一类环磷酰胺双哌嗪季铵盐类抗肿瘤化合物的合成

一类环磷酰胺双哌嗪季铵盐类抗肿瘤化合物的合成

刘墨, 葛泽梅^*, 程铁明, 李润涛^*

北京大学天然药物及仿生药物国家重点实验室; 药学院化学生物学系北京 100191

收稿日期:2009-05-19 修回日期:2009-10-15 出版日期:2009-11-30 发布日期:2009-11-30
通讯作者: 葛泽梅*, 李润涛*

Synthesis of a novel class of cyclophosphamide bis-spiropiperazinium salts

Mo Liu, Ze-Mei Ge^*, Tie-Ming Cheng, Run-Tao Li^*

State Key Laboratory of Natural and Biomimetic Drugs; Department of Chemical Biology, School of Pharmaceutical Science, Peking University, Beijing 100191, China

Received:2009-05-19 Revised:2009-10-15 Online:2009-11-30 Published:2009-11-30
Contact: Ze-Mei Ge*, Run-Tao Li*

摘要/Abstract

摘要：

本文利用药物化学中的拼合原理设计并合成了一系列结构全新的环磷酰胺双哌嗪季铵盐类化合物。在合成该类化合物的过程中, 探索了新的合成路线及分离纯化方法, 对已有的环磷酰胺哌嗪季铵盐类化合物的合成方法起到了很好的补充作用, 为今后合成新类别的环磷酰胺哌嗪季铵盐奠定了基础。

关键词: 环磷酰胺双哌嗪季铵盐, 拼合原理, 合成, 抗肿瘤活性

Abstract: Based on the principle of association, a novel class of cyclophosphamide bis-spiropiperazinium compounds was designed and synthesized. A new method of synthesis, separation and purification for this kind of compounds was also developed.

Key words: Cyclophosphamide bis-spiropiperazinium salt, Cyclophosphamide bis-spiropiperazinium salt, Principle of association, Principle of association, Synthesis, Synthesis, Anti-cancer, Anti-cancer

中图分类号:

R916.41

Supporting: Foundation items: National Natural Science Foundation of China (Grant No. 20472008) and the Major State Basic Research Development Program (Grant No. 2004CB719900).
^*Corresponding author. Tel.: 86-10-82801504; e-mail: zmge@bjmu.edu.cn

刘墨, 葛泽梅^*, 程铁明, 李润涛^*. 一类环磷酰胺双哌嗪季铵盐类抗肿瘤化合物的合成[J]. .

Mo Liu, Ze-Mei Ge^*, Tie-Ming Cheng, Run-Tao Li^* . Synthesis of a novel class of cyclophosphamide bis-spiropiperazinium salts [J]. .

参考文献

[1] (a) Sladek, N.E. Cancer Res. 1972, 32, 1848-1854; (b) Connors, T.A.; Cox, P.J.; Farmer, P.B.; Foster, A.B.; Jarman, M. Biochem. Pharmacol. 1974, 23, 115-129; (c) Friedman, O.M.; Myles, A.; Colvin, M. Adv. Cancer Chemother. 1979, 1, 143-204; (d) Sladek, N.E. Pharmacol. Ther. 1998, 37, 301-355.
[2] Brock, N.; Stekar, J.; Pohl, J.; Niemeyer, U.; Scheffler, G. Arzneim-Forsch. Drug Res. 1979, 29, 659-661.
[3] Eibl, H.; Kolar, C.; Seiler, F.R. EP 72531, 1982.
[4] Moon, K.Y.; Shirota, F.N.; Baturay, N.; Kwon, Ch.H. J. Med. Chem. 1995, 38, 848-851.
[5] (a) Engel, J.; Kleemann, A.; Niemeyer, U. Ger. Offen. DE 3505482, 1985; (b) Scheffler, G.; Niemeyer, U.; Brock, N. US 4618692, 1986.
[6] Boyd, V.L.; Zon, G.; Himes, V.L.; Stalick, J.K.; Mighell, A.D.; Secor, H.V. J. Med. Chem. 1980, 23, 372-375.
[7] Brandt, J.A.; Ludeman, S.M.; Zon, G.; Egan, W.; Todhunter, J.A.; Dickerson, R. J. Med. Chem. 1981, 24, 1404-1408.
[8] Borch, R.F.; Canute, G.W. J. Med. Chem. 1991, 34, 3044-3052.
[9] Ludeman, S.M.; Zon, G. J. Med. Chem. 1975, 18, 1251-1253.
[10] Li, Z.; Han, J.; Jiang, Y.; Browne, P.; Knox, R.J.; Hu, L. Bioorg. Med. Chem. 2003, 11, 4171-4178.
[11] Borch, R.F.; Valente, R.R. J. Med. Chem. 1991, 34, 3052-3058.
[12] Tietze, L.F.; Neumann, M.; Fischer, R. Ger. Offen., DE 3819634, 1989.
[13] Firestone, A.; Mulcahy, R.T.; Borch, R.F. J. Med. Chem. 1991, 34, 2933-2935.
[14] (a) Borch, R.F.; Liu, J.; Schmidt, J.P.; Marakovits, J.T.; Joswig, C. J. Med. Chem. 2000, 43, 2258-2265; (b) Borch, R.F.; Liu, J.; Joswig, C.; Baggs, R.B.; Dexter, D.L.; Mangold, G.L. J. Med. Chem. 2001, 44, 74-77.
[15] Steinberg, G.; Borch, R.F. J. Med. Chem. 2001, 44, 69-73.
[16] Flader, C.; Liu, J.; Borch, R.F. J. Med. Chem. 2000, 43, 3157-3167.
[17] Hernick, M.; Flader, C.; Borch, R.F. J. Med. Chem. 2002, 45, 3540-3548.
[18] Jain, M.; Fan, J.; Baturay, N.Z.; Kwon, C.H. J. Med. Chem. 2004, 47, 3843-3852.
[19] Jiang,Y.Y.; Hu, L.Q. J. Med. Chem. 2006, 49, 4333-4343.
[20] Jiang,Y.Y.; Hu, L.Q. Bioorg. Med. Chem. Lett. 2007, 17, 517-521.
[21] Jiang,Y.Y.; Hu, L.Q. Bioorg. Med. Chem. Lett. 2008, 18, 4059-4063.
[22] Safonova, T.S.; Chernov, V.A.; Minakova, S.M.; Dorokhova, M.I.; Levkovskaya, L.G.; Traven, N.I.; Andreyanova, T.A.; Serochkina, L.A.; Mamaeva, I.E. Khim. Farm. Zh. 1983, 17, 626-629.
[23] Safonova, T.S.; Minakova, S.M.; Chernov, V.A.; Andreyanova, T.A.; Deev, V.V. Khim. Farm. Zh. 1984, 18, 1437-1440.
[24] (a) Li, R.T.; Chen, H.C.; Yang, J.Z. Acta Pharm. Sin. 1995, 30, 63-69; (b) Li, R.T.; Chen, H.C.; Yang, J.Z. Acta Pharm. Sin. 1995, 30, 144-149.
[25] (a) Dong, J.C.; Wang, X.; Li, R.T.; Zhang, H.M.; Cheng, T.M.; Li, C.L. Bioorg. Med. Chem. Lett. 2003, 13, 4327-4329; (b) Liu, H.; Cheng, T.M.; Zhang, H. M.; Li, R.T. Arch. Pharm. Pharm. Med. Chem. 2003, 336, 510-513; (c) Wang, X.; Gao, F.L.; Piao, H.B.; Cheng, T.M.; Li, R.T. Bioorg. Med. Chem. Lett. 2003, 13, 1729-1732; (d) Gao, F.L.; Wang, X.; Zhang, H.M.; Cheng, T.M.; Li, R.T. Bioorg. Med. Chem. Lett. 2003, 13, 1535-1537.
[26] Li, R.T.; Sun, Q.; Ge, Z.M.; Cui, J.R.; Cheng, T.M. CN 1607204, 2005 [Chem. Abstr. 143, 460282].