H-Phosphinic Acids and Active Organophosphorus Compounds

H-次膦酸和活性有机磷化合物

• 批准号: 6772240
• 负责人: Jean-Luc G Montchamp
• 金额: $ 17.16万
• 依托单位: TEXAS CHRISTIAN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6772240
• 关键词: acids; acrolein; aminoacid analog; chemical synthesis; conformation; diphosphonate; drug design /synthesis /production; drug screening /evaluation; gamma aminobutyrate; method development; osteoporosis; pharmacokinetics; phosphorus compounds

DESCRIPTION (provided by applicant): This proposal aims at the development of H-phosphinic acids (RP(O)(OH)H) as synthetic intermediates for the preparation of biologically-active phosphorus-containing compounds. Recent advances in phosphorus-carbon bond formation are the stepping stone for novel applications. Focus is placed on two different health related areas which were chosen to show the synthetic flexibility of H-phosphinic acids: 1) the preparation and evaluation of gamma-aminobutyric acid (GABA) analogs relevant to the treatment of disorders of the central nervous system, where the phosphinic acid functionality is exploited as a carboxylate replacement; and 2) the development of a novel approach for the preparation of bisphosphonates under mild conditions relevant to the treatment of bone-related and other diseases, where the phosphinic acid functionality is a precursor to phosphonic acids. Compounds displaying promising in vitro biological activity will also be evaluated in vivo through consultants. While phosphinic acids are becoming popular pharmacophores in many other medicinal applications, their use in the above two areas has been largely unrealized. Thus, beyond the scope of this proposal, some of the chemistry detailed therein should make a significant contribution to the realm of phosphorus-based medicinal chemistry in general.

描述（由申请人提供）：本提案旨在开发H-次膦酸（RP（O）（OH）H）作为制备生物活性含磷化合物的合成中间体。磷-碳键形成的最新进展是新应用的垫脚石。重点放在两个不同的健康相关领域，选择它们来显示H-次膦酸的合成灵活性：1）与治疗中枢神经系统疾病相关的γ-氨基丁酸（GABA）类似物的制备和评价，其中次膦酸官能团被用作羧酸酯替代物;和2）开发在与治疗骨相关疾病和其它疾病相关的温和条件下制备双膦酸酯的新方法，其中次膦酸官能团是膦酸的前体。在体外表现出有希望的生物活性的化合物也将通过顾问进行体内评价。虽然次膦酸在许多其他医药应用中正成为流行的药效团，但它们在上述两个领域中的用途在很大程度上尚未实现。因此，超出本提案的范围，其中详述的一些化学应该对磷基药物化学领域做出重大贡献。