FR2584722A1 - New substituted amides, their preparation and the medicaments which contain them - Google Patents

Abstract

New substituted amides of general formula (I) in which either R is 2-quinolyl, benzyl, styryl or phenyl substituted with bromine, CF3, alkyloxycarbonyl, or with chlorine in position 3, dialkylamino in position 4 or with 3 alkyloxy and R' is halogen, phenyl, phenoxy, 4-chlorophenoxy or anilino, or R is dichlorophenyl, benzoyl or anilino and R' is halogen, phenyl or anilino, or R is phenyl or alkyloxyphenyl and R' is phenyl, 4-chlorophenoxy, anilino or 1-pyrrolidinyl, the straight or branched alkyl radicals containing 1 to 4 carbon atoms, their preparation and the medicaments which contain them. The new products are useful as immunostimulating agents.

Description

utiles comme antiarythmiques.In the PCT patent application 84 00489 have been described benzamide derivatives of general formula

useful as antiarrhythmics.

In the Dutch patent application 73 05482 and the American patent 3 993 656 were described te derivatives of 1,8-naphthyridines

leur préparation et les médicaments qui les contiennent.The present invention relates to new substituted amides corresponding to the general formula

their preparation and the drugs that contain them.

 In the general formula (I), - either the symbol R represents a quinolyl-2, benzyl, styryl or phenyl radical substituted by a bromine atom, a trifluoromethyl or alkyloxycarbonyl radical or substituted by a chlorine atom in position -3 or a dialcoylamino radical in position -4 or by 3 alkyloxy radicals, and the symbol R 'represents a halogen atom, a phenyl, phenoxy, chloro-4 phenoxy or anilino radical, - or the symbol R represents a dichlorophenyl, benzoyl or anilino radical and the symbol R 'represents a halogen atom, a phenyl or anilino radical, - or the symbol R represents a phenyl or alkyloxyphenyl radical and the symbol R' represents a phenyl, 4-chloro-phenoxy, anilino or pyrrolidinyl radical- 1, it being understood that the alkyl radicals mentioned above are straight or branched and contain 1 to 4 carbon atoms.

dans laquelle R'est défini comme précédemment.According to the invention, the products of general formula (I) in which R is defined as above with the exception of representing an anilino radical, and R ′ has the corresponding definition, can be prepared by the action of an acid of general formula
R - COOH (II) in which R is defined as above, or of a reactive derivative of this acid, on an amine of general formula

in which R is defined as above.

When the acid of general formula (II) is used, the operation is carried out in the presence of a peptide condensing agent such as a carbodiimide (for example dicyclohexylcarbodiimide) or
N, N '-carbonyldiimidazole or 1-ethoxy-2-ethoxycarbonyl-1 dihydro-1,2 quinoline, in an organic solvent such as an ether (for example tetrahydrofuran, dioxane, glyme, diglyme), an amide (for example dimethylformamide) , a nitrile (for example acetonitrile), a chlorinated solvent (for example methylene chloride, dichlorethane or chloroform) or an aromatic hydrocarbon (for example toluene), at a temperature between OOC and the reflux temperature of the reaction mixture. Preferably one operates at 200C.

 When using a reactive acid derivative of general formula (II) it is possible to react the anhydride, a mixed anhydride, an acid halide or an ester [which can be chosen from esters activated or not of the acid of general formula (11) 1. The operation is then carried out either in an organic medium, optionally in the presence of an acid acceptor such as an organic nitrogenous base (for example a trialkylamine, a pyridine, the diaza-1,8 bicyclo t5.4.0] undecene-7 or the diaza-1,5 bicyclo [4.3.0] nonème-5), in a solvent as mentioned above, or a mixture of these solvents, at a temperature between OOC and the reflux temperature of the reaction mixture, either by biphasic hydroorganic medium in the presence of an alkaline or alkaline earth base (soda, potash) or of a carbonate or bicarbonate of an alkali or alkaline earth metal at a temperature between 0 and 400C. It is also possible to operate without solvent at the melting temperature of the reaction mixture. Optionally, the reactive acid derivative can be prepared in situ.

 According to the invention, the products of general formula (I) in which the symbol R is an anilino radical, can be prepared by the action of phenyl isocyanate on an amine of general formula (III) in which R 'represents an atom d 'halogen, a phenyl or anilino radical.

 One generally operates in an organic solvent such as an ether (tetrahydrofuran, dioxane for example), a chlorinated solvent (methylene chloride, dichlorethane, chloroform for example) or an amide (dimethylformamide for example), at a temperature between 0 and 800C.

 The acids of general formula (II) can be prepared by applying the methods below or by analogy with these methods - when the symbol R represents an alkyloxyphenyl radical according to the method described by S.M. Mac ELVAIN and T.P. CARNEY, J. Amer.

Chem. Soc. , 68, 2592 (1946).

- when the symbol R represents an alkyloxycarbonylphenyl radical according to the methods described by KG RUTHERFORD et al.,
J. Org. Chem., 28, 582 (1963), by BH CHASE J. Chem. Soc, 1334 (1963) or by S. KASINA, J. Pharm. Sci., 63, 1155 (1974); - When R is a trialkylphenphenyl radical, according to the method described by E. KASZTREINER et al., Biochem. Pharmacology, 11, 651 (1962).

 The amines of general formula (III) in which the symbol R 'represents a phenoxy, 4-chloro-phenoxy, anilino or pyrrolidinyl-1 radical, can be prepared from the corresponding amine of general formula (III) in which R' is a halogen atom (preferably a chlorine atom), by the action of phenol, 4-chloro-phenol, aniline or pyrrolidine respectively.

 When it is desired to obtain an amine of general formula (III) in which R ′ is a phenoxy or 4-chloro-phenoxy radical, the operation is carried out in basic medium or in the presence of the corresponding alcoholate.

 The reaction is generally carried out in the presence of a strong base (sodium hydroxide, potassium hydroxide, quaternary ammonium hydroxide, sodium ethylate for example), at a temperature between 50 and 1500C, or else in the presence of the corresponding alcoholate ( for example sodium alcoholate), in a solvent such as an amide (dimethylformamide for example) or an ether (tetrahydrofuran, dimethoxyethane for example), or without solvent, in the presence of an excess of hydroxylated derivative at a temperature included between 700C and the reflux temperature of the reaction mixture.

 When the alcoholate is used, it is obtained beforehand by the action of sodium on the alcohol at a temperature between 20 and 80 C, or by the action of sodium hydride at a temperature between 0 and 200C in a solvent such as dimethylformamide, dimethoxyethane, or tetrahydrofuran. It is not necessary to isolate the alcoholate obtained in order to use it in the following reaction.

 When it is desired to obtain an amine of general formula (III) in which R ′ is an anilino or pyrrolidinyl-1 radical, the reaction is carried out with or without solvent at a temperature between 50 and 1500C. As a solvent, dimethylformamide, dichloromethane or tetrahydrofuran are advantageously used.

 The amines of general formula (III) can also be prepared by application of the methods described below in the examples or by application or by analogy with the methods described by - S. CARBONI, Gazz. Chim. Italiana, 96, 1456 (1966); - J.F. HARPER and D.G. WIBBERLEY, J. Chem. Soc., (C) 2985 (1971).

 The new amides according to the present invention can be purified if necessary, by physical methods such as crystallization or chromatography.

 The products of general formula (I) exhibit particularly advantageous immunostimulatory properties.

 The immunostimulatory activity has been demonstrated in vitro at molar concentrations of between 10 5 and 10 in stimulating the cytostatic activity of mouse peritoneal macrophages against P815 tumor cells according to a technique inspired by M.I.C. GYONGYOSSI et al., Cell. Immunol., 45, 1 (1979), and in vivo in mice, stimulation of the defense reactions against infection with Klebsiella pneumoniae is observed at doses between 0.2 and 20 mg / kg i.p. according to a technique inspired by M.A. PARANT et al., Infect. Immun., 27, 826 (1980).

 An advantage of the immunostimulatory activity of the products is their use as an anti-infectious agent, having in particular the possibility of fighting against germs which have become resistant to traditional antibiotics.

 Furthermore, the products according to the invention have low toxicity: their oral LD50 in mice is either between 300 and 900 mg / kg, or greater than 900 mg / kg.

 The following examples, given without limitation, illustrate the present invention.

EXAMPLE 1
To a solution of 3 g of 3-bromo benzoic acid in 50 cm3 of anhydrous tetrahydrofuran, 2.4 g of N, N'carbonyldiimidazole are added. An immediate gas evolution is observed. The mixture is stirred for 2 hours at a temperature in the region of 200C, until the evolution of gas has ended. 2.4 g of 2-amino-7-phenyl-naphthyridin-1.8 are then added and the mixture is heated at reflux for 20 hours. The mixture is poured into 500 cm3 of distilled water. The precipitate formed is separated by filtration, washed with water and dried in air.

 The product obtained (3.8 g - F = 170-1750C) is dissolved in 400 cm3 of boiling acetonitrile. After 4 hours of cooling to 40C, the crystallized solid is separated by filtration, washed with 3 times 10 cm3 of acetonitrile and dried at 40 "C under reduced pressure (0.07 kPa). 3.2 g of N- is obtained (7-phenyl-naphthyridine-1,8 yl-2) 3-bromo benzamide melting at 1750C.

2-amino-7-phenyl-naphthyridine-1,8 can be prepared by applying the method described by JF HARPER, DG WIBBERtEY,
J. Chem. Soc. (C) 2985 (1971).

EXAMPLE 2
The procedure is analogous to that described in Example 1, but starting with 10.4 g of quinoline-2-carboxylic acid, 13 g of N, N'-carbonyldiimidazole and 7.2 g of 2-amino-7-chloro naphthyridine-1,8. After cooling to 40C, the crystallized solid is separated by filtration, washed with 5 times 50 cm3 of distilled water and air dried. The product obtained (7.4 g - F = 260 "C) is dissolved in a mixture of 200 cm3 of dimethylformamide and 200 cm3 of methanol. After 3 hours of cooling to 4 C, the crystallized solid is separated by filtration, washed with 3 times 15 cm3 of methanol and dried at 35 "C under reduced vacuum (0.07 kPa). 3.6 g of
N- (7-chloro-naphthyridine-1,8 yl-2) quinoline carboxamide-2 melting at 275 "C.

EXAMPLE 3
The procedure is analogous to that described in Example 1, but starting with 10.9 g of phenylacetic acid, 13 g of
N, N'-carbonyldiimidazole and 10.8 g of amino-2-chloro-7 naphthyri dine-1,8. The product obtained by precipitation in water (13.5 g; F = 184 "C) is dissolved in 210 cm3 of boiling acetonitrile. After 1 hour of cooling to 40C, the crystallized solid is separated by filtration, washed with 10 cm3 of acetonitrile and dried at 450C under reduced pressure (0.07 kPa). 11.3 g of N- (7-chloro-naphthyridine-1,8 yl-2) phenylacetamide are obtained, melting at 187 "C.

EXAMPLE 4
To a suspension of 7.2 g of 2-amino-7-chloro-naphthyridine-1,8 in 80 cm 3 of pyridine, 7.3 g of cinnamoyl chloride are added. After 2 hours of stirring at 200C, the suspension obtained is poured into 500 cm3 of distilled water. The suspension is filtered, washed with 3 times 50 cm3 of water and dried at 50C under reduced pressure (0.07 kPa). The solid obtained (10.6 g; F = 2630C) is dissolved in 1200 cm3 of boiling propanol-1. After 4 hours of cooling to 40C, the crystallized solid is separated by filtration, washed with 3 times 50 cm3 of propanol-1, 2 times 50 cm3 of diethyl ether and dried at 50 "C under reduced pressure (0.07 kPa 11.4 g of
N- (7-chloro-naphthyridine-1,8 yl-2) phenyl-3 propenamide melting at 263 "C.

EXAMPLE 5
The procedure is analogous to that described in Example 1, but using 6 g of 3-benzoSque acid of 4.9 g of
N, N'-carbonyldiimidazole and 3.6 g of 2-amino-7-chloro-naphthyridine-1,8. The reaction mixture is poured into 100 cm3 of distilled water and extracted with 200 cm3 of methylene chloride. After decantation and drying over magnesium sulfate, the chloromethylenic solution is concentrated to dryness under reduced pressure (4 kPa) to obtain 10.2 g of a solid which is purified by chromatography on a column 3 cm in diameter containing 200 g of silica (0.063-0.2 mm), eluting with a mixture (98-2 by volume) of methylene chloride-methanol. 40 cm3 fractions are collected, fractions 11 to 16 are combined and concentrated to dryness under reduced pressure (4 kPa) to obtain 7.1 g of a solid melting at 2220C.

 This product is dissolved in 300 cm3 of boiling ethanol.

After 2 hours of cooling to 40C, the crystallized solid is separated by filtration, washed with 3 times 20 cm3 of ethanol, 2 times 20 cm3 of diethyl ether and dried at 40 "C under reduced pressure (4 kPa). obtains 8.7 g of N- (chloro-7 naphthyridine-1,8 yl-2) bromo-3 benzamide melting at 2240C.

EXAMPLE 6
The procedure is analogous to that described in Example 1, but starting with 6 g of 3-bromo benzoic acid, 4.9 g of
N, N'-carbonyldiimidazole and 5.9 g of 2-amino-7-phenoxy-naphthyridine-1,8. The product obtained by precipitation in water (9.8 g
F = 188-1920C) is dissolved in 300 cm3 of acetonitrile. After 1 hour of cooling to 49C, the crystallized solid is separated by filtration, washed with 3 times 10 cm3 of acetonitrile and dried at 400C under reduced pressure (0.07 kPa). 5.4 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) bromo-3 benzamide are obtained, melting at 194 ° C.

Amino-2 phenoxy-7 naphthyridine-1,8 can be prepared as follows
Heated for 20 hours at 1200C a mixture composed of 27 g of 2-amino-7-chloro-naphthyridine-1,8, 141 g of phenol and 19.8 g of potassium hydroxide pellets at 85%. The mixture obtained is taken up in 300 cm3 of an aqueous 4N sodium hydroxide solution and extracted with 250 cm3 of methylene chloride.

 The aqueous phase is extracted again with 2 times 200 cm 3 of methylene chloride. The organic extracts are washed with 2 times 150 cm3 of 4N sodium hydroxide then 250 cm3 of distilled water, dried over magnesium sulfate and concentrated to dryness at 400C under reduced pressure (4 kPa).

 The product obtained (30.5 g; F = 190-1940C) is dissolved in 400 cm3 of boiling acetonitrile. After 2 hours of cooling to 40C, the crystallized solid is separated by filtration, washed with 20 cm3 of acetonitrile and dried at 45 "C, under reduced pressure (0.07 kPa). 23.4 g of amino- 2 phenoxy-7 naphthyridine-1,8 melting at 1960C.

EXAMPLE 7
The procedure is analogous to that described in Example 1, but starting with 10 g of 4-trifluoromethyl benzolque acid, 8.4 g of N, N'-carbonyldiimidazole and 5.9 g of d 2-amino-7-chloro-naphthyridine-1,8. The product obtained by precipitation in water (11.5 g; F = 236 "C) is dissolved in 250 cm3 of boiling acetonitrile. After 4 hours of cooling to 40C, the crystallized solid is separated by filtration, washed with 2 times 20 cm3 of acetonitrile and dried at 450C under reduced pressure (0.07 kPa). 9 g of
N- (chloro-7 naphthyridine-1,8 yl-2) trifluoromethyl-4 benzamide melting at 2360C.

EXAMPLE 8
To a suspension of 7.2 g of 2-amino-7-chloro-naphthyridine-1.8 and 4.4 g of methyl potassium terephthalate in 80 cm3 of toluene, 1.55 g of phosphoryl chloride. The reaction mixture is then heated for 5 hours at reflux. The suspension obtained is filtered, washed with 3 times 20 cm3 of toluene, 3 times 20 cm3 of distilled water, 3 times 20 cm3 of ethanol and dried at 500C under reduced pressure (0.07 kPa). The solid obtained (9 g; melting above 2600C) is purified by chromatography on a column 4 cm in diameter containing 150 g of silica (0.040 - 0.063 mm), eluting with a mixture of methylene chloride and methanol ( 98-2 by volume). 50 cm3 fractions are collected, fractions 21 to 72 are concentrated to dryness under reduced pressure (4 kPa) to obtain 5.1 g of a solid which is dissolved in 1000 cm3 of propanol- 1 boiling. After 3 hours of cooling to 40C, the crystallized solid is separated by filtration, washed with 3 times 20 cm3 of propanol-1, 3 times 20 cm3 of diethyl ether and then dried at 500C under reduced pressure (0.07 kPa). 4.3 g of N- (7-chloro-naphthyridine-1,8 yl-2) methoxycarbonyl-4 benzamide are obtained, melting at 2750C.

 Methyl potassium terephthalate can be prepared by the method described by B.W. HOTTEN Ind. Eng. Chem., Int.

Ed., 49, 1691 (1957).

EXAMPLE 9
The procedure is analogous to that described in Example 1, but starting with 14.9 g of 4-dimethylamino-benzoic acid of 14.6 g of N, N'carbonyldiimidazole and 10.8 g of 2-amino-7-chloro-naphthyridine-1,8. The crude product obtained by filtration of the reaction mixture (6.4 g; F = 248 "C) is dissolved in 95 cm3 of boiling dimethylformamide. After 2 hours of cooling to 20" C, 95 cm3 of water are added. The crystallized solid is separated by filtration, washed with 2 times 10 cm 3 of a dimethylformamide water mixture (50-50 by volume), and dried at 45 "C under reduced pressure (0.07 kPa). 6.2 g of N- (7-chloro-naphthyridine-1,8 yl-2) 4-dimethylamino benzamide melting at 2480C.

EXAMPLE 10
The procedure is analogous to that described in Example 1, but starting with 17 g of 3,4,5-trimethoxy benzolque acid, 13 g of N, N'-carbonyldiimidazole and 8.9 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (10.3 g; F = 90 "C) is dissolved in 500 cm3 of boiling ethanol.

After 4 hours of cooling to 40C, the crystallized solid is separated by filtration, washed with 20 cm3 of ethanol and dried at 400C under reduced pressure (0.07 kPa). 8.2 g of N- (7-chloro-naphthyridine-1,8 yl-2)-3,4,5-trimethoxy benzamide, melting at 210 ° C., are obtained.

EXAMPLE 11
The procedure is analogous to that described in Example 1, but starting with 15.3 g of 3,4-dichloro-benzolque acid, 12.9 g of N, N'-carbonyldiimidazole and 8, 9 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (17.6 g; F = 228 "C) is dissolved in 900 cm3 of boiling ethanol.

After 2 hours of cooling to 40C, the crystallized solid is separated by filtration, washed with 2 times 30 cm3 of isopropyl ether and dried at 40 "C under reduced pressure (0.07 kPa). 9.2 g are obtained of N- (7-chloro-naphthyridine-1,8 yl-2) 3,4-dichloro benzamide melting at 230 "C.

EXAMPLE 12
The procedure is analogous to that described in Example 1, but starting from 22.5 g of phenylglyoxylic acid, 32.4 g of N, N'-carbonyldiimidazole and 18 g of 2-amino chloro-7 naphthyridine-1,8. After the reaction mixture has cooled, the crystallized solid is separated by filtration, washed with 5 times 100 cm 3 of distilled water and then 2 times 50 cm 3 of ethyl ether, and air-dried. The product obtained (14.4 g; F above 250 ° C.) is dissolved in a mixture of 100 cm 3 of dimethylformamide and 300 cm 3 of methanol. After 1 hour of cooling to 40 ° C., the crystallized solid is separated by filtration, washed with 3 times 50 cm3 of methanol and dried at 400C under reduced pressure (0.07 kPa), 10.7 g of 2-chloro-phenylglyoxyloylamino-7 naphthyridine-1,8 is obtained, melting at 273 -2750C.

EXAMPLE 13
The procedure is analogous to that described in Example 1, but starting with 12.6 g of benzoic acid, 7.45 g of
N, N'-carbonyldiimidazole and 12.6 g of amino-2 (4-chloro-phenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water (13 g; F = 100 "C) is purified by chromatography on a column 4 cm in diameter containing 200 g of silica (0.040 - 0.063 mm), eluting with methylene chloride and collecting fractions of 100 cm3 Fractions 10 to 25 are concentrated to 9/10 of the initial volume After 2 hours of cooling at OOC, the crystallized solid is separated by filtration, washed with 2 times 5 cm3 of diethyl ether and dried at 400C under reduced pressure (0.07 kPa). 4 g of N - [(4-chloro-phenoxy) -7 naphthyridine-1,8 yl-2j benzamide melting at 1480C are obtained.

Amino-2 (4-chloro-phenoxy) -7 naphthyridine-1,8 can be prepared as follows
A mixture composed of 1.8 g of 2-amino-chloro-7-naphthyridine-1,8, of 12.85 g of chloro-4-phenol and of 1.1 g of potassium hydroxide is heated for 8 hours at 140 ° C. 85% pellets The reaction mixture is poured into 200 cm3 of distilled water and basified to pH = 10 with 4N sodium hydroxide The suspension obtained is filtered and washed with distilled water to pH approximately 7. The solid obtained is air dried to give 2 g of amino-2 (4-chloro-phenoxy) -7 naphthyridine-1,8 melting at 1770C.

EXAMPLE 14
The procedure is analogous to that described in Example 1, but starting with 6.5 g of benzoic acid, 8.6 g of N, N'-carbonyldiimidazole and 8.6 g of amino- 2 (pyrrolidinyl-1) -7 naphthyridine-1.8. The product obtained by precipitation in water (13 g;
F = 1100C) is dissolved in 85 cm3 of boiling acetonitrile. After 2 hours of cooling to 40C the crystallized solid is separated by filtration, washed with 15 cm3 of acetonitrile and dried at 40 "C under reduced pressure (0.07 kPa). 11.5 g of N - [(pyrrolidinyl) are obtained -1) -7 naphthyridine-1,8 yl-2] benzamide melting at 1300C.

Amino-2 (pyrrolidinyl-1) -7 naphthyridine-1,8 can be prepared as follows
A mixture of 36 g of 2-amino-7-chloro-naphthyridine and 250 cm 3 of pyrrolidine is heated for 2 hours at 90 ° C. The suspension obtained is filtered, washed with 150 cm 3 of diethyl ether and then 4 times 100 cm 3 water. 11 g of the solid obtained after air drying (37 g; F = 249 "C) are dissolved in 550 cm3 of boiling acetonitrile. After cooling to 40C for 1 hour, the crystallized solid is separated by filtration, washed with 20 cm3 of acetonitrile and dried at 400C under reduced pressure (0.07 kPa). 8.3 g of amino-2 (pyrrolidinyl-1) -7 naphthyridine-1.8 are obtained, melting at 2510C.

EXAMPLE 15
The procedure is analogous to that described in example 1, but starting with 7.6 g of 4-methoxy-benzolic acid, 9.7 g of N, N'-carbonyldiimidazole and 13.3 g amino-2 phenyl-7 naphthine ridine-1,8. The reaction mixture is poured into 400 cm3 of distilled water and extracted with 2 times 200 cm3 of ethyl acetate. After washing with water and drying over magnesium sulfate, the organic extracts are concentrated to dryness under reduced pressure (4 kPa) to obtain 14.5 g of a thick oil. The oil obtained is purified by chromatography on a column 4.2 cm in diameter containing 300 g of silica (0.040 - 0.063 mm), eluting with methylene chloride. 100 cm3 fractions are collected; fractions 12 to 25 are concentrated to dryness under reduced pressure (4 kPa) to obtain 13.4 g of a solid melting at around 60 "C which is dissolved in 425 cm3 of boiling ethyl acetate. After 2 hours of cooling at 40C, the solid obtained is separated by filtration, washed with 2 times 15 cm3 of ethyl acetate and dried at 400C under reduced pressure (0.07 kPa). 7.5 g of N- (phenyl-7) are obtained naphthyridine-1,8 yl-2) 4-methoxy benzamide melting at 1870C.

 Amino-2-phenyl-7 naphthyridine-1,8 can be prepared according to the method described by J.F. HARPER and D.G. WIBBERLEY J. Chem.

Soc. (C) 2985 (1971).

EXAMPLE 16
The procedure is analogous to that described in Example 1, but starting with 6.1 g of 4-methoxy-benzorque acid, 6.5 g of N, N'-carbonyldiimidazole and 7 g of 2-amino-7-anilino naphthyridine-1,8. The product obtained by precipitation in water (12 g) is dissolved in 140 cm3 of boiling ethanol. After 1 hour of cooling to 40C the crystallized solid is separated by filtration, washed with 10 cm3 of ethanol and dried at 450C under reduced pressure (0.07 kPa). 4.5 g of N- (anilino-7 naphthyridine-1,8 yl-2) methoxy-4 benzamide are obtained, melting at 2450C.

Amino-2 anilino-7 naphthyridine-1,8 can be obtained as follows
A suspension of 9 g of 2-amino-7 chloro-naphthyridine-1,8 in 19.6 g of aniline is heated for 19 hours at 1200C. The suspension obtained is filtered, washed with 3 times 15 cm3 of diethyl ether and air dried. The crude solid obtained (14 g; F = 19O0C) is then dissolved in 700 cm3 of boiling ethanol. After 2 hours of cooling to 40C, the crystallized product is separated by filtration, washed with 25 cm3 of ethanol and air dried. 7.2 g of amino-2-anilino-7 naphthyridin-1.8 are obtained, melting at approximately 2500C.

EXAMPLE 17
To a solution of 17.9 g of 2-amino-7-chloro-naphthyridine-1,8 in 600 cm3 of anhydrous tetrahydrofuran, 15.5 g of phenyl isocyanate are added and the mixture is heated at approximately 60 ° C. for 15 hours.

After the mixture has cooled, the crystallized solid is separated by filtration, washed with 3 times 50 cm 3 of ethyl ether and air-dried. 25.2 g of crude product are obtained, melting at 270 ° C. 15 g of this product are purified under the following conditions: the product is dissolved in a mixture of 200 cm3 of dimethylformamide and 125 cm3 of acetonitrile. After 5 hours of cooling to 200C, the crystallized solid is separated by filtration, washed with 3 times 30- cm3 of acetonitrile and dried at 400C under reduced pressure (0.07 kPa). 10.1 g of N- (7-chloro-naphthyridine) is obtained -1.8 yl-2) -N'-phenylurea melting at 2760C.

 The present invention also relates to the medicaments which contain the products of formula (I) in the pure state or in the form of compositions in which they are associated with an adjuvant, a diluent and / or a coating which are compatible and pharmaceutically acceptable. These drugs can be used orally, rectally, parenterally, percutaneously or intranasally.

 As solid compositions for oral administration, tablets, pills, powders (generally in gelatin capsules) or granules can be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents, such as sucrose, lactose or starch. These compositions can also include substances other than diluents, for example a lubricant such as magnesium stearate.

 As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents such as water or paraffin oil can be used. These compositions can also include substances other than diluents, for example wetting, sweetening or flavoring products.

 The compositions according to the invention for parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil or injectable organic esters, for example ethyl oleate, can be used. These compositions can also contain adjuvants, in particular wetting agents, emulsifiers and dispersants. Sterilization can be done in several ways, for example using a bacteriological filter, incorporating sterilizing agents into the composition, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium.

 The compositions according to the invention for intranasal or parenteral administration can be sterile aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive, almond or coconut oil and injectable organic esters, for example ethyl oleate, can be used. These compositions can also contain adjuvants, in particular wetting agents, emulsifiers or dispersants (soy lecithin). Sterilization can be done in several ways, for example by incorporating sterilizing agents into the composition, by irradiation, by heating or by adding a preservative. They can be presented in the form of sterile solid compositions which will be dissolved at the time of use in a sterile injectable medium.

 The compositions for rectal administration are suppositories which may contain, in addition to the active product, excipients such as cocoa butter or suppo-wax.

 The compositions for percutaneous administration are creams, ointments, lotions and liniments, in which the active product is combined with liquid or pasty excipients, preferably in combination with a vehicle promoting percutaneous migration.

 The drugs and composition according to the invention are particularly useful in human therapy by their anti-infectious and immunorestorative action.

 In human therapy, the doses depend on the desired effect and on the duration of the treatment; they are generally between 1 and 500 mg per day orally, or between 0.1 and 50 mg per day parenterally for an adult.

 In general, the doctor will determine the dosage he considers most appropriate based on age, weight and all other factors specific to the subject to be treated.

 The following examples, given without limitation, illustrate a composition according to the invention.

EXAMPLE A
Tablets containing 5 mg of active product having the following composition - N- (phenyl-7 naphthyridine-1,8 yl-2) bromo-3 are prepared according to the usual technique
benzamide 0.005 g - starch ........................................ 0.100 g - precipitated silica 0.018 g - magnesium stearate ............................... magnesium O, 002 g
EXAMPLE B
An injectable solution having the following composition - N- (7-phenyl-naphthyridine-1,8 yl-2) methoxy-4 is prepared according to the usual technique.
benzamide 0.020 g - propylene glycol 1 cm3 - water for injections qs 2 cm3.

Claims (4)

1 - A new substituted amide derivative, characterized in that it corresponds to the general formula

 in which - either the symbol R represents a quinolyl-2, benzyl, styryl or phenyl radical substituted by a bromine atom, a trifluoromethyl or alkyloxycarbonyl radical, or substituted by a chlorine atom in position -3 or a dialkoylamino radical in position - 4, or by 3 alkyloxy radicals and the symbol R 'represents a halogen atom, a phenyl, phenoxy, chloro-4 phenoxy or anilino radical, - or the symbol R represents a dichlorophenyl, benzoyl or anilino radical and the symbol R' represents a halogen atom, a phenyl or anilino radical, - either the symbol R represents a phenyl or alkyloxyphenyl radical and the symbol R 'represents a phenyl, 4-chloro-phenoxy, anilino or pyrrolidinyl-1 radical, it being understood that the radicals The alkyl mentioned above are straight or branched and contain 1 to 4 carbon atoms. 2 - A process for the preparation of an amide derivative according to claim 1, for which R is defined as in claim 1, with the exception of representing an anilino radical, and R 'has the corresponding definition, characterized in that that we act an acid of general formula  R-COOH in which R is defined as above, or a reactive derivative of this acid on an amine of general formula

 wherein R 'is defined as in claim 1. 3 - A process for the preparation of an amide derivative according to claim 1, for which R is an anilino radical and R 'has the corresponding definition given in claim 1, characterized in that the isocyanate is made to act of phenyl on an amine of general formula

 in which R 'represents a halogen atom, or a phenyl or anilino radical. 4 - Medicinal product, characterized in that it contains at least one product according to claim 1 in the pure state or in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants.