FR2580646A1 - 2(1H)-Quinolinone derivatives, their preparation and their application in therapeutics - Google Patents

Abstract

2(1H)-Quinolinone derivatives corresponding to the formula I: in which: - the pyridyl radical is in position 6 or 7 and is bonded via any one of the 2, 3 or 4 positions; - R1 represents a hydrogen atom or a (C1-4)alkyl radical; - R2 represents a hydrogen atom, a hydroxyl or methoxy radical or a halogen atom; R3 and R4 represent either together a double bond or each a hydrogen atom; and - R5 represents a hydrogen atom or a (C1-4)alkyl radical; as well as their addition salts with pharmaceutically acceptable acids. Application in therapeutics.

Description

 The present invention relates to .2 (1H) -quinolinone derivatives, their preparation and their therapeutic application.

dans laquelle . le radical pyridyle est en position 6 ou 7 et se lie par l'une quelconque des positions 2, 3 ou 4 . R1 représente un atome d'hydrogène ou un radical (C1 4)alkyle, . R2 représente un atome d'hydrogène, le radical hydroxy ou méthoxy ou un atome d'halogène, . R3 et R4 représentent soit ensemble une double liaison soit chacun un atome d'hydrogène, et . R5 représente un atome d'hydrogène ou un radical (C1 4)alkyle. The compounds of the invention correspond to formula (I),

in which . the pyridyl radical is in the 6 or 7 position and binds at any of the 2, 3 or 4 positions. R1 represents a hydrogen atom or a (C1 4) alkyl radical, R2 represents a hydrogen atom, the hydroxyl or methoxy radical or a halogen atom, R3 and R4 together represent a double bond or each a hydrogen atom, and. R5 represents a hydrogen atom or a (C1 4) alkyl radical.

The addition salts of compounds (I) with pharmaceutically acceptable acids form part of the invention.

The compounds of the invention may be prepared according to the reaction scheme given in Appendix 1.

In the general scheme (annex 1) the radicals have the following meanings
R is H or the pyridyl radical,
R'2 is H, OCH3 or a halogen atom,
R 'is C6H5, OEt or OH,
R "is C1 or OEt and
R5 is H or (C1-4) alkyl-
The pyridine radical R of the scheme can be introduced by reaction of the pyridine with a diazo compound before or after the cyclization leading to the quinolinone. The reaction of the diazo with pyridine leads to a mixture of separable isomers by chromatography.

The cyclization is carried out by reaction of an aniline substituted with the radical R '2 and optionally with the pyridyl radical with a chloride of 3-ethoxy or 3-phenyl acryloyl optionally substituted by an R 5 alkyl radical followed by the cyclization itself of the intermediate compound obtained.

The hydrogenation of the quinolinone derivative, substituted with R'2 and optionally with R5 and the pyridyl radical, is carried out by the action of hydrogen in the presence of a catalyst such as palladium on carbon, platinum oxide or rhodium on alumina in the presence of a strong acid such as perchloric acid.

The compounds wherein R2 is OH are obtained from compounds wherein R2 is OCH3 by demethylation.

The compounds of formula (I) in which R 2 is H can be obtained either directly from a nitroaniline (see Reaction Scheme 3) or from compounds (I) in which R 2 is OCH 3 by demethylation, mesylation and elimination of the group OSO2CH
The reaction scheme is exemplified in Annexes 2, 3 and 4 by three specific reaction schemes.

Reaction Scheme 2 (Appendix 2) shows the compounds in which R 2 is OCH 3 for which the introduction of the pyridyl radical is carried out before the cyclization.

Reaction Scheme 3 (Appendix 3) describes the preparation of the compounds in which R 2 is H, the cyclization being carried out after the introduction of the pyridyl radical.

Reaction scheme 4 (Annex 4) makes it possible to obtain the compounds in which R 2 is a halogen atom and for which the cylisation is carried out before the introduction of the pyridyl radical.

According to Reaction Scheme 2, given in Annex 2, a compound is reacted. (II) with pyridine in hydrochloric acid in the presence of sodium nitrite, a mixture of isomers (III) is obtained which is separated by chromatography and then each isomer is reacted with nitric acid to give obtaining the nitrated compound (IV) which is reduced to the compound (V), the latter is reacted with the 3-ethoxy-acryloyl chloride and finally the compound (VI) obtained in compound (I) in which R3 is cyclized and R4 represents a double bond and, if desired, allyl and / or hydrogen this compound
According to the reaction scheme 3, given in Annex 3, the compounds (I) in which R 2 is H can be prepared: starting from an already nitrated compound (VII) described in the literature on which the pyridyl radical is grafted, reduced the nitrated compound (VIII) in amine compound (IX), the latter is reacted with 3-ethoxy-acryloyl chloride and the intermediate compound (X) is cyclized to compound (I) which is hydrogenated and / or alkylated eventually.

According to Reaction Scheme 4 given in Annex 4, the compounds (I) in which R 2 is a halogen atom are prepared: cyclization of the quinoline ring is carried out before fixing the pyridyl radical.

For this purpose, a compound (XI) described in the literature is reacted with 3-phenylacryloyl chloride and then the compound (XII) is cyclized to the compound (XIII) which is converted into a nitro compound (XIV). the compound (XIV) to the amino compound (XV) which is diazated by reaction with sodium nitrite in the presence of hydrochloric acid and the compound (XVI) is reacted with pyridine: a mixture of the three isomers is then obtained of position on the pyridyl ring which is separated by chromatography, and is hydrogenated and / or allyl optionally each isomer obtained.

The following examples illustrate the present invention.

Analyzes and IR and NMR spectra confirm the structure of the compounds.

Example 1 8-Methoxy (4-pyridyl) -6 (1H) -quinolinone and its hydrochloride.

1.1. (4-pyridyl) -4-methoxypyraniline.

This compound is prepared from (4-methoxy-4-nitro-4-phenyl) pyridine by reduction.

The 3- (3-methoxy-4-nitro-phenyl) phenyl or 4-pyridines are obtained in a mixture by the method of Haworth et al., J.

Chem. Soc. 1940, p. 352 from 3-methoxy-4-nitroaniline, itself obtained from 4-nitro-3-methoxyacetanilide.

 In a 100 ml flask, 6.9 g of tin chloride hydrate is introduced into 9.2 ml of concentrated hydrochloric acid.

The reaction mixture is stirred, 2.1 g (9.12 mmol) of 4- (3-methoxy-4-nitrophenyl) pyridine and 5 ml of absolute alcohol are added in portions. The mixture is heated at 70 ° C. for 1 hour 30 minutes. The mixture is poured into 200 ml of water. It is basified with 10N sodium hydroxide and extracted with chloroform. The residue is chromatographed on a silica column with 95/5 CH 2 Cl 2 / MeOH as eluent. The amine is obtained.

1.2. Methoxy-8 (pyrdyl-4) -6 (1H) -quinolinone and its hydrochloride.

In a 250 ml flask, 1.25 g (6.25 mmol) of (4-pyridyl) -4-methoxy-aniline are dissolved in 40 ml of tetrahydrofuran (IHF), the mixture is cooled in an ice bath and dropwise, 860 mg (6.4 mmol) of 3-ethoxyacryloyl chloride in 10 ml of THF. The mixture was stirred overnight at room temperature and added water, basified with K2CO3 and extracted with ethyl acetate. The intermediate compound which is cyclized is obtained in a flask of 20 ml is charged with 1.3 g (4.36 mmol) of this compound. It is heated slightly and stirred for 1 h. Pour the mixture into 200 ml of water, alkalize with
K2CO3 and chloroform extract.

The compound is purified by eluting the organic phases on silica (CH 2 Cl 2 95 / MeOH 5). The hydrochloride of the base obtained is prepared by dissolving 600 mg of base in a solution of 6 ml of N hydrochloric acid in 100 ml of water; the precipitate formed is recrystallized from an alcohol / water mixture - mp = 2680 ° C.

Example 2. 8-Hydroxy-3- (pyridyl) -6 (1H) -quinolinone and its hydrochloride.

1.2 g (4.75 mmol) of 8-methoxy (3-pyridyl) -6 (1H) -quinolone in 20 ml of 48% hydrobromic acid are heated at reflux temperature for one night, at the reflux temperature.

Evaporate to dryness. Water is added to the residue and basified with KHCO3. The base (F = 1430C) is obtained which is converted into hydrochloride. F> 22O0C.

Example 3 8-Chloro (2-pyridyl) -6 (1H) -quinolinone, 8-chloro-3- (3-pyridyl) -6 (1H) -quinolinone, 8-chloro-4-pyridyl-6 (1H) quinolinone and their oxalates.

3.1. 2-Chloro-N- (3-naphthol) aniline (XII).

In a 250 ml Erlenmeyer flask, 8.1 g (63.5 mmol) of o-chloroaniline, 60 ml of anhydrous benzene and 5 ml of pyridine are introduced; while cooling with the aid of an ice bath and with magnetic stirring, 10 g (60 mmol) of cinnamoyl chloride dissolved in 50 ml of anhydrous benzene are added dropwise with the aid of a dropping funnel. After addition, the mixture is stirred at room temperature overnight.

Ethyl acetate is added to dissolve the precipitated product.

The benzene solution is washed twice with 75 ml of water and then twice with 75 ml of a normal solution of HCl and twice with a 10% solution of potassium bicarbonate. The benzene phase is dried over MgSO 4 and evaporated. dried up. Compound (XII) is obtained.

3.2. Chloro-8 (1H) -quinolinone (XIII).

In a 2 1 flask, 82.6 g (320 mmol) of the compound (XII) obtained under 3.1 are introduced. and 514 ml of chlorobenzene.

While stirring, 213.8 g (1600 mmol) of AlCl 3 are added portionwise.

The mixture is heated at 1250 ° C. for 3 hours. The contents of the balloon are then slowly poured into ice. Hexane is added and the mixture triturated. Then filtered and washed with hexane precipitate. We dry it. Compound (xIII) is obtained.

3.3. 8-chloro-6-nitro (1H) -quinolinone (XIV).

In a 1 liter flask, 28 g (156 mmol) of the compound obtained under 3.2 are introduced. 146 ml of acetic acid are added and the reaction mixture is stirred. 56.6 ml of 100% HN0 3 are added in portions. The mixture is then heated at reflux temperature for 1 h 30 min. The contents of the flask are cooled and poured into 800 ml of water. It is stirred.

The precipitate is filtered off and washed with twice 150 ml of water and then twice with 150 ml of 5% KHCO 3 and finally with twice 200 ml of water. The compound (XIV) obtained is dried.

3.4. Amino-6-chloro-8 (1H) -quinolinone (XV).

In a flask of 11, 26.96 g (120 mmol) of the nitrated compound (XIV) and 168 ml of methanol are introduced. While stirring, a small solution of 83.9 g
SnCl2, 2H2O in 67.7 ml concentrated HCl (11N). After the addition is complete, the mixture is heated at 600 ° C. for 2 hours 30 minutes, then at 900 ° C. for 2 hours 30 minutes.

The contents of the flask are then poured into an Erlenmeyer flask of 21. 1.2 parts of KHCO 3 at 20% in water are gently added portion by portion. A yellow suspension is collected and stirred with 400 ml of ethyl acetate. The organic phase is decanted and collected. The emulsion is filtered through celite. The filtrate is extracted 4 to 5 times with ethyl acetate. The organic phase is dried Mg5O4, evaporated to dryness and collected the compound which is purified.

3.5. Chloro-8 (2,3-pyridyl or 4) -6 (1H) -quinolinones.

In a 100 ml Erlenmeyer flask, 14.3 ml of concentrated HCl and 10.1 ml of water are introduced. 7.79 g of the compound (XV) obtained under 3.4 are slowly added. while waving. The mixture is heated a little and then cooled in an ice / salt bath. When the temperature of the mixture is between 0 ° C. and 50 ° C., a solution of 2.8 g of NaNO 2 in 7 ml of water is added dropwise while maintaining the temperature between 0 ° C. and 50 ° C.

The diazonium salt in suspension is then added, cold, dropwise to 40 ml of pyridine heated to 80 C.

The mixture is stirred at 800 ° C. for 1 hour.

10.4 ml of ammonia are then added and then evaporated to dryness. The residue is taken up in 100 ml of 10% KHCO 3, extracted with chloroform, filtered through celite, the chloroform phase dried and evaporated to dryness.

The resulting compound is passed through a silica column using CHCl3 / AcOEt / MeOH 46/50/4 as eluent.

Firstly, 8-chloro-(2-pyridyl) -6 (1H) -quinolinone is obtained. then 8-chloro-3- (pyridyl) -6 (1H) -quinolinone. and finally, 8-chloro-4- (4-pyridyl) -6 (1H) -quinolinone, the respective oxalates of which are formed by reaction with oxalic acid.

3.6. Oxalates.

1.03 g (4 mmol) of base are dissolved in a little hot methanol and 0.5 g (4 mmol) of oxalic acid is dissolved in 10 ml of ethyl acetate. Both solutions are mixed. A little ethyl acetate is added. The methanol is evaporated and allowed to crystallize.

The compound is filtered, washed with ethyl acetate and then with ether and dried. It is recrystallized from an isopropanol / methanol mixture. The melting points of the three oxalates of the respective compounds are 206 ° C, 233 ° C and 260 ° C.

Example 4. (Pyridyl-3) -6 (1H) -quinolinone and its oxalate.

4.1. In a 100 ml flask, 1.35 g of 8-hydroxy-(3-pyridyl) -6 (1H) -quinolinone obtained in Example 2 and 0.70 g of potassium hydroxide in 32.2 ml are mixed. of water.

The mixture is stirred in an ice bath and 0.48 g of mesyl chloride is added in portions. The mixture is stirred and the precipitate formed is filtered off.

4.2. 4.4 g of mesylate thus obtained are dissolved in a solution of 2.68 g of KOH in 268 ml of water. 0.449 of palladium on activated charcoal is added to 10 S and the mixture is placed under a hydrogen atmosphere. The mixture is stirred for 65h. The mixture is acidified with 6N HCl, the catalyst is filtered and the filtrate is basified with potassium bicarbonate.

The product formed is filtered, dried and purified.

((3-Pyridyl) -6 (1H) -quinolinone is obtained. F = 2220C.

4.3. The base is converted into oxalate by reacting it, in solution in methanol, with oxalic acid. The salt obtained is recrystallized from methanol.

F> 260 C.

Example 5. Methyl-1 (pyridyl-3) -6 (1H) -quinolinone.

 0.444 g (2 mmol) of (pyridyl-3) -6 (1H) -quinolinone are dissolved in 2 ml of dimethylformamide, while hot.

Let cool. 0.096 g of sodium hydride at 50% in oil is added. 0.252 g (2 mmol) of methyl sulfate are then added. The mixture is stirred at room temperature for 1 h and then poured into 200 ml of water. It is extracted 3 times with chloroform. The chloroform phase is dried over MgSO4. After elution on a silica column (CHCl 3 90 / MeOH 10), the compound is obtained. sought.

F = 114-120C (Based).

Example 6 (2,3-Pyridyl or 4) -6-methoxy-3,4-dihydro-2 (111) -quinolinone 6.1. Methoxy-8-dihydro-3,4 2 (1H) -quinolinone.

In an autoclave bomb, 20.4 g of 8-methoxy-1 (1H) -quinolinone in solution in 200 ml of absolute alcohol are introduced.

1.7% of 5% Rh / Al and then 35 drops of 70% HClO 4 are added.

It is stirred for 6 hours under 20 kg of hydrogen and at 50 ° C. After six hours the reduction is complete. The hydrogen is removed, the catalyst is filtered off on paper and the alcohol phase is concentrated to 100 ml.

100 ml of water and about 50 ml of 10% potassium bicarbonate are added to the concentrated solution. It is extracted with chloroform, dried over MgSO 4 and filtered, and the compound is chromatographed on 300 g of silica (eluent:
CH2Cl2 20 / AcDEt 80).

After purification, the compound is obtained.

6.2. 8-Methoxy-6-nitro-3,4-dihydro-2 (1H) -quinolinone.

In a 1 liter three-neck flask equipped with an alcohol thermometer, a dropping funnel and stirring, 23.6 g (0.133 mol) of 8-methoxy-3,4-dihydro-2 (1H) are introduced. ) -quinolinone. 210 ml of acetic anhydride are added and stirred to dissolve. The mixture is cooled in an ice / salt bath at 0-5c.

A solution of 8.4 g of nitric acid (d = 1.40) in 70 ml of acetic acid is then added dropwise in half an hour.

1.8 ml of 1,4-nitric acid are again added and the mixture is left standing for a further hour.

The solid is filtered, washed with ethyl acetate and then with ether. The mother liquor is evaporated, the residue is taken up in ethyl acetate, filtered, washed with ether and dried.

The desired compound is obtained which is used directly for the next step.

6.3. Amino-6-methoxy-8-dihydro-3,4 2 (1H) -quinolinone.

In a 1 liter flask, 25.3 g (114 mmol) of 8-methoxy-6-nitro-3,4-dihydro-2 (1H) -quinolinone and 500 ml of absolute alcohol are introduced. 1 g of PtO 2 is added and the mixture is stirred under a hydrogen atmosphere. After 5 hours absorption is complete.

The hydrogen is removed, the catalyst is filtered off on celite and the filtrate is evaporated off.
The residue is taken up in a minimum of isopropanol, the filter and washed with ether. The amino compound is obtained.

6.4. (2,3-pyridyl or 4) -6-methoxy-3,4-dihydro-2 (111) -guinolinone.

In a 500 ml Erlenmeyer flask, 32.8 g (171 mmol) of 6-amino-8-methoxy-3,4-dihydro-2 (1H) -quinolinone are introduced. 61 ml of concentrated HCl and 41 ml of water are added, then another 100 ml of water. The reaction mixture is heated and then cooled in an ice / salt bath. At 1-2 C, 11.8 g (171 mmol) of toluene are added dropwise.
NaNO2 in 30 to 50 ml of water. The diazonium salt formed is added, dropwise, for 1 h 30 - 2 h, to 170 ml of pyridine heated to 60 ° C. 50 ml of 33% aqueous ammonia are added, the mixture is evaporated to dryness and the residue is taken up in 600 ml. to 800 ml of chloroform. It is stirred with potassium carbonate. The chloroform phase is dried, adsorbed on 50 g of silica and chromatography (eluent AcOEt 50 / CH 2 Cl 2 45 / MeOH 5).

The following compounds are obtained in the following order: 2- (8-pyridyl) -8-methoxy-3,4-dihydro-2 (1H) -quinolinone - (3-pyridyl) -6-methoxy-3,4-dihydro-2 (1H) -quinolinone - (6-pyridyl) -6-methoxy-3,4-dihydro-2 (1H) -quinolinone.

whose melting points are given in the table. Board

<SEP> position <SEP> position
<tb> Compound <SEP> on <SEP> kernel <SEP> on <SEP> kernel <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> R5 <SEP> Sel <SEP> or <SEP > base <SEP> F (C)
<tb><SEP> quinoline <SEP> pyridyl
<tb> 1 <SEP> 6 <SEP> 2 <SEP> H <SEP> H <SEP> double <SEP> binding <SEP> H <SEP> HCl <SEP> 220-240
<tb> 2 <SEP> 6 <SEP> 2 <SEP> H <SEP> H <SEP> double <SEP> binding <SEP> H <SEP> HCl <SEP> 224
<tb> 3 <SEP> 6 <SEP> 2 <SEP> H <SEP> OCH3 <SEP> Double <SEP> Link <SEP> H <SEP> Base <SEP> 152
<tb> 4 <SEP> 6 <SEP> 2 <SEP> H <SEP> OCH3 <SEP> double <SEP> binding <SEP> CH3 <SEP> oxalate <SEP> 211-213
<tb> 5 <SEP> 6 <SEP> 2 <SEP> H <SEP> Cl <SEP> double <SEP> binding <SEP> H <SEP> oxalate <SEP> 205-207
<tb> 6 <SEP> 6 <SEP> 3 <SEP> H <SEP> H <SEP> double <SEP> link <SEP> H <SEP> base <SEP> 222
<tb> 7 <SEP> 6 <SEP> 3 <SEP> H <SEP> OH <SEP> double <SEP> link <SEP> H <SEP> base <SEP> 143
<tb> 8 <SEP> 6 <SEP> 3 <SEP> H <SEP> OCH3 <SEP> double <SEP> link <SEP> H <SEP> base <SEP> 200
<tb> 9 <SEP> 6 <SEP> 3 <SEP> H <SEP> Cl <SEP> double <SEP> binding <SEP> H <SEP> oxalate <SEP> 232-234
<tb> 10 <SEP> 6 <SEP> 3 <SEP> H <SEP> OCH3 <SEP> double <SEP> binding <SEP> CH3 <SEP> HCl <SEP> 196
<tb> 11 <SEP> 6 <SEP> 4 <SEP> H <SEP> H <SEP> double <SEP> binding <SEP> H <SEP> oxalate <SEP> 260
<tb> 12 <SEP> 6 <SEP> 4 <SEP> H <SEP> OCH3 <SEP> double <SEP> binding <SEP> H <SEP> HCl <SEP> 268
<tb> 13 <SEP> 6 <SEP> 4 <SEP> H <SEP> Cl <SEP> double <SEP> binding <SEP> H <SEP> oxalate <SEP> 259-261
<tb> 14 <SEP> 6 <SEP> 4 <SEP> H <SEP> OCH3 <SEP> double <SEP> binding <SEP> CH3 <SEP> oxalate <SEP> 245
<tb> Table (continued)

<SEP> position <SEP> position
<tb> Compound <SEP> on <SEP> kernel <SEP> on <SEP> kernel <SEP> R1 <SEP> R2 <SEP> R3 <SEP> R4 <SEP> R5 <SEP> Sel <SEP> or <SEP > base <SEP> F (C)
<tb><SEP> quinoline <SEP> pyridyl
<tb> 15 <SEP> 7 <SEP> 2 <SEP> H <SEP> H <SEP> double <SEP> binding <SEP> H <SEP> maleate <SEP> 231-233
<tb> 16 <SEP> 7 <SEP> 3 <SEP> H <SEP> H <SEP> double <SEP> binding <SEP> H <SEP> HCl <SEP>><SEP> 260
<tb> 17 <SEP> 6 <SEP> 3 <SEP> CH3 <SEP> H <SEP> double <SEP> binding <SEP> H <SEP> Base <SEP> 114-120
<tb> 18 <SEP> 6 <SEP> 2 <SEP> H <SEP> OCH3 <SEP> H <SEP> H <SEP> H <SEP> base <SEP> 118
<tb> 19 <SEP> 6 <SEP> 3 <SEP> H <SEP> OCH3 <SEP> H <SEP> H <SEP> H <SEP> base <SEP> 173
<tb> 20 <SEP> 6 <SEP> 4 <SEP> H <SEP> OCH3 <SEP> H <SEP> H <SEP> H <SEP> basis <SEP> 168
<tb> 21 <SEP> 6 <SEP> 2 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> base <SEP> 212
<tb> 22 <SEP> 6 <SEP> 3 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> basis <SEP> 189
<tb> 23 <SEP> 6 <SEP> 4 <SEP> H <SEP> H <SEP> H <SEP> H <SEP> H <SEP> base <SEP> 267-268
<Tb>
The compounds of the invention have been subjected to pharmacological tests in the cardiovascular field. In particular, the inotropic effect of the compounds on the guinea pig left atrium has been studied.

Hartley albino guinea pigs (strain K) were pretreated with reserpine (5 mg / kg, i.p.) 24 h before the experiment. The positive inotropic effect is measured on the left atrium according to Horli et al. (Arzneim, Forsch 24, 1275: 1974). The preparation is stimulated electrically at a frequency of 205 Hz, at a voltage equal to the threshold voltage increased by 50% (duration 5 msec). The atria, stretched at 0.5 g, is suspended in a solution of Krebs-Henseleit, aerated of a mixture: 95 S 02 and 5 S CO 2 and brought to a temperature of 32 C The composition of the physiological solution is in mM: NaCl 120; KCl 4.80; MgSO4 7H20 1.20; CaCl 2 2H 2 O 2.53; KH2Pu4 1.20; NaHCO3 25; glucose 10. The bath contains phentolamine 3.15 x 10 -4 mM. Before developing the dose-action curve of each compound of the invention, a dose-action curve of isoprenaline is performed to test the sensitivity of the preparation.

The ED50 are determined according to Ariens and Van Rossum Arch.

Int. Phariacodyn. Ther. 99, 32; 1957). The ED50 of the compounds of the invention range from 1.3 × 10 -6 to 3.5 × 10 -5.

The compounds of the invention are cardiac stimulants that can be used for the treatment of heart failure by increasing myocardial contractility.

The invention therefore includes. any pharmaceutical compositions containing the compounds (I) as active ingredients, in combination with any excipients suitable for their administration, in particular orally (tablets, lozenges, capsules, capsules, cachets, solution or oral suspensions) or parenteral.

The daily dosage can range from 50 to 1000 mg.

Annex 1
General scheme

(I) R3 etR4 = double liaison
R2 = OCH3 (I) R3 = R4 = H
R2 = OCH3
Annexe 3
Schéma 3

(I) R3 et R4 =
double liaison
R2 = H (I) R3 = R4 = H
R2 = H
Annexe 4
Schéma 4

Annex 2
Figure 2

(I) R3 and R4 = double bond
R2 = OCH3 (I) R3 = R4 = H
R2 = OCH3
Annex 3
Figure 3

(I) R3 and R4 =
double bond
R2 = H (I) R3 = R4 = H
R2 = H
Annex 4
Figure 4

R3 and R4 = double bond
R2 = Hal
R3 and R4 = H
R2 = Hal

Claims (5)

 wherein the pyridyl radical is in the 6- or 7-position and binds at any of the 2, 3 or 4 positions. R1 represents a hydrogen atom or a (C1 4) alkyl radical, R2 represents a hydrogen atom, the hydroxyl or methoxy radical or a halogen atom.

 Claims 1. Derivatives of 2 (1H) -quinolinone of formula (I) . R3 and R4 together represent a double bond or each a hydrogen atom, and. R5 represents a hydrogen atom or a (C1 4) alkyl radical. R1 is H or CH3. as well as their pharmaceutically acceptable acid addition salts 2. Derivatives according to claim 1, wherein R5 is H or CH3. R3 and R4 are either together a double bond or each a hydrogen atom, and R2 is H, OH, OCH3 or Cl, 3. Process for the preparation of the compounds according to claim 1 or 2, characterized in that a compound of formula

 in which R is H or the pyridyl radical and R'2 is H, OCH 3 or a halogen atom, with a compound of formula

 in which R 'is C6H5, OEt or OH and R "is C1 or OEt and R5 is H or a (C1-4) alkyl radical, to obtain the compound of formula

 that one - is hydrogen - is alkylated first by a compound R1X (X = halogen) and then hydrogen to obtain the compounds (I) in which R2 is H, OCH3 or a halogen atom, and, if it is Desirably, the compounds (I) in which R2 is OCH3 are demethylated to give the compounds (I) in which R2 is the pyridyl radical which can be introduced by reaction of the pyridine with a diazo compound before or after the cyclization leading to quinolinone. reaction which leads to a mixture of isomers separable by chromatography. 4. Medicinal product characterized in that it contains a compound as specified in any one of claims 1 and 2. 5. Pharmaceutical composition characterized in that it contains a compound as specified in any one of claims 1 and 2 in combination with any suitable excipient.