FR2532939A1 - New 4-hydroxy-3-quinolinecarboxylic acid derivatives substituted at position 2, their preparation, their use as medicaments, compositions containing them and new intermediates obtained - Google Patents

Abstract

Compounds of formula (I): in which X represents a hydrogen, a halogen, a C1-5 alkyl, a C1-4 alkoxy, a trifluoromethyl, a trifluoromethylthio or a trifluoromethoxy, R1 represents a hydrogen or a C1-4 alkyl, R2 represents a radical chosen from thiazolyl, 4,5-dihydrothiazolyl, pyridyl, oxazolyl, isoxazolyl, imidazolyl, pyrimidinyl or tetrazolyl radicals optionally substituted with a C1-4 alkyl, or R2 represents a phenyl optionally substituted with at least one radical chosen from the group composed of hydroxyl, C1-4 alkyl, C1-4 alkoxy, trifluoromethyl and nitro radicals and halogen atoms, m represents an integer from 0 to 7, n represents 0, 1 or 2, and R3 a C1-5 alkyl, as well as the addition salts of the products of formula (I) with acids and bases, preparation process, use as medicaments, compositions and new intermediates obtained.

Description

 The present invention relates to new derivatives of 4-hydroxy 3-quinoline carboxylic acid substituted in 2, their preparation process, their application as medicaments, the compositions containing them and the new intermediates obtained.

dans laquelle X, en position 5, 6, 7 ou 8, représente un atome d'hydrogène, un atome d'halogène, un radical alcoyle linéaire ou ramifié, renfermant de 1 à 5 atomes de carbone, un radical alcoxy linéaire ou ramifié renfermant de 1 à 4 atomes de carbone, un radical trifluorométhyle, un radical trifluorométhylthio,ou un radical trifluorométhoxy, R1 représente un atome d'hydrogène, ou un radical alcoyle renfermant de 1 à 4 atomes de carbone, R2 représente un radical choisi parmi les radicaux thiazolyle, 4,5dihydrothiazolyle, pyridinyle, oxazolyle, isoxazolyle, imidazolyle, pyrimidyle et tétrazolyle, éventuellement substitués par un radical alcoyle renfermant de 1 à 4 atomes de carbone ou R2 représente un radical phényle, éventuellement substitué par au moins un radical choisi dans le groupe formé par les radicaux hydroxyt les radicaux alcoyles renfermant de 1 à 4 atomes de carbone, les radicaux alcoxy renfermant de 1 à 4 atomes de carbone, le radical trifluorométhyle, le radical nitro et les atomes d'halogène, m représente un nombre entier pouvant varier de O à 7, n represente 0, 1 ou 2, R3 un radical alcoyle linéaire ou ramifié renfermant de 1à 5 atomes de carbone, ainsi que les sels d'addition des produits de formule (I) avec les acides et les bases.The subject of the invention is the compounds of formula <I)

in which X, in position 5, 6, 7 or 8, represents a hydrogen atom, a halogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms, a linear or branched alkoxy radical containing from 1 to 4 carbon atoms, a trifluoromethyl radical, a trifluoromethylthio radical, or a trifluoromethoxy radical, R1 represents a hydrogen atom, or an alkyl radical containing from 1 to 4 carbon atoms, R2 represents a radical chosen from the radicals thiazolyle, 4,5dihydrothiazolyle, pyridinyle, oxazolyle, isoxazolyle, imidazolyle, pyrimidyle et tétrazolyle, optionally substituted by an alkyl radical containing 1 to 4 carbon atoms or R2 represents a phenyl radical, optionally substituted by at least one radical chosen from the group formed by the hydroxyt radicals, the alkyl radicals containing from 1 to 4 carbon atoms, the alkoxy radicals containing from 1 to 4 carbon atoms, the trifluoromethyl radical, the nitro radical and l he halogen atoms, m represents an integer which can vary from 0 to 7, n represents 0, 1 or 2, R3 a linear or branched alkyl radical containing from 1 to 5 carbon atoms, as well as the addition salts of the products of formula (I) with acids and bases.

 When X represents a halogen atom, it is preferably a chlorine atom.

 When X represents an alkyl radical, it is preferably a methyl, ethyl, n-propyl, n-butyl, n-pentyl, isopropyl or isobutyl radical.

 When X represents an alkoxy radical, it preferably acts on the methoxy, ethoxy or n-propoxy racical.

 When R1 represents an alkyl radical, it preferably starts from the methyl or ethyl radical.

 When R2 represents a heterocyclic radical substituted by an alkyl radical, it is preferably a heterocyclic radical substituted by a methyl or ethyl radical.

 When R2 represents a substituted phenyl radical, it is preferably a phenyl radical substituted by at least one radical chosen from the group formed by hydroxy radicals, methyl or ethyl radicals, methoxy or ethoxy radicals, the trifluoromethyl radical , the nitro radical and the chlorine atom.

 When R3 represents an alkyl radical, it is preferably a methyl or ethyl radical.

 n represents 0, 1 or 2, m represents an integer which can vary from O to 7 which is preferably equal to O or 1, 2 or 3.

 Among the addition salts with acids, there may be mentioned those formed with mineral acids - such as hydrochloric, hydrobromic, sulfuric or phosphoric acids as well as those formed with sulfonic acids such as alkyl or arylsulfonic acids, for example l methanesulfonic or paratoluenesulfonic acid.

 Among the addition salts with bases, mention may be made of those formed with alkali metals such as sodium and potassium and amines, for example trimethylamine or dimethylamine.

 The subject of the invention is in particular the compounds of formula (I) for which X is in position 8 as well as their addition salts with acids and bases. And those for which X represents a trifluoromethyl radical, as well as their salts of 'addition with acids and bases.

 A more particular subject of the invention is the compounds of formula (I) for which R1 represents a hydrogen atom, as well as their addition salts with acids and bases and in particular those for which R2 represents a thiazolyl radical, as well as their addition salts with acids and bases and very particularly those for which R3 represents a methyl radical, as well as their addition salts with acids and bases.

Among the compounds of the invention, there may be mentioned in particular the compounds for which m = 1, and n = 0, 1 or 2, as well as their addition salts with acids and bases and those for which m = 0, n = 0 or n = 1, as well as their addition salts with acids and bases
We also retain the products mentioned in the examples and very particularly - a-hydroxy 2 - / (methylsulfinyl) methyl / N- (2-thiazolyl) 8-
trifluoromethyl 3-quinoline carboxamide and - 4-hydroxy 2- (methylthio) N- (2-thiazolyl) 8 trifluoromethyl 3 ~ quinoline carboxamide.

dans laquelle X conserve la signification donnée ci-dessus, à l'action~d'un acide de formule (III)
R3-S-(CH2)m-COOH (III) dans laquelle m et R3 ont les significations précédentes; ou d'un dérivé fonctionnel de cet acide, pour obtenir un composé de formule (IV) :

dans laquelle X, m et R3 conservent leurs significations précé
Rentes, que l'on soumet à l'action d'un composé de formule (V)

dans laquelle R1 et R2 ont les significations precedentes, pour obtenir un composé de formule (VI)

dans laquelle X, R1, R2, m et R3 conservent leurs significations précédentes, que l'on cyclise en présence d'un agent alcalin, pour obtenir un composé de formule (I) dans laquelle X, R1, R2 et R3 ont leurs significations précédentes et dans laquelle m représente un nombre entier pouvant varier de 1 à 7 et n = 0, que Si désiré, l'on soumet à l'action d'un acide ou d'une base pour en former le sel.The invention also relates to a process for the preparation of products of formula (I) - in which X, R1, R2, R3 have the meaning already given above and in which m represents an integer which can vary from i to 7 and n = 0, characterized in that a compound of formula (II) is subjected

in which X retains the meaning given above, to the action ~ of an acid of formula (III)
R3-S- (CH2) m-COOH (III) in which m and R3 have the above meanings; or a functional derivative of this acid, to obtain a compound of formula (IV):

in which X, m and R3 keep their meanings before
Annuities, which are subjected to the action of a compound of formula (V)

in which R1 and R2 have the above meanings, to obtain a compound of formula (VI)

in which X, R1, R2, m and R3 retain their previous meanings, which are cyclized in the presence of an alkaline agent, to obtain a compound of formula (I) in which X, R1, R2 and R3 have their meanings above and in which m represents an integer which can vary from 1 to 7 and n = 0, that If desired, subject to the action of an acid or a base to form the salt.

 Under the preferred conditions for implementing the invention, the process described above is carried out as follows - the functional derivative of the acid of formula (III) is a halide or an anhydride; - The reaction between the compound of formula (1V) and the compound of formula (V) takes place in the presence of an organolithian or a lithium amide, for example of butyllithium or of hard lithium diisopropylami; the cyclization of the compound of formula (VI) is carried out in the presence of an alkaline agent, such as a hydride or an alkali carbonate, or an amine, for example in the presence of sodium hydride, of sodium carbonate or potassium, piperidine, 4-aminopyridine, dimethylaminopyrldine, triethylamine, 1,5-diazabicyclo / 4,3,0 / pon-5> ene, 1,4-diazabicyclo / 2,2,2 / octane or 1,5-diazabicyclo / 5,4,0 / undec-5-ene.

dans laquelle X et R3 ont leurs significations précédentes, ouun dérivé fonctionnel de cet acide, à l'action d'un dérivé de formule (VIII)

dans laquelle R1 et R2 sont définis comme précédemment, pour obtenir le composé de formule (I) correspondant, défini comme ci-dessusr que l'on soumet, si désiré, à l'action d'un acide ou d'une base pour en former le sel.The invention also relates to a process for preparing the products of formula (I) in which X, R1, R2 and R3 have the meaning given above and in which m = 0, and n = 0, characterized in that the we submit an acid of formula (vii)

in which X and R3 have their previous meanings, or a functional derivative of this acid, to the action of a derivative of formula (VIII)

in which R1 and R2 are defined as above, to obtain the corresponding compound of formula (I), defined as above, which is subjected, if desired, to the action of an acid or a base to form the salt.

 In a preferred embodiment of the process of the invention - as the functional acid derivative, an acid chloride, a lower alkyl ester, an anhydride or a mixed anhydride is used.

the condensation of the acid of formula (VII) or of the functional acid derivative with the compound of formula (viii) takes place in an inert solvent such as, for example, benzene, toluene, methylene chloride, ethyl acetate in the presence of a basic agent such as for example a trialkylalumique derivative, such as trimethylaluminium or triisobutylaluminium.

dans laquelle X conserve la meme signification que précédemment, à l'action d'un agent de sulfuration, on obtient ainsi un composé de formule (X)

dans laquelle X et R3 ont les significations données précédemment, que l'on fait réagir avec un malonate d'alcoyle de formule (XI)

dans laquelle alc représente un radical alcoyle renfermant de 1 à 8 atomes de carbone, en présence d'une base forte, pour obtenir un composé de formule (XII)

que l'on cyclise pour obtenir un composé de formule (xiii)

que l'on saponifie pour obtenir un composé de formule (VII) correspondant

The invention also relates to a preparation process characterized in that to prepare the compound (VII), subjecting a compound of formula (six)

in which X retains the same meaning as above, to the action of a sulphurizing agent, a compound of formula (X) is thus obtained

in which X and R3 have the meanings given above, which are reacted with an alkyl malonate of formula (XI)

in which alk represents an alkyl radical containing from 1 to 8 carbon atoms, in the presence of a strong base, to obtain a compound of formula (XII)

which we cyclize to obtain a compound of formula (xiii)

which is saponified to obtain a compound of formula (VII) corresponding

 In a preferred embodiment of the process for the preparation of the compound of formula (VII): the sulfurizing agent used is an alkali metal thiolate or a thiol used in the presence of a base such as, for example, an alkali metal carbonate or triethylamine.

- The reaction of the compound of formula (IX) with the sulfurizing agent takes place in the presence of an inert solvent such as toluene, benzene, tetrahydrofuran - The alkyl malonate used is ethyl malonate, and the reaction with the compound of formula (x) is carried out in the presence of sodium hydride, the reaction being preferably carried out at a temperature of 100 OC.

- The cyclization of the compound of formula (xii) is carried out by heating, for example at a temperature between 150 ° C. and 25 ° C.

- We saponify the compound of formula (xiii) using soda or potash.

 The invention also relates to a process for the preparation of products of formula (I), in which X, R1, R2 and R3 have the meanings given above and in which m represents an integer which can vary from 0 to 7 and n = 1 or n = 2, characterized in that the products of formula (I) in which n = O are treated with an oxidizing agent to obtain the products of formula (I) defined above, only if desired, it is treated with an acid or a base to form the salt.

The above process is preferably characterized in that the oxidizing agent is hydrogen peroxide in a hydromethanolic medium in the presence of titanium chloride to obtain the products of formula (I) in which n = 1 and in that the oxidizing agent is hydrogen peroxide added with acetic acid, to obtain the products of formula (I) in which n = 2
The compounds of formula (I) as defined above as well as their addition salts with acids and bases have interesting pharmacological properties. They exhibit, in particular, a very good analgesic activity as well as a non-negligible anti-inflammatory activity.

 These properties justify their application in therapy and the subject of the invention is also, as medicaments, the products as defined by formula (I) above, as well as the addition salts with acids and pharmaceutically bases. acceptable of said products of formula (I).

 The subject of the present invention is very particularly, as medicaments, 4-hydroxy 2 - / (methylsufinyl) methyl / N- (2-thiazolyl) 8-trifluoromethyl 3-quinoline carboxamide, as well as its addition salts with pharmaceutically acceptable acids and bases, and 4-hydroxy 2- (methylthio) N- (2 thiazolyl) 8-trifluoromethyl 3-quinoline carboxamide, as well as its addition salts with pharmaceutically acceptable acids and bases.

 The medicaments1 which are the subject of the invention can be used in the treatment of muscle, joint or nerve pain, rheumatic affections, dental pain, zonas and migraines, as well as in the treatment of inflammatory diseases1 in particular arthritis, lumbago , and also as additional treatment in infectious and febrile states.

 The invention extends to pharmaceutical compositions containing, as active principle, the medicaments defined above.

 These pharmaceutical compositions can be administered by the oral, rectal, parenteral or local route by topical application to the skin and mucous membranes.

These compositions may be solid or liquid and may be in the pharmaceutical forms commonly used in human medicine such as, for example, simple or coated tablets1 capsules, granules, suppositories, injections, ointments, creams, gels and aerosol preparations, they are prepared according to the usual methods. The active ingredient can be incorporated therein into excipients usually used in these pharmaceutical compositions, such as tale, gum arabic, lactose, starch, magnesium stearate. , cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives
The dosage varies in particular depending on the route of administration, the condition treated and the subject concerned.

 For example, in adults, it can vary between 20 mg and 2 g of active ingredient per day, orally.

 The compounds of formula (II) used as starting materials for one of the methods of the invention are generally known products, which can be prepared according to the methods indicated in French patent application No. 2 157 874.

 The compounds of formula (IX) used as starting materials for one of the processes of the invention are generally known products. They can be prepared according to the technique of E. KUHLE / Augem. Chem. ed. int. 1, 648 (1962) /.

 The compounds of formula (IV), (VI), (VII), (X), (XII), (XIII) and N- (2-trifluoromethyl phenyl) carbonimide dichloride are new chemicals; the invention therefore relates to these products as new industrial products, in particular as intermediate products necessary for the implementation of the process of the invention.

The following examples illustrate the invention without however limiting it
Example 1 a 4-hydroxy 2- (methylthiométhuyl) N '- (2'-tbiazolyl)' 8-
trifluoromethyl 3-quinoline arbaxairride
Stage A: 2- (methylthiomethyl) 8-tri-fluoromethyl 4H, -3,1-benzoxazine 4-one.

 39.84 g of chloride are mixed in 2-methyl thioacetic acid prepared according to the technique indicated in J Org. Chem.

22 (1957) 1721 and 24.6 g of 2-amino-3-trifluoromethyl benzolque acid prepared according to the method indicated in J Med. Chem 16 (2) 101.6 (1973). It is gradually heated and maintained for 1 hour 20 minutes at 1350C. The excess acid chloride is removed by distillation under reduced pressure around 1250C. The residue obtained is taken up in 150 cm3 of ether, dried, concentrated under reduced pressure, the oil obtained is purified on silica, eluting with chloride of methylene 24.7 g of crude product are recovered, which is mashed in 25 cm 3 of petroleum ether (eb :: 600-800C), drained, washed, dried under reduced pressure at 350C and 20.4 g of product are obtained. expected melting around 48-50 C.

Stage B: 2- (methylthioacetylamino) ss-oxo N- (2-thiazolyl) 3-trifluoromethyl benzene propanamide.

 50 cm3 of a solution of n-butyllithium in hexane grading 1.4 mol per liter are added to OOC, with stirring, in a solution containing 4.86 g of N- (2-thiazolyl) acetamide (Beilstein 27 , 155) and 200 cm3 of tetrahydrofuran. The mixture is cooled to -70 ° C. and 4.7 g of the product obtained in Stage A are added to 50 cm3 of tetrahydrofuran. The solution obtained is poured onto a mixture of water, ice and hydrochloric acid, extracted with ether, washed with an aqueous solution of hydrochloric acid, dried and concentrated under reduced pressure. The residue is pasted in 50 cm3 of ether, drained, washed with ether, dried under reduced pressure at 50 ° C. and 2.5 g of the expected product melting at 1800 ° C. are obtained.

Stage C: 4-hydroxy 2- (methylthipmethyl) N- (2-thiazolyl) 8-tri-fluoromethyl 3-quinoline carboxamide.

 2 g of product obtained in stage B, 20 cm 3 of tetrahydrofuran, 0.584 g of dimethylaminopyridine are mixed, then the solution obtained is stirred for 5 hours at room temperature. The solvent is removed under reduced pressure, the residue is taken up in 20 cm3 of water, 4.8 cm3 of N hydrochloric acid is added, the mixture is stirred for 1 hour at room temperature, drained, washed with water and dried under reduced pressure at 1000C . The crude product obtained is refluxed in 250 cm3 of acetonitrile, cooled, wrung, dried under reduced pressure at 800C and 1.45 g of the expected product melting at 250OC are obtained.

Example 2: 4-hydroxy 2 - / (methylsulfinyl) methyl / N- (2-thiazolyl) 8-trifluorométhtl -3-quinoline carboxamide.

 K cm3 of 30% hydrogen peroxide and 30 cm3 of methanol are introduced with stirring into a mixture of 2 g of product of Example 1, 200 cm3 of methanol, 40 cm3 of water and 10.28 cm3 of a 15% aqueous solution of titanium chloride. The mixture is stirred at room temperature for 30 to 45 minutes, the solution obtained is poured onto a mixture of water and ice, drained, washed with water, dried under reduced pressure at 900C. The crude product obtained is recrystallized from dioxane and then from 95% aqueous ethanol, 1.3 g of expected product melting at 2380C is obtained after drying under reduced pressure at 900C1.

Example 3: 4-bvdroxv 2 - / (metholsulfonyl! Methvl / N- (2-thiazolyl) 8-trifluoromethyl 3-qui-nolé-ine carboxaraide.

 3 g of product of Example 1 are mixed, 60 cm3 of acetic acid, 1.86 cm3 of 30% hydrogen peroxide, heating to 80-820C and maintaining this temperature for 2 hours. The mixture is cooled, the crystals obtained are drained 1 washed with acetic acid and then with ether, dried under pressure reduced to 100 C. The crude product is dissolved at reflux in 70 cm 3 of acetic acid; cooled, drained the crystals obtained, washed with acetic acid and then with ether, dried under reduced pressure at 110 C and 1.7 g of expected product melting at 2750C.

Example 4: 4-hodroxy 2- (methvlthio) N- (2-thiazolvl) 8- trifluo romethyl 3-auinoline carboxamide.

Stage A: N- / 2- (t, riluoromethyl) phenyl / carbonochlorurimido methyl thioate.

methyl thioate.

 10.12 g of triethylamine, 24.2 g of N- (2-trifluoromethyl phenyl) carbonimidoyl dichloride (preparation given below) dissolved in 250 cm3 of toluene are added at -150 ° C., then between -10 and -15 C in 15 minutes. 5.29 g of methyl mercaptan in solution in 15 cm3 of toluene. The mixture is left to return to ambient temperature and then brought to reflux for 1 hour. After cooling, the triethylamine hydrochloride formed is filtered off, then the filtrate is washed with water and then with a 10% aqueous hydrochloric acid solution, then again with dry water and the solvents are removed. at 500C under reduced pressure. The product obtained is distilled and 17.99 g of expected product is collected (eb: 0.3 mmHg = 68-70 C).

Stage B / methylthio // 2- (trifluo, rpmethyl), phenyl / amino / methylene / ethyl propane dioate
13D45 g of ethyl malonate dissolved in 20 cm3 of dimethylformamide containing 3.7 g of 50% sodium hydride in oil in suspension in 150 cm3 of dimethylformamide are added over 15 minutes, the mixture is stirred for 30 minutes at temperature ambient, then added under nitrogen 17.76 g of the product obtained in stage A dissolved in 20 CZ3 of dimethylformamide. Heating is carried out at 95/105 C for 30 minutes After cooling, the mixture obtained is poured onto a mixture of water and d hydrochloric acid at 20S, extracted with ether, washing the ethereal phases with water until neutral, drying, eliminating the solvents at 300C then at 500C under reduced pressure. After distillation of the volatile fractions, the residue is chromatographed, eluting with methylene chloride-petroleum ether (1-1) eb: 60-80 C then methylene chloride. 10.43 g of expected product is obtained.

Analysis: C16 H18 NF3 O4 S = 377.385
Calculated. C% 50.92 8x 4.81 N% 3.71 F% 15 110 S 8.50
Found: 50.9 4.7 3.7 14.9 8.4 Stage C 6 4-hydroxy 2-methylthio 8-trifluoromethyl 3-quinoline ethyl carboxylate.

Gradually heated to 1800C under reduced pressure, 10.74 g of product obtained in the stage and maintained for 30 minutes with stirring. melting at 1050C
Stage D ç 4-hydroxy l- (methythio) N- (2-thiazolyl) 8- trifluoromethyl 3-quinoline carboxami, of
Is introduced under argon and with stirring in 15 minutes between 8 and 12 C, 77 cm3 of a 25% toluene solution of triisobutylaluminium in 16.87 g of 2-aminothiazole dissolved in 370 cm3 of methylene chloride, stirred for 15 minutes the mixture obtained and allowed to return to ambient temperature. 11.18 g of the product obtained in stage C is added in one portion and the mixture is brought to reflux for 28 hours 30 minutes. Cooled, added 380 cm3 of 20% hydrochloric acid, stirred for 75 minutes, wrung, washed with water, dried under reduced pressure at 1000C. The crude product is recrystallized from acetic acid, drained, washed with ether, dried under reduced pressure at 1000C and 6.6 g of the expected product is obtained.

Analysis: C15H10F3N3O2S2 = 385î389
Calculated g C% 46.75 H% 2.61 N% 10.90 F% 14.79 S% 16.64
Found: 46.6 2.6 11.0 15.0 16.3
Preparation of N- (2-trifluoroniethyl phenyl) carbonimide dichloride.

Stage A: N- / 2- (trifluoromethyl) phenyl / formamide.

 108 g of orthotrifluor, omethyl aniline are mixed with 200 cm 3 of formic acid, the mixture is brought to reflux for 30 minutes, cooled and then poured onto a mixture of water and ice. The crystals formed are drained, washed with water and taken up in 750 cm3 of ether. The ethereal phases are washed with water, then with an aqueous solution of sodium hydrogen carbonate at 5%, then again with water, dried, the solvents are removed under reduced pressure and 111.1 g of expected product melting at 790C.

Stage B: N- (2-trifluoromethyl phenyl) carbonimide dichloride.

 63.57 g of sulfuryl chloride are poured into 23S, 42 g of thionyl chloride and then added to the solution in small portions over 75 minutes 89.1 g of N- / 2- (trifluoromethyl) phenyl / formamide. in stage A. It is heated to 220C, stirred for 1 hour, brought to reflux in 2 hours and maintained for 1 hour. The mixture is cooled, the solvents are removed under reduced pressure and an oil is obtained.

Filtered, distilled and collected 100, OS g of expected product.

 (Eb / 7mmEg = 76-770C).

Example 5 4-hydroxy 2- (methylsulfinyl) N- (2-thiazolyl) 8-tri-fluorometh 3-cuinoline carboxamide.

 12.6 cm3 of titanium chloride are added in 15% aqueous solution in 2.312 g of product obtained in Example o suspended in 240 cm3 of methanol and 48 cm3 of water; 4.8 cm3 of a 30% aqueous solution of hydrogen peroxide mixed with 36 cm3 of methanol are then introduced over 15 minutes. The reaction medium is stirred for 20 hours at room temperature, poured onto a water-ice mixture, spin, wash with water, dry under reduced pressure at 10'00-C. The crude product obtained is dissolved in 430 cm3 of tetrahydrofuran at the boil. Onfiltre ;, concentrates up to 150 cm3 under reduced pressure, wrung, washed with tetrahydrofuran then with ether and after drying 'at 100 ° C., 1.79 g of expected product melting at 28.00C,' Example: Pharmaceutical composition.

 Tablets corresponding to the following formula were prepared - product of Example 2 or D o o e c ........... .. ...... 50 mg - Excipient q.s. for one tablet ends at .... ..... 350 mg.

(Detail of the excipient lactose, talc, starch, magnesium stearate).

PHARMACOLOGICAL STUDY 1) Study of analgesic activity
The test used is based on the fact reported by R. POSTER et al., (Fed. Prolo 1959, 1B 412) according to which the intraperitoneal injection of acetic acid causes, in mice, repeated movements of stretching and torsion which may persist for more than 6 hours. Pain relievers prevent or decrease this syndrome, which can be thought of as the exacerbation of diffuse abdominal pain. A 1% acetic acid solution in water is used. The dose triggering the syndrome is under these conditions 0.01 cm3 / g, or 100 mg / kg of acetic acid.

 The product studied is administered orally, half an hour before the injection of acetic acid, the mice having been fasting since the day before the experiment.

The stretches are observed and counted for each mouse during a 15-minute observation period starting immediately after the injection of acetic acid.
The results are expressed by means of the DA50, that is to say the dose which makes it possible to obtain a reduction of 50% in the number of stretches compared to the control animals. The DA50 found was 10 mg / kg for the products of Example 2 and of Example 4 and 15 mg / kg for the products of Example 3 and of Example 5.

2) Study of anti-inflammatory activity.

 The anti-inflammatory activity was determined on the test of plantar edema caused by carrageenan in rats.

 0.05 cm3 of a sterile 1% carrageenan suspension in the tibio-tarsal joint of a hind leg is administered to male rats weighing 130 to 150 g.

 Simultaneously, the product to be studied is administered in a suspension of 0.25% carboxymethylcellulose and 0.02% Tween by mouth.

 The volume of the paw is measured before administration, then 2-hours, 4 hours, 6 hours, 8 hours and 24 hours after.

 The intensity of the inflammation is amxima 4 to 6 hours after the injection of carrageenan. The difference in the volume of the legs of the treated animals and of the controls highlights the anti-inflammatory action of the drug.

 The DA501 c1 is determined, that is to say the dose which makes it possible to obtain a reduction in the edema of 50x.

 The DA50 was found to be 25 mg / kg for the product of Example 4 and 50 mg / kg for the product of Example 2.

Claims (8)

1.- The compounds of formula (I):

 in which X, in position 5, 6, 7 OR 8 represents a hydrogen atom, a halogen atom, a linear or branched alkyl radical containing from 1 to 5 carbon atoms, a linear or branched alkoxy radical containing from 1 with 4 carbon atoms, a trifluoromethyl radical, a trifluoromethylthio radical or a trifluoromethylhowy radical, R1 represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms, R2 represents a radical chosen from thiazolyl radicals, 4, 5 dihydrothiazolyl, pyridinyl, oxazolyl, isosazolyl, imidazolyl, pyrimidyl or tetrazolyl, optionally substituted by an alkyl radical containing 1 to 4 carbon atoms or R2 represents a phenyl radical, optionally substituted by at least one radical chosen from the group formed by hydroxy radicals, alkyl radicals containing from 1 to 4 carbon atoms, alkoxy radicals containing from 1 to 4 carbon atoms, the trifluoromethyl radical, the nitro radical and the halogen atoms, m represents an integer which can vary from 0 to 7, n represents 0, 1 or 2, R3 a linear or branched alkyl radical containing from 1 to 5 carbon atoms, as well as the addition salts of the products of formula (I) with acids and bases.  2.- The compounds of formula (I), as defined in resale cation 1, for which x is in position 8, as well as their addition salts with acids and bases. 3.- The compounds of formula (I), as defined in claim 1 or 2, for which X represents a trifluoromethyl radical, as well as their addition salts with acids and bases 4.- The compounds of formula ( I), as defined in any one of claims 1 to 3, for which R1 represents a hydrogen atom, as well as their addition salts with acids and bases. 5.- The compounds of formula (I), as defined in any one of claims 1 to 4, for which R2 represents a thiazolyl radical, as well as their addition salts with acids and bases. 6.- The compounds of formula (I), as defined in any one of claims 1 to 5, for which R3-represents a methyl radical, as well as their addition salts with acids and bases. 7.- The compounds of formula (I), as defined in any one of claims 1 to 6, for which m = 1 and n = 0, 1 or 2, as well as their addition salts with acids- and the basics. 8.- The compounds of formula (I) as defined in any one of claims 1 to 6, for which m = 0, n = 0 or n = 1, as well as their addition salts with acids and bases 9.- 4-hydroxy 2 - / (methylsulfinyl) methyl / N- (2-thiazolyl) 8  trifluoromethyl 3-quinoline carboxamide 10.- 4-hydroxy 2- (methylthio) N- (2-thiazolyl) 8- trifluoron methyl 3-quinoleine carboxamide. 11.- A process for preparing the products of formula (I), as defined in claim 1, in which X, R1, R2, R3 have the meaning given above and in which m represents an integer which can vary from 1 to 7 and n = 0, characterized in that a compound of formula (II) is subjected

 in which X retains the meaning given above, to the action of an acid of formula (III):  R- 3-S- (CH2) m-COOH (III) in which m and R3 have the above meanings, or a functional derivative of this acid, to obtain a compound of formula (IV):

 in which X, -m and R3 retain their previous meanings, which are subjected to the action of a compound of formula. (V)

 in which R1 and R2 have the above meanings, to obtain a compound of formula (VI)

 in which X, R1, R2, m and R3 retain their previous meanings, which are cyclized in the presence of an alkaline agent, to obtain a compound of formula (i) in which X, R1, R2 and R3 have their meanings above and in which m represents an integer which can vary from 1 to 7 and n = 0, that if desired, subjected to the action of an acid or a base to form the salt thereof. - Process for the preparation of products of formula (I), in which X, R1, R2 and R3 have the meaning given above and in which m = 0 and n = 0, characterized in that an acid of formula ( lives) :

 in which X and R3 have their previous meanings, or a functional derivative of this acid, to the action of a derivative of formula (VIII):

 in which R1 and -R2 are defined as above, to obtain the corresponding compound of formula (I), defined as above, which is subjected, if desired, to the action of an acid or a base to form the salt. 13.- Preparation process according to claim 12, characterized in that to prepare the compound (VII) a compound of formula (IX) is subjected:

 in which X retains the same meaning as in claim 1, to the action of a sulphurizing agent, a compound of formula (X) is thus obtained

 in which X and R3 have the meanings given above, which are reacted with an alkyl malonate of formula (xI)

 in which alk represents an alkyl radical containing from 1 to 8 carbon atoms, in the presence of a strong base, to obtain a compound of formula (XII)

  which we cyclize to obtain a compound of 'formula (xiii)

 which is saponified to obtain a compound of formula (VII) corresponding:

 14, ~ Process for the preparation of products of formula (I), in which ZC, R1, R2 and R3 have the meanings given above and in which m represents an integer which can vary from 0 to 7 and n = i or n = 2 , characterized in that the products of formula (I) in which n = 0 are treated with an oxidizing agent to obtain the products of formula (I) defined above, that, if desired, are treated with un'acide or base to form the salt 15.- Preparation process as defined in claim 14, characterized in that the oxidizing agent is hydrogen peroxide in hydromethtanolic medium in the presence of titanium chloride for obtain the products of formula (I) in which n = 1 and in that the oxidizing agent is hydrogen peroxide added with acetic acid, to obtain the products of formula (I) in which n = 2.  16.- As medicaments, the products of formula (I), as defined in any one of claims i to 8 and their addition salts with pharmaceutically acceptable acids or bases.  % 7.- As medicaments, the products as defined by claims 9 or 10.  18. The pharmaceutical compositions containing, as active principle, at least one of the medicaments as defined by claims 16 or 17. 19 -.- As intermediate products necessary for the implementation of the processes of claims 11, 12 and 13, the products of formula (IV) and (VI) mentioned in claim 11, the products of formula (VII), the N- (2trifluoromethyl phenyl) carbonimide dichloride mentioned in claims 12 and 13.