WO1996026922A1

WO1996026922A1 - Novel sulphonamide bi-tryptamine derivatives, method for preparing same, and use of said derivatives as drugs

Info

Publication number: WO1996026922A1
Application number: PCT/FR1996/000285
Authority: WO
Inventors: Serge Halazy; Michel Perez; Gareth John; Peter Pauwels; Jean-Pierre Valentin; Jean Martinez
Original assignee: Pierre Fabre Medicament
Priority date: 1995-03-02
Filing date: 1996-02-23
Publication date: 1996-09-06
Also published as: FR2731224B1; AU4882796A; FR2731224A1

Abstract

Novel sulphonamide bi-tryptamine derivatives of general formula (I), wherein R, k and X are as defined in the description, are disclosed. A method for preparing said derivatives, the use thereof as drugs, and pharmaceutical compositions containing such derivatives, are also disclosed.

Description

New sulfonamide bi-tryptamine derivatives, process for their preparation and their use as medicaments

The present invention relates to new indole sulfonamides as well as to their methods of preparation, the pharmaceutical compositions containing them and their use as a medicament.

Serotonin or 5-hydroxytryptamine (5HT) plays an important role both at the level of the nervous system and at the cardiovascular level and serotonergic receptors have been identified, whether at the central or peripheral level. It is generally accepted that serotonin can play an important role in various types of pathological conditions such as certain psychiatric disorders (anxiety, depression, aggression, panic attacks, obsessive compulsive disorders, schizophrenia, tendency to suicide), certain neurodegenerative disorders (disease Alzheimer's,

Parkinsonism), migraine, headache and alcoholism-related disorders (cf. E. Zifa and

G. Fillion, Pharm. Reviews, 44, 401, 1992; A. Moulignier, Rev. Neuro. (Paris) 150, 3-

15, 1994; S. Langer, N. Brunello, G. Racagni, J. Mendlecvicz, "Serotonin receptors subtypes: pharmacological significance and clinical implications" Karger ed .; 1992; B.E. Léonard, Int. Clin. Psychopharmacology, 7, 13-21, 1992; D.G. Grahame-Smith, Int.

Clin. Psychopharmacology, 6, Suppl. 4, 6-13, 1992; E. Zifa, G. Fillion, Pharmacological

Reviews, 44, 401-458, 1992; R.W. Fuller, J. Clin. Psychiatry, 53, 36-45, 1992).

The compounds according to the present invention are new compounds having a very high affinity and a very good selectivity for the receptors commonly called SHTj .lce and more particularly for the receptors called HTj3 and 5HTu), according to the new nomenclature recently proposed by P. Humphrey , P. Hartig and D. Hoyer

(TIPS, 14, 233-236, 1993).

Medicines including (alone or in combination with other therapeutic agents), the active ingredients of the present invention find their use in both curative and preventive treatment of diseases related to dysfunction of the SHT _j . I ^ _g receptors including the 5HTiβ receptors , 5HTi £) _α and 5HTιrj) β, to their deregulation or to modifications of the activity of the endogenous ligand (generally serotonin).

The compounds of the present invention are powerful and selective ligands for SHTμiik _g receptors which can act as agonists, partial agonists or antagonists at the level of these receptors, and can therefore find an application in the serotonin-related disorders mentioned above.

Most of the compounds of the present invention are more particularly potent agonists (both in terms of their affinity and in terms of their efficacy or intrinsic) and selective activity of the 5HTIJJ and 5HTιr receptors The agonists of the SHTi.iJkg receptors and more particularly of the HTι _j receptors ₎ exhibit selective vasoconstrictor activity and find their use in the treatment of migraine and vasospastic disorders [(see for example A Doenicke et al., The Lancet, 1, 1309-1311, 1988; MD Ferrari, PR Saxena, Cephalalgia, H, 151-165, 1993; SJ Peroutka, Headache, 30, 5-1 1, 1990; MA. Moskowitz , TiPS, 13, 307-31 1, 1992; W. Feniuk, PP Humphrey, MS Perren, H E. Connor, ET Whalley, J. Neurol., 238, S57-S61, 1991; A V. Deligonis, SJ Peroutka , Headache, 31, 228-231, 1991)].

The compounds of the present invention, which are, for the most part, powerful and selective agonists of the SHT ^ i ^ g receptors, therefore find more particularly their use in the curative and prophylactic treatment of "classic" migraine attacks.

(with aura), "common" (without aura), cluster headache, chronic vascular headache and vasospastic disorders.

The prior art in this field is illustrated in particular by: patent applications EP-0303507-A2, WO 93/14087, WO

94/02460, WO 92/14708 and US patents 4,839,377, GB 2124210A and GB 2162532 A which describe sulfonamides derived from tryptamines (including sumatriptan) as antimigraine; patent applications GB 2191488A, GB 2185020A and GB 2168347A which describe alkylamides derived from tryptamine; the publication describing bivalent indoles as ligands for the 5HTij3 and 5HTJA receptors (Bioorg. Med. Chem. Lett. 5, 123, 1995); European patent applications 0313397. 0486666, 0494774-A1,

0494774, 0497512-A2, 0501568-A1, 0464558, 0548813-A1 and patent application WO 92/13856 and 93/11106 which describe heterocyclic derivatives derived from tryptamine as agonists of 5HT _j -like receptors.

The present invention describes a new class of indole sulfonamides which is unambiguously distinguished from all the derivatives closest to the prior art by their original and different chemical structure, but also by their biological profile and their therapeutic potential since many compounds according to the present invention have a very high affinity and selectivity for "SHT ^" ]. ^^ 'receptors, and remarkable efficiency. The derivatives of the present invention therefore find, for the most part, more particularly their utility as active principles of medicinal compositions for the treatment of migraine and various related disorders.

The present invention relates to derivatives of general formula (I)

(I) in which

R represents an amino residue of formula (i) or (ii)

in which R] and R2, which are identical or different, represent a hydrogen or a linear or branched alkyl comprising from 1 to 6 carbon atoms, and for formula (ii), the dotted line represents an optional double bond k represents an integer between 1 and 2, X is chosen from the following groups of formulas X \ to Xg: Xl - - (CH ₂ ) _n -

X ₂ = - (CH ₂ ) _m -Ar- (CH ₂ ) _p -

Y z

He II

X ₃ = - (CH ₂ ) _m -CNX ₉ -NC- (CH ₂ ) p-

R3 R ₄

(CH ₂ ). _C _ _N N— C (CH ₂ ) _p

^X 5 = m X ₆ = - (CH ₂ ) ny - N - C - X ₁₀ - C - N- (CH ₂ ) _p -

R3 R4

7 = "(CH2 - N - C - (CH ₂ ) _i m

R3

O

X8 = - (CH ₂ ) _m . - N - C - N - (CH ₂ ) _p . -

R ₃ R4

in which

X9 represents X \, X ₂ or Ar

X ₁₀ represents X _h X ₂ , Ar, - CH (OR ₃ ) - (CH ₂ ) _q -,

- CH (OR ₃ ) - (CH ₂ ) q - CH (OR4) - or - (CH ₂ ) _q - CH = CH - n represents an integer between 2 and 12, m and p independently represent an integer included between 1 and

6, m 'and p' independently represent an integer between 2 and 6, q represents zero or an integer between 1 and 6, Y and Z independently represent an oxygen or 2 hydrogens then forming a methylene with the carbon to which they attached,

R and R4 independently represent a hydrogen or an alkyl residue comprising from 1 to 6 carbon atoms,

Ar represents an aromatic or heteroaromatic residue such as phenyl, pyridyl, thienyl, imidazole, it being understood that the substituents to which it is attached can be in various relative positions on the carbon atoms of the aromatic nucleus, their salts, solvates and bioprecursors acceptable for therapeutic use The compounds of formula (I) containing one or more asymmetric centers having isomeric forms The racemates and the pure enantiomers of these compounds as their mixtures in all proportions are also part of this invention.

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 mineral 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, administered to an animal or to a human being, are converted in the body into a compound of formula (I).

Advantageously, R 1 and R _{2, which may be} identical or different, represent hydrogen or methyl.

Preferably, Ar represents a phenyl group disubstituted in ortho, metha or para.

According to different advantageous embodiments of the invention, X represents a group of formula Xj in which n is an integer between 2 and 6, preferably 6, or X represents a group of formula X in which X9 represents X \ and in this case n is equal to 2 or 3, or Ar, Y and Z identical represent an oxygen, and R ₃ and R4 identical represent a hydrogen atom or a methyl group, m and p being defined previously, or X represents a group of formula X4 in which identical Y and Z represent oxygen, and R ₃ represents a hydrogen atom.m and p being defined above, or X represents a group of formula X5 in which identical Y and Z represent oxygen, m and p being defined previously.

The compounds of the present invention are generally prepared by condensation of at least two equivalents of an indolic sulfonamide of general formula (II)

in which R and k are defined as above with an ambident electrophile of formula (III)

LXL (III) in which X is described as above and L represents a leaving group such as a halogen (chlorine, bromine or iodine), a tosylate, a mesylate or a triflate. This condensation reaction is generally carried out in basic medium, preferably using an inorganic (for example sodium or potassium hydride) or organic (such as for example potassium hutylate or diisopropylamide) base. lithium) in an anhydrous polar solvent such as DMF, THF, DMSO, DME, ^t_ butanol at a temperature between - 20 ° and 60 ° C in the presence or not of a co-solvent such as HMPT, DABCO or a crown ether.

The compounds of formula (I) according to the invention can be obtained by then converting a compound of general formula (I) prepared according to the process defined above, or a salt or a derivative comprising a protecting group for such a compound, into another compound of general formula (I).

The use of a number of base equivalents identical to that of compound (II) is generally preferred for this type of transformation. In the case of the preparation of compounds of formula (I) in which sensitive groups or strong base are present, intermediaries (II) and (III) will rather be used, transformed by protective groups suitable for carrying out the condensation which will then be followed by 'a deprotection step to lead to the compound of formula (I).

In the particular case of the compounds of formula (I) in which X = X ₃ , X4 or X5, m = p and Z = Y = oxygen, an alternative but preferred method of preparation consists in condensing at least two equivalents of a derivative d carboxylic acid of formula (IV)

in which R and k are defined as above and P represents OH or Cl or the remainder "COP" represents an activated ester, with a diamine of formula V _a , V _D or V

(Go)

W - NH

HN NH (Vc)

using the methods and techniques well known to those skilled in the art for the preparation of amides from carboxylic acids (or their derivatives) and primary or secondary amines.

For example, when P represents Cl in formula (IV), the condensation with one of the diamines V _a , Vj> or V _c can be carried out in the presence of a base such as a tertiary amine (DBU, DBN , N-methyl morpholine, DEPEA, triethylamine) in an anhydrous solvent such as dichloromethane or THF at a temperature between - 20 ° C and 60 ° C. Likewise, the condensation of intermediate (IV) in which P represents OH with an amine of formula (V) can be carried out directly using peptide coupling reagents such as for example BOP, pyBOP, DCC, HOBT or else ethyl chloroformate.

In the particular case of the compounds of formula (I) in which X represents X, m '= p', R = R4 and X = Y = oxygen, an alternative but particularly appreciated method of synthesis consists in condensing at least two equivalents of an amine of formula VI

in which R, k, m 'and R ₃ are defined as above with an electrophilic derivative of formula (VII)

in which X _IQ is described as above and P represents Cl or OH, or else the "COP" groups each represent an activated ester. The condensation of intermediates VI and VII is carried out by techniques and methods well known for this type of transformation such as for example those described above.

In the particular case of the compounds of formula (I) in which X represents

X7 as defined above, an alternative but particularly appreciated method of synthesis consists in condensing an amine of formula (VI) with a carboxylic acid derivative of formula (IV) by the methods and techniques well known for this type of transformation such as by example those described above.

In the particular case of the compounds of formula (I) in which X represents Xg, m '= p' and R ₃ = R4, an alternative but particularly preferred method of preparation consists in condensing at least two equivalents of an amine of formula (VI) ) with an electrophile such as phosgene (C1COC1), carbonyldiimidazole or any other equivalent synthon which leads to the formation of a symmetrical urea after reaction with a primary or secondary amine.

The intermediates of formula (IV) are prepared by condensation of an intermediate of formula (II) with an electrophile of formula (VIII)

in which R ₃ and m are defined as above, L represents a leaving group such as a halogen (Cl, Br or I), a tosylate, a mesylate or a triflate, followed by deprotection of the ester function. The initial condensation can be carried out in the presence of a base such as sodium or potassium hydride or potassium ^t- butoxide in an anhydrous polar solvent such as DMF, THF, DMSO or DME. The transformation of the ester thus formed into the carboxylic acid of formula (IV) in which P = OH can be accomplished by the conventional methods of hydrolysis of ester into acid such as the use of acidic or basic conditions.

The intermediates of formula (VI) are prepared by condensation of an intermediate of formula (II) with an electrophile of formula (IX)

L- (CH ₂ ) _m '-P (IX)

in which m 'is defined as above L represents a leaving group and P represents a function which will be subsequently transformed into an amine. By way of example, P may represent an NO residue which will be transformed into an amine by a reduction reaction using reagents well known for this type of transformation such as for example SnCl ₂ , H ₂ on palladium or rhodium.

In the particular case of the compounds of formula (I) in which R is represented by the remainder (ii) as defined above, an alternative synthesis method but which should be considered as part of the present invention, consists in condensing an intermediate of formula (X)

(X) in which k and X are defined as above with at least two equivalents of a piperidone of formula (XI)

in which Rj is defined as previously followed by a possible reduction of the intermediate unsaturated piperidine. The initial condensation of the bis-indole derivative of structure corresponding to formula (X) with a piperidone is carried out in the presence of a base such as a sodium alcoholate or pyrrolidine in a polar solvent such as methanol, ethanol or isopropanol at a temperature between 20 and 80 ° C. When it is desired to prepare by this method a compound of formula (I) in which R represents a saturated piperidine, the saturated intermediate obtained as above is then subjected to a reduction of the double bond of the piperidine ring by using for example a hydrogenation reaction at atmospheric pressure of hydrogen in the presence of a metal catalyst such as PtO ₂ . It will be understood that in certain reactions or sequences of chemical reactions which lead to the preparation of compounds of general formula (I) it is necessary or desirable to protect sensitive groups or functions in the synthesis intermediates in order to avoid undesirable side reactions. This can be achieved by using conventional protective groups such as those described in "Protective groups in organic synthesis", TW Greene, J. Wiley & Jones, 1981 and "Protecting groups" by PJ Kocienski, Thieme Verlag, 1994. Protective groups adequate will therefore be introduced and removed at the level of the most appropriate synthetic intermediates to do this and using the methods and techniques described in the references cited above. When it is desired to isolate a compound according to the invention in the form of a salt, for example a salt by addition with an acid, this can be achieved by treating the free base of general formula (I) with an appropriate acid, preferably in equivalent quantity, 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 enantion-selective 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-l-tartaric, acid (+) - di-p-toluoyl-l- tartaric, acid (+) - camphorsulfonic, acid (-) - camphorsulfonic, acid (+) - phenylpropionic, (-) - phenylpropionic acid followed by fractional crystallization and regeneration of the free base. The compounds of formula (I) in which K \ 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 hydrolysed to release the chiral auxiliary.

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

EXAMPLE 1 C- [3- (2-dimethylamino-ethyl) -lH-indo.-5-yl] -N- (4 - {[3- (2-dimethylamino-ethyl) -lH-indol-5-hydrochloride) -ylmethanesulfonyl] -methyl-aminomethyl} - benzyl) -N-methyl-methanesulfonamide

I

3- (2-dimethylamino-ethyl) -1H-indol-5-yl-N-methyl-methanesulfonamide

(Humphrey PPA et al. Drugs of the future 1989,14,35-39) (1.1 g; 3.72 mmol) in solution in dry dimethylformamide (22 ml) is treated at 0 ° C with hydride. sodium (60% in oil) (186 mg; 4.65 mmol). After 1 h of stirring at 0 ° C at room temperature the α.α'-dichloro-xylene (325 mg; 1.86 mmol) is added. After a night of stirring at room temperature the medium is treated with wet sodium sulfate then filtered over sodium sulfate and evaporated to dryness. The syrup obtained is chromatographed on a "Flash" column of silica gel eluted with a dichloromethane / methanol / triethylamine mixture (49.5: 49.5: 1). The pure product is obtained in the form of a colorless syrup which leads, after treatment with hydrochloric acid in ether, to compound 1 in the form of a white powder (467 mg; 33%).

Elemental analysis (C36H50CI2N6O4S2; 1.5H ₂ O)

% calculated: C 54.57; H 6.76; N 10.48; Cl 9.05

% found: C 54.53; H 6.74, N 10.60; Cl 8.94

1 H NMR DMSO-d ₆ (ppm): 2.57 s, 6H; 2.83 s, 12 H; 3.18 m, 4H; 3.32 m, 4H, 4.14 s, 4H; 4.53 s, 4H; 7.17 d, 2H; 7.25 s, 4H, 7.28 d, 2H; 7.40 d, 2H; 7.68 s, 2H; 10.67 s, 2H; 11.15 d, 2H.

Melting point: 140 ° C

EXAMPLE 2 2 - {[3- (2 (dimethylamino-ethyl) -lH-indo - 5-ylmethanesuIfony.] - methyl- amino} -N- [4- (2 - {[3- (2-dimethylamino- ethyl) -1H-indol-5-ylmethanesulfonyl] - methyl-amino} -acetylamino) -phenyl] -acetamide

2A - 2-chloro-N- [4- (2-chloro-acetylamino) -phenyl] -acetamide

1,4-Phenylene diamine (500 mg; 4.62 mmol) in solution in methyl ethyl ketone (18 ml) in the presence of potassium carbonate (1.92 g; 13.86 mmol) is treated at 0 ° C with chloracetyl chloride (0.77 ml; 9.7 mmol). After 1 h of stirring at room temperature, the medium is diluted with ethyl acetate, washed with 2N soda, 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 crude product obtained (1.12 g; 93%) is used without further purification for the next step. 2 - 2 - {(3- (2 (dimethylamino-ethyl) -lH-indol-5-ylmethanesulfonyl] - methyl-amino} -N- [4- (2 - {[3- (2-dimethylamino-ethyl) - 1H-indol-5-ylmethanesuIfonyI] -methyl-amino} -acetylamino) -phenyI] -acetamide

Compound 2 is prepared from 3- (2-dimethylamino-ethyl) -1H-indol-5-yl-

N-methyl-methanesulfonamide (50 mg; 0.17 mmol) and of compound 2A (22 mg; 0.085 mmol) according to the procedure described for the preparation of Example 1. The syrup obtained is chromatographed on a "Flash" column of silica gel eluted with a dichloromethane / methanol triethylamine mixture (49.5: 49.5: 1). The pure product is obtained in the form of a pale yellow syrup which leads, after treatment with hydrochloric acid in ether, to compound 2 in the form of a white powder (10 mg; 15%).

1 H NMR, DMSO-d ₆ (ppm): 2.81 s, 12H; 2.84 s, 6H; 3.05 m, 4H; 3.33 s, 4H; 3.95 s, 4H; 4.52 s, 4H; 7.15 d, 2H; 7.26 d, 2H; 7.35 d, 2H; 7.53 s, 4H; 7.63 s, 2H; 10.10 s, 2H; 11.08 s, 2H.

EXAMPLE 3 C- [3- (2-dimethylamino-ethyl) -1H-indol-5-yl] -N- (4 - {[3- (2-dimethylamino-ethyl) -1H-indol-5- hydrochloride ylmethanesulfonyl] -methyl-amino} -hexyl) -N- methyl-methanesulfonamide

Compound 3 is prepared from 3- (2-dimethylamino-ethyl) -1H-indol-5-yl-

N-methyl-methanesulfonamide (50 mg; 0.17 mmol) and 1,6-dibromohexane (13 μl, 0.085 mmol) according to the procedure described for the preparation of Example L

The syrup obtained is chromatographed on a "Flash" column of silica gel eluted with a dichloromethane / methanol triethylamine mixture (49.5: 49.5: 1). The pure product is obtained in the form of a pale yellow syrup which leads, after treatment with hydrochloric acid in ether, to compound 3 in the form of a white powder (12 mg; 21%). EXAMPLE 4 2 - {[3- (1-methyl-piperidin-4-yl) -lH-indol-5-yl} -4- hydrochloride -4- (methyl- {2- [3- (1-methyl-piperidin- 4-yl) -lH-indol-5-yI] -ethanesulfonyl} - aminomethyl) -benzyl} -ethanesulfonamide

4

Compound 4 is prepared from 2- [3- (1-methyl-piperidin-4-yl) -lH-indol-5-yl] -N-methyl-ethanesulfonamide (250 mg; 0.746 mmol) and a , α'-dichloro- _/ r -xylene (65 mg; 0.373 mmol) according to the conditions described for the preparation of Example 1. The syrup obtained is chromatography on a "Flash" column of silica gel eluted with a mixture of dichloromethane and methanol / triethylamine (49.5: 49.5: 1). The pure product is obtained in the form of a colorless syrup which leads, after treatment with hydrochloric acid in ether, to compound 4 in the form of a white powder (34 mg; 12%).

BIOLOGICAL RESULTS

The human receptors 5HTi £) _α and 5HTij) β were cloned according to the sequences published by M. Hamblin and M. Metcalf, Mol. Pharmacol., 40, 143 (1991) and Weinshenk et al., Proc. Natl. Acad. Sci. 89, 3630 (1992).

Transient transfection and permanent transfection of genes from these receptors was carried out in Cos-7 and CHO-Kj cell lines using an electroporator.

The HeLa HA7 cell line expressing the human 5HTI A receptor was obtained from Tulco (Duke Univ., Durham, N.C., USA) and cultivated according to the method of Fargin et al., J. Biol. Chem. 264, 14848 (1989).

The study of the binding of the derivatives of the present invention with the human 5HTi () _α , 5HTIDR and 5HTI A receptors was carried out according to the method described by P.

Pauwels and C. Palmier (Neuropharmacology, 33, 67, 1994).

The incubation media for these binding measurements include 0.4 ml of cell membrane preparation, 0.05 ml of a tritiated ligand [[3H] -5CT (final concentration: 2 nM) for the 5HTiD _α and 5HTiDβ receptors and [3H] -8OH-DPAT (final concentration: 1 nM) for the 5HT1A receptor] and 0.05 ml of the test molecule (final concentrations: 0.1 to 1000 nM) or 10 μM (final concentration) of serotonin (5HTj £ and 5HTιrjβ) or 1 μM (final concentration) of spiroxatrine

(5HT _{1 A} ).

The study of the inhibition of the formation of cyclic AMP (stimulated by forskolin) mediated by the human 5HTi £ β receptor was carried out in CHO-KI cells transfected by the receptor according to the technique described previously for the 5HTi receptor _β (P. Pauwels and C. Palmier, Neuropharmacology, 33,67,1994).

By way of illustration, the table below compares the results obtained with the compound described as Example No. 1, in comparison with sumatriptan and naratriptan.

Referring to sumatriptan, the compounds of the present invention, as indicated by the illustrative example in the table above, are ligands more affine to the human receptors 5HTij) _α and 5HTιrjβ and are also more agonists powerful at the 5HT _j τ β receptor. These results show that the products of the present invention are particularly useful for the treatment and prevention of migraine and associated disorders.

This is moreover confirmed by the evaluation of the compounds of the present invention which have been identified as particularly potent agonists in the model of contraction of the rabbit saphenous vein rings which has been studied according to a technique adapted from Van-Heuven Nolsen et al. [Eur. J. Pharmacol. 191.375.19901 and Martin and Me Lennan [Naunyn-Schmiedeberg's Arch. Pharmacol. 342.111.19901. Under these conditions, the pD ₂ reflecting the relative potency of the products were determined. Thus, Example 1 of the present invention (pD2 = 6.50) was found to be significantly more powerful than sumatriptan (pD2 = 5.75) or naratriptan (pD2 = 5.68).

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, anxiety, migraine, spasticity, Alzheimer's disease and memory impairment. The present invention also relates, as medicaments, to the compounds of formula (I). It also relates to pharmaceutical compositions comprising at least one compound of general formula (I) as active component, in which it is associated with any pharmaceutically acceptable vehicle, which may be inert or physiologically active. The compositions according to the invention can be used by the oral, nasal, parenteral, rectal or topical route.

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, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable. These compositions can also contain adjuvants, in particular wetting agents, isotonizers, emulsifiers, dispersants 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, excipients 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 means 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 one 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 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 ingredient 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. We can apply on tablets a coating film using suitable film-forming materials, for example methylcellulose or hydroxy-propyl-methyl-cellulose, according to conventional techniques. Sugar tablets can also be coated.

Capsules

mg for one active ingredient capsule 10.0

* starch 1500 89.5 magnesium stearate Codex 0.5

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 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.

Suppositories Active ingredient 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 supplement 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 the dissolution of the active component by means of a dilute acid or alkali or by adding buffer salts. appropriate. The solution is prepared, clarified and introduced into suitable size vials 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.

Inhalation cartridges

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. The oleic acid is mixed with the trichlorofluoromethane at a temperature of 10-15 ° C. and the micronized drug is introduced into the solution using a mixer with a high shearing effect. 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)

(D in which

R represents an amino residue of formula (i) or (ii)

in which Ri, R2, which are identical or different, represent a hydrogen or a linear or branched alkyl comprising from 1 to 6 carbon atoms, and for formula (ii), the dotted line represents an optional double bond k represents an integer between 1 and 2,

X is chosen from the following groups of formulas Xj to Xg: X ₁ = - (CH ₂ ) _n - 2 = "(CH ₂ ) _m - Ar - (CH ₂ ) _p -

Y Z

X ₃ = - (CH ₂ ) _m - C - N - X ₉ - N - C - (CH ₂ ) _p

R3 R4

^R 3

Y

II

-NN— C (CH ₂ ) _p

^X 5 = - - (CH ₂ ) _m - C - YZ

He II

X ₆ = - (CH ₂ ) _m . - N - C - - X ₁₀ - C - N- (CH ₂ ) _p -

I I

R ₃ R4

Xη = - (CH ₂ ) _m - - N - C - (CH ₂ ) _m -

I

R3

O

II

X8 = "(CH ₂ ) _m . - N - C - N - (CH ₂ ) _p . -

I I

R ₃ R4

in which X9 represents Xj, X ₂ or Ar XlO represents Xj, X, Ar, - CH (OR ₃ ) - (CH ₂ ) _q -, - CH (OR ₃ ) - (CH ₂ ) q - CH (OR4) - or - (CH ₂ ) _q - CH = CH - n represents an integer between 2 and 12, m and p independently represent an integer between 1 and 6. m 'and p' independently represent an integer between 2 and 6, q represents zero or an integer between 1 and 6,

Y and Z independently represent an oxygen or 2 hydrogens then forming a methylene with the carbon to which they are attached, R ₃ and R4 independently represent a hydrogen or an alkyl residue comprising from 1 to 5 carbon atoms, Ar represents an aromatic or heteroaromatic residue such as phenyl, pyridyl, thienyl, imidazole it being understood that the substituents to which it is attached can be in various relative positions on the carbon atoms of the aromatic nucleus, their salts, solvates and bioprecursors acceptable for therapeutic use, racemates and the pure enantiomers of these compounds as their mixtures in all proportions.

2. Compounds according to Claim 1, characterized in that R represents an amino residue of formula (i) in which R] and R2 represent a methyl.

3. Compounds according to claim 1, characterized in that R represents an amine residue of formula (ii) in which Rj represents a methyl.

4. Compounds according to one of claims 1 to 3, characterized in that Ar represents a phenyl group disubstituted in ortho, metha or para.

5. Compounds according to one of claims 1 to 3, characterized in that X represents a group of formula X \ in which n is an integer between 2 and 6, preferably 6.

6. Compounds according to one of claims 1 to 4, characterized in that X represents a group of formula X ₃ in which Xo represents Xj and in this case n is equal to 2 or 3, or Ar,

Identical Y and Z represent oxygen, and

Identical R and R4 represent a hydrogen atom or a methyl group, m and p being defined above.

7. Compounds according to one of claims 1 to 3, characterized in that X represents a group of formula X4 in which

Identical Y and Z represent oxygen, and R ₃ represents a hydrogen atom, m and p being defined previously.

8. Compounds according to one of claims 1 to 3, characterized in that X represents a group of formula X5 in which

Identical Y and Z represent oxygen, m and p being defined previously.

9. Process for the preparation of the compounds of formulas (I) according to one of claims 1 to 8 characterized in that at least two equivalents of an indolic sulfonamide of general formula (II) are reacted

L-X-L (III)

in which X is described as above and L represents a leaving group such as a halogen (chlorine, bromine or iodine), a tosylate, a mesylate or a triflate in the presence of a base.

10. A method of manufacturing the compounds of formula (I) according to claim

9, characterized in that a compound of general formula (I) prepared according to the method of claim 9, or a salt or a derivative comprising a protecting group of such a compound, is then converted into another compound of formula general (I).

11. As medicaments, the compounds according to one of claims 1 to 8.

12. Medicament according to claim 11, useful for both curative and preventive treatment of disorders related to serotonin in particular migraine, cluster headache and chronic vascular headaches, depression, obsessive compulsive disorders , bulimia, aggression, alcoholism, nausea, sexual dysfunction, asocial behavior, anxiety, spasticity, Alzheimer's or Parkinson's disease.

13. Pharmaceutical compositions, characterized in that they comprise at least one compound of formula (I) according to one of claims 1 to 8, associated with a pharmaceutically acceptable vehicle.