EP0994857A1

EP0994857A1 - (1h-imidazol-4-yl)piperidine derivatives, preparation and application in therapy

Info

Publication number: EP0994857A1
Application number: EP98932236A
Authority: EP
Inventors: Gérard Cremer; Christian Hoornaert
Original assignee: Sanofi Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1997-07-01
Filing date: 1998-06-19
Publication date: 2000-04-26
Also published as: AR013149A1; AU8220598A; ZA985727B; JP2002507983A; WO1999001435A1; FR2765580A1; FR2765580B1

Abstract

The invention concerns compounds of formula (I) in which R1 and R2 represent each independently of each other either a hydrogen atom, or a (C1-C4) linear or branched alkyl group; R3 and R4 represent each independently of each other either a hydrogen or halogen atom, or (C1-C4) alkyl group, trifluoromethyl, (C1-C4) alkoxy, S(O)pR with R a (C1-C4) linear or branched alkyl group and p = 0 to 2; and A represents either a hydrogen atom, or a (C1-C6) linear or branched alkyl group, phenyl (C1-C4)alkyl, -COR5, -COOR5, -CONHR5, -SO2R5, where R5 is a (C1-C6) linear or branched alkyl group, a (C3-C7) cycloalkyl group; a (C3-C7) cycloalkyl (C1-C5)alkyl group, a (C1-C4) alkoxy (C1-C6) alkyl group, a phenyl group, a phenyl (C1-C4) alkyl group, a phenyl (C1-C4)alkylidene group, or a -COCH2NR6R7 group where R6 is a hydrogen atom or a (C1-C4) linear or branched alkyl group and R7 a (C1-C4) linear or branched alkyl group or acyl or R1, R3 and R4 being such as defined above, A and R2 form a cycle of the type -(CH2)nCO- where n can take a value between 2 and 6, in the form of pharmaceutically acceptable free bases or addition salts to acids The invention is applicable in therapy.

Description

(Ltf-imidazol-4-yl) piperidine derivatives, their preparation and their therapeutic use

The present invention relates to derivatives of (1H-imidazol -4 -yl) piperidine, their preparation and their therapeutic use. The compounds of the invention correspond to formula (I)

in which R ₁ and R ₂ each independently of one another represent either a hydrogen atom or a (0 ₂ -0) straight or branched alkyl group,

R ₃ and R ₄ each independently represent one of the other either a hydrogen atom, or a halogen atom, or a group (0-0 ₄ ) alkyl, or a trifluoromethyl group, or a group (C ₂ -C ₄₎ alkoxy, it ^s ° s (0) _p R group with R (0 ₂ -0 ₄₎ straight or branched alkyl and p = 0 to 2, and a represents either a hydrogen atom or a (C ₂ -C ₆ ) straight or branched alkyl group, or a phenyl (C ₂ -C ₄ ) alkyl group, or a group -C0R ₅ , or a group -COOR ₅ , or a group -C0NHR ₅ , or a group -S0 ₂ R _{5 /} where R ₅ is a (C ₁ -C ₆ ) straight or branched alkyl group, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl group (C ₂ - C ₅ ) alkyl, a group (C ₂ -C ₄ ) alkoxy (C ₂ -C ₆ ) alkyl, a phenyl group, a phenyl group (C ₂ -C ₄ ) alkyl, a phenyl group (C ₂ -C ₄ ) alkylidene, or a group -COCH ₂ NR ₆ R ₇ where R ₆ is a hydrogen atom or a group (C ₂ -C ₄ ) straight alkyl ^? or branched and R ₇ a (C -C ₄ ) straight or branched alkyl group or an acyl group or R- _L , R ₃ and R ₄ being as defined above,

A and R ₂ form a cycle of type - (CH ₂ ) _n CO- where n can take a value between 2 and 6, in the form of free bases or of addition salts with pharmaceutically acceptable acids. According to the invention, the preferred compounds are those for which R ₂ represents a (C ₂ -C ₄ ) straight or branched alkyl group, R ₂ represents either a hydrogen atom or a (C ₂ -C ₄ ) alkyl group straight or branched, R ₃ represents either a hydrogen atom, a halogen atom, or a (C ₁ -C) alkyl group, or a trifluoromethyl group, or a (C ₂ -C ₄ ) alkoxy group, R ₄ represents either a hydrogen atom or a halogen atom, and A represents either a hydrogen atom, or a (C ₁ -C ₆ ) straight or branched alkyl group, or a phenyl (C ₂ -C) group ₄ ) alkyl, either a group -COR ₅ , or a group -COOR ₅ , or a group -CONHR ₅ , or a group -S0 ₂ R ₅ where R ₅ is a group (C ₁ -C ₆ ) straight or branched alkyl , a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C -C ₅ ) alkyl group, a (C ₁ -C ₄ ) alkoxy (C _x -C ₆ ) alkyl group, a phenyl group, a phenyl (C ₁ -C ₄ ) alkyl group, a phenyl (C ₂ -C ₄ ) alkyli group dene, either a group -COCH ₂ NR ₆ R ₇ where R ₆ is a hydrogen atom or a (C ₁ -C ₄ ) straight or branched alkyl group and R ₇ a group (C ₂ -C ₄ ) straight alkyl or branched or an acyl group or

R _x , R ₃ and R ₄ being as defined above, A and R ₂ form a cycle of type - (CH ₂ ) _n C0- where n can take a value between 2 and 6, in the state of free bases or addition salts with pharmaceutically acceptable acids.

Compounds of similar structure are described in European patent applications EP 0507650, EP 0591026 and EP 0591027.

In accordance with the invention, the compounds of formula (I) can be prepared according to the process illustrated in scheme 1 in which the group -C (C ₆ H ₅ ) ₃ represents a triphenylmethyl protective group (trityl group). A compound of formula (II) in which Hal represents a halogen atom and R ₃ and R ₄ are as defined above is reacted with a compound of formula (III) in which R _x is as defined above, in an aprotic solvent such as dimethylformamide in the presence Diagram 1

(Ib)

(the) a base such as diisopropylethylamine, to obtain a compound of formula (IV).

Then when we want to prepare a compound of formula (la) which corresponds to a compound of formula (I) in which A and R ₂ each represent a hydrogen atom, the compound of formula (IV) is subjected to a catalytic hydrogenation under conventional conditions known to those skilled in the art. When we want to obtain a compound of formula (Ib) which corresponds to a compound of formula (I) in which R ₂ represents a hydrogen atom and A is different from a hydrogen atom, then the compound is treated formula (IV) 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 (V) which is subjected to a catalytic hydrogenation and a compound is obtained of formula (VI) then A is introduced by acylation or sulfonylation of the compound of formula (VI), for example with a sulfonyl chloride, a chloroformate, a carbamoyl chloride, an isocyanate, an anhydride or an optionally carboxylic acid chloride followed by a reduction of the acyl group thus introduced and a compound of formula (VII) is obtained from which the imidazole nucleus is deprotected under conventional conditions known to those skilled in the art.

When we want to obtain a compound of formula (Ie) which corresponds to a compound of formula (I) in which R ₂ represents a (C ₁ -C ₄ ) alkyl group and A is different from a hydrogen atom, then either a reductive alkylation of the compound of formula (VI) is carried out, or a compound of formula (VII) is reacted with a compound of formula R ₂ X in which R ₂ represents a group (C _x -C ₄ ) alkyl and X a halogen atom to prepare a compound of formula (VIII) from which the imidazole nucleus is deprotected under conventional conditions known to those skilled in the art. When we want to obtain a compound of formula (Id)

which corresponds to a compound of formula (I) in which A and R ₂ form a ring of type - (CH ₂ ) _n CO- where n can take a value between 2 and 6, then a compound of formula ( VI) with a compound of formula X (CH ₂ ) _n COCl in which X is a halogen atom and n as defined above, then the compound thus obtained is treated with sodium hydride to give a compound which is deprotected the imidazole nucleus under conventional conditions known to those skilled in the art.

The starting compounds are 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 preparation of the compounds of formula (III) is described in the European patent application EP 0507650.

The examples which follow illustrate the invention without limiting it. Micro-analyzes and IR, RM and mass 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.

The ratios (x: y) correspond to the ratio (acid: base). Example 1 (compound # 4)

N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] acetamide

1.1. 4- (5-methyl-1H-imidazol-4-yl) -1- (2-nitrophenyl) piperidine

10 g (42 mmol) of 4- (5-methyl-1H-imidazol-4-yl) piperidine dihydrochloride are suspended in 100 ml of dimethylformamide, to which 26 ml (147 mmol) of diisopropylethylamine and 6.52 are added. g (46.2 mmol) of 2-fluoro-nitrobenzene. The mixture is heated to 85 ° C for

18 hours, the solvents are evaporated off, the residue is taken up in an aqueous sodium bicarbonate solution and extracted with dichloromethane. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol mixture (90/10).

8.9 g of compound are obtained.

Efficiency = 74%

Melting point = 183 ° C

1.2. 4- [5-methyl-1- (triphenylmethyl) -lff-imidazol-4-yl] -1-

(2-nitrophenyl) piperidine In 50 ml of dichloromethane, 3.2 g (11.2 mmol) of 4- (5-methyl-1H-imidazol-4-yl) -1- (2-nitrophenyl) piperidine are added, 1.35 ml (12.3 mmol) of N-methylmorpholine then 3.42 g (12.3 mmol) of trityl chloride. The mixture is stirred overnight, washed with water and the solvent is evaporated. The residue obtained is recrystallized from ether. 5.57 g of product are obtained.

Efficiency = 94%

Melting point = 204-207 ° C

1.3. 2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] benzeneamine

5.57 g (10.54 mmol) of 4- [5-methyl-l- (triphenylmethyl) -lff- imidazol-4-yl] -1- (2 -nitrophenyl) piperidine are added to 60 ml of tetrahydrofuran a suspension of Nickel by Raney. The mixture is stirred under hydrogen atmosphere until discoloration of the supernatant solution, filtered and the solvent is evaporated. The residue is triturated in ice cold ether. 4.4 g of product are obtained. Efficiency = 85%

Melting point = 244 ° C

1.4. N- [2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] phenyl] acetamide In 5 ml of dichloromethane cooled by an ice bath, the following is added 0.5 g (1 mmol) 2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] benzeneamine, 0.22 ml (1.15 mmol ) of JV-methylmorpholine and 0.11 ml (1.15 mmol) of acetic anhydrous, the mixture is stirred for 1 hour at this temperature and then the temperature is allowed to return to ambient. The reaction medium is washed with water, dried and the solvent is evaporated. The product is crystallized from ether. 0.44 g of product is obtained. Yield = 81%

Melting point = 195-196 ° C

1.5. N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] acetamide 0.58 g of N- [2- [4- [5-methyl- l- (triphenylmethyl) -1H- imidazol-4-yl] piperidin-l-yl] phenyl] acetamide in solution in 70 ml of a tetrahydrofuran / water / acetic acid mixture (25/25/50) at reflux temperature and left at this temperature for 1 hour. The solvent is evaporated off, the residue is taken up in dichloromethane and washed with an aqueous solution of sodium bicarbonate. The organic phase is recovered and purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol mixture (90/10). Yield = 81%

Melting point = 142 ° C (ether) Example 2 (compound # 1)

2- [4- (5-methyl-1H-imidazol -4 -yl) piperidin- 1-yl] benzeneamine

1 g (3.5 mmol) of 4- (5-methyl-1H-imidazol-4-yl) -1- (2-nitrophenyl) piperidine is dissolved in 30 ml of tetrahydrofuran and a suspension of nickel of Raney. The mixture is stirred under a hydrogen atmosphere until complete discoloration, filtered and the solvent is evaporated. 0.66 g of product is obtained. Yield = 74% Melting point = 180 ° C (ether)

Example 3 (Compound No. 32) N- [2- [4- (5 -methyl-1H-imidazol -4 -yl) piperidin- 1-yl] phenyl] - 3 -phenylprop-2 -enamide

3.1. N- [2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4- yl] piperidin-1-yl] phenyl] -3-phenylprop-2-enamide Solubilized in 15 ml of dichloromethane , 1 g (2 mmol) of 2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] benzeneamine, 0.17 ml (1.05) is added mmol) of pyridine, the mixture is cooled to 0-10 ° C. and 0.35 g (2.1 mmol) of cinnamoyl chloride dissolved in 5 ml of dichloromethane is added dropwise. The mixture is stirred for 1 hour at this temperature, the temperature is allowed to return to ambient and the reaction medium is poured onto water. The organic phase is collected, concentrated and the residual oil obtained is triturated in ether.

0.975 mg of product is obtained in the form of a white solid. Efficiency = 76%

3.2. N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] -3-phenylprop-2-enamide This compound is obtained from N- [2- [ 4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] phenyl] - 3-phenylprop-2-enamide according to the method described in 1 example 1. 5.

Melting point = 166 ° C (ether)

Example 4 (compound No. 28) [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] 2-methylpropyl carbamate

4.1. [2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl) piperidin-1-yl] phenyl] 2-methylpropyl carbamate This compound is obtained by reacting 0.5 g ( 1 mmol) of 2- [4- [5-methyl-1- (triphenylmethyl) -1H- imidazol -4 -yl] piperidin-1-yl] benzeneamine with 0.1 ml (1.05 mmol) of chloroformate isobutyl under the conditions described in Example 3.1. 0.38 g of product is obtained. Yield = 64% Melting point = 190-191 ° C

4.2. [2- [4- (5-methyl-1H-imidazol -4 -yl) piperidin-1- yl] phenyl] 2-methylpropyl carbamate

This compound is obtained from [2- [4- [5-methyl-1- (triphenylmethyl) - 1H-imidazol -4 -yl) piperidin-1-yl] phenyl] carbamate of 2-methylpropyl according to the method described in 1 example 1.5. Melting point = 157-158 ° C (ether)

Example 5 (compound # 37)

-V-ethyl -N '- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1- yl] phenyl] urea

5.1. N-ethyl -N '- [2- [4- [5-methyl-l- (triphenylmethyl) -1H- imidazol-4-yl] piperidin- 1-yl] phenyl] urea Add 0.5 g (1 mmol ) of 2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] benzeneamine to 5 ml of dichloromethane and the mixture is cooled to 0 ° C. 0.083 ml (1.05 mmol) of ethyl isocyanate is introduced, the mixture is stirred for 1 hour while allowing the temperature to rise to ambient and the solvent is evaporated. The residue is used as is in the next step. 5. 2. N- ethyl -N '- [2 - [4 - (5 -methyl - 1H- imidazol - 4 - yl) piperidin- 1-yl] phenyl] urea This compound is obtained from -V-ethyl-JV' - [2- [4- [5- methyl-1- (triphenylmethyl) -IH-imidazol-4 -yl] piperidin-1-yl] phenyl] urea according to the method described in Example 1.5. Melting point = 202-203 ° C (acetonitrile)

Example 6 (compound # 34)

N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] methanesulfonamide

6.1. N- [2- [4- [5-methyl-1- (triphenylmethyl) -IH- imidazol -4- yl] piperidin- 1-yl] phenyl] methanesulfonamide

This compound is obtained by reacting 0.5 g (1 mmol) of 2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] benzeneamine with 0.082 ml (1.05 mmol) of methanesulfonyl chloride under the conditions described in Example 3.1. 0.58 g of product is obtained. Yield = 100%

6.2. N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] methanesulfonamide

This compound is obtained from N- [2- [4- [5-methyl-l- (triphenylmethyl) -1H-imidazol-4-yl] iperidin-1-yl] phenyl] methanesulfonamide according to the method described in example 1.5. Melting point = 196 ° C (acetonitrile)

Example 7 (compound # 6)

N- [2 - [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] butanamide

7.1. N- [2- [4- [5-methyl-1- (triphenylmethyl) - IH- imidazol -4- yl] piperidin- 1-yl] phenyl] butanamide

Solubilized in 30 ml of dichloromethane 3 g (6 mmol) of 2- [4- [5-methyl-l- (triphenylmethyl) -lH-imidazol-4-yl] piperidin-1-yl] benzeneamine, 0, 51 ml (6.32 mmol) of pyridine and the mixture is cooled to 0-10 ° C. 0.66 ml (6.32 moles) of butyryl chloride dissolved in 5 ml of dichloromethane is introduced dropwise and the mixture is allowed to stir for 1 hour at this temperature. The temperature of the reaction medium is allowed to return to ambient and it is poured onto water. The organic phase is collected, concentrated and the residual oil is triturated in ether.

3.33 g of product are obtained in the form of a white solid. Efficiency = 97%

Melting point = 157 ° C (pasty melting)

7.2. N- [2- [4- (5 -methyl-1H- imidazol -4 -yl) piperidin-1-yl] phenyl] butanamide This compound is obtained from N- [2- [4- [5-methyl- l-

(triphenylmethyl) -IH-imidazol-4 -yl] piperidin-1-yl] phenyl] butanamide according to the method described in Example 1.5. Melting point = 170-173 ° C (ether)

Example 8 (compound 40)

(E) N-methyl -2-butenioate -N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] butanamide (1: 1)

8.1. N-methyl -N- [2- [4- [5-methyl-1- (triphenylmethyl) -1H- imidazol -4 -yl] piperidin- 1-yl] phenyl] butanamide

0.5 g (0.088 mmol) of N- [2- [4- [5-methyl-1 - (triphenylmethyl) - IH- imidazol-4 -yl] piperidin-1-yl] phenyl] butanamide is dissolved in 5 ml of dimethylformamide and 40 mg (0.92 mmol) of sodium hydride at 60% are added. When the evolution of hydrogen has ceased, 0.06 ml (0.97 mmol) of methyl iodide is introduced. After one hour of reaction, the dimethylformamide is evaporated, the residue is taken up in a water-dichloromethane mixture and the organic phase is evaporated. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol mixture (97.5 / 2.5). Yield = 70% 8.2. (E) -2-butenedioate of N-methyl -N- [2 - [4- (5-methyl-1H- imidazol-4-yl) piperidin- 1-yl] phenyl] butanamide (1: 1) This is obtained compound from N-methyl -N- [2- [4- [5- methyl-1- (triphenylmethyl) -lH-imidazol-4-yl] piperidin-1- yl] phenyl] butanamide according to the method described in 1 'example 1.5.

The fumarate is prepared by adding a molar equivalent of fumaric acid in solution in 1 ethanol. Melting point = 146 ° C (ethanol-ether)

Example 9 (compound 3)

N-2 - [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] benzenemethane

9.1. N- 2 - [4- [5-methyl- (1-triphenylmethyl) - IH- imidazol -4- yl] piperidin- 1 -yl] phenyl] benzenemethane A 0.5 g (1 mmol) of 2- [4- [5-methyl-1- (triphenylmethyl) -1H- imidazol-4-yl] piperidin-1-yl] benzeneamine, in solution in 7 ml of toluene, 0.102 ml (1 mmol) of benzaldehyde and 0.05 g are added para-toluene sulfonic acid. The mixture is brought to reflux temperature, the solvent is evaporated and a gum is obtained. The gum thus obtained is dissolved in ethanol and a catalytic hydrogenation is carried out at room temperature in the presence of Raney nickel. The product obtained is purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol mixture (98/2). 0.41 g of product is obtained. Yield = 69%

9.2. N-2 - [4- (5-methyl-1H-imidazol-4 -yl) piperidin-1-yl] phenyl] benzenemethane This compound is obtained from N-2 - [4- [5-methyl- ( 1- triphenylmethyl) -IH- imidazol -4 -y1] piperidin-1-yl] phenyl] benzenemethanamine described in Example 1.5.

Melting point = 154-155 ° C (acetonitrile) Example 10 (compound # 26)

N- (methoxymethyl) -2- [4- (5 -methyl-1H- imidazol- 4 -yl) piperidin- 1 -yl] benzenamine

10.1. N- (methoxymethyl) -2- [4- [5-methyl- (1-triphenylmethyl) -lH-imidazol-4-yl] piperidin-1-yl] benzenamine This compound is obtained by reacting 0.5 g (1 mmol) of 2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] benzeneamine with 0.096 ml (1.05 mmol) of methoxyacetyl chloride in the conditions described in Example 3.1. 0.4 g of product is obtained. Yield = 70% Melting point = 212 ° C

10.2. N- (methoxymethyl) -2- [4- (5-methyl-1H-imidazol-4-yl) piperidin- 1 -yl] benzenamine This compound is obtained from N- (methoxymethyl) -2- [4- [5-methyl- (1-triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] benzenamine according to the method described in Example 1.5. Melting point = 200-203 ° C

Example 11 (Compound # 36) 2- (dimethylamino) -N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] acetamide

11.1. 2- (dimethylamino) -N- [2 - [4- [5-methyl- (1-triphenylmethyl) -lH-imidazol-4-yl] piperidin-1-yl] phenyl] acetamide

0.2 g (1.94 mmol) of dimethylglycine is dissolved in 10 ml of dichloromethane and 0.372 ml (2.13 mmol) of diisopropylethylamine is added. The mixture is cooled to -20 ° C. and 0.25 ml of isobutyl chloroformate is introduced dropwise. The mixture is left stirring at this temperature for 30 minutes, then 0.965 g (1.94 mmol) of 2- [4- [5-methyl-1- (triphenylmethyl) -1H-imidazol-4-yl] piperidin-1 are added. -yl] benzeneamine, solution in 5 ml of dichloromethane. The temperature is allowed to return to ambient for one night. The reaction medium is washed with water and the organic phase is concentrated. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol / methylamine mixture (97/2/1). 0.712 g of compound are obtained. Yield = 65%

11.2. 2- (dimethylamino) -N- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] acetamide This compound is obtained by treating 2- (dimethylamino) -N - [2- [4- [5-methyl- (1-triphenylmethyl) -IH-imidazol -4- yl] piperidin- 1-yl] phenyl] acetamide under the conditions described in Example 1.5. The residue is purified by chromatography on a column of silica gel, eluting with a dichloromethane / methanol / ammonia mixture (92/8 / 0.5). Melting point = 195-198 ° C

Example 12 (compound No. 42)

(E) -2-Butenedioate of 1- [2- [4- (5-methyl-1H-imidazol-4-yl) piperidin-1-yl] phenyl] pyrrolidin-2-one

12.1. 1- [2- [4- [5-methyl- (1-triphenylmethyl) -lH-imidazol- 4-yl] piperidin-1-yl] phenyl] pyrrolidin-2-one

A 0.7 g (1.4 mmol) of 2- [4- [5-methyl-l- (triphenylmethyl) - 1H-imidazol-4-yl] piperidin-1-yl] benzeneamine dissolved in 20 ml of dichloromethane , 0.12 ml (1.47 mmol) of pyridine is added. At a temperature in the region of 5 ° C., 0.165 ml of 4-chlorobutyryl chloride is introduced and then the temperature is allowed to rise to ambient. The reaction medium is washed with water, dried and concentrated. The residue is dissolved in 20 ml of tetrahydrofuran and 70 mg (1.75 mmol) of 60% sodium hydride are added at a temperature of 5 ° C. The reaction medium is left at room temperature overnight, it is taken up in water and extracted with dichloromethane. After drying and evaporation of the organic phase, the gum obtained is crystallized from ether. 0.636 g of product is obtained.

Efficiency = 85%

Melting point = 168-169 ° C

12.2. (E) -2-Butenedioate of 1- [2- [4- (5-methyl -1H-imidazol-4-yl) piperidin-1-yl] phenyl] pyrrolidin-2- one Treat 1- [2- [4- [5-methyl- (1-triphenylmethyl) -1H-imidazol-4-yl] piperidin-1-yl] phenyl] pyrrolidin-2-one under the conditions defined in Example 1.5. The product obtained is purified by chromatography on silica gel, eluting with a dichloromethane / methanol mixture (90/10). The fumarate is crystallized from ethanol. Melting point = 168-169 ° C (ethanol)

Table legend: in column "A"

-cC ₃ H ₇ represents a cyclopropyl group, cCgl ^ a cyclohex group and -C ₆ H ₅ a phenyl group

in the "Salt" column

(x: y) means x moles of acid for y moles of base, the absence of any mention means that the compound is in the basic state, fum. represents a fumarate, HC1 a hydrochloride

in the "Melting point" column

ND means that the melting point has not been determined Board

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 advantage as substances with therapeutic activity.

Thus, the compounds of the invention were subjected to a test for inhibiting the swelling of rabbit blood platelets 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, Académie Press Inc., 1984).

Blood is taken from New Zealand rabbits by cardiac puncture, using a citrate-dextrose anticoagulant. 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 is incubated for 20 minutes in a sodium propionate / propionic acid medium (140 mM) containing potassium chloride (1 mM), magnesium chloride (1 m), glucose (10 mM), all buffered with Hepes (20 mM) at pH 6.7 and the osmolarity of which is approximately 300 mosm / 1. Propionic acid diffuses into the platelets where it dissociates, causing intra-cellular 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 mean platelet volume, makes it possible to estimate the maximum swelling of the platelets. The products to be tested are added to the propionic acid incubation medium at the desired concentrations, before the addition of PRP. The results are expressed as a percentage of inhibition of maximum swelling making it possible to calculate the IC ₅₀ or concentration inhibiting by 50% the maximum swelling.

In this test, the IC ₅₀ 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 pathology such as arterial and pulmonary hypertension, cardiac arrhythmia, cardiac ischemia, cardiac infarction, heart failure and angina pectoris, ischemia of peripheral organs, limbs lower and central nervous system, nephropathies, edemas, fibrosis and cancer, as well as diseases characterized by hyperplasia and enlargement of the vessels or the heart. They can also be used for organ protection in surgery or organ transplant operations.

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

For this purpose they can be presented in all forms 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 from 1 to 4 times a day.

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

Claims

claims

1. Compounds of formula (I)

in which

R ₂ and R ₂ each independently of one another represent either a hydrogen atom or a (C _x -C ₄ ) straight or branched alkyl group, R ₃ and R ₄ each independently represent one of l other either a hydrogen atom, a halogen atom, or a (C -C ₄ ) alkyl group, or a trifluoromethyl group, or a (C ₂ -C ₄ ) alkoxy group, or a group S (0 ) _p R with R group (C ^ C _j ) straight or branched alkyl and p = 0 to 2, and A represents either a hydrogen atom, or a (C ₂ -C ₆ ) straight or branched alkyl group, or a phenyl (C ₂ -C ₄ ) alkyl group, either a group -COR ₅ , or a group -COOR ₅ , or a group -CONHR ₅ , or a group -S0 ₂ R _{5 /} where R ₅ is a group (C ₂ -C ₆ ) straight or branched alkyl, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₅ ) alkyl group, a group (C ₂ -C ₆ ) alkoxy alkyl, a phenyl group, a phenyl (C ₂ -C ₄ ) alkyl group, a phenyl (C ₂ -C ₄ ) alkylidene group, or a group -COCH ₂ NR ₆ R ₇ where R ₆ is a hydrogen atom or a (C ₂ -C ₄ ) straight or branched alkyl group and R ₇ a (C ₂ -C ₄ ) straight or branched alkyl group or an acyl group or R _{1 #} R ₃ and R ₄ being as defined above, A and R ₂ form a cycle of the type - (CH ₂ ) _n C0- where n can take a value between 2 and 6, in the form of free bases or of addition salts with pharmaceutically acceptable acids.

2. Compounds according to claim 1 characterized in that R _x represents a (C ₂ -C) straight or branched alkyl group, R ₂ represents either a hydrogen atom or a (C ₂ -C ₄ ) straight alkyl group or branched, R ₃ represents either a hydrogen atom, a halogen atom, or a (C ₁ -C ₄ ) alkyl group, or a trifluoromethyl group, or a (C ₁ -C ₄ ) alkoxy group, R ₄ represents either a hydrogen atom or a halogen atom, and A represents either a hydrogen atom, or a (C _x -C ₆ ) straight or branched alkyl group, or a phenyl (C ₂ -C _{4) group} ) alkyl, either a group -C0R ₅ , or a group -C00R ₅ , or a group -CONHR ₅ , or a group -S0 ₂ R _{5 /} where R ₅ is a group (C ^ C _g ) straight or branched alkyl, a (C ₃ -C ₇ ) cycloalkyl group, a (C ₃ -C ₇ ) cycloalkyl (C ₂ -C ₅ ) alkyl group, a (C _x -C ₄ ) alkoxy (C ^ Cg) alkyl group, a phenyl group , a phenyl (C ₁ -C ₄ ) alkyl group, a phenyl (C ₁ -C) alkylidene group, or u n group -COCH ₂ NR ₆ R ₇ where R ₆ is a hydrogen atom or a (C ₁ -C ₄ ) straight or branched alkyl group and R ₇ a (C ₁ -C ₄ ) straight or branched alkyl group or a acyl group or

R _x , R ₃ and R ₄ being as defined above,

A and R ₂ form a cycle of the type - (CH ₂ ) _n C0- where n can take a value between 2 and 6, in the form of free bases or of addition salts with pharmaceutically acceptable acids.

3. Process for the preparation of the compounds of formula (la)

in which R _x , R ₃ and R ₄ are as defined in claim 1, process characterized in that a compound of formula (II) is reacted

in which Hal represents a halogen atom with a compound of formula (III)

in an aprotic solvent in the presence of a base to obtain a compound of formula (IV)

which is subjected to catalytic hydrogenation.

4. Process for the preparation of the compounds of formula (Ib)

wherein R _{1 #} R ₃ R ₄ and A are as defined in claim 1, process characterized in that the compound of formula (IV) is treated with triphenylmethyl chloride to prepare a compound of formula (V)

which is subjected to a catalytic hydrogenation and a compound of formula (VI) is obtained

then A is introduced by acylation or sulfonylation, optionally followed by a reduction of the acyl group thus introduced and a compound of formula (VII) is obtained

from which the imidazole nucleus is deprotected.

5. Process for the preparation of the compounds of formula (Ie)

in which R _{1 #} RR ₃ R ₄ and A are as defined in claim 1, process characterized in that either performs a reductive alkylation of the compound of formula (VI), or a compound of formula (VII) is reacted with a compound of formula R ₂ X in which R ₂ represents a (C ₁ -C ₄ ) alkyl group and X an atom halogen to prepare a compound of formula (VIII)

from which the imidazole nucleus is deprotected.

6. Process for the preparation of the compounds of formula (Id)

which corresponds to a compound of formula (I) in which A and R ₂ form a ring of the type - (CH ₂ ) _n CO- where n can take a value between 2 and 6, process characterized in that one reacts a compound of formula (VI) with a compound of formula X (CH ₂ ) _n COCl in which X is a halogen atom and n as defined above, then the compound thus obtained is treated with sodium hydride to give a compound from which the imidazole nucleus is deprotected

7. Medicament, characterized in that it contains a compound according to any one of claims 1 and 2.

8. Pharmaceutical composition characterized in that it contains a compound according to any one of claims 1 and 2 in association with a pharmaceutically acceptable excipient.