Repository logo




Journal Title

Journal ISSN

Volume Title




Degree Level



The levels of piperazine type phenothiazine antipsychotic agents and their numerous metabolites in the tissues of humans and animals administered normal doses are low (low nanogram to subnanogram/gram). Gas chromatography-mass spectrometry (GC/MB) is one of the few methods with the desired sensitivity and specificity to measure these levels accurately. Therefore, deuterium labelled analogues of these drugs were synthesized for the first time, partly with a view to their potential use as ideal internal standards in GC-MS assays. Fluphenazine and trifluoperazine and some of their metabolites were prepared with the deuterium label in the propylpiperazine side chain. Such isotopomers also have potential for use in metabolic and pharmacokinetic studies which would otherwise be difficult to perform. In order to demonstrate this potential, the synthesized deuterium labelled analogues were utilized in examples of such studies with involvement of GC-MB analysis. Furthermore, the availability of the synthesized deuterium labelled analogues led to the elucidation of new electron impact mass spectral fragmentation pathways of the compounds. The synthetic routes employed to label trifluoperazine involved lithium aluminum deuteride reduction of suitable amide and imide precursors. Thus, [2.112]trifluoperazine was obtained by reduction of the amide, 10 -[3 -(4 -methyl -1 -piperazinyl) -3 -oxopropyl] -2 - trifluoromethyl -10H -phenothiazine, while [2H4] - and [2H6]trifluo-perazine were obtained via reduction of the imide, 1 -methylpiperazine -3,5 - dione, which afforded analogues labelled on the piperazine ring. The synthetic routes analogous to those for labelling trifluoperazine were found to be unsuitable for the synthesis of [2H2]_, [2H4] - and [2H6]fluphenazine. As a result, two new synthetic routes to fluphenazine were developed. The first route, utilized to prepare [2H2]fluphenazine, involved labelling of the y -carbon of the propyl chain with two deuterium atoms by lithium aluminum deuteride reduction of 10 -(2 -methoxycarbonylethyl) -2 -trifluoromethyl-10H -phenothiazine. The second route, utilized to prepare [2H 4]- and [2H6]fluphenazine, involved building the piperazine ring stepwise on to the propyl side chain and introduction of the label by lithium aluminum deuteride reduction of the intermediate, imide, 10 -(3 -(3,5 -dioxo -1 -piperazinyl)propyl] -2 -trifluoromethy1-10H-phenothiazine. The isotopic purity of the above deuterated phenothiazines was determined by electron impact mass spectrometry, and was found, for example, to be greater than 96.2% for trifluoperazine. The syntheses of some new deuterium labelled analogues of metabolites of fluphenazine and trifluoperazine are also reported. The compounds prepared were [2H ]trifluoperazine sulfoxide, [2H4]7-hydroxytrifluoperazine, [2H4]1- and [2H6 ]N-desmethyltrifluoperazine and [2H4]fluphenazine sulfoxide. New, important mass spectral fragmentation pathways for fluphenazine and trifluoperazine, which account for several characteristic ions, are proposed following studies on several of their deuterated analogues. These proposed pathways involve C-C cleavage of the piperazine ring under electron impact. They were substantiated by accurate mass measurements and daughter ion (B/E) metastable linked scanning, as well as electron impact studies on two model alkylpiperazines and their deuterated analogues. The piperazine ring opened, N-methylethylenediamine and ethylenediamine metabolites of trifluoperazine are reported to accumulate in parenchymatous tissues during chronic administration. By use of [2H6]trifluoperazine and a GC-MS technique, it was possible for the first time to estimate the kinetics of these metabolites in the liver during chronic administration. In another study, the same ethylenediamine and N -methyl-ethylenedianine metabolites were identified for the first time in rat liver microsomal preparations. These metabolites were detected by the appearance of characteristic clusters of isotope ions in mass spectra of derivatized extracts from the incubation of trifluoperazine and its [2H6] analogue with the microsomal preparation. In fact, a stepwise biotransformation of the piperazine moiety was demonstrated, culminating in the production of the 10 -(3 -aminopropyl) -2 - trifluoromethy1-10H-phenothiazine as the end metabolite. No aldehyde intermediates were detected, although some evidence was obtained that iminium ion intermediates may be involved in the cleavage of the piperazine ring.





Doctor of Philosophy (Ph.D.)


Pharmacy and Nutrition






Part Of