5-羟基-6-嗅-1H-吲哚-3-羧酸乙酯类化合物的合成研究
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摘要
流感是由流感病毒引起的急性呼吸道传染病，严重危害人类的健康。本文介绍了流感病毒的生物学特征，并阐述了抗流感病毒药物的研究进展。
阿比朵尔是一种新型的抗流感病毒药物，它通过激活细胞内的2，5-寡腺嘌呤核苷酸合成酶，间接抑制病毒复制，临床上可用于预防和治疗甲、乙型流感病毒引起的急性呼吸道疾病。
在实验室前期研究的基础上，以阿比朵尔为先导化合物，选择5-羟基-6-溴-1H-吲哚-3-羧酸乙酯为母核，运用拼合及局部修饰等药物设计原理，对吲哚环1、2、4位进行结构改造，设计并合成了20个未见文献报道的新化合物，其结构经质谱、核磁共振氢谱确证。
对吲哚环2位进行的结构改造过程中，运用先导物优化中的同系物变换原理，引入间氯苄硫甲基和苯氧乙硫甲基结构，考察其对抗病毒活性的影响，以求对该位置的改造能够有所突破。
目标化合物的抗流感病毒活性实验正在进行之中。
Influenza is an acute respiratory tract infection caused by influenza viruses and it remains a serious health concern. In this paper we focused on the biological characteristics of influenza virus , and we also described the development of anti-influenza agents.The antiviral activity of Arbidol, a new antiviral agent, is most pronounced against influenza viruses of the A and B antigenic type. Its effect may be due to the activation of 2,5-oligoadenylate synthetase. Arbidol has been developed and licensed for the treatment and prophylaxis of respiratory viral infections.On the basis of early research, arbidol was used as the leading compound. And ethyl 5-hydroxy-6-bromo-1H-indole-3-carboxylate was chosen as elementary structure. Some modifications were made at 1 position、2 position、4 position of the indole nucleus by using the principle of drug design of combination principles and modification principles. 20 target compounds were designed and prepared which hadn't been reported in literatures. The structures of the 20 target compounds were confirmed by MS, ~1H-NMR.In the course of modification at 2 position of indole, the structure of (3-chloro-α-toluenethio)methyl or (β-phenoxyethio)methyl was introduced by using principle of lead optimization to examine the effect on the activity of anti-virus. We expected to make a breakthrough on modification of this position.The test on antivirus activity of these target compounds is in progress.
阿比朵尔是一种新型的抗流感病毒药物，它通过激活细胞内的2，5-寡腺嘌呤核苷酸合成酶，间接抑制病毒复制，临床上可用于预防和治疗甲、乙型流感病毒引起的急性呼吸道疾病。
在实验室前期研究的基础上，以阿比朵尔为先导化合物，选择5-羟基-6-溴-1H-吲哚-3-羧酸乙酯为母核，运用拼合及局部修饰等药物设计原理，对吲哚环1、2、4位进行结构改造，设计并合成了20个未见文献报道的新化合物，其结构经质谱、核磁共振氢谱确证。
对吲哚环2位进行的结构改造过程中，运用先导物优化中的同系物变换原理，引入间氯苄硫甲基和苯氧乙硫甲基结构，考察其对抗病毒活性的影响，以求对该位置的改造能够有所突破。
目标化合物的抗流感病毒活性实验正在进行之中。
Influenza is an acute respiratory tract infection caused by influenza viruses and it remains a serious health concern. In this paper we focused on the biological characteristics of influenza virus , and we also described the development of anti-influenza agents.The antiviral activity of Arbidol, a new antiviral agent, is most pronounced against influenza viruses of the A and B antigenic type. Its effect may be due to the activation of 2,5-oligoadenylate synthetase. Arbidol has been developed and licensed for the treatment and prophylaxis of respiratory viral infections.On the basis of early research, arbidol was used as the leading compound. And ethyl 5-hydroxy-6-bromo-1H-indole-3-carboxylate was chosen as elementary structure. Some modifications were made at 1 position、2 position、4 position of the indole nucleus by using the principle of drug design of combination principles and modification principles. 20 target compounds were designed and prepared which hadn't been reported in literatures. The structures of the 20 target compounds were confirmed by MS, ~1H-NMR.In the course of modification at 2 position of indole, the structure of (3-chloro-α-toluenethio)methyl or (β-phenoxyethio)methyl was introduced by using principle of lead optimization to examine the effect on the activity of anti-virus. We expected to make a breakthrough on modification of this position.The test on antivirus activity of these target compounds is in progress.
引文
[1] Nicholson KG. Clinical features of influenza. Semin Respir Inf, 1992, 7 (1): 26～37
[2] Potter CW. Attenuated influenza vires vaccines. Rev Med Virol, 1994, 4 (4): 279～292
[3] Stamboulian D, Bonvehi PE. Influenza.[J]. Inject Dis Clin North Am, 2000, 14 (1): 141
[4] Leahy MB, Dobbyn HC, Brownlee GG. Hairpin loop structure in the 3'arm of the influenza A virus virion RNA promoter is required for endonuclease activity. J Virol, 2001, 75: 7042
[5] 忻亚娟，陈念良，流行性感冒的预防和控制．国外医学·流行病学传染病学分册 2000，27(6)：275
[6] 李明远主编．微生物学与免疫学，第4版，人民卫生出版社，2000：127～129
[7] Galasso GJ. An assessment of antiviral drags for the management of infectious diseases in humans. Antiviral Res. 1981, 1 (2): 73～96
[8] Markvon IM, Wu W-Y, Kok GB, etc. Rational design of potent siadase-based inhibitors of influenza virus replication. Nature. 1993, 363 (6418): 418～423
[9] Colman PM, Varghese JN, Laver WG. Strucmre of the catalytic and antigenic sites in influenza virus neuraminidase. Nature. 1983, 303(5912): 41～44
[10] Smee DF, Huffman JH, Morrison AC. Cyclopentane Neuramindase inhibitors with potent in vitro anti-influenza virus activity. Antimicrob agents Chemother, 2001, 45 (3): 743～748
[11] Dyason JC, Itzstein M. Anti-influenza virus drug design: Sialidase Inhibitor. Aust J Chem, 2001, 54: 663～670
[12] Schilling M, Povinelli L, Krause P, et al. Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks. Vaccine. 1998, 16: 1771
[13] Hayden FG, Treanor JJ, Betts RF, etc. Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. J Am Med Assoc. 1996, 275 (4): 295～299
[14] Lew W, Chen X, Kim CU. Discovery and development of GS 4104 (oseltamivir): an orally active influenza neuraminidase inhibitor. Current Med Chem, 2000, 7: 663～672
[15] Mc Clellan K, Perry CM. Oseltamivir. Drugs, 2001, 61 (2): 263～283
[16] Glushkov R. G., Fadeeva N. I., Leneval I. A, etc. Molecular biological features of the action of arbidol, a new antiviral drug. Khim Fam Zh, 1992, 26 (2): 8～15
[17] 陈忠斌，王升启，孙志贤．抗流感病毒药物的研究进展．国外医学药学分册．1998，25(2)： 71～75
[18] 陈忠斌，王升启，朱宝珍等．硫代反义寡核苷酸在细胞培养内抗甲型流感病毒活性．病毒学报，1998，14(3：194～197
[19] 王钝，5-羟基-6-溴吲哚-3-羧酸酯类化合物的合成及抗流感病毒活性研究．沈阳药科大学博士学位论文，2003，21～23
[20] Peak D A, Walkins T I. Compounds related to diethyl-ω-aryloxyal kylamines. J. Chem. Soc. 1950, 445
[21] Parham W E, Bhovsac M D. The reaction of Cyclic Sulfoxides with Acetic Anhydride. J. Org Chem. 1963, 28: 2686
[22] Doumaux A R et al. Metal ion-catalyzed peroxide oxidation of organic substrates. Selective synthesis ofimides. J. Am. Chem. Soc. 1969, 91: 3992
[23] Bethell P, Park B K, A simple and convenient method for the oxidation ofsulphides. Synth. Commun. 1993, 23: 1507
[24] Sviridova A V et al. Zhu. Org. Khim. 1971, 7: 2480
[25] Siegl W O, Johnson C R, Chemistry of sulfoxides and related compounds. 3-Substituted thiethanes. Synthesis and oxidation to sulfoxides. J. Org. Chem. 1970, 35: 3657
[26] Baumstark A L, Vasquez P C, Oxidation of sulfides by acyclic alpha-azohydroperoxides. J. Org. Chem. 1983, 48: 65
[27] Venier C G et al. Peroxytrifluoroacetic acid oxidation of sulfides to sulfoxides and sulfones. J. Org. Chem. 1982, 47: 3773
[28] Leonard N J, Johnson C R. Periodate oxideation of sulfides to sulfoxides. J. Org. Chem. 1962, 27: 282
[29] Friedman P, Allen P, Jr. Medium-ring thiacycloalkanes J. Org. Chem. 1965, 30: 780
[30] Hartzell G E, Paige J N. Ethylene episulfoxide. J. Am. Chem. Soc. 1966, 88: 2616
[31] Young T E, Synthesis of 2, 3, 4, 10-tetrahydrothiopyrano[3, 2-b]-1-benzothiopyran and its reaction with o-chloranil. J. Org. Chem. 1973, 38: 1567
[32] Johson C R, Keiser J E. Methyl phenyl sulfoxide. Org. Synth. 1973, Coll. Vol. 5: 791
[33] Lupattelli P et al. 1,1, 1-Trifluoroacetone as an efficient catalyst for the hydrogen peroxide promoted selective oxidation of sulfides to sulfoxides. Synth. Commun. 1997, 27: 441
[34] Alexander Mckillop, Jonathan A, Tarbin. Sodium perborate-A cheap and effective reagent for the oxidation ofonilines and sulphides. Tetrahedron Lett, 1983, 24 (14): 1505
[35] Schultz H S et al. New catalysts for the oxidation of sulfides to sulfones with hydrogen peroxide. J. Org. Chem. 1963, 28: 1140
[36] Page P C B, Graham A E. A simple and convenient method for the oxidation of sulphides. Synth. Commun. 1993, 23: 1507
[37] Jones D N, Green M J. J. Chem. Soc. 1967, c: 532
[38] Paquette LA. α-Halosulfones. A facile conversion of mercaptans to homologans terminal olefins. J. Am. Chem. Soc. 1964, 86: 4383
[39] Lorin C, Pollin R Synthesis. 1998, 1506
[40] Rodriguez C M et al. Simple and efficient oxidation of sulfides to sulfones using catalytic ruthenium tetroxide. Tetrahedron. 1992, 48: 3571
[41] Wittenburg E. J. Prakt. Chem. 1966, 33: 165
[42] Kuhnen L. Oxidation von sulfoxidenmit hydroperoxiden. Angew. Chem. 1966, 78: 937
[43] Amaral M J S. The 2-(p-nitrophenylthio) ethyl group for carboxy-group protection in peptide synthesis. J. Chem. Soc. 1969, C: 2495
[44] Clingman A L, Richtmyer N. K. Aryl thioglycopyranosides, ary glycopyranosyl sulfones, and the novel oxidation-acetylation of aryl 1-thio-β-D-glucopyranosides to 6-o-acetyl-β-D-glucopyranosyl aryl sulfones. J. Org. Chem. 1964, 29: 1782 Yamamoto I et al. Synthesis. Synthesis of chlorovinyI phenyl sulfides and sulfones from diethyl chloro-(phenylthio)-methanephosphonate. 1985, 676
[45] Venier C G et al. Peroxytrifluoroacetic acid oxidation of sulfides to sulfoxides and sulfones.J. Org. Chem. J. Org. Chem. 1982, 47: 3773
[46] Novitskaya N N et al. Oxidation of hydroxyl sulfides. CA. 1969, 70: 46756
[47] Andre B, Charette Carl Bethelette. An expedient approach to E, Z-dienes using the Julia olefination. Tetrahedron Lett, 2001, 42: 5149～5153
[48] Djerassi C, Gorman M, Markley F X et al. Lithium aluminum hydride reaction of xanthates to mercaptans. J. Am. Chem. Soc. 1955, 77: 568
[49] Price C C, Stacy G W. ρ-Nitrophenyl disulfide, ρ-Nitrophenyl sulfide and ρ-Nitrothiophenol. J. Am. Chem. Soc. 1956, 68: 498
[50] Hall W P, Reid E E. A series of α, ω-dimercaptans. J. Am. Chem. Soc. 1943, 65: 1466
[51] Chapman J H, Owen L N. The reaction of toluene-p-sulphonates and methanesulphonates with potassium thioacetate: a new method for the preparation ofthiols. J. Chem. Soc. 1950, 579
[2] Potter CW. Attenuated influenza vires vaccines. Rev Med Virol, 1994, 4 (4): 279～292
[3] Stamboulian D, Bonvehi PE. Influenza.[J]. Inject Dis Clin North Am, 2000, 14 (1): 141
[4] Leahy MB, Dobbyn HC, Brownlee GG. Hairpin loop structure in the 3'arm of the influenza A virus virion RNA promoter is required for endonuclease activity. J Virol, 2001, 75: 7042
[5] 忻亚娟，陈念良，流行性感冒的预防和控制．国外医学·流行病学传染病学分册 2000，27(6)：275
[6] 李明远主编．微生物学与免疫学，第4版，人民卫生出版社，2000：127～129
[7] Galasso GJ. An assessment of antiviral drags for the management of infectious diseases in humans. Antiviral Res. 1981, 1 (2): 73～96
[8] Markvon IM, Wu W-Y, Kok GB, etc. Rational design of potent siadase-based inhibitors of influenza virus replication. Nature. 1993, 363 (6418): 418～423
[9] Colman PM, Varghese JN, Laver WG. Strucmre of the catalytic and antigenic sites in influenza virus neuraminidase. Nature. 1983, 303(5912): 41～44
[10] Smee DF, Huffman JH, Morrison AC. Cyclopentane Neuramindase inhibitors with potent in vitro anti-influenza virus activity. Antimicrob agents Chemother, 2001, 45 (3): 743～748
[11] Dyason JC, Itzstein M. Anti-influenza virus drug design: Sialidase Inhibitor. Aust J Chem, 2001, 54: 663～670
[12] Schilling M, Povinelli L, Krause P, et al. Efficacy of zanamivir for chemoprophylaxis of nursing home influenza outbreaks. Vaccine. 1998, 16: 1771
[13] Hayden FG, Treanor JJ, Betts RF, etc. Safety and efficacy of the neuraminidase inhibitor GG167 in experimental human influenza. J Am Med Assoc. 1996, 275 (4): 295～299
[14] Lew W, Chen X, Kim CU. Discovery and development of GS 4104 (oseltamivir): an orally active influenza neuraminidase inhibitor. Current Med Chem, 2000, 7: 663～672
[15] Mc Clellan K, Perry CM. Oseltamivir. Drugs, 2001, 61 (2): 263～283
[16] Glushkov R. G., Fadeeva N. I., Leneval I. A, etc. Molecular biological features of the action of arbidol, a new antiviral drug. Khim Fam Zh, 1992, 26 (2): 8～15
[17] 陈忠斌，王升启，孙志贤．抗流感病毒药物的研究进展．国外医学药学分册．1998，25(2)： 71～75
[18] 陈忠斌，王升启，朱宝珍等．硫代反义寡核苷酸在细胞培养内抗甲型流感病毒活性．病毒学报，1998，14(3：194～197
[19] 王钝，5-羟基-6-溴吲哚-3-羧酸酯类化合物的合成及抗流感病毒活性研究．沈阳药科大学博士学位论文，2003，21～23
[20] Peak D A, Walkins T I. Compounds related to diethyl-ω-aryloxyal kylamines. J. Chem. Soc. 1950, 445
[21] Parham W E, Bhovsac M D. The reaction of Cyclic Sulfoxides with Acetic Anhydride. J. Org Chem. 1963, 28: 2686
[22] Doumaux A R et al. Metal ion-catalyzed peroxide oxidation of organic substrates. Selective synthesis ofimides. J. Am. Chem. Soc. 1969, 91: 3992
[23] Bethell P, Park B K, A simple and convenient method for the oxidation ofsulphides. Synth. Commun. 1993, 23: 1507
[24] Sviridova A V et al. Zhu. Org. Khim. 1971, 7: 2480
[25] Siegl W O, Johnson C R, Chemistry of sulfoxides and related compounds. 3-Substituted thiethanes. Synthesis and oxidation to sulfoxides. J. Org. Chem. 1970, 35: 3657
[26] Baumstark A L, Vasquez P C, Oxidation of sulfides by acyclic alpha-azohydroperoxides. J. Org. Chem. 1983, 48: 65
[27] Venier C G et al. Peroxytrifluoroacetic acid oxidation of sulfides to sulfoxides and sulfones. J. Org. Chem. 1982, 47: 3773
[28] Leonard N J, Johnson C R. Periodate oxideation of sulfides to sulfoxides. J. Org. Chem. 1962, 27: 282
[29] Friedman P, Allen P, Jr. Medium-ring thiacycloalkanes J. Org. Chem. 1965, 30: 780
[30] Hartzell G E, Paige J N. Ethylene episulfoxide. J. Am. Chem. Soc. 1966, 88: 2616
[31] Young T E, Synthesis of 2, 3, 4, 10-tetrahydrothiopyrano[3, 2-b]-1-benzothiopyran and its reaction with o-chloranil. J. Org. Chem. 1973, 38: 1567
[32] Johson C R, Keiser J E. Methyl phenyl sulfoxide. Org. Synth. 1973, Coll. Vol. 5: 791
[33] Lupattelli P et al. 1,1, 1-Trifluoroacetone as an efficient catalyst for the hydrogen peroxide promoted selective oxidation of sulfides to sulfoxides. Synth. Commun. 1997, 27: 441
[34] Alexander Mckillop, Jonathan A, Tarbin. Sodium perborate-A cheap and effective reagent for the oxidation ofonilines and sulphides. Tetrahedron Lett, 1983, 24 (14): 1505
[35] Schultz H S et al. New catalysts for the oxidation of sulfides to sulfones with hydrogen peroxide. J. Org. Chem. 1963, 28: 1140
[36] Page P C B, Graham A E. A simple and convenient method for the oxidation of sulphides. Synth. Commun. 1993, 23: 1507
[37] Jones D N, Green M J. J. Chem. Soc. 1967, c: 532
[38] Paquette LA. α-Halosulfones. A facile conversion of mercaptans to homologans terminal olefins. J. Am. Chem. Soc. 1964, 86: 4383
[39] Lorin C, Pollin R Synthesis. 1998, 1506
[40] Rodriguez C M et al. Simple and efficient oxidation of sulfides to sulfones using catalytic ruthenium tetroxide. Tetrahedron. 1992, 48: 3571
[41] Wittenburg E. J. Prakt. Chem. 1966, 33: 165
[42] Kuhnen L. Oxidation von sulfoxidenmit hydroperoxiden. Angew. Chem. 1966, 78: 937
[43] Amaral M J S. The 2-(p-nitrophenylthio) ethyl group for carboxy-group protection in peptide synthesis. J. Chem. Soc. 1969, C: 2495
[44] Clingman A L, Richtmyer N. K. Aryl thioglycopyranosides, ary glycopyranosyl sulfones, and the novel oxidation-acetylation of aryl 1-thio-β-D-glucopyranosides to 6-o-acetyl-β-D-glucopyranosyl aryl sulfones. J. Org. Chem. 1964, 29: 1782 Yamamoto I et al. Synthesis. Synthesis of chlorovinyI phenyl sulfides and sulfones from diethyl chloro-(phenylthio)-methanephosphonate. 1985, 676
[45] Venier C G et al. Peroxytrifluoroacetic acid oxidation of sulfides to sulfoxides and sulfones.J. Org. Chem. J. Org. Chem. 1982, 47: 3773
[46] Novitskaya N N et al. Oxidation of hydroxyl sulfides. CA. 1969, 70: 46756
[47] Andre B, Charette Carl Bethelette. An expedient approach to E, Z-dienes using the Julia olefination. Tetrahedron Lett, 2001, 42: 5149～5153
[48] Djerassi C, Gorman M, Markley F X et al. Lithium aluminum hydride reaction of xanthates to mercaptans. J. Am. Chem. Soc. 1955, 77: 568
[49] Price C C, Stacy G W. ρ-Nitrophenyl disulfide, ρ-Nitrophenyl sulfide and ρ-Nitrothiophenol. J. Am. Chem. Soc. 1956, 68: 498
[50] Hall W P, Reid E E. A series of α, ω-dimercaptans. J. Am. Chem. Soc. 1943, 65: 1466
[51] Chapman J H, Owen L N. The reaction of toluene-p-sulphonates and methanesulphonates with potassium thioacetate: a new method for the preparation ofthiols. J. Chem. Soc. 1950, 579