CA2309771C - New substitute dimeric derivatives, their preparation process and the pharmaceutical compositions that contain them - Google Patents

Abstract

The invention relates to novel compounds of formula (I) (see formula I) in which A represents a group of formula (see formula II, III, IV) in which Q represents a sulfur or oxygen atom, R1 R 2 and R 3, which may be identical or different, represent a hydrogen atom or a group R a, where R a represents an alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, polyhaloalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl or heteroarylalkyl group, or heteroarylalkenyl, or R2 and R3 form, with the nitrogen atom which carries them, a group chosen from piperazinyl, piperidinyl and pyrrolidinyl; B represents a group of formula (see formula V, VI, VII, VIII, IX) or -NR2R3, wherein Q, R1, R2 and R3 are as previously defined; G1 and G3, which may be identical or different, represent an alkylene chain containing from 1 to 4 carbons; Cy and Cy ', different, represent (i) a cyclic structure of formula (II) (see formula X) in which X and Y, identical or different, represent a sulfur, oxygen or carbon atom, or a group CH or CH 2, R 4 represents a hydrogen or halogen atom or a group CF 3, hydroxy, carboxy, formyl, amino, NHR a, NR a R 1a, NHCOR a, CONHR a, R a, ORa, COR a or COOR a, where R a is as defined previously and R1a takes all the values of R a, the representation <IMG> means that the bonds are single or double, where G2 substitutes the benzene ring, and G1 substitutes the cycle containing X and Y in the case of Cy, and G2 substitutes the benzene ring and G3 substitutes the ring containing X and Y in the case of Cy ', or (ii) a cyclic structure of the formula (III) <IMG> in Z represents a sulfur or oxygen atom, or a group CH 2, NH, NSO 2 Ph or NR a, where R a is as defined above, D represents a cycl e ben zenic or pyridinic, R4 is as defined previously, the representation <IM G> means that the bond is single or double, it being understood that the valence of the atoms is respected, where G2 substitutes the cycle D, and G1 substitutes the cycle containing Z in the case of Cy, and G2 substitutes the cycle D and G3 substitutes the cycle containing Z in the case of Cy '; G 2 represents a chain of formula (IV): embedded image in which W 1, W 2 and W 3, which may be identical or different, represent a bond, an oxygen or sulfur atom, or a group CH 2, CHR a, NH or NR a where R a is as previously defined, n represents an integer such that 0.ltoreq. n .ltoreq. 6, and m represents an integer such that 0.ltoreq. m .ltoreq. 6, it being understood that one can not have two consecutive heteroatoms and that the chain of formula (IV) thus defined optionally comprises at least one unsaturation; and their enantiomers and diastereoisomers, as well as their addition salts with a pharmaceutically acceptable acid or base. The compounds according to the invention are useful as medicaments for the treatment of disorders related to the melatoninergic system.

Description

The present invention relates to novel substituted dimeric derivatives, their process of preparation and the pharmaceutical compositions containing them.
Dielectric structures in series are known in the prior art naphthalenic (J. Chem.
Soc., Dalton Trans., 1979, (10), pp. 1497-502) studied for their properties of coordination within metal complexes, or indole series for their activity Curare-like (Khim.-Farm, Zh., 1984, 18 (1), pp. 29-31). Otherwise, requests WO 9600720 and WO 9414771 describe mixed dimeric structures useful in as long as 5-HTl ligands or as synthetic intermediates respectively.
The compounds of the present invention, by their original structure, are new and lo have very interesting pharmacological properties concerning receivers melatoninergic.
Numerous studies have highlighted the last ten years the role capital of the melatonin (N-acetyl-5-methoxytryptamine) in many physiological phenomena.
as well as in circadian rhythm control. However, she has a half-life time quite low due to rapid metabolism. It is therefore very interesting to make available to the clinician analogues of the melatonin, metabolically more stable and having an agonist or antagonist, which can expect a therapeutic effect greater than that of the hormone itself.
In addition to their beneficial effect on circadian rhythm disorders (J.
Neurosurg. 1985, 63, 2o pp. 321-341) and sleep (Psychopharmacology, 1990, 100, pp. 222-226), the ligands of the melatoninergic system possess interesting pharmacological properties on the central nervous system, including anxiolytics and antipsychotics (Neuropharmacology of Pineal Secretions, 1990, 8 (3-4), pp. 264-272) and 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). Similarly, these compounds showed activity on some cancers (Melatonin - Clinical Perspectives, Oxford University Press, 1988, pp. 164-165), on ovulation (Science 1987, 227, pp. 714-720), on diabetes (Clinical Endocrinology, 1986, .. -2 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 via specific receptors of the melatonin. Molecular biology studies have shown the existence of several sub-receptor types that can bind this hormone (Trends Pharmacol Sci.
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 functions physiological properties of these receptors, it is of great interest to have ligands specific. In addition, such compounds, by interacting selectively with one or the other 1 o 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 previously mentioned.
The compounds of the present invention in addition to their novelty, show a very strong affinity for melatonin receptors and / or selectivity for one either of the melatoninergic receptor subtypes.
The present invention relates more particularly to compounds of formula (I) AG ~ -Cy-G2-Cy'-G3-B (I) in which A represents a group of formula -NR1C-R2, -NR1 i -NR2R3 or -NR2R3 in which: IQI QQ
Q represents a sulfur or oxygen atom, - R1, R2, R3, identical or different, represent a hydrogen atom or a Ra group (where Ra represents a linear (C -C -C) alkyl group or branched unsubstituted or substituted, linear or branched (C2-C6) alkenyl substituted or substituted, unsubstituted linear or branched (C2-C6) alkynyl or substituted, unsubstituted or substituted cycloalkyl (C3-C8) cycloalkylalkyl (C3-Cg) linear or branched unsubstituted or substituted, polyhaloalkyl (C, -C6) linear or branched, aryl, aryl (C -C) alkyl linear or branched, linear or branched (C2-C6) arylalkenyl, heteroaryl, heteroarylalkyl (Cl-C6) linear or branched or linear or branched (C2-C6) heteroarylalkenyl), or the groups R2 and R3 can also form, with the nitrogen atom which carries them a group chosen from piperazinyl, piperidinyl, or pyrrolidinyl, B represents a group of formula -NR1 i -R2, -NR1 i -NR2R3, -i-NR2R3, -i-OR ', QQQQ
-NR1C-OR2 or -NR2R3 in which Q, R1, R2 and R3 are as defined Q
previously, G ~ and G3, identical or different, represent an alkylene chain containing from 1 to 4 linear or branched carbons optionally substituted by one or more groups, identical or different, chosen from hydroxy, carboxy, formyl, Ra, ORa, COORa or CORa (where Ra is as defined previously), Cy and Cy ', different, represent a cyclic structure of formula (II) X
''; R4 (II) wY
in which 2o * X and Y, identical or different, represent a sulfur atom, oxygen or carbon, or a group CH or CH2, * R4 represents a hydrogen or halogen atom or a group CF3, hydroxy, carboxy, formyl, amino, NHRa, NRaR-a, NHCORa, CONHRa, Ra, ORa, CORa or COORa, (where Ra is as defined previously and Rla can take all the values of Ra), s * representation - means that the links are single or double, it being understood that the valency of the atoms is respected, where G2 substitutes the benzene ring, and G ~ substitutes the ring containing X and Y
in the case of Cy and G2 substitutes the benzene ring and G3 substitutes the ring containing X and Y
to in the case of Cy ', or a cyclic structure of formula (III) D ~ R4 (III) Z
in which Z represents a sulfur or oxygen atom, or a CH 2 group, NH, NSO2Ph or NRa (where Ra is as previously defined), D represents a benzene or pyridine ring, * R4 is as defined previously, * representation - means that the connection is single or double, being understood that the valence of the atoms is respected, Where G2 substitutes the cycle D, and G1 substitutes the cycle containing Z in the Cy's case and GZ substitutes the cycle D and G3 substitutes the cycle containing Z in the Cy 'case, the two Cy and Cy 'cycles of compounds of formula (I), different, being represented both by a structure of formula (II), both by a structure of formula (III), or one by a structure of formula (II) and the other by a structure of formula (III), G2 represents a chain of formula (IV) W
'~ (CH2) n WZ ~ (CH2) m W3 ~ (IV) in which - W1, W2 and W3, identical or different, represent a bond, an atom of oxygen or sulfur, or a group CH2, CHRa, NH or NRa (where Ra is as defined above), n represents an integer such that 0 <n <- 6, m represents an integer such that 0 S m S 6, it being understood that one can not have two consecutive heteroatoms and that the chain of formula (IV) thus defined may comprise one or more unsaturated, Being heard that - "aryl" means naphthyl, phenyl and biphenyl groups, - "heteroaryl" means any mono or bicyclic group, saturated or 2o unsaturated containing 5 to 10 members and containing 1 to 3 selected heteroatoms from nitrogen, sulfur or oxygen, "aryl" and "heteroaryl" groups which may be substituted by a or several radicals, identical or different, selected from hydroxy, carboxy, linear or branched (C1-C6) alkoxy, linear or branched (C1-C6) alkyl, linear or branched polyhaloalkyl (C1-C6), formyl, cyano, nitro, amino, linear or branched alkyl (C 1 -C 6) alkyl, linear (C 1 -C 6) dialkylamino or branched or halogen atoms, - the term "substituted" for the expressions "alkyl", "alkenyl", and "Alkynyl" means that these groups are substituted by one or more radicals, identical or different, selected from hydroxy, (C1-C6) alkoxy linear or branched, linear or branched polyhaloalkyl (C1-C6), amino, linear or branched (C1-C6) alkylamino, linear (C1-C6) dialkylamino or branched or halogen atoms, - the term "substituted" in the expressions "cycloalkyl" and "Cycloalkylalkyl" means that the cyclic portion of these groups is substituted by one or more radicals, identical or different, chosen among hydroxy, linear or branched (C 1 -C 6) alkoxy, polyhaloalkyl (C 1 -C 6) linear or branched, amino, linear or branched (C 1 -C 6) alkylamino, dialkylamino (C ~ -C6) linear or branched or halogen atoms, their enantiomers and diastereoisomers, as well as their addition salts to a acid or a 2o pharmaceutically acceptable base.
Among the pharmaceutically acceptable acids, mention may be made limiting hydrochloric acid, hydrobromic acid, sulfuric acid, phosphonic acid, acetic acid, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulfonic, camphoric, etc.
Among the pharmaceutically acceptable bases, mention may be made limited sodium hydroxide, potassium hydroxide, triethylamine, tertbutylamine, etc.

The preferred compounds of the invention are the compounds of formula (I) for which Cy and Cy ', different, represent a cyclic structure of formula (II) as the naphthalene, tetrahydronaphthalene, 1,4-benzodioxine or chroman nuclei by example, Cy and Cy ', different, represent a cyclic structure of formula (III) as indole, azaindole, benzothiophene or benzofuran, for example, Cy represents a cyclic structure of formula (II) and Cy 'represents a structure cyclic formula (III).
Advantageously, the invention relates to the compounds of formula (I) for which G2 lo represents a single bond, or a group -W4- (CH2) P-W'4- (where W4 and W'4, identical or different, represent an oxygen or sulfur atom, or an NH or NRa group, and p represents an integer such that 1 S p <12) such as for example the group -O- (CH 2) pO- (where p is such than previously defined), or a group of formula -W4- (CH2) P>-W'4- (CH2) p.> - W "a- (where W4, W'4, and W" 4, identical or different, represent an oxygen or sulfur atom, or a group NH or NRa, and p 'and p "are two integers such that 2 <- p' + p"<12) as per example the group -O- (CH2) P ~ -O- (CH2) P "-O- (where p 'and p" are as defined) previously).
The preferred substituents A and B of the invention are the groups NR ~ C (Q) R 2, NR1C (Q) NR2R3 or C (Q) NR2R3 and more particularly NR1COR2 groups or CONR2R3.
Even more particularly, the invention relates to the compounds of formula (I) which are N (2- {7- [2 - ({3- [2- (acetylamino) ethyl) -1-benzofuran-5-yl} oxy) ethoxy] -1-naphthyl}
ethyl) acetamide, N (2- {5- [2- ({8- [2- (acetylamino) ethyl) -2-naphthyl} oxy) ethoxy) -1-benzofuran-3-yl} ethyl) -2-furamide, N (2- {5- [2- ({8- [2- (acetylamino) ethyl) -2-naphthyl} oxy) ethoxy) -IH
pyrrolo [2, 3-b) pyridin-3-yl} ethyl) cyclopropanecarboxamide, _boy Wut_ N (2- {7- [3- ({3- [2- (acetylamino) ethyl] -1-benzothiophen-5-yl}
oxy) propoxy] -I -naphthyl} ethyl) acetamide, N [2- (5 - {[6 - ({8- [2- (acetylamino) ethyl] -2-naphthyl} oxy) hexyl] oxy} -IH
pyrrolo [2,3-b] pyridin-3-yl) ethyl) acetamide N (2- {7- [4 - ({3- [2- (acetylamino) ethyl) -1-benzofuran-5-yl} oxy} butoxy] -1-naphthyl}
ethyl) acetamide, N {2- [5- [4 - ({8- [2- (acetylamino) ethyl] -2-naphthyl} oxy) butoxy] -1-(Phenylsulfonyl) -1H indol-3-yl] ethyl} acetamide, N (2- {7- [4 - ({8- [2- (acetylamino) ethyl] -2-naphthyl} oxy) butoxy] -1,2,3,4-tetrahydro-1-naphthalenyl) ethyl) acetamide, N (2- {5- [4 - ({3- [2- (acetylamino) ethyl] -3a, 7a-dihydro-1-benzofuran-5-yl} oxy) butoxy] -IH indol-3-yl} ethyl) acetamide, N (2- {7- [4 - ({3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy) -1-naphthyl}
ethyl) acetamide, N (2- {5- [4 - ({3- [2- (acetylamino) ethyl) -1-benzothien-5-yl} oxy) butoxy] -1H
indol-3-yl} ethyl) acetamide, N (2- {5- [4 - ({3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} oxy} butoxy] -IH
pyrrolo [2,3-b] pyridin-3-yl} ethyl) acetamide, N (2- {5- [4 - ({3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy] -1H
pyrrolo [2,3-b) pyridin-3-yl} ethyl) acetamide, N (2- {5- [4 - ({3- [2- (acetylamino) ethyl) -1H-indol-5-yl} oxy) butoxy] -1H
pyrrolo [2,3-b) pyridin-3-yl} ethyl) acetamide, N [2- (7- {3- [2- (acetylamino) ethyl) -1-benzofuran-5-yl} -1-naphthyl) ethyl) acetamide, N [3- (5- {8- [2- (acetylamino) ethyl] -2-naphthyl} -1H pyrrolo [2,3-b] pyridin-3-yl) propyl] heptananlide, N [2- (7- {3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} -1-naphthyl) ethyl] acetamide, N [2- (5- {8- [2- (acetylamino) ethyl] -2-naphthyl} -1H pyrrolo [2,3-b] pyridin-3-yl) ethyl] acetamide, N [2- (5- {3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} -1-benzothien-3-yl) ethyl]
acetamide, N [2- (5- {3- [2- (acetylamino) ethyl) -1-benzofuran-5-yl} -1H indol-3-yl) ethyl]
acetamide, N [2- (5- {3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} -1H-pyrrolo b] pyridin-3-yl) ethyl] acetamide, N [2- (5- {3- [2- (acetylamino) ethyl] -1H-indol-5-yl} -1H pyrrolo [2,3-b] pyridin yl) ethyl] acetamide, N [2- (5- {3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} -1H pyrrolo [2,3-diol]
b] pyridin-3-yl) ethyl] acetamide.
Enantiomers, diastereoisomers and addition salts with an acid or a base pharmaceutically acceptable compounds of the invention are integral of the invention.
The present invention also relates to the process for the preparation of composed of formula (I), characterized in that the starting material used is composed of formula (V) AG ~ -Cy-OMe (V) in which A, Gi and Cy are as defined in formula (I), that is subjected to demethylation using conventional agents such as HBr, A1C13, AlBr3, BBr3 or Lewis acid / nucleophilic binary systems as A1C13 / PhCH2SH or BBr3 / Me2S for example, to obtain the compound of formula (VI) A-Gi-Cy-OH (VI) in which A, Gl and Cy are defined as above, ~ which is transformed, in a classical way, by the action of N, N sodium dimethylthiocarbamate, for example, in thiol corresponding formula (VII) AG, -Cy-SH (VII) wherein A, G, and Cy are as previously defined, or corresponding amino derivative of formula (VIII) AG, -Cy-NHR'a (VIII) in which A, G, and Cy are defined as above and R'a can take all the values of Ra as defined in formula (I) and can also represent a hydrogen atom, compounds of formula (VI), (VII) and (VIII) representing the compound of formula (IX) io A_Gl_Cy_W4H (IX) wherein W4 represents an oxygen or sulfur atom, or a group NH
or NRa (where Ra is defined as above), compound of formula (IX) on which is condensed a compound of formula (X) H ~~ (CH2) "~ WZ (CH2) m ~ OH (X) in which Hal represents a bromine, chlorine or iodine atom, and n, W2 and M
are as defined in formula (I), (it being understood that one can not to have two consecutive hetero atoms and that the chain thus defined may include one or more many unsaturations), ~ or a compound of formula (XI) Hal ~ (CHZ) n \ W ~ (CHZ) m_ ~ COOAIk (XI)

two in which Hal, n, m and W2 are defined as above and Alk represents a alkyl radical (it being understood that one can not have two heteroatoms consecutive and that the chain thus defined possibly comprises at least one unsaturated) followed by a reduction, to yield the compound of formula (XII) AG ~ -Cy-W4- (CH2) n -WZ- (CH2) n; OH (XII) wherein A, G1, Cy, W4, n, m and W2 are defined as before (being lo understood that one can not have two consecutive heteroatoms in the web -Wa- (CHZ) n-WZ- (CHz) m OH and that the chain thus defined possibly comprises at less unsaturation), whose hydroxyl function is conventionally transformed into a leaving group like example by action of a mesylate, a tosylate, or a halogenated derivative, for drive 1s to the compound of formula (XII ') A-G1-Cy-W4- (CH2) "- W2- (CH2) m E (XII ') in which A, G ,, Cy, W4, n, W2 and m are defined as above and E
represents a mesyl or tosyl group or a halogen atom, on which a compound of formula (XIII) is made to act 2o B-G3-Cy'-W'4H (XIII) in which B, G3 and Cy 'are defined as in formula (I) and W'4 can take the same values as W4 defined previously, to give the compound of formula (I / a), a particular case of the compounds of formula (I) A-G1-CY-W4- (CH2) n-W2- (CH2) m -W'4-CY'-G3-B (I / a) wherein A, G1, Cy, Cy ', W4, n, W2, m, W'4, G3 and B are as defined previously, or converted using, for example, phenyl bis (trifluoromethane) sulfonimide) basic medium of corresponding trifluoromethanesulfonate of formula (XIV) 1 o A-GI-Cy-OS02CF3 (XIV) in which A, Gl and Cy are defined as above, - on which is made to act, under conditions of catalysis by a derivative of palladium, a derivative of boric acid (RbB (OH) 2) or a derivative of tin (RbSnBu3) (where Rb represents a group of formula (XV) B-G3-Cy'-W3- (CH2) m -W2- (CH2) n-CH2- (XV) wherein B, G3, Cy ', W3, m, WZ and n are as previously defined, it being understood that one can not have two consecutive heteroatoms in the sequence -W3- (CH2) m-W2- and that the chain thus defined may comprise one or more unsaturations), 2o to give the compound of formula (I / b), a particular case of the compounds of formula (I) AG ~ -Cy-CH2- (CH2) n-W2- (CH2) m -Ws-Cy'-G3-B (I / b) wherein A, G, Cy, Cy ', n, WZ, m, W3, G3 and B are defined as previously (with the understanding that one can not have two heteroatoms consecutive sequences in the sequence -W2- (CH2) m-W3- and that the defined string may have one or more unsaturations), compounds of formula (I / c), a particular case of compounds of formula (I) A-Gl-Cy-W, - (CH2) "- W2- (CH2) m -CH2-Cy'-G3-B (I / c) wherein A, G1, Cy, Cy ', W ,, n, W2, m, G3 and B are defined as previously (with the understanding that one can not have two heteroatoms 1o consecutively in the sequence -W ~ - (CH2) "- W2- and that the chain thus defined may have one or more unsaturations), being obtained according to a similar procedure from the compound of formula (XIV ') B-G3-Cy'-OSO2CF3 (XIV ') in which B, G3 and Cy 'are as defined previously, - or that one places, under coupling conditions using derivatives of Nickel or palladium for example, in the presence of a compound of formula (XIV ') to give the compound of formula (I / d), a particular case of compounds of formula (I) 2o AG, -Cy-Cy'-G3-B (I / d) in which A, G 1, Cy, Cy ', G 3 and B are as previously defined, all the compounds (I / a) to (I / d) forming the compound of formula (I) which may be purified if desired by a conventional purification technique, which separate optionally the isomers according to a conventional separation technique and that one converts, where appropriate, into their addition salts with an acid or a base pharmaceutically acceptable.
The compounds of formula (V) are easily accessible to those skilled in the art according to methods described in the literature.
The compounds of the invention and the pharmaceutical compositions containing them prove be useful for the manufacture of a medicament for the treatment of disorders of the 1 o melatoninergic system.
The pharmacological study of the derivatives of the invention has in fact shown that they were are atoxic, endowed with a high affinity for melatonin receptors and had important activities on the central nervous system as well as on the microcirculation which make it possible to establish that the products of the invention are useful in the stress treatment, sleep disorders, anxiety, seasonal depression, pathologies cardiovascular diseases, digestive system pathologies, insomnia and fatigue due to time differences, schizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders related to normal or pathological aging, migraine, losses of memory, Alzheimer's disease, as well as in disorders of the cerebral circulation.
In another area of activity, it appears that in treatment, the products of the invention can be used in sexual dysfunctions, whether they possess 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 treatments of depressions seasonal disorders, sleep disorders, cardiovascular pathologies, insomnia and fatigue due to time differences, appetite disorders and obesity.

For example, the compounds will be used in the treatment of depressions seasonal 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 especially those suitable for oral administration, parenteral, nasal, per. transcutaneous, rectal, perlingual, ocular or respiratory especially single tablets or sugar-coated tablets, sublingual tablets, sachets, packages, lo capsules, glossettes, tablets, suppositories, creams, ointments, gels dermal, and drinkable or injectable ampoules.
The dosage varies according to the sex, age and weight of the patient, the route administration, the nature of the therapeutic indication, or possible treatments associates and ranges from 0.01 mg to 1 g per 24 hours in one or more doses.
The following examples illustrate the invention and do not limit it to any way. The following preparations lead to compounds of the invention or to intermediaries synthesis useful in the preparation of the invention.
Preparation 1: N [2- (7-Hydroxy-1-naphthyl) ethyl] acetamide Under an inert atmosphere, 27.5 mmol of the tribromide complex boron / dimethylsulfide are 2o dissolved in 100 ml of dichloromethane and stirred for 15 minutes at temperature room. A solution of 13.7 mmol of N [2- (7-methoxy-1) naphthyl) ethylacetamide in 50 ml of dichloromethane is added, and the reaction medium is brought to reflux during 30 hours. After cooling, the reaction is hydrolysed with caution and the dichloromethane is evaporated. The medium is then extracted with ethyl acetate, the phases organic compounds are washed with an aqueous solution of sodium bicarbonate 1M potassium. The organic phase is dried over magnesium sulphate and concentrated to lead to the title compound. White solid.
Melting point: 125-126 ° C
By proceeding as in Preparation 1 from the appropriate substrate, gets the Preparations 2 to 35 Preparation 2: N [2- (5-Hydroxy-1-benzofuran-3-yl) ethyl] acetamide Preparation 3: N [2- (5-Hydroxy-1-benzofuran-3-yl) ethyl] cyclopropane carboxamide Preparation 4: N [2- (5-Hydroxy-1-benzofuran-3-yl) ethyl] -2-furamide Preparation 5: N [2- (7-Hydroxy-1-naphthyl) ethyl] benzamide Preparation 6: N [2- (7-Hydroxy-1-naphthyl) ethyl] -3-butenamide Preparation 7: N [2- (5-Hydroxy-1-benzofuran-3-yl) ethyl] -2-methylpropanamide Preparation 8: N [2- (7-Hydroxy-1-naphthyl) ethyl] -2-phenylacetamide Preparation 9: N [2- (5-Hydroxy-1-benzothiophen-3-yl) ethyl] acetamide Preparation 10: N [2- (5-Hydroxy-1H pyrrolo [2,3-b] pyridin-3-yl) ethyl] cyclopropane ts carboxamide Preparation 11: N [2- (5-Hydroxy-1H-indol-3-yl) ethyl] acetamide Preparation 12: N [2- (5-Hydroxy-1H-pyrrolo [2,3-b] pyridin-3-yl) ethyl] acetamide Preparation 13: N [2- (7-Hydroxy-1-naphthyl) ethyl] cyclobutane carboxamide Preparation 14: 2,2,2-Trifluoro-N [2- (7-hydroxy-1-naphthyl) ethyl] acetamide Preparation 15: N - [(6-Hydroxy-2H-chromen-3-yl) methyl] butanamide Preparation 16: N [(6-Hydroxy-2H-chromen-3-yl) methyl] acetamide Preparation 17: N - [(7-Hydroxy-1,4-benzodioxin-2-yl) methyl] -N'-propylurea Preparation 18: N - ((7-Hydroxy-1,4-benzodioxin-2-yl) methyl] acetamide Preparation 19: N (2- (7-Hydroxy-1-naphthyl) ethyl] furamide Preparation 20: N (2- (2-Benzyl-5-hydroxy-1H pyrrolo [2,3-b] pyridin-3-yl) ethyl] acetamide Preparation 21: N [2- (5-Hydroxy-1-benzothiophen-3-yl) ethyl] cyclohexane carboxamide Preparation 22: N Hexyl-2- (5-hydroxy-1-benzofuran-3-yl) acetamide Preparation 23: 2,2,2-Trifluoro-N [2- (5-hydroxy-1-benzothiophen-3-yl) ethyl]
acetamide Preparation 24: N [2- (6-Hydroxy-3,4-dihydro-2H-chromen-4-yl) ethyl] acetamide Preparation 25: N [2- (7-Hydroxy-1,2,3,4-tetrahydro-1-naphthalenyl) ethyl] acetamide Preparation 26: N [2- (7-Hydroxy-1,2,3,4-tetrahydro-1-naphthalenyl) ethyl]
cyclopropane carboxamide Preparation 27: N [2- (7-Hydroxy-1-naphthyl) ethyl] heptanamide Preparation 28: N [2- (5-Hydroxy-1H-indol-3-yl) ethyl] cyclobutane carboxamide Preparation 29: 4- (7-Hydroxy-1-naphthyl) -N isopropylbutanamide Preparation 30: N (2- (5-Hydroxy-1-benzofuran-3-yl) ethyl] -N'-phenylurea Preparation 31: N Benzyl-2- (5-hydroxy-1-benzothiophen-3-yl) acetamide Preparation 32: N [2- (5-Hydroxy-1H-inden-3-yl) ethyl] pentanamide Preparation 33: 3- (5-Hydroxy-1-benzofuran-3-yl) -N methylpropanamide Preparation 34: N [2- (5-Hydroxy-1H-pyrrolo [2,3-b] pyridin-3-yl) ethyl] N-methylurea Preparation 35: 4- (5-Hydroxy-1H-indol-3-yl) -N-methylbutanamide Preparation 36: N [2- (5-Mercapto-1-benzofuran-3-yl) ethyl] acetamide To a solution of potassium hydroxide (10 mmol) dissolved in 15 ml of water and 16 ml of tetrahydrofuran, the product obtained in Step A (9 mmol) is added to now agitation. The solution is cooled with an ice bath and ice and we add drop dropwise dimethylthiocarbamoyl chloride (9 mmol) in solution in the tetrahydrofuran (15 ml) with stirring. After half an hour of agitation while holding the cold, the middle The reaction is extracted with chloroform. The organic phases are grouped, dried on magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken in diphenyl ether (10 ml) and refluxed for one hour under atmosphere nitrogen. The diphenyl ether is evaporated under reduced pressure until a 2o solution of about 2 ml. The 2 ml of still hot distillate are poured with caution in 50 ml of hexane to give after cooling a solid isolated by filtration. The solid thus collected is added to a solution of potassium hydroxide (380 mg) dissolved in a water / methanol mixture (1 ml / 10 ml). The solution is brought to reflux for 12 hours then cooled and concentrated under reduced pressure. The residue is taken with 20 ml of chloroform and extracted 3 times with water. The organic phase is dried on magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica gel to yield the title product.
Preparation 37: N [2- (5-Mercapto-1-benzothiophen-3-yl) ethyl] butanamide Step A: N- ~ 2- (5-Hydroxy-1-benzothiophen-3-yl) ethyl] butanamide The procedure is as in Preparation 1 starting from N [2- (5-Methoxy-1) benzothiophen-3-yl) ethyl] butanamide.
Stage B: N- ~ 2- (5-Mercapto-1-benzothiophen-3-yl) ethyl] butanamide The procedure is as in Preparation 36 starting from the compound obtained at the stage AT.
Preparation 38: N (2- {5-Mercapto-2- [4- (trifluoromethyl) benzyl] -1-benzothiophèn-

3-yl} ethyl) acetamide Tade A: N- (2- ~ 5-Hydroxy-2- (4- (trifluoromethyl) benzyl] -1-benzothiophen-3-yl) ethyl) acetamide The procedure is as in Preparation 1 starting from N (2- {5-Methoxy-2- [4-(trifluoromethyl) benzyl] -1-benzothiophen-3-yl} ethyl) acetamide.
Step B: N- (2- (5-Mercapto-2- (4- (trifluoromethyl) benzyl] -1-benzothiophen-3 yl) ethyl) acetamide The procedure is as in Preparation 36 from the compound obtained in Step A.

Preparation 39: N [2- (7-Mercapto-1,2,3,4-tetrahydro-1-naphthalenyl) ethyl) cyclopropane carboxamide The procedure is as in Preparation 36 starting from the compound obtained in Preparation 26.
Preparation 40: N [2- (5-Amino-1-benzofuran-3-yl) ethyl) acetamide Step A: N- ~ 2- (5-Bromo-1-benzofuran-3-yl) ethyl-acetamide In a 150 ml knit equipped with a dropping funnel, a refrigerant surmounted by a tube filled with calcium chloride, and a mechanical stirrer, the triphenylphosphine (10 mmol) and acetonitrile (70 ml). The solution is cooled using 1o an ice bath while maintaining the agitation and add the bromine (10 mmol). At the end addition, the ice bath is removed and the product obtained is added in the Preparation 2 (8 mmol) The reaction mixture is stirred at 60-70 ° C
until the disappearance of starting product. At the end of the reaction, the mixture is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate, washed with water then with a saturated solution of potassium hydrogencarbonate, and again to the water then dried on magnesium sulfate and concentrated under reduced pressure. The residue is filtered on gel silica to lead to the title product.
B: N- (2- (5-lodo-1-benzofuran-3-yl) ethyl] acetamide A mixture of the product obtained in Step A (2 mmol), potassium iodide (30 mmol) and 2o of copper iodide I (10 mmol) in hexamethylphosphoramide (6 ml) is heated to 150-160 ° C with agitation under nitrogen atmosphere until a conversion 90% is reached. Then dilute hydrochloric acid is added, followed by the ether and the The mixture is then filtered to remove the insoluble copper salts. The organic phase is separated, washed with sodium sulphite solution, water, dried over sulphate magnesium and evaporated to give a residue that is chromatographed on gel silica to lead to the product of the title.

Stage C: N- ~ 2- (S-vinyl-1-benzofuran-3-yl) ethyl-acetamide 15 mmol of the product obtained in stage B, 16 mmol of vinyl tributyltin and 0.43 mmol of (triphenylphosphine) palladium tetrakis, are stirred with 110 ° C during 3 hours in 30 ml of N methylpyrrolidinone. After evaporation of the solvent, residue is taken up in 20 ml of dichloromethane and treated with a 10% aqueous solution fluoride of potassium. After extraction, concentration under reduced pressure and chromatography on silica gel, the product of the pure title is obtained.
Stage D: N- ~ 2- (5-Formyl-1-benzofuran-3-yl) ethyl-acetamide To a solution of 10 mmol of the product obtained in Stage C in a mixture of 50 ml of 10 ml of dioxane and 25 ml of water are added at room temperature.
osmium tetroxide in 2-methyl-2-propanol, then 8.70 g of sodium Periodate. After stirring one night at room temperature, the suspension is filtered, the filtrate concentrated under reduced pressure.
The residue obtained is taken up in dichloromethane. The organic phase is washed with water, dried and evaporated. The residue is purified by gel chromatography of silica for lead to the product of the title.
Stage E: 3- [2- (acetylamino) ethyl] -1-benzofuran-5-carboxylic acid To a solution of 6.88 mmol of the product obtained in stage D in 30 ml acetone are added at room temperature 2.7 g of potassium permanganate in 50 ml a acetone / water mixture (50/50). The solution is stirred for 2 hours at room temperature ambient then 2o filtered. The filtrate is concentrated under reduced pressure and chromatographed on silica gel to lead to the product of the title.
Stage F: 3- [2- (acetylamino) ethyl] -1-benzofuran-3-acid chloride carboxylic 5 mmol of the product obtained in stage E are dissolved in 40 ml of chloride of thionyl. After stirring under an inert atmosphere for 1 hour, the chloride Thionyl is evaporated under reduced pressure to yield the title product.
Stage G: N- ~ 2- (5-Amino-1-benzofuran-3-yl) ethyl-acetamide A solution of the product obtained in stage F (20 mmol) in the dichloromethane (30 ml) containing tetrabutyl ammonium bromide (20 mg) is cooled in a bath of ice.
After addition of the sodium azide (25 mmol) dissolved in 5 ml of water the solution is stirred vigorously at 0 ° C for 2 hours. The organic phase is separated, washed water (2 x 5 ml) and dried over magnesium sulphate. After filtration, add the acid trifluoroacetic acid (30 mmol) and the solution is stirred under reflux for 60 minutes.
hours. After cooling, the organic phase is washed with a saturated solution sodium hydrogencarbonate (2 x 5 ml) and concentrated under reduced pressure.
The residue is then taken up in methanol (20 ml) and water (80 ml) is added and then carbonate of potassium (30 mmol). After stirring at room temperature for 20 hours, the middle The reaction mixture is concentrated under reduced pressure to a volume of 60 ml.
about then extracted 3 times with ether (3 x SO ml). After drying over sodium sulphate, the organic phase is filtered and then evaporated under reduced pressure. The residue is chromatographed on gel silica to lead to the title product.
Preparation 41: N [2- (5-Amino-1-benzothiophen-3-yl) ethyl] pentanamide Step A: N- ~ 2- (5-Hydroxy-1-benzothiophen-3-yl) ethyl] pentanamide 2o The procedure is as in Preparation 1 starting from N [2- (5-Methoxy-1) benzothiophen-3-yl) ethyl] pentanamide.
Step B: N- ~ 2- (5-Amino-1-benzothiophen-3-yl) ethyl] pentanamide The procedure is as in Preparation 40 from the compound obtained in Step A.

_ 23 _ Preparation 42: N {2- [5-Amino-2- (3-methoxybenzyl) -1-benzofuran-3-yl] ethyl}
acetamide Step A: N- ~ 2- ~ S-Hydroxy-2- (3-methoxybenzyl) -1-benzofuran-3-yl] ethyl ~
acetamide The procedure is as in Preparation 1 starting from N {2- [5-methoxy-2- (3-methoxybenzyl) -1-benzofuran-3-yl] ethyl} acetamide.
Stage B: N- (2- (5-Amino-2- (3-methoxybenzyl) -1-benzofuran-3-yl] ethyl ~
acetamide The procedure is as in Preparation 40 from the compound obtained in Step A.
Preparation 43: N [2- (5-Amino-1-benzofuran-3-yl) ethyl] -2-furamide The procedure is as in Preparation 40 starting from the compound obtained in Preparation 4.
Preparation 44: N [2- (5-Amino-1-benzofuran-3-yl) ethyl] N'-cyclopropylurea Step A: N- (2- (S-Hydroxy-1-benzofuran-3-yl) ethyl] N'-cyclopropylurea The procedure is as in Preparation 1 starting from N [2- (5-methoxy-1) benzofuran-3-yl) ethyl] -N'-cyclopropylurea Stage B: N- ~ 2- (5-Amino-1-benzofuran-3-yl) ethyl] N'-cyclopropylurea The procedure is as in Preparation 40 from the compound obtained in Step A.

Preparation 45: 3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl trifluoromethane sulfonate To a solution of 0.07 mol of the compound obtained in Preparation 2 in a liter of dichloromethane are added 60 ml of triethylamine. The reaction medium is increased to reflux until solubilization, then 0.1 mol of phenyl bis (trifluoromethanesulfonimide) and 0.75 mol of potassium carbonate are added. After 4 hours at reflux, the middle is washed with 1 liter of 1M sodium hydrogen carbonate and 1 liter of acid hydrochloric M. The organic phase is dried, concentrated and purified by chromatography on gel silica to lead to the title product.
Preparations 46 to 70 are obtained by proceeding as in Preparation 45.
Preparation 46: 8- [2- (Acetylamino) ethyl] -2-naphthyl trifluoromethanesulfonate Art Product: Preparation 1 Preparation 47: 3- {2 - [(Cyclopropylcarbonyl) amino] ethyl} -1-benzothiophen-5-yl trifluoromethanesulfonate Starting Material: N [2- (5-Hydroxy-1-benzothiophen-3 yl) ethyl] cyclopropanecarboxamide, obtained by proceeding as in Preparation 1 from N [2- (5-methoxy-1-benzothiophen-3-yl) ethyl] cyclopropane carboxamide.
Preparation 48: 8- (2 - {[(Methylamino) carbonyl] amino} ethyl) -2-naphthyl trifluoro-2o methanesulfonate Starting material: N [2- (7-Hydroxy-1-naphthyl) ethyl] -N'-methylurea obtained in proceeding as in Preparation 1 from N [2- (7-methoxy-1) naphthyl) ethyl] -N'-methylurea.

Preparation 49: 3- {2 - [(Anilinocarbonyl) amino] ethyl} -1-benzofuran-5-yl trifluoro-methanesulfonate Starting product: Preparation 30 Preparation 50: 3- [2- (2-Furoylamino) ethyl] -1-benzothiophen-5-yl trifluoromethane sulfonate Starting material: N [2- (5-Hydroxy-1-benzothiophen-3-yl) ethyl] -2-furamide, obtained in proceeding as in Preparation 1 from N [2- (5-methoxy-1) -benzothiophèn-3-yl) ethyl] -2-furamide.
Preparation 51: 3- [2- (Benzylamino) -2-oxoethyl] -1H-indol-5-yl trifluoromethane lo sulfonate Starting material: N Benzyl-2- (5-hydroxy-1H-indol-3-yl) acetamide, obtained in proce-as in Preparation 1 from N benzyl-2- (5-methoxy) 1H indol-3-yl) acetamide.
Preparation 52: 3- [3- (Benzoylamino) propyl] -1H-indol-5-yl trifluoromethane sulfonate Starting material: N [3- (5-Hydroxy-1H-indol-3-yl) propyl] benzamide, obtained in proce-as in Preparation 1 from N [3- (5-methoxy-1H) indol-3-yl) propyl] benzamide.
Preparation 53: 3- [2- (Isobutyrylamino) ethyl) -1-benzothiophen-5-yl 2o trifluoromethanesulfonate Starting material: N [2- (5-Hydroxy-1-benzothiophen-3-yl) ethyl] -2-methylpropanamide, obtained by proceeding as in Preparation 1 from N [2- (5-methoxy-1-benzothiophen-3-yl) ethyl] -2-methylpropanamide.

Preparation 54: 3- [2- (Heptanoylamino) ethyl] -1H pyrrolo [2,3-b] pyridin-5-yl trifluoromethanesulfonate Starting material: N [2- (5-Hydroxy-1H pyrrolo [2,3-b] pyridin-3-yl) ethyl] heptanamide, obtained by proceeding as in Preparation 1 from N [2- (5 1-methoxy-1H pyrrolo [2,3-b] pyridin-3-yl) ethyl] heptanamide.
Preparation 55: 3- [2- (Acetylamino) ethyl] -1H pyrrolo [2,3-b] pyridin-5-yl trifluoro-methanesulfonate Starting product: Preparation 12 Preparation 56: 3- [4- (Cyclopentylamino) -4-oxobutyl] -1-benzofuran-5-yl trifluoro-1 o methanesulfonate Starting material: N Cyclopentyl-4- (5-hydroxy-1-benzofuran-3-yl) butanamide, obtained in proceeding as in Preparation 1 from N cyclopentyl-4- (5-methoxy-1-benzofuran-3-yl) butanamide.
Preparation 57: 3- {2 - [(Cyclopropylcarbonyl) amino) ethyl} -1H pyrrolo [2,3-b]
Pyridin-5-yl trifluoromethanesulfonate Starting product: Preparation 10 Preparation 58: 3- (2 - {[(Allylamino) carbonyl) amino} ethyl) -1-benzothiophen-5-yl trifluoromethanesulfonate Starting material: N Allyl-N '- [2- (5-hydroxy-1-benzothiophen-3-yl) ethyl] urea, obtained 2o proceeding as in Preparation 1 from the N allyl-N'-[2- (5-Methoxy-1-benzothiophen-3-yl) ethyl] urea.

Preparation 59: 3 - [(Acetylamino) ethyl) -1,4-benzodioxin-6-yl trifluoromethane sulfonate Starting product: Preparation 18 Preparation 60: 3- [2- (Isobutyrylamino) ethyl) -1-benzofuran-5-yl trifluoromethane sulfonate Starting product: Preparation 7 Preparation 61: 4- {2 - [(2,2,2-Trifluoroacetyl) amino] ethyl} -3,4-dihydro-2H
chromèn-6-yl trifluoromethanesulfonate Starting material: 2,2,2-Trifluoro-N [2- (6-hydroxy-3,4-dihydro-2H chromene-4-yl) ethyl]
1o acetamide, obtained by proceeding as in Preparation 1 from 2,2,2-trifluoro-N [2- (6-methoxy-3,4-dihydro-2H-chromen-4-yl) ethyl] acetamide.
Preparation 62: 3- (4-Anilino-4-oxobutyl) -1-benzothiophen-5-yl trifluoromethane sulfonate Starting material: 4- (5-Hydroxy-1-benzothiophen-3-yl) -N phenylbutanamide, obtained in proceeding as in Preparation 1 from 4- (5-methoxy-1) benzothiophen-3-yl) -N phenylbutanamide.
Preparation 63: 3 - [(Acetylamino) methyl] -3,4-dihydro-2H-chromen-6-yl trifluoro-methanesulfonate 2o Starting material: N [(6-Hydroxy-3,4-dihydro-2H chromen-3-yl) methyl] acetamide, obtained by proceeding as in Preparation 1 from N [(6-methoxy-3,4-dihydro-2H-chromen-3-yl) methyl] acetamide.

Preparation 64: 3- [2- (Acetylamino) ethyl] -2- [4- (trifluoromethyl) benzyl] -1-benzofuran-5-yl trifluoromethanesulfonate Starting material: N (2- {5-Hydroxy-2- [4- (trifluoromethyl) benzyl] -1-benzofuran 3-yl} ethyl) acetamide, obtained by proceeding as in Preparation 1 from N (2- {5-methoxy-2- [4- (trifluoromethyl) benzyl] -1-benzofuran-3-ethyl) acetamide.
Preparation 65: 3- (2 - {[(Methylamino) carbonyl] amino} ethyl) -1H indol-5-yl trifluoromethanesulfonate Starting material: N [2- (5-Hydroxy-1H-indol-3-yl) ethyl] -N'-methylurea, obtained in 10 proceeding as in Preparation 1 from N [2- (5-methoxy-1H-indol-3-yl) ethyl] -N'-methylurea.
Preparation 66: 4- {2 - [(2,2-Dimethylpropanoyl) amino] ethyl} -3,4-dihydro-2H
chromen-6-yl trifluoromethanesulfonate Starting material: N [2- (6-Hydroxy-3,4-dihydro-2H-chromen-4-yl) ethyl] -2,2-dimethyl propanamide, obtained by proceeding as in Preparation 1 to from N [2- (6-methoxy-3,4-dihydro-2H-chromen-4-yl) ethyl] -2,2-dimethyl-propanamide.
Preparation 67: 3- [2- (Acetylamino) ethyl] -1H indol-5-yl trifluoromethanesulfonate Starting material: N acetylserotonin.
2o Preparation 68: 3 - {[((Cyclohexylcarbonyl) amino] methyl} -1,4-benzodioxin-6-yl trifluoromethanesulfonate Starting material: N [(7-Hydroxy-1,4-benzodioxin-2-yl) methyl] cyclohexane carboxamide, obtained by proceeding as in Preparation 1 from N [(7-methoxy-1,4-benzodioxin-2-yl) methyl] cyclohexane carboxamide.

Preparation 69: 3- [2- (Acetylamino) ethyl] -2- (3-methoxybenzyl) -1-benzothiophene yl trifluoromethanesulfonate Starting material: N {2- [5-Hydroxy-2- (3-methoxybenzyl) -1-benzothiophen-3-yl] ethyl}
acetamide, obtained by proceeding as in Preparation 1 from N {2- [5-methoxy-2- (3-methoxybenzyl) -1-benzothiophen-3-yl]
ethyl} acetamide.
Preparation 70: 3- [3- (Acetylamino) propyl] -1-benzofuran-5-yl trifluoromethane sulfonate Starting material: N [3- (5-Hydroxy-1-benzofuran-3-yl) propyl] acetamide, obtained in 1o proceeding as in Preparation 1 from N [3- (5-methoxy) 1-benzofuran-3-yl) propyl] acetamide.
Preparation 71: N {2- [5-Hydroxy-1- (phenylsulfonyl) -1H indol-3-yl] ethyl} acetamide Tade A: N- (2- [5-Methoxy-1- (phenylsulfonyl) -1H-indol-3-yl] ethyl] acetamide 5 g of melatonin are dissolved in 150 ml of dichloromethane and then 3.41 g of soda and 0.35 g of tetrabutylammonium hydrogen sulfate are added. The environment reaction is then cooled in an ice bath and 4.06 ml of Benzenesulfonyl are added drop by drop. After stirring overnight at room temperature, the excess of soda and the catalyst are filtered, the solvent is evaporated under vacuum and the solid got is recrystallized to yield the title product in the form of crystals white.
2o Melting point: 140-141 ° C
Stage B: N- (2- ~ 5-Hydroxy-1- (phenylsulfonyl) -1H-indol-3ylethyl) acetamide 5 g of the compound obtained in Stage A are dissolved in 100 ml of dichloromethane. The middle The reaction mixture is then cooled in an ice bath and 3.81 ml of boron tribromide are added drop by drop. After stirring for two hours at room temperature, the middle The reaction mixture is poured into 500 ml of water and ice. The precipitate formed is filtered, washed with water and dried in an oven at 50 ° C.
Melting point: 205-206 ° C
Preparation 72: 3- [2- (Acetylamino) ethyl] -1-benzothien-5-yl trifluoromethanesulfonate The procedure is as in Preparation 45 starting from the compound obtained in Preparation 9.
Example 1 N (2- {7 - [2 - ({3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} oxy) ethoxy] -1-naphthyl} ethyl) acetamide Stage A: N ~ 2- ~ 7- (2-Bromoethoxy) naphth-1-ylethyl) acetamide The compound obtained in Preparation 1 (0.009 mol) is dissolved in 20 ml of a mixed Dimethylsulfoxide (6 ml) and butanone (14 ml). 0.027 mol is added of carbonate of potassium and 0.036 mol of dibromoethane, followed by refluxing for 48 hours.
hours. The The reaction medium is then cooled and poured into water. The aqueous phase is extracted by Et20, then the organic phase is washed with water until neutrality of the waters of washing and then dried over magnesium sulphate and evaporated under reduced pressure. The residue got is purified by chromatography on silica gel (eluent: acetone / cyclohexane (2/8)) and recrystallized. White solid.
Melting point: 110-111 ° C
Elemental microanalysis CHN
2o Calculated: 57.15 5.40 4.17 Found: 57.28 5.38 3.91 Step B: N- (2- [2- [2- (2- [2- (acetylamino) ethyl] -1-benzofuran-5-yl] oxy) ethoxy]
I-naphtylJéthyl) acetamide In a 100 ml flask, 0.003 mol of the compound obtained is dissolved in the Preparation 2 and 0.003 mol of the compound obtained in Step A in a mixture consisting of 3 ml of dimethylsulfoxide and 20 ml of butanone. 0.009 mol of carbonate of potassium and a crystal of potassium iodide and heated to reflux for 12 hours. The environment The reaction is then cooled and poured into 100 ml of water. The precipitate formed is drained and recrystallized.
Example 2 N (2- {5- [2 - ({8- [2- (Acetylamino) ethyl] -2-naphthyl} oxy) ethoxy] -1-benzofuran-3-yl} ethyl) cyclopropanecarboxamide The procedure is as in Example 1, replacing in stage B the compound got in Preparation 2 with the compound obtained in Preparation 3.
Example 3 N (2- {5- [2 - ({8- [2- (Acetylamino) ethyl] -2-naphthyl} oxy) ethoxy] -1-benzofuran-3-yl} ethyl) -2-furamide The procedure is as in Example 1, replacing in Stage B the compound obtained in the Preparation 2 with the compound obtained in Preparation 4 Example 4 N (2- {7 - [2 - ({3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} thio) ethoxy] -1-naphthyl} ethyl) benzamide The procedure is as in Example 1, replacing in stage A, the compound obtained in Preparation 1 by the compound got in the Preparation 5, in stage B, the compound obtained in Preparation 2 by the compound got in the Preparation 36.

._ -32-Example 5: N (2- {7 - [2 - ({3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} amino) ethoxy] -1-naphthyl} ethyl) acetamide The procedure is as in Example 1, replacing in stage B the compound got in Preparation 2 by the compound obtained in Preparation 40.
Example 6: N (2- {7 - [2 - ({3- [2- (Isobutyrylamino) ethyl] -1-benzofuran-5-yl} oxy) ethoxy] -1-naphthyl} ethyl) -3-butenamide The procedure is as in Example 1, replacing in stage A, the compound obtained in Preparation 1 by the compound got in the Preparation 6, in stage B, the compound obtained in Preparation 2 by the compound got in the Preparation 7.
Example 7: N (2- {7 - [2 - ({3- [2- (Acetylamino) ethyl] -1-benzothiophen-5-yl} oxy) ethoxy] -1-naphthyl} ethyl) -2-phenylacetamide The procedure is as in Example 1, replacing in stage A, the compound obtained in Preparation 1 by the compound got in the Preparation 5, in stage B, the compound obtained in Preparation 2 by the compound got in the Preparation 9.
Example 8: N (2- {5- [2 - ({8- (2- (Acetylamino) ethyl] -2-naphthyl} oxy) ethoxy] -IH
Pyrrolo [2,3-b] pyridin-3-yl} ethyl) cyclopropanecarboxamide The procedure is as in Example 1, replacing in Step B the product obtained in Preparation 2 with the compound obtained in Preparation 10.

Example 9: N (2- {5- [2 - ({3- [2- (Acetylamino) ethyl] -3a, 7a-dihydro-1-benzofuran-5-yl} oxy) ethoxy] -1-benzothiophen-3-yl} ethyl) acetamide The procedure is as in Example 1, replacing in stage A, the compound obtained in Preparation 1 by the compound got in the Preparation 2, in stage B, the compound obtained in Preparation 2 by the compound got in the Preparation 9.
Example 10: N (2- {5- [2 - ({3- [2- (Acetylamino) ethyl] -1H-indol-5-yl} oxy) ethoxy]
3a, 7a-dihydro-1-benzofuran-3-yl} ethyl) -2-furamide The procedure is as in Example 1, replacing in stage A, the compound obtained in Preparation 1 by the compound got in the Preparation 4, in stage B, the compound obtained in Preparation 2 by the compound got in the Preparation 11.
Example 11: N (2- {5- [2 - ({3- [2- (Acetylamino) ethyl] -1H pyrrolo [2,3-b] pyridin-5-yl} oxy) ethoxy] -3a, 7a-dihydro-1-benzofuran-3-yl} ethyl) -2-methylpropanamide The procedure is as in Example 1, replacing in stage A, the compound obtained in Preparation 1 by the compound got in the Preparation 7, in stage B, the compound obtained in Preparation 2 by the compound got in the Preparation 12.
Example 12: N (2- {7- [3 - ({3- (2- (Acetylamino) ethyl] -1-benzothiophen-5-yl} oxy) propoxy] -1-naphthyl} ethyl) acetamide Step A: N (2- (7- (3-Hydroxypropyloxy) naphthyl) ethyl acetamide In a 100 ml flask, 0.022 mol of the compound obtained is dissolved in the Preparation 1 in 30 ml of dimethylformamide. 0.066 mol of potassium carbonate is added and 0.033 mol 3-bromopropan-1-ol, then the mixture is heated to 80 ° C.
for 4 hours.
The reaction medium is cooled and poured into 100 ml of a solution of HC1 1M. The sentence aqueous solution is extracted 3 times with Et 2 O then the organic phase is dried over MgS04 and evaporated under reduced pressure. The product of the title is obtained after recrystallization. Solid White.
Melting point: 141-142 ° C
Stage B: 3- (~ 8- ~ 2- (Acetylamino) ethyl] -2-naphthyl) oxy) propylmethanesulfonate In a 250 ml flask, the alcohol obtained in stage A is dissolved in 50 ml of dichloromethane and 0.012 mol of triethylamine are added. We cool in a bath of ice-salt at -10 ° C then 0.012 mol of mesyl chloride are added drip under magnetic stirring. The reaction medium is stirred at room temperature while

4 hours. 100 ml of water are then added, followed by extraction with CH2C12. The organic phase is washed with water, dried over MgSO 4 and evaporated under pressure scaled down.
The oil obtained is purified by chromatography on silica gel (eluent acetone / cyclohexane (2/8)).
Stage C: N (2- ~ 7- ~ 3 - ((3- [2- (Acetylamino) ethyl] -1-benzothiophen-5 (yl) oxy) 2o propoxy (1-naphthyl) ethyl) acetamide In a 100 ml flask containing 30 ml of methanol, add in small portions 0.06 g of sodium. When the sodium is totally consumed, 0.0033 is added mol of compound obtained in Preparation 9 and allowed to stir for 20 minutes.
Methanol is evaporated under reduced pressure and the residue is taken up in 15 ml of DMF, then we add 0.0027 mol of the compound obtained in stage B. The reaction medium is then heated to reflux for 12 hours then cooled and poured into 100 ml of water and 10 ml 3M HCl.
After extraction with ethyl acetate, the organic phase is washed with solution of 10% soda and then with water. After drying over MgSO 4, evaporation under pressure reduced from solvent, the title compound is purified by gel chromatography.
silica.
Example 13: N (2- {7- [3 - ({3- [2- (Butyrylamino) ethyl] -1-benzothiophen-5-yl} thio) propoxy) -1-naphthyl} ethyl) cyclobutanecarboxamide The procedure is as in Example 12, replacing in stage A, the compound obtained in Preparation 1 by the compound got in the Preparation 13, in stage C, the compound obtained in Preparation 9 by the compound got in the Preparation 37.
EXAMPLE 14 N {2- [5 - ({3 - [(8- {2 - [(2,2,2-Trifluoroacetyl) amino] ethyl} -2-naphthyl) oxy]
propyl} amino) -1-benzothiophen-3-yl] ethyl} pentanamide The procedure is as in Example 12, replacing in stage A, the compound obtained in Preparation 1 by the compound got in the Preparation 14, in stage C, the compound obtained in Preparation 9 by the compound got in the Preparation 41.
Example 15 N ({5- [3 - ({8- [2- (Acetylamino) ethyl] -2-naphthyl} oxy) propyl] -2H
chromen-3-yl} methyl) butanamide The procedure is as in Example 12, replacing in Stage C the compound of the Preparation 9 with the compound of Preparation 15 Example 16: N (2- {5- [3 - ({3 - [(Acetylamino) methyl] -2H-chromen-6-yl} oxy) propoxy]

1-benzofuran-3-yl} ethyl) cyclopropanecarboxamide The procedure is as in Example 12, replacing in Stage A, the compound of Preparation 1 with the compound of Preparation 16, in Step C, the compound of Preparation 9 with the compound of Preparation 3.
Example 17: N {2- (5- (3 - {[3 - ({[(Propylamino) carbonyl] amino} methyl) -1,4-benzodioxin-6-yl] oxy} propoxy) -1H pyrrolo [2,3-b] pyridin-3-yl] ethyl}
acetamide The procedure is as in Example 12, replacing in Stage A, the compound of Preparation 1 with the compound of Preparation 17, in Step C, the compound of Preparation 9 with the compound of Preparation 12.
Example 18: N ({7- [4 - ({8- [2- (Acetylamino) ethyl] -2-naphthyl} oxy) butoxy] -1,4-benzodioxin-2-yl} methyl) acetamide lane A: ethyl 4- ((8- [2- (acetylamino) ethyl] -2-naphthyl) oxy) butanoate In a 100 ml flask, 0.022 mol of the compound obtained is dissolved in the Preparation 1 in 50 ml of acetonitrile. 0.066 mol of potassium carbonate is added and the reaction is stirred at 80 ° C for 30 minutes. 0.033 mol of ethyl 1-bromobutyrate are then added dropwise and the reaction is stirred for 1 hour at 80 ° C.
Acetonitrile is evaporated under reduced pressure and the residue solubilized in a 1N HCl solution.
After extraction ethyl acetate, washing the organic phase with water, drying over MgSO 4 and evaporation under reduced pressure, the title compound is purified by recrystallization.
Beige solid.
Melting point: 64-66 ° C
Stage B: N (2- ~ 7- (4-Hydroxybutyloxy) naphth-1-yl] ethyl) acetamide 2o In a 250 ml flask, the ester obtained in stage A (0.009 mol) is dissolved in 100 ml anhydrous ether. 0.009 mol of mixed hydride of lithium and aluminum are added by portions and the reaction is stirred for 6 hours at room temperature. The environment reaction is then hydrolysed with a few drops of 1M NaOH and the precipitate formed is filtered.
The filtrate is dried over MgSO4 and evaporated under reduced pressure. The residue obtained is precipitated in a Et20 / Ether (1: 1), filtered and recrystallized. White solid.

_37_ Melting point: 82-84 ° C
Elemental microanalysis CHN
Calculated: 71.73 7.69 4.64 Found: 72.00 7.58 4.45 Stage C: 4 - ((8- ~ 2- (Acetylamino) ethyl] -2-naphthyl) oxy) butyl methanesulfonate The procedure is as in Step B of Example 12 starting from the compound obtained in stage B.
Stage D: N ((7- ~ 4- (~ 8- ~ 2- (Acetylamino) ethyl] -2-naphthyl-oxy) butoxy] -14-benzodioxin-2-yl) methyl) acetamide The procedure is as in Step C of Example 12, replacing the compound got in Preparation 9 with the compound obtained in Preparation 18.
Ex. 19: N {2- [7- (4 - {[3 - [(Acetylamino) ethyl] -2- (3-methoxybenzyl) -1-benzofuran-5-ylJamino} butoxy) -1-naphtylJéthyl} -2-furamide The procedure is as in Example 18, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 19, and in Stage D the composed of the Preparation 9 with the compound of Preparation 42 Example 20: N ({6- [4 - ({3 - [(Acetylamino) ethyl] -2-benzyl-IIH pyrrolo [2,3-b] pyridin

5-yl} oxy) butoxy] -4α, 8α-dihydro-2H-chromen-3-yl} methyl) butanamide The procedure is as in Example 18, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 15, and in Stage D the composed of the Preparation 9 with the compound of Preparation 20 .. -38-Example 21: N (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -2- [4-(Trifluoromethyl) benzyl] -1 benzothiophen-5-yl} thio) butoxy] -1H pyrrolo [2,3-b] pyridin-3-yl} ethyl) cyclopropanecarboxamide The procedure is as in Example 18, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 10, and in Stage D the composed of the Preparation 9 with the compound of Preparation 38 Example 22: N (2- {5- [4 - ({3 - [(Acetylamino) methyl] -4a, 8a-dihydro-2-yl chromen-6-yl} oxy) butoxy) -1-benzothiophen-3-yl} ethyl) cyclohexanecarboxamide The procedure is as in Example 18, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 16, and in Stage D the composed of the Preparation 9 with the compound of Preparation 21 Example 23: 2,2,2-Trifluoro-N (2- {5- [4 - ({3- [2- (hexylamino) -2-oxoethyl) -3a, 7a dihydro-1-benzofuran-5-yl} oxy) butoxy] -1-benzothiophen-3-yl} ethyl) acetamide The procedure is as in Example 18, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 22, and in Stage D the composed of the Preparation 9 with the compound of Preparation 23 Example 24: N (2- {7- [4 - ({4- (2- (Acetylamino) ethyl] -3,4-dihydro-2H-chromen-6 yl}
oxy) butoxy] -1,2,3,4-tetrahydro-1-naphthalenyl} ethyl) acetamide 2o The procedure is as in Example 18, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 24, and in Stage D the composed of the Preparation 9 with the compound of Preparation 25 Exe-; 1V {2- [5 - ({4 - [(8- {2 - [(Cyclopropylcarbonyl) amino] ethyl} -5,6,7,8-tetrahydro-2-naphthalenyl) oxy] butyl} amino) -1-benzofuran-3-yl] ethyl}
2-furamide The procedure is as in Example 18, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 26, and in Stage D the composed of the Preparation 9 with the compound of Preparation 43 Example 26: N (2- {5- [4 - ({8- [2- (Heptanoylamino) ethyl] -2-naphthyl} oxy) butoxy] -1H
indol-3-yl} ethyl) cyclobutanecarboxamide The procedure is as in Example 18, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 27, and in Stage D the composed of the Preparation 9 with the compound of Preparation 28 Example 27: N [2- (5 - {[6 - ({8- [2- (Acetylamino) ethyl] -2-naphthyl} oxy) hexyl) oxy} -pyrrolo [2,3-b] pyridin-3-yl) ethyl] acetamide Step A: N (2- ~ 7- ~ (6-Hydroxyhexyl) oxy] -1-naphthyl-ethyl) acetamide The procedure is as in Step A of Example 12, replacing the 3-bromopropan-1-ol by 6-bromohexan-1-ol. White solid.
Melting point: 58-61 ° C
Elemental microanalysis CHN
2o Calculated: 72.91 8.41 4.25 Found: 73,22 8,17 4,02 Stage B: 6- (~ 8- ~ 2- (Acetylamino) ethyl] -2-naphthyl) oxy) hexyl methanesulfonate The procedure is as in Step B of Example 12. White solid.
Melting point: 66-67 ° C

Stage C: N (2- (S- ~~ 6- (~ 8- ~ 2- (Acetylamino) ethyl] -2-naphthyl ~ oxy) hexyl] oxy ~ -IH
pyrrolo-2,3-b-pyridin-3-yl) ethyl-acetamide The procedure is as in Step C of Example 12, replacing the compound got in Preparation 9 with the compound obtained in Preparation 12.
Example 28: 4- (7 - {[6 - ({3 - [(Acetylamino) methyl] -2H-chromen-6-yl} oxy) hexyl] oxy}

1-naphthyl) -N isopropylbutanamide The procedure is as in Example 27, replacing in Step A the compound got in Preparation 1 with the compound obtained in Preparation 29, and in the stage C the compound obtained in Preparation 9 by the compound obtained in Preparation 16.
Exemula 29: N {[7 - ({6 - [(3- {2 - [(Anilinocarbonyl) amino] ethyl} -1-benzofuran-5-yl) oxy] hexyl} oxy) -1,4-benzodioxin-2-yl] methyl} acetamide The procedure is as in Example 27, replacing in Step A the compound of the Preparation 1 with the compound obtained in Preparation 30, and in Step C
the compound of Preparation 9 with the compound obtained in Preparation 18.
Example 30: N [2- (7 - {[6 - ({3- [2- (Benzylamino) -2-oxoethyl] -1-benzothiophen-5-yl} oxy) hexyl] thio} -1,2,3,4-tetrahydro-1-naphthalenyl) ethyl]
cyclopropanecarboxamide The procedure is as in Example 27, replacing in Stage A, the compound of Preparation 1 with the compound of Preparation 31, 2o - in stage C, the compound of Preparation 9 with the compound of Preparation 26.

Example 31: N [2- (5 - {[6 - ({3- (3- (Methylamino) -3-oxopropyl] -1-benzofuran-5-yl} oxy) hexyl] oxy} -1H-inden-3-yl) ethyl] pentanamide The procedure is as in Example 17, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 32, and in Stage C the composed of the Preparation 9 with the compound of Preparation 33 Example 32 N Cyclopropyl-N '- (2- {5 - [(6 - {[3- (2 - {[(methylamino) carbonyl] amino}
ethyl) -IH pyrrolo [2,3-b] pyridin-5-yl] oxy} hexyl) amino] -1-benzofuran 3-yl} ethyl) urea The procedure is as in Example 27, replacing in Step A the compound of the Preparation 1 with the compound of Preparation 34, and in Stage C the composed of the Preparation 9 with the compound of Preparation 44 Example 33: N [2- (7 - {[6 - ({3- [4- (Methylamino) -4-oxobutyl] -1H-indol-5-yl} oxy) hexyl] oxy} -1-naphthyl) ethyl] -3-butenamide The procedure is as in Example 27, replacing in Stage A, the compound of Preparation 1 with the compound of Preparation 6, in Step C, the compound of Preparation 9 with the compound of Preparation 35.
Example 34: N [2- (7- {3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} -1-naphthyl) ethyl]
acetamide Under nitrogen, 2.76 mmol of the compound obtained in Preparation 45, 2.76 mmol of 2o compound obtained in Preparation 46, 1.94 mmol of dichlorobis (Triphenylphosphine) nickel, 3.87 mmol of triphenylphosphine and 8.30 mmol of zinc are suspension in 20 ml of dry DMF. After heating for 48 hours at 120 ° C. under nitrogen, the middle The reaction is concentrated before dividing the residue obtained between CH 2 Cl 2 and 1M NaHCO3 The organic phase is then dried over Na 2 SO 4 and concentrated in vacuo. The composed of title is separated by chromatography on silica gel.

In Examples 35 to 48, the procedure is as in Example 34 starting from Preparations appropriate.
Example 35: N (2- {5- [8- (2 - {[(Methylamino) carbonyl] amino} ethyl) -2-naphthyl] -1 benzothiophen-3-yl} ethyl) cyclopropanecarboxamide Starting materials: Preparations 47 and 48 Example 36: N {2- [5- (3- {2 - [(Anilinocarbonyl) amino] ethyl} -1-benzofuran-5-yl) -1-benzothiophen-3-yl] ethyl} -2-furamide Starting materials: Preparations 49 and 50 Example 37 2- (5- {3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} -1H indol-3-yl) NOT
to benzylacetamide Starting materials: Preparations 45 and 51 Example 38: N [3- (5- {3- [2- (Isobutyrylamino) ethyl] -1-benzothiophen-5-yl} -IH
indol-3-yl) propyl] benzamide Starting materials: Preparations 52 and 53 Example 39: N [3- (5- {8- [2- (Acetylamino) ethyl] -2-naphthyl} -1H pyrrolo [2,3-b]
pyridin-3-yl) propyl] heptanamide Starting materials: Preparations 46 and 54 Example 4p; 4- (5- {3- [3- (Acetylamino) ethyl] -1H pyrrolo [2,3-b] pyridin-5-yl} -1-benzofuran-3-yl) -N cyclopentylbutanamide Starting materials: Preparations SS and 56 Example 41: N (2- {5- [3- (2 - {[(Allylamino) carbonyl] amino} ethyl) -1-benzothiophene 5-yl) -H-pyrrolo [2,3-b] pyridin-3-yl} ethyl) cyclopropanecarboxamide Starting materials: Preparations 57 and 58 Example 42: N [2- (5- {3 - [(Acetylamino) methyl] -1,4-benzodioxin-6-yl} -IH
pyrrolo [2,3-b] pyridin-3-yl) ethyl] cyclopropanecarboxamide Starting materials: Preparations 57 and 59 Exemula 43: 2-Methyl-N {2- [5- (4- {2 - [(2,2,2-trifluoroacetyl) amino] ethyl} -3,4 2'-dihydro-chromen-6-yl) -1-benzofuran-3-yl] ethyl] propanamide Starting materials: Preparations 60 and 61 Example 44: 4- (5- {3 - [(Acetylamino) methyl] -3,4-dihydro-2H-chromen-6-yl} -1-benzothiophen-3-yl) -N phenylbutanamide Starting materials: Preparations 62 and 63 Ex. 45: N (2- {5- {8- [2- (Acetylamino) ethyl] -2-naphthyl} -2- [4-(Trifluoromethyl) benzyl] -1-benzofuran-3-yl} ethyl) acetamide Starting materials: Preparations 64 and 46 Example 46; 2,2-Dimethyl-N (2- {6- [3- (2 - {((methylamino) carbonyl) amino} ethyl) -1H-indol-5-yl) -3,4-dihydro-2H-chromen-4-yl} ethyl) propanamide Starting materials: Preparations 65 and 66 Example 47: N - [(7- {3- [2- (Acetylamino) ethyl] -1H-indol-5-yl} -1,4-benzodioxin-2-yl) methyl] cyclohexanecarboxamide Starting materials: Preparations 67 and 68 Example 48: N (3- {5- [3- [2- (Acetylamino) ethyl) -2- (3-methoxybenzyl) -1-benzothiophen-5-yl) -1-benzofuran-3-yl} propyl) acetamide Starting materials: Preparations 69 and 70 Example 49: N (2- {7- [4 - ({3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy) -1-naphthyl} ethyl) acetamide Stage A: N- ~ 2- [7- (4-Bromobutoxy) -1-naphthyl] ethylacetamide In a 100 ml flask, 10 mmol of the compound obtained in Preparation 1 are dissolved in 50 ml of acetonitrile. 30 mmol of carbonate of potassium and one let under magnetic stirring at reflux for 30 minutes then 10 mmol of 1,4-dibromobutane are added. After 12 hours under reflux, the acetonitrile is evaporated under vacuum and the residue obtained is taken up in 1M sodium hydroxide solution. The precipitate obtained is filtered and recrystallized to lead to the product of the title.
Stage B: N- (2- ~ 7- [4- (3- (2- (Acetylamino) ethyl] -1-benzofuran-5-yloxy) butoxy]

naphtylJéthyl) acetamide In a 100 ml flask containing 30 ml of methanol, add in small portions the sodium (0.07 g, 0.0030 at.g.). When the sodium is totally consumed, added 3.6 mmol of the compound obtained in Preparation 2. After 20 minutes stirring, the methanol is evaporated under reduced pressure and the residue is taken up in 15 ml of DMF. We 3 mmol of the compound obtained in Step A is then added and the mixture is left to reflux.
while 12 hours. The reaction medium is cooled and poured onto the mixture 100 ml of water and 10 ml of 3M hydrochloric acid. The aqueous phase is extracted twice with ethyl acetate and the organic phase is washed with a 10% sodium hydroxide solution and then with water.
The solid obtained is recrystallized from acetonitrile to yield the product of title.
Melting point: 160-162 ° C
Example 50: N {2- [5- [4 - ({8- [2- (Acetylamino) ethyl] -2-naphthyl} oxy) butoxy] -1-1o (phenylsulfonyl) -1H indol-3-yl] ethyl} acetamide In a 100 ml flask, 10 mmol of the compound obtained is dissolved in the preparation 71 in 50 ml of acetonitrile, then 4.17 g of potassium carbonate are added and the medium is stirred under reflux for 30 minutes. 10 mmol of the compound obtained at the sta of A of Example 49 are then added and heated at reflux for 12 hours.
The acetonitrile is evaporated under vacuum and the residue obtained is taken up by a aqueous solution of 1M soda. The precipitate obtained is filtered and recrystallized in alcohol 95 °.
Melting point: 135-137 ° C
Example 51: N (2- {7- [4 - ({8- [2- (Acetylamino) ethyl] -2-naphthyl} oxy) butoxy] -1,2,3,4 tetrahydro-1-naphthalenyl} ethyl) acetamide 2o The procedure is as in Example 49, replacing in Step B the product got in the Preparation 2 with the product obtained in Preparation 25 Recrystallization in acetonitrile.
Melting point: 63-65 ° C
Example 52: N (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy] -1H indol-3-yl} ethyl) acetamide Step A: Ethyl 4- (~ 3- ~ 2- (Acetylamino) ethyl] -1H-indol-5-yl) oxy) butanoate 5.9 g of the compound obtained in Preparation 11 are dissolved in 100 ml.
acetonitrile, and then 11.22 g of potassium carbonate and 5.81 ml of ethyl 4-bromobutanoate added.
After one night at reflux, the potassium carbonate, acetonitrile is evaporated and the residue taken up in 100 ml of water. It is extracted with 3 times 50 ml of acetate of ethyl then the phase organic is washed with water until neutral pH, dried over magnesium sulphate and evaporated under vacuum. The oil obtained precipitates in isopropyl ether.
Melting point: 107-108 ° C
Stage B: N- ~ 2- (5- (4-Hydroxybutoxy) -1H-indol-3-yl] ethyl-acetamide To a suspension of 1.42 g of aluminum hydride and lithium in 50 ml from THF
anhydrous cooled in an ice bath, a solution is added dropwise 6.2 g compound obtained in Step A in 50 ml of anhydrous THF. After 30 minutes stirring at at room temperature, a 5% sodium hydroxide solution is added dropwise until the stop gaseous release. The precipitate formed is filtered, the organic phase is evaporated and the residue taken up in 70 ml of ethyl acetate. The organic phase is washed water up neutralized, dried over magnesium sulphate and evaporated under vacuum to lead to the product title in the form of an oil.
Tade C: N- (2- ~ S- (4-Bromobutoxy) -1H-indol-3-yl] ethyl-acetamide 3.92 g of the compound obtained in Stage B are dissolved in 50 ml of acetonitrile and 5.31 g of 2o triphenylphosphine and 6.71 g of carbon tetrabromide are added with stirring.
After one night at room temperature, the acetonitrile is evaporated under vacuum and the residue got is purified by column chromatography on silica gel (eluent:
dichloromethane 96/4 methanol).
Oil.

Stage D: N (2- ~ 5- ~ 4- (~ 3- ~ 2- (Acetylamino) ethyl] -1-benzofuran-yl-oxy) butoxy]
HI-indol-3-yl) ethyl) acetamide 0.72 g of the compound obtained in Stage C is dissolved in 20 ml of acetonitrile and then 0.57 g of potassium carbonate and 0.30 g of the compound obtained in Preparation 2 are added. After one night at reflux, the reaction medium is poured out of 200 ml of water and ice cream. The precipitate obtained is filtered, washed with ether, dried and recrystallized to drive to title product in the form of a white powder.
Melting point: 164-166 ° C
Example 53: N (2- {7- [4 - ({3- [2- (Acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy] -1 o 1-naphthyl} ethyl) acetamide The procedure is as in Example 49, replacing in Step B the product obtained in the Preparation 2 with the product obtained in Preparation 9 Recrystallization from acetonitrile / methanol (2/1).
Melting point: 169-170 ° C
Example 54: N (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy] -1H indol-3-yl} ethyl) acetamide The procedure is as in Example 49, replacing in Step A the product obtained in the Preparation 1 with the product obtained in Preparation 9 and in Step B on product obtained in Preparation 2 with the product obtained in Preparation 11.
2o Ex. 55: N (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy] -1H pyrrolo [2,3-b] pyridin-3-yl} ethyl) acetamide The procedure is as in Example 49, replacing in Step A the product obtained in the Preparation 1 with the product obtained in Preparation 9 and in Step B on product obtained in Preparation 2 by the product obtained in Preparation 12.

Example 56: N (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy) -1H pyrrolo [2,3-b] pyridin-3-yl} ethyl) acetamide The procedure is as in Example 49, replacing in Step A the product obtained in the Preparation 1 with the product obtained in Preparation 2 and in Step B on product obtained in Preparation 2 by the product obtained in Preparation 12.
Example 57: N (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -1H-indol-5-yl} oxy) butoxy]

pyrrolo [2,3-b] pyridin-3-yl} ethyl) acetamide The procedure is as in Example 49, replacing in Step A the product obtained in the Preparation 1 with the product obtained in Preparation 11 and in Step B on product obtained 10 in Preparation 2 with the product obtained in Preparation 12.
Examples 58 to 64 are obtained by proceeding as in Example 34 to from Appropriate preparations.
Example 58: N [2- (7- {3- [2- (Acetylamino) ethyl] -1-benzothien-5-yl} -1-naphthyl) ethyl) acetamide IS Starting Products: Preparations 46 and 72.
Ex. 59: N [2- (5- {8- [2- (Acetylamino) ethyl] -2-naphthyl} -1H pyrrolo [2,3-b]
pyridin-3-yl) ethyl] acetamide Starting Products: Preparations 46 and 55.
Example 60: N [2- (5- {3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} -1-benzothien-2o yl) ethyl] acetamide Starting Products: Preparations 72 and 45.

Example 61: N [2- (5- {3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} -11H indol-3-yl) ethyl] acetamide Starting Products: Preparations 67 and 45.
Example 62: N [2- (5- {3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} -1H pyrrolo [2,3-b] pyridin-3-yl) ethyl] acetamide Starting Products: Preparations SS and 45.
Example 63: N [2- (5- {3- [2- (Acetylamino) ethyl) -1H-indol-5-yl} -1H pyrrolo [2,3-b] pyridin-3-yl) ethyl] acetamide Starting Products: Preparations 55 and 67.
Example 64: N [2- (5- {3- [2- (Acetylamino) ethyl] -1-benzothien-5-yl} -1H
pyrrolo [2,3-b] pyridin-3-yl) ethyl] acetamide Starting Products: Preparations 55 and 72.

.. -50-PHARMACOLOGICAL STUDY
EXAMPLE A: Acute Toxicity Study Acute toxicity was assessed after oral administration to batches of 8 mouse (26 ~ 2 grams). The animals were observed at regular intervals at course of 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 low toxicity compounds of the invention.
EXAMPLE B: Study of binding to melatonin receptors on cells of sheep pars tuberalis lo Melatonin receptor binding studies of the compounds of the invention were carried out according to conventional techniques on the cells of the pars sheep tuberalis. The pars tuberalis of fadenohypophysis is characterized, in mammals, by high density of melatonin receptors (Journal of Neuroendocrinology, 1, pp. 1-4 1989).
Protocol 1) Pars tuberalis membranes of sheep are prepared and used as tissue target in saturation experiments to determine the capabilities and affinities of binding for 2- [125] -iodomelatonin.
2) Sheep pars tuberalis membranes are used as the target tissue, with the 2o different compounds to be tested, in competitive binding experiments compared to melatonin.
Each experiment is performed in triplicate and a range of concentrations different is tested for each compound. The results make it possible to determine, after treatment statistically, the binding affinities of the test compound.
Results It appears that the compounds of the invention possess a strong affinity for the melatonin receptors.
EXAMPLE C Meltatin-mt1 and MTz receptor binding study The mt1 or MT2 receptor binding experiments are carried out in using the 2- [~ 25I) -iodomelatonin as reference radioligand. Radioactivity restraint is determined using a liquid scintillation counter.
Competitive binding experiments are then performed in triplicate, with the different the 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 (ICso).
Thus, the ICSO values found for the compounds of the invention demonstrate a link for one or other of the receptor subtypes mt, or MT2, these values being <_ 10 ~ M.
EXAMPLE D Action of the Compounds of the Invention on Circadian Rhythms business locomotor rat The involvement of melatonin in training, through alternation day / night, most circadian rhythms physiological, biochemical and behavioral a allowed to establish a pharmacological model for the search for ligands melatoninergic.
2o The effects of the molecules are tested on many parameters and, in particular, on Circadian rhythms of locomotor activity that represent a reliable marker of the activity of the endogenous circadian clock.

In this study, we evaluate the effects of such molecules on a model experimental particular, namely the rat placed in temporal isolation (darkness permed).
Experimental protocol One month old male rats are submitted upon arrival to the laboratory at a cycle light of 12 hours of light per 24 hours (LD 12:12).
After 2 to 3 weeks of adaptation, they are placed in cages equipped a connected wheel to a registration system to detect the phases of activity locomotive and follow thus 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 the free-course (rhythm reflecting that of the clock endogenous) is clearly established, the rats receive an administration daily of the molecule to be tested.
The observations are made thanks to the visualization of the rhythms business - training of the rhythms of activity by the rhythm of light, - disappearance of training rhythms in permanent darkness, - training by the daily administration of the molecule; effect transient or durable.
Software allows - to measure the duration and the intensity of the activity, the rhythm period at animals in free and during treatment, - to possibly highlight by spectral analysis the existence of components circadian and non-circadian (ultradian for example).

Results It is clear that the compounds of the invention make it possible to act powerful way on the circadian rhythm via the melatoninergic system.
EXAMPLE E: Clear / Dark Cages Test The compounds of the invention are tested in a behavioral model, the test cages clear / obscure, which reveals the anxiolytic activity of the molecules.
The device consists of two polyvinyl boxes covered with PlexiglasTM.
One of these boxes are obscure. One lamp is placed above the other box giving a luminous intensity in the center of it of approximately 4000 lux. A
opaque tunnel plastic 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 up 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 box dark.
After administration of the compounds 30 min before the start of the test, the composed of the invention significantly increase the time spent in the cage illuminated as well as the number of transitions, which shows the anxiolytic activity of the derivatives of the invention.
EXAMPLE F Activity of the. compounds of the invention on the rat caudal artery The compounds of the invention have been tested in vitro on the caudal artery of rat. Receivers 2o melatoninergic are present on these vessels making it a model pharmacological relevant to study the activity of melatoninergic ligands.
The receptor stimulation can induce either vasoconstriction or dilation in function of the studied arterial segment.

Protocol 1 month old rats are used for 2 to 3 weeks on a cycle light / dark 12h / 12h.
After sacrifice, the caudal artery is isolated and maintained in a medium richly oxygenated.
The arteries are then cannulated at both ends, suspended vertically in a organ chamber in a suitable medium and infused via their end proximal. The pressure changes in the infusion rate allow to evaluate the effect vasoconstrictor or vasodilator of the compounds.
The activity of the compounds is evaluated on segments pre-contracted by the phenylephrine lo (1 ~ M). A concentration-response curve is determined non-cumulative by addition of a concentration of the test compound 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 test compound.
Results The compounds of the invention significantly modify the diameter of the arteries caudal pre-constrained by phenylephrine.
EXAMPLE G: PharmacPUTICAL COMPOSITION: Tablets 1000 tablets dosed with 5 mg of N (2- {7- [4 - ({3- [2- (acetylamino) ethyl] -1-benzofuran-5-20 (oxy) butoxy] -1-naphthyl) ethyl) acetamide (Example 49) ................................... 5 g Wheat starch .................................................. .............................
............................ 20 g Starch But................................................. ..........................
.............................. 20 g Lactose................................................. .......................
............................................... 30 g Magnesium stearate .................................................. .............................
............... 2 g Silica .................................................. .............................
........................................... 1 g I ~ ydroxypropylcellulose .................................................. .............................
........... 2 g

Claims (38)

1. Compounds of formula (I):
A-G1-Cy-G2-Cy'-G3-B (I) in which :
A represents a group of formula in which :
Q represents a sulfur or oxygen atom, R1, R2 and R3, which may be identical or different, represent a hydrogen atom or a group R a, where R a represents a linear C1-C6 alkyl group or branched, unsubstituted or substituted, linear or branched C 2 -C 6 alkenyl, no substituted or substituted, linear or branched C 2 -C 6 alkynyl, unsubstituted or substituted, unsubstituted or substituted C3-C8 cycloalkyl, cycloalkylalkyl in C3-C8 linear or branched, unsubstituted or substituted, polyhaloalkyl C1-C6 linear or branched, unsubstituted or substituted aryl, C1-arylalkyl linear or branched, linear or branched C2-C6 arylalkenyl, heteroaryl no substituted or substituted linear or branched C1-C6 heteroarylalkyl, or linear or branched C2-C6 heteroarylalkenyl, or R2 and R3 form, with the nitrogen atom which carries them, a group chosen from piperazinyl, piperidinyl and pyrrolidinyl, B represents a group of formula or -NR2R3, wherein Q, R1, R2 and R3 are as defined previously, ~ G1 and G3, identical or different, represent an alkylene chain containing from 1 to 4 linear or branched carbons, unsubstituted or substituted by one or many groups, identical or different, chosen from hydroxy, carboxy, formyl, R a, OR a, COOR a or COR a, where R a is as defined previously, ~ Cy and Cy ', different, represent a cyclic structure of formula (II):
in which :
X and Y, identical or different, represent a sulfur atom, oxygen or carbon, or a group CH or CH2, * R4 represents a hydrogen or halogen atom or a group CF 3, hydroxy, carboxy, formyl, amino, NHR a, NR a R 1a, NHCOR a, CONHR a, R a, OR a, COR a or COOR a, where R a is as defined previously and R1a, identical or different from R a, represents a grouping R a as defined previously, * the representation means that the links are single or double, it being understood that the valency of the atoms is respected, where G2 substitutes the benzene ring, and G1 substitutes the ring containing X and Y
in the case of Cy, and G2 substitutes the benzene ring and G3 substitutes the ring containing X and Y
in the case of Cy ', or a cyclic structure of formula (III):

in which:
Z represents a sulfur or oxygen atom, or a CH 2 group, NH, NSO2Ph or NR a, where R a is as previously defined, D represents a benzene or pyridine ring, * R4 is as defined previously, * the representation means that the bond is single or double, being understood that the valence of the atoms is respected, where G2 substitutes the cycle D, and G1 substitutes the cycle containing Z in the case of Cy, and G2 substitutes the cycle D and G3 substitutes the cycle containing Z in the Cy 'case, the two Cy and Cy 'cycles of compounds of formula (I), different, being represented both by a structure of formula (II), both by a structure of formula (III), or one by a structure of formula (II) and the other by a structure of formula (III), ~ G2 represents a chain of formula (IV):

in which:
- W1, W2 and W3, identical or different, represent a bond, an atom of oxygen or sulfur, or a group CH2, CHR a, NH or NR a, where R a is as defined previously, n represents an integer such that 0 <= n <= 6, and m represents an integer such that 0 <= m <= 6, provided that one can not have two consecutive heteroatoms and that chain of formula (IV) thus defined optionally comprises at least one unsaturated Being heard that:
the term "aryl" denotes a naphthyl, phenyl or biphenyl group, the term "heteroaryl" denotes a mono or bicyclic group, saturated or unsaturated containing 5 to 10 members and containing 1 to 3 selected heteroatoms among nitrogen, sulfur and oxygen, - the term "substituted" for the terms "aryl" and "heteroaryl"
means that these groups are substituted by one or more identical radicals or different, selected from hydroxy, carboxy, linear C1-C6 alkoxy or branched, linear or branched C1-C6 alkyl, C1-C6 polyhaloalkyl linear or branched, formyl, cyano, nitro, amino, C1-C6 alkylamino linear or branched and linear or branched C1-C6 dialkylamino, or by one or many halogen atoms, - the term "substituted" for the expressions "alkyl", "alkenyl" and "Alkynyl" means that these groups are substituted by one or more radicals, which may be identical or different, chosen from hydroxy and C 1 -C 6 alkoxy radicals linear or branched, linear or branched C1-C6 polyhaloalkyl, amino, linear or branched C1-C6 alkylamino and linear C1-C6 dialkylamino or branched, or with one or more halogen atoms, and the term ~ substituted ~ assigned to the expressions ~ cycloalkyl ~ and ~ cycloalkylalkyl ~ means that the cyclic part of these groups is substituted by one or more radicals, identical or different, chosen among hydroxy, linear or branched C1-C6 alkoxy, polyhaloalkyl C1-C6 linear or branched, amino, linear or branched C1-C6 alkylamino and linear or branched C1-C6 dialkylamino, or by one or more atoms halogen, their enantiomers and diastereoisomers, as well as their addition salts to a acid or a pharmaceutically acceptable base. 2. Compounds of formula (I) according to claim 1, characterized in that Cy and Cy ', different, represent a cyclic structure of formula (II), their enantiomers and diastereoisomers and their addition salts with an acid or a base pharmaceutically acceptable. 3. Compounds of formula (I) according to claim 1, characterized in that Cy and Cy ', different, represent a cyclic structure of formula (III), their enantiomers and diastereoisomers and their addition salts with an acid or a base pharmaceutically acceptable. 4. Compounds of formula (I) according to claim 1, characterized in that Cy represents a cyclic structure of formula (II) and Cy 'represents a cyclical structure of formula (III), their enantiomers and diastereoisomers, as well as their addition salts to a pharmaceutically acceptable acid or base. 5. Compounds of formula (I) according to claim 1, characterized in that G2 represents a single bond, their enantiomers and diastereoisomers, as well as that their salts addition to a pharmaceutically acceptable acid or base. 6. Compounds of formula (I) according to claim 1, characterized in that G2 represents a group -W4- (CH2) p -W'4- in which W4 and W'4, which are identical or different, represent an oxygen or sulfur atom or an NH group or NR has, and p represents an integer such that 1 <= p <= 12, their enantiomers and diastereoisomers, as well as their addition salts with an acid or a pharmaceutically acceptable base. 7. Compounds of formula (I) according to claim 1, characterized in that G2 represents a group -O- (CH2) pO- in which p represents an integer such that 1 <= p <=
12, their enantiomers and diastereoisomers, as well as their addition salts with an acid or a pharmaceutically acceptable base. 8. Compounds of formula (I) according to claim 1, characterized in that A
and B, identical or different, represent a group NR1COR2 or CONR2R3, their enantiomers and diastereoisomers, as well as their addition salts with an acid or a base pharmaceutically acceptable. 9. N- (2- {7- [2 - ({3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} oxy) ethoxy] -1-naph-tyl) ethyl) acetamide and its addition salts with an acid or a base pharmaceutically ac-ceptable. 10. N- (2- {5- [2 - ({8- [2- (acetylamino) ethyl] -2-naphthyl} oxy) ethoxy] -1-benzofuran-3-yl} ethyl) -2-furamide and its addition salts with an acid or a base pharmaceutically acceptable. 11. N- (2- {5- [2 - ({8- [2- (acetylamino) ethyl] -2-naphthyl} oxy) ethoxy] -1H-pyrrolo [2,3-b] pyridin-3-yl} ethyl) cyclopropanecarboxamide and its addition salts with a acid or a pharmaceutically acceptable base. 12. N- (2- {7- [3 - ({3- [2- (acetylamino) ethyl] -1-benzothiophen-5-yl} oxy) propoxy]

naphthyl} ethyl) acetamide and its addition salts with an acid or a base pharmaceutically acceptable. 13. N- [2- (5 - {[6 - ({8- [2- (acetylamino) ethyl] -2-naphthyl} oxy) hexyl] oxy} -1H-pyrrolidinyl lo [2,3-b] pyridin-3-yl) ethyl] acetamide and its addition salts with an acid or a based pharmaceutically acceptable. 14. N- (2- {5- [4 - ({3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy] -1H-indol-3-yl} ethyl) acetamide and its addition salts with an acid or a base pharmaceutically acceptable. 15. N- (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy] -1H-pyrrolidinyl lo [2,3-b] pyridin-3-yl} ethyl) acetamide and its addition salts with an acid or a based pharmaceutically acceptable. 16. N- (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy] -1H-pyrrolidinyl lo [2,3-b] pyridin-3-yl} ethyl) acetamide and its addition salts with an acid or a based pharmaceutically acceptable. 17. N- (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -1H-indol-5-yl} oxy) butoxy] -1H-pyrrolidinyl lo [2,3-b] pyridin-3-yl} ethyl) acetamide, as well as their addition salts with a acid or a pharmaceutically acceptable base. 18. N- (2- {7- [4 - ({3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy] -1-naphthyl} ethyl) acetamide and its addition salts with an acid or a base pharmaceutically acceptable. 19. N- {2- [5- [4 - ({8- [2- (acetylamino) ethyl] -2-naphthyl} oxy} butoxy] -1- (phenyl) sulfonated nyl) -1H-indol-3-yl] ethyl} acetamide and its addition salts with an acid or a based pharmaceutically acceptable. 20. N- (2- {7- [4 - ({8- [2- (acetylamino) ethyl] -2-naphthyl} oxy) butoxy] -1,2,3,4-tetrahydro-1-naphthalenyl) ethyl) acetamide and its addition salts with an acid or a base pharmaceutically acceptable. 21. N- (2- {5- [4 - ({3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} oxy) butoxy] -1H-indol-3-yl} ethyl) acetamide and its addition salts with an acid or a base pharmaceutically acceptable. 22. N- (2- {7- [4 - ({3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} oxy) butoxy] -1-naphthyl} -ethyl) acetamide and its addition salts with an acid or a base pharmaceutically acceptable. 23. N- [2- (7- {3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} -1-naphthyl) ethyl] acetamide and its addition salts with a pharmaceutically acceptable acid or base. 24. N- [3- (5- {8- [2- (acetylamino) ethyl] -2-naphthyl} -1H-pyrrolo [2,3-b] pyridin-3-yl) pro-pyl] heptanamide and its addition salts with an acid or a base pharmaceutically acceptable. 25. N- [2- (7- {3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} -1-naphthyl) ethyl] acetamide and its addition salts with a pharmaceutically acceptable acid or base. 26. N- [2- (5- {8- [2- (acetylamino) ethyl] -2-naphthyl} -1H-pyrrolo [2,3-b] pyridin-3-yl) -ethyl] acetamide and its addition salts with an acid or a base pharmaceutically acceptable. 27. N- [2- (5- {3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} -1-benzothien-3-yl) ethyl] -acetamide and its addition salts with an acid or a pharmaceutically acceptable base acceptable. 28. N- [2- (5- {3- [2- (acetylamino) ethyl] -1-benzofuran-5-yl} -1H-indol-3-yl) ethyl] -acetamide and its addition salts with an acid or a pharmaceutically acceptable base acceptable. 29. N- [2- (5- {3- [2- (Acetylamino) ethyl] -1-benzofuran-5-yl} -1H-pyrrolo [2,3-a b] pyridin-3-yl) ethyl] acetamide and its addition salts with an acid or a base pharmaceutically acceptable. 30. N- [2- (5- {3- [2- (acetylamino) ethyl] -1H-indol-5-yl} -1H pyrrolo [2,3-diol]
b] pyridin-3-yl) ethyl] acetamide. 31. N- [2- (5- {3- [2- (acetylamino) ethyl] -1-benzothien-5-yl} -1H-pyrrolo [2,3-a]
b] pyridin 3-yl) ethyl] acetamide and its addition salts with an acid or a base pharmaceutically acceptable. 32. Process for the preparation of the compounds of formula (I) as defined in the Claim 1, characterized in that the starting material is used composed of formula (V):

A-G1-Cy-OMe (V) in which A, G1 and Cy are as defined in claim 1, that is subjected to demethylation using conventional agents or systems binary acid Lewis / nucleophile, to obtain the compound of formula (VI):

A-G1-Cy-OH (VI) in which A, G1 and Cy are defined as above, .cndot. who is transformed, by the action of sodium N, N-dimethylthiocarbamate, in the corresponding thiol of formula (VII):

A-G1-Cy-SH (VII) in which A, G1 and Cy are as defined above, or corresponding amino derivative of formula (VIII):

A-G1-Cy-NHR'a (VIII) in which A, G1 and Cy are defined as before and R'a represents a hydrogen atom or a group R a as defined above, compounds of formula (VI), (VII) and (VIII) representing the compound of formula (IX):

A-G1-Cy-W4H (IX) wherein W4 represents an oxygen or sulfur atom, or a group NH
or NR a (where R a is defined as above), compound of formula (IX) on which is condensed:
.cndot. a compound of formula (X):
in which Hal represents a bromine, chlorine or iodine atom, and n, W2 and M
are as defined in claim 1, (it being understood that one can not not have two consecutive hetero atoms and that the chain thus defined has eventually at least one unsaturation), .cndot. or a compound of formula (XI):
in which Hal, n, m and W2 are defined as above and Alk represents a alkyl radical (it being understood that one can not have two heteroatoms consecutive and that the chain thus defined possibly comprises at least one unsaturated) followed by a reduction, to obtain a compound of formula (XII):

A-G1-Cy-W4- (CH2) n -W2- (CH2) m-OH (XII) wherein A, G1, Cy, W4, n, m and W2 are defined as before (being heard that one can not have two consecutive heteroatoms in the web -W4- (CH2) n -W2- (CH2) m-OH and that the chain thus defined possibly comprises at less unsaturation), whose hydroxyl function is transformed into a leaving group, by action a mesylate, a tosylate or a halogenated derivative, to obtain a compound of formula (XII '):

A-G1-Cy-W4- (CH2) n -W4- (CH2) mE (XII ') in which A, G1, Cy, W4, n, W2 and m are defined as above and E
represents a mesyl or tosyl group or a halogen atom, on which a compound of formula (XIII) is made to act:

B-G3-Cy'-W'4H (XIII) in which B, G3 and Cy 'are defined as in claim 1 and W'4 take the same values as W4 defined previously, to obtain a compound of formula (I / a):

A-G1-Cy-W4- (CH2) n-W2- (CH2) m, -W'4-Cy'-G3-B (I / a) wherein A, G1, Cy, Cy ', W4, n, W2, m, W'4, G3 and B are as defined previously, ~ or transformed using phenyl bis (trifluoromethanesulfonimide) in middle basic trifluoromethanesulfonate corresponding to formula (XIV):

A-G1-Cy-OSO2CF3 (XIV) in which A, G1 and Cy are defined as above, - on which is made to act, under conditions of catalysis by a derivative of palladium, a derivative of boric acid (R b B (OH) 2) or a derivative of tin (R b S n B u3) (where R b represents a group of formula (XV):

B-G3-Cy'-W3- (CH2) m W2- (CH2) n-CH2- (XV) in which B, G3, Cy ', W3, m, W2 and n are as previously defined, it being understood that one can not have two consecutive heteroatoms in the sequence -W3- (CH2) m-W2- and that the chain thus defined comprises possibly at least one unsaturation), to obtain a compound of formula (I / b):

A-G1-Cy-CH2- (CH2) nW- (CH2) n, -W3-Cy'-G3-B (I / b) wherein A, G1, Cy, Cy ', n, W2, m, W3, G3 and B are defined as previously (with the understanding that one can not have two heteroatoms consecutive sequences in the sequence -W2- (CH2) m-W3- and that the defined string possibly involves at least one unsaturation), compounds of formula (I / c):

A-G1-Cy-W1- (CH2) n-W2- (CH2) n, -CH2-Cy'-G3-B (I / c) wherein A, G1, Cy, Cy ', W1, n, W2, m, G3 and B are defined as previously (with the understanding that one can not have two heteroatoms consecutive sequences in the sequence -W1- (CH2) n W2- and that the chain thus defined possibly involves at least one unsaturation), being obtained from the compound of formula (XIV '):

B-G3-Cy'-OSO2CF3 (XIV ') in which B, G3 and Cy 'are as defined previously, - or that one places, under coupling conditions using derivatives of Nickel or palladium, in the presence of a compound of formula (XIV ') in order to obtain a compound of formula (I / d):

A-G1-Cy-Cy'-G3-B (I / d) in which A, G 1, Cy, Cy ', G 3 and B are as previously defined, all the compounds (I / a) to (I / d) forming the compounds of formula (I) that one purifies where appropriate, from which the isomers are separated and converts, where appropriate, into their addition salts with an acid or a base pharmaceutically acceptable. 33. Process according to claim 32, characterized in that the demethylation of compound of formula (V) is produced by the action of a demethylation agent chosen in the group consisting of HBr, AlCl3, AlBr3 and BBr3. 34. Process according to claim 32, characterized in that the demethylation of compound of formula (V) is produced by the action of an acidic binary system of Lewis / nucleophile. 35. The method of claim 34, characterized in that the system binary acid of Lewis / nucleophile is AlCl3 / PhCH2SH or BBr3 / Me2S. 36. Pharmaceutical composition containing as active ingredient at least one compound according to any one of claims 1 to 31, or a salt thereof of addition with a pharmaceutically acceptable acid or base, in combination with at least a pharmaceutically acceptable excipient. 37. Pharmaceutical composition according to claim 36, characterized in that which is intended for the treatment of disorders related to the melatoninergic system. 38. Use of a compound according to any one of claims 1 to 31, for the manufacture of a medicament for the treatment of disorders related to the system melatoninergic.