FR2592880A2 - 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 phenyl substituted by acyloxy, alkylthio or alkyloxycarbonylamino, or by chloro in -2 or -4, or by 2-alkyloxy, or R is 2- or 4-pyridyl, pyrazinyl, 5,6-dihydrodithiin-2-yl, 5,6-dihydrooxathiin-2-yl, 1,3-dithiolyl, thiazolyl or substituted thienyl or furyl, or R is (2 to 4 C)alkenyl, unsaturated in the alpha position with respect to the carbonyl of the amide, and Het is 1,8-naphthyridin-2-yl, substituted in -7 by halogen, alkyloxy, phenoxy, 3-chloro- or dichlorophenoxy, hydroxyl or cyano, - or R is methoxyphenyl and Het is 1,8-naphthyridin-2-yl, substituted in position -7 by 3-chloro- or dichlorophenoxy, hydroxyl or cyano, - or R is methoxy-3-pyridazinyl and Het is 1,8-naphthyridin-2-yl, substituted in -7 by phenoxy, it being understood that the alkyl and acyl radicals contain 1 to 4 carbon atoms in straight or branched chain, their preparation and the medicaments which contain them. The new products are useful as anxiolytic, hypnotic and muscle-relaxing agents. R-CONH-Het

Description

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

useful as antiarrhythmics.

utiles comme brochodilatateurs et vasodilatateurs périphériques ou comme agents hypotenseurs.In Dutch patent application 73 05482 and American patent 3 993 656, derivatives of napbtyridine-1,8 of structure are described.

useful as peripheral brochodilators and vasodilators or as hypotensive agents.

The main patent concerns new substituted amides corresponding to the general formula
R-CONH-Het (I) their preparation and the medicines containing them.

 In the general formula (I), the symbol R is a cycloalkyl radical containing 3 to 6 carbon atoms, a phenyl radical optionally substituted (by a fluorine atom in position -2, -3 or -4, by an alkyl radical or alkyloxy in position -3 or -4 or by a methylenedioxy radical in position -3 and -4) or a heterocyclyl radical chosen from pyridyl-3, thienyl and pyridazinyl optionally substituted by an alkyl radical (or alkyloxy) and the symbol Het represents a quinolyl-2 or naphthyridine-1,8 yl-2 radical optionally substituted in position -7 by a halogen atom or by an alkyl or alkyloxy radical, it being understood that, when Het represents a quinolyl-2 radical, R is other than phenyl and that the radicals or alkyl portions mentioned above are straight or branched and contain 1 to 4 carbon atoms.

 When the symbol Het contains a halogen substituent, this is chosen from fluorine, chlorine and bromine.

According to the main patent, the products of general formula (I) 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
H2N-Het (III) in which Het is defined as above.

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

 When using a reactive derivative of the acid 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 activated by 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, diaza-1,8 bicyclo (5.4. or undecene-7 or diaza-1,5 bicyclo [4.3.01 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 in a two-phase 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 400 ° C. It is also possible to operate without solvent at the melting temperature of the mixture reactive.

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

 The products of general formula (I) according to the main patent have particularly advantageous pharmacological properties. They show activity as anxiolytics, hypnotics, anticonvulsants, antiepileptic and muscle relaxants of good level highlighted in the tests below.

In particular, they have a good in vitro affinity for benzodiazepine receptor sites at concentrations between 5 and 1000 nM according to the technique described by JC Blanchard and
L. Julou, J. of Neurochemistry, 40, 601 (l983) inspired by the work of Squires and Braestrup, Nature, 266, 732 (1977);
Furthermore, the products according to the main patent have low toxicity: their oral LD50 in mice is between 100 and 900 mg / kg and doses greater than 900 mg / kg.

 The present addition relates to new substituted amides of general formula (I), their preparation and the medicaments containing them.

According to the present addition, in the general formula (I), - either the symbol R represents a phenyl radical substituted by an acyloxy, alkylthio or alkyloxycarbonylamino radical, by a chlorine atom in position -2 or -4 or by two alkyloxy radicals, or represents a heterocyclyl radical chosen from pyridyl-2, pyridyl-4, pyrazinyl, dihydro-5,6 dithiinnyl-2, dihydro-5,6 oxathiinnyle-2, dithiolyl-1,3, thiazolyl or, thienyl or furyl substituted by a halogen atom or by an alkylthio radical, or
R represents an alkenyl radical containing 2 to 4 carbon atoms and the double bond of which is in a relative to the carbonyl group of the amide function, and the symbol Het represents a naphthyridine-1,8 yl-2 radical substituted in position - 7 by a halogen atom or by an alkyloxy, phenoxy, 3-chloro-phenoxy, dichlorophenoxy, hydroxy or cyano radical, - either the symbol R represents a methoxy phenyl radical and the symbol Het represents a naphthyridine-1,8 yl radical- 2 substituted in position -7 by a chloro-3 phenoxy, dichlorophenoxy, hydroxy or cyano radical, - either the symbol R represents a methoxy pyridazinyl-3 radical and the symbol Het represents a naphthyridine-1,8 yl-2 radical substituted in position -7 by a phenoxy radical, it being understood that the alkyl and acyl radicals mentioned above contain 1 to 4 carbon atoms in straight or branched chain.

As in the main patent, when the symbol
Het contains a halogen substituent, this is chosen from fluorine, chlorine and bromine.

 When the symbol R contains a halogen substituent, the latter can also be chosen from fluorine, chlorine and bromine.

 According to the invention, the products of general formula (I) defined according to the addition, can be obtained by the action of an acid of general formula (II) in which R is defined according to the addition, or of a reactive derivative of this acid, on an amine of general formula (III) in which Het is defined according to the present addition.

 The reaction is carried out under the conditions described above in the main patent for the preparation of the amides of general formula (I).

 According to the invention, the amides of general formula (I) in which Het is a naphthyridine-1,8 yl-2 radical substituted in position -7 by a hydroxy radical, can also be prepared from the corresponding amide of formula general (I) in which Het is a naphthyridine-1,8 yl-2 radical substituted in position -7 by a halogen atom (preferably a chlorine atom), by treatment in an acid medium, followed by the hydrolysis of the product obtained.

 The operation is advantageously carried out by treatment with acetic acid optionally in the presence of acetic anhydride or with formic acid at a temperature between 50 ° C. and the reflux temperature of the reaction mixture.

The acids of general formula (II) and their reactive derivatives, can be prepared by applying the methods described below (or by analogy with these methods) or by the methods described below in the examples - when R is acyloxyphenyl, according to Von H. Schbnenberger et al.,
Arz. Forsch., 14, 324 (1964); - when R is dihydro-5,6 dithiinnyle-2, according to KG Gundermann et al., 95, 2076 (1962); - when R is 1,3-dithiolyl according to CH Pittman, JCS Chem.

Comm., 960 (1975); - when R is thiazolyl according to H. Erlenmeyer et al., Helv. Chim.

Acta, 20, 204 (1937) and 25, 1073 (1942); - when R is substituted thienyl, according to HD Hartough, The Chemistry of Heterocyclic compound, thiophen and its derivatives, Interscience Publishers Inc. New-York p. 363 (1952) - when R is furyl substituted, according to the methods described in
Advances in Het. Chem. 7, 377 (1966) and 30, 167 (1982).

The amines of general formula (III) according to the present addition in which Het carries an optionally substituted alkyl or phenoxy substituent, can be prepared from the corresponding amine in which the symbol Het carries a halogen substituent (preferably a chlorine atom ) by the action of a hydroxyl derivative of general formula
R 'OH (Iv) (in which R' represents an alkyl, phenyl, 3-chlorophenyl or dichlorophenyl radical) in basic medium, or by the action 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 of general formula (IV) at a temperature between 20 and 800C, 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.

 The amines of general formula (III) can also be prepared by applying the methods described below in the examples or according to the method described by S. CARBONI, Gazz.

Chim. Italiana, 96, 1456 (1966).

 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) have particularly advantageous pharmacological properties. They show activity as good anxiolytics, hypnotics, and muscle relaxants.

They show in particular a good in vitro affinity for benzodiazepine receptor sites at concentrations between 5 and values close to 1000 nM according to the technique described by JC Blanchard and L. Julou, J. of Neurochemistry, 40, 601 (1983) inspired by the works of Squires and Braestrup, Nature, 266, 732 (1977);
Furthermore, the products according to the invention have a low toxicity: their oral LD50 in mice is equal to or greater than 900 mg / kg.

 The following examples illustrate the present invention.

EXAMPLE 1
To a solution of 14.1 g of 4-chlorobenzolic acid in 90 cm 3 of anhydrous tetrahydrofuran, 14.7 g of
N, N'-carbonyldiimidazole. The mixture is stirred for 1 hour at a temperature in the region of 200C, until the end of gas evolution. 10.8 g of 2-amino-7-chloro-naphthyridine-1.8 are then added and the mixture is heated at reflux for 3 hours.

 The insoluble product is separated by filtration, washed with 3 times 50 cm3 of tetrahydrofuran and dried at 500C under reduced pressure (0.07 kPa). After recrystallization of the product thus obtained in 100 cm3 of propanol-2, 9.3 g of N- (7-chloro-naphthyridine-1,8 yl-2) -4-chloro-benzamide melting at 2680C are obtained.

 The amino-2 chloro-7 naphthyridine-1,8 can be prepared according to the method described by S. CARBONI, Gazz. Chim. Italiana, 96, 1456 (1966).

EXAMPLE 2
To a solution of 12.5 g of 2-chloro-benzolic acid in 250 cm 3 of anhydrous tetrahydrofuran, 12.9 g of N, N'carbonyldiimidazole are added. The mixture is stirred for 2 hours at a temperature close to 200C, until the end of gas evolution. 8.9 g of 2-amino-7-chloro-naphthyridine-1.8 are then added and the mixture is heated at reflux for 22 hours. The reaction mixture is poured into 2000 cm 3 of distilled water, the precipitate formed is separated by filtration, washed with water and air dried. By recrystallization of the product thus obtained, in 180 cm3 of ethanol, 6.9 g of
N- (chloro-7 naphthyridine-1,8 yl-2) chloro-2 benzamide melting at 1800C.

EXAMPLE 3
23.5 g of 4-acetoxy-benzoyl chloride are added dropwise in a solution of 18 g of 2-amino-7-chloro-naphthyridine-1,8 in 215 cm 3 of anhydrous pyridine while maintaining the temperature in the region of 20 "VS.

 The reaction mixture is stirred again for 1 hour at 200C and then poured into 1200 cm3 of water. The precipitate obtained is separated by filtration, washed with 300 cm3 of water and air-dried to give 32.5 g of a solid melting at 220 ° C. By recrystallization from 15.5 g of the product thus obtained, in 400 cm3 of acetonitrile, 11.4 g of N- (7-chloro-naphthyridine-1,8 yl-2) acetoxy-4-benzamide melting at 2200C are obtained.

 Benzoyl-4-acetoxy chloride can be prepared according to the method described by Von H. Schbnenberger et al., Arz. Forsch.

14, 324 (1964).

EXAMPLE 4
The procedure is analogous to that described in example 3, but starting from 40.5 g of 3-acetoyloy Benzoyl chloride of 32 g of 2-amino-7-chloro-naphthyridin-1,8 and 360 cm3 of anhydrous pyridine. After precipitation of the reaction mixture in 2000 cm3 of water, washing with 3 times 500 cm3 of water and drying, 58.8 g of a crystallized solid melts at approximately 195 "C. By recrystallization from 12 g of the product thus obtained obtained in 350 cm3 of acetonitrile, 7.5 g of N- (7-chloro-naphthyridine-1,8 yl-2) acetoxy-3 benzamide are obtained, melting at 2070C.

 Benzoyl-3-acetoxy chloride can be prepared according to the method described by Von H. Schonenberger et al. Arz. Forsch.

14, 324 (1964.

EXAMPLE 5
The procedure is analogous to that described in Example 3, but starting with 3.5 g of 2-amino-7-methoxy-naphthyridine, 4.4 g of 3-acetoylibenzoyl chloride and 40 cm3 of anhydrous pyridine. The reaction mixture is poured into 400 cm3 of water and the precipitate obtained is separated by filtration then washed with 6 times 100 cm3 of water and air dried. By recrystallization of the product thus obtained in 140 cm3 of ethanol, 5.3 g of N- (7-methoxy-naphthyridine-1,8 yl-2) acetoxy-3 benzamide, melting at 1720C, are obtained.

 Amino-2 methoxy-7 naphthyridine-1,8 can be prepared according to the method described in US Pat. No. 3,948,917.

EXAMPLE 6
The procedure is analogous to that described in Example 2, but starting with 20.7 g of 4-methylthio-benzolque acid, 25.1 g of N, N'-carbonyldiimidazole and 27.8 g amino-2 chloro-7 naphthyridine-1,8. The product obtained after precipitation of the reaction mixture in water and drying is purified by chromatography on a 40 mm diameter column containing 300 g of silica (0.06 - 0.20 mm), eluting with a mixture (90 / 10 by volume) of methylene chloride and methylcyclohexane, and collecting fractions of 100 cm3. After dry concentration of fractions 15 to 44, at 40 ° C. under reduced pressure (4 kPa), 8.9 g of a solid are obtained which is recrystallized from 550 cm3 of ethyl acetate. 3 g of N- (chloro-7 naphthyridin-1,8 yl-2) methylthio-4 benzamide melting at 199 "C.

EXAMPLE 7
The procedure is analogous to that described in Example 2 but starting from 10 g of 3-ethoxycarbonylamino-benzolque acid, 7.6 g of N, N'-carbonyldiimidazole and 5.95 g of d 2-amino-7-methoxy-naphthyridine-1,8. The reaction mixture is then poured into 1000 cm3 of water and the precipitate formed is separated by filtration, washed with 10 cm3 of water and dried in air. By recrystallization of the product thus obtained from 100 cm3 of ethyl acetate, 7.3 g of N- (7-methoxy-naphthyridine-1,8 yl-2) ethoxycarbonylamino-3 benzamide, melting at 1200C, are obtained.

BenzoSque-3-ethoxycarbonylamino acid can be prepared as follows
Stirred for 30 minutes at 50C a mixture of 20 g of 3-amino benzorque acid, 730 cm3 of a 1M aqueous solution of sodium bicarbonate and 14 cm3 of ethyl chloroformate. 300 cm3 of 2.5N hydrochloric acid are then added to the reaction mixture. The precipitate formed is separated by filtration, washed with 3 times 200 cm 3 of water and dried at 40 "C under reduced pressure (0.07 kPa). This gives 25 g of 3-ethoxycarbonylamino benzotque acid, melting at 1980C.

EXAMPLE 8
The procedure is analogous to that described in example 2, but starting with 14.6 g of 3,4-dimethoxy benzoic acid, 12.9 g of N, N'-carbonyldiimidazole and 8.9 g of amino-2 chloro-7 naphthyridine-1,8, but heating for 17 hours at reflux. The product obtained after precipitation of the reaction mixture in 1000 cm3 of water and drying is purified by recrystallization from 250 cm3 of acetonitrile. 8.5 g of N- (7-chloro-naphthyri dine-1.8 yl-2)-3,4-dimethoxy benzamide, thus melting at 1960C, are thus obtained.

EXAMPLE 9
The procedure is analogous to that described in Example 2, but starting with 14.56 g of 3,5-dimethoxy benzolque acid, 12.9 g of N, N'-carbonyldiimidazole and 8.9 g of amino-2 chloro-7 naphthyridin-1,8, but heating for 20 hours at reflux.

 The product obtained after precipitation in 2000 cm3 of water and drying is purified by recrystallization from 900 cm3 of acetonitrile. 10.75 g of N- (7-chloro-naphthyridine-1,8 yl-2)-3,5-dimethoxy benzamide are thus obtained, melting at 2350C.

EXAMPLE 10
The procedure is analogous to that described in Example 1, but starting from 7.4 g of pyridinecarboxylic acid-1, 9.7 g of N, N'-carbonyldiimidazole and 8.1 g of amino-2 chloro-7 naphthyridine-1,8, but by carrying out the reaction for 18 hours at a temperature close to 2500 The product obtained after filtration, washing with 60 cm3 of tetrahydrofuran and 120 cm3 of water, then drying , is suspended in 120 cm3 of ethanol and stirred for 1 hour at 250C. The insoluble product is separated by filtration and dried at 450C under reduced pressure (0.07 kPa). 8.2 g of N- (7-chloro-naphthyridine-1,8 yl-2) pyridinecarboxamide-2 are thus obtained, melting at 31,900.

EXAMPLE 11
The procedure is analogous to that described in Example 2, but starting with 6.2 g of pyridinecarboxylic acid-4, 8.1 g of N, N'-carbonyldiimidazole and 9 g of amino- 2 chloro-7 naphthyridine-1,8. The product obtained after precipitation in 500 cm3 of water, washing with 50 cm3 of tetrahydrofuran, then washing with 200 cm3 of water and drying (9.8 g; F = about 2200C) is purified by crystallization from 850 cm3 of acetonitrile . 5.2 g of N- (chloro-7 naphthyridin-1,8 yl-2) pyridinecarboxamide-4 are thus obtained, melting at 2280C.

EXAMPLE 12
The procedure is analogous to that described in Example 1, but starting with 7.5 g of pyrazinecarboxylic-2 acid, 9.7 g of N, N'-carbonyldiimidazole and 10.8 g of 2-amino-7-chloro naphthyridine-1,8. The insoluble product is separated by filtration, washed 3 times 50 cm3 of tetrahydrofuran then with 300 cm3 of water and air dried. The product is suspended in 100 cm3 of acetonitrile. stirred for 1 hour at 250 ° C. and separated by filtration and then dried at 50 ° C. under reduced pressure (0.07 kPa). This gives 11.75 g of N- (7-chloro-naphthyridine-1,8 yl-2) pyrazinecarboxamide-2 melting at 3080C,
EXAMPLE 13
A solution of 14.3 g of dihydro-5,6 dithiinno chloride [1> 41 carbonyl-2 in 50 cm3 of anhydrous pyridine is added over 10 minutes at a temperature of 250 ° C. to a solution of 28.6 g of amino -2 chloro-7 naphthyridine-1,8 in 300 cm3 of anhydrous pyridine. After 3 hours of stirring at a temperature of 250C, the insoluble material is separated by filtration, washed with 2 times 15 cm3 of pyridine then 20 cm3 of isopropyl ether. The filtrate is concentrated to dryness at 60 ° C. under reduced pressure (4 kPa) and the residue is taken up in 200 cm3 of water. The crystallized solid obtained is separated by filtration, washed with 200 cm3 of water and dissolved in 500 cm3 of a chloroform-methanol mixture (90% by volume) The solution obtained is washed with 100 cm3 of a 0.5N solution of hydrochloric acid and then 3 times 100 cm3 of water, dried over sodium sulfate and concentrated to dryness at 600C under reduced pressure (4 kPa).

 The solid obtained is purified by "Flash" chromatography at 40 kPa on a 63 mm diameter column containing 500 g of silica (0.04-0.06 mm), eluting with chloroform and collecting 300 cm3 fractions. After concentrating the fractions 2 to 8 to 60 ° C. to dryness under reduced pressure (4 kPa), 15 g of a solid are obtained which is stirred in suspension in 325 cm 3 of acetonitrile for 1 hour at OOC. The insoluble product is separated by filtration, washed with twice 30 cm3 of acetonitrile and air-dried. 11.9 g of N- (7-chloro-naphthyridine-1.8 yl-2) dihydro-5.6 dithiinno are obtained (1 , 4] carboxamide-2 melting at 237 C.

Dihydro-5,6 dithiinno (1> 4] carbonyl-2 chloride can be prepared as follows
A suspension of 13.1 g of dihydro-5,6 dithiinno (1,4] carboxylic-2 acid in 60 cm3 of thionyl chloride is gradually heated to reflux. After 30 minutes at reflux the solution obtained is concentrated to dry at 500C under reduced pressure (4 kPa) and the oily residue obtained is washed with 2 times 100 cm3 of cyclohexane The decanted oil is dried at 50 C under reduced pressure (4 kPa). 5,6-dihydro-dithiinno [1,4] carbonyl-2 chloride which is used as it is in the following operation.

EXAMPLE 14
The procedure is analogous to that described in Example 2, but starting from 10.9 g of dithiinno t1.4] dihydro-5,6 carboxylic-2 acid of 10.9 g of N, N ' carbonyldiimidazole and 11.9 g of 2-amino-7-phenoxy-naphthyridine-1,8 and heating for 18 hours at reflux. The product obtained after precipitation in water, washing with water and drying (18 g; F = about 240 ° C.) is purified by recrystallization from 150 cm3 of dimethylformamide. 15 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) dithiinno (1> 4] dihydro-5,6 carboxamide-2 are thus obtained, melting at 245 C.

 Dihydro-5,6 dithiinno C1,43 carboxylic-2 acid can be prepared according to K.G. GUNDERMANN et al., Ber 95, 2076 (1962).

EXAMPLE 15
The procedure is analogous to that described in Example 2, but starting with 7.3 g of 5.6-dihydro-5,6-oxathiine-1,4-carboxylic acid> of 9.7 g of N, N'-carbonyldiimidazole and 7.2 g of 2-amino-7-chloro-naphthyridine-1,8. The product obtained by precipitation in water is purified by recrystallization from 60 cm3 of dimethylformamide. 5.9 g of N- (chloro-7 naphthyridine-1,8 yl-2) dihydro-5,6 oxathiine-1,4 carboxamide-2 are thus obtained, melting at 270 ° C.

Dihydro-5> 6 oxathiine-1,4 carboxylic-2 acid can be prepared as follows
To a solution of 15.6 g of mercapto-2 ethanol in 50 cm3 of ethanol> 39 g of ethyl bromopyruvate are added over 20 minutes.

The reaction mixture is stirred for 2 hours then concentrated to dryness under reduced pressure (4 kPa). The oily product obtained (37 g) is added to a mixture of 30 cm3 of 10N sodium hydroxide and 170 cm3 of ethanol.

After 2 hours of heating at reflux, the reaction mixture is concentrated to dryness under reduced pressure (4 kPa), then dissolved in 110 cm3 of distilled water. The precipitate obtained after neutralization with concentrated hydrochloric acid (d = 1.19) is separated by filtration, washed with 3 times 50 cm3 of distilled water and air dried.

10.8 g of dihydro-5,6 oxathiine-1,4 carboxylic-2 are obtained, melting at 1440C.

EXAMPLE 16
The procedure is analogous to that described in Example 2> but starting with 4.6 g of dithiole-1> 3 carboxylic acid-4 and 7.5 g of N>N'-carbonyldiimidazole and 4.2 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water (4> 8 g) is taken up in 300 cm3 of boiling acetonitrile, the insoluble material is removed by filtration and the filtrate is poured into 500 cm3 of water. The precipitate obtained is purified by recrystallization from 650 cm3 of an acetonitrile-water mixture (5/2 by volume). 2.8 g of N- (chloro-7 naphthyridine-1,8 yl-2) dithiole-1> 3 carboxamide-4 are thus obtained, melting at 2350C.

 The dithiole-1,3-carboxylic-4 acid can be prepared by applying the method described by: C.U. Pittman Jr et al., J.C.S. Chem. Comm. 960 (1975).

EXAMPLE 17
The procedure is analogous to that described in Example 2>, but using 4.8 g of thiazolecarboxylic acid-4 of 7> 5 g of N>N'-carbonyldiimidazole and 4.8 g of d 2-amino-chloro-7 naphthyri dine-1> 3. The product obtained by precipitation in water is purified by recrystallization from 350 cm3 of dimethylformamide. 6 g of N- (chloro-7 naphthyridine-1,8 yl-2) thiazolecarboxamide-4 are thus obtained, melting at 3250C.

Thiazolecarboxylic acid-4 can be prepared by applying the method described by: H. Erlenmeyer et al.,
Helv. Chim. Acta, 25, 1073 (1942).

EXAMPLE 18
The procedure is analogous to that described in Example 2, but using 4.5 g of thiazolecarboxylic acid-5, 6.8 g of N, N'-carbonyldiimidazole and 5 g of amino- 2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water is purified by recrystallization from 120 cm3 of a mixture of dimethylformamide acetonitrile (5/5 by volume). 5.5 g of
N- (chloro-7 naphthyridine-1,8 yl-2) thiazolecarboxamide-5 melting at 292 C.

 Thiazolecarboxylic acid-5 can be prepared by applying the method described by H. Erlenmeyer et al., Helv.

Chim. Acta, 20, 204 (1937).

EXAMPLE
The procedure is analogous to that described in example 2, but starting from 9.5 g of 5-chloro thiophenecarboxylic acid-2, 9.5 g of N, N'-carbonyldiimidazole and 8 g of amino-2 chloro-7 naphthyridine-1,8. The product obtained by precipitation in water is purified by recrystallization from 700 cm3 of propanol. 8.3 g of N- (chloro-7 naphthyridine-1,8 yl-2) chloro-5 thiophenecarboxamide-2 are thus obtained, melting at 2750C.

Chloro-5 thiophenecarboxylic-2 acid can be prepared by applying the method described by L. Gattermann et al.,
Chem. Ber., 19, 688 (1886).

EXAMPLE 20
The procedure is analogous to that described in Example 2, but starting with 5.6 g of 5-methylthio-thiophenecarboxylic acid-2, 5.2 g of N, N'-carbonyldiimidazole and 4.3 g of amino-2-chloro-7 naphthyridine-1,8. The product obtained by precipitation in water is purified by recrystallization from 200 cm3 of a dimethylformamide-methanol mixture (5/5 by volume). 6.1 g of N- (chloro-7 naphthyridine-1,8 yl-2) methylthio-5 thiophènecarboxamide-2 are thus obtained, melting at 2350C.

 5-methylthio-thiophenecarboxylic-2 acid can be prepared by applying the method described by J. Cymerman-Craig et al., J. Chem. Soc., 237 (1954).

EXAMPLE 21
The procedure is analogous to that described in Example 2, but starting with 2.9 g of 5-bromo-furanecarboxylic-2 acid, 2.4 g of N, N'-carbonyldiimidazole and 1 , 8 g-amino-2-chloro-7 naphthyridine-1,8. The product obtained by precipitation in water is purified by recrystallization from 100 cm3 of a dimethylformamide-methanol mixture (5/5 by volume). 2.6 g of N- (chloro-7 naphthyridine-1,8 yl-2) bromo-5 furanecarboxamide-2 are thus obtained, melting at 2850C.

EXAMPLE 22
Is added over 30 minutes with stirring, 42 g of acryloyl chloride to a solution of 54 g of 2-amino-7-chloro-naphthyridine-1,8 and 115 g of triethylamine in 1875 cm3 of methylene chloride. The solution obtained is heated for 1 hour at reflux and then poured into 5000 cm3 of isopropyl ether. The precipitate obtained is filtered, washed with 3 times 200 cm3 of isopropyl ether and then 3 times 200 cm3 of water at 40 "C and air dried. The crude product obtained is purified by" Flash "chromatography (under 50 kPa) on a column 60 mm in diameter containing 500 g of silica (0.04 0.06 mm), eluting with a mixture (99/1 by volume) of methylene chloride and methanol and collecting fractions of 100 cm3.

After dry concentration of fractions 5 to 10 at 400C under reduced pressure (4 kPa), 5.85 g of N- (7-chloro-naphthyridine-1.8 yl-2) acrylamide melting at 2000C are obtained.

EXAMPLE 23
To a solution of 9 g of 2-amino-chloro-7 naphthyridine-1,8 and 19 g of triethylamine in 300 cm3 of methylene chloride, 9 g of methacryloyl chloride dissolved in 30 cm3 of methylene chloride. After 30 minutes of reflux, the solution obtained is washed with 150 cm3 of 0.5N hydrochloric acid and twice 150 cm3 of distilled water, then concentrated to dryness under reduced pressure (4 kPa). The solid obtained (13.5 g) is dissolved in 350 cm3 of boiling methanol. After 3 hours of cooling to 40C, the crystallized solid is separated by filtration, washed with 2 times 30 cm3 of methanol and air dried. The isolated product (9 g - F = 1950C) is then added over 5 minutes to 19 cm3 of concentrated sulfuric acid (d = 1.83). The reaction mixture is heated for 10 minutes at 600cl stirred for 1 hour at 250C, then poured in 200 cm3 of distilled water. The precipitate formed is separated by filtration, washed with 5 times 20 cm 3 of distilled water and recrystallized from 70 cm 3 of acetonitrile. 5.4 g of N- (chloro-7 naphthyridine-1,8 yl-2) methacrylamide are thus obtained, melting at 1820C.

EXAMPLE 24
The procedure is analogous to that described in Example 2, but starting with 18.24 g of 4-methoxy benzoic acid, 19.44 g of N, N'-carbonyldimidazole and 20.6 g amino-2 (3-chloro-phenoxy-7) naphthyridine 1,8, heating for 2 hours at reflux.

 The reaction mixture is poured into 1000 cm3 of distilled water and 1000 cm3 of methylene chloride. The aqueous phase is extracted with 250 cm3 of methylene chloride. The organic extracts are combined and then washed with 250 cm3 of distilled water, dried over magnesium sulfate and concentrated to dryness at 500C under reduced pressure (4 kPa). The product obtained is purified by recrystallization from 700 cm3 of acetonitrile. 20 g of N-t (3-chloro-phenoxy) -7 naphthyridin-1,8 yl-21 (4-methoxy-benzamide) thus melting at 1820C are obtained.

Amino-2 (3-chloro-phenoxy) -7 naphthyridin-1,8 can be prepared as follows
17.95 g of 2-amino-7-chloro-naphthyridine-1.8 are added to a mixture preheated to 6O0C of 51.4 g of 3-chloro-phenol and 13.2 g of potassium hydroxide pellets at 85%. The reaction mixture is heated at 120 ° C. for 3 hours. The product is separated by filtration, washed with water to a pH of about 7 and then air dried. 20.6 g of amino-2 (3-chloro phenoxy) -7 naphthyridin-1.8 are obtained, melting at 1660C.

EXAMPLE 25
The procedure is analogous to that described in Example 2, but starting with 8.5 g of 4-methoxy-benzolque acid, 9 g of
N, N'-carbonyldiimidazole and 10.7 g of amino-2 (3,4-dichloro phenoxy) -7 naphthyridine-1,8. The product obtained by precipitation in water is purified by "flash" chromatography (under 30 kPa) on a column 40 mm in diameter containing 200 g of silica (0.04 0.06 mm), eluting with a mixture (9 / 1 by volume) of methylene chloride and methanol and collecting 100 cm 3 fractions.

After dry concentration of fractions 6 to 12 to 40 "C under reduced pressure (4 kPa), 6.35 g of a solid are obtained which is recrystallized from 160 cm3 of acetonitrile. 5.55 g of N are thus obtained - ((3,4-dichloro-phenoxy) -7 naphthyridin-1,8 yl-21 methoxy-4 benzamide melting at 1800C.

Amino-2 (3,4-dichloro phenoxy) -7 naphthyridine-1,8 can be prepared as follows
The procedure is analogous to that described in Example 24 but starting from 17.95 g of 2-amino-7-chloro-naphthyridin-1,8, 65.2 g of 3,4-dichloro-phenol and 13.2 g of potash in 85% pellets, heating at 1259C for 22 hours. By recrystallization of the crude product obtained in 1500 cm3 of acetonitrile, 18 g of amino-2 (3,4-dichloro-phenoxy) -7 naphthyridine-1,8 are obtained, melting at 2060C.

EXAMPLE 26
The procedure is analogous to that described in Example 1, but starting with 8.2 g of 4-methoxy benzoic acid, 8.7 g of N, N'-carbonyldiimidazole and 6.9 g amino-2 cyano-7 naphthyridine-1,8 and heating for 4 hours at reflux. The insoluble product is separated by filtration and the filtrate is poured into 1000 cm3 of water.

The resulting precipitate is filtered, washed with 3 times 75 cm3 of water and air dried. The solid obtained is purified by "flash" chromatography (under 30 kPa) on a 40 mm diameter column containing 170 g of silica (0.04 - 0.06 mm), eluting with pure methylene chloride and collecting fractions of 50 cm3. After dry concentration of fractions 5 to 27 at 400C under reduced pressure (4 kPa), the product obtained is purified by recrystallization from 160 cm3 of dioxane. 1.4 g of N- (cyano-7 naphthyridine-1,8 yl-2) methoxy-4 benzamide are thus obtained, melting at 283 "C.

 Amino-2 cyano-7 naphthyridine-1,8 can be prepared according to the method described in Belgian patent 815,019.

EXAMPLE 27
The procedure is analogous to that described in Example 2, but starting with 2.2 g of 6-methoxy-pyridazinecarboxylic-3 acid, 2.3 g of N, N'-carbonyldiimidazole and 2.7 g of amino-2 phenoxy-7 naphthyridine-1,8. The product obtained by precipitation in water is purified by recrystallization from 300 cm3 of acetonitrile.

3 g of N- (phenoxy-7 naphthyridine-1,8 yl-2) methoxy-6 pyridazinecarboxamide-3 are thus obtained, melting at 950C.

 6-methoxy-pyridazinecarboxylic-3 acid can be prepared by applying the method described by A. Pollak, et al., Monatsh. Chem., 106, 473 (1975).

EXAMPLE 28
A solution of 5 g of N- (7-chloro-naphthyridine-1,8 yl-2) methoxy-benzamide in 60 cm3 of acetic acid and 15 cm3 of acetic anhydride is heated at reflux for 2 hours. The solution is cooled and poured into 750 cm3 of water, the suspension obtained is basified to pH 10 with 1ON sodium hydroxide and the solid is separated by filtration. After washing with water and acetone then drying at 500C under reduced pressure (0.07 kPa), 4 g of N- (hydroxy-naphthyridine-1,8 yl-2) 4-methoxy-benzamide are obtained. at around 3460C. N- (7-chloro-naphthyridine-1,8 yl-2) 4-methoxy benzamide can be prepared according to the method described in the main patent.

 The present invention also relates to medicaments which contain the new products of general 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 or percutaneously.

 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: jon or by heating. They can also be prepared in the form of sterile solid compositions which may be dissolved at the time of use in sterile water or any other 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 medicaments and compositions according to the invention are particularly useful in human therapy for their anxiolytic, hypnotic and muscle relaxant action.

 In human therapy, the doses depend on the desired effect and on the duration of the treatment; they are generally between 10 and 500 mg per day orally for an adult.

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

 The following example, given without limitation, illustrates a composition according to the invention.

EXAMPLE
Tablets containing 10 mg of active product having the following composition are prepared according to the usual technique: - N- (7-chloro-naphthyridine-1,8 yl-2) acetoxy-3
benzamide 0.010 g - starch - 0.200 g - precipitated silica 0.036 g - magnesium stearate ............................... magnesium 0.004 g

Claims (5)

 R - CONH - Het in which - either the symbol R represents a phenyl radical substituted by an acyloxy, alkylthio or alkyloxycarbonylamino radical, by a chlorine atom in position -2 or -4 or by two alkyloxy radicals, or represents a selected heterocyclyl radical among pyridyle-2, pyridyle-4, pyrazinyl dihydro-5,6 dithiinnyle-2, dihydro-5,6 oxathiinnyle-2, dithiolyle-1,3, thiazolyl or, thienyl or furyl substituted by a halogen atom or by a halogen atom alkylthio radical or R represents an alkenyl radical containing 2 to 4 carbon atoms and the double bond of which is in a with respect to the carbonyl group of the amide function, and the symbol Het represents a substituted naphthyridine-1,8 yl-2 radical in position-7 by a halogen atom or by an alkyloxy, phenoxy, 3-chloro-phenoxy, dichlorophenoxy, hydroxy or cyano radical, - either the symbol R represents a methoxy pyridazinyl-3 radical and the symbol Het represents a naphthyridine radical- 1.8 yle-2 positively substituted ion -7 by a phenoxy radical, it being understood that the alkyl and acyl radicals mentioned above contain 1 to 4 carbon atoms in a straight or branched chain.  R E V E NOICATloNS 1 - A new substituted amide characterized in that it corresponds to the general formula 2 - A process for the preparation of a substituted amide according to claim 1, characterized in that lion acts an acid of general formula  R - COOH in which R is defined as in claim 1, or a reactive derivative of this acid, on an amine of general formula:  Het - NH2 in which Het is defined as in claim 1. 3 - A process according to claim 2, characterized in that a reactive derivative of the acid is reacted, chosen from anhydride, a mixed anhydride, an acid halide or an ester. 4 - A process for the preparation of a substituted amide according to claim 1, for which the symbol Het contains a hydroxy substituent, characterized in that the corresponding substituted amide, defined according to claim 1, is treated in acid medium, for which Het is a naphthyridine-1,8 yl-2 radical substituted in position-7 by a halogen atom, then hydrolyzes the product obtained. 5 - Medicinal product, characterized in that it contains at least one amide according to claim 1, in the pure state, or in the form of a pharmaceutical composition in combination with one or more compatible and pharmaceutically acceptable diluents or adjuvants.