CN103833646A - 一种脂肪氨基取代喹唑啉酮衍生物及其制备方法和应用 - Google Patents
一种脂肪氨基取代喹唑啉酮衍生物及其制备方法和应用 Download PDFInfo
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- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本发明公开一种脂肪氨基取代喹唑啉酮衍生物及其制备方法和应用，该衍生物的化学结构式如式（Ⅰ）所示，式中n=1、2、3或4；R1、R2可以相同，也可以不同，分别选自C1-6的烷基、C3-6的环烷基、CH2CH3OCH3或Bn；R3是OH、NH2、NHR4或NR5R6；R4为C1-6的烷基、C3-6的环烷基；R5、R6分别为C1-6的烷基、C3-6的环烷基、哌啶基、吗啉基、哌嗪基或吡咯基；本发明的脂肪氨基取代喹唑啉酮衍生物对多种癌细胞株具有显著的抑制作用，对正常细胞毒性较小，因此可制备为抗肿瘤药物，具有较高的医学价值和市场前景。
Description
技术领域
本发明涉及新药物化合物，具体涉及一种脂肪氨基取代喹唑啉酮衍生物及其制备方法，以及该类化合物在制备抗肿瘤药物中的应用。
背景技术
肿瘤（癌症）是目前严重威胁人类健康和生命安全的主要疾病之一。抗肿瘤药物的研究与开发一直是药物学家关注的热点。寻找高效、高选择性、低毒副作用的抗肿瘤药物是药物研究开发的重要方向之一。
喹唑啉酮类生物碱是生物碱中的一大类，是骆驼宁碱、常山碱、常山酮、色胺酮等药物的主要结构片段。这些生物碱是骆驼蒿、常山、大青叶等中药中的有效成分，具有广泛的生物活性。近年来的研究表明，人工合成的喹唑啉酮类化合物也具有重要的生物活性。例如抗叶酸剂雷替曲塞(Raltitrexed)自1996年在英国上市后，用于晚期结、直肠癌的治疗（Eur.J.Cancer,2002,38,478-486）。而另一喹唑啉酮衍生物AG337能有效地抑制耐药的肿瘤细胞，已进入临床试验（Cancer Chemother.Pharmacol.，1996,37,509-517）。
因此，以喹唑啉酮的母核为基础进行结构改造，是发现具有更好抗癌活性化合物的一条可行途径。在母核内酰胺键的N上引入脂肪胺链可能使化合物活性产生很大的改变或者产生新的药理活性。可以预测以喹唑啉酮结构为母核设计并合成的系列新型生物碱可能会具有较好的抗肿瘤活性。
发明内容
本发明的目的是提供一种脂肪氨基取代喹唑啉酮衍生物。
本发明的另一个目的是提供上述脂肪氨基取代喹唑啉酮衍生物的制备方法。
本发明的另一个目的是提供上述脂肪氨基取代喹唑啉酮衍生物在制备抗肿瘤药物中的应用。
本发明的上述技术目的是通过以下方案予以实现的：
本发明提供的一种脂肪氨基取代喹唑啉酮衍生物，具有如下化学结构通式（I）：
式中R1、R2可以相同，也可以不同，分别选自C1-6的烷基、C3-6的环烷基、CH2CH3OCH3或Bn；R3是OH、NH2、NHR4或NR5R6；R4为C1-6的烷基、C3-6的环烷基；R5、R6分别为C1-6的烷基、C3-6的环烷基、哌啶基、吗啉基、哌嗪基或吡咯基；n=1、2、3或4。
本发明还提供一种脂肪氨基取代喹唑啉酮衍生物的制备方法，
反应通式为：
反应通式中的R1、R2、R3及n如权利要求1中所示；
该制备方法包括如下步骤：
将上述喹唑啉酮衍生物
与反应溶剂乙腈混合，加入碳酸钾作为催化剂，加入上述脂肪胺链，在80℃搅拌10小时，冷却后抽滤，将滤液浓缩收集固体，用硅胶柱层析纯化，得脂肪氨基取代喹唑啉酮衍生物。
上述喹唑啉酮衍生物与脂肪胺链的摩尔比是1:1.2。
反应溶剂乙腈适量加入。
催化剂碳酸钾是过量摩尔比。
本发明的脂肪氨基取代喹唑啉酮衍生物可与药学上可接受的辅助剂混合，制备各种剂型的抗肿瘤药物，如片剂、丸剂、胶囊、注射剂、悬浮剂或乳剂等。
与现有技术相比，本发明具有如下有益效果：
1.本发明的脂肪氨基取代喹唑啉酮衍生物对多种癌细胞株具有显著的抑制作用；
2.本发明的脂肪氨基取代喹唑啉酮衍生物对正常细胞毒性较小，在制备抗肿瘤药物的应用中安全性高；
3.本发明的脂肪氨基取代喹唑啉酮衍生物可以制成各种剂型的抗肿瘤药物，具有很高的医学价值和广阔的市场前景。
具体实施方式
实施例1
14(溴丁烷-二-甲基乙基醚-喹唑啉酮)
取碳酸钾0.235g溶于30ml乙腈中，加热80℃搅拌20Min，加入0.5g
保持80℃搅拌1h，加入0.44g1,4-二溴丁烷，保持80℃搅拌10h，冷却后抽滤，将滤液浓缩收集固体，用硅胶柱层析纯化，得到白色粉末化合物（名称），其化学结构式如式（Ⅱ）所示：
产率：87%；M.P.:169-171℃;1HNMR(400Hz.DMSO-d6)8.28(1H,s),7.5(1H,s),7.2(1H,s,),4.27(2H,d,J=8.0Hz),4.26(2H,t,J=8.0Hz),3.99(2H,s,J=8.0Hz),3.73(4H,t,J=8.0Hz),3.57(2H,t,J=8.0Hz),3.33(m,4H),2.50(2H,d,J=8.0Hz),1.82(s,4H)ESI-MSm/z450.91[M-I]+；元素分析C18H25BrN2O5，理论值C,58.42;H,3.79;N,6.19.实测值C,50.12;H,4.01;N,5.93。
实施例2
化合物6,7-双(2-甲氧基乙氧基）-3–丁基吡咯烷-喹唑啉酮的合成
取碳酸钾0.235g溶于30ml乙腈中，加热80℃搅拌20Min，加入0.5g6,7-双(2-甲氧基乙氧基）喹唑啉酮，保持80℃搅拌1h，加入0.44g4-溴丁基吡咯烷，保持80℃搅拌10h，冷却后抽滤，将滤液浓缩收集固体，用硅胶柱层析纯化，得到白色粉末化合物6,7-双(2-甲氧基乙氧基）-3–丁基吡咯烷-喹唑啉酮，其结构式如式（Ⅲ）所示：
产率：88%；M.P.:169-171℃;1HNMR(400Hz,DMSO-d6)8.28(1H,s),7.48(1H,s),7.16(1H,s),4.26(2H,t,J=4.0Hz),4.22(2H,t,J=4.0Hz),3.94(2H,t,J=6.0Hz),3.73(4H,m),3.41(6H,s),2.38(6H,m),1.72(2H,t,J=7.2Hz),1.64(4H,m),1.43(2H,m)ESI-MSm/z420.09[M-I]+；元素分析C22H33N3O5，理论值C,58.42;H,3.79;N,6.19.实测值C,56.22;H,4.01;N,5.50。
实施例3
化合物6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮的合成
本实施例的制备方法除了用3-溴丙基吗啉代替4-溴丁基吡咯烷外，其余同实施例1，最后得白色粉末化合物6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮，其结构式如式（Ⅳ）所示：
产率：87%；M.P.:169-171℃;1HNMR(400Hz.DMSO-d6)8.26(1H,s),7.48(1H,s),7.15(1H,s),4.27(2H,t,J=4.0Hz),4.20(2H,t,J=4.0Hz),3.99(2H,t,J=4.0Hz),3.72(4H,m),3.49(4H,m),3.36(6H,m),2.31(6H,m),1.86(2H,m)ESI-MSm/z421.22[M-I]+；元素分析C21H31N3O6，理论值C,58.42;H,3.79;N,6.19.实测值C,49.22;H,4.01;N,5.50。
实施例4
6,7-双(2-甲氧基乙氧基）-3-（4-哌啶基甲酸叔丁酯）喹唑啉酮的合成
本实施例的制备方法除了用4-溴哌啶基甲酸叔丁酯代替4-溴丁基吡咯烷外，其余同实施例1，最后得白色粉末化合物6,7-双(2-甲氧基乙氧基）-3-（4-溴哌啶基甲酸叔丁酯）喹唑啉酮其结构式如式（Ⅴ）所示：
产率：87%；M.P.:169-171℃;1HNMR(400Hz.DMSO-d6)8.24(1H,s),7.49(1H,s),7.17(1H,s),4.26(2H,t,J=8.0Hz),4.21(2H,t,J=4HZ),3.95(2H,m),3.86(2H,t,J=4.0Hz),3.72(4H,m),3.36(8H,m),1.98(1H,m),1.53(2H,m),1.39(9H,m),1.12(2H,m)ESI-MSm/z429.21[M-I]+；元素分析C21H28N3O6，理论值C,58.42;H,3.79;N,6.19.实测值C,49.22;H,4.01;N,5.50。
实施例5
7-（苄氧基）-6-甲氧基-3-（3-丙基吗啉）喹唑啉酮的合成
本本实施例的制备方法实施例1，所不同的是用7-（苄氧基）-6-（甲氧基）喹唑啉酮替代6,7-双(2-甲氧基乙氧基）喹唑啉酮，用3-溴丙基吗啉替代4-溴丁基吡咯烷，得白色粉末化合物7-（苄氧基）-6-甲氧基-3-（3-吗啉代丙基）喹唑啉酮，其结构式如式（Ⅵ）所示：
产率：82%；M.P.:169-171℃;1HNMR(400Hz.DMSO-d6)8.27(1H,s),7.50(3H,m),7.44(2H,d,J=8HZ),7.36(1H,m),7.23(1H,s),5.26(2H,s),4.01(2H,t,J=8.0Hz),3.88(3H,s),3.50(4H,m),2,31（6H,m）,1.86(2H,m)ESI-MSm/z409.20[M-I]+；元素分析C23H27N3O4，理论值C,58.42;H,3.79;N,6.19.实测值C,54,79;H,4.01;N,5.92。
实施例6
7-（苄氧基）-6-甲氧基-3-（4-哌啶基甲酸叔丁酯）喹唑啉酮的合成
本实施例的制备方法实施例1，所不同的是用7-（苄氧基）-6-（甲氧基）喹唑啉酮替代6,7-双(2-甲氧基乙氧基）喹唑啉酮，用4-溴哌啶基甲酸叔丁酯替代4-溴丁基吡咯烷，最后得白色粉末化合物7-（苄氧基）-6-甲氧基-3-（3-吗啉代丙基）喹唑啉酮，其结构式如式（Ⅶ）所示：
产率：87%；M.P.:169-171℃;1HNMR(400Hz.DMSO-d6)8.24(1H,s),7.49(3H,m),7.43(2H,d,J=4HZ),7.35(1H,m),7.24(1H,s),5.27(2H,s),3.89(3H,m),,2.67(2H,d,J=8.0Hz),2.51(4H,m),1.98(1H,s),1.52(2H,d,J=12.0Hz),1.39(9H,m),1.1(2H,m)ESI-MSm/z417.27[M-I]+；元素分析C23H27N3O4，理论值C,58.42;H,3.79;N,6.19.实测值C,54,21;H,4.01;N,5.80。
实施例7
7-（苄氧基）-6-（甲氧基）-3-（4-甲基哌啶）喹唑啉酮的合成
本实施例的制备方法实施例1，所不同的是用7-（苄氧基）-6-（甲氧基）喹唑啉酮替代6,7-双(2-甲氧基乙氧基）喹唑啉酮，用4–溴甲基哌啶替代4-溴丁基吡咯烷，最后得白色粉末化合物7-（苄氧基）-6-（甲氧基）-3-（4-甲基哌啶）喹唑啉酮，其结构式如式（Ⅶ）所示：
产率：82%；M.P.:169-171℃;1HNMR(400Hz.DMSO-d6)8.23(1H,s),7.49(3H,m),7.42(2H,t,J=8Hz),7.41(1H,s),5.27(2H,s),3.89(3H,s),3.83(2H,d,J=4.0Hz),2.89(1H,s),2.51(4H,m),2.36(1H,m),1.85(1H,m),1.43(2H,d,J=12.0Hz),1.07(2H,m).ESI-MSm/z417.27[M-I]+；元素分析C22H5N3O3，理论值C,58.42;H,3.79;N,6.19.实测值C,56.34;H,4.01;N,5.50。
实施例8
脂肪氨基取代喹唑啉酮衍生物对肿瘤细胞生长的抑制作用
选择选择实施例4～6制备的化合物，以三种肿瘤细胞株MCF-7(人乳腺癌细胞株)、GLC-82（人肺腺癌细胞株）、PC-3（人前列腺癌细胞株），采用MTT法进行体外细胞毒测定。对数生长期细胞加入不同浓度的脂肪氨基取代喹唑啉酮衍生物，作用48小时后，测定其吸光度。分别计算抑制细胞生长达50%时的化合物浓度，以IC50值表示，结果如表2所示。结果表明，本发明的脂肪氨基取代喹唑啉酮衍生物在体外对这三种肿瘤细胞株均具有较强的抑制作用。因此本发明的脂肪氨基取代喹唑啉酮衍生物可用于制备抗癌的药物。
表1本发明的脂肪氨基取代喹唑啉酮衍生物对肿瘤细胞株生长的抑制作用（IC50/μM）
实施例9脂肪氨基取代喹唑啉酮衍生物急性毒性试验
选择部分具有代表性的化合物（以化合物6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮为例），进行急性毒性试验。取18-22克小鼠随机分六组，每组10只小鼠，分别用生理盐水、DMSO2.5ml/kg、化合物6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮800mg/kg、化合物6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮500mg/kg、化合物6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮250mg/kg、化合物6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮100mg/kg、化合物6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮50mg/kg处理，观察14天，结果可见800mg/kg组小鼠46％死亡，即化合物6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮对小鼠的急性毒性LD50值大约为500mg/kg。因此本发明的6,7-双(2-甲氧基乙氧基）-3–(4-丙基吗啉)喹唑啉酮的急性毒性较小，可用于制备抗癌药物。
Claims (5)
1.一种脂肪氨基取代喹唑啉酮衍生物，其特征在于化学结构式如式I所示：
式中，n=1、2、3或4；
R1、R2可以相同，也可以不同，分别选自C1-6的烷基、C3-6的环烷基、CH2CH3OCH3或Bn；
R3为OH、NH2、NHR4或NR5R6；
R4为C1-6的烷基、C3-6的环烷基；
R5、R6分别为C1-6的烷基、C3-6的环烷基、哌啶基、吗啉基、哌嗪基或吡咯基。
2.一种权利要求1所述的脂肪氨基取代喹唑啉酮衍生物的制备方法，其特征在于：
反应通式为：
反应通式中的R1、R2、R3及n如权利要求1中所示；
该制备方法包括如下步骤：
将上述喹唑啉酮衍生物
与反应溶剂乙腈混合，加入碳酸钾作为催化剂，加入上述脂肪胺链，在80℃搅拌10小时，冷却后抽滤，将滤液浓缩收集固体，用硅胶柱层析纯化，得脂肪氨基取代喹唑啉酮衍生物。
3.根据权利要求2所述的制备方法，其特征在于：上述喹唑啉酮衍生物与脂肪胺链的摩尔比是1:1.2。
4.一种权利要求1所述的脂肪氨基取代喹唑啉酮衍生物在制备抗肿瘤药物中的应用。
5.根据权利要求4所述的应用，其特征在于：所述抗肿瘤药物的剂型为片剂、丸剂、胶囊、注射剂、悬浮剂或乳剂。
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