MXPA01006351A - Diphenylurea compounds - Google Patents

Abstract

Wherein:R1, R2, R3 and R4 independently represent hydrogen, halogen, or alkyl, alkoxy, hydroxy, cyano, optionally substituted amino, nitro, carboxy, alkoxycarbonyl, optionally substituted aminocarbonyl or carbamoyl, L1 and L2 each represents hydrogen or together form -CH2-CH2-, X1, attached at the 2 or 3 position of the aromatic ring, represents a bond, and in that case X2 represents hydrogen, halogen, or alkyl, alkoxy, hydroxy, nitro, cyano or optionally substituted amino, or X1 and X2, together with two adjacent carbon to which they are bonded in the 2, 3 or 4 position of the aromatic ring, form a (C4-C7)cycloalkyl group, wherein one or two -CH2- of the cycloalkyl ring are optionally replaced by oxygen or NH, X3 represents hydrogen, halogen, or alkyl, alkoxy, hydroxy, nitro, cyano or optionally substituted amino, G represents a group selected from:wherein:the broken lines indicate the optional presence of a double bond, Alk represents linear or branched (C1-C6)alkylene, n is 0 or 1, T3 represents alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, T4 represents alkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, and medicinal products containing the same are useful as dual alpha2/5-HT2c antagonist receptors.

Description

NEW COMPOUNDS OF DIFENILUREA, A PROCESS FOR ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT THE THEY CONTAIN DESCRIPTION OF THE INVENTION The present invention relates to new diphenylurea compounds, to a process for their preparation and to pharmaceutical compositions containing them. The invention also relates to its use as mixed ligands of a2 / 5-HT2c. Compounds having a diphenylurea structure have been described in JP Application 11130750 for its serotonergic antagonist properties, and in WO 99 32436 for its use as raf kinase inhibitors. The frontal cortex plays an essential role in the processes that control the affected functions in psychiatric disorders. In particular, it is now accepted that the alteration of onerogenic onagenic transmission is strongly implicated in the etiology of these various disorders. For example, in the case of depression, monoaminergic activity is reduced in the corticolimbic regions.

Among the various auto- and hetero-receptors of monoamine involved in regulatory mechanisms, the receptors of a2-A.R. (autoreceptors) and 5-HT2c have proven to be of greater importance. These two sub-types of receptors act in the same way by inhibiting dopaminergic and adrenergic transmission. On the one hand, a retro-control is exercised by the a2-A.R receivers. on noradrenergic neurons (J. Pharmacol. Exp. Ther., 1994, 270, 958) and on the other hand 5-HT2c receptors exert an inhibition control on dopaminergic and noradrenergic transmission (Neuropharmacology, 1997, 36, 609). In the past, compounds that bind to one or other of these sub-types of receptors have demonstrated their potential in the treatment of a plurality of pathologies. For example, the beneficial role of the a2 antagonist compounds has been studied in the treatment of cognitive disorders (J.

Pharmacol., 1992, 6_, 376), Parkinson's disease (CNS Drugs, 1998,, 1_0_, 189), disorders of the libido and sexual dysfunction (J. Pharmacol., 1997, 11, 72). Similarly, the antagonist compounds of the 5HT2c receptor have proved useful in the treatment of sexual dysfunction (ref J. Pharmacol., Ibid.), Parkinson's disease (Drug News Perspect., 1999, 12, 477). , and also anxiety (Br. J. Pharmacol., 1996, 117, 427) and schizophrenia (Neurosci Lett., 1996, 181, 65). Compounds that have an antagonistic character of a2-A.R. and dual 5-HT2c can be of significant use for clinicians to achieve, with the administration of a single compound, an action significantly improved in the restoration of neurotransmission by means of a synergistic effect. This class of compounds also has a considerable advantage compared to the administration of two different products. The compounds of the invention have a novel structure that confers such a dual antagonistic character of a2 / 5-HT2c, and are consequently useful in the treatment of depression, anxiety, schizophrenia, Parkinson's disease, cognitive disorders, disorders of the libido and sexual dysfunction, sleep disorders, drug abuse, and impulsive behavior disorders. The present invention relates to the compounds of formula (I): J wherein: Ri, R2, R3 and R4 independently represent a hydrogen atom, a halogen atom or an alkyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, amino group (optionally substituted by one or two alkyl groups), nitro, carboxy, alkoxycarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups) or carbamoyl, or, taken in pairs, form together with the carbon atoms to which they are attached a phenyl ring or an aromatic heterocycle having from 5 to 7 members in the ring, and containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, Li and L2 each represent a hydrogen atom, or together form a group -CH2-CH2-, • Xi, united in position 2 or 3 of the aromatic ring, represents a bond, and in this case 25 X; represents a hydrogen atom, a ^ J ~ halogen atom, an alkyl, alkoxy, hydroxy, nitro or cyano group, or an amino group (optionally substituted by one or two alkyl groups), or, Xi and X2, together with two adjacent carbon atoms to which they are attached at position 2, 3 or 4 of the aromatic ring, form a cycloalkyl group of 4 to 7 carbon atoms, wherein one or two -CH2- groups of the ring of Cycloalkyl is optionally replaced by an oxygen atom or an NH group (optionally substituted by an alkyl group), and wherein a carbon atom of the cycloalkyl ring is substituted by the group G, 15 / X3 represents a hydrogen atom, a halogen atom, an alkyl, alkoxy, hydroxy, nitro or cyano group, or an amino group (optionally substituted by one or two alkyl groups), - G represents a group selected from: G, X wherein: • dotted lines indicate the optional presence of a double bond, • Alk represents an alkylene group of 1 to 6 carbon atoms, straight or branched, where, when Gi or G2 contain an imidazoline group, the Alk group is linked in the 2-position of the ring, • n is 0 or 1, • T3 represents an alkyl group, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, < / T4 represents an alkyl, optionally substituted aryl, optionally sun-substituted arylalkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl group, wherein: - the term "alkyl" denotes a straight or branched group containing from 1 to 6 carbon atoms, the term "alkoxy" denotes a linear or branched alkyl-oxy group containing from 1 to 6 carbon atoms, - the term "aryl" denotes a phenyl, naphthyl or biphenyl group, the term "heteroaryl" denotes an aromatic monocyclic group , or a bicyclic group in which at least one of the rings is aromatic, each group contains from 5 to 11 members in the ring, and from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, the term "optionally substituted" associated with the aryl, arylalkyl, heteroaryl and heteroarylalkyl groups denotes that these groups are unsubstituted, or substituted on the cyclic portion by one or more halogen atoms and / or alkyl, alkoxy, hydroxy, mercapto, alkylthio, cyano, amino (optionally substituted by one or two alkyl groups), nitro, carboxy, alkoxycarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups) or groups carbamoyl, wherein the heteroaryl and heteroarylalkyl groups may also be substituted by an oxo group, the enantiomers and diastereoisomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.

-J Among the pharmaceutically acceptable acids, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, acid can be mentioned among the pharmaceutically acceptable acids. fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, naetanesulfonic acid, camphoric acid, etc. Among the pharmaceutically acceptable bases can be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc. In the preferred compounds of formula (I), Ri and R each represent a hydrogen atom - In the compounds of formula (I), R 2 and R 3 are advantageously selected from a hydrogen atom. halogen and an alkyl group. An advantageous embodiment of the invention relates to compounds of formula (I) wherein X is attached at the 2-position of the phenyl ring. Another advantageous embodiment of the invention relates to compounds of formula (I) wherein, when Li and L2 together form a group -CH2-CH2-, R3 and, -J R4, together with the carbon atoms to which they are attached, form a phenyl ring. Preferred compounds of the invention are those in which Xi represents a bond and X2 represents a halogen atom or an alkyl or alkoxy group. Another advantageous embodiment of the invention relates to compounds of formula (I) wherein X 3 represents a hydrogen atom. In the preferred compounds of formula (I), G will advantageously be selected from the groups: G \ G ", G- 15 G'3 Where T3 will be more especially an optionally substituted heteroaryl group or an optionally substituted heteroarylalkyl group. Other preferred compounds of the invention are those wherein Xi and X2, together with the two carbons at positions 2 and 3 of the aromatic ring to which they are attached, form a cycloalkyl group of 4 to 7 carbon atoms, for example a cyclopentyl group.

The preferred aryl group according to the invention is the phenyl group. Among the preferred compounds of the invention, the following, more especially, can be mentioned: N- (3-chloro-4-methylphenyl) -N'-. { 3- [4- (2, 3-dihydro-l, 4-benzodioxin-2-ylmethyl) -1-piperazinyl] phenyl} urea, N- [4-chloro-3- (4,5-di-idro-lH-imidazol-2-ylamino) -phenyl] -N '- (3-chloro-4-methylphenyl) urea, N- (3- chloro-4-methylphenyl) -N '- [2- (lH-imidazol-4-yl) -indan-5-yl] urea, ^ N-. { 3- [4- (2, 3-dihydro-1,4-benzodioxin-2-ylmethyl) -1- piperazinyl] phenyl} -N '- (3, 4-dimethyl phenyl) urea. The invention also extends to a process for the preparation of the compounds of formula (I): A process for the preparation of the compounds of formula (I) is characterized in that an aromatic amine of formula (II) is used as the starting material. : wherein Xi, X2, X3 and G are as defined for formula (I), which is condensed by heating in basic medium with a compound of formula (III): wherein R, R2, R3 and R4 are as defined for formula (I), to provide the compound of formula (I / a): a particular case of the compounds of formula (I) wherein Ri, R2, R3, R4, X :, X2, X3 and G are as defined above, wherein the isocyanate of formula (III) is either available commercially, or is prepared according to known procedures, for example from the corresponding carboxylic acid by reaction with sodium azide and rearrangement of the obtained acyl azide, the compounds of formula (I / a): - can, if necessary , be purified according to a conventional purification technique, - are optionally separated into their isomers according to a conventional separation technique, are, if desired, converted to their addition salts with a pharmaceutically acceptable acid or base. Another process for the preparation of the compounds of formula (I) is characterized in that an amine of formula (IV) is used as the starting material: wherein Li, L2, Ri, R2, R3 and R are as defined for formula (I), which is condensed by heating in basic medium with a compound of formula (V): Or where Xi, X2, X3 and G are as defined for formula (I), to provide the compound of formula (I / b): a particular case of the compounds of formula (I) wherein Li, L2, Ri, R ?, R3, R4, Xi, X2, X3 and G are as defined above, wherein the isocyanate of formula (V) is either commercially available or is prepared according to known procedures, for example from the corresponding carboxylic acid by reaction with sodium azide and rearrangement of the obtained acyl azide, the compounds of formula (I / b): - can, if necessary, be purified according to a conventional purification technique, are optionally separated into their isomers according to a conventional separation technique, are, if desired, converted to their addition salts with a pharmaceutically acceptable acid or base. Another process for the preparation of the compounds of formula (I) is characterized in that an amine of formula (VI) is used as the starting material: wherein XL, X2 and X3 are as defined for formula (I), GN34 represents an NH group or a 1-piperazinyl or 4-piperidinyl group, and P represents a hydrogen atom or a group that protects the amine function, which is condensed by heating in basic medium with a compound of formula (III): where Ri, R2, R3 and 4 are as defined for formula (I), to propose the compound of formula (VI I) wherein Ri, R2, R3, R., X, X2, X3, GN j and P are as defined above, the compound of formula (VII), - when GN 4 represents a 1-piperazinyl group or - piperidinyl, after deprotection when necessary from the amine function, is subjected to a substitution reaction in basic medium to provide the compound of formula (I / c): a particular case of the compounds of formula (I) wherein Ri, R;, R3, R4, Xi, X; and X are as defined in the foregoing, and G34 represents a group G3 or G defined for formula (I), when GN34 represents an NH group, after deprotection when necessary, it is condensed with thiophosgene to provide the compound of formula (VIII): wherein R, R2, R3, R4, X :, X2 and X3 are as defined in the foregoing, which is subject to the action of ethylenediamine to provide the compound of formula (IX): wherein Ri, R2, R3, R, X :, X; and X3 are as defined above, the compound of formula (IX) is subjected to an intramolecular cyclization reaction catalyzed by a palladium compound to provide the compound of formula (I / d): a particular case of the compounds of formula (I) wherein Ri, R2, R3, R4, Xi, X2 and X3 are as defined above, the compounds of formulas (I / c) and (I / d): - they can, if necessary, be purified according to a conventional purification technique, they are optionally separated into their isomers according to a conventional separation technique, - are, if desired, converted to their addition salts with a pharmaceutically acceptable acid or base. The present invention also relates to pharmaceutical compositions comprising as an active ingredient at least one compound of formula (I), alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers. Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral, nasal or transdermal administration, tablets or lozenges, sublingual tablets, gelatin capsules, diamond-shaped tablets, suppositories, creams, ointments can be mentioned more especially. , dermal gels, etc ... The useful dosage varies according to the age and weight of the patient, the nature and severity of the disorder and the route of administration, which can be oral, nasal, rectal or parenteral. In general, the unit dosage is in the range from 0.05 mg to 500 mg for a treatment from 1 to 3 administrations per 24 hours. The following Examples illustrate the invention and do not limit it in any way. The structures of the described compounds were confirmed by standard spectroscopic techniques. The starting materials used are known products, or are prepared according to known procedures.

Preparation A: 3- (, 5-Dihydro-lH-imidazol-2-yl-Methyl) aniline Step 1: 2- (3-Nitrobenzyl) -4,5-dihydro-lH-imidazole dihydrochloride A mixture of 30.7 mmoles (5 g) of 3-nitrophenylacetonitrile and 30 mmoles (7.2 g) of ethylenediamine para-toluenesulfonate is heated at 100 ° C for 1 hour. After cooling to 20 ° C, the mixture was hydrolyzed with 100 ml of a 5 M aqueous solution of sodium hydroxide, and then extracted with dichloromethane. The organic phases were dried over magnesium sulfate and concentrated. The obtained residue was converted to the hydrochloride by the action of an ethanolic HCl solution to provide the expected product.

Step 2: 3- (4,5-Dihydro-lH-imidazol-2-ylmethyl) aniline A solution of 22.7 mmoles (5.5 g) of the product described in the above Step in a mixture of 100 ml of ethanol and 10 ml of water was stirred under a hydrogen atmosphere in the presence of 0.5 g of 10% palladium on carbon. When the absorption of hydrogen ceased, the reaction mixture was filtered and concentrated to provide the expected product.

Preparation B: 3- [1- (4, 5-Dihydro-lH-imidazol * -2-yl) ethyl] aniline Step 1: 2- (3-Nitrophenyl) propane trile A mixture of 62 mmoles (10 g) of 3-nitrophenylacetonitrile, 1.11 moles (100 g) of dimethyl carbonate and 3.1 mmoles (0.43 g) of potassium carbonate was heated by 6 hours at 170 ° C in an autoclave. After cooling, 200 ml of dichloromethane were added, and the organic phase was washed with 100 ml of water and then with 100 ml of a saturated aqueous solution of sodium chloride. The organic phase was dried over magnesium sulfate, and concentrated, the residue obtained was purified by chromatography on silica gel, using as eluent a mixture of cyclohexane / ethyl acetate 90/10, to provide the expected product.

Step 2: 2- [1- (3-Nitro-phenyl) -ethyl] -4,5-dihydro-1H-imidazole The expected product was obtained according to the procedure described in Preparation A, Step 1, using co-or starting the compound described in the Stage above.

Step 3: 3- [1- (4, 5-dihydro-lH-imidazol-2-yl) ethyl] -aniline The expected product was obtained according to the procedure described in Preparation A, Step 2, using as starting material the compound described in the above Step.

Preparation C: 3- [1- (4, 5-dihydro-lH-imidazol-2-yl) -methylethyl] aniline Step 1: 2-Methyl-2- (3-nitrophenyl) propanenitrile 40 ml of 50% sodium hydroxide solution was added to a vigorously stirred solution of 123 mmoles (20 g) of 3-nitrophenylacetonitrile and 369 mmoles (46.5 g) ) of dimethyl sulfate in 200 ml of dimethyl sulfoxide. After stirring for one hour, the reaction mixture was diluted with 2 liters of water, and extracted twice with 1 liter of diethyl ether. The organic phases were dried over sodium sulfate, and concentrated to provide the expected product.

Step 2: 2- [1 -Meti 1-1- (3-nitrophenyl) ethyl] -4,5-dihydro-1H-imidazole The expected product was obtained according to the procedure described in Preparation A, Step 1, using as starting material the compound described in the above Step.

Step 3: 3- [1- (4, 5-Dihydro-lH-imidazol-2-yl) -1-methylethyl] aniline The expected product was obtained according to the procedure described in Preparation A, Step 2, using as Starting material is the compound described in the Stage above.

Preparation D: 4 -Methyl-3- (4-methyl-1-piperazinyl) -aniline Step 1: 4- (2-Methylphenyl) -1-piperazinecarbaldehyde With vigorous stirring, 437 mmole (77 g) of 2-methylphenylpiperaziana was added to a solution of 415 mmole (61.3 g) of trichloroacetaldehyde in 400 ml of dibutyl ether. The reaction mixture was heated to 80 ° C for 1 hour and, after cooling, concentrated to provide the expected product.

Step 2: l-Methyl-4- (2-methylphenyl) piperazine A solution of 437 mmol (90 g) of the compound described in the above Step in 400 ml of tetrahydrofuran was added to a suspension of 568 mmoles (21.6 g) of Lithium tetrahydroaluminate in 300 ml of tetrahydrofuran. The reaction mixture was stirred for 12 hours at 50 ° C. After cooling, the reaction mixture was hydrolysed with 52.5 ml of water and then 48 ml of a 10% aqueous solution of sodium hydroxide, and finally with 88.5 ml of water. The precipitate formed was filtered off over Celite, and the filtrate was concentrated. The residue obtained was taken up in 200 ml of water, and extracted 3 times with 250 ml of dichloromethane. The organic phase was dried over magnesium sulfate, and concentrated to provide the expected product.

Step 3: l-Methyl-4- (2-methyl-5-nitrophenyl) piperazine hydrochloride 416 mmol (64 g) of potassium nitrate in powder form was added to a solution of 347 mmol (100 g) of sodium sulfate. hydrogen of the compound described in the above Step in 500 ml of concentrated sulfuric acid. The stirring was carried out for 5 hours, and the reaction mixture was poured onto 1200 g of ice, and then neutralized with solid potassium carbonate, and extracted 3 times with 500 ml of ethyl acetate. The organic phases were dried and concentrated to provide the expected product. The corresponding hydrochloride was obtained by the action of an ethanolic HCl solution.

Step 4: 4-Methyl-3- (4-methyl-1-piperazinyl) aniline The expected product was obtained according to the procedure described in Preparation A, Step 2, using as the starting material the compound described in the Step above.

Preparation E: 3- [4- < 2, 3-Dihydro-l, 4-benzodioxin-2-ylmethyl) -1-piperazinyl] aniline Step 1: 1- (2,3-Dihydro-l, 4-benzodioxin-2-ylmethyl) -4- (3-nitro phenyl) piperazine A solution of 54.2 mmol (10 g) of 2-chloromethyl-2, 3- dihydro-l, 4-benzodioxine, 54.2 mmoles (9.2 g) of 3-nitrophenylpiperazine and 6 g of potassium hydrogen carbonate in 100 ml of methyl-4-pentanone was heated to reflux for 72 hours. After cooling, the reaction mixture was concentrated. The residue was taken up in 200 ml of water, and extracted with 200 ml of dichloromethane. The organic phase was dried over magnesium sulfate, concentrated and purified by chromatography on silica gel, using as eluent a dichloromethane / methanol / ammonium hydroxide 99/1 / 0.1 mixture, to provide the expected product.

Step 2: 3- [4- (2,3-Dihydro-l, 4-benzodioxin-2-ylmethyl) -1-piperazinyl] aniline The expected product was obtained according to the procedure described in Preparation A, Step 2, using as starting material the compound described in the Stage above.

Preparation F: N3-. { 4, 5-Dihydro-lH-imidazol-2-yl) -4-methyl-1,3-benzenediamine Stage 1: 2-Methyl-5-nitrophenylcarbamothioic acid chloride 2.25 1 of water was added to a solution of 130 mmoles (20 g) of 2-met il-5-ni troaniline in 375 ml of concentrated hydrochloric acid. At a temperature of 0 ° C, 162 mmoles (19 g) of thiophosgene was poured in one portion. The reaction mixture was stirred vigorously for 24 hours at room temperature. The formed precipitate was separated by filtration, and taken up in diethyl ether. The organic phase was washed with water, dried over magnesium sulfate and concentrated to provide the expected product.

Step 2: N- (2-Aminoethyl) -N '- (2-methyl-5-nitrophenyl) -thiourea A solution of 123 mmoles (24 g) of the compound described in the above Step in 1,000 ml of toluene was heated to 60 ° C. 246 mmoles (8.27 ml) of ethylenediamine were rapidly added, and the mixture was heated to 100 ° C for 3 hours. After cooling, the organic phase was washed with 1 M hydrochloric acid solution. The aqueous phase was made alkaline with concentrated sodium hydroxide solution, and then extracted with dichloromethane. The organic phase was washed with water, dried over magnesium sulfate, concentrated and purified by chromatography on silica gel, using as eluent a mixture of dichloromethane / methanol / ammonium hydroxide 90/10/1, to give the product expected.

Step 3: N- (2-Methyl-5-nitrophenyl) -4,5-dihydro-1H-Imidazole-2-amino A hot solution of 38.8 g of potassium hydroxide in 135 ml of water was added at 50 ° C to a solution of 63 mmol (16.0 g) of the compound described in the above Step. With vigorous agitation, at 80 ° C, a hot solution of 72.5 mmol was added (27.2 g) of lead acetate in 135 ml of water.

After 30 minutes, the reaction mixture was filtered over celite and concentrated. The residue was taken in 100 ml of water, and the pH was adjusted to 10.

Following extraction with dichloromethane, the organic phase was dried over magnesium sulfate and concentrated to provide the expected product.

Step: N3- (4, 5-Dihydro-lH-imidazol-2-yl) -4-methyl- 1, 3-benzenediamine The expected product was obtained according to the procedure described in Preparation A, Step 2, using as Starting material is the compound described in the Stage above.

Preparation G: N1- (4,5-Dihydro-lH-imidazol-2-yl) -1,3-benzenediamine Step 1: N- (3-Nitrophenyl) -4,5-dihydro-lH-imidazol-2-amine The expected product was obtained according to the procedure described in Preparation F, Step 2, using as starting material 3-nitrophenyl isocyanate.

Step 2: N1- (4,5-Dihydro-lH-imidazol-2-yl) -1,3-benzenediamine The expected product was obtained according to the procedure described in Preparation A, Step 2, using as starting material the compound described in the above Step.

Preparation H: 2-Methoxy-5- (4-methyl-1-piperazinyl) benzoyl azide A solution of 25 mmol (5.3 g) of phenyl dichlorophosphate in 100 ml of dichloromethane was added to a solution of 20 mmol. g) of 4-methoxy-3- (4-methyl-1-piperazinyl) benzoic acid (described in J. Med. Chem., 1994, 37_, page 2255) and 50 mmol (3.25 g) of sodium azide in 4.05 ml of pyridine. After stirring for 12 hours at room temperature, the organic phase was washed with 100 ml of water, dried over magnesium sulfate and concentrated to provide the expected product.

EXAMPLE 1: N- Hydrochloride. { 3-chloro-4-methylphenyl) - N '- [3- (4,5-dihydro-lH-imidazol-2-ylmethyl) phenyl 3 urea A solution of 4.7 mmol (1 g) of the compound described in Preparation A and 4.7 mmoles (0.7 g) of 3-chloro-4-methyl phenyl isocyanate in 50 ml of dimethylformamide was heated for 2 hours at 100 ° C. after cooling, the reaction mixture was concentrated. The residue obtained was taken up in 200 ml of dichloromethane, and the precipitate obtained was separated by filtration and purified by chromatography on silica gel, using as eluent a dichloromethane / methanol / ammonia mixture 90/10/1, to provide the product expected. The corresponding hydrochloride was obtained by the action of an ethanolic HCl solution. Melting point: 27-229 ° C Elemental microanalysis: Ci8H? ClN40. HCl% C% H% N% C1 Calculated 57.00 5.31 14.77 9.35 Found 56.56 5.41 14.32 9.59 EXAMPLE 2: N- (3-Chloro-4-methyl enyl) -N '- hydrochloride. { 3- [l- < 4,5-dihydro-lH-imidazol-2-yl) tyl] phenyl Jurea The expected product was obtained according to the procedure described in Example 1, with the replacement of the product described in Preparation A with the compound described in Preparation B. Melting point: 100-102 ° C Elemental microanalysis: C? 9H2? ClN40. HCl% C% H% N% C1 Calculated 58.02 5.64 14.24 9.01 Found 58.07 5.95 13.55 8.91 EXAMPLE 3: N- (3-chloro-4-methylphenyl) -N'- hydrochloride. { 3- [l-. { 4, 5-dihydro-lH-imidaz? L-2-yl) -1-methylethyl] enyl} urea The expected product was obtained according to the procedure described in Example 1, with the replacement of the product described in Preparation A with the compound described in Preparation C. Melting point: 232-233 ° C Elemental microanalysis: C20H23C1N0. HCl% C% H% N% C1 Calculated 58.97 5.94 13.75 8.70 Found 58.32 6.11 13.13 9.11 EXAMPLE 4: N- (3-Chloro-4-methyl enyl) - N '- [4-methoxy-3- (4- methyl-l-piperazinyl) -phenyl] urea A mixture of 13.6 mmol (3 g) of 4-methoxy-3- (4-methyl-l-piperazinyl) phenylamine and 13.6 mmol (2.26 g) of 3-chloro-4-methylphenyl isocyanate in 100 ml of toluene was heated to reflux for 2 hours.

After cooling, the precipitate obtained was separated by filtration, and rinsed twice with diethyl ether. The solid obtained was purified by chromatography on silica gel, using as eluent a mixture of dichloromethane / methanol / ammonium hydroxide 96/4 / 0.4, to provide the expected product. The corresponding hydrochloride was obtained by the action of an ethanolic HCl solution. Melting point: 206-208 ° C Elemental microanalysis: C2oH25ClN 02. HCl% C% H% N% C1 Calculated 55.29 6.10 12.90 18.36 Found 55.59 6.14 12.70 18.31 EXAMPLE S: N- (3-Sloro-4-methylphenyl) - N '- [4-methi1-3- (4-methyl-1-piperazinyl) -phenyl] urea hydrochloride The expected product was obtained according to the procedure described in Example 4, with the replacement of 4-methoxy-3- (4-methyl-1-piperazinyl) -phenylamine by the compound described in Preparation D. Melting point: 229-231 ° C Elemental microanalysis: C2oH25ClN40 . HCl% C% H% N% C1 Calculated 58.68 6.40 13.69 17.32 Found 58.16 6.37 13.20 17.16 EXAMPLE 6: N- (3-chloro-4-methylphenyl) -N'- hydrochloride. { 3- [4- < 2, 3-dihydro-1,4-benzodioxin-2-ylmethyl-1-piperazinyl] phenyl} urea The expected product was obtained according to the procedure described in Example 4, with the replacement of 4-methoxy-3- (4-methyl-1-piperazinyl) -phenylamine by the compound described in Preparation E. Fusion: 180-185 ° C Elemental microanalysis: C27H29C1N403.HCl% C% H% N% C1 Calculated 57.30 5.53 9.90 18.79 Found 57.36 5.55 9.63 18.85 EXAMPLE 7: N- < 3-Chloro-4-methylphenyl) - N '- [3- (4, 5-dihydro-lH-imidazol-2-ylamino) -4-methyl enyl] urea The expected product was obtained according to the procedure described in Example 1, with the replacement of the product obtained in Preparation A by the compound described in Preparation F. Melting point: 252-254 ° C Elemental microanalysis: C 8H2oClN50. HCl% C% H% N% C1 Calculated 54.83 5.37 17.76 8.99 Found 54.91 5.25 17.78 9.12 EXAMPLE 8: N- (3-Chloro-4-methylphenyl) -N '- [3- (4,5-dihydro-1H-imidazol-2-Ilamino) phenyl] urea hydrochloride The expected product was obtained in accordance with the procedure described in Example 1, with the replacement of the product obtained in Preparation A with the compound described in Preparation G.

Melting point: 180-185 ° C Elemental microanalysis: C17H18CIN5O. HCl% C% H% N% C1 Calculated 53.01 5.10 18.14 10.3; Found 53.18 5.02 18.25 10.1 EXAMPLE 9: N- [4-chloro-3- (4,5-dihydro-l-imidazol-2-ylamino) phenyl] -N '- (3-chloro-4-methylphenyl) urea hydrochloride Stage a: N- (3-Chloro-4-methylphenyl) -N '- (4-chloro-3-nitrophenyl) urea A solution of 29.8 mmoles (5 g) of 3-chloro-4-methylphenyl isocyanate in 90 ml of toluene was heated to 70 ° C, and 29.8 mmoles (5.15 g) of 4-chloro-3-nitroaniline were added. The solution was heated to reflux for 24 hours. The reaction mixture was cooled using ice, and the formed precipitate was separated by filtration and then rinsed with diethyl ether to provide the expected product.

Step b: N- (3-Amino-4-chloro-phenyl) -N '- (3-chloro-4-methylphenyl) urea A solution of 22.2 mmol (7.5 g) of the compound described in the above Step in 80 ml of a methanol / tetrahydrofuran mixture was heated at 45 ° C in the presence of Raney nickel. While controlling the temperature, 33.3 mmoles (1.61 ml) of hydrazine hydrate were added. The temperature was maintained at 45 ° C for 30 minutes and an additional 33.3 mmoles (1.61 ml) of hydrazine hydrate was added. The mixture was stirred at reflux for 30 minutes. After cooling, the catalyst was removed by filtration, and the filtrate was concentrated. The residue obtained was taken up in diethyl ether, and washed to provide the expected product.

Step c: Chloride of 2-chloro-5 acid. { [(3-chloro-4-methylanilino) carbonyl] amino} phenylcarbamothioic 3.2 moles (0.25 ml) of thiophosgene were added at 5 ° C to a suspension of 3.2 mmoles (0.32 g) of calcium carbonate in a mixture of 15 ml of dichloromethane and 2.2 ml of water. At this temperature, 3.2 mmol (1 g) of the compound described in the Stage above dissolved in dichloromethane were added. After the addition of 4.25 mmoles (0.36 g) of sodium hydrogen carbonate, the reaction mixture was stirred for 15 minutes at room temperature. After filtration over celite, the filtrate was decanted, and the organic phase was washed with water and then with a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate and filtration, the filtrate was concentrated. The residue obtained was taken in diethyl ether and washed to provide the expected product.

Step d: N- [3- ( { [(2-Aminoethyl) amino] carbothioyl.} - amino) -4-chlorophenyl] -N '- (3-chloro-4-methylphenyl) urea 4.4 were added quickly mmoles (0.27 ml) of ethylenediamine to a solution, heated at 60 ° C, of 2.2 mmol (0.78 g) of the compound described in the above Step in 35 ml of toluene. The reaction mixture was heated at 100 ° C for 3 hours. After cooling, the organic phase was washed with a 1 N hydrochloric acid solution (10 ml). The aqueous phase was made alkaline with concentrated sodium hydroxide solution, and then extracted with dichloromethane. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by chromatography on silica gel, using as eluent a mixture of dichloromethane / methanol / ammonium hydroxide 90/10/1 to provide the expected product.

Step e: N- [4-Chloro-3- (4,5-dihydro-1H-imidazo-1-2-ylamino) phenyl] -N '- (3-chloro-4-methylphenyl) urea A hot solution of 16. .5 mmol (1.5 g) of potassium hydroxide in 5.5 ml of water was added to a solution of 1.5 mmol (0.63 g) of the compound described in the above Step in 10 ml of ethanol at 50 ° C. With vigorous stirring a 80 ° C, a warm solution of 1.72 mmol (1.1 g) of lead acetate in 5.5 ml of water was added. After 30 minutes, the mixture was filtered over Celite and the filtrate was concentrated. The residue was taken up in 5 ml of water, the pH was adjusted to 10 and the extraction was carried out with dichloromethane. The organic phase was dried over magnesium sulfate, concentrated and purified by chromatography on silica gel, using as eluent a mixture of dichloromethane / methanol / ammonium hydroxide 90/10/1 to provide the expected product. The corresponding hydrochloride was obtained by the action of an ethanolic HCl solution. Melting point: 255-257 ° C Elemental microanalysis: C17H17CI2 5O. HCl% C% H% N% C1 Calculated 49.23 4.37 16.89 25.65 Encondp 48.82 4.47 16.62 25.44 EXAMPLE 10: N- (3-chloro-4-methylphenyl) -N'- hydrochloride. { 3- [4- (2, 3-dihydro-1,4-benzodioxin-2-ylmethyl) -1-piperazinyl] -4-methoxyphenyl} - urea Step a: 4- (5-. {[[3-Chloro-4-methylanilino] carbonyl] amino] -true-butanolate} -2-m-phenyl phenyl) -1-piperazinecarboxylic acid A solution of 4.4 mmol (10 g) of 4- (5-amino-2-methoxy phenyl) -piperazine-lcarboxylic acid tert-butanolate (described in J. Med. Chera., 1999, page 202) and 37.8 mmoles (5.9 g) of 3-chloro-4-methylphenyl isocyanate in 150 ml of toluene was heated to reflux for 2 hours. The reaction mixture was concentrated, and the residue was taken up in 200 ml of 4 N hydrochloric acid and then heated to reflux for 4 hours. After cooling, the formed precipitate was separated by filtration and treated with a 2 N sodium hydroxide solution to regenerate the corresponding base.

Step b: N- (3-Chloro-4-methylphenyl) -N'-. { 3- [4- (2,3-dihydro-1,4-benzodioxin-2-ylmethyl) -1- piperazinyl] -4-methoxy phenyl} urea A solution of 12.3 mmol (5 g) of the product described in the above Step in a mixture of 100 ml of acetonitrile and 100 ml of diethyl ketone was heated to reflux for 48 hours in the presence of 12.3 mmoles (2.3 g) of 2 -chloromet il-2, 3-dihydro-l, -benzodioxin, 1.3 g of potassium hydrogen carbonate and 100 mg of potassium iodide. After cooling, the mixture was concentrated and the residue obtained was extracted with dichloromethane. The organic phase was dried, concentrated and purified by chromatography on silica gel, using as eluent a mixture of dichloromethane / methanol / ammonium hydroxide 97/3 / 0.3, to provide the expected product. The corresponding hydrochloride was obtained by the action of an ethanolic HCl solution. Melting point: 193-197 ° C Elemental microanalysis: C28H3? ClN404. HCl% C% H% N% C1 Calculated 58.23 5.88 9.58 7.29 Found 58.95 5.72 9.82 8.08 EXAMPLE 11: 6-Chloro-5-fluoro-N- [4-methoxy-3-. { 4-methyl-1-piperazinyl) enyl] -1-indolincarboxamide A solution of 10.9 mmol (3 g) of the compound described in Preparation H in 100 ml of toluene was refluxed for 1 hour. After cooling to 20 ° C, a solution of 10.9 mmols (1.9 g) of 6-cyrocar-5-fluoroindoline in 200 ml of dichloromethane was added, and the reaction mixture was heated to reflux overnight. After returning to room temperature, the reaction mixture was concentrated and purified by chromatography on silica gel, using as eluent a mixture of dichloromethane / methanol / ammonium hydroxide 95/5 / 0.5, to provide the expected product. Melting point: 177-180 ° C Elemental microanalysis: C2? H24ClFN402% C% H% N% C1 Calculated 60.21 5.77 13.37 8.46 Found 59.15 6.05 12.82 8.85 EXAMPLE 12: N- Hydrochloride. { 3- [4 - (2,3-dihydro-1,4-benzodioxin-2-ylmethyl) -1- piperazinyl] phenyl} -1,2-dihydro-3H-benzo [e] indole-3-carboxamide 20 ml of a 20% solution by weight of phosgene in toluene at 20 ° C was added to a solution of 3.12 g of 1, 2-dihydrobenzo [e] indole in 300 ml of toluene. After one hour at 50 ° C, the mixture was heated to 100 ° C with nitrogen bubbling. A toluene solution of 6 g of the compound described in Preparation E was then added at 20 ° C, and the mixture was subsequently heated to 80 ° C for 12 hours. Following the treatment, the residue was purified by chromatography on silica gel, using as eluent a mixture of dichloromethane / methanol / ammonium hydroxide 99/1 / 0.1 The corresponding hydrochloride was obtained by the action of an ethanolic solution of HCl. Melting point: 194-196 ° C Elemental microanalysis: C32H32N4? 3.2HC1% C% H% N% C1 Calculated 64.75 5.79 9.44 11.95 Found 65.17 5.75 9.46 10.88 EXAMPLE 13: 6-Aloro-5-fluoro-N- hydrochloride. { 3- [4- (2,3-dihydro-1,4-benzo-ioxy-2-ylmethyl) -1-piperazinyl] phenyl} -l-2,3-dihydroindolcarboxamide The expected product was obtained using the procedure described in Example 12, with the replacement of 1,2-dihydrobenzo [e] indole by 6-chloro-5-fluoro-2,3-dihydroindole. Melting point: 202-204 ° C Elemental microanalysis: C28H28C1FN 03 • 2HC1% C% H% N% C1 Calculated 56.43 5.07 9.40 17.85 Found 56.22 4.92 9.40 17.98 EXAMPLE 14: N- Dihydrochloride. { 3- [4- (2, 3-dihydro-1,4-benzodioxin-2-ylmethyl) -1- piperazinyl] -4-methoxyphenyl} -N '- (3,4-dimethylphenyl) urea Step 1: 1- (2,3-Dihydrobenzo [1,4] dioxin-2-ylmethyl) -4- (2-methoxy-5-nitrophenyl) iperazine The expected product was obtained using the procedure described in Preparation E, with the replacement of 3-nitrophenylpiperazine with 2-methoxy-5-nitrophenylpiperazine.

Step 2: 3- [4- (2,3-Dihydrobenzo [1,4] dioxin-2-ylmethyl) piperazin-1-yl] -4-methoxy phenylamine The expected product was obtained using the procedure described in Preparation A, Step 2, using as starting material the compound described in the above step.

Stage 3: N- dihydrochloride. { 3- [4- (2, 3-dihydro-l, 4-benzodioxin-2-ylmethyl) -1-piperazinyl] -4-methoxyphenyl} -N'- (3, -dimethyl phenyl) urea The final product was then obtained using the procedure described in Example 4, with the replacement of 4-methoxy-3- (methyl-l-piperazinyl) -phenylamine by the compound described in Step 2 of that Example and with the replacement of 3-chloro-4-methylphenyl isocyanate with 3,4-dimethyl phenyl isocyanate. Melting point: 234-236 ° C Elemental microanalysis: C2gH34 40 .2HC1% C% H% N% C1 Calculated 60.52 6.30 9.73 12.32 Found 60.50 6.23 9.79 12.12 EXAMPLE 15: Hydrochloride of N- (3-sloro-4-fluorophenyl) -N'-. { 3- [4- (2, 3-dihydro-l, 4-benzodioxin-2-ylmethyl) -1-piperazinyl] -4-methoxyphenyl} Urea The expected product was obtained using the procedure described in Example 14, with the replacement of 3,4-dimethylphenyl isocyanate with 3-chloro-4-fluorophenyl isocyanate.

Melting point: 120-130 ° C Elemental microanalysis: C27H28C1FN404. HCl% C% H% N% C1 Calculated 57.56 5.19 9.94 12.58 Found 57.62 5.39 9.59 11.72 EXAMPLE 16: N- Hydrochloride. { 3- [4- (2, 3-dihydro-l, 4-benzodioxin-2-ylmethyl) -1-piperazinyl] -phenyl} -N '- < 3,4-dimethylphenyl) urea The expected product was obtained using the procedure described in Example 4, with the replacement of 4-methoxy-3- (4-methyl-1-piperazinyl) -phenylamine by the compound described in Preparation E, and using 3,4-dimethylphenyl isocyanate instead of 3-chloro-4-methylphenyl isocyanate. Melting point: 228-230 ° C Elemental microanalysis: C28H32N4? 3. HCl% C% H% N% C1 Calculated 66.07 6.53 11.01 6.96 Found 65.80 6.50 10.96 7.37 EXAMPLE 17: N- (3-chloro-4-fluorophenyl) -N'- hydrochloride. { 3- [4- (2,3-dihydro-l, 4-benzodioxin-2-yl-methyl) -1-piperazinyl] phenyl} urea The expected product was obtained using the procedure described in Example 4, with the replacement of 4-methoxy-3- (4-methyl-1-piperazinyl) -phenylamine by the compound described in Preparation E, and using isocyanate 3-chloro-4-fluorophenyl instead of 3-chloro-4-ethyl phenyl isocyanate. Melting point: 132-136 ° C Elemental microanalysis: C26H26C1FN403. HCl% C% H% N% C1 Calculated 58.54 5.10 10.50 13.29 Found. 58.40 5.47 10.02 12.61 EXAMPLE 18: 6-Aloro-5-methyl-N- dihydrochloride. { 4 - [4- (2,3-Dihydro-l, 4-benzodioxin-2-ylmethyl) -1-piperazinyl] phenyl} -1-2, 3-dihydroindolcarboxamide The expected product was obtained using the procedure described in Example 12, with the replacement of 1,2-dihydrobenzo [e] indole by 6-chloro-5-methyl-2, 3- dihydroindole.

Melting point: 174-176 ° C Elemental microanalysis: C29H? ClN 03.2HC1% C% H% N% C1 Calculated 58.84 5.62 9.46 17.97 Found 58.77 5.46 9.16 18.82 EXAMPLE 19: N- (3-Chloro-4-methylphenyl) -N '- [2- (lH-imidazol-4-yl) -indan-5-yl] urea hydrochloride Eta a 1: 2-Bromo-l-indan-2-ylethanone 10 g of pure bromine were quickly added to 0 ° C to a solution of 10 g of 2-acetylindane in 150 ml of anhydrous methanol. After one hour at room temperature, 100 ml of water was added, and the whole was stirred for 12 hours. After extracting twice with 200 ml of diethyl ether each time, and washing the organic phase with a solution of sodium hydrogen carbonate and then with water, the expected product was dried over magnesium sulfate and concentrated.

Step 2: 4-Indan-2-yl-lH-imidazole A mixture of 5.2 g of 2-bromo-l-indan-2-ylethanone and 43.4 ml of formamide was heated at 160 ° C for 30 minutes. At room temperature, 40 ml of water and then 40 ml of 1 N hydrochloric acid were added.

The aqueous phase was washed with dichloromethane, and then neutralized with ammonium hydroxide. Extraction with ethyl acetate gave the expected product after evaporation.

Step 3: 4- (5-Nitroindan-2-yl) -lH-imidazole 5 g of 4-indan-2-yl-lH-imidazole were dissolved at 0 ° C in 140 ml of pure sulfuric acid, and then 1 equivalent of urea nitrate in powder form was added in small portions. The reaction mixture was poured onto ice, made alkaline using sodium hydroxide solution and extracted with ethyl acetate. The expected product was obtained after evaporation.

Step 4: 2- (1H-Imidazol-4-yl) -indan-5-ylamine The hydrochloride of the product obtained in Step 3 was stirred under a hydrogen atmosphere in the presence of 10% palladium on charcoal in ethanol. After filtration and concentration of the solvent, the product was used as such in the next Step.

Step 5: N- (3-chloro-4-methylphenyl) -N '- [2- (lH-imidazol-4-yl) -indan-5-yl] urea hydrochloride A mixture of 5.3 g of the hydrochloride of the product obtained in Step 4, 3.8 g of 3-chloro-4-methylphenyl isocyanate and 150 ml of dimethylformamide was heated at 100 ° C for 2 hours. After the subsequent evaporation of the solvent, the residue was purified by chromatography on silica gel, using as eluent a mixture of dichloromethane / methanol / ammonium hydroxide 97/3 / 0.3. the corresponding hydrochloride was obtained by the action of an ethanolic HCl solution. Melting point: 235-237 ° C Elemental microanalysis: C2oH? 9ClN40.1HC1% C% H% N% C1 Calculated 59.56 5.00 13.89 17.58 Found 58.95 5.17 13.36 17.01 EXAMPLE 20: N- [2- (lH-Imidazol-4-yl) indan-5-yl] -N '- (4-methylsulfanyl-nil) -urea hydrochloride The expected product was obtained using the procedure described in Example 19 , with the replacement of 3-chloro-4-methylphenyl isocyanate with 4-methylothiophenyl isocyanate.

Melting point: 243-245 ° C Elemental microanalysis: C20H20N OS. HCl% C% H% N% C1% S Calculated 59.92 5.28 13.97 8.84 8.00 Found 59.72 5.32 13.26 8.56 7.73 EXAMPLE 21: N- (3,4-dimethyl enyl) -N '- [2- (1H-imidazol-4-yl) -indan-5-yl] urea hydrochloride The expected product was obtained using the procedure described in Example 19, with the replacement of 3-chloro-4-methylphenyl isocyanate with 3,4-dimethylphenyl isocyanate. Melting point: 232-234 ° C Elemental microanalysis: C2? H22N4O.HCl% C% H% N% C1 Calculated 65.88 6.05 14.63 9.26 Found 65.47 6.30 14.29 9.29 EXAMPLE 22: N- (3-Chloro-4-methylphenyl) -N '- [2- (4,5-dihydro-lH-imidazol-2-yl) - 1, 2, 3, 4-tetrahydro-7 hydrochloride -i soquinolinyl 3 urea Step 1: 2- (4,5-Dihydro-lH-imidazol-2-yl) -7-nitro-1,2,3,4-tetrahydroisoquinoline A mixture of 10 g of 7-nitro-l, 2, 3, 4-tetrahydroisoquinoline, 13.7 g of 2-methylsulfanyl-4,5-dihydro-1H-imidazole hydroiodide and 100 ml of methanol were refluxed for 12 hours. The addition of diethyl ether caused the separation of a precipitate, which was taken up in water, neutralized using sodium hydroxide and extracted with dichloromethane.

Step 2: 2- (4,5-Dihydro-1H-imidazol-2-yl) -1,2,3,4-tetrahydro-1-hequinolin-7-ylamine 2 ml of hydrazine hydrate were added to 40 ° C to a suspension of 2 g of the hydrochloride of the product obtained in Step 1, and 2 g of Raney nickel in 50 ml of ethanol. After 2 hours at 50 ° C, the catalyst was removed by filtration and the solvent was evaporated.

Step 3: N- (3-chloro-4-methylphenyl) -N '- [2- (4,5-dihydro-lH-imidazol-2-yl) -1,2,3,4-tetrahydro-7-hydrochloride isoquinolinyl urea The expected product was obtained using the procedure described in Step 5 of Example 19. Melting point: 237-239 ° C Elemental microanalysis: C2oH22ClN50. HCl% C% H% N% C1 Calculated 57.09 5.47 16.65 16.89 Found 57.41 5.51 16.32 16.74 EXAMPLE 23: N- (3-chloro-4-methylphenyl) -N '- hydrochloride. { 3- [2- (IH-imidazol-4-yl) ethyl] phenyl} - urea Step 1: (3-Nitrophenyl) acetaldehyde A mixture of 10 g of 2- (3-nitrophenyl) ethanol, . 1 g of 1-hydroxy-1,2-benzodioxol-3 (1H) -one 1-oxide and 300 ml of tetrahydrofuran was heated to reflux for 6 hours. After filtration and concentration of the solvent, the product was used as such in the next Step.

Step 2: 2- (3-Nitrophenyl) -1- (1-triyl-1H-imidazol-4-yl) ethanol At room temperature, 4.2 ml of 3M ethylmagnesium bromide were added to 5.48 g of 4-iodine. 1-Trityl-1H-imidazole dissolved in 30 ml of dichloromethane. After 1 hour, 1 g of the product obtained in Step 1 was dissolved in 20 ml of dichloromethane. After hydrolysis with a saturated solution of ammonium chloride, extraction with dichloromethane, and then washing the organic phase with water, the solvent was evaporated and the residue was purified by chromatography on silica gel, using a dichloromethane mixture as eluent. / methanol 98/2.

Step 3: 4- [2- (3-N-phenyl) vinyl] -1-trityl-lH-imidazole A mixture of 12.25 g of the product obtained in Step 2, 1 g of para-toluenesulfonic acid and 200 ml of toluene it was heated to reflux for 5 hours. After returning to room temperature, washing the toluene solution with a 0.1 N sodium hydroxide solution and then with water, drying over magnesium sulfate and concentration, the expected product was obtained.

Step 4: 4- [2- (3-Nitrophenyl) vinyl] -1H-imidazole A mixture of 11 g of the product obtained in Step 3, 6 ml of concentrated hydrochloric acid and 150 ml of methanol was heated to reflux for 2 hours . The solvent was concentrated and the residue was taken up in a mixture of isopropanol / diethyl ether. The expected product was obtained by filtering off the precipitate that formed.

Step 5: 3- [2- (1H-Imidazol-4-yl) ethyl] phenylamine The hydrochloride of the product obtained in Step 4 was stirred under a hydrogen atmosphere in the presence of a 90% solution of palladium on carbon at 10 ° C. % in ethanol. After filtration and concentration of the solvent, the product was used as such in the next Step.

Step 6: N- (3-chloro-4-methylphenyl) -N '- hydrochloride. { 3- [2- (iH-imidazol-4-yl) -ethyl] phenyl} urea The expected product was obtained using the procedure described in Step 5 of Example 19.

Melting point: 237-239 ° C Elemental microanalysis: Ci9H? GClN40. HCl% C% H% N% C1 Calculated 58.32 5.15 14.32 18.12 Found 58.40 5.13 13.97 18.35 EXAMPLE 24: N- (3-Chloro-4-ethylphenyl) -N '- hydrochloride. { 3- [2- (4, 5-dihydro-lH-imidazol-2-yl) ethyl] phenyl Jurea Step 1: 3- (3-Nitrophenyl) acrylonitrile At 0 ° C, 75.5 g of diethyl cyanomethylphosphonate dissolved in tetrahydrofuran to a suspension of sodium hydride in tetrahydrofuran. After a contact of 30 minutes at room temperature, 56 g of 3-nitrobenzaldehyde dissolved in tetrahydrofuran were added. After 1 hour, the hydrolysis was carried out with 300 ml of water, and then the solvent was concentrated. Following extraction with dichloromethane, washing the organic phase with water, drying over magnesium sulfate and concentration, the precipitate was taken up in diethyl ether and filtered off.

Step 2: 3- (3-Nitrophenyl) propionitrile 3 g of the product obtained in Step 1, 1159 g of tris (triphenylphosphine) rhodium chloride (I) and 90 ml of benzene were introduced into a cylinder. The whole was heated for 5 hours at 40 ° C under a hydrogen pressure of 5,095 kg / cm 2 (5 bars). The solvent was evaporated and the residue was purified by chromatography on silica gel, using dichloromethane as eluent.

Step 3: 2- [2- (3-Nitro-phenyl) -ethyl] -4,5-dihydro-1H-imidazole 1 g of the product obtained in Step 2 was heated for 2 hours at 160 ° C with 1.32 g of paraffin. ethylene diamine toluene sulfonate. A 0.1N sodium hydroxide solution was then added, and the extraction was carried out with dichloromethane. The organic phase was washed with water, dried over magnesium sulfate and concentrated. The corresponding hydrochloride was obtained by the action of an ethanolic HCl solution.

Step 4: 3- [2- (4, 5-Dihydro-lH-imidazol-2-yl) ethyl] phenylamine The hydrochloride of the product obtained in the Step 3 was stirred under a hydrogen atmosphere in the presence of a 90% solution of palladium on carbon in ethanol. After filtration and concentration of the solvent, the product was used as such in the next Step.

Step 5: N- (3-chloro-4-methylphenyl) -N '- hydrochloride. { 3- [2- (4, 5-dihydro-lH-imidazol-2-yl) ethyl] phenyljurea The expected product was obtained using the procedure described in Step 5 of Example 19. Melting point: 212-214 ° C Elemental microanalysis: C19H21CIN4O. HCl% C% H% N% C1 Calculated 58.02 5.64 14.24 18.03 Found 57.88 5.69 13.98 17.93 EXAMPLE 25: N- (3-Chloro-4-methylphenyl) -N '- [8- (lH-imidazol-4-yl) -5,6,7,8-tetrahydro-2-naphthalenyl] urea hydrochloride Step 1 : Trifluoromethanesulfonic acid 7-nitro-3, 4, 4a, 8a-tetrahydro-naphthalene-1-yl. 9.8 ml of trifluoromethanesulfonic anhydride at 0 ° C was added to a solution of 10 g of 7-nitrotetralone and 11.8 g of 2 , 6-di-tert-butyl-4-ethylpyridine in 365 ml of dichloromethane. After 24 hours at room temperature, concentration to dryness and take the residue in 200 ml of refluxing pentane for 30 minutes, the precipitate formed was separated by filtration. The organic phase was washed with a 1N hydrochloric acid solution and then with water, dried over magnesium sulfate and concentrated.

Step 2: 4- (7-Nitro-3,4,4a, 8a-tetrahydronaphthalen-1-yl) -1-trityl-1H-imidazole At room temperature, 15.34 ml of 3M ethylmagnesium bromide were added to 16.74 g of 4-iodo-1-trityl-1H-imidazole dissolved in 250 ml of tetrahydrofuran. After 1 hour, 76.6 ml of a 1 N solution of zinc chloride in diethyl ether was added. After contact for 1 hour, 12.4 g of the product obtained in Step 1 dissolved in 100 ml of tetrahydrofuran and 2.22 g of tetrakis (triphenylphosphine) palladium (0) were added, and the whole was heated to reflux. Following hydrolysis with a saturated solution of ammonium chloride and extraction with dichloromethane, the organic phase was washed with water. The solvent was then evaporated, and the residue was purified by chromatography on silica gel, using a cyclohexane / ethyl acetate 80/20 mixture as eluent.

Step 3: 8- (1-Trityl-1H-imidazol-4-yl) -4a, 5, 6, 7, 8, 8a-hexahydronaphthalene-2-yla 7.7 g of the product obtained in the Step 2 under a hydrogen atmosphere in the presence of 10% palladium on carbon in a methanol / tetrahydrofuran mixture. After filtration and concentration of the solvent, the product was used as such in the next Step.

Step 4: 8- (1H-Imidazol-4-yl) -4a, 5, 6, 7, 8,8a-hexahydronaphthalen-2-ylamine A mixture of 7.7 g of the product obtained in Step 3, 4.2 ml of hydrochloric acid concentrated and 100 ml of methanol was heated to reflux for 2 hours. After concentration of the solvent, the residue was taken up in a mixture of isopropanol / diethyl ether. The expected product was obtained by filtering off the precipitate.

Step 5: N- (3-chloro-4-methylphenyl) -N '- [8- (1H-imidazol-4-yl) -5,6,7,8-tetrahydro-2-naphthalenylurea urea A 0.7 g mixture of the product obtained in Step 4, 0.55 g of 3-chloro-4-methylphenyl isocyanate and 50 ml of toluene was heated to reflux for 3 hours. The precipitate was then separated by filtration. The corresponding hydrochloride was obtained by the action of an ethanolic HCl solution. Melting point: 255-257 ° C Elemental microanalysis: C21H21CIN4O .1HC1% C% H% N% C1 Calculated 60.44 5.31 13.42 16.99 Found 60.28 5.41 13.02 17.20 EXAMPLE 26: N- (3-Chloro-4-methylphenyl) -N'-11 - (lH-imidazol-4-yl) -5,6,7,8-tetrahydro-2-naphthalenyl] urea hydrochloride Stage 1: 7-Nitro-3, 4-dihydro-lH-2-one At 0 ° C, 100 g of 2-tetralone were dissolved in 460 ml of pure sulfuric acid, and 84.6 g of potassium nitrate in small portions were added in small portions. of dust. The mixture was then poured onto ice, and extracted using dichloromethane. Following evaporation of the solvent, the residue was purified by chromatography on silica gel, using a 90/10 mixture of cyclohexane / tetrahydrofuran as eluent.

Step 2: Trifluoromethanesulfonic acid 7-nitro-3-dihydronaphthalene-2-yl ester The expected product was obtained using the procedure described in Step 1 of Example 25, with the replacement of 7-nitrotetralone by 14.3 g of the product obtained in Stage 1.

Step 3: 4- (7-Nitro-3,4-dihydronaphthalen-2-yl) -1-trityl-1H-imidazole The expected product was obtained using the procedure described in Step 2 of Example 25, with the replacement of the ester 7-Nitro-3, 4, 4a, 8a-tetrahydronaphthalene-1-yl of trifluoromethanesulfonic acid per 11.2 g of the product obtained in Step 2.

Step 4: 7- (1-Trityl-1H-imidazol-4-yl) -5,6,7,8-tetrahydronaphthalen-2-yl-amine 5.5 g of the product obtained in Step 3 were stirred under a hydrogen atmosphere in a mixture of methanol / tetrahydrofuran in the presence of 10% palladium on carbon. After filtration and concentration of the solvent, the product was used as such in the next Step.

Step 5: 7- (1H-Imidazol-4-yl) -5,6,7,8-tetrahydronaphthalen-2-ylamine A mixture of 5.5 g of the product obtained in Step 4, 3.8 ml of concentrated hydrochloric acid and 100 ml of methanol was heated to reflux for 2 hours.

Following the concentration of the solvent, the residue was taken in a mixture of acetone / diethyl ether. The precipitate was separated by filtration and provided the expected product.

Step 6: N- (3-Chloro-4-methylphenyl) -N '- [7- (lH-imidazol-4-yl) -5,6,7,8-tetrahydro-2-naphthalenylurea urea A mixture of 0.9 g of the product obtained in Step 4, 0.71 g of 3-chloro-4-methylphenyl isocyanate and 70 ml of toluene was heated to reflux for 3 hours. The precipitate was separated by filtration, and then recrystallized from a mixture of ethanol / methanol. The corresponding hydrochloride was obtained by the action of an ethanolic HCl solution. Melting point: 206-208 ° C Elemental microanalysis: C2iH2? ClN 0.1HC1% C% H% N% C1 Calculated 60.44 5.31 13.42 16.99 Found 59.84 5.17 13.06 16.88 EXAMPLE 27: N- (3-Chloro-4-methylphenyl) -N '- [4- (lH-imidazol-4-yl) -chroman-6-yl] rea hydrochloride Step 1: 6-Nitrochroman-4-one At -35 ° C, 60g of 4-chromanone were added in small portions to 385 ml of 90% nitric acid.

The whole was poured on ice, and then extracted with dichloromethane. The organic phase was washed with a saturated solution of sodium hydrogen carbonate, and dried over magnesium sulfate and then the solvent was evaporated.

Step 2: Trifluorornenesulfonic acid 6-nitro-2H-chromen-4-yl ester The expected product was obtained using the procedure described in Step 1 of Example 25, with the replacement of 7-nitrotetralone by 20 g of the product obtained in Stage 1 Step 3: 4- (6-Ni tro-2H-chromen-4-yl) -1-trityl-lH-imidazole The expected product was obtained using the procedure described in Step 2 of Example 25, with the replacement of the ester 7 -nitro-3, 4, 4a, 8a-tetrahydronaphthalene-1-yl of trifluoromethanesulfonic acid per 11.1 g of the product obtained in Step 2.

Step 4: 4- (1H-Imidazol-4-yl) -chroman-6-ylamine The hydrochloride of the product obtained in Step 3 was stirred under an atmosphere of hydrogen in ethanol in the presence of 10% palladium on carbon. After filtration and concentration of the solvent, the product was used as such in the next Step. Step 5: N- (3-chloro-4-methylphenyl) -N '- [4- (lH-imidazol-4-yl) -chroman-6-yl] urea hydrochloride A mixture of 0.76 g of the product obtained in the Step 4, 0.59 g of 3-chloro-4-methylphenyl isocyanate and 70 ml of toluene was heated to reflux for 2 hours. The precipitate was separated by filtration, and then recrystallized from a mixture of ethanol / methanol. The corresponding hydrochloride was obtained by the action of an ethanolic HCl solution. Melting point: >260 ° C Elemental microanalysis: C20H19CIN4O2.1HC1% C% H% N% C1 Calculated 57.29 4.81 13.36 16.91 Found 56.83 4.98 12.96 16.63 Examples 28 to 30 were prepared according to the procedures described above.

EXAMPLE 28: N- [3-. { 1H-Imidazol-4-yl) -sroman-6-yl] -1,2-dihydro-3H-benzo [e] indole-3-carboxamide EXAMPLE 29: N- (3-Chloro-4-methylphenyl) -N ' - [3- < 1H-imidazol-4-yl) -chroman-6-yl] urea EXAMPLE 30: N- (3-Chloro-4-methylphenyl) -N '- [3- (1H-imidazol-4-yl) -1,2,3,4-tetrahydro-7-isoquinolinyl] urea PHARMACOLOGICAL STUDY EXAMPLE A: Penile erection test in the rat The test allows the evaluation of the pharmacological agents capacity to inhibit the penile erections caused by the administration of a selective 5-HT2 / RO 60-0175 agonist. Male Wistar rats weighing from 120 to 140 g were placed on the day of the experiment individually in plexiglass observation boxes immediately after they were administered the test compound or carrier. Thirty minutes later, animals RO 60-0175 (1.25 mg / kg, subcutaneous route) were administered and the number of erections that occurred during the 30 minutes that followed was counted.

Results: the compounds of the invention appear to be capable of inhibiting penile erections induced by the administration of the selective 5-HT2c agonist. consequently, they have an antagonistic character with respect to the 5-HT2c receptors. by way of example, the inhibitory concentration 50 (IC 50) of the compound of Example 6 is 0.7 mg / kg.

EXAMPLE B: Mouse test for isolation-induced aggressiveness The animals used were CD-1 male mice. Upon arrival, the mice were isolated in individual boxes with free access to food and water. After a period of isolation of one month, pairs of mice that were constant in their aggressiveness were selected by observing the latent period, the number and duration of attacks when placed in the presence of the other. The test took place once a week. On the day of the test, to each mouse of the pair of mice (resident mouse and mouse intruder) was given a subcutaneous injection of the carrier (control animals) or the test product (treated animals) in a volume of 10 ml / kg. After 30 minutes, the 'Intruder mouse was introduced into the resident mouse box. The latent period of the first attack and the number and duration of the attacks were then measured for a period of three minutes. A product is specifically considered anti-aggressive when it reduces the number and duration of attacks in non-sedating doses.

Results: the compounds of the invention appear to significantly reduce the number and duration of attacks. By way of example, the inhibitory dose 50 (ID50) of the compound of Example 6 is 2.5 mg / kg (subcutaneous administration).

EXAMPLE C: Marble burial test in the mouse This test allows the evaluation of the pharmacological agents capacity to inhibit the spontaneous behavior of burying marbles in the mouse, the inhibition is predictive of an antidepressant and / or anti-impulsive action. NMRI male mice weighing from 20 to 25 g on the day of the experiment were individually placed in Macrolon boxes containing 5 cm of sawdust and covered with a perforated Plexiglas lid. Twenty-four "tiger's eye" glass marbles were distributed evenly over the sawdust, on the periphery of the box. At the end of the 30-minute free exploration, the animals were removed from the box and the number of buried marbles counted.

Results: the compounds of the invention appear to inhibit the spontaneous behavior of marble burial in mice. By way of example, the effective dose 50 (ED5o) of the compound of Example 6 is 0.4 mg / kg.

EXAMPLE D: Determination of affinity for a2 adrenergic receptors in the rat Affinity was determined by competition experiments with [3 H] -RX 821,002. Rat cerebral cortex membranes were prepared and incubated in triplicate for 60 minutes at 22 ° C with 0.4 nM f3H] -RX 821,002 and the test compound in a final volume of 1.0 ml. the incubation buffer contained 50 nM Tris-HCl (pH 7.5), 1 mM EDTA and 100 μM GppNHp. The non-specific binding was determined using 10 μM pentolamine.

Analysis of the data: at the end of the incubation, the incubation medium was filtered through filters of WHATMAN GF / B impregnated with 0.1% polyethylenimine and washed three times with 5 ml of cooled buffer. The radioactivity retained on the filters was determined by liquid scintillation counting. The binding isotherms were analyzed by non-linear regression.

Results: the compounds of the invention exhibit a specific antagonist activity by adrenergic receptors? , for example a pKi of 6.7 for the compound of Example 6.

EXAMPLE E: Pharmaceutical composition Formulation for the preparation of 1,000 tablets, each containing 10 mg of active ingredient Compound of Example 6 10 g Hydroxypropylcellulose 2 g Wheat starch 10 g Lactose 100 g Magnesium stearate 3 g Talc 3 g

Claims (20)

CLAIMS 1. Compounds of formula (I): wherein: Ri, R2, R3 and R independently represent a hydrogen atom, a halogen atom or an alkyl, alkoxy, hydroxy, alkylthio, mercapto, cyano, amino group (optionally substituted by one or two alkyl groups), nitro , carbkoxy, alkoxycarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups) or carbamoyl, or, taken in pairs, form together with the carbon atoms to which a phenyl ring or an aromatic heterocycle is attached having from 5 to 7 members in the ring, and containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, • Li and L each represent a hydrogen atom, or together form a group -CH: -CH2-, V Xi, attached in the 2 or 3 position of the aromatic ring, represents a bond, and in this case X2 represents a hydrogen atom, a halogen atom, an alkyl, alkoxy, hydroxy, nitro or cyano group, or an amino group (optionally substituted by one or two groups lo), or, Xi and X2 together with two adjacent carbon atoms to which they are attached at position 2, 3 or 4 of the aromatic ring, form a cycloalkyl group of 4 to 7 carbon atoms, wherein one or two groups -CH2- of the cycloalkyl ring are optionally replaced by u? oxygen atom or an NH group (optionally substituted by an alkyl group), and wherein a carbon atom of the cycloalkyl ring is substituted by the group G, -X3 represents a hydrogen atom, a halogen atom, an alkyl group , alkoxy, hydroxy, nitro or cyano, or an amino group (optionally substituted by one or two alkyl groups), • f G represents a group selected from:
1. G- wherein: • the dotted lines indicate the optional presence of a double bond, • Alk represents an alkylene group of 1 to 6 straight or branched carbon atoms where, when Gi or G2 contain an imidazoline group, the Alk group is attached at the position 2 of the ring, • n is 0 or 1, / T represents an optionally substituted alkyl, aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, • T_j represents an optionally substituted aryl, arylalkyl optionally sun-substituted , optionally substituted heteroaryl or optionally substituted heteroarylalkyl, wherein: the term "alkyl" denotes a straight or branched group containing from 1 to 6 carbon atoms, - the term "alkoxy" denotes a linear or branched alkyl-oxy group containing from 1 to 6 carbon atoms, - the term "aryl" denotes a phenyl, naphthyl or biphenyl group, the term or "heteroaryl" denotes an aromatic monocyclic group, or a bicyclic group in which at least one of the rings is aromatic, each group contains from 5 to 11 members in the ring, and from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, the term "optionally substituted" associated with the aryl, arylalkyl, heteroaryl and heteroarylalkyl groups denotes that these groups are unsubstituted, or substituted on the cyclic portion by one or more halogen atoms and / or alkyl, alkoxy, hydroxy, mercapto , alkylthio, cyano, amine (optionally substituted by one or two alkyl groups), nitro, carboxy, alkoxycarbonyl, aminocarbonyl (optionally substituted by one or two alkyl groups) or carbamoyl groups, wherein the heteroaryl and • heteroarylalkyl groups may also be substituted by an oxo group, to the enantiomers and diastereoisomers thereof, and also to the addition salts thereof with an acid or pharma base. pharmaceutically acceptable.
2. 2. Compounds of formula (I) according to claim 1, wherein L and L2 each represent a hydrogen atom, the enantiomers and diastereomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base .
3. 3. Compounds of formula (I) according to claim 1, wherein Li and L2 together form a group -CH2-CH2-, the enantiomers and diastereomers thereof, and also the addition salts thereof with an acid or base pharmaceutically acceptable.
4. 4. Compounds of formula (I) according to claim 1, wherein Ri and R4 each represent a hydrogen atom, the enantiomers and diastereomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base .
5. 5. Compounds of formula (I) according to claim 1, wherein R2 and R3 are selected from a halogen atom and an alkyl group, the enantiomers and diastereomers thereof, and also the addition salts thereof with an acid or pharmaceutically acceptable base.
6. 6. Compounds of formula (I) according to claim 1, wherein Xi is attached at the 2-position of the phenyl ring, the enantiomers and diastereomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base acceptable.
7. 7. Compounds of formula (I) according to claim 1, wherein X x represents a bond and X 2 represents a halogen atom or an alkyl or alkoxy group, the enantiomers and diastereomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
8. 8. Compounds of formula (I) according to claim 1, wherein X 3 represents a hydrogen atom, the enantiomers and diastereomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
9. 9. Compounds of formula (I) according to claim 1, wherein R3 and R together with the carbon atoms to which they are attached form a phenyl ring, and Li and L together form a -CH2-CH2- group, enantiomers and diastereoisomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
10. 10. Compounds of formula (I) according to claim 1, wherein G is selected from: G \ G ", G \ G, where T'3 will be more especially an optionally substituted heteroaryl group or a heteroaryl group optionally substituted, the enantiomers and diastereoisomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
11. 11. Compounds of formula (I) according to claim 1, wherein Xi and X2, together with the two carbon atoms at positions 2 and 3 of the aromatic ring to which they are attached, form a cycloalkyl group of 4 to 7 atoms of carbon, the enantiomers and diastereomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
12. 12. Compound of formula (I) which is N- (3-chloro-4-methyl phenyl) -N, -. { 3- [4- (2, 3-dihydro-l, 4-be zodioxin-2-ylmethyl) -1-piperazyl] phenyl} urea, the enantiomers and diastereomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
13. 13. Compound of formula (I) which is N- [4-chloro-3- (4,5-dihydro-1H-imidazo 1-2- i lamino) phenyl] -N '- (3-chloro-4-methylphenyl) urea, the enantiomers and diastereomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
14. 14. Compound of formula (I) which is N- (3-chloro-4-methyl phenyl) -N '- [2- (1H-imidazol-4-yl) -indan-5-yl] urea, the enantiomers and diastereomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
15. 15. Compound of formula (I) which is N-. { 3- [4- (2,3-dihydro-l, 4-benzodioxin-2-ylmethyl) -1-piperazinyl] phenyl} -N '- (3,4-dimethylphenyl) urea, the enantiomers and diastereoisomers thereof, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
16. 16. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that an aromatic amine of formula is used as the starting material (II): wherein Xi, X2, X3 and G are as defined for formula (I), which is condensed by heating in basic medium with a compound of formula (III): wherein Ri, R2, R3 and R are as defined for formula (I), • to provide the compound of formula (I / a): a particular case of the compounds of formula (I) wherein Ri, R, R3, R4, X :, X ?, X3 and G are as defined above, wherein the isocyanate of formula (III) is either commercially available, or is prepared according to known procedures, for example from the corresponding carboxylic acid by reaction with sodium azide and rearrangement of the obtained acyl azide, the compounds of formula (I / a): - can, if necessary, to be purified according to a conventional purification technique, are optionally separated into their isomers according to a conventional separation technique, - are, if desired, converted to their addition salts with a pharmaceutically acceptable acid or base.
17. 17. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that an amine of formula (IV) is used as starting material: (IV) wherein Li, L2, Ri, R2 / R3 and R4 are as defined for formula (I), which is condensed by heating in basic medium with a compound of formula (V): wherein Xi7 X2, X3 and G are as defined for formula (I), to provide the compound of formula (I / b): a particular case of the compounds of formula (I) wherein Li, L2, Ri, R2, R3, X2 X3 and G2 are as defined above, wherein the isocyanate of formula (V) is either commercially available or is prepared according to known procedures, for example from the corresponding carboxylic acid by reaction with sodium azide and rearrangement of the obtained acyl azide, the compounds of formula (I / b): - can, if necessary, be purified according to a conventional purification technique, they are optionally separated into their isomers according to a conventional separation technique, - are, if desired, converted to their addition salts with a pharmaceutically acceptable acid or base.
18. 18. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that an amine of formula (VI) is used as the starting material: wherein Xi, X2 and X3 are as defined for formula (I), GN34 represents an NH group or a 1-piperazinyl or 4-piperidinyl group, and P represents a hydrogen atom or a group that protects the amine function , which is condensed by heating in basic medium with a compound of formula (III): wherein Ri, R2, R3 and R4 are as defined for formula (I), to provide the compound of formula (VII): wherein R x, R 2, R 3, R 4, Xir X 2, X 3, GN 34, and P are as defined above, the compound of formula (VII), - when GN 34 represents a 1-piperazinyl or 4-piperidinyl group, then of deprotection when necessary of the amine function, is subjected to a substitution reaction in basic medium to provide the compound of formula (I / c): (Ic), a particular case of the compounds of formula (I) where Ri, R2, R3, R4 Xi / X2 and X3 are as defined above, and G34 represents a f i group G3 or G4 defined for formula (I), when GN34 represents an NH group, after deprotection when necessary, it is condensed with thiophosgene to provide the compound of formula (VIII): in dc.de Ri, R2, R3, R4, Xi, 2 and 3 are as defined in the foregoing, which is subject to the action of ethylenediamine to provide the compound of formula (IX): wherein Ri, R2, R3, R4, Xi / X2 and X3 are as defined above, the compound of formula (IX) is subjected to an intramolecular cyclization reaction catalysed by a palladium compound to provide the compound of formula (I / d): a particular case of the compounds of formula (I) wherein Ri, R2, R3, Ri, Xi, X2 and 3 are as defined in the above, the compounds of formulas (I / c) and (I / d): - can, if necessary, be purified according to a conventional purification technique, are optionally separated into their isomers according to a conventional separation technique, are, if desired, converted to their addition salts with an acid or base pharmaceutically acceptable.
19. 19. Pharmaceutical compositions comprising as active ingredient at least one compound according to any of claims 1 to 15, alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
20. 20. Pharmaceutical compositions according to claim 19, which contain at least one active ingredient according to any of claims 1 to 15, for use in the preparation of medicaments useful as dual antagonists of a2 / 5-HT2c in the treatment of depression , anxiety, schizophrenia, Parkinson's disease, cognitive disorders, libido disorders, sexual dysfunction, sleep disorders, drug abuse and impulsive behavior disorder. SUMMARY OF THE INVENTION The present invention describes compounds of formula (I): wherein: Ri, R2, R3 and R4 independently represent a hydrogen atom, a halogen atom or an alkyl, alkoxy, hydroxy, cyano, optionally substituted amino, nitro, carboxy, alkoxycarbonyl, optionally substituted aminocarbonyl or carbamoyl group, L and L2 each represent a hydrogen atom, or together they form a group -CH2-CH2-, and Xi, attached at the 2 or 3 position of the aromatic ring, represents a bond, and in this case X2 represents a hydrogen atom , a halogen atom, or an alkyl, alkoxy, hydroxy, nitro or cyano group, or an optionally substituted amino group, or Xi and X2, together with two adjacent carbon atoms to which they are attached at position 2, 3 or 4 of the aromatic ring, form a cycloalkyl group of 4 to 7 carbon atoms, wherein one or two -CH2- groups of the cycloalkyl ring are optionally replaced by an oxygen atom or an NH group, • X3 represents hydrogen, an atom of halogen, or an optionally substituted alkyl, alkoxy, hydroxy, nitro, cyano, or amino group, S G represents a group selected from: G wherein: • / dotted lines indicate the optional presence of a double bond, Alk represents an alkylene group of 1 to 6 straight or branched carbon atoms, V n is 0 or 1, T3 represents an alkyl group, optionally substituted aryl, arylalkyl optionally X substituted, optionally substituted heteroaryl or optionally substituted heteroarylalkyl, • T4 represents an optionally substituted aryl, aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl. 10 Medications