GB2099425A - Benzazepines and benzodiazines - Google Patents

Description

1

SPECIFICATION

Chemical Compounds GB 2 099 425A 1 This invention relates to new benzazepine derivatives, to processes for their preparation and to 5 pharmaceutical compositions containing them.

In British Patent 1, 548,844, there is described, inter alia the compound of formula CH 3 0 1 CH 3 0 6 N CH OCH 3 v 3 CHCHCH2N-CH2-CH2 0MH 3 and pysiologically compatible acid addition salts thereof. These substances possess valuable pharmacological properties, i.e. not only a mild hypotensive effect, but more particularly a 20 selective heart rate reducing effect.

Surprisingly, we have now found that compounds of general formula 1 R A R6 3 R 25 1 - 4 R R G 2 B R 30 wherein IR, R2, R3, IR,, R, IR,3, A, B, E and G are as defined below, and physioligically compatible acid addition salts thereof have superior pharmacological properties, and in particular a more powerful heart rate reducing effect, with a longer duration of activity and reduced side effects.

Thus, according to one feature of the present invention, there are provided compounds of 35 general formula 1 A R6 3 R 40 1 - 4 R 8 G 2 B YR 45 [wherein A represents a group of formula -CH2-CH2-, R7 1 -CH = CH-, -NH-CO-, -CH2-CO- or -C = N- 50 5 5 (wherein R7 represents an alkyl group containing 1 to 3 carbon atoms) and B represents a methylene or carbonyl group, or A represents a -CO-CO- group and B represents a methylene group; E represents an ethylene, n-propylene or n-butylene group (optionally substituted by an 55 alkyl group containing 1 to 3 carbon atoms), and n-propylene group substituted at the 2 position by a hydroxy group or an n-butylene group substituted at the 2- or 3-position by a hydroxy group; G represents a methylene or ethylene group (optionally substitued by an alkyl group containing 1 to 3 carbon atoms); R, and R2, which may be the same or different, each represents a hydroxy group, an alkyl group containing 1 to 3 carbon atoms, or an alkoxy or 60 phenylalkoxy group (in each of which the alkyl part may contain 1 to 3 carbon atoms) or one of the radicals R, or R2 represents a hydrogen atom or R, and R2 together represent an alkylenedioxy group containing 1 or 2 carbon atoms; R, and R, which may be the same or different, each represents a hydrogen or halogen atom, a hydroxy group, an alkyl or alkoxy group each of which may contain 1 to 4 carbon atoms, or a trifluoromethyl or cyano group or 65 GB2099425A 2 one of the radicals R3 or R4 represents a nitro group or R3 and R, together represent an alkylenedioxy group containing 1 or 2 carbon atoms; R. represents a hydrogen atom, a hydroxy or amino group, an alkyl, alkoxy or alkylamino group containing 1 to 3 carbon atoms, a dialkylamino, alkanoylamino, alkoxycarbonyl-amino or bis(alkoxycarbonyl)amino group, in each of which the alkyl part may contain from 1 to 3 carbon atoms, or a methylamino or ethylamino group substituted by a trifluoromethyl group; and R, represents a hydrogen atom, an alkyl group containing from 1 to 3 carbon atoms, or a phenylalkyl, alkanoyl or alkoxycarbonyl group, in each of which the alkyl part may contain from 1 to 3 carbon atoms, or an alkenyl group containing 3 to 5 carbon atoms] and acid addition salts thereof.

It will be appreciated that, for pharmaceutical use, the acid addition salts referred to above 10 will be physiologically compatible acid addition salts, but other acid addition salts may find use, for example in the preparation of the compounds of general formula 1 and their physiologically compatible acid addition salts. The term---acidaddition salts- used herein includes salts formed with organic and inorganic acids.

In the definition of the group A in general formula 1 above, the symbol W indicates the site of 15 attachment to the phenyl nucleus.

Thus, in the compounds of formula 1, R, may, for example, represent a methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1- phenyl-ethoxy, 2 phenylethoxy or 3-phenylpropoxy group; R2 may, for example, represent a hydrogen atom or a methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1- 20 phenylethoxy, 2-phenylethoxy, 2-phenylpropoxy, or 3-phenylpropoxy group; R3 and IR, which may be the same or different, may, for example, each represent a hydrogen, fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, propyl, isopropyl, n-butyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, trifluoromethyl or cyano group or one of the radicals R3 or R, may represent a nitro group; R. may, for example, represent a hydrogen atom or a methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, dipropylamino, methyl ethylamino, ethyl-propylamino, methyl-propylamino, formulamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, isopropoxycarbonylam ino, bis(ethoxy-carbonyi)-amino or,8,fl,,8,-trifluoroethylamino group; R, may, for example, represent a hydrogen atom or a methyl, ethyl, propyl, isopropyl, benzyi, 1-phenylethyl, 2 phenylethyl, 3-phenylpropyl, ally[, buten-2-yI, buten-3-yl, pentenyl, formyl, acetyl, propionyl, methoxy-carbony], ethoxycarbonyl, propoxycarbonyl or isopropoxy-carbonyl group; R, and R2 together and/or R, and R4 together may, for example, represent a methylenedioxy or ethylenedioxy group; E may, for example, represent an ethylene, n- propylene, n-butylene, 1- 35 methyl-ethylene, 2-ethyi-ethylene, 1-propyl-ethylene, 1-methyl-n- propylene, 2-methyl-n-propy lene, 1-ethyl-n-propylene, 3-ethyl-n-propylene, 2-propyl-n-propylene, 2- methyl-n-butylene, 2 hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene group; and G may, for example, represent a methylene, ethylidene, propylidene, n-butylidene, 2methyl-propylidene, ethylene, 1-methyi-ethylene, 2-ethyl-ethylene, 1-propyl-ethylene or 2- methyl-ethylene group. 40 Preferred compounds of general formula 1 are those wherein A represents a group of formula -CH2-CH2-, -CH = CH-, CH3 1 - NHCO-, -CH2-CO- or C = N 5 5 and B represents a methylene or carbonyl group or 50 A represents a -CO- COgroup and B represents a methylene group, E represents an ethylene, npropylene, n-butylene, 2-methyl-n-propylene or 2-hydroxy-npropylene group, G represents a methylene, ethylene or 1-methyl-ethylene group, R, represents a methyl, hydroxy or benxyloxy group or an alkoxy group containing 1 to 3 carbon atoms, R2 represents a hydrogen atom or a methyl, hydroxy or methoxy group, or R, and R2 together represent a methylenedioxy group, R, represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl or nitro group or an alkyl or alkoxy group each containing 1 to 4 carbon atoms, R, represents a hydrogen, chlorine or bromine atom or a methyl, methoxy or cyano group or R, and R, together represent 60 a methylenedioxy group, R, represents a hydrogen atom or a hydroxy, methoxy, amino, acetylamino, ethoxycarbonylamino, bis(ethoxy-carbonyi)-amino, dimethylamino or,8,,8,,8- trifluoroethyi,amino group and R, represents a hydrogen atom, an alkyl group containing 1 to 3 carbon atoms or an ally], benzyi, acetyl or ethoxycarbonyl group.

3 GB2099425A 3 Particularly preferred compounds of general formula 1 are those wherein CH3 1 A represents a -CH2Cl-12-, -CH = CH- or - U = N-group and 5 B represents carbonyl group, or A represents a -CH = CH-, -NH-CO- or -CO-CO5 group and B represents a methylene group; E represents an n-propylene group[ G represents an ethylene group; R, represents a methoxy or a hydroxy group; R2 represents a methoxy group; R3 represents a methoxy or trifluoromethyl group, or a chlorine or bromine atom and R4 represents a methoxy group or a hydrogen, chlorine or bromine atom, or R3 and R4 together represent a methylenedioxy group; R. represents a hydrogen atom or an amino or methoxy group; and R6 represents a hydrogen atom or a methyl, ethyl, n-propyl or allyl group. Examples of particularly preferred compounds of general formula 1 include compounds of formula]a R 5,-".

k-1 CH AM N-CH 2 -CH 2 -CH 2 -N-CH 2 -CH 2 (1a) R:C: 2 -B -&, 2 R, wherein A represents a -CH2-CH2-, -CH = CH- or CH3 1 C = in5 3 R6 R 1 4 group and B represents a carbonyl group, or A represents an - N H-CO- or -CO-CO5 group and B represents a methylene group; R, and R2 each represents a methoxy group; R.

represents a hydrogen atom or a methyl or allyl group; R3 represents a hydrogen atom or a methoxy group at the 3-position, and R, represents a methoxy group at the 4-position, or R3 45 and R4 together represent a 3, 4-methylenedioxy group; and R. represents a hydrogen atom; or R3 at the 3-position represents a chlorine or bromine atom, R4 at the 5- position represents a chlorine or bromine atom, and R. at the 4-position represents an amino group.

The compounds of formula 1 may, for example, be prepared by the following processes, which processes constitute further features of the present invention:

a) Reaction of a compound of general formula 11 R 1 ' R' 2 A"1 1 N-H (11) :1 1 B 1 [wherein A and B are as hereinbefore defined and R,' and R2' each represent a hydroxy group protected by a protective radical (e.g. a trimethylsilyloxy, acetoxy, benzyloxy or tetrachydropyranyloxy group), or represent R, and R2 as hereinbefore defined) with a compound of general 65 formula Ill 4 GB 2 099 425A 4 R6 3 1 R 4 Z - B - N. - G - R 5 (III) [wherein R, E and G are as hereinbefore defined R,', R', and R,' each represents a hydroxy group protected by a protective radical (e.g. a trimethylsilyloxy, acetoxy, benzy[oxy or tetrahydropyranyloxy group) or represents R3, and R, and R, as hereinbefore defined, and Z represents a nuAeophilically exchangeable group such as a halogen atom or a suifonyloxy group (e.g. a chlorine, bromine or iodine atom or a methanesulfonyloxy, p-toluenesuffonyloxy or ethoxysulfonyloxy group)], the corresponding internal quaternary salt of general formula Ilia R6 z E) R 3' G B-J R 4 R 5 (II1a) (wherein E, G, Z, R31, R,, R.' and R. are as hereinbefore defined) optionally being present in 30 the reaction mixture, and optional subsequent cleavage of the protecting group.

The reaction may optionally be carried out in a solvent or mixture of solvents, e.g. acetone, dimethyl-formamide, acetone/dimethylformamide, dimethyisuifoxide or chlorobenzene, and de pending on the reactivity of the radical Z, the reaction is conveniently carried out at temperatures between 0 and 1 WC, preferably, however, at the boiling temprature of the solvent used. It is advantageous to carry out the reaction in the presence of an acid-binding agent, such as, for example, an alcoholate such as sodium methylate, an alkali metal hydroxide such as sodium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodamide, 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, 40 potassium iodide.

The cleavage of the protecting group, where present, is preferably carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol /water, tetrahyd rofu ran /water or dioxan/water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 45 100T, preferably at the boiling temperature of the reaction mixture. The cleavage of a benzyi radical, however, may be carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium /charcoal, in a solvent such as, for example, methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with addition of an acid such as hydrochloric acid at temperatures between 0 and WC (preferably room temperature) and a hydrogen pressure of 1 50 to 7 (preferably 3 to 5) bar.

b) For the preparation of compounds of general formula 1 wherein R. represents a hydrogen atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 to 3 carbon atoms or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part; Reaction of a compound of general formula IV R, 1 N - E - U (IV) 'C- / R 12 GB 2 099 425A 5 with a compound of general formula V R 3 ' - G - V (V) R 4.9 R 5 t wherein A, B, E and G are as hereinbefore defined R,, R21, R3', R,' and R. ' each represent a hydroxy group protected by a protective radical (e.g. a trirnethyl-silyloxy, acetoxy, benzyloxy or tetra hyd ropyranyloxy group) or represent R, R2, R, R, and R, as hereinbefore defined; one of the radicals U and V represents an R,'-NH- group (wherein R,' represents a hydrogen atom, an 15 alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 to 3 carbon atoms, or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part), and the other of the radicals U and V represents a nucleophilically exhangeable group such as a halogen atom or a sulfonyloxy group, (e.g. a chlorine, bromine or iodine atom or a methanesulfonyloxy, p- toluenesulfonyioxy or ethoxysulfonyloxy group); or the radical U together with a hydrogen atom 20 at the P-position of the radical E represents an oxygen atom and V represents an R6'-NHgroup, wherein R6' is as hereinbefore defined, with optional subsequent cleavage of the protective radical, where present.

The reaction is conveniently carried out in a solvent or mixture of solvents such as acetone, diethyl ether, methylfomamide, diemthyiformamide, dimethyisuifoxide, benzene, chlorbenzene, tetrahydrofuran, benzene /tetrahyd rofuran, dioxan or in an excess of the compounds of general formulae IV and/or V used, and optionally in the presence of an acid-binding agent (e.g. an alcoholate such as potassium tert. butylate, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodamide, an alkali metal hydride such as sodium hydride, a tertiary organic base 30 such as triethylamine or pyridine whereby the last two may simultaneously serve as solvents) or a reaction accelerator such as potassium iodide, and, depending on the reactivity of the nucleophilically exchangeable group, the reaction may conveniently be carried out at temperatures from 0 to 1 WC, preferably 50 to 1 2WC, 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 carry out the reaction in the presence of a tertiary organic base or an excess of the amine of general formula V used.

The optional subsequent cleavage of a used protective radical is preferably carried out hydrolytically in an aqueous solvent, e.g. in water, isopropanol /water, tetra hyd rofura n /water or dioxan/water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperature between 0 and 1 OWC, preferably at the boiling temperature of the reaction mixture. The cleavage of a benzyi radical, however, may be carried out hydrogenolytically, 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 addition of an acid such as hydrochloric acid at temperatures between 0 and WC, preferably, however, at room temperature, and a hydrogen pressure of 1 to 7, preferably 3 to 5, bar.

c) For the preparation of compounds of general formula 1 wherein R6 represents a hydrogen atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 to 3 carbon atoms or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part; Reaction of a compound of general formula V1 n 1 1A \ -B / R 2 N - E - H (vir) (wherein A, B, E, R, and R2 are as hereinbefore defined, expect that in the radical E two hydrogen atoms of a -CH2- or CH3- group are replaced by an oxygen atom) with an amine of general formula V11 6 GB2099425A 6 R 3 R4 5 H - N -G 1 1 R 6' R (Vil) wherein G, R3, R, and R. are as hereinbefore defined and R6' represents a hydrogen atom, an alkenyl group containing 3 to 4 carbon atoms, an alkyl group containing 1 to 3 carbon atoms or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part, in the presence of a reducing agent.

The reaction is conveniently carried out in a solvent or mixture of solvents such as for 15 example, methanol, ethanol, ethanol/ethyl acetate or dioxan at temperatures between 0 and 100'C, preferably, however, at temperatures between 20 and 80'C.

It is particularly advantageous to carry out the reductive animation in the presence of a complex metal hydride such as lithium or sodium cyanoborohydride preferably at pH 6-7 and at room temperature, or, for the preparation of compounds of general formula I wherein R, represents a hydrogen atom, in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of pal [ad iu m /charcoal at a hydrogen pressure of 5 bar. By this means, optionally present benzyl groups may simultaneously be split off hydrogenolytically and/or double bonds may be hydrogenated.

d) For the preparation of compounds of general formula I wherein R6 represents a hydrogen 25 atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 to 3 carbon atoms, or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part:

Reaction of a compound of general formula Vill R, 30 A H N N R A f- B / 6 35 R 2 (wherein A, B, E, R, and R2 are as hereinbefore defined and R,' represents a hydrogen atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 to 3 carbon atoms or 40 a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part) with a compound of general formula IX R 3 H - G R 4 R (wherein R3, R4, R, and G are as hereinbefore defined, except that in the radical G two hydrogen atoms of a -CH2- or CI-13- group are replaced by an oxygen atom) in the presence of a reducing agent.

The reaction is conveniently carried out in a solvent or mixture of solvents such as for example methanol, ethanol, ethanol/ethyl acetate or dioxan at temperatures between 0 and 1 OO'C, preferably, however, at temperatures between 20 and 80C.

It is particularly advantageous to carry out the reductive amination in the presence of a complex metal hydride such as lithium or sodium cyanoborohyd ride preferably at pH 6-7 and at 60 room temperature, or, for the preparation of compounds of general formula 1 wherein R6 represents a hydrogen atom, in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of pal lad iu m /charcoal at a hydrogen pressure of 5 bar. By this means, optionally present benzyl groups may simultaneously be split off hydrogenolytically and/or double bonds may be hydrogenated.

0 7 GB2099425A 7 e) For the preparation of compounds of general formula 1 wherein A represents a -NH-COgroup, E represents an ethylene, n-propylene or n- butylene group (optionally substituted by an alkyl group containing 1 to 3 carbon atoms; and R6 does not represent a hydrogen atom: Reaction of a compound of general formula X R 1 R 2 1 1MH 2 H R 3 1 R 6 0 R 0 1 1 4 CH2 - B - N - E (X) R 5 (wherein B and G are as hereinbefore defined, E' represents an ethylene, n-propylene or nbutylene group optionally substituted by an alkyl group containing 1 to 3 carbon atoms, R,', R,', R3' and R,' each represents a hydroxy group protected by a protective radical (e.g. a trimethyl- silyloxy, acetoxy, benzy[oxy or tetrahydropyranyloxy group) or represent R, R2, R3 and R4 as hereinbefore defined, Rj' represents a hydroxy, amino or alkylamino group protected by a protective radical or has the meanings mentioned before for R5 with the exception of the amino 20 or alkylamino group and Rj' has the meanings mentioned before for R,, with the exception of a hydrogen atom or represents a protective group for an amino group) with a carbonic acid derivative of general formula X] W-CO-W (m) [wherein W and W', which may be the same or different, each represent a nucleophilically exchangeable group such as, for example, a chlorine or bromine atom, an alkoxy group containing 1 to 3 carbon atoms (optionally substitued by halogen atoms) or an imidazolyl-(2) group] with optional subsequent cleavage of a protective radical, where present.

The reaction is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, carbon tetrachloride, benzene, tetrahydrofuran, benzene/tetrahydrofuran, dioxan or acetonitrile, conveniently at temperatures between 0 and 1 50'C, preferably, however, at the boiling temperature of the solvent used (e.g. at temperatures between 40 and 1 OO'C) and optionally in the presence of an acid-binding agent such as, for example, potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine or triethylamine, whereby the last two may simultaneously serve as solvents. However, the reaction may be carried out without a solvent, If in a used compound of general formula XI at least one of the radicals W and W' represents an alkoxy group containing 1 to 3 carbon atoms, the reaction is preferably carried out in an excess of the ester as solvent.

The optional subsequent cleavage of a protective radical is preferably carried out hydrolytically in an aqueous solvent, e.g. water, isopropanol /water, tetrahydrof uran /water or dioxan/water, in the presence of an acid such as hydrochloric acid or sulfuric acid or sulfuric acid or in the presence of an alkali base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 1 OO'C, preferably at the boiling temperature of the reaction mixture. The cleavage of a benzyl radical, however, may be carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium /charcoal, in a solvent such as, for example, methanol, ethanol, ethyl acetate or glacial acetic acid optionally with addition of an acid such as hydroxhloric acid at temperatures between 0 and 50'C, preferably, however, at room temperature and a hydrogen pressure of 1 to 7, preferably 3 to 5, bar.

f) For the preparation of compounds of general formula I wherein A represents a -CH,-CH,group, R, and R2 do not represent benzyloxy groups, R. and R, do not represent nitro groups and R6 does not represent a benzyl group or an alkenyl group containing 3 to 5 carbon atoms:

Hydrogenation of a compound of general formula 55 R, CH=CH 6 R \ N - E - N - 0 < 3 (m) B 4 60 R 2 R 5 8 GB 2 099 425A 8 wherein R, R2, R3, R, R5, B, E and G are as hereinbefore defined, except that R3 or R, may not represent a nitro group if R. represents an amino group.

The hydrogenation may be carried out 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, at a hydrogen pressure of 1 to 7, preferably 3 to 5, bar, and at temperatures between 0 and 7WC, preferably, however, at tempratures between 20 and WC. If in a compound of general formula XII R, represents a benzyl group, this group may be replaced during the hydrogen by a hydrogen atom, or if R, and/or R2 represent a benzyioxy group, these radicals may each be replaced by a hydroxy group during the hydrogenation.

g) Reaction of a compound of general formula XIII R rp'3 16 R N -E - N-G R4 (X111) R2.W 1 B RS (wherein R,, R2, R3, R, R,, to R,, A, B, E and G are as hereinbefore defined, whereby, however, 20 at least one of the radicals R, R, R3 and R, must represent a hydroxy group or R5 represents a hydroxy group, an amino group or an alkylamino group containing 1 to 3 carbon atoms or R, represents a hydrogen atom) with a compound of genral formula XIV R8-X (XIV) 25 wherein R, represents an alkyl containing 1 to 3 carbon atoms or (if R. represents a hydrogen atom) an alkenyl group containing 3 to 5 carbon atoms or (if R, or R2 represent a hydroxy group and/or R, represents a hydrogen atom) an alkyl group containing 1 to 3 carbon atoms substitued by a phenyl group, and X represents a nucleophilically exchangeable group such as a 30 halogen atom or a suffonyloxy group, e.g. a chlorine, bromine or iodine atom or a methanesulfonyloxy, ptoluenesuffonyloxy or methoxysulfonyloxy group; or, if at least one of the radicals R, R2, R3, R, and R, represents a hydroxy group, X together with a hydrogen atom at the oz-position of the radical R8 represents a diazo group, or also (if R, represents a hydrogen atom or R, represents an amino or alkylamino group) an oxygen atom.

The reaction is conveniently carried out in a solvent or miture 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.butylate or sodium hydride at temperatures between 0 and 1 WC, preferably, however, at temperatures between 20 and 120'C.

If X represents a nucleophilically exchangeable group, the reaction is preferably carried out with an alkylating agent such as methyl iodide, dimethyl sulfate, ethyl iodide, diethyl sulfate, propyl bromide, ally] bromide, benzyl chlorde, phenylethyl bromide or p-toluenesulfonic acid isopropyl ester in the presence of an acid-binding agent at temperatures between 20 and WC.

The reaction may, however, be carried out without a solvent.

If X together with the hydrogen atom at the a-poition of the radical R,, represents a diazo group, the alylation of a hydroxy group is preferably carried out with diazomethane or diazoethane at temperatures between 0 and WC, or if it represents an oxygen atom, the alkylation of a nitrogen atom may be carried out in the presence of a reducing agent at temperatures between 0 and 120'C, e.g. with formic acid at temperatures betwen 80' and 50 11 O'C or with sodium cya noborohyd ride at room temperature and pH 67.

h) For the preparation of compounds of general formula 1 wherein A does not represent a -CH-CH- group, R3 represents a chlorine or bromine atom and R, represents an amino or alkylamino group:

Halogenation of a compound of general formula XV 0 9 GB2099425A 9 R R 6 1 R 4 R N - E- N - G 2 R 00 (XV) wherein R,, R2, R4, R, B, E and G are as hereinbefore defined, A' represents A as hereinbefore defined with the exception of a -CH = CH- group, and R."" represents an amino group or an alkylamino group containing 1 to 3 carbon atoms.

The reaction is carried out with a halogenating agent, e.g. chlorine, bromine, tribromophe- nol/bromine or phenyl iodide dichloride, preferably in a solvent or mixture of solvents, e.g. in to 100% acetic acid or in tetrachydrofuran in the presence of a compound of a heavy metal such as mercuric oxide and conveniently at temperatures between 0 and 50C.

The compound of general formula XV may be used either as a base or a salt (e.g. as its mono 20, di-, or trihydrochloride). Conveniently 1 or 2 moles (or a slight excess) or halogenating agent 20 per mole of compound of formula XV or its salt may be used.

If a corresponding hydrogen halide salt is obtained during the reaction, this may be directly isolated or, if desired, it may be further purified using a base.

i) For the preparation of compounds of general formula I wherein A represents a -COCO group, E represents an ethylene, n-propylene or n-butylene group (optionally substituted by an 25 alkyl group containing 1 to 3 carbon atoms) and B represents a -CH2- group:

Oxidation of a compound of general formula XVI R R 3 CH2-CO R 6 R 4 vi) R 2 1 N - E - N c (X --nCH 2-CH2 / 1 -c- R 5 35 wherein IR, R2, R3, R4, R5, R6 and G are as hereinbefore defined, and E represents an ethylene, n-propylene or n-butylene group (optionally substituted by an alkyl group containing 1 to 3 40 carbon atoms).

The oxidation is preferably carried out with an oxidizing agent such as potassium permanga nate, selenium dioxide or sodium dichromate in a solvent or mixture of solvents such as, for example water, water/dioxan, glacial acetic acid, water/acetic acid or acetic anydride at temperaturesbetween 0 and 1 OWC, preferably at temperatures between 20 and WC. 45 If according to the invention a compound of general formula 1 is obtained wherein B represents a carbonyl group, this may, if desired, subsequently can be converted by reduction into a corresponding compound of general formula 1 wherein B represents a methylene group; and/or if a compound of general formula 1 is obtained wherein R, 1 A does not represent a -CH = CH- or -C = Im-group and R6 represents a benzyl or 1-phenylethyl group, this may, if desired, subsequently be converted by catalytic hydrogenation into a corresponding compound of general formula I wherein R6 represents a hydrogen atom; and/or if a compound of general formula I is obtained wherein R3 or R4 represents a nitro group, this may, if desired subsequently be converted by reduction into a corresponding compound of general formula I wherein R, represents an amino group; and/or if a compound of general formula I wherein R6 represents a hydrogen atom and/or R. represents an amino group is obtained, this may, if desired, subsequently be converted by acylation into a corresponding compound of general formula I wherein R6 represents an alkanoyl or alkoxycarbonyl group and/or R, represents an alkanoylamino, alkoxycarbonylamino or bis(alkoxycarbonyl)amino group, wherein each aikyl part above may contain from 1 to 3 carbon atoms; and/or if a compound of general formula I is obtained, wherein R. represents an amino 65 GB 2 099 425A 10 group, R6 does not represent a hydrogen atom, and neither R3 nor R, represents a cyano group, this may, if desired, subsequently be converted via a corresponding diazonium salt into a corresponding compound of general formula I wherein R5 represents a hydrogen atom, or a hydroxy or alkoxy group, or R, represents a hydrogen atom and R. represents a halogen atom or a cyano group.

The subsequent reduction may preferably be carried out with a metal hydride such as lithium aluminium hydride or diborane in a solvent such as, for example, diethy! ether, tetrahydrofuran or dioxan at temperatures between 0 and 1 OO'C, preferably, however, at temperatures between 30 and 85'C.

The subsequent reduction or catalytic hydrogenation may be carried out in a solvent such as, 10 for example, methanol, ethanol, ethyl acetate or glacial acetic acid with hydrogen in the presence of a catalyst such as platinum or pal lad ium /charcoal at a hydrogen pressure of 1 to 7, preferably 3 to 5, bar and at temperatures between 0 and 75C, preferably 20 to 50'C. By this means, any nitro and cyano groups which are present may be simultaneously reduced.

The subsequent acylation may be carried out with, for example, acetyl chloride, acetic anhydride, propionic acid anhydride or a corresponding chloroformate, e.g. ethyl chlorformate, which simultaneously may serve as solvent, optionally in a solvent such as, for example, water/tetrahydrofu ran, diethyl ether, tetrahydrofuran or methylene chloride, optionally in the presence of a base such as triethylamine or pyridine, whereby a tertiary organic base simultaneously may serve as solvent, at temperatures between 0 and 1 00C, preferably, however, at room temperature. The reaction may, however, be carried out without a solvent.

The subsequent reaction of a diazonium salt, e.g. of the fluoroborate, the hydrosulfate in sulfuric acid, the hydrochloride or the hydroioldide, may be carried out, if desired, in the presence of copper or a corresponding coper (1) salt such as copper (1) chloride/ hydrochloric acid, copper (1) bromide/hydrobromic acid or trisodiurn copper (1) tetracyanide at pH 7 at slightly elevated temperatures, e.g. at temperatures between 15 and 1 OO'C; the subsequent reaction with hypophosphorous acid is preferably carried out at from - 5 to OC. The diazonium salt necessary for this may be prepared in a solvent such as e.g. water/ hyd roch I oric acid, methanol /hydrochloric acid, ethanol /hydrochloric acid or dioxan /hydrochloric acid, by diazoti zation of a corresponding amino compound with a nitrite, e.g. sodium nitrite or an ester of 30 nitrous acid, at lower temperatures, e.g. at temperatures between - 10 and 5'C.

Further, the compounds of formula I prepared as hereinbefore disclosed may optionally be converted with inorganic or organic acids into heir physiologically compatible acid addition salts, for example by conventional methods such as reacting the compounds as bases with a solution of the corresponding acids in a suitable solvent.

Particularly preferred acids include, for example, hydrochloric, hydrobromic, sulfuric, phos phoric, acetic, lactic, citric, tartaric, succinic, maleic and fumaric acids.

The compounds of general formulae 11 to XVI used as starting materials are partly known from the literature, or may be obtained according to known processes.

Thus, for example, compounds of general formulae IV and Vill can be obtained, for example, 40 by reaction of a corresponding benzazepine with a corresponding halogen compound and optional subsequent reaction with a corresponding amine.The benzazepine of general formula 11 necessary for this can be obtained, for example, by cyclisation of an appropriate compound, e.g. by cyclisation of a compound of general formula XVII 45 R H R 1.111 OCH 3 2 H 2 CO CH 2 - CH --- OCH 3 (xvii) 50 55 or by ring closure of a corresponding o-amino compound and optional subsequent catalytic hydrogenation and/or reduction of the carbonyl group, for example with sodium borohydride/glacial acetic acid (see, for example, EP-Al 0.007.070) and/or oxidation, e.g. with selenium dioxide.

Compounds of general formula VI can be obtained, for example, by reaction of a benzazepine 60 with an appropriate halogen acetal and subsequent hydrolysis.

Compounds of general formula X can be obtained, for example, by reduction of a correspond ing nitro compound.

Compounds of general formulae XII, XIII, XV or XVI can be obtained, for example by reaction of a halogen compound with an appropriate amine and optional subsequent cleavage of 65 C 11 GB2099425A 11 protective radicals, which are used for the protection of hydroxy groups. The compounds of general formula 1 and the physiologically compatible acid addition salts thereof with inorganic or organic acids possess valuable pharmacological properties, particularly a long-lasting heart rate-reducing effect, and a reduction in the 0, requirement of the heart, with only slight side-effects, e.g. only a slight antimuscarinic effect.

For example the following compounds have been tested with regard to their biological properties:

A= 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[Nmethyl-N -(2-(3,4dimethoxy-phenyi)-ethyi)-amino]-propane dihydrochloride, B = 1-[7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yi]-3-[N-methyiN-(2-(3,4-dime- 10 thoxy-phenyi)-ethyi)-amino]-propane hydrochloride, C = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yi]-3[N-meth yl-(2-(3,4dimethoxy-phenyi)-ethyi)-amino]-propane hydrochloride, D = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-1,3-benzo-diazepin-2-one-3-yi]3-[N-m ethyi-(2- (3,4-dimethoxy-phenyi)-ethyi)-amino]-propane, 1 E = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[N(2-(3,4 -dimethoxy- phenyl)-ethyi)-amino]-propane hydrochloride, F= 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[Nmethyl-N -(2-(4-am- ino-3,5-dichloro-phenyi)-ethyi)-amino]-propane, G = 1-[7,8-Dimethoxy-1,3,-diiiydro-2H-3-benzazepin-2-one-3-yl]-3-[Nmethyl-N-(2-( 4-methoxy- 20 phenyl)-ethyi)-aminol-propane hydrochloride, H = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[Nmethyl-N -(2-(4-me- thoxy-phenyi)-ethyi)-amino]-propane hydrochloride, 1 = 1-[7,8-Methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]3-[N-me thyi-N-(2- (3,4-dimelthyoxy-phenyi)-ethyi-amino]-propane hydrochloride, J = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[Nallyi-N -(2-(3,4-di- methoxy-phenyi)-ethyi)-a m ino]-pro pane hydrochloride and K = 1-[7,8-Dimethoxy-1,3,-dihydro-2H-3-benzazepin-2-one-3-yil-3-[N-methyiN-(2-( 3,4-methy- lenedioxy-phenyi)-ethyi)-amino]-propane hydrochloride, in comparison with L= 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-5H-2-benzazepin-1 -one-2-yi]-3-[Nmethyi-N-(2-(3,4- 30 dimethoxy-phenyi)-ethyi)-amino]-propane hydrochloride 1. Effect on heart rate in cats:

The effect of the test substances on the heart rate was investigated for each dose on 7 cats of both sexes, with an average weight of 2.5 to 3.5 kg. To do this, the cats were anaesthetised 35 with Nembutal (30 mg/Itg i.p.) and chloroalose urethane (40 mg/mi of chloralose + 200 mg/m] of urethane, as required). The substance to be tested was injected in aqueous solution into the vena saphena or into the duodenum.

The heart rate was recorded before and after the administration of the substance by means of a Grass tachograph from the electrocardiogram (taken from the chest wall) on a Grass polygraph.

The results are shown in the following table:

Substance Dose Reduction in Half-life 45 mg/kg heart rate (minutes) A 1.0 i.v. -55 % >120 B 1.0 i.v. -45 % > 120 C 1.0 i.v. -44% > 90 50 D 1.0 i.v. -41 % 80 E 1.0 i.v. -45 % > 90 F 1.0 i.v. -51 % >120 L 1.0 i.v. - 8.2% 13 55 2. Effect on heart rate in guinea pig auricles:

Isolated, spontaneously beating auricles from guinea pigs of both sexes, with a body weight of 300 to 400 g, were tested in tyrode solution in an organ bath. The nutrient solution was supplied with Carbogen (95 % 02 + 5 0/0 C02) and kept at a constant temperature of 30'C. The 60 contractions were recorded isometrically by means of a wire strain gauge on a Grass polygraph.

The substances to be tested were added to the organ baths in various concentrations.

From the maximum effects, activity curves were prepared and from them the concentration which reduced the heart rate by 30% ( C-C-r3030) was determined.

The results are shown in the following table:

12 GB 2 099 425A 12 Substance EC-6030 [gg/mi] A 0.030 5 c 0.097 D 0.058 E 0.066 F 0.014 G 0.014 10 H 0.0079 1 0.063 J 0.050 K 0.014 3. Acute toxicity:

The acute toxicity of the test substance was determined as a guide in mice (observation period: 14 days) after intraveneous administration:

Substance Toxicity (LDro) A 89 mg/kg i.v. 1,350 mg/kg p.o.

The compounds of general formula -1 are suitable for the treatment of sinus tachycardia of various origins and for the prophylaxis and treatment 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 1 as 30 hereinbefore defined or a physiologically compatible acid addition salt thereof, in association with one or more pharmaceutical carriers or excipients.

For pharmaceutical administation the compounds of general formula 1 or their physiologically compatible acid addition salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, 35 for example, be presented in a form suitable for oral, rectal or parenteral administation.

Preferred forms include, for example, plain tablets, coated tablets, powders, suppositories, suspensions, drops, ampoules, capsules or juices.

The active ingredient may be incorporated in excipients customarily employed in pharmaceuti cal compositions such as, for example, corn starch, lactose, polyvinyl pyrrolidone, tartaric acid, 40 magnesium stearate, cane sugar, citric acid, microcrystalline cellulose, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.

Suitable dosages for adults are from 0.03 to 0.4 mg, preferably 0.07 to 0. 25 mg, of active ingredient per kg of body weight, according to the invention. Such dosages may, for example be 45 administered 1 or 2 times daily. The total daily dosage may, however, be varied according to the compound used, the subject treated and the complaint concerned.

Advantageously the compositions may be formulated as dosage units, each dosage unit being adapted to supply a fixed dose of active ingredient.

According to a still further feature of the present invention there is provided a method of treating a patient suffering from or susceptible to disorders of heart-rate, including sinus tachycardia and ischaemic cardiac diseases, which comprises administering to the said patient an effective amount of a compound of formula 1, as hereinbefore defined, or a physiologically compatible acid addition salt thereof.

The following non-limiting examples serve to illustrate the present invention.

Preparation of the starting compounds Example A 7,8-Dimethoxy- 1, 3dihydro-2H-3-benzazepin-2-one a) 3,4-Dimethoxyphenylacetic acid chloride 600mf of thionyl chloride were added dropwise to a suspension of 549.4g of 3,4-dimethoxyphenylacetic acid in 600mi of methylene chloride, with stirring, over a period of 2 hours. After the development of gas has ended (16 hours), the mixture was refluxed for a further hour. After the volatile components have been eliminated, the residue was distilled in vacuo.

Yield: 486g (80.8% of theory), 13 GB 2 099 425A 13 Bp: 134-136 C/1.92 mbar b) N-(2,2-dimethyoxyethyl)-3,4-dimethoxyphenylacetamide Whilst cooling with ice, a solution of 485.29 of 3,4-dimethoxyphenylacetic acid chloride in 1. 1 5 litres of methylene chloride at 15 to 2WC was added dropwise to a solution of 246.2mi of aminoacetaldehyde dimethyl acetal and 31 5mi of triethylamine in 2.2 litres of methylene chloride and the mixture was stirred for one hour at 16 to 1 WC. Then it was extracted with water several times, dried over magnesium sulphate and concentrated by evaporation. The oil obtained slowly crystallised out. 10 Yield: 6089 (95% of theory) Melting point: 66-69'C c) 7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one A solution of 600.6g of N-(2,2-dimethoxyethyi)-3,4-dimethoxy-phenylacetamide in 3 litres of concentrated hydrochloric acid was mixed with 3 litres of glacial actic acid. After stand for 17 15 hours at ambient temperature, the mixture was poured on to ice. The crystals precipitated were suction filtered, washed with water until neutral and dried. Yield: 350g (75.4% of theory) Melting point: 234-237'C Example B 7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one A suspension of 21.9g (0.1 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3- benzazepin-2-one and 1.5g of 10% palladium /charcoal in 200mi of glacial acetic acid was hydrogenated at 5WC and at a hydrogen pressure of 5 bar. After the catalyst had been filtered off, the solvent was evaporated 25 in vacuo and the residue was taken up in methylene chloride. After it has been extracted with sodium bicarbonate solution and washed with water, it was dried over magnesium sulphate, evaporated and purified over silica gel with methylene chloride and then with increasing amounts of methanol (up to 10%).

Yield: 12.6g (57% of theory) Melting point: 188-19 1 'C Example C

7, B-Dimethoxy-2,3,4,5-tetrahydro- 1 H-3-benzazepine A solution of 1.8g of glacial acetic acid in 10 mi of dioxan was added dropwise to a suspension 35 of 1.3g (6 mmol) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2one and 1. 1 g (3 mmol) of. sodium borohydride in 20mI of dioxan, the mixture was refluxed for 3 hours, concentrated by evaporation and mixed with water. The mixture was extracted twice by shaking with methylene chloride, the extract was concentrated by evaporation and the residue taken up in ether. After filtering, the ether was eliminated in vacuo. Yield: 1. 1 g (92.7% of theory) Melting point: 86-89C.

Example D

N-[3-[N,.Methyl-N,.(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propyl]-2amino -4,5-dimethoxy-phe- 45 nyi)-acetamide 33.3g (0.07 mol) of N-[3-N-methyl-N'-(2-(3,4-dimethoxy-phenyi)-ethyi)- amino]-propyi]-2-(2-nitro-4,5-dimethoxy-phenyi)-acetamide, dissolved in 500 mi of methanol, were hydrogenated at 25'C and at a hydrogen pressure of 5 bar for 8 hours in the presence of 10% palladium/char- coal. After removal of the catalyst, the solvent was distilled of in vacuo. Yield: 31.5g (100% of theory), viscous oil.

Example E

6,9-Dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2-one 3 ml of polyphosphoric acid were poured on 2.Og (0.007 mol) of N-(2,2- dimethoxyethyl)-2,5dimethoxyphenyl acetamide and stirred for 60 minutes at 90'C. Subsequently the reaction mixture was mixed with ice water, the precipitated product was suction filtered and dried.

Yield: 0.98g (64% of theory), M.p.: 188-191'C.

Example F 7, B-Dimethyl- 1, 3-dihydro-2H3-benzazepin-2-one Prepared analogously to Example E from N-(2,2-dimethoxy-ethyi)-3,4-dimethyiphenylacetamide and polyphosphoric acid.

6 5 Yield: 40.1 % of theory, 14 GB 2 099 425A 14 M.p.: 220-224'C.

Example G

7,8-Dimethoxy-5-methyl- 1, 3-dihydro-3,4-benzodiazepin-2-one 19.5g (0.082 mol) of 2-acetyl-4,5-dimethoxyphenylacetic acid were suspended in 200 ml of ethanol, mixed with 8.2 ml of 98% hydrazine hydrate and refluxed for 6 hours. The reaction mixture was evaporated in vacuo and purified over a silica gel column with methylene chloride and 1 % of ethanol as eluant.

Yield: 9.6g (50% of theory), IR-spectrum (methylene chloride): 3300 cm-' (NH) 2830cm-1 (OCH,) 1650cm(C0) Example H

7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione a) 7,8-Dimethoxy-2-amino-4-bromo-1H-3-benzazepine-hydrobromide 3.7g (0.0 17 mol) of 3,4-dimethyoxy-o-phenylene-diacetonitrile were suspended in 1 Omi of glacial acetic acid and mixed at 2WC with 12m] of 30% hydrobromic acid in glacial acetic acid. 20 After stirring for 3 hours at room temperature, the obtained precipitate was suction filtered, washed with glacial acetic acid and subsequently with acetone/ether and dried.

Yield: 5.3g (82.8% of theory), M.p.: 210-21 'I'C (decomp.).

b) 7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione 5.3g (0. 0 14 mol) of 7,8-dimethoxy-2-amino-4-bromo- 1 H-3-benzazepine-hydrobromide were dissolved in 100 m] of water heated to WC, mixed with 1.39 of anhydrous sodium acetate and heated for 1 hour up to WC. The reaction mixture was cooled, suction filtered, washed with cold water and dried. Yield: 2.99 (88% of theory), M.p.: 23WC (decomp.).

Example 1

N-[-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yl)propyl]met hylamine hydro- 35 chloride Prepared analogously to Example B by catalytical hydrogenation of 1-[7,8- dimethoxy-1,3 dihydro-2H-3-benzazepin-2-one-3-yi]-3-(N-benzyi-methylamino)-propane.

Yield: 87% of theory, M.p.: 11 WC (decomp.).

Example J

1-Chforo-3-[N-methyi-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-aminolpropane a) 3-[N-Methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-aminol-propanol A mixture of 2.19 (0.011 mol of N-methyi-2-(3,4-dimethoxyphenyi)-ethyi- amine and 0.9g (0.011 mol) of methyl acrylate was allowed to rest over night at room temperature. The addition product obtained hereby was dissolved in 40mi of ether and added dropwise with stirring within minutes to a suspension of 0.3g (0.008 mol) of lithium aluminium hydride in 20mi of ether.

After refluxing for 5 hours the reaction mixture was cooled and subsequently 30m] of saturated aqueous sodium sulfate solution were dropped thereto. The precipitate obtained was suction 50 filtered over kieselguhr and the filtrate was extracted with methylene chloride. The organic phase was dried over sodium sulfate and evaporated to dryness.

Yield: 3g (89.7% of theory), ffl-spectrum (methylene chloride): 3600, 3230cm-1 (OH) m/e = 253 (C,,H23NO,; 253.35).

b) 1-Chloro-3-[N-methylN-(2-(3,4-dimethoxy-phenyi)-ethyl)-aminolpropane 2. 75g of benzenesulfonic acid chloride were added to 4g of 3-[N-methy]-N-(2(3,4-dimethoxy- phenyl)-ethyi)-amino]propanol. After standing for 30 minutes the mixture was dissolved in methylene chloride, washed with 30% sodium hydroxide solution and water, dried over sodium sulfate and evaporated in vacuo. After purifying over a silica gel column (eluant: methylene chloride/ethanol) a colourless oil was obtained. Yield: 1 g (17% of theory), C,,H22CIN02 (271.8) c GB2099425A 15 Calc.: C61.86 H8.15 N5.15 Found: 62.00 8.00 4.63 Example K N-Methyl-N-[2-(3,4-dimethyoxy-phenyl)-ethyllacetidinium-bromide 3g (0.011 mol) of 3-[N-methyi-N-(2-(3,4-dimethoxy-phenyi)-ethyi)- amino]propanol were dissolved in 1 5mi of methylene chloride and at 0-5T a solution of 2m] of phosphorus tribromide in 5mi of methylene chloride was dropped thereto. After heating to room temperature the reaction mixture was refluxed for 2 hours, evaporated to dryness, subsequently dissolved in methylene chloride, and washed with 2n sodium hydroxide and water. The organic phase was dried over sodium sulfate and evaporated to dryness. After purifying the crude product over a silica gel column (eluant: methylene chloride/ethanol-100:5) the residue obtained was heated for 40 minutes up to 60-70T. Yield: 1.8g (48% of theory), M.p.: 175-180T.

Example L

7,8-Dimethoxy-2,3-dihydro-1H-3-benzazepine A boiling suspension of 0.8g of lithium aluminium hydride in 1 00mi of absolute dioxan was reacted with 2.29 (0.01 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin- 2-one and subse quently refluxed for 3 hours. Ammonium chloride solution (10%) was added whilst cooling with ice-water and the formed precipitate was suction filtered. The filtrate was evaporated in vacuo to a volume of appox. 20mi, the obtained white precipitate was suction filtered and washed with 25 little dioxan.

Yield: 0.99 (43.8% of theory), M.p.: 162-163T.

Preparation of the end products Example 1 1-[7,8-Dimethoxy-1,3-dihydro-2H3-benzazepin-2-on-3-yll-3-[N-methyl-N-(2-(3, 4-dimethoxy-phenyl)-ethyi)aminol-propane hydrochloride a) 1-(7,8-Dimethoxy-1,3-dihydro-2H-3benzazepin-2-on-3-yl)-3-chioropropane 1 31.5g (0.6 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one were suspended in 900mi of dimethyl-sulphoxide and mixed with 80.8g (0.72 mol) of potassium tert,butoxide, with stirring. After 10 minutes, the solution obtained was added dropwise, whilst being cooled with ice water, to 77mi (0.72 mol) of 1-bromo-3-chloropropane in 300 m] of dimethyisulphox ide. After one hour, the mixture was poured on to ice water. After a short time, the glutinous precipitate began to crystallize. The precipitate was suction filtered, dissolved in acetone, 40 precipitated with water, then suction filtered and dried.

Yield: 155.5g (87.3% of theory) Melting point: 101-103T b) 1-[7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yil-3-[N-methyl-N(2-(3, 4-dimethoxy- 45 phenyl)-ethyl)-aminol-propane hydrochloride 5.9g (0.02 mol) of 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3yl)-3-chloropropane and 1 1.7g (0.06 mol) of of N-methyi-2-(3,4-dimethoxy-phenyi)-ethylamine were heated to 1 OOT for 3 hours, then cooled and dissolved in ethyl acetate/water. The organic phase was removed, washed three times with 1 % acetic acid and extracted by shaking twice with 2N 50 hydrochloric acid. The hydrochloric acid extract was made ammoniacal and extracted with methylene chloride. The solvent of the extract was removed in vacuo, the residue was dissolved in acetone and the hydrochloride was precipitated out with ethereal hydrochloric acid.

Yield: 6.9 (70.3% of theory) Melting point: 190-191T (decomp.).

Example 2

1-[7, B-Dimethoxy-2,3,4,5-tetrahydro- 1 H-3,5-benzodiazepine-2,4-dion-3yi]-3-[N-methyl-N-(2- (3,4-dimethoxy-phenyl)-ethyi)-amino]-propane hydrochloride 4.6g (0.01 mol) of N-[3-[N-methyi-N'-(2-(3,4-dimethoxy-phenyl)-ethyi)amino]-propyi]-2-(2-am- 60 ino-4,5-dimethoxy-phenyl)-acetamide and 3.69 (0.022 mol) of N,N-carbonyi- diimidazole were boiled in 1 00mi of acetonitrile for 33 hours. The solvent was removed in vacuo and the residue purified over alumina (Woelm N, Act. 111) with methylene chloride and 15% acetone as eluant.

The fractions were concentrated by evaporation in vacuo, the residue was dissolved in acetone and precipitated with etherearl hydrochloric acid.

16 GB 2 099 425A 16 Yield: 1. 1 g (21.7% of theory) Melting point: 125-130'C.

Example 3

1-[7,8-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2-(2-amino- 5 3,5-dichforo-phenyl)-aminol-propane Prepared analogously to Example 1 b by reaction of 1-(7,8-dimethoxy-1,3,4, 5-tetrahydro-2H-3- benzazepin-2-one-3-yi)-3-chloro-propane with N-[2-(2-amino-3,5-dichloro- phenyi)-ethyi]methy- lamine. Oil.

LIV-spectrum (ethanol): X max IR-spectrum (dichloromethane):

240nm (0.34) 285rim (0.14) 306nrn (0.10) 2810cm-1 (N-alkyl) 2840cm-1 (OCH3) 1655cm-1 (C= 0) 1520 and 1620cm- Example 4 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyf)-aminol-propane dihydrochloride 5.8g (0.0127 mol) of 1-[7,8-dimethoxy-1,3-dihydro-2H-3benzazepin-2-one-3-yl]-3-[N-methyi-N(2-(3,4-dimethoxy-phenyi)-ethyi)amino]-propane, dissolved in 60mi of glacial acectic acid, were hydrogenated for 5 hours at ambient temperature and at a hydrogen pressure of 5 bar in the presence of 10% pallad iu m /charcoal. The catalyst was filtered off, the filtrate was concentrated by evaporation in vacuo and the residue taken up in methylene ch loride/sem isatu rated potassium carbonate solution. The organic phase was treated with activated charcoal/ bleaching earth, filtered and evaporated in vacuo. Subsequently, the residue was dissolved in acetone and the dihydrochloride was precipitated with ethereal hydrochloric acid. Yield: 6.29 (92% of theory), M.p.: 1137'C (decomp.). When using an equimolar amount of ethanolic hydrochloric acid the hydrochloride was obtained having a melting point of 165-168'C.

Example 5

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[Nmethyl-N -(2-(3,4-dime- thoxy-phenyl)-ethyl)-aminol propane dihydrochloride a) 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-3chloro-pro pane Prepared analogously to Example l a by reaction of 7,8-dimethoxy-1,3,4,5- tetrahydro-2H-3- 40 benzazepin-2-one with 1-bromo-3-chioropropane (yield: 50% of theory) or analogously to Example 4 by catalytic hydrogenation of 1-(7,8-dimethoxy-1,3-dihydro-2H-3benzazepin-2-one-3- yl)-3-chloro-propane (yield: 88% of theory).

M.p.: 84-85'C.

b) 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N -(2-(3,4-dimethoxy-phenyl)-ethyl)-aminol-propane dihydrochloride Prepared analogously to Example 1 b by reaction of 1-(7,8-dimethoxy-1,3,4, 5-tetrahydro-2H-3- benzazepin-2-one-3-yi)-3-chloro-propane with N-methy]-2-(3,4-dimethoxy- phenyi)-ethylamine. 50 Yield: 75.2% of theory, M.p.: 135-1137'C (decomp.).

Example 6

1-[7,8-Dimethoxy-2,3,4,5-tetrahydro-1H-3-benazaepin-3-yll-3-[N-methyl-N(2-( 3,4-dimethoxy- 55 phenyl)-ethyl)-amino]-propane dihydrochloride 2.7g (6 mmol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2one-3-yi]-3-[N-methyl- N-(2-(3,4-dimethoxy-phenyl)-ethyi)-amino]-propane were dissolved in 1 0OmI of absolute ether and 100 mi of absolute tetra hydrofu ran, then mixed with 0.25g of lithium aluminium hydride and refluxed for 3.5 hours. After cooling, a 10% ammonium chloride solution was added, whilst 60 cooling was continued, then the mixture was suction filtered and the filtrate concentrated by evaporation. The residue was purified over a silica gel column with methylene chloride. The fractions were concentrated by evaporation, the residue was dissolved in acetone and the dihydrochloride precipitated with methanolic hydrochloric acid.

Yield: 1.5g (48.5% of theory), 1 17 GB2099425A 17 Melting point: 270-271T (decomp.).

Example 7 1-[7, B-Dimethoxy. 1, 3-dihydro-2H-3-benzazepin-2-one-3-yil3-[Nmethyi-N-(2-(4-methoxy-phenyl)ethyl)-aminol-propane hydrochloride Prepared analogously to Example 1 b by reaction of 1-(7,8-dimethoxy-1,4dihydro-2H-3-benzazepin-2-one-3-yi)-3-chloro-propane with N-methyi-2-(4methoxy-phenyl)-ethylamine. Yield: 76.2% of theory, M.p.: 139-142T.

Example 8 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyl-N-(2-(4-methoxy phenyl)-ethyl)-aminol-propanehydrochloride Prepared analogously to Example 4 by catalytical hydrogenation of 1-[7,8-dimethoxy-1,3dihydro-2H-3benzazepin-2-one-3-yi]-3-[N-methyi-N-(2-(4-methoxy-phenyi)ethy i)-amino]propane. 16 Yield: 73.3% of theory, M.p.: 175-177'C.

Example 9

1-[7,8-Methylendioxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yll-3-[N-methylN-( 2-(3,4-dimethoxy- 20 phenyl)-ethyl)-aminolpropane hydrochloride a) 1-(7,8-Methylenedioxy-1,3-dihydro-2H-benzazepin-2-one-3-yi)-3-chloropropane Prepared analogously to Example 'I a by reaction of 7,8-methylenedioxy-1, 3-dihydro-2H-3- benzazepin-2-one (m.p.: 195'C (decomp.) with 1-bromo-3-chloropropane.

Yield: 7 2. 1 % of theory, M. p.: 7 5 - 7 WC.

b) 1-[7,8-Methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyi-N-( 2-(3,4-dime- thoxy-phenyl)-ethyi)-aminolpropane hydrochloride Prepared analogously to Example 1 b by reaction of 1-(7,8-methylenedioxy1,3-dihydro-2H- benzazepin-2-one-3-yi)-3-chloro-propane with N-methy]-2-(3,4-dimethoxy- phenyi)-ethylamine. 30 Yield: 77.2% of theory, M.p.: 185-187oC.

Example 10

1-[7,8-Methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3y11-3-[Nmet hyl-N-(2-(3,4-di- 35 methoxy-phenyl)-ethyl)-amino]propane hydrochloride Prepared analogously to Example 4 by catalytical hydrogenation of 1-[7,8- methylenedioxy-1,3 d i hyd ro-2 H-3-benzazep i n-2-one-3-yi]-3-[N-methyl-N -(2-(3,4-d i m ethoxy-phenyl)-ethyl)-a m i no] pro pane.

Yield: 77.3% of theory, M.p.: 210-212'C.

Example 11

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yil-3-[Nmethyi-N-(2-(3,4-dime- thoxy-phenyl)-ethyl)-aminol-propane 0.05mi of glacial acetic acid were added at room temperature to a mixture of 0.22g (0.5 mmol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[N(2-(3,4 -dimethoxy-phe- nyi)-ethyi)-amino]propane, 0.5mi of 37% of formalin solution, 2mi of acetonitrile and 0. 1 g of sodium cya noborohyd ride. After 2 hours, further 0.05mi of glacial acetic acid were added and the mixture was stirred for 30 minutes. The further processing was carried out by evaporating, 50 taking up in methylene chloride, washing in 2n sodium hydroxide solution and water. The organic phase which was dried over sodium sulfate was evaporated and purified over silica gel.

Yield: 104mg (45.5% of theory), viscous oil, IR-spectrum (methylene chloride): 1645cm (C0), 151 Ocm (aromatic C = C) M.p. of the dihydrochloride: 1 37T (decomp.).

Example 12

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[Nmethyl-N-(2-(3,4-dime- thoxy-phenyl)-ethyi)-amino]-propane dihydrochloride 229 (0.075 mol) of N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2-one-3-yi)-propy- 1]methylamine were heated with 7.29 (0.036 mol) of 2-(3,4-dimethoxy- phenyl)-ethyl-chloride for 20 hours up to 1 4WC. After dissolving the reaction product in methylene chloride the solution65 GB2099425A 18 was washed twice with 2 n sodium hydroxide solution and twice with water, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel (corn size: 0.063-0.2mm; eluant; methylene chloride/ methanol = 10: 1). The product thus obtained was dissolved in acetone and the dihydrochloride was precipitated with ethereal hydrochloric acid. 5 Yield: 8.Og (45% of theory), M.p.: 135-136C (decomp. ).

Example 13 1-U, B-Dimethoxy- 1, 3,4,5tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyl-N-(2-(4acetylamino-3,5-dichloro-phenyl)-ethyi)-aminolpropane 39 (0.0063 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[Nmethyi-N-(2-(4-amino-3,5-dichloro-phenyi)-ethyi)-amino]propane in 50m] of chloroform and 0.79 (0.007 mol) of triethylamine were mixed at boiling temperature in portions with altogether approx. 0.8mi of acetyl chloride. After boiling for several hours, the reaction mixture was cooled to room temperature and washed with water. The aqueous phase was made strongly alkaline by 15 means of 2n sodium hydroxide solution and extracted with methylene chloride. The separated organic phase was dried over sodium sulfate and evaporated. The crude product thus obtained was purified by chromatography on silica gel (corn size: 0.063-0.2mm, eluant: methylene chloride/ methanol = 8: 1).

M.p.: 144-146'C.

Example 14 1-[7, B-Dimethoxy- 1, 3,4.5-tetrahydro-2H-3-benzazepin-2-one-3yi]-3-[N-methyl-N-(2-(4-amino3,5-dibromo-phenyl)-ethyl)-amino]propane 0.8g (0.005 mol) of bromine were dropped at room temperature with stirring to a solution of 1 g 25 (0.0025 mol) of 1 -[7,8-d i methoxy- 1, 3,4,5-tetrahyd ro-2 H-3- benzazepin-2-one-3yl]-3-[N-m ethyl N-(2-(4-aminophenyl)-ethyl)-amino]propane in 20ml of 95% acetic acid. After approx. 60 minutes the solvent was removed in a rotation evaporator and the residue was distributed between 2n sodium hydroxide solution and methylene chloride. The methylene chloride phase was washed once with water, dried over sodium sulfate and evaporated in vacuo. The obtained 30 oily residue crystallized at room temperature and was recrystallized from absolute ethanol for further purification.

M.P.: 105-11 O'C.

Example 15 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-aminol-propane 0.22g (0.5 mmol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yi]-3-[N-(2(3,4-dimethoxy-phenyi)-ethyi)-amino]propane were heated with 0. 2mi of 37% formalin solution 40 and 0.2m] of 100% formic acid for 20 minutes up to 90-1 OWC. The further processing was 40 carried out analogously to Example 11. Viscous oil.

IR-spectrum (methylene chloride): 1645cm-1 (C0), 151 Ocm - 1 (aromatic C = C) 45 M.p. of the dihydrochloride: 137'C (decornp.).

Example 16

1-[7,8-Dimethoxy-1,3,4.5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[Nmethyl-N -(2-(3,4-dime- thoxy-phenyl)-ethyl)-amino]-propane 1.269 (20 mmol) of sodium cyanoborohyd ride were added to a solution of 3. 29g (10.0 mmol) of N-13-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi)propyi]me thylamine-hy- drochloride and 1.8g (10.0 mmol) of 2-(3,4-dimethoxy-phenyi)-acetaidehyde in 40mi of ethanol, whereby a pH-value of 6-7 was kept by the addition of 2n hydrochloric acid, and stirring was continued for further 48 hours at room temperature. After evaporating the solution in vacuo, the 55 residue was taken up in diluted hydrochloric acid and extracted twice with ether. Subsequently the aqueous phase was made alkaline, extracted thrice with methylene chloride, the organic phase was evaporated and purified over silica gel. Oil.

IR-spectrum (methylene chloride): 1645cm-I(C0) 151 Ocm - 1 (aromatic C = C) M.p. of the dihydrochloride: 137'C (decomp.).

Example 17

Q- 19 GB 2 099 425A 19 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydron-2H-3-benzazepin-2-one-3-yll-3-[Nmethy]-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane 1.26g (20 mmol) of sodium cya noborohyd ride were added to a solution of 2.77g (10 mmol) of 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)propionaideh yde and 1.959 5 (10 mmol) of N-methyl-2-(3,4-dimethoxyphenyi)-ethylamine in 40mi of methanol, whereby a pH-value of 6-7 was adjusted by the addition of hydrochloric acid. At this pH-value the reaction mixture was stirred for 50 hours at room temperature. After evaporating the solution in vacuo, the residue was taken up in diluted hydrochloric acid and extracted thrice with ether. The aqueous phase was made alkaline, extracted thrice with methylene chloride, the organic phase was evaporated and purified over silica gel. Thereby a slight yellow, viscous oil was obtained. 10 M-Spectrum (methylene chloride): 1645cm-I(C0) 151 0cm - 1 (aromatic C = C) M.p. of the dihydrochloride: 137'C (decomp.).

Example 18 1 -[8-Methoxy- 1, 3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yll3-[N-methyl-N(2-(3,4-dimethoxyphenyl)-ethyi)-aminol-propane dihydrochloride a) 1-(8-Methoxy-1,3dihydro-2H-3benzazepin-2-one-3-yl)-3-chforo-propane Prepared analogously to Example 1 a by reaction of 8-methoxy-1,3-dihydro2H-3-benzazepin-2one (m.p.: 189-190'C) with 1-bromo-3-chloropropane. Yield: 23% of theory 1 R-spectrum (methylene chloride): 16 5 5cm - 1 (C0) b) 1-(8-Methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-3chforopropane Prepared analogously to Example 4 by catalytic hydrogenation of 1-(8-methoxy-1,3-dihydro-2H3-benzazepin-2-one-3-yi)-3- chloropropane. Yield: 67% of theory, IR-spectrum (methylene chloride: 1645en-1 (C0).

c) 1-[8-Methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2 -(3,4-dime- 30 thoxy-phenyl)-ethyl)-amino]-propane dihydrochloride Prepared analogously to Example 5b by reaction of 1-(8-methoxy-1,3,4,5- tetrahydro-2H-3benzazepin-2-one-3-yl)-3-chloropropane with N-methyi-2-(3,4-dimethoxyphenyi)-ethylamine.

Yield: 14% of theory, M.p.: 118-121'C.

Example 19 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yil-3-[N-methyl-N-(2-(4-amino-3chloro-phenyi)-ethyl)-aminolpropane Prepared analogously to Example 12 from N-[3-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benza- 40 zepin-2-one-3-yi)-propyi]-methylamine and 2-(4amino-3-chloro-phenyi)-ethyibromide. Oil.

IR-spectrum (methylene chloride): 3380, 3480cm-1 (NH2) 1645cm-'(CO) 45 UVspectrum (ethanol): X max. 238nm (0. 16) 280-290nm (0.05) Example 20

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[NethyiN -(2-(4-amino-3,5- 50 dichforo-phenyi)-ethyi)-amino]propane Prepared analogously to Example 12 from N-[3-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benza- zepin-2-one-3-yl)-propyi]-ethylamine and 2-(4-amino-3,5-dichloro-phenyi)- ethylchloride. Oil.

IR-spectrum (methylene chloride): 3390,3480cm -I (NH2) 1650cm - 2 (CO) UV-spectrum (ethanol): X max: 240nm (0. 13) 280-290nm (0.05) Example 21

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yil-3-[Nmethyi-N-(2-(4-amino3,5-dichloro-phenyi)-ethyl)-aminolpropane Prepared analogously to Example 12 from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H3-benza- zepin-2-one-3-yi)-propyi]methyiamine and 2-(4-amino-3,5-dichloro-phenyi)- ethylchloride. 65 GB2099425A 20 M.p.: 94-104T.

Example 22 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yl]-3-[N-methyl-N-(2-(4-amino3,5-dibromo-phenyl)-ethyl)-amino]propane Prepared analogously to Example 12 from N[3-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl)-propyi]methylamine and 2-(4-amino3,5-dibromo-phenyi)-ethylchloride. M.p.: 108-112T.

Example 23 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methylN-(2-(4-ethoxycarbonylamino-3,5-dichlorophenyl)-ethyi)aminolpropane Prepared analogously to Example 13 from 1-[7,8-dimethoxy-1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[N-methyl-N-(2-(4-amino-3, 5-dichloro-phenyl)-ethyi)-amin o]propane and ethyl 15 chloroformate. Oil.

IR-spectrum (methylene chloride):

UV-spectrum (ethanol): X max:

341 Ocm - 1 (N H) 1650cm-1 (C0-N<) 1735cm-1 (CO-O-) 1800CM-1 (CO-O-) 240rim (shoulder, 0.08) 280-29Onm (0.03) Example 24 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyl-N-(2-(4-bis-(ethoxycarbonyl)-amino-3,5-dichforophenyl)ethyl)-amino]propane Prepared analogously to Example 13 from 1-[7,8dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-y]]-3-[N-methy]-N-(2(4-amino-3,5-dichloro-phenyi)-ethyi)-amin o]propane and ethyl 30 chloroformate. Oil.

IR-Spectrum (methylene chloride): 1650cm-1 (C0-N<) 1730cm-I(CO-0-) 1760cm(CO-O-) 1800CM-I(CO-O-) 228nm (shoulder, 0. 15) 282nrn (0.03) UV-spectrum (ethanol): X max:

Example 25 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyl-N-(2-(4-ethoxycarbonylamino-3-cyano-5-fluoro-phenyl)ethyl)-aminolpropane Prepared analogously to Example 13 from 1-[7,8dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[N-methyi-N-(2(4-amino-3-cyano-5-fluoro-phenyi)-ethyi)-a mino]-propane and 45 ethyl chloroformate in the presence of triethylamine.

ffl-spectrurn (methylene chloride): 3400cm-1 (NH) 2830cm-l(OCH3) 1730, 1650, 1510CM-2 (C0) Example 26

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2-(4-dimethy- lamino-3,5-dichloro-phenyl)-ethyl)-aminolpropane Prepared analogously to Example 11 from 1-[7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benza- 55 zepin-2-one-3-yi]-3-[N-methyi-N-(2-(4-amino-3,5-dichloro-phenyi)-ethyi)amin o]propane, parafor maldehyde and sodium cya n oborohyd ride in methanol. Oil.

IR-spectrum (methylene chloride): 1650cm-1 60 UV-spectrum (ethanol): A max: 227nm (shoulder, 0. 16) 280nm (0. 12) Example 27

1-[7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yi]-3-[N-methyl-N-(2(4 -amino-3,5-di- 65 21 GB 2 099 425A 21 chforo-phenyl)-ethyl)-aminolpropane Prepared analogously to Example 1 b from 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one3-yi)-3-chlorcpropane and 2-(4-amino-3,5-dichloro-phenyl)-N-methyi-ethyiamine. Oil IR-spectrum (methylene chloride): 3390, 3480cm-1 (NH2) 1655cm-'(CO) UV-spectrum (ethanol): X max: 238nm (shoulder, 0.25) 280nm (0.1) 303nm (0. 12) Example 29 1-[7,8-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-ethyl-N-(2-(4-amino-3,5dibromo-phenyl)-ethyl)-amino]propane Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yi)-3-chloro-propane and 2-(4-amino-3, 5-dichloro-phenyi)-N-methyi-ethyi-amine. 25 Oil.

Example 28 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyi-N -(2-(4-amino3,5-dichforo-phenyi)-ethyi)-aminolpropane Prepared analogously to Example 4 from 1-[7,8-dimethoxy-1,3-dihydro-2H-3benzazepin-2-one-15 3-yi]-3-[N-methyi-N-(2-(4-amino-3,5-dichloro-phenyi)-ethyi)-amino]propane and hydrogen in the presence of palladium/coal in glacial acetic acid. M. p.: 94-104T.

IR-spectrum (methylene chloride): 3380, 3480 cm-1 (NH2) 1645 cm-1 (CO) UVspectrum (ethanol): X max: 240 nm (shoulder, 0. 13) 280-290 nm (0.04) Example 30

1-[7, B-Dimethoxy 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yil-3-[Nmethyl-N-(2-(4-amino- 3,5-dichforo-phenyi)-ethyi)-amino]propane Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benza- 35 zepin-2-one-3-yi)-3-chloro-propane and 2-(4-amino-3,5-dichloro-phenyi)N- methyi-ethyi-amine.

M.-p.: 94-104.T.

Example 31

1-[7, B-Dimethoxy 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nisopropyi-N-(2-(4-amino3,5-dichforo-phenyl)-ethyi)-aminolpropane Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3yl)-3-chloro-propane and 2-(4-amino-3,5-dichlorophenyl)-N-isopropyi-ethylamine.

M.p. of the hydrochloride: <9OT (sintering from 70T).

ffl-spectrum (methylene chloride): 3390, 3480cm-1 (NH2) 1650cm-1 (C0) UVspectrum (ethanol): A max: 238 nm (0. 13) 50 280-29Onm (0.05) Example 32 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyi-N -(1-methyl-2-(4amino-3,5-dichlorophenyi)-ethyl)-amino]propane hydrochloride Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3yi)-3-chloropropane and 2-(4-amino-3-dichloro-phenyi)-1methyi-N-methyi-ethylamine. M.p.: 11 8-128T (decomp.).

Example 33 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-(2-(4-amino-3,5-dichlorophenyl)-ethyi)-amino]propane hydrochloride Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1, 3,4,5-tetrahydro-2H-3-benza- zepin-2-one-3-yi)-3-chloropropane and 2-(2-(4-amino-3,5-dichloro-phenyi)- ethylamine.

22 GB 2 099 425A 22 M.p.: 236-241T.

Example 34

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2(4-amino-35 chloro-5-methylphenyl)-ethyl)-aminolpropane Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yi)-3-chloropropane and 2-(4-amino-3chloro-5-methyi-phenyi)-N-methylethylamine. M.p.: 60T (sintering, melting at 73T).

IR-spectrum (methylene chloride): 3390, 3480cm-1 (NH,) 1650cm-'(CO) UVspectrum (ethanol): X max: 237nm (0. 14) 280-290nm (0.05) Example 35

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyi-N-(2-(3,5-di- chloro-4-hydroxy-phenyl)-ethyi)-aminolpropane hydrochloride Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5- tetrahydro-2H-3-benzazepin-2-one-3-yl)-3-chloro-propane and 2-(3,5-dichloro-4-hydroxy-phenyi)N-methyi-ethylamine.

M. p.: 2 2 5T.

Example 36

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N -(2-(3-chforo-5- 25 fluoro-4-#,fl,,6-trifluoro-ethylaminophenyl)-ethyi)-aminolpropane Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benza- zepin-2-one-3yi)-3-chloro-propane and 2-(3-chloro-5-fluoro-4-#,,8,,8- trifluoroethyi-amino-phenyi)N-methyl-ethylarnine.

m/e = 545/547 (C26H32CIF,N303; 546.03) Example 37

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2-(4-amino-3- chforo-5-fluoro-phenyl)-ethyl)-amino]propane Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazep- 35 inp-2-one-3yl)-3-chloro-propane and 2-(4-amino-3-chloro-5-fluoro-phenyl)- N-methylethylamine.

m/e = 463/465 (C2,H31CIFN303; 463.99) Example 38

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyi-N -(2-(4-amino-3- 40 chloro-5-trifluoromethyl-phenyl)-ethyl)-aminolpropane Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5- tetrahydro-2H-3-benzazepin-2-one-3-yi)-3-chloro-propane and 2-(4-amino-3-chloro-5trifluoromethyl-phenyi)-N-methyl- ethylamine. Oil.

45 ffl-spectrum (methylene chloride): 3410, 3510 cm-1 (NH2) 1650 cm-1 (C0) 1610, 1520 cm-1 (C= Q 2800 cm-1 (N-alkyi) 50 2830 cm-1 (OCH3) UV-spectrum (ethanol): A max: 241 nm (0.33) 285 nm (0.10) 310 nm (0.08) 55 Example 39

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyt-N -(2-(4-amino-3- cyano-5-fluoro-phenyl)-ethyl-aminol-propane Prepared analogously to Example 5b from 1-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benza- zepin-2-one-3-yi)-3-chloro-propane and N-methyi-(2-(4-amino-3-cyano-5- fluoro-phenyi)-ethyl)-am- 60 ine.

1 23 GB 2 099 425A 23 IR-spectrum (methylene chloride): 3400, 3490 cm-' (NH2) 2830 cm-1 (OCH3) 2220 cm (CN) 1650-1 (C0) Example 40

1-[7, B-Dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2-one-3-yll-3-[Nbenzyl-N(2-(3,4-dimethoxy-phenyi)-ethyl)-aminol-propane hydrochloride Prepared analogously to Example 1 b from 1-(7,8-dimethoxy-1,3-dihydro-2H3-benzazepin-2-one- 10 3-yl)-3-chloro-propane and 2-(3,4-dimethoxyphenyi)-N-benzyi-ethylamine. Yield: 51 % of theory, M.p.: 102T (decomp.).

Example 41 1-[7,8-Dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2-one-3-yl]-3[N-methyl-N-(2-(3,4-methylenedioxy-phenyl)-ethyl)-aminol-propane hydrochloride Prepared analogously to Example 1 b from 1-(7,8-dimethoxy-1, 3-dihydro-2H-3-benzazepin-2-one3-yl)-3-chloro-propane and 2-(3,4methylenedioxy-phenyi)-N-methyi-ethylamine.

Yield: 48% of theory, M.p.: 160-162T.

Example 42 1-[7, B-Dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2-one-3-yll-3(N-benzyl-methylamino)-propane hydrochloride Prepared analogously to Example 1 b from 1-(7,8-dimethoxy-1, 3-dihydro-2H-3-benzazepin-2-one3-yl)-3-chloro-propane and N-methylbenzylarnine. Yield: 92% of theory, M.p.: 208-209T.

Example 43 1-[7, B-Dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2-one-3-yil-4[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]butane hydrochloride Prepared analogously to Example 1 b from 1-(7,8-dimethoxy-1,3-dihydro-2H3-benzazepin-2-on- 3-yl)-4-chloro-butane and N-methyl-2-(3,4-dimethoxy-phenyi)-ethylamine. Yield: 85% of theory, M.p.: 162-164T.

Example 44 40 1-[8-Propoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl]-2-[Nmethyl-N-(2-(3,4-d imethoxy-phenyl)- 40 ethyl)-amino]-ethane hydrochloride Prepared analogously to Example 1 b from 1-(8-propoxy-1,3dihydro-2H-3-benzazepin-2-one-3yl)-2-chloro-ethane and N-methyl-2-(3,4dimethoxy-phenyl)-ethylamine. Yield: 31 % of theory, M.P.: 155-157T.

Example 45

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-4-[Nmethyl-N-(2-(3,4-dime- thoxy-phenyl)-ethyl)-amino]-butane hydrochloride Prepared analogously to Example 4 by catalytic hydrogenation of 1-[7,8dimethoxy-1,3-dihydro- 50 2H-3-benzazepin-2-one-3-yi]-4-[N-methyi-N-(2-(3,4-dimethoxy-phenyi)ethyi)-a mino]-butane.

M.p.: 192-194T.

Example 46

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N -(2-(3,4-methy- 55 lenedioxy-phenyl)-ethyl)-aminol-propane hydrochloride Prepared analogously to Example 4 by catalytic hydrogenation of 1-[7,8- dimethoxy-1,3-dihydro 2H-3-benzazepin-2-one-3-yl]-3-[N-methy]-N-(2-(3,4-methylenedioxy-phenyi)eth yl)-amino]-pro- pane.

Yield: 72% of theory, M.p.: 191-193T.

Example 47 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-3-one-3yll-3-[N-(2-(3,4-dimethoxy-phe- nyl)-ethyi)-amino]propane hydrochloride 24 GB 2 099 425A 24 Prepared analogously to Example 4 by catalytic hydrogenation of 1-[7,8dimethoxy-1,3-dihydro2H-3-benzazepin-2-one-3-yi]-3-[N-benzyi-N-(2-(3, 4dimethoxy-phenyl)-ethyi)-amino]-propane. Yield: 81 % of theory, M.p.: 152154'C.

Example 48

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Naiiyl-N-(2-(3,4-dimethoxy- phenyl)-ethyl)-aminol-propane hydrochloride 3.1 9 (0.007 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2-one-3-yi]-3-[N-(2- (3,4-dimethoxy-phenyi)-ethyi)-amino]-propane were refluxed for 21 hours with 1.0 g (0.007 10 mol) of potassium carbonate and 0.6 mi (0.007 mol) of allyl bromide in 100 mi of chloroform.

Subsequently the organic phase was extracted with water, dried, evaporated in vacuo and the residue obtained was purified over an aluminium oxide column (300 g, neutral, activity 111) with methylene chloride containing 2% of acetone as eluant.

Subsequently the hydrochloride was precipitated.

Yield: 40% of theory, M.p.: 153-155'C.

Example 49

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yil-3-[Npropyl-N -(2-(3,4-dime- 20 thoxy-phenyl)-ethyl)-aminol-propane hydrochloride Prepared analogously to Example 48 from 1-[7,8-dimethoxy-1,3,4,5- tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[N-(2-(3,4-dimethoxy-phenyi)-ethyi)-amino]propane and 1-bromopropane.

Yield: 53% of theory, M.p.: WC (decomp.).

Example 50 Mixture of isomers of 1-[7,8-dimethoxy-1,3-dihydro-2H-3benzazepin-2-one-3-yi]-3-[N-methyl-N(2-(2- and 4-nitro-phenyl)-ethylaminolpropane Prepared analogously to Example 1 b from 1-(7,8-dimethoxy-1,3-dihydro-2H- 3-benzazepin-2-one3-yi)-3-chloro-propane and N-methy]-2-(4- and 2- nitro-phenyi)-ethylamine. Yield: 70% of theory, ffl-spectrurn (methylene chloride): 1655cm-1 (C0) (N02) 2H (aromat.), 1510 and 1345 cm-1 NMR-spectrum(CDCI,/D2o): 8=8.10ppm,d(J=9Hz), (4-nitro compound), 7.83 ppm, d(J = 7Hz), 2H (aromat.), (2-nitro compound).

Example 51

Mixture of isomers of 1-[7. 8-dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2one-3-yll-3-[N-methyl-N- (2-(2-amino-and 4-amino-phenyl)-ethyl)-amino]propane-hydrochloride Prepared analogously to Example 4 by catalytic reduction of a isomer mixture of 1-[7,8 dimethoxy1,3-dihydro-2H-3-benzazepin-2-one-3-yi]-3-[N-methyi-N-(2-(2- and 4-nitro-phenyl)- 45 ethyl)-amino]propane.

Yield: 34% of theory, M. p.: 1 WC (decomp.) IR-spectrum (methylene chloride): 1660cm1 (C0) C24H3,1\1303 X HCI (446.0) Calc.: C 64.34 H 7.65 N 9.38 C] 7.91 Found: 63.60 7.20 9.28 7.94 Example 52

1-[7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yll-3-[N-methy]-N-(2(4 -acetylamino-phe- 55 nyl)-ethyl)-aminolpropane and 1-[7, B-Dimethoxy1, 3-dihydro-2H-3-benzazepin-2-one-3-yl]-3-[N-methyl-N(2-(2-acetylamino-phe- nyl)-ethyl)-amino]propane 1.8 g (0.004 mol) of a isomer mixture of 1-[7,8-dimethoxy-1,3-dihydro-2H- 3-benzazepin-2-one3-yi]-3-[N-methyi-N-(2-(2- and 4-amino-phenyi)-ethyi)-amino]propane were stirred at room tem perature for 1 hour in a mixture of 10 m] of glacial acetic acid and 10 mi of acetic anhydride.

* Subsequently water was added, the reaction mixture was neutralized with sodium bicarbonate and extracted with methylene chloride. The organic phase was dried and evaporated in vacuo and the residue was chromatographed over aluminium oxide (200 g, neutral, activity IV) (eluant:65 GB2099425A 25 methylene chloride + 1 % methanol).

Yield in 2-acetylamino compound: 0.24 9 (14% of theory), M.p.: 62-66'C.

Yield in 4-acetylamino compound: 0.5 g (28% of theory), M.p.: 69-72'C. 5 Example 53 1-[7, B-Dimethoxy- 1, 3,4; 5-tetrahydro2H- 1, 3-benzodiazepin2-one-3-yll-3-[N-methyl-N(2-(3,4-dimethoxy-phenyi)-ethyl)-aminol-propane a) N-[3-[N'-Methyi-N'-(2-(3,4-dimethoxy-phenyi)-ethyi)-amino]-propyi]-2(2-amin o-4,5-dimethoxy-10 phenyl)-ethylamine 4.5 g (0.01 mol) of N-[3-[N'-methy]-N'-(2-(3,4dimethoxy-phenyi)-ethyl)-amino]-propyll-2-(2amino-4,5-dimethoxy-phenyi)acetamide were dissolved in 100 m[ of tetrahydrofuran and reacted under nitrogen atmosphere with 60 mi of a 1 Molar diborane solution in tetrahydrofu- ran. The clear solution was allowed to rest for 2 days at room temperature and then mixed with 15 20 mi of semi-conc. hydrochloric acid with cooling. The tetrahydrofuran was distilled off in vacuo and the remaining hydrochloric residue was made alkaline with conc. sodium hydroxide solution under cooling. The precipitated oil was taken up in methylene chloride, the organic solution was separated, dried and evaporated in vacuo. The oily residue was purified over silica gel with methylene chloride and 1 % of methanol.

Yield: 2.9 g (67.2% of theory), ffl-spectrurn (methylene chloride): 2830 cm-1 (OCH3) 2800 cm - 1 (N-alkyi) b) 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one-3-yl]-3-[Nmeth yl-(2-(3,4-dime- thoxy-phenyi)-ethyl)-aminolpropane Prepared analogously to Example 2 by reaction of N-[3-[N'-methyi-N'-(2-(3, 4-dimethoxy-phenyi)ethyi)-amino]-propyi]-2-(2-amino-4,5-dimethoxy-phenyi)-ethylamine with N, W-carbonyl diimida zole.

Yield: 0.9 g (61.6% of theory), Mp.: 116-117'C.

Example 54 -

1-[7, B-Dimethoxy-5-methyl- 1, 3-dihydro-2H-3,4-benzodiazepin-2-one-3-yl]3-[N-methyl-N-(2-(3,4- dimethoxY-Phenyl)-ethyi)-aminolpropane dihydrochloride Prepared analogkously to Example 1 b by reaction of 1-(7,8-dimethoxy-5- methyi-1,3-dihydro-2H3,4-benzodiazepin-2-one-3-yi)-3-chloro-propane with N-methyl-2-(3,4dimethoxy-phenyi)-ethyi- amine.

Yield: 24.2% of theory, M.p.: 1OWC.

Example 55

1-[7, B-Dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2-one-3-yll-2-hydroxy-3[N-methyl-N-(2-(3,4-di- methoxy-phenyi)-ethyl)-amino]propane a) 1-(7,8-Dimetlioxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl)-2,3-epoxypropane Prepared analogously to Example 'I a by reaction of 7,8-dimethoxy-1,3- dihydro-2H-3-benzazepin- 45 2-one with epichloro-hydrin.

Yield: 94.5% of theory, IR-spectrum (methylene chloride): 2830 cm 1660 cm(OCH3) 1 (C0) b) 1-[7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yil-2-hydroxy-3[N-meth yl-N-(2-(3,4dimethoxy-phenyi)-ethyl)-aminolpropane 8.25 g (0.03 mol) of 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yi)-2,3epoxy-propane were dissolved in 100 m] of methanol, reacted with 5.85 9 (0.03 mol) of N-methyl-2-(3,4- dimethoxy-phenyi)-ethylamine and refluxed for 3 hours. The methanol was distilled off in vacuo 55 and the residue was purified over a silica gel column with methylene chloride + 1 % of ethanol. Yield: 7.8 9 (55.2% of theory), IR-spectrum (methylene chloride): 3600cm-1 (OH) 1650 cm-1 (C0) 60C26H34N206 (470.6) Calc.: C 66.36 H 7.28 N 5.95 Found: 66.16 7.26 5.80 Example 56

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yll-3-[Nmeth yt-N-(2-(3,4-di- 65 26 GB 2 099 425A 26 methoxy-phenyi)-ethyl)-aminol-propane hydrochloride To a mixture of 150 mi of dioxan and 6 mi of water 3.5 g of selenium dioxide were added at 7WC, stirred for 15 minutes and reacted with 3 g of kieselguhr and 14.8 g (0.03 mol) of 1 [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yi]-3-[N-methyi-N-( 2-(3,4-dime- thoxy-phenyi)-ethyi)-amino]-propane hydrochloride. The mixture was refluxed for 6 hours, cooled and filtered. The filtrate was evaporated in vacuo and the residue was purified over a silica gel column with methylene chloride + 1 % of ethanol. The fractions were evaporated in vacuo, the residue was dissolved in acetone and the hydrochloride was precipitated with ethereal hydrochloric acid. Yield: 13.8 g (90.7 % of theory), M.p.: 196-197'C.

Example 57 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-2-hydroxy-3-[N-methyl-N-(2(3,4-dimethoxy-phenyi)-ethyl)-aminolpropane Prepared analogously to Example 4 by catalytic hydrogenation of 1-[7,8-dimethoxy-1,3-dihydro2H-3benzazepin-2-one-3-yi]-2-hydroxy-3-[N-methy l-N-(2-(3,4-dimethoxy-phenyi)ethyi)-amino] propane, however, in ethanol at 50 bar and 7WC with platinum oxide as catalyst.

Yield: 37.5% of theory, IR-spectrum (methylene chloride): 3470 cm-1 (OH) 1635 cm-1 (C0) C26H3,N,Or, (472.6) Calc.: C 66.08 H 7.68N 5.93 Found: 66.22 7.57 5.85 Example 58

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2-(4-nitro-phenyl)-ethyl)-aminolpropane hydrochloride Prepared analogously to Example 5b by reaction of 1-[7,8-dimethoxy-1,3,4,5tetrahydro-2H-3- benzazepin-2-one-3-yl]-3-chloro-propane with N-methyi-2-(4-nitro-phenyi)- ethylamine. Yield: 56.5% of theory, M p.: 18 2'C.

Example 59

1-[7,8-Dimethoxy-1,3,4.5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N -(2-(3-nitro-4- 35 acetylamino-phenyl)-ethyl)-amino]propane dihydrochloride 0.3 g (1. 18 mmol) of N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3- benzazepin-2-one-3-yi)-propyl]rnethylamine and 0.34 9 (1.3 mmol) of 2-(3-nitro-4-acetyiaminophenyi)-ethy[bromide were refluxed for 1 hour in 5 mi of chlorobenzene and 0.1 mi of pyridine. The reaction mixture was cooled and the precipitated pyridine hydrobromide was suction filtered. The filtrate was 40 evaporated in vacuo and the residue was purified over aluminium oxide (neutral, activity 11) with methylene chloride and 0.5% of ethanol and eluant. The oil thus obtained was dissolved in acetone and the dihydrochloride was precipitated with ethereal hydrochloric acid.

Yield: 230 mg (57.7% of theory), M.p.: 17WC.

Example 60 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yil-3-[N-methyl-N -(2-(4-fluoro-phenyl)-ethyl)-amino]-propane dihydrochloride Prepared analogously to Example 5b by reaction of 1-(7,8-dimethoxy-1,3,4, 5-tetrahydro-2H-3benzazepin-2-one-3-yl)-3-chloro-propane with Nmethy]-2-(4-fluoro-phenyl)-ethylamine. Yield: 68.7% of theory, M.p.: 203T.

Example 61 1-[7, B-Dimethoxy 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-acetyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane 2 g (0. 0045 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yi]-3-[N-(2(3,4A i methoxy-phe nyl)-ethyl)-a m in o]pro pane were reacted with 15 m[ of acetic anhydride and 60 stirred for 30 minutes at room temperature. The mixture was poured on ice water, neutralized 60 with sodium bicarbonate and subsequently extracted with methylene chloride. The organic extract was dried over magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified over aluminium oxide (neutral, activity 11) with methylene chloride as eluant. Yield: 1.5 g (68.5% of theory, 27 GB2099425A 27 IR-spectrum (methylene chloride): 2830cm-1 (OCH,) C27H3,1\1206 (484.6) 1640 cm-1 (C0) Calc.: C 66.92 H 7.49 N 5.78 Found: 66.75 7.44 5.80 Example 62 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-ethoxycarbonyl-N-(2-(3,4dimethoxy-phenyl)-ethyi)-aminolpropane 2.5 g (0.00565 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3-yi]-3-[N-10 (2-(3,4-dimethoxy-phenyi)-ethyi)-amino]propane and 2.45 g (0.024 mol) of triethylamine were dissolved in 20 mi of methylene chloride. After addition of 2.6 g (0.024 mol) of ethyl chloroformate stirring was continued for 30 minutes at room temperature, the solution was washed twice with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified over aluminium oxide (neutral, activity 11) with methylene chloride as eluant. 15 Yield: 1.5 g (51.6% of theory), IR-spectrum (methylene chloride): 1690, 1650 cm-1(C0) C28H38N207 (514.6) Calc.: C 65.30 H 7.44N 5.44 Found: 64.19 7.14 5.27 Example 63

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[Nmeth yi-N-(2-(2,6-di chloro-phenyi)-ethyl)-aminol-propane dihydrochloride Prepared analogously to Example 5b by reaction of 1-(7,8-dimethoxy-1,3,4, 5-tetrahydro-2H-3- 25 benzazepin-2-one-3-yl)-3-chloro-propane with N-methyi-2-(2,6-dichloro- phenyi)-ethylamine.

Yield: 70.5% of theory, M.p.: 147'C.

Example 64 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyl-N-(2-(3,4-dichloro-phenyl)-ethyl)-aminol-propane dihydrochloride Prepared analogously to Example 5b by reaction of 1-(7,8dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3-yi)-3-chloro-propane with N-methyi-2-(3,4-dichloro-phenyl)-ethyi-amine.

Yield: 57.6% of theory, M.p.: 1611,C.

Example 65 1-[7, B-Dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2-one-3-yl]-2[N-methyi-N-(2-(3,4-dimethoxy- phenyl)-ethyi)-amino]ethane a) 1-(7,8-Dimethoxy-1,3-dihydro-2H-3- benzazepin-2-one-3-yi)-2-chloro-ethane Prepared analogously to Example la by reaction of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin2-one with 1chloro-2-bromo-ethane. Yield: 20% of theory, M. p.: 11 4'C. b) 1-[7,8Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yll-2-[N-methyl-N-(2-(3,4dimethoxyphenyl)-ethyl)-amino]ethane Prepared analogously to Example 1 b by reaction of 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin--2-one-3-yi)2-chloro-ethane with N-methyi-2-(3,4-dimethoxy-phenyi)-ethylamine.

Yield: 72% of theory, IR-spectrum (methylene chloride): 2830 cm-1 (OCH3) 2790 cm-1 (N-alkyi) 1655 cm-1 (C0) NIVIR-spectrum (CDC'3):

d = 2.3 ppm, s, 3H (NCH3); 3.85 ppm, s, 12H (OCH3); 6.15 ppm, d(J = 8Hz), 1 H (olefin.); 6.35, d(J = 8Hz), 1 H (olefin.).

Example 66 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yi]-2-[N-math yl-N-(2-(3,4-dimethox phenyl)-ethyl)-aminol-ethane hydrochloride Prepared analogously to Example 4 by catalytical hydrogenation of 1-[7,8- dimethoxy-1,3dihydro-2H-3-benzazepin-2-one-3-yi]-2-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-e thyl)-amino]-eth- ane.

Yield: 59% of theory, M.p.: 1 88-189'C.

28 GB2099425A 28 Example 67

1-[7, B-Dimethoxy- 1, 3.4,5-tetrahydro-2H-3-benzazepin-2,4-dione-3-yll-3[N-methyl-N-(2-(3,4-di- methoxy-phenyl)-ethyl)-amino]-propane hydrochloride a) 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dion-3-yl)-3chforo-p ropane Prepared analogously to Example 'I a by reaction of 7,8-dimethoxy-1,3,4,5- tetrahydro-2H-3- benzazepin-2,4-dion (m.p.: 23WC (decomp.)) with 1 -bromo-3-chloropropane.

Yield: 26% of theory, IR-spectrum (KBr): 1660 cm-1 (C0) b) 1-[7,8-Dimetlioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dion-3-yll-3[N-met hyl-N-(2-(3,4- 10 dimethoxy-phenyl)-ethyl)-aminol-propane hydrochloride Prepared analogously to Example 5b by reaction of 1-(7,8-dimethoxy-1,3,4,5tetrahydro-2H-3benzazepin-2,4-dion-3-yi)-3-chloro-propane with N-methyi-2(3,4-dimethoxy-phenyi)-ethylamine. Yield: 35% of theory, M.p.: 163-164'C.

Example 68

1-[7,8-Benzyloxy-8-hydroxy- 1, 3,4,5-tetraf#ydro-2H-3-benzazepin-2-one3yll-3-[N-methyi-N-(2- (3,4-dimethoxy-phenyi)-ethyi)-aminolpropane a) 1-(7.8-Dihydroxy1,3.4,5-tetrahydro-2H-3-benzazepin-2-one-3-yt)-3chforo-pro pane 8.9 g (0.03 mol) of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2- one-3-yl)-3-chioropropane were dissolved in 100 mi of methylene chloride and reacted at - WC with 2.1 m[ of boron tribromide. After removing the cooling bath the reaction temperature raised to 2WC and at this temperature stirring was continued for 10 hours. The resinous precipitate was made crystalline by addition of 100 nil of water and subsequent stirring for 1 hour. The precipitate 25 was suction filtered and washed with water and methylene chloride. For purification the crystalline product was stirred with acetone and suction filtered.

Yield: 7.3 g (90.2% of theory), M.p.: 177-178'C.

b) 1-(7-Hydroxy-B-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yl)-3-ch ioro-propane 30 and 1-(7-Benzyloxy-8-hydro,yy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl)-3-chloro-propane 19 g (0.07 mol) of 1-(7,8-dihydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2one-3-yf)-3-chioro- propane and 10.6 g of potassium carbonate in 250 mi of dimethyl sulfoxide were reacted with 19.5 g (0. 154 mol) of benzy] chloride. The mixture was stirred for 2 days at room temperature, 3 5 then poured on ice water and extracted several times with ethyl acetate. The organic extracts were washed thrice with water, dried over magnesium sulfate and evaporated in vacuo. The isomer separation was carried out over silica gel with methylene chloride and 3% of acetone as eluant.

Yield in 7-hydroxy compound: 6 g (23.3% of theory), M.p.: 163-165'C, Yield in 8-hydroxy compound: 4.5 g (17.9% of theory), M.p.: 1 85-186'C. c) 1-[7-Benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yil-3-[N -methyl-N-(2(3,4-dimethoxy-phenyl)-ethyl)-aminolpropane Prepared analogously to Example 5b by reaction of 1-(7-benzyioxy-8-hydroxy-1,3,4,5tetrahydro2H-3-benzazepin-2-one-3-yi)-3-chioro-propane with N-methyi-2-(3, 4-dimethoxy-phenyl)-ethylamine. Yield: 75.4% of theory, M.p.: 128-129'C.

Example 69 1-[7-Hydroxy-B-benzyloxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin2-one-3-yl]-3-[N-methyl-N-(2-(3,4dimethoxy-phenyi)-ethyl)-amino]propane 55 Prepared analogously to Example 5b by reaction of 1-(7-hydroxy-8benzyioxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one-3-yi)-3-chloro-propane with N-methyi-2-(3,4dimethoxy-phenyi)-ethyi-amine. Yield: 47.2% of theory, M.p.: 157-158'C.

Example 70

1-[7, B-Dihydroxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2-(3,4-dime- thoxy-phenyl)-ethyl)-aminol-propane 0.52 g (0.001 mol) of 1-[7-hydroxy-8-benzyioxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3yl]-3-[N-methyi-N-(2-(3,4-dimethoxy-phenyi)-ethyi)-amino]propane were hydrogenated for 5 65 29 GB 2 099 425A 29 hours at 2WC and 5 bar in 100 mi of methanol and 0.2 g of palladium /charcoal (10%). The catalyst was suction filtered, the filtrate was evaporated in vacuo and the residue was purified over silica gel with methylene chloride + 1 % of ethanol as eluant. Yield: 0.2 g (43.9% of theory), IR-spectrum (methylene chloride): 3520 em-' (0 H) 1640 em - 1 (C0) C24H32N205 X 1/2 H20 (455.5) Calc.: C 63.28 H 7.74 N 6.15 Found: 63.44 7.77 6.13 Example 71 1[7-Benzyloxy-8-methoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2one-3-yll-3-[N-methyl-N-(2-(3,4dimethoxy-phenyl)-ethyl)-aminolpropane dihydrochloride 0.52 g (0.001 mol) of 1-[7-benzyioxy-8-hydroxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3yi]-3-[N-methyi-N-(2-(3,4-dimethoxy-phenyi)-ethyi)-amino]-propane were dissolved in 30 mi of 15 dimethyl formamide and reacted with 50 mg of 50% sodium hydride dispersion (in oil). The mixture was warmed for 30 minutes up to WC, mixed with 0. 1 mi of dimethyl sulfate and warmed for further 2 hours up to WC. The dimethyl formamide was distilled off in vacuo, the residue was taken up in methylene chloride, the organic phase was washed with water, dried and evaporated in vacuo. The resinous residue was purified over aluminium oxide (neutral, activity 11) with methylene chloride as eluant. The oil obtained was dissolved in acetone and the dihydrochloride was precipitated by reaction with ethereal hydrochloric acid. Yield: 250 mg (41 % of theory), M.p.: 117-120C.

Example 72

1-[7-Methoxy-B-benzyioxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll3-[N-methyi-N-(2- (3,4-dimethoxy-phenyl)-ethyl)-aminolpropane Prepared analogously to Example 71 by reaction of 1-[7-hydroxy-8benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[N-methyi-N-(2-(3,4-dimethoxy-phenyi)ethy i)-amino]-propane 30 with dimethyl sulfate.

Yield: 70% of theory, ffl-spectrum (methylene chloride): 1655 em - 1 (C0) NMR-spectrum (CDC'3/D2o): d = 2.3 ppm, s,3H (NCH3); 51 1 ppm, s,2H (benzyl.); 6.5-6.8 ppm, m,5H (aromat.); 7.4 ppm, s,5H (aromat.). 35 Example 73

1-[7Hydroxy-8-methoxy- 1, 3.4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3[N-methy]-N-(2-(3,4- dimethoxY-phenyl)-ethyi)-amino]propane hydrochloride Prepared analogously to Example 70 from 1-[7-benzyioxy-8-methoxy-1,3,4,5tetrahydro-2H-3- 40 benzazepin-2-one-3-yl]-3-[N-methyi-N-(2-(3,4-dimethoxy-phenyl)-ethyi)amino] propane hydrochlo ride by catalytic debenzylation.

Yield: 45.2% of theory, IR-spectrum (methylene chloride): 3530 em-' (OH) 2830 em - 1 (OCH,) 1650 em' (C0) C25H34N205 x HCl (479.0) Calc.: C 62.69 H 7.36N 5.85 Found: 63.15 7.57 5.64 Example 74

1-[7-Methoxy-8-hydroxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3[N-methyl-N-(2-(3,4- dimethoxy-phenyl)-ethyi)-aminolpropane Prepared analgously to Example 70 from 1-[7-methoxy-8-benzyioxy-1,3,4,5tetrahydro-2H-3benzazepin-2-one-3-yi]-3-[N-methyi-N-(2-(3,4-dimethoxy-phenyi)-ethyi)amino] propane by cata- 55 lytic debenzylation.

Yield: 29.4% of theory, IR-spectrum (methylene chloride): 1640 em - 1 (C0) C2,H3,N205 (442.56) 60 Calc.: C 67.85 H 7.74 N 6.33 Found: 67.50 7.97 6.18 Example75

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yil-3[Nmethyi-N-(2-(3,4-dime- GB 2 099 425A 30 thyl-phenyl)-ethyi)-aminolpropane dihydrochloride Prepared analogously to Example 5b by reaction of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H3benzazepin-2-one-3-yi)-3-chloro-propane with N-methyl-2-(3,4-dimethyiphenyi)-ethylamine. 5 Yield: 54.3% of theory, M.p.: 170172T.

Example 76 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3ylj-3-[N-methyl-N -(2-(4-tert.butyl10 phenyl)-ethyl)-amino]-propane dihydrochloride Prepared analogously to Example 5b by reaction of 1-(7,8dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3-yi)-3-chloro-propane with N-methy]-2-(4-tert.butyi-phenyi)-ethylamine. Yield: 49.4% of theory, M.p.: 146-149T.

Example 77

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2-(4-n-butoxy- phenyl)-ethyl)-aminolpropane Prepared analogously to Example 5b by reaction of 1-(7,8-dimethoxy-1,3,4, 5-tetrahydro-2H-3benzazepin-2-one-3-yi)-3-chloro-propane with N-methyi-2-(4-n-butoxyphenyi)-ethylamine. 20 Yield: 55.3% of theory, M.p.: 67-69T.

Example 78 1-[7,8-Dimethoxy-1,3,4.5-tetrahydro-2H-3-benzazepin-2-one-3yl]-3-[N-methyl-N -(2-(2,4,6-trime- 25 thoxy-phenyl)-ethyl)-aminolpropane Prepared analogously to Example 5b by reaction of 1-(7,8-dimethoxy-1,3,4, 5-tetrahydro-2H-3benzazepin-2-one-3-yl)-3-chloro-propane with N-methyl-2(2,4,6-trimethoxy-phenyl)-ethylamine. Yield:57.8% of theory, 30 fflspectrum (methylene chloride): 1650 cm-1 1520 cm-1 C27H3,3N206 X HCl (523.2) Calc.: C 62.00 H 7.51 N 5.35 Cl 6.77 Found: 61.75 7.52 5.18 7.5 4 (C0) (aromat. C = Q Example 79

1-[7, B-Dimethyl- 1, 3-dihydro-2H-3-benzazepin-2-one-3-yll-3-[N-methyl-N(2-(3,4-dimethoxy-phe- nyl)-ethyl)-amino]propane hydrochloride a) 1-(7,8-Dimethy]-1,3-dihydro-2H-3-benzazepin-2-one-3-yl)-3-chioro- propane Prepared analogously to Example 'I a by reaction of 7,8 d i methyl- 1, 3dihydro-2 H-3-benzazepin- 40 2-one (m.p.: 220-224T) with 1-bromo-3-chloropropane.

Yield: 99% of theory, M.p.: 62-64T.

b) 1-[7,8-Dimethyl-1,3-dihydro-2H-3-benzazepin-2-one-3-yll-3-[N-methyl-N(2-(3, 4-dimethoxy- phenyl)-ethyl)-amino]propane hydrochloride Prepared analogously to Example 1 b by reaction of 1-(7,8-dimethyi-1,3-dihydro-2H-3-benzazepin-2- one-3-y])-3-chloro-propane with N-methyi-2-(3,4-dimethoxy-phenyi)- ethylamine. Yield: 70.9% of theory, M.p.: 105-107T.

Example 80

1-[7,8-Dimethyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[Nmethyl-N -(2-(3,4-dime- thoxy-phenyi)-ethyl)-aminol-propane dihydrochloride Prepared analogously to Example 4 by catalytical hydrogenation of 1-[7,8- dimethyi-1,3-dihydro 2H-3-benzazepin-2-one-3-yl]-3-[N-methyi-N-(2-(3,4-dimethoxy-phenyi)ethyi)-a mino]-propane. 55 Yield: 83.8% of theory, M.p.: 154-157T.

Example 8 1

1-[7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl]-2-methyl-3-[Nmethy l-N-(2-(3,4-dime- 60 thoxy-phenyl)-ethyl)-aminol-propane a) 1-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl)-2-methyl-3chforo-p ropane Prepared analogously to Example 'I a by reaction of 7,8-dimethoxy-1,3- dihydro-2H-3-benzazepin- 2-one with 1 -bromo-2-methyi-3-chloro-propane.

Yield: 97.5% of theory, 1 31 GB2099425A 31 M.p.: 45-47T. b) 1-[7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yil2-methyl-3-[N-methy i-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]propane Prepared analogously to Example 1 b by reaction of 1-(7,8-dimethoxy-1,3dihydro-2H-3-benza- zep i n-2-one-3-yi)-2-methyi-3-ch loro-pro pane with N-methyi-2-(3,4- dimethoxy-phenyl)-ethylamine. Yield: 36% of theory, M.p.: 30-32'C.

Example 82

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yil-2-methyl3-[ N-methyl-N-(2- 10 (3,4-dimethoxy-phenyi)-ethyl)-aminolpropane hydrochloride Prepared analogously to Example 4 by catalytic hydrogenation of 1-[7,8dimethoxy-1, 3-dihydro2H-3-benzazepin-2-one-3-yi]-2-methyi-3-[N-methyl -N-(2-(3,4dimethoxy-phenyi)-ethyi)-amino]propane.

Yield: 73.7% of theory, M.p.:99-1 WC.

Example 83 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin- 1, 2dion-3-yll-3-[N-methyl-N-(2-(3,4-di- methoxy-phenyl)-ethyl)-amino]propane hydrochloride 3 9 of sodium dichromate X 2 H20 were given to 2.45 g (0.005 mol) of 1-[7,8-dimethoxy1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[N-methyl-N -(2-(3,4dimethoxy-phenyi)-ethyi)amino]propane hydrochloride in 50 m] of glacial acetic acid. The mixture was stirred for 2 hours at room temperature, poured on ice water, neutralized with potassium carbonate and extracted several times with methylene chloride. The organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified over a silica gel column with methylene chloride + 1 % of ethanol as eluant. The product thus obtained was dissolved and the hydrochloride was precipitated with ethereal hydrochloric acid. Yield: 1.3 9 (51.3% of theory), M.p.: 197-198T.

Example 84

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin- 1, 2-dion-3-yl]-3[N-methyi-N-(2-(3,4-di- methoxy-phenyl)-ethyi)-amino]propane hydrochloride 1.98 g (4.0 mmol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2-one-3-yi]-3-[N- 35 methyi-N-(2-(3,4-dimethoxy-phenyi)-ethyi)-amino]propane hydrochloride were suspended in 50 mi of acetic anhydride, the suspension mixed with 2.5 mi of acetic anhydride, the suspension mixed with 2.5 9 of potassium permanganate and stirred for 20 minutes at 20T. The reaction mixture was poured on ice water and made ammoniacal with conc. ammonia. The precipitated manganese-dioxide was suction filtered and the filtrate was extracted several times with methylene chloride. The extract was dried over magnesium sulfate, evaporated in vacuo and the residue was purified over a silica gel column with methylene chloride + 1 % of ethanol as eluant. The product thus obtained was dissolved in acetone and the hydrochloride was precipitated with ethereal hydrochloric acid.

Yield: 0.7 g (34.5% of theory), M.p.: 196-197T.

Example 85

1-[6, 9-Dimethoxy- 1, 3-dihydro-2H3-benzazepin-2-one-3-yil-3-[N-methyl-N(2-(3,4-dimethoxy- phenyl)-ethyi)-aminolpropane a) 1-(6,9-Dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2-one-3-yl)-3-chforo- propane Prepared analogously to Example 1 a by reaction of 6,9-di-methoxy-1,3dihydro-2H-3-benzazepn- 2-one (m.p.: 188-191'C) with 1-bromo-3-chloro-propane.

Yield: 27% of theory, M.p.: 97-99T. b) 1-[6,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl]3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]propane Prepared analogously to Example 1 b by reaction of 1-(6,9-dimethoxy-1,3-dihydro-2H3-benzazepin-2-one-3-yl)-3-chloropropane with N-methyl-2-(3,4-dimethoxyphenyi)-ethylamine.

Yield: 90% of theory, IR-spectrum (methylene chloride): 1658 cm-1 (C0) NMR-spectrum (CDC'3/D20): 8 = 2.2 ppm, s, 3H (NCH3); 17-3.8 ppm, 4s, 12H (OCH3); 6.25 ppm, d (J = 9Hz), 1 H (olefin.).

Example 86

32 GB2099425A 32 1-[6,9-Dimethoxy- 1, 3,4.5-tetrahydro-2H-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2-(3,4-dimethoxy-phenyl)-ethyi)-aminolpropane hydrochloride Prepared analogously to Example 4 by catalytic hydrogenation of 1-[6,9dimethoxy-1,3-dihydro2H-3-benzazepin-2-one-3-yi]-3-[N-methyi-N-(2-(3, 4dimethoxy-phenyi)-ethyl)-amino]propane. 5 Yield: 85% of theory, M.p.: 7376T.

Example 87 1-[8, 9-Dimethoxy- 1, 3-dihydro-2H-3-benzazepin-2-one-3-yll-3[N-methyi-N-(2-(3,4-dimethoxy- phenyl)-ethyi)-amino]-propane hydrochloride a) 1-(8,9-Dimethoxy1,3dihydro-2H-3-benzazepin-2-one-3-yl)-3-chforo-propane Prepared analogously to Example l a by reaction of 8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin2one (m.p.: 165-168T) with 1-bromo-3-chloropropane. Yield: 45% of theory, M.p.: 67-71T. b) 1-[8,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one3-yll3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-aminol-propane hydrochloride Prepared analogously to Example 1 b by reaction of 1-(8,9dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yi)-3-chloropropane with Nmethyl-2-(3,4-dimethoxy-phenyi)-ethylamine.

Yield: 64% of theory, M.p.: 64-68T.

Example 88 1-[8, 9-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yl]-3-[N-methyl-N-(2-(3,4-dime- thoxy-phenyi)-ethyi)-amino]-propane hydrochloride Prepared anaogously to Example 4 by catalytic hydrogeneation of 1-[8,9-dimethoxy-1,3-dihydro2H-3benzazepin-2-one-3-yi]-3-[N-methyl-N-(2-(3, 4-dimethoxy-phenyi)-ethyi)amino]propane. Yield: 75% of theory, M.p.: 131-133T.

Example 89

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyi-N -(2-(3,4,5-trime- thoxy-phenyl)-ethyl)-aminolpropane dihydrochloride Prepared analogously to Example 5b by reaction of 1-(7,8-dimethoxy-1,3,4, 5-tetrahydro-2H-3benzazepin-2-one-3-yi)-3-chloro-propane with N-methyi-2-(3,4,5-trimethoxyphenyi)-ethylamine. 35 Yield: 44% of theory, M.p.: 131T (decomp.).

Example 90

Isomer mixture of 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro2H-3-benzazepin-2one-3-yll-3-[N-me- 40 thyPN-(2-(2- and 4-nitrophenyl)-ethyl)-aminolpropane Prepared analogously to Example 1 b from 1-[7,8-dimethoxy-1,3,4,5tetrahydro-2H-3benza- zepin-2-one-3-yi]-3-chloro-propane and Wrnethyl-2-(2- and 4-nitro-phenyl)- ethylamine.

Yield: 72% of theory, ffl-spectrum (methylene chloride): 1650 cm-1 (C0) Example 91

Isomer mixture of 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin2-one-3-yll-3-[N-me- thy]-N-(2-(2- and 4-aminophenyl)-ethyl)-aminolpropane Prepared analogously to Example 4 by catalytic hydrogenation of a isomer mixture of 1-[7,8- 50 dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[N-methyl-N-(2(2 - and 4-nitrophe nyi)-ethyl)-amino]propane.

Yield: 81 % of theory, IR-spectrum (methylene chloride): 1645 cm-1 (C0).

Example 92 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yll-3-[N-methyl-N-(2-(2acetylamino-phenyl)-ethyi)-amino]-propane hydrochloride and 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2one-3-yll-3-[N-methyl-N -(2-(460 acetylamino-phenyl)-ethyt)-aminolpropane hydrochloride Prepared analogously to Example 52 by reaction of a isomer mixture of 1-[7,8-dimethoxy1,3,4,5-tetrahydro-2H-3-benzazepin-2one-3-yi]-3-[N-methyl-N -(2-(2- and 4-amino-phenyi)-ethyi)amino]propane with glacial acetic acid and acetic anhydride. Yield in 2-acetylamino compound: 26% of theory, M.p.: 102-105T (decomp.) z r 33 GB 2 099 425A 33 Yield in 4-acetylamino compound: 49% of theory, M.p.: 89-93'C (decomp.).

Example 93

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[Nmethyl-N -(2-(4-amino- 5 phenyl)-ethyl)-aminolpropane 4.85 9 (0.0107 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3- benzazepin-2-one-3-yi]-3-[Nmethyl- N-(2-(4-acetyla m i no-phenyi)-ethyi)-a m i no]propa ne were stirred for 34 hours at 4WC with mi of methanolic hydrochloric acid. After evaporating the solution, the residue was dissolved in methylene chloride, extracted with sodium bicarbonate solution and washed with water. The 10 organic phase was dried, evaporated in vacuo and the oil obtained was subsequently dried at 5WC in vacuo. Yield: 88% of theory, 1 R-spectrum (methylene chloride): 1645 1 (C0) NMR-spectrum (CDC'3/D20): 8 = 2.25 ppm, s, 3H (NCH,); 3.8 ppm, s, 12H (OCH3); 6.9 ppm, 15 d (J = 7Hz), 2H (aromat.).

Example 94

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2-(4-chloro- phenyl)-ethyi)-aminol-propane dihydrochloride 1.01 g (0.00245 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3-yi]-3[N-methyi-N-(2-(4-amino-phenyi)-ethyi)-amino]propane were dissolved in 5 mI of semi-conc.

hydrochloric acid and diazotized with 0. 17 g (0.00245 mol) of sodium nitrite. Subsequently the solution was stirred at 55'C until no nitrogen escaped. The solution was made weakly alkaline and extracted with methylene chloride. After drying and evaporating in vacuo, the obtained oil 25 was purified over aluminium oxide (200 g, neutral, activity 11) (eluant: methylene chloride + 2% of ethanol) and the dihydrochloride was precipitated from acetone with ethereal hydrochloric acid.

Yield: 21 % of theory, M.p.: 148-151 C.

Example 95

1-[7, B-Dimethoxy-2,3-dihydro- 1 H-3-benzazepin-3-yll-3-[N-methyl-N-(2-(3, 4-dimethoxy-phenyl)- ethyl)-aminolpropane 2.3 g (0.005 mol) of 1-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3- yi]-3-[N-methyi-N35 (2-(3,4-dimethoxy-phenyi)-ethyi)-amino]propane were dissolved in 150 mi of absolute ether, mixed with 0.6 g of lithium aluminium hydride and stirred for 2 hours at room temperature.

With ice cooling 10% ammonium chloride solution was added, the precipitate was suction filtered and the solvent was removed in vacuo. The oily residue was purified over aluminium oxide (neutral, activity 11) with methylene chloride as eluant. Yield: 1. 6 g (72.7% of theory), ffl-spectrum (methylene chloride): 2830 cm-1 (OCH3) 2790 cm - 1 (N-alkyi) C2r, H36N204 (440.6) Calc.: C 70.88 H 8.2 4 N 6.36 Found: 70.50 8.80 6.22 Example 96

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[Nmethyl-N -(2-(4-hydroxy- 50 phenyl)-ethyl)-amino]-propane hydrochloride 1.1 g (2.67 mmol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin2-one-3-yi]-3-[N- methyi-N-(2-(4-amino-phenyi)-ethyi)-amino]propane were dissolved in 10 mi of semi-conc. sul furic acid and diazotized at O'C with 0. 18 g (2.67 mmol) of sodium nitrite. The solution was heated on the steam bath for 20 minutes, diluted with water, made weakly alkaline with sodium 55 hydroxide solution and extracted with methylene chloride. After drying and evaporating in vacuo, the obtained oil was purified over 100 g of aluminium oxide (neutral, activity 11) with methylene chloride + 2% of ethanol as eluant. The hydrochloride was precipitated from acetone/ ethereal hydrochloric acid.

Yield: 0. 17 g (15% of theory), M.p.: 109-112'C (decomp.).

Example 97 1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one3yl]-3-[N-methyl-N-(2-(4-dimethy.- lamino-phenyl)-ethyl)-amino]-propane dihydrochloride 34 GB2099425A 34 Prepared analogously to Example 11 by reaction of 1-[7,8-di-methoxy-1,3,4, 5-tetrahydro-2H-3benzazepin-2-one-3-yi]-3-[N-methyl-N-(2-(4-amino-phenyi)ethyi)-amino]propan e with 37% formalin solution and sodium cya noborohyd ride. Yield: 40% of theory, M.p.: 193-196'C.

Example 98 1[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H- 1, 3-benzodiazepin-2one-3-yll-3-[N-methyi-N-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)arnino]propane a) N-[3-[N-Methyl-N-(2-(4-amino-3,5-dichforo-phenyl)-ethyl)-aminolpropyl]-2-( 2-amino-4,5-di- 10 methoxy-phenyi)-ethylamine hydrochloride Prepared analogously to Example 53a from N-[3-[N'-methyi-N'-(2-(4-amino-3,5-dichloro-phenyl)ethyi)-amino]propyl]-2-(2-amino-4,5-dimethoxy-phenyl)-acetamide and lithium aluminium hydride.

M.P.: 182-188'C (decomp.). b) 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-1,3benzodiazepin-2-one-3-yll-3-[N-me thyl-N-(2-(4amino-3,5-dichforo-phenyl)ethyl)-amiiiolpropane Prepared analogously to Example 53b from N-[3-[N'methy]-N'-(2-(4-amino-3,5-dichloro-phenyi)ethyi)-amino]-propyi]-2-(2amino-4,5-dimethoxy-phenyi)-ethylamine hydrochloride and N,W-car- bonyl diimidazole. M.p.: 163-166'C.

Example 99 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3yll-3-[N-meth yl-N-(2-(4-amino3,5-dichloro-phenyl)-ethyl)-amino]propane Prepared analogously to Example 5b from 1-[7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepi n-2-o ne-3-yl]-3-[N -methyl-N-(2-(4-a m i no-3, 5-d ich loro-ph enyl)-ethyl)-a m i no] propane and selenium dioxide. M.p.: 118-130'C, m/e = 493/495 (C2,H2,C[2N304; 494.43) Example 100 1-[7, B-Dirnethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one3-yll-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-aminol-propane dihydrochloride 1.1 g (5.0 mmol) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one were suspended in 20 m[ of dimethyl sulfoxide and mixed with stirring with 0.6 g (5.3 mmol) of potassium tert.butylate. After 10 minutes the solution was mixed with 2.0 g (7.4 mmol) of 1 -chloro-3[Nmethyl-N-(2-(3,4-d i methoxy-phenyi)-ethyi)-a m i no]pro pane, subsequently stirred for 1 hour at WC, poured on water, extracted with ethyl acetate and the organic phase was evaporated in vacuo. The residue was purified over silica gel with methylene chloride + 10% of methanol as 40 elunat and the dihydrochloride was precipitated from acetone with ethereal hydrochloric acid. M.p.: 136-137'C.

Example 10 1

1-[7,8-Dimethoxy-1,3.4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[methyl-N -(2-(3,4-dime- 45 thoxy-phenyi)-ethyl)-aminol-propane dihydrochloride Prepared analogously to Example 100 from 7,8-dimethoxy-1,3,4,5-tetrahydro- 2H-3-benzazepin- 2-one and N-methyi-N-(2-(3,4-dimethoxy-phenyl)-ethyi)-azetidinium bromide.

M. p.: 13 VC.

Example 102

1-[7, B-Dimethoxy- 1, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yll-3-[Nmethyl-N-(2-(3-amino-4- chforo-phenyl)-ethyl)-amino]propane Prepared analogously to Example 12 by reaction of N-[3-(7,8-dimethoxy-1,3, 4,5-tetrahydro-2H- 3-benzazepin-2-one-3-yi)-propyl]methylamine with 2-(3-amino-4-chloro- phenyi)-ethylchloride. Oil.55 UV-spectrum (ethanol): X max: 238 nrn (0.26) 285 nrn (0. 19) 304 nrn (0.06) 60 IR-spectrum (dichloromethane): 3390 and 3480 cm-1 (NH2) 1650 cm-1 (CO) 2830 cm-1 (OCHO 2795 cm-1 (CH3-N<) 1520 and 1620 cm-1 (C = C) 65 k c GB 2 099 425A 35 Example 1 Tablets containing 10 mg of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one-3-yl]3-[N-methyi-N-(2-(3,4-di-methoxy-phenyl)ethyl)-amino]propane hydrochloride Composition:

1 tablet contains:

Active ingredient 10.0 mg Corn starch 57.0 mg Lactose 48.0 mg Polyvinyl pyrrolidone 4.0 mg 10 Magnesium stearate 1.0 mg 120.0 mg Method of preparation:

The active ingredient, corn starch, lactose and polyvinyl pyrrolidine were mixed together and moistened with water. The moist mixture was forced through a screen with mesh size of 1.5 mm and then dried at about 4WC. The dry granulate was passed through a screen with a mesh size of 1.0 mm and then mixed with magnesium stearate. The finished mixture was compressed in a tablet press with punches 7 mm in diameter and marked with a notch, to form tablets. 20 Weight of tablet: 120 mg Example 11 Coated tablets containing 5 mg of 1-[7, 8-dimethoxy- 1, 3,4,5tetrahydro-2H-3-benzazepin-2-one25 3-yll-3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-aminolpropane hydrochloride 1 Coated tablet core contains:

Active ingredient 5.0 mg Corn starch 41.5 mg Lactose 30.0 mg 30 Polyvinyl pyrrolidine 3.0 mg Magnesium stearate 0.5 mg 80.0 mg 35 Method of preparation The active ingredient,corn starch, lactose and polyvinyl pyrrolidone were thoroughly mixed and moistened with water. The moist mass was forced through a screen with a mesh size of 1 mm, then dried at about 45'C and the granulate was then passed through the same screen. After the 40 addition of magnesium stearate, convex tablet cores with a diameter of 6 mm were produced by compression in a tablet- making machine. The tablet cores thus produced were coated in known manner with a covering consisting essentially of sugar and talc. The finished coated tablets were oolished ith ax.

Weight of coated tablet: 130 mg.

Example 111 Ampoules containing 5 mg of 1-[7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl]3-[N-methyi-N-(2-(3,4-di-methoxyphenyl)-ethyi)-aminolpropane hydrochloride 50 1 Ampoule contains:

Active ingredient 5.0 mg Sorbitol 50.0 mg Water for injection ad 2.0 mi Method of preparation:

In a suitable container, the active ingredient was dissolved in water for injection purposes and the solution was made isotonic with sorbitol. After being filtered through a membrane filter, the solution was decanted into clean, sterilized ampoules under an N, atmosphere and autoclaved 60 for 20 minutes in a current of steam.

Example IV

Suppositories containing 15 mg of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H3-benzazepin-2-one3-ylj-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)ethyl)amino]propane hydrochloride 65 1 Suppository contains:

36 GB2099425A 36 Active ingredient 0.015 g Hard fat (e.g. Witepsol H 19 and W 45) 1.6859 1.700 g Method of preparation: The hard fat was melted. At WC the ground active ingredient was homogeneously dispersed in the melt. It was cooled to WC and poured into slightly pre-cooled suppository moulds.

Example V Drops solution containing 10 mg of 1-[7, 8-dimethoxy- 1, 3,4,5tetrahydro-2H-3-benzazepin-2one-3-yll-3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-aminolpropane hydrochloride per 5 m] 100 m[ of solution contain:

15 Active ingredient 0.2 g Hydroxy ethylcellulose 0.15 g Tartaric acid 0.1 9 Sorbitol solution containing 70% dry matter 30.09 20 Glycerine 10.0 g Benzoic acid 0.15 g Distilled water ad 100.0 mi 25 Method of preparation Distilled water was heated to 7WC. The hydroxy ethylcellulose, benzoic acid and tartaric acid were disolved therein with stirring. The mixture was cooled to ambient temperature and the glycerine and sorbitol solution were added with stirring. At ambient temperature, the active ingredient was added and stirred until completely dissolved. Then the mixture was evacuated, 30 with stirring, in order to eliminate air from the liquid.

Claims (89)

1. CLAIMS 1. Compounds of general formula i

   R- R6 f R A A R 40 2 R [wherein A represents a group of formula -CH,-CH,-, -CH = CH-, R, 1 -NH-CO, -CH2-CO- or- C = N- 5 5 5 (wherein R, represents an alkyl group containing 1 to 3 carbon atoms) and B represents a methylene or carbonyl group, or A represents a -CO-CO- group and B represents a methylene group; E represents an ethylene, n-propylene or n-butylene group (optionally substituted by an alkyl group containing 1 to 3 carbon atoms), an n-propylene group substituted at the 2-position 55 by a hydroxy group or n-butylene group substituted at the 2-or 3-position by a hydroxy group; G represents a methylene or ethylene group (optionally substituted by an alkyl group containing 1 to 3 carbon atoms); R, and R2, which may be the same or different, each represents a hydroxy group, an alkyl group containing 1 to 3 carbon atoms, or an alkoxy or phenylaikoxy group (in each of which the alkyl part may contain 1 to 3 carbon atoms) or one of the radicals R, and R, 60 represents a hydrogen atom or R, together with R2 represents an alkylenedioxy group containing 1 or 2 carbon atoms; R. and R,, which may be the same or different, each represents a hydrogen or halogen atom, a hydroxy group, an alkyl or alkoxy group, each of which may contain 1 to 4 carbon atoms, or a trifluoromethyl or cyano group or one of the radicals R, or R, 65 represents a nitro group or R3 together with R, represents an alkylenedioxy group containing 1 65 W 37 GB 2 099 425A 37 or 2 carbon atoms; R, represents a hydrogen atom, a hydroxy or amino group, an alkyl, alkoxy or alkylamino group containing 1 to 3 carbon atoms, or a dialkylamino, alkanoylamino, alkoxycarbonylamino or bis(alkoxycarbonyl)-amino group, in each of which the alkyl part may contain from 1 to 3 carbon atoms, or a methylamino or ethylamino group substituted by a trifluoromethyl group; and R6 represents a hydrogen atom, an alkyl group containing from 1 to 3 carbon atoms, or a phenylalkyl, alkanoyl or alkoxycarbonyl group, in each of which the alkyl part may contain from 1 to 3 carbon atoms, or an alkenyl group containing 3 to 5 carbon atoms] and acid addition salts thereof.
2. 2. Physiologically compatible acid addition salts of compounds of formula I as defined in claim 1 -
3. 3. Salts as claimed in claim 2 formed with hydrochloric hydrobromic, sulfuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic or fumaric acid.
4. 4. Compounds as claimed in any one of the preceding claims, wherein A represents a -CH2-CH2-1 -CH = CH-, CH, 1 -NI-I-CO-,-CH2-CO-or -C= N 5 5 group and B represents a methylene or carbonyl group, or A represents a CO-CO- group and B represents a methylene group; E represents an ethylene, n-propylene, n-butylene, 2-methyl-npropylene or 2-hydroxy-n-propylene group; G represents a methylene, ethylene, or 1-methylethylene group; R, represents a methyl, hydroxy, or benzyloxy group or an alkoxy group containing 1 to 3 carbon atoms and R2 represents a hydrogen atom or a methyl, hydroxy or methoxy group, or R, and R2 together represent a methylenedioxy group; R3 represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl or nitro group, or an alkyl or alkoxy group containing 1 to 4 carbon atoms each and R, represents a hydrogen, chlorine or bromine atom or a methyl, methoxy or cyano group or R3 and R, together represent a methylenedioxy group; R. represents a hydrogen atom or a hydroxy, methoxy, amino, acetylamino, ethoxycarbonylamino, bis(ethoxycarbonyi)-amino, dimethyl-amino or,8,P,,8,-trifluoroethylamino group; and R, represents a hydrogen atom, an alkyl group containing 1 to 3 carbon atoms or an allyl, benzyi, acetyl or ethoxycarbonyl group.
5. 5. Compounds as claimed in claim 4, wherein A represents a -CH2-CH2-, -CH = CH- or CH3 1 -C = N- group and B represents a carbonyl group, or A represents a -CH = CH- -NH-CO- or -CO-CO- group and B represents a methylene group; E represents an n- propylene group; G represents an ethylene group; R, represents a methoxy or hydroxy group and R2 represents a methoxy group, or R, and R2 together represent a methylenedioxy group; R3 represents a methoxy or trifluoromethyl group or a chlorine or bromine atom and IR,, represents a methoxy group or a hydrogen, chlorine or bromine atom, or R3 and R, together represent a methylene- 50 dioxy group; R,, represents a hydrogen atom or an amino or methoxy group; and R. represents a hydrogen atom or a methyl, ethyl, n-propyl or allyl group.
6. 6. Compounds of general formula la, A R 1 N-CH -CH -CH 2 -N' -CH 2 -CH -&R (Ia) R CH 2 -B/ 2 2 2 3 R6 R 4 wherein A represents a -CH2-CH2-, -CH = CHor 38 GB2099425A 38 CH3 1 -C= N5 group and B represents a carbonyl group, or A represents an -NH-CO5 or -COCO- group and B represents a methylene group; R, and R2 each represents a methoxy group; Rr, represents a hydrogen atom or a methyl or allyl group; R, represents a hydrogen atom or a methoxy group at the 3-position and R, represents a methoxy group at the 4-position or R3 and R, together represent a 3,4-methylenedioxy group, and R. represents a hydrogen atom; or R3 at the 3-position represents a chlorine or bromine atom, R, at the 5- position represents a 15 chlorine or bromine atom and R.. at the 4-position represents an amino group, and acid addition salts thereof with inorganic or organic acids.
7. 7. 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yi]-3-[Nmethyl-N -(2-(3,4- dimethoxy-phenyi)-ethyi)-amino]-propane.
8. 8. 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yi]-3[N-meth yl-N-(2- 20 (3,4-dimethoxy-phenyl)-ethyi)-amino]-propane.
9. 9. 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[Nmethyl-N -(2-(4-am- i no-3, 5-d ich 1 oro phenyl)-ethyl)-a m i no]-pro pane.
10. 10. 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl]-3-[Nmethyi-N -(2-(4- methoxy-phenyl)-ethyi)-aminol-propane.
11. 11. Physiologically compatible acid addition salts of compounds as claimed in any one of claims 6 to 10.
12. 12. Hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic or fumaric acid addition salts of compounds as claimed in any one of claims 6 to 10.
13. 13. Compounds as claimed in claim 1 wherein A represents a group of formula -CH2-CH2-, 30 -CH = CH- or -NH-CO5 B represents a methylene or carbonyl group; R, represents an alkoxy group containing 1 to 3 carbon atoms, R2 represents a hydrogen atom or an alkoxy group containing 1 to 3 carbon atoms, or R, and R2 together represent a methylenedioxy group; R3 and IR, which may be the same or different, each represents a hydrogen atom or an alkoxy group containing 1 to 3 carbon atoms, or R3 and R, together represent a methylenedioxy group; R, represents a hydrogen atom; 40 R, represents a hydrogen atom, an alkyl group containing 1 to 3 carbon atoms (optionally substituted by a phenyl group) or an ally[ group; E represents an ethylene, n-propylene or n butylene group; and G represents an ethylene group.
14. 14. Compounds as claimed in claim 1 as herein described in any one of the Examples.
15. 15. Compounds as claimed in claim 13 as herein described in any one of Examples 1, 2 45 and 4-10.
16. 16. A process for the preparation of compounds as claimed in claim 1, which comprises reacting a compound of general formula 11 R A N - H R 2 (11) (wherein A and B are as defined in claim 1, R,' and R,' each represents a hydroxy group protected by a protective radical or represent R, and R2 as defined in claim 1) with a compound 60 of general formula Ill 01 39 GB 2 099 425A 39 R6 1 R 3' z - 3 - N. - G R 4 R (111) R 5 1 (wherein 116, E and G are as defined in claim 1, R31, R,' and R,' each represent a hydroxy group protected by a protective radical or represent R3, R, and R. as defined in claim 1, and Z represents a nucleophilically exchangeable group) or the corresponding internal quaternary salt 15 thereof, optionally present in the reaction mixture, of general formula Ilia R6 z R r, 1 (D 3 N C- G R 4 R 5 (iiia) (wherein E, G, Z, R,' R,', R,' and R. are as hereinbefore defined) and optionally subsequently cleaving the protective radical or radicals.
17. 17. A process as claimed in claim 16 wherein Z represents a chlorine, bromine or iodine atom, a methanesuffonyloxy, p-toluenesuffonyloxy or ethoxysuifonyloxy group.
18. 18. A process as claimed in claim 16 or claim 17 wherein the reaction is carried out in a solvent.
19. 19. A process as claimed in any one of claims 16 to 18 wherein the reaction is carried out 35 at temperatures between 0 and 1 50T.
20. 20. A process as claimed in claim 18 wherein the reaction is carried out at the boiling point of the solvent.
21. 2 1. A process as claimed in any one of claims 16 to 20 wherein the reaction is carried out in the presence of a base.
22. 22. A process as claimed in any one of claims 16 to 21 wherein at least one protective radical is split off hydrolytically in the presence of an acid or base, or if the protective radical is a benzyi radical, is optionally alternatively split off hydrogenolytically.
23. 23. A process for the preparation of compounds as claimed in claim 1 wherein R, represents a hydrogen atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 45 to 3 carbon atoms, or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part, which comprises reacting a compound of general formula IV R ' \11 N - 3 - U M) C- B / R 2 l.

    with a compound of general formula V GB 2 099 425A 40 R3' G - v (V) R4' R 5 1 (wherein A, B, E and G are as defined in claim 1, IR,', IR,', IR,', R4' and R,' each represent a hydroxy group protected by a protective radical or represent R, R2, IR, R4 and R, as defined in claim 1, one of the radicals U and V represents an Rj-NI-1- group (wherein R,' represents hydrogen atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 15 to 3 carbon atoms, or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part), and the other of the radicals U and V represents a nucleophilically exchangeable group, or the radical U together with a hydrogen atom at the fl-position of the radical E represents an oxygen atom and V represents an R6'-NH- group (wherein R6' is as defined above)] and optionally subsequently cleaving the protective radical.
24. 24. A process as claimed in claim 23 wherein the reaction is carried out in a solvent.
25. 25. A process as claimed in claim 23 or 24 wherein the reaction is carried out at temperatures between 0 and 1 50T.
26. 26. A process as claimed in claim 24 wherein the reaction is carried out at the boiling temperature of the solvent.
27. 27. A process as claimed in any one of claims 23 to 26 wherein the reaction is carried out in the presence of a base.
28. 28. A process as claimed in any one of claims 23 to 27 wherein at least one protective radical is split off hydrolytically in the presence of an acid or base, or, if the protective radical is a benzy] radical, is optionally alernatively split off hydrogenolytically.
29. 29. A process for the preparation of compounds as claimed in claim 1 wherein IR,, represents a hydrogen atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 to 3 carbon atoms or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part, which comprises reacting a compound of general formula V] A \ -- R - G R 3 (1 1 X) N - E - H (VI) 1 -B / - R 4. 40 R 2 R 5 -.

    45 (wherein A, B, E, R, and R, are as defined in claim 1, except that in the radical E two hydrogen atoms of -CH2- or CH,- group are replaced by an oxygen atom) with an amine of general formula V11 50 R 3 R4 H - K - G (VII) 1 55 R6 R (wherein G, IR, R4 and R, are as defined in claim 1 and R6' represents a hydrogen atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 to 3 carbon atoms, 60 or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part) in the presence of a reducing agent.
30. 30. A process as claimed in claim 29 wherein the reaction is carried out in a solvent.
31. 31. A process as claimed in claim 29 or claim 30 wherein the reaction is carried out at temperatures between 0 and 100T.

    R I 41 GB 2 099 425A 41
32. 32. A process as claimed in any one of claims 29 to 31, wherein R6 represents a hydrogen atom and the reaction is carried out in the presence of hydrogen and a hydrogenation catalyst.
33. 33. A process as claimed in any one of claims 29 to 31 wherein the reaction is carried out in the presence of a complex metal hydride at pH 6-7 at room temperature.
34. 34. A process as claimed in claim 33 wherein the complex metal hydride comprises lithium cya noborohyd ride or sodium cyca noborohyd ride.
35. 35. A process for the preparation of compounds as claimed in claim 1 wherein R6 represents a hydrogen atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 to 3 carbon atoms or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part, which comprises reacting a compound of general formula V111 R1 1 11.1 N R " I CB 1.1. 6 R 2 (VIII) (wherein A, B, E, R, and R2 are as defined in claim 1 and R6' represents a hydrogen atom, an alkenyl group containing 3 to 5 carbon atoms, an alkyl group containing 1 to 3 carbon atoms, or a phenylalkyl group containing 1 to 3 carbon atoms in the alkyl part) with a compound of general formula IX (wherein G, R3, R4 and R, are as defined in claim 1, except that in the radical G two hydrogen atoms in a -CH2 or CH3group are replaced by an oxygen atom) in the presence of a reducing agent.
36. 36. A process as claimed in claim 35 wherein the reaction is carried out in a solvent. 40
37. 37. A process as claimed in claim 35 or claim 36 wherein the reaction is carried out at temperatures between 0 and 1 00T.
38. 38. A process as claimed in any one of claims 35 to 37, wherein R. represents a hydrogen atom and the reaction is carried out in the presence of hydrogen and a hydrogenation catalyst.
39. 39. A process as claimed in any one of claims 35 to 37 wherein the reaction is carried out 45 in the presence of a complex metal hydride at pH 6-7 at room temperature.
40. 40. A process as claimed in claim 39 wherein the complex metal hydride comprises lithium cya noborohyd ride or sodium cyanoborohyd ride.
41. 41. A process for the preparation of compounds as claimed in claim 1 wherein A represents a -NH-CO- group, E represents an ethylene, n-propylene or n-butylene group (optionally 50 substituted by an alkyl group containing 1 to 3 carbon atoms) and R, does not represent a hydrogen atom, which comprises reacting a compound of general formula X R1, 55 NH 2 R 3 R H R 6 R 1 f 4 -C[ CH2 - B - N - E 9 - N - G -(' (X) 60 (wherein B and G are as defined in clam 1, E' represents an ethylene, n- propylene or n-butylene group optionally substituted by an alkyl group containing 1 to 3 carbon atoms, IR,', R2', R3' and65 GB2099425A 42 R,' each represent a hydroxy group protected by a protective radical or represent IR, R2, R, and R, as defined in claim 1, Rj' represents a hydroxy, amino or alkylamino group protected by a protective radical or represents R, as defined in claim 1 with the exception of an amino or alkylamino group, and Rj' represents IR,, as defind in claim 1 with the exception of a hydrogen atom or represents a protective group for an amino group) with a carbonic acid derivative of general formula X] W-CO-WI (m) [wherein W and W, which may be the same or different, each represent a nucleophilically 10 exchangeable group, an alkoxy group containing 1 to 3 carbon atoms (optionally substituted by halogen atoms) or an imidazolyi-(2) group] and optionally subsequently cleaving the protective radical.
42. 42. A process as claimed in claim 41 wherein W and W' each represent a chlorine or bromine atom.
43. 43. A process as claimed in claim 41 or claim 42 whein the reaction is carried out in the presence of a base.
44. 44. A process as claimed in any one of claims 41 to 43 wherein the reaction is carried out in a solvent at temperatures between 0 and 1 50T.
45. 45. A process as claimed in claim 44 wherein the reaction is carried out at the boiling 20 temperature of the solvent.
46. 46. A process as claimed in any one of claims 41 to 45 wherein at least one protective radical is split off hydrolytically in the presence of an acid or base, or if the protective radical is a benzyl radical, is optionally alternatively split off hydrogenolytically.
47. 47. A process for the preparation of compounds as claimed in claim 1 wherein A represents 25 a -CH2-CH2- group, R, and R2 do not represent benzyloxy groups, R, and R4 do not represent nitro groups and R, does not represent a benzyi group or an alkenyl group containing 3 to 5 carbon atoms, which comprises hydrogenating a compound of general formula X11 R 1 R 2 (CH=CH R 6 3 N - E N - G R 4 R 5 (Xli) wherein R, R2, R3, R4, R5, B, E and G are as defined in claim 1 except that R3 or R, may not 40 represent a nitro group if R, represents an amino group.
48. 48. A process as claimed in claim 47 wherein the reaction is carried out in a solvent.
49. 49. A process as claimed in claim 47 or claim 48 wherein the hydrogenation is carried out at a hydrogen pressure of 1 to 7 bar.
50. 50. A process as claimed in claim 49 wherein the hydrogen pressure is 3 to 5 bar.
51. 51. A process as claimed in any of claims 47 to 50 wherein the reaction is carried out at temperatures between 0 and 7WC.
52. 52. A process as claimed in claim 51 wherein the temperatures are between 20 and 50T.
53. 53. A process for the preparation of compounds as claimed in claim 1 which comprises reacting a compound of general formula X111 R R3 r 16 1 h 1 1 cc B R -E -N-G-/- - - R4 (Xtil) RS (wherein R, R2, R3, R4, R5, R6, A, B, E and G are as defined in claim 1, whereby however, at least one of the radicals R, R2, R. and R4 represents a hydroxy group or R5 represents a hydroxy group, an amino group or an alkylamino group containing 1 to 3 carbon atoms or R. 60 represents a hydrogen atom) with a compound of general formula XIV R8-X (XIV) wherein R,3 represents an alkyl group containing 1 to 3 carbon atoms or (if R6 represents a 65 z z 43 GB 2 099 425A 43 1 hydrogen atom) an alkenyl group containing 3 to 5 carbon atoms, or (if R, or R2 represents a hydroxy group and/or IR,, represents a hydrogen atom) an alkyl group containing 1 to 3 carbon atoms substituted by a phenyl group, and X represents a nucleophilically exchangeable group; or (if at least one of the radicals IR,, R2, R3, R4 and R. represents a hydroxy group) X together with the hydrogen atom at the a-position of the radical R, may represent a diazo group or (if R6 represents a hydrogen atom or R 5 represents an amino or alkylamino group) an oxygen atom.
54. 54. A process as claimed in claim 53 wherein the nueleophilically exchangeable group X comprises a halogen atom or a sulfonyloxy group.
55. 55. A process as claimed in claim 53 or claim 54 wherein the reaction is caried out in a solvent.
56. 56. A process as claimed in any one of claims 53 to 55 wherein the reaction is carried out at temperatures between 0 and 1 50T.
57. 57. A process as claimed in any one of claims 53 to 56, wherein X represents a nucleophilically exchangeable group and the reaction is carried out in the presence of an acid- binding agent, at temperatures between 20 and 80T.
58. 58. A process as claimed in any of claims 53 to 57 wherein at least one of the radicals R, R2, R3, R4 and R5 represents a hydroxy group and the reaction is carried out with a diazo compound of general formula XIV, at temperatures between 0 and 30T.
59. 59. A process as claimed in any one of claims 53 to 57, wherein R6 represents a hydrogen atom and/or R5 represents a namino or alkylamino group and the reaction is carried out with an 20 aldehyde of general formula XIV in the presence of a reducing agent at temperatures between 0 and 120T.
60. 60. A process as claimed in claim 59 wherein the reaction is carried out in the presence of formic acid as the reducing agent at the boiling temperature of the reaction mixture.
61. 61. A process as claimed in claim 59 wherein the reaction is carried out in the presence of sodium cya no borohyd ride as the reducing agent, at room temperature and at pH 6-7.
62. 62. A process for the preparation of compounds as claimed in claim 1 wherein A does not represent a -CH = CH- group, R3 represents a chlorine or bromine atom and R. represents an amino or alkylamino group, which comprises halogenating a compound of general formula XV R A' R 2 G R 6 R 1 4 R all 5 (XY) wherein IR, R2, IR,, R, B, E and G are as defined in claim 1, A' represents A as defined in claim 1 with the exception of a -CH = CHgroup and IR," " represents an amino group or an alkylamino group containing 1 to 3 carbon atoms.
63. 63. A process as claimed in claim 62 wherein the compound of general formula XV is used in the form of an acid addition salt thereof.
64. 64. A process as claimed in claim 62 or claim 63 wherein the reaction is carried out in a solvent.
65. 65. A process as claimed in any one of claims 62 to 64 wherein the reaction is carried out at temperatures between 0 and 50T. 50
66. 66. A process as claimed in any one of claims 62 to 65 wherein the reaction is carried out 50 in the presence of a heavy metal compound.
67. 67. A process for the preparation of compounds as claimed in claim 1 wherein A represents a -COCO- group, B represents a methylene group E and represents an ethylene, n-propylene or n-butylene group (optionally substituted by an alkyl group containing 1 to 3 carbon atoms), which comprises oxidising a compound of general formula M R 1 CH2-CO R 2 1 -OCH 2 -CH 2 R 3 R 4 60 (xV:0 R 5 44 GB2099425A 44 wherein R, R2, R3, IR, R, R. and G are as defined in claim 1, and E represents an ethylene, npropylene or n-butylene group (optionally substituted by an alkyl group containing 1 to 3 carbon atoms).
68. 68. A process as claimed in claim 67 wherein the reaction is carried out in a solvent. 5
69. 69. A process as claimed in claim 67 or claim 68 wherein the oxidation is carried out using 5 an oxidising agent.
70. 70. A process as claimed in claim 69 wherein the oxidising agent comprises potassium permanganate, selenium dioxide or sodium dichromate.
71. 71. A process as claimed in any one of claims 67 to 70 wherein the reaction is carried out at temperatures between 0 and 1 00T.
72. 72. A process as claimed in claim 71 wherein the temperature range is from 20 to 80T.
73. 73. A process as claimed in any one of claims 16 to 72 wherein a compound of general formula 1 wherein B represents a carbonyl group, initially obtained, is subsequently a carbonyl group, initially obtained, is subsequently converted by reduction into a compound of general formula 1 wherein B represents a methylene group; and/or a compound of general formula 1, wherein A does not represent -CH = CH- or R7 1 -C = N- group and R6 does not represent a benzyl or 1-phenylethyl group, initially obtained is subsequently converted by means of catalytic hydrogenation into a compound of general formula I wherein R6 represents a hydrogen atom; and/or a compound of general formula 1 wherein R3 or R, represents a nitro group, initially obtained, is subsequently converted by 25 reduction into a compound of general formula I wherein R, represents an amino group; and/or a compound of general formula I wherein R6 represents a hydrogen atom and/or R, represents an amino group initially obtained, is subsequently converted by acylation into a compound of general formula I wherein R, represents an alkanoyl or alkoxycarbonyl group and/or R, represents an alkanoylamino, alkoxycarbonylamino or bis(alkoxycarbonyl)amino group, wherein 30 the alkyl part may contain from 1 to 3 carbon atoms each; and/or a compound of general formula I wherein R. represents an amino group, R, does not represent a hydrogen atom and neither R3 nor R, represents a cyano group, initially obtained, is subsequently converted via a diazonium salt into a compound of general forniula I wherein R, represents a hydrogen atom and R3 represents a halogen atom or a cyano group.
74. 74. A process as claimed in any one of claims 16 to 73 wherein a compound of formula I initially obtained is subsequently converted into an acid addition salt thereof or an acid addition salt of a compound of formula I initially obtained is subsequently converted into a compound of formula 1.

    L A
75. 75. A process as claimed in any one of claims 16 to 74 for the preparation of compounds 40 as claimed in claim 13.
76. 76. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of the Examples.
77. 77. A process for the preparation of compounds as claimed in claim 13 substantially as herein described in any one of Examples 1, 2 and 4-10.
78. 78. Compounds as claimed in claim 1 when prepared by a process as claimed in any one of claims 16 to 77.
79. 79. Compounds as claimed in claim 13 when prepared by a process as claimed in claim 75 or 77.
80. 80. Pharmaceutical compositions comprising as active ingredient at least one compound of 50 formula 1 as defined in claim 1 or a physiologically compatible acid addition salt thereof, in association with one or more pharmaceutical carriers or excipients.
81. 81. Compositions as claimed in claim 80 in a form suitable for oral, rectal or parenteral administration.
82. 82. Compositions as claimed in claim 80 or claim 81 in the form of tablets, coated tablets, 55 capsules, drops, suppositories, ampoules, suspensions, powders or juices.
83. 83. Compositions as claimed in any one of claims 80 to 82 in the form of dosage units.
84. 84. Compositions as claimed in any one of claims 80 to 83 wherein the compounds of formula 1 is as defined in claim 13.
85. 85. Pharmaceutical compositions as claimed in claim 80 substantially as herein described. 60
86. 86. Pharmaceutical compositions substantially as herein described in any one of Examples 1 to V.
87. 87. Compounds of general formula 1 as claimed in claim 1 and physiologically compatible acid addition salts thereof for use in a method of treatment of patients suffering from disorders of heart-rate, including sinus tachycardia and ischaemic cardiac diseases.

    11 0 GB 2 099 425A 45
88. 88. A method of treating patients suffering from, or susceptible to, disorders of heart-rate which comprises administering to the said patient an effective amount of a compound of formula 1 as defined in claim 1 or a physiologically compatible acid addition salt thereof.
89. 89. Each and every novel method, process, compound or composition herein disclosed.

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