Nobuhiro Haga

Total Synthesis of Terprenin, a Highly Potent and Novel Immunoglobulin E Antibody Suppressant

Regioselective halogenations and Suzuki reactions ensure proper linkage of the aromatic rings in two total syntheses of terprenin (1). Both routes make it possible to prepare 1 efficiently and in large quantity.

Synthesis and pharmacological properties of ureidomethylcarbamoylphenylketone derivatives. A new potent and subtype-selective nonpeptide CCK-B/gastrin receptor antagonist, S-0509.

A novel series of CCK-B/gastrin receptor antagonists-ureidomethylcarbamoylphenylketone derivatives-were designed, synthesized, and evaluated for activity. Structure-activity relationship studies revealed the importance of a carboxylic acid at substituent R2 and tert-butoxycarbonyl group at R1 in structure A. Compound 7a (S-0509) showed remarkable affinity for the CCK-B/gastrin receptor and a subtype selectivity profile in vitro. Administration (id) of 7a led to excellent inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats with an ED50 value of 0.014 mg/kg. Furthermore, 7a proved to have poor blood-brain permeability by its small effect on enhancement of morphine analgesia. Thus, S-0509 has an increase in selectivity for the peripheral effects of gastrin antagonism from the central effects of CCK-B antagonism.

Potent and subtype-selective CCK-B/gastrin receptor antagonists: 2,4-dioxo-1,5-benzodiazepines with a plane of symmetry

A series of CCK-B/gastrin receptor antagonists, 2,4-dioxo-1,5-benzodiazepine derivatives with a plane of symmetry, were designed, synthesized, and evaluated for antagonistic activity. Structure-activity relationship studies revealed that carbonylmethyl groups at both N-1 and N-5 positions and hydrophilic groups, such as the carboxyl group on the benzene ring attached to the ureido group at the C-3 position, brought about potent affinity and subtype selectivity for CCK-B/gastrin receptors. Several compounds showed excellent in vivo inhibition of gastric acid secretion induced by pentagastrin in anesthetized rats.

Bridged Azibidines. iii. Lead Tetra-Acetae Oxidation of 5-Aminocycloheptene. Synthesis of Dl-2α-Hydroxytrop Ane

Abstract 5-Aminocycloneptene 3 was oxidized with lead tetraacetate in benzane in the presence of anhydrous potasium carbonate at room tamperature giving the bridged aziridine 4 in ca. 90% yield, this providingand additional example of the new nitrenoid reactionwhich was recently discovered in our laboratory. The aziridine 4 was transformed smoothly intothe 2a-substituted tropanes 13 and 17 and a new synthetic route to these important azacycles was thus established.

One-step synthesis of oxazolinoazetidinones from penicillin sulfoxides: potential intermediates for 1-oxacephem synthesis

Abstract Reaction of penicillin sulfoxides with a tervalent phosphorous compound in the presence of a catalytic amount of squaric acid gave oxazolinoazetidinones, potential intermediates for synthesis of 1-oxacephems, in good yields.2β-Chloromethyl- and 6α-methoxypenicillin sulfoxides also undergo this reaction. The reaction contrasts with the well-known Cooper reaction which usually gives thiazolinoazetidinones.

Totalsynthese von Terprenin, einem hochwirksamen Immunglobulin-E-Suppressivum

Regioselektive Halogenierungen und Suzuki-Reaktionen ermoglichen die richtige Verknupfung der aromatischen Ringe in zwei Totalsynthesen von Terprenin 1. Durch beide Reaktionswege kann 1 effizient und in groserer Menge erhalten werden.

Stability problem of the 4-hydroxy-azetidin-2-one system, a possible intermediate in 1-oxacephem synthesis

Reduction of the 4-hydroperoxy-azetidin-2-one (4) at –50 °C gave the 4-hydroxy-azetidin-2-one (6) which was converted into the corresponding trifluoroacetate (7); the 4-hydroxy-azetidin-2-ones, which were not isolated, were unstable at room temperature, and appeared to be unpromising as intermediates for 1-oxacephem synthesis.