HK1143571A - Novel naphthalene derivatives, process for the preparation thereof and pharmaceutical compositions containing same - Google Patents

Description

Naphthalene derivatives, process for their preparation and pharmaceutical compositions containing them

The present invention relates to novel naphthalene compounds, to a process for their preparation and to pharmaceutical compositions containing them.

The compounds of the present invention are novel and possess very valuable pharmacological properties relating to melatonin-capable receptors.

During the last decade, numerous studies have demonstrated the key role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena and in the control of the circadian rhythm. However, due to the fact that it is rapidly metabolized, the half-life of melatonin is very short. Therefore, there is great interest in providing clinicians with melatonin analogs that are more metabolically stable, have agonist or antagonist properties, and can be expected to have therapeutic effects superior to the hormones themselves.

In addition to its resistance to circadian rhythm disorders (j. neurosurg.1985,63pp.321-341) and sleep disorders (Psychopharmacology, 1990,100pp.222-226), ligands of the melatoninergic system also have value in the central nervous systemPharmacological properties, in particular anxiolytic and antipsychotic properties (Neuropharmacology of pinal Secretions, 1990,8(3-4), pp.264-272) and analgesic properties (pharmacophygat, 1987,20pp.222-223) and for the treatment of parkinson's disease (j. neurosurg.1985,63pp.321-341) and alzheimer's disease (Brain Research, 1990,528pp.170-174). Those compounds have also been shown to be effective in certain cancers (Melatonin-Clinical Perspectives, Oxford University Press, 1988, pp.164-165), ovulation (Science 1987,227pp.714-720), diabetes (clinical endocrinology, 1986,24359-364) and in the treatment of obesity (International journal of early Disorders, 1996, 20(4), pp.443-446).

The various effects are exerted by the mediation of specific melatonin receptors. Molecular biological studies have demonstrated that there are a number of receptor subtypes that bind this hormone (Trends pharmacol. sci., 1995,16p.50; WO 97.04094). For various species, including mammals, it has become possible to locate and characterize some of those receptors. To be able to better understand the physiological functions of those receptors, it is highly advantageous to have available selective ligands. Moreover, by selectively interacting with one or other of the receptors, such compounds may be excellent agents for clinicians to treat conditions associated with the melatoninergic system, some of which have been mentioned above.

In addition to the fact that they are novel, the compounds of the present invention also show a very strong affinity for melatonin receptors.

They are also on 5-HT_2CThe receptor has strong affinity, 5-HT_2CThe receptors have the effect of potentiating the properties observed in the case of melatonin-capable receptors, in particular in the case of depression.

More specifically, the present invention relates to compounds of formula (I):

wherein:

R₁represents a straight chain or branched chain (C)₁-C₆) An alkyl group; straight or branched chain (C)₁-C₆) An alkenyl group; straight or branched chain (C)₁-C₆) A haloalkyl group; straight or branched chain (C)₁-C₆) A polyhaloalkyl group; (C)₃-C₈) A cycloalkyl group; (C)₃-C₈) Cycloalkyl- (C)₁-C₆) Alkyl, wherein the alkyl moiety may be linear or branched; an aryl group; aryl radical- (C)₁-C₆) Alkyl, wherein the alkyl moiety may be linear or branched; a heteroaryl group; or heteroaryl- (C)₁-C₆) Alkyl, wherein the alkyl moiety may be linear or branched,

R₂represents a fluorine atom or a linear or branched chain substituted by one or more fluorine atoms (C)₁-C₆) Alkyl, it being understood that:

- "aryl" means phenyl, naphthyl or biphenyl,

- "heteroaryl" means any mono-or bicyclic aromatic group containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,

the defined aryl and heteroaryl groups may be substituted by 1 to 3 groups selected from: straight or branched chain (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, hydroxy, carboxy, formyl, nitro, cyano, straight or branched chain (C)₁-C₆) Haloalkyl, straight-chain or branched (C)₁-C₆) Polyhaloalkyl, alkoxycarbonyl and halogen atoms,

to their enantiomers and diastereomers, and also to their addition salts with pharmaceutically acceptable acids or bases.

Among the pharmaceutically acceptable acids, mention may be made, by way of non-limiting example, of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulfonic acid, camphoric acid, and the like.

Among the pharmaceutically acceptable bases, mention may be made, by way of non-limiting example, of sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, and the like.

Preferred compounds of the invention are compounds of formula (I) wherein R is₁Represents a straight chain or branched chain (C)₁-C₆) Alkyl groups such as methyl or ethyl; or (C)₃-C₈) Cycloalkyl groups such as cyclopropyl or cyclobutyl; or polyhaloalkyl, such as fluoromethyl.

R₂The radical advantageously represents a fluorine atom or a fluoromethyl or 1-fluoroethyl radical.

The present invention even more particularly relates to the following compounds: n- [ 2-fluoro-2- (7-methoxy-1-naphthyl) ethyl ] acetamide, N- [ 2-fluoro-2- (7-methoxy-1-naphthyl) ethyl ] propionamide, N- [ 2-fluoro-2- (7-methoxy-1-naphthyl) ethyl ] cyclopropanecarboxamide, N- [ 2-fluoro-2- (7-methoxy-1-naphthyl) ethyl ] cyclobutanecarboxamide, N- [ 3-fluoro-2- (7-methoxy-1-naphthyl) propyl ] acetamide, 2-fluoro-N- [ 3-fluoro-2- (7-methoxy-1-naphthyl) -propyl ] acetamide and N- [ 4-fluoro-2- (7-methoxy-1-naphthyl) -propyl ] acetamide -methoxy-1-naphthyl) butyl ] acetamide.

Addition salts of preferred compounds of the present invention with pharmaceutically acceptable bases form an integral part of the present invention.

The invention also relates to a process for the preparation of a compound of formula (I), characterized in that a compound of formula (II):

wherein R is₂As defined for formula (I),

reacting a compound of formula (II) with R₁Formula R as defined for formula (I)₁The compounds of formula (I) can be purified according to conventional separation techniques, converted to their addition salts if desired with pharmaceutically acceptable acids or bases, and if appropriate separated into their isomers according to conventional separation techniques.

An advantageous embodiment relates to a process for the preparation of compounds of the formula (I), in which R₂Denotes straight-chain or branched (C) substituted by one or more fluorine atoms₁-C₆) Alkyl, characterized in that a compound of formula (III):

wherein R is₁R represents, as defined for formula (I), a linear or branched chain (C) substituted by one or more OH groups₁-C₆) An alkyl group, a carboxyl group,

reacting a compound of formula (III) with methanesulfonyl chloride to produce a compound of formula (IV):

wherein R is₁R' represents, as defined for formula (I), substituted by one or more OSOs₂Linear or branched (C) substituted by Me radicals₁-C₆) An alkyl group, a carboxyl group,

reacting a compound of formula (IV) with tetrabutylammonium fluoride to produce a compound of formula (I/a), which is a particular case of compounds of formula (I):

wherein R is₂' represents a linear or branched (C) substituted by one or more fluorine atoms₁-C₆) The compounds of formula (I/a) can be purified according to conventional separation techniques, converted, if desired, into their addition salts with pharmaceutically acceptable acids or bases, and, if appropriate, separated into their isomers according to conventional separation techniques.

The compounds of formula (II) and formula (III) are commercially available or can be obtained by the skilled person using conventional chemical reactions described in the literature.

Pharmacological studies of the compounds of the present invention have shown that they are non-toxic, have a strong selective affinity for melatonin receptors and have significant activity in the central nervous system; and in particular their therapeutic properties in sleep disorders, antidepressant, anxiolytic, antipsychotic and analgesic properties as well as in microcirculation, have been found to enable the determination that the compounds of the invention are useful for the treatment of stress, sleep disorders, anxiety, seasonal affective or major depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss and alzheimer's disease, as well as for cerebral circulation disorders. In another active area, it is evident that the compounds of the invention can be used for the treatment of sexual dysfunction, they have ovulation-inhibiting and immunomodulating properties, and they can potentially be used for the treatment of cancer.

The compounds are preferably used for the treatment of major depression, seasonal affective disorder, sleep disorders, cardiovascular conditions, conditions of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity.

For example, the compounds are useful for the treatment of major depression, seasonal affective disorder, and sleep disorders.

The invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) alone or in combination with one or more pharmaceutically acceptable excipients.

In the pharmaceutical compositions of the invention, mention may be made more particularly of those suitable for oral, parenteral, nasal, transdermal or transdermal, rectal, lingual, ocular or respiratory administration, and in particular tablets or dragees (dragees), sublingual tablets, sachets, packs (paquets), capsules, sublingual or rectal dosage forms (glossettes), lozenges, suppositories, creams, ointments, dermal gels and drinkable or injectable ampoules.

The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication or any relevant treatment, and ranges from 0.01mg to 1g/24 hours, administered in one or more divided doses.

The following examples illustrate the invention but do not limit it in any way.

Example 1: n- [ 2-fluoro-2- (7-methoxy-1-naphthyl) ethyl]Acetamide

Step A: methanesulfonic acid 2- (7-methoxy-1-naphthyl) ethyl ester

2- (7-methoxy-1-naphthyl) ethanol (25mmol) and triethylamine (30mmol) were dissolved in 50ml dichloromethane and the reaction mixture was cooled to 0 ℃ using an ice bath. Methanesulfonyl chloride (30mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 2 hours and then poured into 100ml of water. The organic phase is washed with a 1M hydrochloric acid solution and then with water, dried over magnesium sulfate and evaporated. The resulting oil was precipitated with a mixture of diethyl ether/petroleum ether (1/1). The title compound is filtered off with suction and then recrystallized from diisopropyl ether.

Melting point: 60-62 deg.C

Step B: 7-methoxy-1-vinylnaphthalene

The compound obtained in step A (21.4mmol) was dissolved in 120ml of tetrahydrofuran and potassium tert-butylate (64.2mmol) was added in small portions. After stirring for 30 min at ambient temperature, the reaction mixture was evaporated to dryness. The residue obtained is taken up in 150ml of water and the aqueous phase is extracted twice with 60ml of diethyl ether. The organic phase is washed with water, dried over magnesium sulfate, decolorized with vegetable carbon and evaporated. The residue obtained is purified on silica gel (eluent: petroleum ether) to give the title product in the form of a yellow oil.

Step C: 1- (2-bromo-1-fluoroethyl) -7-methoxynaphthalene

The compound obtained in step B (5.4mmol) was dissolved in 25ml of dichloromethane, and then the resulting solution was cooled to 0 ℃ using an ice bath. Triethylamine trihydrofluoride (16.3mmol) and N-bromosuccinimide (6.5mmol) were added. The reaction mixture was stirred at 0 ℃ for 30 minutes and at ambient temperature for 12 hours. The reaction mixture was poured into ice-cold water, neutralized with 28% ammonia solution, and extracted with dichloromethane. The organic phase was washed with 0.1M hydrochloric acid solution, 5% sodium bicarbonate solution and water. The organic phase was dried over magnesium sulfate and the solvent was evaporated off under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel (eluent: petroleum ether/dichloromethane 9/1) to give the title product in the form of a brown oil.

Step D: 1- (2-azido-1-fluoroethyl) -7-methoxynaphthalene

Sodium azide (15.3mmol) was suspended in 10ml of dimethylformamide, tetrabutylammonium bromide (200mg) was added, and the mixture was heated at 70 ℃ for 30 minutes. The compound obtained in step C dissolved in 20ml of dimethylformamide is then added and the mixture is stirred for 2 hours at 70 ℃. At the end of the reaction, 40ml of water are added and the aqueous phase is extracted 3 times with 60ml of diethyl ether. The organic phase is then washed with a 2M hydrochloric acid solution and then with water, dried and evaporated under reduced pressure to give the title product in the form of a yellow oil.

Step E: 2-fluoro-2- (7-methoxy-1-naphthyl) ethylamine hydrochloride

Aluminium chloride (80mmol) dissolved in 200ml of dry ether is added to a suspension of lithium aluminium hydride (80mmol) in 300ml of dry ether at 0 ℃. After stirring for 10 min, the compound obtained in step D (20mmol) dissolved in 200ml of anhydrous ether was added. After 30 minutes, the mixture was carefully hydrolyzed using sodium hydroxide solution (250mmol) in the cold state. The inorganic precipitate formed was then filtered off and washed with a large amount of diethyl ether. The residue obtained after evaporation was taken up in water and the aqueous phase was extracted with dichloromethane. The organic phase is then washed with water, dried and decolorized, then treated with gaseous HCl and evaporated. The resulting oil was precipitated with ethyl acetate, the precipitate formed was filtered off with suction and then recrystallized.

Step F: n- [ 2-fluoro-2- (7-methoxy-1-naphthyl) ethyl]Acetamide

The compound (20mmol) obtained in step E (20mmol) was dissolved in a mixture of water/ethyl acetate (25ml/75ml) cooled to 0 ℃. Potassium carbonate (60mmol) was added, followed by acetyl chloride (26mmol) added dropwise to the reaction mixture. The mixture was stirred vigorously at ambient temperature for 30 minutes. The two phases were separated and the organic phase was washed with 0.1M aqueous hydrochloric acid and then with water. After drying over magnesium sulfate, the organic phase is evaporated under reduced pressure. The resulting residue was recrystallized from a mixture of toluene/cyclohexane (5/5) to give the title product as a white solid.

Melting point: 128-130 deg.C

Elemental microanalysis：

Example 2: n- [ 2-fluoro-2- (7-methoxy-1-naphthyl) ethyl]Propionamide

The same procedure as in example 1 was followed, substituting propionyl chloride for acetyl chloride in step F. Recrystallization from cyclohexane gives the title product in the form of a white solid.

Melting point: 139-141 DEG C

Elemental microanalysis：

Example 3: n- [ 2-fluoro-2- (7-methoxy-1-naphthyl) ethyl]Cyclopropanecarboxamides

The same procedure as in example 1 was followed, substituting propionyl chloride for acetyl chloride in step F. Recrystallization from cyclohexane gives the title product in the form of a white solid.

Melting point: 115 ℃ and 117 DEG C

Elemental microanalysis：

Example 4: n- [ 2-fluoro-2- (7-methoxy-1-naphthyl) ethyl]Cyclobutanecarboxamide

The same operation as in example 1 was performed by using cyclobutyryl chloride instead of acetyl chloride in step F. Recrystallization from cyclohexane gives the title product in the form of a white solid.

Melting point: 112 ℃ and 114 DEG C

Elemental microanalysis：

Example 5: n- [ 3-fluoro-2- (7-methoxy-1-naphthyl) propyl]Acetamide

Step A: 3-amino-2- (7-methoxy-1-naphthyl) -1-propanol hydrochloride

Aluminium chloride (80mmol) dissolved in 200ml of anhydrous ether is added to a suspension of lithium aluminium hydride (80mmol) in 300ml of anhydrous ether at 0 ℃. After stirring for 10 minutes, methyl cyano (7-methoxy-1-naphthyl) acetate (20mmol) dissolved in 200ml of anhydrous ether was added. After 30 minutes, the mixture was carefully hydrolyzed using sodium hydroxide solution (250mmol) in the cold state. The inorganic precipitate formed was then filtered off and washed with a large amount of diethyl ether. The residue obtained after evaporation was taken up in water and the aqueous phase was extracted with dichloromethane. The organic phase is then washed with water, dried and decolorized, then treated with gaseous HCl and evaporated. The resulting oil was precipitated with ethyl acetate, the precipitate formed was filtered off with suction and then recrystallized from acetonitrile to give the title product in the form of a white solid.

Melting point: 164 ℃ and 166 DEG C

Step B: n- [ 3-hydroxy-2- (7-methoxy-1-naphthyl) propyl]Acetamide

The compound obtained in step A (20mmol) was dissolved in a mixture of water/ethyl acetate (25ml/75ml) cooled to 0 ℃. Potassium carbonate (60mmol) was added, followed by acetyl chloride (26mmol) added dropwise to the reaction mixture. The mixture was stirred vigorously at ambient temperature for 30 minutes. The two phases were separated and the organic phase was washed with 0.1M aqueous hydrochloric acid and then with water. After drying over magnesium sulfate, the organic phase is evaporated under reduced pressure. The resulting residue was recrystallized from acetonitrile to give the title product as a white solid.

Melting point: 136 ℃ and 138 DEG C

Step C: methanesulfonic acid 3- (acetylamino) -2- (7-methoxy-1-naphthyl) propyl ester

The compound obtained in step B (10.9mmol) was dissolved in 160ml of dichloromethane, triethylamine (16.8mmol) was added, and the solution was cooled to 0 ℃ using an ice bath. Methanesulfonyl chloride (16.8mmol) was then added dropwise and the mixture was stirred at ambient temperature for 15 minutes. At the end of the reaction, the mixture is poured into water and the organic phase is washed with a 0.5N hydrochloric acid solution, then with a 5% sodium bicarbonate solution and with water. The organic phase is then dried and then evaporated in the cold state. The oil obtained after evaporation was precipitated with diethyl ether. The resulting precipitate was suction filtered off without recrystallization to give the title product as a white solid.

Melting point: 104 ℃ C

Step D: n- [ 3-fluoro-2- (7-methoxy-1-naphthyl) propyl]Acetamide

Tetrabutylammonium fluoride (25.6mmol) was added to a solution of the compound obtained in step C (8.5mmol) in 20ml of anhydrous tetrahydrofuran. The resulting solution was stirred at ambient temperature for 48 hours. The reaction mixture was poured into water and extracted twice with 50ml of diethyl ether. The organic phase was dried over magnesium sulfate. The oil obtained after evaporation of the solvent was purified on a silica gel column (eluent: acetone/cyclohexane 4/6) and recrystallized from cyclohexane to give the title product in the form of a white solid.

Melting point: 87-89 deg.C

Example 6: 2-fluoro-N- [ 3-fluoro-2- (7-methoxy-1-naphthyl) propyl]Acetamide

Step A: 3-amino-2- (7-methoxy-1-naphthyl) -1-propanol hydrochloride

Aluminium chloride (80mmol) dissolved in 200ml of anhydrous ether is added to a suspension of lithium aluminium hydride (80mmol) in 300ml of anhydrous ether at 0 ℃. After stirring for 10 minutes, methyl cyano (7-methoxy-1-naphthyl) acetate (20mmol) dissolved in 200ml of anhydrous ether was added. After 30 minutes, the mixture was carefully hydrolyzed using sodium hydroxide solution (250mmol) in the cold state. The inorganic precipitate formed is then filtered off and washed with a large amount of diethyl ether. The residue obtained after evaporation was taken up in water and the aqueous phase was extracted with dichloromethane. The organic phase is then washed with water, dried and decolorized, then treated with gaseous HCl and evaporated. The resulting oil was precipitated with ethyl acetate, the precipitate formed was filtered off with suction and then recrystallized from acetonitrile to give the title product in the form of a white solid.

Melting point: 164 ℃ and 166 DEG C

Step B: 2-fluoro-N- [ 3-hydroxy-2- (7-methoxy-1-naphthyl) propyl]Acetamide

The compound obtained in step A (20mmol) was dissolved in a mixture of water/ethyl acetate (25ml/75ml) cooled to 0 ℃. Potassium carbonate (60mmol) was added, followed by the addition of fluoroacetyl chloride (26mmol) dropwise to the reaction mixture. The mixture was stirred vigorously at ambient temperature for 30 minutes. The two phases were separated and the organic phase was washed with 0.1M aqueous hydrochloric acid and then with water. After drying over magnesium sulfate, the organic phase is evaporated under reduced pressure. The resulting residue was recrystallized from diisopropyl ether to give the title product as a white solid.

Melting point: 49-51 deg.C

Step C: methanesulfonic acid 3- [ (fluoroacetyl) amino group]-2- (7-methoxy-1-naphthyl) propyl ester

The compound obtained in step B (10.9mmol) was dissolved in 160ml of dichloromethane, triethylamine (16.8mmol) was added, and the solution was cooled to 0 ℃ using an ice bath. Methanesulfonyl chloride (16.8mmol) was then added dropwise and the mixture was stirred at ambient temperature for 15 minutes. At the end of the reaction, the reaction mixture is poured into water and the organic phase is washed with a 0.5N hydrochloric acid solution, then with a 5% sodium bicarbonate solution and with water. The organic phase is then dried and then evaporated in the cold state. The oil obtained after evaporation was precipitated with diethyl ether. The resulting precipitate was suction filtered off without recrystallization to give the title product as a white solid.

Melting point: 122 ℃ C

Step D: 2-fluoro-N- [ 3-fluoro-2- (7-methoxy-1-naphthyl) propyl]Acetamide

Tetrabutylammonium fluoride (25.6mmol) was added to a solution of the compound obtained in step C (8.5mmol) in 20ml of anhydrous tetrahydrofuran. The resulting solution was stirred at ambient temperature for 48 hours. The reaction mixture was poured into water and extracted twice with 50ml of diethyl ether. The organic phase was dried over magnesium sulfate. The oil obtained after evaporation of the solvent was purified on a silica gel column (eluent: acetone/cyclohexane 4/6) and recrystallized from diisopropyl ether to give the title product in the form of a white solid.

Melting point: 82-84 deg.C

Example 7: n- [ 4-fluoro-2- (7-methoxy-1-naphthyl) butyl]Acetamide

This compound was obtained by following the procedure described in steps a to D of example 5 starting from methyl 2-cyano-2- (7-methoxy-1-naphthyl) propionate.

Melting point: 81-82 deg.C

Pharmacological study

Example A: acute toxicity study

Acute toxicity was evaluated after oral administration to groups each comprising 8 mice (26 ± 2 g). Animals were observed at regular intervals during the first day and daily for 2 weeks after treatment. For LD₅₀(the dose that caused death in 50% of the animals) was evaluated, confirming that the compounds of the present invention have low toxicity.

Example B: forced swimming test

The compounds of the invention were tested in a behavioral model, i.e. forced swim test.

The instrument consists of a plexiglas jar filled with water. Animals were each tested for a period of 6 minutes. At the beginning of each test, the animals were placed in the center of the jar. The time taken to not move was recorded. An animal is considered immobile when it stops struggling and remains immobile on the water surface, retaining only those movements that allow the animal to keep its head above the water surface.

After 40 minutes administration prior to the start of the test, the compounds of the invention significantly reduced the time spent without exercise, indicating their antidepressant activity.

Example C: melatonin MT ₁ And MT ₂ Receptor binding studies

Use of 2-¹²⁵I]MT of iodomelatonin as reference radioligand₁Or MT₂Receptor binding assays. The retained radioactivity was measured using a liquid scintillation counter.

Competitive binding experiments were then performed in triplicate using different test compounds. A range of different concentrations of each compound was tested. The results enable the binding affinity (K) of the tested compounds to be determined_i)。

Measured K of the Compound of the invention_iThe values correspondingly demonstrate binding to one of the melatonin-active binding sites or to the other melatonin-active binding sites, said K_iThe value is less than or equal to 10 mu M.

For example, K of the Compound obtained in example 5_i(MT₁) Is 0.1nM, K_i(MT₂) Was 0.2 nM.

Example D: serotonergic 5-HT _2C Receptor binding studies

Use of expression of human 5-HT by stabilization_2CMembrane preparations from CHO cells of the receptor evaluated the affinity of the compound for the receptor.

In [2 ]³H]-Melsuergot (1nM) and 25fmol/ml receptor in the presence of MgCl at pH 7.4 containing 10mM₂And 0.1% BSA in 50mM TRIS buffer. Nonspecific binding was determined in the presence of 10. mu.M mianserin.

The reaction was stopped by adding 50mM TRIS buffer pH 7.4, followed by a filtration step and 3 successive washes: the membrane-bound radioactivity retained on the filters (GF/B pretreated with 0.1% PEI) was determined by liquid scintillation counting.

The results obtained demonstrate that the compounds of the invention are para to 5-HT_2CThe receptor has affinity, K_iThe value was < 10. mu.M.

For example, K of the Compound of example 5_i(5-HT_2C) At 6. mu.M.

Example E: the compounds of the present invention act on the circadian rhythm of rat autonomic activity Function of

Most physiology, biochemistry and behaviors produce circadian rhythms due to day/night alternation, and the involvement of melatonin in the production of said circadian rhythms has made it possible to establish pharmacological models for finding melatonin-ergic ligands.

The effect of the compounds on various parameters, in particular on the circadian rhythm of the autonomic activity, which is a reliable indicator of the endogenous circadian clock activity, was tested.

In this study, the effect of these compounds on a particular experimental model, namely rats placed in time isolation (permanent darkness), was evaluated.

Experimental protocol

Once 1 month old male rats arrive at the laboratory, they are subjected to a 12 hour light cycle every 24 hours (LD 12: 12).

After 2-3 weeks of acclimation, they are placed in cages fitted with wheels connected to a recording system in order to detect the phases of autonomic activity and thereby monitor the circadian rhythm (LD) or circadian rhythm (DD).

Once the recorded rhythm shows a steady production of LD 12:12 with the photoperiod, the rats are placed in permanent darkness (DD).

After 2-3 weeks, rats were administered daily with test compounds when smooth functioning (reflecting the rhythm of the endogenous clock) was clearly established.

The following activity rhythms were observed by visual observation:

the generation of an activity rhythm accompanied by a lighting rhythm,

the absence of rhythm production in permanent darkness,

-the production resulting from daily administration of the compound; transient or persistent effects.

The software package enables:

measuring the duration and intensity of the animal's activity in smooth-running conditions and during the treatment, the duration of the rhythm,

the presence of circadian and non-circadian (e.g. sub-circadian) components (if present) is confirmed by spectral analysis.

Results

The compounds of the invention clearly show a strong effect on the circadian rhythm through the melatoninergic system.

Example F: light (es)Light/dark cage test

The anxiolytic activity of the compounds of the invention was confirmed by testing them in a behavioral model, i.e. light/dark cage assay.

The instrument consists of two plexiglas-covered polyethylene boxes. One of the boxes is in the dark. Above the other cassette is placed a lamp which generates a light intensity of about 4000lux in the center of the cassette. An opaque plastic tunnel separates the light box from the dark box. Animals were each tested for a period of 5 minutes. The floor of each box was cleaned between test sessions. At the beginning of each experiment, mice were placed in the tunnel facing dark boxes. The time spent by the mouse in the light box and the number of passes through the tunnel were recorded after the first entry into the dark box.

The compound of the invention significantly increased the time spent in the illuminated cage and the number of passages through the channel after administration of the compound 30 minutes before the start of the experiment, confirming the anxiolytic activity of the compound of the invention.

Example G: the pharmaceutical composition comprises: tablet formulation

1000 tablets each containing N- [ 3-fluoro-2- (7-methoxy-1-naphthyl) propyl ] in a dose of 5mg

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Claims (11)

1. A compound of formula (I):

wherein:

R₁represents a straight chain or branched chain (C)₁-C₆) An alkyl group; straight or branched chain (C)₁-C₆) An alkenyl group; straight or branched chain (C)₁-C₆) A haloalkyl group; straight or branched chain (C)₁-C₆) A polyhaloalkyl group; (C)₃-C₈) A cycloalkyl group; (C)₃-C₈) Cycloalkyl- (C)₁-C₆) Alkyl, wherein the alkyl moiety may be linear or branched; an aryl group; aryl radical- (C)₁-C₆) Alkyl, wherein the alkyl moiety may be linear or branched; a heteroaryl group; or heteroaryl- (C)₁-C₆) Alkyl, wherein the alkyl moiety may be linear or branched,

R₂represents a fluorine atom or a linear or branched chain substituted by one or more fluorine atoms (C)₁-C₆) Alkyl, it being understood that:

- "aryl" means phenyl, naphthyl or biphenyl,

- "heteroaryl" means any mono-or bicyclic aromatic group containing from 1 to 3 heteroatoms selected from oxygen, sulphur and nitrogen,

the defined aryl and heteroaryl groups may be substituted by 1 to 3 groups selected from: straight or branched chain (C)₁-C₆) Alkyl, straight or branched chain (C)₁-C₆) Alkoxy, hydroxy, carboxy, formyl, nitro, cyano, straight or branched chain (C)₁-C₆) Haloalkyl, straight-chain or branched (C)₁-C₆) Polyhaloalkyl, alkoxycarbonyl and halogen atoms,

their enantiomers and diastereomers, and their addition salts with a pharmaceutically acceptable acid or base.

2. Compounds of formula (I) according to claim 1, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable base, wherein R₂Represents a fluorine atom.

3. Compounds of formula (I) according to claim 1, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable base, wherein R₂Represents a straight chain or branched chain (C)₁-C₆) A haloalkyl group.

4. Compounds of formula (I) according to claim 3, their enantiomers and diastereoisomers and addition salts thereof with a pharmaceutically acceptable base, wherein R₂Represents a fluoromethyl group or a 1-fluoroethyl group.

5. A compound of formula (I) according to claim 1, which is N- [ 3-fluoro-2- (7-methoxy-1-naphthyl) propyl ] acetamide, and its addition salts with pharmaceutically acceptable bases.

6. A compound of formula (I) according to claim 1, which is N- [ 4-fluoro-2- (7-methoxy-1-naphthyl) butyl ] acetamide, and its addition salts with pharmaceutically acceptable bases.

7. Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that compounds of formula (II) are used as starting materials:

wherein R is₂As defined in claim 1, wherein the first and second groups are,

reacting a compound of formula (II) with R₁Formula R as defined in claim 1₁The compounds of formula (I) can be purified according to conventional separation techniques, converted into their addition salts, if desired, with a pharmaceutically acceptable acid or base, and, if appropriate, separated into their isomers according to conventional separation techniques.

8. A process for preparing a compound of formula (I) as claimed in claim 1, wherein R₂Denotes straight-chain or branched (C) substituted by one or more fluorine atoms₁-C₆) Alkyl, characterized in that a compound of formula (III) is used as starting material:

wherein R is₁As defined in claim 1, R represents a linear or branched chain (C) substituted by one or more OH groups₁-C₆) An alkyl group, a carboxyl group,

reacting a compound of formula (III) with methanesulfonyl chloride to produce a compound of formula (IV):

wherein R is₁R' represents, as defined above, substituted by one or more OSOs₂Linear or branched (C) substituted by Me radicals₁-C₆) An alkyl group, a carboxyl group,

reacting a compound of formula (IV) with tetrabutylammonium fluoride to produce a compound of formula (I/a), which is a particular case of compounds of formula (I):

wherein R is₂' represents a linear or branched (C) substituted by one or more fluorine atoms₁-C₆) The compound of formula (I/a) can be purified according to a conventional separation technique, converted into an addition salt thereof with a pharmaceutically acceptable acid or base if necessary, and separated into its isomers according to a conventional separation technique if appropriate.

9. Pharmaceutical composition comprising at least one compound of formula (I) according to any one of claims 1 to 6 or an addition salt thereof with a pharmaceutically acceptable base and one or more pharmaceutically acceptable excipients.

10. The pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of a disorder of the melatoninergic system.

11. The pharmaceutical composition according to claim 9 for the preparation of a medicament for the treatment of sleep disorders, stress, anxiety, major depression or seasonal affective disorders, cardiovascular conditions, conditions of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, parkinson's disease, senile dementia, various disorders associated with normal or pathological ageing, migraine, memory loss, alzheimer's disease, cerebral circulation disorders or sexual dysfunction, for use as an ovulation inhibitor or immunomodulator, or for the treatment of cancer.