NO320417B1 - Esters of (+) - <alpha> - (2,3-dimethoxyphenyl) -1- [2- (4-fluorophenyl) ethyl] -4-piperidinemethanol, pharmaceutical composition comprising these, use of the esters to prepare a pharmaceutical composition, process for the preparation of the esters, as well as their use as an active substance. - Google Patents

Description

The present invention relates to esters of (+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, a pharmaceutical composition comprising these, use of the esters for the production of a pharmaceutical composition, a method for producing the esters, as well as their use as an active substance.

The compound [(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol,] also known as MDL 100,907, is a potent 5HT2A receptor antagonist that is being evaluated clinically for treatment of schizophrenia. J. Pharm. Exp. Ther. 277:968-9881 (1996) incorporated herein by reference. It was described in the U.S. patent 5,134,149.

MDL 100,907 antagonizes the effects of serotonin at the 5HT2a receptor and is thus useful for the treatment of a majority of conditions. However, this compound may also act directly or indirectly to achieve other therapeutic effects than by its 5HT2A antagonism. See e.g. European Journal of Pharmacology 273:273-279 (1995) where MDL 100,907 has been shown to exhibit a tonic inhibitory effect on dopamine efflux in the medial prefrontal cortex. Some of the uses for Ml00,907 have been disclosed in patents and in patent applications, U.S. Pat. patent 5,169,096 discloses compounds with a generic framework comprising Ml00,907 and discloses uses for the treatment of anorexia nervosa, variant angina, Raynaud's phenomenon, coronary vasospasm, prophylactic treatment of migraine, cardiovascular diseases such as hypertension, peripheral vascular diseases, thrombotic episodes, cardiopulmonary emergencies and arrhythmias and has anesthetic properties. See also U.S. U.S. Patent Nos. 4,783,471; 4,912,117 and 5,021,428; 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).

M100,907 was then specifically claimed in U.S. Pat. patent no. 5,134,149 indicating the use for antagonizing serotonin at the 5Ht2 receptor, treating anxiety, variant angina, anorexia nervosa, Raynaud's phenomenon, periodic paralysis, coronaries or peripheral vasospasm, fibromyalgia, extrapyramidal symptoms, arrhythmias, thrombotic disease, transient ischemic attack, drug abuse and psychotic illness such as schizophrenia and mania. See also U.S. Patent No. 5,561,144; 5,700,812; 5,700,813; 5,721,249 issued by the U.S. Patent No. 5,134,149 - and also U.S. Pat. patent no. 5,618,824 obsessive compulsive disorder and PCT/US97/02597 (depressive disorders including major depressive episodes and dysthymia and bipolar disorders), and insomnia and sleep apnea are described.

An object of the present invention is to provide a new compound which, after administration, releases a therapeutically effective amount of MDL 100,907 over an extended period of time. The extended time period means a longer time than a single dose of MDL 100,907 and will last several days, several weeks about a month up to about 6 to about 8 weeks and preferably for more than about 2 weeks to about a month.

There are many advantages to administering a single dose of a compound to a patient that lasts over an extended period of time. Complication problems can be avoided which can be particularly important in patients suffering from psychoses or addictive behavior such as schizophrenia, obsessive compulsive behaviour, depression, anxiety, anorexia and drug addiction. Other advantages include an absence of the typical fluctuations in drug levels achieved with multiple dose therapy through which the patient should experience an improved effectiveness in treatment with lower peak drug concentrations.

While the concept of sustained release formulations is not new, not all compounds are capable of being chemically altered to produce a new compound capable of being metabolized to the active ingredient at a desired rate and over a desired length of time. Other factors contribute to the difficulty in producing a sustained release formulation such as protein binding of other physiologic processes that may affect the therapeutic effect of the active ingredient, see e.g. Biochemical Pharmacology, Vol. 36, No. 10 ppl 715-1722 (1987). Also, the chemically altered compound must be compatible with pharmaceutically acceptable carriers and be stable enough not to significantly degrade to the active ingredient upon shelf storage. In short, the design of an acceptable sustained-release formulation is a difficult, unpredictable task.

The present invention is a compound of formula I:

where R is C4-C20 alkyl, or a stereoisomer or a pharmaceutically acceptable salt thereof.

The present invention also includes:

a pharmaceutical composition comprising the compound of formula I and a pharmaceutically acceptable carrier,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for treating a patient for psychosis,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for treating a patient for bipolar depression,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for treating a patient for depression,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for treating a patient for anxiety,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for the treatment of a patient with obsessive-compulsive disorder,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for treating a patient for substance abuse,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for treating a patient for coronary vasospasms,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for treating a patient for angina,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for treating a patient for thrombotic disease,

use of a compound according to the invention for the preparation of a pharmaceutical composition useful for antagonizing the action of serotonin at the 5HT2A receptor,

compound according to the invention for use as a pharmaceutical active substance and a method for the preparation of a compound of formula I:

where R is C4-C20 alkyl, or a stereoisomer or a pharmaceutically acceptable salt thereof, characterized by reacting an alcohol (5)

with an acid halide of the formulas RC(0)X, an acid anhydride of the formula (RCO)20 or a carboxylic acid of the formula RCO2H where R is as previously defined and X is chlorine or bromine in the presence of a sufficient amount of a suitable base to prepare a compound of formula I.

Terms used here have the following meanings:

a) "Enteroceutically acceptable salts" means either an acid addition salt or a basic addition salt depending on what is possible to prepare with the compounds according to the

the present invention.

"Enteroceutically acceptable acid addition salt" is a non-toxic organic or inorganic acid addition salt to the base compound represented by formula I. Illustrative inorganic acids which form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulphate Illustrative organic acids which form suitable salts include mono-, di- and tri-carboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric -, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzo, hydroxybenzo, phenylacetic, cinnamic, salicylic, 2-phenoxybenzo, p-toluenesulfonic and sulfonic acids such as methanesulfonic acid and 2 -hydroxyethanesulfonic acid. Either the mono- or di-acid salts may be formed and such salts may exist in either an aqueous or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents and which, compared to their free base forms, generally exhibit higher melting points.

"Enteroceutically acceptable base addition salts" means non-toxic organic or inorganic base addition salts of the compound of formula (I) or any of its intermediate compounds. Examples are alkali metal or alkaline earth metal hydroxides such as sodium, potassium, calcium, magnesium or barium hydroxides, ammonia, and aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline. The choice of the appropriate salt may be important so that the ester is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

b) "Stereoisomers" is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It

includes mirror image isomers (enantiomers), geometric (cis/trans) isomers, and isomers of compounds with more than one chiral center that are not mirror images of others (diasteromer isomers).

c) "Alkyl" means a branched or straight-chain alkyl group specified by the amount of carbon atoms in the alkyl group, e.g. C4-C20 alkyl means a four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen or twenty carbon branched or straight chain alkyl or any range of this; for example; but not limited to C5-C20, C1-C15, C3-C15, C5-C15, C7-C15 and C7-C9. d) "Patient" means a warm-blooded animal such as e.g. rats, mice, dogs, cats, guinea pigs and primates such as humans. e) "Treat" or "treatment" means to remedy symptoms, eliminate the cause of symptoms either on a temporary or permanent basis or to prevent or to weaken

the appearance of symptoms of the supposed disorder or condition.

f) "Therapeutically effective amount" means an amount of the compound that is effective in treating the named disorder or condition. g) "Pharmaceutically acceptable carrier" is a non-toxic solvent, dispersant, additive, adjuvant or other material that is mixed with the compound of the present invention to allow the formation of a pharmaceutical composition, i.e. a dosage form capable of being administered to the patient. An example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration. h) The term "restorative sleep" means sleep that produces a rested state after awakening,

i) the term "sleep disorder" means insomnia and constructive sleep open,

j) the term "insomnia" means primary insomnia, insomnia-related other mental disorders and drug-induced insomnia,

k) the term "primary insomnia" means difficulty in initiating sleep, maintaining sleep or having restorative sleep that is not caused by a mental disorder or due to physiological effects of intake or withdrawal from certain substances (substance-induced). Also used here, it also includes circadian insomnia, which is insomnia due to a change in the normal sleep-wake schedule (work shift changes, jet lag, etc.),

1) the term "insomnia related to another mental disorder" means difficulty in initiating sleep, maintaining sleep or having restorative sleep which is caused by an underlying mental disorder such as e.g. depression, anxiety or schizophrenia, m) the term "substance-induced insomnia" means difficulties in initiating sleep, maintaining sleep or having strengthening sleep caused by the physiological effects of taking or withdrawing from certain substances such as caffeine, alcohol, amphetamines, opioids, sedatives, hypnotics and anxiolytics, and n) the term "obstructive sleep apnea" means repeated episodes of upper airway obstruction during sleep and is normally characterized by loud snoring or short gasps alternating with periods of silence. The (+)-isomer of the α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol can be prepared by the method described in U.S. Pat. Patent No. 5,134,149. A suitable procedure follows.

In step A of reaction scheme I, an esterification reaction is carried out between racemic alpha-(2,3-dimethoxyphenyl)-l-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol (structure 1) and the (+)-isomer of alphamethoxyphenyl acetic acid (structure 2). This esterification produces a diastereomeric mixture identified as structure 3. These diastereomers are subjected to silica gel chromatography which separates the two diastereomers, thereby isolating the (+,+) diastereomer depicted in step B. In step C, the (+,+) diastereomer is hydrolysed producing The (+) isomer of alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol.

The esterification reaction can be carried out using techniques known from the prior art. Typically, approximately equivalent amounts of racemic alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol and the (+)-isomer of alpha-methoxyphenylacetic acid are contacted in an organic solvent such as methylene chloride, THF, chloroform or toluene and heated to reflux for a period of time from 5 to 24 hours. The esterification is typically carried out in the presence of an equivalent amount of dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-dimethylaminopyridine (DMAP). The resulting diastereomers can be isolated by filtering the dicyclohexylurea and evaporating the filtrate.

The diastereomers are then subjected to silica gel chromatography which separates the (+,+) and (-,+) diastereomers. This chromatographic separation can be carried out as known from the prior art. A 1:1 mixture of hexane and ethyl acetate is a suitable eluent.

The resulting (+,+) diastereomer is then subjected to a hydrolysis reaction which produces the (+)-enantiomer of the alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol. The hydrolysis is carried out by contacting the diastereomer with an excess of a base such as potassium carbonate in an aqueous alcoholic solution. The hydrolysis is carried out at a temperature of approximately 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]-3-piperidinemethanol can be recovered by dilution with water and extraction with methylene chloride. It is then purified by recrystallization from a solvent system such as cyclohexane/hexane or ethyl acetate/hexane.

Methods for preparing the starting materials for reaction scheme I are known from the prior art. E.g. teacher U.S. Patent No. 4,783,471 how racemic alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol is prepared. Examples no. 1 and 2 in this application also teach suitable procedures. Alternatively, racemic alpha-

(2,3-dimethoxy(myl)-1-[2-(4-flu^) is prepared in the following way. Initially, 4-hydroxypiperidine is subjected to an N-alkylation reaction with p-fluorophenylethyl bromide which produces 4-hydroxy-1-[2 -(4-fluorophenyl)ethyl]-piperidine This compound is brominated with PhaP-B^ producing 4-bromo-1-[2-(4-fluorophenyl)ethyl]piperidine This compound is contacted with Mg thereby forming a Grignard reagent which is then reacted with 2,3-dimethoxybenzaldehyde producing the desired product (±)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.(+)- the isomer of alphamethoxyphenylacetic acid is known from the prior art.

Referring to scheme n, X is chlorine or bromine with chlorine being preferred and R is as previously defined. This reaction scheme shows the production of a sustained release compound of I from the alcohol (5).

The alcohol (5) is reacted with an acid halide (RC(0)X), RCO2H or acid anhydride (RCO)20 in the presence of a sufficient amount of a suitable base. A suitable base is one which allows ester formation from the acid halide or anhydride. Examples of suitable bases are trialkylamines, pyridine such as dimethylaminopyridine, diisopropylethylamines, N-methyl morpholines, with triethylamine being preferred. A sufficient amount of the base can be determined by one skilled in the art, allowing the formation of the compounds of formula I.

Preferably, the base is added to the alcohol (S) 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 which are all readily available, with chloroform being preferred.

The temperature of the reaction can be in a range from about 0-25°C. The reaction can be stirred for from a few hours to overnight to speed up the reaction. Catalyst can also be added to improve reaction times, e.g. 4-dimethylaminopyridine, etc.

The starting materials for the acid halide (RCOX) are readily available to those skilled in the art. E.g. supplies Aldrich Chemical stearoyl chloride, heptadecanoyl chloride, palmitoyl chloride, myristoyl chloride, isovaleryl chloride, valeryl chloride, hexanoyl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanyl chloride, undecanoyl chloride and lauroyl chloride. For those acid halides that are not readily available, a person skilled in the art can easily prepare the desired acid halide. E.g. a carboxylic acid can be mixed with a halide donor to produce the desired acid halide. An example of this is mixing carboxylic acid (0.17 mol), methylene chloride (660 ml) and dimethylformamide (0.5 ml) under a nitrogen atmosphere. Add oxalyl chloride (0.2 mol) over about 5 minutes with stirring. Stir at ambient temperature for 3 hours and evaporate the solvent in vacuo to the acid chloride. Another way is to dissolve the carboxylic acid (10 mmol) in methylene chloride (50 ml). Cool to 0°C, place under nitrogen atmosphere and add dropwise addition of thionyl chloride (11 mmol). Stir at room temperature for several hours and evaporate the volatiles in vacuo to obtain the acid chloride. The carboxylic acids are readily available or can be easily prepared by professionals in the field.

The starting materials for the acid anhydrides (RCO^O) are readily available to those skilled in the art. For example, Aldrich Chemical Company offers butyric anhydride, isobutyric anhydride, valeric anhydride, 2-2, dimethylglutaric anhydride, and phthalic anhydride. Alternatively, acid anhydrides can be synthesized by methods well known in the art.

The starting materials for the acids (RCO 2 H) are readily available or can be synthesized by methods well known in the art. See e.g. Advanced Organic Chemistrv. Reactions. Mechanisms and Structure, 4th ed.. John Wiley & Sons, New York 1992. Aldrich Chemical Company also offers isovaleric acid, valeric acid, tert-butylacetic acid, 2,2-dimethylbutyric acid, 2-ethylbutyric acid, hexanoic acid, 3-methylvaleric acid, 4-methylvaleric acid, heptanoic acid, octanoic acid, 2-propylpentanoic acid, nonanoic acid, decanoic acid, undecanoic acid, lauric acid, tridecanoic acid, myristoleic acid, myristic acid, pensadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid as well as others where R is an alkyl group with carbon atoms.

The following examples are presented to further illustrate the invention. However, they should not be considered as limiting the invention in any way.

EXAMPLE 1 - starting material

Example 1, Steps A-D, demonstrates the preparation of the starting material (±)-alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, Structure 1, Scheme I.

A) 1-(2-f4-fluorophenyl)ethyl-4-piperidinecarboxamide

A solution of 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) was prepared in DMF (280 mL) and stirred under argon at 90-95°C overnight. The cooled solution was concentrated to a white oily solid. The solid was partitioned between water and CH2C12. The layers were separated and the aqueous layer was extracted with CH 2 Cl 2 . The combined organic layers were washed twice with water, dried (MgSO 4 ), filtered and evaporated to an oily solid. The solid was recrystallized from EtOAc to provide 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide as a white powder, mp 177-178°C (dec). Analytical calculated for C14H19FN20:C, 67.18; H, 7.65; N, 11.19. Found: C, 67.25; H, 7.67; N, 11.13.

B) 4-Cano-1-|"2-(4-Fluorophenyl)ethylpiperidine

To stirred phosphorus oxychloride (25 mL, 41.12 g, 268 mmol) and sodium chloride (5.1 g, 87.3 mmol) was added l-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide (8.9 g, 35 .6 mmol) added in portions. After complete addition, the solution was refluxed for two hours. The cooled solution was carefully poured into dilute NH4OH to destroy the POCV. The aqueous solution was cooled to 0°C, then extracted twice with CH 2 Cl 2 . The combined organic layers were dried (MgSCu), filtered and evaporated to provide 8.1 g of an oil active solid. The solid was distilled (bp 150°C, 0.1 mm Hg) to provide a clear, colorless oil which solidified. This material was crystallized from hexane to provide 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine as white needles, mp 47-48°C. Analytical calculated for C14H17FN2: C, 72.39; H, 7.38; N, 12.06. Found: C, 72.62; H, 7.49; N, 12.12.

C) 1 -\ 2 -( 4- fluorophenyl') etvll - 4- piperidinecarboxaldehvd

A stirred solution of 4-cyano-1-[2-(4-fluorophenyl)-ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 mL) under argon at 0 °C gave DIBAL-H (4 .6 ml of a 1.0 M solution in THF, 4.6 mmol) added via a syringe. After stirring overnight at room temperature, 10% aqueous HCl (25 mL) was added and the solution was stirred for 3 hours. The entire mixture was then poured into 10% aqueous NaOH (50 mL), then extracted twice with ether. The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and evaporated to give a pale yellow oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate fractions were combined and evaporated to give an oil. This oil was distilled (bp 166°C, 0.5 mmHg) to provide 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde, obtained as a colorless oil.Analytical calculated for Cm, His, FNO: C, 71.46 ; H, 7.71; N, 5.95. Found: C, 71.08, H, 7.81; N, 5.86.

D) (±Valpha(23-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl1-4-piperidinemethanol

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 a 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) via an addition funnel. The cooling bath was removed and the solution was allowed to stir for two hours. Water was added, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and chromatographed on silica gel, eluting with acetone. The appropriate fractions were combined and evaporated to provide a white solid. The solid was recrystallized from hexane to afford racemic alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol as shiny white needles, mp 126-127°C.

Analytical calculated for C22H28FNO3: 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, demonstrates an alternative route for the preparation of (±)-alpha(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidinemethanol, Structure 1.

A) 1 -( 1.1 -dimethylethyl)-1.4- piperidinedicarboxylic 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) di-tert-butyl dicarbonate (200 g, 916 mmol) was added portionwise. 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 water, brine, dried (MgSO 4 ), filtered and evaporated to a white solid which was recrystallized from EtOAc/hexane (300 mL/200 mL) to provide 1-(1,1-dimethylethyl) -1,4-piperidinedicarboxylic acid as white needles, melting point 147-149°C.

B) 4- N- methoxy- N- methylcarboxamide)- 1 - piperidinecarboxylic acid 1, 1 - dimethyl ester

To a stirred solution of l-(l,l-dimethylethyl)-l,4-piperidinedicarboxylic acid (50.0 g, 218 mmol) in anhydrous CH 2 Cl 2 (500 mL) under N 2 in a 2 L flask was added l,r-carbonyldiimidazole (38 .9 g, 240 mmol) added in portions. After stirring for one hour, N,O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol) was added in one portion. After stirring overnight, the solution was washed twice with 1N HCl, twice with saturated NaHCO 3 , once with brine, dried (MgSO4 ), filtered and evaporated to an oil. Distillation afforded 4-(N-methoxy-N-methylcarboxamide(-1-piperidinecarboxylic acid 1,1-dimethylethyl ester) as a clear oil, bp 120-140°C, 0.8 mm.

C) 4-(2.3- dimeoxybenzoyl)-1- piperidinecarboxylic acid 1.1- dimethyl ester

n-butyl lithium (14.5 mL of a 2.5 M solution in hexane, 36.3 mmol) was added via syringe 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-N-methylcarboxamide)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (9.20 g, 33.8 mmol) in THF (50 mL, anhydrous) via syringe. The cooling dry ice-acetone bath was removed and the mixture was allowed to come to room temperature. After stirring for three hours was saturated

aqueous NH 4 Cl added and the mixture allowed to stir 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 provide a yellow oil. The oil was distilled to provide 4-(2,3-dimethoxybezoyl)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester as a colorless oil. (Boiling point 225-250°C, 0.05 mm). Analytical calculated for Ci9H27N05:C, 65.31; H, 7.79; N, 4.01. Found: C, 65.04; H, 7.92; N, 4.11.

D) 4-(23-dimethoxysulfenyl-4-piperidinevylmethanone).

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 entire solution was poured into ether (900 ml) and allowed to stand overnight. Filtration gave 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate as fine white needles, mp 123°C. Analytical calculated for C14H19NO3.CF3CO2H: C, 52.89; h, 5.55; n, 3.86. Found: C, 52.77; H, 5.62; N, 3.82.

The resulting 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate was dissolved in water, treated with NaOH (10% aqueous) until basic and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried (MgSO 4 ), filtered and evaporated to provide 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone as an oil.

E) (2.3-dimethoxyphenyl)|"1-r2-(4-fluorophenyl)ethyl1-4-piperidinylmethanone monohydrochloride

A solution of 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone (8.00 g, 32.1 mmol) and 2-(4-fluorophenyl)ethyl bromide (6.52 g, 32.1 mmol) was prepared in DMF (90 mL), treated with K2CO3 (7.0 g, 50.7 mmol), then stirred and heated to 80°C overnight. The cooled solution was poured into a separate 2/1 EtOAc/toluene and water. The layers were separated and the aqueous layer was extracted with 2/1 EtOAc/toluene. The combined organic layers were washed twice with water, once with brine, dried (MgSO 4 ), filtered and evaporated to provide 11.0 g of an oil. The oil was chromatographed on silica gel, eluting with EtOAc. The appropriate fractions were combined, concentrated, dissolved in ethyl acetate and treated with HCl/ethyl acetate. (2,3-dimethoxyphenyl)[2-(4-fluorophenyl)ethyl]-4-piperidyl]-methanone monohydrochloride was obtained as a precipitate, mp 225-227°C (decomposition). Analytical calculated for C22H26FNO3.HCl: C, 64.78; H, 6.67; N, 3.43. Found: C, 64.44; H, 6.73; N, 3.41.

F) ( ± )- alpha-( 2J- dimethoxyphenyl)- 1-[ 2-( 4- fluorophenyl) ethyl- 4- piperidine methanol

To a stirred solution of (2,3-dimethoxyphenyl)[l-[2-(4-fluorophenyl)ethyl]-4-piperidinylmethanone (6.0 g, 16.2 mmol) in MeOH (100 mL) at 0°C was added NaBHj (1240 mg , 32.8 mmol) added in two portions over a period of one hour. After stirring overnight, the solution was concentrated to a solid. The solid was separated 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 solid was chromatographed on silica gel eluting with acetone. The appropriate fractions were combined and evaporated to provide a white solid. The solid was recrystallized from cyclohexane to provide (±)-alpha-(2,3-mmethoxyphenyl)-1-[2-(4-fluorophenyl)-ethyl]-4-piperidine methanol as white needles, mp 126-127° C. Analytical calculated for C22H28FNO3: 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 demonstrated the preparation of the alcohol, structure 5.

Preparation<g> of (+)-alpha-(2.3-dimethoxysphenylVl-r2-f4-fluorophenvnetvn-4-piperidinemethanol

A) Preparation of diastereomers

A solution of 3.90 g (10.4 mmol) (±)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol, 1.74 g (10 .4 mmol) S-(+)-alpha-methoxyphenyl acetic acid, 2.15 g (10.4 mmol) of 1,3-dicyclohexylcarbodiimide and 0.1 g of 4-dimethylaminepyridine in chloroform (75 ml) were refluxed for 17 hours, allowed to cool to room temperature and filtered. The filtrate was concentrated and chromatographed on a silica gel column eluting with ethyl acetate/hexane (1:1) to provide two diastereomers, Rf=0.1 and 0.2 (TLC EtOAc/hexane, 1:1). Intermediate fractions were rechromatographed to obtain additional material. These fractions with Rf=0.2 were combined to obtain a single diastereomeric ester, (+,+)-(2,3-dimethoxyphenyl)[l-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methyl -alpha-methoxybenzene acetate.

B) Preparation of (+)-alpha-(2.3-dimethoxyphenylVl-[2-(4-fluorophenyl')ethvll-4-piperidinemethanol

To a solution of 0.97 g (1.9 mmol) of the above-mentioned diastereomeric ester, Rf=0.2, in 25 ml of methanol was added 0.5 g (3.6 mmol) of potassium carbonate and 5.0 ml of water. After stirring for 17 hours 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 obtain (+)-alpha-(2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenyl) ethyl]-4-piperidine methanol, melting point 112-113°C, [ct]D<20> = +13.9°.

EXAMPLE 4

(+)-α-(2,3-dimethyloxyphenyl)-1-[4-fluorophenyl)ethyl]-4-piperidine menthanol decanoate

A mixture of 49.0 g (0.131 mol) (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol, 500 ml CHCl 3 and 16.0 g (0.158 mol) of triethylamine was charged to a one liter, 3-necked flask equipped with a stirrer, thermometer, dropping funnel and a continuous nitrogen purge. A solution of 27.4 g (0.144 mol) of decanoyl chloride in 25 mL of 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 two hours. The progress of the reaction was monitored by TLC (5/95 methanol/CH2Cl2; mark 60F-254 plates, Uv; Rf to (+)-α-(2,3-dimethyloxyphenyl)-1-[2-(4-fluorophenyl)ethyl ]-4-piperidinemethanol - 0.\.23; Rf to title 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 two hours. 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 MgSC-4 and filtered. The filter cake was washed with 200 ml of CH 2 Cl 2 . The filtrate was concentrated at 40°C/50 torr to obtain an oil.

The crude product was purified by flash chromatography (14-29 cm column, 2.035 kg of 230-400 mesh silica gel). The crude product was loaded onto the column by dissolving it in 75 mL of CH 2 Cl 2 . The column was eluted with 241/4 EtOAc/CEbClfe collecting 24 x one liter fractions. The fractions which were homogeneous by TLC were combined and concentrated at 35°C/50 torr followed by 70°C/0.5 torr for one hour to obtain a colorless oil.

MS(M+=528)

Analysis:

Calculated for C32H46FN04(527.73): 72.83% 8.79%H 2.65%N Found: 72.25%C 8.88%H 2.63%N

EXAMPLE 5

(+)-a-(2.3- dimethoxyphenylV 1 -[ 2-( 4- fluorophenyl) ethyl 1- 4- piperidinemethanol hexanoate

To a stirred solution of 2.0 g (5.37 mmol) (+)-α-(2,3-dimethyloxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol in 6 ml of dry methylene chloride was added 0.74 ml (0.537 g, 5.32 mmol) of triethylamine added. The solution was cooled with an ice bath after which 1.07 ml (5.89 mmol) of hexanoic anhydride was added via a syringe. 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 was 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 respectively 2% methanol/methylene chloride. The fractions containing the pure product were combined and concentrated to provide an oil which was dried overnight at 60°C under high vacuum to afford the title compound. The compound was homogeneous by TLC. I (Kbr), NMR (CDCl3) and MS (MH+=472) were consistent with the proposed structure.

Analysis:

Calculated for C28H38FN04: 71.31%C 8.12%H 2.97%N Found: 70.94%C 8.07%H 2.88%N

EXAMPLE 6

(+)-a-(2.3-dimethoxyphenyl)-1- r2-(4-fluorophenyl)ethyl-4-piperidinemethanol octonate

0.74 ml ( 0.537 g, 5.32 mmol) triethylamine added. The solution was cooled in an ice bath after which 1.75 ml (5.89 mmol) octanoic anhydride was added via a syringe. The solution was stirred for several minutes at ice bath temperature and allowed to warm to room temperature. To the solution was then added 66 mg (0.541 mmol) of 4-dimethylaminepyridine. 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 respective methylene chloride, 1% and 2% methanol/methylene chloride. The fractions containing the pure product were combined and concentrated to provide an oil which was dried overnight at 60°C under high vacuum to provide the title compound. The compound was homogeneous by TLC. The IR (KBr), NMR (CDCl 3 ) and MS (MH + =501) were consistent with the proposed structure.

Analysis:

Calculated for: 72.11%C 8.47%H 2.80%N Found: 71.94%C 8.63%H 2.83%N EXAMPLE 7 (+ Va-( 2. 3- dimethoxyphenylV 1 - f 2-( 4- fluorophenyl) ethyl 1- 4- piperidinemethanol hexadecanoate

To a stirred solution of 2.00 g (5.36 mmol) of (+)-α-(2,3-dimethyloxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol in 6 ml of dry methylene chloride was added 0.76 ml (5.46 mmol) of triethylamine added via a syringe after which this solution was cooled in an ice bath. To the solution was added 2.92 g (5.89 mmol) of hexadecanoic anhydride, after which the mixture was stirred at 0°C for 15 minutes. The reaction mixture was allowed to warm to ambient temperature and 65 mg (0.536 mmol) of 4-dimethylaminopyridine was added to the reaction mixture, after which the solution was stirred under nitrogen overnight. The reaction mixture was poured into 50 ml of 0.5 N sodium hydroxide and 50 ml of diethyl ether. Some precipitate was observed and the resulting suspension was extracted with methylene chloride. The methylene chloride layer was washed with water and brine and dried over sodium sulfate, filtered and concentrated to a yellow oil. The oil was dissolved in methylene chloride and purified using a flash chromatography column filled with silica gel and methylene chloride and eluting with the same solvent system followed by respectively 1% and 2.0% methanol/methylene chloride. The appropriate fractions were combined and concentrated to a yellow oil. The oil was dried twice overnight at 60°C under high vacuum to provide the title compound. The title compound was homogeneous by TLC. IR (film), NMR (CDCl3) 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 EXAMPLE 8 (+)- a-(2, 3- dimethoxyphenyl)- 1 -[ 2-( 4- fluorophenyl) ethyl 1- 4-piperidinemethanol 2. 2-dimethyloctanoate

2-hexene-l-mesylate is prepared by adding N,N-diisopropyl ethylamine (12.9 g, 0.1 m) to a solution of trans-2-hexan-l-ol /10.0 g, 0.1 m) (Aldrich ) in 100 ml of methyl chloride. Methanesulfonyl chloride (12.6 g, 0.11 m) in methylene chloride (50 ml) is added dropwise to the solution and stirred at room temperature for 4 hours. The reaction mixture is transferred to a separatory funnel and washed with cold IN HCl (2 hours) and then with saturated NaHCl>3 solution (2 hours). The solution is dried over anhydrous MgSO4, filtered and concentrated under vacuum at 40°C to obtain 2-hexene-1-mesylate.

2,2-Dimethyl-3-octene nitrile is prepared by adding 2-hexene-1-mesylate (11.02 g, 0.05 m) in anhydrous THF (100 mL) to a solution prepared by adding isopbutyronitrile (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 is stirred at reflux for 5 hours, cooled and stirred with cold ethanol (95%) and concentrated under vacuum to remove solvents. After addition of water (50 ml), the mixture is extracted with diethyl ether (3x40 ml). The extracts are washed with water and then with saturated NaCl solution and dried over MgSCv, filtered and concentrated to obtain 2,2-dimethyl-3-octene nitrile.

2,2-dimethyl-3-octenoic acid is prepared by adding 2,2-dimethyl-3-octene nitrile (1.51 g, 0.01 m) to a solution prepared from 15% NaOH in butanol/H2O (2:3 ) (30 ml). The reaction mixture is stirred and kept at reflux for 7 hours, cooled and acidified with 10% hydrochloric acid. The reaction mixture is extracted with diethyl ether and the extract is washed with saturated NaCl and dried over MgSO 4 , filtered and concentrated to obtain 2,2-dimethyl-3-octenoic acid.

2,2-Dimethyl octanoic acid is prepared by dissolving 2,2-dimethyl-3-octenoic acid (0.20 g, 1.1 mmol) in absolute ethanol covered with N2 and 10% palladium on carbon which is then hydrogenated for 6 hours. The catalyst is removed by filtration and the filtrate is concentrated under vacuum to obtain 2,2-dimethyl octanoic acid.

To a stirred solution of (+-α-(2,3-dimethyloxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3.9 g, 10.4 mmol) in 70 ml methylene chloride is added dicyclohexylcarbodiimide (2.15 g, 10.4 mmol), 4-dimethylamine pyridine 0.1 g and 2,2-dimethyloctanoic acid (1.70 g, 10.4 mmol).The resulting solution is stirred and refluxed for 16 hours .The cooled reaction solution is filtered and concentrated to an oil.The resulting oil is chromatographed on silica gel eluting with ethyl acetate/hexane (1:1).Appropriate fractions are collected, heated (40°C) and concentrated under reduced pressure to obtain the title compound.

EXAMPLE 9

This example demonstrates a pharmaceutical composition according to the present invention. In a suitable 100 ml container, place 70 ml sesame oil, NF (sigma), 1.2 g benzyl alcohol, NF and 14.129 g (+)-a-(2,3-dimethyloxyphenyl)-1-[2-(4-fluorophenyl)ethyl ]-4-piperidine menthanol decanoate. Sufficient sesame oil, NF is added to this solution to bring the volume to 100 ml and mixed until homogeneous. This solution can be sterilized and packaged for parenteral injection.

EXAMPLE 10

This example describes a behavioral test (antagonism of DOI-induced behavior) designed to identify compounds that have antagonistic action at the 5HT2a receptor. The compound according to the present invention used in this test was (+)-α-(2,3-dimethyloxyphenyl)-1-[2-(4-lfourphenyl)ethyl]-4-piperidimethanol decanoate Example 4 herein. The 5-HT2A/2C agonist (±)-DO1 HCl (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride) induces several quantifiable behaviors in rates. These behaviors include "shaking" (a rapid head and body shaking also known as wet dog shaking), "forepaw stepping" (rapid front paw steps) and "skin spasms" (paraspinal muscle contractions or dorsal skin contraction). The 5-HT2 antagonists mianserin, ritanserin and methysergide as well as the selective 5-HT2A antagonist MDL 100,907 have been demonstrated to dose-dependently block the behavioral effects of DOI (Pranzatelli, 1990, Neurosci. Let. 11: 74-80; Wettstein et al., 1996, Soc. Neurosci. Abs. 22:481. Significantly, drugs with 5-HT2a antagonist activity have been suggested to have atypical antipsychotic properties in schizophrenic patients (Meltzer et al., 1989, JPET. 251: 238-246, as well as a potential therapeutic effect in a number of other CNS disorders including depression, dysthmia and anxiety (Stefanski & Goldberg, 1997, CNS Drugs, 7: 399-409).

Procedures

Subjects and housing.

Male Sprague-Dawly rats (180 ± 50g) were housed seven per cage and given one week to acclimate to the vivarium. Food and drink were freely available. The temperature and air cycle (12 hours on - 12 hours off) were maintained automatically. Individual rats were tested once. Each test group contained seven animals. Experiments took place in the vivarium room where the animals lived.

Drug manufacturing and administration.

(+)-α-(2,3-Dimethyloxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol decanoate (120 mg/kg equivalent to MDL 100,907 was dissolved in sesame oil and administered intramuscularly to separate groups of rats on day 0 in a volume corresponding to 60 ml/100 g body weight. Vehicle control, the animals were injected with sesame oil alone. (±)-DOIHC1 (3.0 mg/kg, 1 ml/kg body weight) was dissolved in distilled water using by an ultrasound bath and injected intraperitoneally on appropriate test days.

Observation and behavioral analysis

(+)-α-(2,3-Dimethyloxyphenyl)-1 -[2-(4-fluorophenyl)ethyl]-4-piperidinementhanol decanoate-treated rats were tested for antagonism of DOI-induced behavior 1, 5,7,14 ,21,28 and 40 days after the single (+)-α-(2,3-dimethyloxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinementhanol decanoate intramuscular injection. Each rat was tested once.

Immediately after DOI injection, rats were placed under used clear plastic boxes (28L x 25W x 25H cm) which were placed on top of a clean absorbent paper. The rats were continuously monitored by trained observers (blind to treatment) for 30 min for the occurrence of DOI-induced behavior (shaking, skin twitching, and forepaw blocking seizures) and then returned to their home cages. The rats were later used for pharmacokinetic studies. The frequencies of DOI-induced behavior were collected and then summed to provide a single behavior score for each animal.

Data analysis

The mean and standard deviation of the behavior scores for each group were determined. The mean for each treated group was then compared separately to the mean of the vehicle-control group using a one-way analysis of variance (ANOVA) test, followed by a Bonferroni/Dunn post-hoc comparison. The differences between groups were considered statistically significant if p-values were less than or equal to 0.05.

Results

Significantly antagonized DOI-induced behavior in the rats was observed for the full 28 days. The effect was no longer significant at day 40.

EXAMPLE 11

This example demonstrates the single-dose absorption of MDL 100,907 following intramuscular administration (i.m.) of (+)-α-(2,3-dimethyloxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol decanoate, a compound of the the present invention over time.

A total of nine male Wistar rats with a weight of approx. 150-200 grams each dosed i.m. with (+)-α-(2,3-dimethyloxyphenyl)-1 -[2-(4-fluorophenyl)ethyl]-4-piperidine methanol decanoate in sesame oil (equivalent to 120 mg/kg MDL 100,907) on day 0. The rats were anesthetized with lethal i.p. dose of nembutal and blood collected at 3 and 6 hours and different days post-dose (n=5 for each time point) in heparinized vacuum containers. Blood samples were centrifuged for 30 minutes at 5°C and at approximately 2700 rpm. Plasma is removed and stored at -20°C until analysis. The plasma samples were analyzed by a suitable HPLC method. Brains will also be collected at the appropriate time points and stored at -80°C until analyzed by the fixed HPLC method. The results shown in Table 1.

The dosage range at which the compounds of formula I exhibit their ability to block the actions of serotonin at the 5HT2A receptor may vary depending on the particular disease or condition being treated and its severity, the patient, the formulation, and other underlying disease conditions from which the patient is suffering or other drugs that may administered simultaneously to the patient. In general, the compounds of formula I will exhibit their serotonin 5HT2A antagonist properties at doses of between about 0.001 mg/kg patient body weight/day to about 100 mg/kg patient body weight/day. The sustained release formulations may contain multiples of the foregoing doses depending on the period over which the active ingredient is released. The dose of the compound of the present invention can be determined by administering the compound to an animal to determine the plasma level of the active ingredient.

The compound of the present invention may be mixed with a pharmaceutically acceptable carrier capable of being administered by the preferred method to produce a sustained release of the compound of the present invention such that a therapeutically effective amount of the compound (+)-a-(2 ,3-dimeoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol can be administered to the patient over a period of days or weeks. Preferably, the sustained release formulation comprises a compound of formula I and a pharmaceutically acceptable carrier for parenteral administration either as an aqueous suspension, oil solution, oil suspension or emulsion. Some oils that can be used for intramuscular injection are sesame, olive, peanut, corn, almond, cottonseed, peanut and castor oil, with sesame oil being preferred. A pharmaceutically acceptable preservative such as benzyl alcohol may also be added. The sustained release formulation is preferably administered intramuscularly or subcutaneously, where intramuscular administration is preferred although other administration methods such as oral, transdermal, nasal spray, etc. may be used if appropriate for the patients' needs.

Since the compound of the present invention releases (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol ("active ingredient") in the patient for the therapeutic effect is the compound according to the present invention is useful for all indications of use where the active ingredient is useful. Some of these indications for use have been described in the patents issued generally covering the active ingredient (U.S. Patent Nos. 5,134,149; 5,561,144; 5,618,824 and PCT/US97/02597). These references indicate applications for psychosis (including schizophrenia), obsessive-compulsive disorder, thrombotic disease, coronary vasospasm, periodic posturing, anorexia nervosa, Raynaud's phenomenon, fibromyalgia, extra-pyramidal side effects, anxiety, arrhythmia, depression and bipolar depression or substance abuse (eg .cocaine, nicotine, etc.). Some of these indications have been set forth in the patent specifications above and in U.S. Pat. Patent No. 5,561,144; 5,618,824; 4,877,798; 5,134,149 and 5,021,428.

Psychosis as used here is a condition where the patient experiences a strong mental disturbance of organic and/or emotional origin characterized by confusion, disturbance of the personality and loss of contact with reality, often with self-deception, hallucinations or illusions. Representative examples of psychotic diseases that can be treated with the compound of the present invention include schizophrenia, schizophreniform disorder, schizosensitive disorder, delusional disorder, transient psychotic disorder, shared psychotic disorder, psychotic disorder not otherwise specified and drug-induced psychotic disorder. See Diagnostic and Statistical Manual of Mental Disorders, 4th ed., American Psychiatric Association, incorporated herein by reference. The active ingredient is currently included in clinical trials for the treatment of schizophrenia.

Patients with obsessive-compulsive disorder (OCD) fail to inhibit or "get rid of" intrusive, depressing thoughts or images. Since OCD is characterized by a lack of "cognitive exclusion" and by deviant metabolic activity in the circuit connecting the paying cortex and stratum, it has been assumed that OCD patients may exhibit a lack of PPI (prepulse inhibition). The active ingredient has been found to recreate discontinued PPIs. See Psychopharmacology 124:107-116 (1996), R.A. Padich, et al., "5HT modulation of auditory and visual sensorimotor gating: II. Effects of 5HT2A antagonist MDL 100,907 on disruption of sound and light prepluse inhibition produced by 5HT agonists in Wistar rats".

The active ingredient is also effective in preventing acute thrombosis, especially those in the coronary arteries. This compound reduces the rate at which platelets aggregate as a result of minor changes in the endothelial lining of the vasculature and thereby prevents the formation of acute pathological thrombosis. See U.S. Patent No. 5,561,144 for description.

Anxiety, variant agina, anorexia nervosa, Raynaud's phenomenon, and coronary vasospasm used as defined in the 27th edition of Dorland's Illustrated Medical Dictionary.

Fibromyalgia is a chronic disease condition where the patient suffers from a number of symptoms such as e.g. widespread generalized musculoskeletal pain, aching pain, fatigue, morning stiffness and a sleep disturbance that can be characterized as insufficient stage 4 sleep.

Extra-pyrimidal side effects often accompany the administration of neuroleptics such as haloperidol and chlorpromazine. Patients often experience a parkinson-like syndrome where they experience muscle stiffness and tremors. Others experience akathisia and acute dystonic reactions.

The active ingredient increases the duration of the action potential of myocardial tissue producing an increase in the resistance period of this tissue which, under the classification system of Vaughan Williams, exhibits class HI anti-arrhythmic action.

The compound according to the present invention can be used to treat substance abuse in a patient. See T. F: Meert, et al., European Journal of Pharmacology 183: 1924 where 5HT2 antagonist abolishes preference for both alcohol and cocaine in the rodent model of substance abuse. Other animal models such as the rodent self-stimulation model described in R.A. Frank, et al., Behavioral Neuroscience 101: 546-559 (1987) is used to demonstrate the ability of the compound of the present invention to treat substance abuse.

The compound of the present invention is useful for the treatment of patients with depressive disorders and bipolar disorders. In the Diagnostic and Statistical Manual of Mental Disorders (Third Edition-Revised) ("DSM_III_R"), incorporated herein by reference, depressive disorders are defined as major depression, dysthymia, and depressive disorders NOS. We also include in this category severe depressive episodes including chronic type, melancholy and seasonal patterns. Bipolar disorders include bipolar disorder, cyclothymia and bipolar disorder NOS.

A feature of depressive disorders is one or more periods of depression without a history of either manic or hypomanic episodes. A feature of bipolar disorders is the presence of one or more manic or hypomanic episodes usually associated with one or more major depressive episodes. A manic or hypomanic episode is a distinct period during which the dominant mood is either elevated, expansive, or irritable and there are associated symptoms of the manic syndrome as defined in the DSM-II-R. The disturbance is severe enough to cause marked impairment in work or social functioning.

Major depression has one or more major depressive episodes. A major depressive episode is characterized by: (1) at least five of the following) depressed mood, loss of interest in pleasure (anhedonia), significant weight loss or weight gain without dieting, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy , feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or to concentrate, or recurrent thoughts of death including suicide, (2) it cannot be established that an organic factor initiated or maintains the disturbance, (3) it is no delusions or hallucinations for as long as two weeks in the absence of marked mood symptoms, and (4) and it is not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or psychotic disorder

NOS.

Dysthymia has a history of depressed mood for more days than not for at least two years and during the first two years of the disorder, the condition does not meet the criteria for a major depressive episode. The depressed mood of children and teenagers can be expressed as irritation. Also present are at least two of the following: poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration or difficulty making decisions or feelings of hopelessness. These symptoms are not superimposed on a chronic psychotic disorder such as schizophrenia or delusional disorder. Nor can it be determined that an organic factor initiated or maintained the disturbance.

There are many ways to show that the compound of the present invention is useful for the treatment of depressive disorders and bipolar disorders such as 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 ("CMS").

CMS applies mild stressors such as food and water deprivation, low temperature changes, changes in cage mats, etc. Over a period of weeks of exposure to the mild stressors, the animals gradually decrease their consumption of a highly preferred sucrose solution which is maintained (in untreated animals) for several weeks after the cessation of the stress. This decreased sensitivity to reward (the sucrose solution) reflects anhedonia, a symptom of a major depressive episode (see, e.g., Behavioral Pharmacol. 5: Suppl. 1, p. 86 (1994) where lithium, carbamazepine, and ketoconazole were evaluated in CMS ; Psvchopharmacologv 93:358-364 (1987) where tricyclic antidepressants were evaluated in CMS; Behavioral Pharmacology: 5:344-350 (1994) where catechol-O-methyl transferase inhibitor was evaluated in CMS).

The following CMS study was conducted using the active ingredient of the compound of the present invention (hereinafter "MDL 100,907") compared to the known antidepressant compound Impramin.

Male Wistar rats were brought into the laboratory two months before the start of the experiment at which time they weighed approx. 300 g. From Bortifra as described below, the animals lived individually, with food and water freely available and maintained on a 12 hour light/dark cycle (lights on at 08.00) at a temperature of 22 ±°C.

The animals were first trained to consume a 1% sucrose solution, training consisted of eight 1 hour baseline tests in which sucrose was presented in the home cage followed by 14 hours of food and water deprivation, intake was measured by weighing pre-weighed bottles containing the sucrose solution at the end of the test . Accordingly, sucrose intake was monitored under similar conditions at weekly intervals throughout the experiment.

On the basis of sucrose intake in the final baseline test, the animals were divided into two corresponding groups. A group of animals was subjected to a chronic mild stress procedure for a period of nine consecutive weeks. Each week of the stress period consisted of: two periods of food or water deprivation (12 and 14 h), two periods of 45°C inclined cage (12 and 14 h), two periods of intermittent nocturnal light (lights on and off every other hour), two 14 hour periods in a spilled cage (200 ml water in sawdust substrate), two 14 hour periods with two in the same cage, two 14 hour periods with low intensity stroboscopic lighting (ISO flash/min). The stress factors were applied continuously throughout the day and night and randomly distributed. Control animals were placed in a separate room and had no contact with the stressed animals. They were deprived of food and water for 14 h for each sucrose test, but otherwise food and water were freely available in the home cage. On the basis of their sucrose intake scores after 3 weeks of stress, both stressed and control animals were each further divided into corresponding subgroups (n=8), and for the following five weeks they received daily administration of vehicle (1 ml/kg, intraperitoneal 8ip)) imipramine ( 10 mg/kg, ip) or MDL 100,907 (0.002, 0.02 and 0.2 mg/kg orally). All drug injections were in a volume of 1 ml/kg body weight. The drugs were administered at 10:00 a.m. and the sucrose tests were performed 24 hours after the last drug treatment. After five weeks the treatments were stopped and after a week without a final sucrose test was performed. Stress was continuous throughout the treatment period and confiscation.

Results were analyzed by multiple analysis of variance followed by Fisher's LSD test for post hoc comparison of means.

Chronic mild stress causes a gradual decrease in intake of 1% sucrose solution in the final baseline test, sucrose intake was approx. 13 grams in both groups. After three weeks of stress (week 0), intakes remained at 12.4 (±0.4) grams in the control animals, but dropped to 7.2 (±0.2) grams in stressed animals (p<0.001). Such a difference between control and vehicle-treated stressed animals remained at a similar level for the remainder of the experiment.

Imipramine had no significant effect on sucrose intake in the control animals [F(1,84)=0.364; NS]. However, the drug caused a gradual increase in sucrose intake in stressed animals (F(1,84)=16.776; p<0.001). Sucrose intake in imiprarnin-treated stressed animals was significantly increased from week 0 scored after four weeks of treatment (p=0, 05) and after five weeks of treatment there was no significant difference between drug-treated stressed animals and drug- and saline-treated control animals.The increase in sucrose intake in imipramine-treated stressed animals was maintained at a similar level one week after withdrawal of the drug.

MDL 100,907 had no significant effect on sucrose intake in the control animals (treatment effect: F(3,168)=0.821; NS treatment x weeks interaction: F(l5,168=0.499; NS). In stressed animals, MDL 100,907 gradually reverses the CMS-induced the deficit in sucrose intake, resulting in a significant treatment effect [F(3,168)=22.567; p<0.001] and treatment x weeks interaction (F(15,158)=1.559; p=0.05).

In stressed animals treated with two higher doses of MDL 100,907 (0.02 and 0.2 mg/kg), sucrose intake was significantly increased from baseline (week 0) after two (0.02 mg/kg) and three (0, 2 mg/kg) weeks of treatment (respectively p=0.03 and p=0.04). This effect was

increased further during the following weeks and at the end of the treatment period (week 5) the amount of sucrose solution drunk by these animals was compared to that of vehicle-treated control animals and significantly higher than that of vehicle-treated stressed 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 intake throughout the treatment period. Consequently, after five weeks of treatment, the sucrose intake of stressed animals treated with this dose was not different from the intake of vehicle-treated stressed animals (p=0.860) and was significantly lower than the intake of vehicle-treated control animals (p<0.01). One week after withdrawal from treatment, sucrose intakes were not significantly changed in all MDL 100,907-treated control animals (0.002 mg/kg:p=0.2,0.02 mg/kg; p=0.9,0.2 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 must also be used to demonstrate the utility of the compound of the present invention in the treatment of depression such as using the abbreviated Hamilton Psychiatric Rating Scale for Depression. This comprises a series of 17 categories according to which the individual is assessed, e.g. after depressed mood, guilt, suicidal tendencies, insomnia, anxiety etc. to reach a score that indicates to the clinical doctor whether the patient is suffering from depression or not.

Claims (35)

1. Connection characterized by formal: wherein R is C4-C20 alkyl or a stereoisomer or a pharmaceutically acceptable salt thereof. 2. Compound according to claim 1, characterized in that R is a straight-chain alkyl. 3. Compound according to claim 1 or 2, characterized in that R is C5-C20, more preferably C5-C15 and most preferably C9-C15. 4. Compound according to claim 1 or 2, characterized in that R is C4-C15, more preferably C7-C15 and most preferably C7-C9. 5. Compound according to claim 1, characterized in that the compound is (+)-α-(2,3-dimethyloxyphenyl)-1 -[2-(4-fluorophenyl)ethyl]-4-piperidinementhanol decanoate, (+)-α-(2 ,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolhex^ (+)-a-(2,3-dimethoxyphenyl)-1 -[2-(4-fluorophenyl)ethyl]- 4-piperidine methanol hexanoate, (+)-α-(2,3-dimethophenyl)-1-[2-(4-fluorophenyl) or (+)-α-(2,3-Dimethoxyphen<y>1)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol 2,2-dimethyloctanoate. 6. Pharmaceutical composition characterized in that it comprises the compound according to claim 1 and a pharmaceutically acceptable carrier. 7. Pharmaceutical composition according to claim 6, characterized in that R is C9 straight-chain alkyl. 8. Pharmaceutical composition according to claim 6 or 7, characterized in that the pharmaceutically acceptable carrier is a pharmaceutically acceptable oil. 9. Pharmaceutical composition according to claim 8, characterized in that the oil is selected from the group consisting of sesame, olive, peanut, corn, almond, cottonseed, peanut and castor oil, the most preferred oil being sesame oil. 10. Use of a compound according to any one of claims 1-5 for the preparation of a pharmaceutical composition useful for treating a patient for psychosis. 11. Use according to claim 10, where the psychoses are schizophrenia. 12. Use according to claim 10 or 11, where R is C9 straight-chain alkyl. 13. Use according to claim 10, where the composition is for intramuscular or subcutaneous administration. 14. Use of a compound according to claim 1, for the preparation of a pharmaceutical composition useful for treating a patient for bipolar depression. 15. Use of a compound according to claim 1, for the preparation of a pharmaceutical composition useful for treating a patient for depression. 16. Use of a compound according to claim 1, for the preparation of a pharmaceutical composition useful for treating a patient for anxiety. 17. Use of a compound according to claim 1, for the preparation of a pharmaceutical composition useful for the treatment of a patient with obsessive-compulsive disorder. 18. Use of a compound according to claim, for the preparation of a pharmaceutical composition useful for treating a patient for substance abuse. 19. Use of a compound according to claim 1, for the preparation of a pharmaceutical composition useful for treating a patient for coronary vasospasms. 20. Use of a compound according to claim 1, for the preparation of a pharmaceutical composition useful for treating a patient for angina. 21. Use of a compound according to claim 1, for the preparation of a pharmaceutical composition useful for treating a patient for thrombotic disease. 22. Process for the preparation of a compound of formula I: where R is C 4 -C 20 alkyl or a stereoisomer or a pharmaceutically acceptable salt thereof, characterized by reacting an alcohol (5) with an acid halide of the formulas RC(0)X, an acid anhydride: of the formula (RCCO2O or a carboxylic acid of the formula RCO2H where R is as previously defined and X is chlorine or bromine in the presence of a sufficient amount of a suitable base to prepare a compound of formula I. 23. Process according to claim 22, characterized in that X is chlorine. 24. Method according to claim 22, characterized in that R is a straight-chain alkyl. 25. Process according to claim 22, characterized in that R is C5-C20, preferably C5-C15, most preferably C9-C15. 26. Method according to claim 22, characterized in that R is C4-C15, more preferably C7-Q5, most preferably C7-C9. 27. Method according to claim 22, characterized in that R is C9-branched alkyl. 28. Process according to claim 22, characterized in that R is C9 straight-chain alkyl. 29. Process according to claim 22, characterized in that the base is triethylamine. 30. Process according to claim 22, characterized in that R is Cg straight-chain alkyl, the base is triethylamine, X is chlorine and the alcohol (5) is reacted with the acid halide. 31. Method according to any one of claims 22-24, characterized in that the alcohol (5) is reacted with RCOX. 32. Method according to claim 22, characterized in that the alcohol (5) is reacted with (RCO)20. 33. Method according to claim 22, characterized in that the alcohol (5) is reacted with RCO2H. 34. Compound according to claim 1 for use as a pharmaceutical active substance. 35. Use of a compound according to claim 1 for the preparation of a pharmaceutical composition useful for antagonizing the effects of serotonin at the 5H2a receptor.