LU83775A1 - NAPHTYRIDINE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Description

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The present invention relates to derivatives of .1 'hexahydro-2, .3,33,4,5,6 lH-indolo [3,2, l-de ~ | £ naphthyridine-1.5 J, their addition salts with pharmaceutically acceptable acids, their preparation and their therapeutic use.

The compounds of the invention correspond to the general formula (I) f 3 2 r Z (i) dânê iaqüëliè _ is .position 9 or · 10 and represents a hydrogen atom, uj halogen atom or an alkyl radical or alkoxy, and R2 represents a hydrogen atom or a C1-4 alkyl radical.

These compounds have an asymmetric carbon in position 3a.

The racemates and the optically active isomers of the compounds (I) therefore form part of the invention.

The preferred compounds of the invention are those for 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.

The compounds which are more particularly preferred are those for which R1 is a hydrogen atom, fluorine, chlorine or bromine and R2 is a hydrogen atom.

The compounds (I) of the invention can be, for example, prepared by reduction of the compounds of general formula (II) / h (II) 2

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in which - R 'and R_ - have the meanings mentioned 1.2 · above. . ''

The compounds (II) · have already been described in the literature * in particular by TABORSKY R.G. et al., J. Med. Chem. 7 (2), 135-41 (1964), by HAHN G. et al., Ber. 71B, 2163-75 (1938), in French patent 2,434,165 and by the Applicant in

The process of the invention consists in the reduction of the compounds (II) according to a conventional method, for example by treatment of the compound (II) using a hydride, such as the double hydride of lithium and aluminum , in the presence of a Lewis acid, such as aluminum chloride.

The reaction is carried out at one. temperature ranging from - 40 to, + '30 ° C, in a solvent, such as anhydrous ether.

The following examples illustrate the present invention.

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

3 a j * * t EXAMPLE 1 Hexahydro-2,3,3a, 4,5,6 lH-indolo [3,2, l-de] [naphthyridine-1,53 and its methane sulfonate.

- 5.4 g (0.04 mole) of aluminum chloride are placed in a three-liter three-necked flask. 50 ml of ether are added in a single jet

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anhydrous. 2.3 g "(0.06 mole) of lithium aluminum hydride are gradually added to the solution obtained. The suspension obtained is stirred for 10 minutes. A suspension of 5.3 g (0.02 mole) 1,2,3,3a, 4,5,6H hexahydro hydrochloride-indolo [3,2,1-de] [naphthyridine-1,5} -one- 6 in 70 ml of anhydrous tetrahydrofuran, stirred at room temperature for 30 minutes, then cooled in an ice bath and 10 ml of water are added slowly.

The mixture is stirred for 10 minutes and then 10 ml of sodium hydroxide solution (d = 1.38), 150 ml of ethyl acetate and 100 ml of water are successively added. The mixture is stirred for 15 minutes. The organic phase is decanted.

The aqueous phase is extracted with 2 times 60 ml of ethyl acetate. The combined organic extracts are washed with water, dried over sodium sulfate and evaporated in a water bath under vacuum. An oil is obtained which is dried by azeotropic entrainment with toluene. The base obtained is pure in c.c.m. This oil is dissolved in 80 ml of anhydrous lefher. A solution of 2 g (0.02 mole) of methane sulfonic acid in 20 ml of ethanol is added.

We aqite 30 minutes at room temperature. The white precipitate obtained is filtered. It is washed with ether and dried in. * desiccator.

The salt is recrystallized from 80 ml of ethanol.

jL ·. F = 246-248 ° C

f * (f 4 '“<EXAMPLE 2 Chloro-10-hexahydro-2,3,3a, 4,5,6 lH-indolo [3,2,1- de] [naphthÿridine-1,5] and its methane sulfonate .

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2.25 g (0.0168 mol) of anhydrous aluminum chloride, 25 ml of anhydrous ether and f are placed in a 500 cm three-necked flask. 0.96 g (0.0252 mole) of double lithium aluminum hydride. To this suspension is added with stirring a suspension of 2.5 g (0.0084 mole) of chloro-10-hexahydrp-l, 2,3,3a, 4,5 oH-indolof3,2,1-de ] [naphthyridium-1,5] -one-6 in 60 ml of anhydrous tetrahydrofuran. At the end of the introduction, a gray solution is obtained and the mixture is stirred for half an hour. We control by c.c.m. the complete disappearance of the starting product.

The complex is destroyed by the slow addition of 5 ml of water and then with 15 ml of sodium hydroxide solution (d = 1.38). The medium is diluted with 150 ml of water and then extracted 3 times with 70 ml of acetate. The extract is washed with water and then dried over sodium sulfate. We filter. To the filtrate is added 0.9 g (0.0093 mole) of methanesulfonic acid in solution in 2 ml of ethyl acetate.

The precipitate formed is drained. It is recrystallized from approximately 50 ml of methanol in the presence of bleaching black. Filtered while hot. The filtrate leaves crystals. We wring and dry.

Mp 275-278 ° C.

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The following table shows the compounds of the invention which have been prepared by way of examples according to the method described above.

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• BOARD

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Based

Compound R_ or F (° C) salt 1 (ex.l) 'H H m.s. 246 - 248: 2 CH -10 H base 122-3 3 CH O- · ^ ® H m.s. 248-250 3 4 F — 10 H HCl> 300 5 (ex. 2) Cl-10 H base 142-3 m.s. 275-8 6 H CH3 m.s. > 260 7 Cl-9 H m.s. 251 - 253 - -------- 8 Br-10 H m.s. 265 '. .9. CH, 0-9. H m.s., 214-6 / 1 —........ ~ 3 — J --— i -> - 1 6-

The compounds of the invention have been the subject of a pharmacological study.

1. TOXICITY

The lethal dose 50 (LD 50) of the compounds is determined in "CD1 strain mice by graphical method. The LD 50 is from 1 to 500 mg / kg i.p.

2. HYPOXIA HYPOBAKE

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CD1 strain mice are maintained in an oxygen-depleted atmosphere, by carrying out 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 capable of promoting tissue and in particular cerebral oxygenation. The test compounds are administered, in several doses, intraperitoneally, 10 minutes before the test. The percentages of increase in survival time compared to the values obtained in the control animals are calculated. The average active dose (AMD), which increases the survival time by 100%, is determined graphically. The AMD is 10 to 15 mg / kg.

Z. ACTION ON THE DURATION OF "SLEEP" INDUCED BY SODIUM 4-HYDROXY-BUTYRATE.

This action was determined by the influence of a compound.

* ’Over the duration of the“ sleep ”induced by sodium 4-hydroxy-butyrate (GHB) in the curarisë rat.

• The animals used are male rats of Charles River strain of 200 + 20 g. Animals curarized with allofêrine at a rate of 1 mg / kg i.p. are placed under artificial respiration using a mask applied to the muzzle (respiratory rate = 50 / minute: respiratory volume: 14 cm3).

The esophagus is previously ligated to prevent entry / air into the stomach. v 7 "· 'f

Front-parietal and occipital cortical electrodes allow the recording of electrocorticographic activity on a Grass model 79 P polygraph - at a speed of 6mm / sec.

The preparation of the animal is carried out under local anesthesia (xylocaine 2%). The rats are maintained throughout the experiment at constant temperature (37/5 ° C) · · Ten * minutes after the end of the preparation of the rat, a dose of 200 mg / kg of 4-hydroxy-butyrate sodium is injected intravenously into the tail.

A dose of .10 mg / kg of the compound to be studied is administered intraperitoneally 3 minutes after the administration of sodium 4-hydroxy-butyrate.

. = "The tracks are evaluated by a 15-minute period for 75 minutes after the injection of" GHB ". During this analysis period, the total duration of" sleep "is determined. A series of 15 controls allows 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 "sleep" is 25 §. · 40%.

t The pharmacological study of the compounds of the invention shows that they are active in the test of hypobaric hypoxia in mice while being only slightly toxic and that they exert a significant awakening action in the test of "sleep" induced by sodium 4-hydroxybutyrate.

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The compounds of the invention having an antianoxic activity and a psychotropic activity can be used in therapy • for the treatment of disorders of alertness, in particular •: for combating behavioral disorders attributable to cerebrovascular damage and to the cerebral sclerosis in. geriatrics, as well as for the treatment of absences due to head trauma, for the treatment of metabolic ‘encephalopathies ·· *, and for the treatment of depressive states.

The invention therefore includes all pharmaceutical compositions containing the compounds and / or their salts as active ingredients, in combination with any excipients suitable for their administration, in particular by oral or parenteral route.

. The routes of administration can be the oral and parenteral routes.

The daily dosage can range from 10 to 100 mg.

The dosage units can therefore be dosed, for example, from 2 to 50 mg of active substance associated with excipients - usual, and can be in the form of tablets, dragees, capsules, suspensions or oral or injectable solutions, etc.

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Claims (14)

9 ">" 1. Derivatives of hexahydro-2,3,3a, 4,5,6 lH-indolo [3,2,1-de] Jnaphtyridine-1,5] / in the form of racemates or enantiomers, responding to the formula (I) "'ν-οΦ; in which. f R1 is in position 9 or 10 and represents a hydrogen atom, u: halogen atom or an alkyl or alkoxy radical. *" R2 represents an atom hydrogen or an alkyl radical, as well as their pharmaceutically acceptable addition salts with acids. 2. Derivatives according to claim 1, in which R ^ represents a hydrogen or halogen atom, or an alkyl or alkoxy radical, and R ^ represents an alkyl radical. 3. Derivatives according to claim 1, in which represents a halogen atom or an alkyl or alkoxy radical, and R ^ represents a hydrogen atom or a radical - .c1_4 alkyl. 4. Derivatives according to claim 1, in which R ^ represents a hydrogen, chlorine, bromine or fluorine atom, or the methyl or methoxy radical, and. R2 represents a hydrogen atom or the methyl radical. 5. Hexahydro-2,3,3a, 4,5,6 lH-indolo [3,2,1-de] [naphthyridine- / 1,5] and -its pharmaceutically acceptable salts. 10 •, 6. Chloro-10 hexahydro-2,3,3a, 4,5,6, 1H-indolo [3,2,1-deJ [naphthyridine-1,5] and its pharmaceutically acceptable salts. 7. Fluoro-10 hexahydro-2,3,3a, 4,5,6 lH-indolo f ~ 3,2,1-de] £ naphthyridine-1,5] and its pharmaceutically acceptable salts. (( 8. Bromo-10 hexahydro-2,3,3a, 4,5,6, 1H-indolo j ^ 3,2,1-deJ [* naphthyridine-1,5d and its pharmaceutically acceptable salts. * 9. A process for preparing the compounds according to claim 1, a process characterized in that a compound (II) of the form r 1 v (ii) is reduced in which and R2 have the meanings given in claim 1. 10. A method of preparation according to claim 9, characterized .in that is used for reduction a hydride in the presence of a Lewis acid. '11. Medicament characterized in that it contains a compound as specified in any one of claims 1 to 8. s; 12. Pharmaceutical composition characterized in that it contains a compound as specified in any one of claims 1 to 8 in combination with any suitable excipient. 13. Pharmaceutical composition characterized in that it contains the compound specified in claim 5. • I ‘î - 14. Pharmaceutical composition characterized in that it / f / \ contains the compound specified in claim 6, 7 or 8., Γ tumv Λ