FR2727413A1 - New N-2-sulphonamido 5-imidazolyl pentanoyl piperidine derivs. - Google Patents

Abstract

1-(5-(1H-imidazol-4-yl)-1-oxo -2-(2-aminophenyl sulphonamido)- pentyl) piperidine-2-carboxylic acid derivs. of formula (I) and their acid addition salts are new.R1, R2, R5 = H or 1-4C alkyl; R3 = H or 1-6C alkyl; R4 = H, halo or NO2; A = phenyl opt. substd. by F, 1-4C alkyl, amino or CF3; 5-8C cycloalkyl; or heterocycle. Specifically, (I) has (2R, 4R) configuration in the piperidinyl moiety and (S) configuration in the central aminoacid moiety.

Description

The present invention relates to 5- (1H-imidazol-4-yl) -1-oxo-2- (phenylsulfonylamino) pentylpiperidine derivatives, their preparation and their therapeutic application.

dans laquelle
R1 représente soit un atome d'hydrogène, soit un groupe (C1-C4) aikyle, représente soit un atome d'hydrogène, soit un groupe (C1-C4)alkyle droit ou ramifié,
R3 représente soit un atome d'hydrogène, soit un groupe (C1-C6)alkyle droit ou ramifié,
RI représente soit un atome d'hydrogène, soit un atome d'halogène, soit un groupe nitro,
R5 représente soit un atome d'hydrogène, soit un groupe (Cl-C4)alkyle droit ou ramifié et
A représente soit un groupe phényle éventuellement substitué par un atome de fluor ou par un groupe choisi parai les groupes (Cl-C4)alkyle droit ou ramifié, amino et trifluorométhyle, soit un groupe cyclo(C5-C)alkyle, soit un hétérocycle, de préférence un groupe pyridinyle, thiényle, furyle, thiazolyle ou pyrimidyle.The compounds of the invention correspond to formula (I)

in which
R1 represents either a hydrogen atom or a (C1-C4) alkyl group, represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group,
R3 represents either a hydrogen atom or a straight or branched (C1-C6) alkyl group,
RI represents either a hydrogen atom, a halogen atom or a nitro group,
R5 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group and
A represents either a phenyl group optionally substituted by a fluorine atom or a group selected from (C 1 -C 4) straight or branched alkyl, amino and trifluoromethyl groups, or a C 5 -C 8 cycloalkyl group, or a heterocycle, preferably a pyridinyl, thienyl, furyl, thiazolyl or pyrimidyl group.

The compounds of the invention have 3 asymmetric centers depending on the meaning of the substituents.

The preferred configuration of the piperidinyl group is [2R, 4R].

est [S]. The configuration of the central acidic acid part

is S].

The compounds may exist as free bases or addition salts with pharmaceutically acceptable acids.

All these forms are part of the invention.

In the following schemes, the -CPh3 group represents the triphenylethyl group.

According to the invention, the compounds of formula (I) in which A represents either a phenyl group optionally substituted by a fluorine atom or by a group chosen from the straight or branched (C-C 4) alkyl, amino and trifluoromethyl groups, or a heterocycle can be synthesized according to scheme 1.

A boronic derivative of formula (II) is condensed (in which A represents either a phenyl group optionally substituted by a fluorine atom or a chosen group from the straight or branched (C1-C4) alkyl, nitro and trifluoromethyl groups, or a heterocycle) with a derivative of formula (III) (wherein R 'represents a halogen atom), in the presence of a catalyst such as tetrakis (triphenylphosphine) palladium (0) and a base conne for example sodium carbonate or triethylarine, in a protic or aprotic solvent (such as, for example, 1,2-disethoxyethane), to form a compound of formula (IV).

Then,
pathway A: either the compound of formula (IV) is reacted with sulfuryl chloride in the presence of triphenylphosphine or with dichlorotriphenylphosphorane in a solvent
Diagram 1

<tb><SEP> -B (OH) 2 <SEP> m
<tb><SEP> y
<tb><SEP> 4
<tb><SEP> B30H <SEP> 3
<tb><SEP> Flight <SEP> a
<tb> PATH <SEP> Ir <SEP> lrSa <SEP> JDSH
<tb> VOlA <SEP>
<tb><SEP> lllIB <SEP> E
<tb><SEP> AT
<tb><SEP> (VII)
<tb><SEP> oR
<tb><SEP><vur)
<tb><SEP> a
<tb><SEP> It <SEP> I
<tb><SEP> CPh3
<tb><SEP> Mo%
<tb><SEP>("t>
<tb><SEP> P1 <SEP> 1
<tb><SEP> cPh
<tb><SEP> Rs
aprotic such as for example dichloromethane in the presence of a base such as tributylanine and there is obtained a sulfonyl chloride of formula (VII) (in which R represents a hydrogen atom and R 'is equal to R 6) ,
pathway B: the compound of formula (IV) is subjected to hydrogenolysis and a compound of formula (V) is obtained from which a sulphonyl chloride of formula (VII) (in which R 3 and R 4 represent an atom) is prepared; of hydrogen), according to the method described above, or on which is reacted (route C) an aldehyde RCHO (where R represents a group (C1-4) straight or branched alkyl) in an acid medium, in the presence of cyanoborohydride of sodium and there is obtained a compound of formula (VI) from which a sulphonyl chloride of formula (VII) (wherein R3 represents a straight or branched (C1-C6) alkyl group and R4 a hydrogen atom) is prepared) using dichlorotriphenylphosphorane according to the method described above,
- D route: either the compound of formula (IV) is reacted with an aldehyde RCHO (where R represents a (C1-C6) straight or branched alkyl group) in an acidic medium, in the presence of sodium cyanoborohydride, and a compound is obtained of formula (VIa) from which is prepared a sulfonyl chloride of formula (VII) (wherein R3 represents a straight or branched (C1-4) alkyl group and R4 is equal to R *), using dichlorotriphenylphosphorane, according to the method described previously.

Then the compound of formula (VII) thus obtained is coupled with the hydrochloride of the amine of formula (VIII) (in which R 1 represents a hydrogen atom or a (C 5 -C 4) alkyl group, R 2 represents a group (C 1) -C4) straight or branched alkyl and R5 represents either a hydrogen atom or a (C1-C4) straight or branched alkyl group) in an aprotic solvent such as dichloromethane in the presence of a base such as triethylamine, to obtain the compound of formula (IX), the imidazole group being deprotected by the action of trifluoroacetic acid in the presence of anisole in an aprotic solvent such as, for example, dichloroethane or in a mixture of acetic acid: tetrahydrofuran: water under reflux, and a compound of formula (I) (wherein R2 represents a straight or branched (C1-C4) alkyl group.

In the case where it is desired to obtain a compound of Formula (I) in which R 'represents a hydrogen atom, then a saponification of the corresponding compound of formula (I) (in which R2 represents a group (C1- C6) alkyl) under standard conditions known to those skilled in the art.

The compounds of formula (I) in which R 'represents a nitro group are synthesized according to Scheme 1 (route A) from 2-amino-3-iodo-5-nitrobenzenesulfonic acid.

The compounds of formula (I) in which A represents an amino-substituted phenyl group are synthesized from the corresponding compounds of formula (I) in which A represents a phenyl group substituted by a nitro group, by reduction of the nitro group by ammonium forniate in the presence of palladium on carbon as a catalyst.

To obtain the compounds of formula (I) (wherein A represents a cyclo (C 5 -C 8) alkyl group and R 'a hydrogen atom), a compound of formula (III) (in which R 6 represents an atom) is reacted. halogen) with the corresponding cyclo (C 5 -C 8) alkenyl to form a compound of formula (IV) (wherein A represents a cyclo (C 5 -C 8) alkenyl group and R 'a halogen atom), a compound which is hydrogenolyzed to obtain a compound of formula (V) (wherein A represents a cyclo (C 5 -C 8) alkyl group and R 4 represents a hydrogen atom) and then a sulphuryl chloride of formula (VII) (in which A represents a cyclo (C 5 -C 8) alkyl group and R 'represents a hydrogen atom), or RCHO aldehyde is reacted (where
R represents a straight or branched (C1-C6) alkyl group) in an acidic medium, in the presence of sodium cyanoborohydride, and a compound of formula (VI) is obtained from which a sulphonyl chloride of formula (VII) (in which R, represents a straight or branched (C1-C6) alkyl group and R 'a hydrogen atom) using dichlorotriphenylphosphorane according to the method described previously.

Another variant of the process, to obtain the compounds of formula (Ia) (in which A represents either a phenyl group optionally substituted by a fluorine atom or a group chosen from the groups (C1-C4) straight or branched alkyl, amino and trifluoromethyl, a heterocycle and R, represents a hydrogen atom) is illustrated in Scheme 2.

The compound of formula (III) (wherein R6 represents a halogen atom) is reacted with sulfuryl chloride in the presence of triphenylphosphine or with dichlorotriphenylphosphorane in the presence of a base such as tributylanine, in an aprotic solvent such as for example dichlorosethane and a sulfonyl chloride of formula (X) is obtained which is reacted with the hydrochloride of the amine of formula (XI) (in which R 1 represents either a hydrogen atom or a (C -C 4) alkyl) in the presence of a base such as triethylamine in an aprotic solvent such as dichloromethane at a temperature of 0 OC to form a compound of formula (XII) which is reacted with a tributylstanned derivative of Formula ASnBu, (wherein A represents either a phenyl group optionally substituted with a fluorine atom or a group selected from straight or branched (C1-C4) alkyl, nitro and trifluoromethyl, or a heterocyclic group; e) and a compound of formula (XIII) (wherein R 'is equal to R6) is obtained which is hydrolyzed thereby obtaining an acid of formula (XIV) which is reacted with a piperidine of formula (XV) ) (wherein R 1 represents a straight or branched (C 1 -C 4) alkyl group and R 1 represents either a hydrogen atom or a straight or branched (C 1 -C 4) alkyl group) to form a compound of formula (XVI ) of which the imidazole group is deprotected to obtain the compound of formula (Ia).

The compounds of formula (Ia) in which R4 represents a hydrogen atom can be obtained by hydrogenation of the corresponding compounds of formula (Ia) in which R4
Figure 2

représente un atome d'halogène.Figure 2 (continued)

represents a halogen atom.

In the case where it is desired to obtain a compound of formula (Ia) in which R represents a hydrogen atom, then a saponification of the corresponding compound of formula (Ia) (in which R, represents a group (C1 -C4) straight or branched alkyl) under standard conditions known to those skilled in the art.

In the case where it is desired to obtain a compound of formula (Ia) in which A represents a phenyl group substituted with a lino group, the corresponding compound of formula (Ia) in which A represents a phenyl group substituted by a group is treated. nitro by ammonium forniate in the presence of palladium on charcoal catalyst glue to reduce the nitro group.

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

Thus, the derivatives of formula (IV) in which A represents a (C 5 -C 8) cycloalkyl group are prepared from the corresponding cyclo (C 5 -C 8) alkenyl derivatives described by US Pat.
RC Larock et al. in Tetrahedron Letters, (1989), 30, 2603-2606.

The method of preparation of the other compounds of formula (IV) is similar to that described by V. Snieckus et al. in
Tetrahedron Letters, (1987), 28, 5097.

The preparation of the compounds of formulas (VII) and (X) in which R 3 represents a hydrogen atom is carried out according to the method of TS Widlanski et al. described in
Tetrahedron Letters, (1992), 33, 2657-2660.

The preparation of the compounds of formulas (VII) and (X) in which R represents a (CC *) alkyl group is described in the French patent application filed today and entitled "Sulphonyl chloride, their preparation and their use as synthesis intermediaries ".

2-Amino-5-nitro-3-iodobenzenesulfonic acid is prepared from 2-amino-5-nitro-3-benzenesulfonic acid according to the method described by Boyle et al. in J. Chien. Soc., (1919), 119, 1505.

The compounds of formula (VIII) are described in European Patent Application No. EP 94401963.7.

(S) - α-amino-1- (triphenylmethyl) -1H-imidazole-4-pentanoate hydrochloride of 1,1-dimethylethylethyl and (S) -α-amino-2-methyl-1- (triphenylmethyl) 1, 1-dimethylethylethyl-1H-imidazole-4-pentanoate (compounds of formula (XI)) are described in the European patent application
EP 0565396.

The piperidines of formula (XV) in which R 1 represents a hydrogen atom or an ethyl group are described in the form of bases in the European patent EP 0008746.

The following examples illustrate the preparation of certain compounds according to the invention.

The microanalyses and the IR and NMR spectra confirm the structure of the compounds obtained.

The numbers of the compounds exemplified refer to those of the table given below which illustrates the chemical structures and the physical properties of some compounds according to the invention.
Example 1 (Compound No. 2) [2R- [1 (S), 2α, 4ss]] - 1- [2 - [[(2-Amino [1,1'biphenyl] -3-yl) sulfonyl Chloride] amino] -5- (1H-imidazol-4 (5) -yl) -10 oxopentyl] -4-methylpiperidine-2-carboxylic acid ethyl ester
1.1. [2R- [1 (S), 2 &alpha; 4ss]] - 1- [2 - [[(2-Amino [1,1'-biphenyl] -3-yl) sulfonyl] amino] -1-oxo-5-t 1- (triphenylmethyl) -1g-;
imidazol-4-yl] pentyl] -4-methylpiperidine-2-carboxylate
ethyl
1.1.1. 2-amino [1,1'-biphenyl] -3-sulfonyl chloride
1.1.1.1. 2-amino [1,1'-biphenyl] -3-sulfonic acid
1.1.1.1.1. 2-amino-5-bromo [1,1'-biphenyl] -3-acid
sulfonic
at. 2-amino-5-bromobenzenesulfonic acid
A mixture containing 31 g (180 mmol) of 4-bromoaniline and 9.7 g (220 mmol) of sulfuric acid in 200 μl of 1,2-dichlorobenzene is heated at 180 ° C. for 6 hours. The reaction medium is allowed to cool to ambient temperature and then filtered. The residue is washed with dichloromethane.

45 g of product are obtained which is used as it is in the next step.

Melting point => 240 OC
Yield = 97%
b. 2-amino-5-bromo-3-iodobenzenesulfonic acid
45 g (176 mmol) of 2-amino-5-bromobenzenesulfonic acid are added 46 g (282 mmol) of iodine chloride, 400 μl of an aqueous solution of 1 N hydrochloric acid and 400 ml of methanol. The mixture is heated at 90 ° C. for 18 hours, concentrated under reduced pressure and the residue is crystallized from ethanol.

41 g of product are obtained which is used as it is in the next step.

Melting point = 240 C (decomposition)
Yield = 62%
c. 2-amino-5-bromo [1,1'-biphenyl] -3-acid
sulfonic
To a mixture of 37.8 g (100 mmol) of 2-amino-5-bromo-3-iodobenzenesulfonic acid and 32 g (300 mmol) of sodium carbonate in 300 ml of 1,2-dimethoxyethane and 150 ml of 5.8 g (5 mmol) of tetrakis (triphenylphosphine) palladium (0) and 19.5 g (160 mmol) of benzeneboronic acid are added successively under a nitrogen atmosphere. The mixture is heated at reflux temperature for 4 hours and then the reaction medium is concentrated under reduced pressure. The residue is purified by RP 18 reversed phase column chromatography, eluting with an acetonitrile: water (2: 8) mixture. Next, it is dissolved in a mixture containing 300 ml of methanol, 300 ml of 0.1 N hydrochloric acid and 16 ml of 95% sulfuric acid, concentrated to 100 ml under reduced pressure and filtered.

20 g of product are obtained.

Yield = 60%
Melting point = 197.5 OC
1.1.1.1.2. 2-amino [1, 1-biphenyl] -3-acid
sulfonic
20 g (61 mmol) of 2-amino-5-bromo [1,1'-biphenyl] -3-sulfonic acid are placed in a Parr apparatus in the presence of 3 g of 10% palladium on carbon in a mixture. containing 40 ml of ethanol and 100 ml of acetic acid. The reaction medium is heated to 50 ° C. under a pressure of 50 psi (0.35 MPa), filtered through Celite and the filtrate is concentrated under reduced pressure. The residue is recrystallized from an ethanol: pentane mixture.

10 g of product are obtained.

Yield = 66%
Melting point = 241.5 ° C
1.1.1.2. 2-amino chloride [1,1'-biphenyl] -3-
sulfonyl
To a solution of 4.95 g (18.9 mmol) of triphenylphosphine in 20 ml of dichloromethane, 1.44 ml (18 mmol) of sulfuryl chloride are added dropwise at 0 ° C. under a nitrogen atmosphere. The reaction medium is left stirring for 10 minutes at 0 ° C., then a solution containing 2.24 g (9 mmol) of 2-amino [1,1'-biphenyl] -3-sulfonic acid and 2 ml of toluene is added over a period of 5 minutes. 14 ml (9 mmol) of tributylamine in 9 ml of dichloromethane. The mixture is brought to room temperature, is stirred at this temperature for 3 hours and is purified by chromatography on a column of silica gel. eluting with a pentane mixture: dichloromethane (8: 2).

1.9 g of product are obtained in the form of a yellow oil.

Yield = 80%
1.1.2. (2R- (1 (S), 2a, 4ss]] - 1- [2 - [[(2-amino [1,1'-biphenyl] -3-yl) sulfonyl] amino] -1-oxo-5- TL (triphenyl
methyl) -1H-imidazol-4-yl] pentyl] -4-methylpiperidine-2
ethyl carboxylate
To a suspension of 1.8 g (3 mmol) of [2R- [1 (S), 2α], 4ss]]] - 1 - [2-amino-1-oxo-5- [1- (triphenylmethyl) hydrochloride. ethyl (1H-imidazol-4-yl) pentyl] -4-methylpiperidine-2-carboxylate and 9.2 ml (6.6 mmol) of triethylamine in 12 ml of dichloromethane are added dropwise to 0 ° C under a nitrogen atmosphere, 0.88 g (3.3 mmol) of 2-amino [1,1'-biphenyl] -3-sulfonyl chloride dissolved in 3 ml of dichloromethane. The reaction medium is left stirring at this temperature for 6 hours and then it is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane (1:99) mixture.

2 g of product are obtained.

Yield = 83%
Melting point = 66 ° C
1.2. (2R- (1 (S), 2a, 4ss]] - 1- [2 - [[(2-) hydrochloride
amino [1-biphenyl] -3-yl) sulfonyl] amino] -5- (1H-imidazol
4 (5) -yl) -1-oxopentyl] -4-methylpiperidine-2-carboxylate
ethyl
To a solution of 0.398 g (0.5 mmol) of (2R- (1 (S), 2a, 48)] - 1- [2 - [[(2-amino [1, 1-biphenyl] -3- yl) sulfonyl] amino] -1-oxo-5 [1- (triphenylmethyl) -1H-imidazol-4-yl] pentyl] -4-methylpiperidine-2-carboxylate and 0.16 g (1.5 mmol) of anisole in 15.5 l of dichloromethane, 1.5 l of trifluoroacetic acid are added dropwise at 0 ° C. Then the temperature of the mixture is allowed to rise to room temperature, and the mixture is stirred for 7 hours at room temperature. this temperature and concentrated under reduced pressure. The residue is taken up in 50 ml of ethyl acetate, treated with 50 ml of a saturated solution of sodium hydrogencarbonate, dried over magnesium sulphate and concentrated under reduced pressure The last residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95).

0.24 g of product is obtained in base form.

The hydrochloride is prepared by placing 0.24 g (0.4 mmol) of base in 5 ml of a solution of isopropanol in 0.1 N hydrochloric acid and evaporating under reduced pressure.

0.24 g of product is obtained in hydrochloride form.

Melting point = 108 C [+]; D20 = 97.5 (c = 0.2; methanol)
Yield = 79%
Example 2 (Compound No. 9) E2R-El (S), 2a, 4ss]] - 1- [2 - [[(2,3'-diamino [[1,1'-biphenyl] -3-yl) hydrochloride ethyl sulfonyl] amino] -5- (1H-imidazol-4 (5) yl) -1-oxopentyl] -4-methylpiperidine-2-carboxylate
2.1. 2-amino-5-bromo-3'-nitro [1,1'-biphenyl] chloride -
3-sulfonyl chloride
2.1.1. 2-amino-5-bromo-3'-nitro [1,1'-biphenyl] -3-acid
sulfonic
To a solution of 1.9 g (5 mmol) of 2-amino-5-bromo-3iodobenzenesulfonic acid and 1.6 g (15 mmol) of sodium carbonate in 25 ml of 1,2-dimethoxyethane and 12, 5 ml of water, 0.231 g (0.2 mmol) of tetrakis (triphenylphosphine) palladium (0) and 1.42 g (8.5 mmol) of 3-nitrobenzeneboronic acid are added successively under a nitrogen atmosphere. . The reaction medium is heated for 2 hours at 70 ° C. and concentrated under reduced pressure. The residue thus obtained is purified by reversed phase column chromatography.
RP 18 eluting with acetonitrile: water (1: 9).

1.5 g of compound are obtained in the form of sodium sulphonate.

The acid is prepared by crystallization of 1.5 g of sodium sulfonate in 0.3 ml of a methanol mixture: 1N hydrochloric acid and sulfuric acid.

1.3 g of product are obtained.

Yield = 70 S
Melting point = 230 OC
2.1.2. 2-amino-5-bromo-3'-nitro chloride [1,1'-
biphenyl] -3-sulphonyl chloride
To a solution of 1.21 g (4.6 mmol) of triphenylphosphine in 2.3 ml of dichloromethane is added dropwise,
OC under a nitrogen atmosphere, 0.35 μl (4.4 mmol) of sulfuryl chloride. The reaction medium is left stirring for 10 minutes at 0 ° C., then a solution containing 0.82 g (2.2 noles) of 2-amino-5-bromo-3'-nitro [1] acid is added over 5 minutes. 1'-biphenyl] -3-sulfonic acid and 0.52 ml (2.2 mmol) of tributylanine in 2.2 ml of dichloromethane. The mixture is brought to room temperature and is stirred at this temperature for 3 hours. and purified on silica gel column chromatography eluting with dichloromethane.

0.46 g of product is obtained.

Yield = 54%
2.2 [2R- [1 (S), 2α, 4ss]] - 1- [2 - [[(2-amino-5-bromo-3 '
nitro [1,1'-biphenyl] -3-yl) sulfonyl] amino] -1-oxo-5- [1
(Triphenylmethyl) -1H-imidazol-4-yl] pentyl] -4-methyl
ethyl piperidine-2-carboxylate
To a mixture of 0.62 g (1 mmol) of t2R- [1 (S), 2α], 4ss]]] - 1- [2-amino-1-oxo-5- [1- (triphenylmethyl) hydrochloride) ) Ethyl 1-imidazol-4-yl] pentyl] -4-methylpiperidine-2-carboxylate and 0.32 ml (2.3 mmol) of triethylamine in 2 ml of dichloromethane are added dropwise at 0 ° C. under a nitrogen atmosphere, 0.46 g (1.1 mmol) of 2-amino-5-bromo-3'-nitro [1,1'-biphenyl] -3-sulphonyl chloride in solution in 1 ml of dichloromethane . The reaction mixture is left stirring at this temperature for 6 hours and then concentrated under reduced pressure. The residue thus obtained is purified by column chromatography on silica gel, eluting with a methanol / dichloromethane mixture (1: 99).

0.79 g of product is obtained.

Melting point = 103 OC [&alpha;] D20 = = + 44 (c = 0.2; methanol)
Yield = 82%
2.3. [2R- [1 (S), 2 &alpha;, 4ss]] - 1 - [2 - [[(2-amino-5-bromo
3'-nitro [1,1'-biphenyl] -3-yl) sulfonyl] amino] -5- (1H-imidazol-4 (5) -yl) -1-oxopentyl] -4-ethylpiperidine-2
ethyl carboxylate
0.71 g (0.76 mmol) of E2R-E1 (S), 2a, 4ssl]] - 1 - [2 - [[(2-amino-5-bromine) was heated for 1 hour at reflux temperature. 3'-nitro (1,1'-biphenyl) -3-yl) sulfonyl] amino] -1-oxo-5- [1 (triphenylmethyl) -1H-imidazol-4-yl] pentyl] -4-methylpiperidine-2 ethyl carboxylate in a mixture of 4 μl of acetic acid, 5 μl of tetrahydrofuran and 1 μl of water and then concentrated under reduced pressure. The residue is taken up in 50 ml of ethyl acetate and treated with 50 ml of ethyl acetate. It is saturated with sodium hydrogencarbonate and then dried over magnesium sulphate.The residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95).

0.47 g of product is obtained.

Yield = 88 t
Melting point = 87 OC [&alpha;] D20 = + 56 e (c = 0.2; methanol)
2.4. E2R-El (S) hydrochloride, 2a, 4811-1-E2-EE (2,3'-
diamino [[1,1'-biphenyl) -3-yl) sulfonyl] amino] -5- (1 H
imidazol-4-yl) -1-oxopentyl] -4-methylpiperidine-2
ethyl carboxylate
To a solution of 0.52 g (0.76 mmol) of [2R- [1 [(S), 2a, 48]] - [[2 - [[(2-amino-5-bromo-3'-nitro [ 1,1'-biphenyl-3-yl) sulfonyl] amino] -5- (1H-imidazol-4-yl) -1-oxopentyl] -4-methylpiperidine-2-carboxylate ethyl in 10 ml of methanol, 0.96 is added successively. g (15.2 mmol) ammonium formate and 0.11 g palladium on charcoal at 10 t. The reaction medium is heated at reflux temperature for 4 hours and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95).

0.38 g of product is isolated in base form.

The hydrochloride is prepared by placing 0.38 g of base in solution in 15 ml of isopropanol in 0.1 N hydrochloric acid and evaporating under reduced pressure.

Melting point = 145 ° C
Yield = 85 t [&alpha;] D20 = = + 139 (c = 0.2, methanol)
Example 3 (Compound No. 20) [2R- [1 (S), 2α], 4ss]] - 1- [5- (5-methyl-1H-imidazol-4-yl) -1-oxo-2H] hydrochloride Ethyl [[[2- (propylamino) [1,1'-biphenyl] -3-yl] sulfonyl] amino] pentyl] -4-methylpiperidine-2-carboxylate
3.1. E2R-E1 (S), 2a, 4ss]] - 4-methyl-1- [1-oxo-2 - [[2-
(propylamino) [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5
[5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] pentyl]
ethyl piperidine-2-carboxylate
3.1.1. 2- (propylamino) [1,1'-biphenyl] chloride -3-
sulfonyl
3.1.1.1. 2- (propylamino) [1,1'-biphenyl] -3-acid
sulfonic
To a solution containing 5 g (0.02 mol) of 2-amino-1- [1-biphenyl] -3-sulfonic acid, 3.6 ml (0.05 mol) of propanaldehyde and 3.28 g (0, 02 mole) of sodium acetate in 60 ml of water and 15 ml of acetic acid, a solution of 1.9 g (0.03 mole) of sodium cyanoborohydride in 15 ml of water is added dropwise. . The reaction mixture is left stirring for 3 hours at room temperature, concentrated and acidified with 80 ml of a 1N hydrochloric acid solution and 2 ml of a 95% sulfuric acid solution. The mixture is cooled to 0 ° C. and filtered.

5 g of product are obtained.

Yield = 85%
Melting point = 213.5 ° C
3.1.1.2. 2- (propylamino) [1,1'-biphenyl] chloride -
3-sulfonyl chloride
To a solution of 8.2 g (28 mmol) of 2- (propylamino) [1,1'-biphenyl] -3-sulfonic acid and 6.7 ml (28 mmol) of tributlyamine in 14 ml of dichloromethane, a solution of 16.95 g (42 mmol) of dichlorotriphenylphorane in 75 ml of dichloromethane is added dropwise at 0 ° C. under a nitrogen atmosphere. The reaction medium is brought to room temperature and is stirred at this temperature for 6 hours. Purified by column chromatography on fiorisile eluting with ether.

4.35 g of product are obtained.

Yield = 50%
3.1.2. [2R- [1 (S), 2a, 4ss]] - 4-methyl-1- [1-oxo-2 - [[2-
(propylamino) [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5- [5
methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] pentyl]
ethyl piperidine-2-carboxylate
To a mixture of 0.62 g (1 mmol) of t2R- [1 (S), 2α], 4ss]]] - 1 - [2-amino-1-oxo-5- [5-methyl] -hydroxybiphenyl) Ethyl 1- (triphenylmethyl) -1H-imidazol-4-yl] pentyl-4-methylpiperidine-2-carboxylate and 0.30 ml (2.2 mmol) of triethylamine in 2 ml of dichloromethane are added dropwise. dropwise, at 0 ° C. under a nitrogen atmosphere, 0.44 g (1.1 mmol) of 2- (propylamino) [1,1'-biphenyl] -3-sulphonyl chloride dissolved in 2 ml of dichloromethane. The reaction mixture is left stirring at this temperature for 6 hours and then concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with a methanol / dichloromethane (1:99) mixture.

0.69 g of product is obtained.

Yield = 80%
Melting point = 81.5 ° C [α] D 20 = = + 48.5 ° C (c = 0.2, methanol)
3.2. [2R- [1 (S), 2α, 4ss]] - 1- [5- (5-methyl) hydrochloride
1H-Imidazol-4-yl) -1-oxo-2 - [[[2- (propylamino)]] 1,1'-biphe
nyl] -3-yl] sulfonyl] amino] pentyl] -4-methylpiperidine-2
ethyl carboxylate
90 ° C., 0.43 g (0.5 mmol) of [2R- [1 (S), 2α, 4β]] -4-methyl-1- [1-oxo-2- are heated for 1 hour. [[[2- (Propylamino) [1,1'-biphenyl] -3-yl] sulfonyl] amino] -5- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] pentyl] piperidine-2- ethyl carboxylate dissolved in a mixture of 10 ml of acetic acid, 4 ml of tetrahydrofuran and 4 ml of water, and then concentrated under reduced pressure. The residue is treated with 50 ml of ethyl acetate and then with saturated sodium hydrogencarbonate solution, dried over magnesium sulphate and concentrated under reduced pressure. It is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95).

0.22 g of product is obtained in base form.

The hydrochloride is prepared by placing 0.22 g of base in solution in 6 ml of isopropanol in 1 N hydrochloric acid and evaporating under reduced pressure.

0.22 g of product is obtained in hydrochloride form.

Yield = 71%
Melting point = 150 OC [&alpha;] D20 = + 23 (c = 0.2; methanol)
Example 4 (Compound No. 26) E2R-E1 (S), 2a, 4ss]] - 1- [2 - [[[2-Amino-3- (pyridin-2-yl) phenyl] sulfonyl] amino hydrochloride Ethyl 5- (1H-imidazol-4 (5) -yl) 1-oxopentyl] -4-methylpiperidine-2-carboxylate
4.1. [2R- [1 (S), 2α, 4ss]] - 1- [2 - [[[2-amino-5-bromo-3 (pyridin-2-yl) phenyl] sulfonyl] amino] -1-oxo -5-TL
(Triphenylmethyl) -1H-imidazol-4-yl] pentyl] -4-methyl
ethyl piperidine-2-carboxylate
4.1.1. (S) - &alpha;; - [[(2-amino-5-bromo-3-iodophenyl) sulfonyl]
1,1-dimethylethyl amino-1- (triphenylmethyl) -1H-imidazole-4-pentanoate
4.1.1.1. 2-amino-5-bromo-3-iodobenzene chloride
sulfonyl
To a solution containing 7.6 g (20 mmol) of 2-amino-5-bromo-3-iodobenzenesulfonic acid and 4.8 ml (20 mmol) of tributylamine in 20 ml of dichloromethane is added dropwise at 0 ° C. nitrogen atmosphere a solution of dichlorotriphenylphosphorane (9.7 g (37.5 mmol) in 45 ml of dichloromethane). The mixture is brought to room temperature, the stirring is continued for 8 hours and purified by chromatography on a column of silica gel, eluting with a dichloromethane: pentane (2: 8) mixture.

6 g of product are obtained which is used as it is in the next step.

Yield = 75%
4.1.1.2. (S) - &alpha; - [[(2-amino-5-bromo-3-iodophenyl)
sulfonyl] amino] -1- (triphenylmethyl) -1H-imidazol-4
1,1-dimethylethyl pentanoate
To a solution containing 7.8 g (15 mmol) of 1,1-dimethylethyl (S) -α-amino-1- (triphenyl-ethyl) -1H-isidazole-4-pentanoate hydrochloride and 4.6 ml (33 mmol) ) of triethylamine in 100 ml of dichloromethane is added dropwise to
Under a nitrogen atmosphere a solution of 6 g (15 mmol) of 2-amino-5-bromo-3-iodobenzene sulfonyl chloride in 10 ml of dichloromethane. Stirring is maintained at this temperature for 6 hours and then the reaction medium is concentrated under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane (1:99) mixture.

10.2 g of product are obtained which is used as such in the next step.

Yield = 80%
4.1.2. (S) - &alpha; - [[[2-amino-5-bromo-3- (pyridin-2-yl) phenyl]
sulfonyl] amino] -1- (triphenylmethyl) -1H-imidazol-4
1,1-dimethylethyl pentanoate
To a suspension of (S) -a - (((2-amino-5-bromo-3-iodophenyl) sulfonyl] amino] -1- (triphenylsethyl) -1H-imidazole-4, 2.52 g (3 mmol) 1,1-dimethylethylpentanoate in 12 ml of dry toluene is added successively, at room temperature and under a nitrogen atmosphere, 0.17 g (0.15 nil) of tetrakis (triphenylphosphine) palladium (0) and 1 76 g (4.8 mmol) of 2- (tributylstannyl) pyridine The mixture is heated at the reflux temperature for 7 hours and then concentrated under reduced pressure The residue obtained is purified by chromatography on a column of silica gel. eluting with methanol: dichloromethane (1:99).

1.7 g of product are obtained which is used as it is in the next step.

Yield = 72% [&alpha;] D20 = +46 O (c = 0.2; methanol)
4.1.3. (S) -a - [[[2-amino-5-bromo-3- (pyridin-2-yl)) acid
phenyl] sulfonyl] amino] -1- (triphenylmethyl) -1H-imidazole
4-pentanoic acid
At 0 ° C. and protected from humidity, a solution of 2.2 g (2.82 mmol) of (S) -α- [[[2-amino-5)) is saturated with gaseous hydrochloric acid for 10 minutes. 1,1-Dimethylethyl-bromo-3- (pyridin-2-yl) phenyl] sulfonyl] amino] -1- (triphenylmethyl) -1H-imidazole-4-pentanoate in 250 ml of benzene.

After stirring for 2 hours at 0 ° C., the reaction medium is concentrated under reduced pressure and then the residue is taken up in 50 ml of dichloromethane, neutralized with gaseous ammonia and concentrated again under reduced pressure. The residue thus obtained is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane (1:99) mixture.

1.73 g of product are obtained which is used as it is in the next step.

Yield = 85%
Melting point = 95-105 OC [ai20 = + 58 o (c = 0.2, methanol)
4.2. [2R- [1 (S), 2a, 4ss]] - 1- [2 - [[[2-amino-5-bromo-3- (pyridin-2-yl) phenyl] sulfonyl] amino] -1-oxo -5- [1- (triphenyl
nylméthyl) imidazol-4 (5) -yl] pentyl] -4-methylpiperidine
2-ethyl carboxylate
To a solution of 1.51 g (2.1 mmol) of (S) -a - [[[2-amino-5-bromo-3- (pyridin-2-yl) phenyl] sulfonyl] amino] -1 acid ( triphenylmethyl) -1H-imidazole-4-pentanoic acid in 4 ml of dichloromethane, 0.32 g (2.1 mmol) of ethyl (2R-trans) -4-methylpiperidine-2-carboxylate trifluoroacetate and 0, 93 g (2.1 mmol) of (benzo-triazol-1-yl) oxy [tris (dimethylamino)] phosphonium hexafluorophosphate. The reaction mixture is left stirring, 0.69 ml (6.3 mmol) of 4-methylmorpholine are added and stirring is continued for 18 hours at room temperature. The reaction medium is washed with 4 ml of saturated sodium chloride solution, dried and concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloro-methane mixture (2:98).

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

Melting point = 92 ° C
Yield = 25% [&alpha;] D20 = + 30 (c = 0.2; methanol)
4.3. (2R- (1 (S), 2a, 4B]] - 1- [2 - [[(2-amino-5-bromo-3- (pyridin-2-yl) phenyl] sulfonyl] amino] -5- ( LE-imidazole-4 (5) -
yl) -1-oxopentyl] -4-methylpiperidine-2-ethyl carboxylate
A solution of 0.45 g (0.506 mmol) of [2R- [1 (S), 2a, 4ss]] - 1- [2- [[[2-amino-5]) is heated for 1 hour at reflux temperature. Ethyl-bromo-3- (pyridin-2-yl) phenyl] sulfonyl] amino] -1-oxo-5- [1- (triphenylmethyl) -1H-imidazol-4-pentyl] -4-methylpiperidine-2-carboxylate in a mixture containing 4 ml of acetic acid, 5 ml of tetrahydrofuran and 1 ml of water and then concentrated under reduced pressure. The residue is taken up in 50 ml of ethyl acetate, treated with 50 ml of a solution of saturated with sodium hydrogencarbonate and dried over magnesium sulfate. The residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane mixture (5:95).

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

Yield = 85%
Melting point = 82 C [a] 20 = + 46.5 O (c = 0.2; methanol)
4.4. [2R- [1 (S), 2a, 4ss]] - 1- [2 - [[[2-) hydrochloride
amino-3-pyridin-2-yl) phenyl] sulfonyl] amino] -5- (1H-imidazol-4 (5) -yl) -1-oxopentyl] -4-methylpiperidine-2-
ethyl carboxylate
To a solution of 0.227 g (0.43 mmol) of [2R-tl (S), 2a, 4B]] - 1 - [2 - [[[2-amino-5-bromo-3- (pyridin-2 yl) phenyl] sulfonyl] amino] -5- (1H-imidazol-4-yl) -1-oxopentyl] -4-methylpiperidine-2-carboxylic acid ethyl ester in 4 ml of methanol, 0.54 is added successively. g (8.6 mmol) of ammonium formate and 0.05 g of 10% palladium on carbon. The mixture is brought to the reflux temperature for 5 hours and then concentrated under reduced pressure. The residue is purified by chromatography on a column of silica gel, eluting with a methanol: dichloromethane (1: 9) mixture.

0.2 g of product is obtained in base form.

The hydrochloride is prepared by dissolving 0.2 g of base in 7 ml of isopropanol dissolved in u N hydrochloric acid and evaporating under reduced pressure.

0.2 g of product is obtained in hydrochloride form.

Yield = 82%
Melting point = 105 C [a] - = + 123 (c = 0.2; methanol)
Example 5 (Compound No. 27) [2R- [1 (S), 2α, 4ss]] - 1- [2 - [[[2-amino-3- (pyridin-2-yl) phenyl] hydrochloride sulfonyl) amino) -5- (1H-imidazol 4 (5) -yl) -1-oxopentyl] -4-methylpiperidine-2-carboxylic acid
0.25 g (0.44 mmol) of [2R- [1 (S), 2a, 4ss]] - 1- [2 - [[[2-amino-3-pyridin-2-yl] phenyl] sulfonyl ] amino] -5- (1H-imidazol4 (5) -yl) -1-oxopentyl] -4-methylpiperidine-2-carboxylic acid ethyl ester in solution in 0.88 ml of ethanol is added 0.88 ml of 0.1N aqueous sodium hydroxide solution and the mixture is left stirring for 24 hours at room temperature. The reaction medium is neutralized with 18 ml of a solution of isopropanol in 0.1 N hydrochloric acid and concentrated under reduced pressure. The residue thus obtained is purified by reverse phase column chromatography RP 18, eluting with acetonitrile: water (1: 1).

0.13 g of product is obtained in hydrochloride form.

Yield = 50%
Melting point = 132 C t] 20 = + 54 O (c = 0.2; methanol)
Legend of the table
in the column "Salt": "chlor." represents a
hydrochloride in column ""[&alpha;] D20 w: corresponds to c = 0.075;
Methanol Table

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<tb> 2 <SEP> C <SEP> -C2H5 <SEP> -H <SEP> -H <SEP> -CH3 <SEP> SE <CH>. <SEP> 108 <SEP>, <SEP> 97, 5
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<tb><SEP> 7 <SEP> U <SEP> QHs <SEP> U <SEP> U <SEP> -CH3 <SEP> chlor. <SEP> U <SEP> U <SEP> 127
<tb><SEP> H2N
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<tb><SEP> (c = 0.2 <SEP>;<SEP> ethanol
<tb><SEP> 10 <SEP> -H <SEP> -C2H5 <SEP> -H <SEP> -H <SEP> -CH3 <SEP> to H2 <SEP> chior. <SEP> 138 <SEP> + <SEP> 124
<tb><SEP> li <SEP> -H <SEP> -H <SEP> -H <SEP> -H <SEP> -CH3 <SEP> [NH2 <SEP> chlor. <SEP> 155 <SEP> + <SEP> 132.5
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<tb><SEP> 14 <SEP> -H <SEP> -H <SEP> -CH3 <SEP> -H <SEP> -CH3 <SEP> [To <SEP> chlor. <SEP> 140 <SEP> + <SEP> 163
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<tb><SEP> u
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<tb><SEP> 21 <SEP> -H <SEP> -C2H5 <SEP> - (CH2) 4CH3 <SEP> -H <SEP> -CH3 <SEP> to <SEP> chior. <SEP> 45 <SEP> + <SEP> 121
<tb><SEP> o <SEP> u <SEP> u <SEP> u <SEP> u <SEP> u <SEP> o
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<tb> gr: <SEP> Y <SEP> Y <SEP> a <SEP> = N <SEP> ~ <SEP> =
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<Tb>
The compounds of the invention were tested for thrombin and trypsin in vitro in the following tests.

1. Precipitation of human fibrinogen by bovine thrombin.

The test compound or its carrier (10 1) is incubated for 2 minutes at 370 ° C. in a solution of human fibrinogen (200 μl, 2 mg / ml in physiological saline).

Then, 200 ul of bovine thrombin dissolved in distilled water is added. The final concentration of thrombin is 0.5 NIH units / ml. The formation time, expressed in seconds, of a visible fibrin network is shaken and noted. Inhibition of fibrinoformation is quantified by calculating the concentration of compound which increases the precipitation time by 100% (CA 3).

2. Precipitation of human fibrinogen by human thrombin.

The test compound or its carrier (10 μl) is incubated for 2 minutes at 37 ° C in a solution of human fibrinogen (200 μl, 2 mg / ml in saline).

Then, 200 L of human thrombin dissolved in distilled water is added. The final concentration of thrombin is 2 NIH units / ml. The formation time, expressed in seconds, of a visible fibrin network is shaken and noted. Inhibition of fibrinoformation is quantified by calculating the concentration of compound which increases the precipitation time by 100% (CA1).

3. Coagulation of rat plasma with bovine thrombin.

Male CD rats, weighing 150 to 200 g, were anesthetized with nembutal (60 mg / kg, 0.1 ml / kg). Blood is collected from 3.8% trisodium citrate (1 vol / 9 vol of blood) from the retro-orbital sinus. The plasma is prepared by centrifugation at 3600 g for 15 minutes at room temperature. The test compound or its vehicle (10 1) is incubated with 200 μl of plasma at 37 ° C. for 2 minutes before the addition of 200 μl of a bovine thrombin solution. The final thrombin concentration is 0.75 NIH units / ml. Note the coagulation time, expressed in seconds.

Inhibition of thrombin is quantified by calculating the concentration which increases the coagulation time by 100% (CA 3).

4. Rabbit clusters aggregation induced by human thrombin.

The blood is collected by cardiac puncture on trisodium citrate at 3.8% (1 vol / 9 vol of blood). It is centrifuged at 250 g for 10 minutes. The platelet rich plasma (P3P) thus obtained is removed and the platelet count is carried out.

To P3P, 2 ng / ml of prostacyclin in solution was added in ice cold pH 9.0 tris buffer. It is centrifuged at 110 g for 10 minutes and decanted. Prostacyclin, in solution in 50 mM sodium hydroxide at pH 12, is added again so as to have a final concentration of 200 ng / ml. The P3P is again centrifuged at 800 g for 10 minutes. The platelet-poor plasma is removed and the pellet suspended in a tyroid volume containing 200 ng / ml prostacyclin, a volume equal to the initial volume of
P3P. This suspension is centrifuged at 800 g for 10 minutes. It is repeated a second time and under the same conditions, the suspension of the pellet and centrifugation. The final pellet is resuspended in a tyrode solution without prostacyclin and allowed to stand for 2 hours to allow complete elimination of the prostacyclin. The aggregation of these platelets with human thrombin at the final concentration of 0.3 NIH units / ml. The optical density variations are recorded by means of a 4-channel aggregometer. The test compound or its carrier is added to the platelet suspension (maximum added volume of 3 L), 2 minutes before the addition of thrombin. The concentration which inhibits aggregation by 50% (CI) is determined.

In parallel, the compounds of the invention have been tested with respect to the coagulation of ex-vivo rat plasma.

Animals are treated with the test compound or with its vehicle, i.v., orally or subcutaneously, prior to collection of blood. The thrombin time is measured as described in 3.

The compounds of the invention are thrombin inhibitors with CAs and CIS ranging from 104 to 100 M.

They inhibit coagulation of rat plasma at doses of 0.1 to 5 mg / kg i.v. and are also active orally and subcutaneously.

The compounds of the invention may be useful in all clinical indications related to thrombosis or in those where thrombotic complications could occur.

For this purpose they may be presented in any form suitable for oral, parenteral or intravenous administration, such as tablets, dragees, capsules, capsules, suspensions or oral or injectable solutions, etc. in combination with suitable excipients, and dosed to allow administration of 1 to 1000 mg per day and per patient, in one or more doses.

Claims (7)

claims 1. Compounds corresponding to formula (I)

 in which R1 represents either a hydrogen atom or a (C1-C4) alkyl group, R2 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group, R3 represents either a hydrogen atom or a straight or branched (C 1 -C 6) alkyl group, R4 represents either a hydrogen atom, a halogen atom or a nitro group, R5 represents either a hydrogen atom or a (C1-C4) straight or branched alkyl group and A represents either a phenyl group optionally substituted by a fluorine atom or a group selected from the group (C1-C4) straight or branched alkyl, amino and trifluoromethyl, or a cyclo (C5-C) alkyl group, or a heterocycle, in the form of free bases or addition salts with pharmaceutically acceptable acids. 2. Compounds according to claim 1 characterized in that the preferred configuration of the piperidinyl group is t2R, 4R]. 3. Compounds according to any one of claims 1 and 2, characterized in that the configuration of the central amino acid part is [S]. 4. Process for the preparation of the compounds according to Claim 1, characterized in that a sulphonyl chloride of formula (VII) is coupled.

 (wherein A and R, are as defined in claim 1) with the hydrochloride of the amine of formula (VIII)

 (wherein R1 represents a hydrogen atom or a (C1-C4) alkyl group, R2 represents a straight or branched (C1-C4) alkyl group and R5 represents either a hydrogen atom or a (Cx-C4) group straight or branched alkyl) to obtain the compound of formula (IX)

 whose imidazole group is deprotected to obtain a compound of formula (I) (in which R2 represents a straight or branched (C1-C4) alkyl group) which is saponified if it is desired to obtain a compound of formula (I) (in which which R2 represents a hydrogen atom) or which is treated with ammonium formate when A represents a phenyl group substituted with a nitro group to obtain a compound of formula (I) in which A represents a phenyl group substituted by an amino group. 5. Process for the preparation of the compounds of formula (Ia) according to claim 1 (for which R3 represents a hydrogen atom and A represents either a phenyl group optionally substituted by a fluorine atom or by a group chosen from groups (C1 -C4) straight or branched alkyl, amino and trifluoromethyl, a heterocycle), characterized in that a sulfonyl chloride of formula (X) is reacted;

 (wherein R6 represents a halogen atom) with the hydrochloride of the amine of formula (XI)

 (wherein Rt represents a hydrogen atom or a (C1-C4) alkyl group) in the presence of a base in an aprotic solvent to form a compound of formula (XII)

 that is reacted with a derivative of formula  ASnBu3 (in which A represents either a phenyl group optionally substituted by a fluorine atom or by a group chosen from the straight or branched (C1-C4) alkyl or nitro and trifluoromethyl groups, or a heterocycle) and a compound of formula (XIII)

 (wherein R4 is R6) which is hydrolyzed thereby obtaining an acid of formula (XIV)

 that is reacted with a piperidine of formula (XV)

 (wherein R2 represents a straight or branched (C1-C4) alkyl group and R5 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group) to form a compound of formula (XVI)

 whose imidazole group is deprotected to obtain a compound of formula (Ia)

 (wherein R2 represents a straight or branched (C-C4) alkyl group) which is hydrogenated if it is desired to obtain a compound of formula (I) (in which R, is a hydrogen atom), which is saponifies if it is desired to obtain a compound of formula (I) (in which R 2 represents a hydrogen atom) or that it is treated with ammonium formate when A represents a phenyl group substituted with a nitro group in order to obtain a compound of formula (I) wherein A represents a phenyl group substituted by an amino group. 6. Medicinal product characterized in that it contains a compound according to any one of claims 1 to 3. 7. Pharmaceutical composition characterized in that it contains a compound according to any one of claims 1 to 3 in combination with any suitable excipient.