FI85140B - PROCEDURE FOR FRAMSTATING AV NYA THERAPEUTIC ANVAENDBARA N- (1H-INDOL-4-YL) -BENAMIDE DERIVATIVES. - Google Patents

Abstract

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

Description

! 85140

Process for the preparation of new therapeutically useful N- (1H-indol-4-yl) -benzamide derivatives

The invention relates to a process for the preparation of new derivatives of N- (1H-indol-4-yl) -5-benzamide and their salts.

Derivatives of N- (1H-indol-4-yl) -benzamide are disclosed in EP Application Publication No. 213984 (= FI Application No. 862909). These derivatives correspond to the following general formula: wherein R and, independently of one another, denote a hydrogen atom, a linear alkyl radical having 1 to 5 carbon atoms, a branched alkyl radical having 3 to 5 carbon atoms, 3-7 a cycloalkyl radical containing 4 to 7 carbon atoms, a cycloalkylalkyl radical having 4 to 7 carbon atoms or an aralkyl radical having 7 to 12 carbon atoms optionally substituted by 1, 2 or 3 radicals selected from halogen and methyl, ethyl, methoxy, ethoxy , trifluoromethyl, methyl, amino or nitro radicals, or R and Rx together form a saturated or unsaturated heterocycle which may contain another heteroatom which may be an oxygen, sulfur or nitrogen atom, this nitrogen atom being optionally substituted by 1-5 an alkyl radical, a phenyl radical, a substituted phenyl or naphthyl radical, or With an aralkyl radical having 7 to 12 carbon atoms, R3 represents a hydrogen radical of 2 85140 atoms, an alkyl radical having 1 to 5 carbon atoms, an alkoxy radical having 1 to 3 carbon atoms, a chlorine, bromine or iodine atom, a nitro radical or an amino radical optionally substituted by 2 to 5 carbon atoms With an aliphatic acyl group or an alkyl radical having 1 to 5 carbon atoms, a together with b represents an oxy group, or c represents a carbon-carbon bond, b represents a hydrogen atom or together with a represents an oxy group, c represents a hydrogen atom or together with a with a carbon-10 li-carbon bond, A represents a - (CH2) n-chain, where n can have the values 2, 3, 4 or 5 or a - (CH2) n -CH-CH2-chain,

OH

wherein m may have the values 1, 2 or 3, B represents a -CO-NH- or -NH-CO- chain, R2 represents a hydrogen atom, a linear alkyl radical having 1 to 5 carbon atoms or a branched alkyl radical having 3 to 5 carbon atoms.

The disclosed compounds have interesting pharmacological properties and in particular considerable anti-arrhythmic properties. The invention relates to novel compounds within the general formula of this EP patent which have particularly interesting anti-arrhythmic properties.

The invention relates to a process for the preparation of therapeutically useful N- (1H-indol-4-yl) -benzamide derivatives of the formula (I) and to their acid addition salts, e.g.

35 H

ii 3 85140 wherein X represents a hydrogen atom or an alkoxy radical having 1 to 3 carbon atoms, and Y represents a hydrogen atom, a chlorine, bromine or iodine atom, a nitro radical or an amino radical optionally substituted by an aliphatic acyl group having 2 to 5 carbon atoms or one or two alkyl radicals having 1 to 5 carbon atoms.

When X represents an alkoxy radical, it is a methoxy, ethoxy, n-propoxy or isopropoxy radical.

When Y represents an amino radical substituted by an aliphatic acyl group having 2 to 5 carbon atoms, it is preferably an amino radical which is preferably substituted by an acetyl or propionyl radical.

When Y represents an amino radical substituted by one or two alkyl radicals, these are preferably methyl or ethyl radicals.

Addition salts of mineral or organic acids may be formed, for example, with hydrochloric acid, bromine-hydrogen, nitrogen, sulfur, phosphorus, acetic acid, ant, propionic, benzoic, maleic, fumarine, amber, wine , citric, oxalic, glyoxalic and aspartic acids, alkanesulfonic acids such as methane and ethanesulfonic acids, arylsulfonic acids such as benzene and paratoluenesulfonic acids and arylcarboxylic acids.

The invention relates in particular to the preparation of compounds of formula (I) as defined above, in which X represents a methoxy radical and Y represents a hydrogen atom or Y represents a chlorine atom, a nitro-, amino- or acetylamino-radical and X represents a hydrogen atom, as well as their acid addition salts, and in particular Preparation of 2- [3 - [(1,1-dimethylethyl) amino] -2-hydroxypropoxy] -N- (1H-indol-4-yl) -5-nitrobenzamide and its acid addition salts.

4,85140

The process according to the invention is characterized in that the compound of formula (II)

A

/ ^ 0 (II)

H-N

, o

B

wherein X and Y are as defined above, is reacted with a halide of formula (III) 15

Hal-CH0-CH-CH_ (III)

Z \ / Z

O

to give a compound of formula (IV) 20 X

Yx f 0-CH2-CH-CHo s. V / 2 <IV) 25 ho 0 H — li όφ

B

Which is reacted with tert-butylamine to give a compound of formula (I) which, if desired, is reacted with a mineral or organic acid to give a salt.

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

The reaction between compounds of formulas (II) and (III) is preferably carried out in the presence of a base such as potassium or sodium carbonate, NaOH or KOH.

When Y represents a nitro group in a compound of formula (I), Hal preferably represents a bromine atom in a compound of formula (III). The reaction is carried out by heating the compound of formula (IV) while refluxing.

The reaction between the derivative of formula (IV) and tert-butylamine is carried out using an aliphatic alcohol such as methanol or ethanol as the solvent.

When it is desired to prepare a compound of formula (I) in which Y represents an optionally substituted amino radical, a compound of formula (I) in which Y represents a nitro radical may be reduced and, if desired, the amino derivative is reacted with the derivative of the substituent to be obtained.

Corresponding working conditions are well known.

The starting material of the compound of formula (II) can be prepared by the reaction between 4-aminoindole and X- or Y-substituted hydroxybenzoic acid.

The derivatives obtained according to the invention have very interesting pharmacological properties; in particular, they have remarkable antiarrhythmic properties and some compounds have anticalcic properties.

These properties are described later in the experimental section.

These properties support the use of N- (1H-indol-4-yl) -benzamide derivatives of formula (I) as well as their salts as medicaments.

6 85140

Of particular interest among the medicaments according to the invention are those consisting of novel derivatives of N- (1H-indol-4-yl) -benzamide of the formula (I) in which X represents a methoxy radical and Y represents a hydrogen atom or Y represents a chlorine atom, a nitro- , an amino or acetylamino radical and X represents a hydrogen atom, as well as their acid addition salts.

Of these, 2- [3 - [(1,1-dimethylethyl) amino] -2-hydroxypropoxy] -N- (1H-10 indol-4-yl) -5-nitrobenzamide as well as its acid addition salts are of particular interest.

The medicaments according to the invention are used, for example, in the treatment of arrhythmias and pain.

The usual dose, which varies according to the derivative used, the subject to be treated and the cause of the disease, may be, for example, 50 mg to 1 g / day. The derivative of Example 1 can be administered to a patient orally in a daily dose of, for example, 200 mg to 800 mg, for the treatment of ventricular, supraventricular and junction arrhythmias, i.e. 3 mg to 12 mg / kg body weight.

Derivatives of formula (1) as well as their pharmaceutically acceptable acid addition salts can be used in the preparation of pharmaceutical compositions containing them as active ingredient.

The pharmaceutical derivatives of the invention and their pharmaceutically acceptable acid addition salts may be combined with pharmaceutical compositions intended for administration digitally or parenterally.

These pharmaceutical compositions can be, for example, solid or liquid substances and can be present in all pharmaceutical forms commonly used in human medicine, such as, for example, ordinary or coated tablets, capsules, granules, suppositories, injectables; and are prepared by methods similar to talc 7,85140. The active ingredient (s) may be mixed with conventional carriers used in pharmaceutical compositions, such as talc, acacia, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous media, animal or vegetable fats, various paraffinic derivatives, glycine derivatives, dispersing or emulsifying agents and preservatives.

The following examples illustrate the invention without limiting it in any way.

Example 1 2 - [, 3 - ["(1,1-Dimethylethyl) amino] -2-hydroxypropoxy] N- (1H-indol-4-yl) -5-nitrobenzamide and its hydrochloride A solution of 9.8 g of 2- hydroxy-5-nitro-N- (1H-3-indol-4-yl) -benzamide and 40 cm of epibromohydrin Excess epibromohydrin is removed under reduced pressure at 60 ° C, the resin obtained is taken up and dissolved in 100 ml of ethanol and 40 cm: The excess solvent and reagent are removed under reduced pressure at 60 [deg.] C. to give 78 g of crude product. -triethylamine-1, second: eluent: chloroform-5-acetone-4-triethylamine-1) 4.4 g of the compound as a base are obtained, m.p. = 208 ° C.

Hydrochloride formation 3.5 g of the base obtained above are dissolved in a liter of isopropanol and 250 cm 2 of methanol by refluxing, ethyl acetate saturated with hydrochloric acid is added to the solution until the pH is on the acid side. The solution is heated at reflux for 30 minutes, concentrated to about 500 cm, cooled in ice, filtered and dried under reduced pressure at 50 ° C. 2.85 g of the expected compound are obtained, m.p. = 260 ° C. .

β 85140

Analysis:

Calculated: C% 57.08 H% 5.88 N% 12.10 Cl% 7.66 Found: 56.8 6.1 12.0 7.4 2-hydroxy-5-nitro-N- (1H-indole Preparation of 4-yl) -benzamide 5 3

A solution of 6 g of 4-aminoindole, 150 cm of tetrahydrofuran, 8.4 g of 5-nitrosalicylic acid and 12.5 g of dicyclohexylcarbodiimide is heated at reflux for 3 hours. The solution is cooled, filtered, 200 cm <2> of ethyl acetate are added, the excess 4-aminoindole which has not reacted by washing with 1N hydrochloric acid is removed, dried, filtered and evaporated to dryness under reduced pressure at 50 ° C. 20 g of resin are obtained, which is dissolved in a mixture of chloroform and methanol (50/50), filtered, dried under reduced pressure to give 7.5 g of the desired compound, m.p. > 260 ° C. Example 2 5-Amino-2- [3 - [(1,1-dimethylethyl) amino] -2-hydroxypropoxy] -N- (1H-indol-4-yl) benzamide 3

A mixture of 142 g of the compound of Example 1, 5 cm 3 of methanol, a pinch of Raney nickel and 0.2 cm of hydrazine hydrate is heated at reflux for 1 hour. The mixture is filtered, the methanol is removed under reduced pressure at 50 ° C to give 128 mg of the desired compound.

UV Spectrum: 25 ethanol:

Max 219 nm E11 = 443

Max 310 nm = 230

in ethanol, HCl N

O: 10 30 Max 299 nm E11 = 208 £ = 8 200

Infl .: 275 and 332 nm Example 3 5-Acetylamino-2 / 3H-1,1-dimethylethylamino-2-hydroxy-propoxy-N- (1H-indol-4-yl) -benzamide and its neutral oxalate

Step A: 5-Amino-2-hydroxy-N- (1H-indol-4-yl) -: benzamide 9,85140

A mixture of 6 g of the 5-nitro-2-hydroxy-N- (1H-indol-4-yl) -benzamide prepared in Example 1, 600 cm -1 of methanol and 15 cm of 64% hydrazine hydrate is heated at reflux for 2 hours with 6 g of Roney. With nickel.

The resulting solution is filtered, the solvent is removed under reduced pressure at 50 ° C, the residue is taken up in a mixture of chloroform and methanol (1-1), the crystallized compound is filtered off, dried to give 4 g of the desired compound, m.p. > 260 ° C.

Step B: 5-Acetylamino-2-acetoxy-N- (1H-indol-4-10 yl) -benzamide 2.6 g of the compound prepared in the previous step in 70 g of tetrahydrofuran are cooled to 0 / + 5 ° C,

O

followed by the addition of 4.7 cm of acetic anhydride, and the solution is kept at ambient temperature for 3 hours. The solvent is removed under reduced pressure at 50 ° C, the residue is taken up in a mixture of chloroform and methanol (1-1), filtered and, after drying at 80 ° C, 2.7 g of the desired compound are obtained, m.p. = 263 ° C.

False C: 5-Acetylamino-2-hydroxy-N- (1H-indol-4-20yl) -benzamide

To a solution of 1.5 g of the compound obtained above and 150 cm of methanol are added 1.5 g of boron and sodium hydride at ambient temperature, and the mixture is heated under reflux for 2 hours. The methanol is partially removed under reduced pressure at 50 [deg.] C., the mixture is diluted with 200 cm <3> of water and 3,200 cm <3> of ethyl acetate and then extracted with ethyl acetate. The solution is dried, the solvents are removed under reduced pressure at 50 ° C to give 1.35 g of the desired compound, which is used as such in the next step.

Step D: 5-Acetylamino-2 - [(2-oxiranyl) methoxy] -N- (1H-indol-4-yl) -benzamide - · A solution of 3.5 g of the compound prepared in Step C: , 150 cm of acetone, 1.6 g of potassium carbonate and 9 cm of epibromohydrin are heated at reflux for 2 hours. 9 cm of epibromohydrin 10 85-40 are added to the solution again and refluxing is continued for 20 hours. The solution is filtered, washed with acetone, the solvent is removed under reduced pressure at 50 ° C, the residue is taken up in ether, filtered and dried at 80 ° C to give 3.4 g of the expected compound, m.p. = 5 230 ° C.

Step E: 5-Acetylamino-2- [3 - [(1,1-dimethylethyl) amino] -2-hydroxypropoxy] - (1H-indol-4-yl) benzamide and its neutral oxalate

A solution of 3.4 g of the compound obtained above in 3 3 10 200 cm of ethanol and 20 cm of terbutylamine is heated at reflux for one hour. The solvents are removed under reduced pressure at 50 ° C, and the residue is purified by silica gel chromatography (eluent: chloroform-methanol-triethylamine 8-1-1) to give 3.9 g of the desired base.

Preparation of oxalate 2.7 g of base are dissolved in 200 cm @ 3 of ethanol and 330 mg of oxalic acid are added. The solution is filtered, dried at 80 ° C under reduced pressure to give 2.2 g of the desired oxalate, m.p. > 260 ° C.

Analysis: C24HN2O1.1/2 C2H2O4: 423.549 Calculated: C% 62.10 H% 6.46 N% 11.59

Found: 61.9 6.2 11.5

Example 4 2- [3- [E (1,1-Dimethylethyl) amino] -2-hydroxypropoxy] -N- (1H-indol-4-yl) -4-methoxybenzamide and its benzoate Step A: 4-Methoxy-2- [ 1- (2-Oxiranyl) methoxy-N- ... N- (1H-indol-4-yl) -benzamide

Proceed as in step D of Example 3 using • -: 5 g of 4-methoxy-2-hydroxy-N- (11-indol-4-yl) -benzamide, • 3 3::: 30 150 cm acetone, 2.45 g potassium carbonate and 14 cm epichlorohydrin. 7.3 g of the expected compound are obtained, m.p. = 157 ° C.

Step B: 2- [3 - [(1,1-dimethylethyl) amino] -2-hydroxypropoxy] N- (1H-indol-4-yl) -4-methoxybenzamide and its benzoate

Proceed as in Example 3, Step E, using 6 g of the compound prepared in Step A above, 100 cm 3 of ethanol, 9.2 cm of terbutylamine, and reflux the mixture for 3 hours. 6.1 g of the desired base are obtained, which is dissolved in 300 cm of isopropanol under reflux, after which a further 1.8 g of benzoic acid are added. The solution is partially concentrated, cooled with ice, filtered, dried under reduced pressure to give 5.1 g of the desired benzoate. Sp. = 195 ° C in ethanol after recrystallization.

Analysis: C 23 H 29 N 3 O 4 · C 7 H 6 O 2: ^ 33.629 10 Calculated: C% 67.53 H% 6.61 N% 7.87

Found: 67.5 6.7 8.0 Preparation of 4-methoxy-2-hydroxy-N- (1H-indol-4-yl) -benzamide used as starting material for Example 4 3

A solution of 3.96 g of 4-amino-1H-Indola, 70 cm 3 of tetrahydrofuran, 5 g of 2-hydroxy-4-methoxybenzoic acid and 6.2 g of dicyclohexylcarbodiimide is heated under reflux for 24 hours. The solvents are removed under reduced pressure at 50 ° C, the residue is taken up in ethyl acetate and the unreacted 4-aminoindole is removed by washing with 2N hydrochloric acid. The ethyl acetate is removed under reduced pressure, the residue is taken up in ether and dried at 50 ° C. 7.1 g of the expected compound are obtained, m.p. = 190 ° C.

Example 5 5-Chloro-2/3 - [(1,1-dimethylethyl) amino] -2-hydroxy-25-propoxy) -N-1- (1H-indol-4-yl) -benzamide and its neutral oxalate

Step A: 5-Chloro-1 - [(2-oxiranyl) methoxy] -N- (1H-indol-4-yl) -benzamide

Proceed as in Example 3, Step D using 3 g of 5-chloro-2-hydroxy-N- (1H-indol-4-yl) -benzamide, 3,100 cm of acetone, 1.47 g of potassium carbonate and 8.3 cm of epichlorohydrin. 3.35 g of the expected compound are obtained, m.p. = 1 75 ° C.

12 85 1 40

Step B: 5-Chloro-2- [3 - [(1,1-dimethylethyl) amino] -2-hydroxypropoxy] N- (1H-indol-4-yl) benzamide and its neutral oxalate

Proceed as in Example 3, Step E, using 3 5 3 g of the compound obtained in Step A, 60 cm of ethanol and 3 4.6 cm of terbutylamine. 2.6 g of the desired base are obtained, followed by 2.4 oxalate, m.p. > 260 ° C.

Analysis: C22H26ClN3O3 '1/2 C2H2O4: 460'941 Calculated: C% 59.93 H% 5.90 N% 9.12 Cl% 7.69 10 Found: 60.2 5.8 9.1 7, Preparation of 5-chloro-2-hydroxy-N- (1H-indol-4-yl) -benzamide used as starting material in Example 5

A solution of 3.96 g of 4-amino-1H-Indola in 75 cm of tetrahydrofuran and 5.16 g of 5-chlorosalicylic acid and 6.2 g of dicyclohexylcarbodiimide is heated at reflux for 2 hours; 0.62 g of dicyclohexylcarbodiimide are added again, the mixture is refluxed for a further 1 hour, cooled, filtered and the solvents are removed under reduced pressure at 50 ° C. The residue is taken up in ethyl acetate, washed with 2N hydrochloric acid, dried and the ethyl acetate is removed under reduced pressure at 50 ° C. Silica gel chromatography after purification (eluent: chloroform-ethyl acetate 9-1) gives 3.9 g of the desired compound, m.p. = 248 ° C.

Example 6 Extrudates have been prepared according to the following recipe: * "50 mg of the compound of Example 1 --- excipient q.s. to a final extrudate of 100 mg (Excipient in particular: lactose, starch, talc magnesium stearate).

Pharmacological Study 1. Antiarrhythmic effect in rats from male rats weighing 300-350 g who were sleep -1. intraperitoneally at a dose of 1.20 g / kg urethane, the trachea was opened and placed in a ventilator (40-50 in 3 ml inhalation / min).

il 13 8 5 1 40

Needles were placed intradermally to record the electrocardiogram of rats from the DII lead signal.

Test compounds were administered intravenously or orally.

Five minutes after intravenous administration, 10 pg / ml of 0.2 ml of aconitine solution is instilled into the jugular vein of rats and the time of onset of cardiac arrhythmias is observed (10 pg of aconitine corresponds to 0.2 ml of solution perfusion).

10 Results are expressed as the percentage increase in the time to onset of cardiac arrhythmias relative to control animals and as a function of test compound dose. The results shown in the table below show that the compounds of the appended claim have good antiarrhythmic properties.

Example Dose Elongation of time compound_mg / kg_%% 1 2.5 +77% 20 1 +39% 0.5 +17% 4 2.5 +38% 1 +10% • 25 2. Experiment to determine the anticalcetic effect in vitro! " cut rat tail arteries were pooled and maintained in containers containing 25 ml Krebs-sodium bicarbonate buffer (NaCl; 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 ° C and in a gas mixture of 02: 95% - CO 2: 5%.

The preparations were depolarized with a buffer solution containing 100 mM K1 ions (NaCl: 26.7 mM: 100 mM,

MgCl 2: 1.2 mM, NaH 2 PO 4: 1.2 mM, NaHCO 3: 15.5 mM,; glucose: 12.6 mM).

14 85 1 40

Add 250 μl: η of calcium chloride to give an increasing series of solutions with a Ca + 2 ion concentration between 0,1 and 3,0 mM; the concentrations in the arteries are determined and 5 reference sets are also prepared. The experiment was repeated with a Ca + ion series every 15 min and the preparation was washed four times, after each series.

When a stable value is obtained, a test with a series of Ca + ions is performed at different concentrations of the test compound when a stable value is reached.

Concentrations in the arteries depend on the entry of Ca 2+ ions into smooth muscle cells and are affected by depolarization of smooth muscle caused by K + ion and noradrenaline released from presynaptic levels.

15 By repeating the experiment with arteries treated with 6-OH

dopamine, the effect of noradrenaline itself is blocked.

The results are expressed as the CI 50 value (inhibitory concentration 50) as the concentration of test compound that inhibits 50% of the concentration caused by K + ions.

Based on the results in the table below, it is found that the compounds according to the appended claim have a strong anticalcolic effect.

25 • _ Example compound_Cl 50 / μΜ 4 8 5 5.4 30 3. Investigation of acute toxicity

The lethal dose of the compound of Example 1 LD 50 was estimated from the doses administered orally to mice.

:: 'The LDQ value is the maximum dose that -I- did not cause death in 7 days.

The LDQ value obtained is 200 mg / kg.

li

Claims (2)

A process for the preparation of therapeutically useful N- (1H-indol-4-yl) -benzamide derivatives of formula 5 (I) and acid addition salts thereof, X Y // ° Y -Y; CH 3 (D H. X is a hydrogen atom or an alkoxy radical having 1-3 carbon atoms, and Y represents a hydrogen atom, a chlorine, bromine or iodine atom, a nitro radical or an amino radical which is optionally substituted with an aliphatic acyl group containing 2-5 carbon atoms, or with one or two alkyl radicals containing 1-5 carbon atoms, characterized in that a compound of formula (II): α0 αι> Where X and Y are the same as above, reacted with a halogenide having the formula (III) 18 851 40 Hal-CH 2 -CH-CH 2 (III) 2 obtaining a compound of formula (IV): 5 X Yi x0-CH2-CH-CH2 O (IV) H-N όφ H 15 which is reacted with the tert-butyl amine to give a compound of formula (I) which is reacted, if desired, with a mineral acid or organic acid to obtain a site. 2. A process according to claim 1, characterized in that 2- [3 - [(1,1-dimethylethyl) amino] -2-hydroxypropoxy] -N- (1H-indole-4) is prepared. yl) -5-nitrobenzamide and acid addition salts thereof. li