Synthesis of deuterium labelled pharmaceutical compounds with improved efficacy

有机合成涉及从简单的分子制造碳基复杂分子，就像将乐高积木点击在一起形成具有教育意义的大型结构和有趣的结构一样。合成方法已经进步并成倍增加，所以今天我们可以制造复杂的分子，其中一些为人类提供药物和农用制剂。今天，一个非常活跃的领域，特别是在工业实验室中，是合成含氢(D)的药物。用D取代给定药物的氢(H)会导致代谢命运的改变/延缓，并在保持非D分子的生物学效力的同时改变治疗方案。因此，目前批准的药物的D-类似物的开发可能会对这些药物的安全性、有效性和耐受性产生积极影响，解决重要但未得到满足的医疗需求。这项建议旨在通过合成一系列目前重要的上市药物的D-类似物来满足这些需求。这项研究是基于我们在发现和开发定向邻位金属化(DOM)和相关技术制备芳香族和杂芳族分子方面的丰富经验。这类分子是最主要的药物(占现代药物的80%)，并被工业(如孟山都、辉瑞、BMS、默克)用于多公斤合成上市药物。我们对D-分子的制备也有很强的知识基础，因为这是我们DOM合成策略的主干反应。基于这一背景和经验，我们的目标是：a)将D引入市场上可获得的药物中，确立合成的可行性；b)从根本上开发新的合成步骤，用于在早期或中期阶段引入D；以及c)开发缩短已知程序的新路线。我们预计，这项研究将为Sussex Research提供相对于非加拿大竞争对手的优势，从而对加拿大经济产生积极影响，并为加拿大劳动力市场培养高素质的科学家。

Organic synthesis involves making carbon-based complex molecules from simple ones, just as Lego blocks areclicked together to form large educational and playful structures. Methods for synthesis have advanced andmultiplied so that today we can make complicated molecules, some of which provide medicines andagricultural agents for the benefit of humankind. Today, a very active area, especially in industrial laboratories,is the synthesis of deuterium (D)-containing pharmaceuticals. The replacement of hydrogen (H) of a given drugwith D results in modification/retardation of metabolic fate and alters the therapeutic profile while retaining thebiological potency of the non-D molecules. Thus, the development of D-analogues of currently approvedpharmaceuticals could lead to a positive impact on the safety, efficacy and tolerability of these drugs,addressing important but unmet medical needs. This proposal aims to address these needs by the synthesis of aseries of D-analogues of currently significant marketed drugs. The proposed research is based on ourconsiderable experience in the discovery and development of directed ortho metalation (DoM) and relatedtechnologies for the preparation of aromatic and heteroaromatic molecules. These classes of molecules are themainstay of pharmaceuticals (80% of modern drugs) and are used by industry (e.g. Monsanto, Pfizer, BMS,Merck) for the multi-kg synthesis of marketed pharmaceuticals. We also have a strong knowledge base on thepreparation of D-molecules since this is the backbone reaction of our DoM synthetic strategies. Based on thisbackground and experience, our goals are: a) to incorporate D into commercially available drugs, establishingsynthetic feasibility; b) to develop fundamentally new synthetic steps for introduction of D at early or lateintermediate stages; and c) to develop new routes that truncate known procedures. We anticipate that theresearch will provide Sussex Research an advantage over non-Canadian competitors, and thereby will have apositive impact on the Canadian economy as well as train highly qualified scientists for the Canadian labourmarket.