MXPA06005239A - Novel phenyl-pyridinyl-piperazine derivatives, a method for the production thereof and pharmaceutical compositions containing said derivatives - Google Patents

Abstract

Phenyl pyridinyl piperazine derivatives of formula (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. X:C(O) or SO2;R1T or NR3R4;either R3, R4H, 1-6C alkyl, 3-8C cycloalkyl or 3-8C cycloalkyl-1-6C alkyl;or NR3R45-8 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, 3-8C cycloalkyl, 1-6C (polyhalo)alkyl, 1-6C alkoxy, COOH, OH, CN, O, 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, naphthyl 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.;Antiparkinso nian. - MECHANISM 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 FENILPIRIDILPIPERAZ.NA, UN 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, has the role of a neurotransmitter or neuromodulator in physiological or pathophysiological situations. { Annu. Rev. Neur sci., 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, neuro-endocrine regulation, circadian rhythm, cataleptic states, motility, aggression, eating behavior, learning and memorization, and synaptic plasticity (Hass et al. al., Histaminergic Neurons: Morphology and Function, Boca Raton, FL: CRC Press, 1991, pages 196-208, Prog. Neurobiology, 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, 117-123). 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, 19., 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 fight convulsive attacks. { Prog. Neurobiol., 2000, 63, 637-672, Neurosci. Biobenav. 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, Parklnson'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, convulsive attacks, hyperactivity syndrome due to attention deficit, obesity, pain and narcoleptic 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 (1): wherein: X represents a group C (O) or SO2, R-i represents: - an aryl group, - or a group NR3R4 where R3 and R4, which may be identical or different, each representing a hydrogen atom or a straight or branched Ci-Cß alkyl group, a C3-Cd cycloalkyl group or a (C3-C8 cycloalkyl) - (Ci-Cß alkyl) group in which the of alkyl is linear or branched, or R3 and R4, together with the nitrogen atom that bears them, form a ring of 5 to 8 members where 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 a linear or branched C6-C6 alkyl group and / or optionally is substituted by one or more identical or different groups selected from halogen, Linear or branched C? -Cβ, C3-8 cycloalkyl, linear or branched C? -C6 alkoxy, linear or branched Ci-C? Polyhaloalkyl, carboxy, hydroxy, cyano, oxo, nitro and amino (optionally substituted by one or more straight or branched C -? - C6 alkyl groups), R2 represents a group linear or branched d-Cβ alkyl, a C3-C8 cycloalkyl group or a (C3-C8 cycloalkyl) - (Ci-Ce alkyl) group in which the alkyl portion may be linear or branched, with its enantiomers and diastereoisomers, also with the addition salts thereof with a pharmaceutically acceptable acid or base, it being understood that: an aryl group means the phenyl, naphthyl and biphenyl groups, these groups being optionally substituted by one or more identical or different groups selected from halogen, linear or branched Ci-Cß alkyl, linear or branched C?-C6 alkoxy, linear or branched Ci-Ce polyhaloalkyl, carboxy, hydroxy, cyano, nitro and amino (optionally substituted by one or more Cl alkyl groups) -Cβ linear or branched), Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, 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 can be mentioned , without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc. The preferred compounds according to the invention are compounds of formula (1) wherein Ri represents a group NR3R4. The invention relates more particularly to compounds of formula (1) wherein R3 and R4I together with the nitrogen atom carrying them form a ring of 5 to 8 members in which one of the carbon atoms can be replaced by an atom of nitrogen, oxygen or sulfur or by an SO or SO2 group, the ring defined by this is optionally bridged by an alkyl chain and unsubstituted or substituted, preferably by one or more halogen atoms, for example fluorine, or by an alkyl group, for example a methyl group. Even more preferably, the preferred Ri groups are the morphoiinyl, thiomorfoiinyl, piperidyl, piperazinyl, 4- (alkyl) piperazinyl, pyrrolidinyl, 2- (alkyl) -2,5-diazabicyclo [2.2.1] -heptanyl, 2-oxa groups. -5-azabicyclo [2.2.1] heptani1o. X advantageously represents an SO2 group. A preferred R2 group is a cycloalkyl or C2-C6alkyl group more preferably an ethyl, isopropyl or cyclopentyl group. Even more especially, the invention relates to compounds of formula (1) which are: • 4- (. {4- [d- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl-phenyl} -hydrochloride. sulfonyl) morpholine, • 1-isopropyl-4- dihydrochloride. { 5- [4- (piperidin-1-ylsuifonyl) phenyl] -pyridin-2-ii} piperazine, • 1-cyclopentyl-4-dihydrochloride. { 5-β4- (piperidin-1-ylsu-1-phenyl) phenyl] -pyridin-2-yl} piperazine, • 1-cyclopropyl-4-diclohydrate. { 5- [4- (piperidin-1-i! Sulfonyl) phenyl] -pyridin-2-yl} piperazine, • 1-ethyl dihydrochloride] -4-. { 5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine• 1-Cyclobutyl 1,4-dihydrochloride. { 5- [4 - (? I? Eridin-1-iisulfoni1) phenyl] -pyridin-2-yl} piperazine, • 1- (5- {4 - [(4,4-difluoropiperidin-1-yl) sulfonyl] phenyl} - pyridin-2-yl} -4-isopropylpiperazine dihydrochloride, • Dihydrochloride 4- ( { 4- { 6- [4- (Cyclopropylpiperazin-1-yl) pyridin-3-yl] -phenyl} sulfonyl) morpholine, • 1-isopropyl-4-dihydrochloride 5- { 4 - [(4-Methylpiperazin-1-yl) -sulfonyl] phenyl] pyridin-2-yl.] Piperazine, • 4- (. {4- [6- (4- ( isopropylpiperazin-1-yl) pyridin-3-yl] -phenyl.} sulfonyl) thiomorpholine, • 1-Cyclopentyl-4-. {5- [4- (phenylsulfonyl) phenyl] pyridin-2-yl dichlorohydrate} piperazine, • 1-Cyclopentyl-4- {5- [3- (piperidin-1-ylsulfonyl) -phenyl] pyridin-2-yl} piperazine dihydrochloride, 1-isopropyl-4-dichlorohydrate { 5- [4- (pyrrolidin-1-ylsulfonyl) -phenyl] pyridin-2-yl}. Piperazine, • 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] dihydrochloride] -N, N-dimethylbenzenesulfonamide, • N-cyclopentyl-4- [6- (4-isopropyl-1-piperazinii) -3-pyridinyl] benzenesulfonamide, diclohydrate, • Dic 1-cyclopentyl-4-hydrochloride. { 5- [4- (piperidin-1-ylcarbonyl) phenyl] -pyridin-2-yl} piperazine, • 1-isopropii-4- dihydrochloride. { 5- [4- (piperidin-1-ylcarbonyl) phenyl] -pyridin-2-yl} piperazine, • 1-tmethyl-4-dihydrochloride. { 5-t4- (piperidin-1-ylsulfonyl) phenyl] -pyridin-2-yl} piperazine, • N-cyclopropyl-4- [6- (4-isopropylpiperazin-1-yl) -pyridin-3-yl] benzenesulfonamide dihydrochloride, N- (tert-butyl) -4- [6- (4-dihydrochloride -isopropylpiperazin-1-yl) -pyridin-3-yl] benzenesulfonamide, • 4- (. {4- [6- (4- (Isobutyl-piperazin-1-yl) -pyridin-3-yl] -phenyl} -dihydrochloride} sulfonyl) morpholine, • 1-isopropyl-4- (. {4- [6- (4- (isopropiipiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) piperazine dihydrochloride, • Dihydrochloride 4- [6- (4- (isopropylpiperazin-1-yl) pyridin-3-yl] -benzenesulfonamide, • 1,1-dioxyhydrate 4- (. {4- [6- (4- (isopropylpiperazine- 1-yl) pyridin-3-yl] -phenyl.} Sulfonyl) thiomorpholine, • 1-ethyl-4- (. {4- [6- (4- (isopropylpiperazin-1-yl) pyridin-3-trichlorohydrate] -yl] phenyl.}. sulfonii) piperazine, 4- (. {4- [6- (4- (isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} -hydrochloride} suifon!) thiomorphine, • 1 -. {5- [4- (aziridin-1-ylsulfonyl) phenyl] pyridin-2-yl} -4-isopropylpiper dihydrochloride azine, • 1-isopropyl-4- (5-) dihydrochloride. { 4- (2-methylpyrrolidin-1-ylsulfonyl) -phenyl] pyridin-2-yl) piperazine, • 1-isopropyl-4-trichlorohydrate. { 5- [4- (piperazin-1-ylsulfonii) phenyl] -pyridin-2-ii} piperazine, • 1-Cyclohexyl-4- (. {4- [6- (4-isopropyl] i? erazin-1-yl) -pyridin-3-ii] phenylfluoride.) suífonii) piperazine, • Diclohydrate of 1- ( { 4- [6- (4-iso? ropi-piperazin-1-yl) pyridin-3-yl-phenyl}. suphonyl) piperidin-4-one, • 1-isopropyl dihydrochloride 4- (5-. {4- (2-methylpyrrolidin-1-ylsulfonyl) -phenyl] pyridin-2-yl) piperazine, enantiomer 1, • 1-isopropyl-4- (5- {4- (2-methylpyrrolidin-yl-iisulfonii) -phenyl] pyridin-2-yl) piperazine, enantiomer 2, • 2- (. {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl.} sulfonyl) -5-methyl-2,5-diazabicyclo [2.2.1] heptane, • 1 - (. {4- [6- (4-isopropylpiperazin-yl) pyridin-3-trichlorohydrate] il] phenyl.}. suifonyl) -N, N-dimetii-piperidin-4-amino, • Trichlorohydrate of 1-cyclopentii-4- (5-. {4 - [(4-methylpipezip-1 -ii) -sulfonyl] phenyl.}. pyridin-2-yl) piperazine, • 1- (. {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl} suifonyl) dihydrochloride) piperidin-4-ol, • Trici 1- (. {4- [6- (4-isopropiipiperazin-1-yl) pyridin-3-yl] fenii or hydrate} sulfonyl) piperidin-4-ol, • 1-Isopropyl-4- (5-. {3- (4-methylpiperazin-1-ylsulfonyl) -fenii] pyridin-2-yl) piperazine dihydrochloride, • Dihydrochloride of 1 - (5- { 4 - [(4-fluoropiperidin-1-yl) sulfonyl] phene.} - pyridin-2-yl) -4-isopropiipiperazine, • Dicihydrate of 4-. { 4- [6- (4-isopropiipiperazin-1-yl) pyridin-3-yl] benzoyl} morpholine, • 1-isopropyl-4- (5-. {4- (2-methylpiperazin-1-yl) -carbonyl] phenyl} pyridin-2-yl) piperazine trichlorohydrate, • 1- (trichlorohydrate. {4-f6- (4-isopropylpyramine-2-yl) pyridin-3-yl] -philic} -syiphoxy.) -N-métipipyridyl-4-amyphta, • (1S, 4S) -dihydrochloride 5 ^ ( { 4 - [6- (4 ^ isopropylpiperazin-1-ryl) pyridin-3-ii] phenyl}. Suiofii) ^ 2-oxa-5-azabicyclo [2.2.1] heptane, »Trichlorohydrate of 1 = (. {4-f6» (4 ~ isopropylpiperazin Hf) pyridin-3 =. Il] phenol.] Sulfonit) piperidin-4-amine. The invention also relates to a process for the preparation of compounds of formula (I), the process is characterized in that the compound of formula (II) is used as the starting material. wherein R and X are co or defined for the formula (i), and R and R ', which may be identical or different, represent; each a hydrogen atom or a branched linear d-Ce alkyl group, or together they form a linear or branched C? -G6 alkylene chain, which is condensed, in the presence of palladium (0>, with a compound give formula (III): wherein R2 is as defined for formula (1), 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, is separated, when appropriate, efl its isomers according to a conventional separation technology and be converted, Yes, you want, e? its salts add addition? or? pharmaceutically acceptable acid or base. The compounds of formulas (H) and (111) 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 deficiencies associated with brain aging and with neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, PiGk disease, Korsakoff disease and frontal or sub-cortical dementias of vascular origin or other origin, and also e? the treatment of mood disorders, convulsive attacks, hyperactivity syndrome due to attention deficit, obesity, pain and narcoleptic states. The present invention also relates to pharmaceutical compositions comprising as 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, nasal, perlingual, buccal, ocular or respiratory administration may be more particularly mentioned. 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 oral liquid, buccal or ocular administration, they include, in particular, 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, RlvlN, mass spectrometry, etc.).

Preparation 1: 1- (5-Bromop? Rid_n-2-? I) -4-? Sopropi_p_perazine A solution containing 12.1 g of 2,5-dibromopyridine (51.1 mmol), 8.8 ml of -isopropylpiperazine (61.5 mmol) and 9.2 ml of DBU (61.5 mmol) was stirred overnight at 10010 C. The reaction mixture was returned to room temperature and the solution was diluted with water and it was 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 Microanalysis eiementai: 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-cyclopentylpiperazine The procedure is identical to that of Preparation 1, but the 1-isopyropilpiperazine is replaced by 1-cyclopeniylpiperazine. Melting point: 127-128 ° C Preparation ^: t- (d-romoprrrdtn - ^ - ??) - 4-cyclopropyl piperazine The procedure is identical to that of the Preparation, but the T-isopropylpiperazine is replaced by T-cyclopropylpiperazine. Melting point: 110-115 ° C Preparation 4: 1- (5-Bromopyridin-2-U) -4-ethylpiperazine Hl procedure is identical to that of Preparation 1-, but 1-isopropylpiperazine is replaced by 1-eVilpiperazine. Melting point: 66 ° G "Elemental microanalysis: O H-% Theoretical 48.90 5.97 15.55% Experimental 48.98- 6-.1 15.07 Preparation S: 1-. { 5-Bromop? Rid? N-2-? L) -4-c? Clobut] lp] peraz? Na The procedure is identical to that of Preparation 1, but 1-isopropylpiperazine is replaced by 1-cyclobutylpiperazine. Melting point: 98-102 ° C Preparation 6: 1- (S-Bromo-2-p? Ridln-yl) -4-methylpiperazine The procedure is identical to that of Preparation 1, but 1 -sopropylpiperazine is replaced by 4-methylpiperazine. Melting point: 71 -73 ° C Preparation T: t 5-Bromo-2-prrr rn-r?) - 4-rsobutttprperazrna The procedure is identical to that of Preparation, but the isopropypiperazine is replaced by t-isobutypiperazine. Melting point: 80 ° C Elemental microanalysis: C H N Br% Theoretical 52.3 © 6.76 t4.09 26.7S% Experimental 52.28 6V &7? 3-.63- t6.4t EXAMPLE t: Dretorhrdrate of 4- ( { 4-td-í4-? Sopropríprperazrn -? - H) p rr? din - $ - 1 ¥ ¡-f e n H.}. s ulf or norrio rfol i na Stage A: 4-] J (4 - iodophen? Í) suífonil} Morphine To a solution of 5 g of 4-iodobenzenesulonium chloride (0.65 mole) in 500 me of G 2 C 2 was added 46 me of triethylamine (0.33 mole) and then, dropwise,? ml of morphoin (0. 8 moles). Because the reaction is exothermic, the flask was placed in an ice bath until it returned to room temperature. The reaction mixture was stirred for 1 hour at room temperature. After washing the reaction mixture with about 100 ml of HC1 and then with 10 ml of water, the organic phase was dried (gS) and evaporated under reduced pressure. re-suspended in a small amount of isopropyl ether to provide the title product after filtration and drying in vacuo.Miltration point: Í4? -t44 ° ü Step B: [4- (Morpholin-4-ylsulfonyl) phenyl] boronic acid To a solution of 25 g of the compound obtained in Step A (70 \ mmoi) and 26 m of boisopropyl alcohol in 400 ml of cooled THF a-0 ^ C were added, dropwise, during 45 minutes and under a gentle stream of nitrogen, 53 ml of a solution 1.6 IV of BuLi (84.9 mmoles) in hexane. The reaction solution was then stirred for T hour 30 minutes at -60 '° - and subsequently returned at room temperature for 2 hours. The reaction mixture was treated with about 100 ml of HC1N and extracted 3 times with ethyl acetate. The organic phases were collected, washed with brine, dried (? VígS04) and evaporated under reduced pressure. The residue obtained was subjected to chromatography on a column of SÍO2, eluting with CH2Cl2 and then with a mixture of CH2 ~ Cl2 and feOH 98/2 and then '95 / 5. After evaporation of fractions, the residue was triturated in ethyl ether to provide the title product after filtration. Melting point: 104-110 ° C Stage C: 4- (. {4-i6- (4-isopropifpiperazin-1-yl) pyridin-3-yl-phenyl} -phihydrofor). of the compound obtained in Preparation 1 ("38.3 mmoies), 13.5 g of the compound obtained in Step B (49.8 mmoles), 250; dioxane and 190 ml of Na2C 3 'Q.4 in water were introduced into a three-necked flask. The reaction mixture was degassed by bubbling nitrogen through it for 3E > minutes Pá (Q) tetrakistriphenylphosphine (2.21 g, 1.B1 mmoles) was introduced and the reaction mixture was stirred at 100 & 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 ether. A precipitate formed in the course of the extraction, which was separated by filtration, rinsed with water and with a small amount of ethyl acetate to provide, after drying in vacuo, a first batch of the title product in the form of base. The extracted phases were combined with the filtrate, and the organic phase was separated and then washed with brine. The organic phase was dried (MgSO 4) and evaporated under reduced pressure. The evaporation residue was resuspended in ethanoi and separated by filtration to provide, after drying in vacuo, a second batch of the title compound in the ta-base form. The 2 lots were combined and suspended in ethanoi. Ethereal HCi was added and the suspension was filtered to provide the title product. Melting point; 2 &4-256fr Elemental Chromatography: C H N S Cí Theoretical 52.48 6.41 11.13 6.37 14.08% Experimental 52.62 6.40 T0.9 6.50 14.45 E EMP O tt orr? Orft? DratG of -lsoproprl-4-. { ? -t4- (pVperídrn-1 rrsulronr?) fenrllprrrdrn - ^ - ri} prperazine Stage A: l-. { (4-iodophene) suphioni] piperidine The procedure is identical to Stage A of Example 1, but the morpholine is replaced by piperidine. Elemental microanalysis: C H N S I% Theory 37.62 4.02 3.B9 9.13 36.13% Experimental 37.91 4.G8 4.01 8.93 36.54 Step B: [4- (Piperidin-1-ylsulfonyl) phenyl] boronic acid The procedure is identical to Stage B of Example 1, starting from the product obtained in Step A. Melting point: 110 ° C Step C: l-Isopropyl-4-hydrochloride. { 5- [4- (piperidin-1-iisuifonyl) -iino] pyridin-2-yl} pi perazi na The procedure is identical to Stage C of Phase 1, starting with the product obtained in Stage B.

Melting point: 249-252 ° C Elemental macroanalysis: C H N S Cl% Theoretical 55.08 6.83 1 1.17 6.39 14.14% Experimental 54.83 7.00 1 1.05 6.18 13.74 EXAMPLE 3: 1-Cyclopentyl-4- dihydrochloride. { 5- [4- (piperidln-1- _.su.fonii) feni_] pir.ain-2-i ..}. p_perazine The procedure is identical to Step C of Example 2, but the product of Preparation 1 is replaced by the product obtained in Preparation 2. Melting point: 241 -243 ° C Elemental microanalysis: CHNS Ct% Theoretical 56.92 6.88 10.62 6.08 13.44% Experimental 56.65 7.11 10.37 6.13 13.07 EXAMPLE 4: 1-ciciopropii-4- Diciorhydrate. { d- [4- (piperidin-1-iisulfonii) fenii] pyridin-2-ii} Piperazine The product of Step B of Example 2 was reacted with the compound obtained in Preparation 3, under the conditions described in Step C of Example 1. Melting point: 204-208 ° C Elemental microanalysis: CHNS Cl% Theoretical 55.31 6.46 11.22 6.42 14.20% Experimental 56.01 6.74 11.14 5.81 13.99 EXAMPLE 5: 1-Ethyl-4- Dicuhydrate. { 5- [4- (piperidin-1-yisulfonii) fenii] pyridin-2-ii} Piperazine The product from Step B of Example 2 was reacted with the compound obtained in Preparation 4, under the conditions described in Step C of Example 1. Melting point: 245-247 ° C Elemental microanalysis: CHNS% Theoretical 54.20 6.62 11.49 6.58 14.54% Experimental 54.87 7.01 11.56 6.12 14.92 EXAMPLE ß: 1-Cliobutyl-4- dihydrochloride. { 5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridine-2-ii} Piperazine The product of Step B of Example 2 was reacted with the compound obtained in Preparation 5, under the conditions described in Step C of Example 1. Melting point: 250-253 ° C Elemental microanalysis: CHNS Cl% Theoretical 57.77 6.79 11.23 6.43 13.81% Experimental 57.54 6.84 11.00 6.04 11.69 EXAMPLE 7: 1- (5- {4 - [(4,4-difluoropiperidin-1-yl) sulfonyl] phenyl] -pyridine-2-li.} -4-lsopropyl-pyridine Step A: 4,4-Difluoro-1 - [(4-iodophenyl) sulfonyl] piperidine The procedure is identical to Step A of Example 1, but the morpholine is replaced by 4,4-difluoropiperidine. Melting point: 148-150 ° C Elemental microanalysis: C H N S I% Theoretical 34.12 3.12 3.62 8.28 32.78% Experimental 34.62 3.27 3.66 8.30 33.36 Stage B: Acid. { 4 - [(4,4-Difluoropiperidin-1-yl) sulfonyl] phenyl} boronic The procedure is identical to Step B of Example 1, starting from the product obtained in Step A. Melting point: 289 ° C Step C: 1- (5- {4 - [(4,4-difluoropiperidin-1-yl) sulfonyl] phenyl} pyridin-2-yl} -4-isopropylpiperazine dihydrochloride The procedure is identical to Step C of Example 1, starting from the product obtained in Step B. Melting point: 260-262 ° C Elemental microanalysis: CHNS Cl% Theoretical 51.4 6.00 10.42 5.97 13.19% Experimental 51.07 5.85 10.03 6.07 13.84 EXAMPLE 8: 4- (. {4- {6} [4- (cycloproplipiperazin-1-yl) pyridin-3-yl] phenyl} sulfonyl) morpholine hydrochloride The product of Step B of Example 1 was reacted with the compound obtained in Preparation 3, under the conditions described in Step C of Example 1. Melting point: 220 ° C Elemental microanalysis: CHNS Ci% Theoretical 52.69 6.03 11.17 6.39 14.14% Experimental 52.67 6.04 10.83 6.35 14.22 EXAMPLE 9: 1-isopropyl-4- (5-. {4 - [(4-methyl-piperazin-1-yl) -sulfonyl-2-ylpyridin-2-yl} piperazine dichloride.

Step A: 1 - [(4-lodofenii) sulfonii)] - 4-methiipiperazine The procedure is identical to Step A of Example 1, but the morpholine is replaced by 4-methylpiperazine.

Melting point: 8 8-82 82 ° C Stage B: l-Metif-4-. { [4- (4,4I5I5-tetramethyl-1,3I2-dioxaborolan-2-yl) -phenii] suifonii} piperazine 5.4 g of the compound obtained in Step A (14.75 mmoles), 4.52 g of bis (pinacolato) borane (19.18 mmoies), 4.34 g of potassium acetate (44.25 mmoies) and 50 ml of dimethyiiformamide were introduced into a two-necked flask. mouths of 100 mi. The reaction mixture was degassed by bubbling a stream of nitrogen through it for 30 minutes; and then 165 mg of palladium acetate (0.737 mmol) was added. The reaction mixture was stirred under a gentle stream of nitrogen for 2 hours 30 minutes at 85 ° C. After cooling to room temperature, the reaction mixture was diluted with water and extracted with CH 2 Cl 2. The organic phases were collected, washed with brine, dried and evaporated under reduced pressure. The obtained residue was subjected to chromatography on SiO2 (CH2Cl2 / MeOH 95, / d) to give the title product as a creamy white solid. Melting point: 126-136 ° C Step C: 1-isopropii-4- (5-. {4 - [(4-metiipiperazin-1-yl) suifonii] phenyl] pyridin-2-yl} piperazine dihydrochloride The procedure is identical to Step C of Example 1, starting from the product obtained in Stage B above.

Melting point: 254-258 ° C Elemental microanalysis: C H N S Cl% Theoretical 49.96 6.56 12.66 5.80 19.23% Experimental 50.57 6.55 12.50 5.82 18.50 EXAMPLE 10: 4- (. {4- [6- (4- (Sopropypiperazin «1-yl) pyridin-3-yl] phenyl] sulfonyl) thiomorpholine Step A: 1 - [(4-lodofenyl) sulfonyl)] thiomorpholine The procedure is identical to Step A of Example 1, but the morpholine is replaced by thiomorpholine. Melting point: 131 ° C Step B: [4- (Thiomorpholin-4-ylsulfonyl) phenyl] boronic acid The procedure is identical to Step B of Example 1, starting from the product obtained in Step A. Melting point: > 300 ° C Step C: 4- (. {4- [6- (4- (Isopropylpiperazin-1-yl) pyridin-3-yl] phenyl] sulfonyl) thiomorpholine dihydrochloride The procedure is identical to Step C of Example 1 , starting from the product obtained in Stage B. Melting point: 248-253 ° C Elemental microanalysis: CHNS Cl% Theoretical 50.86 6.21 10.78 12.34 13.65% Experimental 51.51 6.41 10.35 11.74 13.95 EXAMPLE 11: 1-Cyclopentyl-4-diclohydrate. { S- [4- (phenylsulfonyl) phenyl] pyridin-2-yl} ? iperazine Step A: 1-Bromo-4- (phenylsulfopyl) benzene To a solution of 199 μi of bromobenzene (1.88 mmole) and 361 μl of benzenesulfonyl chloride (2.83 mmole) in 4 ml of trifluoroacetic acid were added, in succession, 83 mg of indium chloride (0.376 mmol) and then, dropwise, 25 μl of trifluoromethanesulfonic acid. The reaction mixture was stirred for 2 hours at 70 ° C and then returned to room temperature and diluted with ice-cold water. After turning it alkaline to pH 10 by adding concentrated sodium hydroxide solution, the reaction mixture was extracted with CH2Ct2. The organic phases were collected, washed with saturated NaCl, dried (MgSO4) and evaporated under reduced pressure to give the title product as a white solid. Melting point: 95-99 ° C Elemental microanalysis: C H S Br Theoretical 48.50 3.05 10.79 26.89% Experimental 48.21 3.21 11.17 27.32 Step B: [4- (Phenylsulfonyl) phenyl] boronic acid The procedure is identical to Step B of Example 1, starting from the product obtained in Step A. Melting point: 287-290 ° C Step C: 1-cyclopentyl-4- dihydrochloride. { 5- [4- (phenylsuiphenyl) phenyl] pyridine-2-ii} piperazine The procedure is identical to Step C of Example 1, starting with the product obtained in Step B and replacing the product of Preparation 1 with the product of Preparation 2. Melting Point: 155-159 ° C Elemental Microanalysis: CHNS Cl% Theory 59.99 6.00 8.07 6.16 13.62% Experimental 60.36 5.86 7.95 5.99 13.99 EXAMPLE 12: 1-Cyclo-dichlorhydrate-4-enyl. { 5- [3- (piperidin-1-iisuifonii) fenii] pyridin-2-ii} piperazine Step A: 1 - [(3-Bromophenyl) sulfonyl] piperidine The procedure is identical to Step A of Example 1, starting with 3-bromobenzenesuiphenyl chloride and piperidine. Melting point: 87 ° C Elemental microanalysis: C H N S Br Theoretical 43.43 4.64 4.60 10.54 26.27% Experimental 43.71 4.75 4.72 1 1 -02 26.37 Step B: [3- (Piperidin-1-ylsulfonyl) phenyl] boronic acid The procedure is identical to Step B of Example 1, starting from the product obtained in Step A. Melting point: 1 15-1 19 ° C Step C: 1-Cyclopentyl-4- dihydrochloride. { 5- [3- (piperidin-1-ylsulfonyl) fenii] pyridin-2-ii} Piperazine The procedure is identical to Step C of Example 1, starting from the product obtained in Step B and replacing the product of Preparation 1 with the compound obtained in Preparation 2. Melting point: 229-231 ° C Elemental Microanalysis: CHNS Cl% Theory 56.92 6.88 10.62 6.08 13.44% Experimental 56.76 6.92 10.42 5.91 13.47 EXAMPLE 13: 1-Isopropyl-4- Diciorhydrate. { 5- [4-. { pyrrolidin-1-isuifonli) phenyl] pyridin-2-yl} piperazine Stage A: 1-. { (4-lodofenyl) suphonyl] pyrrolidine The process is identical to Step A of Example 1, but the morpholine is replaced by pyrrolidine. Melting point: 126 ° C Elemental microanalysis: C H N S I% Theoricq 35.62 3.59 4.15 9.51 37.64% Experimental 37.13 3.80 4.19 9.29 36.89 Step B: [4- (Pyrrolidin-1-ylsulfonyl) phenyl] boronic acid The procedure is identical to Step B of Example 1, starting from the product obtained in Step A. Melting point: 306 ° C Stage C: 1-isopropyl-4-diclohydrate. { 5- [4- (pyrrolidin-1-itsuifonyl) f eni t] pyridin-2-ii} pi perazi na The procedure is identical to Step C of Example 1, starting from the product obtained in Step B. Melting point: 240 ° C Elemental microanalysis: C H N S Cl% Theoretical 54.20 6.62 11.49 6.58 14.54% Experimental 54.32 6.54 11.18 6.57 15.23 EXAMPLE 14: 4- [6- (4-isopropiipiperazin-1-ii) pyridin-3-yl] -N, N-dimethylbenzenesulfonamide diclohydrate Step A: 4-mud-N, N-dimethylbenzenesulfonamide The procedure is identical to Step A of Example 1, but the morpholine is replaced by dimethiamine. Melting point: 128 ° C Elemental microanalysis: C H N S I% Theoretical 30.88 3.24 4.50 10.31 40.79% Experimental 31.56 3.32 4.41 10.10 39.50 Stage B: Acid. { 4 - [(Dimethylamino) sulfonyl] phenyl} boronic The procedure is identical to Step B of Example 1, starting from the product obtained in Step A. Melting point: 306 ° C Stage C: 4- [6- (4-isopropiipipetazin-1-yl) pyridine dihydrochloride 3-yl] -N, N-dimethylbenzenesulfonamide The procedure is identical to Step C of Example 1, starting from the compound obtained in Step B. Melting point: 240 ° C Elemental microanalysis: CHNS Cl% Theory 52.06 6.55 12.14 6.95 15.52 % Experimental 52.39 6.68 1 1.69 6.91 15.74 EXAMPLE 15: N-Cyclopentyl-4- [6- (4-isopropyl-1-piperazyl) -3-pyridinyl] benzenesulfonamide dihydrochloride Step A: N-Cyclopentyl-4-iodobenzenesulfonamide The procedure is identical to Step A of Example 1, but the morpholine is replaced by cyclopentylamine.

Step B: N-Cyclopentyl-4- (4,4,5,5-tetramethi-1) 3I2-dioxaborolan-2-yl) -benzenesulfonamide The procedure is identical to Step B of Example 9, starting from the product obtained in Stage A.

Step C: N-Cyclopentyl-4 ~ [6- (4-isopropyl-1-piperazinyl) -3-pyridinyl] benzenesulfonamide dihydrochloride The procedure is identical to Step C of Example 1, starting from the product obtained in Step B.

EXAMPLE 16: 1-Cyclopenti-4-diclohydrate. { 5- [4- (piperidin-1-ylcarbonyl) phenyl] -pyridin-2-yl} piperazine Step A: 1- (4-lodobenzoyl) piperidine To a suspension of 4.0 g of 4-iodobenzoic acid (16.13 mmoles) in 40 ml of CH2Cl2 was added 3.65 ml of diisopropylethylamine (20.97 mmoles) and then, after 10 minutes, 5.18 g of TBTU (16.13 mmoles). After stirring for a further 10 minutes, 1.60 ml of piperidine (16.13 mmol) were added and the reaction mixture was stirred overnight at room temperature. The reaction mixture was washed 3 times with water and then once with saturated NaCl. After drying (MgSO4) and evaporation under reduced pressure, the residue was subjected to chromatography on silica (CH2Cl2 acetone 9/1) to give the title product. Melting point: 115-118 ° C Step B: [4- (Piperidin-1-ylcarbonyl) phenyl] boronic acid The procedure is identical to Step B of Example 1, starting from the compound obtained in Step A. Melting point: 135-140 ° C Step C: 1-Cyclopentyl-4-dihydrochloride. { 5- [4- (piperidin-1-ylcarbonyl) phenyl] pyridin-2-it} piperazine The procedure is identical to Step C of Example 1, starting with the compound obtained in Step B and the compound obtained in Preparation 2. Melting point: 227-230 ° C Elemental microanalysis: CHN Cl% Theory 63.54 7.38 11.40 14.43 % Experimental 63.45 7.42 1 1.31 14.46 EXAMPLE 17: 1-Sodpropyl-4- dihydrochloride. { 5- [4- (piperidin-1-ylcarbonii) phenyl] pyridin-2-yl} piperazine The procedure is identical to Step C of Example 16, but the product obtained in the Preparation is replaced by the compound obtained in Preparation 1. Melting point: 240-243 ° C Elemental microanalysis: CHN Cl% Theoretical 61.93 7.36 12.04 15.23% Experimental 62.14 7.35 1 1.62 15.33 EXAMPLE 18: 1-methyl-4-dihydrochloride. { 5- [4- (piperidin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine The product from Step B of Example 2 was reacted with the compound obtained in Preparation 6, under the conditions described in Step C of Example 1. Melting point: 250-255 ° C Elemental microanalysis: CHNS Cl% Theory 53.27 6.39 11.83 6.77 14.98% Experimental 53.51 6.40 1 1.82 6.71 15.16 EXAMPLE 19: N-cyclopropyl-4- [6- (4-isopropylpiperazin-1-yl) -pyridin-3-yl] benzenesuifonamide dihydrochloride Step A: N-Cyclopropyl-4-iodobenzenesulfonamide The procedure is identical to Step A of Example 1, but the morpholine is replaced by cyclopropylamine.

Step B: N-Cyclopropyl-4- (4,4,5l5-tetramethyl-1, 3,2-dioxaborolan-2-yl) benzenesulfonamide The procedure is identical to Step B of Example 9, starting from the product obtained in the Step A. Melting point: 99 ° C Step C: N-Cyclopropyl-4- [6- (4-isopropiipiperazin-1-yl) -pyridin-3-yl] benzenesuifonamide dihydrochloride The procedure is identical to Step C of Example 1, starting from the product obtained in Stage B. Melting point: 269 ° C Elemental microanalysis: CHNS Cl% Theoretical 53.27 6.39 11.83 6.77 14.98% Experimental 53.22 6.44 11.66 6.51 14.98 EXAMPLE 20: N- (tert-Butyl) -4- [6- (4-isopropylpiperazin-1-H) -pyridin-3-yl] benzenesulfonamide dihydrochloride Step A: N- (tert-Butyl) -4-iodobenzenesulfonamide The procedure is identical to Step A of Example 1, but the morpholine is replaced by tert-butylamine. Melting point: 121 ° C Step B: N- (tert-Butyl) -4- (4,4,5,5-tetramethyl-1,2,2-dioxaborolan-2-yl) -benzenesulfonamide The procedure is identical to Step B of Example 9, starting from the product obtained in Stage A.

Step C: N- (tert-butyl) -4 ~ [6- (4-isopropylpiperazin-1-yl) -pyridin-3-ylbenzenesulfonamide dihydrochloride The procedure is identical to Step C of Example 1, starting from the product obtained in Stage B. Melting point: 215-230 ° C Elemental microanalysis: CHNS Cl% Theoretical 53.98 7.00 11.45 6.55 14.48% Experimental 54.19 7.05 1 1.16 5.25 14.52 EXAMPLE 21: 4- (. {4- [6- (4- (Isobutylpiperazin-1-yl) pyridin-3-yl] phenyl] sulfonyl) morpholine dihydrochloride The product obtained in Step B of Example 1 was reacted with the compound obtained in Preparation 7, under the conditions described in Step C of Example 1. Melting point: 137 ° C Elemental microanalysis: CHNS Cl% Theory 53.76 6.65 10.90 6.24 13.11% Experimental 54.14 6.57 10.74 6.06 13.04 EXAMPLE 22: 1-Isopropyl-4- (. {4- [6- (4- (iso? Ropilpiperazin-1-yl) pyridin-3-yl] phenyl dichloride} sulfonyl) piperazine Step A: 1 - [(4-lodofenyl) suifonyl] -4-isopropiipiperazine The procedure is identical to Step A of Example 1, but the morpholine is replaced by 1-isopropylpiperazine. Melting point: 139 ° C Stage B: 1-lsopropyl-4-. { [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) phenyl] sulfonyl} piperazine The procedure is identical to Step B of Example 9, starting from the product obtained in Step A.

Step C: 1-Isopropyl-4- ({4- [6- (4- (isopropylpiperazin-1-yl) pyridin-3-ylphenyl} sulfonyl) piperazine dihydrochloride The procedure is identical to Step C of the Example 1, starting from the product obtained in Step B. Melting point: 290 ° C Elemental microanalysis: CHNS Cl% Theoretical 51.68 6.94 12.05 5.52 18.3% Experimental 51.35 7.39 1 1.77 5.35 18.5 EXAMPLE 23: 4- [6- ( 4- (isopropipipiperazin-1-ii) pyridin-3-yl-benzenesuifonamide Step A: 4-lodobenzenesuifonamide The procedure is identical to Step A of Example 1, but the morpholine is replaced by gaseous ammonia. Melting point: 173 ° C Step B: 4- (4,4,5,5-tetramethi-1, 3,2-dioxaborolan-2-yl) -benzenesulfonamide The procedure is identical to Step B of Example 9, starting from the product obtained in Step A .

Step C: 4- [6- (4- (Isopropylpiperazin-1-ii) pyridin-3-yl] -benzenesulfonamide dihydrochloride The procedure is identical to Step C of Example 1, starting from the product obtained in Step B. Melting point: 297-301 ° C Elemental microanalysis: CHNS Cl% Theoretical 49.88 6.05 12.93 7.4 16.36% Experimental 50.05 6.21 12.58 7.39 16.46 EXAMPLE 24: 1,1-dioxide dihydrochloride 4- (. {4-E6- ( 4- (isopropylpiperazin-1-ii) pyridin-3-yl] -phenyl} sulfonyl) thomorphofiin To a suspension of 400 mg of the product obtained in Example 10 (0.76 mmol) in a mixture of 3 ml of acetone and 12 ml of water was added 266 mg of 4-methylmorpholine N-oxide. (2.27 mmoies) and 34 μl of a 2.5% solution of osmium tetroxide in tert-butanol. After stirring for 16 hours at room temperature, the reaction mixture was treated with a saturated solution of sodium bisulfite and 10% in sodium hydrogen carbonate. The mixture was extracted with CH2Cl2, and the organic phases were dried over MgSO4 and evaporated under reduced pressure. The residue was treated with methanolic HCl to provide, after filtration, the title product as a white solid. Melting point: 278-280 ° C Elemental microanalysis: CHNS Ci% Theoretical 47.91 5.85 10.16 11.63 12.86 or%, Experimental 48.57 5.68 10.08 11.73 13.58 EXAMPLE 25: Trichiorhydrate of 1-etii-4- (. {4-t6- ( 4- (isopropylpiperazin-1-yl) pyridin-3- ii] phenii.}. Sulfonii) piperazine Step A: 1 - [(4-Lodofenyl) sulfonyl] -4-etiipiperazine The procedure is identical to Step A of Example 1, but the morpholine is replaced by 1-ethylpiperazine. Melting point: 148 ° C Elemental microanalysis: C H N S I% Theory 37.90 4.51 7.37 8.43 33.37% Experimental 37.74 4.50 7.16 8.22 31.85 Stage B: 1 -Etil-4-. { [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) -phenyl] sulfonyl} piperazine The procedure is identical to Step B of Example 9, starting from the product obtained in Step A.

Step C: 1-Ethyl-4- (. {4- [6- (4- (isopropylpiperazin-1-yl) pyridin-3-yl] phenyl] -sulfonyl) piperazine trichloride The procedure is identical to the Step C of Example 1, starting from the product obtained in Step B. Melting point: 249 ° C Elemental microanalysis: CHNS Cl% Theoretical 50.84 6.75 12.35 5.66 18.76% Experimental 50.33 6.53 1 1.84 5.26 18.76 EXAMPLE 26: 4- (. {4- [6- (4- (Iso? Ropil? Iperazin-1-yl)? Iridin-3-yl] phenyl} -s-hydroxide. olina tiomorf To a solution of 183 ml of NalO 4 (0.86 mmoies) in 8 ml of water was added 424 mg of the product of Example 10, and the reaction mixture was stirred for 1 hour at room temperature. The mixture was extracted with CH2Cl2 and the organic phases were dried over MgSO4. After evaporation under reduced pressure, the residue was treated with methanolic HCl to provide, after filtration, the title product as a white solid. Melting point: 265 ° C Elemental microanalysis: C H N S Cl% Theoretical 49.68 6.04 10.53 12.06 12.66% Experimental 49.91 6.14 10.03 11.95 12.39 EXAMPLE 27: Dicohydrate of 1 -. { 5- [4- (aziridin-1-ylsulfonyl) phenyl] pyridin-2-yl} -4-isopropylpiperazine Step A: 1-Cyclopropyl-4 - [(4-iodophenyl) sulfonyl] piperazine The procedure is identical to Step A of Example 1, but the morpholine is replaced by 1-cyclopropylpiperazine. Melting point: 169 ° C Stage B: 1 -Cyclopropyl-4-. { [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-ii) fenii] sulfonyl} piperazine The procedure is identical to Step B of Example 9, starting from the product obtained in Step A.

Step C: 1 - Dichlorohydrate. { 5- [4- (aziridin-1-ylsulfonyl) phenyl] pyridin-2-yl} -4-isopropylpiperazine The procedure is identical to Step C of Example 1, starting from the product obtained in Step B. Melting point: 149 ° C Elemental microanalysis: C H N S Cl% Theoretical 55.34 6.87 12.91 5.91 13.07 or%. Experimental 55.22 7.01 12.52 5.99 12.98 EXAMPLE 28: 1-Isopropyl-4- (5-. {4- (2-methylpyrrolidin-1-ylsulfonyl) phenyl] pyridin-2-yl) piperazine dihydrochloride Step A: 1 - [(4-lodofenyl) sulfonyl] -2-methylpyrrolidine The procedure is identical to Step A of Example 1, but the morpholine is replaced by 2-methyl-pyrrolidine. Melting point: 76 ° C Stage B: Acid. { 4 - [(2-Methylpyrrolidin-1-yl) sulfonyl] phenyl} The procedure is identical to Step B of Example 1, starting from the product obtained in Step A. Melting point: 125-128 ° C Step C: 1-Isopropyl-4- (5-. {4- (2-methylpyrrolidin-1-ylsulphonyl) phenyl] pyridin-2-yl) piperazine dihydrochloride The procedure is identical to Step C of Example 1, starting from of the product obtained in Stage A. Melting point: 208-213 ° C Elemental microanalysis: CHNS Cl% Theoretical 55.08 6.83 11.17 6.39 14.14% Experimental 55.27 6.77 10.95 6.27 14.47 EXAMPLE 29: 1-Isopropyl-4-trlhydrochloride. { 5-t4- (piperazin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine Step A: 4 - [(4-iodophenyl) sutfonii] piperazine-1-tert-butylcarboxylate The procedure is identical to Step A of Example 1, but the morpholine is replaced by piperazine-1-carboxylic acid tert-butyl ester.

Step B: Acid (4- { [4- (tert-butoxycarbonyl) piperazin-1-yl] sulfonyl.} - phenyl) boronic acid The procedure is identical to Step B of Example 1, starting from the product obtained in Stage A.

Step C: 4- ( { 4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl] -sulfonyl) piperazine-1-tert-butylcarboxylate The procedure is identical to Step C of Example 1, starting from the product obtained in Step A. Melting point: 194 ° C Stage D: 1-isopropii-4- trichiorhydrate. { 5- [4- (piperazin-1-ylsulfonyl) phenyl] pyridin-2-yl} piperazine The deprotection was carried out in a 1/1 mixture of dioxane and methanolic HCl. Melting point: 265-273 ° C Elemental microanalysis: C H N S Cl% Theoretical 49.03 6.36 12.99 5.95 19.73% Experimental 49.63 6.49 12.86 6.2 20.39 EXAMPLE 30: 1-cyclohexyl-4- (. {4- [6- (4-isopro-ylpiperazin-1-yl) -pyrid? N-3-yl] phenyl] sulfonyl) piperazipadihydrochloride Step A: 1-Cyclohexyl-4 - [(4-iodophenyl) sulfonyl] piperazine The procedure is identical to Step A of Example 1, but the morpholine is replaced by 1-cydohexylpiperazine. Melting point: 174-177 ° C Elemental microanalysis: C H N S I% Theoretical 44.25 5.34 6.45 7.38 29.22% Experimental 44.16 5.33 6.37 7.00 29.07 Stage B: 1-Cyclohexyl-4-. { [4- (4I4,5,5-tetramethyl-1 I3,2-dioxaborolan-2-yl) phenyl] sulfonyl} Piperazine Et procedure is identical to Step B of Example 9, starting from the product obtained in Step A.

Step C: 1-Cyclohexyl-1-4- ({4- {4- (4-isopropylpiperazin-1-yl) -pyridin-3-yl] phenyl} sulfonyl) pi perazine dihydrochloride The procedure is identical to Stage C of Example 1, starting from the product obtained in Stage B. Melting point: 276-281 ° C Elemental microanalysis: CHNS Ci% Theory 57.52 7.41 1 1.98 5.48 12.13% Experimental 58.01 7.32 12.18 5.2 12.86 EXAMPLE 31: 1 - (. {4- [6- (4-isopropyipiperazin-1-yl) pyridin-3-yl] -phenyl] -sulfonyl) piperidin-4-one diclohydrate Step A: 8 - [(4-lodofenyl) sulfonyl] -1,4-dioxa-8-azaspiro [4.5] decane The procedure is identical to Step A of Example 1, but the morpholine is replaced by 1.4. -dioxa-8-azaspiro [4,5] -decano. Melting point: 166-169 ° C Step B: [4- (1,4-Dioxa-8-azaspiro [4.5] dec-8-ylsulfonyl) phenyl] boronic acid The procedure is identical to Step B of Example 1, starting from the product obtained in Step A. Melting point: 146-148 ° C Step C: 8- (. {4-t6- (4-isopropylpiperazin-1 -ii) pyridin-3-ii] phenii.]. Suifonyl) -1, 4 -dioxa-8-azaspiro [4.5] decane The procedure is identical to Step C of Example 1, starting from the product obtained in Step B. Melting point: 215 ° C Elemental microanalysis: CHNS% Theoretical 61.70 7.04 1 1.51 6.59% Experimental 61.28 7.05 11.54 6.58 Step D: 1 - (. {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] -phenyl} sulfonii) piperidin-4-one diclohydrate A suspension of 400 mg of the product obtained in Step C (0.82 mmoies) in 5 ml of 1N HCi was stirred for 1 hour at 80 ° C. After neutralization of the reaction mixture using 10% NaHCO3 ai, the precipitate was filtered off, washed with water and dried. The white solid was suspended in ethanoi and dissolved by adding methanolic HCl. The solution was evaporated to dryness and the residue was taken up in a mixture of ethanol / ethyl ether to provide the expected product after filtration. Melting point: > 260 ° C Elemental microanalysis: CHNS Cl% Theoretical 53.59 6.26 10.87 6.22 13.75% Experimental 54.25 6.25 10.84 6.51 13.48 EXAMPLE 32: 1-isopropyl-4- (5-. {4- (2-methylpyrrolidin-1-dioriorh? ilsulfoniI) -phenyl] pyridin-2- ii) piperazine, enantiomer 1 The two enantiomers of the compound described in Example 28 (in the form of the free base) were separated by chiral chromatography on a Chiralpak AD column, using a methanol mixture / acetonitrile / diethylamine 150/850/1 as eluent. The hydrochlorides were obtained by treatment with methanolic HCl. Enantiomer 1: Melting point: 243-247 ° C Elemental microanalysis: C H N S Cl% Theoretical 55.08 6.83 11.17 6.39 14.14% Experimental 55.31 6.84 10.96 6.37 14.58 EXAMPLE 33: 1-Iso? Ropil-4- (5-. {4- (2-methylpyrroline-1-ylsulphonyl) -phenyl] pyridin-2-yl) piperazine dichlorohydrate, enantiomer 2 The two enantiomers of the compound described in he Example 28 (in the form of the free base) were separated by chiral chromatography on a Chiralpak AD column, using a mixture of methanol / acetonitrile / diethylamine 150/850/1 as a solvent. The hydrochlorides were obtained by treatment with methanolic HCl.

Enantiomer 2: Melting point: 245-249 ° C Mi ero elemental analysis: C H N S Cl% Theoretical 55.08 6.83 11.17 6.39 14.14% Experimental 55.41 6.75 1 1.12 6.32 14.85 EXAMPLE 34: 2- ( { 4- [6- (4-isopropyl-piperazin-1-yl) -pyridin-3-yl] -phenoxy} -sulfonyl) -5-methyl-2,5-diazabicyclo [2.2.1 ] - heptane Step A: 2 - [(4-1-O-phenyl) sulfonyl] -5-methyl-2,5-diazabicyclo [2.2.1] -heptane The procedure is identical to Step A of Example 1, but the morpholine is replaced by 2- methyl-2,5-diazabicyclo- [2.2.1] heptane. Melting point: 149-152 ° C Stage B: 2-Met1-5-. { [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaborothane-2-l) phenyl] sulfonyl} -2.5-diazabicyclo [2.2.1] heptane The procedure is identical to Step B of Example 9, starting from! product obtained in Stage A.

Step C: 2- ( {4-i6- (4-isopropy1piperazin-1-y1) pyridin-3-yl] phenii.]. Suifonii) -5-methyl-2,5-diazabicyclo1.2.2.1] - heptane procedure is identical to Step C of Example 1, starting from the product obtained in Step B. Melting point: 194-198 ° C Elemental microanalysis: CHNS% Theoretical 63.27 7.30 15.37 7.04% Experimental 63.09 7.36 14.73 6.76 EXAMPLE 35: 1 - (. {4- [6- (4-Isopropyl-piperazin-1-yl) pyridin-3-yl] phenyl] -sulfonyl) -N, N-dimethyl-piperidin-4-amine trichlorohydrate To a suspension of 242 mg of the product obtained in Example 32 (0.54 mmol) in 2 ml of ethanol was added 89 mg of dimethylamine hydrochloride (1.09 mmol), 153 μl of Et3N (1.09 mmol) and 323 μl of titanium isopropoxide. (IV) (1.08 mmol). After stirring for 16 hours at room temperature, 52 mg of NaCNBH4 (0.82 mmol) were added and stirring was continued for 5 hours at room temperature. The reaction mixture was treated by the addition of 28% ammonium hydroxide solution and the mixture was extracted with CH2Cl2. The organic phases were dried over MgSO 4 and after evaporation under reduced pressure, the residue was purified by chromatography on a silica column, eluting with a 96/4 mixture of CH 2 Cl 2 / MeOH.

The trichlorohydrate was obtained by treating the base with methanolic HCl to provide, after filtration, the title product as a white solid. Melting point: 283-286 ° C Elemental microanalysis: C H N S Cl% Theoretical 51.68 6.94 12.05 5.52 18.3% Experimental 51.81 7.08 12.08 4.81 17.86 EXAMPLE 36: 1-Cyclopentyl-4- (5. {4 - [(4-methyl-piperazin-1-yl) -sulfonyl] -phenyl] -pyridin-2-yl) pi? Erazine trichlorohydrate Step A: 4- ( { 4- [6- (4-Cyclopentyl-piperazin-1-yl) -pyridin-3-yl] -phenyl] -sulfonyl) -piperazine-1-carboxylic acid-tert-butyl ester The product of the Step B of Example 29. was reacted with the compound obtained in Preparation 2, under the conditions described in Step C of Example 1. Melting point: 235-238 ° C Elemental microanalysis: CHNS% Theoretical 62.68 7.44 12.60 5.77% Experimental 62.56 7.46 12.36 5.89 Stage B: 1 -Cic1openti1-4-. { 5- [4- (piperazin-1-i1sulfoni1) phenyl jpyridin-2- 11.}. piperazine The deprotection was carried out in a 1/1 mixture of dioxane and methanolic HCl. The base was reformed by treatment with NaHCO3.

Step C: 1-Cyclopentyl-4- (5- {4-l- (4-methylpiperazin-1-yl) sulfonyl] phenyl} pyridin-2-yl) piperazine trichlorohydrate A suspension of 500 mg of the product obtained in ia Step B (1.10 mmol), 270 mg of sodium acetate (3.29 mmol) and 66 mg of paraformaldehyde (2.19 mmol) in 10 ml of ethanol was stirred overnight at room temperature. Then 138 mg of NaCNBH3 (2.19 mmol) were added in several portions to the reaction mixture and stirring was continued for 6 hours at room temperature. The reaction mixture was concentrated under reduced pressure, the residue was taken up in 1N HCl and the mixture was stirred for 30 minutes at room temperature. Then the mixture was made alkaline by adding 1N NaOH and the white precipitate that formed was separated by filtration. The precipitate was resuspended in warm ethanol and after adding ethereal HCl, a solution was obtained which resulted in the crystallization of the title product at room temperature. Melting point: 263-267 ° C I elementary lysoanalysis: C H N S C S% Theoretical 51.86 6.61 12.09 5.54 18.37% Experimental 52.25 6.68 1 1.96 5.33 18.94 EXAMPLE 37: 1- (. {4- [6- (4-isopropypiperazin-1-yl) pyridin-3-yl] phenyl] sulfonyl) piperidin-4-ol dihydrochloride To a suspension of 1 g of the product obtained in Example 32 (2.26 mmol) in 20 ml of methanol was added, in several portions, 257 mg of NaBH 4 and the reaction mixture was stirred for 2 hours at room temperature. After adding 40 ml of water, the reaction mixture was extracted with CH2Cl2, and the organic phases were combined, dried over MgSO4 and evaporated under reduced pressure. The residue was resuspended in ethanol and separated by filtration. The solid was dissolved in methanolic HCi, the solution was evaporated to dryness and the residue was triturated in ethyl ether to give the title product after filtration. Melting point: 162 ° C Elemental microanalysis: C H N S Cl% Theoretical 53.38 6.62 10.83 6.2 13.7% Experimental 53.64 6.79 10.88 6.03 12.63 EXAMPLE 38: 1-Isopropyl-4-dicarbohydrate. { 5-. { 3- (4-methylpiperazin-1-ylsulfonyl) -phenyl] pyridin-2- i) piperazine Step A: 4 - [(3-Bromophenyl) sulfonyl] piperazine-1-tertbutylcarboxylate The procedure is identical to Step A of Example 1, but the morpholine is replaced by tert-butyl piperazine-1-carboxylate and the chloride of 4-iodobenzenesulfonyl by 3-bromobenzenesulfonyl chloride.

Step B: (3- {[4- (tert-Butoxycarbonyl) piperazin-1-yl] sulfonyl} - phenyl) boronic acid The procedure is identical to Step B of Example 1, starting from the product obtained in Stage A. Melting point: 225 ° C Step C: 4- ( { 3- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl] -sulfonyl) -piperazine-1-tert-butylcarboxylate The procedure is identical to Step C of Example 1, starting from the product obtained in Step B.

Stage D: 1-lsopropyl-4-. { 5- [3- (piperazin-1-iisuIfonii) phenyl] pyridin-2-yl) piperazine The procedure is identical to Step B of Example 37, starting from the product obtained in Step C.

Step E: 1-Isopropyl-4- (5-. {3- (4-methylpiperazin-1-ylsulfonyl) -phenyl] pyridin-2-yl) piperazine dihydrochloride The procedure is identical to Step C of Example 37, starting from the product obtained in Stage D. Melting point: 168 ° C Elemental microanalysis: CHNS Cl% Theoretical 49.96 6.56 12.66 5.8 19.23% Experimental 50.07 6.14 12.55 5.67 19.47 EXAMPLE 39: 1- (5- {4 - [(4-fluoropiperidin-1-yl) sulfonyl] phenyl} pyridin-2-yl) -4-isopropylpiperazine dihydrochloride Step A: 4-Fluoro-1 - [(4-iodophenyl) sulfonyl] piperidine The procedure is identical to Step A of Example 1, but the morpholine is replaced by 4-fluoropiperidine. Melting point: 130-133 ° C Stage B: Acid. { 4 - [(4-fluoropiperidin-1-yl) sulfonyl] phenyl} boronic The procedure is identical to Stage B of Example 1, starting from the product obtained in Step A.

Step C: 1- (5- {4 - [(4-fluoropiperidin-1-yl) sulfonyl] phenyl} -pyridin-2-yl) -4-isopropylpiperazine dihydrochloride The procedure is identical to Step C of Example 1, starting from the product obtained in Step B. Melting point: 243-247 ° C Elemental microanalysis: CHNS Cl% Theoretical 53.18 6.4 10.78 6.17 13.65% Experimental 52.91 6.4 10.6 5.79 13.46 EXAMPLE 40: 4- Hydrochloride. { 4- [6- (4-isopropylp? Perazin-1-yl) pipdin-3-yl] benzoyl} morpholine Step A: 4- (4-lodobenzoyl) morpholine The procedure is identical to Step A of Example 16, but the piperidine is replaced by morpholine.

Step B: [4- (Morpholin-4-ylcarbonyl!) Phenyl] boronic acid The procedure is identical to Step B of Example 1, starting from the product obtained in Step A. Melting point: 116 ° C Stage C: Dihydrochloride of 4-. { 4- [6- (4-isopropypiperazin-1-yl) pyridin-3-ii] benzoyl} morfo1ina The procedure is identical to Stage C of Example 1, starting from the product obtained in Stage B. Melting point: 224 ° C Elemental microanalysis: C H N Cl% Theoretical 59.1 6.9 11.99 15.17% Experimental 58.68 6.91 11.6 15.05 EXAMPLE 41: 1-Isopropyl-4- (5-. {4- (2-methyl-piperazin-1-yl) -carbonyl] -phenyl} -pyridin-2- (ii) piperazine trichlorohydrate Step A: 1- (4-lodobenzoyl) -4-metiipiperazine The procedure is identical to Step A of Example 16, but the piperidine is replaced by 1-methylpiperazine.

Step B: 1-Methyl-4- [4- (4,4,5,5-tetramethyl-1, 3,2-dioxaboroyl-2-yl) -benzoyljpiperazine The procedure is identical to Step B of Example 9, starting from of the product obtained in Step A. Melting point: 92 ° C Step C: 1-Isopropyl-4- (5-. {4- (2-methyl-piperazin-1-yl) -carbonyl] -phenoxy trichiorhydrate}. pyridin-2-ii) piperazine The procedure is identical to Step C of Example 1. starting from the product obtained in Step B. Melting point: 288 ° C Elemental microanalysis: CHN Cl% Theoretical 55.76 7.02 13.55 20.57% Experimental 55.40 7.02 13.08 20.13 EXAMPLE 42: 1 - (. {4- [6- (4-isopropyl-piperazin-1-yl) pyridin-3-yl] phenyl] -sulfonyl) -N-methyl-piperidin-4-amine trichlorohydrate The procedure is identical to Example 35, but the dimethylamine hydrochloride is replaced by 2 M methylamine in methanol. Melting point: 284-288 ° C Elemental microanalysis: CHNS Cl% Theoretical 50.84 6.75 12.35 5.66 18.76% Experimental 50.87 6.81 12.13 5.23 18.91 EXAMPLE 43: (1S, 4S) -5- (. {4- [6- (4- isopropylpiperazin-1-yl) pyridin-3-yl] phenyl}. Sulfonyl) -2-oxa-5-azabicyclo [2.2.1] heptane Step A: (1S, 4S) -5 - [(4-iodophenyl) sulfonyl] -2-oxa-5-azabicyclo [2.2.1] heptane The procedure is identical to Step A of Example 1, but the morpholine is replaced by (1S, 4S) -2-oxa-5-azabicyclo- [2.2.1] heptane. Melting point: 146-148 ° C Stage B: Acid. { 4 - [(1 S, 4 S) -2-Oxa-5-azabicyclo [2.2.1] hept-5-yl-sulfonyl] phenyl} boronic The procedure is identical to Stage B of Example 1, starting from the product obtained in Step A.

Step C: (1S, 4S) -5- (. {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl] sulfonyl) -2-oxa-5-dihydrochloride -azabicyclo- [2.2.1] heptane The procedure is identical to Step C of Example 1, starting from the product obtained in Step B. Melting point: 238-242 ° C Elemental microanalysis: CHNS Cf% Theoretical 53.59 6.26 10.87 6.22 13.75% Experimental 53.36 6.34 10.62 5.86 13.80 EXAMPLE 44: 1- (. {4- [6- (4-isopropylpiperazin-1-yl) pyridin-3-yl] phenyl] sulfonyl) piperidin-4-amine trichlorohydrate The procedure is identical to Example 35, but the dimethylamine hydrochloride is replaced by NH3. Melting point: 293-294 ° C Elemental microanalysis: C H N S Ci Theoretical 49.96 6.56 12.66 5.80 19.23% Experimental 49.68 6.84 12.34 5.76 19.18 PHARMACOLOGICAL STUDY OF COMPOUNDS OF THE INVENTION EXAMPLE A: Brain levels of Nt-methyl-histamine 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 the H3 type. 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 N -methylamine was performed by radioimmunoassay (RIA) using a test kit. The tisuiary levels of Nt-methylhistamine were expressed in μg / g of fresh brain. The comparison of 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 1, 5 and 9, administered in doses of 10 mg / kg PO and the compound of Example 21, administered in a dose of 3 mg / kg PO, increased the endogenous brain concentrations of Nt. -methylhistamine of 105%, 197%, 121% and 168% respectively. These results demonstrate that the compounds of the present invention are powerful antagonists of central histamine receptors of the H3 type.

EXAMPLE B: Eiectroencephalographic 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 slow-wave delta band activity (1 -4 Hz), which predominates during slow wave sleep and disappears during wakefulness and the 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. By way of example, the compound of Example 1, administered in a dose of 0.3 mg / kg, significantly reduces the delta power of the slow wave for 150 minutes, a sign of cortical activation and wakefulness. At a dose of 3 mg / kg a significantly delayed sleep latency is additionally observed: the first episode of slow wave sleep occurs 73 ± 5 minutes after the administration of the compound of Example 1 while in the control group, this first Slow wave sleep episode occurs in 45 ± 5 minutes.

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

Claims (10)

1. CLAIMS 1. Compounds of formula (I): wherein: X represents a group C (O) or SO ?, Ri represents - an aryl group, - Q a group NR3R4 where R3 and R4, which may be identical or different, each represent a hydrogen atom or a linear or branched C? -C6 alkyl group, a C3-C8 cycloalkyl group or a (C3-C8 cycloalkyl) - (C? -C6 alkyl) group in which the alkyl portion is linear or branched, or R3 and R t together with the nitrogen atom that carries them, form 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 ring defined by this is optionally bridged by a linear or branched d-Cβ alkyl group and / or is optionally substituted by one or more identical or different groups selected from halogen, C-C & amp; linear or branched, C3-C8l cycloalkyl linear or branched Ci-Cß akoxy, linear or branched Ci-Cß poiihaloaikyl, carboxy, hydroxy, cyano, oxo, nitro and amino (optionally substituted by one or more Ci-alkyl groups) Linear or branched Cβ), R 2 represents a linear or branched Ci-Cß alkyl group, a C3-Cs cycloalkyl group or a (C3-Cs cycloalkyl) - (Ci-Cß alkyl) group in which the alkyl may be linear or branched, it being understood that: an aryl group means the phenyl, naphthyl and biphenite groups, these groups being optionally substituted by one or more identical or different groups selected from halogen, straight or branched C1-C6 alkyl, alkoxy Linear or branched Ci-Cβ, linear or branched C 1 -C 6 polyhalo-alkyl, carboxy, hydroxy, cyano, nitro and amino (optionally substituted by one or more linear or branched Ci-Cβ alkyl groups), their enantiomers and diastereoisomers, and also ias salts and adding them with a pharmaceutically acceptable acid or base.
2. 2. Compounds of formula (I) according to claim 1, wherein R3 and R4, together with the nitrogen atom carrying them, form a ring of 5 to 8 members in which one of the carbon atoms can be replaced by a carbon atom. nitrogen, oxygen or sulfur or by an SO or S 2 group, the anitide defined by this is optionally bridged by an alkyl chain, its enantiomers and diastereoisomers, and also the addition salts thereof with a pharmaceutically acceptable acid or base. acceptable.
3. 3, Compounds of formula (I) according to claim 1, wherein Ri represents a morfoiinyl, thiomorpholinyl, piperidyl, piperazinyl, 4- (aiquif) piperazinium, pyrrolidinium, 2- (alkyl) -2,5-diazabicyclo [2.2. 1] -heptanyl or 2-oxa-5-azabicicio [2.2.1] -heptaniio, 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 X represents a S 2 group, their enantiomers and diastereomers, and also 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, its enantiomers and diastereoisomers, and also the addition salts of fos itself with a pharmaceutically acceptable acid or base.
6. 6. Compound of formula (i) according to claim 1, which is 4- (. {4- [6- (4-.soprapylpiperazin-1-yl) pyridin-3 l.] Phenyl} sulfonyl dihydrochloride) morpholine and also the addition salts thereof with a pharmaceutically acceptable acid or base
7. 7. Processes for the preparation of compounds of formula (t) according to claim 1, characterized in that the compound of formula (fl) is used as the starting material: wherein Rt and X are as defined for formula (t), and R and R. which may be identical or different, each represent a hydrogen atom or a linear or branched Ci-Cβ alkyl group, Together they form a linear to branched d-Ce alkylene chain, the. which is condensed, and presence of palladium (Q), can a compound of formula (Ul): wherein R2 is as defined for formula (I), and Hai represents a halogen atom, to provide the compound of formula (1), 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.
8. 8. Pharmaceutical compositions comprising as active ingredient a compound according to any of claims 1 to 6, in combination with one or more inert, non-toxic, pharmaceutically acceptable carriers or excipients.
9. 9. Pharmaceutical compositions according to claim 8, which comprise as an active ingredient a compound according to any of claims 1 to 6, for use in the synthesis of a drug as an antagonist of central histamine receptors of type H3.
10. 10. Pharmaceutical compositions according to claim 8, comprising at least one active ingredient a compound according to any of claims 1 to 6, 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, seizures, hyperactivity syndrome due to attention deficit, obesity, pain and narcoieptic states. tt. Pharmaceutical compositions according to claim 8, comprising at least one active ingredient according to any of claims t to 6", for use as a medicament in the treatment of cognitive deficiencies associated with Aízhermer's disease, Parkinson's disease, Pick's disease, Korsakoff's disease and frontal or sub-cortical dementias of vascular origin or other origin.