MXPA01003535A - Esters of (+)-alpha-( 2,3- dimethoxyphenyl) -1-[2-(4- fluorophenyl) ethyl]-4- piperidinemethanol and their use as prodrugs of the 5ht2a receptor antagonist mdl 110,907 - Google Patents

Abstract

The present invention is directed to esters of (+)-&agr;-(2, 3-Dimethoxyphenyl)- 1-[2-(4-fluorophenyl)ethyl]- 4-piperidinemethanol, of formula (I) wherein R is C4-C20alkyl, pharmaceutical formulations, methods of making and methods of using these esters. These compounds antagonize the effects of serotonin at the 5HT2A receptor and are useful in treating various conditions such as, for example, psychoses such as schizophrenia.

Description

ESTERS OF (+) - ALPHA- (2, 3-DIMETOXYPENYL) -1- [2- (- FLU0R0FENIL) ETHYL] -4-PIPERIDINMET.AN0L AND ITS USE AS PROFÁ-RLYLACOS OF THE RECEPTOR ANTAGONIST 5HT2A, MDL 110.907 The compound (+) -a- (2, 3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, also known as MDL 100.907, is a potent 5HT: receptor antagonist that is being evaluated clinically for the treatment of schizophrenia. J. Pharm. Exp. Ther. 277: 968-9881 (1996) which is incorporated herein by reference. It was described in U.S. Patent 5,134,149, which is incorporated herein by reference. MDL 100, 907 antagonizes the effects of serotonin on the 5HT receptor and is therefore useful for the treatment of various conditions. However, this compound can also act directly or indirectly to achieve therapeutic effects other than through its antagonism of 5HT2A. For example, see European Journal of Pharmacology 273: 273-279 (1995) where it is shown that MDL 100,907 exerts a tonic inhibitory influence on dopamine efflux in the mid-prefrontal cortex. Some of the uses of M100,907 have been divided into patents or patent applications. US Patent 5,169,096 claimed compounds having a generic scope encompassing M100,907 and disclosed uses of the treatment of anorexia nervosa, variant angina, Raynaud's phenomenon, coronary vasospasm, prophylactic treatment of migraine, cardiovascular diseases such as hypertension, vascular disease peripheral, thrombotic episodes, cardiopulmonary emergencies and arrhythmias, and has anesthetic properties. See also US Patent Nos. 4,783,471; 4,912,117; and 5,021,428, which are divisions of U.S. Patent No. 5,169,096. See also US Patent Nos. 4,877,798 (fibromyalgia), 4,908,369 (insomnia); 5,106,855 (glaucoma); EP 319 962 (anxiety); EP 337 136 (extrapyramidal symptoms). All the aforementioned documents are incorporated herein by reference. M100,907 was then specifically claimed in US Patent No. 5,134,149 which disclosed uses of antagonizing serotonin at the 5Ht2 receptor, anxiety treatment, variant angina, anorexia nervosa, Raynaud's phenomenon, intermittent claudication, coronary or peripheral vasospasm, fibromyalgia , extrapyramidal symptoms, arrhythmias, thrombotic disease, transient ischemic attacks, drug abuse, psychotic illness such as schizophrenia and mania. See also Patents North American Nos. 5,561,144; 5,700; 812; 5,700,813; ,721,249 - divisional of the North American Patent No. ,134,149 - and also US Patent No. 5,618,824 (obsessive compulsive disorder) and PCT / US97 / 02597 (depressive disorders including major depressive episode and dysthymia, and bipolar disorder), as well as insomnia and sleep apnea as described in the patent application number, which is incorporated herein by reference. It is an object of the present invention to provide a new compound that after its administration, releases a therapeutically effective amount of MDL 100,907 over an extended period of time. The extended period of time means a time greater than a single dose of MDL 100.907, and may last several days, several weeks, approximately one month to approximately 6 to 8 weeks, and preferably from approximately 2 weeks to approximately one month. There are many advantages in the administration of a single dose of a compound to a patient that lasts for an extended period of time. Compliance problems that can be particularly important in patients suffering from psychosis or addictive behaviors such as schizophrenia, compulsive obsessive behavior, depression, anxiety, anorexia and drug addiction can be avoided. Other advantages include the absence of the typical oscillations of the drug level that is achieved with a multiple dose therapy through which the patient must experience improved efficacy in treatment with lower peak drug concentrations. While the concept of prolonged release formulations is not a novel concept, not all compounds can be chemically altered to produce a new compound capable of being metabolized into the active ingredient at a desired rate and for the desired period of time. Other factors contribute to the difficulty of preparing a sustained release formulation such as protein binding and other physiological processes that may affect the therapeutic effect of the active ingredient, see, eg, Biochemical Pharmacology, volume 36, No. 10, pages 1715- 1722 (1987), which is incorporated herein by reference. Likewise, the chemically altered compound must be compatible with pharmaceutically acceptable carriers and must be sufficiently stable so as not to be substantially degraded in storage in the active ingredient. In summary, the design of an acceptable formulation for prolonged release is a difficult, unpredictable task. COMPENDIUM OF THE INVENTION The present invention is a compound of the formula I: FORMULA I wherein R is C4-C2o alkyl, or a stereoisomer or a pharmaceutically acceptable salt thereof. The present invention also comprises: a pharmaceutical composition comprising the compound of the formula I and a pharmaceutically acceptable carrier; a method for antagonizing the effects of serotonin at the 5HT receptor; which comprises administering a compound of formula I to a patient in need of such administration; a method for treating a patient for a disease state comprising administering to the patient requiring said therapy a therapeutically effective amount of a compound of formula I wherein the disease state is psychosis (including schizophrenia), disorder compulsive obsessive, thrombotic disease, coronary vasospasm, anxiety, anorexia nervosa, Raynaud's phenomenon, fibromyalgia, extrapyramidal side effects, anxiety, arrhythmia, depression, bipolar depression, insomnia, sleep apnea, Raynaud's phenomenon, or drug abuse; and a method for making the compounds comprising the reaction of an alcohol of structure (5) shown below with an acid halide, acid anhydride, or carboxylic acid in the presence of a sufficient amount of an appropriate base. DETAILED DESCRIPTION OF THE INVENTION The terms used herein have the following meanings: a) "pharmaceutically acceptable salts" This term refers to either an acid addition salt or a base addition salt as much as possible for its preparation with the compounds of the present invention. The term "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic acid addition salt of the base compounds represented by formula I. Illustrative inorganic acids that form suitable salts include hydrochloric, hydrobromic, sulfuric acid , phosphoric and acid metal salts such as sodium monohydrogen metaphosphate and potassium hydrogensulfate. Illustrative organic acids which form suitable salts include the monocarboxylic, dicarboxylic and tricarboxylic acids. Illustrative examples of these examples are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymelic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2 -phenoxybenzoic acid, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethane sulfonic acid. Either the monoacid or diacid salts can be formed, and these salts can exist in either hydrated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and in comparison with their free base forms generally demonstrate higher melting points. The term "pharmaceutically acceptable basic addition salts" refers to non-toxic organic or inorganic basic addition salts of the compounds of the formula (I) or any of their intermediates. Examples are hydroxides of alkali metals or alkaline earth metals such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonia and organic, aliphatic, alicyclic or aromatic amines such as methylamine, tri-ethylamine and picoline. The selection of the appropriate salt can be important such that the ester is not hydrolyzed. The selection criteria for the appropriate salt are known to the person skilled in the art. b) "stereoisomers" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric isomers (cis / trans), and isomers of compounds with more than a chiral center that are not mirror images between them (diastereoisomers). c) "Alkyl" refers to a straight or branched chain alkyl group specified by the amount of carbon atoms in the alkyl group, for example, C4-C20 alkyl refers to a straight or branched chain alkyl having four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty carbon atoms or any range within this framework, such as, for example, without limitation, C5-C20, Cl-C15, C3-C15, C5-C15, C7-C15, and C7-C9. d) The term "patient" refers to a warm-blooded animal such as rats, mice, dogs, cats, guinea pigs, and primates such as humans. e) "Treat" c "treatment" refers to the relief of symptoms, elimination of the cause of the symptoms either temporarily or permanently, or to avoid or diminish the appearance of symptoms of a named disorder or condition. f) The term "therapeutically effective amount" refers to an amount of the compound that is effective for the treatment of the disorder or condition named. g) The term "pharmaceutically acceptable carrier" refers to ur. solvent, dispersant, excipient, adjuvant or other non-toxic material that is mixed with the compound of the present invention in order to allow the formation of a pharmaceutical composition, ie, a dosage form capable of being administered to the patient. An example of a vehicle of this type is a pharmaceutically acceptable oil typically used for parenteral administration. h) The term "restorative sleep" refers to a dream that produces a resting state upon awakening; i) the term "sleep disorder" refers to insomnia and Obstructive Sleep Apnea; j) the term "insomnia" refers to primary insomnia, insomnia related to another mental disorder, as well as insomnia induced by substance; k) the term "primary insomnia" refers to the difficulty of falling asleep, maintaining sleep or having a restorative sleep that is not caused by a mental disorder or caused by the physiological effects of taking or stopping certain substances (induction by substance ). As it is used here, it also includes insomnia of the circadian rhythm which is an insomnia due to the change of the normal sleep-wake regime (change of shift, changes caused by airplane displacements, etc); 1) the term "insomnia related to another mental disorder" refers to the difficulty of falling asleep, maintaining sleep or having a restorative sleep that is caused by an underlying mental illness such as depression, anxiety or schizophrenia; ) the term "substance-induced insomnia" refers to the difficulty of falling asleep, maintaining sleep or having restorative sleep, caused by the physiological effects of taking or stopping certain substances such as caffeine, alcohol, amphetamine, opioids, sedatives, hypnotics and anxiolytics; and n) the term "Obstructive Sleep Apnea" refers to repeated episodes of upper airway obstruction during sleep and is usually characterized by loud snoring or brief gasps that alter with episodes of silence. The (+) - isomer of (2-, 3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol can be prepared by methods described in US Pat. No. 5,134,149.

A suitable method is presented below. SCHEME I - Initial materials on In step A of Reaction Scheme I, an esterification reaction is carried out between racemic alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol. (structure 1) and the (+) isomer of alpha-methoxyphenylacetic acid (structure 2). This esterification produces the diastereomeric mixture identified as structure 3. These diastereomers are subjected to chromatography on silica gel separating the two diastereomers, thus isolating the diastereomer (+, +) as shown in step B. In step C, the diastereomer (+, +) is hydrolysed which produces the (+) isomer of alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -. - piperidinemethanol. The esterification reaction can be carried out using known techniques. Typically, approximately equivalent amounts of racemic alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol and the (+) - isomer of alpha-methoxyphenylacetic acid come into contact in a organic solvent such as for example methylene chloride, THF, chloroform or toluene and heated to reflux for a period of time which is within a range of 5 to 24 hours. The esterification is typically carried out in the presence of an equivalent amount of dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-dimethylaminopyridine (DMAP). The resulting diastereomers can be isolated by filtration of the dicyclohexylurea and evaporation of the filtrate. The diastereomers are then subjected to chromatography on silica gel separating the diastereomers (+, +) and (-, +). This chromatographic separation can be carried out as is known in the art. A 1: 1 mixture of hexane and ethyl acetate is a suitable eluent.

The resulting diastereomer (+, +) is then subjected to a hydrolysis reaction that produces the (+) - enantiomer of alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol . The hydrolysis is effected by contacting the diastereomer with an excess of a base such as, for example, potassium carbonate in an aqueous alcoholic solution. The hydrolysis is carried out at a temperature of about 15 to 30 ° C for a period of time which is within a range of 2 to 24 hours. The resulting (+) - isomer of alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol can then be recovered by dilution with water and extraction with methylene chloride. It is then purified by recrystallization from a solvent system such as cyclohexane / hexane or ethyl acetate / hexane. Methods for the production of the starting materials of Reaction Scheme I are known in the art. For example, U.S. Patent No. 4,783,471 teaches how to prepare racemic alpha- (2,3-diyethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol. This patent is incorporated herein by reference. Examples 1 and 2 of this application also teach suitable methods. Alternatively, racemic alpha- (2, 3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -piperidinemethanol can be prepared in the following manner. Initially 4-hydroxypiperidine is subjected to an N-alkylation reaction with p-fluorophenylethyl bromide which produces 4-hydroxy-1- [2- (4-fluorophenyl) ethyl] -piperidine. This compound is brominated with Ph ^ P-Br ^ which produces 4-brcmo-l- [2- (4-fluorophenyl) ethyl] piperidma. This compound is put in contact with Mg forming a Grignard reagent which then reacts with 2,3-dimethoxybenzaldehyde which produces the desired product (±) -alpha- (2,3-dimethoxyphenyl) -1- [2- ( 4- fluorophenyl) ethyl] -4-p? Per? Dinmetanol. The (+) - isomer of alpha-methoxyphenylacetic acid is known in the art. i n -QOTTVMI. TT FORMULA I With reference to scheme II, X is chlorine or bromine, chlorine 5 being preferred and R is in accordance with the previously defined. This reaction scheme shows the formation of the sustained release compounds of the formula I from the alcohol (5). The alcohol (5) reacts with an acid halide (RC (O) X), RC02H or acid anhydride (RCO) in the presence of a sufficient amount of appropriate base. An appropriate base is a base that allows the formation of mat from an acid halide or anhydride. Examples of suitable bases are trialkylase, pyridine as for example dimethylaminopyridine, diisopropylethylamines, N-methylmorpholines, with triethylamine being preferred. A sufficient amount of the base can be determined by an expert in? the matter which allows the formation of the compounds of the formula I. 15 Preferably, the base is added to alcohol (5) acid in an appropriate solvent. Examples of solvents all of which are readily available, with the The temperature of the reaction can be within a range of about 0 to 25 ° C. The reaction mixture can be stirred for a few hours until overnight to increase the reaction. 25 catalysts can also be added to improve the reaction times, for example, 4-dimethylaminopyridine or the like. The starting materials for the acid halide (RCOX) are readily available to those skilled in the art. For example, the company Aldrich Chemical provides stearoyl chloride, heptadecanoyl chloride, palmitoyl chloride, myristoyl chloride, isovaleryl chloride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonaoyl chloride, decanoyl, undecanoyl chloride and lauroyl chloride. For acid halides that are not readily available, one skilled in the art can prepare the desired acid halide. For example, a carboxylic acid can be mixed with a halide donor in order to produce the desired acid halide. An example of this is the mixture of carboxylic acid (0.17 mol), methylene chloride (660 mL) and dimethylformamide (0.5 mL) under a nitrogen atmosphere. Oxaiyl chloride (0.2 mol) is added over a period of about 5 minutes with stirring. It is stirred at room temperature for 3 hours and the solvent is evaporated in vacuo to the acid chloride. Another method is to dissolve the carboxylic acid (10 μmol) in methylene chloride (50 mL). It is cooled to 0 ° C, placed under a nitrogen atmosphere and thionyl chloride (11 mmol) is added dropwise. It is stirred at room temperature for several hours and the volatiles are supported in vacuo to provide the acid chloride. The carboxylic acids are readily available or can be easily processed by experts in the art. The starting materials for acid anhydrides (RC0) 0 are readily available to those skilled in the art. For example, the company Aldrich Chemical provides butyric anhydride, isobutyric anhydride, valeric anhydride, 2,2-dimethylglutaric anhydride, and phthalic anhydride. Alternatively, acid anhydrides can be synthesized by methods well known in the art. Initial materials for acids (RC02H) are readily available or can be synthesized by methods well known in the art. For example, see Advanced Organic Chemistry, Reactions, Mechanism, and and structure), 4th ed. John Wiley & Sons, New York 1992, which is incorporated herein by reference. The company Aldrich Chemical Company also offers isovaleric acid, valeric acid, tert-b-thyl acetic acid, 2, 2-dimethylbutyric acid, 2-ethylbutyric acid, hexanoic acid, 3-methylvaleric acid, 4-methylvaleric acid, heptanoic acid, octanoic acid, SC luO U.pCYTC3.X? OX CO aC X nO _ 3.U.2T 1 CO SC 1 QO 1l 2 X CÍT C3.p.01 CO / 3.C XQ.O Myristoleic, myric acid, pentadecenoic acid, palmitic acid / heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid, as well as others wherein R is between four and twenty alkyl groups. The following examples are presented only to further illustrate the invention. However, they should not be considered as limiting the invention in any way.

Example 1, steps A-D, demonstrates the preparation of the initial material (±) -alpha- (2, 3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, 'structure 1, Scheme T A) 1- [2- (4-fluorophenyl) ethyl] -4-piperidinecarbpxamide A solution of isonipecota ida (10.9 g, 85.0 mmol), bromide rf pC ¿- _, a temperature of 90-95 ° C during the night. The cooled solution was concentrated to a white oily solid. The solid was divided between water and CHC1; The layers -u. -i. T-n c-combined organic layers were washed twice with water, dried (MgSO,), filtered, and evaporated to an oily solid. The solid was recrystallized from EtOAc to give 1- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxamide as a white powder, melting point 177-178 ° C (dec.). Calculated for C; 4H ::. FN_0: C, 67.18; H, 7.65; N, 11.19. Found: C, 67.25; H, 7.67; N, 11.13. B) 4-cyano-l- [2- (4-fluorophenyl) ethyl] piperidine To stirred phosphorus oxychloride (25 L, 41.12 g, 268 mmol) and sodium chloride (5.1 g, 87.3 mmol) was added in portions - [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxamide (8.9 g, 35.6 mmol). After finishing the addition, the solution was refluxed for 2 hours. The cooled solution was carefully poured into dilute NH 4 OH to destroy POCI 3. The aqueous solution was cooled to a temperature of 0 ° C, and then extracted 2 times with CHC1. The combined organic layers were dried (MgSO), filtered and evaporated to provide 8.1 g of an oily solid. The solid was distilled (boiling point 150 ° C, 0.1 mm Hg), This material was crystallized from hexane to provide 4-cyano-1- [2- (4-fluorophenyl) ethyl] piperidine as white needles, melting point 47-48 ° C. Calculated C) 1- [2- (Fluorophenyl) ethyl] -4-piperidinecarboxaldehyde c L l l j ^ x a la l ü \ l, and j,. _ > u 1 111 and ¿. U uj-j, / Cl 0 ° C DIBAL-H (4.6 L of a 1.0 M solution in THF, 4.6 mmol) was added through a syringe. After stirring overnight at room temperature, a 10% aqueous solution of HCl (25 L) was added and the solution was stirred for 3 hours. The whole mixture was then poured into 10% aqueous NaOH (50 mL), then extracted twice with ether. 5 The combined organic layers were washed with brine, dried (MgSO,), filtered, and evaporated to give a pale yellow oil. The oil was subjected to gel chromatography. silica, eluting with EtOAc. The appropriate fractions were combined and evaporated to provide an oil. This oil was distilled (boiling point 166 ° C, 0.05 mm Hg) to give l- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxaldehyde, obtained as a colorless oil. Calculated for C ^ H ^ FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08, H, 7.81; N, 5.86. i D i-, j \) a ± a \, ~ > ui iuci ia i i i i i). . { -i i. x. \ ** ± * i * c u * ¡- 1 piperidinmethanol After stirring for 2.5 hours, the solution was cooled to a temperature of -78 ° C and treated with l- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxaldehyde (1.30 g, 5.5 g of cooling bath was removed). and the stirring of the solution was allowed for 2 hours.Water was added, the layers were separated, and the aqueous layer was extracted with EtOAc The combined organic layers were washed with brine, dried (MgSO.sub.4), filtered, and chromatographed on silica gel eluting with acetone The appropriate fractions were combined and evaporated to give a white solid The solid was recrystallized from hexane to give alpha (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinmethanol racemic in the form of bright white needles, melting point 126-127 ° C. Calculated for C2H_ = FNO;: C, 70.75; H, 7.56; N, 3.75. Found: C, 70.87; H, 7.65; N, 3.68 EXAMPLE 2 - initial material Example 2, AF steps, demonstrate an alt form Preparation of (±) -alpha (2, 3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) -ethyl] -4-piperidinemethanol, structure 1. A) 1- (1,1-dimethylethyl) acid 1-piperidinecarboxylic acid To isonipecotic acid (107.5 g, 832 mmol) stirred in INN NaOH (40 g NaOH in 900 raL of H: 0) and tert-butanol (1800 mL) was added di-tert-butyl dicarbonate (200 g), 916 mmol) in portions. After stirring overnight, the solution was concentrated and the resulting water layer was acidified with aqueous HCl. The aqueous acid layer was extracted 3 times with ether. The combined organic layers were washed with water, brine, dried (MgSO.), Filtered and evaporated to a white solid, which was recrystallized from EtOAc / hexane (300 mL / 200 mL) to give acid 1- ( 1,1-dimethylethyl) -1,4-piperidinecarboxylic acid as white needles, melting point 147-149 ° C. B) 4- (N-methoxy-N-methylcarboxaptido-1-piperidinecarboxylic acid A) 1,4-dimethylethyl ester a stirred solution of 1- (1,1-dimethylethyl) -1,4-piperidinecarboxylic acid (50.0 g, 218 mmol) in H; C1_ anhydrous (500 L) in N; 1, 1'-carbonyldiimidazole (38.9 g, 240 mmol) was added in portions in a 2 liter flask. After stirring for 1 hour, N, O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol) was added in one portion. After stirring overnight, the solution was washed twice with IN HCl, twice with saturated NaHCOj, once with brine, dried (MgSO, a), filtered and evaporated in an oil. Distillation afforded 4- (N-methoxy-N-methylcarboxamido) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester in the form of a clear oil, boiling point 120-140 ° C, 0.8 mm. C) 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid 1-l-dimethylethyl ester. N-Butyllithium (14.5 mL of a 2.5 M solution in hexane, 36.3 mmol) was added via a stirred veratrol syringe. (5.00 g, 36.2 mmol) in THF (50 mL, anhydrous) in argon at a temperature of 0 ° C. The ice bath was removed and the mixture was stirred for 90 minutes. The mixture was cooled to a temperature of -78 ° C and treated with 4- (N-methoxy-N-methylcarboxamido) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (9.20 g, 33.8 mmol) in THF (50 mL , anhydrous) through a syringe. The acetone bath at dry ice cooling temperature was removed and the mixture was allowed to return to room temperature. After stirring for 3 hours, saturated aqueous NHC1 was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried (MgSO), filtered, and evaporated to give an amber oil. The oil was chromatographed on silica gel, eluting with 20% EtOAc in hexane. The appropriate fractions were combined and evaporated to an amber oil. The oil was distilled to provide 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester in the form of a colorless oil. (Boiling point 225-250 ° C, .05 mm). Calculated for C15H: -NO;: C, 65.31; H, 7.79; N, 4.01. Found: C, 65.04; H, 7.92; N, 4.11. D) 4- (2,3-dimethoxyphenyl) -4-piperidinylmethanone 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid (1, 1-dimethylethyl ester (7.75 g, 22.2 mmol) was dissolved in trifluoroacetic acid (50%). mL, 650 mmol) and stirred for 45 minutes. The whole solution was drained in ether (900 mL) and allowed to stand overnight. Filtration afforded 4- (2,3-dimethoxyphenyl) -4-piperidinylptetanone trifluoroacetate in the form of fine white needles, melting point 123 ° C. Calculated for C? H19N03.CF3CO; H: C, 52.89; H, 5.55; N, 3.86. Found: C, 52.77; H. 5.62; N, 3.82. The resulting 4- (2, 3-dimethoxyphenyl) -4-piperidinylmethanone trifluoroacetate was dissolved in water, treated with NaOH (10% aqueous) until basic, and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried (MgSO 4), filtered, and evaporated to give 4- (2,3-dimethoxyphenyl) -4-piperidinylmethanone in the form of an oil.

E) (2,3-dimethoxyphenyl) [l- [2- (4-fluorophenyl) ethyl] -4-piperidinyl] ethanone monohydrochloride A solution of 4- (2,3-dimethoxyphenyl) -4-piperidinylmethanone (8.00 g, 32.1 mol) and 2- (4-fluorophenyl) ethyl bromide (6.52 g, 32.1 mmol) was prepared in DMF (90 mL), treated with K_CO; (8.0 g, 50.7 mmol), then stirred and heated to a temperature of 80 ° C under argon overnight. The cooled solution was drained in a ratio of 2/1 EtOAc / toluene and water. The layers were separated and the aqueous layer was extracted with 2/1 EtOAc / toluene. The combined organic layers were washed twice with water, once with brine, dried (MgSO 4), filtered and evaporated to provide 11.0 g of an oil. The oil was subjected to chromatography on silica gel, eluting with EtOAc. The appropriate fractions were combined, concentrated, dissolved in ethyl acetate, and treated with HCl / ethyl acetate. There was obtained (2,3-dimethoxyphenyl) [1- [2- (4-fluorophenyl) ethyl] -4-piperidinyl] -methanone monohydrochloride in the form of a precipitate, mp 225-227 ° C (dec.). Calculated for C;: H;,; FN03.HC1: C, € 4.78; H, 6.67; N, 3.43. Found: C, 64.44; H, 6.732; N, 3.41. F) (±) -alpha- '2,3-dimethoxyphenyl) -l- 2- (4-fluorophenyl) ethyl] -4-piperidinemethanol To a stirred solution of (2,3-dimethoxyphenyl) [l- [2- ( 4-fluorophenyl) ethyl] -4-piperidinyl] methanone (6.0 g, 16.2 mmol) in MeOH (100 mL) at a temperature of 0 ° C was added NaBH (1240 mg, 32.8 mmol) in two portions, over a period of one hour. After stirring overnight, the solution was concentrated in a solid. The solid was divided between water and ether. The layers were separated and the aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried (MgSO), filtered, and evaporated to a solid. The solid was subjected to chromatography on silica gel, eluting with acetone. The appropriate fractions were combined and evaporated to give a white solid. The solid was recrystallized from cyclohexane to give (±) -alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) -ethyl] -4-piperidinemethanol as white needles, melting point 126-127 ° C. Calculated for C 22 H 28 FN 0 3: C, 70.75; H, 7.56; N, 3.75. Found: C, 70.86; H, 7.72; N, 3.93. EXAMPLE 3 - Initial material This example demonstrates alcohol preparation, structure Preparation of (+) - alpha- (2,3-diptetoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol A) Preparation of diastereomers A solution of 3.90 g (10.4 mmol) of (±) -alpha- (2,3-amethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, 1.74 g (10.4 mmol) of S- (+) - alpha-methoxyphenylacetic acid, 2.15 g (10.4 g) mmol) of 1,3-dicyclohexylcarbodiimide and 0.1 g of 4-dimethylaminopyridine in chloroform (75 mL) was refluxed for 17 hours, allowed to cool to room temperature and filtered. The filtrate was concentrated and chromatographed on a column of silica gel eluting with ethyl acetate / hexane (1: 1) to give two diastereomers, Rf = 0.1 and 0.2 (TLC EtOAc / hexane, 1: 1). Intermediate fractions were rechromatographed to provide additional material. These fractions with Rf = 0.2 were combined to provide a diastereomeric ester, (+, +) - (2,3-dimethoxyphenyl) [l- [2- (4-fluorophenyl) ethyl] -4-piperidinyl] methyl-alpha acetate. -methoxybenzene. 3) Preparation of (+) - alpha - (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol To a stirred solution of 0.97 g (1.9 mmol) of the diastereomeric ester mentioned above , Rf = 0.2, in 25 mL of methanol 0.5 g (3.6 mmol) of potassium carbonate and 5.0 mL of water were aggressed. After stirring for 17 hours at room temperature, the reaction mixture was diluted with water and extracted twice with methylene chloride. The cor bred extracts were washed with water, brine and dried in MgSC. After filtration, the filtrate was concentrated to an oil and crystallized from 40 L of cyclohexane / hexane (1: 1) to give (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine etar.ol, mp 112-113 ° C, [a] "= + 13.9 ° EXAMPLE 4 Decanoate of (+) -a- (2, 3-dimethioxifer. ? l) -1- [2- (4-fluorophenyl) et l -4-piperidinemethanol A mixture of 49.0 g (0.131 mol) of (+) -a- (2,3-dimethoxyphenyl) -I- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, 500 L of CHC13 and 16.0 g ( 0.158 mol) of triethylamine was loaded into a 3-liter necked flask equipped with a stirrer, thermometer, dropping funnel, and a continuous nitrogen purge. A solution of 27.4 g (0.144 mol) of decanoyl chloride in 25 mL of CHC13 was added for 5 minutes while maintaining a reaction temperature of 20-25 ° C. The resulting solution was stirred at 20-25 ° C for two hours. hours. The progress of the reaction was monitored by TLC (5/95 methanol / CH2Cl2; Merck plates 60F-254; UV; Rf of (+) - a- (2, 3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ) ethyl] -4-piperidine ethanol - 0.23, Rf of compound titled - 0.55). An additional 2.8 g (0.015 mol) of decanoyl chloride (Aldrich) and 1.6 g (0.016 mol) of triethylamine was added to the reaction mixture and stirred continuously for two hours. The reaction mixture was diluted with 500 mL of CHCCl: and washed with 150 mL of K: CO: - 5%, 250 L of H: 0 and 250 L of saturated NaCl. The organic phase was dried in 500 g of MgSO 4 and filtered. The filter cake was washed with 200 L of CH-C1; The filtrate was concentrated at a temperature of 40 ° C / 50 torr to provide an oil. The crude product was purified by flash chromatography (14 x 29 cm column, 2035 kg 230-400 mesh silica gel). The crude product was loaded into the column by dissolving in 75 L of E? L zr * -? * - The column was eluted with 24 L of 1/4 EtOAc / CH: Cl_ collecting 24 one liter fractions. The fractions that showed homogeneity according to TLC were combined and concentrated at a temperature of 35 ° C / 50 torr followed by 70 ° C / 0.5 torr for one hour to provide a colorless oil. MS (M + = 528) Analysis: Calculated for C: -; HIFO: (527.73): 72.83% C 8.79% H 2.65% N Found: 72.25% C 8.88% H 2.63% N EXAMPLE 5 Hexanoate of: +) - a- (2,3-dimethoxyphenyl) -l- [2- (4-flucro-phenyl) ethyl-4-piperidine-methane To a stirred solution of 2.0 g (5.37 mmol) of (+) -a- (2, 3-dimethyloxyphenii) -1- [2- (4-fluorophenyl) ethyl] - -piperidinemethanol in 6 L of dry methylene chloride was added. added 0.74 mL (0.537 g, 5.32 mmol) of triethylamine. The solution was cooled in an ice bath after which 1.07 mL (5.89 mmol) of hexanoic anhydride was added via syringe. The solution was stirred for several minutes at ice bath temperature and allowed to warm to room temperature. To the solution was added 66 mg (0.541 mmol) of 4-di-ethylaminopyridine. The mixture was stirred overnight at room temperature, poured into ice / water / 0.5M NaOH, extracted with ether, and filtered and concentrated to an oil. The oil was dissolved in methylene chloride, and methane! at 2% / methylene chloride, respectively. Fractions containing the pure product were combined and concentrated to provide an oil that was dried overnight at a temperature of 60 ° C, under high vacuum to provide the title compound. The compound was homogeneous according to TLC. IR (Kbr), NMR (CDC1?) And MS (MH * = 472) were consistent with a proposed structure. / Analysis: Calculated for C; .H; .FN0: 71.31% C 8.12% H 2.97% N Found: 70.94% C 8.07% H 2.88% N EXAMPLE 6 Octanoate of; +) -a- (2, 3-dimethoxyphenyl) -1- [2- (4-fluorophenylethyl] -4-piperi in methanol OCH, To a stirred solution of 2.0 g (5.37 mmol) of (+) -a- (2,3-dimethyloxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol in 6 mL of dry methylene chloride 0.74 L (0.537 g, 5.32 mmol) of triethylamine was added. The solution was cooled in an ice bath after which 1.75 mL (5.89 mmol) of octanoic anhydride was added by syringe. The solution was stirred for several minutes at ice bath temperature and allowed to warm to room temperature. To the solution were then added 66 mg (0.54 1 mmol) of 4-dimethylaminopyridine. The mixture was stirred, washed with water and saturated sodium chloride. The organic extract was dried (Na2SO4), filtered and concentrated to form an oil. The oil was dissolved in methylene chloride and purified by flash chromatography on silica gel, eluting with methylene chloride, 1% methanol and 2% methylene chloride, respectively. Fractions containing the pure product were combined and concentrated to provide an oil that was dried overnight at a temperature of 60 ° C under high vacuum to provide the title compound. The compound was homogeneous according to TLC. The IR (KBr), NMR (CDC12) and MS (MH + = 501) were consistent with the proposed structure. Analysis: Calculated for C-3rH4: FN0: 72.11% C 8.47% H 2.80% N Found 71.94% C 8.63H 2.83% N EXAMPLE 7 Hexadecanoate; +) -a- (2, 3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol To a stirred solution of 2.00 g (5.36 mmol) of (+) - a- (2,3-dimethyloxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethane in 6 mL of dry methylene chloride 0.76 L (5.46 rn ol) of triethylamine was added through a syringe after which the solution was cooled in an ice bath. To the solution was added 2.92 g (5.89 mmol) of hexadecanoic acid anhydride after which the mixture was stirred at a temperature of 0 ° C for 15 minutes. The reaction mixture was allowed to warm to room temperature and to the reaction mixture was added 65 mg (0.536 mmol) of 4-dimethylaminopyridine after which the solution was stirred under nitrogen overnight. The reaction mixture was poured into 50 L of 0.5 N sodium hydroxide and 50 mL of diethyl ether. A certain precipitate was observed and the resulting suspension was extracted with methylene chloride.

The methylene chloride layer was washed with water and brine, and dried over sodium sulfate, filtered and concentrated to form a yellow oil. The oil was dissolved in methylene chloride and purified by using flash chromatography column packed with silica gel and methylene chloride and eluted with the same solvent system followed by 1% and 2% methanol / methylene chloride, respectively. The appropriate fractions were combined and concentrated until a yellow oil was obtained. The oil was dried twice overnight at a temperature of 60 ° C under high vacuum to provide the title compound. The compound was homogeneous according to TLC. IR (film, NMR (CDC13) and MS (MH + = 612) were consistent with the proposed structure. Analysis: Calculated for C4H3.FNO_;: 74.59% C 9.55IH 2.29% N Found: 74.34% C 9.45% H 2.29% N EXAMPLE 8 2, 2-dimethyloctanoic acid (+) -a- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol 2-Hexen-1-mesylate is prepared by the addition of N, N-diisopropylethylamine (12.9 g, 0.1 m) to a solution of trans-2-hexen-l-ol (10.0 g, 0.1 m) (Aldrich) in 100 ml. mL of methylene chloride. Methanesulfonyl chloride (12.6 g, 0.11 m) in methylene chloride (50 mL) is added dropwise with stirring at room temperature for 4 hours. The reaction mixture is transferred to a separatory funnel and washed with cold 1N HCl (2 times) and then with a saturated NaHCO- (2 times) solution. The solution is dried in anhydrous MgSO 4, filtered and concentrated, under vacuum at 40 ° C to provide 2-hexen-1-mesylate. 2, 2-Dimethyl-3-octene nitrile is prepared by the addition of 2-hexen-l-mesylate (11.02 g, 0.05 m) in anhydrous THF (100 mL) to a solution prepared by the addition of isobutyronitrile (3.7 g). , 0.053 m) in THF (25mL) after treatment with NaH (60% in mineral oil) (2.1 g, 0.053 m) in dry THF (50mL). The resulting reaction mixture is stirred at reflux for 5 hours, cooled and stirred with cold (95%) ethanol and concentrated in vacuo to remove solvents. After addition of water (50mL) the mixture is extracted with diethyl ether (3x40p.L). The extracts are washed with water and then a saturated solution of NaCl and dried in MgSO, filtered and concentrated to provide 2,2-dimethyl-3-octene nitrile. 2, 2-Dimethyl-3-octenoic acid is prepared by the addition of 2,2-dimethyl-3-octene nitrile (1.51 g, 0.01 m) to a solution prepared from 15% NaOH in butanol / H: 0 (2: 3) (30 L). The reaction mixture is stirred and refluxed for 7 hours, cooled and acidified with 10% hydrochloric acid. The reaction mixture is extracted with diethyl ether and the extract is washed with saturated NaCl and dried over MgSO4, filtered and concentrated to give 2,2-dimethyl-3-octenoic acid. The 2,2-dimethyloctanoic acid is prepared by dissolving 2,2-dimethyl-3-octenoic acid (0.20 g, 1.1 mmol) in absolute ethanol in N2 and 10% palladium in carbon which is then hydrogenated for 6 hours. The catalyst is removed by filtration and the filtrate is concentrated under vacuum to provide acid., 2-dimethyl-3-octenoic. To a stirred solution of (+) -a- (2,3-dimethyloxyphenyl) -1- [2- (4-fluorophenyl) ethyl j-4-piperidinemethanol (3.9 g, 10.4 mmol) in 70 ml of methylene chloride was added. add dicyclohexylcarbodiirnide (2.15 g, 10.4 mmol), 4-dimethylaminoinopyridine 0.1 g, and 2,2-dimethyloctanoic acid (1.70 g, 10.4 mmol). The resulting solution is stirred and refluxed for 16 hours. The cooled reaction solution is filtered and concentrated to an oil. The resulting oil is chromatographed on silica gel and eluted with ethyl acetate / hexane (1: 1). Appropriate fractions are collected, said fractions are heated (40 ° C) and concentrated under reduced pressure to provide the title compound. EXAMPLE 9 This example demonstrates a pharmaceutical composition of the present invention. In a suitable 100 mL volumetric vessel, place 70 mL of Sesame Oil (sesame oil) NF (Sigma), 1.2 g of benzyl alcohol, NF and 14,129 g of decanoate of (+) -a- (2, 3- dimethyloxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol. To this solution is added a sufficient amount of Sesame Oil (sesame oil) NF to bring the volume to 100 mL and mix until homogeneous. This solution can be sterilized and packaged for parenteral injection. EXAMPLE 10 This example describes a behavior test (antagonism of behavior induced by DOI), designed to identify compounds that have an antagonistic activity in the 5HT2 ?. The compound of the present invention in this test was decanoate of (+) -a- (2,3-dimethyloxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol-example 4 here. The 5-HT2A / 2C agonist of (±) -DOI HCl (1- (2, 5-dimethoxy-4-iodophenyl) -2-aminopropane hydrochloride induces several quantifiable behaviors in rats.These behaviors include "tremors" (a rapid shaking of the head and body, such as in the case of wet dog tremors), "tapping of the front legs" (rapid treading of the front legs) as well as "cutaneous spasms" (paraspinal muscle contractions or shaking) dorsal cutaneous) The 5-HT2 antagonists mianserin, ritanserin and methiserguide as well as the selective 5-HT2A antagonist MDL 100.907 block the effects on DOI behavior in a dose-dependent manner (Pranzatelli, 1990, Neurosci, Let. : 74-80 ettstein et al., 1996, Soc. Neurosci, Abs.22: 481) Significantly, drugs with 5-HT2A antagonist activity have been proposed which have atypical antipsychotic properties in schizophrenic patients (Meltzer et al. , 1989, JPET 251 : 238-246), as well as a potential therapeutic activity in numerous other central nervous system disorders including depression, dysthymia and anxiety (Stefanski & Goldberg, 1997, CNS Drugs, 7: 399-409). Methods Subjects and housing Male Sprague-Dawley rats (180 ± 50 g) were housed at seven rats per cage and acclimated to the vivarium for one week. Food and water were freely available. The temperature and light cycle (12 hours of light - 12 hours without light) was maintained automatically. The individual rats were tested once. Each test group contained seven animals, the experiments were carried out in the vivarium room where the animals were housed. Pharmacological preparation and administration Decanoate of (+) -a- (2,3-dimethyloxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethane (120 mg / kg equivalent to MDL 100.907) was dissolved in oil of sesame and was administered intramuscularly to separate groups of rats on day 0 in a volume equal to 60 mL / 100 g of body weight. Control animals received only sesame oil. (±) -DOI HCl (3.0 mg / kg, I mL / kg of body weight) was dissolved in distilled water with the help of an ultrasonic bath, and injected intraperitoneally on the appropriate examination days. Observation and evaluation of behavior Rats treated with decanoate of (+) -a- (2,3-dimethyloxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol were tested to determine the antagonism of the behaviors induced by DOI 1, 5, 7, 14, 21, 28 and 40 days after a single intramuscular injection of decanoate of (+) -a- (2, 3-dimethyloxyphenyl) -1- [2- (4- fluorophenyl) ethyl] -4-piperidinmetanci, each rat was tested once Immediately after the injection of DOI, the rats were placed under inverted clear plastic boxes (28 cm long x 25 wide x 25 high) placed on the part of a clean absorbent paper Rats were continuously observed by trained observers (blind in relation to treatment) for 30 minutes to determine the occurrence of DOI-induced behaviors (tremors, skin spasms, as well as tapping of the front legs) and then returned to their cages The rats were subsequently used for pharmacokinetic studies. The frequencies of behaviors induced by DOI were recorded and then added together to provide a unique behavioral result for each animal. Data Analysis The mean and standard error of the behavior results of each group was determined. Each treatment group mean was then compared separately with the mean of the control group that received the vehicle, using a one-way analysis of variance analysis (ANOVA)., followed by a Bonferroni / Dunndsr post-hoc comparison. The differences between the groups were considered statistically significant if the p values were less than 0.05 or equal to 0.05. Results A significantly induced DOI-induced behavior was observed in the rats during a 28-day period. The effect was no longer significant for day 40. EXAMPLE 11 This example demonstrates the absorption of a single dose of MDL 100.907 after intramuscular administration (im) of decanoate of (+) -a- (2,3-dimethyloxyphenyl) -1 - [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, a compound of the present invention with the passage of time. A total of ninety ninety Wistar male rats weighing approximately 150-200 grams each receive an i.m. of decanoate of (+) -a- (2, 3-dimethyloxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol in sesame oil (equivalent to 120 mg / kg of MDL 100.907) day 0. Rats are anesthetized with a dose ip Nembutal lethality and blood is collected at three and six hours, and several days after administration (n = 5 for each time point) in heparinized vacuum vessels. The blood samples are centrifuged for 30 minutes at a temperature of 5 ° C to about 2700 revolutions per minute. The plasma is removed and stored at -20 ° C until the test. Plasma samples are analyzed through an appropriate HPLC method. The brains are also collected at the aforementioned time points and a temperature of -80 ° C is stored until analysis by the appropriate HPLC method. The results are shown in Table 1. Time (+) - a- (2,3-decanoate (days) dimethyloxyphenyl) dimethyloxyphenyl) -1- [2- (4-fluorophenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol ethyl] -4-piperidinemethanol (ng / mL) -MDL 100.97 - example 4 here (ng / mL) 0.125 21.48 ± 8.00 54.18 ± 13.33 0. 25 24.30 ± 7.65 53.79 ± 17.13 1 32.00 ± 10.48 54.08 ± 17.98 2 25.59 ± 8.90 21.61 ± 7.39 3 25.48 ± 4.65 '38.95 ± 5.64 4 31.82 ± 10.22 52.02 ± 12.92 6 32.84 ± 11.83 41.87 ± 14.64 8 34.93 ± 11.36 28.70 ± 9.16 12 19.89 ± 5.65 21.00 ± 12.79 11.67 ± 6.18 52.36 ± 15.20 19 6.37 ± 2.19 40.06 ± 8.44 22 15.93 ± 2.45 46.30 ± 9.31 26 15.51 ± 7.15 38.92 ± 9.35 29 13.22 ± 4.54 43.71 ± 10.81 41 9.88 ± 3.81 24.12 ± 9.15 The dosage range in which the compounds of formula I exhibit their ability to block the effects of serotonin in the 5HT ^ receptor may vary according to the particular disease or particular condition to be treated and its severity, the patient, the formulation and other underlying disease states that the patient is suffering from, and other drugs that can be administered concurrently to the patient. In general. The compounds of formula I exhibit their 5HT; ...: serotonin antagonist properties in dosages ranging from about 0.001 mg / kg body weight per day to about 100 mg / kg body weight / day. The sustained release formulations may contain multiple of the above dosages according to the period during which the active ingredient is released. The dosage of the compounds of the present invention can be determined by administering the compound to an animal and by determining the plasma level of the active ingredient.

The compounds of the present invention can be mixed with a pharmaceutically acceptable carrier capable of being administered by the preferred route in order to produce a sustained release of the compound of the present invention such that a therapeutically effective amount of the compound (+) - a- (2,3-dimethyloxyphenyl) -1- [2- (4-fluorophenyl-ethyl] -4-piperidinemethanol can be delivered to the patient over a period of days or weeks Preferably, the sustained release formulation comprises a compound of the formula I and a pharmaceutically acceptable carrier for parenteral administration either in the form of an aqueous suspension, oil solution, oil suspension or erulsion., Such oils that can be used for intramuscular injection are sesame oil, olive oil, of peanut, corn, almond, cottonseed, and castor oil, sesame oil being preferred. Acceptable mind such as benzyl alcohol can also be added. The prolonged release formulation is preferably administered intramuscularly or subcutaneously, intramuscular administration being preferred, even when other routes of administration such as oral, transdermal, nasal spray, etc. are administered. They can be used as appropriate to the needs of the patient. Since the compounds of the present invention release (+) -a- (2,3-dimethyloxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol ("Active Ingredient") in a patient for the therapeutic effect, the compounds of the present invention They are useful for all indications of use for which the Active Ingredient is useful. Some of those indications for use have been described in the patents issued that generically encompass the Active Ingredient (US Patent No. 4,783,471) or that specifically embrace the Active Ingredient (US Patent Nos. 5,134,149; 5,561,144; 5,618,824; and PCT / US97 / 02597), all incorporated here by reference. These references disclose uses of psychosis (including schizophrenia) obsessive seizure disorder, thrombotic disease, coronary vasospasm, intermittent claudication, anorexia nervosa, Raynaud's phenomenon, fibromyalgia, extrapyramidal side effects, anxiety, arrhythmia, depression, as well as bipolar depression or drug abuse (for example, ***e, nicotine, etc.). Some of these indications have been disclosed in the patents described above and in US Pat. Nos. 5,561,144; 5,618,824; 4,877,798; 5,134,149; and 5,021,428; all of which are incorporated here by reference. Psychoses, as used here, are conditions in which the patient experiences a major mental disorder of organic and / or emotional origin characterized by a personality disorder and loss of contact with reality, often with delirium, hallucinations or illusions. Representative examples of psychotic diseases that can be treated with the compounds of the present invention include schizophrenia, schizophreniform disorder, schizoaffective disorder, delirium disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder not otherwise specified, as well as induced psychotic disorder by substance.

See Diagnostic and Statistical Manual of Mental Disorders (Manual of Diagnosis and Statistics of Diseases Mental), 4th. edition, American Psychiatric Association, which is incorporated herein by reference. The Active Ingredient is currently in clinical trials for the treatment of schizophrenia. Patients with obsessive-compulsive disorders (OCD) do not inhibit or "control" intrusive, disturbing ideas or images. Since OCD is characterized by a deficiency of "cognitive control" and an aberrant rabbatic activity in circuits that relate the orbital cortex to the stratum, it has been predicted that patients with OCD may present a poor pre-stimulation inhibition (PPI). The active ingredient restores the deranged PPI. See Psychopharmacol ogy 124: 107-116 (1996), R.A. Padich, et al., "5HT modulation of auditory and visual sensorimotor gating: II. Effects of 5HT2A antagonist MDL 100.907 on disruption of sound and light prepluse inhibition produced by 5HT agonists in Wistar rats" (modulation by 5HT of sensorimotor auditory and visual control : Effects of 5HT? A agonist of MDL 100.907 on the inhibition disorder of sound and light pre-pulsed produced by 5HT agonists in Wistar rats). The Active Ingredient is also effective for the prevention of acute thrombosis, especially coronary artery thrombosis. This compound decreases the rate at which platelets aggregate as a result of minor alterations in the endothelial lining of the vasculature and thus prevent the formation of acute pathological thrombi. See U.S. Patent No. 5,561,144 for description. Anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon and coronary vasospasm are used in the manner defined in edition 27 of Dorland's Illustrated Medical Dictionary, which is incorporated herein by reference. Fibromyalgia is a chronic disease state where the patient suffers from numerous symptoms such as generalized musculoskeletal pain, pain, fatigue, morning stiffness as well as sleep disorder that can be characterized as an inadequate stage 4 sleep. Extrapyramidal side effects frequently accompany the administration of neuroleptic agents such as haloperidol and chlorpromazine. The patient frequently experiences a Parkinson's syndrome, where patients experience muscle stiffness and tremors. Other patients present akathisia as well as acute dystonic reactions. The Active Ingredient increases the duration of the potential action of myocardial tissue producing an increase in the refractory period of this tissue, which, according to Vaughan Williams classification system, presents a class III anti-arrhythmic activity. The compounds of the present invention can be used to treat drug abuse in the patient. See, T.F. Meert, et al., European Journal of Pharmacology, 183: 1924, where a 5HT2 antagonist cancels the preference for alcohol and ***e in the rodent model of drug abuse. Other animal models such as the rodent self-stimulation model described in R.A. Frank, et al., Behavioral Neuroscience 101: 546-559 (1987) may be employed to demonstrate the ability of the compound of the present invention to treat drug abuse. The compounds of the present invention are useful in the treatment of patients with depressive disorders and bipolar disorders. In the Diagnostic and Statistical Manual of Mental Disorders (third revised edition) ("DSM-III-R"), which is incorporated herein by reference, depressive disorders are defined as major depression, disti ia, as well as depressive disorder NOS. We have included in this category a major depressive episode that includes chronic type, melancholy, stationary pattern. Bipolar disorders include bipolar disorder, cyclothymia as well as bipolar disorder NOS. A characteristic of depressive disorders is one or several periods of depression without a history of manic or hypomanic episodes. A characteristic of bipolar disorders is the presence of one or several manic or hypomanic episodes usually accompanied by one or several major depressive episodes. A manic or hypomanic episode is a distinct period during which the predominant mood is either elevated, expansive or irritable and there are associated symptoms of manic syndrome as defined in DSM-III-R. The disorder is severe enough to cause a significant impact in terms of professional or social functioning. Major depression has one or several major depressive episodes. A major depressive episode is characterized by: (i) at least five of the following: depressed mood, loss of interest in pleasure (anedonia), significant weight loss or significant weight gain when not on a diet, insomnia either hypersomnia, agitation or psychomotor retardation, fatigue or loss of energy, feeling of lack of value or excessive or inappropriate guilt, diminished ability to think or concentrate or recurrent thoughts of death including suicide; (2) it can not be established that an organic factor initiated and maintained the disorder; (3) there is no delirium or hallucinations for up to two weeks in the absence of prominent mood symptoms; and (4) it does not appear in addition to schizophrenia, schizophreniform disorder, delirium disorder or psychotic disorder NOS. The disti ia has a history of a depressed mood most of the time during at least two years and during the first two years of the disorder the condition does not meet the criteria for a major depressive episode. Depressed mood in children and adolescents can be demonstrated through irritability. It also presents at least two of the following: lack of appetite or excess of appetite, insomnia or hypersomnia, low energy or fatigue, low self-esteem, insufficient concentration or difficulty making decisions or feeling of hopelessness. These symptoms are not combined with a chronic psychotic disorder such as schizophrenia or delirium disorder. It can not be determined that an organic factor has initiated and maintained the disorder. There are many ways to show that the compound of the present invention is useful in the treatment of depressive disorders and bipolar disorders such as in animal models. See, for example, "Animal Models as simulations of depression", by Paul Willner, TIPS 12: 131-136 (April 1991); "Animal Models of Depression: An overview" (Models of Depression Animals: General), by Paul Willner, Pharm. Ther. 45: 425-455 (1990), both are incorporated herein by reference. One model of this type is the mild chronic depression depression model ("CMS") 1. CMS employs mild stressors such as food and water deprivation, small temperature changes, changes in cagemates, etc. Over a period of weeks of exposure to mild stressors, the animals gradually reduce their intake of a highly preferred sucrose solution which persists (in untreated animals) for several weeks after the suspension of stress.This diminished sensitivity to reward (the sucrose solution) it reflects an anemia, a symptom of major depressive episode (see, for example, Behavioral Pharmacol.5: Suppl.1, page 86 (1994) where lithium, carbamazepine and ketoconazole were evaluated in CMS; Psychopharmacology 93: 358-364 (1987) ) where a tricyclic antidepressant was evaluated in CMS, Behavioral Pharmacology: 5: 344-350 (1994) where a catechol-O-methyltransferase inhibitor was evaluated in CMS). CMS was carried out using the Active Ingredient of the compounds of the present invention (hereinafter "MDL 100.907") compared to imipramine, a known antidepressant compound. Male Wistar rats were taken to the laboratory two months before the start of the experiment and at that time they weighed approximately 300 grains. Except as described above, the animals were housed individually, with free water and aliquots, and were kept in a 12-hour light / dark cycle (lights on at 8 AM) at a temperature of 22 ± ° C.

The animals were then trained to consume a 1% sucrose solution; the training consisted of eight baseline tests of 1 hour where the sucrose was presented, in the domicile cage, after 14 hours of deprivation of water and food; Intake was measured by the weight of previously weighed bottles containing the sucrose solution at the end of the test. Subsequently, sucrose consumption was monitored under similar conditions at weekly intervals throughout the experiment. Based on their sucrose intakes in the final baseline test, the animals were divided into two corresponding groups. A group of animals underwent a mild chronic stress procedure for a period of 9 consecutive weeks. Each week of stress consisted of: two periods of food or water deprivation (12 and 14 hours), two periods of inclination of the cage at 45 degrees (12 and 14 hours), two periods of intermittent illumination during the night (lights on and off every 2 hours), two periods of 14 hours of dirty cage (200 ml of water in Sawdust bed), two periods of 14 hours of accommodation in pairs, two periods of 14 hours of low intensity strobe lighting (150 flashes / minute). The stress agents were applied continuously during the day and night and programmed randomly. The control animals were housed in a separate room and had no contact with the animals under stress. They were deprived of food and water during the 14 hours prior to each sucrose test, but other than that the food and water were freely available in the home cage. Based on their intake of sucrose, scores were determined after 3 weeks of stress, both in the case of stressed animals and in the case of control animals and these results were further divided into corresponding subgroups (n = 8) and for five subsequent weeks they received daily vehicle administrations (1 ml / kg, intraperitoneally (ip)) of imipramine (10 mg / kg, ip) or MDL 100.907 (0.002, 0.02 and 0.2 mg / kg orally).

All drug injections were in a volume of 1 ml / kg of body weight. The drugs were administered at 10 AM and sucrose tests were performed 24 hours after the last pharmacological treatment. After five weeks, the treatments were finished and after a week of removal a final sucrose test was performed. Stress continued during the period of treatment and withdrawal. The results were analyzed by multiple analysis of variance, followed by Fisher's LSD test for post hoc comparisons of means. The mild chronic tension caused a gradual decrease in the consumption of sucrose solution to 1%, in the final baseline test, the intake of sucrose was approximately 13 grams in both groups. After three weeks of stress (week 0), intakes remained at a level of 12.4 grams (± 0.4) in control animals but dropped to 7.2 grams (± 0.2) in stressed animals (p <0.001). Said difference between control animals and stressed animals treated with the vehicle persisted at a similar level for the remainder of the experiment. Imipramine had no significant effect on the intake of sucrose in control animals [F (1, 84) = 0.364; NS]. However, the drug caused a gradual increase in the intake of sucrose in stressed animals (F (1, 84) = 16,776, p <0.001.] The intake of sucrose in stressed animals treated with imipramine was significantly increased from the Results of week 0 after 4 weeks of treatment (p = 0.05) and after five weeks of treatment there were no significant differences between the stressed animals treated with drug and the control animals treated with drug and saline. Sucrose intake in stressed animals treated with imipramine was maintained at similar levels one week after drug discontinuation.MCD 100,907 had no significant effect on sucrose intake in control animals [treatment effect: F.3, 168) = 0.821; NS treatment x weeks of interaction: F (15, 168 = 0.499, NS] In stressed animals, CDM 100,907 caused a gradual inversion of the CMS-induced deficit in sucrose intake, which resulted in a significant treatment effect [F (3, 168) = 22,567, p <0.001] and treatment x weeks of interaction F (15,158) = 1,559, p = 0.05]. In stressed animals treated with two higher doses of MDL 100.907 (0.02 and 0.2 mg / kg), intakes of sucrose were significantly increased from the initial results (week 0) after two (0.02 mg / kg) and three (0.2 mg / kg) weeks of treatment (p = 0.03 and p = 0.04, respectively). This effect was increased during the following additional weeks, and at the end of the treatment period (week 5) the amount of sucrose solution obtained by these animals was comparable to the amount of the vehicle-treated controls and significantly greater than the amount of the stressed animals treated with vehicle (0.02 mg / kg: p <0.001, 0.2 mg / kg, p <0.002). In the lowest dose of 0.002 mg / kg, MDL 100.907 had no significant effect on the intake of sucrose during the entire treatment period. Consequently, after five weeks of treatment, the sucrose intake of stressed animals treated with this dose did not present a difference in intakes of the stressed animals treated with vehicle (p = 0.860) and was significantly lower than the intakes of the controls. treated with vehicle (p <0.01). One week after stopping treatment, sucrose intakes were not significantly changed in all control animals treated with MDL 100.907 (0.002 mg / kg: p = 0.2, 0.02 mg / kg: p = 0.9, 0.2 mg / kg: p = 0.4) and stressed animals treated with MDL 100, 907 (0.002 mg / kg: p = 0.6, 0.02 mg / kg: p = 0.8, 0.2 mg / kg: p = 0.6). Of course, clinical trials on humans can also be used to show the usefulness of the compound of the present invention for the treatment of depression using for example the Hamilton psychiatric qualification scale abbreviated for depression. This scale includes a series of 17 categories in which the individual is qualified, for example, in terms of depressed mood, sense of guilt, suicidal tendencies, insomnia, anxiety, etc., to achieve a result that tells the doctor if the patient is suffering from depression or not.

Claims (55)

1. CLAIMS 1. A compound of formula I: FORMULA I wherein R is C4-C alkyl: -, or a stereoisomer - or a pharmaceutically acceptable salt thereof.
2. 2. The compound according to claim 1 wherein R is straight chain alkyl.
3. 3. The compound according to claim 1 or 2 wherein R is C = -C;
4. 4. The compound according to claim 1 or 2 wherein R is C4-C:?.
5. 5. The compound according to claim 1 or 2 wherein R is C9-C15.
6. 6. The compound according to claim 1 or 2 wherein R is C-Z-C * -? .
7. 7. The composition according to claim 1 or 2 wherein R is C->. -C: =.
8. 8. The compound according to claim 1 or 2 wherein R is C7-C6.
9. 9. The compound according to claim 1 wherein the compound is (+) - a- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinir-ethanol decanoate.
10. 10. The compound according to claim 1 wherein the compound is (+) -a- (2, 3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol hexanoate.
11. 11. The compound according to claim 1 wherein the compound is (+) - a- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinnetanoi octanoate.
12. The compound according to claim 1 wherein the compound is (+) - a- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol hexadecanoate.
13. The compound according to claim 1 wherein the compound is 2,2-dimethyloctanoate of (+) - a- (2,3-dimethoxyphenyl) -l- [2- (4-fluorophenyl) ethyl] -4- piperidinmethanol.
14. 14. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
15. 15. The pharmaceutical composition according to claim 14 wherein R is straight chain C9 alkyl.
16. 16. The pharmaceutical composition according to claim 14 wherein the pharmaceutically acceptable carrier is a pharmaceutically acceptable oil.
17. 17. The pharmaceutical composition according to claim 16 wherein the oil is selected from the group consisting of sesame oil, olive, peanut, corn, almond, cottonseed, and castor oil.
18. 18. The pharmaceutical composition according to claim 17 wherein the oil is sesame oil.
19. 19. The pharmaceutical composition according to claim 14 wherein R is straight chain C9 alkyl and the carrier is sesame oil.
20. 20. The method for antagonizing the effects of serotonin at the 5HT2r receptor, which comprises administering a therapeutically effective amount of a compound according to claim 1 to a patient in need of said compound.
21. 21. The method according to claim 20 wherein R is straight chain C9 alkyl.
22. 22. The method according to claim 20 wherein the compound is administered intramuscularly or subcutaneously.
23. 23. The method according to claim 20 wherein the compound is administered intramuscularly, and the effects of serotonin on the 5HT2A receptor are antagonized from about 2 weeks to about one month.
24. 24. A method for the treatment of a patient for psychosis that comprises the administration to the patient requiring such therapy of a quantity? Therapeutically effective of a compound according to claim 1.
25. 25. The method according to claim 24 wherein the psychosis is schizophrenia.
26. 26. The method according to claim 24 wherein R is straight chain C9 alkyl.
27. 27. The method according to claim 25 wherein R is straight chain alkyl C.
28. 28. The method according to claim 24 wherein the compound is administered intramuscularly or subcutaneously.
29. 29. The method according to claim 25 wherein the compound is administered intramuscularly, and the patient is treated from about 2 weeks to about one month.
30. 30. A method for treating a patient for bipolar depression, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.
31. 31. A method for the treatment of a patient for depression, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.
32. 32. A method for treating a patient for anxiety, comprising administration to the patient.
33. A method for treating a patient for obsessive-compulsive disorder, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1, wherein said method comprises administering to a patient a therapeutically effective amount of a compound according to claim 1. 1.
34. 34. A method for the treatment of a patient for drug addiction, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.
35. 35. A method for the treatment of a patient for coronary vasospasm, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.
36. A method for the treatment of a patient for angina comprising administration to the patient of a therapeutically effective amount of a compound according to claim 1.
37. A method for treating a patient for thrombotic disease, comprising administering to the patient a therapeutically effective amount of a compound according to claim 1.
38. A method for making a compound of the formula I: FORMULA I wherein R is C4-C alkyl; or a stereoisomer or a pharmaceutically acceptable salt thereof; comprising the reaction of an alcohol (5) with an acid halide of the formula RC (0) X, an acid anhydride of the formula (RCO); or a carboxylic acid of the formula RC02H wherein R is in accordance with the previously defined and X is a chlorine or bromine atom, in the presence of a sufficient amount of an appropriate base to make the compound of the formula I. 39aN.
39. The method according to claim 38 wherein X is chloro.
40. 40. The method according to claim 38 wherein R is straight chain alkyl.
41. 41. The method according to claim 38 wherein R is C; -C: -:.
42. 42. The method according to claim 38 wherein R is C-C: 5.
43. 43. The method according to claim 38 wherein R is C6-C: 5.
44. 44. The method according to claim 38 wherein R is C-Ci3.
45. 45. The method according to claim 38 wherein R is C-Cc
46. 46. The method according to claim 38 wherein R is branched chain C9 alkyl.
47. 47. The method according to claim 38 wherein R is straight chain C9 alkyl.
48. 48. The method according to claim 38 wherein the base is triethylamine.
49. 49. The method according to claim 38 wherein R is straight chain C9 alkyl, the base is triethylamine, X is chlorine and the alcohol (5) reacts with the acid halide.
50. 50. The method according to claim 38 wherein the alcohol (5) reacts with RCOX.
51. 51. The method according to claim 38 wherein the alcohol (5) reacts with (RC0) 20.
52. 52. The method according to claim 38 wherein the alcohol (5) reacts with RC02H.
53. 53. The method according to claim 38 wherein the alcohol (5) reacts with RCOX wherein R is straight chain C9 alkyl and X is chloro.
54. 54. A compound according to claim 1 for use as a pharmaceutically active substance.
55. 55. The use of a compound according to claim 1 for the preparation of a pharmaceutical composition useful for antagonizing the effects of serotonin at the 5HT2a receptor.