N-Acyl Tryptophan Derivs as Opiate Potentiators
(Rated as: interesting)
Abridged for brevity.
Pharmaceutical use of derivatives of tryptophan
N-acylated derivatives of L-tryptophan of general formula (I), in which R is selected from the group consisting of: (a) a phenyl group, mono-substituted or di-substituted in the meta and para positions with halogens, linear or branched alkyl groups containing from 1 to 9 carbon atoms, the cyano group or the trifluoromethyl group, (b) a benzyloxy group, mono-substituted or di-substituted in the meta and para position with substituents selected from those indicated at (a), and (c) a benzydryloxy group. The derivatives are used in therapy, particularly for human pain relief, in the treatment of pathological conditions of the central nervous system and of pathological intestinal conditions.
The applicants have now discovered that these N-acyl derivatives of tryptophan have an unexpected but extremely interesting therapeutic activity, that is, that of potentiating the analgesic activity of morphine and other analgesic-narcotic and non-narcotic drugs.
The method of preparation of the compounds of the invention consists of an acylation reaction under Schotten-Bauman conditions. Thus one mole of L-tryptophan is reacted with one mole of a suitable acyl chloride in the presence of two moles of base (generally sodium bicarbonate or hydroxide) at a temperature of between 0-10°C. for a period of 1-24 hours.
Example 1 (See Cpd 1, Tbl A)
To a solution containing 20.4 g (0.1 moles) of L-tryptophan in 100 ml of 1N sodium hydroxide cooled to 5°C., there are added 100 ml of 1N sodium hydroxide and 18.9 g (0.1 moles) of p-fluorobenzyl chloroformate dissolved in 150 ml of ethyl acetate, simultaneously, under agitation and cooling, over a period of about 30 minutes. The mixture is left to react for twelve hours. The layers are separated and the slightly-alkaline aqueous phase is acidified; N-p-fluorocarbobenzoxy-L-tryptophan is precipitated and separated by filtration. The crude compound is recrystallised from MeOH-H2O (1:1) to give 23.6g (66% yield), mp 122-124°C. TLC (see note in the table) Rf: 0.40.
All the compounds of the invention were made by the same method.