FR2462438A1 - NOVEL DERIVATIVES OF 6-ALKYL-7-PHENYL-1,6-NAPHTHYRIDINE-5 (6H) -ONE, THEIR PREPARATION AND THEIR APPLICATION AS MEDICAMENTS - Google Patents

Abstract

THE SUBJECT OF THE INVENTION IS THE NEW DERIVATIVES OF 6-ALKYL-7-PHENYL-1-1,6-NAPHTYRIDINE-5 (6H) -ONE RESPONDING TO THE FORMULA: (CF DRAWING IN BOPI) IN WHICH R REPRESENTS A GROUP ALKYL, R MEANS HYDROGEN, A HALOGEN OR A -CF GROUP, ALKYL, ALCOXY, ALKYLTHIO OR AMINO POSSIBLY SUBSTITUTED, R REPRESENTS HYDROGEN, A HALOGEN OR A -CF GROUP, ALKYL, ALCOXY, ALKYLTHIO OR AMINO POSSIBLY SUBSTITUTES, R REPRESENTS HYDROGEN, A HALOGEN OR A -CF GROUP, ALKYL OR ALCOXHY A HALOGEN OR AN ALKYL OR ALCOXY GROUP, AND THEIR PREPARATION. THESE COMPOUNDS CAN BE USED THERAPEUTICALLY, AS ACTIVE INGREDIENTS OF MEDICINAL PRODUCTS.

Description

The present invention aims to

  new derivatives of 6-alkyl-7-phenyl-1,6-naphthylidine

  (6H) -one, their preparation and their application in

  therapeutic, as active ingredients of drugs.

  The invention relates more particularly

  derivatives of 6-alkyl-7-phenyl-1,6-naphthyridine

  (6H) -one of formula I o

N '1

N R2 ()

3 R4

  wherein R 1 is an alkylene group containing 1 to 4 carbon atoms, R 2 is a hydrogen or halogen atom, an alkyl, alkoxy or alkylthio group each containing 1 to 4 carbon atoms, a trifluoromethyl group or a -NR5R6 -R5 and R6 each stand, independently of one another, a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms, R3 represents a hydrogen or halogen atom, a trifluoromethyl group or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms, and R4 denotes a hydrogen or halogen atom or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms, and the salts which these compounds form with acids

minerals or organic.

  In the compounds of formula I, the symbols R 1 to R 4 preferably have the meanings given below, either individually or in combination: R 1 represents an alkyl group containing from 1 to 3 carbon atoms, in particular a methyl or ethyl group, in particular a methyl group; R2 represents a hydrogen or halogen atom, a methylthio, ethylthio or trifluoromethyl group, a dimethylamino group located at the 2 or 3 position or an alkyl group containing from 1 to 3 carbon atoms, in particular a hydrogen atom, fluorine or chlorine, a methyl or ethyl group or a dimethylamino group located at the 2 or 3 position, in particular a fluorine or chlorine atom, a methyl or ethyl group or a dimethylamino group at position 3, more particularly a chlorine or a methyl group in position 2; R3 denotes a hydrogen or halogen atom or an alkyl group containing from 1 to 3 carbon atoms, in particular a hydrogen, fluorine or chlorine atom or a methyl or ethyl group, in particular a hydrogen atom; ;

  R4 represents a hydrogen atom.

  Among the compounds of formula I, the preferred compounds are those in which R 1 denotes an alkyl group containing from 1 to 3 carbon atoms, R 2 represents a hydrogen, fluorine or chlorine atom,

  a methyl or ethyl group or a dimethyl-

  amino located in position 2 or 3, R3 is hydrogen, fluorine or chlorine or methyl or ethyl, and R4 is hydrogen, especially those in which R1 is methyl or ethyl, R2 represents a fluorine or chlorine atom, a methyl or ethyl group or a dimethylamino group located in the 3-position, and R3 and R4 each signify a hydrogen atom, more particularly those in which R1 signifies a methyl group, R2 represents a a fluorine or chlorine atom, a methyl or ethyl group or a dimethylamino group in position 3, and

  R3 and R4 each signify a hydrogen atom.

  As another group of preferred compounds of formula I from those mentioned above, mention may be made of those in which at least one of the ortho positions of the phenyl group is occupied by a

hydrogen or fluorine atom.

  Halogen means fluorine,

chlorine or bromine.

  Another class of preferred compounds of formula I are those in which R 1 is alkyl of 1 to 4 carbon atoms, R 2 is hydrogen or halogen, trifluoromethyl, alkyl or alkoxy each containing 1 to 4 carbon atoms or a residue -NR5R6 already specified, R2 to be located ortho or meta when it means a residue -NR5R6, and R3 and R4 each have one of the meanings indicated

upper.

  US Patent 4,154,837 discloses a

  large family of derivatives of 6-alkyl-7-bis-

  methoxyphenyl-benzyl-isoquinoline-1 (2H) -one and 6-alkyl-7-bismethoxyphenyl-naphthyridine-5 (6H) -one;

  these compounds are used as intermediate products.

  time, this US patent does not mention the compounds

  of the present invention and their use.

  According to the process of the invention, in order to prepare the compounds of formula I, a compound of formula VII or a compound of formula VIII No i 2 (VII) R 4 R 2 is dehydrated.

+ 3 (VIII)

  in which R1 to R4 have the meanings already given,

or their mixtures.

  As a suitable dehydrating agent, a strong mineral or organic acid can be used

  such as trifluoroacetic acid, p-toluene acid,

  sulfonic acid, methanesulfonic acid, sulfuric acid,

  perchloric acid or, preferably, chloroacid

  water or trifluoromethanesulfonic acid.

  The reaction may be carried out in an inert solvent such as an alcohol, for example methanol or ethanol, tetrahydrofuran, methylene chloride or chloroform. Advantageously, the temperature is between 0 ° and the reflux temperature of the reaction mixture, in particular between 50 and 50.degree.

  reflux temperature (preferably 100), more particularly

between 70 and 80.

  The compounds of formula I thus obtained can then be isolated and purified according to the usual methods. If desired, the compounds of formula I can be converted to their acid addition salts by reaction with inorganic or organic acids. From the salts, the compounds of formula I can be liberated

  by proceeding according to known methods.

  Suitable salts of the compounds of formula I are the hydrochloride, the hydrobromide,

  iodhydrate, phosphates, sulphate, perchloride

  spleen, methanesulfonate, ethanesulfonate,

  benzenesulfonate and p-toluenesulfonate.

  The compounds of formulas VII and VIII are new; they are part of the present invention

  as well as their preparation process.

  To prepare compounds of formulas VII

  and VIII, a compound of formula V-

  ONHR1 (V) N CH3 wherein R1 has the meaning already given, with a strong base so as to obtain a dianion which is reacted with a compound of formula VI X

3 2 (VI)

  in which R ', R3 and R4 have the meanings already given and X represents a cyano group or a residue

  -COOR7 o R7 means a methyl, ethyl or n-group

  propyl, preferably ethyl, and when a compound of formula VI where X is cyano is used, the resulting compound is hydrolyzed.

  As strong bases appropriate for trans-

  form the compound of formula V into a dianion, it is possible to use very strong bulky bases such as lithium di-alkylamides whose alkyl groups

  contain 1 to 4 carbon atoms, dicyclohexyl-

  lithium amide or lithium N-alkyl-N-cyclohexylamides, the alkyl radical of which contains 1 to 4 carbon atoms, for example lithium diethylamide, lithium N-cyclohexyl-N-isopropylamide or, more

  particularly, lithium diisopropylamide.

  The reaction may be carried out in an anhydrous aprotic solvent, for example toluene, 1,2-dimethoxyethane, dimethyl ether of

  diethylene glycol or, preferably, tetrahydrofuran.

  It is advantageously carried out at a temperature of between -60 and 25, preferably between -30 and -5, under an inert atmosphere, for example nitrogen. The subsequent reaction of the dianion with the compound of formula VI can be carried out without isolation of the dianion, under

  similar conditions and in the same solvents.

  When a compound of formula VI is used where X is a COOR7 residue, it may form a

  mixture of compounds of formulas VII and VIII.

  When using a compound of formula VI where X represents a cyano group, an intermediate compound corresponding to the formula X O CNHR is formed.

CH = C NH2

  tNtCH = C 2 (X) R4 in which R1 to R4 have the meanings already

1 4

  data. This compound of formula X can be transformed

  in a compound of formula VIII by hydrolysis.

  The hydrolysis of the compound of formula X can be carried out in the presence of an aqueous acid. When a weak acid is used, a compound of formula VII is obtained; when a strong acid is employed, at least a partial conversion is formed into a compound of formula I. The reaction is carried out in an inert solvent such as tetrahydrofuran or ethanol,

  at a temperature between 25 and 75.

  The compounds of formula X are new and

  are part of the present invention.

  The compounds of formulas VII, VIII and X thus obtained can then be isolated and purified according to the usual methods; they can also be

  put into play for the next reaction without being isolated.

  The compounds of formula V can be prepared according to the following reaction scheme: H 2 N

C = CHCOOR + CH = CHCHO -

  H C Z 7 2 basic conditions 3 (II) COOR

+ R -NH - V

  dehydrogenation CH3 in the presence of sulfur (III) (IV) In the compounds of formulas II, III and IV,

  the symbols R7 and R1 have the meanings already given.

  The compounds of formulas II, III and IV are known or can be prepared according to methods

  known, from known products.

  The following examples illustrate the present invention without in any way limiting its scope. Temperatures are in degrees Celsius; the

  ambient temperature is between 20 and 30.

Example 1

  a) Ethyl ester of 2-methylnicotinic acid

  To a mixture consisting of 800 ml of 3-amino

  ethyl crotonate, 30 ml of piperidine and 1.4 liter of isopropanol, 540 ml of acrolein are added slowly with stirring at 25 ° -30 ° and in the course of 2 hours. After heating the mixture under reflux for 3.5 hours, it is evaporated to dryness under reduced pressure, the evaporation residue is heated to 1000 and then 610 g of sulfur are added thereto. The mixture is then heated for 2 hours at 1000 and then for 90 minutes.

  at 125. The mixture is allowed to cool to

  At room temperature, 1 liter of chloroform was added, filtered through diatomaceous earth and the filter cake was washed with chloroform. The filtrate and chloroform wash liquors are combined and extracted three times with 1 liter of 2N hydrochloric acid each time. The acidic aqueous phases are then combined and then, while cooling, alkalinized by addition of a 2N sodium hydroxide solution. The basic aqueous solution is extracted three times with 1 liter of chloroform each time, the chloroform extracts are combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated under reduced pressure. . An oily evaporating residue is thus obtained which is purified by distillation under high vacuum. The ethyl ester of 2-methylnicotinic acid obtained in its pure state

tip at 73-77 under 0.7 mm Hg.-

  b) N-methyl-2-methyl-nicotinamide Heated for 4 hours at 400 200 g

  (1.21 moles) of ethyl ester of 2-methyl-

  Nicotinic acid and 1 liter of a 40% aqueous solution of methylamine. The reaction mixture is then evaporated under reduced pressure. A thick oil is thus obtained which is distilled at 121-1330 at 0.24 mmHg. N-methyl-2-methyl-nicotinamide and

obtained background at 69-72.

  c) 7- (2-Chloroheenyl) -7,8-dihydro-7-hydroxy-6-methyl: 1,6-n: Ehtrie-S (61 fl-one) A solution of 42.3 ml of diisopropylamine in 300 ml of anhydrous tetrahydrofuran is added, with stirring at a temperature between -5 and -10 and under a nitrogen atmosphere, 189 ml (302.4 "r rles) of a 1.6 M solution of n-butyl lithium in To the resulting lithium diisooropylamide solution, 21.5 g (144 mmol) of N-methyl-2 are slowly added with stirring at a temperature between -20 and -30 and under a nitrogen atmosphere. -methyl-nicotinamide dissolved in 150 ml of anhydrous tetrahydrofuran The reaction mixture is stirred for a further period

  another 2 hours at the same temperature and under

  nitrogen. To this mixture, then slowly add

  stirring at a temperature between -20 and -30 ° C. under a nitrogen atmosphere, a solution of 26.8 g (145 mmol) of freshly distilled ethyl chlorobenzoate in 150 ml of anhydrous tetrahydrofuran and continue stir all under the same conditions for another 90 minutes. The reaction is stopped by adding 250 ml of concentrated aqueous sodium chloride solution and extracted three times with ethyl acetate. The ethyl acetate extracts are combined, the overall solution is washed 4 times with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered and filtered. evaporated under reduced pressure to obtain a thick oil. This oil is chromatographed on a column of silica gel, eluting first with methylene chloride and then with a mixture of chloroform with 3% methanol. When eluted with this mixture of chloroform and methanol, the product of the reaction is obtained in the crude state which is crystallized from ether. The product thus obtained melts at 144-146. We also obtain a

  second amount of this product melting at 144-146.

  These two quantities are combined and recrystallized in toluene, which gives a product melting at

143-145.

  The mother liquors obtained during the second crystallization and the recrystallization are combined

  in toluene and evaporated under reduced pressure.

  The residue is then dissolved in acetone and treated with 0.9 g of gaseous hydrochloric acid,

  which gives a crystallized product.

  d) 7- (2-chloro-phenyl) -6-methyl-1,6-naphthyridine-5 (6H) -one 7.8 g of the product obtained under c) are suspended (mp = 143-145), in 50 ml of absolute ethanol

  then 1.1 g of chlorhydric acid are bubbled into it.

  gaseous drique. After evaporating the reaction mixture to near dryness, the crystalline product obtained under (c) after treatment with hydrochloric acid is added to 100 ml of absolute ethanol. The mixture is then heated under reflux for minutes, cooled by addition of ice and water and alkalized by addition of

  sodium hydroxide solution. The solution is extracted

  With methylene chloride, the methylene chloride solution is dried over anhydrous sodium sulfate, filtered and evaporated in vacuo.

  reduced pressure to give 7- (2-chlorophenyl)

  6-methyl-1,6-naphthyridine-5 (6H) -one in the crude state.

  After recrystallization from absolute ethanol,

this product melts at 152-153.

Example 2

  a) N: methyl-2- (m-dimethylaminobenzoylmethyl) nicotinamide 263 ml (420 mmol) of a 1.6 M solution of n-butyllithium are slowly added under stirring at -10 and under a nitrogen atmosphere. hexane

  to a solution of 58.7 ml (420 mmol) of diisopropyl-

  amine in 200 ml of anhydrous tetrahydrofuran. To this resulting solution of lithium diisopropylamide, a solution of 30 g (200 mmol) of N-methyl-2-methylnicotinamide in 200 ml of anhydrous tetrahydrofuran is slowly added at a temperature between -20 and -30. The red mixture is shaken

  which was formed for another 2 hours at a

  between -20 and -30 and under a nitrogen atmosphere. A solution of 38.6 g (200 mmol) of ethyl dimethylaminobenzoate in 100 ml of anhydrous tetrahydrofuran is then slowly added, with stirring at a temperature between -20 and -30 and under a nitrogen atmosphere, and stir for one hour at the same temperature. After quenching the reaction by adding 250 ml of saturated sodium chloride solution, the reaction mixture is extracted three times with ethyl acetate. The ethyl acetate extracts are combined, the overall solution is washed 4 times with water and once with saturated sodium chloride solution, dried over anhydrous sodium sulphate and evaporated. evaporated under reduced pressure. A thick oil is obtained which is dissolved in a small amount of isopropanol and is chromatographed on silica gel, eluting with chloroform containing 5% isopropanol. The last major fraction collected is rechromatographed on silica gel and eluted with chloroform containing 2% isopropanol. The largest fraction contains the product

in raw state.

  b) 7- (m-dimethylaminophenyl) -6-methyl-1,6-nahtyridin-5 (6H) -one The crude product obtained in Example 2a) is dissolved in ethanol and the solution is bubbled into this solution. 4.3 g of gaseous hydrochloric acid and the reaction mixture is heated for 5 minutes to 70. This gives a solid product melting at 197-220 with decomposition and a second solid product melting at 224-226 with decomposition. These two products are combined and recrystallized in ethanol, which gives

  a solid product melting at 221-232 with decomposition

  tion. The mother liquors of each crystal are combined

  and recrystallization, resulting in two further quantities of products melting at 193-216 with decomposition. The crystallized products obtained are dissolved in water, an excess of sodium hydroxide solution is added and the mixture is extracted.

  the basic solution with methylene chloride.

  After drying the methylene chloride extract on anhydrous sodium sulphate, filter

  and evaporated under reduced pressure. It is chromato-

  then graph the evaporation residue on gel

  of silica eluting with ethyl acetate.

  After the large fractions are pooled, the mixture is recrystallized from a mixture of acetone and

  pentane to give 7- (m-dimethylaminophenyl) -6-

  methyl-1,6-naphthyridine-5 (6H) -one melting at 118-120.

Example 3

  a) Nzmethl-2- (4-chloro-aminosoyl) nicotinamide A solution of lithium diisopropylamide in anhydrous tetrahydrofuran is prepared by slowly adding, with stirring at 20 ° and under a nitrogen atmosphere, 292 ml (467.2 g). mmol) of a 1.6 M solution of n-butyllithium in hexane to a solution of 70 ml of diisopropylamine in 400 ml of anhydrous tetrahydrofuran. A solution of 35 g (233.3 mmol) of N-methyl-2-methyl-nicotinamide in 400 ml of N-methyl-2-methyl-nicotinamide is then slowly added with stirring at -20 under a nitrogen atmosphere and over 30 minutes. anhydrous tetrahydrofuran, with the solution of lithium diisopropylamide. The mixture is stirred for a further minute at -20 and under a nitrogen atmosphere. After allowing the mixture to warm to room temperature over a period of 30 minutes, 500 ml of water are added. The organic phase is washed with 500 ml of saturated sodium chloride solution and the aqueous phase is extracted 4 times, each time with 100 ml of methylene chloride. The washed organic phase and the 4 methylene chloride extracts were combined, charcoal treated, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The product in the crude state is thus obtained which, after recrystallization in a

  mixture of diethyl ether and methyl chloride

  Lie, give a yellow solid; this one melts at 140-145 after a new recrystallization in a mixture

  of diethyl ether and methylene chloride.

  b) N-N-thy1-2- (4-chlorobenzoylmethyl) -nicotinamide

  22 g (76.5 mmol) of N-methyl-

  2- (4-chloro-D-aminostyryl) -nicotinamide in a medium

  80 ml of tetrahydrofuran and 40 ml of ethanol are added and a mixture of 40 ml of acetic acid and 40 ml of water is added. After stirring the reaction mixture at 40 for 4 hours,

  alkalizes to pH 9 by addition of a hydrochloric acid

  sodium hydroxide and extracted with diethyl ether

  ethyl acetate and methylene chloride. The 3 organic phases are combined, the overall solution is treated with charcoal, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a yellow solid. Recrystallization of this product from ethanol gave a yellow-green solid, mp 162 ° -163 °. c) Proceeding as described in Example 2b) the compound obtained under b) is reacted with trifluoromethanesulfonic acid, which gives

  7- (4-chlorophenyl) -6-methyl-1,6-naphthyridine-5 (6H) -

one melting at 139-140.

  By proceeding as described in Examples 1 to 3, the compounds of formulas VII, VIII and X can be prepared.

  specified in the following Table I.

BOARD

  I Compound R-Point RR fde R1 2 3 R4 fusion

formula........... _.

VII CH3 2-CH3 H H oil

VII CH3 3-CF3 H1390

VII CH3 3-OCH3 4-OCH3H 157

  VII CH3 H H H 141 (with decomposition)

VII CH3 2-OCH3HH

VII CH3 2-F H H

VII CH3 2-F 6-F H

  VIII CH 4 -CH H H 12df-1340 3 (at the crude state) VIII CH3 3-Cl H H 200o206 VIII C2H5 2-Cl H H VIII CH3 p-N (CH2 H H 1732

X CH H H H 159 -161

X CH 4-CH H H 88 -116

(in raw state)

246243-8

  By proceeding as described in Examples 1 to 3, the compounds of formula I can be prepared.

  specified in the following Table II.

  (Table II see next page) jExamplePoint-R1. R2R

R 1R 2 ..... R 3 ... R4. -.qSiOII ...

3-OCH3

H 4 -CH 3 3 -Cl 3-CF 3

2-OCH3

  2-F 2 -F 2-Cl 2 -CH 3 Cl 2 -CH 3 2-CH 3 2 -Br 2 -CH 3 Cl

2-N (CH3) 2

2-CH3

2-SCH3

2-Cl 2-C1

4-OCH3

  H H H H H H H H H H H H 4 CH 3 6 -Cl H H H H H H H H H H H H H H H H H 6-CH 3 H H H H H H H

4-N (CH3) 2

136 -137

 -90t5

- -134

1430-

- - 154

:. 121 -123

162 -163

 -136

104 -106

153 -155

the hydrochloride

at 222-229 (with

  composition) methanesulfonate melts at 210 -220 (with decomposition) I CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -C2H5-C3H7 i-C3H7

E-C4H9

  -C2H5 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3 -CH3HH In the tests carried out on laboratory animals, the compounds of formula I are distinguished

  by interesting pharmacodynamic properties.

  The compounds of formula I exert a muscular relaxation action, as shown by the mouse bar test and the study of

spinal reflexes in the cat.

  The ability of the mice to hold on a horizontal bar rotating at a given speed before and after administration of the test compound was determined. We proceed according to the modified method described

  by Dunham and Miya in J.Am. Pharm.Assoc. 45, 208, (1957).

  Animals that successfully grip the bar three times for 60-90 seconds are tested for the test and administered the test compound orally or intraperitoneally. 30 and 60 minutes later, the test is repeated. We compare the time during which the mice manage to stay on the

  bar to that obtained with the control animals. adminis-

  orally or intraperitoneally, the compounds of formula I significantly decrease the

  during which the mice manage to grip.

  The ability of compounds of formula I to decrease monosynaptic (patellar) and polysynaptic (flexor) reflexes in male cats has been demonstrated. Answers are recorded using an appropriate device. The test compound is administered in the saphenous vein. Administered at doses of between 0.5 and 50 mg / kg, the compounds of formula I reduce spinal reflexes

Of the cat.

  Similar results are obtained when the test compound is administered intravenously

to a spinal male cat in C-1.

  The compounds of formula I exert other

share an anti-inflammatory action.

  The anti-inflammatory action of the compounds of formula I has been demonstrated by the inhibition they exert on the edema caused by carrageenin on the rat's paw. The procedure is as described by C. A. Winter et al. in Proc.Soc.Exp.Biol., Med. 11, 544 (1962). The compound is administered orally one hour before the injection of a suspension of

  carrageenin in the plantar region of a hindlimb

  pool. Three hours after the injection, edema is measured which has developed and compared with the control animals. When administered orally at a dose of between 10 and 200 mg / kg, the compounds of formula

  I significantly inhibit edema caused by carrageenan.

  Thanks to these properties, the compounds of formula I can be used therapeutically as

  muscle relaxants or as anti-inflammatory agents.

  They will be prescribed at daily doses of between about 1 and 1000 mg of active substance, preferably between 10 and 1000 mg, which will advantageously be administered in several unit doses each containing from 0.25 to 500 mg at a rate of 2 to 4 times a day,

or in delay form.

  As medicaments, the compounds of formula I can be administered orally or parenterally, either alone or in the form of appropriate pharmaceutical compositions, such as tablets, powders, granules, capsules, elixirs,

  suspensions, syrups or solutions or suspen-

  Injectable emulsions, dispersions or emulsions.

  Pharmaceutical preparations intended for oral administration may contain, in addition to the active substance, one or more organic or inorganic excipients acceptable from the point of view

  pharmaceutical products, as well as sweeteners,

  binders, dyes, preservatives etc ...

  For the preparation of tablets we can use,

  as excipients, calcium carbonate, carbon dioxide

  sodium nate, lactose, talc, etc., granulation and disintegrating agents such as starch, alginic acid, etc., binders such as starch, gelatin, gum arabic, etc. lubricants such as magnesium stearate, stearic acid, talc, etc. The tablets may or may not be coated. The purpose of the coating is, inter alia, to retard the decomposition and absorption of the active substance in the gastrointestinal tract and thereby produce a delayed effect. Suspensions, sirôps and elixirs may contain, in addition to the substance

  active agents, suspending agents such as methyl-

  cellulose, gum tragacanth, sodium alginate etc., wetting agents such as lecithin, stearate

  polyoxyethylene, polyoxyethylene mono-oleate

  sorbitan, and preservatives such as methyl p-hydroxy benzoate, ethyl and propyl.

  The capsules may contain the active substance either alone or in admixture with solid inert excipients, such as, for example, starch, lactose, calcium carbonate, calcium phosphate and kaolin. The solutions, suspensions, dispersions and injectable emulsions may be prepared in a known manner and contain, in addition to the active substance, suitable solvents, solubilizers, dispersing agents or wetting agents and suspending agents.

  identical or similar to those mentioned above.

  Preferred drug forms are solid compositions, particularly tablets

  and liquid or solid content capsules.

  The compounds of formula I can be administered

  both in the free state and in the form of their pharmaceutically acceptable salts, the activity of which is

  is of the same order as those of the corresponding free squares.

Claims (16)

  1. Novel derivatives of 6-alkyl-7-phenyl-   1,6-naphthyridin-5 (6H) -one ,. characterized in that they correspond to the formula I R1 NR2 R4   wherein R 1 is an alkyl group containing 1 to 4 carbon atoms, R 2 is a hydrogen or halogen atom, an alkyl, alkoxy or alkylthio group each containing 1 to 4 carbon atoms, a trifluoromethyl group or a remain -NR5R6 where R5 and R6 mean each, independently one. on the other side, a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms, R3 represents a hydrogen or halogen atom, a trifluoromethyl group or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms, and R4 represents a hydrogen or halogen atom or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms, and the salts that these compounds form with the acids minerals or organic.   2. Novel derivatives of 6-alkyl-7-phenyl-   1,6-naphthyridine-5 (6H) -one, characterized in that they correspond to the formula I (I) IR2 in which R denotes an alkyl group containing from 1 to 3 carbon atoms, R2 represents a hydrogen atom , fluorine or chlorine,   a methyl or ethyl group or a dimethyl-   amino located in position 2 or 3, R3 is hydrogen, fluorine or chlorine or methyl or ethyl, and R4 is hydrogen, and the salts that these compounds form with acids minerals or organic.   3. Novel derivatives of 6-alkyl-7-phenyl-   1,6-naphthyridine-5 (6H) -one, characterized in that they correspond to the formula IOR e 1 (R) R 2 R 4 in which R 1 denotes a methyl or ethyl group, R 2 represents a fluorine or chlorine atom , a methyl or ethyl group or a dimethylamino group located at the 3-position, and R3 and R4 each signify a hydrogen atom, and the salts that these compounds form with acids minerals or organic.   4. New derivatives of 6-alkyl-7-phenyl-1,6-naphthyridine-5 (6H) -one, characterized in that they are   selected from 7- (m-dimethylaminophenyl) -6-methyl-1,6   naphthyridine-5 (6H) -one, 7- (4-chlorophenyl) -6-methyl-   1,6-naphthyridine-5 (6H) -one, 7- (2-fluorophenyl) -6-   methyl-1,6-naphthyridine-5 (6H) -one, 7- (2,6-difluoro-   phenyl) -6-methyl-1,6-naphthyridine-5 (6H) -one, and 7- (2-   methylphenyl) -6-methyl-1,6-naphthyridine-5 (6H) -one, and the salts that these compounds form with acids minerals or organic.   5.- 7- (2-Chlorophenyl) -6-methyl-l, 6-   naphthyridine-5 (6H) -one, and salts thereof   form with mineral or organic acids.   6. A process for the preparation of 6-alkyl-7-phenyl-1,6-naphthyridine-5 (6H) -one derivatives corresponding to the formula-I o R 1 N - R2   wherein R 1 is alkyl of 1 to 4 carbon atoms, R 2 is hydrogen or halogen, alkyl, alkoxy or alkylthio each containing 1 to 4 carbon atoms, trifluoromethyl or a residue -NR5R6 where R5 and R6 each independently of one another means a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms, R3 represents a hydrogen or halogen atom, a trifluoromethyl group or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms, and R4 represents a hydrogen or halogen atom or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms, and their salts, characterized in that a compound of formula VII or of formula VIII is dehydrated (VII) R4 O R2 (VIII) (Z - R   in which R 1 to R 4 have the meanings already given, or mixtures thereof, and, if appropriate, converting the compounds of formula I thus obtained into their salts by reaction.   with mineral or organic acids.   7.- The therapeutic application of   Derivatives of 6-alkyl-7-phenyl-1,6-naphthyridine-5 (6H) -   one specified in any one of claims 1 to   , as active ingredients of drugs. 8. A medicament, characterized in that it contains, as active principle, a derivative of 6-alkyl-7-phenyl-1,6-naphthyridine-5 (6H) -one corresponding to formula I o R1 ()   wherein R 1 is an alkyl group containing 1 to 4 carbon atoms, R 2 is a hydrogen or halogen atom, an alkyl, alkoxy or alkylthio group each containing 1 to 4 carbon atoms, a trifluoromethyl group or a residue -NR5R6 where R5 and R6 each independently of one another means a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms, R3 represents a hydrogen atom or of halogen, a trifluoromethyl group or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms, and R4 represents a hydrogen or halogen atom or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms , in the free state or in the form of an acceptable salt from the point pharmacy.   9.- A medicament, characterized in that it contains, as active ingredient, at least one   6-alkyl-7-phenyl-1,6-naphthyridine-5 (6H) derivatives   one specified in any of the claims   2 to 4, in the free state or in the form of an acceptable salt from the pharmaceutical point of view.   10.- A drug, characterized in that   contains, as active substance, 7- (2-chlorophenyl) -   6-methyl-1,1,6-naphthyridine-5 (6H) -one, in the free state or in the form of a pharmaceutically acceptable salt. 11. A pharmaceutical composition, characterized in that it contains, as a principle   at least one derivative of 6-alkyl-7-phenyl-   1,6-naphthyridine-5 (6H) -one specified in any one of   Claims 8 to 10, in association with   excipients and vehicles acceptable from the point of view pharmaceutical.   12.- New derivatives of 6-alkyl-7-   phenyl-7-hydroxy-7,8-dihydro-1,6-naphthyridine-5 (6H) -one, characterized in that they correspond to the formula VII o (VII) R4 in which R1 signifies an alkSle group containing 1 to 4 carbon atoms, R2 represents a hydrogen or halogen atom, an alkyl, alkoxy or alkylthio group each containing from 1 to 4 carbon atoms, a trifluoromethyl group or a residue -NR5R6 o R5 and R6 each signify , independently of one another, a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms, R3 represents a hydrogen or halogen atom, a trifluoromethyl group or an alkyl or alkoxy group containing each of 1 to 3 carbon atoms, and R4 is a hydrogen or halogen atom or an alkyl or alkoxy group each containing 1 to 3 carbon atoms.   13. New 2-benzoylmethyl-nicotinamides, characterized in that they correspond to formula VIII O 1MR R2   Wherein R 1 is an alkylene group containing 1 to 4 carbon atoms, R 2 is a hydrogen or halogen atom, an alkyl, alkoxy or alkylthio group each containing 1 to 4 carbon atoms; carbon, a trifluoromethyl group or a residue -NR5R6 where R5 and R6 each independently of one another means a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms, R3 represents an atom of hydrogen or halogen, a trifluoromethyl group or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms, and R denotes a hydrogen or halogen atom or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms.   14.- A process for preparing the compounds   of formulas VII and VIII specified in claims 12 and   13, characterized in that a compound of formula V ONHR is reacted H3 (V)   in which R1 has the meaning given to the   12 or 13, with a strong base, so as to obtain a dianion which is reacted with a compound of formula VI X 3R 2 (VI)   R43R2 wherein R2, R3 and R4 have the meanings given in claim 12 or 13 and X represents a cyano group or a residue -COOR7 where R7 is a methyl, ethyl or n-propyl group, and when one is involved a compound of formula VI wherein X is a cyano group, the resulting compound is hydrolyzed. 15. New 2- (p-amino-styryl) nicotinamides; characterized in that they correspond to the formula X O C-NHR N CH = C NH2 2   Wherein R 1 is an alkylene group containing 1 to 4 carbon atoms, R 2 is a hydrogen or halogen atom, an alkyl, alkoxy or alkylthio group each containing 1 to 4 carbon atoms, a trifluoromethyl group; or a residue -NR5R6 wherein R5 and R6 each signify, independently of one another, a hydrogen atom or an alkyl group containing from 1 to 3 carbon atoms, R3 represents a hydrogen or halogen atom , a trifluoromethyl group or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms, and R4 represents a hydrogen or halogen atom or an alkyl or alkoxy group each containing from 1 to 3 carbon atoms.   16. A process for the preparation of the compounds of formula X specified in claim 15, characterized in that a compound of formula V UR1 is reacted. W 11 (V) d - CH3   in which R1 has the meaning given to the   15, with a strong base so as to obtain a dianion which is then reacted with a compound of formula VI (VI)   3 2 in which R2 to R have the meanings given in rec.   claim 15 and X represents a cyano group.