UBC Theses and Dissertations

UBC Theses Logo

UBC Theses and Dissertations

Thietanes as potential MAO inhibitors and analgetics Haya, Katsuji


Thietane derivatives were synthesized as potential monoamine oxidase (MAO) inhibitors. These derivatives were useful in studying the electronic and steric requirements of the tranylcypromine type of MAO inhibitors in drug-receptor interactions. The synthesis of these thietanes also gave further information on the physical and chemical properties of thietanes and their dioxides. The reaction of 3-chloro-l-phenylpropylene oxide-1,2 with, sodium sulfhydride gave 3-hydroxy-2-phenylthietane. In order to provide a basis for the chemical manipulations that can be performed without ring cleavage, a number of reactions were performed on this thietane. The thietane could be oxidized to the corresponding thietane 1,1-dioxide with m-chloroperben-zoic acid, then converted to 2-phenylthiete 1,1-dioxide through the treatment of the sulfonate ester with triethylamine. Treatment of the thietane 1,1-dioxide with base gave benzyl methyl sulfone whereas treatment with concentrated acid gave benzyl methyl ketone. Preliminary experiments were performed, which indicated that the 3-hydroxyl could be replaced to give 3-amino-2-phenylthietane, the thietane analogue of tranylcypromine desired for MAO inhibition studies. During the course of the studies the synthesis of 2-benzyl-3-hydroxythietane was sought. This led to the synthesis of l-chloro-4-phenylbutylene oxide-1,2 which was reacted with sodium sulfhydride to give 3-hydroxy-2- phenylthiolane. This result is discussed in relation to a proposed mechanism, whereby nucleophilic attack of the sulfhydride ion occurs at the most electron deficient carbon of the epoxide. As a possible route to 3-amino-2-phenoxythietane, several enamines prepared from phenoxyacetaldehyde were subjected to a cycloaddition reaction with methyl sulfene. A number of acyclic substitution products were obtained. These results are discussed in relation to the mechanism of the cycloaddition reaction. Cycloaddition of l-dimethyl-3-phenylpropene with methyl sulfene gave 2-benzyl-3-dimethyl-aminothietane 1,1-dioxide, which was reduced with LiAlH₄ to 2-benzyl-3-dimethylaminothietane. Exposure of 2-benzyl-3-dimethylaminothietane 1,1-dioxide to the amine oxide elimination procedure gave 2-benzylthiete 1,1-dioxide. A number of thietane derivatives were of sufficient similarity to tranylcypromine to warrant in vitro studies for MAO inhibition. A radioisotopic assay method using rat liver homogenates as the enzyme source and ¹⁴C-tyramme as the substrate was employed. 2-Benzyl-3-dimethylaminothietane was also tested for in vivo MAO inhibition by a dopamine potentiation procedure. The results of these studies are discussed in relation to structure activity relationships. The high in vitro activity of 2-benzyl-3-dimethylamino-thietane was taken as evidence to support the hypothesis that the electronic and steric properties in the cyclopropyl ring of tranylcypromine, in the ground state, is important in the attachment of tranylcypromine to MAO. A number of thietane derivatives were prepared as potential narcotic analgetics of the methadone type. These derivatives are conformationally more restricted than methadone and thus may be useful in elucidating the pharmacophoric conformation of methadone and related analgetics. Cycloaddition of an appropriate enamine and sulfene gave the synthesis of 3-dimethylamino-2-phenylthietane 1,1-dioxide, 3-dimethylamino-4-methyl-2-phenylthietane 1,1-dioxide,. 4-methyl-3-morpholino-2-phenylthietane 1,1-dioxide, and r-2,c-3,t-4 - and r-2,t-3,c-4- 3-dimethylamino-4-dimethylaminomethyl-2-phenylthietane 1,1-dioxide. Treatment of the first three of these compounds in the amine oxide elimination procedure gave 2-phenylthiete 1,1-dioxide and 4-methyl-2-phenylthiete 1,1-dioxide. Addition of HCN in the presence of catalytic amounts of KCN to the thietes gave 3-cyano-2-phenylthietane 1,1-dioxide and 3-cyano-4-methyl-2-phenylthietane 1,1-dioxide. Reduction of these nitriles with diborane gave the corresponding primary amines which were dimethylated with HCO₂H and HCHO to give trans-3-dimethylaminomethyl-2-phenylthietane 1,1-dioxide and t-3-dimethylaminomethyl-c-4-methyl-r-2-phenylthietane 1,1-dioxide. The reaction of several α-alkylstyrenes with cyanosulfene gave the corresponding acyclic substitution products, which were rationalized on the basis of a 2-step cycloaddition mechanism of sulfenes to enamines. None of the compounds tested showed significant analgetic activity in an in vitro test based on the inhibition of the contractions of an electrically stimulated guinea pig ileum. Included in this dissertation are discussions on the elucidation of the configuration of the synthesized thietanes from their nmr spectra. The mass spectral characteristics of thietanes and thietane 1,1-dioxides are discussed in some detail.

Item Media

Item Citations and Data


For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use.