DE3104884A1 - PHARMACEUTICAL PREPARATION - Google Patents

Description

- 3 DESCRIPTION

The invention relates to pharmaceutical preparations or drugs which contain a naphthyridine derivative as an active ingredient and which are used to treat disorders of consciousness and states of depression are suitable.

The naphthyridine derivative contained in the claimed pharmaceutical preparation or the medicinal product corresponds of formula I below

(D

This compound is obtained starting from tryptamine
formula

CH ₂ -CH ₂ -NH ₂

by reacting this compound with ketoglutaric acid the
formula

COOU- (CiI.,) ₀ -CO-CiK) II

followed by a cyclization of the resulting intermediate of formula

HOOC

COOH

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PYNTHELABO TER MEER MÜLLER STEINMEISTE * s _ET 45

in a hydrochloric acid medium, which leads to the hydrochloride of the compound of the formula I and which can be obtained in the form of the base by making it alkaline with the aid of sodium carbonate.

The following example serves to illustrate the preparation of the compound of formula I.

example

Production of 1,2,3,3a, 4,5-hexahydro-6H-indolo £ 3,2,1-d, eJ £ 1.53naphthyridin ~ 6-one hydrochloride

1. Condensation of tryptamine with -ketoglutaric acid To a solution of 73 g (0.456 mol) of tryptamine in 1000 ml of methanol is added 100 g (0.685 mol) of (^ .- ketoglutaric acid) with stirring and the resulting solution is stirred for about 16 hours at room temperature The medium is then concentrated to dryness, the residue obtained is taken up in 1000 ml of water, the compound is filtered off with suction and dried.

2. Cyclization of the intermediate

A reaction mixture of 119 g of the in the is stirred Stage 1 obtained compound and 1200 ml of ethanol. The suspension is heated to reflux temperature and then introduces gaseous hydrogen chloride, which is done quickly at the beginning and after dissolving initiates more slowly. These conditions are maintained for 5 hours. Do stop the reaction it is cooled and the precipitate formed in the course of the reaction is filtered off. That way it gets the hydrochloride of the compound of formula I, which melts at 280 ° C.

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TER SEA. MÜLLER · STEINMEISTER

ISFffl

ILABO

The IR and NMR spectra are consistent with the structure indicated.

To liberate the base, the hydrochloride is dissolved in water and made alkaline by adding sodium carbonate. A crystalline product is obtained which, after suction, gives the compound of the formula I in the form of the base. The material melts after recrystallization from ethyl acetate at 149 ⁰ C.

The compound of formula I has in the test of hypobaric hypoxia has been shown to be pharmacologically active.

Hypobaric hypoxia

Mice of the CD1 strain are kept in an oxygen-depleted atmosphere by applying a partial vacuum (253 mbar (190 mm Hg), which corresponds to an oxygen content of 5.25%). The survival time of the animals is then determined. This time is extended by means which favor the oxygen supply of the tissue and especially the brain. The compounds studied are administered in various dosages by the intraperitoneal route 10 minutes prior to the examination. then the percentage of the increase in survival time compared to that of the control animals is calculated obtained values. The mean active dose (MAD), which increases survival time by 100%, is determined graphically.

This dose bolrihjt: for animals do the ei] i n (iuiicj:; i | ein'ilU '! I pharmaceutical preparations used as active ingredient compound of formula I 6 to 9 mg / kg.

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GYNTHELABO SEa? 46

_{The DA 1f) r)} value of this compound determined by the oral route is 21 mg / kg.

Furthermore, the effect of this compound on the duration of sleep was investigated with curare rats treated with sodium 4-hydroxybutyrate became.

The animals used are male rats of the Charles River tribe weighing 200 + 20 g. The animals curarized by intraperitoneal administration of 1 mg / kg alloferin are artificially ventilated with the aid of a mask placed on the snout (breathing frequency: 50 / min; breathing volume: 14 cm ³ ). To prevent air from entering the stomach, the esophagus was tied off with a ligature beforehand.

With the help of frontal occipital and frontal parietal cortical probes was the electrocorticographic activity with the help of a multiple recorder (Grass model 79 P) measured at a writing speed of 6 mm / s.

The animals are prepared under local anesthesia (2% xylocaine). The rats are maintained throughout the study at a constant temperature of 37.5 ⁰ C. Ten minutes after the completion of the preparation of the rat, a dose of 200 mg / kg sodium 4-hydroxybutyrate is injected intravenously in the region of the tail.

3 minutes after the administration of the sodium 4-hydroxybutyrate the compound to be tested is given in a dose of 30 mg / kg by the intraperitoneal route.

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TER MEER ■ MÜLLER · STEINMEISTEH

SYNTHELABO SET 4 6

The curves obtained are evaluated over a period of 15 minutes for 75 minutes the injection of sodium 4-hydroxybutyrate. While the total duration of the "sleep" is determined from this analysis time. With the help of 15 control animals, the duration of sleep caused by sodium 4-hydroxybutyrate.

Statistical analysis of the results is done using the Mann-Whitney "U" test.

The percentage deviation, based on the control animals, is -38% for compound I.

On the other hand, the compound of the formula I has a lethal 50% dose (DL ₅₀ ) of 110 mg / kg, which was determined graphically in mice of the CD1 strain when administered intraperitoneally.

The compound of formula I, which has been shown to be active in mice in the study of hypobaric hypoxia, thus develops an antianoxic effect and can therefore be used in therapy for the treatment of behavioral disorders, which are a consequence of cerebral vascular damage and age-related cerebral sclerosis, and for the treatment of Metabolic encephalopathies are used.

The compound of the formula I can be administered orally in the form of tablets, gel beads, capsules, coated tablets, solutions or suspensions or by the parenteral route in the form of solutions. The daily dose can vary from 1 to 100 mg of the compound of formula I extend.

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The pharmaceutical preparations according to the invention optionally contain the compound of the formula I in the form of mixtures with other active ingredients and adjuvants, diluents, carrier materials and / or auxiliaries that are common in pharmacy are.

The galenic or pharmacological production of the preparations is carried out using methods known per se Procedures.

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Claims (2)

PAT E N TA N WA LTE TER MEER-MÜLLER-STEINMEISTER Balm European Patent Office approved representatives - Professional Representatives before the European Patent Office Mandatalres agrees pres! Office european dei brevets Dipl.-Chem. Dr. N. ter Meer Dipl -Ing. H. Steinmeister Dipl.-tng. F. E. Müller _. ,,. _ Triftstrasse 4, Siekerwall 7, D-8OOO MÜNCHEN 22 D-48OO BIELEFELD SET 46 February 11, 1981 SYNTHELABO 1 and 1 to Avenue de Villars 75007 Paris, France Pharmaceutical preparation Priority: February 12, 1980, France, No. 80 03 PATENT CLAIMS 1. Pharmaceutical preparation containing a naphthyridine derivative of formula I. in combination with a customary, suitable binder, carrier material and / or auxiliary. TER MEER · MÜLLER · STEINMEISTE. " SYNTHELABO SET 46 2. Medicinal products, characterized that it is made from a naphthyridine derivative of the formula I. and a conventional binder, carrier material and / or auxiliary. Pharmaceutical preparation for the treatment of behavioral disorders, which are a consequence of cerebral vascular damage and senile cerebral sclerosis, as well as for the treatment of metabolic encephalopathies, characterized by a content of a naphthyridine derivative of the formula I. 130082/0517