CN105884789A - 10-氟喜树碱类衍生物及其制备方法及用途 - Google Patents
10-氟喜树碱类衍生物及其制备方法及用途 Download PDFInfo
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明公开如式1示10氟‑喜树碱类衍生物,以及这类化合物的制备方法和其在制备
Description
技术领域
本发明涉及一种生物碱的衍生物其制备方法及用途,确切讲本发明涉及一种10-氟喜树碱类衍生物,以及这类化合物的制备方法和其在制备抗肿瘤药物中的用途。
背景技术
含氟药物在临床治疗药物中占有相当比重,将氟原子或含氟基团引入到小分子药物中, 是药物化学结构改造的重要研究策略之一。在药物中引入含氟或者含氟基团将会对药物的生物性质方面产生重要的影响。截至目前,有20%~25%的医药分子和30%的农药分子含有至少一个氟原子,这都要归于氟本身对于药物的重要影响,目前以氟为修饰的衍生药物已经成为药物开发的热点,其中一些含氟药物,如立普妥、氟达拉滨、5-Fu和氟西汀等药物已商品化。根据近年来人们对于药物的开发研究经验和药物的构效关系研究表明:将氟原子或含氟基团引入到小分子药物当中,通过调节药物小分子的物理化学特性改变小分子的药代动力学性质,增强药物在靶组织的分布, 提高药物的生物利用度;通过影响化合物的构象,增强配体与靶标蛋白的相互结合能力以及对其它靶标蛋白的选择性;通过阻断易代谢位点进而改变药物代谢的途径及代谢速率, 延长药物在体内的作用时间,提高药物代谢稳定性等特点((1)J. Fluorine Chem. 2006,127, 1013.;(2)Org. Process Res. Dev. 2008,12, 305.;(3)有机化学,2011,31, 1785)。利用这些特点, 在药物设计过程中引入氟原子以及含氟基团,在提高小分子药效的同时, 改变其药代动力学特性,使其发展成为临床治疗药物。
鉴于氟原子以及含氟基团在其药物结构优化和开发中的优点,本发明以天然源抗肿瘤物质喜树碱为先导,可望通过在喜树碱10位引入氟原子,同时,以喜树碱-抗肿瘤构效关系为依据,以10-氟喜树碱或10-氟-7-乙基-喜树碱为先导结构,设计合成了10-氟-20-双磷酰化喜树碱或7-乙基-10-氟-20-双磷酰化喜树碱;和10-氟-20-磺酰脒喜树碱或7-乙基-10-氟-20-磺酰脒喜树碱。
发明内容
本发明提供一种喜树碱类化合物物,同时提供这类化合物的制备方法及用途。
本发明的喜树碱类化合物是如式1示10氟-喜树碱类衍生物,
R1=H或Et,R2=式2示化合物磷酰或式3示磺酰脒化合物。
本发明的10氟-喜树碱类衍生物的制备方法包括下述步骤:
以10-喜树碱或10-氟-7乙基喜树碱为原料, 经与N-Boc-甘氨酸酯化,进而脱保护获得10-氟-20-甘氨酸-喜树碱三氟乙酸盐或7-乙基-10-氟-20-甘氨酸-喜树碱三氟乙酸盐中间体,以10-氟-20-甘氨酸-喜树碱三氟乙酸盐或7-乙基-10-氟-20-甘氨酸-喜树碱三氟乙酸盐为原料中间体,在其20-位进一步衍生合成10-氟-20-双磷酰化喜树碱或7-乙基-10-氟-20-双磷酰化喜树碱;和10-氟-20-磺酰脒喜树碱或7-乙基-10-氟-20-磺酰脒喜树碱,参见式4。
本发明的10氟-喜树碱类衍生物的制备方法可以是:将1当量的10-氟-20-甘氨酸-喜树碱三氟乙酸盐或1当量的7-乙基-10-氟-20-甘氨酸-喜树碱三氟乙酸盐溶于四氢呋喃中,再在其中加入1.2当量的三乙胺搅拌直至溶液变为澄清透明状态,然后再在其中加入1.2当量的37%甲醛水溶液和1.2当量的亚磷酸二乙酯,搅拌均匀后再加入0.2~0.6当量的三氯化铁,在53摄氏度下回流反应1,反应完毕后直接将反应液浓缩得油状固体,以氯仿/甲醇为洗脱剂将前述油状固体其进行柱层析纯化得到纯品。
本发明的10氟-喜树碱类衍生物的制备方法也可以是:将1当量的10-氟-20-甘氨酸-喜树碱三氟乙酸盐或1当量7-乙基-10-氟-20-甘氨酸-喜树碱三氟乙酸盐溶于二氯甲烷中,再在其中加入1.2当量的三乙胺搅拌直至溶液变为澄清透明状态,然后在氮气保护下加入1当量的对甲氧基苯乙炔、1.2当量的对甲基苯磺酰叠氮和0.1当量的碘化亚铜,混合物在常温搅拌下反应,反应完毕后加入氯化铵水溶液和二氯甲烷的混合液淬灭反应,浓缩后得固体残渣用氯仿/甲醇为洗脱剂进行柱层析纯化得到纯品。
在前述的制备方法中,其层析用硅胶柱采用200~300目的柱层析用硅胶。
本发明的10氟-喜树碱类衍生物可以在制备抗肿瘤药物中的应用,更为具体的是:可以在制备治疗人肺腺癌的药物中的应用,或者在制备治疗人乳腺癌的药物中的应用;或者在制备治疗人口腔表皮样癌的药物中的应用:或者在制备治疗人口腔表皮样癌细胞耐药株肿瘤的药物中的应用。
本发明以现有喜树碱的构效关系研究为指导,在喜树碱10位引入氟原子,这将有可能通过改变其生物性质方面的参数,从而得到活性更高、毒性更低的喜树碱衍生物。
经体外抗肿瘤活性筛选结果表明,式I的化合物对人肺腺癌细胞(A549)、人乳腺癌细胞株(MDA-MB-231)、人口腔表皮样癌细胞(KB)、人口腔表皮样癌细胞耐药株(KBvin)和人乳腺癌细胞(MCF-7)表现出较强的抑制活性,且所有化合物的活性高于目前临床药物伊立替康。因此,本发明制备的喜树碱类化合物可用于制备抗肿瘤的药物,且结构新颖、合成工艺简单、产品纯度高,对肿瘤细胞表现出较强的抑制作用,具有优良的应用前景。
具体实施方式
一、制备实施例
实施例1:目标化合物10-氟树碱(Ia)的合成
①氟化试剂F-TEDA-PF6的合成方法:将1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(F-TEDA-BF4)(3mmol)加入圆底烧瓶,并加入9mL水将其溶解,在常温下将六氟磷酸铵(18mmol)加入其中,室温下搅拌反应1小时。然后将此浑浊的反应液进行抽滤,将滤饼用水反复冲洗若干次,最后再用乙醚冲洗滤饼,将滤饼晾干,即为氟化试剂F-TEDA-PF6。
②10-三氟甲磺酸酯喜树碱的合成方法:将10-羟基喜树碱(1eq)加入圆底烧瓶中,加入适量DMF进行溶解,在室温下加入三乙胺(2eq)和N-苯基双(三氟甲烷磺酰)亚胺(1.5eq),然后将此反应液在50摄氏度下反应4小时。TLC监测反应完毕后,将反应液减压浓缩,得到固体残渣。以氯仿/甲醇为洗脱剂将其进行柱层析纯化得到纯品。
③10-三正丁基锡基喜树碱的合成方法:将10-三氟甲磺酸酯喜树碱(1eq)加入到封管中, 在加入氯化锂(5eq)和四三苯基膦钯(0.05eq),然后用带有气球的橡皮塞封住管口。将封管内空气反复用置换排空3~5次,然后用注射器将双三丁基锡(2eq)和适量的二氧六环打入封管内。将此混合物加热至100摄氏度反应24小时,反应结束后将其冷却至室温,加入二氯甲烷淬灭反应,减压浓缩呈油状固体。以氯仿/甲醇为洗脱剂将其进行柱层析纯化得到纯品。
④10-氟喜树碱的合成方法:将10-三正丁基锡基喜树碱(1eq)加入到圆底烧瓶内,加入适量干燥丙酮将其溶解,然后避光条件下加入三氟甲烷磺酸银(2eq),溶液呈棕黄色,室温搅拌15分钟后再将F-TEDA-PF6加入到上述反应液中,溶液呈黄色,反应半小时后TLC监测,反应完毕。加入二氯甲烷淬灭反应,然后减压浓缩反应液得固体残渣,以氯仿/甲醇为洗脱剂将其进行柱层析纯化得到纯品。
产率: 43%; 1H NMR (DMSO-d 6 , 400 MHz)δ: 8.68 (s, 1H, C7-H), 8.26 (d,1H,J=8Hz, C9-H), 7.98 (d, 1H, J=8Hz, C12-H), 7.80 (t, 1H,J=8Hz, C11-H),7.34 (s, 1H, C14-H), 6.55 (s, 1H, C20-OH), 5.43 (s, 2H, C17-H), 5.30 (s, 2H,C5-H), 1.93-1.82 (m, 2H, C19-H), 0.89 (t, 3H,J=8Hz, C18-H); MS-ESI m/z:389.4 [M+Na]+.。
实施例2:目标化合物 Ib的合成
与实施例1同,仅以7-乙基-10羟基喜树碱代替10-羟基喜树碱。反应所得产物检测数据如下:产率: 47%; 1H NMR (DMSO-d 6 , 400 MHz)δ: 8.25 (d, 1H,J=8Hz, C9-H), 8.07(d, 1H, J=8Hz, C12-H), 7.78 (t, 1H,J=8Hz, C11-H), 7.33 (s, 1H, C14-H), 6.54(s, 1H, C20-OH), 5.44 (s, 2H, C17-H), 5.33 (s, 2H, C5-H), 3.24-3.17 (m, 2H,C7-CH 2 -CH3), 1.91-1.84 (m, 2H, C19-H), 1.32 (t, 3H,J=8Hz, C7-CH2-CH 3 ), 0.89(t, 3H,J=8Hz, C18-H); MS-ESI m/z: 417.3 [M+Na]+.。
其反应参见反应式7
。
实施例3:目标化合物 Ic的合成
原料10-氟-20-甘氨酸-喜树碱三氟乙酸盐的合成:将10-氟喜树碱(1eq)置于圆底烧瓶中,加入适量的干燥二氯甲烷,将其置于冰浴中,待其冷却至零摄氏度,依次加入N-Boc-甘氨酸(3eq)和DMAP(3eq),搅拌均匀后,将DIPC(4.5eq)逐滴加入到反应液中,冰浴条件下反应半小时后撤去冰浴,在常温条件下反应12小时,TLC监测反应进程。反应完毕后,加入二氯甲烷淬灭反应,然后减压浓缩得油状固体,以氯仿/甲醇为洗脱剂将其进行柱层析纯化得到纯品。将所得产品溶于二氯甲烷/三氟乙酸=1/1的溶液中,搅拌过夜,减压浓缩得油状固体,用乙醚洗涤后得黄色粉末状固体,即为所得产品。其反应参见式9
。
Ic的合成:将10-氟-20-甘氨酸-喜树碱三氟乙酸盐(1eq)溶于适量二氯甲烷中,加入三乙胺(1.2eq)搅拌直至溶液变为澄清透明状态。然后在氮气保护下加入对甲氧基苯乙炔(1eq),对甲基苯磺酰叠氮(1.2eq)和碘化亚铜(0.1eq),混合物在常温搅拌下反应,TLC检测反应进程。约半小时,反应完毕。加入氯化铵水溶液和二氯甲烷的混合液淬灭反应。减压浓缩后得固体残渣,以氯仿/甲醇为洗脱剂将其进行柱层析纯化得到纯品。其反应参见反应式10
。
反应所得产物检测数据如下:产率: 21%; 1H NMR (DMSO-d 6 , 400 MHz)δ: 8.90(br, 1H, NH), 8.67 (s, 1H, C-7), 8.19 (d, 1H,J=8Hz, C9-H), 7.97 (d, 1H, J=8Hz, C12-H), 7.76 (t, 1H,J=8Hz, C11-H), 7.51-7.49 (m, 2H, Ar-H), 7.20-7.18(m, 2H, Ar-H), 7.10 (s, 1H, C14-H), 7.03-7.01 (m, 2H, Ar-H), 6.78-6.76 (m,2H, Ar-H), 5.48 (s, 2H, C17-H), 5.30 (s, 2H, C5-H), 4.39-4.33 (m, 1H, -COCH 2 NH-), 4.27-4.21 (m, 1H, -COCH 2 NH-), 4.01 (s, 2H, -CH 2 -Ar), 3.66 (s, 3H, -OCH3), 2.21 (s, 3H,CH 3 -Ar), 2.13-2.09 (m, 2H, C19-H), 0.85 (t, 3H,J=8Hz,C18-H); MS-ESI m/z: 747.8 [M+Na]+.实施例4:目标化合物 Id的合成
与实施例3同,仅以7-乙基-10-氟喜树碱代替10-氟喜树碱。反应所得产物检测数据如下:产率: 22%; 1H NMR (DMSO-d 6 , 400 MHz)δ: 8.90 (br, 1H, NH), 8.67 (s, 1H, C-7), 8.19 (d, 1H,J=8Hz, C9-H), 8.07 (d, 1H, J=8Hz, C12-H), 7.77 (t, 1H,J=8Hz, C11-H), 7.52-7.50 (m, 2H, Ar-H), 7.19-7.17 (m, 2H, Ar-H), 7.08 (s, 1H,C14-H), 7.01-6.99 (m, 2H, Ar-H), 6.78-6.75 (m, 2H, Ar-H), 5.50 (s, 2H, C17-H), 5.33 (s, 2H, C5-H), 4.35-4.33 (m, 1H, -COCH 2 NH-), 4.26-4.24 (m, 1H, -COCH 2 NH-), 4.00 (s, 2H, -CH 2 -Ar), 3.65 (s, 3H, -OCH3), 3.21-3.19 (m, 2H, C7-CH 2 -CH3), 2.19 (s, 3H,CH 3 -Ar), 2.13-2.09 (m, 2H, C19-H), 1.28 (t, 3H,J=8Hz,C7-CH2-CH 3 ), 0.86 (t, 3H,J=8Hz, C18-H); MS-ESI m/z: 775.7 [M+Na]+.
实施例5:目标化合物 Ie的合成
Ie的合成:将10-氟-20-甘氨酸-喜树碱三氟乙酸盐(1eq)溶于适量四氢呋喃中,加入三乙胺(1.2eq)搅拌直至溶液变为澄清透明状态。然后加入甲醛水溶液(1.2eq)和亚磷酸二乙酯(1.2eq),搅拌均匀后再加入催化量的三氯化铁。最后,在53摄氏度下回流反应16小时。TLC监测反应完毕后直接将反应液减压浓缩得油状固体,以氯仿/甲醇为洗脱剂将其进行柱层析纯化得到纯品。其反应参见式13
。
反应所得产物检测数据如下:产率: 14%; 1H NMR (DMSO-d 6 , 400 MHz)δ: 8.69(s, 1H, C-7), 8.22 (d, 1H,J=8Hz, C9-H), 7.99 (d, 1H, J=8Hz, C12-H), 7.81 (t,1H,J=8Hz, C11-H), 7.08 (s, 1H, C14-H), 5.53 (s, 2H, C17-H), 5.33 (s, 2H, C5-H), 4.48-4.41 (m, 2H, -COCH 2 NH-), 4.13 (s, 4H, -NCH2P-), 3.76-3.47 (m, 8H, -OCH 2 CH3), 2.19-2.12 (m, 2H, C19-H), 0.99-0.96 (m, 12H, -OCH2 CH 3 ), 0.93 (t, 3H,J=8Hz, C18-H); MS-ESI m/z: 746.6 [M+Na]+.
实施例6:目标化合物 If的合成
。
与实施例5同,仅以7-乙基-10-氟喜树碱代替10-氟喜树碱。反应所得产物检测数据如下:产率: 15%; 1H NMR (DMSO-d 6 , 400 MHz)δ: 8.22 (d, 1H,J=8Hz, C9-H), 8.08(d, 1H, J=8Hz, C12-H), 7.80 (t, 1H,J=8Hz, C11-H), 7.05 (s, 1H, C14-H), 5.53(s, 2H, C17-H), 5.37 (s, 2H, C5-H), 4.48-4.42 (m, 2H, -COCH 2 NH-), 4.13 (s,4H, -NCH2P-), 3.76-3.59 (m, 8H, -OCH 2 CH3), 3.23-3.21 (m, 2H, C7-CH 2 -CH3), 2.17-2.13 (m, 2H, C19-H), 1.29 (t, 3H,J=8Hz, C7-CH2-CH 3 ), 1.01-0.99 (m, 12H, -OCH2 CH 3 ), 0.93 (t, 3H,J=8Hz, C18-H); MS-ESI m/z: 634.8 [M+Na]+.
二、化合物Ia-f的抗肿瘤活性的试验方法及结果
本发明的药理实验采用磺酰罗丹明B(sulforhodamine B,SRB)比色法。肿瘤细胞培养选用10%胎牛血清(FBS)的RPMI-1640培养基,将肿瘤细胞接种于96孔板,每个孔培养3-5×103个细胞,加入不同浓度的待测试目标化合物溶液。培养72小时后,每孔加入预冷的三氯乙酸溶液(50%,w/v)固定细胞,冰箱中固定30分钟。待96孔板室温下晾干后,每孔加入0.04%(w/v)的SRB染液(1%的乙酸配制,购自Sigma Chemical公司),染色30分钟后倒掉染液,用乙酸冲洗4次,去除未结合的染料,室温晾干。用100µL非缓冲Tris-base碱液溶解与细胞蛋白结合的染料,水平摇床上振荡20分钟,采用ELx800吸收光酶标仪(美国Bio-Tek公司生产,操作软件Gen5)测定515nm处吸收值。所有试验设3个平行组或重复三次。化合物Ia-f的细胞毒活性测试结果见表1。
表1 化合物Ia-f的细胞毒活性试验结果
注:(1)筛选方法:磺酰罗丹明B比色法;(2)作用时间:48小时;(3)化合物编号Ia-f分别为前述实施例1至实施例6所得产物。
Claims (10)
1.如式1示10氟-喜树碱类衍生物,
其中:R1=H或Et,R2=式2示化合物或式3示化合物。
2.权利要求1所述的10氟-喜树碱类衍生物的制备方法,其特征在于如式4所示,即包括下述步骤:
以10-喜树碱或10-氟-7乙基喜树碱为原料, 经与N-Boc-甘氨酸酯化,进而脱保护获得10-氟-20-甘氨酸-喜树碱三氟乙酸盐或7-乙基-10-氟-20-甘氨酸-喜树碱三氟乙酸盐中间体,以10-氟-20-甘氨酸-喜树碱三氟乙酸盐或7-乙基-10-氟-20-甘氨酸-喜树碱三氟乙酸盐为原料中间体,在其20-位进一步衍生合成10-氟-20-双磷酰化喜树碱或7-乙基-10-氟-20-双磷酰化喜树碱;和10-氟-20-磺酰脒喜树碱或7-乙基-10-氟-20-磺酰脒喜树碱。
3.根据权利要求2所述的10氟-喜树碱类衍生物的制备方法,其特征在于:将1当量的10-氟-20-甘氨酸-喜树碱三氟乙酸盐或1当量的7-乙基-10-氟-20-甘氨酸-喜树碱三氟乙酸盐溶于四氢呋喃中,再在其中加入1.2当量的三乙胺搅拌直至溶液变为澄清透明状态,然后再在其中加入1.2当量的甲醛水溶液37%和1.2当量的亚磷酸二乙酯,搅拌均匀后再加入0.2~0.6当量的三氯化铁,在53摄氏度下回流反应1,反应完毕后直接将反应液浓缩得油状固体,以氯仿/甲醇为洗脱剂将前述油状固体其进行柱层析纯化得到纯品。
4.根据权利要求2所述的10氟-喜树碱类衍生物的制备方法,其特征在于:将1当量的10-氟-20-甘氨酸-喜树碱三氟乙酸盐或1当量7-乙基-10-氟-20-甘氨酸-喜树碱三氟乙酸盐溶于二氯甲烷中,再在其中加入1.2当量的三乙胺搅拌直至溶液变为澄清透明状态,然后在氮气保护下加入1当量的对甲氧基苯乙炔、1.2当量的对甲基苯磺酰叠氮和0.1当量的碘化亚铜,混合物在常温搅拌下反应,反应完毕后加入氯化铵水溶液和二氯甲烷的混合液淬灭反应,浓缩后得固体残渣用氯仿/甲醇为洗脱剂进行柱层析纯化得到纯品。
5.根据权利要求2-4所述的任一方法,其特征在于层析用硅胶柱采用200~300目的柱层析用硅胶。
6.权利要求1所述的10氟-喜树碱类衍生物在制备抗肿瘤药物中的应用。
7.根据权利要求1所述的10氟-喜树碱类衍生物在制备治疗人肺腺癌的药物中的应用。
8.根据权利要求1所述的10氟-喜树碱类衍生物在制备治疗人乳腺癌的药物中的应用。
9.根据权利要求1所述的10氟-喜树碱类衍生物在制备治疗人口腔表皮样癌的药物中的应用。
10.根据权利要求1所述的10氟-喜树碱类衍生物在制备治疗人口腔表皮样癌细胞耐药株肿瘤的药物中的应用。
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CN111689978A (zh) * | 2019-03-11 | 2020-09-22 | 兰州大学 | 一种喜树碱20-位修饰的磺酰胺类化合物及其制备方法和用途 |
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CN108690035A (zh) * | 2017-12-25 | 2018-10-23 | 兰州大学 | 一种7-乙基-10-氟-喜树碱-20-肉桂酯类化合物、制备方法和用途 |
CN111689978A (zh) * | 2019-03-11 | 2020-09-22 | 兰州大学 | 一种喜树碱20-位修饰的磺酰胺类化合物及其制备方法和用途 |
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