INDOLE DERIVATIVE HAVING PROLONGED IMMUNOSTIMULATING ACTIVITY AND PHARMACEUTICAL COMPOSITIONS THEREFROM

Abstract: N-[N'-acetyl(glycinyl)]-5-methoxytryptamine, of formula (I) is characterized by a markedly prolonged immunostimulating activity.

Description: INDOLE DERIVATIVE HAVING PROLONGED IMMONOSTIMOLATING ACTIVITY AND PHARMACEUTICAL COMPOSITIONS THEREFROM The present invention relates to an indole deriva¬ tive having prolonged im-nunostimulating activity, namely N-[N 1 -acetyl(glycinyl)]-5-methoxytryptamine, of formula (I) CH,0 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 eguimolar doses of YS-2051 and melatonin, the following advantages for YS-2051 were evidenced from the pharmacokinetic data of melatonin plasmatic concentrations: Maximal concentration: + 57% in case of YS-2051 Half-life time: +104% in case of YS-2051 Area under curve: +120% in case of YS-2051 The invention also relates to a process for the preparation of YS-2051, characterized in that 5- methoxytryptamine (II) is reacted with a N-acetylgly- cine reactive derivative , of formula (III), according to scheme 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 pre¬ sence 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°C, then 2.6 ml of isobutyl chloroformate (0.02 mole) are added, with stirring, keeping temperature below 5°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 C 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 138-140°C; it is soluble in alcohols and ketones, poorly soluble in wa¬ ter. The structure of the compound is confirmed by the elementary analysis, as well as by the H-NMR spectrum. p.p.m integration multiplicity assignment 1.95 3H singlet CH 3 CO 2.82 2H triplet J-7Hz CH 2 C= 3.3-3.6 2H multiplet, CH 2 CH 2 NH triplet after deuter. 3.72 2H doublet J-7Hz, CH 2 CO singlet after deuter. 3.83 3H singlet CH 3 o 6.7-7.3 4 H 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 phar a- ceutical compositions containing compound YS-2051, op¬ tionally together with conventional additives, exci- pients 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 suspen- sions of the active ingredient.

Claims: CLAIMS 1. N-[N'-acetyl (glycinyl) J-5-methoxytryptamine, of formula (I) H 2. Pharmaceutical compositions having prolonged immunostimulating activity, containing compound (I) as the active ingredient. 3. A process for the preparation of compound (I), characterized in that 5-methoxytryptamine (II) is reac¬ ted with a N-acetylglycine reactive derivative, of for¬ mula (III), according to the scheme below: wherein X is a halogen atom or an alkoxy or alkoxycar- bonyloxy residue. 4. The use of compound (I) for the preparation of pharmaceutical compositions having prolonged immunostimulating activity.

Inventors: QUADRO GIUSEPPE, QUADRO, GIUSEPPE
Applicants: QUADRO GIUSEPPE, YASON SRL, QUADRO, GIUSEPPE, YASON S.R.L.
Application year: 1992
Main classification: C07D209
IPC codes: C07D209