FR2765221A1 - 4 - [(1H-IMIDAZOL-4-YL) PIPERIDIN-1-YL] ANILIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE - Google Patents

Abstract

The invention concerns compounds of formula (I) in which R1 represents a hydrogen atom or a linear or branched (C1-C4) alkyl group; R2 represents a linear or branched (C1-C6) alkyl, cyclo(C3-C7) alkyl or cyclo(C3-C7)alkyl(C1-C5) alkyl group; R3 represents a -OR4, -O(CH2)nNR5R6, -NHC(NH)NH2, -NHC(NH)N(CH3)2, -NR5R6, -NR5(CH2)nNR6R7 group, a group (a), X being selected among the oxygen and sulphur atoms and the -CHR8, -NR8, -SO- and -SO2- groups; R4, R5, R6, R7 and R8 being a hydrogen atom, a linear or branched (C1-C6)alkyl, cyclo (C3-C7)alkyl, cyclo(C3-C7)alkyl(C1-C5)alkyl, phenyl, phenyl(C1-C6)alkyl or heteroaryl group; m = 1 or 2 and n = 2, 3 or 4. The invention is applicable in therapy.

Description

The present invention relates to 4- [(1H-imidazol-4-yl) piperidin-1-yl] anilide derivatives, their preparation and their therapeutic application.

dans laquelle
R1 représente soit un atome d'hydrogène, soit un groupe (C1-C4)alkyle droit ou ramifié,
R2 représente soit un groupe (C1-C6)alkyle droit ou ramifié, soit un groupe cyclo(C3-C7)alkyle, soit un groupe cyclo(C3-C7)alkyle(Cl-Cs)alkyle et
R3 représente soit un groupe -OR4, soit un groupe -O(CH2)nNR5R6, soit un groupe -NHC(NH)NH2, soit un groupe -NHC(NH)N(CH3)2, soit un groupe -NR5R6, soit un groupe -MR5 (CH2) NR6R7, soit un groupe

The compounds of the invention correspond to formula (I)

in which
R1 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group,
R2 represents either a straight or branched (C1-C6) alkyl group, a (C3-C7) cycloalkyl group or a (C3-C7) alkyl (C1-C8) alkyl group and
R3 is either -OR4, -O (CH2) nNR5R6, -NHC (NH) NH2, -NHC (NH) N (CH3) 2, -NR5R6, or group -MR5 (CH2) NR6R7, a group

X being selected from oxygen and sulfur atoms and -CHR8, -NR8, -SO- and -SO2-, wherein R4, R51, R6, R7 and R8 are independently of one another; hydrogen, either a straight or branched (C1-C6) alkyl group, a (C3-C7) cycloalkyl group, a (C3-C7) alkyl (C1-C8) alkyl group, a phenyl group, or a phenyl (C1-C6) alkyl group, ie a 5- to 6-membered heteroaryl group, the heteroatoms being chosen from sulfur and nitrogen oxygen atoms, m is equal to 1 or 2 and n is equal to 2; , 3 or 4, in the form of free bases or addition salts with pharmaceutically acceptable acids.

According to the invention, the compounds of formula (I) can be prepared according to the methods illustrated in Schemes 1 and 2; in these schemes the group -C (C6H5) 3 represents a triphenylmethyl protecting group (trityl group).

To prepare the compounds of formula (Ia) and (Ib), a compound of formula (II) in which Hal represents a halogen atom is reacted with an alcohol of formula ROH in which R represents a group (C1-C6) straight or branched alkyl and there is obtained a compound of formula (III) which is reacted with a compound of formula (IV) in which R 1 is as defined above, in an aprotic solvent such as dimethylformamide in the presence of a base as the
N, N-diisopropylethylamine, to obtain a compound of formula (V) which is treated with triphenylmethyl chloride in a solvent such as dichloromethane in the presence of a base such as N-methylmorpholine to prepare a compound of formula ( VI) which is subjected to a catalytic hydrogenation and a compound of formula (VII) is obtained which is reacted with a compound of formula R 2 COX wherein X represents a halogen atom and R 2 is as defined above and a compound of formula (VIII) is obtained.

Then, if it is desired to prepare a compound of formula (Ia) which corresponds to a compound of formula (I) in which R3 represents a group -OR4, R4 being a hydrogen atom or a straight or branched (C1-C6) alkyl group then the imidazole nucleus of the corresponding compound of formula (VIII) is deprotected under standard conditions known to those skilled in the art, and the ester function is optionally hydrolysed.

noyau imidazole dans des conditions classiques connues de l'homme du métier.If it is desired to prepare a compound of formula (Ib) which corresponds to a compound of formula (I) in which R 3 represents either an -NHC (NH) NH 2 group or a -NHC (NH) N (CH 3) 2 group, then the corresponding compound of formula (VIII) is reacted with a compound of formula H2NC (NH) N (Rg) 2 in which Rg represents either a hydrogen atom or a methyl group in order to obtain a compound of formula (XI) whose we deprotect the
Diagram 1

imidazole nucleus under standard conditions known to those skilled in the art.

When it is desired to obtain a compound of formula (Ic) which corresponds to a compound of formula (I) in which R3 represents either a group -OR4 (R4 being a cyclo (C3-C7) alkyl, cyclo (C3-C7) group alkyl (C 1 -C 6) alkyl, phenyl, phenyl (C 1 -C 6) alkyl or heteroaryl of 5 to 6 sides, the heteroatoms being selected from oxygen atoms of sulfur and nitrogen), or a group -O (CH 2) nNR5R6, either a group -NR5R6, or a group -NR5 (CH2) nNR6R7 (R5, R6, R7 and n being as defined above), or a group

X being selected from oxygen and sulfur atoms and -CHR8, -NR8, -So- and -SO2- groups and R8 and m being as defined above, then proceed as in scheme 2.

The corresponding compound of formula (VIII) is treated in a basic medium and a compound of formula (IX) is obtained which is reacted with a compound of formula R 3 H (R 3 being as defined above) in an aprotic solvent such as dimethylformamide in the presence of 1,4-carbonyldiimidazole to prepare a compound of formula (X) which is deprotected imidazole nucleus under standard conditions known to those skilled in the art.

In an alternative according to the invention, the compounds of formula (Ic) can be prepared by reacting the corresponding compounds of formula (Ia) in which R3 represents a group -OR4, R4 being a hydrogen atom, with a compound of formula R3H in an aprotic solvent such as dimethylformamide in the presence of a base such as N, N-diisopropylethylamine and 1,4-carbonyldiimidazole and then carrying out a deprotection of the imidazole nucleus under standard conditions known to those skilled in the art.

Figure 2

The starting compounds are 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 preparation of the compounds of formula (IV) is described in European Patent Application EP 0507650.

The following examples illustrate the invention without limiting it. Microanalyses and IR, NMR and mass spectra confirm the structure of the compounds obtained. The numbers of the exemplified compounds refer to those of the table given below which illustrates the chemical structures and the physical properties of some compounds according to the invention.

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

Example 1 (Compound No. 11)
N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -5 - [(4-methylpiperazin-1-yl) carbonyl] phenyl] cyclopropanecarboxamide 1.1. 3 - [(cyclopropylcarbonyl) amino] -4- [4- (5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl]
methyl benzoate
1.1.1 3-amino-4- [4- (5-methyl-1- (triphenylmethyl) -1H-
imidazol-4-yl) piperidin-1-yl] benzoate
methyl
a) methyl 4-fluoro-3-nitrobenzoate
5 g (27 mmol) of 4-fluoro-3-nitrobenzoic acid are dissolved in 50 ml of methanol, 7.88 ml (108 mmol) of thionyl chloride are added at ambient temperature and the mixture is heated for a 2 hours at reflux temperature. The reaction medium is evaporated to dryness and the residue is taken up in 150 ml of dichloromethane. Washed successively with 2 times 10 ml of a saturated aqueous solution of sodium hydrogencarbonate and then with 50 ml of water and dried over magnesium sulfate.

5.37 g of product is obtained.

Yield = 91%
Melting point = 70 OC
b) 4- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -3-
methyl nitrobenzoate
10 g (10 mmol) of 4- (5-methyl-1H-imidazol-4-yl) piperidine dihydrochloride are suspended in a mixture of dichloromethane (10 ml) and dimethylformamide (2 ml) to which 6.89 g is added. ml (40 mmol)
N, N-diisopropylethylamine. The mixture is cooled to -5 ° C. and 1.9 g (10 mmol) of methyl 4-fluoro-3-nitrobenzoate dissolved in 5 ml of dichloromethane are added dropwise. The temperature of the mixture is allowed to return to 0 ° C. and then stirred for 3 hours at this temperature, the reaction mixture is washed with 3 times 10 ml of water, dried over magnesium sulphate and the solvents are evaporated off.

After trituration in ether, 2.2 g of product is obtained in the form of a beige powder.

Yield = 67 8
Melting point = 108 OC
c) 4- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazole-4-
methyl yl] piperidin-1-yl] -3-nitrobenzoate
190 g (58 mmol) of methyl 4- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -3-nitrobenzoate are suspended in 190 ml of dichloromethane at room temperature. 9.6 ml (87 mmol) of N-methylmorpholine and then 16.44 g (64 mmol) of trityl chloride are added. The mixture is stirred for 48 hours at room temperature and 200 ml of dichloromethane are added. Washed with 2 times 150 ml of water.

It is dried over magnesium sulfate, filtered and evaporated to dryness. The residue obtained is crystallized from ether.

27 g of product are obtained.

Yield = 79%
Melting point = 228 OC
d) 3-amino-4- [4- [5-methyl-1- (triphenylmethyl) -1H-
methyl imidazol-4-yl] piperidin-1-yl] benzoate
10 g (17.02 mmol) of 4- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] -3- in 4 g of tetrahydrofuran (10 g, 17.02 mmol) are added. methyl nitrobenzoate and a suspension of Raney nickel. The mixture is stirred under a hydrogen atmosphere until the supernatant solution is decolourized, filtered and the solvent evaporated. The residue is triturated in ice-cold ether and filtered.

9.74 g of product are obtained.

Yield = 95 W
Melting point = 260 OC
1.1.2. 3 - [(cyclopropylcarbonyl) amino] -4- [4- [5-methyl-1-
(Triphenylmethyl) imidazol-4-yl] piperidin-1-
yl] methyl benzoate
25 g (45 mmol) of 3-amino-4- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl are suspended in 255 ml of dichloromethane. methyl benzoate and the mixture is cooled to 0 ° C. under nitrogen. 3.74 g (47 mmol) of pyridine are added, then 4.94 g (47 mmol) of cyclopropanecarbonyl chloride are added dropwise and the reaction mixture is stirred for 1 hour at this temperature. The mixture is allowed to return to room temperature, 200 ml of dichloromethane are added and the mixture is washed twice with 150 ml of water. It is dried over sodium sulphate, filtered and evaporated to dryness. The residue is taken up in ether, filtered and dried.

25.8 g of product are obtained.

Yield = 91.9%
1.1.3. 3 - [(cyclopropylcarbonyl) amino] -4- [4- [5-8
methyl-1- (triphenylmethyl) -1H-imidazol-4-yl]
piperidin-l-yl] benzoic acid
13 g (20.8 mmol) of 3 - [(cyclopropylcarbonyl) amino] -4- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl) are suspended in 150 ml of methanol. ] piperidin-1-yl] benzoate methyl, 62.42 ml of a 1M aqueous sodium hydroxide solution (62.42 mmol) and heated at reflux temperature for 3.5 hours. The mixture is left overnight at room temperature, 400 ml of water are added and the methanol is evaporated. It is acidified to pH 4 with a 3 M aqueous hydrochloric acid solution, filtered and the compound obtained is dried at 50 ° C.

12.1 g of product are obtained.

Yield = 95 8
Melting point = 237 OC 1.2. N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -5 - [(4-methylpiperazin-1-yl) carbonyl] phenyl] cyclopropane
carboxamide
2.2 g (3.6 mmol) of 3 - [(cyclopropylcarbonyl) amino] -4- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol acid are suspended in 100 ml of dichloromethane. -4-yl] piperidin-1-yl] benzoic acid, 1.4 ml (8 mmol) of
N, N-diisopropylethylamine and then the mixture is cooled to 0 ° C. 0.52 ml (4.6 mmol) of N-methylpiperazine dissolved in 30 ml of dichloromethane are then added, the stirring is continued at this temperature for 15 minutes and then 2.4 g (4.6 mmol) of benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate. The temperature of the mixture is allowed to rise to ambient temperature overnight, 100 ml of dichloromethane are added and the organic phase is washed successively with 50 ml of an 8% aqueous solution of sodium hydrogencarbonate, 100 ml of 15% aqueous solution of sodium chloride and then 50 ml of a 30% aqueous solution of sodium chloride. Filtered and dried over magnesium sulfate. ON filtered and evaporated to dryness. The residue is taken up in 100 ml of ether and wrung out.
2.1 g of tritylated derivative is obtained, which is taken up in 57.6 ml of tetrahydrofuran, 60 ml of water and 60 ml of acetic acid are added and then the mixture is heated for 3 hours at 80.degree. The reaction medium is taken up in ether and the product is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol: ammonia (90: 12: 1) mixture.

1.12 g of product is obtained after crystallization from ethyl acetate.

Yield = 69%
Melting point = 188 OC
Example 2 (Compound No. 2) Methyl 4- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -3 - [(1-oxobutyl) amino] benzoate 2.1. [4- [5-methyl-1- (triphenylmethyl) imidazol-4-
yl] piperidin-1-yl] -3 - [(1-oxobutyl) amino] benzoate
methyl
Under nitrogen, 6.3 g (10.62 mmol) of 3-amino-4- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] benzoate are added. of methyl suspension in 55 ml of dichloromethane and the mixture is cooled to 0-5 OC. Then 0.95 ml (11.74 mmol) of pyridine and 1.16 ml (11.15 mmol) of butyryl chloride are added and stirring is continued for 1 hour at 0-5 OC. The temperature of the mixture is allowed to return to room temperature and stirred overnight at this temperature. 90 ml of dichloromethane are added, the mixture is washed with twice 80 ml of water and dried over magnesium sulphate. It is filtered and evaporated to dryness.

6.5 g of product are obtained in the form of an amorphous compound.

Yield = 98% 2.2. 4- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -3- [(I-
methyl oxobutyl) amino] benzoate
4- [4- [5-Methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] - 3 - [(1oxobutyl) amino] 6 g (10.5 mmol) are solubilized] methyl benzoate in 170 ml of tetrahydrofuran, 170 ml of water and 340 ml of acetic acid are added and the mixture is heated at reflux temperature for 5 hours. The reaction medium is evaporated, the residue is taken up in ether and filtered. The product is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol: ammonia mixture (92: 8: 0.5).

3.3 g of product are obtained after crystallization from ether.

Yield = 82%
Melting point = 166-170 OC
Example 3 (Compound No. 1) 4- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -3 - [(1-oxobutyl) amino] benzoic acid
2.9 g (7.87 mmol) of 4- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -3 - [(1-oxobutyl) amino] benzoate are solubilized. In 50 ml of methanol, 0.630 g (15.74 mmol) of sodium hydroxide are added and the mixture is heated at reflux temperature for 2 hours. The methanol is evaporated, the residue is taken up in 70 ml of water and the pH is adjusted to 6.5 with aqueous 3N hydrochloric acid solution. The mixture is filtered and dried under vacuum at 60 ° C.

2.68 g of product are obtained.

Yield = 92 8
Melting point = 291 OC (fusion with decomposition)
Example 4 (Compound No. 6)
N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -5- (piperidin-1-ylcarbonyl) phenyl] butanamide
Method A A.4.1. 4- [4- [5-methyl-1- (triphenylmethyl) -1H-
imidazol-4-yl] piperidin-l-yl] -3 - [(l-oxobutyl)
amino] benzoic
12 g (19.46 mmol) of 4- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] -3 - [1- methyl oxo-butyl) amino] benzoate in suspension in 120 ml of methanol, 38.93 ml (38.93 mmol) of a 0.1N aqueous sodium hydroxide solution are added and the reaction medium is brought to the reflux temperature during 2 hours. The methanol is evaporated, the mixture is cooled to 0-5 ° C., acidified to pH 4 with a 3N aqueous hydrochloric acid solution and the reaction medium is left overnight at this temperature. Filtered, filtered and dried over phosphorus pentoxide under vacuum at 70 ° C.

10.75 g of product are obtained.

Yield = 90%
A.4.2. N- [2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] -5- (piperidin-1-ylcarbonyl) phenyl]
butanamide
Under nitrogen, 1.5 g (2.45 mmol) of 4- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] -3- [ (1-oxobutyl) amino] benzoic acid suspended in 10 ml of dimethylformamide, 0.44 mg (2.69 mmol) of 1,4-carbonyldiimidazole are added and the mixture is heated at 40 ° C. for 2 hours. Piperidine (0.208 g, 2.45 mmol) is then added and the mixture is left overnight at 80 ° C.

The dimethylformamide is evaporated, the residue is taken up in 100 ml of dichloromethane and then washed with twice 35 ml of water. It is dried over sodium sulphate, filtered and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol (95: 5) mixture.

1.0 g of product is obtained.

Yield = 60%
A.4.3. N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -5- (piperidin-1-ylcarbonyl) phenyl] butanamide
1 g (1.47 mmol) of N- [2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] -5- (piperidine) was solubilized. 1-ylcarbonyl) phenyl] butanamide in 25 ml of tetrahydrofuran, 25 ml of water and 50 ml of acetic acid are added and the mixture is heated at reflux temperature for 2 hours. The reaction medium is evaporated and the residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol (90:10) mixture.

0.3 g of product is obtained after crystallization from ether.

Yield = 54%
Melting point = 139-141.5 OC
Method B
Under nitrogen, 0.7 g (1.89 mmol) of 4- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -3 - [(1 (oxobutyl) amino] benzoic acid suspended in 7 ml of dimethylformamide, 0.34 g (2.08 mmol) of 1,4-carbonyldiimidazole are added and the mixture is heated at 60 ° C. for 2 hours. The temperature of the reaction medium is allowed to drop to 40 ° C., 0.16 g (1.89 mmol) of piperidine is added and the mixture is heated at 85 ° C. for 2 hours. The dimethylformamide is evaporated, the residue is taken up in ether and purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol (90:10) mixture. The appropriate fractions are pooled, evaporated to dryness and recrystallized from water / methanol (1: 1). It is filtered and dried under vacuum over phosphorus pentoxide.

0.215 g of product is obtained.

Yield = 26%
Melting point = 139-141.5 OC
Example 5 (Compound No. 4) 4- [4- (5-methyl-1H-imidazol-4-yl) -piperidin-1-yl] -3 - [(1-oxobutyl) amino] -N- (phenylmethyl) benzamide 5.1. 4- [4- [5-methyl-1- (triphenylmethyl) imidazol-4-yl]
piperidin-l-yl] -3 - [(1-oxobutyl) amino] -N- (phenylmethyl)
benzamide
Under nitrogen, 1.5 g (2.44 mmol) of 4- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] -3- [ (1-oxobutyl) amino] benzoic acid suspended in 9 ml of dimethylformamide, 0.44 g (2.69 mmol) of 1,4-carbonyldiimidazole are added and the mixture is heated at 60 ° C. for 2 hours.

The temperature of the reaction medium is allowed to return to 50 ° C. and 0.26 g (2.44 mmol) of phenylmethylamine are added and the mixture is then heated at 80 ° C. overnight. It is evaporated to dryness, the residue is taken up in 100 ml of dichloromethane and washed successively with 40 ml of a 0.1M aqueous acetic acid solution and then with 40 ml of water. It is dried over magnesium sulfate, filtered and evaporated to dryness. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol (95: 5) mixture.

1.55 g of product are obtained.

Yield = 90% 5.2. 4- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] -3 - [(1-
oxobutyl) amino] -N- (phenylmethyl) benzamide
1.55 g (2.21 mmol) of 4- [4- [5-methyl-1 (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] -3 - [(loxobutyl) amino is solubilized. ] -N- (phenylmethyl) benzamide in 35 ml of tetrahydrofuran, 35 ml of water and 70 ml of acetic acid are added and the mixture is heated at reflux temperature for 3 hours. The reaction medium is evaporated and the product is purified by chromatography on a column of silica gel, eluting with a dichloromethane: methanol (90:10) mixture. Fractions are pooled, evaporated to dryness and allowed to crystallize from methanol: water. It is filtered and dried under vacuum over phosphorus pentoxide at 60 ° C.

0.455 g of product is obtained.

Yield = 45%
Melting point = 233-235 OC
Legend of the table
in the "R2" column, -c (C3H7) represents a cyclopropyl group,
in the "Salt" column, "fum" represents a fumarate; the ratios in parentheses represent the ratio (acid: base); the absence of any mention means that the compound is in base form,
in the "Melting Point" column, (d) coresponds to a decomposition merger.

Board

<tb><SEP><SEP> Point of
<tb> NO <SEP> R1 <SEP> R2 <SEP> R3 <SEP> Salt
<tb><SEP> merge <SEP> (0C)
<tb> 1 <SEP> -CH3 <SEP> -C3H7 <SEP> -OH <SEP> - <SEP> 291 <SEP> (d)
<tb> 2 <SEP> -CH3 <SEP> -C3H7 <SEP> -OCH3 <SEP> - <SEP> 166-170
<tb> 3 <SEP> -CH3 <SEP> -C3H7 <SEP> -NHCH3 <SEP> 138-144
<tb><SEP> \ NH
<tb> 4 <SEP> -CH, <SEP> -C, H, <SEP> 233-235
<tb> 6 <SEP> -CH3 <SEP> -C3H7 <SEP> - <SE> NS <SEP> - <SEP> 139-141.5
<tb> 7 <SEP> / m <SEP> - <SEP> 123-129
<tb> 7 <SEP> -CH3 <SEP> -C3H7 <SEP> -N <SEP> N-CH3
<tb><SEP> \ ff
<tb> 8 <SEP> -CH3 <SEP> -CH2CH (CH3) 2 <SEP> - <SEP> N3 <SEP> - <SEP> 177
<tb> 9 <SEP> -CH3 <SEP>;<SEP> -CH2CH (CH3) <SEP> 2 <SEP> -N <SEP> N <SEP> - <SEP> - <SEP> 120 <SEP> (d)
<tb><SEP> M
<Tb>

<tb><SEP><SEP> Point of
<tb> NO <SEP> R1 <SEP> R2 <SEP> R3 <SEP> Salt
<tb><SEP> merge <SEP> (0C)
<tb> 10 <SEP> -CH3 <SEP> -c <SEP> (C3H7) <SEP> -E <SEP> - <SEP> 240 <SEP> (d)
<tb> 11 <SEP> -CH3 <SEP> -c (C3H7) <SEP> -N <SEP> N-cH <SEP> - <SEP> 188
<tb><SEP> M
<tb><SEP> smoked
<tb> 12 <SEP> -CH3 <SEP> -c (C3H7) <SEP> N <SEP> Ne <SEP><1: 1) <SEP> 130 <SEP> (d)
<tb> 13 <SEP> -CH3 <SEP> -c (C3H7) <SEP> N <SEP> N43 <SEP> ~ <SEP> 233-237
<tb> 14 <SEP> -CH3 <SEP> -c (C3H7) <SEP> -NHCH (NH) NH2 <SEP> - <SEP> 236-241.5
<Tb>
The compounds of the invention have been the subject of pharmacological studies which have demonstrated their inhibitory properties of the sodium / proton exchanger and their interest as substances with therapeutic activity.

Thus, the compounds of the invention were subjected to a rabbit blood platelet swelling inhibition test in an acid medium according to the method of Grinstein et al. (In
Methods in Enzymology, Fleisher S. And Flusher B., Vol 173, pp 777-790, Academic Press Inc., 1984).

Blood is collected from rabbits by cardiac puncture
New Zealanders, using a citratedextrose anticoagulant. The platelet rich plasma (PRP) is obtained by centrifugation at 1200 rpm for 20 minutes at room temperature. After measuring the initial average platelet volume, an aliquot of PRP was incubated for 20 minutes in a propionate medium of sodium / propionic acid (140 mM) containing potassium chloride (1 mM), magnesium chloride (1 mM), glucose (10 mM) all buffered with Hepes (20 mM) at pH 6.7 and whose osmolarity is about 300 mosm / l. Propionic acid diffuses into the platelets where it dissociates, causing intracellular acidification and activation of the sodium / proton antiport. The influx of sodium ions is accompanied by a capture of water which causes the swelling of the platelets. The measurement of the mean platelet volume at the end of the incubation, minus the initial platelet mean volume, makes it possible to estimate the maximum swelling of the platelets. The test products are added to the propionic acid incubation medium at the desired concentrations prior to the addition of PRP. The results are expressed as a percentage of inhibition of maximum swelling for calculating the IC 50 or inhibiting concentration of 50% maximum swelling.

In this test, the ICos of the most interesting compounds of the invention are less than 10 μM.

As such, they can be used in the treatment and prevention of various forms of pathologies such as arterial and pulmonary hypertension, cardiac arrhythmia, cardiac ischemia, cardiac infarction, heart failure and angina. chest, ischemia of peripheral organs, lower limbs and central nervous system, nephropathies, edema, fibrosis and cancers, as well as diseases characterized by hyperplasias and hypertrophies of vessels or heart.

They can also be used for the protection of organs in surgery or organ transplantation operations.

The compounds of the invention may be used alone or in combination with other substances such as nitrates, calcium antagonists, beta-blockers, antithrombotics, thrombolytics, salicylates.

For this purpose they may be presented in any form suitable for oral or parenteral administration, such as tablets, dragees, capsules, capsules, suspensions or oral or injectable solutions, etc. in combination with suitable excipients. These forms are dosed to allow administration of 1 to 1000 mg / kg of 1 to 4 times per day.

They may also be presented in any form suitable for transdermal or sublingual administration.

Claims (6)

claims 1. Compounds of formula (I)

 in which R1 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group, R2 represents either a straight or branched (C1-C6) alkyl group, a (C3-C7) cycloalkyl group or a (C3-C7) alkyl (C1-C5) alkyl group and R3 is either -OR4, -O (CH2) nNRsR6, -NHC (NH) NH2, -NHC (NH) N (CH3) 2, or -NR5R6, or a group -NRS (CH2) nNR6R7, a group

X being selected from oxygen and sulfur atoms and -CHR8, -NRs, -SO- and -SO2-, wherein R4, R5, R6, R7 and Re independently of one another are an atom hydrogen, either a straight or branched (C1-C6) alkyl group, a cyclo (C3-C7) alkyl group, a cyclo (C3-C7) alkyl (C1-C8) alkyl group, or a phenyl group either a phenyl (C 1 -C 6) alkyl group or a 5- to 6-membered heteroaryl group, the heteroatoms being selected from the oxygen atoms of sulfur and nitrogen, m is 1 or 2 and n is equal to 2, 3 or 4, as well as their addition salts with pharmaceutically acceptable acids. 2. Process for the preparation of the compounds of formula (Ia) according to claim 1

 in which R1 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group, R2 represents either a straight or branched (C1-C6) alkyl group or a (C3-C7) alkyl cyclo group, or a cyclo (C 3 -C 7) alkyl (C 1 -C 6) alkyl group and R 4 represents either a hydrogen atom or a straight or branched (C 1 -C 6) alkyl group, characterized in that the core is deprotected; imidazole of a compound of formula (VIII)

 in which R represents a straight or branched (C1-C6) alkyl group to obtain a compound of formula (Ia) in which R4 represents a straight or branched (C1-C6) alkyl group and, if necessary, hydrolysis is carried out if necessary of the ester function to obtain a compound of formula (Ia) wherein R4 represents a hydrogen atom. 3. Process for the preparation of the compounds of formula (Ib) according to claim 1

 in which R1 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group, R2 represents either a straight or branched (C1-C6) alkyl group or a cyclo (C1-C7) alkyl group, either a cyclo (C 3 -C 7) alkyl (C 1 -C 5) alkyl group and R 8 represents either a hydrogen atom or a methyl group, characterized in that a compound of formula (VIII) is reacted

 in which R represents a straight or branched (C1-C6) alkyl group, R1 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group and R2 represents either a (C1-C6) straight alkyl group or branched, either a cyclo (C3-C7) alkyl group, or a (C3-C7) cycloalkyl (C1-C8) alkyl group, with a compound of the formula H2NC (NH) N (Rg) 2 in which Rg represents either a hydrogen atom or a methyl group to obtain a compound of formula (XI)

  which is deprotected the imidazole nucleus. 4. Process for preparing the compounds of formula (Ic)

 in which R1 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group, R2 represents either a straight or branched (C1-C6) alkyl group or a (C3-C7) alkyl cyclo group, either a cyclo (C3-C7) alkyl (C1-C5) alkyl group and R3 represents either a group -OR4 (R4 being a cyclo (C3-C7) alkyl, a cyclo (C3-C7) alkyl (C1-Cs) alkyl group phenyl, phenyl (C1-C6) alkyl or heteroaryl), either a group -O (CH2) nNR5R6, a group -NRSR6, or a group NR5 (CH2) NR6R7 (R5, R6, R7 and n being as defined in claim 1), a group

 which is deprotected the imidazole nucleus.

 that is reacted with a compound of formula R3H where R3 is as defined above and a compound of formula (X) is obtained

  in which R represents a straight or branched (C1-C6) alkyl group, R1 represents either a hydrogen atom or a straight or branched (C1-C4) alkyl group and R2 represents either a (C1-C6) straight alkyl group or branched, either a cyclo (C 3 -C 7) alkyl group or a cyclo (C 3 -C 7) alkyl (C 1 -C 6) alkyl group, in a basic medium and a compound of formula (IX) is obtained

X being chosen from oxygen and sulfur atoms and -CHR8, -NR8, -SO- and -SO2- and R8 and m being as defined in claim 1, characterized in that it is treated a compound of formula (VIII) 5. Medicinal product characterized in that it contains a compound according to claim 1. 6. Pharmaceutical composition characterized in that it contains a compound according to claim 1 in association with a pharmaceutically acceptable excipient.