CN116903611A - 一种酞嗪酮类化合物、其制备方法、包含其药物组合物及其应用 - Google Patents
一种酞嗪酮类化合物、其制备方法、包含其药物组合物及其应用 Download PDFInfo
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- CN116903611A CN116903611A CN202210096000.0A CN202210096000A CN116903611A CN 116903611 A CN116903611 A CN 116903611A CN 202210096000 A CN202210096000 A CN 202210096000A CN 116903611 A CN116903611 A CN 116903611A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Abstract
本发明提供了一种酞嗪酮类化合物、其制备方法、包含其药物组合物及其应用,具体地,所述化合物具有式I所示结构,其可与MTA协同抑制PRMT5,可用于制备治疗与MTAP‑/‑相关的癌症的药物。
Description
技术领域
本发明涉及药物化学领域,更具体而言,本发明涉及一种酞嗪酮类化合物,其可以作为MTA协同的PRMT5抑制剂,制备用于治疗MTAP-/-相关的癌症的药物。
背景技术
蛋白质精氨酸N-甲基转移酶(PRMT)根据产生的甲基精氨酸的种类分为I型、II型和III型。I型主要催化甲基从S-腺苷-L-甲硫氨酸(SAM)转移到蛋白质L-精氨酸的胍基的ω氨氮上生成单甲基精氨酸(MMA)以及将第二个甲基转移到胍基的同一个ω氨氮上产生不对称二甲基精氨酸(aDMA);II型主要催化生成MMA以及将第二个甲基转移到另一个ω氨氮上产生对称二甲基精氨酸(sDMA);III型仅催化生成MMA。其中,PRMT5是一种II型蛋白精氨酸甲基转移酶,在调节细胞进程中起着重要作用,包括DNA修复、细胞周期进展、转录调控和RNA剪接等。PRMT5的上调可导致多种癌症,包括肝癌、乳腺癌、皮肤癌、胰腺癌、头颈癌、肠癌、肺癌、胃癌、食管癌、肾癌、膀胱癌、尿道癌、前列腺癌、睾丸癌、子宫癌、卵巢癌、阴道癌、输卵管癌症、胆管癌、多发性骨髓瘤、脊髓神经纤维瘤、星形细胞瘤、神经胶质瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、肉瘤。
甲硫腺苷磷酸化酶(MTAP)位于p16/CDKN2a基因附近,并在大约15%的人类癌症中与p16/CDKN2a共缺失。这种共缺失导致恶性肿瘤的预后差,缺乏有效的分子靶向治疗。MTAP是甲硫腺苷(MTA)的代谢酶,催化MTA转化为腺苷和5-甲硫基核糖-1-磷酸。在肿瘤细胞中,MTAP缺失导致MTA的积聚,由于MTA结构上和SAM类似,可竞争性抑制PRMT5,形成PRMT5-MTA复合物。基于这一复合物设计的小分子抑制剂,可以选择性地杀死肿瘤细胞,对正常细胞影响小,提高药物安全性。
我们相信在MTAP缺失的癌症中,MTA协同抑制PRMT5活性将为多种癌症提供治疗益处。目前缺乏有效的分子靶向治疗,因此有必要开发新的MTA协同的PRMT5抑制剂,其能够在MTA浓度升高的情况下抑制PRMT5活性,用于治疗MTAP缺失的相关癌症。
发明内容
本发明目的是提供一种更加高效、成药性更好的MTA协同的PRMT5抑制剂。
本发明的第一方面,提供一种式I所示的化合物、或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,
其中,
R1a和R1b各自独立地为氢或C1-C3烷基,或者R1a和R1b一起构成氧代(=O),或者R1a和R1b与它们相连的碳原子形成的3-5元碳环基;其中,所述烷基或碳环基可任选地被卤素或C1-C3烷基取代;
R2a和R2b各自独立地为氢或C1-C3烷基,或者R2a和R2b一起构成氧代(=O);其中,所述烷基可任选地被卤素或C1-C3烷基取代;
q为1或2;
R3选自:C6-C10芳基-L-或5-10元杂芳基-L-,其中,所述芳基、杂芳基可任选地被1-3个R’取代;
每个R’各自独立地选自:卤素、氨基、氰基、氧代(=O)、C1-C3羟基烷基、-Y-C1-C3烷基、3-10元碳环基-L’-Y-、3-10元杂环基-L’-Y-、C6-C10芳基-L’-Y-或5-10元杂芳基-L’-Y-,其中,所述的烷基、芳基、杂芳基、碳环基、杂环基可任选地被1-3个R”取代;
每个R”独立地选自:氰基、氧代(=O)、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基或3-8元杂环基;
每个Y各自独立地选自:不存在、-O-、-S-、-NRc-、-NRcCO-、-SO-、-SO2-、-CH(OH)-或-CO-;
每个L和L’各自独立地选自:不存在或-CRdRe-;
Rc、Rd和Re各自独立地选自:氢或C1-C3烷基;其中,所述烷基可任选地被卤素或C1-C3烷基取代;
R4为H、卤素、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基;
X1、X2、X3各自独立地为CR5或N,并且X1、X2和X3最多同时有两个为N;
每个R5各自独立地选自:H、卤素、羟基、氨基、氰基、-C1-C3烷基、-C1-C3羟基烷基、C2-C4烯基或C2-C4炔基;其中,所述烷基、C2-C4烯基或C2-C4炔基可任选地被卤素或C1-C3烷基取代。
在另一优选例中,R1a和R1b各自独立地为氢或者R1a和R1b一起构成氧代(=O)。
在另一优选例中,q为1。
在另一优选例中,R2a和R2b各自独立地为氢或者R2a和R2b一起构成氧代(=O);q为1。
在另一优选例中,R3选自:
其中,
每个R6各自独立地选自:卤素、氨基、氰基、氧代(=O)、C1-C3羟基烷基、-Y-C1-C3烷基、3-10元碳环基-L’-Y或-3-10元杂环基-L’-Y-,其中,所述的烷基、碳环基、杂环基可任选地被1-3个R”取代;
每个R”独立地选自:氰基、氧代(=O)、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基或3-8元杂环基;
每个Y各自独立地选自:不存在、-O-、-S-、-NRc-、-NRcCO-、-SO-、-SO2-、-CH(OH)-或-CO-;
每个L和L’各自独立地选自:不存在或-CRdRe-;
Rc、Rd和Re各自独立地选自:氢或C1-C3烷基;
m为0、1、2、3或4;
R7为H或C1-C3烷基。
在另一优选例中,R4为H、卤素、C1-C3烷基、C1-C3卤代烷基或C1-C3烷氧基;优选地,R4为H、氯、氟、甲基、乙基、甲氧基或三氟甲基。
在另一优选例中,X1为CR5;X2为N;X3为CR5;每个R5各自独立地为H、卤素、羟基、氨基、氰基、-C1-C3羟基烷基、C2-C4烯基或C2-C4炔基;
优选地,X1为CH;X2为N;X3为CH。
在另一优选例中,每个R6各自独立地选自:卤素、氨基、氰基、氧代(=O)、C1-C3羟基烷基、C1-C3烷基、C1-C3卤代烷基、C1-C3烷基-O-、C3-C6环烷基、C3-C6环烷基-O-、C3-C6环烷基CH2-、C3-C6环烷基CH2-O-、-CONRcC3-C6环烷基、CONRcC1-C3烷基、CONRcC1-C3卤代烷基。
在另一优选例中,R1a、R1b、R2a、R2b、R3、R4、R5、R6、q、X1、X2、X3、Y、L和L’为实施例中各具体化合物所对应基团。
在另一优选例中,所述化合物选自下组:
在另一优选例中,所述化合物为实施例中所示化合物。
本发明第二方面,提供一种药物组合物,其中,所述药物组合物包括:
(1)治疗有效量的选自第一方面所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物和氘代物中的一种或多种作为活性成分;和
(2)任选地,药学上可接受的载体。
9.如第一方面所述的化合物,其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物或氘代物或第二方面所述的药物组合物在制备用于预防或治疗MTAP-/-相关的癌症的药物中的用途。
在另一优选例中,所述癌症选自:肝癌、乳腺癌、皮肤癌、胰腺癌、头颈癌、肠癌、肺癌、胃癌、食管癌、肾癌、膀胱癌、尿道癌、前列腺癌、睾丸癌、子宫癌、卵巢癌、阴道癌、输卵管癌症、胆管癌、多发性骨髓瘤、脊髓神经纤维瘤、星形细胞瘤、神经胶质瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、肉瘤。
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。限于篇幅,在此不再一一累述。
具体实施方式
本发明人经过广泛而深入地研究,首次意外地开发了一种可有效抑制MTA协同的PRMT5的酞嗪酮类化合物,可用于制备治疗与MTAP-/-相关的癌症的药物。在此基础上,完成了本发明。
术语说明
除非另外定义,否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。
如本文所用,术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…构成”、或“由…构成”。
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,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
基团定义
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4THED."Vols.A(2000)and B(2001),Plenum Press,New York)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-C6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、芳基烷基、杂芳基烷基取代的氨基,例如,单烷基氨基、二烷基氨基、烷基酰氨基、芳基烷基氨基、杂芳基烷基氨基。
“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”是指完全饱和的直链或支链的烃链基,仅由碳原子和氢原子组成、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1个或多个单键与分子的其余部分连接,例如包括但不限于甲基、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。就本发明而言,术语“烷基”优选指含有1至6个碳原子的烷基。
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1个或多个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。
本文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、含有至少一个碳-碳三键、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1个或多个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、1-丙炔基、1-丁炔基、庚炔基、辛炔基等。
在本申请中,作为基团或是其它基团的一部分,术语“碳环(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,更优选3至6个碳原子(即C3-C6),且其为饱和或不饱和环(即环烷基、环烯基等)并可经由任何适宜的碳原子通过1个或多个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,碳环基中的碳原子可以任选地被氧化。碳环基的实例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基、2,3-二氢化茚基、八氢-4,7-亚甲基-1H-茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、环戊烯基、环己烯基、环己二烯基、1H-茚基、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[1.1.1]戊烷、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“环烷基”是指上述完全饱和的碳环(基),典型的环烷基包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、金刚烷基等。
在本申请中,作为基团或是其它基团的一部分,术语“环烯基”是指部分不饱和的碳环(基),典型的环烯基包括但不限于环丁烯基、环戊烯基、环己烯基等。
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1个或多个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-氮杂双环[2.2.2]辛烷基、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,即C6-C10芳基)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碳环基或杂环基稠合,条件是芳基经由芳香环上的原子通过1个或多个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碳环基或杂环基稠合,条件是杂芳基经由杂芳香环上的原子通过1个或多个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,术语“不存在”是指被上文所定义的基团的两侧直接通过化学键相连。例如,“A-B-C中B是不存在”表示“A-C”。
在本申请中,中的/>表示基团R的连接位置。
在本申请中,除权利要求中特殊说明外,“任选地”、“任选”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,“任选取代的芳基”表示芳基上的氢被取代或未被取代,且该描述同时包括被取代的芳基与未被取代的芳基。例如,在没有明确列出取代基的情况下,本文所用的术语“任选取代的”、“被取代的”或“被……取代”意指给定的原子或基团上的一个或多个氢原子独立地被一个或多个、例如1、2、3或4个取代基取代,所述取代基独立地选自:氘(D)、卤素、-OH、氧代(=O)、巯基、氰基、-CD3、-C1-C6烷基(优选-C1-3烷基)、C2-C6烯基、C2-C6炔基、环烷基(优选C3-C8环烷基)、芳基、杂环基(优选3-8元杂环基)、杂芳基、芳基-C1-C6烷基-、杂芳基-C1-C6烷基-、C1-C6卤代烷基-、-OC1-C6烷基(优选-OC1-C3烷基)、-OC2-C6烯基、-O环烷基、-O杂环基、-O芳基、-O杂芳基、-OC1-C6烷基苯基、-C1-C6烷基-OH(优选-C1-C4烷基-OH)、-C1-C6烷基-SH、-C1-C6烷基-O-C1-C6烷基、-OC1-C6卤代烷基、-NH2、-C1-C6烷基-NH2(优选-C1-C3烷基-NH2)、-N(C1-C6烷基)2(优选-N(C1-C3烷基)2)、-NH(C1-C6烷基)(优选-NH(C1-C3烷基))、-N(C1-C6烷基)(C1-C6烷基苯基)、-NH(C1-C6烷基苯基)、-N(C1-C6烷基)(芳基)、-NH(芳基)、硝基、-C(O)-OH、-C(O)OC1-C6烷基(优选-C(O)OC1-C3烷基)、-CONRiRii(其中Ri和Rii是H、D和C1-6烷基,优选C1-3烷基)、-NHC(O)(C1-C6烷基)、-NHC(O)(苯基)、-N(C1-C6烷基)C(O)(C1-C6烷基)、-N(C1-C6烷基)C(O)(苯基)、-C(O)C1-C6烷基、-C(O)杂芳基(优选-C(O)-5-7元杂芳基)、-C(O)C1-C6烷基苯基、-C(O)C1-C6卤代烷基、-OC(O)C1-C6烷基(优选-OC(O)C1-C3烷基)、-S(O)2-C1-C6烷基、-S(O)-C1-C6烷基、-S(O)2-苯基、-S(O)2-C1-C6卤代烷基、-S(O)2NH2、-S(O)2NH(C1-C6烷基)、-S(O)2NH(苯基)、-NHS(O)2(C1-C6烷基)、-NHS(O)2(苯基)和-NHS(O)2(C1-C6卤代烷基),其中所述的烷基、烯基、炔基、环烷基、苯基、芳基、杂环基和杂芳基中的每一个任选被一个或多个选自以下的取代基进一步取代:卤素、-OH、氧代(=O)、-NH2、环烷基、3-8元杂环基、C1-C4烷基、C1-C4卤代烷基-、-OC1-C4烷基、-C1-C4烷基-OH、-C1-C4烷基-O-C1-C4烷基、-OC1-C4卤代烷基、氰基、硝基、-C(O)-OH、-C(O)OC1-C6烷基、-CON(C1-C6烷基)2、-CONH(C1-C6烷基)、-CONH2、-NHC(O)(C1-C6烷基)、-NH(C1-C6烷基)C(O)(C1-C6烷基)、-SO2(C1-C6烷基)、-SO2(苯基)、-SO2(C1-C6卤代烷基)、-SO2NH2、-SO2NH(C1-C6烷基)、-SO2NH(苯基)、-NHSO2(C1-C6烷基)、-NHSO2(苯基)和-NHSO2(C1-C6卤代烷基)。当一个原子或基团被多个取代基取代时,所述取代基可以相同或不同。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。
在本发明中,(C1-C4烷基)2氨基,代表2个C1-C4烷基取代的胺,例如可以是等。
本发明中“多个”是指2、3或4个。
活性成分
如本文所用,“本发明化合物”或“活性成分”指式I所示的化合物,并且还包含其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合。
“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),例如可参见GeraldGübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004;A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010;Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIA OFPRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and TechnicalLtd.,Essex,1991,809-816;Heller,Acc.Chem.Res.1990,23,128。
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。
药物组合物和施用方法
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。
通式(I)所述化合物可以与已知的治疗或改进相似病状的其他药物联用。联合给药时,原来药物的给药方式和剂量可以保持不变,而同时或随后服用式I的化合物。当式I化合物与其它一种或几种药物同时服用时,可以优选使用同时含有一种或几种已知药物和式I化合物的药用组合物。药物联用也包括在重叠的时间段服用式I化合物与其它一种或几种已知药物。当式I化合物与其它一种或几种药物进行药物联用时,式I化合物或已知药物的剂量可能比它们单独用药的剂量低。
可以与通式(I)所述化合物进行药物联用的药物或活性成分包括但不局限为:PD-1抑制剂(如纳武单抗、派姆单抗等)、PD-L1抑制剂(如度伐单抗、阿特珠单抗atezolizumab等)、CD47抗体(如Hu5F9-G4,CC-90002等)、CD20抗体(如利妥昔单抗、伊布单抗等)、KRAS抑制剂(如AMG510等)、ALK抑制剂(如色瑞替尼、艾乐替尼、布加替尼、劳拉替尼、奥卡替尼)、EGFR抑制剂(如阿法替尼、吉非替尼、厄洛替尼、拉帕替尼、达克替尼、艾克替尼、奥希替尼等)、VEGFR抑制剂(如索拉非尼、帕唑帕尼、瑞戈非尼、卡博替尼、舒尼替尼等)、PI3K抑制剂(如Dactolisib、Taselisib等)、BTK抑制剂(如依鲁替尼、替拉布替尼、阿卡布替尼、泽布替尼、维卡布替尼等)、HDAC抑制剂(如Vorinostat、Fimepinostat、Givinostat、Tucidinostat等)、CDK抑制剂(如帕博西尼、Ribociclib、Abemaciclib等)、MEK抑制剂(如司美替尼(AZD6244)、Trametinib等)、ERK抑制剂(如BVD523、HH2710等)、mTOR抑制剂(如Vistusertib等)、SHP2抑制剂(如RMC-4630、JAB-3068)、SOS1抑制剂(如BI1701963等)、PRMT1抑制剂、MAT2A抑制剂或其组合。
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。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
本发明所述“肿瘤”包括但不限于肺癌、胰腺癌、结直肠癌、白血病、尤文氏肉瘤、乳腺癌、前列腺癌、T细胞淋巴瘤、B细胞淋巴瘤、恶性横纹肌瘤、滑膜肉瘤、子宫内膜瘤、胃癌、肝癌、肾癌、黑色素瘤、卵巢癌、脑胶质瘤、胆管癌、鼻咽癌、宫颈癌、头颈癌、食管癌、甲状腺癌和膀胱癌等疾病。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,例如在Goodman and Gilman,ThePharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington’s,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。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。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
化合物的制备方法
以下方案中描述了制备式I所示化合物的方法。在某些情况下,可以改变执行反应方案的步骤的顺序,以促进反应或避免不需要的副反应产物。本发明的化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。
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、烯丙基等。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、9-芴基甲氧基羰基、苄基、对甲氧基苄基、烯丙基、烯丙基氧羰基、对甲苯磺酰基、特戊酰基、三氟乙酰基等。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。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in OrganiSynthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。
通常,在制备流程中,各反应通常在惰性溶剂中,在室温至回流温度(如0常,在制备流,优选10选在制备流程中下进行。反应时间通常为0.1小时-60小时,较佳地为0.5-48小时。
优选地,所述式I化合物可通过如下方法制备:
(1)化合物a与b发生还原胺化反应或先生成亚胺再发生亲和加成反应得到化合物c;
(2)化合物c在缩合剂存在下,发生缩合反应或在碱存在下发生氨解反应生成化合物d;
(3)化合物d与化合物e发生Suzuki反应生成化合物I;
优选地,化合物d还可以通过化合物f和化合物b在碱存在下直接生成化合物d。
优选地,所述缩合剂选自下组:二环己基碳二亚胺、二异丙基碳二亚胺、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐、1-羟基-7-偶氮苯并三氮唑、1-羟基苯并三唑、N-羟基丁二酰亚胺、N,N,N,N′-四甲基-O-(7-氮杂苯并三唑-1-基)六氟磷酸脲、苯并三氮唑-N,N,N,N'-四甲基脲六氟磷酸盐、1H-苯并三唑-1-基氧代三(二甲氨基)磷鎓六氟磷酸盐、丙基磷酸酐、2-羟基吡啶氮氮化物、1H-苯并三唑-1-基氧三吡咯烷基六氟磷酸盐或其组合;
所述碱选自下组:氢化钠、甲醇钠、乙醇钠、叔丁醇钾、叔丁醇钠、氢氧化钠、氢氧化钾、正丁基锂、二异丙基氨基锂、六甲基二硅基氨基锂、六甲基二硅基氨基钠、六甲基二硅基氨基钾、碳酸钾、碳酸铯、碳酸钠、三乙胺、二异丙基乙基胺、1.8-二氮杂二环[5.4.0]十一烷-7-烯、或其组合;
其中,R1a、R1b、R2a、R2b、R3、R4、X1、X2和X3的定义如上所述。
相对于现有技术,本发明具有以下有益效果:
(1)本发明提供了一种结构新颖的如式I所示的化合物或其药学上可接受的盐;
(2)本发明化合物可与MTA协同抑制PRMT5,其可用于制备治疗与MTAP-/-相关的癌症的药物。
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了,所述实施例仅仅是帮助理解本发明,不应视为对本发明的具体限制。
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,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。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
各实施例中,1H NMR由BRUKER AVANCE NEO 400MHz型核磁共振仪记录,化学位移以δ(ppm)表示;液质联用(LCMS)由Shimadzu LC-20AD,SIL-20A,CTO-20AC,SPD-M20A,CBM-20A,LCMS-2020型质谱仪记录;制备HPLC分离使用Gilson-281型号液相色谱仪。
实施例
1、中间体A的制备
(1)化合物A-1的合成参考专利WO2021050915A1。
MS-ESI[M+H]+,计算值354,实测值354。
1H NMR(400MHz,DMSO-d6)δ12.69(s,1H),8.26(s,1H),8.17(d,J=8.4Hz,1H),8.02(dd,J=1.6,8.4Hz,1H),4.41(d,J=6.0Hz,2H),1.40(s,9H)。
(2)向化合物A-1(200mg,565μmol)的二氧六环(5.0mL)溶液中,加入频哪醇硼酸酯(175mg,689μmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(40.0mg,54.7μmol)和醋酸钾(115mg,1.17mmol)。反应液在氮气保护下80℃搅拌1小时。反应液加入水(10.0mL),用乙酸乙酯(10.0mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=10:1)分离得到化合物A。
MS-ESI[M+H]+,计算值320,实测值320。
2、中间体B的制备
(1)0℃下,向化合物B-1(100g,399mmol)的四氢呋喃(1000mL)溶液中,滴加异丙基氯化镁(2.0mol/L,240mL)的四氢呋喃溶液。反应液在氮气保护下25℃搅拌4小时。-70℃下向反应液中加入干冰(3.0kg),25℃搅拌4小时。反应液加入水(300mL),减压浓缩除去四氢呋喃。水相用乙酸乙酯(200mL×3)洗涤,水相用盐酸(4.0mol/L)调节pH值到1,析出固体,过滤,得到滤饼为化合物B-2。
1H NMR(400MHz,DMSO-d6)δ8.82(d,J=6.8Hz,2H),2.60(s,3H)。
(2)向化合物B-2(10.0g,46.3mmol)的甲醇(120.mL)溶液中加入二氯亚砜(10.0mL,138mmol)。反应液在80℃下搅拌12小时。反应液加入水(50.0mL),用饱和碳酸氢钠水溶液调节pH到7,用乙酸乙酯(100mL×2)萃取,合并有机相,用饱和氯化钠水溶液(100mL×1)洗涤。无水硫酸钠干燥,过滤并减压浓缩,得到化合物B-3。
MS-ESI[M+H]+,计算值230,实测值230。
1H NMR(400MHz,CDCl3)δ8.86-8.92(m,1H),8.74-8.79(m,1H),3.94(d,J=4.4Hz,3H),2.63-2.73(m,3H)。
(3)向化合物B-3(1.0g,4.35mmol)的乙酸(15.0mL)溶液中,加入二氧化硒(1.0g,9.01mmol)。反应液在氮气保护下130℃搅拌2小时。反应液过滤,减压浓缩,得到化合物B。
MS-ESI[M+H]+,计算值246,实测值246。
1H NMR(400MHz,CDCl3)δ10.25(s,1H),9.07(d,J=4.0Hz,2H),3.90(s,1H))。
3、中间体C的制备
(1)向化合物C-1(4.00g,27.4mmol)的乙醇(60.0mL)溶液中,滴加甲基肼(4.74g,103mmol,5.42mL)。反应液在氮气保护下70℃搅拌4小时。反应液过滤,得到滤饼为化合物C。
MS-ESI[M+H]+,计算值173,实测值173。
1H NMR(400MHz,CDCl3)δ7.41-7.47(m,1H),7.33-7.40(m,2H),3.88(s,3H)。
4、中间体D的制备
(1)向化合物D-1(2.50g,17.1mmol)的乙醇(40.0mL)溶液中,滴加水合肼(3.19g,62.5mmol,3.10mL)。反应液在氮气保护下70℃搅拌15小时。反应液过滤,得到滤饼为化合物D-2。
MS-ESI[M+H]+,计算值159,实测值159。
1H NMR(400MHz,DMSO-d6)δ7.65(d,J=8.0Hz,1H),7.48(d,J=8.0Hz,1H),7.4-7.4(m,1H),5.10(s,2H)。
(2)向化合物D-2(2.08mg,13.2mmol)的丙酮(30.0mL)溶液中加入碳酸钾(2.00g,14.5mmol)和硫酸二甲酯(2.18g,17.3mmol,1.64mL)。反应液在氮气保护下25℃搅拌12小时,加入硫酸二甲酯(2.50g,19.8mmol,1.88mL),反应液在氮气保护下25℃下继续搅拌16小时。反应液加入水(20.0mL),用二氯甲烷(50.0mL×3)萃取,合并有机相,用饱和氯化钠水溶液(20.0mL×3)洗涤。无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇=1:0到10:1)分离得到化合物D。
MS-ESI[M+H]+,计算值173,实测值173。
1H NMR(400MHz,DMSO-d6)δ7.60(d,J=8.0Hz,1H),7.31(d,J=8.0Hz,1H),7.12-7.24(m,1H),5.76(s,2H),3.88(s,3H)。
实施例1合成化合物1
(1)向中间体B(1.20g,4.92mmol)的二氯甲烷(20.0mL)溶液中加入化合物C(650mg,3.77mmol)和乙酸(210mg,3.50mmol)。反应液在氮气保护下25℃搅拌12小时,加入氰基硼氢化钠(500mg,7.96mmol),反应液在氮气保护下25℃下搅拌2小时。反应液加入水(10.0mL),用二氯甲烷(10.0mL×3)萃取,合并有机相,用饱和氯化钠水溶液(10.0mL×3)洗涤。无水硫酸钠干燥,过滤,减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到3:1)分离得到化合物1-1。
MS-ESI[M+H]+,计算值402,实测值402。
1H NMR(400MHz,CDCl3)δ8.80(d,J=13.2Hz,2H),7.28-7.41(m,3H),5.15(s,2H),4.12(s,3H),3.80(s,3H)。
(2)向化合物1-1(170mg,425μmol)的四氢呋喃(5.0mL)溶液中加入叔丁醇钠(62.0mg,645μmol)。反应液在25℃下搅拌2小时。反应液加入水(10.0mL),用乙酸乙酯(10.0mL×3)萃取,合并有机相用饱和氯化钠水溶液(10.0mL×2)洗涤,无水硫酸钠干燥,过滤并减压浓缩,粗品经硅胶柱层析法(石油醚/乙酸乙酯=1:0到2:1)分离得到化合物1-2。
MS-ESI[M+H]+,计算值370,实测值370。
1H NMR(400MHz,CDCl3)δ9.16(s,1H),8.99(s,1H),7.74(d,J=8.4Hz,1H),7.60-7.66(m,1H),7.53-7.59(m,1H),5.13(s,2H),4.17(s,3H)。
(3)向化合物1-2(15.0mg,40.7μmol)的二氧六环(3.0mL)溶液中,加入化合物A(150mg,118μmol)、水(1.0mL)、碳酸钾(90mg,651μmol)和甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(30mg,35.4μmol)。反应液过滤,减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇=1:0到25:1)分离得到化合物1-3。
MS-ESI[M+H]+,计算值563,实测值563。
1H NMR(400MHz,CDCl3)δ10.21(s,1H),9.33(s,1H),9.01(s,1H),8.60(d,J=7.2Hz,1H),8.27(s,1H),7.99(d,J=6.0Hz,1H),7.70(d,J=8.4Hz,1H),7.61(d,J=7.2Hz,1H),7.49-7.56(m,1H),5.31(s,2H),4.67(s,2H),4.13(s,3H),1.33(s,9H)。
(4)向化合物1-3(3.0mg,5.33μmol)的二氯甲烷(1.0mL)溶液中加入盐酸的二氧六环溶液(4.0mol/L,0.50mL)。反应液在25℃下搅拌20分钟。反应液减压浓缩,得到化合物1的盐酸盐。
MS-ESI[M+H]+,计算值463,实测值463。
1H NMR(400MHz,MeOD)δ9.07-9.15(m,1H),9.00(s,1H),8.43(d,J=8.4Hz,1H),8.04-8.13(m,2H),7.92(d,J=8.8Hz,1H),7.70(d,J=7.2Hz,1H),7.55-7.62(m,1H),4.68(s,2H),4.13(s,2H),4.08(s,3H)。
实施例2合成化合物2
(1)向中间体B(198mg,813μmol)的甲苯(10.0mL)溶液中加入化合物D(140mg,813μmol)和钛酸四异丙酯(462mg,1.63mmol)。反应液在氮气保护下80℃搅拌12小时,加入氰基硼氢化钠(102mg,1.63mmol),反应液在氮气保护下80℃下搅拌2小时,补加氰基硼氢化钠(102mg,1.63mmol),反应液在氮气保护下40℃继续搅拌12小时。反应液加入水(20.0mL),用二氯甲烷(50.0mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩,粗品经制备高效液相色谱法(C18-6,100mm×30mm 5μm,A:水(甲酸);B:乙腈,26%-56%:15分钟)分离得到化合物2-1。
MS-ESI[M+H]+,计算值388,实测值388。
1H NMR(400MHz,DMSO-d6)δ8.90(s,1H),8.78(s,1H),7.65-7.75(m,1H),7.42-7.46(m,1H),7.21-7.27(m,1H),4.80(d,J=6.0Hz,2H),4.15(s,1H),3.81(s,3H)。
(2)向化合物2-1(25.0mg,64.7μmol)的N,N-二甲基甲酰胺(1.0mL)溶液中加入丙基磷酸酐(1.8mg,97.1μmol,57.8μL,50.0%)和二异丙基乙基胺(25.1mg,194μmol,33.8μL)。反应液在25℃下搅拌1小时。反应液加入水(20.0mL),用二氯甲烷(50.0mL×3)萃取,合并有机相用饱和氯化钠水溶液(50.0mL×2)洗涤,无水硫酸钠干燥,过滤并减压浓缩,得到化合物2-2。
MS-ESI[M+H]+,计算值368,实测值368。
(3)向化合物2-2(40.0mg,109μmol)的二氧六环(3.0mL)溶液中,加入化合物A(173mg,217μmol)、水(1.0mL)、碳酸钾(45.0mg,326μmol)和甲烷磺酸(2-二环己基膦基-2',4',6'-三-异丙基-1,1'-联苯基)(2'-氨基-1,1'-联苯-2-基)钯(II)(9.2mg,10.9μmol)。反应液加入水(20.0mL),用乙酸乙酯(50.0mL×3)萃取,合并有机相用饱和氯化钠水溶液(50.0mL×2)洗涤,无水硫酸钠干燥,过滤并减压浓缩,粗品经硅胶柱层析法(二氯甲烷/甲醇=1:0到10:1)分离得到化合物2-3。
MS-ESI[M+H]+,计算值563,实测值563。
(4)向化合物2-3(20.0mg,35.6μmol)的二氯甲烷(1.0mL)溶液中加入三氟乙酸(0.20mL)。反应液在25℃下搅拌60分钟。反应液减压浓缩,粗品经制备高效液相色谱法(Welch Xtimate C18,100mm×30mm 0μm,A:水(甲酸);B:乙腈,5%-35%:10分钟)分离得到化合物2的甲酸盐。
MS-ESI[M+H]+,计算值463,实测值463。
1H NMR(400MHz,MeOD)δ9.23-9.25(m,1H),9.11-9.13(m,1H),8.56-8.60(m,1H),8.23-8.26(m,1H),8.20-8.22(m,1H),7.99-8.03(m,1H),7.71(s,1H),7.45-7.50(m,1H),5.34-5.46(m,2H),4.54-4.60(m,2H),4.18-4.20(m,3H)。
生物实验例
I.有或无MTA的情况下对PRMT5抑制活性
实验原理:TR-FRET PRMT5测定是以PRMT5/MEP50复合蛋白为酶,组蛋白H4(1-21)生物素化肽为底物,Eu3+-穴状标记的甲基化组蛋白H4精氨酸3 3H4R3(me)抗体及ULight-链霉亲和素作为检测试剂。该测定分酶促、检测两个步骤,TR-FRET信号与甲基化的组蛋白H4(1-21)生物素化肽浓度成正比。在有或无MTA的情况下进行检测,以确定化合物是否表现出MTA的协同作用。
实验材料:Bicine购自Sigma、氯化钠购自Sigma、二硫苏糖醇购自Sigma、猪皮明胶购自Sigma、吐温-20购自Sigma、SAM购自NEB、Ultra Eu-抗甲基化组蛋白H4精氨酸3抗体购自PE、ULight-链霉亲和素购自PE、LANCE检测缓冲液购自PE、组蛋白H4(1-21)生物素化肽Ac-SGRGKGGKGLGKGGAKRHRKVGG-K购自GL Biochem、PRMT5/MEP50,FLAG-tag,His-tag(HEK293来源)购自BPS、384孔分析板购自Gerinier、384-LDV板购自LABCYTE、培养箱购自Grant-bio公司、酶标仪购自TECAN。
实验方法:
(1).制备缓冲液:20mM Bicine(pH7.6,);25mM氯化钠;2mM二硫苏糖醇(DTT);0.005%猪皮明胶;0.01%吐温-20;无MTA或含0.0026mM MTA。
(2).将待测化合物溶于DMSO,制备10mM储备液。将待测化合物用缓冲液稀释成最高浓度为10μM,3倍稀释,复孔检测。
(3).取适量的PRMT5蛋白酶(4.16μM)母液,加入缓冲液以配置0.0076μM的PRMT5酶反应液。在阳性对照孔中加入缓冲液(5μL/孔),其余每孔加入5μL酶反应液。1000r/min离心30s,放于室温培养箱中孵育30min。
(4).取适量的100%SAM(32000μM)母液及100μM的组蛋白H4(1-21)生物素化肽。首先用缓冲液将SAM母液稀释10倍,并用缓冲液配置含0.32μM组蛋白H4(1-21)生物素化肽、2.6μM SAM(10%)底物混合液。每孔加入5μL底物混合液,1000r/min离心30s,放于室温培养箱中进行孵育90min。
(5).取适量的Eu-抗甲基化组蛋白H4精氨酸3抗体(625nM)、ULight-链霉亲和素(10000nM)及10×LANCE检测缓冲液。用超纯水稀释成含4nM Eu-抗甲基化组蛋白H4精氨酸3抗体,53.3nM ULight-链霉亲和素及1×LANCE检测缓冲液的检测混合液。每孔加入10μL检测混合液,1000r/min离心30s,放于室温培养箱中进行孵育60min。用PerkinElmerEnVision 2105多模式酶标仪读取检测信号(激发光为320/340nm,发射光为665nm),用GraphPad Prism 5.0软件计算化合物的IC50,其结果见表1。
实验结果表明:本发明化合物可有效抑制MTA协同的PRMT5,可用于制备治疗与MTAP-/-相关的癌症的药物。
II.HCT116 MTAP-/-和HCT 116wt细胞增殖抑制活性
实验原理:HCT116 MTAP-/-细胞MTAP缺失,MTA水平升高;HCT 116wt细胞MTAP未缺失,MTA水平正常。通过这两株细胞确定化合物是否表现出MTA协同抑制活性。
实验材料:HCT116 MTAP-/-和HCT 116wt细胞购自Horizon;CellTiter-Glo试剂购自Promega(货号为G7571);RPMI-1640购自ATCC(货号为30-2001):胎牛血清(FBS)购自EXCELL(货号为FND500);青霉素-链霉素购自Gibco(货号为15140-122);0.25%胰蛋白酶-乙二胺四乙酸消化液(Trypsin-EDTA)购自Gibco(货号为25200-072);二甲亚砜(DMSO)购自Sigma(货号为D2650);96孔板购自Corning(货号为3610);培养箱购自NuAire(型号为NU-5700E);倒置显微镜购自Nikon(型号为TS-100);自动细胞计数仪购自Life technologies(型号为Countess II);酶标仪购自PerkinElmer(型号为Envision);数据处理软件为GraphPadPrism 5.0。
试验方法:将处于对数生长期的HCT116 MTAP-/-或者HCT116wt细胞重新悬浮于生长培养基(RPMI-1640+10%FBS)并稀释至目标密度(5000/mL)。将上述细胞悬浮液按照每孔100μL接种至96孔板中;在37℃,5%CO2培养箱中孵育过夜。培养基作为背景对照组。用80μL无血清的培养基饥饿细胞4小时。将待测化合物溶解在DMSO中,配制成浓度为10mmol/L的储备液。首先用DMSO将储备液稀释至2mmol/L(200X),再3倍梯度稀释,共10个浓度。取各浓度的上述溶液3μL,分别用297μL生长培养基稀释(2X)。然后按80μL/孔加入接种细胞的96孔板中。将加入待测化合物的细胞置于37℃,5%CO2培养箱中孵育120小时。室温下平衡96孔板,每孔中加入40μL CellTiter-Glo试剂,涡旋器上混合2分钟,室温孵育60分钟,EnVision酶标仪读取发光值,用GraphPad Prism 5.0software软件计算化合物的IC50,其结果见表2。
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 (10)
1.一种式I所示的化合物、或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,
其中,
R1a和R1b各自独立地为氢或C1-C3烷基,或者R1a和R1b一起构成氧代(=O),或者R1a和R1b与它们相连的碳原子形成的3-5元碳环基;其中,所述烷基或碳环基可任选地被卤素或C1-C3烷基取代;
R2a和R2b各自独立地为氢或C1-C3烷基,或者R2a和R2b一起构成氧代(=O);其中,所述烷基可任选地被卤素或C1-C3烷基取代;
q为1或2;
R3选自:C6-C10芳基-L-或5-10元杂芳基-L-,其中,所述芳基、杂芳基可任选地被1-3个R’取代;
每个R’各自独立地选自:卤素、氨基、氰基、氧代(=O)、C1-C3羟基烷基、-Y-C1-C3烷基、3-10元碳环基-L’-Y-、3-10元杂环基-L’-Y-、C6-C10芳基-L’-Y-或5-10元杂芳基-L’-Y-,其中,所述的烷基、芳基、杂芳基、碳环基、杂环基可任选地被1-3个R”取代;
每个R”独立地选自:氰基、氧代(=O)、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基或3-8元杂环基;
每个Y各自独立地选自:不存在、-O-、-S-、-NRc-、-NRcCO-、-SO-、-SO2-、-CH(OH)-或-CO-;
每个L和L’各自独立地选自:不存在或-CRdRe-;
Rc、Rd和Re各自独立地选自:氢或C1-C3烷基;其中,所述烷基可任选地被卤素或C1-C3烷基取代;
R4为H、卤素、C1-C6烷基、C1-C6卤代烷基或C1-C6烷氧基;
X1、X2、X3各自独立地为CR5或N,并且X1、X2和X3最多同时有两个为N;
每个R5各自独立地选自:H、卤素、羟基、氨基、氰基、-C1-C3烷基、-C1-C3羟基烷基、C2-C4烯基或C2-C4炔基;其中,所述烷基、C2-C4烯基或C2-C4炔基可任选地被卤素或C1-C3烷基取代。
2.如权利要求1所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,R1a和R1b各自独立地为氢或者R1a和R1b一起构成氧代(=O)。
3.如权利要求1-2中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,R2a和R2b各自独立地为氢或者R2a和R2b一起构成氧代(=O);q为1。
4.如权利要求1-3中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,R3选自:
其中,
每个R6各自独立地选自:卤素、氨基、氰基、氧代(=O)、C1-C3羟基烷基、-Y-C1-C3烷基、3-10元碳环基-L’-Y或-3-10元杂环基-L’-Y-,其中,所述的烷基、碳环基、杂环基可任选地被1-3个R”取代;
每个R”独立地选自:氰基、氧代(=O)、卤素、C1-C6烷基、C1-C6卤代烷基、C1-C6烷氧基、C1-C6卤代烷氧基或3-8元杂环基;
每个Y各自独立地选自:不存在、-O-、-S-、-NRc-、-NRcCO-、-SO-、-SO2-、-CH(OH)-或-CO-;
每个L和L’各自独立地选自:不存在或-CRdRe-;
Rc、Rd和Re各自独立地选自:氢或C1-C3烷基;
m为0、1、2、3或4;
R7为H或C1-C3烷基。
5.如权利要求1-3中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,R4为H、卤素、C1-C3烷基、C1-C3卤代烷基或C1-C3烷氧基;优选地,R4为H、氯、氟、甲基、乙基、甲氧基或三氟甲基。
6.如权利要求1-3中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,X1为CR5;X2为N;X3为CR5;每个R5各自独立地为H、卤素、羟基、氨基、氰基、-C1-C3羟基烷基、C2-C4烯基或C2-C4炔基;
优选地,X1为CH;X2为N;X3为CH。
7.如权利要求1-6中任一项所述的化合物,或其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物、氘代物或其组合,其特征在于,所述化合物选自下组:
8.一种药物组合物,其特征在于,所述药物组合物包括:
(1)治疗有效量的选自权利要求1~7中任一项中所述的化合物、其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物和氘代物中的一种或多种作为活性成分;和
(2)任选地,药学上可接受的载体。
9.如权利要求1-7中任一项所述的化合物,其药学上可接受的盐、对映异构体、非对映异构体、互变异构体、顺反异构体、溶剂化物、多晶型物或氘代物或如权利要求8所述的药物组合物在制备用于预防或治疗MTAP-/-相关的癌症的药物中的用途。
10.如权利要求9所述的用途,其特征在于,所述癌症选自:肝癌、乳腺癌、皮肤癌、胰腺癌、头颈癌、肠癌、肺癌、胃癌、食管癌、肾癌、膀胱癌、尿道癌、前列腺癌、睾丸癌、子宫癌、卵巢癌、阴道癌、输卵管癌症、胆管癌、多发性骨髓瘤、脊髓神经纤维瘤、星形细胞瘤、神经胶质瘤、急性淋巴细胞白血病、慢性淋巴细胞白血病、霍奇金淋巴瘤、非霍奇金淋巴瘤、肉瘤。
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