Terrence Michael Hotten

The synthesis and biological activity of some known and putative metabolites of the atypical antipsychotic agent olanzapine (LY170053)

Abstract 4′-N-desmethyl olanzapine (2), olanzapine 4′-N-oxide (3) and 2-hydroxymethyl olanzapine (5), have been prepared and their pharmacology compared to that of the parent compound olanzapine (1). The 4′-N-quaternary glucuronide (8) has also been prepared.

Bicyclo[2.2-1]heptanes as novel triple re-uptake inhibitors for the treatment of depression

A series of substituted naphthyl containing chiral [2.2.1] bicycloheptanes were prepared utilizing asymmetric Diels-Alder chemistry. This paper describes structure-activity relationships in this series. The N-methyl 2-naphthyl analogue (16d) and its des-methyl analogue (17d) are active triple re-uptake inhibitors both in vivo and in vitro.

A new route to nitriles. Dehydration of aldoximes using 2,4,6-trichloro-s-triazine (cyanuric chloride)

Nitriles are produced in good yields when aldoximes are treated with 2,4,6-trichloro-s-triazine in the presence of pyridine under mild conditions.

Heteroarene-fused benzodiazepines. Part 1. Synthesis of thieno-[2,3-b][1,5]-, -[3,2-b][1,5]-, and -[3,4-b][1,5]-benzodiazepinones

The synthesis of the 4H-thieno-[2,3-b][1,5]-, -[3,2-b][1,5]-, and -[3,4-b][1,5]-benzodiazepinone ring systems is described. Sodium methylsulphinylmethanide was used for the intramolecular cyclisation of the intermediate amino-esters (5), (9), and (14). However, attempted cyclisation of ethyl 2-(2-amino-4-fluoroanilino)-5-ethyl-thiophen-3-carboxylate (5b) with sodium hydride at a higher temperature caused rearrangement to a benzimidazolone (12).

s-Triazines. Part V. Synthesis and hydrolytic stability of 2,4-dihalogeno-6-heteroaryl-s-triazines

The first and second hydrolysis rate coefficients for the title compounds are discussed in terms of variation of the heteroaryl substituent (substituted phenyl, furyl, pyrrolyl, or thienyl) and of the halogen substituents (X = F, Cl, I, or CCl3). Electron-withdrawing substituents in the aryl rings enhance the rate coefficients, which are linearly related to the pKa values of the analogous dioxo-products (III) for phenyl, thienyl, or pyrrolyl substituents. Evidence is presented to show that the rate-determining step in the hydrolysis is nucleophilic attack on the triazine rather than carbon–halogen bond rupture.

Anomalous Proton NMR Deshielding in Anilinopyrazoles

Abstract In connection with the synthesis of thienobenzodiazepines and certain heterocyclic analogues1, a number of anilino heterocycle precursors were prepared. Their proton NMR spectra were generally unexceptional with the exclusion of one of the pyrazole isomers which showed a remarkable deshielding of one proton signal in the aniline ring. Further investigations have inferred that this low field shift can be attributed to through speace deshielding by a proximal pyrazole nitrogen lone pair.

Chemistry of adamantane. Part IX. 1,2-Difunctional adamantanes; synthesis and reactions of protoadamantane-4-spiro-oxiran

The synthesis of protoadamantane-4-spiro-oxiran {octahydrospiro[2,5-methano-1H-indene-7,2′-oxiran]} and its isomerisation to protoadamantane-4-carbaldehyde are described. Electrophilic cleavage of the oxiran ring with simultaneous rearrangement gives 1,2-difunctional adamantane derivatives. Reactions of lithium carbenoids, from benzylidyne chloride and benzylidene bromide, with protoadamantan-4-one mainly lead to protoadamantan-4-yl phenyl ketone. 4-Phenylprotoadamantan-4-ols on treatment with acid preferentially undergo elimination to give 4-phenylprotoadamantene.