四氢喹啉类化合物的合成及镇痛活性的研究
摘要
本论文是关于4-(1H-吡咯-2-基)-1，2，3，4-四氢喹啉类化合物的合成及镇痛活性与构效关系的研究。
四氢吡咯里嗪并[2，1-c]喹啉类化合物是在对芳氨甲基吡里酮衍生物Z-47的结构改造过程中发现的具有较强镇痛作用的吡里酮衍生物。本论文是在对其结构研究的基础上，对四氢吡咯里嗪并[2，1-c]喹啉类化合物的结构做进一步的简化，以强化其镇痛活性为目的，并结合阿片类镇痛药吗啡衍生物和哌替啶的构效关系，设计合成了二十个未见文献报道的4-(1H-吡咯-2-基)-1，2，3，4-四氢喹啉类化合物，其结构经~1H-NMR，MS确定。
以醋酸致小鼠扭体法对所合成的目标化合物进行镇痛活性试验。结果表明，以200mg／kg剂量小鼠灌胃给药，多数化合物显示出一定程度的镇痛作用，其中以FLY-1、FLY-6、FLY-12、FLY-14、FLY-15的镇痛作用较强，值得深入研究。初步总结了该类化合物的构效关系规律。
The study on synthesis and structure-activity relationships (SAR) of 4-(1H-pyrrol-2-yl)-tetrahydroquinoline derivatives is reported in this paper.
Tetrahydropyrrolizino[2, 1-c]quinoline derivatives were discovered to be a lead compound with highly analgesic activities. Based on the SAR of tetrahydropyrrolizino[2, 1-c]quinoline derivatives and Oripavine analgesic agents, twenty new compounds of 4-(1H-pyrrol-2-yl)-tetrahydroquinoline derivatives were designed and synthesized. Their chemical structures were characterized by ~1H-NMR and MS.
Acid-induced mice writhing was used to evaluate the analgesic activity. Pharmacological studies showed that most of the synthesized compounds displayed notable analgesic activities at a dose of 200 mg/kg. The activities of compounds FLY-1, FLY-6, FLY-12, FLY-14, FLY-15 are comparable to that of morphine at a dose of 10 mg/kg. They could be regarded as valuable compounds for further study. Some new SAR of these compounds was summarized.
四氢吡咯里嗪并[2，1-c]喹啉类化合物是在对芳氨甲基吡里酮衍生物Z-47的结构改造过程中发现的具有较强镇痛作用的吡里酮衍生物。本论文是在对其结构研究的基础上，对四氢吡咯里嗪并[2，1-c]喹啉类化合物的结构做进一步的简化，以强化其镇痛活性为目的，并结合阿片类镇痛药吗啡衍生物和哌替啶的构效关系，设计合成了二十个未见文献报道的4-(1H-吡咯-2-基)-1，2，3，4-四氢喹啉类化合物，其结构经~1H-NMR，MS确定。
以醋酸致小鼠扭体法对所合成的目标化合物进行镇痛活性试验。结果表明，以200mg／kg剂量小鼠灌胃给药，多数化合物显示出一定程度的镇痛作用，其中以FLY-1、FLY-6、FLY-12、FLY-14、FLY-15的镇痛作用较强，值得深入研究。初步总结了该类化合物的构效关系规律。
The study on synthesis and structure-activity relationships (SAR) of 4-(1H-pyrrol-2-yl)-tetrahydroquinoline derivatives is reported in this paper.
Tetrahydropyrrolizino[2, 1-c]quinoline derivatives were discovered to be a lead compound with highly analgesic activities. Based on the SAR of tetrahydropyrrolizino[2, 1-c]quinoline derivatives and Oripavine analgesic agents, twenty new compounds of 4-(1H-pyrrol-2-yl)-tetrahydroquinoline derivatives were designed and synthesized. Their chemical structures were characterized by ~1H-NMR and MS.
Acid-induced mice writhing was used to evaluate the analgesic activity. Pharmacological studies showed that most of the synthesized compounds displayed notable analgesic activities at a dose of 200 mg/kg. The activities of compounds FLY-1, FLY-6, FLY-12, FLY-14, FLY-15 are comparable to that of morphine at a dose of 10 mg/kg. They could be regarded as valuable compounds for further study. Some new SAR of these compounds was summarized.
引文
[1] Wongchanapa, I. W.; Tsang, B. K.; He, Z. Differential involvement of opioid receptors in interathecal butorphanol-induced analgesia: compared to morphine. Pharmacol. Biochem. Behar, 1998, 59(30), 723-725
[2] 彭司勋．药物化学[M]．北京：人民卫生出版社，1995，132-135
[3] Gates, M.; Tschudi, M. The synthesis of morphine. J. Am. Chem. Soc., 1956, 78, 1380-1393
[4] Elad, D.; Ginsburg, D. The synthesis of morphine. J. Am. Chem. Soc., 1954, 76, 312-313
[5] Martin, W. R.; Eades, C. G.; Thomposon, J. A.; et al. The effects of morphine and nalorphine like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther., 1976, 197(3), 517-532
[6] Goldstein, A.; Naidu, A. Multiple opioid receptors: ligand selectivity profiles and binding site signatures. Mol. Pharmacol., 1989, 36, 265-272
[7] Chem, N. I. Opioid analgesics: comparalive features and prescribing guildlines. Drugs, 1996, 51(5), 713-737
[8] Weiss, U. Derivatives of morphine Ⅰ 14-hydroxydihydro morphine. J. Am. Chem. Soc., 1955, 77, 5891-5892
[9] Fister, K. P.; Tishler, M. US Patent 1955, 2715626
[10] Gardock, K. J.; practical, K. A. Synthesis of fentayl. Toxicol. Appl. Pharmacol., 1964, 6, 593-595
[11] 朱连友，王智贤，嵇汝运等．3-甲基芬太尼类衍生物的合成．药学学报，1981，16(2)，97-99
[12] 朱友成，方苏南，葛邦等．强效镇痛剂研究Ⅱ：3-甲基芬太尼类衍生物的合成及镇痛活性．药学学报，1981，16(2)，97-104
[13] 朱友成，吴瑞琴，仇达萍等．强效镇痛剂研究Ⅶ：1-β-羟基-3-甲基芬太尼及有关化合物非对映异构体的合成及镇痛活性．药学学报，1983，18(12)，900-904
[14] 王智贤，朱连友，陈建新等．羟甲基芬太尼对映异构体的合成和镇痛活性．药学学报，1993，28(4)，905-906
[15] Patel, S. S.; Spencer, C. M. Remifentanii. Drugs, 1996, 52(3), 417-427
[16] Beekett, A, H. Analgesices and their antagonists: some steric and chemical considerations. J. Pharm. Pharmacol., 1956, 8(11), 848-859
[17] Horan, P. J.; Ho, I. k. Comparative pharmacological and biological studies between butorphanol and morphine. Pharmacol. Biochem. Behav., 1989, 34, 847-854
[18] Oh, K. W.; Makimura, M.; Jaw, S. P.; et al. Effects of β-funaltrexamine on butorphanol dependence. Pharmacol. Biochem. Behav., 1992, 42, 29-34
[19] Dayer, P.; Desmenles, J.; Collart, L. Pharmacologic du tramadol. Drugs, 1997, 53(supp12), 18-24
[20] Lee, C. R.; Mctavish, D.; Sorkin, E. M. Tramadol: A preliminary review of its pharmacodynamic and pharmacokinetic properties. Drugs, 1993, 43, 313-340.
[21] 李剑．四氢毗咯里嗪并喹啉类化合物的合成和抗炎镇痛作用[学位论文]，沈阳：沈阳药科大学，2003
[22] 张守芳，高文方，郑红等．3H-1，2-二氢-1-吡里酮衍生物的合成．药学学报，1988，23(1)，28-33
[23] 刘向莉．3H-1，2-二氢吡里酮衍生物的合成及其抗炎镇痛活性研究[学位论文]，沈阳：沈阳药科大学，1993
[24] 王颖煜．氨甲基吡里酮类化合物的合成和抗炎镇痛作用[学位论文]，沈阳：沈阳药科大学，2000
[25] Shaojie Wang; Fushuang Liu; Shoufang Zhang. Mannich Reaction 2, 3-dihydro-1-pyrrolizinone. Chin. Chem. Lett., 1996, 7(1), 9-10
[26] Shoufang Zhang; Xinxian Zhao; Wenfang Gao; et al. Aminopyrrolizinone analogues for anti-inflammatory and analgesia. US 5616604, Apr. 01, 1997
[27] 张守芳，高文方，伍湘谨等．新氨基吡咯里嗪酮类化合物．CN：1104642A，1994
[28] Beckett, A. H.; Casy, A. F. Synthetic analgesics: stereochemical considerations. J Pharm. Pharmacol., 1954, 6(12), 986-999
[29] Rauckman, B. S.; Tidwell, M. Y.; Johnson, J. V.; et al. 2, 4-Diamino-5-(6-quinoly-lmethyl)-and-[(tetrahydro-6-quinolyl)methyl]pyrimidine derivatives. J. Med. Chem., 1989, 32(8), 1927-1935
[30] Yasuo, Kikugawa; Kunio, Saito; Schun-ichi, Yammada. Reduction of heterocycles with pyridine: borane in acetic acid. Synth., 1978, 6, 447-448
[31] Gribble, G. W.; Heald, P. W. Reactions and Alkylation of quionline and isoquinoline with carboxylic acids. Synth., 1975, 10, 650-652
[32] Shun-Ichi, Murahashi; Yasushi, Imada; Yoshiaki, Him. Selective synthesis of 1, 2, 3, 4-tetrahydroquinolines and N-formyl-1, 2, 3, 4-tetrahydroisoquinolines. Tetrahedron Letters, 1987, 28(1), 77-80
[33] Shun-Ichi, Murahashi; Yasushi, Imada; Yoshiaki, Hira. Rhodium catalyzed hydrogenation of quinolines and isoquinolines under water-gas shift conditions. Bull. Chem. Soc. Jpn., 1989, 62(9), 2968-2976
[34] Long, R.; Schofield, K. Some alkylquinoline-5: 8-quinones, J. Chem. Soc., 1953, 3161-3167
[35] Magnus, P.; Fairhurst, S. A.; Parry, D. Synthetic and mechanistic studies on the Azabicyclo[7.3.1] enediyne core and Naphtho[2,3-h]quinoline potties of Dynemicin A. J. Am. Chem. Soc., 1997, 119, 5591-5605
[36] Lauer, W. M.; Kaslow, C. E. 4-Methylcarbostyril. Org. Synth., Coll. Vol. Ⅲ, 1955, 580-581
[37] Price, C. C.; Roberts, R. M. 4, 7-Dichloroquinoline. Org. Synth., Coll. Vol. Ⅲ, 1955, 272-275
[38] Chen, B.; Huang, X.; Wang, J. A versatile synthesis of 2-aikyl and 2-aryl 4-quinolines. Synth., 1987, 482-486
[39] Manske, R. H. F.; Kulka, M. The Skraup synthesis of quinolines. Org. React., 1953, 7, 59-73
[40] Clarke, H. T.; Davis, A. W. Quinoline. Org. Synth., Coll. Vol. Ⅰ, 1932, 478-482
[41] Mosher, H. S.; Whimore, F. C. 6-Methoxy-8-nitroquionline. Org. Synth., Coll. Vol. Ⅲ, 1955, 568-573
[42] Song, Z.; Mertzman, M.; Hughes, D. L. Improved synthesis of quinolines by Skraup reaction, J. Heterocycl. Chem., 1993, 30, 17-21
[43] Katritrky, A. R.; Bogumila, Rachwal; Stanislaw, Rachwal. A convenient synthesis of 4-(dialkylamino)tetrahydroquinolines. J. Org. Chem., 1995, 60(13), 3993-4001
[44] Katritrky, A. R.; Nichols, D. A.; Baozhen, Yang; et al. Lewis acid assisted reaction of N-(α-aminoalkyl)-benzotriazoles and unactivated alkenes for the facile synthesis of 2, 4-, and3, 4substitued 1, 2, 3, 4-tetrahydroquinolines. J. Heterocycl. Chem., 1997, 34(4), 1259-1262
[45] 孟繁浩，张守芳．2-酰基吡咯的合成及Vilsmeier反应的研究．精细化工，1996，13(1)，16-18
[46] Ashpk, K. G.; Mahendra, D. N. Efficient process for the cyclization of diastereomeric alcohol to a trans amide in the synthesis of dopamine D1 Agonist, ABT-431. Synth. Commun., 1999, 29(11), 1835-1841
[47] Jakob, meisenheimer. Attrmpts to prepare optically active compounds of tervalent nitrogen. Ber., 1924, 57, 1744-1759
[48] Kamm, O.; Marvel, C. S. Alkylene Rromides. Org. Synth., Coll. Vol. 1, 25-35
[2] 彭司勋．药物化学[M]．北京：人民卫生出版社，1995，132-135
[3] Gates, M.; Tschudi, M. The synthesis of morphine. J. Am. Chem. Soc., 1956, 78, 1380-1393
[4] Elad, D.; Ginsburg, D. The synthesis of morphine. J. Am. Chem. Soc., 1954, 76, 312-313
[5] Martin, W. R.; Eades, C. G.; Thomposon, J. A.; et al. The effects of morphine and nalorphine like drugs in the nondependent and morphine-dependent chronic spinal dog. J. Pharmacol. Exp. Ther., 1976, 197(3), 517-532
[6] Goldstein, A.; Naidu, A. Multiple opioid receptors: ligand selectivity profiles and binding site signatures. Mol. Pharmacol., 1989, 36, 265-272
[7] Chem, N. I. Opioid analgesics: comparalive features and prescribing guildlines. Drugs, 1996, 51(5), 713-737
[8] Weiss, U. Derivatives of morphine Ⅰ 14-hydroxydihydro morphine. J. Am. Chem. Soc., 1955, 77, 5891-5892
[9] Fister, K. P.; Tishler, M. US Patent 1955, 2715626
[10] Gardock, K. J.; practical, K. A. Synthesis of fentayl. Toxicol. Appl. Pharmacol., 1964, 6, 593-595
[11] 朱连友，王智贤，嵇汝运等．3-甲基芬太尼类衍生物的合成．药学学报，1981，16(2)，97-99
[12] 朱友成，方苏南，葛邦等．强效镇痛剂研究Ⅱ：3-甲基芬太尼类衍生物的合成及镇痛活性．药学学报，1981，16(2)，97-104
[13] 朱友成，吴瑞琴，仇达萍等．强效镇痛剂研究Ⅶ：1-β-羟基-3-甲基芬太尼及有关化合物非对映异构体的合成及镇痛活性．药学学报，1983，18(12)，900-904
[14] 王智贤，朱连友，陈建新等．羟甲基芬太尼对映异构体的合成和镇痛活性．药学学报，1993，28(4)，905-906
[15] Patel, S. S.; Spencer, C. M. Remifentanii. Drugs, 1996, 52(3), 417-427
[16] Beekett, A, H. Analgesices and their antagonists: some steric and chemical considerations. J. Pharm. Pharmacol., 1956, 8(11), 848-859
[17] Horan, P. J.; Ho, I. k. Comparative pharmacological and biological studies between butorphanol and morphine. Pharmacol. Biochem. Behav., 1989, 34, 847-854
[18] Oh, K. W.; Makimura, M.; Jaw, S. P.; et al. Effects of β-funaltrexamine on butorphanol dependence. Pharmacol. Biochem. Behav., 1992, 42, 29-34
[19] Dayer, P.; Desmenles, J.; Collart, L. Pharmacologic du tramadol. Drugs, 1997, 53(supp12), 18-24
[20] Lee, C. R.; Mctavish, D.; Sorkin, E. M. Tramadol: A preliminary review of its pharmacodynamic and pharmacokinetic properties. Drugs, 1993, 43, 313-340.
[21] 李剑．四氢毗咯里嗪并喹啉类化合物的合成和抗炎镇痛作用[学位论文]，沈阳：沈阳药科大学，2003
[22] 张守芳，高文方，郑红等．3H-1，2-二氢-1-吡里酮衍生物的合成．药学学报，1988，23(1)，28-33
[23] 刘向莉．3H-1，2-二氢吡里酮衍生物的合成及其抗炎镇痛活性研究[学位论文]，沈阳：沈阳药科大学，1993
[24] 王颖煜．氨甲基吡里酮类化合物的合成和抗炎镇痛作用[学位论文]，沈阳：沈阳药科大学，2000
[25] Shaojie Wang; Fushuang Liu; Shoufang Zhang. Mannich Reaction 2, 3-dihydro-1-pyrrolizinone. Chin. Chem. Lett., 1996, 7(1), 9-10
[26] Shoufang Zhang; Xinxian Zhao; Wenfang Gao; et al. Aminopyrrolizinone analogues for anti-inflammatory and analgesia. US 5616604, Apr. 01, 1997
[27] 张守芳，高文方，伍湘谨等．新氨基吡咯里嗪酮类化合物．CN：1104642A，1994
[28] Beckett, A. H.; Casy, A. F. Synthetic analgesics: stereochemical considerations. J Pharm. Pharmacol., 1954, 6(12), 986-999
[29] Rauckman, B. S.; Tidwell, M. Y.; Johnson, J. V.; et al. 2, 4-Diamino-5-(6-quinoly-lmethyl)-and-[(tetrahydro-6-quinolyl)methyl]pyrimidine derivatives. J. Med. Chem., 1989, 32(8), 1927-1935
[30] Yasuo, Kikugawa; Kunio, Saito; Schun-ichi, Yammada. Reduction of heterocycles with pyridine: borane in acetic acid. Synth., 1978, 6, 447-448
[31] Gribble, G. W.; Heald, P. W. Reactions and Alkylation of quionline and isoquinoline with carboxylic acids. Synth., 1975, 10, 650-652
[32] Shun-Ichi, Murahashi; Yasushi, Imada; Yoshiaki, Him. Selective synthesis of 1, 2, 3, 4-tetrahydroquinolines and N-formyl-1, 2, 3, 4-tetrahydroisoquinolines. Tetrahedron Letters, 1987, 28(1), 77-80
[33] Shun-Ichi, Murahashi; Yasushi, Imada; Yoshiaki, Hira. Rhodium catalyzed hydrogenation of quinolines and isoquinolines under water-gas shift conditions. Bull. Chem. Soc. Jpn., 1989, 62(9), 2968-2976
[34] Long, R.; Schofield, K. Some alkylquinoline-5: 8-quinones, J. Chem. Soc., 1953, 3161-3167
[35] Magnus, P.; Fairhurst, S. A.; Parry, D. Synthetic and mechanistic studies on the Azabicyclo[7.3.1] enediyne core and Naphtho[2,3-h]quinoline potties of Dynemicin A. J. Am. Chem. Soc., 1997, 119, 5591-5605
[36] Lauer, W. M.; Kaslow, C. E. 4-Methylcarbostyril. Org. Synth., Coll. Vol. Ⅲ, 1955, 580-581
[37] Price, C. C.; Roberts, R. M. 4, 7-Dichloroquinoline. Org. Synth., Coll. Vol. Ⅲ, 1955, 272-275
[38] Chen, B.; Huang, X.; Wang, J. A versatile synthesis of 2-aikyl and 2-aryl 4-quinolines. Synth., 1987, 482-486
[39] Manske, R. H. F.; Kulka, M. The Skraup synthesis of quinolines. Org. React., 1953, 7, 59-73
[40] Clarke, H. T.; Davis, A. W. Quinoline. Org. Synth., Coll. Vol. Ⅰ, 1932, 478-482
[41] Mosher, H. S.; Whimore, F. C. 6-Methoxy-8-nitroquionline. Org. Synth., Coll. Vol. Ⅲ, 1955, 568-573
[42] Song, Z.; Mertzman, M.; Hughes, D. L. Improved synthesis of quinolines by Skraup reaction, J. Heterocycl. Chem., 1993, 30, 17-21
[43] Katritrky, A. R.; Bogumila, Rachwal; Stanislaw, Rachwal. A convenient synthesis of 4-(dialkylamino)tetrahydroquinolines. J. Org. Chem., 1995, 60(13), 3993-4001
[44] Katritrky, A. R.; Nichols, D. A.; Baozhen, Yang; et al. Lewis acid assisted reaction of N-(α-aminoalkyl)-benzotriazoles and unactivated alkenes for the facile synthesis of 2, 4-, and3, 4substitued 1, 2, 3, 4-tetrahydroquinolines. J. Heterocycl. Chem., 1997, 34(4), 1259-1262
[45] 孟繁浩，张守芳．2-酰基吡咯的合成及Vilsmeier反应的研究．精细化工，1996，13(1)，16-18
[46] Ashpk, K. G.; Mahendra, D. N. Efficient process for the cyclization of diastereomeric alcohol to a trans amide in the synthesis of dopamine D1 Agonist, ABT-431. Synth. Commun., 1999, 29(11), 1835-1841
[47] Jakob, meisenheimer. Attrmpts to prepare optically active compounds of tervalent nitrogen. Ber., 1924, 57, 1744-1759
[48] Kamm, O.; Marvel, C. S. Alkylene Rromides. Org. Synth., Coll. Vol. 1, 25-35