FR2806723A1 - 8-OXO-5,8-DIHYDRO-6H-DIBENZO [α, g] QUINOLIZINE-13-PROPANOIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE - Google Patents

Abstract

Compounds of general formula (I) (CF DRAWING IN BOPI) in which X represents a hydrogen or halogen atom or an alkyl, alkoxy or trifluoromethyl group, and R represents either a hydrogen atom or an alkyl, cycloalkylmethyl group , phenylmethyl, or a group of general formula -CO-NR1 R2 in which R1 and R2 each represent a hydrogen atom or an alkyl group, or represent together, with the nitrogen atom which carries them, a morpholinyl ring or piperidinyl, or else a group of general formula -CO-R3, in which R3 represents an alkyl group. Application in therapy.

Description

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Derivatives of 8-oxo-5,8-dihydro-6H-dibenzo [a, g] quinolizine-13-propanoic acid, their preparation and their therapeutic application.

dans laquelle X représente un atome d'hydrogène ou d'halogène ou un groupe

(C1~C3) alkyle, (C1~C3) alcoxy ou trifluorométhyle, et R représente - un atome d'hydrogène ou un groupe (C1-C4) alkyle, (C3-C5) cycloalkylméthyle, phénylméthyle, - un groupe de formule générale -CO-NR1R2 dans laquelle R1 et R2, indépendamment l'un de l'autre, représentent chacun un atome d'hydrogène ou un groupe (C1-C4)alkyle, ou bien représentent ensemble, et avec l'atome d'azote qui les porte, un cycle morpholinyle ou pipéridinyle, ou bien - un groupe de formule générale -CO-R3, dans laquelle R3 représente un groupe (C1-C4)alkyle. The subject of the present invention is compounds of general formula (I)

wherein X represents a hydrogen or halogen atom or a group

(C1-C3) alkyl, (C1-C3) alkoxy or trifluoromethyl, and R represents - a hydrogen atom or a (C1-C4) alkyl, (C3-C5) cycloalkylmethyl, phenylmethyl group - a group of general formula -CO-NR1R2 wherein R1 and R2, independently of each other, each represents a hydrogen atom or a (C1-C4) alkyl group, or together represent, and with the nitrogen atom which gate, a morpholinyl or piperidinyl ring, or a group of the general formula -CO-R3, wherein R3 represents a (C1-C4) alkyl group.

The preferred compounds of the invention are those in the formula of which X is in the 10 position and is methyl or trifluoromethyl and R is alkyl, particularly methyl.

According to the invention, the compounds of general formula (I) can be prepared according to a process illustrated by the following scheme.

A dibenzoquinolizine derivative of general formula (II), in which X is as defined above, is reacted,

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 with boron tribromide, in a chlorinated solvent, for example dichloromethane, at a temperature of -70 to +25 C.

A phenol derivative of general formula (III), which is reacted with trifluoromethanesulphonic anhydride, is obtained in a chlorinated solvent, for example dichloromethane, in the presence of a base, for example pyridine, at a temperature of 0 to +25 C.

On obtient un dérivé de formule générale (IV) qu'on soumet à un couplage au palladium(O) avec l'acétate de palladium, par exemple en présence d'oxyde de carbone, d'une base, par Diagram

A derivative of general formula (IV) is obtained which is subjected to a palladium (O) coupling with palladium acetate, for example in the presence of carbon monoxide, of a base, by

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 triethylamine, in a mixture of protic solvents, for example N, N-dimethylformamide and methanol, and in the presence of a catalytic amount of 1,1'-bis (diphenylphosphino) ferrocene, to obtain the derivative of general formula (V).

The latter is reduced by a hydride, for example sodium borohydride, in an ethereal solvent, for example tetrahydrofuran, in the presence of methanol, to obtain the alcohol of general formula (Ia), which corresponds to the compounds of the invention. when R represents a hydrogen atom.

In order to prepare the compounds of the general formula (I) in which R represents an alkyl, cycloalkylmethyl or phenylmethyl group, the alcohol of the general formula (Ia) is reacted with a halide of the general formula R-Hal, in which Hal represents an atom halogen, in the presence of a base, for example sodium hydride, in an ethereal solvent such as tetrahydrofuran.

In order to prepare the compounds of the general formula (I) in which R represents a group of the general formula -CO-N (CH 3) 2, the alcohol of the general formula (la) is deprotonated with a base, for example sodium hydride in a polar solvent, for example N, N-dimethylformamide, and the resulting compound is reacted with N, N-dimethylcarbamoyl chloride.

Finally, and generally, to prepare the compounds of general formula (I) in which R represents a group of general formula -CO-NR1R2, the alcohol of general formula (la) is reacted with phenylmethyl chloroformate, in the presence of a base, for example pyridine, in a chlorinated solvent, for example dichloromethane, and finally an amine of general formula HNR: R 2 is added, in which R 1 and R 2 are as defined above.

To prepare the compounds of general formula (I) in

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 where X represents a methyl group, a compound of general formula (I) in which X represents a trifluoromethyl group can be treated with a reducing agent such as triethylsilane in the presence of aluminum chloride, in a chlorinated solvent such as dichloromethane, at a temperature of 0 to 30 C.

In order to prepare the compounds of the general formula (I) in which X represents a (C 1 -C 3) alkoxy group, a derivative analogous to the compound of the general formula (IV) is used, with an iodo group instead of the trifluorosulfonyloxy group. This iodinated derivative can itself be prepared by a method analogous to that described in patent application EP-0719776.

The starting compounds of general formula (II) can be prepared by methods analogous to those described in this same patent application EP-0719776.

The compounds of general formula (V) are new and form part of the invention.

The examples which follow illustrate the preparation of some compounds according to the invention. The elemental microanalyses and the I.R. and R.M.N. spectra confirm the structures of the compounds obtained.

The numbers indicated in parentheses in the titles of the examples correspond to those in the 1st column of Table 1 given below.

In the compound names, the dash "-" is part of the word, and the dash "~" is only used for the cut at the end of the line; it must be deleted in the absence of a cut, and must not be replaced by a normal dash or a space.

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Example 1 (Compound N1).

2-Hydroxymethyl-N-methyl-8-oxo-10- (trifluoromethyl) -5,8dihydro-6H-dibenzo [a, g] quinolizine-13-propanamide.

1.1 2-Hydroxy-N-methyl-8-oxo-10- (trifluoromethyl) -5,8-dihydro-6-H-dibenzo [a, g] quinolizine-13-propanamide.

In a two-necked flask of 2 l, a solution of 15 g (35 mmol) of 2-methoxy-N-methyl-8-oxo-10- (trifluoro-methyl) -5,8-dihydro-6H-dibenzo [a , g] quinolizine-13-propanamide in 750 ml of dichloromethane, cooled to -70 ° C., and 100 ml (100 mmol) of a 1 N solution of boron tribromide in dichloromethane are added dropwise. At the end of the addition the mixture is allowed to rise to room temperature and the stirring is maintained for 4 hours.

The mixture is hydrolyzed by addition of water, the precipitate obtained is collected by filtration, washed with water and then with diethyl ether and dried under reduced pressure.

15 g of compound are isolated in the form of a white solid.

Melting point: 271-274C.

1. 2. Methyl- [3- (methylamino) -3-oxopropyl] -8-oxo-10- (trifluoromethyl) -5,8-dihydro-6H-dibenzo- [a, g] quinolizin-2-yl trifluoromethanesulfonate .

A solution of 22.6 g (53.9 mmol) of 2-hydroxy-N-methyl-8-oxo-10- (trifluoromethyl) -5,8-dihydro-6-H is introduced into a 3-necked flask. -dibenzo [a, g] quinolizine-13propanamide dissolved in 400 ml of dichloromethane, 26 ml (336 mmol) of pyridine are added and the mixture is cooled to 0 ° C. with an ice bath. 13.6 ml (80.84 mmol) of trifluoromethanesulfonic anhydride are added dropwise, the ice bath is removed and stirring is maintained for 4 hours at room temperature.

The mixture is hydrolyzed by adding water and then 1 N hydrochloric acid, the insoluble material is collected by filtration, the filtrate is extracted with dichloromethane, the organic phase is dried over sodium sulphate, filtered and the mixture is evaporated. solvent under reduced pressure. A residue is isolated which is combined with the insoluble material collected during the first filtration, the whole is taken up with ethyl ether, and

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 the solid is collected by filtration. 23.8 g (43.34 mmol) of compound are obtained in the form of a white solid.

Melting point: 236-237 ° C.

1,13- [3- (Methylamino) -3-oxopropyl] -8-oxo-10-trifluoro-methyl) -5,8-dihydro-6-H-dibenzo- [a, g] quinolizine-2- methyl carboxylate.

6.2 g (11.3 mmol) of 13- [3- (methylamino) -3-oxopropyl] -8-oxo-10- (trifluoromethyl) -5,8-trifluoromethanesulphonate are introduced into a 250 ml flask. dihydro-6H-dibenzo [a, g] quinolizin-2-yl in solution in 50 ml of N, N-dimethylformamide and 9.2 ml of methanol, and 0.38 g (0.68 mmol) are then introduced successively. ) of 1,1'-bis (diphenylphosphino) ferrocene, 0.076 g (0.34 mmol) of palladium acetate and 3.2 ml (22.6 mmol) of triethylamine. The flask is purged with carbon monoxide, and the mixture is then stirred for 4 hours at room temperature under a carbon monoxide atmosphere.

The mixture is hydrolyzed with water and extracted several times with ethyl acetate. The organic phases are combined, dried over sodium sulphate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 7/3 mixture of sodium acetate. ethyl and cyclohexane.

4.9 g of ester are obtained in the form of a white solid.

Melting point: 246-248C.

1. 4. 2-Hydroxymethyl-N-methyl-8-oxo-10- (trifluoromethyl) -
5,8-dihydro-6H-dibenzo [a, g] quinolizine-13-propanamide.

7.2 g (15.7 mmol) of 13- [3- (methylamino) -3-oxopropyl] -8-oxo-10-trifluoromethyl) -5,8, dihydro- Methyl 6-H-dibenzo- [a, g] quinolizine-2-carboxylate in 12.7 ml of methanol and 100 ml of tetrahydrofuran, 11.84 g (314 mmol) of sodium borohydride are added in small portions. and the mixture is refluxed for 12 hours.

It is cooled to room temperature, the excess hydride is destroyed by addition of water and acetic acid, and the mixture is extracted several times with ethyl acetate.

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The organic phases are combined, dried over sodium sulfate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with ethyl acetate.

5.5 g of compound are obtained in the form of a white solid.

Melting point: 186-189 C.

Example 2 (Compound N 5).

2-Methoxymethyl-N-methyl-8-oxo-10- (trifluoromethyl) -5,8-dihydro-6H-dibenzo [a, g] quinolizine-13-propanamide.

10-(trifluorométhyl)-5,8-dihydro-6H-dibenzo[a,g)quinolizine- 13-propanamide en solution dans 15 ml de tétrahydrofurane, on ajoute 0,135 g (3,4 mmoles) d'hydrure de sodium à 60% dans de l'huile, on agite le mélange pendant 30 min à température ambiante, on ajoute 0,21 ml (3,4 mmoles) d'iodométhane et on maintient l'agitation à température ambiante pendant 12 h. In a two-necked flask of 50 ml, under a nitrogen atmosphere, 1.2 g (2.79 mmol) of 2-hydroxymethyl-N-methyl-8-oxo

10- (trifluoromethyl) -5,8-dihydro-6H-dibenzo [a, g) quinolizine-13-propanamide dissolved in 15 ml of tetrahydrofuran, 0.135 g (3.4 mmol) of sodium hydride at 60.degree. % in oil, the mixture is stirred for 30 min at room temperature, 0.21 ml (3.4 mmol) of iodomethane is added and stirring is maintained at room temperature for 12 h.

The mixture is hydrolyzed by addition of water and hydrochloric acid, and the mixture is extracted several times with ethyl acetate. The organic phases are combined, dried over sodium sulphate, filtered, the solvent is evaporated under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with a 9/1 mixture of sodium acetate. ethyl and cyclohexane, followed by a 95/5 mixture of ethyl acetate and methanol.

After recrystallization from ethyl acetate, 0.5 g of compound is obtained.

Melting point: 212-213C.

Example 3 (Compound N 9).

N-methyl-2- (propoxymethyl) -8-oxo-10- (trifluoromethyl) -5,8-dihydro-6H-dibenzo [a, g] quinolizine-13-propanamide.

In a 25 ml flask under a nitrogen atmosphere, 60 mg (1.58 mmol) of 60% sodium hydride in oil is placed, washed with pentane, suspended in 3 ml of N, N-dimethylformamide is added, in fractions,

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 0.5 g (1.16 mmol) of 2-hydroxymethyl-N-methyl-8-oxo-10- (trifluoromethyl) -5,8-dihydro-6H-dibenzo [a, g] quinolizine-13-propanamide and the mixture is stirred at room temperature for 30 minutes.

0.255 g (1.5 mmol) of 1-iodopropane is added and stirring is continued at room temperature for 12 hours.

The mixture is hydrolyzed by addition of water and hydrochloric acid, and the mixture is extracted several times with ethyl acetate. The organic phases are combined, dried over sodium sulfate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with ethyl acetate.

After recrystallization from a mixture of ethyl acetate and cyclohexane, 0.21 g of compound is obtained.

Melting point: 187-189 C.

Example 4 (Compound N 17).

10-(trifluorométhyl)-5,8-dihydro-6H-dibenzo[a,g]quinolizin-2- yl]méthyle. [13- [3- (methylamino) -3-oxopropyl] -8-oxo dimethylcarbamate

10- (trifluoromethyl) -5,8-dihydro-6H-dibenzo [a, g] quinolizin-2-yl] methyl.

10-(trifluorométhyl)-5,8-dihydro-6H-dibenzo[a,g]quinolizine- 13-propanamide en solution dans 3 ml de N,N-diméthylformamide, on agite le mélange à température ambiante pendant 10 min, on ajoute 0,164 g (1,53 mmoles) de chlorure de diméthylcarbamoyle et on poursuit l'agitation à température ambiante pendant 2 h. In a 25 ml three-necked flask under a nitrogen atmosphere, 0.062 g (1.53 mmol) of sodium hydride are placed and washed with tetrahydrofuran, a solution of 0.55 g (1.27 g) is added. moles) of 2-hydroxymethyl-N-methyl-8-oxo

10- (trifluoromethyl) -5,8-dihydro-6H-dibenzo [a, g] quinolizine-13-propanamide dissolved in 3 ml of N, N-dimethylformamide, the mixture is stirred at room temperature for 10 minutes, added 0.164 g (1.53 mmol) dimethylcarbamoyl chloride and stirring was continued at room temperature for 2 h.

The excess hydride is hydrolyzed by the addition of water and hydrochloric acid, ethyl acetate is added, the insoluble material is collected by filtration, and the filtrate is extracted several times with sodium acetate. 'ethyl. The organic phases are combined, dried over sodium sulphate, filtered and the solvent is evaporated under reduced pressure. The residue is taken up with ethyl ether and collected

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 by filtration, the two insoluble fractions are combined and recrystallized from ethyl acetate with a few ml of methanol.

0.214 g of compound is obtained in the form of a white solid.

Melting point: 207-210 C.

Example 5 (Compound N 21).

[13- [3- (Methylamino) -3-oxopropyl] -8-oxo-10- (trifluoromethyl) -5,8-dihydro-6H-dibenzo [a, g] quinolizin-2-yl Morpholine-4-carboxylate ]methyl.

In a 50 ml flask, under a nitrogen atmosphere, a solution of 0.4 g (0.93 mmol) of 2-hydroxymethyl-N-methyl-8-oxo-10- (trifluoromethyl) -5,8-dihydro is placed 6 H -dibenzo [a, g] quinolizine-13-propanamide in 5 ml of dichloromethane, 0.132 g (1.67 mmol) of pyridine and 0.25 g (1.58 mmol) of benzoyl chloride are added successively, and the mixture is stirred mixing at room temperature for 1 h.

1.74 g (20 mmol) of morpholine are added and stirring is continued at room temperature for 3 h.

The mixture is hydrolyzed by addition of water and hydrochloric acid, and the mixture is extracted several times with dichloromethane. The organic phases are combined, dried over sodium sulphate, filtered, the solvent is evaporated off under reduced pressure and the residue is purified by chromatography on a column of silica gel, eluting with 95/5 of ethyl acetate. and methanol.

After recrystallization from ethyl acetate with a few ml of methanol, 0.26 g of compound is obtained in the form of a white solid.

Melting point: 235-237 ° C.

Table 1 which follows illustrates the chemical structures and the physical properties of some compounds of the invention.

In the "R" column of this table, "NC5H10" refers to a piperidin-1-yl group and "NC4H8O" refers to a morpholin-1-yl group. Table 2 which follows also illustrates some intermediate compounds of general formula (V).

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Table 1

<Tb>
<tb> N <SEP> X <SEP> R <SEP> F <SEP> (C)
<Tb>
<tb> 1 <SEP> 10-CF3 <SEP> H <SEP> 186-189
<tb> 2 <SEP> 10-CH3 <SEP> H <SEP> 205-207
<tb> 3 <SEP>'<SEP> 10-OCH3 <SEP> H <SEP> 219-221
<tb> 4 <SEP> H <SEP> CH3 <SEP> 138-140
<tb> 5 <SEP> 10-CF3 <SEP> CH3 <SEP> 212-213
<tb> 6 <SEP>;<SEP> 10-CH3 <SEP> CH3 <SEP> 149-151
<Tb>
<tb> 7 <SEP> 10-CF3 <SEP> CH2CH3 <SEP> 195-197
<tb> 8 <SEP> H <SEP> (CH2) 2CH3 <SEP> 117-119
<tb> 9 <SEP> 10-CF3 <SEP> (CH2) 2CH3 <SEP> 187-189
<tb> 10 <SEP> 10-CH3 <SEP> (CH2) 2CH3 <SEP> 130-132
<tb> 11 <SEP> 10-Ci <SEP> (CH2) 2CH3 <SEP> 138-140
<Tb>

12 10-CF3 CH2CC3H~5 161-163

12 10-CF3 CH2CC3H ~ 5 161-163

<Tb>
<tb> 13 <SEP> 10-CF3 <SEP> CH2C6H5 <SEP> 170-172
<tb> 14 <SEP> 10-CF3 <SEP> COCH3 <SEP> 212-214
<tb> 15, <SEP> 10-CF3 <SEP> CONHCH3 <SEP> 229-232
<tb> 16 <SEP> 10-CH3 <SEP> CONHCH3 <SEP> 190-192
<tb> 17 <SEP> 10-CF3 <SEP> CON <SEP> (CH3) <SEP> 207-210
<tb> 18 <SEP> 10-CH3 <SEP> CON (CH3) 2 <SEP> 191-193
<Tb>
<tb> 19 <SEP> 10-CF3 <SEP> CONC5H10 <SEP> 162-164
<tb> 20 <SEP> 10-CH3 <SEP> CONC5H10 <SEP> 194-196
<tb> 21 <SEP> 10-CF3 <SEP> CONC4H8O <SEP> 235-237
<tb> 22 <SEP> 10-CH3 <SEP> CONC4H8O <SEP> 206-207
<Tb>

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Table 2

<Tb>
<tb> N <SEP> X <SEP> F <SEP> (C)
<tb> 1 <SEP> 10-CF3 <SEP> 246-248
<tb> 2 <SEP> 10-OCH3 <SEP> 117-119
<tb> 3 <SEP> 10-Ci <SEP> 211-212
<Tb>

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 The compounds of the invention have been subjected to tests which have demonstrated their interest as substances with therapeutic activities.

Thus, unlike the dibenzoquinolizine derivatives known and described in the patent application EP-0719776 as selective ligands # 5 vs # 1 and # 2, the compounds of the invention are selective functional # 2 and / or # 3 agonists vs cal that is to say that they have a selectivity for the subtypes # 2 and / or # 3 in terms of intrinsic activity demonstrated by the so-called "patch clamp" technique.

Evaluation of the functional selectivity by the so-called "patch clamp" method.

recombinants a=3YL, 5P2Y2 et a332Yz Transfection des cellules HEK 293 : les vecteurs d'expression pCDM8 contenat les ADN codant pour les sous-unités [alpha]1, [alpha]3, [alpha]5, ss2 et Y2 sont préparés individuellement après amplification dans les bactéries E. Coli, puis sont précipités par la méthode de précipitation au phosphate de calcium à la surface des cellules rénales en culture HEK 293 à demi-confluence (Faure-Halley et coll., Eur. J. Pharmacol. (1993) 246 286-287). Les vecteurs d'expression sont mélangés dans un rapport 1/4/0,2 pour [alpha]x, ss2 et Y2 respectivement. Les cellules sont incubées pendant 24 h puis prélévées pour les expériences de patch-clamp. 1. Human renal embryonic cells (transfected HEK 293 expressing GABAA receptor subtypes

recombinants a = 3YL, 5P2Y2 and a332Yz Transfection of HEK 293 cells: pCDM8 expression vectors containing the DNAs coding for the [alpha] 1, [alpha] 3, [alpha] 5, ss2 and Y2 subunits are prepared individually after amplification in E. coli bacteria, and then precipitated by the calcium phosphate precipitation method on the surface of renal cells in half-confluent HEK 293 culture (Faure-Halley et al., Eur J. Pharmacol. 1993) 246-286-287). The expression vectors are mixed in a 1/4 / 0.2 ratio for [alpha] x, ss2 and Y2 respectively. The cells are incubated for 24 h and then sampled for patch-clamp experiments.

2. Primary cultures of raccoon spinal cord dorsal root ganglion expressing the native GABAA receptor subtype [alpha] 2ssx [gamma] y.

The primary dorsal root ganglion culture is made from 1-day old rat spinal cord.

After dissection of the spine, 10 to 15 ganglia are extracted. After trypsination, the cells of these ganglia are dissociated by a trituration managed using a Pasteur pipette lapped. The cells are then

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 suspended in a basic Eagle culture medium containing 10% fetal calf serum, 25 mM potassium chloride, 2 mM glutamine, 100 μg / ml gentamicin and 50 ng / ml NGF (nerve growth factor, or nerve growth factor). Aliquots containing approximately 0.25 # 10 6 cells are deposited on glass slides previously coated with lamimine and placed in 12-well Corning plates. The cells are incubated at 37 ° C. in a humidified atmosphere containing 5% of CO2 and 95% of air. 48 h after seeding, 1 μM of cytosine-D-arabinoside is added to each well to prevent proliferation of non-neuronal cells. After 7 to 10 days of culture, the slides are transferred to the measurement chamber for patch-clamp experiments.

3. Electrophysiology.

The "whole cell" patch-clamp method described by Hamill et al. (Pfluegers Archives (1981) 391 85-100) with an intrapipette medium containing cesium chloride to block potassium currents and buffered with Ca2 + (pCa = 10-αM, pH = 7.2). Since the potential of the cells is set at -20 mV, the application of GABA at the concentration of 1 μM causes an inward current carried by the Cl- ions whose amplitude can be modulated by the compounds studied. The effects of the compounds are evaluated by the ratio between the GABA-dependent current observed in the presence of the test compound and the current observed in the presence of GABA alone.

It is thus observed that the compounds of the invention increase the GABA-induced chloride current at concentrations of 0.1 to 10 μM, but in a different manner depending on the subunits.

Compounds of the invention are complete agonists on native [alpha] 2ss2 [gamma] y GABAA receptor subtypes or on recombinant native [alpha] 3ss2 [gamma] 2 GABAA receptor subtypes and partial agonists on recombinant GABAA receptor subtypes [alpha] 1ss2 [gamma] 2.

In other words, the compounds of the invention are α 2 and / or α 3 agonists selective for [alpha] 1 in terms of functional activity.

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 Study of membrane bonds vis-à-vis a population of modulator sites # 1, # 2, # 5.

Using the experimental protocols described in the patent application EP-0719776, in the study of membrane bonds with respect to modulator sites # 1 (benzodiazepine type I) associated with GABAA receptors containing the subunits [alpha] 1, it is determined that the most active compounds of the invention have an IC50 of 0.6 to 10 nM.

In the study of membrane bonds with respect to the modulator sites # 2 (benzodiazepine type II) associated with the GABAA receptors containing mainly the α2 and α3 subunits, it is determined that the most active compounds of the invention have an IC50 of 0.8 to 10 nM. Finally, in the study of membrane bonds with respect to modulator sites # 5 (benzodiazepines associated with GABAA receptors containing the? Subunit), it is determined that the most active compounds of the invention have an IC 50 value of 0. , 8 to 10 nM.

[Membrane binding of [3H] flumazenil to stable transfected cells expressing recombinant [alpha] 3ss2 [gamma] 2 receptor.

Using the experimental protocol described in the patent application EP-0719776, in the study of the [3 H] flumazenil membrane bonds with respect to the stable transfected cells expressing the recombinant [alpha] 3ss2 [gamma] 2 receptor, it is determined that the IC 50's of the most active compounds range from 4 to 40 nM.

Thus, the compounds of the invention have an equivalent affinity for the different sub-types of receptors studied, but an intrinsic differentiated activity, since they are complete agonists a2 and / or a3 and partial agonists [alpha] 1, and their functional activities give them particular properties.

The results of these tests performed on the compounds of the invention suggest that they can be used in the treatment of disorders related to disorders of the

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 GABAergic transmission of GABAA receptors associated with [alpha] 2 and / or [alpha] 3 subunits such as anxiety, epilepsy, spasticity and muscle contractures, without the sedative effects associated with the subunit [alpha ] 1.

Therefore, the present invention also relates to pharmaceutical compositions containing an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable solvate, and mixed, where appropriate, with suitable excipients.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

The pharmaceutical compositions according to the invention can thus be intended for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal, rectal, intraocular administration.

The unit dosage forms may be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches, suppositories. For topical administration we can consider ointments, lotions and eye drops.

Said unit forms are dosed to allow a daily administration of 0.001 to 20 mg of active ingredient per kg of body weight, according to the dosage form.

In order to prepare tablets, a pharmaceutical carrier which may be composed of diluents, for example lactose, microcrystalline cellulose or starch, and formulation adjuvants such as binders, polyvinylpyrrolidone, is added to the active ingredient, which may or may not be micronized. hydroxypropyl methylcellulose, etc.), flow agents such as silica, lubricants such as magnesium stearate, stearic acid, glycerol tribehenate, sodium stearyl fumarate. Wetting agents or surfactants such as sodium lauryl sulphate may also be added.

The realization techniques can be compression

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 direct, dry granulation, wet granulation or hot melt.

The tablets may be bare, sugar-coated, for example with sucrose, or coated with various polymers or other suitable materials. It can be designed to allow rapid, delayed or sustained release of the active ingredient through polymer matrices or specific polymers used in the coating.

To prepare capsules the active ingredient is mixed with dry pharmaceutical vehicles (simple mixing, dry or wet granulation, or hot melting), liquid or semi-solid.

The capsules may be hard or soft, film-coated or not, so as to have a rapid, prolonged or delayed activity (for example for an enteral form).

A composition in the form of syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably acaloric, methylparaben or propylparaben as antiseptic, a flavoring agent and a dye.

Water-dispersible powders and granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or dispersing agents such as polyvinylpyrrolidone, as well as with sweeteners and taste-correcting agents.

For rectal administration, suppositories prepared with binders melting at the rectal temperature, for example cocoa butter or polyethylene glycols, are used.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions containing pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol, are used.

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The active ingredient may also be formulated in the form of microcapsules, optionally with one or more supports or additives, or with a polymer matrix or with a cyclodextrin (transdermal patches, sustained-release forms).

The topical compositions according to the invention comprise a medium compatible with the skin. They may be in the form of aqueous, alcoholic or aqueous-alcoholic solutions, gels, water-in-oil or oil-in-water emulsions having the appearance of a cream or gel, microemulsions, aerosols, or in the form of vesicular dispersions containing ionic and / or nonionic lipids. These galenic forms are prepared according to the usual methods of the fields considered.

The pharmaceutical compositions according to the invention may contain, besides a compound of general formula (I), other active ingredients which may be useful in the treatment of the disorders and diseases indicated above.

The subject of the invention is also the use of a compound of general formula (I) for the preparation of a medicinal product intended for the treatment of disorders related to GABAergic transmission disorders of GABAA receptors, in particular of anxiety, epilepsy, spasticity or muscle contractures.

Finally, the subject of the invention is a method for treating diseases related to disorders of GABAergic transmission of GABAA receptors, in particular of anxiety, epilepsy, spasticity or muscle contractures, a method of administering to patients an effective dose of a compound of general formula (I).

Claims (9)

 (C3-CS) cycloalkylmethyl, phenylmethyl, - a group of general formula -CO-NR1R2 wherein R1 and R2, independently of each other, each represents a hydrogen atom or a (C1-C4) alkyl group or together with the nitrogen atom carrying them, represent a morpholinyl or piperidinyl ring, or a group of the general formula -CO-R3, wherein R3 represents a (C1-C4) alkyl group.

 (C1-C3) alkyl, (C1-C3) alkoxy or trifluoromethyl, and R represents - a hydrogen atom or a (C1-C4) alkyl group,

 wherein X represents a hydrogen or halogen atom or a group

 1. Compound of general formula (I) 2. Compound according to claim 1, characterized in that X is in position 10 and represents a methyl or trifluoromethyl group and R represents an alkyl group. 3. Compound according to claim 2, characterized in that R represents a methyl group. 4. Process for the preparation of a compound according to claim 1, characterized in that a compound of general formula (V) is reduced <Desc / Clms Page number 19>  which corresponds to the compound of general formula (I) when R represents a hydrogen atom, then, if desired, the alcohol of general formula (la) is reacted with a halide of general formula R-Hal, in which Hal represents a halogen atom, in the presence of a base, and then, if it is desired to prepare a compound of general formula (I) in which R represents a group of general formula -CO-N (CH 3) 2, a deprotonation of the alcohol of general formula (la) with a base, then reacting the compound obtained with N, N-dimethylcarbamoyl chloride, and finally, if it is desired to prepare a compound of general formula (I) in which R represents a group of general formula -CO-NR1R2, the alcohol of general formula (la) is reacted with phenylmethyl chloroformate, in the presence of a base, and finally an amine of general formula HNR1R2 is added, in which R1 and R2 are as defined in the dream ndication 1.

 wherein X is as defined in claim 1, to obtain an alcohol of general formula (la)

5. Drug characterized in that it consists of a compound according to one of claims 1 to 3. <Desc / Clms Page number 20> 6. Pharmaceutical composition characterized in that it contains a compound according to one of claims 1 to 3, associated with an excipient. 7. Compound of general formula (V), as defined in claim 4, required as an intermediate in the process according to claim 4. 8. Use of a compound of general formula (I), as defined in claim 1, for the preparation of a medicament for the treatment of diseases related to disorders of GABAergic transmission of GABAA receptors. 9. Use according to claim 8, for the preparation of a medicament for the treatment of anxiety, epilepsy, spasticity or muscle contractures.