Synthesis of deuterium labelled pharmaceutical compounds with improved efficacy

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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.