4-Substituted Quinoline Derivatives, Method and Intermediates for Their Preparation and Pharmaceutical Compositions Containing Them

Abstract

The present invention relates to 4-substituted quinoline derivatives of general formula I:

Description

EXAMPLE 1

Ethyl (RS)-2-aminomethyl-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate hydrochloride may be prepared in the following manner:

1). 88.4 cm³ of a 4N hydrochloric acid solution in dioxane are added at a temperature in the region of 20° C. to 15.37 g (35.37 mmol) of ethyl (RS)-2-tert-butyloxycarbonylaminomethyl)-5-(3-fluoro-6-methoxy-quinolin-4-pentanoate in solution in 268 cm³ of ethanol. After stirring for 15 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure to give 11.72 g of ethyl (RS)-2-aminomethyl-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate hydrochloride in the form of a yellow solid.

EI MS spectrum: m/z 334 [M+], m/z 178 (base peak).

Ethyl (RS)-2-(tert-butyloxycarbonylaminomethyl)-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate may be prepared in the following manner:

2). A solution of 12.43 g (48.3 mmol) of ethyl (RS)-2-(tert-butyloxycarbonylaminomethyl)pent-4-enoate in 150 cm³ of tetrahydrofuran is added at a temperature in the region of 0° C., under an argon atmosphere, to 144.9 cm³ (72.45 mmol) of a solution of 0.5M 9-BBN (9-borabicyclo[3.3.1]nonane)/THF. After heating the reaction mixture to a temperature in the region of 20° C. and then stirring for 3.25 hours at a temperature in the region of 20° C., 14.64 g (48.3 mmol) of 3-fluoro-4-iodo-6-methoxyquinoline in suspension in 370 cm³ of tetrahydrofuran and then 30.76 g (145 mmol)of potassium phosphate and 1.06 g (1.449 mmol) of PdCl₂dppf ([1,1′-bis(diphenylphosphino)ferrocene]palladium chloride) are successively added. After stirring for 16 hours at the reflux temperature, the reaction mixture is cooled and then filtered on Celite®. The Celite® is rinsed with tetrahydrofuran. The filtrate is then concentrated to dryness under reduced pressure (2.7 kPa). The residue is taken up in ethyl acetate, washed with water and then with a saturated aqueous sodium chloride solution. The organic phase is dried and concentrated to dryness under reduced pressure (2.7 kPa) to give 30.6 g of a brown oil which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 by volume)]. 15.37 g of ethyl (RS)-2-(tert-butyloxycarbonyl-aminomethyl)-5-(3-fluoro-6-methoxyquinolin-4-yl)-pentanoate are obtained in the form of a yellow oil.

EI MS spectrum: m/z 434 [M+], m/z 204 (base peak). 3-Fluoro-4-iodo-6-methoxyquinoline may be prepared according to the method described in patent WO 2002/40474-A2.

Ethyl (RS)-2-(tert-butyloxycarbonylaminomethyl)pent-4-enoate may be prepared in the following manner:

3). 147 cm³ (174 mmol) of lithium bis(trimethylsilyl)-amide in 1M solution in tetrahydrofuran are added dropwise at a temperature in the region of −78° C., under an argon atmosphere, to 18.9 g (87 mmol) of ethyl 3-tert-butyloxycarbonylaminopropionate in solution in 203 cm³ of tetrahydrofuran. After stirring for 0.5 hour at a temperature in the region of −78° C., 7.51 cm³ (87 mmol) of allyl bromide are added. After stirring for 5 hours at a temperature in the region of −78° C., the temperature is allowed to change from −78° C. to a temperature in the region of 20° C. over 1.5 hours. The reaction medium is then hydrolyzed with 150 cm³ of water. The organic phase is separated by decantation, diluted with ethyl acetate, washed with water and with a saturated aqueous sodium chloride solution, dried and then concentrated to dryness under reduced pressure (2.7 kPa) to give 16.7 g of a colorless oil which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. 12.43 g of ethyl (RS)-2-(tert-butyloxycarbonylaminomethyl)pent-4-enoate are obtained in the form of a colorless oil.

CI MS spectrum: m/z 258 [M+H]+(base peak).

Ethyl 3-tert-butyloxycarbonylaminopropionate may be prepared in the following manner:

4). 59.9 cm³ or triethylamine and then 46.88 g of di-tert-butyl dicarbonate are successively added at a temperature in the region of 20° C., under an argon atmosphere, to 30 g (195 mmol) of β-alanine ethyl ester hydrochloride in solution in 1000 cm³ of dichloromethane. After stirring for 20 hours at a temperature in the region of 20° C., the reaction mixture is successively washed with twice 500 cm³ of water, twice 500 cm³ of a 0.1N aqueous hydrochloric acid solution and twice 500 cm³ of a saturated aqueous sodium bicarbonate solution. The organic phase is dried and then concentrated to dryness under reduced pressure (2.7 kPa) to give 45.6 g of a colorless oil which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (8/2 by volume)]. 40.5 g of ethyl 3-tert-butyloxycarbonylaminopropionate are obtained in the form of a colorless oil. EI MS spectrum: m/z 258 [M+H]+(base peak).

EXAMPLE 2

Ethyl (RS)-2-{[(E)-(2,5-difluorophenyl)allylamino]-methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate 1.5 cm³ of triethylamine and 0.816 g of (E)-2-(2,5-difluorophenyl)propenal in solution in 100 cm³ of diethyl ether are added at a temperature in the region of 0° C., under an argon atmosphere, to 2 g (5.393 mmol) of ethyl (RS)-2-aminomethyl-5-(3-fluoro-6-methoxy-quinolin-4-yl)pentanoate obtained in example 1 in solution in 142 cm³ of diethyl ether. After stirring for 1 hour at room temperature, 0.816 g of magnesium sulfate is added. After stirring for 1 hour at room temperature, the reaction mixture is filtered, the magnesium sulfate is rinsed with diethyl ether and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give an oil which is diluted with 242 cm³ of ethanol. 0.204 g of sodium borohydride is added to this solution which is cooled to a temperature in the region of 0° C., under an argon atmosphere. After stirring for 15 minutes at a temperature in the region of 0° C. and then for 16 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is diluted with 100 cm³ of ethyl acetate, washed with water and then with a saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 3.3 g of a residue which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitril (98/1/1 by volume)]. 1.38 g of ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)penanoate are obtained in the form of a pale yellow oil.

EI MS spectrum: m/z 486 [M+.], m/z 153 (base peak).

(E)-3-(2,5-Difluorophenyl)propenal may be prepared in the following manner:

10.6 g of 2,5-difluorobenzaldehyde are added at a temperature in the region of 20° C. to 22.7 g (74.6 mmol) of (triphenylphosphoranylidene)acetaldehyde in solution in 650 cm³ of toluene. After stirring for 4 hours at a temperature in the region of 80° C., the reaction medium is is concentrated to dryness under reduced pressure (2.7 kPa) to give 28.42 g of brown residue which is taken up in 120 cm³ of diisopropyl ether. After stirring for 1 hour at room temperature, the solution is filtered and the solid residue is taken up in 120 cm³ of diisopropyl ether. After stirring for 1.5 hours at room temperature, the solution is filtered and then the two filtrates are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give 11.69 g of a yellow solid which is purified by flash chromatography [eluent: ethyl acetate/cyclohexane (1/1 by volume)]. 9.32 g of a pale yellow solid are obtained, which solid is recrystallized in the hot state from 20 cm³ of diisopropyl ether to give 6.66 g of (E)-3-(2,5-difluorophenyl)propenal in the form of a pale yellow solid melting at 88° C.

MS EI spectrum: m/z 168 [M+].

EXAMPLE 3 AND EXAMPLE 4

Enantiomers A (levorotatory) and B (dextrorotatory) of ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]-methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate

The ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)-allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate (0.750 g) obtained in example 2 in solution in 15 cm³ of ethanol and 60 cm³ of heptane is injected onto a column 8 cm in diameter and 35 cm in length containing 1200 g of chiral stationary phase: Chiralpak ADTM having a particle size of 20 μm. The elution is carried out with a mobile phase [heptane/ethanol/methanol (96/2/2 by ovlume)] at a flow rate of 140 ml/min, the detection is carried out by UV at 254 nm. The enantiomer A (levorotatory), of undetermined absolute configuration, which elutes first, is recovered and then concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. to give 0.359 g of a colorless oil. The enantiomer B (dextrorotatory), of undetermined absolute configuration, which elutes second, is recovered and then concentrated under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. to give 0.369 g of a colorless oil.

Enantiomer A (levorotatory) of ethyl 2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate [α]D20 -4.7+/−0.4 [methanol (c=0.5), 589 nm)]. ¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δin ppm): 1.12 (t, J=7 Hz: 3H); 1.64 (unresolved complex: 4H); 1.99 (broad unresolved complex: 1H); from 2.50 to 2.70 (mt: 2H); 2.74 (mt: 1H); 3.08 (mt: 2H); from 3.20 to 3.35 (mt: 2H); 3.96 (s: 3H); 4.05 (q, J=7 Hz: 2H); 6.44 (dt, J=16 and 5.5 Hz: 1H); 6.59 (broad d, J=16 Hz: 1H); 7.11 (mt: 1H); 7.24 (doublet of t, J=9.5-4.5 Hz: 1H); 7.36 (d, J=3 Hz: 1H); 7.40 (dd, J=9 and 3 Hz: 1H): 7.44 (mt: 1H); 7.97 (d, J=9 Hz: 1H); 8.69 (d, J=0.5 Hz: 1H).

IR spectrum (CCl₄) 2939; 2831; 1729; 1621; 1508; 1491; 1468; 1263; 1231; 1182; 1034; 971 and 832 cm⁻¹.

EI MS spectrum: m/z 486 [M]+., m/z 153 (base peak). Enantiomer B (dextrorotatory) of ethyl 2-{(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate

[α]D20+3.0+/−0.5 [methanol (c=0.5), 589 nm)]. ¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.11 (t, J=7 Hz: 3H); 1.65 (unresolved complex: 4H); from 2.50 to 2.65 (mt: 2H); 2.75 (dd, J=11 and 8 Hz: 1H); 3.09 (mt: 2H); from 3.20 to 3.35 (mt: 2H); 3.96 (s: 3H); 4.04 (q, J=7 Hz: 2H); 6.44 (dt, J=16 and 5.5 Hz: 1H); 6.60 (broad d, J=16 Hz: 1H); 7.12 (mt: 1H); 7.24 (ddd, J=10-9 and 5 Hz: 1H); 7.36 (d, J=3 Hz: 1H); 7.39 (dd, J=9 and 3 Hz: 1H): 7.45 (mt: 1H); 7.96 (d, J=9Hz: 1H); 8.68 (d, J=0.5 Hz: 1H).

IR spectrum (CC1₄) 2939; 2831; 1729; 1621; 1508; 1491; 1468; 1263; 1231; 1182; 1034; 971 and 832 cm⁻¹.

EI MS spectrum: m/z 486 [M]+., m/z 153 (base peak).

EXAMPLE 5

(RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid 7.08 cm³ of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.41 g (0.843 mmol) of ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate obtained in example 2 in solution in 22 cm³ of dioxane. After stirring under reflux for 20 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a pale yellow oil which is purified by flash chromatography [eluent: chloroform/methanol (13/2 by volume)+0.5% of an aqueous solution of ammonia at 20%]. 0.295 g of 2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid is obtained in the form of white solid melting at 130° C.

IR spectrum (KBr) 2942; 1622; 1509; 1491; 1231; 1146; 1030; 979; 831 and 727 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃) ₂SO d6, δin ppm): from 1.50 to 1.75 (mt: 4H); 2.42 (mt: 1H); from 2.65 to 2.75 (mt: 2H); 3.08 (mt: 2H); from 3.20 to 3.50 (mt: 2H); 3.96 (s: 3H); 6.48 (dt, J=16 and 6 Hz: 1H); 6.65 (broad d, J=16 Hz: 1H); 7.13 (mt: 1H); 7.24 (doublet of t, J=9.5 and 5 Hz: 1H); 7.38 (mt: 2H); 7.47 (ddd, J=10-6 and 3 Hz: 1H); 7.95 (mt: 1H); 8.68 (broad s: 1H).

ES+MS spectrum: m/z 459 [M+H]+ (base peak).

EXAMPLE 6

Enantiomer A of 2-{[(E)-3-(2,5-difluorophenyl)-allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid (undetermined absolute configuration) 6.18 cm³ of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.358 g (0.736 mmol) of enantiomer A (levorotatory) of ethyl 2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate obtained in example 3 in solution in 20 cm³ of dioxane. After stirring under reflux for 20 hours, the bottom phase is removed and the top phase is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 5 cm³ of water and 20 cm³ of dichloromethane. The aqueous phase is acidified with 1N hydrochloric acid to a pH value in the region of 7. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 3 cm³ of water and 15 cm³ of acetonitrile. After stirring for 2 hours at room temperature, the reaction mixture is filtered. The residue is washed with acetonitrile and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. for 2 hours to give 0.293 g of a white solid which is purified by flash chromatography [eluent: chloroform/methanol (12/3 by volume)+0.5% of an aqueous solution of ammonia at 20%]. A white solid is obtained which is triturated in a mixture of 9 cm³ of acetonitrile and 1 cm³ of water. After filtration, the white solid is dried under reduced pressure (2.7 kPa) at a temperature in the region 35° C. for 16 hours to give 0.158 g of enantiomer A of 2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid (undetermined absolute configuration) in the form of a white solid melting at 168° C; [α]D20 0+/−0.4 [dimethyl sulfoxide (c=0.5,), 589 nm)].

¹H NMR spectrum (300 MHz, (CD₃) ₂SO d6, δin ppm) : from 1.50 to 1.75 (mt: 4H); from 2.40 to 2.60 (mt: 1H); from 2.65 to 2.80 (mt: 2H); 3.08 (mt: 2H); from 3.20 to 3.50 (mt: 2H); 3.97 (broad s: 3H); 6.47 (dmt, J=16 Hz: 1H); 6.64 (broad d, J=16 Hz: 1H); 7.13 (mt: 1H); 7.24 (mt: 1H); from 7.30 to 7.50 (mt: 3H); 8.06 (broad d, J=9 Hz: 1H); 8.68 (broad s, 1H).

IR spectrum (KBr) 2940; 1648; 1621; 1592; 1509; 1492; 1432; 1363; 1234; 1148; 1029; 988; 831; 791 and 728 cm¹.

EI MS spectrum: m/z 458 [M]+., m/z 153 (base peak).

EXAMPLE 7

Enantiomer B of 2-{[(E)-3-(2,5-difluorophenyl)allyl-amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid (undetermined absolute configuration) 6.08 cm³ of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.352 g (0.724 mmol) of enantiomer B (dextrorotatory) of ethyl 2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate obtained in example 4 in solution in 20 cm³ of dioxane. After stirring under reflux for 20 hours, the bottom phase is removed and the top phase is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 5 cm³ of water and 20 cm³ of dichloromethane. The aqueous phase is acidified with iN hydrochloric acid to a pH value in the region of 7. The reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by 2 successive flash chromatographies [eluent: chloroform/methanol (12/3 by volume)+0.5% of an aqueous solution of ammonia at 20%]. A white solid is obtained which is triturated in a mixture of 9 cm³ of acetonitrile and 1 cm³ of water. After filtration, the white solid is dried under reduced pressure (2.7 kPa) at a temperature in the region 35° C. for 16 hours to give 0.136 g of enantiomer B of 2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid (undetermined absolute configuration) in the form of a white solid melting at 166° C.; [α]D20 0 −3.4+/−0.4 [dimethyl sulfoxide (c=0.5,), 589 nm)].

¹H NMR spectrum (300 MHz, (CD₃) 2SO d6, δ in ppm): from 1.50 to 1.75 (mt: 4H); 2.41 (mt: 1H); from 2.65 to 2.75 (mt: 2H); 3.07 (mt: 2H); from 3.20 to 3.50 (mt: 2H); 3.96 (s: 3H); 6.47 (dt, J=16 Hz and 6 Hz: 1H); 6.65 (broad d, J=16 Hz: 1H); 7.13 (mt: 1H); 7.25 (doublet of t, J=9.5-4.5 Hz: 1H); 7.39 (mt: 2H); 7.47 (ddd, J=9.5-6 and 3 Hz: 1H); 7.96 (mt: 1H); 8.68 (broad s: 1H).

IR spectrum (KBr) 2940; 1648; 1621; 1592; 1509; 1492; 1432; 1363; 1234; 1148; 1029; 988; 831; 791 and 728 cm⁻¹.

EI MS spectrum: m/z 458 [M]+., m/z 153 (base peak).

EXAMPLE 8

(RS)-2-{[3-(2,5-difluorophenyl)propylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid 6.88 cm³ of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.4 g (0.819 mmol) of ethyl (RS)-2-{[3-(2,5-difluorophenyl)-propylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate obtained in solution in 22 cm³ of dioxane. After stirring under reflux for 20 hours, the bottom phase is removed and the top phase is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.42 g of a yellow oil which is purified by flash chromatography [eluent: chloroform/methanol (12/3 by volume)+0.5% of an aqueous solution of ammonia at 20%]. 0.344 g of (RS)-2-{[3-(2,5-difluorophenyl)propylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid is obtained in the form of a white solid melting at 186° C.

IR spectrum (KBr) 2947; 1645; 1621; 1509; 1496; 1470; 1229; 1140; 1033; 833; 789 and 721 cm⁻¹.

ES+MS spectrum: m/z 461 [M+H]+(base peak).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): 1.54 (mt: 1H); from 1.60 to 1.85 (mt: 5H); 2.30 (mt: 1H); from 2.55 to 2.85 (mt: 6H); 3.08 (mt: 2H); 3.97 (s: 3H); 7.10 (mt: 1H); from 7.15 to 7.25 (mt: 2H); 7.38 (mt: 2H); 7.96 (mt: 1H); 8.69 (broad s: 1H).

Ethyl (RS)-2-{[3-(2,5-difluorophenyl)propylamino]-methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate may be prepared in the following manner:

31 cm³ of ethanol and 0.4 g (0.822 mmol) of ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate are added at room temperature, under an argon atmosphere, to 0.043 g (0.405 mmol) of 10% palladium on carbon. The reaction medium is purged 5 times with argon and then hydrogenated at a pressure of 2 bar of hydrogen at room temperature for 6 h. The catalyst is filtered on Celite®, the Celite® is rinsed with 3 times 5 cm³ of ethanol and then the filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.459 g of ethyl (RS)-2-{[3-(2,5-difluorophenyl)-propylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate in the form of a colorless oil.

EI MS spectrum: m/z 488 [(M+.], m/z 204 (base peak).

EXAMPLE 9

Ethyl (RS)-2-({N-[(E)-3-(2,5-difluorophenyl)allyl]-N-methylamino}methyl)-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate may be prepared in the following manner:

0.988 g (32.9 mmol) of formaldehyde is added at a temperature in the region of 0° C., under an argon atmosphere, to 0.87 g (1.788 mmol) of ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate obtained in example 2 in solution in 200 cm³ of ethanol. After stirring for 0.25 hour at a temperature in the region of 0° C., 1.516 g (7.15 mmol) of sodium triacetoxy-borohydride are added. After stirring for 20 hours at room temperature, 0.494 g of formaldehyde and 0.758 g of sodium triacetoxyborohydride are again added. After stirring for 3 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa), diluted with 50 cm³ of ethyl acetate and then washed with water and then with a saturated aqueous sodium chloride solution. The organic phase is dried, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.778 g of ethyl (RS)-2-({N-[(E)-3-(2,5-difluorophenyl)allyl]-N-methylamino}methyl)-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate in the form of a white oil.

EI MS spectrum: m/z 500 [M+.], m/z 153 (base peak).

EXAMPLE 10

Sodium (RS)-2-({N-[(E)-3-(2,5-difluorophenyl)allyl]-N-methylamino}methyl)-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate 13.05 cm³ of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.778 g (1.554 mmol) of ethyl (RS)-2-({N-[(E)-3-(2,5-difluoro-phenyl)allyl]-N-methylamino}methyl)-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate obtained in example 9 in solution in 40 cm³ of dioxane. After stirring under reflux for 16 hours, the bottom phase is removed and the top phase is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 40 cm³ of ethyl acetate and 10 cm³ of water. The pH of the aqueous phase is adjusted to 1 by adding a 1N aqueous hydrochloric acid solution. The organic phase is separated by decantation, washed with water and then with a saturated aqueous sodium chloride solution, dried, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) to give 0.625 g of sodium (RS)-2-({N-[(E)-3-(2,5-difluorophenyl)allyl]-N-methyl-amino}methyl)-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate in the form of a white solid melting between 60-70° C.

IR spectrum (KBr) 2945; 1621; 1590; 1509; 1490; 1468; 1428; 1231; 1145; 1030; 974; 830 and 727 cm⁻¹.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.50 to 1.75 (mt: 4H); 2.16 (broad s: 3 H); 2.32 (mt: 1H); from 2.35 to 2.60 (mt: 2H); 3.04 (mt: 2H); 3.13 (broad d, J=5.5 Hz: 2H); 3.95 (s: 3H); 6.40 (dt, J=16 and 5.5 Hz: 1H); 6.59 (broad d, J=16 Hz: 1H); 7.11 (mt: 1H); 7.23 (broad doublet of t, J=9.5 and 6 Hz: 1H); 7.36 (broad d, J=9: 1H); 7.37 (broad s: 1H); 7.45 (mt: 1H); 7.94 (broad d, J=9 Hz: 1H); 8.65 (broad s: 1H).

ES+MS spectrum: m/z 473 {M+H]+(base peak).

EXAMPLE 11

(RS)-5-(3-Fluoro-6-methoxyquinolin-4-yl)-2-{[2-(thiophen-2-ylsulfanyl)ethylamino]methyl}pentanoic acid 5.28 cm³ of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.3 g (0.629 mmol) of ethyl (RS)-5-(3-fluoro-6-methoxy-quinolin-4-yl)-2-{[2-(thiophen-2-ylsulfanyl)ethyl-amino]methyl}pentanoate in solution in 22 cm³ of dioxane. After stirring under reflux for 20 hours, the bottom phase is removed and the top phase is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm³ of dichloromethane and in a 1N aqueous hydrochloric acid solution qs pH=7. The organic phase is separated by decantation and the aqueous phase is extracted with dichloromethane. The organic phases are combined, dried and then concentrated to dryness under reduced pressure to give a white solid which is stirred in 8 cm³ of acetonitrile at a temperature in the region of 0° C. After filtration and drying in an oven under reduced pressure (2.7 kPa) at a temperature in the region of 35° C. for 4 hours, 0.252 g of (RS)-5-(3-fluoro-6-methoxyquinolin-4-yl)-2-{[2-(thiophen-2-ylsulfanyl)-ethylamino]methyl}pentanoic acid is obtained in the form of a white solid melting at 170° C.

IR spectrum (KBr) 2951; 1649; 1510; 1468; 1400; 1361; 1225; 1031; 847; 831; 785; 702 and 691 cm⁻¹.

ES+MS spectrum: m/z 449 {M+H]+(base peak).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.55 to 1.80 (mt: 4H); 2.39 (mt: 1H); from 2.60 to 2.80 (mt: 4H); 2.88 (t, J=6.5 Hz: 2H); 3.17 (mt: 2H); 3.97 (s: 3H); 7.05 (dd, J=3.5 and 5.5 Hz: 1H); 7.21 (broad d, J=3.5 Hz: 1H); 7.38 (broad s: 1H); 7.40 (broad d, J=9 Hz: 1H); 7.61 (d, J=5.5 Hz: 1H); 7.98 (d, J=9 Hz: 1H); 8.69 (broad s: 1H).

Ethyl (RS)-5-(3-fluoro-6-methoxyquinolin-4-yl)-2-{[2-(thiophen-2-ylsulfanyl)ethylamino]methyl}pentanoate may be prepared in the following manner.

0.686 g (3.237 mmol) of sodium triacetoxyborohydride is added at a temperature in the region of 15° C., under an argon atmosphere, to 0.4 g (1.079 mmol) of ethyl (RS)-2-aminomethyl-5-(3-fluoro-6-methoxyquinolin-4-yl)-pentanoate hydrochloride obtained in example 1 and 0.303 cm³ of triethylamine (2.158 mmol) in solution in 15 cm³ of dichloromethane, followed dropwise by a freshly prepared solution of (thiophen-2-ylsulfanyl)acetaldehyde (1.079 mmol) in toluene. After stirring for 2 hours at room temperature, 4 cm³ of water are added. The organic phase is separated by decantation, washed with water and then with a saturated aqueous sodium chloride solution, dried and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.529 g of a pale yellow oil which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (96/2/2 by volume)]. 0.3 g of ethyl (RS)-5-(3-fluoro-6-methoxyquinolin-4-yl)-2-{[2-(thiophen-2-ylsulfanyl)-ethylamino]methyl}pentanoate is obtained in the form of a pale yellow oil.

ES+MS spectrum: m/z 477 [M+H]+(base peak).

The solution of (thiophen-2-ylsulfanyl)acetaldehyde (1.079 mmol) in toluene may be prepared as follows.

0.188 cm³ (1.079 mmol) of N,N-diisopropylethylamine is added at a temperature in the region of 15° C., under an argon atmosphere, to 0.106 cm³ (1.079 mmol) of 2-thiophenethiol in solution in 4 cm³ of toluene. After stirring for 0.5 hour at room temperature, the reaction medium is cooled to a temperature in the region of 5° C. and 0.167 cm³ (1.316 mmol) of a 50% aqueous chloroacetaldehyde solution is added. After stirring for 1 hour at room temperature, the organic phase is separated by decantation, washed with twice 5 cm³ of water, dried over anhydrous magnesium sulfate, filtered and then used immediately as it is in the next step.

Ethyl (RS)-2-aminomethyl-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate may be prepared as described in example 6.

EXAMPLE 12

(RS)-2-{[2-(2,5-Difluorophenylsulfanyl)ethylamino]-methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid 3.6 cm³ of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.31 g (0.612 mmol) of ethyl (RS)-2-{[2-(2,5-difluoro-phenylsulfanyl)ethylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate in solution in 6.2 cm³ of dioxane and 6.2 cm³ of methanol. After stirring under reflux for 18 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kpa) to give a residue which is purified by flash chromatography [eluent: dichloromethane/methanol (90/10 and then 80/20 by volume)]. 0.26 g of a residue is obtained which is triturated in 50 cm³ of ethyl ether for 18 hours at room temperature. After filtration, washing of the solid with successively 10 cm³ of ethyl ether and 3 times 10 cm³ of pentane and then drying, 0.273 g of (RS)-2-{[2-(2,5-difluorophenylsulfanyl)-ethylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid is obtained in the form of a white solid melting between 182-187° C.

IR spectrum (KBr) 2946; 1643; 1620; 1578; 1509; 1483; 1403; 1229; 1189; 1032; 907; 832 and 757 cm⁻¹.

ES+MS spectrum: m/z 479 [M+H]+(base peak).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm): from 1.50 to 1.75 (mt: 4H); 2.42 (mt: 1H); from 2.60 to 2.90 (mt: 4H); 3.06 (mt: 2H); 3.10 (t, J=6.5 Hz: 2H); 3.96 (s: 3H); 7.09 (mt: 1H); from 7.20 to 7.40 (mt: 2H); 7.38 (broad s: 1H); 7.40 (dd, J=9 and 2.5 Hz: 1H); 7.97 (d, J=9 Hz: 1H); 8.69 (broad s: 1H). Ethyl (RS)-2-{[2-(2,5-difluorophenylsulfanyl)ethyl-amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate: 0.377 g (1.49 mmol) of 2-(2-bromoethylsulfanyl)-1,4-difluorobenzene in solution in 10 cm³ of acetonitrile and then 0.746 g (5.4 mmol) of potassium carbonate and 0.247 g (1.49 mmol) of potassium iodide are added at a temperature in the region of 20° C., under an argon atmosphere, to 0.5 g (1.35 mmol) of ethyl (RS)-2-aminomethyl-3-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate hydrochloride obtained in example 1 in solution in 15 cm³ of acetonitrile. After stirring under reflux for 17 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 25 cm³ of ethyl acetate and washed with water. The organic phase is dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: cyclohexane/ethyl acetate (7/3 and then 5/5 by volume)]. 0.34 g of ethyl (RS)-2-{[2-(2,5-difluorophenylsulfanyl)ethylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate is obtained in the form of a yellow oil.

ES+MS spectrum: m/z 507 [M+H]+(base peak).

1-(2-Bromoethylsulfanyl)(2,5-difluoro)benzene may be prepared according to the method described in patent application WO 2002/40474.

EXAMPLE 13

(RS)-2-{[2-(2,5-Difluorophenoxy)ethylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid 5.2 cm³ of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.43 g (0.877 mmol) of ethyl (RS)-2-{[2-(2,5-difluorophenoxy)-ethylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate in solution in 10 cm³ of dioxane and 10 cm³ of methanol. After stirring under reflux for 20 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: chloroform/methanol (12/3 by volume)+0.5% of an aqueous solution of ammonia at 20%]. 0.37 g of (RS)-2-{[2-(2,5-difluorophenoxy)ethylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid is obtained in the form of a white solid melting at 179° C.

IR spectrum (KBr) 2961; 1622; 1567; 1513; 1472; 1409; 1321; 1229; 1204; 1156; 1102; 1030; 950; 901; 852; 802; 783; 718 and 699 cm⁻¹.

ES+MS spectrum: m/z 463 [M+H]+(base peak).

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6, δ in ppm) : from 1.45 to 1.75 (mt: 4H); 2.36 (mt: 1H); from 2.60 to 2.80 (mt: 2H); 2.93 (t, J=5.5 Hz: 2H); 3.06 (mt: 2H); 3.97 (s: 3H); 4.11 (t, J=5.5 Hz: 2H); 6.76 (mt: 1H); 7.12 (ddd, J=10.5-6.5 and 3 Hz: 1H); 7.24 (ddd, J=10.5-9.0 and 5.5 Hz: 1H); 7.39 (dd, J=9 and 2.5 Hz: 1H); 7.41 (broad s: 1H); 7.96 (d, J=9 Hz: 1H); 8.69 (broad s: 1H).

Ethyl (RS)-2-{[2-(2,5-difluorophenoxy)ethylamino]-methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate may be prepared in the following manner:

0.39 g (1.65 mmol) of 2-(2-bromoethoxy)-1,4-difluorobenzene in solution in 10 cm³ of acetonitrile and then 0.83 g (6 mmol) of potassium carbonate and 0.27 g (1.65 mmol) of potassium iodide are added at a temperature in the region of 20° C., under an argon atmosphere, to 0.56 g (1.5 mmol) of ethyl (RS)-2-amino-methyl-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate hydrochloride obtained in example 1 in solution in 20 cm³ of acetonitrile. After stirring under reflux for 20 hours, the reaction mixture is cooled to room temperature and then poured over 20 cm³ of water and 30 cm³ of ethyl acetate. The aqueous phase is separated by decantation, saturated with sodium chloride and then extracted with 3 times 30 cm³ of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.74 g of a brown oil which is purified by flash chromatography [eluent: ethyl acetate/cyclohexane (9/1 by volume)]. 0.43 g of ethyl (RS)-2-{[2-(2,5-difluorophenoxy)ethyl-amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)-pentanoate is obtained in the form of a yellow oil.

ES+MS spectrum: m/z 491 [M+H]+(base peak).

2-(2-Bromoethoxy)-1,4-difluorobenzene may be prepared according to the method described in patent application WO 2002/40474.

EXAMPLE 14

(RS)-2-{[N-[(E)-3-(2,5-difluorophenyl)allyl]-N-(2-fluoroethyl)amino]methyl}-5-(3-fluoro-6-methoxy-quinolin-4-yl)pentanoic acid 6.1 cm3 of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.387 g (0.727 mmol) of ethyl (RS)-2-{[N-[(E)-3-(2,5-difluoro-phenyl)allyl]-N-(2-fluoroethyl)amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate in solution in 20 cm³ of dioxane. After stirring under reflux for 20 hours, the bottom phase is removed and the top phase is concentrated to dryness under reduced pressure (2.7 kPa) to give 0.297 g of a residue which is purified by flash chromatography [eluent: dichloromethane/acetonitrile/methanol (94/3/3 by volume and then 90/5/5 by volume with 0.2% of an aqueous solution of ammonia at 20%). 0.146 g of (RS)-2-{[N-[(E)-3-(2,5-difluorophenyl)allyl]-N-(2-fluoro-ethyl)amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid is obtained in the form of a white solid melting at 120° C.

¹H NMR spectrum (400 MHz, (CD₃)₂SO d6, δ in ppm) : from 1.55 to 1.75 (mt: 4H); from 2.45 to 2.70 (mt: 2H); from 2.70 to 2.95 (mt: 3H); 3.08 (mt: 2H); from 3.25 to 3.45 (mt: 2H); 3.96 (s: 3H); 4.49 (dt, J=47 and 5.5 Hz: 2H); 6.44 (dt, J=16 and 6.5 Hz: 1H); 6.65 (broad d, J=16 Hz: 1H); 7.13 (mt: 1H); 7.24 (doublet of t, J=9.5 and 5 Hz: 1H); 7.37 (d, J=3 Hz: 1H); 7.40 (dd, J=9 and 3 Hz: 1H); 7.47 (ddd, J=10-6 and 3 Hz: 1H); 7.96 (d, J=9 Hz: 1H); 8.68 (broad s: 1H).

IR spectrum (CC1₄) 2957; 2831; 1709; 1622; 1509; 1491; 1468; 1429; 1232; 1033; 973 and 832 cm⁻¹.

MS DCI spectrum m/z=505 [MH]+(base peak).

Ethyl (RS)-2-{[N-[(E)-3-(2,5-difluorophenyl)allyl]-N-(2-fluoroethyl)amino]methyl}-5-(3-fluoro-6-methoxy-quinolin-4-yl)pentanoate may be prepared in the following manner:

0.781 g (5.65 mmol) of potassium carbonate, 0.188 g (1.13 mmol) of potassium iodide and 2.08 g (16.38 mmol) of 1-bromo-2-fluoroethane are added at a temperature in the region of 20° C., under an argon atmosphere, to 0.55 g (1.13 mmol) of ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate obtained in example 2 in solution in 30 cm³ of acetonitrile. After stirring under reflux for 24 hours, 2.08 g (16.38 mmol) of 1-bromo-2-fluoroethane are again added. After stirring under reflux for another 24 hours, the reaction mixture is cooled to room temperature. 30 cm³ of water and 20 cm³ of ethyl acetate are added. The organic phase is separated by decantation, washed successively with water and with a saturated aqueous sodium chloride solution, dried and concentrated to dryness under reduced pressure (2.7 kPa) to give 0.72 g of an orange-colored oil which is purified by flash chromatography [eluent: dichloromethane/acetonitrile/methanol (98/1/1 by volume)]. 0.387 g of ethyl (RS)-2-{[N-[(E)-3-(2,5-difluorophenyl)allyl]-N-(2-fluoroethyl)amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate is obtained in the form of a yellow oil.

ES+MS spectrum m/z=533 [MH]+(base peak).

EXAMPLE 15

(RS)-2-{[N-[(E)-3-(2,5-Difluorophenyl)allyl]-N-(2-hydroxyethyl)amino]methyl}-5-(3-fluoro-6-methoxy-quinolin-4-yl)pentanoic acid 3.1 cm³ of a 5N aqueous sodium hydroxide solution are added at a temperature in the region of 20° C. to 0.278 g (0.524 mmol) of ethyl (RS)-2-{[N-[(E)-3-(2,5-difluorophenyl)allyl]-N-(2-hydroxyethyl)amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate in solution in 5.6 cm³ of dioxane and 5.6 cm³ of ethanol. After stirring under reflux for 20 hours, the reaction medium is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: dichloromethane-methanol (gradient 100/0 to 70/30 by volume). 0.132 g of a residue is obtained which is triturated in a volume of 10 cm³ of isopropyl ether and 10 cm³ of pentane for 0.5 hour. After filtration, washing of the solid with pentane and then drying, 0.099 g of (RS)-2-{[N-[(E)-3-(2,5-difluorophenyl)allyl]-N-(2-hydroxyethyl)amino]methyl}-5-(3-fluoro-6-methoxy-quinolin-4-yl)pentanoic acid is obtained in the form of a yellow solid melting at 57° C.

¹H NMR spectrum (300 MHz, (CD₃)₂SO d6 with addition of a few drops of CD3COOD d4, 6 in ppm): from 1.50 to 1.75 (mt: 4H); from 2.60 to 2.85 (mt: 4H); from 2.80 to 2.95 (mt: 1H); 3.06 (mt: 2H); from 3.35 to 3.55 (mt: 2H); 3.54 (t, J=6 Hz: 2H); 3.93 (s: 3H); 6.42 (dt, J=16 and 6.5 Hz: 1H); 6.70 (broad d, J=16 Hz: 1H); from 7.00 to 7.25 (mt: 2H); from 7.25 to 7.45 (mt: 3H); 7.96 (d, J=9 Hz: 1H); 8.64 (broad s: 1H).

IR spectrum (KBr) 3070; 2938; 2869; 1710; 1621; 1510; 1490; 1469; 1429; 1361; 1231; 1145; 1028; 975; 830 and 726 cm⁻¹.

CI MS spectrum: m/z 503 [M+H]+(base peak).

Ethyl (RS)-2-{[N-[(E)-3-(2,5-difluorophenyl)allyl]-N-(2-hydroxyethyl)amino]methyl}-5-(3-fluoro-6-methoxy-quinolin-4-yl)pentanoate may be prepared in the following manner:

0.69 g (5 mmol) of potassium carbonate and 0.12 cm³ (1.5 mmol) of iodoethanol are added at a temperature in the region of 20° C., under an argon atmosphere, to 0.486 g (1 mmol) of ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate obtained in example 2 in solution in 25 cm³ of acetonitrile. After stirring under reflux for 20 hours, 0.12 cm³ (1.5 mmol) of iodoethanol is again added. After stirring under reflux for another 20 hours, 2 cm³ of iodoethanol are again added. After stirring under reflux for 7 hours, the reaction mixture is cooled to room temperature and then filtered. The residue is washed with acetonitrile. The filtrate is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is purified by flash chromatography [eluent: dichloromethane and then ethyl acetate/cyclohexane (7/3 by volume)]. 0.305 g of ethyl (RS)-2-{[N-[(E)-3-(2,5-difluoro-phenyl)allyl]-N-(2-hydroxyethyl)amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate is obtained in the form of a yellow oil.

ES+MS spectrum m/z 531 [M+H]+(base peak).

Claims

1. A 4-substituted quinoline derivative, which corresponds to general formula I

2. The derivative of general formula (I) as defined in claim 1, wherein: R1, R′1, R′2, R′3, R′4 and R′5 are identical or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a methylene radical substituted with alkyloxy;m and n are equal to 1 or 2; andR3 represents a radical alk-Ro3 for which alk is an alkylene radical and Ro3 represents alkyloxy, alkylthio, alkylamino, dialkylamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, N-cycloalkyl-N-alkylamino, —N-(cycloalkyl)2, phenyl, phenoxy, phenylthio, phenylamino, N-alkyl-N-phenylamino, N-cycloalkyl-N-phenylamino, phenylalkyloxy, phenyl-alkylthio, phenyl-alkylamino, N-alkyl-N-phenyl-aminoalkyl, N-cycloalkyl-N-phenylalkylamino, hetero-aryloxy, heteroarylthio, heteroarylamino, N-alkyl-N-heteroarylamino, N-cycloalkyl-N-heteroarylamino, heteroarylcarbonyl, heteroarylalkyloxy, heteroaryl-alkylthio, heteroarylalkylamino, N-alkyl-N-hetero-arylaminoalkyl, N-cycloalkyl-N-heteroarylaminoalkyl (the heteroaryl parts cited above being mono- or bicyclic), —NRaRb or —CO—NRaRb for which Ra and Rb are defined as in claim 1, or alternatively Ro3 represents —CR′b=CR′c-R+a for which R′a represents phenyl, phenylalkyl, heteroaryl or heteroarylalkyl, phenoxyalkyl, phenylthioalkyl, phenylaminoalkyl, N-alkyl-N-phenylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl-N-heteroarylaminoalkyl, heteroarylthio, (the heteroaryl parts cited above being mono- or bicyclic), or phenylthio, and for which R′b and R′c represent hydrogen, alkyl or cycloalkyl, or alternatively Ro3 represents a radical —C≡C—Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, heteroarylaminoalkyl, N-alkyl-N-heteroarylaminoalkyl, (the heteroaryl parts cited above being mono- or bicyclic),or alternatively Ro3 represents a radical —CF2-phenyl or mono- or bicyclic —CF2-heteroaryl;it being understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or portions mentioned above may be optionally substituted as envisaged in claim 1;R2, R4, R5, Y and Z are as defined in claim 1;in its enantiomeric or diastereoisomeric forms or mixtures of these forms, and/or where appropriate in E or Z form or mixtures thereof, and its salts.

3. The derivative of general formula (I) as defined in claim 1, wherein: R1, R′1, R′2, R′3, R′4 and R′5 are identical or different and represent a hydrogen or halogen atom or an alkyl or alkyloxy radical, or represent a methylene radical substituted with alkyloxy;m and n are equal to 1;Y represents a group CH2, CHOH, CHF, CHNH2 or C=O;R2 represents a radical COOR, CH2—COOR, CH2OH or CH2CH2OH, R being as defined in claim 1;Z represents a group CH2;R3 represents a radical alk-Ro3 for which alk is an alkylene radical and Ro3 represents cycloalkyloxy, cycloalkylthio, phenyl, phenoxy, phenylthio, phenylalkyloxy, phenylalkylthio, heteroaryloxy, heteroarylthio, heteroarylalkyloxy, heteroaryl-alkylthio, (the heteroaryl parts cited above being mono- or bicyclic),or alternatively Ro3 represents —CR′b=CR′c-R′a for which R′a represents phenyl, phenylthioalkyl, heteroaryl, heteroarylalkyl, phenoxyalkyl, phenyl-thioalkyl, heteroaryloxyalkyl, heteroarylthioalkyl (the heteroaryl parts cited above being mono- or bicyclic), or phenylthio, and for which R′b and R′c represent hydrogen, alkyl or cycloalkyl,or alternatively Ro3 represents a radical —C≡C—Rd for which Rd is alkyl, phenyl, phenylalkyl, phenoxyalkyl, phenylthioalkyl, N-alkyl-N-phenylaminoalkyl, mono- or bicyclic heteroaryl, heteroarylalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, (the heteroaryl parts cited above being mono- or bicyclic);R4 represents a hydrogen atom or an alkyl radical optionally substituted with R6, where R6 represents an OH radical or a fluorine atom;R5 is a hydrogen atom or an alkyl group;it being understood that the phenyl, benzyl, benzoyl or heteroaryl radicals or portions mentioned above may be optionally substituted as envisaged above;in its enantiomeric or diastereoisomeric forms or mixtures of these forms, and/or where appropriate in Z or E form or mixtures thereof, and its salts.

4. The derivative of general formula (I) as defined in claim 3, wherein: Y and Z represent a group CH2;R2 represents a radical COOR or CH2—COOR, R being as defined in claim 1;R5 is a hydrogen atom;

5. Any one of the derivatives of general formula (I) as claimed in claim 1, whose names follow: ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate;ethyl (RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate;(RS)-2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl}-5-(3 -fluoro-6-methoxyquinolin-4-yl)pentanoic acid;2-{[(E)-3 -(2,5-difluorophenyl)allylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid;2-{[(E)-3-(2,5-difluorophenyl)allylamino]methyl }-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid;(RS)-2-{[3 -(2,5-difluorophenyl)propylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid;ethyl (RS)-2-({N-[(E)-3-(2,5-difluorophenyl)allyl]-N-methylamino}methyl)-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate;sodium (RS)-2-({N-[(E)-3-(2,5-difluorophenyl)allyl]-N-methylamino}methyl)-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoate;(RS)-5-(3-fluoro-6-methoxyquinolin-4-yl)-2-{[2-(thiophen-2-ylsulfanyl)ethylamino]methyl}pentanoic acid;(RS)-2-{[2-(2,5-difluorophenylsulfanyl)ethylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid;(RS)-2-{[2-(2,5-difluorophenoxy)ethylamino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid;(RS)-2-{[N-[(E)-3-(2,5-difluorophenyl)allyl]-N-(2-fluoroethyl)amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid;(RS)-2-{[N-[(E)-3-(2,5-difluorophenyl)allyl]-N-(2-hydroxyethyl)amino]methyl}-5-(3-fluoro-6-methoxyquinolin-4-yl)pentanoic acid;

6. A method for preparing the derivatives of general formula (I) as defined in claim 1, wherein the chain R3 defined in claim 1 is condensed with the 4-substituted quinoline derivative of general formula (II)

7. The method as claimed in claim 6, wherein the condensation of the chain R3 with the nitrogen is carried out by the action of a derivative of general formula (IIa): R3-X   (IIa)

8. The method as claimed in claim 6, wherein when R3 represents a radical -alk-Ro3 for which alk is an alkyl radical and Ro3 represents a radical —C≡C—Rd in which Rd is as defined in claim 1, a condensation of an alkynyl halide HC≡C-alk-X for which alk is defined as above and X is a halogen atom is carried out, followed by substitution of the chain with an appropriate radical Rd.

9. The method as claimed in claim 6, wherein when R3 represents a radical -alk-Ro3 for which alk is an alkyl radical and Ro3 represents a phenoxy, phenylthio, phenylamino, heteroaryloxy, heteroarylthio or heteroarylamino radical, the reaction is carried out by constructing the chain by first condensing a chain HO-alk-X for which X is a halogen atom, and then either by converting the hydroxyalkyl chain obtained to a haloalkyl, methanesulfonylalkyl or p-toluenesulfonylalkyl chain and finally by causing an aromatic derivative having the structure R3H or R3H2 to act in a basic medium, or by causing the aromatic derivative to act directly under dehydration conditions.

10. The method as claimed in claim 6 for the preparation of compounds of general formula (I) in which R4 represents an alkyl group optionally substituted with R6, a product of general formula (I) where R4 represents a hydrogen atom being subjected to the action of appropriate alkylating reagents.

11. The method as claimed in claim 6, wherein the derivatives of general formula (II) for which Y is a group CHR, Z is a group CH2 and m and n are defined as in the preceding claims, are prepared by condensing a heteroaromatic derivative of general formula (III):

12. The derivatives of general formula (II) as defined in claim 6.

13. The derivatives of general formula (IV) as defined in claim 11.

14. As medicaments, the derivatives of general formula (I) as defined in claim 1.

15. As medicaments, the derivatives of general formula (I) as defined in claim 2.

16. A pharmaceutical composition, which contains at least one medicament as claimed in claim 1, in the pure state or in combination with one or more compatible and pharmaceutically acceptable diluents and/or adjuvants.