GB2130213A - Benzazepines and benzodiazepines - Google Patents

Abstract

Compound of general formula I <IMAGE> (wherein R1 to R6, A, B, E and G are as defined in claim 1) and acid addition salts thereof. The new compounds have valuable pharmacological properties, in particular a heart-rate lowering effect. Processes for preparing the new compounds and pharmaceutical compositions containing them are also described.

Description

SPECIFICATION Chemical compounds This invention relates to new benzazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to the use of these compounds in the treatment of disorders of heart-rate.

British Patent No. 1,548,844 decribes, inter alia, the compound of formula

and the physiologically acceptable acid addition salts thereof, which has valuable pharmacological properties, i.e. in particular a selective heart-rate lowering effect in addition to a mild hypotensive effect.

It has surprisingly now been found that the compounds of the present invention have superior pharmacological properties, namely, in particular, a stronger heart-rate lowering effect with a longer duration of activity and fewer side effects.

Thus, according to one feature of the present invention, we provide compounds of general formula I

[wherein R1 represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, an alkoxy group with 1 to 3 carbon atoms or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with an alkylenedioxy group with 1 or 2 carbon atoms;; R3 represents a hydrogen, fluorine, chlorine or bromine atom, a nitro or trifluoromethyl group or an alkyl or alkoxy group each having 1 to 3 carbon atoms and R4 represents a hydrogen atom, an amino group or an alkoxy, alkylamino or dialkylamino group (each alkyl moiety having 1 to 3 carbon atoms and the alkyl moieties in the dialkylamino group being the same or different), or R3 and R4 together represent an alkylenedioxy group with 1 or 2 carbon atoms; R5 represents a hydrogen, chlorine or bromine atom; R6 represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms; E represents an n-alkylene group with 2 to 4 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms; B represents a thiocarbonyl, carbonyl or methylene group;; G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms (wherein, so long as B represents a methylene or carbonyl group, a methylene group may optionally be replaced by a carbonyl group), or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G; and A represents a group of formula -CH2-C142-, -CH=CH-, -NH-CO-, -CH2-CO-, 5 5

--N=CH--, 5

(wherein R, represents an alkyl group with 1 to 3 carbon atoms and R8 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms substituted by a phenyl, methoxy-phenyl or dimethoxyphenyl group); with the provisos that (i) when A represents a group of formula -CH2-CH2-, -CH=CH-, -NH-CO-, -CH2-CO- or

(wherein R7 is as hereinbefore defined); B may not represent a methylene or carbonyl group unless G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R, and R2 each represents a hydrogen atom or R1 represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms (except in the case of A representing a -CH2CH2- group, R1 and R2 representing methoxy groups in the 7- and 8-positions, E representing an n-propylene group, Re representing a methyl group, G representing an ethylene group, R5 representing a hydrogen atom, and R3 and R4 either both representing hydrogen atoms or representing respectively a 3-nitro and a 4-amino group, in which case B may represent a carbonyl group);; (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R1 and R2 each represents a hydrogen atom or R1 represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms; and (iii) when A represents a group of formula -N=CH-,

(wherein R8 is as hereinbefore defined), B represents a methylene group] and acid addition salts of the aforementioned compounds.

The term "acid addition salts" as used herein refers to salts formed with organic and inorganic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic and fumaric acids.

For pharmaceutical use the acid addition salts will, of course, be physiologically acceptable acid addition salts, but other acid addition salts may find use, for example in the preparation of the compounds of general formula I and their physiologically acceptable acid addition salts.

The definitions given hereinbefore for the groups R1 to Rat E and G include the following: R1 may be a hydrogen, fluorine, chlorine or bromine atom, or a trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, amino, methyla mino, ethyla mino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-npropylamino, methyl-isopropylamino or ethyl-n-propylamino group, R2 may represent a hydrogen, fluorine, chlorine or bromine atom, or a methoxy, ethoxy, n-propoxy or isopropoxy group or together with R1 may represent a methylenedioxy or ethylenedioxy group, R3 may represent a hydrogen, fluorine, chlorine or bromine atom, or a nitro, trifluoromethyl, methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy or isopropoxy group, R4 may represent a hydrogen atom, or a methoxy, ethoxy, n-propoxy, isopropoxy, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-npropylamino, diisopropylamino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropylamino or ethyl-n-propylamino group or together with R3 may represent a methylenedioxy or ethylenedioxy group, Rs may represent a hydrogen, chlorine or bromine atom, R6 may represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, allyl, n-buten-(2)-yl or n-penten-(2)-yI group, R7 may represent a methyl, ethyl, n-propyl or isopropyl group, Rs may represent a hydrogen atom or a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2 (4-m ethoxyphenyl)-ethyl, 2-(3,4-dimethoxyphenyl)-ethyl, 3-(4-methoxyphenyl)-propyl or 3-(3,4dimethoxyp.henyl)-propyl group, E may represent an ethylene, n-propylene, n-butylene, 1-methyl-ethylene, 2-ethyl-ethylene, 1propyl-ethylene, 1-methyl-n-propylene, 2-methyl-n-propylene, 1-ethyl-n-propylene, 3-ethyl-npropylene, 2-propyl-n-propylene or 2-methyl-n-butylene group and G may represent a methylene, ethylidene, n-propylidene, n-butylidene, 2-methyl-propylidene, ethylene, 1-methyl-ethylene, 2-ethyl-ethylene, 1-propyl-ethylene, 2-methyl-ethylene, n-propylene, nbutylene, n-pentylene, 1-methyl-n-propylene, 1 -methyl-butylene, 1 -methyl-n-pentylene, 1-ethyí-n- propylene, 2-ethyl-n-propylene, 1 -methyl-n-butylene, methylenecarbonyl, ethylenecarbonyl, npropylenecarbonyl, n-butylenecarbonyl, carbonylmethylene, carbonylethylene, carbonyl-n-propylene, carbonyl-n-butylene, methyleneca rbonyl methylene, ethylenecarbonylmethylene, 2-hydroxyethylene, 2hydroxy-n-propylene, 3-hydroxy-n-propylene, 2-hydroxy-n-butylene, 3-hydroxy-n-butylene, 4-hydroxyn-butylene or 2-hydroxy-n-pentylene group; the group R1 is preferably in the 8 position, R2 in the 7 position, R3 in the 3 position, R4in the 4 position and R5 in the 5 position of the phenyl nucleus in question.

However, preferred compounds are compounds of general formula la

[wherein R1 represents a hydrogen, chlorine or bromine atom or a trifluoromethyl, methoxy, amino, methylamino or dimethylamino group, and R2 represents a hydrogen, chlorine or bromine atom or a methoxy group, or R1 and R2 together represent a methylenedioxy group; R3 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl, methoxy, trifluoromethyl or nitro group, and R4 represents a hydrogen atom or an amino, methoxy, methylamino or dimethylamino group, or R3 and R4 together represent a methylenedioxy group; R5 represents a hydrogen, chlorine or bromine atom; Re represents a hydrogen atom or a methyl or allyl group; B represents a thiocarbonyl, carbonyl or methylene group;; G represents an n-alkylene group with 2 to 5 carbon atoms (wherein, so long as B represents a methylene or carbonyl group, a methylene group may optionally be replaced by a carbonyl group), or a methylene-n-hydroxy-alkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G; and A represents a group of formula

with the provisos that (i) when A represents a group of formula -CH2-CH2- or -CH=CH-, B represents a thiocarbonyl group, and may also represent a carbonyl group when G represents an n-alkylene group with 3 to 5 carbon atoms, an n-alkylene group with 2 to 5 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-nhydroxyaikylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R1 and R2 each represents a hydrogen atom or R1 represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and R2 represents a hydrogen, chlorine or bromine atom or a methoxy group;; (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 5 carbon atoms, an n-alkylene group with 2 to 5 carbon atoms herein a methylene group is replaced by a carbonyl group, or a methylene-nhydroxyalkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R1 and R2 each represents a hydrogen atom or R1 represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and R2 represents a hydrogen, chlorine or bromine atom or a methoxy group; and (iii) when A represents a group of formula -N=CH- 5

B represents a methylene group] and acid addition salts thereof.

The compounds 1 -(7 8-dimethoxy- 1,3 ,4,5-tetra hydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyí- N-(2-phenylethyl)-amino]-propane, and 1 -(7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on 3-yl)-3-[N-methyl-N-(2-(4-amino-3-nitro-phenyl)-ethyl)-a mino]-propane, and acid addition salts of these compounds, are also preferred compounds of the invention.

Particularly preferred are those compounds of general formula la above wherein A represents a -CH2-CH2- group; B represents a -CO- or -CS- group; R1 represents a methoxy, amino, methylamino or dimethylamino group, and R2 represents a hydrogen atom or a methoxy group or R1 and R2 together represent a methylenedioxy group; R3 represents a hydrogen, fluorine, chlorine or bromine atom or a methoxy or trifluoromethyl group, and R4 represents a methoxy, amino, methylamino or dimethylamino group or R3 and R4 together represent a methylenedioxy group; R5 represents a hydrogen, chlorine or bromine atom; Re represents a methyl group; and G represents an n-alkylene group with 3 to 5 carbon atoms, a

group, or (if B represents a -CS- group and/or R1 represents an amino, methylamino or dimethylamino group) a -CH2CH2- group, and acid addition salts thereof.

Also mentioned as compounds of the invention are those wherein R1 and R2 each represents a methoxy group; R3 represents a methoxy group or a hydrogen or chlorine atom; R4 represents a methoxy, amino or dimethylamino group; R5 represents a hydrogen or chlorine atom; Re represents a methyl group; G represents a n-alkylene group with 3 to 5 carbon atoms or a

group or (if B represents a thiocarbonyl group or A represents a group of formula

a -CH2-CH2- group; and either A represents a -CH2-CH2- group and B represents a thiocarbonyl or (if G represents an n-alkylene group with 3 to 5 carbon atoms) a carbonyl group, or A represents a

group and B represents a methylene group, and acid addition salts of these compounds.

The following compounds are specifically mentioned as exampies of compounds of the invention: 1-(7 ,8-dimethoxy- 1 ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yI)-3-[N-methyl-N-(3-(3,4- dimethoxyphenyl)-propyl)-amino]-propane, 1 -(1 -hydroxy-7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2- (3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, 1 -(7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino- 3,5-dichloro-phenyl)-propyl)-amino]-propane, 1 -(7 8-dimethoxy- 1 ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-phenyl- ethyl)-amino]-propane, and 1 -(7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4-amino- 3-nitro-phenyl)-ethyl)-amino]-propane, and acid addition salts of these compounds.

The compounds of general formula I and their acid addition salts may, for example, be prepared by the following processes, which processes constitute further features of the present invention: a) reacting a compound of general formula II

with a compound of general formula Ill

wherein R2, R3, R5, A, B, E and G are as hereinbefore defined, R1, and R4' each represents an amino or alkylamino group protected by a protecting group or they each have the meanings given for R1 and R4 hereinbefore, one of the groups U and V represents an R,--NHH- group wherein Re is as hereinbefore defined, and the other group U or V represents a nucleophilically exchangeable group such as, for example, a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom or a methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group), and optionally subsequently splitting off any protecting group used.

The reaction may conveniently be carried out in a solvent or mixture of solvents such as, for example, acetone, diethylether, methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan or in an excess of the compounds of general formula II and/or lil used and optionally in the presence of an acid-binding agent, e.g. an alkoxide such as potassium tert. butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, whilst the latter may also serve as solvents at the same time, or a reaction accelerator such as potassium iodide, and, depending on the reactivity of the nucleophilically exchangeable group, conveniently at temperatures of between 0 and 1 500C, preferably at temperatures of between 50 and 1 200C, e.g. at the boiling temperature of the solvent used. However, the reaction may also be carried out without a solvent.It is, however, particularly advantageous to perform the reaction in the presence of a tertiary organic base or an excess of the amine of general formula Ill used.

The optional subsequent splitting off of a protecting group used is preferably effected hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as, for example, hydrochloric or sulphuric acid or in the presence of an alkli metal base such as, for example, sodium hydroxide or potassium hydroxide at temperatures of between 0 and 1000C, preferably at the boiling temperature of the reaction mixture.

However, a benzyl group may also be split off by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as, for example, palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures of between 0 and 500C, but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar.

b) In order to prepare compounds of general formula I wherein A represents a --CH2--CH2--, --CH=CH--, --NH--CO--, --COCO--, --CH2--CO--, 5 5

B represents a -CH2- or -CO- group: reacting a compound of general formula IV

(wherein R2 is as hereinbefore defined, A' represents a -CH2-CH2-, -CH=CH-, -NH-CO-, -COCO-, -CH2-CO-, 5 5

group wherein R7 represents an alkyl group with 1 to 3 carbon atoms, B' represents a -CH2- or -CO- group and R,' represents an amino or alkylamino group protected by a protecting group or has the meanings given for R1 hereinbefore), with a compound of general formula V

(wherein R3,R5,Re, E and G are as hereinbefore defined, R4, represents an amino or alkylamino group protected by a protecting group or has the meanings given for R4 hereinbefore and Z represents a nucleophilically exchangeable group such as, for example, a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom, or a methanesulphonyloxy, ptoluenesulphonyloxy or ethoxysulphonyloxy group), and optionally subsequently splitting off any protecting group used.

The reaction may optionally be carried out in a solvent or mixture of solvents, e.g. in acetone, dimethylformamide, acetone/dimethylformamide, dimethylsulphoxide or chlorobenzene, and conveniently, depending on the reactivity of the group Z, at temperatures of between 0 and 1 500C, but preferably at the boiling temperature of the solvent used. It may be advantageous to work in the presence of an acid-binding agent, for example, an alkoxide such as sodium methoxide, an alkali metal hydroxide such a sodium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as, for example, potassium iodide.

The optional subsequent splitting off of a protecting group used is preferably effected hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures of between 0 and 1 000C, preferably at the boiling temperature of the reaction mixture.However, a benzyl group may also be split off by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as, for example, hydrochloric acid at temperatures of between 0 and 500C, but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar.

c) In order to prepare compounds of general formula I wherein A does not represent a

or -CO-CO- group: reacting a compound of general formula VI

(wherein B, E, R1 and R2 are as hereinbefore defined but in the group E two hydrogen atoms in a -CH2- or -CH3 group of the group E are replaced by an oxygen atom, and A" represents a -CH2-CH2-, -CH=CH-, -NH-CO-, -CH2-C0-, -N=CH-, 5 5 5

group wherein R7 represents an alkyl group with 1 to 3 carbon atoms), with an amine of general formula VII

(wherein G and R3 to Re are as hereinbefore defined), in the presence of a reducing agent.

The reaction may conveniently be carried out in a suitable solvent or mixture of solvents such as, for example, methanol, ethanol, ethanol/ethyl acetate or dioxan at temperatures of between 0 and 1 000C, but preferably at temperatures of between 20 and 800 C.

It is particularly advantageous to carry out the reductive amination in the presence of a complex metal hydride such as, for example, lithium or sodium cyanoborohydride, preferably at a pH of 6-7 and at ambient temperature or, in order to prepare compounds of general formula I wherein R6 represents a hydrogen atom, in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium/charcoal under a hydrogen pressure of 5 bar. Any double bonds present may be hydrogenated.

d) In order to prepare compounds of general formula I wherein A does not represent a

or -CO-CO- group: reacting a compound of general formula VIII

(wherein B,E,R1, R2 and Re are as hereinbefore defined and A" represents a -CH2-CK2-, -CH=CH-, -NH-CO-, -CH2-CO-, -N=CH-, 5 5 5

group wherein R7 represents an alkyl group with 1 to 3 carbon atoms) with a compound of general formula IX

(wherein R3 to R5 and G are as hereinbefore defined, but in the group G two hydrogen atoms in a -CH2- or-CH3 group of the group G are replaced by an oxygen atom), in the presence of a reducing agent.

The reaction may conveniently be carried out in a suitable solvent or mixture of solvents such as, for example, methanol, ethanol, ethanol/ethyl acetate or dioxan at temperatures of between 0 and 1 O00C, but preferably at temperatures of between 20 and 800C.

It is particularly advantageous to carry out the reductive amination in the presence of a complex metal hydride such as lithium or sodium cyanoborohydride, preferably at a pH of 6 to 7 and at ambient temperature or, in order to prepare compounds of general formula I wherein Re represents a hydrogen atom, in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of pailadium/charcoal under a hydrogen pressure of 5 bar. Any double bonds present may be hydrogenated.

e) In order to prepare compounds of general formula I wherein A represents a -CH2-CH2- group, B represents a methylene or carbonyl group and Re does not represent an alkenyl group with 3 to 5 carbon atoms: hydrogenating a compound of general formula X

(wherein R1 to Re, E and G are as hereinbefore defined and B' represents a methylene or carbonyl group).

The hydrogenation may be effected in a solvent or mixture of solvents such as, for example, methanol, ethanol, ethyl acetate or glacial acetic acid with catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium/charcoal, under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar, and at temperatures of between 0 and 750C, but preferably at temperatures of between 20 and 5O0C.

f) In order to prepare compounds of general formula I wherein B represents a -CS- group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety: reacting a compound of general formula Xl (wherein

R1 to Re, A and E are as hereinbefore defined and G' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety), with a sulphur-introducing agent.

The reaction is carried out with a sulphur-introducing agent such as, for example, phosphorus pentasulphide or 2,4-bis-(4-methoxyphenyl)-1 ,3-dithia-2,4-diphosphetane-2,4-disulphide, conveniently in a solvent such as, for example, toluene or xylene at temperatures of between 50 and 1 500C, e.g. at the boiling temperature of the reaction mixture.

g) In order to prepare compounds of general formula I wherein A represents

group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxy-alkylene group with 1 to 4 carbon atoms in the alkylene moiety: reducing a compound of general formula XII (wherein

R1 to Re, E and G are as hereinbefore defined).

The reaction is carried out in the presence of a suitable reducing agent such as, for example, a metal hydride, e.g. sodium borohydride, lithium aluminium hydride or diborane, in a suitable solvent such as, for example, water/methanol, methanol/ether, tetrahydrofuran, dioxan or ether/tetrahydrofuran at temperatures of between 0 and 8O0C, but preferably at temperatures of between 1 5 and 400C. In the reaction, any CO group present in the G group is also reduced to a CHOH group.

h) In order to prepare compounds of general formula I, wherein A represents a

group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety: reacting a compound of general formula XIII (wherein

R, to Re and E are as hereinbefore defined and G' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety), with a compound of general formula XIV

(wherein R9 represents a hydroxy group or has the meanings given for R8 hereinbefore), optionally with subsequent reduction.

The reaction may conveniently be effected in a solvent such as, for example, ethanol, dioxan or glycol or in a melt at elevated temperatures, e.g. at temperatures of between 50 and 1 75 OC. The optional subsequent reduction may be effected with a reducing agent such as a complex metal hydride, e.g. lithium aluminium hydride, with catalytically activated hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium/charcoal under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar, or with hydrazine/Raney nickel in a suitable solvent such as, for example, methanol, ethanol, ethyl acetate or glacial acetic acid at temperatures of between 0 and 1 000C, but preferably at temperatures of between 20 and 500C.

i) In order to prepare compounds of general formula I wherein A represents an -N=CH- group and Re represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms: reacting a compound of general formula XV

(wherein R1 to R5, B, E and G are as hereinbefore defined and Re' represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms), with an orthoformic acid ester.

The reaction may preferably be carried out in a solvent such as, for example, ethanol, toluene, dimethoxyethane or in an excess of the orthoester used at temperatures of between 100 and 2000C.

It may also be advantageous for any -NH2 or =NH groups present to be protected by protecting groups, e.g. acetyl, benzoyl, ethoxycarbonyl or benzyl groups, during the reaction.

Any protecting groups used during the reaction are subsequently split off, e.g. acyl groups are preferably removed hydrolytically in the presence of an acid or base whilst benzyl groups are preferably removed by hydrogenolysis, e.g. with hydrogen in the presence of a hydrogenation catalysts such as palladium/charcoal or platinum.

j) In order to prepare compounds of general formula I wherein A does not represent a -COCO- group and G represents a methylene-n-hydroxyalkylene group: reducing a compound of general formula XVI

(wherein R1 to Re, B and E are as hereinbefore defined, A"' has the meanings given for A hereinbefore, with the exception of the -COCO- group, and G" represents a methylene-n-alkylene group, wherein the alkylene moiety contains 1 to 4 carbon atoms and a methylene group of the alkylene moiety is replaced by a carbonyl group).

The reduction is preferably carried out with a metal hydride such as, for example, sodium borohydride or lithium aluminium hydride, or with diborane, in a suitable solvent such as, for example, ethanol, ethanol/water, methanol or isopropanol at temperatures of between 0 and 500C, but preferably at temperatures of between 10 and 250C.

k) In order to prepare compounds of general formula I wherein R3 represents a nitro group and R4 represents an amino group: hydrolysis of a compound of general formula XVII

(wherein R1, R2, R5, Re, A, B, E and G are as hereinbefore defined, and acyl represents an acyl group such as, for example, an acetyl, ethoxycarbonyl or benzoyl group).

The acyl group used may preferably be split off by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as, for example, hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures of between 0 and 100 C, preferably at the boiling temperature of the reaction mixture. However, the reaction is preferably carried out in the presence of an alcoholic acid, e.g. with methanolic or ethanolic hydrochloric acid.

I) In order to prepare compounds of general formula I wherein A represents a -CH2-CH2-, -CH=CH-, -NH-CO-, -CH2-CO-, -N=CH-,

group and one of the groups R1, R2, R3 orR4 represents an alkoxy, alkylamino or dialkylamino group or R6 represents an alkyl or alkenyl group: reacting a compound of general formula XVIII

(wherein R1 to Re, B and E are as hereinbefore defined, but at least one of the groups R1 to R4 must represent a hydroxy group or R1 or R4 must represent an amino or alkylamino group or Re must represent a hydrogen atom, A' represents a -CH2-CH2-, -CH=CH-, -NH-CO-, -CH2-CO-, -N=CH-, 5 5 5

group wherein R7 represents an alkyl group with 1 to 3 carbon atoms, and G"' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, wherein a methylene group may be replaced by a carbonyl group), with a compound of general formula XIX R10--X (XIX) (wherein RXO represents an alkyl group with 1 to 3 carbon atoms or, if Re represents a hydrogen atom, an alkenyl group with 3 to 5 carbon atoms and X represents an nucleophilically exchangeable group such as, for example, a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulphonyloxy, ptoluenesulphonyloxy or methoxysulphonyloxy group or, if at least one of the groups R1 to R4 represents a hydroxy group, X together with a hydrogen atom in the a position of the group R10 represents a diazo group or, if Re represents a hydrogen atom or R1 or R4 represents an amino or alkylamino group, X may also represent an oxygen atom).

The reaction may conveniently be carried out in a solvent or mixture of solvents such as diethyl ether, methanol, acetone, tetrahydrofuran, dioxan, acetonitrile, pyridine or dimethylformamide, optionally in the presence of a base such as potassium carbonate, potassium hydroxide, potassium tert.

butoxide or sodium hydride at temperatures of between 0 and 1 500C, but preferably at temperatures of between 20 and 1 200C.

If B represents a -CH2- or -CO- group and X represents a nucleophilically exchangeable group, the reaction is preferably carried out with an alkylating agent such as, for example, methyl iodide, dimethyl sulphate, ethyl iodide, diethyl sulphate, propyl bromide, allyl bromide or isopropyl ptoluenesulphonate in the presence of an acid-binding agent at temperatures of between 20 and 800C.

However, the reaction may also be carried out without a solvent.

If X together with a hydrogen atom in the a position of the group R10 represents a diazo group, in order to alkylate a hydroxy group the reaction is preferably carried out with a diazoalkane such as, for example, diazomethane or diazoethane at temperatures of between 0 and 30"C, or if X represents an oxygen atom, in order to alkylate the nitrogen atom the reaction is preferably carried out in the presence of a reducing agent at temperatures of between 0 and 1 2O0C, e.g. with formic acid at temperatures of between 80 and 11 00C or with sodium cyanoborohydride at ambient temperature and atapHof6to7.

m) In order to prepare compounds of general formula I wherein A represents a -COCO- group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group may optionally be replaced by a carbonyl group: oxidising a compound of general formula XX

(wherein R1 to Re, E and G are as hereinbefore defined.

The oxidation may preferably be carried out with an oxidising agent such as, for example, potassium permanganate, selenium dioxide or sodium dichromate in a suitable solvent or mixture of solvents such as, for example, water, water/dioxan, glacial acetic acid, water/acetic acid or acetic anhydride at temperatures of between 0 and 1 000C, preferably at temperatures of between 20 and 800 C.

n) In order to prepare compounds of general formula I wherein A represents a -CH2-CO- 5 group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group may optionally be replaced by a carbonyl group: oxidising a benzazepine of general formula XXI (wherein

R1 to Re, B, E and G are as hereinbefore defined).

The oxidation may be effected with ruthenium tetroxide in a suitable solvent or mixture of solvents such as chloroform/water, methylene chloride/water or carbon tetrachloride/water at temperatures of between 0 and 1 000C, preferably at temperatures of between 20 and 500C. However, the reaction is preferably carried out in a two-phase system such as methylene chloride/water, chloroform/water or carbon tetrachloride/water with a catalytic quantity of ruthenium dioxide in the presence of a suitable oxidising agent such as, for example, sodium periodate which products ruthenium tetroxide in situ.

o) In order to prepare compounds of general formula I wherein R1 is in the 7 position, A represents a -CH2CH2- group and B represents a -CO- group: cyclising a compound of general formula XXII (wherein

R1 to R5, G and E are as hereinbefore defined, Re' represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms, and Y represents a group suitable for cyclisation).

Y may represent, for example, a carboxy or nitrile group, an ester group (such as a methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or benzyloxycarbonyl group), a thioester group (such as an ethylthiocarbonyl, phenylthiocarbonyl or pyridylthiocarbonyl group), an acyloxycarbonyl group (such as an acetoxycarbonyl or trifluoroacetylcarbonyl group) or an amide group (such as an aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or phenylaminocarbonyl group).

The reaction is optionally carried out in the presence of a suitable condensing agent and optionally in a pressure vessel in a solvent such as xylene, dimethylglycol ether, tetralin or sulpholane at elevated temperatures, e.g. at temperatures of between 100 and 2500 C, but preferably at temperatures of between 140 and 1 8O0C. However, the reaction may also be carried out without a solvent.

Suitable condensing agents include, for example, N,N'-dicyclohexylcarbodiimide, thionyl chloride, 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-ch loropyridinium iodide or N-methyl-24luoro-pyridinium tosylate, N,N'dicyclohexylcarbodiimide/4-dimethylaminopyridine, chlorosulphonyl isocyanate or N,N'carbonyldiimidazole.

It may also be advantageous for any HO, NH or NH2 groups present to be protected by means of protecting groups, e.g. acetyl, benzoyl, ethoxycarbonyl or benzyl groups, during the reaction.

If Y in a compound of general formula XXII represents a nitrile or amide group, the reaction is preferably effected so that a corresponding compound is converted, by alkaline or acidic hydrolysis, e.g.

by means of methanol/hydrochloric acid or ethanol/sodium hydroxide solution at the boiling temperature of the reaction mixture, into a corresponding carboxy compound which is subsequently cyclised.

Any protecting groups used during the reaction are subsequently split off, e.g. acyl groups are preferably removed by hydrolysis in the presence of an acid or base whilst benzyl groups are preferably removed by hydrogenolysis e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal or platinum.

The compounds of general formula I, initially obtained, may subsequently be converted into the acid addition salts thereof, for example by conventional methods such as reacting the compounds as bases with an acid in a suitable solvent. Acid addition salts of these compounds, initially obtained, may subsequently be converted into the corresponding compounds of general formula I or into different acid addition salts thereof.

The compounds of general formulae II to XXII used as starting materials are known from the literature in some cases or may be obtained by methods known per se.

Thus, for example, a starting compound of general formulae II and VIII may be obtained by reacting a corresponding benzazepine with a corresponding halogen compound and optionally subsequently reacting it with a corresponding amine. The benzazepine of general formula IV required for this is obtained by cyclising a corresponding compound, e.g. by cyclising a compound of general formula XXIII

or of general formula XXIV

if R1 and R2 do not represent alkoxy groups, optionally followed by catalytic hydrogenation and/or reduction of the carbonyl group using sodium borohydride/glacial acetic acid, for example (see published European Patent Application No. 7070) and/or oxidation, e.g. with selenium dioxide.

A compound of general formula VI used as starting compound may be obtained, for example, by reacting a corresponding benzazepine with a corresponding haloacetal with subsequent hydrolysis.

A compound of general formula XV used as starting material may be obtained by reduction of a corresponding nitro compound which is in turn obtained by acylation or alkyiation of a corresponding amine.

Compounds of general formulae X to XIII, XVI to XVII, XVIII, XX and XXI used as starting materials may preferably be obtained by reacting a corresponding halogen compound with a corresponding amine and optionally subsequently splitting off any protecting groups used to protect the hydroxy groups.

A compound of general formula XXII used as starting material may be obtained, for example, by chloromethylation of a compound of general formula XXV (wherein

R1, R2 and E are as hereinbefore defined and W represents a protected hydroxy group, e.g. an acetoxy, benzoyloxy or 4-nitrobenzoyloxy group), further reacting it with an alkali metal cyanide, converting the group W into a suitable leaving group such as that of the chlorine, bromine or iodine atom or of the methylsulphonyloxy or 4-methylphenylsulphonyloxy group and subsequently reacting with an amine of general formula VII (wherein

R3 to Re and G are as hereinbefore defined), with optional subsequent hydrolysis and/or esterification or amidation.

As already mentioned hereinbefore, the new compounds of general formula I and the physiologically acceptable addition salts thereof have valuable pharmacological properties, more particularly a long-lasting heart rate lowering activity and the effect of reducing the O2 requirement of the heart, with very few side effects, e.g. only a slight antimuscarinic effect.

For example, the following compounds A= 1 -(7,8-dimethoxy- 1,3 ,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yi)-3-[N-methyl-N-(3-(3 ,4- dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride, B= 1 -(7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-thion-3-yl)-N-[N-methyl-N-(2-(3,4- dimethoxy-phenyl)-ethyl)-amino]-propane, C=1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2- hydroxy-2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, D=1-(1-(1-hydroxy-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N (2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, E= 1 -(7,8-dimethoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4- amino-3-nitro-phenyl)-ethyl)-amino]-propane hydrochloride, F=1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(4-(4- dimethylamino-phenyl)-butyl)-amino]-propane hydrobromide, G= 1 -(7 ,8-dimethoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2- phenyiethyl)-amino]-propane dihydrochloride, H= 1 -(7,8-dimethoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(5-(3,4- dimethoxy-phenyl)-pentyl)-amino]-propane hydrochloride and 1=1 -(7,8-dimethoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4- amino-3,5-dichlorophenyl)-propyl)-amino]-propane have been tested by comparison with K= 1 -(7,8-dimethoxy- 1,3 ,4,5-tetrahydro-5H-2-benzazepin- 1 -on-2-yl)-3-[N-methyl-N-(2-(3,4- dimethoxy-phenyl)-ethyl)-am ino]-propane hydrochloride for their biological properties as follows: Effect on heart rate in rats The effect of the test substances on heart rate was investigated in two rats with an average weight of 250 to 300 g for each dose. The rats were anaesthetised with pentobarbital (50 mg/kg i.p.

and 20 mg/kg s.c.). The test substances were injected in aqueous solution into the jugular vein (0.1 ml/1 00 g).

The blood pressure was measured using a cannula inserted in a carotid artery and the heart rate was recorded from an ECG (llnd or Illrd reading) obtained using needle electrodes. The heart rate of the animals in the control period was between 350 and 400 beats per minute (b/min).

The following tabie contains the values found: Reduction in heart rate measured 20 minutes after administration Substance Dose {mg/kg) of substance (b/min) A 5.0 -183 2.5 -85 1.0 -51 B 5.0 -255 2.5 -134 1.0 -73 C 5.0 -173 2.5 -137 D 5.0 -117 2.5 -73 1.0 -83 E 5.0 -130 F 5.0 -123 2.5 -91 1.0 -94 G 5.0 -135 2.5 -110 1.0 -80 H 5.0 -75 5.0 -175 K 5.0 -18 The compounds prepared according to the invention do not have any toxic side effects of any kind when administered in therapeutic doses. Thus, for example, when substances A and D are administered intravenously to mice, even in a high dosage of 20 mg/kg, no toxic side effects can be detected.

In view of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of sinus tachycardia of various origins and for the prophylaxis and therapy of ischaemic cardiac diseases.

According to a yet further feature of the present invention, there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of general formula I as hereinbefore defined or a physiologically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient.

For pharmaceutical administration the compounds of the invention may be incorporated into conventional preparations in either solid or liquid form, optionally together with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral administration. Preferred forms include, for example, tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups and suppositories.

The active ingredient may be incorporated in inert carriers and/or diluents customarily employed in pharmaceutical compositions, such as, for example, corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, carboxymethyl cellulose, paraffin derivatives, fatty substances of animal or vegetable origin (e.g. hard fat), various wetting, dispersing, emulsifying, or preservative agents, or mixtures thereof.

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient. The dose required is conveniently from 0.03 to 0.4 mg/kg of body weight (preferably from 0.07 to 0.25 mg/kg of body weight) administered once or twice per day.

Depending on the kind and the body weight of the patient to be treated, on the kind and the seriousness of the disease, on the type of preparation and on the route of administration as well as on the period or interval over which the administration takes place, it may however be necessary to deviate from the above dosages. Thus, it may be sufficient in some cases to administer less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. The optimal dosage and type of administration of the active ingredients which are necessary in each case can easily be assessed by one skilled in the art.

Thus, according to a still further feature of the present invention, there is provided a method of preventing or relieving ischaemic cardiac diseases, or of relieving sinus tachycardia in a patient, which comprises administering to the said patient an effective amount of a compound of general formula I as defined above or a physioiogically acceptable acid addition salt thereof.

The following non-limiting Examples are intended to illustrate the invention more fully: Preparation of the starting compounds Example A 1 -(7,8-Dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-N-methyl-amino-propane- hydrochloride a) 1 -(7,8-Dimethoxy- 1 ,3-d ihydro-2H-3-benzazepin-2-on-3-yl)-3-N-methyl-N-benzyl-a mino-propane hydrochloride Prepared analogously to Example 1 b by reacting 1 -(7,8-dimethoxy-1 ,3-dihydro-2H-3- benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-benzylamine.

Yield: 92.1% of theory.

Melting point: 208-2090C.

b) 1 -(7,8-Dimethoxy-1 ,3 ,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-N-methyl-a mino-propane hydrochloride Prepared analogously to Example 5 by catalytic hydrogenation of 1 -(7,8-dimethoxy-1 ,3-dihydro- 2 H-3-benzazepin-2-on-3-yl)-3-N-methyl-N-benzyl-aminopropane.

Yield: 87% of theory.

Melting point: 1 100C (decomposition).

Example B 1 ,3,4,5-Tetrahydro-2H-3-benzazepin-2-one a) N-(2-Phenyl-ethyl)- 1 -chloro-acetamide 38.7 ml (0.3 mol) of 2-phenylethylamine and 45.9 ml (0.033 mol) of triethylamine are dissolved in 30 ml of methylene chloride and mixed with 26.4 ml (0.33 mol) of chloroacetyl chloride, dissolved in 1 50 ml of methylene chloride, at 1 OOC. After 1 hour's stirring at ambient temperature, the product is extracted with 1% acetic acid and with water, dried over magnesium sulphate and concentrated by evaporation in vacuo.

Yield: 54.2 g (91.4% of theory).

M.p. 64--650C.

b) 1 ,3,4,5-Tetrahydro-2 H-3-benzazepin-2-one 54.0 g (0.373 mol) of N-(2-phenyl-ethyl)-1-chloroacetamide are mixed with 73.8 g (0.55 ml) of aluminium chloride and stirred for 13 hours at 1 30--1 40 OC. After the aluminium chloride has been destroyed with ice water, the product is extracted with methylene chloride, washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and the residue obtained is purified over silica gel using methylene chloride plus 3% ethanol as eluant.

Yield: 6.22 g (14.1% of theory).

Melting point: 1 58-1 600C.

Example C 1-(7-Bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane 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 OC), dissolved in 600 ml of glacial acetic acid, were hydrogenated in the presence of 5 g of 10% palladium/charcoal at a temperature of 800C under a hydrogen pressure of 5 bar for 12 hours. After filtering off the catalyst the solvent was removed in vacuo. The obtained residue was mixed with water and neutralised with potassium carbonate. The precipitate was suction filtered, washed with water and dried.

Yield: 51.1 g (89.1% of theory).

Melting point: 160161 OC.

b) 7-Bromo- and 9-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 6.4 g#2.03 ml (0.04 ml) of bromine were dropped into a solution of 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 at a temperature between 30 and 50C whilst stirring. After 15 minutes, the reaction mixture was poured into ice-water and neutralized with potassium carbonate. The precipitate was suction filtered, washed with a little water and dried. The isomers were separated by means of chromatography over silica gel using ethyl acetate as eluant.

Yield: 5.7 g (52.8% of theory) of 9-bromo-isomer.

IR spectrum (methylene chloride): 3,400 cm-' (NH) 1,660 cm-' (CO) 4.1 g (38% of theory) of 7-bromo-isomer.

IR-spectrum (potassium bromide): 3,200 cm-1 (NH) 1,665 cm~1 (CO).

c) 1 -(7-Bromo-8-methoxy- 1 ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-chloro-propane 0.24 g of 55% sodium hydride dispersion in oil were added to a mixture of 1.35 g (5 mol) of 7 bromo-8-methoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 15 ml of dimethylsulfoxide at room temperature. After stirring at room temperature for 30 minutes and at a temperature between 350 and 400C for 10 minutes, the obtained solution was added to 0.79 g (5.5 mol) of 1 -bromo-3-chloropropane in 5 ml of dimethylsulfoxide. After stirring at room temperature for 2 hours, the mixture was poured into ice-water and extracted with methylene chloride four times. The methylene chloride extracts were washed with water, dried and evaporated in vacuo. The obtained residue was purified over silica gel using ethyl acetate as eluant.

Yield: 210 mg (12% of theory).

Melting point: 1 19-1200C.

Example D 7-N itro-8-m ethoxy-1 3,4,5-tetra hydro-2H-3-benzazep in-2-one 765 mg (4 mol) of 8-methoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-one were added to a mixture of 1 5 ml of concentrated nitric acid and of 1.5 ml of fuming nitric acid at a temperature between 3 and 50C whilst stirring. After stirring at this temperature for further 30 minutes, the mixture was poured into ice-water and neutralised with potassium carbonate. The formed precipitate was suction filtered, washed with water and dried. The yellow crystals were purified over silica gel using ethyl acetate as eluant to separate the corresponding 9-nitro- and 7,9-dinitro-isomers.

Yield: 400 mg (42.3% of theory).

Melting point: 204--2050C (decomp.).

Preparation of the end products: Example 1 1 -(7,8-Dimethoxy-1 ,3,4,5-tetrahydrn-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4 dimethoxy-phenyl)-propyl)-a mino]-propane hydrochloride a) 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane 1.1 g (0.005 mol) of 7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-one are suspended in 15 ml of absolute dimethylsulphoxide and mixed with 0.67 g (0.006 mol) of potassium tert. butoxide with stirring. After 10 minutes, the suspension obtained is added dropwise to 0.64 ml (0.006 mol) of 1-bromo-3-chloro-propane in 10 ml of dimethylsulphoxide, whilst cooling with ice water. After 1 hour the mixture is poured on to water. After a short time the viscous precipitate begins to crystallise.The precipitate is suction filtered, dissolved in acetone, precipitated again with water, then suction filtered and dried.

Yield: 0.75 g (50.0% of theory).

Melting point: 84-850C.

b) 1 -(7,8-Dimethoxy- 1,3 ,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4- dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride 5.55 g (0.0186 mol) of 1 -(7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)-3 chloro-propane, 2.6 ml (0.0886 mol) of triethylamine and 3.9 g (0.0186 mol) of N-methyl-3-(3,4dimethoxyphenyl)-propylamine are heated to 850C for 4 hours, then cooled and dissolved in methylene chloride/water. The organic phase is separated off, extracted once more with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and the residue obtained is purified over silica gel using methylene chloride plus 3% ethanol as eluant.The oily residue obtained is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 3.45 g (36.6% of theory).

Melting point: 220-221 OC.

Example 2 1 -(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-yl)-3-[N-methyl-N-(2-phenyl-ethyl)- amino]-propane dihydrochloride Prepared analogously to Example 1 b by reacting 1 -(7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-3- benzazepin-2-on-3-yl)-3-chloro-propane with N-m ethyl-2-phenylethyla mine.

Yield: 43.2% of theory.

Melting point: 1 650C decomposition.

Example 3 1 -(1,3,4,5-Tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)- ethyl)-amino]-propane hydrochloride a) 1-(1,3,4,5-Tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane Prepared analogously to Example 1a by reacting 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on with 1bromo-3-chloro-propane.

Yield: 13.4% of theory.

IR Spectrum (methylene chloride): 1660 cm-1 (CO).

b) 1 -(1 ,3,4,5-Tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-m ethyl-N-(2-(3,4-dimethoxy-phenyl) ethyl)-amino]-propane hydrochloride Prepared analogously to Example 1 b by reacting 1-(1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3- yl)-3-chloro-propane with N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amine.

Yield: 29.2% of theory.

Melting point: 160-1620C.

Example 4 1-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(5-(3,4dimethoxy- phenyl)-pentyl)-amino]-propane hydrochloride a) 1-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane Prepared analogously to Example 1 a by reacting 7,8-dimethoxy-1 ,3-dihydro-2H-3-benzazepin-2- one with 1-bromo-3-chloropropane.

Yield: 87.3% of theory.

Melting point: 1 01--1 03 OC.

b) 1-(7,8-Dimethoxy-1,3-dihydro-2H-benzazepin-2-on-3-yl)-3-[N-methyl-N-(5-(3,4-dimethoxyphenyl)- pentyl)-amino]-propane hydrochloride Prepared analogously to Example 1 b by reacting 1 -(7,8-dimethoxy-1 ,3-dihydro-2H-3- benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-(5-(3,4-dimethoxy-phenyl)-pentyl)-amine.

Yield: 67.3% of theory.

Melting point: 1 58-1 6O0C.

Example 5 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(5-(3,4- dimethoxy-phenyl)-pentyl)-amino]-propane hydrochloride 3.23 g (0.0065 mol) of 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl- N-(5-(3,4-dimethoxy-phenyl)-pentyl)-amino]-propane, dissolved in 30 ml of acetic acid, are hydrogenated at ambient temperature under a hydrogen pressure of 5 bar in the presence of 10% palladium/charcoal for 3.5 hours. The catalyst is filtered off, the filtrate is concentrated by evaporation in vacuo and the residue is taken up in methylene chloride/15% potassium carbonate solution. The organic phase is separated off, dried over magnesium sulphate and rotated in vacuo and the residue obtained is purified over silica gel using methylene chloride plus 4% ethanol as eluant. The residue obtained is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 2.1 g (60.3% of theory).

Melting point: 165-1660C.

Example 6 1 -(7,8-Dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-thion-3-yI)-3-[N-methyl-N-(2-(3,4- dimethoxy-phenyl)-ethyl)-amino]-propane 2.28 g (0.005 mol) of 1 -(7,8-dimethoxy-l ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl )-3-[N- methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane are dissolved in 10 ml of absolute toluene and refluxed for 50 minutes with 1.0 g (0.0025 mol) of 2,4-bis-(4-methoxy-phenyl)-1 ,3-dithia-2,4- diphosphetane-2,4-disulphide. After the solvent has been rotated in vacuo, the residue obtained is purified over aluminium oxide with methylene chloride plus 2% ethanol as eluant.

Yield: 1.45 g (61.4% of theory).

C26H3eN2O4S (472.6).

Calc: C 66.07 H 7.68 N 5.93 S 6.78 Found: 66.10 7.71 5.56 6.76 Example 7 1 -(7,8-Dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3,4- dimethoxy-benzoyl-methyl)-amino]-propane hydrochloride Prepared analogously to Example 1 b by reacting 1 -(7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-3- benzazepin-2-on-3-yl)-3-N-methyl-amino-propane with a-bromo-3,4-dimethoxy-acetophenone.

Yield: 1.29 g (77.0% of theory).

Melting point: 1 9O0C.

Example 8 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-hydroxy-2- (3,4-di methoxyphenyl)-ethyl)-amino]-propane 0.92 g (0.002 mol) of 1 -(7,8-di methoxy-l ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N- methyl-N-(3,4-dimethoxy-benzoyl-methyl)-amino]-propane are dissolved in 6 ml of ethanol, mixed with 0.38 g (0.01 mol) of sodium borohydride and stirred for 2 hours at 250C. After the solvent has been evaporated in vacuo, the mixture is dissolved in methylene chloride, extracted with water, dried over magnesium sulphate and concentrated by evaporation in vacuo and the residue obtained is purified over aluminium oxide using methylene chloride plus 1% ethanol as eluant.

Yield: 0.5 g (54% of theory).

IR spectrum (methylene chloride); 1655 cm-1 (CO) C2eH 3eN2Oe (472.6).

Calc: C 66.08 H 7.68 N 5.93 Found: 66.01 7.62 5.80 Example 9 1 -[7,8-Di methoxy-1 -(2-(3,4-dimethoxy-phenyl)-ethylamino)- I ino)-l ,3,4,5-tetrahydro-2H-3- benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane dihydrochloride 2.45 9(5 mmol) of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-3-[N- methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane and 2 g of 2-(3,4-dimethoxy-phenyl)ethyl-amine are heated to 1 5O0C for 3 hours. The reaction mixture is purified over aluminium oxide N (activity II) using methylene chloride and 5% acetone as eluant.The fractions are concentrated by evaporation, the residue obtained is dissolved in 100 ml of methanol and hydrogenated for 6 hours at 50 C under a hydrogen pressure of 5 bar in the presence of 0.5 g of 10% palladium/charcoal. After the uptake of hydrogen has ended the catalyst is removed by suction filtering, the filtrate is concentrated by evaporation and the residue is purified over silica gel using methylene chloride and 5% ethanol as eluant. The residue obtained is dissolved in acetone and the dihydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 0.6 g (53.6% of theory).

Melting point: 222-2240C (decomposition).

Example 10 1-(1-Hydroxy-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2- (3,4-di methoxyphenyl)-ethyl)-amino]-propane 2.35 g (5 mmol) of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-3-[N- methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane are dissolved in 100 ml of methanol and 5 ml of water, then 0.2 g of sodium borohydride are added in batches thereto, with stirring. After it has all been added, the mixture is stirred for a further 15 minutes, mixed with 10 ml of 2N hydrochloric acid, made alkaline with methanolic ammonia decolorised with fuller's earth and then filtered and concentrated by evaporation in vacuo. The residue is dissolved in methylene chloride, any undissolved salts are filtered off and the filtrate is concentrated by evaporation.

Yield: 1.65 g (69.9% of theory), viscous oil.

IR spectrum (methylene chloride): 3400 cm-1 (OH) 2840 cm-l (methoxy) 2800 cm~1 (N-alkyl) 1660 cm-' (CO).

C26H36N206 (472.59).

Calc: C66.08 H 7.68 N 5.93 Found: 65.87 7.75 5.73 Example 11 1 -(7,8-Dimethoxy-1,3-dihydro-2H-3,5-benzodiazepin-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy- phenyl)-ethyl )-am ino]-propane dihydrochloride 4.3 g (10 mmol) of N-[2-(2-amino-4,5-dimethoxyphenyl)-ethyl]-N'-methyl-N'-(2-(3,4- dimethoxy-phenyl)-ethyl)-1 ,3-diaminopropane are refluxed for 18 hours in 30 ml of triethyi orthoformate, then concentrated by evaporation in vacuo and the residue is purified over silica gel with methylene chloride plus 3% methanol as eluant. The residue obtained is dissolved in acetone and the dihydrochloride is precipitated by the addition of ethereal hydrochloric acid.

Yield: 1.6 g (31.1% of theory).

Melting point: 232--2340C.

Example 12 1 -(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3- nitro-phenyl)-ethyl)-amino]-propane hydrochloride 1.0 g (1.75 mmol) of 1 -(7,8-Dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)-3-[N- methyl-N-(2-(4-acetamino-3-nitro-phenyl)-ethyl)-amino]-propane is heated in 50 ml of methanolic hydrochloric acid for two hours to 45 to 500C. The reaction solution is concentrated by evaporation, dissolved in methylene chloride, washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulphate and the solvent is distilled off in vacuo. After the residue has been purified over silica gel with methylene chloride and 5% ethanol as eluent, the hydrochloride is precipitated from acetone by the addition of ethereal hydrochloric acid.

Yield: 0.4 g (43.1% of theory).

Melting point: 207-208 0C (decomposition).

Example 13 1 -(1 -Oximino-7,8-dimethoxy-I ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N- (3,4-dimethoxyphenyl)-ethyl)-amino]-propane hydrochloride 3.6 g (6.8 mmol) of 1 -(7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2 H-3-benzazepin- 1 ,2-dion-3-yI)-3-[N- methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, 0.57 g of hydroxylamine hydrochloride and 0.87 g of sodium carbonate are refluxed for eight hours in 100 ml of ethanol. The solvent is distilled off in vacuo, the residue is dissolved in water/methylene chloride and the organic phase is separated off, dried over magnesium sulphate and concentrated by evaporation.The residue is purified over silica gel using methylene chloride and 5% ethanol as eluent The residue obtained is dissolved in acetone and the hydrochloride is precipitated by the addition of ethereal hydrochloric acid.

Yield: 2.4 g (67.6% of theory).

Melting point: 156-1580C.

Example 14 1 -(1 -Amino-7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2- (3,4-dimethoxyphenyl)-ethyl)-a mino]-propane dihydrochloride 1.6 g (3.3 mmol) of 1 -(1 -oximino-7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3- yl)-3-[methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane are added to 1 50 ml of ethanol and mixed with 1.5 ml of 98% hydrazine hydrate and 1 g of Raney nickel and the mixture is refluxed for seven hours. In order to complete the reaction, a further 1.5 ml of 98% hydrazine hydrate and 1 g of Raney nickel are added and the mixture is refluxed for a further three hours. The catalyst is removed by suction filtering, the solvent is distilled off in vacuo and the residue is purified over silica gel with methylene chloride and 10% methanol. The dihydrochloride is precipitated from an acetone solution by the addition of ethereal hydrochloric acid.

Yield: 0.8 g (44.6% of theory).

Melting point: 232-2340C, m/e=471.

Example 15 1 -(7,8-Dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4- dimethylamino-phenyl)-propyl)-amino]-propane dihydrochloride 5.7 g (19.4 mmol) of 1 -(7,8-dimethoxy-phenyl- 1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)- 3-N-methyl-amino-propane and 4.7 g (19.4 mmol) of 3-(4-dimethylamino-phenyl)-propyl bromide are heated to 1 300C for 13 hours after the addition of 3.3 ml of ethyldiisopropylamine. The reaction mixture is dissolved in chloroform and 25% sodium hydroxide solution, the organic phase is separated off, washed with water, dried over magnesium sulphate and concentrated by evaporation.After the residue obtained has been purified over silica gel with methylene chloride and 5% methanol as eluent, the dihydrochloride is precipitated from acetone with ethereal hydrochloric acid.

Yield: 0.6 g (5.9% of theory).

Melting point: 191--1920C (decomposition).

Example 16 1 -(7,8-Di methoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)-3-[N-methyl-N-(4- dimethylamino-phenyl)-butyl)-amino]-propane-hydrobromide Prepared analogously to Example 1 5 from 1 -(7,8-dimethoxy-phenyl-1 ,3,4,5-tetrahydro-2H-3- benzazepin-2-on-3-yl)-3-N-methyl-amino-propane and 4-(4-dimethylaminophenyl)-butyl bromide.

Yield: 10.3% of theory.

Melting point: 116-11 80C.

Example 17 1 -(1 -Hydroxy-7,8-dimethoxy-2,3,4,5-tetrahydr 1 H-3-benzazepin-3-yl)-3-[N-methyl-N-(2-(3,4- di methoxyphenyl )-ethyl)-amino]-propane dihydrochloride 2.45 g (5 mmol) of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-3-[N- methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane are dissolved in a mixture of 100 ml of ether and 50 ml of tetrahydrofuran and then 0.76 g of lithium aluminium hydride are added in batches, with stirring. The resulting mixture is refluxed for one hour, cooled with ice water and mixed with 15% ammonium chloride solution. The hydroxide precipitate is suction filtered and washed with ether and the filtrate is concentrated by evaporation.After the residue obtained has been dissolved in acetone, the dihydrochloride is precipitated with methanolic hydrochloric acid.

Yield: 2.2 g (82.7% of theory).

Melting point: 210-2120C.

Example 18 1 -(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-lN-methyl-N-(s(4-amino- 3,5-dibromo-phenyl)-amino]-propane hydrobromide 1.1 g (3.6 mmol) of 1 -(7,8-dimethoxy-phenyl-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)-3- N-methyl-amino-propane and 1.4 g (3.6 mmol) of 4-(4-amino-3,5-dibromo-phenyl)-butyl bromide are heated to 1 3O0C for two hours in 3 ml of ethyl-diisopropylamine. Then the excess amine is distilled off in vacuo and the residue obtained is purified over silica gel using methylene chloride and 2% ethanol as eluant. The fractions are combined in vacuo, the residue is triturated with acetone and the precipitate formed is suction filtered.

Yield: 0.6 g (27.9% of theory).

Melting point: 159--1610C.

Example 19 1 -(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4- di methoxy-phenyl)-propyl)-amino]-propane hydrochloride 2.6 g (5 mmol) of the sodium salt of N-[3-[N'-methyl-N'-(3-(3,4-dimethoxyphenyl)-propyl)- amino]-propyl]-2-(2-carboxymethyl-4,5-dimethoxyphenyl)-ethylamine are heated to 2O00C in 30 ml of sulfolane for two hours. After cooling, the mixture is diluted with 3 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with water, dried over magnesium sulphate and the solvent is concentrated by evaporation in vacuo. The residue is dissolved in acetone and the hydrochloride is precipitated by the addition of methanolic hydrochloric acid.

Yield: 1.8 g (71% of theory).

Melting point: 220-221 OC.

Example 20 I -(7,8-Dimethoxy-I ,3,4,5-tetrahydro-2H-3-benzazepin-1 ,2-dion-3-yl-3-[N-methyl-N-(3-(3.4- dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride 1.7 g (0.0154 mmol) of selenium dioxide are added at 7O0C to 70 ml of 1,4-dioxan and 2.8 ml of water. After 15 minutes, 1.4 g of Celite (RTM) and 6.9 g (0.0147 g) of 1 -(7,8-dimethoxy-1 3,4,5- tetra hydro-2 H-3-benzazepin-2-on-3-yl)-3-[N- methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-a mino]propane are added and the resulting mixture is refluxed for 40 hours. After cooling, the undissolved constituents are removed by suction filtering, the filtrate is rotated and the residue obtained is purified over silica gel with methylene chloride+4% ethanol as eluent.The product is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 2.36 g (29.2% of theory).

Melting point: 189-1920C.

Example 21 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4-amino- 3,5-dichloro-phenyll-2-hydroxy-ethyl)-amino]-propane Prepared from 1 -(7,8-dimethoxy- 1,3 ,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-methyl N-(4-amino-3,5-dichloro-benzoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 8.

Yield: 71.6% of theory.

Melting point: 122-1260C.

IR spectrum (methylene chloride): 3400 cm~', 3495 cm-' (N H2), 1650 cm-l (CO).

UV spectrum (ethanol): 240 nm (0.14) 290 nm (0.06) 314 nm (shoulder; 0.02).

Example 22 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(2-amino- 3,5-dichloro-phenyl)-2-hydroxy-ethyl)-amino]-propane Prepared from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl- N-(2-amino-3,5-dichloro-benzoylmethyl)-amino]-propane and sodium borohydride analogously to Example 8.

Yield: 45% of theory, resin.

IR spectrum (methylene chloride): 3360 cm-1 3450 cm-' (N H2) 1650 cm-1 (lactam-CO).

UV spectrum (ethanol): 240 nm (0.13) 280-290 nm (0.045) 310 nm (shoulder; 0.03).

Example 23 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3- [N-methyl-N-(2-(3-amino-4- chloro-phenyl)-2-hydroxy-ethyl )-a mino]-propane Prepared from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl- N-(3-amino-4-chloro-benzoyl-methyl)-aminoj-propane and sodium borohydride analogously to Example 8.

Yield: 55% of theory, resin.

IR spectrum (methylene chloride): 3380 cm-1, 3470 cm-1 (N H2) 1650 cm-1 (lactam-CO).

UV spectrum (ethanol): 236 nm (0.13) 282-292 nm (0.055) 310 nm (shoulder; 0.02).

Example 24 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3- chloro-S4luoro-phenyl)-2-hydroxy-ethyl)-a mino]-propane Prepared from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl N-(4-amino-3-chloro-5-fluoro-benzoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 8.

Yield: 48% of theory, foam.

IR spectrum (methyiene chloride): 3390 cm~', 3480 cm-1 (N H2) 1645 cm-1 (lactam-CO).

UV spectrum (ethanol): 238 nm (0.18) 282-292 nm (0.07).

Example 25 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3- chloro-5-methyl-phenyl)-2-hydroxy-ethyl)-amino]-propane Prepared from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl- N-(4-amino-3-chloro-5-methyl-benzoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 8.

Yield: 25% of theory, foam.

IR spectrum (methylene chloride): 3380 cm-1 3470 cm-1 (NH2) 1650 cm-1 (lactam-CO).

UV spectrum (ethanol): 239 nm (0.15) 280-290 nm (0.05) 305 nm (shoulder; 0.01).

The following compounds may be prepared analogously to the preceding Examples: 1 -(7-methoxy- 1 3,4,5-tetrahyd ro-2H-3-benzazepi n-2-on-3-yl)-3-[N-methyl-N-(3-(3 4- dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride, melting point 172-1 750C, 1-(7-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5- dichloro-phenyl)-propyl)-amino]-propane, 1-(7-trifluoromethyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4- di methoxy-phenyl)-ethyl )-am ino]-propane, 1 -(7-trifluoromethyl- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4- dimethoxy-phenyl)-propyl)-amino]-propane, 1 -(7-trifluoromethyl- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4- amino-3,5-dichloro-phenyl)-propyl)-amino]-propane, 1 -(7-methylamino- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3- [N-methyl-N-(2-(3,4 dimethoxy-phenyl)-ethyl)-amino]-propane, 1-(7-methylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4- dimethoxy-phenyl)-propyl)-amino]-propane, 1-(7-methylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino- 3,5-dichloro-phenyl)-propyl)-amino]-propane, 1 -(7-dimethyla m ino- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4- dimethoxy-phenyl)-ethyl)-amino]-propane;IR spectrum (methylene chloride): 1660 cm-1 (CO), 1 -(7-dimethylam ino- 1 ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4- dimethoxy-phenyl)-propyl)-a m ino]-propane, 1-(7-dimethylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4- amino-3,5-dichloro-phenyl)-propyl)-amino]-propane, 1 -(7,8-dichloro- 1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)-3-[N-methyl-N-(2-(3,4- dimethoxy-phenyl)-ethyl)-amino]-propane, 1-(7,8-dichloro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4- dimethoxy-phenyl)-propyl)-amino]-propane, 1 -(7 ,8-dichloro- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino- 3,5-dichloro-phenyl)-propyl)-amino]-propane, 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-hydroxy-3- (3,4-dimethoxy-phenyl)-propyl)-amino]-propane.

Oil; C2,H38N206 (486.6).

Calc: C66.64 H 7.87 N 5.76 Found: 66.61 7.95 5.74 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-(2-hydroxy-3-(4- amino-3,5-dichloro-phenyl)-propyl)-amino]-propane, 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-hydroxy-3- (4-amino-3,5-dichloro-phenyl)-propyl)-amino]-propane, 1 -(7,8-dimethoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-hydroxy-3- (3,4-dimethoxy-phenyl)-propyl)-amino]-propane, 1 -(7,8-dimethoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino- 3,5-dichloro-phenyl)-propyl)-amino]-propane, melting point:: 92-93 0C, 1 -(1 -hyd roxy-7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3- (3,4-dimethoxy-phenyl)-propyi)-amino]-propane, 1 -(7-dimethylamino-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N- (3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane, 1 -(7-dimethylamino-8-methoxy- 1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N- (2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, IR spectrum (methylene chloride): 1650 cm-1 (CO), 1 -(7-bromo-8-methoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4- dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride, melting point: 198-1 990C (decomp.), 1 -(7-bromo-8-methoxy- 1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)-3-[N-methyl-N-(2-(3,4- dimethoxy-phenyl)-ethyl)-a mino]-propane, NMR spectrum (CDCl3): 7.2 ppm (1 H, s, aromat.), 6.6 ppm (1 H, s, aromat.), 2.3 ppm (3H, s, N-CH3).

1 -(7-Chloro-8-methoxy- 1,3 ,4,5-tetra hydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4- dimethoxy-phenyl)-propyl)-amino]-propane', 1 -(7-chloro-8-methoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4- dimethoxy-phenyl)-ethyl)-a mino]-propane, 1 -(7,8-dimethoxy- 1,3 ,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)-3-[N-(3-(3 ,4-dimethoxy- phenyl)-propyl)-amino]-propane, IR spectrum (methylene chloride): 1645 cm-' (CO), melting point of the hydrochloride: 1 58-1 590C, 1 -(7,8-dimethoxy- 1 3,4,5-tetra hydro-2 H-3-benzazepin-2-on-3-yI)-3-[N-(3-(4-amino-3,5- dichloro-phenyl)-propyl)-amino]-propane, and 1 -(7,8-dimethoxy- 1,3 ,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-(2-hydroxy-3-(3,4- dimethoxy-phenyi)-propyl)-a mino]-propane.

Example I Tablets containing 10 mg of 1 -(7,8-dimethoxy-1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3- [N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride Compositions: 1 Tablet contains: Active substance 10.0 mg Corn starch 57.0 mg Lactose 48.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 1.0 mg 120.0 mg Method The active substance, corn starch, lactose and polyvinylpyrrolidone are mixed together and moistened with water. The moist mixture is forced through a screen with a mesh size of 1.5 mm and then dried at about 450C. The dry granulate is passed through a 1.0 mm mesh screen and mixed with magnesium stearate. The finished mixture is compressed in a tablet press with punches measuring 7 mm in diameter having a dividing slot, to form tablets.

Weight of tablet: 120 mg.

Example II Coated-tablets containing 5 mg of I -(7,8-dimethoxy-I ,3,4,5-tetrahydro-2H-3-benzazepin-2-on- 3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-a mino]-propane hydrochloride 1 Tablet core contains: Active substance 5.0 mg Corn starch 41.5 mg Lactose 30.0 mg Polyvinylpyrrolidone 3.0 mg Magnesium stearate 0.5 mg 80.0 mg Method The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is forced through a screen with a mesh size of 1 mm, dried at about 450C and the granulate is then passed through the same screen. After the addition of magnesium stearate, convex tablet cores measuring 6 mm in diameter are compressed in a tablet making machine. The tablet cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with wax. Weight of coated tablet: 1 30 mg.

Example III Ampoules containing 5 mg of 1 -(7,8-dimethoxy-I ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)- 3-[N-methyl-N-(3-(3,4-d imethoxy-phenyl)-propyl)-amino]-propane hydrochloride 1 Ampoule contains: Active substance 5.0 mg Sorbitol 50.0 mg Water for injection ad 2.0 ml Method In a suitable mixing vessel the active substance is dissolved in water for injections and the solution is made isotonic with sorbitol.

After being filtered through a membrane filter, the solution is transferred, under a current of N2, into clean sterilised ampoules and autoclaved for 20 minutes in a current of water vapour.

Example IV Suppositories containing 15 mg of 1 -(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on- 3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl )-propyl)-amino]-propane hydrochloride 1 Suppository contains: Active substance 0.015 g Hard fat (e.g. Witepsol (RTM) H 19 8 W 45) 1.685 g 1.700 g Method The hard fat is melted. At 380C the ground active substance is homogeneously dispersed in the melt. It is cooled to 350C and poured into slightly chilled suppository moulds.

Example V Drops solution containing 10 mg of 1 -(7,8-dimethoxy-I ,3,4,15-tetrahydro-2H-3-benzazepin-2-on- yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride per 5 ml 100 ml of solution contain: Active substance 0.2 g Hydroxyethyl cellulose 0.15 g Tartaric acid 0.1 g Sorbitol solution (70 /O dry content) 30.0 9 Glycerol 10.0 g Benzoic acid 0.15g Distilled water ad 100 ml Method Distilled water is heated to 700C. The hydroxyethyl cellulose, benzoic acid and tartaric acid are dissolved therein with stirring. The solution is cooled to ambient temperature and the glycerol and sorbitol solution are added with stirring. At ambient temperature the active substance is added and stirred until completely dissolved. Then the liquid is evacuated, with stirring, to eliminate any air.

Claims (90)

Claims

1. Compounds of general formula I

[wherein R1 represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, an alkoxy group with 1 to 3 carbon atoms or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms, or R1 and R2 together represent an alkyienedioxy group with 1 or 2 carbon atoms;; R3 represents a hydrogen, fluorine, chlorine or bromine atom, a nitro or trifluoromethyl group or an alkyl or alkoxy group each having 1 to 3 carbon atoms and R4 represents a hydrogen atom, an amino group or an alkoxy, alkylamino or dialkylamino group (each alkyl moiety having 1 to 3 carbon atoms and the alkyl moieties in the dialkylamino group being the same or dfflerent), or R3 and R4 together represent an alkylenedioxy group with 1 or 2 carbon atoms; R5 represents a hydrogen, chlorine or bromine atom; Re represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms; E represents an n-alkylene group with 2 to 4 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms;; B represents a thiocarbonyl, carbonyl or methylene group; G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms (wherein, so long as B represents a methylene or carbonyl group, a methylene group may optionally be replaced by a carbonyl group), or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G; and A represents a group of formula

(wherein R7 represents an alkyl group with 1 to 3 carbon atoms and R8 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms substituted by a phenyl, methoxy-phenyl or dimethoxyphenyl group); with the provisos that (i) when A represents a group of formula

(wherein R7 is as hereinbefore defined) B may not represent a methylene or carbonyl group unless G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R, and R2 each represents a hydrogen atom or R1 represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms (except in the case of A representing a -CH2CH2-group, R, and R2 representing methoxy groups in the 7- and 8-positions, E representing an n-propylene group, Re representing a methyl group, G representing an ethylene group, R5 representing a hydrogen atom, and R3 and R4 either both representing hydrogen atoms or representing respectively a 3-nitro and a 4-amino group, in which case B may represent a carbonyl group);; (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R1 and R2 each represents a hydrogen atom or R, represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms; and (iii) when A represents a group of formula

(wherein R8 is as hereinbefore defined), B represents a methylene group] and acid addition salts of the aforementioned compounds.

2. Compounds as claimed in claim 1 wherein the group R, is in the 7-position, the group R2 is in the 8-position, the group R3 is in the 3-position, the group R4 is in the 4-position and the group R5 is in the 5-position of the respective phenyl nucleus.

3. Compounds of general formula la

[wherein R, represents a hydrogen, chlorine or bromine atom or a trifluoromethyl, methoxy, amino, methylamino or dimethylamino group; R2 represents a hydrogen, chlorine or bromine atom or a methoxy group, or R, and R2 together represent a methylenedioxy group; R3 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl, methoxy, trifluoromethyl or nitro group; R4 represents a hydrogen atom or an amino, methoxy, methylamino or dimethylamino group, or R3 andR4 together represent a methylenedioxy group; R5 represents a hydrogen, chlorine or bromine atom; Re represents a hydrogen atom or a methyl or allyl group; B represents a thiocarbonyl, carbonyl or methylene group;; G represents an n-alkylene group with 2 to 5 carbon atoms (wherein, so long as B represents a methylene or carbonyl group, a methylene group may optionally be replaced by a carbonyl group), or a methylene-n-hydroxy-alkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G; and A represents a group of formula

with the provisos that (i) when A represents a group of formula -CH2-CH2- or -CH=CH-, B represents a thiocarbonyl group, and may also represent a carbonyl group when G represents an n-alkylene group with 3 to 5 carbon atoms, an n-alkylene group with 2 to 5 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-nhydroxyalkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R, and R2 each represents a hydrogen atom or R, represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and R2 represents a hydrogen, chlorine or bromine atom or a methoxy group; ; (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 5 carbon atoms, an n-alkylene group with 2 to 5 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-nhydroxyalkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R, and R2 each represents a hydrogen atom or R, represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and R2 represents a hydrogen, chlorine or bromine atom or a methoxy group; and (iii) when A represents a group of formula

B represents a methylene group], and acid addition salts thereof.

4. Compounds as claimed in claim 3, wherein A represents a -CH2-CH2- group; B represents a -CO- or -CS- group; R, represents a methoxy, amino, methylamino or dimethylamino group, and R2 represents a hydrogen atom or a methoxy group or R, and R2 together represent a methylenedioxy group, R3 represents a hydrogen, fluorine, chlorine or bromine atom or a methoxy or trifluoromethyl group, and R4 represents a methoxy, amino, methylamino or dimethylamino group or R3 and R4 together represent a methylenedioxy group, R5 represents a hydrogen, chlorine or bromine atom, Re represents a methyl group and G represents an n-alkylene group with 3 to 5 carbon atoms, a

group or (if B represents a -CS- group and/or R, represents an amino, methylamino or dimethylamino group) a -CH2CH2- group.

5. Compounds as claimed in claim 3 wherein R, and R2 each represents a methoxy group; R3 represents a methoxy group or a hydrogen or chlorine atom; R4 represents a methoxy, amino or dimethylamino group; R5 represents a hydrogen or chlorine atom; Re represents a methyl group; G represents an n-alkylene group with 3 to 5 carbon atoms or a

group or (if B represents a thiocarbonyl group or A represents a group of formula

a -CH2-CH2- group; and either A represents a -CH2-C H2- group and B represents a thiocarbonyl or (if G represents an n-aikylene group with 3 to 5 carbon atoms) a carbonyl group, or A represents a

group and B represents a methylene group.

6.1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4- dimethoxy-phenyl)-propyl)-amino]-propane and acid addition salts thereof.

7. 1 -(1 -Hydroxy-7,8-dimethoxy- 1 ,3,4,5-tetrahydro-2 H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N- (2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane and acid addition salts thereof.

8. 1 -(7,8-Dimethoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4- amino-3,5-dichloro-phenyl)-propyl)-amino]-propane and acid addition salts thereof.

9. 1 -(7,8-Dimethoxy- 1 ,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yI)-3-[N-methyl-N-(2- phenylethyl)-aminoj-propane and acid addition salts thereof.

10.1 -(7,8-Dimethoxy- 1,3 ,4,5-tetrahydrn-2H-3-benzazepin-2-on-3-yl)-3-[N-methyI-N-(2(4- amino-3-nitro-phenyl)-ethyl)-amino]-propane and acid addition salts thereof.

11. Acid addition salts of compounds as claimed in any preceding claim formed with hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic and fumaric acids.

12. Physiologically acceptable acid addition salts of compounds as claimed in any one of claims 1 to 10.

13. Compounds as claimed in claim 1 as herein specifically described.

14. Compounds as claimed in claim 1 as herein specifically described in any of Examples 1 to 25.

1 5. A process for the preparation of compounds as claimed in claim 1 which comprises reacting a compound of general formula II

with a compound of general formula Ill

(wherein R2, R3, Rs, A, B, E and G are as defined in claim 1, R,' and R4, each represents an amino or alkylamino group protected by a protecting group or represent R, and R4 as defined in claim lone of the groups U and V represents an RGNH-- group wherein Re is as defined in claim 1, and the other group U or V represents a nucleophilically exchangeable group), and optionally subsequently splitting off any protecting group used.

16. A process as claimed in claim 1 5 wherein the nucleophilically exchangeable group U or V is a halogen atom or a sulphonyloxy group.

17. A process as claimed in claim 15 or claim 16 wherein the optional subsequent splitting off of a protecting group is effected hydrolytically or hydrogenolytically.

18. A process as claimed in any one of claims 15 to 17 wherein the reaction is carried out in the presence of an acid-binding agent or a reaction accelerator.

19. A process as claimed in any one of claims 15 to 18 wherein the reaction is carried out at temperatures of between 0 and 1 500 C.

20. A process as claimed in any one of claims 1 5 to 19 wherein the reaction is carried out in a solvent at the boiling temperature of the reaction mixture.

21. A process for the preparation of compounds as claimed in ciaim 1 wherein A represents a -CH2-CH2-, -CH=CH-, -NH-CO-, -COCO-, -CH2-CO-, 5 5

group and B represents a -CH2- or -CO- group, which comprises reacting a compound of general formula (IV)

(wherein R2 is as defined in claim 1, A' represents a -CH2-CH2-, -CH=CH-, -NH-CO-, -COCO-, -CH2-C0-, 5 5

group wherein R7 represents an alkyl group with 1 to 3 carbon atoms, B' represents a -CH2- or -CO- group and R1, represents an amino or alkylamino group protected by a protecting group or represents R1 as defined in claim 1) with a compound of general formula (V)

(wherein R3, R5, R6,E and G are as defined in claim 1, R4, represents an amino or alkylamino group protected by a protecting group or represents R4 as defined in claim 1, and Z represents a nucleophilically exchangeable group) and optionally subsequently splitting off any protecting group used.

22. A process as claimed in claim 21 wherein Z represents a halogen atom or a sulphonyloxy group.

23. A process as claimed in claim 21 or claim 22 wherein the optional subsequent splitting off of a protecting group is effected hydrolytically or hydrogenolytically.

24. A process as claimed in any one of claims 21 to 23 wherein the reaction is carried out in the presence of an acid-binding agent or a reaction accelerator.

25. A process as claimed in any one of claims 21 to 24 wherein the reaction is carried out at temperatures of between 0 and 150 C.

26. A process as claimed in any one of claims 21 to 25 wherein the reaction is carried out in a solvent at the boiling temperature of the reaction mixture.

27. A process for the preparation of compounds as claimed in claim 1 wherein A does not represent a

or -CO-CO- group, which comprises reacting a compound of general formula VI

(wherein B, E, R, and R2 are as defined in claim 1 but in the group E two hydrogen atoms in a -CH2- or -CH3 group of the group E are replaced by an oxygen atom, and A" represents a -CH2-CH2-, -CH=CH-, -NH-CO-, -CH2-CO-, --N=CH--, 5 5 5

group wherein R7 represents an alkyl group with 1 to 3 carbon atoms), with an amine of general formula VII

(wherein G and R3 to Re are as defined in claim 1), in the presence of a reducing agent.

28. A process as claimed in claim 27, wherein a complex metal hydride or hydrogen in the presence of a hydrogenation catalyst is used as a reducing agent.

29: A process as claimed in claim 27 or claim 28 wherein the reaction is carried out in a solvent at temperatures of between 0 and 100 C.

30. A process for the preparation of compounds as claimed in claim 1 wherein A does not represent

or -CO-CO- group, which comprises reacting a compound of general formula VIII (wherein

B, E, R1, R2 and Re are as defined in claim 1 and A" represents a -CH2-CH2-, -CH=CH-, -NH-CO-, -CH2-CO-, -N=CH-, 5 5 5

group wherein R7 represents an alkyl group with 1 to 3 carbon atoms), with a compound of general formula IX

(wherein R3 to R5 and G are as defined in claim 1, but in the group G two hydrogen atoms in a -CH2- or -CH3 group of the group G are replaced by an oxygen atom) in the presence of a reducing agent.

31. A process as claimed in claim 30, wherein a complex metal hydride or hydrogen in the presence of a hydrogenation catalyst is used as a reducing agent.

32. A process as claimed in claim 30 or claim 31, wherein the reaction is carried out in a solvent at temperatures of between 0 and 1 O00C.

33. A process for the preparation of compounds as claimed in claim 1 wherein A represents a CH2-CH2- group, B represents a methylene or carbonyl group and Re does not represent an alkenyl group with 3 to 5 carbon atoms, which comprises hydrogenating a compound of general formula X

(wherein R, to Re, E and G are as defined in claim 1, and B' represents a methylene or carbonyl group).

34. A process as claimed in claim 33, wherein the hydrogenation is effected with catalytically activated hydrogen.

35. A process as claimed in claim 33 or claim 34 wherein the hydrogenation is carried out under a hydrogen pressure of 1 to 7 bar at temperatures of between 0 and 750C.

36. A process as claimed in claim 35 wherein the temperatures are between 20 and 500 C.

37. A process for the preparation of compounds as claimed in claim 1 wherein B represents a --CSS- group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxy-alkylene group with 1 to 4 carbon atoms in the alkylene moiety, which comprises reacting a compound of general formula XI

(wherein R, to Re, A and E are as defined in claim 1 and G' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety) with a sulphur-introducing agent.

38. A process as claimed in claim 37, wherein the sulphur-introducing agent is phosphorus pentasulphide or 2,4-bis-(4-methoxyphenyl)- 1 3-dith ia-2,4-diphosphetane-2,4-disu Iphide.

39. A process as claimed in claim 37 or claim 38 wherein the reaction is carried out at temperatures of between 50 and 1 5O0C.

40. A process as claimed in any one of claims 37 to 39 wherein the reaction is carried out in a solvent at the boiling temperature of the reaction mixture.

41. A process for the preparation of compounds as claimed in claim 1 wherein A represents a

group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxy-alkylene group with 1 to 4 carbon atoms in the alkylene moiety, which comprises reducing a compound of general formula XII

(wherein R, to R6, E and G are as defined in claim 1).

42. A process as claimed in claim 41 wherein the reduction is carried out using a metal hydride as reducing agent.

43. A process as claimed in claim 41, wherein the reduction is carried out using sodium borohydride, lithium aluminium hydride or diborane as reducing agent.

44. A process as claimed in any one of claims 41 to 43 wherein the reduction is carried out in a solvent at temperatures of between 0 and 8O0C.

45. A process for the preparation of compounds as claimed in claim 1 wherein A represents a

group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, which comprises reacting a compound of general formula XIII

(wherein R, to Re and Eare as defined in claim 1 and G' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety), with a compound of general formula XIV

(wherein Rs represents a hydroxy group or represents R8 as defined in claim 1) optionally with subsequent reduction.

46. A process as claimed in claim 45, wherein the optional subsequent reduction is effected using a complex metal hydride, catalytically activated hydrogen or hydrazine/Raney nickel as reducing agent.

47. A process as claimed in claim 45 or claim 46 wherein the reaction is carried out in a solvent or in a melt at temperatures of between 50 and 1750C.

48. A process for the preparation of compounds as claimed in claim 1 wherein A represents an -N=CH- group and Re represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms, which comprises reacting a compound of general formula XV (wherein

R1 to R,, B, E and G are as defined in claim 1 and Re' represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms) with an orthoformic acid ester.

49. A process as claimed in claim 48, wherein any -NH2 or =NH groups in the compound of general formula XV is protected by protecting groups, the said protecting groups being subsequently split off after the reaction.

50. A process as claimed in claim 49, wherein the protecting groups are selected from acetyl, benzoyl, ethoxycarbonyl and benzyl groups and the subsequent splitting off is effected hydrolytically or hydrogenolytically.

51. A process as claimed in any one of claims 48 to 50, wherein the reaction is carried out in a solvent and/or in the presence of an excess of the orthoformic acid ester and at temperatures of between 100 and 2000C.

52. A process for the preparation of compounds as claimed in claim 1, wherein A does not represent a -COCO- group and G represents a methyiene-n-hydroxyalkylene group, which comprises reducing a compound of general formula XVI

(wherein R, to Re, B and E are as defined in claim 1, A"' represents A as defined in claim 1 with the exception of the -COCO- group, and G" represents a methylene-n-alkylene group, wherein the alkylene moiety contains 1 to 4 carbon atoms and a methylene group of the alkylene moiety is replaced by a carbonyl group).

53. A process as claimed in claim 52 wherein the reduction is carried out using a metal hydride or diborane as reducing agent.

54. A process as claimed in claim 52 or claim 53 wherein the reduction is carried out in a solvent at temperatures of between 0 and 5O0C.

55. A process for the preparation of compounds as claimed in claim 1 wherein R3 represents a nitro group and R4 represents an amino group, which comprises hydrolysing a compound of general formula XVII

(wherein R1, R2, R5, Re, A, B, E and G are as defined in claim 1, and Acylrepresents an acyl group).

56. A process as claimed in claim 55 wherein the acyl group is an acetyl, ethoxycarbonyl or benzoyl group.

57. A process as claimed in claim 55 or claim 56 wherein the acyl group is hydrolysed in an aqueous solvent in the presence of an acid or an alkali metal base at temperatures of between 0 and 1 O00C.

58. A process as claimed in claim 55 or claim 56 wherein the hydrolysis is carried out in methanolic or ethanolic hydrochloric acid.

59. A process for the preparation of compounds as claimed in claim 1 wherein A represents a --CH2--CH2--, -CH=CH-, -NH-CO-, -CH2-CO-, -N=CH-, 5 5 5 -COCO- or

group and one of the groups R,, R2, R3 or R4 represents an alkoxy, alkylamino or dialkylamino group or Re represents an alkyl or alkenyl group, which comprises reacting a compound of general formula XVII I

(wherein R1 to R6, B and E are as defined in claim 1 but at least one of the groups R, to R4 must represent a hydroxy group or R, or R4 must represent an amino or alkylamino group or Re must represent a hydrogen atom, A' represents a -CH2-CH2-, -CH=CH, -NH-CO-, -CH2-CO-, -N=CH-, 5 5 5 -COCO- or

group wherein R7 represents an alkyl group with 1 to 3 carbon atoms, and G"' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, wherein a methylene group may be replaced by a carbonyl group), with a compound of general formula XIX R10-X (XIX) (wherein R10 represents an alkyl group with 1 to 3 carbon atoms or, if Re represents a hydrogen atom, an alkenyl group with 3 to 5 carbon atoms, and X represents a nucleophilically exchangeable group or, if at least one of the groups R, to R4 represents a hydroxy group, X together with a hydrogen atom in the a position of the group R10 represents a diazo group or, if Re represents a hydrogen atom or R, or R4 represents an amino or alkylamino group, X may also represent an oxygen atom).

60. A process as claimed in claim 59 wherein the group X in the compound of general formula XIX is a halogen atom or a sulphonyloxy group.

61. A process as claimed in claim 59 or claim 60 wherein B represents a methylene or carbonyl group and the reaction is carried out with an alkylating agent.

62. A process as claimed in claim 61 wherein the alkylating agent used is methyl iodide, dimethyl sulphate, ethyl iodide, diethyl sulphate, propyl bromide, allyl bromide or isopropyl p-toluenesulphonate in the presence of an acid-binding agent.

63. A process as claimed in any one of claims 59 to 61 wherein X together with a hydrogen atom in the a-position of the group R10 represents a diazo group and the reaction is carried out with a diazoalkane at temperatures of between 0 and 300C.

64. A process as claimed in any one of claims 59 to 61, wherein X represents an oxygen atom and the reaction is carried out in the presence of a reducing agent at temperatures of between 0 and 12O0C.

65. A process as claimed in any one of claims 59 to 64 wherein the reaction is carried out in the presence of a solvent.

66. A process for the preparation of compounds as claimed in claim 1 wherein A represents a -COCO- group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group may optionally be replaced by a carbonyl group, which comprises oxidising a compound of general formula XX

(wherein R, to Re, E and G are as defined in claim 1).

67. A process as claimed in claim 66 wherein the oxidation is carried out using potassium permanganate, selenium dioxide or sodium dichromate as oxidising agent.

68. A process as claimed in claim 66 or claim 67 wherein the oxidation is carried out in a solvent at temperatures of between 0 and 100 C.

69. A process for the preparation of compounds as claimed in claim 1 wherein A represents a -CH2-C0- group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group may be optionally replaced by a carbonyl group, which comprises oxidising a compound of general formula XXI

(wherein R1 to Re, B, E and G are as defined in claim 1).

70. A process as claimed in claim 69 wherein the oxidation is carried out using ruthenium tetroxide, optionally produced in situ in the reaction mixture, as oxidising agent.

71. A process as claimed in claim 69 or claim 70, wherein the reaction is carried out in a solvent and at temperatures of between 0 and 100 C.

72. A process for the preparation of compounds as claimed in claim 1 wherein R, is in the 7position, A represents a -CH2CH2- group and B represents a -CO- group, which comprises cyclising a compound of general formula XXII

(wherein R1 to R5, G and E are as defined in claim 1, Re' represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms and Y represents a group suitable for cyclisation).

73. A process as claimed in claim 72 wherein Yin the compound of general formula XXII represents a carboxy, nitrile, ester, thioester, acyloxycarbonyl or amide group.

74. A process as claimed in claim 72 or claim 73 wherein the cyclisation is carried out in the presence of a condensing agent.

75. A process as claimed in any one of claims 72 to 74 wherein any HO-, =NH or -NH2 groups present are protected by protecting groups during the cyclisation, the said protecting groups being subsequently split off after the reaction.

76. A process as claimed in any one of claims 72 to 75 wherein the cyclisation is carried out in a solvent at temperatures of between 100 and 2500C.

77. A process as claimed in any one of claims 15 to 76, wherein a compound of general formula I, initially obtained, is subsequently converted into an acid addition salt thereof, or an acid addition salt of a compound of general formula I, initially obtained, is subsequently converted into a compound of general formula I or into a different acid addition salt thereof.

78. A process for the preparation of compounds as claimed in claim 1 substantially as herein described.

79. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any of Examples 1 to 25.

80. Compounds of general formula I as defined in claim 1 and acid addition salts thereof when prepared by a process as claimed in any one of claims 1 5 to 79.

81. Compounds of general formula I as defined in claim 1 and physiologically acceptable acid addition salts thereof for use in a method of preventing or relieving ischaemic cardiac diseases or of relieving sinus tachycardia.

82. Pharmaceutical compositions comprising, as active ingredient, at least one compound of general formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient.

83. Pharmaceutical compositions as claimed in claim 82 in a form suitable for oral, rectal or parenteral administration.

84. Pharmaceutical compositions as claimed in claim 82 or claim 83 in the form of tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups and suppositories.

85. Pharmaceutical compositions as claimed in any one of claims 82 to 84 in the form of dosage units.

86. Pharmaceutical compositions substantially as herein described.

87. Pharmaceutical compositions substantially as herein described in any of Examples I to V.

88. A method of preventing or relieving ischaemic cardiac diseases or of relieving sinus tachycardia in a patient, which comprises administering to the said patient, an effective amount of a compound of general formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof.

89. Use of compounds as claimed in claim 1 in the treatment of sinus tachycardia and the prophylaxis and therapy of ischaemic cardiac diseases.

90. Each and every novel method, process, compound, composition and use herein disclosed.