FR2710067A1 - Process for the preparation of 2-amino-5-(1H-imidazol-4-yl)-1-oxopentylpiperidine - Google Patents

Abstract

Process for the preparation of compounds of formula (1) in which R1 represents either a hydrogen atom or a (C1-C4)alkyl group, R2 represents either a hydrogen atom or a (C1-C4)alkoxycarbonyl group or a carboxyl group or a sodium carboxylate group or a -CH2OR4 group, where R4 is a hydrogen atom or a (C1-C4)alkyl or (C1-C4)acyl group, or a -CONR5R6 group or -CN4R5 group, where R5 is a hydrogen atom or a (C1-C4)alkyl group and R6 is a hydrogen atom or a (C1-C4)alkyl or hydroxyl or (C1-C4)alkoxy or (C1-C3)alkoxyphenyl group, R3 represents a (C1-C4)alkyl group and Ar represents either a 1-naphthyl group substituted by a di(C1-C4)alkylamino group or a 6,7-di(C1-C4)alkoxy-1-naphthyl group or an 8-quinolyl group substituted in the 3-position by a (C1-C4)alkyl group or a 1,2,3,4-tetrahydro-8-quinolyl group substituted in the 3-position by a (C1-C4)alkyl group or a 1H-indazol-7-yl group.

Description

dans laquelle Rt représente soit un atome d'hydrogène, soit un groupe (C-C4) alkyle,
R2 représente soit un atome d'hydrogène, soit un groupe (C1-C4)alcoxycarbonyle, soit un groupe carboxylique, soit un groupe carboxylate de sodium, soit un groupe -CH2OR4 où R4 est un atome d'hydrogène, un groupe (C1-C4)alkyle ou (C1-C4)acyle, soit un groupe -CONR5R6, soit un groupe -CN,RS où R5 est un atome d'hydrogène ou un groupe (C-C4)alkyle et R6 est un atome d'hydrogène, un groupe (C-C4)alkyle ou hydroxy ou (C-C4)alco- xy ou (C-C3)alcoxyphényle,
R3 représente un groupe (C-C4)alkyle et
Ar représente soit un groupe naphtalén-l-yle substitué par un groupe di(C-C4)alkylamino, soit un groupe 6,7-di(C1-C4)alcoxy naphtalén-l-yle, soit un groupe quinoléin-8-yle substitué en 3 par un groupe (C-C4)alkyle, soit un groupe 1,2,3,4-tétrahydroquinoléin-8-yle substitué en 3 par un groupe (C-C4)al- kyle, soit un groupe lH-indazol-7-yle.The subject of the present invention is a process for the preparation of 2-amino-5- (1H-imidazol-4-yl) -1-oxopentylpiperidine derivatives of formula (1)

in which Rt represents either a hydrogen atom or a (C-C4) alkyl group,
R2 represents either a hydrogen atom, or a (C1-C4) alkoxycarbonyl group, or a carboxylic group, or a sodium carboxylate group, or a group -CH2OR4 where R4 is a hydrogen atom, a group (C1- C4) alkyl or (C1-C4) acyl, either a group -CONR5R6, or a group -CN, RS where R5 is a hydrogen atom or a (C-C4) alkyl group and R6 is a hydrogen atom, a (C-C4) alkyl or hydroxy or (C-C4) alkoxy or (C-C3) alkoxyphenyl group,
R3 represents a (C-C4) alkyl group and
Ar represents either a naphthalen-1-yl group substituted by a di (C-C4) alkylamino group, or a 6,7-di (C1-C4) alkoxy naphthalen-1-yl group, or a quinoline-8-yl group substituted at 3 with a (C-C4) alkyl group, i.e. a 1,2,3,4-tetrahydroquinoline-8-yl group substituted at 3 with a (C-C4) alkyl group, or a 1H-indazol group -7-yle.

The method according to the invention is described in diagram 1 on the following page.

et en présence d'une base comme la triétéhylamine et on obtient un composé de formule (2) que l'on déprotège à chaud en milieu acide dans un solvant tel que le tétrahydrofurane.A compound of formula (I) in which R1, R2 and R3 are as defined above is reacted with a compound of formula ArSO2Cl in which Ar is as defined above in a solvent such as for example dichloromethane
Diagram 1

and in the presence of a base such as triethylamine and a compound of formula (2) is obtained which is deprotected while hot in an acid medium in a solvent such as tetrahydrofuran.

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

Thus the compounds of formula (I) are described in the French patent application of the applicant filed today and having for title "Derivatives of l- [2-amino-5- [l- (triphenyl methyl) -lH-imidazol- 4-yl) -i-oxopentyl) piperidine, their preparation and their use as synthesis intermediates. "
Compounds of formula ArSO2Cl for which Ar represents a 3-methyl-1,2,3,4-tetrahydroquinolFin-8-yle group are described in the French patent application of the applicant filed today and having the title "Preparation process of 1,2,3,4-tetrahydroquinoline-8-sulfonyl acids and chlorides and their use as synthesis intermediates ".

The following examples illustrate the process according to the invention.

Microanalyses and IR and NMR spectra confirm the structure of the compounds obtained.

Example 1 2R- [1 (2S, 3S), 2a, 4ss] 1- [5- (1H-imidazol-4-yl) -2 - [[(3- methyl-1,2,3,4-tetrahydroquinoline- 8-yl) sulfonyl] amino] -1-oxopentyl] -4-methylpiperidine-2-methanol 1.1. [2R- [1 (2S), 2a, 4B)] acetate hydrochloride - [l- [2-
amino-l-oxo-5- [1- (triphenylmethyl) -1H-imidazol-4-yl) pen-
tyl] -4-methylpiperidin-2-yl) methyl 1.1.1. triphenyl chloride [[(1-triphenylmethyl) -1H-imida-zol-4-ylmethyl] phosphonium
To 670 ml of a solution of 105.5 g (294 mmol) of 4- (chlo romethyl) -1- (triphenylmethyl) -1H-imidazole in dimethylformamide, 77.7 g (296 mmol) of triphenylphosphine are added. The mixture is heated at 80 ° C. for 3 hours. The solvent is evaporated, the crude is taken up in ether and triturated. The precipitate is filtered and dried under vacuum over phosphorus pentoxide.

162 g of product are obtained in the form of yellowish crystals.

Melting point = 210 OC Yield = 89% 1.1.2. (S, E) -2- [[(phenylmethoxy) carbonyl] amino] -5- [1- (triphé-
nylmethyl) -1H-imidazol-4-yl] pent-4-enoate of 1, 1-di-
methylethyl
50.93 g (820 mmol) of triphenyl [[1-triphenylmethyl) -1H-imidazol-4-yl] methyl] phosphonium chloride dissolved in 333 ml of tetrahydrofuran are introduced into a three-necked flask under argon. Drop & drop, & - 70 OC, 51.2 ml of a 1.6 M solution of n-butyllithium in hexane (820 mmol) are added. After 30 minutes of stirring at -70 ° C., the reaction medium is quickly poured into 270 ml of a 0.253 M solution, cooled to 70 ° C., of (S) -4-oxo-2 - [[(phenylmethoxy) 1,1-dimethylethyl carbonyl] amino] butanoate in tetrahydrofuran (683 mmol). The mixture is allowed to return to room temperature overnight. The mixture is hydrolyzed with 280 ml of a saturated aqueous solution of sodium chloride. The aqueous phase is separated from the organic phase and extracted with 2 times 140 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate and evaporated to dryness. Purification is carried out by chromatography on a silica gel column, eluting with a hexane / ethyl acetate gradient.

A mixture of cis and trans olefin is obtained.

For the cis form:
Melting point = 66 OC
Rf = 0.30 thexane / ethyl acetate (60/40))
For the trans form:
Rf = 0.15 thexane / ethyl acetate (60/40))
Yield = 40% 1.1.3. (S, E) -2 - [[(phenylmethoxy) carbonyl] amino-5- [1- (triphenylmethyl) -1H-imidazol-4-yl] -4-pentanoic acid
3.9 g (6.37 mmol) of the trans compound obtained in the preceding step are placed in 80 ml of benzene and then a stream of gaseous hydrochloric acid is passed to 0 C until saturation. Then allowed to stir for 4 hours at room temperature and then evaporated to dryness. The residue is taken up in 20 ml of dichloromethane, neutralized with ammonia and purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol mixture (90:10).

3 g of product are obtained.

Melting point = 180 OC (decomposition) 1.1.4. [2R- [1 (lS), 2a, 4SJJ- [1 - [[2- (acetyloxy) nethyl) -4-ne-thyl-piperidin-1-yl] carbonyl] -4- [1- (triphenylmethyl) -
1H-imidazol-4-yl] but-3-enyl] phenylmethyl carbamate
To a solution of 1.14 g (3 mmol) of (2R-trans) - (4-methylpiperidin-2-yl) methyl acetate trifluoroacetate in 20 ml of dichloromethane, 1.67 g are added to 0 OC (3 mmol) of the compound obtained in the preceding step, 1.5 ml of N, N-diisopropylethylamine then 1.5 g (3.3 mmol) of hexafluorophosphate from [(benzotriazol-1-yl) oxyJtris (dimethylamino) phosphonium. The mixture is left overnight at room temperature and then poured onto 100 ml of ethyl acetate. Wash successively with 100 ml of a 0.1 N hydrochloric acid solution, 100 ml of a saturated sodium hydrogencarbonate solution, 100 ml of a saturated solution of sodium chloride and then dry over magnesium sulfate and evaporated to dryness.

1.4 g of product are obtained in the form of a solid.

Melting point = 59 OC 1.1.5. [2R- [1 (2S), 2a, 48JJ- [1- t2-amino-1-oxo-5-tl- (triphenylmethyl) -lH-imidazol-4- acetate hydrochloride
yl] pentyl] -4-methylpiperidin-2-yl] methyl
1.3 g (1.8 mmol) of the compound obtained in the previous step are placed in a Parr flask and 30 ml of ethanol and 0.4 g of 10% palladium on carbon are added. It is hydrogenated at 50 psi for 8 hours then filtered and the catalyst is drained. The filtrate is collected and evaporated to dryness. The residue is taken up in 20 ml of 0.1 N hydrochloric isopropanol and then evaporated to dryness.

1.12 g of product are obtained in the form of the hydrochloride.

Rf = 0.55 [methyl isobutyl ketone / acetic acid / water (60/20/20)] 1.2. acid chloride (s) -3-methyl-1,2,3,4-tetrahydroqui-
nolein-8-sulfonic 1.2.1. (S) -methyl methyl-2-nitrobenzenepropanoate
Under a nitrogen atmosphere and with stirring, 9.5 g (42 mmol) of methyl (R) -3-iodo-2-methylpropanoate are placed in 90 ml of benzene containing 4.4 g of the Zn (Cu) pair and 5.5 ml of dimethylacetamide. The mixture is stirred for 15 minutes at room temperature and then heated to 60 ° C. for 3 hours.

Then allow the mixture to return to room temperature and add 1 g of bis (tri-O-tolylphosphine) palladium acetate suspended in 2 ml of benzene then 7.5 g (30 mmol) of 2-iodo-3 -nitrobenzene in solution in 20 ml of benzene. The mixture is heated, left at 60 ° C. for 1 hour, 100 ml of ethyl acetate are added and then the reaction medium is filtered on celite. The filtrate is washed with 100 ml of a 1N hydrochloric acid solution and then with 100 ml of water and dried over magnesium sulfate. The residue is purified by chromatography on a column of silica gel, eluting with a hexane / ethyl acetate mixture (90/10).

3 g of product are obtained in the form of an oil which will be used as is in the next step.

1.2.2. (S) -3-methyl-3,4-dihydroquinoline-2 (1H) -one
Method 1
In 40 ml of methanol 3 g (14 mmol) of the product obtained in the previous step are placed and 100 mg of platinum oxide are added. It is hydrogenated under a pressure of 50 psi in a Parr apparatus for 8 hours then filtered, the catalyst is drained and the filtrate is evaporated to dryness. The residue is recovered and triturated in ether. It is recrystallized from ethyl ether.

1.5 g of product are obtained in the form of crystals.

Melting point = 117-119 OC
Method 2
Under a nitrogen atmosphere and with stirring, 31 g (135 mmol) of (R) -3-iodo-2-methylpropanoate methyl are placed in 310 ml of benzene containing 19.75 g of the couple Zn (Cu) and 20, 3 ml of dimethylacetamide. The mixture is heated to 60 ° C. for 3 hours and then cooled to room temperature. 2.92 g of bis (tri-O-tolylphosphine) palladium acetate are added all at once and then 19.75 g (90 mmol) of 2-iodoaniline dissolved in 50 ml of benzene. The mixture is heated for 1 hour at 50 ° C. and then the mixture is allowed to return to room temperature. Filtered on celite, washed with 2 times 100 ml of ethyl acetate and the filtrates are combined. They are washed successively with 2 times 100 ml of a 1 N hydrochloric acid solution, with 100 ml of a saturated solution of sodium hydrogencarbonate and with 50 ml of a saturated solution of sodium chloride. It is dried over magnesium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with dichloromethane.

4.9 g of product are obtained.

Melting point = 118-120 OC 1.2.3. (S) -3-methyl-1,2,3,4-tetrahydroquinoline
In 6 ml of tetrahydrofuran, 0.8 g (5 mmol) of the compound obtained in the preceding step is placed and 17.5 ml of a 1 M solution of borane in tetrahydrofuran. The mixture is heated at reflux for 1 hour and 5 ml of water are slowly added. Then the pH of the reaction medium is adjusted to 1 with a 1 N solution of hydrochloric acid and then heated to reflux for 2 hours. The mixture is allowed to cool, it is evaporated, the residue is taken up in 50 ml of ethyl acetate and washed with twice 50 ml of a sodium hydrogen carbonate solution. It is dried over magnesium sulfate and evaporated to dryness. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with dichloromethane.

0.6 g of product is obtained in the form of an oil which will be used as it is in the next step.

[a], = + 79 (c - 3, methanol) 1.2.4. (S) -5-methyl-5,6-dihydro-2H, 4H-thiazolo [5,4,3-ij] quinoline-2 -one
40.5 ml of toluene and then 2.28 ml (27 mmol) of chlorocarbonylsulfenyl chloride are placed under a nitrogen atmosphere and with stirring. The reaction medium is cooled to -50 ° C. and then a mixture of 3.5 g (23 mmol) of the compound obtained in the previous step and 3.24 g (28 mmol) of N, N-dimethylbenzeneamine in solution are added slowly in 130 ml of toluene. The mixture is allowed to return to room temperature, 100 ml of toluene are added and the mixture is heated to 80 ° C. for 3 hours. The mixture is allowed to cool and washed with 2 times 100 ml of a 1 N hydrochloric acid solution and then with 100 ml of a saturated Nazi solution.

It is dried over magnesium sulphate and then evaporated to dryness. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with dichloromethane.

4.3 g of product are obtained.

Melting point = 54-56 OC 1.2.5. (S) -8,8'-dithiobis (3-methyl-1,2,3,4-tetrahydroquino-
leine)
1.4 g (6.8 mmol) of the compound obtained in the previous step are taken up in 14 ml of 3 N alcoholic potassium hydroxide and the mixture is heated at reflux for 6 hours. The reaction medium is poured into 50 ml of water and the pH of the mixture is adjusted to 4-5 with hydrochloric acid. The mixture is extracted with ether, the ethereal phase is collected, washed over magnesium sulfate and evaporated to dryness. The residue is taken up in 50 ml of benzene and 10 g of alumina are added. The mixture is stirred in air for 18 hours, the alumina is filtered and washed with dichloromethane. The filtrates are combined and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with a cyclohexane: ethyl acetate mixture (95: 5).

0.8 g of yellow product is obtained.

Melting point = 78-80 OC 1.2.6. (S) -3-methyl-1,2,3,4-tetrahydroquinoline-8- acid
sulfonic
0.8 g (4.5 mmol) of the compound obtained in the preceding step is dissolved in 4.51 g of a 95% sulfuric acid solution, the reaction medium is placed in an ice bath and added slowly 1.49 ml of 35% hydrogen peroxide. Then water and then ice are added to the reaction medium and the precipitate thus obtained is filtered. It is washed successively with 5 ml of ice water, 3 times 20 ml of ether and then 10 ml of ice-cold methanol. Finally, rinse with ether and dry in an oven under reduced pressure.

0.5 g of product is obtained.

Melting point = 255 C (decomposition) [] D = + 38 [c = 0.2; methanol: water (80:20)] 1.2.7. (S) -3-methyl-1,2,3,4 acid chloride
tetrahydroquinoline-8-sulfonic
1.07 g of triphenylphosphine are dissolved in 7.5 ml of dichloromethane at 0 ° C. 0.3 ml of sulfuryl chloride is added dropwise under a nitrogen atmosphere at 0 ° C., then the mixture is allowed to return to ambient temperature. A solution containing 0.47 g (2.1 mmol) of the acid obtained in the preceding step, 0.3 ml of triethylamine and 12 ml of dichloromethane is then added slowly. The mixture is stirred for 1 hour at room temperature and then the reaction medium is poured onto 200 ml of pentane. It is filtered, the filtrate is evaporated to dryness, the residue is taken up in 100 ml of pentane and evaporated to dryness.

0.4 g of product is obtained, which is used as it is in the next step.

1.3. 2R- [1 (2S, 3S), 2a, 4JJ-1- [5- (1H-imidazol-4-yl) -2 - [(((3-
methyl-1,2,3,4-tetrahydroquinoline-8-yl) sulfonyl] amino] - l-oxopentyl] -4-methylpiperidine-2-methanol
To 0.6 g (0.9 mmol) of the hydrochloride obtained according to the method described in Example 1.1, 0.4 g of the compound obtained in Example 1.2 dissolved in 10 ml of dichloromethane is added to 0 OC and 0.38 ml of triethylamine in 10 ml of dichloromethane. The mixture is left stirring overnight at room temperature and then the mixture is washed successively with 10 ml of a 0.2 N solution of hydrochloric acid, 10 ml of a saturated solution of sodium hydrogen carbonate and 10 ml of saturated sodium chloride solution. The reaction medium is filtered, dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: ethanol mixture (96: 4).

0.96 g of product is obtained.

Melting point = 49 OC.

1.4. [2R- [1 (2S, 35), 2, 4S) acetate J-1- (5- (1H-imidazol-4-
yl) -2 - [[(3-methyl-1,2,3,4-tetrahydroquinoline-8-yl)
sulfonyl] amino] -1-oxopentyl] -4-methylpiperidine-2-yl]
methyl
0.65 g (0.74 mmol) of the compound obtained in the previous step is placed in 10 ml of acetic acid. 2 ml of water and 8 ml of tetrahydrofuran are added, then the mixture is heated at 80 ° C. for 1 hour. The reaction medium is evaporated to dryness and the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: ethanol mixture (90:10).

0.4 g of pure product is obtained.

Melting point = 47 OC 1.5. 2R- [1 (2S, 3S), 2a, 4ss]] - 1- [5- (1H-imidazol-4-yl) -2 - [[(3-
methyl-1,2,3,4-tetrahydroquinoline-8-yl) sulfonyl] amino] -
1-oxopentyl] -4-methylpiperidine-2-methanol
0.4 g (0.75 mmol) of the compound obtained in the preceding step is placed in 2 ml of methanol, the mixture is cooled to 0 ° C. and 1.5 ml of a 1 N sodium hydroxide solution is added dropwise. The mixture is left stirring for 2 hours at 0 ° C., the methanol is evaporated off and the residue is suspended in a dichloromethane: water mixture (50:50). The organic phase is recovered which is dried over magnesium sulphate and evaporated to dryness.

The residue is taken up in an equivalent of a 1 N hydrochloric acid solution and purified by chromatography on a column of silica gel, eluting with a gradient of 0.01 N hydrochloric acid and acetonitrile (0 to 100 % acetonitrile). The fractions containing the product are combined and lyophilized.

0.3 g of product is obtained.

Melting point = 90 C [α] D = + 110 (c = 0.2; methanol)
Example 2 2R- [1 (2S, 3R), 2a, 48J) -1- [5- (1H-imidazol-4-yl) -2 - ([(3-methyl-1,2,3,4-tetrahydroquinoline) -8-yl) sulfonyl] amino] -1-oxopentyl] -4-methylpiperidine-2-methanol 2.1. (R) -3-methyl-1,2,3,4-tetrahydro acid chloride
quinoline-8-sulfonic 2.1.1. (R) -3-methyl-1,2,3,4-tetrahydroquinoline-8-acid, sulic acid
From methyl (S) -3-iodo-2-methylpropanoate, according to the process described in Example 1.2, (R) -3-methyl-1,2,3,4-tetrahydroquinoline- acid is obtained. 8-sulfonic.

Melting point = 255 OC (decomposition) [a), = - 39 [c = 0.2; methanol: water (50:50) 1 2.1.2. (R) -3-methyl-1,2,3,4-tetrahydro acid chloride
quinoline-8-sulfonic
From the compound obtained in Example 2.1.1 and according to the method described in Example 1.2, the chloride of (R) -3-methyl-1,2,3,4-tetrahydroquinoline-8 acid is obtained -sulfonic.

2.2. 2R- [1 (2S, 3R), 2a, 4BJ) -1- [5- (ÎH-imidazol-4-yl) -2 - [[(3-
methyl-1,2,3,4-tetrahydroquinoline-8-yl) sulfonyl] amino] - 1-oxopentyl] -4-methylpiperidine-2-methanol
From the chloride of (R) -3-methyl-1,2, 3,4-tetrahydroquinoline-8-sulfonic acid and the compound described in Example 1.1, according to the method described in Example 1.3., the expected product is obtained.

[] D = 39 (c = 0.2); methanol
The compounds obtained by the process according to the invention have antithrombotic properties and are described in European patent application no. 93400772.5 of the applicant.

Claims (3)

 which is deprotected while hot in an acid medium.

 in which R1, R2 and R3 are as defined in claim 1 with a compound of formula ArSO2Cl in which Ar is as defined in claim 1 and a compound of formula (2) is obtained

Ar represents either a naphthalen-1-yl group substituted by a di (CI-C4) alkylamino group, or a 6,7-di (C1-C4) alkoxy naphthalen-1-yl group, or a quinoline-8-yl group substituted at 3 with a (C1-C4) alkyl group, i.e. a 1,2,3,4-tetrahydroquinoline-8-yl group substituted at 3 with a (C1-C4) alkyl group, or an LH-indazol group -7-yle, process characterized in that a compound of formula (I) is reacted R3 represents a (C1-C4) alkyl group and R2 represents either a hydrogen atom, or a (c1-c4) alkoxycarbonyl group, or a carboxylic group, or a sodium carboxylate group, or a group -CH2OR4 where R4 is a hydrogen atom, a group (C- C4) alkyl or (C1-C4) acyl, either a group -CONR5Rf, or a group -CN4R5 where Rf is a hydrogen atom or a group (C1-C4) alkyl and R6 is a hydrogen atom, a group (C-C4) alkyl or hydroxy or (C1-C4) alcohol or (C1-C3) alkoxyphenyl, R1 represents either a hydrogen atom or a (C1-C4) alkyl group,  in which

 Claims 1. Process for the preparation of compounds of formula (1) 2. Compounds of formula (1)

 in which R1 represents either a hydrogen atom or a (Cs-C4) alkyl group, R2 represents either a hydrogen atom, or a (C1-C4) alkoxycarbonyl group, or a carboxylic group, or a sodium carboxylate group, or a group -CH2OR, where R4 is a hydrogen atom, a group (C1 -C4) alkyl or (C1-C4) acyl, either a group -CONRfRf, or a group -CN4R5 where Rf is a hydrogen atom or a group (C1-C4) alkyl and Rf is a hydrogen atom, a (C1-C4) alkyl or hydroxy or (C1-C4) alkoxy or (C1-C3) alkoxyphenyl group, R3 represents a (C1-C4) alkyl group and Ar represents either a naphthalen-1-yl group substituted by a di (C-C4) alkylamino group, or a 6,7-di (CI-C4) alkoxy naphthalen-1-yl group, or a quinoline-8-yl group substituted in 3 with a (C-C4) alkyl group, i.e. a 1,2,3,4-tetrahydroquinoline-8-yl group substituted in 3 by a (C1-C4) alkyl group, or a 1H-indazol group -7-yle, obtained by the process according to claim 1. 3. Compounds according to Claim 2, characterized in that R1 represents either a hydrogen atom or a (Ct-C4) alkyl group, R2 represents either a carboxylic group, or an ethoxycarbonyl group, or a hydroxycarboxamide group, or a hydroxymethyl group, or an 1H-tetrazolyl group, R3 represents a methyl or ethyl group and Ar represents a 3-methyl-1,2,3,4-tetrahydroquinoline-8-yl group.