BG65206B1 - 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 compounds antagonize the effects of serotonin at the 5HT2A receptor and are used for the treatment of various conditions, such as for example, psychoses such as schizophrenia. They have the formula wherein R is C4-C20 alkyl. The invention also relates to their pharmaceutical forms, to methods for their preparation and application.

Description

The compound (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl] -4-piperidinethanol, known as MDL 100,907, is a potential 5HT _2A receptor antagonist clinically tested for the treatment of schizophrenia (J. Pharm. Exp. Ther. 227: 968-9881 (1996), US 5 134 149).

BACKGROUND OF THE INVENTION

MDL 100,907 antagonizes the effects of serotonin at the 5HT _2A receptor and as such is useful for the treatment of various disease states. However, this compound may also act directly or indirectly to produce therapeutic effects other than its 5HT _2A antagonism. For example, see European Journal of Pharmacology 273: 273-279 (1995), where MDL 100,907 is seen to exert a tonic inhibitory effect on dopamine flow in the medial prefrontal cortex. Some of the applications of MDL 100,907 are described.

For example, US 5,169,096 describes compounds having such a range that includes който100,907 and applications for the treatment of anorexia nervosa, variant angina, the phenomenon of Reynold, coronary vasospasm, prophylactic treatment of migraine, cardiovascular diseases such as hypertension, peripherbiliary periphery cardiopulmonary emergencies and arrhythmias, and has anesthetic properties. See also, US 4,783,471; US 4,912,117; US 5,021,428, US 5,169,096, US 4,877,798 (fibromyalgia), US 4,908,369 (insomnia); US 5,106,855 (glaucoma); EP 319,962 (concern); EP 337 136 (Extrapyramidal Symptoms). All patents mentioned above are included in the literature.

M100,907 is also known from U.S. Pat. No. 5,134,149, which describes applications of serotonin antagonization at the 5Ht2 receptor, treatment of anxiety, variant angina, anorexia nervosa, Reynold's phenomenon, intermittent limping, coronary or peripheral vasospasmagrhythmias, fibroids, platelet diseases, transient ischemic attacks, drug abuse, and psychotic conditions such as schizophrenia and mania. See also US 5,561,144; US 5,700,813; US 5,721,249, divided into US 5,134,149, and also US 5,618,824 (compulsive neurosis state) and PCT / US1997 / 002597 (depressive states including major episode of depression and dysthymia and bipolar state), and insomnia and sleep apnea (respiratory arrest). sleep state).

It is an object of the present invention to provide a novel compound which, upon administration, releases a therapeutically effective amount of MDL 100,907 over a given period of time. A time period covered means a time longer than a single dose of MDL 100,907 and which would last several days, several weeks, about a month and even from 6 to 8 weeks, and preferably from about 2 weeks to about one month.

There are many advantages to administering a single dose of a compound to a patient that continues beyond a given period of time. It can avoid the problems of complaints, which is of particular importance for a patient suffering from psychosis or acquired behaviors such as schizophrenia, obsessive neurosis behavior, depression, anxiety, anorexia and drug dependence. Other advantages include the absence of typical oscillations at the drug level achieved with multiple dose therapy during which the patient experiences improved treatment efficacy with a lower peak of drug concentration.

Insofar as the concept of sustained release formulations is not new, not all compounds can be chemically modified to produce a new compound that can be metabolized into the active ingredients to the desired extent and over the desired length of time. Other factors determine the difficulty of formulation is sustained release, such as binding protein and other physiological processes that may influence the therapeutic effect of the active ingredient, see, for example, Biochemical Pharmacology, vol. 36, No. 1 10 pp. 1715-1722 (1987), incorporated herein by reference. The chemically modified compound must also be compatible with pharmaceutically acceptable carriers and be sufficiently stable so that it does not substantially disintegrate to the active ingredient upon storage. In short, creating acceptable sustained release dosage forms is a difficult, unpredictable task.

SUMMARY OF THE INVENTION

The present invention relates to a compound of formula I

Formula I wherein R is C ₄ -C ₂₀ -alkyl, or a stereoisomer or pharmaceutically acceptable salt thereof.

The present invention also relates to: a pharmaceutical composition comprising a compound of formula I together with a pharmaceutically acceptable carrier, use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical composition for administration to a patient suffering from a disease condition caused by of the effects of serotonin at the 5HT _2A receptor, where the disease state is psychosis (including schizophrenia), a state of compulsive neurosis, thrombotic diseases, coronary vasospasm, anxiety, anor neurosis, Reynolds phenomenon, fibromyalgia, extrapyramidal side effects, arrhythmia, depression, bipolar depression, insomnia, sleep apnea, drug dependence and method for the preparation of compounds consisting of an alcohol interaction of structural formula (5), below, with acid halide, acid anhydride or carboxylic acid in the presence of a sufficient amount of a suitable base.

Detailed description of the invention

The terms used here have the following meanings:

(a) "Pharmaceutically acceptable salt" means any of the possible salts of a compound of the invention that is an acid addition salt or an alkaline addition salt.

A "pharmaceutically acceptable acid addition salt" is any addition salt of the basic compounds represented by Formula I with non-toxic organic or inorganic acid. Illustrative inorganic acids that form the appropriate salts are hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulphate. Illustrative organic acids which form the appropriate salts are mono-, di-tritarboxylic acids. Examples of such acids are acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, maleic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenyloacetic, cinnamic, salicyloxybenzoxylic acid acid and sulfonic acid and such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Mono- or di-acid salts may also be formed, and such salts may exist in both hydrated and substantially unhydrated form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and which, in comparison with their free base forms, generally exhibit higher melting points.

"Pharmaceutically acceptable basic addition salts" means the non-toxic organic or inorganic basic addition salts of the compounds of Formula (I) or any of their intermediates. Examples are alkali metals or alkaline earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides; ammonium and aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picoline. Selection of the appropriate salt may be important to prevent the ester from hydrolyzing. The criterion for selecting the appropriate salt is known to those skilled in the art;

b) “Stereoisomers” is a generic term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes isomers that represent mirror images (enantiomers), geometric (cis / trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of another (diastereoisomers);

c) "Alkyl" means a branched or unbranched alkyl group specified by the amount of carbon in the alkyl group, e.g. C ₄ -C _2O means four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty carbon branched or unbranched chains or branches intervals, for example, but not limited to C ₅ -C ₂₀ , C ₁ -C ₃ , C ₃ -C ₁₅ , C ₅ -C ₁₅ , C ₇ -C ₁₅ and C ₇ -C ₉ ;

d) "Patient" means a warm-blooded animal, such as a rat, mouse, dog, cat, guinea pig, and primates, incl. people;

e) "Treat" or "cure" means the relief of symptoms, the elimination of the causes of these symptoms, both temporarily and on a permanent basis, or to prevent or delay the onset of symptoms of the said malaise or condition;

f) "Therapeutically effective amount" means an amount of a compound that is effective in treating a particular malaise or condition;

g) "Pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the compound of the present invention in order to allow the formation of a pharmaceutical composition, i. e. a dosage form that can be administered to the patient. One example of such a carrier is a pharmaceutically acceptable oil commonly used for parenteral administration;

h) the term "restorative sleep" means a dream that leads to a state of rest upon awakening;

(i) the term "sleep disturbance" means insomnia or obstructive sleep apnea;

j) the term "Insomnia" means primary insomnia, insomnia associated with another mental disorder and substance-induced insomnia;

k) The term "Primary insomnia" means difficulty in falling asleep, in prolonged sleep or in the presence of restorative sleep which is not caused by a mental impairment or due to the physiological effects of taking or rejecting certain substances (induced by substances). As used herein, it also includes the Circadian rhythm of insomnia, which is insomnia due to changes in the normal pattern of wake-up (border changes, plane crossings, etc.);

l) The term "Insomnia associated with another mental disorder" means difficulty in falling asleep, in prolonged sleep or in the presence of restorative sleep, which is caused by stressed mental disorders, such as depression, anxiety or schizophrenia;

s) The term “substance-induced insomnia” means difficulty in falling asleep, prolonged sleep, or having a restorative sleep that is caused by the physiological effects of taking or rejecting certain substances such as caffeine, alcohol, amphetamine, opioids, sedatives, hypnotics and anxiolytics; and

p) The term “Obstructive sleep apnea” means recurrent episodes of upper airway obstruction during sleep and is usually characterized by severe snoring or short suffocation, alternating with episodes of lull.

The (+) - isomer of alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol can be prepared by the methods described in US 5,134,149. One suitable method is:

SCHEME I- Starting materials

0CH ₃

£ t <30 A e C-T ε p b f ug _{U (/} j

F 3

Stage C.

In step A of reaction Scheme I, an esterification reaction is carried out between the racemic alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol (structure 1) and (+) - alfamethoxyphenylacetic acid isomer (structure 2). This esterification produces a diastereomeric mixture identified as structure 3. These diastereomers are chromatographed on silica gel, which separates the two diastereomers, thereby isolating the (+, +) diastereomer as shown in Step B. In Step C, ( +, +) The diastereomer is hydrolyzed to produce the (+) isomer of the alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol.

The esterification reaction can be carried out using techniques known in the art. Typically, approximately equivalent amounts of racemic alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol and (+) - isomers of alpha-methoxyphenylacetic acid in an organic solvent such as metal chloride, THF, chloroform , or toluene and heated to reflux for a time ranging from 5 to 24 hours. The esterification is usually 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 dicyclohexylurea and evaporation of the filtrate.

The diastereomers are then chromatographed on silica gel, which separates the (+, +) and (-, +) diastereomers. Chromatographic separation may be carried out in a manner 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-piperidine methanol. Hydrolysis is carried out by contacting the diastereomer with an excess of a base such as potassium carbonate and aqueous alcoholic solution. The hydrolysis is carried out at a temperature of about 15 to 30 ° C for a period of time from 2 to 24 hours. The resulting (+) - isomer of alpha- (2,3-dimethoxyphenyl) -1- [2 (4-fluorophenyl) ethyl] -4-piperidine methanol can then be recovered by dilution with water and extraction with metal chloride. It is then purified by recrystallization from a solvent system such as cyclohexane / hexane or ethyl acetate / hexane.

Methods for preparing starting materials from Reaction Scheme I are known in the art. US 4,783,471 discloses the preparation of racemic alpha- (2,3-dimethoxyphenyl) -1- [2 (4-fluorophenyl) ethyl] -4-piperidinethanol, and suitable methods are also described in Examples 1 and 2 of this description. Conversely, racemic alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol can be prepared as follows. Initially, 4-hydroxypiperidine was subjected to a N-alkylation reaction with p-fluorophenylethyl bromide, which resulted in 4-hydroxy-1- [2- (4-fluorophenyl) ethyl] -piperidine. This compound is brominated with N, N-Br-Br, which gives 4bromo-1- [2- (4-fluorophenyl) ethyl] -piperidine. This compound comes into contact with Mg, thus forming a Grignard Reagent, which is then reacted with 2,3dimethoxybenzaldehyde and resulting in the desired product (±) -alpha- (2,3dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4piperidine methanol. (+) - Isomeric alfamethoxyphenylacetic acid is known in the art.

SCHEME II

FORMULA I

According to Scheme II, X is chloro or bromo, with chlorine being preferred and R being as defined above. This reaction scheme shows the preparation of sustained-release compounds of Formula I from alcohol (5).

The alcohol (5) is reacted with an acid halide (RC (O) X, RCO ₂ H or acid anhydride (RCO) ₂ O in the presence of a sufficient amount of a suitable base. A suitable base is one which allows the formation of an acid halide or anhydride ester. Examples of suitable bases are trialkylamines, pyridine such as dimethylamino pyridine, diisopropyl ethyl amines, N-methyl morpholines, with triethylamine are preferred A sufficient amount of the base can be obtained by one of ordinary skill in the art that enables the preparation of the compounds of Formula I.

Preferably, the base is added to the alcohol (5) and this mixture is added dropwise to the acid halide or acid anhydride in a suitable solvent. Examples of suitable solvents are chloroform, methylene chloride, or toluene, all of which are available, preferably chloroform.

The reaction temperature may be in the range of about 0-25 ° C. The reaction mixture may be stirred from several hours to overnight to accelerate the reaction. A catalyst may then be added to accelerate the reaction, e.g. 4-dimethylaminopyridinylidr. similar.

Acid halide starting materials (RCOX) are prepared by those skilled in the art. For example, for example, Aldrich, for example, sterol chloride, heptadecanoyl chloride, palmitoil chloride, myristoyl chloride, isovaleric chloride, valeryl chloride, hexanoyl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, octanoyl chloride, octane, For those acidic halides that are not prepared readily, one of ordinary skill in the art may obtain them if desired. For example, a carboxylic acid may be mixed with a halide donor to obtain the desired acid halide. One example is the mixing of carboxylic acid (0.17 mol), methylene chloride (660 ml) and dimethylformamide (0.5 ml) in a nitrogen atmosphere. Oxalyl chloride (0.2 mol) was added over about 5 minutes with stirring. The mixture was stirred at ambient temperature for 3 hours and the solvent was evaporated in vacuo to the acid chloride. Another method is to dissolve the carboxylic acid (10 mmol) in methylene chloride (50 ml). Cool to 0 ° C, place under nitrogen and add thionyl chloride (11 mmol) dropwise. It was stirred at room temperature for several hours and the volatiles were evaporated in vacuo to give the acid chloride. Carboxylic acids are prepared or readily obtainable by those skilled in the art.

Acidic anhydride (RCO) ₂ O starting materials are prepared readily for those skilled in the art. For example, Aldrich Chemical Company offers butyric anhydride, isobutyric anhydride, valeric anhydride, 2-2, dimethylglutaric anhydride, and phthalic anhydride. Conversely, acidic anhydrides can be synthesized by methods well known in the art.

The starting materials for the acids (RCO ₂ H) are prepared in advance or can be synthesized by methods well known in the art. For example, see Advanced Organic Chemistry, Reactions, Mechanisms, and Structure, 4 ^{th ed., John Wiley & Sons} , New York 1992, incorporated herein by reference. Aldrich Chemical Company also offers isovaleric acid, valeric acid, tert-butylacetic acid, 2,2-dimethylbutyric acid, hexanoic acid, 3-methyl valeric acid, heptanoic acid, 2-propylpentanoic acid, nanoic acid, decanoic acid, decanoic acid, decanoic acid , tridecanoic acid, myristolic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nondecanoic acid, eicosanoic acid, and also others where R is from four to two ET alkyl groups.

The examples below illustrate the invention without limitation.

Examples of carrying out the invention

Example 1 - starting material

Example 1. Steps A-D show the preparation of the starting material (±) -alpha (2,3dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4piperidine methanol, structure 1, Scheme I.

A) 1- [2- (4-Fluorophenyl) ethyl] -4-piperidinecarboxamide

A solution of isonipecodamide (10.9 g, 85.0 mmol), 2- (4-fluorophenyl) ethyl bromide (15.7 g, 77.3 mmol) and KjCO ₃ (2.3 g, 167 mmol) was obtained in DMF (280 ml) and stirred in atmosphere. of argon at 90-95 ° C overnight. The cooled solution was concentrated to a white solid. The latter is partitioned between water and CH ₂ Cl ₂ . The combined organic layers were washed twice with water, dried (MgSO ₄ ), filtered and evaporated to a solid. The oil was recrystallized from EtOAc to give 1- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxamide as a white powder, mp 177178 ° C.

Analysis content for C ₁₄ H ₁₉ FN ₂ O: C, 67.18; H, 7.65; N, 11.19. Found: C, 76.25; H, 7.67; N, 11.13.

B) 4-cyano-1- [2- (4-fluorophenyl) ethyl] piperidine

To the stirred phosphorus oxychloride (25 ml, 41.12 g, 268 mmol) and sodium chloride (5.1 g, 87.3 mmol) was added 1- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxamide (8.9 g, 35.6 mmol) ) in pieces. After complete addition, the solution was stirred at reflux for 2 h. The cooled solution was carefully poured into dilute NH ₄ OH to destroy POCl ₃ . The aqueous solution was cooled to 0 ° C, then extracted 2 times with CH ₂ Cl ₂ . The combined organic layers were dried (MgSO ₄ ). filtered and evaporated to give 8.1 g of a solid oil. The oil was then distilled (boiling point 150 ° C, 0.1 mm Hg) to give a clear, colorless oil which solidified. This material was crystallized from hexane to give 4-cyano-1- [2- (4-fluorophenyl) ethyl] piperidine as white needles, mp 47-48 ° C. Analysis content for C ₁₄ H ₁₇ FN _2: C, 72.39; H, 7.38; N, 12.06. Found: C, 72.62; H, 7.49; N, 12.12.

C) 1- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxaldehyde

To a stirred solution of 4-cyano-1- [2- (4-fluorophenyl) -ethyl] piperidine (1.00 g, 4.3 mmol in THF (20 ml) in argon medium at 0 ° C was added DIBAL-H (4.6 ml in THF 4.6 After stirring overnight at room temperature, 10% aqueous HCl (25 ml) was added and the solution was stirred for 3 h. The whole mixture was then poured into 10% aqueous NaOH (50 ml). ), and then extracted twice with ether. The combined organic layers were washed, dried (MgSO _4), filtered and evaporated to give a pale yellow oil. The oil was chromatographed on silica gel, eluting with E The appropriate fractions were combined and evaporated to give an oil, which was distilled (boiling 166 ° C, 0.05 mm Hg) to give 1- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxaldehyde, obtained as a colorless oil.

Analysis content for C ₁₄ H ₁₈ FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08; H, 7.81; N, 5.86.

D) (±) -alpha (2,3-dimethoxyphenyl) -1- [2 (4-fluorophenyl) ethyl] -4-piperidinethanol

To a stirred solution of veratrol (0.93 g, 6.7 mmol) in THF (20 ml) under argon at 0 ° C was added n-BuLi (2.7 ml of 2.5 M solution in hexane, 6.75 mmol). After stirring for 2.5 h, the solution was cooled to -78 ° C and treated with 1- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxaldehyde (1.30 g, 5.5 mmol) in THF (25 ml). the help of a funnel. The cooling bath was removed and the solution allowed to stir for 2 h. 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 ₄ ), filtered and chromatographed on silica gel, eluting with acetone. Appropriate fractions were combined and evaporated to give a white solid. The latter was recrystallized from hexane to give the racemic alpha (2,3-dimethoxyphenyl) 1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol as a bright white slurry, mp 126- 127 ° C.

Content for C ₂₂ H ₂₈ FNO ₃ : C, 70.75; H, 7.56; N, 3.75. Found: C, 70.87; H, 7.65; N, 3.68.

Example 2 - starting material

Example 2. Steps A-F show an alternative method of preparing (±) -alpha (2,3dimethoxyphenyl) -1- [2- (4-fluorophenyl) -ethyl] 4-piperidinomethanol, structure 1.

A) 1- (1,1-Dimethylethyl) -1,4-piperidinecarboxylic acid

To isonipecotinic acid (107.5 g, 832 mmol) stirred in 1N NaOH (40 g NaOH in 900 ml H ₂ O) 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 aqueous layer was acidified with aqueous HCl. This acidic aqueous layer was extracted three times with ether. The combined organic layers were washed with brine, brine, dried (MgSO ₄ ), filtered and evaporated to a white solid which was recrystallized from EtAc / hexane (300 ml / 200 ml) to give 1- (1,1- dimethylethyl) -1,4-piperidinecarboxylic acid as white needles, mp 147-149 ° C.

B) 4- (N-methoxy-14-methylcarboxamido) 1-piperidinecarboxylic acid 1,1-dimethyl ester

To a stirred solution of 1- (1,1-dimethylethyl) -1,4-piperidinedicarboxylic acid (50.0 g, 218 mmol) in anhydrous CH ₂ Cl ₂ (500 ml) under N ₂ atmosphere in two-liter flasks was added portionwise 1,1'-Carbonyldiimidazole (38.9 g, 240 mmol). After stirring for 1 h, N, N-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol) was added portionwise. After stirring overnight, the solution was washed twice with 1 N HCl, twice with saturated NaHCO ₃ , once with brine, dried (MgSO ₄ ), filtered and evaporated to an oil. Distillation gave 4- (L-methoxy-N-methylcarboxamido) -1-piperidinecarboxylic acid 1,1-dimethyl ester as a light oil, mp 120-140 ° C, 0.8 mm.

C) 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid 1,1-dimethyl ester n-butyl lithium (14.5 ml of 2.5 M solution in hexane, 36.3 mmol) was added through a funnel to a stirred solution of veratrol (5.00 g, 36.2 mmol) in THF (50 ml, anhydrous) under argon at 0 ° C. The ice bath was removed and the mixture was allowed to stir for 90 minutes. The mixture was cooled to -78 ° C and treated with 4- (N-methoxy-methylcarboxamido) -1-piperidinecarboxylic acid 1,1-dimethyl ester (9.20 g, 33.8 mmol) in THF (50 ml, anhydrous) through a funnel. The ice-acetone cooling bath was removed and the mixture allowed to reach room temperature. After stirring for 3 h, saturated aqueous NH ₄ Cl 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 ₄ ), filtered and evaporated to give an amber oil. The oil was chromatographed on silica gel, eluting with 20% EtOAc in hexane. Appropriate fractions were combined and evaporated to an amber oil. The oil was distilled to give 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester as a colorless oil (mp 225-250 ° C, 0.05 mm).

Analysis content for C ₁₉ H ₂₇ NO ₅ : 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 stirred for 45 min. The whole solution was poured into ether (900 ml) and allowed to stand overnight. Filtration gave 4- (2,3-dimethoxyphenyl) -4-piperidinylmethanone trifluoroacetic acid as fine white needles, mp 123 ° C.

Content for C ₁₄ H ₁₉ NO ₃ . CF ₂ CO ₂ H: C, 52.89; H, 5.55; N, 3.86. Found: C, 52.7; 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 as an oil.

E) (2,3-dimethoxyphenyl) [1- [2- (4-fluorophenyl) ethyl] -4-piperidinyl] methanone monohydrochloride

A solution of 4- (2,3-dimethoxyphenyl) -4-piperidinylmethanone (8.00 g, 32.1 mmol) and 2- (4fluorophenyl) ethyl bromide (6.52 g, 32.1 mmol) was obtained in DMF (90 ml), treated with 2- CO2 (7.0 g, 50.7 mmol) was then stirred and heated at 80 ° C under argon overnight. The cooled solution was cast portionwise 2/1 EtOAc / toluene. The combined organic carriers were washed twice with water, once with brine, dried (MgSO ₄ ), filtered and evaporated to give 11.0 g of oil. The oil was chromatographed on silica gel eluting with EtOAc. Appropriate fractions were combined, concentrated, dissolved in ethyl acetate and treated with HCl / ethyl acetate. (2,3-dimethoxyphenyl) [1- [2- (4-fluorophenyl) ethyl] -4-piperidinyl] -methanone monohydrochloride was obtained as a precipitate, mp 225227 ° C.

Content for C ₂₂ H ₂₆ FNO ₃ . HCl: C, 64.78; H, 6.67; N, 3.43. Found: C, 64.44; H, 6.73; N, 3.41.

F) (±) -alpha (2,3-dimethoxyphenyl) -1- [2 (4-fluorophenyl) ethyl] -4-piperidinethanol

To a stirred solution of (2,3dimethoxyphenyl) [1- [2- (4-fluorophenyl) ethyl] -4piperidinyl] methanone in (6.0 g, 16.2 mmol) in MeOH (100 ml) at 0 ° C was added NaBH ₄ (1240 mg, 32.8 mmol) in two portions over a period of 1 h. After stirring for 1 h, the solution was concentrated to a solid. The latter is distributed in portions 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 ₄ ), filtered and evaporated to a solid. The latter was chromatographed on silica gel, eluting with acetone. Appropriate fractions were combined and evaporated to give a white salt. The salt was recycled from cyclohexane to give (±) -alpha (2,3dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4piperidine methanol as white needles, mp 126-127 ° C.

Content for C ₂₂ H ₂₈ FNO ₃ . C, 70.75; H, 7.56; N, 3.75. Found: C, 70.86; H, 7.72; N, 3.93.

Example 3 - starting material

This example shows the preparation of alcohol, structure 5.

A) Preparation of diastereoisomers

To a solution of 3.90 g (10.4 mmol) (+) alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol, 1.74 g (10.4 mmol) of 8 - (+ ) -alpha-methoxyphenylacetic acid, 2.15 g (10.4 mmol) of 1,3-dicyclohexylcarbodiimide and 0.1 g of 4-dimethylaminopyridine in chloroform (75 ml) was refluxed for 17 h, allowed to cool to room temperature and allowed to cool. it filters. The filtrate was concentrated and chromatographed on silica gel on a column eluting with ethyl acetate / hexane (1: 1) to give two diastereomers, Rf = 0.1 and 0.2 (TLC EtOAc / hexane, 1: 1). The intermediate fractions were rechromatographed to obtain additional material. The fractions with Rf = 0.2 were combined to give a separate diastereomeric ester, (+, +) - (2,3-dimethoxyphenyl) [1- (4fluorophenyl) ethyl] -4-piperidinyl] methyl-alpha-methoxybenzene acetate.

B) Preparation of (+) - alpha- (2,3dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4piperidine methanol

To a stirred solution of 0.97 g (1.9 mmol) of the above ester isomer ester, Rf = 0.2, 0.5 g (3.6 mmol) of potassium carbonate and 5.0 ml of water were added in 25 ml of methanol. After stirring for 17 h at room temperature, the reaction mixture was diluted with water and extracted twice with methylene chloride. The combined extracts were washed with water, brine and dried over MgSO ₄ . After filtration, the filtrate was concentrated to an oil and crystallized from 40 ml of cyclohexane / hexane (1: 1) to give (+) - alpha- (2,3-dimethoxyphenyl) 1- [2- (4-fluorophenyl) ethyl] - 4-piperidinethanol, mp 112-113 ° C, [alpha] _n ²⁰ = + 13.9 °.

Example 4.

(+) - alpha (2,3-dimethoxyphenyl) -1- [2- (4fluorophenyl) ethyl] -4-pipersidine methanol decanoate

Mixture of 49.0 g (0.131 mol) of (+) - alpha (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol, 500 ml CHCl ₃ and 16.0 g (0.158 mol) triethylamine is charged into a 1 liter, three-necked flask fitted with a stirrer, thermometer, dropper and continuous nitrogen purification. A solution of 27.4 g (0.144 mol) of decanoyl chloride in 15 ml of CHCl ₃ was added over 5 minutes while maintaining a reaction temperature of 20-25 ° C. The resulting solution was stirred at 20-25 ° C for 2 h. The development of the reaction was monitored by TLC (5/95 methanol / CH ₂ Cl ₂ ; Merck 60F-254 plates;

UV; Rf of (+) - alpha- (2,3-dimethoxyphenyl) -1- [2 (4-fluorophenyl) ethyl] -4-piperidinethanol, 0.23; Rf of said compound (-0.55). An additional 2.8 g (0.015 mol) of decanoyl chloride (Aldrich) and 1.6 g (0.016 mol) of triethylamine were added to the reaction mixture and stirring was continued for 2 h. The reaction mixture was diluted with 500 ml CH ₂ Cl ₂ and washed with 250 ml 5% K ₂ CO ₃ , 250 ml H ₂ O and 250 ml saturated NaCl. The organic phase was dried over 500 g of MgSO ₄ and filtered. The filtrate was washed with 200 ml CH ₂ Cl ₂ . The filtrate was concentrated at 40 ° C to give an oil.

The crude product was purified by flash chromatography (14 x 29 cm column, 2.035 kg of 230-400 mesh silica gel). The crude product is loaded onto a column by dissolving it in 75 ml of CH ₂ Cl ₂ CH ₂ Cl ₂ . The column was eluted with 24 V V ₄ EtOAc / CH ₂ Cl ₂ , collecting 24 x 1 1 fractions. The fractions that were homogeneous by TLC were combined and concentrated at 3 5 ° C / 5 0 T followed by 70 ° C / 0.5 T for 1 h to give a colorless oil.

MS (M + = 528)

Analysis:

Calculated for C ₃₂ H _{4 (5} FNO ₄ (527.73): C, 72.83%; H, 8.79%; N, 2.65%).

Found: C, 72.25%; H, 8.88%; N, 2.63%.

Example 5.

(+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4fluorophenyl) ethyl] -4-piperidinethanol hexanoate

To a stirred solution of 2.0 g (5.37 mmol) (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4fluorophenyl) ethyl] -4-piperidinethanol in 6 ml of dry methylene chloride was added 0.74 ml (0.537 g, 5.32 mmol) of triethylamine. The solution was cooled in an ice bath and then 1.07 ml (5.89 mmol) of hexanol anhydride was added through a funnel. The solution was stirred for several minutes at ice bath temperature and allowed to warm to room temperature. 66 mg (0.541 mmol) of 4 dimethylaminopyridine are then added to the solution. The mixture was stirred overnight at room temperature, poured onto ice / water / 0.5 M NaOH, extracted with ether and filtered and concentrated to an oil. The oil was dissolved in methylene chloride and 2% methanol / methylene chloride, respectively. The pure product containing the fractions was combined and concentrated to provide an oil which was dried overnight at 60 ° C under high vacuum to give the title compound. The compound was homogenized by TLC. IR (Kbr), NMR (CDCl ₃ ) and MS (MH + = 472) were consistent with the proposed structure.

Analysis:

Calculated for C ₂ H ₃₈ FNO ₄ : C, 71.31%; H, 8.12%; N, 2.97%

Found: C, 70.94%; H, 8.07%; N, 2.88%.

Example 6

(+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4fluorophenyl) ethyl] -4-piperidinethanol oxanoate

To a stirred solution of 2.0 g (5.37 mmol) (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine methanol in 6 ml of dry methylene chloride, was added 0.74 ml (0.537 g, 5.32 mmol) of triethylamine. The solution was cooled in an ice bath and then 1.07 ml (5.89 mmol) octanol anhydride was added through a funnel. The solution was stirred for several minutes at ice bath temperature and allowed to warm to room temperature. 66 mg (0.541 mmol) of 4-dimethylaminopyridine are then added to the solution. The mixture was stirred, washed with water and saturated sodium chloride. The organic extract was dried (Na ₂ SO ₄ ), filtered and concentrated to an oil. The oil was dissolved in methylene chloride and purified by flash chromatography on silica gel, eluting with methylene chloride, 1% and 2% methanol / methylene chloride, respectively. The pure product containing the fractions was combined and concentrated to afford an oil which was dried overnight at 60 ° C under high vacuum to give the title compound. The compound was homogenized by TLC. IR (Kbr), NMR (CDCl ₃ ) and MS (MH + = 501) are consistent with the proposed structure.

Analysis:

Calculated for C ₃₀ H ₄₂ FNO ₄ : C, 72.11%; H, 8.47%; N, 2.80%

Found: C, 70.94%; H, 8.63%; N, 2.83%.

Example Ί.

(+) - alpha- (2,3-dimethoxyphenyl) -1- (2- (4fluorophenyl) ethyl] -4-piperidinemethanolhexadecanoate

(+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol in 6 ml of dry methylene chloride was added 0.76 ml (0.46 g) of triethylamine through a funnel, then the solution is cooled in an ice bath. 2.92 g (5.89 mmol) of hexanol anhydride were added to the solution, then stirred at 0 ° for 15 min at ice bath temperature and allowed to warm to room temperature. The mixture was allowed to warm to ambient temperature and 65 mg (0.536 mmol) of 4-dimethylaminopyridine were added to the reaction mixture, then the mixture was stirred overnight under a nitrogen atmosphere. The reaction mixture was poured into 50 ml of 0.5 N sodium hydroxide and 50 ml of diethyl ether. Little precipitation 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 a yellow oil. The oil was dissolved in methylene chloride and purified by flash chromatography column packed with silica gel and methylene chloride and eluted with the same solvent system, followed by 1% and 2.0% methanol / methylene chloride, respectively. The appropriate fractions were combined and concentrated to a yellow oil. The latter was dried twice at 60 ° C under high vacuum to give the title compound. The compound was homogenized by TLC. IR (film), NMR (CDCl ₃ ) and MS (MH + = 612) are consistent with the proposed structure.

Analysis:

Calculated for

C ₂₄ H ₃₀ FNO ₄ : C, 74.59%; H, 9.55%; N, 2.29%

Found: C, 74.34%; H, 9.45%; N, 2.29%. Example 8.

(+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4fluorophenyl) ethyl] -4-piperidinethanol 2,2-dimethyloctanoate

2-Hexen-1-mesylate was obtained by adding N, N-diisopropyl ethyleneamine (12.9 g, 0.1 m) to a solution of trans-2-hexen-1-ol (10.0 g, 0.1 m) (Aldrich) in 100 ml. metal chloride. Methanesulfonyl chloride (12.6 g, 0.11 m) in metal chloride (50 ml) was added dropwise to the solution with stirring at room temperature for 4 h. The reaction mixture was transferred to a separator tube and washed with cold 1N HCl (2 times) and then with saturated HaNaHCO ₃ solution (2 times). The solution was dried over anhydrous MgSO ₄ , filtered and concentrated in vacuo at 40 ° C to give 2-hexene-1-mesylate.

2.2-dimethyl-3-octene nitrile was obtained by adding 2-hexene-1-mesylate (11.02 g, 0.05 m) in anhydrous THF (100 ml) to a solution obtained by the addition of isobutyro nitrile (3.7 g, 0.053 m) in THF (25 ml) after treatment with NaH (60% in mineral oil) (2.1 g, 0.053 m) in dry THF (50 ml). The resulting reaction mixture was refluxed for 5 h, cooled and stirred with cold ethanol (95%) and concentrated in vacuo to remove the solvents. After addition of water (50 ml), the mixture was extracted with diethyl ether (3 x 40 ml). The extracts were washed with water and then with saturated NaCl solution and dried over MgSO ₄ , filtered and concentrated to give 2,2-dimethyl-3-octene nitrile.

2.2-Dimethyl-3-octenoic acid was obtained by the addition of 2,2-dimethyl-3-octene nitrile (1.51 g, 0.01 m) to a solution obtained from 15% NaOH in butanol / H ₂ O (2: 3) ( 30 ml). The reaction mixture was stirred and refluxed for 7 hours, cooled and acidified with 10% hydrochloric acid. The reaction mixture was extracted with diethyl ether and the extract was washed with saturated NaCl and dried over MgSO ₄ , filtered and concentrated to give 2,2-dimethyl-3-octanoic acid.

2,2-Dimethyl octanoic acid was obtained by dissolving 2,2-dimethyl-3-octanoic acid (0.20 g, 1.1 mmol) in absolute ethanol, covered with N ₂ and 10% palladium on carbon, which was then hydrogenated to 6 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 2.2dimethyl octanoic acid.

To a stirred solution of (+) - alpha- (2,3dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4piperidine methanol (3.9 g, 10.4 mmol) in 70 ml of methylene chloride was added dicyclohexylcarbodiimide (2.15 g, 10.4 mmol), 4-dimethylamino pyridine 0.1 g and 2,2-dimethyloctanoic acid (1.70 g, 10.4 mmol). The resulting solution was stirred and refluxed for 16 h. The cooled reaction solution was filtered and concentrated to an oil. The resulting oil was chromatographed on silica gel, eluting with ethyl acetate / hexane (1: 1). The appropriate fractions were cooled, warmed (40 ° C) and concentrated under reduced pressure to give the above compound.

Example 9.

This example shows a pharmaceutical composition of the present invention. Place 70 ml mustard oil, NF (Sigma), 1.2 g benzyl alcohol, NF and 14,129 g (+) - alpha- (2,3-dimethoxyphenyl) -1- [2 (4-fluorophenyl) in a suitable 100 ml flask. ) ethyl] -4-piperidinomethanol decanoate. A sufficient amount of mustard oil, NF, was added to this solution to reach a volume of 100 ml and mixed until homogenized. This solution can be sterilized and packaged for parenteral injection.

Example 10.

This example describes a behavior test (DOI-induced antagonism) designed to identify substances that have antagonist activity at the 5HT _2A receptor. The compound of the present invention used in this test is (+) - alpha (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol decanoate-example 4 above. The 5-HT _2a / 2C agonist (+) - DOI HCl (1- (2,5-dimethoxy-4-iodophenyl) -2-aminopropane hydrochloride) induces a different amount-dependent behavior in rats. These behaviors include shaking (rapid shaking of the head and body, such as wet dog shaking), tapping with the front paw (rapid tapping with the front paw), and skin-shaking (paraspinal muscle contractions or dorsal cutaneous contractions). 5-HT ₂ antagonists myasterin, ritasterin and metisergide, as well as selective

5-HT _2a MDL 100 907 antagonist show dose-dependent blocking of the behavioral effects of DOI (Pranzatelli, 1990, Neurosci. Let. 11: 74-80; Wettstein et al., 1996, Soc. Neurosci. Abs. 22: 481) . It should be noted that drugs with

5-HT _2A antagonist activity has been hypothesized to have atypical antipsychotic properties in schizophrenic patients (Meltzer et al., 1989, JPET. 251: 238-246), as well as potential therapeutic activity in many other central nervous disorders system (CNS) including depression, dysthymia, and anxiety (Stefanski & Goldberg, 1997; CNS Drugs, 7: 399-409).

Methods

Subjects and cultivation

Male Sprague-Dawley rats (180 ± 50 g) were reared seven per cell and allowed to acclimate for 1 week in the vivarium. Water and food are freely available. The temperature and light cycle (12 h light, 12 h dark) are automatically maintained. Individual rats were tested once. Each test group consisted of seven animals. The experiments are carried out in the vivarium room where the animals are reared.

Preparation of Drugs and Their Application (+) - Alpha- (2,3-dimethoxyphenyl) -1- [2- (4fluorophenyl) ethyl] -4-piperidinethanol decanoate (120 mg / kg eq of MDL 100,907) was dissolved in mustard oil and dissolved administered intramuscularly to individual groups of rats on Day 0 in a volume equal to 60 ml / 100 g body weight. Control animals are injected with sesame oil on their own. (±) -DOI HCl (3.0 mg / kg, 1 ml / kg body weight) was dissolved in distilled water using an ultrasonic bath and injected intraperitoneally on a suitable test day.

Behavior Monitoring and Investigation Rats treated with (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol decanoate were tested for antagonism of DOI-induced behavior at 1.5, 7, 14, 21, 28 and 40 days after intramuscular injection of (+) - alpha- (2,3-dimethoxyphenyl) -1 [2- (4-fluorophenyl) ethyl] -4-piperidine methanol decanoate. Each rat was tested once. Immediately after injection with DOI, rats were placed under inverted light plastic boxes (28L x 25W x 25H cm), which had clean absorbent paper at the top. Rats were continuously monitored for 30 min for the onset of DOI-induced behaviors (shaking, fluttering, and patting with the front paw) and then returned to their cells. Rats were then used for pharmacokinetic studies. The frequencies of DOI-induced behaviors are recorded and then summed to determine the behavior of each animal.

Data from the analysis

Determine the mean and standard error of the behavioral records for each group. Each value of the treated group was then compared separately with the value of the control group using one-way analysis of variance (ANOVA) followed by orBonfenoni / Dunn post-hoc comparison. The differences between the groups are considered statistically significant if the p values are less than or equal to 0.05.

Results

Significantly DOI-induced antagonism behavior in rats was observed for all 28 days. The effect is not so significant on day 40.

Example 11.

The example shows the absorption of a single dose of MDL 100907 after intramuscular administration (im) of (+) - alpha- (2,3-dimethoxyphenyl) -1 [2- (4-fluorophenyl) ethyl] -4-piperidinethanol decanoate, a compound of the present invention , The whole time.

A total of ninety male Wistar rats weighing approximately 150-200 g each were administered intramuscularly (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol decanoate sinapeno oil (equivalent to 120 mg / kg MDL 100 907) on Day 0. Rats were anesthetized with lethal integroperitoneal dosemembutal and blood collected at 3 and 6 hours and on different days after injection (n = 5 at each indicated time) in heparinized containers. The blood samples were centrifuged for 3 0 min at 5 ° C and approximately 2700 rpm. Plasma was removed and stored at -20 ° C until assay. Plasma samples are analyzed by appropriate HPLC method. The brains should also be harvested at the above points and stored at -80 ° C until analyzed by the appropriate HPLC method. The results are shown in Table 1.

Table 1

Time (days) (+) - a- (2,3- Dimethoxyphenyl) -1- [2 (4-fluorophenyl) ethyl] -4piperidine methanol (ng / mL) -MDL 100,907 (+) -? - (2,3Dimethoxyphenyl) -1- [2 (4-fluorophenyl) ethyl] -4-piperidinethanol decanoate - Example 4 (ng / mL) 0.125 21.48 ± 8.00 54.18 ± 13.33 0.25 24.30 ± 7.65 53 ± 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 15 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 dose interval at which the compounds of formula I exhibit their ability to block the effects of serotonin at the 5HT _2A receptor may vary depending on the particular disease or condition being treated and its strength, patient, formula, other disease-stressing conditions, the patient is suffering from and other medicines that can be competitively administered to the patient. In general, the compounds of formula I will exhibit their serotonin 5HT _2A antagonist properties at doses from about 0.001 mg / kg of patient body weight / day to about 100 mg / kg of patient body weight / day. The sustained release formulations may comprise a plurality of the above dosages depending on how long the active ingredient is released. The dose of the compounds of the present invention can be determined by administering the compound to an animal and determining the plasma level of the active ingredient.

The compound of the present invention may be mixed with a pharmaceutically acceptable carrier, which may be advantageously administered in order to produce sustained release of the compound of the present invention such that a therapeutic amount of the compound (+) - alpha- (2,3dimethoxyphenyl) -1- [2- (4-Fluorophenyl) ethyl] -4-piperidine methanol can be delivered to the patient over a period of days to weeks. Preferably, sustained release formulations include a compound of formula I and a pharmaceutically acceptable carrier for parenteral administration both in aqueous suspension and in oily solution, oily suspension or emulsion. Some fats that can be used for intramuscular injection are mustard, olive, almond, corn, peanut, cotton, coconut and castor oil, as mustard oil is preferred. A pharmaceutically acceptable preservative such as benzyl alcohol may also be added. The sustained release form is preferably administered intramuscularly or subcutaneously, with the intramuscular being preferred though other routes of administration such as oral, transdermal, nasal spray, and the like. could also be used if appropriate for the needs of the patient.

Insofar as the compounds of the present invention release (+) - alpha- (2,3dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4piperidine methanol ("Active ingredient") to the patient for the therapeutic effect, the compounds of the present invention are applicable for all indications to which the active ingredient is applicable. Some of these indications are described in general publications covering the active ingredient (US 4,783,471) or specifically covering the active ingredient (US 5,134,149; US 5,561,144; US 5,618,824 and PCT / US1997 / 002597), all included in the literature. These references describe use in psychosis (including schizophrenia), conditions of compulsive neurosis, thrombosis, coronary vasospasm, intermittent limping, anorexia neurosis, Reynolds phenomenon, fibromyalgia, extrapyramidal side effects, anxiety, anxiety, anxiety e.g., cocaine, nicotine, etc.). Some of these indications are described in US 5,561,144; US 5,618,824; US 4,877,798; US 5,134,149 and US 5,021,428; all incorporated by reference.

Psychoses, as used herein, are conditions in which patients experience a strong mental disability of organic and / or emotional origin, characterized by personality disorder and loss of contact with reality, often with delusions, hallucinations or illusions. Representative examples of mental illnesses that can be treated with the compounds of the present invention include schizophrenia, schizophrenic malaise, schizoaffective malaise, illusory malaise, short mental illness, shared mental state, mental illness not otherwise specified and induced by substances psychologically ill. See Diagnostic and Statistical Manual of Mental Disorders, 4 ^th ed., American Psychiatric Association, incorporated herein by reference. The active ingredient is undergoing clinical trials for the treatment of schizophrenia.

Patients in a state of obsessive neurosis (OCD) fail to inhibit or open up intrusively, experiencing thoughts or images. Insofar as OCD is characterized by deficient cognitive opening and by aberrant metabolic activity in circumferentially touching the orbital cortex and straitum, it has been suggested that OCD patients may exhibit insufficient PPI (prepulsive inhibition). The active ingredient has been found to restore impaired PPI. See Psychopharmacology 124: 107-116 (1996), RA Padich, et al., “5HT modulation of auditory and visual sensorimotor gating: II. Effects of 5HT _2a MDL 100,907 Antagonist on Disruption of Sound and Light Prepluse Inhibition Produced by 5HT Agonists in Wistar Rats ”.

The active ingredient is also effective in preventing acute thrombosis, especially those of the coronary arteries. This compound lowers the rate of platelet aggregation as a result of a slight alteration in the endothelial lining of the vasculature and therefore prevents the formation of acute pathological thrombi (US 5,5 61,144).

Anxiety, variant angina, anorexia nervosa, the Reynolds phenomenon, and coronary vasospasm are used herein in the manner defined in the 27th edition of Dorland's Illustrated Medical Dictionary, incorporated herein by reference.

Fibromyalgia is a condition of chronic disease in which the patient suffers from various symptoms, for example, widespread generalized musculoskeletal pain, cramping, fatigue, morning stiffness and sleep disturbance, which can be characterized as stage 4 sleep deprivation.

Extrapyramidal side effects often accompany the use of neuroleptic agents such as haloperidol and chlorpromazine. The patient often has a similar Parkinson's disease, with muscular rigidity and tremors. Others have akathisia and acute dystonic reactions.

The active ingredient increases the duration of action of potentially myocardial tissue, producing an increase in the refractive period of that tissue, which, according to the Vaughan Williams classification system, exhibits Class III antiarrhythmic activity.

The compound of the present invention can be used to treat drug dependence in a patient. See T. F. Meert, et al., European Journal of Pharmacology 183: 1924, where the 5HT ₂ antagonist destroys preference for both alcohol and cocaine in a rodent model for drug dependence. Other animal models such as the rodent mulling model described in R A. Frank, et al., Behavioral Neuroscience 101: 546-559 (1987) can be used to demonstrate the ability of the compounds of the present invention to cure drug dependence .

The compounds of the present invention are useful in the treatment of patients with depressive states and bipolar conditions. In the Diagnostic and Statistical Manual of Mental Disorders 9Third Edition-Revised ("DSM-III-R") included in the literature, depressive states are defined as severe depression, dysthymia and depressive state NOS. We also include in this category a strong depressive episode, including chronic type, melancholy and seasonal pattern. Bipolar states include bipolar state, cyclothymia and bipolar NOS state.

Characteristic of depressive states is one or more periods of depression with no history of manic or hypomaniacal episodes. Characteristic of bipolar conditions is the presence of one or more manic or hypomaniacal episodes, usually accompanied by one or more episodes of severe depression. A manic or hypomaniacal episode is a distinct period during which the predominant condition is both elevated, expansive or irritable and associated symptoms of manic syndrome, as defined in DSM-III-R, are present. The harassment is strong enough to cause disturbance in the exercise of activities or social functions.

Severe depression has one or more severe episodes of depression. A severe episode of depression is characterized by (1) at least five of the following conditions: low mood, loss of interest in pleasure (anhedonia), significant weight loss or weight gain without dieting, insomnia, or somnolence, psychomotor agitation or slowness, fatigue or loss of energy, feelings of wordlessness or excess or wrongful guilt, reduced ability to think or concentration of repetitive thoughts of death, including suicide; (2) no organic factor can be identified to initiate and sustain the disorder; (3) no delusions or hallucinations for two weeks in the absence of pronounced mood symptoms; and (4) there is no superposition of schizophrenia, schizophrenic malformation, placement disorder, or psychotic NOS.

Dysthymia has a history of depressed mood for more than two years and during the first two years the condition does not respond to a strong depressive episode. Depressed mood in children and adults can manifest as irritability. There are also two of the following: poor appetite or over-appetite, insomnia or somnolence, low energy or fatigue, poor self-esteem, poor concentration or difficulty making decisions or feelings of hopelessness. These symptoms are not over-exposed to chronic psychotic malaise such as schizophrenia or illusory malaise. Furthermore, it is not possible to determine whether an organic factor initiates and maintains disturbance.

There are many ways to show that the compound of the present invention is useful in the treatment of depressive disorders and bipolar disorders, for example in animal models. See, for example, "Animal Models as Stimulations of Depression" by Paul Willner, TIPS 12: 131-136 (April 1991); Animal Models of Depression: An Overview by Paul Willner, Pharmac. Ther. 45: 425-455 (1990), both sources included in the literature. One such model is the Chronic Mild Stress Model of Depression (“CMS”).

CMS uses soft stress factors such as food and water withdrawal, small temperature changes, changes in growing cells, and more. Over a period of weeks with such mild stressors, the animals gradually reduce their consumption of the highly preferred sugar solution, which persists (in untreated animals) for several weeks after the cessation of stress. This reduced sensitivity of remuneration (sugar solution) is reflected in anhedonia, a symptom of a severe episode of depression (see, for example, Beharvioral Pharmacol. 5: Suppl. 1. p. 86 (1994), where lithium, carbamazepine and ketoconazole are determined in CMS; Psychopharmacology 93: 358364 (1987), where a tricyclic antidepressant is defined in CMS; Beharvioral Pharmacol. 5: 344350 (1994), where a catechol-O-methyl transferase inhibitor in CMS is determined).

Using the active ingredient of the compounds of the present invention (hereinafter MDL 100,907), the study described below was performed in comparison with the reported antidepressant imipramine.

Male Wistar rats were brought to the laboratory two months before the start of the experiment when their weight was approximately 300 g. Except as described below, the animals were reared individually, with free access to food and water, and a 12 hour light / dark cycle (light 8 AM) at 22 + ° C.

Animals are first taught to consume 1% sugar solution; the training consists of eight one-hour basic tests in which the sugar is present, in its own cell, followed by the withdrawal of food and water for 14 hours; acceptance is determined by weighing the bottles containing the sugar solution before and after the test. Accordingly, the consumption of the sugar solution was observed under similar conditions at weekly intervals throughout the experiment.

Based on the acceptance of sugar in the final basic test, the animals are divided into two marked groups. One group of animals undergoes a chronic mild stress procedure for 9 consecutive weeks. Each week of the stress regime consists of: two periods of withdrawal of food and water (12 and 14 h), two periods of tilting of the cell at 45 degrees (12 and 14 h), two periods of intermittent illumination at night (light on and off every 2 h), two 14-hour contaminated cell periods (200 ml of water in contaminated beds), two 14-hour cohabitation periods, two 14-hour stroboscopic illumination periods (150 pulses / min). Stressors are applied continuously throughout the day and night and are intermittent from time to time. Control animals are kept in a separate room and have no contact with stressed animals. They are deprived of food and water for 14 hours before each sugar test, but then food and water are freely available in the home cage. Based on the degree of their sucrose intake in the next 3 weeks of stress, both groups - stressed and control, are further divided into labeled subgroups (n = 8) and for the next five weeks they receive daily solvent intakes ( 1 ml / kg, intraperitoneally (ip) imitrapine (10 mg / kg, ip) or MDL 100,907 (0.002,0.02 and 0.2 mg / kg orally) All drug injections are in a volume of 1 ml / kg body weight. at 10 AM and the sugar test is carried out 24 hours after the last drug treatment. After five weeks, drug treatment is discontinued. After a week or so, a final sugar test takes place and stress continues throughout the treatment and cessation period.

The results are analyzed by multiple variant analysis, followed by the Fisher LSD benchmarking test.

Chronic low stress causes a gradual decrease in consumption of 1% sugar solution, in the final basic test, sugar intake is approximately 13 g in both groups. For the next three weeks of stress (Week 0), intake remained 12.4 (± 0.4) g in controls but decreased to 7.2 (± 0.2) g in stressed animals (p <0.001). Such a difference between control and stressed solution-treated animals maintained a similar level to the rest of the experiment.

Imipramine had no significant effect on the sugar intake of control animals [F (1,84) = 0.364; NS] However, the drug causes a gradual increase in sugar intake in stressed animals (F (1, 84) = 16.776; pO.001]. Sugar intake of imipramine-treated stressed animals was significantly increased from week 0 after four weeks of treatment ( p = 0.05) and after five weeks of treatment there was no significant difference between drug-treated and salt and drug-treated animals, and the increase in sugar intake in imipramine-treated animals was maintained at a similar level one week after drug removal. .

MDL 100,907 had no significant effect on sugar intake in control animals [Treatment effect: F (3,168) = 0.821; NS treatment x Weekly interactions: F (15,168 = 0.499; NS]. In stressed animals, MDL 100,907 gradually recovered the CMS-induced deficiency in sugar intake, resulting in a significant treatment effect [F93,168) = 22,567; p <0.001] and treatment x weekly interactions [F (15,158) = 1.559; p = 0.05].

In stressed animals treated with two high doses of MDL 100,907 (0.02 and 0.2 mg / kg), sugar intake was significantly increased from baseline (week 0) after two (0.02 mg / kg) and three (0.2 mg / kg) weeks from treatment (p = 0.03 and p = 0.04, respectively). The effect increased in the coming weeks, and at the end of the experimental period (week 5) the amount of sugar solution drank from these animals was comparable to that of the solution-treated controls and significantly higher than that of the stress-treated animals ( 0.02 mg / kg: p <0.001, 0.2 mg / kg: p-0.002).

At lower doses of 0.002 mg / kg, MDL 100,907 had no significant effect on sugar intake during the full treatment period. Consequently, after five weeks of treatment, the consumption of sugar by the stressed animals treated with this dose did not differ from that of the solution treated stressed animals (p = 0.860) and was significantly lower than the solution treated controls (p < 0.01). One week after stopping treatment, sugar intake was slightly changed in all MDL-treated 100,907 controls (0.002 mg / kg: p = 0.2,0.02 mg / kg: p = 0.4) and stressed animals (0.002 mg / kg: p = 0.6 , 0.02 mg / kg: p = 0.8, 0.2 mg / kg: p = 0.6).

Of course, human clinical trials can also be used to demonstrate the utility of the compound of the present invention for the treatment of depression using the Hamilton Hamilton Psychiatric Scale to evaluate depression. It includes a series of 17 categories in which each individual is evaluated, for example, low mood, guilt, suicide, insomnia, anxiety, and more. to achieve a degree that indicates clinically whether or not the patient is suffering from depression.

Claims

Claims (53)

An (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl] ethyl] -4-piperidinomethanol ester, which is a compound of formula I formula I wherein R is C ₄ - C ₂₀ -alkyl, or a stereoisomer or pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein R is straight-chain alkyl. A compound according to claims 1 or 2, wherein R is C ₅ -C ₂₀ -alkyl. A compound according to claims 1 or 2, wherein R is C ₄ -C ₁₅ -alkyl. A compound according to claims 1 or 2, wherein R is C ₉ -C ₁₅ alkyl. A compound according to claims 1 or 2, wherein R is C ₅ -C ₁₅ -alkyl. A compound according to claims 1 or 2, wherein R is C ₇ -C ₁₃ alkyl. A compound according to claims 1 or 2, wherein R is C ₇ -C ₉ alkyl. The compound according to claim 1, wherein the compound is (+) - alpha- (2,3dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4piperidine methanol decanoate. The compound of claim 1, wherein the compound is (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol hexanoate. The compound of claim 1, wherein the compound is (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol octanoate. The compound of claim 1, wherein the compound is (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine methanol hexadecanoate. The compound of claim 1, wherein the compound is (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol 2,2-dimethyloctanoate. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier. A pharmaceutical composition according to claim 14, wherein R is C ₉ alkyl is a straight carbon chain. 16. A pharmaceutical composition according to claim 14, wherein the pharmaceutically acceptable carrier is a pharmaceutically acceptable oil. Pharmaceutical composition according to claim 16, characterized in that the oil is selected from the group consisting of sesame, olive, peanut, corn, almond, cotton, coconut and castor oil. 18. A pharmaceutical composition according to claim 17, wherein the oil is sesame oil. 19. A pharmaceutical composition according to claim 14, wherein R is straight-chain C ₉ alkyl and the carrier is sesame oil. Use of a compound according to claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition useful for administration to a patient suffering from a disease condition caused by the effects of serotonin at the 5HT _2A receptor. The use of claim 20, wherein R is C ₉ -alkyl being a straight carbon chain. The use of claim 20, wherein the compound is administered intramuscularly or subcutaneously. The use of claim 20, wherein the compound is administered intramuscularly and the effects of serotonin at the 5HT _2A receptor are antagonized from about 2 weeks to about one month. Use according to claim 20 for administration to a patient suffering from psychosis. The use of claim 24, wherein the psychosis is schizophrenia. The use of claim 24, wherein R is C ₉ -alkyl is a straight carbon chain. The use according to claim 25, wherein R is straight-chain C ₉ -alkyl alkyl. The use of claim 24, wherein the compound is administered intramuscularly or subcutaneously. The use of claim 25, wherein the compound is administered intramuscularly and the patient is treated from about 2 weeks to one month Use according to claim 20 for administration to a patient suffering from bipolar depression. Use according to claim 20 for administration to a patient suffering from depression. Use according to claim 20 for administration to a patient suffering from anxiety. Use according to claim 20 for administration to a patient suffering from obsessive neurosis. Use according to claim 20 for administration to a patient suffering from a drug dependency. Use according to claim 20 for administration to a patient suffering from coronary vasospasm. Use according to claim 20 for administration to a patient suffering from angina. Use of a compound of claim 1 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition useful for administration to a patient suffering from a thrombotic disease. 38. A process for the preparation of a compound of formula I 0 A base ₃ Jy ^0CH 3 ΓΥ and F formula I wherein R is C ₄ -C ₂₀ -alkyl, or a stereoisomer or pharmaceutically acceptable salt thereof, comprising the reaction of an alcohol of formula (5) (S) with an acid halide of formula RC (O) X, an acid anhydride of formula (RCO) ₂ O or a carboxylic acid an acid of formula RCO ₂ H, wherein R has the above meanings and X is chloro or bromo, in the presence of a sufficient amount of a suitable base, to give the compound of formula I. The method of claim 38, wherein X is chloro. 40. The method of claim 38, wherein R is straight chain alkyl. The method of claim 38, wherein R is C ₅ -C ₂₀ -alkyl. The method of claim 38, wherein R is C ₄ -C ₁₅ alkyl. A method according to claim 38, wherein R is C ₉ -C ₁₃ alkyl. The method of claim 38, wherein R is C ₇ -C ₁₃ -alkyl. The method of claim 38, wherein R is C ₇ -C ₉ -alkyl. 46. A method according to claim 38, characterized in that R is C ₉ alkyl with branched carbon chain. A method according to claim 38, wherein R is straight-chain C ₉ -alkyl alkyl. The method of claim 38, wherein the base is triethylamine. A method according to claim 38, wherein R is C ₉ -alkyl straight A carbon chain, the base is triethylamine, X is chloro, and the alcohol (5) is reacted with an acid halide. A method according to claim 38, wherein the alcohol (5) is 3 0 works with RCOX. 51. The method of claim 38, wherein the alcohol (5) is reacted with (RCO) ₂ O. 52. The method of claim 38, wherein the alcohol (5) is reacted with RCO ₂ H. 53. The method of claim 38, wherein the alcohol (5) is reacted with RCOX, wherein R is C, _9- alkyl with straight 4o is a carbon chain and X is chloro.