Molecular design of purines and purine nucleosides for potential xanthine oxidase inhibitory activity

具有潜在黄嘌呤氧化酶抑制活性的嘌呤和嘌呤核苷的分子设计

• 批准号: 09680570
• 负责人: NAGAMATSU Tomohisa
• 金额: $ 2.18万
• 依托单位: OKAYAMA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1999
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09680570/
• 关键词: purine; pyrazolopyrimidine; triazolopurine; pyrazolotriazolopyrimidine; allopurinol; xanthine oxidase inhibition; structure-activity relationship; キサンチンオキシダーゼ; 尿酸生成酵素阻害; 通風治療薬; XO阻害剤; サンチンオキシダーゼ

Allopurinol is known to inhibit xanthine oxidase (XO) and is now widely employed in treatment of gout and hyperuricemia resulting from uric acid. Allopurinol is relatively non-toxic. However, some allopurinol toxicities and a life-threatening toxicity syndrome have been reported after its use. Although XO inhibitory activities have recently discovered in some synthetic compounds, no clinically effective XO inhibitors for the treatment of hyperuricemia have been developed since allopurinol was introduced for clinical use in 1963. Here we established new, convenient, and general syntheses of 7H-purines, 7-β-D-ribofuranosyl-7H-[1, 2, 4]triazolo[3, 4-I]purines, 9H-1, 2, 4-triazolo[3, 4-I]purines, 1H-pyrazolo[3, 4-d]pyrimidines and 7H-pyrazolo[4, 3-e]-1, 2, 4-triazolo[4, 3-c]pyrimidines as new class of potential XO inhibitors.Their inhibitory activities against bovine milk xanthine in vitro were investigated, and the above compounds prepared in this study exhibited mostly from several times … More to several hundred times more potent activities than allopurinol.(1) The introduction of arylaldehyde hydrazones at the 6-position of 7H-purine-2(3H)-one and at the 4-position of 1H-pyrazolo[3, 4-d]pyrimidin-6(7H)-one markedly increased their activities, being from 10-fold to 900-fold more active than allopurinol. In contrast the 2-oxo derivatives of the purine and the 6-xo derivatives of the pyrazolopyrimidine, the derivatives substituted by a chloro, amino or thioxo group at the 2-position or at the 6-position showed a tendency to decrease the activity.(2) The tricycle heterocycles, 9H-1, 2, 4-triazolo[3, 4-I]purines, generally showed more potent inhibitory activities than that of allopurinol, but less inhibitory activities compared with the purines.(3) The tricyclic heterocycles, 7H-pyrazolo[4, 3-e]-1, 2, 4-triazolo[4, 3-c]pyrimidin-5(6H)-ones, showed mostly potent inhibitory activities, being from 30-fold to 800-fold more active than allopurinol and some compound showed a 760-fold more potent activity than that of allopurinol.It was demonstrated that the oxo group and the arylmethylidenehydrazino group on the ring of the above heterocycles might be important for the inhibitory activity. Less

已知别嘌呤醇抑制黄嘌呤氧化酶（XO），并且现在广泛用于治疗痛风和由尿酸引起的高尿酸血症。别嘌呤醇相对无毒。然而，一些别嘌呤醇毒性和危及生命的毒性综合征已报告后，其使用。虽然最近在一些合成化合物中发现了XO抑制活性，但自从1963年别嘌呤醇被引入临床使用以来，还没有开发出临床有效的XO抑制剂用于治疗高尿酸血症。本文建立了7 H-嘌呤、7-β-D-呋喃核糖基-7 H-[1，2，4]三唑并[3，4-I]嘌呤、9 H-1，2，4-三唑并[3，4-I]嘌呤、1 H-吡唑并[3，4-d]嘧啶和7 H-吡唑并[4，3-e]-1，2，4-三唑并[4，3-c]嘧啶类化合物作为一类新的XO抑制剂，研究了它们对牛乳黄嘌呤的体外抑制活性，结果表明，所合成的化合物对牛乳黄嘌呤的体外抑制活性最强，抑制倍数最高 ...更多信息 到比别嘌呤醇强几百倍的活性。(1)在7 H-嘌呤-2（3 H）-酮的6位和1H-吡唑并[3，4-d]嘧啶-6（7 H）-酮的4位引入芳醛腙显著提高了它们的活性，比别嘌呤醇的活性高10倍至900倍。相反，嘌呤的2-氧代衍生物和吡唑并嘧啶的6-氧代衍生物，在2-位或6-位被氯、氨基或硫代基团取代的衍生物显示出降低活性的趋势。(2)三环杂环化合物9 H-1，2，4-三唑并[3，4-I]嘌呤的抑制活性普遍高于别嘌呤醇，但低于嘌呤类化合物。(3)三环杂环化合物，7 H-吡唑并[4，3-e]-1，2，4-三唑并[4，3-c]嘧啶-5（6 H）-酮，表现出最强的抑制活性，比别嘌呤醇的活性高30倍至800倍，一些化合物显示出760-结果表明，该化合物环上的氧代基和芳亚甲基肼基是其活性的主要来源，上述杂环化合物可能对抑制活性很重要。少

项目成果

Tomohisa Nagamatsu: "Novel Xanthine Oxidase Inhibitor Studies. Part 2. Synthesis and Xanthine Oxidase Inhibitory Activities of 2-Substituted 6-Alkylidenehydrazino- or 6-Arylmethylidene-hydrazino-7H-purines and 3- and/or 5-Substituted 9H-1,2,4-Triazolo[3,4

Tomohisa Nagamatsu：“新型黄嘌呤氧化酶抑制剂研究。第 2 部分。2-取代的 6-亚烷基肼基-或 6-芳基亚甲基-肼基-7H-嘌呤和 3-和/或 5-取代的 9H-1 的合成和黄嘌呤氧化酶抑制活性，

Tomohisa Nagamatsu: "Facile and General Syntheses of 2-Oxo-and 2-Thioxo-purines and 5-Oxo-and 5-Thioxo-7H-[1,2,4]-triazolo[3,4-i]purines as New Classes of Potent Xanthine Oxidase Inhibitors" Heterocycles.(印刷中). (1998)

Tomohisa Nagamatsu：“2-氧代-和 2-硫代-嘌呤以及 5-氧代-和 5-硫代-7H-[1,2,4]-三唑并[3,4-i]嘌呤的简单通用合成是新的有效黄嘌呤氧化酶抑制剂的类别”杂环。（印刷中）。（1998）

Tomohisa Nagamatsu: "Novel Xanthine Oxidase Inhibitor Studies. Part 2. Synthesis and Xanthine Oxidase Inhibitory Activities of 2-Substituted 6-Alkylidenehydrazino- or 6-Arylmethylidene-hydrazone-7H-purines and 3- and/or 5-Substituted 9H-1,2,4-Triazolo[3,4

Tomohisa Nagamatsu：“新型黄嘌呤氧化酶抑制剂研究。第 2 部分。2-取代的 6-亚烷基肼基-或 6-芳基亚甲基-腙-7H-嘌呤和 3-和/或 5-取代的 9H-1 的合成和黄嘌呤氧化酶抑制活性，

Tomohisa Nagamatsu: "Facile and General Syntheses of 3- and/or 5-Substituted 7-β-D-Ribofuranosyl-7H-[1, 2, 4]triazolo[3, 4-I]purines as a New Class of Potential Xanthine Oxidase Inhibitors"Synthesis. No. 4. 655-663 (1999)

Tomohisa Nagamatsu：“3-和/或5-取代的7-β-D-呋喃核糖基-7H-[1, 2, 4]三唑并[3, 4-I]嘌呤的简单通用合成作为一类新的潜在黄嘌呤氧化酶抑制剂的合成。No.4.655-663(1999)

Tomohisa Nagamatsu: "Facile and General Syntheses of 3- and/or 5-Substituted 7H-Pyrazolo[4, 3-e]-1, 2, 4-triazolo[4, 3-c]pyrimidines as a New Class of Potential Xanthine Oxidase Inhibitors"Chemical Commun.. No. 16. 1461-1462 (1999)

Tomohisa Nagamatsu：“3-和/或5-取代的7H-吡唑并[4, 3-e]-1, 2, 4-三唑并[4, 3-c]嘧啶的简单通用合成作为一类新的潜在黄嘌呤