MXPA00003468A - Halogen substituted tetracyclic tetrahydrofuran derivatives - Google Patents

Abstract

This invention concerns the compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein n is zero, 1, 2, 3, 4, 5 or 6;X is CH2 or O;R1 and R2 each independently are hydrogen, C1-6alkyl, C1-6alkylcarbonyl, halomethylcarbonyl or C1-6alkyl substituted with hydroxy, C1-6alkyloxy, carboxyl, C1-6alkylcarbonyloxy, C1-6alkyloxycarbonyl or aryl;or R1 and R2 taken together with the nitrogen atom to which they are attached may form a morpholinyl ring or an optionally substituted heterocycle;R3 and R4 are both halogen;or R3 is halogen and R4 is hydrogen;or R3 is hydrogen and R4 is halogen;and aryl is phenyl or phenyl substituted with 1, 2 or 3 substituents selected from halo, hydroxy, C1-6alkyl and halomethyl. The compounds of formula (I) may be used as therapeutic agents.

Description

TETRACICLIC DERIVATIVES OF TETRAHIDROFURANO HALOGEN REPLACED DESCRIPTIVE MEMORY This invention relates to tetracyclic tetrahydrofuran substituted halogen derivatives having antipsychotic, cardiovascular and gastrokinetic activity, and to their preparations; it also refers to compositions that comprise them, as well as to their use as a medicine. WO 97/38991, published October 23, 1997, discloses tetracyclic tetrahydrofuran derivatives. The WO documents 96/14320 and WO 96/14321 describe isoxazolidine containing tetracyclic derivatives, which have antipsychotic, cardiovascular and gastrokinetic activity. An article by Monkovic et al. (J. Med. Chem. (1973), 16 (4), pp. 403-407) describes the synthesis of (±) -3,3a, 8,12b-tetrahydro- / V-methyl-2 - / acid - dibenzo [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine oxalic. Said compound was synthesized as a potential antidepressant; however, it was found that this particular tetrahydrofurfuryl amine derivative is inactive as an antidepressant at a dose of 300 mg / kg. The present compounds differ structurally from compounds known in the art for their specific substitution model in the dibenzoazepine ring and in the presence of a tetrahydrofuran ring instead of an isoxazolidine ring and are furthermore distinguished by their valuable pharmacological and psychochemical properties. This invention relates to compounds of the formula (I) the N-oxide forms, the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, wherein: n is zero, 1, 2, 3, 4, 5 or 6; X is CH2 or O; R1 and R2 are each independently hydrogen, C1 alkyl. 6, C-i-β alkylcarbonyl, halogenomethylcarbonyl or Ci-β alkyl substituted with hydroxy, C?-6 alkyloxy, carboxyl, alkylcarbonyloxy Ci-β, C alquilo ?. alquilo alkyloxycarbonyl or aryl; or R1 and R2 together with the nitrogen atom to which they adhere can form a morpholinyl ring or a radical of formula: (a B C e) wherein: R9, R10, R11 and R12 are independently hydrogen, halogen, halogenomethyl or C? -β alkyl; m is 0, 1, 2, or 3; R 13, R 14, R 15 and R 16 are independently hydrogen, C 1 -alkyl. 6, aryl or arylcarbonyl; or R15 and R16 together can form a bivalent alkanediyl radical C -5 R17 is hydrogen, Ci-β alkyl, C?-6 alkylcarbonyl, halogenomethylcarbonyl, C?-6 alkyloxycarbonyl, aryl, di (aryl) methyl or C?-6 alkyl substituted with hydroxy, C alquilo-6 alkyloxy , carboxyl, C 1 -C 6 alkylcarbonyloxy, C 1 -C 6 alkyloxycarbonyl, or aryl; R3 and R4 are both halogen; or .ja ^^ a ^^ iaag ^ a ^ sSaiiaa »^ ..».,. ^ ».

R3 is halogen and R4 is hydrogen; or R3 is hydrogen and R4 is halogen; and aryl is phenyl or phenyl substituted with 1, 2, or 3 substituents selected from halogen, hydroxy, C? -6 alkyl and halogenomethyl. In the preceding definitions, alkyl C? -6, defines straight or branched chain saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, 1-methylpropyl, 1, 1- dimethylethyl, pentyl, hexyl; C 4-5 alkanediyl defines branched or straight chain bivalent saturated hydrocarbon radicals having from 4 to 5 carbon atoms, such as, for example, 1,4-butanediyl, 1,5-pentanediyl; Halogen is generic for fluorine, chlorine, bromine and iodine. The term "halogenomethyl" includes mono-, di-, and trihalogenomethyl. Examples of halogenomethyl are fluoromethyl, difluoromethyl and particularly trifluoromethyl. The pharmaceutically acceptable addition salts, as mentioned above, comprise the therapeutically active non-toxic acid addition and base addition salt forms which the compounds of formula (I) can form. The acid addition salt form of a compound of formula (I) occurring in its free form as a base can be obtained by treating the free base form of the compound of formula (I) with an appropriate acid such as an inorganic acid , for example, hydrohalic acid, for example, hydrochloric, or hydrobromic, sulfuric, nitric, phosphoric acid and similar acids; or an organic acid, such as for example ^ ^^ ^^ g jülgij the following acids: acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic , p-aminosalicylic, pamoic and similar acids. Particular acid addition salts include hydrochloric acid and [R- (R *, R *)] -2-3-dihydroxybutanedioic acid (other names are for example tartaric acid, d-tartaric acid and L-tartaric acid). The compounds of formula (I) containing acidic protons can be converted into their therapeutically active non-toxic base, i.e., metal or amine, addition salt forms by treatment with appropriate organic and inorganic bases. Salt forms of suitable bases include, for example, ammonium salts, salts of alkali and metal salts of alkaline earths, for example, lithium, sodium, potassium, magnesium, calcium and the like, salts with organic bases, for example, salts of benzathine, of? / - methyl-D-glucamine, of hydrabamine and salts with amino acids, such as for example, arginine, lysine, and the like. Conversely, said salt forms can be converted to free forms by treatment with an appropriate acid or base. The term addition salt used above also comprises the solvates that the compounds of the formula (I) as well as the salts thereof can form. Said solvates are for example hydrates, alcoholates and the like. The / V-oxide forms of the compounds of formula (I) comprise those compounds of formula (I), wherein one or several nitrogen atoms are oxidized to form the so-called N-oxide, particularly those? / - oxides wherein the nitrogen containing the substituents R1 and R2 is? / - oxidized. The term "stereochemically isomeric forms", as used above and hereinafter, defines all possible stereoisomeric forms, wherein the compounds of formula (I) may exist; thus, they also include enantiomers, enantiomeric mixtures, and diastereomeric mixtures. Unless indicated or stated otherwise, the chemical designation of compounds denotes the mixture, and in particular the racemic mixture, of all possible stereochemically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. The same applies to the intermediates, as described herein, used to prepare final products of the formula (I). Attempts are made to include the stereochemically isomeric forms of the compounds of the formula (I) and mixtures of said forms, in the formula (I). The pure stereoisomeric forms of the compounds and intermediates, as mentioned above, are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term "intermediates or compounds stereoisomerically pure" concerns compounds or intermediates having a stereoisomeric excess of at least 80% (ie minimum 90% of one isomer and máximo10% of the other possible isomers) up a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess from 94% up to 100% and even more in particular, which have a stereoisomeric excess of 97% up to 100%. The terms "enantiomerically pure" or "diastereomerically pure" or equivalent terms should be understood in a similar manner, but then considering the enantiomeric excess, respectively the diastereomeric excess of the mixture in question. The numbering of the tetracyclic ring system present in the compounds of formula (I), as defined by the nomenclature of Chemical Abstracts is shown in formula (I ').

The compounds of formula (I) have at least three asymmetric centers, principally carbon atom 2, carbon atoms 3a and carbon atom 12b. The carbon atoms 3a and 12b are part of a strengthened ring system. In this case, where more than 2 asymmetric carbon atoms are present in a ring system, the highest substituent in priority (according to the sequence standards given in Cahn-Ingold-Prelog) of the reference carbon atom , which is defined as the carbon atom that has the lowest number of rings, is arbitrarily always in the "a" position of the median plane determined by the ring system. The position of the highest priority substituent of the other asymmetric carbon atoms, in relation to the position of the highest substituent on the reference atom, is referred to as "a" or "ß". "a" means that the highest priority substituent is on the same side of the midplane determined by the ring system, and "ß" means that the substituent of the highest priority is on the other side of the midplane determined by the system. rings Of some compounds of formula (I) and of the intermediates used in their preparation, the absolute stereochemical configuration was not determined experimentally. In those cases, the stereochemically isomeric form that was individualized, in the first place, is designated as "A" and the second as "B", without further reference to the actual stereochemical configuration. However, said isomeric forms "A" and "B" can be unambiguously characterized due to their optical rotation, in case "A" and "B" have an enantiomeric relationship. A person skilled in the art can determine the absolute configuration of said compounds using advanced ote methods, such as, for example, X-ray diffraction. For example, compound 4 having the stereochemical descriptor A- (2a, 3aβ, 12b) denotes the pure enantiomer having either (a) [2R- (2a, 3aβ, 12ba)] configuration wherein the carbon atom 2 is the reference atom having the R configuration, and the substituent -CH 2 -N (CH3) 2 is on the a side of the midplane, the carbon atom 3a has the S configuration because the hydrogen substituent is on the other side of the midplane relative to the substituent -CH2-N (CH3) 2 and the carbon atom 12b has the R configuration because the hydrogen substituent is on the same side of the midplane relative to the substituent -CH2-N (CH3) 2, or (b) the configuration [2S- (2a, 3aβ, 12ba)] wherein the atom of carbon 2 has the configuration S, the carbon atom 3a has the configuration R and the carbon atom 12b has the S configuration. When the term "compounds of formula (I)" is subsequently used, it also means including pharmaceutically acceptable addition salts, stereoisomeric forms, and also / V-oxide forms. A special group of compounds are those compounds of formula (I), wherein the two hydrogen atoms attached to the carbon atoms 3a and 12b are on opposite sides of the median plane determined by the tetracyclic ring system. Interesting compounds are those compounds of formula (I) wherein R 1 and R 2 are each independently hydrogen or C 6 alkyl, or wherein R 1 and R 2 together with the nitrogen atom to which they are attached, thus form a morpholinyl ring or a radical of formula (c) or (e); particularly interesting are those compounds of formula (I) wherein R1 and R2 are each independently hydrogen or methyl; more in particular both R1 and R2 are methyl. Other interesting compounds are those compounds of formula (I) wherein X is CH2. Still other interesting compounds are those compounds of formula (I) wherein n is 1, 2 or 3, more specifically, n is 1. Particular compounds are those compounds of formula (I), wherein R3 is hydrogen and R4 is halogen , more specifically fluorine. Other particular compounds are those compounds of formula (I), wherein R4 is hydrogen and R3 is halogen, more specifically fluorine. Still other particular compounds are those compounds of formula (I) wherein R3 and R4 are both halogen, more specifically fluorine. Preferred compounds are those compounds of formula (I), wherein the two hydrogen atoms attached to the carbon atoms 3a and 12b are on opposite sides of the median plane determined by the ring system, n is 1 and R1 and R2 are methyl . The most preferred compounds are 11-fluoro-3,3a, 8,12b-tetrahydro- / V, / V-dimethyl-2 / - / - d- benzo-ÜÉÉ [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine; the stereochemically isomeric forms and the pharmaceutically acceptable addition salts thereof, and the? / -oxide forms thereof, more particularly, those stereoisomeric forms wherein the two hydrogen atoms attached to the carbon atoms 3a 12b are in opposite sides of the median plane determined by the ring system such as, for example, (±) - (2a, 3aβ, 12ba) -11-fluoro-3,3a, 8,12b-tetrahydro- / V, γ and -dimethyl- 2H-dibenzo- [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine and (±) - (2a, 3aa, 12bβ) -11-fluoro-3,3a, 8,12b -tetrahydro- / V,? / - dimethyl-2H-dibenzo- [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine. The compounds of formula (I) can be prepared, in general, by the N-alkylation of an intermediate of formula (II) with an intermediate of formula (III), wherein W is a suitable leaving group, such as for example halogen. In the intermediates (II) and (III), R1 to R4, n and X, are as defined in the compounds of formula (I). Said N-alkylation can be conveniently carried out in an inert reaction solvent, such as for example methanol, tetrahydrofuran, methyl isobutyl ketone, N, N-dimethylformamide or dimethyl sulfoxide, and optionally, in the presence of the appropriate base. Agitation and elevated temperatures, for example, reflux temperature, can increase the speed of the reaction. Alternatively, said N-alkylation can also be developed using the procedure described in Monkovic et al. (J. Med. Chem. (1973), 16 (4), p.403-407), which includes the use of a pressurized reaction vessel. (lll) (ll) The compounds of formula (I) can, in addition, be converted, following the transformation reactions known in the art. In addition, the compounds of the formula (I) can be converted to the corresponding N-oxide forms, following the procedures known in the art for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction can be carried out, generally, by reaction of the initial material of the formula (I) with an appropriate inorganic or organic peroxide. Suitable inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal, or alkaline earth metal peroxides, for example, sodium peroxide, potassium peroxide; suitable organic peroxides may comprise peroxyacids, such as, for example, benzenecarboperoxoic acid or substituted halogenobenzenecarboperoxoic acid, for example, 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkylhydroperoxides, for example, tert-butylhydroperoxide. Suitable solvents are for example water, lower alkanols, for example, ethanol and the like, hydrocarbons, for example, toluene, ketones, for example, 2-butanone, halogenated hydrocarbons, for example dichloromethane and mixtures of said solvents. The pure stereochemically isomeric formulas of the compounds of formula (I) can be obtained by the application of the procedures known in the art. The diastereomers can be separated by physical methods, such as selective crystallization and chromatographic techniques, for example countercurrent distribution, liquid chromatography, and the like. The compounds of formula (I) as prepared in the processes described above, are generally racemic mixtures of enantiomers that can be separated from one another, following the resolution procedures known in the art. The racemic compounds of formula (I) which are sufficiently basic or acidic can be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid, respectively with a suitable chiral base. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by alkali or acid. An alternative way of separating the enantiomeric forms of the compounds of the formula (I) includes liquid chromatography using a chiral fixed phase. Said pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the m & • ims ^^^^. ^^^.

Suitable initial materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously use enantiomerically pure starting materials. The aforementioned intermediates are commercially available or can be made following the procedures known in the art. For example, intermediates of formula (III) can be prepared according to the procedure described by Monkovic et al. (J. Med. Chem. (1973), 16 (4), p.403-407). In another alternative form, the intermediates of formula (III), wherein n is 1, said intermediates being represented by the formula (III-a), can also be prepared by reacting an epoxide derivative of the formula (IV) with a reagent of Grignard of formula (V), wherein Y is suitably halogen, thus forming an intermediate of formula (VI) which can subsequently be cyclized, according to methods known in the art, as described in Monkovic et al. .

(IV) (V) (VI) ci ll-a) Epoxides of formula (IV) can be prepared using procedures known in the art, such as peroxidation of an intermediate of formula (VII) with a suitable peroxide, such as m-chloroperbenzoic acid.

(Vile) The compounds of the present invention show affinity with 5-HT2 receptors, particularly with 5-HT2A and 5HT2c (nomenclature as described by D. Hoyer in "Serotonin (5-HT) in neurological and psychiatric disorders", edited by MD Ferrari and published in 1994, by the Boerhaave Commission of the University of Leiden). The antagonistic properties of serotonin of the present compounds can be demonstrated by their inhibitory effect in "The 5-hydroxytryptophan test in rats", which is described in Drug Dev. Res., F3"237-244 (1988). In addition, the compounds of the present invention show interesting pharmacological activity in the "mCPP Test in rats", which is described below and in the "Combined Apomorphine, Tryptamine, Norepinephrine (ATN) Test in Rats", which is described in Arch. Int. Pharmacodyn, 227, 238-253 (1997). The compounds of the present invention have favorable psychochemical properties. For example, they are chemically stable compounds, in particular when compared to the compounds described in WO 96/14320 and WO 96/14321. The compounds of the present invention also have a rapid onset of action. Taking into account these psychochemical and pharmacological properties, the compounds of the formula (I) are useful as therapeutic agents in the treatment or prevention of disorders of the central nervous system, such as anxiety, depression and mild depression, bipolar disorders, sleep and sexual disorders, psychosis, undefined psychosis, schizophrenia, migraine, personality disorders, or obsessive-compulsive disorders, social phobia or panic attacks, organic mental disorders, mental disorders in children, aggression, memory disorders and disorders in the attitude of people of the third age, addition, obesity, bulimia, and similar disorders. In particular, the present compounds can be used as anxiolytic agents, antipsychotics, antidepressants, antimigraine and as agents that have the potential to dominate the addictive properties of drugs of abuse. The compounds of formula (I) can be used as therapeutic agents in the treatment of motor disorders. It may be advantageous to use the present compounds in combination with classical therapeutic agents for such disorders. The compounds of the formula (I) can also be used in the treatment or prevention of damage to the nervous system caused by trauma, apoplectic attack, neurodegenerative disease and the like.; cardiovascular disorders such as high blood pressure, thrombosis, syncope and the like; and gastrointestinal disorders such as gastrointestinal system mode dysfunction and the like. Taking into account the foregoing uses of the compounds of the formula (I), the present invention further provides a method of treatment for warm-blooded animals suffering from such diseases, said method comprising the systemic administration of a therapeutically effective amount of a compound of formula (I) for the treatment of the disorders described above, in particular, for the treatment of anxiety, psychosis, schizophrenia, depression, migraine, sleeping disorders, and addictive properties of drugs of abuse . The present invention further relates to compounds of formula (I), as defined above for use as a medicament, in particular, the compounds of formula (I) can be used for the manufacture of a medication for the treatment of anxiety, psychosis, schizophrenia, depression, migraine, sleeping disorders, and addictive properties of drugs of abuse. Those experts in the treatment of such diseases could determine the daily therapeutically effective amount that arises from the results of the tests obtained that are presented below. A therapeutically effective daily amount would be about 0.01 mg / kg. to approximately 10 mg / kg. of body weight, more preferably about 0.05 mg / kg. to approximately 1 mg / kg. of body weight. For the purpose of easy administration, the compounds in question may be formulated in various pharmaceutical forms. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound, optionally in the form of the addition salt, as the active ingredient, is combined in a deep mixture with a pharmaceutically acceptable carrier which can take a wide variety of forms, They depend on the desired preparation formula of administration. These pharmaceutical compositions are desirable in unit dosage form suitable, preferably, for oral, rectal, percutaneous or parenteral injection. For example, in preparing the compositions in oral dosage form, any normal pharmaceutical medium, such as, for example, water, glycols, oils, alcohols, and the like, could be used in the case of oral liquid preparations, such as suspensions, syrups. , elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most convenient oral dosage unit formula wherein solid pharmaceutical carriers are obviously employed. In the case of parenteral compositions, the carrier will generally comprise sterile water, at least in large part, although other ingredients may be included, for example, to achieve solubility. Injectable solutions, for example, can be prepared, wherein the vehicle comprises saline solution, glucose solution or a mixture of saline and glucose. Injectable solutions containing compounds of formula (I) can be formulated in an oil for prolonged action. Suitable oils for this purpose are, for example, peanut oil, sesame oil, cottonseed oil, corn oil, soybean oil, synthetic glycerol esters of long chain fatty acids and mixtures of these and other oils. Injectable suspensions may also be prepared, in which case suitable liquid carriers, suspending agents and the like may be employed. In compositions suitable for percutaneous administration, the vehicle optionally comprises a penetrating agent and / or suitable moisturizing agent, optionally combined with suitable additives of any kind, in minor proportions, whose additives do not cause any significant deleterious effect on the skin .

Said additives may facilitate administration to the skin and / or may be useful for preparing the desired compositions. These compositions can be administered in various ways, for example, in the form of a transdermal patch, such as a cream or ointment. The acid or base addition salts of the formula (I) are more suitable in the preparation of the aqueous compositions, due to their increased solubility in water in the corresponding acid or base form. In order to increase the solubility and / or the stability of the compounds of the formula (I) in the pharmaceutical compositions, it may be conveniently to employ α-, β-, or β-cyclodextrins or their derivatives, in particular substituted hydroxyalkyl cyclodextrins, by example, 2-hydroxypropyl-β-cyclodextrin. In addition, the cosolvents, such as alcohols can improve the solubility and / or the stability of the compounds of the formula (I) in the pharmaceutical compositions. Other convenient ways to increase the solubility of the compounds of the present invention in the pharmaceutical compositions are described in WO 97/44014. More particularly, the present compounds can be formulated into a pharmaceutical composition comprising a therapeutically effective amount of particles comprising a solid dispersion including (a) a compound of formula (I), and (b) one or more water-soluble polymers. pharmaceutically fciíiátm & Mt * M M M? Mi Mi Mií ^ J acceptable. The term "a solid dispersion" defines a system in the solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed or more or less throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or completely homogeneous or comprises a phase as defined in thermodynamics, said solid dispersion is referred to as a "solid solution". They are, in general, easily bioavailable to the organisms to which they are administered. The term "solid dispersion" also comprises dispersions that are less homogeneous than solid solutions. Said dispersions are not chemically and physically completely complete, or comprise more than one phase. The water-soluble polymer in the particles is a polymer having an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution in solution at 20 ° C. Preferred water soluble polymers are hydroxypropylmethylcellulose or HPMC. HPMC having a methoxy degree of substitution of about 0.8 to about 2.5 and a molar hydroxypropyl substitution of about 0.05 to about 3.0 are generally soluble in water. The methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. The molar substitution of hydroxypropyl refers to the average number of moles of propylene oxide that have reacted with each anhydroglucose unit of the cellulose molecule. The particles, as defined above, can be prepared by first preparing a solid dispersion of the components, and then optionally, grinding or milling said dispersion. There are several techniques for preparing solid dispersions, including melt extrusion, spray drying and solution evaporation, with melt extrusion being preferred. It is especially convenient to formulate the aforementioned pharmaceutical compositions in dosage form for easy administration and uniformity of dosage. Dosage unit formulations as used in the specification and claims of the present invention, refer to physically discrete units adapted as unit doses, each unit containing a predetermined amount of active ingredient calculated to produce the desired therapeutic effect, in association with the required pharmaceutical vehicle. Examples of such dosage unit forms are tablets (including labeled or coated tablets), capsules, pills, powders, wafers, suspensions or injectable solutions, teaspoons, spoons and the like and multiples thereof separately. The following examples are intended to illustrate and not limit the scope of the present invention.

EXPERIMENTAL PART A. PREPARATION OF INTERMEDIARY COMPOUNDS EXAMPLE A1 a) LiAIH4 (0.0686 mol) was added dropwise to a suspension of AICI3 (0.0718 mol) in tetrahydrofuran (75 ml) cooled on an ice bath and under N2 atmosphere. The mixture was stirred for 10 minutes at 0 ° C. A solution of 2-fluoro-5H-dibenzo [a, d] cyclohepten-5-one was added dropwise (0.0653 moles, prepared as described in DE 3,644,462) in tetrahydrofuran (75 ml), and the resulting reaction mixture was warmed to room temperature. Then, the reaction mixture was stirred and refluxed for two hours. The mixture was cooled on an ice bath. Water was added and CH2Cl2. The organic layer was washed with saturated aqueous NaHCO 3 solution, dried, filtered, and the solvent was evaporated, giving a yield of 13.16 g. (96%) of 2-fluoro-5H-dibenzo [a, d] cycloheptene (intermediate 1). b) Metachloroperbenzoic acid (0.0501 mol) was dissolved in CHCl3 (40 ml). The solution was dried, filtered and the filtrate was added dropwise to a solution of intermediate 1 (0.0417 mol) and 1,4-benzenediol (0.26 g) in CHCl 3 (70 ml), stirred at a temperature of 60 ° C. The reaction mixture was stirred for 2.5 hours at 60 ° C, then cooled on an ice bath, washed with a 10% aqueous Na 2 C 3 solution and brine, dried, filtered and the filtrate was evaporated, giving a yield of 10.42 g of 3-fluoro-6,10b-dihydro-1 aH-dibenzo- [3,4: 6,7] cyclohept [1,2-b] oxirene (intermediate 2). c) Bromo-2-propenyl-magnesium (0.0542 moles) was added dropwise to a solution of intermediate 2 (0.04956 moles) in tetrahydrofuran (120 ml) under N2 atmosphere. The reaction mixture was stirred for 30 minutes at room temperature, then stirred and refluxed for 2 hours. The reaction mixture was cooled on an ice bath, washed with a 20% solution of NH 4 Cl and extracted with ethyl acetate. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified and separated into two regioisomers by HPLC analysis on silica gel (eluent: hexanes / ethyl acetate 9/1). Two groups of pure fractions were collected and their solvent was evaporated, giving a yield of 4.79 g (36%) of (±) -trans-8-fluoro-10,11-dihydro-11- (2-propenyl) -5H- dibenzo [a, d] -cyclohepten-10-ol (intermediate 3) and 2.52 g (19%) of (trans) -2-fluoro-10,11-dihydro-11- (2-propenyl) -5H-d benzo [a, d] -cyclohepten-10-ol (intermediate 4). d) Pyridinium tribromide (0.0175 mol) was added in portions to a solution of intermediate 3 (0.0175 mol) in CHCl3 (80 ml), cooled on an ice bath. The reaction mixture was stirred for one hour at room temperature. Water was added. The mixture was stirred for 5 minutes. The organic layer was separated, washed with water, dried, filtered and the solvent was evaporated. The residue was purified by short column chromatography on silica gel (eluent: hexanes / CH2Cl2 4: 1, then 1: 1). The pure fractions were collected and the solvent was evaporated, yielding 5.02 g (83%) of (±) - [(2-a, 3aβ, 12ba) + (2a, 3aa, 12bβ)] - 2- (bromomethyl) ) -11-fluoro-3,3a, 8,12b-tetrahydro-2H-dibenzo [3,4: 6,7] cyclohepta [1,2-b] furan (intermediate 5). Similarly, (±) - [(2, 3aß, 12ba) + 2a, 3aa, 12bβ)] - 2- (bromomethyl) -5-fluoro-3,3a, 8,12b-tetrahydro-2H-dibenzo was prepared [3,4: 6,7] cyclohepta [1,2-b] furan (intermediate 6). In analogous manner to intermediate 6, the following intermediates were also prepared: (2a, 3aβ, 12b) -2- (bromomethyl) -5-fluoro-3,3a, 8,12b-tetrahydro-2H-dibenzo [3, 4: 6,7] cyclohepta [1,2-b] furan (intermediate 7); and [(2, 3aß, 12b) + (2a, 3aa, 12bβ)] - 2- (bromomethyl) -5,11-difluoro-3,3a, 8,12b-tetrahydro-2H-dibenzo [3,4: 6 , 7] cyclohepta [1,2-b] furan (intermediate 8).

B. PREPARATION OF FORMULA COMPOUNDS (I) EXAMPLE B.1 a) N, N-dimethylamine (gas) was bubbled into a mixture of intermediate 5 (0.0145 moles) and CaO (5.28 g) in tetrahydrofuran (100 ml) for 8 minutes. The reaction mixture was stirred in a Parr reactor for 16 hours at 125 ° C. The mixture was cooled to room temperature. The solid was filtered and the filtrate was cooled to room temperature. The solid was filtered and the filtrate was evaporated. The residue was washed in a saturated aqueous solution of NaHC 3, then extracted with CH 2 Cl 2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was purified by short open column chromatography on silica gel (eluent: CH2Cl2 / CH3OH / NH3) 98/2). The desired fractions were collected and the solvent was evaporated, yielding (±) - [(2a, 3aβ, 12ba) + (2a, 3aa, 12bβ)] - 11-fluoro-3,3a, 8,12b-tetrahydro -N, N-dimethyl-2H-dibenzo [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine (compound 1). b) Compound 1 was dissolved in diethyl ether (20 ml) and converted to the hydrochloric acid salt (1: 1) by dropwise addition of 6N HCl / 2-propanol. The solvent was evaporated. The residue was triturated under boiling of 2-propanone, filtered and dried, yielding 2.17 g (43%) of (±) - [(2a, 3aβ, 12ba) -11-fluoro-3,3a hydrochloride. , 8,12b-tetrahydro-N, N-dimethyl-2H-dibenzo [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine (compound 2); melting point of 239.1 ° C). After having repeated the procedures in steps a) and b) with more initial material, the solvent of the mother liquor (remaining after filtering compound 2) was evaporated. The residue was purified by HPLC over RP-18 (eluent: (0.5% ammonium acetate in H2O) / gradient elution of CH3OH / CH3CN). The pure fractions were collected and the solvent was evaporated, giving a yield of 0.400 g of (±) - [(2a, 3aa, 12bβ) -11-fluoro-3,3a, 8,12b-tetrahydro-N, N-dimethyl -2H-dibenzo [3,4: 6,7] cyclohepta [1,2-b] furan-2- || & % héiüüg i3 É SÉ methanamine (compound 3).

EXAMPLE B.2 a) Compound 2 (0.005 moles) was converted to the free base by treatment with aqueous NH 4 OH and extraction with CH 2 Cl 2. The separated organic layer was dried, filtered and the solvent was evaporated. The residue of the free base was separated into its enantiomers by chiral column chromatography on Chiralcel OJ (eluent: hexane / ethanol 90/10). Two groups of pure fractions were collected and the solvent was evaporated, yielding 0.702 g (45%) of A- (2a, 3aβ, 12ba) -11-fluoro-3,3a, 8,12b-tetrahydro-N, N-dimethyl-2H-dibenzo [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine (compound 4) and 0.670 g (43%) of B- (2a, 3aß, 12ba) -11-fluoro-3-3a, 8,12b-tetrahydro-N, N-dimethyl-2H-dibenzo [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine (compound 5) . Analogously, compound 3 was separated into A- (2a, 3aa, 12bβ) -11-fluoro-3,3a, 8,12b-tetrahydro-N, N-dimethyl-2H-dibenzo [3,4: 6, 7] cyclohepta [1,2-b] furan-2-methanamine (compound 6) and B- (2a, 3aa, 12bβ) -11-fluoro-3,3a, 8,12b-tetrahydro-N, N-dimethyl- 2 H -dibenzo [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine (compound 7). b) Compound 5 (0.0584 mol) was stirred in ethanol (280 ml) at room temperature. A solution of L-tartaric acid (0.0584 mol) in ethanol (50 ml) (dissolved by application of heat) was added at room temperature and the mixture was stirred for 4 hours at room temperature. The precipitate was filtered and dried (vacuum 40 ° C, 16 hours), yielding 19.1 g (71%) of [B- (2a, 3aß, 12ba) -11-fluoro-3,3a, 8, 12b-tetrahydro-N, N-dimethyl-2H-dibenzo [3,4: 6,7] cyclohepta [1,2-b] furan-2-methanamine (+) [RR *, R *)] - 2,3 -dihydroxybutanedioate (1: 1) (compound 11).

EXAMPLE B.3 A mixture of intermediate 5 (0.0030 mol) and morpholine (0.0075 mol) was stirred for 3 hours at 100 ° C, then cooled to room temperature and more morpholine (0.0075 mol) was added and the reaction mixture was stirred for one hour. at 100 ° C, then cooled to room temperature and treated with CH 2 Cl 2. The precipitate was filtered and the filtrate was evaporated.

The resulting oil was purified by short open column chromatography on silica gel (eluent: CH2Cl2 / CH3OH 98/2). The pure fractions were collected and the solvent was evaporated. The residue was dissolved with diethyl ether and converted to the hydrochloric acid salt (1: 1). The precipitate was filtered and dried, giving a yield of 0.82 g (70%) of hydrochloride of [(2a, 3aβ, 12ba) + (2a, 3aa, 12bβ)] - 11-fluoro-3,3a, 8,12b-tetrahydro-2- (4-morpholinylmethyl) -2H-dibenzo [3,4: 6, 7] cyclohepta [1,2-b] furan (compound 19, melting point 281.1 ° C). Table 1 gives a list of compounds of the formula (I) which were prepared analogously to one of the procedures described above.

TABLE 1 A list of compounds of formula which are prepared analogously to one of the reaction processes described above is given in Table 2 below.

C. TECHNICAL EXAMPLE EXAMPLE C.1"Test of mCPP in rats" Rats were treated with the compound at a variable dose at a time before the T test of one hour and with 1 mg / kg. of mCPP (metachlorophenylpiperazine), injected intravenously, 15 minutes before the test. After the previous time (T) to the test, the treated rats were subjected to the "Rats open field test", as described in Drug Dev. Res. 18, 1199-144 (1989), but using a source of infrared light instead of a Kleverlux® light source (12V / 20W). The dose at which 40% or more of the rats to which a test had been made showing suppression of mCPP-induced effects, i.e., antagonism of mCPP, was defined as active dose. Compounds Nos. 2 and 8 up to and including 16 were active at a test dose of 2.5 mg / kg. or less. Other compounds were not tested and were not active at a higher dose. A complete antagonism of the effects induced by mCPP was observed, which meant that 100% of the rats tested showed a complete suppression of the induced effects of mCPP, in the case of compounds Nos. 2 and 10 at a dose of 2.5 mg / kg. or less. In order to test the onset of rapid action of a test compound to reverse the induced effects of mCPP, the preceding experiment was repeated, whereby the rats were treated intravenously with mCPP at a pretest time (T) of 15 minutes and intravenously with the test compound at several doses at a pre-test time (T) of five minutes. Compounds Nos. 2, 8, 9, 11 and 12 were active at a test dose of 2.5 mg / kg. or less, and so it was proved that they had a quick start to action.

EXAMPLE C.2"Test of apomorphine, tryptamine and norepinephrine (ATN) in rats" The antipsychotic activity of the compounds of the subject is demonstrated by the experimental data obtained from the test of apomorphine (APO), tryptamine (TRY) and norepinephrine (ÑOR) in rats. Said combined test of apomorphine, tryptamine and norepinephrine is described in Arch. Int. Pharmacodyn., 227, 238-253 (1977), and provides an empirical evaluation of the relative specificity with which drugs can affect particular neurotransmitter systems in a central (SNC), as well as peripheral. In particular, the test demonstrates the antagonistic activity of the tested compounds of the formula (I) on dopamine (preventing the symptoms produced by the dopamine agonist apomorphine such as, for example, agitation and stereotyping), on serotonin (avoiding the symptoms central serotonin-produced tryptamine agonists, such as, for example, bilateral clonic seizures, tremors, delayed locomotion and peripheral symptoms, such as for example cyanosis) and on norepinephrine (avoiding or delaying death with administration of the a-agonist norepinephrine ). The favorable pharmacological property of the present compounds in comparison with the compounds specifically described in WO 97/38991, lies in the ability to present antagonism to the central symptoms produced by apomorphine and tryptamine. Table 3 compares ED50 values in mg / kg. (effective dosage at which induced symptoms receive antagonism in 50% of the rats tested) for compounds numbers 9, 11, 12 and 13 with the following compounds, as described in WO 97/38991: Observations to determine if a test compound exhibits antagonism to centrally induced symptoms, were developed to present antagonism to apomorphine in 30 minutes and antagonism to tryptamine in 90 minutes after subcutaneous administration of the test compound TABLE 3 Present invention WO 97/38991 Comp. No. I ED50 (mg / kg) Compound | ED50 (mg / kg) Interaction of apomorphine Antagonism of agitation and stereotyping Interaction of tryptamine Antagonism of bilateral clonic seizures Delayed locomotion disease D. EXAMPLE OF COMPOSITION The "active ingredient" (I.A.), as used in all examples, refers to a compound of formula (I), an acid addition salt Pharmaceutically acceptable, a stereochemically isomeric form thereof or an N-oxide form thereof.

EXAMPLE D.1 Oral solution 15 Methyl 4-hydroxybenzoate (9 g) and 4-hydroxybenzoate propyl (1 g) were dissolved in boiling purified water (4 I). In 3 liters of this solution, 2,3-dihydroxybutanedioic acid (10 g) and then I.A. (20 g). The latter solution was combined with the remaining part of the first solution and 1,2,3-propanetriol (12 I) and a solution of 70% sorbitol (3 I) was added. Sodium saccharin (40 g) was dissolved in water (500 ml), and raspberry essence (2 ml) and gooseberry essence (2 ml) were added. The last solution was combined with the first one, it was added Faf water in sufficient quantity at a volume of 20 I, providing an oral solution comprising 5 mg of the active ingredient per teaspoon (5 ml). The resulting solution was placed in suitable containers.

EXAMPLE D.2 Film-coated tablets Preparation of the tablet core Al (100 g), lactose (570 g) and starch (200 g) were mixed well and then the mixture was humidified with a solution of sodium dodecylsulfate (5 g) and polyvinyl pyrrolidone (10 g) in water (2000 ml). The wet powder mixture was sieved, dried and sieved again. Then, microcrystalline cellulose (100 g) and hydrogenated vegetable oil (15 g) were added. Everything was mixed well and compressed into tablets, giving 10,000 tablets, each containing 10 mg of the active ingredient.

Cover To a solution of methyl cellulose (10 g) in denatured ethanol (75 ml), a solution of ethyl cellulose (5 g) in dichloromethane (150 ml) was added. Then dichloromethane (75 ml) and 1,2,3-propanetriol (2.5 ml) were added. The polyethylene glycol (10 g) was melted and dissolved in dichloromethane (75 ml). The latter solution was added to the former and then magnesium octadecanoate (2.5 g), polyvinylpyrrolidone (5 g) and concentrated color suspension (30 ml) were added, and everything was homogenized. The cores of the tablets were coated with the mixture thus obtained in an apparatus for making the cover.

EXAMPLE D.3 Injectable solution Methyl 4-hydroxybenzoate (1.8 g) and 4-hydroxybenzoate propyl (0.2 g) were dissolved in boiling water (500 ml) for injection. After cooling to approximately 50 ° C, while stirring, lactic acid (4 g), propylene glycol (0.05 g) and I .A were added. (4 g). The solution was cooled to room temperature and supplemented with water for injection in sufficient quantity to 1000 ml, giving a solution comprising 4 mg / ml of I.A. It was sterilized by filtration and placed in sterile containers. ¡¿¿¿<

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - A compound of formula a form of? / -oxide, a pharmaceutically acceptable addition salt or a stereochemically isomeric form thereof, wherein: n is zero, 1, 2, 3, 4, 5 or 6; X is CH2 or O; R1 and R2 are each independently hydrogen, d-β alkyl, C-? 6 alkylcarbonyl, halogenomethylcarbonyl or Ci-β alkyl substituted with hydroxy, C-? 6 alkyloxy, carboxyl, Ci-β alkylaryloxy, C-? - alkyloxycarbonyl 6 or aril; or R1 and R2 together with the nitrogen atom to which they adhere can form a morpholinyl ring or a radical of formula: (a B C D E) wherein: R9, R10, R11 and R12 are independently hydrogen, halogen, halogenomethyl or C1-6alkyl; m is 0, 1, 2, or 3; R 3, R 14, R 15 and R 16 are independently hydrogen, C 6 alkyl, aryl or arylcarbonyl; or R15 and R16 together can form a bivalent C-alkanediyl radical.; R 17 is hydrogen, C 1 -C 6 alkyl, Ci-β alkylcarbonyl, halogenomethylcarbonyl, C?-6 alkyloxycarbonyl, aryl, di (aryl) methyl or C -? 6 alquilo alkyl substituted with hydroxy, C? _ Alquilo alkyloxy, carboxyl, alkylcarbonyloxy C -? - 6, Ci-βalkyloxycarbonyl, or aryl; R3 and R4 are both halogen; or R3 is halogen and R4 is hydrogen; or R3 is hydrogen and R4 is halogen; and aryl is phenyl or phenyl substituted with 1, 2, or 3 substituents selected from halogen, hydroxy, C-? 6 alkyl and halogenomethyl.

2. A compound, as expressed in claim 1, wherein X is CH2

3. - A compound, as set forth in claim 1 or 2, wherein the hydrogen atoms bonded to the carbon atoms 3a and 12b are on opposite sides of the median plane determined by the tetracyclic ring system.

4. A compound, as expressed in any of claims 1 to 3, wherein R3 is halogen and R4 is hydrogen.

5. A compound, as expressed in any of claims 1 to 4, wherein n is 1.

6. A compound, as expressed in any of claims 1 to 5, wherein both R and R2 are each one independently selected from hydrogen or Ci-β alkyl, or when they are together with the nitrogen atom to which they adhere to form a morpholinyl ring or radical of formula (c) or (e).

7. A compound, as set forth in claim 1, wherein the compound is 11-fluoro-3,3a, 8,12b-tetrahydro-A /, / V-dimethyl-2 / - -dibenzo- [3, 4: 6,7] cyclohepta [1,2-b] furan-2-methanamine, a stereochemically isomeric form or a pharmaceutically acceptable addition salt thereof, or a? / -oxide form thereof.

8. A composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound, as expressed in any of claims 1 to 7.

9. A compound, as expressed in any of the claims 1 to 7, for use as a medicament.

10. The use of a compound, as expressed in claims 1 to 7, in the manufacture of a medicament for treating anxiety, psychosis, schizophrenia, depression, migraine, sleeping disorders, and addictive properties of drugs of abuse .

11. A process for the preparation of a compound, as described in claim 1, characterized in that: a) an intermediate of the formula (II) is N-alkylated with an intermediate of formula (III) (lll) (ll) wherein the intermediates (II) and (III) R1 to R4, n and X, are defined as in claim 1, and W is a suitable leaving group; in an inert reaction solvent and optionally in the presence of a suitable base; b) conversion of compounds of formula (I) to each other, following the transformations known in the art and further, if desired, converting the compounds of the formula (I) into a therapeutically active non-toxic acid addition salt, by treatment with an acid, or a therapeutically active non-toxic acid addition salt by treatment with a base, or conversely, converting the acid addition form to the free base by treatment with alkali, or converting the addition salt of the base into a free acid by acid treatment; and, if desired, preparing the stereochemically isomeric forms or N-oxide forms thereof.