HK1098143A - Derivatives of n-"phenyl(piperidine-2-yl) methyl benzamide, preparation method thereof and applications of same in therapeutics - Google Patents

Description

N- [ phenyl (piperidin-2-yl) methyl ] benzamide derivatives, their preparation and their therapeutic use

The compounds of the invention correspond to general formula (I),

wherein R is₁Represents a hydrogen atom, or linear or branched (C) optionally substituted by one or more fluorine atoms₁-C₇) Alkyl, or (C)₃-C₇) Cycloalkyl or (C)₃-C₇) Cycloalkyl- (C)₁-C₃) Alkyl, or phenyl (C) optionally substituted by one or two methoxy groups₁-C₃) Alkyl, or (C)₂-C₄) Alkenyl or (C)₂-C₄) An alkynyl group,

x represents a hydrogen atom, or one or more selected from a halogen atom, a trifluoromethyl group, and a linear or branched (C)₁-C₄) Alkyl and (C)₁-C₄) A substituent of the alkoxy group, and a substituent of the alkoxy group,

R₂represents a group selected from: naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzotriazolyl, benzisothiazolyl, indolinyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridinyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl, and optionally substituted with one or more substituents selected from the group consisting of: a halogen atom and (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, thio (C)₁-C₄) Alkyl, or optionally substituted by a halogen atom and trifluoromethyl, (C)₁-C₄) Alkyl and (C)₁-C₄) Phenyl substituted with one or more substituents of alkoxy.

The compounds of the general formula (I) can be present in the form of the threo racemate (1R, 2R; 1S, 2S) or in the enantiomeric form (1R, 2R) or (1S, 2S); may be present as the free base or as an acid addition salt.

In U.S. patent No.5254569, compounds structurally similar to the compounds of the present invention are described as analgesics, diuretics, anticonvulsants, anesthetics, sedatives and cerebroprotective agents by a mechanism of action on opioid receptors. A structurally similar use as 5-HT is described in patent application EP-0499995₃Other compounds that are antagonists, useful in the treatment of psychiatric disorders, neurological disorders, gastric symptoms, nausea and vomiting.

Preferred compounds of the invention are active against opioid receptors or 5-HT₃Receptors not active, but acting as glycinesAcid transporters (transporteurs) glyt1 and/or glyt2 showed particular activity as specific inhibitors.

Wherein R may be prepared by the process described in scheme 1 below₁A compound of formula (I) other than a hydrogen atom.

The coupling of the diamines of the formula (II) with the activated acids or acid chlorides of the formula (III) in which R is present in formula (II) is effected by methods known to the skilled worker₁And X is as defined above (R)₁Not a hydrogen atom), Y in the general formula (III) represents an activated OH group or a chlorine atom and R₂Is as defined above.

Scheme 1

Diamines of general formula (II) can be prepared by the method described in scheme 2 below.

Scheme 2

The Weinreb amides of formula (IV) and phenyllithium derivatives of general formula (V) wherein X in formula (V) is as defined above, are reacted at-30 ℃ to room temperature in an ethereal solvent such as diethyl ether; to give the ketone of the formula (VI) which is reacted at a temperature of between-78 ℃ and room temperature in an ethereal solvent, such as tetrahydrofuran, with a reducing agent, such as K-Selectride^®Or L-Selectride^®(potassium or lithium tri-sec-butyl borohydride) to the threo-configured alcohol of formula (VII). The carbamate of formula (VII) is then reduced to the threo N-methyl aminoalcohol of formula (VIII) by the action of a mixed hydride, such as lithium aluminum di-hydride, in an ether solvent, such as tetrahydrofuran, at a temperature between room temperature and reflux temperature. The threo alcohols of the formula (VIII) are subsequently converted in two steps into threo intermediates of the formula (II) in which R₁Represents a methyl group: first, at a temperature of 0 ℃ to room temperatureM. the alcohol functional group is converted to an electrophilic group, e.g. a mesylate group, via the action of methanesulfonyl chloride in the presence of a base such as triethylamine in a chlorinated solvent such as dichloromethane; the electrophilic groups are then reacted in an alcohol such as ethanol and liquid ammonia at-50 ℃ in a closed medium such as a reaction vessel between-50 ℃ and room temperature.

The carbamates of formula (VII) can also be deprotonated (reproteger) in an alcohol, such as methanol, using a strong base, such as aqueous potassium hydroxide, to give threo amino alcohols of formula (IX); followed by the use of the formula R in a polar solvent such as N, N-dimethylformamide in the presence of a base such as potassium carbonate at a temperature between room temperature and 100 deg.C₁Halogenated derivatives of Z are N-alkylated at R₁In Z, R1 is as defined above except for hydrogen atom, and Z represents a halogen atom. The alcohol of the formula (X) thus obtained is subsequently treated in the manner described in relation to the alcohol of the formula (VIII).

Alternative to the alternative process described in scheme 3 below, wherein R is₁Represents a methyl group, and X represents a hydrogen atom. For example, the pyridine oximes of formula (XI) are quaternized by the action of methyl trifluoromethanesulfonate in an ether solvent such as diethyl ether at room temperature. The pyridinium salt of formula (XII) thus obtained is then subjected to a hydrogenation treatment in a mixture of an alcohol and an aqueous acid, such as ethanol and 1N hydrochloric acid, under a hydrogen atmosphere in the presence of a catalyst such as platinum oxide. The resulting diamine of formula (II) is in the form of an 9/1 threo/erythro mixture of the two diastereomers, wherein in formula (II) R is₁Represents a methyl group, and X represents a hydrogen atom. It can be purified, for example, by salt formation with oxalic acid and subsequent recrystallization of the oxalate salt formed from an alcohol and ether solvent, e.g., methanol and diethyl ether, to give the pure threo diastereomer (1R, 2R; 1S, 2S).

Scheme 3

R₁Compounds of general formula (II) representing a hydrogen atom can be prepared according to scheme 2, as follows: the compound of the general formula (I) is adopted, wherein R₁Represents an optionally substituted phenylmethyl group, for example by deprotonation of the nitrogen of the piperidine ring with an oxidizing agent or a Lewis acid, such as boron tribromide, or by hydrogenolysis, i.e. an alkenyl group, preferably an allyl group, and with Pd⁰The complex deprotonates the nitrogen to give R₁A compound of the general formula (I) represents a hydrogen atom.

Furthermore, chiral compounds of formula (I) corresponding to the (1R, 2R) or (1S, 2S) enantiomer of the threo diastereomer can be prepared in the following manner: separating the racemic compound by High Performance Liquid Chromatography (HPLC) in a chiral column; or by isolating the racemic amine of formula (II) using a chiral acid such as tartaric acid, camphorsulfonic acid, dibenzoyltartaric acid or N-acetylleucine; by partial and preferential recrystallization of diastereomeric salt forms in an alcohol-type solvent; alternatively, the enantioselective synthesis according to scheme 2 is carried out by employing a chiral Weinreb amide of formula (IV).

Racemic or chiral Weinreb amides of formula (IV), as well as ketones of formula (VI), can be prepared according to methods analogous to those described in Eur.J.Med.Chem., 35, (2000), 979-. Phenyl lithium compounds of general formula (IV) wherein X represents a hydrogen atom are commercially available. Substituted derivatives thereof may be prepared according to methods similar to those described in Tetrahedron lett, 57, 33, (1996), 5905-. The pyridine oximes of general formula (XI) can be prepared according to a process similar to that described in patent application EP-0366006. The amines of formula (IX) wherein X represents a hydrogen atom can be prepared in the chiral series according to the method described in U.S. Pat. No. 2928835. Finally, amines of formula (XIII) may be prepared according to a method similar to that described in chem.pharm.Bull., 32, 12, (1984), 4893-4906 and Synthesis, (1976), 593-595.

Acids and acid chlorides of general formula (III) are commercially available, except for 4- [ 2-chloro-3 (trichloromethyl) phenyl ] -1H-imidazole-2-carboxylic acid, which can be prepared under conditions similar to those described in patent application EP-0365030 and U.S. Pat. No. 3336300.

The following examples illustrate the preparation of various compounds of the present invention. Elemental microanalysis, IR and NMR spectroscopy and HPLC on chiral columns confirmed the structure and enantiomeric purity of the resulting compounds.

The numbers given in parentheses in the example titles correspond to the numbers in the first column in the table below.

Example 1 (Compound N4)

Su-type-2, 5-dichloro-N- [ (1-methyl-2-piperidinyl) (phenyl) -methyl ] -3-thiophenecarboxamide hydrochloride 1: 1

1.1. Trifluoromethanesulfonic acid 2- (benzyloxyiminophenylmethyl) -1-methylpyridinium salt

To a suspension of 35g (120mmol) of phenyl (pyridin-2-yl) methanone O-benzyl oxime in 200ml of diethyl ether, 17.4ml (120mmol) of methyl trifluoromethanesulfonate were added dropwise at 0 ℃ and the mixture was stirred at room temperature for 3 hours. The precipitate formed was collected by filtration and dried under reduced pressure.

49g of product are obtained, which can be used in the following step.

1.2. Threo- (1-methylpiperidin-2-yl) phenylmethanamine oxalate (ethanedioate) 2: 1

14.8g (31.89mmol) of 2- (benzyloxyiminophenyl-methyl) -1-methylpyridinium trifluoromethanesulfonate and 0.74g of platinum oxide are placed in 50ml of ethanol and 50ml of 1N hydrochloric acid in a Parr flask and subjected to a hydrotreatment for 5 hours.

The ethanol was evaporated under reduced pressure, the residue was extracted with dichloromethane, the aqueous phase was separated, an aqueous ammonia solution was added thereto, and the mixture was extracted with dichloromethane. After the combined organic phases were washed, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure, 6.7g of an oily product containing 10% of the erythro diastereomer was obtained.

The 6.7g of base is dissolved in methanol and the oxalate salt is prepared by the action of two equivalents of oxalic acid dissolved in a very small amount of methanol.

The resulting salt was purified by recrystallization from a mixture of methanol and diethyl ether.

Finally, 4.7g of the pure threo diastereoisomeric ethanedioic acid salt were obtained.

Melting point: 156 ℃ and 159 ℃.

1.3. Su-type-2, 5-dichloro-N- (1-methyl-2-piperidinyl) (phenyl) methyl ] thiophene-3-carboxamide hydrochloride 1: 1

0.768g (4mmol) of 2, 5-dichlorothiophene-3-carboxylic acid dissolved in 15ml of dichloromethane was added to a 100ml round-bottom flask, then 0.651ml (4.7mmol) of triethylamine and 0.447ml (4.7mmol) of ethyl chloroformate were added and the reaction mixture was stirred at room temperature for 2 hours.

0.80g (3.9mmol) of threo- (1-methyl-piperidin-2-yl) phenylmethylamine, dissolved in 15ml of dichloromethane, are added and stirring is continued at room temperature for 12 hours.

The mixture was treated with water and extracted several times with dichloromethane. After washing the organic phase with water and subsequently with 1N aqueous sodium hydroxide solution, drying over sodium sulfate, filtration and evaporation of the solvent under reduced pressure, the residue is purified by column chromatography on silica gel, eluting with a mixture of 97/3-95/5 of dichloromethane and methanol.

0.6g of oily product is obtained, the hydrochloride of which is prepared by addition of a 0.1N solution of hydrochloric acid in 2-propanol.

After evaporation of the solvent under reduced pressure, the resulting white solid was recrystallized from a mixture of isopropyl ether and 2-propanol.

0.474g of hydrochloride was finally isolated as a white solid.

Melting point: 216 ℃ and 217 ℃.

Example 2 (Compound N.cndot.5)

2, 5-dichloro-N- [ (S) - [ (2S) -1-methyl-2-piperidinyl ] - (phenyl) methyl ] thiophene-3-carboxamide hydrochloride 1: 1

2.1.1, 1-Dimethylethyl (2S) -2-benzoylpiperidine-1-carboxylic acid ester

11.8g (43.3mmol) of1, 1-dimethylethyl (2S) -2- (N-methoxy-N-methylcarbamoyl) piperidine-1-carboxylate are added under nitrogen to 100ml of anhydrous diethyl ether in a 500ml round-bottom flask, the medium is cooled to-23 ℃ and 21.6ml (43.2mmol) of a 1.8M solution of phenyllithium in 70/30 mixture of cyclohexane and diethyl ether is added dropwise, and the mixture is stirred at room temperature for 3 hours. After hydrolysis with saturated aqueous sodium chloride, the aqueous phase was separated and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure, and the residue is purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane.

4.55g of solid product are obtained.

Melting point: 123 ℃ and 125 ℃.

[α]²⁵ _D＝-25.4°(c＝2.22；CH₂Cl₂)ee＝97.2％。

2.2.1, 1-Dimethylethyl (1S) -2- [ (2S) -hydroxy (phenyl) -methyl ] piperidine-1-carboxylate

To 170ml of anhydrous tetrahydrofuran in a 500ml round bottom flask under nitrogen was added 4.68g (16.2mmol) of1, 1-dimethylethyl (2S) -2-benzoylpiperidine-1-carboxylate, the solution was cooled to-78 ℃ and 48.5ml (48.5mmol) of 1M L-Selectride was added dropwise^®(lithium tri-sec-butylborohydride) A solution which is L-Selectride^®Solution in tetrahydrofuran, the mixture was stirred at room temperature for 5 hours.

The resulting mixture was slowly hydrolyzed under cold conditions with 34ml of water and 34ml of 35% aqueous hydrogen peroxide, and the mixture was warmed to room temperature while stirring for 2 hours.

The resulting mixture was extracted with water and ethyl acetate, and the aqueous phase was separated and extracted with ethyl acetate. After washing the combined organic phases, drying over sodium sulfate, filtration and evaporation, the residue is purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane.

4.49g of a pale yellow oil are obtained.

[α]²⁵ _D＝+63.75°(c＝0.8；CH₂Cl₂)ee＝97.8％。

(1S) - [ (2S) - (1-methylpiperidin-2-yl) ] phenylmethanol

In 50ml of anhydrous tetrahydrofuran in a 200ml two-necked flask under a nitrogen atmosphere, 2.96g (78.1mmol) of lithium aluminum dihydride was added, the mixture was refluxed, 4.49g (15.4mmol) of a solution of1, 1-dimethylethyl (1S) -2- [ (2S) -hydroxy (phenyl) methyl ] piperidine-1-carboxylate in 35ml of tetrahydrofuran was added, and the mixture was kept refluxed for 3.5 hours.

The resulting mixture was cooled and slowly hydrolyzed with 0.1M potassium sodium tartrate solution and stirred overnight. The final mixture was filtered, the precipitate was washed with tetrahydrofuran, and then concentrated under reduced pressure.

2.95g of a colorless oily product were obtained.

(1S) - [ (2S) - (1-methyl-piperidin-2-yl) phenyl ] methylamine

Under nitrogen, 2.95g (14.4mmol) of (1S) - [ (2S) - (1-methyl-piperidin-2-yl) ] phenylmethanol and 2ml (14.4mmol) triethylamine are added to 70ml of anhydrous dichloromethane in a 250ml round-bottomed flask, the medium is cooled to 0 ℃ and 1.1ml (14.4mmol) of methanesulfonyl chloride are added and the mixture is slowly returned to room temperature over 2 hours and concentrated under reduced pressure.

Liquid ammonia was added to a reaction vessel equipped with a magnetic stirrer, and cooled to-50 ℃, and a solution of the above prepared methanesulfonate ester in 30ml of anhydrous ethanol was added, and the reaction vessel was closed and stirred for 48 hours.

The mixture was transferred to a round bottom flask, the solvent was evaporated under reduced pressure and the amine was isolated as an oily product which was used in the next step.

2.5.5.1: 1 of 2, 5-dichloro-N- [ (1S) - [ (2S) -1-methyl-2-piperidinyl ] (phenyl) methyl ] thiophene-3-carboxamide hydrochloride

To 15ml of methylene chloride in a 250m l round-bottomed flask were added 0.37g (1.88mmol) of 2, 5-dichlorothiophene-3-carboxylic acid, followed by 0.31ml (2.25mmol) of triethylamine and 0.21ml (2.25mmol) of ethyl chloroformate, and the resulting mixture was stirred at room temperature for 1 hour.

0.38g (1.88mmol) of (1S) - [ (2S) - (1-methyl-piperidin-2-yl) -phenylmethylamine, dissolved in 10ml of dichloromethane, are added and stirring is continued at room temperature for 12 hours.

The mixture is treated with water and extracted several times with dichloromethane, the organic phases are combined, washed with 1N aqueous sodium hydroxide solution, dried over sodium sulfate and filtered, and the filtrate is concentrated under reduced pressure.

The crude residue was purified by column chromatography on silica gel eluting with a mixture of 98/2 containing 0.1% aqueous ammonia in dichloromethane and methanol. 0.368g of oily product was obtained, the hydrochloride of which was prepared by addition of a 0.1N solution of hydrogen chloride in 2-propanol.

After evaporation of the solvent under reduced pressure, the solid was recrystallized from a mixture of 2-propanol and isopropyl ether.

The hydrochloride was finally isolated as a 0.36 pale yellow solid.

Melting point: 134 ℃ and 136 DEG C

134-136℃[α]²⁵ _D＝+45.6(c＝0.99)；CH₃OH。

Example 3 (Compound N18)

Threo-4- [ 2-chloro-3- (trifluoromethyl) phenyl ] -N- [ (1-methyl-2-piperidinyl) (phenyl) methyl ] -1H-imidazole-2-carboxamide hydrochloride 1: 1 0.1g (0.344mmol) of 4- (2-chloro-3- (trifluoromethyl) phenyl ] -1H-imidazole-2-carboxylic acid, 0.066g (0.344mmol) of 1- [3- (dimethylamino) propyl ] -3-ethyl-carbodiimide hydrochloride and 0.047g (0.344mmol) of 1-hydroxy-benzotriazole dissolved in 10ml of dichloromethane are stirred at room temperature for 5 minutes.

To a few ml of dichloromethane was added 0.072g (0.344mmol) of threo- (1-methyl-piperidin-2-yl) phenylmethanamine (prepared according to example 1.2) and stirring was continued for 6 hours.

The mixture is treated with water and extracted several times with dichloromethane, the organic phase is washed with water and subsequently with 1N aqueous sodium hydroxide solution, washed with saturated sodium chloride solution, dried over sodium sulfate and filtered, and the solvent is evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of dichloromethane and methanol.

91mg of the product was obtained, the hydrochloride of which was prepared by addition of a 0.1N solution of hydrochloric acid in 2-propanol. The solvent was partially evaporated under reduced pressure, and after crystallization, 104mg of a solid white compound was obtained.

Melting point: 188 ℃ C. & lt 195 ℃ C. & gt

The following table lists the chemical structures and physical properties of various compounds according to the invention.

In the column "salt" - "denotes the compound in base form and" HCl "denotes the hydrochloride.

The optical rotation of the compound N DEG 5 is [ alpha ]]²⁵ _D＝+45.6°(c＝0.99)；CH₃OH。

Watch (A)

The compounds of the invention were subjected to a series of pharmacological tests which verified their value as therapeutically active substances.

Studies of Glycine transport in SK-N-MC cells expressing the native human vector glyt1

By measuring the bound radioactivity in the presence or absence of the test compound, in SK-N-MC cells (human neuroepithelial cells) expressing the natural human vector glyt1 was investigated¹⁴C]Glycine uptake. Cells were cultured in monolayer form on plates pretreated with 0.02% fibronectin for 48 hours. On the day of the assay, the culture medium was removed and Krebs-HEPES buffer ([4- (2-hydroxyethyl) -1-piperazine) at pH 7.4 was used]Ethanesulfonic acid) to wash the cells. Pre-incubation at 37 ℃ for 10 minutes in the presence of buffer (control) or test compound at various concentrations or 10mM glycine (determination of non-specific uptake) was followed by addition of 10. mu.M¹⁴C]Glycine (specific activity 112 mCi/mmol). The incubation was continued at 37 ℃ for 10 minutes and the reaction was cooled by washing twice with Krebs-HEPES buffer, pH 7.4. After addition of 100. mu.l liquid scintillator and stirring for 1 hour, the cell-bound radioactivity was estimated. In Microbeta Tri-Lux^TMCountingAnd counting on the device. According to IC₅₀Determination of the potency, IC, of a Compound₅₀Is the concentration of compound that reduces the specific uptake of glycine by 50%, determined by the difference in radioactivity bound between the control and the experimental group that received 10mM glycine.

IC of Compounds of the invention in this assay₅₀About 0.01-10. mu.M.

Studies of glycine transport in spinal cord homogenates in mice

The carrier glyt2 in murine spinal cord homogenate was studied by measuring the bound radioactivity in the presence or absence of the test compound¹⁴C]Glycine uptake.

After euthanizing animals (male OF1 Iffa Credo mice, weighing 20-25g on the day OF the experiment), the spinal cord OF each animal was quickly removed, weighed and stored on ice. The sample was homogenized in Krebs-HEPES buffer ([4- (2-hydroxyethyl) -1-piperazine ] ethanesulfonic acid) at pH 7.4 at a ratio of 25ml/g to tissue.

In the presence of Krebs-HEPES buffer at pH 7.4 and various concentrations of test compound, or 10mM glycine, 50. mu.l of homogenate was preincubated at 25 ℃ for 10 minutes to determine the nonspecific uptake. Then added at 25 ℃ for 10 minutes¹⁴C](specific activity: 112mCi/mmol) to a final concentration of 10. mu.M. The reaction was cooled by vacuum filtration through a tube mounted on a Microbeta Tri-Lux^TMSolid scintillators on the counter estimate radioactivity. According to IC₅₀Determination of the potency, IC, of a Compound₅₀Is a concentration that reduces glycine-specific uptake by 50% as determined by the difference in radioactivity bound between the control and the experimental group receiving 10mM glycine.

IC of Compounds of the invention in this assay₅₀About 0.01-10. mu.M.

These results indicate that the compounds of the invention are useful in the treatment of behavioral disorders and neuroleptic-induced acute or chronic extrapyramidal symptoms associated with dementia, psychosis, especially schizophrenia (for disturbed form) and progressive (for progressive), in the treatment of various forms of anxiety, panic, phobias, obsessive-compulsive disorders, in the treatment of various forms of depression, including dysthymia, in the treatment of disorders caused by intoxication or alcohol withdrawal, sexual behavior disorders, eating disorders, and in the treatment of migraine.

Furthermore, the compounds of the invention are useful for the treatment of painful muscle contractures in rheumatology and acute myelopathology, for the treatment of spastic contractures originating from the spinal cord or the brain, for symptomatic treatment of mild to moderate acute and subacute pain, for the treatment of severe and/or chronic pain, neuropathic pain and intractable pain, for the treatment of parkinson's disease and parkinsonian-like symptoms originating from neurodegeneration or induced by neuroleptics, for the treatment of epilepsy, mixed forms of epilepsy and other epileptic syndromes, both simple and complex symptoms, partly primary and secondary, alone or in addition to another anti-epileptic treatment, for the treatment of sleep apnea, and for neuroprotection (neuroprotection).

Accordingly, the subject of the present invention is also pharmaceutical compositions containing an effective dose of at least one compound according to the invention, in the form of a base or of a pharmaceutically acceptable salt or solvate, where appropriate in admixture with suitable excipients.

The excipients are selected according to the pharmaceutical form and the desired mode of administration.

Thus, the pharmaceutical composition of the present invention is administered orally, sublingually, subcutaneously, intramuscularly, intravenously, topically, intratracheally, intranasally, transdermally, rectally, or intraocularly.

The unit administration form may be, for example, tablets, capsules, granules, powders, oral or injectable solutions or suspensions, transdermal patches or suppositories. Ointments, lotions and eye drops are contemplated for topical administration.

The dosage of the unit form (unit forms) is such that it can be administered daily in a galenical form at 0.01-20mg of active substance per kg of body weight.

To prepare tablets, to the micronized or non-micronized active substance, a pharmaceutical carrier is added, which can be constituted by diluents such as lactose, microcrystalline cellulose or starch, formulation aids such as binders (polyvinylpyrrolidone, hydroxypropylmethylcellulose, etc.), glidants such as silicon dioxide, and lubricants such as magnesium stearate, stearic acid, glyceryl tribehenate (glyceryl tribehenate) or sodium stearyl fumarate. Wetting agents or surfactants, such as sodium lauryl sulfate, may also be added.

The preparation technology can be direct tabletting, dry granulation, wet granulation or hot melting.

The resulting tablets may be pure, sugar-coated, e.g., coated with sucrose or coated with various polymers or other suitable materials. They can be designed to release the active substance rapidly, with delay or continuously through the polymer matrix or the specific polymer in which the coating is applied.

To prepare capsules, the active substance is mixed with a dry pharmaceutical carrier (simple mixing, dry or wet granulation or hot melt), or a liquid or semi-solid pharmaceutical carrier.

The resulting capsules may be hard or soft, with or without a thin film coating, to have rapid, sustained or delayed activity (e.g., for enteral forms).

Compositions in the form of syrups or elixirs or for administration in the form of droplets may contain the active substance in combination with a sweetener, preferably a non-caloric sweetener, methyl or propylparaben as preservatives, a flavoring and a dye.

The water-dispersible powders and granules may contain the active substance in admixture with dispersing or wetting agents, or dispersing agents such as polyvinylpyrrolidone, and sweetening and flavouring agents.

For rectal administration, suppositories are used which are made with binders which melt at the rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or injectable sterile solutions containing pharmaceutically compatible dispersing and/or wetting agents, for example propylene glycol or butylene glycol, are employed.

The active substance may also be formulated in the form of microcapsules optionally with one or more carriers or additives, or alternatively with a polymeric matrix or with a cyclodextrin (transdermal patch, sustained release form).

The topical compositions of the present invention comprise a medium that is compatible with the skin. They may in particular be of the form: an aqueous, alcoholic or hydro-alcoholic solution, a gel, a water-in-oil or oil-in-water emulsion with a cream or gel-like appearance, a microemulsion or an aerosol, or alternatively a vesicular dispersion containing ionic and/or non-ionic lipids. These galenic forms are prepared according to the usual methods in the art.

Finally, the pharmaceutical compositions of the invention may contain, in addition to the compounds of general formula (I), other active substances useful in the treatment of the above-mentioned disorders and diseases.

Claims (5)

1. A compound of formula (I) in the form of a free base or of an addition salt with an acid

Wherein R is₁Represents a hydrogen atom, or linear or branched (C) optionally substituted by one or more fluorine atoms₁-C₇) Alkyl, or (C)₃-C₇) Cycloalkyl or (C)₃-C₇) Cycloalkyl- (C)₁-C₃) Alkyl, or phenyl (C) optionally substituted by one or two methoxy groups₁-C₃) Alkyl, or (C)₂-C₄) Alkenyl or (C)₂-C₄) An alkynyl group,

x represents a hydrogen atom, or one or more selected from a halogen atom, a trifluoromethyl group, and a linear or branched (C)₁-C₄) Alkyl and (C)₁-C₄) A substituent of the alkoxy group, and a substituent of the alkoxy group,

R₂represents a group selected from: naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxazolyl, triazolyl, benzothienyl, benzofuranyl, benzimidazolyl, benzothiazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzotriazolyl, benzisothiazolyl, indolinyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridinyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, tetrahydroquinolinyl, and tetrahydroisoquinolinyl, and optionally substituted with one or more substituents selected from the group consisting of: a halogen atom and (C)₁-C₄) Alkyl, (C)₁-C₄) Alkoxy, thio (C)₁-C₄) Alkyl, or optionally substituted by a halogen atom and trifluoromethyl, (C)₁-C₄) Alkyl and (C)₁-C₄) Phenyl substituted with one or more substituents of alkoxy.

2. A medicament, characterized in that it consists of a compound according to claim 1.

3. Pharmaceutical composition, characterized in that it comprises a compound according to claim 1 and excipients.

4. The use of a compound of claim 1 for the manufacture of a medicament for the treatment of: dementia, behavioral disorders associated with psychosis, for the treatment of different types of anxiety, panic attacks, phobias, obsessive compulsive disorders, for the treatment of different types of depression, for the treatment of disorders due to alcoholism or alcohol withdrawal, sexual behavior disorders, eating disorders and for the treatment of migraine.

5. The use of a compound of claim 1 for the manufacture of a medicament for the treatment of: contracture, pain, parkinson's disease and parkinson's-like disease, alone or in addition to another anti-epileptic treatment for the treatment of epilepsy, mixed forms of epilepsy and other epileptic syndromes, sleep apnea, neuroprotection.