Morpholino ring

PPMP) and then to replace the morpholino ring with a pyrrolidino ring (P4) (95). Later substitutions within the phenyl ring were examined (96) and the 4 hydroxy derivative was found to be the most potent inhibitor (IC50 for the GC synthase is 90 nM). 

X-ray crystallographic analysis demonstrated that the epoxyketone pharmacophore of epoxomicin forms a covalent adduct as a morpholino ring [50] with the amino terminal threonine of the 20S proteasome. Epoxomicin draws its specificity from the uniqueness of the proteasomal N-terminal threonine non-proteasomal proteases lack an N-terminal nucleophilic residue and thus cannot form a stable covalent morpholino adduct with the epoxomicin epoxyketone pharmacophore [50],... 

The N-basicity of the commonly used amines (pyrrolidine > piperidine > morpholine) drops by 2-3 orders of magnitude as a consequence of electron pair delocalization in the corresponding enamines. This effect is most pronounced in morpholino enamines (see table below). Furthermore there is a tendency of the five-membered ring to form an energetically favorable exocyclic double bond. This causes a much higher reactivity of pyrroUdino enamines as compared to the piperidino analogues towards electrophiles (G.A. Cook, 1969). 

Acryloyl chloride can be used to cause ring enlargement with the production of a bicyclodiketone when it is treated with a cyclohexanone enamine. This is shown by the reaction of acryloyl chloride (25) with 1-N-morpholino-1-cyclohexene (26), affording diketone 27 upon hydrolysis (32,33). 

The synthesis of this ring system was achieved by the reaction of the ketene aminal 79 with 3-morpholino-l-ethyl-l,2,4-triazinium tetrafluoro-borate 78 to give 80 (89IZV494). Cyclization of 78 with the bifunctional nucleophile 81 gave the pyrrolo[3,2-e][l,2,4]triazinones 82 (88TL1431). This reaction represents the first example of orthocyclization onto the 1,2,4-triazine ring by the addition of dienophiles at C-5,6 (Scheme 20). 

Structural features of AAI important for cannabinergic activity are the 3-aroyl moiety and the 1-chain, which must contain nitrogen, most often in a heterocyclic ring (e.g., piperidino or morpholino). This chain can... 

Formation of a pyridine ring onto bis-heterocycles is another route to these tricyclic systems. Reaction of 4-amino-2-morpholino-5-(2-morpholinothiazoM-yl)thiazolc 154 with the Vilsmeier reagent proceeds by direct cyclization to the bis-thiazolylpyridine 155 (Equation 36) <1997JHC1291>. 

O-Alkylation of 4-hydroxy-3-morpholino-l,2,5-thiadiazole 132 has been achieved with the chiral cyclic chloro-methyl sulfite 133 which subsequently suffers ring opening on treatment with simple alcohols <2001RCB436> or alkylamines <2002RJ0213> to afford the timolol analogues 134 with very little racemization (Scheme 20). This indicated an almost exclusive attack of the oxy anion on the exocyclic carbon atom and is a significant improvement on the previous oxirane method, which suffers from racemization. An alternative biocatalytic asymmetric synthesis of (A)- and (R)-timolol has also appeared <2004S1625>. 

In the course of studies on the synthesis of [l,2,4]triazolo[3,4-A][l,2,4,5]tetrazines, Kotschy et al. investigated the alkylation of the morpholino derivative 13 of this ring system <2000ARK259>. It has been found that ethylation carried out with triethyloxonium tetrafluoroborate took place exclusively on the five-membered ring and yielded a mixture of 1-ethyl 14 and 2-ethyl 15 quaternary salts. 

---