1‐Substituted 2‐Azaspiro[3.3]heptanes: Overlooked Motifs for Drug Discovery

Abstract

The 2-substituted piperidine core is found in drugs (18 FDA-approved drugs), however, their spirocyclic analogues remain unknown. Described here is the synthesis of spirocyclic analogues for 2-substituted piperidines and a demonstration of their validation in drug discovery.

Synthesis and applications of highly functionalized 1-halo-3-substituted bicyclo[1.1.1]pentanes

“…Bicyclo[1.1.1]pentanes (BCPs) have shown particularly impressive results in this field as surrogates for 1,4-disubstituted arenes, tert -butyl, and alkyne groups, imparting desirable properties such as membrane permeability, solubility and metabolic stability. 3 , 4 Examples include BCP analogues of the γ-secretase inhibitor BMS-708, 163 ( 1 , Fig. 1a ) 5 and resveratrol ( 2 ), 6 in which the BCP serves as a bioisostere for a p -substituted arene due to its comparable positioning of substituents; and of the pulmonary arterial hypertension agent bosentan ( 3 , Fig.…”

Saturated Bioisosteres of ortho‐Substituted Benzenes

“…[2] During the last decade,h owever,t he concept "escape from flatland", [3] has already changed the way how medicinal chemists think-these days small compact F(sp 3 )-rich structures are especially prevalent in drug discovery projects. [4,5] In particular, the replacement of benzene rings with saturated bioisosteres has become an important strategy to obtain novel patent-free molecules with improved biological activity and physico-chemical profile. [6] In 2012, Stepan and colleagues from Pfizer replaced the substituted phenyl fragment in a gsecretase inhibitor Avagacestat with the bicyclo[1.1.1]pentyl skeleton ( Figure 1).…”

1‐Substituted 2‐Azaspiro[3.3]heptanes: Overlooked Motifs for Drug Discovery

“…We first measured the experimental logD (pH 7.5) values of the N-protected models 18, 20, 22,and 24,and compared the data with those of the parent piperidines 19, 21, 23,a nd 25 (Table 2). [19] Thermal ellipsoids shown at 30 %probability. X-ray crystallographic analysis of 4b.…”

“…Thes tructure of 4b was confirmed by an X-ray analysis ( Figure 3). [19] Thec arboxylic acid 1 can also be replaced by substituted cyclobutanecarboxylic acids.F or example,t he acid 11 gave the corresponding products 2d and 9d (Table 1). Given the masked carbonyl function, both 2d and 9d can be considered as scaffolds with three points of diversity.…”

“…X-ray crystallographic analysis of 4b. [19] Thermal ellipsoids shown at 30 %probability. Angewandte Chemie Zuschriften 21, 23,a nd 25 because of ah igher molecular weight.…”