Design and Synthesis of Backbone-Fused, Conformationally Constrained Morpholine-Proline Chimeras

Abstract

We report the synthesis of two novel bridged morpholine-proline chimeras 4 and 5, which represent rigid conformationally locked three-dimensional structures wherein the lone pairs of electrons on oxygen and nitrogen are oriented in spatially different "east−west" and "north−west" directions, respectively. In combination with the presence of a carboxylic acid, the electronic features of these compounds may be useful in the context of peptidomimetic design of biologically relevant compounds. Quantitative estimates of the basicity of the nitrogen atoms were obtained using conceptual density functional theory analysis.

Occurrence of Morpholine in Central Nervous System Drug Discovery

“…As mTOR has a deeper pocket as compared to PI3K, the introduction of substituents on the morpholine ring, such as an ethylene bridge between positions 3 and 5 or a methyl group at position 3, have been studied in order to develop selective and highly brain penetrant mTOR kinase inhibitors . In particular, the introduction of the bridged morpholine moiety is often beneficial for CNS candidates, as they are effective in decreasing lipophilicity, partly because of an enhancement of the polar surface area resulting from conformational changes. , For example, PQR620, containing two 3,5-bridged morpholines, inhibits mTOR kinase potently and selectively, and showed antitumor effects in vitro and in vivo , with promising benefits in CNS indications due to its brain/plasma distribution ratio . Similarly, compound 27 , possessing two 3-methylmorpholines, is a potent, orally available, and specific ATP-competitive mTOR inhibitor with selectivity against all Class I PI3K isoforms and other kinases (Figure ).…”

“…Also, it can be added to enhance the potency toward a target protein, as the oxygen atom can form hydrogen bonds, while the relatively electron-deficient ring can establish hydrophobic interactions . Finally, the flexible conformation resulting from the equilibrium between the chairlike and skew-boat topologies provides the optimal features for a suitable scaffold directing the appendages in the right position. , Morpholine has also an improved CYP3A4 profile, prolonged bioavailability, and optimal clearance, being oxidized easily into nontoxic derivatives. − A plethora of morpholine derivatives have already been present in the market for several decades (Figure ). Just to give some examples, doxapram (1976), phendimetrazine (1979), moclobemide (1992), reboxetine (1997), and aprepitant (2003) − are drugs with applications in several CNS diseases, mainly as anxiolytics and/or antidepressants.…”

“…23 Finally, the flexible conformation resulting from the equilibrium between the chairlike and skew-boat topologies provides the optimal features for a suitable scaffold directing the appendages in the right position. 24,25 Morpholine has also an improved CYP3A4 profile, prolonged bioavailability, and optimal clearance, being oxidized easily into nontoxic derivatives. 17−22 A plethora of morpholine derivatives have already been present in the market for several decades (Figure 1).…”

X-ray Crystal Structure and Hirshfeld Analysis of Gem-Aminals-Based Morpholine, Pyrrolidine, and Piperidine Moieties

“…Nevertheless, gem-diamines are widely used in medicinal products, because the existence of a lone pair on the nitrogen atom will increase and improve the lipophilicity and the solubility of the pharmaceutical targets [14][15][16]. Given to the prevalence of diamines, there is a need for doing structure elucidation and also studying their chemical insights [17]. The symmetric as well as asymmetric catalysis, in particular in pharmaceutical industry, are continually seeking for rapid synthetic routes to novel heterocyclic structures for earlystage drug discovery, as well as safe, robust and environmentally friendly routes for large scale production.…”

Synthesis of Bridged Bicyclic Amines by Intramolecular Amination of Remote C–H Bonds: Synergistic Activation by Light and Heat

“…Currently, strategies to synthesize diverse bridged amines are limited. State-of-the-art methodologies typically target the related classes of spirocyclic or fused aza-cycles , or target specific ring types in the context of natural product synthesis. , As a consequence, bridged aza-cycles remain underrepresented in medicinal chemistry optimization campaigns, not because of a lack of interest but because of the barrier to synthesizing these structures.…”