EP2167460A2

EP2167460A2 - Novel naphthalene derivatives, process for the preparation thereof and pharmaceutical compositions containing same

Info

Publication number: EP2167460A2
Application number: EP08827457A
Authority: EP
Inventors: Saïd YOUS; Mohamed Ettaoussi; Ahmed Sabaouni; Pascal Berthelot; Michaël SPEDDING; Philippe Delagrange; Daniel-Henri Caignard; Mark Millan
Original assignee: Laboratoires Servier SAS
Current assignee: Laboratoires Servier SAS
Priority date: 2007-07-02
Filing date: 2008-07-01
Publication date: 2010-03-31
Also published as: MA31577B1; US20100168244A1; JP2010531859A; FR2918372A1; US7947852B2; BRPI0814402A2; KR20100029262A; AR070005A1; ZA201000024B; CA2691586A1; UA94828C2; WO2009022063A3; AU2008288373B2; AU2008288373A1; WO2009022063A2; EA201000083A1; FR2918372B1; CN101687777A

Abstract

Compounds of formula (I): in which: R1 is an alkyl, alkenyl, haloalkyl, polyhaloalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, and X is an N-OR2 group in which R2 is a hydrogen atom or an alkyl group. Medicaments.

Description

NOVEL NAPHTHALENIC DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING SAME

The present invention relates to novel naphthalenic derivatives, process for their preparation and pharmaceutical compositions containing them.

The compounds of the present invention are novel and have very interesting pharmacological characteristics concerning melatoninergic receptors.

Numerous studies have highlighted over the last ten years the important role of melatonin (N-acetyl-5-methoxytryptamine) in many physiopathological phenomena as well as in the control of circadian rhythms. However, it has a relatively low half-life due to rapid metabolism. It is therefore very interesting to be able to provide the clinician with melatonin analogues, which are metabolically more stable and have an agonist or antagonist character, which can be expected to have a therapeutic effect greater than that of the hormone itself.

In addition to their beneficial effect on circadian rhythm disorders (J. Neurosurg, 1985, 63, pp. 321-341) and sleep (Psychopharmacology, 1990, 100, pp. 222-226), the melatoninergic system ligands possess interesting pharmacological properties on the central nervous system, including anxiolytics and antipsychotics

(Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272), Analgesics

(Pharmacopsychiat., 1987, 20, pp. 222-223), as well as for the treatment of Parkinson's disease (J. Neurosurg, 1985, 63, pp. 321-341) and Alzheimer's (Brain Research, 1990,

528, pp. 170-174). Likewise, these compounds have shown an activity on certain cancers

(Melatonin - Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), on ovulation (Science 1987, 227, pp. 714-720), on diabetes (Clinical Endocrinology, 1986,

24, pp. 359-364), and in the treatment of obesity (International Journal of Eating Disorders, 1996, 20 (4), pp. 443-446).

These different effects are exerted through specific receptors of the melatonin. Molecular biology studies have shown the existence of several receptor subtypes capable of binding this hormone (Trends Pharmacol., S., 1995, 16, p.50, WO 97.04094). Some of these receptors could be localized and characterized for different species, including mammals. In order to better understand the physiological functions of these receptors, it is of great interest to have selective ligands. In addition, such compounds, by selectively interacting with either of these receptors, may be for the clinician excellent drugs for the treatment of pathologies related to the melatoninergic system, some of which have been mentioned previously.

The compounds of the present invention in addition to their novelty, show a very high affinity for melatonin receptors.

They moreover have a strong affinity for the 5-HT ₂ c, which has the effect of reinforcing the properties observed with melatoninergic receptors, especially in the field of depression.

The present invention relates more particularly to the compounds of formula (I):

in which :

R ₁ represents an alkyl (Ci-C ₆₎ linear or branched, alkenyl (Ci-C ₆₎ linear or branched haloalkyl (Ci-C ₆₎ linear or branched polyhaloalkyl (Ci-C ₆₎ linear or branched cycloalkyl (C ₃ -C ₈ ), cycloalkyl (C ₃ -C ₈ ) alkyl (C ₁ -C ₆ ), the alkyl portion may be linear or branched, aryl, aryl (C ₁ -C ₆ ) alkyl, the alkyl part may be linear or branched , heteroaryl or heteroarylalkyl (Ci-C ₆ ) whose alkyl part may be linear or branched

X represents an N-OR _{2 group} in which R ₂ represents a hydrogen atom or a linear or branched (C ₁ -C ₆ ) alkyl group,

it being understood that: the oxime = N-OR ₂ may be of Z or E configuration,

"aryl" means a phenyl, naphthyl or biphenyl group,

with "heteroaryl" is meant any mono or bicyclic aromatic group containing 1 to 3 heteroatoms chosen from oxygen, sulfur and nitrogen, the aryl and heteroaryl groups thus defined being capable of being substituted with 1 to 3 groups chosen from alkyl (C ₁ -C ₆₎ linear or branched alkoxy (C ₁ -C ₆₎ linear or branched, hydroxy, carboxy, formyl, nitro, cyano, halo (C ₁ -C ₆₎ linear or branched polyhaloalkyl (C ₁ -C ₆₎ -straight or branched, alkyloxycarbonyl, or halogen atoms,

their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids, mention may be made, without limitation, of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic and methane acids. sulfonic, camphoric, etc.

Among the pharmaceutically acceptable bases, mention may be made, without limitation, of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, and the like.

The preferred compounds of the invention are the compounds of formula (I) for which R ₁ represents a linear or branched (Ci-C ₆ ) alkyl group such as, for example, the methyl group.

Advantageously, the group R ₂ represents a hydrogen atom or a methyl group. - AT -

Even more particularly, the invention relates to compounds which are N - [(2E) -2- (hydroxyimino) -2- (7-methoxy-1-naphthyl) ethyl] acetamide, iV - [(2Z) -2 - (hydroxyimino) -2- (7-methoxy-1-naphthyl) ethyl] acetamide, and N - [(2E) -2- (methoxyimino) -2- (7-methoxy-1-naphthyl) ethyl] acetamide.

The addition salts with an acid or a pharmaceutically acceptable base of the preferred compounds of the invention form an integral part of the invention.

The invention also extends to the process for the preparation of the compound of formula (I), characterized in that the compound of formula (II) used is the starting material:

that mesyl chloride is subjected to the action of the compound of formula (III):

that is placed in a basic medium to yield the compound of formula (IV):

that is subjected to oxidation to yield the compound of formula (V)

that is subjected to the action of trimethylsilyl cyanide to yield the compound of formula (VI):

that is subjected to a reduction to yield the compound of formula (VII)

that the compound of formula RiCOCl in which R 1 is as defined in formula (I) is subjected to the action of giving the compound of formula (VIII):

in which R ₁ is as defined above, that is subjected to the action of potassium chlorochromate to yield the compound of formula (IX):

in which R ₁ is as defined above, on which the compound of formula R ₂ O -NH ₂ in which R ₂ is as defined in formula (I) is condensed to yield the compound of formula (I) which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and the isomers are optionally separated by a conventional separation technique.

The compound of formula (II) is accessible to those skilled in the art by conventional chemical reactions and described in the literature.

The pharmacological study of the derivatives of the invention has shown that they are atoxic, endowed with a high selective affinity for melatonin receptors and have important activities on the central nervous system and, in particular, have been noted. therapeutic properties on sleep disorders, antidepressant, anxiolytic, antipsychotic, analgesic and microcirculation properties, which make it possible to establish that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depression or major depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, disorders of the appetite, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, as well as disorders of the cerebral circulation. In another field of activity, it appears that in the treatment, the products of the invention can be used in malfunctions they possess the properties of ovulation inhibitors, immunomodulators and that they are likely to be used in the treatment of cancers.

The compounds will preferably be used in the treatment of major depression, seasonal depression, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, appetite disorders and obesity.

For example, the compounds will be used in the treatment of major depression, seasonal depression and sleep disorders.

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

Among the pharmaceutical compositions according to the invention, mention may be made, more particularly, of those which are suitable for oral, parenteral, nasal, percutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets. , sachets, packets, capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and oral 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 possibly associated treatments and ranges between 0.01 mg and 1 g per 24 hours. in one or more takes.

The following examples illustrate the invention and do not limit it in any way. Example 1: 7V - [(2Z) -2- (Hydroxyimino) -2- (7-methoxy-1-naphthyl) ethyl] acetamide

Step A: 2- (7-Methoxy-1-naphthyl) ethyl methanesulfonate

2- (7-methoxy-1-naphthyl) ethanol (25 mmol) and triethylamine (30 mmol) are dissolved in 50 ml of dichloromethane and the reaction mixture is cooled to 0 ° C. with an ice bath. Mesyl chloride (30 mmol) is added dropwise and the reaction mixture is stirred at ambient temperature for 2 hours, then poured into 100 ml of water. The organic phase is washed with a 1M hydrochloric acid solution and then with water, dried over magnesium sulphate and evaporated. The oil obtained precipitates in a diethyl ether / petroleum ether mixture (1/1). The title product is drained and then recrystallized from diisopropyl ether. Melting point: 60-62 ⁰ C

Stage B: 7-Methoxy-1-vinylnaphthalene

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

Stage C: 7-Methoxy-1-naphthaldehyde

The compound obtained in Stage B (13.4 mmol) and osmium tetraoxide (0.16 mmol) are dissolved in 70 ml of a tetrahydrofuran / water mixture (1/1). The sodium periodate (26.9 mmol) is added in small portions and the reaction mixture is stirred for 2 hours at room temperature. The reaction medium is poured into 50 ml of a 5% solution of sodium hydrogencarbonate, the insoluble matter is filtered and the aqueous phase is extracted with 2 times 75 ml of ether. The organic phase is washed with water, decolorized and evaporated. The precipitate obtained is recrystallized from cyclohexane and gives the title product as a white solid. Melting point: 61-6S ° C

Stage D: (7-Methoxy-1-naphthyl) [(trimethylsilyl) oxy] acetonitrile

The methyltriphenylphosphonium iodide (5.7 mmol) is dissolved in 250 ml of anhydrous dichloromethane, under argon, and then the trimethylsilyl cyanide (170.8 mmol) and the compound obtained in Stage C (56.9 mmol). are added. The reaction medium is stirred at ambient temperature for 72 hours and then 200 ml of water are added. The two phases are separated and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are combined, dried over magnesium sulphate and evaporated under reduced pressure. The precipitate is filtered off with ether and recrystallized from cyclohexane to yield the title product as a white solid. Melting point: 123-125 ° C

Stage E: 2-Amino-1- (7-methoxy-1-naphthyl) ethanol, hydrochloride

In a three-necked flask under argon, lithium aluminum hydride (37.1 mmol) is suspended in 200 ml of diethyl ether. The compound obtained in Stage D (18.6 mmol), solubilized in 50 ml of tetrahydrofuran, is added dropwise. The reaction medium is stirred at room temperature for 1 hour. The excess lithium aluminum hydride is destroyed by successive additions of 1.4 ml of water, 1.4 ml of 15% sodium hydroxide and 4.2 ml of water. The formed mineral precipitate is removed by filtration and washed with 50 ml of tetrahydrofuran. The filtrate is dried over magnesium sulphate and evaporated under reduced pressure. The oil obtained is solubilized in 100 ml of diethyl ether and treated with diethyl ether saturated with gaseous hydrochloric acid. The diethyl ether is evaporated under reduced pressure, the solid obtained is drained and recrystallized from acetonitrile to yield the title product in the form of a white solid. Melting point: 207-209 ⁰ C Stage F: N- [2-Hydroxy-2- (7-methoxy-1-naphthyl) ethyl] acetamide

The compound obtained in Step E (20 mmol) is dissolved in a water / ethyl acetate mixture (25 ml / 75 ml) cooled to 0 ° C. Potassium carbonate (60 mmol) is added and the acetyl chloride (26 mmol) is added dropwise to the reaction medium. The whole is stirred vigorously for 30 minutes at room temperature. The two phases are separated and the organic phase is washed with a 0.1M aqueous hydrochloric acid solution and then with water. After drying over magnesium sulphate, the organic phase is evaporated under reduced pressure. The resulting residue is recrystallized from acetonitrile to yield the title product as a white solid. Melting point: 173-175 ° C

Stage G: N- [2- (7-Methoxy-1-naphthyl) -2-oxoethyl] acetamide

The compound obtained in Stage F (7.7 mmol) is dissolved in 200 ml of anhydrous dichloromethane. This solution is added to a suspension of potassium acetate (0.23 g) and pyridinium chlorochromate (11.6 mmol) in 50 ml of dichloromethane. The reaction medium is stirred at room temperature for 2 hours. It is then filtered on celite. The filtrate is washed with water, decolorized on vegetable charcoal and evaporated under reduced pressure. The residue obtained is triturated in diethyl ether, drained and recrystallized from diisopropyl ether to yield the title product in the form of a white solid. Melting point: 122-124 ° C

Stage H: N - [(2Z) -2- (Hydroxyimino) -2- (7-methoxy-1-naphthyl) ethyl] acetamide

In a 100 ml flask, the compound obtained in Step G (4.2 mmol) is dissolved in 25 ml of methanol. Hydroxylamine hydrochloride (16.8 mmol) and pyridine (21.1 mmol) are added and the reaction mixture is refluxed with magnetic stirring for 3 hours. After cooling, the reaction medium is poured into 50 ml of water. The precipitate formed is drained, washed with water and recrystallized from toluene to yield the title product in the form of a white solid. Melting point: 136-138 ° C

Example 2 N - [(2 E) -2- (Hydroxyimino) -2- (7-methoxy-1-naphthyl) ethyl] acetainide

The procedure is as in Example 1. The precipitate formed in Stage H is drained, washed with water and recrystallized from acetonitrile to yield the title product in the form of a white solid.

Melting point: 157-159 ° C

Elemental microanalysis:

% C H N

Calculated: 66.16 5.92 10.29

Found: 65.93 5.85 10.21

Example 3: V-1 (2E) -2- (Methoximino> -2- (7-methoxy-1-naphthyl) ethyl] acetamide

The procedure is as in Example 1, replacing in Step H the hydroxylamine hydrochloride with O-methylhydroxylamine hydrochloride. The title product, recrystallized from diisopropyl ether, is obtained in the form of a white solid. Melting point: 110-112 ⁰ C

Elemental microanalysis:

% C H N

Calculated: 67.12 6.34 9, 78

Found: 67.11, 6.34, 9.53 PHARMACOLOGICAL STUDY

EXAMPLE A: Acute Toxicity Study

Acute toxicity was assessed after oral administration to batches of 8 mice (26 ± 2 grams). The animals were observed at regular intervals during the first day and daily for two weeks after treatment. The LD 50, resulting in the death of 50% of the animals, was evaluated and showed the low toxicity of the compounds of the invention.

EXAMPLE B: Forced Swimming Test

The compounds of the invention are tested in a behavioral model, the forced swimming test.

The apparatus consists of a Plexiglas cylinder filled with water. The animals are tested individually during a 6-minute session. At the beginning of each test, the animal is placed in the center of the cylinder. The downtime is recorded. Each animal is judged immobile when it ceases to struggle, and remains on the surface of the water, motionless, making only the movements allowing it to keep its head out of the water.

After administration 40 minutes before the start of the test, the compounds of the invention significantly reduce the duration of immobilization attesting to their antidepressant activity.

EXAMPLE C: MTi and MT receptor binding study melatonin

The MT ₁ or MT ₂ receptor binding experiments are carried out using the

2- [I] -iodomelatonin as reference radioligand. The retained radioactivity is determined using a liquid scintillation counter.

Competitive binding experiments are then performed in triplicate, with the various compounds to be tested. A range of different concentrations is tested for each compound. The results make it possible to determine the binding affinities of the compounds tested (Ki).

Thus, the values of K; found for the compounds of the invention attest to a binding for one or the other melatoninergic binding sites, these values being <10 .mu.M. By way of example, the compound obtained in Example 2 has a Ki (MT ₁ ) of 7 nM and a K ₁ (MT ₂ ) of 0.8 nM.

EXAMPLE D Study of Serotoninergic Receptor Binding 5-HTiC

The affinity of the compounds for human 5-HT receptor ₂ c is evaluated on membrane preparations from CHO cells stably expressing that receptor. The incubation is carried out in 50 mM TRIS buffer, pH 7.4 containing 10 mM MgCl ₂ and 0.1% BSA, in the presence of [ ³ H] mesulergine (1 nM) and 25 fmol / ml of receiver. Nonspecific binding is determined in the presence of 10 μM mianserin. The reaction is stopped by the addition of 50 mM TRIS buffer, pH 7.4 followed by a filtration step and 3 successive rinses: the radioactivity bound to the membranes remaining on the filters (GF / B pretreated with 0.1% PEI) is counted as liquid scintillation.

The results obtained show that the compounds of the invention have affinity for the 5-HT _2C with Kj <10 microM.

EXAMPLE E Action of the Compounds of the Invention on the Circadian Rhythms of Rat Locomotor Activity

The involvement of melatonin in the training, by the day / night alternation, of most of the circadian physiological, biochemical and behavioral rhythms has made it possible to establish a pharmacological model for the search for melatoninergic ligands. The effects of the molecules are tested on many parameters and, in particular, on the circadian rhythms of locomotor activity that represent a reliable marker of endogenous circadian clock activity.

In this study, we evaluate the effects of such molecules on a particular experimental model, namely the rat placed in temporal isolation (permanent darkness).

Experimental protocol

One-month-old male rats are subjected to a light cycle of 12 hours of light per day as soon as they arrive at the laboratory (LD 12:12).

After 2 to 3 weeks of adaptation, they are placed in cages equipped with a wheel connected to a recording system in order to detect the phases of locomotor activity and thus to follow the diurnal (LD) or circadian (DD) rhythms. ).

As soon as the recorded rhythms show a stable training by the light cycle

LD 12: 12, the rats are put in permanent darkness (DD).

Two to three weeks later, when the free-course (rhythm reflecting that of the endogenous clock) is clearly established, the rats receive a daily administration of the molecule to be tested.

The observations are made thanks to the visualization of the rhythms of activity:

- training of the rhythms of activity by the rhythm of light,

- disappearance of the training of the rhythms in permanent darkness, - training by the daily administration of the molecule; transient or lasting effect.

Software allows:

- to measure the duration and the intensity of the activity, the period of the rhythm in the animals in free course and during the treatment,

- Possibly highlight by spectral analysis the existence of circadian and non-circadian components (ultradian for example).

Results

It is clear that the compounds of the invention allow to act in a powerful way on the circadian rhythm via the melatoninergic system. EXAMPLE F: Clear / Dark Cages Test

The compounds of the invention are tested in a behavioral model, the light / dark cages test, which reveals the anxiolytic activity of the molecules.

The device consists of two polyvinyl boxes covered with Plexiglas. One of these boxes is obscure. One lamp is placed above the other box giving a luminous intensity in the center of it of approximately 4000 lux. An opaque plastic tunnel separates the clear box from the dark box. The animals are tested individually during a 5 min session. The floor of each box is cleaned between each session. At the beginning of each test, the mouse is placed in the tunnel, facing the dark box. The time spent by the mouse in the lighted box and the number of transitions through the tunnel are recorded after the first entry in the dark box. After administration of the compounds 30 min before the start of the test, the compounds of the invention significantly increase the time spent in the illuminated cage and the number of transitions, which shows the anxiolytic activity of the derivatives of the invention.

EXAMPLE G: Pharmaceutical Composition: Tablets

1000 tablets dosed with 5 mg of N - [(2E) -2- (hydroxyimino) -2- (7-methoxy-1-naphthyl) ethyl] acetamide (Example 2) 5 g

Wheat starch 20 g

Corn starch 20 g Lactose 30 g

Magnesium stearate 2 g

Silica 1 g

Hydroxypropylcellulose 2 g

Claims

Compounds of formula (I)

in which :

R ₁ represents an alkyl (Ci-C ₆₎ linear or branched, alkenyl (Ci-C ₆₎ linear or branched haloalkyl (Ci-C ₆₎ linear or branched polyhaloalkyl (C ₁ -C ₆₎ linear or branched, cycloalkyl (C ₃ -C ₈₎ cycloalkyl (C ₃ -C ₈₎ alkyl (Ci-C ₆₎ whose alkyl moiety may be linear or branched, aryl, aryl (C ₁ -C ₆₎ alkyl where the alkyl part may be linear or branched, heteroaryl or heteroarylalkyl (C ₁ -C ₆ ) whose alkyl part may be linear or branched,

Being heard that :

the oxime = N-OR ₂ may be of Z or E configuration; "aryl" means a phenyl, naphthyl or biphenyl group; "heteroaryl" means any mono or bicyclic aromatic group containing 1 to 3 heteroatoms selected from oxygen, sulfur and nitrogen, the aryl and heteroaryl groups so defined may be substituted by 1 to 3 groups selected from alkyl (Ci-C ₆₎ linear or branched alkoxy (Ci-C ₆₎ linear or branched, hydroxy, linear carboxy, formyl, nitro, cyano, haloalkyl (Ci-C ₆ ) or branched, linear or branched (C ₁ -C ₆ ) polyhaloalkyl, alkyloxycarbonyl, or halogen atoms,

I ₁ A compound of formula (I) according to claim 1 for which R represents an alkyl group (C ₁ -C ₆₎ linear or branched, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable base.

Compounds of formula (I) according to claim 1 wherein R ₂ represents a methyl group, their enantiomers and diastereoisomers, and addition salts thereof with a pharmaceutically acceptable base.

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

5; Compound of formula (I) according to claim 1 which is 7V - [(2E) -2- (hydroxyimino) -2- (7-methoxy-1-naphthyl) ethyl] acetamide, and its addition salts with a pharmaceutically acceptable base.

§ ₂ A process for preparing the compound of formula (I) according to claim 1 characterized in that there is used as starting material the compound of formula (II):

that is subjected to the action of mesyl chloride to lead to the compound of formula

(III):

that is placed in a basic medium to yield the compound of formula (IV)

which is subjected to oxidation to yield the compound of formula (V):

that is subjected to a reduction to yield the compound of formula (VII):

that the compound of formula R ₁ COCl in which R ₁ is as defined in claim 1 is subjected to the action of giving the compound of formula (VIII):

in which R ₁ is as defined above, which is subjected to the action of potassium chlorochromate to yield the compound of formula (IX):

in which R ₁ is as defined above, on which the compound of formula R ₂ O -NH ₂ in which R ₂ is as defined in claim 1 is condensed to yield the compound of formula (I) which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with a pharmaceutically acceptable acid or base and from which the isomers are optionally separated by a conventional separation technique.

Pharmaceutical compositions containing at least one compound of formula (I) according to any one of claims 1 to 5 or one of their addition salts with a base pharmaceutically acceptable in combination with one or more pharmaceutically acceptable excipients.

8. Pharmaceutical compositions according to claim 7, useful for the manufacture of medicaments for treating disorders of the melatoninergic system.

9- Pharmaceutical compositions according to claim 7, useful for the manufacture of medicaments for the treatment of sleep disorders, stress, anxiety, major depression or seasonal depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet lag, schizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, memory loss, Alzheimer's disease, cerebral circulation disorders, as well as sexual dysfunction , as ovulation inhibitors, immunomodulators and in the treatment of cancers.