Design and Synthesis of A Diverse Morpholine Template Library

Abstract

Efficient and general procedures have been developed for the solution-phase preparation of substituted morpholine derivatives, and a library has been produced around generic structure 1. This library was designed with proprietary modeling software for use as a general screening library. The 30 R1 reagents were phenols, and the 275 R2 reagents were taken from five different reagent classes, giving a variety of product classes in the final library of 8250 potential products. All of the library members were generated from a common intermediate, mesylate (5), which was synthesized efficiently, in bulk, in three steps from N-benzylethanolamine (2). High-throughput chemistry using robotics was carried out to produce the 7907 library members, which were individually characterized by reversed-phase LC/MS analysis.

First In Vivo Evaluation of a New Morpholine Analog

“…Data in column 2 express, as pKi, the ability to inhibit the binding of [ 125 I]NKA to human tachykinin NK 2 receptor expressed in CHO cells membrane preparation. Those in column 3 express, as pK B , the ability of the same compounds to inhibit, in a competitive manner, the contraction induced by the NK 2 selective agonist [ßAla 8 ]NKA(4-10) in isolated guinea-pig colon. From these data, it appears that compounds (4)-(7) are as potent as compound (2), and significantly less potent than compound (3), especially in the functional test.…”

“…Indeed, morpholine is one of the most familar amines to medicinal chemists. More than 100 drugs were enumerated in 2003 to contain this structural feature [8], which could, in principle, be restyled and found innovative by suitable replacement. Aware of the ready accessibility of compound (1) and its enantiomer [9], we have speculated for a long time not only on its use as single fragment, but also as the monomer of an oligomeric material (1a).…”

Balancing focused combinatorial libraries based on multiple GPCR ligands

“…Combinatorial chemistry has become a major force in drug discovery and development, with attention in recent years shifting from generalized libraries [17] to ones focused on particular target proteins [3]. Docking and scoring against the target is a viable approach when enough structural information is available, but this is generally not the case for GPCRs such as serotonergic and chemokine receptors.…”

“…For combinatorial designs that involve a di-substituted scaffold, for example, intermediates generated in the first reaction step are often synthesized and purified in bulk (i.e., on a multi-gram scale), then parallel synthesis and high-throughput microscale chromatography are used to synthesize and purify products obtained from secondary reactions [17]. Hence cost considerations lead to unsymmetrical designs in which m (the number of primary reagents required) is considerably smaller than m¢ (the number of secondary reagents).…”

Synthesis of Chiral Five-, Six-, and Seven-Membered Heterocycles from (S)-3-Hydroxy-γ-butyrolactone

“…7 The six-memberedring morpholinones or morpholines contained in compounds 3-6 are heterocyclic compounds that are of medicinal importance as well; they are present in many drug classes either as core structures or as functional groups that improve pharmacokinetic properties. 8 Compound 3 is a selective rat 5-hydroxytryptamine 1B (5-HT 1B ) receptor antagonist. 9 The aminomethyl morpholine 4 has shown activity against checkpoint kinase 1 (CHK1), 10 and may have applications in anticancer therapies.…”