IL44585A - Esters of 2-((4-quinolyl)amino)-benzoic acids their preparation and pharmaceutical compositions containing them - Google Patents

Description

SYNTHELABO 44585/2 The present invention relates to esters of 2-[(4-quinolyl)amino]-benzoic acids and their addition salts with pharmaceutically tolerated acids, their preparation, and medicines containing them.

Such compounds are described in , • French Patent SpecificationjNo. 2,168,227 They can be used as analgesic and anti-inflammatory medicines.

The present invention provides new 2-[(¾-quinolyl)-amino]-benzoic acid esters which have markedly improved therapeutic properties. These compounds have the formula in which. represents a chlorine atom or a CF3 or SCF3 group, and R2 represents a phenyl radical which' is unsubstituted or substituted by one or two substituents chosen from CI, CH3, CF3, OCP3 and SCF3, provided that the phenyl radical is substituted when represents a chlorine atom in 7 position. The invention also provides the addition salts of the compounds of formula CD with pharmaceutically tolerated acids.

The compounds of the invention are prepared by a transesterification reaction, which may be represented by the following equation j (II) (III) In these formulae R^ and R2 have the meanings given above and R represents an allyl radical or, when R^ represents SCF^, a methyl radical. The transesterification is advantageously carried out at the boiling point of an apolar solvent, for example, an aromatic hydrocarbon such as benzene, toluene, or xylene, in the presence of an alkali metal alcoholate and/or an alkali metal which reacts with the alcohol of the formula (III).

The compounds of the invention can also be prepared by a condensation in accordance with the following equation : X CH2-CH2 (I) + H (V) In these formulae, R^ and 2 have the meanings given above and X represents a halogen atom, and preferably chlorine. This condensation is advantageously carried out at the reflux temperature of a polar solvent, and in particular in an optionally acidified aqueous medium.

The following Examples illustrate the invention. The compounds of Examples 1 to 20 were prepared by the transesterification process and those of Examples 21 to 26 by the condensation process.

EXAMPLE 1 2-( h 1 -Phenyl-pjperazino )-ethyl 2-( 7 r -trifluoromethyl-thio-*i '-quinolyl-amino)-benzoate and its dihydro-chloride [(I), 1 = SCF3 in the 7-position; R2 = CgH,.

Code number: SL 72-244] A mixture of 18.9 g (0.05 mol) of methyl 2-( 7 ' -trifluoromethylthio-¾ 1 -quinolyl-amino )-benzoate, 15.95 g (0.075 mol ) of 2-(V-phenyl-piperazino)-ethanol, 0,025 g of sodium and 100 ml of anhydrous toluene is heated at the reflux temperature for 5 hours, while the methanol formed during the reaction is slowly distilled.

A slight amount of insoluble matter is removed by hot filtration, and the toluene is evaporated. The residual product is dissolved in methylene chloride, the solution obtained is washed several times with water, dried over anhydrous magnesium sulphate and filtered, and the solvent is evaporated from the filtrate. The oily product obtained is dissolved in boiling isopropanol, the solution is cooled, and the precipitate is filtered off washed with isopropyl alcohol and dried in vacuo. ethyl 2-(7 *-trifluoromethylthio-4'-quinolyl-amino )-benzoate are collected; m.p. 120°C.

Analysis: C29H27P3N402S (M. . = 552.62) Base determination: Equivalent , calculated : 276.3 found: 281.9.

Its dihydrochloride is prepared by adding 40 ml. (0.04 mol) of N hydrochloric acid to a solution of 11.05 g. (0.02 mol) of base in 70 ml. of methylene chloride. The salt which has separated out. is filtered off, washed with water, dried and recrystallxsed from 250 ml. of ethanol. 9.5 g. (yield = 76%) of light yellow 2-(4'-phenyl-piperazino )r-ethyl 2-( 71-trifluoromethylthio-41-quinolyl-amino )-benzoate dihydrochloride, m.p. 230-232°C« , are collected.

Analysis: C2gH29Cl2F3N402S (M.W. = 625.54) Calculated %: C 55.68, H 4.67, N 8.96, F 9.11 Ionised CI 11.33 Found %: 55.50 4.47 8.85 9.15 11.32 55.40 4.50 8.80 9.13 ES-AMPLE 2 2- ( 41-m-Trifluoromethylphenyl-piperazino )-ethyl 2-( 7 '-chloro-4*-quinolyl-amino )-benzoate and its dihydrochloride.

[(I) 5 = CI in the 7-position; R2 = Code number: SL 72-391].

A mixture of 17.3 g. (0.051 mol) of allyl 2-( 7*-chloro-4'-quinolyl-amino )-benzoate, 13.7 g. (0.05 mol) of 2-(4,-m-trifluoromethylphenyl-pipera2ino)-ethanol, 100 ml. of anhydrous toluene and 0.03 g. of sodium is heated at the reflux temperature, while the alcohol formed during the reaction is slowly distilled off. Heating is continued until the starting ester has disappeared completely (as verified by thin layer chromatography), if necessary adding a little toluene to compensate for that which is entrained during the distillation. After the end of the reaction, the solvent is evaporated and the residue is taken up in isopropyl alcohol. The solution crystallises on cooling. The crystals are filtered off and dried, and 22.5 g. (yield = 80%) of 2-(4,-ro-trifluoro-methylphenyl-piperazino)-ethyl 2-( 71-chloro-41"-quinolyl-amino )-benzoate are finally collected, m.p. 100-102°C.

Analysis: C29H26C1F3N402 (M.W. = 555) Calculated %: CI 6.39 Found %: 6.10 The dihydrochloride is prepared by adding 16 ml, of a 5N solution of hydrochloric acid in ethanol to a solution of 22,20 g. (0.04 mol) of the base in 200 ml. of methylene chloride. After the solvents have been evaporated, the residue is crystallised from 250 ml. of isopropanol in 21.95 g. (yield = 87.4%) of 2-(4'-m-trifluoromethylphenyl-piperazino )-ethyl 2-( 7 '-chloro-4*-quinolyl-amino )-benzoate dihydrochloride, m.p. 217°C. , are collected.

Analysis: C29H28C13F3N4°2 (M'W* = 627·93) Calculated % (anhydrous): C 55.47, H 4.49, N 8.92, F 9.08 (Taking into account the 1.1% water content measured by a Karl Fischer determination): 54.48 4.56 8.82 8.99 Found*: 54.76 4.68 8.47 9.20 54.99 4.63 8.68 9.05 EXAMPLE 3 2- [4'-( 2" , 3"-Diethyl-phenyl )-piperazino]-ethyl 2-(7'-chloro-4,-quinolyl-amino)-benzoate and its dihydrochloride.

[(I); = CI in the 7-position; I¾2 = Code number: SL 72-248].

Following the procedure of Example 2, but starting from 16.9 g. (0.05 mol) of allyl 2-( 7 '-chloro-4» quinolyl-amino )-benzoate and 14 g. (0.06 mol) of 2-[4'-(2" ,3"-dimethylphenyl)-piperazino]-ethanol, 22.6 g. (yield = 87.9%) of 2-[4'-(2" ,3"-dimethyl-phenyl)-piperazino]-ethyl 2-(7·-σϊι1θΓθ-4'-quinolyl-amino )-benzoate are obtained, m.p. 126°C.

Analysis: C3()H31C1 402 (M.W. = 515.06) Calculated %: CI 6.89 Found %: 6.87 2- [4'-( 2" , 3"-Dimethyl-phenyl )-piperazino]-ethyl 2-( 7 '-chloro-4'-quinolyl-amino )-benzoate dihydrochloride, prepared like the dihydrochloride of Example 2, melts at 220°C.

Analysis: C30H33C13N402 (M.W. = 587.98) Calculated %: C 61.28, H 5.66, N 9.53, Ionised CI 12.06 Found 61.15 5.75 9.46 12.03 61.18 5.73 9.40 EXAMPLE 4 2-( 41-|>-Chlorophenyl-piperazino )-ethyl 2- ( 71-chloro-4' quinolyl-amino )-benzoate and its dihydrochloride [(I) j = CI in the 7-positionj ¾ = -<^ ^>— CI Code number: RC 72-165], By following the procedure of Example 2 and reacting 16.9 g. (0.05 mol) of allyl 2-( 7'-chloro-4'-quinolyl-amino )-benzoate and 24 g. (0.1 mol) of 2-( 4'-pj-chlorophenyl-piperazino )-ethanol , 2-( '-p_-chlorophenyl-piperazino )-ethyl 2-(71-chloro-41-quinolyl-amino )-benzoate is prepared in a 60% yield, m.p. 145 °C.

Analysis: C28H26C12N2°4 (M,W# = 521· 5) Calculated %: CI 13.61 Found %: 13.55. 2-( '-p-Chlorophenyl-piperazino )-ethyl 2-( 7 '-chloro— 1-quinolyl-amino )-benzoate dihydrochloride, prepared in an identical manner to the dihydrochloride of Example 2, melts at 240°C.

Analysis: C28H2SC14N4°2 iM,W* = 594·37> Calculated %: C 56.48, H 4.75, N 9.42, CI 23.85 Found %: 56.45 4.60 9.39 23.60.

EXAMPLE 5 2- (4'-Phenyl-piperazino )-ethyl 2- ( 7 '-trifluoro-methyl-41 quinolyl-amino )-benzoate and its dihydrochloride [(I) j Rj^ = CP3 in the 7-position; = C6H5 Code number: SL 72-242], A mixture of 18.6 g. (0.05 mol) of allyl 2-( 7 **-trifluoromethyl- 1-quinolyl-amino )-benzoat , 1 . g. (0.07 mol) of 2-(4'-phenyl-piperazino)-ethanol, 100 ml. of anhydrous toluene and 0.02 g, of sodium is heated for five hours at the reflux temperature, while the alcohol formed during the reaction is distilled off. The solution is allowed to cool, a slight amount of insoluble matter is filtered off, the toluene is evaporated from the filtrate, and the residue is dissolved in diethyl ether. The ether solution is washed several times with water, dried over magnesium sulphate and filtered, the solvent is evaporated from the filtrate, and the remaining oily product is dissolved in 200 ml. of boiling isopropyl alcohol. The solution is chilled, the precipitate is filtered off, and 20.1 g. (yield = 79%) of 2- (4 '-phenyl-piperazino )-ethyl 2- ( 71-trifluoromethyl-41-quinolyl-amino )-benzoate, m.p. 130°C«, are finally collected.

Analysis: C29H27P3N402 (M. . = 520.56) Base determination: Equivalent, calculated 260.2 Found 257.

The dihydrochloride is prepared by adding 40 ml. of an solution of hydrochloric acid (0.04 mol) to 10.4 g. (0.02 mol) of base dissolved in 50 ml. of methylene chloride. The precipitate is filtered off, dried and recrystallised from 120 ml. of ethanol. 9.2 g. (yield = 78%) of 2-<4,-phenyl-piperazino)-ethyl 2-(7·-trifluoromethyl- '-quinolyl-amino )- enzoate dihydrochloride are obtained, m.p. 210°C.

Analysis: C29H29C12F3N402 (M. . = 593.48) Calculated % (anhydrous) C 58.69, H 4.93, N 9.44, F 9.60 (Talcing into account the 0.7% water content measured by a Karl Fischer determination): 58.27 4.97 9.37 9.53 Found % : 58.17 5.01 9.36 9.50.

EXAMPLE 6 2-(41 -K»Trifluoromethylphenyl-piperazino)-ethyl 2-( 7 '-trifluoromethyl-41-quinolyl-amino)-benzoate and its dihydrochloride.

[(I); = CF3 in the 7-position, R2 Code number: SL 73.017], A mixture of 18.65 g. (0.05 mol) of allyl 2-(7'-trifluoromethyl-4,-quinolyl-amino)-benzoate, 16,2 g. (0.059 mol) of 2-(4'-m^trifluoromethylphenyl-piperazino)-ethanol, 150 ml. of anhydrous toluene and 0,03 g. of sodium is heated under reflux for two and a half hours, while the allyl alcohol formed during the reaction is slowly removed by distillation. A slight amount of insoluble matter is filtered off and the toluene is evaporated from the filtrate. The residue is dissolved in a mixture of methylene chloride and acetone (8:2) and this solution is passed through a silica column. Elution is carried out with the same mixture of solvents and the eluate is collected in 50 ml. fractions. These fractions are examined by thin layer chromatography. Those which contain the desired almost pure ester are combined and the solvent is driven off from them. The residual product is triturated in a mixture of ether and petroleum ether, filtered off and dried. 16.8 g. (yield = 57%) of 2-(4'-m-trifluoromethylphenyl)-piperazino )-ethyl 2-(7 ·-trifluoromethyl-41-quinolyl-amino )-benzoate, m.p. 83-90°C. , are thus isolated, Analysis: C30H26F6N4°2 (M*W* = 588·557> Base determination: Equivalent calculated 294.2 found 298.

(Code number of the base: SL 73.033).

The dihydrochloride is prepared by dissolving 15.3 g. (0.026 mol) of the above base in 75 ml. of methylene chloride and adding 13 ml. of a 4N aqueous solution of hydrochloric acid. The salt which has precipitated is filtered off and recrystallised from isopropyl alcohol. 16.15 g. (yield = 94%) of 2-(4'-m-trifluoromethylphenyl-piperazino)-ethyl 2-(71-trifluoromethyl-4'-quinolyl-amino )-benzoate dihydrochloride, m.p. 230°C., are thus collected.

Analysis: C30H28C12F6N4°2 (M*?7* = 661;5) Calculated %: C 54.47, H 4.27, N 8.47, CI 10.72 Pound %: 54.58 4.21 8.44 10.75.

EXAMPLE 7 2-( 41-rjfr-Chlorophenyl-piperasino )-ethyl 2-( 7 '-chloro- '-quinolyl-amino )-benzoate and its dihydrochloride.

CI in the 7-position, Code number: SL 73-018], 16.9 g. (0.05 mol) of allyl 2-(7 ,-chloro-4'-quinolyl-amino)-benzoate and 12.7 g. (0.0527 mol) of 2-(4,-m-chloro-phenyl-pipera2ino)-ethanol and 150 ml. of anhydrous toluene are introduced into a 250 ml. distillation flask equipped with a magnetic stirrer. A few drops of toluene are distilled off to entrain any traces of moisture, and 0.03 g. of sodium are added. A slow distillation is then effected for three hours to remove the allyl alcohol as it is formed. Insoluble matter is removed by hot filtration, the toluene is evaporated from the filtrate, and the residue is recrystallised from isopropyl alcohol. 22.85 g. (yield = 83%) of 2-(4'-itv-chlorophenyl-piperazino)-ethyl 2-(7 ,-chloro-4,-quinolyl-amino)-benzoate, m.p. 122°C. , are collected.

Analysis: C28H26C12N4°2 (M»W» = 521.4) Base determination: Equivalent, calculated 521.4 found 522.

The dihydrochloride is prepared by dissolving 13.035 g. (0.025 mol) of base in 60 ml. of methylene chloride and adding 12.5 ml. of 4N hydrochloric acid thereto. The dihydrochloride which has precipitated is filtered off, washed with methylene chloride, dried in vacuo at 60°C,, and recrystallised from alcohol. It melts at 216°C.

Analysis: C28H28C14N402 (M,W- = 59 ·37> Calculated %: C 56.58, H. 4.75, 0 5.38, N 9.43 total ionised CI 23.86 CI 11.93 Found %: C 56.68, H 4.89, 0 5.50, N 9.47 total ionised CI 23.75 CI 11.95 EXAMPLE 8 2-( 1-m^-Trifluoromethoxyphenyl-piperazino )~ethyl 2-(7 l-chlorO'-4l^quinolyl-amino )-benzoate and its dihydrochloride.

[(I) 5 = CI in the 7-position, = Code number: SL 73,030], A mixture of 16.9 g. (0.05 mol) of allyl 2-(7,-chloro-4,-guinolyl-amino)-ben2oate, 15.5 g. (0.0535 mol) of 2-(4,~m-trifluoromethoxyphenyl-piperazino)~ethanol, 0.03 g. of sodium and 100 ml. of anhydrous toluene is heated at the reflux temperature for two and a half hours, following the procedure of the preceding Examples. After cooling, a slight amount of insoluble matter is filtered off and the toluene is evaporated from the filtrate. The residue is taken up in an 8:2 mixture of methylene chloride and acetone and this solution is chromatographed on a silica column. The fractions containing the desired ester are combined and the solvents are driven off. 26.6 g. of oily aminoester are thus obtained.

The dihydrochloride is prepared therefrom by dissolving the aminoester base in methylene chloride and adding the calculated amount of 4N hydrochloric acid solution in ethanol. Since the salt remains in solution, the solution is evaporated to dryness and the residue is crystallised from isopropyl alcohol. 24 g. (yield: 74.5%) of 2-( 4'-m-trifluoromethoxyphenyl-piperazino )-ethyl 2-(71-chloro-4*-quinolyl-amino)-benzoate dihydrochloride, m.p. approximately 228°C. , are obtained.

Analysis: C^H^Cl^.-^^ (M. . = 643.93) Calculated %: C 54.09, H 4.38, N 8.70, CI 11.01 Found %.- 53.99 4.41 8.75 10.92.

EXAMPLE 9 2- ( '-m-Trifluoromethylthiophenyl-piperazino )-ethyl 2-( 71-chloro- '-quinolyl-amino )-bonzoate and its dihydrochloride.

[(I)| ¾ * CI in the 7-positionj R2 Code number: SL 73-031], By following the procedure of the preceding Examples but using 22,36 g, (0.066 mol) of allyl 2-(7l-chloro-4,-quinolyl-amino)-benzoate, 21 g. (0.0685 mol) of 2-(4,-m-trifluoromethylthiophenyl-piperazino)-ethanol, 34 g. of basic aminoester are obtained after chromatography on a silica column and evaporation to dryness of the fractions containing the desired ester.

The base is converted into its dihydrochloride by adding the calculated amount of hydrochloric acid in ethanol to a solution of the base in methylene chloride. After evaporation of the solvents and recrystallisation of the product from isopropyl alcohol, 32 g. (yield = 73.6%) of 2- ( 4 *-m-trifluoromethylthiophenyl-piperazino )-ethyl 2-( 71 -chloro-41 -quinolyl-amino )-benzoate dihydrochloride, m.p. 230°C. , are collected.

Analysis: C29H28C13F3N402S (M.W. = 659.99) Calculated % : C 52.77, H 4.27, N 8.43, Cl~10.74 Found % i 52.70 4.27 8.39 10.66 EXAMPLE 10 2- ( '-m-Chlorophenyl-piperazino )-ethyl 2- ( 7 '-trifluoro-methyl-4'-guinolyl-amino )-benzoate and its dihydrochloride.

[(I); ss CF3 in the 7-position, Code number: SL 73-045], By reacting a mixture of 11.2 g. (0.0465 mol) of 2-(4*-m^chlorophenyl-piperazino)-ethanol and 15.58 g. (0.0419 mol) of allyl 2-(7»-trifluoromethyl-4'-quinolyl-amino )-benzoate in toluene, and by following the procedure of the preceding Examples, a solid is obtained after removing the solvent, and this solid is recrystallised from isopropyl alcohol. 13.2 g. (yield = 65%) of 2-(4'-m-chlorophenyl-piperazino )-ethyl 2- ( 7 ·-trifluoromethyl- *-quinolyl-amino)-benzoate, m.p. 125 °C. , are thus collected.

Analysis: C29H26C1F3N4°2 ^M-w- = 555 ) Calculated % : C 62.76, H 4.72, N 10.09 Found % : 62.84 4.67 9.88.

The dihydrochloride is prepared by dissolving the above base in methylene chloride, and adding the calculated amount of a 4N solution of hydrochloric acid in ethanol.

The solvents are evaporated and the dihydrochloride is recrystallised from isopropanol. 2-(4'-nH-Chlorophenyl-piperazino )-ethyl 2-( 7 *-trifluoromethyl-4*-quinolyl-amino )-benzoate dihydrochloride melts with decomposition at 240°C.

Analysis: C29H28C13F3T4°2 ^1' ' = 627·9> Calculated % : C 55.47, H 4.49, N 8.92 ionised total CI 11.31 CI 16.94 F 9.08 Found % i C 55.54, H 4.72 N 8.79 ionised total CI 11.35 CI 17.07 F 9.04.

EXAMPLE 11 2-[4'-(3"-Chloro-2"-methy1-phenyl )-piper zino]-ethyl 2-( 7 '-chloro—4'-quinolyl-amino )-benzoate and its dihydrochloride.

[(I) j = CI in the 7-position, R2 = Code number: SL 73-046], Using the procedure of the preceding Examples, 9.5 g. (0.0373 mol) of 2-[4'-( 3"-chloro-2"-methyl-phenyl )-piperazino]-ethanol and 11.8 g. (0.035 mol) of allyl 2-(7'-chloro-4,-quinolyl-amino)-benzoate are reacted in toluene. The solvent is evaporated and the oily residue is triturated in petroleum ether until solidification takes place. The product is filtered off, dried in air and recrystallised from isopropyl alcohol, 15.15 g. (yield = 81%) of 2-[4,-(3"-chloro-2"-methyl-phenyl)-piperazino]-ethyl 2-( 7'-chlorc—4'-quinolyl-amino)-benzoate, m.p. 122°C. , are thus collected.

Analysis: G29H28C12K4?2 (K»wv = 535.38) Calculated % : C 65.06, H 5.27, N 10.46 Found % : 65.00 5.29 10.44.

The dihydrochloride is prepared by dissolving the above base in methylene chloride and adding a calculated amount of 4N hydrochloric acid in ethanol. The solvents are evaporated and the dihydrochloride is recrystallised from isopropyl alcohol. The 2-[4,-(3"-chloro-2"~methyl-phenyl )-piperazino]-ethyl 2-(7 ,-chloro-4'~quinolyl-amino)-benzoate dihydrochloride obtained melts with decomposition at 210°C.

Analysis: C29H30C14N402 (M.W. = 608.3) total (*) Calculated % : C 56.34, H 5.07, 0 6.58, N 9.06 CI 22.95 Pound % : 56.50 4.96 6.49 9.18 22.79.

(K) Calculated by taking into account a 1.5% water content measured by the Karl Fischer method.

EXAMPLE 12 2-[4'-( 3"-Chloro-2"-methyl-phenyl )-piperazino]-ethyl 2-( 7 *-trifluoromethyl-4*-quinolyl-amino )-benzoate and its dihydrochloride.

[(I) j = Code number: SL 73-047].

A mixture of 5.4 g. (0.021 mol) of 2-[4,-(3"-chloro-2"-methyl-phenyl )-piperazino]-ethanol and 7.5 g. (0.02 mol) of allyl 2-( 7 '-trifluoromethyl-4*quinolyl- amino )-benzoate is reacted in toluene, following the procedure of the preceding Examples. The toluene is evaporated and the residue is crystallised from petroleum ether. The crystals are filtered off, dried in air and recrystallised from isopropyl alcohol. 10.5 g. (yield = 92%) of 2-[4,-(3"-chloro-2,,-.methyl-phenyl)-pipera2ino]~ ethyl 2-( 71-trifluoromethyl-4'-quinolyl-amino )-benzoate, m.p. 130°C. , are thus obtained.

Analysis: C30H28C1F3N4°2 iM«W,« = 569.03) Calculated %: C 62.32, H 4.96, N 9.85 Pound % : 63.36 5.14 9.84.

The dihydrochloride is prepared by dissolving the base in methylene chloride and adding a calculated amount of a 4 solution of hydrochloric acid in ethanol. The dihydrochloride is filtered off and recrystallised from isopropyl alcohol. 2- [41-( 3"-Chloro-2"-methyl-phenyl )-piperazino]-ethyl 2-( 7 '-trifluoromethyl- 1-quinolyl-amino )-benzoate dihydrochloride, m.p. 230°C. , with decomposition is thus obtained.

Analysis: C30H30C13F3N4°2 .(M'W« = 641.95) (x) Calculated % : C 56.04, H 4.88, N 8.72 Found % : 55.36 4.73 8.50 (x) Calculated taking into account a 0.15% water content measured by the Karl Fischer method.

EXAMPLE 13 2-( 4*-m^Trifluoromethylthiophenyl-piperazino )-ethyl 2-( 7 '-trifluoromethyl-4'-quinolyl-amino )-benzoate and its dihydrochloride.

Code number; SL 73-048], By reacting 12 g, (0.039 mol) of 2-(4'-m-trifluoromethylthiophenyl-piperazino)-ethanol and 13,9 g, (0,037 mol) of allyl 2-(7 '-trifluoromethyl-4'-quinolyl-amino )-benzoate in toluene, following the technique of the preceding Examples, an oil is obtained after evaporation of the solvent, and this oil is chrom tographed on a silica column and eluted v/ith a 4:1 mixture of chloroform and acetone, 20 g, (yield = 86%) of 2-(4*-m-trifluoromethylthiophenyl-piperazino )~ethyl 2- ( 7 ·-trifluoromethyl-4,-quinolyl-amino)-ben2oate are thus obtained as a pale yellow oil.

Analysis: ( . , = 620.62) Calculated % : C 58.06, H 4.22, N 9.03 Found % : 57.98 4.27 8.95.

The dihydrochloride is prepared by dissolving the oily base in methylene chloride and adding a calculated amount of a 4N solution of hydrochloric acid in ethanol. The solvents are evaporated and the residue is recrystall— ised from isopropyl alcohol. 2-(4'-¾-Trifluoromethylthio-phenyl-piperazino )-ethyl 2-( 71-trifluoromethyl-4'-quinolyl-amino )-benzoate dihydrochloride, m.p. 220 °C. , with decomposition is thus obtained.

Analysis: C30H28C12P6N4°2S iM*w» = 693.54) Calculated % s C 51.95, H 4.07, CI 10.22 Found % : 51.94 4.00 10.14.

EXAMPLE 14 2-(48-^-Trifluoromethoxyphenyl-piperasino )-ethyl 2-( 7 '-trifluorometh l-41-quinolyl-amino )-benzoate and its dihydrochloride.

[CD j ¾ = CF3 in the 7-position; = Code number: SL 73-051], 10.12 g. (0.035 mol) of 2-( ·-m-trifluoromethoxy-phenyl-piperazino )-ethanol and 12,4 g. (0.0333 mol) of allyl 2-( 71-trifluoromethyl- '-quinolyl-amino )-benzoate are reacted in toluene, following the procedure of the preceding Examples. The toluene is evaporated and the oil obtained is purified by chromatography on a silica column, eluting with a 9:1 mixture of chloroform and acetone. The solvent is evaporated and 16.5 g. (yield = 95%) of 2-( 41-m-trifluoromethoxyphenyl-piperazino )-ethyl 2- ( 7 '-trifluoromethyl- 1-quinolyl-amino )-benzoate are obtained as an oil which cannot be crystallised.

Analysis: 604.56) Calculated % : C 59.60, H 4.33, 9.27 Found % : 59.35 4.26 9.10 The dihydrochloride is prepared by dissolving the above base in methylene chloride and adding a calculated amount of a 4 solution of hydrochloric acid in ethanol. The solvents are evaporated, the residue is triturated in diethyl ether and the 2-( 4'-m-trifluoromethoxyphenyl-piperazino )-ethyl 2-( 71-trifluoromethyl-4*-quinolyl-amino )-benzoate dihydrochloride obtained is recrystallised from isopropyl alcohol. It then melts at 270-272°C. , with decomposition.

Analysis: C30H2QC12F6N403 (M.W. = 677.48) Calculated % : C 53.19 , H 4.17, N 8.27, P 16.82, CI 10.47 Found % : 53.17 4.11 8.13 16.69 10.52.

EXAMPLE 15 2-( '-m-Trifluoromethylthiophenyl-piperazino )-ethyl 2- ( 71-trifluoromethylthio- 1-quinoly 1-amino )-benzoate and its dihydrochloride.

Code number: SL 73-069 ] .

Using the procedure of the preceding Examples, a mixture of 11.35 g. (0.03 mol) of methyl 2~( 7 '-trifluoro-methyl-thio-4'-quinolyl-amino)-benzoate, 9.8 g. (0.032 mol) of 2-( *-m-trifluoromethylthiophenyl-piperazino )-ethanol, 150 ml. of toluene and 0.03 g. of sodium is heated for three hours. The oil is purified by chromatography on a silica column and the pure oily base obtained is crystallised by trituration in petroleum ether. 15.9 g. (yield = 81%) of 2-( 1-m-trifluoromethylthio-phenyl-piperazino )-ethyl 2-( 7 *-trifluoromethylthio-4*-quinolyl-amino )-benzoate are thus obtained. After recrystallisation from isopropyl alcohol, it melts at 90°C.

Analysis: C3oH26P6N4°2S2 *M«W» = 652.69) Calculated % : C 55 .20 , H. 4.01 , N 8.58 Found % i 54.62 4.00 8.46 2-( 1-m-Trifluoromethylthiophenyl-piperazino )-ethyl 2- ( 7 '-trifluoromethylthio- 1-quinolyl-amino )-benzoate dihydrochloride , prepared as in the preceding Examples, melts at 220°CVv after recrystallisation from ethyl alcohol.

Analysis: C30H28C12F6N4°2S2 <Μ·Τ'Τ· = 725.61) Calculated % : C 49.60, H 3.89, N 7.72, CI 9.77 Found % : 49.58 3.85 7.59 9.81 EXAMPLE 16 2- [41-( 311 ,5 "-Di-trifluoromethyl-phenyl )-piperazino]-ethyl 2- ( 71-trifluoromethyl-41-quinolyl-amino )-benzoate and its dihydrochloride.

[(I)j Rj s CF3 in the 7-position; = Code number: SL 73-070], By heating 11.17 g. (0.03 mol) of allyl 2- (7 '-trifluoromethyl-4' -quinolyl-amino )-benzoate, 11.3 g. (0.33 mol) of 2- [ '-(3" ,5"-di-trifluoromethyl-phenyl )-piperazinoj-ethanol, 150 ml. of toluene and 0.03 g. of sodium for two hours thirty minutes, 16.7 g. (yield = 85%) of 2- [4'-(3" ,5"-di-trifluoromethyl-phenyl)-piperazino]-ethyl 2-[ 71 -trifluoromethyl- '-quinolyl-amino )-benzoate are obtained after the usual treatment, and this product, after recrystallisation from isopropyl alcohol, melts at 114°C.

Analysis: C3iH25P9N °2 M»W» = 656.58) Calculated % : C 56.71, H 3.83, N 8.53 Found % x 56.76 3.93 8.67 2-[ '- ( 3" ,5 "-Di-trifluoromethyl-phenyl )-pipera-zino]-ethyl 2-( 7 '-?trifluoromethyl-4'-quinolyl-amino )-benzoate dihydrochloride, prepared as in the preceding Examples, melts at 238°C., after recrystallisation from ethyl alcohol.

Analysis: G31H27C12P9N 02 Code number: SL B 179). 10.76 g. (0.0289 mol ) of allyl 2-(8'-trifluoro-methyl-4'-guinolyl-amino)-benzoate, 8.23 g. (0.03 mol) of 2-( 1-m-trifluoromethylphenyl-piperazino )-ethanol and 150 ml. of anhydrous toluene are introduced into a distillation apparatus. The mixture is heated at the reflux temperature, and approximately 10 ml. of toluene are slowly distilled in order to entrain traces of water present in the reaction mixture. 0.06 g. of sodium is then added and the whole is heated for 3 hours with continuous slow distillation to remove the allyl alcohol formed during the trans-?esterification reaction. The disappearance of the starting ester is checked by thin layer chromatography. The boiling reaction mixture is filtered to remove a slight amount of insoluble matter and the toluene is evaporated from the filtrate. A gummy residue is obtained and is triturated in petroleum ether. The precipitate which separates out is filtered off, washed with petroleum ether, dried in vacuo and recrystallised from isopropyl alcohol. 13.8 g. (yield = 81%) of 2-(4'-m-trifluoromethylphenyl-piperazino)-ethyl 2-(81-trifluoromethyl-4'-quinolyl-amino )-benzoate, m.p. 114°C. , are obtained.

Analysis: C3oH26F6N4°2 *Μ·¥· = 588.557) Calculated % : C 61.22, H 4.45, N, 9.52 Found % : 61.01 4.72 9.40.

EXAMPLE 18 2-( *-m-Chlorophenyl-piperazino )-ethyl 2-(8'-trifluoro-methy1-41-quinolyl-amino)-benzoate Code number: SL B 180).

A mixture of 10.76 g. (0.0289 mol) of allyl 2- (8'-trifluoromethyl-4'-quinolyl-amino )-benzoate, 7.21 g. (0.03 mol) of 2-(4'-ni-chlorophenyl^piperazino)-ethanol, 0.07 g. of sodium and 150 ml. of anhydrous toluene is heated at the reflux temperature for 3 hours, following the procedure described in Example 17. The reaction mixture is filtered hot, and the toluene is evaporated from the filtrate. The residual paste-like product is triturated in petroleum ether and the precipitate which separates out is filtered off, washed, dried in vacuo and recrystallised from ethanol. 13 g. (yield = 81%) of 2-(41-m-chlorophenyl-piperazino )-ethyl 2-( 81-trifluoromethyl-4'-quinolyl-amino )-benzoate , m.p. 140°C., are obtained.

Analysis: C^H^CIF-N ,0, (M. . = 555.04) Calculated % C 62.76, H 4.72, N 10.09, CI 6.39 Pound % 62.68 4.75 9.96 6.46 6.30.

EXAMPLE 19 2-(41-Phenyl-piperazino )-ethyl 2-(8 '-trifluoromethyl-41-quinolyl-amino)-benzoate. in the 8-position; Code number: SL B 181).

Following the technique of Example 17, a mixture of 10.76 g. (0.0289 mol) of allyl 2-(8*-trifluoromethyl-4'■ quinolyl-amino )-benzoate, 7.426 g. (0.036 mol) of 2-( 4'-phenyl-piperazino )-ethanol, 0.07 g. of sodium and 150 ml. of toluene is heated at the reflux temperature for approximately 3 hours. The reaction mixture is filtered and the toluene is evaporated from the filtrate, A solid residue is obtained which is washed with water, dried in vacuo and recrystallised from 2-propanol. 13 g. (yield = 86%) of 2-( 4*-phenyl-piperazino )-ethyl 2-(8 '-trifluoromethy1-4*-quinolyl-amino )-benzoate, m.p. 147°C., are thus obtained.

Analysis: C29H27P3 402 (M.W. 520.559) Calculated % : C 66.91, H 5.61, N 10.76 Found % : 66.84 5.44 10.76 66.89 5.50 EXAMPLE 20 2-( 4·-m-Trifluoromethylthiophenyl-piperazino )-ethyl 2-( 8 '-trifluoromethyl-41-quinolyl-amino )-benzoate CF_ in the 8-positionj Code number: SLB 182).

Following the procedure of Example 17, a , mixture of 10.76 g. (0.0289 mol) of allyl 2-(8-trifluoro-methyl-4-quinolyl-amino)-benzoate, 10.11 g. (0.033 mol) of 2-( 4-m-trifluoromethylthiophenyl-piperazino )-ethanol , 0.05 g. of sodium and 150 ml. of toluene is heated at the reflux temperature for 2 hours 30 minutes. The hot mixture is filtered, the toluene is evaporated from the filtrate and the gummy residue is triturated in petroleum ether. The precipitate which separates out is filtered off, dried in vacuo and recrystallised from 2-propanol. 15.6 g. (yield = 86%) of 2-(4'-mrtrifluoromethylthiophenyl-piperazino )-ethyl 2- ( 81-trifluoromethyl-4 '-quinolyl-amino)-benzoate, m.p. 128°C. , are obtained.

Analysis: 6P6N4°2S ( M*W* . = 610 * 621 * Calculated % : C 58.06, H 4.22, N 9.03 Pound % : 57.97 4.35 8.96.

EXAMPLE 21 2- ( 4'-m-Trifluoromethylphenyl-piperazino )-ethyl 2- ( 7 '-trifluoromethy1-4'-quinolyl-amino )-benzoate ] 9.23 g. (0.0235 mol) of 2-(4'-m-trifluoromethyl-phenyl-piperazino )-ethyl 2-amino-benzoate, 7 g. (0.03 mol) of 4-chloro-7-trifluoromethyl-quinoline, 100 ml. of water and 20 ml. of 2N hydrochloric acid are introduced into a 250 ml. flask. This mixture is heated at the reflux temperature for two hours. The reaction mixture is allowed to cool, neutralised with a saturated solution of sodium bicarbonate, and extracted with methylene chloride. The organic phase is decanted, washed with water, dried over magnesium sulphate and filtered. The solvent is driven off from the filtrate and the residual solid is triturated in petroleum ether. The precipitate is filtered off and recrystallised from isopropyl alcohol. 10.95 g. (yield = 79.1%) of 2~(4«-ro-trifluoro-methyl-phenyl-piperazino )-ethyl 2-( 71-trifluoromethyl- '-quinolyl-amino )-benzoate, m.p. 88-90°C., are thus obtained, EXAMPLE 22 2-( 1-m-Trifluoromethylphenyl-piperazino )-ethyl 2-( 71-chloro- '-quinolyl-amino )-benzoate [(I) ¾ » CI in the 7-position, R4 = ] 11.65 g. (0.025 mol) of 2-( 4»-m-trifluoromethylphenyl-piperazino )-ethyl 2-amino-benzoate dihydrochloride are added to a suspension of 4.95 g. (0.025 mol) of 4, 7-dicliloro-quinoline in 100 ml. of water, and this mixture is heated at the reflux temperature for two hours, A further 4.95 g. (0.025 mol) of 4, 7-dichloro-quinoline are added, and heating is continued until the reaction is complete. The mixture is cooled, and the precipitate which has formed is filtered off, washed with water, dried and recrystallised from isopropyl alcohol. 10.5 g. (yield = 66.8%) of 2-(4*-¾-trifluoromethyl-phenyl-piperazino )-ethyl 2-( 71-chloro-41-quinolyl-amino )-benzoate dihydrochloride are thus obtained.

The base is liberated by adding a saturated solution of sodium bicarbonate to a suspension of this V dihydrochloride in water, and extraction with methylene chloride. The organic layer is isolated, washed several times with water, dried over magnesium sulphate and filtered. The solvent is evaporated from the filtrate and the solid residue is recrystallised from isopropyl alcohol. 6.75 g. (yield = 72.6%) of 2-( O-'-in-trifluoromethyl-phenyl-piperazino )-ethyl 2-( 7 '-chloro-41-guinolyl-amino )-benzoate$ m.p. 100-102 °C., are obtained.

EXAMPLE 23 2-(4'-m-Chlorophenyl-piperazino)-ethyl 2-( 71-chloro-4'-quinolyl-amino )-benzoate [(I), Rj^ = CI in the 7-position, R4 = y ] CI 12.5 ml. of 2N hydrochloric acid are added to a suspension of 6.44 g. (0.0325 mol) of , 7-dichloro-quinoline and 9 g. (0.025 mol) of 2-( 4'-m^chlorophenyl-piperazino)-ethyl anthranilate in 75 ml. of water. This mixture is heated at the reflux temperature for three hours, and then allowed to cool. The base is liberated by adding a saturated solution of sodium bicarbonate, and extracted with methylene chloride. The organic solution is decanted, washed several times with water, dried over sodium sulphate and filtered. The solvent is driven off from the filtrate and the residue is recrystallised from isopropyl alcohol. 9.95 g. (yield = 76.4%) of 2-(4,-mrchlorophenyl-piperazino)-ethyl 2-(7,-chloro-4'-quinolyl-amino)-benzoate, m.p. 122°C. , are collected.

EXAMPLE 24 2-( 1-m-Trifluoromethylthiophenyl-piperazino )-ethyl 2-( 7 '-trifluoromethyl-4'-quinolyl-amino )-benzoate [(I), Rx = -CF3 in the 7-position, ¾ = - ] SCF3 A suspension of 5.80 g. (0.025 mol) of 4-chloro-7-trifluoromethyl-quinoline and 9.96 g. (0.02 mol) of 2-(4,-m^trifluoromethylthiophenyl-piperazino )-ethyl 2-amino-benzoate dihydrochloride in 100 ml. of water is heated at the reflux temperature for four hours. The reaction mixture is cooled, and the precipitate is filtered off, washed with water, dried in vacuo in the presence of phosphorus pentoxide and recrystallised from isopropyl alcohol. 10.7 g. (yield = 77.490) of 2-(4'-¾-trifluoro-methylthiophenyl-piperazino )-ethyl 2-( 7 '-trifluoromethyl-4'-quinolyl-amino)-benzoate dihydrochloride, m.p. 220 °C. , are obtained.

To obtain the base, a solution of sodium bicarbonate is added to the suspension of the dihydrochloride in water and the mixture is extracted with methylene chloride. The organic layer is washed with water, dried over sodium sulphate and filtered. The solvent is evaporated from the filtrate, and the base is obtained as an oil, which is purified by passage through a silica column (eluant, chloroform-acetone: 80-20). After evaporation of the solvents, 7.85 g. (yield = 82%) of 2-( 4*-m-trifluoromethylthiophenyl-piperazino )-ethyl 2- ( 71-trifluoromethyl-41-quinolyl-amino )-benzoate are obtained as a pale yellow oil.

EXAMPLE 25 2-(4'-Phenyl-piperazino )-ethyl 2-( 8 '-chloro- 1 -quinolyl-amino )-benzoate [(I), * CI in the 8-position, R2 = C6H5 4.95 g. (0.025 mol) of 4,8-dichloro-quinoline, 6,5 g. (0.02 mol) of 2-( 4'-phenyl-piperazino )-ethyl 2-amino-benzoate, 75 ml. of water and 10 ml. of 2N hydrochloric acid are heated at the reflux temperature for three hours. The base is liberated by adding a saturated solution of sodium bicarbonate to the reaction mixture. The precipitate obtained is filtered off, drained, washed several times with water, dried in vacuo in the presence of phosphorus pentoxide, and recrystallised from ethanol. 6.70 g. (yield = 68.7%) of 2-( 41-phenyl-piperazino)-ethyl 2-(8,~chloro- l-guinolyl-amino)-benzoate, m.p. 164°C. , are thus obtained.

EXAMPLE 26 2-( 1- henyl-piperasino )-ethyl 2-( 71-trifluoromethyl- '-quinolyl-amino )-benzoate [(I), j^ = CF3 in the 7-position, = CgHg], 23.1 g. (0.1 mol) of 4-chloro-7-trifluoromethyl-quinoline are added to a solution of 19.85 g. (0.05 mol) of 2-(4'-phenyl-piperazino )-ethyl 2-amino-benzoate dihydrochloride in 500 ml. of methanol. The pH of the mixture is adjusted to 2 by adding hydrochloric acid.

The mixture is heated at the reflux temperature for eight hours. The mixture is filtered, the methanol is evaporated and the residue is taken up in a saturated solution of sodixxm bicarbonate to liberate the base which is extracted with methylene chloride. The organic solution is washed with water, dried over sodium sulphate and filtered. The solvent is evaporated from the filtrate, and the residue isiscrystallised from isopropyl alcohol. 13.5 g. (yield = 52%) of 2-( '-phenyl-piperazino)-ethyl 2-( 7 •-trifluoro-methyl-4'-quinolyl-amino)-benzoate, m.p. 130°C,, are obtained.

The compounds of the invention possess valuable pharmacological properties which make them useful for human and/or veterinary therapy.

Acute toxicity Tests were carried out on mice of both sexes, of the Swiss strain, of average weight 20 g. (- 2g.). The 50% lethal doses were calculated according to Miller and Tainter (Proc. Soc. Exp. Biol. Med. 1944, 57. 261). The results are given in Table I.

TABLE I COMPOUND ACUTE TOXICITY, MICE, CODE NO. ORAL ADMINISTRATION LD50* mg/kg 72-165 > 2,000 72-242 >3,000 72-244 1,200 72-248 1,900 72-391 2,500 73-017 1,500 73-018 4,000 73-030 >4,000 73-031 3,000 73-033 4,000 73-045 >4,000 73-046 2,000 73-047 3,000 73-048 4,000 73-051 >4,000 73-069 2,200 73-070 >4,000 SLB 179 >3_000 SLB 180 >3,000 SLB 181 2,000 SLB 182 >3,000 Amidopyrine 850 Phenylbutazone 600 Glafenine 3,500 *LD50 = 50% lethal dose Analgesic Activity This activity was investigated by two different methods: 1. Effect against pain induced, in Swiss mice, by the intraperitoneal injection of phenylquinone, in accordance with the experimental procedure of Siegmund (Proc. Soc. Exp. Biol. Med., 1957, 95, 729), modified by Cheymol (C.R. Soc. Biol., 1963, 157. 521) and Brittain (Nature, London, 1963, 20, 895). The results are given in Table II below. 2. Test using a plate heated by acetone vapours, carried out on Swiss mice, in accordance with the description by Woolfe ( J. Pharmacol. Exp. Therap. , 1944, 80, 300) with the modifications by Chen (Science 1951, 113, 631), Eddy (J. Pharmacol. Exp. Therap., 1953, 107. 385) and Boissier (Anesth. Analog., 1956, 13, 569).

Table HI below gives the results obtained.

TABLE II *AD50 = 50½ active dose TABLE III *MAD = mean active dose.

The results obtained in the Siegmund test, which demonstrates analgesic effects of the peripheral type, show that the compounds of the invention (72-242, 72-244, 72-248, 72-391, 73-017, 73-018, 73-033, 73-045, 73-046, 73-047, 73-048, 73-051, SLB 179, 180, 181 and 182) are generally much more active than the well-known analgesic agents used for comparison purposes (amidopyrine and glafenine).

In the heated plate test, which demonstrates analgesic effects of_the central type, the compounds (72-391, 73-017, 73-018, 73-033, 73-045 and SLB 179) show an activity which is greater than that of amidopyrine.

This greater activity is considerable in the case of the compounds 73-017, 73-018 and 73-033. In the case of the other compounds of the invention, the central component is, as in the case of glafenine, much less strong.

Anti-inflammatory activity This activity was determined by the test involving oedema of the paw, induced in Sherman rats by the method of Winter and colleagues (Proc. Soc. E>∑p. Biol. Med., 1962, 111, 544). The results are summarised in Table IV.

TABLE IV *AD40 = 40% active dose.

These results show that the compounds of the invention have anti-inflammatory effects. These effects, which never exceed those of phenylbutazone administered at the same dosage, must be considered by taking into account the analgesic activity of the compounds of the invention which manifests itself at doses very much lower than the anti-inflammatory doses.

These experimental data show that the invention provides compounds having a very marked dissociation between analgesic and anti-inflammatory properties, in favour of the analgesic activity. This dissociation is of great value when it is considered that anti-inflammatory activity is frequently associated with mediocre or distinctly poor tolerance by the mucous membranes of the digestive tract.

Finally, and surpr singly, the toxicity of the majority of the compounds of the invention virtually does not increase at all with their activity, so that their therapeutic index is very much greater than that of glafenine. j Certain 2-[ (4-quinolyl) amino]-benzoic acid esters having anti-inflammatory and analgesic properties are known from German Offenlegungsschrift 1,925,607 (which corresponds to Israel Patent Specification 32208).

It has surprisingly been found that the compounds of the present invention have a substantially higher therapeutic index than the most closely related known compounds. 44585/2 The results show that the compounds of the invention can be used in human and veterinary therapy, and especially in the treatment of various algias, especially if they accompany inflammatory affections. The method of administration can be oral, rectal or parenteral, the active substances being used in conjunction with the usual excipients for these pharmaceutical forms. In the case of oral administration, for which tablets, dragees, capsules, gelatine-coated pills, potable solutions and the like, are used, the unit dose is 20 to 200 mg, the maximum dai?_y dosage being 1 g. In the case of rectal administration, these figures are, respectively, from 50 to 400 mg. and 1 g. , and in the case of parenteral administration, they are, respectively, from 10 to 50 mg. and 0.5 g.

The invention accordingly includes within its scope pharmaceutical compositions comprising, in association with a compatible pharmaceutically acceptable diluent, a compound of formula I or a pharmaceutically tolerated acid addition salt thereof.

Claims (1)

1. Compounds of the formula in which represents a chlorine atom or a C 3 or CF^ radical, and 1*2 represents a phenyl radical which is unsubstituted or substituted by one or two CI, CH3, CF3, OCF3, or SCF3 radicals, the phenyl radical being substituted when represents a chlorine atom in 7 position, and itc addition salts with pharmaceutically tolerated acids. 2. 2-( h«-Phenyl-piperazino )-ethyl 2-( 71 - trifluoromethylthio- -quinolyl-amino>-benzoate and its pharmaceutically tolerated acid addition salts. 3. 2-( k '-m- rifluoromethylphenyl-piperazino )- ethyl 2-(7^-chloro-4,-quinolyl-amino)-benzoate and its pharmaceutically tolerated acid addition salts. k. 2-0«-(2",3"-Dimethyl-phenyl )-piperazino]- ethyl 2-(7,-chloro-¾,-quinolyl-amino)-benzoate and its pharmaceutically tolerated acid addition salts. 5. 2-(V-p-Chlorophenyl-piperazino)-ethyl 2-( 7 ' -chlorp-¾i-quinolyl-amino )-benzoate and its pharmaceutically tolerated acid addition salts. 6. 2-( V-Phenyl-piperazino)-ethyl 2-(7'- trifluorcroethyl- -quinolyl-amino )-benzoate and its pharmaceutically tolerated acid addition salts. 7. 2-( U1 -m-Trifluoromethylphenyl-piperazino)- ethyl 2-(7* -trifluoromethyl-¾ ' -quinolyl-amino )-benzoate and its pharmaceutically tolerated acid addition salts, 8. 2-( k' -m-Chlorophenyl-piperazino )-ethyl 2-( 71 -chloro-4' -quinolyl-amino )-benzoate and its pharmaceutically tolerated acid addition salts.. 9. 2-(k1 -m-Trifluoromethoxypheny1- pipe azino )-ethyl 2-( 7 ' -chloro-¾ ' -quinolyl-amino)- benzoate and its pharmaceutically tolerated acid addition salts, 10. 2-( h' -m-Trifluoromethylthiophenyl- piperazino )-ethyl 2-( 71 -chloro- ' -quinolyl-amino )-benzoate and its pharmaceutically tolerated acid addition salts. 11. 2-(k1 -m-Chlorophenyl-piperazino )-ethyl 2-(7'-trifluoromethyl- *-quinolyl-amino )-benzoate and its pharmaceutically tolerated acid addition salts. 12. 2-[h '-( 3"-chloro-2"-methyl-phenyl )- piperazino]-ethyl 2-( 7 i-chloro-^ ' -quinolyl-amino )- benzoate and its pharmaceutically tolerated acid addition salts, 13. 2-[ -(3"-Chloro-2"-methyl-pheny1)- piperazino]-ethyl 2-(71 -trifluoromethyl-4' -quinolyl- amino)-benzoate and its pharmaceutically tolerated acid addition salts. 1¾ . 2-( k ' -m-Trifluoromethylthiophenyl-piperazino )-ethyl 2-( 7 '-trifluoromethyl-¾' -quinolyl-amino)-benzoate and its pharmaceutically tolerated acid addition salts. 15. 2-( k 1 -m-Trifluoromethoxyphenyl-piperazino)-ethyl 2-( 7 ' -trifluoromethyl-V-quinolyl-amino )-benzoate and its pharmaceutically tolerated acid addition salts. 16. 2-( h 1 -m-Trifluoromethylthiophenyl-piperazino )-ethyl 2-( 7 *-trifluoromethylthio-¾ ' -quinolyl-amino)-benzoate and its pharmaceutically tolerated acid addition salts. 17. 2-0,-(3M ,5 "-Di-trifluoromethy1-phenyl)-piperazino]-ethyl 2-( 7 * -trifluoromethyl-¾ * -quinolyl-amino )-benzoate and its pharmaceutically tolerated acid addition salts, 18. 2-( -m-Trifluoromethylthiophenyl-piperazino )-ethyl 2-(8-trifluoromethyl-4-quinolyl-amino)-benzoate and its pharmaceutically tolerated acid addition salts. 19. 2-( 4-m-Trifluoromethylphenyl-piperazino )-ethyl 2-(8-trifluoromethyl- -quinolyl-amino)-benzoate and its pharmaceutically tolerated acid addition salts. 20. 2-( -m-Chlorophenyl-piperazino )-ethyl 2-(8-trifluoromethyl-4-quinolyl-amino)-benzoate and its pharmaceutically tolerated acid addition salts, 21. 2-( ¾-Phenyl-piperazino )-ethyl 2-( 8-trifluoro-methyl-4-quinolyl-amino )-benzoate and its pharmaceutically tolerated acid addition salts. 22. Process for the preparation of a compound as claimed in claim 1 , which comprises ttansesterifying an ester of the formula: with an alcohol of the formula: in which and R2 are as defined in claim 1, and R represents an allyl radical or, when R^ represents SCP^, a methyl radical, in an apolar solvent, in the presence of an alkali metal alcoholate and or an alkali metal. 23. Process for the preparation of a compound as claimed in claim 1, which comprises reacting a quinoline derivative of the formula in a polar solvent, with an anthranilic acid ester of the formula in which and R2 are as defined in claim 1, and X.v represents a halogen atom. 2k. Process according to claim 22, substantially as described in any one of Example 1 to 20, 25. Process according to claim 23, substantially as described in any one of Examples 21 to 26, 26. A compound as claimed in claim 1, when prepared by a process as claimed in any of claims 22 to 25. 27. A pharmaceutical composition comprising, in association with a compatible pharmaceutically acceptable diluent, a compound as claimed in any of claims 1 to 21 or 26 or a pharmaceutically tolerated acid addition salt thereof.