CN117088821A - 喹喔啉化合物、其制造方法及用途 - Google Patents
喹喔啉化合物、其制造方法及用途 Download PDFInfo
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- CN117088821A CN117088821A CN202310977136.7A CN202310977136A CN117088821A CN 117088821 A CN117088821 A CN 117088821A CN 202310977136 A CN202310977136 A CN 202310977136A CN 117088821 A CN117088821 A CN 117088821A
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- alkyl
- phenyl
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- alkoxy
- halogen
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- -1 Quinoxaline compound Chemical class 0.000 title claims description 62
- 238000000034 method Methods 0.000 title abstract description 25
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title description 15
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- 125000000623 heterocyclic group Chemical group 0.000 claims description 49
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Abstract
一种治疗与蛋白质激酶有关的疾病或病症的化合物,其具有式(I)的结构,其中,L是NR8或O;R1、R2、R3、R4、R5、R6及R7如本文中所定义。式(I)所示的化合物可用于蛋白质激酶的抑制。本文公开了使用式(I)所示的化合物、其立体异构体、其互变异构体及其医药上可接受的盐于活体外、原位及活体内诊断、预防或治疗哺乳动物细胞中的此类病症或相关病理症状的方法。
Description
本申请是申请日为2015年6月15日、申请号为201580038477.1、发明名称为“喹喔啉化合物、其制造方法及用途”的专利申请的分案申请。
技术背景
技术领域
本发明涉及一种新型的化学化合物及其用于治疗和制备的方法。特别地,本发明涉及某些经取代的喹喔啉化合物,及其于抑制、调节及/或调制特定激酶和其相关信号转导通路的用途。
现有技术
蛋白激酶(PKs)在细胞信号转导通路中扮演着重要的角色,其调控多种细胞功能,例如:细胞分化、增殖、迁移、存活和凋亡等。这类酶催化ATP的磷酸根转移到基质蛋白上的酪氨酸、丝氨酸或苏氨酸的残基。激酶的磷酸化和磷酸酶的去磷酸化反应参与无数细胞过程,响应不同的细胞内信号或细胞外信号、细胞功能的调节和细胞运转的活化或去活化。
异常PK活性已被证实与癌症以及代谢、免疫和神经系统疾病有关。因此,蛋白激酶已成为治疗人类疾病的具有吸引力的目标。PK抑制剂,即阻断PK活性的化合物,已开发并广泛应用于临床治疗。虽然超过30种PK抑制剂已被批准用于疾病的治疗,例如癌症治疗,但仍然需要一种新的PK抑制剂来治疗各种疾病或克服抗药性。鉴别出可特异性抑制信号转导及细胞增殖的有效的小分子化合物,将有益于以调节PK活性来调节和调控对于导致癌症过程所必需的不适当细胞增殖、分化或代谢。
发明内容
本发明的具体实施方式基于出乎意料地发现某些喹喔啉化合物可以抑制蛋白激酶(例如B-RAF、B-RAFV600E、C-Raf)的活性。这些性质实现了将这些喹喔啉化合物用于治疗蛋白激酶有关的疾病,包括癌症。
在一方面,本发明的实施方式涉及式(I)所示的喹喔啉化合物
或其立体异构体或药学上可接受的盐,其中L是NR8或O,R1、R2、R3、R4、R5、R6及R7如下文中所定义。
根据上述实施方式中的任一者,式(I)的R1选自由氢、卤素、NR9R10、OR11、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,其中R9、R10、R11、Ra、Rb、Rc及Rd独立地如下文中所定义。
根据上述实施方式中的任一者,式(I)的R2选自由氢、卤素、硝基、CN、OR11、COR12及NR13R14所构成的组,限制条件为只有当R1是NR9R10时,R2才为氢或卤素,其中R9、R10、R11、R12、R13及R14独立地如下文中所定义。
根据上述实施方式中的任一者,式(I)的R3选自由氢、卤素、羟基、偶氮基、氰基、硝基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,限制条件为只有当R1是NR9R10时,R3才为氢或卤素,其中Ra、Rb、Rc、R9及R10独立地如下文中所定义。
根据上述实施方式中的任一者,式(I)的R4、R5及R6独立地选自由氢、卤素、羟基、氨基、CN、C1-C4烷基、烷氧基C1-C4烷氧基、二烷基氨基、C1-C4烷氧基及杂环基所构成的组。
根据上述实施方式中的任一者,式(I)的R7是C1-C4烷基、C1-C4卤烷基或芳基。
根据上述实施方式中的任一者,R8选自由氢、SO2R15、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基及3元至6元杂环基所构成的组,其中该烷基、烯基、炔基、环烷基及杂环基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,其中R15、Ra、Rb、Rc及Rd独立地如下文中所定义。
根据上述实施方式中的任一者,R9及R10独立地选自由氢、COR15、SO2R15、OR16、NR17R18、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,限制条件为只有当R9及R10不为氢或C1-C4烷基时,R2及R3才独立地选自氢或卤素,其中R15、R16、R17、R18、Ra、Rb、Rc及Rd独立地如下文中所定义。
或者,R9及R10可以与它们所连接的氮原子共同形成3元至6元杂环基,其可任选地被卤素、氧或C1-C3烷基取代。
根据上述实施方式中的任一者,R11选自由氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,其中Ra、Rb、Rc及Rd独立地如下文中所定义。
根据上述实施方式中的任一者,R12选自由氢、OR19、NR20R21、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,其中R19、R20、R21、Ra、Rb、Rc及Rd独立地如下文中所定义。
根据上述实施方式中的任一者,R13及R14独立地选自由氢、COR15、SO2R15、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,其中R15、Ra、Rb、Rc及Rd独立地如下文中所定义。
根据上述实施方式中的任一者,R15选自由C1-C4烷基、C1-C4卤烷基及芳基所构成的组。
根据上述实施方式中的任一者,R16选自由氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,其中Ra、Rb、Rc及Rd独立地如下文中所定义。
根据上述实施方式中的任一者,R17及R18独立地选自由氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,其中Ra、Rb、Rc及Rd独立地如下文中所定义。
根据上述实施方式中的任一者,R19选自由氢、C1-C4烷基、C1-C4卤烷基及芳基所构成的组。
根据上述实施方式中的任一者,R20及R21独立地选自由氢、C1-C4烷基、C1-C4卤烷基及芳基所构成的组。
根据上述实施方式中的任一者,各Ra独立地是氢或C1-C4烷基。
根据上述实施方式中的任一者,各Rb及Rc独立地选自由氢、SO2R7及C1-C4烷基所构成的组,其中该C1-C4烷基可任选地被卤素取代,其中R7如上文中所定义。
根据上述实施方式中的任一者,各Rd独立地选自由卤素、氧基、C1-C4烷基及C1-C4烷氧基所构成的组,其中该C1-C4烷基及C1-C4烷氧基可任选地被卤素取代。
本发明的优选实施方式涉及选自由以下所构成的组的化合物:N1-3-[(3-{2,6-二氟-3-[(丙基磺酰基)氨基]苯胺基}-6-喹喔啉基)氨基]-2,4-二氟苯基-1-丙烷磺酰胺,N1-(3-{[3-(2,6-二氟苯胺基)-6-喹喔啉基]氨基}-2,4-二氟苯基)-1-丙烷磺酰胺,N1-{3-[(5-氨基-3-甲氧基-6-喹喔啉基)氨基]-2,4-二氟苯基}-1-丙烷磺酰胺,N1-{2,4-二氟-3-[(3-甲氧基-5-硝基-6-喹喔啉基)氨基]苯基}-1-丙烷磺酰胺,N1-{2,4-二氟-3-[(3-甲氧基-5-硝基-6-喹喔啉基)氨基]苯基}-3-氟-1-丙烷磺酰胺,N1-(2,4-二氟-3-{[3-(2-吗啉代乙氧基)-5-硝基-6-喹喔啉基]氨基}苯基)-1-丙烷磺酰胺,N1-(2,4-二氟-3-[3-(2-甲氧基乙氧基)-5-硝基-6-喹喔啉基]氨基苯基)-1-丙烷磺酰胺,N1-(7-{2,6-二氟-3-[(丙基磺酰基)氨基]苯胺基}-2-喹喔啉基)-1-环丙烷羧酰胺,N1-[3-({3-[2-(二甲基氨基)乙氧基]-5-硝基-6-喹喔啉基}氨基)-2,4-二氟苯基]-1-丙烷磺酰胺,N1-{3-[(5-氰基-3-甲氧基-6-喹喔啉基)氨基]-2,4-二氟苯基}-1-丙烷磺酰胺,N1-(2,4-二氟-3-{[3-(2-氟苯胺基)-6-喹喔啉基]氨基}苯基)-1-丙烷磺酰胺,N1-(2,4-二氟-3-{[3-(3-吡啶基氨基)-6-喹喔啉基]氨基}苯基)-1-丙烷磺酰胺,N1-(3-{[3-(2,4-二氟苯胺基)-6-喹喔啉基]氨基}-2,4-二氟苯基)-1-丙烷磺酰胺,N-{2,4-二氟-3-[(3-甲氧基-5-硝基-6-喹喔啉基)氨基]苯基}甲烷磺酰胺,N1-{3-[(5-氰基-3-羟基-6-喹喔啉基)氨基]-2,4-二氟苯基}-1-丙烷磺酰胺,N1-(3-{[5-氰基-3-(2-吗啉代乙氧基)-6-喹喔啉基]氨基)-2,4-二氟苯基)-1-丙烷磺酰胺,N-(3-(5-氰基-3-乙氧基喹喔啉-6-基氨基)-2,4-二氟苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-(二甲基氨基)喹喔啉-6-基氨基)-2,4-二氟苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-2,4-二氟苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-(甲氨基)喹喔啉-6-基氨基)-2,4-二氟苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-2,6-二氟苯基)丙烷-1-磺酰胺,N-(5-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-2-氟苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-4-氟苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-乙氧基喹喔啉-6-基氨基)-4-氟苯基)苯磺酰胺,N-(3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-4-氟苯基)苯磺酰胺,N-(3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-4-氟苯基)甲烷磺酰胺,N-(3-(5-氰基-3-乙氧基喹喔啉-6-基氨基)-4-氟苯基)甲烷磺酰胺,N-(3-(5-氰基-3-(二甲基氨基)喹喔啉-6-基氨基)-4-氟苯基)丙烷-1-磺酰胺,N-(2,4-二氟-3-(5-甲酰基-3-甲氧基喹喔啉-6-基氨基)苯基)丙烷-1-磺酰胺,6-(2,6-二氟-3-(丙基磺酰胺基)苯基氨基)-3-甲氧基喹喔啉-5-羧酸,6-(2,6-二氟-3-(丙基磺酰胺基)苯基氨基)-3-甲氧基喹喔啉-5-羧酸甲酯,N-(2,4-二氟-3-(3-甲氧基-7-甲基喹喔啉-6-基氨基)苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-2,4-二氟苯基)-3-氟丙烷-1-磺酰胺,N-(3-(5-氰基-3-乙氧基喹喔啉-6-基氨基)-2,4-二氟苯基)-3-氟丙烷-1-磺酰胺,N-(3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-4-氟苯基)苯磺酰胺,N-(3-(5-氰基-3-乙氧基喹喔啉-6-基氨基)-4-氟苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-(二甲基氨基)喹喔啉-6-基氨基)-4-氟苯基)苯磺酰胺,N-(3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-2-甲基苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-4-甲基苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-4-甲基苯基)丙烷-1-磺酰胺,N-(3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-4-氟苯基)甲烷磺酰胺,N-(3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-2,4-二氟苯基)-N-乙基丙烷-1-磺酰胺,N-(3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-2,4-二氟苯基)-N-甲基丙烷-1-磺酰胺,N-(3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-2-甲基苯基)丙烷-1-磺酰胺,N-(5-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-2-甲基苯基)丙烷-1-磺酰胺,N-(2-氯-3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-4-氟苯基)丙烷-1-磺酰胺,N-(2-氯-3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-4-氟苯基)苯磺酰胺,N-(2-氯-3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-4-氟苯基)丙烷-1-磺酰胺,N-(2-氯-3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-4-氟苯基)苯磺酰胺,及,N-(2-氰基-3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)苯基)丙烷-1-磺酰胺。
本发明的另一方面涉及用于预防或治疗由蛋白质激酶调制/介导或与蛋白质激酶有关的疾病或病症的方法。该蛋白质激酶可包括但不限于B-Raf、B-RafV600E、C-Raf、MEK1等。一种例示性的用于预防或治疗由蛋白质激酶介导/介入或与蛋白质激酶有关的疾病或病症的方法包含对需要此类治疗的个体(例如哺乳动物)给予有效剂量的本发明化合物、或其立体异构体、互变异构体、溶剂合物、前药或药学上可接受的盐。这类疾病或病症的示例包括但不限于过度增殖性疾病(例如癌症,包括黑色素瘤及皮肤的其他癌症),神经退化性疾病,心脏肥大,疼痛,偏头痛及神经创伤性疾病,肾脏疾病(例如多囊性肾脏疾病)等。
本发明的另一方面提供本发明的化合物用于制造治疗过度增殖性疾病的药物的用途。在进一步的实施方式中,该过度增殖性疾病可为癌症(或者更进一步,是本文中所定义的特定癌症)。
本发明的另一方面提供本发明的化合物用于制造治疗与蛋白质激酶有关的疾病或病症的药物的用途,所述疾病或病症是例如过度增殖性疾病(例如癌症,包括黑色素瘤及皮肤的其他癌症),神经退化性疾病,心脏肥大,疼痛,偏头痛及神经创伤性疾病,肾脏疾病(例如多囊性肾脏疾病)。该蛋白质激酶可为B-Raf,且该药物为B-Raf抑制剂。
本发明的另一方面提供一种药物组合物,包含本发明化合物、其立体异构体、互变异构体、溶剂合物、前药或药学上可接受的盐,以及医药上可接受的载剂或赋形剂。
本发明的其他方面及优点经由以下叙述及后附的权利要求而更明确。
发明详述
定义
详参特定实施方式,结合结构及化学式对实施方式的示例进行说明。当描述列举实施方式时,应理解,其并非用来将本发明限定于这些实施方式。相反地,本发明欲涵盖所有的替代物、改良物及均等物,其均可涵盖于权利要求书所限定的范围内。本领域技术人员将可确认许多可用于实施本发明的类似于或相当于本文中所描述的方法及材料。本发明并不在任何方面受限于本文中所描述的方法及材料。在一件或多件并入本文的文献及类似材料与本申请不同或矛盾的情况下,包括但不限于所定义的术语、术语用法、所描述的技术等,则均以本申请为主。
除非另有说明,否则术语“烷基”是指包含1至20个碳原子的直链或支链单价饱和烃。该描述中的数值范围在于包含所定义的范围内的任何数值,如同单独的数值已被分别公开一样。例如,具有1至20个碳原子的烷基将包括C1、C2…C20以及C1-C20、C1-C15、C1-C10、C1-C6、C1-C4等。烷基的例子包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基及叔丁基。
术语“烯基”是指包含2至20个碳原子(例如C2-C10)及一或多个双键的直链或支链单价烃。烯基的例子包括但不限于乙烯基、丙烯基、烯丙基及1,4-丁二烯基。
术语“炔基”是指包含2至20个碳原子(例如C2-C10)及一或多个三键的直链或支链单价烃,烯基的例子包括但不限于乙炔基、1-丙炔基、1-丁炔基及2-丁炔基,及1-甲基-2-丁炔基。
术语“烷氧基”是指-O-烷基基团,其中该烷基部分如上述所定义。烷氧基的例子包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基及叔丁氧基。
术语“酰氧基”是指-O-C-(O)-R基团,其中R可为H、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基或杂芳基。
术语“氨基”是指NH2。术语“烷基氨基”是指-N(R)-烷基基团,其中R可为H、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基或杂芳基。
术语“环烷基”是指具有3至30个碳原子(例如C3-C6或C3-C12)的单价饱和烃环。环烷基的例子包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基及金刚烷基。
术语“环烯基”是指具有3至30个碳原子(例如C3-C6或C3-C12)以及一或多个双键的单价非芳族烃环系统。环烯基的例子包括环戊烯基、环己烯基及环庚烯基。
术语“杂环烷基”是指具有一或多个杂原子(例如O、N、S或Se)的单价非芳族5元至8元单环、8元至12元双环、或11元至14元三环系统。杂环基的例子包括但不限于哌嗪基、吡咯烷基、哌啶基、二噁烷基、吗啉基及四氢呋喃基。
术语“杂环烯基”是指具有一或多个杂原子(例如O、N、S或Se)及一或多个双键的单价非芳族5元至8元单环、8元至12元双环、或11元至14元三环系统。
术语“芳基”是指单价6碳单环、10碳双环或14碳三环芳环系统。芳基的例子包括、但不限于苯基、萘基及蒽基。
术语“芳氧基”是指-O-芳基。术语“芳基氨基”是指-N(R)-芳基,其中R可为H、烷基、烯基、炔基、环烷基、环烯基、杂环烷基、杂环烯基、芳基或杂芳基。术语“杂芳基”是指具有一或多个杂原子(例如O、N、S或Se)的单价芳族5元至8元单环、8元至12元双环、或11元至14元三环系统。杂芳基的例子包括吡啶基、呋喃基、咪唑基、苯并咪唑基、嘧啶基、噻吩基、喹啉基、吲哚基、噻唑基、吡咯基、异喹啉基、嘌呤基、噁唑基、吡唑基及咔唑基。在所有这些术语中,“芳基”部分如上述所定义。
术语“卤素”是指F、Cl、Br或I。
上述的烷基、烯基、炔基、环烷基、杂环烷基、环烯基、杂环烯基、氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、芳基及杂芳基可以是经取代或未经取代的。氨基、烷基氨基、芳基氨基、烷氧基、芳氧基、环烷基、杂环烷基、环烯基、杂环烯基、芳基及杂芳基上可能的取代基包括但不限于C1-C10烷基、C2-C10烯基、C2-C10炔基、C3-C20环烷基、C3-C20环烯基、C1-C20杂环烷基、C1-C20杂环烯基、C1-C10烷氧基、芳基、芳氧基、杂芳基、杂芳氧基、氨基、C1-C10烷基氨基、芳基氨基、羟基、卤素基团、氧基(O=),硫酮基(S=)(thioxo),硫基、C1-C10烷硫基、芳硫基、C1-C10烷基磺酰基、芳基磺酰基、酰基氨基、氨基酰基、氨基硫酰基、脒基、巯基、酰胺基、硫脲基、硫氰基、磺酰胺基、胍基、脲基、氰基、硝基、酰基、硫酰基、酰氧基、脲基(carbamido)、氨甲酰基(-C(O)NH2)、羧酸基(-COOH)、及羧酸酯。另一方面,烷基、烯基或炔基上可能的取代基包括上述除了C1-C10烷基以外的全部取代基。环烷基、环烯基、杂环烷基、杂环烯基、芳基及杂芳基也可彼此稠合。
Raf抑制剂
本文提供可用于治疗或预防与蛋白质激酶(例如B-Raf)调制/介导的或与蛋白质激酶有关)的疾病、症状和/或病症的化合物及该化合物的药物组合物。
在一种实施方式中,提供式(I)化合物
或其立体异构体、互变异构体、溶剂合物、前药及药物上可接受的盐,其中:
L是NR8或O;
R1选自由氢、卤素、NR9R10、OR11、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代;
R2选自由氢、卤素、硝基、CN、OR11、COR12及NR13R14所构成的组,限制条件为只有当R1是NR9R10时,R2才为氢或卤素;
R3选自由氢、卤素、羟基、偶氮基、氰基、硝基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,限制条件为只有当R1是NR9R10时,R3才能为氢或卤素;
R4、R5及R6独立地选自由氢、卤素、羟基、氨基、CN、C1-C4烷基、烷氧基C1-C4烷氧基、二烷基氨基、C1-C4烷氧基及杂环基所构成的组;
R7是C1-C4烷基、C1-C4卤烷基或芳基;
R8选自由氢、SO2R15、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基及3元至6元杂环基所构成的组,其中该烷基、烯基、炔基、环烷基及杂环基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代;
R9及R10独立地选自由氢、COR15、SO2R15、OR16、NR17R18、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代,限制条件为只有当R9及R10不为氢或C1-C4烷基时,R2及R3才独立地选自氢或卤素;
R9及R10与它们所连接的氮原子共同形成3元至6元杂环基,其可任选地被卤素、氧或C1-C3烷基取代;
R11选自由氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代;
R12选自由氢、OR19、NR20R21、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代;
R13及R14独立地选自由氢、COR15、SO2R15、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代;
R15选自由C1-C4烷基、C1-C4卤烷基及芳基所构成的组;
R16选自由氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代;
R17及R18独立地选自由氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基可任选地被卤素、氧基(除了苯基或杂芳基的情况)、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基可任选地被Rd取代;
R19选自由氢、C1-C4烷基、C1-C4卤烷基及芳基所构成的组;
R20及R21独立地选自由氢、C1-C4烷基、C1-C4卤烷基及芳基所构成的组;
其中,各Ra独立地为氢或C1-C4烷基;
其中,各Rb及Rc独立地选自由氢、SO2R7及C1-C4烷基所构成的组,其中该C1-C4烷基可任选地被卤素取代;
其中,各Rd独立地选自由卤素、氧基、C1-C4烷基及C1-C4烷氧基所构成的组,其中该C1-C4烷基及C1-C4烷氧基可任选地被卤素取代。
本领域技术人员应知,在上述式(I)中,不同取代基的所有组合或排列均落入本发明的范围内。这些化合物可藉由使用容易获得的材料/试剂及已知化学反应而制得。基于本领域的公知常识及本公开的揭示,本领域技术人员应能够制备及使用这些化合物,无需过度实验。
以下反应流程(反应流程1至反应流程14)提供可用于制备式(I)化合物的示例性操作。然而,本领域技术人员应理解,这些示例仅供例示的目的,在未背离本发明的范围内,改良及变化是可能的。根据本发明的实施方式合成的喹喔啉化合物可以任何已知技术纯化,例如藉由快速管柱层析法,高性能液体层析法,结晶法,或其它任何适当的方法。
中间物I
反应流程1
在0℃下,将浓硝酸(1.1当量)逐滴加入苯甲酸乙酯(1)(1.0当量)于发烟硫酸(1.25M)中的混合物中。将此混合物留置于室温下并搅拌1小时。接着,将反应混合物倒入冰中,并以乙酸乙酯(EtOAc)萃取水相。将有机层分离,以饱合碳酸氢钠(NaHCO3)及水清洗,干燥,然后浓缩,获得产物2。
在N2气氛中,将10%(wt.)Pd/活性碳(0.05当量)加入已装入3-硝基苯甲酸乙酯(2)(1.0当量)的烧瓶中。添加甲醇(0.25M)至该烧瓶中,并在2个H2气球气压下搅拌至过夜。待反应完成后,以N2气体充入烧瓶,并将反应混合物以硅藻土过滤。移除挥发物以得到粗制3-氨基苯甲酸乙酯(3)。
将烷基-1-磺酰基氯化物(1.2当量)缓慢添加至放置在冷水浴中的3-氨基苯甲酸乙酯(3)(1.1当量)于吡啶(0.5M)中的溶液中。将反应混合物在室温下搅拌1小时,然后倒入冷水中。以EtOAc萃取水相。将有机层分离,以饱合NH4Cl及盐水清洗,于MgSO4中干燥,过滤,并且浓缩,以获得3-(N-烷基磺酰基)亚磺酰胺基)苯甲酸乙酯(4)。
将1N的NaOH水溶液(3.0当量)加入3-(N-烷基亚磺酰胺基)苯甲酸乙酯(4)(1.0当量)于4:1THF/MeOH(0.2M)中的溶液中。并使反应混合物在室温下搅拌过夜。在真空中移除大部分的有机溶剂。将1N的HCl缓慢添加至该混合物中,然后将所获得的固体过滤,并以水清洗。将此物质以Et2O清洗,以获得3-烷基亚磺酰胺基苯甲酸(5)。
中间物II
反应流程2
在N2气氛中及在0℃下,将N,N-二异丙基乙基胺(2.0当量)及氯甲基甲基醚(2.0当量)加入酚(6)(1.0当量)于干燥CH2Cl2的溶液中。将所得的黄色混合物在0℃下搅拌30分钟,然后于室温下静置过夜。以10% NaOH水溶液将有机混合物稀释,并以二氯甲烷萃取。将有机层合并,用MgSO4干燥,过滤,并且在真空中浓缩。粗制产物在二氧化硅管柱中纯化。用乙酸乙酯于己烷中的洗脱液获得所需的产物7。
在氮气中并于-70℃下,在甲氧基甲氧基苯(7)(1.0当量)于THF(0.35M)中的溶液中,用10分钟逐滴加入1.4M的正丁基锂于己烷(0.99当量)中的溶液。将混合物在-70℃下搅拌1.5小时,然后倾析至粉碎的干冰中。一旦发泡作用消失,使混合物回温至室温(RT),并添加水。水溶液以醚萃取2次,以提供化合物8。将化合物8溶解于甲醇中,并通过添加浓盐酸酸化至pH值为1。将所得悬浮液以超声波处理5分钟,然后以CH2Cl2萃取两次。经合并的CH2Cl2萃取物以MgSO4干燥,并于真空中蒸发,以提供产物9。
在冷水浴中,将烷基磺酰氯(1.2当量)缓慢添加至3-羟基苯甲酸(9)(1.0当量)于三乙胺(0.5M于CH2Cl2中)中的溶液中。将反应混合物于室温下搅拌1小时.添加水,将有机层分离,以水及盐水清洗,然后以MgSO4干燥,过滤并浓缩,以提供产物10。
中间物III
反应流程3
对苯甲酸(11)(1当量)于THF(0.25M)中的溶液添加三乙胺(2.3当量)及叠氮磷酸二苯酯(DPPA)(1.15当量)。将反应混合物于室温下搅拌3小时,然后回温至80℃并保持2小时。添加水,将反应混合物于80℃下搅拌15小时。将反应混合物以EtOAc稀释,以饱和NaHCO3水溶液及盐水清洗有机层。于减压下移除溶剂,残余物经由二氧化硅管柱层析法纯化,以提供化合物12。
中间物IV
反应流程4
将溴(1.0当量)缓慢添加至经取代的喹喔啉(20)于乙酸(0.1M)的溶液中。将反应混合物于室温下搅拌1.5小时。通过过滤收集所得固体并用己烷清洗,以提供7-溴取代的喹喔啉(14)。
将7-溴取代的喹喔啉(14)(1.0当量)于POCl3(1.0M)中的悬浮液加热以回流6小时。然后使所得的澄清溶液冷却至室温,并加入水进行淬冷。以过滤收集所得固体,以提供7-溴-2-氯取代的喹喔啉(15),可接着进行以下步骤而无需进一步的纯化。
中间物V
反应流程5
将乙醛酸或乙醛酸烷酯及经取代的4-氯苯-1,2-二胺(16)在有机溶剂中搅拌6小时。使所得的产物纯化,以提供7-氯取代的喹喔啉酮(17)。
将7-氯取代的喹喔啉酮(17)(1.0当量)于POCl3(1.0M)中的悬浮液加热以回流6小时。然后使所得的澄清溶液冷却至室温并通过水淬冷。通过过滤收集所得固体,以提供2,7-二氯取代的喹喔啉(18),可接着进行以下步骤而无需进一步的纯化。
中间物VI
反应流程6
在室温下对2-氯取代的喹喔啉(19)(1.0当量)于R13OH(0.5M)中的溶液添加碳酸钾(1.1当量),并将反应在40℃加热2小时。冷却后,将反应混合物过滤并于真空中浓缩。所得的残余物以乙酸乙酯稀释,以盐水清洗,用MgSO4干燥,并于真空中浓缩,以提供化合物20。
中间物VII
反应流程7
于室温下对2-氯取代的喹喔啉(19)(1.0当量)于R11R12NH(0.5M)中的溶液添加三乙胺(1.1当量),并将反应在60℃加热2小时。冷却后,将反应混合物过滤并于真空中浓缩。所得的残余物以乙酸乙酯稀释,以盐水清洗,用MgSO4干燥,并于真空中浓缩,以提供化合物21。
中间物VIII
反应流程8
对7-溴取代的喹喔啉(22)(1.0当量)于硫酸中的溶液添加硝酸。将此反应混合物于室温下搅拌8小时。将混合物倒入冰-H2O混合物中,并且过滤。以乙酸乙酯清洗固体,以提供7-溴-8-硝基取代的喹喔啉(23)。
对7-溴-8-硝基取代的喹喔啉(23)(1.0当量)于乙酸乙酯/二甲基甲酰胺(6:1)中的溶液添加氯化锡(II)(SnCl2;10.0当量)。将此反应混合物于100℃下搅拌16小时。冷却后,将反应混合物于真空中浓缩。所得的残余物以乙酸乙酯稀释,以饱和NaHCO3水溶液及盐水清洗,用MgSO4干燥,并于真空中浓缩,以提供6-溴取代的喹喔啉-5-胺(24)。
中间物IX
反应流程9
在-10℃下,对7-溴取代的喹喔啉-5-胺(24)(1.0当量)、氯化氢(1.5当量)及亚硝酸钠(1.1当量)于H2O中的溶液添加碘化钾(1.2当量)。将此反应混合物于室温下搅拌16小时。将粗制反应混合物以EtOAc稀释,将有机层以盐水清洗,用MgSO4干燥,并且过滤。于减压下移除溶剂,残余物经由二氧化硅凝胶管柱层析法纯化,以提供7-溴-8-碘取代的喹喔啉(25)。
于密封试管中,将7-溴-8-碘取代的喹喔啉(25)(1.0当量)、氰化钾(2.0当量)、碘化铜(1.1当量)及1,10-菲咯啉单水合物(0.2当量)于二甲基甲酰胺中的溶液于110℃下加热24小时。将反应混合物过滤并以甲醇清洗,在真空中去除溶剂。粗制的反应混合物以EtOAc稀释,有机层以饱和NaHCO3水溶液及盐水清洗,用MgSO4干燥,并且过滤。于减压下去除乙酸乙酯,残余物经由二氧化硅凝胶管柱层析法纯化,以提供7-溴-8-氰基取代的喹喔啉(26)。
终产物I
反应流程10
将经取代的喹喔啉酮(27)(1.0当量)、碳酸铯(3.0当量)、Pd(OAc)2(0.1当量)、化合物12(1.0当量)及4,5-双二苯基膦-9,9-二甲基氧杂蒽(xantphos)(0.02当量)于二噁烷(0.3M)中的溶液于110℃下加热2小时。将溶液过滤,以甲醇清洗,并于真空中浓缩。残余物经由二氧化硅凝胶管柱层析法纯化,以提供喹喔啉化合物28。
上述反应流程说明可以如何制备本发明的喹喔啉化合物。本领域技术人员应知涉及的反应及所使用的试剂是本领域已知的。因此,基于以上教示和本领域的公知常识,如本文中所定义的具有各种取代基的喹喔啉化合物可由本领域技术人员制备,无需发明性尝试。
本文提到的喹喔啉化合物可以含有非芳香族双键和一个或多个不对称中心,例如:位于连接于核心芳香环的取代基。因此,这些化合物可作为消旋物和外消旋混合物、单一对映体、单个非对映立体异构体、非对映体混合物,以及顺式或反式异构体形式存在。所有这些异构体形式都含括在本发明范围的内。本发明的喹喔啉化合物可具有酸性或碱性官能团(例如:在取代基上),所述官能团可以形成盐类,特别是药学上可接受的盐类。这种盐类的形成为制药工业中的常规做法。可用于本发明的喹喔啉化合物的盐的例子包括供碱性官能基用的盐酸盐、硫酸盐、甲酸盐、乙酸盐、苹果酸盐、及琥珀酸盐等,及供酸性官能基用的氢氧化物、铵、及烷基铵等。此种喹喔啉盐类在本发明的范围内。类似地,酸性或碱性基团可以被官能基化,例如形成酯。这样的官能化衍生物会在体内水解。因此,此类衍生物可以作为本发明的喹喔啉化合物的前药。前药的形成只涉及常规技能,本领域技术人员无需过多的实验即可理解如何制备及使用此类前药。
本发明的范围还包含(1)一种药物组合物,其包含有效剂量的至少一种本发明的喹喔啉化合物及药学上可接受的载剂,(2)一种用于治疗蛋白激酶相关疾病的方法(例如癌症),其通过给予需要此类治疗的个体所需有效剂量的此类喹喔啉化合物的方式来达成;以及(3)降低至少一种蛋白激酶活性的方法,其通过使本发明的至少一种喹喔啉化合物与至少一种蛋白激酶接触来实现。
在此术语“蛋白激酶相关的疾病/病症”或“与蛋白质激酶相关疾病/病症”,或“由蛋白质激酶调节的疾病/病症”,是指一种有PK活性异常表征的疾病/病症或者是可透过改变至少一PK活性的方式来治疗的疾病或病症。异常的PK活性会是PK基因表达水平提高所引起的或是在正常时不会发生的情况下表达PK所引起的。在此所描述的PK相关疾病/病症,包括但不限于,癌症、糖尿病、过度增殖疾病、肾脏过度增殖性疾病、肾脏疾病、冯希伯-林岛氏疾病(von Hippel-Lindau disease)、再生狭窄、纤维症、牛皮癣、骨关节炎、类风湿性关节炎、发炎性疾病、免疫疾病如自体免疫性疾病(如AIDS、红斑狼疮等)、心血管疾病(如动脉粥状硬化)和血管增殖性疾病如异常血管新生。
术语“治疗”是指对于患有蛋白激酶相关疾病或出现病征的个体或者易患病的体质,给予喹喔啉化合物,其目的是治愈、恢复、减轻、缓解、改变、矫正、改善、改进、影响或降低疾病的风险、症状或易患病的体质。例如,癌症治疗是指治疗导致肿瘤生长或肿瘤细胞生长的抑制、肿瘤生长的退化(即,其降低可检测肿瘤的大小),或癌症的消失。
术语“有效剂量”是指在个体中达到预期治疗效果所需的活性剂剂量。有效剂量可根据本领域技术人员以本领域的已知技术、给药途径、赋形剂的使用,以及可能同时使用其它药物而有所差异。有效剂量的测定,对于本领域的技术人员来说,无需过度实验仅需要常规技能,即可确定预定用途的有效剂量。需要治疗的个体可为哺乳动物。术语“哺乳动物”是指人类或非人类的哺乳动物,例如:狗、猫、猪、牛、绵羊、山羊、马、大鼠、或小鼠。
可通过本发明方法治疗的癌症,包括任何异常的细胞或组织的生长,例如:肿瘤,无论是恶性的、前恶性或非恶性的。癌症的特征在于细胞不受控制的增殖,而该细胞可能侵入或不侵入周围组织,因此,可能转移或不转移至新的身体部位。癌症包括上皮细胞癌,而上皮细胞癌包括鳞状细胞癌、腺癌、黑色素瘤和肝癌。癌症还包括肉瘤,这是间质细胞起源的肿瘤;肉瘤包括成骨肉瘤、白血病和淋巴瘤。癌症可以包括一个或多个肿瘤细胞类型。术语“癌症"举例但不限于,肺癌、结肠癌、结肠直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、膀胱癌、胃癌、肾癌、唾液腺癌、卵巢癌、子宫体癌、子宫颈癌、口腔癌、皮肤癌、脑癌、淋巴瘤和白血病。还包括抗药性癌症(包括但不限于多药耐药性的癌症)。
本发明所述的化合物可以与放射线疗法、免疫疗法、单克隆抗体疗法、激素疗法、使用其它药物的化疗及/或手术合并施予哺乳动物。合并治疗不需发生在同一时间,可以是连续,或是相互及/或与休息和恢复期交替进行。
根据本发明的一些实施方式,治疗如癌症等与蛋白激酶有关疾病的方法,包括将有效剂量的本发明至少一种喹喔啉化合物和至少一种化疗药物施予哺乳动物。化疗药物的实例包括但不限于在此所述的PK抑制剂,(例如伊马替尼(imatinib)甲磺酸盐、吉非替尼(gefitinib)、达沙替尼(dasatinib)、埃罗替尼(erlotinib)、拉帕替尼(lapatinib)、舒尼替尼(sunitinib)、尼洛替尼(nilotinib)及索拉菲尼(sorafenib));抗体,其包括:例如曲妥珠单抗(trastuzumab)、利妥昔单抗(rituximab)、西妥昔单抗(cetuximab)及贝伐单抗(bevacizumab);米托蒽醌(mitoxantrone);地塞米松(dexamethasone);泼尼松(prednisone);及替莫唑胺(temozolomide);烷化剂(例如美法仑(melphalan)、苯丁酸氮芥(chlorambucil)、白消安(busulfan)、噻替派(thiotepa)、异环磷酰胺(ifosfamide)、卡莫司汀(carmustine)、洛莫司汀(lomustine)、司莫司汀(semustine)、链脲霉素(streptozocin)、胺烯咪胺(decarbazine)及环磷酰胺(cyclophosphamide));有丝分裂抑制剂;抗代谢物(例如截瘤达锭(capecitibine)、吉西他滨(gemcitabine)、5-氟尿嘧啶(5-fluorouracil)或5-氟尿嘧啶/甲酰四氢叶酸(leucovorin)、氟达拉滨(fludarabine)、阿糖胞苷(cytarabine)、巯嘌呤(mercaptopurine)、硫鸟嘌呤、喷托他丁(pentostatin)及胺甲蝶呤(methotrexate));细胞循环抑制剂;酶;荷尔蒙;抗荷尔蒙;生长因子抑制剂;植物碱及萜类化合物;拓扑异构酶抑制剂(例如依托泊苷(etoposide)、替尼泊苷(teniposide)、喜树碱(camptothecin)、拓扑替康(topotecan)、依立替康(irinotecan)、多柔比星(doxorubicin)及柔红霉素(daunorubicin));抗肿瘤抗生素(例如放线菌素D(actinomycinD)、博莱霉素(bleomycin)、丝裂霉素C(mitomycin C)、亚德里亚霉素(adriamycin)、道诺霉素(daunorubicin)、伊达比星(idarubicin)、多柔比星(doxorubicin)及聚乙二醇脂质体多柔比星(pegylated liposomal doxorubicin));长春花生物碱(vinca alkaloid)(例如长春碱(vinblastine)及长春地辛(vindesine));铂化学治疗剂(例如顺铂(cisplatin)、卡铂(carboplatin)及奥沙利铂(oxaliplatin));沙利度胺(thalidomide)及有关类似物(例如CC-5013及CC-4047);单株抗体;及抗血管生成剂。
术语“接触”在此是指利用一种方法将本发明的化合物与至少一种PK处在一起,该化合物可通过与PK本身作用而直接降低PK的活性,或通过与另一种和PK活性有关的分子作用而间接降低PK的活性。“接触”可以发生在体外或体内,例如:将本发明的化合物给予含至少一种PK的试管、具有生长的全细胞的培养皿、或哺乳动物。以PK为标靶的实例包括但不限于EGFR、CDK1、Aurora A&B激酶、MAP、CDK2、Raf、NEK(包括NEK 4a、NEK 4b、NEK 5与NEK 6)、BUB1、VEGFR、C-MET、HER2、HER3、HER4、IR、IGF-IR、IRR、PDGFRct、PDGFRO、CSFIR、C-Kit、C-fms、Flk-1 R、Flk4、KDRlFlk-1、FLT-1、FLT3、FGFR-1、FGFR-2、FGFR-3、FGFR4、Src、Frk、Btk、Csk、Abl、ZAP70、Fes、Fps、Fak、Jak、Ack、Yes、Fyn、Lyn、Lck、Blk、Hck、Fgr、Aur2和Yrk。
为了实施本发明的方法,上述药物组合物可以经由口服、肠胃外(parenterally)、喷雾吸入、局部表面涂用、直肠、鼻腔、脸颊、阴道或植入式储药槽(implanted reservoir)的方式给药。术语“肠胃外”包括皮下、皮内、静脉内、肌内、关节内、动脉内、滑膜内、胸骨内、脊髓内、患处内和颅内注射或注入技术。根据本发明的一些实施方式,本发明的喹喔啉化合物通过静脉注射方式给药,合适的载体可包括但不限于生理盐水或磷酸缓冲盐水(PBS),以及含有增稠剂和增溶剂的溶液,例如葡萄糖,聚乙二醇溶液和聚丙二醇及其混合物。
无菌可注射组合物,如无菌可注射水性或油性悬浮液,可根据本领域中已知技术使用合适的分散剂或润湿剂(如TWEEN 80)和悬浮剂来配制。无菌注射制剂也可以是无毒的肠胃外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液,例如1,3-丁二醇的溶液形式。可接受的赋形剂和溶剂中可采用甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外,无菌且无挥发性油(fixed oil)常用作溶剂或悬浮介质(例如:合成的单或双甘油酯)。脂肪酸(如油酸及其甘油酯衍生物)可用于制备注射剂,天然的药学上可接受的油,如橄榄油或蓖麻油,尤其是其聚氧乙烯化型态,同样可用于注射剂的制备中。这些油溶液或悬浮液也可以含有长链醇稀释剂或分散剂,或羧甲基纤维素或类似的分散剂。其它常用的界面活性剂(如Tweens、或Spans)或其他类似的乳化剂或常用于制备药学上可接受的固体、液体或其它剂型的生物可利用度增强剂也可以用于制备目的。
用于口服给药的组合物可以是任何口服可接受的剂型,包括但不限于胶囊、锭剂、乳液和水性悬浮液、分散液和溶液。在用于口服用锭剂的情况下,常用的载体包括乳糖和玉米淀粉。通常还可加入润滑剂,比如硬脂酸镁。对于以胶囊形式的口服给药而言,可用的稀释剂包括乳糖和干燥玉米淀粉。当口服施予水性悬浮液或乳剂时,活性成分可悬浮或溶解在与乳化剂或悬浮剂结合的油相中。如果需要,可加入某些甜味剂,调味剂或着色剂。鼻用气雾剂或吸入组合物可根据药物制剂领域中众所熟知的技术来制备。含有喹喔啉化合物的组合物也可以用于直肠给药的栓塞剂形式来给予。
药物组合物中的载体必须是“可接受的”,即能够与组合物中的活性成分相容(优选能够使其稳定化)且对待治疗的个体无害。一种或多种增溶剂(例如环糊精),其可与有活性的喹喔啉化合物形成更易溶解的复合物可作为递送活性化合物的药物载体。其它载体的实例包括胶体二氧化硅、硬脂酸镁和十二烷基硫酸钠。
适合的体外测定可用于初步评估本发明的喹喔啉化合物在诸如抑制肿瘤细胞生长的抗癌活性方面的功效。可进一步检查这种化合物在治疗癌症方面的疗效。例如:化合物可以施用于具有癌症的动物(例如,小鼠模型),接着评估其治疗效果。也可基于这些结果来确定适当的剂量范围和给药途径。
无需进一步说明,以上的描述已经充分地实现本发明。因此,以下的实施例应被解释为仅是说明性的,而非用以限制本发明的范围。
实施例
例示性的喹喔啉化合物列于表1中,这些化合物的计算质谱(mass)数据及观察得到的ESI-MS数据提供于表2中。
表1喹喔啉化合物
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表2计算质谱数据及观察得到的ESI-MS数据
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生物活性
生物活性
检测多种式I化合物对多种蛋白质激酶的抑制能力。下文简要说明不同的分析方法。
1.B-Raf激酶分析
本文中所公开的受测化合物对激酶活性的抑制能力,通过在该受测化合物的存在下定量基质中并入的[33P]的量来评价。标准的分析条件为5ng的重组B-Raf激酶(昂斯特生物技术公司(Upstate Biotechnology))与500ng MEK1(Map-erk激酶,K97R)于分析缓冲液(8μM ATP、0.5μCi[33P]ATP(特异活性3000Ci/毫摩尔,帕金埃尔默公司(PerkinElmer))、50mM Tris/HCl(pH7.5)及1mM EGTA、1mM Na3VO4、1%2-巯基乙醇、0.1% Brij 35及0.2mg/ml BSA),最终体积为25μL。反应于30℃下作用30分钟,并通过加入3%磷酸终止反应,以细胞收集器(ulifilter harvester,PerkinElmer)将产物收集到96孔GF/B微量多孔盘(UniFilter,PerkinElmer)中,并用微板闪烁计数器(TopCount microplatescintillation counter,PerkinElmer)计数。抑制剂的IC50值通过测试各化合物的3倍连续稀释浓度而得,每种化合物进行重复测试(duplication)。所得的结果以线性回归软件(GraphPad Prism 4;图形软件有限公司(GraphPad Software Inc.))进行分析。
表1中所列经选择的化合物的抑制活性总结于表3中。IC50值定义为激酶(B-Raf激酶)最大活性被抑制一半时测试化合物的浓度。+表示该浓度(IC50值)为10,000~1,000nM;++表示该浓度为1,000-300nM;以及+++表示该浓度为小于300nM。
表3
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2.B-RafV600E激酶分析
本文中所公开的受测化合物对激酶活性的抑制能力,通过在该受测化合物的存在下定量基质中并入的[33P]的量来评价。标准的分析条件为5ng的重组B-RafV600E激酶(Upstate Biotechnology)与500ng MEK1(K97R)于分析缓冲液(8μM ATP、0.5μCi[33P]ATP(特异活性3000Ci/毫摩尔,PerkinElmer)、50mM Tris/HCl(pH7.5)及1mM EGTA、1mM Na3VO4、1%2-巯基乙醇、0.1% Brij 35及0.2mg/ml BSA),与受测化合物(以4% DMSO稀释)或单独DMSO(对照组),最终体积为25μL。反应于30℃下作用30分钟,并通过加入3%磷酸终止反应,以细胞收集器(ulifilter harvester,PerkinElmer)将产物收集到96孔GF/B微量多孔盘(UniFilter,PerkinElmer)中,并用微板闪烁计数器(TopCount microplatescintillation counter,PerkinElmer)计数。抑制剂的IC50值通过测试各化合物的3倍连续稀释浓度而得,并进行重复测试。所得的结果以线性回归软件(GraphPad Prism 4;GraphPad Software Inc.)进行分析。
表1中所列经选择的化合物的抑制活性总结于表4中。IC50值定义为激酶(B-RafV600E激酶)最大活性被抑制一半时测试化合物的浓度。。+表示该浓度(IC50值)为10,000~1,000nM;++表示该浓度为1,000-300nM;以及+++表示该浓度为小于300nM。
表4
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3.C-Raf激酶分析
本文中所公开的受测化合物对激酶活性的抑制能力,通过在该受测化合物的存在下定量基质中并入的[33P]的量来评价。标准的分析条件为2ng的重组C-RafV600E激酶(Upstate Biotechnology)与500ng MEK1(K97R)于分析缓冲液(8μM ATP、0.5μCi[33P]ATP(特异活性3000Ci/毫摩尔,PerkinElmer)、50mM Tris/HCl(pH7.5)及1mM EGTA、1mM Na3VO4、1%2-巯基乙醇、0.1% Brij 35及0.2mg/ml BSA),与受测化合物(以4% DMSO稀释)或单独DMSO(对照组),最终体积为25μL。反应于30℃下作用30分钟,并通过加入3%磷酸终止反应,以细胞收集器(ulifilter harvester,PerkinElmer)将产物收集到96孔GF/B微量多孔盘(UniFilter,PerkinElmer)中,并用微板闪烁计数器(TopCount microplatescintillation counter,PerkinElmer)计数。抑制剂的IC50值通过测试各化合物的3倍连续稀释浓度而得,并进行重复测试。所得的结果以线性回归软件(GraphPad Prism 4;GraphPad Software Inc.)进行分析。
经选择的化合物的抑制B-Raf激酶的活性总结于表5中。IC50值定义为激酶(C-Raf激酶)最大活性被抑制一半时测试化合物的浓度。+表示该浓度(IC50值)为10,000~1,000nM;++表示该浓度为1,000-300nM;以及+++表示该浓度为小于300nM。
表5
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4.细胞增殖分析
如上所述,本发明化合物可用于治疗与蛋白质激酶有关的疾病或病症。该与蛋白质激酶有关的疾病可为癌症、糖尿病、肾脏疾病、冯希伯-林岛氏疾病、囊肿纤维症、牛皮癣、骨关节炎、过度增殖性病症、肾脏的过度增殖性病症、再狭窄、囊肿纤维症、牛皮癣、骨关节炎、自体免疫疾病或血管增殖性病症。该癌症可为肺癌、大肠癌、结肠癌、乳腺癌、前列腺癌、肝癌、胰脏癌、膀胱癌、胃癌、肾脏癌、唾液腺癌、卵巢癌、子宫体癌、子宫颈癌、口腔癌、皮肤癌、脑癌、淋巴瘤或白血病。
化合物对细胞生长的抑制能力通过使用CellTiterTM-96分析法来量测。化合物的细胞毒性在下列细胞中进行评估:B-RafV600E突变的A375黑色素瘤细胞、B-RafV600E突变的COLO205大肠癌细胞及具有野生型B-Raf(B-Rafwt)及NRASQ61R突变的SK-MEL-2黑色素瘤细胞。A375及COLO205细胞培养于37℃、5% CO2环境下含有10%FCS的DMEM培养基中。SK-MEL-2细胞培养于37℃、5% CO2环境下含有10%FCS的MEM培养基中。将A375、COLO205及SK-MEL-2细胞分别以2000、2000及4000细胞/孔的量接种至96孔平盘中,并培养过夜。然后将这些细胞以递增浓度的受测化合物处理并再培养72小时。培养结束时,将CellTiterTM-96一号水溶液试剂(Aqueous One Solution Reagent(Promega))加入其中并再培养4小时。使用微量盘样品测读机(microplate reader,Molecular Devices)测定490nm处的吸光度来测定细胞的存活率。
将生长抑制百分率对应于化合物浓度的结果以线性回归软件(GraphPad Prism5)进行分析来计算该半抑制浓度(IC50)值。表1中所列经选择的化合物的抗增殖活性总结于表6中。+表示该浓度(IC50值)为10,000~1,000nM;++表示该浓度为1,000-300nM;以及+++表示该浓度为小于300nM。
表6
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表6的数据清楚显示本发明的化合物可抑制癌细胞生长,特别是表达为B-Raf突变的癌细胞。因此,这些化合物可用于治疗癌症。
本发明的某些实施方式涉及治疗与蛋白质激酶有关疾病的方法。根据本发明一种实施方式的一种方法包含给予需此治疗的个体有效量的本发明化合物。
虽然本发明已描述有限数量的实施例,本领域的技术人员基于本发明公开的帮助,可了解在不偏离本说明书所述范围的情况下能衍生出其他实施方式。因此,本发明的范围应仅受限于本案的权利要求书。
Claims (11)
1.式(I)所示的化合物,
或其药物上可接受的盐,
其中L为NH;
R1选自由氢、卤素、NR9R10、OR11、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基任选地被卤素、氧基、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基任选地被Rd取代,其中,所述氧基取代为除了苯基或杂芳基的情况;
R2选自由硝基及CN所构成的组;
R3选自由氢及卤素所构成的组;
R4选自卤素;
R5选自卤素;
R6选自由氢、卤素及C1-C4烷基所构成的组;
R7是C1-C4烷基、C1-C4卤烷基或苯基;
R9及R10独立地选自由氢、COR15、SO2R15、OR16、NR17R18、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基任选地被卤素、氧基、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基任选地被Rd取代,其中,所述氧基取代为除了苯基或杂芳基的情况;或
R9及R10与它们所连接的氮原子共同形成3元至6元杂环基,所述杂环基任选地被卤素、氧或C1-C3烷基取代;
R11选自由氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基任选地被卤素、氧基、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基任选地被Rd取代,其中,所述氧基取代为除了苯基或杂芳基的情况;
R15选自由C1-C4烷基、C1-C4卤烷基及芳基所构成的组,其中,所述芳基为单价6碳单环、10碳双环或14碳三环芳环系统;
R16选自由氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C1-C6烷氧基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基任选地被卤素、氧基、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基任选地被Rd取代,其中,所述氧基取代为除了苯基或杂芳基的情况;
R17及R18独立地选自由氢、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C6环烷基、苯基、3元至6元杂环基及5元至6元杂芳基所构成的组,其中该烷基、烯基、炔基、环烷基、苯基、杂环基及杂芳基任选地被卤素、氧基、ORa、SRa、NRbRc、苯基、C1-C4烷基、C1-C4烷氧基及环丙基取代,其中该烷基、烷氧基及环丙基任选地被Rd取代,其中,所述氧基取代为除了苯基或芳杂基的情况;
其中各Ra独立地为氢或C1-C4烷基;
其中各Rb及Rc独立地选自由氢、SO2R7及C1-C4烷基所构成的组,其中该C1-C4烷基任选地被卤素取代;
其中各Rd独立地选自由卤素、氧基、C1-C4烷基及C1-C4烷氧基所构成的组,其中该C1-C4烷基及C1-C4烷氧基任选地被卤素取代。
2.如权利要求1所述的化合物,其中R3为氢。
3.如权利要求1至2中任一项所述的化合物,其中R6为氢。
4.如权利要求1至2中任一项所述的化合物,其中R4及R5为氟。
5.如权利要求3所述的化合物,其中R4及R5为氟。
6.一种化合物,其中该化合物为:
N1-{2,4-二氟-3-[(3-甲氧基-5-硝基-6-喹喔啉基)氨基]苯基}-1-丙烷磺酰胺,
N1-{2,4-二氟-3-[(3-甲氧基-5-硝基-6-喹喔啉基)氨基]苯基}-3-氟-1-丙烷磺酰胺,
N1-(2,4-二氟-3-{[3-(2-吗啉代乙氧基)-5-硝基-6-喹喔啉基]氨基}苯基)-1-丙烷磺酰胺,
N1-(2,4-二氟-3-[3-(2-甲氧基乙氧基)-5-硝基-6-喹喔啉基]氨基苯基)-1-丙烷磺酰胺,
N1-[3-({3-[2-(二甲基氨基)乙氧基]-5-硝基-6-喹喔啉基}氨基)-2,4-二氟苯基]-1-丙烷磺酰胺,
N1-{3-[(5-氰基-3-甲氧基-6-喹喔啉基)氨基]-2,4-二氟苯基}-1-丙烷磺酰胺,
N-{2,4-二氟-3-[(3-甲氧基-5-硝基-6-喹喔啉基)氨基]苯基}甲烷磺酰胺,
N1-{3-[(5-氰基-3-羟基-6-喹喔啉基)氨基]-2,4-二氟苯基}-1-丙烷磺酰胺,
N1-(3-{[5-氰基-3-(2-吗啉代乙氧基)-6-喹喔啉基]氨基)-2,4-二氟苯基)-1-丙烷磺酰胺,
N-(3-(5-氰基-3-乙氧基喹喔啉-6-基氨基)-2,4-二氟苯基)丙烷-1-磺酰胺,
N-(3-(5-氰基-3-(二甲基氨基)喹喔啉-6-基氨基)-2,4-二氟苯基)丙烷-1-磺酰胺,
N-(3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-2,4-二氟苯基)丙烷-1-磺酰胺,
N-(3-(5-氰基-3-(甲氨基)喹喔啉-6-基氨基)-2,4-二氟苯基)丙烷-1-磺酰胺,
N-(3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-2,6-二氟苯基)丙烷-1-磺酰胺,
N-(3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-2,4-二氟苯基)-3-氟丙烷-1-磺酰胺,
N-(3-(5-氰基-3-乙氧基喹喔啉-6-基氨基)-2,4-二氟苯基)-3-氟丙烷-1-磺酰胺,
N-(2-氯-3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-4-氟苯基)丙烷-1-磺酰胺,
N-(2-氯-3-(5-氰基-3-甲氧基喹喔啉-6-基氨基)-4-氟苯基)苯磺酰胺,
N-(2-氯-3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-4-氟苯基)丙烷-1-磺酰胺,或,
N-(2-氯-3-(5-氰基-3-吗啉代喹喔啉-6-基氨基)-4-氟苯基)苯磺酰胺。
7.一种药物组合物,其包含如权利要求1至6中任一项所述的化合物、或其盐,及药学上可接受的载剂。
8.权利要求1至6中任一项所述的化合物在制备用于治疗蛋白质激酶相关疾病的药物中的应用。
9.如权利要求8所述的应用,其中该蛋白质激酶相关疾病是癌症、糖尿病、肾脏疾病、纤维症、骨关节炎、自体免疫疾病或血管增殖性病症。
10.如权利要求9所述的应用,其中该蛋白质激酶相关疾病是癌症。
11.如权利要求10所述的应用,其中该癌症是肺癌、结肠癌、直肠癌、乳腺癌、前列腺癌、肝癌、胰腺癌、膀胱癌、胃癌、肾脏癌、唾液腺癌、卵巢癌、子宫体癌、子宫颈癌、口腔癌、皮肤癌、脑癌、淋巴瘤或白血病。
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