MXPA01005608A - Novel 3-alkoxybenzylamine derivatives and their useas medicines for treating schizophrenia - Google Patents

Abstract

The invention concerns novel 3-alkoxybenzylamine derivatives of general formula (1) used as medicines in particular as antipsychotic drug.

Description

NOVEDOUS DERIVATIVES OF 3-ALCOXIBENCILAMINE AND ITS USE AS MEDICINES TO TREAT SCHIZOPHRENIA BACKGROUND OF THE INVENTION Dopamine is a neuromediator that is involved in controlling motor skills, cognitive functions and moods, and is involved in the compensation circuit. Five types of dopaminergic receptor (D1-D5) have been cloned and their levels of expression and brain distributions analyzed. Among these five types of receptor, at least two types have sophormas (Proc. Nati, Acad. Sci. USA 1998, 95, 7731). Although pharmacologically different, these five types of dopaminergic receptor have been grouped into two subfamilies: The Di subfamily, comprising the Di and D5 receptors, and the D2 family comprising the D2, D3 and D receptors. It is possible to differentiate the pharmacological action of the Di and D2 subfamilies, but it is generally difficult to differentiate the function of the various types within each subfamily. A dysfunction of dopaminergic transmission is involved in the symptomatology of disorders of the central nervous system such as schizophrenic psychosis (Neuropsychopharmacol., 1988, 1, 179), certain neurodegenerative diseases such as, for example, Parkinson's disease (Neurodegeneratives Diseases; Jolles, G; Stutzmann, JM; Eds; Academic Press, 1994, chapter 8), depression (J. Clin. Psychiatry, 1998, 59 (Suppl 5), 60), and dependence on certain substances such as, for example, cocaine, tobacco or alcohol (Cell 1997, 90, 991; Nature 1997, 388, 586). Thus, for example, central D2-type dopamine receptor antagonists are a conventional and clinically effective method for treating the positive symptoms of schizophrenic psychosis. However, most compounds with such a mechanism of action also induce adverse side effects such as symptoms of the Parkinson's type (Pharmacotherapy 1996, 16, 160) and / or neuroendocrine disorders (Acta Psychiatry Scand, 1989, 352, 24). . Mewshaw et al. (Bioorg, Med. Chem. Lett, 1998, 8, 295) have exposed phenoxyethylamines of the formula: wherein X represents a hydrogen atom, a hydroxyl group, an amino group or a metharisulfonamide group, Y represents a hydrogen atom or a halogen atom and Ar is a phenyl or 2-thienyl group, as partial agonists of the receptors of type D2. Patents WO 98/08817, EUA 5760070, WO 98/08843 and WO 98/08819 respectively set out 4-aminoethoxyindoles and 4-aminoethoxyindolones as dopamine agonists of type D2 or inhibitors of dopamine release synthesis.

Unangst et al (J. Med. Chem. 1997, 40, 4026) have exposed aryloxyalkylamines of the formula: wherein X represents an oxygen or sulfur atom or a CH2 group; R1 is a hydrogen or chlorine atom, a hydroxyl or hydroxymethyl group, a nitro group or a hydroxycarbonyl residue; R2 and R3 represent a hydrogen atom, a halogen atom or a methyl group. These compounds are active in the dopaminergic system, in particular in the D4 type receptors, and are potentially useful for treating schizophrenia. WO 97/23482 discloses octahydropyrrolo [1,2-a] pyrazines of the formula: wherein X represents, among others, a hydrogen atom; m and n = 0, 1 or 2, and R1 is an aromatic, unsubstituted, heterocyclic or non-heterocyclic, polycyclic, or non-polycyclic group. These compounds have affinity to dopaminergic receptors and in particular to type D4 receptors.

Patents FR 2 702 211, JP 51 048 627, JP 51 052 146, DE 2 450 616 and WO 96/31461 disclose 2- [2- (alkoxy) phenoxy] ethylamine derivatives of the formula: wherein R is a C1-C4 alkyl group and Ri represents a chain of 4-benzenebutyl, 4-piperidinemethyl or 4-benzamidobutyl. These compounds are claimed as ligands of the 5-HTIA subtype receptors (FR 2 702 211 and WO 96/31461) or hypotensive and tranquilizing agents (JP 51 048 627, JP 51 052 146 and DE 2 450 616). Patent EP 707 007 discloses aplamines with double activity simultaneously antagonistic to receptors of type D2 and agonists to subtype 5-HTIA receptors, which are useful as antipsychotic agents. Compound EMD-12830 (Drug Data Report 1998, 21) of the formula is claimed: as an atypical antipsychotic agent (ie, an agent less likely to induce side effects of the Parkinson's type than conventional antipsychotic agents).

DE 2 364 685 discloses phenoxyalkylamines, in particular N- [2- (2-methoxyphenoxy) ethyl] pyrid-3- or 4-ylmethanamine are claimed as hypotensive agents. Angstein et al (J. Med. Chem. 1965, 8, 356) have exposed aryloxyalkylamines that are active in the cardiovascular system. Among the exposed compounds is N- [2- (2-methoxyphenoxy) ethyl-2-benzofuranmeta-namine. Goldenberg et al (Chim, Ther, 1973, 8 259) have reported, among others, N- [2- (2-methoxyphenoxy) etl-2-benzofuranmetanamines as agents with peripheral vasodilatory properties. 4-Methoxy-3- [2 - [(phenylmethyl) amino] ethoxy] phenol is exposed in J. Labelled Compd. Radiopharm. 1993, 33, 1091 and N- [2- (2-methoxyphenoxy) ethyl] furfurylamine is exposed in FR 1 336 684. 3- (cyclopentyloxy) benzenemethanamide derivatives of the formula are claimed: wherein R represents a hydroxyl or methoxy group and Ri represents an aromatic group or a substituted acyl or thioacyl group, as phosphodiesterase inhibitors in patents WO 97/46561, WO 95/20578, WO 95/04045, WO 94/02465 and WO 93/15044 or as active agents in the treatment of heart failure in the U.S. patent. 4 971 959. Patent WO 92/00968 discloses derivatives of the formula: wherein R represents a cycloalkyl group of C -Cβ and X is a hydrogen, fluorine or chlorine atom, which are claimed for their activity in the control of disorders dependent on the production of TNF. WO 98/01417 discloses aromatic and heteroaromatic compounds of the formula: wherein Ar2 is, inter alia, an aromatic group optionally substituted with a non-cyclic lower alkoxy group. These compounds are claimed as inductive calcium receptors.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to a novel family of compounds corresponding to the general formula (1) Formula 1 The compounds of this invention have antidopaminergic antivity in particular in the receptors of the subfamily D2. In this regard, the compounds of the invention are useful in the treatment of conditions resulting from dopaminergic hyperactivity, such as schizophrenic symptoms and dependence of certain substances. However, the antagonist activity of the products of the invention is exerted on D2-type receptors only during transient dopaminergic hyperstimulation. In the absence of dopaminergic activity, ie when the concentration of dopamine varies within the proportions that are acceptable for the normal functioning of the neurons, the compounds of the invention do not induce dopaminergic hyperactivity. The compounds of the invention are therefore useful in the treatment of schizophrenic symptoms and have the advantage of being potentially free of the adverse side effects produced by excessive blocking of D2-type receptors, such as Parkinson's-type symptoms and / or endocrine disorders, at doses that are therapeutically effective in treating schizophrenic psychosis. The compounds of the invention therefore differ from those of the prior art in their chemical form and mechanism of action.

DETAILED DESCRIPTION OF THE INVENTION More specifically, the present invention relates to novel compounds corresponding to the general formula (1): wherein: Xi is a hydrogen atom, chlorine or fluorine; X2 has the same meaning as X-i; Ri represents: - a hydrogen atom, chlorine or fluorine; - a substituent R4, a hydroxyl group (OH), an alkoxy group (OR4), an alkylcarbonyloxy group (OC (O) R4), an alkylcarbonyl group (C (0) R4), an amino group (NH2), a group alkylamino (NHR4), an alkylamino group (N (R4) 2), an alkylcarbonylamino group (NHC (0) R) and a cyano (CN) group; R2 is a substituent R4 or an alkoxy group (OR4); R3 has the same meaning as R1; R 4 represents: a linear or branched C 1 -C 5 alkyl radical optionally substituted with 1 or 2 fluorine atoms, or a hydroxyl group (OH) and optionally containing a double bond. - a 3, 4, 5 or 6-membered cycloalkyl radical optionally substituted with 1 or 2 fluorine atoms and optionally containing a double bond; Y is an oxygen atom or a fluoromethylene (CHF) or difluoromethylene (CF2) group; z is a methylene group (CH2), optionally substituted with 1 or 2 methyl groups (CH3) or fluoromethyl (CH F); A represents: a 3, 4, 5 or 6 membered cycloalkyl radical or a 7 or 8 membered bicyclic radical optionally containing a double bond, an oxo function (= 0), a hydroxyl group (OH), a methoxy group (CH3) or 1 or 2 fluorine atoms; - a non-aromatic 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms chosen from nitrogen, oxygen and sulfur, optionally substituted with an oxo (= O) function, a hydroxyl group (OH), a methoxy group (OCH3) or 1 or 2 halogen atoms. The invention also relates to the addition salts and optionally to the hydrates of the addition salt of the compounds of the general formula (1) with pharmaceutically acceptable organic acids or mineral acids. A subject of the invention are also pharmaceutical compositions containing, as active ingredient, at least one of the derivatives of the formula (1) or one of the salts thereof or hydrate of the salts thereof in combination with one or more pharmaceutically acceptable excipients, adjuvants or vehicles. Some examples that may be mentioned are inclusion complexes, in particular the inclusion complexes formed by the compounds of the invention with β-cyclodextrins. The pharmaceutical compositions according to the invention are compositions that can be administered orally, nasally, sublingually, rectally or parenterally. It is generally advantageous to formulate such pharmaceutical compositions in unit dosage form. In this case, each dose comprises a predetermined amount of the active principle, combined with the vehicle, excipients and / or adjuvants that are suitable, calculated to obtain a given therapeutic effect. As an example of unit dosage forms that can be administered orally, mention may be made of tablets, gel capsules, granules, powders and solutions or oral suspensions. Formulations that are suitable for the chosen form of administration are known and described, for example, in: Remington, The Science and Practice of Pharmacy, 19th edition, 1995, Mack Publishing Company and can thus be easily prepared by an expert in The technique. It is known that the dosage varies from one individual to another, according to the nature and severity of the condition, the route of administration chosen and the weight, age and sex of the patient, and the effective doses also to which they have been determined. consequently in function of these parameters by a person specialized in the field. As a guide, effective doses can vary between 0.001 and 100 mg / kg / day. The compounds of the formula (1) can exist in various tautomeric forms. Although not explicitly reported in the present patent application to simplify the graphic representation of structural formulas, such tautomeric forms are nevertheless included in the field of application of the invention. When the compounds of the invention comprise an asymmetric carbon atom, the invention relates both to racemic mixtures and to various enantiomers of the compound under consideration, and also to mixtures thereof in all proportions. According to a specific feature of the present invention, R 2 represents an isopropoxy. According to another specific feature of the present invention, Y represents an oxygen atom and Z represents a methylene group. According to another particular characteristic of the present invention, A is chosen from the groups cyclopentyl, cyclohexyl, 2-cyclohexenyl and bicyclo [2.2.1] hept-5-en2-yl. The compounds of the general formula (1) can be prepared in which: - Y has the same meaning as above. - z represents a methylene radical optionally substituted with a methyl or fluoromethyl group, - Xi, X2, R-i, R2, R3, R4 and A have the same meaning as above, according to the procedure described in scheme A.

Scheme A The compound of the formula (1) is prepared by a conventional reductive animation reaction between the compound of the formula (2), in which w represents a hydrogen atom or a methyl or fluoromethyl radical, and the primary amine of the formula (3). The expression "a conventional reductive animation reaction" means that the compound of the formula (2) and the amine (3) are reacted in the appropriate solvent and that the mixture of reagents (2) and (3) is then subjected to reducing agent according to a method that is well known to those skilled in the art. The compounds of the formula (1) are purified in accordance with one or more methods chosen between crystallization and / or liquid phase chromatography techniques. If so desired, then they can be: salified using a pharmaceutically acceptable acid; - use in the formation of an inclusion complex.

The process for preparing the primary amines of the formula (3) depends on the nature of the substituents Xi, Ri and R2 contained by the benzene nucleus. The derivative of the formula (4a), which is a precursor of the primary amine (3), can be obtained in which: - X1 is a nitrogen, chlorine or fluorine atom, - R1 is a hydrogen or fluorine atom, a formyl group, a nitro group or a hexycarbonyl group (C (O) OEt), by the process described in scheme B Scheme B 4-n troca tecol is rented with regioselectivity using a 2-halogenopropane to give a derivative (5-3; R1 = NO2) according to an experimental protocol similar to that described in Org. Prep. Procedure Int. 1992, 23, 753. 2-hydroxy-3-isopropoxybenzaldehyde (5-2; R1 = CHO) is a compound that is known in the chemical literature (Heterocycles 1984, 22 (9), 1995). The preparation of 2-isopropoxy-5-ethoxycarbonylphenol (5-1; R1 = C? 2Et) in EP 579 223 is exposed. A conventional Williamson reaction (J. Med. Chem. 1989, 32, 105) between the appropriate compounds of the formula (5) and 1-bromo-2-chloroethane gives the corresponding chloroether, which, by reaction with potassium-phthalimide (Gabriel synthesis) gives the protected amines of the formula (4a) in which R1 is H, CHO, NO2, C? 2Et and X1 is a hydrogen atom. Under conditions similar to those used to convert the phenol of the formula (5) to the protected amine of the formula (4a), the 5-fluoro-2-hydroxyacetophenone is converted to the protected amine of the formula (7; R = CH2CH2NPht). A Bayer-Williger reaction carried out in the compound of the formula (7), Synth. Commun 1989, 11/12, 2001, followed by the basic hydrolysis reaction of the phenol intermediate formate of the formula (6; R = CH2CH2NPht). The alkylation of the phenol of the formula (6) under the usual conditions gives the compound of the formula (4a) in which Ri is a fluorine or chlorine atom and Xi is a hydrogen atom. The inversion of the order of incorporation of the alkyl residues in the intermediates of the formulas (7) and (6) gives access, under experimental conditions identical to those described above, to the compounds of the formula (4a) in which Ri it is a hydrogen atom and Xi is a fluorine or chlorine atom. The amine derivatives of the formula (4b-f), which are precursors of the primary amines (3), can be obtained in which: - Xi is a hydrogen atom, - Ri is a group R, C (0) R4, OH or OR4, according to the procedure described in scheme C.

Scheme C The compound of the formula (4a-2) is the intermediate used to prepare the protected amines of the formulas (4b-g).

According to the route to: a conventional Wittig reaction between the intermediate of the formula (4a-2) and methyltriphenylphosphonium iodide gives the vinyl derivative of the formula (4b). The derivative of the formula (4b) can be: - either directly used in the preparation of the compounds of the formula (1) in which R4 is a vinyl group; - or reducing, under conventional hydrogenation conditions, catalyzing with transition metals, to give the compound of the formula (4c); - or oxidation, according to the conventional Wacker reaction (Org Synth 1988, 67, 12) to give the compound of the formula (4d). A procedure similar to the procedure described by route can then be repeated using the acetone (4d) to give the compound of the formula (4e). The use of an unstabilized phosphonium Nest, derived from a higher alkane halide, gives access to the derivatives of the formula (4b-e) in which Ri represents a R or C (O) R4 group different from a methyl group . The ketone function can also be reduced to the derivative of formula (4d) to a secondary alcohol function such as, for example, that present in compound 4h. According to route b: the Bayer-Villiger reaction under conditions identical to those described for the preparation of the phenol of the formula (6) from the intermediate of the formula (7), Scheme B, gives the phenol of the formula (4f) which can then be rented, under the usual conditions, to give the derivatives of the formula (4g).

The derivatives of the formula (4i) are obtained, which are precursors of the primary amines (3), in which: - Xi is a hydrogen atom, - R? is a group NH2, NHFU, N (R4) 2 or NHC (0) R4, according to the procedure described in scheme D.

Scheme D The intermediate of the formula (4a-6) is prepared by means of a Mitsunobu reaction between the compound of the formula (5, Ri = NO2, scheme A) and tert-butyl (2-hydroxyethyl) carbamate (Eur. J. Med. Chem. 1995, 30, 387). The reduction of the nitro function of the compound of the formula (4a-6), J. Org. Chem. 1987, 52, 1844, gives the amine of the formula (4g-2). The acylation of the amine of the formula (4g-2), under conventional experimental conditions, gives the derivative of the formula (4i) in which R1 is a group (R4CONH). The derivatives of the formula (4i) in which R 1 represents a group NHR 4 or N (R) 2 are prepared easily from the compound of the formula (4g-2) by means of reactions which are well known to those skilled in the art. The technique. The compounds of the formulas (4j) or (4k): formula 4j formula 4k wherein Xi, Ri and R4 have the same meaning as above, are prepared according to procedures similar to those described for the preparation of the compounds of the formula (4a-y) from suitably substituted phenols, which are commercially obtainable or they are prepared according to methods known in the chemical literature. The primary amines of the formula (3), prepared by deprotection of the compounds of the formula (4a-i), are used immediately in the next step of reductive animation (scheme A). The methods for deprotecting the amines of the formulas (4a-i) are described in Scheme E.

Scheme E The deprotection of the compounds of the formula (4a-h) is carried out by moderate heating (60 ° C) of the derivatives of the formula (4a-h) in the presence of an excess of 2-aminoethanole (route to ). The deprotection of the compounds of the formula (4i) is carried out by treating a solution of compounds (4i) in dichloromethane with an excess of trifluoroacetic acid (route b). The process for preparing the aldehydes of the formula (2), scheme A, depends on the nature of the substituent R3. The aldehydes of the formula (2a) are prepared in which: - R3 is a hydrogen atom or an OCH3 group, - A has the same meaning as above, by the process described in scheme F.

Scheme F 3-Hydroxybenzaldehyde or 2-ethoxy-5-hydroxybenzaldehyde, prepared according to J. Org. Chem. 174, 39, 2437, using the cycloalkane haiogenide or the appropriate cycloalkene halide, under conditions which are identical to those described above for the formation of the ether of the formula (5) of 4-nitrocatechol (Scheme B) to give the compounds of the formula (2a) in which R3 is a hydrogen atom or a methoxy group. However, when A represents a bicyclic group, for example a bicyclo [2.2.1] hept-5-ene group, the etherification reaction is preferably carried out under consideration using the appropriate bicyclic alcohol by means of a Mitsunobu reaction in accordance with a process which is identical to that described in J. Med. Chem. 1991, 24, 291. The aldehydes of the formulas (2b) are prepared in which: - R3 is a fluorine atom or a chlorine atom, - A has the same meaning as above, by the procedure described in scheme G.

Scheme G The appropriate 3-methyl-4-halogenophenol (R3 = Cl or F) is alkylated under conditions identical to those used for the preparation of the compound of the formula (2a) from the corresponding phenol (scheme F). The compound of the formula (8) is then selectively brominated to the methyl group in the benzylic position (J: Med. Chem. 1982, 25, 1204) to give the the formula (9) which is oxidized to the aldehyde of the formula (2b) according to the method developed by Kornblum (J. Org. Chem. 1986, 51, 1264). The aldehydes of the formula (2c) can be prepared in which: -X2 is a fluorine or chlorine atom, -A has the same meaning as above, according to the method which is identical to that disclosed in WO 92/00968. The compounds of the formulas (4a-i) and (2a-c) constitute the group of compounds of the formulas (4) and (2).

SCHEME A SCHEME B SCHEME C 4b 4f alkylation 4g SCHEME D 4a-6 4g-2 4g-2 / • ^ ^^^ N Boc O ' SCHEME E 4i SCHEME F SCHEME G The following examples illustrate the invention without, however, limiting its scope. In the following examples: (i) the progress of the reaction is monitored by thin layer chromatography (TLC) and reaction times are therefore only mentioned as a guide. (ii) Different crystalline forms can give different melting points; the melting points referred to in the present patent application are those of the products prepared according to the method described and are uncorrected. (Ii) The structure of the products obtained according to the invention is confirmed by nuclear magnetic resonance (NMR) and infrared spectra (IR) and elemental analysis, and the purity of the final products is verified by TLC. (iv) The NMR spectra are recorded in the indicated solvent. The chemical changes (d) are expressed in parts per million (ppm) in relation to tetramethylsilane. The multiplicity of signals is indicated by: s, singlet; d, doublet; t, triplet; q, quadruple; m, multiplet; b, broad. (v) The various symbols for the units have their usual meaning; mg (milligram); g (gram); mi (milliliter); ° C (degrees Celslus); mmol (millimole); nmol (nanomol); cm (centimeter). (vi) Abbreviations have the following meaning; P.f. (melting point); P.e. (Boiling point). (vii) In the present application, the pressures are given in millibars; the expression "room temperature" means a temperature between 20 ° C and 25 ° C.

EXAMPLE 1 2-lsopropoxy-5-nitrophenol (5) A solution of 15.5 g of 4-nitrocatechol (100 mmol) in 200 ml of N, N-dimethylformamide at 0 ° C is added dropwise to a suspension at room temperature. 60% sodium hydride in oil (4.2 g, 105 mmol). At the end of the addition (1 hour), the dark red solution is stirred at 0 ° C for 1.5 hours and then 10.5 ml of 2-iodopropane (105 mmol) is added dropwise. Then the Mix at 80 ° C and stir for 16 hours. It is then cooled to room temperature, the solvent is removed by evaporation and the dark red oil is dissolved in dichloromethane (300 ml). The solution is washed with water and then with saturated aqueous sodium chloride solution, the organic phase is dried over sodium sulphate and filtered, and the solvent is removed by evaporation. The expected product was isolated by chromatography on a silica column (eluent: 80/20 cyclohexane / ethyl acetate). 10.5 g of a yellow oil is recovered which solidifies: Yield: 53% M.p .: 139 ° C 1 H NMR (DMSO d6) d: 1.31 (d., 6H); 4.76 (m, 7.24 (d, 1 H), 7.63 (d, 1 H), 7.76 (dd, 1 H).

EXAMPLE 2 2-f2- (2-Acetyl-5-fluorophenoxy) ethyl] isoindol-1,3-dione (7) Step 1 1- [2- (2-Chloroethoxy) -4-fluorophenoxy] ethanone 40.5 ml of 1-bromo-2-chloroethane (490 mmole) are added to a solution of 25 g of 1- [2-hydroxy-4- fluorophenol] ethanone (162 mmol) in 2-butanone (400 ml), followed by 45 g of potassium carbonate (320 mmol) and 1.26 g of potassium iodide (7.59 mmol).

The mixture is heated at 80 ° C with vigorous stirring for 60 hours and then cooled to room temperature and poured into ice water. The resulting mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. The organic phase is then washed over magnesium sulfate and filtered, and the solvent is removed by evaporation. The product is crystallized from the mixture of cyclohexane and ethyl acetate. 15.7 g of a white solid are recovered: Yield: 45% M.p .: 67 ° C 1 H NMR (CDCl 3) d: 2.66 (s, 3 H), 3.91 (t, 2 H); 4.32 (t, 2H); 6.62 (dd, 1 H); 6.76 (dt, 1 H); 7.85 (dt, 1 H).

Step 2 2- [2- (2-Acetyl-5-flurorphenoxy) ethyl] isoindole-1,3-dione A mixture of 14.6 g of potassium phthalimide (79 mmoles) and 15 g of 1- [2- ( 2-chloroethoxy) -4-fluorophenyl] ethanone (69.2 mmoles) in 150 ml of N, N-dimethyl-fomamide at 150 ° C for 6 hours. The mixture is then cooled and the solvent is removed by evaporation in vacuo. The solid obtained is taken up in dichloromethane and the organic phase is washed with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is removed by evaporation. The product obtained is purified by crystallization from a mixture of cyclohexane and ethyl acetate. 18.2 g of a white solid are obtained: Yield: 76% M.p.:140°C 1 H NMR (CDCb) d: 2.55 (s, 3H), 4.19 (t, 2H); 6.67 (m, 2H); 6.69 (m, 1 H); 7.77 (m, 2H); 7.80 (m, 2H). IR (KBr) v: 1774, 1716, 1679, 1605 and 1590 cm "1.

EXAMPLE 3 2- [2- (5-Fluoro-2-hydroxyphenoxy) ethyl] isoindol-1,3-dione (6) A solution of 26 g of metachloroperbenzoic acid is stirred (at 55%, 82.9 mmol) in 220 ml of dichloromethane for one hour and then transferred to a separatory funnel. The aqueous phase is separated and an organic phase is placed in a round bottom flask and cooled to 0 ° C. 18 g of 2- [2- (2-acetyl-5-fluorophenoxy) ethyl] isoindol-1,3-dione (55 mmol) are added portionwise and the mixture is stirred at room temperature for 16 hours. 6.9 g of sodium bicarbonate (82 mmoles) are then introduced portionwise and the mixture is stirred for 1 hour. The mixture is then concentrated in vacuo and 200 ml of methanol are added, followed by 15.2 g of potassium carbonate (110 mmol). The mixture is stirred at room temperature for 4 hours, the solvent is removed by evaporation and replaced with 200 ml of dichloromethane, and the mixture is washed with water and with saturated aqueous sodium chloride solution. The aqueous phase is dried over sodium sulfate and filtered, and the solvent is removed by evaporation. The product of dichloromethane. 14 g of the title product are obtained in the form of a white solid: Yield: 84% M.p.:172°C 1 H NMR (DMSO d6) d: 3.95 (t, 2H), 4.22 (t, 2H); 6.58 (dt, 1 H); 6. 75 (t, 1H); 6.85 (m, 1H); 7.64 (m, 4H); 8.77 (s, 1H (interchangeable)).

EXAMPLE 4 2- [2- (2-lsopropoxyphenoxy) ethyl] isondol-1,3-dione (4a-1) Working as in example 2, but replacing 1- [2-hydroxy-4-fluorophenoxy] ethanone with 2-isopropoxyphenol in step 1: Total yield: 96% Pf: 72 ° C 1 H NMR (CDCl 3) d: 1.24 ( d, 6H), 4.13 (t, 2H); 4.26 (t, 2H); 4.40 (m, 1 H); 6.88 (m, 4H); 7.72 (m, 2H); 7.84 (m, 2H).

EXAMPLE 5 3- [2- (1,3-Dioxo-1,3-dihydroisoindol-2-yl) ethoxy] -4-lsopropoxybenzaldehyde Í4.L2} Working as in example 2, but replacing 1- [2-hydroxy-4-fluorophenoxy] ethanone with 3-hydroxy-4-isopropoxybenzaldehyde in step 1, prepare the title compound as a white powder: Total yield : 95% Mp: 110 ° C Analysis C20H19NO5 Calculated: C67.98 H5.42 N3.96 Found: 67.55 5.30 4.29 1H NMR (CDCl3) d: 1.28 (d, 6H), 4.19 (t, 2H); 4.32 (t, 2H); 4.54 (m, 1 H); 6.91 (d, 1 H); 7.43 (m, 2H); 7.74 (m, 2H); 7.84 (m, 2H); 9.83 (s, 1 H).

EXAMPLE 6 2- [2- (5-Nitro-2-isopropoxyphenoxy) ethyl] isondol-1,3-dione (4a-3) Working as in example 2, but. replacing 1- [2-hydroxy-4-fluorophenoxy] ethanone with 2-isopropoxy-4-nitrophenol in step 1, prepare the title compound as a yellow oil which is crystallized: Total yield: 85% P.f.:132°C 1 H NMR (DMSO d 6) d: 1.12 (d, 6H), 4.02 (t, 2H); 4.37 (t, 2H); 4.64 (m, 1H); 7.12 (d, 1 H); 7.77 (d, 1 H); 7.86 (m, 5H) EXAMPLE 7 2- [2- (5-Fluoro-2-isopropoxyphenoxy) ethyl] isondol-1,3-dione (4a -4) Working as in example 2, but replacing 2-isopropoxyd-nitrophenol with 2- [2- (5-fluoro-2-hydroxyphenoxy) ethyl] isoindol-1,3-dione, the title compound is obtained in the form of a solid white: Yield: 77% Mp: 68 ° C 1 H NMR (CDCl 3) d: 1.20 (d, 6H), 4.14 (t, 2H); 4.23 (t, 2H); 4.30 (m, 1 H); 6.56 (dt, 1 H); 6.65 (dd, 1 H); 6.79 (dd, 1 H); 7.73 (m, 2H); 7.86 (m, 2H).

EXAMPLE 8 2- [2- (lsopropoxy-5-vinylphenoxy) ethyl] isondol-1,3-dione (4b) 0.42 g of potassium tert-butoxide (3.75 mmol) is added in portions to a suspension of 1.34 g of methyltriphenylphosphonium bromide (3.75 mmole) in 7.5 ml of tetrahydrofuran. The mixture is stirred for one hour at room temperature and then cooled to 0 ° C. A solution of 1.20 g (3.4 mmoles) of 3- [2- (1,3-dioxo-1,3-dihydroisoindole-2-) is then introduced. il) ethoxy] -4-2-isopropoxybenzaldehyde in 7 ml of tetrahydrofuran. The mixture is then stirred at room temperature for 16 hours, after which it is poured into a saturated aqueous solution of ammonium chloride. This mixture is extracted with dichloromethane, the organic phase is washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered and the solvent is removed by evaporation in vacuo. The residue is purified by chromatography on a silica column (eluent: 80/20 cyclohexane / ethyl acetate). 0.77 g of a yellow oil is obtained Yield: 64% P.f.:78°C 1 H NMR (CDCl 3) d: 1.25 (d, 6H), 4.14 (t, 2H); 4.28 (t, 2H); 4.42 (m, 1 H); 5.13 (d, 1 H); 5.58 (d, 1 H); 6.63 (dd, 1 H); 6.89 (d, 1 H); 6.92 (dd, 1 H); 7.01 (d, 1 H); 7.73 (m, 2H); 7.84 (m, 2H).

EXAMPLE 9 2- [2- (5-Ethyl-2-isopropoxyphenoxy) ethyl] isondol-1,3-dione (4c) 2- [2- (isopropoxy-5-vinylphenoxy) ethyl] isoindol-1,3-dione (1.51 mmol) in 8 ml of methanol. Yield: 100% P.f.:61°C 1 H NMR (CDCl 3) d: 1.20 (t, 3H), 1.22 (d, 6H); 2.56 (q, 2H); 4.22 (t, 2H); 4.26 (t, 2H); 4.33 (m, 1 H); 6.71 (dd, 1 H); 6.76 (m, 2H); 7.74 (mm, 2H); 7.83 (m, 2H).

EXAMPLE 10 2- [2- (5-Hydroxy-2-lsopropoxyphenoxy) ethyl] isondol-1,3-dione (4f) 2- [2- (acetyl-5-fluorophenoxy) -eti] lsoindole-1,3-dione with 3- [2- (1,3-dioxo-1,3-dihydroisoindol-2-yl) ethoxy ] -4-S-propoxybenzaldehyde Yield: 65% Mw: 123 ° C 1 H NMR (CDCl 3) d: 1.20 (d, 6H), 4.14 (t, 2H); 4.26 (t, 2H); 4.68 (s, 1 H interchangeable)); 6.30 (dd, 1 H); 6.46 (d, 1 H); 6.74 (d, 1 H); 7.73 (m, 2H); 7.85 (m, 2H). IR (KBr) v: 3252, 1711 and 1511 crt? 1.

EXAMPLE 11 2- [2- (2,5-Disopropoxy-phenoxy) ethylessondol-1,3-dione (4g) 2- [2- (5-fluoro-2-hydroxyphenoxy) -ethyl] -isoindole-1,3-dione with 2- [2- (5-hydroxy-2-isopropoxyphenoxy) ethyl] isoindol-1,3-dione , Pf: 66 ° C 1 H NMR (CDCl 3) d: 1.20 (d, 6H); 1.28 (d, 6H); 4.12 (t, 2H); 4.22 (t, 2H); 4.26 (m, 1 H); 4.42 (m, 1 H); 6.35 (dd, 1 H); 6.50 (d, 1H); 6.76 (d, 1H); 7.72 (m, 2H); 7.85 (m, 2H).

EXAMPLE 12 [2- (5-Acetylamino-2-isopropoxyphenoxy) ethyl] -carbamate (4i) tert-butyl ester The title compound is obtained in the form of an orange oil: Yield: 80 1 H NMR (CDCl 3) d: 1.33 (d, 6H); 1.45 (s, 9H); 2.15 (s, 3H); 3.46 (dt, 2H); 4.04 (t, 2H); 4.43 (m, 1H); 5.28 (s, 1H); 6.96 (d, 1H); 7.06 (d, 1 H); 7.27 (dd, 1 H).

EXAMPLE 13 3- (dicyclo [2.2.11hept-5-en-2-yloxy) benzaldehyde (2a-1) 3 g of bicyclo [2.2.1] hept-5-en-2-ol (27.2 mmoles) and then 7.86 g of triphenylphosphine (30 mmoles) are introduced at 0 ° C to a solution of 3.66 g of 3-hydroxybenzaldehyde (30 g). mmoles) in tetrahydrofuran (40 ml) and then 13.6 ml of ethyl azodicarboxylate (40% in toluene, 30 mmol) are added dropwise. The mixture is stirred at 75 ° C for 48 hours, the solvent is then removed by evaporation, the residue is taken up in dichloromethane and the residue is washed. mix with normal aqueous solution of sodium hydroxide, water and then saturated aqueous solution of sodium chloride. The resulting solution is dried over magnesium sulfate, filtered and concentrated. The title product is isolated by chromatography on a silica column (eluent: 88/2 cyclohexane / ethyl acetate), 0.6 g of a colorless oil is obtained. Yield: 10% 1 H NMR (CDCl 3) d: 1.34 (m, 1 H); 1.42 (m, 1 H); 1.53 (m, 1 H); 1.74 (m, 1H); 2.89 (s, 1 H); 2.99 (s, 1 H); 4.38 (d, 1 H); 6.10 (m, 1 H); 6.35 (m, 1 H); 7.28 (m, 1 H); 7.40 (s, 1H); 7.46 (m, 2H); 9.97 (s, 1 H).

EXAMPLE 14 2-methoxy-5-cyclopentyloxybenzaldehyde (2a-2) .45 g of potassium carbonate (39.4 mmole) and 4.2 ml of bromocyclopentane (39.4 mmole) are added to a solution of 4 g of 5-hydroxy-2-methoxybenzaldehyde (26.3 mmole) in 27 ml of acetonitrile. The mixture is stirred for 16 hours at 80 ° C and then poured into ice water and extracted with ether, and the organic phase is washed with a normal aqueous solution of sodium hydroxide and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is removed by evaporation in vacuo. The title product is isolated by distillation in a flask oven (T = 200 ° C, P = 10 mbar). 4.13 g of a pale yellow oil are obtained: Yield: 71% 1 H NMR (CDC) d: 1.58-1.63 (m, 2H); 1.83-2.06 (m, 6H); 3.89 (s, 3H); 4.73 (m, 1 H); 6.94 (d, 1 H); 7.11 (dd, 1 H); 7.28 (d, 1 H); 10.40 (s, 1H).

EXAMPLE 15 5-Cyclopentyloxy-2-fluorobenzaldehyde (2b-1) Step 1 4-Cyclopentyloxy-1-fluoro-2-methylbenzene (8) Working as in example 14, but replacing the 5-hydroxy-2-methoxybenzaldehyde with 4-fluoro-3-methylphenol, the title product is obtained in form of a pale yellow oil: Yield: 75% 1 H NMR (CDCl 3) d: 1.60 (m, 2H); 1.77-1.90 (m, 6H); 2.22 (s, 3H); 4.68 (m, 1H); 6.60 (m, 1H); 6.67 (m, 1H); 6.84 (t, 1H).

Step 2 2-Bromomethyl-4-cyclopentyloxy-1-fluorobenzene (9) 4.81 g of N-bromosuccinimide (27 mmoles) and 0.6 g of benzoyl peroxide (2 mmoles) are introduced into a solution of 5 g of 4-cyclopentyloxy. -1-fluoro-2-methylbenzene (25.8 mmol) in carbon tetrachloride (130 ml). The mixture is heated at 80 ° C for 17 hours, then another 2.29 g of N-bromosuccinimide (12.89 mmoles) and 0.3 g of peroxide are added. of benzoyl (1 mmol) and the treatment is continued for 12 hours. The mixture is then cooled to room temperature and filtered through Celite. The original solution is concentrated and the black oil obtained is purified by chromatography on a silica column (eluent: 88/12 cyclohexane / ethyl acetate). 4.63 g of an orange oil are obtained: Yield: 66% 1 H NMR (CDCl 3) d: 1.60 (m, 2H); 1.79-1.86 (m, 6H); 4.66 (m, 2H); 4.68 (m, 1 H); 6.69 (d, 1H); 6.89 (t, 1H); 7.18 (d, 1 H).

Step 3 5-Cyclopentyloxy-2-fluorobenzaldehyde 1.9 ml of s-collidine (14.3 mmol) are introduced into a solution of 3 g of 2-bromomethyl-4-cyclopentyloxy-1-fluorobenzene (11 mmol) in 65 ml of sulfoxide of dimethyl. The mixture is heated at 150 ° C for 25 minutes and then cooled to room temperature. The solvent is removed by evaporation and the title product is isolated by chromatography on a silica column (eluent: 96/4 cyclohexane / ethyl acetate). 1.1 g of a yellow oil are obtained. Yield: 48% 1 H NMR (CDCl 3) d: 1.61 (m, 2H); 1.68-1.72 (m, 4H); 1.88 (m, 2H); 4.33 (m, 1 H); 7.24-7.32 (m, 3H); 10.16 (s, 1 H) EXAMPLE 16 (3-Cyclopentyloxybenzyl) [2- (2-isopropoxyphenoxy) ethyl-1-amine (1-1) Step 1 2- (2-lsopropoxyphenoxy) ethylamine (3a-1) 1.10 g of 2- [2- (2-iopropoxyphenoxy) etl] lsoindole-1,3-dione (3.38 mmol) are added to 4 ml of ethanolamine (66.3 mmoles) and the solution is then maintained at 60 ° C for 2 hours. The mixture is poured into ice water and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and filtered, and separated by solvent removal in vacuo. 0.66 g of the title product is obtained in the form of a pale yellow oil, which is used directly in the next step without further purification: Yield: 100% 1 H NMR (DMSO d 3) d: 1.24 (d, 6H); 1.46 (s, 2H (exchangeable), 2.84 (t, 2H), 3.89 (t, 2H), 4.48 (m, 1H), 6.87 (m, 2H), 6.95 (m, 2H).

Step 2-Cyclopentyloxybenzyl) [2- (2-isopropoxyphenoxy) ethyl] amine 0.5 g of 2- (2-isopropoxyphenoxy) ethylamine (2.56 mmoles) and 0.49 [3-cyclopentyloxybenzaldehyde space (2.56 g) are mixed together. mmoles) in 20 ml of toluene. The solution is refluxed for 12 hours, while the formed water is continuously removed. The toluene is then evaporated off, the residue is taken up in 20 ml of methanol and the solution is cooled to 0 ° C. 0.28 g of potassium borohydride (5.12 mmol) is added in portions and the mixture is stirred for 3 hours at room temperature. The methanol is evaporated off, the residue is taken up in dichloromethane and the organic phase is washed with water and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is removed by evaporation in vacuo. The title product is isolated by chromatography on a silica column (eluent: 98 / 1.5 / 0.5 dichloromethane / methanol / aqueous ammonia). Is obtained 0. 77 g of the title product in the form of a pale yellow oil: Yield: 81% 1 H NMR (CDCl 3) d: 1.31 (d, 6H); 1.60 (m, 4H); 2.07 (m, 2H); 3.03 (t, 2H); 3.85 (s, 2H); 4.13 (t, 2H); 4.47 (m, 1 H); 4.76 (m, 1 H); 6.75 (dd, 1 H); 6.91 (m, 6H); 7.40 (t, 1 H) Preparation of the salt: se: 0.77 g of the title product (2.08 mmol) are dissolved in 10 ml of ethanol, followed by the addition of 0.18 g of oxalic acid (2.08 mmol) in 10 ml of ethanol. The solution is concentrated, the Salt is precipitated and the concentrated solution is filtered. The salt is dried under vacuum at 50 ° C. 0.83 g of the title compound is obtained in the form of oxalate, a white crystalline powder: Mp: 170 ° C C25H32NO7 Analysis Calculated%: C 65.34 H 7.24 N 3.05 Found: 65.45 7.29 3.07 H NMR (DMSO d6) d: 1.24 (d , 6H); 1.58 (m, 2H); 1.69 (m, 4H); 1.92 (m, 2H); 3.26 (t, 2H); 4.24 (t, 2H); 4.26 (s, 2H); 4.55 (m, 1 H); 4.81 (m, 1H); 6.87-6.97 (m, 3H); 7.01-7.10 (m, 4H); 7.32 (t, 1 H); IR (KBr) v: 1612, 1686 and 2973 crt? 1. The compounds of the formula (1), obtained from the intermediates or similar intermediates of examples 1 to 15, according to a procedure similar to that of example 16 and comprising the desired substituents, appear courted in Table 1 following.

TABLE 1 1-11 H H CH3CO H oxalate 169 NH 1-12 H H oxalate 159 1-13 H H oxalate 110 1-14 H H oxalate 132 1-15 H H oxalate 140 1-16 H Cl oxalate 118 1-17 H H oxalate 192 1-18 H H oxalate 175 1-19 H H oxalate 170 Pharmacological study of the compounds of the invention 1.- Measurement of the affinity of the compounds of the invention to the D2 receptors. The affinity of the compounds of the invention to the D2-type receptors was determined by measuring the displacement of (H) YM-09151-2 (NET-1004 70-87 Ci / mmol), according to the method described in Naunyn-Schimiedeberg's Arch. Pharmacol. Methods, 1985, 329, 333. The values of pKi (-log Ki) are given in the form of an ± SEM average in at least 3 experiments. Table 2 gives, by way of example, the values of pKi (D2) for certain compounds of the invention compared to Risperidone. 2.- Evaluation of the receptor antagonist activity of D2 and the cataleptogenic effects of the compounds of the invention in vivo. The text demonstrating the in vivo antidopaminergic activity of the compounds of the invention is based on the invention of the behavior patterns induced by methyl phenylate, average in rats, according to the method described in J. Pharmacol. Exp. Ther. 1993, 267, 181. The test to evaluate the propensity of the products of the invention to induce extrapyramidal side effect is based on its cataleptogenic power, measured in rats, according to the method described in Eur. J. Pharmacol. 1996, 313, 25. By way of example, the values obtained after the intraperitoneal administration are indicated in Table 2 in comparison with the reference substances: Risperidone.

TABLE 2 It is inferred from this study that the compounds of the invention have high affinity to D2 type receptors and also powerful antidopaminergic activity in vivo. Surprisingly, however, the compounds of the invention do not induce cataleptogenic effects, or induce them only at very high doses, in comparison with Risperidone. Risperidone is an atypical antipsychotic agent used clinically (Inpharma® 1998, 1156, 5). In this regard, the compounds of the invention which are capable of modifying the effects of endogenous dopamine are useful in the treatment of dopaminergic disorders such as schizophrenia, such neurodegenerative diseases and dependence on cocaine or alcohol or similar substances.

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - Compounds of the general formula (1) Formula 1 wherein: Xi is a hydrogen atom, chlorine or fluorine; X2 has the same meaning as X-i; R1 represents: a hydrogen, chlorine or fluorine atom; a substituent R4, a hydroxyl group (OH), an alkoxy group (OR4), an alkylcarbonyloxy group (OC (O) R4), an alkylcarbonyl group (C (O) R4), an amino group (NH2), an alkylamino group (NHR4), an alkylamino group (N (R4) 2), an alkylcarbonylamino group (NHC (O) R4) and a cyano (CN) group; R2 is a substituent R4 or an alkoxy group (OR4); R3 has the same meaning as R-i; R 4 represents: a linear or branched C 1 -C 5 alkyl radical optionally substituted with 1 or 2 fluorine atoms, or a hydroxyl group (OH) and optionally containing a double bond; a 3, 4, 5 or 6 membered cycloalkyl radical optionally substituted with 1 or 2 fluorine atoms and optionally containing a double bond; Y is an oxygen atom or a fluoromethylene (CHF) or difluoromethylene (CF2) group; z is a methylene group (CH2), optionally substituted with 1 or 2 methyl groups (CH3) or fluoromethyl (CH2F); A represents: a 3, 4, 5 or 6 membered cycloalkyl radical or a 7 or 8 membered bicyclic radical optionally containing a double bond, an oxo function (= 0), a hydroxyl group (OH), a methoxy group ( CH3) or 1 or 2 fluorine atoms; a non-aromatic 5- or 6-membered heterocyclic group containing 1 or 2 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with an oxo function (= 0), a hydroxyl group (OH), a methoxy group (OCH 3) or or 2 halogen atoms, as well as the addition salts thereof with pharmaceutically acceptable mineral or organic acids and the hydrates of these salts, these various compounds possibly being in the form of pure enantiomers or mixtures of enantiomers in all proportions, including mixtures racemic

2. Compound of the general formula (1) according to claim 1, further characterized in that: R2 represents an isopropoxy.

3. Compound of the general formula (1) according to any of claims 1 and 2, further characterized in that: Y represents an oxygen atom, Z represents a methylene group.

4. Compound of the general formula (1) according to one of claims 1 to 3, further characterized in that: A is chosen from cyclopentyl, cyclohexyl, 2-cyclohexenyl and bicyclo [2.2.1] hept-5-en groups -2-ilo.

5. Compounds of the general formula (1) according to one of claims 1 to 4, further characterized in that they are chosen from: (3-cyclopentyloxybenzyl) [2- (2-isopropoxy-phenoxy) etl. ] amine, (3- cyclopentyloxybenzyl) [2- (2-isopropoxyphenoxy) ethyl] amine, (3-cyclohexenylloxy) benzyl] [2- (2-iopropoxyphenoxy) ethyl] amine, [3- (bicyclo [2.2.1] hept-5 -in-2-yloxy) benzyl] [2- (2-isopropoxyphenoxy) ethyl] amine, (3-cyclopentyloxybenzyl) [2- (5-fluoro-2-isopropoxyphenoxy) ethyl] amine, (3-cyclopentyloxy benzyl) L) [2- (2-isopropoxy-5-methoxyphenoxy) ethyl] amine, (3-cyclopentyloxybenzyl) [2- (2,5-diisopropoxyphenoxy) ethyl] amine, (3-cyclopentyloxybenzyl) [2- (2-isopropoxy-5-vinylphenoxy) ethyl] amine, (3-cyclopentyloxybenzyl) [2- (2-isopropoxy-5-ethylphenoxy) ethyl] amine, 1-. { 3- [2- (3-cyclopentiioxybenzylammon) ethoxy] -4-isopropoxyphenyl-ketanone, N-. { 3- [2- (3-cyclopentyloxybenzylamino) ethoxy] -4-isopropoxyphenyl-acetamide, (5-cyclopentyloxy-2-fluorobenzyl) [2- (2-isopropoxyphenoxy) ethyl] amine, (2-chloro-5-cyclopentyloxybenzyl) ) [2- (2-isopropoxyphenoxy) ethyl] amine, (5-cyclopentyloxy-2-methoxybenzyl) [2- (2-isopropoxyphenoxy) ethyl] amine, (5-cyclopentyloxy-2-methoxybenzyl) [2- (5 -fluor-2-isopropoxyphenoxy) etl] amine, (4-chloro-2-cyclopentyloxybenzyl) [2- (2-isopropoxyphenoxy) ethyl] amine, (3-cyclopentyloxybenzyl) [4-fluoro-2- Sopropoxyphenoxy) etl] amine, (3-cyclopentyloxybenzyl) [2- (2-isopropylphenoxy) ethyl] amine) 1 { 3- [2- (3-Cyclopentyloxybenzylamino) ethoxy] -4-isopropoxyphenyl} ethanol.

6. As a medicament, the compounds of the formula (1) according to one of claims 1 to 5. 7.- Pharmaceutical composition, further characterized in that it comprises at least one compound of the formula (1) in accordance with one of claims 1 to 5, or a pharmaceutically acceptable salt of a compound of the formula (1) and a suitable excipient. 8. Use of a compound of the formula (1) or a pharmaceutically acceptable salt of a compound of the formula (1), according to one of claims 1 to 5, in an amount sufficient for the preparation of a medicament for treat schizophrenia. 9. Use of a compound of the formula (1) or a pharmaceutically acceptable salt of a compound of the formula (1), according to one of claims 1 to 5, in an amount sufficient for the preparation of a medicament for treat dependence 10. Use of a compound of the formula (1) or a pharmaceutically acceptable salt of a compound of the formula (1), according to one of claims 1 to 5, in an amount sufficient for the preparation of a medicament for treat neurodegenerative diseases.