甘油酯、以及合成的聚合物诸如聚乙烯吡咯烷酮、PEG等。在组合物的栓剂形式中,低熔点蜡诸如但不限于脂肪酸甘油酯的混合物任选地与熔化的可可脂组合。
在某些实施方案中,使用一种或多种生理上可接受的载体以任何常规方式配制药物组合物,所述载体包含促进活性化合物加工成可药用制剂的赋形剂和助剂。适当的制剂取决于选择的施用途径。任何药学上可接受的技术、载体和赋形剂视情况任选地使用。以常规方式制备包含结构(I)的化合物的药物组合物,诸如,仅作为示例,借助于常规混合、溶解、造粒、糖衣丸制造、研磨、乳化、包囊、包埋或压缩过程。
药物组合物包含至少一种药学上可接受的载体、稀释剂或赋形剂和至少一种结构(I)的化合物(本文描述为活性成分)。活性成分呈游离酸或游离碱形式,或呈药学上可接受的盐形式。另外,本文所述的方法和药物组合物包括使用具有相同类型的活性的这些化合物的N-氧化物、晶型(也被称作多晶型物)、以及活性代谢物。本文所述的化合物的所有互变异构体均被包括在本文所呈现的化合物的范围内。另外,本文所述化合物涵盖未溶剂化形式以及与药学上可接受的溶剂诸如水、乙醇等的溶剂化形式。本文中呈现的化合物的溶剂化形式也被认为是在本文中公开的。此外,药物组合物任选地包括其它药物或药学试剂、载体、辅助剂,诸如防腐剂、稳定剂、润湿剂或乳化剂、溶液促进剂、用于调节渗透压的盐、缓冲剂和/或其它治疗上有价值的物质。
用于制备包含本文所述化合物的组合物的方法包括用一种或多种惰性的、药学上可接受的赋形剂或载体配制化合物以形成固体、半固体或液体。固体组合物包括、但不限于粉剂、片剂、可分散颗粒剂、胶囊剂、扁囊剂和栓剂。液体组合物包括其中溶解有化合物的溶液、包含化合物的乳液、或含有包含本文中公开的化合物的脂质体、胶束或纳米颗粒的溶液。半固体组合物包括、但不限于凝胶、悬浮液和乳膏剂。本文所述的药物组合物的形式包括液体溶液或悬浮液、适用于在使用前溶解或悬浮在液体中的固体形式,或作为乳液。这些组合物还任选地含有少量无毒的助剂物质,诸如润湿剂或乳化剂、pH缓冲剂等。
在某些实施方案中,包含至少一种结构(I)的化合物的药物组合物示例性地采取液体形式,其中所述药剂存在于溶液、悬浮液或两者中。通常,当组合物作为溶液或悬浮液施用时,第一部分药剂存在于溶液中,且第二部分药剂以颗粒形式存在于液体基质中的悬浮液中。在某些实施方案中,液体组合物包括凝胶制剂。在其它实施方案中,所述液体组合物是水性的。
在某些实施方案中,有用的水性悬浮液含有一种或多种聚合物作为悬浮剂。有用的聚合物包括水溶性聚合物诸如纤维素聚合物(例如,羟丙基甲基纤维素)和不溶于水的聚合物诸如交联的含羧基的聚合物。本文所述的某些药物组合物包含粘膜粘附的聚合物,例如选自羧甲纤维素、卡波姆(丙烯酸聚合物)、聚(甲基丙烯酸甲酯)、聚丙烯酰胺、聚卡波非、丙烯酸/丙烯酸丁酯共聚物、海藻酸钠和葡聚糖。
有用的药物组合物还任选地包括有助于结构(I)的化合物的溶解的增溶剂。术语“增溶剂”通常包括导致试剂的胶束溶液或真溶液的形成的试剂。某些可接受的非离子型表面活性剂,例如聚山梨酯80,可以用作增溶剂,眼科可接受的二醇、聚二醇(例如,聚乙二醇400)和二醇醚也可以用作增溶剂。
此外,有用的药物组合物任选地包括一种或多种pH调节剂或缓冲剂,包括酸,诸如乙酸、硼酸、柠檬酸、乳酸、磷酸和盐酸;碱诸如氢氧化钠、磷酸钠、硼酸钠、柠檬酸钠、醋酸钠、乳酸钠和三羟基甲基氨基甲烷;和缓冲剂诸如柠檬酸盐/右旋糖、碳酸氢钠和氯化铵。这样的酸、碱和缓冲剂以将组合物的pH保持在可接受范围内所需的量被包括。
此外,有用的组合物还任选地包括使组合物的同渗浓度(osmolality)达到可接受范围所需的量的一种或多种盐。这样的盐包括具有钠、钾或铵阳离子和氯离子、柠檬酸根、抗坏血酸根、硼酸根、磷酸根、碳酸氢根、硫酸根、硫代硫酸根或亚硫酸氢根阴离子的盐;合适的盐包括氯化钠、氯化钾、硫代硫酸钠、亚硫酸氢钠和硫酸铵。
其它有用的药物组合物任选地包括一种或多种防腐剂以抑制微生物活性。合适的防腐剂包括含汞物质诸如硼酸苯汞(merfen)和硫柳汞;稳定的二氧化氯;和季铵化合物诸如苯扎氯铵、鲸蜡基三甲基溴化铵和西吡氯铵。
再其它有用的组合物包括一种或多种表面活性剂以增强物理稳定性或用于其它目的。合适的非离子型表面活性剂包括聚氧乙烯脂肪酸甘油酯和植物油,例如,聚氧乙烯(60)氢化蓖麻油;和聚氧乙烯烷基醚和烷基苯基醚,例如,辛苯昔醇10、辛苯昔醇40。
再其它有用的组合物包括一种或多种抗氧化剂以在需要时增强化学稳定性。合适的抗氧化剂包括,仅作为示例,抗坏血酸和焦亚硫酸钠。
在某些实施方案中,将水性悬浮液组合物包装在单剂量的不可重新封闭的容器中。可替换地,使用多剂量可重新封闭的容器,在这种情况下,通常在组合物中包括防腐剂。
在可替代的实施方案中,使用用于疏水性药物化合物的其它递送系统。脂质体和乳剂是在本文中有用的递送媒介物或载体的例子。在某些实施方案中,还使用有机溶剂诸如N-甲基吡咯烷酮。在另外的实施方案中,使用持续释放系统递送本文所述的化合物,诸如含有治疗剂的固体疏水聚合物的半透性基质。各种持续释放是在本文中有用的。在某些实施方案中,持续释放胶囊剂释放化合物数周直至超过100天。根据治疗试剂的化学性质和生物稳定性,采用额外的用于蛋白稳定的策略。
在某些实施方案中,本文所述的制剂包含一种或多种抗氧化剂、金属螯合剂、含硫醇的化合物和/或其它通用稳定剂。这样的稳定剂的例子包括、但不限于:(a)约0.5%至约2%w/v甘油,(b)约0.1%至约1%w/v甲硫氨酸,(c)约0.1%至约2%w/v单硫代甘油,(d)约1mM至约10mM EDTA,(e)约0.01%至约2%w/v抗坏血酸,(f)0.003%至约0.02%w/v聚山梨酯80,(g)0.001%至约0.05%w/v.聚山梨酯20,(h)精氨酸,(i)肝素,(j)硫酸葡聚糖,(k)环糊精,(l)戊聚糖多硫酸酯和其它类肝素,(m)二价阳离子诸如镁和锌;或(n)其组合。
在某些实施方案中,在药物组合物中提供的一种或多种化合物的浓度小于100%、90%、80%、70%、60%、50%、40%、30%、20%、19%、18%、17%、16%、15%、14%、13%、12%、11%、10%、9%、8%、7%、6%、5%、4%、3%、2%、1%、0.5%、0.4%、0.3%、0.2%、0.1%、0.09%、0.08%、0.07%、0.06%、0.05%、0.04%、0.03%、0.02%、0.01%、0.009%、0.008%、0.007%、0.006%、0.005%、0.004%、0.003%、0.002%、0.001%、0.0009%、0.0008%、0.0007%、0.0006%、0.0005%、0.0004%、0.0003%、0.0002%或0.0001%w/w、w/v或v/v。
在某些实施方案中,一种或多种化合物的浓度大于90%、80%、70%、60%、50%、40%、30%、20%、19.75%、19.50%、19.25%、19%、18.75%、18.50%、18.25%、18%、17.75%、17.50%、17.25%、17%、16.75%、16.50%、16.25%、16%、15.75%、15.50%、15.25%、15%、14.75%、14.50%、14.25%、14%、13.75%、13.50%、13.25%、13%、12.75%、12.50%、12.25%、12%、11.75%、11.50%、11.25%、11%、10.75%、10.50%、10.25%、10%、9.75%、9.50%、9.25%、9%、8.75%、8.50%、8.25%、8%、7.75%、7.50%、7.25%、7%、6.75%、6.50%、6.25%、6%、5.75%、5.50%、5.25%、5%、4.75%、4.50%、4.25%、4%、3.75%、3.50%、3.25%、3%、2.75%、2.50%、2.25%、2%、1.75%、1.50%、125%、1%、0.5%、0.4%、0.3%、0.2%、0.1%、0.09%、0.08%、0.07%、0.06%、0.05%、0.04%、0.03%、0.02%、0.01%、0.009%、0.008%、0.007%、0.006%、0.005%、0.004%、0.003%、0.002%、0.001%、0.0009%、0.0008%、0.0007%、0.0006%、0.0005%、0.0004%、0.0003%、0.0002%或0.0001%w/w、w/v或v/v。
在某些实施方案中,一种或多种化合物的浓度是在大约0.0001%至大约50%、大约0.001%至大约40%、大约0.01%至大约30%、大约0.02%至大约29%、大约0.03%至大约28%、大约0.04%至大约27%、大约0.05%至大约26%、大约0.06%至大约25%、大约0.07%至大约24%、大约0.08%至大约23%、大约0.09%至大约22%、大约0.1%至大约21%、大约0.2%至大约20%、大约0.3%至大约19%、大约0.4%至大约18%、大约0.5%至大约17%、大约0.6%至大约16%、大约0.7%至大约15%、大约0.8%至大约14%、大约0.9%至大约12%、大约1%至大约10%w/w、w/v或v/v范围内。
在某些实施方案中,一种或多种化合物的浓度是在大约0.001%至大约10%、大约0.01%至大约5%、大约0.02%至大约4.5%、大约0.03%至大约4%、大约0.04%至大约3.5%、大约0.05%至大约3%、大约0.06%至大约2.5%、大约0.07%至大约2%、大约0.08%至大约1.5%、大约0.09%至大约1%、大约0.1%至大约0.9%w/w、w/v或v/v范围内。
在某些实施方案中,一种或多种化合物的量等于或小于10g、9.5g、9.0g、8.5g、8.0g、7.5g、7.0g、6.5g、6.0g、5.5g、5.0g、4.5g、4.0g、3.5g、3.0g、2.5g、2.0g、1.5g、1.0g、0.95g、0.9g、0.85g、0.8g、0.75g、0.7g、0.65g、0.6g、0.55g、0.5g、0.45g、0.4g、0.35g、0.3g、0.25g、0.2g、0.15g、0.1g、0.09g、0.08g、0.07g、0.06g、0.05g、0.04g、0.03g、0.02g、0.01g、0.009g、0.008g、0.007g、0.006g、0.005g、0.004g、0.003g、0.002g、0.001g、0.0009g、0.0008g、0.0007g、0.0006g、0.0005g、0.0004g、0.0003g、0.0002g或0.0001g。
在某些实施方案中,一种或多种化合物的量超过0.0001g、0.0002g、0.0003g、0.0004g、0.0005g、0.0006g、0.0007g、0.0008g、0.0009g、0.001g、0.0015g、0.002g、0.0025g、0.003g、0.0035g、0.004g、0.0045g、0.005g、0.0055g、0.006g、0.0065g、0.007g、0.0075g、0.008g、0.0085g、0.009g、0.0095g、0.01g、0.015g、0.02g、0.025g、0.03g、0.035g、0.04g、0.045g、0.05g、0.055g、0.06g、0.065g、0.07g、0.075g、0.08g、0.085g、0.09g、0.095g、0.1g、、0.15g、0.2g、、0.25g、0.3g、、0.35g、0.4g、、0.45g、0.5g、0.55g、0.6g、、0.65g、0.7g、0.75g、0.8g、0.85g、0.9g、0.95g、1g、1.5g、2g、2.5、3g、3.5、4g、4.5g、5g、5.5g、6g、6.5g、7g、7.5g、8g、8.5g、9g、9.5g或10g。
在某些实施方案中,一种或多种化合物的量的范围为0.0001-10g、0.0005-9g、0.001-8g、0.005-7g、0.01-6g、0.05-5g、0.1-4g、0.5-4g或1-3g。
治疗方法
本公开内容的化合物可用于治疗疾病。本文公开的化合物为药物递送策略提供了靶向方案。此外,由于其能够包括几乎任何治疗部分,所以结构(I)的化合物会提供优于先前已知化合物的明显优势。生物活性部分(例如,治疗剂)可以可逆地或不可逆地连接并递送至靶标。
因此,在某些实施方案中,所述化合物可用在不同的治疗疾病或病症的方法中。一个实施方案提供了治疗疾病的方法,所述方法包括给有此需要的受试者施用治疗有效量的结构(I)的化合物或包含结构(I)的化合物的组合物,其中至少一个M是有效的用于治疗疾病的生物活性部分。在更具体的实施方案中,每个M是有效的用于治疗疾病的生物活性部分。
在某些实施方案中,所述疾病生物活性部分降解蛋白。在某些更具体的实施方案中,所述蛋白是淀粉样蛋白或tau蛋白。在某些实施方案中,所述疾病是淀粉样变性或阿尔茨海默氏病。在某些实施方案中,所述疾病是前列腺癌、胰腺癌或乳腺癌。在某些实施方案中,所述疾病是肿瘤疾病、心血管疾病、肾疾病、代谢疾病或呼吸疾病。
在某些实施方案中,所述疾病是肺病或中枢神经系统疾病。在更具体的实施方案中,所述疾病是转移性的去势抵抗性的前列腺癌或转移性的乳腺癌。在某些实施方案中,所述方法包括给有此需要的受试者施用治疗有效量的根据本文公开的实施方案中的任一个的化合物或根据本文公开的实施方案中的任一个的组合物,其中每个M独立地是有效的用于治疗疾病的生物活性部分。
在某些实施方案中,所述疾病是癌症,且每个M独立地是抗癌药物。在某些实施方案中,M的至少一次出现具有以下结构之一:
在某些实施方案中,M的每次出现具有以下结构之一:
例如,在某些实施方案中,本公开内容提供了治疗实体瘤、多发性骨髓瘤、神经胶质瘤、透明细胞肾细胞癌、前列腺癌、卵巢癌、非小细胞肺癌、GI恶性肿瘤、急性淋巴细胞性白血病、急性髓细胞白血病、肾细胞癌症、结肠直肠癌症、上皮癌、胰腺和胃癌、肾细胞癌、非霍奇金淋巴瘤、转移性的肾细胞癌、恶性间皮瘤、胰腺、卵巢和/或肺腺癌、B-细胞恶性肿瘤、乳腺癌、黑素瘤、复发性多发性骨髓瘤、小细胞肺癌、CD22-阳性的B细胞恶性肿瘤、霍奇金淋巴瘤/间变性大细胞淋巴瘤或HER2-阳性的乳腺癌的方法。
在前述实施方案中的某些中,所述疾病是癌症。例如,在某些实施方案中,所述癌症是乳腺癌、非霍奇金淋巴瘤、急性髓性白血病、多发性骨髓瘤、胃癌、肾细胞癌、实体瘤、卵巢癌、前列腺癌、结肠直肠癌、胰腺癌、小细胞肺癌、弥漫性大B细胞性淋巴瘤、赘生物、泌尿道上皮癌、ALL、CLL、胶质母细胞瘤、霍奇金淋巴瘤、淋巴瘤、间皮瘤、非小细胞肺癌、复发性头颈癌或其组合。
某些实施方案也涉及治疗哺乳动物(例如,人)中的过度增殖障碍的方法,所述方法包括给所述哺乳动物施用治疗有效量的化合物或其药学上可接受的盐、酯、前药、溶剂化物、水合物或衍生物。在某些实施方案中,所述方法涉及治疗癌症诸如急性髓性白血病、青少年中的癌症、儿童期肾上腺皮质癌、AIDS有关的癌症(例如,淋巴瘤和卡波西氏肉瘤)、肛门癌、阑尾癌(appendix cancer)、星形细胞瘤、非典型畸胎样、基底细胞癌、胆管癌、膀胱癌、骨癌、脑干神经胶质瘤、脑肿瘤、乳腺癌、支气管肿瘤、伯基特淋巴瘤、类癌肿瘤、非典型畸胎样、胚胎肿瘤、生殖细胞肿瘤、原发性淋巴瘤、宫颈癌、儿童癌症、脊索瘤、心脏肿瘤、慢性淋巴细胞白血病(CLL)、慢性髓细胞白血病(CML)、慢性髓性增殖性(myleoproliferative)障碍、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T-细胞淋巴瘤、肝外原位导管癌(DCIS)、胚胎肿瘤、CNS癌、子宫内膜癌、室管膜瘤、食管癌、成感觉神经细胞瘤、尤因肉瘤、颅外生殖细胞肿瘤、性腺外生殖细胞肿瘤、眼癌、骨纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌肿瘤、胃肠道间质肿瘤(GIST)、生殖细胞肿瘤、妊娠滋养细胞肿瘤、毛细胞白血病、头颈癌、心脏癌、肝癌、霍奇金淋巴瘤、下咽癌、眼内黑素瘤、胰岛细胞肿瘤、胰腺神经内分泌肿瘤、肾癌、喉癌、唇与口腔癌、肝癌、原位小叶癌(LCIS)、肺癌、淋巴瘤、不明原发灶的转移性鳞状颈癌、中线道癌(midline tract carcinoma)、口腔癌、多发性内分泌赘生物综合征、多发性骨髓瘤/浆细胞赘生物、蕈样肉芽肿病、骨髓增生异常综合征、骨髓增生异常/骨髓增殖性赘生物、多发性骨髓瘤、梅克尔细胞癌、恶性间皮瘤、骨恶性纤维组织细胞瘤和骨肉瘤、鼻腔与鼻旁窦癌、鼻咽癌、神经母细胞瘤、非霍奇金淋巴瘤、非小细胞肺癌(NSCLC)、口癌、唇与口腔癌、口咽癌、卵巢癌、胰腺癌、乳头状瘤病、副神经节瘤、鼻旁窦和鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、胸膜肺母细胞瘤、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、移行细胞癌、视网膜母细胞瘤、横纹肌肉瘤、唾液腺癌、皮肤癌、胃(胃的)癌、小细胞肺癌、小肠癌、软组织肉瘤、T-细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤和胸腺癌、甲状腺癌、肾盂和输尿管的移行细胞癌、滋养细胞肿瘤、儿童期罕见癌、尿道癌、子宫肉瘤、阴道癌、外阴癌或病毒诱导的癌。在某些实施方案中,所述方法涉及治疗非癌性过度增殖障碍诸如皮肤良性增生(例如,银屑病)、再狭窄良性增生或前列腺良性增生(例如,良性前列腺肥大(BPH))。
某些特定实施方案提供了用于治疗肺癌的方法,所述方法包括给有此需要的受试者施用有效量的上述的化合物中的任一种(或包含它们的药物组合物)。在某些实施方案中,所述肺癌是非小细胞肺癌(NSCLC),例如腺癌、鳞状细胞肺癌或大细胞肺癌。在其它实施方案中,所述肺癌是小细胞肺癌。用公开的化合物可治疗的其它肺癌包括、但不限于腺肿瘤、类癌肿瘤和未分化的癌。
因此,在前述方法的某些实施方案中,R2是包含与靶向部分(诸如抗体、细胞表面受体激动剂、细胞表面受体拮抗剂等)的共价连接的连接基。例如,表皮生长因子受体(EGFR)抑制剂、肝细胞生长因子受体(HGFR)抑制剂、胰岛素-样生长因子受体(IGFR)抑制剂、叶酸或MET抑制剂。
在甚至更多的实施方案中,所述方法进一步包括诱导细胞凋亡。
在某些实施方案中,所述治疗疾病的方法进一步包括:
(a)提供结构(I)的化合物,例如,其中R2或R3之一是包含与分析物分子的共价键的连接基,且R2或R3中的另一个是H、OH、烷基、烷氧基、烷基醚或-OP(=Ra)(Rb)Rc;且
(b)通过其可视性能检测所述化合物。
在某些实施方案中,所述分析物分子是核酸、氨基酸或其聚合物(例如,多核苷酸或多肽)。在更多的实施方案中,所述分析物分子是酶、受体、受体配体、抗体、糖蛋白、适配体或朊病毒。
在某些实施方案中,所述提供进一步包括将结构(I)的化合物与分析物分子混合。
因此,本发明化合物的实施方案可用于任意数目的方法,包括、但不限于:药物递送;量化细胞凋亡;实现治疗药物递送;量化细胞凋亡;以及诊断和治疗疾病,诸如血癌。
除上述方法外,结构(I)的化合物的实施方案可用于不同的学科和方法,包括、但不限于:癌症治疗和成像,例如通过在结构(I)的化合物中包括靶向部分诸如抗体或糖或优先结合癌细胞的其它部分;和/或药物递送。
在某些实施方案中,治疗方法包括治疗具有肿瘤细胞的肿瘤,所述肿瘤细胞具有肿瘤细胞受体。在某些实施方案中,肿瘤细胞具有在每个细胞1,000至100,000、1,000至50,000、1,000至25,000个受体、1,000至10,000个受体范围内的受体。例如,在某些实施方案中,肿瘤细胞具有每个细胞约1,000个、约10,000个或小于100,000个受体。
本公开内容的实施方案不限于癌症的治疗。事实上,关于本公开内容的化合物和方法可以适用的疾病、症状、病症、适应症和治疗的类型,本公开内容没有特别限制。也就是说,本公开内容提供了用于治疗或预防多种疾病的化合物、组合物和方法。例如,通过选择合适的生物部分或生物部分的组合,可以修饰本文公开的化合物和组合物,以根据需要治疗特定疾病。基于本公开内容,对于本领域普通技术人员而言,如何修饰当前公开的化合物和组合物以便治疗、预防或靶向疾病、症状或临床适应症将是显而易见的。
因此,本公开内容的方法包括施用本公开内容的化合物用于治疗疾病、病症、或疾病或病症的症状,预防疾病或疾病或病症的症状,预防性地治疗疾病、病症或疾病或病症的症状,鉴定处于风险中的受试者并治疗疾病、病症、或疾病或病症的症状,减缓或停止疾病、病症、或疾病或病症的症状的进展,增加具有疾病、病症、或疾病或病症的症状的受试者的存活率,改善疾病的症状、病症、或疾病或病症的症状,等的方法。
此外,疾病、病症、症状、病痛、副作用、病、综合症、生物事件、生物异常、医学病症、生病、病态、病理学等意图被包括在本公开内容中并且也没有特别限制;例子包括、但不限于癌、炎症、疼痛、疼痛控制、炎性疾病、感染性疾病、病毒感染、遗传性障碍、细菌感染、真菌感染、皮肤病症、内分泌病症、眼障碍、肠疾病、神经学障碍、肝障碍、肺感染、心脏病症和障碍、精神疾病(例如,进食障碍、心境障碍、人格障碍)、诺如病毒感染、血液传播的病原体、原虫感染、病毒性肝炎、HIV/AIDS、糖尿病、硬化、克罗恩氏和结肠炎、狼疮、关节炎、变态反应和哮喘、乳糜泻、多软骨炎、硬皮病、肝病、心脏病、获得性疾病、急性疾病、慢性病症或疾病、先天性疾病或障碍、遗传性疾病或障碍、医源性疾病、特发性疾病、原发性疾病、继发性疾病、晚期疾病或类似疾病。上述可以是急性的、慢性的、临床的、突然发作的(flare-up)、进行性的、难治性的、亚临床的、局部的、播散性的、全身性的等。任何前述示例可以包括由空气传播的、食物传播的、感染或生活方式事件引起。
在某些实施方案中,所述生物活性部分是抗生素药物。在某些具体实施方案中,M在每次出现时独立地是抗生素药物,且靶向部分是对传染性疾病抗原特异性的抗体。本文中使用的抗生素药物包括衍生物。也就是说,抗生素药物已被修饰或衍生化,使得该药物可缀合或连接至另一分子(例如,以包括Q部分)。
示例性的抗生素部分可以包括治疗细菌物种的化合物,所述细菌物种包括、例如,以色列放线菌(Actinomyces israelii)、炭疽芽孢杆菌(Bacillus anthracis)、脆弱拟杆菌(Bacteroides fragilis)、百日咳博德特氏菌(Bordetella pertussis)、疏螺旋体属种(Borrelia sp.)、布鲁杆菌属种(Brucella sp.)、空肠弯曲杆菌(Campylobacter jejuni)、衣原体属种(Chlamydia sp.)、鹦鹉热嗜衣原体(Chlamydophila psittaci)、梭菌属种(Clostridium sp.)、白喉棒杆菌(Corynebacterium diphtheria)、埃里希氏体属种(Ehrlichia sp.)、肠球菌属种(Enterococcus sp.)、埃希氏菌属种(Escherichia sp.)、土拉热弗朗西丝氏菌(Francisella tularensis)、流感嗜血杆菌(Haemophilus influenza)、幽门螺杆菌(Helicobacter pylori)、肺炎克雷伯氏菌(Klebsiella pneumoniae)、嗜肺军团菌(Legionella pneumophila)、钩端螺旋体属种(Leptospira sp.)、单核细胞增生李斯特菌(Listeria monocytogenes)、分枝杆菌属种(Mycobacterium sp.)、肺炎支原体(Mycoplasma pneumoniae)、奈瑟球菌属种(Neisseria sp.)、铜绿假单胞菌(Pseudomonasaeruginosa)、星形诺卡氏菌(Nocardia asteroids)、立克次氏体属立克次氏体(Rickettsia rickettsia)、沙门氏菌属种(Salmonella sp.)、志贺氏菌属种(Shigellasp.)、葡萄球菌属种(Staphylococcus sp.)、链球菌属种(Streptococcus sp.)、苍白密螺旋体(Treponema pallidum)、霍乱弧菌(Vibrio cholera)、和鼠疫耶尔森氏菌(Yersiniapestis)。此外,可以治疗的细菌物种包括药物抗性株,诸如甲氧西林抗性的金黄色葡萄球菌(MRSA)、万古霉素抗性的肠球菌(VRE)和通常与医院获得性(医院源的)感染相关的各种多药抗性的(MDR)菌株,包括鲍氏不动杆菌(Acinetobacter baumannii)、肺炎克雷伯菌(Klebsiella pnuemoniae)和阴沟肠杆菌(Enterobacter cloacae)。在另一个实施方案中,用结构(I)的化合物可以治疗的细菌性疾病或病症可以是,例如,炭疽、百日咳、莱姆病、布鲁菌病、胃肠脓肿、回归热、肠炎、血性腹泻、非典型肺炎、肉毒中毒、破伤风、细菌性脑膜炎、坏疽、细菌性心内膜炎、麻风、军团病(Legionnaire’s disease)、钩端螺旋体病、结核病、鼠疫、霍乱、坏死性筋膜炎、伤寒和诺卡菌病。
在某些更具体的实施方案中,所述抗生素药物是β-内酰胺抗生素。β-内酰胺抗生素包括包含青霉素类、单环内酰胺类、碳青霉烯类和头孢菌素类的化合物。在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是苯唑西林、双氯西林、萘夫西林、阿莫西林、氨苄西林、哌拉西林、氯唑西林、氟氯西林、甲氧西林、苯唑西林、替莫西林、苄青霉素(青霉素G)、阿美西林(青霉素O)、苯氧甲基青霉素(青霉素V)、美西林、羧苄西林、替卡西林、阿洛西林、美洛西林、头孢唑林、头孢氨苄、头孢菌素C、头孢噻肟、头孢地尼、头孢匹罗、比阿培南、多立培南、厄他培南、法罗培南、亚胺培南、美罗培南、帕尼培南、雷珠培南、替比培南、噻烯霉素、氨曲南、替吉莫南、诺卡杀菌素A、α,ε-二氨基-β-羟庚二酸β-内酰胺(Tabtoxinineβ-lactam)、来那培南、托莫培南、头孢唑林(Cefazolinm)、头孢氨苄、头孢羟氨苄、头孢匹林、头孢西酮、头孢氮氟、头孢拉定、头孢沙定、头孢替唑、头孢来星、头孢乙腈、头孢洛宁、头孢噻啶、头孢噻吩、头孢曲秦、头孢克洛、头孢替坦、头霉素、头孢西丁、头孢丙烯、头孢呋辛、头孢呋辛酯、头孢孟多、头孢米诺、头孢尼西、头孢雷特、头孢替安、头孢拉宗、头孢唑南、头孢美唑、碳头孢烯(氯碳头孢)、头孢克肟、头孢曲松、头孢他啶、头孢哌酮、头孢地尼、头孢卡品、头孢达肟、头孢唑肟、头孢甲肟、头孢噻肟、头孢匹胺、头孢泊肟、头孢布烯、头孢托仑、头孢他美、头孢地秦、头孢咪唑、头孢磺啶、头孢特仑、头孢噻林、氧头孢烯、氟氧头孢、头孢吡肟、头孢唑兰、头孢匹罗、头孢喹肟、头孢洛林酯、头孢洛赞、头孢比普、头孢噻呋、头孢喹肟或头孢维星。
在其它实施方案中,所述抗生素药物是四环素抗生素。更具体地,在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是多西环素、四环素、米诺环素、脱甲氯环素、金霉素、土霉素、赖甲环素、美他环素、罗利环素、替吉环素、依拉环素、萨瑞环素、奥玛环素、氯莫环素、脱甲氯环素、甲氯环素、美他环素或青哌环素。
在其它实施方案中,所述抗生素药物是喹诺酮抗生素。喹诺酮抗生素包括大亚组荧光喹诺酮类。具体地,在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是奥索利酸(Uroxin)、罗索沙星(Eradacil)、环丙沙星(Zoxan、Ciprobay、Cipro、Ciproxin)、氟罗沙星(Megalone、Roquinol)、洛米沙星(Maxaquin)、那氟沙星(Acuatim、Nadoxin、Nadixa)、诺氟沙星(Lexinor、Noroxin、Quinabic、Janacin)、氧氟沙星(Floxin、Oxaldin、Tarivid)、培氟沙星(Peflacine)、芦氟沙星(Uroflox)、巴洛沙星(Baloxin)、格帕沙星(Raxar)、左氧氟沙星(Cravit、Levaquin)、帕珠沙星(Pasil、Pazucross)、司帕沙星(Zagam)、替马沙星(Omniflox)、克林沙星、加替沙星(Zigat、Tequin)(Zymar-opth.)、莫西沙星(Avelox、Vigamox)、西他沙星(Gracevit)、普卢利沙星、贝西沙星(Besivance)、德拉沙星(Baxdela)、吉米沙星(Factive)、奥泽沙星、托氟沙星、西诺沙星(Cinobac)、萘啶酸(NegGam、Wintomylon)、吡咯米酸(Panacid)、吡哌酸(Dolcol)、奈诺沙星或依诺沙星。
在另一个实施方案中,所述抗生素药物是林可酰胺类抗生素。在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是克林霉素、林可霉素或吡利霉素。
在某些实施方案中,所述抗生素药物是大环抗生素。大环抗生素包含包括大环内酯类、酮内酯类、氟酮内酯类和多烯类的组。在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是两性霉素B、阿奇霉素、硼霉素、卡波霉素A、塞红霉素、克拉霉素、地红霉素、红霉素、非达米星、氟红霉素、交沙霉素、吉他霉素、麦迪霉素、米卡霉素、竹桃霉素、利福平(或利福平)、利福布汀、利福喷汀、利福拉齐、利福昔明、利福霉素SV、罗他霉素、罗红霉素、索利霉素、螺旋霉素、泰利霉素、醋竹桃霉素或泰洛星。
在某些实施方案中,所述抗生素药物是磺酰胺抗生素(磺胺或磺胺药物)。磺酰胺抗生素通过如下发挥其抑菌作用:抑制二氢蝶酸合酶(DHPS),从而中断叶酸合成和生物体的合成核酸的能力。在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是磺胺异噁唑、磺胺醋酰、磺胺嘧啶、磺胺二甲嘧啶、磺胺异氧唑(磺胺异噁唑)、磺胺索嘧啶(磺胺异嘧啶)、磺胺硝苯、磺胺地索辛、磺胺甲氧嗪、磺胺对甲氧嘧啶、磺胺多辛、磺胺林、Terephtyl、磺胺甲噁唑或磺胺噁唑。
在某些实施方案中,所述抗生素药物是糖肽抗生素。在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是万古霉素、替考拉宁、替拉凡星、雷莫拉宁、奥利万星或decaplanin。
在某些实施方案中,所述抗生素药物是氨基糖苷抗生素。氨基糖苷抗生素通过蛋白合成抑制发挥它们的生物学效应。在更具体的实施方案中,对于M的至少一次出现或在M的每次出现时,M是链霉素、双氢链霉素、新霉素、新霉素B、巴龙霉素、核糖霉素、卡那霉素、阿米卡星、阿贝卡星、卡那霉素B、地贝卡星、妥布霉素、大观霉素、潮霉素B、安普霉素、嘌呤霉素、诺尔丝菌素、庆大霉素、奈替米星、西索米星、普拉唑霉素、异帕米星、威达米星或阿司米星。
在某些实施方案中,所述抗生素药物是噁唑烷酮抗生素。噁唑烷酮抗生素通过蛋白合成抑制发挥它们的生物学效应。在某些具体实施方案中,对于M的至少一次出现或在M的每次出现时,M是依哌唑胺、利奈唑胺、Posizolid、Radezolid、Ranbezolid、Sutezolid或特地唑胺。
在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是平板霉素、氯霉素、甲硝唑、甲氧苄啶、阿地普林、溴莫普林、氯法齐明、艾拉普林、四氧普林或呋喃妥因。
在某些实施方案中,所述生物活性部分是抗真菌药物。在某些具体实施方案中,M在每次出现时独立地是抗真菌药物,且靶向部分是对传染性疾病抗原特异性的抗体。本文中使用的抗真菌药物包括衍生物。也就是说,抗真菌药物已被修饰或衍生化,使得该药物可缀合或连接至另一分子(例如,以包括Q部分)。
用本公开内容的化合物可以治疗的真菌物种包括,例如;念珠菌属种(Candidasp.)、曲霉菌属种(Aspergillus sp.)、隐球菌属种(Cryptococcus sp.)、组织胞浆菌属种(Histoplasma sp.)、肺囊虫属种(Pneumocystis sp.)和葡萄状穗霉属种(Stachybotryssp.)。另外,需要治疗的真菌物种包括新出现的药物抗性株,诸如耳念珠菌(Candidaauris)、光滑念珠菌(glabrata)和克鲁氏念珠菌(krusei),它们对现有治疗选择表现出显著的抗性,并由于它们经常是卫生中心获得性感染而引起公共卫生问题。
在某些实施方案中,对于M的至少一次出现或在M的每次出现时,用结构(I)的化合物可以治疗的真菌疾病或病症可以是,例如aspirgillosis,侵袭性念珠菌病、甲癣或组织胞浆菌病。
在某些实施方案中,所述抗真菌药物是多烯。在更具体的实施方案中,对于M的至少一次出现或在M的每次出现时,M是两性霉素B、克念菌素、非律平、哈霉素、那他霉素、制霉菌素和龟裂杀菌素;烯丙胺诸如阿莫罗芬、布替萘芬、萘替芬和特比萘芬;棘球白素诸如阿尼芬净、卡泊芬净和米卡芬净;或唑类,其可以分为咪唑诸如联苯苄唑、布康唑、克霉唑、益康唑、芬替康唑、异康唑、酮康唑、卢立康唑、咪康唑、奥莫康唑、奥昔康唑、舍他康唑、硫康唑和噻康唑;三唑类诸如阿巴康唑、艾氟康唑、氟环唑、氟康唑、艾沙康唑、伊曲康唑、泊沙康唑、丙环唑、雷夫康唑、特康唑和伏立康唑;和噻唑、阿巴芬净。
在某些更具体的实施方案中,对于M的至少一次出现或在M的每次出现时,M是环吡酮、氟胞嘧啶或5-氟胞嘧啶、灰黄霉素、托萘酯、orotomide、米替福新、吡罗克酮乙醇胺盐、碘醌醇、氯碘羟喹、吖啶琐辛或夫马洁林。
在某些实施方案中,所述生物活性部分是抗寄生虫药物。在某些具体实施方案中,M在每次出现时独立地是抗寄生虫药物,且靶向部分是对传染性疾病抗原特异性的抗体。本文中使用的抗寄生虫药物包括衍生物。也就是说,抗寄生虫药物已被修饰或衍生化,使得该药物可缀合或连接至另一分子(例如,以包括Q部分)。
用本公开内容的化合物可以治疗其相关疾病的寄生生物包括原生生物诸如疟原虫属种(Plasmodium sp.)(疟疾)、利什曼原虫属种(Leishmania sp.)(利什曼病)、锥虫属种(Trypanosoma sp.)(非洲锥虫病/睡眠病、Chagus疾病)、贾第虫属(Giardia sp.)(贾第虫病/河狸热(beaver fever))、刚地弓形虫(Toxoplasma gondii)(弓形虫病)和隐孢子虫属种(Cryptosporidium sp.)(隐孢子虫病);和阿米巴(amobae)诸如溶组织内阿米巴(Entamoeba histolytica)(阿米巴病)。
在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是氯喹、阿莫地喹、乙胺嘧啶(达拉匹林)、氯胍、磺胺多辛、磺胺甲氧嗪、甲氟喹、巴龙霉素、阿托伐醌、伯氨喹、青蒿素、两性霉素B、蒿甲醚、青蒿琥酯、双氢青蒿素、蒿乙醚、多西环素、克林霉素、卤泛群、二氯尼特、依氟鸟氨酸、呋喃唑酮、美拉胂醇、甲硝唑、硝呋米腙、硝唑沙奈、奥硝唑、巴龙霉素硫酸盐、喷他脒、乙胺嘧啶、喹匹拉明或替硝唑。
在某些实施方案中,所述生物活性部分是抗病毒药。在某些具体实施方案中,M在每次出现时独立地是抗病毒药,且靶向部分是对传染性疾病抗原特异性的抗体。本文中使用的抗病毒药包括衍生物。也就是说,抗病毒药已被修饰或衍生化,使得该药物可缀合或连接至另一分子(例如,以包括Q部分)。
用本公开内容的化合物可以治疗的病毒性疾病包括,例如HIV、Zika、埃博拉、乙型肝炎和丙型肝炎和流感。
在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是聚乙二醇化的干扰素-α-2a/2b、恩替卡韦、富马酸替诺福韦酯(tenofovir disoproxil fumarate)、阿那匹韦(asunaprevir)、利巴韦林(tribavirin)、beclabuvir、达卡他韦(daclatasvir)、达塞布韦(dasabuvir)、格佐匹韦(grazoprevir)、帕利瑞韦(paritaprevir)、西咪匹韦(simeprevir)、索非布韦或维帕他韦。
在其它实施方案中,所述抗病毒药治疗HIV。在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是核苷/核苷酸逆转录酶抑制剂诸如阿巴卡韦、拉米夫定、富马酸替诺福韦酯和齐多夫定;非核苷逆转录酶抑制剂诸如依法韦仑或奈韦拉平;蛋白酶抑制剂诸如阿扎那韦、达芦那韦、洛匹那韦和利托那韦;或,整合酶抑制剂诸如多替拉韦或拉替拉韦。
在另一个实施方案中,所述抗病毒药治疗流感。例如,在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是拉尼米韦、奥司他韦、培拉米韦、扎那米韦或巴洛沙韦玛波西酯(baloxavir marboxil)。
在某些实施方案中,所述抗病毒药治疗埃博拉。例如,在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是法匹拉韦、brincidofovir、galidesivir(BCX4430、免疫霉素-A)、JK-05或AVI-7537。
在某些实施方案中,所述生物活性部分是用于治疗免疫学或抗炎性病症的药物。在某些具体实施方案中,M在每次出现时独立地是免疫学药物,且靶向部分是对疾病/病症相关抗原特异性的抗体。本文中使用的免疫学药物包括衍生物。也就是说,免疫学药物已被修饰或衍生化,使得该药物可缀合或连接至另一分子(例如,以包括Q部分)。
在某些实施方案中,所述疾病或病症是哮喘、类风湿性关节炎、狼疮、多发性硬化、银屑病、克罗恩氏病、结肠炎或器官排斥疗法。因此,在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是皮质类固醇(例如,泼尼松)、甲氨蝶呤、吗替麦考酚酯或硫唑嘌呤。在某些实施方案中,结构(I)的化合物包含与治疗性抗体诸如Humira(即,阿达木单抗)的共价键。
在某些实施方案中,所述疾病或病症是银屑病。因此,在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是阿维A、泼尼松、类视色素、甲氨蝶呤、环孢菌素、硫鸟嘌呤、依那西普(Enbrel)、英夫利昔单抗(Remicade)、阿达木单抗(Humira)、乌司奴单抗(Stelara)、戈利木单抗(Simponi)、apremilast(Otezla)、苏金单抗(Cosentyx)或Ixekizumab(Taltz)。
在某些实施方案中,所述疾病或病症是克罗恩氏病或结肠炎。在某些更具体的实施方案中,对于M的至少一次出现或在M的每次出现时,M是柳氮磺吡啶、美沙拉秦、巴柳氮、奥沙拉秦、泼尼松、氢化可的松、巯基嘌呤、硫唑嘌呤、环孢菌素、甲氨蝶呤、布地奈德、环丙沙星、甲硝唑或硫唑嘌呤。在某些实施方案中,结构(I)的化合物包含与治疗性抗体诸如英夫利昔单抗(Remicade)、阿达木单抗(Humira)、维多珠单抗(Entyvio)、塞妥珠单抗、那他珠单抗(Tysabri)、ustenkinumab(Stelara)或戈利木单抗(Simponi)的共价键。
在某些实施方案中,所述疾病或病症是哮喘。在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是皮质类固醇、长效β激动剂(例如,沙美特罗、白三烯)、奥马佐单抗、扎鲁司特或氟替卡松。
在某些实施方案中,所述疾病或病症是多发性硬化。在某些实施方案中,对于M的至少一次出现或在M的每次出现时,M是羟氯喹、甲氨蝶呤、硫唑嘌呤、麦考酚酯、泼尼松、甲泼尼龙、贝利木单抗或利妥昔单抗(Rituxan)。
在某些实施方案中,所述疾病或病症是器官排斥。在更具体的实施方案中,对于M的至少一次出现或在M的每次出现时,M是泼尼松龙、氢化可的松、西罗莫司、依维莫司、环孢菌素、他克莫司、麦考酚酯或硫唑嘌呤、巴利昔单抗、达克珠单抗或利妥昔单抗。
在某些实施方案中,所述疾病或病症是狼疮。在更具体的实施方案中,对于M的至少一次出现或在M的每次出现时,M是羟氯喹、甲氨蝶呤、硫唑嘌呤、麦考酚酯、泼尼松、甲泼尼龙、贝利木单抗或利妥昔单抗(Rituxan)。
在某些实施方案中,所述疾病或病症是类风湿性关节炎。在更具体的实施方案中,对于M的至少一次出现或在M的每次出现时,M是泼尼松、甲氨蝶呤、吗替麦考酚酯、来氟米特、羟氯喹、柳氮磺吡啶、硫唑嘌呤、阿巴他塞(Orencia)、阿达木单抗(Humira)、阿那白滞素(Kineret)、巴瑞替尼(Olumiant)、塞妥珠单抗(Cimzia)、依那西普(Enbrel)、戈利木单抗(Simponi)、英夫利昔单抗(Remicade)、利妥昔单抗(Rituxan)、sarilumab(Kevzara)、托珠单抗(Actemra)或托法替尼(Xeljanz)。
在某些实施方案中,要通过施用结构(I)的化合物治疗的疾病或病症是:骨髓的消融;急性坐骨疼痛;变应性哮喘;ALS和多发性硬化;阿尔茨海默氏病;淀粉样变性;血管性水肿;血管生成;血管肉瘤;强直性脊柱炎;炭疽(预防和治疗);关节炎;哮喘;特应性疾病;非典型溶血性尿毒症综合征;自身免疫性肝炎;炭疽芽孢杆菌孢子;B-细胞恶性肿瘤;心血管疾病;脉络膜和视网膜新生血管形成;慢性哮喘;慢性乙型肝炎;狗中特应性皮炎的临床体征;难辨梭状芽胞杆菌结肠炎;冷凝集素疾病;克罗恩氏病;冷吡啉-相关的周期性综合征;巨细胞病毒感染;糖尿病;糖尿病性肾病和动静脉移植物通畅(arteriovenous graftpatency);杜兴肌营养不良;血脂异常;埃博拉病毒;湿疹;纤维化;继发于年龄相关性黄斑变性的地图样萎缩;胶质母细胞瘤;移植物抗宿主病;血友病A;失血性休克;心脏病发作,中风,创伤性休克;恶性血液病;新生儿溶血性疾病;乙型肝炎;HIV感染;高胆固醇血症;免疫学上介导的炎症性障碍;传染性疾病/甲型流感;炎症;气道、皮肤和胃肠道的炎症;炎性肠病;侵袭性的念珠菌属感染;青少年特发性关节炎;狼疮肾炎;黄斑变性(湿型);医学上照顾的下呼吸疾病(medically attended lower respiratory disease);黑素瘤;偏头痛;多发性硬化;由矫形外科废弃(orthopedic disuse)和肌肉衰减症引起的肌肉萎缩;肌萎缩障碍;肌营养不良;肌生成抑制蛋白抑制剂;新生血管年龄相关性黄斑变性;视神经脊髓炎;医院获得性肺炎;眼血管疾病;肿瘤学/免疫适应症;器官移植排斥;骨关节炎;骨髓炎(成像);骨质疏松症;骨质疏松症,骨转移等;帕金森病;阵发性睡眠性血红蛋白尿症;经皮冠状动脉介入;斑块状银屑病;血小板聚集抑制剂;狂犬病的暴露后预防;器官移植排斥的预防;原发性全身性淀粉样变性;进行性核上性麻痹;铜绿假单胞菌感染;银屑病;银屑病关节炎;狂犬病(预防);中风后运动功能的恢复;复发性多形性胶质母细胞瘤;青光眼外科手术以后瘢痕形成的减少;心脏外科手术的副作用的减少;呼吸道合胞病毒;达比加群的抗凝血作用的逆转;Rh疾病;风湿性疾病;类风湿性关节炎;脓毒症;严重变应性障碍;严重哮喘和慢性自发性荨麻疹;镰状细胞病;SLE,皮肌炎,多肌炎;实体恶性肿瘤;金黄色葡萄球菌感染;系统性红斑狼疮;全身性硬皮病;血栓栓塞(诊断);血栓性血小板减少性紫癜,血栓形成;甲状腺性眼疾病;TNF;溃疡性结肠炎;葡萄膜炎,类风湿性关节炎银屑病;病毒感染;湿性年龄相关性黄斑变性;白血细胞疾病;X连锁低磷酸血症或其组合。
可以与本公开内容的化合物组合的其它治疗剂可见于Goodman和Gilman的“ThePharmacological Basis of Therapeutics”(由Hardman、Limbird和Gilman编的第十版)或Physician’s Desk Reference,它们二者通过引用整体并入本文。
取决于所治疗的病症,本文所述的化合物可以与本文公开的药剂或其它合适的药剂组合使用。因此,在某些实施方案中,本公开内容的一种或多种化合物将与如上所述的其它药剂共同施用。当用于组合疗法中时,本文所述的化合物与第二药剂同时或分开施用。这种组合施用可以包括在相同剂型中同时施用两种药剂、在分开的剂型中同时施用和分开施用。也就是说,本文所述的化合物和上述任何药剂可以一起配制在相同剂型中并同时施用。可替换地,本公开内容的化合物和上述任何药剂可以同时施用,其中两种药剂存在于分开的制剂中。在另一个替代方案中,本公开内容的化合物可以紧随上述任何药剂施用,或反之亦然。在分开施用方案的某些实施方案中,本公开内容的化合物和上述任何药剂相隔几分钟、或相隔几小时、或相隔几天施用。
在某些实施方案中,所述方法进一步包括施用选自以下的额外治疗剂:抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂、激酶抑制剂、蒽环类抗生素和EGFR抑制剂、烷化剂和它们的组合。
在某些更具体的实施方案中,所述方法进一步包括施用选自以下的额外治疗剂:抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂、激酶抑制剂、蒽环类抗生素和EGFR抑制剂、烷化剂和它们的组合。
在某些实施方案中,所述额外治疗剂包含澳瑞他汀F、单甲基澳瑞他汀F、单甲基澳瑞他汀E、paciltaxol、SN-38、卡奇霉素、安曲霉素、abbeymycin、chicamycin、DC-81、mazethramycin、新茴霉素A、新茴霉素B、porothramycin prothracarcin、西班米星、西伯里亚霉素、托马霉素、DM1细胞毒、emtansine、伊立替康、喜树碱、托泊替康、silatecan、科西特康、依沙替康、勒托替康、吉马替康、贝洛替康和卢比替康。
下面提供的实施例和制备进一步说明和举例说明本公开内容的化合物和制备此类化合物的方法。应当理解,本公开内容的范围不以任何方式受限于以下实施例和制备的范围。在以下实施例中以及贯穿整个说明书和权利要求书,除非另外指出,否则具有单个立构中心的分子和部分作为外消旋混合物存在。除非另外指出,否则具有两个或多个立构中心的那些分子和部分作为非对映异构体的外消旋混合物存在。通过本领域技术人员已知的方法,可以得到单一对映异构体/非对映异构体。
制备方法
本文公开的实施方案提供了许多优点,包括控制与聚合物偶联的生物活性部分或荧光染料部分和任何后续靶向部分的数量的能力。还可以选择聚合物主链的组成以提供合乎需要的溶解度特性,例如,通过控制带电部分的引入(例如数目、频率、间距等)。除了由主链的组成提供的特性之外,可以选择侧链以提供用于调节本文公开的化合物的溶解度的来源。
本文公开的实施方案还提供了可以有利地包括多种治疗剂的化合物,例如,用于互补或协同治疗策略。此外,本公开内容的实施方案提供了可用于同时靶向、治疗和检测的治疗剂、靶向部分和染料部分(例如,荧光团)的组合。将聚合物-药物构建体与靶向试剂(诸如抗体、抗体片段、蛋白或其它临床上感兴趣的试剂)偶联的容易性为多种感兴趣的应用(例如,表面化学、测定开发等)提供了实用性。
某些实施方案的化合物还提供了其它合乎需要的特性,包括增强的渗透性和保留效果。除了提供必要的溶解度特性之外,可以调整本发明化合物的实施方案的化学特征以调节化合物的渗透患病细胞/组织并保留在其内部的能力。这些特征允许通过增加渗透和通过增强保留来增加效力来有效递送生物活性剂。
因此,应当理解,如上所述的结构(I)的化合物的任何实施方案,以及如上所述本文关于结构(I)的化合物中的R1、R2、R3、R4、R5、La、Lb、L1、L2、L3、M、m和/或n变量所述的任何具体选择,可以独立地与结构(I)的化合物的其它实施方案和/或变量组合以形成上文未具体阐述的本公开内容的实施方案。另外,如果在一个特定实施方案和/或权利要求中关于任何特定R1、R2、R3、R4、R5、La、Lb、L1、L2、L3、M、m和/或n变量列出了选择列表,则应当理解,每个单独的选择都可以从特定实施方案和/或权利要求中删除,并且剩余的选择列表将被认为在本公开内容的范围内。
应当理解,在本说明书中,所描述的式的取代基和/或变量的组合只有在这样的贡献导致稳定的化合物时才是允许的。
本领域技术人员还将理解,在本文所述的方法中,中间体化合物的官能团可能需要通过合适的保护基保护。这样的官能团包括羟基、氨基、巯基和羧酸。羟基的合适保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如,叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。氨基、脒基和胍基的合适保护基包括叔丁氧基羰基、苄氧基羰基等。巯基的合适保护基包括-C(O)-R”(其中R”是烷基、芳基或芳基烷基)、对甲氧基苄基、三苯甲基等。羧酸的合适保护基包括烷基、芳基或芳基烷基酯。根据本领域技术人员已知的和如本文所述的标准技术,可以添加或除去保护基。保护基的应用详细描述于Green,T.W.和P.G.M.Wutz,Protective Groups in Organic Synthesis(1999),第3版,Wiley。本领域技术人员会理解,保护基也可以是聚合物树脂诸如Wang树脂、Rink树脂或2-氯三苯甲基-氯化物树脂。
此外,以游离碱或酸形式存在的本公开内容的所有化合物可以通过本领域技术人员已知的方法用合适的无机或有机碱或酸处理而转化为其盐。本公开内容的化合物的盐可以通过标准技术转化为其游离碱或酸形式。
以下反应方案说明了制备本公开内容的化合物的示例性方法。应当理解,本领域技术人员能够通过类似方法或通过结合本领域技术人员已知的其它方法来制备这些化合物。还理解,本领域技术人员将能够以如下所述的类似方式,通过使用适当的起始组分并根据需要修改合成参数来制备以下未具体说明的结构(I)的其它化合物。一般而言,起始组分可以从诸如以下来源获得:Sigma Aldrich、Lancaster Synthesis,Inc.、Maybridge、Matrix Scientific、TCI和Fluorochem USA等,或根据本领域技术人员已知的来源合成(参见例如,Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,第5版(Wiley,2000年12月)),或如本公开内容中所述制备。
反应方案I
反应方案I解释了用于制备可用于制备结构(I)的化合物的中间体的示例性方法,其中R1、L1、L2和M如上面所定义,R2和R3如上面所定义或是其受保护变体且La是任选的连接基。参考反应方案1,结构a的化合物可以购买或通过本领域普通技术人员众所周知的方法制备。在本领域已知的Suzuki偶联条件下a与M-X(其中X是卤素诸如溴)的反应产生结构b的化合物。结构b的化合物可以用于制备如下所述的结构(I)的化合物。
反应方案II
反应方案II解释了用于制备可用于制备结构(I)的化合物的中间体的替代方法。参考反应方案II,其中R1、La、Lb、L1、L2和M如上面所定义,且R2和R3如上面所定义,或是其受保护变体,使结构c的化合物(其可以购买或通过众所周知的技术制备)与M-G'反应以产生结构d的化合物。在这里,G和G'代表具有互补反应性的官能团(即,反应以形成共价键的官能团)。G’可以是M的侧基或是M的结构主链的一部分。La'是选择的中间体,使得上述反应将La'转化成La。G和G'可以是本文描述的任何数目的官能团,诸如分别是炔烃和叠氮化物,分别是胺和活化酯,或分别是胺和异硫氰酸酯,等。
通过在众所周知的自动化DNA合成条件下与具有以下结构(e)的亚磷酰胺化合物的反应,可以从结构b或d之一制备结构(I)的化合物:
其中每个L独立地是任选的连接基。
DNA合成方法是本领域众所周知的。简而言之,将两个醇基,例如上面中间体b或d中的R2和R3,分别用二甲氧基三苯甲基(DMT)基团和2-氰基乙基-N,N-二异丙基氨基亚磷酰胺基官能化。将亚磷酰胺基偶联至醇基,通常在有活化剂诸如四唑存在下,随后用碘氧化磷原子。可以用酸(例如,氯乙酸)除去二甲氧基三苯甲基以暴露游离醇,其可以与亚磷酰胺基反应。通过用氨水处理,可以在寡聚化以后除去2-氰基乙基。
在寡聚化方法中使用的亚磷酰胺的制备也是本领域众所周知的。例如,通过与DMT-Cl反应,可以将伯醇(例如,R3)保护为DMT基团。然后通过与适当的试剂诸如2-氰基乙基N,N-二异丙基氯亚磷酰胺反应,可以将仲醇(例如,R2)官能化为亚磷酰胺。用于制备亚磷酰胺和它们的寡聚化的方法是本领域众所周知的。
根据上述的众所周知的亚磷酰胺化学,通过中间体b或d和e的寡聚化制备结构(I)的化合物。通过将亚磷酰胺偶联重复期望的次数,将期望数目的n个重复单元掺入分子中。
在某些实施方案中,从下述亚磷酰胺(e)中的一种或多种制备结构(I)的化合物:
在示例性实施方案中,所述G部分可以选自本文描述的任何Q部分,包括在表1中提供的那些具体例子。在某些实施方案中,G在每次出现时独立地包含适合用于反应的部分,所述反应包括:铜催化的叠氮化物和炔烃的反应以形成三唑(Huisgen 1,3-偶极环加成),二烯和亲二烯体的反应(Diels-Alder),应变促进的炔烃-硝酮环加成,应变的烯烃与叠氮化物、四嗪或四唑的反应,烯烃和叠氮化物[3+2]环加成,烯烃和四嗪逆需求Diels-Alder,烯烃和四唑光反应和各种置换反应,诸如通过亲电子原子上的亲核攻击对离去基团的置换。
在某些实施方案中,G在每次出现时独立地是包含醛、肟、腙、炔烃、胺、叠氮化物、酰基叠氮化物、酰基卤化物、腈、硝酮、巯基、二硫化物、磺酰卤、异硫氰酸酯、亚氨酸酯、活化酯、酮、α,β-不饱和羰基、烯烃、马来酰亚胺、α-卤代酰胺、环氧化物、氮丙啶、四嗪、四唑、膦、生物素或硫杂丙环官能团的部分。
在其它实施方案中,G在每次出现时独立地包含炔烃或叠氮基。在其它实施方案中,G在每次出现时独立地包含氨基、异硫氰酸酯或活化酯基。在不同的实施方案中,G在每次出现时独立地包含反应基团,其能够在与互补反应基团反应后形成包含烯烃、酯、酰胺、硫代酸酯、二硫化物、碳环、杂环或杂芳基基团的官能团。例如,在一些实施方案中,杂芳基是三唑基。
在某些实施方案中,如下制备结构(I)的化合物:根据上述的亚磷酰胺化学进行中间体b或d和e的寡聚化,使得可以引入多个不同的连接基团(例如,“La基团”),其具有如本文中所述的多种不同的释放机制(例如通过酯酶、组织蛋白酶B、体内水解等)或在生理条件下是不可裂解的。此外,这些化合物可以被修饰成包括一个或多个相同或不同的M部分。因此,可以定制或“程序化”结构(I)的化合物,使得M部分从分子的其余部分“释放”或分离,例如,以在特定生理条件下诱导药理学作用。因而,作为可以全身施用且具有微小毒副作用的靶向治疗剂,结构(I)的化合物是特别有用的。
通过将亚磷酰胺偶联重复期望的次数和通过选择适当的亚磷酰胺单体化合物,例如,上面提供的结构(e)的化合物,完成期望数目的重复单元和期望的连接基(“La基团”)向分子中的引入。
下面的结构(f)的化合物代表了具有多种不同La基团和M基团的结构(I)的化合物的一个代表性非限制性例子:
其中Ma-Md各自代表不同的M部分且连接基包含官能团(四唑、肟、二硫化物和酯;分别从左至右),所述官能团具有不同的裂解方法(肟-酸性水解;二硫化物–通过TCEP(体外)或谷胱甘肽(体内)还原;酯-酯酶或碱水解)或是不可裂解的(三唑)。
结构(I)的化合物可以包括多个生物活性部分(M基团),例如,可以基于互补或协同治疗策略来选择M基团。另外,本公开内容的实施方案提供了可以用于同时靶向、治疗和检测的治疗剂、靶向部分和染料部分(例如,荧光团)的组合。将聚合物-药物构建体与靶向试剂(诸如抗体、抗体片段、蛋白、糖部分、受体、受体配体、朊病毒、适配体、酶或其它临床上感兴趣的试剂)偶联的容易性为多种感兴趣的应用(例如,表面化学、测定开发等)提供了实用性。用于制备结构(I)和/或(II)的化合物的方法以及使用自动化DNA合成技术用于化合物制备的方法描述于PCT公开号WO 2015/027176、WO 2016/138461和WO 2016/183185,它们都通过引用将其整体并入本文。
提供以下实施例是为了例证而非限制的目的。
实施例
一般方法
使用MassLynx 4.1采集软件在Waters/Micromass Quattro micro MS/MS系统(以仅MS模式)上进行质谱分析。在染料上为LC/MS使用的流动相是100mM 1,1,1,3,3,3-六氟-2-丙醇(HFIP),8.6mM三乙胺(TEA),pH 8.亚磷酰胺,并且还使用Waters Acquity UHPLC系统分析前体分子,其具有保持在45℃的2.1mm×50mm Acquity BEH-C18柱,采用乙腈/水流动相梯度。在Waters/Micromass Quattro micro MS/MS系统(以仅MS模式)上使用鎓阳离子输注增强的电离(tropylium cation infusion enhanced ionization)获得单体中间体的分子量。在Cary Eclipse波谱光度计上记录激发和发射特性实验。
除非另有说明,否则所有反应均在氮气气氛下在烘箱干燥的玻璃器皿中进行。商购可得的DNA合成试剂购自Glen Research(Sterling,VA)。无水吡啶、甲苯、二氯甲烷、二异丙基乙基胺、三乙胺、乙酸、吡啶和THF购自Aldrich。所有其它化学品均从Aldrich或TCI购买,并不经额外纯化按原样使用。
实施例1
NHS活化
使用标准的偶联条件合成NHS活化的M部分。也就是说,将含有羧基的M部分溶解在二氯甲烷中并向混合物中加入N,N'-二环己基碳二亚胺(DCC)和N-羟基琥珀酰亚胺(NHS)。然后将终产物在必要时纯化并用于下一个合成步骤。可替换地,可以将M部分修饰成包括羧基基团,例如,使用下面实施例3中所示的合成策略。
实施例2
单体合成
使NHS活化的M与胺二醇反应,随后加入三苯甲基保护基以得到三苯甲基保护的中间体。然后使三苯甲基保护的中间体与3-((氯(二异丙基氨基)磷烷基(phosphaneyl))氧基)丙腈反应以得到最终的亚磷酰胺产物。然后将最终的亚磷酰胺产物用于自动化DNA合成以将包含M的部分(例如,作为代表性的生物活性部分或染料部分)掺入到结构(I)的化合物的实施方案中。
实施例3
M-PEG-叠氮化物的合成
根据上面显示的反应顺序合成M-PEG-叠氮化物。使2-(2-(2-叠氮基乙氧基)乙氧基)乙烷-1-胺与二氢呋喃-2,5-二酮反应以得到中间体4-((2-(2-(2-叠氮基乙氧基)乙氧基)乙基)氨基)-4-氧代丁酸。使该中间体与全氟苯酚反应以得到4-((2-(2-(2-叠氮基乙氧基)乙氧基)乙基)氨基)-4-氧代丁酸酯,将其偶联至M胺以得到期望的产物,M-PEG-叠氮化物。通过LC-MS证实期望的产物的存在。
实施例4
聚合后修饰1
如在以上反应顺序中所示,将结构(II)的一种示例性化合物(其具有3个侧基胺官能团)与NHS活化的M部分偶联(注-为了清楚起见,没有画出结构(II)的化合物的所有结构特征)。使用硼酸盐缓冲的H2O/DMSO混合物(1:3)与氯化镁进行反应。反应成功地将M部分添加至3个胺官能团中的每一个以得到结构(I)的代表性化合物,其通过LC-MS进行鉴定。
实施例5
聚合后修饰2
将具有3个侧基炔基官能团的结构(II)的一种示例性化合物偶联至M-PEG-叠氮化物。反应条件包括CuSO4、三(3-羟丙基三唑基甲基)胺(THPTA)和抗坏血酸钠。在pH 7.6的含有60%DMS的磷酸盐缓冲的水性溶剂中进行反应。在室温进行反应并通过LC-MS证实期望的产物的存在。La代表亚杂烷基连接基。
实施例6
活化和抗体缀合
使用标准的还原条件(即,TCEP)除去结构(I)的代表性化合物的硫醇保护基,并将去保护的硫醇用1,1'-(乙烷-1,2-二基)双(1H-吡咯-2,5-二酮(双马来酰亚胺基乙烷或“BMOE”)官能化以得到6-2。平行地,用TCEP处理UCHT-1抗体以还原二硫键。以5:1的聚合物:抗体的摩尔比,使还原的抗体与6-2(1.5g)反应。
实施例7
VAL-CIT-PABC(VCP)亚磷酰胺单体合成
使4-硝基苯酚活化的Val-Cit-PABC碳酸酯与3-(3-氨基丙氧基)丙烷-1,2-二醇反应(步骤1),随后加入三苯甲基保护基以得到三苯甲基保护的中间体(步骤2)。然后使三苯甲基保护的中间体与3-((氯(二异丙基氨基)磷烷基)氧基)丙腈反应以得到最终的亚磷酰胺产物。然后可以将最终的亚磷酰胺产物用在合成中以得到结构(I)的化合物。
实施例8
吡啶基二硫化物亚磷酰胺单体合成
使N-羟基琥珀酰亚胺活化的吡啶基二硫化物与3-(3-氨基丙氧基)丙烷-1,2-二醇反应,随后加入三苯甲基保护基以得到三苯甲基保护的中间体。然后使三苯甲基保护的中间体与3-((氯(二异丙基氨基)磷烷基)氧基)丙腈反应以得到最终的亚磷酰胺产物。然后可以将最终的亚磷酰胺产物用在合成中以得到结构(I)的化合物。
实施例9
乙基氨基二硫化物亚磷酰胺单体合成
将来自实施例8的三苯甲基保护的吡啶基二硫化物与半胱胺反应,随后加入Fmoc保护基以得到受保护的乙基氨基二硫化物中间体。该中间体然后与3-((氯(二异丙基氨基)磷烷基)氧基)丙腈反应以得到最终的亚磷酰胺产物。然后可以将最终的亚磷酰胺产物用在合成中以得到结构(I)的化合物。
实施例10
N-羟基邻苯二甲酰亚胺亚磷酰胺单体合成
在Mitsunobu条件下使N-羟基邻苯二甲酰亚胺与(2,2-二甲基-1,3-二氧杂环戊烷-4-基)甲醇反应,随后在酸性条件下去保护以得到二醇中间体。然后使二醇中间体与DMTr-Cl和吡啶反应以将伯醇保护为三苯甲基衍生物。随后与3-((氯(二异丙基氨基)磷烷基)氧基)丙腈的反应得到最终的亚磷酰胺产物。然后可以将最终的亚磷酰胺产物用在合成中以得到结构(I)的化合物。
实施例11
结构(II)的代表性化合物的合成(合成1)
使在实施例7中描述的Val-Cit-PABC亚磷酰胺单体在适当的条件下反应以得到Fmoc保护的聚合物,其经历随后的碱促进的去保护步骤(例如,与哌啶在DMF中)以提供结构(II)的化合物。如在例如上面实施例4中所述,可以将胺官能团偶联至M部分(为了清楚起见,没有画出结构(II)的化合物的所有结构特征)。
实施例12
结构(II)的代表性化合物的合成(合成2)
在适当的条件下使在实施例8中描述的吡啶基二硫化物亚磷酰胺单体反应以得到吡啶基二硫化物单体。将该聚合物还原(例如用TCEP)会裂解二硫化物,剩下巯基(-SH),其可以用于M部分的后合成引入,这通过例如与另一个巯基或马来酰亚胺基团的反应实现(为了清楚起见,没有画出结构(II)的化合物的所有结构特征)。
实施例13
结构(II)的代表性化合物的合成(合成3)
在适当的条件下使在实施例9中描述的乙基氨基二硫化物亚磷酰胺单体反应以得到N-Fmoc保护的聚合物,其经历随后的碱促进的去保护步骤(例如,与哌啶在DMF中),以提供具有乙基胺官能化的二硫化物的本发明的化合物。胺官能团可以偶联至M部分,如例如在上面实施例4中所述(为了清楚起见,没有画出结构(II)的化合物的所有结构特征)。
实施例14
结构(II)的代表性化合物的合成(合成4)
在适当的条件下使在实施例10中描述的N-羟基邻苯二甲酰亚胺亚磷酰胺单体反应以得到邻苯二甲酰亚胺聚合物衍生物,使其与肼反应以形成烷氧基胺官能团。使烷氧基胺与互补基团(例如醛或酮)反应,以形成与M部分的肟连接(为了清楚起见,没有画出结构(II)的化合物的所有结构特征)。
实施例15
结构(I)的聚合物的示例性合成
可以应用DNA合成方法来构建结构(I)的化合物。单体(例如,亚磷酰胺单体)可以商业购买(例如,从ChemGenes Corporation,Wilmington Mass.)或使用本文描述的方法合成(参见,例如,实施例2和7-10)。M部分的引入如下完成:在DNA合成步骤中,通过包括M部分作为单体的部分,或在聚合后修饰步骤中(例如,如在实施例4-6和11-14中所述)。下面显示了一个示例性的DNA合成方案。
代表性DNA合成循环
通常通过除去保护基(例如二甲氧基三苯甲基,DMTr)以暴露游离的-OH(羟基)基团来开始寡聚化(步骤1,去三苯甲基化)。在随后的偶联步骤中,引入亚磷酰胺单体,其与游离的OH基团反应,从而形成与磷的新共价键,伴随二异丙基胺基团的丢失(步骤2,偶联)。将得到的亚磷酸三酯氧化(例如用I2和吡啶)成更稳定的磷酸酯(步骤3,氧化),且加帽(cap)步骤使任何剩余的游离OH基团不具有反应性(步骤4,加帽)。新产物磷酸酯寡聚体含有DMTr保护的OH基团,其可以去保护以重新启动合成循环,使得另一个亚磷酰胺单体可以附加至寡聚体。
通过选择亚磷酰胺单体,在步骤2发生定制化。选择L、M和G的性质,使得合成期望的结构(I)的化合物。M和G可以任选地不存在以在M和/或G部分之间掺入期望的间隔。本领域普通技术人员可以选择多种单体类型以得到含有多个治疗剂和/或其它部分(例如,染料)且在连接基基团中同时存在差异的本发明的化合物。
在本说明书中提及的所有美国专利、美国专利申请公开、美国专利申请、外国专利、外国专利申请和非专利公开,包括2019年4月11日提交的美国临时专利申请号62/832,726和2019年7月22日提交的美国临时专利申请号62/877,151,在与本说明书不矛盾的程度上以其整体通过引用并入本文。
从前述内容应当理解,虽然出于例证的目的已经在本文中描述了本公开内容的具体实施方案,但是在不背离本公开内容的精神和范围的情况下可以做出各种修改。因此,本公开内容不受所附权利要求限制。
Claims (91)
1.具有以下结构(I)的化合物或其立体异构体、药学上可接受的盐或互变异构体:
其中:
M在每次出现时独立地是生物活性部分或其片段、生物活性部分的前药或其片段、荧光染料、成像剂或放射性同位素结合位点,条件是M的至少一次出现不是荧光染料;
La在每次出现时独立地是任选的生理学上可裂解的连接基且Lb在每次出现时独立地是任选的生理学上不可裂解的连接基,前提条件是,La和Lb一起的至少一次出现包含超过4个碳;
L1和L2在每次出现时独立地是任选的亚烷基、亚烯基、亚炔基、亚杂烷基、亚杂烯基、亚杂炔基或杂原子连接基;
L3在每次出现时独立地是亚烷基、亚烯基、亚炔基、亚杂烷基、亚杂烯基或亚杂炔基连接基;
R1在每次出现时独立地是H、烷基或烷氧基;
R2和R3各自独立地是H、OH、SH、烷基、烷氧基、烷基醚、杂烷基、-OP(=Ra)(Rb)Rc、Q或其保护形式或L';
R4在每次出现时独立地是O-、S-、OZ、SZ或N(R6)2,其中Z是阳离子且每个R6独立地是H或烷基;
R5在每次出现时独立地是氧代、硫代或不存在;
Ra是O或S;
Rb是OH、SH、O-、S-、ORd或SRd;
Rc是OH、SH、O-、S-、ORd、OL'、SRd、烷基、烷氧基、杂烷基、杂烷氧基、烷基醚、烷氧基烷基醚、磷酸酯、硫代磷酸酯、磷酰烷基、硫代磷酰烷基、磷酰烷基醚或硫代磷酰烷基醚;
Rd是抗衡离子;
Q在每次出现时独立地是包含反应基团的部分或其保护形式,其能够与靶向部分上的互补反应基团Q′形成共价键;
L'在每次出现时独立地是包含与Q的共价键的连接基、靶向部分、包含与靶向部分的共价键的连接基、包含与固体载体的共价键的连接基、包含与固体载体残基的共价键的连接基、包含与核苷的共价键的连接基或包含与结构(I)的另一种化合物的共价键的连接基;
m在每次出现时独立地是0或更大的整数;且
n是1或更大的整数。
2.具有以下结构(I)的化合物或其立体异构体、药学上可接受的盐或互变异构体:
其中:
M在每次出现时独立地是生物活性部分或其片段、生物活性部分的前药或其片段、荧光染料、成像剂或放射性同位素结合位点,条件是M的至少一次出现不是荧光染料;
La在每次出现时独立地是任选的生理学上可裂解的连接基且Lb在每次出现时独立地是任选的生理学上不可裂解的连接基,前提条件是,La和Lb一起的至少一次出现包含碳、氧和氮;
L1和L2在每次出现时独立地是任选的亚烷基、亚烯基、亚炔基、亚杂烷基、亚杂烯基、亚杂炔基或杂原子连接基;
L3在每次出现时独立地是亚烷基、亚烯基、亚炔基或亚杂炔基连接基;
R1在每次出现时独立地是H、烷基或烷氧基;
R2和R3各自独立地是H、OH、SH、烷基、烷氧基、烷基醚、杂烷基、-OP(=Ra)(Rb)Rc、Q或其保护形式或L';
R4在每次出现时独立地是O-、S-、OZ、SZ或N(R6)2,其中Z是阳离子且每个R6独立地是H或烷基;
R5在每次出现时独立地是氧代、硫代或不存在;
Ra是O或S;
Rb是OH、SH、O-、S-、ORd或SRd;
Rc是OH、SH、O-、S-、ORd、OL'、SRd、烷基、烷氧基、杂烷基、杂烷氧基、烷基醚、烷氧基烷基醚、磷酸酯、硫代磷酸酯、磷酰烷基、硫代磷酰烷基、磷酰烷基醚或硫代磷酰烷基醚;
Rd是抗衡离子;
Q在每次出现时独立地是包含反应基团的部分或其保护形式,其能够与靶向部分上的互补反应基团Q′形成共价键;
L'在每次出现时独立地是包含与Q的共价键的连接基、靶向部分、包含与靶向部分的共价键的连接基、包含与固体载体的共价键的连接基、包含与固体载体残基的共价键的连接基、包含与核苷的共价键的连接基或包含与结构(I)的另一种化合物的共价键的连接基;
m在每次出现时独立地是0或更大的整数;且
n是1或更大的整数。
4.根据权利要求3所述的化合物,其中
x1和x2各自独立地是0-3的整数;且
x3和x4在每次出现时独立地是0-3的整数。
5.根据权利要求3或4中的任一项所述的化合物,其中x1是1或0且x2是1或0。
6.根据权利要求3-5中的任一项所述的化合物,其中x1是0且x2是1。
7.根据权利要求3-5中的任一项所述的化合物,其中x1是1且x2是0。
8.根据权利要求1-7中的任一项所述的化合物,其中对于m的至少一次出现,L3是C1-C6亚烷基。
9.根据权利要求1-8中的任一项所述的化合物,其中对于m的每次出现,L3是C1-C6亚烷基。
11.根据权利要求10所述的化合物,其中y的至少一次出现是2。
12.根据权利要求10或11中的任一项所述的化合物,其中y在每次出现时是2。
13.根据权利要求10-12中的任一项所述的化合物,其中x1、x2、x3或x4的至少一次出现是1且y在每次出现时是2。
14.根据权利要求1-13中的任一项所述的化合物,其中La的至少一次出现存在。
15.根据权利要求1-14中的任一项所述的化合物,其中La的至少一次出现包含酰胺键、酯键、磷酸二酯键、二硫键、双键、三键、醚键、腙、氨基酸序列、酮、二醇、氰基、硝基或其组合。
16.根据权利要求15所述的化合物,其中La包含被分选酶识别的氨基酸序列。
17.根据权利要求16所述的化合物,其中所述氨基酸序列是Leu-Pro-X-Thr-Gly,其中X是任何氨基酸残基。
18.根据权利要求1-17中的任一项所述的化合物,其中La的至少一次出现是包含3个或更多个碳的连接基。
19.根据权利要求1-18中的任一项所述的化合物,其中La的至少一次出现是包含至少一个氮的连接基。
21.根据权利要求1-20中的任一项所述的化合物,其中La的每次出现包含酰胺键、酯键、磷酸二酯键、二硫键、双键、三键、醚键、腙、氨基酸序列、酮、二醇、氰基、硝基或其组合。
22.根据权利要求1-21中的任一项所述的化合物,其中La的每次出现是包含3个或更多个碳的连接基。
23.根据权利要求1-22中的任一项所述的化合物,其中La的每次出现是包含至少一个氮的连接基。
26.根据权利要求1-25中的任一项所述的化合物,其中La的至少一次出现包含一个或多个氨基酸残基。
27.根据权利要求26所述的化合物,其中La的至少一次出现包含缬氨酸。
30.根据权利要求1-29中的任一项所述的化合物,其中La的每次出现包含一个或多个氨基酸残基。
31.根据权利要求30所述的化合物,其中La的每次出现包含缬氨酸。
34.根据权利要求1-33中的任一项所述的化合物,其中Lb的至少一次出现存在。
35.根据权利要求1-34中的任一项所述的化合物,其中Lb的至少一次出现包含硫醚键。
38.根据权利要求1-37中的任一项所述的化合物,其中Lb在每次出现时存在。
39.根据权利要求1-38中的任一项所述的化合物,其中Lb的每次出现包含硫醚键。
42.根据权利要求1-41中的任一项所述的化合物,其中R4在每次出现时独立地是OH、O-或ORd。
43.根据权利要求1-42中的任一项所述的化合物,其中R5在每次出现时是氧代。
44.根据权利要求1-43中的任一项所述的化合物,其中R1在每次出现时是H。
45.根据权利要求1-44中的任一项所述的化合物,其中R2和R3各自独立地是H、OH或-OP(=Ra)(Rb)Rc。
46.根据权利要求1-44中的任一项所述的化合物,其中R2是H且R3是-OP(=Ra)(Rb)Rc、Q或包含与Q的共价键的连接基。
47.根据权利要求1-46中的任一项所述的化合物,其中R3是-OP(=Ra)(Rb)Rc或L'。
48.根据权利要求47所述的化合物,其中Rc是OL'。
49.根据权利要求47或48所述的化合物,其中L'是靶向部分或与靶向部分的连接基。
50.根据权利要求49所述的化合物,其中L'是与靶向部分的连接基,所述连接基包含环氧烷烃或磷酸二酯部分或其组合。
52.根据权利要求51所述的化合物,其中n”是6。
53.根据权利要求1-52中的任一项所述的化合物,其中所述靶向部分是抗体、细胞表面受体激动剂或细胞表面受体拮抗剂。
54.根据权利要求53所述的化合物,其中所述抗体、细胞表面受体激动剂或细胞表面受体拮抗剂是表皮生长因子受体(EGFR)抑制剂、肝细胞生长因子受体(HGFR)抑制剂、胰岛素-样生长因子受体(IGFR)抑制剂、叶酸或MET抑制剂。
55.根据权利要求53所述的化合物,其中所述靶向部分是单克隆抗体。
56.根据权利要求55所述的化合物,其中所述单克隆抗体是阿昔单抗、阿达木单抗、阿仑珠单抗、阿利西尤单抗、阿维巴坦、巴利昔单抗、贝那利珠单抗、贝洛托舒单抗、兰妥莫单抗、布罗达单抗、布洛舒单抗、卡那奴单抗、卡拉西单抗、培化舍珠单抗、达克珠单抗、地舒单抗、度匹鲁单抗、依库珠单抗、艾美赛珠单抗、厄瑞努单抗、依洛尤单抗、瑞玛奈珠单抗、伽奈珠单抗、戈利木单抗、古塞库单抗、伊巴珠单抗、艾达赛珠单抗、英夫利昔单抗、Itolizumab、Ixekizumab、拉那利尤单抗、洛吉维单抗、美泊珠单抗、那他珠单抗、奥托萨昔单抗、奥瑞珠单抗、奥马佐单抗、帕利珠单抗、雷珠单抗、瑞希巴库单抗、瑞利珠单抗、Rmab、罗维珠单抗、芦利珠单抗、Sarilumab、苏金单抗、替曲吉珠单抗、Thiomab、托珠单抗、乌司奴单抗、维多珠单抗、阿利鲁单抗、阿克托舒单抗、阿杜那单抗、Afasevikumab、阿非莫单抗、阿尼鲁单抗、安芦珠单抗(IMA-638)、阿塞珠单抗、阿托木单抗、巴匹珠单抗、BCD-100、柏替木单抗、贝索单抗、比西单抗、比玛卢单抗、比美吉珠单抗、泊特埃单抗、布来鲁单抗、布索组单抗、伯考赛珠单抗、Brazikumab、布雷奴单抗、布洛赛珠单抗、卡芦单抗、卡罗妥昔单抗、西利珠单抗、克拉扎珠单抗、克立昔单抗、康赛珠单抗、考韦昔单抗、CR6261、Crenezumab、立赞利珠单抗、克罗特度单抗、德帕妥昔组单抗、莫福汀、地洛妥单抗生物素、迪扎米珠单抗、地利伏单抗、多玛洛珠单抗、度司妥单抗、依美昔单抗、埃巴单抗、依法珠单抗、依芬古单抗、埃迪鲁单抗、依来努单抗、依诺凯组单抗、Eptinezumab、厄利珠单抗、Etrolizumab、依维苏单抗、艾韦单抗、Fanolesomab、法拉莫单抗、Faricimab、法司努单抗、泛维珠单抗、非扎奴单抗、法兰妥单抗、夫来库单抗、伏妥珠单抗、芳妥珠单抗、福拉韦单抗、弗洛西单抗、福拉奴单抗、更汀芦单抗、加维莫单抗、吉伏组单抗、瑾司鲁单抗、戈利昔单抗、Gosuranemab、伊利尤单抗、Inclacumab、伊诺莫单抗、Iomab-B、凯利昔单抗、Lampalizumab、兰洛珠单抗、拉韦昔单抗、来金珠单抗、Lenvervimab、乐德木单抗、来利珠单抗、利韦单抗、利格利珠单抗、洛迪赛珠单抗、培戈-鲁利珠单抗、马塔西单抗、玛弗利木单抗、美替木单抗、米吉珠单抗、莫维珠单抗、莫罗单抗CD3、奈巴库单抗、奈莫利珠单抗、NEOD001、尼塞韦单抗、奥度莫单抗、奥仑达利珠单抗、奥洛组单抗、OMS721、奥匹努单抗、奥替苏单抗、奥昔珠单抗、Otilimab、奥塞芦单抗、奥扎奈珠单抗、奥利组单抗、帕昔单抗、帕诺库单抗、帕考珠单抗、帕利珠单抗、PDR001、珀雷吉珠单抗、培克珠单抗、普拉鲁单抗、洛扎利珠单抗、泊奈组单抗、Porgaviximab、Prasinezumab、普立昔单抗、PRO 140、奎利珠单抗、雷韦单抗、雷泮赛珠单抗、Ranevetmab、Ravagalimab、雷夫利珠单抗、瑞法奈珠单抗、瑞加韦单抗、瑞拉利单抗、利努苏单抗、Risankizumab、罗来度单抗、洛莫索珠单抗、罗利珠单抗、SA237、萨特利珠单抗、司韦单抗、SHP647、西法木单抗、辛妥珠单抗、西利珠单抗、Sirukumab、苏兰珠单抗、Sonepcizumab、Spartalizumab、司他芦单抗、硫索单抗、舒他伏单抗、舒利单抗、舒维组单抗、苏托舒单抗、他度珠单抗、他利珠单抗、坦妥维单抗、他尼珠单抗、替非珠单抗、阿替莫单抗、替奈昔单抗、替利珠单抗、替妥木单抗、特折鲁单抗、替布利珠单抗、托利珠单抗、曲罗芦单抗、曲戈卢单抗、妥韦单抗、乌洛鲁单抗、乌珠单抗、伐利苏单抗、维帕莫单抗、维森库单抗、维西珠单抗、沃巴利珠单抗、阿佐莫单抗、曲妥珠单抗、吉妥珠单抗、brentuximab、沃瑟妥珠单抗、洛沃妥珠单抗、cantuzumab、bivatuzumaborinotuzumab或伐达妥昔单抗。
61.根据权利要求1-60中的任一项所述的化合物,其中m的至少一次出现是1-15的整数。
62.根据权利要求1-61中的任一项所述的化合物,其中m的至少一次出现是1-10的整数。
63.根据权利要求1-62中的任一项所述的化合物,其中m的至少一次出现是1-5的整数。
64.根据权利要求1-63中的任一项所述的化合物,其中m的每次出现是1-15的整数。
65.根据权利要求1-64中的任一项所述的化合物,其中m的每次出现是1-10的整数。
66.根据权利要求1-65中的任一项所述的化合物,其中m的每次出现是1-5的整数。
67.根据权利要求1-66中的任一项所述的化合物,其中n是1-100的整数。
68.根据权利要求1-67中的任一项所述的化合物,其中n是1-10的整数。
69.根据权利要求1-68中的任一项所述的化合物,其中M的至少一次出现是抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂、激酶抑制剂、蒽环类抗生素和EGFR抑制剂或烷化剂。
70.根据权利要求1-69中的任一项所述的化合物,其中M的至少一次出现是抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂或烷化剂。
71.根据权利要求1-70中的任一项所述的化合物,其中M在每次出现时独立地是抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂、激酶抑制剂、蒽环类抗生素和EGFR抑制剂或烷化剂。
72.根据权利要求1-71中的任一项所述的化合物,其中M在每次出现时独立地是烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂或烷化剂。
73.根据权利要求1-70中的任一项所述的化合物,其中M的至少一次出现选自:澳瑞他汀F、单甲基澳瑞他汀F、单甲基澳瑞他汀E、paciltaxol、SN-38、卡奇霉素、安曲霉素、abbeymycin、chicamycin、DC-81、mazethramycin、新茴霉素A、新茴霉素B、porothramycinprothracarcin、西班米星、西伯里亚霉素、托马霉素、DM1细胞毒、emtansine、伊立替康、喜树碱、托泊替康、silatecan、科西特康、依沙替康、勒托替康、吉马替康、贝洛替康和卢比替康。
76.选自表2的化合物。
77.组合物,其包含权利要求1-76中的任一项所述的化合物和药学上可接受的载体。
78.治疗疾病的方法,所述方法包括给有此需要的受试者施用治疗有效量的根据权利要求1-76中的任一项所述的化合物或根据权利要求77所述的组合物,其中至少一个M是有效地治疗疾病的生物活性部分。
79.根据权利要求78所述的方法,其中每个M是有效地治疗疾病的生物活性部分。
80.根据权利要求78或79中的任一项所述的方法,其中所述疾病是癌症。
81.根据权利要求80所述的方法,其中所述癌症是乳腺癌、非霍奇金淋巴瘤、急性髓性白血病、多发性骨髓瘤、胃癌、肾细胞癌、实体瘤、卵巢癌、前列腺癌、结肠直肠癌、胰腺癌、小细胞肺癌、弥漫性大B细胞性淋巴瘤、赘生物、泌尿道上皮癌、ALL、CLL、胶质母细胞瘤、霍奇金淋巴瘤、淋巴瘤、间皮瘤、非小细胞肺癌、复发性头颈癌或其组合。
82.根据权利要求78-81中的任一项所述的方法,其中所述方法进一步包括施用选自以下的额外治疗剂:抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂、激酶抑制剂、蒽环类抗生素和EGFR抑制剂、烷化剂和它们的组合。
83.根据权利要求78-81中的任一项所述的方法,其中所述方法进一步包括施用选自以下的额外治疗剂:抗赘生物剂、烯二炔抗肿瘤抗生素、美坦生类化合物、拓扑异构酶抑制剂、激酶抑制剂、蒽环类抗生素和EGFR抑制剂、烷化剂和它们的组合。
84.根据权利要求82所述的方法,其中所述额外治疗剂包含澳瑞他汀F、单甲基澳瑞他汀F、单甲基澳瑞他汀E、paciltaxol、SN-38、卡奇霉素、安曲霉素、abbeymycin、chicamycin、DC-81、mazethramycin、新茴霉素A、新茴霉素B、porothramycin prothracarcin、西班米星、西伯里亚霉素、托马霉素、DM1细胞毒、emtansine、伊立替康、喜树碱、托泊替康、silatecan、科西特康、依沙替康、勒托替康、吉马替康、贝洛替康和卢比替康。
85.根据权利要求78或79中的任一项所述的方法,其中所述疾病生物活性部分降解蛋白。
86.根据权利要求85所述的方法,其中所述蛋白是淀粉样蛋白或tau蛋白。
87.根据权利要求78、79、85或86中的任一项所述的方法,其中所述疾病是淀粉样变性或阿尔茨海默氏病。
88.根据权利要求78、79、85或86中的任一项所述的方法,其中所述疾病是前列腺癌、胰腺癌或乳腺癌。
89.根据权利要求78、79、85或86中的任一项所述的方法,其中所述疾病是肿瘤疾病、心血管疾病、肾疾病、代谢疾病或呼吸疾病。
90.根据权利要求78、79、85或86中的任一项所述的方法,其中所述疾病是肺疾病或中枢神经系统疾病。
91.根据权利要求78、79、85或86中的任一项所述的方法,其中所述疾病是转移性的去势抵抗性的前列腺癌或转移性的乳腺癌。
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