Indole derivative having prolonged immunostimulating activity an

Details Indole derivative having prolonged immunostimulating activity an Indole derivative having prolonged immunostimulating activity an

1995-12-01

1997-02-18

Henley, III, Raymond

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

548491, A61K 3140, C07D20904

Patent

active

056042540

DESCRIPTION:

BRIEF SUMMARY
This Application is a 371 of PCT/EP92102737 filed Nov. 27, 1992.
The present invention relates to an indole derivative having prolonged immunostimulating activity, namely N-[N'-acetyl(glycinyl)]-5-methoxytryptamine, of formula (I) ##STR2##
The immunomodulating and immunostimulating properties of 5-methoxytryptamine, or melatonin, have been evidenced in successive stages by G. J. M. Maestroni and A. Conti: in 1986 in normal rats, in 1987 on the primary anti-body response in the mouse, in 1988 in mice in which stress had been induced by a Vaccinia Virus injection; and by various Authors more recently. However, the therapeutic use of melatonin is limited as drug effective levels in blood stream can be attained for only short times, after acute administration.
Now it has surprisingly been found that compound (I) (which hereinafter will also be called YS-2051), besides having a higher membrane affinity, also allows to obtain markedly higher and more prolonged plasmatic concentrations after oral administration.
In fact, after administration of equimolar doses of YS-2051 and melatonin, the following advantages for YS-2051 were evidenced from the pharmacokinetic data of
melatonin plasmatic concentrations:
The invention also relates to a process for the preparation of YS-2051, characterized in that 5methoxytryptamine (II) is reacted with a N-acetylglycine reactive derivative, of formula (III), according to scheme ##STR3## wherein X is a halogen atom, preferably chlorine, or an alkoxy or alkoxycarbonyloxy residue.
Alternatively, X can be the hydroxy group, in which case the reaction will be carried out in the presence of agents such as N'-dicyclohexyl-carbodiimide or carbonyldiimidazole.
The following example illustrates the process of the invention.


EXAMPLE

2.34 g of N-acetylglycine (0.02 mole) are
dissolved in 200 ml of a mixture of 1:1 toluene-chloroform and 2.8 ml of triethylamine (0.02 mole+5%). The mixture is cooled to 0.degree. C., then 2.6 ml of isobutyl chloroformate (0.02 mole ) are added, with stirring, keeping temperature below 5.degree. C., to form the mixed anhydride. After 10 minutes, a solution of 3.80 g of 5-methoxytryptamine (0.02 mole ) in 80 ml of chloroform, cooled at 0.degree. C., is added.
The mixture is stirred at room temperature for 20 hours, the precipitate is pump filtered, washing with 10% HCl, then with water. The precipitate is dissolved in acetone, dried over sodium sulfate and solvent is evaporated off under reduced pressure. The residue is recrystallized from isopropyl ether/isopropyl alcohol, to obtain 2.2 g of amide (I).
The obtained compound melts at 138.degree.-140.degree. C.; it is soluble in alcohols and ketones, poorly soluble in water. The structure of the compound is confirmed by the elementary analysis, as well as by the .sup.1 H-NMR spectrum.


______________________________________ p.p.m. integration multiplicity assignment ______________________________________ 1.95 3H singlet CH.sub.3 CO 2.82 2H triplet J = 7Hz CH.sub.2 C.dbd. 3.3-3.6 2H multiplet, CH.sub.2 CH.sub.2 NH triplet after deuter. 3.72 2H doublet J = 7Hz, CH.sub.2 CO singlet after deuter. 3.83 3H singlet CH.sub.3 O 6.7-7.3 4H multiplet aromatici 7.9 1H triplet J = 7Hz, NHCO it disappears upon deuter. 8.12 1H triplet J = 7Hz, NHCO it disappears upon deuter. 10.65 1H broad singlet NH it disappears upon deuter. ______________________________________
The present invention further relates to pharmaceutical compositions containing compound YS-2051, optionally together with conventional additives, excipients and adjuvants. Examples of said formulations are capsules, tablets, granulates containing 10 to 100 mg of YS-2051 per unit dose, or 1-10% solutions or suspensions of the active ingredient.
1. N-[N'-acetyl(glycinyl)]-5-methoxytryptamine, of formula (I) ##STR4##
2. A process for the preparation of compound (I) of formula ##STR5## which comprises the step of an reacting N-acetyl glycine reactive derivative of formula III ##STR6## wherein X is halogen or alcox

REFERENCES:
G. W. Bennett et al., J. Recept. Res. vol. 7, No. 1-4, pp. 555-579 1987.
R. Besselievre et al., Biomed. Express, vol. 33, No. 7, pp. 226-228 1980.
M. Strahilevitz et al., Biol. Psychiatr. vol. 3, pp. 27-236 1971.
I. D. Pletnev, Khim. Geterotsikl. Soedin., No. 1, pp. 76-80 1972.
P. N. Stefanescu, Chemical Abstracts, vol. 70, abst. No. 37594, p. 326 of Rev. Chim. (Bucharest), 19(8), pp. 444-447 1986.

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