IE60779B1 - "New n-(1h-indol-4-yl)benzamide derivatives and also their salts, their application by way of medicinal products and the compositions containing them" - Google Patents

Abstract

Products of formula (I): in which one of the substituents X and Y denotes alkyl (C1-C5), alkoxy (C1-C3), chlorine, bromine, iodine, nitro or amino optionally substituted by an aliphatic acyl (C2-C5) or 2 alkyls (C1-C5) and the other substituent denotes a hydrogen, it being understood that Y does not denote methoxy and X chlorine, and their addition salts with acids. The products (I) are endowed with antiarrhythmic properties and some have anticalcic properties.

Description

The invention relates to new N-(.1H-indol-4-yl )benzamide derivatives and also their salts, their application by way of medicinal products and the compositions containing them.

N-(1 Η-1ndoI-4-yI) benz amide derivatives are des10 cribed in European Patent Application No .86/401,528.4. These derivatives correspond to the following general formula : in which R and R-j denote, independently of one another, a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms, a branched alkyl radical containing from. 3 to 5 carbon atoms, a cycloalkyl radical containing from 3 to 7 carbon atoms, a cycloalkylalkyl radical containing from 4 to 7 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms, optionally substi-. tuted with 1, 2 or 3 radicals chosen from the group consisting of halogen and methyl, ethyl, methoxy, ethoxy, tri fluoromethyl, methylthio, amino and nitro radicals, or R and Ri together form a saturated or unsaturated heterocycle which can contain a second hetero atom chosen from oxygen, sulphur and nitrogen atoms, this nitrogen atom optionally being substituted with an alkyl radical containing from 1 to 5 carbon atoms, with a phenyl, substituted phenyl or naphthyl radical or with an aralkyl radical containing from'7 to 12 carbon atoms, R3 denotes a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 3 carbon atoms, a chlorine, bromine or iodine atom, a nitro radical or an amino radical optionally substituted with an aliphatic acyl group containing from 2 to 5 carbon atoms or an alkyl radical containing from 1 to 5 carbon atoms, a together with b denotes an oxo group, or together with c denotes a carbon-carbon bond, b denotes a hydrogen atom, or together with a an oxo group, c denotes a hydrogen atom, or together with a denotes a carbon-carbon bond, A denotes a chain -(CHgln- which n can assume the values 2, 3, 4 or 5, or a chain -(CHjpm-CH-CHg- in which m can OH assume the values 1, 2 or 3, B denotes a -CO-NH- or -NH-COchain, and R2 denotes a hydrogen atom, a linear alkyl radical containing from 1 to 5 carbon atoms or a branched alkyl radical containing from 3 to 5 carbon atoms.

These compounds are described as possessing advantageous pharmacological properties and, in particular, exceptional antiarrhythmic properties. The present invention relates to new compounds comprised within the general formula of this European patent application, these new compounds being endowed with especially advantageous antiarrhythmic properties.

The subject of the present invention is hence compounds of formula (I): (I) in which one or other of the substituents X or Y denotes an alkyl radical containing from 1 to 5 carbon atoms, an - 3 alkoxy radical containing from 1 to 3 carbon atoms, a chlorine, bromine or iodine atom, a nitro radical or an amino radical optionally substituted with an aliphatic acyl group containing from 2 to 5 carbon atoms or one or two alkyl radicals containing from 1 to 5 carbon atoms, and the other substituent denotes a hydrogen atom, with the proviso that Y does not denote a methoxy group and X a chlorine atom, and also their addition salts with acids.

When X or Y denotes an alkyl radical, the latter is preferably a methyl or ethyl radical, but they can also denote an n-propyl, isopropyl, n-butyl, -isobutyl, tertbutyl or n-pentyl radical.

When X or Y denotes an alkoxy radical, it is preferably a methoxy, ethoxy, π-propoxy or isopropoxy radical.

When X or Y denotes an amino radical substituted with an aliphatic acyl group containing from 2 to 5 carbon atoms, it is preferably an amino radical preferably substituted with an acetyl or propionyl radical.

When X or Y denotes an amino radical substituted with one or two alkyl radicals, the latter are preferably methyl or ethyl radicals.

The addition salts with inorganic or organic acids can be, for example, the salts formed with hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic and aspartic acids, alkanesulphonic acids such as methane- and ethanesulphonic acids, arylsulphonic acids such as benzene- and paratoluenesulphonic acids, and arylcarboxylic acids.

The invention relates, in particular, to the compounds of formula (I) which are characterized in that X denotes a methoxy, nitro, amino or acetylamino radical and Y denotes a hydrogen atom, or alternatively Y denotes a chlorine atom, a nitro, amino or acetylamino radical and X denotes a hydrogen atom, and also their addition salts with acids, and more especially 2-<3-C(1,1-dimethylethyl)amino]-2-hydroxypropoxy>-N-(1H-indol-4-yl)-5-nitrobenzamide and also its addition salts with acids.

The compounds of formula (I) of the present invention may be prepared by a process similar to that described in European Patent Application No. 86/401,528.4.

The process for preparing the products of the present application is characterized in that a compound of formula (11) : H (II) in which X and Y have the above meanings, is reacted with a halide of formula (III): Hal-CH2-qH-CH2 (III) to obtain a compound of formula (IV):· which is reacted with tert-butylamine to obtain a compound of formula (I) which, if desired, is subjected to the action of an inorganic or organic acid to obtain a salt.

When X or Y denotes an alkyl or alkoxy group or a chlorine, bromine or iodine atom in the compound of formula (II), Hal is preferably a chlorine atom in the compound of formula (III).

The reaction of the compound of formula (II) with the compound of formula (III) is then preferably carried out in the presence of a base such as potassium carbonate or sodium carbonate, sodium hydroxide or potassium hydroxide .

When X or Y denotes a nitro group in the compound of formula (II), Hal is preferably a bromine atom in the compound of formula (III). The reaction is then carried out by heating the compound of formula (IV) under reflux.

The reaction of the derivative of formula (IV) with tert-butylamine is carried out using a solvent such as an aliphatic a I coholf or example methanol or ethanol.

When it is desired to prepare a compound of formula (1) in which X or Y denotes an optionally substituted amino radical, it is possible to reduce the compound of formula (I) in which X or Y denotes a nitro radical and, where appropriate, the amino derivative is reacted with a derivative of the substituent which it is desired to obtain.

The corresponding working conditions are known to those versed in the art.

The starting substance of formula (II) may be prepared by reaction of 4-aminoindole with a hydroxybenzoic. acid substituted with X or Y.

The derivatives which are the subject of the present invention possess very advantageous pharmacological properties; they are endowed, in particular, with exceptional antiarrhythmic properties and some of the products possess calcium-antagonistic properties.

These properties are illustrated later in the experimental part.

These properties justify the use of the N—(1H— indol-4-yl)benzamide derivatives of formula (I), and also their salts, by way of medicinal products.

The subject of the present patent application is thus also the application, by way of medicinal products, - 6 O'f the N-( 1H-indol-4-yl/benzamide derivatives as defined by the formula (I), and also of their addition saIts with pharmaceuticalIy acceptable acids.

Among the medicinal products which are the subject of the invention, the medicinal products preferably selected are characterized in that they consist of the new N-(1H-indoI-4-yI)benzamide derivatives corresponding to the formula (I), characterized in that X denotes a methoxy, nitro, amino or acetylamino radical and Y denotes a hydrogen atom, or alternatively Y denotes a chlorine atom or a nitro, amino, acetylamino radical and X denotes a hydrogen atom, and also their addition salts with acids.

Among these products, 2-<3-[(1,1-dimethyIethyI)amino3-2-hydroxypropoxy}-N-(1H-indol-4-yl)-5-nitrobenzamide, and also its addition salts with acids, are most especially selected.

The medicinal products according to the invention find their application, for example, in the treatment of arrhythmias .

The usual dose, which varies according to the derivative used, the subject and the condition in question, can be, for example, from 50 mg to 1 g per day. Orally in man, the derivative of Example 1 can be administered at a daily dose of 200 mg to 800 mg, for example for the treatment of ventricular, supraventricular and junctional arrhythmias, equivalent to approximately 3 mg to 12 mg per kilogram of body weight.

The subject of the invention is also the pharmaceutical compositions which contain at least one of the abovementioned derivatives or one of its addition salts with pharmaceutically acceptable acids, by way of active princ iple.

By way of medicinal products, the derivatives corresponding to the formula (I) and their addition salts with pharmaceutically acceptable acids can be incorporated into pharmaceutical compositions intended for enteral or parenteral administration.

These pharmaceutical compositions can be, for example, solid or liquid, and can be presented in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or sugar-coated tablets, gelatin capsules, granules, suppositories or injectable preparations; they are prepared according to the usual methods. The active principle or principles can be incorporated therein with excipients customarily employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fats of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersant or emulsifying agents and preservatives .

The examples which follow illustrate the present invention without, however, limiting it.

Example 1; 2--C3-C(1,1-d.imethylethyl)amino]-2-hydroxypropoxy>-N-(lH-indol-4-yl)-5-nitrobenzamide and its hydrochloride. 9.8 g of 2-hydroxy-5-nitro-N-(lH-indol-4-yl)-benzamide are heated under reflux for 1 hour with 40 cm^ of epibromohydrin. The excess epibromohydrin is removed under reduced pressure at 60°C, the resin obtained is taken up with 100 cm^ of ethanol and 40 cm^ of tert-butylamine and the mixture is heated under reflux for 2 hours. The excess solvent and reagent is removed under reduced pressure at 60°C and 78 g of crude product are obtained. Purification is performed by two successive chromatographic, runs on silica (1st: eluant: chIoroform/methanol/tri ethylamine 8:1:1; 2nd: eluant: chloroform/acetone/triethylamine 5:4:1). 4.4 g of product are recovered in the form of the base. M.p. 208°C.

Formation of the hydrochloride 3.5 g of base prepared above are dissolved in one litre of isopropanol and 250 cm^ of methanol at the reflux and a saturated solution of hydrochloric acid in ethyl acetate is added until the pH is acid. The mixture is heated for 30 minutes under reflux, concentrated to approx imately 500 cm\ chilled, filtered and dried under reduced pressure at 50°C. 2.85 g of expected product are obtained. M.p. > 260°C.

Analysis: Calculated: ClX 57.08 HX 5.88 NX 12.10 ClX 7.66 Found : 56.8 6.1 12.0 7.4 Preparation of 2-hydroxy-5-πitro-N-(1 H-indoI-4-yI) benzam i de g of 4-aminoindole, 150 cm^ of tetrahydrofuran, 8.4 g of 5-nitros a Iicy I ic acid and 12.5 g of dicyclohexylcarbodiimide are heated under reflux for 3 hours.

The mixture is cooled and filtered, 200 cm^ of ethyl acetate are added, the excess unreacted 4-aminoindole is removed by washing with 1N hydrochloric acid and the mixture is dried, filtered and evaporated to dryness under reduced pressure at 50°C. 20 g of resin are obtained, which is made into a paste with a chIoroform/methano I (50:50) mixture, filtered and dried under reduced pressure, and 7.5 g of expected prbduct are obtained. M.p. > 260°C. Example 2: 5-amino-2-<3-[(1,1-dimethylethyl)amino]-2hydroxypropoxy)--N-(1H-indol-4-yl)-benzamide. 142 mg of product of Example 1, 5 cm^ of methanol, a pinch of Raney nickel and 0.2 ci7 of hydrazine hydrate are heated for 1 hour under reflux. The mixture is filtered, the methanol is removed under reduced pressure at 50°C and 128 mg of expected product are obtained.

UV spectrum: ethanol: Max. 219 nm E^ = 443 Max. 310 nm e] = 230 n 1 in ethanol, HCl Max. 299 nm E^ = 208 ε = 8,200 Infl. : 275 and 332 nm Example 3: 5-acetylamino-2-<3-C(1,1-dimethylethyl)amino]2-hydroxypropoxy>-N-(1H-indoI-4-yI) benz amide and its neutral oxalate.

Stage A: 5-amino-2-hydroxy-N-(lH-indol-4-yl)benzamide.

A suspension comprising 6 g of 5-nitro-2-hydroxyN-(1H-indol-4-yl)benzamide prepared in Example 1, 600 cm^ of methanol and 15 cm^ of 64X strength hydrazine hydrate I - 9 is heated under reflux for 2 hours in the presence of 6 g of Raney nickel. The solution obtained is filtered, the solvent removed under reduced pressure at 50°C, the residue taken up with a chloroform/methanol (1:1) mixture and the crystallized product filtered off and dried, and 4 g of expected product are collected. M.p. > 260°C.

Stage B: 5-acetylamino-2-acetoxy-N-(1H-indol-4-yl)benzam i de . 2.6 g of product prepared in the preceding stage, suspended in 70 cm^ of tetrahydrofuran, are cooled to between 0 and +5°C, 4.7 cm^ of acetic anhydride are then added and the mixture is then maintained at room temperature for 3 hours. The solvent is removed under reduced pressure at 50°C, the residue taken up in a chloroform/ methanol (1:1) mixture, .the resulting mixture is filtered and 2.7 g of expected product are obtained after drying at 80°C. M.p. 263°C.

Stage C: 5-acetylamino-2-hydroxy-N-(1H-indol-4-yl)benzamide. 1.5 g of sodium borohydride is added at room temperature to a suspension containing 1.5 g of product obtained in the preceding stage and 150 cm^ of methanol, and the mixture is heated for 2 hours under reflux. The methanol is partially removed under reduced pressure at 50°C, and the mixture is diluted with 200 cm^ of water and 200 cm^ of ethyl acetate and then extracted with ethyl acetate. The -extracts are dried, the solvents are removed under reduced pressure at 50°C and 1.35 g of expected product is collected, which is used without further treatment for the following stage.

Stage D: 5-acetylamino-2-C(2-oxiranyl)methoxy]-N-(1Hindol-4-yl)benzamide. 3.5 g of product prepared as in stage C, 150 cm^ of acetone, 1.6 g of potassium carbonate and 9 cii? of epi35 bromohydrin are heated under reflux for 2 hours. 9 cm^ of epi bromohydrin are added again and refluxing is continued for 20 hours. After filtration, washing with acetone and removal of the solvent under reduced pressure at 50°C, the residue is taken up in ether and, after filtration and - 10 drying at 80° C , 3.4 g of expected product are recovered. M.p. 230°C.

Stage E : 5-acetylamino-2-<3-C(1,1-dimethylethyl)aminoJ2-hydroxypropoxy}-N-(1H-indol-4-yl)benzamide and its neutral oxalate. 3.4 g of the product obtained above is heated under reflux for 1 hour in 200 cm^ of ethanol and 20 cm of tert-butylamine. The solvents are removed under reduced pressure at 50°C, the residue is chromatographed on silica (eluant: chIoroform/methano I/triethyI amine 8:1:1) and 3.9 g of expected base are collected.

Preparation of the oxalate. 2.7 g of base are dissolved in 200 cm^ of ethanol and 330 mg of oxalic acid are added. The product is filtered off and dried at 80°C under reduced pressure and 2.2 g of the expected oxalate are obtained. M.p. > 260°C. Analysis: C24H3QN4O4.1/2 C2H2O4 : 423.549 Calculated: CX 62.10 HX 6.46 NX 11.59 Found : 61.9 6.2 11.5 Example 4: 2-{3-C(1,1-dimethylethyl)amino3-2-hydroxypropoxy>-N-(lH-indol-4-yl)-4-methoxybenzamide and its benzoate .

Stage A; 4-methoxy-2-E(2-oxiranyl)methoxy]-N-(1H-indol4-yl)benzamide.

The procedure is as in stage D of Example 3, starting with 5 g of 4-methoxy-2-hydroxy-N-(lH-indol-4yl )t>enzamide, 150 ci? of acetone, 2.45 g of potassium carbonate and 14 cm^ of epichlorohydrin. 7.3 g of expected product are obtained. M.p. 157°C.

Stage B: 2-<3-C(1,1-dimethylethyl)amino]-2-hydroxypropoxy>-N-(1H-indol-4-yl)-4-methoxybenzamide and its benzoate.

The procedure is as in stage E of Example 3, starting with 6 g of the product prepared in stage A above, 100 cm^ of ethanol and 9.2 cm^ of tert-butylamine, refluxing being maintained for 3 hours. 6.1 g of expected base are obtained, which is dissolved in 300 cm^ of isopropanol at the reflux, and 1.8 g of benzoic acid is then added. The mixture is partially concentrated, chilled - 11 and filtered, the product is dried under reduced pressure and 5.1 g of expected benzoate are obtained. M.p. 195°C after reerystallization in ethanol.

Analysis: C23H29N3O4.C7H6O2 : 533.629 Calculated: CX 67.53 HX 6.61 NX 7.87 Found : 67.5 6.7 8.0 Preparation of 4-methoxy-2-hydr0xy-N-(1H-indoI-4-yI)benzamide used at the start of Example 4. 3.96 g of 4-amino-1H-indoIe, 70 cm^ of tetrahydro10 furan, 5 g of 2-hydroxy-4-methoxybenzoic acid and 6.2 g of dicyclohexylcarbodiimide are heated under reflux for 24 hours. The solvent is removed under reduced pressure at 50°C, the residue taken up in ethyl acetate and the unreacted 4-aminoindole removed by washing with 2N hy15 drochloric acid. The ethyl acetate is removed under reduced pressure, the residue taken up with ether and the product dried at 50°C. 7.1 g of expected product are obtained. M.p. 190°C.

Example 5: 5-chloro-2-(3-C(1,1-dimethylethyl)amino]-220 hydroxypropoxy>-N-(1H-indoI-4-yI)benzamide and its neutral oxalate.

Stage A: 5-chloro-1-C(2-oxiranyl)methoxy]-N-(lH-indol-4y I) b e η z a m i d e .

The procedure is as in stage D of Example 3, starting with 3 g of 5-chloro-2-hydroxy-N-(1H-indol-4-yl)benzamide, 100 cm^ of acetone, 1.47 g of potassium carbona-te and 8.3 cm^ of epichlorohydrin. 3.35 g of expected product are obtained. M.p. 175°C.

Stage 8: 5-chloro-2-<3-C(1,1-dimethylethyl)amino]-2-hy30 droxypropoxy}-N-(1H-indol-4-yl)benzamide and i ts neutral oxalate.

The procedure is as in stage E of Example 3, starting with 3 g of product obtained in stage A, 60 cm^ of ethanol and 4.6 cm^ of tert-butyI amine. 2.6 g of ex35 pected base are obtained, and then 2.4 g of oxalate.

M.p. > 260°C.

Analysis: ¢22^26^N3O3.1/2 C2^2®4 : 460.941 Calculated: Cl 59.93 HX 5.90 NX 9.12 CIX 7.69 Found : 60.2 5.8 9.1 7.9 - 12 Preparation of 5-chIoro-2-hydroxy-N-(1H-indoI-4-yI)benzam i de used at the start of Example 5. 3.96 of 4-amino-lH-indole in 75 cm^ of tetrahydrofuran are heated under reflux with 5.16 g of 5-chlorosalicylic acid and 6.2 g of dicyclohexylcarbodiimide for 2 hours; 0.62 g of dicyclohexylcarbodiimide is added again, the mixture is heated for a further 1 hour under reflux, cooled and filtered and the solvent is removed under reduced pressure at 50°C. The residue is taken up in ethyl acetate and the resulting mixture washed with 2 N hydrochloric acid and dried, and the ethyl acetate is removed under reduced pressure at 30°C. After chromatography of the residue on silica (eluant: chIorof orm/ethy I acetate 9:1), 3.9 g of expected product are recovered.

M.p. 248°C.

Example 6: Tablets corresponding to the following formula are prepared: product of Example 1.......................... 50 mg excipient qs for a finished tablet weighing... 100 mg (detail of the excipient: lactose, starch, talc, magnesium stearate).

Pharmacological study 1). Antiarrhythmic action in rats Male rats weighing 300-350 g, anaesthetized intraperitoneally using 1.20 g/kg of urethane, are tracheotomi.zed and subjected to artificial respiration (40-50 3-ml iqsuff lations/minute).

Needles are implanted subcutaneously so as to record the electrocardiogram of the rats using the signal from Oil leads.

The test products are administered intravenously or orally.

Five minutes after the intravenous administration of the product, the jugular vein of the rats is perfused with 10 pg/min of a solution of aconitine, and the time taken for the onset of the disorders of cardiac rhythm is noted (10 pg of aconitine corresponding to the perfusion of 0.2 ml of solution).

The results a re ' expressed as a percentage prolongation of the time taken for the onset of the disorders of cardiac rhythm compared with controls and in terms of the dose of test product. The results recorded in the table below show that the products of the present patent application are endowed with exceptional antiarrhythmic proper ties.

Product of Example, Dose Percentage prolonga- administered i.v. in mg/kg tion of the time 1 2.5 + 77% 1 + 39% 0.5 + 17% 4 2.5 + 38% 1 + 10% 2). Test of calcium-antagonistic activity in vitro Rat caudal arteries are cut into a spiral, connected to tension gauges and maintained in cells containing 25 ml of Krebs sodium bicarbonate buffer (NaCl: 120.8 mM; KCl: 5.9 mM; MgCl?: 1-2 mM; NaH?P04: 1.2 mM; NaHC03: 15.5 mM; glucose: 12.6 mM) at 37°C, gassed with a 95% 0?/5% CO? mixture.

The preparations are depolarized with a buffer solution containing K+ ions at a concentration of 100 mM (NaCl: 26.7 mM; KCl: 100 mM; MgCl?: 1.2 mM; NaH?P04: 1.2 mM; NaHC03: 15.5 mM; glucose: 12.6 mM).

Calcium chloride is added in a volume of 25 μΐ so as to obtain a series of increasing concentrations of Ca^+ ions ranging from 0.1 to 3.0 mM; the contractions of the arteries are recorded and a control series is thus established. The operation is repeated with the series 2 + of Ca ions every 15 minutes and the preparation is washed four times after each series.

When a stable response is obtained, the operation with the series of Ca^+ ions is performed in the presence of different concentrations of the test product, until a stable response is obtained.

The contractions of the arteries depend on the entry of Ca^+ ions into the cells of the smooth muscles, and are caused by the depolarization of the smooth muscle by the K+ ions and by the action of the noradrenaline released at presynaptic level. By starting the operation again with arteries denervated by the action of 6-OH-dopamine, the specific action due to noradrenaline is eliminated.

The results are expressed as IC5Q (inhibitory concent rationjg), the concentration of the test product which inhibits by 50% the contraction due to K+ ions.

From the results recorded in the table below, it is observed that the products of the present patent appli15 cation possess strong ca I cium-antagonistic activity.

Product of Example XC5Q in pM 4 8 5 5.4 3). Study of the acute toxicity The lethal dose LDq of the compound of Example 1 was assessed after oral administration after oral adminis25 tration in mice.

LDq designates the maximum dose causing no mortality in the course of 7 days.

The LDq was found to be 200 mg/kg.

Claims (11)

1. Compounds of formula (I): (I) in which one or other of the substituents X or Y represents an alkyl 15 radical containing 1 to 5 carbon atoms, an alkoxy radical containing 1 to 3 carbon atoms, a chlorine, bromine or iodine atom, a nitro radical or an amino radical optionally substituted by an aliphatic acyl group containing 2 to 5 carbon atoms or one or two alkyl radicals containing 1 to 5 carbon atoms and the other substituent 20 represents a hydrogen atom, it being understood that Y cannot be the methoxy group and that X cannot be a chlorine atom, as well as their addition salts with acids.

2. Compounds of formula (I), as defined in claim 1, wherein X 25 represents a methoxy, nitro, amino or acetylamino radical and Y represents a hydrogen atom, as well as their addition salts with acids.

3. 2-[3-[(l,l-dimethylethyl)-amino]-2-hydroxy-propoxy]-N-(lH-indol 30 4-yl)-5-nitro benzamide, as well as its addition salts with acids.

4. Preparation process for products of formula (I), wherein a compound of formula (II): - 16 V Λ. (ZZ) t in which X and Y have the previous meanings, is reacted with a halide of formula (III): to obtain a compound of formula (IV): O-CH—CH-CH, (IV) όν> which is reacted with tertbutyl amine to obtain a compound of formula (I) which, if desired, is subjected to the action of a mineral or organic acid to obtain a salt.

5. Medicaments, wherein they are constituted by the derivatives of N-(IH-indol-4-yl)-benzamide, as defined by the formula (I) of claim 1, as well as by their addition salts with pharmaceutically acceptable acids.

6. Medicaments, wherein they are constituted by the derivatives of N-(IH-indo1-4-yl)-benzamide, as defined in claim 2. - 17

7. Medicaments, wherein they are constituted by the derivatives of N-(lH-indol-4-yl)-benzamide, as defined in claim 3.

8. Pharmaceutical compositions, wherein they contain as active 5 ingredient, at least one of the medicaments defined in one of claims 5 to 7.

9. Compound of formula (I), as defined in claim 1, substantially as hereinbefore described by way of Example.

10. A process for the preparation of products of the formula (I), as defined in claim 1, substantially as hereinbefore described by way of Example.

11. Products of formula (I), as defined in claim 1, whenever prepared by a process as claimed in claim 4 or claim 10.