WO1995001334A1 - Arylamine-derived indole compounds as selective 5ht1d and 5ht1b receptor ligands - Google Patents

Abstract

Novel arylamine-derived indole compounds, methods for preparing same, and therapeutical uses thereof. The compounds have general formula (I), wherein R1, is, in particular, an arylamine radical of formulae (a), (b), wherein R'1 is, in particular, a hydrogen atom, a straight or branched alkyl radical or a phenyl or benzyl radical; V is a hydrogen atom or a straight or branched alkyl radical; Z is C=0, SO2, or (CH2)n wherein n is from 1 to 5; and R2, R'2, R3, R4, R5 and R6, which are the same or different, are, in particular, a hydrogen atom or a straight or branched alkyl radical.

Description

 INDOLIC COMPOUNDS DERIVED FROM ARYLAMINES AS SELECTIVE LIGANDS

5HT _1D AND 5HT _1β RECEPTORS

The present invention relates to new indole compounds derived from arylamines, to processes for their preparation and to their therapeutic uses.

Over the past twenty years, considerable progress has been made in understanding the biochemistry and physiology of serotonin or 5-hydroxytryptamine (5-HT) both at the level of the central nervous system and at the cardiovascular level. Serotonin has thus been shown to play a role in certain diseases such as depression, pain, obsessive convulsive disorders, obesity, schizophrenia, anxiety, certain sexual dysfunctions, migraine. and other vasopastic disorders. The discovery of the different subclasses of serotonin receptors has stimulated the search for selective ligands (cf. RA Glennon, Neuroscience & 'Biobehavioral Reviews, 14, 35-47, 1990; AW Schmidt, SJ Peroutka, FASEB J. â, 2242-2249, 1989) in order to better understand the pharmacological significance of each of these receptor subtypes, and to be able to identify new selective therapeutic agents, non-toxic and devoid of undesirable side effects (S. Langer, N. Brunello , G. Racagni, J. Mendlewicz, "Serotonin receptors subtypes: pharmacological significance and clinical implications" Karger ed. (1992); BE Léonard, Int. Clin. Psychopharmacology, 7, 13-21 (1992); DG Grahame-Smith, Int. Clin. Psychopharmacology, £, supplement 4.6-13 (1992) The compounds according to the present invention are powerful and selective ligands for the 5) hydroxytryptamine receptors and more particularly for the receptor recently described as a 5HTIB receptor. and / or SHTID. The medicaments according to the present invention find their use in both curative and preventive treatment of diseases linked to dysfunction of the 5HTι receptors (including the 5HTIA receptors,

5HTIB, 5HTu 5HTχ _E and 5HT _I F), to their deregulation or to modifications of the endogenous ligand (generally serotonin).

The patent application FR-A-2 671 971 describes a class of 5-O-carboxymethylated derivatives of tryptamine which are endowed with a good affinity for the 5HT _I D receptors and can consequently act as therapeutic agents for migraine treatment. However, the application FR 2 671 971 in no case describes or suggests the arylamine derivatives described in the present invention. The present invention relates to compounds of formula I:

their preparation and the drugs containing them.

In formula I:

Ri represents an arylamine radical of formula:

in which :

R'i represents a hydrogen atom, a branched or linear alkyl radical, a phenyl or benzyl radical, or an acyl radical (COR "ι) in which R" ι is a branched or linear alkyl radical, a phenyl or benzyl radical .

V represents one or more substituents, identical or different, which can be in various positions on the aromatic ring to which they are attached, such as hydrogen, a branched or linear alkyl radical (optionally substituted by OH, NH ₂ , NHR " _! , SR "ι, OR" i, COR "ι, NHCOR" ι, NHSθ ₂ R "ι, a phenyl radical (which can itself be variously substituted), benzyl, cycloalkyl, a halogen (F, Cl, Br or I), a nitrile (CN), a nitro (NO ₂ ), a hydroxyl (OH), an ether (OR "ι), an acyl (COR" ι), a thioalkyl (SR "ι), an amine (NH ₂ or NHR "ι), an amide (NHCOR" ι), a sulfonamide (NHSO ₂ R "ι) or a heterocycle such as an imidazole, 'triazole, thiazole, pyrrole, furan or thiophene. R" ι represents a linear alkyl radical or branched, a phenyl radical (which can itself be variously substituted), benzyl or cycloalkyl.

X and Y independently represent a methylene group (CH ₂ ), an amino residue (NR "ι), an oxygen (O) or a sulfur (S). W represents a branched or linear alkyl radical optionally substituted by an alcohol, alkoxy group , thiol, alkylthio or amine, a phenyl, benzyl or cycloalkyl radical.

Z represents C = O, SO ₂ , (CH2) n, CO (CH ₂ ) n, or SO ₂ (CH ₂ ) _n , in which n is an integer between 1 and 5. R ₂ represents an atom of hydrogen, a branched or unitary alkyl radical or a phenyl, benzyl, cycloalkyl, pyrrole, furan, pyridinyl, thiophenyl radical, optionally substituted with one or more substituents chosen from halogen atoms and alkyl, aryl, acyl, alkoxy and alkylthio. R ' ₂ represents a hydrogen atom, a branched or linear alkyl radical or a phenyl radical.

R3 represents a hydrogen atom, a branched or linear alkyl radical or a benzyl or phenethyl radical.

R ₄ represents a hydrogen, chlorine, fluorine or bromine atom or a linear or branched alkyl radical.

R ₅ represents a hydrogen atom, a branched or linear alkyl radical or a benzyl or phenethyl radical.

R ₆ represents a hydrogen atom, a linear or branched alkyl radical, an acyl (COR ₇ ), acyloxy (Cθ ₂ R ₇ ) or acylamino (CONHR) radical in which R ₇ represents a linear or branched alkyl radical, or a variously substituted phenyl radical.

Their salts, solvates and bioprecursors acceptable for therapeutic use. In the above definitions and those which will be cited below, unless otherwise stated, the alkyl, alkoxy or alkylthio radicals contain 1 to 6 carbon atoms in a straight or branched chain, the cycloalkyl portions contain 3 to 7 carbon atoms and the polycycloalkyl portions contain 7 to 12 carbon atoms. In the formula, the halogen atoms are preferably the chlorine, fluorine and bromine atoms.

The compounds of formula I containing 1 or more asymmetric centers have isomeric forms. The racemates and pure enantiomers of these compounds are also part of this invention.

The invention also includes the salts, solvates (for example hydrates) and bioprecursors of these compounds acceptable for therapeutic use.

Among the salts acceptable for the therapeutic use of indoles of general formula I, mention will be made of salts formed by addition with organic or inorganic acids and for example hydrochlorides, hydrobromides, sulfates, fumarates and maleates. Other salts may be useful in the preparation of the compounds of formula I, for example adducts with creatinine sulfate. The expression "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 to a human being, are converted into the organism into a compound of formula I.

A preferred class of compounds according to the invention consists of those which correspond to the general formula la:

in which Ri, R ₂ , R ₅ and Rg are defined as above in formula I and their salts, solvates (for example hydrates) and bioprecursors acceptable for therapeutic use.

The invention also includes the preparation by the general methods described below of the compounds of general formula I and their salts, solvates (for example hydrates) or bioprecursors acceptable for therapeutic use.

In general, the compounds of general formula I are prepared by condensation of a derivative of general formula II:

in which Ri, Z, R ₂ , R ' ₂ are defined as in formula I and X is defined as a leaving group such as a halogen (preferably a bromine, iodine or chlorine atom), a mesylate , a tosylate or triflate with a serotonin derivative of general formula III:

in which the residues R ₃ , R ₄ , R ₅ and R- _$ are defined as described above in formula I except that Re cannot be a hydrogen. The preparation of the derivatives of formula I in which Rβ is hydrogen is carried out by hydrolysis of a derivative of formula I in which, R ₆ is a group COR or CO ₂ R ₇ , preferably CO ₂ R ₇ in which R ₇ is preferably a tbutyl or benzyl residue. The transformation of the compounds of formula in which Rg is a CO ₂ ^t Bu group (BOC) into compounds of formula I in which Rs is hydrogen is preferably carried out using an acid (such as hydrochloric acid or l 'trifluoroacetic acid) in an organic solvent such as ether, tetrahydrofuran, toluene, dichloromethane or chloroform at a temperature between -15 ° C and 40 ° C.

The transformation of the compounds of formula I in which Rg is a CO ₂ CH ₂ C ₆ H _{5 group} (commonly called Z) into compounds of formula I in which Rg is hydrogen is preferably carried out by catalytic hydrogenation preferably using palladium on carbon as a catalyst, under atmospheric hydrogen pressure, in a solvent such as THF, ethanol, isopropanol which may contain up to 10% acetic or citric acid, at a temperature between 0 ° and 40 ^β C.

The preparation of the derivatives of formula I by condensation of the derivatives of formula II with the derivatives of formula III can be carried out, in general, in the presence of an organic base (NaH, KH, Et ₃ N, DBU, DBN, TMP, DIPEA, * BuOK) or inorganic (K ₂ CCs, KHCO ₃ , NaH∞ ₃ , CS ₂ CC5, KOH, NaOH, CaCO ₃ ...) in an anhydrous solvent such as THF, DMF, DMSO, acetone, diethyl ketone, methyl ethyl ketone, acetonitrile or DME at a temperature between 20 ° and 140 ° C, in the presence or not of a salt as catalyst and which can be Kl, BU ₄ NI, Lil, AgBF. ₄ ,

AgClO Ag ₂ C0 ₃ , KF, B11 ₄ NF or CsF. The choice of experimental conditions for carrying out the condensation between the derivatives of formula II and III to obtain the derivatives of formula I is obviously dependent on the nature of the substituents in the reactants II and III and more particularly on the nature of the groups Z, R ₂ and R ' ₂ . For example, when Z is a carbonyl function (CO), R2 is a hydrogen atom and X a halogen, the condensation between II and III to give I is preferably carried out at 80 ° C., in methyl ethyl ketone, in the presence of an excess of K ₂ CO ₃ and of a catalytic amount of Kl. When Z is a carbonyl group and R ₂ and R ' ₂ are both different from hydrogen, the preferred method consists in reacting a derivative of formula III with this derivative of formula II, in the presence of a salt of silver such as silver tetrafluoroborate and an inorganic base such as K ₂ CO ₃ .

When group Z is defined as (CH2) _n, the condensation between derivatives II and III is carried out in a solvent such as DMF or DMSO, in the presence of a base such as DBU or DIPEA, at 100 ° C. in the presence of

Kl or Bu NI in catalytic quantity. An alternative and particularly appreciated method consists in condensing derivatives II and III, in neutral condition, in DMF, in the presence of a large excess of a fluoride such as KF, CsF or BU ₄ NF. The compounds of general formula II in which the substituents

Ri, R ₂ , R ' ₂ and X are defined as above and are prepared by methods which differ according to the nature of the residue Z. This is how the derivatives of formula II in which Z is a carbonyl group forming part of 'an amide function are obtained by reaction of the arylamines of general formula IV.

Rl - H

(IV)

in which the residue Ri is defined as in formula I, with a derivative of formula V

\ R ' ₂

in which R ₂ and R ' ₂ are defined as in formula I and Z represents C = O. This reaction which makes it possible to prepare the derivatives of formula II in which Z = CO and X = C1 from arylamines IV and acid chlorides V is a well-known amide formation reaction from an amine and an acid chloride and can be carried out in a solvent such as dichloromethane, THF, chloroform, acetone , methyl ethyl ketone, DME or acetonitrile, at a temperature between -20 ° and 80 ° C, in the presence of a base such as a tertiary amine (DBU, Et ₃ N, DIPEA) or inorganic bases such that carbonates

(KHCO ₃ , NaHCO ₃ , K ₂ CO ₂ , Na ₂ Cp ₃ , CaCO ₃ , CS ₂ CO ₃ ) soda or potash.

The derivatives of formula II in which Z represents a group - (CH ₂ ) _n - are generally prepared by condensation of an arylamine of formula IV with a derivative of formula VI

R '„

(VI)

in which X represents a leaving group such as chlorine, bromine, iodine, a mesylate, tosylate, triflate group, R ₂ and R ′ ₂ are defined as in formula I and X ′ can be either identical to X, either represents an OR 'group in which R' is defined as a protective group for an alcohol such as a silylated ether (SiME ₃ , SitBuMe ₂ , SiC ₆ H ₅ Me), a tetrahydropyran or a benzyl or a trityl. It is understood that, in the case where X 'is different from X, the condensation between the arylamine of formula IV and the intermediate VI is followed by the hydrolysis of the protective group OR' to give an alcoholic derivative which is transformed into a leaving group, which leads to compounds II in which Ri, R ₂ , R ' ₂ and X are defined as above. In the procedure mentioned above, the hydrolysis of the OR 'function into alcohol is carried out by the methods described and appropriate according to the nature of R' (refer to the work of TW Greene, "Protective groups in organic synthesis ", John Wiley & Sons, 1981) and the transformation of the alcohol thus obtained into a leaving group (so as to obtain the compounds II) is carried out by the techniques and methods well known for this type of transformation, such as use of SOCl ₂ or POCI ₃ in dichloromethane for the formation of derivatives of formula II in which X = C1, the use of PBr ₃ or Br ₂ PPh ₃ for the formation of derivatives of formula II in which X = Br, the use of PI ₃ or P ₂ I ₄ for the formation of derivatives of formula II in which X = l, the use of tosyl chloride for the formation of derivatives of formula II in which X = OTos, the use of mesyl chloride for the formation of derivatives of formula II in which X≈OMes and finally the use of triflic anhydride for the formation of derivatives of formula II in which X = OTf.

The derivatives of formula II in which Z = Sθ ₂ are generally prepared by reaction of the arylamine derivatives of general formula IV in which the group Ri is defined as in general formula I with a derivative of formula V in which R ₂ and R ' ₂ are defined as in formula I and Z represents SO.

The compounds of general formula I in which Z = (CH ₂ ) _n can also be prepared by another process which consists in treating an arylamine of general formula IV:

Rl-H

(TV)

in which Ri is defined as in general formula I, with a serotonin derivative of general formula VII:

in which the residues R ₂ , R ' ₂ , R ₃ , R ₄ , R ₅ and Re are defined as described previously in the formula, except that Re cannot be hydrogen and X is defined as a leaving group such as a halogen (preferably a bromine, iodine or chlorine atom), a mesylate, a tosylate or a triflate or the precursor of a leaving group such as hydroxyl radical.

The preparation of the derivatives of formula I in which Rg is a hydrogen by the general process (B) (condensation of intermediates IV and VII is carried out by hydrolysis of a derivative of formula I in which Re is an amine protecting group as described previously.

The preparation of the derivatives of formula I in which Z represents a residue by this process is carried out by condensation between an arylamine derivative of formula IV in which Ri is defined as above and an intermediate of general formula VII in which X is a leaving group such as a halogen (preferably a bromine, chlorine or iodine atom), a mesylate, a tosylate or a triflate, Z represents - (Ch2) _n ^_ _> R2 _> R'2 »R ₃ , R4, 5 e R → c, are defined as in formula I. This reaction can be carried out in the presence of an organic base (NaH, tBuOK, DBU, DIPEA) or inorganic (KOH, K ₂ CO ₃ , NaHCO ₃ , CS ₂ CO3 ) in an anhydrous solvent such as THF, DMF, DMSO,

Pacetonitrile or methyl ethyl ketone at a temperature between 20 and 100 ° C.

The intermediates of formula VII can be prepared by condensation of a serotonin derivative of formula III:

in which R3, R ₄ , R ₅ and R g are defined as in formula I except that R → _$ must be different from hydrogen with a derivative of formula

(IX) in which X 'and X "can be halogens (chlorine, bromine or iodine) simultaneously if R ₂ and R' ₂ are hydrogen, X" can be an OR group where R is a conventional protective group such as a silyl group (trimethylsilyl, triethylsilyl, tbutyldimethylsilyl), benzyl, tetrahydropyranyl or trityl and X 'represents a leaving group such as a halogen (preferably a chlorine, an iodine or a bromine), an OMes, an OTos or an OTf.

This condensation reaction between intermediates VIII and IX as described above is carried out in basic medium (in the presence of a base such as NaH, KH, tβuOK, K ₂ CO ₃ , Cs ₂ CO ₃ , DIPEA, DBU) in a anhydrous solvent such as DMSO, DMF, THF, acetonitrile, methyl ethyl ketone or DME at a temperature between 0 ° C and 100 ° C.

In the particular case of derivatives of formula I in which Ri, R ₃ , R ₄ , R ₅ are described as above but where Z represents - (CH ₂ ) _n - and R (, is different from COR, a preferred synthesis method consists in reducing the corresponding derivatives of formula I in which Z represents CO by a reducing agent which makes it possible to transform an amide into an amino such as borane (BH ₃ .Me ₂ S) or UAIH ₄ using the well-known methods and techniques for this type of reduction.

It is also necessary to consider as part of this invention the possibility of transforming derivatives of formula I initially prepared as described above into new derivatives of formula I, by techniques and methods well known to those skilled in the art. Thus, and by way of example, the derivatives of formula I in which R ₃ represents a hydrogen can be produced into derivatives of formula I in which R ₃ represents an alkyl, benzyl or acyl residue by reaction respectively with a alkyl, benzyl halide or an acid chloride or acid anhydride, in basic medium by the methods and techniques well known for this type of reaction and which, by way of example, are described in "The Chemistry of Indoles "edited by RS Sundberg volume 18 of" Organic Chemistry, A Series of Monograph ", Académie Press, NY, 1970. It will be understood that in some of the above transformations, it may be necessary or desirable to protect possible sensitive groups of the molecule in question in order to avoid undesirable side reactions. This can be achieved by the use of conventional protecting groups such as those described in "Protective Groups in Organic Synthesis" ed. JF Me Owie, Plenum Press, 1973, and in TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, 1981. Protective groups can be removed at any suitable later stage, using the methods and techniques also described in references cited above. It is thus that in certain particular cases it may be necessary to protect the indole nitrogen during the preparation of compounds of formula I in which R ₃ represents a hydrogen.

When it is desired to isolate a compound according to the invention in the form of a salt, for example in the form of a salt formed by addition with an acid, this can be achieved by treating the free base of general formula I with an appropriate acid preferably in an equivalent amount, or with creatinine sulfate in an appropriate solvent.

When the processes described above for preparing the compounds of the invention give mixtures of stereoisomers, these isomers can be separated by conventional methods such as preparative chromatography.

When the new compounds of general formula I have one or more asymmetric centers, they can be prepared in the form of a racemic mixture or in the form of enantiomers, either by enantioselective synthesis or by resolution. The compounds of formula I having at least one asymmetric center can for example be separated into their enantiomers by the usual techniques such as the formation of diastereomeric pairs by formation of a salt with an optically active acid such as the acid (-) di -p-toluoyl-1-tartaric, (+) di- p-toluoyl-1-tartaric, (+) camphor sulfonic acid, (-) camphor sulfonic acid, (+) phenylprop acid ionic, (-) phenylpropionic acid, followed by fractional crystallization and regeneration of the free base. The compounds of formula I in which Rg is a hydrogen comprising at least one asymmetric center can also be resolved by the formation of diastereomeric amides which are separated by chromatography and hydrolysis to release the chiral auxiliary.

In general, the compounds of formula I can be purified by the usual methods, for example by crystallization (in particular when the compounds of formula I are isolated in the form of a salt), chromatography or extraction.

The following examples illustrate the invention without, however, limiting its scope.

Example 1 - 4-chloro N-ftryptamine 5-0-carboxymethyl) aniline hydrochloride:

1A - 5-hvdroχγtrγpfaτιιiτιe- terbutylcarbamate:

The creatine sulphate monohydrate salt of serotonin (20 g, 49.3 mmol) is treated with diterbutyl dicarbonate (16.1 g, 74 mmol) in water (360 ml) in the presence of 2N sodium hydroxide (72 ml) to ambient temperature. After 1 hour the reaction is diluted with ethyl acetate (600 ml) and stirred for 10 minutes. The 2 phases obtained are separated by decantation; the organic phase is washed with water, dried over sodium sulfate, filtered and then evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane / methanol mixture (20: 1; v / v). The pure compound is isolated in the form of brown syrup (11.1 g; 81%).

Elementary analysis (C ₁₅ H ₂₀ N ₂ O5),% calculated: C 65.20; H 7.30; N 10.14; % found: C 64.15; H 7.47; N 9.77. Proton nuclear magnetic resonance spectrum. CDCU (ppm): 1.44 s, 9H (tβu); 2.86 t, 2H (CH ₂ ); 3.45 m, 2H (CH ₂ ); 4.68 s, 1H (NH); 5.59 s, 1H (OH); 6.77-7.26 m, 4H (Ar); 7.99 s, 1H (NH).

1 B - 4-chloro N- (terbutylcarbamate-trvptamine 5-O- carboxymethyl) aniline:

The 4-chloroaniline (500 mg; 3.92 mmol) in solution in methyl ethyl ketone (15 ml) in the presence of calcium carbonate (1.17 g; 11.75 mmol) at 0 ° C. is treated, drop by drop, with chloroacetyl chloride (0.37 ml); 4.7 mmol). After 2 hours of stirring at 0 ° C., the medium is diluted with ethyl acetate and then filtered through celite. Celite is washed alternately with sodium hydroxide (2N) and ethyl acetate. The phases are decanted; the organic phase is washed with water and then with a saturated sodium chloride solution and finally dried over sodium sulfate, filtered and evaporated to dryness. The raw syrup obtained is redissolved in methyl ethyl ketone (8 ml) in the presence of the LA product (433 mg; 1.57 mmol), potassium carbonate (525 mg; 3.93 mmol) and potassium iodide ( 26 mg; 0.16 mmol). The mixture is brought to reflux for 7 hours then left overnight at room temperature. The medium is then diluted with ethyl acetate, washed with sodium hydroxide (2N), with water and then with a saturated solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane / acetone mixture (20: 1; v / v). The pure compound is isolated (488 ml; 70%) in the form of a colorless syrup. Proton nuclear magnetic resonance spectrum. CDCh (ppm): 1.44 s, 9H ( ^t Bu); 2.91 1.2H (CH ₂ ); 3.43 m, 2H (CH ₂ ); 4.65 s, 3H (COCH ₂ CM-NH); 6.92 dd,

1H (Ar); 7.06-7.61 m, 7H (Ar); 8.16 s, 1H (NH), 8.46 s, 1H (NH). 1 - 4-chloro N- hydrochloride (tryptamine 5-O-carboxymethyl) aniline:

Compound 1B (200 mg; 0.45 mmol) in solution in toluene (10 ml) is treated with trifluoroactic acid (1.2 ml). After 1 hour of stirring at room temperature, the mixture is diluted with ethyl acetate, washed with sodium hydroxide (2N), with water and then with a saturated solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and evaporated.

The syrup obtained is chromatographed on a column of silica gel eluted with a chloroform / methanol / ammonia mixture (80: 9: 1, v / v). The pure product is isolated in the form of a beige solid (116 mg; 75%). The compound obtained is diluted in dichloromethane and the hydrochloride is formed by adding the necessary amount of hydrochloric acid in ether. Elementary analysis (Cι ₈ Hι ₈ N ₃ O ₂ Cl ₂ ); % calculated: C 56.85; H 5.04; N 10.25; % found: C 56.86; H 5.08; N 10.61.

Proton nuclear magnetic resonance spectrum. DMSO-dpJppm):

2.98 s, 4H (CH ₂ ); 4.72 s, 2H (COCH ₂ O); 6.90 dd, 1H (Ar); 7.20-7.77 m, 7H (Ar);

8.01 s, 3H (NH ₃ +); 10.41 s, 1H (NH); 10.89 s, 1H (NH). Melting point: 240 ° C.

Example 2 - 4-Fluoro N- hydrochloride (tryptamiπe 5-O- carboxymethyl) aniline:

Compound 2 is obtained from 4-fluoroaniline (0.426 ml; 4.5 mmol), chloroacetyl chloride (0.430 ml; 5.4 mmol) and 5-hydroxytryptamine LA terbutylcarbamate (497 mg; 1, 8 mmol) according to the procedure described for the preparation of Example 1. The purification of the product in base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 16.5: 1.5; v / v). The pure product is isolated in the form of a white powder (400 mg; 68%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 2.

Elementary analysis (GsHio tCbFCl). % calculated: C 59.42; H 5.26; N 11.55; % found: C 59.91; H 5.31; N 11.42.

Proton nuclear magnetic resonance spectrum. DMSO-D ^ (ppm):

2.98 m, 4H (CH ₂ ); 4.70 s; 2H (COCH ₂ O); 6.86 dd, 1H (Ar); 7.12 - 7.75 m, 7H (Ar); 10.28 s, 1H (NH); 10.87 s, 1H (NH). Melting point: 230 ° C.

EXAMPLE 3 N- (tryptamine 5-O-carboxymethyl) 1-naphthylamine hydrochloride

Compound 2. is obtained from 1- (naphthylamine) (0.338 ml); 1.8 mmol), chloroacetyl chloride (0.172 ml; 2.16 mmol) and 5-hydroxytryptamine A terbutylcarbamate (198 mg; 0.72 mmol) according to the procedure described for the preparation of the example

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a chloroform / methanol / ammonia mixture (80: 19: 1; v / v). The product is obtained in the form of a slightly yellow syrup (137 mg; 53%) which, after treatment with hydrochloric acid in ether, with hydrochloride of compound 3 ..

Elementary analysis (C ₂₂ H _{22 3} O ₂ CI),% calculated: C 66.75; H 5.60; N 10.61; % found: C 67.10; H 5.61; N 10.46. Proton nuclear magnetic resonance spectrum. DMSO-dft (ppm):

3.02 s, 4H (CH ₂ ); 4.87 s, 2H (COCH ₂ O); 6.96 dd, 1H (Ar); 7.24-8.01 m, 1 H (Ar + NH ₃ +); 10.21 s, 1H (NH); 10.91 s, 1H (NH). Melting point: 228 ° C.

EXAMPLE 4 7-Methoxy N-ftrvptamine 5-O-carboxymethyl) 1-naphthylamine hydrochloride:

Compound 4 is obtained from 7-methoxy 1-naphthylamine (500 mg; 2.88 mmol), chloroacetyl chloride (0.276 ml; 3.46 mmol) and 5-hydroxytryptamine LA terbutylcarbamate (318 mg ; 1.15 mmol) according to the procedure described for the preparation of Example! __ .. The purification of the product in the form of the base is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80 : 18.5: 1.5; v / v). The pure product is isolated in the form of a beige powder (304 mg; 58%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 4.

Elementary analysis (C ₂₃ H ₂₄ N ₃ O ₃ Cl),% calculated: C 64.86, H 5.68; N 9.87; % found: C 64.72; H 5.78; N 9.73.

Proton nuclear magnetic resonance spectrum. DMSO-d ^ (ppm):

2.91 m, 4H (CH ₂ ); 3.64 s, 3H (OMe); 4.87 s, 2H (COCH ₂ O); 6.95 dd, 1H (Ar); 7.14- 7.88 m, 9H (Ar); 10.09 s, 1H (NH); 10.84 s, 1H (NH). Melting point: 160 ° C (decomposition). Example 5 4-amino hydrochloride rN- (trvptamine 5-O-carboxymethvDI biphenyl:

Compound 5. is obtained from 4-aminobiphenyl (3 g; 17.7 mmol), chloroacetyl chloride (1.7 ml; 21.2 mmol) and 5-hydroxytryptamine LA terbutylcarbamate (1.9 g; 7.08 mmol) according to the procedure described for the preparation of the example. The purification of the product in base form is carried out by chromatography on a column of silica gel eluted with a chloroform / methanol / ammonia mixture (80: 9: 1; v / v). The product is obtained in the form of a white powder (1.14 g; 42%) which, after treatment with hydrochloric acid in ether, leads to the hydrochloride monohydrate of compound 5 ..

Elementary analysis (C ₂₄ H ₂ 6N ₃ O ₃ Cl),% calculated: C 65.50; H 5.95; N 9.54; % found: C 66.97; H 5.95; N 9.45.

Proton nuclear magnetic resonance spectrum. DMSO-ck (ppm):

3.01 s, 4H (CH ₂ ); 4.75 s, 2H (COCH ₂ O); 6.90 dd, 1H (Ar); 6.92-7.84 m, 12H (Ar); 8.09 s, 3H (NH ₃ +); 10.38 s, 1H (NH); 10.91 s, 1H (NH).

Melting point: 173 ° C.

Example 6 4-amino hydrochloride rN- (trvptamine 5-O-carboxymethyl) 4'-methyl biphenyl:

Compound 6. is obtained from 4-amino 4'-methylbiphenyl (ref. Byron, DJJChem. Soc. (C), 840-845 (1966)) (500 mg; 2.73 ml), chloroacetyl chloride (0.261 ml, 3.27 mmol) and 5-hydroxytryptamine 1A terbutylcarbamate (361 mg; 1.31 mmol) according to the procedure described for the preparation of the example. The purification of the product in base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 18.5: 1.5, v / v). The pure product is isolated in the form of a white powder (340 mg; 65%) which, after treatment with hydrochloric acid in ether, leads to the hydrochloride of the compound £.

Elementary analysis (C ₂₅ H ₂₆ N ₃ O ₂ Cl),% calculated: C 68.88; H 6.01; N 9.64; % found: C 69.93; H 6.16; N 9.76

Proton nuclear magnetic resonance spectrum. DMSO-dft (ppm):

2.33 s, 3H (Me); 2.96 m, 4 H (CH ₂ ); 4.73 s, 2H (COCH ₂ O); 6.90 dd, 1H (Ar); 7.06- 7.80 m, 11H (Ar); 10.27 s, 1H (NH); 10.84 d, 1H (NH). Melting point: 173 ° C (polymorphism).

EXAMPLE 7 4-amino hydrochloride TN-methyl N-fptptamine 5-O-carboxymethyl) 1 biphenyl:

Compound 7. is obtained from (N-methyl) 4-amino-p-biphenyl (428 mg; 2.33 mmol), chloroacetyl chloride (0.225 ml; 2.80 mmol) and terbutylcarbamate from 5 -hydroxytryptamine LA (255 mg; 0.932 mmol) according to the procedure described for the preparation of Example 1. The purification of the product in base form is carried out by chromatography on a column of silica gel eluted with a chloroform / methanol / ammonia mixture (80: 18.5: 1.5, v / v). The pure product is isolated in the form of a colorless syrup (190 mg; 51%) which leads, after treatment with hydrochloric acid in ether, with the hydrochloride of compound 7.

Elementary analysis (C ₂ 5H ₂ 6N3O ₂ CI),% calculated: C 68.88; H 6.01; N 9.64; % found: C 68.81; H 6.09; N 9.44. Proton nuclear magnetic resonance spectrum. DMSO-dfi (ppm):

3.02 m, 4H (CH ₂ ); 3.28 s, 3H (Me); 4.53 s, 2H (COCH ₂ O); 6.63-7.79 m, 1 p.m. (Ar);

8.08 s, 3H (NH ₃ +) î 10.85 d, 1H (NH).

Melting point: 235 ° C (decomposition).

Example 8 - 4-AminorN- hydrochloride (tryptamine 5-O- carboxymethvm 3.2 ^> -dimethyl biphenyl:

Compound & is obtained from 3,2'-dimethyl 4-aminobiphenyl

(633 mg; 3.20 mmol), chloroacetyl chloride (0.310 ml; 3.84 mmol) and 5-hydroxytryptamine LA terbutylcarbamate (345 mg; 1.28 mmol) according to the procedure described for the preparation of l 'example J _^ . Purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol ammonia mixture (80: 18.5: 1.5, v / v). The pure product is isolated (166 mg; 33%) and leads, after treatment with hydrochloric acid in ether, to the hydrochloride hemihydrate of compound 8. Elemental analysis (C ₂ 6H ₂₉ N ₃ θ ₂ , ₅ Cl), % calculated: C 68.03; H 6.36; N 9.15; % found: C 69.04; H 6.45; N 8.94.

Proton nuclear magnetic resonance spectrum. DMSO-dfi (ppm):

2.22 s, 3H (Me); 2.24 s, 3H (Me); 2.97-3.07 m, 4H (CH ₂ ); 4.76 s, 2H (COCH ₂ O);

6.90 dd, 1H (Ar); 7.13-7.53 m, 10H (Ar); 7.96 s, 3H (NH3 +); 9.56 s, 1H (NH);

10.91 s, 1H (NH). Melting point: 128 ° C. Example 9 4-amino hydrochloride fN-ftryptamine 5-O- (- methyl-carboxymethvDI biphenyl:

Compound 9. is obtained from 4-aminobiphenyl (1 g; 5.91 mmol), α-methyl-chloroacetyl chloride (0.68 ml; 7.09 mmol) and 5-hydroxytryptamine terbutylcarbamate LA (631 mg; 2.28 mmol) according to the procedure described for the preparation of Example. L The purification of the product in the form of the base is carried out by chromatography on a column of silica gel eluted with a chloroform / methanol / ammonia mixture (80: 1; 1, v / v). The pure product is isolated (451 mg; 50%) and leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound â.

Elementary analysis (C ₂₅ H ₂₆ N ₃ O ₂ Cl),% calculated: C 68.88; H 6.01; N 9.64; % found: C 68.50; H 6.07; N 9.24.

Proton nuclear magnetic resonance spectrum. DMSO-dfi (ppm):

1.56 d, 3H (Me); 2.98 s, 4H (CH ₂ ); 5.02 q, 1H (CO-CHMe-O); 6.35 dd, 1H (Ar); 7.19-7.82 m, 12 H (Ar); 8.02 s, 3H (NH ₃ +); 10.47 s, 1H (NH); 10.85 d, 1H (NH).

Melting point: 184 ° C.

Example 10 - 3-amino N- hydrochloride (trvptamine 5-O-carboxymethyl) fluoranthene:

Compound 10 is obtained from 3-aminofluoranthene (400 mg; 1.84 mmol), chloroacetyl chloride (0.176 ml; 2.21 mmol) and 5-hydroxytryptamine 1A terbutylcarbamate (202 mg; 0.74 mmol) according to the procedure described for the preparation of Example 1_. The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 18: 2, v / v). The pure product is isolated (224 mg; 70%) and leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 1Q, Elemental analysis (C ₂₈ H ₂₆ N ₃ O ₃ Cl),% calculated: C 66.46; H 5.58; N 8.30; % found: C 66.70; H 5.04; N 8.10.

Proton nuclear magnetic resonance spectrum. DMSO-d _f Jppm):

3.02 s, 2H (CH ₂ ); 3.35 s, 2H (CH ₂ ); 4.94 s, 2H (CO-CH ₂ -O); 6.97 dd, 1H (Ar); 7.23-

8.16 m, 15 H (Ar + NH ₃ +); 10.44 s, 1H (NH); 10.91 d, 1H (NH). Melting point: 187 ° C (decomposition).

Example 11 - 2-amino N- hydrochloride (tryptamine 5-O-carboxymethyl) fluorene:

H

1 1

Compound JJL is obtained from 2-aminofluorene (1 g; 5.52 mmol), chloroacetyl chloride (0.53 ml; 6.6 mmol) and 5-hydroxytryptamine 1A terbutylcarbamate (610 mg; 2 , 2 mmol) according to the procedure described for the preparation of the example. The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a chloroform / methanol / ammonia mixture (80: 18.5: 1 , 5, v / v). The pure product is isolated (560 mg; 64%) and leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 11. Elementary analysis (C ₂₅ H ₂₄ N3O ₂ CI),% calculated: C 69.20; H 5.57; N 9.68; % found: C 69.31; H 5.63; N 9.59.

Proton nuclear magnetic resonance spectrum. DMSO-dft (ppm):

3.00 m, 4 H (CH ₂ ); 3.91 s, 2H (ArCH ₂ Ar): 4.74 s, 2H (CO-CH ₂ -O); 6.90 dd, IH

(Ar); 7.20-8.02 m, 10 H (Ar); 10.28 s, 1H (NH); 10.86 s, 1H (NH). Melting point: 168 ° C.

Example 12 - 4-nitro N- (trvptamine 5-O-carboxymethyl) aniline hydrochloride:

Compound 12. is obtained from 4-nitroaniline (1 g; 7.24 mmol), chloroacetyl chloride (0.58 ml; 7.24 mmol) and 5-hydroxytryptamine LA terbutylcarbamate (800 mg ; 2.90 mmol) according to the procedure described for the preparation of the example

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 18: 2; v / v). the pure product is isolated in the form of a yellow-orange syrup (462 mg; 45%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 12. Elemental analysis (Cι ₈ Hi9N ₄ O ₄ Cl , 3/4 H ₂ O),% calculated: C 53.47; H 5.11; NOT

13.86; % found: C 54.26; H 5.11; N 13.42.

Proton nuclear magnetic resonance spectrum. DMSO-dfi (ppm):

2.91 m, 4H (CH ₂ ); 4.79 s, 2H (COCH ₂ O); 6.86 dd, 1H (Ar); 7.17-7.31 m, 3H (Ar);

7.97 d, 2H (Ar); 8.22 d, 2H (Ar); 10.84 s, 1H (NH). Melting point: 73 ° C (decomposition). Example 13 - N-ftryptamine 5-O-carboxymethyl hydrochloride) 1.2.3.4-tetrahydroquinoline:

Compound 13. is obtained from 1,2,3,4-tetrahydroquinoline (0.94 ml; 7.51 mmol), chloroacetyl chloride (0.60 ml; 7.51 mmol) and terbutylcarbamate. 5-hydroxytryptamine 1A (928 mg; 3.36 mmol) according to the procedure described for the preparation of Example 1.

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 18.5: 1.5; v / v). The pure product is isolated in the form of a colorless syrup (841 mg; 70%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 13. Elemental analysis (C ₂₁ H ₂₄ N ₃ O ₂ CI 1.2 H ₂ O),% calculated: C 61.89; H 6.53; NOT

10.31; % found: C 61.60; H 6.21; N 10.03.

Proton nuclear magnetic resonance spectrum. DMSO-Sft (ppm): 1.91 m, 2H (CH ₂ ); 2.66 1.2H (CH ₂ ); 2.98 m, 4H (CH ₂ ); 3,781.2H (CH ₂ ); 4.91 s, 2H

(COCH ₂ O); 6.70 dd, 1H (Ar); 7.01-7.60 m, 7H (Ar); 8.06 s, 3H (NH ₃ +) 10.86 s, IH

(NH).

Melting point: 119-120 ° C. EXAMPLE 14 4-chloro N- hydrochloride (trvptamine 5-O-methylsulfonyl) aniline:

Compound 14 is obtained from 4-chloroaniline (1 g; 7.84 mmol), chloromethanesulfonyl chloride (1.17 g; 7.84 mmol) and 5-hydroxytryptamine LA terbutylcarbamate (866 mg; 3 , 13 mmol) according to the procedure described for the preparation of Example 1.

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 18: 2; v / v). The pure product is isolated in the form of a colorless syrup (600 mg; 46%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 14.

Example 15 - 4-nitro N- (N-dimethyltryptamine 5-O-carboxymethyl) aniline hydrochloride:

Compound 1 is obtained from 4-nitroaniline (200 mg; 1.45 mmol), chloroacetyl chloride (0.12 ml; 1.45 mmol) and bufotenine (118 mg; 0.58 mmol) according to the procedure described for the preparation of Example 1. The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (85: 14: 1; v / v). The pure product is isolated in the form of a yellow-orange syrup (137 mg; 62%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 15.

Example 16 - N- hydrochloride (trvptamine 5-O-ethvP 1-naphthylamine:

Compound 3. (200 mg; 0.55 mmol), dissolved in anhydrous ethyl ether (5 ml), is treated with lithium aluminum hydride

(62 mg; 1.65 mmol) at room temperature. After 6 hours of stirring, the reaction is stopped by adding wet sodium sulfate, then diluted with ethyl acetate, filtered through celite and evaporated to dryness.

The syrup obtained is purified by chromatography on a column of silica gel eluted with a chloroform / methanol / ammonia mixture

(80: 18: 2; v / v). The product is obtained in the form of a colorless syrup (154 mg;

81%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound lf>.

EXAMPLE 17 4-nitro 2-methoxy N- hydrochloride (tryptamine 5-0-carboxymethyl) aniline

Compound 7 is obtained from 2-methoxy 4-nitro aniline (1.5 g; 8.92 mmol), chloroacetyl chloride (0.71 ml; 8.92 mmol) and 5- terbutylcarbamate hydroxytryptamine 1A (1.37 g; 4.95 mmol) according to the procedure described for the preparation of Example 1.

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 19: 1; v / v). The pure product is isolated in the form of yellow crystals (600 mg; 32%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 17. Elemental analysis (C ₁₉ H ₂₁ N ₄ O ₅ CI , 0.5 H ₂ O),% calculated: C 53.09; H 5.16; NOT

13.03; Cl 8.25; % found: C 53.86; H 5.16; N 12.61; Cl 8.36.

Proton nuclear magnetic resonance spectrum. DMSO-d ^ (ppm): 3.01 m, 4H (CH ₂ ); 4.03 s, 3H (MeO); 4.85 s, 2H (COCH ₂ O); 6.87 dd, 1H (Ar); 7.21-

7.35 m, 3H (Ar); 7.84-7.97 m, 2H (Ar); 8.14 s, 3H (NH ₃ +); 8.44-8.49 d, 1H (Ar);

9.55 s, 1H (NH); 10.97 d, 1H (NH).

Melting point: 175 ° C (decomposition). Example 18 - 4-nitro N- (trvρtamine 5-O- carboxypropyl) aniline hydrochloride:

Compound 18. is obtained from 4-nitroaniline (1 g; 7.24 mmol), 4-bromobutyryl chloride (0.84 ml; 7.24 mmol) and 5-hydroxytryptamine 1A terbutylcarbamate ( 800 mg; 2.90 mmol) according to the procedure described for the preparation of Example 1.

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a mixture - dichloromethane / methanol / ammonia (80: 19: 1; v / v). The pure product is isolated in the form of yellow crystals (388 mg; 35%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of the compound there. Elemental analysis (C ₂₀ H ₂₃ N ₄ O ₄ CI , 0.5 H ₂ O),% calculated: C 56.14; H 5.65; NOT

13.09; Cl 8.25; % found: C 56.16; H 5.55; Cl 12.89.

Proton nuclear magnetic resonance spectrum. DMSO-dft (ppm):

2.08 m, 2H (CH ₂ ); 2.62 1.2H (CH ₂ ); 3.01 s, 4H (CH ₂ ); 4.01 1.2H (CH ₂ O); 6.70 dd,

1H (Ar); 7.08-7.24 m, 3H (Ar); 7.87-8.20 m, 7H (Ar + NH ₃ +); 10.83 s, 1H (NH); 10.89 s, 1H (NH).

Melting point: 230 ° C (decomposition).

EXAMPLE 19 4-amino hydrochloride N- (tryptamine 5-0-carboxymethyl) aniline

O

12 19A- 4-amino N- (terbutylcarbamate-tryptamine 5-0- ca boxymethyl) aniline

Compound 19A is obtained from the intermediate obtained during the synthesis of Example 2. Thus, 4-nitro N- (terbutylcarbamate-tryptamine 5-O-carboxymethyl) aniline (2 g; 4.4 mmol) dissolved in methanol (130 ml), is reduced by hydrogen (atmospheric pressure) in the presence of a catalytic amount of palladium on carbon (5%). After 4 hours of stirring at room temperature, the medium is filtered through "celite; the celite is washed alternately with methanol and then with dichloromethane.

The syrup obtained is chromatographed on a column of silica gel eluted with a chloroform / acetone mixture (7: 1; v / v). The pure compound is isolated in the form of white foam (1.86 g; 99%).

Proton nuclear magnetic resonance spectrum. DMSO-dfJppm):

1.39 s, 9H (tBu); 2,761.2H (CH ₂ ); 3.19 m, 2H (CH ₂ ); 4.58 s, 2H; 4.92 s, 2H; 6.50 d,

2H (Ar); 6.90-7.31 m, 7H; 9.59 s, 1H (NH); 10.71 s, 1H (NH).

EXAMPLE 19 4-amino hydrochloride N- (tryptamine 5-0-carboxymethyl) aniline

The compound there (500 mg; 1.18 mmol) is prepared from compound 19A according to the procedure described for the preparation of the example. The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (85: 14: 1; v / v). The product is obtained in the form of a white powder (350 mg; 92%) which, after treatment with hydrochloric acid in ether, gives the expected hydrochloride. Elementary analysis

1.5 H ₂ O),% calculated: C 50.95; H 5.94; N 13.20; Cl 16.71; % found: C 50.96; H 5.63; N 12.88; Cl 16.53. Proton nuclear magnetic resonance spectrum. DMSO-d ^ (ppm): 2.99 s, 4H (CH ₂ ); 4.73 s, 2H (COCH ₂ 0); 6.86 dd, 1H (Ar); 7.21-7.33 m, 5H (Ar); 7.76 d, 2H (Ar); 8.06 s, 3H (NH ₃ +); 10.13 s, 3H (NH ₃ +); 10.45 s, 1H (NH); 10.89 s, 1H (NH). Melting point: 183 ° C.

EXAMPLE 20 4-rN- hydrochloride (trvptamine 5-0- carboxymethvDI benzamide

The product 19A (560 mg; 1.32 mmol) in solution in pyridine (15 ml) is treated at 0 ° C with benzoyl chloride (153 μl; 1.32 mmol). After 3 hours of stirring at room temperature the medium is diluted with ethyl acetate and washed successively with a saturated solution of copper sulphate, water, and finally with a saturated solution of sodium chloride. The organic phase is dried over sodium sulfate, filtered and evaporated to dryness. A light beige solid is obtained (648 mg; 93%). This compound is then deprotected according to the method described for the preparation of Example 1. The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80:18: 1.5; v / v). The pure product is isolated in the form of a beige solid which leads, after treatment with hydrochloric acid in ether, to compound 2Q. Elementary analysis (C ₂ 5H ₂₅ N ₄ O ₃ CLH ₂ O),% calculated: C 62.17; H 5.63; NOT

11.60; Cl 7.34; % found: C 62.24; H 5.46; N 10.98; Cl 7.64.

Proton nuclear magnetic resonance spectrum. DMSO-dft (ppm):

3.04 m, 4H (CH ₂ ); 4.69 s, 2H (COCH ₂ O); 6.93-7.93 m, 16H; 10.08 s, 1H (NH); 10.25 s, 1H (NH); 10.87 s, 1H (NH). Melting point: 218 ° C. EXAMPLE 21 4-rN-ftryptamine 5-0 hydrochloride carboxymethvDI acetamide

Compound 21 is obtained from compound 19A (535 mg; 1.26 mmol) and acetic anhydride (210 μl; 2.20 mmol) according to the procedure described for the preparation of Example 2Q.

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 18.5: 1.5; v / v). The pure product is isolated in the form of a yellow syrup which leads, after treatment with hydrochloric acid in ether, to compound 21 (304 mg; 60%). Elemental analysis (C ₂ oH ₂₃ N ₄ O ₃ Cl, 1.6 H ₂ O + excess 0.4 HCl),% calculated: C

53.83; H 6.01; N 12.55; Cl 11.12; % found: C 53.56; H 5.62; N 12.28; Cl 11.05. Proton nuclear magnetic resonance spectrum. DMSO-dfi (ppm):

2.02 s, 3H (CH ₃ ); 2.99 s, 4H (CH ₂ ); 4.68 s, 2H (COCH ₂ O); 6.87 dd, 1H (Ar); 7.20-

7.62 m, 7H (Ar); 8.02 s, 3H (NH ₃ +); 9.98 S, 1H (NH); 10.12 S, 1H (NH); 10.88 s,

1H (NH).

Melting point: 157 ° C.

EXAMPLE 22 4-rN- hydrochloride (tryptamine 5-0- carboxymethyl) methanesulfonamide

Product 22 is obtained from compound 19A (600 mg; 1.41 mmol) and methanesulfonic chloride (109 μl; 1.41 mmol) according to the procedure described for the preparation of Example 2.

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 18.5: 1.5; v / v). The pure product is isolated in the form of a pale yellow syrup which leads, after treatment with hydrochloric acid in ether, to compound 22 (430 mg; 70%). Proton nuclear magnetic resonance spectrum. DMSO-d (ppm):

2.90 m, 7H (CH ₃ + CH ₂ ); 4.67 s, 2H (COCH ₂ O); 6.83 dd, 1H (AR); 7.01-7.65 m, 7H

(Ar); 8.03 s, 3H (NH ₃ +); 9.58 s, 1H (NH); 10.20 s, 1H (NH); 10.85 s, 1H (NH).

EXAMPLE 23 4-cvano N- hydrochloride (tryptamine 5-0- carboxymethyl) aniline

Compound 23. is obtained from 4-cyano aniline (1 g; 8.46 mmol), chloroacetyl chloride (0.67 ml; 8.46 mmol) and 5-hydroxytryptamine JA terbutylcarbamate (1 , 3 g; 4.70 mmol) according to the procedure described for the preparation of Example 1.

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 19: 1; v / v). The pure product is isolated in the form of syrup (1.13 g; 60%) which leads, after treatment with hydrochloric acid in ether, to the hydrochloride of compound 23.

Elementary analysis (C ₁₉ H ₁₉ N ₄ O ₂ CI, 1 H ₂ O),% calculated: C 58.69; H 5.44; NOT

14.41; Cl 9.12; % found: C 58.90; H 5.09; N 14.03; Cl 9.30.

Proton nuclear magnetic resonance spectrum. DMSO-dft (ppm):

2.96 s, 4H (CH ₂ ); 4.76 s, 2H (COCH ₂ O); 6.83 dd, 1H (Ar); 7.19-7.29 m, 3H (Ar); 7.75-7.98 m, 7H (Ar + NH ₃ +); 10.74 s, 1H (NH); 10.86 s, 1H (NH).

Melting point: 161 ° C. EXAMPLE 24 4-aττιinomethyl N- hydrochloride (trvptamine 5-O-carboxymethyl) aniline

Compound 2 is synthesized from the intermediate obtained during the synthesis of Example 23. Thus, 4-cyano N- (terbutylcarbamate-tryptamine 5-O-carboxymethyl) aniline (3.01 g; 6.93 mmol) in solution in tetrahydrofuran (100 ml) in the presence of ammonia (8.7 ml) is reduced by hydrogen (atmospheric pressure) in the presence of a catalytic amount of Nikel de Raney (2%). After 7 hours of stirring at "room temperature, the medium is filtered through celite; the latter is washed with tetrahydrofuran and the solvent is evaporated under vacuum.

The syrup obtained is chromatographed on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (80: 19.5: 0.5; v / v). The pure compound is isolated in the form of a white powder (1.99 g; 66%).

The product 24 is then prepared from this intermediate according to the procedure described for the preparation of Example 1.

The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol / ammonia mixture (85: 14: 1; v / v). The product is obtained in the form of a colorless syrup (1.1 g; 71%) which, after treatment with hydrochloric acid in ether, gives the expected hydrochloride. EXAMPLE 25 4- (Methanesulfonamide-methyl) N- (trvptamine 5-0-carboχymethyl) aniline hydrochloride

The product 25. is obtained from the intermediate 4-aminomethyl

N- (terbutylcarbamate-tryptamine 5-O-carboxymethyl) aniline obtained during the synthesis of Example 24. (600 mg; 1.37 mmol) and methanesulfonic chloride (104 μl; 1.41 mmol) according to the predure described for the preparation of Example 2Q. The purification of the product in the base form is carried out by chromatography on a column of silica gel eluted with a dichloromethane / methanol ammonia mixture (80: 18.5: 1.5; v / v). The pure product is isolated in the form of a pale yellow syrup which leads, after treatment with hydrochloric acid in ether, to compound 25. (248 mg; 41%).

AFFINITY STUDY FOR 5-HTι _D RECEPTORS

This study is carried out according to the technique described by Pauwels et al. (Biochem Pharmacol. 1993 in press).

Preparation of membranes

Sheep brains are removed from the local slaughterhouse and transported on ice. The caudate nuclei are removed, weighed and homogenized with Polytron for 20 sec (speed 6-7) in 20 volumes of 50 mM Tris-HCl, pH 7.7. The homogenate is centrifuged for 10 min at 48,000 g with an L5 50E centrifuge (Beckman).

The pellet taken up in 20 volumes of 50 mM Tris-HCl, pH 7.7 is placed in a water bath at 37 ° C for 10 min, then recentrifuged for 10 min at 48,000 g. The pellet then obtained is immediately frozen in fractions of 0.5 g of tissue.

Affinities

The pellet is thawed and homogenized with a Dounce in 80 volumes of 50 mM Tris-HCl, pH 7.7 containing 4 mM CaCl ₂ 10 μM pargyline and 0.1% ascorbic acid.

The affinity is achieved at 25 ° C. by incubating for 30 min:

- 0.1 ml of buffer or 10 μM in final concentration of sumatriptan to obtain the non-specific binding,

- 0.8 ml of membrane, - 0.1 ml of 3H-5-HT (15 to 30 Ci / mM, New England Nuclear France).

The incubation is terminated by rapid filtration on GF / B filters and rinsing with 3 times 3 ml of ice-cold buffer, using a Brandel harvester making it possible to filter 48 samples. The filters are introduced into vials containing 4 ml of emulsifier-safe scintillating liquid (Packard) and the radioactivity measured with a Tri-carb 4640 counter (Packard).

The IC 50 (concentration which inhibits the specific affinity by 50%) is determined graphically. The affinities of the various products forming part of this invention for the other receptors were measured according to the techniques described in the following references: * 5-HT _1A and _B Peroutka SJ Pharmacological differentiation and characterization of 5- HTIA, 5-HT IB and 5 -HTιc binding sites in rat cortex frontal. J. Neurochem.,

45, 529-540, 1986.

* 5-HTιc

Pazos A., Hoyer D. and Palacios J.M. The Binding sites of serotonergic ligands to the porcine choroid plexus: characterization of a new type of serotonin recognition site. Eur. J. PharmacoL, 106, 539-546, 1985.

* 5-HT ₂

Leysen J.E., Niemegeers C.J.E., Van Nueten J.M. and Laduron P.M. 3H- ketanserine (R 41468), a selective 3H ligand for serotonin 2 receptor biding sites. Mol. PharmacoL, 21, 301-330, 1982. * αl

Leslie Morrow A. and Creese I. Characterization of αl-adrenergic receptors subtypes in rat brain: a reassessment of 3H-WB4101 and 3H prazosin binding. Mol. PharmacoL 29, 321-330, 1986. * α2

Mallard NJ, Tyacke R., Hudson AL and Nutt DS Comparative binding studies of 3H-idazoxan and 3H-RX821002 in the rat brain. Brit. J. PharmacoL 102, 221P, 1991. * D2 Nisnik HB, Grigoriadis DE, Pri-Bar L, Buchman O. and Seeman P. Dopamine D2 receptors selectively labeled by a benzamide neuroleptic: 3H- YM-09159-2 Naunyn-Schmiedeberg's Arch . PharmacoL 329,333-343, 1985.

The new indole compounds derived from arylamines forming part of this invention are ligands having exceptional affinity for HTI D and related receptors as demonstrated by the examples described above. Many compounds which form an integral part of the present invention also have the advantage of being particularly selective for the 5 HTID receptor compared to the 5 HT _IA , 5 HT ic, 5 HT ₂ , αl, α2, D ₂ receptors. . The selectivity of certain compounds of the present invention and in particular their preferential affinity for the 5 HTID receptor compared to the 5 HT _IA receptor represents a very significant advantage compared to the ligands for the 5 HTID receptor known hitherto (cf. Annual Reports Medicinal

Chemistry, vol 27, chapter 3, p. 25; Académie Press, 1992).

In human therapy, the compounds of general formula I according to the invention are particularly useful for the treatment and prevention of disorders linked to serotonin in the central nervous system and the vascular system. These compounds can therefore be used in the treatment and prevention of depression, obsessive compulsive disorders, bulimia, aggression, alcoholism, smoking, hypertension, nausea, sexual dysfunction , asocial behavior, schizophrenia, anxiety, migraine, Alzheimer's disease and memory impairment.

The present invention also relates to medicaments consisting of at least one compound of formula I in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active. The medicaments according to the invention can be used orally, parenterally, rectally or topically.

As solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle 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 can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a dye, a coating (dragees) or a varnish. As liquid compositions for oral administration, there may be used pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or oil paraffin. These compositions can include substances other than diluents, for example wetting, sweetening, thickening, flavoring or stabilizing products.

The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, a polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other suitable organic solvents, can be used. These compositions may also contain adjuvants, in particular wetting, isotonizing, emulsifying, dispersing and ^{'stabilizers.} Sterilization can be done in several ways, for example by aseptic filtration, by incorporating sterilizing agents into the composition, by irradiation or by heating. 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 any other sterile injectable medium.

The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipents such as cocoa butter, semi-synthetic glycerides or polyethylene glycols.

The compositions for topical administration can be, for example, creams, lotions, eye drops, mouthwashes, nasal drops or aerosols.

The doses depend on the desired effect, on the duration of the treatment and on 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 orally 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 dosage based on age, weight and all other factors specific to the subject to be treated. The following examples illustrate compositions according to 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 They can be prepared by direct compression or by wet granulation. The direct compression procedure is preferred, but it may not be suitable in all cases depending on the doses and the physical properties of the active component.

A - By direct compression mg for an active component tablet (Example 2) 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 mesh opening of 250 μm side, it is mixed with the excipients and it is compressed using 6.0 mm punches. Tablets with other mechanical strengths can be prepared by varying the compression weight with the use of appropriate punches. B - Wet granulation mg for one tablet active component (example 1) 10.0 lactose Codex 74.5 starch Codex 10.0 corn starch pregelatinized Codex 5.0 magnesium stearate 0 5

Compression weight 100.0

The active component is passed through a sieve with a mesh opening of 250 μm and mixed with lactose, starch and pregelatinized starch. The mixed powders are moistened with purified water, they are granulated, dried, sieved and mixed with magnesium stearate. The lubricated granules are put into tablets as for the formulas by direct compression. A coating film can be applied to the tablets using suitable film-forming materials, for example methylcellulose or hydroxypropyl-methyl-cellulose, according to conventional techniques. Sugar tablets can also be coated. Mg capsules for one active component capsule (example 2) 10.0

* starch 1500 89.5 magnesium stearate Codex Q

Filling weight 100.0

* a form of directly compressible starch from the firm Colorcon Ltd., Orpington, Kent, United Kingdom.

The active component is passed through a sieve with a mesh opening of 250 μm and mixed with the other substances. The mixture is introduced into hard gelatin capsules No. 2 on an appropriate filling machine. Other dosage units can be prepared by changing the filling weight and, if necessary, changing the size of the capsule. Syrup mg per 5 ml dose active ingredient (example 12) 10.0 sucrose Codex 2750.0 glycerin Codex 500.0 buffer) flavor) color) q.s. preservative) distilled water 5.0 The active component, the buffer, the flavor, the color and the preservative are dissolved in part of the water and the glycerin is added. The remainder of the water is heated to 80 ° C. and the sucrose is dissolved therein and then cooled. The two solutions are combined, the volume is adjusted and mixed. The syrup obtained is clarified by filtration. Active component suppositories (Example 3) 10.0 mg

* Witepsol H15 supplement to 1.0 g

* brand sold for Adeps Solidus of the European Pharmacopoeia. A suspension of the active component in Witepsol H15 is prepared and introduced into a suitable machine with 1 g suppository molds. Liquid for administration by intravenous injection g / 1 active component 2.0 water for injection Codex complement to 1000.0 Sodium chloride can be added to adjust the tone of the solution and adjust the pH to maximum stability and / or to facilitate dissolving the active component by means of a dilute acid or alkali or by adding appropriate buffer salts. The solution is prepared, clarified and introduced into ampoules of appropriate size which are sealed by melting the glass. The liquid for injection can also be sterilized by heating in an autoclave according to one of the acceptable cycles. The solution can also be sterilized by filtration and introduced into a sterile ampoule under aseptic conditions. The solution can be introduced into the ampoules in a gaseous atmosphere. Cartridges for inhalation g / cartridge active ingredient micronized 1.0 lactose Codex 39.0

The active component is micronized in a fluid energy mill and made into fine particles before mixing with lactose for tablets in a high energy mixer. The powder mixture is introduced into hard gelatin capsules No. 3 on an appropriate encapsulating machine. The contents of the cartridges are administered using a powder inhaler. Pressure aerosol with metering valve mg / dose for 1 can micronized active ingredient 0.500 120 mg oleic acid Codex 0.050 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 fluid energy mill and put into the state of fine particles. Oleic acid is mixed with trichlorofluoromethane at a temperature of 10-15 ° C and introduced in the solution using a mixer with high shearing effect the micronized drug. The suspension is introduced in measured quantity into aluminum aerosol cans on which are fixed appropriate metering valves delivering a dose of 85 mg of the suspension; dichlorodifluoromethane is introduced into the boxes by injection through the valves.

Claims

1. Compounds corresponding to the general formula (I)

in aque e

Ri represents an arylamine radical of formula:

in which :

Ri represents a hydrogen atom, a branched or linear alkyl radical, a phenyl or benzyl radical, or an acyl radical (COR "ι) in which R" ι is a branched or linear alkyl radical, a phenyl or benzyl radical

V represents one or more substituents, identical or different, which can be in various positions on the aromatic nucleus to which they are attached, such as hydrogen, a branched or linear alkyl radical, (optionally substituted by OH, NH ₂ , NHR "ι, SR "OR" ι, COR "ι, NHCOR" ι, NHSθ ₂ R "ι), a phenyl radical (which can itself be variously substituted), benzyl, cycloalkyl, a halogen (F, Cl, Br or I), a nitrile (CN), a nitro (NO ₂ ), a hydroxyl (OH), an ether (OR "ι), an acyl (COR" ι), a thioalkyl (SR "ι), an amine (NH ₂ or NHR "i) an amide (NHCOR" ι), a sulfonamide (NHSθ ₂ R "ι) or a heterocycle such as an imidazole, triazole, thiazole, pyrrole, furan or thiophene. R "ι represents a linear or branched alkyl radical, a phenyl radical (which can itself be variously substituted), benzyl or cycloalkyl.

X and Y independently represent a methylene group (CH ₂ ), an amino residue (NR "ι), an oxygen (O) or a sulfur (S). W represents a branched or linear alkyl radical optionally substituted by an alcohol, alkoxy group , thiol, alkylthio or amine, a phenyl, benzyl or cycloalkyl radical.

Z represents C = O, SO ₂ , (CH ₂ ) n, CO (CH ₂ ) n, or SO ₂ (CH ₂ ) _n , in which n is an integer between 1 and 5. R ₂ represents an atom d hydrogen, a branched or unitary alkyl radical or a phenyl, benzyl, cycloalkyl, pyrrole, furan, pyridinyl, thiophenyl radical, optionally substituted with one or more substituents chosen from halogen atoms and alkyl, aryl, acyl, alkoxy radicals and alkylthio. R ' ₂ represents a hydrogen atom, a branched or linear alkyl radical or a phenyl radical.

R ₃ represents a hydrogen atom, a branched or linear alkyl radical or a benzyl or phenethyl radical.

R ₄ represents a hydrogen, chlorine, fluorine or bromine atom or a linear or branched alkyl radical.

R ₅ represents a hydrogen atom, a branched or linear alkyl radical or a benzyl or phenethyl radical.

R ₆ represents a hydrogen atom, a linear or branched alkyl radical, an acyl (COR), acyloxy (Cθ ₂ R) or acylamino (CONHR) radical in which R represents a Unary or branched alkyl radical, or a phenyl radical variously substituted.

Their therapeutically acceptable salts, solvates and bioprecursors, the compounds of formula (I) containing one or more asymmetric centers which can also be in the form of racemic mixtures or of pure enantiomers.

2. Compounds according to claim 1, characterized in that R 1 represents an aryl group such as a phenyl or a naphthyl optionally substituted by one or more substituents chosen from halogen atoms and alkyl, acyl, alkoxy, alkylthio or nitro.

3. Compounds according to claim 1, characterized in that R represents a phenyl optionally substituted by an aryl (such as a phenyl) or a heterocycle such as an imidazole, a triazole, thiazole, pyrrole, furan or thiophene.

4. Compounds according to claim 1, characterized in that Z represents CO.

5. Compounds according to claim 1, characterized in that Z represents SO ₂ .

6. Compounds according to claim 1, characterized in that Z represents (CH ₂ ) _n in which n is between 1 and 5.

7. Compounds according to claim 1, characterized in that R ₂ and R ' ₂ represent a hydrogen.

8. Compounds according to claim 1, characterized in that R ₂ represents a hydrogen.

9. Compounds according to claim 1, characterized in that R ₂ represents a methyl.

10. Compounds according to claim 1, characterized in that R 'i represents a hydrogen.

11. Compounds according to claim 1, characterized in that R ₃ represents a hydrogen.

12. Compounds according to claim 1, characterized in that R ₄ represents a hydrogen.

13. Compounds according to claim 1, characterized in that R ₅ and

R _ô represent hydrogen.

14. Compounds according to claim 1, characterized in that R ₅ is an alkyl radical, linear or branched.

15. Compounds according to claim 1, characterized in that R ₅ and R _Ô represent an alkyl radical, linear or branched.

16. Compounds according to one of claims 1 to 15, in the form of a salt acceptable for therapeutic use, characterized in that these salts are hydrochlorides, hydrobromides, sulfates, fumarates or maleates.

17. Compounds according to one of claims 1 to 16, characterized in that they are chosen from the following compounds:

- 4-chloro N- hydrochloride (tryptamine 5-O-carboxymethyl) aniline

- 4-fluoro N- hydrochloride (tryptamine 5-O-carboxymethyl) aniline

- N- (tryptamine 5-O-carboxymethyl) 1-naphthylamine hydrochloride - 7-methoxy N- (tryptamine 5-O-carboxymethyl 1- naphthylamine hydrochloride

- 4-amino hydrochloride [N- (tryptamine 5-O-carboxymethyl)] biphenyl

- 4-amino hydrochloride [N- (tryptamine 5-O-carboxymethyï)] 4'- methyl biphenyl

- 4-amino hydrochloride [N-methyl N- (tryptamine 5-O-carboxymethyl)] biphenyl

- 4-amino hydrochloride [N- (tryptamine 5-O-carboxymethyl)] 3,2'- dimethyl biphenyl - 4-amino hydrochloride [N- (tryptamine 5-O- (α- m et hyl - carboxymethyl)] biphenyl

- 3-amino N- hydrochloride (tryptamine 5-O-carboxymethyl) fluoranthene

- 2-amino N- hydrochloride (tryptamine 5-O-carboxymethyl) fluorene - 4-nitro N hydrochloride (tryptamine 5-O-carboxymethyl-aniline

- N- hydrochloride (tryptamine 5-O-carboxymethyl) 1,2,3,4- tetrahydroquinoline

- 4-chloro N- hydrochloride (tryptamine 5-O-methylsulfonyl) aniline

- 4-nitro hydrochloride N- (N-dimethyltryptamine 5-O-carboxymethyl) aniline - N- hydrochloride (tryptamine 5-O-ethyl) 1-naphty lamine

18. Process for preparing the compounds of general formula (I) according to claim 1 or their salts, solvates or bioprecursors acceptable for therapeutic use, characterized in that a compound of general formula (II) is reacted

in which Ri, Z and R ' ₂ have the meanings indicated with reference to the general formula (I) and where X is defined as a leaving group such as a halogen (bromine, iodine or chlorine), an O-mesylate, a O-tosylate or an O-triflate, with a serotonin derivative of general formula (III)

σπ) in which R ₃ , R ₄ , ₅ and g have a meaning indicated with reference to the general formula (I).

19. Process for the preparation of the compounds of formula (I) in which Z represents CO and R ′ ₂ represents a hydrogen, characterized in that a compound of general formula (V) is reacted

in which R ₂ has the meaning indicated with reference to the general formula (I) with, first of all, a derivative of general formula (IV)

Ri - H

(IV) in which Ri is defined as above, then with a derivative of general formula (III) in which R ₃ , R ₄ , R ₅ and Rg are defined as in the general formula (I).

20. Method according to one of claims 18 and 19, characterized in that a compound of general formula (I) or a salt or protected derivative of such a compound is converted into another compound of general formula (I) and / or a compound of general formula (I) or a salt of such a compound is converted into a salt, solvate or bioprecursor acceptable for pharmaceutical use.

21. Pharmaceutical compositions containing, as active ingredients, a compound according to one of claims 1 to 17 in combination with an acceptable pharmaceutical vehicle, for both curative and preventive treatment of disorders linked to serotonin, to depression, obsessive-compulsive disorder, anxiety, schizophrenia, aggression and / or alcoholism and / or associated behavior, migraine or other vasospasmodic disorders, eating disorders such as bulimia and anorexia , to sexual dysfunctions.