Solid-phase synthesis of quinazoline-2,4-diones and their analogues from resin-bound compounds with primary amines.

Solid-phase organic synthesis of heterocyclic compounds on solid-support has been a focus of recent investigations because of the potential applicability of these compounds toward a variety of drug targets. Among the various heterocycles, we have been especially interested in quinazoline-2,4-diones because of the wide range of their bioactivities. Therefore, in this article we review methods for the solid-phase synthesis of quinazoline-2,4-diones and their analogues. Since all of these heterocycles can be speedily derivatized from resin-bound primary amines, incorporating the amines at the 3N-position of quinazoline-2,4-diones or corresponding positions of its analogues, it becomes possible to efficiently compare the bioactivities of these quinazoline-2,4-diones and their analogues. Various methods of solid-phase synthesis described herein should be practical and useful tools for the medicinal chemist in supporting drug discovery initiatives.

Rational design, synthesis, and structure-activity relationships of novel factor Xa inhibitors: (2-substituted-4-amidinophenyl)pyruvic and -propionic acids.

An inhibitor of factor Xa (fXa), the m-substituted benzamidine AXC1578 (1a), was structurally modified with the aim of increasing its potency. In particular, pyruvic acid and propionic acid substituents were incorporated into the P1 benzamidine moiety to introduce a favorable interaction with the oxy-anion hole in the catalytic triad region of fXa. This strategy was based on computational docking studies using the extracted active site of fXa. The validity of the computational model was supported by the acquisition of X-ray crystal structures of the 1a-trypsin and 3b-trypsin complexes (the homology around the active sites of fXa and trypsin is high). The above modifications significantly increased the inhibitory activity toward fXa, whereas the high selectivity for fXa versus thrombin was maintained or enhanced. Compounds 3b, 3c, 3e, and 4b are considered to be potential lead compounds for the development of orally active anticoagulant drugs because they demonstrated potent activity when administered orally to cynomolgus monkeys.

Efficient synthesis of 2,4-disubstituted 1,2,4-benzothiadiazin-3-one 1,1-dioxides on solid support.

The first solid-phase synthesis of 1,2,4-benzothiadiazin-3-one 1,1-dioxides has been developed. Synthesis of the title compounds was achieved by the reduction of 2-nitrobenzenesulfonamides, followed by cyclization with carbonyldiimidazole. Because 1,2,4-benzothiadiazin-3-one 1,1-dioxides have been known to possess various bioactivities, this method is useful from the viewpoint of new drug discovery. In addition to the excellent purity of the title compounds, a large number of compounds can be synthesized with this method, because this synthesis includes four diversity points.