NEW METHODOLOGIES FOR THE SYNTHESIS OF AMINO DERIVATIVES AS NICOTINIC RECEPTOR

烟碱受体氨基衍生物的合成新方法

• 批准号: 7381562
• 负责人: MARGARITA ORTIZ
• 金额: $ 21.16万
• 依托单位: UNIVERSITY OF PUERTO RICO
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381562
• 关键词: NEW; METHODOLOGIES; SYNTHESIS; AMINO; DERIVATIVES

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Chiral amino derivatives are important organic compounds, which have been used as building blocks for the synthesis of a variety of pharmaceutical compounds and as auxiliaries and.catalysts in many enan!ioselective organic preparations. Many synthetic drugs, in particular, antibiotics, aministamines, alpha- and beta- adrenoreceptors agonists and antagonist, contain chiral carbons centers with amino groups. In our laboratory we are developing novel methods for the synthesis of amino derivatives that can be applied for the preparation of biologically active molecules. The main goal of this project is to develop novel organic synthetic methodology for the preparation of potential nicotinic acetyl choline receptor (nACHRs) agonist that will be valuable for the treatment of neuron-degenerative diseases, such Alzheimer and Parkinson. The acquired knowledge and expertise through our previous studies on the synthesis and reduction of aromatic N-substituted silyl-, silyloxy-, boryl- and boryloxy imino derivatives with boron reagents will be directed toward the synthesis of nicotine analogues. Our aim is to design novel chiral organoborane reagents and synthetic systems that can accomplish high enantioselectivities or diastereoselectivities in the proposed organic transformations. Based on our previous knowledge on the synthesis of arylalkyl amines and organoborane chemistry, we plan to investigated the development and reactivity of new chiral B-substituted-l,3,2-oxazaborolidines and 1,3,2-dioxaborinane-H systems for the synthesis of pyridylalky methanamino ligands. The mechanistic aspects of these processes including the structural factors affecting the reactivity and stereochemical outcome will be addressed. In addition, we will continue to study a Beckman type of rearrangement reaction of discovered in our laboratory, in which aromatic silylated oximes are converted to aniline derivatives. This reaction will be investigated for the synthesis of aromatic heterocyclic amines and amino substituted pyridines, which are active ligands for nicotinic receptors. The proposed methodology will not only contribute significantly, to the development of new organic reaction via borane reagents, but will also explore new routes for the preparation of novel amino pyridine derivatives that will be studied as potential nicotinic receptors ligands. To accomplish our previous stated goals, we have established the following specific objectives: 1. To prepare new organo-borohydride reagents and fully characterize them by B, C and H NMR spectra and X-ray analysis. 2. To investigate the reduction of prochiral model N-substituted-imines with borane and the previously prepared organoboranes reagents, and study the structural factor that affect the stereo-selectivity. 3. To study of use of B-substituted-l,3,2-oxazaborolidines for the C-C bond formation and subsequent transformation of the boronic acid derivatives to amino derivatives. 4. To establish protocols for the synthesis of new amino pyridine and racemic and enantio-enrich arylpyridylmetanamines as nicotinic receptor agonist: 5. To study the borane reduction of pyridyl substituted imines for the synthesis of alkyl and heterocyclic aminopyridines. 6. To test these new amino pyridine and racemic and enantio-enrich arylpyridylmetanamines as potential agonists for neuronal nicotinic receptors (nAChRs) using voltage clamp techniques and recombinant expression of nAChRs in oocytes. 7. To study the optimal stereochemistry of chiral reagents and transition states for the proposed enantioselective reactions using molecular modeling method. Molecular modeling will also be used to establish the correlation between agonist's structure and observed and calculated affinities for the nACH Receptor.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。手性氨基衍生物是一类重要的有机化合物，在许多药物合成中被用作结构单元和助剂及催化剂。碘选择性有机制剂。许多合成药物，特别是抗生素、氨基胺、α-和β-肾上腺素受体激动剂和拮抗剂，含有带有氨基的手性碳中心。在我们的实验室中，我们正在开发新的方法，用于合成氨基衍生物，可用于制备生物活性分子。该项目的主要目标是开发新型有机合成方法，用于制备潜在的烟碱乙酰胆碱受体（nACHRs）激动剂，这将对治疗神经退行性疾病（如阿尔茨海默病和帕金森病）有价值。通过我们以前对用硼试剂合成和还原芳香族N-取代的甲硅烷基-、甲硅氧基-、硼基-和硼氧基亚氨基衍生物的研究获得的知识和专业知识将用于合成尼古丁类似物。我们的目标是设计新的手性有机硼烷试剂和合成系统，可以实现高的对映体选择性或非对映体选择性在拟议的有机转化。基于我们以前对芳烷基胺的合成和有机硼烷化学的了解，我们计划研究新的手性B-取代的-1，3，2-氧杂硼杂环戊烷和1，3，2-二氧杂硼杂环己烷-H体系的发展和反应性，用于合成吡啶基烷基甲氨基配体。这些过程的机制方面，包括影响反应性和立体化学结果的结构因素将得到解决。此外，我们将继续研究在我们的实验室中发现的贝克曼型重排反应，其中芳香族甲硅烷基肟转化为苯胺衍生物。该反应将用于合成烟碱受体的活性配体芳香杂环胺和氨基取代的吡啶。所提出的方法不仅将有助于显着，通过硼烷试剂的新的有机反应的发展，但也将探索新的路线，用于制备新的氨基吡啶衍生物，将被研究为潜在的烟碱受体配体。 为了实现我们先前提出的目标，我们制定了以下具体目标：1。合成了新的有机硼氢化物试剂，并用B、C、H NMR和X射线衍射对其进行了表征。 2.研究了硼烷和已合成的有机硼烷试剂对前手性模型N-取代亚胺的还原反应，并研究了影响立体选择性的结构因素。 3.研究B-取代的-1，3，2-恶唑硼烷用于C-C键形成和随后将硼酸衍生物转化为氨基衍生物的用途。 4.建立新型烟碱受体激动剂氨基吡啶、外消旋和对映体富集的芳基吡啶基间胺的合成方法。研究吡啶基取代亚胺的硼烷还原反应合成烷基和杂环氨基吡啶。 6.为了测试这些新的氨基吡啶和外消旋和对映体富集的芳基吡啶基间胺作为神经元烟碱受体（nAChRs）的潜在激动剂，使用电压钳技术和卵母细胞中nAChRs的重组表达。 7.利用分子模拟方法研究手性试剂的最佳立体化学和对映选择性反应的过渡态。还将使用分子建模来建立激动剂结构与观察到的和计算出的nACH受体亲和力之间的相关性。