β-Phenylethylamines and β-Amino Alcohols of Potential Pharmacological Interest

Abstract

The biological properties of some tetrahydroisoquinolines, piperazines, and piperidines are described with particular reference to derivatives with analgesic or C.N.S. activity. A brief account is given of the development of narcotic analgesic antagonists. The mechanism of action of sympathomimetic amines is described together with the biological properties of some β-phenylethanolamine derivatives. The difficulties involved in the direct 1-alkylation of pyrrole are discussed and a summary is given of the methods most usually employed. The biological properties of some pyrroles are described. The practical work described in this thesis is divided into three sections. The first concerns the preparation of alkyl and acyl derivatives of 1,2,3,4-tetrahydroisoquinoline, 1-phenylpiperazine, and 4-diphenylmethylpiperidine. In the second part the synthesis of β-amino alcohols, by the fission of epoxides with amines, is discussed. Cyclisation of the β-amino alcohols gave examples of the oxazolidine, 2-oxazolidinone, 2-oxathiazolidinone, 2-morpholinone, and morpholine-2,3-dione ring systems. A previously claimed synthesis of 3,5-diphenyloxazolidin-2-one, from phosgene and styrene oxide, is shown to yield the 3,4-diphenyl isomer. The possible conformation of 4-cyclohexyl-6-phenylmorpholine-2,3-dione is discussed on the basis of n.m.r. data. Preparation of the N-amino derivative of 2-cyclohexylamino-1-phenylethanol is described together with the cyclisation to yield the first reported example of the 2H-1,3,4-oxadiazine-2-thione ring system. The preparation of some novel 1-substituted pyrroles, from the reaction of methyl pyrrole-2-carboxylate and epoxides, is described in the third part. Examples of the 1H-pyrrolo [2,1-c][ 1,4] oxazine and the novel 4H-pyrrolo [2,1-c] [1,4] benzoxazine ring systems are described. A mechanism is suggested for the reaction of pyrrole salts with epoxides. Various unsuccessful attempts to cyclise 1-substituted vinylpyrrole-2-carboxylic acids to pyrrole [2,1-c] [1,4] oxazines are described. The photochemical isomerisation of trans-1-styrylpyrrole-2-carboxylic acid is discussed. Mass spectral data of some 1-substituted pyrroles is presented. In conclusion the pharmacological results of a selected number of compounds are reported and discussed. 1-Cyclopropylmethyl-4-phenylpiperazine has interesting C.N.S. activity and produces effects similar to chlorpromazine.