FR2792316A1 - 1-AMINOETHYLINDOLE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION - Google Patents

Abstract

Compounds of general formula (I) (CF DRAWING IN BOPI) in which: A represents a hydrogen atom, a halogen or a hydroxy,B and D represent, independently of one another, a hydrogen atom or a C1-3 alkyl group R1 represents a hydrogen atom a C1-4 alkyl group, C1-2 fluoroalkyl, C1-2 perfluoroalkyl group, R2 represents a hydrogen atom, a halogen, a C1-6 alkyl group, C3- 6 cycloalkyl, C1-2 fluoroalkyl, C1-2 perfluoroalkyl or a phenyl,R3 and R4 represent, independently of each other, a hydrogen atom, a halogen or a C1-6 alkyl group, R5 and R6 represent , independently of each other, a hydrogen atom, a C1-6 alkyl or C1-2 fluoroalkyl group or R5 and R6 together form a C2-6 alkylene chain to give with the nitrogen to which they are attached a heterocycle such as, for example, a piperidyl, azetidinyl or pyrrolidyl, this heterocycle being optionally substituted by a C1-4 alkyl group. Application in therapy.

Description

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 The present invention relates to 1-amino ethylindole derivatives, their preparation and their therapeutic application.

(I) dans laquelle : A représente un atome d'hydrogène, un halogène ou un hydroxy, B et D représentent, indépendament l'un de l'autre, un atome d'hydrogène ou un groupe C1-3 alkyle, R1 représente un atome d'hydrogène un groupe C1-4 alkyle, C1-2 fluoroalkyle ou C1-2 perfluoroalkyle, R2 représente un atome d'hydrogène, un halogène, un groupe C1-6 alkyle, C3-6 cycloalkyle, C1-2 fluoroalkyle, C1-2 perfluoroalkyle ou un phényle, R3 et R4 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un halogène ou un groupe C1-6 alkyle, R5 et R6 représentent, indépendamment l'un de l'autre, un atome d'hydrogène, un groupe C1-6 alkyle ou C1-2 fluoroalkyle, ou R5 et R6, ensemble, forment une chaîne C2-6 alkylène pour donner avec l'azote auquel ils sont rattachés un hétérocycle tel que, par exemple, une pipéridyle, azétidinyle ou pyrrolidyle, cet hétérocycle étant éventuellement substitué par un groupe C1-4 alkyle. The compounds correspond to the general formula (I)

(I) in which: A represents a hydrogen atom, a halogen or a hydroxyl, B and D represent, independently of one another, a hydrogen atom or a C1-3 alkyl group, R1 represents a hydrogen atom C1-4 alkyl, C1-2 fluoroalkyl or C1-2 perfluoroalkyl group, R2 represents a hydrogen atom, a halogen, a C1-6 alkyl, C3-6 cycloalkyl, C1-2 fluoroalkyl, C1 group; 2-perfluoroalkyl or phenyl, R3 and R4 represent, independently of one another, a hydrogen atom, a halogen or a C1-6 alkyl group, R5 and R6 represent, independently of one another , a hydrogen atom, a C1-6 alkyl or C1-2 fluoroalkyl group, or R5 and R6, together, form a C2-6 alkylene chain to give with the nitrogen to which they are attached a heterocycle such as, for example , a piperidyl, azetidinyl or pyrrolidyl, this heterocycle being optionally substituted by a C1-4 alkyl group.

A group of preferred compounds are those of formula (I) wherein A represents hydroxy.

Another group are those for which B and D represent

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 a hydrogen.

Of these, the compounds for which R2, R3 and R4 independently of one another are hydrogen, halogen or C1-4alkyl are particularly preferred.

In the present application: - C1-z (or C3-z), where z can take the values between 2 and 6, represents a carbon chain which can have from 1 (or 3) to z carbon atoms, - the term alkyl or alkenyl represents respectively a linear or branched chain alkyl or alkenyl, - Pg represents a protecting group; Examples of protecting groups as well as methods of protection and deprotection are given in Protective group in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons, Inc., New York), and - halogen represents an iodine atom , bromine, chlorine or fluorine.

The compounds of general formula (I) may comprise one or more asymmetric carbon atoms. They can therefore exist as enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including the racemic mixtures are part of the invention.

The compounds of general formula (I) may be in free base form or addition salts with pharmaceutically acceptable acids, which are also part of the invention.

The compounds of the invention may be prepared according to methods illustrated by the following schemes.

The compounds of formula (I), wherein A represents a hydroxy group, may be prepared according to the process described in Scheme 1.

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Selon ce procédé, on fait réagir un dérivé éthényl de formule IV avec un oxydant tel que l'acide métachloroperbenzoïque, de sorte à former un époxyde ou, alternativement et préférentiellement pour le contrôle de la stéréochimie avec un oxydant tel que le tétroxyde d'osmium de sorte de former un diol de formule III. Le groupe hydroxy géminé au groupe B (ou D) de ce dernier est sélectivement activé en un groupe partant, de manière connue par un homme du métier, par exemple par formation d'un tosylate, puis traité en milieu basique pour donner le composé de formule II. On prépare ensuite le composé de formule (I) selon l'invention à partir de ce composé en faisant réagir celui-ci avec une amine NHR5R6 en excès, dans un solvant organique tel que le chloroforme, l'acétonitrile ou le tétrahydrofurane. Les significations de R1, R2, R3, R4, R5, R6 et B dans chacun des composés de formules II, III, IV et de l'amine NHR5R6, sont celles indiquées pour la formule (I) . Diagram 1

According to this process, an ethenyl derivative of formula IV is reacted with an oxidant such as metachloroperbenzoic acid, so as to form an epoxide or, alternatively and preferentially for the control of stereochemistry with an oxidant such as osmium tetroxide so as to form a diol of formula III. The hydroxyl group geminated at group B (or D) of the latter is selectively activated in a leaving group, in a manner known to a person skilled in the art, for example by forming a tosylate, and then treated in a basic medium to give the compound of formula II. The compound of formula (I) according to the invention is then prepared from this compound by reacting it with an excess NHR 5 R 6 amine, in an organic solvent such as chloroform, acetonitrile or tetrahydrofuran. The meanings of R 1, R 2, R 3, R 4, R 5, R 6 and B in each of the compounds of formulas II, III, IV and amine NHR 5 R 6 are those indicated for formula (I).

The compounds of formula (I) according to the invention, for which A is a hydrogen atom, can be prepared by dehydroxylation of a corresponding compound of formula (I), where A is a hydroxyl group.

The dehydroxylation reaction can be carried out, in a manner known to those skilled in the art, by reaction with triethylsilane and trifluoroacetic acid or according to

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 method described by A.G. Myers et al. (J. Am Chem Soc.

1997 ; 119: 8572-8573).

The compounds of formula (I), for which A represents a halogen, can be prepared from the compound of formula (I), in which A is a hydroxyl group, according to standard methods known to those skilled in the art, such as for example by the action of acid halides, SOC12, PCl5, PC13 or POCI3 'by the DAST (diethylaminosulfur trifluoride) or alternatively by activation of this group, in a manner known to those skilled in the art, so as to obtain a group nucleophug W, such as a mesyl, tosyl group and from this compound by reacting it with a nucleophilic group.

The ethenyl derivative of formula IV may itself be prepared from an indole derivative of formula V, where Y represents a nucleofuge group such as a halogen or an activated hydroxy group, for example triflate, by palladium coupling of Stille with a compound of formula VI, B and D having the same meanings as for the compounds of formula (I), under the conditions defined by DR Mc Kean et al. (J. Org. Chem.

1987; 52: 492).

Alternatively, the ethenyl derivative of formula IV may be prepared from an aldehyde derivative of formula VI by a Wittig reaction under conditions conventional to those skilled in the art. The compounds of formula VI may themselves be prepared by formylation of a halogenated derivative of formula V wherein Y is halogen in the presence of N, N-dimethylformamide and butyllithium. The formylation reaction can be carried out in an organic solvent such as tetrahydrofuran, N, N-dimethylformamide or a mixture of these solvents, according to the following reaction scheme (2):

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Il existe de nombreuses préparations, connues de l'homme du métier, des composés de formule V selon l'invention, parmi celles-ci, certaines qui ont été employées font appel aux procédés ci-dessous. Figure 2

There are numerous preparations, known to those skilled in the art, of the compounds of formula V according to the invention, of which, some of those employed employ the following methods.

Thus, the compounds of formula V can be prepared according to Scheme 3 by a Madelung reaction. The reaction conditions used are those defined by J. Heindl et al (DE 79-2908279).

Selon ce schéma, une N-acyl o-alkylaniline de formule VII, préparée selon des méthodes connues de l'homme du métier c'est à dire l'acylation de l'aniline correspondante et pour laquelle Y représente un hydroxy ou un méthoxy, est chauffée en présence d'une base forte, tel que l'amidure de sodium, pour former un dérivé indole de formule V substituée en position 4 par le groupe Y. Les significations de R2, R3 et R6 des composés de formule V et VII sont celles indiquées dans la formule I. Figure 3

According to this scheme, an N-acyl o-alkylaniline of formula VII, prepared according to methods known to those skilled in the art, that is to say the acylation of the corresponding aniline and for which Y represents a hydroxyl or a methoxy, is heated in the presence of a strong base, such as sodium amide, to form an indole derivative of formula V substituted in position 4 by the group Y. The meanings of R 2, R 3 and R 6 of the compounds of formula V and VII are those indicated in formula I.

Alternatively, the compounds of formula V for which Y

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 represents a halogen, hydroxy or methoxy can be prepared by a Fisher reaction under the conditions defined by Cross, P. et al (WO95 / 06046 p.44), according to scheme 4.

Selon ce procédé, la cyclisation est obtenue en traitant une aryl hydrazone d'aldéhyde ou de cétone de formule VIII en présence d'agent acide tel que le l'acide polyphosphorique (PPA). L'aryl hydrazone de formule VIII provenant de la condensation, connue de l'homme du métier, entre l'hydrazine de formule IX et un aldéhyde ou une cétone de formule X. Les significations de R1, R2, R3 et R6 des composés de formule V, VIII, IX et X sont celles indiquées dans la formule I. Figure 4

According to this method, the cyclization is obtained by treating an aryl hydrazone of aldehyde or ketone of formula VIII in the presence of an acidic agent such as polyphosphoric acid (PPA). The aryl hydrazone of formula VIII derived from the condensation, known to those skilled in the art, between the hydrazine of formula IX and an aldehyde or ketone of formula X. The meanings of R1, R2, R3 and R6 of the compounds of Formula V, VIII, IX and X are those indicated in formula I.

Compounds of formula IV wherein Y is methoxy can be hydrolyzed according to methods known to those skilled in the art to give compounds of formula IV wherein Y is hydroxy. The hydroxy group can then be converted to a leaving group according to standard methods known to those skilled in the art.

The starting materials for syntheses of the compounds of formula (I) are directly commercially available, are known in the literature or can be synthesized by conventional methods known to those skilled in the art.

The following examples illustrate the methods and techniques suitable for the preparation of this invention without, however, limiting the scope of the claim. Microanalyses and NMR and IR spectra confirm the structures of the compounds.

Example 1: 1 (N) -methyl-2-ethylindole-4- (1-diethylamino) -2-

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 hydroxyethyl) indole (1) 3-hydroxy-2-methylaniline 10.1 g of 2-methyl-3-nitrophenol, 70 ml of methanol and 0.70 g of palladium on carbon are introduced into a 100 ml Parr flask. (5%). The bottle is subjected to 50 psi hydrogen pressure for 2 hours. The reaction medium is filtered and evaporated to give 7.79 g of 3-hydroxy-2-methylaniline in the form of an oil.

(2) 3-Hydroxy-2-methylpropioanilide 11.57 g of 3-hydroxy-2-methylaniline, 95 ml of dichloromethane and 14.4 ml of triethylamine are introduced into a 250 ml flask. The reaction medium is cooled to 0 ° C. with the aid of an ice bath. 8.6 ml of propionyl chloride are added dropwise and the stirring is maintained for 16 hours. 40 ml of water are added and decanted. The organic phase is washed with 40 ml of water, dried over magnesium sulphate and concentrated. 10.98 g (yield: 99%) of 3-hydroxy-2-methylpropioanilide-F: 127-129C are obtained.

(3) 2-ethyl-4-hydroxyindole In a three-necked 500 ml, 32 g of a suspension of sodium amide in toluene, 74 ml of diethylaniline and 5.3 g of 3-hydroxy-2 are introduced. méthylpropioanilide. The temperature of the mixture is brought to 215 ° C. in 45 minutes. The reaction medium is stirred for 30 min. The temperature is brought to 90 ° C. and the reaction medium is hydrolysed dropwise with water. The medium is extracted with diethyl ether (2 × 250 mL) and acidified to pH 2 with 4N hydrochloric acid. The medium is again extracted with diethyl ether (3 × 250 mL). These latter organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography column on silica (elution solvent ethyl acetate: cyclohexane 1: 9). gets 3.1 g of 2-ethyl-4-

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 hydroxyindole (yield: 75%) - F: 120 C.

(4) 1 (N) -methyl-2-ethyl-4-methoxyindole 30 ml of dimethylformamide and 2.5 g of 2-ethyl-4-hydroxyindole are introduced into a 100 ml flask. It is cooled to 0 ° C. with an ice bath and 0.93 g of sodium hydride is added. The reaction mixture is stirred at 0 ° C. for 15 min, 2.9 ml of iodomethane is added and the reaction mixture is stirred for 3 h at room temperature. It is poured into 200 ml of water and extracted with 200 ml of ethyl acetate. The organic phase is decanted and washed with brine (3 × 100 mL), dried over magnesium sulphate and concentrated. 2.9 g of 1 (N) -methyl-2-ethyl-4-methoxyindole (yield: 99%) are obtained.

(5) 1 (N) -methyl-2-ethyl-4-hydroxyindole 2.99 g of 1 (N) -methyl-2-ethyl-4-methoxyindole and 100 ml of dichloromethane are introduced into a 250 ml flask. . The reaction mixture is cooled to -78 ° C. and 2.9 ml of boron tribromide are added dropwise. The reaction mixture is brought to room temperature and basified with 75 ml of a saturated solution of sodium hydrogencarbonate. The mixture is decanted and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are combined, dried over magnesium sulfate and concentrated. 2.6 g of 1 (N) -methyl-2-ethyl-4-hydroxyindole are obtained (yield: 97%) - F: 79 C.

(6) 1 (N) -methyl-2-ethyl-4-trifluoromethanesulfonyloxyindole 2.6 g of 1 (N) -methyl-2-ethyl-4-hydroxyindole and 40 ml of dimethylformamide are introduced into a 100 ml bicol. . The mixture is cooled to 0 ° C. and 0.42 g of sodium hydride is added. Stir 30 min. And a solution of 4.82 g of 4-nitrophenyl trifluoromethanesulfonate in 15 ml of dimethylformamide is added. After stirring for 2 hours at room temperature, poured into 100 ml of water and extracted with 150 ml.

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 of ethyl acetate. The organic phase is decanted, washed with brine (3 x 50 mL), dried over magnesium sulfate and concentrated. The residue is purified by chromatography column on silica (elution solvent ethyl acetate: cyclohexane 1: 9).

5.2 g (yield: 99%) of 1 (N) -methyl-2-ethyl-4-trifluoromethanesulfonyloxyindole are obtained in the form of an oil.

(6) 1 (N) -methyl-2-ethyl-4-vinylindole 5.2 g of 4-trifluoromethanesulfonyloxy-1 (N) -methyl-2-ol are introduced into a 250 ml three-necked flask equipped with a condenser. ethylindole, 45 ml of dioxane, 4.75 ml of tributylvinyltin, 1.88 g of lithium chloride and 0.69 g of palladium tetrakistriphenylphosphine. The reaction medium is degassed by bubbling nitrogen for 30 minutes and then refluxed for 4 hours. The solvent is evaporated and the residue is purified by chromatographic column on silica (elution solvent ethyl acetate: cyclohexane 2: 98).

3.2 g (yield: 99%) of 4-vinyl-1 (N) -methyl-2-ethylindole are obtained in the form of an oil.

(7) (+) - 1 (N) -methyl-2-ethyl-4- (1,2-dihydroxyethyl) indole In a tricolor of 500 ml, 25 g of AD-mix a, 100 ml of tert-butanol are introduced. and 150 mL of water. The mixture is cooled to 0 ° C. with an ice bath and 3.2 g of 4-vinyl-1 (N) -methyl-2-ethylindole are added. After stirring for 2 h at 0 ° C., 25 g of sodium sulphite are added and the reaction mixture is stirred for 1 h at room temperature. It is poured into 50 ml of water and extracted with ethyl acetate (2 × 100 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatographic column on silica (elution solvent dichloromethane: methanol 99: 1). 1.7 g of (+) - 1 (N) -methyl-2-ethyl-4- (1,2-dihydroxyethyl) indole (yield: 52%) are obtained. F: 108 C, [a] 20D = + 54.8 (C = 1, methanol).

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(8) (+) - 1 (N) -methyl-2-ethyl-4- (1-hydroxy-2-tyloxyethyl) indole 1.6 g of (+) - 1 (N) are introduced into a 100 ml flask - methyl-2-ethyl-4- (1,2-dihydroxyethyl) indole, 40 ml of dichloromethane and 1.5 ml of triethylamine. The reaction medium is cooled to 0 ° C. and 1.4 g of tosyl chloride are added. Stirring is maintained for 6 hours at room temperature and the reaction mixture is poured into 40 ml of water. Decanted and extracted with 50 mL of dichloromethane. The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography column on silica (elution solvent dichloromethane). 2.2 g of (+) -1 (N) -methyl-2-ethyl-4- (1-hydroxy-2-tosyloxyethyl) indole (yield: 81%) (9) 1 (N) -methyl- 2-ethyl-4- (1-diethylamino-2-hydroxyethyl) indole and 1 (N) -methyl-2-ethyl-4- (2-diethylamino-1-hydroxyethyl) indole are introduced into a 100 ml flask. 2 g of (+) -1 (N) -methyl-2-ethyl-4- (1-hydroxy-2-tosyloxyethyl) indole, 12 ml of diethylamine and 10 ml of chloroform. The reaction mixture is refluxed for 2 h and concentrated. The residue is purified by chromatography column on silica (chloroform elution solvent: acetone: methanol: ammonia 98: 2: 0.2: 0.2). 0.07 g of 1 (N) -methyl-2-ethyl-4- (1-diethylamino-2-hydroxyethyl) indole is obtained in the form of an oil, 0.32 g of 1 (N) -methyl-2- ethyl-4- (2-diethylamino-1-hydroxyethyl) indole in the form of an oil and 0.456 g of regioisomer mixture.

(10) 1 (N) -methyl-2-ethyl-4- (1-diethylamino-2-hydroxyethyl) indole fumarate 1 (N) -methyl-2-ethyl-4- (1-diethylamino) -2 is added - hydroxyethyl) indole 1.5 equivalents of fumaric acid dissolved in a minimum of ethanol. The mixture is concentrated, crushed

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 in ethyl acetate and filtered and then dried in a desiccator under vacuum over phosphorus pentoxide to give (N) -methyl-2-ethyl-4- (1-diethylamino-2-hydroxyethyl) indole F fumarate: 153 C.

EXAMPLE 2 Using substantially the same process as that of Example 1, another compound of formula (I) according to the invention was prepared. These compounds are those of the table below.

Example 3 The hydrochloric salts described in the table are prepared in the following manner: An excess of a solution of hydrochloric acid in anhydrous isopropanol is added to the compound according to the invention in base form. The salt obtained is then concentrated under vacuum, recrystallized from ethyl acetate or ethyl ether and then dried in a desiccator under vacuum over phosphorus pentoxide.

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Board

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## EQU1 ## > (C)
## EQU1 ##
<tb> 133
<tb> 2 <SEP> Me <SEP> And <SEP> H <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H- <SEP> Oil
<tb> 3 <SEP> Me <SEP> And <SEP> H <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H <SEP> fumarate <SEP> 153
<tb> 4 <SEP> Me <SEP> Ph <SEP> H <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H- <SEP> Oil
<tb> 5 <SEP> Me <SEP> Ph <SEP> H <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H <SEP> HCl <SEP> 178-
<tb> 181
<tb> 6 <SEP> Me <SEP> Me <SEP> H <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H- <SEP> Oil
<tb> 7 <SEP> Me <SEP> Me <SEP> H <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H <SEP> fumarate <SEP> 153-
<tb> 155
<tb> 8 <SEP> And <SEP> Me <SEP> H <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H- <SEP> Oil
<tb> 9 <SEP> And <SEP> Me <SEP> H <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H <SEP> HCl <SEP> 162
<tb> 10 <SEP> Me <SEP> Me <SEP> F <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H- <SEP> Oil
<tb> 11 <SEP> Me <SEP> Me <SEP> F <SEP> And <SEP> And <SEP> H <SEP> OH <SEP> H <SEP> H
<tb> 12 <SEP> Me <SEP> Me <SEP> H <SEP> H <SEP> -CH <SEP> (R) <SEP> (Me) <SEP> (CH2) <SEP> 4- <SEP > OH <SEP> H <SEP> H- <SEP> oil
## EQU1 # > OH <SEP> H <SEP> H
<Tb>
In these tables: - HCl represents a hydrochloride, - "-" represents a compound in free form, - Me represents a methyl group, - Et represents an ethyl group, - Ph represents a phenyl group, Moreover, all the compounds of the Table are pairs of enantiomers: The stereochemistry of carbon bearing group A (OH) is not defined.

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The compounds of the invention have been subjected to biological tests intended to demonstrate their contractile activity on the urethral and arterial smooth muscles.

1. The in vitro activity of the compounds of the invention has been studied on the urethral and arterial smooth muscles. These tests were carried out on New Zealand female rabbits weighing from 3 to 3.5 kg. The animals were killed by vertebral dislocation, then rings of mesenteric artery and ureter tissue were removed. These tissue rings were immersed in a modified Krebs solution, oxygenated with a mixture of 95% O 2 and 5% CO 2. Each tissue sample was tensioned at 1 g and then phenylephrine was added at cumulative doses and the dose / response curve was established. After rinsing the samples, the test compound was introduced at cumulative doses and the dose / response curve was established. The contractile effect of each compound is evaluated by the calculation of pD2 (negative logarithm of the agonist concentration that induces 50% of maximal contraction) as well as by the maximum effect representing the percentage of maximum contraction obtained with phenylephrine. (% Emax).

The results obtained show that the compounds in accordance with the invention have: a pD2 urethra, usually between 4 and 8, a pD2 artery usually less than 3, an Emax urethra greater than 30, usually between 40 and 90; , * a% Emax artery usually less than 5.

2. The in vitro activity of the compounds of the invention has been studied on the saphenous veins of micro-pig Yucatan. The fabric is cut into a helix and is mounted in an organ chamber in a modified oxygenated Krebs solution.

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 by a mixture of 95% O2 and 5% C02 maintained at 37 C. The vessel is connected to an isometric sensor at a basal tension of 1 g and is connected to a polygraph for recording the voltage variations.

The viability of each preparation is tested by prestimulation with 3M norepinephrine. After rinsing, the compound to be studied is introduced and its response concentration curve is constructed cumulatively until a maximum response is obtained. The contractile effect of each compound is evaluated by calculating the EC50 (concentration producing 50% of the maximum response).

The compounds of the invention have made it possible to obtain a venoconstructive activity with an EC50 value usually between 1 M and 100 M.

The compounds of the invention can be used in the treatment of venous insufficiency and venous ulcer.

3. The in vivo activity of the compounds of the invention on blood pressure and urethral was studied in anesthetized rats and rabbit, according to the following protocols: * Anesthetized rats The technique used is adapted from that described by D.

Martin, D. Jammes and I. Angel, Life Sci., 57: 387-391, 1995. Wistar rats are anesthetized. The catheters are introduced into the abdominal aorta (via the femoral artery) and the jugular vein. Another catheter is introduced into the urethra (via a bladder purse). Blood pressure, urethral and heart rate are recorded continuously. The compounds to be tested are administered intravenously. Four doses of compound, with an interval of 10 minutes, are evaluated.

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The results are expressed in doses (g / kg) necessary to increase the urethral pressure by 50% (ED50) and decrease the heart rate by 10% (ED10).

The compounds of the invention thus tested, made it possible to obtain: an ED50 lower than the ED10 (approximately 3 to 10 times).

Usually the ED50 is between 3 and 300 g / kg and the ED10 born not reached.

Rabbits The experiments are carried out on New Zealand female rabbits weighing between 3 and 4 kg, anesthetized with a mixture of Ketamine and Xylazine. The catheters are introduced for the descending aorta into the femoral artery, into a jugular vein and into the urethra (1.5 cm below the bladder neck).

The compounds to be tested are administered 5 to 15 days after the operation, by intravenous administration (i v.) In 5 minutes, and in a single dose (of 100 or 1000 g / kg).

The increase in urethral pressure (PU) and arterial pressure (BP) compared with basal, urethral and arterial pressure was measured here. The results obtained are expressed as a percentage of premedicamentous values at 5 minutes after intravenous (i.v.) administration.

Compounds of the invention thus tested, allowed an increase in PU greater than 50%, usually between 50 and 350% after intravenous administration, and usually between 50 and 200% after gavage. The increase in BP was always less than 10%, usually 0%.

All the above results show that the compounds of the invention have a strong contractile action

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 urethral and low arterial contractile action.

They can be used as a medicament, particularly as a contracting agent for smooth muscle, and even more particularly, in the treatment of stress urinary incontinence. In this indication, the compounds according to the invention have a good efficacy and, usually, lesser side effects than the drugs conventionally used for such a treatment, in particular with regard to the side effects affecting the cardiovascular system, in particular the arterial beds.

The compounds according to the invention can also be used for the treatment of venous insufficiency, migraine, gastrointestinal disorders and as a vasoconstrictor of the nasal mucosa.

The compounds according to the invention may be presented in different pharmaceutical forms suitable for oral, rectal, vaginal or parenteral administration and topical application, where appropriate in combination with at least one pharmaceutical excipient. Suitable dosage forms are, for example, tablets, capsules, dragees, capsules, oral or injectable solutions, syrups and suppositories.

These dosage forms can be assayed to allow a daily dose of 1 g / kg to 100 mg / kg.

Claims (4)

 R2v R5 .R6 R1-N B (i) A in which. R4 A represents a hydrogen atom, a halogen or a hydroxyl, B and D represent, independently of one another, a hydrogen atom or a C1-3 alkyl group, R1 represents a hydrogen atom a C1-C4 alkyl, C1-2 fluoroalkyl or C1-2 perfluoroalkyl, R2 represents a hydrogen atom, a halogen, a C1-C6 alkyl, C3-6 cycloalkyl, C1-2 fluoroalkyl, C1-2 perfluoroalkyl group or a phenyl, R3 and R4 represent, independently of one another, a hydrogen atom, a halogen or a C1-6 alkyl group, R5 and R6 represent, independently of one another, an atom of hydrogen, a C1-6 alkyl or C1-2 fluoroalkyl group, or R5 and R6, together, form a C2-6 alkylene chain to give with the nitrogen to which they are attached a heterocycle, this heterocycle being optionally substituted by a C1 group -4-alkyl, and optionally in enantiomeric form, of diastereoisomer, or mixture of these different forms, including m racemic mixture as well as the addition salts with pharmaceutically acceptable acids of one of these forms.

 1. Compound of formula (I) 2. Process for the preparation of a compound of formula (I) according to claim 1, in which A is a hydroxy group, characterized in that an oxirane derivative of formula II is reacted.

<Desc / Clms Page number 18>  with an amine NHR5R6, the meanings of R1, R2, R3, R4, B and D of the oxirane of formula II and R5 and R6 of said amine, being those defined for the compound of formula (I) according to claim 1 . 3. Medicinal product characterized in that it consists of a compound according to claim 1. 4. Pharmaceutical composition characterized in that it comprises a compound according to claim 1 and one or more suitable excipients.