FR2738823A1 - 3-Substd. di:hydro-quinolinone(s) - Google Patents

Abstract

Thieno-pyridinyl piperazinyl dihydro quinolinones of formula (I) and their salts, in racemic or enantiomeric form, are new. R1, R2 = H, halogen, NH2, OH, NO2, CN, 1-6C alkyl or alkoxy, CF3, OCF3, COOH, COOR4, CONH2, CONHR4, CONR4R5, SR4, SO2R4, OSO2CF3, NHCOR4, NHSO2R4, or N(R4)2; R3 = H, 1-4C alkyl , (CH2)pOH, (CH2)pNH2, (CH2)nCOOH, (CH2)nCOOR4, (CH2)nCONH2, (CH2)nCONHOH, (CH2)pSH, (CH2)nSO3H, (CH2)nSO2NH2, (CH2)nSO2NHR4, (CH2)nSO2NR4R5, (CH2)nCONHR4, (CH2)nCONR4R5, (CH2)pNHCOR4, -(CH2)pNHSO2R4, or (CH2)pOCOR4; R4, R5 = 1-4C alkyl; n = 1-4; and p, m = 2-4.

Description

The present invention relates to 3 - [- [4- (thieno [3,2-c] pyridin-4-yl] piperazin-1-yl] alkyl] -3,4-dihydroquinolin-2 (1H) -one derivatives. , their preparation and their application in therapeutics.

dans laquelle
R1 et R2 représentent chacun indépendamment l'un de l'autre, soit un atome d'hydrogène, soit un atome d'halogène, soit un groupe amino, soit un groupe hydroxy, soit un groupe nitro, soit un groupe cyano, soit un groupe (C1-C6)alkyle, soit un groupe (Cl-C6)alcoxy, soit un groupe trifluorométhyle, soit un groupe trifluorométhoxy, soit un groupe -COOH, soit un groupe -COOR4, soit un groupe -CONH2, soit un groupe -CONHR4, soit un groupe -CONR4R5 soit un groupe -SR41 soit un groupe -S02R4, soit un groupe -OSO2CF3, soit un groupe -NHCOR4, soit un groupe -NHSO2R4, soit un groupe -N(R4)2 où R4 et R5 sont chacun un groupe (C1-C4)alkyle,
R3 représente soit un atome d'hydrogène, soit un groupe (C1-C4)alkyle, soit un groupe -(CH2)pOH, soit un groupe -(CH2)pNH2, soit un groupe -(CH2)nCOOH, soit un groupe -(CH2)nCOOR4, soit un groupe -(CH2)nCONH2, soit un groupe -(CH2)nCONHOH, soit un groupe -(CH2)pSH, soit un groupe -(CH2)nSO3H, soit un groupe -(CH2)nSO2NH2, soit un groupe -(CH2)nSO2NHR4, soit un groupe -(CH2)nSO2NR4R5, soit un groupe -(CH2)nCONHR4, soit un groupe -(CH2)nCONR4R5,soit un groupe -(CH2)pNHCOR4, soit un groupe -(CH2)NHSO2R4,soit un groupe -(CH2)pOCOR4, où R4 et R5 sont chacun un groupe (C1-C4)alkyle, n est égal à 1, 2, 3 ou 4, p est égal à 2, 3 ou 4 et m est égal à 2, 3 ou 4, ainsi que leurs sels d'addition aux acides ou bases pharmaceutiquement acceptables.The compounds of the invention correspond to formula (I)

in which
R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, an amino group, a hydroxy group, a nitro group, a cyano group or a (C1-C6) alkyl, either a (C1-C6) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -COOH group, a -COOR4 group, a -CONH2 group, or a group - CONHR4, a -CONR4R5 group, a -SR41 group, a -SO2R4 group, an -OSO2CF3 group, an -NHCOR4 group, -NHSO2R4 group, or a -N (R4) 2 group where R4 and R5 are each a (C1-C4) alkyl group,
R3 represents either a hydrogen atom, a (C1-C4) alkyl group, a - (CH2) pOH group, a - (CH2) pNH2 group, a - (CH2) nCOOH group, or a - (CH2) nCOOR4, either a - (CH2) nCONH2 group, a - (CH2) nCONHOH group, a - (CH2) pSH group, a - (CH2) nSO3H group or a - (CH2) nSO2NH2 group, either a - (CH2) nSO2NHR4 group, a - (CH2) nSO2NR4R5 group, a - (CH2) nCONHR4 group, a - (CH2) nCONR4R5 group, a - (CH2) pNHCOR4 group, or a - (CH2) group CH2) NHSO2R4, a - (CH2) pOCOR4 group, where R4 and R5 are each a (C1-C4) alkyl group, n is 1, 2, 3 or 4, p is 2, 3 or 4 and m is 2, 3 or 4, as well as their addition salts with pharmaceutically acceptable acids or bases.

The compounds of formula (I) may exist in the form of pure racemates or enantiomers which are also part of the invention.

According to the invention, the compounds of formula (I) can be synthesized according to scheme 1.

An ortho-nitro-benzaldehyde of formula (II) (in which R1 and R2 are as defined above) is reacted with the α- [γ-butyrolactonylidene] triphenylphosphorane of formula (III) under reflux of an aprotic solvent such as tetrahydrofuran or toluene and there is obtained a compound of formula (IV) which is converted into dihydroquinolinone of formula (V) (in which m is equal to 2), by a reduction-cyclization reaction, or under hydrogen in a mixture of acetic acid / tetrahydrofuran in the presence of palladium, or under hydrogen in tetrahydrofuran in the presence of platinum and anhydrous ortho-phosphoric acid when R1 or
R2 represents a halogen atom, ie without additional hydrogen, in the presence of zinc and concentrated hydrochloric acid in N-methyl pyrrolidone, when R1 or R2 represents a group -OSO2CF3. Then, if it is desired to obtain a compound of formula (Ia) (in which R 3 represents a hydrogen atom and m is equal to 2), the alcohol of formula (V) obtained above is oxidized to the aldehyde of formula (VI) preferably 1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3 (1H) -one (Dess-Martin reagent) in dichloromethane or the tetrapropylammonium perruthenate / N-system. methyl morpholine N-oxide, in the presence of molecular sieve 4A, also in dichloromethane and the compound thus obtained is condensed with 4- (piperazin-1-yl) thieno [3,2-c] pyridine of formula (VII), by a reductive amination reaction in the presence of titanium tetraisopropoxide and sodium cyanoborohydride in ethanol.

ou sur le composé de formule (VI) correspondants (dans lesquelles m est égal à 2), une homologation de une ou deux unités méthyléniques suivant des méthodes connues de l'homme du métier puis on continue selon le schéma 1.To prepare the compounds of formula (Ia) (in which m is equal to 3 or 4), the compound of formula (V) is produced
Diagram 1

or on the corresponding compound of formula (VI) (in which m is equal to 2), an homologation of one or two methylenic units according to methods known to those skilled in the art and then continuing according to scheme 1.

When it is desired to prepare a compound of formula (Ib) in which R 3 is different from a hydrogen atom, then the alcohol of formula (V) (in which m is equal to 2) is converted into a compound of formula ( VIII) (in which P represents a protecting group, for example a trialkylsilyl group), by reaction with a compound such as, for example, tertbutyldimethylsilyl chloride, and the compound (VIII) thus obtained is reacted with an electrophilic agent of R3Br type or R3I (wherein R3 is as defined above) in the presence of a base such as sodium hydride, at a temperature between room temperature and the reflux of tetrahydrofuran.After deprotection, for example by means of tetrabutylammonium fluoride in tetrahydrofuran, an alcohol of formula (IX) (in which m is equal to 2) is obtained which is converted into a derivative of formula (X) (in which X represents a leaving group, for example a chlorine atom). or bromine and m is 2), for example by reaction with thionyl chloride in chloroform or dibromotriphenylphosphorane in dichloromethane or compounds of formula (X) (wherein X represents a leaving group such as methanesulfonyloxy groups trifluoromethanesulfonyloxy or para-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 compound of formula (X) is condensed with 4 - (piperazin-1-yl) thieno [3,2-c] pyridine of formula (VII) in the pure phase or in a solvent such as acetonitrile or dimethylformamide, at a temperature of between 20 and 150 ° C., in the presence of of a base such as sodium bicarbonate.

If it is desired to prepare a compound of formula (Ib) (in which m is equal to 3 or 4), one carries out on the corresponding compound of formula (V) or on the compound of formula (IX) (in which m is equal to 2) a homologation of one or two methylenic units according to methods known to those skilled in the art and then continue according to scheme 1.

It is also possible to obtain a compound of formula (Ib) (in which R 3 is different from a hydrogen atom) from the corresponding compound of formula (Ia) (in which R 3 represents a hydrogen atom), by alkylation with an electrophilic agent by means of a base such as sodium hydride or potassium hydroxide in a solvent such as tetrahydrofuran, in the presence or absence of a phase transfer catalyst such as tetrabutylammonium bromide.

The starting compounds are commercially available or described in the literature or may be prepared according to methods described therein or which are known to those skilled in the art.

Thus, 5-methoxy-2-nitrobenzaldehyde is prepared from 5-hydroxy-2-nitrobenzaldehyde according to J. Het. Chem. 16, p 221 (1979).

Α- [γ-Butyrolactonylidene] triphenylphosphorane is prepared according to H. Zimmer et al. J. Het. Chem. 2, p 95 (1965) and
Helv. Chim. Acta 46, p. 1580 (1963), from α-bromobutyrolactone.

The method of synthesizing compounds of formula (V) by a reduction-cyclization reaction is described in T. Jean et al., J. Med. Chem., 16, p 663 (1973).

Hydrogenation methods in the presence of halogen or triflate are published in German Patent DE3006748 and in T. Rossi et al., J. Am. Chem. Soc., 115, p 5843 (1993), respectively.

The method of oxidation of alcohols by the reagent of
Dess-Martin is described in D. Dess and J. Martin J. Org.

Chem. 48, p 4155 (1983) and R. Ireland and L. Liu, J. Org.

Chem. 58, p 2899 (1993).

The method for the oxidation of alcohols with tetrapropylammonium perruthenate / N-methyl morpholine N-oxide is adapted from that described by W. Griffith et al. J.C.S. Chem. Comm., P 1625 (1987).

The method of bromination of alcohols and ethers silylated by dibromotriphenylphosphorane is inspired by those of
J. Aizpurua J. Org. Chem., 51, p. 4941 (1986) and J. Sandri et al. Synth. Common. 22, p 2945 (1992).

The 4- (1-piperazinyl) thieno [3,2-c] pyridine of formula (VII) is synthesized according to J.S. NEW et al. J. Med. Chem., 32, pp 1147-56 (1989).

The following examples illustrate the invention. Microanalyses and IR, NMR and mass spectra confirm the structure of the compounds obtained.

The numbers of the exemplified compounds refer to those of the table, given below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

The ratio (x: y) corresponds to the ratio (acid: base).

Example 1 (Compound No. 2) 1-methyl-3- [2- [4-thieno [3,2-c] pyridin-4-yl] piperazin-1-yl] ethyl] -3,4-dihydroquinoline hydrochloride 2 (1H) one (2: 1) 1.1 3 - [(2-nitrophenyl) methylene] -dihydrofuran-2 (3H) -one
To 15.0 g (99.3 mmol) of 2-nitrobenzaldehyde in 270 ml of tetrahydrofuran is added 30.0 g (87 mmol) of α-butyrolactonylidene triphenylphosphorane, the reaction mixture is refluxed for 7 hours then we leave him at rest at night. The solvent is evaporated and the crude product is purified by chromatography on silica eluting with dichloromethane.

20.0 g of the expected product are obtained.

Melting point = 95 OC
Yield = 92% 1.2. 3 - [(2-hydroxyethyl) 3,4-dihydroquinolin-2 (1H) -one
A mixture of 8.3 g (38 mmol) of 3 - [(2-nitrophenyl) methylene] -dihydrofuran-2 (3H) -one and 1 g (38 mmol) was subjected to 40 psi (0.3 MPa) of hydrogen for 3 hours. 6 g of 5% palladium on carbon in 100 ml of acetic acid at room temperature; the catalyst is filtered off and the filtrate is evaporated to dryness. The residue is triturated in diisopropyl ether and 6.0 g of the expected product are obtained.

Melting point = 95 OC
Yield = 83% 1.3. 3- [2- [[(1,1-dimethylethyl) dimethylsilyloxy] ethyl] -3,4-dihydroquinolin-2 (1H) -one
To 5.0 g (26 mmol) of 3 - [(2-hydroxyethyl) -3,4-dihydroquinoline-2 (1H) -one and 2.6 g (39 mmol) of imidazole in 50 ml of dimethylformamide, 9.8 g (65 mmol) of tertbutyldimethylsilyl chloride are added and the solution is stirred at room temperature for 2 hours. Then the solvent is evaporated under vacuum and the residue is taken up in 300 ml of ether. This solution is washed twice with water and the organic phase is dried over magnesium sulfate and then concentrated.

7.3 g of the desired silyl ether are obtained in the form of an oil.

Yield = 97% 1.4. 3- (2-hydroxyethyl) -1-methyl-3,4-dihydroquinolin-2 (1H)
one
To 7.0 g (24.3 mmol) of 3- [2 - [[(1,1-dimethylethyl) dimethylsilyloxy] ethyl] -3,4-dihydroquinolin-2 (1H) -one in 150 ml of tetrahydrofuran at ambient temperature, 1.1 g (37 mmol) of 60% sodium hydride in oil are added. 3.0 ml (48 mmol) of methyl iodide are left in contact for 30 minutes and stirred for 20 hours at room temperature. Then the reaction medium is evaporated to dryness, the residue is taken up in 100 ml of tetrahydrofuran, 25 ml of a solution of 1 M tetrabutylammonium fluoride in tetrahydrofuran are added and the mixture is stirred at ambient temperature for 2 hours. The solvent is evaporated off. the residue is taken up in 300 ml of ether and washed several times with water. The organic phase is dried over magnesium sulfate, concentrated and the crude product is purified by chromatoflash, eluting with a methanol / dichloromethane mixture (2:98).

5 g of the expected product are obtained in the form of an oil.

Yield = 100% overall 1.5. 3- (2-chloroethyl) -1-methyl-3,4-dihydroquinolin-2 (1H) -
one
1.7 ml (23.3 mmol) of thionyl chloride are added dropwise to a solution of 2.0 g (10 mmol) of 3- (2-hydroxyethyl) -1-methyl-3,4-dihydroquinoline -2 (1H) -one in 40 ml of chloroform at room temperature and the solution is refluxed for 2.5 hours. Then the solvents are evaporated and the oil obtained is used as it is.

1.6. 1-methyl-3- [2- [4-thieno [3,2-c] pyridin-4-yl] piperazin-1-yl] ethyl] -3,4-dihydroquinolin-2 (H) hydrochloride
one (2: 1)
1.0 g of 3- (2-chloroethyl) -1-methyl-3,4-dihydroquinolin-2 (1H) -one and 2.0 g (9 mmol) of 4 are heated to 110-120 ° C. (1-piperazinyl) thieno [3,2-c] pyridine for 4 hours, then left for 20 hours at room temperature. The crude product is purified by chromatoflash on silica eluting with a methanol / dichloromethane mixture (5:95) containing traces of ammonia.

0.5 g of the expected product is obtained.
Yield = 30%.

The product is taken up in 3 ml of methanol and 10 ml of ether and salified with 15 ml of anhydrous 1.5 M hydrochloric ether.

0.3 g of the dihydrochloride is obtained
Melting point = 210 OC
Example 2 (Compound No. 4) 6-Methoxy-3- [2- [4-thieno [3,2-c] pyridin-4-yl] piperazin-1-yl] ethyl] -3,4-dihydroquinoline hydrochloride 2 (1H) -one (2: 1) 2.1. 3- [((5-methoxy-2-nitrophenyl) methylene] -dihydrofuran
2 (3H) -one
To 5.0 g (27 mmol) of 5-methoxy-2-nitrobenzaldehyde in 200 ml of toluene was added 8.3 g (24 mmol) of α- [γ-butylolactonylidene] triphenylphosphorane. The reaction mixture is refluxed for 6 hours and allowed to cool overnight. The precipitate formed is filtered off and dried under vacuum.

4.0 g of the expected product are obtained.

Melting point = 98 OC
Yield = 62% 2.2. 3- (2-hydroxyethyl) -6-methoxy-3,4-dihydroquinoline 2 (1H) -one
Hydrogen is hydrogenated at room temperature for 2.5 hours at 30 psi (0.2 MPa), 2.5 g (10 mmol) of 3 - [(5-methoxy-2-nitrophenyl) methylene] dihydrofuran -2 (3H) -one and 0.4 g of 5% palladium on carbon in 50 ml of tetrahydrofuran and 0.25 ml of acetic acid. The catalyst is filtered and the filtrate is evaporated.

The residue is taken up in a minimum of dichloromethane where the product crystallizes.

1.4 g of the expected product are obtained.

Melting point = 90 ° C
Yield = 70% 2.3. 6-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-3-
acetaldehyde
6.1 g (14 mmol) of 1,1,1-triacetoxy-1,1-dihydro-1,2-benzodioxol-3 (1H) -one in 100 ml of dichloromethane at 2.7 g are added dropwise. (12 mmol) 3- (2-hydroxyethyl) -6-methoxy-3,4-dihydroquinolin-2 (1H) -one in 25 ml of dichloromethane at room temperature. After the addition, the reaction medium is stirred at this temperature for 20 hours. 90 ml of dichloromethane and 90 ml of a saturated aqueous sodium bicarbonate solution containing 19 g of sodium sulphate are then added. Stir vigorously for 30 minutes. The organic phase is decanted and the aqueous phase is re-extracted with dichloromethane. The organic phases are combined, washed with water, dried over magnesium sulphate and concentrated.

2.4 g of an amorphous solid is obtained which is used as it is.

Yield = 95% 2.4. 6-methoxy-3- [2- [4-thieno [3,2-c] pyridin-4-yl] piperazin-1-yl] ethyl] -3,4-dihydroquinoline hydrochloride
léin-2 (1H) -one (2: 1)
1.0 g (4.5 mmol) of 6-methoxy-2-oxo-1,2,3,4-tetrahydroquinoline-3-acetaldehyde, 1.0 g (4.5 g) are stirred at room temperature for 4 hours. mmol) of 4- (1-piperazinyl) thieno [3,2-c) pyridine and 2.6 ml (9.12 mmol) of titanium tetraisopropoxide in 5 ml of absolute ethanol. 1.0 g (18 mmol) of sodium cyanoborohydride are added to this paste and the mixture is stirred slowly at ambient temperature for 10 hours. The reaction medium is diluted with 200 ml of dichloromethane and treated with 100 ml of a saturated aqueous solution of ammonium chloride. The organic phase is decanted and the concentrate is concentrated. The crude product is purified on silica eluting with a methanol / dichloromethane (5:95) mixture containing traces of ammonia.

0.6 g of the expected product is obtained in the form of a thick oil.

Yield = 33%.

0.32 g (0.75 mmol) of this compound are dissolved in 5 ml of methanol, 0.4 ml of 3N hydrochloric ether are added and the product is left to crystallize and then drained and rinsed. with ether. After drying under vacuum, 0.20 g of the expected product is obtained in the form of dihydrochloride.

Melting point = 240 OC
Board

<SEP><SEP> Point of <SEP> Merge
<tb> No <SEP> R1 <SEP> R2 <SE> R3 <SEP> m <SEP> Sel <SEP> (C)
<tb> 1 <SEP> H <SEP> H <SEP> H <SEP> 2 <SEP> 2 <SEP> HCl <SEP> 260
<tb> 2 <SEP> H <SEP> H <SEP> CH3 <SEP> 2 <SEP> 2 <SEP> HCl <SEP> 210
<tb> 3 <SEP> 6-CH3 <SEP> H <SEP> H <SEP> 2 <SEP> 2 <SEP> HCl <SEP> 248 <SEP>
<tb> 4 <SEP> 6-OCH3 <SEP> H <SEP> H <SEP> 2 <SEP> 2 <SEP> HCl <SEP> 240
<tb> 5 <SEP> 6-C1 <SEP> H <SEP> CH3 <SEP> 2 <SEP> 2 <SEP> HCl <SEP> 160
<tb> 6 <SEP> 6-OCH3 <SEP> H <SEP> CH3 <SEP> 2 <SEP> 2 <SEP> HCl <SEP> 265
<tb> 7 <SEP> 6-OSO2CF3 <SEP> H <SEP> CH3 <SEP> 2 <SEP> 2 <SEP> HCl <SEP> 225
<Tb>
Notes: in the column 'Salt', '2HCl' represents a dihydrochloride.

The compounds of the invention have been the subject of pharmacological studies which have demonstrated their serotonin antagonistic properties and their interest as substances with therapeutic activity.

Thus, the compounds of the invention were subjected to an inhibition test of the vasopressor effect of serotonin. Male rats (Sprague-Dawley, Charles River France) weighing 250 to 300 g, pentobarbital sodium anesthesia (60 mg / kg / ip) and maintained under artificial respiration (Harvardn-frequency respirator breath rate of 70 ml per minute, air volume 1 ml per 100 g body weight). The animals are amylated using a metal rod inserted through the orbit of the right eye and down the vertebral column. The right and left vagus nerves are divided (bivagotomy), the carotid artery is ligated. right, the left carotid artery being catheterized in order to measure the arterial pressure using a pressure cell (StathamTM type P23Db). A femoral vein is catheterized for the administration of various compounds. Intravenous serotonin-mediated increases in mean arterial blood pressure were measured at a dose of 30 μg / kg. The compounds of the invention or the vehicle are administered for 5 minutes (for i.v. studies) or 75 minutes (for oral studies) prior to administration of serotonin. The compounds of the invention are administered in doses ranging from 0.001 to 10 mg / kg. The percent inhibition of the serotonin control response is used to assess the serotonin antagonistic potential of the compounds of the invention.

The compounds of the invention were also tested in a model of sumatriptan vasoconstriction of the saphenous vein isolated from dogs (antagonistic activity at the 5-HT1-like receptor according to HUMPHREY et al., In Br. J. Pharmacol 1988, 94, 1123).

Saphenous veins of Beagle or Anglopoitevins dogs are taken under pentobarbital anesthesia administered by intravenous injection. The vessel is cut into a helix 0.4 cm wide and divided into segments 0.5 cm in length. Each fragment, mounted between two clamshells, is placed in an isolated organ container containing 20 ml of physiological Krebs solution of the following composition (mM): NaCl 118; KCl 4.7; MgCl 2 1.2; CaCl2 2.6; NaHCO3 25; Glucose 11.1; ascorbic acid 0.11. The organ, maintained at 37 C under a carbogen stream (95% 2-5% CO2) at pH 7.4 is connected to a Hugo Sachs isometric sensor type 351 at a basal tension of 2 g , and connected to a Gould 2400S polygraph allowing the recording of voltage variations.

The acquisition of the data is automated by microinformatic system. After a rest period of 90 minutes interspersed with frequent rinses during which the basal tension is readjusted, the organ is stimulated by 3 WM norepinephrine to verify its viability. A sumatriptan contractile concentration-response curve is then constructed cumulatively between 10 nM and 10 WM. When the maximum contraction is obtained (plateau of the effect at two consecutive concentrations of sumatriptan), the preparation is thoroughly rinsed by interposing periods of rest to allow the organ to return to the initial tension. The test compound is then added to the organ bath 15 minutes before a second sumatriptan concentration-response curve is constructed.

The contraction responses obtained in the presence of the compound are expressed as a percentage of the maximum contraction observed during the first sumatriptan curve. The curves are analyzed by non-linear regression to determine the Emax (maximum response) and the EC50 (concentration producing 50% of the maximum response). The antagonistic potential of the compounds is estimated by calculating the KB dissociation constant according to the equation KB = [concentration of the compound in M] / (CR - 1) where CR represents the EC50 ratio of sumatriptan in the presence and in the absence of the compound . The result is expressed as pA2 = - log KB.

The pA2 of the compounds of the invention are greater than 6.

Compounds of the invention have also been tested for inhibition of [3H] spiroperidol binding to serotoninergic 5-HT2 receptors of the rat cerebral cortex.

For this test, the brains of rats are removed, the cortex is dissected and homogenized with OOC in 20 volumes of a mixture containing, per liter, 50 mmol of buffer.
Tris / HCl pH 7.4, 120 mmol NaCl and 5 mmol KCl.

The homogeneous mixture is centrifuged at 40000 xg for 10 minutes and then the pellet is recovered twice, washed by suspending it in the same buffer mixture, homogenized again and centrifuged. Finally, the final pellet is diluted in the same buffer mixture at a rate of 500 mg of wet tissue per 10 ml of buffer. The tissue is then incubated for 10 minutes at 37 ° C. in the presence of 10 μl of pargyline, then incubation for 20 minutes at 37 ° C in the presence of 3H-spiroperidol (specific activity: 19 Ci per mmol) at a concentration of 0.3 nM and compound to be studied at concentrations ranging from 0.0001 to 100 WM. Aliquots of 1 ml are removed and filtered under vacuum, the filters are washed twice with 5 ml of cold buffer, dried and the radioactivity measured.

In order to evaluate the activity of the compounds, the percentage inhibition curve of the specific binding of 3H-spiroperidol is established as a function of the concentration of displacing drug. The IC50 concentration, which inhibits 50% of the specific binding, is graphically determined.

The specific binding is defined as the link displaced by 100 WM of 5-HT.

The IC50 of the compounds of the invention are less than 1 WM.

The results of these tests have shown that the compounds of the invention have serotonin antagonistic properties.

As such, they can be used in the treatment and prevention of various forms of diseases involving serotonin, such as arterial, venous, pulmonary, portal, renal or ocular hypertension, cardiac, renal, ocular or cerebral ischemia. heart failure, myocardial infarction, angina, coronary or peripheral vasospasms, thromboses (alone or as adjuvants to thrombolysis), arteritis, intermittent claudication, restenosis after angioplasty and various pathological conditions associated with atherosclerosis, disturbances of microcirculation or pulmonary dysfunctions. They can also be used alone or in combination with other substances in vascular graft surgery.

The compounds of the invention may be used in combination with other cardiovascular or cardiopulmonary substances, such as antithrombotics, thrombolytics, anti-blockers, calcium antagonists, thromboxane antagonists, thromboxane inhibitors synthetase.

For this purpose, these compounds may be presented in any form suitable for oral administration, or parenteral, such as tablets, dragees, capsules, capsules, topical ocular formulations in combination with suitable excipients. These forms are dosed to allow administration of 0.1 mg to 1 g, one to several times a day.

They can also be presented in any form suitable for transdermal administration.

Claims (6)

claims 1. Compounds of formula (I)

 in which R 1 and R 2 each independently represent a hydrogen atom, a halogen atom, an amino group, a hydroxy group, a nitro group, a cyano group or a (C1-C6) alkyl, either a (C1-C6) alkoxy group, a trifluoromethyl group, a trifluoromethoxy group, a -COOH group, a -COOR4 group, a -CONH2 group, or a group - CONHR4, a -CONR4Rs group, a -SR4 group, a -SO2R4 group, -OSO2CF3 group, -NHCOR4 group, -NHSO2R4 group, or a -N (R4) 2 group where R4 and R5 are each a (C1-C4) alkyl group, R3 represents either a hydrogen atom, a (C1-C4) alkyl group, a - (CH2) pOH group, a - (CH2) pNH2 group, a - (CH2) nCOOH group, or a - (CH2) nCOOR4, either a - (CH2) nCONH2 group, a - (CH2) nCONHOH group, a - (CH2) pSH group, a - (CH2) nSO3H group or a - (CH2) nSO2NH2 group, either a - (CH2) nSO2NHR4 group, a - (CH2) nSO2NR4Rs group, a - (CH2) nCONHR4 group, a - (CH2) nCONR4Rs group, a (CH2) pNHCOR4 group, or a - (CH2) group ) pNHSO2R4, that is a group - (CH2) pOCOR4 where R4 and R5 are each a (C1-C4) alkyl group, n is 1, 2, 3 or 4, p is equal to 2, 3 or 4 and m is equal to 2, 3 or 4, in the form of pure racemates or enantiomers, as well as their addition salts with pharmaceutically acceptable acids or bases. 2. Process for the preparation of the compounds of formula (Ia) according to claim 1 (in which R3 represents a hydrogen atom), characterized in that 4- (piperazin-1-yl) thieno [3] is reacted. , 2-c] pyridine of formula (VII)

 with a compound of formula (VI)

 (wherein R1, R2 and m are as defined in claim 1) under reductive amination conditions. 3. Process for the preparation of the compounds of formula (Ib) according to claim 1 (in which R3 is different from a hydrogen atom), characterized in that 4- (piperazin-1-yl) is reacted. thieno [3,2-c] pyridine of formula (VII)

 with a compound of formula (X)

 (wherein R1, R2, R3 and m are as defined in claim 1 and X represents a leaving group). 4. Process for the preparation of the compounds of formula (Ib) according to claim 1 (in which R 3 is other than a hydrogen atom), characterized in that a compound of formula (Ia) (in which R 3 represents a hydrogen atom) by alkylation with an electrophilic agent. 5. Medicinal product characterized in that it contains a compound according to claim 1. 6. Pharmaceutical composition characterized in that it contains a compound according to claim 1 in association with any pharmaceutically acceptable excipient.