Synthetic Studies of Imidazole C-nucleosides aimed at Novel Histomine Ligands

针对新型组胺配体的咪唑 C-核苷的合成研究

• 批准号: 08672462
• 负责人: KURIHARA Takushi
• 金额: $ 1.41万
• 依托单位: Osaka University of Pharmaceutical Sciences
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-08672462/
• 关键词: histamine; H_3; receptor; agonist; antagonist; imidazole; C-nucleoside; conformation; ヒスタミンH_2拮抗薬; イミダゾールC-ヌクレオシド; 消化性潰瘍治療薬; シメチジン; 光延反応

We recently reported the beta-stereoselective synthesis of C-4 linked imidazole nucleosides, On the basis of what we have now, we became interested in the synthesis of the four possible stereoisomerers of a novel imidazole C-nucleoside (ICN) analogues in which the imidazole and amino groups were restricted across a tetrahydrofuran ring. A synthetic route to the four possible stereoisomers of a novel 2' 3' dideoxyimidazole C-nucleoside derivative was at first developed via the efficient use of PhSe group from L-glutamic acid. The key intermediates selenolactols were successively derived to the respective 5 arnino-2', 3' -dideoxy-ICN derivatives in excellent yields Their enantiomers were provided via nucleosides from D-glutarnic acid by the same methodology. The four isomers of 5' Amino-2', 3' didehydro-2' 3' dideoxy-ICN were also synthesized via oxidative elimination the C2'-phenylselenyl group of the intermediates. Further, 4(5)-(5-aminomethylfuran-2-yl)-1H-imidazole (5) was synthesized starting from D-ribose. Of particular interest, only (+)-4(5)-{(2R,5R)-5-(aminomethyl)-tetrahydrofuran-2-yl}imidazole named imifuramine, was identified as a H_3 agonist by in vivo brain microdialysis.

我们最近报道了C-4连接的咪唑核苷的β-立体选择性合成，在此基础上，我们对一种新型咪唑C-核苷（ICN）类似物的四种可能的立体异构体的合成产生了兴趣，其中咪唑和氨基被限制在四氢呋喃环上。首次利用L-谷氨酸的PhSe基团，合成了一种新的2' 3'双脱氧咪唑C-核苷衍生物的四种可能的立体异构体。关键中间体硒代乳醇以优异的产率依次衍生为相应的5氨基-2 '，3' -双脱氧-ICN衍生物。它们的对映体通过D-戊二酸的核苷以相同的方法提供。5'氨基-2'，3'二氨基-2'，3'二脱氧-ICN的四个异构体也是通过氧化消除中间体的C2'-苯硒基而合成的。以D-核糖为原料合成了4（5）-（5-氨甲基呋喃-2-基）-1H-咪唑（5）。其中，（+）-4（5）-{（2 R，5 R）-5-（氨甲基）-四氢呋喃-2-基}咪唑（imifuramine）是一种H_3受体激动剂。

项目成果

S.Harusawa: "Synthesis of Imifuramine and Its Stereoisomers Exhibiting Histamine H_3-Agonistic Activity" Tetrahedron Letters. 55・in press. (1999)

S.Harusawa：“具有组胺 H_3 激动活性的咪呋胺及其立体体的合成”，《四面体快报》55·出版（1999 年）。

S.Harusawa: "Efficient and β-Stereoselective Synthesis of 4(5)-(β-D-Ribofuranosyl)- and 4(5)-(2-Deoxyribofuranosyl)imidazoles." J.Org.Chem.61・13. 4405-4411 (1996)

S.Harusawa：“4(5)-(β-D-呋喃核糖基)-和 4(5)-(2-脱氧呋喃核糖基)咪唑的高效和 β-立体选择性合成。J.Org.Chem.61・13。” -4411 (1996)

S.Harusawa: "Stereoselective Synthesis of the C-4 Linked Imidazole Nucleosides Using Modified Mitsunobu Reaction." Tetrahedron Letters. 36・18. 3165-3168 (1995)

S.Harusawa：“利用改进的 Mitsunobu 反应立体选择性合成 C-4 连接的咪唑核苷”36・18（1995）。

S.Harusawa: "Efficient and beta-Stereoselective Synthesis of 4(5)-Methy1-5(4)-(5-amino-5-deoxy-beta-D-ribofuranosy1)imidazole and Related Compounds Exhibiting Antiulcer Activity" Chem.Pharm.Bull.45. 53-61 (1997)

S.Harusawa：“高效、β-立体选择性合成 4(5)-Methy1-5(4)-(5-amino-5-deoxy-beta-D-ribofuranosy1)imidillo 及相关化合物表现出抗溃疡活性” Chem.Pharm

S.Harusawa: "Efficient and β-Stereoselective Synthesis of 4(5)-(β-D-Ribofuranosyl)-and 4(5)-(2-Deoxyribofuranosyl) Imidazoles." J. Org. Chem.16・13. 4405-4411 (1996)

S. Harusawa：“4(5)-(β-D-呋喃核糖基)-和 4(5)-(2-脱氧呋喃核糖基)咪唑的高效和 β-立体选择性合成”J. Org. 4405。 -4411 (1996)