MXPA06005180A - Novel phenyl-pyridinyl-piperazine derivatives, a method for the production thereof and pharmaceutical compositions containing said derivatives - Google Patents

Abstract

Phenyl pyridinyl piperazine derivatives (I), their enantiomers and diastereoisomers, acid and base addition salts are new. Phenyl pyridinyl piperazine derivatives of formula (I), their enantiomers and diastereoisomers, acid and base addition salts are new. R1NR3SO2R4;R3H or 1-6C alkyl;R41-6C alkyl, T or NR5R6;either R5, R6R3, 3-8C cycloalkyl or 3-8C cycloalkyl-1-6C alkyl;NR5R65-8 membered ring (where C is optionally replaced by S, N, O, SO or SO2) (optionally bridged by a 1-6C alkyl and/or optionally to be substituted by T1);T1halo, 1-6C (polyhalo)alkyl, 1-6C alkoxy, COOH, OH, CN, NO2, NH2 (optionally substituted by 1-6C alkyl);R21-6C alkyl, 3-8C cycloalkyl, 3-8C cycloalkyl-1-6C alkyl;and T:aryl e.g. phenyl, naphtyl or biphenyl (all optionally substituted by T1). An independent claim is included for the preparation of (I). [Image]- ACTIVITY:Nootropic;Neuroprotective;Cerebroprotective;Anticonvulsant;Tranquilizer;Anorectic;Analgesic;CNS-Gen.;Antiparkinsonian. - MECHA NISM OF ACTION:Central histaminergic H3 receptor antagonist. The antagonistic activity of (I) against central histaminergic H3 receptor antagonist was tested. The results showed that (I) exhibited a significant antagonistic activity against central histaminergic H3 receptor antagonist.

Description

NEW COMPOUNDS OF FENILPIRIDILPIPERAZINE, A PROCESS FOR YOUR PREPARATION AND COMPOSITIONS PHARMACEUTICALS THAT CONTAIN THEM The present invention relates to novel phenylpyridylpiperazine compounds, to a process for their preparation and to pharmaceutical compositions containing them. The compounds of the present invention are especially valuable from a pharmacological point of view, due to their specific interaction with central histamine receptors of type H3 and can be used in the treatment of neuropathologies associated with brain aging, mood disorders, eating behavior and sleep-wake rhythm, and attention deficit hyperactivity syndrome. The aging of the population due to an increased life expectancy at birth has brought with it a great increase in the incidence of neuropathologies related to age and especially Alzheimer's disease. The main clinical manifestations of brain aging and especially of age-related neuropathologies are deficiencies in memory and cognitive functions, which can lead to dementia. Recent neuropharmacological studies have shown that, in the central nervous system, histamine, via central histaminergic systems, plays the role of a neurotransmitter or neuromodulator in physiological or pathophysiological situations (Annu Rev. Neurosci., 1986, 9, 209-254 Physiol. Rev., 1991, 71, 1-51). Thus, it has been shown that histamine is involved in various physiological and behavioral processes, such as thermoregulation, neuroendocrine regulation, circadian rhythm, cataleptic states, motility, aggression, eating behavior, learning and memory, and slnáptica plasticity (Hass et al. , Histaminergic Neurons: Morphology and Function, Boca Raton, FL: CRC Press, 1991, pages 196-208, Prog. Ne? Robiology, 2001, 63, 637-672). Of the 3 sub-types of histamine receptors (Hi, H2, and H3) it was initially shown that the H3 receptor is a pre-synaptic autoreceptor that controls the release of histamine (Nature, 1987, 327. 1 17-123) . Its activation inhibits the release and synthesis of histamine by a negative feedback mechanism (Neuroscience, 1987, 23, 149-157). The existence of presynaptic heteroreceptors capable of modulating the release of some neuropeptides and of many neurotransmitters, such as noradrenaline, serotonin, dopamine, GABA, acetylcholine and glutamate, was subsequently demonstrated (TiPS, 1998, 1_9, 177-183). Studies in animals have shown that an increase in extra-synaptic histamine levels via blocking H3-type receptors by H3 antagonists makes it possible to promote surveillance states, learning and memory processes, regulate food intake, and to combat convulsive attacks (Prog. Neurobiol., 2000, 63, 637-672, Neurosci. Biobehav, Rev., 2000, 24, 107-113). As a result, the potential therapeutic indications for H3 antagonists are the treatment of cognitive deficits associated with brain aging and with neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease and frontal dementias or sub -cortical of vascular origin or other origin, and the treatment of mood disorders, seizures, hyperactivity syndrome due to attention deficit, obesity, pain and neuroleptic states. The compounds of the present invention, in addition to having a novel structure, possess pharmacological properties that are entirely surprising and valuable in this field. More specifically, the present invention relates to the compounds of formula (I): wherein: R 1 represents a group NR 3 SO 2 R, wherein: - R 3 represents a hydrogen atom or a linear or branched Ci-Cβ alkyl group, - R represents a linear or branched C? -C6 alkyl group, an aryl group or a group NR5R6, wherein: R5 and RT, which may be the same or different, each represent a hydrogen atom or an alkyl group of linear or branched Ci-Ce, a C3-C8 cycloalkyl group, or a group (C3-C8 cycloalkyl) - (Ci-Ce alkyl) in which the alkyl portion is linear or branched, or R5 and Re, together with the nitrogen atom that carries them, forms a ring of 5 to 8 members in which one of the carbon atoms can be replaced by a nitrogen, oxygen or sulfur atom or by an SO or SO2 group, the The ring defined by this is optionally bridged by a straight or branched C?-C6 alkyl group and / or optionally substituted by one or more identical or different groups selected from halogen, straight or branched Ci-Ce alkyl, alkoxy Linear or branched Ci-Cβ, linear or branched Ci-Cβ polyhaloalkyl, carboxy, hydroxy, c ian, nitro and amino (optionally substituted by one or more linear or branched Ci-Cβ alkyl groups), R 2 represents a linear or branched d-Cß alkyl group, a C3-C8 cycloalkyl group or a (C3 cycloalkyl group -C8) - (Ci-Cß alkyl) in which the alkyl portion can be linear or branched, it being understood that: an aryl group means the phenyl, naphthyl and biphenyl groups, these groups being optionally substituted by one or more identical groups or different selected from halogen, linear or branched C? -C6 alkyl, linear or branched Ci-Ce alkoxy, linear or branched C? -C6 polyhaloalkyl, carboxy, hydroxy, cyano, nitro and amino (optionally substituted by one or more linear or branched d-Ce alkyl groups), with their enantiomers and diastereoisomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base. Among pharmaceutically acceptable acids there can be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid. , tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulfonic acid, camphoric acid, etc. Among the pharmaceutically acceptable bases, there can be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, ter- butylamine, etc ... More especially, the invention relates to compounds of formula (I) wherein R represents an alkyl group, for example a methyl group.

Preference is given to the group R3 being a hydrogen atom. Advantageously, the invention relates to compounds of formula (I) wherein R5 and Re, together with the nitrogen atom that bears them, form a 5- to 8-membered ring wherein one of the carbon atoms can be replaced by a nitrogen, oxygen or sulfur atom or by an SO or SO2l group for example a morpholino group. Preference is given to the R2 group being a isopropyl, cyclopropyl or cyclopentyl group. Even more especially, the invention relates to compounds of formula (I) which are: N- dihydrochloride. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] -phenyl} benzenesulfonamide, • N- dihydrochloride. { 4- [6- (4-Cyclopentyl-piperazin-1-yl) pyridin-3-yl] -phenyl} benzenesulfonamide, • N- dihydrochloride. { 4- [6- (4-cyclopentyl-1-p-piperazinyl) -3-pyridinyl] -phenyl} methanesulfonamide, • N- dihydrochloride. { 4- [6- (4-cyclopropylpiperazin-1-yl) pyridin-3-yl] -phenyl} methansulfonamide, • N- dihydrochloride. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] -phenyl} morpholin-4-sulfonamide, • N- dihydrochloride. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] -phenyl} methanesulfonamide, • N- Dicihydrate. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] -phenyl} propan-2-sulfonamide, • N- dihydrochloride. { 4- [6- (4-Cyclopenti) piperazin-1-yl) pyridin-3-yl] -phenyl} -4-fluorobenzenesulfonamide, • N- dihydrochloride. { 4- [6- (4-cyclopentyl-piperazin-1-yl) pyridin-3-yl] -phenyl} -3-fluorobenzenesulfonamide, • N- dihydrochloride. { 4- [6- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl] -phenyl} -2-fluorobenzenesulfonamide. The invention also relates to a process for the preparation of compounds of formula (1), the process is characterized in that the compound of formula (I I) is used as the starting material: wherein R ^ is as defined for formula (I), and R and R \ the quates may be identical or different, each representing a hydrogen atom or a linear or branched Ci-Cβ alkyl group, or together form a straight or branched Ci-Ce alkylene chain, which is condensed, in the presence of palladium (0), with a compound of formula (11): wherein R2 is as defined for formula (I), and Hal represents a halogen atom, to provide the compound of formula (I), the compound of formula (I) is purified, if necessary, according to a conventional purification technique, it is separated, where appropriate, in its isomers according to a conventional separation technique and converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base. The compounds of formulas (II) and (III) defined in the foregoing are either commercially available or are obtained by conventional reactions of organic chemistry. By virtue of their pharmacological properties as ligands of the histamine H3 receptor, the compounds of the present invention are useful in the treatment of cognitive deficits associated with brain aging and with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, of Pick, Korsakoff's disease and frontal or sub-cortical dementias of vascular origin or other origin, and also in the treatment of mood disorders, seizures, hyperactivity syndrome due to attention deficit, obesity, pain and neuroleptic states. The present invention also relates to pharmaceutical compositions comprising as an active ingredient at least one compound of formula (I), an isomer thereof or an addition salt thereof with a pharmaceutically acceptable acid or base, alone or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers. Among the pharmaceutical compositions according to the invention, those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), percutaneous or transcutaneous, intravaginal, rectal administration may be especially mentioned., nasal, perlingual, buccal, ocular or respiratory. Pharmaceutical compositions according to the invention for parenteral injections especially include sterile aqueous and non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile powders for the reconstitution of injectable solutions or dispersions. The pharmaceutical compositions according to the invention for solid oral administration especially include tablets or lozenges, sublingual tablets, sachets, capsules and granules, and for liquid oral, buccal or ocular administration especially include emulsions, solutions, suspensions, drops, syrups and aerosols.

Pharmaceutical compositions for rectal or vaginal administration are preferably suppositories and those for percutaneous or transcutaneous administration especially include powders, aerosols, creams, ointments, gels and patches. The pharmaceutical compositions mentioned above illustrate the invention but do not limit it in any way. Among the inert, non-toxic, pharmaceutically acceptable excipients or carriers there may be mentioned, without implying any limitation, diluents, solvents, preservatives, wetting agents, emulsifiers, dispersants, binders, bulking agents, disintegrants, retardants, lubricants, lubricating agents. absorbency, suspending agents, colorants, flavorings, etc. The useful dosage varies according to the age and weight of the patient, the route of administration, the pharmaceutical composition used, the nature and severity of the disorder, and whether some associated treatments are being taken. The dosage is in the range from 10 mg to 1 g per day in one or more administrations. The following Preparations and Examples illustrate the invention but do not limit it in any way. The starting materials used are known products or are prepared according to known procedures. The structures of the compounds described in the Examples were determined according to the usual spectrophotometric techniques (infrared, NMR, mass spectrometry, etc.).

Preparation 1: 1 - (5-Bromopyridin-2-yl) -4-isopropyl piperazine A solution containing 12.1 g of 2,5-dibromopyridine (51.1 mmol), 8.8 ml of 1-isopropylpiperazine (61.5 mmol) and 9.2 ml of DBU (61.5 mmol) were stirred overnight at 100 ° C. The reaction mixture was returned to room temperature and the solution was diluted with water and extracted with ethyl acetate. The organic phases were collected, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue was chromatographed on a SiO2 column, eluting with a mixture of CH2Cl2 / MeOH 98/2 and then 96/4 to give the title product. Melting point: 76-78 ° C Elemental microanalysis: C H N Br% Theoretical 50.72 6.38 14.79 28.12% Experimental 50.96 6.47 14.53 28.33 Preparation 2: 1- (5-Bromopyridin-2-yl) -4-cyclopentyl piperazine The procedure is identical to that of Preparation 1, but 1-isopropylpiperazine is replaced by 1-cyclopentyl piperazine. Melting point: 127-128 ° C Preparation 3: 1 - (5-Bromopyridin-2-yl) -4-cyclopropylpiperazine The procedure is identical to that of Preparation 1, but 1-isopropylpiperazine is replaced by 1 - cyclopropylpiperazine. Melting point: 1 10-1 15 ° C EXAMPLE 1: N- dihydrochloride. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} benzene sulfonamide Step A: N- (4-Iodophenyl) benzenesulfonamide To a solution of 2.0 g of 4-iodoaniline (9.13 mmole) in 40 ml of acetonitrile was added 1.48 ml of pyridine (18.26 mmole) and then, dropwise, a solution of 1.28 ml of benzenesulfonyl chloride (10 mmol) in 20 ml of acetonitrile. The reaction mixture was stirred overnight at room temperature and the acetonitrile was removed by evaporation under reduced pressure. The residue was taken up in 1N HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and evaporated under reduced pressure. The oily residue obtained was triturated in isopropyl ether until the title compound crystallized. Melting point: 141-145 ° C Stage B: N- [4- (4,4,5,5-Tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl] -benzenesulfonamide 500 mg of the compound obtained in Step A (1.39 mmoles), 389 mg of bis (pinacolato) diborane (1.53 mmoles), 410 mg of potassium acetate (4.18 mmoles) and 5 ml of dimethylformamide were introduced into a 25 ml two-neck flask. The reaction mixture was degassed by bubbling through it a stream of nitrogen for 30 minutes, and then 16 mg of palladium acetate (0.07 mmol) was added. The reaction mixture was stirred under a gentle stream of nitrogen for 7 hours at 85 ° C. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried and evaporated under reduced pressure. The evaporation residue was triturated in heptane to provide, after filtration, the title product as a white solid. Melting point: 157-160 ° C Step C: N- Dihydrochloride. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] pheniI} benzenesulfonamide 226 mg of the compound obtained in Preparation 1 (0.79 mmol), 300 mg of the compound obtained in Step B (0.83 mmol), 3 ml of dioxane and 3 ml of 0.4 M Na2COs aqueous solution were placed in a two-necked flask. mouths of 25 ml. The reaction mixture was degassed by bubbling nitrogen through it for 30 minutes. Pd (0) tetrakistriphenylphosphine (45 mg, 0.04 mmol) was introduced and the reaction mixture was stirred at 90 ° C under a gentle stream of nitrogen for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extracted phases were combined, washed with brine, dried (MgSO4) and evaporated under reduced pressure. The residue obtained was subjected to chromatography on SiO 2 (CH 2 Cl 2 / MeOH / NH 4 OH 96/4 / 0.4) to give the title product as the base. The base was dissolved in ethereal HCl and then the solution was concentrated and filtered to give the title product as the hydrochloride. Melting point: 160-163 ° C Elemental microanalysis: C H N S Cl% Theoretical 56.58 5.93 1 1.00 6.29 13.92% Experimental 55.36 6.3 10.62 6.32 13.67 EXAMPLE 2: N- dihydrochloride. { 4- [6- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl] -phenyl} benzenesulfonamide The product obtained in Step B of Example 1 was reacted with the compound obtained in Preparation 2, under the conditions described in Step C of Example 1. Melting point: 162-167 ° C Elemental microanalysis: CHNS Cl % Theoretical 58.31 6.02 10.46 5.99 13.24% Experimental 58.71 6.05 10.53 6.03 12.66 EXAMPLE 3: N- dihydrochloride. { 4- [6- (4-cyclopentyl-1-piperazinyl) -3-pyridinyl] phenyl} methansulfonamide Step A: N- (4-lodofenyl) methanesulfonamide The procedure is identical to that of Stage A of the Example 1, but the benzenesulfonyl chloride is replaced by methanesulfonic anhydride. Melting point: 1 18-120 ° C Elemental microanalysis: C H N S I% Theoretical 28.30 2.71 4.71 10.79 42.71% Experimental 28.67 2.83 4.70 1 1.22 43.44 Step B: N- [4- (4,4,5,5-Tetramethyl-1, 3,2-dioxaborolan-2-yl) pheny] -methanesulfonamide The procedure is identical to Step B of Example 1, but starting from the product obtained in Stage A above. Melting point: 180-182 ° C Stage C: N- Dihydrochloride. { 4- [6- (4-cyclopentyl-1-piperazinyl) -3-pyridinyl] phenyl} methanesulfonamide The procedure is identical to Step C of Example 1, starting from the product obtained in Step B and replacing the compound obtained in Preparation 1 with the compound obtained in Preparation 2. Melting point: 227-229 ° C Elemental microanalysis : CHNS Cl% Theoretical 53.27 6.39 1 1.83 6.77 14.98% Experimental 53.22 6.41 1 1.43 6.85 14.89 EXAMPLE 4: N- dihydrochloride. { 4- [6- (4-cyclopropylpiperazin-1-yl) pyridin-3-yl] phenyl} methanesulfonamide The product obtained in Step B of Example 3 was reacted with the compound obtained in Preparation 3, under the conditions described in Step C of Example 1. Melting point: 197 ° C Elemental microanalysis: CHNS Cl% Theoretical 51 .24 5.88 12.58 7.20 15.92% Experimental 51.70 5.78 12.21 6.81 15.93 Example 5: N- dihydrochloride. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} morfol i n-4-sulfonamide Step A: N- (4-lodofenyl) morfoin-4-sulfonamide To a solution of 10 g of 4-iodoaniline (45.6 mmoles) in 200 ml of acetonitrile was added 6.41 ml of Et3N (45.6 mmoles) and 8.47 g of sodium chloride. morpholin-4-sulfonyl (45.6 mmoles). The reaction mixture was stirred for 16 hours at room temperature. The acetonitrile was removed by evaporation in vacuo, and the residue was taken up in 1N HCl and extracted with CH2Cl2. The organic phases were combined, washed with brine, dried (MgSO4) and treated with animal charcoal to provide the title product. Melting point: 91 ° C Step B: N- [4- (4,4,5,5-Tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyI] -morpholine-4-sulfonamide The procedure is identical to Step B of Example 1 , starting from the product obtained in Stage A. Melting point: 158-161 ° C Step C: N- Dihydrochloride. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} morpholin-4-sulfonamide The procedure is identical to Step C of Example 1, starting from the product obtained in Step B.

Melting point: 194-198 ° C Elemental microanalysis: C H N S Cl% Theoretical 50.96 6.41 13.51 6.18 13.67% Experimental 50.90 6.79 13.23 6.09 13.46 EXAMPLE 6: N- dihydrochloride. { 4- [6- (4-isopro-ylpiperazin-1-yl) pyridin-3-yl] phenyl} methanesulfonamide The product of Step B of Example 3 was reacted with the compound obtained in Preparation 1, under the conditions described in Step C of Example 1. Melting point: 191 ° C Elemental microanalysis: CHNS Cl% Theoretical 50.19 6.25 12.32 7.05 17.15% Experimental 50.14 6.10 1 1.49 6.58 17.25 EXAMPLE 7: N- dihydrochloride. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] -phenyl} propan-2-sulfonamide Step A: N- (4-lodofenyl) propan-2-sulfonamide The procedure is identical to Step A of Example 5, replacing the morpholin-4-sulfonyl chloride with propan-2-sulfonyl chloride. Melting point: 96 ° C and Elemental microanalysis: C H N S I% Theoretical 33.24 3.72 4.31 9.86 39.03% Experimental 33.21 3.38 4.17 9.74 38.37 Step B: N- [4- (4! 4,5,5-Tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl] -propan-2-sulfonamide The procedure is identical to Step B of Example 1 , starting from the product obtained in Stage A. Melting point: 192 ° C Elemental microanalysis: CHNS% Theoretical 55.40 7.44 4.31 9.86% Experimental 55.46 7.33 4.54 10.11 Step C: N- Dihydrochloride. { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} propan-2-sulfonamide The procedure is identical to Step C of Example 1, starting from the product obtained in Step B. Melting point: 165 ° C Elemental microanalysis: CHNS Cl% Theory 53.05 6.78 1 1 .78 6.74 14.91% Experimental 53.05 7.07 11.58 6.47 14.62 EXAMPLE 8: N- dihydrochloride. { 4- [6- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl] -phenyl} -4-f I uorobenzenesulfonamide Stage A:. { 4- [6- (4-Cyclopentyl-piperazin-1-yl) pyridin-3-yl] phenol} Amine The procedure is identical to Step C of Example 1, using [4- (4, 4, 5, 5-tetramethyl-1, 3, 2-di oxaborolan-2-yl) phenyl] amine. Melting point: 160- 162 ° C Stage B: N- dihydrochloride. { 4- [6- (4-cyclopentyl-piperazin-1-yl) -pyridin-3-yl] -phenyl} -4-Fluorobenzenesulfonamide A suspension containing 200 mg (0.620 mmol) of the product obtained in Step A and 302 mg (1.55 mmol) of 4-fluorophenylsulfonic acid chloride in 2 ml of pyridine was stirred for 3 hours at 80 ° C. After cooling to room temperature, the reaction mixture was precipitated by adding water. The precipitate was collected by filtration, dissolved in a mixture of CH2Cl2 / MeOH, absorbed on about 1 g of silica and subjected to chromatography on a silica column, eluting with a mixture of CH2Cl2 / MeOH / NH3 98/2 / 0.2. The hydrochloride was formed by taking the base in ethanol and adding ethereal HCl. Melting point: 256-262 ° C Elemental microanalysis: C H N S Cl% Theoretical 56.42 5.64 10.12 5.79 12.81% Experimental 56.03 5.73 9.77 5.45 12.74 EXAMPLE 9: N- dihydrochloride. { 4- [6- (4-Cyclopentyl-piperazin-1-yl) pyridin-3-yl] phenyl} -3-f Iuorobenzenesulfonamide The procedure is identical to Example 8, but using 3-fluorophenylsulfonic acid chloride in Step B. Melting point: 167-170 ° C Elemental microanalysis: CHNS Cl% Theoretical 56.42 5.64 10.12 5.79 12.81% Experimental 56.72 5.60 9.96 5.67 12.86 EXAMPLE 10: N- dihydrochloride. { 4- [6- (4-Cyclo? Entyl? Iperazin-1-yl) pyridin-3-yl] phenyl} -2-fluorobenzenesulfonamide The procedure is identical to Example 8, but using 2-fluorophenylsulfonic acid chloride in Step B. Melting point: 248-253 ° C Elemental microanalysis: CHNS Cl% Theoretical 56.42 5.64 10.12 5.79 12.81% Experimental 56.46 5.63 9.87 5.47 12.80 PHARMACOLOGICAL STUDY OF COMPOUNDS OF THE INVENTION EXAMPLE A: Brain levels of Nt-methylhistamine in the NMRI mouse The purpose of this study, which was carried out according to the method of Taylor et al. (Biochem. Pharm., 1992, 44, 1261-1267), is to evaluate the ex vivo activity of the compounds of the present invention as antagonists of central histamine receptors of type H3. This activity is revealed by measuring, after intraperitoneal treatment with the test compounds, the central levels of Nt-methylhistamine, which is a major metabolite of histamine. An increase in brain concentrations of Nt-methylhistamine indicates an increase in histamine turnover by blocking central histamine receptors of type H3. NMRI mice (18-20 g) were treated intraperitoneally or orally with compounds of the present invention or with their carrier (20 ml / kg). One hour after the pharmacological treatment, the animals were sacrificed and their brains were removed, frozen in liquid nitrogen, weighed and homogenized in HCIO4 0.1 N at 4 ° C. The homogenized products were subjected to centrifugation (15,000g, 17 minutes , 4 ° C). The supernatants were recovered and divided into aliquots. The aliquots were frozen in liquid nitrogen and stored at -80 ° C until analysis.

The determination of brain levels of Nt-methylhistamine was performed by radioimmunoassay (RIA) using a test kit. Tissue levels of Nt-methylhistamine were expressed in μg / g of fresh brain. The comparison of the brain levels of Nt-methylhistamine between animals treated with the carrier (controls) and the animals treated with the compounds of the present invention was performed by analysis of variance of single factor followed, if necessary, by a complementary analysis ( Dennett's test). The results showed that, in doses from 1 to 10 mg / kg PO, the compounds of the present invention are capable of increasing the endogenous brain concentrations of Nt-methylhistamine by 100%. By way of example, the compounds of Examples 4 and 7, administered in doses of 10 mg / kg and 3 mg / kg PO, respectively, allowed an increase in the endogenous brain concentrations of Nt-methylhistamine to be obtained of 162% and 138% respectively. These results demonstrate that the compounds of the present invention are powerful antagonists of central histamine receptors of the H3 type.

EXAMPLE B: Electroencephalographic recordings on freely moving rats Male adult Wistar rats were implanted chronically with electrodes placed on the frontal and parietal cortex. A cortical electroencephalogram (EEG) of rats placed in cages was recorded in a room with attenuation of sound. The compounds and the vehicle were administered in a random order at 10:00 AM on the same days with a minimum of 3 days between each administration, allowing each rat to serve as its own control. The absolute power of the activity of the slow wave delta band (1 -4 Hz), which predominates during slow wave sleep and disappears during wakefulness and rapid eye movement sleep, was averaged over successive 30 minute periods . For 30 minutes, the low and high values of the slow wave delta power are signs of wakefulness and sleep, respectively. The results indicate that the compounds of the present invention increase the wakefulness (decrease in the activity of the delta band) for doses in the range between 0.3 and 3 mg / kg IP.

EXAMPLE C: Pharmaceutical composition. Formula for the preparation of 1, 000 tablets, each containing 100 mg of N- dihydrochloride. { 4- [6- (4-cyclopentyl-1-piperazinyl) -3-pyridinyl] phenyl} methanesulfonamide (Example 3) 100 g Hydroxypropylcellulose 2 g Wheat starch 10 g Lactose 100 g Magnesium stearate 3 g Talc 3 g

Claims (12)

CLAIMS 1. Compounds of formula (I): wherein: RT represents a group NR3SO2R4, wherein: - R3 represents a hydrogen atom or a linear or branched Ci-C3 alkyl group, - R4 represents a linear or branched C6-6 alkyl group, an aryl group or a group NR5R6, wherein: Rs and Re, which may be the same or different, each represent a hydrogen atom or a linear or branched Ci-Cβ alkyl group, a C3-C8 cycloalkyl group, or a group ( C3-C8 cycloalkyl) - (C-? -C6 alkyl) in which the alkyl portion is linear or branched, or R5 and Re, together with the nitrogen atom that bears them, forms a ring of 5 to 8 members wherein one of the carbon atoms can be replaced by a nitrogen, oxygen or sulfur atom or by an SO or SO2 group, the ring defined by this is optionally bridged by an alkyl group of
1. Ci-Ce linear or branched and / or optionally is substituted by one or more identical or different groups selected from halogen, linear or branched C? -C6 alkyl, linear or branched C? -C3 alkoxy, linear C1-C6 polyhaloalkyl or branched, carboxy, hydroxy, cyano, nitro and amino (optionally substituted by one or more linear or branched Ci-Cß alkyl groups), R2 represents a linear or branched Ci-Cβ alkyl group, a C3-Cd cycloalkyl group or a group (C3-Cd cycloalkyl) - (d-Ce alkyl) in which the alkyl portion can be linear or branched, it being understood that: an aryl group means the phenyl, naphthyl and biphenyl groups, these groups are optionally substituted by one or more identical or different groups selected from halogen, linear or branched C? -C6 alkyl, linear or branched Ci-Ce alkoxy, linear or branched C-? -C6 polyhaloalkyl, carboxy, hydroxy, cyano, nitro and amino (optionally substituted by one or more straight or branched C-i-Cß alkyl groups), their enantiomers and diastereoisomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
2. 2. Compounds of formula (I) according to claim 1, wherein R 4 represents an alkyl group, its enantiomers and diastereomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
3. 3. Compounds of formula (I) according to claim 1, wherein R 3 represents a hydrogen atom, its enantiomers and diastereoisomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
4. 4. Compounds of formula (I) according to claim 1, wherein Rs and R6, together with the nitrogen atom that bears them, form a ring of 5 to 8 members, wherein one of the carbon atoms can be replaced by an atom of nitrogen, oxygen or sulfur or by an SO or SO2 group, their enantiomers and diastereoisomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
5. 5. Compounds of formula (I) according to claim 1, wherein R 2 represents an isopropyl group, their enantiomers and diastereoisomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
6. 6. Compounds of formula (I) according to claim 1, wherein R 2 represents a cyclopropyl or cyclopentyl group, their enantiomers and diastereoisomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base.
7. 7. Compound of formula (I) according to claim 1, which is N- dihydrochloride. { 4- [6- (4-cyclopentyl-1-piperazinyl) -3-pyridinyl] phenyl} methanesulfonamide and also the addition salts thereof with a pharmaceutically acceptable acid or base.
8. 8. Process for the preparation of compounds of formula (I) according to claim 1, characterized in that the compound of formula (II) is used as the starting material: wherein Ri is as defined for formula (I), and R and R \ which may be identical or different, each represents a hydrogen atom or a linear or branched d-Cß alkyl group, or together form a C? -C6 linear or branched alkylene chain, which is condensed, in the presence of palladium (0), with a compound of formula (11): (10) * ^ n wherein R2 is as defined for formula (), and Ha! -represents a halogen atom, to provide the compound of formula (I), the compound of formula (I) is purified, if necessary, in accordance with a conventional purification technique is separated, where appropriate, in its isomers according to a conventional separation technique and converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base.
9. 9. Pharmaceutical compositions comprising as active ingredient a compound according to any of claims 1 to 7 in combination with one or more inert, non-toxic, pharmaceutically acceptable carriers or excipients.
10. 10. Pharmaceutical compositions according to claim 9, which comprise as active ingredient a compound according to any of claims 1 to 7, for use in the synthesis of a drug as an antagonist of central histamine receptors of the H3 type.
11. 1. Pharmaceutical compositions according to claim 9, comprising at least one active ingredient, a compound according to any of claims 1 to 7, for use, as a medicament, in the treatment of cognitive deficiencies associated with brain aging and with neurodegenerative diseases. and in the treatment of mood disorders, convulsive attacks, hyperactivity syndrome due to attention deficit, obesity, pain and neuroleptic states.
12. 12. Pharmaceutical compositions according to claim 9, comprising at least one active ingredient according to any of claims 1 to 7, for use as a medicament in the treatment of cognitive deficiencies associated with Alzheimer's disease, Parkinson's disease, Pick's disease, disease of Korsakoff and frontal or sub-cortical dementias of vascular origin or other origin.