GB2068731A

GB2068731A - Naphthyridine derivative useful in therapy and pharmaceutical compositions containing the same

Info

Publication number: GB2068731A
Application number: GB8104135A
Authority: GB
Original assignee: Synthelabo SA
Current assignee: Synthelabo SA
Priority date: 1980-02-12
Filing date: 1981-02-11
Publication date: 1981-08-19
Also published as: JPS56127313A; IT1135422B; LU83128A1; BE887468A; IL62114A0; ZA81919B; IT8119667A0; DE3104884A1; FR2475394A1; AU6714581A; NL8100645A; FR2475394B1

Abstract

The compound of formula <IMAGE> and its salts are useful in therapy in the treatment of behavioural disorders attributable to cerebral vascular damage or cerebral sclerosis caused by age or of metabolic encephalopathies. They may be made into pharmaceutical compositions with appropriate carriers.

Description

SPECIFICATION Naphthyridine derivative useful in therapy and pharmaceutical compositions containing the same The present invention relates to pharmaceutical compositions useful in the treatment of vigilance disorders and depressive states.

The naphthyridine derivative of the formula

was described by Hahn etal, Chem. Ber. 1938 pp.

2163-2175. It is obtained from tryptamine:

by reaction with ketoglutaric acid, COOH-(CH2)2-CO-COOH, followed by cyclisation, in a hydrochloric acid medium, of the resulting intermediate of formula:

which cyclisation leads to the hydrochloride of the compound (I), which can be obtained in the form of the base by alkalisation with Na2CO3.

The aforesaid publication does not suggest that the compound of formula I possesses any pharmacological or chemotherapeutic activity.

It has now unexpectedly been discovered that the aforesaid compound is useful in the treatment of behavioural disorders attributable to cerebral vascular damage or cerebral sclerosis caused by age, and of metabolic encephalopathies.

The present invention accordingly provides the aforesaid compound and its non-toxic acid addition salts for use in therapy in the treatment of the said conditions. It also provides pharmaceutical compositions comprising the compound offormula I ora non-toxic pharmaceutically acceptable acid addition salt thereof in association with a compatible pharmaceutically acceptable carrier, which is normally a solid or semi-solid diluent, a syrup, an elixir, or a sterile injectable liquid.

The following Example illustrates the preparation of the compound of formula (I).

EXAMPLE Preparation of 1,2,3,3a,4,5- hexahydro - 6H - indolo [3,2,1 - d.e.] - [1,5] naphthyridin - 6 - one hydrochloride.

1) Condensation of tryptamine with e -ketoglutaric acid.

100 g (0.685 mol) of cu-ketogl uta ric acid are added, while stirring, to a solution of 73 g (0.456 mol) of tryptamine in 1,000 ml of methanol and the resulting solution is stirred for about 16 hours at the temperature ofthe laboratory. The medium is concentrated to dryness; the resulting residue is taken up in 1,000 ml of water. The compound is filtered off and dried.

The resulting intermediate melts at 215 C.

2) Cyclisation of the intermediate.

A mixture of 119 9 of the intermediate in 1,200 ml of ethanol is stirred and heated to the refluxtemper- ature. Hydrogen chloride gas is then bubbled in, rapidly at the start and then slowly after dissolution has taken place. These conditions are maintained for 5 hours. At the end of the reaction, the mixture is cooled and the precipitate formed during the reaction is filtered off. The hydrochloride of the compound of formula (I), which melts at 280"C, is obtained. The IR and NMR spectra are in aggreement with the structure.

To free the base, the hydrochloride is dissolved in water and the solution is rendered alkaline by adding sodium carbonate. This yields a crystalline mass which, when filtered off, provides the compound of formula (I) in the form of the base. It melts at 149"C after recrystallisation from ethyl acetate.

The compound of formula (I) has been shown to be active in pharmacology in increasing the resistance of mice to hypoxia caused by pressure reduction. The test was conducted as follows. Mice of the CD1 strain are kept in an oxygen-depleted atmosphere produced by creating a partial vacuum (190 mm of mercury, corresponding to 5.25% of oxygen).

The survival time of the animals is noted. This time is increased by agents which are capable of assisting the oxygenation of tissues and in particular of the brain. The compound under test is administered intraperitoneally in several doses, 10 minutes before the experiment. The percentage increases in the survival time, relative to the values obtained for control animals, are calculated. The mean active dose (MAD), that is to say the dose which increases the survival time by 100%, is determined graphically.

This dose is 6to 9 mg/kg for the compound (I).

Determined orally, the AD 100 of the same compound is 21 mg/kg.

Furthermore, the compound of formula I reduces the duration of sleep induced in curarised rats by sodium 4-hydroxybutyrate (GHB). The test was conducted as follows.

The animals used are male rats of the Charles River strain, weighing 200 + 20 g. The animals, which have been curarised with Alloferine at a rate of 1 mg/kg, administered intraperitoneally, are placed under artificial respiration with the aid of a mask applied to the snout (breathing rate: 50/minute; breathing volume: 14 cc). The oesophagus is ligated beforehand in order to prevent air from entering the stomach. Fronto-parietal and -occipital cortical electrodes make it possible to record the electrocorticographic activity on a model 79 P Grass polygraph at a speed of 6 mm/second.

The animal is prepared under local anaesthetic (2% Xylocaine). The rats are kept at a constant temperature (37.5 C) throughout the experiment. Ten minutes after the rat has been prepared, a 200 mg/kg dose of Na 4-hydroxybutyrate is injected intravenously into the tail. a 30 mg/kg dose ofthe compound to be studied is administered intraperitoneally 3 minutes after the administration of the sodium 4-hydroxybutyrate.

The graphs are evaluated at 15-minute intervals for 75 minutes afterthe injection of "GHB". During this period, the total duration of the "sleep" is determined. A series of 15 controls makes it possible to specify the duration of the "GHB sleep". Statistical analysis of the results is carried out using the Mann-Whitney "U" test. The % deviation, relative to the controls, is -38% for the compound of formula I.

Furthermore, the compound of formula (I) has an LD 50, i.e. the 50 percent lethal dose determined on mice of the DC1 strain by a graphical method, of 110 mg/kg, when administered intraperitoneally.

The compound of formula (I) thus possesses an anti-hypoxia action and can be used in therapy for the treatment of the behavioural disorders which can be attributed to cerebral vascular damage and to the cerebral sclerosis encountered in geriatrics, and for the treatment of metabolic encephalopathies.

The daily dose can range from 1 to 100 mg of the compound of formula (I).

In the pharmaceutical compositions of the invention, the compound of formula I can be administered orally in the form of tablets, sugar-coated pills, capsules, coated tablets, suppositories, solutions or suspensions containing sweetening or flavouring agents, or parenterally in the form of a sterile aqueous or other injectable solution.

The pharmaceutical compositions of the invention contain the compound of formula (I), mixed, if appropriate, with other active substances, and the adjuvants, diluents, vehicles or excipients which are customary in pharmacy.

Thus the tablets, pills and capsules may contain, in addition to the compound of formula I, also conventional solid diluents such as starch, sucrose, lactose, and dextrose as well as conventional tabletting agents and lubricants. The liquid compositions for oral administration may contain conventional sweetening, flavouring, and colouring agents and perfumes. Sterile solutions or suspensions for injection may contain sterile injectable organic liquids or water.

The pharmacological of Galenical preparation is carried out in accordance with the conventional methods.

Claims

1. The compound oftheformula:

or a non-toxic acid addition salt thereof for use in therapy in the treatment of behavioural disorders attributable to cerebral vascular damage or cerebral sclerosis caused by age or of metabolic encephalopathies.

2. A pharmaceutical composition comprising the compound of formula I in claim 1 or a non-toxic pharmaceutically acceptable acid addition salt thereof in association with a compatible pharmaceutically acceptable carrier.

3. A composition according to claim 2, in which the said carrier is a solid or semi-solid, a syrup or elixir, or a sterile injectable liquid.

4. A composition according to claim 2, in the form of a tablet, sugar-coated pill, capsule, coated tablet, suppository, a sweetened or flavoured solution or suspension, or a sterile injectable solution or suspension.