CN116041371A - 7-羰基星孢菌素衍生物及其制备方法和应用 - Google Patents
7-羰基星孢菌素衍生物及其制备方法和应用 Download PDFInfo
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Abstract
本发明公开了一类7‑羰基星孢菌素衍生物及其制备方法和应用。本发明还公开了该类型典型18个化合物的化学合成方法,合成路线简单,易于操作和实施,并且所需试剂易于购买。本发明公开的化合物具有显著的PIM‑1激酶抑制活性和优异的激酶选择性,可用于开发由PIM‑1激酶异常表达引起的相关疾病或病症的治疗药物。
Description
技术领域
本发明涉及医药技术领域,具体涉及一类7-羰基星孢菌素衍生物及其制备方法和在医药领域的应用。本发明的7-羰基星孢菌素衍生物可作为或用于制作选择性抑制PIM-1的低副作用药剂,特别适用于治疗PIM-1活性相关的疾病或病症。
背景技术
PIM激酶属于钙/钙调蛋白激酶(CAMK)家族,主要存在PIM-1、PIM-2和PIM-3三种亚型。它们的氨基酸序列具有高度的同源性,PIM-1和PIM-2的相似率为61%,PIM-1和PIM-3的相似率为71%,PIM-2和PIM-3的相似率为44%。
PIM激酶的三种亚型在不同组织中的表达量存在差异,PIM-1在造血细胞、淋巴细胞以及前列腺细胞中高度表达,PIM-2在淋巴细胞和脑细胞中高度表达,而PIM-3在乳腺细胞、肾细胞和脑细胞中高度表达。
PIM激酶的过表达不仅会导致癌细胞增殖,还会导致癌细胞对传统化疗、放疗、免疫抑制剂雷帕霉素等治疗策略产生耐药性。PIM激酶与其他致癌途径的相互作用则会导致癌细胞生长、增殖和逃避凋亡,如PI3K/mTOR/AKT信号通路。多种促癌信号分子是PIM激酶的下游靶标,如MYC、CDC25、BAD等,而PIM激酶的表达受到JAK-STAT、NF-κB等通路的调节。
由于PIM-2和PIM-3的结构信息相对比较缺乏,PIM-1成为PIM激酶家族中被广泛研究的对象。经过二十多年的开发研究,已经设计出众多具有不同杂环骨架的PIM-1激酶抑制剂,但是只有少数化合物进入临床研究,目前还没有PIM-1激酶抑制剂获批上市。
星孢菌素是一种广谱激酶抑制剂,是最具代表性的吲哚咔唑类化合物,其多个衍生物如Midostaurin、Lestaurtinib、UCN-01等已获批上市或进入临床研究,表明该类化合物极具开发前景,但是激酶选择性差、副作用大一直是阻滞该类化合物进一步开发的重要因素。
发明人研究总结现有的吲哚咔唑类化合物对PIM-1激酶抑制作用的构效关系,发现C-7位羰基对PIM-1激酶活性抑制非常重要,因此对7-羰基星孢菌素进行结构修饰,以获得具有PIM-1激酶高选择性抑制活性的衍生物。
本发明是以7-羰基星孢菌素为先导化合物,进行化学合成获得一系列衍生物,并测定了该类型化合物的PIM-1激酶抑制作用,结果表明7-羰基星孢菌素衍生物对PIM-1具有很好的抑制作用,尤其是化合物17对PIM-1激酶抑制作用显著,IC50为5.9nM,效果优于阳性对照药TP-3654(IC50为31.1nM)。另外,进一步探究发现,化合物17具有优异的PIM-1激酶选择性抑制作用,有非常好的开发前景。
本发明可为该类型化合物治疗由PIM-1激酶异常表达引起的相关疾病或病症的药物开发提供参考。
发明内容
本发明提供了一类7-羰基星孢菌素衍生物或其可药用的盐,所述7-羰基星孢菌素衍生物具有如下式(I)所示结构:
式(I)中:
L选自-(CH2)n-、-(CH2)nNH-、-(CH2)nO-、-(CH2)nC(=O)O-、
-(CH2)nC(=O)NH-、-(CH2)nS-、-(CH2)nS(=O)-、-(CH2)nS(=O)2-、-(OCH2CH2O)n-、-(CH2CH2O)n-、-(OCH2CH2OCH2)n-、-(CH2CH2OCH2)n-、-(CH2CH2OCH2CH2)n-、亚烯基、亚炔基、亚环烷基、亚杂芳烃基或它们的任意组合,其中n表示1至10的自然数;
R选自H、卤素、羟基、氨基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、-C(=O)R1、-OC(=O)R1、-C(=O)OR1、-OR1、-SR1、-S(=O)R1、-S(=O)2R1、-S(=O)2NR1R2、-NR1R2、-C(=O)NR1R2、-NR1C(=O)R2、-NR1C(=O)OR2、-NR1S(=O)2R2、-NR1C(=O)NR1R2、-C1-6亚烷基-NR1R2、-C1-6亚烷基-O(P=O)(OH)2和-O-C1-6亚烷基-NR1R2;
上述烷基、亚烷基、烯基、炔基、环烃基、杂环基在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代:卤素、羟基、氧代、氨基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-10元杂环基、=N-OR1、-C(=NH)NH2、-C(=O)R1、-OC(=O)R1、-C(=O)OR1、-OR1、-SR1、-S(=O)R1、-S(=O)2R1、-S(=O)2NR1R2、-NR1R2、-C(=O)NR1R2、-NR1C(=O)R2、-NR1C(=O)OR2、-NR1S(=O)2R2、-NR1C(=O)NR1R2、-C1-6亚烷基-NR1R2、-O-C1-6亚烷基-NR1R2;
R1和R2在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基和3-10元杂环基;或者当R1和R2与同一氮原子连接时,R1和R2连同其所连接的原子任选地共同构成3-12元杂环。
进一步的,所述7-羰基星孢菌素衍生物可选自以下化合物1-18中的任一种:
本发明还提供了一种药物组合物,包含所述的7-羰基星孢菌素衍生物或其可药用的盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明还提供了所述的7-羰基星孢菌素衍生物或其可药用的盐或所述的药物组合物在制备用于抑制PIM-1激酶的药物中的应用。
本发明还提供了所述的7-羰基星孢菌素衍生物或其可药用的盐或所述的药物组合物在制备用于治疗和/或预防与PIM-1激酶异常活性相关的疾病的药物中的应用。
所述疾病可以为癌症。
所述癌症优选为白血病、淋巴瘤、多发性骨髓瘤、乳腺癌、子宫内膜癌、卵巢癌、阴道癌、输卵管癌、宫颈癌、肾癌、膀胱癌、尿路上皮癌、尿道癌、前列腺癌、睾丸癌、结直肠癌、肉瘤、骨癌、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、鼻咽癌、口腔癌、肺癌、肺泡癌、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、神经纤维瘤、神经胶质瘤、神经母细胞瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌或胃肠道间质瘤。
优选地,所述淋巴瘤为霍奇金氏疾病或非霍奇金淋巴瘤(例如套细胞淋巴瘤、弥漫性大B细胞淋巴瘤、滤泡中心淋巴瘤、边缘区B细胞淋巴瘤、淋巴浆细胞淋巴瘤和外周T细胞淋巴瘤);所述肺癌为非小细胞肺癌(NSCLC)(包括鳞状细胞癌、腺癌和大细胞癌等)或小细胞癌(SCLC);所述肾癌为肾细胞癌、透明细胞和肾嗜酸细胞瘤;所述白血病为慢性淋巴细胞性白血病(CLL)、急性成淋巴细胞性白血病(ALL)、T-细胞急性成淋巴细胞性白血病(T-ALL)、慢性髓细胞性白血病(CML)或急性骨髓性白血病(AML);所述结直肠癌为结肠癌或直肠癌;所述肉瘤为软骨肉瘤。
本发明进一步涉及一种抑制PIM-1激酶的方法,其包括给予所需患者治疗有效量的所述7-羰基星孢菌素衍生物或其可药用的盐、或包括其的药物组合物。
本发明进一步涉及一种治疗和/或预防与PIM-1异常活性相关的疾病的方法,其包括给予所需患者治疗有效量的所述7-羰基星孢菌素衍生物或其可药用的盐、或包括其的药物组合物。
所述疾病涵盖内容可与上文介绍相同。
可将活性化合物制成适合于通过任何适当途径给药的形式,通过常规方法使用一种或多种药学上可接受的载体来配制本发明的组合物。因此,本发明的活性化合物可以配制成用于口服给药、注射(例如静脉内、肌肉内或皮下)给药,吸入或吹入给药的各种剂型。本发明的化合物也可以配制成例如片剂、硬或软胶囊、水性或油性混悬液、乳剂、注射液、可分散性粉末或颗粒、栓剂、锭剂或糖浆等剂型。
作为一般性指导,活性化合物优选是以单位剂量的方式,或者是以患者可以以单剂自我给药的方式。本发明化合物或组合物的单位剂量的表达方式可以是片剂、胶囊、扁囊剂、瓶装药水、药粉、颗粒剂、锭剂、栓剂、再生药粉或液体制剂。合适的单位剂量可以是0.1~1000mg。
本发明的药物组合物除活性化合物外,可含有一种或多种辅料,所述辅料选择以下成分:填充剂(稀释剂)、粘合剂、润湿剂、崩解剂或赋形剂等。根据给药方法的不同,组合物可含有0.1至99%重量的活性化合物。
片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药用的赋形剂。这些赋形剂可以是惰性赋形剂、造粒剂、崩解剂、粘合剂和润滑剂。这些片剂可以不包衣或可通过掩盖药物的味道或在胃肠道中延迟崩解和吸收,因而在较长时间内提供缓释作用的已知技术将其包衣。
也可用其中活性成分与惰性固体稀释剂或其中活性成分与水溶性载体或油溶媒混合的软明胶胶囊提供口服制剂。
水混悬液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。此赋形剂是悬浮剂、分散剂或湿润剂。水混悬液也可以含有一种或多种防腐剂、一种或多种着色剂、一种或多种矫味剂和一种或多种甜味剂。
油混悬液可通过使用活性成分悬浮于植物油,或矿物油配制而成。油悬浮液可含有增稠剂。可加入上述的甜味剂和矫味剂,以提供可口的制剂。可通过加入抗氧化剂保护这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。油相可以是植物油,或矿物油或其混合物。适宜的乳化剂可以是天然产生的磷脂,乳剂也可以含有甜味剂、矫味剂、防腐剂和抗氧剂。此类制剂也可含有缓和剂、防腐剂、着色剂和抗氧剂。
本发明的药物组合物可以是无菌注射水溶液形式。可以使用的可接受的溶媒或溶剂有水、林格氏液和等渗氯化钠溶液。无菌注射制剂可以是其中活性成分溶于油相的无菌注射水包油微乳可通过局部大量注射,将注射液或微乳注入患者的血流中。或者,最好按可保持本发明化合物恒定循环浓度的方式给予溶液和微乳。为保持这种恒定浓度,可使用连续静脉内递药装置。这种装置的实例是DeltecCADD-PLUS.TM.5400型静脉注射泵。
本发明公开的药物组合物可以是用于肌肉和皮下给药的无菌注射水或油混悬液的形式。可按已知技术,用上述那些适宜的分散剂或湿润剂和悬浮液配制该混悬液。无菌注射制剂也可以是在肠胃外可接受的无毒稀释剂或溶剂中制备的无菌注射溶液或混悬液。此外,可方便地用无菌固定油作为溶剂或悬浮介质。为此目的,可使用任何调和固定油。此外,脂肪酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。可通过将药物与在普通温度下为固体但在直肠中为液体,因而在直肠中会融化而释放药物的适宜的无刺激性赋形剂混合来制备这些药物组合物。
可通过加入水来制备水混悬的可分散粉末和颗粒给予本发明化合物。可通过将活性成分与分散剂或湿润剂、悬浮剂或一种或多种防腐剂混合来制备这些药物组合物。
如本领域技术人员所熟知的,药物的给药剂量依赖于多种因素,包括但并非限定于以下因素:所用具体化合物的活性、疾病的严重性、患者的年龄、患者的体重、患者的健康状况、患者的行为、患者的饮食、给药时间、给药方式、排泄的速率、药物的组合等;另外,最佳的治疗方式如治疗的模式、日用量或可药用的盐的种类可以根据传统的治疗方案来验证。
本发明还提供了化合物1-18的制备方法,以7-羰基星孢菌素为初始底物,合成路线如下:
采用酰卤法合成化合物1-11:将初始底物分别和具有不同基团的酰氯在N,N-二异丙基乙胺(DIPEA)和氯仿,或者,N,N-二异丙基乙胺和无水N,N-二甲基甲酰胺(DMF)的混合环境中反应,分别得到化合物1-11;
采用酸酐法合成化合物12-15:将初始底物分别和不同的酸酐在4-二甲氨基吡啶(DMAP)和二甲基亚砜(DMSO)的混合环境中反应,分别得到化合物12-15;
采用鎓盐类缩合剂法合成化合物16:将初始底物和辛二酸在N,N-二异丙基乙胺、N,N-二甲基甲酰胺、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)的混合环境中反应,得到化合物16;
采用CDI缩合剂法合成化合物17:将化合物12先在N,N'-羰基二咪唑(CDI)和N,N-二甲基甲酰胺的混合环境中反应,再加入盐酸羟胺继续反应,得到化合物17;
将化合物12和3-氨基吡唑在N,N-二异丙基乙胺、N,N-二甲基甲酰胺、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)的混合环境中反应,得到化合物18。
上述制备方法反应共1-2步,易于操作和实施。
本发明与现有技术相比,有益效果有:
本发明公开的化合物具有显著的PIM-1激酶抑制活性和优异的激酶选择性,可用于开发由PIM-1激酶异常表达引起的相关疾病或病症的治疗药物。
本发明所涉及的化合物合成路线简单,易于操作和实施,并且所需试剂易于购买。衍生的化合物17对PIM-1激酶的抑制作用优于处在临床研发阶段的阳性药物TP-3654,并且具有优异的激酶选择性,在临床上针对性特异性治疗方面更有优势。
具体实施方式
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操作方法,通常按照常规条件,或按照制造厂商所建议的条件。
实施例1.衍生物的合成
化合物1-8的合成步骤如下:
称取10.0mg(0.021mmol)7-羰基星孢菌素于25mL反应瓶中,加入2mL氯仿溶解,然后加入40μL(0.230mmol)DIPEA和40μL(0.476mmol)丙酰氯,在30℃条件下搅拌反应4h。采用薄层色谱监测反应进程。减压浓缩后用HPLC进行制备,流动相为85%甲醇-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物1(4.0mg,产率约35.8%,tR=18min)。
根据上述反应,将反应物更换成正丁酰氯,流动相改为87%甲醇-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物2(4.0mg,产率约34.9%,tR=17min);将反应物更换成正戊酰氯,流动相改为87%甲醇-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物3(6.1mg,产率约51.9%,tR=20min);将反应物更换成己酰氯,流动相改为90%甲醇-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物4(8.0mg,产率约66.4%,tR=18min);将反应物更换成庚酰氯,流动相改为92%甲醇-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物5(4.5mg,产率约36.5%,tR=18min);将反应物更换成辛酰氯,流动相改为93%甲醇-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物6(4.9mg,产率约38.8%,tR=19min);将反应物更换成环丙基甲酰氯,流动相改为85-100%甲醇-水-0.05%TFA梯度洗脱,流速为10mL/min,检测波长为318nm,得到化合物7(4.7mg,产率约41.2%,tR=18min);将反应物更换成2-噻吩甲酰氯,流动相改为85-100%甲醇-水-0.05% TFA梯度洗脱,流速为10mL/min,检测波长为318nm,得到化合物8(5.6mg,产率约45.6%,tR=19min)。
化合物9-11的合成步骤如下:
称取10.0mg(0.021mmol)7-羰基星孢菌素于25mL反应瓶中,加入2mL无水DMF溶解,然后加入20μL(0.115mmol)DIPEA和7.8mg(0.042mmol)胡椒酸酰氯,在30℃条件下搅拌反应4h。采用薄层色谱监测反应进程。减压浓缩后用HPLC进行制备,流动相为68%乙腈-水,流速为10mL/min,检测波长为318nm,得到化合物9(6.1mg,产率约46.6%,tR=16min)。
根据上述反应,将反应物更换成3-甲基巴豆酰氯,流动相改为80%乙腈-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物10(6.1mg,产率约为52.1%,tR=15min);将反应物更换成3-苯基丙烯酰氯,流动相改为80%乙腈-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物11(5.9mg,产率约为46.4%,tR=19min)。
化合物12-15的合成步骤如下:
称取10.0mg(0.021mmol)7-羰基星孢菌素、3.2mg(0.032mmol)丁二酸酐和1.0mgDMAP于25mL反应瓶中,加入3mL DMSO溶解,在30℃条件下搅拌反应8h。采用薄层色谱监测反应进程。加入50mL水,用等体积的乙酸乙酯萃取3次以除去大部分的DMSO,减压浓缩乙酸乙酯相。然后用HPLC进行制备,流动相为52%乙腈-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物12(5.5mg,产率约45.5%,tR=21min)。
根据上述反应,将反应物更换成戊二酸酐,流动相改为50%乙腈-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物13(3.0mg,产率约为24.2%,tR=34min);将反应物更换成3-硫代戊二酸酐,流动相改为58%乙腈-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物14(2.8mg,产率约为22.0%,tR=21min);将反应物更换成己二酸酐,流动相改为60%乙腈-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物15(2.5mg,产率约为19.7%,tR=19min);
化合物16的合成步骤如下:
称取7.3mg(0.042mmol)辛二酸和11.8mg(0.031mmol)HATU于25mL反应瓶中,加入2mL DMF溶解,然后加入20μL(0.115mmol)DIPEA,在30℃条件下搅拌反应1h。最后加入10.0mg(0.021mmol)7-羰基星孢菌素,在65℃条件下搅拌反应8h。采用薄层色谱监测反应进程。减压浓缩后用HPLC进行制备,流动相为60%乙腈-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物16(3.2mg,产率约24.2%,tR=27min)。
化合物17的合成步骤如下:
称取15.0mg(0.026mmol)化合物12和8.4mg(0.052mmol)CDI于25mL反应瓶中,加入2mL DMF溶解,在30℃条件下搅拌反应1h,最后加入7.2mg(0.104mmol)盐酸羟胺,在30℃条件下搅拌反应8h。采用薄层色谱监测反应进程。减压浓缩后用HPLC进行制备,流动相为58%乙腈-水-0.05% TFA,流速为10mL/min,检测波长为318nm,得到化合物17(2.6mg,产率约14.0%,tR=11min)。
化合物18的合成步骤如下:
称取12.0mg(0.021mmol)化合物12和12.2mg(0.032mmol)HATU于25mL反应瓶中,加入2mL DMF溶解,然后加入20μL(0.115mmol)DIPEA,在30℃条件下搅拌反应1h,最后加入2.0mg(0.024mmol)3-氨基吡唑,在65℃条件下搅拌反应8h。采用薄层色谱监测反应进程。减压浓缩后用HPLC进行制备,流动相为65%乙腈-水,流速为10mL/min,检测波长为318nm,得到化合物18(2.0mg,产率约为12.4%,tR=20min)。
实施例2.化合物的鉴定
化合物1:黄色固体。HRESIMS found m/z 559.1957[M+Na]+(calcd forC31H28N4O5Na,559.1957).1H NMR(600MHz,DMSO-d6):δ11.14(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.43(t,J=8.0Hz,1H),7.40(t,J=8.0Hz,1H),7.06(dd,J=8.8,6.0Hz,1H),5.07(ddd,J=13.1,4.6,2.4Hz,1H),4.26–4.23(m,1H),2.80(s,3H),2.75–2.69(m,1H),2.66(s,3H),2.39–2.35(m,5H),2.28(td,J=13.1,6.0Hz,1H),1.05(t,J=7.3Hz,3H).13C NMR(151MHz,DMSO-d6):δ173.6,171.2,170.9,139.8,137.7,130.6,128.8,127.2,126.9,125.0,124.9,122.8,121.5,120.9,120.7,120.7,119.6,116.1,115.2,113.6,109.9,95.0,83.3,82.5,60.4,47.8,30.7,29.2,26.9,26.4,9.2.
化合物2:黄色固体。HRESIMS found m/z 551.2297[M+H]+(calcd for C32H31N4O5,551.2294).1H NMR(600MHz,DMSO-d6):δ11.13(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.45–7.38(m,2H),7.05(dd,J=8.8,6.0Hz,1H),5.06(ddd,J=13.0,4.6,2.4Hz,1H),4.26–4.23(m,1H),2.80(s,3H),2.75–2.69(m,1H),2.67(s,3H),2.37(s,3H),2.33(td,J=7.4,4.2Hz,2H),2.28(td,J=13.0,6.0Hz,1H),1.58(h,J=7.4Hz,2H),0.93(t,J=7.4Hz,3H).13C NMR(151MHz,DMSO-d6):δ172.8,171.2,170.9,139.8,137.7,130.5,128.7,127.2,126.9,125.0,124.9,122.8,121.4,120.9,120.7,120.6,119.6,116.1,115.2,113.6,109.9,95.0,83.3,82.4,60.4,47.8,35.0,30.9,29.2,26.8,18.0,13.9.
化合物3:黄色固体。HRESIMS found m/z 565.2447[M+H]+(calcd for C33H33N4O5,565.2451).1H NMR(600MHz,DMSO-d6):δ11.13(s,1H),9.26(d,J=8.0Hz,1H),9.08(d,J=8.0Hz,1H),8.03(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.55(t,J=8.0Hz,1H),7.45–7.37(m,2H),7.05(dd,J=8.8,6.0Hz,1H),5.05(ddd,J=13.1,4.6,2.5Hz,1H),4.25–4.22(m,1H),2.80(s,3H),2.74–2.68(m,1H),2.66(s,3H),2.37(s,3H),2.34(td,J=7.4,2.1Hz,2H),2.27(td,J=13.1,6.0Hz,1H),1.53(p,J=7.4Hz,2H),1.37–1.29(m,2H),0.89(t,J=7.4Hz,3H).13C NMR(151MHz,DMSO-d6):δ173.0,171.2,170.9,139.8,137.6,130.5,128.7,127.2,126.9,125.0,124.9,122.8,121.5,120.9,120.7,120.6,119.6,116.1,115.2,113.6,109.8,95.0,83.3,82.4,60.4,47.8,32.8,30.9,29.2,26.8,26.7,22.0,14.0.
化合物4:黄色固体。HRESIMS found m/z 579.2612[M+H]+(calcd for C34H35N4O5,579.2607).1H NMR(600MHz,DMSO-d6):δ11.14(s,1H),9.26(d,J=8.0Hz,1H),9.08(d,J=8.0Hz,1H),8.03(d,J=8.0Hz,1H),7.72(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.55(t,J=8.0Hz,1H),7.45–7.37(m,2H),7.05(dd,J=8.8,6.0Hz,1H),5.05(ddd,J=13.1,4.6,2.4Hz,1H),4.25–4.22(m,1H),2.79(s,3H),2.75–2.68(m,1H),2.66(s,3H),2.36(s,3H),2.33(td,J=7.2,1.7Hz,2H),2.27(td,J=13.1,6.0Hz,1H),1.58–1.51(m,2H),1.35–1.25(m,4H),0.91–0.84(m,3H).13C NMR(151MHz,DMSO-d6):δ173.0,171.2,170.9,139.8,137.6,130.5,128.7,127.2,126.9,125.0,124.9,122.8,121.5,120.9,120.7,120.6,119.6,116.1,115.2,113.6,109.8,95.0,83.3,82.4,60.4,47.8,33.1,31.1,30.9,29.2,26.8,24.3,22.1,14.0.
化合物5:黄色固体。HRESIMS found m/z 593.2764[M+H]+(calcd for C35H37N4O5,593.2764).1H NMR(600MHz,DMSO-d6):δ11.14(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.46–7.37(m,2H),7.06(dd,J=8.8,6.1Hz,1H),5.05(ddd,J=13.1,4.6,2.4Hz,1H),4.26–4.22(m,1H),2.80(s,3H),2.75–2.69(m,1H),2.68(s,3H),2.37(s,3H),2.34(td,J=7.2,2.0Hz,2H),2.27(td,J=13.1,6.1Hz,1H),1.54(p,J=7.2Hz,2H),1.34–1.20(m,6H),0.90–0.83(m,3H).13C NMR(151MHz,DMSO-d6):δ173.0,171.2,170.9,139.8,137.7,130.5,128.7,127.2,126.9,125.0,124.9,122.8,121.4,120.9,120.7,120.6,119.6,116.1,115.2,113.6,109.9,95.0,83.3,82.4,60.4,47.8,33.1,31.3,30.9,29.2,28.6,26.8,24.5,22.2,14.1.
化合物6:黄色固体。HRESIMS found m/z 607.2926[M+H]+(calcd for C36H39N4O5607.2920).1H NMR(600MHz,DMSO-d6):δ11.14(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.03(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.45–7.37(m,2H),7.05(dd,J=8.8,6.1Hz,1H),5.05(ddd,J=13.1,4.6,2.5Hz,1H),4.26–4.21(m,1H),2.80(s,3H),2.74–2.68(m,1H),2.67(s,3H),2.37(s,3H),2.35–2.31(m,2H),2.27(td,J=13.1,6.1Hz,1H),1.54(p,J=7.2Hz,2H),1.31–1.22(m,8H),0.88–0.82(m,3H).13C NMR(151MHz,DMSO-d6):δ173.0,171.2,170.9,139.8,137.7,130.5,128.7,127.2,126.9,125.0,124.9,122.8,121.4,120.9,120.7,120.6,119.6,116.1,115.2,113.6,109.9,95.0,83.3,82.4,60.4,47.8,33.1,31.3,30.9,29.2,28.9,28.7,26.8,24.6,22.2,14.1.
化合物7:黄色固体。HRESIMS found m/z 549.2138[M+H]+(calcd for C32H29N4O5549.2138).1H NMR(600MHz,DMSO-d6):δ11.13(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.02(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.55(t,J=8.0Hz,1H),7.46–7.37(m,2H),7.05(dd,J=8.8,6.1Hz,1H),5.02(ddd,J=13.0,4.5,2.5Hz,1H),4.28–4.23(m,1H),2.98(s,3H),2.79–2.71(m,1H),2.70(s,3H),2.35(s,3H),2.30(td,J=13.0,6.1Hz,1H),1.99–1.91(m,1H),0.93–0.73(m,4H).13C NMR(151MHz,DMSO-d6):δ173.3,171.1,170.9,139.9,137.7,130.5,128.7,127.2,126.8,124.9,124.9,122.8,121.4,120.9,120.7,120.6,119.6,116.1,115.2,113.6,109.8,95.0,83.2,82.4,60.4,48.3,31.0,29.2,26.8,11.3,7.5,7.1.
化合物8:黄色固体。HRESIMS found m/z 591.1694[M+H]+(calcd for C33H27N4O5S591.1702).1H NMR(600MHz,DMSO-d6):δ11.14(s,1H),9.27(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.06(d,J=8.0Hz,1H),7.83(d,J=5.0Hz,1H),7.73(d,J=8.0Hz,1H),7.65–7.54(m,3H),7.46–7.38(m,2H),7.18(s,1H),7.13–7.03(m,1H),5.01(s,1H),4.48(s,1H),3.06(s,3H),2.96–2.87(m,1H),2.68(s,3H),2.46–2.27(m,4H).13C NMR(151MHz,DMSO-d6):δ171.1,170.9,164.1,139.8,137.9,137.7,130.6,130.4,129.7,128.8,127.5,127.2,126.9,125.0,125.0,122.8,121.5,121.0,120.7,120.7,119.6,116.1,115.2,113.5,109.8,95.0,83.4,82.4,60.3,48.7,33.6,29.1,27.0.
化合物9:橙色固体。HRESIMS found m/z 629.2032[M+H]+(calcd for C36H29N4O7629.2036).1H NMR(600MHz,Chloroform-d):δ9.39(d,J=8.0Hz,1H),9.25(d,J=8.0Hz,1H),7.77(d,J=8.0Hz,1H),7.61(t,J=8.0Hz,1H),7.57–7.52(m,2H),7.47(t,J=8.0Hz,1H),7.44(t,J=8.0Hz,1H),7.32(d,J=8.0Hz,1H),6.96(s,1H),6.93(s,1H),6.86(s,1H),6.78(s,1H),6.03(s,2H),5.21(s,1H),4.22(s,1H),2.92(s,3H),2.82(s,1H),2.78–2.69(m,1H),2.56(s,3H),2.44(s,3H).13C NMR(151MHz,Chloroform-d):δ171.9,169.9,169.7,149.2,147.8,139.5,137.9,131.6,130.2,129.4,127.2,127.1,126.5,126.3,123.8,122.6,121.9,121.4,121.3,121.0,119.6,117.4,116.7,116.5,113.4,111.7,108.4,101.7,94.9,84.9,82.6,60.5,49.8,34.5,29.0,28.1.
化合物10:黄色固体。HRESIMS found m/z 563.2291[M+H]+(calcd for C33H31N4O5563.2294).1H NMR(600MHz,DMSO-d6):δ11.14(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.05(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.46–7.38(m,2H),7.07(dd,J=8.7,6.2Hz,1H),5.97(s,1H),5.09–4.98(m,1H),4.31(s,1H),2.82(s,3H),2.79–2.72(m,1H),2.70(s,3H),2.39(s,3H),2.29(td,J=13.0,6.2Hz,1H),1.94(s,3H),1.83(s,3H).13C NMR(151MHz,DMSO-d6):δ171.1,170.9,167.8,146.9,139.9,137.7,130.5,128.7,127.2,126.8,124.9,124.9,122.8,121.4,120.9,120.7,120.7,119.6,118.2,116.1,115.2,113.7,109.9,95.0,83.3,82.4,60.4,47.7,31.6,29.3,26.8,26.1,20.0.
化合物11:黄色固体。HRESIMS found m/z 611.2292[M+H]+(calcd for C37H31N4O5611.2294).1H NMR(600MHz,DMSO-d6):δ11.15(s,1H),9.26(d,J=8.0Hz,1H),9.10(d,J=8.0Hz,1H),8.05(d,J=8.0Hz,1H),7.78–7.71(m,3H),7.65–7.60(m,2H),7.56(t,J=8.0Hz,1H),7.47–7.37(m,5H),7.25(d,J=15.4Hz,1H),7.10(dd,J=8.8,6.1Hz,1H),5.18(ddd,J=13.0,4.7,2.5Hz,1H),4.36(s,1H),3.03(s,3H),2.83–2.78(m,1H),2.70(s,3H),2.41(s,3H),2.37(td,J=13.0,6.1Hz,1H).13C NMR(151MHz,DMSO-d6):δ171.2,170.9,166.4,142.3,139.8,137.7,135.1,130.6,129.8,129.0,128.9,128.8,128.2,128.2,127.2,126.9,125.0,124.9,122.8,121.5,120.9,120.7,120.7,119.6,118.7,116.1,115.2,113.6,109.9,95.0,83.3,82.4,60.4,48.4,31.2,29.2,26.8.
化合物12:黄色固体。HRESIMS found m/z 581.2037[M+H]+(calcd for C32H29N4O7581.2036).1H NMR(600MHz,DMSO-d6):δ12.09(s,1H),11.14(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.03(d,J=8.0Hz,1H),7.75(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.45–7.38(m,2H),7.09–7.04(m,1H),5.01(ddd,J=13.1,4.5,2.5Hz,1H),4.23(s,1H),2.83(s,3H),2.75–2.67(m,4H),2.63–2.55(m,3H),2.46–2.43(m,1H),2.36(s,3H),2.29(td,J=13.1,6.2Hz,1H).13C NMR(151MHz,DMSO-d6):δ174.1,172.0,171.1,170.9,139.8,137.7,130.5,128.7,127.2,126.9,125.0,124.9,122.8,121.4,120.9,120.7,120.6,119.6,116.1,115.2,113.6,109.8,95.0,83.2,82.4,60.4,48.1,30.8,29.3,29.0,28.4,26.8.
化合物13:黄色固体。HRESIMS found m/z 595.2189[M+H]+(calcd for C33H31N4O7595.2193).1H NMR(600MHz,DMSO-d6):δ11.13(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.43(t,J=8.0Hz,1H),7.40(t,J=8.0Hz,1H),7.06(dd,J=8.8,6.1Hz,1H),5.06(ddd,J=13.1,4.5,2.4Hz,1H),4.26(s,1H),2.80(s,3H),2.76–2.70(m,1H),2.68(s,3H),2.42–2.38(m,2H),2.38(s,3H),2.31(t,J=7.4Hz,2H),2.27(td,J=13.1,6.1Hz,1H),1.78(p,J=7.4Hz,2H).13C NMR(151MHz,DMSO-d6):δ174.4,172.5,171.2,170.9,139.8,137.6,130.6,128.7,127.2,126.9,125.0,124.9,122.8,121.4,120.9,120.7,120.6,119.6,116.1,115.2,113.6,109.8,95.0,83.3,82.4,60.4,47.8,33.0,32.3,30.8,29.2,26.8,20.1.
化合物14:黄色固体。HRESIMS found m/z 613.1761[M+H]+(calcd forC32H29N4O7S 613.1757).1H NMR(600MHz,DMSO-d6):δ11.13(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.05(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.57(t,J=8.0Hz,1H),7.46–7.38(m,2H),7.07(dd,J=8.8,6.0Hz,1H),5.00(ddd,J=13.0,4.5,2.4Hz,1H),4.26(s,1H),3.66–3.56(m,2H),3.45–3.37(m,2H),2.86(s,3H),2.80–2.72(m,1H),2.70(s,3H),2.38(s,3H),2.29(td,J=13.0,6.0Hz,1H).13CNMR(151MHz,DMSO-d6):δ171.2,171.1,170.9,169.1,139.8,137.7,130.5,128.7,127.2,126.9,125.0,125.0,122.7,121.4,120.9,120.7,120.6,119.6,116.1,115.2,113.5,109.9,95.0,83.1,82.4,60.4,48.4,34.2,33.3,31.4,29.2,26.5.
化合物15:黄色固体。HRESIMS found m/z 609.2347[M+H]+(calcd for C34H33N4O7609.2349).1H NMR(600MHz,Methanol-d4):δ9.25(d,J=8.0Hz,1H),9.04(d,J=8.0Hz,1H),7.83(d,J=8.0Hz,1H),7.53–7.48(m,2H),7.39(d,J=8.0Hz,1H),7.34–7.29(m,2H),6.76(dd,J=9.4,4.4Hz,1H),5.15(ddd,J=13.2,5.6,1.8Hz,1H),4.01(s,1H),2.86(s,3H),2.74–2.67(m,1H),2.46–2.41(m,3H),2.40(s,3H),2.37(s,3H),2.34(t,J=6.7Hz,2H),1.71–1.63(m,4H).13C NMR(151MHz,Methanol-d4):δ177.2,175.8,172.4,172.2,140.7,139.0,132.4,130.7,127.8,127.7,126.7,126.5,124.6,123.2,121.8,121.6,121.5,120.4,117.9,116.8,113.2,109.7,96.0,85.5,83.8,60.5,49.8,34.5,34.3,31.6,29.1,28.5,25.5,25.4.
化合物16:黄色固体。HRESIMS found m/z 637.2671[M+H]+(calcd for C36H37N4O7637.2662).1H NMR(600MHz,DMSO-d6):δ11.96(s,1H),11.13(s,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.73(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.43(t,J=8.0Hz,1H),7.40(t,J=8.0Hz,1H),7.06(dd,J=8.6,6.3Hz,1H),5.06(ddd,J=13.5,4.4,2.4Hz,1H),4.25(s,1H),2.81(s,3H),2.75–2.69(m,1H),2.68(s,3H),2.37(s,3H),2.36–2.32(m,2H),2.29–2.24(m,1H),2.21(t,J=7.3Hz,2H),1.59–1.53(m,2H),1.53–1.47(m,2H),1.35–1.25(m,4H).13C NMR(151MHz,DMSO-d6):δ174.6,172.9,171.2,170.9,139.9,137.7,130.5,128.7,127.2,126.9,125.0,124.9,122.8,121.4,120.9,120.7,120.6,119.6,116.1,115.2,113.5,109.8,95.0,83.3,82.4,60.4,47.8,33.7,33.0,30.9,29.2,28.5,28.5,26.8,24.5,24.4.
化合物17:黄色固体。HRESIMS found m/z 596.2145[M+H]+(calcd for C32H30N5O7596.2145).1H NMR(600MHz,DMSO-d6):δ11.14(s,1H),10.43(d,J=1.4Hz,1H),9.26(d,J=8.0Hz,1H),9.09(d,J=8.0Hz,1H),8.70(d,J=1.4Hz,1H),8.03(d,J=8.0Hz,1H),7.74(d,J=8.0Hz,1H),7.62(t,J=8.0Hz,1H),7.56(t,J=8.0Hz,1H),7.46–7.37(m,2H),7.06(dd,J=8.8,6.0Hz,1H),5.03(ddd,J=13.5,4.6,2.4Hz,1H),4.24–4.18(m,1H),2.82(s,3H),2.76–2.66(m,4H),2.64–2.55(m,3H),2.36(s,3H),2.32–2.25(m,2H).13C NMR(151MHz,DMSO-d6):δ172.0,171.2,170.9,168.7,139.8,137.7,130.6,128.7,127.2,126.9,125.0,124.9,122.8,121.5,121.0,120.7,120.7,119.6,116.1,115.2,113.5,109.9,95.0,83.3,82.4,60.4,48.0,30.8,29.2,28.5,27.4,26.8.
化合物18:黄色固体。HRESIMS found m/z 646.2413[M+H]+(calcd for C35H32N7O6646.2414).1H NMR(600MHz,Methanol-d4):δ9.28(d,J=8.0Hz,1H),9.08(d,J=8.0Hz,1H),7.83(d,J=8.0Hz,1H),7.58–7.49(m,3H),7.43(d,J=8.0Hz,1H),7.34(t,J=8.0Hz,2H),6.80(dd,J=9.1,4.3Hz,1H),6.51(s,1H),5.15(dd,J=13.4,5.5Hz,1H),4.07(s,1H),2.93(s,3H),2.81–2.70(m,5H),2.50–2.45(m,1H),2.45–2.43(m,3H),2.40(s,3H).13C NMR(151MHz,Methanol-d4):δ174.8,172.6,172.4,172.3,154.7,140.8,139.1,132.4,130.8,127.9,127.7,126.7,126.5,124.7,123.3,121.9,121.7,121.5,121.1,120.5,117.9,116.9,113.3,109.8,96.1,92.7,85.4,83.9,60.5,49.9,31.7,31.5,29.6,29.2,28.4.
实施例3.化合物的PIM-1激酶抑制活性和激酶选择性实验
PIM-1、TRKA、TRKB、FLT3、PKCδ、PKCε、PKCη、PAK4、PLK1、ROCK2、IKKβ激酶抑制活性均采用基于时间分辨荧光技术的KinEASETM激酶试剂盒测定。以7-羰基星孢菌素(7OSTA)和TP-3654作为阳性对照,平行设置3个复孔。具体操作步骤为:
①配制Kinase buffer,并用其配制待测化合物、阳性药、底物、激酶、ATP;
②在384孔微孔板中每孔依次加入2μL底物、2μL激酶(阴性对照组不加激酶)、4μL待测化合物或阳性药(阳性对照组加入4μL buffer,阴性对照组加入6μL buffer)、2μLATP,微孔板封膜后离心混匀;
③根据不同激酶类型在37℃培养箱中孵育特定时间;
④用XL-665、抗体、detection buffer配制检测溶液,每孔加入10μL,微孔板封膜后离心混匀,并在室温下静置1小时;
⑤用多功能微孔板检测仪分别检测620nm和665nm波长下的荧光值强度F1和F2。计算信号比率=F2/F1×10000,然后用Graphpad Prism 8软件计算IC50值。
表1:化合物1-18与阳性对照的PIM-1激酶抑制活性(IC50/nM)
化合物 | PIM-1 | 化合物 | PIM-1 |
1 | 41.0 | 11 | >1000 |
2 | 83.0 | 12 | 42.9 |
3 | >1000 | 13 | 39.1 |
4 | >1000 | 14 | 53.8 |
5 | >1000 | 15 | 61.1 |
6 | >1000 | 16 | 65.9 |
7 | 444.7 | 17 | 5.9 |
8 | 52.4 | 18 | 32.4 |
9 | >1000 | 7OSTA(对照) | 5.4 |
10 | 81.4 | TP-3654(对照) | 31.1 |
表2:化合物17和7OSTA的激酶选择性(IC50/nM)
激酶 | 化合物17 | 7OSTA |
PIM-1 | 5.9 | 5.4 |
TRKA | 4.0 | 0.4 |
FLT3 | 5.3 | 15.3 |
PKCδ | 10.4 | 1.4 |
TRKB | 13.6 | 2.4 |
PKCε | 69.0 | 2.3 |
PKCη | 73.2 | 2.1 |
PAK4 | 240.2 | 37.0 |
PLK1 | 420.9 | 308.1 |
ROCK2 | 561.7 | 35.9 |
IKKβ | >1000 | >1000 |
结果表明,本发明合成的大部分7-羰基星孢菌素衍生物对PIM-1激酶具有很好的抑制作用,尤其是化合物17对PIM-1激酶抑制作用显著,IC50为5.9nM,效果优于阳性对照药TP-3654(IC50为31.1nM)。另外,将化合物17和7OSTA对TRKA、TRKB、FLT3、PKCδ、PKCε、PKCη、PAK4、PLK1、ROCK2、IKKβ激酶的抑制活性进行检测,发现化合物17具有优异的PIM-1激酶选择性抑制能力,说明该化合物可用于进一步开发PIM-1选择性抑制剂。
最后,还需要说明的是,术语“包括”、“包含”或者其任何其他变体意在涵盖非排他性的包含,从而使得包括一系列要素的过程、方法、物品或者设备不仅包括那些要素,而且还包括没有明确列出的其他要素,或者是还包括为这种过程、方法、物品或者设备所固有的要素。
尽管已描述了本发明的优选实施例,但本领域内的技术人员一旦得知了基本创造性概念,则可对这些实施例做出另外的变更和修改。所以,所附权利要求意欲解释为包括优选实施例以及落入本发明范围的所有变更和修改。
显然,本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样,倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内,则本发明也意图包含这些改动和变型在内。
Claims (10)
1.7-羰基星孢菌素衍生物或其可药用的盐,其特征在于,所述7-羰基星孢菌素衍生物具有如下式(I)所示结构:
式(I)中:
L选自-(CH2)n-、-(CH2)nNH-、-(CH2)nO-、-(CH2)nC(=O)O-、-(CH2)nC(=O)NH-、-(CH2)nS-、-(CH2)nS(=O)-、-(CH2)nS(=O)2-、-(OCH2CH2O)n-、-(CH2CH2O)n-、-(OCH2CH2OCH2)n-、-(CH2CH2OCH2)n-、-(CH2CH2OCH2CH2)n-、亚烯基、亚炔基、亚环烷基、亚杂芳烃基或它们的任意组合,其中n表示1至10的自然数;
R选自H、卤素、羟基、氨基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C3-10环烃基、3-10元杂环基、-C(=O)R1、-OC(=O)R1、-C(=O)OR1、-OR1、-SR1、-S(=O)R1、-S(=O)2R1、-S(=O)2NR1R2、-NR1R2、-C(=O)NR1R2、-NR1C(=O)R2、-NR1C(=O)OR2、-NR1S(=O)2R2、-NR1C(=O)NR1R2、-C1-6亚烷基-NR1R2、-C1-6亚烷基-O(P=O)(OH)2和-O-C1-6亚烷基-NR1R2;
上述烷基、亚烷基、烯基、炔基、环烃基、杂环基、在每次出现时各自任选地被一个或多个独立地选自下列的取代基取代:卤素、羟基、氧代、氨基、氰基、硝基、C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烃基、3-10元杂环基、=N-OR1、-C(=NH)NH2、-C(=O)R1、-OC(=O)R1、-C(=O)OR1、-OR1、-SR1、-S(=O)R1、-S(=O)2R1、-S(=O)2NR1R2、-NR1R2、-C(=O)NR1R2、-NR1C(=O)R2、-NR1C(=O)OR2、-NR1S(=O)2R2、-NR1C(=O)NR1R2、-C1-6亚烷基-NR1R2、-O-C1-6亚烷基-NR1R2;
R1和R2在每次出现时各自独立地选自H、C1-6烷基、C3-10环烃基和3-10元杂环基;或者当R1和R2与同一氮原子连接时,R1和R2连同其所连接的原子任选地共同构成3-12元杂环。
3.一种药物组合物,其特征在于,包含权利要求1或2所述的7-羰基星孢菌素衍生物或其可药用的盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
4.根据权利要求1或2所述的7-羰基星孢菌素衍生物或其可药用的盐或根据权利要求3所述的药物组合物在制备用于抑制PIM-1激酶的药物中的应用。
5.根据权利要求1或2所述的7-羰基星孢菌素衍生物或其可药用的盐或根据权利要求3所述的药物组合物在制备用于治疗和/或预防与PIM-1激酶异常活性相关的疾病的药物中的应用。
6.根据权利要求5所述的应用,其特征在于,所述疾病为癌症。
7.根据权利要求6所述的应用,其特征在于,所述癌症为白血病、淋巴瘤、多发性骨髓瘤、乳腺癌、子宫内膜癌、卵巢癌、阴道癌、输卵管癌、宫颈癌、肾癌、膀胱癌、尿路上皮癌、尿道癌、前列腺癌、睾丸癌、结直肠癌、肉瘤、骨癌、粘液瘤、横纹肌瘤、平滑肌瘤、纤维瘤、脂肪瘤、畸胎瘤、咽喉癌、鼻咽癌、口腔癌、肺癌、肺泡癌、间皮瘤、小肠癌、胃癌、食道癌、胰腺癌、肝癌、胆管癌、神经纤维瘤、神经胶质瘤、神经母细胞瘤、成神经细胞瘤、黑色素瘤、皮肤癌、基底细胞癌、鳞状细胞癌、甲状腺癌、头颈癌、唾液腺癌或胃肠道间质瘤。
8.根据权利要求7所述的应用,其特征在于,所述结直肠癌为结肠癌或直肠癌。
9.根据权利要求7所述的应用,其特征在于,所述肉瘤为软骨肉瘤。
10.根据权利要求2所述的7-羰基星孢菌素衍生物的制备方法,其特征在于,以7-羰基星孢菌素为初始底物,合成路线如下:
采用酰卤法合成化合物1-11:将初始底物分别和具有不同基团的酰氯在N,N-二异丙基乙胺和氯仿,或者,N,N-二异丙基乙胺和无水N,N-二甲基甲酰胺的混合环境中反应,分别得到化合物1-11;
采用酸酐法合成化合物12-15:将初始底物分别和不同的酸酐在4-二甲氨基吡啶和二甲基亚砜的混合环境中反应,分别得到化合物12-15;
采用鎓盐类缩合剂法合成化合物16:将初始底物和辛二酸在N,N-二异丙基乙胺、N,N-二甲基甲酰胺、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯的混合环境中反应,得到化合物16;
采用CDI缩合剂法合成化合物17:将化合物12先在N,N'-羰基二咪唑和N,N-二甲基甲酰胺的混合环境中反应,再加入盐酸羟胺继续反应,得到化合物17;
将化合物12和3-氨基吡唑在N,N-二异丙基乙胺、N,N-二甲基甲酰胺、2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯的混合环境中反应,得到化合物18。
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