4-氨基水杨酸抗炎性肠病衍生物的合成研究
|
摘要
炎性肠病(inflammatory bowel diseases,IBD)包括溃疡性结肠炎(ulcerative colitis,UC)和克隆病(Crohn's Disease,CD)，是一组发病机理不明的慢性肠道炎症性疾病。在欧美国家发病率较高，近年来亚洲国家的发病率也逐渐升高。柳氮磺胺吡啶(Sulfusalazine,SASP)和5-氨基水杨酸(5-aminosalicylic acid,5-ASA)一直以来都是治疗IBD的主要药物。近年来有研究表明4-ASA在IBD的治疗上与5-ASA有同样高的疗效。但是直接口服的4-ASA很快就会在小肠上段吸收，只有少量能到达结肠发挥治疗作用，因此研究一种结肠特定性的4-ASA前体药物是很有必要的。体外试验表明，5-氨基水杨酸(5-ASA-Gly)可作为5-ASA结肠特定性给药的前体药物，基于4-ASA是5-ASA的同分异构体，而且化学结构相似，所以可以选择甘氨酸作为4-ASA结肠特定性前体药物的载体。本文探索了一条4-ASA衍生物—4-ASA-Gly的多步合成工艺，得到了目标产物4-ASA-Gly和五个中间体产物，对合成的目标产物和中间产物用熔点、薄层色谱、FT-IR、~1H-NMR和~(13)C-NMR进行了详细的表征，给出了它们的结构。本课题的研究工作为合成新型的高效低毒4-ASA类抗炎性肠病药物奠定了基础。
Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease, which have been popular among Europeans and Americans, are now getting increased in Asian countries such as Japan, Korea, and China since the end of the 1990's. The exact etiology of the IBD is not yet clearly understood. For many years, sulphasalazine (SASP) and 5-aminosalicylic acid(S-ASA) have been used in the treatment of IBD. Recently, 4-ASA has been reported as highly effective as 5-ASA in the maintenance treatment of IBD. But after oral ingestion uncoated 4-ASA is rapidly absorbed in the upper intestinal tract. So delivery of orally administered 4-ASA specifically to the colon is highly desirable. Results from in vitro experiments suggested that 5-ASA-Gly is a colon-specific prodrug of 5-ASA. As 4-ASA is an isomer of 5-ASA and they have the similar structure, glycine can be choosed as a colon-specific carrier. In this paper, we investigated the synthetic route in the conjugating reaction of glycine and 4-ASA, and five in
termediates have been prepared. We characterized their structures. They are characterized by melting point, TLC, FT-IR, 'H-NMR and 13C-NMR spectra properties in details. Their structures are given out. By our studying, we have provided a suitable synthesis route for further exploring new compounds in the treatment of IBD.
Inflammatory bowel diseases (IBD) such as ulcerative colitis and Crohn's disease, which have been popular among Europeans and Americans, are now getting increased in Asian countries such as Japan, Korea, and China since the end of the 1990's. The exact etiology of the IBD is not yet clearly understood. For many years, sulphasalazine (SASP) and 5-aminosalicylic acid(S-ASA) have been used in the treatment of IBD. Recently, 4-ASA has been reported as highly effective as 5-ASA in the maintenance treatment of IBD. But after oral ingestion uncoated 4-ASA is rapidly absorbed in the upper intestinal tract. So delivery of orally administered 4-ASA specifically to the colon is highly desirable. Results from in vitro experiments suggested that 5-ASA-Gly is a colon-specific prodrug of 5-ASA. As 4-ASA is an isomer of 5-ASA and they have the similar structure, glycine can be choosed as a colon-specific carrier. In this paper, we investigated the synthetic route in the conjugating reaction of glycine and 4-ASA, and five in
termediates have been prepared. We characterized their structures. They are characterized by melting point, TLC, FT-IR, 'H-NMR and 13C-NMR spectra properties in details. Their structures are given out. By our studying, we have provided a suitable synthesis route for further exploring new compounds in the treatment of IBD.
引文
[1] 张林国，唐旭东，赵百孝，等编．结肠炎．北京：科学技术文献出版社，2000，36～37
[2] 欧阳钦．我国炎症性肠病研究的概况与展望．中华消化杂志，1993，13(8)：31～32
[3] 欧阳钦．炎症性肠病诊断治疗的最新进展．中国使用内科杂志，2000．20(1)：17～19
[4] Azad Khan Ak, Piris J, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. The Lancet, 1977, ⅱ: 892～895
[5] Klotz U, Maier K, Fischer C, et al. Therapeutic efficacy of sulphasalazine and its metabolites in patients with ulcerative colitis and crohn's disease. The New England Journal of Medicine, 1980, 303: 1499～1502
[6] Carlo C, Giorgio G, Enrico B, et al. Amino acid derivatives of 5-ASA as novel prodrugs for intestinal drug delivery. Dig. Dis. Sci., 1994, 39(12): 2601～2606
[7] Van Hees PAM, Bakker JH, Tongeren JHM. Effects of sulphapyridine, 5-aminosalicylic acid and placebo in patients with idiopathic proctits: a study to determine the active therapeutic moiety of sulphasalazine. Gut, 1980, 21:632～635
[8] 胡伏莲，林庚金，袁爱力，等．美沙拉嗪治疗炎症性肠病的疗效及安全性．中国新药杂志，2001，10(3)：201～204
[9] 杨希雄，陈军．氨基水杨酸类药物治疗溃疡性结肠炎．医药导报，2001，20(11)：722～723
[10] Campieri M, Lanfranchi GA, Berton F, et al. A double-blind clinical trial to compare the effect of 4-aminosalicylic acid in
topical treatment of ulcerative colitis. Digestion, 1984, 29: 204～208
[11] Ginsberg AL, Beck LS, Mclintosh TM, et al. Treatment left-sided ulcerative colitis with 4-aminosalicylic acid enemas: A double blind placebo-controlled trial. Ann Intern Med, 1988, 108:195～199
[12] Schreiber S, Howaldt S, Raedler A. Oral 4-aminolicylic acid versus 5-aminolicylic acid slow release tablets. Double blind, controlled pilot study in the maintenance treatment of Crohn's ileocolitis. Gut, 1994, 35: 1081～1085
[13] O'Donnell LJD, Arvind AS, Hoang P, et al. Double blind, controlled trial of 4-aminosalicylic acid and prednisolone enemas in distal ulcerative colitis. Gut, 1992, 33: 947～949
[14] 马洪升，欧阳钦，陈岱云，等．三种灌肠剂治疗左半结肠溃疡性结肠炎疗效观察．临床内科杂志，1999，16(3)：144～146
[15] 康景銮，杨永福．PAS灌肠治疗溃疡性结肠炎疗效观察．中国肛肠病杂志，1992，3(1)：19～20
[16] Jung YJ, Lee JS, Kim YM. Synthesis and in vitrol/in vivo evaluation of 5-aminosalicyl-glycine as a colon-specific prodrug of 5-amino-salicylic acid. Journal of pharmaceutical Sciences, 2000, 89(5): 594～602
[17] Jung YJ, Lee JS, Kim YM, et al. Synthesis and evaluation of 5-aminosalicyl-glycine as a potential colon-specific prodrug of 5-aminolicylicacid. Arch. Pharm. Res., 1998, 21(2): 174～178
[18] 苏俊，马成禹．甾体雌激素类化合物的氢解脱苄研究．化学试剂，1999，21(4)，196～198；222
[2] 欧阳钦．我国炎症性肠病研究的概况与展望．中华消化杂志，1993，13(8)：31～32
[3] 欧阳钦．炎症性肠病诊断治疗的最新进展．中国使用内科杂志，2000．20(1)：17～19
[4] Azad Khan Ak, Piris J, Truelove SC. An experiment to determine the active therapeutic moiety of sulphasalazine. The Lancet, 1977, ⅱ: 892～895
[5] Klotz U, Maier K, Fischer C, et al. Therapeutic efficacy of sulphasalazine and its metabolites in patients with ulcerative colitis and crohn's disease. The New England Journal of Medicine, 1980, 303: 1499～1502
[6] Carlo C, Giorgio G, Enrico B, et al. Amino acid derivatives of 5-ASA as novel prodrugs for intestinal drug delivery. Dig. Dis. Sci., 1994, 39(12): 2601～2606
[7] Van Hees PAM, Bakker JH, Tongeren JHM. Effects of sulphapyridine, 5-aminosalicylic acid and placebo in patients with idiopathic proctits: a study to determine the active therapeutic moiety of sulphasalazine. Gut, 1980, 21:632～635
[8] 胡伏莲，林庚金，袁爱力，等．美沙拉嗪治疗炎症性肠病的疗效及安全性．中国新药杂志，2001，10(3)：201～204
[9] 杨希雄，陈军．氨基水杨酸类药物治疗溃疡性结肠炎．医药导报，2001，20(11)：722～723
[10] Campieri M, Lanfranchi GA, Berton F, et al. A double-blind clinical trial to compare the effect of 4-aminosalicylic acid in
topical treatment of ulcerative colitis. Digestion, 1984, 29: 204～208
[11] Ginsberg AL, Beck LS, Mclintosh TM, et al. Treatment left-sided ulcerative colitis with 4-aminosalicylic acid enemas: A double blind placebo-controlled trial. Ann Intern Med, 1988, 108:195～199
[12] Schreiber S, Howaldt S, Raedler A. Oral 4-aminolicylic acid versus 5-aminolicylic acid slow release tablets. Double blind, controlled pilot study in the maintenance treatment of Crohn's ileocolitis. Gut, 1994, 35: 1081～1085
[13] O'Donnell LJD, Arvind AS, Hoang P, et al. Double blind, controlled trial of 4-aminosalicylic acid and prednisolone enemas in distal ulcerative colitis. Gut, 1992, 33: 947～949
[14] 马洪升，欧阳钦，陈岱云，等．三种灌肠剂治疗左半结肠溃疡性结肠炎疗效观察．临床内科杂志，1999，16(3)：144～146
[15] 康景銮，杨永福．PAS灌肠治疗溃疡性结肠炎疗效观察．中国肛肠病杂志，1992，3(1)：19～20
[16] Jung YJ, Lee JS, Kim YM. Synthesis and in vitrol/in vivo evaluation of 5-aminosalicyl-glycine as a colon-specific prodrug of 5-amino-salicylic acid. Journal of pharmaceutical Sciences, 2000, 89(5): 594～602
[17] Jung YJ, Lee JS, Kim YM, et al. Synthesis and evaluation of 5-aminosalicyl-glycine as a potential colon-specific prodrug of 5-aminolicylicacid. Arch. Pharm. Res., 1998, 21(2): 174～178
[18] 苏俊，马成禹．甾体雌激素类化合物的氢解脱苄研究．化学试剂，1999，21(4)，196～198；222