FURTHER STUDY OF SOME 1-SUBSTITUTED THEOBROMINE COMPOUNDS

¹ Lilly Research Laboratories, Eli Lilly and Company, Indianapolis 6

A series of 1-substituted theobromine derivatives has been investigated for some of their pharmacologic actions with the following results:

1. From the median lethal doses by intravenous injection in mice, the compounds showed the following order of decreasing toxicity: allyl > ethyl > crotyl > methyl (caffeine) > propyl > butyl > <I>iso<I>amyl > methallyl > methoxyethyl. The median convulsive doses revealed the same order except that the butyl and iso amyl derivatives were not convulsants.

2. Caffeine, allyl theobromine, and propyl theobromine inhibited weight gain of young rats when fed for 28 days in percentages of 0.3 and 0.5 in the food. Smaller amounts did not have any effect. Allyl theobromine inhibited growth of young rats to a much greater extent than the other 2 substances.

3. Caffeine was more stimulating to motor activity of rats in spring-suspended cages than the theobromine compounds which have the same action. By the same procedure, theophylline was shown to be stronger than caffeine, but much less effective than d-amphetamine sulfate.

4. Propyl theobromine produced much greater respiratory stimulation than any other member of this series, when given to dogs deeply anesthetized with phenobarbital sodium. Compared with caffeine, nikethamide, and lobeline, the propyl derivative was more than 6 times as effective as the first 2 compounds and twice as active as lobeline.

5. In tests of diuretic action, rats showed greater urine outputs with caffeine than with 1-substituted theobromines. In dogs, the diuretic potency had the following order: propyl > ethyl > methyl (caffeine) > methallyl > butyl > allyl > methoxyethyl iso amyl. The crotyl derivative had an inhibiting effect on the urine output.

6. Allyl theobromine, propyl theobromine, caffeine, and theophylline were tested in a few human subjects in a dose of 200 mg. given orally. There was evidence that propyl theobromine was more powerful in increasing the urine output than caffeine; and that the latter, in turn, was slightly more powerful than the other two products. Untoward symptoms were observed—more with allyl and propyl theobromines.