CN101851237B - 一种螺环化合物及其制备方法和应用 - Google Patents
一种螺环化合物及其制备方法和应用 Download PDFInfo
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- CN101851237B CN101851237B CN201010205187A CN201010205187A CN101851237B CN 101851237 B CN101851237 B CN 101851237B CN 201010205187 A CN201010205187 A CN 201010205187A CN 201010205187 A CN201010205187 A CN 201010205187A CN 101851237 B CN101851237 B CN 101851237B
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- dichloro
- fluorophenyl
- amino
- ethoxy
- spiro
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Abstract
本发明公开一类如式(I)和(II)所示的螺环化合物(包括消旋体、对映异构体及别的立体异构体)或其在药学上可接受的盐、水合物、溶剂合物或前药,还公开了该类化合物的制备方法及应用:这类化合物是蛋白激酶,例如c-Met等酪氨酸激酶的抑制剂,并可用于治疗因这些酪氨酸激酶的异常活性引起的疾病,例如肿瘤等,或者用于制备治疗这些疾病的药物。
Description
技术领域
本发明属于有机化学和药物化学领域,具体涉及螺环类化合物,其制备方法和应用。
背景技术
癌症连同心血管疾病是严重威胁人类健康及生命的两大类疾病,尤其是癌症近几年的发病率及死亡率呈快速上升趋势,已超越心血管疾病成为人类健康的头号杀手。
肿瘤的增殖、凋亡、转移等与细胞内外的一系列信号转导通路中某个环节的异常密切相关。在这些信号转导途径中,一类重要的分子就是蛋白质激酶。蛋白激酶活性的异常不仅与肿瘤直接相关,也是导致一系列其他与炎症或增殖反应有关的人类疾病,例如类风湿性关节炎、心血管和神经系统疾病、哮喘、银屑病等的主要原因。目前已知有四百多种人类疾病与蛋白激酶直接或间接相关,这使得蛋白激酶成为继G-蛋白偶联受体之后的另一大类重要药物靶标。
肝细胞生长因子受体(hepatocyte growth factor receptor or HGFR)或称c-Met,属酪氨酸受体激酶。其配体是肝细胞生长因子(hepatocyte growth factor or HGF)。
c-Met由Cooper等人发现(Cooper,C.S.et al Nature 1984,311,29-33)。1984年他们在研究人骨肉瘤Hos细胞系时,克隆出了一个具有转化活性的片段,定名为c-Met。c-Met位于人类7号染色体长臂(7q31)。c-Met基因大小约110kb,包括21个外显子。c-Met蛋白是由c-Met原癌基因编码的蛋白产物。c-Met的配体是肝细胞生长因子,也称离散因子(scatter factor)。到目前为止,c-Met是肝细胞生长因子(HGF)唯一的高亲和性受体。HGF与c-Met细胞表面配体结合部位结合导致c-Met受体之间的多聚及位于细胞质内部分自身的多个酪氨酸残基的磷酸化(Bottaro,D.P.et al Science 1991,251,802-804;Naldini,L.et al Oncogene 1991,6(4),501-504)。酪氨酸的磷酸化调节c-Met的细胞内吞、酶催化活性及底物结合。c-Met的激活导致多种底物蛋白的酪氨酸磷酸化,例如Gab1、Grb2、Shc、c-Cbl,从而进一步活化信号传递蛋白PI3K、Akt、PLC-γ、STAT、ERK1及ERK2(Birchmeier,C.et al Nature Rev Mol.Cell Biol.2003,4,915-925)。c-Met受体和HGF在许多组织中均有表达,其正常表达主要是集中在来源于上皮(epithelial)和间质(mesenchymal)的细胞。在哺乳动物的发育和组织修复过程中,c-Met受体和HGF也已被证明对上皮细胞-间质细胞相互作用非常重要,并对细胞的迁移、入侵、增殖、存活、血管新生、形态分化、三维微管结构的形成等发挥调控作用。
在正常生理情况下,c-Met受体和HGF的结合和表达对哺乳动物的发育及组织内环境的稳定至关重要,但失控的c-Met受体和HGF与肿瘤的转移进程极其相关。c-Met受体和HGF在许多肿瘤组织中异常高表达,其表达程度与病人的恶性预后紧密相关。活化c-Met激酶的点突变已在下列肿瘤中检测到:遗传性乳头状肾细胞瘤(hereditarypapillary renal carcinoma)、偶发性乳头状肾细胞瘤(sporadic papillary renal carcinoma)、肺癌、头颈癌、儿童肝细胞癌、胃癌等。另外c-Met受体基因扩增也在下列肿瘤中检测到:胃癌、转移的结肠癌、食道腺癌。
正是由于c-Met在肿瘤发生、发展及转移中的重要性,许多公司及研究机构都致力于研发c-Met的抑制剂,下面是一些例子:
Christensen等人报导PHA-665752作为小分子化合物c-Met抑制剂:Christensen,J.G.et al Cancer Res.2003,63,7345-7355。
Zou等人报导PF-2341066作为小分子化合物c-Met抑制剂:Zou,H.Y.et al CancerRes.2007,69,4408-4417。
US2006/0293358A1,WO2005/068473A1,WO2006/086484A1,WO2007/035428A1,WO2007/036630A1,WO2007/041379A1,WO2007/064797A1,WO2007/075567A1,WO2007/111904A2,WO2006/021886A 1,WO2004/076412A2,WO2006/021881A2,US2006/0046991A1,US2005/0009840A1等专利文件公开了一系列杂环化合物作为c-Met激酶抑制剂,并且对癌症等疾病具有治疗作用。
如上所述,c-Met酪氨酸激酶抑制剂已有多篇文献报道,也有一些针对c-Met或HGF的单克隆抗体及合成小分子化合物正在1-3期临床试验,但是,由于众所周知的临床试验的不确定性,目前还没有一个c-Met或HGF抑制剂被批准成药。因此,研发新的c-Met抑制剂仍非常必要。
发明内容
本发明的第一个目的,就在于提供一类具有蛋白激酶抑制活性的螺环类化合物。
本发明的第二个目的,在于提供所述螺环类化合物的制备方法。
本发明的第三个目的,在于提供一种包含所述螺环类化合物的药物组合物。
本发明还有一个目的,在于提供所述螺环类化合物用于制备治疗蛋白激酶异常活性引起的疾病的药物的应用。
根据本发明,所述具有蛋白激酶抑制活性的化合物为具有以下式(I)和(II)所示的螺环类化合物,
其中,
X为CH或N;
R和R’独立选自H、C1-6烷基,且R1中的每一个氢可独立地被一个或多个相同或不同的G0取代;
R1选自H、-CN、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C6芳基、C5-6杂芳基、C3-6杂脂环基、R4O-、R4R5N-、R4S(=O)m-、R4R5NS(=O)m-、R4C(=O)-、R4R5NC(=O)-、R4OC(=O)-、R4C(=O)O-、R4R5NC(=O)O-、R4C(=O)NR6-、R4R5NC(=O)NR6-、R4OC(=O)NR6-、R4S(=O)mNR6-、R4R5NS(=O)mNR6-、R4R5NC(=NR7)NR6-、R4R5NC(=CHNO2)-、R4R5NC(=N-CN)-、R4R5NC(=NR6)-、R4S(=O)(=NR7)NR6-或R4R5NS(=O)(=NR6)-,且R1中的每一个氢可独立地被一个或多个相同或不同的G1取代;
R2选自H或C1-6烷基,且R2中的每一个氢可独立地被一个或多个相同或不同的G2取代;
R3独立选自H、卤素、CN、NO2、NH2、NMe2、NHMe、OH、OCH3、OEt、OCF3,CF3、cyclopropyl或C1-6烷基,且R3中的每一个氢可独立地被一个或多个相同或不同的G3取代;
R4、R5、R6及R7独立地选自:H、C1-6烷基、C3-6环烷基、C6芳基、C5-6杂芳基、C3-6杂脂环基;当R4和R5连接于同一氮原子上时,可与该氮原子一起形成一个C3-6杂脂环,这个C3-6杂脂环可另外包含一个或多个O、N、S(=O)m等杂原子;且R4、R5、R6及R7中的每一个氢可独立地被一个或多个相同或不同的G4取代;
G0、G1、G2、G3及G4独立地选自H、-OH、-NH2、-CN、-CF3、卤素、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C6芳基、C5-6杂芳基、C3-6杂脂环基、C1-6烷氧基、C3-6环烷氧基、C6芳氧基、C5-6杂芳氧基、C3-6杂脂环氧基、C1-6烷氨基、C3-6环烷氨基、C6芳氨基、C5-6杂芳氨基、C3-6杂脂环氨基、C1-6烷氧基-CO-、C3-6环烷氧基-CO-、C6芳氧基-CO-、C5-6杂芳氧基-CO-、C3-6杂脂环氧基-CO-、C1-6烷氨基-CO-、C3-6环烷氨基-CO-、C6芳氨基-CO-、C5-6杂芳氨基-CO-或C3-6杂脂环氨基-CO-;
n=0-4;
m=0-2;
R和R’独立选自H、C1-6烷基,且R1中的每一个氢可独立地被一个或多个相同或不同的G0取代。
根据本发明的一个优选实施例,所述化合物的分子结构如式(Ia)所示:
其中,一个优选实施例中,R1选自H、C1-6烷基、C3-6环烷基、C6芳基、C5-6杂芳基、C3-6杂脂环基、R4S(=O)m-、R4R5NS(=O)m-、R4C(=O)-、R4R5NC(=O)-、R4OC(=O)-、R4R5NC(=NR6)-、R4R5NC(=N-CN)-、R4R5NC(=CHNO2)-或R4R5NS(=O)(=NR6)-,且R1中的每一个氢可独立地被一个或多个相同或不同的G1取代。另一个优选实施例中,R1选自H、甲基、乙基、异丙基、叔丁基、环丙基、甲酰基、乙酰基、丙酰基、异丙酰基、2-氨基-2-甲基丙酰基、氨基甲酰基、甲氨基甲酰基、二甲氨基甲酰基、乙氨基甲酰基、二乙氨基甲酰基、甲磺酰基、乙磺酰基、丙磺酰基、环丙磺酰基、苯磺酰基或对甲苯磺酰基。且R1中的每一个氢可独立地被一个或多个相同或不同的G1取代。
根据本发明的一个优选实施例,所述化合物的分子结构如式(Ib)所示:
其中,一个优选实施例中,R1选自H、C1-6烷基、C3-6环烷基、C6芳基、C5-6杂芳基、C3-6杂脂环基、R4S(=O)m-、R4R5NS(=O)m-、R4C(=O)-、R4R5NC(=O)-、R4OC(=O)-、R4R5NC(=NR6)-、R4R5NC(=N-CN)-、R4R5NC(=CHNO2)-或R4R5NS(=O)(=NR6)-,且R1中的每一个氢可独立地被一个或多个相同或不同的G1取代。另一个优选实施例中,R1选自H、甲基、乙基、异丙基、叔丁基、环丙基、甲酰基、乙酰基、丙酰基、异丙酰基、2-氨基-2-甲基丙酰基、氨基甲酰基、甲氨基甲酰基、二甲氨基甲酰基、乙氨基甲酰基、二乙氨基甲酰基、甲磺酰基、乙磺酰基、丙磺酰基、环丙磺酰基、苯磺酰基或对甲苯磺酰基。且R1中的每一个氢可独立地被一个或多个相同或不同的G1取代。
根据本发明,所述具有蛋白激酶抑制活性的化合物为具有以下式(II)所示的螺环类化合物,
式中:
X为CH或N;
R和R’独立选自H、C1-6烷基,且R1中的每一个氢可独立地被一个或多个相同或不同的G0取代;
R1选自H、-CN、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C6芳基、C5-6杂芳基、C3-6杂脂环基、R4O-、R4R5N-、R4S(=O)m-、R4R5NS(=O)m-、R4C(=O)-、R4R5NC(=O)-、R4OC(=O)-、R4C(=O)O-、R4R5NC(=O)O-、R4C(=O)NR6-、R4R5NC(=O)NR6-、R4OC(=O)NR6-、R4S(=O)mNR6-、R4R5NS(=O)mNR6-、R4R5NC(=NR7)NR6-、R4R5NC(=CHNO2)-、R4R5NC(=N-CN)-、R4R5NC(=NR6)-、R4S(=O)(=NR7)NR6-或R4R5NS(=O)(=NR6)-,且R1中的每一个氢可独立地被一个或多个相同或不同的G1取代;
R2选自H或C1-6烷基,且R2中的每一个氢可独立地被一个或多个相同或不同的G2取代;
R3独立选自H、卤素、CN、NO2、NH2、NMe2、NHMe、OH、OCH3、OEt、OCF3,CF3、cyclopropyl或C1-6烷基,且R3中的每一个氢可独立地被一个或多个相同或不同的G3取代;
R4、R5、R6及R7独立地选自:H、C1-6烷基、C3-6环烷基、C6芳基、C5-6杂芳基、C3-6杂脂环基;当R4和R5连接于同一氮原子上时,可与该氮原子一起形成一个C3-6杂脂环,这个C3-6杂脂环可另外包含一个或多个O、N、S(=O)m等杂原子;且R4、R5、R6及R7中的每一个氢可独立地被一个或多个相同或不同的G4取代;
G0、G1、G2、G3及G4独立地选自H、-OH、-NH2、-CN、-CF3、卤素、C1-6烷基、C3-6环烷基、C2-6烯基、C2-6炔基、C6芳基、C5-6杂芳基、C3-6杂脂环基、C1-6烷氧基、C3-6环烷氧基、C6芳氧基、C5-6杂芳氧基、C3-6杂脂环氧基、C1-6烷氨基、C3-6环烷氨基、C6芳氨基、C5-6杂芳氨基、C3-6杂脂环氨基、C1-6烷氧基-CO-、C3-6环烷氧基-CO-、C6芳氧基-CO-、C5-6杂芳氧基-CO-、C3-6杂脂环氧基-CO-、C1-6烷氨基-CO-、C3-6环烷氨基-CO-、C6芳氨基-CO-、C5-6杂芳氨基-CO-或C3-6杂脂环氨基-CO-;
n=0-4;
m=0-2。
根据本发明的一个优选实施例,所述化合物的分子结构式(II)中,R和R’独立选自H或甲基。
根据本发明的另一个优选实施例,所述化合物的分子结构式(II)中,R和R’为H;R1选自H、C1-6烷基、C3-6环烷基、C6芳基、C5-6杂芳基、C3-6杂脂环基、R4S(=O)m-、R4R5NS(=O)m-、R4C(=O)-、R4R5NC(=O)-、R4OC(=O)-、R4R5NC(=NR6)-、R4R5NC(=N-CN)-、R4R5NC(=CHNO2)-或R4R5NS(=O)(=NR6)-,且R1中的每一个氢可独立地被一个或多个相同或不同的G1取代。R1更进一步选自H、甲基、乙基、异丙基、叔丁基、环丙基、甲酰基、乙酰基、丙酰基、异丙酰基、2-氨基-2-甲基丙酰基、氨基甲酰基、甲氨基甲酰基、二甲氨基甲酰基、乙氨基甲酰基、二乙氨基甲酰基、甲磺酰基、乙磺酰基、丙磺酰基、环丙磺酰基、苯磺酰基或对甲苯磺酰基。且R1中的每一个氢可独立地被一个或多个相同或不同的G1取代。
根据本发明,所述螺环类化合物优先选自下述所列化合物(表1):
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-乙基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-正丙基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-异丙基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-叔丁基基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-环丙基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-环丁基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-环戊基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-环己基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲醛;
1’-乙酰基-5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-正丙酰基-5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-异丙酰基-5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-环丙酰基-5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-环丁酰基-5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-环戊酰基-5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-环己酰基-5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-N-甲基-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-N,N-二甲基-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(吗啉-4-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(4-甲基哌嗪-1-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(哌嗪-1-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(2-氨基-2-甲基丙酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(2-羟基-2-甲基丙酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
[5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
[5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-乙基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
[5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-苯基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
[5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-对甲苯基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-乙基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-正丙基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-异丙基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-叔丁基基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-环丙基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-环丁基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-环戊基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-环己基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲醛;
1’-乙酰基-6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-正丙酰基-6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-异丙酰基-6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-环丙酰基-6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-环丁酰基-6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-环戊酰基-6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
1’-环己酰基-6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-N-甲基-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-N,N-二甲基-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(吗啉-4-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(4-甲基哌嗪-1-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(哌嗪-1-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(2-氨基-2-甲基丙酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(2-羟基-2-甲基丙酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
[6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
[6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-乙基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
[6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-苯基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
[6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-对甲苯基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-乙基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-异基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-环基螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-N-甲基-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-N,N-二甲基-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-(吗啉-4-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-(4-甲基哌嗪-1-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲醛;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-(2-氨基-2-甲基丙酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-甲基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-乙基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-异基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-环基螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-N-甲基-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-N,N-二甲基-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-(吗啉-4-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-(4-甲基哌嗪-1-甲酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲醛;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-(2-氨基-2-甲基丙酰基)螺[吲哚啉-3,4’-哌啶]-2-酮;
6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-甲基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮;
3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-5-(1’-甲基螺[吲哚啉-3,4’-哌啶]-5-基)吡啶-2-胺;
3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-5-(1’,2,2-三甲基螺[吲哚啉-3,4’-哌啶]-5-基)吡啶-2-胺;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-1’-甲醛;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2,2-二甲基-螺[吲哚啉-3,4’-哌啶]-1’-甲醛;
1-[5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-1’-基]乙酮;
1-[5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2,2-二甲基-螺[吲哚啉-3,4’-哌啶]-1’-基]乙酮;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2,2-二甲基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-5-(1’-甲基磺酰基螺[吲哚啉-3,4’-哌啶]-5-基)吡啶-2-胺;
3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-5-(2,2-二甲基-1’-甲基磺酰基-螺[吲哚啉-3,4’-哌啶]-5-基)吡啶-2-胺;
3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-5-(1’-甲基螺[吲哚啉-3,4’-哌啶]-6-基)吡啶-2-胺;
3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-5-(1’,2,2-三甲基螺[吲哚啉-3,4’-哌啶]-6-基)吡啶-2-胺;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-1’-甲醛;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2,2-二甲基-螺[吲哚啉-3,4’-哌啶]-1’-甲醛;
1-[6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-1’-基]乙酮;
1-[6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2,2-二甲基-螺[吲哚啉-3,4’-哌啶]-1’-基]乙酮;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2,2-二甲基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺;
3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-5-(1’-甲基磺酰基螺[吲哚啉-3,4’-哌啶]-6-基)吡啶-2-胺;
3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-5-(2,2-二甲基-1’-甲基磺酰基-螺[吲哚啉-3,4’-哌啶]-6-基)吡啶-2-胺。
本发明所述的化合物包括消旋体、对映异构体及别的立体异构体或其中药学上可接受的盐、水合物、溶剂合物或前药。
以下使用的通式表示符号,例如,halo等,除非另有说明,只适用于本部分。
本发明所述的螺环化合物可通过化学合成得到,其中一种合成方法是将式(III)所示的化合物与式(IV)所示的化合物进行Suzuki偶联反应制成螺环目标化合物,其中,Suzuki偶联反应是本技术领域中人员熟悉的有机化学反应。
化合物(III)可以通过与文献(WO2004/076412A2&WO2006/021881A2)类似的方法制备。
化合物(IV)和(IV’)由如下方法合成:
其中halo=Cl、Br、I等;R1与权利要求1中的定义一样;Base=LiN(SiMe3)2、NaN(SiMe3)2、KN(SiMe3)2、LiN(Pr-i)2、KOBu-t、NaH等。
根据本发明的一个优选实施例,本发明的化合物具有蛋白激酶抑制活性。因此,本发明的另一个方面,提供了一种本发明的化合物(包括消旋体及对映异构体,或其在药学上可接受的盐、溶剂合物或前药)用于治疗因蛋白质激酶,尤其是c-Met异常活性引起的疾病,例如癌症的方法,或者是用于制备治疗因蛋白激酶,尤其是c-Met异常活性引起的疾病,例如癌症的药物的应用。优选的,所述化合物为式(I)、(Ia)、(Ib)和(II)的化合物(包括消旋体及对映异构体,或其在药学上可接受的盐、溶剂合物或前药;更优选的,所述化合物为表1中所列的化合物,包括消旋体及对映异构体,或其在药学上可接受的盐、溶剂合物或前药。
根据本发明,所述治疗是通过将本发明的化合物(包括消旋体及对映异构体,或其在药学上可接受的盐、溶剂合物或前药)与蛋白激酶,例如c-Met接触,从而抑制其激酶催化活性。
本发明所述的化合物在体外人造环境下(例如生化条件或细胞中)与酪氨酸激酶c-Met接触,抑制其激酶催化活性,对酪氨酸激酶c-Met的活性有抑制作用,可用于制备酪氨酸激酶c-Met的抑制剂。所述的c-Met抑制剂以上述式(I)化合物为活性成分,可以制成各种医学上常用的具体剂型,其中式(I)化合物的有效含量可根据需要实验确定。
本发明所述的c-Met是指肝细胞生长因子受体(hepatocyte growth factor receptor orHGFR),属酪氨酸受体激酶,其配体是肝细胞生长因子(hepatocyte growth factor orHGF)。
使用有效剂量的本发明所述的化合物可治疗哺乳动物,例如人类,因蛋白激酶异常活性引起的疾病,例如癌症。
本发明所述的癌症包括但不限于:肺癌、骨癌、胰腺癌、皮肤癌、头或颈癌、皮肤或眼内黑素瘤、子宫癌、卵巢癌、直肠癌、肛门区癌、胃癌、结肠癌、乳腺癌、输卵管癌、子宫内膜癌、宫颈癌、阴道癌、阴户癌、何杰金病、食道癌、小肠癌、内分泌系统癌、甲状腺癌、甲状旁腺癌、肾上腺癌、软组织肉瘤、尿道癌、阴茎癌、前列腺癌、慢性或急性白血病、淋巴细胞性淋巴瘤、膀胱癌、肾或输尿管癌、肾细胞癌、肾盂癌、中枢神经中枢系统(CNS)赘生物、原发性CNS淋巴瘤、脊柱轴肿瘤、脑干神经胶质瘤、垂体腺瘤、胃肠间质肿瘤、肾细胞癌、结肠直肠癌、非小细胞肺癌、神经内分泌胶肿瘤、小细胞肺癌、肥大细胞增多症、神经胶质瘤、肉瘤、急性髓细胞样白血病、前列腺癌、淋巴瘤及这些癌症的任何组合。
发明所述的另外的疾病包括但不限于:银屑病(或称牛皮癣)、肝硬化、糖尿病、涉及血管新生的疾病、涉及再狭窄的疾病、眼睛疾病例如AMD、风湿性关节炎及别的炎症、免疫系统疾病例如自免疫疾病(例如,爱滋病等)、心血管疾病例如动脉粥样硬化、肾脏疾病等。
本发明所述的化合物可与其他抗肿瘤药物共同使用从而起到协同(synergistic)或加合(additive)效应的方法。这些抗肿瘤药包括但不限于:有丝分裂抑制剂、烷基化剂(例如氟尿嘧啶(fluorouracil or 5-FU)、Leukovorin、UFT、capecitabine、gemcitabine、cytarabine、busulfan、improsulfan、piposulfan、benzodepa、carboquone、meturedepa、uredepa、altretamine、triethylenemelamine、chlorambucil、cyclophosphamide、dacarbazine等)、抗代谢类药物(例如,methotrexale、pteropterin、mercaptopurine、thioguanine等)、细胞周期抑制剂、拓扑异构酶抑制剂、生物反应调节基、抗体、细胞霉素、微管作用剂(例如,紫杉醇(Taxol)、多烯紫杉醇(Taxotere)、埃坡霉素A&B(Epothilone A&B等))、铂络合物(例如,卡铂、顺铂等)、抗生素类药(例如,博来霉素、更生霉素等)、激素类药(例如,性激素类、肾上皮质激素类等)、植物类药(例如,长春新碱、秋水仙碱、喜树碱等)、蛋白激酶抑制剂( 等)、HDAC抑制剂(例如,(SAHA)等)、抗炎药物(例如,非甾体抗炎药(NSAIDs)、选择性或非选择性环氧化酶2(COX2)抑制剂等),例如,传统的NSAIDs(例如,布洛芬、奈普生、乙酰水杨酸等)及选择性的COX2抑制剂(例如,塞来昔布伐地昔布帕瑞昔布艾托昔布等)及这些药物的任何组合。
本发明提供了一种本发明中的化合物与其他的肿瘤疗法,例如放射线疗法、介入疗法等一同使用的方法。
本发明一种药物组合物,该药物组合物包含有上述本发明的任何化合物或其在药学上可接受的盐、溶剂合物或前药,优选的,所述化合物为如式(Ia)及式(Ib)所示的化合物;更优选的,所述化合物为权利要求8中所列的化合物(包括消旋体及对映异构体),或其在药学上可接受的盐、溶剂合物或前药。所述药物组合物还可以包含有一种或多种药学上可接受的载体。
根据本发明的一个优选实施例,所述化合物(包括消旋体及对映异构体)或其在药学上可接受的盐、溶剂合物或前药具有抑制c-Met激酶活性,其IC50值小于5μM、优选的是小于2μM、更优选的是小于1μM、进一步优选的是小于500nM、更进一步优选的是小于300nM、再进一步优选的是小于200nM、再更进一步优选的是小于100nM、最优选的是小于50nM。本领域中的专业人员在一定的测试条件下很容易测定这些化合物的IC50值。
根据本发明的一个优选实施例,所述药物组合物的制剂形式可为如下之任何一种:片剂、胶囊、注射剂、气雾剂、凝胶剂、栓剂、丸剂、糖浆、眼药水、滴剂、膏剂、贴剂、乳剂等。
术语的定义
除非特别说明,在本申请的权力要求及其它部分使用的术语的意思以下面定义的为准。在本节中使用的可变基团,例如Ra、Rb、m等只适用于本节。另外,本节中定义的许多基团都可以另外被取代。在本节中所列的典型的取代基只是起示例的作用,并非用来限制本申请的权力要求及其它部分的内容。
“药学上可接受的盐”指本发明中的化合物与无机或有机酸、或者无机或有机碱通过化学反应形成的盐,这种盐保留本发明中的化合物的生物活性及有效性。所述的无机或有机酸的例子为:盐酸、氢溴酸、氢碘酸、硫酸、硝酸、碳酸、磷酸、高氯酸、醋酸、柠檬酸、草酸、乳酸、苹果酸、水杨酸、酒石酸、甲磺酸、乙磺酸、苯磺酸、取代的苯磺酸(例如,对甲基苯磺酸)、异烟酸、油酸、鞣酸、泛酸、抗坏血酸、丁二酸、马来酸、龙胆酸、富马酸、葡萄糖酸、糖醛酸、葡萄糖二酸或蔗糖酸、甲酸、苯甲酸、谷氨酸、双羟萘酸、山梨酸等。所述的无机或有机碱的例子为氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铁、氢氧化钙、氢氧化钡、氢氧化铝、氢氧化镁、氢氧化锌、氨水、氢氧化有机季铵盐、碳酸钠、碳酸钾、碳酸锂、碳酸钙、碳酸钡、碳酸镁、碳酸化有机季铵盐、碳酸氢钠、碳酸氢钾、碳酸氢锂、碳酸氢钙、碳酸氢钡、碳酸氢镁、碳酸氢化有机季铵盐等。
“溶剂合物”指本发明中的化合物与化学上常用的溶剂以共价键、氢键、离子键、范德华(Van der Waals)力、络合、包合(inclusion)等形成的稳定物质,其中的溶剂例如:甲醇、乙醇、丙醇、丁醇、乙二醇、丙二醇、聚乙二醇、丙酮等。
“水合物”指溶剂合物,其中的溶剂为水。
“前药(prodrug)”指通过化学合成或物理的方法将本发明中的化合物转化为另一种化合物,当这种化合物被给予哺乳动物后,在其体内被转化成本发明中由式I代表的化合物。利用“前药”方法通常是为了克服药物化合物本身不良或欠佳的物理化学性质或成药性(drug-likeness)。
“消旋体、对映异构体及别的立体异构体”指化合物具有相同的分子式及分子量,然而由于原子之间的不同键合方式及空间安排顺序而形成不同的化合物,这样的化合物叫异构体或称立体异构体。当这些立体异构体互为镜像关系,即看起来很像,却不能完全重合,就如左手与右手,这些化合物叫对映异构体。对映异构体的绝对构型通常用(R)-及(S)-或R-及S-来标示。具体确定对映异构体的绝对构型的规则见Chapter 4 of“Advanced Organic Chemistry,”4th edition(by J.March,John Wiley and Sons,New York,1992)。(R)-及(S)-对映异构体对偏振光具有相反的旋转作用,即左旋和右旋。当(R)-及(S)-对映异构体按1∶1的比例混合或存在时,该混合物对偏振光没有旋转作用,这时该混合物称为消旋体。
本发明中的化合物还可能存在互变异构体(tautomers)、旋转异构体(rotamers)、顺反异构体等,这些概念都可在J.March的“Advanced Organic Chemistry,”4th edition中找到并得到理解。只要这些异构体具有与本发明中的化合物相同的抑制蛋白激酶活性的作用,这些异构体也涵盖于本发明中。
本发明中的化合物被给予例如人的哺乳动物后,根据本领域的常识,很有可能在动物体内被不同的酶代谢成各种代谢产物,只要这些代谢产物具有与本发明中的化合物相同的抑制蛋白激酶活性的作用,这些代谢产物也涵盖于本发明中。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂合物、水合物或前药与别的化学成分,例如药学上可接受的载体,混合。药物组合物的目的是促进给药给动物的过程。
“药学上可接受的载体”指药物组合物中的非活性成分,例如但不限于:碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶(gelatin)、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
前述的药物组合物中,除了包括药学上可接受的载体外,还可以包括在药(剂)学上常用的辅剂,例如:抗细菌剂、抗真菌剂、抗微生物剂、保质剂、调色剂、增溶剂、增稠剂、表面活性剂、络合剂、蛋白质、氨基酸、脂肪、糖类、维生素、矿物质、微量元素、甜味剂、色素、香精或它们的结合等。
“烷基”指具有指定数目碳原子的直链或支链的饱和碳氢化合物基团,例如C1-12烷基指含最少1个,最多12个碳原子的直链或支链基团。C0烷基代表一个共价单键。本发明中的烷基包括但不限于:甲基、乙基、丙基、丁基、异丙基、新戊基、2-甲基-1-己基等。烷基中的一个或全部氢原子可被下列基团取代:环烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb,其中,Ra及Rb分别选自:氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等,并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“环烷基”或“环烷”指具有指定数目碳原子的单、双或多环的碳氢化合物基团,双环或多环时,可以以稠合(两个环或多个环共用两个相邻的碳原子)或螺合(两个环或多个环共用一个碳原子)的形式结合,例如C1-12环烷基指含最少1个,最多12个的单、双或多环的碳氢化合物基团。C0环烷基代表一个共价单键。环烷基中可以含有不饱和的双键或三键,但不具有完全共轭的π电子体系。本发明中的环烷基包括但不限于:环丙基、环丁基、环己基、环戊烯基、环庚三烯基、金刚烷等:
环烷基或环烷中的一个或全部氢原子可被下列基团取代:烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb,其中,Ra及Rb分别选自:氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等,并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“烯基”指含有至少两个碳原子及一个双键的烷基。本发明中的烯基包括但不限于:乙烯基、2-丙烯基、1-戊烯基等。
“炔基”指含有至少两个碳原子及一个三键的烷基。本发明中的炔基包括但不限于:乙烯基、2-丙烯基、1-戊烯基等。
“卤素”指氟、氯、溴或碘。
“烷氧基”指具有指定数目碳原子的烷基通过氧原子与其他基团相连,即烷基-O-。本发明中的烷氧基包括但不限于:甲氧基、乙氧基、丙氧基、丁氧基、环戊氧基、环己氧基、异丙氧基、新戊氧基、2-甲基-1-己氧基等。
“环烷氧基”指具有指定数目碳原子的环烷基通过氧原子与其他基团相连,即环烷基-O-。本发明中的环烷氧基包括但不限于:环丙烷氧基、环丁烷氧基、环己烷氧基等。
“芳基”指由6-12个碳原子组成的单环、双环或多环基团,其中至少有一个环具有完全共轭的π电子体系并符合N+2规则,即具有芳香性,但整个基团不必全部共轭。芳基也可以以亚芳基的形式出现,即芳基结构中与其他基团有两个或以上的连接点。本发明中的芳基包括但不限于:苯基、萘基、茚基、二氢化茚基、四氢化萘等。芳基中的一个或全部氢原子可被下列基团取代:烷基、环烷基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb,其中,Ra及Rb分别选自:氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等,并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“杂芳基”指由5-12个除了氢原子以外的原子组成的单环、双环或多环基团,其中至少一个原子为O、N、S(=O)m(其中m=0-2)、P或Si,并且,其中至少有一个环具有完全共轭的π电子体系并符合N+2规则,即具有芳香性,但整个基团不必全部共轭。杂芳基也可以以亚杂芳基的形式出现,即杂芳基结构中与其他基团有两个或以上的连接点。本发明中的杂芳基包括但不限于:砒啶、砒碇酮、四氢砒碇酮、咪啶、吡嗪、哒嗪、咪唑、噻唑、噻吩、呋喃、吲哚、氮杂吲哚、苯并咪唑、吲哚啉、吲哚酮、喹咛等:
杂芳基中的一个或全部氢原子可被下列基团取代:烷基、环烷基、芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb,其中,Ra及Rb分别选自氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等,并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“杂脂环基或杂脂环”指由3至12个除了氢原子以外的原子组成的单环、双环或多环烷基或烷,其中至少一个原子为O、N、S(=O)m(其中m=0-2)、P或Si。这种环中除单键外,还可含有双键或叁键,但这些双键或叁键不构成全部共轭的芳香结构。这些单环、双环或多环烷基或烷可以以稠环、桥环或螺环的形式存在。本发明中的杂脂环基或杂脂环包括但不限于:哌啶、吗啉、哌嗪、吡咯烷、吲哚啉、四氢吡啶、四氢呋喃、托品醇等:
杂脂环基或杂脂环中的一个或全部氢原子可被下列基团取代:烷基、环烷基、芳基、杂芳基、杂脂环、卤素、氨基、羟基、氰基、硝基、羧基、巯基、氧基(oxo)、烷氧基、芳氧基、烷基巯基、芳基巯基、羰基、硫羰基、C-酰胺基、N-酰胺基、O-氨羰氧基、N-氨羰氧基、O-硫代氨羰氧基、N-硫代氨羰氧基、C-酯基、O-酯基及-NRaRb,其中,Ra及Rb分别选自:氢、烷基、环烷基、芳基、乙酰基、羰基、磺酰基、三氟甲磺酰基等,并且Ra及Rb连同氮原子可形成5-或6-元杂脂环。
“芳氧基”指芳基通过氧原子与其他基团相连,即芳基-O-。本发明中的芳氧基包括但不限于:苯氧基、萘氧基等。
“杂芳氧基”指杂芳基通过氧原子与其他基团相连,即杂芳基-O-。本发明中的杂芳氧基包括但不限于:4-砒啶氧基、2-噻吩氧基等。
“烷氨基”指具有指定数目碳原子的烷基通过氮原子与其他基团相连,即烷基-NH-或(烷基)2N-。本发明中的烷氨基包括但不限于:甲氨基、乙氨基、丙氨基、二甲氨基等。
“环烷氨基”指具有指定数目碳原子的环烷基通过氮原子与其他基团相连,即环烷基-NH-或(环烷基)2N-。本发明中的环烷氨基包括但不限于:环丙烷氨基、环丁烷氨基等。
“芳氨基”指芳基通过氮原子与其他基团相连,即芳基-NH-或(芳基)2N-。本发明中的芳氨基包括但不限于:苯氨基、萘氨基、二苯氨基等。
“杂芳氨基”指杂芳基通过氮原子与其他基团相连,即杂芳基-NH-或(杂芳基)2N-。本发明中的杂芳氨基包括但不限于:4-砒啶氨基、3-噻吩氨基等。
“氨基”指H2N-或其中氢原子被取代的H2N-,即RaHN-及RaRbN-。
“oxo”或“氧基”指=O,即氧原子通过双键与碳或N、S、P等杂原子相连接。被氧基取代的例子包括但不限于:
“羟基”指-OH。
“硝基”指-NO2。
“羧基”指-CO2H。
“巯基”指-SH。
“烷基巯基”指烷基-S-。
“芳基巯基”指芳基-S-。
“羰基”指-C(=O)-。
“硫羰基”指-C(=S)-。
“C-酰胺基”指-C(=O)NRaRb。
“N-酰胺基”指C(=O)NRa。
“O-氨羰氧基”指-O-C(=O)NRaRb。
“N-氨羰氧基”指O-C(=O)NRa-。
“O-硫代氨羰氧基”指-O-C(=S)NRaRb。
“N-硫代氨羰氧基”指O-C(=S)NRa-。
“C-酯基”指-C(=O)ORa。
“N-酯基”指C(=O)O-。
“乙酰基”指CH3C(=O)-。
“磺酰基”指-SO2Ra。
“三氟甲磺酰基”指CF38O2-。
药物组合物及其应用
本发明中的化合物(包括消旋体、对映异构体及别的立体异构体)或其在药学上可接受的盐、水合物、溶剂合物或前药通过制剂(formulation)过程,与适合的药学上可接受的载体及药学上常用的辅剂制备成容易给药的药物组合物。这个药物组合物用于治疗哺乳动物,例如人类病人,因蛋白激酶的异常活动引起的疾病,例如癌症。
给药途径
本发明中的药物组合物的给药途径包括但不限于:口服(例如片剂或胶囊)、注射(例如,静脉注射、皮下注射、肌肉注射、眼球注射、腹腔注射等)、肛塞(栓剂)、眼滴、鼻孔吸入或喷雾等。也可使用药物释放系统,例如,脂质体(liposome)、缓释技术等,其中优先选用的方法为口服及注射,更优先选用的方法为口服。
制剂方法
本发明中的化合物的制剂过程采用医药工业常用的方法,例如,混合、溶解、制粒、研磨、乳化、胶囊、糖衣、冷冻干燥、冷冻喷雾等。
药物组合的制剂形式可为如下之任何一种:片剂、胶囊、注射剂、气雾剂、凝胶剂、栓剂、丸剂、糖浆、眼药水、滴剂、膏剂、贴剂、乳剂等。制剂及给药技术见“Remington’sPharmacological Sciences,”Mack Publishing Co.,Easton,PA最新版本。
口服给药的制剂形式可以是,但不限于,片剂、胶囊、糖浆、凝胶、丸剂、悬浮液等。制剂使用的载体、辅剂及赋形剂为,但不限于,碳酸钙、磷酸钙、各种糖(例如,乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、聚维酮(PVP)、凝胶(gelatin)、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
注射给药的制剂形式为,但不限于,无菌溶液、悬浮液、乳剂等。
肛塞给药的制剂形式为,但不限于,栓剂、凝胶剂等。
鼻孔吸入给药的制剂形式为,但不限于,喷雾剂、气雾剂等。
本发明中的化合物可以以药学上可接受的盐的形式存在于制剂中,用于形成盐的无机或有机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硫酸、硝酸、碳酸、磷酸、高氯酸、醋酸、柠檬酸、草酸、乳酸、苹果酸、水杨酸、酒石酸、甲磺酸、乙磺酸、苯磺酸、取代的苯磺酸(例如,对甲基苯磺酸)、异烟酸、油酸、鞣酸、泛酸、抗坏血酸、丁二酸、马来酸、龙胆酸、富马酸、葡萄糖酸、糖醛酸、葡萄糖二酸或蔗糖酸、甲酸、苯甲酸、谷氨酸、双羟萘酸、山梨酸等。用于形成盐的无机或有机碱包括但不限于:氢氧化钠、氢氧化钾、氢氧化锂、氢氧化铁、氢氧化钙、氢氧化钡、氢氧化铝、氢氧化镁、氢氧化锌、氨水、氢氧化有机季铵盐、碳酸钠、碳酸钾、碳酸锂、碳酸钙、碳酸钡、碳酸镁、碳酸化有机季铵盐、碳酸氢钠、碳酸氢钾、碳酸氢锂、碳酸氢钙、碳酸氢钡、碳酸氢镁、碳酸氢化有机季铵盐等。
给药量
为了发挥本发明中的化合物对疾病(例如,癌症)的治疗作用,化合物或其药物组合物的给药必须达到有效剂量。有效剂量的估计及确定对于本领域的专业人员都应能做到。对于本发明中的许多化合物,有效剂量可从生化及细胞中测试开始估算,例如,测量本发明中的化合物在生化条件或细胞条件下抑制蛋白激酶的活性至50%所需要的浓度,即IC50值,再根据动物模型(例如,小鼠、大鼠等)中,在一定喂药量的条件下,测试血液中化合物的浓度,对比细胞中的IC50值而估算在动物中要引起与细胞中同等或更好蛋白质激酶活性抑制所需要的给药有效剂量,由动物数据最后估计在人体中的有效剂量。这其中还需考虑化合物在一定浓度下对包括人在内的动物可能引起的毒性。
本发明中的化合物在前述药物组合物中的含量范围为0.001-100%。该药物组合物施用于包括人在内的哺乳动物的有效剂量为每日每千克体重0.1-500毫克,优化的剂量为每日每千克体重使用1-100毫克。在这个有效剂量范围内,本发明中的化合物发挥其抑制蛋白激酶活性及治疗因异常蛋白激酶活性引起的疾病(例如癌症)的药理作用。
药物的使用频率依所使用的化合物或其药物组合物及应用的疾病而有所变化,本发明中的药物组合物通常是每日给药1-6次,优化的给药频率为每日给药1-3次。
药物包装
本发明中的药物组合物的包装类似一般西药的包装形式,以下是一些例子,但不限于这些:
固体形式的药物组合物一般制成片剂、丸剂或胶囊剂,这些药物可直接装入玻璃、塑料、纸质或金属瓶中,瓶外贴上关于药名、成分、有效成分的含量、生产或过期日、适用的疾病、用法与用量、可能的副作用、紧急情况时的联系信息、保管及储存信息、生产厂家的信息、其他注意事项等的标签,瓶内附上小册子,该册子上除了具有瓶外标签所有信息外,还包括本发明中的药物组合物的更加详细的信息,例如化合物结构、分子量、物理化学性质、作用机理、IC50值、药物动力学、药物热力学、毒理学数据、代谢情况、临床实验数据等信息,还包括国家药品及食品管理局的批准文件信息等。有时,瓶内还需放入干燥剂等以保持药物的质量。
液体形式的药物组合物一般装入玻璃、塑料或金属瓶或软管中,外包装与内附小册与固体药物类似。这些玻璃、塑料或金属瓶或软管被装入另外的塑料或纸盒中,这些塑料或纸盒中还需放入防止液体泄漏的缓冲及保护填充物。如果是气雾剂形式的液体药物,一般装入耐压的金属或塑料容器中,该容器附有减压阀等装置。
具体实施方式
以下结合具体实施例对本发明作进一步详细说明,以便公众进一步理解本发明的有益效果。
下面是将在实施例中出现的英文缩写及相应的中文含义。如果实施例中出现没有列于此的缩写,则代表普遍接受的含义。
DMSO:二甲基亚砜
TMS:四甲基硅烷
DCM:二氯甲烷
CDCl3:氘代氯仿
CD3OD:氘代甲醇
DME:1,2-二甲氧基乙烷
THF:四氢呋哺
aq.:水溶液
TLC:薄层色谱
LC-MS:液相色谱-质谱联用
g:克
mg:毫克
mmol:毫摩尔
μM:微摩尔
μL:微升
nM:纳摩尔
M:摩尔浓度
N:当量浓度
m/z:质荷比
δ:化学位移
EDC.HCl:1-乙基-3-(3-二甲基氨基丙基)碳二亚胺盐酸盐。
一般实验条件:
核磁共振氢谱及碳谱于Varian INOVA 500NB仪器上获得(氘代DMSO、氘代氯仿、氘代甲醇等为溶剂,TMS为内标)。质谱由液相色谱-质谱联用仪获得(采用ESI或APCI离子源ZQ4000,美国Waters公司)。紫外光谱由日本日立公司的UV-3010紫外分光光度计测得。红外光谱使用NICOLET6700红外光谱分析仪(KBr压片)。高效液相色谱使用Waters 2695ZORBAX高效液相色谱仪(Bx-C85μ150×4.6mm色谱柱)。熔点的测定使用Electrothermal数字式熔点仪IA9100,并且未校正。
起始原料、试剂及溶剂一般从下列供应商购买:Beta-Pharma,Shanghai;Shanghai PIChemicals;AndaChem,Taiyuan;Shanghai FWD Chemicals;Sigma-Aldrich,Milwaukee,WI,USA;Acros,Morris Plains,NJ,USA;Frontier Scientific,Logan,Utah,USA;Alfa Aesar,Ward Hill,MA,USA等或利用文献报道的方法合成。除非特别指出,溶剂一般不经干燥,而直接使用供应商的产品或经过分子筛干燥。无水溶剂直接使用供应商(例如Sigma-Aldrich)的产品或经CaH或金属钠蒸出。
实施例1:5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
步骤1、5-溴-3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-2-氨基吡啶
1-1、制备1-(2,6-二氯-3-氟苯基)乙醇
在0℃度及氮气保护下,将1-(2,6-二氯-3-氟苯基)乙酮(30g,145mmol)溶解于80毫升甲醇中,于该溶液中分批缓慢加入NaBH4(12.07g,319mmol),加完后,此混合物在室温下搅拌6小时,冷至0℃,小心加入4N盐酸淬灭反应直到pH为2左右。此混合物用旋转蒸发仪浓缩,加入乙醚(300mL)及水(300mL)。分液,水相用乙醚(2×300mL)提取,有机相合并、干燥(Na2SO4)、浓缩得到油状的目标产物28.5g(得率:94%)。1H-NMR(CDCl3,500MHz):δ(ppm)1.65(d,J=7.2Hz,3H),5.56(q,J=7.2Hz,1H),7.01-7.04(m,1H),7.24-7.31(m,1H)。
1-2、1-(2,6-二氯-3-氟苯基)乙基醋酸酯
在0℃度下,将步骤1-1得到的1-(2,6-二氯-3-氟苯基)乙醇(25g,120mmol)溶解在二氯甲烷(180mL)中,然后加入Et3N(58.6mL,420mmol)及4-二甲基氨基吡啶(2.92g,23.9mmol),搅拌下,缓慢滴加醋酸酐(13.6ml,143.5mmol)。加完后,此混合物在0℃下搅拌2小时,然后加入水(40mL)。室温搅拌5小时后,加入乙醚(300mL)。分液,水相用乙醚(2×300mL)提取,有机相合并并依次用4N盐酸(80mL)、饱和NaHCO3水溶液(80mL)及饱和食盐水(100mL)洗涤。干燥(Na2SO4)、浓缩得到油状目标产物27.3g(得率:91%)。1H-NMR(CDCl3,500MHz):δ(ppm)1.65(d,J=7.2Hz,3H),2.01(s,3H),6.40(q,J=7.2Hz,1H),7.01-7.04(m,1H),7.23-7.29(m,1H)。
1-3、(1S)-1-(2,6-二氯-3-氟苯基)乙醇和(1R)-1-(2,6-二氯-3-氟苯基)乙醇
下述三篇文献公开了使用猪肝酯酶催化的酯水解手性拆分1-(2,6-二氯-3-氟苯基)乙基醋酸酯制备该化合物的方法:(a)Ohno,M.;Otsuka,M.Org.React.1989,37,1;(b)Zhu,L.-M.;Tedford,M.C.Tetrahedron 1990,46,6587;(c)Tamm,C.PureAppl.Chem.1992,64,1187。
根据上述文献所公开的技术信息,本发明中所采用的具体合成步骤如下所述:于一装有pH计的三颈瓶中加入水(200mL)、1M K2HPO4水溶液(1.5mL)、1M KH2PO4水溶液(0.6mL)及猪肝酯酶(120mg,~15600units from Sigma-Aldrich,Catalog#46058,Enzyme Commission 3.1.1.1,CAS#9016-18-6)。将步骤1-2获得的1-(2,6-二氯-3-氟苯基)乙基醋酸酯(24g,95.6mmol)缓慢滴加入上述溶液中,反应期间,用1M NaOH水溶液调节反应混合物的pH保持在6.5-8.5之间,用高效液相色谱及TLC跟踪反应直到约50%的酯转化成醇(大约需25小时)。反应至50%的转化率时,加入乙醚(300mL),用硅藻土过滤所得混合物,并用乙醚(3×100mL)洗涤滤渣。分液,水相用乙醚(2×300mL)提取,有机相合并、干燥(Na2SO4)、浓缩得到油状粗产物。所得油状粗产物经硅胶柱色谱(石油醚/乙酸乙酯:9/1)纯化便得到目标产物(1S)-1-(2,6-二氯-3-氟苯基)乙醇(9.793g,得率:49%),[α]D 25:-11.7°(c=5.6,二氯甲烷)及回收(1R)-1-(2,6-二氯-3-氟苯基)乙基醋酸酯(11.882g,得率:49.5%)。该两个产物在上述柱色谱条件下很易分开,分别得到纯产物。
O℃下,往上述回收的(1R)-1-(2,6-二氯-3-氟苯基)乙基醋酸酯(1.04g,4mmol)中滴加甲醇钠的甲醇溶液(0.5M,8mL,4mmol)。所得混合物升至室温并搅拌6h。小心地滴加0.1M HCl(aq)调节pH至5-6。混合物用乙酸乙酯(3x 20mL)提取。有机相合并、干燥、浓缩得到白色固体产物(1R)-1-(2,6-二氯-3-氟苯基)乙醇(769mg,产率:92%)。[α]D 25:+12.1°(c=5.2,二氯甲烷)。
1-4、3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-2-硝基吡啶
将步骤1-3获得的(1S)-1-(2,6-二氯-3-氟苯基)乙醇(2.09g,10mmol)溶解在的干THF(80毫升)中。然后,在室温及氮气保护下,加入3-羟基-2-硝基吡啶(1.54g,11mmol)及三苯基磷(3.409g,13mmol),等完全溶解后,冷至0℃,加入偶氮二甲酸二异丙酯(DIAD,2.63g,13mmol),加完后,此混合物在0℃下搅拌16小时,旋转蒸发除去溶剂,油状残渣用硅胶柱色谱(石油醚/乙酸乙酯:4/1)纯化得白色固体目标产物(3.046g,得率:92%)。1H-NMR(CDCl3,500MHz):δ(ppm)1.86(d,J=6.4Hz,3H),6.10(q,J=6.4Hz,1H),7.09(dd,J=7.6,8.8Hz,1H),7.21(dd,J=8.4,1.2Hz,1H),7.31(dd,J=4.8,8.8Hz,1H),7.37(dd,J=4.8,8.0Hz,1H),8.04(dd,J=1.6,4.4Hz,1H)。质谱m/z:330.94[M+H,35Cl,35Cl],332.92[M+H,35Cl,37Cl]。
1-5、3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-2-氨基吡啶
取步骤1-4获得的3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-2-硝基吡啶(2.649g,8mmol)溶于乙醇(15mL)中,加入铁粉(3.575g,64mmol)混合,在氮气保护下于90℃油浴中剧烈搅拌,用注射器加入0.8mL 1M HCl(aq),过10分钟后,再加入0.8mL 1M HCl(aq)。继续搅拌30分钟,TLC显示反应结束。冷至室温,用硅藻土过滤,滤渣用乙醇(3×10mL)洗涤。合并有机相,旋转蒸发除去溶剂得浅棕色固体目标产物(2.41g,得率:100%)。1H-NMR(CDCl3,500MHz):δ(ppm)1.81(d,J=6.8Hz,3H),5.03(s,br,2H),6.01(q,J=6.8Hz,1H),6.47(dd,J=4.8,7.6Hz,1H),6.70(d,J=8.0Hz,1H),7.05(t,J=8.8Hz,1H),7.28(dd,J=4.0,8.0Hz,1H),7.57(d,J=5.2Hz,1H)。质谱m/z:301.00[M+H,35Cl,35Cl],302.77[M+H,35Cl,37Cl]。
1-6、5-溴-3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-2-氨基吡啶
将步骤1-5获得的3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-2-氨基吡啶(1.506g,5mmol)溶解在乙腈(20mL)中。然后,在0℃度及搅拌下,于分批加入N-溴代丁二酰亚胺(0.908g,5.1mmol),加完后,继续搅拌30分钟。旋转蒸发除去溶剂,粗产物用硅胶柱色谱纯化得到白色固体目标产物(1.045g,得率:55%)。1H-NMR(CDCl3,500MHz):δ(ppm)1.81(d,J=6.8Hz,3H),4.85(s,br,2H),6.98(q,J=6.8Hz,1H),6.82(d,J=2.0Hz,1H),7.08(t,J=8.4Hz,1H),7.31(dd,J=4.8,8.8Hz,1H),7.65(d,J=2.0Hz,1H)。质谱m/z:378.84[M+H,35Cl,35Cl,79Br],380.82[M+H,35Cl,35Cl,81Br or 35Cl,37Cl,79Br],382.80[M+H,35Cl,37Cl,81Bror 37Cl,37Cl,79Br]。
步骤2、1’-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮
2-1、5-溴-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
5-溴-吲哚啉-2-酮(1.272g,6mmol)悬浮于THF(15mL)中,并冷至-78℃,搅拌下滴加1M NaN(SiMe3)2的THF溶液(30mL,30mmol)。加完后于-78℃搅拌30分钟,然后加入2-氯-N-(2-氯乙基)-N-甲基乙胺盐酸盐固体(1.155g,6mmol)。加完后继续搅拌30分钟,然后升至室温搅拌两天。TLC显示反应结束,往该粉红色悬浮液中小心加入4M盐酸水溶液(10mL),然后用浓氨水调节至pH≈9,并用DCM提取(3×80mL)。有机相合并、干燥(Na2SO4)、浓缩得到的粗产物用硅胶柱色谱(7M NH3的甲醇溶液/DCM:5/95)纯化得到目标产物(1.38g,得率:78%)。1H-NMR(CD3OD,500MHz):δ(ppm)1.86-1.92(m,2H),1.94-1.98(m,2H),2.44(s,3H),2.62-2.68(m,2H),2.86-2.91(m,2H),6.76(d,J=7.6Hz,1H),7.33(dd,J=1.2,7.6Hz,1H),7.44(d,J=1.6Hz,1H),7.81(s,br,1H)。质谱m/z:294.99[M+H,79Br],296.82[M+H,81Br]。
2-2、1’-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮
在氮气下,往步骤2-1中得到的5-溴-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮(147.6mg,0.5mmol)、联片呐醇硼酸酯(140mg,0.55mmol)及醋酸钾(147mg,1.5mmol)的DMSO溶液(0.2ml)中加入PdCl2(dppf).CH2Cl2(20.4mg,0.025mmol),往所得溶液中鼓入氮气2分钟,然后于80℃度下搅拌16小时。LC-MS显示反应结束,冷至室温后,加入水(2mL),用DCM提取(3×5mL)。有机相合并、干燥(Na2SO4)、浓缩得到的目标产物(170mg,得率:100%)。质谱m/z:342.07[M+H],343.08[M+H,100%],344.11[M+H]。
步骤3、5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
将步骤1-6获得的5-溴-3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-2-氨基吡啶(75.8mg,0.2mmol)、步骤2-2获得的1’-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮(82mg,0.24mmol)和碳酸钾(82.9mg,0.6mmol)溶解在DME/水混合溶液(4/1,2.0ml)。然后,在氮气下,加入Pd(PPh3)4(11.6mg,0.01mmol),往所得混合物中鼓入氮气2分钟,然后于80℃度下搅拌18小时。LC-MS显示反应结束,冷至室温后,加入水(5mL),用DCM提取(3×10mL)。有机相合并、干燥(Na2SO4)、浓缩得到的粗产物用硅胶柱色谱(7M NH3的甲醇溶液/DCM:5/95)纯化得到目标产物(88.6mg,得率:86%)。1H-NMR(CDCl3,500MHz):δ(ppm)1.86(d,J=6.4Hz,3H),1.93-2.02(m,4H),2.44(s,3H),2.66-2.72(m,2H),2.89-2.93(m,2H),4.87(s,br,2H),6.11(q,J=6.4Hz,1H),6.88(d,J=8.0Hz,1H),6.94(d,J=1.2Hz,1H),7.06(t,J=8.4Hz,1H),7.19(dd,J=1.2,8.0Hz,1H),7.31(m,1H),7.36(s,1H),7.66(s,br,1H),7.80(d,J=2.0Hz,1H)。质谱m/z:515.05[M+H,35Cl,35Cl],517.03[M+H,35Cl,37Cl]。
实施例2:6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
步骤1、1’-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮
1-1、6-溴-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
按照实施例1中步骤2-1的方法,从可买到的6-溴-吲哚啉-2-酮制备,得率:82%。所得目标产物的分析数据如下:1H-NMR(CD3OD,500MHz):δ(ppm)1.90-1.98(m,4H),2.44(s,3H),2.64-2.68(m,2H),2.86-2.92(m,2H),7.05(d,J=2.0Hz,1H),7.16-7.21(m,2H),7.91(s,br,1H)。质谱m/z:295.00[M+H,79Br],296.78[M+H,81Br]。
1-2、1’-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮
以步骤1-1所获得的6-溴-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮和市售的联片呐醇硼酸酯为原料,按照实施例1中的步骤2-2的方法制备,得率:95%。所得目标产物的分析数据如下:质谱m/z:342.06[M+H],343.04[M+H,100%],344.12[M+H]。
步骤2、6-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
将实施例1中的步骤1-6获得的5-溴-3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-2-氨基吡啶、本实施例中步骤1-2获得的1’-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮,按照实施例1中步骤3的方法制备。得率:82%。1H-NMR(CDCl3,500MHz):δ(ppm)1.86(d,J=6.4Hz,3H),1.91-1.95(m,2H),1.97-2.03(m,2H),2.45(s,3H),2.65-2.72(m,2H),2.89-2.95(m,2H),5.12(s,br,2H),6.12(q,J=6.4Hz,1H),6.94-7.00(m,3H),7.06(t,J=8.4Hz,1H),7.31(m,1H),7.35(d,J=7.2Hz,1H),7.90(d,J=2.0Hz,1H),9.28(s,br,1H)。质谱m/z:515.05[M+H,35Cl,35Cl],517.03[M+H,35Cl,37Cl]。
实施例3:5-[6-氨基-5-[(2,6-二氯-3-氟苯基)甲氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
步骤1、5-溴-3-(2,6-二氯-3-氟苄氧基)-2-氨基吡啶
1-1、2,6-二氯-3-氟苯甲酸
氢氧化钠(13g,325mmol)的水(110mL)溶液冷至-5℃剧烈搅拌下滴加液溴(12.5g,78.2mmol),加完后,加入预先冷至10℃二噁烷(75mL)。上述混合物于剧烈搅拌下,滴加入预先冷至5℃的1-(2,6-二氯-3-氟苯基)乙酮(5g,21.2mmol)的二噁烷(330mL)及水(90mL)溶液。加完后,于室温搅拌2小时,然后90℃搅拌30分钟。TLC跟踪显示起始原料消失,用浓盐酸酸化至pH≈9。所得混合物旋转蒸发至干,加入水(20mL),并用乙醚(2×80mL)提取,有机相合并、干燥(Na2SO4)、浓缩得到油状产物,冷却后固化为的略带黄色的透明固体(3.4g,得率:67%)。1H-NMR(CDCl3,500MHz):δ(ppm)7.21(dd,J=8.0,8.8Hz,1H),7.35(dd,J=4.4,9.2Hz,1H),9.79(s,br,1H)。质谱m/z(ES-):207.11[M-H,35Cl,35Cl],209.10[M-H,35Cl,37Cl]。
1-2、2,6-二氯-3-氟苄醇
往盛有2,6-二氯-3-氟苯甲酸(3g,14.35mmol)烧瓶中滴加1M BH3.THF(43mL,43mmol),加完后搅拌回流24小时。TLC显示反应完成,加入甲醇(50mL)破坏过量的硼烷,减压蒸除溶剂及生成的三甲基硼酸酯,重复上述过程两次得到粘稠产物2.1克,得率:75%。1H-NMR(CDCl3,500MHz):δ(ppm)2.09(t,J=6.4Hz,1H),4.97(d,J=6.4Hz,2H),7.09(t,J=8.8Hz,1H),7.32(dd,J=4.8,9.1Hz,1H)。质谱m/z(ES-):193.08[M-H,35Cl,35Cl],195.12[M-H,35Cl,37Cl]。
1-3、3-(2,6-二氯-3-氟苄氧基)-2-硝基吡啶
按照实施例1中步骤1-4的方法,从2,6-二氯-3-氟苄醇(本实施例中步骤1-2)和3-羟基-2-硝基吡啶制备,得率:90%。1H-NMR(CDCl3,500MHz):δ(ppm)5.45(s,2H),7.20(dd,J=8.0,9.2Hz,1H),7.37(dd,J=4.8,9.2Hz,1H),7.59(dd,J=4.4,8.4Hz,1H),7.74(dd,J=1.2,8.4Hz,1H),8.17(dd,J=1.6,4.4Hz,1H)。质谱m/z:316.89[M+H,35Cl,35Cl],318.89[M+H,35Cl,37Cl]。
1-4、3-(2,6-二氯-3-氟苄氧基)-2-氨基吡啶
按照实施例1中步骤1-5的方法,从3-(2,6-二氯-3-氟苄氧基)-2-硝基吡啶(本实施例中步骤1-3)制备,得率:95%。1H-NMR(CDCl3,500MHz):δ(ppm)4.65(s,br,2H),5.31(s,2H),6.66(dd,J=5.2,8.0Hz,1H),7.14(dd,J=1.2,8.0Hz,1H),7.18(dd,J=8.4,9.2Hz,1H),7.37(dd,J=4.8,8.8Hz,1H),7.73(dd,J=1.6,5.6Hz,1H)。质谱m/z:286.95[M+H,35Cl,35Cl],288.85[M+H,35Cl,37Cl]。
1-5、5-溴-3-(2,6-二氯-3-氟苄氧基)-2-氨基吡啶
按照实施例1中步骤1-6的方法,从3-(2,6-二氯-3-氟苄氧基)-2-氨基吡啶(本实施例中步骤1-4)制备,得率:60%。1H-NMR(CDCl3,500MHz):δ(ppm)4.68(s,br,2H),5.28(s,2H),7.21(dd,J=8.0,8.8Hz,1H),7.24(dd,J=2.0Hz,1H),7.39(dd,J=4.8,9.2Hz,1H),7.78(d,J=2.0Hz,1H)。质谱m/z:364.83[M+H,35Cl,36Cl,79Br],366.77[M+H],368.69[M+H]。
步骤2、5-[6-氨基-5-[(2,6-二氯-3-氟苯基)甲氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
将本实施例中的步骤1-5获得的5-溴-3-(2,6-二氯-3-氟苄氧基)-2-氨基吡啶、实施例1中步骤2-2获得的1’-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮,按照实施例1中步骤3的方法制备。得率:85%。1H-NMR(CDCl3,500MHz):δ(ppm)1.92-2.02(m,4H),2.43(s,3H),2.65-2.71(m,2H),2.90-2.91(m,2H),4.92(s,br,2H),5.52(s,2H),6.89(d,J=8.4Hz,1H),6.90(d,J=1.2Hz,1H),7.06(t,J=8.0Hz,1H),7.21(dd,J=1.2,8.0Hz,1H),7.31(m,1H),7.37(s,1H),7.79(s,br,1H),7.80(d,J=2.0Hz,1H)。质谱m/z:501.06[M+H,35Cl,35Cl],503.04[M+H,35Cl,37Cl]。
实施例4:6-[6-氨基-5-[(2,6-二氯-3-氟苯基)甲氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
按照实施例1中步骤3的方法,从实施例3中步骤1-5得到的5-溴-3-(2,6-二氯-3-氟苄氧基)-2-氨基吡啶及实施例2中步骤1-2得到的1’-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮酯制备,得率:78%。1H-NMR(CDCl3,500MHz):δ(ppm)1.96-2.00(m,2H),2.01-2.12(m,2H),2.46(s,3H),2.66-2.73(m,2H),2.90-2.96(m,2H),5.30(s,br,2H),6.94-7.01(m,3H),7.07(t,J=8.4Hz,1H),7.30(m,1H),7.34(d,J=7.2Hz,1H),7.89(d,J=2.0Hz,1H),8.56(s,br,1H)。质谱m/z:501.06[M+H,35Cl,35Cl],503.04[M+H,35Cl,37Cl]。
实施例5:5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
步骤1、5-溴-2-氨基-3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪
在0℃下,NaH(80mg of NaH in mineral oil,2mmol)加入(1R)-1-(2,6-二氯-3-氟苯基)乙醇(418mg,2mmol。见实施例1步骤1-3)的无水THF(6mL)中,搅拌半个小时,滴加2-氨基-3,5-二溴吡嗪(506mg,2mmol)的THF(6mL)溶液。所得混合物升至室温后,加热回流20小时。TLC显示反应基本完成。冷至室温后,加入水(10mL),混合物用乙酸乙酯提取3次(3x20mL),有机相合并、干燥、浓缩、残留物用柱色谱纯化(1-3MeOH in hexanes)得到594mg产物,产率:78%。1H-NMR(CDCl3,500MHz):δ(ppm)1.83(d,J=7.2Hz,3H),5.12(s,br,2H),6.73(q,J=6.8Hz,1H),7.05(t,J=8.0Hz,1H),7.28(dd,J=4.8,8.8Hz,1H),7.58(s,1H)。质谱m/z:379.83[M+H,35Cl,35Cl,79Br],381.81[M+H,35Cl,35Cl,81Br],383.79[M+H,35Cl,37Cl,81Br]。
步骤2、5-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
将本实施例中步骤1获得的5-溴-2-氨基-3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪、实施例1中步骤2-2获得的1’-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮,按照实施例1中步骤3的方法制备。得率:54%。1H-NMR(CD3OD,500MHz):δ(ppm)1.85(d,J=6.8Hz,3H),1.85-1.88(m,2H),1.97-2.04(m,2H),2.46(s,3H),2.76-2.82(m,2H),2.97-3.02(m,2H),6.74(q,J=6.4Hz,1H),6.85(d,J=8.0Hz,1H),7.15(t,J=8.4Hz,1H),7.41(dd,J=4.8,9.2Hz,1H),7.54(dd,J=1.6,8.0Hz,1H),7.69(d,J=1.8Hz,1H),7.81(dt,J=2.0,8.0Hz,1H),7.87(s,1H)。质谱m/z:515.92[M+H,35Cl,35Cl],517.90[M+H,35Cl,37Cl]。
实施例6:6-[5-氨基-6-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪-2-基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮
将实施例5中步骤1获得的5-溴-2-氨基-3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]吡嗪、实施例2中步骤1-2获得的1’-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-2-酮,按照实施例1中步骤3的方法制备。得率:67%。1H-NMR(CD3OD,500MHz):δ(ppm)1.85(d,J=6.8Hz,3H),1.88-1.96(m,4H),2.48(s,3H),2.76-2.82(m,2H),2.98-3.05(m,2H),6.75(q,J=6.4Hz,1H),7.16(t,J=8.8Hz,1H),7.31(d,J=2.0Hz,1H),7.36-7.43(m,3H),7.88(s,1H)。质谱m/z:515.99[M+H,35Cl,35Cl],517.90[M+H,35Cl,37Cl]。
实施例7:3-[(1R)-1-(3-氟苯基)乙氧基]-5-(1’-甲基螺[吲哚啉-3,4’-哌啶]-5-基)吡啶-2-胺
在0℃下,往5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基螺[吲哚啉-3,4’-哌啶]-2-酮(实施例1,51.5mg,0.1mmol)的THF溶液(3mL)中滴加LiAlH4的THF溶液(0.5M,0.2mL,0.1mmol),所得混合物于室温搅拌4h。小心滴加水淬灭,混合物用乙酸乙酯提取3次(3x 10mL),有机相合并、干燥、浓缩、残留物用柱色谱纯化(1-3 MeOH in hexanes)得到24mg产物,产率:56%。质谱m/z:433.56[M+H]。
实施例8:5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酸叔丁酯
步骤1、2-氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-1’-甲酸叔丁酯
1-1、5-溴-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酸叔丁酯
按照实施例1中步骤2-1相同的方法,采用可购买的5-溴-吲哚啉-2-酮和双(2-氯乙基)氨基甲酸叔丁酯制备,产率75%。质谱m/z:381.02[M+H,79Br],383.04[M+H,81Br]。
1-2、2-氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-1’-甲酸叔丁酯
按照实施例1中步骤2-2相同的方法制备,产率66%。质谱m/z:质谱m/z:429.42[M+H]。
步骤2、5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酸叔丁酯
通过实施例1中步骤1-6获得的5-溴-3-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-2-氨基吡啶与本实施例步骤1-2中得到的2-氧基-5-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)螺[吲哚啉-3,4’-哌啶]-1’-甲酸叔丁酯按照实施例1中步骤3的方法制备,得率:73%。质谱m/z:601.05[M+H,35Cl,35Cl],603.10[M+H,35Cl,37Cl]。
实施例9:5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮双盐酸盐
将实施例8获得的5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酸叔丁酯(601mg,1.0mmol)溶解于DCM(10mL),然后滴加4MHCl的二噁烷溶液(5mL),室温搅拌1小时,抽干溶剂得到570mg(得率:100%)产物,不用纯化,直接用于下面反应。其分析数据如下:质谱m/z:501.40[M+H,35Cl,35Cl],503.38[M+H,35Cl,37Cl]。
实施例10:5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲醛
将甲酸(6.9mg,0.15mmol)及EDC.HCl(28.8mg,0.15mmol)悬浮于DCM(20mL)中,在搅拌下,滴加二异丙基乙基胺(38.5mg,0.3mmol)。加完后于室温搅拌半小时,加入实施例9获得的5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮双盐酸盐(57.4mg,0.1mmol),继续搅拌2小时。旋转蒸发除去溶剂,得到的粗产物用硅胶柱色谱(7M NH3的甲醇溶液/DCM:5/95)纯化得到目标产物(42.3mg,得率:80%)。质谱m/z:529.32[M+H,35Cl,35Cl],531.41[M+H,35Cl,37Cl]。
实施例11:5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺
将实施例9获得的5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮双盐酸盐(57.4mg,0.1mmol)溶解于DCM(2mL)中,然后加入Me3Si-NCO(28.8mg,0.25mmol)及二异丙基乙基胺(64.2mg,0.5mmol),所得混合物室温搅拌16小时,减压抽干溶剂,粗产物用硅胶柱色谱(7M NH3的甲醇溶液/DCM:5/95)纯化得到目标产物(42.4mg,得率:78%)。质谱m/z:544.12[M+H,35Cl,35Cl],546.20[M+H,35Cl,37Cl]。
实施例12:N-[2-[5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基螺[吲哚啉-3,4’-哌啶]-1’-基]-1,1-二甲基-2-氧基-乙基]甲酸叔丁酯
将实施例9获得的5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮双盐酸盐(57.4mg,0.1mmol)溶解于DCM(2mL)中,然后加入2-(叔丁氧羰基氨基)-2-甲基丙酸(30.4mg,0.15mmol),EDC.HCl(28.8mg,0.15mmol)及滴加二异丙基乙基胺(77mg,0.6mmol),所得混合物室温搅拌16小时,减压抽干溶剂,粗产物用硅胶柱色谱(7MNH3的甲醇溶液/DCM:5/95)纯化得到目标产物(61.1mg,得率:89%)。质谱m/z:686.42[M+H,35Cl,35Cl],688.37[M+H,35Cl,37Cl]。
实施例13:5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-(2-氨基-2-甲基丙酰基)螺[吲哚啉-3,4’-哌啶]-2-酮双盐酸盐
将实施例12获得的N-[2-[5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-2-氧基螺[吲哚啉-3,4’-哌啶]-1’-基]-1,1-二甲基-2-氧基-乙基]甲酸叔丁酯(34.3mg,0.05mmol)溶解于DCM(5mL),然后滴加4M HCl的二噁烷溶液(2mL),室温搅拌1小时,抽干溶剂得到33mg(得率:100%)产物双盐酸盐。质谱m/z:586.46[M+H,35Cl,35Cl],588.42[M+H,35Cl,37Cl]。
实施例14:[5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-甲基磺酰基-螺[吲哚啉-3,4’-哌啶]-2-酮
将实施例9获得的5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮双盐酸盐(57.4mg,0.1mmol)溶解于DCM(2mL),加入甲基磺酰氯(12.5mg,0.11mmol)及二异丙基乙基胺(38.5mg,0.30mmol),所得混合物于室温搅拌6小时,减压抽干溶剂,粗产物用硅胶柱色谱(7M NH3的甲醇溶液/DCM:5/95)纯化得到目标产物(39.4mg,得率:68%)。质谱m/z:579.32[M+H,35Cl,35Cl],581.39[M+H,35Cl,37Cl]。
实施例15:5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-1’-乙基螺[吲哚啉-3,4’-哌啶]-2-酮
将实施例9获得的5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮双盐酸盐(57.4mg,0.1mmol)溶解于DCM(1mL),加入乙醛(4.8mg,0.11mmol),二异丙基乙基胺(38.5mg,0.30mmol)及NaB(OAc)3H(84.8mg,0.4mmol),所得混合物于室温搅拌8小时,减压抽干溶剂,粗产物用硅胶柱色谱(7M NH3的甲醇溶液/DCM:5/95)纯化得到目标产物(29.1mg,得率:55%)。质谱m/z:529.27[M+H,35Cl,35Cl],531.30[M+H,35Cl,37Cl]。
实施例16:5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]-N,N-二甲基-2-氧基-螺[吲哚啉-3,4’-哌啶]-1’-甲酰胺
将实施例9获得的5-[6-氨基-5-[(1R)-1-(2,6-二氯-3-氟苯基)乙氧基]-3-吡啶基]螺[吲哚啉-3,4’-哌啶]-2-酮双盐酸盐(57.4mg,0.1mmol)溶解于DCM(2mL)中,然后加入Me2NCOCl(12.9mg,0.12mmol)及二异丙基乙基胺(64.2mg,0.5mmol),所得混合物室温搅拌8小时,减压抽干溶剂,粗产物用硅胶柱色谱(7M NH3的甲醇溶液/DCM:5/95)纯化得到目标产物(53.2mg,得率:93%)。质谱m/z:572.22[M+H,35Cl,35Cl],574.32[M+H,35Cl,37Cl]。
实施例17
本例为上述实施例1-16所制得的化合物抑制酪氨酸激酶c-Met活性的效果实验,具体实验方法如下所述。
1、c-Met生化半抑制浓度(IC50)实验
c-Met生化半抑制浓度(IC50)使用含200ng/μL生物素化的聚(Glu,Tyr)、0.334mM钒酸盐、2μM(Km)的三磷酸腺苷(ATP)的384-孔板。缓冲液:50mM HEPES(pH=7.4)、5mM MgCl2、5mM MnCl2及1%甘油。化合物以DMSO溶液形式加入,最终的DMSO浓度为1%。c-Met酶用下面的缓冲液稀释成最佳浓度:50mM Tris(pH=7.4)、1%甘油,0.03%Brij35、0.24mM EGTA、1mM DTT及0.003%BSA。加入酶引发反应,并让反应于室温进行1小时。适合量的PT66供受体珠加入孔中,1小时后用AlphaQuest读板。半抑制浓度为至少两次测试的平均值。
2、MKN45细胞中c-Met半抑制浓度(IC50)实验
MKN45胃癌细胞(购自日本Riken Cell Bank)接种到含10%FCS的RPMI164096孔细胞培养板内,培养48小时后,化合物的DMSO溶液加入到细胞液内,化合物的最终浓度范围为0.0001-10μM。孵育4小时后,用PBS(4℃)在冰上洗涤细胞两次之后,每孔加入110μL细胞裂解液,置冰上裂解20分钟后,将100μL细胞裂解物转移到预先结合有c-Met抗体的96孔实验板中,置于4℃过夜。第二天将96孔实验板内的细胞裂解物弃去,在室温下用PBST洗涤4次,加入兔抗c-Met酪氨酸磷酸化(pYpYpY1230/1234/1235)抗体,于室温孵育2小时后,弃去抗体并洗涤两次,之后加入抗兔IgG辣根过氧化氢酸酶,置室温30分钟后洗涤3次。随后每孔加100μL底物TMB(四甲基联苯胺),反应30分钟后,加入反应终止液。测试波长450纳米的吸收值,将数据通过Excel Fit软件分析处理得到IC50曲线和数值。半抑制浓度为至少两次测试的平均值。
在实施例1-16中制备的化合物的半抑制浓度结果参见下表(表2):
表2
化合物 | c-Met的生化IC50值,nM | MKN45细胞中c-Met的IC50值,μM |
1 | ++++ | 0.020 |
2 | ++++ | 0.019 |
3 | +++ | 10 |
4 | +++ | 9 |
5 | ++++ | 0.023 |
6 | ++++ | 0.012 |
7 | ++ | 8.4 |
8 | Not determined | Not determined |
9 | ++++ | 0.028 |
10-16 | Not determined | Not determined |
脚注:++++:≤50nM;+++:51-100nM;++:≥100nM,但<100μM。
由上表所列数据可看出,本发明中的化合物绝大多数无论在生化条件还是在癌细胞中,均能非常有效地抑制c-Met激酶的活性。
Claims (8)
2.权利要求1所述的螺环化合物,其分子结构如式(Ia)所示:
其中,R1与权利要求1中的R1相同。
5.权利要求4所述的螺环化合物,其分子结构如式(IIa)所示:
其中,R1与权利要求4中的R1相同;R和R’独立选自H或甲基。
7.权利要求1-5之一所述化合物在制备抑制c-Met活性的抑制剂中的应用。
8.一种c-Met活性抑制剂,该抑制剂中含有抑制有效剂量的权利要求1-5之一所述化合物。
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