CN109942665B - 雷公藤内酯醇衍生物及其制备方法和应用 - Google Patents
雷公藤内酯醇衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一种雷公藤内酯醇衍生物及其制备方法和应用。该雷公藤内酯醇衍生物的结构如通式I所示,各取代基的定义如说明书和权利要求书所述。本发明的雷公藤内酯醇衍生物,具有较佳的免疫抑制活性和抗肿瘤活性,毒性低,安全性高,具有较好的开发和应用前景。
Description
技术领域
本发明涉及药物化学领域,具体地,涉及一种具有抗肿瘤活性、免疫抑制活性的雷公藤内酯醇衍生物及其制备方法和应用。
背景技术
天然产物一直是新型抗肿瘤药物结构的主要来源,但这些化合物往往存在较差的药代动力学性质,在临床上仅有为数不多的纯天然产物开发成为抗肿瘤药物。
中药植物雷公藤(Tripterygium wilfordii)(TW)是常见的抗肿瘤药物研究对象,目前从中提取获得的化合物雷公藤内酯醇是雷公藤的重要有效成分,研究发现其具有抗炎、抗肿瘤及免疫抑制活性。同时,研究发现雷公藤甲素还具有较大的毒性及多种不良反应,这严重影响了雷公藤内酯醇的开发利用。体内实验表明,雷公藤内酯醇的安全范围很窄,2倍或4倍于有效剂量的雷公藤内酯醇就可以引起动物死亡,甚至有研究报道其有效剂量与致死剂量十分接近。毒理学研究发现,雷公藤内酯醇的不良反应涉及胃肠道、肾脏、心脏、肝脏、造血系统及生殖系统等多种组织器官。因此,对雷公藤内酯醇进行结构改造,获得高效低毒的雷公藤内酯醇衍生物,使其在发挥抗肿瘤及其他生物活性的同时避免毒性,这成为科研中的重要研究方向。
文献调研发现,目前针对雷公藤内酯醇的结构改造主要集中在C14位羟基,C7/C8环氧,C12/C13环氧,以及不饱和内酯环。其中,针对不饱和内酯环的结构改造主要在于将内酯环转化为呋喃环,或转化为内酰胺,或将内酯环打开以达到增加水溶性的目的,但这两种策略都会导致衍生物活性的降低甚至消失。
发明内容
本发明的目的在于提供一种结构新颖的雷公藤内酯醇衍生物及其制备方法和应用。
本发明的第一方面,提供一种如通式I所示的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,
式中,
R1是取代或未取代的以下基团:C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C8环烯基、C2-C6炔基、C6-C10芳基、C7-C15芳基烷基或4-8元杂芳基;
Y是O、NH或S;
R2是取代或未取代的以下基团:C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C8环烯基、C2-C6炔基、C6-C10芳基、C7-C15芳基烷基、4-8元杂芳基或-C(=O)R4,其中R4是取代或未取代的以下基团:C1-C6烷基、C3-C8环烷基、C2-C6烯基、C3-C8环烯基、C2-C6炔基、C6-C10芳基、C7-C15芳基烷基或4-8元杂芳基;
表示双键或单键,当为双键时,R3是O;当为单键时,R3是OR5、F或SH,R5选自:H、Boc、TBS、TES、CH2SCH3、CH2OCH3、-OP(=O)(OH)2、-OP(=O)(OBn)2、-CH2OP(=O)(OH)2、-CH2OP(=O)(OBn)2、-COOH、单糖、叶酸及叶酸类似物或单克隆抗体;
各X独立为H、OH或卤素;
上述各取代独立指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、-OH、NH2、CN、COOH、-OP(=O)(OH)2、未取代或卤代的C1-C8烷基、未取代或卤代的C3-C8环烷基、未取代或卤代的C1-C8烷氧基、未取代或卤代的C2-C6烯基、未取代或卤代的C2-C6炔基、未取代或卤代的C2-C6酰基、未取代或卤代的C2-C6酰胺基、未取代或卤代的5~8元芳基、未取代或卤代的5~8元杂芳基、未取代或卤代的4~8元饱和杂环或碳环;其中,上述各杂芳基独立包含选自下组的1-3个杂原子:N、O或S。
本发明中,Boc为叔丁氧羰基,TBS为叔丁基二甲基硅基,TES为三乙基硅基。
在另一优选例中,R3是OH或OBoc、OCH2OP(=O)(OH)2、-OCH2OP(=O)(OBn)2、OTBS、OTES、OCH2SCH3、OCH2OCH3。在另一优选例中,R3是OH。在另一优选例中,R3是β-OH。在另一优选例中,R3是OBoc、OCH2OP(=O)(OH)2或-OCH2OP(=O)(OBn)2。
在另一优选例中,至多一个X为OH。
在另一优选例中,14位碳的构型为α-构型或β-构型。
在另一优选例中,各X均为H。
在另一优选例中,Y是O。
在另一优选例中,R1是取代或未取代的以下基团:C1-C4烷基、C3-C6环烷基、C6-C10芳基或4-8元杂芳基,所述取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、-OH、未取代或卤代的C1-C4烷基、未取代或卤代的C1-C3烷氧基。
在另一优选例中,R1是环己基、正丙基、正丁基、苯基、2-呋喃基、对甲基苯基、对甲氧基苯基或对三氟甲基苯基。
在另一优选例中,R2是取代或未取代的以下基团:C1-C4烷基、C7-C10芳基烷基、4-6元杂芳基或-C(=O)R4,其中R4是取代或未取代的以下基团:C1-C4烷基、C3-C6环烷基、C6-C10芳基、C7-C15芳基烷基或4-8元杂芳基,所述取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、-OH、未取代或卤代的C1-C4烷基、未取代或卤代的C1-C3烷氧基。
在另一优选例中,R2是C1-C4烷基、C7-C10芳基烷基或(CO)R4。在另一优选例中R2是甲基、乙基、丙基或丁基。在另一优选例中,R4是取代或未取代的以下基团:C1-C4烷基、C3-C6环烷基、C6-C10芳基或4-8元杂芳基。
在另一优选例中,R4是环己基、正丁基、正丙基、苯基、2-呋喃基、对甲基苯基、对三氟甲基苯基或对甲氧基苯基。
在另一优选例中,R1和R2是相同或不同的。
在另一优选例中,R1和R4是相同或不同的。
在另一优选例中,所述化合物为:
本发明的第二方面,提供一种组合物,其特征在于,所述组合物包含第一方面所述的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药;以及杂质,其中,
基于组合物的总重量计,所述杂质的含量为0.1-2wt%,较佳为0.2-1wt%,更佳为0.3-0.6wt%。
在另一优选例中,第一方面所述的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药的重量占组合物总重量的98wt%-99.9wt%,较佳为99-99.8wt%,更佳为99.2-99.6wt%或99.3-99.5wt%。
本发明的第三方面,提供第一方面所述的化合物的制备方法,所述制备方法包括以下步骤:
R2为-C(=O)R4,R1=R4,所述制备方法包括以下步骤:雷公藤内酯醇与酰化试剂得到式II化合物,式II化合物衍生得到式III化合物,其中所述酰化试剂为R1COCl、R1COBr或R1COOCOR1;
或者R2为-C(=O)R4,R1≠R4,所述制备方法包括以下步骤:雷公藤内酯醇分别与第一酰化试剂、第二酰化试剂反应得到式II化合物,式II化合物衍生得到式III化合物,所述第一酰化试剂为R1COCl、R1COBr或R1COOCOR1,所述第二酰化试剂为R4COCl、R4COBr、R4COOCOR4;
各式中,R1、R4、R5的定义如第一方面所述。
一种典型的反应步骤如下所示:
本发明的第四方面,提供一种药物组合物,包含:
第一方面所述的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药;和
药学上可接受的载体。
本发明的第四方面,提供第一方面所述的化合物、或其药学上可接受的盐、或其对映异构体、非对映异构体、互变异构体、溶剂化物、多晶型物或前药,或者第三方面所述的药物组合物的用途,
a)制备治疗肿瘤的药物;
b)制备诱导细胞凋亡的药物;和/或
c)制备免疫抑制药物。
在另一优选例中,所述肿瘤选自下组:白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌。
在另一优选例中,所述肿瘤优选胰腺癌、前列腺癌、卵巢癌或脑癌。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。说明书中所揭示的各个特征,可以被任何提供相同、均等或相似目的的替代性特征取代。限于篇幅,在此不再一一赘述。
附图说明
图1为荷瘤小鼠体重随时间变化结果图。
图2为体重数据图。
具体实施方式
本申请的发明人经过广泛而深入地研究,首次通过C-19双键化在雷公藤内酯醇引入修饰基团,并进一步衍生化从而获得了一系列新型且具有高活性(较佳的免疫抑制活性和抗肿瘤活性)、高安全性(毒性低)的雷公藤内酯醇衍生物,具有较好的开发和应用前景。在此基础上,完成了本发明。
术语
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本发明主题作任何限制。在本申请中,除非另有具体说明,否则使用单数时也包括复数。必须注意,除非文中另有清楚的说明,否则在本说明书和权利要求书中所用的单数形式包括所指事物的复数形式。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
可在参考文献中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。
当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,-CH2O-等同于-OCH2-。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手册和论文,均通过引用方式整体并入本文。
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如,C1-6烷基是指具有总共1至6个碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。
除前述以外,当用于本申请的说明书及权利要求书中时,除非另外特别指明,否则以下术语具有如下所示的含义。
在本申请中,术语“卤素”是指氟、氯、溴或碘。
“羟基”是指-OH基团。
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。
“羰基”是指-C(=O)-基团。
“硝基”是指-NO2。
“氰基”是指-CN。
“氨基”是指-NH2。
“取代的氨基”是指被一个或两个如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。
“羧基”是指-COOH。
在本申请中,作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中),术语“烷基”意指仅由碳原子和氢原子组成、不含不饱和键、具有例如1至12个(优选为1至8个,更优选为1至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团。烷基的实例包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。
在本申请中,作为基团或是其它基团的一部分,术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“炔基”意指仅由碳原子和氢原子组成、含有至少一个三键和任选的一个或多个双键、具有例如2至14个(优选为2至10个,更优选为2至6个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团,例如但不限于乙炔基、丙-1-炔基、丁-1-炔基、戊-1-烯-4-炔基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烷基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基,其可包括稠合环体系、桥环体系或螺环体系,具有3至15个碳原子,优选具有3至10个碳原子,更优选具有3至8个碳原子,且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明,环烷基中的碳原子可以任选地被氧化。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。
在本申请中,作为基团或是其它基团的一部分,术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明,否则杂环基可以为单环、双环、三环或更多环的环体系,其可包括稠合环体系、桥环体系或螺环体系;其杂环基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化;且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中,一个或多个环可以是下文所定义的芳基或杂芳基,条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言,杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团,更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于:吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7-二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。
在本申请中,作为基团或是其它基团的一部分,术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言,芳基可以为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。
在本申请中,术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。
在本申请中,作为基团或是其它基团的一部分,术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明,否则杂芳基可为单环、双环、三环或更多环的环体系,还可以与上文所定义的环烷基或杂环基稠合,条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化;氮原子可任选地被季铵化。就本发明的目的而言,杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团,更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、三唑基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁三唑基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]三唑并[4,3-b]哒嗪、[1,2,4]三唑并[4,3-a]吡嗪、[1,2,4]三唑并[4,3-c]嘧啶、[1,2,4]三唑并[4,3-a]吡啶、咪唑并[1,2-a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。
在本申请中,术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。
在本申请中,“任选的”或“任选地”表示随后描述的事件或状况可能发生也可能不发生,且该描述同时包括该事件或状况发生和不发生的情况。例如,“任选地被取代的芳基”表示芳基被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。
“立体异构体”是指由相同原子组成,通过相同的键键合,但具有不同三维结构的化合物。本发明将涵盖各种立体异构体及其混合物。
当本发明的化合物中含有烯双键时,除非另有说明,否则本发明的化合物旨在包含E-和Z-几何异构体。
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子,且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体,以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备,或者使用常规技术进行拆分,例如采用结晶以及手性色谱等方法。
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成,或者使用例如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)。
在本申请中,术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的,与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等;有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐:伯胺类、仲胺类及叔胺类,被取代的胺类,包括天然的被取代胺类、环状胺类及碱性离子交换树脂,例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。
“多晶型物”是指本发明的某些化合物在固体状态下由于存在两种或两种以上不同分子排列而产生的不同固体结晶相。本发明的某些化合物可以存在多于一种晶型,本发明旨在包括各种晶型及其混合物。
通常,结晶化作用会产生本发明化合物的溶剂化物。本发明中使用的术语“溶剂化物”是指包含一个或多个本发明化合物分子与一个或多个溶剂分子的聚集体。溶剂可以是水,该情况下的溶剂化物为水合物。或者,溶剂可以是有机溶剂。因此,本发明的化合物可以以水合物存在,包括单水合物、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。本发明化合物可形成真实的溶剂化物,但在某些情况下,也可以仅保留不定的水或者水加上部分不定溶剂的混合物。本发明的化合物可以在溶剂中反应或者从溶剂中沉淀析出或结晶出来。本发明化合物的溶剂化物也包含在本发明的范围之内。
本发明还包括上述化合物的前药。在本申请中,术语“前药”表示可在生理学条件下或通过溶剂分解而被转化成本发明的生物活性化合物的化合物。因此,术语“前药”是指本发明的化合物的药学上可接受的代谢前体。当被给予有需要的个体时,前药可以不具有活性,但在体内被转化成本发明的活性化合物。前药通常在体内迅速转化,而产生本发明的母体化合物,例如通过在血液中水解来实现。前药化合物通常在哺乳动物生物体内提供溶解度、组织相容性或缓释的优点。前药包括已知的氨基保护基和羧基保护基。
在本申请中,“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药,利于活性成分的吸收进而发挥生物活性。
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
在本申请中,“药学上可接受的载体”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本发明所述“肿瘤”,“细胞增殖异常相关疾病”等包括但不限于白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌等疾病。
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。
本文所用的术语“治疗”和其它类似的同义词包括以下含义:
(i)预防疾病或病症在哺乳动物中出现,特别是当这类哺乳动物易患有该疾病或病症,但尚未被诊断为已患有该疾病或病症时;
(ii)抑制疾病或病症,即遏制其发展;
(iii)缓解疾病或病症,即,使该疾病或病症的状态消退;或者
(iv)减轻该疾病或病症所造成的症状。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术。在优选的实施方案中,本文讨论的化合物和组合物通过口服施用。
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗,其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中,例如施用三种或更多种活性成分。
本领域技术人员还应当理解,在下文所述的方法中,中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基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。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基还可为聚合物树脂。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件(如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件)或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1:化合物CK21S-001的制备
1.1化合物CK21S-001的合成
氮气保护下,将化合物雷公藤内酯醇(180mg,0.5mmol)加入三颈圆底烧瓶中,加入无水四氢呋喃(25mL),降温至-20℃,并在此温度下逐滴加入2,2,6,6-四甲基哌啶锂的四氢呋喃/甲苯溶液(0.75mL,2.0M,1.5mmol),保持温度搅拌30min后缓慢滴加苯甲酰氯(0.105mL,0.75mmol),滴毕继续搅拌反应1h后滴加2-呋喃甲酰氯(0.105mL,0.75mmol)。继续保持-20℃搅拌反应2h后加碳酸钠水溶液(10%)淬灭反应,乙酸乙酯(25mL×3)萃取,合并的有机相,无水硫酸钠干燥,减压浓缩。粗产品经硅胶色谱柱分离提纯(二氯甲烷:乙酸乙酯),收集得到目标产物(白色固体,255mg,产率90%),将上述产品在混合有机溶剂中进一步重结晶得到终产品(213mg,产率85%,纯度大于99%)。
1H NMR(400MHz,CDCl3):δ7.76(d,J=1.6Hz,1H),7.74(d,J=1.2Hz,2H),7.54(dd,J1=0.8Hz,J2=3.6Hz,1H),7.44~7.36(m,3H),6.63(dd,J1=1.6Hz,J2=3.6Hz,1H),3.79(d,J=2.8Hz,1H),3.40(d,J=2.4Hz,1H),3.17(d,J=9.2Hz,1H),2.97~2.89(m,2H),2.63~2.56(m,2H),2.37~2.33(m,2H),2.21(q,J=6.4Hz,1H),1.93(t,J=13.6Hz,1H),1.57(s,3H),1.56~1.51(m,1H),1.43(s,3H),1.12(s,3H),1.15~1.08(m,1H),0.96(d,J=7.2Hz,3H),0.84(d,J=7.2Hz,3H).13C NMR(100MHz,CDCl3):δ171.3,167.9,155.9,151.4,150.5,148.2,142.7,142.3,134.6,132.4,131.5,129.9,129.5,129.1,128.9,128.6,128.0,121.5,113.3,112.6,73.1,60.0,65.6,65.4,60.7,56.9,56.4,56.3,53.9,40.8,36.7,35.9,30.1,29.1,27.9,24.6,17.8,17.7,16.8,14.8.MS calcd for C32H30O9(M+):559.2,found 559.2.
1.2化合物CK21S-001-b的合成
室温下,将CK21S-001(558mg,1mmol)投入干燥的圆底烧瓶中,加入10mL乙酸乙酯,溶解后分别加入N,N-二甲基吡啶(DMAP,0.6g,5mmol)及二碳酸二叔丁酯(0.65g,3mmol),室温反应过夜。反应结束,加乙酸乙酯(150mL)稀释,有机相分别用稀盐酸(50mL)、水(50mL)及饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗产品经硅胶色谱柱分离提纯(正己烷:乙酸乙酯),收集得到目标产物(白色固体,0.6g,90%,纯度大于98%)。
1H NMR(400MHz,CDCl3):δ7.77(d,J=0.8Hz,2H),7.75(dd,J1=2.0Hz,J2=3.2Hz,1H),7.54(dd,J1=0.8Hz,J2=3.6Hz,1H),7.44~7.36(m,3H),6.65(dd,J1=1.6Hz,J2=3.6Hz,1H),4.53(s,1H),4.12(q,J=7.2Hz,1H),3.702(d,J=2.8Hz,1H),3.41(d,J=2.4Hz,1H),3.03(d,J=6.0Hz,1H),3.94~2.88(m,1H),2.56~2.52(m,1H),2.39~2.31(m,2H),1.94~1.86(m,2H),1.60(s,3H),1.58~1.50(m,1H),1.49(s,9H),1.33~1.24(m,4H),1.13(s,3H),1.15~1.08(m,1H),0.96(d,J=5.6Hz,3H),0.88(t,J=7.2Hz,3H),0.82(d,J=6.8Hz,3H).MS calcd for C37H38O11(M+):659.2,found 659.2.
实施例2:化合物CK21S-002的制备
2.1化合物CK21S-002的合成
采取与制备CK21S-001类似的方法制备得到CK21S-002,产率89%,纯度大于99%。不同点在于用对甲氧基苯甲酰氯代替实施例1中的苯甲酰氯及呋喃甲酰氯,其它条件相同。
1H NMR(400MHz,CDCl3):δ8.20(d,J=8.8Hz,2H),7.71(d,J=8.8Hz,2H),7.03(d,J=8.8Hz,2H),6.92(d,J=8.8Hz,2H),3.87(s,3H),3.83(s,3H),3.79(d,J=3.2Hz,1H),3.37(d,J=3.2Hz,1H),3.02(d,J=9.6Hz,1H),2.84~2.78(m,1H),2.71(d,J=6.4Hz,1H),2.59~2.53(m,2H),2.35~2.32(m,2H),2.19~2.12(m,1H),1.92~1.85(m,1H),1.53~1.50(m,1H),1.15(s,3H),1.12~1.09(m,1H),0.90(d,J=6.8Hz,3H),0.81(d,J=6.8Hz,3H).13C NMR(100MHz,CDCl3):δ168.3,164.6,164.1,160.7,150.4,141.2,133.6,132.7,132.7,129.8,129.8,127.7,124.5,120.2,114.4,114.4,114.1,114.1,72.9,65.9,65.3,60.8,60.1,56.5,55.5,55.4,53.7,40.7,36.7,29.3,28.0,24.6,17.6,17.5,16.7,15.0.MScalcd for C36H36O10(M+):629.3,found 629.3.
2.2化合物CK21S-002-b的合成
采取与制备CK21S-001-b类似的方法,由CK21S-001-a制备得到CK21S-002-b,产率90%,纯度大于99%。
1H NMR(400MHz,CDCl3):δ8.21(d,J=8.8Hz,2H),7.72(d,J=9.2Hz,2H),7.05(d,J=9.2Hz,2H),6.92(d,J=8.8Hz,2H),4.35(s,1H),3.89(d,J=6Hz,1H),3.88(s,3H),3.83(s,3H),3.70(d,J=3.2Hz,1H),3.38(d,J=2.8Hz,1H),2.80~2.78(m,2H),2.55~2.52(m,1H),2.34~2.30(m,2H),1.91~1.80(m,2H),1.47(s,9H),1.11(s,3H),1.12~1.05(m,1H),0.89(d,J=6.8Hz,3H),0.79(d,J=6.8Hz,3H).MS calcd for C41H44O12(M+):729.3,found729.3.
实施例3:化合物CK21S-003的制备
3.1化合物CK21S-003的合成
采取与制备CK21S-001类似的方法制备得到CK21S-003,产率90%,纯度大于99%。不同点在于用对三氟甲基苯甲酰氯代替实施例1中的苯甲酰氯及呋喃甲酰氯,其它条件相同。
1H NMR(400MHz,CDCl3):δ8.36(d,J=8.0Hz,2H),7.88(d,J=8.0Hz,2H),7.81(d,J=8.0Hz,2H),7.67(d,J=8.0Hz,2H),3.82(d,J=3.2Hz,1H),3.44(d,J=3.2Hz,1H),3.04(d,J=10Hz,1H),2.68~2.58(m,3H),2.55(d,J=10Hz,1H),2.40~2.37(m,2H),2.20~2.13(m,1H),2.00~1.90(m,1H),1.60(m,1H),1.18(s,3H),1.16~1.13(m,1H),0.90(d,J=7.2Hz,3H),0.83(d,J=7.2Hz,3H).13C NMR(100MHz,CDCl3):δ167.3,163.3,150.0,143.2,136.4,136.1,135.1,131.6,131.5,131.3,130.9,130.4,128.3,126.3,125.6,73.0,65.8,65.5,60.1,60.1,56.2,54.0,40.9,36.8,29.1,28.0,24.7,17.7,17.5,16.7,14.9.MScalcd for C36H30O8F6(M+):705.2,found 705.2.
3.2化合物CK21S-003-b的合成
采取与制备CK21S-001-b类似的方法,制备得到CK21S-003-b,产率92%,纯度大于98%。
1H NMR(400MHz,CDCl3):δ8.37(d,J=8.0Hz,2H),7.89(d,J=8.4Hz,2H),7.81(d,J=8.0Hz,2H),7.67(d,J=8.4Hz,2H),4.36(s,1H),3.73(d,J=2.8Hz,1H),3.44(d,J=2.8Hz,1H),2.72(d,J=6.0Hz,1H),2.63~2.57(m,2H),2.38~2.36(m,2H),1.96~1.84(m,2H),1.62~1.59(m,1H),1.46(s,9H),1.19~1.16(m,1H),1.14(s,3H),0.86(d,J=6.8Hz,3H),0.80(d,J=7.2Hz,3H).MS calcd for C41H38O10F6(M+):805.2,found 805.2.
实施例4:化合物CK21S-004的制备
4.1化合物CK21S-004的合成
采取与制备CK21S-001类似的方法制备得到CK21S-004,产率88%,纯度大于99%。不同点在于用2-呋喃甲酰氯代替实施例1中的苯甲酰氯,其它条件相同。
1H NMR(400MHz,CDCl3):δ7.74~7.72(m,1H),7.54(dd,1H),7.49(d,1H),7.17(d,1H),6.63(q,1H),6.56(q,1H),3.77(d,J=3.2Hz,1H),3.38(d,J=2.4Hz,1H),3.18(d,J=10Hz,1H),3.01(d,J=3.2Hz,1H),3.04~2.97(m,1H),3.62(d,J=10Hz,1H),2.54~2.50(m,1H),2.40~2.32(m,1H),2.23~2.16(m,1H),1.96~1.87(m,1H),1.57~1.50(m,2H),1.17(s,3H),1.13~1.10(m,1H),0.95(d,J=7.2Hz,3H),0.823(d,J=7.2Hz,3H);13C NMR(100MHz,CDCl3):δ167.4,155.6,150.0,148.0,145.1,144.2,142.6,140.3,128.7,124.6,121.6,115.5,113.0,112.6,73.2,66.1,65.4,60.6,60.2,56.3,54.0,40.4,36.7,29.1,28.0,24.4,17.8,17.7,16.8,14.8.MS calcd for C30H28O10(M+):549.18,found 549.17.
4.2化合物CK21S-004-b的合成
采取与制备CK21S-001-b类似的方法得到CK21S-004-b,产率93%,纯度大于99%。1HNMR(400MHz,CDCl3):δ7.76(d,J=0.8Hz,1H),7.55(d,J=3.2Hz,1H),7.50(d,J=1.2Hz,1H),7.17(d,J=3.2Hz,1H),6.66(dd,J=1.6Hz,3.6Hz,1H),6.56(dd,J=1.6Hz,3.6Hz,1H),4.54(s,1H),3.68(d,J=3.2Hz,1H),3.40(d,J=2.8Hz,1H),3.08(d,J=6.4Hz,1H),3.03~2.97(m,1H),2.50~2.47(m,1H),2.35~2.31(m,2H),1.93~1.85(m,2H),1.49(s,9H),1.25(m,1H),1.13(s,3H),1.08~1.05(m,1H),0.93(d,J=6.8Hz,3H),0.80(d,J=6.8Hz,3H).MS calcd for C35H36O12(M+):649.2,found 649.2.
实施例5:化合物CK21S-005的制备
5.1化合物CK21S-005的合成
采取与制备CK21S-001类似的方法制备得到CK21S-005,产率80%,纯度大于99%。反应条件相同。1H NMR(400M,CDCl3):δ8.25(dd,J=1.6Hz,8Hz,2H),7.76(dd,J=1.6Hz,8.4Hz,2H),7.67(m,1H),7.58(t,J=7.2Hz,2H),7.43~7.38(m,3H),3.80(d,J=3.2Hz,1H),3.39(d,J=2.8Hz,1H),2.98(d,J=10Hz,1H),2.75~2.69(m,1H),2.63~2.58(m,1H),2.56(d,J=6.4Hz,1H),2.53(d,J=10Hz,1H),2.40~2.32(m,2H),2.21~2.14(m,1H),1.88(dd,J=14.0Hz,13.2Hz,1H),1.55~1.52(m,1H),1.18~1.11(m,1H),1.15(s,3H),0.92(d,J=7.2Hz,3H),0.82(d,J=6.8Hz,3H);13C NMR(100MHz,CDCl3):δ168.1,164.5,150.3,142.2,134.4,133.5,131.9,130.5,129.9,129.2,128.9,128.6,128.1,128.0,72.8,65.8,65.3,60.7,60.0,56.5,53.7,40.7,36.7,29.3,27.9,24.6,17.8,17.6,16.7,15.0.MScalcd for C34H32O8(M+):569.2,found 569.2.
5.2化合物CK21S-005-b的合成
采取与制备CK21S-001-b类似的方法制备得到CK21S-005-b,产率90%,纯度大于99%。1H NMR(400M,CDCl3):δ8.26(dd,J=1.6Hz,8Hz,2H),7.76(dd,J=1.6Hz,8.4Hz,2H),7.67(m,1H),7.58(t,J=7.2Hz,2H),7.44~7.38(m,3H),4.30(d,J=3.2Hz,1H),3.70(d,J=2.8Hz,1H),3.40(d,J=10Hz,1H),2.75~2.68(m,1H),2.62(d,J=8.0Hz,1H),2.58~2.54(m,1H),2.33~2.27(m,2H),1.91~1.81(m,2H),1.49(s,9H),1.11(s,3H),0.92(d,J=7.2Hz,3H),0.82(d,J=6.8Hz,3H);13C-NMR(100MHz,CDCl3):δ168.1,164.5,150.3,142.2,134.4,133.5,131.9,130.5,129.9,129.2,128.9,128.6,128.1,128.0,82.9,73.9,63.4,63.1,61.6,58.6,55.2,54.5,40.8,36.7,29.3,27.9,24.6,17.8,17.7,16.7,15.5.MScalcd for C39H40O10(M+):669.2,found 669.2
实施例6:化合物CK21S-006的制备
采取与制备CK21S-001类似的方法制备得到CK21S-006,产率75%,纯度大于95%。不同点在于用环己基甲酰氯代替实施例1中的呋喃甲酰氯,其它条件相同。
1H NMR(400MHz,CDCl3):δ7.67(d,J=2.0Hz,1H),7.65(d,J=1.6Hz,1H),7.43~7.35(m,2H),3.86(d,J=2.8Hz,1H),3.50(d,J=2.8Hz,1H),3.42(d,J=10.4Hz,1H),3.37(d,J=6.4Hz,1H),3.0(t,J=4.8Hz,1H),2.71(d,J=10.4Hz,1H),2.62~2.55(m,2H),2.37~2.32(m,2H),2.28(q,J=6.8Hz,1H),2.22~2.16(m,2H),1.97(dd,J1=13.2Hz,J2=2.0Hz,1H),1.90~1.84(m,2H),1.73(d,J=11.6Hz,1H),1.63~1.53(m,2H),1.39~1.24(m,4H),1.20(s,3H),1.17~1.12(m,1H),1.01(d,J=7.2Hz,3H),0.87(d,J=7.2Hz,3H).MScalcd for C34H38O8(M+):575.2,found 575.2。
采取与制备CK21S-001-b类似的方法制备得到CK21S-006-b。
实施例7:化合物CK21S-007的制备
采取与制备CK21S-001类似的方法,由Triptonide制备得到CK21S-007,产率91%,纯度大于98%。
1H NMR(400MHz,CDCl3):δ8.22~8.25(m,2H),7.77~7.79(m,2H),7.59~7.63(m,1H),7.49~7.54(m,2H),7.37~7.41(m,3H),3.94(d,J=2.8Hz,1H),3.71(d,J=2.8Hz,1H),2.79~2.85(m,1H),2.56~2.61(m,2H),2.33~2.45(m,2H),2.20~2.29(m,1H),1.88(dd,J1=13.6Hz,J2=14.8Hz,1H),1.54~1.58(m,1H),1.19~1.28(m,1H),1.09(s,3H),0.93(d,J=6.8Hz,3H),0.87(d,J=6.8Hz,3H)。MS calcd for C34H30O8(M+):567.2,found567.2.
实施例8:化合物CK21S-008的制备
将化合物CK21S-001(57mg,0.1mmol)投入干燥过的三颈圆底烧瓶中,加入3mL二氯甲烷溶解,降温至0℃,抽取DAST F试剂(0.3ml,2.289mmol),滴加入反应体系中,充分搅拌,体系慢慢显示微黄色,反应4h后,加入饱和NaHCO3溶液淬灭反应。加乙酸乙酯稀释。有机相分别用水(10mL)、饱和碳酸钠(10mL)及饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩。粗产品经硅胶色谱柱分离提纯(二氯甲烷:乙酸乙酯),收集得到目标产物CK21S-008(白色固体,40mg,产率70%)。1H NMR(400M,CDCl3)δ0.89(d,J=6.9Hz,3H),1.18(d,J=6.9Hz,3H),1.13(s,3H),1.23-1.28(m,1H),1.51-1.54(m,1H),1.83~1.90(m,1H),1.92~1.99(m,1H),2.25-2.36(m,2H),2.58~2.61(m,1H),2.74~2.80(m,1H),2.98~2.99(d,J=6.4Hz,1H),3.34(t,J=2.8Hz,1H),3.70(t,J=1.6Hz,1H),4.95(d,1H),7.38~7.45(m,3H),7.47~7.49(m,1H),7.56~7.60(m,2H),7.67~7.70(m,1H),7.75~7.78(m,2H),8.23~8.25(m,1H);19F NMR(400M,CDCl3)δ213.49。MS calcd for C34H31FO7(M+):571.2,found571.3.
实施例9:化合物CK21S-001-b’的制备
以CK21S-005为原料,采用与文献(J.Med.Chem.,2015,58,9334)类似的方法合成得到CK21S-001-b’。1H NMR(400MHz,CDCl3):δ8.25(d,J=5.2Hz,2H),7.74(d,J=4.8Hz,2H),7.68(t,1H),7.61(t,2H),7.43~7.38(m,3H),4.94(d,J=8Hz,1H),4.85(d,J=8Hz,1H),3.69(d,J=2Hz,1H),3.38(d,J=2Hz,1H),3.21(s,1H),2.62~2.72(m,2H),2.44(d,J=4Hz,1H),2.35~2.33(m,2H),2.29~2.24(m,1H),2.13(s,3H),1.86(t,1H),1.59~1.57(m,1H),1.16~1.09(m,1H),1.13(s,3H),0.90(d,J=4.4Hz,3H),0.78(d,J=4.4Hz,3H).13CNMR(100MHz,CDCl3):δ168.1,164.5,150.5,142.2,134.4,133.5,132.0,130.5,129.8,129.3,129.0,128.6,128.1,128.0,75.6,64.1,63.8,60.8,58.4,54.9,53.8,40.7,36.8,29.6,29.0,26.1,24.4,17.7,17.3,16.7,15.0,14.8.MS calcd for C36H36O12S(M+):628.2,found 628.2.
实施例10:化合物CK21S-009的制备
化合物CK21S-001-b’进一步衍生得到化合物CK21S-009-b,化合物CK21S-009-b进一步脱除苄基得到化合物CK21S-009,具体操作如下:
室温下,将CK21S-001-b’(300mg,0.48mmol)溶于二氯甲烷(10mL),并加入分子筛(300mg),置换氮气,在15~20℃搅拌。另外将NIS(碘代琥珀亚酰胺)(129mg,0.57mmol),磷酸二苄酯(159mg,0.57mmol)溶于四氢呋喃(10mL),然后缓慢滴加到反应液中,滴加结束后,保持室温反应3h,反应结束后,先将反应液过滤,再加入二氯甲烷(120mL)稀释,然后加入0.1M硫代硫酸钠(10mL)进行脱色,再用饱和碳酸钠水溶液和饱和氯化钠水溶液进行洗涤,有机相干燥,浓缩,得产物CK21S-009-b 300mg,不经过柱纯化,直接进行下一步反应。
将钯碳催化剂(160mg)置于四氢呋喃(12mL)中,然后降温至0℃,保持搅拌,另将CK21S-009-b(300mg)溶于THF(12mL),然后缓慢加入上述反应液中,加完后,置换氢气,使用氢气球保持反应处于氢气氛围,在室温下反应2h。反应结束后,过滤反应液,然后加入少量碳酸钠水溶液(50mg Na2CO3,4mL),调节pH至8~9左右,加入少量水和甲醇,冻干,冻干后使用制备液相进行纯化,得到目标产物(白色固体,80mg,纯度大于99%)。1H NMR(400MHz,CDCl3)δ8.20(d,J=7.6Hz,2H),7.76~7.79(m,1H),7.65~7.71(m,4H),7.42~7.51(m,3H),7.27(s,2H),4.89~4.97(m,2H),3.75(d,J=2.8Hz,1H),3.38(d,J=2.8Hz,1H),3.32(s,1H),2.73~2.82(m,2H),2.31~2.40(m,2H),2.22~2.26(m,2H),1.81(t,J=14Hz,1H),1.23~1.30(m,1H),1.10~1.11(m,1H),0.97(s,3H),0.82(d,J=6.4Hz,3H),0.65(d,J=6.8Hz,3H).13C NMR(100MHz,CDCl3):δ167.2,164.3,150.3,141.9,135.0,131.9,131.7,130.0,129.8,129.4,128.9,128.7,127.6,126.9,90.7,75.7,63.7,62.9,60.5,59.8,54.7,53.3,36.1,28.6,25.3,23.8,17.3,17.2,16.8,15.0.31P-NMR(400MHz,CDCl3):δ-2.1.MScalcd for C35H35O12P(M-):677.2,found 627.2.
实施例11:检测小分子化合物CK21S-001、CK21S-001-b、CK21S-002、CK21S-002-b、CK21S-003、CK21S-003-b、CK21S-004、CK21S-004-b、CK21S-005、CK21S-005-b、CK21S-006、CK21S-006-b、CK21S-007、CK21S-008、CK21S-009和Triptolide体外抗肿瘤活性
肿瘤细胞包括AsPC-1(人胰腺癌细胞)、PC-3(人前列腺癌细胞)和SK-OV-3(人卵巢癌细胞),细胞的来源和培养基见下表1。
表1肿瘤细胞信息表
雷公藤甲素作为阳性对照;试验药物的工作浓度为1μM、0.33μM、0.11μM、0.037μM、0.012μM、0.004μM、1.4nM和0.46nM)。肿瘤细胞复苏后,用相应的完全培养基重悬,置于5%CO2,37℃培养。取对数生长期肿瘤细胞,以相应的完全培养基调整细胞浓度,每孔加入90μL细胞悬液每类细胞数量见下表2,置于5%CO2,37℃培养过夜后,加入各浓度的试验药物,继续培养48小时。最后用Promega CellTiter-Glo Luminescent Cell Viability Assay Kit进行检测。
表2细胞铺板密度
细胞系 | 细胞数/孔(96孔板) |
AsPC-1 | 5000 |
PC-3 | 5000 |
SK-OV-3 | 3000 |
化合物CK21S-001、CK21S-001-b、CK21S-002、CK21S-002-b、CK21S-003、CK21S-003-b、CK21S-004、CK21S-004-b、CK21S-005、CK21S-005-b、CK21S-006、CK21S-006-b、CK21S-007、CK21S-008、CK21S-009和Triptolide体外抗肿瘤活性IC50值见表3,化合物均具有体外抗肿瘤活性,且活性和阳性对照Triptolide的活性相差不大。
表3体外抗肿瘤活性IC50(μM)
实施例12:
检测小分子化合物CK21S-001、CK21S-001-b、CK21S-002、CK21S-002-b、CK21S-003、CK21S-003-b、CK21S-004、CK21S-004-b、CK21S-005、CK21S-005-b、CK21S-006、CK21S-006-b、CK21S-007、CK21S-008、CK21S-009和Triptolide体外免疫抑制活性
小鼠脾脏淋巴细胞制备
BALB/c小鼠脱脊椎处死,无菌取其脾脏,制备单细胞悬液,调至所需浓度。
细胞增殖试验
常规制备4×106个/ml脾脏淋巴细胞悬液,于96孔板中每孔加细胞100μL,加入50μL不同浓度受试样品,同时加入ConA(终浓度5μg/mL)诱导T淋巴细胞活化增殖,或者LPS(终浓度10μg/mL)50μL诱导B淋巴细胞活化增殖,另设相应的阳性对照及无刺激本底对照。37℃,5%CO2培养箱中培养48h。培养结束前8h掺入0.25μCi 3H-thymidine。培养结束时,将培养板冻存于-20℃冰箱,待测。测定时用细胞收集仪将细胞收集至玻璃纤维膜上,加入闪烁液后于Beta计数仪上读取掺入细胞DNA的3H-胸腺嘧啶核苷酸量,以cpm值代表细胞增殖的情况。
化合物CK21S-001、CK21S-001-b、CK21S-002、CK21S-002-b、CK21S-003、CK21S-003-b、CK21S-004、CK21S-004-b、CK21S-005、CK21S-005-b和Triptolide体外免疫抑制活性IC50值见表4,化合物均具有体外免疫抑制活性,且活性和阳性对照Triptolide的活性相当。
表4体外免疫抑制活性IC50(μM)
实施例13:
检测小分子化合物CK21S-005和Triptolide的体内抗肿瘤活性
将人胰腺癌细胞AsPC-1通过皮下接种法接种在雄性裸鼠右侧侧腹部皮下。荷瘤小鼠被随机分成5组,分别为阴性对照组(Control,n=8,空白乳剂,i.p./i.v.,qd);Triptolide组(Triptolide,n=8,0.25mg/kg,i.v.,qd);阳性对照组(吉西他滨,n=8,50mg/kg,i.p.,tiw);CK21S-005乳剂组(CK21S-005乳剂,n=8,5mg/kg,i.p./i.v.,qd);CK21S-005乳剂组(CK21S-005乳剂,n=8,2.5mg/kg,i.p./i.v.,qd)。小鼠按分组进行给药,直至实验结束。在2周给药期间,监测肿瘤大小和荷瘤小鼠体重随时间的变化,以及实验结束时的瘤体称重,来综合评价药物CK21S-005对肿瘤生长的抑制效果。
其中乳剂的配制方法如下:称取处方量的注射用油,加热至70-90℃,称取处方量原料分散于油相中,剪切搅拌使彻底溶解,形成油相;称取处方量的注射用水,水浴加热至70℃,加入处方量的磷脂,助乳化剂,甘油等,剪切使分散,形成水相;在高速剪切条件下,将油相缓慢加入水相,剪切3-15min,形成初乳;初乳在400-1000bar压力条件下高压均质3-6次形成均匀分布的乳剂;乳剂分装至玻璃容器(比如安剖)后,121℃,15分钟进行湿热灭菌;灭菌后样品送QC实验室进行检验。
根据肿瘤体积和瘤重数据显示(见图1):CK21S-005乳剂5mg/kg(标记为5mpk)、CK21S-005乳剂2.5mg/kg(标记为2.5mpk)、Triptolide乳剂0.25mg/kg静脉或腹腔给药对胰腺癌AsPC-1荷瘤小鼠有显著性抑制作用,显著优于阳性对照吉西他滨组。
根据小鼠体重数据显示(见图2):CK21S-005乳剂(2.5mg/kg、5mg/kg)、Triptolide乳剂0.25mg/kg给药(静脉或腹腔给药)后小鼠体重明显降低。Triptolide乳剂(0.25mg/kg)在连续i.v.给药第6天起,小鼠陆续出现死亡,尾部出现严重溃烂,尸体解剖见全肺呈黑色坏死,5/8的小鼠发生死亡。Triptolide乳剂在该剂量下的毒性大,为致死剂量。CK21S-005乳剂组小鼠未见死亡,8只小鼠全部存活至给药结束,由此可见CK21S-005的安全性优于Triptolide。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (15)
1.一种如通式I所示的化合物、或其药学上可接受的盐、或其对映异构体、或其非对映异构体,
式中,
R1是取代或未取代的以下基团:C3-C8环烷基、C6-C10芳基、C7-C15芳基烷基或4-8元杂芳基;
Y是O或NH;
R2是-C(=O)R4,其中R4是取代或未取代的以下基团:C3-C8环烷基、C6-C10芳基、C7-C15芳基烷基或4-8元杂芳基;
各X独立为H;
上述各取代独立指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、C1-C8烷基、C1-C8烷氧基;
其中,上述各杂芳基独立包含选自下组的1-3个杂原子:N、O或S。
2.如权利要求1所述的化合物,其特征在于,Y是O。
3.如权利要求1所述的化合物,其特征在于,R1是取代或未取代的以下基团:C3-C6环烷基、C6-C10芳基或4-8元杂芳基,所述取代指基团上的一个或多个氢原子被选自下组的取代基取代:未取代或卤代的C1-C4烷基、C1-C3烷氧基。
4.如权利要求1所述的化合物,其特征在于,R4是取代或未取代的以下基团:C3-C6环烷基、C6-C10芳基、C7-C15芳基烷基或4-8元杂芳基,所述取代指基团上的一个或多个氢原子被选自下组的取代基取代:卤素、C1-C4烷基、C1-C3烷氧基。
5.如权利要求1所述的化合物,其特征在于,R3是OH、OBoc、OCH2OP(=O)(OH)2、-OCH2OP(=O)(OBn)2、OCH2SCH3或OCH2OCH3。
6.如权利要求1所述的化合物,其特征在于,R3是β-OH。
7.如权利要求1所述的化合物,其特征在于,R1是环己基、正丙基、正丁基、苯基、2-呋喃基、对甲基苯基、对甲氧基苯基或对三氟甲基苯基。
8.如权利要求1所述的化合物,其特征在于,R1和R4相同。
9.如权利要求1所述的化合物,其特征在于,R1和R4不同。
10.如权利要求1所述的化合物,其特征在于,R4是环己基、苯基、2-呋喃基、对甲基苯基、对三氟甲基苯基或对甲氧基苯基。
12.如权利要求1所述的化合物的制备方法,其特征在于,R2为-C(=O)R4,R1=R4,所述制备方法包括以下步骤:雷公藤内酯醇与酰化试剂得到式II化合物,式II化合物衍生得到式III化合物,其中所述酰化试剂为R1COCl、R1COBr或R1COOCOR1;
或者R2为-C(=O)R4,R1≠R4,所述制备方法包括以下步骤:雷公藤内酯醇分别与第一酰化试剂、第二酰化试剂反应得到式II化合物,式II化合物衍生得到式III化合物,所述第一酰化试剂为R1COCl、R1COBr或R1COOCOR1,所述第二酰化试剂为R4COCl、R4COBr、R4COOCOR4;
各式中,R1、R4、R5的定义如权利要求1所述。
13.一种药物组合物,其特征在于,所述药物组合物包含:
权利要求1所述的化合物、或其药学上可接受的盐、或其对映异构体、或其非对映异构体;和
药学上可接受的载体。
14.如权利要求1所述的化合物、或其药学上可接受的盐、或其对映异构体、或其非对映异构体或者权利要求13所述的药物组合物的用途,其特征在于,用于:
a)制备治疗肿瘤的药物;
b)制备诱导细胞凋亡的药物;和/或
c)制备免疫抑制药物。
15.如权利要求14所述的用途,其特征在于,所述肿瘤选自下组:白血病、胃肠间质瘤、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、宫颈癌、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌。
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