T614衍生物的合成和阿司匹林及其衍生物的糖基化结构修饰研究
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摘要
本论文由两部分组成，即T614衍生物的合成和阿司匹林及其衍生物的糖基化结构修饰研究。
概述了非甾体抗炎药环氧酶-2抑制剂的研究进展，设计以β-萘酚烃化、氨基对甲苯磺酰化及苯环乙酰化对T614的中间体进行结构修饰，合成出了1个T614衍生物及16个中间体侧链修饰物，为寻找具有优化活性的先导物进行了探索性研究。
论文首先实验打通了合成T614衍生物的路线，由4-氯-3-硝基茴香醚出发经过七步全合成反应得到最终产品——3-甲酰胺基-6-苯氧基-7-对甲苯磺酰胺基苯并吡喃酮，在参考原始文献的基础上作出了出色的改进和创新，获得成功。
为对阿司匹林类化合物的结构及活性进行改造和优化，本论文采用乙酰基保护的溴代葡萄糖和水杨酸及其衍生物在相转移催化剂作用下反应，制得的糖苷再经乙酰化或催化氢化后乙酰化和脱乙酰化，实验合成了8个阿司匹林及其衍生物的葡萄糖基化修饰物及天然产物水杨苷。实验方法简便、重现性好，收率高，有较大实用价值。
对上述化合物利用高效液相色谱分析了纯度，并经红外光谱、核磁共振谱、质谱表征和结构确证。
This thesis consisted of two sections, the synthesis of T614's derivatives and studies on the structure modifying of Aspirin and its derivatives in carbohydrate.
At this article we briefly summarized the progress in research of the Non-steroidal Anti-inflammatory Drugs - Cyclooxygenase-2 inhibitors, designed on the structure modifying of T614 by p-naphthol alkylation, anmino tosylation and benzol acetylation, mainly prepared one derivative of T614 and 16 lateral-chained structure modified compounds of its parted intermediates, the exploratory research had been done in order to search after the lead compounds possessing improved biological activities.
The novel methods for the synthesis of T614's derivatives were described, the total synthetical process included seven steps from 4-chloro-3-nitroanisole in which some improvements and innovations of the methods compare to the reference were worked out. In the end, we obtained the termination-product with high overall yield-3-(acylamino) -6-phenoxy-7-(p-tolylsulfonylamino) -4H-1 -benzopyran-4-one.
To modify the structure and optimize the activities of Aspirin, a series of glucosides of Aspirin and its derivatives also natural product-Salicin were prepared via using bromo-glucose protected by acetyl and salicylic acid and its derivatives reacted by way of phase transfer catalysis, then applied the acetylation or catalytic hydrogenation before acetylation and deacetyltion to the corresponding acquired glucosides. These methods were proved to be relatively simple and stable with high yields and superior practical value.
The purities of most compounds above were analyzed by HPLC, Their structures were confirmed and characterized by MS, NMR and IR.
概述了非甾体抗炎药环氧酶-2抑制剂的研究进展，设计以β-萘酚烃化、氨基对甲苯磺酰化及苯环乙酰化对T614的中间体进行结构修饰，合成出了1个T614衍生物及16个中间体侧链修饰物，为寻找具有优化活性的先导物进行了探索性研究。
论文首先实验打通了合成T614衍生物的路线，由4-氯-3-硝基茴香醚出发经过七步全合成反应得到最终产品——3-甲酰胺基-6-苯氧基-7-对甲苯磺酰胺基苯并吡喃酮，在参考原始文献的基础上作出了出色的改进和创新，获得成功。
为对阿司匹林类化合物的结构及活性进行改造和优化，本论文采用乙酰基保护的溴代葡萄糖和水杨酸及其衍生物在相转移催化剂作用下反应，制得的糖苷再经乙酰化或催化氢化后乙酰化和脱乙酰化，实验合成了8个阿司匹林及其衍生物的葡萄糖基化修饰物及天然产物水杨苷。实验方法简便、重现性好，收率高，有较大实用价值。
对上述化合物利用高效液相色谱分析了纯度，并经红外光谱、核磁共振谱、质谱表征和结构确证。
This thesis consisted of two sections, the synthesis of T614's derivatives and studies on the structure modifying of Aspirin and its derivatives in carbohydrate.
At this article we briefly summarized the progress in research of the Non-steroidal Anti-inflammatory Drugs - Cyclooxygenase-2 inhibitors, designed on the structure modifying of T614 by p-naphthol alkylation, anmino tosylation and benzol acetylation, mainly prepared one derivative of T614 and 16 lateral-chained structure modified compounds of its parted intermediates, the exploratory research had been done in order to search after the lead compounds possessing improved biological activities.
The novel methods for the synthesis of T614's derivatives were described, the total synthetical process included seven steps from 4-chloro-3-nitroanisole in which some improvements and innovations of the methods compare to the reference were worked out. In the end, we obtained the termination-product with high overall yield-3-(acylamino) -6-phenoxy-7-(p-tolylsulfonylamino) -4H-1 -benzopyran-4-one.
To modify the structure and optimize the activities of Aspirin, a series of glucosides of Aspirin and its derivatives also natural product-Salicin were prepared via using bromo-glucose protected by acetyl and salicylic acid and its derivatives reacted by way of phase transfer catalysis, then applied the acetylation or catalytic hydrogenation before acetylation and deacetyltion to the corresponding acquired glucosides. These methods were proved to be relatively simple and stable with high yields and superior practical value.
The purities of most compounds above were analyzed by HPLC, Their structures were confirmed and characterized by MS, NMR and IR.
引文
1 彭司勋主编．药物化学-回顾与发展[M]．第一版．北京：人民卫生出版社，2002
2 赵丽琴，张守芳．环氧化酶-2 选择性抑制剂研究进展[J]．中国药物化学杂志．1999，9(2)：139-143
3 Jones, M K, et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into Mechanisms and implications for cancer growth and ulcer healing[J]. Nature Medicine, 1999, 5:1418-1421
4 Edith Lares, et al. Aspirin for cancer[J]. Nature Medicine, 1999, 5:1348-1349
5 Fu J Y, Masferrer J L, Seibert K, et al. The induction and suppression of prostaglandin H_2 synthase (cyclooxygenase) in human monocytes[J]. J Biol Chem, 1990,265:16737
6 Seibert K, Zhang Y, Leahy K, et al. Pharmacological demonstration of the role of cyclooxygenase-2 in inflammatory and pain[J]. Proc. Acad. Sci USA, 1994, 91:12013
7 彭司勋主编．药物化学进展(1)[M]．第一版．北京：化学工业出版社，2001
8 Gans K R, Galbaith W, Roman R J, et al. Anti-inflammatory and safety profile of DUP697, a novel orally effective prostaglandin synthesis inhibitor[J]. J Pharmacol Exp Ther, 1990.254(1):180
9 Silvestre J, Lesson PA, Castaner J. JTE-522. Drugs Fut., 1998, 23:598
10 Shamim, S M; Islam, Farida, et al. Acetylsalicylic acid (aspirin): therapeutic uses[J], Pakistan Journal of Pharmacology, 2003, 18(1), 7-12
11 NCX-4016. Drugs Fut., 2000,25:1215-1217
12 Kalgutkar A S, Crews BC, Rowlinson S W, et al. Aspirin-like molecules that covalently inactivate cylooxygenase-2[J]. Science, 1998,280:1268
13 Davis R, Brogden R N, et al. Nimesulide, an update on its pharmacodynamic and pharmacokinetic properties and therapeutic efficiency[J]. Drugs, 1994,48:431
14 Futaki N, Takahashi S, Yokoyama M, et al. NS-398, a new anti-inflammatory agent, selectively inhibits COX-2 activity in vitro[J]. Prostaglandins, 1994,47-55
15 Prous J, Mealy N, Castaner J, et al. T614. Drugs Fut, 1993,18:714
16 Kuriyama, Kohji, Higuchi, Chikahisa, et al. A novel anti-rheumatic drug, T-614, stimulates osteoblastic ifferentiation in vitro and bone morphogenetic protein
-2-induced bone formation in vivo[J]. Biochemical and Biophysical Research Communications, 2002,299(5):903-909 (English)
17 Tetsuji Sawada, Shiori Hashimoto, et al. Inhibition of L-leucine methyl ester mediated killing of THP-1, a human monocytic cell line, by a new anti-inflammatory drug, T614[J]. Immunopharmacology, 2000(49):285-294
18 Tanaka K, Kawasaki H, Kurata K, et al. T614 inhibits the induction of cyclooxygenase-2 in air-pouch type inflammatory model in mice[J]. Jpn J Pharmacol, 1995,67:3
19 Indabas T, Tanaka R, et al. Synthesis and anti-inflammatory activity of 7-methanesulfonylamino-6-phenoxychromones, antiarthritic effect of the 3-forylamino compound (T614) in chronic inflammatory disease models[J]. Chem. Pharm. Bull., 2000,48(1): 131-139
20 高河勇，王丽，徐丽英，黄金华．7-甲磺酰胺基-6-苯氧基-4-色满酮衍生物的合成及抗炎活性研究[J]．中国药物化学杂志．2003(55)：260-263
21 仉文升，李安良主编．药物化学[M]．第一版．北京：高等教育出版社，1999
22 周宏灏主编．药理学[M]．第一版．北京：科学出版社，2003
23 Takano S, Yoshida C, Inaba T, et al. 4H-1-benzopyran-4-one derivatives of its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient[P]. US:4954518,1990-09-04, (CA1989,111:214389t)
24 仇缀百主编．药物设计学[M]．第一版．北京：高等教育出版社，1999
25 Inaba T, Tekeno T, Nagaki H, et al. Preparation of 3-(acylamino) -6-phenoxy-7-alkylsulfonylamino-4H-1-benzopyran-4-ones[P]. JP, 05 125072, 1993-05-21. (CA1993,119:225821u)
26 闻韧主编．药物合成反应[M]．第二版．北京：化学工业出版社，2003
27 Chen F M F, Benoition N L. Synthesis,1979, (9):709
28 Christopher E Anson et al. Flavonoid derivatives as organometallic bioprobes[J]. J of Organometallic Chemistry. 2003,668:101-122
29 Nagaki H, Yamada M, Inaba T, et al. Preparation of anti-inflammatory benzopyranones[P]. JP:0597840,1993-04-20
30 黄庆云，贾承胜，吴俊，胡士高．α-溴-(2-羟基-4-甲磺酰胺基-5-苯氧基)苯乙酮的合成[J]．中国医药工业杂志．2003，34(3)：112-113
31 段新方，张站斌，段新红．5，3＇，4＇-三羟基6，7-二甲氧基黄酮的另法全合成[J]．有机化学．2003，23(4)：353-355
32 Hart, Robert G., Leonard, Anne D, Talbert, Robert L Edwin, et al. Aspirin dosage
and thromboxane synthesis in patients with vascular disease[J]. Pharmacotherapy, 2003,23(5): 579-584 (English)
33 Nishakawa Y, Yoshimoto K, et al. Chemical and biochemical studies on carbohydrate esters. Antitumor activity of unsaturated-fatty acids and their ester derivatives against ehrlich ascites carcinoma[J]. Chem. Pharm. Bull., 1976,24(4):756
34 彭司勋主编．药物化学进展(2)[M]．第一版．北京：化学工业出版社，2003
35 Akao, Teruaki, Yoshino, Tetsuro, et al. Evaluation of salicin as an antipyretic prodrug that does not causegastric injury[J]. Planta Medica(English), 2002,68(8): 714-718
36 高锦明主编．植物化学[M]．第一版．北京：科学出版社，2003
37 Yaegashi T, Nokata K I, Sawada S, Yokokura T, et al. Chemical modification of an antitumor alkaloid, 20(S)-camptothecin: glycosides, phosphates and sulfates of 7-ethyl-10-hydroxycamptothecin[J]. Chem. pharm, bull., 1992,40:131
38 Takahashi T, Tsukamoto H, Yamada H. Design and synthesis of a water soluble taxol analogue: Taxol-sialyl conjugate[J]. Bioorg.Med. Chem.Lett., 1998,8:113
39 张贵君主编．中药鉴定学[M]．第一版．北京：科学出版社，2002
40 Thomas Maeder, Sweet Medicine[J]. Science, 2002,9:24-31
41 Walker S, Sofia M J, Kogan N A, et al. Cation facial anbiphiles: a promise class of transfection reagents[J]. Proc. Natl. Acd. Sci. USA. 1997,93:1585
42 Gaisser S, Leadlay P F. Sugaring the pill by design[J]. Nature Biotechnol., 1998, 16:19
43 Yukiko Watanabe, Masao Shiozak, et al, Synthesis and biological activity of 4',8-O-dihydroxyisoflavon-7-yl-α-D-hexopyranosides[J]. Carbohydrate Research. 2001 (335):283-289
44 Ajit Varki Edit, Essentials of Glycobiology[M]. 1st Ed, New York: Cold Spring Habor Laboratory Press 1999
45 Veyhl M, Wagner R K, Volk C, et al. Transport of the new chemotherpaeutic agent β-D-glucosylsophramide mustard(D-19575) into tumor cells is mediated by the Na~+-D-glucose contransporter SAAT1[J]. Proc. Ntl. Acad. Sci. USA. 1998,95:2914
46 杜灿屏，刘鲁生，张恒主编．21世纪有机化学发展战略[M]．第一版．北京：化学工业出版社，2002
47 Carbohydrates and Glycobiology special report[J]. Science, 2001, Vol 291, 2337-2378
48 李润涛，王永富，朱茜，蔡孟深．相转移催化法在糖苷化反应中的应用[J]．化学通报．1999，3：6-11
49 李雯，刘宏民．对位取代苯酚甙类化合物的相转移催化合成与表征[J]．有机化学．2002，22(12)：1034-039
50 Martos M. B, Korosy F. Preparation of Acetobrome-sugars[J]. Nature, 1950,165:369
51 孙关中，刘景英．糖类修饰阿司匹林结构的研究[J]．天津医科大学学报．2003，9(1)：19-20
52 盛龙生编著．药物分析[M]．第一版．北京：化学工业出版社，2003
53 宁永成编著．有机化合物结构鉴定与有机波谱学[M]．第二版．北京：科学出版社，2001
54 周俊，杨雁宾，杨崇仁．天麻甙及其类似物的合成[J]．化学学报．1980，38(2)：162-165
55 Aldirch, Handbook of Fine Chemicals and Laboratory Equipment[M]. 2003-2004 CHINA, 1636
56 Fabio Ponticelli et al. Synthesis and antiperoxidant activity of new phenolic O-glycosides[J]. Carbohydrate Research. 2001,330:459-468
57 Smite E, Kellogg R M, Doren H A Van, et al. Reliable method for the synthesis of aryl β-D-glucopyranosides, using boron trifluride-diethyl ether as catalyst[J]. Chem.Soc.,Perkin Trans.□, 1996:2873-2877
58 Mcauliffe J C, Hingdsgaul O, Carbohydrate Drugs-An Ongoing Challenge [J].Chemistry & Industry, 1997,170-174
59 Jie Jack Li 原著，荣国斌译，有机人名反应及机理[M]．第二版．上海：华东理工大学出版社，2003
60 冯金城编著．有机化合物结构分析与鉴定[M]．第一版．北京：国防工业出版社，2003
2 赵丽琴，张守芳．环氧化酶-2 选择性抑制剂研究进展[J]．中国药物化学杂志．1999，9(2)：139-143
3 Jones, M K, et al. Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into Mechanisms and implications for cancer growth and ulcer healing[J]. Nature Medicine, 1999, 5:1418-1421
4 Edith Lares, et al. Aspirin for cancer[J]. Nature Medicine, 1999, 5:1348-1349
5 Fu J Y, Masferrer J L, Seibert K, et al. The induction and suppression of prostaglandin H_2 synthase (cyclooxygenase) in human monocytes[J]. J Biol Chem, 1990,265:16737
6 Seibert K, Zhang Y, Leahy K, et al. Pharmacological demonstration of the role of cyclooxygenase-2 in inflammatory and pain[J]. Proc. Acad. Sci USA, 1994, 91:12013
7 彭司勋主编．药物化学进展(1)[M]．第一版．北京：化学工业出版社，2001
8 Gans K R, Galbaith W, Roman R J, et al. Anti-inflammatory and safety profile of DUP697, a novel orally effective prostaglandin synthesis inhibitor[J]. J Pharmacol Exp Ther, 1990.254(1):180
9 Silvestre J, Lesson PA, Castaner J. JTE-522. Drugs Fut., 1998, 23:598
10 Shamim, S M; Islam, Farida, et al. Acetylsalicylic acid (aspirin): therapeutic uses[J], Pakistan Journal of Pharmacology, 2003, 18(1), 7-12
11 NCX-4016. Drugs Fut., 2000,25:1215-1217
12 Kalgutkar A S, Crews BC, Rowlinson S W, et al. Aspirin-like molecules that covalently inactivate cylooxygenase-2[J]. Science, 1998,280:1268
13 Davis R, Brogden R N, et al. Nimesulide, an update on its pharmacodynamic and pharmacokinetic properties and therapeutic efficiency[J]. Drugs, 1994,48:431
14 Futaki N, Takahashi S, Yokoyama M, et al. NS-398, a new anti-inflammatory agent, selectively inhibits COX-2 activity in vitro[J]. Prostaglandins, 1994,47-55
15 Prous J, Mealy N, Castaner J, et al. T614. Drugs Fut, 1993,18:714
16 Kuriyama, Kohji, Higuchi, Chikahisa, et al. A novel anti-rheumatic drug, T-614, stimulates osteoblastic ifferentiation in vitro and bone morphogenetic protein
-2-induced bone formation in vivo[J]. Biochemical and Biophysical Research Communications, 2002,299(5):903-909 (English)
17 Tetsuji Sawada, Shiori Hashimoto, et al. Inhibition of L-leucine methyl ester mediated killing of THP-1, a human monocytic cell line, by a new anti-inflammatory drug, T614[J]. Immunopharmacology, 2000(49):285-294
18 Tanaka K, Kawasaki H, Kurata K, et al. T614 inhibits the induction of cyclooxygenase-2 in air-pouch type inflammatory model in mice[J]. Jpn J Pharmacol, 1995,67:3
19 Indabas T, Tanaka R, et al. Synthesis and anti-inflammatory activity of 7-methanesulfonylamino-6-phenoxychromones, antiarthritic effect of the 3-forylamino compound (T614) in chronic inflammatory disease models[J]. Chem. Pharm. Bull., 2000,48(1): 131-139
20 高河勇，王丽，徐丽英，黄金华．7-甲磺酰胺基-6-苯氧基-4-色满酮衍生物的合成及抗炎活性研究[J]．中国药物化学杂志．2003(55)：260-263
21 仉文升，李安良主编．药物化学[M]．第一版．北京：高等教育出版社，1999
22 周宏灏主编．药理学[M]．第一版．北京：科学出版社，2003
23 Takano S, Yoshida C, Inaba T, et al. 4H-1-benzopyran-4-one derivatives of its salt, process for producing the same and pharmaceutical composition comprising the same as active ingredient[P]. US:4954518,1990-09-04, (CA1989,111:214389t)
24 仇缀百主编．药物设计学[M]．第一版．北京：高等教育出版社，1999
25 Inaba T, Tekeno T, Nagaki H, et al. Preparation of 3-(acylamino) -6-phenoxy-7-alkylsulfonylamino-4H-1-benzopyran-4-ones[P]. JP, 05 125072, 1993-05-21. (CA1993,119:225821u)
26 闻韧主编．药物合成反应[M]．第二版．北京：化学工业出版社，2003
27 Chen F M F, Benoition N L. Synthesis,1979, (9):709
28 Christopher E Anson et al. Flavonoid derivatives as organometallic bioprobes[J]. J of Organometallic Chemistry. 2003,668:101-122
29 Nagaki H, Yamada M, Inaba T, et al. Preparation of anti-inflammatory benzopyranones[P]. JP:0597840,1993-04-20
30 黄庆云，贾承胜，吴俊，胡士高．α-溴-(2-羟基-4-甲磺酰胺基-5-苯氧基)苯乙酮的合成[J]．中国医药工业杂志．2003，34(3)：112-113
31 段新方，张站斌，段新红．5，3＇，4＇-三羟基6，7-二甲氧基黄酮的另法全合成[J]．有机化学．2003，23(4)：353-355
32 Hart, Robert G., Leonard, Anne D, Talbert, Robert L Edwin, et al. Aspirin dosage
and thromboxane synthesis in patients with vascular disease[J]. Pharmacotherapy, 2003,23(5): 579-584 (English)
33 Nishakawa Y, Yoshimoto K, et al. Chemical and biochemical studies on carbohydrate esters. Antitumor activity of unsaturated-fatty acids and their ester derivatives against ehrlich ascites carcinoma[J]. Chem. Pharm. Bull., 1976,24(4):756
34 彭司勋主编．药物化学进展(2)[M]．第一版．北京：化学工业出版社，2003
35 Akao, Teruaki, Yoshino, Tetsuro, et al. Evaluation of salicin as an antipyretic prodrug that does not causegastric injury[J]. Planta Medica(English), 2002,68(8): 714-718
36 高锦明主编．植物化学[M]．第一版．北京：科学出版社，2003
37 Yaegashi T, Nokata K I, Sawada S, Yokokura T, et al. Chemical modification of an antitumor alkaloid, 20(S)-camptothecin: glycosides, phosphates and sulfates of 7-ethyl-10-hydroxycamptothecin[J]. Chem. pharm, bull., 1992,40:131
38 Takahashi T, Tsukamoto H, Yamada H. Design and synthesis of a water soluble taxol analogue: Taxol-sialyl conjugate[J]. Bioorg.Med. Chem.Lett., 1998,8:113
39 张贵君主编．中药鉴定学[M]．第一版．北京：科学出版社，2002
40 Thomas Maeder, Sweet Medicine[J]. Science, 2002,9:24-31
41 Walker S, Sofia M J, Kogan N A, et al. Cation facial anbiphiles: a promise class of transfection reagents[J]. Proc. Natl. Acd. Sci. USA. 1997,93:1585
42 Gaisser S, Leadlay P F. Sugaring the pill by design[J]. Nature Biotechnol., 1998, 16:19
43 Yukiko Watanabe, Masao Shiozak, et al, Synthesis and biological activity of 4',8-O-dihydroxyisoflavon-7-yl-α-D-hexopyranosides[J]. Carbohydrate Research. 2001 (335):283-289
44 Ajit Varki Edit, Essentials of Glycobiology[M]. 1st Ed, New York: Cold Spring Habor Laboratory Press 1999
45 Veyhl M, Wagner R K, Volk C, et al. Transport of the new chemotherpaeutic agent β-D-glucosylsophramide mustard(D-19575) into tumor cells is mediated by the Na~+-D-glucose contransporter SAAT1[J]. Proc. Ntl. Acad. Sci. USA. 1998,95:2914
46 杜灿屏，刘鲁生，张恒主编．21世纪有机化学发展战略[M]．第一版．北京：化学工业出版社，2002
47 Carbohydrates and Glycobiology special report[J]. Science, 2001, Vol 291, 2337-2378
48 李润涛，王永富，朱茜，蔡孟深．相转移催化法在糖苷化反应中的应用[J]．化学通报．1999，3：6-11
49 李雯，刘宏民．对位取代苯酚甙类化合物的相转移催化合成与表征[J]．有机化学．2002，22(12)：1034-039
50 Martos M. B, Korosy F. Preparation of Acetobrome-sugars[J]. Nature, 1950,165:369
51 孙关中，刘景英．糖类修饰阿司匹林结构的研究[J]．天津医科大学学报．2003，9(1)：19-20
52 盛龙生编著．药物分析[M]．第一版．北京：化学工业出版社，2003
53 宁永成编著．有机化合物结构鉴定与有机波谱学[M]．第二版．北京：科学出版社，2001
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