WO2000061553A1 - 2-aminoethyl-indole derivatives, their preparation and therapeutic use - Google Patents

Abstract

The invention concerns a compound of formula (I) wherein: A represents a hydrogen atom or a hydroxy; B represents a hydrogen atom, a C1-C3 alkyl group; R1 represents a hydrogen atom, a C1-C4 alkyl, C1-C4 fluoroalkyl or C1-C2 perfluoroalkyl group; R2 represents a hydrogen atom, a halogen, a C1-C6 alkyl, C2-C4 alkenyl group or a phenyl; R3 and R6, identical or different, represent each a hydrogen atom, a halogen, a C1-C4 alkyl or C1-C4 fluoroalkyl or C1-C2 perfluoroalkyl group; R4 and R5, identical or different, represent a hydrogen atom, a C1-C4 alkyl or C2-C4 alkenyl group, excluding compounds for which R2 and R3 simultaneously represent a hydrogen atom. The invention has therapeutic uses.

Description

 2-aminoethyl-indole derivatives, their preparation and their therapeutic use

The present invention relates to 2-aminoethyl-indole derivatives, their preparation and their therapeutic use.

Consequently, the first subject of the present invention is a compound of general formula (I):

dans laquelle :

in which :

- A represents a hydrogen atom or a hydroxy,

- B represents a hydrogen atom, a Cι_ ₃ alkyl group,

Ri represents a hydrogen atom, a Cι_ ₄ alkyl, Cι_ ₄ fluoroalkyle or Cι_ ₂ perfluoroalkyle group,

- R ₂ represents a hydrogen atom, a halogen, a Cι_ ₆ alkyl group, C ₂ - ₄ alkenyl, or a phenyl,

- R ₃ and R ₆ , identical or different, each represent a hydrogen atom, a halogen, a Cι_ ₄ alkyl, Cι_ ₄ fluoroalkyle or Cι_ ₂ perfluoroalkyle group,

- R ₄ and R ₅ , identical or different, represent a hydrogen atom, a Cι_ ₄ alkyl or C ₂ _ ₄ alkenyl group, to the exclusion of the compounds for which R ₂ and R ₃ simultaneously represent hydrogen.

The preferred compounds according to the invention are those for which A represents a hydroxy and more particularly the compounds for which A represents a hydroxy and B represents a hydrogen atom. Among these, the compounds comprising radicals having the following meanings are preferred:

* Ri represents a methyl or an ethyl,

* R ₂ represents a Cι_ ₄ alkyl group, more preferably a methyl, ethyl or i-propyl; or a phenyl or a CF ₃ group _/ more particularly a methyl, ethyl or phenyl;

* R ₃ represents a hydrogen atom,

* R ₄ and R ₅ represent, each independently of one another, methyl or ethyl, preferably ethyl, and

* R ₆ represents a hydrogen atom.

As preferred compounds, mention may be made of the following compounds: - (1H) -2-methylindole-4- (2-diethylamino-1-hydroxyethylindole;

- 1 (N) -methyl-2-ethylindole-4- (2-diethylamino-1-hydroxyethylindole;

- 1 (N) -methyl-2-phenylindole-4- (2-diethylamino-1-hydroxyethylindole;

- 1 (N) -methyl-2-methylindole-4- (2-diethylamino-1-hydroxyethylindole;

- 1 (N) -ethyl-2-methylindole-4- (2-diethylamino-1-hydroxyethylindole; and - 1 (N) -methyl-2-methyl-3-fluoroindole-4- (2-diethylamino-1-hydroxyethylindole .

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

The compounds of general formula (I) can be in the form of free base or of addition salts with acids, which also form part of the invention. These salts, according to the present invention, include those with mineral or organic acids which allow suitable separation or crystallization of the compounds of formula (I), such as picric acid, oxalic acid or an optically active acid, for example a tartaric acid, a dibenzoyltartaric acid, a mandelic acid or a camphosulphonic acid, and those which form physiologically acceptable salts, such as the hydrochloride, hydrobromide, citrate, sulphate, hydrogen sulphate, dihydrogenphosphate, maleate, fumarate, pamoate, 2-naphthalenesulphonate, paratoluenesulfonate. Although the pharmaceutically acceptable salts are preferred, the other salts are part of the present invention. These salts can be prepared, according to methods known to a person skilled in the art, for example, by reaction of the compound of formula (I) in base form with the acid in an appropriate solvent, such as an alcoholic solution or a organic solvent, then separation of the medium which contains it by evaporation of the solvent or by filtration.

The hydrochloric acid salts are preferred.

In the context of the present invention, the following definitions are intended:

- Cι- _Z (or C ₂ _ _z ), where z can take the values of 2 to 4, a carbon chain being able to have from 1 or 2 to z carbon atoms,

- alkyl, a saturated, linear or branched aliphatic group; for example, a Cι_ alkyl group represents a carbon chain of 1 to 4 carbon atoms, linear or branched, more particularly methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, tertbutyl, preferably methyl, ethyl, propyl , isopropyl,

- alkenyl, a mono or polyunsaturated, linear or branched aliphatic group, preferably comprising 1 or 2 ethylenic unsaturations,

- perfluoroalkyle, an alkyl in which all the hydrogens have been substituted by fluors, for example CF ₃ ,

- polyfluoroalkyle, an alkyl part of which hydrogens has been substituted with fluors for example

CF ₂ H and

- halogen atom, fluorine, chlorine, bromine or iodine.

A second subject of the present invention is processes for preparing the compounds of formula (I).

Thus, these compounds can be prepared by methods, illustrated in the diagrams which follow, the operating conditions of which are conventional for a person skilled in the art.

1. The compounds of formula (I), in which A represents a hydroxy group, can be prepared according to reaction scheme 1.

Diagram 1

According to this process, an aldehyde of formula II is reacted with a stannate of formula III. The meanings of Ri, R ₂ , R ₃ , R, R5, Rε and B of the compounds of formula II or III are those indicated in formula I. This reaction can be carried out in an organic solvent such as tetrahydrofuran (THF) , in the presence of n-butyl lithium.

The compounds of formula II can be prepared by a reaction for formylation of an indole derivative of formula IV, according to Scheme 2. The reaction can be carried out by means of a catalysis with palladium according to the process described by Kotsuki H. et al. (Synthesis 1996, 470-472) or alternatively, by lithiation of the indole derivative of formula IV and treatment with N, N-dimethylformamide (DMF). For the quinoline derivative of formula IV, Y represents a nucleofuge group such as for example a halogen or an activated hydroxy group such as a triflate group.

Diagram 2

The compounds of formula III can be prepared by a person skilled in the art according to the method described by A.R. Katrizky et al. (Synthesis 1994, 907).

The compounds of formula IV can be synthesized according to methods known to a person skilled in the art, among these, some which have been used call on the methods described below.

Thus, the compounds of formula IV 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).

Diagram 3

V IV According to this scheme, an N-acyl o-alkylaniline of formula V in which Y represents a hydroxy or a methoxy, prepared according to methods known to those skilled in the art, that is to say the acylation of the corresponding aniline, is heated in the presence of a strong base, such as sodium amide, to form an indole derivative of formula IV, in which Ri is hydrogen, substituted in position 4 by the group Y. The meanings of R ₂ , R ₃ and R ₆ of the compounds of formula IV and V are those indicated in formula I. The compounds of formula IV in which R 1 represents a hydrogen can then be transformed into compounds of formula IV in which R 1 is as defined in the formula (I ) according to methods known to those skilled in the art.

Alternatively, the compounds of formula IV for which Y represents a halogen, hydroxy or methoxy group can be prepared by a Fisher reaction under the conditions defined by Cross, P. et al (WO95 / 06046 p.44), according to the scheme 4. Diagram 4

According to this process, the cyclization is obtained by treating an aryl hydrazone of aldehyde or ketone of formula VI in the presence of an acid agent such as polyphosphoric acid (PPA). The aryl hydrazone of formula VI can come from the condensation, according to methods known to a person skilled in the art, of a hydrazine of formula VII with an aldehyde or a ketone of formula VIII. The meanings of Ri, R ₂ , R ₃ and Rε of the compounds of formula IV, VI, VII and VIII are those indicated in formula I.

The compounds of formula IV, in which Y represents a methoxy group, can be hydrolyzed according to methods known to those skilled in the art to give compounds of formula IV in which Y represents a hydroxy.

The hydroxy group can then be transformed into a leaving group according to conventional methods known to those skilled in the art.

2. The compounds of formula (I) according to the invention, for which A is a hydroxy group, can also be prepared according to reaction scheme 5.

Diagram 5

According to this process, an ethenyl indole derivative of formula X is reacted with an oxidant such as osmium tetroxide (in racemic or chiral series by using AD-mix-α or AD-mix-β) so as to form a diol of formula IX in which W represents a hydroxy. The hydroxy group twinned with group B of the diol thus obtained can then be optionally activated selectively, in a manner known to those skilled in the art, so as to obtain the compound of formula IX, in which W represents a nucleofuge group, such as a tosyle group, an acetyl group or a bromine atom. The compound of formula (I) according to the invention is then prepared from the compound of formula IX, by reacting the latter with an amine NHR ₄ R ₅ . The meanings of Ri, R ₂ , R ₃ , R ₄ , R ₅ , Rε and B in each of the compounds of formula XII or XIII and of the amine NHR ₄ R ₅ , are those indicated in formula (I). The ethenyl quinoline derivative of formula X can itself be prepared by palladic coupling of Stille, under the conditions defined by DR Me Kean et al. (J. Org. Chem., 52; 1987: 492), from a derivative of formula IV as defined above for which Y represents a nucleofuge group, such as a halogen or an activated hydroxy group, such than a triflate group.

Alternatively, the ethenyl indole derivative of formula X can be prepared from an aldehyde derivative of formula II as defined above, by an ittig reaction under conditions standard for a person skilled in the art.

3. The compounds of formula (I) according to the invention, for which A is a hydroxy group, can also be prepared according to the following reaction scheme (6):

Diagram 6

According to this process, the compound of formula (I) is prepared by reacting an oxirane derivative of formula XI with an amine NHR ₄ R ₅ . The meanings of Ri, R ₂ , R ₃ , R ₄ , R5, Rε and B of the oxirane derivative of formula XIV and of said amine, are those indicated above in formula I.

The oxirane derivative of formula XI can be prepared according to one of the following processes:

* by reaction of trimethylsulfonium iodide on the aldehyde of formula II described above;

by the action of a peracid such as acid metachloroperbenzoic acid on the ethenyl benzofuran derivative of formula X, under conditions standard for a person skilled in the art;

* by treating in a basic medium the derivative of formula IX for which W represents a nucleofuge group, such as a tosyl group, an acetyl group or a bromine atom.

4. 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 hydroxy group.

The dehydroxylation reaction can be carried out, in a manner known to those skilled in the art, by reaction with triethylsilane and trifluroacetic acid or according to the method described by A. G. Myers et al. (J. Am. Chem. Soc.

1997; 119: 8572-8573).

The following examples illustrate the methods and techniques used for the preparation of this invention, without however limiting the scope of the claim. Elementary micro-analyzes and NMR, IR or mass spectra confirm the structures of the compounds obtained.

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

(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 (5%) are introduced into a 100 ml bottle of Parr. The bottle is subjected to a hydrogen pressure of 50 psi for 2 h. The reaction medium is filtered and evaporated to provide 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. using an ice bath. 8.6 mL of propionyl chloride are added dropwise and stirring is continued for 16 h. 40 ml of water are added and decanted. The organic phase is washed with 40 mL of water, dried over magnesium sulfate and concentrated. 10.98 g are obtained (yield: 99%) of 3-hydroxy-2-methylpropioanilide - mp: 127-129 ° C.

(3) 2-ethyl-4-hydroxyindole

32 g of a suspension of sodium amide in toluene, 74 ml of diethylaniline and 5.3 g of 3-hydroxy-2-methylpropioanilide are introduced into a 500 ml three-necked flask. 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 hydrolyzed drop by drop with water. The medium is extracted with diethyl ether (2x250 mL) and acidified to pH = 2 using 4N hydrochloric acid. The medium is again extracted with diethyl ether (3x250 mL). These last organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatographic column on silica (elution solvent ethyl acetate: cyclohexane 1: 9). 3.1 g of 2-ethyl-4-hydroxyindole are obtained (yield: 75%) - mp: 120 ° C.

(4) 1 (N) -methyl-2-ethyl-4-methoxyindole

30 L of dimethylformamide and 2.5 g of 2-ethyl-4-hydroxyindole are introduced into a 100 ml flask. It is cooled to 0 ° C. in 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 are added and the reaction medium 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 (3x100 mL), dried over magnesium sulfate and concentrated. 2.9 g of 1 (N) -methyl-2-ethyl-4-methoxyindole are obtained (yield: 99%) - M: 92 ° C.

(5) 1 (N) -methyl-2-ethyl-4-hydroxyindole

2.9 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 ambient temperature and basified with 75 ml of a saturated solution of sodium hydrogencarbonate. 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%) - mp: 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. Shake 30 min. And a solution of 4.82 g of 4-nitrophenyl trifluoromethanesulfonate in 15 ml of dimethylformamide is added. After 2 h of stirring at room temperature, poured into 100 ml of water and extracted with 150 ml 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 chromatographic 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-ethylindole, 45 ml of dioxane, 4.75 ml of tributylvinyltin, 1.88 g are introduced into a 250 ml three-necked flask fitted with a condenser. 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 h. The solvent is evaporated off and the residue is purified by chromatographic column on silica (elution solvent ethyl acetate: cyclohexane 2:98).

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

(7) (+) -1 (N) -methyl-2-ethyl-4- (1,2-dihydroxyethyl) indole

25 g of AD-mix α, 100 ml of tert-butanol and 150 ml of water are introduced into a 500 ml three-necked flask. The mixture is cooled to 0 ° C. in an ice bath and 3.2 g of 4-vinyl-1 (N) -methyl-2-ethylindole are added. After 2 hours of stirring at 0 ° C., 25 g of sodium sulfite are added and the reaction mixture is stirred for 1 hour at room temperature. Pour onto 50 ml of water and extract with ethyl acetate (2x100 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by a chromatographic column on silica (elution solvent dichloromethane: methanol 99: 1). 1.7 g of (+) - 1 (N) -methyl-2-ethyl-4- (1,2-dihydroxyethyl) indole are obtained (yield: 52%) F: 108 ° C, [α] ²⁰ _D = +54.8 (C-≈l, methanol).

(8) (* +) -1 (N) -methyl-2-ethyl-4- (1-hydroxy-2-tosyloxyethyl) indole

1.6 g of (+) - l (N) - 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 chloride tosyle are added. Stirring is continued for 6 h at room temperature and the reaction mixture is poured onto 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 a chromatographic column on silica (elution solvent dichloromethane). 2.2 g of (+) -1 (N) -methyl-2- ethyl-4- (1-hydroxy-2-tosyloxyethyl) indole are obtained (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

2.2 g of (+) - l (N) - methyl-2-ethyl-4- (l-hydroxy-2-tosyloxyethyl) indole, 12 ml of diethylamine and 10 ml of liquid are introduced into a 100 ml flask. chloroform. The reaction mixture is refluxed for 2 h and concentrated. The residue is purified by a chromatographic 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 mixture of regioisomers.

(10) 1 (N) -methyl-2-ethyl-4- (2-diethylamino-1-hydroxyethyl) indole hydrochloride

2 equivalents of hydrochloric acid in isopropanol are added to 1 (N) -methyl-2-ethyl-4- (2-diethylamino-1-hydroxyethyl) indole. The mixture is concentrated, triturated in diethyl ether and filtered then dried in a desiccator under vacuum over phosphoric anhydride to give the hydrochloride of 1 (N) -methyl-2-ethyl-4- (2-diethylamino-1-hydroxyethyl) indole - F: 148-149 ° C, [α] ²⁰ _D = +67.7 (C = l, methanol). Example 2

By essentially reproducing the same process of Example 1, with the appropriate starting materials, other compounds of formula (I) were prepared, in accordance with the invention, listed in the table below.

BOARD

In these tables: - HC1 represents a hydrochloride,

- "-" represents a compound in free form, - Me represents a methyl group;

- And represents an ethyl group,

- Ph represents a phenyl group,

- i-Bu represents an iso-butyl group,

- Bn represents a benzyl group

Furthermore, all of the compounds in the Table are pairs of enantiomers: The stereochemistry of carbon carrying the group A (OH) is not defined.

The compounds of the invention were subjected to biological tests intended to demonstrate their selective smooth muscle contracting activity.

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 female New Zealand rabbits weighing 3 to 3.5 kg. The animals were killed by vertebral dislocation, and then rings of tissue from the mesenteric arteries and urethra were removed. These tissue rings were immersed in a modified Krebs solution, oxygenated by a mixture of 95% of 0 ₂ and 5% of CO ₂ . Each tissue sample was subjected to a tension of 1 g and then phenylephrine was introduced at cumulative doses and the dose / response curve was established. After rinsing the samples, the compound to be studied was introduced at cumulative doses and the dose / response curve established. The contractile effect of each compound is evaluated by calculating pD ₂ (negative logarithm of the agonist concentration which induces 50% of the maximum contraction) as well as by the Maximum effect representing the percentage of the maximum contraction obtained with the phenylephrine (% E _ma χ) •

The results obtained show that the compounds in accordance with the invention have:

* a pD2 urethra greater than 2.5, usually between 4 and 8, more generally between 5 and 8, * a pD2 artery less than 3,

* a% E _max urethra greater than 30, usually between 40 and 90,

* a% E _max artery equal to zero.

2. The in vivo activity of the compounds of the invention on the blood and urethral pressure was studied in the anesthetized rat 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 pouch). Blood pressure, urethral pressure and heart rate are continuously recorded. The test compounds are administered intravenously. Four doses of compound, with an interval of 10 minutes, are evaluated.

The results are expressed in doses (μg / 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 EDIO (approximately 3 to 10 times). Usually 1ΕD50 is between 3 and 300 μg / kg and the EDIO born not reached.

All of the above results show that the compounds of the invention have a strong urethral action and weak arterial action.

They can be used as a medicament, in particular as a contracting agent for smooth muscles, and more particularly still, in the treatment of urinary incontinence, in particular stress urinary incontinence. In this indication, the compounds according to the invention exhibit good efficacy and, usually, less side effects than the drugs conventionally used for such treatment, in particular as regards the side effects affecting the arteries.

The compounds of the invention were subjected to biological tests intended to demonstrate their venoconstrictor activity.

1. The in vitro activity of the compounds of the invention was studied on the saphenous veins of Yucatan micro-pigs. The tissue is cut in a helix and mounted in a tank with isolated organs in a modified Krebs solution oxygenated with a mixture of 95% 0 ₂ and 5% C0 ₂ maintained at 37 ° C. The vessel is connected to an isometric sensor at a basal voltage of 1 g and connected to a polygraph allowing the recording of blood pressure variations. The viability of each preparation is tested by pretimulation with noradrenaline 3μM. After rinsing, the compound to be studied is introduced and its concentration-response curve constructed cumulatively until a maximum response is obtained. The contractile effect of each compound is evaluated by calculation of the EC ₅₀ (concentration producing 50% of the maximum response).

The compounds of the invention have made it possible to obtain a venoconstrictor activity with an EC ₅₀ value usually between 1 μM and 100 μM.

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

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

The use of the compounds according to the invention for the preparation of a medicament intended for treating pathologies in which a smooth muscle contracting agent brings a therapeutic benefit forms an integral part of the invention.

On the other hand, the use of the compounds according to the invention for the preparation of a medicament intended to treat the pathologies mentioned above forms an integral part of one invention.

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, a compound according to the invention.

Thus, these pharmaceutical compositions contain an effective dose of a compound according to the invention or of a pharmaceutically acceptable salt or hydrate thereof, and one or more suitable pharmaceutical excipients.

Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, intratracheal, intranasal, transdermal or rectal administration, the active principle of formula (I) above, its salt or hydrate if necessary, can be administered in unit administration form, in mixture with conventional pharmaceutical excipients, to animals and beings humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit dosage forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual, buccal, intratracheal, intranasal forms of administration. subcutaneous, intramuscular or intravenous administration and forms of rectal or vaginal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.1 mg and 50 mg per kg of body weight per day. Although these dosages are examples of an average situation, there may be special cases where higher or lower dosages are appropriate, such dosages also belong to the invention. According to usual practice, the appropriate dosage for each patient is determined by the doctor according to the method of administration, the weight and the response of said patient.

Each unit dose may contain from 0.1 to 1000 mg, preferably from 0.1 to 500 mg, of active ingredient in combination with one or more pharmaceutical excipients. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 0.5 to 5000 mg, preferably 0.5 to 2500 mg.

For example, when preparing a solid composition in the form of tablets, the main active ingredient is mixed with a pharmaceutical excipient, such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative, or other materials. The tablets can be made by different techniques, direct compression, dry granulation, wet granulation or hot melting.

According to a second example, 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.

For parenteral administration, aqueous suspensions, isotonic 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 present invention according to another of its aspects, also relates to a method for treating the pathologies indicated above which comprises the administration of a compound according to the invention or one of its salts, or hydrates.

Claims

1. Compound of formula (I)

in which : - A represents a hydrogen atom or a hydroxy, - B represents a hydrogen atom, a Cι_ ₃ alkyl group, - Ri represents a hydrogen atom, a Cι_ ₄ alkyl, Cι- ₄ fluoroalkyle or Cχ_ ₂ perfluoroalkyle group, - R ₂ represents a hydrogen atom, a halogen, a Cι_ ₆ alkyl group, C ₂ _ ₄ alkenyl, or a phenyl, - R ₃ and R ₆ , identical or different, each represent a hydrogen atom, a halogen , a group C ₁ - ₄ alkyl, Cι_ ₄ fluoroalkyle or Cι- ₂ perfluoroalkyle, - R ₄ and R ₅ , identical or different, represent a hydrogen atom, a Cι_ ₄ alkyl or C ₂ - alkenyl group, to the exclusion of the compounds for which R ₂ and R ₃ simultaneously represent a hydrogen atom, and optionally in the form of addition salts with pharmaceutically acceptable acids. 2. Compound according to claim 1, characterized in that: A represents hydroxy and B represents a hydrogen atom. 3. Compound according to claim 1 or 2, characterized in that: * Ri represents a methyl or an ethyl, * R ₂ represents methyl, ethyl or i-propyl; or a group CF ₃ , * R ₃ represents a hydrogen atom, * R ₄ and R ₅ represent, each independently of one another, methyl or ethyl, and * Rβ represents a hydrogen atom. 4. Compound according to claim 1 characterized in that it consists of: - (1H) -2-methylindole-4- (2-diethylamino-1-hydroxyethylindole; - 1 (N) -methyl-2-ethylindole-4- (2-diethylamino-1-hydroxyethylindole; - 1 (N) -methyl-2-phenylindole-4- (2-diethylamino-1-hydroxyethylindole; - 1 (N) -methyl-2-methylindole-4- (2-diethylamino-1-hydroxyethylindole; - 1 (N) -ethyl-2-methylindole-4- (2-diethylamino-1-hydroxyethylindole; or - 1 (N) -methyl-2-methyl-3-fluoroindole-4- (2-diethylamino-1-hydroxyethylindole. 5. Process for the preparation of a compound of formula (I) according to claim 1, characterized in that an aldehyde of formula II is reacted

with an aminoalkyl stannate derivative of formula III R4 III _R5 .N ^ .Sn (C ₄ H ₉ ) ₃ B the meanings of Ri, R ₂ , R ₃ , R ₄ , R5, Rβ and B of the aldehyde of formula II and of the aminoalkyl stannate derivative of formula III being those defined for the compound of formula (I) according to claim 1, to give a compound of formula (I) in which A is hydroxy and optionally this compound is dehydroxylated to give a compound of formula (I) in which A is hydrogen. 6. 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 XI is reacted R2 R3 XI R6 with an amine NHR ₄ R ₅ , the meanings of Ri, R ₂ , R ₃ , R ₆ and B of the oxirane of formula XVI and of R ₄ and R ₅ of said amine, being those defined for the compound of formula (I) according to claim 1. 7. Process for the preparation of a compound of formula (I) according to claim 1, in which A represents a hydroxy, characterized in that a compound of formula IX is reacted, after activation of the hydroxy group,

in which W represents a nucleophuge group, with an amine NHR ₄ R ₅ , the meanings of Ri, R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and B of the compound of formula XIII and of said amine, being those defined for the compound of formula (I) according to claim 1. 8. Pharmaceutical composition characterized in that it contains a compound of formula (I) according to one of claims 1, 2, 3 or 4 in combination with one or more pharmaceutically acceptable excipients. 9. Use of a compound of formula (I) according to any one of claims 1, 2, 3 or 4 for the preparation of a medicament intended to treat a pathology in which a smooth muscle contracting agent provides a therapeutic benefit . 10. Use of a compound of formula (I) according to claim 11 characterized in that the pathology consists of urinary incontinence.