WO2005012282A1

WO2005012282A1 - Novel 2-thiosubstituted benzothiophene derivatives, method for production of and pharmaceutical compositions comprising the same

Info

Publication number: WO2005012282A1
Application number: PCT/FR2004/001676
Authority: WO
Inventors: Saïd YOUS; Christophe Mesangeau; Daniel Lesieur; Caroline Bennejean; Jean Albert Boutin; Valérie Audinot; Philippe Delagrange; Pierre Renard
Original assignee: Les Laboratoires Servier
Priority date: 2003-07-04
Filing date: 2004-06-30
Publication date: 2005-02-10
Also published as: FR2857011B1; FR2857011A1; AR044996A1

Abstract

Compounds of formula (I), where R1 = halogen, alkyl or alkoxy, R2 = substituted or non-substituted phenyl and R3 = alkyl, alkenyl, cycloalkyl or cycloalkylalkyl. The invention further relates to medicaments.

Description

NOVEL BENZOTHIOPHENE 2-THIOSUBSTITUED DERIVATIVES, THEIR PREPARATION PROCESS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

The present invention relates to new 2-thiosubstituted benzothiophene derivatives, their preparation process and the pharmaceutical compositions containing them.

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

Numerous studies have highlighted over the past ten years the crucial role of melatonin (N-acetyl-5-methoxytryptamine) in many pathophysiological phenomena as well as in controlling the circadian rhythm. However, it has a fairly short half-life due to rapid metabolism. It is therefore very interesting to be able to provide the clinician with analogues of melatonin, metabolically more stable and having an agonist or antagonist character, from which one can expect a therapeutic effect greater than that of the hormone itself.

In addition to their beneficial action on circadian rhythm disorders (J. Neurosurg. 1985, 63, pp. 321-341) and sleep (Psychopharmacology, 1990, 100, pp. 222-226), the ligands of the melatoninergic system have interesting pharmacological properties on the central nervous system, in particular 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 diseases of

Parkinson (J. Neurosurg. 1985, 63, pp. 321-341) and Alzheimer's (Brain Research, 1990, 528, pp. 170-174). Likewise, these compounds have shown 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 various effects are exerted via specific melatonin receptors. Molecular biology studies have shown the existence of several sub- receptor types that can bind this hormone (Trends Pharmacol. Sci., 1995, 16, p. 50; WO 97.04094). Some of these receptors could be located and characterized for different species, including mammals. In order to be able to better understand the physiological functions of these receptors, it is of great interest to have selective ligands. In addition, such compounds, by interacting selectively with one or the other of these receptors, can be, for the clinician, excellent drugs for the treatment of pathologies linked 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 strong affinity for the melatonin receptors and / or a selectivity for one or the other of the melatoninergic binding sites.

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

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

in which :

* R ¹ represents a halogen atom, an alkyl group (Cι-C ₆ ) linear or branched, or an alkoxy group (Cι-C ₆ ) linear or branched, R ² represents a phenyl group unsubstituted or substituted by one to three groups chosen from hydroxy, linear or branched (C] -C ₆ ) alkyl, linear or branched alkoxy (Cι-C ₆ ), carboxy, formyl, nitro, cyano, linear or branched polyhaloalkyl (Cι-C ₆ ) and d atoms 'halogen,

* R represents an alkyl _(Cι-C6) linear or branched substituted or unsubstituted alkenyl, _(Cι-C6) linear or branched substituted or unsubstituted cycloalkyl (C -C ₈ ), or cycloalkyl (C -C ₈ ) alkyl (Cι-C ₆ ), the alkyl part of which can be linear or branched, it being understood that:

the term “substituted” applied to “alkyl” and “alkenyl” means that these groups are substituted by one or more halogen atoms, or by one or more groups chosen from linear and branched hydroxy and alkoxy (Cι-C ₆ ),

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

Among the pharmaceutically acceptable acids, non-limiting mention may be made of hydrochloric, hydrobromic, sulfuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methane acids. sulfonic, camphoric, etc.

Among the pharmaceutically acceptable bases, non-limiting mention may be made of sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

The preferred compounds of the invention are the compounds of formula (I) for which

R ¹ represents a halogen atom such as fluorine, chlorine or bromine.

R advantageously represents a phenyl group substituted by a halogen atom.

The preferred group R is alkyl, for example the methyl, ethyl, "-propyl or" -butyl groups, as well as the alkyl group substituted by a halogen atom, such as, for example, the bromomethyl, bromoethyl, bromopropyl or bromobutyl groups.

Still more particularly, the invention relates to N- (2- {5-bromo-2 - [(4-bromophenyl) thio] -l -benzothien-3-yl} ethyl) acetamide, 2-bromo-N- ( 2- {5-fluoro-2 - [(4-fluorophenyl) thio] - 1 -benzothien-3-yl} ethyl) acetamide, N- (2- {5-fluoro-2 - [(4-fluoro- phenyl) thio] -1-benzothien-3-yl} ethyl) cyclobutanecarboxamide, N- (2- {5-fluoro-2 - [(4-fluorophenyl) thio] - 1 -benzothien-3-yl} ethyl) propanamide .

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

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

in which R ¹ and R ² are as defined in formula (I), which are placed in the presence of potassium cyanide to yield the compound of formula (III):

1 _ in which R and R are defined as above, which is subjected to the action of a reducing agent such as BH ₃ to yield the compound of formula (IV):

1 in which R and R are as defined above, on which the acid chloride of formula R ³ COCl is condensed in which R ³ is as defined in formula (I) or the corresponding symmetrical anhydride, to lead to the compound of formula (I):

in which R. 1, τ R> 2 and. r R3 are as defined above,

which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with an acid or a pharmaceutically acceptable base and from which the isomers are optionally separated according to a conventional separation technique .

The compounds of formula (II) are either commercial or accessible to a person 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 non-toxic, endowed with a strong selective affinity for the melatonin receptors and possess important activities on the central nervous system and, in particular, it has been noted therapeutic properties for sleep disorders, antidepressant, anxiolytic, antipsychotic, analgesic properties as well as for microcirculation, which make it possible to establish that the products of the invention are useful in the treatment of stress, sleep disorders, anxiety, seasonal depressions or major depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, 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 in 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 sexual dysfunctions, that they have properties of inhibitors of ovulation, of immunomodulators and that they are likely to be used in the treatment of cancer. The compounds will preferably be used in the treatment of major depression, seasonal depressions, 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 depressions and sleep disturbances.

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, there may be mentioned, more particularly those which are suitable for oral, parenteral, nasal, per or transcutaneous, rectal, perlingual, ocular or respiratory administration and in particular simple or coated tablets, sublingual tablets , sachets, packages, capsules, lollipops, tablets, 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; N- (2- {5-Fluoro-2-f (4-fluorophenyl) thiol-1-benzothien-3-yl} ethyl) cyclobutane carboxamide

Stage A: 3- (Bromomethyl) -5-fluoro-2 - [(4-fluorophenyl) thio] -1-benzothiophene

In a 250 ml flask, 2.5 g of 5-fluoro-2 - [(4-fluorophenyl) thio] -3-methyl-1-benzothiophene are dissolved in 100 ml of anhydrous carbon tetrachloride, then 1.6 g of N-bromosuccinimide and 0J g of benzoyl peroxide are added to the reaction medium which is then stirred for 4 hours under irradiation with a halogen lamp. At At the end of the reaction, the reaction mixture is cooled. The succinimide formed during the reaction is filtered and the carbon tetrachloride is evaporated under reduced pressure. The residue obtained is purified by chromatography on silica gel and the title product is recrystallized from acetonitrile. White powder.

Melting point: 114-116 ° C

Stage B: {5-Fluoro-2 - [(4-fluorophenyl) thio] -1-benzothien-3-yl} acetonitrile

0.49 g of potassium cyanide are reduced to powder and suspended in 20 ml of dimethyl sulfoxide. After 15 minutes of stirring, 1.4 g of the compound obtained in stage A are added slowly. The reaction mixture is left under stirring for 1 hour and then poured into water. The precipitate obtained is filtered and then recrystallized from a toluene / cyclohexane mixture (9.5 / 0.5) to yield the title product in the form of a white solid. Melting point: 127-129 ° C

Stage C: 2- {5-Fluoro-2 - [(4-fluorophenyl) thio] -1-benzothien-3-yl} ethylamine, hydrochloride

In a 50 ml bicol, 1 g of the compound obtained in stage B are dissolved in 10 ml of anhydrous THF and stirred. 9.45 ml of BH ₃ -THF complex are then added under a nitrogen atmosphere. After 3 hours of reflux, 2.63 ml of 6M hydrochloric acid are added dropwise. The reaction mixture is then left at reflux for 1 hour. It is then evaporated to dryness and taken up in diethyl ether. The precipitate obtained is drained and then recrystallized from a methanol / ethyl acetate mixture (9/1) to yield the title product in the form of a white powder. Melting point: 230-233 ° C

Stage D: N- (2- {5-Fluoro-2 - [(4-fluorophenyl) thio] -1-benzothien-3-yl} ethyl) cyclobutane carboxamide

0.5 g of the compound obtained in stage C are dissolved in an ethyl acetate / water mixture and then 0.51 g of potassium carbonate are added. The reaction mixture is cooled to by means of an ice bath and 0.25 g of cyclobutanoic acid chloride are added dropwise with magnetic stirring. After 2 hours of reaction, the two phases are separated. The organic phase is washed with a 1M hydrochloric acid solution, with a 10% potassium carbonate solution and then with water. It is then dried and evaporated to dryness and the residue obtained is recrystallized from toluene to yield the title product in the form of a white powder. Melting point: 157-160 ° C

Example 2: N- (2- (5-Fluoro-2 - [(4-fluorophéιιyl) thio1-l-benzothièn-3-yl} ethyl) propanamide

The procedure is carried out as in stage D of Example 1, replacing the chloride of cyclobutanoic acid with the chloride of propanoic acid. Recrystallization solvent: cyclohexane. White powder. Melting point: 141-144 ° C

Example 3: 2-Bromo-N- (2- {5-fluoro-2-f (4-fluorophéιιyl) thiol-l-beπzothièn-3- yl} eth yQacetamide

The procedure is carried out as in stage D of Example 1, replacing the chloride of cyclobutanoic acid with the chloride of bromoacetic acid. Recrystallization solvent: toluene / cyclohexane (2/1). White powder.

Melting point: 133-136 ° C

Example 4; N- (2- {5-Bromo-2 - [(4-bromophenyl) thiol-1-benzothien-3-yl | eth vDacetamide

Stage A: 5-Bromo-3- (bromomethyl) -2 - [(4-bromophenyl) thio] -1-benzothiophene

We proceed as in stage A of Example 1, replacing the 5-fluoro-2 - [(4- fluorophenyl) thio] -3-methyl-1-benzothiophene with 5-bromo-2 - [(4-fluorophenyl) thio] -3-methyl-1-benzothiophene.

Stage B: {5-Bromo-2 - [(4-bromophenyl) thio] -1-benzothien-3-yl} acetonitrile

The procedure is carried out as in stage B of Example 1 starting from the compound obtained in stage A.

Stage C: 2- {5-Bromo-2 - [(4-bromophenyl) thio] -1-benzothien-3-yl} ethylamine, hydrochloride

The procedure is carried out as in stage C of Example 1 starting from the compound obtained in stage B.

Stage D: N- (2- {5-Bromo-2 - [(4-bromophenyl) thio] -1-benzothien-3-yl} ethyl) acetamide

The procedure is carried out as in stage D of Example 1 starting from the compound obtained in stage C and replacing the chloride of cyclobutanoic acid by the chloride of acetic acid. Melting point: 158-160 ° C

PHARMACOLOGICAL STUDY

EXAMPLE A Study of acute toxicity

Acute toxicity was assessed after oral administration in groups of 8 mice (26 ± 2 grams). The animals were observed at regular intervals during the first day and daily during the two weeks following the 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 device consists of a plexiglass cylinder filled with water. Animals are tested individually during a 6 minute session. At the start of each test, the animal is placed in the center of the cylinder. The downtime is recorded. Each animal is judged immobile when it stops struggling, and remains on the surface of the water, immobile, only making the movements allowing it to keep the head above water.

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

EXAMPLE C:

1. Study of binding to the MTi and MT ₂ melatonin receptors

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

2- [ ¹²⁵ I] -iodomelatonin as a reference radioligand. The radioactivity retained is determined using a liquid scintillation counter.

Competitive binding experiments are then carried out in triplicate, with the different 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 (IC ₀ ).

2. Linkage study at the MT site. melatonin

The binding experiments on the MT ₃ sites are carried out on hamster brain membranes using 2- [ ^I25 I] iodomelatonin as radioligand. The membranes are incubated for 30 minutes with 2- [ ¹²⁵ I] iodomelatonin at a temperature of 4 ° C. and different concentrations of the compounds to be tested. After incubation, the membranes are quickly filtered and then washed with cold buffer using a filtration system. The fixed radioactivity is measured by a scintillation counter. The IC ₅₀ values (concentration inhibiting the specific binding by 50%) are calculated from the competition curves according to a non-linear regression model. Thus, the IC ₅₀ values found for the compounds of the invention attest to a bond for one or other of the melatoninergic binding sites, these values being <10 μM.

By way of example, the compound of Example 4 has an IC ₅₀ (MTi) of 8D0 ^"8 M and an IC ₅₀ (MT ₂ ) of 1D0 ^{" 9} M.

EXAMPLE D Study of the binding to 5-HT2T serotonergic receptors

The affinity of the compounds for the human 5-HT ₂ c receptor is evaluated on membrane preparations of CHO cells stably expressing this receptor. 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] Mesulergin (1 nM) and 25 fmol / ml of receiver. The non-specific binding is determined in the presence of 10 μM mianserin.

The reaction is stopped by adding 50 mM TRIS buffer, pH 7.4 followed by a filtration step and 3 successive rinses: the radioactivity linked to the membranes remaining on the filters (GF / B pretreated with PEI 0.1%) is counted in liquid scintillation.

The results obtained show that the compounds of the invention are affine for the 5-HT ₂ r receptor> In particular, the compound of Example 3 has a K, (5HT _2C ) of

100 nM.

EXAMPLE E; Action of the compounds of the invention on circadian rhythms of locomotor activity in rats

The involvement of melatonin in the training, by day / night alternation, of most physiological, biochemical and behavioral circadian 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 which represent a reliable marker of the activity of the endogenous circadian clock. 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

Male rats one month old are subjected as soon as they arrive at the laboratory to a light cycle of 12 hours of light per 24 hours (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 follow the nycthemeral (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 free flow (rhythm reflecting that of the endogenous clock) is clearly established, the rats receive a daily administration of the test molecule.

The observations are made by visualizing the activity rhythms:

- training of activity rhythms by the light rhythm,

- disappearance of the training of rhythms in permanent darkness,

- training through daily administration of the molecule; transient or lasting effect.

Software allows:

- to measure the duration and 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 (ultradians for example). Results

It is clear that the compounds of the invention make it possible to act powerfully on the circadian rhythm via the melatoninergic system.

EXAMPLE F: Test of light / dark cages

The compounds of the invention are tested in a behavioral model, the test of light / dark cages, which makes it possible to reveal the anxiolytic activity of the molecules.

The device consists of two polyvinyl boxes covered with Plexiglas. One of these boxes is obscure. A lamp is placed above the other box giving a light intensity in the center thereof of approximately 4000 lux. An opaque plastic tunnel separates the light 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 start of each test, the mouse is placed in the tunnel, facing the dark box. The time spent by the mouse in the lit 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 lighted cage as well as the number of transitions, which shows the anxiolytic activity of the derivatives of the invention.

EXAMPLE G Activity of the Compounds of the Invention on the Caudal Artery of the Rat

The compounds of the invention were tested in vitro on the rat caudal artery. Melatoninergic receptors are present on these vessels which makes them a significant pharmacological model for studying the activity of melatoninergic ligands. Stimulation of receptors can induce either vasoconstriction or vasodilation depending on the arterial segment studied. Protocol

1 month old rats are accustomed for 2 to 3 weeks to a 12h / 12h light / dark cycle.

After sacrifice, the caudal artery is isolated and maintained in a richly oxygenated environment. The arteries are then cannulated at both ends, suspended vertically in an organ chamber in an appropriate medium and perfused via their proximal end. Changes in pressure in the infusion rate allow the vasoconstrictor or vasodilator effect of the compounds to be assessed.

The activity of the compounds is evaluated on segments pre-contracted by phenylephrine (1 μM). A concentration-response curve is determined in a non-cumulative manner by adding a concentration of the compound studied on the pre-contracted segment. When the observed effect has reached equilibrium, the medium is changed and the preparation left 20 minutes before the addition of the same concentration of phenylephrine and a new concentration of the compound studied.

Results

The compounds of the invention significantly modify the diameter of the caudal arteries preconstructed by phenylephrine.

EXAMPLE H Pharmaceutical composition: Tablets

1000 tablets containing 5 mg of N- (2- {5-Bromo-2 - [(4-bromophenyl) thio] -1-benzothien-3- yl} ethyl) acetamide (Example 4 5 g

Wheat starch 20 g

Corn starch 20 g

Lactose 30 g

Magnesium stearate 2 g Silica 1 g

Hydroxypropylcellulose 2 g

Claims

1- Compounds of formula (I):

in which :

* R ¹ represents a halogen atom, an alkyl group (Cι-C ₆ ) linear or branched, or an alkoxy group (Cι-C ₆ ) linear or branched,. R represents a phenyl group unsubstituted or substituted with one to three groups selected from hydroxy, alkyl _(Cι-C6) straight or branched alkoxy _(Cι-C6) linear or branched, carboxy, formyl, nitro, cyano, polyhaloalkyl ( Cι-C ₆ ) linear or branched and halogen atoms,. R represents an unsubstituted or substituted linear or branched (Cι-C ₆ ) alkyl (Cι-C ₆ ), unsubstituted or substituted linear or branched alkenyl (Cι-C ₆ ), cycloalkyl (C ₃ -C ₈ ), or cycloalkyl (C ₃ -C ₈ ) alkyl (Cι-C ₆ ), the alkyl part of which may be linear or branched, it being understood that:

2- Compounds of formula (I) according to claim 1 for which R represents a halogen atom, their enantiomers and diastereoisomers as well as their addition salts with a pharmaceutically acceptable acid or base. 3- Compounds of formula (I) according to claim 1 for which R ² represents a phenyl group substituted by a halogen atom, their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base.

4- Compounds of formula (I) according to claim 1 for which R ³ represents an alkyl group, their enantiomers and diastereoisomers, as well as their addition salts with an acid or a pharmaceutically acceptable base.

5- Compounds of formula (I) according to claim 1 for which R ³ represents an alkyl group substituted by a halogen atom, their enantiomers and diastereoisomers, as well as their addition salts with an acid or a pharmaceutically acceptable base.

6- Compound of formula (I) according to claim 1 which is N- (2- {5-bromo-2 - [(4-bromophenyl) thio] -1-benzothien-3-yl} ethyl) acetamide, its enantiomers as well as its addition salts with a pharmaceutically acceptable acid or base.

7- Compound of formula (I) according to claim 1 which is 2-bromo-N- (2- {5-fluoro-2-

[(4-fluorophenyl) thio] -1-benzothien-3-yl} ethyl) acetamide, its enantiomers and its addition salts with a pharmaceutically acceptable acid or base.

8- Compound of formula (I) according to claim 1 which is N- (2- {5-fluoro-2 - [(4-fluorophenyl) thio] -1-benzothien-3-yl} ethyl) cyclobutanecarboxamide, its enantiomers as well as its addition salts with a pharmaceutically acceptable acid or base.

9- Compound of formula (I) according to claim 1 which is N- (2- {5-fluoro-2 - [(4-fluorophenyl) thio] -1-benzothien-3-yl} ethyl) propanamide, its enantiomers as well as its addition salts with a pharmaceutically acceptable acid or base. 10- Process for preparing the compounds of formula (I) according to claim 1 characterized in that the compound of formula (II) is used as starting material:

1? in which R and R are defined as above, which is subjected to the action of a reducing agent such as BH to yield the compound of formula (IV):

in which R ¹ and R ² are as defined above, on which the acid chloride of formula R ³ COCl is condensed in which R ³ is as defined in formula (I) or the corresponding symmetrical anhydride, to lead to the compound of formula (I):

in which R .1, r R> 2 e „t, r R3 are as defined above,

which can be purified according to a conventional separation technique, which is converted, if desired, into its addition salts with an acid or a pharmaceutically acceptable base and from which the isomers are optionally separated according to a conventional separation technique . 11- Pharmaceutical compositions containing at least one compound of formula (I) according to any one of claims 1 to 9 or one of their addition salts with a pharmaceutically acceptable acid or base in combination with one or more pharmaceutically acceptable excipients.

12- Pharmaceutical compositions according to claim 11 useful for the manufacture of medicaments for treating disorders of the melatoninergic system.

13- Pharmaceutical compositions according to claim 11 useful for the manufacture of medicaments for the treatment of sleep disorders, stress, anxiety, major depression or seasonal depressions, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jetlag, 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, disorders of the cerebral circulation, as well as in sexual dysfunctions , as ovulation inhibitors, immunomodulators and in the treatment of cancer.