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

基本信息

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

项目摘要

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

已知同素醇抑制黄嘌呤氧化酶（XO），现在使用lop酸的lop醇，但是，lopurinlol溶液是相对无毒的在某些合成化合物高度血症高脂Sinced中的抑制作用HABE恢复在1963年引入了临床用途。7H-嘌呤，7-β-D-核呋喃糖基-7H- [1，2，2，4] [3，4-I-I-I-I-I ] PURINES，9H-1、2、4-三唑[3、4-i]嘌呤，1H-pyrazolo [3，4-D]嘧啶和7H-Pyrazolo [4，3-e] -1-1，2，4-- 4--三唑[4，3 -c]嘧啶作为对牛牛奶黄氨酸在体外进行的新一类Vities，这项研究中的上述作用主要是从严重性时间出现的……ENT活动比同素醇3H）和一种。 1H-pyrazolo的4位[3，4-D]显着增加了其活性，而异硫醇则与同硫醇相比。显示出降低活性的趋势。 6H） - 一种，大多数表现出强大的不自然活动，比其他素醇的活性30倍，而某些化合物则比其他素醇的强度更高。对抑制活性很重要