吡咯并吡嗪酮类化合物的合成及抗炎镇痛活性研究
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摘要
本论文是关于吡咯并[1，2-a]吡嗪-1-酮类化合物的合成及其抗炎镇痛活性的研究。
有机合成实验室在对吡咯里嗪酮类抗炎镇痛剂的研究过程中发现，吡里酮的结构类似物吡嗪酮具有显著的抗炎镇痛作用，一些已合成的吡嗪酮衍生物具有明显的抗炎镇痛活性，预示着该类化合物抗炎镇痛作用的构效关系具有广阔的研究前景。本课题是在吡嗪酮类化合物已有的研究基础上，设计合成二十一个未见文献报道的新型吡嗪酮类化合物，从而进行深入的抗炎镇痛构效关系研究，其结构经~1H-NMR，MS确证。
以二甲苯致小鼠耳肿胀法和醋酸致小鼠扭体法对所合成的目标化合物分别进行了抗炎和镇痛活性试验，结果表明，以200mg／kg的剂量灌胃给药，WLY-113，WLY-115，WLY-119具有一定的镇痛作用；WLY-103，WLY-114，WLY-119具有一定的抗炎作用，并总结了一些初步的构效关系规律。
The synthesis and structure-activity relationship(SAR) of the novel nonsteroidal anti -inflammatory agents,pyrrolo[l,2-a]pyrazine-l-one derivatives were reported in this dissertation.
In the research of pyrrolizinones of nonsteroidal anti-inflammatory drugs(NSAIDs),it has been proved that pyrazinones showed remarkable anti-inflammatory and analgesic activities. Based on the SAR of pyrazinones and their analogues reported in our laboratory, twenty-one new pyrazinone derivatives were designed and synthesized for further study of the SAR, which structures have been confirmed by ~1H-NMR and MS. They have not been found in literatures.
Anti-inflammatory and analgesic activities were evaluated with xylene-induced ear edema and acetic acid-induced writhing in mice, respectively. The results of pharmacological tests show that some synthesized compounds have anti-inflammatory and/or analgesic activities. Some new SAR of these compounds is discussed from the studies above.
有机合成实验室在对吡咯里嗪酮类抗炎镇痛剂的研究过程中发现，吡里酮的结构类似物吡嗪酮具有显著的抗炎镇痛作用，一些已合成的吡嗪酮衍生物具有明显的抗炎镇痛活性，预示着该类化合物抗炎镇痛作用的构效关系具有广阔的研究前景。本课题是在吡嗪酮类化合物已有的研究基础上，设计合成二十一个未见文献报道的新型吡嗪酮类化合物，从而进行深入的抗炎镇痛构效关系研究，其结构经~1H-NMR，MS确证。
以二甲苯致小鼠耳肿胀法和醋酸致小鼠扭体法对所合成的目标化合物分别进行了抗炎和镇痛活性试验，结果表明，以200mg／kg的剂量灌胃给药，WLY-113，WLY-115，WLY-119具有一定的镇痛作用；WLY-103，WLY-114，WLY-119具有一定的抗炎作用，并总结了一些初步的构效关系规律。
The synthesis and structure-activity relationship(SAR) of the novel nonsteroidal anti -inflammatory agents,pyrrolo[l,2-a]pyrazine-l-one derivatives were reported in this dissertation.
In the research of pyrrolizinones of nonsteroidal anti-inflammatory drugs(NSAIDs),it has been proved that pyrazinones showed remarkable anti-inflammatory and analgesic activities. Based on the SAR of pyrazinones and their analogues reported in our laboratory, twenty-one new pyrazinone derivatives were designed and synthesized for further study of the SAR, which structures have been confirmed by ~1H-NMR and MS. They have not been found in literatures.
Anti-inflammatory and analgesic activities were evaluated with xylene-induced ear edema and acetic acid-induced writhing in mice, respectively. The results of pharmacological tests show that some synthesized compounds have anti-inflammatory and/or analgesic activities. Some new SAR of these compounds is discussed from the studies above.
引文
[1] Jones R. Non-steroid anti-inflammatory drug prescribing: past, present and future. Am J Med. 2001. 110(Suppl 1A): 4-7.
[2] Sneader W. The discovery of aspirin: a reappraisal. BMJ, 2000, 321: 1591-1594.
[3] Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol, 1971, 231: 232-235.
[4] VANE JR. The fight against rheumatism: from willow bark to COX-1 sparing drugs[J]. J Physiol Pharmacol, 2000, 51(4): 573-586.
[5] ERMERT L, DIERKES C, ERMERT M. Immunhistochemical expression of cyclooxygenase isoenzymea and downstream enzymea in human lung tumors[J]. Clin Cancer Res, 2003, 9(5): 1604-1610.
[6] Ferraz JG, Sharkey KA, Reuter BK, et al. Induction of cyclooxygenase 1 and 2 in the rat stomach during endotoxemia: role in resistance to damage[J]. Gastroenterology, 1997, 113(1): 195-204.
[7] Simmons DL, Botting RM, Robertson PM, et al. Induction of an acetaminophen sensitive cyclooxygenase with reduced sensitivity to nonsteroid anti-inflammatory drugs. J Proc Natl Acad Sci, 1999, 96: 3275-3280.
[8] CHANDRASEKHARAN NV, DAI H, ROOS KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression[J]. Proc Natl Acad Sci USA, 2002, 99(21): 13926-13931.
[9] WARNER TD, MITCHELL JA. Cyclooxygenase-3(COX-3): Filling in the gaps toward a COX continuum[J]. Proc Natl Acad Sci USA, 2002, 99(21): 13371-13373.
[10] Smith TJ. Cyclooxygenases as the principal targets for the actions of NSAIDs. Rheum Dis Clin North Am, 1998, 24: 501.
[11] MARNETT LJ. Struture, function and inhibition of cyclooxygenases[J]. Ernst Schering Res Found Workshop, 2000, 31: 65-83.
[12] LANZO CA, BEECHEM JM, TALIEY J, et al. Investigation of the binding of isoform-selective inhibition to prostaglandin endoperoxide synthases using fluorescence spectro- scopy[J]. Biochemistry, 1998, 37(1): 217-226.
[13] RIENDEAU D, PERCIVAL MD, BRIDEAU C, et al. Etoricoxib(MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2[J]. J Pharmacol Exp Ther, 2001, 296(2): 558-566.
[14] DE LEFAL X. JULEMONT F. BENOIT V. et al. First and second generations of COX-2 selective inhibitiors[J]. Mini Rev Med Chem, 2004, 4(6): 597-601.
[15] STICHTENOTH DO, FROLICH JC. The Second generation of COX-2 inhibitors[J]. Drugs, 2003, 63(1): 33-45.
[16] BRUNE K, HINZ B. Selective cyclooxygenase-2 inhibitors: similarities and differences[J]. Scand J Rheumatol, 2004, 33(1): 1-6.
[17] SORBERA LA, RAMIS I. Cimicoxib[J]. Drug Fut, 2004, 29(4): 325-330.
[18] HIROMASA H, IMAMURA K, HARUTA J, et al. 4-(4-Cycloalkyl/aryl-oxatol-5-yl) bentene-sulfonamides as selective cyclooxygenase-2 inhibitiors: enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522[J]. J Med Chem, 2002, 45(7): 1511-1517.
[19] CHEN Y, ZHANG GG, NEILLY J, et al. Enhancing the bioavailability of ABT-963 using solid dispension containing Pluronic F-68[J]. Int J Pharm, 2004, 286(1-2): 69-80.
[20] SORBERA LA, CASTANER M, BAYES M, et al. Lumiracoxib[J]. Drug Fut, 2002, 27(8): 740-747.
[21] KALGUTKAR AS, CREWS BC, ROWLINSON SW, et al. Aspirin-like molecules that eovalently inactivate cyclooxygenase-2[J]. Science, 1998, 280(5367): 1268-1270,
[22] LEVOIN N, CHRETIEN F, LAPICQUE F, et al. Synthesis and biological testing of Aeyl-CoA-ketoprofen conjugates as selective irreversible inhibitiors of COX-2[J]. Bioorg Med Chem, 2002, 10(3): 753-757.
[23] Fors-Hutclinson A W, Bay MA, Doig MV, et al. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes[J], Nature, 1980, 286(5770): 264-265.
[24] 张孝仁．新颖的LOX/COX-2 抑制剂-Licofelone[J]．中国制药信息，2003，19(1)：27-29．
[25] http://www.unismed.com.cn/yykx/122526.htm[DB/OL].
[26] Dingle JT, et al. Effect of tenidap on cartilage integnity in vitro. Ann Rheum Dis, 1993, 52(4): 292.
[27] MONCADA S, PALMER R M J, HIGGS E A. The Discovery of Nitric Oxide as the Endogenous Nitrovasodilator[J]. Hypertension, 1988, 12: 365-372.
[28] MONCADA S, PALMER R M J, HIGGS E A. Nitric Oxide: Phydiology, Patbophysiology, and Pharmacology[J]. Pharmacological Reviews, 1991, 43(2): 109-141.
[29] MONCADA S, RADOMSKI M W, PALMER R M J. Endothelium-Derived Relaxing Factor: Identification as Nitric Oxide and Role in the Control of Vascular Tone and Platelet Function[J]. Biochem Pharmacol, 1988, 37: 2495-2501.
[30] MONCADA S, PALMER R M J, HIGGS E A. Biosynthesis of Nitric Oxide From L-arginine: a Pathway for Regulation of Cell Function and Communication[J]. Biochem Pharmacol, 1989, 38: 1079-1115.
[31] CLANCY R M, LESZCZYNSK A-PIZIAK J, ABRAMSON SB. Nitric Oxide, an Endothelial Cell Relaxation Factor, Inhibits Neutrophil Superoxide Anion Production Via a Direct Action on the NADPH Oxidase[J]. J Clin Invest, 1992, 90: 1116-1121.
[32] KUBES P M, SUZUKIM, GRANGER D N. Nitric Oxide: an Endogenous Modulator of leukocyte Adhesion [J]. Proc Natl Acael Sci USA, 1991, 88: 4651-4655.
[33] WALLACE J L, CHIN B C. New Generation NSAIDs: The Benefit Without the Risk[J]. Drug Today, 1997, 33: 371-378.
[34] ELLIOTT S N, MCKNIGHT W, CIRINO G, et al. A Nitric Oxide Releasing Nonsteroidal Anti-inflammatory Drug Accelerates Gastric Ulcers Healing in Rats[J]. Gastroenterology, 1995, 109: 524-530.
[35] KITAGAWA H, TAKEDA F, KOHEI H. Effect of Endothelium-derived Relaxing Factor on the Gastric Lesion Induced by HCl in Rats[J]. J Pharm Exp Ther, 1990, 253: 1133-1137.
[36] MITCHELL J A, CIRION G, AKARASEREENONT P, et al. Flurbiprofen Nitroxybutylester: A Novel Anti-inflammatory Drug Devoid of Ulcerogenic Activity, Inhibits Cyclooxy-genase-1 and Cyclooxygenase-2 [J]. Can Phyiol Pharmacol, 1994, 72: 270.
[37] TAKAEACHI K, UKAWA H, KONOKA A, et al. Effect of Nitric Oxide Releasing Aspirin Derivative on Gastric Functional and Ulcerogenic Responses in Rats: Comparision with Plain Aspirin[J]. J Pharmacol Exp Ther, 1995, 286: 115-121.
[38] CUZZOLIN L, CONFORT A, ADAMI A, et al. Anti-inflammatory Potency and Gastro-intestinal Toxicity of a New Compound, NO-naproxen[J]. Pharmacol Res, 1995, 31: 61-65.
[39] WALLACE J L, BAK K, MCKIGHT W, et al. Cyclooxygenase-1 Contributes to Inflammatory Responses in Rats and Mice: Implications for Gastrointestinal Toxicity[J]. Gastroenterology, 1998, 115: 101-109.
[40] DAVIES N M, ROSTCH A G, APPLEYCERD C B, et al, NO-naproxen vs Naproxen: Ulcerogenic, Analgesic and Anti-inflammatory Effects[J]. Aliment Pharmacol Ther, 1997, 11: 69-79.
[41] BOBERT M, CLANCY, STEVEN B. Nitric Oxide: A Novel Mediator of Inflammation[J]. Pris Soc Exp Biol Med, 1995, 210(2), 93-101.
[42] Morimoto A, Watanable T. Pyrrole lactam derivatives with antiprotozoa antitrichomonas blood sugar decreasing and gastric juice apoleptic activity[P]. JP: 7427877, 1974.
[43] Dumas DJ. Total synthesis of Peramine[J]. J. Org,. Chem., 1988, 53: 4650-4653.
[44] Rowan DD, Hunt MB, Gaynor DL. Peramine, a novel insect feeding deterrent from ryegrass infected with the endophyte acreminum loliae[J]. J. Chem. Soc., Chem. Commun., 1986. 935-936.
[45] Hiroshi U, Masashi T, Kobayashi J. Mukanadins A-C, new bromopyrrole alkaloids from marine sponge agelas nakamurai[J]. J. Nat. Prod., 1999, 62: 1581-1583.
[46] Banwell MG, Bray AM, Willis AC, et al. First syntheses of pyrrolo ketopiperazine marine natural products (±)-longamide, (±)-longamide B, (±)-longamide B methyl ester and (±)-hanishin[J]. New. J. Chem., 1999, 23(7): 687-690.
[47] 刘吉云．吲哚里嗪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，1996．
[48] Auzzj G, Bruni F, Cecchi L, et al. 2-Phenylpyrazolo[1,5-a]pyrimidin-7-ones. A new class of nonsteroidal snit-inflammatory drugs devoid of ulcerogenic activity[J]. J. Med. Chem., 1983, 26: 1706-1709.
[49] 庞冀燕，孙光，傅德才等．二氢吡咯并吡嗪酮衍生物的合成和抗炎镇痛作用[J]．中国药物化学杂志2002，12(2)：82-85．
[50] 傅德才．吡咯吡嗪酮和吡咯噁嗪酮衍生物的合成及抗炎镇痛作用研究[学位论文]．沈阳，沈阳药科大学，2002．
[51] 王绯．吡嗪酮类化合物的合成和抗炎镇痛构效关系研究[学位论文]．沈阳，沈阳药科大学，2004．
[52] Brimble MA, Brimble MT, Hodges R, et al. Synthesis of 2-methylpyrrolo [1,2-a]pyrazin-1(2H)-one[J]. Aust. J. Chem., 1988, 41: 1583-1590.
[53] Brimble MA, Rowan WW. Synthesis of the insect feeding deterrent Peramine via Michale Addition a pyrrole anion to a nitroalkene[J]. J. Chem. Soc. Perkin Trans. 1, 1990, 311-314.
[54] Denis MB, Robert EJ, Noel FA, et al[J]. Ethyl pyrrole-2-carboxylate. Organic Synthesis, 1970, 51: 100.
[55] Hodge P, Richard RW. Improved synthetic routes to pyrrole-2-carboxylic acid and its derivatives[J]. J. Chem. Soc., 1963, 2543-2545.
[2] Sneader W. The discovery of aspirin: a reappraisal. BMJ, 2000, 321: 1591-1594.
[3] Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol, 1971, 231: 232-235.
[4] VANE JR. The fight against rheumatism: from willow bark to COX-1 sparing drugs[J]. J Physiol Pharmacol, 2000, 51(4): 573-586.
[5] ERMERT L, DIERKES C, ERMERT M. Immunhistochemical expression of cyclooxygenase isoenzymea and downstream enzymea in human lung tumors[J]. Clin Cancer Res, 2003, 9(5): 1604-1610.
[6] Ferraz JG, Sharkey KA, Reuter BK, et al. Induction of cyclooxygenase 1 and 2 in the rat stomach during endotoxemia: role in resistance to damage[J]. Gastroenterology, 1997, 113(1): 195-204.
[7] Simmons DL, Botting RM, Robertson PM, et al. Induction of an acetaminophen sensitive cyclooxygenase with reduced sensitivity to nonsteroid anti-inflammatory drugs. J Proc Natl Acad Sci, 1999, 96: 3275-3280.
[8] CHANDRASEKHARAN NV, DAI H, ROOS KL, et al. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: Cloning, structure, and expression[J]. Proc Natl Acad Sci USA, 2002, 99(21): 13926-13931.
[9] WARNER TD, MITCHELL JA. Cyclooxygenase-3(COX-3): Filling in the gaps toward a COX continuum[J]. Proc Natl Acad Sci USA, 2002, 99(21): 13371-13373.
[10] Smith TJ. Cyclooxygenases as the principal targets for the actions of NSAIDs. Rheum Dis Clin North Am, 1998, 24: 501.
[11] MARNETT LJ. Struture, function and inhibition of cyclooxygenases[J]. Ernst Schering Res Found Workshop, 2000, 31: 65-83.
[12] LANZO CA, BEECHEM JM, TALIEY J, et al. Investigation of the binding of isoform-selective inhibition to prostaglandin endoperoxide synthases using fluorescence spectro- scopy[J]. Biochemistry, 1998, 37(1): 217-226.
[13] RIENDEAU D, PERCIVAL MD, BRIDEAU C, et al. Etoricoxib(MK-0663): preclinical profile and comparison with other agents that selectively inhibit cyclooxygenase-2[J]. J Pharmacol Exp Ther, 2001, 296(2): 558-566.
[14] DE LEFAL X. JULEMONT F. BENOIT V. et al. First and second generations of COX-2 selective inhibitiors[J]. Mini Rev Med Chem, 2004, 4(6): 597-601.
[15] STICHTENOTH DO, FROLICH JC. The Second generation of COX-2 inhibitors[J]. Drugs, 2003, 63(1): 33-45.
[16] BRUNE K, HINZ B. Selective cyclooxygenase-2 inhibitors: similarities and differences[J]. Scand J Rheumatol, 2004, 33(1): 1-6.
[17] SORBERA LA, RAMIS I. Cimicoxib[J]. Drug Fut, 2004, 29(4): 325-330.
[18] HIROMASA H, IMAMURA K, HARUTA J, et al. 4-(4-Cycloalkyl/aryl-oxatol-5-yl) bentene-sulfonamides as selective cyclooxygenase-2 inhibitiors: enhancement of the selectivity by introduction of a fluorine atom and identification of a potent, highly selective, and orally active COX-2 inhibitor JTE-522[J]. J Med Chem, 2002, 45(7): 1511-1517.
[19] CHEN Y, ZHANG GG, NEILLY J, et al. Enhancing the bioavailability of ABT-963 using solid dispension containing Pluronic F-68[J]. Int J Pharm, 2004, 286(1-2): 69-80.
[20] SORBERA LA, CASTANER M, BAYES M, et al. Lumiracoxib[J]. Drug Fut, 2002, 27(8): 740-747.
[21] KALGUTKAR AS, CREWS BC, ROWLINSON SW, et al. Aspirin-like molecules that eovalently inactivate cyclooxygenase-2[J]. Science, 1998, 280(5367): 1268-1270,
[22] LEVOIN N, CHRETIEN F, LAPICQUE F, et al. Synthesis and biological testing of Aeyl-CoA-ketoprofen conjugates as selective irreversible inhibitiors of COX-2[J]. Bioorg Med Chem, 2002, 10(3): 753-757.
[23] Fors-Hutclinson A W, Bay MA, Doig MV, et al. Leukotriene B, a potent chemokinetic and aggregating substance released from polymorphonuclear leukocytes[J], Nature, 1980, 286(5770): 264-265.
[24] 张孝仁．新颖的LOX/COX-2 抑制剂-Licofelone[J]．中国制药信息，2003，19(1)：27-29．
[25] http://www.unismed.com.cn/yykx/122526.htm[DB/OL].
[26] Dingle JT, et al. Effect of tenidap on cartilage integnity in vitro. Ann Rheum Dis, 1993, 52(4): 292.
[27] MONCADA S, PALMER R M J, HIGGS E A. The Discovery of Nitric Oxide as the Endogenous Nitrovasodilator[J]. Hypertension, 1988, 12: 365-372.
[28] MONCADA S, PALMER R M J, HIGGS E A. Nitric Oxide: Phydiology, Patbophysiology, and Pharmacology[J]. Pharmacological Reviews, 1991, 43(2): 109-141.
[29] MONCADA S, RADOMSKI M W, PALMER R M J. Endothelium-Derived Relaxing Factor: Identification as Nitric Oxide and Role in the Control of Vascular Tone and Platelet Function[J]. Biochem Pharmacol, 1988, 37: 2495-2501.
[30] MONCADA S, PALMER R M J, HIGGS E A. Biosynthesis of Nitric Oxide From L-arginine: a Pathway for Regulation of Cell Function and Communication[J]. Biochem Pharmacol, 1989, 38: 1079-1115.
[31] CLANCY R M, LESZCZYNSK A-PIZIAK J, ABRAMSON SB. Nitric Oxide, an Endothelial Cell Relaxation Factor, Inhibits Neutrophil Superoxide Anion Production Via a Direct Action on the NADPH Oxidase[J]. J Clin Invest, 1992, 90: 1116-1121.
[32] KUBES P M, SUZUKIM, GRANGER D N. Nitric Oxide: an Endogenous Modulator of leukocyte Adhesion [J]. Proc Natl Acael Sci USA, 1991, 88: 4651-4655.
[33] WALLACE J L, CHIN B C. New Generation NSAIDs: The Benefit Without the Risk[J]. Drug Today, 1997, 33: 371-378.
[34] ELLIOTT S N, MCKNIGHT W, CIRINO G, et al. A Nitric Oxide Releasing Nonsteroidal Anti-inflammatory Drug Accelerates Gastric Ulcers Healing in Rats[J]. Gastroenterology, 1995, 109: 524-530.
[35] KITAGAWA H, TAKEDA F, KOHEI H. Effect of Endothelium-derived Relaxing Factor on the Gastric Lesion Induced by HCl in Rats[J]. J Pharm Exp Ther, 1990, 253: 1133-1137.
[36] MITCHELL J A, CIRION G, AKARASEREENONT P, et al. Flurbiprofen Nitroxybutylester: A Novel Anti-inflammatory Drug Devoid of Ulcerogenic Activity, Inhibits Cyclooxy-genase-1 and Cyclooxygenase-2 [J]. Can Phyiol Pharmacol, 1994, 72: 270.
[37] TAKAEACHI K, UKAWA H, KONOKA A, et al. Effect of Nitric Oxide Releasing Aspirin Derivative on Gastric Functional and Ulcerogenic Responses in Rats: Comparision with Plain Aspirin[J]. J Pharmacol Exp Ther, 1995, 286: 115-121.
[38] CUZZOLIN L, CONFORT A, ADAMI A, et al. Anti-inflammatory Potency and Gastro-intestinal Toxicity of a New Compound, NO-naproxen[J]. Pharmacol Res, 1995, 31: 61-65.
[39] WALLACE J L, BAK K, MCKIGHT W, et al. Cyclooxygenase-1 Contributes to Inflammatory Responses in Rats and Mice: Implications for Gastrointestinal Toxicity[J]. Gastroenterology, 1998, 115: 101-109.
[40] DAVIES N M, ROSTCH A G, APPLEYCERD C B, et al, NO-naproxen vs Naproxen: Ulcerogenic, Analgesic and Anti-inflammatory Effects[J]. Aliment Pharmacol Ther, 1997, 11: 69-79.
[41] BOBERT M, CLANCY, STEVEN B. Nitric Oxide: A Novel Mediator of Inflammation[J]. Pris Soc Exp Biol Med, 1995, 210(2), 93-101.
[42] Morimoto A, Watanable T. Pyrrole lactam derivatives with antiprotozoa antitrichomonas blood sugar decreasing and gastric juice apoleptic activity[P]. JP: 7427877, 1974.
[43] Dumas DJ. Total synthesis of Peramine[J]. J. Org,. Chem., 1988, 53: 4650-4653.
[44] Rowan DD, Hunt MB, Gaynor DL. Peramine, a novel insect feeding deterrent from ryegrass infected with the endophyte acreminum loliae[J]. J. Chem. Soc., Chem. Commun., 1986. 935-936.
[45] Hiroshi U, Masashi T, Kobayashi J. Mukanadins A-C, new bromopyrrole alkaloids from marine sponge agelas nakamurai[J]. J. Nat. Prod., 1999, 62: 1581-1583.
[46] Banwell MG, Bray AM, Willis AC, et al. First syntheses of pyrrolo ketopiperazine marine natural products (±)-longamide, (±)-longamide B, (±)-longamide B methyl ester and (±)-hanishin[J]. New. J. Chem., 1999, 23(7): 687-690.
[47] 刘吉云．吲哚里嗪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，1996．
[48] Auzzj G, Bruni F, Cecchi L, et al. 2-Phenylpyrazolo[1,5-a]pyrimidin-7-ones. A new class of nonsteroidal snit-inflammatory drugs devoid of ulcerogenic activity[J]. J. Med. Chem., 1983, 26: 1706-1709.
[49] 庞冀燕，孙光，傅德才等．二氢吡咯并吡嗪酮衍生物的合成和抗炎镇痛作用[J]．中国药物化学杂志2002，12(2)：82-85．
[50] 傅德才．吡咯吡嗪酮和吡咯噁嗪酮衍生物的合成及抗炎镇痛作用研究[学位论文]．沈阳，沈阳药科大学，2002．
[51] 王绯．吡嗪酮类化合物的合成和抗炎镇痛构效关系研究[学位论文]．沈阳，沈阳药科大学，2004．
[52] Brimble MA, Brimble MT, Hodges R, et al. Synthesis of 2-methylpyrrolo [1,2-a]pyrazin-1(2H)-one[J]. Aust. J. Chem., 1988, 41: 1583-1590.
[53] Brimble MA, Rowan WW. Synthesis of the insect feeding deterrent Peramine via Michale Addition a pyrrole anion to a nitroalkene[J]. J. Chem. Soc. Perkin Trans. 1, 1990, 311-314.
[54] Denis MB, Robert EJ, Noel FA, et al[J]. Ethyl pyrrole-2-carboxylate. Organic Synthesis, 1970, 51: 100.
[55] Hodge P, Richard RW. Improved synthetic routes to pyrrole-2-carboxylic acid and its derivatives[J]. J. Chem. Soc., 1963, 2543-2545.
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