AU617094B2 - New 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 - 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

Australia PATENTS ACT 1952 61709 4orm 0 COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. CI: Application Number: Lodged: Complete Specification-Lodged: Accepted: Lapsed: Published: Priority: Related Art: S I 0.

Name of Applicant: Address of Applicant: Actual Inventor: Address for Service: TO BE COMPLETED BY APPLICANT

ROUSSEL-UCLAF

35, Boulevard des Invalides, 75007 Paris, France.

FRAN90IS CLEMENCE, JACQUES GUILLAUME and GILLES HAMON.

CALLINANS Patent Attorneys, of 48-50 Bridge Road, Richmond, State of Victoria, Australia.

"NEW INDOLECARBOXAMIDE DERIVATIVES AS WELL AS SALTS THEREOF, PROCESS AND INTERMEDIATES FOR Complete Specification for the invention entitled: PREPARATION, APPLICATION OF THESE DERIVATIVES BY WAY OF MEDICINAL PRODUCTS AND COMPOSITIONS CONTAINING THEM" The following statement is a full description of this invention, including the best method of performing it known to me:-* 'Note: The description is to be typed in double spacing, pica type face, in an area not exceeding 250 mm in depth and 160 mm in width, on tough white paper of good quality and it is to be inserted inside this form.

i la The present invention relates to indolecarboxamide derivatives as well as salts thereof, to the process and S intermediates for preparation, to the application of these I derivatives by way of medicinal products and to the com- S 5 positions containing them.

The subject of the invention is indolecarboxamide derivatives as well as the addition salts thereof with inorganic or organic acids, characterized in that they correspond to the general formula 10 6 n

(I)

b SI a

Q.

S in which either R 2 and R 3 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

-CH

2 -CH-CH?- chain and either R 1 denotes a hydrogen atom

\H

and R denotes a radical chosen from 1,1-dimethylpropyl, eC 3

CH

3

CH

3

CH

3 -C-C -C-CH 2

-C-CH

3 or -C-CH2OH radicals, or else CH3 CH3 CH 3 CH3 R and R 1 together form, with the nitrogen atom to which they are attached, a morpholine ring, 2 -2or R 2 and R 3 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)3chain, R 1 denotes a hydrogen atom and R a radical chosen from 1,1-dimethyLpropyL, cycLohexyl, cycLohexyLmethyl,

CH

3 propyL, isopropyL or -C-CH20H radicals,

CH

3 or R 2 and R 3 each denote a hydrogen atom, B denotes NH-CO-, C being on the indoLe side, b denotes a hydrogen 0 S 10 atom and a and c together form a second bond between the carbons which bear them, A denotes a -(CH 2 3 chain,

R

1 denotes a hydrogen atom and R denotes a radical chosen from cycLopentyl, cycLohexyL, 1,1-dimethyLpropyL or

OCH

3 -CHZ-CH2- radicals,

OCH

3 or'R 2 and R 3 denote a hydrogen atom, B denotes -NH-CO-, -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 -(CH 2 4 chain,

R

1 denotes a hydrogen atom and R denotes a 1,1-dimethyLethyl group, or R 2 denotes a methyl radical and R 3 denotes a hydrogen atom, B denotes -NH-CO-, 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 -CH 2

-CH-CH

2 chain and R denotes a 1,1-dimethylethyL

SOH

group, or the substituents R 1 and R form, with the nitrogen atom to which they are attached, a group N-Z in which Z denotes a group -(CH2)n or a group Vs^/xy 3

-CH

in which groups nI can assume the vaLues 1, 2 or 3 and X,

X

1

X

2

X

3

X

4

X

5 and X 6 which may-be identical or different, denote a hydrogen atom, an alkyL radical containing from 1 to 3 carbon atoms, an aLkoxy radical containing from 1 to 3 carbon atoms, a halogen atom, a nitro, amino, monoaLkyLamino or dialkylamino radical, with the prdviso that X, X 1 and X 2 do not aLL three denote a hydrogen atom, A denotes a chain -(CH2)n in which n can assume the values 2, 3, 4 or 5 or a chain -(CH 2 )m-CH-CH2 oH in which m can assume the values 1, 2 or 3, 8 denotes a -CO-NH- or -NH-CO- chain, R 3 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 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 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 R 2 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 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 radicals 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 and in that which i I' 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 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 aLkyl radicals are preferably methyL or ethyl.

When X, X 1

X

2

X

3

X

4

X

5 and X 6 are halogen S;t atoms, they are preferably chlorine atoms, but they can also denote fluorine, bromine or iodine atoms.

SThe term aliphatic acyL containing from 2 to carbon atoms preferably denotes an acetyl or propionyL Sradical.

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 S 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, citric, oxalic, glyoxylic and aspartic acids, alkanesulphonic acids such as methane- or ethanesulphonic acids, arylsulphonic acids such as benzene- or para-toluenesulphonic acid, and arylcarboxylic acids.

Among the products which are the subject of the invention, there may be mentioned, in particular, the derivatives corresponding to the formula above as well as the addition salts thereof with inorganic or organic acids, characterized in that, in the said formula the substituents R 1 and R form, with the nitrogen atom to i i which they are attached, a group -N N-Z in which Z has the above meaning, A denotes a -CH 2

-CH-CH

2 or 0H -(CH2)3- or -(CH 2 4 chain, R 3 denotes a hydrogen atom,

R

2 denotes a hydrogen atom or 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 foLLowing names: 2-{3-C(1,1-dimethyLpropyL)aminol-2-hydroxypropoxy}-N- (1H-indoL-4-yL)benzamide and its benzoate and its neutraL oxal ate, 2-{3-C(1,1-dimethyLthyL)aminol-2-hydroxyp.opoxyl-N-(1methyL-1H-indol-4-yL)benzamide and its hydrochLoride, 2-{2-hydroxy-3-C(1,1,3,3-tetramethyLbutyL)aminolpropoxy}- N-(1H-indoL-4-yL)benzamide, and 2-{2-hydroxy-3-C4-(diphenyLmethyL)-1-piperazinyL]propoxyl-N-(1H-indoL-4-yL)benzamrnide and its neutral oxalate.

The subject of the invention is also a process for preparing the products as defined by the formuLa above as well as the salts thereof, characterized in that a derivative of the formula

OH

(II)

FF

in which 8, R 2 and R 3 have the meaning already stated, is reacted with a halide of the formula III: HaL-G (III) fr t 6 in which HaL denotes a chlorine, bromine or iodine atom and -G denotes a group of formula -(CH2)n-D, 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): -0

(IV)

RZ

in which B, R 2 and R 3 have the meaning already stated, and 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 0 amine of formula H-N

(V

R1 in which R and R 1 have the meaning already stated, to obtain a product of formula (IA): N N

S(IA)

in which A, B, R, R 1

R

2 and R 3 have the meaning already stated, which is isolated and, if desired, salified.

When it is desired to obtain a chain of formula 7 -(CH2)n- for A, if a halide of formula III having the following formula is used: Hal-(CH2)n-D in which D denotes a chlorine, bromine or iodine atom and Hal has the meaning already stated, -it is preferable to use two different hiaogens 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 S<o 10 bromide.

When a hydroxylated halide of formula (III) is 9 used, corresponding to the formula (III'): 0 o0 oa HO-(CH2)n-HaL (III') O 00 in which n and HaL have the meaning already stated, in order to react it with the derivative of formula it

S..

o is then preferable to work in the presence of triphenyl- 0 00 *o0o' phosphine and ethyl azodicarboxylate in tetrahydrofuran.

Advantageously, a sulphonate of the derivative of o 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"): 0 0o 0 TsO-(CH 2 )n-Hal (III") in which T S denotes a tosyl (4-methylbenzenesulphonate) radical and n and Hal have the meaning already stated.

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 agent such as a tetrabutylammonium 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 F- I 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, 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 directly as solvent.

When it is desired to obtain a chain of formula -(CH2)m-CHCH 2 for A, a halide of formula

OH.

Hal-(CH2)m-CH-CH2 is used; in this case, Hal preferably 0 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 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-CH-CH 2 with the amine 0 of formula is carried out either directly using the 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 in which A denotes a chain a derivative of formula II is reacted with a derivative of formula (VI): Hal-(CH2)'n-N.

(VI)

R

in which Hal, n, R and R 1 have the meaning already stated, to obtain the desired derivative of formula IA, which is isolated and, if desired, salified.

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 in which the substituents R 1 and R form, with the nitrogen atom to which they are attached, a group N .Z in which Z has the meaning already stated, characterized in that a product of formula (IV):

(IV)

in which 8, R 2

R

3 and G' have the meaning aLready stated, is reacted with an amine of formula H-N_ N-Z in which Z has the meaning aLready stated, to obtain a product of formuLa (IB): (18)

RE

in which A, 8, R 2

R

3 and Z have the meanings already, stated, which is either isoLated and, if desired, salified, or, if desired, subjected to the action of a halogenating agent to obtain a product of formula (VII): 10

S(VII)

R

in which Hall denotes a bromine or chLorine atom, which is subjected to a hydrolysis to obtain a compound of formuLa (IC):

(I

C

in which A, B, R 2

R

3 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 in which A denotes a chain a product of formuLa (II):

OH

in which 8, R 2 and R 3 have the above meanings, is reacted with a compound of formuta (VIII): \Ha -(H2 N- (VII I~ N ^S H a:lHZ n 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 (Ic).

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

The halogenation of the derivatives of formulae

I

A may be performed, for example, using the brominecontaining pyridine complex of formula: H r in the case of bromination. It is advantageously carried out using an N-halosuccinimide, preferably N-bromo- or Nchlorosuccinimide: the reaction is performed in dioxane or preferably in acetic acid. The product of formula (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- S 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 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.

The derivatives which are the subject of the present application possess very advantageous pharmacological properties; they are endowed, in particular, with i; L I 12 certain antiarrhythmic properties. In addition, some derivatives which are the subject of the present application possess, moreover, calcium-antagonistic and betablocking, hypotensive and vasodilatory properties.

These properties are illustrated later in the experimental part.

These properties justify the. use of the new benzamide derivatives and the salts thereof by way of medicinal products.

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 pharmaceutically acceptable acids.

Among the preferred medicinal products of the invention, there are selected more especially the derivatives corresponding to the formula above, as well as the addition salts thereof with pharmaceutically acceptable inorganic or organic acids, characterized in that, in the said formula the substituents R 1 and R form, with the nitrogen atom to which they are attached, a group -k N-Z in which Z has the above meaning, A denotes a -CH 2

-CH-CH

2 or -(CH 2 3 or -(CH 2 4 chain,

OH

R

3 denotes a hydrogen atom, R 2 denotes a hydrogen atom or 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 following names: 2-C3-E(1,1-dimethylpropyl)amino3-2-hydroxypropoxy}-N- (1H-indol-4-yl)benzamide and its benzoate and its neutral oxalate, 2-C3-C(1,1-dimethylethyl)aminol-2-hydroxypropoxy}-N-(1methyl-1H-indol-4-yl)benzamide and its hydrochloride, 2 -<2-hydroxy-3-C(1,1,3,3-tetramethyLbutyl)amino3propoxy}- I 13 N-(1H-indol-4-yl)benzamide, and 2-{2-hydroxy-3-E4-(diphenylmethyL)-1-piperazinyl]propoxy)-N-( H-indol-4-yl)benzamide and its neutral oxalate.

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 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 pharmaceutically acceptable acids, by way of 3* active principle.

By way of medicinal products, the derivatives oO which are the subject of the present application, and the o* addition salts thereof with pharmaceutically acceptable acids, may be incorporated in pharmaceutical compositions o 25 designed for administration via the digestive tract or *oo 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 example, 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 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-yl)benzamide used at the start of Example No. 1 92 cm 3 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-aminoindole in 250 cm of chloroform, 9.6 cm 3 of methyl salicylate are then added, i t -L _L 7 1 L J .J^ 1

I

lu tne mixture is oroughn to reTFux Tor 4u nours and cooLed to room temperature, 300 cm 3 of N hydrochloric acid and 300 cm 3 of methylene chloride are added, the organic phase is washed with water, dried, and taken to dryness under reduced pressure at 500C, the residue is made into a paste with ether, filtered and dried at 60 0 C under reduced pressure and 9.4 g of the expected product, m.p.

232 0 C, are obtained.

UV spectrum (ethanol): infl. 216 nm infl. 233 nm infl. 262 nm infl. 303 nm infl. 314 nm C1 El

I

E f

E

El 1 595 680 S 187 S 482 S 494 E 17, 200 12,200 12,500 Example 1 2--3-C(1,1-Dimethylpropyl)amino3-2-hydroxypropoxy}-N-(1H-indol-4-yl)benzamide and its neutral oxalate Stage A 2-C(2-Oxiranyl)methoxy3-N-(IH-indol-4-yl)benzamide 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 3 of acetone is heated to reflux for 30 hours under an inert atmosphere with 11 cm 3 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 fractions having Rf 0.45 are taken to dryness, the residue made into a paste with ether, filtered and dried under reduced pressure at 600C, and 3.65 g of the expected product, m.p. 171 0 C, are obtained.

Stage 8 2-C3-C(1,1-DimethyLpropyL)amino]-2-hydroxypropoxyl- N-(1H-indol-4-yL)benzamide and its neutral oxalate.

Base: '"r ;3 i

I

ii 4 4 4 4 10 3.5 g of product of stage A dissolved in 35 cm 3 of ethanol is heated to reflux with stirring and under an inert atmosphere for 5 hours with 3 cm 3 of tert-pentylamine, the solvent is evaporated off, the residue purified by chromatography on silica (eluant: methylene chloride/ 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 3 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 0

C,

is obtained.

Example 2 2-C3-(4-Morpholinyl)-2-hydroxypropoxy3-N-(1Hindol-4-yl)benzamide and its hydrochloride The procedure is as described in stage B of 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 solution of hydrochloric acid in methylene chloride.

Melting point of the hydrochloride after recrystallization in ethanol: 210 0

C.

Example 3: 2-C3-C(1,1-Dimethylpropyl)amino]propoxy}-N-(1Hindol-4-yl)benzamide and its hydrochloride Stage A 2-(3-Chloropropoxy)-N-(IH-indol-4-yl)benzamide.

A solution of 5 g of 2-hydroxy-N-(1H-indol-4-yl)benzamide, 400 cm 3 of tetrahydrofuran, 1.8 cm 3 of 3chloropropanol and 5.7 g of triphenylphosphine is prepared with stirring and under an inert atmosphere, 3.4 cm 3 of lurs~--~-aa~ 16 ethyl azodicarboxylate are added slowly, the mixture is Left for 5 hours with stirring, 5.7 g of triphenylphosphine and 1.8 cm 3 of 3-chloropropanol are added, followed by 3.4 cm of ethyl azodicarboxylate added slowly, the mixture is left again with stirring for 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 dried under reduced pressure, and 5.5 g of the expected product, m.p. 140 0 C, are obtained.

Stage B 2-{3-CC1,1-Dimethylpropyl)amino]propoxy>-N-(1Hindol-4-yl)benzamide and its hydrochloride.

Base: 2 g of product of stage A in 20 cm 3 of ethanol are heated to 1200C for 5 hours with 2 cm 3 of tertpentylamine 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 (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 3 of isopropanol at 50 0 C, a saturated solution of hydrochloric acid in ethyl acetate is added until the pH is acid, the mixture is chilled, filtered and dried, the product recrystallized in isopropanol and 1.7 g of the expected product obtained.

M.p. 216 0

C.

Example 4 2-C3-(Cyclohexylamino)propoxy]-N-(1H-indoL-4yl)benzamide and its hydrochloride The procedure is as described in Example 3, but by replacing tert-pentylamine by cyclohexylamine and chromatography on silica (eluant: CHCl 3 /ethyl acetate/ TEA 2.1 g of expected product, m.p. 148°C (base) are obtained, and the hydrochloride, which melts at 214 0 C after recrystallization in isopropanol, is then formed.

1.

17 Example 5 2-{3-C(CycloexyLmethyL)aminolpropoxyl-N-(1Hindol-4-yI)benzamide and its hydrochloride The procedure is as described in Example 3, but replacing tert-pentyamine with cyclohexylmethyLamine, and S the expected product is obtained, and then its hydrochloride which is recrystaltized in ethanoL. M p. 228 0

C.

ExampLe 6 2-{4-C(1,1-DimethyLethyL)aminolbutoxy)-N-(1HindoL-4-y)benzamide and its acid fumarate The procedure is as in ExampLe 3, but at 500 C and replacing tert-pentyLamine by tert-butyLamine and 2-(3chLoropropoxy)-N-(1H-indoL-4-y)benzamide by 2-(4-bromobutoxy)-N-( 1H-indoL-4-yt)benzamide, and with chromatography on siLica (eluant: CHCL 3 /acetone/TEA the residue is taken up with ether to obtain the expected product, m.p. 147 0 C (base). The acid fumarate, which melts at 224-225 0 C with subLimation after recrystaLLization in ethanol, is prepared.

Preparation of 2-(4-bromobutoxy)-N-(1H-indo-4-yL)benzamide A suspension of 7.5 g of 2-hydroxy-N-(1H-indoL-4yl)benzamide and 8.28 g of potassium carbonate in 150 cm 3 of acetone is brought to reflux for 1 h 15 min with 18 cm 3 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 chromatography on silica (eluant: methylene chloride/ethyl acetate followed by recrystallization in ethyl acetate, and the expected product, m.p. 1350C, is obtained.

ExampLe 7 2-{3-C (1,1-DimethyLethyL aminol-2-hydroxypropoxy}-N-(1-methyL-1H-indol-4-yl)benzamide and its hydrochloride Stage A 2-C(2-Oxirany)methoxyj-N-(1-methyL-1H-indoL-4yL)benzamide.

The procedure is as described in Example 1, stage A, but starting with 2-hydroxy-N-(1-methyL-1H-indol-4-yl)benzamide to obtain the expected product, m.p. 160 0

C.

Stage The procedure is as described in Example 1, stage 6, but starting with the product obtained above and 18 replacing tert-pentylamine by tert-butylamine to obtain the expected product, m.p. 130 0 C (base). The hydrochLoride, which melts at 195 0 C after recrystaltization in isopropanoL, is prepared.

Preparation of the starting 2-hydroxy-N-(1-methyL-1H-indoL- 4-y)benzamide of ExampLe 7 A solution of 5 g of 1-methyL-1H-indo-4-amine, prepared according to Steven V. Ley Chem. Soc. Chem.

Corn. 1982 p. 1356), 4.7 g of saLicyLic acid and 7 g of dicyclohexylcarbodiimide in 80 cm 3 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 by chromatography on silica (eluant methylene chloride) and 5.5 g of the expected product, m.p. 211 0 C, are obtained.

Example 8 2-t3-C(1,1-Dimethy-2-propynyL)aminoJ-2hydroxypropoxyl-N-(1H-indol-4-yL)benzamide and its neutral 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-dimethylpropargyamine.

3.77 g of expected base are obtained after chromatography on silica (eluant: chloroform/ethyl acetate/triethylamine 6:3:1).

Neutral oxalate 3.09 g of base are dissolved in 100 cm 3 of ethanol and 0.497 g of oxaLic acid is added. The mixture is chilled, filtered and dried under reduced pressure at 800C, the product is recrystallized in ethano and 2.5 g of expected neutral oxalate, m.p. 160 0 C, are obtained.

Analysis C 23

H

2 5

N

3 0 3 872.984 Calculated C% 66.04 H% 6.00 N% 9.63 Found 65-.9 6.0 4 19 Example 9 2-{2-Hydroxy-3-C(1,1,3,3-tetramethyLbutyL)aminolpropoxy3N-(1H-indol-4-yL)benzamide The procedure is as in Example 1, stage B, starting with 5 g of the product prepared as in stage A of 3 ExampLe 1 and 4.9 cm of tert-octyLamine. 4.27 g of expected product are obtained. M.p. 140 0

C.

Analysis C 2 6

H

3 5

N

3 0 3 437.587 Calculated C% 71.37 H% 8.06 N% 9.60 Found 71.6 8.3 Example 10 2-{3-C(1,1-Dimethyl-2-hydroxyethyL)aminol-2hydroxypropoxyl-N-(1H-indo-4-y)benzamide and its neutral oxalate Ii; 1* IIr I; I 11111 The procedure is as in Example 1, stage 8, starting with 4 g of the product prepared as in stage A of Example 1 and 1.3 cm 3 of 2-amino-2-methy-1-propano, 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 0

C.

Analysis C 22

H

2 7

N

3 0 4 884.99 Calculated C% 62.43 H% 6.38 N% 9.50 Found 62.3 6.6 9.4 Example 11 1H-IndoL-4-yL )-2-3-(propyLamino)propoxyjbenzamide and its hydrochloride The procedure is as in stage B of Example 3, starting with 4.5 g of product prepared as in stage A of Example 3 and 6.5 cm 3 of N-propylamine. After chromatography on silica (eluant chloroform/ethyl acetate/triethylamine 3.20 g of expected base are obtained.

3 g of this base are converted to the hydrochloride as described in Example 3. 2 g of expected hydrochLoride are recovered. M.p. 2020C.

Analysis C 2 1

H

2 5

N

3 0 2 387.913 Calculated C% 65.02 H% 6.76 CL% 9.14 NZ 10.83 Found 64.9 6.7 9.3 10.7 Example 12 N-(1H-Indo-4-y)-2-{3-C(1-methyethv)aminolpropoxy)benzamide and its hydrochLoride The procedure is as in Example 11, starting with 4 g of starting substance and 10 cm 3 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 0

C.

AnaLysis C 2 1

H

2 5

N

3 0 2 HCL 387.913 Calculated C% 65.02 H% 6.76 CL% 9.14 NZ 10.83 Found 65.0 6.9 9.0 10.8 ExampLe 13 2--3-(1,1-DimethyL-2-hydroxyethy)aminolpropoxy)-N-(1H-indoL-4-yl)benzamide and its neutra fumarate The procedure is as described in Example 3, stage B, starting with 3 g of product prepared as in stage A of Example 3 and 5 cm 3 of 2-amino-2-methy-1-propano.

After chromatography on silica (eluant chloroform/ methanol/triethyLamine 90:5:5), 2.1 g of base are obtained.

Neutral fumarate Using 1.85 g of base and 5.63 g of fumaric acid, 1.323 g of expected neutral fumarate is obtained.

M.p. 1860C.

Analysis (C 2 2

H

2 7

N

3 0 3 2

.C

4

H

4 0 4 879.031 Calculated C% 65.59 H% 6.65 N% 9.56 Found 65.5 6.9 9.3 Example 14 N-E2-3-C(1-MethyhylethyL)aminolpropoxy}phenyL]- 1H-indole-4-carboxamide and its hydrochLoride Stage A N-C2-(3-Bromopropoxy)phenyL -1H-indoLe-4-carboxamide.

A suspension is prepared comprising 2 g of hydroxyphenyl)-1H-indole-4-carboxamide and 2.18 g of potassium carbonate in 20 cm 3 of acetone, 3.2 cm 3 of 1,3-dibromopropane are added and the mixture is brought to reflux for 1 and a half hours, and filtered, the solvent is removed under reduced pressure and the residue chromatographed on silica (eluant: chloroform/ethy acetate/triethylamine 6:3:1) and 2.37 g of expected product are obtained. M.p. 145 0

C.

Stage B N-E2-(3-C(1-MethyLethyL)aminolpropoxyphenyl]- 1H-indole-4-carboxamide and its hydrochloride.

The procedure is as in stage 8 of Example 3, starting with 4 g of product prepared in stage A above and cm 3 of isopropylamine. After chromatography on siLica (eluant chloroform/ethyl acetate/triethylamine jT~ 21 2.91 g of base are obtained, and then 2.5 g of hydrochLoride. M.p. 234 0

C.

Analysis C 2 1

H

2 5

N

3 0 2

HCL

Calculated C% 65.02 H% 6.76 CL% 9.14 N% 10.83 Found 65.3 6.8 9.3 10.7 ExampLe 15 N-{2-C3-(CycLopentamino)propoxylphenyi1-- 1H-indoLe-4-carboxamide airi it: hydr-ochloride The procedure is as in Example 14, stage B, starting with 4 g of product prepared in stage A and 2.11 cm 3 of cyclopentylamine, and 3.3 g of expected base are obtained, and then 2.8 g of hydrochloride. M.p. 244 0

C.

Analysis C 2 1

H

27

N

3 0 2 .HCL 413.95 Calculated C% 66.74 H% 6.82 CI% 8.56 N% 10.15 Found 66.9 6.8 8.4 9.9 ExampLe 16 N-{2-C3-(CycLohexylamino)propoxyjphenyJ-1HindoLe-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 cm 3 of cycLohexyLamine, and 1.8 g of expected base and 1.7 g of expected hydrochLoride are obtained. M.p. 260 0

C.

AnaLysis C 2 4

H

2 9

N

3 0 2 .HCI 427.979 Calculated C% 67.35 H% 7.06 CI% 8.28 N% 9.82 Found 67.1 7.1 8.4 9.7 Example 17 N-C2--C3-E(1,1-Dimethylpropyl)aminolpropoxy)phenyL]-1H-indole-4-carboxamide and its hydrochloride The procedure is as in Example 14, stage B, startwith 4 g of the starting substance and 5 cm 3 of tertamylamine. 2.90 g of expected base are obtained, and tIen 2.5 g of expected hydrochLoride from 2.7 g of base.

M.p. 230 0

C.

Analysis C 23

H

2 9

N

3 0 2 .HCL 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-{E2-(3,4-DimethoxyphenyL)ethyLaminopropoxylphenyl}-1H-indoe-4-carboxamide and its hydrochloride The procedure is as in Example 14, stage 8, starting with 3 g of the starting substance and 2.31 cm 3 of homoveratrylamine, and, after chromatography on silica 22 (eluant chloroform/methanoL 2.75 g of expected base are obtained, and then 1.75 g of hydrochloride from 2.55 g of base. M.p. 182 0

C.

Analysis C 28

H

3 1

N

3 0 4 .HCL 510.038 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-(2-Hydroxy-3-C4-(diphenylmethyL)-1-piperazinyL]propoxy)-N-(lH-indoL-4-y)benzamide and its neutral oxalate The procedure is as in Example 1, stage B, starting with 3.08 g of 2-C(2-oxiranyl)methoxyJ-N-(1H-indoL-4yL)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), 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.

1700C.

AnaLysis (C3 5

H

3 6

N

4 0 3 2

-C

2

H

2 0 4 1211.44 Calculated C 71.38 H% 6.15 N% 9.24 Found 71.4 6.3 9.1 ExampLe 20 1H-IndoL-4-yL )-2-C4-{4-C2-(3,4,5-trimethoxypheny)ethyl]-1-piperazinyltbutoxylbenzamide and its difumarate g of 2-(4-bromobutoxy)-N-(1H-indo-4-yL)benzamide, prepared as in Example 6, 2.71 g of 1-C2-(.3,4,5trimethoxyphenyl)ethyllpiperazine (Hoechst AG German Patent 3,347,173) and 0.683 g of sodiumn carbonate in cm 3 of ethanoL are heated to 60 0 C for 10 hours. The mixture is cooLed, poured into water and extracted with 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.

Difumarate Using 2.52 g of base and 498 mg of fumaric acid, 1.718 g of expected difumarate is obtained. M.p. 182- 183 0

C.

Analysis (C 34

H

42

N

4 0 5 2

.C

8

H

8 0 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-E(1,1-DimethylpropyL)aminol-2-hydroxy- Propoxy}-N-(1H-indol-4-yI)benzamide benzoate 1.11 g of benzoic acid are added to a soLution of 3.6 g of -base obtained in stage B of Example 1. The mixture is chiled, filtered and dried under reduced pressure at 90 0 C, and 3 9 of expected product are obtained after recrystallization in isopropanoL. M.p. 170 0

C.

Analysis Ca 3

H

2 9

N

3 0 3 511.615 Calculated C% 69.91 HZ 6.82 N% 8.12 Found 69.9 6.8 8.2 Example 22 2-{2-Hydroxy-3-C4-(diphenyLmethy)-l-piperazinyl]propoxy}-N-( 1-methyl-1H-indoL-4-yL)benzamide and 15 its hydrochloride 000 ooPo The procedure is as in Example 1, stage 8, starting with 4 g of 2-E(2-oxiranyl)methoxyj-N-(1-methy-lH- *0 indoL-4-y)benzamide prepared in Example 7 and 6.3 g of 900 diphenylmethylpiperazine. 5.95 g of base are obtained, and then 4.9 g of expected hydrochloride. M.p. 196 0

C

after recrystallization in ethanol.

00 Analysis C 36

H

3 8

N

4 0 3 .HCL 611.19 .000 Calculated C% 70.76 HZ 6.43 CI% 5.80 N% 9.17 Found 70.4 6.3 5.9 9.1 0 25 In a manner similar to that already described in the examples, the following product is also prepared: 2-C2-hydroxy-3-EE4-bis(4-fluorophenyl)methyLJ-l-piper- 0 azinylpropoxylphenyL)-N-(1H-indoL-4-yL)benzamide.

0:0000" Example 23 T'blets corresponding to the following formula were prepared: 2-{3-EC1,1-dimethypropy)amino)-2-hydroxypropoxy}-N-(1H-indoL-4-yL)benzamide neutral oxalate 50 mg excipient q.s. for a finished tablet weighing 100 mg.

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

A

-24 Example 24 Tablets corresponding to the foLLowing formuLa were prepared: 2-(3-[(1,1-dimehyhylethyL)amino-2hydroxypropoxy}-N-(1-methyl-1H-indoL-4- K yl)benzamide 100 mg Excipient q.s. for a finished tablet weighing 150 mg.

(DetaiL of the excipient: lactose, starch, taLc, magnesium stearate).

PHARMACOLOGICAL STUDY 1) Affinity for betal-adrenergic receptors The technique is modelled on that of M'hLer and Okada Science. VoL. 198 p. 849-851 (1977).

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 m' ixture 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 0

C.

The pellet is suspended in 120 mL of 50 mM Tris- HCL buffer pH 7.7, and centrifuged at 30,000 g for 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 at 37 0 C in the presence of C H3dihydroalprenoLoL at a 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 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.

The radioactivity of the filters is measured by liquid scintillation.

The affinity of the test product for beta 1 adrenergic receptors is given relative to propanolol as the reference product.

CD concentration of propanolol inhibiting 50% of the specific binding of C 3 H]dihydroaLprenoLoL.

T ~F IL II1 ii- 25 CX concentration of the test product inhibiting 50% of the specific binding of E 3 H]dihydroalprenolol.

The relative affinity is given by the relation ARL 100 CD

CX

The following results were obtained: I Product of I ARL in S Example 1 1 1 28 I I 7 44 I I 21 1 It is observed that some products of the patent application possess exceptional affinity for beta 1 adrenergic receptors.

2) Affinity for beta2-adrenergic receptors The technique is modelled on that of M'hler 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 mixture at 1,000 g for 20 minutes at 0 0 C, the supernatant is centrifuged at 30,000 g for 15 minutes at 0 to The pellet is suspended in 120 ml of 50 mM Tris- HCI buffer pH 7.7, and centrifuged at 30,000 g for minutes at 0 to +40C. 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 at 37 0 C in the presence of C H]dihydroaLprenolol at a conentatin o 1 9 concentration of 10 9 M, i) alone, ii) with increasing concentrations of the test product or iii) in order to determine the non-specific binding, with non-radioactive propranolol at a concentration of 105 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 beta 2 adrenergic receptors is given relative to propanolol as the reference product.

CD concentration of propanoLol inhibiting 50% of the specific binding of C 3 H3dihydroalprenolol.

CX concentration of the test product inhibiting 50% of the specific binding of C 3 H]dihydroalprenolol.

The relative affinity is given by the relation ARL 100 CD

CX

The following results were obtained: Product of ARL in E armple 1 7 81 S21 I 27 It is observed that some products of the patent application possess exceptional affinity for beta 2 adrenergic receptors.

3) Antiarrhythmic action in rats Male rats weighing 300 to 350 g, anaesthetized intraperitoneally using 1.20 g/kg of urethane, are tracheotomized and subjected to artificial respiration (40-50 insufflations of 3 mt/minute).

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

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 pg/min in a volume of 0.2 ml of a solution of aconitine, and the time taken for the onset of the disorders of cardiac rhythm is i. 27 no ted.

The results are expressed as a percentage pro- Longation 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 a-pplication are endowed with good antiarrhythmic properties.

.0 Product of Dose Percentage prolongation Example in mg/kg of the time 1 I 1 mg/kg I 14 mg/kg I 54 mg/kg 95 3 1 2.5 mg/kg 38 15 mg/kg 99 mg/kg I 147 I I 4 I mg/kg 24 1 2.5 mg/kg I 34 mg/kg I 83 5 0.5 mg/kg I 28 S1 mg/kg 1 43 S2.5 mg/kg I 71 1 5 mg/kg I 97 I I 28 Product of Examp Le 7 9 11 13 14 16 17 Dose i n mg/ kg mg/kg 110 mg/kg I2.5 mg/kg mg/kg 110 mg/kg 1 mg/k g mg/kg I 1 mg/kg mg/kg 2.5 mg/kg mg/kg 110 mg/kg I1 mg/kg mg/kg I1 mg/kg I2.5 mg/k g mg/kg I1 mg/kg mg/kg I1 mg/kg mg/kg I1 mg/kg I2.5 mg/kg mg/kg Percentage proLongation in the time 25 59 47 116 42 76 173 21 s0 34 57 156 29 86 49 1 83

I,

44~ 167 b 29 Product of B:ose in Percentage proLongation ExampLe mg/kg in the time 18 2.5 mg/kg I 62 1 5 mg/kg 142 1 110 mg/kg I 193 1 I I 19 2.5 mg/kg 67 mg/kg 1 127 1 10 ng/kg 203 5 mg/kg I 44 i 110 mg/kg I 67 1 I I I 21 1 2.5 mg/kg 1 53 i 5 mg/kg I 79 1 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 mL of Krebs sodium bicarbonate buffer (NaCI 120.8 mM; KCL 5.9 mM; MgCL 2 1.2 mM; NaH 2

PO

4 1.2 mM; NaHCO 3 15.5 mM; glucose 12.6 mM) at 37 0 C, gassed with a 95% 02/5% C0 2 mixture.

The preparations are depolarized with a buffer solution containing K+ ions at a concentration of 100 mM (NaCL 26.7 mM; KCI 100 mM; MgCL 2 1.2 .mM; NaH 2 PO4 1.2 mM; NaHCO 3 15.5 mM; glucose 12.6 mM).

Calcium chloride is added in a volume of 250 .l so as to obtain a series of increasing concentrations of Ca2+ 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 2 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 Ca2 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 2 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-OHdopamine, the specific action due to noradrenaLine is eliminated.

The results are expressed as IC 5 0 (inhibitory concentration 5 0 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.

I' Product of I i i Example 1 I S1 3 1 8 4 1.8 5 3.9 6 6.3 7 8.8 8 J 9 9 1 0.44 13 8,4 19 0.25 2.8 22 3 Study of the acute toxicity The Lethal doses LDO of the different test compounds were assessed after oral administration in mice.

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

The results obtained are as follows: MMMMM c I 31 Product of I Example LD in mg/kg 1' 400 3 100 6 400 7 17 200 19 I 400 I I 6) Study of the hypotensive activity of the product of Example 19 on anaesthetized normotensive rats Sprague-DawLey 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 cm3/kg.

The pressure is noted at times 5 minutes and 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. affter 30 mins. after administration admi n'strati on I I I 13 I 10 mg/kg l 55 13 1

Claims (10)

1. New compounds of the formula S(I) C LRL in which i either R 2 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 -CH 2 -CH-CH 2 chain and either R 1 denotes a hydrogen atom OH and R denotes a radical chosen from 1,1-dimethyLpropyl, H3 3 CH 3 CH 3 -i -C-CH 2 -C-CH 3 or -CH2H radicaLs, or else CH 3 CH 3 CH 3 CH R and R 1 together form, with the nitrogen atom to which they are attached, a morpholine ring, or R 2 and R 3 each denote a hydrogen atom, B denotes a S-CO-NH- chain, NH being on the indole side, b denotes a hydrogen atom and a and c together form a second bond ii jbetween the carbons which bear them, A denotes a -(CH2) 3 chain, R 1 denotes a hydrogen atom and R a radical chosen from 1,1-dimethyLpropyL, cycLohexyl, cyclohexylmethyL, CH 3 propyL, isopropyl or -C-CH 2 0H radicals, CH 3 or R 2 and R 3 each denote a hydrogen atom, B denotes NH-CO-, C being on the indole side, b denotes a hydrogen 0 atom and a and c together form a second bond between the carbons which bear them, A denotes a -(CH 2 3 chain, R 1 denotes a hydrogen atom and R denotes a radical chosen from cyclopentyl, cyclohexyl, 1,1-dimethylpropyl or 33 -CH 2 -CH 2 OCH 3 radicals, OCH 3 or R 2 and R 3 denote a hydrogen atom, B denotes -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 -(CH 2 chain, R 1 denotes a hydrogen atom and R denotes a 1,1-dimethyl- o ethyl group, o or R 2 denotes a methyl radical and R 3 denotes a hydro- 0000 .oooo gen atom, B denotes -NH-CO-, NH being on the indoLe side, oO b denotes a hydrogen atom and a and c together form a oo0 second bond between the carbons which bear them, A denotes a -CHCH 2 H-CH 2 chain and R denotes a 1,1-dimethylethyl SOH group, or the substituents R 1 and R form, with the nitrogen 0 0 atom to which they are attached, a group -N M-Z in which Z denotes a group -(CH 2 or a group X2 o o o-C in which groups n I can assume the values 1, 2 or 3 and X, X 1 X 2 X 3 X 4 X 5 and X 6 which may be identical or different, denote a hydrogen atom, an alkyL radical con- taining from 1 to 5 carbon atoms, an aLkoxy radical con- taining from 1 to 3 carbon atoms, a halogen atom, a nitro, amino, monoalkyLamino or dialkylamino radical, with the proviso that X, X 1 and X 2 do not all three denote a hydrogen atom, A denotes a chain -(CH2)n- in which n can assume the values 2, 3, 4 or 5 or a chain -(CH 2 )m-CH-CH 2 OH in which m can assume the values 1, 2 or 3, B denotes a k. .II -I-re ,I, 34 -CO-NH- or -NH-CO- chain, R 3 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 which is optionally substituted with an aLi- phatic 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 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 R 2 denotes a hydrogen atom, a Linear alkyL radical containing from 1 to 5 carbon atoms or a branched alkyL radical con- taining 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 radicals 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, as well as the addition salts thereof with inorganic or organic acids.

2. Compounds of formula as defined in Claim 1, in which the substituents R 1 and R form, with the nitrogen atom to which they are attached, a group Z-N N-in which Z has the above meaning, A denotes a -CH 2 -CH-CH 2 or OH -(CH2)3- or -(CH 2 4 chain, R 3 denotes a hydrogen atom, R 2 denotes a hydrogen atom or a methyl radical, b denotes a hydrogen atom and a and c together form a second bond between the carbons which bear them as well as the addi- tion salts thereof with inorganic or organic acids.

3. 2-C3-C(1,1-Dimethylpropyl)aminol-2-hydroxypropoxy}- N-(1H-indoL-4-yl)benzamide and its benzoate and its neutral oxalate.

4. 2-C3-C(1,1-Dimethylethyl)aminol-2-hydroxypropoxy>- 35 N-(1-methyl-IH-indol-4-yL)benzamide and its hydrochloride. 2-{2-Hydroxy-3-C(1,1,3,3-tetramethylbutyl)aminol- propoxy}-N-(1H-indol-4-yL)benzamide and 2-{2-hydroxy-3-C4- (diphenyLmethyl)-1-piperazinyllpropoxy}-N-(IH-indoL-4-yl)- benzamide and its neutral oxalate.

6. Process for preparing derivatives as defined by the formuLa of Claim I, as well as the salts thereof, characterized in that a derivative of the formula (II): U f to OH 8 (II) in which B and R 3 have the meaning already stated and R 2 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 -(CH 2 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, O to obtain a derivative of formula (IV): (IV) in which B, R 2 and R 3 have the meaning already stated, and 4 -36- G' denotes a group of formula -(CH 2 )n-HaL in which n and Hal have the meaning already stated, or a group of formula -(CH 2 )n-CH-CH 2 defined above, which is reacted with an 0 amine of formula R H-N (V) in which R and R 1 have the meaning already stated, to obtain a product of formula (IA): <1* S<(IA in which A, B, R, R 1 R 2 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 R and R 1 form, with the nitrogen atom to which they are attached, a group -N N-Z in which Z has the meaning already stated, the corresponding product of formula (IB): N0 0 S(Ig) R2 in which A, B, R2, R 3 and Z have the meanings already stated, is subjected to the action of a halogenating agent to obtain a product of formula (VII): 37 B -(VII) I I R2 in which A, 8, R 2 R3 and Z have the meanings already I-A-W H z stated and Hal denotes a bromine or chLorine atom, which is subjected to a hydroLysis to obtain a compound of formuLa (Ic): in which A, B, R 2 R 3 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 c.R derivative of formuLa (VI): in which HaL, n, R and R 1 have the meaning aLready stated, to obtain the derivative of formuLa (IA) 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 R and R 1 form, with the nitrogen atom to which they are attached, a group -c o-Z in which Z has the meaning already stated, the corresponding pro- duct of formula (Is) is subjected to a haLogenating agent and then to a hydrolytic reagent to obtain the product -38- of formula which is isolated and, if desired, salified.

7. Medicinal products, characterised in that they consist of the new benzamide derivatives as defined by Claim 1, as well as the addition salts thereof with pharmaceutically acceptable acids.

8. Medicinal products, characterised 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 pharmaceutically acceptable acids.

9. Pharmaceutical compositions, characterised in that they contain, by way o 0o o° of active principle, at least one of the medicinal products as defined in one of 000 o Claims 7 and 8. S 10. By way of new industrial compounds, the compounds of formula (VII) o. as defined in Claim 6.

11. A compound of formula as claimed in any one of Claims 1 to substantially as hereinbefore described with reference to any one of Examples 1 to

22. o0 12. Processes claimed in Claim 6, substantially as hereinbefore described, O 00 S with reference to any one of Examples 1 to 22. 0 0o I3. A pharmaceutical composition as claimed in Claim 9, substantially as 0 hereinbefore described with reference to either Examples 23 or 24. 0 S D A T E D this 19th day of February 1991 ROUSSEL-UCLAF By its Patent Attorneys:' CALLINAN LAWRIE i r x