CN115490705A - N-大环酰胺类化合物、其制备方法及其作为药物的应用 - Google Patents
N-大环酰胺类化合物、其制备方法及其作为药物的应用 Download PDFInfo
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Abstract
本发明涉及具有结构通式(I)和结构通式(II)所示结构的N‑大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐,其中L、X、Y、Z、R1、A、B、C各自如本申请说明书中所定义。本发明还涉及具有结构通式(I)和结构通式(II)所示结构的N‑大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐在医药方面的应用,
Description
技术领域
本发明涉及医药领域,具体涉及N-大环酰胺类化合物、其制备方法及其在医药方面的应用。
背景技术
人类增生性疾病通常涉及体内细胞生长和/或分裂控制异常,从而使得身体内细胞不受控制的生长,从而导致肿瘤形成和最终死亡(Jessica L.Counihan,ElizabethA.Grossman,and Daniel K.Nomura.Cancer Metabolism:Current Understanding andTherapies.Chem.Rev.2018,118,6893-6923)。
随着人类生活水平的提高,临床上对癌症的治疗提出了越来越高的要求。一方面疗效需要进一步提高,另外一方面也需要继续降低相关副作用、改善预后生活质量。靶向肿瘤治疗药物就应运而生。在众多的靶向抗肿瘤药物中,蛋白激酶(“激酶”)抑制剂作为抗肿瘤药物,取得了较大的成功,成为了靶向抗肿瘤药物中重要的一类(Kinase inhibitors:the road ahead.Fleur M.Ferguson,and Nathanael S.Gray.Nature Review DrugDiscovery,2018.Volume 17,353–377)。
细胞的生长、分裂和凋亡受到信号级联放大(signaling cascade)或细胞信号传导途径(cell-signaling pathway)所控制。而激酶介导的蛋白质磷酸化作用在上述信号传导中起到重要的作用。研究发现,癌症的发生和生长与细胞的信号传导、细胞周期的调节、细胞凋亡的诱导和肿瘤血管的生长等密切相关。激酶主要负责细胞内信号转导过程的控制。激酶的异常表达,与很多疾病特别是肿瘤的发生发展有着密切的联系(Evolution ofSmall Molecule Kinase Drugs.Helen Louise Lightfoot,Frederick Woolf Goldberg,and Joerg Sedelmeier.ACS Med.Chem.Lett.2019,10,153-160.Kinase Inhibitors forthe Treatment of Immunological Disorders:Recent Advances.Marian C.Bryan andNaomi S.Rajapaksa.J.Med.Chem.2018,61,9030-9058)。
Janus激酶(JAK),包括JAK1、JAK2、JAK3和TYK2,属于细胞质蛋白激酶,与I型和II型细胞因子受体作用,调节细胞因子信号转导(Advantages of targeting the tumorimmune microenvironment over blocking immune checkpoint in cancerimmunotherapy.Signal Transduction and Targeted Therapy(2021)6:72-85)。JAK家族的下游底物包括转录蛋白的信号转导剂和激活剂(STAT)。JAK/STAT信号转导涉及很多异常免疫反应,如变态反应、哮喘、自身免疫病如移植排斥、类风湿性关节炎、肌肉缩性侧索硬化和多发性硬化以及实体和血液恶性肿瘤如白血病、淋巴瘤等(Kinase Inhibitors for theTreatment of Immunological Disorders:Recent Advances.Marian C.Bryan and NaomiS.Rajapaksa.J.Med.Chem.2018,61,9030-9058)。
调节JAK激酶的化合物以及含有这些化合物的组合,似乎可以为各种患者提供实质性的治疗效果。因此,迫切需要开发出可用于更多相关蛋白激酶的抑制剂,确切的说,需要开发更多的JAK家族激酶抑制剂(Christoph Rummelt,Sivahari P.Gorantla,ManjaMeggendorfer,Anne Charlet,Cornelia Endres,KonstanzeFlorian H.Heidel,Thomas Fischer,Torsten Haferlach,Justus Duyster,Nikolas vonBubnoff.Activating JAK-mutations confer resistance to FLT3 kinase inhibitorsin FLT3-ITD positive AML in vitro and in vivo.Leukemia,2020:1–13.https://doi.org/10.1038/s41375-020-01077-1)。
新颖的大环类结构可以作为激酶抑制剂的重要结构单元。US20170022202A1报道了Compound_1及其同类物的合成方法与作为激酶抑制剂的应用。而中南大学的Compound_2则是激酶及HDAC抑制剂,可有潜在的医学应用(CN101365703A;WO2007058628A1)。Incyte公司报道了大量具有多种激酶抑制活性的大环化合物(WO2009132202A2),其代表化合物如compound_3所示。Polyphor公司以大环化合物的合成作为重要的平台,先后合成并且筛选了各种不同类型的化合物,Compound_4为其代表化合物之一。Polyphor公司的大环化合物潜在具有各种不同的医学应用(WO2013139697A1)。
目前已经有大环类激酶抑制剂作为候选药物特别是抗肿瘤药物进入了临床试验的各种不同阶段,并且展示出了良好的应用前景。如何开拓此类化合物的适应症及进一步降低相关潜在副作用,一方面需要临床研究的开展,另一方面也需要有更多各种各样作用更强的、新的激酶抑制剂药物。
发明内容
针对现有药物的不足,本发明提供了一种N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐,其化学结构如结构通式(I)或结构通式(II)所示:
在结构通式(I)或结构通式(II)中,
L为下式所示的基团:
-L1-L2-,
式中L1的一端与A基团相连,L2的一端与X基团相连;
L1选自:共价键、烷基、-O-、-S-、-N(R2)-、烷基-O-,-O-烷基、烷基-O-烷基、烷基-S-、-S-烷基、烷基-S-烷基、烷基-N(R2)-、-N(R2)-烷基或烷基-N(R2)-烷基;
L2选自:共价键、烷基、烷基-CH=CH-或-CH=CH-烷基;
X选自:共价键、-O-、-S-或-N(R2)-;
Y选自:-O-、-S-、-N(R2)-、-N(R2)-CO-、-O-烷基、-S-烷基、-N(R2)-烷基或-N(R2)-CO-烷基;
Z选自:共价键或烷基,该烷基的碳链中可以有一个碳或者多个碳被杂原子取代;
R1基团选自:氢、烷基、卤代烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、氨基、烷基氨基、氨基烷基、羧基、烷基羧基、酰基氨基、烷基酰基氨基、烷基磺酰基或烷基酰基,其中各基团可被任选取代;
或者R1基团选自以下基团中的一种:
其中m代表0~3;
R2、R3和R4各自独立地选自:H、烷基、卤代烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、氨基、烷基氨基、氨基烷基、羧基、烷基羧基、酰基氨基、烷基酰基氨基、烷基磺酰基或酰基,其中各基团可被任选取代;
A基团选自:
R5基团选自:H、卤素、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、酰基氨基、烷基磺酰基或酰基,其中各基团可被任选取代;
B基团选自以下基团中的一种:
R5和R6基团各自独立地选自:H、卤素、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、羧基、烷基羧基、酰基氨基、烷基酰基氨基、烷基磺酰基或酰基,其中各基团可被任选取代;
C基团选自:
式中的其中任意一端与Y基团相连。
本发明结构通式(I)和结构通式(II)中的化合物,其中:
L1选自烷基,该烷基的碳链中可以有一个碳或者多个碳被杂原子取代;
L2优选选自:-C1-C5烷基或-CH=CH-(C1-C5烷基);
Y优选选自:-O-、-O-烷基、-N(R2)-烷基或-N(R2)-CO-烷基;
Z优选选自:C1-C2烷基;
R1优选选自以下基团中的一种:
更优选选自以下基团中的一种:
其中m代表0~3;
B基团优选选自以下基团中的一种:
本发明结构通式(I)和结构通式(II)中的化合物,包括以下化合物:
本文所用的术语“未取代的”表示不存在取代基或仅有的取代基为氢。
本文所用的术语“任选取代”表示该基团可经一或多个非氢取代基进一步取代或稠合。这些取代基独立选自下面的一或多个基团:卤素、=O、=S、-CN、-NO2、-CF3、-OCF3、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、烷氧基、羟基烷基、氨基、烷基氨基、氨基烷基、酰基氨基、烷基磺酰基和酰基。
“卤素”是指氟、氯、溴和碘。
作为基团或基团的部分,“烷基”为C1-C14直链或支链脂族烃基团,另有说明的除外。
“杂原子”指S、O和N原子。
“杂烷基”指C1-C14直链或支链烷基,其中一个或者多个碳被杂原子取代,杂原子的定义如上所述。
“环烷基”是指饱和或部分饱和的单环、稠环或螺环的碳环。以3-9个碳原子组成的环为优先选择。该基团可为末端基团或桥连基团。
“环烯基”是指非芳香性单环或多环环系。其中至少含有一个碳-碳双键且每环优选具有5-10个碳原子。该基团可为末端基团或桥连基团。
“杂环烷基”是指至少含有一个杂原子的环烷基。优选含有1-3个杂原子。优选的环为3-14元环,更优先选择的环为4-7元环。环烷基、杂原子的定义如上所述。该基团可为末端基团或桥连基团。
作为基团或基团的部分,“芳基”表示可被任选取代的单环或稠多环、芳香族的碳环,每环优选包含5至12个原子。该基团可为末端基团或桥连基团。
作为基团或基团的部分,“杂芳基”指含有芳环的基团,其在芳环的环原子中具有一或多个杂原子。杂原子的定义如上所述。该基团可为末端基团或桥连基团。
“环烷基烷基”表示环烷基-烷基,其中环烷基和烷基部分如上所述,该基团可为末端基团或桥连基团。
“芳基烷基”是指:(芳基-烷基)-的基团。其中,芳基和烷基见本文有关定义。该基团可为末端基团或桥连基团。
“杂芳基烷基”是指(杂芳基-烷基)-的基团。其中,芳基和烷基部分见本文有关定义。该基团可为末端基团或桥连基团。
“芳基杂烷基”是指(芳基-杂烷基)-的基团。其中,芳基和杂烷基见本文有关定义,该基团可为末端基团或桥连基团。
“环烷基杂烷基”是指(环烷基-杂烷基)-的基团。其中,环烷基和杂烷基见本文有关定义。该基团可为末端基团或桥连基团。
“杂环烷基杂烷基”是指(杂环烷基-杂烷基)-的基团。其中,杂环烷基和杂烷基见本文有关定义。该基团可为末端基团或桥连基团。
“杂芳基杂烷基”是指(杂芳基-杂烷基)-的基团。其中,杂芳基和杂烷基见本文有关定义。该基团可为末端基团或桥连基团。
“氨基烷基”是指(氨基-烷基)-的基团。其中,烷基见本文有关定义。该基团可为末端基团或桥连基团。
“烷氧基”指-O-烷基,其中烷基如本文所定义。该烷氧基优选C1-C6烷氧基。该基团可为末端基团或桥连基团。
除非另有说明,否则“烷基氨基”指单烷基氨基和二烷基氨基。“单烷基氨基”指-NH-烷基,其中烷基如上定义。“二烷基氨基”指-N(烷基)2,其中各烷基可以相同或不同,且都符合本文关于烷基的定义。该基团可为末端基团或桥连基团。
除非指定,否则“芳基氨基”包括单芳基氨基和二芳基氨基。“单芳基氨基”表示式芳基-NH-,其中芳基如上定义。二芳基氨基表示式(芳基)2N-,其中各芳基可以相同或不同,且都符合本文对芳基的定义。该基团可以为末端基团或桥连基团。
“酰基”表示烷基-CO-,其中烷基如本文所定义。该基团可以为末端基团或桥连基团。
“酰基氨基”表示(酰基-氨基)-的基团,其中酰基、烷基如本文所定义。该基团可以为末端基团或桥连基团。
“烷基磺酰基”指-S(O)2-烷基,其中烷基如本文所定义。该基团可以为末端基团或桥连基团。
“羟基烷基”是指-烷基-羟基的基团。其中烷基如本文所定义。
术语“医药用盐”或“药学上可接受的盐”指保留所需生物活性的以上鉴定的化合物的盐,包括药学上可接受的酸加成盐和碱加成盐。结构通式(I)和结构通式(II)中所示化合物的酸加成盐可从无机酸或有机酸制备。无机酸可以但不限于为盐酸、磷酸和硫酸。合适的有机酸可以为但不限于甲酸、乙酸、丙酸、琥珀酸、烷基磺酸、乙醇酸、葡糖酸、乳酸、苹果酸、柠檬酸、酒石酸、反丁烯二酸、顺丁烯二酸、芳基磺酸。结构通式(I)所示化合物的碱加成盐包括但不限于从锂、钠、钾、钙、镁、铝和锌制备的金属盐,以及从胆碱、吗啉、二乙醇胺等有机碱制备的有机盐。
结构通式(I)和结构通式(II)中所示化合物的包括异构体形式,包括非对映异构体、对映异构体、互变异构体和处于“E”或“Z”构型异构体的几何异构体或E和Z异构体的混合物。实施例中的一些化合物可以作为单一立体异构体、外消旋体和/或对映异构体和/或非对映异构体的混合物而存在。
此外,结构通式(I)和结构通式(II)中应包含该化合物的溶剂化和未溶剂化的形式。
在结构通式(I)和结构通式(II)中,当A基团为B基团为C基团为X为-O-,Y为-NH-CO-,L1为烷基-O-,L2为烷基-CH=CH-时,Z为烷基时,相应的化合物可以用合成路线一所示的方法来合成:
合成路线一
具体的说,如合成路线一所示,选择合适的硼化合物I在铃木(Suzuki)偶联条件下与具有合适取代基的嘧啶衍生物II反应得到联芳基化合物化合物III。在合适的碱存在的条件下,化合物III与烯基溴化物IV发生缩合反应得到化合物V。另一方面,以选择合适的化合物VI为原料,与相应的取代基的嘧啶衍生物VII缩合得到中间体VIII。经过还原、单保护后得到X。上述所得到的中间体V,在碱性条件下,与化合物X缩合,得到化合物中间体XI。该中间体XI经格鲁布斯II代(Grubbs II)催化剂催化发生关环复分解反应(Ring-ClosingMetathesis)得到大环中间体XII。在酸性条件下脱除保护基团得到化合物XIII。在合适的试剂与溶剂的作用下,化合物XIII与XIV和XV反应,分别得到目标化合物XVI和XVII。
其中R1、R5和R6如前文所定义,r、s、t、u独自独立代表0~5。
本发明还提供了上述技术方案中任一项所述的N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐在医药方面的应用。
本发明还提供了一种药物组合物,其包含上述技术方案中任一项所述的N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐,以及药学上可接受的稀释剂、赋形剂、载体中的一种或多种。
本发明还提供了上述技术方案中任一项所述的N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐或上述技术方案中所述的药物组合物的用途,可选地与其它一种药物或多种药物联合应用,用于制备抑制一种激酶或多种激酶的药物。
本发明所述的用途中,所述激酶选自:CDK2、CDK3、CDK4、CDK5、CDK6、CDK9、PCTAIREK、PCTAIRE2、PCTAIRE3、CAK/MO15、Dm2、Dm2c、Ddcdc2、DdPRK、LmmCRKK、PfC2R、EhC2R、CfCdc2R、cdc2+、CDC28、PHO85、KIN28、FpCdc2、MsCdc2B、OsC2R、PDGFR-b、PDGFR-a、CSF1R、c-kit、Flk2、FLT1、FLT2、FLT3、FLT4、TYK2、JAK1、JAK2、HOP或它们的功能等效物。
本发明还提供了上述技术方案中任一项所述的N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐或上述技术方案中所述的药物组合物的用途,其用于制备用于治疗由细胞增殖和/或血管新生的破坏所导致、与该破坏关联或伴随的病症的药物。
本发明所述的用途中,所述病症可以是增生性疾病。
本发明所述的用途中,所述增生性疾病可以是癌症。
本发明所述的用途中,所述增生性疾病可以选自:骨髓增生性疾病(慢性特发性骨髓纤维化、真性红细胞增多、特发性血小板增多症、慢性髓细胞性白血病)、骨髓化生、慢性骨髓单核细胞性白血病、急性髓细胞性白血病、青少年骨髓单核细胞性白血病、急性前髓细胞性白血病、急性淋巴细胞性白血病、急性成红细胞性白血病、急性B细胞白血病、白细胞增多、霍奇金病、B细胞淋巴瘤、急性T细胞白血病、乳腺癌、卵巢癌、结肠癌、前列腺癌、黑色素瘤、骨髓异常增生综合征、瘢痕瘤、成视网膜细胞瘤、乳腺恶性肿瘤、结肠恶性肿瘤、子宫内膜增生、骨肉瘤、鳞状细胞癌、非小细胞肺癌、黑色素瘤、肝细胞癌、胰腺恶性肿瘤、髓细胞性白血病、子宫颈癌、纤维瘤、结肠腺癌、神经胶质瘤、成胶质细胞瘤、少突神经胶瘤、淋巴瘤、卵巢癌、再狭窄、星形细胞瘤、膀胱肿瘤或肌肉骨骼肿瘤。
本发明所述的用途中,所述增生性疾病可以选自:前列腺癌、成视网膜细胞瘤、乳腺恶性肿瘤、结肠恶性肿瘤、子宫内膜增生、骨肉瘤、鳞状细胞癌、非小细胞肺癌、黑色素瘤、肝细胞癌、胰腺恶性肿瘤、髓细胞性白血病、子宫颈癌、纤维瘤、结肠腺癌、T细胞白血病、神经胶质瘤、成胶质细胞瘤、少突神经胶瘤、淋巴瘤、卵巢癌、再狭窄、星形细胞瘤、膀胱肿瘤、肌肉骨骼肿瘤或阿尔茨海默病。
本发明所述的用途中,所述增生性疾病可以选自:急性髓细胞性白血病、急性前髓细胞性白血病、急性淋巴细胞性白血病、骨髓异常增生综合征、白细胞增多、青少年骨髓单核细胞性白血病、急性B细胞白血病、慢性髓细胞性白血病、急性T细胞白血病、骨髓增生性疾病或慢性骨髓单核细胞性白血病。
具体实施方式
在下列实施例中,除非另有指明,所有温度单位为摄氏度。
各种起始原料和试剂均来自市售。供应商包括但不限于:Aldrich ChemicalCompany、Lancaster Synthesis Ltd等等。除非另有指明,市售原料和试剂均不经进一步纯化直接使用。
玻璃器皿用烘箱干燥和/或加热干燥。反应用玻璃硅胶-60F254平板(0.25mm)(TLC)上进行跟踪。分析性薄层层析并以适当的溶剂比例(v/v)加以展开。以TLC上反应起始原料耗尽时为反应终点。
1H-NMR图谱是用Bruker仪器(300MHz或者400MHz)测定而得,化学位移用ppm表示。使用氯仿作为参照标准(7.25ppm)或四甲基硅烷内标准(0.00ppm)。视需要,也可以使用其它NMR常用的溶剂。1H-NMR的表示方法:s=单峰,d=双重峰,t=三重峰,m=多重峰,br=加宽的,dd=双重峰的双重峰,dt=三重峰的双重峰。若提供偶合常数时,其单位为Hz。
质谱是用MS仪测定得到,离子化方式可为ESI或APCI。
下面的实施例仅仅是用来说明所发明的具体化合物的合成方法。但在合成方法上并没有任何限制。在实施例中未列出的化合物,也可以用与下面同样的合成路线与合成方法,选择适当的起始原料,在有必要的地方稍加适当的常识性的反应条件调整即可制备。
实施例1
合成路线一
(1)3-(2-氯-嘧啶-4-基)-苯甲醇(III-1)
向反应瓶中加入化合物3-羟甲基苯硼酸(II-1,35.2g,231.5mmol)、2,4-二氯嘧啶(I-1,30.0g,201.3mmol)、碳酸钠(32.0g,302.0mmol)的饱和溶液、四三苯基膦钯(11.6g,10.1mmol)、乙二醇二甲醚(300mL),然后氮气置换三次,用氮气保护。升温到80℃反应3小时。反应体系经过TLC点板(PE/EA=2:1)检测,在紫外线分析仪254nm下显示原料消失,产品不再增多,判断反应终止。加饱和氯化铵溶液淬灭反应,再加入100mL二氯甲烷,搅拌10分钟后,静置分层,收集有机相。水相用二氯甲烷50mL×2萃取,合并有机相,弃去水相。有机相用50mL饱和食盐水洗涤,静置分层后,弃去水相,有机相用适量无水硫酸钠干燥。干燥完成后,滤除干燥剂,滤液减压浓缩至干,得残余物。将残余物过快速柱(洗脱体系为乙酸乙酯/石油醚,比例由1:20逐步增加到1:3),收集相应产品的洗脱液,将洗脱液减压浓缩至干,得化合物III-1(39g,88.2%)。1H NMR(400MHz,DMSO-d6):δ8.67(d,J=5.2Hz,1H),8.09(s,1H),7.97(dd,J=1.4and 6.8Hz,1H),7.65(d,J=5.2Hz,1H),7.55-7.47(m,2H),4.79(d,J=6.0Hz,2H),2.36(t,J=6.0Hz,1H)。MS(m/z):243(M Na)+。
(2)4-(3-(烯丙氧基甲基)-苯基)-2-氯嘧啶(V-1)
向反应瓶中加入化合物III-1(5.0g,22.7mmol)、3-溴丙烯(IV-1,25mL)、氢氧化钾(2.5g,45.4mmol)、四丁基碘化铵(0.4g,1.1mmol),搅拌室温过夜。反应体系经过TLC点板(PE/EA=2:1)检测,在紫外线分析仪254nm下显示原料消失,产品不再增多,判断反应终止。加入水30mL,搅拌10分钟后,静置分层,收集有机相。水相用二氯甲烷20mL×2萃取,合并有机相,弃去水相。有机相用20mL饱和食盐水洗涤,静置分层后,弃去水相,有机相用适量无水硫酸钠干燥。干燥完成后,滤除干燥剂,滤液减压浓缩至干,得残余物。将残余物过快速柱(洗脱体系为乙酸乙酯/石油醚,比例由1:20逐步增加到1:5),收集相应产品的洗脱液,将洗脱液减压浓缩至干,得化合物V-1(5g,84.7%)。1H NMR(400MHz,DMSO-d6):δ8.64-7.47(m,6H),6.07-5.94(m,2H),5.37-5.22(m,4H),4.61(s,2H),4.09(d,2H,J=10.8Hz)。MS(m/z):261(MH)+。
(3)1-((烯丙基)甲基)-3,5-二硝基苯(VIII-1)
向反应瓶中加入3,5-二硝基苯甲醇(VI-1,20.0g,119.1mmol)、3-溴丙烯(VII-1,100mL)、氢氧化钾(16.7g,297.8mmol)、四丁基碘化铵(2.2g,6mmol),搅拌室温过夜。反应体系经过TLC点板(PE/EA=5:1)检测,在紫外线分析仪254nm下显示原料消失,产品不再增多,判断反应终止。加入水200mL,搅拌10分钟后,静置分层,收集有机相。水相用二氯甲烷50mL×2萃取,合并有机相,弃去水相。有机相用100mL饱和食盐水洗涤,静置分层后,弃去水相,有机相用适量无水硫酸钠干燥。干燥完成后,滤除干燥剂,滤液减压浓缩至干,得残余物。将残余物过快速柱(洗脱体系为乙酸乙酯/石油醚,比例由1:50逐步增加到1:10),收集相应产品的洗脱液,将洗脱液减压浓缩至干,得化合物VIII-1(10.4g,43.3%)。
(4)1-((烯丙基)甲基)-3,5-二氨基苯(XI-1)
向反应瓶中加入化合物VIII-1(7.7g,32.4mmol)、无水乙醇(85mL),然后升温到50℃,再向反应瓶中加入铁粉(10.9g,194.1mmol)和氯化铵(20.6g,388.2mmol)的水溶液,然后回流反应4小时。反应体系经过TLC点板(PE/EA=2:1)检测,在紫外线分析仪254nm下显示原料消失,产品不再增多,判断反应终止。体系降到室温,抽滤除去铁粉,再把滤液减压浓缩至干,得残余物加入水中,用饱和碳酸氢钠调pH=7,加入乙酸乙酯20mL,搅拌10分钟后,静置分层,收集有机相。水相用乙酸乙酯30mL×2萃取,合并有机相,弃去水相。有机相用30mL饱和食盐水洗涤,静置分层后,弃去水相,有机相用适量无水硫酸钠干燥。干燥完成后,滤除干燥剂,滤液减压浓缩至干,得残余物。将残余物过快速柱(洗脱体系为乙酸乙酯/石油醚,比例由1:10逐步增加到1:3),收集相应产品的洗脱液,将洗脱液减压浓缩至干,得化合物XI-1(5g,87.7%)。
(5)3-烯丙基-3-叔丁氧羰基氨基-苯胺(X-1)
向反应瓶中加入化合物IX-1(5.0g,28.1mmol)、四氢呋喃(50mL),然后降温到0℃,再把(Boc)2O(5.8g,26.7mmol)溶解到四氢呋喃(50mL)中滴入反应体系,然后恢复室温反应过夜。反应体系经过TLC点板(PE/EA=2:1)检测,在紫外线分析仪254nm下显示原料消失,产品不再增多,判断反应终止。加水100mL和乙酸乙酯30mL,搅拌10分钟后,静置分层,收集有机相。水相用乙酸乙酯30mL×2萃取,合并有机相,弃去水相。有机相用30mL饱和食盐水洗涤,静置分层后,弃去水相,有机相用适量无水硫酸钠干燥。干燥完成后,滤除干燥剂,滤液减压浓缩至干,得残余物。将残余物过快速柱(洗脱体系为乙酸乙酯/石油醚,比例由1:20逐步增加到1:8),收集相应产品的洗脱液,将洗脱液减压浓缩至干,得化合物X-1(4.7g,60.3%)。
(6)大环中间体(XI-1)的合成
向反应瓶中加入化合物V-1(3.3g,12.6mmol)、化合物X-1(3.5g,12.6mmol)、碳酸铯(10.3g,31.5mmol)、X-PHOS(0.6g,1.3mmol)、三(二亚苄基丙酮)二钯(0.6g,0.6mmol)、二氧六环(55mL),升温至100℃反应过夜。反应体系经过TLC点板(PE/EA=3:1)检测,在紫外线分析仪254nm下显示原料消失,产品不再增多,判断反应终止。加入饱和氯化铵30mL淬灭反应,加入乙酸乙酯20mL,搅拌10分钟后,静置分层,收集有机相。水相用乙酸乙酯20mL×2萃取,合并有机相,弃去水相。有机相用20mL饱和食盐水洗涤,静置分层后,弃去水相,有机相用适量无水硫酸钠干燥。干燥完成后,滤除干燥剂,滤液减压浓缩至干,得残余物。将残余物过快速柱(洗脱体系为乙酸乙酯/石油醚,比例由1:20逐步增加到1:5),收集相应产品的洗脱液,将洗脱液减压浓缩至干,得化合物XI-1(4.5g,71.4%)。
(7)大环中间体(XII-1)的合成
向反应瓶中加入化合物XI-1(4.5g,9.0mmol)、三氟乙酸(1.6mL)、Zhan Catalyst1B(0.7g,0.9mmol)、二氯甲烷(1350mL),升温至50℃反应3小时。反应体系经过TLC点板(PE/EA=2:1)检测,在紫外线分析仪254nm下显示原料消失,产品不再增多,判断反应终止。降到室温然后减压浓缩至干,得残余物。将残余物过快速柱(洗脱体系为乙酸乙酯/石油醚,比例由1:20逐步增加到1:3),收集相应产品的洗脱液,将洗脱液减压浓缩至干,得化合物XII-1(2.1g,50%)。
(8)大环中间体(XIII-1)的合成
向反应瓶中加入化合物XII-1(2.1g,4.4mmol)、EA/HCl(20mL),然后室温反应1小时。反应体系经过TLC点板(PE/EA=2:1)检测,在紫外线分析仪254nm下显示原料消失,产品不再增多,判断反应终止。直接将体系减压浓缩至干,得残余物。然后加入水中,再用饱和碳酸氢钠调pH=8,有固体析出,抽滤,滤饼用水洗两次,然后滤饼烘干得到粗品。将粗品过快速柱(洗脱体系为甲醇/二氯甲烷,比例由1:100逐步增加到1:30),收集相应产品的洗脱液,将洗脱液减压浓缩至干,得化合物XIII-1(1.6g,97%)。MS(m/z):375(MH)+.1H NMR(400MHz,DMSO_d6)δ4.00-4.06(m,4H),4.35(s,2H),4.52(s,2H),5.01(s,2H),5.77-5.81(m,2H),6.30(s,1H),6.35(s,1H),7.40-7.42(d,1H),7.53-7.54(d,2H),7.84(s,1H),8.02-8.04(d,1H),8.28(s,1H),8.51-8.53(d,1H),9.47(s,1H).
(9)大环中间体(XVI-A)的合成
向反应瓶中加入化合物XIII-1(500.0mg,1.3mmol)、化合物XIV-1(248.3mg,1.6mmol)、HATU(760.4mg,2.0mmol)、二甲基亚砜(6mL),然后降温到5℃,再把N,N-二异丙基乙胺(335.9mg,2.6mmol)滴入体系,然后氮气保护,室温反应过夜。反应体系经过LC-MS检测,原料消失,产品不再增多,判断反应终止。向体系中加入冰水,有固体析出,然后抽滤,滤饼用水洗两次,滤饼烘干得到粗品。将粗品通过制备液相(Xbridge C18,5μm 19×150mm/水-乙腈/35-70-8min-300m)制备得到化合物XIV-1(102mg,纯度98%by HPLC)。MS(m/z):512(MH)+.1H NMR(400MHz,DMSO_d6)δ1.72-1.75(d,4H),2.48(s,4H),3.23-3.24(d,2H),4.01-4.10(m,4H),4.47-4.54(d,4H),5.74-5.85(m,2H),6.30-6.34(d,1H),6.75-6.81(m,1H),7.36(s,1H),7.45-7.48(m,2H),7.52-7.57(m,2H),8.04-8.06(d,1H),8.26-8.32(d,2H),8.56-8.57(d,1H),9.82(s,1H),10.04(s,1H).
(10)大环中间体(XVII-1)的合成
向反应瓶中加入化合物XIII-1(500.0mg,1.3mmol)、XV-1(112.0mg,1.6mmol)、HATU(760.4mg,2.0mmol)、二甲基亚砜(6mL),然后降温到5℃,再把N,N-二异丙基乙胺(335.9mg,2.6mmol)滴入体系,然后氮气保护,室温反应过夜。反应体系经过LC-MS检测,原料消失,产品不再增多,判断反应终止。向体系中加入冰水,有固体析出,然后抽滤,滤饼用水洗两次,滤饼烘干得到粗品。将粗品通过制备液相(Xbridge C18,5μm19×150mm/水+乙腈/30-70-8min-300m)制备得到化合物XVII-1(110mg)。MS(m/z):427(MH)+。1H NMR(400MHz,DMSO_d6)δ4.01-4.09(m,4H),4.40(s,1H),4.46-4.53(d,4H),5.76-5.81(m,2H),7.25(s,1H),7.43-7.48(m,2H),7.54-7.56(d,2H),8.04-8.06(d,1H),8.25(s,1H),8.37(s,1H),8.56-8.57(d,1H),9.84(s,1H),10.81(s,1H).
其它实施例:
选用合适的起始原料和合适的反应试剂,表1中的化合物均按上述合成路线一来合成。
表1可用本发明方法合成的具有结构通式(I)和结构通式(II)的化合物
药理试验
本发明化合物的生物学功效可通过酶抑制活性、细胞增殖抑制活性等多方面来评估。其中,化合物的酶抑制活性、细胞增殖抑制活性等等的测定方法可使用但不限于下面方法来进行。
酶抑制活性的测定方法:
采用放射性同位素标记法检测系列化合物对人重组蛋白激酶的活性,由Eurofins公司提供。将待测化合物与相应的蛋白激酶缓冲液(20mM丙磺酸盐(MPOS,pH=7.0),1mMEDTA,0.1%β-巯基乙醇,0.01%Brij-35,5%甘油,和1mg/mL BSA)混合,加入反应体系(100μM反应底物KKRNRTLTV,8mM pH 7.0的MOPS,10mM MgAcetate,0.2mM的EDTA和一定浓度的γ-33P-ATP)。加入MgATP复合的溶液后反应开始,室温条件下反应40min,加入5μl的3%的磷酸溶液终止反应。接着把10μl的反应溶液滴到滤器上并用75mM的磷酸溶液洗三次,每次5分钟,之后再用甲醇洗一次,进行干燥和闪光计数。
表2表示单浓度(1μM)抑制活性。而表3则为部分化合物的IC50。
表2单浓度(1μM)抑制活性
表3部分化合物的IC50
细胞增殖抑制活性:
人类癌细胞系购自ATCC。根据ATCC的工作说明书将其培养于培养基中。采用XL-拟合绘制剂量反应曲线以确定化合物的IC50值。IC50定义为抑制50%细胞生长所需要的化合物浓度。如下表所示,本发明化合物抑制细胞增殖。数据显示,本发明化合物对于抑制肿瘤细胞的生长有活性。细胞的增殖抑制检测可用MTT法来测定(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide,MTT;3-(4,5-二甲基噻唑-2)-2,5-二苯基四氮唑溴盐,噻唑蓝)。
首先在培养皿中培养细胞,将处于对数生长期的细胞按特定数量接种于96孔板中(贴壁细胞3000-5000个/孔,悬浮细胞10000-30000个/孔),每孔100微升,然后放入5%CO2、37℃环境的孵箱中培养。过夜之后,加入100微升使用指定的培养基配制好的不同浓度梯度药物,每个浓度梯度设置3个复孔,保证结果的准确性,并且设置空白对照组和溶剂对照组。加好药之后放入孵箱,培养72h。并在MTT实验当天预先配好MTT测试液(溶于生理盐水的5mg/ml MTT溶液,4℃避光保存),每孔加入20μl MTT溶液,放入孵箱继续培养2-4h,然后每孔再加入50μl的20%SDS水溶液放置过夜后,上酶标仪检测570nm处吸光度值,以计算药物对肿瘤细胞的体外增殖抑制率。一般对照组的吸光度值应在0.8-1.2之间为正常值。取得吸光度值数据之后使用GraphPad Prism6.03软件拟合抑制率变化曲线并算出IC50值。
药物抑制率计算:相对细胞增殖抑制率=[(对照组A570-实验组A570)/对照组A570×100%,其中A570代表在570nm处的吸光度值。
表4本发明化合物对8种细胞模型的MTT研究结果汇总
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (14)
1.一种N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐,其化学结构如结构通式(I)或结构通式(II)所示:
在结构通式(I)或结构通式(II)中,
L为下式所示的基团:
-L1-L2-,
式中L1的一端与A基团相连,L2的一端与X基团相连;
L1选自:共价键、烷基、-O-、-S-、-N(R2)-、烷基-O-,-O-烷基、烷基-O-烷基、烷基-S-、-S-烷基、烷基-S-烷基、烷基-N(R2)-、-N(R2)-烷基或烷基-N(R2)-烷基;
L2选自:共价键、烷基、烷基-CH=CH-或-CH=CH-烷基;
X选自:共价键、-O-、-S-或-NR2-;
Y选自:-O-、-S-、-N(R2)-、-N(R2)-CO-、-O-烷基、-S-烷基、-N(R2)-烷基或-N(R2)-CO-烷基;
Z选自:共价键或烷基,该烷基的碳链中可以有一个碳或者多个碳被杂原子取代;
R1基团选自:氢、烷基、卤代烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、氨基、烷基氨基、氨基烷基、羧基、烷基羧基、酰基氨基、烷基酰基氨基、烷基磺酰基或烷基酰基,其中各基团可被任选取代;
或者R1基团选自以下基团中的一种:
其中m代表0~3;
R2、R3和R4各自独立地选自:H、烷基、卤代烷基、环烷基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、氨基、烷基氨基、氨基烷基、羧基、烷基羧基、酰基氨基、烷基酰基氨基、烷基磺酰基或酰基,其中各基团可被任选取代;
A基团选自:
B基团选自以下基团中的一种:
R5和R6基团各自独立地选自:H、卤素、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、羧基、烷基羧基、酰基氨基、烷基酰基氨基、烷基磺酰基或酰基,其中各基团可被任选取代;
C基团选自:
式中的其中任意一端与Y基团相连。
2.根据权利要求1所述的N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐,其特征在于,
L1选自烷基,该烷基的碳链中可以有一个碳或者多个碳被杂原子取代;
L2选自:烷基、烷基-CH=CH-或-CH=CH-烷基;
R1基团选自以下基团中的一种:
其中m代表0~3;
X选自:-O-、-S-或-N(R2)-;
Y选自:-O-、-N(R2)-、-O-烷基、-S-烷基、-N(R2)-烷基或-N(R2)-CO-烷基;
B基团选自:
R5和R6基团各自独立地选自:H、卤素、烷基、卤代烷基、杂烷基、环烷基、环烯基、杂环烷基、芳基、杂芳基、环烷基烷基、芳基烷基、杂芳基烷基、环烷基杂烷基、杂环烷基杂烷基、杂芳基杂烷基、芳基杂烷基、羟基、羟基烷基、烷氧基、氨基、烷基氨基、氨基烷基、羧基、烷基羧基、酰基氨基、烷基酰基氨基、烷基磺酰基或酰基,其中各基团可被任选取代;
C基团选自:
式中的其中任意一端与Y基团相连。
5.权利要求1-4中任一项所述的N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐在医药方面的应用。
6.一种药物组合物,其包含权利要求1-4中任一项所述的N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐,以及药学上可接受的稀释剂、赋形剂、载体中的一种或多种。
7.权利要求1-4中任一项所述的N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐或权利要求6中所述的药物组合物的用途,可选地与其它一种药物或多种药物联合应用,用于制备抑制一种激酶或多种激酶的药物。
8.根据权利要求7所述的用途,其特征在于,所述激酶选自:CDK2、CDK3、CDK4、CDK5、CDK6、CDK9、PCTAIREK、PCTAIRE2、PCTAIRE3、CAK/MO15、Dm2、Dm2c、Ddcdc2、DdPRK、LmmCRKK、PfC2R、EhC2R、CfCdc2R、cdc2+、CDC28、PHO85、KIN28、FpCdc2、MsCdc2B、OsC2R、PDGFR-b、PDGFR-a、CSF1R、c-kit、Flk2、FLT1、FLT2、FLT3、FLT4、TYK2、JAK1、JAK2、HOP或它们的功能等效物。
9.权利要求1-4中任一项所述的N-大环酰胺类化合物或其异构体、非对映体、对映体、前药、药学上可接受的盐或权利要求6中所述的药物组合物的用途,其用于制备用于治疗由细胞增殖和/或血管新生的破坏所导致、与该破坏关联或伴随的病症的药物。
10.根据权利要求9所述的用途,其特征在于,所述病症是增生性疾病。
11.根据权利要求10所述的用途,其特征在于,所述增生性疾病是癌症。
12.根据权利要求10所述的用途,其特征在于,所述增生性疾病选自:骨髓增生性疾病(慢性特发性骨髓纤维化、真性红细胞增多、特发性血小板增多症、慢性髓细胞性白血病)、骨髓化生、慢性骨髓单核细胞性白血病、急性髓细胞性白血病、青少年骨髓单核细胞性白血病、急性前髓细胞性白血病、急性淋巴细胞性白血病、急性成红细胞性白血病、急性B细胞白血病、白细胞增多、霍奇金病、B细胞淋巴瘤、急性T细胞白血病、乳腺癌、卵巢癌、结肠癌、前列腺癌、黑色素瘤、骨髓异常增生综合征、瘢痕瘤、成视网膜细胞瘤、乳腺恶性肿瘤、结肠恶性肿瘤、子宫内膜增生、骨肉瘤、鳞状细胞癌、非小细胞肺癌、黑色素瘤、肝细胞癌、胰腺恶性肿瘤、髓细胞性白血病、子宫颈癌、纤维瘤、结肠腺癌、神经胶质瘤、成胶质细胞瘤、少突神经胶瘤、淋巴瘤、卵巢癌、再狭窄、星形细胞瘤、膀胱肿瘤或肌肉骨骼肿瘤。
13.根据权利要求10-12中任一项所述的用途,其特征在于,所述增生性疾病选自:前列腺癌、成视网膜细胞瘤、乳腺恶性肿瘤、结肠恶性肿瘤、子宫内膜增生、骨肉瘤、鳞状细胞癌、非小细胞肺癌、黑色素瘤、肝细胞癌、胰腺恶性肿瘤、髓细胞性白血病、子宫颈癌、纤维瘤、结肠腺癌、T细胞白血病、神经胶质瘤、成胶质细胞瘤、少突神经胶瘤、淋巴瘤、卵巢癌、再狭窄、星形细胞瘤、膀胱肿瘤、肌肉骨骼肿瘤或阿尔茨海默病。
14.根据权利要求10-12中任一项所述的用途,其特征在于,所述增生性疾病选自:急性髓细胞性白血病、急性前髓细胞性白血病、急性淋巴细胞性白血病、骨髓异常增生综合征、白细胞增多、青少年骨髓单核细胞性白血病、急性B细胞白血病、慢性髓细胞性白血病、急性T细胞白血病、骨髓增生性疾病或慢性骨髓单核细胞性白血病。
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