CZ20011331A3 - Esters (+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol a their use as prodrugs of 5HT2A receptor antagonist MDL 110, 907 - Google Patents

Abstract

The present invention is directed to esters of (+)- alpha -(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

Technical field

The present invention relates to (+) - alpha- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol esters and their use as prodrugs of the 5HT2A receptor antagonist MDL 110,907.

BACKGROUND OF THE INVENTION

The compound (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol, also known as MDL 100,907, is a potent 5HT ₂ and a receptor antagonist currently clinically tested for the treatment of schizophrenia, J. Pharm. Exp. Ther. 277: 968-9881 (1996), incorporated herein by reference. The compound has been disclosed in US Patent 5,143,149, which is incorporated herein by reference.

MDL 100,907 antagonizes the action of serotonin at the 5HT ₂ and receptor and is therefore useful in the treatment of many diseases. However, this compound can also directly or indirectly achieve therapeutic effects other than just 5HT ₂ and antagonism. For example, it has been shown in European Journal of Pharmacology 273: 273-279 (1995) that MDL 100,907 has an enhanced inhibitory effect on dopamine efflux in the middle prefrontal cortex. Some of the uses of MDL 100,907 in patents or patent applications.

U. S.

Patent

5, 196, 096, wherein the claimed compounds have a general breadth, including

MDL 100,907, discloses its use for the treatment of anorexia, angina,

Raynaud's phenomenon, coronary angiospasm, prophylactic treatment of migraine, has been described: na · · pops byla byla byla byla byla byla pops pops pops pops pops pops pops Cardiovascular diseases such as hypertension, peripheral vascular diseases, thrombotic events, cardiopulmonary crisis states and arrhythmias, and further describes its anesthetic effects. See also U.S. Patent Nos. 4,783,471, 4,912,117 and 5,021,428, which are sections of U.S. Patent 5,169,096. See also U.S. Patent No. 4,877,798 (fibromyalgia), 4,908,369 (insomnia), 5,106,855 (glaucoma), EP 319 962 (anxiety), EP 337 136 (extrapyramidal symptoms). All previous patents are incorporated herein by reference.

Compound M100,907 was specifically claimed in U. S.

No. 5,134,149, which discloses use for antagonizing serotonin to 5HT ₂ receptors, for treating anxiety, angina, anorexia, Raynaud's phenomenon, intermittent claudication, coronary or peripheral angiospasm, fibromyalgia, extrapiramide symptoms, arrhythmias, ischemic drugs, thrombotic diseases, thrombotic diseases, psychotic diseases such as schizophrenia and mania. See also U.

S. Patent

No. 5,561,144,

5,700,812,

5, 721,249, which are U. S. sections.

U.S. Pat.

5,134,149 and also U.

S. Patent (obsessive-compulsive disorder) and PCT / US97 / 02597 (depressive disorders including seizures of severe depression and annoyance, and bipolar disorders) as well as insomnia and sleep apnea as described in patent application number ......., including here as a reference.

It is an object of the present invention to provide a novel compound that upon administration releases a therapeutically effective amount of MDL

100,907 over a longer period of time. A longer time interval refers to a time longer than a single dose of MDL 100,907 and should last for several days, several weeks, one month to about 6 to 8 weeks, and preferably about 2 weeks to one month.

························································ · · ·· ···

There are many advantages when administering a single dose to a patient whose effect lasts for a longer period of time. Regular administration problems can be avoided, which may be particularly important in patients suffering from psychoses or addictive behaviors such as schizophrenia, obsessive-compulsive disorder, depression, anxiety, anorexia and drug addiction. Other advantages include the absence of typical fluctuations in drug levels in the body that occur with multiple dose therapy, which means improved patient efficacy at a lower maximum drug concentration.

Although the concept of sustained release formulations is not new, not all compounds are capable of chemical conversion to new substances, which are then metabolized to the active ingredients at the desired rate and within the required time. Other factors contributing to the difficulty of preparing sustained release formulations are, for example, protein binding or other physiological processes that may affect the therapeutic efficacy of the active ingredient, see, e.g., Biochemical Pharmacology, vol. 36, no. 10, p. 1715 -1722 (1987), which is incorporated herein by reference. Also, the chemically modified compound must be compatible with pharmaceutically acceptable carriers and must be stable enough to prevent degradation to the active ingredient upon storage. In short, designing acceptable sustained release formulations is a difficult and difficult to predict task.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I:

wherein R is C 4 -C 20 alkyl or a stereoisomer or a pharmacologically acceptable salt thereof. The invention further includes:

a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier, a method of antagonizing the action of serotonin at the 5HT _2A receptor, comprising administering a compound of formula I to a needy patient, a method of treating patients having a disease state, comprising administering a therapeutically effective amount of a compound of formula I are psychoses (including schizophrenia), obsessive-compulsive disorder, thrombotic diseases, coronary angiospasm, anxiety, anorexia, Raynaud's phenomenon, fibromyalgia, extrapyramidal side effects, anxiety, arrhythmia, depression, bipolar depression, insomnia, sleep apnea, sleep disorder or sleep apnea and a process for preparing compounds of formula I, comprising reacting an alcohol of formula 5 with acyl halides, acid anhydrides or carboxylic acids in the presence of a sufficient amount of a suitable base.

The terms used herein have the following meanings:

a) "Pharmaceutically acceptable salt" refers to either an acid addition salt or a base addition salt that may be formed with the compounds of the invention.

"A pharmaceutically acceptable acid addition salt is any non-toxic organic or inorganic acid addition salt of a base of Formula I. Examples of inorganic acids that form suitable addition salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and metal acid salts such as such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Examples of organic acids forming suitable addition salts include mono-, di- and tri-carboxylic acids. Examples can be illustrated e.g.

acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, citric acid, fumaric acid, antaric acid, ascorbic acid, malic acid, glutaric acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, 2-phenoxybenzoic acid, p-toluenesulfonic acid and sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Salts with mono- or diacids may be formed and such salts may exist in hydrated or anhydrous form. In general, the acid addition salts of the compounds of the invention are more soluble in water and various hydrophilic organic solvents, and usually exhibit higher melting points compared to the free bases from which they were prepared.

"Pharmaceutically acceptable base addition salts" refers to non-toxic inorganic or organic base addition salts of compounds of Formula I or any intermediates thereof. Examples are alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium or barium hydroxide, ammonia and aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethylamine and picoline. The choice of the corresponding salt may be important due to ester hydrolysis. Selection criteria for a particular salt will be known to one skilled in the art.

b) “Stereoisomer is generally the term for all isomers of a single molecule that differ only in the orientation of their atoms in space. It includes mirror isomers (enantiomers), geometric isomers (cis / trans) and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers).

c) "Alkyl refers to a branched or straight alkyl group, as specified by the number of carbon atoms in the alkyl group, eg C 4 to C 20 alkyl refers to straight or branched alkyl groups having four, five, six, seven, eight, nine, ten, eleven, twelve , thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty carbon atoms, examples of alkyl groups include C5-C20, C1-C15, C3-C15, C5-C15, C7-C15, and C7-C9 alkyls.

(d) 'Patient refers to a warm-blooded animal such as a rat, mouse, dogs, cats, guinea pigs and primates such as humans.

e) “Heal” or “heal” refers to the alleviation of symptoms, the elimination of the causes of symptoms, either permanently or temporarily; refers to the prevention or retardation of the symptoms of said diseases or disorders.

(f) "Therapeutically effective amount" means an amount of a compound that is effective in the treatment of said disorders or diseases.

g) A "pharmaceutically acceptable carrier" is a non-toxic solvent, dispersing agent, vehicle, adjuvant or other material that is mixed with a compound of the invention to obtain a formulation or pharmaceutical composition, i.e., a dosage form capable of being administered to a patient. An example of such a carrier is a pharmaceutically acceptable oil, typically used for parenteral administration.

(h) The term 'restorative sleep' refers to sleep which, after awakening, leads to rest.

(i) The term 'sleep disorder' refers to insomnia and obstructive sleep apnea;

(j) 'insomnia' means primary insomnia, insomnia related to other mental disorders, and drug-induced insomnia;

(k) the term 'primary insomnia' refers to difficulty falling asleep, maintaining sleep or trouble sleeping, not caused by a mental disorder or psychological effects caused by taking substances (insomnia induced by drugs) or withdrawal symptoms. In the present invention, the term also includes circadian insomnia, which is insomnia induced by changes in the normal sleep cycle (site changes, time changes during rapid travel, and the like).

«·« «« «« «« «« «« «« «« «« «« «« ««

The term "insomnia associated with other mental disorders" refers to difficulty falling asleep, maintaining sleep, or having difficulty sleeping as a result of the physiological effects of taking (or withdrawal) certain substances such as caffeine, alcohol, amphetamine, opiates, sedatives, hypnotics and anxiolytics; the term "obstructive sleep apnea" refers to repeated short-term stopping of breathing (upper respiratory tract episodes) during sleep, and is typically characterized by loud snoring or short exhalation, followed by silent periods.

The (+) - isomer of α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol can be prepared by the methods described in U.S. Patent 5,134,149. A description of a suitable method follows.

• • •

Scheme I - Starting materials

F · · · · · · · · 4 · * · * 4 * 4 4 4 * * * * * * * * *

In Step A of Reaction Scheme I, esterification is performed between the racemic α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol (structure 1) and the (+) - amethoxy-phenylacetic isomer. acid (acid 2). This esterification produces the diastereomeric mixture described by formula 3. These diastereomers are subjected to silica gel chromatography, where they are separated into two diastereomers and the (+, +) - diastereomer can be isolated as shown in step Β. In Step C, the (+, +) - di-diastereomer is hydrolyzed to form the (+) - isomer of the α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine-methanol.

The esterification reaction can be performed using techniques known in the art. Typically, equivalent amounts of the (+) - isomer of the α- (2,3-dimethoxyphenylHi - (4-fluorophenyl) ethyl] -4-piperidinemethanol and the (+) - isomer of α-methoxyphenylacetic acid are mixed in an organic solvent such as dichloromethane , THF, chloroform or toluene and heated to boiling for 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), resulting diastereomers can be isolated by filtering the dicyclohexylurea.

The diastereomers are then subjected to silica gel chromatography to separate them into the (+, +) and (+, -) diastereomers. This chromatographic separation can be carried out by methods known in the art. A suitable eluent is a 1: 1 mixture of hexane and ethyl acetate.

«· 4 4 4 4 f f f f f f f f f f f f f f f f f f f f f f f f

The resulting (+, +) diastereomer is then subjected to a hydrolytic reaction to give the (+) - enantiomer of the α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol. Hydrolysis is accomplished by reacting the diastereomer with an excess of a base such as potassium carbonate in an aqueous-alcoholic solution. The hydrolysis is carried out at temperatures of 15 to 30 ° C for 2 to 24 hours. The resulting (+) - isomer of α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol can be obtained by dilution with water and extraction with dichloromethane. It is then purified by recrystallization from a solvent mixture such as cyclohexane / hexane or ethyl acetate / hexane.

Methods for producing starting materials in Reaction Scheme I are known in the art. For example, US Patent 4,783,471 describes the preparation of racemic α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol. This patent is incorporated herein by reference. Examples 1 and 2 of this application also describe suitable methods. Alternatively, racemic α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol can be prepared as follows. 4-Hydroxypiperidine is subjected to an N-alkylation reaction with p-fluorophenylethyl bromide to give 4-hydroxy-1- [2- (4-fluorophenyl) ethyl] piperidine. This compound is brominated with Ph3P.Br ₂ forming brom1--4 [2- (4-fluorophenyl) ethyl] piperidine. This compound is then reacted with Mg to form a Grignard reagent which is subsequently reacted with 2,3-dimethoxybenzaldehyde to give the desired product (±) α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] - Of 4-piperidinomethanol. The (+) - isomer of amethoxyphenylacetic acid is known in the art.

Scheme II

In Scheme II, X denotes bromine or chlorine, wherein chlorine is preferred and R is as defined above. This reaction scheme illustrates a process for the preparation of a sustained release compound of Formula I from alcohol 5.

The alcohol is allowed to react

RCO 2 H or an acid anhydride with an acyl halide (RC (O) X), (RCO) 2 O in the presence of a sufficient amount of a suitable base.

A suitable base which allows ester formation

Examples of suitable bases are dimethylaminopyridine, methyl morpholines, the halide being anhydride.

such as

Acids or trialkylamines, pyridine diisopropylethylamines, triethylamine are preferred.

Sufficient base to allow the formation of compounds of formula (I) may be determined by one skilled in the art.

Preferably, the base is added to the alcohol 5 and this mixture is added dropwise to the acyl halide or acid anhydride in the appropriate solvent. Examples of suitable solvents are chloroform,

dichloromethane or toluene, all of which are readily available, with chloroform preferred.

The reaction temperature may range from 0 to 25 ° C. The reaction mixture may be stirred for several hours to overnight. Catalysts may also be added to accelerate the reaction, e.g., 4-dimethylaminopyridine and the like.

Acyl halide starting materials (RCOX) are readily available to those skilled in the art. E.g. Aldrich Chemical Company provides stearoyl chloride, heptadecanoyl chloride, palmitoyl chloride, valeryl chloride, octanoyl chloride, undecanoyl chloride and myristoyl chloride, hexanoyl chloride, nonanoyl chloride, lauroyl chloride. When isovaleryl chloride, heptanoyl chloride, decanoyl chloride are halides which are not available, one skilled in the art can readily prepare them.

For example, carboxylic acids can be mixed with a halide donor to form the desired acyl halide. An example of this is the use of a mixture of carboxylic acid (0.17 mol), dichloromethane (660 ml) and dimethylformamide (0.5 ml) under a nitrogen atmosphere. Add oxalyl chloride (0.2 mol) followed by stirring for 5 minutes. Stirring for 3 h at room temperature and evaporation of the solvent in vacuo gave the acyl chloride. Another method is to dissolve the cyrboxylic acid (10 mmol) in 50 mL of dichloromethane. Cool the solution to 0 ° C and add thionyl chloride (11 mmol) under a nitrogen atmosphere. Stirring at room temperature for several hours followed by removal of the volatiles under vacuum results in the formation of acyl chloride. Carboxylic acids are readily available or can be made by those skilled in the art.

* E e e e e e e e * * * * * * * * * * * * * * * * * * ···

The starting materials for acid anhydrides (RCO) ₂ O are readily available to those skilled in the art. E.g. Aldrich Chemical provides butyric anhydride, isobutyric anhydride, valeric anhydride, 2,2-dimethylglutaric anhydride and acid anhydride

Alternatively, acid anhydrides can be synthesized by methods known in the art.

Company of phthalic acid.

Acid starting materials (RCOOH) are readily available or can be synthesized by methods known in the art. See, e.g., Advanced Organic Chemistry, Reactions, Mechanisms and

Structure, 4th Edition, John Wiley & Sons, New York 1992, incorporated herein by reference. Aldrich Chemical Company also provides isovaleric acid, valeric acid, terbutylacetic acid, 2,2-dimethylbutyric acid, 2-ethylbutanoic acid, hexanoic acid, 3-methylvaleric acid, 4-methylvaleric acid, heptanoic acid, octanoic acid, 2-propylpentanoic acid, non-propylpentanoic acid, , decanoic acid, undecanoic acid, lauric acid, tridecanoic acid, myristolic acid, myristic acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid, as well as others wherein two are four to four of the alkyl groups .

The following examples are provided to illustrate the invention and are not intended to limit the scope of the invention.

· * * * * * * * * * * * ···

DETAILED DESCRIPTION OF THE INVENTION

Example 1 - Starting materials

Example 1, steps A-D, shows the preparation of the starting (±)? X (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine-methanol, structure 1 in Scheme I.

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

Isonipecotamide (10.9 g, 85.0 mmol), 2- (4-fluorophenyl) ethyl bromide (15.7 g, 77.3 mmol) and K 2 CO 3 (2.3 g, 167 mmol) were dissolved in 280 mL of DMF and the solution was stirred under argon at 90-95 ° C overnight. The cooled solution was concentrated to an oily solid which was partitioned in a water-dichloromethane system. The layers were and the aqueous layer was extracted with dichloromethane.

separate

The combined organic layers were washed twice with water, dried over magnesium sulfate, filtered and evaporated to give an oily residue. Recrystallization from ethyl acetate as white fluorophenyl) ethyl] -4-piperidinecarboxamide powder, melting point: 177-178 ° C (dec.). Analysis for

C ₁₄ H ₁₉ FN ₂ O: C, 67.18; H, 7.65; N, 11.19. Found: C, 67.25;

H, 7.67; N, 11.13.

B) 4-Cyano-1- [2- (4-Fluorophenyl) ethyl] piperidine

To a stirred mixture of phosphorus oxychloride (25 mL, 41.12 g, 268 mmol) and sodium chloride (5.1 g, 87.3 mmol) was added portionwise 1- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxamide (8.9 g, 35.6 mmol). After the addition was complete, the mixture was heated to boiling for 2 hours. The cooled solution was carefully poured into dilute NH ₄ OH to decompose POCl ₃ . The aqueous solution was cooled to 0 ° C, then extracted twice with dichloromethane. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to give 8.1 g distilled (boiling point: 150 ° C, oil)

0.1 mmHg) of oil which has solidified. This material from hexane to piperidine in

Analysis for substances. The material was crystallized to give colorless 4-cyano-1- [2- (4-fluorophenyl) ethyl] white needles, m.p. 47-48 ° C.

form

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 solution of 4-cyano-1- [2- (4-fluorophenyl) ethyl] -piperidine (1.00 g, 4.3 mmol) in 20 mL THF under argon at 0 ° C was added DIBAL-H (syringe). 4.6 mL of 1.0 M solution in THF, 4.6 mmol). The mixture was stirred overnight at room temperature, then 10% aqueous HCl (25 mL) was added and the mixture was stirred for 3 hours. The whole mixture was then poured into 10% aqueous NaOH solution (50 mL) and extracted twice with ether. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated to give a light yellow oil. The oil was chromatographed on silica gel using ethyl acetate as eluent. The appropriate fractions were combined and evaporated to give an oil. This oil was distilled (boiling point: 166 ° C, 0.05 mmHg) to give 1- [2- (4-fluorophenyl) ethyl] 4-piperidinecarboxaldehyde as a colorless oil. Analysis for C ₁₄ H ₁₈ FNO: C, 71.46; H, 7.71; N, 5.95. Found: C, 71.08; H, 5.86.

D) (±) α- (2,3-Dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol

To a stirred solution of veratrol (0.93 g, 6.7 mmol) in 20 mL of THF was added a solution of nBuLi (2.7 mL of a 2.5 M solution in hexane, 6.75 mmol) under argon at 0 ° C. The mixture was stirred for 2 h, then the solution was cooled to -78 ° C and left to stand at -78 ° C. React with a solution of 1- [2- (4-fluorophenyl) ethyl] -4-piperidinecarboxaldehyde (1.30 g, 5.5 mmol) in 25 mL THF, which was added via an addition funnel. The cooling bath was removed and the solution was allowed to stir for 2 h. Water was then added, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and chromatographed on silica gel using AcOEt as eluent. The appropriate fractions were combined and evaporated to give a white solid. The material was crystallized from hexane to give racemic α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol as shiny white needles, mp 126-127 ° C.

Analysis 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 materials

Example 2, steps A to F, shows an alternative method of preparing (±) α- (2,3-dimethoxyphenyl) -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 1 N NaOH solution (40 g NaOH in 900 mL water) and tert-butanol (1800 mL) was added portionwise di-tert-butyl dicarbonate (200 g, 916 mmol). . The mixture was stirred overnight, then the solution was concentrated and the resulting aqueous layer was acidified with aqueous HCl. The acidified solution was then extracted 3 times with ether. The combined organic layers were washed with water, brine, dried over MgSO ₄ , filtered and evaporated to give a solid which was recrystallized from EtOAc / hexane (300 mL / 200 mL) to give a solid. 1- (1,1-dimethylethyl) -1,4-piperidinecarboxylic acid as white needles, m.p. 147-149 ° C.

B) 4- (N-Methoxy-N-methylcarboxamido) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester

To a stirred solution of piperidinecarboxylic acid anhydrous dichloromethane was added in portions with an atmosphere of 1.240 mmol). The mixture was stirred

1- (1,1-dimethylethyl) -1,4 (50,0 g, 218 mmol) in 500 ml in a 2 L flask under nitrogen

1'-Carbonyldiimidazole (38.9 g, h) was added all at once

N, O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol). The mixture was stirred overnight, the solution was washed twice with 1N HCl, washed twice with saturated NaHCO 3 solution, washed once with brine, dried over MgSO ₄ , filtered and scalded to give an oil. Distillation gave 4- (N-methoxy-N-methylcarboxamido) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester as a colorless oil, boiling point: 120-140 ° C, 0.8 mmHg.

C) 4- (2,3-Dimethoxybenzoyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester n-Butyllithium (14.5 mL of a 2.5 M solution in hexane, 36.3 mmol) was added via syringe at 0 ° C under nitrogen. of a stirred solution of veratrol (5.00 g, 36.2 mmol) in 50 mL of anhydrous THF. The ice bath was then removed and the mixture was allowed to stir for 90 minutes. The mixture was then cooled to -78 ° C and treated with 4- (N-methoxy-N-methylcarboxamido) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester (9.20 g, 33.8 mmol) in 50 mL of anhydrous THF, which was added via syringe. The cooling bath (acetone, dry ice) was removed and the mixture was allowed to warm to room temperature. The mixture was stirred for 3 h, saturated aqueous ammonium chloride solution was added and the mixture was allowed to stir overnight. The layers were: · · The aqueous layer was extracted with ether. The combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated to an amber oil. The oil was chromatographed on silica gel using 20% ethyl acetate in hexane as eluent. The appropriate fractions were combined and evaporated to give 4- (2,3-dimethoxybenzoyl) -1-piperidinecarboxylic acid 1,1-dimethylethyl ester as a colorless oil (boiling point: 225-250 ° C, 0.05 mmHg).

Analysis 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-piperidinomethanone

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 solution was then poured into 900 mL of ether and allowed to stand overnight. Filtration gave 4- (2,3-dimethoxyphenyl) -4-piperidinomethanone trifluoroacetate as fine white needles, melting point: 123 ° C.

Analysis for C ₁₄ H ₉ NO ₃ . CF ₅ CO ₂ 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-piperidinomethanone trifluoroacetate was dissolved in water, NaOH (10% aqueous solution) was added until basic, and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated to give 4- (2,3-dimethoxyphenyl) -4-piperidinomethanone as an oil.

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

A solution of 4- (2,3-dimethoxyphenyl) -4-piperidinomethanone (8.00 g, 32.1 mmol) and 2- (4-fluorophenyl) ethyl bromide (6.52 g, 32.1 mmol) in 90 mL of DMF was mixed with K ₂ CO ₃ (7.0 g, 50.7 mmol) and stirred overnight at 80 ° C under argon. The cooled solution was poured into ethyl acetate water (2: 1). The layers were separated and the aqueous layer was extracted with EtOAc / toluene 2: 1. The combined organic phases were washed twice with water, once with brine, dried over MgSO ₄ , filtered and evaporated to give 11.0 g of an oil. This oil was chromatographed on silica gel using ethyl acetate as eluent. The appropriate fractions were combined, concentrated, dissolved in ethyl acetate and treated with HCl / ethyl acetate. (2,3-Dimethoxyphenyl) - [1- [2- (fluorophenyl) ethyl] -4-piperidinyl] methanone monohydrochloride was obtained as a precipitate, m.p. 225-227 ° C (dec.).

Analysis 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) (±) α- (2,3-Dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine-methanol

To a stirred solution of (2,3-dimethoxyphenyl) - [1- [2 (fluorophenyl) ethyl] -4-piperidinyl] methanone (6.0 g, 16.2 mmol) in 100 mL of methanol was added at 0 ° C over an hour in two portions of NaBH ₄ (1240 mg, 32.8 mmol). The mixture was stirred overnight and the solution was concentrated to a solid which was partitioned between ether and water. The layers were separated and the aqueous was extracted with ether. The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and evaporated to dryness. The solid residue was chromatographed on silica gel using acetone as eluent. The appropriate fractions were combined and evaporated to give a white solid, which was crystallized from cyclohexane to give (±) α- (2,3-dimethoxyphenyl) -1- [2- (421 fluorophenyl) ethyl] -4-piperidinomethanol as white needles, melting point: 126-127 ° C.

Analysis 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 illustrates the preparation of an alcohol of formula 5.

Preparation of (±) α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol

A) Preparation of diastereomers

A solution of 3.90 g (10.4 mmol) of (±) α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol,

1.74 mmol) of S - (+) - α-methoxyphenylacetic acid,

2.15 mmol)

1,3-dicyclohexylcarbodiimide

0, 1

4-Dimethylaminopyridine in 75 mL of chloroform was heated to reflux for 17 h. The mixture was then cooled to room temperature and filtered. The filtrate was concentrated and chromatographed on silica gel using ethyl acetate / hexane (1: 1) to give two diastereomers, Rf

0.1 and 0.2 (TLC EtOAc / hexane 1: 1). The combined undivided fractions were chromatographed once more to give additional material. Fractions with Rf = 0.2 were combined to give the ester of a single diastereomer of (+, +) - (2,3-dimethoxyphenyl) [1- (2- (4-fluorophenyl) ethyl] -4-piperidinyl] methyl-α-methoxybenzacetate.

B) Preparation of (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol

To a solution of 0.97 g (1.9 mmol) of the above diastereomeric ester, Rf

0.2, in 25 ml of methanol was

0.5 g (3.6 mmol) of potassium carbonate and 5.0 ml of water were added. The mixture was stirred for 17 h at room temperature, diluted with water and extracted with dichloromethane. The combined extracts were washed with water, brine and dried over MgSO 4. After filtered! the filtrate was concentrated to an oil and crystallized from 40 mL of cyclohexane / hexane 1: 1 to give (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol, melting point: 112-113 ° C, [α] _D ²⁰ = + 13.9 °.

Example 4 (+) - α- (2,3-Dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanoldecanoate

A mixture of 49.0 g (0.131 mol) of (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol, 500 ml of chloroform and 16.0 g (0.158 mol) The triethylamine was placed in a 1 liter, three necked flask equipped with a stirrer, a thermometer, a dropping funnel and a nitrogen inlet. Then a solution of 27.4 g (0.144 mol) of decanoyl chloride in 25 ml of chloroform was added over 5 minutes while maintaining the temperature of the mixture between 20-25 ° C. The resulting solution was stirred at the same temperature for an additional 2 h. The progress of the reaction was monitored by TLC (5/95 methanol / CH ₂ Cl ₂ , Dipstick 60F-254, Rf (+) - α- (2,3-dimethoxyphenyl) 1- [ 2- (4-Fluorophenyl) ethyl] -4-piperidinomethanol is 0.23, Rf

the title compound is 0.55). An additional 2.8 g (0.015 mol) of decanoyl chloride (Aldrich) and 1.6 g (0.016 mol) of triethylamine were then added to the reaction mixture and the mixture was stirred for an additional 2 h. The reaction mixture was diluted with 500 ml of dichloromethane and washed with 250 ml. 5% K ₂ CO ₃ solution, 250 ml water and 250 ml brine. The organic phase was dried over 500 g MgSO ₄ and filtered. The filter cake was washed with 200 mL of dichloromethane. The filtrate was concentrated at 40 ° C / 50 torr to give an oil.

The crude product was purified by flash chromatography (14x29 cm column, 2.035 kg silica gel, 230-400 mesh). The crude product was loaded onto the column as a solution in 75 mL of dichloromethane. The column was eluted with 24 L of EtOAc / dichloromethane 1/4 and 24 L fractions were collected. Fractions were checked by TLC and the corresponding fractions were concentrated at 35 ° C / 50 torr and then dried for 1 hour at 75 ° C / 0.5 Torr to give a colorless oil.

MS (M ^& lt ^{; +} & gt ^; = 528)

Analysis

Calculated for C ₃ H ₄₆ FNO ₄ (527.73): 72.83% C 8.79% H 2.65% N Found: 72.25% C 8.88% H 2.63% N

Example 5 (+) - α- (2,3-Dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol hexanoate

ch ₃

To a stirred solution of 2.0 g (5.37 mmol) of (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine-methanol in 6 mL of dry dichloromethane was added 0.74 mL (0.537 g, 5.32 mmol) of triethylamine. The solution was cooled in an ice bath, and 1.07 mL (5.89 mmol) of hexanoic anhydride was added via syringe. The solution was stirred in an ice bath for several minutes and then warmed to room temperature. To the solution was then added 66 mg (0.541 mmol) of 4-dimethylaminopyridine. The mixture was stirred overnight and poured into ice / water / 0.5M NaOH. After extraction with ether and filtration, the mixture was concentrated to an oil. The oil was dissolved in dichloromethane and chromatographed on silica gel using 2% methanol / dichloromethane as eluent. Fractions containing pure product were combined and concentrated to give an oil which was dried overnight at 60 ° C under high vacuum to give the title compound. The compound was homogeneous by TLC. IR (KBr), NMR (CDCl 3) and MS (MH ⁺ = 472) were consistent with the proposed structure. Analysis

Calculated for C28H38FNO4: 71.31% C 8.12% H 2.97% N Found: 70.94% C 8.07% H 2.88% N

Example 6 (+) - α- (2,3-Dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol octanoate

O

• ·

To a stirred solution of 2.0 g (5.37 mmol) of (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol in 6 mL of dry dichloromethane was added 0, 74 mL (0.537 g, 5.32 mmol) of triethylamine. The solution was cooled in an ice bath and then 1.75 ml (5.89 mmol) of octanoic anhydride was added via syringe. The solution was stirred in an ice bath for several minutes and then warmed to room temperature. To the solution was then added 66 mg (0.541 mmol) of 4-dimethylaminopyridine. The mixture was stirred, washed with water and saturated sodium chloride solution. The organic extract was dried over sodium sulfate, filtered, and concentrated to an oil. The oil was dissolved in dichloromethane and chromatographed on silica gel using dichloromethane and dichloromethane, respectively. with 1% and 2% methanol / dichloromethane as eluent. Fractions containing pure product were combined and concentrated to give an oil which was dried overnight at 60 ° C under high vacuum to give the title compound. The compound was homogeneous by TLC. IR (KBr), NMR (CDCl ₃ ) and MS (MH ⁺ = 501) were consistent with the proposed structure.

Analysis

Calculated for _C2 8H3 ₈ FNO _4: 72.11% C 8.47% H 2.80% N Found: 71.94% C 8.63% H 2.83% N

Example 7 (+) - α- (2,3-Dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol hexadecanoate

O

To a stirred solution of 2.0 g (5.36 mmol) of (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol in 6 mL of dry dichloromethane was added 0 76 ml (5.46 mmol) of triethylamine and the solution was cooled in an ice bath. To the solution was then added 2.92 g (5.89 mmol) of octanoic anhydride and the mixture was stirred at 0 ° C for 15 minutes. The reaction mixture was then warmed to room temperature and 65 mg (0.536 mmol) of 4-dimethylaminopyridine was added to the solution. The mixture was then stirred under a nitrogen atmosphere overnight. The reaction mixture was poured into 50 mL of 0.5 N NaOH solution and 50 mL of diethyl ether. A precipitate was observed and the resulting suspension was extracted with dichloromethane. The organic layer was washed with water and saturated sodium chloride solution and dried over sodium sulfate. Filtration and concentration gave a yellow oil. The oil was dissolved in dichloromethane and chromatographed on silica gel using dichloromethane and dichloromethane, respectively. with 1% and 2% methanol / dichloromethane as eluent. The appropriate fractions were combined and concentrated to give a yellow oil. The oil was dried twice at 60 ° C under high vacuum overnight to give the title compound. The compound was homogeneous by TLC. IR (film), NMR (CDCl ₃ ) and MS (MH ⁺ = 612) were consistent with the proposed structure.

Analysis

Calculated for C24H30FNO4: 74.59% C 9.55% H 2.29% N Found: 74.34% C 9.45% H 2.29% N • (+) - α- (2,3-Dimethoxyphenyl) ) -1- [2- (4-fluorophenyl) ethyl] -427

EXAMPLE 8 Piperidine Methanol 2,2-Dimethyloctanoate

2-Hexene-1-mesylate was prepared by adding N, N-diisopropylethylamine (12.9 g, 0.1 mol) to a solution of trans-2-hexen-1-ol (10.0 g, 0.1 mol) in 100 mL of dichloromethane. To this solution was added dropwise methanesulfonyl chloride (12.6 g, 0.11 mol) in 50 mL of dichloromethane, and the mixture was stirred for 4 h at room temperature. The reaction mixture was then transferred to a separatory funnel and washed with cold 1N HCl (twice) followed by saturated NaHCO 3 solution (twice). The solution was dried over MgSO ₄ , filtered, and concentrated in vacuo at 40 ° C to give 2-hexene-1-mesylate.

2,2-Dimethyl-3-octenenitrile was prepared by adding 2-hexene-1-mesylate (11.02 g, 0.05 mol) in 100 mL anhydrous THF to a solution formed by mixing isobutyronitrile (3.7 g, 0.053 mol) in 25 mL THF and NaH (60% in mineral oil) (2.1 g, 0.053 mol) in 50 mL dry THF. The resulting reaction mixture was stirred under reflux for 5 h, cooled and stirred with ice-cold ethanol (95%). The solvent was then removed by concentration in vacuo. Water (50 ml) was added and the mixture was extracted with diethyl ether (3 x 40 ml). The extracts were washed with water and then with saturated NaCl solution, dried over MgSO ₄ , filtered and concentrated to give 2,2-dimethyl-3-octenenitrile.

2,2-Dimethyl-3-octenic acid was prepared by adding 2,2-dimethyl-3-octenenitrile (1.51 g, 0.01 mol) to a solution prepared from 15% NaOH in butal / water (2: 3, 30 mL) ). The reaction mixture was stirred at reflux for 7 h, cooled and acidified with 10% hydrochloric acid. The reaction mixture was extracted with diethyl ether and the organic layer was washed with brine, dried over MgSO ₄ , filtered, and concentrated to give 2,2-dimethyl-3-octenic acid.

2.2-Dimethyloctanoic acid was prepared by dissolving 2,2-dimethyl-3-octenic acid (0.20 g, 1.1 mmol) in absolute ethanol degassed with N ₂ , adding 10% palladium on carbon followed by six hours hydrogenation. The catalyst was filtered off and the filtrate was concentrated in vacuo to give 2,2-dimethyloctanoic acid.

To a stirred solution of (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanol (3.9 g, 10.4 mmol) in 70 mL of dichloromethane was added dicyclohexylcarbodiimide ( 2.15 g, 10.4 mmol), 4-dimethylaminopyridine (0.1 g) and 2,2-dimethyloctanoic acid (1.70 g, 10.4 mmol). The resulting solution was stirred at reflux for 16 h. The cooled reaction mixture was filtered and concentrated to an oil. The resulting oil was chromatographed on silica gel using ethyl acetate / hexane (1: 1) as eluent. The appropriate fractions were combined, heated to 40 ° C, and concentrated under reduced pressure to give the title compound.

Example 9

This example shows a pharmaceutical composition of the invention.

In a suitable 100 mL volumetric flask was placed 70 mL of sesame oil, NF (Sigma), 1.2 g benzyl alcohol, NF and

14.129 g of (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) • ·

ethyl] -4-piperidine-methanoldecanoate. To this solution was added a quantity of sesame oil to a total volume of 100 ml and the mixture was homogenized. This solution may be sterilized and packaged for parenteral injection.

Example 10

This example describes a behavioral assay (antagonism of DOI-induced behavior) defined to identify compounds exhibiting 5HT ₂ antagonist activity and receptors. The compound of the invention used in this assay was (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanedecanoate - Example 4. 5-HT 2A / 2C agonist ( ±) -DOI HCl (1- (2,5-dimethoxy-4-iodophenyl) 2-aminopropane hydrochloride) induces several quantifiable behaviors in rats. These behaviors include "shaking (rapid shaking of the head and body, like a wet dog shaking the body)," knocking of the front foot (rapid treading of the front foot), and "skin tremors (paraspinal muscle contractions or dorsal skin tearing). 5-HT2 antagonists, mianserin, ritanserin, and methysergide, as well as the selective 5-HT2A antagonist MDL 100,907, have been shown to block dose-related behavioral effects (DOran, Pranzatelli, 1990, Neurosci. Let. 11: 74-80;

Wettstein et al., 1996, Soc. Neurosci. Abs. 22: 481). Drugs with 5-HT ₂ and antagonist activity have been found to possess atypical antipsychotic properties in schizophrenic patients (Meltzer et al., 1989, JPET.251: 238-246), as well as potential therapeutic activity in many central nervous system disorders including depression , annoyance and anxiety (Stefanski & Goldberg, 1997, CNS Drugs, 7: 399-409).

»···· * *»

Methods

Subjects and their cultivation

Male Sprague-Dawley rats (180 ± 50 g) were housed seven per cage and allowed to acclimatize in the vivarium for 1 week. Water and food were freely available. Temperature and light cycle (12 h light, 12 h dark) were maintained automatically. Individual rats were tested once. Each test group contained seven animals. The experiments were carried out in a vivarium where the rats were kept.

Preparation of the drug and its administration (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine methanoldecanoate (120 mg / kg equivalent to MDL 100,907) was dissolved in sesame oil and was intramuscularly administered to groups of animals on Day 0 in a volume of 60 ml / 100 g body weight. Control animals were injected with an equal volume of sesame oil. (±) -DOI HCl (3.0 mg / kg, 1 ml / kg body weight) was dissolved in distilled water using an ultrasonic bath and injected intraperitoneally on the respective day of testing.

Observation and determination of behavior

Rats injected with (+) - α- (2,3-Dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanoldecanoate were tested for antagonism of DOI-induced behavior 1, 5, 7,

14, 21, 28 and 40 days after intramuscular injection of (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine-methanoldecanoate. Each rat was tested once. Immediately after the DOI injection, rats were placed under clean inverted plastic boxes (28 cm x 25 cm x 25 cm, length, width, height) that were placed on clean absorbent paper. The rats were continuously monitored by a trained person (who did not know whether or not rats were injected with the active substance) for 30 minutes and monitored for the appearance of DOI induced behavior (shaking, skin tremors and foreping) and then returned to their home cage. Rats were later used for pharmacokinetic studies. The DOI induced behavior frequencies were recorded and then summed. This gave an individual behavior score for each rat.

Data analysis

Mean value and standard error of behavioral score of each group were determined. Each drug injection group was then compared separately to the mean value of the control group (sesame oil injection) using a one-factor variant assay (ANOVA) and then using the Bonferroni / Dunn post-hoc comparison method. Group differences were considered statistically significant when p values were less than or equal to 0.05.

Results

Significantly antagonized DOI-induced behavior in rats was observed throughout the 28 days. The effect was not significant after 40 days.

Example 11

This experiment demonstrates the absorption of a single dose of MDL 100.907 following intramuscular administration of (i.m.) (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanoldecanoate, a compound of the invention.

• »

A total of ninety Wistar rats weighing between 150-200 g were injected with (+) - α- (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinomethanedecanoate in sesame oil (equivalent to 120 mg) / kg MDL 100, 907) on day 0. Rats were anesthetized with lethal ip the dose of nembutal and blood was collected at 3 and 6 hours, and on designated days after dosing (n = 5 for each time point) in a heparinized vial. Blood samples were centrifuged for 30 minutes at 5 ° C and 2700 rpm. Plasma was removed and stored at -20 ° C until assay. Plasma samples were analyzed using the appropriate HPLC method. At the above time points, brains were also collected and stored at -80 ° C until analysis by a suitable HPLC method. The results are summarized in Table 1.

• · • ·

Table 1 Time (days) (+) - α- (2,3-Dimethoxyphenyl) (+) ^{_ _} Oc (2, 3-Dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] —1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol -4-piperidinomethanoldeka- (ng / ml) - MDL 100,907 noate - Example 4 (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 15 Dec 11, 67 + 6, 18 52.36 ± 15.20 19 Dec 6.37 ± 2 , 19 40.06 + 8.44 22nd 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 i : 3 , 81 24.12 + 9, 15

The dosage range at which the compounds of Formula I possess the ability to block the action of serotonin at the 5HT _2A receptor may vary depending on the particular disease or conditions and severity, the patient, the composition used, the disease state of the patient and other drugs that the patient simultaneously takes. In general, the compounds of Formula I will exhibit their serotonin 5HT _2A antagonist properties at doses of from 0.001 mg / kg body weight of patient / day to about 100 mg / kg body weight of 4 weight / day. Sustained release formulations may contain multiples of the aforementioned doses depending on the time period over which the active ingredient is to be released. Dosages of the compounds of this invention can be determined by administering the compound to animals and determining the concentration of active ingredient in blood plasma.

The compounds of the invention may be admixed with a pharmaceutically acceptable carrier capable of administration in a preferred manner to provide sustained release of the compound of the invention so that a therapeutically effective amount of (+) - α- (2,3-dimethoxyphenyl) -1- [ 2- (4-fluorophenyl) ethyl] -4-piperidine-methanol in a few days or weeks. Sustained release compositions preferably comprise a compound of Formula I and a pharmaceutically acceptable carrier for parenteral administration either as an aqueous suspension, an oil solution, an oil suspension or an emulsion. Some of the sesame oils useful for intramuscular injection are, for example, oil, olive oil, peanut oil, corn oil, oil, cottonseed sesame oil, pharmaceutically benzyl alcohol.

preferably administered intramuscularly or subcutaneously, with peanut oil, oil, peanut oil and castor oil being preferred. An acceptable preservative of sequential oil formulations may be added with almond, with intramuscular administration being preferred as a release, although other modes of administration such as oral, transdermal, nasal spray and the like may be used as desired.

Since the compounds of the present invention release (+) - and (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol ("Active Ingredient") to the patient for therapeutic effect, the compounds of the present invention are: · Suitable for all indications of use where the active ingredient is useful. Some of these indicated uses have been described in patients exposed to the general administration of the active ingredient (US Patent 5,134,149; 5,561,144; 5,618,824 and PCT / US97 / 02597, which are incorporated herein by reference). disorders, thrombotic disease, coronary angiospasm, intermittent claudication, anorexia, Raynaud's disease, fibromyalgia, extrapyramidal side effects, anxiety, arrhythmia, depression and bipolar depression or drug dependence (eg, cocaine, nicotine and the like) have been reported. in the patents described above and in US Patent Nos. 5,561,144, 5,618,824, 4,877,798, 5,134,149 and 5,021,428, which are incorporated herein by reference.

Psychoses herein refer to conditions where a patient suffers from a significant mental disorder of organic and / or emotional origin, characterized by a disintegration of the personality, loss of contact with reality, often desilusion, hallucinations or visions. Representative examples of psychotic disorders that can be treated with the compounds of this invention include schizophrenia, schizophreniform disorders, schizoaffective disorders, mirage, brief psychotic disorders, shared psychotic disorders, otherwise unspecified psychotic disorders and chemical-induced psychotic disorders. See Diagnosis and Statistical Manual of Mental Disorders, 4th Edition, American Psychiatry Association, incorporated herein by reference. The active ingredient is currently in clinical practice for the treatment of schizophrenia.

Patients with obsessive-compulsive disorder (OCD) are unable to get rid of or avoid torture thoughts or ideas. Since OCD is characterized by a lack of cognitive ability and changes in metabolic activity in circuits connecting the orbital cortex to the cortex of the striatum, it has been predicted that OCD patients may exhibit insufficient PPI (prepulse inhibition). The active ingredient was found to restore PPI. See Psychopharmacology 124: 107-116 (1996), RA Padich, et al., &Quot; 5HT modulation of auditory and visual sensorimotor gating: II. Effects of 5HT _2A antagonists MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5HT antagonists in Wistar rats.

The active ingredient is also effective in preventing acute thrombosis, especially in coronary arteries. This compound reduces the rate of platelet aggregation as a result of minor changes in the endothelial lining of the vasculature and thus prevents the emergence of acute pathological thrombi. See the description in U.S. Patent 5,561,144.

Anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon, and coronary angiospasm have the same meaning as defined in the 27th edition of Dorlan's Illustrated Medical Dictionary, incorporated herein by reference.

Fibromyaligia is a condition of chronic disease in which the patient suffers from numerous symptoms such as general muscle pain, stabbing pain, fatigue, morning stiffness, and sleep disorders that may be characterized by inadequate sleep phase 4.

Extrapyramidal effects are often accompanied by the administration of neuroleptic agents such as haloperidol and chlorpromazine. Patients often suffer from a similar syndrome to paarkinson's disease, with muscle stiffness and tremor. Other patients suffer from akathisia and acute dystonic reactions.

The active ingredient increases the duration of the potential action of myocardial tissue, thereby increasing the treatment-resistant period of

»This tissue, so according to the classification system

Williams shows class 3 antiarrhythmic activity.

They could be

Vaughan

Compounds of the invention for treating drug addiction in patients.

See T. F.

used

Meert, et al., European Journal of Pharmacology wherein the 5HT ₂ antagonist eliminates both alcohol and cocaine preferences in a rodent model of drug dependence.

Other animal models, such as the rodent self-simulation model described in R.A., may be used to demonstrate the ability of the compounds of this invention to treat drug addiction.

Behavioral Neuroscience 101: 546-559 (1987).

The compounds of the invention are

Frank, useful in and bipolar treatment of patients with depressive disorder disorders. In the Diagnostic and Statistical Manual of Mental Disorders (Third Revised Edition) ("DSM-III-R!"), Incorporated herein by reference, depressive disorders are defined as major depression, dysthymia, and depressive disorder NOS. We also included a major depressive episode in this category including chronic type, melancholy and seasonal distribution. Bipolar disorders include bipolar dysfunction, cyclothymia, and bipolar NOS disorder.

The feature of depressive disorders is one or more periods without a history of manic or hypomanic seizures. A feature of bipolar disorders is the presence of one or more manic or hypomanic seizures, usually accompanied by one or more major depressive seizures. Manic and hypomanic seizures are different periods during which the dominant mood is either elevated, expansive, or irritable and there are concomitant symptoms of Manic Syndrome as defined in DSMIII-R. The disorder is so severe that it causes increased disturbance in working at work or in society.

The major depression has one or more episodes. The episodes of major depression are characterized by: (1) at least the following five depressed moods, loss of interest in entertainment (anhedonia),

significant weight loss without diet, insomnia or excessive sleepiness, psychomotor activity or retardation, fatigue or loss of energy, feelings of uselessness

or increased or increased. inadequate guilt by reducing the ability to think or concentrate or returning thoughts of death, including suicide; (2) it is not possible to determine that the fault is

caused by a maintained by organic factor; (3) does not

up to two weeks of no imagination or hallucinations in the absence of significant moody symptoms; (4) there is no overlap with schizophrenia, schizophreniform disorder, delusions or psychotic NOS disorder.

Annoyance has a history of depressed mood for several days to two years, and does not meet the criteria for a major depression during the first two years of the disorder. Depressed mood in children and adolescents may prove irritable. At least two of the following factors are also present: poor appetite or overeating, insomnia or increased sleepiness, lack of energy or exhaustion, low self-esteem, poor concentration or difficulty in deciding or feeling hopeless. These symptoms do not overlap with chronic psychotic disorders such as schizophrenia or misconceptions. It cannot be determined that the disorder is caused and maintained by an organic factor.

There are many ways to show that a compound of the invention is useful in the treatment of depressive disorders and bipolar disorders, such as in animal models. See, e.g., "Animal Models as Simulations 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 of which are incorporated herein by reference. One such model is the Chronic Mild Stress Model of Depression (CMC).

CMC uses weak stressors such as lack of food and water, small temperature changes, cage changes, and the like. The animals are exposed to weak stressors for several weeks, while the animals gradually reduce the consumption of the highly preferred sucrose solution, which persists (in animals without similar stresses) several weeks after the end of the stress of the animals.

This reduced sensitivity to recovery (sucrose solution) reflects anhedonia, a symptom of a major depression attack (see, eg, Behavioral Pharmacol. 5: Suppl. 1., p.

(1994), where lithium, carbamazepine and ketoconazole were evaluated in CMC; Psychopharmacology 93: 358-364 (1987) where a tricyclic antidepressant was evaluated in CMC; Behavioral Pharmacology: 5: 344-350 (1994) where the catechol-O-methyltransferase inhibitor was evaluated in CMC).

The following CMC study was performed using the active ingredient of a compound of the invention (hereinafter referred to as "

MDL 100,907) compared to the known antidepressant compound

Imipramine.

Male Wistar rats were brought to the laboratory 2 months prior to the start of the experiments, at which time they weighed approximately 300 g. Unless otherwise stated, rats were housed separately with freely available food and water and maintained on a 12 hour light / dark cycle (at 8 am) and at a temperature of 22 ° C.

The animals were first trained to consume 1% sucrose solution, training consisted of eight one-hour baseline tests when sucrose was administered to the cage, followed by a 14-hour lack of food and water; consumption was measured by weighing pre-weighed bottles containing 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 consumption in the final baseline test, the animals were divided into two equal groups. One group of animals was subjected to chronic mild stress for 9 consecutive weeks. Each week, the stress regime consisted of the following: two periods of food and water scarcity (12 and 14 hours), two periods of inclined cage of 45 degrees (12 and 14 hours), two periods of intermittent night illumination (lights on and off every 2 hours ), two 14-hour periods of soiled cage (200 ml of water with wood sawdust), two 14-hour periods of pairing, two 14-hour periods of low intensity stroboscopic illumination (150 flashes / min). Stressors were applied continuously throughout the day and night and were randomly distributed. Control animals were housed in a separate room and were not in contact with stressed animals. They were separated from food and water 14 hours prior to each sucrose test, but otherwise diet and water were freely available based on weeks of sucrose consumption animals were both stressed divided into equal subgroups (n = following 5 of their scores after stressing weeks intraperineally).

0.02 drugs were in a volume of 1 of their cages. The following 3 and so

8) and received daily vehicle control (1 ml / kg, or MDL imipramine (10 mg / kg, ip) and 0.2 mg / kg orally). All injections ml / kg body weight. Drugs were continuously during the period of administration and absence.

administered at 10 am and sucrose tests were performed hours after the last drug administration. After five weeks, drug administration was stopped and after one week of absence the final sucrose test was performed. Stress was performed

Results were analyzed by multiple analysis of variance according to Fisher's LSD test for post hoc comparison of mean values.

Chronic mild stress causes a gradual decrease in the consumption of 1% sucrose solution, in the final baseline test the consumption of sucrose was approximately 13 g in both groups.

After three weeks of stress (Week 0), control group consumption remained at 12.4 (± 0.4) g, but in stressed animals, the difference between control and stressed animals remained at a similar level for the remainder of the experiment.

Imipramine had no significant effect on sucrose consumption in control animals [F (1,84) = 0.364; NS]. However, the drug caused a gradual increase in sucrose consumption in stressed animals [F (1.84) = 16.776; p <0.001). Sucrose consumption in imipramine-treated animals was significantly increased from Week 0 after four weeks of administration (p = 0.05), and after five weeks of administration there was no significant difference between stressed animals treated with imipramine and control animals treated with imipramine. drug or brine. The increase in sucrose consumption in imipramine-treated animals was maintained at the same level one week after the absence of the drug.

MDL 100,907 had no significant effect on sucrose consumption in control animals administered:

NS administration weeks of interaction:

gradually turning which leads

NS]. U stressed

CMS-induced for significant effect

Administration x weeks of animals

MDL 100,907 sucrose consumption deficit, administration of interaction p = 0.05].

• ·

In stressed animals receiving two higher doses of MDL 100.907 (0.02 and 0.2 mg / kg), sucrose consumption was significantly increased from baseline (Week 0) to two (0.02 mg / kg) and three (0 , 2 mg / kg) weeks of administration (p = 0.03 and p = 0.04). This effect was further increased over the following weeks and at the end of the administration period (Week 5) the amount of sucrose drunk was comparable to that of vehicle-treated control animals and was significantly higher than that of stressed vehicle-treated animals (0.02 mg / kg: p <0.001, 0.2 mg / kg: p = 0.002).

At the lowest dose of 0.002 mg / kg, MDL 100.907 had no significant effect on sucrose solution consumption over the entire administration period. Consequently, after five weeks, the consumption of sucrose in stressed animals treated with this dose did not differ from that of stressed animals treated with vehicle (p = 0.860) and was significantly lower than that of control animals treated with vehicle (p <0 , 01). One week after the absence of administration, sucrose consumption was not significantly altered in all control animals receiving MDL 100.907 (0.002 mg / kg: p = 0.2, 0.02 mg / kg: p = 0.9, 0.2 mg / kg: p = 0.4) even in 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 may also be used to demonstrate the usefulness of the compounds of the invention in the treatment of depression using the Shortened Hamilton Psychiatric Rating Scale for Depression. This includes a series of 17 categories in which, for example, depressed mood, guilt, suicidal tendencies, insomnia, anxiety, etc., are individually evaluated to achieve a score showing clinicians whether or not the patient is depressed.

Claims (20)

Ν Τ O V É PATE 1. wherein R is alkyl having 4 to 20 carbon atoms, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof 2. A compound of formula I according to claim I, straight alkyl chain. 3. A compound of the formula according to claims up to 20 carbon atoms. A compound of the formula according to claims up to 15 carbon atoms. 5. A compound of the formula according to claims up to 15 carbon atoms. 6. A compound of the formula according to claims up to 15 carbon atoms. A compound of the formula according to claims up to 15 carbon atoms. acceptable where it is 2, 2, 2, where where where where my has my has A compound of formula I according to claims 1 and 2, wherein R has from 7 to 9 carbon atoms. A compound of the formula I according to claim 1, wherein the compound is (+) - (α) - (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol decanoate. A compound of formula (I) according to claim 1, wherein the compound is (+) - (α) - (2,3-dimethoxyphenyl) -1- [2-fluorophenyl) ethyl] -4-piperidinemethanol hexanoate. A compound of formula I according to claim 1, wherein the compound is (+) - (α) - (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinethanol octanoate. A compound of formula I according to claim 1, wherein the compound is (+) - (α) - (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol hexadecanoate. A compound of formula (I) according to claim 1, wherein the compound is (+) - (α) - (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol 2,2-dimethyloctanoate. A pharmaceutical composition comprising a compound of formula (I) according to claim 1 and a pharmaceutically acceptable carrier. Pharmaceutical preparation according to claim 14, characterized by a chain having 9 carbon atoms. in that R is equal to alkyl • The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable carrier is a pharmaceutically acceptable oil. The pharmaceutical composition of claim 16, wherein the oil is selected from the group consisting of sesame oil, olive oil, arachis oil, corn oil, almond oil, cottonseed oil, peanut oil and castor oil. The pharmaceutical composition of claim 17, wherein the oil is sesame oil. 19. A pharmaceutical composition according to claim 14 wherein R is a straight alkyl chain having 9 carbon atoms and the carrier is sesame oil. 20. A method of antagonizing the effects of serotonin at the 5HT _2A receptor, wherein the patient in need a therapeutically effective amount of a compound of Claim 1. 21. A method of antagonizing the effects of serotonin at the 5HT _2A receptor according to claim 20, characterized in that R is a straight alkyl chain having 9 carbon atoms. The method of antagonizing the action of serotonin at the 5HT _2a receptor of claim 20, wherein the compound is administered intramuscularly or subcutaneously. • • • 23. A method of antagonizing the action of serotonin at the 5HT _2A receptor, wherein the compound is administered intramuscularly and the action of serotonin at the 5HT _2A receptor is antagonized for 2 weeks to about one month. 24. A method of treating a patient with psychosis comprising administering to said patient a therapeutic amount of a compound of claim 1. 25. z n Method of treatment patients with psychosis, the psycho according to zou j e Claim 24 schizof ren: v y ie. and c and 26. Method of treatment patients with psychosis, according to claim 24, v y z n and whatever C i is that R is straight alkyl chain having 9 carbon atoms. 27 Mar: Method of treatment patients with psychosis, according to Claim 25 v y z n and more C This means that R is straight alkyl chain having 9 carbon atoms. 28. Method of treatment patients with psychosis, according to Claim 24 v y z n and whatever C i se t i m that administering the compound intramuscularly or subcutaneously. 29. Method of treatment patients with psychosis, according to Claim 25 v y z n and whatever C i is that administering the compound intramuscularly and the patient is treated for 2 weeks to one month. 30. A method of treating patients with bipolar depression, comprising administering to a patient a therapeutically effective amount of a compound of claim 1. 31. A method of treating a depressed patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1. 32. A method of treating anxiety patients, comprising administering to the patient a therapeutically effective amount of a compound of claim 1. 33. A method of treating a patient with an obsessive-compulsive disorder comprising administering to the patient a therapeutically effective amount of a compound of claim 1. 34. A method of treating a drug addicted patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1. 35. A method of treating patients having coronary angiospasm, comprising administering to a patient a therapeutically effective amount of a compound of claim 1. 36. A method of treating angina patients, comprising administering to the patient a therapeutically effective amount of a compound of claim 1. 37. A method of treating a patient with a thrombotic disease, comprising administering to the patient a therapeutically effective amount of a compound of claim 1. * · 38. A process for the preparation of a compound of formula I wherein R is a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, comprising reacting an alcohol of formula 5 with an acyl halide of formula RC (O) X, an acid anhydride of formula (RCO) ₂ O, or a carboxylic acid of formula RCO ₂ H, wherein R is as defined above and X is chloro or bromo, in the presence of a sufficient amount of a suitable base to form a compound of formula I. 39. Way production compounds of general interest formulas I according to claim 38, v y z n a č u by that X is chlorine. 40. Way production compounds of general interest formulas I according to claim 38, v y z n a č u by that R is straight alkyl string. · · · · *> * *>>>>>>>>>>>>>>>>>>>> A process for the preparation of a compound of formula (I) according to claim 38, characterized in that R has 5 to 20 carbon atoms. A process for the preparation of a compound of formula (I) according to claim 38, wherein R has 4 to 15 carbon atoms. A process for the preparation of a compound of formula I according to claim 38, characterized in that R has 9 to 15 carbon atoms. A process for the preparation of a compound of formula I according to claim 38, characterized in that R has 7 to 15 carbon atoms. A process for the preparation of a compound of formula (I) according to claim 1 38 wherein R has 7 to 9 carbon atoms. A process for producing a compound of formula (I) according to claim 1 38, wherein R is a branched alkyl chain having 9 carbon atoms. A process for the preparation of a compound of formula I according to claim 1 38, wherein R is a straight alkyl chain having 9 carbon atoms. A process for the preparation of a compound of formula I according to claim 1 38, wherein the base is triethylamine. V v · ♦ * v v v v v v v v v v v v v v v 49. A process for the preparation of a compound of formula I as claimed in claim 38, wherein R is a straight chain of 9 carbon atoms, the base is triethylamine, X is chlorine and the alcohol of formula 5 is reacted with an acyl halide. A process for the preparation of a compound of formula I according to claim 38, characterized in that the alcohol of formula 5 is reacted with RCOX. 51. A process for the preparation of a compound of formula I according to claim 38, wherein the alcohol of formula 5 is reacted with (RCO) ₂ O. 52. A method for preparing a compound of formula I according to claim 38, characterized in that the alcohol of formula 5 is reacted with an RCO ₂ H, 53. A process for the preparation of a compound of formula (I) according to claim 38, wherein the alcohol of formula (5) is reacted with RCOX, wherein R is a straight chain alkyl of 9 carbon atoms and X is chlorine. A compound of formula I according to claim 1 for use as a pharmaceutically active substance. Use of a compound of formula I according to claim 1 for the preparation of a pharmaceutical composition useful for antagonizing the action of serotonin at the 5HT _2A receptor. 56. A method of treating patients with (+) - (a) - (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidine-methanol, comprising administering to the patient an effective amount of a compound of the following: or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R is alkyl having 4 to 20 carbon atoms.