WO2003011856A1

WO2003011856A1 - Aminoalkylimidazole derivatives preparation and therapeutic use thereof

Info

Publication number: WO2003011856A1
Application number: PCT/FR2002/002677
Authority: WO
Inventors: Gregorio Del Sol Moreno; Juan Antonio Diaz Martin; Maria Dolores Jimenez-Bargueno; Ulpiano Martin-Escudero Perez; Magali Romanach Ferrer
Original assignee: Sanofi-Synthelabo
Priority date: 2001-07-27
Filing date: 2002-07-26
Publication date: 2003-02-13
Also published as: FR2827863A1; AR034909A1

Abstract

The invention concerns a compound of formula (I), wherein: A represents a C0-C6 alkyl group, optionally substituted by a halogen atom, a hydroxy or a phenyl; and R1, R2, R3 and R4 independently of one another represent a hydrogen, halogen atom, a hydroxy, a nitro, cyano, trifluoromethyl, C1-C3 alkyl, phenyl, C1-C3 alkoxy, phenoxy, C1-C3 alkyl-carbonyloxy, benzoyloxy, -C(O)OH, C(O)O-C1-C3-alkyl, -C(O)O-phenyl, -CONH2-, -C(O)NH-C1-C3 alkyl or C(O)N(C1-C3 alkyl)2 group, and its salts, N-oxides and hydrates. The invention is applicable in therapeutics.

Description

AMINOALKYLIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC USE

The subject of the present invention is aminoalkylimidazole derivatives, their preparations and their therapeutic applications, in particular in the treatment of obesity and diabetes.

Consequently, the first subject of the present invention is the compounds corresponding to formula (I)

in which :

A represents a Co-β alkyl group, the alkyl group possibly being substituted by a halogen atom, a hydroxy or a phenyl, and R1, R2, R3 and R4 independently represent one of the others a hydrogen atom, d 'halogen, hydroxy, nitro, cyano, trifluoromethyl,

C ₁ . ₃ alkyl, phenyle, Cι _-3 alkoxy, phenoxy, C1. ₃ alkyl-carbonyloxy, benzoyloxy,

-C (O) OH, -C (0) O-Cι _-3 alkyl, -C (O) O-phenyl, -CONH ₂ , -C (0) NH-C _1-3 alkyl or

-C (0) N (Cι- ₃ alkyl) ₂ .

The present invention also relates to the salts, N-oxides and hydrates of the compounds corresponding to formula (I).

In the context of the present invention, the following definitions are intended: - Cχ_z, where x and z can take the values from 0 to 6, a carbon chain being able to have from x to z carbon atoms, however when x takes the value 0, C ₀ represents a bond; for example C ₁ - ₃ indicates a carbon chain which can have from 1 to 3 carbon atoms; C ₀ - ₆ indicates a bond or a carbon chain which can have from 1 to 6 carbon atoms; - alkyl, a saturated, linear or branched aliphatic group unless otherwise specified; for example, a Cι _-4 alkyl group represents a carbon chain of 1 to 4 carbon atoms, linear or branched, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, preferably methyl, ethyl, propyl or isopropyl; - alkoxy, an alkyloxy group with saturated, linear or branched aliphatic chain;

- halogen atom, fluorine, chlorine, bromine or iodine.

The compounds of formula (I) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures are part of the invention.

When a compound according to the invention can be in the form of different tautomers, the invention comprises all the tautomers of these compounds.

The compounds of formula (I) can be presented either as free base or as addition salt (s) with acids, which also form part of the invention. These salts, according to the present invention, include those with mineral or organic acids which allow proper separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, by example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphosulfonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, the hydrobromide, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the maleate, the fumarate, 2-naphthalenesulfonate, paratoluenesulfonate and trifluoroacetate. Although the pharmaceutically acceptable salts are preferred, the other salts are part of the present invention. These salts can be prepared, according to methods known to a person skilled in the art, for example, by reaction of the compound of formula (I) in base form with the acid in an appropriate solvent, such as an alcoholic solution or a organic solvent, then separation of the medium which contains it by evaporation of the solvent or by filtration.

On the other hand, in the context of the present invention, the term “protective group Pg” is intended to mean a group which makes it possible on the one hand to protect a reactive function such as a hydroxy or an amine during synthesis and on the other hand to regenerate the intact reactive function at the end of the synthesis. Examples of protective groups as well as methods of protection and deprotection are given in Protective groups in Organic Synthesis, Greene et al., 2 ^nd Ed. (John Wiley & Sons, Inc., New York). The preferred compounds according to the invention are chosen from the following subgroups, in which:

^* A represents an unsubstituted Co-salkyl group and more particularly an unbranched Co-salkyl group; and / or ^* R1, R2, R3 and R4 independently of one another represent a hydrogen atom, a halogen atom, a hydroxy, a Cι _-3 alkyl or d- ₃ alkoxy group, and preferably a methyl or a hydrogen atom.

The preferred compounds result more particularly from the combination of the characteristics of subgroups of preferred compounds as indicated above.

In particular, the following subgroup of compounds is particularly preferred:

^* A represents an unbranched and unsubstituted Co-salkyl group; and

^* R1, R2, R3 and R4 represent a hydrogen atom;

In the context of the present invention, the compounds of the table below are preferred and more particularly the following compounds:

^* 4- (2,5-dihydropyrrol-1-ylmethyl) -1 H-imidazole;

^* 4- [4- (3-methyl-2,5-dihydropyrrol-1 -yl) butyl] -1 H-imidazole; ^* 4- [3- (2,5-dihydropyrrol-1 -yl) propyl] -1 H-imidazole;

^* 4- {4 - [(2fî ^* , 5S ^* ) -2,5-dimethyl-2,5-dihydropyrrol-1 -yl] butyl} -1 H-imidazole;

^* 4- [4- (2,5-dihydropyrrol-1 -yl) butyl] -1 H-imidazole;

^* 4- [5- (2,5-dihydropyrrol-1 -yl) pentyl] -1 H-imidazole;

^* 4- [6- (2,5-dihydropyrrol-1-yl) hexyl] -1 H-imidazole; and * 4- [4- (3,4-dimethyl-2,5-dihydropyrrol-1 -yl) butyl] -1 H-imidazole.

A second subject of the present invention is processes for preparing the compounds of formula (I) according to the invention.

Thus, the compounds of formula (I) can be prepared according to the methods represented in schemes 1 and 2.

Diagram 1

According to the method of scheme 1, the compounds of formula (I) are prepared by amino reduction, in which R1, R2, R3, R4 and A are defined as in formula (I), reacting 2,5- dihydropyrrole of formula (III), in which R1, R2, R3 and R4 are defined as in formula (I) and optionally pre-protected, with a carbonyl derivative of formula (II), in which Pg represents an appropriate protective group such as for example a triphenyl-methyl, in the presence of a reducing agent. The reaction can be carried out in the presence of a reducing agent such as for example sodium cyanoborohydride or sodium borohydride in a protic or aprotic solvent, such as methanol, ethyl acetate, N, N-dimethylformamide, water or a mixture of these solvents, at a temperature between 0 and 100 ⁹ C, to give the compound of formula (la). The compound of formula (la) is then deprotected according to conditions known to a person skilled in the art for example, when Pg represents a triphenyl-methyl, this is deprotected in an acid medium, in the presence of aqueous hydrochloric acid in a solvent such as butanone at a temperature between 0 ⁹ C and 80 ^Q C or trifluoroacetic acid in a solvent such as dichloromethane at a temperature between 0-C and 40 ⁹ C, to give the compound of formula (I) . Alternatively, the compounds of formula (I) can be synthesized according to the process described in scheme 2.

Diagram 2

According to the method of scheme 2, the compounds of formula (I) are prepared by substitution, in which R1, R2, R3, R4 and A are defined as in formula (I), by reacting the 2,5-dihydropyrrole of formula (III), as defined above, with a halogen derivative of formula (IV), in which X represents a halogen atom, such as a chloro, bromo or iodine and Pg represents an appropriate protective group such as for example a dimethylsulfamoyl, in the presence of a base such as for example potassium carbonate, sodium carbonate or triethylamine. The reaction can be carried out in a protic or aprotic solvent, such as methanol, ethyl acetate, N, N-dimethylformamide, acetonitrile or a mixture of these solvents, at a temperature between 0 and 100 ^e C, to give the compound of formula (la). The compound of formula (la) is then deprotected according to conditions known to a person skilled in the art for example, when Pg represents a dimethylsulfamoyl group, this is deprotected in an acid medium, in the presence of aqueous hydrochloric acid at a temperature included between 0 ^S C and 80 ⁹ C, to give the compound of formula (I). The starting compounds (II), (IV) and the aminocycles of formula (III) are directly commercially available, can be synthesized by conventional methods known to those skilled in the art or are known in the literature such as for example in J. Med. Chem., 34, 725-736 (1991); Recl. Trav. Chim. Netherlands, 112, 123-125 (1993); Chem. Ber., 124, 791-801 (1991); Tetrahedron Lett., 33, 273-276 (1992); J. Org. Chem., 45, 2139-2145 (1980) or Tetrahedron, 40, 8785-8788 (1999).

The present invention also relates to the intermediate of formula (III): 3,4-dimethyl-2,5-dihydro-1 H-pyrrole.

The following examples illustrate the methods and techniques suitable for the preparation of this invention, without however limiting the scope of the claim. Elementary micro-analyzes and NMR, IR or mass spectra confirm the structures of the compounds obtained.

Example 1

4- [3- (2,5-dihydropyrrol-1-yl) propyl] -1 H-imidazole diethanedioate

1.1. 4- [3- (2,5-Dihydropyrrol-1 -yl) propyl] -1 -trityl-1 H-imidazole

To a solution of 5.3 g (0.014 mole) of 3- (1 -trityl-1 H-imidazol-4-yl) propionaldehyde in 50 ml of dry toluene, 5.37 ml (0.018 mole) of titanium is added ( IV) isopropoxide, then the mixture is stirred for 10 min at room temperature under a nitrogen atmosphere and 1.0 g (0.014 mole) of 3-pyrroline is added. After 1 h, 27 ml of isopropyl alcohol and 2.72 g (0.043 mol) of sodium cyanoborohydride are added and the mixture is stirred overnight at room temperature. A solution of 20 g of ammonium fluoride in 200 ml of water is added, the mixture is stirred for 5 h. and extracted with 3 times 300 ml of ethyl acetate. The organic phases are washed with brine, dried with sodium sulfate and concentrated to dryness. The residue is purified by chromatography on silica gel, using the eluent mixture methanol / dichloromethane: 2/98. 1.76 g of 4- [3- (2,5-Dihydropyrrol-1 -yl) propyl] -1 -trityl-1 H-imidazole are obtained in the form of a yellowish oil. Yield 29%.

1.2. 4- [3- (2,5-dihydropyrrol-1-yl) propyl] -1 H-imidazole diethanedioate

A solution of 1.7 g (0.004 mole) of 4- [3- (2,5-Dihydropyrrol-1 -yl) propyl] -1 -trityl-1 H- imidazole in 25 ml of methanol and 95 ml of solution aqueous 6N hydrochloric acid is stirred for 3 hours at 50-60 ⁹ C. The mixture was concentrated. The residue is dissolved in 30 ml of water and washed with 3 times 50 ml of diethyl ether. We basifies the organic phase at 0 ° C with a 10N sodium hydroxide solution to pH 14 and extracted with 5 times 150 ml of ethyl acetate. The organic phases are washed with brine, dried with anhydrous potassium carbonate and evaporated to dryness. 0.51 g of 4- [3- (2,5-dihydropyrrol-1-yl) propyl] -1 H-imidazole is obtained in the form of a colorless oil. Yield 71%. To a solution of 0.51 g (0.0029 mole) of the product obtained in 10 ml of ethanol is added a solution of 0.52 g (0.0058 mole) of ethanodioic acid in 10 ml of ethanol. The precipitate formed is filtered and washed with 2 ml of cold ethanol, it is filtered and then dried. 0.83 g of a white solid with a melting point of 142-143 ° C. is obtained. Yield 81%.

Example 2: 4- [4- (2,5-dihydropyrrol-1-yl) butyl] -1 H-imidazole di- (£) -but-2-enenedioate

2.1. 4- [4- (2,5-dihydropyrrol-1-yl) butyl] -N, N-dimethyl-1 H-imidazole-1-sulfonamide To a solution of 5.5 g (0.014 mole) of 2- [tert -butyl (dimethyl) sylyl] -4- (4-chlorobutyl) - N, N-dimethyl-1 H-imidazole-1-sulfonamide in 50 ml of acetonitrile, 1.0 g (0.014 mol) of 3- pyrroline, 6.0 g (0.043 mole) of potassium carbonate and 1, 1 g (0.007 mole) of sodium iodide, followed by stirring for 4 days at 80 ⁹ C. the reaction mixture is filtered and the filtrate is concentrated dryness. The residue is purified by chromatography on silica gel, using the eluent mixture methanol / dichloromethane: 5/95. 1.35 g of 4- [4- (2,5-dihydropyrrol-1-yl) butyl] -N, N-dimethyl-1 H-imidazole-1-sulfonamide are obtained in the form of a yellowish oil. Yield 31%.

2.2. Di- (£) -but-2-enenedioate of 4- [4- (2,5-dihydropyrrol-1 -yl) butyl] -1 H-imidazole A solution of 1.3 g (0.004 mole) of 4- [ 4- (2,5-dihydropyrrol-1-yl) butyl] -N, N-dimethyl-1 H-imidazole-1-sulfonamide in 25 ml of aqueous 6N hydrochloric acid solution is stirred overnight at 80 ^Q C. The mixture is concentrated. The residue is dissolved in 35 ml of water and washed 3 times with 50 ml of diethyl ether, then it is basified at 0 ° C with solid sodium carbonate and extracted with 5 times 75 ml of diethyl ether. The organic phases are washed with brine, dried with anhydrous sodium sulfate and evaporated to dryness. 0.68 g of 4- [4- (2,5-dihydropyrrol-1-yl) butyl] -1 H-imidazole is obtained in the form of a colorless oil (yield 79%). To a solution of 0.67 g (0.0035 mole) of the product obtained in 20 ml of ethanol is added a solution of 0.82 g (0.007 mole) of - (E) -but-2- enenedioic acid in 25 ml of ethanol. The precipitate formed is filtered and washed with 3 ml of cold ethanol, and dried. 1.14 g of a white solid with a melting point of 146-148 ° C. are obtained. Yield 60%. Example 3:

3.1 Terf-butyl ester of 3,4-dimethyl-2,5-dihydro-pyrrole-1-carboxylic acid

Nitrogen gas is bubbled for 20 minutes in 120 ml of dry dichloromethane. The ricyclenhexylphosphine dichloride [1, 3-bis (2,4,6-trimethylphenyl) -4,5-dihydroinidazol-2-ylidene] [benzylidine] of ruthenium (IV) (250 mg, 0.29 mmol), is added and the solution is stirred for 5 minutes. The bis- (2-methyl-allyl) -carbamic acid tert-butyl ester (1.32 g, 5.88 mmol) is added and the solution is stirred for 5 days under a nitrogen atmosphere. The flask is ventilated and the solution stirred for 1 hour under a normal atmosphere. The solvent is evaporated, 100 ml of n-heptane are added and the suspension is stirred for 15 minutes and filtered. The solvent is evaporated in vacuo and the oil is purified by chromatography on silica gel (dichloromethane / methanol: 99: 1). 590 mg (50%) of ferf-butyl ester of 3,4-dimethyl-2,5-dihydro-pyrrole-1-carboxylic acid are obtained in the form of an oil.

3.2. 3,4-Dimethyl-2,5-dihydro-1 H-pyrrole chloride:

1.5 g (7.6 mmol) of 3,4-dimethyl-2,5-dihydro-pyrrole-1-carboxylic acid ferf-butyl ester is stirred for 24 h with a mixture of 50 ml of acid 6N hydrochloric acid and 50 ml of methanol at 20 ° C. The solvent is evaporated in vacuo. The rest of the water is removed by adding 100 ml of ethanol and evaporating again. 1 g of 3,4-dimethyl-2,5-dihydro-1 H-pyrrole chloride is obtained in the form of a brown oil.

3.3. 4- [4- (3,4-dimethyl-2,5-dihydropyrrol-1 -yl) butyl] -1 -trityl-1 H-imidazole

A mixture of 3- (1 -trityl-1 H-imidazol-4-yl) butiraldehyde (840 mg, 2.2 mmol), 3,4-dimethylpyrroline (215 mg, 2.2 mmol) and acetic acid (2.2 ml) in 25 ml of dry tetrahydrofuran is stirred for 1 h. Solid sodium cyanoborohydride (207 mg, 3.3 mmol) is added in small portions for 15 min and the resulting mixture is stirred at 25 ° C for 24 h. The reaction is stopped with a saturated aqueous solution of ammonium chloride (25 ml), stirred for 1 h, extracted with ethyl acetate (2x70 ml), dried over sodium sulfate and evaporated to dryness. The resulting oil is purified by flash chromatography, with an eluent mixture of methanol / dichloromethane: 2/98, to give 150 mg of 4- [4- (3,4-dimethyl-2,5- dihydropyrrol-1 -yl ) butyl] -1 -trityl-1 H-imidazole in the form of an oil.

RMN HT (CDCI ₃ ): 1.62 (s, 6H), 1.50-1.80 (m, 4H), 2.60-2.80 (m, 4H), 3.45 (s, 4H),

6.2 (s wide, 1 H), 6.75 (s, 1 H), 7.55 (s, 1 H). The following table illustrates the chemical structures and the chemical properties of certain compounds of formula (I) according to the invention. These compounds were synthesized according to the methods described above.

Board

F (° C) indicates: melting point in ° C - (dec.) Indicates: decomposition The compounds of the invention of formula (I) have been the subject of pharmacological tests which have shown their interest as active substances in therapy.

More particularly, the compounds of the invention are antagonists of the H ₃ histamine receptor. H ₃ receptors are known to those skilled in the art and their therapeutic value has been described in the literature (“Histamine H ₃ receptor antagonists” Exp. Opinion Ther. Patents (2000) 10 (7): 1045-1055 ).

Thus, the compounds of the invention of formula (I) were subjected to an in vitro affinity test on the native histamine receptor of type H ₃ in a membrane preparation of the adult rat brain by the specific binding of [ ³ H] -N-α- methylhistamine at this receptor, according to methods described by Korte, A. et al. in Biochem. Biophys. Res. Common. 168, 979-986 (1990) and by West, RE Jr. et al. in Mol. Pharmacol. 38, 610-613 (1990).

The Ki of the compounds of the invention with respect to the H ₃ receptors are between 0.1 nM and 5.0 μM, and more particularly between 0.4 nM and 5.0 μM.

They have also been tested for their antagonistic effects on the histamine H ₃ receptor, by quantifying the antagonistic effect in vitro of each product on the H ₃ receptors involved in an inhibitory effect on the contraction of the ileum. electrically stimulated guinea pig distal, according to the method described by Hew, RWS et al. in Br. J. Pharmacol. 101, 621 -624 (1990).

The pA ₂ of the compounds of the invention with respect to the maximum relaxing effect of R-α-methylhistamine on the “control” preparation, in the presence of the solvent, are between 6 and 8, and more particularly between 6.2 and 7.9.

The results of the biological tests show that the compounds of the invention are antagonists of the histamine type H ₃ receptor.

On the other hand, the compounds of the invention of formula (I) were the subject of tests in vivo showing their ability to reduce the food intake in the fasted rat 24h.

The experiments were carried out on Wistar rats. The rats were placed individually in transparent plastic cages 48x26, 5x21, 5 cm. These cages were placed in a room isolated from any noise, at a temperature of 20 to 22 ° C, with a light cycle from 7 a.m. to 7 a.m., rats having free access to water and food.

Before carrying out the experiment, the rats were fasted for 24 hours with, however, access to ad libitum water. On the day of the experiment, the vehicle or the compound according to the present invention is administered, i.p. or p.o., 15 or 30 minutes before the provision of a known quantity of food (30g).

Each hour, for 6 hours, the amount of food ingested by the rat is measured.

It has been shown that the DA ₅ o (mg / kg ip or po) of the compounds of the invention vis-vis the intake of food may be less than 10.

The results of the tests show that the compounds of the invention make it possible to reduce food intake in animals. Thus, they make it possible to control weight gain, to treat obesity or to help with weight loss, in animals, but also in humans.

Consequently, these compounds can be used in the treatment of pathologies in which a type H ₃ histamine receptor antagonist has a therapeutic benefit. Especially such pathologies are obesity and diabetes. Also, these compounds can be used in the treatment of diseases of the central nervous system such as vigilance and sleep disorders, Alzheimer's disease and other dementias, Parkinson's disease, attention deficit disorder in children. hyperkinetics, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive impairment, depression and anxiety. Depression and anxiety states include, for example, anticipatory type anxiety (before surgery, before dental treatment, etc.), anxiety caused by dependence or withdrawal from alcohol, drugs, mania, seasonal affective disorders, migraines and nausea. They can also be used in the treatment of sexual dysfunction, hypertension, dizziness and travel sickness.

The use of the compounds according to the invention for the preparation of a medicament intended to treat the pathologies mentioned above forms an integral part of the invention. According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound according to the invention.

Thus, these pharmaceutical compositions contain an effective dose of a compound according to the invention or of a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutical excipients.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, its salt or hydrate, if any, can be administered in unit administration form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal administration forms, subcutaneous, intramuscular or intravenous administration and forms of rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.1 μg and 50 mg per kg of body weight per day. Although these dosages are examples of an average situation, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient.

Each unit dose may contain from 0.1 to 1000 mg, preferably from 1 to 500 mg, of active ingredient in combination with a pharmaceutical excipient. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 1 to 2500 mg. For example, when preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative or other materials. The tablets can be produced by different techniques, direct compression, dry granulation, wet granulation or hot melting.

According to a second example, a preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.

For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.

The present invention according to another of its aspects, also relates to a method of treatment of the pathologies indicated above which comprises the administration of a compound according to the invention or one of its salts, N-oxides or hydrates.

Claims

Claims:

1. Compound of formula (I)

in which :

A represents a C ₀ - ₆ alkyl group, the alkyl group possibly being branched by a halogen atom, a hydroxy or a phenyl and R1, R2, R3 and R4 independently represent one of the others a hydrogen atom, d halogen, hydroxy, nitro, cyano, trifluoromethyl, C- | ₃ alkyl, phenyle, Cι- ₃ alkoxy, phenoxy, Cι _-3 alkyl-carbonyloxy, benzoyloxy, -C (O) OH, -C (O) O-Cι _-3 alkyl, -C (O) O-phenyl, - CONH ₂ , -C (O) NH-Cι _-3 alkyl or -C (O) N (C _1-3 alkyl) _{2 as} well as its salt, N-oxide or hydrate.

2. Compound according to Claim 1, characterized in that:

^* A represents an unsubstituted Co-salkyl group and R1, R2, R3 and R4 independently of one another represent a hydrogen, halogen atom, a hydroxy, a C1- ₃ alkyl or C1 group. ₃ alkoxy.

3. Compound of formula (I) according to claim 1 characterized in that:

* A represents an unbranched and unsubstituted Co-salkyl group;

^* R1, R2, R3 and R4 represent a hydrogen atom or a methyl.

4. Compound of formula (I) according to claim 1 characterized in that it consists of:

^* 4- (2,5-dihydropyrrol-1-ylmethyl) -1 H-imidazole;

^* 4- [4- (3-methyl-2,5-dihydropyrrol-1-yl) butyl] -1 H-imidazole;

^* 4- [3- (2,5-dihydropyrrol-1-yl) propyl) -1 H-imidazole; ^* 4- {4 - [(2H ^* , 5S ^* ) -2,5-dimethyl-2,5-dihydropyrrol-1 -yl] butyl} -1 H-imidazole;

* 4- [4- (2,5-dihydropyrrol-1 -yl) butyl] -1 H-imidazole;

^* 4- [5- (2,5-dihydropyrrol-1 -yl) pentyl] -1 H-imidazole;

^* 4- [6- (2,5-dihydropyrrol-1 -yl) hexyl] -1 H-imidazole; and

^* 4- [4- (3,4-dimethyl-2,5-dihydropyrrol-1 -yl) butyl] -1 H-imidazole.

5. Compound characterized in that it consists of 3,4-dimethyl-2,5-dihydro-1 H-pyrrole.

6. Method for preparing a compound of formula according to one of claims 1 to 4 characterized in that: a compound of formula (la) is deprotected

wherein R1, R2, R3, R4, and A are as defined in claim 1 and Pg represents a protecting group to give the compound of formula (I) according to claim 1.

7. Pharmaceutical composition containing a compound of formula (I) according to one of claims 1 to 4, or its salt, N-oxide or hydrate, and at least one pharmaceutical excipient.

8. Use of a compound of formula (I) according to any one of claims 1 to 4, or its salt, N-oxide or hydrate, for the preparation of a medicament intended to treat a pathology where an antagonist of a histamine type H ₃ receptor provides a therapeutic benefit.

9. Use of a compound of formula (I) according to any one of claims 1 to 4, or its salt, N-oxide or hydrate, for the preparation of a medicament intended for treating obesity and diabetes

10. Use of a compound of formula (I) according to any one of claims 1 to 4, or its salt, N-oxide or hydrate, for the preparation of a medicament intended to treat disorders of alertness and sleep, Alzheimer's disease and other dementias, Parkinson's disease, attention deficit disorder in hyperkinetics, memory and learning disorders, epilepsy, schizophrenia, moderate cognitive impairment , depression, anxiety, sexual dysfunction, high blood pressure, dizziness, and travel sickness.