DE3522552A1 - Novel heteroaromatic amine derivatives, pharmaceuticals comprising these compounds, and their preparation - Google Patents

Abstract

The present invention relates to novel heteroaromatic amine derivatives of the general formula <IMAGE> in which A is a -CH2-CH2-, -CH=CH- or -CH2-CO- group and B is a methylene, carbonyl or thiocarbonyl group, or A is a -CO-CO- or <IMAGE> and B a methylene group, E is a straight-chain alkylene group which is optionally substituted by an alkyl group, G is a straight-chain alkylene group which is optionally substituted by an alkyl group, R1 is a hydrogen, chlorine or bromine atom, a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxyl, alkoxy or phenylalkoxy group, R2 is a hydrogen, chlorine or bromine atom, a hydroxyl, alkoxy, phenylalkoxy or alkyl group, or R1 and R2 together are an alkylenedioxy group, R3 is a hydrogen atom, an alkenyl, alkyl or phenylalkyl group and Het is a 5- or 6-membered heteroaromatic ring which contains one oxygen, sulphur or nitrogen atom, two nitrogen atoms or one nitrogen atom and one oxygen or sulphur atom and which is bonded via a carbon or nitrogen atom and to which additionally a phenyl ring can be fused, or an imidazo[1,2-a]pyridyl group in which the carbon skeleton of the abovementioned heteroaromatic radicals is [lacuna] by a halogen atom, an alkyl, hydroxyl, alkoxy, phenylalkoxy, phenyl, dimethoxyphenyl, nitro, amino, acetylamino, carbamoylamino, N-alkyl-carbamoylamino, ... Original abstract incomplete.

Description

The present invention relates to new heteroaromatic amine derivatives of the general formula their N-oxides, their acid addition salts, in particular their physiologically tolerable acid addition salts with inorganic or organic acids, processes for their preparation and medicaments containing these compounds.

The new compounds have valuable pharmacological properties, in particular a long-lasting heart rate-lowering effect and a reducing effect on the O ₂ requirement of the heart.

In the above general formula I means

A a

-CH ₂ -CH ₂ -, -CH = CH- or -CH ₂ -CO- group
5

and

B is a methylene, carbonyl or thiocarbonyl group or
A a and B is a methylene group,

E one optionally by an alkyl group with 1 to 3 Straight-chain alkylene group substituted by carbon atoms with 2 to 4 carbon atoms,

G is optionally an alkyl group with 1 to 3 Straight-chain alkylene group substituted by carbon atoms with 1 to 5 carbon atoms,

R _{1 is} a hydrogen, chlorine or bromine atom, a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxyl, alkoxy or phenylalkoxy group, where each alkyl moiety can contain 1 to 3 carbon atoms,

R _{2 is} a hydrogen, chlorine or bromine atom, a hydroxyl, alkoxy, phenylalkoxy or alkyl group, where each alkyl portion can contain 1 to 3 carbon atoms, or

R ₁ and R ₂ together represent an alkylenedioxy group with 1 or 2 carbon atoms,

R _{3 is} a hydrogen atom, an alkenyl group with 3 to 5 carbon atoms, an alkyl or phenylalkyl group, where the alkyl part can each contain 1 to 3 carbon atoms, and

Het one bound via a carbon or nitrogen atom 5- or 6-membered heteroaromatic ring, which one oxygen, sulfur or nitrogen atom, two nitrogen atoms or a nitrogen atom and an oxygen or Contains sulfur atom, and in addition a phenyl ring may be fused, or an imidazo [1,2-a] pyridyl group, in which the carbon skeleton of those mentioned above Residues by a halogen atom, an alkyl, hydroxy, Alkoxy, phenylalkoxy, phenyl, dimethoxyphenyl, nitro, Amino, acetylamino, carbamoylamino, N-alkylcarbamoylamino, Hydroxymethyl or alkoxymethyl group mono- or disubstituted or substituted by a methylenedioxy group can be and at the same time an existing one Imino group in the heteroaromatic mentioned above Residues by an alkyl, phenylalkyl or phenyl group may be substituted, those mentioned above Alkyl parts each contain 1 to 3 carbon atoms can.

For the meanings mentioned in the definition of the residues comes for example

for R ₁ that of hydrogen, fluorine, chlorine or bromine atom, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy , Methylthio, ethylthio, isopropylthio, nitro, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino , Methyl-n-propylamino, methyl-isopropalamino, ethyl-n-propylamino, benzyloxy, 1-phenylethoxy, 1-phenylpropoxy, 2-phenylethoxy or 3-phenylpropoxy group,

for R ₂ that of hydrogen, chlorine or bromine, methyl, ethyl, n-propyl, isopropyl, hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, benzyloxy, 1- Phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy or 3-phenylpropoxy group or together with R ₁ that of the methylenedioxy or ethylenedioxy group,

for R ₃ that of the hydrogen atom, the methyl, ethyl, n-propyl, isopropyl, benzyl, 1-phenylethyl, 2-phenylethyl, 1-phenylpropyl, 1-methyl-1-phenylethyl, 3 -Phenylpropyl, allyl, n-butene (2) yl or n-pentene (2) yl group and

for E the ethylene, n-propylene, n-butylene, 1-methyl-ethylene, 2-ethyl-ethylene, 1-propyl-ethylene, 1-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,

for G the methylene, ethylidene, n-propylidene, n-butylidene, 2-methyl-propylidene, ethylene, 1-methyl-ethylene, 2-ethyl-ethylene, 1-propyl-ethylene, 2-methyl-ethylene, n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, 1-methyl-n-butylene, 1-methyl-n-pentylene, 1-ethyl-n-propylene, 2-ethyl-n-propylene or 1-ethyl-n-butylene group and

for Het those of pyrrolyl-2, pyrrolyl-3, N-methyl-pyrrolyl 2-, N-methyl-pyrrolyl-3-, 1,2-dimethyl-pyrrolyl-3-, 2,5- Dimethyl-pyrrolyl-3-, furyl-2-, furyl-3-, 5-methyl-furyl-2-, 2-methyl-furyl-3-, 5-nitro-furyl-2-, 5-methoxymethyl- furyl-2-, benzo [b] furyl-2-, benzo [b] furyl-3-, 7-methyl-benzo [b] furyl-3-, 4-methoxy-benzo [b] furyl-3-, 5-methoxy benzo [b] furyl-3-, 6-methoxy-benzo [b] furyl-3-, 7-methoxy- benzo [b] furyl-3-, 5-methoxy-3-phenyl-benzo [b] furyl-2-, Thienyl-2-, thienyl-3-, 5-methyl-thienyl-2-, 3-methyl-thienyl-2-, 2,5-dimethylthienyl-3-, 5-chlorothienyl-2-, 5-bromothienyl-2-, 5-phenylthienyl-2-, 2-phenylthienyl-3-, Benzo [b] thienyl-2-, benzo [b] thienyl-3-, 2,5-dimethyl- benzo [b] thienyl-3-, 5-methyl-benzo [b] thienyl-3-, 5-chloro benzo [b] thienyl-2-, 5-bromo-benzo [b] thienyl-3-, 4-methoxy- benzo [b] thienyl-3-, 5-methoxy-benzo [b] thienyl-3-, 6-methoxy- benzo [b] thienyl-3-, 7-methoxy-benzo [b] thienyl-3-, 5,6-  Dimethoxy-benzo [b] thienyl-3-, 5,6-methylenedioxy- benzo [b] thienyl-3-, Pyrazolyl-1, pyrazolyl-3-, 3,5-dimethylpyrazolyl-1-, 1,5-dimethyl-pyrazolyl-3-, imidazolyl-1-, imidazolyl-2-, Imidazolyl-4-, imidazolyl-5-, 1-methyl-imidazolyl-4-, 1-benzyl-imidazolyl-4-, 5-nitro-2-methyl-imidazolyl-1-, 2- (3,4-dimethoxyphenyl) imidazolyl-5-, benzo [d] imidazolyl-1-, 2-benzyl-benzo [d] imidazolyl-1-, benzo [d] imidazolyl-2-, Imidazo [1,2-a] pyridyl-3, oxazolyl-4, oxazolyl-5, Isoxazolyl-3-, 3-methyl-isoxazolyl-5-, 5-methyl-isoxazolyl-3-, 3,5-dimethyl-isoxazolyl-4-, 4-methyl-thiazolyl-5-, Benzo [d] oxazolyl-2-, benzo [d] isoxazolyl-3-, benzo [d] thiazolyl-2-, 5-ethoxy-benzo [d] thiazolyl-2-, benzo [d] isothiazolyl-3-, Benzo [d] pyrazolyl-1, benzo [d] pyrazolyl-3, pyridyl-2-, Pyridyl-3, pyridyl-4, pyridyl-3-N-oxide, 4-nitro-pyridyl-2-, 4-amino-pyridyl-2-, 4-acetylamino-pyridyl-2-, 4-carbamoylamino-pyridyl-2-, 4-N-methyl-carbamoylamino-pyridyl-2-, 2-chloro-pyridyl-3-, 2-chloro-pyridyl-4-, 6-chloro-pyridyl-2-, 6-hydroxymethyl-pyridyl-2-, quinolyl-2-, isoquinolyl-1-, 2-methyl-quinolyl-4-, 7-methyl-quinolyl-2-, 4-chloro-quinolyl-2-, 6,7-dimethoxy-quinolyl-4-, 6,7-dimethoxy-isoquinolyl-4- or 6,7-dimethoxy-isoquinolyl-4-N-oxide Group considered.

However, preferred compounds are the compounds of the general formula in the

A a and B is a methylene group or

A represents a -CH ₂ -CH ₂ - or -CH = CH group and B represents a carbonyl or thiocarbonyl group.

E is an n-propylene group,

G is an ethylene or n-propylene group,

R _{1 is} a chlorine atom or bromine atom, a methyl, methoxy, nitro, amino, methylamino or dimethylamino group,

R _{2 is} a chlorine or bromine atom, a methyl or methoxy group or R ₁ and R ₂ together are a methylenedioxy or ethylenedioxy group,

R _{3 is} a hydrogen atom, a methyl or allyl group and

Het a pyrroyl-2-, pyrroyl-3-, N-methyl-pyrroyl-2-, N-methyl-pyrrolyl-3-, furyl-2-, benzo [b] furyl-2-, 7-methyl- benzo [b] furyl-3-, 6-methoxy-benzo [b] furyl-3-, 5-methoxy- 3-phenyl-benzo [b] furyl-2-, thienyl-2-, thienyl-3-, 5-methyl- thienyl-2-, 5-bromothienyl-2-, benzo [b] thienyl-3-, 6-methoxy benzo [b] thienyl-3-, 5,6-dimethoxy-benzo [b] thienyl-3-, 2,5-dimethyl-benzo [b] thienyl-3-, pyrazolyl-1, pyrazolyl-3-, 1,5-dimethyl-pyrazolyl-3-, imidazolyl-1, imidazolyl-4-, 1-methyl-imidazolyl-4-, 2- (3,4-dimethoxy-phenyl) imidazolyl-5-, Benzo [d] imidazolyl-1-, 2-benzyl-benzo [d] imidazolyl-1-, Imidazo [1,2-a] pyridyl-3, oxazolyl-4, oxazolyl-5, Isoxazolyl-3-, 3-methyl-isoxazolyl-5-, 4-methyl-thiazolyl-5-, Pyridyl-2, pyridyl-3, pyridyl-4-, pyridyl-3-N-  oxide, 4-nitro-pyridyl-2-, 4-amino-pyridyl-2-, 4-acetylaminopyridyl-2-, 4-carbamoylamino-pyridyl-2-, 4-N-methyl carbamoylamino-pyridyl-2-, 6,7-dimethoxy-quinolyl-4-, 6,7- Dimethoxy-isoquinolyl-4- or 6,7-dimethoxy-isoquinolyl- 4-N-oxide group, and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids.

Particularly preferred compounds of the above general Formula Ia, however, are those in which

A is a -CH ₂ -CH ₂ - or -CH = CH- and B is a carbonyl or thiocarbonyl group,

E is an n-propylene group,

G is an ethylene or n-propylene group,

R ₁ and R ₂ each represent a methoxy group or R ₁ and R ₂ together represent a methylenedioxy group,

R _{3 is} a hydrogen atom or a methyl group and

Het a pyrrolyl-2, pyrrolyl-3, N-methyl-pyrrolyl-2-, N-methyl-pyrrolyl-3-, thienyl-2-, thienyl-3-, 5-methyl-thienyl-2-, 5-bromothienyl-2-, pyrazolyl-1, pyrazolyl-3-, Imidazolyl-1-, isoxazolyl-3-, benzo [b] furyl-3-, 7-methyl- benzo [b] furyl-3-, 6-methoy-benzo [b] furyl-3-, benzo [b] thienyl-3-, 6-methoxy-benzo [b] thienyl-3-, 5,6-dimethoxy-benzo [b] thienyl-3-, Benzo [d] imidazolyl-1-, imidazo [1,2-a] pyridyl-3- or pyridyl group, and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids.

According to the invention, the new compounds are obtained according to the following Method:  

a) implementation of a compound of the general formula with a compound of the general formula

in the
A, B, E, G and Het are as defined in the beginning,
R ₁ 'represents a hydroxyl, amino or alkylamino group protected by a protective radical or has the meanings mentioned for R ₁ at the outset,
R ₂ 'represents a hydroxyl group protected by a protective radical or has the meanings mentioned for R ₂ at the outset,
one of the radicals U or V is the R ₃ 'NH group, where R ₃ ' represents a protective group for an amino group or has the meanings mentioned for R ₃ , and the other of the radicals U or V is a nucleophilic leaving group such as a halogen atom or represents a sulfonyloxy group, for example a chlorine, bromine or iodine atom, the methanesulfonyloxy, p-toluenesulfonyloxy or ethoxysulfonyloxy group, and, if appropriate, subsequent cleavage of a protective radical used.

As a protective residue for a hydroxy group, for example the trimethylsilyl, acetyl, benzoyl, benzyl or tetrahydropyranyl group and

as a protective residue for an amino or alkylamino group Acetyl, benzoyl, ethoxycarbonyl or benzyl group into consideration.  

The reaction is advantageously carried out in a solvent or solvent mixture such as acetone, diethyl ether, methylformamide, Dimethylformamide, dimethyl sulfoxide, benzene, chlorobenzene, Tetrahydrofuran, benzene / tetrahydrofuran, dixan or in an excess of the general compounds used Formulas II and / or III and optionally in the presence an acid binding agent, e.g. an alcoholate like Potassium tert-butoxide, an alkali hydroxide such as sodium or Potassium hydroxide, an alkali carbonate such as potassium carbonate, an alkali amide such as sodium amide, an alkali hydride such as Sodium hydride, a tertiary organic base such as triethylamine or pyridine, the latter at the same time can also serve as a solvent, or a reaction accelerator like potassium iodide depending on reactivity of the nucleophilically exchangeable radical is expedient at temperatures between 0 and 150 ° C, preferably at temperatures between 50 and 120 ° C, e.g. at the boiling temperature of the solvent used. The implementation can, however, also be carried out without a solvent will. However, the implementation in Presence of a tertiary organic base or an excess of the amine of the general formula III used carried out.

The subsequent subsequent splitting off of one used Protective residue is preferably hydrolytically in one aqueous solvents, e.g. in water, isopropanol / water, Tetrahydrofuran / water or dioxane / water, in the presence an acid such as hydrochloric acid or sulfuric acid or in the presence an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at the boiling point of the reaction mixture. The secession a benzyl radical, however, is preferably hydrogenolytic, e.g. with hydrogen in the presence of a catalyst like palladium / carbon in a solvent like methanol,  Ethanol, ethyl acetate or glacial acetic acid if necessary with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, preferably however from 3 to 5 bar.

b) For the preparation of compounds of the general formula I in which A is the —CH ₂ —CH ₂ group, B is the methylene or carbonyl group and R _{3 is} not an alkenyl group having 3 to 5 carbon atoms:

Hydrogenation of a compound of the general formula in the
R ₁ to R ₃ , E, G and Het are as defined above and B 'represents the methylene or carbonyl group.
The hydrogenation is carried out in a solvent or solvent mixture such as methanol, ethanol, ethyl acetate or glacial acetic acid with catalytically excited hydrogen, for example with hydrogen in the presence of platinum or palladium / carbon, at a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar, and at temperatures between 0 and 75 ° C, but preferably at temperatures between 20 and 50 ° C.

If an alkenyl group in a compound of the general formula IR ₃ means that during the reduction this is simultaneously converted into the corresponding alkyl group or R ₁ and / or R _{2 is} a benzyloxy group, this is converted into the corresponding hydroxy group during the reduction.

c) for the preparation of compounds of the general formula I, in which B represents a thiocarbonyl group:

Implementation of a compound of the general formula in the
R ₁ to R ₃ , A, E, G and Het as defined in the introduction, with a sulfur-introducing agent.

The implementation is carried out using a sulfur-introducing agent such as Phosphorus pentasulfide or 2,4-bis (4-methoxyphenyl) -1,3-dithia- 2,4-diphosphetane-2,4-disulfide expediently in a solvent such as toluene or xylene at temperatures between 50 and 150 ° C, e.g. at the boiling point of the reaction mixture, carried out.

d) for the preparation of compounds of the general formula I,
in the A one represents:
Reduction of a compound of the general formula in the
R ₁ to R ₃ , E, G and Het are as defined above.

The reaction is carried out in the presence of a suitable reducing agent such as a metal hydride, e.g. Sodium borohydride, in a suitable solvent such as water / methanol or Methanol / ether, at temperatures between 0 and 80 ° C, preferably however at temperatures between 15 and 40 ° C, carried out.

e) For the preparation of compounds of the general formula I in which A represents -CH ₂ -CH ₂ - or -CH = CH- and B represents a methylene group:

Reduction of a compound of the general formula in the
R ₁ to R ₃ , E, G and Het are as defined in the introduction and
A 'represents a -CH ₂ -CH ₂ - or -CH = CH group.

The reduction is preferably carried out with a metal hydride such as Lithium aluminum hydride or diborane or with a complex from borane and a thioether, e.g. with borane-dimethyl sulfide complex, in a suitable solvent such as diethyl ether or tetrahydrofuran at temperatures between 0 and 50 ° C, but preferably at temperatures between 10 and 25 ° C.

f) for the preparation of compounds of the general formula I, in which A represents the -COCO group:

Oxidation of a compound of the general formula in the
R ₁ to R ₃ , E, G and Het are as defined above.

The oxidation is preferably carried out with an oxidizing agent such as potassium permanganate, selenium dioxide or sodium dichromate in a suitable solvent or solvent mixture such as Water, water / dioxane, glacial acetic acid, water / acetic acid or acetic anhydride at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.

g) reaction of a compound of the general formula in the
A, B, E, R ₁ and R _{2 are} as defined above, but in the radical E two hydrogen atoms in a -CH ₂ - or CH ₃ group of the radical E are replaced by an oxygen atom, with a compound of the general formula in the
R ₃ , G and Het are as defined in the introduction, in the presence of a reducing agent.

The reaction is conveniently carried out in a suitable manner Solvents or solvent mixtures such as methanol, ethanol, Ethanol / ethyl acetate 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 of a complex metal hydride such as lithium or sodium cyanoborohydride is particularly advantageous, preferably at a pH of 6-7 and at room temperature, or for the preparation of compounds of the general formula I in which R _{3 represents} a hydrogen atom in the presence of Palladium / carbon carried out at a hydrogen pressure of 5 bar. In this case, any benzyl groups which may be present can be split off hydrogenolytically and / or double bonds hydrated.

h) implementation of a compound of formula in the
R ₁ 'represents a hydroxyl, amino or alkylamino group protected by a protective radical or has the meanings mentioned for R ₁ , and
R ₂ 'represents a protected hydroxyl group or has the meanings mentioned for R ₂ .
with a compound of the general formula in the
E, G and Het are as defined in the beginning,
R ₃ 'represents a protective group for an amino group or has the meanings mentioned for R ₃ , and
W represents a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine, bromine or iodine atom, the methanesulfonyloxy, p-toluenesulfonyloxy or ethoxysulfonyloxy group and, if appropriate, subsequent cleavage of a protective radical used.

As a protective residue for a hydroxy group, for example the trimethylsilyl, acetyl, benzoyl, benzyl or tetrahydropyranyl group and as a protective residue for an amino or alkylamino group Acetyl, benzoyl, ethoxycarbonyl or benzyl group into consideration.  

The reaction is advantageously carried out in a solvent or solvent mixture such as methylformamide, dimethylformamide, Dimethyl sulfoxide, benzene, chlorobenzene, tetrahydrofuran, Benzene / tetrahydrofuran or dioxane in the presence of a acid binding agent, e.g. an alcoholate such as potassium tert-butylate, an alkali hydroxide such as sodium or potassium hydroxide, an alkali carbonate such as potassium carbonate, an alkali amide such as sodium amide or an alkali hydride like sodium hydride expediently at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 50 ° C carried out.

The subsequent subsequent splitting off of one used Protective residue is preferably hydrolytically in one aqueous solvents, e.g. in water, isopropanol / water, Tetrahydrofuran / water or dioxane / water, in the presence an acid such as hydrochloric acid or sulfuric acid or in the presence an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at the boiling point of the reaction mixture. The secession of a benzyl radical, however, is preferably hydrogenolytic, e.g. with hydrogen in the presence of a catalyst like palladium / carbon in a solvent like methanol, Ethanol, ethyl acetate or glacial acetic acid if necessary with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, preferably however from 3 to 5 bar.

The compounds of general formula I obtained also in their acid addition salts, especially in their physiologically compatible acid addition salts with inorganic or transfer organic acids. As acids come here, for example, hydrochloric acid, hydrobromic acid, Sulfuric acid, phosphoric acid, acetic acid, lactic acid, Citric acid, tartaric acid, succinic acid, maleic acid or Furmaric acid into consideration.  

The compounds of the general used as starting materials Formulas II to XII are known from the literature in some cases or they are obtained by methods known per se.

For example, a starting compound of the general formula II is obtained by reacting a corresponding benzazepine with a corresponding halogen compound and optionally by subsequent reaction with a corresponding amine. The corresponding benzazepine which is unsubstituted in the 3-position is obtained by cyclization of a corresponding compound, for example by cyclization of a compound of the general formula or the general formula optionally subsequent catalytic hydrogenation and / or reduction of the carbonyl group, for example with sodium borohydride / glacial acetic acid (see EP-Al 0.007.070) and / or oxidation, for example with selenium dioxide.

A compound of the general used as a starting material Formulas IV to VIII are preferably obtained by reaction a corresponding halogen compound with a corresponding one Amine and optionally subsequent cleavage of protective residues used to protect hydroxy and / or Amino groups can be used.

A compound of the general formula IX is obtained, for example by implementing an unsubstituted in the 3-position corresponding benzazepines with a corresponding Halogen acetal or halogen ketal and subsequent hydrolysis.

As already mentioned at the beginning, the new compounds of the general formula I and their physiologically tolerable acid addition salts with inorganic or organic acids have valuable pharmacological properties, in particular with low central side effects, a long-lasting heart rate-lowering effect and a reduction in the heart's O ₂ requirement.

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

The necessary to achieve a corresponding effect Dosage is expediently once or twice 0.03 to 1 mg / kg body weight daily, preferably 0.07 up to 0.5 mg / kg body weight. For this purpose, the invention Compounds of general formula I prepared as well as their physiologically acceptable acid addition salts with inorganic or organic acids, optionally in Combination with other active substances, together with one or several inert customary carriers and / or diluents, e.g. with cornstarch, milk sugar, cane sugar,  microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, Citric acid, tartaric acid, water, water / Ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, Propylene glycol, carboxymethyl cellulose or fatty Substances such as hard fat or their suitable mixtures, in common pharmaceutical preparations such as tablets, Coated tablets, capsules, powders, suspensions, drops, ampoules, Work in juices or suppositories.

The following examples are intended to explain the invention in more detail:  

Preparation of the starting compounds Example A 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one a) 3,4-Dimethoxy-phenylacetic acid chloride

600 ml of thionyl chloride are added dropwise with stirring to a suspension of 549.4 g of 3,4-dimethoxyphenylacetic acid in 600 ml of methylene chloride over 2 hours. After the evolution of gas has ended (16 hours), the mixture is boiled under reflux for another hour. After the volatile components have been removed, the residue is distilled in vacuo. Yield: 486 g (80.8% of theory),
Kp: 134-136 ° C / 1.95 mbar

b) N- (2,2-Dimethoxyethyl) -3,4-dimethoxy-phenylacetamide

A solution of 485.2 g of 3,4-dimethoxy-phenylacetic acid chloride is added while cooling with ice in 1.1 l methylene chloride at 15-20 ° C to a solution of 246.2 ml of aminoacetaldehyde dimethyl acetal and 315 ml of thriethylamine in 2.2 l of methylene chloride were added dropwise and stirred for one hour at 16-18 ° C. Then will extracted several times with water, dried over magnesium sulfate and evaporated. The oil obtained crystallizes slowly through.

Yield: 608 g (95% of theory),
Melting point: 66-69 ° C.

c) 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one

A solution of 600.6 g of N- (2,2-dimethoxyethyl) -3,4-dimethoxy-phenylacetamide in 3 l of concentrated hydrochloric acid is mixed with 3 l of vinegar. After standing at room temperature for 17 hours, the mixture is poured onto ice. The precipitated crystals are filtered off, washed neutral with water and dried.
Yield: 350 g (75.4% of theory),
Melting point: 234-237 ° C.

Example B 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

A suspension of 21.9 g (0.1 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one and 1.5 g of palladium / carbon (10%) in 200 ml of glacial acetic acid is added 50 ° C and a hydrogen pressure of 5 bar hydrogenated. After filtering off the catalyst, the solvent is evaporated in vacuo and the residue is taken up in methylene chloride. After extraction with sodium bicarbonate solution and washing with water, the mixture is dried over magnesium sulfate, concentrated and purified over silica gel with methylene chloride and then with increasing proportions of methanol (up to 10%).
Yield: 12.6 g (57% of theory),
Melting point: 188-191 ° C.

Example C 7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

To a suspension of 1.3 g (6 mmol) of 7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 1.1 g (3 mmol) of sodium borohydride in 20 ml of dioxane a solution of 1.8 g of glacial acetic acid in 10 ml of dioxane, boiled under reflux for 3 hours, concentrated and decomposed with water. The mixture is extracted twice with methylene chloride, the extract is concentrated and the residue is taken up in ether. After filtration, the ether is removed in vacuo.
Yield: 1.1 g (92.7% of theory),
Melting point: 86-89 ° C.

Example D 6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one

2.0 g (0.007 mol) of N- (2,2-dimethoxyethyl) -2,5-dimethoxyphenyl-acetamide are poured over with 3 ml of polyphosphoric acid and stirred at 90 ° C. for 60 minutes. Then ice water is added, the precipitated product is suctioned off and dried.
Yield: 0.98 g (64% of theory).
Melting point: 188-191 ° C

Example E 7,8-dimethyl-1,3-dihydro-2H-3-benzazepin-2-one

Prepared analogously to Example D from N- (2,2-dimethoxyethyl) -3,4-dimethyl-phenylacetamide and polyphosphoric acid.
Yield: 40.1% of theory.
Melting point: 220-224 ° C.

Example F 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione a) 7,8-Dimethoxy-2-amino-4-bromo-1H-3-benzazepine hydrobromide

3.7 g (0.017 mol) of 3,4-dimethoxy-o-phenylene-diacetonitrile are suspended in 10 ml of glacial acetic acid and 12 ml of 30% hydrobromic acid in glacial acetic acid are added at 20 ° C. The mixture is stirred for 3 hours at room temperature, the precipitate is filtered off, washed with glacial acetic acid and then with acetone / ether and dried.
Yield: 5.3 g (82.8% of theory),
Melting point: 210-211 ° C (dec.).

b) 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione

5.3 g (0.014 mol) of 7,8-dimethoxy-2-amino-4-bromo-1H-3benzazepine hydrobromide are dissolved in 100 ml of hot water at 85 ° C., 1.3 g of anhydrous sodium acetate are added and the mixture is left for one hour 90 ° C heated. The reaction mixture is cooled, suction filtered, washed with cold water and dried.
Yield: 2.9 g (88% of theory),
Melting point: 235 ° C (dec.).

Example G N- [3- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) propyl] methylamine hydrochloride

5.9 g (0.020 mol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 14 g (0.45 mol) methylamine are heated in the containment tube at 130 ° C for one hour. The cooled reaction product is taken up in semi-concentrated sodium hydroxide solution and extracted with methylene chloride. After drying and concentrating the extract, the hydrochloride is precipitated from acetone / ether with ethereal hydrochloric acid.
Yield: 5.2 g (80% of theory),
Melting point: 110 ° C (decomp.).

Example H 7,8-dimethoxy-2,3-dihydro-1H-3-benzazepine

2.2 g (0.01 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one are added to a boiling suspension of 0.8 g of lithium aluminum hydride in 100 ml of absolute dioxane and then Heated under reflux for 3 hours. 10% ammonium chloride solution is added while cooling with ice water and the precipitate formed is suction filtered. The filtrate is concentrated in vacuo to a volume of about 20 ml, the precipitated white precipitate is suction filtered and washed with a little dioxane.
Yield: 0.9 g (43.8% of theory),
Melting point: 162-163 ° C.

Example I 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3-chloropropane a) 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) - 3-chloropropane

131.5 g (0.6 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin- 2-one are suspended in 900 ml of dimethyl sulfoxide and stirred with 80.8 g (0.72 mol ) Potassium tert-butoxide added. After 10 minutes, the solution obtained is added dropwise to 77 ml (0.72 mol) of 1-bromo-3-chloropropane in 300 ml of dimethyl sulfoxide while cooling with ice water. After an hour you pour on ice water. After a short time the greasy precipitate begins to crystallize. The precipitate is filtered off, dissolved in acetone, precipitated again with water, filtered off and dried.
Yield: 155.5 g (87.3% of theory),
Melting point: 101-103 ° C

b) 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2- on-3-yl) -3-chloropropane

59.2 g (0.2 mol) of 1- (7,8-dimethoxy-1,3-dihydro-2H-3benzazepin-2-one-3-yl) -3-chloropropane are present in 500 ml of glacial acetic acid hydrogenated by 5 g of 10% palladium-carbon for 6 hours at 50 ° C. and 5 bar. The catalyst is suctioned off, the glacial acetic acid is distilled off in vacuo and the residue is neutralized with potassium carbonate after the addition of water. The precipitate is filtered off, washed free of salt with water and dried.
Yield: 53 g (89% of theory),
Melting point: 85-86 ° C

Example J 1- (7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl) -3- chloropropane

1.5 g (0.005 mol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane are obtained in 20 ml of tetrahydrofuran dissolved and after addition of 0.55 ml (0.0044 mol) of boron trifluoride etherate and 3 ml (0.006 mol) of a 2 molar solution of borane-dimethyl sulfide in toluene heated to reflux for two hours. Then a further 3 ml of the borane-dimethyl sulfide solution are added and the mixture is refluxed again for two hours. After decomposition with methanol, the solvents are distilled off and the residue is heated to 100 ° C. for 10 minutes with 6 ml of semi-concentrated hydrochloric acid. The reaction product is extracted with ethyl acetate, the acidic aqueous phase is made alkaline and extracted again with ethyl acetate. The extract is dried, concentrated and purified on an alumina column (activity level II-III) with methylene chloride.
Yield: 0.55 g (39% of theory),
Melting point: 62-64 ° C

Example K 3- (N-methyl-2-aminoethyl) benzo [b] thiophene a) Benzo [b] thienyl-3-acetic acid-N-methyl-amide

A solution of 2.3 g (0.012 mol) of benzo [b] thienyl-3-acetic acid in 40 ml of ethyl acetate is mixed in portions with 2.0 g (0.012 mol) of carbonyl-diimidazole and stirred for five hours at room temperature. After adding 7 ml of an 18% solution of methylamine in ethyl acetate, the mixture is stirred for a further three hours, whereupon the mixture is extracted with 1 M sodium hydroxide solution, the organic phase is washed with water, dried over sodium sulfate and, after concentration on a silica gel column, purified by chromatography.
Yield: 0.98 g (40% of theory),
Melting point: 123-124 ° C

b) 3- (N-methyl-2-aminoethyl) benzo [b] thiophene

In a refluxed solution of 1.9 g (0.0093 mol) of benzo [b] thienyl-3-acetic acid-N-methyl amide and 1.3 g (0.0093 mol) of boron trifluoride etherate in 40 ml of tetrahydrofuran 0.85 g (0.011 mol) of borane-dimethyl sulfide (1.1 ml of a 10 M solution in tetrahydrofuran) are slowly added dropwise and the mixture is heated under reflux for a further 4.5 hours. After concentrating the mixture, the mixture is heated to 100 ° C., mixed with 1.6 ml of 6 M hydrochloric acid and kept at this temperature for 30 minutes. Allow to cool, add 2.3 ml of 6 M sodium hydroxide solution, saturate with potassium carbonate and extract with ether. The extract is washed, dried, concentrated and purified on an aluminum oxide column of activity level II.
Yield: 0.85 g (48% of theory),
Oil, R _f value: 0.40 (aluminum oxide, methylene chloride / methanol = 50: 1).

Example L 2- (N-methyl-2-amino-ethyl) furan a) 2- (N-Formyl-2-amino-ethyl) furan

10.0 g (0.090 mol) of 2- (2-amino-ethyl) furan are refluxed with 80 ml (1.0 mol) of ethyl formate for 12 hours. The reaction product is concentrated and distilled in vacuo.
Yield: 11.6 g (93% of theory),
Boiling point: 140 ° C / 0.06 Torr

b) 2- (N-methyl-2-amino-ethyl) furan

1.4 g (0.010 mol) of 2- (N-formyl-2-amino-ethyl) furan are added dropwise at 0-5 ° C. under nitrogen in a suspension of 0.50 g (0.013 mol) of lithium aluminum hydride in 20 ml of ether , Stirred for 30 minutes at room temperature and then heated to reflux for 7 hours. After cooling, it is decomposed with dilute sodium hydroxide solution and suction filtered. The organic phase is dried, concentrated and distilled in vacuo. Yield: 1.0 g (80% of theory),
Boiling point: 110 ° C / 12 Torr
R _f value: 0.78 (aluminum oxide, methylene chloride / methanol = 9: 1).

Example M 1- (7-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one- 3-yl) -3-chloropropane a) 8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

56.8 g (0.3 mol) of 8-methoxy-1,3-dihydro-2H-benzazepin-2-one (melting point: 190-191 ° C), dissolved in 600 ml of glacial acetic acid, become 10 in the presence of 5 g % palladium-carbon at 80 ° C and 5 bar hydrogenated for 12 hours. The catalyst is suctioned off and the acetic acid is distilled off in vacuo. The residue is mixed with water, neutralized with potassium carbonate, the precipitate which has separated out is filtered off with suction, washed with water and dried.
Yield: 51.1 g (89.1% of theory),
Melting point: 160-161 ° C.

b) 7-bromo and 9-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepine 2-on

To 7.4 g (0.04 mol) of 8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 100 ml of 80% acetic acid are stirred at 3-5 ° C 6.4 g = 2.03 ml (0.04 mol) of bromine was dropped in 10 ml of glacial acetic acid. After 15 minutes, the mixture is poured onto ice water, neutralized with potassium carbonate, the precipitate is filtered off with suction, washed with a little water and dried. The isomer mixture obtained is separated chromatographically on a silica gel column (eluent: ethyl acetate).
Yield: 5.7 (52.8% of theory) 9-bromo isomer
IR spectrum (methylene chloride): 3220 cm ^-1 (NH)
1660 cm ^-1 (C = O)
4.1 g (39% of theory) of 7-bromo isomer
IR spectrum (calcium bromide): 3220 cm ^-1 (NH)
1665 cm ^-1 (CO)

c) 1- (7-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2- on-3-yl) -3-chloropropane

To 1.35 g (5 mmol) of 7-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 15 ml of dimethyl sulfoxide are added 0.24 g (5.5 mmol ) Added sodium hydride dispersion in oil (55%) and stirred for 1/2 hour at room temperature and 10 minutes at 35-40 ° C. The solution is added dropwise to 0.79 g (5.5 mmol) of 1-bromo-3-chloropropane in 5 ml of dimethyl sulfoxide with stirring. The mixture is then stirred for 2 hours at room temperature, poured onto ice water and extracted 4 times with methylene chloride. The methylene chloride extracts are washed several times with water, dried and concentrated in vacuo.
The residue is purified on a silica gel column using ethyl acetate as the eluent.
Yield: 210 mg (12% of theory),
Melting point: 119-120 ° C.

Example N 1- (7-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) - 3-chloropropane a) 7-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

3.1 g (0.0136 mol) of N-chloroacetyl-N- (2- (3-methoxy-phenyl) ethyl) amine are dissolved in 270 ml of ethanol and 1530 ml of water and for 10 hours under a nitrogen atmosphere at 20-25 ° C exposed with a high pressure mercury lamp. The solution is concentrated to a volume of approx. 400 ml, sodium bicarbonate is added and the mixture is shaken out several times with ethyl acetate. The extracts are dried over magnesium sulfate and concentrated, and the residue is purified on a silica gel column using ethyl acetate as the eluent.
Yield: 820 mg (31.5% of theory),
Melting point: 152-154 ° C.

b) 1- (7-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3-chloropropane

1.15 g (6 mmol) of 7-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin- 2-one are dissolved in 30 ml of absolute tetramethyl urea, with 300 mg of 55% sodium hydride dispersion (in Oil) and stirred under a nitrogen atmosphere at 20-25 ° C for 2 hours. The reaction mixture obtained is added dropwise with stirring at 15-20 ° C. under nitrogen to 1.6 g (7.8 mmol) of 1-chloro-3-iodopropane, dissolved in 20 ml of tetramethylurea, and the mixture is stirred for 3 hours at room temperature. Then about 300 ml of ethyl acetate are added and the mixture is extracted 6 times with water. The organic solution is dried over magnesium sulfate, concentrated and the residue is purified on a silica gel column with methylene chloride and increasing proportions of ethanol (up to 2%).
Yield: 410 mg (25.5% of theory),
IR spectrum (methylene chloride): 1650 cm ^-1 (CO).

Example O 1- (7-nitro-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2- on-3-yl) -3-chloropropane

28.5 g (0.106 mol) of 1- (8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane are concentrated in 350 ml Nitric acid stirred at 20-25 ° C for 1/2 hour. The solution is poured onto ice water, neutralized with potassium carbonate and extracted twice with methylene chloride. The extract is dried over magnesium sulfate, concentrated in vacuo and the residue is purified on a silica gel column using ethyl acetate as the eluent.
Yield: 11 g (33.2% of theory),
Melting point: 127-128 ° C.

Example P 1- (1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dion-3-yl) -3- chloropropane a) 2-Amino-4-bromo-1H-3-benzazepine hydrobromide

Prepared from 5.0 g (0.032 mol) of o-phenylenediacetonitrile analogously to Example Fa.
Yield: 8.0 g (78.6% of theory)

b) 1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione

Made from 8.0 g (0.025 mol) of 2-amino-4-bromo-1H-3benzazepine hydrobromide analogous to example Fb.
Yield: 3.7 g (66.1% of theory),
Melting point: 189-191 ° C

c) 1- (1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione-3-yl) - 3-chloropropane

3.5 g (0.020 mol) of 1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione are suspended in 30 ml of dimethylformamide and 2.5 g of potassium tert-butoxide are added with stirring. After 10 minutes, the solution obtained is added dropwise to 3.5 ml of 1-bromo-3-chloropropane in 20 ml of dimethylformamide while cooling with ice. After an hour you pour on ice water. After a short time, the greasy precipitate crystallizes. The precipitate is filtered off, dissolved in acetone, precipitated again with water, filtered off and dried.
Yield: 4.7 g (90.4% of theory).

Example Q 3- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) - propionaldehyde a) 3- (7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) - propionaldehyde diethylacetal

Prepared analogously to Example I / a by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 3-chloropropionaldehyde diethylacetal.
Yield: 93.3% of theory.

b) 3- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) - propionaldehyde

3.5 g (0.01 mole) of 3- (7,8-dimethoxy-1,3-dihydro-2H-3benzazepin- 2-on-3-yl) propionaldehyde diethyl acetal in 50 ml of 2 n sulfuric acid and 50 ml ethanol heated to 40 ° C for 2 hours. The alcohol is distilled off in vacuo, the residue is made alkaline with cooling with saturated potassium carbonate solution and shaken out several times with ethyl acetate. The ethyl acetate extract is shaken out twice with 5% sodium hydrogen sulfite solution. The bisulfite extract is acidified with concentrated hydrochloric acid and heated to 40 ° C. in vacuo for 1/2 hour to remove the sulfur dioxide. Saturated potassium carbonate solution is then added, the mixture is extracted several times with methylene chloride, dried over magnesium sulfate and evaporated.
Melting point: 95-96 ° C
Yield: 1.7 g (61.8% of theory),

Production of the end products: example 1 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one- 3-yl) -3- [N-methyl-N- (2- (6-methoxy-benzo [b] thienyl-3) - ethyl -) - amino] propane dihydrochloride

0.80 g (0.0027 mol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 0.60 g (0.0027 mol) of 3- (N-methyl-2-amino-ethyl) -6-methoxybenzo [b] -thiophene are heated to 60 ° C. in 5 ml of triethylamine for 30 minutes. The temperature is then raised to reflux and maintained for 3 hours. After the triethylamine has been distilled off, the mixture is heated at 100 ° C. for a further 5 hours. The product obtained is purified on a silica gel column using methylene chloride / methanol = 25: 1 as the eluent, taken up in methanol and precipitated as hydrochloride with ethereal hydrochloric acid.
Yield: 0.69 g (46% of theory), R _f value of the free base: 0.48 (silica gel,
Methylene chloride / methanol = 9: 1).

Example 2 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (4- (imidazolyl-1) butyl) amino] propane

1.65 g (0.0050 mol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- (N-methyl -amino) propane hydrochloride are refluxed with 0.80 (0.0050 mol) of 4- (imidazolyl-1) -1-chlorobutane and 2.6 g (0.020 mol) of anhydrous potassium carbonate in dimethylformamide for two hours. The solvent is distilled off, the residue is taken up in semi-concentrated sodium hydroxide solution and extracted with chloroform. The extract is washed with brine, dried with sodium sulfate, concentrated and purified on an aluminum oxide column (activity level II, eluent: methylene chloride).
Yield: 0.91 g (44% of theory),
R _f value: 0.53 (silica gel, methylene chloride / methanol = 9: 1).

Example 3 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione- 3-yl) -3- [N-methyl-N- (2- (pyridyl-4) ethyl) amino] propane dihydrochloride monohydrate

1.55 g (0.0066 mol) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione are dissolved in 40 ml of dimethylformamide with gentle heating. After cooling to 0 ° C., 0.9 g (0.008 mol) of potassium tert-butoxide are added, stirring is continued for 5 minutes and then 1.7 g (0.0066 mol) of 3- [N-methyl-N- (2- (pyridyl-4) ethyl) amino] -1-bromopropane. The mixture is stirred overnight at room temperature, the solvent is spun off and the residue is purified on a silica gel column (elution with methylene chloride / ethanol). The cleaned base is taken up in methanol and the hydrochloride is precipitated with ethereal hydrochloric acid.
Yield: 0.75 g (23% of theory), R _f value of free base: 0.25 (silica gel, methylene chloride / ethanol = 9: 1).

Example 4 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-thione- 3-yl) -3- [N-methyl-N- (3- (furyl-2) propyl) amino] propane

0.80 g (0.0020 mol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- [N-methyl -N- (3- (furyl-2) propyl) amino] propane and 0.40 g (0.0010 mol) 2,4-bis (4-methoxyphenyl) 1,3-dithia-2 , 4-diphosphetane-2,4-disulfide are suspended in 10 ml of toluene and boiled under reflux for 3 hours. It is then rotated in and purified on a silica gel column with methylene chloride and increasing proportions of methanol.
Yield: 0.26 g (29% of theory), R _f value: 0.58 (silica gel, methylene chloride / methanol = 9: 1).

Example 5 1- (7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-3-yl) -3 [N- methyl-N- (furyl-2) ethyl) amino] propane

A solution of 0.77 g (0.0020 mol) of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3- [N-methyl- N- (2- (furyl-2) -ethyl) -amino] propane in 5 ml of absolute dioxane is added dropwise to a boiling suspension of 0.2 g (0.005 mol) of lithium aluminum hydride in 20 ml of absolute dioxane and kept at the reflux temperature for 2 hours. Then it is decomposed with sodium hydroxide solution, filtered off with suction and cleaned over a silica gel column.
Yield: 0.50 g (67% of theory), R _f value: 0.70 (silica gel, methylene chloride / methanol = 9: 1).

Example 6 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (3- (thienyl-2) propyl) amino] propane hydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-yl) -3-chloropropane with 2- (3- Methylamino-propyl) -thiophene and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid. Yield: 21% of theory,
R _f value of the free base: 0.40 (silica gel, methylene chloride / methanol = 9: 1).

Example 7 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2-furyl-2) ethyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 2- ( 2-methylamino-ethyl) furan.
Yield: 50% of theory, R _f value: 0.44 (silica gel, methylene chloride / methanol = 9: 1).

Example 8 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (3- (furyl-2) propyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 2- ( 3-methylamino-propyl) furan.
Yield: 48% of theory, R _f value: 0.44 (silica gel, methylene chloride / methanol = 9: 1).

Example 9 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (thienyl-2) ethyl) amino] propane dihydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 2- ( N-methyl-2-amino-ethyl) -thiophene and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 42% of theory,
Melting point: 215 ° C (dec.).

Example 10 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (thienyl-3) ethyl) amino] propane dihydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 3- ( N-methyl-2-amino-ethyl) -thiophene and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 40% of theory,
Melting point: 185 ° C (dec.).

Example 11 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (imidazolyl-4) ethyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 4- ( N-methyl-2-amino-ethyl) imidazole.
Yield: 45% of theory,
R _f value: 0.60 (aluminum oxide, methylene chloride / methanol = 10: 1).

Example 12 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (3- (5,6-dimethoxy-benzo [b] thienyl-3) - propyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 3- ( 2-methylamino-ethyl) -5,6-dimethoxy-benzo [b] thiophene. Yield: 43% of theory, R _f value: 0.27 (silica gel, methylene chloride / methanol = 9: 1).

Example 13 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (imidazo [1,2-a] pyridyl-3) ethyl) amino] propane hydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- (N-methylamino) propane with 2- (imidazo [1,2-a] pyridyl-3) ethyl chloride and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 17% of theory,
Melting point: 130 ° C (dec.).

Example 14 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (benzo [b] thienyl-3) ethyl) amino] propane hydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 3- ( N-methyl-2-amino-ethyl) -benzo [b] thiophene and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 65% of theory,
Melting point: 195 ° C (dec.).

Example 15 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (4- (thienyl-2) butyl) amino] propane dihydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 2- ( N-methyl-4-amino-butyl) thiophene and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid. Yield: 30% of theory R _f value of the free base: 0.55 (silica gel, methylene chloride / methanol = 9: 1).

Example 16 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (imidazolyl-1) ethyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 1- ( N-methyl-2-amino-ethyl) imidazole.
Yield: 52% of theory,
R _f value: 0.55 (aluminum oxide, methylene chloride / methanol = 20: 1).

Example 17 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (1-methylimidazolyl-4) ethyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 1-methyl -4- (N-methyl-2-amino-ethyl) imidazole.
Yield: 45% of theory,
R _f value: 0.70 (aluminum oxide, methylene chloride / methanol = 20: 1).

Example 18 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (benzo [b] thienyl-3) -1-methyl-ethyl) - amino] propane hydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 3- ( N-methyl-2-aminopropyl) benzo [b] thiophene and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 29% of theory,
R _f value of free base: 0.65 (silica gel, methylene chloride / methanol = 5: 1).

Example 19 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (furyl-2) ethyl) amino] propane hydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 2- ( 2-Methylamino-ethyl) furan and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid. Yield: 67% of theory, R _f value of free base: 0.57 (silica gel, methylene chloride / methanol = 9: 1).

Example 20 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (1H-benzo [d] imidazolyl-1) ethyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 1- ( 2-methylamino-ethyl) -1H-benzo [d] imidazole.
Yield: 62% of theory, R _f value: 0.57 (silica gel, methylene chloride / methanol = 9: 1).

Example 21 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (2-benzyl-1H-benzo [d] imidazolyl-1) - ethyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 1- ( 2-methylamino-ethyl) -2-benzyl-1H-benzo [d] imidazole.
Yield: 20% of theory,
R _f value: 0.49 (silica gel, methylene chloride / methanol = 9: 1).

Example 22 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (4-methylthiazolyl-5) ethyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 4-methyl -5- (N-methyl-2-amino-ethyl) thiazole and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 18% of theory,
Melting point: 196-197.5 ° C (dec.).

Example 23 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (1-methyl-pyrrolyl-2) -ethyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 1-methyl -2- (N-methyl-2-amino-ethyl) pyrrole.
Yield: 11% of theory, R _f value: 0.76 (aluminum oxide N, methylene chloride / ethanol = 19: 1).

Example 24 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (picolyl-2) amino] propane dihydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with N- ( Picolyl-2) -methylamine and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 54% of theory,
R _f value of the free base: 0.50 (silica gel, methylene chloride / ethanol = 4: 1).

Example 25 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (picolyl-3) amino] propane dihydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with N- ( Picolyl-3) -methylamine and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 20% of theory,
Melting point: 176-178 ° C.

Example 26 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (pyridyl-4) ethyl) amino] propane dihydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 4- ( 2-Methylamino-ethyl) pyridine and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 19% of theory,
Melting point: 116-118 ° C.

Example 27 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (pyridyl-2) ethyl) amino] propane dihydrochloride

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 2- ( 2-Methylamino-ethyl) pyridine and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 6.4% of theory,
Melting point: 165-167 ° C.

Example 28 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (6,7-dimethoxy-isoquinolinyl-4) -ethyl) - amino] propane dihydrochloride monohydrate

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with 6.7 -Dimethoxy-4- (2-methylamino-ethyl) -isoquinoline and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 22% of theory, R _f value of the free base: 0.60 (silica gel, ethyl acetate / ethanol / ammonia = 50: 45: 5).

Example 29 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (pyridyl-3) ethyl) amino] propane dihydrochloride semihydrate

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-yl) -3-chloropropane with 3- (2- Methylamino-ethyl) pyridine and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 27% of theory,
Melting point: 110-112 ° C

Example 30 1- (7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl) - 3- [N-methyl-N- (2- (pyridyl-4) ethyl) amino] propane

Prepared analogously to Example 1 by reacting 1- (7,8-dimethoxy-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl) -3-chloropropane with 4- (2-methylamino- ethyl) pyridine and subsequent precipitation of the hydrochloride with ethereal hydrochloric acid.
Yield: 25% of theory
Melting point: 110-112 ° C

Example 31 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (pyridyl-4) ethyl) amino] propane dihydrochloride

1.1 g (0.0040 mol) of 3- (7,8-dimethoxy-1,3-dihydro-2H-3benzazepin-2-one-3-yl) propionaldehyde are dissolved in 30 ml of ethanol in the presence of 0.60 g (0.0044 mol) of 4- (2-methylamino-ethyl) pyridine and 0.2 g of 10% palladium-carbon at 50 ° C for 20 hours at 5 bar. It is suctioned off from the catalyst, concentrated, purified on an aluminum oxide column of activity level II-III with methylene chloride / ethanol as the eluent and the hydrochloride is precipitated with ethereal hydrochloric acid.
Yield: 0.98 g (62% of theory),
Melting point: 116-118 ° C.

Analogous to the above examples, the following compounds will be obtained:

1- (7-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one- 3-yl) -3- [N-methyl-N- (2- (thienyl-3) ethyl) amino] propane

1- (7-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) - [N-methyl-N- (2- (thienyl-2) ethyl) amino] propane

1- (1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- [N- methyl-N- (2- (benz [b] thienyl-3) ethyl) amino] propane

1- (7,8-dimethyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one- 3-yl) -3- [N-methyl-N- (2- (benzo [b] furyl-2) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one- 3-yl) -3- [N-methyl-N- (2- (benzo [b] furyl-2) ethylamino] propane

1- (7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one-3-yl) - 3- [N-methyl-N- (2- (6-methoxy-benzo [b] furyl-3) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one- 3-yl) -3- [N-methyl-N- [3- (2- (3,4-dimethoxyphenyl) imidazolyl-5) - propyl] amino] propane  

1- (7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one-3-yl) -3- [N-methyl-N- (2- (5-methoxy-3-phenyl-benzo [b] furyl-2) -ethyl) - amino] propane

1- (7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2- on-3-yl) -3- [N-methyl-N- (2-thienyl-3) ethyl) amino] propane

1- (7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one- 3-yl) -3- [N-methyl-N- (2- (6-methoxy-benzo [b] furyl-3) -ethyl) - amino] propane

1- (7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2- on-3-yl) -3- [N-methyl-N- (2- (5,6-dimethoxy-benzo [b] thienyl-3) - ethyl) amino] propane

1- (7,8-Dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one-3-yl-3- [N-methyl-N- (2- (7-methyl-benzo [b] furyl-3) -ethyl) -amino] propane
1- (7,8-Dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl) - 3- [N-methyl-N- (3- (thienyl-2) propyl) -amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-thione- 3-yl) -3- [N-methyl-N- (2- (thienyl-2) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-1,2-dione- 3-yl) -3- [N-methyl-N- (2- (thienyl-2) ethyl) amino] propane

1- (1-Hydroxy-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine 2-one-3-yl) -3- [N-methyl-N- (2- (thienyl-2) ethyl) amino] propane

1- (7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-3-yl) -3- [N- methyl-N- (3- (thienyl-2) propyl) amino] propane  

1- (7,8-methylenedioxy-2,3-dihydro-1H-3-benzazepin-2-one-3-yl) - 3- [N-methyl-N- (3- (thienyl-2) propyl) amino] propane

1- (7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one-3-yl) -3- [N-methyl-N- (3- (5-methylthienyl-2) propyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one- 3-yl) -3- [N-methyl-N- (3- (5-bromothienyl-2) propyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (thienyl-2) ethyl) amino] propane

1- (7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-2-one-3-yl) -3- [N-methyl-N- (2- (2,5-dimethyl-benzo [b] thienyl-3) -ethyl) - amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (N-methyl-pyrrolyl-3) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (pyrrolyl-3) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (3-methyl-isoxazolyl-5) -ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (isoxazolyl-3) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (oxazolyl-4) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (oxazolyl-5) ethyl) amino] propane  

1- (7,8-Dimethoxyy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (pyrazolyl-3) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (2,3-dimethylpyrazolyl-5) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (pyridyl-4) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (pyridyl-3) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (pyridyl-3-N-oxide) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (4-nitro-pyridyl-2) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (4-aminopyridyl-2) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (4-acetylamino-pyridyl-2) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (4-carbomoylamino-pyridyl-2) -ethyl) - amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (4-N-methylcarbamoylamino-pyridyl-2) - ethyl) amino] propane  

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (6,7-dimethoxyisoquinolyl-4-N-oxide) - ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3- [N-methyl-N- (2- (6,7-dimethoxyquinolyl-4) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-1,2-dione- 3-yl) -3- [N-methyl-N- (2- (pyridyl-4) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-1,2-dione- 3-yl) -3- [N-methyl-N- (2- (pyridyl-3) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-1,2-dione- 3-yl) -3- [N-methyl-N- (2- (pyridyl-3-N-oxide) ethyl) amino] propane

1- (1-Hydroxy-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine 2-one-3-yl) -3- [N-methyl-N- (2- (pyridyl-3) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione- 3-yl) -3- [N-methyl-N- (2- (pyridyl-4) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione- 3-yl) -3- [N-methyl-N- (2- (pyridyl-3) ethyl) amino] propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione- 3-yl) -3- [N-methyl-N- (2- (6,7-dimethoxyisoquinolyl-4) ethyl) - amino] propane  

Example I 10 mg tablets 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H- 3-benzazepin-2-one-3-yl) - [N-methyl-N- (3- (thienyl-2) propyl) - amino] propane hydrochloride production method

The active ingredient, corn starch, milk sugar and polyvinyl pyrrolidone are mixed and moistened with water. The damp Mixture is pressed through a sieve with a mesh size of 1.5 mm and dried at approx. 45 ° C. The dry granules is passed through a sieve with a mesh size of 1.0 mm and mixed with magnesium stearate. The finished mixture presses one on a tablet press with stamps of 7 mm in diameter, which are provided with a partial notch to form tablets. Tablet weight: 120 mg

Example II Drag´es to 5 mg 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3- benzazepin-2-one-3-yl) -3- [N-methyl-N- (3- (thienyl-2) propyl) - amino] propane hydrochloride production method

The active ingredient, corn starch, milk sugar and polyvinyl pyrrolidone are mixed well and moistened with water. The moist mass is pressed through a sieve with a mesh size of 1 mm, dries at approx. 45 ° C and then hits the granules through the same sieve. After adding magnesium stearate are domed on a tableting machine Pressed cores with a diameter of 6 mm. The so manufactured drag 'cores are used in a known manner covered with a layer consisting essentially of sugar and Talc exists. The finished drages are polished with wax.

Drag weight: 130 mg

Example III Amules of 5 mg 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3- benzazepin-2-one-3-yl) -3- [N-methyl-N- (3- (thienyl-2) propyl) - amino] propane hydrochloride

1 ampoule contains:
Active substance 5.0 mg
Sorbitol 50.0 mg
Water for injections ad 2.0 mg

production method

The active ingredient is dissolved in water in a suitable batch vessel dissolved for injection purposes and the solution isotonic with sorbitol posed.  

After filtration through a membrane filter, the solution is poured into cleaned and sterilized ampoules with N ₂ gassing and autoclaved in flowing steam for 20 minutes.

Example IV 15 mg suppositories 1- (7,8-dimethoxy-1,3,4,5-tetrahydro- 2-H-3-benzazepin-2-one-3-yl) -3- [N-methyl-N- (3- (thienyl-2) - propyl) amino] propane hydrochloride Production method:

The hard fat is melted. The ground fat is melted at 38 ° C Active substance homogeneously dispersed in the melt. It will cooled to 35 ° C and in weakly pre-cooled suppository forms poured out.

Example V Drop solution with 10 mg 1- (7,8-dimethoxy-1,3,4,5-tetrahydro- 2H-3-benzazepin-2-one-3-yl) -3- [N-methyl-N- (3- (thienyl-2) - propyl) amino] propane hydrochloride

100 ml solutions contain:
Active substance 0.2 g
Hydroxyethyl cellulose 0.15 g
Tartaric acid 0.1 g
Sorbitol solution 70% dry matter 30.0 g
Glycerin 10.0 g
Benzoic acid 0.15 g
Dest. Water to 100 ml

Production method:

Dest. Water is heated to 70 ° C. This is while stirring Hydroxyethyl cellulose, benzoic acid and tartaric acid dissolved. It is cooled to room temperature and the glycerin and added the sorbitol acid with stirring. At room temperature the active ingredient is added and until completely dissolved touched. Then the juice is vented evacuated with stirring.

Claims (29)

1. New heteroaromatic amine derivatives of the general formula in the
A is a -CH ₂ -CH ₂ -, -CH = CH- or -CH ₂ -CO group
5and
B is a methylene, carbonyl or thiocarbonyl group or
A a and B is a methylene group,
E is a straight-chain alkylene group with 2 to 4 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms,
G is a straight-chain alkylene group with 1 to 5 carbon atoms, optionally substituted by an alkyl group with 1 to 3 carbon atoms,
R _{1 is} a hydrogen, chlorine or bromine atom, a trifluoromethyl, nitro, amino, alkylamino, dialkylamino, alkyl, hydroxyl, alkoxy or phenylalkoxy group, where each alkyl part can contain 1 to 3 carbon atoms.
R _{2 is} a hydrogen, chlorine or bromine atom, a hydrooxy, alkoxy, phenylalkoxy or alkyl group, where each alkyl part can contain 1 to 3 carbon atoms, or
R ₁ and R ₂ together represent an alkylenedioxy group with 1 or 2 carbon atoms,
R _{3 is} a hydrogen atom, an alkenyl group with 3 to 5 carbon atoms, an alkyl or phenylalkyl group, where the alkyl part can each contain 1 to 3 carbon atoms, and
Het has a 5- or 6-membered heteroaromatic ring which is bonded via a carbon or nitrogen atom and which contains one oxygen, sulfur or nitrogen atom, two nitrogen atoms or one nitrogen atom and one oxygen or sulfur atom and to which a phenyl ring can additionally be fused , or an imidazo [1,2-a] pyridyl group in which the carbon skeleton of the heteroaromatic radicals mentioned above is replaced by a halogen atom, an alkyl, hydroxyl, alkoxy, phenylalkoxy, phenyl, dimethoxyphenyl, nitro, amino, Acetylamino, carbamoylamino, N-alkyl-carbamoylamino, hydroxymethyl or alkoxymethyl group may be mono- or disubstituted or substituted by a methylenedioxy group and, at the same time, a substituted imino group in the heteroaromatic radicals mentioned above may be substituted by an alkyl, phenylalkyl or phenyl group may be, wherein the above-mentioned alkyl parts each contain 1 to 3 carbon atoms ten can mean their N-oxides and their acid addition salts. 2. New heteroaromatic amine derivatives of the general formula in the
A a and B is a methylene group or
A represents a -CH ₂ -CH ₂ - or -CH = CH group and B represents a carbonyl or thiocarbonyl group,
E is an n-propylene group,
G is an ethylene or n-propylene group,
R _{1 is} a chlorine atom or bromine atom, a methyl, methoxy, nitro, amino, methylamino or dimethylamino group,
R _{2 is} a chlorine or bromine atom, a methyl or methoxy group or R ₁ and R ₂ together are a methylenedioxy or ethylenedioxy group,
R _{3 is} a hydrogen atom, a methyl or allyl group and
Het a pyrollyl-2, pyrrolyl-3, N-methyl-pyrrolyl-2, N-methyl-pyrrolyl-3, furyl-2, benzo [b] furyl-2-, 7-methylbenzo [b] furyl-3-, 6-methoxy-benzo [b] furyl-3-, 5-methoxy-3-phenyl-benzo [b] furyl-2-, thienyl-2-, thienyl-3-, 5-methyl-thienyl -2-, 5-bromothienyl-2-, benzo [b] thienyl-3-, 6-methoxy-benzo [b] thienyl-3-, 5,6-dimethoxy-benzo [b] thienyl-3-, 2,5-dimethyl-benzo [b] thienyl-3, pyrazolyl-1, pyrazolyl-3, 1,5-dimethyl-pyrazolyl-3, imidazolyl-1, imidazolyl-4-, 1-methyl-imidazolyl -4-, 2- (3,4-Dimethoxyphenyl) imidazolyl-5-, benzo [d] imidazolyl-1-, 2-benzyl-benzo [d] imidazolyl-1-, imidazo [1,2-a ] pyridyl-3, oxazolyl-4, oxazolyl-5, isoxazolyl-3-, 3-methyl-isoxazolyl-5-, 4-methylthiazolyl-5, pyridyl-2, pyridyl-3, pyridyl -4-, pyridyl-3-N-oxide, 4-nitro-pyridyl-2-, 4-amino-pyridyl-2-, 4-acetylamino-pyridyl-2-, 4-carbamoylamino-pyridyl-2-, 4 -N-methyl-carbamoylamino-pyridyl-2, 6,7-dimethoxy-quinolyl-4, 6,7-dimethoxy-isoquinolyl-4 or 6,7-dimethoxy-isoquinolyl-4-N-oxide group , and their acid addition salts. 3. New compounds of general formula Ia according to claim 2, in which
A is a -CH ₂ -CH ₂ - or -CH = CH- and B is a carbonyl or thiocarbonyl group,
E is an n-propylene group,
G is an ethylene or n-propylene group,
R ₁ and R ₂ each represent a methoxy group or R ₁ and R ₂ together represent a methylenedioxy group.
R _{3 is} a hydrogen atom or a methyl group and
Het a pyrrolyl-2, pyrrolyl-3, N-methyl-pyrrolyl-2, N-methyl-pyrrolyl-3, thienyl-2, thienyl-3-, 5-methyl-thienyl-2-, 5 -Bromothienyl-2-, pyrazolyl-1-, pyrazolyl-3-, imidozolyl-1-, isoxazolyl-3-, benzo [b] furyl-3-, 7-methylbenzo [b] furyl-3-, 6-methoy-benzo [b] furyl-3-, benzo [b] thienyl-3-, 6-methoxy-benzo [b] thienyl-3-, 5,6-dimethoxy-benzo [b] thienyl-3-, Benzo [d] imidazolyl-1, imidazo [1,2-a] pyridyl-3 or pyridyl group mean, and their acid addition salts. 4. 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) - 3- [N-methyl-N- (thienyl-2) propyl) amino] propane and its acid addition salts with inorganic or organic acids. 5. 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) - 3- [N-methyl-N- (thienyl-3 -) propyl) amino] propane and its acid addition salts with inorganic or organic Acids. 6. Physiologically acceptable acid addition salts of the compounds according to claims 1 to 5 with inorganic or organic acids. 7. Medicaments containing a compound of the general Formula I according to claims 1 to 5 or its physiological compatible acid addition salt according to claim 6 in addition to one or more inert carriers and / or Thinners. 8. Process for the manufacture of a medicament for treatment of sinus tachycardia and ischemic heart disease, characterized in that by non-chemical means a compound according to claims 1 to 5 or its Physiologically acceptable acid addition salt according to claim 6 in one or more inert carriers and / or diluents are incorporated. 9. Use of a compound according to claims 1 to 6 for the treatment of sinus tachycardia and Ischean heart disease.   10. A process for the preparation of new heteroaromatic amine derivatives according to claims 1 to 6, characterized in that
a) a compound of the general formula with a compound of the general formula in the
A, B, E, G and Het are as defined in claims 1 to 5,
R ₁ 'represents a hydroxyl, amino or alkylamino group protected by a protective radical or has the meanings mentioned for R ₁ in Claims 1 to 5,
R ₂ 'represents a hydroxyl group protected by a protective radical or has the meanings mentioned for R ₂ in Claims 1 to 5,
one of the radicals U or V represents the R ₃ 'NH group, where R ₃ ' represents a protective group for an amino group or has the meanings mentioned for R ₃ in claims 1 to 5, and
the other of the radicals U or V represents a nucleophilic leaving group, reacted and, if appropriate, subsequently a protective radical used is split off or
b) for the preparation of compounds of the general formula I in which A represents the -CH ₂ -CH ₂ group, B the methylene or carbonyl group and R ₃ does not represent an alkenyl group having 3 to 5 carbon atoms, a compound of the general formula in the
R ₁ to R ₃ , E, G and Het are as defined in claims 1 to 5 and
B 'represents the methylene or carbonyl group, is hydrogenated or
c) for the preparation of compounds of general formula I, in which B represents a thiocarbonyl group, a compound of general formula in the
R ₁ to R ₃ , A, E, G and Het are as defined in claims 1 to 5, is reacted with a sulfur-introducing agent or
d) for the preparation of compounds of the general formula I,
in the A one represents a compound of the general formula in the
R ₁ to R ₃ , E, G and Het as defined in claims 1 to 5 is reduced or
e) for the preparation of compounds of general formula I, in which A represents a -CH ₂ -CH ₂ - or -CH = CH- and B represents a methylene group, a compound of the general formula in the
R ₁ to R ₃ , E, G and Het are as defined in claims 1 to 5 and
A 'represents a -CH ₂ -CH ₂ - or -CH = CH group, is reduced or
f) For the preparation of compounds of general formula I, in which A represents the -COCO group, a compound of general formula in the
R ₁ to R ₃ , E, G and Het are as defined in claims 1 to 5, is oxidized or
g) a compound of the general formula in the
A, B, E, R ₁ and R _{2 are} as defined in claims 1 to 5, but in the radical E two hydrogen atoms in a -CH ₂ - or CH ₃ group of the radical E are replaced by an oxygen atom, with one Compound of the general formula in the
R ₃ , G and Het are as defined in claims 1 to 5, is reacted in the presence of a reducing agent or
h) a compound of the formula in the
R ₁ 'represents a hydrooxy, amino or alkylamino group protected by a protective radical or has the meanings mentioned for R ₁ in claims 1 to 5, and R ₂ ' represents a hydroxyl group protected by a protective radical or which represents R ₂ in the claims 1 to 5 meanings mentioned,
with a compound of the general formula in the
E, G and Het are as defined in claims 1 to 5, R ₃ 'represents a protective group for an amino group or has the meanings mentioned for R ₃ in claims 1 to 5, and
W represents a nucleophilic leaving group, is reacted and, if appropriate, subsequently a protective residue used is split off and
if desired, a compound of the general formula I thus obtained is subsequently converted into its acid addition salt, in particular into its physiologically compatible acid addition salt, with an inorganic or organic acid. 11. The method according to claim 10, characterized in that the reaction is carried out in a solvent. 12. The method according to claims 10a and 11, characterized in that the reaction in the presence of an acid-binding Is carried out. 13. The method according to claims 10a and 11, characterized in that the splitting off of protective residues is hydrolytic or hydrogenolytically. 14. The method according to claims 10a and 11, characterized in that the reaction at temperatures between 0 and 150 ° C, e.g. at the boiling point of the solvent used, is carried out. 15. The method according to claims 10b and 11, characterized in that the catalytic hydrogenation at a hydrogen pressure from 1 to 7 bar, but preferably from 3 to 5 bar, and at temperatures between 0 and 75 ° C, preferably however carried out at temperatures between 20 and 50 ° C. becomes. 16. The method according to claim 10c, characterized in that the reaction with phosphorus pentasulfide or 2,4-bis (4-methoxy-phenyl) - 1,3-dithia-2,4-diphosphentane-2,4-disulfide becomes. 17. The method according to claims 10c, 11 and 16, characterized characterized in that the reaction at temperatures between 50 and 150 ° C, e.g. at the boiling point of the reaction mixture, is carried out. 18. The method according to claim 10d, characterized in that the reaction with a metal hydride such as sodium borohydride is carried out.   19. The method according to claims 10d, 11 and 18, characterized characterized in that the reaction at temperatures between 0 and 80 ° C, preferably at temperatures between 15 and 40 ° C, is carried out. 20. The method according to claim 10e, characterized in that the reaction with a metal hydride such as lithium aluminum hydride or diborane or with a complex of borane and a thioether, e.g. with the complex of diborane and dimethyl sulfide, is carried out. 21. The method according to claims 10e, 11 and 18, characterized characterized in that the reaction at temperatures between 0 and 25 ° C, but preferably at temperatures between 10 and 25 ° C. 22. The method according to claims 10f and 11, characterized in that oxidation with potassium permanganate, selenium dioxide or sodium dichromate is carried out. 23. The method according to claims 10f, 11 and 22, characterized characterized in that the oxidation at temperatures between 0 and 100 ° C is carried out. 24. The method according to claims 10g and 11, characterized in that implementation in the presence of a complex Metal hydride is carried out. 25. The method according to claims 10g and 11, characterized in that for the preparation of compounds of general formula I, in which R _{3 represents} a hydrogen atom, the reaction is carried out in the presence of hydrogen and palladium / carbon. 26.A method according to claims 10g, 11, 24 and 25, thereby characterized in that the reaction at temperatures between 0 and 100 ° C, but preferably at temperatures between 20 and 80 ° C, is carried out.   27. The method according to claims 10h and 11, characterized in that the reaction in the presence of an acid-binding Is carried out. 28. The method according to claims 10h and 11, characterized in that the splitting off of protective residues is hydrolytic or hydrogenolytically. 29. The method according to claims 10h and 11, characterized in that the reaction at temperatures between 0 and 150 ° C, e.g. at the boiling point of the solvent used, is carried out.