Synthesis of deuterium labelled pharmaceutical compounds with improved efficacy

有机合成包括从简单的碳基分子制造复杂的碳基分子，就像乐高积木被点击在一起形成大型的教育和有趣的结构一样。合成方法的进步和增加，使今天我们可以制造复杂的分子，其中一些提供药物和农业制剂造福人类。今天，一个非常活跃的领域，特别是在工业实验室中，是含氘(D)药物的合成。用D取代给定药物的氢(H)会导致代谢命运的修饰/延缓，并在保留非D分子的生物学效力的同时改变治疗概况。因此，开发目前批准的**药物的d类似物可能对这些药物的安全性、有效性和耐受性产生积极影响，**解决重要但未满足的医疗需求。该提案旨在通过合成一系列当前重要上市药物的d -类似物来满足这些需求。该研究是基于我们在发现和开发定向邻位金属化（DoM）以及制备芳香和杂芳香分子的相关技术方面的丰富经验。这类分子是药物的主要成分（占现代药物的80%），并被工业（如孟山都、辉瑞、BMS、默克）用于多公斤级上市药物的合成。我们对d分子的制备也有很强的知识基础，因为这是我们的DoM合成策略的主要反应。基于这一背景和经验，我们的目标是：a)将D纳入市售药物，建立合成的可行性；b)开发全新的合成步骤，在早期或晚期**中间阶段引入D；c)开发截断已知程序的新路线。我们预计这项研究将为苏塞克斯研究所提供优于非加拿大竞争对手的优势，从而将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 are**clicked together to form large educational and playful structures. Methods for synthesis have advanced and**multiplied so that today we can make complicated molecules, some of which provide medicines and**agricultural 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 drug**with D results in modification/retardation of metabolic fate and alters the therapeutic profile while retaining the**biological potency of the non-D molecules. Thus, the development of D-analogues of currently approved**pharmaceuticals 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 a**series of D-analogues of currently significant marketed drugs. The proposed research is based on our**considerable experience in the discovery and development of directed ortho metalation (DoM) and related**technologies for the preparation of aromatic and heteroaromatic molecules. These classes of molecules are the**mainstay 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 the**preparation of D-molecules since this is the backbone reaction of our DoM synthetic strategies. Based on this**background and experience, our goals are: a) to incorporate D into commercially available drugs, establishing**synthetic feasibility; b) to develop fundamentally new synthetic steps for introduction of D at early or late**intermediate stages; and c) to develop new routes that truncate known procedures. We anticipate that the**research will provide Sussex Research an advantage over non-Canadian competitors, and thereby will have a**positive impact on the Canadian economy as well as train highly qualified scientists for the Canadian labour**market.