FR2827863A1 - New dihydropyrrolyl alkyl imidazole derivatives having histamine receptor antagonist activity for treatment of obesity, diabetes, and central nervous system disorders - Google Patents

Abstract

Dihydropyrrolyl alkyl imidazole derivatives (I), their salts, N-oxides, and hydrates are new. Dihydropyrrolyl alkyl imidazole derivatives of formula (I), their salts, N-oxides, and hydrates are new. A = 0-6C alkyl (optionally substituted by halogen, OH or phenyl); R1, R2, R3, and R4 = H, halogen, OH, NO2, CN, CF3, 1-3C alkyl or alkoxy, phenyl, phenoxy, 1-3C alkyl carbonyloxy, benzyloxy, -COOH, -COOalkyl(1-3C), -COOphenyl, -CONH2, -CONH-alkyl(1-3C), or -CON(alkyl of 1-3C)2.

Description

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AMINOALKYLIMIDAZOLE DERIVATIVES, THEIR PREPARATION AND THEIR USE
The present invention relates to aminoalkyl-imidazole derivatives, their preparations and their applications in therapy, particularly in the treatment of obesity and diabetes.

dans laquelle : A représente un groupe Co. alkyle, le groupe alkyle pouvant être substitué par un atome d'halogène, un hydroxy ou un phényle, et R1, R2, R3 et R4 représentent indépendamment l'un des autres un atome d'hydrogène, d'halogène, un hydroxy, un groupe nitro, cyano, trifluorométhyle,

C1-3 alkyle, phényle, C1-3 alcoxy, phénoxy, Calkyle-carbonyloxy, benzoyloxy, -C (O) OH,-C (O) O-C,-, alkyle,-C (0) 0-phényle,-CONH2,-C (O) NH-Cl-3alkyle ou -C (O) N (C1-3 alkyle) 2' La présente invention a pour objet également les sels, N-oxydes et hydrates des composés répondant à la formule (1). Accordingly, the present invention firstly provides the compounds of formula (1)

in which: A represents an alkyl group, the alkyl group may be substituted by a halogen atom, a hydroxy or a phenyl, and R1, R2, R3 and R4 represent, independently of one another, a hydrogen atom; , halogen, hydroxy, nitro, cyano, trifluoromethyl,

C1-3 alkyl, phenyl, C1-3 alkoxy, phenoxy, calkylcarbonyloxy, benzoyloxy, -C (O) OH, -C (O) OC, -, alkyl, -C (O) O -phenyl, -CONH2, The present invention also relates to the salts, N-oxides and hydrates of the compounds corresponding to formula (1). ## STR2 ##

In the context of the present invention, the following terms are understood: - Cx-z, where x and z can take the values from 0 to 6, a carbon chain that can have x to z carbon atoms, however when x takes the value
0, Co represents a bond; for example C1-3 indicates a carbon chain which may have from 1 to 3 carbon atoms; Co. e indicates a bond or a carbon chain may have from 1 to 6 carbon atoms; alkyl, a saturated, linear or branched aliphatic group unless otherwise specified; for example, a Calkyl group represents a carbon chain of 1 to 4 carbon atoms, linear or branched, more particularly a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertbutyl, preferably a methyl, ethyl, propyl or isopropyl;

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 alkoxy, a linear or branched saturated aliphatic chain alkyloxy group; - halogen atom, fluorine, chlorine, bromine or iodine.

The compounds of formula (1) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the 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 (1) may be present either as free base or as acid addition salt (s), which are also part of the invention. These salts, according to the present invention, include those with inorganic or organic acids which allow a suitable separation or crystallization of the compounds of formula (1), such as picric acid, oxalic acid or an optically active acid, by examples are tartaric acid, dibenzoyltartric acid, mandelic acid or camphorsulfonic acid, and those which form physiologically acceptable salts, such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogenphosphate, maleate, fumarate, 2-naphthalenesulphonate, para-toluenesulphonate and trifluoroacetate. Even though the pharmaceutically acceptable salts are preferred, the other salts are part of the present invention. These salts may be prepared according to methods known to those skilled in the art, for example by reacting the compound of formula (1) in base form with the acid in a suitable solvent, such as an alcoholic solution or a organic solvent, and 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 "protecting group Pg" is intended to mean a group which makes it possible on the one hand to protect a reactive function such as a hydroxyl or an amine during a synthesis and on the other hand to regenerate the reactive function intact at the end of synthesis. Examples of protecting groups as well as protection and deprotection methods are given in Protective groups in Organic Synthesis, Greene et al., 2nd Ed.

(John Wiley & Sons, Inc., New York).

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The preferred compounds according to the invention are chosen from the following subgroups, in which: A represents a Cl-alkyl group and more particularly a Cl, unbranched alkyl group; and / or R1, R2, R3 and R4 represent, independently of one another, a hydrogen, halogen, a hydroxy, a C1-3 alkyl or C1-3 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.

* 4-[3- (2, 5-dihydropyrrol-1-yl) propyl]-1 H-imidazole ; * 4- {4-[ (2R*, 58*) -2, 5-diméthyl-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 ; et * 4-[6- (2, 5-dihydropyrrol-1-yl) héxyl]-1 H-imidazole. La présente invention a pour second objet des procédés de préparation des composés de formule (1) selon l'invention. In particular, the following subgroup of compounds is particularly preferred: A represents a non-branched C1-alkyl group; and R1, R2, R3 and R4 represent a hydrogen atom; In the context of the present invention, the compounds of the following table are preferred and more particularly the following compounds: 4- (2,5-dihydropyrrol-1-ylmethyl) -1H-imidazole; 4- [4- (3-methyl-2,5-dihydropyrrol-1-yl) butyl] -1H-imidazole;

4- [3- (2,5-dihydropyrrol-1-yl) propyl] -1H-imidazole; 4- {4- [4- (2R *, 58 *) -2,5-dimethyl-2,5-dihydropyrrol-1-yl] butyl} -1H-imidazole; 4- [4- (2,5-dihydropyrrol-1-yl) butyl] -1H-imidazole; 4- [5- (2,5-dihydropyrrol-1-yl) pentyl] -1H-imidazole; and * 4- [6- (2,5-dihydropyrrol-1-yl) hexyl] -1H-imidazole. The subject of the present invention is processes for the preparation of the compounds of formula (1) according to the invention.

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Schéma 1

R2 RI R2 \J- X A H HNR4 R3 r, lN : y (111) N A R4 Y < "'. Thus, the compounds of formula (1) can be prepared according to the methods shown in Schemes 1 and 2.

Diagram 1

## STR2 ## wherein R 1 is R 1

Selon le procédé du schéma 1, on prépare par amino-réduction les composés de formule (1), dans laquelle Ri, R2, R3, R4 et A sont définis comme dans la formule (1), en faisant réagir le 2, 5-dihydropyrrole de formule (III), dans laquelle R1, R2, R3 et R4 sont définis comme dans la formule (1) et éventuellement pré-protégés, avec un dérivé carbonylé de formule (II), dans laquelle Pg représente un groupe protecteur approprié tel que par exemple un triphényl-méthyle, en présence d'un réducteur. La réaction peut être réalisée en présence d'un réducteur tel que par exemple le cyanoborohydrure de sodium ou le borohydrure de sodium dans un solvant protique ou aprotique, tel que le méthanol, l'acétate d'éthyle, la N, N-dimethylformamide, l'eau ou un mélange de ces solvants, à une température comprise entre 0 et 100 C, pour donner le composé de formule (la). Le composé de formule (la) est ensuite déprotégé selon des conditions connues de l'homme du métier par exemple, lorsque Pg représente un triphényl-méthyle, celui-ci est déprotégé en milieu acide, en présence d'acide chlorhydrique aqueux dans un solvant tel que le butanone à une température comprise entre OOC et 800C ou l'acide trifluoroacétique dans un solvant tel que le dichlorométhane à une température comprise entre 0 C et 40 C, pour donner le composé de formule (1). ## STR2 ## ## STR2 ## ## STR2 ##

According to the method of Scheme 1, the compounds of formula (1) in which R 1, R 2, R 3, R 4 and A are defined as in formula (1) are prepared by amino-reduction, by reacting the 2,5 dihydropyrrole of formula (III), wherein R1, R2, R3 and R4 are defined as in formula (1) and optionally pre-protected, with a carbonyl derivative of formula (II), in which Pg represents a suitable protecting group such as for example a triphenylmethyl, in the presence of a reducing agent. The reaction may 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 or N, N-dimethylformamide, water or a mixture of these solvents, at a temperature between 0 and 100 C, to give the compound of formula (la). The compound of formula (Ia) is then deprotected under conditions known to those skilled in the art, for example, when Pg represents a triphenyl-methyl, it is deprotected in an acidic medium, in the presence of aqueous hydrochloric acid in a solvent such as butanone at a temperature between 0OC and 800C or trifluoroacetic acid in a solvent such as dichloromethane at a temperature between 0 C and 40 C, to give the compound of formula (1).

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 Alternatively, the compounds of formula (1) can be synthesized according to the method described in scheme 2.

R2 R1Q R3 R2 N R3 \ " ('" NANsi-/- ir \s, {1 H' (III) R3 1 N N Pg CV) pg' () a) t R2 R1Q R3 NAN R4 \J'-/R4 N H (1)

Selon le procédé du schéma 2, on prépare par substitution les composés de formule (1), dans laquelle R1, R2, R3, R4 et A sont définis comme dans la formule (1), en faisant réagir le 2, 5-dihydropyrrole de formule (III), tel que défini précédemment, avec un dérivé halogéné de formule (IV), dans laquelle X représente un atome d'halogène, tel qu'un chloro, bromo ou iode et Pg représente un groupe protecteur approprié tel que par exemple un diméthylsulfamoyle, en présence d'une base telle que par exemple la carbonate de potassium, de sodium ou la triethylamine. La réaction peut être réalisée dans un solvant protique ou aprotique, tel que le méthanol, l'acétate d'éthyle, la N, N-dimethylformamide, l'acétonitrile ou un mélange de ces solvants, à une température comprise entre 0 et 100 C, pour donner le composé de formule (la). Le composé de formule (la) est ensuite déprotégé selon des conditions connues de l'homme du métier par exemple, lorsque Pg représente un groupe diméthylsulfamoyle, celui-ci est déprotégé en milieu acide, en présence d'acide chlorhydrique aqueux à une température comprise entre OOC et 80 C, pour donner le composé de formule (1). Figure 2

## STR5 ## wherein R 1 R 3 R 3 R 3 N N R 3 R 4 R 3 NH (1)

According to the process of Scheme 2, the compounds of formula (1) in which R1, R2, R3, R4 and A are defined as in formula (1) are prepared by substitution, by reacting the 2,5-dihydropyrrole of formula (III), as defined above, with a halogenated derivative of formula (IV), in which X represents a halogen atom, such as a chloro, bromo or iodine, and Pg represents a suitable protective group such as, for example dimethylsulfamoyl in the presence of a base such as, for example, potassium carbonate, sodium carbonate or triethylamine. The reaction may 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 of between 0 and 100 ° C. to give the compound of formula (Ia). The compound of formula (Ia) is then deprotected under conditions known to those skilled in the art, for example, when Pg represents a dimethylsulphamoyl group, the latter is deprotected in acidic medium, in the presence of aqueous hydrochloric acid at a temperature of between OOC and 80 C, to give the compound of formula (1).

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The starting compounds (II), (IV) and 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 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, 219-2145 (1980) or Tetrahedron, 40, 8785-8788 (1999).

The following examples illustrate the methods and techniques suitable for the preparation of this invention without, however, limiting the scope of the claim.

The elemental micro-analyzes and the NMR, IR or mass spectra confirm the structures of the compounds obtained.

Example 1 4- [3- (2,5-Dihydropyrrol-1-yl) propyl] -1H-imidazole diethanedioate 1.1. 4- [3- (2,5-Dihydropyrrol-1-yl) propyl] -1-trityl-1H-imidazole To a solution of 5.3 g (0.014 mole) of 3- (1-trityl-1H-imidazole) 4-yl) propionaldehyde in 50 ml of dry toluene is added 5.37 ml (0.018 mole) of titanium (IV) isopropoxide, then stirred for 10 min at room temperature under a nitrogen atmosphere and 1.0 is added g (0.014 mol) of 3-pyrroline. 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-1H-imidazole are obtained in the form of a yellowish oil.

Yield 29%.

1.2. 4- [3- (2,5-Dihydropyrrol-1-yl) propyl] -1H-imidazole diethanedioate A solution of 1.7 g (0.004 moles) of 4- [3- (2,5-dihydropyrrol-1- yl) propyl] -1-trityl-1Himidazole in 25 ml of methanol and 95 ml of aqueous 6N hydrochloric acid solution is stirred for 3 h at 50-60 C. The mixture is concentrated. The residue is dissolved in 30 ml of water and washed with 3 times 50 ml of diethyl ether. The organic phase is basified at 0 ° C. with 1N 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

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 anhydrous potassium and evaporated to dryness. 0.51 g of 4- [3- (2,5-dihydropyrrol-1-yl) propyl] -1H-imidazole is obtained in the form of a colorless oil. Yield 71%. To a solution of 0.51 g (0.0029 mol) of the product obtained in 10 ml of ethanol is added a solution of 0.52 g (0.0058 mol) of ethanodioic acid in 10 ml of ethanol.

The precipitate formed is filtered off and washed with 2 ml of cold ethanol, filtered and 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] -1H-imidazole di- (E) -but-2-enedioate 1.1. 4- [4- (2,5-Dihydropyrrol-1-yl) butyl] -N, N-dimethyl-1H-imidazole-1-sulfonamide To a solution of 5.5 g (0.014 mole) of 2- [4- -butyl (dimethyl) -silyl] -4- (4-chlorobutyl) -N, N-dimethyl-1H-imidazole-1-sulfonamide in 50 ml of acetonitrile, 1.0 g (0.014 mol) of 3-pyrroline are added 6.0 g (0.043 mol) of potassium carbonate and 1.1 g (0.007 mol) of sodium iodide, followed by stirring for 4 days at 80 ° C. The reaction mixture is filtered and the filtrate is concentrated to dryness. The residue is purified by chromatography on silica gel, using the methanol / dichloromethane eluent mixture: 5/95. 1.35 g of 4- [4- (2,5-dihydropyrrol-1-yl) butyl] -N, N-dimethyl-1H-imidazole-1-sulfonamide is obtained in the form of a yellowish oil.

Yield 31%.

1.2. 4- [4- (2,5-Dihydropyrrol-1-yl) butyl] -1H-imidazole di- (E) -but-2-enedioate A solution of 1.3 g (0.004 mol) of 4- [4- (4- (2,5-dihydropyrrol-1-yl) butyl] -1H-imidazole 4- (2,5-Dihydropyrrol-1-yl) butyl] -N, N-dimethyl-1H-imidazole-1-sulfonamide in 25 ml of 6N aqueous hydrochloric acid solution is stirred overnight at 80 ° 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 basified to OOC 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 sulphate and evaporated to dryness. 0.68 g of 4- [4- (2,5-dihydropyrrol-1-yl) butyl] -1H-imidazole is obtained in the form of a colorless oil (Yield 79%). To a solution of 0.67 g (0.0035 mol) of the product obtained in 20 ml of ethanol is added a solution of 0.82 g (0.007 mol) of - (E) -but-2-enedioic acid in 25 ml of ethanol. The precipitate formed is filtered and washed with 3 ml of cold ethanol and dried. 1.1 g of a white solid with a melting point of 146 ° -148 ° C. are obtained. Yield 60%.

The following table illustrates the chemical structures and the chemical properties of certain compounds of formula (1) according to the invention. These compounds were synthesized according to the methods described above.

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Board

<Tb>
<tb> R2
<tb> F (C)
<tb> R1 <SEP>#
<tb> N <SEP> A <SEP># R3 <SEP> (salt)
<tb> N #
<tb> R4
<tb> 1. <SEP> 197-198
<tb> N #
<tb> (di-Ethanedioate)
<tb> 2. <SEP> - (CH2) 3N # <SEP> 127-129
<tb># CH3 <SEP> (di-Ethanedioate)
<tb> 3. <SEP> - (CH2) 2- <SEP> 142-143
<tb> N #
<tb> (di-Ethanedioate)
<tb> 4. <SEP> H3C
<tb> - (CH2) 3- <SEP>#<SEP> 104-107 <SEP> (Dec.)
<tb> N #
<tb> (sesdqui-Ethanedioate)
<tb>#
<tb> H3C
<tb> 5. <SEP> - (CH2) 3- <SEP> 146-148
<tb> N #
<tb> (di- (E) -but-2-ededioate)
<tb> 6. <SEP> - (CH2) 4- <SEP> 88-91
<tb> N #
<tb> (di-Ethanedioate)
<tb> 7. <SEP> - (CH2) 5- <SEP> 68-75
<tb> N #
<tb> (di-Ethanedioate. <SEP> 0.5
<tb> ethanol)
<Tb>
F (C) indicates: melting point in C- (dec.) Indicates: decomposition

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 The compounds of the invention of formula (1) have been the subject of pharmacological tests which have shown their interest as therapeutically active substances.

More particularly, the compounds of the invention are H3 histamine receptor antagonists. H3-type receptors are known to those skilled in the art and their therapeutic interest has been described in the literature (Histamine H3 receptor antagonists, Exp.Virment Ther., Patents (2000) 10 (7): 1045-1055).

Thus, the compounds of the invention of formula (1) have been subjected to an in vitro affinity test on the native H3-type histamine receptor in a membrane preparation of adult rat brain by the specific binding of 3H] -N-methylhistamine to this receptor, according to methods described by Korte, A. et al. in Biochem. Biophys. Res. Common. 168, 799-986 (1990) and by West, R. E. Jr. et al. in Mol. Pharmacol. 38, 610-613 (1990).

The Ki of the compounds of the invention with respect to H3 receptors are between 0.1 nM and 5.0 μM, and more particularly between 0.4 nM and 5.0 AM.

They were also tested for their histamine Ha receptor antagonist effects, by quantifying the in vitro antagonistic effect of each product on the H3 receptors involved in an inhibitory effect on the contraction of the distal ileum. electrically stimulated guinea pig, according to the method described by Hew, RWS et al. in Br. J. Pharmacol. 101, 661-624 (1990).

The pA2 of the compounds of the invention with regard to the maximum relaxing effect of R-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 Hg-type histamine receptor antagonists.

Thus, these compounds may be employed in the treatment of conditions in which a Type H3 histamine receptor antagonist provides therapeutic benefit. In particular, such pathologies are obesity and diabetes.

Also, these compounds can be used in the treatment of diseases of the central nervous system such as disorders of alertness and sleep, Alzheimer's disease and other dementias, attention disorders in children

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 hyperkinetic, memory and learning disorders, epilepsy or schizophrenia.

On the other hand, the compounds of the invention of formula (1) have been tested in vivo showing their ability to reduce food intake in fasting rat 24h.

The experiments were performed on Wistar rats. Rats were individually placed in clear plastic cages 48 * 26.5 * 21.5 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 am to 7 pm, rats having free access to water and food .

Before performing the experiment, the rats were fasted for 24 hours with access to water ad libitum. On the day of the experiment, the vehicle or 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 DAgos (mg / kg i.p. or p.o..) of the compounds of the invention with respect to food intake can be less than 10.

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

Therefore, these compounds can be used in the treatment of conditions in which a Type H3 histamine receptor antagonist provides therapeutic benefit. In particular, such pathologies are obesity and diabetes. Also, these compounds can be used in the treatment of diseases of the central nervous system such as disorders of alertness and sleep, Alzheimer's disease and other dementias, attention disorders in hyperkinetic children, memory disorders and learning, epilepsy or schizophrenia.

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.

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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 a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutical excipients.

The 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 ingredient of formula (1) above its salt or if desired hydrate, may be administered in unit dosage form, in admixture with conventional pharmaceutical excipients, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, oral, intratracheal, intranasal, dosage 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 may vary between 0 mg and 50 mg per kg of body weight per day. Although these assays are examples of average conditions, there may be special cases where higher or lower dosages are appropriate, such assays also belong to the invention. According to the usual practice, the dosage appropriate to each patient is determined by the physician according to the mode 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 may be administered 1 to 5 times per 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

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 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 made by different techniques, direct compression, dry granulation, wet granulation or hot melt.

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

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

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 (9)

 in which: A represents a CO-6 alkyl group, the alkyl group may be branched by a halogen atom, a hydroxy or a phenyl and R1, R2, R3 and R4 represent, independently of one another, a hydrogen atom; , halogen, hydroxy, nitro, cyano, trifluoromethyl, C1-3 alkyl, phenyl, C1-3 alkoxy, phenoxy, C1-3 alkylcarbonyloxy, benzoyloxy, -C (O) OH, -C (O) ) O-C1-3 alkyl, -C (O) O -phenyl, -CONH2, -C (O) NHY-C1-3 alkyl or -C (O) N (C1-3 alkyl) 2 and its salt, N-oxide or hydrate.

Claims: 1. Compound of formula (1) 2. Compound according to claim 1, characterized in that: A represents a C1-alkyl group and R1, R2, R3 and R4 represent, independently of each other, a hydrogen, halogen or hydroxy atom, a C1-alkyl or C1-3 alkoxy group. 3. Compound of formula (1) according to claim 1 characterized in that: * A represents a non-branched C1-alkyl group; R1, R2, R3 and R4 represent a hydrogen atom; and 4. Compound of formula (1) according to claim 1 characterized in that it consists of: * 4- (2,5-dihydropyrrol-1-ylmethyl) -1H-imidazole;

 4- [4- (3-methyl-2,5-dihydropyroyl-1-yl) butyl] -1H-imidazo) e; 4- [3- (2,5-dihydropyrrol-1-yl) propyl] -1H-imidazole; 4- {4- [(2R *, 5S *) - 2,5-dimethyl) -2,5-dihydropyrro) -1-yl] butyl} -1H-imidazo); 4- [4- (2,5-dihydropyrrol-1-yl) butyl] -1H-imidazole; 4- [5- (2,5-dihydropyrrol-1-yl) pentyl] -1H-imidazole; and * 4- [6- (2,5-dihydropyrrol-1-yl) hexyl] -1H-imidazole. <Desc / Clms Page number 14>  wherein R1, R2, R3, R4, and A are as defined in claim 1 and Pg is a protecting group to give the compound of formula (1) according to claim 1.

 R2 R1 R3 N AN R4 <J N Pg (la)

 5. Process for the preparation of a compound of formula according to one of Claims 1 to 4, characterized in that: a compound of formula (Ia) is deprotected 6. Pharmaceutical composition containing a compound of formula (1) according to one of claims 1 to 4, or its salt, N-oxide or hydrate, and at least one pharmaceutical excipient. 7. Use of a compound of formula (1) according to any one of claims 1 to 4, or its salt, N-oxide or hydrate, for the preparation of a medicament for treating a pathology where an antagonist of a histamine H3 receptor provides therapeutic benefit. 8. Use of a compound of formula (1) according to any one of claims 1 to 4, or its salt, N-oxide or hydrate, for the preparation of a medicament for treating obesity and diabetes 9. Use of a compound of formula (1) according to any one of claims 1 to 4, or its salt, N-oxide or hydrate, for the preparation of a medicament for treating disorders of alertness and sleep, Alzheimer's disease, attention disorders in hyperkinetic children, memory and learning disorders, epilepsy or schizophrenia.