FR2802531A1 - New piperidinyl-substituted phenoxypropanolamine derivatives, as beta-3-adrenergic receptor agonists are useful for treating irritable bowel syndrome, obesity, diabetes, glaucoma or depression - Google Patents

Abstract

N-(Piperidinyl or piperidinylalkyl)-3-amino-1-(4-hydroxy-phenoxy)-2-propanol derivatives (I) and piperidine derivative intermediates (III') are new. Phenoxypropanolamines of formula (I) and their salts or solvates are new. R1 = H, -S(O)z-T, -S(O)z-T'-R3, SO2NHT, NHCOT, COT or NHSO2T; T = 1-4C alkyl; T' = 1-4C alkylene; m, n = 0-2; A = NHR2-substituted phenyl, NHR2-substituted 2-pyridinyl or R4-substituted phenyl; R2 = SO2R3, COR3 or COT; R3 = phenyl (optionally substituted by T, OR, a heterocycle or 1 or 2 halo); R4 = H, halo, 1-6C alkyl, OT, COOH, COOT, CN, CONR5R6, NO2, NHSO2T or SO2NR5R6; z = 1 or 2; R5, R6 = H, T, Ph or -T'-Ph. Independent claims are included for: (1) the preparation of (I); and (2) new amine intermediates of formula (III') and their salts or solvates. (i) P'' = H; and A' = NHR2-substituted phenyl or NHR2-substituted 2-pyridinyl; or (ii) P'' = tert. butoxycarbonyl; and A' = R'4-substituted phenyl; R'4 = COOH, COOT, CONR'4R'5 or NHSO2T; R'5, R'6 = H or T.

Description

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 The present invention relates to new phenoxypropanolamines, pharmaceutical compositions containing them, a process for their preparation and intermediates in this process.

 BE 902897 describes aryloxypropanolamines carrying a 4-piperidininyl-lsubstituted group on the amine, these compounds having an ss1-blocking and a-blocking activity.

un groupe 4-pipéridinyl-1-substitué sur l'amine. J Org Chem., 1988, 63: 889: 894, describes other aryloxypropanolamines bearing

a 4-piperidinyl-1-substituted group on the amine.

 It has now been found that phenoxypropanolamines carrying a 1- (pyrid-2-yl) -piperidin-4-yl radical on the amine have agonist activity against (33-adrenergic) receptors.

où

R, représente l'hydrogène, un groupe -S(O)z-(CI-C4)Alk, (SO)z-(CC4)R3, un groupe SO2-NH-(Ci-C4)Alk, un groupe NHCO(Ci-C4)Alk, un groupe -CO(C,-C4)Alk, un groupe -NHS02-(CrC4)Alk ou un halogène. Thus, the present invention relates, according to one of its aspects, to phenoxypropanolamines of formula (I)

or

R represents hydrogen, a group -S (O) z- (CI-C4) Alk, (SO) z- (CC4) R3, a group SO2-NH- (Ci-C4) Alk, a group NHCO ( Ci-C4) Alk, a group -CO (C, -C4) Alk, a group -NHS02- (CrC4) Alk or a halogen.

(C,-C4)alkyle, un groupe (Ci-C4)alkoxy, ou par un ou deux halogènes, m et n sont indépendamment 0,1 ou 2; z est 1 ou 2; X est N ou CH; et leurs sels ou solvates. R2 represents a group -SO2-R3, -CO-R3 or -CO- (Ci-C4) Alk; R3 represents a phenyl group optionally substituted by a group

(C, -C4) alkyl, a (Ci-C4) alkoxy group, or by one or two halogens, m and n are independently 0.1 or 2; z is 1 or 2; X is N or CH; and their salts or solvates.

 In the present description the term "(C1-C4) Alk" denotes a monovalent radical of a saturated C1-C4 hydrocarbon with straight or branched chain.

 The salts of the compounds of formula (I) according to the present invention also include the addition salts with pharmaceutically acceptable inorganic or organic acids such as the hydrochloride, the bromohydrate, the sulfate, the hydrogen sulfate, the dihydrogen phosphate, the citrate, maleate, tartrate, fumarate, gluconate, methanesulfonate, 2-naphthalenesulfonate, etc., as addition salts which allow proper separation or crystallization of the compounds of formula (I), such as

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picrate, oxalate or addition salts with optically active acids, for example camphosulfonic acids and mandelic or substituted mandelic acids
The optically pure stereoisomers, as well as mixtures of isomers of the compounds of formula (I), due to the asymmetric carbons or to the sulfinyl group in the meaning of Ri, in any proportion, form part of the present invention.

 Preferred compounds of the present invention include the compounds of formula (I) wherein X represents N and the NHR2 group is in the 5 position of pyridine.

 Other preferred compounds are those where the group (C1-C4) Alk is a methyl or ethyl group.

 Still other preferred compounds are those where n and m are zero.

dans laquelle R1 est tel qu'indiqué ci-dessus, P' est un groupe protecteur et L est un groupe de formule (a) ou (b)

où Gp est un groupe partant tel que le tosylate, le mésylate ou un halogène, avec une amine de formule (III)

dans laquelle n, m, R2 et X sont tels que définis ci-dessus, en clivant le groupe P' selon les méthodes usuelles et éventuellement transformant le composé de formule (I) ainsi obtenu en l'un de ses sels. The compounds of formula (I) can be prepared by treating a compound of formula (II)

in which R1 is as indicated above, P 'is a protective group and L is a group of formula (a) or (b)

where Gp is a leaving group such as tosylate, mesylate or a halogen, with an amine of formula (III)

in which n, m, R2 and X are as defined above, by cleaving the group P 'according to the usual methods and optionally transforming the compound of formula (I) thus obtained into one of its salts.

 More particularly, the reaction between the compounds of formula (II) and (III) is carried out in an organic solvent, such as a lower alcohol such as methanol, ethanol and isopropanol; dimethyl sulfoxide; a linear or cyclic ether; an amide such as dimethylformamide or dimethylacetamide; using

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 at least equimolecular quantities of the reactants, possibly in small excess of amine.

The reaction temperature is between room temperature and the reflux temperature of the chosen solvent, preferably less than 180 ° C.
As protecting groups P ′, it is possible to use the usual protecting groups for hydroxy groups such as for example methoxyethoxymethyl (MEM), benzyl, benzoyl or silyl ethers such as for example tertbutyldimethylsilylether (TBDMS).

 The cleavage of these protecting groups is carried out according to the usual methods for the chosen protecting group; in the case of the benzyl group, for example, by hydrogenation in the presence of a catalyst such as Pd / C in a suitable solvent or by hydrolysis using an acid such as trifluoroacetic acid, depending on the reactivity of the group Ri present; in the case of MEM or TBDMS, an acid such as trifluoroacetic acid can also be used; in the case of benzoyl, a transesterification reaction can be carried out with an alkanol in basic medium.

 The epoxides of formula (II) are compounds known in the literature or they can be prepared by methods analogous to those described in the literature.

Certain epoxides of formula (II) are for example described in WO 96/04233 and in US 4,396,629.

 The amines of formula (III) are new compounds and constitute another aspect of the present invention.

dans laquelle P" est un groupe protecteur tel tert-butoxycarbonyl et le carbobenzyloxy et X est tel que définis ci-dessus, avec un radical CI-R2 où R2 est tel que décrit précédemment, dans un solvant convenable, tel que par exemple la pyridine, le diméthylformamide ou le diméthylsulfoxide et par élimination du groupe P" par hydrogénation ou traitement en milieu acide tel que l'acide chlorhydrique dans l'éthyle acétate ou dans l'éthanol,
Les amines de départ de formule (IV) peuvent être préparées par réaction des pyridines convenables de formule (V)

These amines can be prepared by reaction of the compounds of formula (IV)

in which P "is a protective group such as tert-butoxycarbonyl and the carbobenzyloxy and X is as defined above, with a radical CI-R2 where R2 is as described above, in a suitable solvent, such as for example pyridine , dimethylformamide or dimethylsulfoxide and by elimination of the P "group by hydrogenation or treatment in an acid medium such as hydrochloric acid in ethyl acetate or in ethanol,
The starting amines of formula (IV) can be prepared by reaction of the suitable pyridines of formula (V)

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où n est tel que défini ci-dessus et P" représente un groupe protecteur, dans un solvant organique en présence d'une base. where Hal represents a halogen and X, R2 and m are as defined above, with a piperidine of formula (VI) below

where n is as defined above and P "represents a protective group, in an organic solvent in the presence of a base.

 As reaction solvent, it is possible to use, for example, dimethylformamide, pyridine, dimethyl sulfoxide, a linear or cyclic ether or a chlorinated solvent such as dichloromethane.

 As the base, an alkali hydroxide, an alkali carbonate such as potassium carbonate or a tertiary amine such as triethylamine can be used, for example.

 The above condensation reaction is completed in a few hours, normally in 2-12 hours.

 The reaction temperature is between room temperature and the reflux temperature of the chosen solvent.

 As protecting groups P ", it is possible to use the protecting groups indicated for the products of formula (IV).

 The cleavage of these protective groups is carried out according to the usual methods described the protective group chosen; in the case of tert-butoxycarbonyl for example, the cleavage is normally carried out by acid hydrolysis.

 The compounds of formula (I) have shown a very potent affinity for ss3 receptors.

 The activity of the compounds of the present invention with respect to the ss3 activity has been demonstrated using in vitro tests on the human colon according to the method described in EP-B-436435 and in T Croci et al, Br. J. Pharmacol., 1997, 122: 139P.

 More particularly, it has been found that the compounds of formula (I) are much more active on the isolated colon than on the atrium and on the trachea.

 These surprising properties of the compounds of formula (I) make it possible to envisage their use as drugs with ss3 action.

 In addition, the compounds of formula (I) are not very toxic; their acute toxicity is compatible with their use as medicaments for the treatment of diseases in which the compounds having an affinity for the ss3 receptor find their application. The compounds of formula (I), as well as their pharmaceutically acceptable salts, can therefore be indicated for example in the treatment of gastrointestinal diseases such as irritable bowel syndrome, as modulators of intestinal motility, as lipolytics, anti-

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 obesity, anti-diabetic, psychotropic, anti-glaucomatous, healing, anti depressants, tocolytics.

 The use of the compounds of formula (I) above, as well as that of their pharmaceutically acceptable salts and solvates for the preparation of the above drugs, constitutes a further aspect of the present invention.

 For such use, mammals which require such treatment are administered an effective amount of a compound of formula (I) or of a pharmaceutically acceptable salt and solvate thereof.

 The compounds of formula (I) above and their pharmaceutically acceptable salts and solvates can be used in daily doses of 0.01 to 20 mg per kg of body weight of the mammal to be treated, preferably in daily doses of 0, 1 to 10 mg / kg. In humans, the dose may preferably vary from 0.5 mg to 1500 mg per day, in particular from 2.5 to 500 mg depending on the age of the subject to be treated, the type of treatment, prophylactic or curative, and the severity of the condition. The compounds of formula (I) are generally administered in dosage units of 0.1 to 500 mg, preferably 0.5 to 100 mg of active principle, one to five times a day.

 Said dosage units are preferably formulated in pharmaceutical compositions in which the active principle is mixed with a pharmaceutical excipient.

 Thus, according to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound of formula (I) above or one of its pharmaceutically acceptable salts and solvates.

 In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal administration, the active ingredients of formula (I) above, their pharmaceutically acceptable salts and solvates can be administered in unit administration forms, in admixture with conventional pharmaceutical carriers, to animals and humans, for the treatment of the above-mentioned conditions. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, subcutaneous administration forms , intramuscular or intravenous, forms of local administration and forms of rectal administration.

 When preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose or other suitable materials or they can be treated so that they have an activity.

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 prolonged or delayed and that they continuously release a predetermined amount of active ingredient.

 A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.

A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and a suitable color.
Water dispersible powders or granules may contain the active ingredient in admixture with dispersing agents or wetting agents, or suspending agents, such as polyvinylpyrrolidone, as well as with sweeteners or correctors taste.

 For local administration, the active principle is mixed in an excipient for the preparation of creams or ointments or it is dissolved in a vehicle for intraocular administration, for example in the form of eye drops.

 Suppositories are used for rectal administration which are prepared with binders that melt at rectal temperature, for example cocoa butter or polyethylene glycols.

 For parenteral administration, aqueous suspensions, saline solutions or sterile injectable solutions are used which contain pharmacologically compatible dispersing agents and / or wetting agents, for example propylene glycol or butylene glycol.

 The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

 According to another of its aspects, the present invention relates to a method of treatment of pathologies which are improved by a P3-agonist action, which comprises administering a compound of formula (I) or one of its pharmaceutically acceptable salts or solvates.

 The compounds of formula (I), in particular the compounds (I) labeled with an isotope, can also be used as laboratory tools in biochemical tests.

 The compounds of formula (I) bind to the P3-adrenergic receptor. These compounds can therefore be used in an ordinary binding test, in which an organic tissue is used where this receptor is particularly abundant, and the quantity of compound (I) displaced by a test compound is measured, to evaluate the affinity of said compound vis-à-vis the binding sites of this particular receptor.

 Another specific object of the present invention is therefore a reagent usable in biochemical tests, which comprises at least one suitably labeled compound of formula (I).

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 The examples which follow illustrate the invention better.

lb) 5-[((4-isopropylphényl)sulfonyl)amino]-2-(4-tert-butoxycarbonylamino pipéridino)-pyridine On dissout 0,4 g (0,0013 mole) du produit de l'étape précédente dans 10 ml de pyridine. On y ajoute 0,3 g (0,0013 mole) de chlorure de 4-isopropylbenzènesulfonyle et on chauffe à 50 C pendant 2 heures. On évapore le solvant (avec les précautions pour l'acide chlorhydrique), on reprend le résidu dans de l'acétate d'éthyle et de l'eau. EXAMPLE 1 la) 5-amino-2- (4-tert-butoxycarbonylaminopiperidino) -pyridine 2 g (0.0062 mole) of 5-nitro-2- (4-tert-butoxycarbonylpiperidino) - pyridine are mixed in 40 ml of ethanol and 60 ml of tetrahydrofuran 0.04 g of 10% Pd / C is added and hydrogenation is carried out at 40 C at ambient pressure for 7 hours. Filter, the solvent is evaporated and 2 g of the title compound are obtained in the form dark oil.

lb) 5 - [((4-isopropylphenyl) sulfonyl) amino] -2- (4-tert-butoxycarbonylamino pipéridino) -pyridine 0.4 g (0.0013 mol) of the product from the previous step is dissolved in 10 ml of pyridine. 0.3 g (0.0013 mol) of 4-isopropylbenzenesulfonyl chloride is added thereto and the mixture is heated at 50 ° C. for 2 hours. The solvent is evaporated off (with the precautions for hydrochloric acid), the residue is taken up in ethyl acetate and water.

le) 5-[((4-isopropyIphényl)suIfonyl)amino]-2-(4-aminopipéridino)-pyridine dichlorhydrate On chauffe au reflux pendant 4 heures 2,1 g (0,0042 mole) du produit de l'étape précédente dans 20 ml d'acétate d'éthyle et 20 ml d'une solution environ gazeux 3N d'acide chlorhydrique en acétate d'éthyle. On évapore le solvant sous pression réduite, on reprend le résidu dans de l'acétone, on filtre, on lave le précipité à l'acétone et on obtient 1,8 g du produit du titre qui est cristallisé dans de l'éthanol. P. f 270-273 C. ld) 5-[((4-isopropylphényl)sulfonyl)amino]-2-(4-((3-(4-(benzyloxy)phénoxy)-2- hydroxypropyl)amino)pipéridino)-pyridine On chauffe au reflux pendant 20 heures 0,239 g (0,935 mole) de 4-benzyloxy-l-(2,3- époxypropoxy) benzène, 0,35g (0,935 mmole) du produit de l'étape précédente sous forme de base dans 10 ml d'éthanol. On évapore le solvant sous pression réduite et on purifie par flash-chromatographie sur colonne de gel de silice en éluant par un mélange chlorure de méthylène/méthanol = 95/5. On obtient 0,37 g du produit du titre sous forme de produit vitreux.

le) 5-[((4-isopropylphényl)sulfonyl)amino)-2-(4-((3-(4-hydroxyphénoxy)-2- hydroxypropyl)amino)pipéridino)-pyridine On mélange 0,37 g (0,586 mmole) du produit de l'étape précédente, 10 ml d'éthanol, 10 ml de tétrahydrofurane et 0,037 g de Pd/C à 10%. On hydrogène à 40 C et pression ambiante pendant 8 heures. On filtre, on évapore le solvant sous pression réduite et on purifie par flash-chromatographie sur colonne de gel de silice en éluant The two phases are separated, the organic phase is washed with water, dried and the solvent is evaporated off under reduced pressure. Purification is carried out by flash chromatography on a silica gel column, eluting with a cyclohexane / ethyl acetate mixture = 6/4. The title product is obtained. Pf 208 C.

le) 5 - [((4-isopropyIphenyl) suIfonyl) amino] -2- (4-aminopiperidino) -pyridine dihydrochloride 2.1 g (0.0042 mol) of the product from the preceding stage is refluxed for 4 hours in 20 ml of ethyl acetate and 20 ml of an approximately gaseous 3N solution of hydrochloric acid in ethyl acetate. The solvent is evaporated off under reduced pressure, the residue is taken up in acetone, filtered, the precipitate is washed with acetone and 1.8 g of the title product are obtained which is crystallized from ethanol. P. f 270-273 C. ld) 5 - [(((4-isopropylphenyl) sulfonyl) amino] -2- (4 - ((3- (4- (benzyloxy) phenoxy) -2- hydroxypropyl) amino) piperidino) -pyridine Heated at reflux for 20 hours 0.239 g (0.935 mole) of 4-benzyloxy-1- (2,3-epoxypropoxy) benzene, 0.35 g (0.935 mmol) of the product from the previous step in the form of a base 10 ml of ethanol. The solvent is evaporated off under reduced pressure and purified by flash chromatography on a column of silica gel, eluting with a methylene chloride / methanol mixture = 95/5. 0.37 g of the title product is obtained in the form of a glassy product.

le) 5 - [((4-isopropylphenyl) sulfonyl) amino) -2- (4 - ((3- (4-hydroxyphenoxy) -2- hydroxypropyl) amino) piperidino) -pyridine 0.37 g (0.586 mmol) is mixed ) of the product from the previous step, 10 ml of ethanol, 10 ml of tetrahydrofuran and 0.037 g of Pd / C at 10%. Hydrogenated at 40 C and ambient pressure for 8 hours. Filtered, the solvent is evaporated off under reduced pressure and purified by flash chromatography on a column of silica gel, eluting

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(méthylsulf nyl)phénoxy)-2-hydroxypropyl)amino)pipéridino)-pyridine On chauffe au reflux pendant une nuit 0 27 g (0,00084 mole) de 4-benzyloxy-3méthylsulfinyI-l-[(2,3-époxypropoxy)]-benzène (préparé selon US 4,396,629/exemple 3) et 0 33g (0,00088 mole) du produit de l'exemple le) sous forme de base dans 10 ml de éthanol. On évapore le solvant et on purifie le brut de réaction par flashchromatographie en éluant par un mélange CH2Cl2/méthanol = 9/1. On obtient le produit du titre sous forme de solide vitreux

2b) 5-[((4-isopropylphényl)sulfonyl)amino]-2-(4-((3-(4-hydroxy-3- (méthylsulfinyl)phénoxy)-2-hydroxypropyl)amino)pipéridino)-pyridine On chauffe pendant 5 heures à 55 C 0,4g (0,0006 mole) du produit de l'étape précédente dans 10 ml de CF3COOH. On évapore le solvant sous pressione reduite, on dissout le brut dans de l'acétate d'éthyle, on lave à l'aide d'une solution aqueuse saturé en bicarbonate et on sèche. Le produit ainsi obtenu est purifié par flashchromatographie en éluant par un mélange CH2Cl2/ méthanol = 9/1 et puis par un mélange CH2Cl2/ méthanol = 85/1. On obtient le produit du titre P.f.: 128-130 C EXEMPLE 3

5- [( (4-isopropylphényl)sulfonyl)amino ]-2-( 4-( (3-( 4-hydroxy-3-méthansulfonyl amino)phénoxy)-2-hydroxypropyl)amino)pipéridino)-pyridine Le produit du titre est obtenu par condensation du produit de l'étape le) sous forme

de base avec le 4-(benzyloxy)-3-(N-tert-butoxycarbonyl-méthanesulfonylamino)-1- (2,3-époxypropoxy) -benzène (obtenu selon la procédure décrite dans WO 96/04233) et clivage des groupes protecteurs méthanesulfonyle, par hydrolyse acide et benzyle, par hydrogénation.with a methylene chloride / methanol mixture 9/1 The title product is obtained P. f 72-75 C EXAMPLE 2 2a) 5 - [(((4-isopropylphenyl) sulfonyl) amino] -2- (4 - ((3 - (4- (benzyloxy) -3-

(methylsulf nyl) phenoxy) -2-hydroxypropyl) amino) piperidino) -pyridine The mixture is refluxed overnight 0 27 g (0.00084 mole) of 4-benzyloxy-3methylsulfinyI-1 - [(2,3-epoxypropoxy) ] -benzene (prepared according to US 4,396,629 / example 3) and 0 33g (0.00088 mole) of the product of example le) as a base in 10 ml of ethanol. The solvent is evaporated off and the crude reaction product is purified by flash chromatography, eluting with a CH2Cl2 / methanol = 9/1 mixture. The title product is obtained in the form of a glassy solid.

2b) 5 - [((4-isopropylphenyl) sulfonyl) amino] -2- (4 - ((3- (4-hydroxy-3- (methylsulfinyl) phenoxy) -2-hydroxypropyl) amino) piperidino) -pyridine Heated for 5 hours at 55 C 0.4 g (0.0006 mole) of the product from the previous step in 10 ml of CF3COOH. The solvent is evaporated off under reduced pressure, the crude is dissolved in ethyl acetate, washed with a saturated aqueous bicarbonate solution and dried. The product thus obtained is purified by flash chromatography eluting with a CH2Cl2 / methanol mixture = 9/1 and then with a CH2Cl2 / methanol mixture = 85/1. The title product Pf is obtained: 128-130 C EXAMPLE 3

5- [(((4-isopropylphenyl) sulfonyl) amino] -2- (4- ((3- (4-hydroxy-3-methansulfonyl amino) phenoxy) -2-hydroxypropyl) amino) piperidino) -pyridine The title product is obtained by condensation of the product of step le) in the form

base with 4- (benzyloxy) -3- (N-tert-butoxycarbonyl-methanesulfonylamino) -1- (2,3-epoxypropoxy) -benzene (obtained according to the procedure described in WO 96/04233) and cleavage of the protective groups methanesulfonyl, by acid hydrolysis and benzyl, by hydrogenation.

Claims (8)

 a group -CO (CI-C4) Alk, a group -NHS02- (C1-C4) A1k or a halogen; R2 represents a group -SO2-R3, -CO-R3 or -CO- (C1-C4) Alk; R3 represents a phenyl group optionally substituted by a (C1-C4) alkyl group, a (C1-C4) alkoxy group, or by one or two halogens; m and n are independently 0, 1 or 2; z is 1 or 2; X is N or CH; and their salts or solvates.

 Ri represents hydrogen, a group -S (O) z- (CI-C4) Àlk, (SO) z- (Ci- C4) R3, a group SO2-NH- (C, -C4) Alk, a group NHCO (C1-C4) Alk,

 or

 CLAIMS 1. Compounds of formula (I) 2. Compounds according to claim 1 of formula 1 in which X is N and where R2 is in position 5 of pyridine. 3. Compounds according to claim 1 where n and m are each zero. 4. Compounds according to claim 1 wherein the group (Ci-C4) Alk is a methyl or ethyl group. 5. Process for the preparation of the compounds of formula (I) characterized in that a compound of formula (II) is reacted

 in which RI is as indicated in claim 1 and P 'is a protective group and L is a group of formula (a) or (b),

<Desc / Clms Page number 10>  in which n, m, R2 and X are as defined above by cleaving the group P 'according to the usual methods and optionally transforming the compound of formula (I) thus obtained into one of its salts.

 with an amine of formula (III) 6. Pharmaceutical composition containing, as active principle, a compound according to claims 1 to 4. 7. Use of a compound according to claims 1 to 4 for the preparation of drugs indicated in irritable bowel syndrome, or with modulating action of intestinal motility, lipolytic, anti-obesity, anti-diabetic, psychotropic, anti-glaucomatous , healing, anti depressant or tocolytic. 8. Compounds of formula (III)

 wherein R2 represents a group -SO2-R3, -CO-R3 or -CO- (C1-C4) Alk; R3 represents a phenyl group, optionally substituted by a (C1-C4) alkyl group, a (C1-C4) alkoxy group, or by one or two halogens; n and m independently represent 0.1 or 2; X is N or CH; and their salts or solvates.