- 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-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.