MXPA06005840A - Benzoxazine derivatives and uses thereof - Google Patents

Abstract

or pharmaceutically acceptable salts, solvates or prodrugs thereof, where R1, R2, R3, R4, R5, R6, R7, R8, R9, X, Y and m are as defined herein. Also provided are compositions containing these compounds, the use of these compounds for the manufacture of medicaments as well as methods for preparing compound of formula (I).

Description

BENZOXAZINE DERIVATIVES AND USE OF THEM Description of the invention The present invention relates to benzoxazine derivatives, to the associated compositions, to their uses for the manufacture of medicaments and to the methods used to obtain them. The actions of the neurotransmitter 5-hydroxytryptamine (5-HT), as the brain's main modulator neurotransmitter, are mediated by a large number of receptor families, called 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5 -HT5, 5-HT6 and 5-HT7. Based on the high level of MRSrA 5-HT6 receptor in the brain, it has been found that the 5-HT6 receptor can play a role in the pathology and treatment of central nervous system disorders. Especially selective 5-HT6 ligands have been identified as potentially useful for the treatment of certain CNS disorders, for example Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychoses, epilepsy. , obsessive-compulsive disorders, migraine, Alzheimer's disease (enlargement of cognitive memory), sleep disorders, eating disorders, for example anorexia and bulimia, panic attacks, hyperactivity disorders with deficit of attention (ADHD), the disorder REF .: 172931 for attention deficit disorder (ADD), abstinence from the use of drugs or drugs, for example cocaine, alcohol, nicotine and benzodiazepines, schizophrenia and also the disorders associated with spinal cord trauma and / or cranial injuries, for example hydrocephalus. It is believed that such compounds may also be useful for the treatment of certain gastrointestinal (Gl) disorders, for example intestinal functional disorders. See, for example, B.L. Roth et al., J. Pharmacol. Exp. Ther. , 1994, 268, pages 1403-1412, D. R. Sibley et al., Mol. Pharmacol., 1993, 43, 320-327, A.J. Sleight et al., Neurotransmission, 1995, 11, 15 and A. J. Sleight et al., Serotonin ID Research Alert, 1997, 2 (3), 115-8. Some 5-HT6 modulators have already been published, but there remains a need for compounds that are useful for modulating the 5-HT6 and / or other 5-hydroxy-triptamine receptors mentioned above. The present invention provides compounds of the formula (I): or a pharmaceutically acceptable salt, solvate thereof, wherein: m is a number from 0 to 3; X is N or CH; Y is -S02- or -CH2-; each R1 is independently halo, C_-C_2alkyl, halo-C! -C? 2alkyl, C? -C? 2alkoxy, cyano, hydroxy-Cx-C6alkyl, C1-C12alkoxy-C? -C12alkyl, -S02Ra, -C (= 0) -NRbRc, -S02-NRRc, -SRb, -N (Rb) -C (= 0) -Rc, -C (= 0) -R, or -N (Rb) -S02-Ra, wherein each Ra is independently C? -C? 2alkyl or halo-C_-C-2alkyl and each of Rb and Rc is independently hydrogen, C? -C12alkyl or halo-C1-C? 2alkyl, R2 is aryl or heteroaryl optionally substituted by C? C_2alkyl, halo-C_-C__alkyl, C? -C? 2alkoxy or cyano; each of R3 and R4 is independently C_-C12alkyl, hydroxy- _-C2_2alkyl or C? -C? 2alkoxy-C? -C? 2alkyl, or R3 and R4 together with the carbon atom to which they are attached can forming a cyclic group of 3 to 6 ring atoms which optionally includes a heteroatom selected from N, O and S; and each of R5, R6, R7, R8 and R9 are independently hydrogen or C_-C12alkyl, or R9 and one of R5, R6, R7, or R8 together with the atoms to which they are attached form a heterocycloamino ring having 5 to 7 atoms in the ring. The present invention further provides obtaining methods, compositions containing the compounds of the formula (I), as well as methods for the use thereof. The compounds in question include the 2,2-dialkyl substituents and other types of disubstitution at the 2-position of the benzoxazine ring system which, surprisingly, results in a higher affinity with the 5-hydroxytryptamine receptors, in particular with 5-HT-6, that which is observed in the compounds only hydrogen is present in position 2 of the cyclic benzoxazine system. Unless stated otherwise, the following terms used in this application, including the description and the claims, have the meanings indicated below. It should be noted that the singular forms "one", "one", "the" or "the", used in the description and the appended claims, also encompass plural referents, unless the context explicitly dictates otherwise. "Agonist" means a compound that extends the activity of another compound or receptor site. "Alkyl" means a monovalent, straight-chain or branched saturated hydrocarbon portion, consisting exclusively of carbon and hydrogen atoms, possessing from one to twelve carbon atoms. "Lower alkyl" means an alkyl group having one to six carbon atoms. Examples of alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like. "Alkylene" means a saturated, linear, divalent hydrocarbon moiety having one to six carbon atoms or a branched divalent hydrocarbon moiety having three to six carbon atoms, eg, methylene, ethylene, 2-, 2- dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene, etc. "Alkoxy" means a portion of the formula -OR, wherein R is an alkyl moiety defined above. Examples of alkoxy portions include but are not limited to: methoxy, ethoxy, isopropoxy, and the like. "Alkoxyalkyl" means a portion of the formula -RaRb, wherein R is alkoxy, as defined, and Rb is alkylene as defined above. Examples of alkoxyalkyl radicals are methoxyethyl, ethoxyethyl, 2,3-dimethoxypropyl, and the like. "Antagonists" means a compound that decreases or prevents the action of another compound or receptor site. "Aryl" means a monovalent cyclic aromatic hydrocarbon portion, which contains a mono-, bi- or tricyclic aromatic ring. The aryl group may be optionally substituted as indicated in the description. Examples of aryl portions include but are not limited to: substituted phenyl, naphthyl, phenanthryl, fluorenyl, indenyl, pentalenyl, azulenyl, oxydiphenyl, biphenyl, methylene diphenyl, aminodiphenyl, diphenylsulfidyl, diphenylsulfonyl, diphenylisopropylidenyl, benzodioxanyl, benzofuranyl, benzodioxilyl, benzopyranyl, benzoxazinyl , benzoxazinonyl, benzopiperadinil, benzopiperazinyl, benzopyrrolidinyl, benzomorpholinyl, methylenedioxyphenyl, ethylenedioxyphenyl, etc., including the partially hydrogenated derivatives thereof. "Arylalkyl" and "aralkyl", which may be used interchangeably, mean a -RaRb moiety in which Ra is an alkylene group and Rb is an aryl group as defined above; - examples of arylalkyl benzyl, phenylethyl, 3- (3-chlorophenyl) -2-methylpentyl, and the like. "Cycloalkyl" means a saturated monovalent carbocyclic moiety, consisting of mono- or bicyclic rings. The cycloalkyl may be optionally substituted by one or more substituents, each substituent independently of its appearance may be hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino or dialkylamino, unless explicitly stated otherwise. Examples of cycloalkyl moieties include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc., including the partially unsaturated derivatives thereof. "Cycloalkylalkyl" means a portion of the formula -R'-R ", wherein R 1 is alkylene and R" is cycloalkyl, as defined above. "Heteroalkyl" means an alkyl moiety defined above, in which one, two or three hydrogen atoms have been replaced by a substituent independently chosen from the group consisting of -0Ra, -RbRc and -S (0) nRd (wherein n is an integer from 0 to 2), assuming that the point of attachment of the heteroalkyl portion is a carbon atom, wherein R is hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; R5 and Rc independently of each other are hydrogen, acyl, alkyl, cycloalkyl or cycloalkylalkyl; and when n is 0, Rd is hydrogen, alkyl, cycloalkyl or cycloalkylalkyl, and when n is 1 or 2, Rd is alkyl, cycloalkyl, cycloalkylalkyl, amino, acylamino, monoalkylamino or dialkylamino. Representative examples include but are not limited to: 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl, 1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl, 2-hydroxyethyl- l-methylpropyl, 2-aminoethyl, 3-aminopropyl, 2-tne-tinylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl, aminosulfonylpropyl, methylaminosulfonylmethyl, methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like. "Hydroxyalkyl" means a portion of the formula H0-Rc- in which Rc is alkylene, as defined. Examples of hydroxyalkyl groups are hydroxyethyl, hydroxypropyl, 2,3-dihydroxypropyl, and the like. "Heteroaryl" means a monocyclic or bicyclic portion of 5 to 12 ring atoms, having at least one aromatic ring having one, two or three heteroatoms chosen from N, O and S, the other ring atoms are C, assuming that the point of attachment of the heteroaryl portion will be located in the aromatic ring. The heteroaryl portion may be optionally substituted in the manner already defined. Examples of the heteroaryl moieties include but are not limited to: imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, benzothienyl, thiophenyl, furanyl, pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidyl, quinolinyl, isoquinolinyl. , benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, indolyl, isoindolyl, triazolyl, triazinyl, quinoxalinyl, purinyl, quinazolinyl, quinolizinyl, naphthyridinyl, pteridinyl, carbazolyl, azepinyl, diazepinyl, acridinyl, etc., optionally substituted, including partially hydrogenated derivatives thereof. The terms "halo" and "halogen", which may be used interchangeably, mean a fluorine, chlorine, bromine or iodine substituent. "Haloalkyl" means alkyl as defined above, wherein one or more hydrogens have been replaced by the same or different halogens. Examples of haloalkyls include -CH2C1, -CH2CF3, -CH2CC13, perfluoroalkyl (e.g., -CF3), and the like. "Heterocycloamino" means a saturated ring in which at least one atom of the ring is N, NH or N-alkyl and the other ring atoms form an alkylene group. "Heterocyclyl" means a monovalent saturated portion, formed by one, two or three rings, which incorporates one, two, three or four heteroatoms (chosen from nitrogen, oxygen and sulfur). The heterocyclyl ring may be optionally substituted as defined above. Examples of heterocyclyl moieties include but are not limited to: piperidinyl, piperazinyl, homopiperazinyl, azepinyl, pyrrolidinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyridinyl, pyridazinyl, pyrimidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolidinyl, benzothiazolidinyl, benzoazolidinyl, dihydrofuryl, tetrahydrofuryl, dihydropyranyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dihydroquinolinyl, dihydroisoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc., optionally substituted, including the partially unsaturated derivatives thereof. "Optionally substituted", when used in association with "aryl", "phenyl", "naphthalenyl", "heteroaryl" or "heterocyclyl", means an aryl, phenyl, heteroaryl or heterocyclyl moiety that is optionally independently substituted by one, two, three or four substituents, preferably one or two substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkyl , haloalkoxy, heteroalkyl, -COR (where R is hydrogen, alkyl, phenyl or phenylalkyl), - (CR'R ") n-COOR (wherein n is an integer from 0 to 5, R1 and R "independently of each other are hydrogen or alkyl and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl) or - (CR'R") n -C0NRaRb (wherein n is an integer from 0 to 5, R 'and R "independently of each other are hydrogen or alkyl and Ra and Rb independently of each other are hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl.

"Leaving group" means the group having this meaning conventionally associated in synthetic organic chemistry, ie, an atom or group displaceable under the conditions of substitution reaction. Examples of leaving group include but are not limited to: halogen, alkane- or arylene-sulfonyloxy, for example methanesulfonyloxy, ethanesul-foniloxy, thiomethyl, benzenesulfonyloxy, tosyloxy and thienyl-oxy, dihalophosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like. "Modulator" means a molecule that interacts with a target. Interactions include but are not limited to: agonist, antagonist, et cetera, as defined above.

"Optional" or "optional" means that the event or circumstance described below may occur, but not in an obligatory manner and that the description contemplates the cases in which the event or circumstance occurs and the cases in which it does not occur. "Pathological state" means any disease, condition, symptom or indication. "Inert organic solvent" or "inert solvent" means that the solvent is inert under the reaction conditions described in relation thereto, including for example benzene, toluene, acetonitrile, tetrahydrofuran, N, N-dimethylformamide, chloroform, methylene or di-chloromethane, dichloroethane, diethyl ether, ethyl acetate, acetone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like. Unless otherwise stated, the solvents used in the reactions of the present invention are inert solvents. "Pharmaceutically acceptable" means that it is useful for making the pharmaceutical composition which is generally safe, non-toxic, does not disturb the biological or other aspect and includes that it is acceptable for human pharmaceutical use and also for the veterinarian. "Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined above and which possess the desired pharmacological activity of the parent compound. Such salts include: acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or formed with organic acids, for example acetic acid, benzenesulfonic acid, benzoic acid, camphor sulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethane-sulphonic acid, lactic acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, etc .; or the salts formed when an acidic proton in the original compound is displaced with a metal ion, for example, an alkali metal ion, an alkaline earth ion or an aluminum ion; or coordinates with an inorganic or organic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide. The preferred pharmaceutically acceptable salts are the salts formed by acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, maleic acid, phosphoric acid, tartaric acid, citric acid, sodium, potassium, calcium, zinc and magnesium. It is understood that all references to pharmaceutically acceptable salts include the solvent addition forms (solvates) and the crystalline forms (polymorphs), defined herein, of the same acid addition salt. The term "prodrug" (prodrug) denotes any compound that releases the original active principle of formula I "in vivo" when such a prodrug is administered to a mammalian subject. The prodrugs of a compound of formula I are obtained by modifying one or more functional groups existing in the compound of formula I in such a way that the modifications can be eliminated "in vivo" to liberate the original compound. Prodrugs include the compounds of formula I, wherein a hydroxy, amino or sulfhydryl group of a compound of formula I is attached to any group that can be removed "in vivo" to regenerate the free hydroxyl, amino or sulfhydryl group, respectively. Examples of prodrugs include but are not limited to: esters (e.g., acetate, formate and benzoate derivatives), carbamates (e.g., N, N-dimethylaminocarbonyl) of hydroxy functional groups of the compounds of formula I, N-derivatives acyl (for example, N-acetyl), N-bases of Mannich, Schiff bases and enaminones of amino functional groups, oximes, acetals, ketals and enol esters of functional groups ketone and aldehyde of compounds of the formula I, et cetera, see Bundegaard , H. "Design of Prodrugs" pp. 1-92, Elsevier, New York-Oxford (1985), etcetera. "Protective group" means the group that selectively blocks a reactive site from a ultifunctional compound so that the chemical reaction can be carried out selectively at another unprotected reactive site, in the sense conventionally associated with this term in synthetic chemistry . Certain processes of this invention rely on protecting groups to block reactive nitrogen and / or oxygen atoms in the reactants. For example, the terms "amino protecting group" and "nitrogen protecting group" are used interchangeably and mean suitable organic groups to protect the nitrogen atom against any unwanted reaction during synthesis procedures. Examples of nitrogen protecting groups include but are not limited to: trifluoroacetyl, acetamido, benzyl (Bn), benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC), and the like. The person skilled in the art will know how to choose the best group, attending to the facility for its later elimination and the suitability to resist unaltered the immediate reactions. "Solvates" means solvent addition forms that contain stoichiometric or non-stoichiometric amounts of solvent. Some compounds have a tendency to retain a fixed molar ratio of solvent molecules within their crystalline solid state, thereby forming a solvate. If the solvent is water, the solvate formed is a hydrate, when the solvent is an alcohol, then the solvate formed is an alcohol. Hydrates are formed by combining one or more water molecules with one of the substances in which the water retains its molecular status of H20, such combination is able to form one or more hydrates. "Subject" means mammals and not mammals. Mammals means any member of the group of mammals, including humans, but not limited to it; non-human primates, for example chimpanzees and other species of apes and monkeys; animals of cattle interest, for example cows, horses, sheep, goats and pigs; domestic animals, for example rabbits, dogs and cats; laboratory animals, including rodents, for example rats, mice and guinea pigs; etc. Examples of non-mammals include but are not limited to: birds, et cetera. The term "subject" does not denote a particular age or sex. "Therapeutically effective amount" means an amount of a compound that, when administered to a subject to treat a disease state, is sufficient for the treatment of such a disease state to be effective. The "therapeutically effective amount" can vary depending on the compound, the pathological condition to be treated, the severity and the disease to be treated, the age and the relative state of health of the subject, the route and the method of administration. , the criterion of the doctor or veterinarian, and other factors. The terms "have the meaning defined above" when referring to a variable incorporate by reference the broad definition of the variable and also the preferred definitions, plus. preferred and especially preferred thereof, if any. The "treatment" of a pathological state includes: (i) the prevention of the pathological state, that is, the action that prevents the clinical symptoms from developing in a subject that may be exposed or predisposed to contract a pathological condition, but that still does not present the symptoms of such pathological state. (ii) the inhibition of the pathological state, that is, the interruption of the development of the pathological state or of its clinical symptoms, or (iii) the mitigation of the pathological state, that is, the action that causes a temporary or permanent regression of the pathological state or of its clinical symptoms. The terms "treatment", "contact" and "reaction" referred to a chemical reaction mean the addition or mixing of two or more reagents under suitable conditions to obtain the indicated and / or desired product. It should be noted that the reaction produced by the indicated and / or desired product may not result directly from the combination of two reactants initially added, that is, it may be necessary to obtain one or more intermediates in the reaction mixture, which subsequently lead to the formation of the indicated and / or desired product. In general, the nomenclature used in this application is based on the AUTONOM ™ v.4.0 program, a computerized system of the Beilstein Institute to generate the systematic nomenclature according to the IUPAC. For convenience, the IUPAC numbering of the positions of the compounds representative of the isoquinoline compounds of the invention is illustrated in the following formula: The chemical structures presented are obtained using the ISIS v. Program. 2.2. Any open valence of a carbon, nitrogen or oxygen atom of the structures indicates the presence of a hydrogen atom. The invention provides compounds of the formula (I): or a pharmaceutically acceptable salt or solvate thereof, wherein: m is a number from 0 to 3; m is preferably 0 or 1; X is N or CH; X is preferably N; Y is -S02- or -CH2-; And it is preferably -S02-; each Rx independently of its appearance is halo, C_-C? 2alkyl, haloC? -C? 2alkyl, C? -C12alkoxy, cyano, hydroxyC? -C? 2alkyl, alkoxyCx-C? 2alkyl, -S02Ra, -C (- 0) -NRbRc, -S02 -NRbRc, -SRb, -N (R) -C (= 0) -Rc, -C (= 0) -R, or -N (Rb) -S02-Ra, wherein each Ra independently of its appearance is C_-C_2alkyl or haloC? -C? 2alkyl, and each of Rb and Rc independently of each other is hydrogen, C_-C_2alkyl, or haloC? -C_2alkyl; R2 is aryl or heteroaryl optionally substituted by C? -C? _alkyl, halo, haloC_-C? Alkyl, C? -C? 2alkoxy or cyano; each of R3 and R4 independently of each other is C? ~ C? 2alkyl, hydroxyC_- _.2alkyl or alkoxyC? -C? 2alkyl, or R3 and R4 together with the carbon atom to which they are attached can form a cyclic group from 3 to 6 atoms in the ring optionally including a heteroatom selected from N, 0 and S; R3 and R4 are preferably C_-C_2alkyl; and each of R5, R6, R7, R8 and R9 independently of each other is hydrogen or C? -C? 2alkyl, or R9 and one of R5, R6, R7, or R8 together with the atoms to which they are attached form a heterocycloamino ring that has 5 to 7 atoms in the ring. It is assumed that the scope of this invention encompasses not only the different isomers that may exist, but also covers the different mixtures of isomers that may be formed. In addition, the scope of the present invention also encompasses the solvates and salts of the compounds of the formula I. If any one of R1, R3, R4, R5, R6, R7, R8 and R3 is C? -C? 2alkyl, then it will preferably be C_-C6alkyl, and more preferably Ci-C4 alkyl. In certain modalities, Y is -S02. In certain embodiments, m is 0 or 1. In certain embodiments, X is N. In certain embodiments, R1 is halo, C_-C__alkyl, haloC_-C12alkyl, C? -C_2alkoxy, cyano, hydroxyC? -C12alkyl or alkoxyC? -C12alkyl . In certain embodiments, R2 is halophenyl. In certain embodiments, Y is -S02, m is 0 or 1, X is N, R1 is halo, C? -C? 2alkyl, haloC? -C? 2alkyl, C? -C12alkoxy, cyano, hydroxyC? -C? 2alkyl or alkoxyC? -C? 2alkyl and R2 is halophenyl.

In certain embodiments, R2 is aryl, preferably optionally substituted phenyl or optionally substituted naphthyl. More preferably, R 2 is phenyl, 2-fluorophenyl, 2-chlorophenyl, 3,4-dichlorophenyl, 4-chlorophenyl, 3-chlorophenyl, 4-methoxyphenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 2, 4-dichlorophenyl, 3-methanesulfonylaminophenyl, 2-methanesulfonylphenyl, 2-carbamoylphenyl, 3-methanesulfonylphene, 4-methanesulfonylphenyl, 3-fluorophenyl, naphthyl, 2,4-difluorophenyl, 2-cyanophenyl, 2-chloro-4-fluorophenyl, 2-methyl-5-fluorophenyl or 5-chloronaphthyl. In specific embodiments, R 2 is phenyl or phenyl substituted by halogen. More preferably, R2 is phenyl or halophenyl, for example 2-halophenyl, 3 -halophenyl or 4-halophenyl. In specific embodiments, R 2 may be phenyl substituted by 2-position chlorine or phenyl substituted by fluorine in position 2. In certain embodiments, R 3 and R 4 are C_-C_ 2 alkyl. In other embodiments, R3 and R4 together with the carbon atom to which they are attached can form a cyclic group of 3 to 6 ring atoms which optionally includes a heteroatom selected from N, O and S. In specific forms of embodiment, R3 and R 4 are methyl, or R 3 and R 4 together with the carbon atom to which they are attached can form a ring or cyclobutyl group. In certain embodiments, the compounds of the formula (I) are more specifically adjusted to the formula (II): wherein: n is a number from 0 to 5; n is preferably a number from 0 to 2; each R10 independently of its appearance is Cx-C? 2alkyl, halo, haloC? -C? 2alkyl, C? -C? 2alkoxy or cyano; and m, R1, R3, R4 and R9 have the meanings defined above.

In certain embodiments of the compounds of formula II, n is 0 or 1. In certain embodiments of the compounds of formula II, R 10 is halogen. In certain embodiments of the compounds of formula II, n is 0 or 1 and R10 is halogen. Some of the representative compounds of the formula I are listed in the following table 1, together with the melting point or the mass spectrum data. The melting points correspond to the hydrochloride salts, unless otherwise indicated. Table 1.

Structure Name p.f. M + H 4-benzenesulfonyl) -2,2- 213.6-dimethyl-1-8-piperazin-1-yl-215.0 ° C 3,4-dihydro-2H-benzo [1,4] -oxazine 4- (2-fluoro-benzenesulfonyl) - 194.8- 2.2 ~ spiso-cyclobutane-8- 207.6 ° C piperazin-1-yl-3,4-dihydro-2H-benzo [1,] -oxazine 4- (3-Fluoro-benzenesulfonyl) 200.1- 2, 2-spiro-cyclobutane-8- 206.1 ° C Piperazin-1-yl-3,4-dihydro-2H-benzo [1,4] -oxazine 4- (2-chloro-benzenesulfonyl) - 191.7- 2, 2-spiro-cyclobutane-8- 194.3 ° C piperazin-1-yl-3,4-dihydro-2H-benzo [1,4] -oxazine In another aspect, the present invention provides a composition containing a therapeutically effective amount of a compound of the formula (I) and a pharmaceutically acceptable excipient. Another aspect of the invention provides a method for treating a CNS pathological condition of a subject which comprises administering to said subject a therapeutically effective amount of a compound of the formula (I). The pathological state preferably includes psychosis, schizophrenia, manic depression, neurological disorders, memory disorders, attention deficit disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease or Huntington's disease. Yet another aspect of the present invention provides a method for treating a disorder of the gastrointestinal tract of a subject, which comprises administering to said subject a therapeutically effective amount of a compound of the formula (I). Another aspect of the present invention provides a method for obtaining a compound of the formula (I). In a specific embodiment, specific compounds of the formula I, hereinafter referred to as compounds of the formula I, can be obtained: according to a method consisting of the following steps a) the reaction of a compound of the formula with a compound of formula b to get compound of the formula c b) cyclization of the compound of formula c to obtain a compound of formula d c) reducing the compound of formula d to obtain a compound of formula e d) the reaction of the compound of the formula e with a compound of the formula f to obtain a compound e formula g e) reacting the compound of the formula g with a compound of the formula h - R NH - k to obtain the compound of the formula i in which R 1, R 3, R 4, R 9, R 10, m and n have the meanings defined above. In another embodiment, specific compounds of the formula I, designated as compounds of the formula m, can be obtained: according to a method consisting of the following steps: a) the reaction a compound of the formula d with a compound of formula j to obtain a compound of the formula k b) the reduction of the compound of the formula k to obtain a compound of the formula I c) the reaction composed of the formula I with a compound of the formula h FCN NH to obtain the compound of the formula m, wherein R1, R3, R4, R9, R10, m and n have the meanings defined above. In another embodiment, compounds of the formula I, named below, are compounds of the formula q: according to a method consisting of the following steps: a) the reaction of a compound of formula g with a compound of the formula n to obtain a compound of the formula or b) dehydration of the compound of the formula or to obtain a compound of the formula p c) dehydrogenation of the compound of the formula p to obtain the compound of the formula q, wherein R 1, R 3, R 4, R 9, R 10, m and n have the meanings defined above. In the reaction schemes, which are presented and described below, these methods are illustrated in greater detail.

The starting materials and reagents used to obtain these compounds are commercial products supplied, for example, by the company Aldrich Chemical Co. or can be obtained by methods known to those skilled in the art, described for example in the following references: Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, 1991, volumes 1-15; Rodd's Chemistry of Carbon Compounds, Elsevier Science Publishers, 1989, volumes 1-5 and supplements; and Organic Reactions, Wiley & Sons: New York, 1991, volumes 1-40. The following reaction schemes are merely illustrative of some methods for obtaining the compounds of the present invention and in these reaction schemes various modifications can be introduced, which those skilled in the art already know that can be applied to the description contained in this application. . The starting materials and intermediates of the reaction schemes can be isolated and purified, if desired, employing conventional techniques, including, but not limited to, the following: filtration, distillation, crystallization, chromatography, and so on. These materials can be characterized by conventional techniques that allow to determine their physical constants and their spectral data. Unless otherwise indicated, the reactions described are preferably carried out in an atmosphere of an inert gas at atmospheric pressure, in a temperature range between -78 ° C and 150 ° C, more preferably between 0 ° C. and 125 ° C, and with special preference conveniently at room temperature, for example, 20 ° C. In the following reaction scheme A, a viable synthesis process is illustrated to obtain specific compounds of the formula (I), in which R1, R3, R4, m and n have the meanings defined above.

REACTION SCHEME A In step 1 of reaction scheme A an orthoaminophenol a is alkylated on N by reaction with a b acid halide to obtain the benzamide compound c. This reaction can be carried out in a dry polar aprotic solvent, at a low temperature, in the presence of an amine base. The acid halide b can be, for example, 2-bromo-2-methyl-propionyl bromide (in which each of R3 and R4 are methyl), 2-bromo-2- (2-hydroxyethyl) bromide ) -butyroyl (in which each of R3 and R4 are 2-hydroxyethyl), 2-bromo-2- (2-methoxyethyl) -propionyl bromide (in which R3 is 2-methoxy-ethyl and R4 is methyl) ), 1-bromo-cyclobutane-carbonyl bromide (in which R3 and R4 together with the carbon atom they share form a cyclobutyl ring), and so on. In many cases, the bromo groups of the acid halide b can be replaced by chlorine or other leaving groups. In step 2, the benzamide compound c is cyclized to obtain the benzoxazinone compound d. This cyclization can be carried out by heating the benzamide compound c in the presence of a weak base, for example potassium carbonate in a polar aprotic solvent. The benzoxazinone compound d from step 2 is reduced in step 3 to obtain benzoxazine e. In the reduction of step 4, for example, borane-type reducing agents or borane complexes, sodium cyanoborohydride, Raney nickel / hydrazine, etc. can be used. In step 4, the benzoxazine e is subjected to a sulfonylation reaction by treatment with an arylsulfonyl halide f_ to obtain the arylsulfonyl-benzoxazine g. The sulfonylation reaction of step 4 can be carried out easily in a polar aprotic solvent, in the presence of an amine base. It should be mentioned that the arylsulfonyl halide f can be replaced by heteroarylsulfonyl chlorides, for example pyridinesulfonyl chlorides, thienosulfonyl chlorides, furansulfonyl chlorides, and the like. In step 5 an amination reaction is carried out, in which the arylsulfonylbenzoxazine c is treated with the piperazine compound h in the presence of a palladium catalyst in a non-polar solvent, obtaining a piperazinyl-arylsulfonyl-benzoxazine i_. The compound i. is a compound of formula (I) according to this invention, wherein X is N, Y is -S02-, R2 is optionally substituted phenyl and R5, R6, R7 and R8 are hydrogen. Compound i is more specifically a compound of formula (II), described above. In cases where R9 is hydrogen, BOC groups or other suitable protection strategies can be used to protect the corresponding nitrogen atom from the piperazine ring i. and, after the aminating reaction, in step 5 deprotection can be performed to remove this BOC group or any other protecting group. Many variations of the procedure described above are possible and will be easily understood by those skilled in the art in view of this description. One such variation, represented in reaction scheme B, can be applied to obtain compounds of the formula (I) in which Y is -CH2- instead of -S02-.

REACTION SCHEME B In step 1 of reaction scheme B, benzoxazinone d (obtained in the manner described in reaction scheme A) is subjected to N-benzylation by reaction with benzyl bromide j_, obtaining the N-benzylbenzoxazinone compound k . The N-benzylbenzoxazinone compound k can then be reduced in step 2 to obtain an N-benzyl-benzoxazine 1. The N-benzyl-benzoxazine 1 is then subjected to an amination by reaction with the piperazine h (represented in the reaction scheme A), obtaining a piperazinyl-benzylbenzoxazine m, which is a compound of the formula (I) wherein X is N, Y is -CH-, R2 is optionally substituted phenyl and R5, Rs, R7 and R8 are hydrogen.

When R9 is hydrogen, an appropriate protection / deprotection strategy may be applied during the amination reaction, as indicated above. Another variation of the process of the reaction scheme A, represented in the reaction scheme C, can be used to obtain compounds of the formula (I), wherein X is CH instead of N.

REACTION SCHEME C In step 1 of reaction scheme C, the arylsulfonylbenzoxazine g (obtained in the manner described above, in step 4 of reaction scheme A) is treated with an alkyllithium reagent, for example n-butyllithium, in a anhydrous polar aprotic solvent and at dry ice / acetone temperature to obtain a lithiated intermediate (not shown), wherein the bromo group of compound g is replaced by lithium. This lithiated intermediate compound is then reacted directly "in situ" with the heterocyclic ketone n to perform an alkylation and obtain an arylsulfonylbenzoxazine substituted by heterocyclyl or. The heterocyclic ketone n can be, for example, a piperidone as represented, or alternatively a pyrrolidinone or azepinone, all of which are commercial products. When R9 is hydrogen, a Boc protecting group or other removable protective strategies may be used in order to protect the exposed nitrogen from the heterocyclic ketone n and the corresponding nitrogen from the heterocyclyl or arylsulfonyl-benzoxazine substituted. In step 2 the arylsulfonylbenzoxazine substituted by heterocyclyl or by treatment with a weak acid is dehydrated, obtaining the compound p, in which the heterocyclyl portion is partially unsaturated. In certain embodiments, this dehydration may take place spontaneously, with step 2 becoming unnecessary. In step 3, the compound p_ of step 3 is hydrogenated to obtain the substituted benzoxazine compound g. This reaction can be carried out by hydrogenation using a platinum or palladium catalyst under mild ethanolic conditions. The benzoxazine compound g is a compound of the formula (I) wherein X is CH, Y is -S02- and R2 is optionally substituted phenyl. The procedure of reaction scheme C can also be applied to the compound N-benzylbenzoxazinone k instead of the arylsulfonylbenzoxazine g, obtaining compounds of the formula (I) wherein X is CH, Y is -CH2- and R2 is optionally substituted phenyl. In the following section of the examples, more specific details of obtaining compounds of the formula I are presented. The compounds of the invention have affinity to one or more 5-hydroxytryptamine receptors, including 5-HT 1, 5-HT 2, 5-HT 3, 5-HT 4, 5-HT 5, 5-HT 6, and / or 5-HT 7. The compounds generally have a selective affinity for the 5-HT 6 receptor and as such are expected to be useful for the treatment of certain CNS disorders, for example Parkinson's disease, Huntington's disease, anxiety, depression, manic depression, psychosis, epilepsy, obsessive-compulsive disorders, migraine, Alzheimer's disease (cognitive memory expansion), sleep disorders, eating disorders, for example anorexia and bulimia, panic attacks, attention deficit hyperactivity disorders (ADHD), attention deficit disorder (ADD), abstinence from the use of drugs or drugs, for example cocaine, alcohol, nicotine and benzodiazepines, schizophrenia and also the disorders associated with spinal trauma and / or cranial injuries, for example hydrocephalus. It is further expected that said compounds will be useful for the treatment of certain disorders of the gastrointestinal tract (Gl), for example the functional intestinal disorder. The pharmacology of the compounds of this invention is determined by methods recognized in the art. In Example 4 the "in vitro" techniques for determining the affinities of the test compounds on the 5-HT6 receptor are described by radioligand binding assays and functional assays. The present invention includes pharmaceutical compositions containing at least one compound of the present invention or a single isomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or a solvate thereof, together with at least one pharmaceutically acceptable excipient. and optionally other therapeutic and / or prophylactic ingredients. In general, the compounds of the present invention will be administered in a therapeutically effective amount by any of the acceptable modes of administration for agents intended for similar purposes. Suitable dosing ranges are, for example, 1-500 mg per day, preferably 1-100 mg per day and with special preference 1-30 mg per day, depending on many factors, for example the severity of the disease. treat, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication to which the administration is directed and the preferences and experience of the physician attending to the patient. A person skilled in treating these diseases will be able, without needing to experiment unnecessarily and based on his personal knowledge and the description of this application, to evaluate the therapeutically effective amount of the compounds of the present invention for a given disease. In general, the compounds of the present invention will be administered in the form of pharmaceutical formulations containing them and are suitable for oral (including buccal and sublingual), rectal, nasal, topical, pulmonary, vaginal or parenteral administration (including intramuscular administration). , intra-arterial, intrathecal, subcutaneous and intravenous) or in a form suitable for administration by inhalation or insufflation. The preferred mode of administration is generally oral using a convenient regimen of daily doses that can be adjusted according to the severity of the condition. A compound or compounds of the present invention, together with one or more conventional adjuvants, excipients or diluents, can be incorporated into the form of the pharmaceutical compositions and unit doses. The pharmaceutical compositions and dosage unit forms may contain conventional ingredients in conventional proportions, with or without additional active compounds or principles, and the unit dosage forms may contain any suitable effective amount of the active ingredient, in accordance with the desired daily dosage range. that will be applied. The pharmaceutical compositions can be administered in the form of solids, for example filled tablets or capsules, semisolids, powders, persistent release formulations or liquids, for example solutions, suspensions, emulsions, elixirs or filled capsules for oral use.; or in the form of suppositories for rectal or vaginal use; or in the form of sterile injectable solutions for parenteral use. Formulations containing one (1) milligram of active principle or, with greater amplitude, 0.01 to one hundred (100) milligrams per tablet, are therefore representative and suitable unit dosage forms. The compounds of the present invention can be formulated in a wide variety of dosage forms for oral administration. The pharmaceutical compositions and dosage forms may contain a compound or compounds of the present invention or pharmaceutically acceptable salts thereof, itself as the active ingredient. The pharmaceutically acceptable excipients may be solid or liquid. Solid preparations include powders, tablets, pills, capsules, seals (hollow wafers), suppositories and dispersible granules. A solid excipient may further contain one or more substances that further act as diluents, flavors, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulating material. In powders, the excipient is in general a finely divided solid, mixed with the finely divided active ingredient. In tablets, the active ingredient is usually mixed with the excipient which has a sufficient binding capacity in suitable proportions and is compacted to acquire the desired shape and size. The powders and tablets preferably contain one (1) to seventy (70) percent active ingredient. Suitable excipients include but are not limited to: magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, cocoa butter, etc. . The term "preparation" designates the formulation of the active compound together with the encapsulating material as an excipient, giving rise to a capsule in which the active principle, with or without excipient, is enveloped by the excipient, which is associated therewith. . Seals (wafers, hollows) and pills are also included. Tablets, powders, capsules, pills, seals (wafers) and pills can have solid forms suitable for oral administration. Other suitable forms for oral administration include preparations in liquid form, including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions or solid form preparations which are intended to be converted into liquid form preparations immediately before use. The emulsions can be prepared in solutions, for example, in aqueous propylene glycol solutions or they can contain emulsifying agents, for example lecithin, sorbitol monooleate or acacia. Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers and thickeners. Aqueous suspensions can be prepared by dispersing the finely divided active component in water with a viscous material, for example natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other known suspending agents. The solid form preparations include solutions, suspensions and emulsions and, in addition to the active component, may contain colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like. The compounds of the present invention can be formulated for parenteral administration (eg, by injection, eg bolus injection or continuous infusion) and can be presented in unit dosage forms in ampoules, pre-packaged syringes, small volume infusion containers. or multidose containers, which also contain a preservative. The compositions may also take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous excipients, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil) and injectable organic esters (e.g., ethyl oleate) and may contain formulatory agents , for example preservatives, wetting agents, emulsifiers or suspension, stabilizers and / or dispersants. Alternatively, the active ingredient can be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization of the solution for reconstitution before use in a suitable vehicle, for example, sterile, pyrogen-free water. The compounds of the present invention can also be formulated for topical administration on the epidermis in the form of ointments, creams or lotions or in the form of transdermal plaster (patch). The ointments and the creams can be formulated, for example, with an aqueous or oily base, by adding suitable thickeners and / or gelling agents. The lotions can be formulated on an aqueous or oily basis and will generally carry one or more emulsifying agents, stabilizers, dispersants, suspending agents, thickeners or colorants. Formulations suitable for topical administration in the mouth include diamond-shaped lozenges containing an active ingredient in a flavored base, usually sucrose and acacia or tragacanth.; the tablets containing the active ingredient in an inert base, for example gelatin and glycerin or sucrose and acacia; and oral lotions containing the active ingredient in a suitable liquid excipient. The compounds of the present invention can be formulated for administration in the form of suppositories. First a low melting point wax is melted, for example a mixture of fatty acid glycerides or cocoa butter and then the active ingredient is dispersed therein homogeneously, for example by stirring. The molten homogeneous mixture is then poured into molds of the appropriate volume, allowed to cool and solidify. The compounds of the present invention can be formulated for vaginal administration. Pessaries, buffers, creams, gels, pastes, foams or sprays which contain, in addition to the active ingredient, suitable excipients are known as suitable in the art. The compounds of the present invention can be formulated for nasal administration. The solutions or suspensions are applied directly to the nasal cavity by conventional means, for example, with an eyedropper, a pipette or a nebulizer. The formulations can be administered in the form of single or multi-dose. In the latter case of an eyedropper or pipette, the use may be made by the same patient that a suitable predetermined volume of the solution or suspension is administered. In the case of the nebulizer, the use can be made for example by means of a spray pump that atomizes a fixed, measured amount. The compounds of the present invention can be formulated for aerosol administration, especially for the respiratory tract, including intranasal administration. In general, the compound should have a small particle size, for example in the order of five (5) microns or less. Such a particle size can be obtained by means already known in the art, for example by micronization. The active ingredient is supplied in a pressurized container containing a suitable propellant, for example a chlorofluorinated hydrocarbon (CFC), for example, dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane or. carbon dioxide or other appropriate gas. Conveniently, the aerosol may also contain a surfactant, for example lecithin. The dose of drug can be controlled by a calibrated valve. Alternatively, the active ingredients may be supplied in the form of dry powder, for example a powdery mixture containing the compound in a suitable powder base, for example lactose, starch, starch derivatives, for example hydroxypropylmethylcellulose and polyvinylpyrrolidone (PVP). The powdery excipient will form a gel in the nasal cavity. The powder composition can be presented in unit dosage form, for example in capsules or cartridges for example, gelatin or in blister packs, from which the powder can be administered by means of an inhaler. If desired, the formulations can be manufactured with an enteric coating, adapted to the continued or controlled release of the active ingredient. For example, the compounds of the present invention can be formulated in transdermal or subcutaneous drug delivery devices. These delivery systems are advantageous in the case that a continuous delivery is necessary and when the submission or compliance of a treatment regime by the patient is crucial. The compounds of transdermal delivery systems are often incorporated into a solid, adhesive support on the skin. The compound of interest can be further combined with a penetration enhancer, for example, azone (1-dodecylazacycloheptan-2-one). Delivery systems with continuous release are inserted subcutaneously into the subdermal layer by surgery or injection. Subdermal implants encapsulate the compound in a soluble lipid membrane, for example, silicone rubber or a biodegradable polymer, for example, polylactic acid. The pharmaceutical preparations are preferably present in unit dosage forms. In such forms the preparation is subdivided into unit doses containing appropriate quantities of the active ingredient. The unit dosage form can be a packaged preparation, the package contains discrete quantities of the preparation, for example packaged tablets, capsules and powders in vials or ampoules. The unit dosage form can also be a capsule, a tablet, a seal (hollow wafer) or even a tablet, or it can be an appropriate number of any of them in packaged form. Other pharmaceutically suitable excipients and their formulations are described in Remington: The Science and Practice of Pharmacy 1995, coordinated by E. W. Martin, publisher Mack Publishing Company, 19th edition, Easton, Pennsylvania. Examples 6-12 describe representative pharmaceutical formulations containing a compound of the present invention.

EXAMPLES The following preparations and examples are presented to allow the experts in the material a better understanding and practice of the present invention. They should not be taken as limitations of the scope of the present invention, but merely as illustrative and representative thereof.

Example 1 4- (2-Fluoro-benzenesulfonyl) -2,2-dimethyl-8-piperazin-1-yl-3,4-dihydro-2H-benzo [1,4] oxazine In this example, a method for obtaining compounds is described of the formula (I) based on the synthesis procedure of the following reaction scheme D.

REACTION SCHEME D Stage 1 2-bromo-N- (3-bromo-2-hydroxy-phenyl) -2-methyl-propionamide Pyridine (1.8 mL, 22.3 mmol) is added to a solution of 2-amino-6-bromo-phenol (4,198 g, 22.3 mmol) in dry CH2C12 (200 mL). The mixture is cooled with ice and then a solution of 2-bromo-2-methylpropionyl bromide (2.8 ml, 22.6 mmol) is added slowly. The mixture is stirred at room temperature for one hour and poured onto CH2C12 and water. The organic phase is washed with water, dried and concentrated in vacuo to give crude 2-bromo-N- (3-bromo-2-hydroxy-phenyl) -2-methylpropionamide, which is used directly in the Stage 2 without further purification. Step 2 8-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one The 2-bromo-N- (3-bromo-2-hydroxy-phenyl) -2-methyl-propionamide from stage 1 is dissolved in DMF (200 ml) and to the DMF solution is added K2C03 (613 g, 45158 mmoles). The mixture is heated at 150 ° C overnight, then cooled and poured into a water / ethyl acetate mixture. The organic fraction is washed with brine. The organic fraction is dried with MgSO 4, concentrated in vacuo and the resulting brown residue is purified by flash chromatography, obtaining 8-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one in the form of white solid (84.6%). MS: (M-H) "256.

Step 3 8-bromo-2, 2-dimethyl-3,4-dihydro-2H-benzo [1,4] oxazine Dissolve 8-bromo-2,2-dimethyl-4H-benzo [1,4] oxazin-3-one from step 2 (768.30 mg, 3.0 mmol) dry tetrahydrofuran (THF) and heat the solution to reflux. 0.3 ml of dimethyl borane-dimethylsulfide (BH3.DMS) 10 M in THF is added dropwise to the reaction mixture and the reaction mixture is boiled under reflux for 1 hour. A solution of 10% HCl in ethanol is then added dropwise to the reaction mixture until a white precipitate is formed, after which the reflux is continued for 10 minutes. The reaction mixture was cooled and the precipitate was filtered off, washed with ether and air dried, yielding 770 mg of the hydrochloride of 8-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo [ 1,4] oxazine (92%) as a white solid. MS: (M + H) 280.

Step 4 8-bromo-4- (2-fluoro-benzenesulfonyl) -2, 2-dimethyl-3,4-dihydro-2H-benzo [1,4] oxazine Dissolve the hydrochloride of 8-bromo-2,2-dimethyl-3, -dihydro-2H-benzo [1,4] oxazine (518 mg, 2.14 mmol) in 5 ml of methylene chloride, then add pyridine. (253.85 g, 3.21 mmol). The reaction mixture was stirred at room temperature and 2-fluorobenzenesulfonyl chloride (416.37 mg, 2.14 mmol) was added dropwise, then stirring was continued at room temperature for 2 hours. The reaction mixture is then kept under boiling at reflux for 1 hour and cooled to room temperature. The reaction mixture is diluted with 5 ml of methylene chloride and 10% HCl in water is added. The organic phase is separated, washed with water, then with a saturated solution of NaHCO 3 and dried (Na 2 SO 4). The solvent is removed under reduced pressure and the residue is purified by flash chromatography (EtOAc in hexane, from 5% to 20%), obtaining 610 g (71.3%) of the 8-bromo-4- (2-fluorophore). benzenesulfonyl) -2,2-dimethyl-3,4-dihydro-2H-benzo [1,4] oxazine in the form of an oil that solidifies at rest, from p. f. : 108 0-110. 1 C . MS: (M + H) 401. Step 5: Tert-butyl ester 4- [4- (2-fluoro-benzenesulfonyl) -2,2-dimethyl-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl] -piperazine-1 carboxylate A solution of 8-bromo-4- (2-fluoro-benzenesulfonyl) -2,2-dimethyl-3,4-dihydro-2H-benzo [1,4] oxazine is added (450 mg, 1124 mmol) and 1-Boc-piperazine (209.4 mg, 1124 mmol) in 5 ml of toluene to a hot, degassed mixture of Pd2 (dba) 3 (= tris (dibenzylideneacetone) dipalladium (O), 20.59 mg , 0.022 mmole), BINAP (= 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl, 35.0 mg, 0.056 mmole) and NaOt-Bu (151.26 mg, 1.57 mmole) in 5 ml of toluene. The solution is heated with stirring at 90 ° C for 2 hours and then allowed to cool to room temperature. Ethyl acetate is added to the reaction mixture, which is then filtered through Celite. The filtrate is washed with water (2 x 15 ml) and brine (1 x 15 ml) and dried with MgSO 4, after which the organic fraction is concentrated in vacuo. The resulting residue is purified by flash chromatography (15% to 30% ethyl acetate in hexane), yielding 470 mg (0.93 mmol) of 4- [4- (2-fluoro-benzenesulfonyl) -2,2-dimethyl3,4 -dihydro-2H-benzo [1,4] oxazin-8-yl] -piperazine-1-carboxylic acid tere-butyl ester. MS: (M + H) 506. Step 6: 4- (2-Fluoro-benzenesulfonyl) -2,2-dimethyl-8-piperazin-1-yl-3, -dihydro-2H-benzo [1,4] oxazine The tert-butyl ester acid 4- [4- (2-fluoro-benzenesulfonyl) -2,2-dimethyl-3,4-dihydro-2H-benzo [1,4] -oxazin-8-yl] - is dissolved. piperazine-1-carboxylate (470 mg, 0.93 mmol) in 3 ml ethanol. To this solution is added 1 ml of a 10% hydrochloric acid solution in ethanol. The mixture is heated at 100 ° C (steam bath) for 15 minutes and then cooled to room temperature, at which time a white crystalline solid forms. The solid is collected by filtration and dried at 70 ° C under vacuum, yielding 160 mg of 4- (2-fluoro-benzenesulfonyl) -2,2-dimethyl-8-piperazin-1-yl-3, 4-dihydro. -2H-benzo [1,4] oxazine in the form of the hydrochloride salt, of mp. 222.9-227.1 ° C. MS: (M + H) 479. The solution is allowed to cool to room temperature and after filtering and drying in a vacuum-connected oven, 0.115 g of the hydrochloride salt of 4-benzyl-8-piperazin-1-yl is collected. -4H-benzo [1,4] oxazin-3-one as a slightly yellow powder. MS: 324 (M + H) +, m.p. = 235.9-236.2 ° C. Various additional compounds are obtained by applying the above procedure and substituting the 2-fluorobenzenesulfonyl chloride in step 4 for the relevant substituted benzenesulfonyl chlorides or for pyridine-sulfonyl chlorides and / or substituting the 2-bromo-2-methyl bromide. propionyl in step 2 by 1-bromo-cyclobutanecarbonyl bromide. These compounds are listed in table 1 above. Example 5 This example illustrates the "in vitro" radioligand binding studies of the compound of the formula (I). The binding activity of compounds of this invention "in vitro" is determined as follows. Duplicate determinations of ligand affinity are made by competitive binding of LSD [H3] to cell membranes derived from HEK293 cells stably expressing the human 5-HT6 recombinant receptor. This cell line is prepared according to the method described by Monsma et al. , Molecular Pharmacology, vol. 43, pp. 320-327 (1993).

All determinations are made in an assay buffer containing 50 mM Tris-HCl, 10 mM MgSO4, 0.5 mM EDTA, 1 mM ascorbic acid, pH 7.4 at 37 ° C, in a reaction volume of 250 microliters. The test tubes containing LSD [H3] (5 nM), competitor ligand, and membrane are incubated in a shaking water bath for 60 min. at 37 ° C, they are filtered on Packard GF-B plates (pre-impregnated with 0.3% PEI) using a Packard 96-well cell harvester and washed 3 times in 50 mM ice-cooled Tris-HCl. The LSD [H3] fixed by radioactive counting per minute is determined using a Packard TopCount device. The displacement of the LSD [H3] of the binding sites is quantified by adjusting the concentration concentration data to a 4 parameter logical equation: (Bmax-basal binding = basal + I + 1Q-Hí7 / (log [ní / Hog / C50 where Hill is the slope of Hill, [ligand] is the concentration of competing radioligand and IC50 is the concentration of radioligand that causes a specific semi-maximal fixation of radioligand. The specific fix window or window is the difference between the Bmax and the basal parameters. By applying the procedures of Example 5, the compounds of the formula (I) are tested and found to be 5-HT6 antagonists. Surprisingly, the compounds of the formula (I) in which R3 and R4 are methyl, or in which R3 and R4 together form a cyclobutyl group, have an affinity with 5-HT6 around logarithmic order or more than the corresponding compounds in which R3 and R4 are hydrogen. This unexpected result is illustrated with greater abundance by the pKi values shown in Table 2.

Example 6 The cognitive enhancement properties of the compounds of the invention are tested in an animal cognitive model: the object recognition work model. Male 4-month-old Wistar rats are used for this (Charles River, Holland). The compounds are prepared daily, dissolved in physiological saline and tested in three doses. The administration is always executed via i.p. (volume injected: 1 ml / kg) 60 minutes before IT. After 30 minutes of injection of the compound, scopolamine hydrobromide is injected. Two equal test groups are formed with 24 rats and are tested by two experimenters. The order of testing the doses is determined randomly. The tests are carried out using a double-blind study. All rats are treated once with each of the expected doses. The recognition test of an object is carried out according to the method proposed by Ennaceur, A., Delacour, J. 1988, A new one-test test for neurobiological studies of memory in rats. 1: Behav behavior data. Brain Res. 31, 47-59. It is noted that in relation to this date, the best method known by the applicant to carry out the invention, is that which is clear from the present description of the invention.

Claims (25)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, characterized in that: m is a number from 0 to 3; X is N or CH; Y is -S02- or -CH2-; each R1 is independently halo, C? -C_2alkyl, halo_C_C_2alkyl, C_C_2alkoxy, cyano, hydroxyCi_C6alkyl, C_C_2C_2alkoxyC_C;, 2alkyl, -S02Ra, -C (= 0) -NRbRc, -S02-NRbRc, -SRb, -N (Rb) -C (= 0) -Rc, -C (= 0) -Rb, or -N (R) -S02-Ra, wherein each Ra is independently C? -C? 2alkyl or halo-Cx ~ C_2alkyl and each of Rb and Rc is independently hydrogen, C? -C? 2alkyl or halo-C_-C? 2alkyl, R2 is aryl or heteroaryl optionally substituted by C_-C_2alkyl , halo-C? -C? 2alkyl, C? -C12alkoxy or cyano; each of R3 and R4 is independently C_-C12alkyl, hydroxy-C? -C? 2alkyl or C? -C? 2alkoxy-C? -C12alkyl, or R3 and R4 together with the carbon atom to which they are attached can form a cyclic group of 3 to 6 ring atoms optionally including a heteroatom selected from N, O and S; and each of Rs, R6, R7, R8 and R9 are independently hydrogen or C? -C? __ alkyl, or R9 and one of R5, Rs, R7, or R8 together with the atoms to which they are attached form a heterocycloamino ring which has 5 to 7 atoms in the ring.

2. The compound according to claim 1, characterized in that Y is -S02-.

3. The compound according to claim 2, characterized in that X is N.

4. The compound according to claim 3, characterized in that R2 is aryl.

5. The compound according to claim 3, characterized in that R2 is optionally substituted phenyl.

6. The compound according to claim 5, characterized in that R3 and R4 with C? -C_2 alkyl.

The compound according to claim 6, characterized in that m is 0 or 1.

8. The compound according to claim 7, characterized in that R1 is halogen, C alquilo?-C? 2 alkyl, C?-C haloalkyl. 2 2, alkoxy cyano, hydroxyalkyl C_-C3 or (C1-C12 alkoxy) -alkyl C_-C_2.

9. The compound according to claim 8, characterized in that R2 is halophenyl.

10. The compound according to claim 9, characterized in that R2 is 2-halophenyl, 3-halophenyl or 4-halophenyl.

11. The compound in accordance with the claim 10, characterized in that R2 is 2-fluorophenyl or 2-chlorophenyl.

12. The compound according to claim 6, characterized in that R3 and R4 are methyl.

The compound according to claim 6, characterized in that R3 and R4 together with the carbon atom to which they are attached can form a cyclic group of 3 to 6 ring atoms which optionally includes a heteroatom selected from N, O and S.

The compound according to claim 6, characterized in that R3 and R4 together with the carbon atom to which they are attached can form a cyclobutyl group.

15. The compound of claim 1, characterized in that it conforms to formula (II): wherein: n is a number from 0 to 5; each R10 independently of its appearance is alkyl, halo, haloalkyl, alkoxy or cyano; and m, R1, R3, R4 and R9 have the meanings defined in claim 1.

16. The compound of claim 15, characterized in that n is 0 or 1.

17. The compound of claim 16, characterized in that R10 is halogen.

18. A method for obtaining a compound of the formula i: characterized in that it consists of the following steps: a) the reaction of a compound of the formula a with a compound of formula b to get compound of the formula c b) cyclization of the compound of formula c to obtain a compound of formula d c) reducing the compound of formula d to obtain a compound of formula e d) the reaction of the compound of the formula e with a compound of the formula f to obtain a compound of the formula g e) the reaction of the compound of the formula g with a compound of the formula h h to obtain the compound of the formula i wherein R1, R3, R4, R9, R10, m and n have the meanings defined in claim 15.

19. A method of preparing a compound of the formula m: characterized in that it consists of the following steps a) the reaction a compound of the formula d with a compound of formula j to obtain a compound of the formula k b) the reduction of the compound of the formula k to obtain a compound of the formula I c) the reaction composed of the formula I with a compound of the formula h R $ Ú n to obtain the compound of the formula m, wherein R1, R3, R4, R9, R10, m and n have the meanings defined in claim 15.

20. A method of preparing a compound of the formula q: characterized in that it consists of the following steps: a) the reaction of a compound of formula g with a compound of the formula n to obtain a compound of the formula or b) dehydration of the compound of the formula or to obtain a compound of the formula p c) dehydrogenation of the compound of the formula p to obtain the compound of the formula q, wherein R1, R3, R4, R9, R10, m and n have the meanings defined in claim 15.

21. A compound characterized in that it is obtained according to a process described in claims 18 to 20.

22. A pharmaceutical composition, characterized in that it contains an effective amount of the compound according to claim 1 mixed with a pharmaceutically acceptable carrier.

23. The use of a compound of the formula I according to claims 1 to 17 for the manufacture of a medicament useful for the treatment of a disease of the central nervous system of a subject.

24. Use according to claim 23, wherein the disease is selected from psychosis, schizophrenia, manic depression, neurological disorders, memory disorders, attention deficit disorders, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease. , eating disorders and Huntington's disease.

25. The use of a compound of the formula I according to claims 1 to 17 for the manufacture of a medicament useful for the treatment of disorders of the gastrointestinal tract of a subject.