Graduate Thesis Or Dissertation
 

A medicinal chemical study of Mannich bases derived from selected 2-phenylindolizines

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  • In a search for new therapeutic agents, a series of Mannich bases derived from the following 2-phenylindolizines were prepared: 2-phenylindolizine, 1, 2-diphenylindolizine, 3-methyl-2-phenylindolizine, 3-ethyl-2-phenylindolizine, and 1-(2-hydroxyethyl)-2-phenylindolizine. The investigation was based on the speculation that indolizine analogs of physiologically active indoles might be useful medicinally. A certain group of indoles, all of which have pronounced activity on the central nervous system, have in their structure a characteristic grouping, >N-C=C-C-C-N<, representing a spatial arrangement which might be a contributing factor in determining their activities. Examples of indoles with this intramolecular spread are bufotenine, psilocin, reserpine and lysergic acid diethylamide (LSD). Since Mannich bases substituted at the C-1 position of the indolizine ring possess the same intramolecular spread as the foregoing indoles, it was reasoned that such compounds might also exert activity on the central nervous system. In a broader approach to the problem of finding new physiologically active compounds, three classes of Mannich bases were prepared based on the point of attachment of the dialkylaminomethyl group to the indolizine nucleus as follows: substitution at the C-1 position, substitution at the C-3 position and substitution at both the C-1 and C-3 positions. The indolizines were prepared by the Chichibabin synthesis, which involves the heating of 1-phenacyl-2-picolinium bromides in aqueous sodium bicarbonate solution. In general, the Mannich reaction was carried out by pre-mixing the formaldehyde with the secondary amine and allowing to stand for periods varying from 15 minutes to one hour. This mixture was then added to the dioxane solution of the indolizine and the resulting reaction mixture allowed to stand at room temperature for 24 to 48 hours. In some cases the product crystallized on evaporation of the solvent accompanied by scratching with a glass stirring rod. In cases where no crystallization occured on evaporation, the oily residue was washed, dried and taken up in a minimum of alcohol or acetone and allowed to stand in the refrigerator for periods ranging from five days to three weeks, whereupon crystallization occurred in several instances. One of the compounds prepared, 1-diethylaminomethyl-3-methyl-2- phenylindolizine, exerted a depressant action on the central nervous system when injected intraperitoneally in mice as a suspension in gum acacia. The approximate LD₅₀ for this compound was found to be in the range of 70 to 100 milligrams per kilogram of body weight. The new compounds that were prepared in this study are: 1-dimethylaminomethyl-3-methyl-2-phenylindolizine, 1-diethylaminomethyl-3-methyl-2-phenylindolizine, 3-methyl-2-phenyl-1-pyrrolidinomethylindolizine, 3-methyl-2-phenyl-1-piperidinomethylindolizine, 3-methyl-1-morpholinomethyl-2-phenylindolizine, 3-methyl-1-methylphenylaminomethyl-2-phenylindolizine, 1-dimethylaminomethyl-3-ethyl-2-phenylindolizine, 1-diethylaminomethyl-3-ethyl-2-phenylindolizine, 3-ethyl-2-phenyl-1-pyrrolidinomethylindolizine, 3-ethyl-2-phenyl-1-piperidinomethylindolizine, 3-ethyl-1-morpholinomethyl-2-phenylindolizine, 3-ethyl-1-(4-methylpiperazinomethyl)-2-phenylindolizine, 1-(2-hydroxyethyl)-2-phenylindolizine, 1-(2-hydroxyethyl)-2-phenyl-3-pyrrolidinomethylindolizine, 3-dimethylaminomethyl-1 , 2-diphenylindolizine, 3-diethylaminomethyl-1, 2-diphenylindolizine, 3-diisopropylaminomethyl-1 , 2-diphenylindolizine, 1, 2-diphenyl-3-pyrrolidinomethylindolizine, 1, 2-diphenyl-3-piperidinomethylindolizine, 1, 2-diphenyl-3-morpholinomethylindo-lizine, 1, 2-diphenyl-3-methyïphenylaminomethylindolizine, 1, 2-diphenyl-3-(4-methylpiperazinomethyl)indolizine, 1, 3-his(dimethylaminomethyl)-phenylindolizine, 1 , 3-bis(pyrrolidinomethyl)-2-phenylindolizine, 1 , 3-bis(piperidinomethyl)-2-phenylindolizine, 1, 3-bis(morpholinomethyl)-2-phenylindolizine, bis(3-ethyl-2-phenyl-1-indolizinyl)methane and bis(3-methyl-2-phenyl-1-indolizinyl)-methane.
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