MXPA97003250A - Tetraciclic derivatives of oxazepine and tiazepinasused with affinity to the receptor of 5- - Google Patents

Abstract

The present invention relates to the compounds of formula (I), the pharmaceutically acceptable salts and the stereoisomeric forms thereof, and also the N-oxide forms thereof. In said formula, R 1 and R 2 are each independently hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, trihalomethylcarbonyl, C 1-6 alkyl substituted with hydroxy, C 1-6 alkyloxy, carboxyl, C 1-6 alkylcarbonyloxy, C 1-6 alkyloxycarbonyl or aryl; or R1 and R2 taken together with the nitrogen atom to which they are attached can form a morpholinyl ring or an optionally substituted heterocycle, R3 and R10 are each independently hydrogen, halogen, cyano, hydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro amino, mono- or di (C 1-6 alkyl) amino, C 1-6 alkylcarbonylamino, aminosulfonyl, mono- or di (C 1-6 alkyl) -aminosulfonyl, C 1-6 alkyl, C 1-6 alkyloxy, C 1-6 alkylcarbonyl, C 1 -6 alkyloxycarbonyl, R 11 is hydrogen, C 1-6 alkyl or trifluoromethyl, R 12 is hydrogen, C 1-6 alkyl, cyano or trifluoromethyl, n is 0 to 6, and X is 0, S, S (-O) or S (= O) 2. The compounds of formula (I) can be used as therapeutic agents in the treatment or prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders.

Description

TETRQCICLIC DERIVATIVES OF OXOZEPINfl AND TIQZEPIlMft SUBSTITUTED WITH AFFINITY TO THE 5-HT2 RECEIVER DESCRIPTIVE RISK This invention relates to substituted tetracyclic oxazepine and thiazepine derivatives having antipsychotic, cardiovascular and gastrokinetic activity, as well as to their preparations; it also refers to compositions comprising them, as well as to their use as a medicament. Compounds of similar structure are described in U.S. Patent No. 4,039,558, which discloses pyrrolidinodibenzo-azepine, pyrrolyl, o-dibenzo-oxazepine pyrrolidinodibenzo-thiazepi and pyrrolidinodibenzo-diazepine derivatives, which have anti-istaminic, sedative and antidepressant properties. EP-A-0,421,823 describes similar dibenzopyrazine-azepine or 'z-benzo-pyrido-pyrazine-azepine derivatives having antiallergic and antiasthmatic activities. The present compounds thus differ in the presence of an isoxazolidine ring, as well as in their pharmacological properties. This invention relates to compounds of formula (Ti) the pharmaceutically acceptable acidic or basic addition salts and the stereochemically isomeric forms thereof, and also the N-oxide forms thereof, wherein: R and R2 are each independently hydrogen, alkyl, -C -A alkylcarbonyl, trihalogen ethylcarbonyl, Cx-.6 alkyl substituted with hydroxy, CX_? Alkyloxy, carboxyl, C? _6 alkylcarbonyloxy, C? -6-alkyloxycarbonyl or aryl; or R and Rz taken together with the nitrogen atom to which they are attached; united can form a morpholinyl ring or a radical of formula: wherein: R 3, RX *, R S and R * are each independently hydrogen, halogen, trifluoromethyl or C _? I rent; rn is 1.2, or 3; R 7,, RXT, R?,; ' and Rao are each independently hydrogen or C _? I rent; or R 9 and Rzo taken together can form a bivalent C 1 alkanediyl radical; R2 is hydrogen; C- - alkyl; C? .- < s alkyl carbonyl; trihalogen eti 1 carbonyl; C -eS, alkyloxycarbonyl; aril; di (aryl netyl; C-is alkyl substituted with hydroxy, C? alkyloxy, carboxyl, C? - < alkylcarbonyloxy, Ci-s alkyloxycarbonyl or aryl; R3, R *, R¡B, R, S, R "7, R ^ ** and R a are each independently hydrogen, halogen, cyanohydroxy, trifluoromethyl, trifluoromethoxy, carboxyl, nitro, amino, mono- or di (C ..- < & alkyl) arnino , C? _ "& alkylcarbonylamino, aminosulfonyl, mono- or diCX- ^ alkyl) arninosulfonyl, C? _, Alkyl, C? _. Alkyloxy, C _? Alkylcarbonyl, C? _? Alkyloxycarbonyl; Rx is hi R.sub.ogen, C?. ß alkyl or trifluoromethyl, R 2 is hydrogen, C? _ alkyl, cyano or trifluoromethyl, n is zero, 1,2,3,4,5 or 6, X is 0, S, S (= 0 ) or S (= 0) a; aryl is phenyl; or phenyl substituted with 1.2 or 3 substituent atoms selected from halogen, hydroxy, C? alkyl and tri-loromethyl In the above definitions, C? -6 alkyl defines radicals of straight and branched chain saturated hydrocarbons having from 1 to 6 carbon atoms such such as, for example, methyl, ethyl, propyl, butyl, 1-methylproyl, 1,1-dimethylethyl, pentyl, hexyl; C + ~? alkanediyl defines straight and branched chain saturated bivalent hydrocarbon radicals having from 4 to 5 carbon atoms such as, for example, 1,4-butanediyl, 1,5-pentanediyl; Halogen is generic for fluoro, chlorine, bromine and iodine. The pharmaceutically acceptable addition salts as mentioned above are intended to comprise the therapeutically active forms of non-toxic addition acid salts which the compounds of formula (I) are capable of forming. Said salts can be obtained by treatment of the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, for example, hydrochloric or brornhydric, sulfuric, nitric, phosphoric and similar acids; or organic acids, such as, for example, acetic, hydroxyacetic, propanoic, lactic, pyruvic, oxalic, rnalonic, succinic, rnaleic, phyharic, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesul phonic, cyclic, salicylic, p-aminosalicylic, paronoic and similar acids. The compounds of formula (I) containing acidic protons can also be converted to their therapeutically active forms of non-toxic addition or metal addition salts by treatment with appropriate organic and inorganic bases. Suitable basic salt forms include, for example, ammonium salts, alkali salts and alkaline earth metal salts, for example, lithium, sodium, potassium, magnesium, calcium salts and similar salts, salts with organic bases , for example, the benzathine, N-methyl-D-glucarnine and hydrabamine salts, and the salts with such amino acids as, for example, arginine, lysine and similar amino acids. conversely, said salt forms can be converted to the free forms by treatment with an appropriate base or acid. The term "addition salt", as used above, also includes solvates, which compounds of formula (I) as well as salts thereof, are capable of forming. Said solvates are, for example, hydrates, alcoholates and the like. The N-oxy forms or the compounds of formula (I) are intended to comprise those compounds of formula (I), wherein one or several nitrogen atoms are oxidized to the so-called N-oxide, particularly those N-oxides wherein the nitrogen possessing the substituent atoms R and R2 is N-oxidized. The term "stereoquincically isomeric forms", as used above and as used below, defines all possible isomeric forms in which the compounds of formula (I) may occur. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture, in particular the racemic mixture, of all possible stereochemically isomeric forms, and said mixtures contain all the diastereomers and enantiomers of the basic molecular structure. The stereochemically isomeric forms of the compounds of formula (I) and the mixtures of said forms are obviously intended to be included by the formula (I) The numbering of the tetracyclic ring system present in the compounds of formula (I), as it is defined in the Chemical Pbstracts nomenclature, it is shown in the formula (I ').

The compounds of formula (I) exist co or isomers "cis" and "trans". Said terms refer to the position of the substituent atoms in the isoxazolidine ring and are in accordance with the Chemical Abstracts nomenclature. The nomenclature is unusual in that the carbon atom 3b, being part of a cyclic system, is not considered as a relevant substituent atom of the 3a carbon atom. When the configuration is established, the substituent atom is considered at carbon atom 3a (ie "Z") and the substituent atom with the highest priority over carbon atom 2 (ie, either "T" or " Y"). When "Z" and the substituent atom that has the highest priority on the carbon atom 2 are on the same side of the median plane determined by the isoxazolidine ring, the configuration is designated as "cis" and if not, the configuration it is designated as "trans". The compounds of formula (I) have at least two asymmetric centers, namely the carbon atom 3a possessing the substituent atom R x and the carbon atom 2 possessing the substituent atom R a. Said asymmetric centers and any other asymmetric center that may be present are indicated by the letters R and S. Each time it is used later, the term compounds of formula (I) is intended to also include acid addition salts pharmaceutically acceptable, the basic addition salts and all the stereoisomeric forms and also the N-oxide forms. Particular groups of compounds of formula (I) are those in which one or more of the following restrictions apply: a) R and Ra are each independently hydrogen, Cx- ^ alkyl, trihalogen ethylcarbonyl, Cx- ^ alkyl substituted with carboxyl or C6-alkyloxycarbonyl, or R and R2 taken together with the nitrogen atom to which they are attached form an orpholinyl ring or a radical of formula (b), (c), (d), (e); b) Rxs and R * are hydrogen; c) R 7"and R ß are hydrogen and is 1 or 2; d) R1 and ao are taken together to form a C + -» bivalent alkanediyl radical; e) RZ? is hydrogen, C -A alkyl, di (aryl netyl) , C? -, 5, alkyloxycarbonyl, trihalogenomethylcarbonyl, Cl-? Alkyl substituted with hydroxy, carboxyl, C? ~ "&Alkyloxycarbonyl; f) R3, R *, Rs, R, ¿, are each independently hydrogen, halogen, trifluoromethyl, C6-6alkyloxycarbonyl, C6-alkylaminocarbonyl, carboxyl, g) R7, Ra, R9, RiD are each independently hydrogen, halogen, trifluoromethyl, C? -thi-alkyloxycarbonyl, C? -to-alkylammonosulfonyl , carboxyl, h) R? and Ria are hydrogen, i) X is 0, S or S (= 0) Interesting compounds are those compounds of formula (I) or subgroups as defined above, wherein Ra, Ra, R ?, R- ?,? Or l, and R a> are hydrogen, and in particular, R * and Re and R «» are each independently selected from C? -? Alkyloxycarbonyl and carboxyl, preferably R, Ra and R "are each independently selected from hydrogen, halogen, trifluoromethyl and Cx- ^ alkylaminosulfonyl. Also interesting compounds are those compounds of formula (I) or subgroups as defined above, wherein n is 1, 2 or 3 and X is O. More interesting compounds are those compounds of formula (I) or eubroups as defined above, where n is 1 and X is S or S (= 0).

More interesting compounds are those interesting compounds in which Rx and R? are each independently selected from hydrogen, methyl, Cx- * alkyl substituted with carboxyl or Cx-6alkyloxycarbonyl; or Rx and R »are considered together with the nitrogen atom to which they are bound from a morpholinyl ring? a radical of formula (b), (c) or (e). Preferred compounds are those compounds of formula (I) wherein X is 0; n is 1,2 or 3; "X and R2 are both methyl, or together with the nitrogen atom to which they are attached form a radical of formula (b) in which R15 and Rie are both hydrogen, or a radical of formula (e) in which R2? is hydrogen, C -? alkyl or trifluoro ethylcarbonyl; R * and R9 are independently selected from hydrogen, halogen, trifluoromethyl, C- 's alkyl-a-inosulfonyl; R3, Rs to R and RIO to R a being hydrogen. The most preferred compounds are: cis-2-C (dimethylamino) methyl3-3.3a-dihydro-N-rnethyl-2H-dibenzCb, f] isoxazoloC2,3-d3-Cl, 43oxazepin-ll-eul fonarnide; cis ~ ll ~ chloro-3,3a-dihydro-2- (l-? iperazinyl-phenyl) -2H-dibenz [b, f] isoxazolo C2,3-d3-Cl-43-oxazepine; cis-2-CC3,3a-dihydro-ll- (trifluoromethyl) -2H-dibenzCb, f isoxazoloi-3-d3Cl, 43-oxazepin-2-yl methyl-lH-isoindol-l, 3- (2H) -dione; and cis-11-chloro-3, 3a-dihydro-N, N-imethyl- ^ indibenzyl, f "3 -isoxazoloC2,3-d3Cl, 43-oxazepin-2-propanamine; the stereochemically isomeric forms and the pharmaceutically acceptable acid addition salts thereof, as well as their N-or i or forms. Interestingly, the compounds of formula (I) are quite easy to synthesize. In general, they can be prepared by a 1,3-di-olar cycloaddition of a dienophile of formula (III) and an intermediate of formula (II). In the intermediaries (II) and (III) and in any other intermediary mentioned below, R a Rx2; X and n are as defined above, unless otherwise indicated. Said 1,3-dipolar cycloaddition can be conveniently carried out by mixing the reactants, optionally in a solvent inert to the reaction, such as, for example, an aromatic solvent, for example, toluene; an ether, for example, tetrahydrofuran, or a mixture of said solvents. Agitation and elevated temperatures, or higher pressure, can accelerate the speed of the reaction. The reaction of the intermediate (II) with the intermediate (III) in practice is regioelective, producing the compounds of formula (I). m (ID In this preparation and the following preparations, the reaction products can be isolated from the reaction medium and, if necessary, can be further purified according to the methodologies generally known in the art, such as, for example, extraction Crystallization, trituration and chromatography The compounds of formula (I) can also be converted into each of the following transformations known in the art: For example, a) A compound of formula (I), wherein R and Rs together with the nitrogen atom to which they are attached form a radical of formula (b) and can be converted to the corresponding primary amine by treatment with hydrazine or aqueous alkali; b) a compound of formula (I), wherein R or R "is trifluoro ethylcarbonyl, can be converted to the corresponding primary or secondary amine by hydrolysis with aqueous alkalis; c) a compound of formula (I), wherein R a is C? -A alkyl substituted with C? -alkylcarbonyloxy, can be hydrolyzed in a compound of formula (I), wherein R or Ra is Cx- ^ substituted alkyl with hydroxy; d) a compound of formula (I), wherein x and Ra are both hydrogen, can be mono- or di-N-alkylated to the corresponding amine form; e) a compound of formula (I), wherein x and s »are both hydrogen, can be N-acylated to the corresponding amide; f) a compound of formula (I), containing a C? -6 alkyloxycarbonyl group, can be hydrolyzed to the corresponding carboxylic acid. The compounds of formula (I) wherein X is other than S, can be converted to the corresponding N-oxide forms following the procedures known in the art for the conversion of a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction can be carried out generally by reacting the starting material of formula (I), with 3-phenyl-2- (phenylsulfonyl) -oxaziridine or with an appropriate organic or inorganic 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 benzenecarboperoxoic acid substituted with halogen, for example, 3-chlorobenzenecarboxyroxoic acid, peroxoalkanoic acids, for example, peroxoacetic acid, alkyl idroperoxide, for example, hydroperoxide t-butyl. Suitable solvents are, for example, water, lower alkanes, for example, ethanol and the like, hydrocarbons, for example, toluene, ketones, for example, 2-butanone, halogenated hydrocarbons, for example, dichloroethane, and mixtures of said solvents. Intermediates of formula (II), wherein X is 0, S (= 0) or S (= 0) 2, said intermediates are represented by the formula (Il-a), they can be prepared by the oxidation of an intermediate of formula (IV) with an appropriate oxidizing agent, such as, for example, 2-benzenesulfonyl-3-phenyl-oxaziridine, hydrogen peroxide, t-butyl hydroxy peroxide, or ethachloroperbenzoic acid. sv) (H-a) X = 0, S (= 0) or S (= 0) 2 Said oxidation is carried out in a solvent inert to the reaction at temperatures ranging from -20 ° C to 50 ° C, preferably between 0 ° C and room temperature. Suitable solvents are, for example, water; chlorinated hydrocarbons, for example, chloroform; aromatic hydrocarbons, for example, toluene; alcohols, for example, rnetanol; ketone, for example, 4-methyl-2-pentanone; or a mixture of said solvents. When peroxide oxidants are used, the speed of the reaction may be increased by the use of metal catalysts such as, for example, N aWOA VO (acetylacetonate) 2, Ti (OBu) ^ and MoOs. (Acetylacetonate) a, optionally under an atmosphere inert to the reaction such as, for example, argon.

Alternatively, intermediates of formula (II), wherein R is hydrogen and R 2 to R or are defined as or made above but other than the nitro group, said intermediates are represented by the formula (II ~ b), can be prepared by reducing the nitro group of an intermediate of formula (V) in the presence of water and an appropriate reducing agent such as, for example, zinc or iron; this is subsequently followed by intramolecular cyclization in situ in the presence of a weak acid such as, for example, ammonium chloride or acetic acid. Said reductive cyclization is carried out in a solvent inert to the reaction such as, for example, 1,4-dioxane. Agitation and elevated temperatures can increase the speed of the reaction. In the intermediate (V), R3 to R or are defined as in the intermediates of formula (Il-b).

Stereochemically isomeric forms of the compounds of formula (I) can be obtained by the application of methods known in the art. Diasterers 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 methods described above, are generally racemic mixtures of enantiomers that can be separated from one another following art-known resolution procedures. The racemic compounds of formula (I), which are sufficiently basic or acidic, can be converted into the corresponding diastereomeric salt forms by reaction with an appropriate chiral acid, respectively chiral base. Said forms of diastereomeric salts are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by means of alkali or acid. An alternative way to separate the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a stationary chiral phase. Said pure stereochemically isomeric forms can also be derived from the corresponding stereochemically isomeric pure forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific preparation methods. These methods will advantageously use enantiomerically pure starting materials.

The pharmacological activity of the compounds of interest is elucidated by one or more of the following tests; 5-HT2 receptor binding assays in vitro; the combined test of apornorphine, tryptamine and norepinephrine in rats, which is described in Arch. Int. Pharmacodyn. , 227, 238-253 (1977); the "mCPP Test on Rats"; and the "Elevated and Illuminated Plus Maze Test on Rats". The last two tests are described below. Additionally, the present compounds show interesting pharmacological activity in the "Tail Suspension Test", and also in the "LSD Drug Discrirnination Test", which is described in Drug Dev. Res. 18, 119-144 (1989). Another interesting property of the compounds of formula (I) is that they suppress the stereotypic behavior induced by amphetamines in rats. In view of its pharmacological properties, the compounds of formula (I), are useful as therapeutic agents in the treatment or prevention of central nervous system disorders such as anxiety, depression and moderate depression, bipolar disorders, sexual and sleep disorders, psychosis, extreme psychosis, schizophrenia , migraine, personality disorders or obsessive-compulsive disorders, social phobias or panic attacks, organic mental disorders, mental disorders in children, aggression, memory disorders and attitude disorders in elderly people, addiction, obesity, bulimia, and similar disorders. In particular, the present compounds can be used as anxiolytics, antidepressants and as agents that have the potential to abolish the addictive properties due to drug abuse. The compounds of formula (I) can also 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 trades. The compounds of this invention can also serve as therapeutic agents in the treatment or prevention of damage to the nervous system caused by trauma, stroke, neurodegenerative diseases and the like.; cardiovascular disorders such as high blood pressure, thrombosis, stroke and the like; and gastrointestinal disorders such as motility dysfunction of the gastrointestinal system and the like. The present compounds may also be useful as anticonvulsant agents. In view of the above uses of the compounds of formula (I), it follows that the present invention also provides a method of treating warm-blooded animals suffering from said diseases, and said method comprises the systemic administration of a therapeutic amount of a compound of formula (I), effective in the treatment of the disorders described above. Thus, the present invention also relates to compounds of formula (I) as defined above for use as a medicament, in particular for use as a medicament for treating the disorders described above. Experts in the treatment of such diseases can determine the effective therapeutic daily amount from the results of the tests presented below. An effective therapeutic daily amount would be from about 0.001 mg / kg to almost 10 g / kg of body weight, more preferably from almost 0.005 mg / kg to almost 1 mg / kg of body weight. To facilitate its administration, the compounds of interest can be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of the particular compound is used, optionally in the form of the addition salt, since the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which can be widely used. variety of forms, depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in the form of appropriate unit doses, preferably, for administration orally, rectally, percutaneously or by parenteral injection. For example, in the preparation of the compositions in oral dosage form, any of the usual pharmaceutical means, such as, for example, water, glycols, oils, alcohols and the like can be used in the case of liquid oral preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binding substances, disintegrating agents and the like, in the case of powders, pills, capsules and tablets. Due to the ease of administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutical carriers are obviously used. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, although other ingredients may be included, for example, to facilitate solubility. Injectable solutions may be prepared, for example, in which the vehicle comprises saline, glucose solution or a mixture of saline and glucose solution. 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 esters of glycerol 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 used. In compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and / or an appropriate wetting agent, optionally combined with appropriate additives of any nature in minor proportions, whose additives do not cause significant adverse effects 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, as a transdermal patch, as a dot application or as an ointment. The acid or basic addition salts of the compounds of formula (I), due to their greater solubility in water on the corresponding base or acid form, are obviously more appropriate in the preparation of aqueous compositions. In order to improve the solubility and / or the stability of the compounds of formula (I) in the pharmaceutical compositions, it can be advantageous to use a-, β-, t-cyclodextrins or their derivatives, in particular hydroxyalkyl-substituted cyclodextrins, for example. -hydroxy-propyl- | 3-cyclodextrin. Also, co-solvents such as alcohols can improve the solubility and / or stability of the compounds of formula (I) in the pharmaceutical compositions. It is especially advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage form to facilitate administration and uniformity of dosage. The unit dosage form as used herein in the specification and claims, refers to physically defined units appropriate as unit doses, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect, in association with the pharmaceutical carrier. required. Examples of such unit dosage forms are tablets (including labeled or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoons, tablespoons and the like, as well as segregated multiples thereof. The following examples are intended to illustrate and not to limit the scope of the present invention.

EXPERIMENTAL PART fl.PREPARATION PE LQS INTERMEDIARIES Hereinafter, "EtOAc" means ethylacetate, "DMF" means dimethylformamide and "RT" "means room temperature.

EXAMPLE 1 a) A mixture of l- (2-propenyl) piperazine (6.6 g) and 2- Ethylpentanoate (11.3 ml) in ethanol (100 ml) was stirred and refluxed for 1 hour 30 minutes. The solvent was evaporated, yielding 9.6 g (80%) of 4- (2-propenyl) -l-piperazine-ethyl propanoate (intermediate 1). b). A mixture of intermediate 1 (7.5 g) in a solution of hydrochloric acid (35%) (20 ml), acetic acid (20 ml) and water (10 ml) was stirred and refluxed for 4 hours. The mixture was cooled on an ice bath and NaOH (50%) was added, so that the mixture was at a pH of almost 6, and the solvent was evaporated. The residue was treated with EtOAc, the precipitate was filtered and the filtrate was evaporated. The oily residue was dissolved in toluene and the solvent was evaporated. The residue was purified by short open column chromatography on silica gel (eluent: HzCl2 / CH3? H / NH3) B / 2. The pure fractions were collected and evaporated, yielding 5.3 g (81%) of 4- (2-propenyl) -.! - piperazinepropanoic acid (intermediate 2).

EXAMPLE 2 A mixture of 2-hydroxybenzaldehyde (16.7 g) and AlsOa / KF (65.5 g) in DMF was heated to .1.20 ° C under an atmosphere of a and 4-brorno-l ~ fluoro-2-nitrobenzene (30 g) in DMF was added. The mixture was stirred at 120 ° C for 3 hours. The precipitate was filtered and the filtrate was evaporated. The residue was purified by open column chromatography on silica gel (eluent 1: hexane / CH2C? A / AcOEt8 / l / l; eluent 2: CHaClsj./2- propanone 9/1) and the pure fractions were collected, yielding 26 g (59%) of 2- (4-bromo-2-nitrophenoxy) benzaldehyde (intermediate 3). Analogously, 5-chloro-2- (2-nitrophenoxy) benzaldehyde was prepared (intermediate 4).

EXAMPLE 3 a) 1,4-Dichloro-2-nitrobenzene (31.6 g) was added to a mixture of 2,2'-dithiodibenzaldehyde (41 g) and potassium carbonate (41.3 g) in methanol (820 rnl), and the mixture of The reaction was stirred and refluxed for 2 hours. Additional 1,4-dichloro-2-nitrobenzene (31.6 g) was added, and the reaction mixture was stirred and refluxed for 2 hours. Water was added and the mixture was extracted with CHaCl ». The separated organic layer was evaporated and the residue was purified by open column chromatography on silica gel (eluent: hexane / EtOAc 97.5 / 2.5), the pure fractions were collected and the solvent was evaporated, yielding 37 g (84%) of 2 - [(4-chloro-2-nitrophenyl) thio3benzaldehyde (intermediate 5). Analogously, 2-CC2-nitro-4- (trifluoromethyl) phenyl thio3benzaldehyde (intermediate 6) was prepared. b) A mixture of potassium peroxyrnonosulfate (35.6 g) in water (120 ml) was added dropwise to a mixture of intermediate 5 (8.5 g) in methanol (120 ml) and cooled on an ice bath, and the mixture was stirred at RT for 7 hours. The solvent was evaporated, water was added and the precipitate was filtered. The residue was filtered by flash chromatography on silica gel (eluent: CHaCl2 / CH30H 98/2). The pure fractions were collected and evaporated, yielding 4.8 g (51%) of 2-C (4-chloro-2-nitrophenyl) sulfinyl-3-benzaldehy or (intermediate 7).

EXAMPLE 4 a) LiAl UdM) in tetrahydrofuran (100 ml) was added dropwise to a mixture of 3-chlorodibenzCb, C1-, 43-oxazepin-ll (10H) -one (12.3 g) (prepared as described in Indian 3. Chem. 1974, 12 (3), 227-35) in 1,4-dioxane (400 ml) under an atmosphere of Na. The mixture was stirred, refluxed for 1 hour 30 minutes, cooled and water was added dropwise. The mixture was acidified and extracted with EtOAc. The organic layer was dried with NaaSO *, filtered and evaporated. The residue was purified by open column chromatography on silica gel (eluent: CHaCl2). The pure fractions were collected and evaporated, yielding 9.74 g (84%) of 3-chloro-10,11-dihydrodibenzCb, f Cl, 43oxazepine (intermediate 8). 3-Phenyl-2- (phenylsphonyl) oxaziridine (36.4g) was added to a mixture of intermediate 8 (15.4g) in trichloroethane (700ml), and the mixture was stirred at RT for 1 hour. The solvent was evaporated and the residue was purified by open column chromatography on silica gel (eluent: CHaCi2). The pure fractions were collected and evaporated, yielding 8.6 g (34%) of 10-oxide of 3-chlorodibenzCb, f3Cl, 43oxazepine (intermediate 9).

EXAMPLE 5 A mixture of intermediate 3 (10 g) and zinc (10.3 g) in 1,4-dioxane (200 ml) and water (15 ml) was stirred at RT. Ammonium chloride (4.3 g) in water (17 ml) was added dropwise at a temperature below 25 ° C and the mixture was stirred at RT for 1 hour. The precipitate was filtered and the filtrate was evaporated. The residue was treated with water and extracted with CHaCia / CHaOH 9/1. The organic layer was dried, filtered and evaporated. The residue was purified by open-column chromatography on silica gel (eluent Hadz / hexane / EtOAc 5/4/1, eluent 2: CHsCl2 / 2-propanone 9/1). The pure fractions were collected and evaporated, yielding 2.2 g (24%) of 10-oxide of 8-bromodibenz-Cb, f3Cl, 43oxazepine (intermediate 10). Analogously, they were prepared B. PREPARATION OF COMPOUNDS PE FORMULA (I? EXAMPLE 6 A mixture of intermediate 15 (2.6 g) and N, N-d? Methyl-2-pro? En-l-amine (2.9 rnl) in toluene (40 ml) was stirred at 80 ° C for 2 hours. The solvent was evaporated and the residue purified by column chromatography on silica gel (solvent: 3.5 / 6 / 0.5). The pure fractions were collected and evaporated. The residue was converted to the oxalic acid salt (1: 1) in CsHsOH at RT, yielding 1 g (63%) of (±.) - 3, 3a-dihydro-N, N-dimethyl-2H-dibenz ethanedioate. [b, f3isoxazoloC2,3-d3Cl, 43-oxaze? in-2-r-methanamine (1: 1); p.f. 179.6 ° C (compound 1).

EXAMPLE 7 Following the same procedure as in Example 6, but using tetrahydrofuran co or solvent, (+.) - cis-11-chloro-3,3a-dihydro-N, N-dirnetyl-2H-dibenzC ethanoate was also prepared, f3-isoxazoloC2,3-dCl, 433 oxazep? n-2-netanamine (1: 1); p.f. 154.4 ° C (compound 2).

EXAMPLE 8 A mixture of (+.) - cis-l-Cll-chloro-3, 3a-dihi ro-2H-dibenzCb, f3ísoxazoloC2,3-d Cl, 43-oxazepin-2-yl) rnetyl3-4- (trifluoroacetyl ) piperazine (7.1 g), following the procedure of Example 7, and potassium carbonate (4.2 g) in methanol (300 rnl) and water (43 rnl) was stirred at RT for 2 hours. The solvent was evaporated. The residue was treated with water, extracted with CHaCl2 and the separated organic layer was evaporated. The residue (5.1 g) was purified by flash chromatography on silica gel (eluent: CH2Cla / CH30H 9 / 1.8 / 2 to 7/3) and the pure fractions were collected and evaporated. The residue (4.2g) was converted to the oxalic acid salt (2: 3 in C2Ha0H at room temperature, yielding 3.9 g, (47%) of (+.) - cis-ll-chloro-3,3a- ethanedioate. dihydro-2- (1-piperazinylmethyl) -2H-dibenzCb, f isoxazoloC2,3-d Cl, 43oxazepine (2: 3), pf-> 250.0 ° C (compound 3).

EXAMPLE 9 Cie-2-C (dimethylamino) methyl 3-3, 3a-dihydro-2H-dibenzC, 3isoxazoloC2,3-d3Cl, 43oxazepin-1-carboxylate-ethanedioate of (±) -methyl (1: 1) (1.53 g), prepared following the procedure of Example 7, in ethanol (60 i), was added dropwise to a mixture of sodium hydroxide (0.3 g) in water (7.5 ml), and the mixture was stirred and refluxed for two hours . The solvent was evaporated in vacuo and the residue was acidified with HCl (4N) to a pH of 3.6. The precipitate was filtered, dried with P_aO »and purified by short pad column chromatography on silica gel (eluent: CHaCla / (CH3OH / NHa) 7/3). The pure fractions were collected and evaporated, and the residue (1 g) was treated with CHaClz / CaHaOl-l / HaO 25ml / 5ml / 5rnl. The precipitate was filtered and dried, yielding 0.5 g (38%) of (+.) - cis-2-C (dimethylarnino) methyl-3,3a-dihydro-2H-dibenzCb, f3isoxazolo [2,3-d3Cl , 43-oxazepine-ll-carboxylic acid i have hydrated; p.f. 229.8 ° C (compound).

EXAMPLE 10 A mixture of (+.) - cis-2-C [3,3a-dihydro-ll- (trifluoromethyl) -2H-dibenztb, f3isoxazolo-C2,3-d3Cl, 43oxazepin-2-yl3methyl-3-lH-odoindol-l , 3 (2H) -dione (2.53 g), prepared following the procedure of example 7, and hydrazine hydrate (0.28 ml) in ethanol (30 nl), was stirred at 80 ° C for 5 hours. The precipitate was filtered and the filtrate was evaporated. The oily residue (3.3 g) was purified by flash chromatography on silica gel (eluent: CHaCla / CH3OH 9.5 / 0.5). Pure fractions were collected and evaporated, and the oily residue (0.7 g) was converted to the oxalic acid salt (1: 1) at C »Ha0H at RT, yielding 0.8 g (35%) of ethanedioate (±) - cis-3,3a-dihydro-ll (trifluoromethyl) -2H-dibenzCb, f3-isoxazoloC2,3-d3Cl, 43oxazepin-2-methanamine (1: 1); p.f. 250 ° C (compound 5). Tables 2 to 5 include compounds that were prepared in a similar manner, as in one of the examples mentioned above.

C.EJEMPLQ PHARMACOLOGICAL EXAMPLE is "PE TEST MCPP IN RATS" Rats were treated with the test compound at a variable dose between 0.0025 mg / kg and 40 mg / kg of body weight, at a preliminary test time T ranging from 5 to 480 minutes, and at 1 mg / kg of CPP ( metaclorophenylpiperazine), injected intravenously, 15 minutes before performing the test. After the preliminary test time T elapsed, the treated rats were subjected to the "Open Field Test on Rats", as described in Drug Dev. Res. 18, 119-144 (1989), but using a light source infrared instead of a KleverluxR light source (12V / 20U). An active dose was defined as a dose at which 40% of the rats subjected to the test showed suppression of the effects induced by the inCPP, ie, antagonism by mCPP. The scale of activity of a test compound was determined by the ratio of the HAD (highest active dose) to the LAD (lowest active dose). The compounds with the number 9 and 11 had a ratio (HAD over LAD) of 4 or more. Compounds with numbers 2, 3, 5-7, 10, 13, 14, 16, 18-21, 26, 28, 33, 38, 44 48, 50 and 52 showed antagonism by mCPP in at least one dose tested .

EXAMPLE 12. "PROOF OF THE HIGHEST LABYRINTH AND ILLUMINATED IN RATS" The "highest maze and illuminated test in rats" is described in Drug Dev. Res. 18, 119-144 (1989). An active dose of a test compound in said test was defined as a dose at which 40% of the rats subjected to the test explored the illuminated corridors of the labyrinth. The activity scale was measured in the same way as in Example 11. The compounds with the number 3, 8,17,1,9,21,40,51,53 and 54 had a ratio (HAD over LAD) of 4 or more. Compounds with numbers 1,2,4-6,9-13,16,18,22,26-30,32,33,36,39, 41,43,44,46,47,49,50 and 52 showed activity in at least one dose in one or more of the rats subjected to the test.

P. EXAMPLES PE COMPOSITIONS "Active ingredient" (A.I.), as used throughout these examples, refers to a compound of formula (I), a pharmaceutically acceptable acid addition salt, a stereochemically isomeric form thereof or a form of N-oxide of it.

EXAMPLE 13i ORAL DROPS 500 grams of A. I was dissolved in 0.5 1 of 2-hydroxypropanoic acid and 1.5 1 of polyethylene glycol at 60-80 ° C. After cooling to 30-40 ° C, 35 1 of polyethylene glycol was added and the mixture was stirred well. Then, a solution of 1750 grams of sodium saccharin in 2.5 1 of purified water was added and, while stirring, 2.5 1 of cocoa flavor and polyethylene glycol in sufficient quantity were added to a volume of 50 1, giving a solution of drops orally containing 10 mg / ml of AI The resulting solution was poured into appropriate containers.

EXAMPLE 14; ORAL SOLUTION 9 grams of methyl 4-hydroxybenzoate and 1 gram of propyl 4-hydroxybenzoate were dissolved in 4 1 of purified purified water. In 3 1 of this solution, 10 grams of 2,3-dihydroxybutanediic acid were first dissolved and then 20 grams of AI. The last solution was combined with the remaining part of the first solution and 12 1 of 1, 2, 3 were added. propanotriol and 3 1 of sorbitol solution at 70%. 40 grams of sodium saccharin were dissolved in 0.5 1 of water and 2 ml of raspberry essence and 2 ml of white currant essence were added. The last solution was combined with the first, water was added in sufficient quantity to a volume of 20 1, giving an oral solution containing 5 mg of the active ingredient per teaspoon (5 ml). The resulting solution was poured into appropriate containers.

EXAMPLE / I5; PE MOVIE REVESTIBLE TABLETS Preparation of the core of the tablet A mixture of 100 grams of AI, 570 grams of lactose and 200 grams of starch was mixed well and subsequently subsumed with a solution of 5 grams of sodium dodecyl sulfate and 10 grams of polyvinylpyrrolidone in almost 200 ml of water. The wet powder mixture was screened, dried and sieved again. Then, 100 grams of icrocrystalline cellulose and 15 grams of hydrogenated vegetable oil were added. Everything was mixed well and compressed into tablets, giving 10,000 tablets, each containing 1.0 g of the active ingredient.

Coating To a solution of 10 grams of methyl cellulose in 75 ml of denatured ethanol was added a solution of 5 grams of ethyl cellulose in 150 ml of dichloromethane. Then, 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were added. 10 grams of polyethylene glycol were melted and dissolved in 75 ml of dichloromethane. The last solution was added to the first and then 2.5 grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentrated colored suspension were added, and everything was homogenized. The core of the tablets was coated with the mixture thus obtained in a coating apparatus.

EJEPLQ 16; INJECTABLE SOLUTION 1. 8 grams of methyl-hydroxybenzoate and 0.2 grams of propyl 4-hydroxybenzoate were dissolved in almost 0.5 1 of boiling water for injection. After cooling to about 50 ° C., 4 grams of lactic acid, 0.05 grams of propylene glycol and 4 grams of AI were added while stirring.The solution was cooled to room temperature and supplemented with water for injection in sufficient quantity to give 1 1 , giving a solution containing 4 mg / l of AI, the solution was sterilized by filtration and poured into sterile containers.

Claims (4)

1. NOVELTY DF Ifl INVENTION
2. REIVINPICACIQNES
3. A compound of formula the acidic or basic pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof, and also the N-oxide forms thereof, wherein: R and Rz are each independently hydrogen; Ca.- ^ alkyl; C? -, &alkylcarbonyl; trihalo ethylcarbonyl; Cx-6 alkyl substituted with hydroxy, C ^ -alkyloxy, carboxyl, C- ^ alkylcarbonyloxy, C- ^ alkyloxycarbonyl or aryl; or R and Ra taken together with the nitrogen atom to which they are attached can form a norpholinyl ring or a radical of the formula: wherein: R a, R 1 -, R 3 - 13 and R *** are each independently hydrogen, halogen, rifluoromethyl or Ci - "alkyl; is 1,2 or 3; 7", R &, R < 5 > and R2s are each independently hydrogen or C-? Alkyl, or Ri and R320 taken together can form a bivalent radical C_-alkanediyl, R2 is hydrogen, C-? (C 1-6 alkylcarbonyl, trihalomethylcarbonyl, C- ^ alkyloxycarbonyl, aryl, di (apl) methyl, Cx- ^ alkyl substituted with hydroxy, Ci-6alkyloxy, carboxyl, Cx- ^ alkylaryloxy, C- " alkyloxycarbonyl ", R &sub3;, R ' Ra, R &sub3;, R &sub3;, R & R, and R-0 are each independently hydrogen, halogen, cyano, hydroxy, trifluoromethyl, trifluoromethyl, carboxyl, nitro, ammo, mono- or di (C-? alk?) amino, Cx- ^ acarbylcarbonyl, n-n-sulfonyl, mono- or di (Cx-? alkyl-Jarninosulfonyl, C? - 's alkyl, C? -alkyloxy , C-? Alkylcarbonyl, C? -? Alkyloxycarbonyl, R is hydrogen, C? - < salkyl or trifluoromethyl; Ria is hydrogen, Cx- ^ alkyl, cyano or rifluoromethyl; n is zero, 1,2,3,4, 5 or 6, X is 0, S, S (= 0) or S (= 0) 2, aryl is phenyl, or phenyl substituted with 1,2 or 3 substituent atoms selected from halogen, hydroxy, Cx- * alkyl and riofluoromethyl. 2. A compound in accordance with the claim 1, wherein Ra, Rs, R *, R7, R3-0, R: L and Rxa are hydrogen. 3. A compound in accordance with the claim 2, wherein n is 1,2 or 3. 4, - A compound according to claim 3, wherein R1 and Ra are each independently selected from hydrogen, methyl, C? -? Alkyl substituted with carboxyl or Cx-? Alkyloxycarbonyl; or Rx and Rz taken together with the nitrogen atom to which they are attached form an orpholinyl ring or a radical of formula (b), (c) or (e). 5. A compound according to claim 1, wherein the compounds are cis-2-C (dimethylamino) methyl] -3,3a-dihydro-N-methyl-2H-dibenzCb, fHisoxazoloC2, 3-dlili1 / 4] oxazepin-ll-sulfonamides; cis-ll ~ chloro-3,3a-dihydro-2- (1-piperazinylmethyl) -2H-dibenzCb, f] isoxazolo [2, 3-d] - C 1, 4 loxazepine; cis-2-CC3,3a-dihydro-ll- (trifluorometii) -2H-dibenzCb, f] isoxazoloC2,3-d] Cl, 4Hoxazepin-2-yl] rnetyl-lH-isoindol-l, 3- (2H) -dione; cis-ll-chloro-3,3a-dihydro-N, N-dimethyl-2H-dibenz [b, f3isoxazoloC2,3, -dHl, 4-oxazepi-2-propanamine; the stereochemically isomeric forms, pharmaceutically acceptable acid addition salts and N-oxide forms thereof. 6. A composition comprising a pharmaceutically acceptable carrier and, as an active ingredient, a therapeutically effective amount of a compound as claimed in any of claims 1 to 5. 7. A process for preparing a composition as claimed in claim 6, wherein a pharmaceutically acceptable carrier is intimately mixed with a therapeutically effective amount of a compound as claimed in any of claims 1 to 5. 8. The use of a compound as claimed in any one of the claims. 5 in the preparation of a medicament for the treatment or prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders. 9. - A formula intermediary wherein R3 to R: L are defined as in claim 1, an acidic or basic addition salt thereof or a stereoisomeric form thereof. 10. A process for the preparation of a compound as claimed in claim 9, characterized by: a) an intermediate of formula (IV), wherein R3_ to Rll are as defined in claim 1 and X is oxidized with an appropriate oxidizing agent, producing a compound of formula (Il-a);
4. 4. 1. b) the nitro group of an intermediate of formula (V), wherein X is defined as in claim 1 and Ra a Rxo is defined as in claim 1 but other than the nitro group, is reduced in the presence of water and an agent suitable reducing agent, and subsequently an intramolecular cyclization is carried out in the intermediate thus formed in the presence of a weak acid, yielding a formula (II-b) compound, wherein X is defined as in claim 1 and R3 to R a they are defined as in claim 1 but different from the nitro group. eleven . - A process for preparing a compound as claimed in claim 1, characterized by: a) a dienophile of formula (III) is reacted with an intermediate of formula (II): (H) wherein in the intermediates (II) and (III) R a RX2 !, X and n are defined as in claim 1; b) the conversion of compounds of formula (I) to each other according to transformations known in the art and, if desired, the conversion of the compounds of formula (I) into a non-toxic and therapeutically active addition acid addition salt by treatment with an acid, or in a non-toxic and therapeutically active basic addition salt by treatment with a base or, conversely, the conversion of the addition salt to the free base by treatment with alkali, or the conversion of the basic addition salt in the free acid by acid treatment; and, if desired, the preparation of stereochemically isomeric formulas or N-oxide forms thereof.