MXPA00001958A - Indole derivatives as 5-ht1b and 5-ht1d agonists - Google Patents

Abstract

The invention concerns novel indole piperazine derivatives of formula (I). It also concerns a method for preparing said compounds and their use as therapeutically active substances, in particular for treating or preventing diseases related to the dysfunction of 5-HT1-like receptors.

Description

INDOL DERIVATIVES AS AGONISTS OF 5-HYDROXYRIPTAMINE 1B AND 5-HYDROXYRIPTAMINE 1D DESCRIPTIVE MEMORY The present invention relates to novel heterocyclic compounds derived from indole piperazines as well as their method of preparation, the pharmaceutical compositions containing them and their use as a medicine. Serotonin or 5-hydroxytryptamine (5-HT) plays an important role both at the level of the nervous system and at the cardiovascular level. Serotoninergic receptors have been identified both centrally and peripherally. It is generally accepted that serotonin plays an important role in several types of pathological conditions such as - certain psychiatric disorders such as anxiety, depression, aggressiveness, panic attacks, obsessive-compulsive disorders, schizophrenia, suicidality, - certain neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, - migraine, headache, and - alcohol-related disorders (see E. Zifa, G. Fillio, Pharm. Reviews, 44, 401, 1992; A. Moulignier, Rev. Neuro. (Paris ) 150, 3-15, 1994, S. Langer, N. Brunello, G. Racagni, J.

Mendlecvicz, "Serotonin receptor subtypes: pharmacological significance and clinical implications" Karger Ed .; (1992); B.E. Leonard, Int. Clin. Psychopharmacology, 7, 13-21 (1992); R.W. Fuller; J. Clin. Psychiatry, 53, 36-45 (1992); D.G. Grahame-Smith, Int. Clin, Psychopharmacology, 6. Suppl. 4, 6-13, (1992). The compounds according to the present invention are novel compounds that have a high affinity and a very good selectivity for the receptors commonly called 5-HTα-affin and more specifically for the receptors called 5-HT1B and 5-HT1 D. , alone or in combination with other therapeutic agents, which include one or more active ingredients of the present invention find their use in the treatment, both curative and preventive, of diseases related to the dysfunction of 5-HT? -afine receptors including receptors 5-HT-IB and 5-HT-ID, with its deregulation, with modifications of the activity of the endogenous ligand which is generally serotonin. The compounds of the present invention are potent agonists, both at the level of their affinity and at the level of their efficacy or intrinsic activity, and selective agonists for the 5-HT? B and 5-HT-? D receptors. Agonists for 5-HT-? -fine receptors and more specifically for 5-HTIB receptors, show selective vasoconstrictive activity and find their use in the treatment of migraine and vasospastic disorders (A. Doenicke et al., The Lancet, 1, 1309-131 1, 1988; MD Ferrari, PR Saxena, Cephalalgia, 13, 151-165, 1993; SJ Peroutka, Headache, 30, 5-11, 1990; MA Moskowitz, TiPS, 13, 307-311, 1992; W. Feniuk, PP Humphrey, MS Perren, HE Connor, ET Whalley, J. Neurol, 238, pp. 57-61, 1991, AV Deligonis, SJ Peroutka, Headache, 31, 228-231, 1991). The compounds of the present invention, which are mostly potent and selective agonists for the 5-HTβB and 5-HT-ID receptors, therefore find their use more specifically in the curative and prophylactic treatment of conventional migraine attacks. , with aura, common migraine, without aura, vascular facial pain, chronic vascular headache and vasospastic disorders. The prior art in this field is particularly illustrated by: > Patent applications EP-A2-0303507, WO 93/14087, WO 94/02460, WO 92/14708, and U.S. Patents 4,839,377, GB-A-2124210 and GB-A-2162532 disclosing sulfonamides derived from tryptamines , including sumatriptan, such as antimigraine drugs, > Patent applications GB-A-2191488, GB-A-2185020 and GB-A-2168347 disclosing alkylamides derived from tryptamine. > French patent applications FR-A-2,699,918 and FR-A-2,707,639 disclosing novel indole compounds derived respectively from piperazines and arylamines as ligands for the 5-HT1B and 5-HT-ID receptors. > Application for the patent of invention FR-A-2,724,933 which describes novel aromatic ethers derived from indole as ligands for 5-HT? D receptors. > European Patent Applications EP-A-0313397, EP-A-0486666, EP-A1- 0494774, EP-A-0494774, EP-A2-0497512, EP-A1-0501568, EP-A-0464558, EP-A1 - 0548813 and international applications WO 92/13856 and 93/11106 which describe heterocyclic derivatives obtained from tryptamine as agonists for 5-HT-α-affin receptors. The present invention describes a novel class of piperazines derived from aminoindole which is distinguishable from all previous derivatives of the art because of its novel and different chemical structure, but also because of its biological profile and its therapeutic potential since many compounds according to the present invention show a very high affinity and selectivity for 5-HT-? B and 5-HT-ID receptors, a remarkable efficiency and a particularly advantageous hemodynamic profile. The derivatives of the present invention, therefore, find their utility more specifically as active ingredients of medicinal compositions for the treatment of migraine and several similar disorders. The present invention relates to compounds of general formula (I).

(I) where, HET represents a heterocycle selected from Ri and R2, which are identical or different, represent a hydrogen atom R'i, CF3, CH2CF3, C6H5, CH2C6H5, OH, OR SH, SR, Cl, F, Br, I, CN, NH2, NHR'1 , NR'ÍR'S, NO2, NH-NH2, NH-NHR'-, NHOH, NHCO2R '?, NHCONH2 > NHCONR ^ R'2, NHSO ^, S02R ', S02NH2, S02NHR' ?, COR '-I, CO2R' ?, CONH2, CONHR'- ,, CONR ^ R'a which may be in the ortho or meta position on the aromatic ring, R3 and R, which are identical or different, represent a hydrogen atom, a linear or branched radical containing carbon consisting of 1 to 6 carbon atoms or a phenethyl or benzyl residue, Y and Z, which are identical or different, represent CH or N, X represents O, S or NR, R5? Re and R7, which are identical or different, represent a hydrogen atom, a linear or branched alkyl residue consisting of 1 to 6 carbon atoms or a phenyl residue which is optionally substituted by a linear or branched residue of alkyl consisting of 1 to 6 carbon atoms, a halogen atom, CF3? OCH3, CN or NO2, R't and R! 2, which are identical or different, represent a linear or branched residue of the alkyl group consisting of 1 to 6 carbon atoms or a phenyl residue which is optionally substituted by a linear or branched alkyl residue consisting of 1 to 6 carbon atoms, Cl, Br, F, I, OCH 3, OH, NO 2, SCH 3, as well as their salts, solvates and bioprecursors acceptable for therapeutic use. The term "bioprecursors" as used in the present invention, applies to compounds whose structure differs from that of the compounds of formula (I) but which, when administered to an animal or a human being, become the body of a compound of formula (!) • Among the compounds of the general formula (I) which are included in the present invention, a class of compounds which is particularly appreciated corresponds to the compounds of the general formula (I) wherein Ri, R2, R3 and R4 each represents a hydrogen atom. Another class of compounds included in the present invention which are particularly appreciated corresponds to the compounds of the general formula (I) wherein HET represents a pyridyl or pyrimidyl residue. A third class of compounds included in the present invention, which are particularly appreciated, correspond to the compounds of the general formula (I) wherein HET represents a 5-membered heterocycle containing from 1 to 3 heteroatoms selected from O, S or N. Among the compounds of the general formula (I) in the form of salts that are acceptable for therapeutic use, salts formed by addition with inorganic acids are preferred., selected from the hydrochlorides, hydrobromides, sulphates, fumarates, maleates, methanesulfonates and succinates. Other salts can be used in the preparation of the compounds of formula (I), for example the adducts with creatinine sulfate. The present invention also relates to a method for preparing the compounds of the general formula (I) which consists in the condensation of an aromatic piperazine of the general formula (II) (II) wherein HET, Ri and R2 are defined according to the general formula (I) with a carboxylic acid or a carboxylic acid derived from the general formula (III) (III) wherein R'3 and R'4 are respectively identical to R3 and R4 which are defined according to the general formula (I), or R'3 or R'4 are precursors of or protecting groups for R3 and R4. which will be converted into R3 and R4 after the condensation of (II) with (III), and L represents OH, Cl, O-alkyl or the group -C (= O) L representing the activated form of a suitable carboxylic acid for the formation of an amide by reacting with an amine. A particularly appreciated variant of the method of preparation of the invention uses an amine of formula (II) and a compound of formula (III) wherein L represents Cl, in the presence of an organic or inorganic base such as pyridine, DMAP, DBU, K2CO3 , Cs2CO3 or Na2CO3 in an anhydrous polar aprotic solvent such as THF, DME, dichloromethane, at a temperature between -20 ° C and 40 ° C.

A second particularly appreciated variant of the method of preparation of the invention utilizes the condensation of an amine of formula (II) with a compound of formula (III) wherein L represents OH, in the presence of a tertiary amine such as triethylamine, diisopropylethylamine, pyridine. , DMAP, N-methyl-morpholine, in a polar aprotic solvent such as THF, dichloromethane, DCE, ethyl acetate, chloroform, DMF, by reacting with an active agent such as EDC, DCC, BOP, PyBOP, at a temperature between -10 ° C and 35 ° C. One method that is particularly appreciated in the context of this second variant is to treat the compound of formula (III) wherein L represents ethyl chloroformate OH in the presence of a base such as, for example, a tertiary amine such as N-methylmorpholine, in a polar aprotic solvent such as dichloromethane, dichlorethane, THF and DME, at a temperature between -20 ° C and 0 ° C followed by the addition of the amine of general formula (II). In the specific case of the compounds of formula (I) wherein R3 and t represent a hydrogen atom, the synthesis method consists in condensing a heteroaromatic piperazine of general formula (II) with a carboxylic acid or a derivative of this carboxylic acid of general formula (III) wherein R'3 represents a hydrogen atom and R'4 represents a t-butoxycarbonyl protecting group according to the methods and techniques previously described and then hydrolyzing the t-butoxycarbonyl protecting group in an acidic medium, with the aid, for example of hydrochloric acid or trifluoroacetic acid.

Another method of preparing the compounds of general formula (I) included in the present invention is to convert an arylpiperazide derived from tryptamine of general formula (IV) (IV) wherein R1 and R, R'3 and R'4 are defined according to the above and P represents OS? 2CF3, Br, I or CN for a compound of the general formula (I) through various methods and techniques which will essentially depend of the nature of P in the precursor (IV) and in the nature of HET in the compound of general formula (I). Accordingly, the compounds of the general formula (IV) in which P represents I, Br, or OSO 2 CF 3 can be converted to compounds of the general formula (I) by condensation with a boronic acid of the formula HEP-B (OH) 2 in presence of palladium according to the method known to those skilled in the art called "Suzuki copulation". The compounds of the general formula (IV) in which P represents CN are used as precursors of several compounds of the general formula (I) as explained in the following scheme: It is clearly understood that, in the case where R'3 and R'4 are different from R3 and R, the conversions indicated in this scheme involve the use of additional reactions to convert R'3, R'4 into R3? R4 Accordingly, the preparation of the compounds of the general formula (I) wherein R3 and R4 represent a hydrogen atom by the methods described in the above scheme uses a precursor of general formula (IV) wherein R'3 = H and R4 = COOlBu and an additional reaction which is intended to restore the primary amine such as the use of an acid such as hydrochloric acid or trifluoroacetic acid. The aromatic piperazines of the general formula (11) are prepared by various methods and techniques known to those skilled in the art of preparing arylpiperazines. In general, these intermediary piperazines are prepared from a precursor of the general formula (V) (V) where HET, R-i and R2? they are as described above, by reacting with an acid such as hydrochloric acid or preferably trifluoroacetic acid. The intermediates of formula (V) are accessible from the intermediates of the general formula (VI) (VI) where P is as described above. The conversion of the arylpiperazines of formula (VI) to arylpiperazines of formula (V) is carried out by several methods and techniques described above for the conversion of the intermediates of the general formula (IV) to compounds of formula (I). In the specific case where, in the general formula (V) at least one of the substituents of Ri 0 R2 is a group that attracts electrons, for example, NO2? CF3, CN or CO2R, attached to the ortho position on the aromatic ring with respect to the piperazine residue, an alternative method for obtaining arylpiperazines of formula (V) consists of condensing N-BOC-piperazine with an electrophile of the general formula (Vile).

(VII) where HET and R2 are as defined above and Ri is a substituent that attracts electrons, in the presence of an organic or inorganic base at a temperature between 20 and 100 ° C. The intermediates of the general formula (II) can also be prepared from anilines of the general formula (VIII) (VIII) where HET, R-i and R2, are defined according to the general formula I, after the reaction with electrophiles of formula (IX) or (X) (IX) (X) wherein Q represents a chlorine, a bromine, a iodine, a tosylate or a mesylate and Rx represents an amine protecting group, for example, a t-butoxycarbonyl, which will subsequently be deprotected. The condensation of anilines of the general formula (IX) is preferably carried out in an anhydrous polar solvent such as DMF, acetonitrile, THF, butanol, t-butanol, or DMSO, generally at the reflux temperature of the solvent used, in the presence of a organic or inorganic base such as potassium carbonate, sodium or calcium. The intermediates of the general formula (II) can also be prepared by condensation of anilines of the general formula (HIV) with amino acid derivatives of formula (X), in the presence of acetic anhydride, followed by the reduction of the intermediate diketopiperazide thus formed with, for example, a borane and finally decomposition of the protecting group, for example, in an acidic medium if it involves a residue of t-butoxycarbonyl. The methods that make it possible to convert a derivative of formula (I) to another derivative of formula (I) in which at least one of the substituents HET, R-i, R2 > R3 or R4 is different, by means of techniques and methods known to those skilled in the art their inclusion in the present invention should also be considered. Therefore, and by way of example, the derivatives of the general formula (I) wherein Ri represents NH2 by known methods and techniques for this type of reduction as described for example in Comprehensive Organic Transformation, R.C. Larock, V.C.H., p. 412 1989, among which may be mentioned atmospheric hydrogenation catalysed by palladium on carbon, the use of SnCl 2 or zinc or alternatively radio catalyst in the presence of hydrazine. The compounds of formula (I) wherein Ri represents NH 2 can also be converted into derivatives of formula (I) wherein Ri represents NR 8 R g, NHCO 2 R b, NHCOR s Rg, NHSO 2 R 8 > by methods and techniques known to those skilled in the art to convert an aromatic amine to amide, carbamate, urea or sulfonamide. In the context of this invention, it is also necessary to consider the preparation of compounds of formula (I) from other compounds of formula (I) which are distinguishable by the nature of the HET residue. Accordingly, the derivatives of the general formula (I) wherein HET represents a tetrazole residue can be converted to derivatives of formula (I) wherein HET represents an oxadiazole according to the following scheme: It is evident that in some chemical reactions or reaction sequences leading to the preparation of compounds the general formula (I), it is necessary or desirable to protect possible sensitive groups in the synthesis intermediates in order to avoid undesirable side reactions. This can be achieved by the use, ie, introduction and deprotection, of conventional protecting groups such as those described in "Protective Groups in Organic Synthesis", T.W. Greene, John Wiley & Sons, 1981, and "Protecting Groups", P.J. Kocienski Thieme Verlag, 1994. Suitable protecting groups will therefore be introduced and eliminated during the most convenient step for this, using methods and techniques described in the aforementioned references.

When it is desired to isolate a compound according to the invention in the form of a salt, for example an addition salt with an acid, this can be achieved by treating the free base of the general formula (I) with a suitable acid, preferably at an equivalent amount. The present invention also relates to the compounds of formula (I) for their application as therapeutically active substances. The present invention relates more specifically to the compounds of formula (I) for the treatment or prevention of disorders related to serotonin, for the treatment or prevention of migraine, vascular facial pain, chronic vascular headache, for the treatment or prevention of depression , obsessive-compulsive disorders, bulimia, aggressiveness, alcoholism, nausea, sexual dysfunction, antisocial behavior, anxiety, spasticity, Alzheimer's and Parkinson's diseases. The present invention also relates to pharmaceutical compositions containing, as an active ingredient, at least one compound of formula (I) and a pharmaceutically acceptable excipient. The compositions according to the invention can be used orally, nasally, parenterally, rectally or topically. As solid compositions for oral administration, tablets, pills, powders in the form of gelatin capsules or lozenges, granules can be used. In these compositions, the active ingredient according to the invention is mixed with one or more inert diluents such as starch, cellulose, sucrose, lactose or silica, under a stream of argon. These compositions may also comprise substances other than diluents, for example, one or more lubricants such as magnesium stearate or talc, a dye, a coating or a polishing powder. As liquid compositions for oral administration, pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs may be used which contain inert diluents such as water, ethanol, glycerol, vegetable oils or paraffin oil. These compositions may comprise substances other than diluents, for example, humectants, sweeteners, thickeners, flavorings or stabilizers. Sterile compositions for parenteral administration may preferably be solutions that are aqueous or non-aqueous, suspensions, or emulsions. As a solvent or vehicle, it is possible to use water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents. These compositions may also contain adjuvants, in particular wetting agents, isotonisers, emulsifiers, dispersants and stabilizers. The sterilization can be carried out in different ways, for example by aseptic filtration, by incorporation of sterilizing agents to the composition, by irradiation or by heat. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or in any other sterile injectable medium.

Compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semi-synthetic glycerides or polyethylene glycols. The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwash, nasal drops or aerosols. Doses depend on the desired effect, the duration of treatment and the route of administration used; they are generally between 0.001 g and 1 g, preferably between 0.005 g and 0.25 g per day, preferably by the oral route for an adult with unit doses ranging from 0.1 mg to 500 mg of active substance, preferably from 1 mg to 50 mg. In general, the doctor will determine the appropriate dose according to age, weight and all other specific factors of the subject to be treated. The following examples illustrate the invention, without limiting, however, the scope thereof.

EXAMPLE 1 Fumarate of 2-r3- (2-Aminoetin-1H-indol-5-yloxp-1-f4-r4- (5-phenyl-T1, 3,41-oxadiazol-2-yl) -phenypiperazin-1-yletanone 1A) N-tert-butoxycarbonyl-4- (4-cyanophen-Q-piperazine 1- (4-cyanophenyl) piperazine (5.0 g, 26.7 mmol) in solution in dichloromethane (100 ml) in the presence of triethylamine (5.6 ml, 40.0 mmol) was treated with di-tert-butyl dicarbonate (6.4 g, 29.3 mmol) After stirring for 1 hour at room temperature, the medium is diluted with dichloromethane and washed with water, the organic phase is dried over sodium sulfate, filtered and evaporated to dryness. Dry to give intermediate 1A (7.7g, 100%) as a beige solid. 1B) N-terbutoxycarbonyl-4-r4- (2H-tetrazol-5-ipphenylpiperazine Intermediate 1A (6.0 g, 20.8 mmol) in solution in xylene (76 ml), under nitrogen, is treated with azidatrimethyltin ( 6.25 g, 31.3 mmoles) After stirring for 24 hours at 110 ° C, the reaction medium is brought to room temperature and the formed precipitate is filtered on concreted glass and then washed with toluene and with petroleum ether. purify by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonium hydroxide mixture in the 80/19/1 proportions to give the compound 1B (5.75 g, 87%) as a colored solid White. 1C) 1- [4- (5-phenyl- [1.S-loxadiazole] -iD-phenylpiperazine Compound 1 B (1.5 g, 4.54 mmol) in solution in pyridine (15 ml) is heated at 60 ° C, under nitrogen, during 10 minutes, then benzoyl chloride (1.3 ml, 11.35 mmol) is added and the mixture is heated to reflux for 3 hours To complete the reaction (0.5 ml, 4.54 mmol), benzoyl chloride is added again and the mixture is heated 1 hour more at reflux.The reaction medium is then brought to room temperature, diluted with ethyl acetate, washed successively with water, with a saturated solution of copper sulfate, with water and finally with a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness The beige-colored solid obtained is taken up in toluene (46 ml) and treated with trifluoroacetic acid (6 ml), after stirring for 1 hour at room temperature , the medium is diluted with ethyl acetate, washed with hydroxide of sodium (2N) and then with water and finally with a saturated solution of sodium chloride. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a mixture of dichloromethane / methanol / ammonium hydroxide in the proportions 95 / 4.5 / 0.5 to give the pure compound 1C (800 mg, 57%). 1) Fumarate of 2-r3- (2-Aminoethyl) -7H-indol-5-yloxy-1- (4-r4- (5-phenyl-H, 3,4-loxanediazole-2-yl) phenyl n-piperazin-1-ethyltetanone 3- [2- (N-tert-butoxycarbonyl) aminoethyl] -7H-indol-5-oxoacetic acid (763 mg, 2.28 mmol), or SerBOC acid (Bioorg. Med. Chem) Lett., 5, 1995, 663-666), in solution in dichloromethane (9 ml), in the presence of N-methylmorpholine (0.27 ml, 2.50 mmol), treated at -10 ° C under nitrogen with ethyl chloroformate ( 0.24 ml, 2.50 mmol) After stirring for 10 minutes at -10 ° C, intermediate 1C (769 mg, 2.50 mmol) is added and the mixture is stirred at -10 ° C at room temperature for 2 hours. It is diluted with ethyl acetate, washed successively with water, with a sodium bicarbonate solution and finally with a saturated solution of sodium chloride, the organic phase is dried over sodium sulphate, filtered and evaporated to dryness. is chromatographed on a column of silica gel eluted with a dichloromethane mixture / acetone in proportions ranging from 8/1 to 4/1 to give the coupling product (1.19 g; 84%). This compound is taken up in toluene (30 ml) and treated with trifluoroacetic acid (3.9 ml) at room temperature for 1 hour. The medium is diluted with ethyl acetate and then basified by the addition of 2N sodium hydroxide.

The precipitate formed is isolated by filtration and then washed with water, with ethyl acetate and with water. This solid is purified by chromatography on a column of silica gel eluted with a mixture of dichloromethane / methanol / ammonium hydroxide in the proportions 90/9/1 to give the expected product in the form of a base (746 mg; 75%). This product is taken up in methanol and then salified by the addition of fumaric acid (165 mg, 1.43 mmol) to give a white solid. 1 H NMR DMSO-d 6 (ppm): 2.92 t, 2H; 3.03 t, 2H; 3.33-3.50 m, 4H; 3.60-3.75 m, 4H; 4.83 s, 2H; 6.41 s, 2H; 6.80 dd, 1 H; 7.10-7.20 m, 4H; 7.26 d, 1 H; 7.59-7.65 m, 3H; 7.96 d, 2H; 8.08-8.12 m, 2H; 10.81 s, 1 H Elemental analysis (C34H34N6O7.1.5H2O)% calculated: C 61.35 H 5.60 N 12.62% found: C 61.14 H 5.43 N 12.70 Melting point: 170 ° C Mass spectrum: m / z 523 (MH +) EXAMPLE 2 Fumarate of 2-r3- (2-aminoetin-f H-indol-S-yloxyM -. {4-r4- (5-o-tolyl-T1, 3,41-oxadiazol-2-yl) -phenylpiperazine-1 - il.}.

Compound 2 is prepared from intermediate 1B (1.0 g, 3.03 mmol), o-toluoyl chloride (0.99 ml, 7.55 mmol) and SerBOC acid (576 mg, 1.72 mmol) in accordance with the procedure described for the preparation of Example 1 1 H NMR DMSO-d 6 (ppm): 2.68 s, 3 H, 2.93 t, 2 H; 3.04 t, 2H; 3.30-3.50 m, 4H; 3.60-3.75 m, 4H; 4.83 s, 2H; 6.42 s, 2H; 6.80 d, 1 H; 7.11-7.20 m, 4H; 7.26 d, 1 H; 7.40-7.53 m, 3H; 7.95 d, 2H; 8.04 d, 1 H; 10.83 s, 1 H Elemental analysis C35H36N6O7.1.5H2O% calculated: C 61.85 H 5.78 N 12.36% found: C 62.07 H 5.74 N 12.26 Melting point: 123 ° C Mass spectrum: m / z 537 (MH +) EXAMPLE 3 Fumarate of 2-r3- (2-amynoethyl) -7H-indol-5-loxi-1 -. { 4-r4- (5-p-tolyl-p, 3,4-oxadiazol-2-yl) phenylpiperazin-1-yletanone Compound 3 is prepared from intermediate 1B (900 mg, 2.72 mmol), p-toluoyl chloride (1.0 ml, 7.6 mmol) and SerBOC acid (186 mg, 0.55 mmol) in accordance with the procedure described for the preparation of Example 1 1 H NMR DMSO-d 6 (ppm): 2.41 s, 3H; 2.94 t, 2H; 3.03 t, 2H; 3.32-3.48 m, 4H; 3.65-3.71 m, 4H; 4.84 s, 2H; 6.42 s, 2H; 6.80 dd, 1 H; 7.10-7.18 m, 3H; 7.20 s, 1 H; 7.27 d, 1 H; 7.43 d, 2H; 7.98 dd, 4H; 10.83 s, 1 H. Elemental analysis: C35H36N6O7.2H2O% calculated: C 61.04 H 5.85 N 12.20% found: C 60.84 H 5.60 N 12.07 Mass spectrum: m / z 537 (MH +) Melting point: 135 ° C EXAMPLE 4 Fumarate of 2-r33- (2-aminoetin-1H-indol-5-yloxp-1 -. {4-r4- (5-methyl-n, 3,4-oxadiazol-2-yl) -phenypiperazine-1 -iron Compound 4 is prepared from intermediate 1 B (205 mg, 0.62 mmol), acetyl chloride (0.16 ml, 2.23 mmol) and SerBOC acid (84 mg, 0.25 mmol) in accordance with the procedure described for the preparation of example 1. 1 H NMR DMSO-d 6 (ppm): 2.55 s, 3H; 2.90-3.10 m, 4H; 3.30-3.40 m, 4H; 3.68 width s, 4H; 4.83 s, 2H; 6.46 s, 2H; 6.80 d, 1 H; 7.08-7.29 m, 5H; 10.86 s, 1 H. Elemental analysis: C29H32N6? 7.1.6H2O% calculated: C 57.63 H 5.87 N 13.96% found: C 58.02 H 5.80 N 13.56 Melting point: 145-150 ° C EXAMPLE 5 Fumarate of 2-r3- (2-amynoethyl) -i H-indol-S-iloxyl-1-f4-r4- (4,5-dihydrooxazol-2-yl) phenylpiperazin-1-yl} Etanone 5A) N-tert-butoxycarbonyl-4-r4- (4,5-dihydrooxazol-2-p-phenyl-piperazine) A mixture of ethanolamine (0.91 ml, 15.0 mmol), glycerol (2.7 g), ethylene glycol (5.6 g) is heated. and potassium carbonate (2.1 g, 15.0 mmol) at 105 ° C for 30 min., then intermediate 1A (2.3 g, 8.04 mmol) is added and the mixture is heated for 5 days at 105 ° C. filter into a concreted glass and wash with water and petroleum ether to give compound 5A (988 mg, 37%) as a beige solid. 5B) 4- | "4- (4,5-D¡h¡drooxazol-2-yl) phenyl-1-piperazine Compound 5A (826 mg, 2.49 mmol) in a solution in toluene (20 ml) is treated at room temperature with trifluoroacetic acid (2.75 ml) After 1 hour, the medium is evaporated to dryness and coevaporated 3 times with toluene The product obtained is taken up in methanol (20 ml) and triethylamine (8 ml), stirred for 15 minutes at room temperature and finally evaporated to dry The solid obtained is purified by chromatography on a column of silica gel eluted with a mixture of dichloromethane / methanol / ammonium hydroxide in the proportions 90/9/1 to give intermediate 5B.

) Fumarate of 2-r3- (2-Aminoethyl) -1H-indol-5-yloxp-1-f4-r4- (4,5-dihydroxazol-2-yl) phenyl] pperazin- 1-l) ethanone Compound 5 is prepared from intermediate 5B (576 mg, 2.48 mmol) and SerBOC acid (694 mg, 2.07 mmol) in accordance with the procedure described for the preparation of Example 1 of 1C. H NMR DMSO-d6 (ppm): 2.94 t, 2H; 3.05 t, 2H; 3.25-3.38 m, 4H; 3.55-3.72 m, 4H; 3.89 t, 2H; 4.33 t, 2H; 4.82 s, 2H; 6.45 s, 2H; 6.80 dd, 1 H; 7.00 d, 2H; 7.14 d, 1 H; 7.19 d, 1H; 7.26 d, 1 H; 7.71 d, 2H; 10.84 s, 1H Elemental analysis C29H33N5O7.2.9H2O% calculated: C 56.56 H 6.35 N 11.37% found: C 56.84 H 6.06 N 11.35 Melting point: 170 ° C Mass spectrum: m / z 448 (MH +) EXAMPLE 6 2-R3- (2-aminoethyl) / 7-ynol-5-yloxy-p-1-r4- (4-oxazol-2-ylphenyl) piperazine-1-yletanone hydrochloride 6A) 4- (4-Oxazol-2-ylphenyl) piperazine Intermediate 5A (597 mg, 1.80 mmol) in xylene solution (8 ml) is treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (450 mg, 1.98 mmol). The mixture is heated for 50 minutes under reflux and then evaporated to dryness. The black solid obtained is purified by chromatography on a column of silica gel eluted with a mixture of hexane / ethyl acetate in the proportions 3/1 to give a yellow solid (59 mg, 10%). This compound is deproed in accordance with the procedure described for the preparation of compound 5B from compound 5A to give the trifluoroacetic acid salt of compound 6A as a beige solid (54 mg, 100%). 6) Fumarate of 2-r3- (2-aminoetid-D-7 / - / - indol-5-yloxy-1-4- (4-oxazol-2-ylphenol) pperazin-1-yl-ethanone Compound 6 is prepared from intermediate 6A (54 mg, 0.16 mmol) and SerBOC acid (53 mg, 0.16 mmol) in accordance with the procedure described for the preparation of Example 1 of 1 C. 1 H NMR DMSO-d 6 (ppm): 2.90 -3.00 m, 2H, 3.00-3.10 m, 2H, 3.25-3.40 m, 4H, 3.59-3.74 m, 4H, 4.83 s, 2H, 6.81 dd, 1 H, 7.08 d, 2H, 7.14 s, 1 H, 7.21 s, 1 H, 7.25-7.31 m, 2H, 7.83 d, 2H, 7.90 s wide, 3H, 8.11 s, 1 H, 10.85 s, 1 H Elemental analysis C25H27N5O3 2. 2HCI, 3.5H2O% calculated C 51.00 H 6.20 N 11.89% found: C 51.21 H 5.82 H 11.70 Melting point: 64-66 ° C (degradation) Mass spectrum: m / z 446 (MH +) EXAMPLE 7 Fumarate 2-r3- (2-aminoethyl) - Ay-indo-5-yloxp-1-r4- (4-benzothiazol-2-ylphenyl) pipetrazin-1-yletanone Treat 2-aminothiophenol (0.32 ml, 3.0 mmol) in tetrahydrofuran solution (10 ml) under nitrogen at room temperature, with sodium hydride (60% in oil) (480 mg, 12.0 mmol). The medium is heated to 60 ° C and then intermediate 1A (861 mg, 3.0 mmol) is added. The mixture is maintained at 60 ° C for 3 hours 30 minutes and subsequently cooled to 5 ° C and neutralized by the addition of ammonium chloride. The mixture is extracted with ethyl acetate and subsequently with dichloromethane. The organic phases are combined, dried over sodium sulfate and evaporated to dryness. The resulting syrup is purified by chromatography on a column of silica gel eluted with a dichloromethane / ethyl acetate mixture in proportions 20/1 to give the condensation product (760 mg, 64%). Compound 7 is prepared from the preceding intermediate which is deproed and subsequently condensed with SerBOC acid (170 mg; 0. 51 mmol) in accordance with the procedure described for the preparation of Example 1. 1 H NMR DMSO-d 6 (ppm): 2.95-3.04 m, 4H; 3.30-3.45 m, 4H; 3. 68 wide s, 4H; 4.84 s, 2H; 6.44 s, 2H; 6.80 dd, 1 H; 7.08-7.29 m, 5H; 7.35- 7.53 m, 2H; 7.92-7.98m, 3H; 8.07 d, 1 H; 10.85 s, 1 H Elemental analysis: C29H29N5O2S.0.8C4H4O4.1.3H2O% calculated: C 61.48 H 5.57 N 11.09% found: C 61.02 H 5.42 N10.73 Melting point: 156-160 ° C Mass spectrum: m / z 512 (MH +) EXAMPLE 8 2-R3- (2-aminoetin-7rt-indol-5-yloxp-1 -! 4-r4- (2H-tetrazol-5-yl) fenippiperazin-1-i Detanone hydrochloride It is treated 4- (4- { 2- [3- (2- {N-tert-butoxycarbonyl}. Amino-ethyl) -1 H -indol-5-yloxy] acetyl}. Piperazin-1 -yl) benzo-nitrile (J. Med. Chem., 1995, 38, 3602-3607) (400 mg, 0.79 mmol) in solution in xylene (5 ml), under nitrogen, with trimethyltin azide (310 mg, 1.50 mM). mmoles). The mixture is heated for 5 days at 110 ° C and then the precipitate formed is filtered on a specific glass and washed with toluene to give a cream colored solid. This compound is purified by chromatography on a column of silica gel eluted with a mixture of methane / methanol / ammonium hydroxide in the proportions 85/14/1 to give a yellow powder (350 mg, 81%). This intermediate is deproed in accordance with the conditions described for the preparation of compound 5B from compound 5A, to give a compound 8 (209 mg, 73%) isolated in the form of a hydrochloride. 1 H NMR DMSO-d 6 (ppm): 2.95-3.05 m, 4H; 3.38 width s, 4H; 3.67 width s, 4H; 4.82 s, 2H; 6.80 dd, 1 H; 7.11-7.28 m, 5H; 7.80-7.95 m, 5H; 10.84 s, 1 H. Melting point: 225-227 ° C Mass spectrum: 447 (MH +) EXAMPLE 9 2-R3- (2-Aminoethyl) -1-t-indol-5-yloxyl-l-r4- (4-pyridin-4-ylphenyl) piperazin-1-yletanone fumarate 9A) 2-Chloro-1-((4-hydroxyphenyl) piperazin-1-cyltanone 4-Hydroxyphenylpiperazine (8 g, 44.9 mmol) in solution in methyl ethyl ketone (43 ml), in the presence of potassium carbonate (15.5 g; 112 mmoles), at 0 ° C and dropwise with chloracetyl chloride (5.4 ml, 67.2 mmol). After stirring for 1 hour 30 minutes at 0 ° C, the medium is diluted in ethyl acetate, filtered on celite, washed with water and subsequently with a sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and evaporated. The product obtained is purified by chromatography on a column of silica gel eluted with a mixture of dichloromethane / methanol / ammonium hydroxide in the proportions 95 / 4.5 / 0.5 to give compound 9A (8.2 g, 72%) in the form of a Solid beige. 9B) 2-Chloro-1-r (4-trifluorosulfonate-phenyl) piperazin-1-yletanone Compound 9A (7.8 g, 30.6 mmol) in solution in dichloromethane (428 ml), in the presence of triethylamine (10.6 ml, 76.5 mmol) ) is treated under nitrogen at 0 ° C, with triflic anhydride (7.7 ml, 45.9 mmol). After stirring for 1 hour at 0 ° C to room temperature, the medium is diluted with dichloromethane, washed with a sodium bicarbonate solution and subsequently with a sodium chloride solution. The organic phase is dried over sodium sulphate and subsequently filtered and evaporated to dryness. The product obtained is purified by chromatography on a column of silica gel eluted with a dichloromethane / acetone mixture in the proportions 100/1 to give the product 9B (10.8 g, 91%). 9C 2-r 3 - (2- (N-tert-butoxycarbonylaminoethyl) -7 H -indole-5-yloxp-1-r 4 - (4-trifluorosulfonate-phenyl) piperazin-1-ethanone 3 - [2- (N-tert-butoxycarbonyl) aminoethyl] -1H-indol-5-ol (J.

Med: Chem., 1995, 38, 3602-3607) (3.5 g, 12.68 mmol) in solution in methylethyl ketone (140 ml), in the presence of potassium carbonate (4.37, 31.7 mmol) and potassium iodide (0.21 g; 1.26 mmole) at room temperature with intermediate 9B (10.8 g, 27.9 mmoles). The mixture is heated under reflux for 8 hours and then brought to room temperature and stirred overnight. The medium is diluted with ethyl acetate, washed with water and then with a sodium chloride solution. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The product obtained is purified by chromatography on a column of silica gel eluted with a mixture of dichloromethane / ethyl acetate in the proportions 9/1 to give the product 9C (3.87 g, 49%). 9 2-r3- (2-Aminoethyl) -7H-indol-5-yloxp-1-r4- (4-pyridin-4-ylphenyl) piperazin-1-yl-ketanone A mixture of intermediate 9C (600 mg, 0.96 mmole), 4-pyridinylboronic acid (117 mg, 1.44 mmol), lithium chloride (121 mg, 2.88 mmol) and palladium tetrakis (115 mg, 0.134 mmol) in a mixture of dimethoxyethane (3.1 ml) and 2M sodium carbonate (1.3 ml) ) is heated at 105 ° C and under nitrogen for 23 hours. The medium is diluted with ethyl acetate, washed with sodium hydroxide (2N) and subsequently with water, and finally with a solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The product obtained is purified by chromatography on a column of silica gel eluted with a mixture of dichloromethane / methanol / ammonium hydroxide in the proportions 99/1 / 0.1 and subsequently the proportions 90/9/1 to give a syrup (259 mg 49%). This compound is deprotected under the conditions described for the preparation of compound 5B of compound 5A to give compound 9 (142 mg, 67%) isolated as fumarate. 1 H NMR DMSO-d 6 (ppm): 2.92 s, 2H; 3.03 s, 2H; 3.20-3.35 m, 4H; 3.66 d, 4H; 4.82 s, 2H; 6.41 s, 2H; 6.80 d, 1H; 7.08 d, 2H; 7.13 s, 1H; 7.18 s, 1H; 7.26 d, 1H; 7.50-7.65 m, 2H; 7.72 d, 2H; 8.54 s, 2H; 10.81 s, 1H Elemental analysis: C27H29N5O2.1.1C4H4? 4.1.65H2O% calculated: C 61.53 H 6.03 N 11.43% found: C 61.63 H 5.85 N 11.03 Melting point: 176 ° C Mass spectrum: m / z 456 (MH + ) EXAMPLE 10 2-r3- (2-Aminoethyl) - 'H-indol-5-yloxy-1-r4- (4-thiophen-2-yl-phenyl) piperazin-1-yl-ethanone Compound 10 is prepared from intermediate 9C (600 mg, 0.96 mmole) and 2-thiopheneboronic acid (184 mg, 1.44 mmole) according to the procedure described for the preparation of example 9. 1 H NMR DMSO-d6 (ppm): 2.86 t, 2H; 2.97 t, 2H; 3.18-3.26 m, 4H; 3.60-3.70 m, 4H; 4.81 s, 2H; 6.36 s, 1H; 6.80 dd, 1H; 7.00 d, 2H; 7.05-7.15 m, 2H, 7.16d, 1H, 7.25d, 1H, 7.33d, 1H, 7.40dd, 1H, 7.51 d, 2H; 10.78 s, 1H Elemental analysis C26H28N4O2S1.0.5C4H4O4.1H2O% calculated: C 62.27 H 6.01 N 10.44% found: C 63.03 H 5.85 N 10.80 Melting point: 154-156 ° C Mass spectrum: m / z 461 (MH +) EXAMPLE 11 Fumarate of 2-r3- (2-aminoethyl) -7H-indol-5-yloxy1-1-r4- (4-thiophen-3-ylphenyl) piperazin-1-yletanone Compound 11 is prepared from intermediate 9C (600 mg, moles) and 3-thiopheneboronic acid (184 mg, 1.44 mmoles) in accordance with the procedure described for the preparation of example 9. 1 H NMR DMSO-d6 (ppm): 2.90-3.05 m , 4H; 3.10-3.20 m, 4H; ncho s, 4H; 4.82 s, 2H; 6.41 s, 1 H; 6.79 dd, 1 H; 6.98 d, 2H; 7.15 dd, 2H; , 1 HOUR; 7.48 d, 1H; 7.56-7.60 m, 3H; 7.76 d, 1H; 10.82 s, 1H Elemental analysis C26H28N4? 2S? .6.64H4? 4.1.2H2O% calculated: C 62.22 H 5.96 N 10.22% found: C 61.88 H 5.78 N 9.88 Melting point: 139-141 ° C The following examples illustrate compositions in accordance with the invention. In these examples, the term "active component" designates one or more (generally one) of the compounds of formula (I) according to the present invention.

Tablets can be prepared by direct compression or by wet granulation. The direct compression method is preferred, but may not be suitable in all cases depending on the doses and physical properties of the active component.

A - By direct compression mg for an active component tablet 10.0 microcrystalline cellulose B.P.C. 89.5 magnesium stearate 0.5 100.0 The active component is passed through a sieve with a side mesh opening of 250 μm, mixed with the excipients and the mixture is compressed with the aid of 6.0 mm cubes. It is possible to prepare tablets having other mechanical resistances by modifying the compression weight with the use of suitable dies.

B - Wet granulation mg for one tablet active component 10.0 lactose Codex 74.5 Codex starch 10.0 pregelatinized corn starch Codex 5.0 magnesium stearate 0.5 weight under compression 100.0 The active component is passed through a sieve with a mesh aperture of 250 μm and mixed with lactose, starch and pregelatinized starch. The mixed powders are moistened with purified water, converted into granules, dried, passed through the sieve and mixed with magnesium stearate. The lubricated granules are made in tablets in the same way as the direct compression formulas. It is possible to apply a coating film to the tablets by means of suitable film-forming materials, for example methylcellulose or hydroxypropylmethylcellulose, in accordance with conventional techniques. It is also possible to coat tablets with sugar.

Capsules mg for a capsule active component 10.0 * starch 1500 89.5 mg Codex 0.5 filling weight 100.0 * a directly compressible form of starch obtained from the company Colorcon Ltd, Orpington, Kent, United Kingdom. The active component passes through a sieve with a mesh size of 250 μm and mixes with the other substances. The mixture is filled into No. 2 hard gelatin capsules in a suitable filling machine. It is possible to prepare other dosage units by modifying the filling weight and, when necessary, by changing the size of the capsule.

Syrup mg per dose of 5 my active component 10.0 sucrose Codex 2750.0 glycerin Codex 500.0 pH regulator sweetener coloring is. 5.0 distilled water preservative The active component, pH regulator, sweetener, colorant and preservative are dissolved in a portion of water and glycerin is added. The remaining water is heated to 80 ° C and the sucrose dissolves therein and the mixture is subsequently cooled. The two solutions are combined, the volume is adjusted and the solution is mixed. The syrup obtained is clarified by filtration.Suppositories active component 10.0 mg * Witepsol H15 rest for 1.0 g * brand marketed for Adeps Solidus of the European Pharmacopoeia A suspension of the active component is prepared in Witepsol H15 and introduced in a suitable machine with 1 suppository molds- Liquid for administration by intravenous injection g /? active component 2.0 water for injection codex rest for 1000.0 It is possible to add sodium chloride to adjust the tonicity of the solution and adjust the pH to maximum stability and / or to facilitate the dissolution of the active component by means of an alkali or a dilute acid or adding suitable pH regulating salts. The solution is prepared, rinsed and placed in ampoules of adequate size that are sealed by melting the glass. It is also possible to sterilize the liquid for injection by heating in an autoclave in accordance with one of the acceptable cycles. It is also possible to sterilize the solution by filtration and place it in sterile ampoules under aseptic conditions. The solution can be introduced in ampoules in a gaseous atmosphere.

Cartridges for inhalation g / cartridge active component micronized 1.0 lactose Codex 39.0 The active component is micronized in a grinder using fluid energy and converted to fine particles before mixing it with lactose for tablets in a high energy mixer. The pulverulent mixture is filled into No. 3 hard gelatin capsules in a suitable encapsulating machine. The content of the cartridges is administered with the help of a powder inhaler.

Pressurized aerosol with measuring valve mg / dose per 1 package micronized active component 0.500 120 mg Codex 0.050 acid oleic acid 12 mg trichlorofluoromethane for pharmaceutical use 22.25 5.34 g dichlorodifluoromethane for pharmaceutical use 60.90 14.62 g The active component is micronized in a disposer using energy from fluid and it turns into fine particles. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10 to 15 ° C and the micronized drug is introduced into the solution with the aid of a mixer with a high shear effect. The suspension is introduced in an amount measured in aluminum cans for aerosol, to which are attached suitable measuring valves that provide a dose of 85 mg of suspension; the dichlorodifluoromethane is introduced into the cans by injection through the valves.

Pharmacological properties The derivatives of the present invention are highly selective agonists for 5-HT? B? D receptors. And in particular for human 5-HTID and 5-HT? B receptors. The binding study of some examples of the compounds of the present invention with these receptors was developed according to the method described by P. PAUWELS and C. PALMIER (Neuropharmacology 33, 67, 1994). This method shows that these compounds have an affinity of less than 100 nM for human 5HT1D and 5HT? B receptors. The derivatives of the present invention are also capable, like serotonin, of inducing the constriction of the rings of the rabbit saphenous vein that is mediated by the 5HT- | B receptors. The technique used was adapted from Van Heuven-Nolsen D. et al. (Eur. J. Pharmacol., 191, 375, 1990). and of Martin G.R. and McLennan (Naunyn-Schmideberg's Arch. Pharmacol., 342, 111, 1990). These pharmacological results illustrate the advantages of the compounds of the present invention which are novel and potent 5HT? B and 5HTI D receptor agonists. In human therapy, the compounds of the general formula (I), according to the invention, are particularly useful for the treatment and prevention of disorders related to serotonin at the level of the central nervous system and the vascular system. Therefore, these compounds can be used in the treatment and prevention of depression, obsessive-compulsive disorders, bulimia, aggression, alcoholism, nicotine addiction, hypertension, nausea, sexual dysfunction, antisocial behavior, anxiety, migraine, spasticity, Alzheimer's disease and memory disorders.

Claims (11)

NOVELTY OF THE INVENTION CLAIMS

1. - The compounds corresponding to the general formula (I) 0 where, HET represents a heterocycle chosen from

Ri and R2, which are identical or different, represent a hydrogen atom, R'i, CF3, CH2CF3, C6H5, CH2C6H5, OH, OR '! SH, SR'- ,, Cl, F, Br, I, CN , NH2, NHR'-i, NR '? R2, NO2, NH-NH2, NH-NHR'L NHOH, NHCO2R' ?, NHCONH2, NHCONR'iR'2, NHSO2R1, SO2R '?, S02NH2, S02NHR' ?, COR'-i, C02R'I, CONH2, CONHR'1, CONR '? R'2, which can be found in an ortho or meta position in the aromatic ring, R3 and R4, which are identical or different, represent an atom of hydrogen, a linear or branched radical containing carbon comprising from 1 to 6 carbon atoms or a residue of benzyl or phenethyl, Y and Z, which are identical or different, represent CH or N, X represents O, S or NR7 , R5, R6 and R7, which are identical or different, represent a hydrogen atom, a linear or branched alkyl residue comprising from 1 to 6 carbon atoms or a phenyl residue which is optionally substituted with a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, a halogen atom, CF3, OCH3, CN or NO2, R'1 and R'2, which are identical or different, represent a linear or branched alkyl group comprising from 1 to 6 carbon atoms or a phenyl residue which is optionally substituted with a linear or branched alkyl residue comprising from 1 to 6 carbon atoms, Cl, Br, F, I, OCH 3, OH, NO 2, SCH 3, as well as their salts and solvates which are acceptable for therapeutic use. 2. The compounds according to claim 1, further characterized in that R-i, R2, R3 and R4 each represents a hydrogen atom.

3. The compounds according to claim 1 or 2, further characterized in that HET represents a pyridyl or pyrimidyl residue.

4. The compounds according to claim 1 or 2, further characterized in that HET represents a 5-membered heterocycle and contains from 1 to 3 heterogeneous atoms chosen from O, S or N.

5. The compounds according to one of the claims from 1 to 4, in the form of salts that are acceptable for therapeutic use, further characterized in that said salts are chosen from hydrochlorides, hydrobromides, sulfates, fumarates, maleates, methanesulfonates and succinates.

6. A method for preparing the compounds of the general formula I according to claim 1, characterized in that an intermediate of the general formula (II) (N) wherein HET, Ri and R2 are defined as in the general formula (I) is reacted with a carboxylic acid or a carboxylic acid derived from the general formula (III) (III) wherein R'3 and R 'are identical to R3 and R4 as defined in general formula (I), or R'3 and R'4 are precursors or protecting groups for R3 and R4 which will be converted to R3. and R4 after the condensation of (II) with (III) and L represents OH, Cl, O-alkyl or the group -C (= O) L representing the activated form of a carboxylic acid.

7. The compounds according to claims 1 to 5, for their application as therapeutically active substances.

8. The compounds according to claim 7, for the treatment or prevention of disorders related to serotonin.

9. The compounds according to claim 7, for the treatment or prevention of migraine, vascular facial pain and chronic vascular headache.

10. The compounds according to claim 7, for the treatment or prevention of depression, obsessive-compulsive disorders, bulimia, aggression, alcoholism, nausea, sexual dysfunction, antisocial behavior, anxiety, spasticity, Alzheimer's and Parkinson's.

11. Pharmaceutical compositions containing as active ingredient, at least one compound according to one of claims 7 to 10 and pharmaceutically acceptable excipients.