CN109912589B - 谷氨酰胺酰氨基正己酰咔啉羧酸苄酯,其制备,活性和应用 - Google Patents
谷氨酰胺酰氨基正己酰咔啉羧酸苄酯,其制备,活性和应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及下面结构的(3S)-N-(6-谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯,涉及它的制备方法,涉及它的抗肿瘤作用。因而本发明涉及它在制备抗肿瘤药物中的应用。本发明属于生物医药领域。
技术背景
恶性肿瘤严重威胁人类健康。其中肺癌是最具侵略性的人类癌症之一。对于肺癌患者晚期的患者,通常10%-15%的人只能存活5年。在过去的30年里这种困难的局面尚未显著有所改善。在很多临床病例中,肺癌在被诊断之前已经转移到周围组织。肿瘤转移,尤其是肿瘤肺转移是肿瘤患者死亡的最大风险。至今,仍然没有可预防肿瘤转移的抗肿瘤药物用于临床。炎症则会进一步恶化肿瘤及肿瘤转移患者的预后。至今,更没有可预防炎症及肿瘤转移的抗肿瘤药物用于临床。发明具有抗肿瘤,抗肿瘤转移和抗炎三重作用的药物是抗肿瘤药物研究的前沿。发明人的前期发明(专利申请公布号CN 106349148A,申请号CN201510409682.6)曾经公开,在0.2μmol/kg剂量下氨基酸苄酯取代的双吲哚乙酸醇具有抗肿瘤,抗肿瘤转移和抗炎三重作用(左式)。发明人对这类双吲哚乙醇氨基酸酸苄酯发挥抗肿瘤作用的最低有效剂量是0.2μmol/kg不满意。剂量偏高。在过去的两年里,发明人一直在寻找最低有效剂量比0.2μmol/kg低的抗肿瘤作用化合物。最终发明人发现,6-谷氨酰胺酰氨基己酸修饰的四氢咔啉羧酸苄酯在0.02μmol/kg剂量下具有抗肿瘤作用。因为药物的毒副作用都可以随剂量降低而消失,所以有效剂量降低10倍表明了这种结构修饰有突出的技术效果。于是,发明人提出了本发明。
发明内容
本发明的第一个内容是提供下面结构的(3S)-N-(6-谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯。
本发明的第二个内容是提供(3S)-N-(6-谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯的制备方法,该方法包括:
(1)在稀硫酸的催化下,L-色氨酸苄酯和甲醛进行Pictet-Spengler反应生成(3S)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯;
(2)在氢氧化钠水溶液(2M),水与二氧六环混合溶液中6-氨基己酸与二碳酸二叔丁酯(Boc)2O反应生成6-叔丁氧羰氨基己酸;
(3)在N,N-二环己基碳二亚胺(DCC)和N-羟基苯并三氮唑(HOBt)存在下,在无水四氢呋喃中,6-叔丁氧羰氨基己酸与(3S)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯反应,得到(3S)-N-(6-叔丁氧羰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯;
(4)冰浴下在氯化氢的乙酸乙酯溶液中(4M),(3S)-N-(6-叔丁氧羰基氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯脱除Boc得(3S)-N-(6-氨基正己酰基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯;
(5)在N,N-二环己基碳二亚胺和N-羟基苯并三氮唑存在下,在无水四氢呋喃中,(3S)-N-(6-氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯与Boc-L-Gln反应,得到(3S)-N-(6-叔丁氧羰谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯;
(6)冰浴下在氯化氢的乙酸乙酯溶液中(4M),(3S)-N-(6-叔丁氧羰谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯脱除Boc得(3S)-N-(6-谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯。
本发明的第三个内容是评价(3S)-N-(6-谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯对S180小鼠肿瘤生长的抑制作用。
附图说明
图1.(3S)-N-(6-谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯的合成路线.ⅰ)HCHO,H2O,H2SO4;ⅱ)N,N-二环己基碳二亚胺(DCC),N-羟基苯并三氮唑(HOBt),N-甲基吗啉,四氢呋喃;ⅲ)二氧六环,氢氧化钠水溶液,二碳酸二叔丁酯(Boc)2O;ⅳ)氯化氢/乙酸乙酯(4M)。
具体实施方式
为了进一步阐述本发明,下面给出一系列实施例。这些实施例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
实施例1制备(3S)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(1)
冰浴下向300mL水缓慢加入1.5mL浓H2SO4,搅拌3min。之后加入5.00g(15.1mmol)L-色氨酸苄酯盐酸盐和6mL甲醛溶液(40%)。室温搅拌72h,TLC显示L-色氨酸苄酯盐酸盐消失。反应液在冰浴下用浓氨水调溶液pH为7,过滤。滤饼用100mL乙酸乙酯溶解,得到的溶液用饱和氯化钠水溶液洗(40mL×3),之后用无水硫酸钠干燥。过滤,滤液减压浓缩。残留物经硅胶柱层析纯化(二氯甲烷:甲醇=90:1)得1.9g(41%)目标化合物,为黄色油状固体。ESI-MS(m/e):307[M+H]+。
实施例2制备6-叔丁氧羰氨基己酸(2)
将5.00g(38.2mmol)6-氨基己酸(EACA)用50mL蒸馏水悬浮。得到的悬浮液于冰浴下加入10mL氢氧化钠水溶液(2M),搅拌至溶解。往得到的溶液中加9.2g(42.2mmol)(Boc)2O与20mL二氧六环的溶液并用氢氧化钠水溶液(2M)调pH至9,搅拌30min。撤去冰浴,室温搅拌至TLC显示6-氨基己酸消失。冰浴下反应液用饱和KHSO4水溶液调节pH至7,减压浓缩除去二氧六环。冰浴下反应液用饱和KHSO4水溶液调节pH至2,用乙酸乙酯萃取(50mL×3)。乙酸乙酯层用饱和NaCl水溶液洗(40mL×3),用无水硫酸钠干燥。过滤,滤液减压浓缩得8.0g(91%)目标化合物,为无色油状物。ESI-MS(m/e):232[M+H]+。
实施例3制备(3S)-N-(6-叔丁氧羰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(3)
将4.15g(18mmol)叔丁氧羰基-6-氨基己酸用80mL无水四氢呋喃溶解,冰浴下加入2.46g(18.2mmol)N-羟基苯骈三氮唑(HOBt)和4.04g(19.6mmol)N,N-二环己基碳二亚胺(DCC),搅拌60分钟。之后,往得到反应液加5.06g(16.5mmol)(3S)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯与80mL无水四氢呋喃的溶液。反应混合物于冰浴下用N-甲基吗啉(NMM)调pH至9,室温搅拌24小时。TLC显示(3S)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯消失。反应液过滤,滤液减压浓缩,残留物加乙酸乙酯溶解。溶液依次用饱和NaHCO3水溶液洗(40mL×3),饱和NaCl水溶液洗(40mL×3),饱和KHSO4水溶液洗(40mL×3),饱和NaCl水溶液洗(40mL×3),饱和NaHCO3水溶液洗(40mL×3),饱和NaCl水溶液洗(40mL×3)。乙酸乙酯层用无水Na2SO4干燥,过滤,滤液减压浓缩,残留物经硅胶柱层析纯化(二氯甲烷:甲醇=160:1)得5.43g(64%)目标化合物,为黄色油状固体。ESI-MS(m/e):520[M+H]+。
实施例4制备(3S)-N-(6-氨基正己酰基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(4)
冰浴下将3.4g(6.6mmol)(3S)-N-(叔丁氧羰基氨基正己酰基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯用40mL氯化氢的乙酸乙酯溶液(4M)溶解,搅拌3小时,TLC显示(3S)-N-(叔丁氧羰基氨基正己酰基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯消失。搅拌下将反应混合物减压浓缩至干。残留物加无水乙酸乙酯溶解,溶液再减压浓缩至干。该操作重复三次。残留物加无水乙醚充分洗,得2.8g(94%)目标化合物,为棕褐色固体。ESI-MS(m/e):420[M+H]+;Mp223-226℃。1H NMR(300MHz,DMSO-d6:δ/ppm=10.963(d,J=11.4Hz,1H),7.894(s,3H),7.458(d,J=7.5Hz,1H),7.327(t,J=7.5Hz,1H),7.204(dd,J1=1.5Hz,J2=7.2Hz,1H),7.158-6.972(m,6H),5.607(d,J=4.7Hz,1H),5.059(s,2H),4767(d,J=15.6Hz,1H),4.610(d,J=17.4Hz,1H),3.426(m,1H),3.021(m,1H),2.754(m,2H),2.613(m,1H),2.389(m,1H),1.568-1.546(m,4H),1.399-1.323(m,2H)。
实施例5制备(3S)-N-(6-叔丁氧羰谷氨酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(5)
将1.04g(4.2mmol)Boc-Gln和0.57g(4.2mmol)N-羟基苯骈三氮唑(HOBt)用30mL无水四氢呋喃溶解,冰浴下加入0.87g(4.2mmol)N,N-二环己基碳二亚胺(DCC),搅拌40分钟。之后,往得到反应液中加0.58g(4.2mmol)(3S)-N-(6-氨基正己酰基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯与30mL无水四氢呋喃的溶液,冰浴下用N-甲基吗啉(NMM)调pH至8,室温搅拌12小时。TLC显示(3S)-N-(6-氨基正己酰基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯消失,反应液过滤,滤液减压浓缩,残留物加100mL乙酸乙酯溶解。溶液依次用饱和NaHCO3水溶液洗(40mL×3),饱和NaCl水溶液洗(40mL×3),饱和KHSO4水溶液洗(40mL×3),饱和NaCl水溶液洗(40mL×3),饱和NaHCO3水溶液洗(40mL×3),饱和NaCl水溶液洗(40mL×3)。乙酸乙酯层用无水Na2SO4干燥,过滤,滤液减压浓缩,残留物经硅胶柱层析纯化(二氯甲烷:甲醇=60:1)得到0.30g(13%)标题化合物,为淡黄色固体。ESI-MS(m/z):648[M+H]+。
实施例6制备(3S)-N-(6-谷氨酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯(6)
将600mg(3S)-N-(6-叔丁氧羰谷氨酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯于冰浴下加入16mL氯化氢的乙酸乙酯溶液(4M)并搅拌2h,TLC(乙酸乙酯:水:冰醋酸=3:1:1.2)显示(3S)-N-(6-叔丁氧羰谷氨酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯消失。反应液减压浓缩至干。残留物加无水乙酸乙酯溶解,再减压浓缩至干。该操作重复三次。残留物加无水乙醚充分洗,之后经C18柱层析纯化(甲醇:水=30:70)并冻干得到320mg(63%)标题化合物,为淡黄色固体。ESI-MS(m/e):548[M+H]+.Mp123-124℃;1HNMR(300MHz,DMSO-d6:δ/ppm=10.979(d,J=12.0Hz,1H),8.577(dd,J1=5.1Hz,J2=10.5Hz,1H),8.238(s,3H),7.507(s,1H),7.455(d,J=7.8Hz,1H),7.330(t,J=7.8Hz,1H),7.240-7.074(m,8H),5.604(d,J=4.5Hz,1H),5.059(s,2H),4770(d,J=15.6Hz,1H),4.632(d,J=17.1Hz,1H),3.750(dd,J1=4.8Hz,J2=6.3Hz,1H),3.450(m,1H),3.161-3.056(m,3H),2.569(m,1H),2.429(m,1H),2.185(m,2H),1.944(m,2H),1.558(m,2H),1.453(m,2H),1.334(m,2H)。
实验例1评价化合物6的抗肿瘤活性
1)化合物6a-e用生理盐水溶解,阿霉素用生理盐水溶解作为阳性对照,生理盐水作为阴性对照;
2)化合物6的口服剂量为0.02μmol/kg,化合物4的口服剂量为0.2μmol/kg,生理盐水的口服剂量为0.2mL/20g,阿霉素腹腔注射剂量为2μmol/kg。肿瘤接种5天后开始给药,连续给药10天,共给药10次。
3)实验动物为ICR雄性小鼠(清洁级),体重20±2g,每组12只小鼠。
4)瘤源为小鼠S180肉瘤,购自北京大学医学部动物实验中心,自行传代维持。
5)无菌条件下抽取接种生长旺盛的S180腹水瘤瘤液,用生理盐水稀释成(1:2)的液体充分混合,将肿瘤细胞悬液用新鲜配制的0.2%台盼蓝染色,混匀后按白细胞计数方法计数,染蓝色者为死细胞,不染色者为活细胞。按细胞浓度=4大方格内活细胞数/4×104×稀释倍数=细胞数/mL计算细胞浓度。按细胞存活率=活细胞数/(活细胞数+死细胞数)×100%计算细胞存活率。
将存活率大于90%的瘤液用匀浆法制备成2.0×107个/mL的细胞悬液,于鼠腋皮下接种,0.2mL/只,制造S180荷瘤小鼠。肿瘤接种5天后给药。治疗组小鼠每日口服化合物4剂量为0.2μmol/kg,或化合物6a口服剂量为0.02μmol/kg。空白组小鼠每日口服生理盐水剂量为0.2mL/20g。阳性对照组小鼠每日腹腔注射阿霉素剂量为2μmol/kg。连续给药十天,第十一天称小鼠体重,乙醚麻醉,脱颈椎处死小鼠,然后用镊子固定小鼠右腋肿瘤生长部位,剪开皮肤,暴露肿瘤,钝性剥离,称重。实验数据采用t检验和方差分析,瘤重以(均值±SDg)表示。结果见表1。由表1可以看出,在0.02μmol/kg口服剂量下,化合物6不仅可有效地抑制小鼠的瘤重生长,而且活性与阿霉素没有显著性差异。化合物6的有效剂量是阿霉素的1/100。本发明有显著的技术效果。
表1 化合物6的抗肿瘤活性
a)与生理盐水比p<0.05;b)与生理盐水比p<0.01,与阿霉素比p>0.05;n=12。
Claims (3)
2.权利要求1的(3S)-N-(6-谷氨酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯的制备方法,该方法由以下步骤构成:
(1)在稀硫酸的催化下,L-色氨酸苄酯和甲醛进行Pictet-Spengler反应生成(3S)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯;
(2)在氢氧化钠水溶液(2M),水与二氧六环混合溶液中6-氨基己酸与二碳酸二叔丁酯(Boc)2O反应生成6-叔丁氧羰氨基己酸;
(3)在N,N-二环己基碳二亚胺(DCC)和N-羟基苯并三氮唑(HOBt)存在下,在无水四氢呋喃中,6-叔丁氧羰氨基己酸与(3S)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯反应,得到(3S)-N-(6-叔丁氧羰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯;
(4)冰浴下在氯化氢的乙酸乙酯溶液中(4M),(3S)-N-(6-叔丁氧羰基氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯脱除Boc得(3S)-N-(6-氨基正己酰基)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯;
(5)在N,N-二环己基碳二亚胺和N-羟基苯并三氮唑存在下,在无水四氢呋喃中,(3S)-N-(6-氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯与Boc-L-Gln反应,得到(3S)-N-(6-叔丁氧羰谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯;
(6)冰浴下在氯化氢的乙酸乙酯溶液中(4M),(3S)-N-(6-叔丁氧羰谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯脱除Boc得(3S)-N-(6-谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯。
3.权利要求1的(3S)-N-(6-谷胺酰胺酰氨基正己酰)-2,3,4,9-四氢-β-咔啉-3-羧酸苄酯在制备抗肿瘤药物中的应用。
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