HUP0200517A2 - Esters of (+)-alpha-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol and their use as prodrugs of the 5ht2a receptor antagonist mdl 110,907 - Google Patents

Abstract

Esters of (2,3-dimethoxy-phenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine methanol (MDL 100907) (I), are new. Esters of (+)-alpha-(2,3-dimethoxy- phenyl)-1-[2(4-fluorophenyl)ethyl]-4-piperidine methanol of formula (I) and their stereoisomers and salts are new. [Image] R : 4-20C alkyl. ACTIVITY : Neuroleptic; Antimanic; Antidepressant; Tranquilizer; Antiaddictive; Cardiant; Antianginal; Thrombolytic; Eating-Disorders-Gen.; Vasotropic; Antiarrhythmic; Sedative. (+)-alpha-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl(ethyl]-4- piperidine methanol decanoate (120 mg/kg equivalent to MDL-100907) was administered to (+/-)-DOI HCl injected male Sprague-Dawley rats. (+/-)-DOI HCl induces several quantifiable behaviours in rats. Significantly antagonized DOI-induced behavior in the rats was observed for a full 28 days. The effect was no longer significant at day 40. MECHANISM OF ACTION : Antiserotonin-2A.

Description

TF/SM

P02 00517

Esters of (+)-a-(2,3-dimethoxyphenyl)-1 -[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol and their use as precursors of the 5HT2A receptor antagonist MDL 110907

PUBLICATION COPY

(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, also known as MDL 100907, is a potent 5HT2A receptor antagonist used clinically for the treatment of schizophrenia. J. Pharm. Exp. Ther. [277:968-9881 (1996)] is referenced. The compound is described in U.S. Patent No. 5,134,149, which is also incorporated herein by reference.

MDL 100907 antagonizes the effects of serotonin at the 5HT _2A receptor, making it useful for treating a variety of conditions. However, this compound may also exert other therapeutic effects, directly or indirectly, that are distinct from 5HT2A antagonism. See, for example, European Journal of Pharmacology 273:273-279 (1995), where MDL 100907 was shown to have a potent inhibitory effect on dopamine efflux in the medial prefrontal cortex.

Some uses of MDL 100907 are described in patents or patent applications. U.S. Patent No. 5,169,096 generally covers MDL 100907 and discloses the use of the compounds for the prophylactic treatment of anorexia nervosa, variable angina, Raynaud's syndrome, coronary artery spasm, migraine, and for the treatment of cardiovascular diseases such as hypertension, peripheral vascular disease, thrombotic episodes, cardiopulmonary emergencies, and arrhythmias.

94247-7500 TF/SM and describe their anesthetic effects. See also U.S. Patents 4,783,471, 4,912,117 and 5,021,428, which are assignments of U.S. Patent 5,169,096. See also U.S. Patents 4,877,798 (fibromyalgia), 4,908,369 (insomnia), 5,106,855 (glaucoma), and EP 319,962 (anxiety) and EP 337,136 (extrapyramidal symptoms). All of the foregoing are incorporated herein by reference.

Subsequently, MDL 100907 was specifically claimed in U.S. Patent No. 5,134,149, which discloses use for antagonizing serotonin at the 5HT2 receptor, treating anxiety, variable angina, anorexia nervosa, Raynaud's syndrome, intermittent claudication, coronary or peripheral vasospasm, fibromyalgia, extrapyramidal symptoms, arrhythmias, thrombotic disorders, transient ischemic attacks, drug addiction, and psychotic disorders such as schizophrenia and mania. See also U.S. Patents 5,561,144, 5,700,812, 5,700,813, 5,721,249, which are assignments of U.S. Patent 5,134,149, and U.S. Patent 5,618,824 (obsessive-compulsive disorder) and International Application PCT/US97/02597 (depressive disorders, including major depressive episode and mood disorder and bipolar disorders), and U.S. Patent Application No. ..., which disclose sleep disorders and sleep apnea, which are incorporated herein by reference.

The present invention is in part directed to the provision of a novel compound which, upon administration, releases an effective amount of MDL 100907 over a sustained period of time. The sustained effect is a longer duration than that of a single dose of MDL 100907, and may last for a few days, a few weeks, about a month to about 6 or 8 weeks, preferably about 2 weeks to about a month. There are several advantages to administering a compound to a patient in a single dose that is effective over a longer period of time. This avoids problems with co-administration, which may be particularly important in patients with psychosis or drug dependence, such as schizophrenia, obsessive-compulsive disorder, depression, anxiety, anorexia, and drug/drug addiction. Additional advantages include the absence of the usual drug level fluctuations that occur with multiple dose treatment, so that the patient experiences a more favorable effect during treatment, with lower peak drug concentrations.

The concept of sustained-release formulations is not new, but not all compounds can be chemically modified to produce a new compound that is capable of being metabolized to the desired extent and over the desired period of time to the corresponding active ingredient. Additional factors contribute to the difficulty of preparing sustained-release formulations, such as protein binding and other physiological processes that may affect the therapeutic effect of the active ingredient, see e.g. Biochemical Pharmacology, Vol. 36, No. 10, pp. 1715-1722 (1987), which is incorporated herein by reference. In addition, the chemically modified compound must be compatible with pharmaceutically acceptable carriers and must be stable enough not to degrade significantly to the active ingredient during storage. In short, designing a suitable sustained-release formulation is a complex and unpredictable task.

The present invention relates to compounds of general formula (I), wherein

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

The present invention also provides:

- a pharmaceutical composition comprising the compound of general formula (I) and a pharmaceutically acceptable carrier;

- a method for antagonizing the effects of serotonin at the 5HT2A receptor, comprising administering a compound of formula (I) to a patient in need thereof;

- a method for treating a patient, comprising administering to the patient in need of such treatment a therapeutically effective amount of a compound of general formula (I), where the disease is psychosis (including schizophrenia), obsessive-compulsive disorder, thrombotic disease, coronary artery spasm, anxiety, anorexia nervosa, Raynaud's syndrome, fibromyalgia, extrapyramidal side effects, arrhythmia, depression, bipolar depression, sleep disorder, sleep apnea or drug/drug addiction; and

- a process for preparing the compounds, in which a compound of formula (5) is reacted with an acid halide, acid anhydride or carboxylic acid in the presence of a suitable amount of base (see reaction scheme 2).

The meaning of certain terms used in this specification is detailed below.

a) the term "pharmaceutically acceptable salts" refers to acid addition or base addition salts which can be formed with the compounds of the invention.

The term "pharmaceutically acceptable acid addition salt" refers to the salts of the compounds of the general formula (I) of the base type with non-toxic organic or inorganic acids. Examples of inorganic acids suitable for such salt formation are: hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and also metal salts of acids, such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Examples of organic acids suitable for the above salt formation include mono-, di- and tricarboxylic acids. Suitable acids include e.g. are: acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, malic acid, hydroxymalic 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. Mono- or di-acid salts can be prepared and such salts can exist in hydrated or essentially anhydrous forms. In general, the acid addition salts of these compounds are more soluble in water and many hydrophilic organic solvents and generally have higher melting points than the free base form.

The term "pharmaceutically acceptable base addition salts" refers to the addition salts of the compounds of formula (I) or any intermediate thereof formed with a non-toxic organic or inorganic base. Examples include: 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, triethylamine and picoline. In selecting suitable salts, it is important that the ester is not hydrolyzed.

b) The term “stereoisomers” generally encompasses all isomers of a single molecule that differ in the spatial orientation of the atoms. The term includes mirror image isomers (enantiomers), geometric isomers (cis/trans isomers), and isomers of compounds with more than one chiral center that are not in a mirror image relationship (diastereoisomers).

c) The term “alkyl” refers to straight or branched chain alkyl groups, which can be characterized by the number of carbon atoms in the alkyl group, for example, the term C4-C20 alkyl refers to straight or branched chain alkyl groups containing 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms, or any smaller group selected from these, examples of which include: C5-C20, C4-C15, C5-C15, C7-C15 and C7-C9.

d) By "patient" we mean a warm-blooded animal such as a rat, mouse, dog, cat, guinea pig and primates such as humans.

e) “Treatment” means the alleviation of symptoms, the elimination of the causes of symptoms, temporarily or permanently, or the prevention or reduction of the appearance of symptoms of the disorder or condition in question.

• · *· *·· · ·

f) "Therapeutically effective amount" means the amount of the compound that is effective in treating the disorder or condition in question.

g) "Pharmaceutically acceptable carrier" is a non-toxic solvent, dispersant, additive, adjuvant or other substance which can be mixed with a compound of the present invention to enable the preparation of a pharmaceutical composition, i.e., a dosage form suitable for administration to a patient. An example of such a carrier is a pharmaceutically acceptable oil, such as is commonly used for parenteral administration.

h) The term “regenerative sleep” refers to sleep that results in a rested state upon awakening.

i) The term “sleep disorder” means insomnia and obstructive sleep apnea.

j) The term “insomnia” includes primary insomnia, insomnia associated with other mental disorders, and drug-induced insomnia.

k) The term “primary insomnia” refers to difficulty falling asleep, maintaining sleep, or developing restorative sleep that is not caused by a mental disorder or the physiological effects or consequences of taking certain substances (substance-induced insomnia). As used herein, it includes circadian rhythm insomnia, which is caused by a change in the normal sleep-wake cycle (shift work, jet lag, etc.).

I) The term “insomnia associated with another mental disorder” refers to difficulty falling asleep, difficulty maintaining sleep, or difficulty in developing restorative sleep, caused by the presence of a mental disorder, such as depression, anxiety, or schizophrenia.

m) The term “substance-induced insomnia” refers to difficulty falling asleep, maintaining sleep, or developing restorative sleep caused by the physiological effects or consequences of taking certain substances, such as caffeine, alcohol, amphetamines, opioids, sedatives, hypnotics, and tranquilizers.

n) The term “obstructive sleep apnea” refers to recurrent episodes of upper airway obstruction during sleep, usually characterized by silent episodes alternating with loud snoring or brief gasping for air.

The (+)-isomer of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol can be prepared by the methods described in U.S. Patent No. 5,134,149.

A suitable method is described in Schemes 1 and 2, where Scheme 1 describes the starting materials, while Scheme 2 describes the preparation of the esters of formula (I).

In step A) of Scheme 1, an esterification reaction is carried out between racemic α-(2,3-dimethoxyphenyl)-1-(2-(4-fluorophenyl)ethyl]-4-piperidinemethanol [compound (1)] and the (+)-isomer of α-methoxyphenylacetic acid (2). This esterification results in the diastereomeric mixture of formula (3). These diastereomers are separated by chromatography on silica gel to give the two diastereomers in step B).

-diastereomer. In step C), the (+,+)-diastereomer is hydrolyzed to give the (+)-isomer of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol.

The esterification reaction can be carried out by methods known in the art. Typically, approximately equivalent amounts of racemic α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol and the (+)-isomer of α-methoxyphenylacetic acid are contacted in an organic solvent such as methylene chloride, THF, chloroform or toluene and the mixture is heated at reflux for 5-24 hours. The esterification is typically carried out in the presence of equivalent amounts of dicyclohexylcarbodiimide (DCC) and a catalytic amount of 4-dimethylaminopyridine (DMAP). The resulting diastereomers can be isolated by filtration of the dicyclohexylurea and evaporation of the filtrate.

The diastereomers are then subjected to chromatography on silica gel to separate the (+) and (-) diastereomers. Chromatographic separation can be performed by any of the methods known in the literature. A 1:1 mixture of hexane and ethyl acetate can be used as a suitable eluent.

The resulting (+,+)-diastereomer is then hydrolyzed to give the (+)-enantiomer of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. The hydrolysis can be carried out by contacting the diastereomer with an excess of base (e.g. potassium carbonate) in an aqueous-alcoholic solution. The hydrolysis can be carried out at about 15-30 °C for 2-24 hours. The (+)-isomer of the resulting α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol can be recovered by extraction with methylene chloride followed by evaporation with water. The resulting material is then purified by recrystallization, which can be carried out using e.g. cyclohexane/hexane or ethyl acetate/hexane solvent systems.

Methods for preparing the starting materials in Scheme 1 are known in the literature. For example, U.S. Patent No. 4,783,471 teaches the preparation of a racemic mixture of α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. This patent is incorporated by reference and its contents are incorporated herein by reference. Examples 1 and 2 of this specification also describe suitable methods. Alternatively, racemic α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol can be prepared as follows. First, 4-hydroxypyridine is subjected to N-alkylation with p-fluorophenylethyl bromide to give 4-hydroxy-1-[2-(4-fluorophenyl)ethyl]piperidine. This compound PhaPBra is reacted with magnesium to form a Grignard reagent, which is then reacted with 2,3-dimethoxybenzaldehyde to give the desired (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol. The (+)-isomer of α-methoxyphenylacetic acid is also known from the literature.

In Scheme 2, X is chlorine or bromine, with chlorine being preferred, and R is as defined above. This scheme illustrates the preparation of sustained release compounds of formula (I) from alcohols of formula (5).

Accordingly, the alcohol of formula (5) is reacted with an acid halide of formula RC(O)X, an acid of formula RCO2H or an acid anhydride of formula (RCO) ₂ O • · ·· 4*« 4 · in the presence of a sufficient amount of base. By a sufficient amount of base is meant an amount that allows the ester formation from the acid halide or anhydride. Examples of suitable bases are: trialkylamines, pyridine, such as dimethylaminopyridine, diisopropylethylamines, N-methylmorpholines, with triethylamine being preferred. The amount of base required to form the compounds of formula (I) can be determined by a person skilled in the art.

Preferably, the base is added to the alcohol of formula (5) and the mixture is then added dropwise to a solution of the acid halide or anhydride in a suitable solvent. Examples of suitable solvents include chloroform, methylene chloride or toluene, which are readily available, with chloroform being preferred.

The reaction temperature may be, for example, in the range of about 0-25°C. The reaction mixture may be stirred, for example, for a period of time ranging from a few hours to overnight stirring to complete the reaction. Catalysts may also be used to reduce the reaction time, such as 4-dimethylaminopyridine or the like.

Acid halides of the general formula RC(O)X are readily available to one skilled in the art. For example, the following are available from Aldrich Chemical: stearoyl chloride, heptadecanoyl chloride, palmitoyl chloride, myristoyl chloride, isovaleryl chloride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, undecanoyl chloride, and lauroyl chloride. Acid halides that are not readily available commercially can be prepared by one skilled in the art. For example, the carboxylic acid can be mixed with a halogen donor compound to provide the desired acid halide. The following procedure is an example of this. Carboxylic acid (0.17 mmol), methylene chloride (660 mL), and dimethylformamide (0.5 mL) are mixed under a nitrogen atmosphere. Oxalyl chloride (0.2 mol) is added at about 5 minutes, with stirring. Stirring is continued at ambient temperature for about 3 hours, then the solvent is evaporated in vacuo to give the acid chloride. In another possible procedure, the carboxylic acid (10 mmol) is dissolved in methylene chloride (50 ml), the mixture is cooled to 0 °C, placed under a nitrogen atmosphere, and then thionyl chloride (11 mmol) is added dropwise. After stirring for a few hours and evaporation of the volatiles in vacuo, the acid chloride is obtained. Carboxylic acids are readily available or can be easily prepared by a skilled person.

Anhydrides of the general formula (RCO)2O are readily available to those skilled in the art. For example, butyric anhydride, isobutyric anhydride, valeric anhydride, 1,2-dimethylglutaric anhydride, and phthalic anhydride are available from Aldrich Chemical. Alternatively, the anhydrides can be prepared according to methods well known in the art.

Acids of the general formula RCO2H are readily available or can be prepared by methods well known in the art, see, e.g., Advanced Organic Chemistry, Reactions, Mechanisms and Structure, 4th edition, John Wiley & Sons, New York, 1992, the contents of which are incorporated herein by reference. In addition, the following acids are also available from Aldrich Chemical Company: 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, myristyl acid, pentadecanoic acid, palmitic acid, heptadecanoic acid, stearic acid, nonadecanoic acid, eicosanoic acid, and other acids in which the R moiety is an alkyl group of 4-20 carbon atoms.

The following examples illustrate the invention in more detail, but are not intended to limit the scope of the invention.

Example 1 (starting material)

Steps A)-D) of Example 1 illustrate the preparation of the starting material (±)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol of formula (1) (see Scheme 1).

A) 1-12-(4-Fluorophenyl)ethyl 1-4-piperidinecarboxamide

A solution of isonipecotamide (10.9 g, 85.0 mmol), 2-(4-fluorophenyl)ethyl bromide (15.7 g, 77.3 mmol) and K2CO3 (2.3 g, 167 mmol) was prepared in DMF (280 mL) and stirred overnight at 90-95 °C under argon. The cooled solution was concentrated to give a white oily solid. The resulting solid was partitioned between water and _CH2Cl2 . The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined organic layers were washed twice with water, dried (MgSO4), filtered and concentrated to an oily solid. The solid was recrystallized from EtOAc _to give 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide as a white powder. M.p.: 177-178 °C (decomposes).

Elemental analysis based on the formula C14H19FN2O: calculated: C 67.18; H 7.65; N 11.19; found: 67.25; 7.67; 11.13.

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

To phosphorus oxychloride (25 mL, 41.12 g, 268 mmol) and sodium chloride (5.1 g, 87.3 mmol) was added 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxamide (8.9 g, 35.6 mmol) in portions while stirring. After the addition was complete, the solution was refluxed for 2 h. The cooled solution was carefully poured into dilute _NH4OH solution to destroy the _POCl3 . The aqueous solution was cooled to 0 °C and extracted twice with _CH2Cl2 . The combined organic layers were dried (MgSO4), filtered, and evaporated to give 8.1 g of an oily solid. This solid was distilled (bp = 150 °C, 13.3 Pa) to give a clear colorless oil which solidified. This material was recrystallized from hexane to give 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine as white needles. M.p.: 47-48 °C.

Elemental analysis based on the formula C14H17FN2: calculated: C 72.39 H 7.38; N 12.06; found: 72.62; 7.49; 12.12.

C) To a stirred solution of i-[2-(4-Fluorophenyl)ethyl]-4-piperidinecarboxaldehyde 4-cyano-1-[2-(4-fluorophenyl)ethyl]piperidine (1.00 g, 4.3 mmol) in THF (20 ml) under argon at 0 °C was added DIBAL-Ht (4.6 ml of a 1.0 M solution in THF, 4.6 mmol) via a metering syringe. After stirring at room temperature overnight, 10% aqueous HCl solution (25 ml) was added and the solution was stirred for 3 h. The entire mixture was poured into 10% NaOH solution (50 ml) and extracted twice with diethyl ether. The combined organic layers were washed with NaCl solution, dried (MgSO ₄ ), filtered, and evaporated to give a pale yellow oil. The oil was chromatographed on silica gel using EtOAc as eluent. The appropriate fractions were combined and evaporated to give an oil. This oil was distilled (b.p. 166 °C, 6.6 Pa) to give 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde as a colorless oil.

Elemental analysis based on the formula _Ci4H18FNO : calculated: C 71.46; H 7.71; N 5.95; found: 71.08; 7.81; 5.86.

D) (+)-a(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]4-piperidinemethanol

To a stirred solution of veratrol (0.93 g, 6.7 mmol) in THF (20 mL) at 0 °C under argon 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 a solution of 1-[2-(4-fluorophenyl)ethyl]-4-piperidinecarboxaldehyde (1.30 g, 5.5 mmol) in THF (25 mL) via addition funnel. The cooling bath was removed and the solution was stirred for 2 h. Water was added, the layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with NaCl solution, dried (MgSO4), filtered, and chromatographed on silica gel using acetone as eluent. The appropriate fractions were combined and evaporated to give a white solid. This solid was recrystallized from hexane to give racemic a(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidin methanol as shiny white needles. M.p. 126-127 °C.

Elemental analysis based on the formula C22H28FNO3: calculated: C 70.75; H 7.56; N 3.75; found: 70.87; 7.65; 3.68.

Example 2 (starting material)

Steps A)-F) of Example 2 provide an alternative preparation route for the preparation of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]piperidinemethanol of formula (1)

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

To a stirred mixture of isonipecotic acid (107.5 g, 832 mmol) in 1 N NaOH (41 g NaOH dissolved in 900 mL H ₂ O) and tert-butanol (1800 mL) was added di(tert-butyl)dicarbonate (200 g, 916 mmol) in portions. After stirring overnight, the solution was concentrated and the resulting aqueous layer was acidified with aqueous HCl. This aqueous acidic layer was extracted three times with diethyl ether. The combined organic layers were washed with water and NaCl, dried (MgSO4), filtered and evaporated to give a white solid which was recrystallized from EtOAc/hexane (300 mL/200 mL) to give 1-(1,1-dimethylethyl)-1,4-piperidinedicarboxylic 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 mixture of -(1,1-dimethylethyl)-1,4-piperidinedicarboxylic acid (50.0 g, 218 mmol) in anhydrous CH ₂ Cl ₂ (500 mL) in a 2-liter flask under nitrogen was added 1,1'-carbodiimidazole (38.9 g, 240 mmol) in portions. After stirring for 1 hour, N,O-dimethylhydroxylamine hydrochloride (23.4 g, 240 mmol) was added in one portion. After stirring overnight, the solution was washed twice with 1 N HCl, twice with saturated NaHCO 3 , once with NaCl, dried (MgSO 4 ), filtered, and evaporated to give an oil. This oil was distilled to give 4-(N-methoxy17

-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethyl ethyl ester as a colorless oil. Boiling point: 120-140 °C, 106.4 Pa.

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 a metering 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 stirred for 90 min. The mixture was cooled to -78 °C and treated with a solution of 4-(N-methoxy-N-methylcarboxamido)-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (9.20 g, 33.8 mmol) in THF (50 mL, anhydrous) via a metering syringe. The dry ice/acetone cooling bath was removed and the mixture was allowed to warm to room temperature. After stirring for 3 h, saturated aqueous NaCl was added and the mixture was stirred overnight. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with NaCl, dried (MgSO4), filtered and evaporated to give an amber oil. The oil was chromatographed on silica gel using 20% EtOAc in hexane as eluent. The appropriate fractions were combined and evaporated to give an amber oil. The oil was distilled to give 4-(2,3-dimethoxybenzoyl)-1-piperidinecarboxylic acid 1,1-dimethyl ester as a colorless oil. (Boiling point: 225-250 °C, 6.6 Pa).

J : ·:>·.* • *·· *··4 · « « v * . * «Μ * 4

Elemental analysis based on the formula C19H27NO5: calculated: C 65.31; H 7.79; N 4.01; found: 65.04; 7.92; 4.11.

D) 4-(2,3-Dimethoxyphenyl)-4-piperidinylmethane

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 the mixture was stirred for 45 min. The entire solution was poured into diethyl ether (900 mL) and the resulting mixture was allowed to stand overnight. Filtration gave 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate as fine white needles. M.p. 123 °C.

Elemental analysis based on the formula C14H19NO3· CF3CO2H:

Calcd: C 52.89; H 5.55; N 3.86;

found: 52.77; 5.62; 3.82.

The resulting 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone trifluoroacetate was dissolved in water, treated with NaOH (10% aqueous solution) until basic, and the mixture was extracted three times with dichloromethane. The combined organic layers were washed with NaCl solution, dried (MgSO4), filtered and evaporated to give 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone as an oil.

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

A solution of 4-(2,3-dimethoxyphenyl)-4-piperidinylmethanone (8.00 g, 32.1 mmol) and 2-(4-fluorophenyl)ethyl bromide (6.52 g, 32.1 mmol) in DMF (90 mL) was prepared, treated with K2CO3 (7.0 g, 50.7 mmol), and stirred overnight at 80 °C under argon. The cooled solution was poured onto a mixture of ¹⁹ U. L·?·: ·*·· y of EtOAc/toluene (2/1) and water. After equilibrium was reached, the layers were separated and the aqueous layer was extracted with EtOAc/toluene (2/1). The combined organic layers were washed twice with water and once with brine, dried (MgSO4), filtered and evaporated to give 11.0 g of an oil. This oil was chromatographed on silica gel using EtOAc as eluent. The appropriate fractions were combined, concentrated, dissolved in ethyl acetate and treated with HCl/ethyl acetate to give (2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]-methanone monohydrochloride as a precipitate. Mp 225-227 °C (dec.).

Elemental analysis based on the formula C22H26FNO3 · HCl: calculated: C 64.78; H 6.67; N 3.43; found: 64.44; 6.73; 3.41.

F) To a stirred solution of (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinylmethanol (2,3-Dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methane (6.0 g, 16.2 mmol) in MeOH (100 mL) at 0 °C was added NaBH ₄ (1240 mg, 32.8 mmol) in two portions over a period of one hour. After stirring overnight, the solution was concentrated to a solid. The solid was partitioned between water and diethyl ether. The layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with NaCl, dried (MgSO ₄ ), filtered, and evaporated to a solid. The solid was chromatographed on silica gel using acetone as eluent. The appropriate fractions were combined and evaporated to give a solid. The solid was recrystallized from cyclohexane to give (+)20

-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol in the form of white needles, mp: 126-127 °C.

Elemental analysis based on the _{formula C22H28FNO3} : calculated: C 70.75; H 7.56; N 3.75; found: 70.86; 7.72; 3.93.

Example 3 (starting material)

This example demonstrates the preparation of the alcohol of formula (5). (+)-α-(2,3-Dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]-4-piperidinylmethanol

A) Preparation of diastereomers

A solution of 3.90 g (10.4 mmol) (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, 1.74 g (10.4 mmol) S-(+)-α-methoxyphenylacetic acid, 2.15 g (10.4 mmol) 1,3-dicyclohexylcarbodiimide and 0.1 g 4-dimethylaminopyridine in chloroform (75 ml) was refluxed for 17 h, cooled to room temperature and filtered. The filtrate was concentrated and chromatographed on a silica gel column using a 1:1 mixture of ethyl acetate/hexane as eluent. The two diastereomers were thus obtained with R _f = 0.1 and 0.2 (thin layer chromatography separation, EtOAc/hexane, 1:1). The intermediate fractions were rechromatographed to give additional material. Fractions with retention times of R _f = 0.2 were combined to give a diastereomeric ester, (+, +)-(2,3-dimethoxyphenyl)-[1-[2-(4-fluorophenyl)ethyl]-4-piperidinyl]methyl-α-methoxybenzeneacetate.

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

To a stirred solution of 0.97 g (1.9 mmol) of the above diastereomeric ester (R _f = 0.2) in 25 mL of methanol was added 0.5 g (3.6 mmol) of potassium carbonate and 5.0 mL of water. Filter at room temperature. Wash the filter cake with 200 mL of CH ₂ Cl 2 . Concentrate the filtrate at 40 °C and 6650 Pa to give an oil.

The crude product was purified by flash chromatography (14x29 cm column, 2.035 kg 230-400 mesh silica gel). The crude product was dissolved in 75 ml _CH2Cl2 and applied to the column. The column was eluted with 24 liters of 1:4 EtOAc/CH2Cl2 and 24 1 liter fractions were collected. Fractions that were found to be homogeneous by thin layer chromatography were combined and concentrated at 35 °C at 6650 Pa and then at 70 °C at 66.5 Pa for 1 hour to give a colorless oil.

MS (M ⁺ ) = 528.

Elemental analysis based on the formula C32H46FNO4 (527.73): calculated: C% 72.83; H% 8.79; N% 2.65;

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

Example 5 (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolhexanoate [Compound of formula (PLD ₅ )]

To a solution of 2.0 g (5.37 mmol) of (+)-α-(2,3-dimethoxyphenyl)-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. The solution was cooled in an ice bath, and 1.07 ml (5.89 mmol) of hexane anhydride was added via a metering syringe. The solution was stirred at ice bath temperature for a few minutes, then 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, then poured onto ice/water/0.5 M NaOH, extracted with diethyl ether, filtered, and concentrated to an oil. The oil was dissolved in methylene chloride and the resulting solution was dissolved in 2% methanol/methylene chloride. The fractions containing the crude product were combined and concentrated. The resulting oil was dried overnight at 60 °C under high vacuum to give the title compound. The compound was found to be homogeneous by thin layer chromatography. The resulting compound was found to be consistent with the proposed structure by IR (KBr), NMR (CDCl3), and MS (MH ⁺ = 472).

Elemental analysis based on the formula C28H38FNO4: calculated: C% 71.31; H% 8.12; N% 2.97; found: 70.94; 8.07; 2.88.

Example 6 (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol octanoate [see compound of formula (PLDe)]

To a stirred solution of 2.0 g (5.37 mmol) of (+)-α-(2,3-dimethoxyphenyl)-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. The solution was cooled in an ice bath, and then 1.75 ml (5.89 mmol) of octanoic anhydride was added using a metering syringe. The solution was stirred at the temperature of the ice bath for a few minutes, then allowed to warm to room temperature. Then 66 mg (0.541 mmol) of 4-dimethylaminopyridine was added to the solution. The mixture was stirred, washed with water and saturated NaCl solution. The organics were dried (Na ₂ SO 4 ), filtered, and concentrated to an oil. The oil was dissolved in methylene chloride and flash chromatographed on silica gel using methylene chloride, 1% and 2% methanol/methylene chloride as eluents. The fractions containing the crude product were combined and concentrated. The resulting oil was dried overnight at 60 °C under high vacuum to give the title compound. The compound was found to be homogeneous by thin layer chromatography. The resulting compound was found to be consistent with the proposed structure by IR (KBr), NMR (CDCl ₃ ), and MS (MH ⁺ = 501).

Elemental analysis based on the formula C30H42FNO4: calculated: C% 72.11; H% 8.47; N% 2.80;

found: 71.94; 8.63 2.83.

Example 7 (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol hexadecanoate [see compound of formula (PLD7)]

To a stirred solution of 2.00 g (5.36 mmol) of (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol in 6 mL of dry methylene chloride was added 0.76 mL (5.46 mmol) of triethylamine using a dropping funnel and the solution was cooled in an ice bath. To the solution was added 2.92 g (5.89 mmol) of hexadecane anhydride and the mixture was stirred at 0 °C for 15 min. The reaction mixture was allowed to warm to ambient temperature and 65 mg (0.536 mmol) of 4-dimethylaminopyridine was added and the solution was stirred overnight under nitrogen. The reaction mixture was poured into a mixture of 50 mL of 0.5 N sodium hydroxide and 50 mL of diethyl ether. A precipitate was observed, after which the resulting suspension was extracted with methylene chloride. The methylene chloride layer was washed with water and NaCl solution, dried over sodium sulfate, filtered, and concentrated to a yellow oil. The oil was dissolved in methylene chloride and flash chromatographed on a silica gel column using methylene chloride as eluent, followed by 1% and 2.0% methanol/methylene chloride. The appropriate fractions were combined and concentrated to a yellow oil. The oil was dried at 60 °C under high vacuum for two nights to give the title compound. The compound was found to be homogeneous by thin layer chromatography. The resulting compound was found to be consistent with the proposed structure by IR (film), NMR (CDCl ₃ ), and MS (MH ⁺ = 612).

Elemental analysis based on the formula C24H30FNO4: calculated: C% 74.59; H% 9.55; N% 2.29;

found: 74.34; 9.45; 2.29.

Example 8 (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl-4-piperidinemethanol dimethyloctanoate [see compound of formula (PLD ₈ )]

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

2,2-Dimethyl-3-octenonitrile was prepared by adding to a solution of 2-hexene-1-mesylate (11.02 g, 0.05 mol) in anhydrous THF (100 ml) a solution obtained by treating a solution of isobutyronitrile (3.7 g, 0.053 mol) in THF (25 ml) with a mixture of NaH (60% mineral oil, 2.1 g, 0.053 mol) in THF (50 ml). The resulting reaction mixture was stirred at reflux for 5 h, cooled, then stirred with cold ethanol (95%) and finally concentrated in vacuo to remove the solvents. After addition of water (50 ml), the mixture was extracted with diethyl ether (3x40 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-octenonitrile.

2,2-Dimethyl-3-octenoic acid was prepared by adding 2,2-dimethyl-3-octene nitrile (1.51 g, 0.01 mol) to a 2:3 mixture of 15% NaOH in butanol and water (30 mL), and the reaction mixture was refluxed with stirring for 2 h, then cooled and acidified with 10% HCl. The reaction mixture was extracted with diethyl ether, the extract was washed with saturated NaCl, dried over MgSO ₄ and filtered to give 2,2-dimethyl-3-octenoic acid.

2,2-Dimethyloctanoic acid was prepared by dissolving 2,2-dimethyl-3-octenoic acid (0.20 g, 1.1 mmol) in ethanol under a nitrogen blanket, adding 10% palladium on carbon, and hydrogenating the mixture for 6 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 2,2-dimethyloctanoic acid.

(+) _{_} To a stirred solution of _(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (3.9 g, 10.4 mmol) in 70 mL of methylene chloride 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 refluxed for 16 h with stirring. The reaction mixture was filtered and concentrated to an oil. The resulting oil was chromatographed on silica gel using a 1:1 mixture of ethyl acetate/hexane as eluent. The appropriate fractions were collected, heated (40 °C) and concentrated under reduced pressure to give the title compound.

Example 9

This example describes a pharmaceutical composition according to the present invention.

In a suitable 100 ml container, add 70 ml of sesame oil, NF (Sigma), 1.2 g of benzyl alcohol, NF and 14.129 g of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol decanoate. To this solution, add an appropriate amount of sesame oil, NF to make the volume 100 ml and stir the mixture until it is homogeneous. This solution can be sterilized and packaged for parenteral injection.

10, example

This example describes a behavioral assay (antagonism of DOI-induced behavior) designed to identify compounds that have antagonistic activity at the 5HT ₂ a receptor. The compound of the present invention used in this assay was (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol decanoate (see Example 4). The 5-HT2A/2C agonist (±)-DOI-HCl [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride] induces several measurable behaviors in rats. These behaviors include “shakes” (rapid head and body shaking, similar to a wet dog shaking itself), “front paw tapping” (rapid front paw stepping), and “skin twitches” (muscle contractions near the spine or twitching of the back skin). The 5HT2 antagonists mianserin, ritanserin and methysergide, as well as the selective 5HT2A antagonist MDL 100907, blocked the behavioral effects of DÓI in a dose-dependent manner (Pranzatelli, 1990, Neurosci. Let. 11. 74-80;

Wettstein et al., 1996, Soc. Neurosci. Abs. 22:481). Significantly, 5HT ₂ A-antagonist drugs have been suggested to have atypical antipsychotic properties in schizophrenic patients (Meltzer et al., 1989, JPET, 251:238-246) and to have potent therapeutic activity in a number of other central nervous system disorders, including depression, mood disorders, and anxiety (Stefanski & Goldberg, 1997, CNS Drugs, 7:399-409).

Proceedings

Experimental animals and conditions

Seven Sprague-Dawley rats (180 + 50 g) were housed per cage. The animals were acclimated to the vivarium for one week. Food and water were freely available. The temperature and light cycle (12 hours light and 12 hours dark) were maintained automatically. Each rat was tested once. Each test group consisted of two animals. The tests were performed in the vivarium room where the animals were kept.

Preparation and use of the active ingredient (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol decanoate (equivalent to 120 mg/kg MDL 100907) was dissolved in sesame oil and administered intramuscularly to the different groups of rats on day 0 in a volume corresponding to 60 ml/100 g of body weight. Control animals receiving vehicle received only sesame oil injection.

(+)-D0l-HCl (3.0 mg/kg, 1 ml/kg body weight) was dissolved in distilled water using an ultrasonic bath and injected intraperitoneally on the appropriate test days.

Observation and behavioral assessment In rats treated with (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanoldecanoate, we examined the antagonism of DOI-induced behavior on days 1, 5, 7, 14, 21, 28, and 40 after a single intramuscular injection of (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanoldecanoate. Each rat was examined once. After DOI injection, the rats were immediately placed under inverted transparent plastic cages (length: 28 cm, width: 25 cm, height: 25 cm), the tops of which were previously covered with clean absorbent paper. Rats were continuously monitored by trained observers (blinded to treatment) for 30 min for the occurrence of DOI-induced behaviors (tremors, skin twitches, and forepaw tapping attacks) and then returned to their original cages. Rats were subsequently used in pharmacokinetic studies. The frequency of DOI-induced behaviors was recorded and summed to provide a simple behavioral score for each animal.

Data analysis

The mean and standard error of the behavioral score for each group were determined. The mean for each treatment group was then compared separately with the mean for the vehicle control group using a one-way analysis of variance (ANOVA) test followed by Bonferroni/Dunn post hoc comparisons. Differences between groups were considered statistically significant if the p value was 0.05 or less.

Results

Significant antagonism of DOI-induced behavior was observed in rats over 28 days. On day 40, the effect was no longer significant.

Example 11

This example shows the absorption of a single dose of MDL 100907 over time following intramuscular (i.m.) administration of a compound of the present invention, (+)-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanoldecanoate.

Ninety male Wistar rats, weighing approximately 150-200 grams, were each given ( + )-α-(2,3-Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol decanoate (equivalent to 120 mg/kg MDL 100907) intramuscularly in sesame oil on day 0. The rats were given a lethal i.p. dose of the anesthetic nembutal and blood was collected 3 and 6 hours later and on various days after administration (n = 5 at each time point) into a heparinized vacuum container. Blood samples were centrifuged at approximately 2700 rpm at 5 °C for 30 minutes. Plasma was removed and stored at -20 °C until assayed. Plasma samples were analyzed by an appropriate HPLC method. Brain samples were also collected at the above time points and stored at -80°C until analysis by the appropriate HPLC method. The results are shown in Table 1 .

Table 1

Time (days) (+)-a-(2,3- -Dimethoxyphenyl)-1 -[2 -(4-fluorophenyl)ethyl]-4- -piperidine methanol MDL 100907 (ng/ml) (+)-a-(2,3- - -Dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanoldecanoate - 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 9.89 ± 5.65 21.00 ± 12.79 15 11.67 ±6.18 52.36 ± 15.20 19 6.37 ± 2.19 40.06 ± 8.44 22 15.93 ± 2.45 46.30 ± 9.31 26 15.51 ± 7.15 38.92 ± 9.35 29 13.22 ±4.54 43.71 ± 10.81 41 3.88 ± 3.81__________í 24.12 ±9.15________

The dosage range at which the compounds of formula (I) can exert their serotonin inhibitory activity at the 5HT _2A receptor may vary depending on the particular disease, the condition to be treated and its severity, the patient, the composition, other existing diseases affecting the patient and other medications that may be administered to the patient at the same time. In general, the compounds of formula (I) show their serotonin 5HT _2A antagonistic properties at a dose of about 0.001 mg/kg body weight/day to about 100 mg/kg body weight/day. Sustained-release formulations may contain multiples of the previous doses depending on the duration of release of the active ingredient. The dosage of the compounds of the present invention can be determined by administering it to an animal and determining the level of the active ingredient in the plasma.

The compounds of the present invention may be admixed with a pharmaceutically acceptable carrier suitable for the desired route of administration to provide sustained release of the compound of the present invention such that a therapeutically effective amount of (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol decanoate is provided to the patient for days or weeks. Preferably, the sustained release formulation comprises a compound of formula (I) and a pharmaceutically acceptable carrier suitable for parenteral administration, which may be an aqueous suspension, an oily solution, an oily suspension or an emulsion. Some oils suitable for intramuscular injection include sesame, olive, arachis, corn, almond, cottonseed, hazelnut and castor oil, preferably sesame oil. A pharmaceutically acceptable preservative such as benzyl alcohol may also be added. The sustained release formulation is preferably administered intramuscularly or subcutaneously, with intramuscular administration being preferred, although other routes of administration, such as oral, transdermal, nasal spray, etc., may be used if the patient's needs permit.

Since the compounds of the present invention release (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (“active agent”) in the patient’s body to achieve a therapeutic effect, the compounds of the present invention are suitable for all indications for which the active agent is suitable. Some indications for use are described in the patents generally applicable to the active agent (U.S. Patent No. 4,783,471) or in the patents specifically applicable to the active agent (U.S. Patent Nos. 5,134,149; 5,561,144; 5,618,824 and PCT/US97/02597), which are incorporated herein by reference. These references describe use in psychosis (including schizophrenia), obsessive-compulsive disorder, thrombotic disease, coronary artery spasm, intermittent claudication, anorexia nervosa, Raynaud's syndrome, fibromyalgia, extra-pyramidal side effects, anxiety, arrhythmia, depression and bipolar depression, or drug addiction (e.g., cocaine, nicotine, etc.). Some of these indications are described in the aforementioned patents and U.S. Patent Nos. 5,561,144, 5,618,824, 4,877,798, 5,134,149, and 5,021,428, all of which are incorporated herein by reference.

Psychoses, as used herein, are conditions in which the patient exhibits signs of a major mental disorder of organic and/or emotional origin, characterized by personality disorder, loss of contact with reality, and often delusions, hallucinations, and illusions. Representative examples of psychotic disorders treatable with the compounds of the present invention include schizophrenia, schizophreniform disorder, schizoaffective psychosis, delusions, brief psychotic disorder, intermittent psychotic disorder, psychotic disorder not otherwise specified, and drug-induced psychotic disorder. See: Diagnostic and Statistical Manual of Mental Disorders, 4th edition, American Psychiatric Association, which is incorporated herein by reference. The drug is currently in clinical trials for the treatment of schizophrenia. ‘

Patients with obsessive-compulsive disorder (OCD) are unable to inhibit or suppress intrusive thoughts or ideas. Since OCD is characterized by inadequate “cognitive inhibition” and abnormal metabolism in circuits involving the orbital cortex and striatum, it was expected that OCD patients would exhibit inadequate PPI (prepulse inhibition). We found that the drug restored the disrupted PPI. See Psychopharmacology 124:107-116 (1996), RA Padich et al., “5HT modulation of auditory and visual sensorimotor gating: II. Effects of 5HT ₂ a antagonist MDL 100,907 on disruption of sound and light prepulse inhibition produced by 5HT agonists in Wistar rats.”

The active ingredient is also effective in preventing acute thrombosis, particularly in coronary arteries. This compound reduces the degree of platelet aggregation as a result of minor changes in the endothelial lining of the vascular system, thus preventing the formation of acute pathological thrombi (see the description in U.S. Patent No. 5,561,144).

The terms anxiety, variable angina, anorexia nervosa, Raynaud's syndrome, and coronary spasm are used according to Dorland's Illustrated Medical Dictionary, 27th edition, which is incorporated herein by reference.

Fibromyalgia is a chronic pathological condition in which the patient suffers from a number of symptoms, such as widespread generalized muscle pain, aches, fatigue, morning stiffness, and sleep disturbance, characterized by stage 4 sleep deprivation.

Extrapyramidal side effects often accompany the administration of neuroleptics such as haloperidol and chlorpromazine. Patients often present with Parkinson's disease-like symptoms, including muscle rigidity and tremor. Others may experience akathisia and acute dystonia.

The active substance increases the duration of the action potential of myocardial tissue, thereby increasing the refractory period in this tissue, which demonstrates class III anti-arrhythmic activity according to the Vaughan Williams classification.

The compounds of the present invention may be useful in the treatment of drug addiction in humans. See TF Meert et al., European Journal of Pharmacology 183: 1924, where a _5HT2 antagonist abolished both alcohol and cocaine preference in a rodent model of drug addiction. Other animal models, such as those of RA Frank et al. [Behavioral Neuroscience 101:546-559 (1987)], may also be useful in demonstrating the utility of the compounds of the present invention in the treatment of drug addiction.

The compounds of the present invention are useful in the treatment of patients suffering from depressive disorders and bipolar disorders. In the Diagnostic and Statistical Manual of Mental Disorders (IIIth revised edition, abbreviated as “DSM-III-R”), which is incorporated herein by reference, the definition of depressive disorders includes major depression, dysthymia (a mood disorder), and depressive disorder NOS. We also include major depressive episode - including the chronic type, melancholia, and seasonal pattern - in this category. Bipolar disorders include bipolar disorder, cilothymia, and bipolar disorder NOS.

Depressive disorders are characterized by one or more episodes of depression without a history of manic or hypomanic episodes. Bipolar disorders are characterized by one or more episodes of manic or hypomanic episodes, often accompanied by one or more major depressive episodes. A manic or hypomanic episode is a distinct period during which the prevailing mood may be elevated, tense, or irritable, and symptoms associated with the manic syndrome, as defined in DSM-III-R, are present. The disorder is severe enough to cause significant impairment in occupational and social functioning.

Major depression is characterized by one or more major depressive episodes. A major depressive episode is characterized by: (1) the presence of 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 weakness, feelings of worthlessness or excessive or inappropriate guilt, impaired thinking and concentration, or recurrent thoughts of death, including suicide; (2) there is no evidence that an organic factor has precipitated and maintained the disturbance; (3) there are no delusions or hallucinations for two weeks in the absence of the dominant mood symptoms; and (4) it is not associated with schizophrenia, schizophreniform disorder, delusions, or psychotic disorder NOS.

Dysthymia is characterized by a history of depressed mood for several days but less than two years, and the condition does not meet the criteria for a major depressive episode in the first two years of the disorder. Depressed mood may present as irritability in children and adolescents. Two of the following are also present: loss of appetite or increased appetite insomnia or hypersomnia, weakness or fatigue, low self-esteem, difficulty concentrating, indecisiveness, or feelings of hopelessness. These symptoms are not associated with a chronic psychotic disorder such as schizophrenia or delusions. Furthermore, no organic factor can be identified that triggers and maintains the disorder.

There are many ways to demonstrate that the compounds of the present invention are 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); Paul Willner: “Animal Models of Depression: An overview” Pharmac. Ther. 45:425-455 (1990), which are incorporated herein by reference.

One such model is the “chronic mild stress” model of depression (“CMS”).

CMS employs mild stressors such as food and water deprivation, small temperature fluctuations, cage mate changes, etc. When animals are exposed to mild stressors for weeks, they gradually reduce their intake of a highly preferred sucrose solution, which persists for weeks (in untreated animals) after the stressor has been removed. This reduced sensitivity to self-reward (sucrose solution) reflects anhedonia, a symptom of major depressive episode [see, e.g., Behavioral Pharmacol. 5: Chap. 1, p. 86 (1994), where the effects of lithium, carbamazepine, and ketoconazole were evaluated in CMS; Psychopharmacology 93:358-364 (1987), where a tricyclic antidepressant was evaluated in CMS; Behavioral Pharmacology: 5:344-350 (1994), where a catechol-O-methyl transferase inhibitor is evaluated in CMS],

The following CMS study was conducted using the active compound of the present invention (hereinafter referred to as “MDL 100907”) in comparison with the known antidepressant imipramine.

Male Wistar rats were brought to the laboratory two months before the start of the experiment, when they weighed approximately 300 g. Unless otherwise described below, animals were housed individually, had free access to food and water, were maintained on a 12-h light/dark cycle (lights on at 8 a.m.) and maintained at 22 ± 2 °C.

Animals were first trained to consume a 1% sucrose solution, consisting of eight 1-h trials in which sucrose was administered in the familiar cage after 14 h of food and water deprivation; consumption was determined by weighing the bottles containing the sucrose solution before and after the trial. Sucrose consumption was then monitored at weekly intervals under similar conditions throughout the experiment.

At the final baseline test, the animals were divided into two matched groups based on their sucrose consumption. One group of animals was exposed to chronic mild stress continuously for 9 weeks. The stress challenge consisted of the following each week: two food or water deprivations (12 and 14 hours), two 45° tilting of the cage (12 and 14 hours), two nighttime intermittent lighting (light-dark alternation every two hours), two 14-hour periods of cage soiling (200 ml of water on sawdust substrate), two 14-hour periods of pair housing, and two 14-hour periods of low-intensity stroboscopic lighting (150 flashes/min). The stressors were applied continuously during the day and night and were randomly selected. The control animals were kept in a separate room and had no contact with the stressed animals. Food and water were withheld for 14 h before each sucrose test, but otherwise food and water were freely available in their home cages. After 3 weeks of stress, both stressed and control animals were further divided into matched subgroups (n=8) based on their sucrose consumption and received daily doses of vehicle [1 ml/kg, intraperitoneally (ip)], imipramine (10 mg/kg, ip), or MDL 100907 (0.002, 0.02, and 0.2 mg/kg orally) for an additional five weeks. Each injection was administered at a volume of 1 ml/kg body weight. The agents were administered in the morning, and a sucrose test was performed 24 h after the last treatment. After five weeks, treatments were terminated and a final sucrose test was performed after one week of withdrawal. Stressors were continued throughout the treatment and withdrawal periods.

The results were analyzed by multiple analysis of variance with Fisher's post hoc test for comparison of means.

Chronic mild stress caused a gradual decrease in consumption of 1% sucrose solution, with sucrose consumption at the last baseline test being approximately 13 grams in both groups. Three weeks after stress (which occurred at week 0), consumption remained at 12.4 (± 0.4) grams in controls, while it fell to 7.2 (± 0.2) grams in stressed animals (p<0.001). This difference between filler-treated controls and stressed animals remained at similar levels throughout the remainder of the experiment.

Imipramine had no significant effect on sucrose consumption in control animals [F(1,84) = 0.364; NS]. However, in stressed animals, the drug caused a progressive increase in sucrose consumption [F(1,84) = 16.776; p < 0.001]. In stressed animals treated with imipramine, sucrose consumption increased significantly from the 0-week value 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 controls. The increased sucrose consumption in stressed animals treated with imipramine remained at a similar level for one week after drug withdrawal.

MDL 100907 had no significant effect on sucrose consumption in control animals [Treatment efficacy: F(3,168) = 0.821, NS, treatment x duration in weeks: F(15,168) = 0.499, NS], In stressed animals, MDL 100907 gradually restored the CMS-induced sucrose consumption deficit and resulted in significant treatment efficacy: [F(3,168) = 22.567; p<0.001] and treatment x duration in weeks [F(15,158) = 1.559; p = 0.05],

Stressed animals treated with the two higher doses of MDL 100907 (0.02 and 0.2 mg/kg) had significantly higher sucrose consumption than baseline (week 0) after two (0.02 mg/kg) and three (0.2 mg/kg) weeks of treatment (p = 0.03 and p = 0.04, respectively). This effect was further enhanced in the following weeks, and at the end of the treatment period (week 5) the amount of sucrose solution consumed by these animals was comparable to that consumed by vehicle-treated controls and significantly greater than that consumed by filler-treated stressed animals (0.02 mg/kg: p < 0.001, 0.2 mg/kg: p < 0.002).

The lowest dose (0.002 mg/kg) of MDL 100907 had no significant effect on sucrose consumption during the entire treatment period. Consequently, after five weeks of treatment, sucrose consumption in stressed animals treated with this dose was not different from that of stressed animals treated with vehicle (p=0.860) and was significantly lower than that of vehicle-treated controls (p<0.01). One week after treatment withdrawal, sucrose consumption did not change significantly in any of the MDL 100907-treated controls (0.002 mg/kg:p=0.2, 0.02 mg/kg:p=0.9, 0.2 mg/kg:p=

0.4) and not 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, clinical trials in humans can also be used to demonstrate the compound of the present invention, such as using the Abbreviated Hamilton Psychiatric Rating Scale for Depression. This uses a 17-category system to rate an individual for, for example, depressed mood, guilt, suicidal tendencies, sleep disturbance, tension, etc., resulting in a score that indicates to the practitioner whether or not the patient is suffering from depression.

Claims (56)

Patent claims 1. Compounds of formula (I), their stereoisomers and pharmaceutically acceptable salts, wherein R is an alkyl group having 4-20 carbon atoms. 2. Compounds according to claim 1, wherein R is a straight chain alkyl group. 3. Compounds according to claim 1 or 2, wherein R is an alkyl group having 5-20 carbon atoms. 4. Compounds according to claim 1 or 2, wherein R is an alkyl group having 4-15 carbon atoms. 5. Compounds according to claim 1 or 2, wherein R is C9-C15 alkyl. 6. Compounds according to claim 1 or 2, wherein R is an alkyl group having 5-15 carbon atoms. 7. Compounds according to claim 1 or 2, wherein R is an alkyl group having 7-15 carbon atoms. 8. Compounds according to claim 1 or 2, wherein R is C7-C9 alkyl. 9. The compound of claim 1, (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanoldecanoate. 10. The compound of claim 1, (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanolhexanoate. 11. The compound of claim 1, (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol octanoate. 12. The compound of claim 1, (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol hexadecanoate. 13. The compound of claim 1, (+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol-2,2-dimethyloctanoate. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier. 15. The pharmaceutical composition according to claim 14, wherein R in the active ingredient is a straight-chain alkyl group having 9 carbon atoms. 16. The pharmaceutical composition of claim 14, wherein the pharmaceutically acceptable carrier is a pharmaceutically acceptable oil. 17. 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, hazelnut oil and castor oil. 18. The pharmaceutical composition of claim 17, wherein the oil is sesame oil. 19. The pharmaceutical composition of claim 14, wherein R in the active ingredient is a C9 straight-chain alkyl group and the carrier is sesame oil. 20. A method for antagonizing the action of serotonin at the 5HT2A receptor, comprising administering to a patient in need thereof an effective amount of a compound according to claim 1. 21. The method according to claim 20, characterized in that in the active ingredient R is a straight-chain alkyl group having 9 carbon atoms. 22. The method of claim 20, wherein the compound is administered intramuscularly or subcutaneously. 23. The method of claim 20, wherein the compound is administered intramuscularly and antagonizes the effect of serotonin on the 5HT _2A receptor for a period of about 2 weeks to about 1 month. 24. A method for treating a patient suffering from psychosis, comprising administering to the patient in need thereof an effective amount of a compound according to claim 1. 25. The method of claim 24, wherein the psychotic disorder is schizophrenia. 26. The method of claim 24, wherein in the active ingredient R is a straight-chain alkyl group having 9 carbon atoms. 27. The method of claim 25, wherein R in the active ingredient is a straight-chain alkyl group having 9 carbon atoms. 28. The method of claim 24, wherein the compound is administered intramuscularly or subcutaneously. 29. The method of claim 25, wherein the compound is administered intramuscularly and the patient is treated for a period of time ranging from about 2 weeks to about 1 month. 30. A method of treating a patient suffering from bipolar depression, comprising administering to the patient an effective amount of a compound according to claim 1. 31. A method of treating a patient suffering from depression, comprising administering to the patient an effective amount of a compound according to claim 1. 32. A method of treating a patient suffering from anxiety, comprising administering to the patient an effective amount of a compound according to claim 1. 33. A method of treating a patient suffering from obsessive-compulsive disorder, comprising administering to the patient an effective amount of a compound according to claim 1. 34. A method for treating a patient suffering from drug addiction, comprising administering to the patient an effective amount of a compound according to claim 1. 35. A method of treating a patient suffering from coronary artery stenosis, comprising administering to the patient an effective amount of a compound according to claim 1. 36. A method of treating a patient suffering from angina, comprising administering to the patient an effective amount of a compound according to claim 1. 37. A method of treating a patient suffering from a thrombotic disease, comprising administering to the patient an effective amount of a compound according to claim 1. 38. A process for the preparation of compounds of formula (I) - in which R is an alkyl group having 4-20 carbon atoms - or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, characterized in that an alcohol of formula (5) is reacted with an acid halide of formula RC(O)X, an acid anhydride of formula (RCO) ₂ O or a carboxylic acid of formula RCO ₂ H - in which R is as defined above and X is a chlorine or bromine atom - in the presence of a sufficient amount of a suitable base. 39. The process according to claim 38, characterized in that a starting material is used in which X represents a chlorine atom. 40. The process of claim 38, wherein a starting material is used in which R is a straight chain alkyl group. 41. The process of claim 38, wherein a starting material is used in which R is an alkyl group having 5-20 carbon atoms. 42. The process of claim 38, wherein the starting material is a C4-C15 alkyl group. 43. The process of claim 38, wherein the starting material is a C9-C15 alkyl group. 44. The process of claim 38, wherein a starting material is used in which R is an alkyl group having 7-15 carbon atoms. 45. The process of claim 38, wherein the starting material is a C7-C9 alkyl group. 46. The process of claim 38, wherein the starting material is a C9 branched alkyl group. 47. The process of claim 38, wherein a starting material is used in which R is a straight-chain alkyl group having 9 carbon atoms. 48. 46. The process according to claim 38, characterized in that triethylamine is used as the base. 49. The process according to claim 38, characterized in that a starting compound is used, where R is a straight-chain alkyl group of 9 carbon atoms, X is a chlorine atom, triethylamine is further used as a base, and the alcohol of formula (5) is reacted with an acid halide. 50. The process of claim 38, wherein the alcohol of formula (5) is reacted with a compound of the general formula RC(O)X. 51. The process of claim 38, wherein the alcohol of formula (5) is reacted with a compound of the general formula (RCO) ₂ O. 52. The process of claim 38, wherein the alcohol of formula (5) is reacted with a compound of the general formula RCO ₂ H. 53. The process of claim 38, wherein the alcohol of formula (5) is reacted with a compound of the general formula RC(O)X, wherein R is a straight-chain alkyl group of 9 carbon atoms and X is a chlorine atom. 54. Use of compounds of general formula (I) as pharmaceutically active substances. 55. Use of the compounds according to claim 1 for the preparation of pharmaceutical compositions useful for antagonizing the action of serotonin at the 5HT ₂ A receptor. 49 1:. ’ / < till ♦ · · · • - ** W 56. A method for treating a patient with (+)-α-(2,3-dimethoxyphenyl)-1-(2-(4-fluorophenyl)ethyl]-4-piperidinemethanol, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) wherein R is an alkyl group having 4-20 carbon atoms, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. The authorized person: DANUBIA Patent and Trademark Office Ltd. Dr. Ferenc Török, Patent Attorney