MXPA98002028A - Quinolein-2 (1h) -ona derivatives as seroton antagonists - Google Patents

Abstract

Compounds of formula (I) are described, wherein A is a 4- (thieno [3,2-c) pyridin-4-yl) piperazin-1-yl or 4- (4-fluorobenzoyl) piperidin-1-yl group , R1 and R2 are each independently a hydrogen or a halogen atom or an amino group, hydroxy, nitro, cyano, (C1-C6) alkyl (C1-C6) alkoxy, trifluoromethyl, trifluromethoxy, -COOH, -COOR4, -CONH2 , -CONHR4, -CONR4R5, -SR4, -SO2R4, -NHCOR4, -NHSO2R4, or -N (R4) 2, wherein R4 and R5 are each a (C1-C4) alkyl group, R3 is a hydrogen atom or a group (C1-C4) alkyl, - (CH2) pOH, - (CH2) pNH2, - (CH2nCOOH, - (CH2) nCOOR4, - (CH2) nCONH2, - (CH2) nCONHOH, - (CH2) pSH, - ( CH2) nSO3H, - (CH2) nSO3NH2, - (CH2) nSO2NHR4, - (CH2) nS02NR4R5, - (CH2) nCONHR4, - (CH2) nCONR4R5, - (CH2) pNHSO2R4, - (CH2) nNHCOR4, or - (CH2) ) pOCOR4, where R4 and R5 are each a (C1-C4) alkyl group, n is 1.2.34, p is 2.3 or 4 and m is 2.3 or 4. The compounds are useful in therapeutic applications.

Description

DERIVATIVES OF QUINOLEIN-2 (1 H) -ONA AS SEROTONIN ANTAGONISTS The present invention relates to 2 (1 H) -quinolone derivatives, to their preparation and to their use in therapy. The compounds of the invention correspond to the formula (I) wherein A represents either a 4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl or a 4- (4-fluorobenzoyl) -1-piperidyl group, Ri and R2 represent each one, independently of the other, either a hydrogen atom, or a halogen atom, or an amino group or a hydroxyl group, or a nitro group, or a cyano group, or a (C? -C6) alkyl group, or a (d-C6) alkoxy group, or a trifluoromethyl group, or a trifluoromethoxy group, or a -COOH group, or a -COOR4 group, or a -CONH2 group, or a -CONHR group or a -CONHR4R5 group, or a group -SR4, or a group -SO2R4, or a group -NHCOR, or a group -NHSO2R4, or a group -N (R) 2, wherein R4 and Rs are each a group (C? -C4) alkyl, or a group - (CH2) pOH, or a group - (CH2) PN H2, or a group - (CH2) nCOOH, or a group - (CH2) pCOOR4, or a group - (CH2) "CONH2, or a group - (CH2) pCONHOH, or a group - (CH2) PSH, or a group - (CH2) nSO3H, or a group - (CH2) NSO2NH2, or a group - (CH2) nSO2NHR4, or a group - (CH2) nSO2NR4R5, or a group - (CH2) nCONHR4, or a group - (CH2) n CONR4Rs, or a group - (CH2) nNHSO2R, or a group - (CH2) pNHCOR4, or a group - (CH2) pOCOR, where R4 and R5 are each a group (C? -C4) alkyl, n is equal to 1, 2, 3 or 4, p is equal to 2, 3 or 4 and m is equal to 2, 3 or 4 as well as their addition salts with pharmaceutically acceptable acids or bases. According to the invention, the compounds of formula (I) can be synthesized according to Scheme 1. Reaction 4- (acetyloxy) -2H, 3H-pyran, 2,6-dione is reacted with a compound of formula (II) (in which R and R2 are as defined above and R3 is a hydrogen atom or a group (C? -C4) alkyl) at room temperature in a polar solvent such as acetic acid. After drying, the compound of formula (III) thus obtained is cyclized in the presence of an inorganic or organic acid, preferably anhydrous, such as a concentrated sulfuric acid, polyphosphoric acid or trifluoromethanesulfonic acid, at a temperature of between 10 and 150. ° C, and a substituted or unsubstituted 2-oxo-1,2-dihydro-4-quinol -neacetic acid of formula (IV) is obtained, which is esterified with an alcohol of formula RβOH (where R6 is a group ( C? -C4) alkyl) by any method of esterification, Scheme 1 (II) (V) (IV) (VID (VI) preferably by the action of thionyl chloride. The ester of formula (V) thus obtained is then reduced with a hydride in an aprotic solvent such as, for example, lithium aluminum hydride in dioxane or excess sodium borohydride in tetrahydrofuran under reflux, or lithium borohydride in tetrahydrofuran at temperature environment, to obtain an alcohol of formula (VI) (in which m is equal to 2); the compounds of formula (VI) in which m is equal to 3 or 4 are obtained from those in which m is equal to 2 by homologation techniques known to a person skilled in the art. The compounds of formula (VI) (in which m is equal to 2, 3 or 4) are then activated to compounds of formula (VII) (in which X represents a leaving group such as a chlorine or bromine atom) ), for example by reaction with thionyl chloride in chloroform under reflux, or dibromotriphenylphosphorane at room temperature in dichloromethane, or to compounds of formula (Vi l) (in which X represents a leaving group such as methanesulfonyloxy, trifluoromethanesulfonyloxy or para-groups). toluenesulfonyloxy), for example by reaction with a sulfonic anhydride or a sulfonic acid chloride in the presence of a base such as pyridine or triethylamine. Finally, the compounds of formula (Vi l) are reacted with 4- (1-piperazinyl) thieno [3,2-c] pyridine or with 4- (4-fluorobenzoyl) piperidine with or without an aprotic or protic solvent, the presence of an inorganic base, between 20 and 150 ° C, preferably in acetonitrile or dimethylformamide in contact with sodium bicarbonate, and a compound of formula (I) is obtained.

To prepare a compound of formula (Ib) (in which R3 is different from a hydrogen atom), the alkylation of the corresponding compound of formula (la) (in which R3 represents a hydrogen atom) can be carried out using an electrophilic agent of the type R3Br or R3I, such as, for example, feri-butyl bromoacetate, bromomethanesulfonamide,? / - methylbromomethanesulfonamide, bromoacetamide,? / - methylbromoacetamide, /,? / - dimethylbromoacetamide or 2-bromoethyl acetate, in the presence of such a base as sodium hydride or potassium hydride, in an aprotic solvent such as tetrahydrofuran or dimethylformamide, in the presence or otherwise of a phase transfer catalyst such as tetrabutylammonium bromide. Then, if it is desired to prepare the compounds of formula (Ib) in which R3 represents a group - (CH2) nCOOH, a de-esterification of the corresponding compounds of the formula (Ib) is carried out in which R3 represents a group - (CH2) nCOOR4. If it is desired to prepare the compounds of formula (Ib) in which R3 represents a group - (CH2) pOH, a de-acetylation of the corresponding compounds of formula (Ib) is carried out in which R3 represents a group - (CH2) pOCOR4. To obtain a compound of formula (I) in which R1 and / or R2 represents (n) a cyano group, -CONH2, or -COOH or a group -COOR4, -SR4 or -SO2R4 where R4 is a group (C? -C) alkyl, with the cyclization of the compound of formula (III) being disadvantageous to the quinolone of formula (IV), the synthesis of the corresponding compounds of formulas (V) and (VI) being conducted in accordance with the Schemes 2 and 3.

According to Scheme 2, a compound of formula (Va), corresponding to a compound of formula (V) (in which Ri represents an iodine atom, R 2 and R 6 are as defined above and R 3 is a hydrogen atom or a group (C? -C4) alkyl) is reacted with a cyanide salt in the presence of a copper salt in a polar solvent such as dimethylformamide or? / - methylpyrrolidone, or with trimethylsilyl cyanide in the presence of a palladium, preferably tetrakis (triphenylphosphine) palladium [0] in triethylamine under reflux, to obtain a compound of formula (Vb), which can be converted to either a compound of formula (Vid) and then to a compound of formula (VIe) ) (in which R7 is a hydrogen atom or a (C1-C) alkyl group, or converted to a carboxamide derivative of formula (Vc) by standard methods known to a person skilled in the art.

Scheme 2 - (Va) (Vb) (VC) According to Scheme 3, a compound of formula (Via), corresponding to a compound of formula (VI) (in which Ri represents an iodine atom, R2 is as defined before, R3 is a hydrogen atom or a group (C? -C) alkyl and m is equal to 2), it is reacted with a thiolate such as sodium thiomethoxide, in the presence of tetrakis (triphenylphosphine) palladium [0] in an alcohol such as ethanol, propanol or n-butanol, to prepare a compound of formula (Vlb) (in which R4 is a (C? -C) alkyl group, which can be converted by oxidation to a compound of formula ( Vlc).

Scheme 3 To obtain the compounds of formula (I) in which Ry and / or R2 represents (n) a nitro or amino group or a group -N HCOR4, -N HSO2R4 or -N (R4) 2 where R is a group (C? C4) alkyl, the synthesis of the corresponding compounds of formula (Vil) is conducted according to Scheme 4.

The nitration is carried out of a compound of formula (VII), corresponding to a compound of formula (VII) (in which Ry is a hydrogen atom, X a halogen atom and R3 a hydrogen atom or a group (C ? -C) alkyl), to obtain a compound of formula (Vllb), which is converted to a compound of formula (Vllc) by reduction with hydrogen, said compound is converted to either a compound of formula (Vlld) by reaction with a carboxylic acid chloride of the formula R 4 COCl, or a compound of the formula (V 1 le) by reaction with sulfonic acid chloride of the formula R SO 2 Cl, or a compound of the formula (V 11 f) by a? / dialkylation reaction. These compounds are then reacted with 4- (1-piperazinyl) thieno [3,2-c] pyridine or with 4- (4-fluorobenzoyl) piperidine according to Scheme 1.

Scheme 4 (Vlld) To prepare the compounds of formula (I) in which Rt and / or R 2 represents (n) a hydroxyl group, a de-alkylation of the corresponding alkoxylated compounds of formula (I) (in which Ri and / or R 2) represents (an) alkoxy group) can be carried out under standard conditions known to a person skilled in the art, such as, for example, a treatment with 48% hydrobromic acid. The starting compounds are commercially available or are described in the literature , or they can be prepared according to methods which are described therein, or which are known to a person skilled in the art. Thus, 4- (acetyloxy) -2H, 3 / - / - p? ran -2,6-d ?one is prepared from 3-oxoglutaric acid according to EG FRANDSEN and N JACOBSEN, J. Chem Soc Perkin I, pp 933-6 (1978) The cichzation process is adapted from those described in the European Patent Applications EP 0364327 and EP0577325 The introduction of a nitpho in the co The formula (V) is made according to the methodology described by N CHANTAN IYT HANAFUSA, J Org Chem. 5J_, pp 4714-4716 (1986) The aromatic nucleophilic substitution of iodinated iodines with thiolates is based on the T MIG method ITAL et al, Bull Chem. Soc Japan, 53, pp. 1385 (1980) The 4- (1-p? Peraz? N? L) thieno [3,2-c] p? R? D? Na is synthesized in accordance to JSN EW et al, J. Med. Chem. 32, No. 6, PP 1 147-56 (1989) The following examples illustrate the invention without limiting it. The microanalysis and the mass spectrum, NMR and IR confirm the structure of the obtained compounds. The numbers of the exemplified compounds refer to those in the table given below, which illustrates the chemical structures and physical properties of a few compounds according to the invention. The proportions (x: y) correspond to the proportion (acid / base).

Example 1 (Compound No. 27) 6-Methoxy-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] -2 (1 H) hydrochloride -quinolone (2: 1) 1. 1 . 3- (Acetyloxy) -5 - [(4-methoxy penyl) methylamino] -5-oxo-2-pentenoic acid. 27 g (158 mmol) of 4- (acetyloxy) -2H, 3H-pyran-2,6-dione are added with vigorous stirring at room temperature to a solution of 20.0 g (146 mmol) of N-methyl-4-methoxyaniline. in 100 ml of acetic acid. After 5 hours of stirring at room temperature, 700 ml of cold water are added and the mixture is left stirring for 30 minutes. A beige solid is obtained, which is drained, washed with water, ground in diethyl ether and dried over phosphorus pentoxide at 40 ° C. 24 hours. 28. 1 g of product are obtained in the form of a solid. Melting point = 85-88 ° C. Performance = 76% 1 .2. 6-Methoxy-2-oxo-1,2-dihydro-4-quinolineacetic acid 41 g (133 mol) of 3- (acetoxy) -5 - [(4-methoxyphenyl) methylamino] -5-oxo-2-pentenoic acid they are added in small portions to 70 ml of sulfuric acid (96-97%) at room temperature, and the mixture is then heated to 80 ° C with stirring for 1 hour 30 minutes. After cooling, the reaction medium is poured into 100 g of ice and 100 ml of water, the mixture is stirred for 15 minutes and the solid is drained and washed copiously with water before being dried for 48 hours at 50 ° C. 14.9 g of a mixture of 6-methoxy-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetic acid and 6-methoxy-2-oxo-1,2-dihydro-4-quinolineacetic acid are collected. Performance 45% 1 .3. Methyl 6-methoxy-2-oxo-1,2-dihydro-4-quinolineacetate 16 ml (219 mmol) of thionyl chloride are added dropwise to a stirred suspension of 16.8 g (68 mmol) of an acid mixture 6-methoxy-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetic acid and 6-methoxy-2-oxo-1,2-dihydro-1-quinolineacetic acid in 250 ml of methanol at room temperature, and the agitation is then maintained for 16 hours. The solvent is evaporated under vacuum and the residue is taken up in 400 ml of dichloromethane. The mixture is washed with saturated sodium bicarbonate and then with water, and the organic phase is dried over sodium sulfate. After filtration and concentration, 12.6 g of a mixture of the two esters (71%) is obtained. The two esters were separated by flash chromatography on silica gel, extracting with a methanol / dichloromethane mixture (3:97). 4.0 g of methyl 6-methoxy-1-methyl-2-oxo-1,2-dihydro-4-quinoline acetate, melting point = 129-130 ° C and 7.8 g of methyl 6-methoxy-2-oxo-1, 2-dihydro-4-quinolineacetate, Melting point = 223-224 ° C were obtained. 1 .4. 4- (2-hydroxyethyl) -6-methoxy-2- (1 H) -quinolone 1.4 g of sodium borohydride (37 mmol) are added to a suspension of 3.1 g (12.5 mmol) of methyl 6-methoxy 2-oxo-1,2-dihydroquinolinecetate in 100 ml of dry tetrahydrofuran and 1 ml of methanol at room temperature, and the reaction medium was heated to reflux for 16 hours. After cooling to 5 ° C, 1 ml of methanol is added in the form of drops, then, after 30 minutes, 0.5 g of sodium borohydride is added and the reaction medium is heated for an additional 8 hours. After cooling and treatment with 5 ml of methanol, the solvents are evaporated and the residue is taken up with 200 ml of dichloromethane and 100 ml of 1N hydrochloric acid. The organic phase is separated, washed with water and dried over sodium sulfate. sodium. After filtration and concentration under vacuum, 1.95 g of the expected alcohol are obtained. Performance = 72% fifteen. 4- (2-Chloroethyl) -6-methoxy-2 (1 fLy) -quinolone 3.4 ml (46.6 mmol) of thionyl chloride are added while stirring at room temperature to a suspension of 3.1 1 g (14.2 mmol) of 4- (2-hydroxyethyl) -6-methoxy-2 (1 H) -quinolone in 50 ml of chloroform and 3 drops of dimethylformamide. The suspension is refluxed for 14 hours (total solubilization). After cooling to room temperature, 50 ml of water are added dropwise to the reaction medium and the mixture is allowed to stir for 30 minutes. The organic phase is recovered, separated after the establishment has taken place, washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated under vacuum. 3.2 g of a pale yellow solid are obtained. Melting point = 231-232X Yield = 94% 1. 6. 6-Methoxy-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] -2 (1 H) -quinolone hydrochloride (2: 1) 1.2 g (5 mmol) of 4- (2-chloroethyl) -6-methoxy-2 (1 H) -quinolone are added to a suspension of 1.2 g (5.5 mmol) of 4- (1-piperazinyl) ) thieno [3,2-c] pyridine and 0.44 g (5.25 mmol) of sodium bicarbonate in 15 ml of acetonitrile, and the reaction mixture is then heated to reflux for 10 hours. After evaporation of the solvent under vacuum, the residue is taken up in 100 ml of dichloromethane and washed successively with a solution of saturated aqueous sodium bicarbonate and then with water. After drying over sodium sulfate, filtration and condensation of the filtrate, the crude product is purified by flash chromatography on silica, extracting with a mixture of methanol / dichloromethane (5:95) containing traces of aqueous ammonia. 0.50 g of the product is obtained in base form. Yield = 24% The dihydrochloride is prepared in a mixture of methanol / hydrochloric acid / ether. Melting point = 254 ° C (decomposition) Example 2 (Compound No. 28) 4- [2- [4- (4-Fluorobenzoyl) -1-piperidyl] ethyl] -6-methoxy-2 (1 H) -quinolone hydrochloride (1: 1) A mixture of 1 . 1 g (4.6 mmol) of 4- (2-chloroethyl) -6-methoxy-2 (1 H) -quinolone, 1.0 g (5.5 mmol) of 4- (4-fluorobenzoyl) piperidine and 0.38 g (4.6 mmol) ) of sodium bicarbonate in 20 ml of acetonitrile is heated at reflux for 8.5 hours. The reaction medium is then evaporated to dryness and the crude product is purified by flash chromatography on silica, extracting with a methanol / dichloromethane (5: 95) mixture containing traces of aqueous ammonia. 0.53 g of the expected product is obtained in base form. Yield = 30% The hydrochloride is prepared in a methanol / hydrochloric acid mixture. Melting point = 237 ° C (decomposition) Example 3 (Compound No. 4) 6-Chloro-4- [2- [4- (4-f-luorobenzoyl) -1-piperidyl] ethyl] -1-methyl-2 (1 H) -quinolone hydrochloride (1; 1) 3.1. 3- (Acetyloxy) 5 - [(4-chlorophenyl) methylamino] 5-oxo-2-pentenoic acid 19.8 g (16 mmol) of 4- (acetyloxy) -2H, 3H-? Iran-2,6-dione are added in small portions to a stirred solution of 15.0 g (106 mmol) of 4-chloro-β-methylbenzenamine in 40 ml of pure acetic acid. The reaction medium was stirred for 3 hours at 35 ° C. It was allowed to cool to room temperature and was diluted in 10 ml of ice water. The solid is drained, washed copiously with water and dried at 40 ° C for 48 hours. 25 g of the expected compound are obtained in the form of an amorphous solid, which is used in the next step without further treatment. Performance = 77% 3. 2 6-Chloro-1-methyl-2-oxo-1,2-dihydro-4-quinoline acetic acid 25.5 g (81.8 mmol) of 3- (acetyloxy) -5 - [(4-chlorophenyl) methylamino] - 5-Oxo-2-pentenoic is introduced in small portions in 40 ml of concentrated sulfuric acid at room temperature with vigorous stirring, and the reaction medium is then heated at 85 ° C for 60 minutes. After cooling, this solution is poured into a mixture of 500 g of ice and 500 ml of water. The gray solid obtained in this way is drained, washed with water and then ground in ether and dried for 24 hours at 40 ° C. 9.47 g of the expected product were obtained, said product is used in the next step without additional treatment.

Performance = 46% 3. 3. Methyl 6-chloro-1-methyl-1,2-dihydro-4-quinoline-acetate 1 ml (147 mmol) of thionyl chloride are added dropwise for about 30 minutes to a stirred suspension of 12.5 g. (49 μmol) of 6-chloro-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetic acid in 150 ml of methanol. The mixture is stirred for 17 hours at room temperature and the solvent is brought under vacuum. The residue is dissolved in 400 ml of dichloromethane, and then washed with a solution of saturated aqueous sodium bicarbonate and then with water. After drying over sodium sulfate, the organic phase is filtered and the filtrate condensed. 11.16 g of expected product are obtained. Yield = 85% Melting point = 99-101 ° C 3. 4. 6-Chloro-4- (2-hydroxyethyl) -1-methyl-2 (1 H) -quinolone 3.0 g (79 mmol) of sodium borohydride are added to a suspension of 5.9 g (23.4 mmol) of methyl 6 -chloro-1-methyl-1,2-dihydro-4-quinoline-acetate in 10 ml of methane! and 100 ml of dry tetrahydrofuran, and the mixture is heated then heated to reflux for 9 hours. After cooling, the solvents are evaporated under vacuum and the residue is taken up in 400 ml of dichloromethane and 100 ml of 3 N hydrochloric acid. The organic phase is washed with water, dried over sodium sulfate and filtered, and the filtrate is condensed. The crude product is purified by flash chromatography on silica, extracting with a methanol / dichloromethane mixture (5:95). 5.9 g of the expected alcohol are obtained. Yield = 92% Melting point = 169-170 ° C 3. 5. 6-Chloro-4- (2-clproethyl) -1-methyl-2 (1 H) -quinolone 5.5 ml (75 mmol) of thionyl chloride are added dropwise to a suspension of 5.9 g (24.8 mmol). ) of 6-chloro-4- (2-hydroxyethyl) -1-methyl-2 (1 H) -quinolone in 120 ml of chloroform, two drops of pyridine and two drops of dimethylformamide. The reaction medium is heated to a gentle reflux for 2.5 hours and then treated as described in Example 1 .5. 5.4 g of the expected product were obtained. Yield = 86% Melting point = 120-122 ° C 3. 6. 6-Chloro-4- [2- [4- (4-fluorobenzoyl) -1-piperidyl] ethyl] -1-methyl-2 (1 H) -quinolone hydrochloride (1: 1) A mixture of 0.90 g ( 3.5 mmol) of 6-chloro-4- (2-chloroethyl) -1-methyl-2 (1 / - /) quinolone, 0.71 g (4.0 mmol) of 4- (4-fluorobenzoyl) piperidine and 0.60 g (7.0 mmol) ) of sodium bicarbonate in 15 ml of acetonitrile is heated at reflux for 11 hours. The reaction medium is then evaporated to dryness and the crude product is purified by flash chromatography on silica, extracting with a methanol / dichloromethane mixture (4:96) containing traces of aqueous ammonia. 0.86 g of the expected product are obtained in base form. Yield = 62% The hydrochloride is prepared in a mixture of methanol / hydrochloric acid / ether. Melting point = 244ßC (decomposition) Example 4 (Compound No. 5) 6-Fluoro-1-methyl-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl hydrochloride] -2 (1 / L /) - quinolone (2: 1) 4. 1 . 3- (Acetoxy) -5 - [(4-fluorophenyl) methylamino] -5-oxo-2-pentenoic acid 9.93 g (58.4 mmol) of 4- (acetyloxy) -2H, 3 / - / - pyran-2,6 -dione are added in small portions to a stirred solution of 6.64 g (53.1 mmol) of? / -methyl-4-fluoroaniline in 25 ml of pure acetic acid. The reaction medium is stirred for 2 hours at 35 ° C, allowed to cool to room temperature and diluted in 500 ml of ice water. The obtained solid is recovered and drained, washed copiously with water and dried in an oven (40 ° C) for 48 hours. 12.05 g of the expected compound are obtained in the form of an amorphous solid, which is melted below 50 ° C. Performance = 76% 4. 2. 6-Fluoro-1-methyl-2-oxo-1,2-dihydro-4-quinoline acetic acid 31.8 g (107 mmol) of 3- (acetyloxy) -5- [(4-fluorophenyl) methylamino] -5- acid oxo-2-pentenoic acid are introduced in small portions in 130 ml of concentrated sulfuric acid at room temperature with vigorous stirring, and the reaction medium is then heated at 90 ° C. for 90 minutes, after cooling, this solution is emptied into a mixture of 500 g of ice and 500 ml of water The gray solid thus obtained is drained, washed with water, then ground in ether and dried for 24 hours at 40 ° C. 1 1 .37 g of product are obtained Melting point = 230 ° C Yield = 45% 4. 3. Methyl 6-fluoro-methyl-2-oxo-1,2-dihydro-4-quinolineacetate 16 ml (219 mmol) of thionyl chloride are added dropwise in about 30 minutes to a stirred suspension of 11. 37 g (49.38 mmol) of a mixture of 6-fluoro-1-methyl-2-oxo-1,2-dihydro-4-quinilinacetic acid in 120 ml of methanol. The mixture is stirred overnight (13 hours) at room temperature and the solvent is removed under vacuum. The residue is dissolved in 400 ml of dichloromethane, and then washed with saturated aqueous sodium bicarbonate solution and then with water. After drying over sodium sulfate, filtration and concentration of the filtrate, 9.6 g of expected product are obtained. Yield = 78% Melting point = 134-135 ° C 4.4. 6-Fluoro-4- (2-hydroxyethyl) -1-methyl-2 (1 H) quinolone 3.78 g (100 mmol) of sodium borohydride are added to a suspension of 8.0 g (32 mmol) of methyl 6-fluoro- 1-methyl-2-oxo-1,2-dihydro-4-quinoline-acetate in 100 ml of dry tetrahydrofuran, and the mixture was refluxed for 20 hours. After cooling to 5 ° C, 2 ml of methanol are added in the form of drops, an additional 3 g of sodium borohydride are added and the mixture is refluxed for 12 hours. The solvents are evaporated under vacuum and the residue is taken up in 400 ml of dichloromethane and 150 ml of 2N hydrochloric acid, the organic phase is washed with water, then dried over sodium sulfate and filtered, and the filtrate is concentrated. 4.7 g of the expected alcohol are obtained. Yield = 66% Melting point = 153- 154 ° C 4. 5. 4- (2-Chloroethyl) -6-fluoro-1-methyl-2 (1 H) -quinolone 3 ml (41 mmol) of thionyl chloride are added dropwise to a suspension of 2.2 g (9.95 mmol). ) of 6-fluoro-4- (2-hydroxyethyl) -1-methyl-2 (1 / - /) - quinolone in 100 ml of chloroform, two drops of pyridine and two drops of dimethylformamide. The reaction medium is heated to a gentle reflux for 4.5 hours. After cooling to room temperature, 50 ml of water are added dropwise to the reaction medium and the mixture is allowed to stir for 30 minutes. The organic phase is recovered, separated after the establishment has taken place, washed with water, dried over magnesium sulfate and filtered. The filtrate is concentrated in vacuo. 2.36 g of the expected chloride are obtained. Yield = 98% Melting point = 141-142 4. 6. 6-Fluoro-1-methyl-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] -2 hydrochloride (1 H-quinolone ( 2: 1) 1.4 g (5.8 mmol) of 4- (2-chloroethyl) -6-fluoro-1-methyl-2 (1 H) -quinolone are added to a mixture of 1.3 g (5.9 mmol) of 4- (1-piperazinyl) thieno [3,2-c] pyridine and 0.50 g (5.95 mmol) of sodium bicarbonate in 20 ml of acetonitrile, and the reaction medium is heated at 55-60 ° C for 18 hours The solvent is evaporated and the residue is taken up in 100 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate solution and then with water.The organic phase was dried over sodium sulfate and filtered, and the filtrate was condensed. The crude product is purified by chromatography on silica, extracting with a mixture of methanol / dichloromethane (5:95) containing traces of aqueous ammonia 0.70 g of expected product is obtained in base form Yield = 27% The base is dissolved in 10 ml of methanol and salified with an excess of a solution 2 N of hydrochloric acid in ether. The precipitate obtained is drained, recrystallized from methanol and dried under vacuum. 0.38 g of the dihydrochloride is obtained. Melting point = 280 ° C (decomposition) Example 5 (Compound No. 10) 7-Fluoro-2-oxo-4- [2- [4- (thieno [3,2-c] pyridin-4-hydrochloride il) -1-piperazinl] ethyl] -1,2-dihydro-1 -quinoline acetic acid (2: 1) 2.9 ml of a 0.5 M solution of feri-butyl bromoacetate in tetrahydrofuran are added in the form of drops to a mixture of 0.50 g (1.23 mmol) of 7-fluoro-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] -2 (1 H) quinolone ( prepared from 3-fluoroaniline according to the method described in Example 4), 0.10 g (1.79 mmol) of freshly ground potassium hydroxide and 0.12 g (mmol) of tetrabutylammonium bromide in 20 ml of tetrahydrofuran at 0- 5 ° C. After 30 minutes at 0-5 ° C, the temperature is allowed to rise to room temperature and stirring is continued for 6 hours. The solvent is evaporated under vacuum and the residue is taken up in 100 ml of dichloromethane, and the organic phase is washed with water, dried over sodium sulfate and condensed. The crude product is purified by flash chromatography on silica, extracting with a mixture of methanol / dichloromethane (5:95) containing traces of aqueous ammonia, and 0.48 g of feri-butyl? / -acetate is obtained in the form of a colorless oil. thick. Yield = 75% 50 ml of a 3 N solution of hydrochloric acid in ethyl acetate are added to this oil, and the mixture is stirred at room temperature for 4 hours. It is evaporated to dryness and the white solid obtained is ground with ether and dried under vacuum. 0. 47 g of the expected acid are obtained in the form of the dihydrochloride. Yield = 87% Melting point = 218-220 ° C (decomposition) Example 6 (Compound No. 12) 7-Fluoro-2-oxo-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] - hydrochloride 1, 2, -dihydro-1-quinolineacetamide (2: 1) 3.9 ml of a 0.5 M solution of bromoacetamide in tetrahydrofuran are added dropwise to a stirred mixture of 0.53 g (1.3 mmol) of 7-fluoro- 4- [2- [4- (Thieno [3,2-c] pyridin-4-yl) ethyl] -2 (1 H) -quinolone, 0.1 g (1.79 mmol) of ground potassium hydroxide and 0.13 g (0.4 mmol) of tetrabutylammonium bromide in 25 ml of tetrahydrofuran at 0-5 ° C. After 30 minutes, the temperature was allowed to rise to room temperature and the mixture was stirred at this temperature for 20 hours. The reaction medium was evaporated to dryness under vacuum and the residue was taken up in 100 ml of dichloromethane. This solution was washed with water. The organic phase was dried over magnesium sulfate and concentrated. The crude product was ground in an ether / dichloromethane (1: 3) mixture, and then drained and purified by chromatography on silica, extracting with a mixture of methanol / ethyl acetate (10: 90) and then with a mixture of methanol / dichloromethane (10:90) containing traces of aqueous ammonia. 0.30 g of a white solid is obtained, said solid is converted to dihydrochloride in a mixture of 2 M hydrochloric acid / ether / methanol. 0.32 g of dihydrochloride is obtained.

Melting point = 280 ° C (decomposition) Example 7 (Compound No. 20) 1-methyl-2-oxo-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] -1-hydrochloride] , 2-dihydro-6-quinolinecarbonitrile (2: 1) 7.1. Methyl 6-cyano-1-methyl-2-oxo-1,2-dihydro-4-quinolineacetate 1.1 ml of trimethylsilyl cyanide (8.4 mmol) followed by 0.15 g (0. 13 mmol) of tetrakistriphenylphosphine palladium are added to a solution of 0.50. g (1.4 mmol) of methyl 6-iodo-1-methyl-2-oxo-1,2-dihydro-4-quinoline-acetate (prepared from / V-methyl-4-iodaniline according to the method described in Example 1 ) in 6 ml of anhydrous triethylamine. The reaction medium is then heated to reflux for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the medium is poured into 60 ml of toluene and 60 ml of water. The organic phase is washed with water and the initial aqueous phase is extracted again with dichloromethane. The organic phases are combined, dried over sodium sulfate and concentrated under vacuum. The residue is purified by flash chromatography on silica, extracting with a methanol / dichloromethane mixture (5:95). 0.313 g of the expected nitrile is obtained. Yield = 87% Melting point = 202-203 ° C 7. 2 6-cyano-4- (2-hydroxyethyl) -1-methyl-2 (I W) -quinolone 7.2.1. 6-Cyano-1-methyl-2-oxo-1,2-dihydro-4-quinoline acetic acid 10.4 ml of a 0.5 N solution of lithium hydroxide (5.2 mmol) are added as drops to 1,221 g (4.7 mmol) of methyl 6-cyano-1-methyl-2-oxo-1,2-dihydro-4-quinoline acetate in 10 ml of methanol at 0-5 ° C. The temperature was allowed to rise to room temperature and the reaction medium was stirred for 2 hours. It was drained in 250 ml of ice water and acidified to pH 2-3 with 4N hydrochloric acid. The white precipitate formed is drained, washed with water and then dried under vacuum at 40 ° C. 0.85 g of the expected product is obtained. Yield = 75% Melting point = 238 ° C 7. 2.2. 6-cyano-4- (2-hydroxyethyl) -1-methyl-2 (1 H) -quinolone 0.22 ml (1.58 mmol) of triethylamine is added to a suspension of 0.365 g (1.51 mmol) of acid. -cyano-1-methyl-2-oxo-1,2-dihydro-4-quinoline acetic acid in 10 ml of tetrahydrofuran at -10 ° C, and 0.16 ml (1.6 mmol) of ethyl chloroformate is then added in the form of drops. After stirring at -10 ° C for 45 minutes, the reaction medium is filtered and the solids are rinsed with 3 x 8 ml of tetrahydrofuran. 0.25 g (6.61 mmol) of sodium borohydride and then 0.94 ml of methanol are added to the filtrate at 5-10 ° C. After stirring at 5-10 ° C for 2 hours, 13 ml of 1 N hydrochloric acid solution are added. The mixture is extracted with dichloromethane and then with ethyl acetate. The organic phases are dried over sodium sulfate and then concentrated in vacuo. 0.315 g of product is obtained.

Yield = 92% Melting point = 231-233 ° C. 7. 3. 4- (2-Bromoethyl) -6-cyano-1-methyl-2 (1 H) -quinolone 0.24 g (1.05 mmol) of 6-cyano-4- (2-hydroxyethyl) -1-methyl-2 ( 1 H) -quinolone is added in small amounts to 0.48 g (1.14 mmol) of dibromotriphenylphosphorane in 14 ml of dichloromethane at room temperature. After 75 minutes of stirring at room temperature, the reaction medium is drained in 200 ml of dichloromethane and the mixture is washed with water. The organic phase is dried over sodium sulfate, filtered and condensed under vacuum. The white residue is ground in diethyl ether. The solid obtained is taken up in a minimum of dichloromethane, the mixture is filtered rapidly through a layer of silica, extracting with ether, and the filtrate is evaporated. 0.20 g of product is obtained, said product is used without additional treatment. Performance = 65% 7. 4. 1-methyl-2-oxo-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] -2 (1 H) -quinolone hydrochloride (2: 1) A mixture of 0.19 g (0.65 mmol) of 4- (2-bromoethyl) -6-cyano-1-methyl-2- (1 H) -quinolone, 0. 15 g (0.65 mmol) of 4- (1-piperazinyl) thieno [3,2-cjpyridine and 0.09 g (0.1 1 mmol) of sodium bicarbonate in 10 ml of acetonitrile is heated at 55 ° C for 36 hours. The reaction medium is evaporated to dryness, the residue is taken up in 100 ml of chloroform and the organic phase is washed with water. Dry over sodium sulfate and concentrate, and the crude product is purified by flash chromatography on silica, extracting with a methanol / dichloromethane (1: 9) mixture containing traces of aqueous ammonia. 0.21 1 g of base is obtained in the form of a colorless oil. Yield = 48% The dihydrochloride is prepared in a mixture of methanol / ether / 2N hydrochloric acid. 0.182 g of product is obtained in the form of the dihydrochloride. Melting point = 200 ° C (decomposition) Example 8 (Compound No. 17) 6-Hydroxy-1-methyl-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl-2 hydrochloride ( 1 H) -quinolone (2: 1) 0.47 g (1.08 mmol) of 6-methoxy-1-methyl-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] -2 (1 H) -quinolone (obtained from methyl 6-methoxy-1-methyl-2-oxo-1,2-dihydro-4-quinoline acetate according to Example 1), is added to 25 ml of 48% hydrobromic acid, and the mixture is refluxed for 3 hours. After cooling, the gray precipitate is filtered, washed with cold water and dried under vacuum at 40 ° C. 0.444 g of the product is obtained in the form of the dihydrobromide. Yield = 71% 0.14 g (0.24 mmol) of this product is taken up in 20 ml of 3.7 N hydrochloric acid in anhydrous methanol, and the mixture is stirred at room temperature for 3 hours. The precipitate is drained, rinsed with diethyl ether and dried in an oven. 0.1 12 g of the expected product is obtained. Yield = 95% Melting point = 227 ° C (decomposition) Example 9 (Compound No. 18) 6-Nitro-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] -2 (1 H) hydrochloride -quinolone (2: 1) 9.1. 4- (2-Chloroethyl) -6-nitro-2 (1 H) -quinolone 20.0 g (96.4 mmol) of 4- (2-chloroethyl) -2 (1 H) quinolone are added in small amounts to a mixture of 120 ml of 65% nitric acid and 80 ml of concentrated sulfuric acid cooled to 5 ° C, and the mixture is heated at 45 ° C for 2 hours. The reaction medium is poured into 600 ml of ice water, and the pale yellow precipitate is drained, rinsed with water and dried in vacuo. 22.5 g of the expected product are obtained. Yield = 92% Melting point = 239-237 ° C 9. 2. Hydrochloride of 6-nitro-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] ethyl] -2 (1 H) -quinolone (2: 1) ) A mixture of 1 g (3.96 mmol) of 4- (2-chloroethyl) -6-nitro-2 (1 H) -quinolone, 0.87 g (4 mmol) of 4- (1-piperazinyl) thieno [3,2 -c] pyridine and 0.5 g (5.95 mmol) of sodium bicarbonate in 10 ml of dimethylformamide is heated at 50 ° C for 20 hours. The residue is then filtered and washed with water, 200 ml of water are added to the filtrate and the formed precipitate is drained and dried under vacuum. 1.28 g of the expected product are obtained in base form. Yield = 74% The hydrochloride is prepared in a mixture of methanol / ether / hydrochloric acid. Melting point = 242 ° C (decomposition) Example 10 (Compound No. 16) 6-Amino-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] et -2 (1 H) hydrochloride quinolone (3: 1) 10.1. 6-amino-4- (2-chloroet -2 (1 H) -quinolone hydrochloride (1: 1) 0.70 g of palladium on charcoal 5% Pd) is added to a suspension of 3.5 g (13.8 mmol) of 4 - (2-Chloroet -6-nitro-2 (1 H) -quinolone in 300 ml of methanol at room temperature, and the mixture was stirred under a hydrogen pressure of 0.06 MPa for 3 hours. The catalyst is filtered and the filtrate is condensed. 2.97 g of the product are obtained in base form. The hydrochloride is prepared in a mixture of methanol / ether / hydrochloric acid. Melting point > 290 ° C . 2. 6-amino-4- [2- [4- (Thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] et -2 (1 H) -quinolone hydrochloride (3: 1) ) A mixture of 0.35 g (1.35 mmol) of 6-amino-4- (2-chloroet -2 (1 H) -qujnolone hydrochloride, 0.33 g (1.5 mmol) of 4- (1-piperzinyl) ) thieno [3,2-cjpyridine and 0.17 g (2 mmol) of sodium bicarbonate in 10 ml of dimetormamide is heated at 60 ° C for 24 hours. After cooling to room temperature, the reaction medium is diluted in 50 ml of water and the crude product is extracted with chloroform. The organic phase is dried over sodium sulfate and concentrated. The crude product is purified by flash chromatography on silica, extracting first with a mixture of methanol / etacetate (6.5: 93.5) containing traces of trietmine and then with a mixture of methanol / dichloromethane (6.5: 93.5) comprising traces of aqueous ammonia. 0. 14 g of product is obtained in base form. Yield = 26% The trihydrochloride is then prepared under standard conditions. Melting point = 233 ° C (decomposition) Example 1 1 (Compound No. 33) 6-Acetylamino-4- [2- [4- (thieno [3,2-c] pyridin-4-yl] -1-piperazinyl] et -2 (1 H) hydrochloride quinolone (2: 1) 1 1.1 6-Acetylamino-4- (2-chloroet -2 (1 H) -quinolone hydrochloride (1: 1) 0.75 ml (5.39 mmol) of trietmine and then 0.35 ml (4.9 mmol ) of acetyl chloride are added to a suspension of 1.0 g (4.49 mmol) of 6-amino-4- (2-chloroet -2 (1 H) quinolone in 50 ml of chloroform at room temperature. The mixture is stirred for 16 hours and then diluted in 200 ml of chloroform. The suspension is washed with 1N aqueous hydrochloric acid solution and the precipitate is drained. 0.72 g of the expected product is obtained. Performance = 60% 1 1 .2. 6-Acetylamino-4- [2- [4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl] et -2 (1 H) -quinolone hydrochloride (2: 1) mixture of 0.35 g (1.32 mmol) of 6-acetylamino-4- (2-chloroet -2 (1 H) -quinolone hydrochloride, 0.38 g (1.75 mmol) of 4- (1-piperazinyl) thieno [3,2-c] pyridine and 0.17 g (2 mmol) of sodium bicarbonate in 10 ml of dimetormamide is heated at 60 ° C for 24 hours.

After cooling to room temperature, the reaction medium is diluted in 100 ml of water and allowed to stand overnight at 5 ° C.

The solid formed is drained and dried under vacuum. The crude product is purified by flash chromatography on silica, extracting first with a mixture of methanol / etacetate (5:95) and then with a mixture of methanol / dichloromethane (10:90) comprising traces of aqueous ammonia. 0.20 g of product is obtained in base form. Yield = 34% The dihydrochloride is then prepared under standard conditions. Melting point = 225 ° C (decomposition) Legend for the table: -in the "Salt" column: HCl represents a hydrochloride, the proportions (x: y) correspond to the ratio (acid / base), where there is no input present , this means that the compound is in base form. -in the column "Melting point": "(d)" corresponds to fusion with decomposition.

O c o -o o o o (X) VO CS. CM CM (O?? •• U "X CM x • -« X CM GM X X U X u 2 2 X n O O O 2 CC O or O or < s? (to X X or X X i I o or I i to. X i . to. i I I 0 (NI £ 5 The compounds of the invention were subjected to pharmacological studies, which demonstrated their antagonist properties to serontonin and its value as substances that have therapeutic activity. In this way, the compounds of the invention were subjected to a test of inhibition of the vasopressor effect of serotonin. Male rats (Sprague-Dawley, Charles River France) weighing 250 to 300 g are used, which were anesthetized with sodium pentobarbitone (60 mg / kg / ip) and kept under artificial respiration (Harvard ™ respirator - respiratory velocity 70 ml per minute, air volume 1 ml per 100 g of body weight). The animals are read by cutting the marrow using a metal bar, inserted via the orbit of the right eye, inserted along the spine. The left and right vagus nerves are sectioned (bivagotomy) and the right carotid artery is ligated, with the left carotid artery being catheterized in order to measure blood pressure using a pressure cell (StathamMR type P23Db). A femoral vein is catheterized for the purpose of administration of several compounds. Increases in serotonin-induced major blood pressure, administered intravenously at a dose of 30 μg / kg, are measured. The compounds of the invention or the vehicle are administered 5 minutes (for studies via route i.v.) or 75 minutes (for studies via the oral route) before administration of serotonin. The compounds of the invention are administered in doses ranging from 0.001 to 10 mg / kg. The percentage of inhibition of the serotonin control response is used in order to assess the potential serotonin antagonist of the compounds of the invention.

The compounds of the invention were also tested in a "sumatriptan" vasoconstriction model of isolated dog saphenous vein (antagonistic activity at the 5-HTY-like receptor according to HUMPHREY et al., In Br. J. Pharmacol., 1988, 94 1 123). The saphenous veins of Beagle or Anglo-Poitevin dogs are removed under pentobarbitone anesthesia administered by intravenous injection. The glass is cut into spirals 0.4 cm wide and then divided into 0.5 cm long segments. Each fragment, mounted between two cable staples, is placed in an isolated organ cell containing 20 ml of a physiological solution of Krebs of the following composition (mM): NaCl 1 18; KCl 4.7; MgCl 2 1.2; CaCl2 2.6; NaHCO3 25; glucose 1.1; ascorbic acid 0.1 1. The organ, maintained at 37 ° C under a stream of carbogen (95% O2 / 5% CO2) at pH 7.4, is bonded to a Hugo Sachs type 351 isometric calibrator under a baseline voltage of 2 g, and connected to a Gould 2400S polygraph allowing the voltage changes to be recorded. The acquisition of data is automated via a microcomputer system. After a period of 90 minutes at rest interspersed with frequent rinsings, during which the baseline tension is readjusted, the organ is stimulated with 3 μM noradrenaline in order to check its viability. A concentration versus contractile response curve is then constructed for sumatriptan in an accumulated manner between 10 nM and 1 0 μM. When the maximum contraction is obtained (plateau of the effect in two consecutive concentrations of sumatriptan), the preparation is rinsed copiously, interspersing periods of rest to allow the organ to return to the initial tension. The compound under study is then added to the organ bath 15 minutes before a second concentration-response curve for sumatriptan is constructed. The contractile responses obtained in the presence of the compound are expressed as a percentage of the maximum contraction observed in the first sumatriptan curve. The curves are yzed by non-linear regression, so that the Emax (maximum response) and the ECS0 (concentration that produces 50% of the maximum response) are determined. The antagonist potential of the compounds is estimated by calculating the dissociation constant KB according to the equation KB = [concentration of the compound in M] / (CR-1) where CR represents the proportion of EC50 values of sumatriptan in the presence and absence of the compound. The result is expressed as pA2 = -log KB. The pA2 values of the compounds of the invention are greater than 6. The compounds of the invention were also subjected to an inhibition test of the binding of [3H] spiroperidol to the serotonergic 5-HT2 receptors of the cerebral cortex of the rat. For this test, rat brains were removed and the bark was dissected and homogenized at 0 ° C in 20 volumes of a mixture containing, per liter, 50 mmol of Tris-HCl buffer at pH 7.4, 120 mmol of NaCl and mmol of KCl. The homogenous mixture is centrifuged at 4000 x g for 10 minutes and then, twice, the pellet is recovered, washed by suspending it in the same buffer mixture, homogenized again and centrifuged. Finally, the final pellet is diluted in the same buffer mixture in the proportion of 500 mg of wet tissue per 10 ml of buffer. The tissue is then subjected to a previous incubation for 10 minutes at 37 ° C in the presence of 10 μmol / l of pargyline, and subsequently to an incubation for 20 minutes at 37 ° C in the presence of [3 H] spiroperidol (specific activity : 19 Ci per mmol) at a concentration of 0.3 nM and of compound under study at concentrations qμe ranging from 0.001 to 100 μM. Aliquots of 1 ml are taken and filtered under vacuum, the filters were washed twice with 5 ml of cold buffer and dried, and the radioactivity was measured. To evaluate the activity of the compounds, a curve is plotted for the inhibition percentage of specific [3 H] spiroperidol binding as a function of the drug concentration of displacement.

The ICso, the concentration which inhibits 50% of the specific ligation, is determined graphically. The specific ligation is defined as the ligation shifted by 100 μM 5-HT. The IC 50 values of the compounds of the invention are less than 1 μM. The results of these tests showed that the compounds of the invention show serotonin antagonist properties. On this basis, they can be used in the treatment and prevention of various forms of pathologies involving serotonin, such as arterial hypertension, venous, pulmonary, portal, renal or ocular, cardiac, renal, ocular or cerebral ischemia or ischemia. lower limbs, heart failure, myocardial infarction, angina, coronary or peripheral vasospasm, thrombosis (the compounds themselves or as adjuvants in thrombolysis), arthritis, intermittent claudication, restenosis after angioplasty and various pathological conditions associated with atherosclerosis, with disorders of the microcirculation or with pulmonary dysfunction.

They can also be used, alone or in combination with other substances, in vascular graft operations. The compounds of the invention can be used in combination with other substances having cardiovascular or cardiopulmonary activity, such as antithrombotics, thrombolytics, β-blockers, calcium antagonists, thromboxane antagonists and thromboxane synthetase inhibitors. To this end, these compounds can be presented in all forms suitable for oral or parenteral administration, such as tablets, "dragées", capsules, including hard gelatin capsules and topical ocular formulations, in combination with suitable excipients. The doses present in these forms are such as to allow administration of 0. 1 mg to 1 g, one to several times a day. They can also be presented in all forms suitable for transdermal administration.

Claims (9)

1. CLAIMS 1 . Compounds of formula (I) wherein A represents either a 4- (thieno [3,2-c] pyridin-4-yl) -1-piperazinyl group or a 4- (4-fluorobenzoyl) -1-piperidyl group, Ri and R2 represent each one, independently of the other, either a hydrogen atom, or a halogen atom, or an amino group or a hydroxyl group, or a nitro group, or a cyano group, or a (d-C6) alkyl group, or a group (C? -C6) alkoxy, or a trifluoromethyl group, or a trifluoromethoxy group, or a -COOH group, or a -COOR4 group, or a -CON H2 group, or a -CONHR4 group, or a group- C0NH R4R5, or a group -SR, or a group -SO2R, or a group -NHCOR4, or a group -NHSO2R4, or a group -N (R4) 2, where R4 and Rs are each a group (C? - C4) alkyl, or a group - (CH2) pOH, or a group - (CH2) PN H2, or a group - (CH2) nCOOH, or a group - (CH2) nCOOR4, or a group - (CH2) nCON H2 , or a group - (CH2) nCON HOH, or a group - (CH2) PSH, or a group - (CH2) nSO3H, or a group - (CH2) NSO2NH2, or a group - (CH2) nSO2N HR4, or a group group - (CH2) nSO2N R4R5, or a group - (CH2) nCONH R4, or a group or - (CH2) nCONR4R5, OR a group - (CH2) nNHSO2R4, or a group - (CH2) pNHCOR, or a group - (CH2) POCOR4, where R4 and R5 are each a (C? -C4) alkyl group , n is equal to 1, 2, 3 or 4, p is equal to 2, 3 or 4 and m is equal to 2, 3 or 4 as well as its addition salts with pharmaceutically acceptable acids or bases.
2. 2. Compounds according to claim 1, characterized in that m equals 2.
3. 3. Compounds according to any of claims 1 and 2, characterized in that Ri, in position 6 or 7 in the quinolone represents either an atom of hydrogen, fluorine or chlorine, or an amino, hydroxyl, nitro, cyano, (C? -C6) alkyl, methoxy, trifluoromethoxy, acetylamino, methylsulfonylamino or dimethylamino group, and R2 represents a hydrogen atom.
4. 4. Compounds according to any of claims 1 to 3, characterized in that R3 represents either a hydrogen atom or a group (C? -C6) alkyl, or a group - (CH2) p0H, or a group - (CH2) nCOOH , or a group - (CH2) nCOOR4, or a group - (CH2) nCON H2, or a group - (CH2) nCONH R4, or a group - (CH2) pCONR4Rs, or a group - (CH2) pOCOR4, where R4 and Rs are each a group (C1-C4) alkyl, n is equal to 1, 2, 3 or 4, and p is equal to 2, 3 or 4.
5. 5. Compounds according to any of claims 1 to 4, characterized in that n is equal to 1 and p equals 2.
6. Process for preparing the compounds according to claim 1, characterized in that 4- (1-piperazinyl) thieno [3,2-cjpyridine or 4- ( 4-fluorobenzoyl) piperidine with a compound of formula (Vi l) in which R, R2, R3 and m are as defined in claim 1 and X represents a leaving group.
7. 7. Process for preparing the compounds of formula (Ib) wherein A, R, R2 and m are as defined in claim 1 and R3 is different from a hydrogen atom, characterized in that a compound of formula (Ia) it is reacted with an electrophilic agent.
8. 8. Medical product, characterized in that it contains a compound according to any of claims 1 to 5.
9. 9. Pharmaceutical composition, characterized in that it contains a compound according to any of claims 1 to 5, in combination with any pharmaceutically acceptable excipient.