FR2802529A1 - 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-1-group substituted on the amine, these compounds having an ss1-blocking and a-blocking activity.

J. Org. Chem., 1988, 63: 889-894, describes other aryloxypropanolamines carrying a 4-piperidinyl-1-group substituted on the amine
It has now been found that certain phenoxypropanolamines carrying a piperidin-4-yl radical on the amine have an agonist activity with respect to ss3adrenergic receptors.

où

Ri représente l'hydrogène, un halogène, un groupe -S(O)Z-(CI-C4)Alk, un groupe -CO(CI-C4)Alk, un groupe -NHS02-(CI-C4)Alk, un groupe NHCO(CI-C4)Alk ou -SO2NH(CI-C4)Alk ; R2 représente l'hydrogène ou un groupe (C1-C6)Alk, un groupe (Ci-

C4)alcoxy, un halogène, -COOH, -COO(C1-C.)Alk, -CN, -CONR3R4, -N02, -NHSO2(C,-C4)Alk ou - SOZNR3R4; m et n sont indépendamment 0, 1 ou 2; R3 et R4 représentent indépendamment l'hydrogène ou un groupe (C1-C4)Alk,

phényle ou phényl(CI-C4)alkyle z est 1 ou 2 et leurs sels ou solvates. Thus, the present invention relates, according to one of its aspects, to phenoxypropanolamines of formula (I)

or

R1 represents hydrogen, a halogen, a group -S (O) Z- (CI-C4) Alk, a group -CO (CI-C4) Alk, a group -NHS02- (CI-C4) Alk, a group NHCO (CI-C4) Alk or -SO2NH (CI-C4) Alk; R2 represents hydrogen or a group (C1-C6) Alk, a group (Ci-

C4) alkoxy, halogen, -COOH, -COO (C1-C.) Alk, -CN, -CONR3R4, -N02, -NHSO2 (C, -C4) Alk or - SOZNR3R4; m and n are independently 0, 1 or 2; R3 and R4 independently represent hydrogen or a (C1-C4) Alk group,

phenyl or phenyl (CI-C4) alkyl z is 1 or 2 and their salts or solvates.

 In the present description, the terms "(C1-C4) Alk" and "(Cl-C6) Alk" respectively denote a monovalent radical of a saturated straight or branched chain C1-C4 or Ci-Ce hydrocarbon.

 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.

 In addition, when the compounds of formula (I) have a free carboxy group the salts also include the salts with mineral bases, preferably those with alkali metals such as sodium or potassium, or with organic bases.

 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 R1, in any proportion, form part of the present invention.

 Preferred compounds of the present invention include compounds of formula (I) where the group R2 is in the 4 position of benzene.

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

C4)Alk, -CN, -NO2, -CONR2R3, - NHS02-(CI-C4)Alk, -SO2NR3R4 . Other preferred compounds are those where R2 is chosen from -COOH, -COO (C1-

C4) Alk, -CN, -NO2, -CONR2R3, - NHS02- (CI-C4) Alk, -SO2NR3R4.

 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 X 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)

en clivant le groupe P' selon les méthodes usuelles et éventuellement transformant le composé de formule (I) ainsi obtenu en 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 X 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)

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.

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 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 at least equimolecular amounts of the reagents, optionally in small excess of amine.

 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 usual protecting groups for hydroxy groups such as for example methoxyethoxymethyl (MEM) or optionally substituted benzyl.

 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 with trifluoroacetic acid; in the case of methoxyethoxymethyl (MEM), an acid such as trifluoroacetic acid can also be used.

 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.

où Hal représente un halogène et R2 et m sont telsque définis ci-dessus, avec une pipéridine de formule (V) ci-dessous

où n est tel que défini ci-dessus et P" représente un groupe protecteur, dans un solvant organique en présence d'une base, suivie par clivage du groupe P" des composés de formule (VI) ainsi obtenus.

The amines of formula (III) can be prepared by reaction of the suitable benzenes of formula (IV)

where Hal represents a halogen and R2 and m are as defined above, with a piperidine of formula (V) below

where n is as defined above and P "represents a protective group, in an organic solvent in the presence of a base, followed by cleavage of the group P" of the compounds of formula (VI) thus obtained.

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 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 ", there may be used acyl groups, such as formyl, acetyl, propionyl phenylacetyl, phenoxyacetyl and the like; an alkoxycarbonyl group such as tert-butoxycarbonyl and the like; an alkoxyalkylcarbonyl group such as methoxypropionyl and the like; a substituted alkoxycarbonyl group, such as trichloroethoxycarbonyl and the like; a substituted alkylcarbonyl group such as monochloromethylcarbonyl, monochloroethylcarbonyl, dichloromethylcarbonyl similar trichloromethylcarbonyl, trichloroethylcarbonyl arylcarbonylcarbonyl arylcarbonylcarbonylaroxycarbonyl, trichloroethylcarbonyl, trichloroethylcarbonyl, trichloroethylcarbonyl, trichloroethylcarbonyl, trichloroethylcarbonyl, trichloroethylcarbonyl, trichloropropylcarbonyl, trichloroethylcarbonyl, and trichloropropylcarbonyl; ; a benzyl group; a substituted benzyl group; an optionally substituted diphenylmethyl group; an optionally substituted trityl group, such as 4-methoxyphenyldiphenylmethyl or di- (4methoxyphenyl) phenylmethyl; u n silylant group such as trimethylsisyl or ethyldimethylsilyl or tert-butyldimethylsilyl and the like.

 Said protecting groups can be cleaved according to conventional methods, for example by reduction or hydrolysis. A more detailed description of these amino-protecting groups as well as the methods for their preparation and their elimination is given for example by T. W. Greene, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1981 and by J.F.W. McPime, "Protective Groups in Organic Chemistry", Plenum Press, 1973. In the case of tert-butoxycarbonyl for example, the cleavage is normally carried out by acid hydrolysis.

 Some of the intermediate amines of formula (III) are new.

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où P est l'hydrogène ou un groupe protecteur P" ; n et m sont 0,1 ou 2 ;

R2 est un groupe choisi parmi -COOH, -COO(CI-C4)Alk, -CONR 3R 4, -NHS02(CI-C4)Alk ; R 3 et R 4 représentent indépendamment l'hydrogène ou un groupe(Ci-C4)Alk ; à la condition que lorsque P est l'hydrogène, n est 0 et m est 1, R2 n'est pas un groupe CON(CH2CH3)2; ainsi que leurs sels. Thus according to another of its aspects the present invention relates to new products of formula (VII)

where P is hydrogen or a protecting group P "; n and m are 0,1 or 2;

R2 is a group chosen from -COOH, -COO (CI-C4) Alk, -CONR 3R 4, -NHS02 (CI-C4) Alk; R 3 and R 4 independently represent hydrogen or a (Ci-C4) Alk group; provided that when P is hydrogen, n is 0 and m is 1, R2 is not a CON (CH2CH3) 2 group; as well as their salts.

 Particularly preferred compounds of formula (VII) are those where P is chosen from hydrogen and tert-butoxycarbonyl, n is 0, m is 0 or 1 and R2 is COO (C1-C4) Alk.

 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 action drugs (33.

 In addition, the compounds of formula (I) are not very toxic; in particular, 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, antiobesity agents, anti-diabetic, psychotropic, anti-glaucomatous, healing, anti depressants.

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 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 from 0 to 500 mg, preferably from 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 a prolonged or delayed activity and that they continuously release a predetermined quantity of active principle.

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 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 an appropriate 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 an 03-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).

 The examples which follow illustrate the invention better.

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 PREPARATION 1 4-tert-butoxycarbonylamino-piperidine.

25 g (0.13 mole) of 4-amino-1-benzylpiperidine, 36.2 ml (0.26 mole) of triethylamine and 31.2 g (0.143 mole) of di- are mixed at room temperature for 2 hours. tert-butyl-dicarbonate in 200 ml of dimethylformamide The mixture is poured into water, extracted with ethyl acetate, washed with water and the product thus obtained is crystallized from 200 ml of isopropyl ether 33 g of 1-benzyl-4-tert-butoxycarbonylamino-piperidine are obtained, which is hydrogenated in a mixture of 200 ml of ethanol and 100 ml of tetrahydrofuran in the presence of 3 g of 10% Pd / C. After filtration of the catalyst, the title compound is isolated. P.f. 157-160 C.

4-tert-butoxycarbonylamino-1-(4-éthoxycarbonylphenylméthyl)-pipéridine On chauffe sous agitation pendant 6 heures à 50 C un mélange de 2,01 g (0,010 mole) du produit obtenu dans la préparation 1 et 2 g (0,010 mole) de 4chlorométhyl-éthoxycarbonylbenzene dans 40 ml de diméthylformamide. On verse dans de l'eau, on extrait à l'acetate d'éthyle et on lave avec de l'eau. Le produit est filtré et séché. Le brut ainsi obtenu est purifié par flash-chromatographie en éluant par un mélange cyclohéxane/acétate d'éthyle = 1 :1. On obtient le composé du titre. PREPARATION 2

4-tert-butoxycarbonylamino-1- (4-ethoxycarbonylphenylmethyl) -piperidine A mixture of 2.01 g (0.010 mole) of the product obtained in preparation 1 and 2 g (0.010 mole) is stirred for 6 hours at 50 ° C. of 4chloromethyl-ethoxycarbonylbenzene in 40 ml of dimethylformamide. Pour into water, extract with ethyl acetate and wash with water. The product is filtered and dried. The crude product thus obtained is purified by flash chromatography, eluting with a cyclohexane / ethyl acetate mixture = 1: 1. The title compound is obtained.

P.f. : 74-76 C.

4-amino-l-( 4-éthoxycarbonylphenylméthyl)-pipéridine Le produit obtenu par la préparation 2 est chauffé au réflux pendant 5 heures dans une solution contenant 15 ml de acétate d'éthyle et 15 ml de HCL en acétate d'éthyle (à peu près 3N). Après refroidissement, on filtre, on lave à l'acétone et on sèche le produit sous pression réduite. Le produit du titre est obtenu sous forme de chlorhydrate dihydraté par cristallisation dans une solution d'éthanol. P.f. : 290- 293. PREPARATION 3

4-amino-1- (4-ethoxycarbonylphenylmethyl) -piperidine The product obtained by preparation 2 is heated under reflux for 5 hours in a solution containing 15 ml of ethyl acetate and 15 ml of HCL in ethyl acetate (at about 3N). After cooling, it is filtered, washed with acetone and the product is dried under reduced pressure. The title product is obtained in the form of hydrochloride dihydrate by crystallization from an ethanol solution. Pf: 290-293.

PREPARATION 4 4-tert-butoxycarbonylamino-1- (4-ethoxycarbonylphenyl) -piperidine 21.6 g (0.10 mol) of the product of Preparation 1 is heated at 80 ° C. for 55 hours with 9.06 g (0.01 mole) of (4-ethoxycarbonyl-1-fluoro) benzene and 14.9 g of K2CO3 in 200 ml of dimthylformamide. The K2CO3 is filtered, the solution is poured into water, extracted with ethyl acetate and the solvent is evaporated. The crude reaction product is purified by flash chromatography, eluting with a cyclohexane / ethyl acetate mixture = 8: 2. The title product is obtained which is crystallized from ethyl acetate. M.P. = 138 -140

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 PREPARATION 5 4-amino-1- (4-ethoxycarbonylphenyl) -piperidine.

9.74 g (0.023 mol) of the product of preparation 4 are dissolved in 60 ml of ethyl acetate and 80 ml of a 3N solution of HCl in ethyl acetate are added. The mixture is heated at reflux for 5 hours, the solvent is evaporated, acetone is added and filtered.

4-tert-butoxycarbonylamino-1-{4-méthoxycarbonylphényl)-pipéridine A une suspension de 456 mg de CS2 C03 dans 2 ml de toluène anhydre on ajoute 3 mg (0,01 mmole) de Pd (OAC)2, 10 mg (0,015mmole), de BINAP 215mg (1,2 mmole) de 4-bromo-méthoxycarbonylbenzène et 240 mg de produit de la prépartaion 1 (1,2 mmole). On chauffe à 100 et après 2 jours on ajoute 2 ml de dioxane, 3 mg de Pd (OAC)2 et 10 mg de BINAP On chauffe encore pendant deux jours à 110 puis on arrête la réaction On verse dans de l'eau et on extrait à l'acétate d'éthyle Le produit est purifié par flash chromatographie en éluant par un mélange acétate d'éthyle/cyclohexane P.f.:162-165. The title product is obtained which crystallizes from ethanol P f = 240-242 PREPARATION 6

4-tert-butoxycarbonylamino-1- {4-methoxycarbonylphenyl) -piperidine To a suspension of 456 mg of CS2 C03 in 2 ml of anhydrous toluene is added 3 mg (0.01 mmol) of Pd (OAC) 2, 10 mg ( 0.015mmol), BINAP 215mg (1.2mmol) of 4-bromo-methoxycarbonylbenzene and 240mg of prepartaion 1 product (1.2mmol). The mixture is heated to 100 and after 2 days 2 ml of dioxane, 3 mg of Pd (OAC) 2 and 10 mg of BINAP are added. It is further heated for two days to 110, then the reaction is stopped. extract with ethyl acetate The product is purified by flash chromatography, eluting with an ethyl acetate / cyclohexane mixture Pf: 162-165.

PREPARATION 7 4- (phenylmethoxy) -3- (N-tert-butoxycarbonyl-methansulfonylamino) -l- (2,3-epoxypropoxy) -benzene.

4-benzyloxy-3-méthylsulfinyl-1-[(2,3-époxypropoxy)]-benzène Le produit du titre a été obtenu suivant la procédure décrite dans US 4,396,629 PREPARATION 9 4-benzyloxy-l-[(2,3-époxypropoxy)]-benzène Le produit du titre a été obtenu suivant la procédure décrite dans WO 96/04233 (procédure 7) EXEMPLE 1

3-[l-(4-éthoxycarbonylphénylméthyl)-4-pipéridinylamino]-l-(4hydroxyphénoxy)-2-propanol la/ 3-[1-(4-éthoxycarbonylphénylméthyl)-pipéridinylaminoJ-1-(4-méthoxy- éthoxy-méthoxyphenoxy)-2-propanol On chauffe au reflux pendant 17 heures 0,86 g (0,0033 mole) de 4-(méthoxy- éthoxy-méthoxy)-I-(2,3-époxypropoxy)-benzène et 0,83 g (0,0033 mole) du produit obtenu dans la préparation 3 sous forme de base libre dans 40 ml de méthanol. On évapore le solvant sous pression réduite et on sèche le produit. On The title product was obtained according to the procedure described in WO 96/04233 (procedure 96) PREPARATION 8

4-benzyloxy-3-methylsulfinyl-1 - [(2,3-epoxypropoxy)] - benzene The title product was obtained according to the procedure described in US 4,396,629 PREPARATION 9 4-benzyloxy-1 - [(2,3-epoxypropoxy )] - benzene The title product was obtained according to the procedure described in WO 96/04233 (procedure 7) EXAMPLE 1

3- [1- (4-ethoxycarbonylphenylmethyl) -4-piperidinylamino] -1- (4hydroxyphenoxy) -2-propanol la / 3- [1- (4-ethoxycarbonylphenylmethyl) -piperidinylaminoJ-1- (4-methoxy- ethoxy-methoxyphenoxy ) -2-propanol Refluxed for 17 hours 0.86 g (0.0033 mole) of 4- (methoxy-ethoxy-methoxy) -I- (2,3-epoxypropoxy) -benzene and 0.83 g ( 0.0033 mol) of the product obtained in preparation 3 in the form of the free base in 40 ml of methanol. The solvent is evaporated off under reduced pressure and the product is dried. We

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lb/ 3-[1-(4-éthoxycarbonylphénylméthyl)-4-pipéridinylamino]-1-(4- hydroxyphénoxy)-2-propanol On chauffe à 40 C pendant 8 heures un mélange contenant 0,7 g (0,0014 mole) du produit obtenu dans l'étape précédente et 1,1ml (0,014 mole) de CF3 COOH dans 40 ml de chlorure de méthylène. On évapore le solvant et on ajoute de l'ammoniac. On extrait à l'acétate d'éthyle, on anhydrifie et on évapore le solvant Le brut de réaction est purifié par flash-chromatographie en éluant par chlorure de méthylene/méthanol =9 :1. On obtient le composé du titre P.f 180-184 C EXEMPLE 2

3-[l-(4-éthoxycarbonyIphényl)-4-pipéridinylamino]-l-(4-hydroxyphénoxy)-2propanol 2a/ 3-[1-(4-éthoxycarbonylphényl)-pipéridinylamino]-1-(4- benzyloxyphenoxy)-2-propanol On chauffe au reflux pendant 20 heures 1,03 g (0,004 mole) du produit de la préparation 9 et 1 g (0,004 mole) du produit de la préparation 5 dans 50 ml d'éthanol. On évapore le solvant et on purifie le brut de réaction par flashchromatographie en éluant par un mélange CH2Cl2/méthanol = 9:1. purifies the reaction crude by flash chromatography, eluting with methanol. The product is crystallized from isoprophylic ether P f: 73-75 C

lb / 3- [1- (4-ethoxycarbonylphenylmethyl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol A mixture containing 0.7 g (0.0014 mol) is heated at 40 ° C. of the product obtained in the previous step and 1.1 ml (0.014 mole) of CF3 COOH in 40 ml of methylene chloride. The solvent is evaporated off and ammonia is added. Extraction is carried out with ethyl acetate, anhydrification and the solvent are evaporated. The reaction crude is purified by flash chromatography, eluting with methylene chloride / methanol = 9: 1. The title compound Pf 180-184 C is obtained. EXAMPLE 2

3- [1- (4-ethoxycarbonyIphenyl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2propanol 2a / 3- [1- (4-ethoxycarbonylphenyl) -piperidinylamino] -1- (4-benzyloxyphenoxy) -2 -propanol 1.03 g (0.004 mole) of the product of preparation 9 and 1 g (0.004 mole) of the product of preparation 5 are heated at reflux for 20 hours in 50 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. Pf 112 -114.

2b / 3- [1- (4-ethoxycarbonylphenylmethyl) -4-piperidinylamino] -1- (4-hydroxyphenoxy) -2-propanol
Hydrogenated at 40 ° C. at ambient pressure for eight hours 1.15 g (0.0023 mol) of the product from the previous step in 20 ml of ethanol + 20 ml of THF in the presence of 0.1 g of palladium on carbon at 10%. 150 ml of hydrogen are absorbed.

 It is filtered and the solvent is evaporated. It is crystallized from ethyl acetate. The title product is obtained. P.f. 158 -161.

3-[1-(4-éthoxycarbonylphényl)-4-pipéridinylamino]-1-[(4-hydroxy)-3- (méthansulphonylamino)-phénoxy]-2-propanol 3a/ 3-[1-(4-éthoxycarbonylphényl)-4-pipéridinylamino]-1-[(4-benzyloxy)-3- (méthansulphonylamino)-phénoxy]-2-propanol On mélange 1 g (0,004 mole) du produit de la préparation 5 avec 1,35 g (0,003 mole) du produit de la préparation 7 et 0,2 g de perchlorate de lithium dans 50 ml de CH3CN. On laisse sous agitation pendant 24 heures à la température ambiante, puis on chauffe à 40 pendant huit heures. EXAMPLE 3

3- [1- (4-ethoxycarbonylphenyl) -4-piperidinylamino] -1 - [(4-hydroxy) -3- (methansulphonylamino) -phenoxy] -2-propanol 3a / 3- [1- (4-ethoxycarbonylphenyl) - 4-piperidinylamino] -1 - [(4-benzyloxy) -3- (methansulphonylamino) -phenoxy] -2-propanol 1 g (0.004 mole) of the product of preparation 5 is mixed with 1.35 g (0.003 mole) of the product of preparation 7 and 0.2 g of lithium perchlorate in 50 ml of CH3CN. The mixture is left stirring for 24 hours at room temperature and then heated to 40 for eight hours.

The solvent is evaporated off and the product thus obtained is treated at 40 for eight hours with a solution of hydrochloric acid in ethyl acetate. We evaporate the

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chromatographie en éluant par un mélange CH2Cl2-méthanol = 9:1 . On obtient le produit du titre P.f. 130 -132 .

3b/ 3-[l-(4-éthoxycarbonylphényl)-4-pipéridinylamino]-l-[(4-hydroxy)-3- (méthansulphonylamino )-phénoxy ]-2-propanol 0,8 g (0,0013 mole) du produit de l'étape précédente sont soumis à hydrogénation en présence de 0,1g de palladium sur carbone (10%) dans 15 ml d'éthanole + 15 ml de THF. Après huit heures de réaction à 40 et à la pression ambiante, on filtre et on évapore le solvant. On purifie le brut de réaction par flash-chromatographie en éluant par un mélange CH2Cl2/méthanol = 95. 5. On obtient le produit du titre qui cristallise dans l'isopropanole P f. 140 -143 . solvent, treatment with NaHCO3 solution, extraction with ethyl acetate, the solvent is further evaporated and the reaction crude is purified by flash-

chromatography eluting with a CH2Cl2-methanol mixture = 9: 1. The title product Pf 130-132 is obtained.

3b / 3- [1- (4-ethoxycarbonylphenyl) -4-piperidinylamino] -1 - [(4-hydroxy) -3- (methansulphonylamino) -phenoxy] -2-propanol 0.8 g (0.0013 mole) product of the previous step are subjected to hydrogenation in the presence of 0.1 g of palladium on carbon (10%) in 15 ml of ethanole + 15 ml of THF. After eight hours of reaction at 40 and at ambient pressure, the mixture is filtered and the solvent is evaporated. The crude reaction product is purified by flash chromatography, eluting with a CH2Cl2 / methanol = 95 mixture. 5. The title product is obtained, which crystallizes from isopropanole P f. 140 -143.

3-[l-(4-éthoxycarbonyIphényl)-4-pipéridinylamino]-l-[(4-hydroxy)-3- (méthysulphinyl)-phénoxy]-2-propanol 4a/ 3-[l-(4-éthoxycarbonylphényI)-4-pipéridinylamino]-l-[(4-benzyloxy)-3- (méthysulphinyl)-phénoxy)-2-propanol On chauffe au reflux pendant une nuit 0,8 g (0,0032 mole) du produit de la préparation 5 avec 1 g (0,0031mole) du produit de la préparation 8 dans 50 ml d'éthanole On évapore le solvant et on purifie le brut de réaction par flash- chromatographie en éluant par un mélange CH2Cl2/méthanol = 95 :5. obtient le produit du titre P.f. 135 -137 .

EXAMPLE 4

3- [l- (4-ethoxycarbonyIphenyl) -4-piperidinylamino] -l - [(4-hydroxy) -3- (methysulphinyl) -phenoxy] -2-propanol 4a / 3- [l- (4-ethoxycarbonylphenyI) - 4-piperidinylamino] -1 - [(4-benzyloxy) -3- (methysulphinyl) -phenoxy) -2-propanol 0.8 g (0.0032 mol) of the product of preparation 5 is heated at reflux overnight. 1 g (0.0031 mol) of the product of preparation 8 in 50 ml of ethanole The solvent is evaporated and the reaction crude is purified by flash chromatography, eluting with a CH2Cl2 / methanol = 95: 5 mixture. obtains the product of the title Pf 135 -137.

4b / 3- [1- (4-ethoxycarbonylphenyl) -4-piperidinylamino] -1 - [(4-hydroxy) -3- (methysulphinyl) -phenoxy] -2-propanol Heated to 55 for seven hours 0.98 g (0.0017 mole) of the product from the previous step in 20 ml of CF3COOH. The solvent is evaporated off, a bicarbonate solution is added and the mixture is extracted with ethyl acetate. The solvent is evaporated off and the reaction crude is purified by flash chromatography, eluting with a CH2Cl2 / methanol = 9: 1 mixture. The title product is obtained. P.f. 78 -80.

Claims (11)

C4) Alk, phenyl or phenyl (C1-C4) alkyl; z is 1 or 2; and their salts or solvates. R3 and R4 independently represent hydrogen or a group (Ci-  -CONR3R4, -NO2, -NHS02 (CI-C4) Alk or -SO2NR3R4; m and n are independently 0, 1 or 2,

 -CO (CI-C4) Alk, a group -NHSO2- (Ci-C4) Alk, a group -NHCO (C-C4) A1k or -SO2NH (Ci-C4) Alk; R2 represents hydrogen or a (C1-C6) Alk group, a (C, -C4) alkoxy group, a halogen, -COOH, -COO (C1-C4) Aly, -CN,

 in which R represents hydrogen, a group -S (O) z- (C1-C4) Alk, a group

 CLAIMS I. Compounds of formula (I) 2. Compounds according to claim 1 wherein R2 is in position 4 of benzene. 3. Compounds according to claim 1 where n and m are each zero. 4. Compounds according to claim 1, in which the group (Ci-C4) Alk is a methyl or ethyl group. 5. Compounds according to claim 1 where R2 is chosen from COOH groups,

 COO (Ci-C4) Alk, -CN, -NO2, NHS02- (Ci-C4) AIk and -SÛ2NR3R4 6. 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, P 'is a protective group and X is a group of formula (a) or (b), <Desc / Clms Page number 13>  in which n, m and R2 are as indicated in claim 1, the group P ′ is cleaved and optionally the compound of formula (I) thus obtained is converted into one of its salts.

 where Gp is a leaving group, with an amine of formula (III)

7. Compounds of formula (VII)

 or P is hydrogen or a protecting group; n and m are 0.1or 2; R2 is a group selected from -COOH, -COO (C, -C4) Alk, -CONR 3R 4, -NHSO2 (C1-C4) Alk; R 3 and R 4 independently represent hydrogen or a group (CI- C4) Alk; on the condition that when P is hydrogen, n is zero and m is 1, R 2 is not a CON (CH2CH3) 2 group; as well as their salts. 8. A compound according to claim 7 where P is chosen from hydrogen and tert-butoxycarbonyl, n is zero, m is 0 or 1 and R 2 is - COO (C1-C4) Alk. 9. Compound according to claim 6 chosen from 4-tert-butoxycarbonylamino- 1- (4-ethoxycarbonyl-phenylmethyl) -piperidine, 4 -tert-butoxycarbonylamino-1- (4-methoxycarbonyl-phenyl) -piperidine, and their salts pharmaceutically acceptable. 10. Use of a compound according to claims 1 to 5 for the preparation of medicaments indicated in irritable bowel syndrome, or with modulating action of intestinal motility, lipolytic, anti-obesity, anti-diabetic, psychotropic, anti-glaucomatous , healing, anti depressant.  11. Pharmaceutical composition comprising as active principle at least one compound of formula (I) as defined in claims 1 to 5, or one of its pharmaceutically acceptable salts.