Synthesis of Azaspirocycles and their Evaluation in Drug Discovery

Abstract

In modern drug discovery, high-throughput screening may generate promising lead compounds that are less than ideal with respect to important parameters such as absorption, distribution, metabolism, and excretion (ADME). In the process of lead optimization, various structural features are fine-tuned and physicochemical properties such as the basicity (pK a [1] ), lipophilicity (logD), solubility (Sol int ), and clearance rates (CL int ) are improved.[2] Herein, we introduce heteroatom-substituted spiro [3.3]heptanes as viable and promising surrogates for piperazines, piperidines, morpholines, and thiomorpholines-all of which are common building blocks in medicinal chemistry (Figure 1).The vast majority of compounds generated in pharmaceutical and chemical research contain saturated and unsaturated six-and five-membered rings that may be fused or linked.[3] In striking contrast, four-membered rings are found comparatively rarely. As previously described with oxetanes, the incorporation of four-membered heterocycles into druglike scaffolds provides an opportunity to uniquely tune the physicochemical and biochemical properties of the parent compound.[4] Furthermore, these structures allow the exploration of novel chemical space in biology and medicine. [5] We have suggested a number of useful ways of perceiving oxetanes as structural analogues. For example, oxetanes may be considered as structural mimics of carbonyl groups; consequently 2-oxa-6-azaspiro[3.3]heptane has a close structural resemblance to azetidin-3-one. Interestingly, this same oxetanyl spiroazetidine also exhibits similarities to morpholine. [6] In view of the use of saturated heterocycles in medicinal chemistry, [7] we turned our attention to other members of the spiro[3.3]heptane family. For a survey of fundamental physicochemical and biochemical properties, we chose molecules of topological C 2 symmetry with a common piperonyl-tagged [6] azetidine moiety as model compounds. 2,6-Diazaspiro[3.3]heptanes 2-7 and azetidine-thietane spirocycles 9-11 were prepared from dibromide 1 [8] (Scheme 1). After removal of the N-tosyl group of common

Synthesis of Fluorine‐Containing 3,3‐Disubstituted Oxetanes and Alkylidene Oxetanes

“…[1][2][3][4] In particular, azetidines, oxetanes and cyclobutanes have attracted much attention in drug discovery and have been introduced to modify the biological profile or the pharmacokinetic properties of new drugs. [5][6][7][8][9][10][11][12][13][14] These cycles can be found in antibacterial agents, protein kinase inhibitors, and in radiotracer ligands ( Figure 1). [8,11,12] The synthesis of such strained cycles has been well documented, [1][2][3][4] and the main direct routes are based on cyclization or cycloaddition reactions of functionalized substrates and functionalization of four-membered cyclic ketones.…”

Tyrosine kinase inhibitor Thiotanib targets Bcr-Abl and induces apoptosis and autophagy in human chronic myeloid leukemia cells

“…Compared with imatinib, the 4-methylpiperazin-1-yl of Thiotanib has been changed to 2-thia-6-azaspiro [3.3] heptan-6-yl. Previous studies indicated that the important pharmacokinetic properties of heteroatomsubstituted spiro [3.3] heptanes such as lipophilicity and metabolic stability may be advantageously altered when compared with their traditional piperidine, piperazine, or thiomorpholine counterparts (Burkhard et al 2010). Interestingly, this modulating did not affect the bio-effects of Thiotanib.…”

tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon–Nitrogen Bond Forming Reactions

“…The preparation of diazaspiro [3.3] heptane 5 [16] by intramolecular alkylation triggered with tBuOK in THF, evidences that four-membered heterocyclization is also possible with tert-butanesulfinamide nucleophiles, but such reactions are not common. By contrast, five-membered ring formation by displacement of a halide leaving group is far more usual and has been implemented in several ways (Scheme 2).…”