SK17602000A3 - N-BENZODIOXANYLMETHYL-1-PIPERIDYL-METHYLAMINE COMPOUNDS HAVINGì (54) AFFINITY FOR 5-HT RECEPTORS - Google Patents

Abstract

Compounds of formula (I) including pharmaceutically acceptable salts thereof in which R represents H or F, their preparation and their use in the treatment of depression, anxiety, psychoses, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug addiction, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behaviour, panic attacks, eating disorders, anorexia, cardiovascular and cerebrovascular disorders, migraine, non-insulin dependent diabetes melitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, prostatic hypertrophy, drug-induced extrapyramidal symptoms or spasticity are described.

Description

Technical field

The present invention relates to novel therapeutic agents that exhibit affinity for 5-HT _1A and / or α 1 and / or D ₂ receptors, a process for their preparation, pharmaceutical compositions containing them and their use in the treatment of CNS disorders, depression, anxiety , psychoses (e.g., schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug abuse, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive disorder, anesthesia, cardiovascular and cerebrovascular diseases, migraine, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, neuroendocrine disorders, stress, prostate hypertrophy, drug-induced extrapyramidal symptoms, and spasticity. BACKGROUND OF THE INVENTION

WO 93/17017 describes [(benzodioxanyl-, benzofuranyl- and benzopyranyl) alkylamino] alkyl-substituted 2-pyrimidinyl compounds having vasoconstrictive activity. These compounds are claimed to be useful in the treatment of conditions related to vasodilation.

WO95 / 07274 discloses compounds of formula I (R ¹ )

The Q-T

Ar ³

R ⁴

O) and pharmaceutically acceptable salts thereof, wherein A is methylene or -O-;

B represents methylene or -O-; and g is 0, 1, 2, 3 or 4;

-2 ······················································ · · ·

R ¹ represents halogen, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkylthio, hydroxy, acyloxy, hydroxymethyl, cyano, alkanoyl, alkoxycarbonyl, optionally N-substituted carbamoyl, carbamoylmethyl, sulfamoylmethyl, sulfamoylmethyl, one or two alkyl groups, or two adjacent R ¹ groups together with the carbon atoms to which they are attached, form a fused benzene ring;

R ² is H, alkyl or alkoxy;

R ³ and R ^4, which are the same or different, represent H or an alkyl group;

U represents an alkylene chain optionally substituted by one or more alkyl groups;

Q represents a divalent group of formula IIa, IIb or IIc ^X1

N-V- <- (Ha),

X '

in which

V represents a bond or an alkylene chain optionally substituted with one or more alkyl groups;

V N represents an alkylene chain optionally substituted with one or more alkyl groups;

• e ····

-3 · e ···· · · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

X is a bond or an alkylene chain; and

X predstavuje represents an alkylene chain, provided that the total number of carbon atoms in X and X predstavuje is 3 or 4;

R ⁵ represents H or an alkyl group; and

T represents an optionally substituted aromatic group which optionally contains one or more N atoms, provided that T is not 2-pyrimidinyl when A is -O-;

are described as being useful in the treatment of central nervous system disorders such as depression, anxiety, psychoses (e.g. schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug abuse, drug abuse, cognitive disorders, cognitive disorders, senile dementia, obsessive-compulsive behavior, panic attacks, eating disorders, anorexia, cardiovascular and cerebrovascular diseases, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, neuroendocrine system disorders, stress and hypertrophy.

Surprisingly, it has been found that certain compounds selected from the group generally described in WO95 / 07274, but not specifically named or exemplified therein, exhibit increased activity as well as increased selectivity over the compounds disclosed in the examples of WO95 / 07274.

SUMMARY OF THE INVENTION

The present invention relates to compounds of formula I

including pharmaceutically acceptable salts thereof, wherein R is H or F.

Specific compounds of the present invention are φφ φφφφ

-4 ·· φ φ • S S S S (S) - (-) - 1- [1- (4-fluoro-2-methoxyphenyl) β-piperidin-4-yl] -N - (7-Trifluoromethyl-2,3-dihydro-1,4-benzodioxin-2-ylmethyl) methylamine, and

(R) - (-) - 1- [1- (2-Methoxyphenyl) piperid-4-yl] -N- (7-trifluoromethyl-2,3-dihydro-1,4-benzodioxin-2-ylmethyl) methylamine and their pharmaceuticals acceptable salts.

The compounds of the present invention are more preferred than those known in the art because of their selectivity in receptor binding assays and their excellent oral activity.

The compounds of formula I may exist in the form of salts with pharmaceutically acceptable acids. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g. (+) tartrates, (-) - tartrates, or mixtures thereof, including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. The compounds of formula I and their salts may exist in the form of solvates (e.g. hydrates).

Certain compounds of formula I and salts thereof may exist in more than one crystalline form and the present invention includes all crystalline forms and mixtures thereof. Certain compounds of formula I and salts thereof may also exist in the form of solvates, for example hydrates, and the present invention includes all solvates and mixtures thereof.

The present invention also relates to pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula I or a salt thereof, together with a pharmaceutically acceptable diluent or carrier.

As used herein, the term active compound refers to a compound of formula I or a salt thereof. In therapeutic use, the active compound may be administered orally, rectally, parenterally or topically, preferably orally. Thus, the therapeutic compositions of the present invention may be in the form of any of the known pharmaceutical compositions for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are well known in the art of pharmacy. Compositions ·· ······

The present invention may contain 0.1-99% by weight of the active compound. The compositions of the invention are generally prepared in unit dosage form. Preferably, the unit dose of active ingredient is 1 to 500 mg. The excipients used to prepare such compositions are excipients known in the pharmaceutical art.

Compositions for oral administration are preferably compositions of the invention and these are the known pharmaceutical forms for such administration, for example tablets, capsules, syrups and aqueous or oily suspensions. The excipients used to prepare such compositions are excipients known in the pharmaceutical art. Tablets may be prepared by mixing the active compound with an inert diluent, such as calcium phosphate, in the presence of disintegrating agents, such as corn starch, and lubricating agents, such as magnesium stearate, and tableting the mixture using known procedures. Tablets are formulated in a manner known to those skilled in the art to achieve sustained release of the compounds of the present invention. Such tablets may optionally be provided with an enteric coating using known techniques, for example using cellulose acetate phthalate. Similarly, capsules, for example hard or soft gelatin capsules, containing the active compound with or without the addition of excipients, can be prepared using conventional procedures, and optionally provided with enteric coatings using known procedures. Tablets and capsules can usually contain 1 to 500 mg of active compound each. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of a non-toxic suspending agent, such as sodium carboxymethylcellulose, and oily suspensions containing the compound of the present invention in a suitable vegetable oil, for example peanut oil.

The active compound may be formulated into granules with or without additional excipients. The granules may be ingested directly by the patient or may be added to a suitable liquid carrier (e.g. water) prior to ingestion. The granules may contain disintegrants (for example, pharmaceutically acceptable noise formulations formed from an acid and a carbonate or bicarbonate salt) to facilitate dispersion in the liquid medium.

································

Compositions of the invention suitable for rectal administration are the known pharmaceutical forms for such administration, for example, cocoa butter laces or polyethylene glycol bases.

Compositions of the invention suitable for parenteral administration are the known pharmaceutical forms for such administration, for example, sterile suspensions or sterile solutions in a suitable solvent.

Compositions for topical administration may comprise a matrix in which the pharmacologically active compounds of the present invention are dispersed such that the compounds are kept in contact with the skin to administer the compounds transdermally. Suitable transdermal compositions can be prepared by mixing the pharmaceutically active compound with a stop vehicle, such as mineral oil, petrolatum and / or wax, for example paraffin wax or beeswax, together with possible transdermal accelerators such as dimethylsulfoxide or propylene glycol. Alternatively, the active compounds may be dispersed in a pharmaceutically acceptable cream or ointment base. The amount of active compound contained in the topical composition should be such that a therapeutically effective amount of the compound is delivered over a period of time for which the topical composition is expected to be applied to the skin.

The compounds of the present invention may also be administered by continuous infusion either from an external source, for example, by intravenous infusion from a source of the compound located within the body. Internal sources include implanted containers containing a compound to be infused, which is continuously released by, for example, osmosis, and implants which may be (a) a liquid such as a suspension or solution in a pharmaceutically acceptable oil of the compound to be infused, for example, in the form of a very water-soluble derivative, such as a dodecanoate salt or ester, or (b) a solid in the form of an implanted substrate, for example a synthetic resin or a waxy material, for a compound to be infused. This support may be a single body containing all the compounds or a series of several bodies, each containing a portion of the compound to be administered. Amount of effective e · ···· · · ··· ·· ····

The compound present in the internal source should be such that a therapeutically effective amount of the compound is delivered over a long period of time.

In some formulations, it may be advantageous to use the compounds of the present invention in the form of particles of very small size, such as obtained by fluid energy milling.

In the compositions of the present invention, the active compound may optionally be combined with other compatible pharmacologically active ingredients.

Pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I or a salt thereof can be used to treat depression, anxiety, psychoses (e.g. schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug abuse, drug abuse, cognitive , Alzheimer's disease, senile dementia, obsessive-compulsive behavior, panic attacks, eating disorders, anorexia, cardiovascular and cerebrovascular diseases, migraine, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, prosthetic disorders, neuroendocrine disorders, neuroendocrine disorders extrapyramidal symptoms and spasticity in man. While the precise amount of active compound administered in such treatment will depend on a variety of factors, such as the age of the patient, the severity of the condition and the prior medical history, and is always within the discretion of the attending physician. 1000 mg, preferably 5 to 500 mg, administered in a single dose or in divided doses one or more times per day.

The ability of the compounds of formula I to interact with 5-hydroxy-tryptamine (5-HT) receptors has been demonstrated using the following assays, which determine the ability of the compounds to inhibit the tritiated ligand binding to 5-HT receptors in vitro and in particular to 5-HT _1A receptors.

Hippocampus tissue from male Charles River CD rats weighing between 150-250 g was homogenized in ice-cold 50 mM

Tris-HCl buffers (pH 7.7) measured at 25 ° C, 1: 40 w / v) and centrifuged 9

- 8 - ::

At 30,000 g at 4 ° C for 10 minutes. The granules were rehomogenized in the same buffer, incubated at 37 ° C for 10 minutes, and centrifuged at 30,000 g at 4 ° C for 10 minutes. The final granules were resuspended in 50 mM Tris-HCl buffer (pH 7.7) containing 4 mM CaCl ₂ , 0.1% Laskorbic acid and 10 μΜ pargyline hydrochloride (equivalent to 6.25 mg wet tissue weight / ml) and used immediately in bonding tests. Aliquots (400 μΙ; equivalent to 2.5 mg wet weight tissue / tube) of this suspension were added to tubes containing ligand (50 μΙ; 2 nM) and distilled water (50 μΙ; full binding) or 5-HT (50 μΙ). ; 10 μΜ; non-specific binding) or test compound (50 μΙ; at a single concentration of 10 ⁶ M or at 10 concentrations ranging from 10 ¹¹ to 10 ³ M). The ligand was [ ³ H] 8-hydroxy-2 (dipropylamino) tetralin ([ ³ H] 8-OH-DPAT) and the mixture was incubated at 25 ° C for 30 minutes before incubation was terminated by rapid filtration.

The filters were washed with ice-cold Tris-HCl buffer and dried. Filters were punched into vials, scintillation fluid was added, and radioactivity was determined using a liquid scintillation counter. The percentage of displacement of specific binding of the tritiated ligand was calculated for a single concentration (10 µM) of the test compound. Displacement curves were then constructed for those compounds that displaced > 50% specific binding of the tritiated ligand at 10 ⁶ M using a range of compound concentrations. The concentration that gave 50% inhibition of specific binding (IC ₅₀ ) was obtained from the curve. The inhibition coefficient Ki was then calculated using the equation

IC50

K i = 1 + ([ligand] / K D) wherein [ligand] represents the concentration of the tritiated ligand used and K d represents the equilibrium dissociation constant for the ligand.

The ability of the compounds of formula I to interact with adrenoceptor binding sites has been demonstrated using the following assays to determine the ability of the compounds to inhibit the binding of a tritiated ligand to adrenoceptors in vitro and in particular to α _- adrenoceptors.

·· ···· · · · ··· ·· ··· ·

-9 ·· · · · · · · · · · · · · · · · · · · · · · ·

Whole cortical tissue from the brain of male Charles River CD rats weighing between 150 and 250 g was homogenized in ice-cold 50 mM Tris-HCl, pH 7.6 (at 25 ° C; 1:40 w / v) and centrifuged. at 1000 g at 4 ° C for 10 minutes. The supernatant was centrifuged at 30,000 g at 4 ° C for 10 minutes. The granules were rehomogenized in 50 mM Tris-HCl, pH 7.6 (1.40 w / v) and centrifuged at 30,000 g at 4 ° C for 10 minutes. The final granules were resuspended in 50 mM Tris-HCl, pH 7.6 (equivalent to

12.5 mg wet weight tissue / ml) and were used immediately in the binding assays. Aliquots (400 μΙ; equivalent to 5 mg wet weight tissue / tube) of this suspension were added to tubes containing ligand (50 μΙ; 0.1 nM) and distilled water (50 μΙ; full binding) or phentolamine (50 μΙ; 5 μΜ; non-specific binding) or test compound (50 μΙ; at a single concentration of 10θΜ or at 10 concentrations ranging from 10 ^{11 11} to 10 ^{3 3} M). The ligand was [7-methoxy ³ H] prazosin and the mixture was incubated at 30 ° C for 30 minutes before the incubation was terminated by rapid filtration.

The filters were washed with ice-cold Tris-HCl buffer and dried. Filters were punched into vials, scintillation fluid was added, and radioactivity was determined using a liquid scintillation counter. The percent displacement of specific binding of the tritiated ligand was calculated for a single concentration (10 ^-6 M) of the test compound. Displacement curves were then constructed for those compounds that displaced > 50% specific binding of the tritiated ligand at 10 ⁶ M using a range of compound concentrations. The concentration that gave 50% specific binding inhibition (IC 50) was obtained from the curve. The inhibition coefficient Ki was then calculated using the equation

IC50

K i = 1 + ([ligand] / K D) in which [ligand] represents the concentration of the tritiated ligand used and K D represents the equilibrium dissociation constant for the ligand.

The ability of the compounds of formula I to interact with dopamine receptors was demonstrated using the following assays to determine the ability of the compounds of formula (I) to determine the ability of the compounds of formula (I). · ·

- ίο- ::

The compounds inhibit the binding of the tritiated ligand to the dopamine receptors in vitro, and in particular to the D ₂ dopamine receptors.

Striatal brain tissue from male Charles River CD rats weighing between 140 and 250 g was homogenized in ice-cold 50 mM Tris-HCl buffer (pH 7.7 then measured at 25 ° C) and centrifuged at 40,000 g for 10 min. minutes. The granules were resuspended in Tris salt buffer (50 mM TrisHCl buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl ₂ and 1 mM MgCl ₂ with the addition of 6 mM ascorbic acid; pH 7.7 was measured at 25 ° C), and centrifuged again at 40,000 g for 10 minutes. The final granules were stored at -80 ° C. Prior to each test, the granules were resuspended in Tris salt buffer (equivalent to 2 mg wet tissue weight / ml). Aliquots (720 μΙ; equivalent to 1.44 mg wet weight tissue / tube) of this suspension were then added to tubes containing ligand (40 μΙ; 1 nM) and buffer Tris salts (40 μΙ; full binding) or spiroperidol (40 μΙ). ; 10 nM; non-specific binding) or test compound (40 μΙ; at a single concentration of 10 uM or at 6 concentrations ranging from 10 ^"11 to 10" ⁴ M). The ligand was triturated with (S) -sulpiride and the mixture was incubated at 4 ° C for 40 minutes before the incubation was terminated by rapid filtration.

The filters were washed with ice-cold Tris-HCl buffer and dried. Filters were punched into vials, scintillation fluid added and left for approximately 20 hours before being determined by scintillation spectrophotometry. The percent displacement of specific binding of the tritiated ligand was calculated for a single concentration (10θΜ) of the test compound. Displacement curves were then constructed for a range of concentrations of those compounds that displaced > 50% specific binding of the tritiated ligand at 10-θ M. The concentration that gave 50% specific binding inhibition (IC 50) was obtained from the curve. The coefficient of inhibition of Ki was then calculated using the equation

IC50

K = 1 + ([ligand] / 1 <D) wherein [ligand] represents the concentration of the tritiated ligand used and Kq represents the equilibrium dissociation constant for the ligand.

································

-11 ·· ···

The K i values obtained in the above assays for 5-HT _1A , ai and D ₂ binding for each of the final products of Examples 1,2 and Comparative Example A are summarized in Table 1 below. From these data it is evident that the compounds of the present invention of the invention exhibit significantly lower affinity for the adrenoreceptor than the previously described compounds. This is important because it is known in the art that α 1 receptor antagonism mediates serious side effects such as hypotension, sedation and sexual dysfunction. Thus, compounds that interact preferentially with the D ₂ and 5-HT _1A receptors while showing less interaction with the α 1 receptors are preferred.

Table 1

Example number Ki (nM) value for 5-HT _1A d ₂ ai 1 23 65 183 2 31 54 404 A 22 44 53

Antagonism of apomorphine-induced climbing in mice

A group of 10 male mice weighing 18-35 g (maximum range 10 g) was treated with the test compound or vehicle control using oral administration. 30 minutes later, mice were injected subcutaneously with apomorphine (0.88 mg / kg). Immediately after the injection of apomorphine, mice were placed in test cages and the climbing behavior was evaluated for each mouse after 10 and 20 minutes on a simple scale ranging from 0 to 2.

Values were calculated ED ₅ o (dose causing 50% of the control score) for the test compounds and 95% levels of significance. ED ₅₀ values were calculated as free base equivalents and are given in Table 2 together with Comparative Example A. The compounds of the invention are orally effective than previously described compounds. More potent compounds are preferred because they are less likely to produce systemic toxicological effects on organs that are not therapeutic targets.

-12 ················

· · T t t t t t t t t t t t t • t • • • • • • •

Table 2

Example ED50 mg / kg) 1 1 2 1.8 A 5

Hereinafter, a process for preparing compounds of formula I will be described. These processes form a further object of the present invention. The processes are preferably carried out at atmospheric pressure, at a temperature in the range from 0 to 200 ° C, preferably in the range from 20 to 150 ° C. The substituents have the meanings defined in the above formula I unless otherwise stated.

Compounds of formula I may be prepared by reaction of a compound of formula II

wherein Z represents a leaving group, for example toluene-4-sulfonyloxy, with a compound of formula III

wherein R is as defined above, optionally in the presence of a suitable solvent or solvent mixture, for example, a hydrocarbon, for example toluene, or a polar solvent, for example dimethylformamide, or a mixture thereof, optionally in the presence of a base such as potassium carbonate at range from 0 to 250 ° C.

The invention is further illustrated by the following examples, which are given in the form of exemplary embodiments. The final product of each of these examples was characterized by one or more of the following methods: gas-liquid chromatography; high performance liquid ·· ···· ··

- 1399 · t t 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13 13

chromatography; elemental analysis, nuclear magnetic resonance spectroscopy and infrared spectroscopy.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Part A

a) A solution of 5-fluoro-2-nitrophenol (25.0 g) in dry dimethylformamide (100 ml) was added dropwise with stirring to a suspension of sodium hydride (7.0 g of a 60% dispersion in mineral oil) in one hour. dry dimethylformamide (250 mL) under nitrogen. The mixture was stirred for one hour and then iodomethane (10.0 mL) was added dropwise. The mixture was further stirred and heated on a steam bath for 3.5 hours. Additional iodomethane (2.5 mL) was added and the mixture was stirred at 95-100 ° C for one hour and then allowed to cool overnight. Concentrated aqueous ammonia solution (15.0 ml; specific gravity 0.880) was added dropwise and the mixture was stirred for 15 minutes. The mixture was poured into water (1.5 L), acidified with aqueous sodium hydroxide solution (5 M) and extracted with dichloromethane (4 x 400 mL). The combined organic extracts were washed with water, brine, dried, filtered and evaporated to give a liquid which was dissolved in ether (500 mL), washed with water, brine, dried, filtered and evaporated to give an oil which was redissolved in ether and the previous washing and drying process was repeated to give an oil which was triturated with petroleum ether, boiling 60-80 ° C and allowed to stand overnight. The solid formed was collected by filtration and dried under vacuum to give 4-fluoro-2-methoxynitrobenzene. The structure was confirmed by ¹ H NMR.

b) A solution of 4-fluoro-2-methoxynitrobenzene (23.7 g) in industrial methylated spirits (400 mL) was hydrogenated at room temperature using 10% palladium on activated carbon as a catalyst. After theoretical hydrogen sorption, the mixture was filtered to remove the catalyst, and the filtrate was evaporated to give 4-fluoro-2-methoxyaniline as an oil.

· · • · • · ···· • · · · · · • · • · 9999 9 • · · • · • · • · • · · · · · · • · · · · ·

c) A mixture of 4-fluoro-2-methoxyaniline (5.7 g) and 4-carbamoyl-1- (2,4-dinitrophenyl) pyridinium chloride (22.4 g, prepared as described in WO 95/07274) and methanol (350 mL) was stirred and boiled under reflux for two hours. The mixture was cooled in an ice-water bath and filtered. The filtrate was evaporated under reduced pressure to give a solid which was triturated with boiling acetone (900 mL). The mixture was allowed to cool and the product was collected by filtration and washed with acetone to give 4-carbamoyl-1- (4-fluoro-2-methoxyphenyl) pyridinium chloride.

d) The product of step c) (13.2 g), ammonium formate (26.6 g) and 10% palladium on charcoal (6.6 g) were stirred under nitrogen while industrial methylated spirits (250 ml) were added. . The mixture was stirred vigorously and allowed to boil under reflux under a nitrogen atmosphere for 3.5 hours while the sublimed ammonium formate was washed back into the reaction vessel with water. The mixture was allowed to cool and then filtered through a filter aid which was washed with industrial methylated spirits, ethyl acetate and water. The filtrate was evaporated under reduced pressure and the residue was partitioned between water (1 L) and ethyl acetate (500 mL). The mixture was made strongly alkaline with 5M sodium hydroxide solution. The aqueous layer was separated and extracted with ethyl acetate (3 x 500 mL). The combined ethyl acetate extracts were dried, filtered and evaporated to give 1- (4-fluoro-2-methoxyphenyl) piperidine-4-carboxamide.

e) The product of step d) (10.4 g) was suspended in tetrahydrofuran (300 ml) and added portionwise with stirring to a suspension of lithium aluminum hydride (34 g) in tetrahydrofuran (100 ml) under nitrogen on an ice-bath. Water. The mixture was stirred in an ice-water bath for 1.5 hours, then stirred at room temperature for 19 hours. Water (20 ml) was carefully added to the reaction mixture, followed by 5 M sodium hydroxide solution (20 ml) and water (40 ml). The mixture was stirred for one hour, then filtered through a filter aid, washing the aid with ether (700 mL). The filtrate was separated and the organic phase was dried, filtered and evaporated to give a resin which was triturated with dichloromethane (100 mL) and filtered to remove some solids. The filtrate was evaporated to give an oil which was purified by

· · • · • · ···· • · · · · · • · • · ···· • • · · • · • · · · · · · · · · · · · · · · ·

flash column chromatography on silica using methanol followed by methanol / triethylamine (10: 1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give 1- (4-fluoro-2-methoxyphenyl) piperidine-4-methylamine.

Part B

a) Hexamethylenetetramine (47.5 g) was added portionwise with stirring to the solution

Of 4-trifluoromethylphenol (50 g) in trifluoroacetic acid (680 ml) and the mixture was heated at reflux temperature for 24 hours. After cooling, water (355 mL) was added followed by aqueous sulfuric acid (50% v / v, 190 mL) and the reaction mixture was stirred at room temperature for 4 hours. The aqueous acidic phase was extracted with diethyl ether (3 x 500 mL). The combined organic extracts were washed with hydrochloric acid (5 M, 3 x 500 mL), then with water (500 mL) and dried over magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica eluting with petroleum ether (b.p. 40-60 ° C) and ethyl acetate 4: 1. Appropriate fractions were combined and the solvent was removed under reduced pressure to give 5-trifluoromethyl-2-hydroxybenzaldehyde (25 g) as a pale pink solid.

b) A mixture of (R) -glycidyl 4-toluenesulfonate (24 g), 5-trifluoromethyl-2-hydroxybenzaldehyde (20 g) and potassium carbonate (16 g) in dimethylformamide (550 ml) was stirred and heated at 60 ° C. for 72 hours. After cooling, brine (1.51) was added and the resulting mixture was extracted with ether (4 x 500 mL). The combined ether extracts were washed with brine (2 x 500 mL), then with water (500 mL) and dried over magnesium sulfate. The residue was purified by flash column chromatography on silica eluting with petroleum ether (t 40-60 ° C) and ethyl acetate 3: 1 to give (R) -5-trifluoromethyl-2- (2,3-epoxypropoxy) benzaldehyde ( 18.7 g) as a yellow oil.

c) A mixture of the product from the previous reaction (18.7 g) and 3-chloroperoxybenzoic acid (57-86%, 48.7 g) in dichloromethane (1 L) was heated under reflux for 24 hours, then allowed to cool to room temperature. · · · · · · · · · · · · · · · · · · · · · · · · · · · · The mixture was washed with saturated aqueous sodium bicarbonate solution (3 x 700 mL), water (2 x 700 mL) and brine (700 mL), then dried over magnesium sulfate. The solvent was evaporated to give crude (R) -5-trifluoromethyl-2- (2,3-epoxypropoxy) phenyl formate (16.7 g).

d) A mixture of the product from the previous reaction (16.7 g), tetrahydrofuran (220 ml) and saturated aqueous potassium carbonate solution (175 ml) was stirred vigorously at room temperature for 24 hours. Water (500 mL) was added and the organic phase was discarded. The aqueous phase was extracted with ethyl acetate (3 x 300 mL) and the combined organic extracts were dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by flash column chromatography on silica eluting with petroleum ether (bp 40 to 60 ° C) and ethyl acetate 4: 1 incremented to 1: 1. The appropriate fractions were combined and the solvent was combined. was removed under reduced pressure to give (S) -7-trifluoromethyl-2,3-dihydro-1,4-benzodioxin-2-ylmethanol (12 g) as a yellow oil.

e) A solution of 4-toluenesulfonyl chloride (9.6 g) in dichloromethane (60 ml) was added dropwise to a solution of the product from the previous reaction (10.7 g) and 4-dimethylaminopyridine (6.7 g) in dichloromethane (90 ml) at a temperature between 0 to 5 ° C. The mixture was stirred at room temperature for 4 hours then allowed to stand for 18 hours. The solution was washed with dilute hydrochloric acid (5 M, 2 x 300 mL), dried over magnesium sulfate, and the solvent was removed under reduced pressure to give (R) -7-trifluoromethyl-2,3-dihydro-1,4-benzodioxine 2-ylmethyl 4-toluenesulfonate (15.5 g) as a white solid.

Part C •

4-Toluenesulfonate from Part B (e) (4.3 g), methylamine from Part A (e) (2.4 g), potassium carbonate (2.4 g), toluene (80 mL) and dimethylformamide (30 mL) were added. stirred and heated at reflux temperature for 24 hours. The mixture was allowed to cool, poured into water (1.5 L) and then extracted into ethyl acetate (3 x 350 mL). The combined organic extracts were extracted with 5 M hydrochloric acid (3 x 250 mL). The combined acidic extracts were basified with 5M sodium hydroxide solution and

-17 were extracted with ethyl acetate (3 x). 250 ml) and these organic extracts were dried, filtered and evaporated to give an oil. This oil was dissolved in ether (100 mL) and dried over potassium carbonate. The mixture was filtered and evaporated to give an oil which was purified by flash column chromatography on silica using ethyl acetate / petroleum ether, b.p. 60-80 ° C (9: 1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give an orange oil which was dissolved in ether (100 mL) and hydrogen chloride gas was passed through the solution for 15 minutes. The precipitate that formed was collected by filtration and dried under vacuum at 80 ° C for 23 hours to give (S) - (-) - 1- [1- (4-fluoro-2-methoxyphenyl) piperidine-4- yl] -N- (7-trifluoromethyl-2,3-dihydro-1,4-benzodioxin-2-ylmethyl) methylamine dihydrochloride, m.p. 230-231 ° C.

Example 2

A mixture of 1- [1- (2-methoxyphenyl) piperid-4-yl] methylamine (3.3 g, prepared as described in WO 95/07274), (R) -7-trifluoromethyl-1,4-benzodioxane- 2-ylmethyl 4-toluenesulfonate (3.0 g), potassium carbonate (2.5 g), toluene (22 ml) and dimethylformamide (10 ml) were allowed to boil under stirring for 18 hours. The mixture was cooled, poured into water (100 mL) and extracted with ethyl acetate. The combined organic extracts were washed with dilute hydrochloric acid (2 x 200 mL) and the acidic extracts were basified with concentrated sodium hydroxide solution and then extracted with ethyl acetate (200 mL). These organic extracts were dried, filtered and evaporated to give an oil which was purified by flash column chromatography on silica using ethyl acetate / methanol (95: 5) as the mobile phase to give an oil which was treated with gaseous hydrogen chloride as described in Example 1 to give (S) - (-) - 1- [1- (2-methoxyphenyl) piperid-4-yl] -N- (7-trifluoromethyl-2,3-dihydro-1, 4-Benzodioxin-2-ylmethyl) methylamine dihydrochloride, m.p. 243 DEG-245 DEG C. with decomposition. Comparative Example A (S) - (-) - N- (7-Chloro-1,4-benzodioxan-2-ylmethyl) -1- (1- (2-methoxyphenyl) piperid-4-yl) methylamine (also known as ( S) - (-) - N- (7-Chloro-2,3-dihydro-1,4-benzodioxin-2-methyl) -1- (1- (2-methoxyphenyl) piperid-4-yl) methylamine) was prepared as is described in WO 95/07274.

Claims (11)

PATENT CLAIMS a including pharmaceutically acceptable salts thereof, wherein R is H or F. The compound of claim 1 which is (S) - (-) - 1- [1- (4-fluoro-2-methoxyphenyl) piperid-4-yl] -N- (7-trifluoromethyl-2,3-dihydro-1). (4-benzodioxin-2-ylmethyl) methylamine and its pharmaceutically acceptable salts. The compound according to claim 1 which is (S) - (-) - 1- [1- (2-methoxyphenyl) piperid-4-yl] -N (7-trifluoromethyl-2,3-dihydro-1; 4-Benzodioxin-2-ylmethyl) methylamine and its pharmaceutically acceptable salts. Pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I according to any one of claims 1 to 3, together with a pharmaceutically acceptable diluent or carrier. 5. A method of treating depression, anxiety, psychosis, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug abuse, drug abuse, cognitive disorders, Alzheimer's disease, senile dementia, obsessive-compulsive behavior, panic attacks, anxiety panic disorders, panic attacks, cardiovascular and cerebrovascular diseases, migraine, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, disorders of the neuroendocrine system, stress, prostate hypertrophy, drug-induced extrapyramidal symptoms or spasticity, characterized in that the therapeutically comprises: of claims 1 to 3, to a patient in need of such treatment. The method of claim 5, for treating schizophrenia. ·· ···· -19 ······························· · ·· ·· ·· · The method of claim 5, for treating anxiety. A compound of formula I according to any one of claims 1 to 3, for use as a medicament. A compound of formula I according to any one of claims 1 to 3, for use as a medicament for the treatment of depression, anxiety, psychoses, tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug abuse, drug abuse, cognitive disorders, Alzheimer's diseases, senile dementia, obsessive-compulsive behavior, panic attacks, eating disorders, anorexia, cardiovascular and cerebrovascular diseases, migraine, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, neuroendocrine abnormalities, stress, neuroendocrine abnormalities, stress disorders or spasticity. Use of a compound of formula I according to any one of claims 1 to 3, for the manufacture of a medicament for the treatment of depression, anxiety, psychoses, tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, sexual dysfunction, drug abuse, drug abuse, cognitive disorders, Alzheimer's diseases, senile dementia, obsessive-compulsive behavior, panic attacks, eating disorders, anorexia, cardiovascular and cerebrovascular diseases, migraine, non-insulin-dependent diabetes mellitus, hyperglycemia, constipation, arrhythmia, neuroendocrine abnormalities, stress, neuroendocrine abnormalities, stress disorders or spasticity. A process for the preparation of a compound of formula I according to claim 1, comprising reacting a compound of formula II wherein Z is a leaving group with a compound of formula and III wherein R is as defined above, optionally in the presence of a suitable solvent or solvent mixture, optionally in in the presence of a base, at a temperature in the range of 0 to 250 ° C.