DE3242344A1 - Novel alkylenediamino derivatives, their preparation and medicaments containing these compounds - Google Patents

Abstract

The present invention relates to novel alkylenediamino compounds of the general formula <IMAGE> in which A represents a group of the formula <IMAGE> or <IMAGE> R2 represents a hydrogen or halogen atom, an alkyl, amino, nitro, alkylamino, dialkylamino, trifluoromethyl, alkoxy, alkylthio, hydroxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl or cyclic alkyleneimino group, R3 represents a halogen atom, an alkoxy or alkanoylamino group or, together with R2, an alkylenedioxy group, R4 represents a hydrogen atom or an alkoxy group, R5 represents a halogen atom, an alkyl group, or a phenylureido, hydroxyl, alkoxy, alkylamino, dialkylamino or cyclic alkyleneimino group and R6 represents a hydrogen or halogen atom, or an alkyl or alkoxy group, B represents a group of the formula -CO-, -CH2-CO-, -CH2-CH2- or <IMAGE>, R1 represents a hydrogen atom, an alkyl, alkanoyl or alkoxycarbonylalkyl group or an imidazolylcarbonyl group and R represents a group of the formula <IMAGE> E represents an n-alkylene group which is optionally substituted by an alkyl group. G represents an n-alkylene group which is optionally substituted by an alkyl group, R7 represents a hydrogen atom, an alkyl group or an alkenyl group, R8 and R9, which can be identical or different, represent hydrogen or halogen atoms, alkyl or alkoxy groups, trifluoromethyl or cyano groups or R8, together with R9, represents an alkylenedioxy group and R10 represents a hydrogen atom, an alkyl, alkoxy, amino, alkylamino or ... Original abstract incomplete.

Description

New alkylenediamine derivatives, their production and

Medicaments containing these compounds The present invention relates to new alkylenediamino compounds of the general formula their addition salts, in particular their physiologically acceptable addition salts with inorganic or organic acids or bases and processes for their preparation. The new compounds have valuable pharmacological properties, in particular heart rate lowering effects.

In the above general formula I, A denotes a group of the formulas in which R2 is a hydrogen or halogen atom, an alkYlr amino, nitro, alkylamino, dialkylamino, trifluoromethyl, alkoxy, alkylthio, hydroxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl or cyclic alkyleneimino group with 4 to 3 carbon atoms in the alkylene part, R3 is a halogen atom, an alkoxy or alkanoylamino group or together with R2 an alkylenedioxy group with 1 or 2 carbon atoms, R4 is a hydrogen atom or an alkoxy group, R5 is a halogen atom, an alkyl group with 1 to 5 carbon atoms, a phenylureido, hydroxy, alkoxy, Alkylamino, dialkylamino or cyclic alkylenimino groups with 4 to 8 carbon atoms in the alkylene part and R6 represents a hydrogen or halogen atom, an alkyl or alkoxy group, where the above-mentioned groups in each alkyl part can each contain 1 to 3 carbon atoms, B a group of Formulas -CO-, -CH2-CO-, -CH2-CH2 - or R1 is a hydrogen atom, an alkyl, alkanoyl or alkoxycarbonylalkyl group each having 1 to 3 carbon atoms in the alkyl part or an imidazolylcarbonyl group and R is a group of the formula in which an n-alkylene group with 2 to 4 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, G is an n-alkylene group with 2 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, R7 is a hydrogen atom Alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms, R8 and g, which can be the same or different, hydrogen or halogen atoms, alkyl or alkoxy groups each with 1 to 3 carbon atoms, trifluoromethyl or cyano groups or Rs together with Rg is an alkylenedioxy group with 1 or 2 carbon atoms and R10 is a hydrogen atom, an alkyl, alkoxy, amino, alkylamino or dialkylamino group with 1 to 3 carbon atoms in each alkyl part.

For the definition of the radicals R1 to R10, E and G at the beginning The meanings mentioned come, for example, for R1 that of the hydrogen atom, the Methyl, ethyl, propyl, isopropyl, formyl, acetyl, propionyl, methoxycarbonylmethyl, Ethoxycarbonylmethyl, propoxycarbonylmethyl, 1-ethoxycarbonylmethyl, 2-ethoxycarbonylethyl or 3-ethoxycarbonylpropyl group, for R2 that of hydrogen, fluorine, chlorine or Bromine atoms of methyl, ethyl, propyl, isopropyl, amino, nitro, methylamino, Ethylamino, propylamino, dimethylamino, diethylamino, diisopropylamino, methylethylamino, Ethyl propylamino, trifluoromethyl, methoxy, ethoxy, isopropoxy, methylthio ' Ethylthio-, propylthio-, hydroxymethyl -, 1 -hydroxyethyl-, 1 -hydroxy-n-propyl-, 2-hydroxyethyl, 3-hydroxypropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, Propoxycarbonylmethyl-1-ethoxycarbonylethyl-, hydroxycarbonylmethyl-; 1-hydroxycarbonylethyl, Pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino or octamethyleneimino group, for R3 that of the fluorine, chlorine or bromine atom, the methoxy, ethoxy, propoxy, isopropoxy, Formylamino, acetylamino or propionylamino group or together with R2 the methylenedioxy or ethylenedioxy group, for R4 that of the hydrogen atom, the methoxy, ethoxy or propoxy group, for R5 that of the chlorine, bromine or iodine atom, the methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 3-phenyl-ureido, Hydroxy, methoxy, ethoxy, propoxy, methylamino, ethylamino, isopropylamino, Dimethylamino, diethylamino, dipropylamino, methyl-ethylamino, methyl-isopropylamino, Pyrrolidino, piperidino, hexamethyleneimino or octamethyleneimino group, for R6 that of the hydrogen, chlorine or bromine atom, the methyl, ethyl, isopropyl, Methoxy, ethoxy or propoxy group, for R7 that of the hydrogen atom, the methyl, Ethyl-, propyl-, isopropyl-, allyl-, butene- (2) -yl-, pentene- (2) -yl- or isobutene- (2) -yl group, for R8 or Rg that of the hydrogen, fluorine, chlorine or bromine atom, the methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, trifluoromethyl or Cyano group or for 8 together with Rg that of the methylenedioxy or ethylenedioxy group, for R10 that of the hydrogen atom, the methyl, ethyl, propyl, methoxy, ethoxy, isopropoxy, Amino, methylamino, ethylamino, propylamino, dimethylamino, diethylamino, Dipropylamino or ethyl propylamino group, for E that of the ethylene, n-propylene, n-butylene, 1-methylethylene, 2-ethyl-ethylene, 1-propyl-ethylene, 9-methyl-n-propylene, 2-methyl-n-propylene, 1-ethyl-n-propylene, 3-ethyl-n-propylene, 2-propyl-n-propylene or 2-methyl-n-butylene group and for G that of ethylene, n-propylene, n-butylene, n-pentylene, Methyl-ethylene, 2-methyl-ethylene, 1-propylethylene, 2-ethyl-ethylene, 1 1-methyl-n-propylene, 2-methyl-n-propylene, 3-methyl-n-propylene, 1-ethyl-n-propylene or 1-propyl-n-propylene group into consideration.

Another object of the present invention are new pharmaceuticals, containing a compound of the above general formula I or its physiological Compatible addition salt with an inorganic or organic acid or Base, and also the new physiologically compatible addition salts with inorganic ones or organic acids or bases of the compounds of the above general formula I, except N- / 3- / N'-methyl-N '- (2- (4-amino-3,5-dichlorophenyl) -ethyl) -amino / -propylU-2- (2-amino-4,5-dimethoxyphenyl) -ethylamine-hydrochloride.

Another preferred subject of the present invention are the new compounds of the above-mentioned general formula I, excluded but N-t3- / Ñ'-methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl] -amino] -propyl] -2- (2-amino-4,5-dimethoxyphenyl ) -acetamide, N- [3- [N'-methyl-N '- (2- (3,4-dimethoxy-phenyl) -amino7-propyl2-2- (2-amino-4,5-dimethoxyphenyl) -ethylamine and s-L3-LN '- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino / -propyl / -2- (2-amino-4,5-dimethoxyphenyl) - ethylamine and their addition salts, in particular their physiologically acceptable addition salts with inorganic or organic acids or bases.

Preferred compounds of the above general formula I, however, are those in which B is as defined at the outset, R1 is a hydrogen atom, a methyl, Acetyl, ethoxycarbonylmethyl or imidazolylcarbonyl group, R2 is a hydrogen, Chlorine or bromine atom, a methyl, trifluoromethyl, amino, methylamino, ethylamino, Propylamino, dimethylamino, piperidino, methoxy, methylthio, hydroxymethyl, Hydroxycarbonylmethyl or methoxycarbonylmethyl group, R3 a chlorine atom, a Methoxy or acetylamino or together with R2 the methylenedioxy group, R4 a hydrogen atom or a methoxy group, R5 a chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, a hydroxy, methoxy, ethoxy, 3-phenylureio or Octamethyleneimino group, R6 a hydrogen, chlorine or bromine atom, a methyl, Methoxy or ethoxy group, R7 is an alkyl group with 1 to 3 carbon atoms or an allyl group, R8 a hydrogen, chlorine or bromine atom, a methyl, trifluoromethyl or methoxy group, Rg is a hydrogen, fluorine, chlorine or bromine atom, a methyl or Methoxy group or R8 and Rg together the methylenedioxy group, R10 a hydrogen atom, a methyl, methoxy, amino or dimethylamino group, E and G each represent a straight-chain alkylene group having 2 to 4 carbon atoms, and their addition salts, in particular their physiologically acceptable addition salts with inorganic or organic acids or bases.

However, particularly preferred compounds of the above general formula I are those in which A is a group of the formulas in which a hydrogen atom, a methoxy or amino group and R5 is an isobutyl, tert-butyl, methoxy or ethoxy group, QH B a -CO-, -CH2-CH2- or -CH-CH2- group and R -a Group of formula in which R8 is a chlorine atom or a methoxy group, Rg is a chlorine atom or a methoxy group and R10 is a hydrogen atom, a methoxy or amino group, and their physiologically acceptable addition salts with inorganic or organic acids.

According to the invention, the new compounds of general formula I are obtained by the following process: a) For the preparation of compounds of general formula I in which R1 represents a hydrogen atom, an alkyl or alkoxycarbonylalkyl group with 1 to 3 carbon atoms in each alkyl part: reaction of a compound of general formula A - B - X, (in) in which A and B are defined as above and X represents a nucleophilic leaving group, or the lactone thereof optionally formed in the reaction mixture, if R2 is the hydroxymethyl group and B is the -CO- or -CH2-CO- group, with an amine of the general formula in which R is as defined at the outset and R1 'represents a hydrogen atom, an alkyl or alkoxycarbonylalkyl group having 1 to 3 carbon atoms in each alkyl part.

If B in a compound of the general formula II means the -CO- and -CH2CO- group, then comes as a nucleophilic leaving group for the remainder X, for example a chlorine or bromine atom, a methoxy, ethoxy, phenoxy, benzyloxy, methylthio, Ethylthio, acetoxy, benzoyloxy, imidazolyl or ethoxycarbonyloxy groups into consideration.

If B in a compound of the general formula II is -CH2-CH2 - or Group, the nucleophilic leaving group for the radical X is, for example, a chlorine, bromine or iodine atom, a sulfonyloxy group such as the methanesulfonyloxy or p-toluenesulfonyloxy group.

The reaction is expediently carried out in a solvent such as methylene chloride, Chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, Acetonitrile or dimethylformamide, optionally in the presence of an inorganic one Base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which can also serve as a solvent, and optionally in the presence of an activating and / or dehydrating agent at temperatures between -25 and 2500C, but preferably at temperatures between -100C and the boiling point of the solvent used. Here needs a functional derivative of a possibly formed in the reaction mixture Compound of the general formula II not to be isolated, furthermore, the reaction can also be carried out without a solvent. Furthermore, during the implementation water produced by azeotropic distillation, e.g. by heating with toluene on the water separator or by adding a drying agent such as magnesium sulfate or molecular sieve are separated.

As activating and / or dehydrating agents, for example a chloroformic acid ester such as ethyl chloroformate, thionyl chloride, phosphorus trichloride, Phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-carbonyldiimidazole, a phosphate such as diethyl chlorophosphonate or bis (o-nitrophenyl) phenylphosphonate, a phosphorane such as (2,2,2-trifluoroethoxy) triphenylphosphorane, an N-alkyl-pyridinium salt such as N-methyl-2-chloro-pyridinium iodide or N-methyl-2-fluoropyridinium tosylate, N, N'-dicyclohexyl-carbodiimide / 4-dimethyl aminopyridine or chlorosulfonyl isocyanate.

b) For the preparation of compounds of the general formula I in which B is the -CH2-CH2 group, R1 is a hydrogen atom or an alkyl group, R2 is not a nitro group and R3 is not an alkanoylamino group: Reduction of a compound of the general formula in which A, R1 and R are as defined at the outset and B 'represents the -CH2CO group.

The reduction is preferably carried out in a solvent such as diethyl ether, Tetrahydrofuran or dioxane with a suitable metal hydride such as lithium aluminum hydride or diborane at temperatures between 0 and 100 ° C., but preferably at temperatures between 25 and 850C.

c) For the preparation of compounds of the general formula I in which R5 is an alkoxy, alkylamino, dialkylamino or cyclic alkyleneimino group and R6 is a hydrogen atom, an alkyl or alkoxy group: Reaction of a compound of the general formula in which B, R1 and R are as defined at the outset and A 'denotes a pyridine radical in which one of the radicals 5 or R6 has the meanings mentioned for R 5 and R6 and the other of the radicals Rg 5 or R 6 is a nucleophilic leaving group such as represents a halogen atom or an alkylthio group, for example a chlorine or bromine atom, a methylthio or ethylthio group, with a compound of the general formula Ii - R5, (VI) in which R5 'is an alkoxy, alkylamino, dialkylamino or cyclic alkyleneimino group having 4 to 8 carbon atoms, wherein the above-mentioned alkyl parts can each contain 1 to 3 carbon atoms.

The reaction is carried out in a solvent such as xylene, if appropriate in the presence of an alkali salt of a compound of the general formula VI at increased Temperatures, e.g. at temperatures between 50 and 1750C, but preferably at the boiling point of the solvent used. The implementation however, it can also be carried out without a solvent.

d) For the preparation of compounds of general formula I in which B is the Group represents: Reductive amination of a compound of the general formula A - CO - CHO, (VII) in which A is as defined at the outset, which may be formed in the reaction mixture, with an amine of the general formula in which R is as defined at the outset and R1 'represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

The reaction is expediently carried out in a suitable solvent or mixed solvents such as methanol, ethanol or dioxane at temperatures between 0 and 100 ° C., but preferably at temperatures between 20 and 80 ° C., carried out.

The reductive amination in the presence is particularly advantageous a complex metal hydride such as sodium borohydride, lithium or sodium cyanoborohydride preferably at a pH of 6-7 and at room temperature, or in the presence a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium / carbon at a hydrogen pressure of 5 bar.

e) For the preparation of compounds of the general formula I in which R1 is a hydrogen atom and R2 in the o-position is a hydroxycarbonylmethyl radical: hydrolysis of a compound of the general formula in which R, R3 and R as The reaction takes place in an aqueous solvent, for example

in water, ethanol / water, isoropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 50 and 1000C, but preferably in the presence of an alkali base and at the boiling temperature of the reaction mixture.

If a compound of the general formula is obtained according to the invention I, in which R1 is a hydrogen atom, R2 is an amino or alkylamino group, R3 is a fIydroxygruppe, 5 a hydroxy or alkylamino group, R7 a hydrogen atom and / or R10 represents an amino or alkylamino group, this can be achieved by means of alkylation, Acylation and / or by means of N, N'-carbonyldiimidazole into a corresponding compound of the general formula I, in which R1 is an alkyl, alkanoyl or imidazolylcarbonyl group, R2 is an alkylamino or dialkylamino group, R3 is an alkoxy or alkanoylamino group, R5 is an alkoxy or dialkylamino group, R7 is an alkyl or alkenyl group and / or R10 represents, converts and / or obtains an alkylamino or dialkylamino group a compound of the general formula I in which R2 represents a nitro group, this can be converted into a corresponding amino compound by means of reduction and / or a compound of the general formula I is obtained in which R2 is a hydroxycarbonylalkyl group represents, this can be converted into a corresponding alkoxycarbonylalkyl compound by esterification of the general formula I convert.

Post-alkylation is carried out with an alkylating agent, e.g. Methyl iodide, dimethyl sulfate, ethyl iodide or propyl bromide in the presence of an acid-binding agent By means of or with an aldehyde in the presence of a reducing agent, e.g.

with formaldehyde / formic acid or sodium cyanoborohydride, at temperatures carried out between 0 and 1200C.

The subsequent acylation is carried out with acylating agents such as N, N'-carbonyl-diimidazole, Acetyl chloride, acetic anhydride or propionic anhydride, which at the same time also can serve as a solvent, optionally in a solvent such as water / tetrahydrofuran, Diethyl ether, tetrahydrofuran or methylene chloride, optionally in the presence a base such as triethylamine or pyridine, with a tertiary organic base at the same time can also serve as a solvent, at temperatures between 0 and 100 ° C, preferably but carried out at room temperature. The reaction can also be carried out without a solvent be performed.

The subsequent reduction is expediently carried out in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid with hydrogen in the presence a catalyst such as platinum or palladium / carbon at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, or with Raney nickel / hydrazine and at temperatures between 0 and 750C, but preferably at temperatures between 20 and 500C.

The subsequent esterification is expediently carried out in a suitable Solvent, e.g. in an appropriate alcohol, pyridine, toluene or dioxane, in the presence of an acid-activating and / or dehydrating agent such as thionyl chloride, Hydrogen chloride, ethyl chloroformate, N, N'-dicyclohexylcarbodiimide or N, N'-carbonyldiimidazole or by transesterification, e.g. with a corresponding carbonic acid diester, at temperatures between 0 and 50 ° C., but preferably at room temperature.

The compounds of general formula I obtained can be also in their addition salts, especially in their physiologically compatible ones Salts with inorganic or organic acids or bases if R2 is a hydroxycarbonylalkyl radical represents, convict. The acids here are, for example, hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, Maleic acid or fumaric acid and, as bases, sodium hydroxide, potassium hydroxide or cyclohexylamine into consideration.

The compounds of the general formulas used as starting materials II to VIII are partially known from the literature or they are obtained from those known from the literature Procedure.

For example, a compound of the general formula is obtained in this way II by reacting a corresponding hydroxy compound with a corresponding one Halogenating agent, a compound of the general formula IV by conversion the corresponding acetic acid into the corresponding amide, a compound of the general Formula V by alkylation or

Acylation of a corresponding amine, a compound of the general Formula VII by selenium dioxide oxidation of a corresponding aceto compound and a compound of the general formula VIII by appropriate alkylation of a corresponding benzazepine derivative (see European patent application No. 82 103 931.0).

As already mentioned at the beginning, the new compounds have the general Formula I and their physiologically acceptable acid addition salts with inorganic or organic acids or bases have valuable pharmacological properties, in particular a heart rate lowering effect and a reduction in the 02 requirement of the heart. In addition, some of these are valuable intermediate products for production of the compounds described in European application 82 103 931.0, in particular when R2 is an amino, hydroxycarbonylmethyl or alkoxycarbonylmethyl group in the o-position represents.

For example, the compounds A = 2,4,5-trimethoxy-benzoic acid-3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propylamide, B = 2-chloro-4, S-dimethoxy-benzoic acid-3-tÑ-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl] -amino] -propylamide, C = 2-methoxy-4-methylmercapto-benzoic acid-3-N-methyl-N (2- (3,4-dimethoxy-phenyl) -ethyl) -amino9-propylamide, D = 2-tert-butyl-pyridine-4-carboxylic acid-3-N-methyl-W- (2- (3,4-dimethoxyphenyl) -ethyl) -aminog-propylamide, E = 2-isobutyl-pyridine-4-carboxylic acid-3-tN-methyl-N- (2- (3, 4-dimethoxyphenyl) -ethyl] -amino] -propylamide, F = 2-ethoxypyridine-4-carboxylic acid-3- / t-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino) -propylamide, G = N- [3- [N'-methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propy-2- (4, 5-dimethoxyphenyl) -ethylamine-dihydrochloride and H Lö- = '-Methyl-N' - (2- (3,4-dimethoxyphenyl) -ethyl) -amino / -propylU-2-hydroxy- 2- (4,5-dimethoxyphenyl) -ethylamine-dihydrochloride examined for their biological properties as follows: 1. Effect on heart rate on cats: The effect of the substances under investigation on the heart rate was per dose on 4 to 7 cats of both sexes of average weight from 2.5-3.5 kg examined. For this the cats were with Chloralose (80 mg / kg IV) anesthetized. The substance to be examined was in aqueous solution injected into the saphenous vein.

The heart rate was recorded before and after administration of the substance with the help of a Grass tachograph from the electrocardiogram (chest wall recording) on a Grass polygraph: The following table contains the values found: Substance dose, mg / kg iv heart rate duration of action reduction in% (half-life, min) A 5 - 47 40 B 5 - 23 15 C 5-35 30 D 5 - 44 30 E 5 - 31 30 F 5 - 34 20 2. Effect on the heart rate in guinea pig atria: Isolated spontaneously beating atria from guinea pigs of both sexes with a body weight of 300-400 g were examined in an organ bath in Tyrode's solution. The nutrient solution was supplied with Carbogen (95% 02 + 5% CO 2) and kept constant at 37 ° C. The contractions were recorded isometrically using a strain gauge on a Grass polygraph. The substances to be examined were added to the organ baths in various concentrations.

The following table shows the EC30, the dose at which a 30% reduction in heart rate was graphically determined on the average of 4 atria: Substance EC30 teg / ml7 A 1.9 B 3.3 C 0.52 D 0.87 E 1.4 F 1.5 G 0.29 H 0.24 The compounds prepared according to the invention have no toxic side effects in therapeutic doses.

For example, after intravenous administration of the substances Even in a high dose of 20 mg / kg in mice, G and H did not have any toxic side effects to be observed.

Because of their pharmacological properties, they are suitable according to the invention manufactured compounds for the treatment of sinus tachycardias of various origins and for the prophylaxis and therapy of ischemic heart diseases.

The dosage required to achieve an appropriate effect is expediently 0.10 to 1.5 mg / kg body weight two to four times a day, preferably 0.2 to 1.0 mg / kg body weight. For this purpose, according to the invention prepared compounds of general formula I and their physiologically acceptable Acid addition salts with inorganic or organic acids, optionally in Combination with other active substances, together with an or several inert usual carriers and / or thinners, e.g. with corn starch, Lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, Citric acid, tartaric acid, water, water / ethanol, water / glycerine, water / sorbitol, Water / polyethylene glycol, propylene glycol, carboxymethyl cellulose or fatty ones Substances such as hard fat or their suitable mixtures in common pharmaceutical preparations such as tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, juices or work in suppositories.

The following examples are intended to explain the invention in more detail: example 1 2,4,5-Trimethoxy-benzoic acid-3-t-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amineq / -propylamide a) 2,4,5-Trimethoxybenzoyl chloride A suspension of 4.2 g (0.02 mol) of 2,4,5-trimethoxybenzoic acid 3 ml of thionyl chloride are added in 10 ml of chloroform and then 2 hours refluxed. The resulting solution is concentrated in vacuo.

Yield: 4.6 g (100 e of theory) b) 2,4,5-trimethoxy-benzoic acid-3-tN-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminq / -propylamide A solution of 4.6 g of 2,4,5-trimethoxybenzoyl chloride is obtained while cooling with ice in 10 ml of methylene chloride at 15-20 ° C. to a solution of 5.05 g (0.02 mol) of 3-tN-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino-propylamine and 2.8 ml (0.02 mol) of triethylamine in 20 ml of methylene chloride were added dropwise and one Stirred at 20 ° C. for 0 hour. It is then extracted several times with water, over Magnesium sulfate and dried over silica gel with methylene chloride and increasing Part of ethanol purified.

Yield: 4.2 g (47.2% of theory), -1 IR spectrum (methylene chloride): 1640 cm (CO) C24H34N206 (446.6) Calc .: C 64.55 H 7.67 N 6.27 Found: 64.80 7.35 6.33 example 2 2-Chloro-4,5-dimethoxy-benzoic acid-3-t-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino-propylamide 3.25 g (0.015 mol) of 2-chloro-4,5-dimethoxy-benzoic acid are dissolved in 42 ml of absolute tetrahydrofuran dissolved and 2.7 g (0.0165 mol) of N, N'-carbonyldiimidazole were added. After 2 hours Stirring at room temperature, 3.8 g (0.015 mol) of 3-EN-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) amino] propylamine are added to the crude solution, dissolved in 5 ml of absolute tetrahydrofuran, added dropwise and at 20 ° C. for a further 3 hours touched. After the formation of a white, finely crystalline precipitate, the batch becomes concentrated in a rotary evaporator, dissolved in methylene chloride, extracted with sodium hydroxide solution and washed with water washed. The organic phase is dried over magnesium sulfate and over aluminum oxide Purified with methylene chloride and increasing proportions of ethanol.

Yield: 3.2 g (47.5% of theory) IR spectrum (methylene chloride): 1650 cm (CO) C23 31 2 5 (451.0) Calc .: C 61.25 H 6.93 Cl 7.86 N 6.21 Found: 60.94 6.89 8.23 6.04 Example 3 2-Methoxy-4-methylmercapto-benzoic acid-3- / N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl] -amino] -propylamide Prepared analogously to the example ib by reacting 2-methoxy-4-methylmercapto-benzoyl chloride with 3- / N-methyl-N- (2 (3, 4-dimethoxyphenyl) -ethyl) -aminoJ-propylamine Yield: 48.8% of theory, Melting point: 64-66 ° C Example 4 5-Bromo-2,4-dimethoxy-benzoic acid 3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino7-propylamide Prepared analogously to Example 2 by reacting 5-bromo-2,4-dimethoxy-benzoic acid with 3-8N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino / propylamine.

Yield: 47.5% of theory, melting point: 82-83 ° C. Example 5 2,4,5-trimethoxy-benzoic acid-N-z3-N'-methyl-NE- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propyl] -N-methyl-amide Prepared analogously to Example 1b by reacting 2,4,5-trimethoxy-benzoyl chloride with 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propyl-N'-methylamine.

Yield: 26.1% of theory, IR spectrum (methylene chloride): 1625 cm 1 (CO) C25 36 2 6 (460.6) Calc .: C 65.20 H 7.88 N 6.08 Found: 65.27 7.83 6.06 Example 6 4,5-dimethoxy-2-methylmercapto-benzoic acid-3-tÑ-methyl-N- (2- (3, 4-dimethoxyphenyl) -ethyl) -aminq / -propylamide Prepared analogously to Example 2 by reacting 4,5-dimethoxy-2-methylmercapto-benzoic acid with 3-LN-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino / -propylamine.

Yield: 32.6% of theory, IR spectrum (methylene chloride): 1640 cm (CO) 24 34 2 5 (462.6) Calc .: C 62.31 H 7.41 N 6.06 S 6.93 Found: 61.91 7.25 5.98 6.90 Example 7 2,4-Dimethoxy-benzoic acid 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminq / -propylamide Prepared analogously to Example 2 by reacting 2,4-dimethoxybenzoic acid with 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino2-propylamine.

Yield: 53.0% of theory, -1 IR spectrum (methylene chloride): 1640 cm -1 (CO) C23H32N205 (416.5) Calc .: C 66.32 H 7.74 N 6.73 Found: 66.27 7.46 6.28 Example 8 5-Chloro-2- (piperidyl-1) -benzoic acid-3-N-methyl-N- (2- (3,4-dimethoxyphenyl) -ettyl) -amino-propylamide Prepared analogously to Example 2 by reacting 5-chloro-2- (piperidyl-1) benzoic acid with 3- / N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino / propylamine.

Yield: 49.2% of theory, IR spectrum (methylene chloride): 1650 cm (CO) C26H36ClN303 (474.1) Calcd .: C 65.88 H 7.65 Cl 7.48 N 8.86 Found: 65.88 7.16 7.63 8.74 Example 9 4-Acetamino-2-methoxy-benzoic acid-3-EN-methyl-N- (2 <3, 4-dimethoxyphenyl) -ethyl) -aminq / -propylamide Manufactured analogously to the example 2 by reacting 4-acetamino-2-methoxy-benzoic acid with 3-LN-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino-propylamine.

Yield: 76.2% of theory, -1 IR spectrum (methylene chloride): 1640 cm (CO) C24H33N305 (443.5) calc. : C 64.99 H 7.56 N 9.47 Found: 64.93 7.16 9.37 Example 10 4,5-Dimethoxy-2-nitro-benzoic acid-3-t-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -aminog-propylamide Prepared analogously to Example 2 by reacting 4,5-dimethoxy-2-nitro-benzoic acid with 3-LN-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino7-propylamine.

Yield: 65.0% of theory, IR spectrum (methylene chloride): 1660 cm -1 (CO) 23 31 3 7 (461.5) Calc .: C 60.00 H 6.78 N 9.13 Found: 60.30 7.03 9.05 example 11 2-Amino-4,5-dimethoxy-benzoic acid 3- / N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino2-propylamide 4.6 g (0.01 mol) 4,5-dimethoxy-2-nitro-benzoic acid-3-ßN-methyl N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminoJ-propylamide, dissolved in 300 ml of ethanol, are at room temperature hydrogenated for 8 hours under a hydrogen pressure of 5 bar in the presence of Raney nickel. The catalyst is filtered off, and the filtrate is concentrated in vacuo and passed over silica gel Purified with methylene chloride and increasing proportions of ethanol.

Yield: 2.74 g (63.7 units of theory), -1 IR spectrum (methylene chloride): 1640 cm (CO) C23H 33N305 (431.5) Calc .: C 64.02 H 7.71 N 9.74 found: 63.95 7.79 9.30 Example 12 4,5-Dimethoxy-2-N, N'-dimethylamino-benzoic acid 3- / N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amineQ / -propylamide 4.3 g (0.01 mol) of 2-amino-4,5-dimethoxy-benzoic acid-3-tÑ-methyl-N-t2- (3,4-dimethoxyphenyl) -ethyl) -amino-propylamide, 8 ml (0.1 mol) of 40% strength aqueous formaldehyde solution and 1.9 g (0.03 mol) of sodium cyanoborohydride in 40 ml of acetonitrile are mixed with 1 ml of acetic acid at room temperature for 10 minutes offset. After stirring for 2 hours, a further 1 ml of acetic acid is added dropwise. 30 minutes is stirred, diluted with 150 ml of diethyl ether, 3 times with 40 ml of 1 molar Potassium hydroxide solution and extracted once with 40 ml of water and dried over magnesium sulfate. The filtrate is concentrated in vacuo and over aluminum oxide with methylene chloride and increasing proportion of ethanol purified.

Yield: 1.4 g (30.4% of theory), IR spectrum (methylene chloride): 1650 cm (CO) C25 37 3 5 (459.6) Calc .: C 65.34 H 8.11 N 9.14 Found: 65.63 7.87 9.07 Example 13 3,4-Dimethoxyphenylacetic acid-3-t-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino / -propylamide Prepared analogously to Example 2 by reacting 3,4-dimethoxyphenylacetic acid with 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminog-propylamine.

Yield: 50.0% of theory, IR spectrum (methylene chloride): 1660 cm (CO) C24H34N205 (430.5) Calc .: C 66.95 H 7.96 N 6.50 Found: 66.66 7.83 6.54 Example 14 N- ~ 3- / N'-methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -amino / -propylL-2- (4t5-dimethoxyphenyl) -ethylamine-d-hydrochloride 12.9 g (0.03 mol) of 3,4-dimethoxyphenylacetic acid 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminol-propylamide are dissolved in 400 ml of absolute tetrahydrofuran and at room temperature under nitrogen for 45 minutes with 180 ml of a one molar solution of diborane in tetrahydrofuran offset. It is stirred for 26 hours at 200 ° C. and, after addition of 60 ml, 6 molar Hydrochloric acid concentrated in vacuo. The approach is based on concentrated sodium hydroxide solution Adjusted to pH 9 and extracted 3 times with 200 ml of methylene chloride each time. The organic Phase is over magnesium sulfate dried, concentrated in vacuo and the residue obtained over alumina with methylene chloride and increasing Part of ethanol purified. The product obtained in this way is dissolved in acetone and with ethereal hydrochloric acid precipitates the dihydrochloride.

Yield: 7.35 g (50.1% of theory), melting point: 189-190.50C Example 15 N-Acetyl-N-L3- / Ñ'-methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -amineJ-propyl2-2- (4,5-dimethoxyphenyl) - ethylamine 1.67 g (0.004 mol) N- / 3- / N'-methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -amino / -propyl / -2- (4.5 -dimethoxyphenyl) -ethylamine are dissolved in 10 ml (0.1 mol) of acetic anhydride and stirred at 200C for 2 hours. It is adjusted to pH 9 with saturated potassium carbonate solution, with methylene chloride extracted, dried over magnesium sulfate and concentrated in vacuo.

Yield: 1.1 g (58.5% of theory), IR spectrum (methylene chloride): 1640 cm 1 (CO) m / e = 458 Example 16 N- [3- [N'-Methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propyl] -2 -hydroxy-2- (4,5-dimethoxyphenyl) -ethylamine dihydrochloride 2.52 g (0.014 mol) of 3,4-dimethoxyacetophenone are dissolved in 12 ml of dioxane and 0.7 ml of water dissolved, 1.63 g (0.0147 mol) of selenium dioxide were added and the mixture was refluxed for 2 hours. The residue is filtered off with suction, the filtrate with 3.53 g (0.014 mol) of 3- / N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino7-propylamine Stirred for one hour at 35 ° C, diluted with 100 ml of absolute ethanol, 2.0 g (0.053 Mol) sodium borohydride added and 12 hours at room temperature touched. Remaining sodium borohydride is destroyed with acetone and then in vacuo constricted. The residue obtained is dissolved in methylene chloride, extracted with water, dried over magnesium sulfate and over alumina with methylene chloride and increasing Part of ethanol purified. The product obtained in this way is dissolved in acetone and with ethereal hydrochloric acid precipitates the hydrochloride.

Yield: 1.7 g (23.9% of theory), melting point: 172-1750C Example 17 2- (1-Phenyl-ureido-3) -pyridine-3-carboxylic acid 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propylamide Prepared analogously to Example 2 from 2-phenyl-ureido-pyridine-3-carboxylic acid and 3-tN-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminog-propylamine.

Yield: 16% of theory, C26 33 5 4 (479.6) Calcd .: C 65.12 H 6.94 N 14.60 Found: 64.54 6.50 14.62 Example 18 2-tert-Butyl-pyridine-4-carboxylic acid-3- / N-methyl-N- (2- (3,4-dimethoxyphenyl ) -ethyl) -amino] -propyiantide Prepared analogously to Example 2 from 2-tert-butyl-pyridine-4-carboxylic acid and 3-rN-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino / -propylamine.

Yield: 54.6% of theory, C24 35 3 3 (413.6) Calc .: C 66.79 H 8.64 N 9.74 Found: 67.05 8.01 10.14 Example 19 2-Isobutyl-pyridine-4-carboxylic acid 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propylamide Prepared analogously to Example 2 from 2-isobutyl-pyridine-carboxylic acid and 3- / N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino / propylamine.

Yield: 74.2% of theory, 24 35 3 3 (413.6) Calc .: C 66.79 H 8.64 N 9.74 Found: 66.60 8.40 10.10 Example 20 2-Ethoxypyridine-4-carboxylic acid 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -amino / -propylamide Prepared analogously to Example 2 from 2-ethoxypyridine-4-carboxylic acid and 3- / N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminoJ-p ropylamine.

Yield: 57.5% of theory, C22H31N304 (401.5) calc .: C 65.81 H 7.78 N 10.47 Found: 65.60 7.60 10.16 Example 21 2-Chloro-pyridine-3-carboxylic acid 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -amino / -propylamide Prepared analogously to Example 2 from 2-chloro-pyridine-3-carboxylic acid, 3- / N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminoU-propylamine.

Yield: 83.3% of theory, C20H26C1N303 (391.9) calc .: C 61.29 H. 6.68 N 10.72 Cl 9.05 Found: 60.85 6.28 10.37 9.90 Example 22 2-Octamethyleneimino-pyridine-3-carboxylic acid-3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminoJ-propylamide 3.5 g (8.9 mmol) of 2-chloro-pyridine-3-carboxylic acid 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) ) amino / propylamide and 7 g (55 mmol) of octamethyleneimine are heated to 130 ° C. for 3 hours. The excess Octamethyleneimine is distilled off in vacuo. The remaining crude product will Purified over silica gel.

Yield: 1.7 g (22.2% of theory), 28 42 4 3 (482.7) calc .: C 64.84 H 7.92 N 9.42 Found: 64.60 7.70 9.27 Example 23 2-Hydroxy-6-methyl-pyridine-3-carboxylic acid 3- [N-methyl-N- (2- (3 , 4-dimethoxy-phenyl) -ethyl) -amino-propylamide Prepared analogously to Example 2 from 2-hydroxy-6-methyl-pyridine-3-carboxylic acid and 3-8N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminol-propylamine.

Yield: 13.5 * of theory, C21H29N304 (387.5) calc .: C 62.20 H 7.71 N 10.31 Found: 61.90 7.59 10.00 Example 24 2-Chloro-6-methyl-pyridine-3-carboxylic acid-3-tN-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propylamide Prepared analogously to Example 2 from 2-chloro-6-methyl-pyridine-3-carboxylic acid and 3- [N-methyl-N- (2-3,4-dimethoxyphenyl) -ethyl) -amino-propylamine.

Yield: 51.4% of theory, C21H28C1N303 (405.9) calc .: C 61.14 H. 6.95 N 10.35 Cl 8.73 Found: 61.25 6.99 10.75 8.29 Example 25 4,6-dichloropyridine-3-carboxylic acid-3- / Ñ-methyl-N- ( 2- (3,4-dimethoxyphenyl) ethyl) amino] propylamide Prepared analogously to Example 2 from 4,6-dichloropyridine-3-carboxylic acid and 3- / N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) amino / propylamine.

Yield: 61.2% of theory, C20H25C12N303 x HCl (462.8) calc .: C 51.90 H 5.66 N 9.08 Cl 22.98 Found: 51.72 5.59 9.40 22.85 Example 26 4,6-Diethoxypyridine-3-carboxylic acid-3- / N-methyl -N- <2- <3, 4-dimethoxy-phenyi) -ethyl) -aminoJ-propylamide To a solution of Sodium ethylate, prepared from 0.7 g (14.6 mmol) of sodium hydride (50% in bl) in 50 ml of absolute xylene and 1.83 ml of absolute ethanol, a suspension of 1.3 G (3.05 mmol) 4,6-dichloro-pyridine-3-carboxylic acid-3- / N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminog-propylamide given. The reaction mixture is refluxed for 3 hours and then concentrated to dryness. The residue is taken up in methylene chloride with water washed and the methylene chloride phase after drying over sodium sulfate Evaporated dry. The crude product obtained is over silica gel with ethyl acetate / ethanol / conc. Ammonia (90: 10: 0.5) purified.

Yield: 1.1 g (80% of theory), C24H35N305 (445.6) found: C 64.50 H 7.70 N 8.77 Calc .: 64.70 7.92 8.42 Example 27 2-Hydroxymethyl-4,5-dimethoxy-phenylacetic acid-3-L-methyl-N- (2- (3, 4-dimethoxyphenyl) -ethyl) -amino-proD [lamid 6.2 g (0.03 mol) 6,7-dimethoxy-isochroman-one-2 and 7.6 g methyl-N- (2- (3, 4 Dimethoxy-phenyl) -ethyl) -amino-propylamine are in 100 ml of ethanol for 4 hours refluxed. The solvent is distilled off in vacuo and the residue Purified by column chromatography on silica gel.

Eluant: methylene chloride + 1% ethanol.

Yield: 10.3 g (74.6% of theory) (viscous b1) -1 IR spectrum (Methylene chloride): 3600 cm (OH) 1650 cm (CO) 1515 cm (Amid-II) Example 28 2-Nitro-4,5-dimethoxyphenyl acetic acid-3- / N-methyl-N- (2- (3, 4-dimethoxyphenyl) -ethyl) -amino] -propyiamide Prepared analogously to Example 2 from 2-nitro-4,5-dimethoxyphenylacetic acid and 3- / N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -aminol-propylamine.

Yield: 94.6% of theory, melting point: 102-103 ° C. Example 29 N-imidazolyl-N- / 3- / Ñ'-methyl-N'-l2- (3,4-dimethOxy-phenyl) -ethyl) -amino] -propyl] -2- (2-n-propylamino-4,5-dimethoxyphenyl) -ethylamine 2.4 g (5 mmol) N- [3- [N'-methyl-N '- (2- (3,4-dimethoxyphenyl) - ethyl) -amino / -propyl / -2- (2-n-propylamino-4,5-dimethoxyphenyl) -ethylamine and 1.6 g (9.5 mmol) of N, N'-carbonyldiimidazole are in 100 ml of acetonitrile for 3 hours refluxed. The solvent is distilled off in vacuo, the residue dissolved in ethyl acetate and extracted 3 times with 2N sodium hydroxide solution and once with water. The organic phase is dried over magnesium sulfate, concentrated and dried over silica gel Purified with methylene chloride and 1% methanol.

Yield: 1.3 g (52% of theory), IR spectrum (methylene chloride): 3390-1 cm (NH) 2830 cm 1 (methoxyl) 2800 cm (N-alkyl) 1660 cm 1 (CO) Example 30 N- / 3- / '-Methyl-N' - (2- <3, 4-dimethoxyphenyl) -ethyl) -aminoJ-propylU-2- (2-amino-4,5-dLmethoxyphenyl) -ethylamine trihydrochloride To 0.8 g of lithium aluminum hydride in 150 ml of dioxane are added with stirring and reflux 4.5 g (10 mmol) of 2-amino-4,5-dimethoxyphenylacetic acid 3-tN-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino 2-propylamide, dissolved in 150 ml of dioxane, added dropwise. The suspension is refluxed for 6 hours heated and after cooling with water, 0.8 ml of 15% sodium hydroxide solution and then mixed with 2.4 ml of water. The precipitated hydroxide is suctioned off, washed with tetrahydrofuran and the filtrate concentrated in vacuo. The residue is purified over silica gel with methylene chloride and 10% methanol as the eluent. The trihydrochloride is precipitated from acetone by adding ethereal hydrochloric acid.

Yield: 2.5 g (46.3% of theory), melting point: 186-188 ° C. (decomp.).

Example 31 N-L3- / Ñ'-Methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -aminof-propylS-2- (2-carboxymethyl-4,5-dimethoxyphenyl) -ethylamine sodium salt 4.9 g (10 mmoles) of 1- / 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl / -3- / N-methyl-N - (2- (3, $ -dimethoxyphenyl) -ethylamino / -propane hydrochloride are in one Mixture of 60 ml of 25% sodium hydroxide solution and 50 ml of ethanol under reflux for 50 hours cooked. The alcohol is distilled off in vacuo and the aqueous-alkaline residue extracted several times with methylene chloride. The extract is made over magnesium sulfate dried, concentrated in vacuo. To remove the remaining starting material the residue is dissolved in water and 8 hours in a liquid extractor with Ether extracted. The aqueous solution is concentrated in vacuo.

Yield: 3.5 g (70.5% of theory), IR spectrum (methylene chloride): 1600 cm 1 (COO Example 32 N- / 3-LN'-methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -amino / -propyl / -2- (2-carbmethoxymethyl-4,5- dimethoxyphenyl) ethylamine dihydrochloride In a solution of 1.25 g (2.5 mmol) N- / 3- / Ñ'-methyl-N '- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyl] - 2- (2-hydroxycarbonyl-methyl-4,5-dimethoxyphenyl) -ethylamine, sodium salt hydrogen chloride is passed in under reflux in 100 ml of methanol for 3 hours. That Solvent is distilled off in vacuo, the residue in 15% sodium hydroxide solution dissolved and extracted with methylene chloride. The organic phase is separated washed with water, dried over magnesium sulfate and concentrated. The residue is purified over silica gel with methylene chloride + 3% methanol as the eluent. The dihydrochloride is precipitated from acetone with ethereal hydrochloric acid.

Yield: 850 mg (60.7% of theory), melting point: 144-1450C.

Example 33 N-Carbethoxymethyl-N-3, 4-dimethoxyphenacetyl-N'-methyl-N - / 2- (3,4-dimethoxyphenyl) -ethyS 3-diaminopropane Prepared analogously to Example 2 from 3,4-dimethoxyphenylacetic acid and N-carbethoxymethyl-N'-methyl-N'-t2- (3,4-dimethoxyphenyl) -ethyl / 1,3-diaminopropane.

Yield: 58.1% of theory, IR spectrum (methylene chloride): 2830 cm 1 (methoxyl) -1 2800 cm (N-alkyl) -1 1745 cm (ester-CO) 1645 cm (amide-CO) example 34 4,5-Dimethoxy-2-methyl-benzoic acid 3- [methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propylamide Prepared analogously to Example 1b by reacting 4,5-dimethoxy-2-methyl-benzoyl chloride with 3-LN-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino-propylamine.

Yield: 23.3% of theory, IR spectrum (methylene chloride): 1650 cm (CO) 24 34 2 5 Calc .: C 66.95 H 7.96 N 6.51 Found: 66.14 7.85 6.40 Example 35 N- / 3-eN'-methyl-N '- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino7-propy2-2- (2-amino-4,5-dimethoxy- phenyl) ethylamine hydrochloride Prepared analogously to Example 30 from 2-amino-4,5-dimethoxyphenylacetic acid 3- / N-methyl-N- (2- (4-amino-3,5-dichlorophenyl) -ethyl) -amino / propylamide and lithium aluminum hydride.

Melting point: 182-1880C (dec.).

Example 36 2-Amino-4,5-dimethoxyphenylacetic acid-3-8N-methyl-N- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amine / -proPylamide 12.7 g of 2-nitro-4,5-dimethoxyphenylacetic acid-3- / N-methyl-N- (2- (4-amino-3, 5-dichlorophenyl) -ethyl) -amino] -propylamide are dissolved in 150 ml of methanol in the presence of 2 g of Raney nickel hydrogenated at room temperature and 3 bar hydrogen pressure. Filter from the The catalyst is removed and the filtrate is concentrated in vacuo. The amine thus obtained is a bl; Yield: 12 g (100% of theory), -1 IR spectrum (methylene chloride): 1660 cm (CO-N # 3390, 3490 cm (NH2) W spectrum (ethanol): 242 nm (0.16) 300 nm (0.075) example 37 N-L3- / N'-methyl-N '- (3- (3,4-dimethoxyphenyl) -amine ~ / -propyl / -2- (2-carboxymethyl-4, 5-dimethoxyphenyl) ethylamine sodium salt Prepared analogously to Example 31 from 1- [7,8-dimethoxy-1,3,4, tetrahydro-2H-3-benzazepin-2-on-3-yl] -3- [N- methyl-N- (3- (3,4-dimethoxyphenyl) -propyl) -amino / -propane, Yield: 72.4% of theory, IR spectrum (methylene chloride): 1600 cm (COO).

Example I Tablets containing 40 mg of 2,4,5-trimethoxy-benzoic acid-3-8Ñ-methyl-N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -amino / -propylamide Composition: 1 tablet contains: Active ingredient 40.0 mg lactose 94.0 mg corn starch 40.0 mg polyvinylpyrrolidone 5.0 mg Magnesium stearate 1.0 mg 180.0 mg Manufacturing process: The active ingredient is mixed with milk sugar and corn starch and mixed with polyvinylpyrrolidone in water Solution moistened. The moist mass is passed through a sieve with 1.6 mm mesh size beaten and dried at 45 ° C. in a circulating air drying cabinet. The dry granules is passed through the same sieve again and mixed with magnesium stearate. the the finished mixture is compressed into tablets.

Tablet weight: 180 mg Tablet diameter: 8 mm Shape: biplane with facet on both sides and one-sided dividing notch.

Example II Dragees with 20 mg of 2,4,5-trimethoxy-benzoic acid-3-Ñ-methyl-N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -amino / -propylamide 1 tablet core contains: active substance 20.0 mg lactose 70.0 mg corn starch 25.2 mg Polyvinyl pyrrolidone 4.0 mq magnesium stearate 0.8 mg 120.0 mg Manufacturing process: The production of granules takes place analogously to Example I. The finished granules are compressed to form Draqee cores.

Core weight: 120.0 mg Core diameter: 7.0 mm Radius of curvature: 6.0 mm In a known manner, a layer consisting essentially of sugar is placed on the kernels and talc is applied. The finished tablet cores are polished with wax.

Example III Ampoules with 15 mg of 2,4,5-trimethoxy-benzoic acid-3-t-methyl-N- (2- (3Z4-dimethoxyphenyl) -ethyl) -amino / -propvlamide 1 ampoule contains: active substance 15.0 mg tartaric acid 4.0 mg polyethylene glycol 600 100.0 mg 1 N hydrochloric acid 0.2 mg water for injections ad 5.0 ml Manufacturing process: The active ingredient and additives are dissolved in water for injections, sterile filtered and filled into 5 ml ampoules.

Example IV Suppositories with 50 mo of 2,4, S-trimethoxy-benzoic acid-3- / N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -aminoU-proplamide 1 suppository contains: active substance 50.0 mg hard fat (e.g. Witepsol H 19 and Witepsol W 45) 1 450.0 mg 1 500.0 mg Manufacturing process: The hard fat is melted. At 38 ° C., the ground active substance is homogeneously dispersed in the melt. These is then cooled to 350C and poured into slightly pre-cooled molds.

Suppository weight: 1.5 g

Claims (24)

Patent claims 1. Alkylenediamino compounds of the general formula in which A is a group of formulas in which R2 is a hydrogen or halogen atom, an alkyl, amino, nitro, alkylamino, dialkylamino, trifluoromethyl, alkoxy, alkylthio, elydroxyalkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl or cyclic alkyleneimino group with 4 to 8 carbon atoms in the alkylene part, a halogen atom, an alkoxy or alkanoylamino group or together with R2 an alkylenedioxy group with 1 or 2 carbon atoms, R4 a hydrogen atom or an alkoxy group, R5 a halogen atom, an alkyl group with 1 to 5 carbon atoms, a phenylureido, hydroxy, Alkoxy, alkylamino, dialkylamino or cyclic alkyleneimino groups with 4 to 8 carbon atoms in the alkylene part and R6 represents a hydrogen or halogen atom, an alkyl or alkoxy group, where the above-mentioned groups in each alkyl part can contain 1 to 3 carbon atoms, B a group of the formulas -CO-, -CH2-CO-, -CH2-CH2- or R1 is a hydrogen atom, an alkyl, alkanoyl or alkoxycarbonylalkyl group each having 1 to 3 carbon atoms in the alkyl part or an imidazolylcarbonyl group and R is a group of the formula in which E is an n-alkylene group with 2 to 4 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, G is an n-alkylene group with 2 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, R7 is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms, R8 and Rg, which can be identical or different, hydrogen or halogen atoms, alkyl or alkoxy groups each with 1 to 3 carbon atoms, trifluoromethyl or cyano groups or R8 together with R9 represents an alkylenedioxy group having 1 or 2 carbon atoms and R10 represents a hydrogen atom, an alkyl, alkoxy, amino, alkylamino or dialkylamino group each having 1 to 3 carbon atoms in each alkyl part, and their addition salts. 2. alkylenediamino compounds of the general formula I according to claim 1, in which A, 8, R1 and R are as defined in claim 1, with the exception of N- / 13- / ~ N'-methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -aminoJ -propyl / -2- (2-amino-4,5-dimethoxyphenyl) -acetamide, N- [3- [N'-methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -amino7- propyl7-2- (2-amino-4,5-dimethoxyphenyl) -ethylamine and N- [3 N-93-N '- (2- (4-amino-3,5-dichlorophenyl) -ethyl) -amino / -propy17-2- (2-amino-4,5-dimethoxyphenyl) -ethylamine , and their addition salts. 3. alkylenediamino compounds of the general formula I according to claim 1, in which B is as defined in claim 1, R1 is a hydrogen atom, a methyl, Acetyl, ethoxycarbonylmethyl or imidazolylcarbonyl group, R2 a hydrogen, chlorine or bromine atom, a methyl, trifluoromethyl, amino, methylamino, Ethylamino, propylamino, dimethylamino, piperidino, methoxy, methylthio, hydroxymethyl, Hydroxycarbonylmethyl or methoxycarbonylmethyl group, R3 a chlorine atom, a Methoxy or acetylamino group or together with R2 the methylenedioxy group, R4 a hydrogen atom or a methoxy group, R5 a chlorine or bromine atom, an alkyl group with 1 to 4 carbon atoms, a hydroxy, methoxy, ethoxy, 3-phenylureido or Octamethyleneimino group, R6 a hydrogen, chlorine or bromine atom, a methyl, Methoxy or ethoxy group, R7 is an alkyl group with 1 to 3 carbon atoms or an allyl group, R8 a hydrogen, chlorine or bromine atom, a methyl, trifluoromethyl or methoxy group, Rg is a hydrogen, fluorine, chlorine or bromine atom, a methyl or Methoxy group or together with R8 the methylenedioxy group, R10 a hydrogen atom, a methyl, methoxy, amino or dimethylamino group, E and G each a straight chain Mean alkylene group having 2 to 4 carbon atoms, and their addition salts. 4. alkylenediamino compounds of the general formula I according to claim 1, in which A is a group of the formulas in which R2 is a hydrogen atom, a methoxy or amino group and R is an isobutyl, tert-butyl, methoxy or ethoxy group, B is a -CO-, -CH2-CH2- or Group and R a group of the formula represent in which R8 is a chlorine atom or a methoxy group, Rg is a chlorine atom or a methoxy group and R10 is a hydrogen atom, a methoxy or amino group, and their acid addition salts. 5. alkylenediamino compounds of the general formula I according to claim 4, in which A and B are as defined in claim 4, R8 in the 3-position is a methoxy group, Rg in the 4-position is a methoxy group and R10 is a hydrogen atom, and their acid addition salts. 6. 2,4, 5-Trimethoxy-benzoic acid-3- / N-methyl-N- (2- (3, 4-dimethoxyphenyl) -ethyl) -aminoJ-propylamide and its acid addition salts. 7. N-L3-N'-methyl-N '- (2- (3,4-dimethoxyphenyl) -ethyl) -aminoU-propyl7-2- (4,5-dimethoxyphenyl) -ethylamine and its acid addition salts. 8. N-L3- LN'-methyl-N'- (2- (3, Q-dimethoxyphenyl) -ethyl) -amine7-propylS-2-hydroxy-2- (4,5-dimethoxyphenyl) - ethylamine and its acid addition salts. 9. Physiologically acceptable addition salts of the compounds according to claims 1 to 8. 10. Physiologically acceptable addition salts of the compounds according to Claims 1 to 8, with the exception of N- / 3- / N'-methyl-N '- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino / -propylJ -2- (2-amino-4,5-dimethoxyphenyl) ethylamine hydrochloride. 11. Medicaments containing a compound of the general formula I according to Claims 1 to 8 or its physiologically acceptable addition salt according to claims 9 and 10 in addition to one or more inert carriers and / or Thinners. 12. Use of a compound of general formula I according to the Claims 1 to 8 or its physiologically acceptable addition salt qemaß den Claims 9 and 10 for the treatment of sinus tachycardias and for prophylaxis or Therapy of ischemic heart disease. 13. Process for the preparation of the compounds according to claims 1 to 10, characterized in that a) for the preparation of a compound of the general formula I in which R1 represents a hydrogen atom, an alkyl or alkoxycarbonylalkyl group having 1 to 3 carbon atoms in each alkyl part , a compound of the general formula A - B - X, (in) in which A and B are as defined at the outset and X represents a nucleophilic leaving group, or the lactone thereof optionally formed in the reaction mixture if R2 is the hydroxymethyl group in the o-position and B represent the -CO- or -CH2-CO- group, with an amine of the general formula in which R is as defined at the outset and R1 'represents a hydrogen atom, an alkyl or alkoxycarbonylalkyl group having 1 to 3 carbon atoms in each alkyl part, is reacted or b) for the preparation of a compound of general formula I in which B is -CH2-CH2 -Group, R1 is a hydrogen atom or an alkyl group, R2 is not a nitro group and R3 is not an alkanoylamino group, a compound of the general formula in which A, R1 and R are as defined at the outset and B 'represents the -CH2CO group, is reduced or c) for the preparation of a compound of the general formula I in which R5 is an alkoxy, alkylamino, dialkylamino or cyclic alkyleneimino group and R6 represent a hydrogen atom, an alkyl or alkoxy group, a compound of the general formula in which B, R1 and R are as defined at the outset and A 'denotes a pyridine radical in which one of the radicals R5 or R6 has the meanings mentioned for R5 and R6 and the other of the radicals R5 or R6 is a nucleophilic leaving group such as a halogen atom or represents an alkylthio group, with a compound of the general formula H - R5 ', (VI) in which R51 represents an alkoxy, alkylamino, dialkylamino or cyclic alkyleneimino group having 4 to 8 carbon atoms, the above-mentioned alkyl parts each having 1 to 3 carbon atoms may contain, is reacted or d) for the preparation of a compound of the general formula I in which B is the Group represents a compound of the general formula A - CO - CHO, (VII) in which A is as defined at the outset, with an amine of the general formula, which may be formed in the reaction mixture in which R is as defined at the outset and R1 'represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms, is reacted in the presence of a reducing agent or e) for the preparation of compounds of the general formula I in which R1 is a hydrogen atom and R2 in 0- Position represents a hydroxycarbonylmethyl radical, a compound of the general formula in which R, R3 and R4 are as defined at the outset, is hydrolyzed and, if desired, then a compound of the general formula I obtained according to the invention, in which R1 is a hydrogen atom, R2 is an amino or alkylamino group, R5 is a hydroxy or alkylamino group, R7 is a hydrogen atom and / or R10 represents an amino or alkylamino group, by means of alkylation, acylation and / or by means of N, N'-carbonyldiimidazole in a corresponding compound of the general formula I in which R1 is an alkyl, alkanoyl or imidazolylcarbonyl group, R2 is an alkylamino or Dialkylamino group, R3 is an alkoxy or alkanoylamino group, R7 is an alkyl or alkenyl group and / or R10 is an alkylamino or dialkylamino group and / or a compound of the general formula I in which R2 is a nitro group is converted into a corresponding amino compound is converted and / or a compound of the general formula I obtained in which R2 represents a hydroxycarbonylalkyl group, is converted into a corresponding alkoxycarbonylalkyl compound of the general formula I by means of esterification and / or a compound of the general formula I obtained in its addition salts, in particular in its physiologically acceptable salts with inorganic or organic acids or bases, if R2 represents a hydroxycarbonylalkyl radical, is convicted. 14. The method according to claim 13, characterized in that the implementation is carried out in a solvent. 15. The method according to claims 13a and 14, characterized in that that the reaction is carried out in the presence of an acid-binding agent. 16. The method according to claims 13a, 13 and 14, characterized in that that the reaction at temperatures between -25 and 2500C, but preferably at Temperatures between -100C and the boiling point of the solvent used, is carried out. 17. The method according to claims 13b and 14, characterized in that that the reduction is carried out with a suitable metal hydride. 18. The method according to claims 13b, 14 and 17, characterized in that that the reaction at temperatures between 0 and 100 ° C, but preferably at Temperatures between 25 and 850C. 19. The method according to claims 13c and 14, characterized in that that the reaction with an alkali salt of the compound used of the general Formula VI is carried out. 20. The method according to claims 13c, 14 and 19, characterized in that that the reaction at elevated temperatures, but preferably at temperatures between 50 and 1750C. 21. The method according to claims 13d and 14, characterized in that that the reaction in the presence of a complex metal hydride or with hydrogen is carried out in the presence of a hydrogenation catalyst. 22. The method according to claims 13d, 14 and 21, characterized in that that the reaction is carried out at room temperature. 23. The method according to claims 13e and 14, characterized in that that the hydrolysis is carried out in the presence of an acid or base. 24. The method according to claims 13e, 14 and 23, characterized in that that the hydrolysis at temperatures between 50 and 1000C, but preferably at the boiling point of the reaction mixture is carried out.