CN105884686A - 10-取代吖啶-3(10)-酮类化合物、其制备方法及其用途 - Google Patents
10-取代吖啶-3(10)-酮类化合物、其制备方法及其用途 Download PDFInfo
- Publication number
- CN105884686A CN105884686A CN201510038299.4A CN201510038299A CN105884686A CN 105884686 A CN105884686 A CN 105884686A CN 201510038299 A CN201510038299 A CN 201510038299A CN 105884686 A CN105884686 A CN 105884686A
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- Prior art keywords
- compound
- formula
- methylacridine
- substituted
- phenyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 89
- 239000003504 photosensitizing agent Substances 0.000 claims abstract description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 41
- 238000006243 chemical reaction Methods 0.000 claims description 34
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 30
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 28
- 229910052799 carbon Inorganic materials 0.000 claims description 28
- 239000001257 hydrogen Substances 0.000 claims description 26
- 229910052739 hydrogen Inorganic materials 0.000 claims description 26
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- 150000002431 hydrogen Chemical class 0.000 claims description 22
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- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 18
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 18
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052794 bromium Inorganic materials 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
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Abstract
本发明涉及光动力学治疗中的光敏剂,具体涉及如式I所示的10-取代吖啶-3(10)-酮类化合物、其制备方法及其作为光动力学治疗中的光敏剂的用途。
Description
技术领域
本发明涉及光动力学治疗(Photodynamic therapy,PDT)中的光敏剂,具体涉及10-取代吖啶-3(10)-酮类化合物、其制备方法及其作为光动力学治疗中的光敏剂的用途。
背景知识
利用光来进行疾病的治疗已经有三千多年的历史了,古埃及、古印度、古中国人民就曾利用光来治疗各种疾病,包括牛皮癣、佝偻病、白癜风和皮肤癌。其实早在一百多年前,研究人员就已经发现了某些化合物和光结合能诱导细胞凋亡。1900年,德国的医学生Oscar Raab发现吖啶橙经闪电的激发能够杀死草履虫。1903年,Herman Von Tappeiner和A.Jesionek用曙红和白光来治疗皮肤癌。他们把这种现象定义为“光动力学作用”(Nat.Rev.Cancer 2003,3(5),380-387)。
PDT是利用光敏剂发生光动力反应从而进行疾病的诊断和治疗的一种新技术。肿瘤的光动力学治疗是指病人注射或口服一定剂量的光敏剂,一段时间后,光敏剂会汇聚在肿瘤组织中,然后再用特定波长的光照射该部位,在基态氧存在的情况下,光敏剂吸收光能,进而发生一系列的光化学反应,产生大量的活性氧而损伤附近的癌细胞,从而达到治疗肿瘤的目的。目前,人们认为光动力学治疗肿瘤的机制主要有三个方面:对肿瘤的直接杀伤作用;破坏肿瘤组织的微血管,造成血管的封闭,供血不足;免疫调节作用。和常规的手术治疗、放疗、化疗等治疗肿瘤的手段相比,PDT具有选择性杀死肿瘤细胞,对正常组织损伤小,毒副作用小、可以重复治疗,不会产生耐药,可以消灭隐性癌病灶等一系列优点,患者依从性比较好,尤其适宜年老体弱、不能手术或化疗的患者。
PDT需要三个必不可少的因素:光敏剂(photosensitizers,PS)、光照和氧气。这三要素分开并没有治疗作用,只有联合起来才能发生光化学反应,从而治疗疾病。其中,光敏剂是最重要的因素。从临床经验来看,一个理想的光敏剂应该具备以下条件:具有较好的化学稳定性;具有一定的水溶性;具有高效的产生单线态氧的能力;暗毒性小,光毒性强;肿瘤细胞选择性;具有良好的吸收光谱。
目前,已上市或在研的用于癌症的光动力学治疗的光敏剂主要包括卟啉类和非卟啉类。非卟啉类光敏剂主要有竹红菌素类、含硫氧氮的染料类、氟硼吡咯类以及5-氨基酮戊酸等(Journal of Photochemistry and Photobiology C:Photochemistry Reviews 2011,12,46-67)。目前,临床上应用的光敏剂主要是以卟啉类为主,包括Photofrin、Temoporfin、Hiporfin(喜泊分)、Photochlor和Talaporfin等。上述光敏剂对PDT起了很大的推动作用,然而,他们还存在着很多缺陷。例如,Photofrin和喜泊分等都是多种卟啉衍生物的混合物制剂,其有效成分尚不明确,因而尚无可控的质量标准,且给药物的安全性带来不确定因素。更严重的问题在于,上述光敏剂在用药后4-6周内都难以从体内完全清除(尤其是在皮肤中的存留时间可长达数周),因此,患者需要很长时间生活在避光环境下以避免皮肤光毒性副反应。此外,卟啉类化合物具有很大的芳香结构体系,其水溶性很差,为了改善药物的水溶性所做的结构改造增加了药物的合成难度和生产成本,导致卟啉类光敏剂药物的价格昂贵。
总之,研制新型安全、有效的PDT光敏剂具有重大临床应用价值。
关于10-取代吖啶-3(10)-酮类化合物很少有文献报道(Berichte der DeutschenChemischen Gesellschaft[Abteilung]B:Abhandlungen 1943,76B,1187-96),而且没有任何有关该类化合物的生物活性报道,更没有将该分子作为PDT光敏剂的报道。
发明内容
本发明公开了如式I所示的10-取代吖啶-3(10)-酮类化合物或其药学上可接受的盐或溶剂化物,所述式I化合物具有如下结构:
其中R1为非取代或X取代的1~6碳的直链或支链烷烃、非取代或X取代的3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基;
R2为氢、氟、氯、溴、碘、羟基、氨基、-OR5、-NR5R6、1~6碳的直链或支链烷烃,且R2为任意位置的单取代或多取代,可相同也可不同;
R3为氢、氟、氯、溴、碘、1~6碳的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基、苯环上各种取代的苄基、烯丙基或炔丙基;
R4为氢、氟、氯、溴、碘、1~6碳的直链或支链烷烃、羟基、氨基、-OR7或-NR7R8,且R4为任意位置的单取代或多取代,可相同也可不同;
R5为1~6碳的非取代或X取代的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基、烯丙基或炔丙基;
R6为氢、1~6碳的非取代或X取代的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基、烯丙基或炔丙基;
X为氟、氯、溴、碘、羟基、氨基、-OR7或-NR7R8,且X为单取代或多取代,可相同也可不同;
R7为1~6碳的非取代或取代的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基、烯丙基或炔丙基;
R8为氢、1~6碳的非取代或取代的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基、烯丙基或炔丙基。
本发明的式I化合物优选R1为甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基或苄基;优选R2为氢、氟、氯、溴、羟基、氨基或-OR5,其中优选R5为甲基、乙基、丙基、丁基、异丁基、仲丁基、叔丁基、环丙甲基、环丁甲基、苄基、烯丙基、炔丙基、3-羟基正丙基、2-羟基乙基、2,3-二羟基丙基或3-氯正丙基;优选R3为氢、甲基、乙基、丙基、丁基、异丙基、异丁基、苯基或取代的苯基;优选R4为氢、氟、氯、溴、碘、羟基、氨基、甲基或乙基。
本发明的式I化合物更优选R1为甲基、乙基、丙基、丁基或苄基;更优选R2为氢、6-氯、7-氯、6-羟基、6-甲氧基、6-乙氧基、6-正丙氧基、6-环丙甲氧基、6-苄氧基、6-炔丙氧基、6-烯丙氧基、6-(3-羟基丙氧基)、6-(2-羟基乙氧基)或6-(2,3-二羟基丙氧基);更优选R3为氢、乙基、苯基或取代的苯基;更优选R4为氢、氯、溴、羟基或甲基。
本发明优选的式I化合物如下:
10-甲基吖啶-3(10)-酮(I-1);
10-乙基吖啶-3(10)-酮(I-2);
10-丙基吖啶-3(10)-酮(I-3);
10-丁基吖啶-3(10)-酮(I-4);
10-苄基吖啶-3(10)-酮(I-5);
6-氯-10-甲基吖啶-3(10)-酮(I-6);
7-氯-10-甲基吖啶-3(10)-酮(I-7);
6-甲氧基-10-甲基吖啶-3(10)-酮(I-8);
6-羟基-10-甲基吖啶-3(10)-酮(I-9);
6-苄氧基-10-甲基吖啶-3(10)-酮(I-10);
6-乙氧基-10-甲基吖啶-3(10)-酮(I-11);
6-丙氧基-10-甲基吖啶-3(10)-酮(I-12);
6-环丙甲氧基-10-甲基吖啶-3(10)-酮(I-13);
6-烯丙氧基-10-甲基吖啶-3(10)-酮(I-14);
6-炔丙氧基-10-甲基吖啶-3(10)-酮(I-15);
6-(2-羟基乙氧基)-10-甲基吖啶-3(10)-酮(I-16);
6-(3-羟基丙氧基)-10-甲基吖啶-3(10)-酮(I-17);
6-(2,3-二羟基丙氧基)-10-甲基吖啶-3(10)-酮(I-18);
9-乙基-10-甲基吖啶-3(10)-酮(I-19)。
本发明的另一个目的是提供了如式I所示10-取代吖啶-3(10)-酮类化合物的制备方法,如下反应式:
具体包括以下步骤:
(1)式II化合物与式VII化合物以及铜粉在碱性条件下加热发生乌尔曼偶联反应,制得式III化合物;所采用的碱性试剂选自碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠、氢氧化钠、氢氧化钾,优选碳酸钾;采用的溶剂选自于DMF、DMSO、正丁醇、正戊醇、乙二醇、甲苯,优选正戊醇;采用的温度选自于50℃~200℃,优选140℃~160℃;
(2)式III化合物在酸性条件下发生分子内的环合,制得式IV化合物;所采用的酸选自硫酸、多聚磷酸PPA、Eaton's酸(质量比P2O5∶CH3SO3H=1∶10)或三氯化铝,优选PPA或Eaton's酸;所采用的温度选自于0℃~200℃,优选50℃~110℃;
(3)式IV化合物经过还原、氧化制得式V化合物;所采用的还原剂选自于硼氢化钠、腈基硼氢化钠、硼氢化钾、硼烷-四氢呋喃或氢化铝锂,优选四氢铝锂;还原所采用的溶剂选自于二氯甲烷、THF、乙醚、甲苯,优选乙醚和甲苯;还原所采用的温度选自于50℃~200℃,优选110℃;所采用的氧化剂选自于高锰酸钾、重铬酸钾、次氯酸钠、三氯化铁、双氧水、氧气或DDQ,优选三氯化铁;氧化所采用的溶剂选自于甲醇、乙醇、异丙醇、二氯甲烷、四氢呋喃、水的一种或多种混合使用,优选乙醇和水;氧化所采用的温度选自于0℃~100℃,优选50℃;
(4)式V化合物与卤代烃R1Y反应得到式VI化合物;其中,卤代烃R1Y中的R1如式I化合物中所定义,Y为碘、氯或溴;优选的卤代烃选自于碘甲烷、溴甲烷、碘乙烷、溴乙烷、1-碘丙烷、1-溴代丙烷、1-碘正丁烷、1-溴正丁烷、溴代环丙甲基、溴苄,优选碘甲烷、碘乙烷、1-碘丙烷、1-碘正丁烷或溴苄;所采用的溶剂选自于二氯甲烷、乙腈、乙酸乙酯、DMF、DMSO、甲苯或四氢呋喃,优选DMF;所采用的温度选自于0℃~200℃,优选40℃~80℃;
(5)式VI化合物经过脱甲基反应,然后在碱性条件下异构化得到式Ia化合物;所采用的脱甲基的试剂选自于氢碘酸水溶液、氢溴酸水溶液、浓盐酸、BBr3、BI3、BCl3、Me3SiI或吡啶盐酸盐,优选45%的氢碘酸水溶液或40%的氢溴酸水溶液;碱化试剂选自于碳酸钠、碳酸氢钠、氢氧化钠、碳酸钾、氢氧化钾或三乙胺,优选碳酸氢钠饱和水溶液;脱甲基所采用的温度选自于0℃~200℃,优选100℃~130℃;
(6)式Ia化合物与格式试剂R3MgY发生亲核加成,然后被氧化得到式I化合物;其中,格式试剂R3MgY中的R3如式I化合物中所定义,Y为碘、氯或溴;优选的格式试剂选自于甲基溴化镁、乙基溴化镁、丙基溴化镁、苯基溴化镁、烯丙基溴化镁、环己基溴化镁或丁基溴化镁,优选乙基溴化镁或苯基溴化镁;亲核加成反应所采用的溶剂选自于无水四氢呋喃、无水二氯甲烷、无水甲苯、无水乙醚,优选无水二氯甲烷和四氢呋喃;亲核加成反应的温度选自于-50℃~100℃,优选-10℃~25℃;氧化反应所采用的氧化剂选自于O2、三氯化铁、DDQ、高锰酸钾、重铬酸钾、次氯酸钠或双氧水,优选三氯化铁;其中氧化反应所采用的溶剂选自于甲醇、乙醇、异丙醇、二氯甲烷、四氢呋喃、水的一种或多种混合使用,优选乙醇和水的混合溶剂;其中氧化反应所采用的温度选自于0℃~100℃,优选50℃。
在上述反应式中,R1、R2、R3和R4的定义如式I化合物中所定义。
本发明的另一个目的是提供式I化合物或其药学上可接受的盐或溶剂化物作为新型光敏剂在疾病的光动力学防治方面的用途。所述疾病包括恶性肿瘤、癌前病变或良性病变;其中所述的恶性肿瘤是实体瘤;其中所述的实体瘤选自于肺癌、皮肤癌、黑色素瘤、食管癌、膀胱癌、头颈部癌、鼻咽癌、支气管癌、乳腺癌、宫颈癌、胰腺癌、肝癌、胃癌、胆管癌、前列腺癌、脑肿瘤、结肠癌或上述实体瘤切除后的癌残留;其中所述的癌前病变选自于粘膜白斑、萎缩性胃炎、宫颈糜烂、乳腺囊性增生、老年日光性角化病、色素性干皮病或胃肠道息肉;其中所述的良性病变选自于视网膜黄斑变性、鲜红斑痣、银屑病、类风湿性关节炎、血管成形术后再狭窄、红斑狼疮皮损、类风湿性关节炎或动脉粥样硬化斑块。
本发明人通过对式I化合物的深入研究,首次发现该类化合物具有抗肿瘤活性。尤其令人惊讶的是,可见光照射能够极显著地增强式I化合物的抗肿瘤活性。例如,通过式I化合物对肺癌细胞的光动力学实验发现,给予一段时间可见光照射后,式I化合物的细胞毒活性比无光照条件下增强了200~10000倍,且对正常细胞具有一定的选择性。因此,式I化合物作为新型的PDT光敏剂有望用于制备光动力学防治肿瘤的药物。
本发明还提供了一种光动力学防治疾病的药物组合物,其中含有治疗有效量的式I化合物或其药学上可接受的盐或溶剂化物和药学上可接受的载体。所述药物组合物可以是注射剂、冻干制剂、软膏剂、搽剂、普通片剂或胶囊、缓控释片剂或胶囊、颗粒剂、散剂、糖浆剂或口服液。
附图说明
图1化合物I-1的核磁共振氢谱;
图2化合物I-1的紫外-可见吸收光谱;
图3化合物I-5的核磁共振氢谱;
图4化合物I-5的紫外-可见吸收光谱;
图5化合物I-6的核磁共振氢谱;
图6化合物I-6的紫外-可见吸收光谱;
图7化合物I-7的核磁共振氢谱;
图8化合物I-7的紫外-可见吸收光谱;
图9化合物I-8的核磁共振氢谱;
图10化合物I-8的紫外-可见吸收光谱;
图11化合物I-10的核磁共振氢谱;
图12化合物I-10的紫外-可见吸收光谱。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中,以下所述的实施例是为了更好的阐述本发明,并不是用来限制本发明的范围。
实施例1
10-甲基吖啶-3(10)-酮(I-1)的制备:
步骤一:
分别称取20g邻氯苯甲酸(II-1)(127.74mmol,1eq),20g的碳酸钾(144.71mmol,1.131eq)和658mg的铜粉(10.34mmol,0.081eq)于500mL的三颈瓶中。再加入170mL的正戊醇溶解,氮气保护。搅匀后,滴加16.8mL的间氨基苯甲醚(134.51mmol,1.053eq),升温至140℃回流24h。待反应完毕,停加热冷却,蒸去溶剂戊醇,加入100mL水溶解过量的盐,再滴加2N HCl酸化,调pH至3~4,有大量的黑色固体析出。抽滤,滤饼再用二氯甲烷溶解,再依次水洗,2NHCl洗,饱和食盐水洗,无水硫酸钠干燥。浓缩,硅胶柱层析(石油醚∶乙酸乙酯∶冰醋酸=200∶10∶0.2),得27g土色固体,2-((3-甲氧基苯基)氨基)苯甲酸(III-1),收率87.0%。
步骤二:
称取约111g的多聚磷酸PPA(328.87mmol,4eq)于250mL单颈瓶中,110℃加热30min左右,使多聚磷酸能顺利搅拌。缓慢加入20g的2-((3-甲氧基苯基)氨基)苯甲酸(III-1)(82.22mmol,1eq),继续加热3h。TLC检测反应完毕后,停止加热,冷却后冰浴中滴加约100mL的水,水解多聚磷酸,接着滴加20%的氢氧化钠溶液,碱化,调pH至8~9左右,有黄色絮状固体生成。抽滤,滤饼依次用200mL水洗,200mL的乙醚洗,红外灯下烘干,得到18g黄白色固体,1-甲氧基吖啶-9(10H)-酮和3-甲氧基吖啶-9(10H)-酮混合物(IV-1a和IV-1b),两异构体收率97.2%。
步骤三:
将18g的1-甲氧基吖啶-9(10H)-酮和3-甲氧基吖啶-9(10H)-酮混合物(IV-1a和IV-1b)(79.91mmol,1eq)溶于180mL的乙醚中,搅匀后,冰浴中缓慢分批加入12.5g的四氢铝锂(399.57mmol,5eq)。待其氢气释放完毕,加入180mL甲苯,移至油浴中,113℃回流12小时。TLC检测反应完毕,停加热,待其冷却后,冰浴中缓慢加入十水硫酸钠淬灭四氢铝锂,直至不再放出气体。抽滤,滤饼反复用二氯甲烷洗,直至TLC检测滤饼中没有产物残留。收集滤液,浓缩旋干。将得到的粗品溶于300mL的乙醇和60mL的水的混合溶液中,再加入39g的无水三氯化铁(239.73mmol,3eq),50℃加热半个小时。蒸去大部分的溶剂乙醇,加入约100mL的水和200mL的二氯甲烷,搅匀。滴加饱和的碳酸氢钠溶液中和,调pH至7~8。抽滤,黑色粘稠状滤饼反复用二氯甲烷洗,直至TLC检测滤饼中无产物。收集滤液,分出有机相,水相用二氯甲烷萃取(100mLx 3),合并有机相,依次水洗,饱和食盐水洗,无水硫酸钠干燥。旋干硅胶柱层析(石油醚∶乙酸乙酯=50∶1)分出4g棕黑色固体3-甲氧基吖啶(V-1b),产率23.9%。
步骤四:
将1.5g 3-甲氧基吖啶(V-1b)(7.17mmol,1eq)溶于50mL的DMF,滴加约2.68mL碘甲烷(43.01mmol,6eq),50℃加热24h。蒸去剩余的碘甲烷,抽滤,滤饼依次用少量的DMF、二氯甲烷、乙醚洗去滤饼中未反应的原料,红外灯下烘干得到1.60g的棕黄色固体3-甲氧基-10-甲基吖啶碘铵盐(VI-1),产率63.5%。
步骤五:
将1.40g的3-甲氧基-10-甲基吖啶碘铵盐(VI-1)(3.99mmol,1eq)溶于41mL的45%的氢碘酸溶液中(247.17mmol,62eq)(d=1.7g/mL),呈黄色混悬液。升温至125℃,加热回流24h。待原料反应完毕,停止加热,缓慢加入碳酸氢钠饱和溶液中和氢碘酸,调pH至7~8。随后加入约50mL的二氯甲烷,搅匀后,分出有机相。水相再用二氯甲烷萃取五遍(50mLx 5)。合并有机相,依次水洗、饱和食盐水洗,无水硫酸钠干燥。浓缩,硅胶柱层析(二氯甲烷∶甲醇=50∶1),分出610mg的橘红色固体,10-甲基吖啶-3(10)-酮(I-1),收率73.1%。1H NMR(300MHz,MeOD)δ8.44(s,1H),8.05-7.78(m,3H),7.64(d,J=9.3Hz,1H),7.52-7.38(m,1H),6.83(d,J=9.3Hz,1H),6.42(s,1H),3.91(s,3H);13C NMR(75MHz,MeOD)δ182.43,146.07,141.02,139.48,134.11,133.26,130.48,128.34,123.33,122.77,121.71,115.19,99.03,34.19;ESI MS m/z 210.1[M+H]+;HRMS forC14H11NO+H cacld 210.0919 found 210.0912.
实施例2
10-乙基吖啶-3(10)-酮(I-2)的制备
将202mg(0.97mmol,1eq)的3-甲氧基吖啶(V-1b)溶于2mL的DMF中,再滴加约0.47mL(5.79mmol,6eq)的碘乙烷,70℃加热52h。停止反应后,蒸除溶剂DMF,柱层析(二氯甲烷∶甲醇=100∶1)除去未反应的原料,收集到320mg的粗品,直接投下一步。将粗品溶于10.1mL(60.14mmol,62eq)的45%的氢碘酸水溶液中,125℃回流28h。停加热,待反应冷却后,滴加饱和的碳酸氢钠溶液中和氢碘酸,并碱化pH至7~8,再用二氯甲烷反复萃取(20mL x 5),合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥。蒸干柱层析(二氯甲烷∶甲醇=50∶1),得到45mg的橘红色的固体10-乙基吖啶-3(10)-酮(I-2),两步合并收率20.8%。1H NMR(300MHz,MeOD)δ8.48(s,1H),7.98-7.81(m,3H),7.67(d,J=9.3Hz,1H),7.56-7.32(m,1H),6.84(d,J=9.3Hz,1H),6.47(s,1H),4.52(q,J=7.1Hz,2H),1.45(t,J=7.2Hz,3H);13C NMR(75MHz,MeOD)δ184.36,146.75,143.19,140.39,136.25,135.39,132.62,130.28,125.30,124.79,123.78,116.85,100.51,44.16,12.58;ESI MS m/z 224.1[M+H]+;HRMS for C15H13NO+Hcacld 224.1075 found 224.1081.
实施例3
10-丙基吖啶-3(10)-酮(I-3)的制备
反应步骤参照实施例2,得到50mg的橘红色固体10-丙基吖啶-3(10)-酮(I-3),两步合并收率22.0%。1H NMR(300MHz,MeOD)δ8.68(s,1H),8.01(d,J=8.2Hz,1H),7.98-7.87(m,2H),7.82(d,J=9.3Hz,1H),7.51(t,J=7.1Hz,1H),6.95(d,J=9.2Hz,1H),6.56(s,1H),4.51(t,2H),1.93(m,2H),1.17(t,J=7.4Hz,3H);13CNMR(75MHz,MeOD)δ183.67,147.12,143.82,140.84,136.48,135.55,132.71,130.03,125.51,124.82,123.95,117.27,100.88,50.53,21.57,11.65;ESI MS m/z238.1[M+H]+;HRMS for C16H15NO+H cacld 238.1232 found 238.1237.
实施例4
10-丁基吖啶-3(10)-酮(I-4)的制备
反应步骤参照实施例2,得到30mg的橘红色的固体10-丁基吖啶-3(10)-酮(I-4),两步合并收率16.8%。1H NMR(300MHz,MeOD)δ8.62(s,1H),8.01(d,J=7.9Hz,1H),7.93(d,J=2.5Hz,2H),7.79(d,J=9.3Hz,1H),7.57-7.43(m,1H),6.91(d,J=9.2Hz,1H),6.52(s,1H),4.61-4.45(m,2H),1.96-1.80(m,2H),1.65(dq,J=14.4,7.3Hz,2H),1.10(t,J=7.3Hz,3H);13C NMR(75MHz,MeOD)δ183.08,145.38,141.29,138.81,134.27,133.60,130.78,128.65,123.37,123.11,121.98,115.16,98.90,46.97,28.21,19.59,12.72;ESI MS m/z252.1[M+H]+;HRMSfor C17H17NO+H cacld 252.1388 found 252.1394.
实施例5
10-苄基吖啶-3(10)-酮(I-5)的制备
反应步骤参照实施例2,得到60mg的橘红色固体10-苄基吖啶-3(10)-酮(I-5),两步合并收率21.9%。1H NMR(300MHz,MeOD)δ8.64(s,1H),7.98(d,J=7.9Hz,1H),7.74(dd,J=11.6,8.3Hz,3H),7.43(t,J=7.2Hz,1H),7.33-7.15(m,3H),7.06(d,J=7.1Hz,2H),6.84(d,J=9.2Hz,1H),6.38(s,1H),5.72(s,2H);13C NMR(75MHz,MeOD)δ182.71,146.05,141.79,139.57,134.44,134.13,133.69,130.74,128.80,128.54,127.50,125.67,123.69,123.21,121.90,115.48,99.84,51.01;ESIMS m/z 286.1[M+H]+;HRMS for C20H15NO+H cacld 286.1232 found 286.1238.
实施例6
6-氯-10-甲基吖啶-3(10)-酮(I-6)的制备
步骤一:
分别称取20g的2,4-二氯苯甲酸(II-2)(104.71mmol,1eq),29g的K2CO3(209.40mmol,2eq),240mg的铜粉(3.77mmol,0.036eq),溶于160mL的戊醇中,随后逐渐升温。待其搅匀后,滴加19.34g的间氨基苯甲醚(157.06mmol,1.5eq)升温至137℃回流24h。停加热,蒸去戊醇,加入适量的水(20mL)溶解部分的盐,再加入约120mL的2N盐酸中和,逐渐有黑色固体析出。抽滤,滤饼经甲醇两次重结晶,红外灯下烘干,得到15g的灰绿色固体4-氯-2-((3-甲氧基苯基)胺)苯甲酸(III-2),收率51.6%。
步骤二:
将15g的4-氯-2-((3-甲氧基苯基)胺)苯甲酸(III-2)溶于50mL的自制的Eaton's酸中(质量比P2O5∶CH3SO3H=1∶10),搅匀,升温至50℃,加热8h。停加热,冰浴中缓慢滴加约30mL的水,不断有大量的黄色固体析出,抽滤,滤饼用少量的水洗,乙醚洗,黄绿色滤饼红外灯下干燥。粗品DMF和甲醇混合溶剂(DMF∶CH3OH=4∶1)重结晶两次得到7g苍白色的固体3-氯-6-甲氧基吖啶-9(10H)-酮(IV-2b),收率49.9%。
步骤三:
将7g的3-氯-6-甲氧基吖啶-9(10H)-酮(IV-2b)(26.96mmol,1eq)溶于90mL的无水乙醚中,冰浴中缓慢加入5.11g的LiAlH4(134.78mmol,5eq)。待其氢气释放完毕,加入90mL的无水甲苯,升温至110℃回流12h。停加热,冷却后冰浴中缓慢加入十水硫酸钠淬灭,直至无气泡产生。抽滤,滤饼用二氯甲烷洗涤多次,滤液浓缩。将得到的粗品的中间体溶于250mL乙醇和50mL水的混合溶剂中,加入13.1g的无水FeCl3(80.88mmol,3eq),50℃反应1h。停加热,蒸去部分的乙醇溶剂,缓慢加入饱和的碳酸氢钠约300mL左右中和。调pH至7~8左右,再加入约200mL的二氯甲烷。搅匀后抽滤,滤饼反复用二氯甲烷冲洗,直至TLC检测滤饼中无产物。滤液分出有机相,水相再用二氯甲烷萃取三遍(100mLx 3),合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥。蒸干柱层析(石油醚∶乙酸乙酯=25∶1)得到6.1g的黄绿色的固体3-氯-6-甲氧基吖啶(V-2b),两步收率92.9%。
步骤四:
称取1.1g的3-氯-6-甲氧基吖啶(V-2b)(4.51mmol,1eq)溶于50mL的DMF中,呈黄绿色溶液。然后滴加1.69mL的碘甲烷(27.08mol,6eq)。升温至45~50℃,反应24h。停加热,抽滤,滤饼依次用少量的二氯甲烷洗,乙醚洗,红外灯下烘干,得到1.20g的橘黄色的固体3-氯-6-甲氧基-10-甲基吖啶碘铵盐(VI-2),产率69.0%。
步骤五:
将220mg的3-氯-6-甲氧基-10-甲基吖啶碘铵盐(VI-2)(0.57mmol,1eq)溶于5.71mL的45%氢碘酸水溶液中(35.37mmol,62eq),升温至125℃左右,回流24h。停加热,冷却后,滴加饱和的碳酸氢钠溶液中和氢碘酸,调pH至7~8。加入10mL的二氯甲烷搅匀,反应液由棕黄色变成深红色。分出有机相,水相再用二氯甲烷萃取五遍(10mLx 5)。合并有机相,依次水洗,饱和食盐水洗,无水硫酸钠干燥。浓缩,硅胶柱层析(二氯甲烷∶甲醇=50∶1),得到114mg的橘红色固体6-氯-10-甲基吖啶-3(10)-酮(I-6),产率82.1%。1H NMR(300MHz,MeOD)δ8.31(s,1H),7.92-7.67(m,2H),7.57(d,J=9.3Hz,1H),7.33(d,J=8.3Hz,1H),6.76(d,J=9.1Hz,1H),6.32(s,1H),3.81(s,3H);13C NMR(75MHz,MeOD)δ182.85,162.35,151.95,145.52,139.37,133.00,131.29,128.27,123.29,122.57,119.65,114.54,98.96,33.86;ESI MS m/z 244.1[M+H]+;HRMS for C14H10ClNO+Hcacld 244.0529 found 244.0524.
实施例7
7-氯-10-甲基吖啶-3(10)-酮(I-7)的制备
反应步骤参照实施例6,得到84mg的橘红色固体7-氯-10-甲基吖啶-3(10)-酮(I-7),产率73.3%。1H NMR(300MHz,DMSO-d)δ8.26(s,1H),7.93(d,J=2.2Hz,1H),7.83(d,J=9.3Hz,1H),7.70(dd,J=9.2,2.3Hz,1H),7.57(d,J=9.5Hz,1H),6.60(d,J=9.4Hz,1H),6.10(s,1H),3.75(s,3H);13C NMR(75MHz,DMSO-d)δ182.85,145.56,138.43,136.64,133.29,132.85,131.35,128.90,126.54,124.84,122.33,117.71,100.63,35.05;ESI MS m/z 244.1[M+H]+;HRMS forC14H10ClNO+H cacld 244.0529found 244.0533.
实施例8
6-甲氧基-10-甲基吖啶-3(10)-酮(I-8)的制备
称取3.5g的3-氯-6-甲氧基-10-甲基吖啶碘铵盐(VI-2)溶于25%的醋酸-吡啶溶液中(17mL吡啶-50mL醋酸)升温至100℃加热24h。原料反应完,停加热,蒸去过量的吡啶及其醋酸,再加入约40mL左右的饱和碳酸氢钠溶液,中和剩余的醋酸,调pH至7~8。再加入约50mL的甲醇,抽滤,滤除析出的盐。滤液浓缩蒸去部分溶剂,再次加入50mL的甲醇,再次滤除析出的盐。这样反复加入甲醇,浓缩,析出,抽滤3~5次。滤液蒸干,柱层析(二氯甲烷∶甲醇=25∶1),得到2.0g橘黄色的固体6-甲氧基-10-甲基吖啶-3(10)酮(I-8),收率92.1%。1HNMR(300MHz,MeOD)δ8.21(s,1H),7.67(d,J=8.9Hz,1H),7.48(d,J=9.2Hz,1H),6.98(d,J=7.9Hz,2H),6.74(d,J=9.0Hz,1H),6.39(s,1H),3.97(s,3H),3.77(s,3H);13C NMR(75MHz,MeOD)δ180.55,164.78,144.97,141.18,140.51,132.66,131.71,126.05,119.40,116.22,114.10,98.85,96.25,54.85,33.85;ESI MSm/z 240.1[M+H]+;HRMS for C15H13NO2+H cacld 240.1025found 240.1026.
实施例9
6-羟基-10-甲基吖啶-3(10)-酮(I-9)的制备
称取1.06g的6-甲氧基-10-甲基吖啶-3(10)-酮(I-8)(4.43mmol,1eq),溶于45mL的45%的氢碘酸水溶液中(274.67mmol,62eq),升温至125℃,回流24h。反应完毕后停加热,冷却后加入饱和的碳酸氢钠溶液中和氢碘酸,调pH至7~8,再加入约200mL的正丁醇分出有机相,水相再用正丁醇萃取(100mL x 5)。合并有机相,再反复用饱和食盐水洗,直至洗去大部分残留碘化钠(碘化钠烤板显色)。无水硫酸钠干燥。浓缩,硅胶柱层析(二氯甲烷∶甲醇=25∶1)得到2g左右的粗品(含有大量的盐)。再用甲醇反复溶解,滤过除盐,浓缩得到900mg的黄绿色固体6-羟基-10-甲基吖啶-3(10)-酮(I-9),收率90.2%。1H NMR(300MHz,DMSO-d)δ8.64(s,1H),7.84(d,J=8.9Hz,2H),6.94(s,1H),6.92-6.88(m,3H),3.88(s,3H);13C NMR(75MHz,DMSO-d)δ179.24,168.89,149.10,145.13,143.74,134.07,132.03,126.65,120.29,119.25,114.60,109.23,100.23,36.30;ESI MS m/z226.1[M+H]+;HRMS for C14H11NO2+H cacld 226.0868 found 226.0863.
实施例10
6-苄氧基-10-甲基吖啶-3(10)-酮(I-10)的制备
分别称取90mg的6-羟基吖啶酮(I-9)(0.40mmol,1eq),165mg的碳酸钾(1.20mmol,3eq)溶于4mL的DMF中,再分批滴加82mg(0.48mmol,1.2eq)的溴化苄,室温搅拌5h。停反应,分别加入5mL的水和10mL的二氯甲烷,分出有机相,水相再用二氯甲烷萃取(10mLx 5)。合并有机相,依次水洗,饱和食盐水洗,无水硫酸钠干燥。浓缩柱层析(二氯甲烷∶甲醇=30∶1),分出64mg橘红色固体6-苄氧基-10-甲基吖啶-3(10)-酮(I-10),收率50.7%。1H NMR(300MHz,MeOD)δ8.26(s,1H),7.73(d,J=8.9Hz,1H),7.57-7.46(m,3H),7.45-7.28(m,3H),7.16(s,1H),7.09(dd,J=8.9,2.0Hz,1H),6.77(dd,J=9.2,1.6Hz,1H),6.41(s,1H),5.26(s,2H),3.80(s,3H);13C NMR(75MHz,MeOD)δ181.98,164.08,145.76,141.61,140.76,136.05,133.18,132.25,128.28,127.95,127.47,127.07,120.15,116.74,114.65,99.41,98.11,70.36,34.27;ESI MS m/z 316.1[M+H]+;HRMS for C21H17NO2+H cacld 316.1338 found 316.1345.
实施例11
6-乙氧基-10-甲基吖啶-3(10)-酮(I-11)的制备
反应步骤参照实施例10,得到23mg橘黄色的固体6-乙氧基-10-甲基吖啶-3(10)-酮(I-11)。收率39.5%。1H NMR(300MHz,MeOD)δ8.59(s,1H),7.87(d,J=8.9Hz,1H),7.75(d,J=9.1Hz,1H),7.23-7.04(m,2H),6.92(d,J=8.9Hz,1H),6.70(s,1H),4.27(dd,J=13.8,6.9Hz,2H),3.99(s,3H),1.50(t,J=6.9Hz,3H);13C NMR(75MHz,MeOD)δ180.68,167.89,147.91,145.09,144.87,136.06,135.19,127.80,122.62,120.15,118.52,102.11,99.92,67.31,37.55,16.09;ESI MSm/z 254.1[M+H]+;HRMS for C16H15NO2+H cacld 254.1181 found 254.1176.
实施例12
6-丙氧基-10-甲基吖啶-3(10)-酮(I-12)的制备
反应步骤参照实施例10,得到75mg的橘红色固体6-丙氧基-10-甲基吖啶-3(10)-酮(I-12),收率70.1%。1H NMR(300MHz,MeOD)δ8.12(s,1H),7.56(d,J=8.9Hz,1H),7.40(d,J=9.2Hz,1H),6.86(dd,J=8.8,1.7Hz,1H),6.79(s,1H),6.70(d,J=9.1Hz,1H),6.34(s,1H),4.00(t,J=6.5Hz,2H),3.66(s,3H),1.85(m,2H),1.10(t,J=7.4Hz,3H);13C NMR(75MHz,MeOD)δ181.02,166.22,146.40,142.90,142.67,134.48,133.58,127.29,120.98,118.10,116.44,100.77,98.40,71.67,35.84,23.48,10.83;ESI MS m/z 268.1[M+H]+;HRMS for C17H17NO2+H cacld268.1338 found 268.1342.
实施例13
6-环丙甲氧基-10-甲基吖啶-3(10)-酮(I-13)的制备
反应步骤参照实施例10,得到40mg橘黄色固体6-环丙甲氧基-10-甲基吖啶-3(10)-酮(I-13),收率35.8%。1H NMR(300MHz,MeOD)δ8.08(s,1H),7.59(d,J=8.9Hz,1H),7.40(d,J=9.3Hz,1H),6.92(dd,J=8.8,1.9Hz,1H),6.86(s,1H),6.67(dd,J=9.2,1.3Hz,1H),6.28(s,1H),3.95(d,J=7.0Hz,2H),3.67(s,3H),0.86(dq,J=23.9,12.0Hz,1H),0.68(q,J=5.9Hz,2H),0.43(q,J=4.7Hz,2H);13C NMR(75MHz,MeOD)δ181.66,164.35,145.37,141.38,140.45,132.92,131.96,126.75,119.62,116.27,114.40,99.20,97.16,73.20,34.04,9.43,2.22;ESI MS m/z280.1[M+H]+;HRMS for C18H17NO2+H cacld 280.1338found 280.1343.
实施例14
6-烯丙氧基-10-甲基吖啶-3(10)-酮(I-14)的制备
反应步骤参照实施例10,得到35mg的橘红色的固体6-烯丙氧基-10-甲基吖啶-3(10)-酮(I-14),收率33.0%。1H NMR(300MHz,MeOD)δ8.27(s,1H),7.69(dd,J=19.1,6.2Hz,1H),7.55(dd,J=12.9,6.4Hz,1H),7.09-6.96(m,2H),6.76(dd,J=9.2,1.3Hz,1H),6.42(s,1H),6.13(ddd,J=22.5,10.5,5.3Hz,1H),5.51(m,1H),5.36(dd,J=10.5,1.1Hz,1H),4.72(d,J=5.1Hz,2H),3.80(s,3H);13C NMR(75MHz,MeOD)δ180.77,163.63,145.13,141.17,140.52,132.72,131.80,127.92,126.20,119.58,116.80,116.33,114.24,98.89,97.32,68.77,33.87;ESI MS m/z 266.1[M+H]+;HRMS for C17H15NO2+H cacld 266.1181 found 266.1175.
实施例15
6-炔丙氧基-10-甲基吖啶-3(10)-酮(I-15)的制备
反应步骤参照实施例10,得到45mg的橘红色的固体6-炔丙氧基-10-甲基吖啶-3(10)-酮(I-15),收率42.7%。1HNMR(300MHz,MeOD)δ8.46(s,1H),7.88(d,J=8.9Hz,1H),7.68(d,J=9.3Hz,1H),7.33(s,1H),7.16(dd,J=8.9,2.1Hz,1H),6.85(d,J=9.2Hz,1H),6.52(s,1H),5.02(d,J=2.3Hz,2H),3.95(s,3H),3.12(s,1H);13C NMR(75MHz,MeOD)δ181.28,162.36,145.49,141.11,140.49,132.81,131.84,126.64,120.10,116.67,113.88,98.95,98.11,82.23,76.16,55.56,33.89;ESIMS m/z 264.1[M+H]+;HRMS for C17H13NO2+H cacld 264.1025found 264.1028.
实施例16
6-(2-羟基乙氧基)-10-甲基吖啶-3(10)-酮(I-16)的制备
称取90mg的6-羟基-10-甲基吖啶-3(10)-酮(I-9)(0.40mmol,1eq),165mg的碳酸钾(1.20mmol,3eq)以及催化量的碘化钠溶于4mL的DMF中,再滴加150mg的2-溴乙醇(1.20mmol,3eq),60℃搅拌48h。停反应后,直接蒸干柱层析(二氯甲烷∶甲醇∶三乙胺=100∶5∶0.2)分出38mg的橘黄色的固体6-(2-羟基乙氧基)-10-甲基吖啶-3(10)-酮(I-16),收率35.3%。1H NMR(300MHz,MeOD)δ8.82(s,1H),8.03(d,J=9.0Hz,1H),7.92(d,J=9.1Hz,1H),7.41(s,1H),7.29(d,J=8.7Hz,1H),7.06(d,J=9.0Hz,1H),6.91(s,1H),4.37(m,2H),4.16(s,3H),4.00(m,2H);13C NMR(75MHz,MeOD)δ178.37,167.11,146.89,144.63,144.13,135.10,134.22,125.94,121.83,119.65,117.87,100.83,99.17,72.00,61.38,36.54;ESI MS m/z 270.1[M+H]+;HRMS for C16H15NO3+H cacld 270.1130found270.1136.
实施例17
6-(3-羟基丙氧基)-10-甲基吖啶-3(10)-酮(I-17)的制备
反应步骤参照实施例16,得到40mg的橘黄色的固体6-(3-羟基丙氧基)-10-甲基吖啶-3(10)-酮(I-17),收率35.3%。1H NMR(300MHz,MeOD)δ8.52(s,1H),7.85(d,J=8.9Hz,1H),7.72(d,J=9.2Hz,1H),7.19(s,1H),7.09(d,J=8.9Hz,1H),6.90(d,J=9.1Hz,1H),6.61(s,1H),4.33(t,J=6.2Hz,2H),3.96(s,3H),3.81(t,J=6.1Hz,2H),2.10(m,2H);13C NMR(75MHz,MeOD)δ181.61,166.38,147.09,143.43,143.14,134.74,133.87,127.84,121.48,118.54,116.63,101.13,98.91,67.11,59.29,36.12,33.08;ESI MS m/z 284.1[M+H]+;HRMS forC17H17NO3+H cacld 284.1287 found 284.1281.
实施例18
6-(2,3-二羟基丙氧基)-10-甲基吖啶-3(10)-酮(I-18)的制备
称取90mg的6-羟基-10-甲基吖啶-3(10)-酮(I-9)(0.40mmol,1eq),165mg的碳酸钾(1.20mmol,3eq)以及催化量的碘化钠溶于4mL的DMF中,再滴加111mg(1.20mmol,3eq)的2-(氯甲基)环氧乙烷。80℃反应20h。停止反应后,直接蒸干柱层析(二氯甲烷∶甲醇∶三乙胺=100∶5∶0.2)分出40mg橘黄色固体6-(2,3-二羟基丙氧基)-10-甲基吖啶-3(10)-酮(I-18),收率33.4%。1H NMR(300MHz,MeOD)δ8.68(s,1H),7.93(d,J=8.9Hz,1H),7.82(d,J=9.1Hz,1H),7.30(s,1H),7.19(d,J=8.7Hz,1H),6.99(d,J=9.1Hz,1H),6.77(s,1H),4.43-4.33(m,1H),4.33-4.23(m,1H),4.17-4.09(m,1H),4.05(s,3H),3.77(d,J=4.4Hz,2H);13C NMR(75MHz,MeOD)δ179.34,166.68,146.86,144.08,143.69,134.98,134.09,130.13,121.64,119.16,117.41,101.10,99.08,71.60,71.48,63.83,36.51;ESI MSm/z300.1[M+H]+;HRMS for C17H17NO4+H cacId 300.1236found 300.1241.
实施例19
9-乙基-10-甲基吖啶-3(10)-酮(I-19)的制备
量取4.4mL的乙基溴化镁(4.40mmol,20eq)于干燥并且氮气保护的两颈瓶中,然后于-10℃缓慢滴加45mg的10-甲基吖啶-3(10)-酮(I-1)(0.22mmol,1eq)的无水二氯甲烷溶液。滴毕,原料的橘红色逐渐褪去,反应液变成灰色。维持低温环境,继续搅拌1h。随后加水淬灭,滤过,收集滤液。滤液用二氯甲烷萃取(10mLx 5),合并有机相,水洗,饱和食盐水洗,无水硫酸钠干燥,旋干得粗品中间体。再将该粗品溶于5mL乙醇和1mL水的混合溶剂中,加入107mg的无水三氯化铁(0.66mmol,3eq),50℃反应。半个小时后停加热,蒸去大部分的溶剂,加入5mL水和10mL的二氯甲烷搅匀。分出有机相,水相再用二氯甲烷萃取(10mLx 5),合并有机相,依次水洗、饱和食盐水洗,无水硫酸钠干燥。旋干硅胶柱层析(二氯甲烷∶甲醇=50∶1),得到24mg的橘红色固体9-乙基吖啶-3(10)-酮(I-19),收率46.0%。1H NMR(300MHz,MeOD)δ8.35(d,J=8.4Hz,1H),8.20(d,J=9.7Hz,1H),8.04(d,J=8.6Hz,1H),7.92(t,J=7.6Hz,1H),7.56(t,J=7.5Hz,1H),6.97(d,J=9.9Hz,1H),6.59(s,1H),4.08(s,3H),3.55(q,J=7.4Hz,2H),1.42(t,J=7.5Hz,3H);13C NMR(75MHz,MeOD)δ182.32,156.93,147.26,140.87,135.26,130.37,129.55,127.89,124.96,122.10,121.00,117.53,100.99,36.38,22.49,16.05;ESI MS m/z 238.1[M+H]+;HRMS for C16H15NO+Hcacld 238.1232found 238.1227.
实施例20
式I化合物作为PDT光敏剂的细胞毒活性评价
1、实验目的:检测可见光对式I化合物的抗肿瘤活性的影响,以及式I化合物对癌细胞和正常细胞的选择性差异。
2、实验材料:96孔细胞培养板购自Costar公司;DMEM高糖培养基购自Gibco公司;RPMI1640培养基购自Gibco公司;胎牛血清购自Gibco公司;DMSO购自Sigma公司;EnoGeneCellTM Counting Kit-8(CCK-8)细胞活力检测试剂盒由南京恩晶生物科技有限公司提供。
3、实验仪器:ChemBase CBS-CJ-1FD超净工作台;三洋二氧化碳培养箱;倒置显微镜;美国热电MK3酶标仪。光源参数:功率:9w电压220V~240V色温:6500K频率:50/60Hz。
4、受试药物:式I化合物。样品用DMSO配制成母液使用,使用时用完全培养基稀释使用,DMSO终浓度不超过0.01%;阳性对照药:紫杉醇注射液,太极集团四川太极制药有限公司,5mL:30mg。
5、细胞株:人肺癌细胞NCI-H460;细胞培养于含10%胎牛血清的RPMI1640中培养基;人胚肺成纤维细胞HELF;细胞于含10%小牛血清的DMEM高糖培养基中培养。
6、实验方案:取活细胞比例达90%以上的细胞进行实验。细胞增殖抑制试验采用EnoGeneCellTM Counting Kit-8(CCK-8)细胞活力检测试剂盒。细胞消化、计数、制成浓度为1×105个/mL的细胞悬液,96孔板中每孔加入100μL细胞悬液(每孔1×104个细胞);96孔板置于37℃,5%CO2培养箱中培养24小时;每孔加入100μL相应的含药物的培养基,同时设立阴性对照组,DMSO溶媒对照组,光照组,每组5个复孔;96孔板置于37℃,5%CO2培养箱中培养72小时;其中光照组在加药后4-6小时后给予可见光照射,照射时间为12小时左右,然后继续培养。每孔加入10μL CCK-8溶液,将培养板在培养箱内孵育1-4小时,用酶标仪测定在450nm处的OD值,计算抑制率并采用GraphPad Prism 5软件计算出IC50值。
7、实验结果:式I化合物对人肺癌细胞NCI-H460及人胚肺成纤维细胞HELF的体外增殖活性的IC50见下表:
实验结果表明,在没有光照的情况下化合物I-1、I-6、I-7、I-8和I-10对人肺癌细胞NCI-H460具有一定的抑制活性,而对人胚肺成纤维细胞HELF的抑制作用很弱,存在明显的选择性。其中,化合物I-5对两种细胞均没有明显的抑制作用。给予一段时间的可见光照射后,各化合物对人肺癌细胞NCI-H460增殖的抑制作用均具有极显著的增强,其抗肿瘤活性增强了200~10000倍。其中,化合物I-10对NCI-H460的抗增殖活性的IC50可以达到3.687nM。另一方面,光照也能增强化合物对人胚肺成纤维细胞HELF的抑制作用。虽然光照都能明显增强化合物对肺癌细胞NCI-H460和胚肺成纤维细胞HELF的体外增殖活性,但是此时大部分化合物仍能表现出一定的选择性。因此,从以上细胞水平测试的结果来看,式I化合物具有成为光动力学治疗药物的潜力。尤其重要的是,本发明化合物在无光照情况下具有很好的安全性,且在光照下具有一定的肿瘤选择性,因此有望开发成为更安全、有效的PDT光敏剂。
实施例21
片剂
将实施例1中制得的化合物I-1(50g)、羟丙甲基纤维素E(150g)、淀粉(200g)、聚维酮K30适量和硬脂酸镁(1g)混合,制粒,压片。
Claims (10)
1.如式I所示的10-取代吖啶-3(10)-酮类化合物或其药学上可接受的盐或溶剂化物:
其中R1为非取代或X取代的1~6碳的直链或支链烷烃、非取代或X取代的3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基;R2为氢、氟、氯、溴、碘、羟基、氨基、-OR5、-NR5R6、1~6碳的直链或支链烷烃,且R2为任意位置的单取代或多取代,可相同也可不同;R3为氢、氟、氯、溴、碘、1~6碳的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基、苯环上各种取代的苄基、烯丙基或炔丙基;R4为氢、氟、氯、溴、碘、1~6碳的直链或支链烷烃、羟基、氨基、-OR7或-NR7R8,且R4为任意位置的单取代或多取代,可相同也可不同;且当R1为甲基时,R2、R3和R4至少有一个不是氢;
R5为1~6碳的非取代或X取代的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基、烯丙基或炔丙基;
R6为氢、1~6碳的非取代或X取代的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基、烯丙基或炔丙基;
X为氟、氯、溴、碘、羟基、氨基、-OR7或-NR7R8,且X为单取代或多取代,可相同也可不同;
R7为1~6碳的非取代或取代的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基、烯丙基或炔丙基;
R8为氢、1~6碳的非取代或取代的直链或支链烷烃、3~6碳的环烷基、苯基、各种取代的苯基、苄基或苯环上各种取代的苄基、烯丙基或炔丙基。
2.根据权利要求1所述的式I化合物,其特征在于,所述的式I化合物中:R1为甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基或苄基;R2为氢、氟、氯、溴、羟基、氨基或-OR5,其中R5为甲基、乙基、丙基、丁基、异丁基、仲丁基、叔丁基、环丙甲基、环丁甲基、苄基、烯丙基、炔丙基、3-羟基正丙基、2-羟基乙基、2,3-二羟基丙基或3-氯正丙基;R3为氢、甲基、乙基、丙基、丁基、异丙基、异丁基、苯基或取代的苯基;R4为氢、氟、氯、溴、碘、羟基、氨基、甲基或乙基;且当R1为甲基时,R2、R3和R4至少有一个不是氢。
3.根据权利要求1所述的式I化合物,其特征在于,所述的式I化合物中:R1为甲基、乙基、丙基、丁基或苄基;R2为氢、6-氯、7-氯、6-羟基、6-甲氧基、6-乙氧基、6-正丙氧基、6-环丙甲氧基、6-苄氧基、6-炔丙氧基、6-烯丙氧基、6-(3-羟基丙氧基)、6-(2-羟基乙氧基)或6-(2,3-二羟基丙氧基);R3为氢、乙基、苯基或取代的苯基;R4为氢、氯、溴、羟基或甲基;且当R1为甲基时,R2、R3和R4至少有一个不是氢。
4.根据权利要求1所述的式I化合物,其特征在于,所述的式I化合物包括下列化合物:
10-乙基吖啶-3(10)-酮(I-2);
10-丙基吖啶-3(10)-酮(I-3);
10-丁基吖啶-3(10)-酮(I-4);
10-苄基吖啶-3(10)-酮(I-5);
6-氯-10-甲基吖啶-3(10)-酮(I-6);
7-氯-10-甲基吖啶-3(10)-酮(I-7);
6-甲氧基-10-甲基吖啶-3(10)-酮(1-8);
6-羟基-10-甲基吖啶-3(10)-酮(I-9);
6-苄氧基-10-甲基吖啶-3(10)-酮(I-10);
6-乙氧基-10-甲基吖啶-3(10)-酮(I-11);
6-丙氧基-10-甲基吖啶-3(10)-酮(I-12);
6-环丙甲氧基-10-甲基吖啶-3(10)-酮(I-13);
6-烯丙氧基-10-甲基吖啶-3(10)-酮(I-14);
6-炔丙氧基-10-甲基吖啶-3(10)-酮(I-15);
6-(2-羟基乙氧基)-10-甲基吖啶-3(10)-酮(I-16);
6-(3-羟基丙氧基)-10-甲基吖啶-3(10)-酮(I-17);
6-(2,3-二羟基丙氧基)-10-甲基吖啶-3(10)-酮(I-18);
9-乙基-10-甲基吖啶-3(10)-酮(I-19)。
5.如权利要求1所述的式I化合物的制备方法,如下反应式:
具体包括以下步骤:
(1)式II化合物与式VII化合物以及铜粉在碱性条件下加热发生乌尔曼偶联反应,制得式III化合物;
(2)式III化合物在酸性条件下发生分子内的环合,制得式IV化合物;
(3)式IV化合物经过还原、氧化制得式V化合物;
(4)式V化合物与卤代烃R1Y反应得到式VI化合物,其中,卤代烃R1Y中的R1如式I化合物中所定义,Y为碘、氯或溴;
(5)式VI化合物经过脱甲基反应,然后在碱性条件下异构化得到式Ia化合物;
(6)式Ia化合物与格式试剂R3MgY发生亲核加成,然后被氧化得到式I化合物,其中,格式试剂R3MgY中的R3如式I化合物中所定义,Y为碘、氯或溴;
在上述反应式中,R1、R2、R3和R4的定义如式I化合物中所定义。
6.如权利要求1至4中任一项所述的式I化合物或10-甲基吖啶-3(10)-酮(化合物I-1)或其药学上可接受的盐或溶剂化物作为光敏剂在疾病的光动力学防治方面的用途。
7.如权利要求6的用途,其特征在于,所述疾病包括恶性肿瘤、癌前病变或良性病变。
8.如权利要求7的用途,其特征在于,所述的恶性肿瘤是实体瘤,其选自于肺癌、皮肤癌、黑色素瘤、食管癌、膀胱癌、头颈部癌、鼻咽癌、支气管癌、乳腺癌、宫颈癌、胰腺癌、肝癌、胃癌、胆管癌、前列腺癌、脑肿瘤、结肠癌或上述实体瘤切除后的癌残留。
9.如权利要求7的用途,其特征在于,所述的癌前病变或良性病变选自于粘膜白斑、萎缩性胃炎、宫颈糜烂、乳腺囊性增生、老年日光性角化病、色素性干皮病、胃肠道息肉、视网膜黄斑变性、鲜红斑痣、银屑病、类风湿性关节炎、血管成形术后再狭窄、红斑狼疮皮损、类风湿性关节炎或动脉粥样硬化斑块。
10.一种光动力学防治疾病的药物组合物,其中含有治疗有效量的如权利要求1至4中任一项所述的式I化合物或10-甲基吖啶-3(10)-酮(化合物I-1)或其药学上可接受的盐或溶剂化物和药学上可接受的载体。
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CN110699677B (zh) * | 2019-10-21 | 2022-07-15 | 威海海洋生物医药产业技术研究院有限公司 | 一种碳钢表面的甲基吖啶盐的自组装膜及抗腐蚀性能 |
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