CN113717158A - 2-(n-(吡啶-2-基)氨基)喹啉衍生物及其应用 - Google Patents
2-(n-(吡啶-2-基)氨基)喹啉衍生物及其应用 Download PDFInfo
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- CN113717158A CN113717158A CN202110977008.3A CN202110977008A CN113717158A CN 113717158 A CN113717158 A CN 113717158A CN 202110977008 A CN202110977008 A CN 202110977008A CN 113717158 A CN113717158 A CN 113717158A
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- amino
- hydrogen atom
- pyridin
- cancer
- halogen atom
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- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
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Abstract
本发明的目的是提供新型2‑(N‑(吡啶‑2‑基)氨基)喹啉衍生物及其制备方法,以及该类化合物在制备预防和/或治疗肿瘤药物中的应用。通式(Ⅰ)所示的化合物或其药学上可接受的盐:其中,R1为氢原子,卤素原子或者取代的芳香基;R2为氢原子或者卤素原子;R3为氢原子,卤素原子,C1‑2烷基或者取代的杂环基;R4为氢原子,取代或者未取代的羟基;本发明的衍生物可以与其他活性成分组合使用,只要它们不产生其他不利的作用。本发明的药物组合物可配制成若干种剂型,其中含有药物领域中常用的一些赋型剂,用于本发明药物组合物的载体是药物领域中可得到的常见类型,本发明活性化合物可作为唯一的抗癌药物使用,或者与一种或多种其它抗肿瘤药物联合使用。
Description
技术领域:
本发明属于医药技术领域,具体涉及具有抗肿瘤活性的2-(N-(吡啶-2-基)氨基)喹啉衍生物及其药学上可接受的盐,这些化合物的制备方法,以该类衍生物为活性成分的药物组合物,以及在制备治疗和/或预防各种癌症的药物中的用途。
背景技术:
癌症是目前除心血管疾病之外死亡率最高的疾病,已成为世界范围的一个主要公共卫生问题。由于人口老龄化趋势、环境污染加剧、不良生活习惯等诸多原因,全球癌症的发病率和死亡率仍在逐年攀升。美国癌症研究协会年度报告指出2040年全球癌症患者总数将达到2750万,并且有1630万患者因此去世。世界卫生组织资料统计,癌症治疗过程中花销巨大已经使其成为大量贫困人口出现的重要原因,因此癌症的预防和治疗工作任重而道远。
癌症的治疗策略包括手术切除、放疗、化疗以及靶向药物治疗。手术切除和放疗是早、中期肿瘤局部治疗的有效方法,但对于中、晚期恶性肿瘤往往因局部治疗不彻底而导致残留病灶复发或远处转移使病情进一步加重。化疗是目前晚期癌症全身性治疗的重要方法之一,某些肿瘤通过化疗已经可以达到根治的目的。常用的细胞毒化疗药物包括烷化剂、抗代谢药、生物碱等,患者服用该类药物进行治疗,虽然生存期得到了延长,却需要承受药物带来的严重毒副作用。药物靶向治疗是当前肿瘤治疗领域的研究热点,靶向药物通过作用于肿瘤特异性分子靶标实现选择性杀伤癌细胞,而避免对人体正常细胞的伤害。例如,CYP17选择性抑制剂醋酸阿比特龙(Abiraterone acetate)和雄激素受体拮抗剂恩杂鲁胺(Enzalutamide)是FDA批准的两个前列腺癌靶向治疗药物,临床试验结果显示相比于传统的化疗药物,二者具有更好的治疗效果以及安全性,凸显出药物靶向治疗的优势。随着人们对癌症相关信号通路的不断深入研究,越来越多的蛋白分子被报道有望成为癌症的治疗靶标。例如血管内皮生长因子受体和肝细胞生长因子受体的酪氨酸激酶抑制剂卡博替尼(Cabozantinib)、肉瘤病毒基因酪氨酸激酶抑制剂达沙替尼(Dasatinib)、雷帕霉素靶蛋白抑制剂坦西莫司(Temsirolimus)、抗凋亡蛋白Bcl-2抑制剂Oblimersen以及组蛋白去乙酰酶抑制剂伏立诺他(Vorinostat)等多个靶向药物已经上市或进入II/III期临床研究阶段。
喹啉衍生物具有特殊的理化性质和生物学活性,在抗炎、抗菌、抗病毒和抗肿瘤方面得到广泛的应用。本发明人设计并合成了一系列2-(N-(吡啶-2-基)氨基)喹啉衍生物,经细胞水平活性评价,所合成的化合物具有较好的抗肿瘤细胞增殖活性。
发明内容:
本发明的目的是提供新型2-(N-(吡啶-2-基)氨基)喹啉衍生物及其制备方法,以及该类化合物在制备预防和/或治疗肿瘤药物中的应用。
本发明涉及通式(Ⅰ)所示的化合物或其药学上可接受的盐:
其中,
R1为氢原子,卤素原子或者取代的芳香基;
R2为氢原子或者卤素原子;
R3为氢原子,卤素原子,C1-2烷基或者取代的杂环基;
R4为氢原子,取代或者未取代的羟基;
限定条件是当R1为氢原子或者卤素原子时,R3不能为氢原子、卤素原子或者C1-2烷基。
优选为:
其中,
R2为氢原子或者卤素原子;
R4为氢原子,取代或者未取代的羟基;
R6、R7为氢原子,C1-2烷基,取代或者非取代的氨基;
X为CH或者氮原子
Y为CH2、O、NH或者NCH3;
n为0-2的整数;
限定条件是当R1为氢原子或者卤素原子时,R3不能为氢原子、卤素原子或者C1-2烷基。
进一步优选为:
其中,
R2为氢原子或者卤素原子;
R4为氢原子,取代或者未取代的羟基;
R6、R7为氢原子,取代或者非取代的氨基;
Y为CH2、O、NH或者NCH3;
n为0~2的整数;
限定条件是当R1为氢原子或者卤素原子时,R3不能为氢原子、卤素原子或者C1-2烷基。
进一步优选为:
其中,
特别优选的化合物包括:
(S)-2-(N-(4-(3-氨基哌啶-1-基)吡啶-2-基)氨基)喹啉
(R)-2-(N-(4-(3-氨基哌啶-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-吗啉基吡啶-2-基)氨基)喹啉
2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-哌啶基吡啶-2-基)氨基)喹啉
2-(N-(4-(哌嗪-1-基)吡啶-2-基)氨基)喹啉
(S)-2-(N-(4-(3-氨基吡咯烷-1-基)吡啶-2-基)氨基)喹啉
(R)-2-(N-(4-(3-氨基吡咯烷-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-(1,4-二氮杂庚烷-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-(4-甲基-1,4-二氮杂庚烷-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-5-氯-8-甲氧基喹啉
2-(N-(4-吗啉基吡啶-2-基)氨基)-5-氯-8-甲氧基喹啉
2-(N-(4-吗啉基吡啶-2-基)氨基)-5,7-二氯-8-甲氧基喹啉
2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-5,7-二氯-8-甲氧基喹啉
2-(N-(4-哌啶基吡啶-2-基)氨基)-5,7-二氯-8-甲氧基喹啉
(S)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基哌啶-1-基)羰基)苯基喹啉
(R)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基哌啶-1-基)羰基)苯基喹啉
2-(N-(吡啶-2-基)氨基)-7-(3-(吗啉-4-基)羰基)苯基喹啉
2-(N-(吡啶-2-基)氨基)-7-(3-(4-甲基哌嗪-1-基)羰基)苯基喹啉
2-(N-(吡啶-2-基)氨基)-7-(3-(哌啶-1-基)羰基)苯基喹啉
2-(N-(吡啶-2-基)氨基)-7-(3-(哌嗪-1-基)羰基)苯基喹啉
(R)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基吡咯烷-1-基)羰基)苯基喹啉
除非另外指出,本发明所用的术语“卤素”是指氟、氯、溴或碘,优选氯和溴;“烷基”是指直链或支链的烷基。
本发明包括药物组合物,该组合物含有通式(I)的2-(N-(吡啶-2-基)氨基)喹啉衍生物及其药物上可接受的赋型剂。所述药物上可接受的赋型剂是指任何可用于药物领域的稀释剂、辅助剂和/或载体。本发明的衍生物可以与其他活性成分组合使用,只要它们不产生其他不利的作用,例如过敏反应。
本发明的药物组合物可配制成若干种剂型,其中含有药物领域中常用的一些赋型剂,例如,口服制剂(如片剂,胶囊剂,溶液或混悬液);可注射的制剂(如可注射的溶液或混悬液,或者是可注射的干燥粉末,在注射前加入注射用水可立即使用);局部制剂(例如软膏或溶液)。
用于本发明药物组合物的载体是药物领域中可得到的常见类型,包括:口服制剂用的粘合剂、润滑剂、崩解剂、助溶剂、稀释剂、稳定剂、悬浮剂、色素、矫味剂等;可注射制剂用的防腐剂、加溶剂、稳定剂等;局部制剂用的基质、稀释剂、润滑剂、防腐剂等。药物制剂可以经口服或胃肠外方式(例如静脉内、皮下、腹膜内或局部)给药,如果某些药物在胃部条件下是不稳定的,可将其配制成肠衣片剂。
通过体外活性筛选,我们发现本发明衍生物具有较好的抗肿瘤活性,因此本发明衍生物可以用于制备治疗和/或预防各种癌症的药物,如乳腺、肺、结肠、直肠、胃、前列腺、膀胱、子宫、胰腺和各种血液癌。
本发明活性化合物可作为唯一的抗癌药物使用,或者与一种或多种其它抗肿瘤药物联合使用。联合治疗通过将各个治疗组分同时、顺序或隔开给药来实现。
下文中提供的实施例和制备例进一步阐明和举例说明本发明化合物及其制备方法。应当理解,下述实施例和制备例的范围并不以任何方式限制本发明的范围。
合成路线一:
Scheme 1.Synthesis of 4a–i.Reagents and conditions:a)m-CPBA,CHCl3,r.t.,16h;b)2-amino-4-fluoropyridine,p-TsCl,10%KOH,CH2Cl2,r.t.,5h;c)nitrogenheterocycles,DIEA,CH3CH2OH,80℃,10h;d)nitrogen heterocycles,DIEA,CH3CH2OH,80℃,10h;TFA,CH2Cl2,25℃,2h.
合成路线二:
Scheme 2.Synthesis of 10a–e.Reagents and conditions:a)methyl iodide,K2CO3,acetone,r.t.to 60℃,8h;b)m-CPBA,CHCl3,r.t.,16h;c)2-amino-4-fluoropyridine,p-TsCl,10%KOH,CH2Cl2,r.t.,5h;d)nitrogen heterocycles,DIEA,CH3CH2OH,80℃,10h;e)concentrated HCl,100℃,10h.
合成路线三:
Scheme 3.Synthesis of 15a–e.Reagents and conditions:a)m-CPBA,CHCl3,r.t.,16h;b)2-aminopyridine,p-TsCl,10%KOH,CH2Cl2,r.t.,5h;c)3-boronobenzoicacid,Pd(OAc)2,PPh3,Na2CO3,n-propanol/H2O,90℃,6h;d)different nitrogenheterocycle,HATU,DMAP,DIEA,THF,25℃,4h;e)different nitrogen heterocycle,HATU,DMAP,DIEA,THF,25℃,4h;TFA,CH2Cl2,r.t.,2h.
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。凡基于本发明上述内容所实现的技术均属于本发明的范围。
实施例1:(S)-2-(N-(4-(3-氨基哌啶-1-基)吡啶-2-基)氨基)喹啉的制备
步骤A:喹啉氮氧化物的制备
将喹啉(3.51g,27mmol)溶于100mL氯仿中,冷却至0℃后分批加入间氯过氧苯甲酸(9.49g,55mmol),搅拌30分钟。转移至25℃反应16小时,TLC监测反应。反应完全后,用饱和碳酸氢钠溶液淬灭反应,分离有机相。水相用二氯甲烷(50mL×3)萃取,合并有机相,饱和食盐水洗一次,无水硫酸钠干燥5小时。过滤后减压蒸干溶剂,柱层析分离纯化得棕色固体。收率为90%。
步骤B:2-(N-(4-氟吡啶-2-基)氨基)喹啉的制备
将喹啉氮氧化物(1.45g,10mmol)溶于60mL二氯甲烷中,加入对甲苯磺酰氯(1.9g,10mmol)和2-氨基-4-氟吡啶(1.15g,10mmol),室温搅拌30分钟。加入40mL 10%的氢氧化钾溶液,继续搅拌5小时,TLC监测反应。反应完成后,分离有机相,水相用二氯甲烷(50mL×2)萃取,合并有机相,无水硫酸钠干燥5个小时。过滤后减压浓缩,柱层析纯化后得到浅黄色固体。收率为56%。
步骤C:(S)-2-(N-(4-(3-Boc-氨基哌啶-1-基)吡啶-2-基)氨基)喹啉的制备
将2-(N-(4-氟吡啶-2-基)氨基)喹啉(478mg,2mmol)溶于50mL无水乙醇中,室温搅拌下加入N,N-二异丙基乙胺(DIEA,1.4mL,8mmol)和(S)-3-Boc-氨基哌啶(800mg,4mmol),氮气保护。加热至80℃继续反应10小时,TLC监测反应。反应完成后,冷却至室温减压浓缩,加入适量水用乙酸乙酯萃取3次(20mL×3),合并有机层,饱和NaCl溶液洗一次,无水硫酸钠干燥。减压浓缩后柱层析纯化得到白色固体。收率65%。
步骤D:(S)-2-(N-(4-(3-氨基哌啶-1-基)吡啶-2-基)氨基)喹啉的制备
将(S)-2-(N-(4-(3-Boc-氨基哌啶-1-基)吡啶-2-基)氨基)喹啉(210mg,0.5mmol)溶于8mL干燥的二氯甲烷中,室温下缓慢滴加1mL三氟乙酸溶液,继续搅拌2小时,TLC监测。反应完全后,减压浓缩,加入适量饱和碳酸氢钠溶液调节PH至9-10,析出白色固体,柱层析纯化。收率60%。
LC-MS m/z:320.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:9.71(br s,1H),8.19(s,1H),8.10-8.08(d,1H),7.91-7.90(d,1H),7.76-7.75(d,1H),7.73-7.71(d,1H),7.63-7.60(m,1H),7.53-7.51(d,1H),7.34-7.32(t,1H),6.51-6.49(m,1H),3.86-3.84(m,1H),3.77-3.74(m,1H),2.96-2.91(m,1H),2.89-2.86(m,1H),2.78-2.74(m,1H),1.95-1.91(m,1H),1.81-1.78(m,1H),1.59-1.53(m,1H),1.38-1.33(m,1H);13C NMR(DMSO-d6)δ:156.5,155.5,154.1,148.3,147.0,137.3,129.9,127.9,127.0,124.2,123.6,115.0,103.9,96.5,53.1,47.2,46.7,32.0,23.0.
实施例2:(R)-2-(N-(4-(3-氨基哌啶-1-基)吡啶-2-基)氨基)喹啉的制备
按照实施例1的制备方法,制备标题化合物。LC-MS m/z:320.3[M+H]+;1H NMR(600MHz,DMSO-d6)δ:9.70(br s,1H),8.18(d,1H),8.09-8.08(d,1H),7.91-7.90(d,1H),7.76-7.75(d,1H),7.72-7.71(d,1H),7.62-7.60(m,1H),7.53-7.52(d,1H),7.34-7.32(t,1H),6.50-6.49(dd,1H),3.87-3.84(m,1H),3.77-3.75(m,1H),2.94-2.89(m,1H),2.84-2.82(m,1H),2.74-2.71(m,1H),1.94-1.91(m,1H),1.80-1.77(m,1H),1.57-1.52(m,1H),1.37-1.32(m,1H).
实施例3:2-(N-(4-吗啉基吡啶-2-基)氨基)喹啉的制备
按照实施例1的制备方法,制备标题化合物。LC-MS m/z:307.3[M+H]+;1H NMR(600MHz,DMSO-d6)δ:9.81(br s,1H),8.16(s,1H),8.11-8.10(d,1H),7.96-7.95(d,1H),7.77-7.74(t,2H),7.63-7.60(t,1H),7.53-7.52(d,1H),7.35-7.33(t,1H),6.55-6.54(d,1H),3.79-3.78(t,4H),3.34-3.32(t,4H);13C NMR(DMSO-d6)δ:157.2,154.9,154.0,147.4,146.8,137.6,130.0,128.0,127.1,124.3,123.8,114.9,103.7,96.0,66.3,46.6.
实施例4:2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)喹啉的制备
按照实施例1的制备方法,制备标题化合物。LC-MS m/z:320.3[M+H]+;1H NMR(600MHz,DMSO-d6)δ:9.78(br s,1H),8.13(s,1H),8.11-8.09(d,1H),7.93-7.92(d,1H),7.76-7.75(d,1H),7.72-7.71(d,1H),7.63-7.60(m,1H),7.54-7.53(d,1H),7.34-7.32(m,1H),6.54-6.52(dd,1H),3.38-3.36(m,4H),2.49-2.48(m,4H),2.25(s,3H);13C NMR(DMSO-d6)δ:156.8,155.3,154.1,148.0,147.0,137.4,130.0,128.0,127.0,124.3,123.6,114.9,103.9,96.3,54.6,46.2,46.1.
实施例5:2-(N-(4-哌啶基吡啶-2-基)氨基)喹啉的制备
按照实施例1的制备方法,制备标题化合物。LC-MS m/z:305.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:9.70(br s,1H),8.15(s,1H),8.10-8.08(d,1H),7.90-7.89(d,1H),7.76-7.75(d,1H),7.67-7.66(d,1H),7.62-7.60(t,1H),7.56-7.54(d,1H),7.34-7.31(t,1H),6.50-6.49(d,1H),3.40(s,4H),1.63(s,6H);13C NMR(DMSO-d6)δ:157.1,153.2,150.7,148.6,148.4,142.0,130.3,129.9,127.9,125.7,124.5,119.8,106.2,98.4,66.2,46.4.
实施例6:2-(N-(4-(哌嗪-1-基)吡啶-2-基)氨基)喹啉的制备
按照实施例1的制备方法,制备标题化合物。LC-MS m/z:306.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:9.84(br s,1H),8.21(s,1H),8.11-8.09(d,1H),7.99-7.98(d,1H),7.76-7.75(m,2H),7.62-7.59(m,1H),7.50-7.48(d,1H),7.35-7.32(m,1H),6.60-6.58(t,1H),3.55-3.53(t,4H),3.23-3.21(t,4H),1.23-1.21(t,1H);13C NMR(DMSO-d6)δ:158.7,156.3,155.3,154.0,146.9,137.6,130.0,128.0,127.1,124.3,123.8,114.9,104.2,96.7,44.0,43.0.
实施例7:(S)-2-(N-(4-(3-氨基吡咯烷-1-基)吡啶-2-基)氨基)喹啉的制备
按照实施例1的制备方法,制备标题化合物。LC-MS m/z:306.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:9.64(br s,1H),8.08-8.06(d,1H),7.86-7.84(m,2H),7.75-7.74(d,1H),7.70-7.67(m,1H),7.62-7.59(t,1H),7.50-7.49(d,1H),7.33-7.31(t,1H),6.13-6.12(m,1H),3.63(t,1H),3.51-3.46(m,2H),3.04-3.02(m,1H),2.12-2.09(m,1H),1.79-1.76(m,1H),1.28-1.18(m,1H);13C NMR(DMSO-d6)δ:154.7,154.2,153.5,147.7,147.1,137.2,129.9,128.0,126.9,124.2,123.4,115.0,102.3,94.8,55.8,51.2,45.9,34.4.
实施例8:(R)-2-(N-(4-(3-氨基吡咯烷-1-基)吡啶-2-基)氨基)喹啉的制备
按照实施例1的制备方法,制备标题化合物。LC-MS m/z:306.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:7.94-7.92(d,1H),7.91-7.89(d,1H),7.79-7.77(d,1H),7.73(s,1H),7.66-7.64(d,1H),7.61-7.57(t,1H),7.34-7.30(t,1H),7.22-7.20(d,1H),6.13-6.11(dd,1H),3.78-3.74(m,1H),3.66-3.57(m,2H),3.49-3.43(m,1H),3.16-3.12(m,1H),2.27-2.22(m,1H),1.88-1.83(m,1H);13C NMR(DMSO-d6)δ:153.9,153.7,153.3,146.9,146.4,137.4,129.5,127.5,126.9,124.3,123.5,114.2,102.3,94.6,55.8,51.2,45.8,34.7.
实施例9:2-(N-(4-(1,4-二氮杂庚烷-1-基)吡啶-2-基)氨基)喹啉的制备
按照实施例1的制备方法,制备标题化合物。
LC-MS m/z:320.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:9.11(br s,1H),8.40-8.38(d,1H),8.20-8.16(m,2H),7.93-7.92(d,1H),7.79-7.77(t,1H),7.53-7.51(t,1H),7.30-7.28(d,1H),6.93(m,1H),6.81(m,1H),3.92(s,2H),3.71(s,2H),3.24(m,2H),3.12-3.08(dd,2H),2.13(s,2H),1.23(m,1H).
实施例10:2-(N-(4-(4-甲基-1,4-二氮杂庚烷-1-基)吡啶-2-基)氨基)喹啉的制备
按照实施例1的制备方法,制备标题化合物。LC-MS m/z:334.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:9.68(br s,1H),8.09-8.07(d,2H),7.86-7.85(d,1H),7.76-7.74(d,1H),7.67-7.66(d,1H),7.62-7.60(m,1H),7.50-7.48(d,1H),7.34-7.31(m,1H),6.35-6.33(dd,1H),3.61(t,2H),3.56-3.54(t,2H),3.37-3.35(m,2H),2.72-2.71(t,2H),2.30(s,3H),1.99-1.97(dd,2H).
实施例11:2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-5-氯-8-甲氧基喹啉的制备
步骤A:5-氯-8-甲氧基喹啉的制备
将5-氯-8-羟基喹啉(1.8g,10mmol)溶于200mL丙酮中,加入研磨干燥的无水碳酸钾(2.7g,20mmol),室温搅拌30分钟。缓慢滴加碘甲烷(2.8g,20mmol),室温搅拌过夜,TLC监测反应。反应完成后,减压蒸去溶剂,加入适量水,二氯甲烷(150mL×3)萃取,合并有机相,饱和氯化钠溶液洗一次,无水硫酸钠干燥过夜。过滤后减压蒸去溶剂,无需纯化可直接用于下一步反应。收率90.0%。
步骤B:5-氯-8-甲氧基喹啉氮氧化物的制备
按照实施例1中步骤A的制备方法,制备标题化合物。
步骤C:2-(N-(4-甲基苯磺酰基)-N-(4-氟吡啶-2-基)氨基)喹啉的制备
按照实施例1中步骤B的制备方法,制备标题化合物。
步骤D:2-(N-(4-甲基苯磺酰基)-N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-5-氯-8-甲氧基喹啉的制备
按照实施例1中步骤C的制备方法,制备标题化合物。
步骤E:2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-5-氯-8-甲氧基喹啉的制备
将2-(N-(4-甲基苯磺酰基)-N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-5-氯-8-甲氧基喹啉(913mg,1.70mmol)置于50mL茄型瓶中,加入10mL浓盐酸。加热至100℃回流反应10小时,TLC监测反应。反应完成后,减压蒸去溶剂,加入20mL水,冰浴下用饱和碳酸钾溶液调节PH至弱碱性。二氯甲烷(30mL×2)萃取,合并有机相,无水硫酸钠干燥过夜。过滤后减压浓缩,柱层析后得到白色粉末状固体。
LC-MS m/z:384.1[M+H]+;1H NMR(600MHz,DMSO-d6)δ:8.61-8.60(d,1H),7.74-7.71(m,2H),7.55-7.54(d,1H),6.99-6.97(d,2H),6.53(s,1H),4.02(s,3H),3.58(s,4H),2.51(t,4H),2.33(s,3H).
实施例12:2-(N-(4-吗啉基吡啶-2-基)氨基)-5-氯-8-甲氧基喹啉的制备
按照实施例11的制备方法,制备标题化合物。LC-MS m/z:371.2[M+H]+;1H NMR(600MHz,CDCl3)δ:8.27(m,3H),8.03(m,1H),7.39(s,1H),7.19(m,1H),6.43(s,1H),4.05(s,3H),3.90(s,4H),3.45(s,4H).
实施例13:2-(N-(4-吗啉基吡啶-2-基)氨基)-5,7-二氯-8-甲氧基喹啉的制备
按照实施例11的制备方法,制备标题化合物。LC-MS m/z:405.2[M+H]+;1H NMR(600MHz,CDCl3)δ:8.33(s,1H),8.28-8.26(d,1H),8.03(d,1H),7.40(s,1H),7.17(m,1H),6.44(m,1H),4.05(s,3H),3.90(s,4H),3.46(s,4H);13C NMR(DMSO-d6)δ:157.2,154.3,153.4,149.7,147.8,142.6,134.6,127.5,126.6,124.3,122.0,114.9,103.5,96.7,66.6,61.4,46.5.
实施例14:2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-5,7-二氯-8-甲氧基喹啉的制备
按照实施例11的制备方法,制备标题化合物。LC-MS m/z:418.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:10.14(br s,1H),8.38(s,1H),8.28-8.26(d,1H),7.97-7.96(d,1H),7.60-7.58(d,2H),6.57-6.56(m,1H),3.97(s,3H),3.44(t,4H),2.56(s,4H),2.30(s,3H);13C NMR(DMSO-d6)δ:156.9,154.0,153.6,149.5,142.4,134.5,127.4,126.6,124.3,122.0,115.2,103.6,96.6,61.4,54.7,53.0,46.1.
实施例15:2-(N-(4-哌啶基吡啶-2-基)氨基)-5,7-二氯-8-甲氧基喹啉的制备
按照实施例11的制备方法,制备标题化合物。LC-MS m/z:403.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:10.06(s,1H),8.33(s,1H),8.27-8.26(d,1H),7.93-7.92(d,1H),7.60-7.59(d,2H),6.54-6.52(dd,1H),3.98(s,3H),3.45(m,4H),1.64(s,6H).
实施例16:(S)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基哌啶-1-基)羰基)苯基喹啉的制备
步骤A:7-溴喹啉氮氧化物的制备
按照实施例1中步骤A的制备方法,制备标题化合物。
步骤B:2-(N-(吡啶-2-基)氨基)-7-溴喹啉的制备
按照实施例1中步骤B的制备方法,制备标题化合物。
步骤C:3-(2-(N-(吡啶-2-基)氨基)喹啉-7-基)苯甲酸的制备
室温下,将2-(N-(吡啶-2-基)氨基)-7-溴喹啉(600mg,2mmol)溶于3.6mL正丙醇溶剂中,加入3-羧基苯硼酸(395mg,2.4mmol)、醋酸钯(0.01mmol)、三苯基膦(0.02mmol)及碳酸钠溶液(2mol/L,2.4mmol),加入0.7mL水。反应液加热至90℃后继续搅拌6小时,TLC监测反应。反应完成后冷却至室温,减压蒸去溶剂,柱层析纯化得白色固体。收率80%。
步骤D:(S)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-Boc-氨基哌啶-1-基)羰基)苯基喹啉的制备
将3-(2-(N-(吡啶-2-基)氨基)喹啉-7-基)苯甲酸(170mg,0.5mmol)溶于20mL四氢呋喃中,加入HATU(228mg,0.6mmol)、DMAP(75mg,0.6mmol)和DIEA(77mg,0.6mmol),室温搅拌下加入(S)-3-Boc-氨基哌啶(120mg,0.6mmol)继续搅拌4h。TLC监测反应完全,蒸干溶剂,用二氯甲烷重新溶解所得固体,水洗三遍,饱和氯和钠溶液洗一遍,无水硫酸钠干燥,柱层析得淡黄色固体。
步骤E:(S)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基哌啶-1-基)羰基)苯基喹啉的制备
按照实施例1中步骤D的制备方法,制备标题化合物。LC-MS m/z:424.3[M+H]+;1HNMR(600MHz,DMSO-d6)δ:10.09(s,1H),8.65-8.64(d,1H),8.30-8.29(dd,1H),8.18-8.16(d,1H),8.03(s,1H),7.91-7.90(d,1H),7.89-7.88(d,1H),7.81-7.78(m,2H),7.71-7.70(d,1H),7.59-7.57(t,1H),7.55-7.54(d,1H),7.41-7.40(d,1H),6.99-6.97(m,1H),4.34-4.19(m,1H),3.59-3.51(m,1H),3.01-2.93(m,1H),2.81-2.69(m,1H),2.65-2.58(m,1H),1.87-1.85(d,1H),1.65-1.62(m,2H),1.45-1.41(m,1H).13C NMR(DMSO-d6)δ:167.4,159.2,159.0,158.8,158.6,155.3,150.7,148.4,139.8,130.7,130.0,128.4,125.5,124.0,120.5,120.3,118.6,116.6,114.6,106.0,96.3,51.9,49.7,46.3,40.5,29.3.
实施例17:(R)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基哌啶-1-基)羰基)苯基喹啉的制备
按照实施例16的制备方法,制备标题化合物。LC-MS m/z:424.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:10.09(s,1H),8.66-8.65(d,1H),8.30-8.29(dd,1H),8.18-8.16(d,1H),8.04(s,1H),7.93-7.91(d,1H),7.90-7.88(d,1H),7.83(s,1H),7.81-7.78(m,1H),7.71-7.70(d,1H),7.60-7.58(t,1H),7.55-7.54(d,1H),7.43-7.42(d,1H),6.99-6.98(m,1H),3.66-3.65(m,1H),3.50-3.48(m,1H),3.08(m,1H),2.94-2.90(m,1H),2.83(m,1H),1.89(m,1H),1.64-1.63(m,2H),1.48(m,1H).
实施例18:2-(N-(吡啶-2-基)氨基)-7-(3-(吗啉-4-基)羰基)苯基喹啉的制备
按照实施例16的制备方法,制备标题化合物。LC-MS m/z:411.3[M+H]+;1H NMR(600MHz,DMSO-d6)δ:10.09(s,1H),8.66-8.65(d,1H),8.30-8.29(d,1H),8.18-8.17(d,1H),8.05(s,1H),7.94-7.92(d,1H),7.90-7.88(d,1H),7.84(s,1H),7.81-7.79(t,1H),7.72-7.71(d,1H),7.61-7.59(t,1H),7.55-7.54(d,1H),7.46-7.44(d,1H),6.99-6.97(t,1H),3.68-3.41(m,8H);13C NMR(DMSO-d6)δ:168.8,153.8,153.7,147.6,146.9,140.4,140.0,137.9,136.8,136.5,129.2,128.3,128.1,126.3,125.4,124.1,123.4,122.3,116.9,114.5,112.5,66.0,47.8.
实施例19:2-(N-(吡啶-2-基)氨基)-7-(3-(4-甲基哌嗪-1-基)羰基)苯基喹啉的制备
按照实施例16的制备方法,制备标题化合物。LC-MS m/z:324.3[M+H]+;1H NMR(600MHz,DMSO-d6)δ:10.09(s,1H),8.66-8.64(d,1H),8.29-8.28(d,1H),8.18-8.16(d,1H),8.03(s,1H),7.93-7.91(d,1H),7.89-7.88(d,1H),7.80-7.78(m,2H),7.71-7.69(dd,1H),7.60-7.58(t,1H),7.54-7.53(d,1H),7.42-7.41(d,1H),6.99-6.97(m,1H),3.67(s,2H),3.40(s,2H),2.43(s,2H),2.34(s,2H),2.32(s,3H);13C NMR(DMSO-d6)δ:169.2,154.3,154.2,148.1,147.5,140.9,140.5,138.3,137.3,137.2,129.7,128.8,128.6,126.6,125.8,124.6,123.9,122.8,117.4,115.0,113.0,55.1,47.5,46.0.
实施例20:2-(N-(吡啶-2-基)氨基)-7-(3-(哌啶-1-基)羰基)苯基喹啉的制备
按照实施例16的制备方法,制备标题化合物。LC-MS m/z:409.3[M+H]+;1H NMR(600MHz,DMSO-d6)δ:10.09(s,1H),8.66-8.64(d,1H),8.30-8.29(dd,1H),8.18-8.16(d,1H),8.03(s,1H),7.91-7.90(d,1H),7.89-7.88(d,1H),7.81-7.79(m,2H),7.71-7.69(dd,1H),7.60-7.57(t,1H),7.55-7.53(d,1H),7.41-7.40(d,1H),6.99-6.97(m,1H),3.63(s,2H),3.34(s,2H),1.64-1.63(m,2H),1.59(s,2H),1.49(s,2H);13C NMR(DMSO-d6)δ:169.1,154.3,154.2,148.1,147.5,140.9,140.4,138.3,137.9,137.3,129.6,128.8,128.3,126.4,125.6,124.6,123.9,122.8,117.4,115.0,113.0,48.6,25.7,24.5.
实施例21:2-(N-(吡啶-2-基)氨基)-7-(3-(哌嗪-1-基)羰基)苯基喹啉的制备
按照实施例16的制备方法,制备标题化合物。LC-MS m/z:410.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:10.09(s,1H),8.66-8.64(d,1H),8.30-8.29(dd,1H),8.18-8.16(d,1H),8.03(s,1H),7.91-7.90(d,1H),7.89-7.87(d,1H),7.81-7.78(m,2H),7.71-7.69(dd,1H),7.59-7.57(t,1H),7.55-7.53(d,1H),7.41-7.40(d,1H),6.99-6.97(m,1H),3.59(bs,2H),3.32(bs,2H),2.77(bs,2H),2.67(bs,2H),1.23(s,1H).
实施例22:(R)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基吡咯烷-1-基)羰基)苯基喹啉的制备
按照实施例16的制备方法,制备标题化合物。LC-MS m/z:410.2[M+H]+;1H NMR(600MHz,DMSO-d6)δ:10.09(s,1H),8.66-8.65(d,1H),8.30-8.29(d,1H),8.18-8.17(d,1H),8.03(s,1H),7.92-7.90(m,2H),7.89-7.88(d,1H),7.81-7.78(m,1H),7.71-7.70(d,1H),7.60-7.57(m,1H),7.55-7.53(m,2H),6.99-6.97(m,1H),3.66-3.62(m,1H),3.61-3.56(m,1H),3.53-3.49(m,1H),3.44-3.42(m,1H),3.14-3.12(m,1H),2.00-1.97(m,1H),1.67-1.61(m,1H),1.23(s,2H).
实施例23:本发明产物体外抗增殖活性研究
1.实验方法
细胞传代:当细胞长满培养皿80%-90%时,用0.25%胰酶消化细胞,然后用新的培养基将细胞重悬,将细胞按适当比例传代。
化合物工作液浓度的配制:将20mM化合物储存液用100%DMSO稀释至6mM,再使用培养基将化合物进一步稀释成5X工作液待用。
细胞接种及药物处理:将细胞接种于96孔细胞板中,每孔接种80μL细胞悬液,细胞板置于37℃,5%CO2培养箱,孵育24小时(细胞密度:PC-3为2000细胞/孔;KG-1为6000细胞/孔)。每孔加入20μL浓度为150μM的化合物工作液(终浓度为30uM),细胞板置于37℃,5%CO2培养箱。其中,PC-3细胞避光孵育96小时,KG-1细胞避光孵育72小时。结束孵育后,向细胞板中加入CCK8,10μL/孔,置于37℃,5%CO2培养箱中孵育4小时。在Envision上测定450nm波长处的吸光度,计算抑制率。
抑制率计算:%抑制率=(ODs-ODNC)/(ODSTSP-ODNC)×100%。其中:ODS:检测孔吸光值(细胞+培养基+待测化合物);ODNC:阴性孔吸光值(细胞+培养基+DMSO);ODSTSP:STSP孔吸光值(细胞+培养基+10μM STSP)
2.实验结果
Table 1.The anti-proliferative activities of target compounds.
a-表示还未进行活性测试
上述试验结果表明,本发明要保护的通式的化合物具有良好抗肿瘤细胞增殖作用。本发明的化合物具有很好的工业应用前景。
Claims (10)
5.如下的衍生物或其药学上可接受的盐:
(S)-2-(N-(4-(3-氨基哌啶-1-基)吡啶-2-基)氨基)喹啉
(R)-2-(N-(4-(3-氨基哌啶-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-吗啉基吡啶-2-基)氨基)喹啉
2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-哌啶基吡啶-2-基)氨基)喹啉
2-(N-(4-(哌嗪-1-基)吡啶-2-基)氨基)喹啉
(S)-2-(N-(4-(3-氨基吡咯烷-1-基)吡啶-2-基)氨基)喹啉
(R)-2-(N-(4-(3-氨基吡咯烷-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-(1,4-二氮杂庚烷-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-(4-甲基-1,4-二氮杂庚烷-1-基)吡啶-2-基)氨基)喹啉
2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-5-氯-8-甲氧基喹啉
2-(N-(4-吗啉基吡啶-2-基)氨基)-5-氯-8-甲氧基喹啉
2-(N-(4-吗啉基吡啶-2-基)氨基)-5,7-二氯-8-甲氧基喹啉
2-(N-(4-(4-甲基哌嗪-1-基)吡啶-2-基)氨基)-5,7-二氯-8-甲氧基喹啉
2-(N-(4-哌啶基吡啶-2-基)氨基)-5,7-二氯-8-甲氧基喹啉
(S)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基哌啶-1-基)羰基)苯基喹啉
(R)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基哌啶-1-基)羰基)苯基喹啉
2-(N-(吡啶-2-基)氨基)-7-(3-(吗啉-4-基)羰基)苯基喹啉
2-(N-(吡啶-2-基)氨基)-7-(3-(4-甲基哌嗪-1-基)羰基)苯基喹啉
2-(N-(吡啶-2-基)氨基)-7-(3-(哌啶-1-基)羰基)苯基喹啉
2-(N-(吡啶-2-基)氨基)-7-(3-(哌嗪-1-基)羰基)苯基喹啉
(R)-2-(N-(吡啶-2-基)氨基)-7-(3-(3-氨基吡咯烷-1-基)羰基)苯基喹啉
6.一种药物组合物,其特征在于:包含权利要求1-5中任何一项所述的衍生物或其药学上可接受的盐,以及药学上可接受的赋形剂。
7.权利要求1-5中任何一项所述的化合物或其药学上可接受的盐在制备用于治疗和/或预防各种癌症疾病药物中的应用。
8.权利要求6所述的药物组合物在制备用于治疗和/或预防各种癌症疾病药物中的应用。
9.如权利要求7所述的应用,其特征在于,所述的癌症为乳腺癌、肺癌、结肠癌、直肠癌、胃癌、前列腺癌、膀胱癌、子宫癌、胰腺癌或各种血液癌。
10.如权利要求8所述的应用,其特征在于,所述的癌症为乳腺癌、肺癌、结肠癌、直肠癌、胃癌、前列腺癌、膀胱癌、子宫癌、胰腺癌或各种血液癌。
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