Year

1995

Degree Name

Doctor of Philosophy

Department

University of Wollongong. Dept. of Chemistry

Abstract

The general aim of this work was to develop 5-hydroxytryptamine potentiators based on [1] benzothiophene-containing compounds.

The synthetic work for this project comprised three parts. The first part (Chapter 2) deals with the preparation of new 3-chloro-[1]benzothiophene-2-amide derivatives and amide reduced analogues. The amides were prepared in moderate to good yields by reaction of 3-chloro-[1]benzothiophene-2-carbonyl chloride 21 with various amino acids or other amines. Preparation of the corresponding amines was attempted by three approaches. Direct reduction of the amides with various reducing agents was not successful. With the second approach, the reductive-amination of 3-chloro-[1]benzothiophene-2-carbaldehyde 32 with glycinate or sarcosinate afforded the methylene amines. Nucleophilic substitution of 3-chloro-[1]benzothien-2-ylmethyl tosylate 33 with glycinate or sarcosinate proved to be a better procedure to prepare the methylene amines.

The second part (Chapter 3) involved modification of the other [1]benzothiophene ring substituents. A number of substituents were placed at positions 5 and 6 respectively in order to increase the compounds' activity. Most of the work, however, centred on modification of the 3-position by introducing H, CI, Br, F, OCH3, OCH2CH3 and OH groups to determine whether there is any interaction between the 3-substituent and the amide nitrogen NH and the effect of this on the serotonin potentiation activity. The ring sulfur of N-[3-chloro-[l]benzothien-2-oyl]glycine 19 was also oxidised with m - chloroperoxybenzoic acid to the corresponding sulfoxide 122.

In the third part (Chapter 4), a series of [1]benzothiophene-fused oxaza medium ring derivatives 142,160,161 and 162 were successfully synthesised. Both aromatic and aliphatic nucleophilic substitutions were investigated to prepare the [1]benzothieno[1,4]oxazepine-5[H]-one derivative 142, and as a result a convenient and efficient method of preparing medium ring-containing [1]benzothiophenes was established, in which 8-, 9-, and 10-membered ring systems were prepared. This methodology is potentially generalisable to other fused heterocyclic ring systems.

Molecular modelling was utilised in conjunction with pharmacological tests to help rationalise the structural modifications to improve the compounds' activity. The global minimum conformations were determined using molecular mechanics with Biosym Insight/Discover software. Comprehensive conformational analyses and molecular superimpositions were conducted. The pharmacological testing of the [1]benzothiophene derivatives was carried out by others at Monash University. More than ten, mostly achiral compounds including the 7-membered ring compound 142, were found to possess moderate 5-HT potentiation activity in the rat cardiovascular model. The pharmacological screening indicated that the most likely mechanism for the potentiation was via 5-HT uptake inhibition. Such inhibitiors are of great interest as antidepressants.

Based on the pharmacological tests and the molecular modelling results, a pharmacophore including the [1]benzothiophene ring with appropriate substituents, an amide nitrogen with a specific distance from the fused ring and a specific intramolecular hydrogen bonding interaction was proposed for activity of the [1]benzothiophene-based 5-HT potentiators.

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Unless otherwise indicated, the views expressed in this thesis are those of the author and do not necessarily represent the views of the University of Wollongong.