IE52160B1

IE52160B1 - Naphthyridine derivatives

Info

Publication number: IE52160B1
Application number: IE2722/81A
Authority: IE
Original assignee: Synthelabo
Priority date: 1980-11-21
Filing date: 1981-11-20
Publication date: 1987-07-22
Also published as: IE812722L; CA1162544A; GB2087889B; AT379594B; NZ199008A; SE8106918L; AU546924B2; JPS57116070A; GR78026B; IT1195292B; ATA501381A; PT74019B; BE891204A; LU83775A1; GB2087889A; FR2494693B1; IT8125212A0; NL8105282A; NO813945L; ES507317A0

Abstract

2,3,3a,4,5,6-Hexahydro-1H-indolo[3,2,1-de][1,5-naphthyridine] derivatives of the general formula: in which R1 is in the 9- or 10- position and represents a hydrogen atom, a halogen atom or a C1-4 alkyl or C1-4 alkoxy radical and R2 represents a hydrogen atom or a C1-4 alkyl radical, and pharmaceutically acceptable acid addition salts thereof are new compounds useful in therapy as they possess an anti- anoxia action and a psychotropic action. They can be prepared by reduction of the carbonyl group of corresponding 1,2,3,3a,4,5-hexahydro- 6H-indolo[3,2,1-de][1,5-naphthyridine]-6-one derivatives, which are known compounds, to methylene.

Description

The present invention relates to 2,3,3a,4?5 ,6-hexahydro-lH-indolo[3,2,1-de][l,5naphthyridine] derivatives, their addition salts with pharmaceutically acceptable acids, their preparation and pharmaceutical compositions containing them.

The naphthyridine derivatives of the present invention are those compounds of the general formula: in which is in the 9- or 10-position and represents 10 a hydrogen atom, a halogen atom or a 4 alkyl or C^_4 alkoxy radical and Rj represents a hydrogen atom or a alkyl radical, and pharmaceutically acceptable acid addition salts thereof.

These compounds contain an asymmetric 15 carbon atom in the 3a-position. The racemates and the optically active isomers of the compounds of general formula (I) form part of the present invention.

The preferred compounds of the invention are those in which represents a hydrogen, chlorine, bromine or fluorine atom or the methyl or methoxy radical and R2 represents a hydrogen atom or the methyl radical and, more particularly! those in which R^ represents a hydrogen» fluorine» chlorine or bromine atom and R2 represents a hydrogen atom.

The compounds of general formula (I) can be prepared» for example» by reducing the compounds of the general formula: in which R^ and R2 are as hereinbefore defined, or an acid addition salt thereof, e.g. the hydrochloride.

The compounds of general formula (II) have 15 already been described in the literature, in particular by R.G. Taborsky et al., J. Med. Chem. 7 (2), 135-41 (1964), by G. Hahn et al., Ber. 71B, 2163-75 (1938), in French Patent 2434165 and by Patent Specification No. 44989.

The process of the invention consists in reducing the compounds of general formula (II) in accordance with a conventional method for the conversion of the carbonyl group (ZIC=O) to methylene (i.e. -CH.,-), for example by treating a compound of general formula (II) with a hydride» such as lithium aluminium hydride, in the presence of a Lewis acid such as aluminium chloride. The reaction is generally carried out at a temperature of from -40 to +80°C in an organic solvent such as an anhydrous ether.

Pharmaceutically acceptable acid addition salts of the naphthyridine derivatives of general formula (I), e.g. methanesulphonates, mandelates, fumarates, citrates and hydrochlorides, may be obtained by methods known per se, for example by treatment of the naphthyridine base in a solvent medium, e.g. an ether, with the appropriate acid in a solvent medium, e.g. an alkanol.

By the term ‘methods known per se1 as used in this specification is meant methods heretofore used or described in the literature.

The following Examples illustrate the preparation of naphthyridine derivatives of the present invention.

The analyses and the IR and NMR spectra confirm the structure of the compounds.

EXAMPLE I 213,3a,4,5,6-Hexahydro-lH—indolcf 3,2,1-de][l, 5naphthyridine] and its methanesulphonate .4 g (0.04 mol) of aluminium chloride are placed in a one litre three-necked flask. 50 ml of anhydrous diethyl ether are added all at once. 2.3 g (0.06 mol) of lithium aluminium hydride are added gradually to the solution obtained. The suspension obtained is stirred for 10 minutes.

A suspension of 5.3 g (0.02 mol) of l,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][1,5-naphthyridine]-6-one hydrochloride in 70 ml of anhydrous tetrahydrofuran is added gradually thereto. The mixture is stirred at ambient temperature for 30 minutes. It is then cooled in an ice-bath and 10 ml of water are added slowly.

The mixture is stirred for 10 minutes and 10 ml of sodium hydroxide solution (d = 1.38), 150 ml of ethyl acetate and 100 ml of water are then added successively. The mixture is stirred for 15 minutes. The organic phase is decanted. The aqueous phase is extracted twice with 60 ml of ethyl acetate. The combined organic extracts are washed with water, dried over sodium sulphate and evaporated in vacuo on a water-bath. This yields an oil, which is dried by azeotropic distillation with toluene. The base obtained is pure according to thin layer chromatography.

This oil is solubilised in 80 ml of anhydrous diethyl ether. A solution of 2 g (0.02 mol) of methanesulphonic acid in 20 ml of ethanol is added. The mixture is stirred for 30 minutes at ambient temperature. The white precipitate obtained is filtered off, washed with diethyl ether and dried in a desiccator. The methanesulphonate salt of the naphthyridine product is recrystallised from 80 ml of ethanol. Its melting point is 246-248°C.

EXAMPLE 2 -Chloro-2,3,3a,4,5,G-hexahydro-lH-indolor3,2,l-deirii5-naphthyridine1 and its methanesulphonate 2.25 g (0.0168 mol) of anhydrous aluminium chloride, 25 ml of anhydrous diethyl ether and 0.96 g (0.0252 mol) of lithium aluminium hydride are placed in a 500 cc three-necked round-bottomed flask. A suspension of 2.5 g (0.0084 mol) of 10-chloro1,2,3,3a,4,5-hexahydro-6H-indolo[3,2,1-de][l,5naphthyridineJ-6-one hydrochloride in 60 ml of anhydrous tetrahydrofuran is added to the resulting suspension, whilst stirring. When the introduction has ended, a grey solution is obtained, which is stirred for half an hour. The complete disappearance of the starting material is monitored by thin layer chromatography.

The complex is destroyed by slowly adding 5 ml of water and then 15 ml of sodium hydroxide solution (d - 1.38). The medium is diluted with 150 ml of water and extraction is then carried out three times with 70 ml of ethyl acetate. The extract is washed with water and then dried over sodium sulphate.

It is filtered.

A solution of 0.9 g (0.0093 mol) of methanesulphonic acid in 2 ml of ethyl acetate is added to the filtrate. The resulting precipitate is filtered off( and recrystallised from about 50 ml of methanol in the presence of decolorising charcoal. The mixture is filtered hot. The filtrate deposits crystals. These are filtered off and dried. The methanesulphonate of the naphthyridine product melts at 275-278°C.

The following Table shows the compounds of the invention which were prepared by way of examples in accordance with the method described above.

CompoundR1R2 Base or salt Melting point (°C) 1 H H m.s. 246-248 (Example 1) 2 io-ch3 H base 122-3 3 10-CH30 H m.s. 248-250 4 10-F H HCl >300 5 10-C1 H base 142-3 (Example 2) m.s. 275-8 6 H ch3 m-s. >260 7 9-C1 H m.s. 251-253 8 10-Br H m.s. 265 9 9-CH30 H m.s. 214-6 (m.s. = methanesulphonate) The compounds of the invention formed the subject of a pharmacological study. 1. TOXICITY The 50% lethal dose (LD 50) of the compounds is determined on mice of the CD1 strain by a graphical method. The LD 50 is from 120 to 500 mg/kg» administered intraperitoneally. 2. HYPOXIA CAUSED BY PRESSURE REDUCTION Mice of the CD1 strain are kept in an oxygendepleted 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 compounds studied are 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. The MAD is from 10 to 15 mg/kg. 3. ACTION ON THE DURATION OF THE SLEEP INDUCED BY SODIUM 4-HYDROXBUTYRATE This action was determined by the influence 5S160 of a compound on the duration of the sleep induced in curarised rats hy sodium 4-hydroxybutyrate (GMB).

The animals used are male rats of the Charles River strain, weighing 200 + 20 g. The 5 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 fronto-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% strength xylocaine). The rats are kept at constant temperature (37.5°C) throughout the experiment. Ten minutes after the rat has been prepared, a 200 mg/kg dose of sodium 4-hydroxybutyrate is injected intravenously into the tail.

A 10 mg/kg dose of the 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 after the injection of the B2160 GHB. During this period of analysis, 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 reduction in the duration of the sleep is from 25 to 40%.

The pharmacological study of the compounds of the invention shows that they are active in the test for the hypoxia caused in mice by pressure reduction, whilst at the same time being only slightly toxic, and that they exert a significant waking action in the test for the sleep induced by sodium 4-hydroxybutyrate.

The compounds of the invention, which possess an anti-anoxia action and a psychotropic action, can be used in therapy for the treatment of vigilance disorders, in particular for combating the behavioural disorders which can be attributed to cerebral vascular damage and to the cerebral sclerosis encountered in geriatrics, and also for the treatment of epileptic vertigo due to cranial traumatisms, for the treatment of metabolic encephalopathies and for the treatment of depressive states. 53160 The invention consequently includes pharmaceutical compositions containing, as active ingredient, a naphthyridine derivative of general formula (I), or a pharmaceutically acceptable acid addition salt thereof, in association with any excipients which are suitable for their administration, in particular their oral or parenteral administration.

The methods of administration can be oral and parenteral.

The daily posology can range from 10 to 100 mg of naphthyridine derivative. The dosage units can therefore contain, for example, 2 to 50 mg doses of active substance associated with customary excipients, and can be presented in the form of tablets, coated tablets, capsules, suspensions or solutions to be taken orally or injected.

Particularly preferred naphthyridine derivatives of the invention are 2,3,3a,4,5,6hexahydro-lH-indolo[3,2,1-de][1,5-naphthyridine] , -chloro-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de][1,5-naphthyridineJ , 10-fluoro-2,3,3a,4,5,6hexahydro-lH-indolo[3,2,1-de][l,5-naphthyridine] and 10-bromo-2,3,3a,4,5,6-hexahydro-lH-indolo[3,2,1-de][l,5-naphthyridine], and their pharmaceutically acceptable acid addition salts.

Claims

1. 2,3,3a,4,5» 6-Hexahydro-lH-indoloΓ3,2,1-de1Γ1,5-naphthyridine1 derivatives, in the form of racemates or enantiomers, of the general formulas in which is in the 9- or 10-position and represents a hydrogen atom, a halogen atom or a C 1 _ 4 alkyl or C 1 _ 4 alkoxy radical and R 2 represents a hydrogen atom or a Cj__ 4 alkyl radical, and pharmaceutically acceptable 10 acid addition salts thereof.

2. Naphthyridine derivatives according to claim 1 in which R^ represents a hydrogen or halogen atom or a 4 alkyl or C^_ 4 alkoxy radical and R 2 represents an alkyl radical, and pharmaceutically 15 acceptable acid addition salts thereof.

3. Naphthyridine derivatives according to claim 1 in which R^ represents a halogen atom or a C^_ 4 alkyl or C-^_ 4 alkoxy radical and R 2 represents a hydrogen atom or a C 1-4 alkyl radical, and pharmaceutically 20 acceptable acid addition salts thereof.

4. Naphthyridine derivatives according to claim 1 in which represents a hydrogen, chlorine, bromine or fluorine atom or the methyl or methoxy radical and Rj represents a hydrogen atom or the methyl radical, 5. And pharmaceutically acceptable acid addition salts thereof.

5. Naphthyridine derivatives according to claim 1 in which represents a hydrogen, fluorine, chlorine or bromine atom and R 2 represents 10 a hydrogen atom, and pharmaceutically acceptable acid addition salts thereof.

6. 2,3i3a,4,5,6-Hexahydro-lH-indolo[3,2,1-de][l,5-naphthyridine] and its pharmaceutically acceptable acid addition salts. 15

7. 10-Chloro-2,3,3a,4,5,6-hexahydro-lHindolof3,2,1-de]Γ1,5-naphthyridine] and its pharmaceutically acceptable acid addition salts.

8. 10-Fluoro-2,3,3a,4,5,6-hexahydro-lHindolo[3,2,1-de][l,5-naphthyridine] and its 20 pharmaceutically acceptable acid addition salts.

9. 10-Bromo-2,3,3a,4,5,6-hexahydro-lHindolo[3,2,1-de][1,5-naphthyridine] and its pharmaceutically acceptable acid addition salts.

10. A process for the preparation of a 25 naphthyridine derivative of the general formula depicted in claim 1 which comprises reducing the carbonyl group of a compound of the general formula: (wherein R^ and R 2 are as defined in claim 1), or an acid addition salt thereof, to methylene.

11. A process according to claim 10 in which a hydride, in the presence of a Lewis acid, is used for the reduction.

12. A process according to claim 10 in which the reduction of the carbonyl group to methylene is carried out with lithium aluminium hydride in the presence of aluminium chloride.

13. A process according to claim 10, 11 or 12 followed by the step of converting by methods known per se a naphthyridine derivative of the general formula depicted in claim 1 so obtained into a pharmaceutically acceptable acid addition salt.

14. Pharmaceutical compositions which comprise, as active ingredient, at least one naphthyridine derivative as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable acid addition salt thereof, in association with any suitable excipient.

15. Naphthyridine derivatives of the general formula depicted in claim 1, wherein and R 2 are as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, for use as a medicament in 5 the treatment of behavioural disorders which can be attributed to cerebral vascular damage and to the cere bral sclerosis encountered in geriatrics, and also for the treatment of epileptic vertigo due to cranial traumatisms, for the treatment of metabolic encephalo10 pathies and for the treatment of depressive states.