IE873441L - Indolecarboxamide derivatives. - Google Patents

Abstract

Products (I): <IMAGE> in which either R2, R3 = H, B = COHN, b = H, a and c = double bond, or <IMAGE> or R1 and R with N = morpholine, or A = -(CH2)3, R1 = H, R = 1,1-dimethylpropyl, cyclohexyl, cyclohexylmethyl, propyl, isopropyl, <IMAGE> or R1, R2, R3 = H, B = NHCO, b = H, a and c = double bond, or A = -(CH2)3, R = cyclopentyl, cyclohexyl, 1,1-dimethylpropyl, <IMAGE> or A = -(CH2)4, R = 1,1-(dimethylethyl), or R2 = CH3, R3 = H, B = NHCO, b = H, a and c = double bond, <IMAGE> R = 1,1-(dimethylethyl), or R1 and R with <IMAGE> A = -(CH2)n, <IMAGE> R3 = H, C1-C5 alk, C1-C5 Oalk, Cl, Br, I, NO2, HN2, optionally substituted, a and b = oxo or a and c = double bond, R2 = H, alk, alkenyl, alkynyl, optionally substituted aralkyl, cycloallylalkyl, their preparation, their application as antiarrhythmic medications.

Description

6 •; ? 0 7 - 1 - Indolecarboxamide derivatives as well as salts thereof, process and intermediates for preparation, application of these derivatives by way of medicinal products and compositions containing them 5 The present invention relates to indolecarboxamide derivatives as well as salts thereof, to the process and intermediates for preparation, to the application of these derivatives by way of medicinal products and to the composition containing them. 10 European Patent Application No. 0,213,984 describes products derived from indolecarboxamide having antiarythmic properties.

European Patent Application Nos. 0,150,139 and 0,201,400 describe products having antiarythmic properties. 15 However the products in these applications have a different structure to that of the present application.

The subject of the invention is indolecarboxamide derivatives as 20 well as the addition salts thereof with inorganic or organic acids, characterized in that they correspond to the general formula (I): A 25 35 O—ft — hf (I) I in which 1 either R2 and R^ each denote a hydrogen atom, B denotes a -C0NH-30 chain, NH being on the indole side, b denotes a hydrogen atom, a and c together form a second bond between the carbons which bear them, A denotes a -CH2-CH-CH2- chain and either Rj denotes a hydrogen atom noh and R denotes a radical chosen from 1,1-dimethylpropyl, o0H radicals, or else ch, ch, l J ch, \3 CH, \3 C-CHC-, -C- -CH2-C-CH3 or -C 1 / / CH3 CH3 ch3 CH3 R and R^ together form, with the nitrogen atom to which they are attached, a morpholine ring, - 2 - - or R2 and R3 each denote a hydrogen atom, B denotes a -CO-NH- chain, NH being on the indole side, b denotes a hydrogen atom and a and c together form a second bond between the carbons which bear them, A denotes a -(CH2)3~ 5 chain, R-j denotes a hydrogen atom and R a radical chosen from 1,1-dimethyIpropyI, cyclohexyl, eye lohexyImethyl, CH3 propyl, isopropyl or -C-CH2OH radicals, i CH3 - ££ Rj and R3 each denote a hydrogen atom, B denotes NH-C0-, C being on the indole side, b denotes a hydrogen 0 10 atom and a and c together form a second bond between the carbons which bear them, A denotes a -((^2)3- chain, R-] denotes a hydrogen atom and R denotes a radical chosen from cyclopentyl, cyclohexyl, 1,1-dimethylpropyI or och3 -CH2-CH2 \=J\ radicals, OCH3 15 - 0£ R2 ar>d R3 denote a hydrogen atom, B denotes -NH-C0-, -NH being on the indole side, b denotes a hydrogen atom and a and c together form a second bond between the carbons which bear them, A denotes a -(^2)4- chain, R1 denotes a hydrogen atom and R denotes a 1,1-dimethyl-20 ethyl group, - o_r R2 denotes a methyl radical and R3 denotes a hydrogen atom, B denotes -NH-C0-, NH being on the indole side, b denotes a hydrogen atom and a and c together form a second bond between the carbons which bear them, A denotes 25 a -CH2-CH-CH2~ chain and R denotes a 1,1-dimethylethyl ^0H group, - ojr the substituents R-j and R form, with the nitrogen \ t which Z denotes a group or a group atom to which they are attached, a group -tf N-Z i n \ ( - 3 - iX.Xi -CH NX <# *5 in which groups n-j can assume the values 1, 2 or 3 and X , *1* x2' x3' x4' x5 anc* x6' which may-be identical or different, denote a hydrogen atom, an alkyl radical con-5 taining from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 3 carbon atoms, a halogen atom, a nitro, amino, monoalkylamino or dialkylamino radical, with the proviso that X, X 1 and Xj do not all three denote a hydrogen atom, A denotes a chain in which n can 10 assume the values 2, 3, 4 or 5 or a chain -(CH2)m-CH-CH2- ^OH in which m can assume the values 1, 2 or 3, 9 denotes a -CO-NH- or -NH-CO- chain, 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 15 chlorine, bromine or iodine atom, a nitro radical or an amino radical which is optionally substituted with an aliphatic acyl group containing from 2 to 5 carbon atoms or with an alkyl radical containing from 1 to 5 carbon atoms, a denotes together with b an oxo group, or together 20 with c denotes a second bond between the carbons which bear them, b denotes a hydrogen atom or together with a an oxo group, c denotes a hydrogen atom or together with a denotes a second bond between the carbons which bear them, and R2 denotes a hydrogen atom, a linear alkyl 25 radical containing from 1 to 5 carbon atoms or a branched alkyl radical containing from 3 to 5 carbon atoms or an alkenyl or alkynyl radical containing from 2 to 5 carbon atoms or an aralkyl radical containing from 7 to 12 carbon atoms which is optionally substituted with 1, 2 or 3 radi-30 cals chosen from the group consisting of halogen atoms and methyl, ethyl, methoxy, ethoxy, trifluoromethyl, methylthio, amino and nitro radicals or a cycloalkylalkyl radical containing from 4 to 7 carbon atoms.

In the general formula (I) and in that which - 4 - follows, the term linear alkyl radical containing from 1 to 5 carbon atoms preferably denotes a methyl, ethyl or propyl radical.

The term branched alkyl radical containing from 3 5 to 5 carbon atoms preferably denotes an isopropyl or tert-butyl radical.

The term alkoxy radical denotes a methoxy, ethoxy or propoxy radical.

In the alkylamino or dialkylamino moieties, the 10 alkyl radicals are preferably methyl or ethyl.

When X, X-j, X£, X3, X4, X5 and X$ are halogen atoms, they are preferably chlorine atoms, but they can also denote fluorine, bromine or iodine atoms.

The term aliphatic acyl containing from 2 to 5 15 carbon atoms preferably denotes an acetyl or propionyl radi cal.

The terms alkenyl and alkinyl radical containing from 3 to 5 carbon atoms preferably denote an allyl or propargyl radical. 20 The term cycloalkylalkyl radical containing from 4 to 7 carbon atoms preferably denotes a cyclopropylmethyl or cyclobutylmethyl radical.

The term aralkyl radical containing from 7 to 12 carbon atoms preferably denotes a benzyl or phenethyl 25 radical.

The addition salts with inorganic or organic acids can be, for example, the salts formed wih hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, 30 citric, oxalic, glyoxylic and aspartic acids, alkane- sulphonic acids such as methane- or ethanesulphon i c acids,-arylsulphonic acids such as benzene- or para-toluene-sulphonic acid, and arylcarboxylic acids.

Among the products which are the subject of the 35 invention, there may be mentioned, in particular, the derivatives corresponding to the formula (I) above as well as the addition salts thereof with inorganic or organic acids, characterized in that, in the said formula (I), the substituents R-j and R form, with the nitrogen atom to - 5 - which they are attached, a group in w^ich Z has the above meaning, A denotes a -CH2-CH-CH2 or ^OH -(CH2>3- or -(CH2)4~ chain, R3 denotes a hydrogen atom, R2 denotes a hydrogen atom or a methyl radical, b denotes 5 a hydrogen atom and a and c together form a second bond between the carbons which bear them.

Among the products of the invention, there may be mentioned more especially the products having the following names: 10 2--C3-C(1,1-dimethylpropyl)amino]-2-hydroxypropoxy>-N-(1H-indol-4-yl)benzamide and its benzoate and its neutral oxalate, 2--C3-C(1,1-dimethylethyl )amino]-2-hydroxypropoxy>-N-( 1-methyl-1H-indol-4-yl)benzamide and its hydrochloride, 15 2--C2-hydroxy-3-C(1,1,3,3-tetramethylbutyl)amino]propoxy>-N-(1H-indol-4-yl)benzamide, and 2--C2 -hydroxy-3 -C4-(diphenylmethyl)-1-piperazinyl]-propoxy>-N-(1H-indol-4-yI)benzamide and its neutral oxalate. 20 The subject of the invention is also a process for preparing the products as defined by the formula (I) above as well as the salts thereof, characterized in that a derivative of the formula (II): (II) 25 in which B, R2 and R3 have the meaning already stated, is reacted with a halide of the formula III: Hal-G (III) - 6 - in which Hal denotes a chlorine, bromine or iodine atom and -G denotes a group of formula -(CH2)n~Dr in which D denotes a chlorine, bromine or iodine atom or a hydroxy radical or a sulphonate of this hydroxy radical, and n has the meaning already stated, or -G denotes a group -(CH2)m~CH"CH2 in which m has the meaning already stated, 0 to obtain a derivative of formula (IV): (IV) in which B, R2 and R3 have the meaning already stated, and 10 G' denotes a group of formula -(CH2)n~Hal- which n and Hal have the meaning already stated, or a group of formula -(CH2)n~CH~CH2 defined above, which is reacted with an ^0 amine of formula (V): ,R \ (v) R1 15 in which R and R -j have the meaning already stated, to obtain a product of formula (I/\): (IA) in which A, B, R, R-j, R2 and R3 have the meaning already stated, which is isolated and, if desired, salified. 20 When it is desired to obtain a chain of formula - 7 - -(CH2)n~ for A, if a haLide of formula following formula is used: III having the Hal-(CH2>n-D in which 0 denotes a chlorine, bromine or iodine atom and 5 Hal has the meaning already stated, -it is preferable to use two different halogens in order to avoid the condensation of two molecules of derivative of formula IV. Thus, for example, if D denotes a chlorine atom, a halide will be chosen for Hal which is more reactive than the 10 bromide.

When a hydroxylated halide of formula (III) is used, corresponding to the formula (III'): H0-(CH2)n~Hal (III ' ) in which n and Hal have the meaning already stated, in 15 order to react it with the derivative of formula (II), it is then preferable to work in the presence of triphenyl-phosphine and ethyl azodicarboxyI ate in tetrahydrofuran.

Advantageously, a sulphonate of the derivative of formula (III') is used; in this case, it is preferable to 20 use as sulphonate of the hydroxylated halide of formula (III') its tosylate of formula (III"): Ts0-(CH2)n-Hal (III") in which T§ denotes a tosyl (4-methylbenzenesulphonate) radical and n and Hal have the meaning already stated. 25 The reaction is then performed by phase transfer, preferably using as the aqueous phase an aqueous solution of an alkali metal hydroxide, such as potassium or sodium hydroxide, and as the water-immiscible organic phase a solvent such as benzene, in the presence of a transfer 30 agent such as a tetrabutylammon ium quaternary ammonium salt, in particular the bromide or hydrogen sulphate.

The reaction of the product of formula IV with the amine of formula V is carried out, for example, in an - 8 - inert organic solvent such as dioxane, benzene, toluene or dimethylformamide, or alternatively an alcohol, preferably ethanol, preferably in the presence of a condensing agent such as an alkali metal carbonate or bicarbonate, 5 for example potassium carbonate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, or a tertiary amine such as triethylamine: It is also possible to work using the amine of formula (V) directly as solvent. When it is desired to obtain a chain of formula 10 - (CH2) m"<-H-CH2_ for A, a halide of formula OH.

Hal-(CH2)m~c^~^2 used; in this case, Hal preferably denotes a chlorine atom. The reaction of the derivative of the formula (II) with the halide of formula (III) is then preferably carried out in the presence of a base such 15 as potassium carbonate or sodium carbonate, sodium hydroxide or potassium hydroxide.

The reaction of the derivative of formula (IV.) in which G denotes a chain -(CH2)m~<*H-CH2 with the amine N/ of formula (V) is carried out either directly using the 20 amine as solvent, or using a solvent such as an aliphatic alcohol, for example ethanol.

In a variant of the process described above for preparing the derivatives of formula (I) in which A denotes a chain -(CH2)n-, a derivative of formula II 25 is reacted with a derivative of formula (VI): R1 HaMCH2VN' CVI) in which Hal, n, R and R-j have the meaning already stated, to obtain the desired derivative of formula 1^, which is isolated and, if desired, salified. 30 The derivative of formula (VI) is reacted in the form of free amine, or preferably in the form of a salt such as a hydrochloride.

The subject of the invention is also a process for - 9 - preparing the derivatives of formula (I) in which the substituents R-) and R form, with the nitrogen atom to which they are attached, a group -hf^N-Z ' ""n w^ich Z V J has the meaning already stated, characterized in that a 5 product of formula (IV): (IV) in which B, R2, R3 and G' have the meaning already stated, is reacted with an amine of formula (V'): /—V (y,) H-N ,N-Z \ / 10 in which Z has the meaning already stated, to obtain a product of formula (Ig): (la) in which A, B, R£, R3 and Z have the meanings already stated, which is either isolated and, if desired, salified, 15 or, if desired, subjected to the action of a halogenating agent to obtain a product of formula (VII): - 10 - 10 (VII) in which Hal -j denotes a bromine or chlorine atom, which is subjected to a hydrolysis to obtain a compound of formula (I c ): 0—A—* 2 W (I r) in which A, B, R2, R3 and Z have the above meanings, which is isolated and, if desired, salified by the action of an inorganic or organic acid.

In a variant of the process described above for preparing the derivatives of formula (I) in which A denotes a chain -(CH2a Product of formula (II): *3 (II) in which B, R2 and R3 have the above meanings, is reacted with a compound of formula (VIII): 15 Hal-(CH2)n-^N-Z (VIII) in which Hal denotes a chlorine, bromine or iodine atom - 11 - and n and Z have the above meanings, to obtain a corresponding compound of formula (Ig) which is converted, if desired, to the corresponding compound of formula (Iq).

The reaction of the product of formula (IV) with 5 the amine of formula (V') is carried out according to conditions identical to those described for the reaction of the products of formulae (IV) and.(V).

The reaction of the product of formula (II) with the compound of formula (VIII) is carried out according 10 to the conditions described for the reaction of the products (II) and (VI).

The halogenation of the derivatives of formulae Ifl may be performed, for example, using the bromine-containing pyridine complex of formula: 15 ll ' • HBr in the case of bromination. It is advantageously carried out using an N-halosuccinimide, preferably N-bromo- or N-chlorosuccinimide: the reaction is performed in dioxane or preferably in acetic acid. The product of formula 20 (VII) obtained is preferably a chlorinated product.

The hydrolysis of the product of formula (VII) is preferably carried out using an inorganic acid such as phosphoric acid, sulphuric acid or preferably hydrochloric acid in aqueous solution. This solution may be used con-25 centrated, but preferably dilute, for example in normal solution. It is possible to use, in addition, a solvent such as an aliphatic alcohol, for example ethanol.

The products of formula (II) used at the start of the processes described above are products which are known 30 or may be prepared as described in European Patent Application 0,213,984.

The products of formula (VII) as defined above are products of formula (VII) by way of new industrial products. 35 The derivatives which are the subject of the present application possess very advantageous pharmacological properties; they are endowed, in particular, with - 12 - certain antiarrhythmic properties. In addition, some derivatives which are the subject of the present application possess, moreover, calcium-antagonistic and beta-blocking, hypotensive and vasodilatory properties. 5 These properties are illustrated later in the experimental part.

These properties justify the. use of the new benz-amide derivatives and the salts thereof by way of medicinal products. 10 The subject of the present patent application is thus also the application, by way of medicinal products, of the new benzamide derivatives as defined above, as well as the addition salts thereof with pharmaceutical^ acceptable acids. 15 Among the preferred medicinal products of the invention, there are selected more especially the derivatives corresponding to the formula (I) above, as well as the addition salts thereof with pharmaceutically acceptable inorganic or organic acids, characterized in that, 20 in the said formula (I), the substituents R-j and R form, with the nitrogen atom to which they are attached, a group JW-Z in which Z has the above meaning, A denotes a -CH2-CH-CH2 or -<<^2)3- or -(CH2)4- chain, \h R3 denotes a hydrogen atom, R2 denotes a hydrogen atom or 25 a methyl radical, b denotes a hydrogen atom and a and c together form a second bond between the carbons which bear them.

Among the products of the invention, there may be mentioned more especially the products having the follow-30 ing names: 2--C3-C(1,1-dimethylpropyl)amino]-2-hydroxypropoxy>-N-(1H-indol-4-yl)benzamide and its benzoate and its neutral oxalate, 2--C3-C (1,1-dimethylethyl)amino]-2-hydroxypropoxy}-N-(1-35 methyl-1H-indol-4-ylJbenzamide and its hydrochloride, 2--C2-hydroxy-3-C C 1,1,3,3-tetramethylbutyl)amino3propoxy>- - 13 - N-(1H-indol-4-yl)benzamide, and 2--C2-hydroxy-3-C4-(diphenylmethyl)-1-piperazinyl]-propoxy}-N-(1H-indol-4-yI)benzamide and its neutral oxalate. 5 The medicinal products which are the subject of the present invention find, for example, their application in the treatment of arrhythmias and angina.

The usual dose, which varies according to the derivative used, the subject treated and the condition in 10 question, may be, for example, from 50 mg to 1 g per day. Orally in man, the derivative of Example 1 may 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 15 to 12 mg per kilogram of body weight.

The subject of the invention is lastly the pharmaceutical compositions which contain at least one of the abovementioned derivatives or one of the addition salts thereof with pharmaceuticalIy acceptable acids, by way of 20 active principle.

By way of medicinal products, the derivatives which are the subject of the present application, and the addition salts thereof with pharmaceutical^ acceptable acids, may be incorporated in pharmaceutical compositions 25 designed for administration via the digestive tract or parenterally.

These pharmaceutical compositions can be, for example, solid or liquid, and can take the pharmaceutical forms commonly used in human medicine, such as, for ex-30 ample, simple or sugar-coated tablets, gelatine capsules, capsules, granules, suppositories and injectable preparations; they are prepared according to the usual methods. The active principle or principles may be incorporated therein with excipients customarily employed in these 35 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. - 14 - Examples of implementation of the invention will now be given without implied limitation.

Preparation of 2-hydroxy-N-(1H-indol-4-yI)benzamide used at the start of Example No. 1 5 92 cm^ of a solution of triisobutylaluminium, dissolved at a concentration of 1.1 mol/l in toluene, are added slowly with stirring and under an inert atmosphere to a solution of 6.6 g of 4-aminoindoIe in 250 cm^ of chloroform, 9.6 cm^ of methyl salicylate are then added, 10 the mixture is brought to reflux for 20 hours and cooled to room temperature, 300 cm"* of N hydrochloric acid and 300 cm^ of methylene chloride are added, the organic phase is washed with water, dried, and taken to dryness under reduced pressure at 50°C, the residue is made into 15 a paste with ether, filtered and dried at 60°C under reduced pressure and 9.4 g of the expected product, m.p. « 232°C, are obtained.

UV spectrum (ethanol); 1nfl. 216 nm - 1 595 infl. 233 nm E{ - 680 <£*17,200 1nfl. 262 nm e{ = 187 infl. 303 nm e[ - 482 12,200 1nf1. 314 nm eJ = 494 £- 12,500 Example 1 : 2--C3-C(1,1-0imethylpropyl)amino3-2-hydroxy-25 propoxy>-N-(1H-indol-4-yl)benzamide and its neutral oxalate Stage A : 2-[(2-0xiranyl)methoxy]-N-(1H-indol-4-yI)benzam i d e A solution of 3.5 g of 2-hydroxy-N-(1H-indol-4-yl)-benzamide and 1.9 g of potassium carbonate in 100 cm^ of acetone is heated to reflux for 30 hours under an inert atmosphere with 11 cm^ of epichlorohydrin, the insoluble material is filtered off, the filtrate taken to dryness, - 15 - the residue purified by chromatography on silica (eluant : chloroform/acetone/TEA 6:3:1), fractions having Rf 0.45 are taken to dryness, the residue made into a paste with ether, filtered and dried under reduced pressure at 60°C, 5 and 3.65 g of the expected product, m.p. 171°C, are obtained.

Stage B : 2--C3-C (1, 1-D i me thy I p r opy I) am i no ]-2-hydr oxyp r opoxy >-N-(1H-indol-4-yI)benzamide and its neutral oxalate.

Base: 10 3.5 g of product of stage A dissolved in 35 c m ^ of ethanol is heated to reflux with stirring and under an inert atmosphere for 5 hours with 3 cm^ of tert-pentyl-amine, the solvent is evaporated off, the residue purified by chromatography on silica (eluant: methylene chloride/ 15 methanol 9:1) and 3.5 g of the expected product obtained. Formation of the neutral oxalate: 2.4 g of above base are dissolved in 20 cm^ of ethanol, 0.245 g of dehydrated oxalic acid is added, the salt formed is filtered off, dried and recrystallized in 20 ethanol and '1.83 g of the expected product, m.p. * 180°C, is obtained.

Example 2 : 2-C3-(4-Morpholinyl)-2-hydroxypropoxy]-N-(1H-indol-4-yl)benzamide and its hydrochloride The procedure is as described in stage B of 25 Example 1, starting with 4 g of product of stage A of Example 1 and 1.7 cm^ of morpholine. 4.12 g of expected product are obtained after chromatography on silica (eluant: chloroform/ethyl acetate/triethylamine 6:3:1).

The hydrochloride is prepared with a saturated 30 solution of hydrochloric acid in methylene chloride.

Melting point of the hydrochloride after recrystal-lization in ethanol: 210°C.

Example 3: 2--C3-C(1,1-Dimethylpropyl)amino]propoxy>-N-(1H-indol-4-yl)benzamide and its hydrochloride 35 Stage A : 2-(3-Chloropropoxy)-N-(1H-indol-4-ylJbenzamide.

A solution of 5 g of 2-hydroxy-N-(1H-indol-4-yl)-benzamide, 400 cm^ of tetrahydrofuran, 1.8 cm^ of 3-chloropropanol and 5.7 g of triphenylphosphine is prepared with stirring and under an inert atmosphere, 3.4 cm^ of - 16 - ethyl azodicarboxylate are added slowly, the mixture is left for 5 hours with stirring, 5.7 g of triphenylphos-phine and 1.8 cm^ of 3-chloropropanol are added, followed by 3.4 cm^ of ethyl azodicarboxylate added 5 slowly, the mixture is left again with stirring for 15 hours and taken to dryness, the residue purified by chromatography on silica (eluant: benzene/ethyl acetate 95:5), the fractions having Rf 0.15 are taken to dryness, the residue is made into a paste with ether, filtered and 10 dried under reduced pressure, and 5.5 g of the expected product, m.p. = 140°C, are obtained.

Stage B : 2--C3-C (1, 1-0 i me t hy I p r opy I) am i no ]p r opo xy >-N-(1H-indol-4-yl)benzamide and its hydrochloride.

Base: 15 2 g of product of stage A in 20 cm^ of ethanol are heated to 120°C for 5 hours with 2 cm^ of tert-pentylamine and in the presence of 0.84 g of potassium carbonate, the mixture is filtered, the solvent evaporated off, the residue purified by chromatography on silica 20 (eluant : methylene chloride/methanol 9:1) and 2 g of the expected product are obtained.

Hydrochloride: 1.45 g of base are dissolved in 20 cm^ of iso-propanol at 50°C, a saturated solution of hydrochloric 25 acid in ethyl acetate is added until the pH is acid, the mixture is chilled, filtered and dried, the product re-crystallized in isopropanol and 1.7 g of the expected product obtained.

M.p. = 216°C. 30 Example 4 : 2-C3-(Cyclohexylamino)propoxy]-N-(lH-indol-4-yl)benzamide and its hydrochloride The procedure is as described in Example 3, but by replacing tert-pentylamine by cyclohexylamine and chromatography on silica (eluant: CHCl3/ethyl acetate/ 35 TEA 6:3:1), 2.1 g of expected product, m.p. = 148°C (base) are obtained, and the hydrochloride, which melts at 214°C after recrysta 11ization in isopropanol, is then formed. - 17 - Example 5 : 2--C3-C(Cyclohexylmethyl)amino]propoxy}-N-(1H- indol-4-yl)benzamide and its hydrochloride The procedure is as described in Example 3, but replacing tert-pentylamine with cyclohexylmethylamine, and 5 the expected product is obtained, and then its hydrochloride which is recrystalIized in ethanol. M.p. = 228°C. Example 6 : 2--C4-C ( 1,1-Dimethylethyl)amino]butoxy>-N-( 1H-indol-4-yl)benzamide and its acid fumarate The procedure is as in Example 3, but at 50°C and 10 replacing tert-pentylamine by tert-butyI amine and 2-(3-chloropropoxy)-N-(1H-indoI-4-yI)benzamide by 2-(4-bromo-butoxy)-N-(1H-indol-4-yI)benzamide, and with chromatography on silica (eluant: CHClj/acetone/TEA 6:3:1), the residue is taken up with ether to obtain the expected 15 product, m.p. = 147°C (base). The acid fumarate, which melts at 224-225°C with sublimation after recrystalliza-tion in ethanol, is prepared.

Preparation of 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benzamide A suspension of 7.5 g of 2-hydroxy-N-(1H-indol-4-20 yl)benzamide and 8.28 g of potassium carbonate in 150 cm^ of acetone is brought to reflux for 1 h 15 min with 18 cm^ of 1,4-dibromobutane, the mixture is left to cool, the precipitate filtered off and rinsed with acetone, the filtrate taken to dryness, the residue purified by 25 chromatography on silica (eluant: methylene chloride/ethyl acetate 9:1), followed by recrystallization in ethyl acetate, and the expected product, m.p. = 135°C, is obta ined.

Example 7 : 2--C3-C(1,1-0imethylethyl)amino]-2-hydroxy-30 propoxy}-N-(1-methyl-1H-indol-4-yl)benzamide and its hydrochlor ide Stage A : 2-C(2-0xiranyI)methoxy]-N-(1-methyl-lH-indol-4-yI)benzam ide.

The procedure is as described in Example 1, stage 35 A, but starting with 2-hydroxy-N-( 1-methyl-lH-indol-4-yl)-benzamide to obtain the expected product, m.p. = 160°C. Stage B : The procedure is as described in Example 1, stage B, but starting with the product obtained above and - 18 - replacing tert-pentylamine by tert-butyI amine to obtain the expected product, m.p. = 130°C (base). The hydrochloride, which melts at 195°C after recrysta 11ization in isopropanol, is prepared. 5 Preparation of the starting 2-hydroxy-N-(1-methyI-1H-indoI-4-yl)benzamide of Example 7 A solution of 5 g of 1-methyl-1H-indol-4-amine, prepared according to Steven V. Ley (J. Chem. Soc. Chem. Com. 1982 p. 1356), 4.7 g of salicylic acid and 7 g of 10 dicyclohexylcarbodi imide in 80 c m ^ of tetrahydrofuran is brought to reflux for 24 hours, 20% of salicylic acid and of dicyclohexylcarbodiimide are added after 5 hours of refluxing, the mixture is filtered, the filtrate evaporated under reduced pressure, the residue purified 15 by chromatography on silica (eluant : methylene chloride) and 5.5 g of the expected product, m.p. = 211°C, are obtained.

Example 8 : 2--C3-C(1,1-Dimethyl-2-propynyl)amino]-2-hydroxypropoxy>-N-(1H-indoI-4-yI)benzamide and its neutral 20 oxalate The procedure is as in stage B of Example 1, starting with 4 g of the product prepared as in stage A of Example 1 and 1.5 cm^ of 1,1-dimethylpropargylamine. 3.77 g of expected base are obtained after chromatography 25 on silica (eluant: chloroform/ethyl acetate/triethylamine 6:3:1).

Neutral oxalate 3.09 g of base are dissolved in 100 cm^ of ethanol and 0.497 g of oxalic acid is added. The mixture 30 is chilled, filtered and dried under reduced pressure at 80°C, the product is recrystallized in ethanol and 2.5 g of expected neutral oxalate, m.p. = 160°C, are obtained. Analysis : C23H25N3O3 = 872.984 Calculated : C% 66.04 H% 6.00 N% 9.63 35 Found : 65.9 6.0 9.5 - 19 - Example 9 : 2--C2-Hydroxy-3-C(1,1,3,3-tetramethylbutyl)-amino]propoxy3N-(1H-indol-4-yl)benzamide The procedure is as in Example 1, stage 8, starting with 5 g of the product prepared as in stage A of Example 1 and 4.9 cm^ of tert-octylamine. 4.27 g of expected product are obtained. M.p. 140°C.

Analys is : C26H35N3Q3 = 437.587 Calculated Found 10 Example 10 CX 71.37 H% 8.06 N% 9.60 71.6 8.3 9.5 2--C3-C(1,1-Dimethyl-2-hydroxyethyl)amino]-2- hydroxypropoxy>-N-(lH-indol-4-yl)benzamide and its neutral oxalate The procedure is as in Example 1, stage B, starting with 4 g of the product prepared as in stage A of 15 Example 1 and 1.3 cm^ of 2-amino-2-methyl-1-propanol, and 3.33 g of expected base are obtained and converted to the neutral oxalate as described in Example 8. 2.8 g of expected oxalate are obtained. M.p. = 180°C.

Analysis : ^22^27^3^4 = 884.99 20 Calculated Found Example 11 CX 62.43 H% 6.38 N% 9.50 62.3 6.6 9.4 N-(1H-Indol-4-yl)-2-C3-(propylamino)propoxy]- benzamide and its hydrochloride The procedure is as in stage B of Example 3, 25 starting with 4.5 g of product prepared as in stage A of Example 3 and 6.5 cm^ of N-propylamine. After chromatography on silica (eluant : chloroform/ethyl acetate/tri-ethylamine 6:3:1), 3.20 g of expected base are obtained. 3 g of this base are converted to the hydrochloride as 30 described in Example 3. 2 g of expected hydrochloride are recovered. M.p. = 202°C.

Analys i s : C21H25N3O2 ® 387.913 Calculated : C% 65.02 H% 6.76 Cl% 9.14 NX 10.83 Found : 64.9 6.7 9.3 10.7 35 Example 12 : N-(1H-Indol-4-yl) -2--C3-C (l-methylethyl)amino]-propoxy>benzamide and its hydrochloride The procedure is as in Example 11, starting with 4 g of starting substance and 10 cm^. of isopropylamine. 2.93 g of expected base are obtained, and 1.79 g of - 20 - expected hydrochloride from 2.6 g of base. Hydrochloride: m.p. 180°C.

Analys is : ^21^25^3^2' HCl = 387.913 Calculated : CX 65.02 H% 6.76 Cl% 9.14 N% 10.83 5 Found : 65.0 6.9 9.0 10.8 Example 13 : 2--C3-C(1,1-Dimethyl-2-hydroxyethyl)aminol)-propoxy>-N-C1H-indoI-4-yI)benzamide and its neutral fumarate The procedure is as described in Example 3, stage 10 B, starting with 3 g of product prepared as in stage A of Example 3 and 5 cm^ of 2-amino-2-methyI-1-propanoI.

After chromatography on silica (eluant : chloroform/ methanol/triethylamine 90:5:5), 2.1 g of base are obtained, Neutral fumarate 15 Using 1.85 g of base and 5.63 g of fumaric acid, 1.323 g of expected neutral fumarate is obtained. M.p. 186°C.

Analys is : (C22H27N3O3)2•C4H4O4 = 879.031 Calculated : Z% 65.59 H% 6.65 N% 9.56 20 Found : 65.5 6.9 9.3 Example 14 : N-C2--C3-C(1-Methylethyl)amino3propoxy>phenyl3-1H-indoIe-4-carboxamide and its hydrochloride Stage A : N-C2-(3-Bromopropoxy)phenyI]-1H-indoIe-4-carbox-am i de. 25 A suspension is prepared comprising 2 g of N-(2- hydroxyphenyI)-1H-indole-4-carboxamide and 2.18 g of potassium carbonate in 20 cm^ of acetone, 3.2 cm^ of 1,3-dibromopropane are added and the mixture is brought to reflux for 1 and a half hours, and filtered, the solvent 30 is removed under reduced pressure and the residue chromato-graphed on silica (eluant: chloroform/ethyl acetate/tri-ethylamine 6:3:1) and 2.37 g of expected product are obtained. M.p. 145°C.

Stage B : N-C2-t3-C(1-MethylethyI)aminolpropoxyJphenyI]-35 lH-indole-4-carboxamide and its hydrochloride.

The procedure is as in stage B of Example 3, starting with 4 g of product prepared in stage A above and 4.5 cm^ of isopropylamine. After chromatography on silica (eluant : chloroform/ethyl acetate/triethylamine - 21 - 6:3:1), 2.91 g of base are obtained, and then 2.5 g of hydrochloride. M.p. 234°C.

Analys is : C2iH25N302» HCl = Calculated : C% 65.02 H% 6.76 Cl% 9.14 N% 10.83 5 Found : 65.3 6.8 9.3 10.7 Example 15 : N--C2-C3-(Cyclopentylamino)propoxy]phenyl>-1H-indole-4-carboxamide and its hydrochloride The procedure is as in Example 14, stage B, starting with 4 g of product prepared in stage A and 2.11 cm3 10 of cyclopentylamine, and 3.3 g of expected base are obtained, and then 2.8 g of hydrochloride. M.p. 244°C. Analysis : C21H27N3O2.HCI = 413.95 Calculated : CZ 66.74 H% 6.82 Cl% 8.56 N% 10.15 Found : 66.9 6.8 8.4 9.9 15 Example 16 : N--C2-C3-(Cyclohexylamino)propoxy3phenyl>-1H-indole-4-carboxamide and its hydrochloride The procedure is as in Example 14, stage B, starting with 2.5 g of starting substance and 1.5 cm3 of cyclohexylamine, and 1.8 g of expected base and 1.7 g of 20 expected hydrochloride are obtained. M.p. 260°C.

Analysis : C24H29N3O2•HCI = 427.979 Calculated : C% 67.35 H% 7.06 Cl% 8.28 N% 9.82 Found : 67.1 7.1 8.4 9.7 Example 17 : N-C2--C3-C(1,1-Dimethylpropyl)amino]propoxy>-25 phenyl3-1H-indole-4-carboxamide and its hydrochloride The procedure is as in Example 14, stage B, start-with 4 g of the starting substance and 5 cm3 of tert-amylamine. 2.90 g of expected base are obtained, and then 2.5 g of expected hydrochloride from 2.7 g of base. 30 M.p. 230°C.

Analysis : C23H29N3O2•HCI = 415.967 Calculated : C% 66.41 H% 7.27 Cl% 8.52 N% 10.1 Found : 66.4 7.3 8.6 10.1 Example 18 : N--C2-C3--CC2-(3,4-Dimethoxyphenyl)ethyl3-35 amino>propoxy]phenyl>-1H-indole-4-carboxamide and its hydrochloride the procedure is as in Example 14, stage B, starting with 3 g of the starting substance and 2.31 cm3 of homoveratrylamine, and, after chromatography on silica - 22 - (eluant : chloroform/methanol 9:1), 2.75 g of expected base are obtained, and then 1.75 g of hydrochloride from 2.55 g of base. M.p. = 182°C.

Analysis : C28^3 1N3O4.HCI = 510.038 5 Calculated : C% 65.94 H% 6.32 Cl% 6.95 N% 8.24 Found : 65.9 6.2 6.7 8.2 Example 19 : 2--C2-Hydroxy-3-C4-(diphenylmethyl)-1-piper-azinyl3propoxy>-N-(1H-indol-4-yI)benzamide and its neutral oxalate 10 The procedure is as in Example 1, stage B, start ing with 3.08 g of 2-C(2-oxiranyl)methoxy]-N-(1H-indol-4-y I)benzamide, prepared as in stage A of Example 1, and 5.2 g of 1-(diphenylmethyl)piperazine. After chromatography on silica (eluant: chloroform/ethyl acetate 7:3), 15 5.12 g of expected base are obtained, and then 3.22 g of expected neutral oxalate from 4.36 g of base. M.p. = 170°C.

Analysis : (C35H36N4Q3)2 .C2H2Q4 = 1211.44 Calculated : C 71.38 H% 6.15 N% 9.24 20 Found : 71.4 6.3 9.1 Example 20 : N-(1H-Indol-4-yl)-2-C4--C4-C2-(3,4,5-tri-methoxyphenyl)ethyl]-1-piperazinyl>butoxy]benzamide and its d i fumarate 2.5 g of 2-(4-bromobutoxy)-N-(1H-indol-4-yl)benz-25 amide, prepared as in Example 6, 2.71 g of 1-C2-(3,4,5-trimethoxyphenyI )ethyl]piperazine (Hoechst AG German Patent 3,347,173) and 0.683 g of sodium carbonate in 25 cm3 of ethanol are heated to 60°C for 10 hours. The mixture is cooled, poured into water and extracted with 30 ethyl acetate, the extract is washed with water and dried and the solvents are removed under reduced pressure. The residue is chromatographed on silica (eluant : chloroform/ acetone/triethylamine 6:3:1) and 3.51 g of expected base are recovered. 35 D i fumarate Using 2.52 g of base and 498 mg of fumaric acid, 1.718 g of expected difumarate is obtained. M.p. 182-183°C.

Analysis : (C34H42N4O5)2•^8^8^8 = 818.895 - 23 - Calculated : C% 61.60 HZ 6.15 N% 6.84 Found : 61.3 6.1 6.6 Example 21 : 2--C3-[(1,1-Dimethylpropyl)amino]-2-hydroxy-propoxy>-N-(lH-indol-4-yl)benzamide benzoate 5 1.11 g of benzoic acid are added to a solution of i 3.6 g of base obtained in stage 8 of Example 1. The mixture is chilled, filtered and dried under reduced pressure at 90°C, and 3 g of expected product are obtained after recrystallization in isopropanol. M.p. 170°C. 10 Analysis : C23H29N3O3 = 517.615 Calculated : CZ 69.91 H% 6.82 N% 8.12 Found : 69.9 6.8 8.2 Example 22 : 2--C2-Hydroxy-3-[4-(diphenylmethyl)-1-piper-azinyl3propoxy>-N-(1-methyl-1H-indol-4-yI)benzamide and 15 its hydrochloride The procedure is as in Example 1, stage B, starting with 4 g of 2-C(2-oxiranyl)methoxy]-N-(1-methyl-1H-indol-4-yl)benzamide prepared in Example 7 and 6.3 g of diphenylmethylpiperazine. 5.95 g of base are obtained, 20 and then 4.9 g of expected hydrochloride. M.p. 196°C after recrystallization in ethanol.

Analys is : C36H33N403.HCl = 611.19 Calculated : C% 70.76 HZ 6.43 Cl% 5.80 NZ 9.17 Found : 70.4 6.3 5.9 9.1 25 In a manner similar to that already described in the examples, the following product is also prepared: 2-C2-hydroxy-3-[[4-bis(4-fluorophenyl)methyl]-1-piper-azinyl]propoxy]phenyl]-N-(1H-i ndol-4-yI)benzamide.

Example 23 : 30 Tablets corresponding to the following formula were prepared: 2--C3-C(1,1-dimethylpropyl)amino]-2-hydroxy-propoxy>-N-(lH-indol-4-yl)benzamide neutral oxalate 50 mg 35 excipient q.s. for a finished tablet weighing 100 mg.

(Detail of the excipient: lactose, starch, talc, magnesium stearate). - 24 - Example 24 : Tablets corresponding to the following formula were prepared: 2-{3-[(1,1-dimethylethyl)amino]-2-5 hydroxypropoxy>-N-(1-methyl-1H-indol-4- yDbenzamide 100 mg Excipient q.s. for a finished tablet weighing 150 mg.

(Detail of the excipient: lactose, starch, talc, magnesium 10 stearate).

PHARMACOLOGICAL STUDY 1) Affinity for betai~adrenergic receptors The technique is modelled on that of Mohler and Okada : Science. Vol. 198 p. 849-851 (1977). 15 10 cortexes removed from the brains of male rats weighing 150 g on average are homogenized in 90 ml of 0.32 M sucrose. After centrifugation of the homogenized mixture at 1,000 g for 20 minutes at 0°C, the supernatant is centrifuged at 30,000 g for 15 minutes at 0 to +4°C. 20 The pellet is suspended in 120 ml of 50 mM Tris- HCl buffer pH 7.7, and centrifuged at 30,000 g for 15 minutes at 0 to +4°C. The new pellet obtained is suspended in 480 ml of 50 mM Krebs Tris-HCl buffer pH 7.7. 2 ml of suspension is then incubated for 10 minutes 25 at 37°C in the presence of C^Hldihydroalprenolol at a -9 concentration of 10 M, i) alone, ii) with increasing concentrations of the test product or iii) in order to determine the non-specific binding, with non-radioactive -5 propranolol at a concentration of 10 M. 30 The incubated suspensions are filtered on Whatman GF/C, and the filters are washed with three times 5 ml of Krebs Tris-HCl buffer pH 7.7 at 0°C.

The radioactivity of the filters is measured by liquid scintillation. 35 The affinity of the test product for beta-j- adrenergic receptors is given relative to propanolol as the reference product.

CD = concentration of propanolol inhibiting 50% of the specific binding of C^H]dihydroalprenolol. - 25 - = concentration of the test product inhibiting 50% specific binding of C^HJdihydroalprenolol.

The relative affinity is given by the relation = 100 CJ) CX The following results were obtained: Product of 1 ARL in ? 1 Example 1 I 1 1 28 1 7 I 44 I 21 1 20 | I t It is observed that some products of the patent application possess exceptional affinity for beta-j-adrenergic receptors. 2) Affinity for beta2-adrenergic receptors 10 The technique is modelled on that of Mohler and Okada : Science. Vol. 198 p. 849-851 (1977).

The cerebella removed from the brains of male rats weighing 150 g on average are homogenized in 90 ml of 0.32 M sucrose. After centrifugation of the homogenized 15 mixture at 1,000 g for 20 minutes at 0°C, the supernatant is centrifuged at 30,000 g for 15 minutes at 0 to +4°C.

The pellet is suspended in 120 ml of 50 mM Tris- HCl buffer pH 7.7, and centrifuged at 30,000 g for 15 minutes at 0 to +4°C. The new pellet obtained is sus- 20 pended in 480 ml of 50 mM Krebs Tris-HCl buffer pH 7.7. 2 ml of suspension is then incubated for 10 minutes at 37°C in the presence of C^HJdihydroalprenolol at a -9 concentration of 10 M, i) alone, ii) with increasing concentrations of the test product or iii) in order to 25 determine the non-specific binding, with non-radioactive propranolol at a concentration of 10~^ M.

The incubated suspensions are filtered on Whatman GF/C, and the filters are washed with three times 5 ml of Krebs Tris-HCl buffer pH 7.7 at 0°C. - 26 - The radioactivity of the filters is measured by liquid scintillation.

The affinity of the test product for betaj-adrenergic receptors is given relative to propanolol as 5 the reference product.

CD = concentration of propanolol inhibiting 50% of the k specific binding of C^Hldihydroalprenolol.

CX « concentration of the test product inhibiting 50% of the specific binding of C^H]dihydroalprenolol. 10 The relative affinity is given by the relation ARL = 100 a> CX The following results were obtained: ' Product of I ARL in % ■ Example 1 | I 1 1 15 I 7 | 81 1 21 I 27 1 It is observed that some products of the patent 15 application possess exceptional affinity for betaj-adrenergic receptors. 3) Antiarrhythmic action in rats Male rats weighing 300 to 350 g, anaesthetized intraperitoneal ly using 1.20 g/kg of urethane, are 20 tracheotomized and subjected to artificial respiration (40-50 insufflations of 3 ml/minute).

Needles are implanted subcutaneously so as to record the electrocardiogram of the rats using the signal from DII leads. 25 The test products are administered intravenously.

Five minutes after the intravenous administration of the product, or 1 hour after oral administration, the jugular vein of the rats is perfused with 10 yg/min in a volume of 0.2 ml of a solution of aconitine, and the time 30 taken for the onset of the disorders of cardiac rhythm .is - 27 - noted.

The results are 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 good antiarrhythmic properties.

Product of 1 1 Dose i i Percentage prolongation .

Example i n 1 mg /'kg of the time | 1 1 1 . mg/kg I 14 * 1 * \ i S 1 mg/kg ! 54 % I I § mg/kg i 1 95 % 1 1 3 I 2.5 1 mg/kg | 38 % 1 1 5 mg/kg I 99 % 1 1 10 mg/kg l ! 147 % 1 1 4 I 1 1 mg/kg I 24 % ■ 1 I 2.5 mg/kg | 34 % i 1 5 mg/kg | | 83 % 1 1 5 1 I 0.5 1 mg/kg | 28 2 | ] 1 mg/kg | 43 * 1 4 1 1 2.5 mg/kg | 71 « 1 * 1 1 5 1 mg/kg | 1 97 V 1 1 - 28 - Product of Examp I e Dose in mg/kg Percentage p ro I onga t.i on in the time 1 6 1 1 | 5 mg/kg [ 54 or * i * 1 |10 mg/kg | ( 1 99 % 1 I 7 1 1 I 2.5 mg/kg i 12 % l 1 5 mg/kg | 43 * 1 110 mg/kg 1 | I 125 o f JO I 1 9 1 1 1 1 mg/kg I 25 % I ' I 2.5 mg/kg | 1 r 59 % 1 1 10 I 1 | 1 mg/kg | 47 % I | 5 mg/kg 1 J ! 116 % ! 1 U 1 i 1 2.5 mg/kg 1 42 % 1 1 5 mg/kg | 76 9 1 * 1 |10 mg/kg 1 | 1 173 Of 1 * 1 1 13 1 1 1 1 mg/kg | 21 * \ * 1 | 2.5 mg/kg | 1 1 50 % ] I 14 1 I 1 1 mg/kg I 34 1 ' % 1 I 2.5 mg/kg | 57 **> 1 1 5 mg/kg I 1 1 156 % 1 i 15 1 | 1 1 mg/kg [- 29 9 1 4 ( I 2.5 mg/kg | | | • 86 * \ * 1 I 16 1 I 1 1 mg/kg 1 49 % I 1 2.5 mg/kg 1 1 1 83 % 1 1 17 I I 1 1 mg/kg | 50 » 1 n i I 2.5 mg/kg | 90 « I a 1 1 5 mg/kg | 167 i n 1 - 29 - . Product of ■ Examp le i 9.ose in i mg/kg Percentage prolongation j in the time | | IS 1 I 2.5 mg/kg 62 Of I * 1 1 5 mg/kg 142 % 1 110 1 mg/kg 193 % 1 i 19 1 | 2.5 mg/kg 67 9 I ,9 | 1 5 mg/kg 127 % 1 110 r mg/kg 203 % 1 I 20 | 5 mg/kg 44 or 1 * 1 110 1 mg/kg 67 % 1 1 21 1 I 2.5 mg/kg 53 * i * I 1 1 5 mg/kg 79 % I 4) 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; MgCl2 : 1.2 mM; NaH2P<>4 : 1.2 mM; NaHC03 : 15.5 mM; glucose : 12.6 mM) at 37°C, gassed with a 95% 02/5% C02 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; MgCl2 : 1.2.mM; NaH2P04 : 1.2 mM; NaHCOj : 15.5 mM; glucose : 12.6 mM).

Calcium chloride is added in a volume of 250 ul 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 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 - 30 - 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 6-0H-dopamine, the specific action due to noradrenaline is eliminated.

The results are expressed as IC50 (inhibitory concentration5g), 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 application possess strong calcium-antagonistic activity.

T Product of 1 Example J IC5Q in mm- [ I 1 I 2.5 | 1 3 1 8 | 1 4 i 1-8 I J 5 1 3.9 | 1 6 1 6.3 | 1 7 1 8.8 | I 8 1 9 | 1 9 1 0.44 | 1 13 I 8.4 | 1 19 1 0.25 | 1 20 1 2.8 * | 1 22 1 3 | 1 1 5) Study of the acute toxicity The lethal doses LDg of the different test compounds were assessed after oral administration in mice.

LDg designates the maximum dose causing no mortality in the course of 8 days.

The results obtained are as follows: - 31 - Product of Exampl e 1 •' 1 > 400 3 ! 80 5 1 100 6 1 > 400 7 80 17 1 200 19 1 I 400 LD in mg/kg 4 6) Study of the hypotensive activity of the product of Example 19 on anaesthetized normotensive rats Sprague-Daw Iey male rats (CR) are anaesthetized intraperitoneally with pentabarbital sodium (60 mg/kg).

A jugular vein is catheterized for the injection of the product, and a carotid artery is catheterized for recording the arterial blood pressure.

The test product is dissolved in 10% ethanol and then injected in a volume of 1 cm^/kg.

The pressure is noted at times 5 minutes and 30 minutes after the injection of the product.

The table below shows the variations expressed as a percentage of the arterial blood pressure after administration of the test product compared with the initial control arterial blood pressure.

Results: Dose 5 mins. after ' 30 mins. after adm i ni s-t rati on 1 adm i n~i"s"t ration 1 | 10 mg/kg 1 | - 55 1 1 1 - 13 1

Claims (1)

1. - 32 -CLAIMS 1. New compounds of the formula (I): R 6 (I) a in which - either R2 and R3 each denote a hydrogen atom, B denotes a -CONH- chain, NH being on the indole side, b denotes a hydrogen atom, a and c together form a second bond between the carbons which bear them, A denotes a -CH2-CH-CH2- chain and either R1 denotes a hydrogen atom OH and R denotes a radical chosen from 1,1-dimethylpropyl, R and R1 together form, with the nitrogen atom to which they are attached, a morpholine ring, ~ £1 r2 anc* R3 each denote a hydrogen atom, B denotes a -CO-NH- chain, NH being on the indole side, b denotes a hydrogen atom and a and c together form a second bond between the carbons which bear them, A denotes a -(^2)3- chain, R-j denotes a hydrogen atom and R a radical chosen from 1,1-dimethylpropyl, cyclohexyl, cyclohexyImethyl , CH3 I propyl, isopropyl or -C-CH2OH radicals, CH3 - o£ R2 and R3 each denote a hydrogen atom, B denotes NH-CO-, C being on the indole side, b denotes a hydrogen atom and a and c together form a second bond between the carbons which bear them, A denotes a -(^2)3- chain, R-j denotes a hydrogen atom and R denotes a radical chosen from eyelopentyl, cyclohexyl, 1,1-dimethylpropyl or 0 - 33 - rv OCH- radicals, OCH- - £r Rj and R3 denote a hydrogen atom, B denotes 5 -NH-CO-, -NH being on the indole side, b denotes a hydro gen atom and a and c together form a-second bond between the carbons which bear them, A denotes a -((^2)4- chain, denotes a hydrogen atom and R denotes a 1,1-dimethyl-ethyl group, 10 - ££ r2 denotes a methyl radical and R3 denotes a hydrogen atom, B denotes -NH-C0-, NH being on the indole side, b denotes a hydrogen atom, and a and c together form a second bond between the carbons which bear them, A denotes a -CH2-CH-CH2- chain and R denotes a 1,1-dimethylethyl 15 ^OH group, - ££ the substituents R-j and R form, with the nitrogen 20 25 atom to which they are attached, a group ,X which Z denotes a group -(CH2) 'nl -a&: 1 -N M-Z in or a group in which groups n^ can assume the values 1, 2 or 3 and X, x 1 ✓ *2' x3' *4, *5 X$, which may be identical or 30 different, denote a hydrogen atom, an alkyl radical containing from 1 to 5 carbon atoms, an alkoxy radical containing from 1 to 3 carbon atoms, a halogen atom, a nitro, amino, monoaLkylamino or dialkylamino radical, with the proviso that X, X-N-(1H-indol-4-yI)benzamide and its benzoate and its neutral oxalate. 4. 2--C3-C ( 1,1-0i methyl ethyl) ami no ]-2-hydroxypropoxy>- 10 15 20 35 - 35 - N-(1-methyl-lH-indol-4-yl)benzamide and its hydrochloride, 5. 2--C2-Hydroxy-3-C (1, 1,3,3-tetramethylbutyI )amino]-propoxy>-N-( lH-indol-4-yl )benzamide and 2--C2-hydroxy-3-C4-(diphenylmethyl)-1-piperazinyI]propoxy>-N-(1H-indol-4-yl)-benzamide and its neutral oxalate. 6. Process for preparing derivatives as defined by the formula (I) of Claim 1, as well as the salts thereof, characterized in that a derivative.of the formula (II): (II) in which B and R3 have the meaning already stated and R£ denotes a hydrogen atom or a methyl, is reacted either with a halide of the formula (III): Hal-G (III) in which Hal denotes a chlorine, bromine or iodine atom and -G denotes a group of formula -(CHj^"0' in which 0 25 denotes a chlorine, bromine or iodine atom or a hydroxy radical or a sulphonate of this hydroxy radical, and n has the meaning already stated, or -G denotes a group -(CH2)m~cH-CH2 in which m has the meaning already stated, 0 30 to obtain a derivative of formula (IV): (IV) in which B, R2 and R3 have the meaning already stated, and - 36 - G* denotes a group of formula -(CH2)n-Hal in which n and Hal have the meaning already stated, or a group of formula -(CH2)n-CH-CH2 defined above, which is reacted with an N/ amine of formula (V): in which R and R-j have the meaning already stated, to obtain a product of formula (I/\): (I«) in which A, B, R, R-j, R2 and R3 have the meaning ^already stated, which is either isolated and, if desired, sali-fied, or alternatively, in the case where, in the product of formula (Ifi), R and R-j form, with th~e nitrogen atom to which they are attached, a group ^N-Z in which Z. has the meaning already stated, the corresponding product of formula (Ig): o—A—/d Z have the meanings already stated and Hal <| denotes a bromine or chlorine atom, which is subjected to a hydrolysis to obtain a compound of formula (1(0: in which A, B, R2, R3 and Z have the meanings already stated, which is isolated and, if desired, salified, or the said product of formula (II) is reacted with a derivative of formula (VI): in which Hal, n, R and R-j have the meaning already stated, to obtain the derivative of formula (I/\) in which A denotes a -(CH2)n~ chain, which is isolated and, if desired, salified, or in the case where, in the product of formula (I/\), R and R -j form, with the nitrogen atom ' *-». R (VI) to which they are attached, a group in which Z has the meaning already stated, the corresponding product of formula (Ig) is subjected to a halogenating agent and then to a hydrolytic reagent to obtain the product - 38 - of formula (1(0, which is isolated and, if desired, salified. 7. Medicinal products, characterized in that they consist of the new benzamide derivatives as defined by Claim 1, as well as the addition salts thereof with pharmaceuticaIly acceptable acids. 8. Medicinal products, characterized in that they consist of: the new benzamide derivatives as defined in any one of Claims 2 to 5, as well as the addition salts thereof with pharmaceutical^ acceptable acids. 9. Pharmaceutical compositions, characterized in that they contain, by way of active principle, at least one of the medicinal products as defined in one of Claims 7 and 8. 10. By way of new industrial compounds, the compounds of formula (VII) as defined in Claim 6. 11. Process according to claim 6, substantially as described herein by way of Example. 12. Compounds of the formula I as defined in claim 1 when prepared by the process of claim 6 or 11. Dated this 18th day of December 1987. BY: TOMKINS & CO., Applicants' Agents, (Signed): /O V*/ 5, 'Dartmouth Road, DUBLIN 6.