NZ206305A

NZ206305A - Benzazepine and benzodiazepine derivatives and pharmaceutical compositions

Info

Publication number: NZ206305A
Application number: NZ206305A
Authority: NZ
Inventors: M Reiffen; J Heider; V Austel; N Haud; W Kobinger; C Lillie
Original assignee: Thomae Gmbh Dr K
Priority date: 1982-11-18
Filing date: 1983-11-17
Publication date: 1986-10-08
Also published as: EP0109636A2; ES532662A0; YU226283A; ATE40118T1; IE56261B1; GB2130213B; CS239947B2; JPH0441144B2; ES8502689A1; FI834174A0; HU193189B; GR81253B; PL139449B1; GB2130213A; DK527483D0; ES8502424A1; GB8330731D0; IE832692L; FI834174A; IL70258A

Abstract

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

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £06305 Priority Di-Tfj(.s): ./£ \((-%. £ .2 Complete Specification Filed: Ciass: Publication Date: • -O. Journal, No: /«i .? 20 IAW1ISSS // NOV Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION "CHEMICAL COMPOUNDS" -i-,WE DR. KARL THOMAE GESELLSCHAFT MIT BESCHRANKTER HAFTUNG a body corporate organised under the laws of the Federal Republic of Germany of Biberach an der Riss Federal Republic of Germany hereby declare the invention, for which -I-/we pray that a patent may be granted to-ffte-/us, and the method by which it is to be performed, to be particularly described in and by the following statement -1- ffollowsd bv oaee 1 A.) - la - 206305 Chemical Compounds This invention relates to new benzazepine derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to the use of these compounds in the treatment of disorders of heart-rate. 5 New Zealand Patent No. 185,081 describes, inter alia, the compound of formula CH.,0 \ OCH. ch3O/^J CH2CH2CH2N-CH2CH2 T: »N—( and the physiologically acceptable acid addition salts thereof, which has valuable pharmacological properties, i.e. in particular a selective heart-10 rate lowering effect in addition to a mild hypotensive effect. It has surprisingly now been found that the compounds of the present invention have superior pharmacological properties, namely, in particular, 15 a stronger heart-rate lowering effect with a longer duration of activity and fewer side effects. Thus, according to one feature of the present invention, we provide compounds of general formula I - 2 - 206305 n-E-3J-G " (i) [wherein R^ represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, an alkoxy 5 group with 1 to 3 carbon atoms or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, fluorine, 10 chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms, or R^ and R2 together represent an alkylenedioxy group with 1 or 2 carbon atoms; R^ represents a hydrogen, fluorine, chlorine or bromine atom, a nitro or trifluoromethyl group 15 or an alkyl or alkoxy group each having 1 to 3 carbon atoms and R^ represents a hydrogen atom, an amino group or an alkoxy, alkylamino or dialkylamino group (each alkyl moiety having 1 to 3 carbon atoms and the alkyl moieties in the dialkylamino group 20 being the same or different) , or R^ and R^ together represent an alkylenedioxy group with 1 or 2 carbon atoms; R5 represents a hydrogen, chlorine or bromine atom; Rg represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 25 3 to 5 carbon atoms; E represents an n-alkylene group with 2 to 4 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms; B represents a thiocarbonyl, carbonyl or 30 methylene group; G represents an n-alkylene group with 1 to/ ^ 5 carbon atoms optionally substituted by an alkyl- n X\ 206305 - 3 - group with 1 to 3 carbon atoms (wherein, so long as B represents a methylene or carbonyl group, a methylene group may optionally be replaced by a carbonyl group), or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G; and A represents a group of formula -CH2-CH2~, ?7 10 -CH=CH-, -NH-CO- , -CH2-C0-, -C=N-, -N=CH-, OH OH NOH NHRg I I li I -CHCO-, -CH-CH2-, -C-C0-, -CH-CO- or -CO-CO- (wherein 5 5 5 5 represents an alkyl group with 1 to 3 carbon atoms and Rg represents a hydrogen atom or an alkyl 15 group with 1 to 3 carbon atoms substituted by a phenyl, methoxy-phenyl or dimethoxyphenyl group); with the provisos that (i) when A represents a group of formula -CH2-CH2", -CH=CH-, -NH-CO-, -CHj-CO-, or -C=N-, 20 (wherein R^ is as hereinbefore defined) B may not represent a methylene or carbonyl group unless G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl 25 group with 1 to 3 carbon toms, an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to M ot !v^ ^ V EO, . £=> V ^ - 4 - 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R^ and R2 each represents a hydrogen atom or R^ represents a fluorine, chlorine 5 or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, 10 fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms (except in the case of A representing a -CH2CH2- group, R^ and R2 representing methoxy groups in the 7- and 8- positions, E representing 15 an n-propylene group, Rg representing a methyl group, G representing an ethylene group, Rg representing a hydrogen atom, and Rj and R^ either both representing hydrogen atoms or representing respectively a 3-nitro and a 4-amino group, in which case B may 20 represent a carbonyl group); (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl 25 group with 1 to 3 carbon atoms, an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 30 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R^ and R2 each represents a hydrogen atom or R^ represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an 35 amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, 206305 - 5 - be the same or different) and R2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms; and (iii) when A represents a group of formula OH OH NOH HN-Rg 5 -N=CH-, -CH-C0-, -CH-CH2-, -C-CO- or -CH-CO- (wherein Rg is as hereinbefore defined), B represents a methylene group] and acid addition salts of the aforementioned compounds. 10 The term "acid addition salts" as used herein refers to salts formed with organic and inorganic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic and fumaric acids. 15 For pharmaceutical use the acid addition salts will, of course, be physiologically acceptable acid addition salts, but other acid addition salts may find use, for example in the preparation of the compounds of general formula I and their physio-20 logically acceptable acid addition salts. The definitions given hereinbefore for the groups R^ to Rg, E and G include the following: R^ may be a hydrogen, fluorine, chlorine or bromine atom, or a trifluoromethyl, methoxy, ethoxy, n-25 propoxy, isopropoxy, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethyl-amino, di-n-propylamino, diisopropylamino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropyl-amino or ethyl-n-propylamino group, 30 R2 may represent a hydrogen, fluorine, chlorine or bromine atom, or a methoxy, ethoxy, n-propoxy - 5 - 506305 be the same or different) and R2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms; and (iii) when A represents a group of formula OH OH NOH H^"R8 I I II I 5 -N=CH—, -CH-C0-, -CH-CH2-, -C-CO- or -CH-C0-, (wherein Rg is as hereinbefore defined) B represents a methylene group] and acid addition salts of the aforementioned compounds. The term "acid addition salts" as used herein 10 refers to salts formed with organic and inorganic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic and fumaric acids. For pharmaceutical use the acid addition 15 salts will, of course, be physiologically acceptable acid addition salts, but other acid addition salts may find use, for example in the preparation of the compounds of general formula I and their physiologically acceptable acid addition salts. 20 The symbol "5", when used herein to designate a particular atom in certain of the alternative definitions of the substituent A, signifies that the atom thus designated is directly connected to the aromatic nucleus adjacent to substituent A. 25 The definitions given hereinbefore for the groups R^ to Rg, E and G include the following: R^ may be a hydrogen, fluorine, chlorine or bromine atom, or a trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, amino, methylamino, ethylamino, 30 n-propylamino, isopropylamino, dimethylamino, diethyl-amino, di-n-propylamino, diisopropylamino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropyl-amino or ethyl-n-propylamino group, \ R2 may represent a hydrogen, fluorine, chlorine 35 or bromine atom, or a methoxy, ethoxy, n-propoxy . V "k w y 2 0 WT? _ *.4) > <S ^ ^8-7 V,--^' ^ >* - 6 - or isopropoxy group or together with may represent a methylenedioxy or ethylenedioxy group, may represent a hydrogen, fluorine, chlorine or bromine atom, or a nitro, trifluoromethyl, methyl, 5 ethyl, n-propyl, methoxy, ethoxy, n-propoxy or isopropoxy group, R4 may represent a hydrogen atom, or a methoxy, ethoxy, n-propoxy, isopropoxy, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethyl- 10 amino, diethylamino, di-n-propylamino, diisopropylamino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropylamino or ethyl-n-propylamino group or together with R^ may represent a methylenedioxy or ethylenedioxy group, 15 Rg may represent a hydrogen, chlorine or bromine atom, Rg may represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, allyl, n-buten-(2)-yl or n-penten-(2)-yl group, 20 R7 may represent a methyl, ethyl, n-propyl or isopropyl group, Rg may represent a hydrogen atom or a benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-(4-methoxyphenyl)-ethyl, 2-(3,4-dimethoxyphenyl)- 25 ethyl, 3-(4-methoxyphenyl)-propyl or 3-(3,4-dimethoxy-phenyl) -propyl group, E may represent an ethylene, n-propylene, n-butylene, 1-methyl-ethylene, 2-ethyl-ethylene, 1-propyl-ethylene, 1-methyl-n-propylene, 2-methyl- 30 n-propylene, 1-ethyl-n-propylene, 3-ethyl-n-propylene, 2-propyl-n-propylene or 2-methyl-n-butylene group 206305 - 7 - and G may represent a methylene, ethylidene, n-propylidene, n-butylidene, 2-methyl-propylidene, ethylene, 1-methyl-ethylene, 2-ethyl-ethylene, 5 1-propyl-ethylene, 2-methyl-ethylene, n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, 1-methyl-butylene, 1-methyl-n-pentylene, 1-ethyl-n-propylene, 2-ethyl-n-propylene, 1-methyl-n-butylene, methylenecarbonyl, ethylenecarbonyl, n-propylene-10 carbonyl, n-butylenecarbonyl, carbonylmethylene, carbonylethylene, carbonyl-n-propylene, carbonyl-n-butylene, methylenecarbonylmethylene, ethylene-carbonylmethylene, 2-hydroxyethylene, 2-hydroxy-n-propylene, 3-hydroxy-n-propylene, 2-hydroxy-n-15 butylene, 3-hydroxy-n-butylene, 4-hydroxy-n-butylene or 2-hydroxy-n-pentylene group; the group is preferably in the 3-position, R^ in the 4-position and R5 in the 5-position of the phenyl nucleus in question. However, preferred compounds are compounds 20 of general formula la n-ch2ch2ch2 4 (la) [wherein R^ represents a hydrogen, chlorine or bromine 25 atom or a trifluoromethyl, methoxy, amino, methylamino or dimethylamino group, and R2 represents a hydrogen, chlorine or bromine atom or a methoxy group, or R^ and R2 together represent a methylenedioxy group; .i'-O. 2 0C2i,5 - 8 - r3 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl, methoxy, trifluoromethyl or nitro group, and R4 represents a hydrogen atom or an amino, methoxy, methylamino or dimethylamino 5 group, or and R^ together represent a methylenedioxy group; Rg represents a hydrogen, chlorine or bromine atom; Rg represents a hydrogen atom or a methyl 10 or allyl group; B represents a thiocarbonyl, carbonyl or methylene group; G represents an n-alkylene group with 2 to 5 carbon atoms (wherein, so long as B represents 15 a methylene or carbonyl group, a methylene group may optionally be replaced by a carbonyl group), or a methylene-n-hydroxy-alkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the 20 left of the group G; and A represents a group of formula -CH2-CH2~, 25 30 oh oh noh l l II —ch=ch-, —n=ch-, -ch-ch,- , -ch-co-, -c co-, 5 5 5 5 nh2 nh-ch2ch2—°ch3 -ch-co-, -ch-co- och3 or -coco-; 5 5 with the provisos that (i) when A represents a group of formula -ch2-ch2- or -ch=ch-, B represents a thiocarbonyl group, and may also represent a carbonyl group when G represents an n-alkylene group with 3 to 5 carbon atoms, an n-alkylene group with 2 to 5 crbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the 2 0 ^ 4s /T ^.x £*» - 9 - nitrogen atom to the left of the group G, and/or R-^ and R2 each represents a hydrogen atom or R^ represents a chlorine or bromine atom or a trifluoro-methyl, amino, methylamino or dimethylamino group 5 and R2 represents a hydrogen, chlorine or bromine atom or a methoxy group; (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 10 5 carbon atoms, an n-alkylene group with 2 to 5 carbon atoms herein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the 15 nitrogen atom to the left of the group G, and/or R^ and Rj each represents a hydrogen atom or R^ represents a chlorine or bromine atom or a trifluoro-methyl, amino, methylamino or dimethylamino group and Rj represents a hydrogen, chlorine or bromine 20 atom or a methoxy group; and (iii) when A represents a group of formula -N=CH- 5 OH OH NOH NHn NH-CH0CH.,-^~VoCH.a I I II | 2 | i l 3 -CH-CH2-, -CH-CO-, -C-C0-, -CH-CO- or -CH-CO- OCH3 25 5 5 5 5 5 B represents a methylene group] and acid addition salts thereof. The compounds 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-30 2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-{2-phenyl-ethyl)-amino]-propane, and l-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3-nitro-phenyl)-ethyl)-amino]-propane, and acid addition salts of these compounds, are 35 also preferred compounds of the invention. Particularly preferred are those compounds of general formula la above wherein A represents a -CH2-CH2- group? 2 0 7 mry a J - 10 - B represents a -CO- or -CS- group; R^ represents a methoxy, amino, methylamino or dimethylamino group,and Rj represents a hydrogen atom or a methoxy group or R^ and R2 together represent 5 a methylenedioxy group; R3 represents a hydrogen, fluorine, chlorine or bromine atom or a methoxy or trifluoromethyl group, and R^ represents a methoxy, amino, methylamino or dimethylamino group or R3 and R^ together represent 10 a methylenedioxy group; Rg represents a hydrogen, chlorine or bromine atom; Rg represents a methyl group; and G represents an n-alkylene group with 3 to OH I 15 5 carbon atoms, a -CH2-CH- group, or (if B represents a -CS- group and/or R^ represents an amino, methylamino or dimethylamino group) a -CH2CH2- group, and acid addition salts thereof. Also mentioned as compounds of the invention 20 are those wherein ' "~ R^ and R2 each represents a methoxy group; R3 represents a methoxy group or a hydrogen or chlorine atom; R4 represents a methoxy, amino or dimethylamino 25 group; Rg represents a hydrogen or chlorine atom; Rg represents a methyl group; G represents a n-alkylene group with 3 to 5 OH 1 30 carbon atoms or a -CH^-CH- group or (if B represents a thiocarbonyl group or A represents a group of formula 2 - 11 - OH I -CH-CO- ) a -CH2-CH2- group; and either A represents a -CH2-CH2- group and B represents a thiocarbonyl or (if G represents an n-alkylene group with 3 5 to 5 carbon atoms) a carbonyl group, or OH l A represents a -CH-CO- group and B represents a methylene group, and acid addition salts of these compounds. 10 The following compounds are specifically mentioned as examples of compounds of the invention: 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane, 15 1-(l-hydroxy-7,8-dimethoxy-l,3,4,5-tetrahydro- 2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-20 3,5-dichloro-phenyl)-propyl)-amino]-propane, 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-phenyl-ethyl)-amino]-propane, and 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-25 benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3-nitro-phenyl)-ethyl)-amino]-propane, and acid addition salts of these compounds. The compounds of general formula I and their acid addition salts may, for example, be prepared 30 by the following processes, which processes constitute further features of the present invention: a) reacting a compound of general formula II A ^sN-E-U 20630 sr w O 12 - with a compound of general formula III R i-V (III) R 5 (wherein R2r Rj* Rg» Af B, E and G are as hereinbefore 5 defined, R^' and R^' each represents an amino or alkylamino group protected by a protecting group or they each have the meanings given for R^ and R^ hereinbefore, one of the groups U and V represents an Rg-NH-10 group wherein Rg is as hereinbefore defined, and the other group U or V represents a nucleophilically exchangeable group such as, for example, a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom or a methanesulphonyloxy, 15 p-toluenesulphonyloxy or ethoxysulphonyloxy group), and optionally subsequently splitting off any protecting group used. The reaction may conveniently be carried out in-a solvent or mixture of solvents such as, 20 for example, acetone, diethylether, methylformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxan or in an excess of the compounds of general formula II and/or III used and optionally in the 25 presence of an acid-binding agent, e.g. an alkoxide such as potassium tert.butoxide, an alkali metal hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an 30 alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or 2 0 & - 13 - pyridine, whilst the latter may also serve as solvents at the same time, or a reaction accelerator such as potassium iodide, and, depending on the reactivity of the nucleophilically exchangeable group, conveniently 5 at temperatures of between 0 and 150°C, preferably at temperatures of between 50 and 120°C, 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 10 to perform the reaction in the presence of a tertiary organic base or an excess of the amine of general formula III used. The optional subsequent splitting off of a protecting group used is preferably effected 15 hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water in the presence of an acid such as, for example, hydrochloric or sulphuric acid or in the presence of an alkali metal base such as, for example, sodium 20 hydroxide or potassium hydroxide at temperatures of between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group may also be split off by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst 25 such as, for example, palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures of between 0 and 50°C, but preferably at ambient 30 temperature, and under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar. b) In order to prepare compounds of general formula I wherein A represents a -CH2-CH2-, -CH=CH-, -NH-CO-, -COCO-, -CH--CO-, 5 5 2 ?7 35 —C=N- or -N=CH- group and 5 5 B represents a -CH2- or -CO- group: 2f\ ■kJ - 14 - reacting a compound of general formula IV (IV) (wherein 1*2 is as hereinbefore defined, 5 A* represents a -CH2-CH2-, -CH=CH-, -NH-CO- ?7 -COCO-, -CH--CO-, -N=CH- or -C=N- group wherein 5 5 R<7 represents an alkyl group with 1 to 3 carbon atoms, B' represents a -CI^- or -CO- group and 10 ' represents an amino or alkylamino group protected by a protecting group or has the meanings given for R^ hereinbefore), with a compound of general formula V 15 (wherein R^, Rgr Rg* E and G are as hereinbefore defined, R^' represents an amino or alkylamino group protected by a protecting group or has the meanings given for R^ hereinbefore and 20 Z represents a nucleophilically exchangeable group such as, for example, a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom, or a methanesulphonyloxy, p-toluenesulphonyl-oxy or ethoxysulphonyloxy group), and optionally 20 V«^y - 15 - subsequently splitting off any protecting group used. The reaction may optionally be carried out in a solvent or mixture of solvents, e.g. in acetone, 5 dimethylformamide, acetone/dimethylformamide, dimethyl-sulphoxide or chlorobenzene, and conveniently, depending on the reactivity of the group Z, at temperatures of between 0 and 150°C, but preferably at the boiling temperature of the solvent used. 10 It may be advantageous to work in the presence of an acid-binding agent, for example, an alkoxide such as sodium methoxide, an alkali metal hydroxide such as sodium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide 15 such as sodium amide, an alkali metal hydride such as sodium hydride or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as, for example, potassium iodide. The optional subsequent splitting off of 20 a protecting group used is preferably effected hydrolytically in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as hydrochloric acid or sulphuric acid or in the presence of an 25 alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures of between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, a benzyl group may also be split off by hydrogenolysis, e.g. with hydrogen in the 30 presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as, for example, hydrochloric acid at temperatures of between 0 and 50°C, but preferably 35 at ambient temperature, and under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar. 20 <C /i - 16 - c) In order to prepare compounds of general formula NH-Rq I 8 I wherein A does not represent a -CH-CO- or -CO-CO-group: ^ f*ro * 3 reacting a compound of general formula VI Ri \ a" N-E-H (VI) (wherein B, E, R^ and Rj are as hereinbefore defined but in the group E two hydrogen atoms in a -CH2- or -CHj group of the group E are replaced by an 10 oxygen atom, and A" represents a -CH2-CH2-f -CH=CH-, -NH-CO-, OH OH NOH 5 i I ii -CH--CO-, -N=CH-, -CH-CO-, -CH-CH,-, -C-CO- or 5 z 5 5 5 5 ?7 —C-N- group wherein R7 represents an 5 ' 15 alkyl group with 1 to 3 carbon atoms), with an amine of general formula VII H-,-0 R„ (VII) (wherein G and R3 to Rg are as hereinbefore defined), in the presence of a reducing agent. - 17 - 2 0 £ 3; The reaction may conveniently be carried out in a suitable solvent or mixture of solvents such as, for example, methanol, ethanol, ethanol/ethyl acetate or dioxan at temperatures of between 0 5 and 100°C, but preferably at temperatures of between 20 and 80°C. It is particularly advantageous to carry out the reductive amination in the presence of a complex metal hydride such as, for example, lithium 10 or sodium cyanoborohydride, preferably at a pH of 6-7 and at ambient temperature or, in order to prepare compounds of general formula I wherein Rg represents a hydrogen atom, in the presence of a hydrogenation catalyst, e.g. with hydrogen 15 in the presence of palladium/charcoal under a hydrogen pressure of 5 bar. Any double bonds present may be hydrogenated. d) In order to prepare compounds of general formula HN-Rq l o I wherein A does not represent a -CH-CO- or -CO-CO- 5 20 group: reacting a compound of general formula VIII (VIII) (wherein B, E, R^, r2 an(3 ^ are as hereinbefore defined 25 and A" represents a -CH2-CH2-, -CH=CH-, -NH-CO-, 2 0 6 3 0 5 OH NOH I I •' or -CH,-CO-, -N=CH-, -CH-CO-, -CH-CH--, -C-CO- 5 2 5 5 5 5 ?7 -C=N- group wherein R, represents an alkyl 5 ' group with 1 to 3 carbon atoms) with a compound of general formula IX 10 (IX) (wherein R^ to Rg and G are as hereinbefore defined, but in the group G two hydrogen atoms in a -CHj-or -CHg group of the group G are replaced by an oxygen atom), in the presence of a reducing agent. The reaction may conveniently be carried out in a suitable solvent or mixture of solvents such as, for example, methanol, ethanol, ethanol/ethyl 15 acetate or dioxan at temperatures of between 0 and 100°C, but preferably at temperatures of between 20 and.80°C. It is particularly advantageous to carry out the reductive amination in the presence of 20 a complex metal hydride such as lithium or sodium cyanoborohydride, preferably at a pH of 6 to 7 and at ambient temperature or, in order to prepare compounds of general formula I wherein Rg represents a hydrogen atom, in the presence of a hydrogenation 25 catalyst, e.g. with hydrogen in the presence of palladium/charcoal under a hydrogen pressure of 5 bar. Any double bonds present may be hydrogenated. 206305 - 19 - e) In order to prepare compounds of general formula I wherein A represents a -CHj-CHj- group, B represents a methylene or carbonyl group and Rg does not represent an alkenyl group with 3 to 5 carbon atoms: 5 hydrogenating a compound of general formula X (wherein R^ to Rg, E and G are as hereinbefore defined and B' represents a methylene or carbonyl group). 10 The hydrogenation may be effected in a solvent or mixture of solvents such as, for example, methanol, ethanol, ethyl acetate or glacial acetic acid with catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium/charcoal, 15 under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar, and at temperatures of between 0 and 75°C, but preferably at temperatures of between 20 and 50°C. f) In order to prepare compounds of general formula 20 I wherein B represents a -CS- group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with ^ 1 to 4 carbon atoms in the alkylene moiety: 25 reacting a compound of general formula XI CXI) 2 /?* ., s\ ■ - 20 - (wherein to R6, A and E are as hereinbefore defined and 5 G' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety), 10 with a sulphur-introducing agent. The reaction is carried out with a sulphur-introducing agent such as, for example, phosphorus pentasulphide or 2,4-bis-(4-methoxypheny1)-1,3-dithia-2,4-diphosphetane-2,4-disulphide, conveniently 15 in a solvent such as, for example, toluene or xylene at temperatures of between 50 and 150°C, e.g. at the boiling temperature of the reaction mixture. g) In order to prepare compounds of general formula OH OH i I I wherein A represents a -CH-CO- or -CH-CHj- group 20 5 5 and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxy-alkylene group with 1 to 4 carbon atoms 25 in the alkylene moiety: reducing a compound of general formula XII HrCHf _ K n/1 J-E-N-G— \4^R4 , . (XII) Rr - 21 - 506305 (wherein to Rg/ E and G are as hereinbefore defined). The reaction is carried out in the presence of a suitable reducing agent such as, for example, 5 a metal hydride (e.g. sodium borohydride or lithium aluminium hydride) or diborane, in a suitable solvent such as, for example, water/methanol, methanol/ether, tetrahydrofuran, dioxan or ether/tetrahydrofuran at temperatures of between 0 and 80°C, but preferably 10 at temperatures of between 15 and 40°C. In the reaction, any CO group present in the G group is also reduced to a CHOH group. h) In order to prepare compounds of general formula I, wherein HN-Rq NOH / 0 li 15 A represents a -CH—CO- or -C-CO- group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety: 20 reacting a compound of general formula XIII (XIII) (wherein and R^ to Rg and E are as hereinbefore defined V V £ e i M. 2 0 6 ^ q 5 - 22 - G' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms 5 in the alkylene moiety), with a compound of general formula XIV H ^ N - Rg (XIV) H 10 (wherein Rg represents a hydroxy group or has the meanings given for Rg hereinbefore), optionally with subsequent reduction. The reaction may conveniently be effected in a solvent such as, for example, ethanol, dioxan 15 or glycol or in a melt at elevated temperatures, e.g. at temperatures of between 50 and 175°C. The optional subsequent reduction may be effected with a reducing agent such as a complex metal hydride, e.g. lithium aluminium hydride, with catalytically 20 activated hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium/charcoal under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar, or with hydrazine/Raney nickel in a suitable 25 solvent such as, for example, methanol, ethanol, ethyl acetate or glacial acetic acid at temperatures of between 0 and 100°C, but preferably at temperatures of between 20 and 50°C. i) In order to prepare compounds of general formula 30 I wherein A represents an -N=CH- group and R^ represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms: reacting a compound of general formula XV - 23 - 2 /? *2? (XV) (wherein to Rg, B, E and G are as hereinbefore defined and Rg' represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 5 to 5 carbon atoms), with an orthoformic acid ester. The reaction may preferably be carried out in a solvent such as, for example, ethanol, toluene, dimethoxyethane or in an excess of the orthoester 10 used at temperatures of between 100 and 200°C. It may also be advantageous for any -NHj or =NH groups present to be protected by protecting groups, e.g. acetyl, benzoyl, ethoxycarbonyl or benzyl groups, during the reaction. 15 Any protecting groups used during the reaction are subsequently split off, e.g. acyl groups are preferably removed hydrolytically in the presence of an acid or base whilst benzyl groups are preferably removed by hydrogenolysis, e.g. with hydrogen in 20 the presence of a hydrogenation catalyst such as palladium/charcoal or platinum. j) In order to prepare compounds of general formula I wherein A does not represent a -COCO- group and G represents a methylene-n-hydroxyalkylene group: 25 Reducing a compound of general formula XVI (XVI) 24 (wherein R^ to Rg, B and E are as hereinbefore defined, A"' has the meanings given for A hereinbefore, 5 with the exception of the -COCO- group, and G" represents a methylene-n-alkylene group, wherein the alkylene moiety contains 1 to 4 carbon atoms and a methylene group of the alkylene moiety is replaced by a carbonyl group). 10 The reduction is preferably carried out with a metal hydride such as, for example, sodium borohydride or lithium aluminium hydride, or with diborane, in a suitable solvent such as, for example, ethanol, ethanol/water, methanol or isopropanol at temperatures 15 of between 0 and 50°C, but preferably at temperatures of between 10 and 25°C. k) In order to prepare compounds of general formula I wherein R^ represents a nitro group and R^ represents an amino group: 20 hydrolysis of a compound of general formula XVII r 1 NO 2 NH-Acyl (XVII) R 2 R 5 (wherein R^r R2' R5' R6' A' B' E and G are as hereinbefore defined, and 2 0 fS ,5 - 25 - ^ Acyl represents an acyl group such as, for example, an acetyl, ethoxycarbonyl or benzoyl group). The acyl group used may preferably be split off by hydrolysis in an aqueous solvent, e.g. in 5 water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid such as, for example, hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at tempera-10 tures of between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, the reaction is preferably carried out in the presence of an alcoholic acid, e.g. with methanolic or ethanolic hydrochloric acid. 15 1) In order to prepare compounds of general formula I wherein A represents a -CH2-CH2-, -CH=CH-, -NH-CO-, ?7 -CH2-CO-, -N=CH-, -COCO- or -C=N- group and one of the groups R^, R2, R^ or R^ represents an alkoxy, alkylamino or dialkylamino group or Rg represents 20 an alkyl or alkenyl group: reacting a compound of general formula XVIII (wherein R^^ to Rg, B and E are as hereinbefore defined, 25 but at least one of the groups R^ to R4 must represent a hydroxy group or or R4 must represent an amino 206305 - 26 - or alkylamino group or Rg must represent a hydrogen atom, A* represents a -CH=CH-, -NH-CO-, -CH--CO-, -N=CH-, -COCO- or -C=N- group wherein 5 5 5 5 R^ represents an alkyl group with 1 to 3 carbon atoms, and G"1 represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, wherein a 10 methylene group may be replaced by a carbonyl group), with a compound of general formula XIX R10 - X (XIX) (wherein *10 represents an alkyl group with 1 to 3 15 carbon atoms or, if Rg represents a hydrogen atom, an alkenyl group with 3 to 5 carbon atoms and X represents an nucleophilically exchangeable group such as, for example, a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or 20 iodine atom, a methanesulphonyloxy, p-toluenesulphonyl-oxy or methoxysulphonyloxy group or, if at least one of the groups R^ to R^ represents a hydroxy group, X together with a hydrogen atom in the a position of the group R^q represents a diazo group 25 or, if Rg represents a hydrogen atom or or R4 represents an amino or alkylamino group, X together with a hydrogen atom in the a position of the group R10 may also represent an oxygen atom). The reaction may conveniently be carried 30 out in a solvent or mixture of solvents such as diethyl ether, methanol, acetone, tetrahydrofuran, dioxan, acetonitrile, pyridine or dimethylformamide, optionally in the presence of a base such as potassium carbonate, potassium hydroxide, potassium tert.butoxide 206305 - 27 - or sodium hydride at temperatures of between 0 and 150°C, but preferably at temperatures of between 20 and 120°C. If B represents a -CI^- or -CO- group and 5 X represents a nucleophilically exchangeable group, the reaction is preferably carried out with an alkylating agent such as, for example, methyl iodide, dimethyl sulphate, ethyl iodide, diethyl sulphate, propyl bromide, allyl bromide or isopropyl 10 p-toluenesulphonate in the presence of an acid-binding agent at temperatures of between 20 and 80°C. However, the reaction may also be carried out without a solvent. If X together with a hydrogen atom in the 15 a position of the group R^q represents a diazo group, in order to alkylate a hydroxy group the reaction is preferably carried out with a diazoalkane such as, for example diazomethane or diazoethane at temperatures of between 0 and 30°C, or if X together with a hydrogen atom in the a position of the group 20 R1q represents an oxygen atom, in order to alkylate the nitrogen atom the reaction is preferably carried out in the presence of a reducing agent at temperatures of between 0 and 120°C, e.g. with formic acid at temperatures of between 80 and 110°C or with sodium 25 cyanoborohydride at ambient temperature and at a pH of 6 to 7. m) In order to prepare compounds of general formula I wherein A represents a -COCO- group and G represents 30 an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group may optionally be replaced by a carbonyl group: oxidising a compound of general formula XX \ N - 5 MAY 1986 - 28 - 206305 (wherein R^ to Rg, E and G are as hereinbefore defined. 5 The oxidation may preferably be carried out with an oxidising agent such as, for example, potassium permanganate, selenium dioxide or sodium dichromate in a suitable solvent or mixture of solvents such as, for example, water, water/dioxan, 10 glacial acetic acid, water/acetic acid or acetic anhydride at temperatures of between 0 and 100°C, preferably at temperatures of between 20 and 80°C. n) In order to prepare compounds of general formula I wherein A represents a -CH9-C0- group and G represents 5 * 15 an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group may optionally be replaced by a carbonyl group : oxidising a benzazepine of general formula XXI 20 R2 (XXI) 2.0630. - 29 - 10 15 (wherein to Rg» B, E and G are as hereinbefore defined). The oxidation may be effected with ruthenium tetroxide in a suitable solvent or mixture of solvents such as chloroform/water, methylene chloride/water or carbon tetrachloride/water at temperatures of between 0 and 100°C, preferably at temperatures of between 20 and 50°C. However, the reaction is preferably carried out in a two-phase system such as methylene chloride/water, chloroform/water or carbon tetrachloride/water with a catalytic quantity of ruthenium dioxide in the presence of a suitable oxidising agent such as, for example, sodium periodate which produces ruthenium tetroxide in situ. o) In order to prepare compounds of general formula I wherein R^ is in the 7 position, A represents a -CH2CH2- group and B represents a -CO- group: cyclising a compound of general formula XXII 20 (XXII) 25 (wherein R^ to Rg, G and E are as hereinbefore defined, Rg' represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms and Y represents a group suitable for cyclisation) 206305 - 30 - Y may represent, for example, a carboxy or nitrile group, an ester group (such as a methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or benzyloxycarbonyl group), a thioester group (such as an ethylthiocarbonyl, 5 phenylthiocarbonyl or pyridylthiocarbonyl group), an acyloxycarbonyl group (such as an acetoxycarbonyl or trifluoroacetylcarbonyl group) or an amide group (such as an aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or phenylaminocarbonyl group). 10 The reaction is optionally carried out in the presence of a suitable condensing agent and optionally in a pressure vessel in a solvent such as xylene, dimethylglycol ether, tetralin or sulpholane at elevated temperatures, e.g. at temperatures 15 of between 100 and 250°C, but preferably at temperatures of between 140 and 180°C. However, the reaction may also be carried out without a solvent. Suitable condensing agents include, for example, N,N'-dicyclohexylcarbodiimide, thionyl chloride, 20 a phosphonate such as diethyl chlorophosphonate or bis(o-nitrophenyl)-phenylphosphonate, a phosporane such as (2,2,2-trifluoroethoxy)-triphenylphosphorane, an N-alkyl-pyridinium salt such as N-methyl-2-chloro-pyridinium iodide or N-methyl-2-fluoro-pyridinium 25 tosylate, N,N*-dicyclohexylcarbodiimide/4-dimethyl-aminopyridine, chlorosulphonyl isocyanate or N,N'-carbonyldiimidazole. It may also be advantageous for any HO, NH or NH2 groups present to be protected by means 30 of protecting groups, e.g. acetyl, benzoyl, ethoxycarbonyl or benzyl groups, during the reaction. If Y in a compound of general formula XXII represents a nitrile or amide group, the reaction is preferably effected so that a corresponding 35 compound is converted, by alkaline or acidic hydrol^s^s/ e.g. by means of methanol/hydrochloric acid or ethanol/sodium hydroxide solution at the boiling temperature of the reaction mixture, into a corres 20 1 ft - 31 - ponding carboxy compound which is subsequently cyclised. Any protecting groups used during the reaction are subsequently split off, e.g. acyl groups are 5 preferably removed by hydrolysis in the presence of an acid or base whilst benzyl groups are preferably removed by hydrogenolysis e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal or platinum. 10 The compounds of general formula I, initially obtained, may subsequently be converted into the acid addition salts thereof, for example by conventional methods such as reacting the compounds as bases with an acid in a suitable solvent. Acid addition 15 salts of these compounds, initially obtained, may subsequently be converted into the corresponding compounds of general formula I or into different acid addition salts thereof. The compounds of general formulae II to XXII 20 used as starting materials are known from the literature in some cases or may be obtained by methods known per se. Thus, for example, a starting compound of general formulae II and VIII may be obtained by 25 reacting a corresponding benzazepine with a corresponding halogen compound and optionally subsequently reacting it with a corresponding amine. The benzazepine of general formula IV required for this is obtained by cyclising a corresponding compound, e.g. by 30 cyclising a compound of general formula XXIII X°CH3 -CH~-CH (XXIII) - 32 - 206305 or of general formula XXIV if and Rj do not represent alkoxy groups, optionally followed by catalytic hydrogenation and/or reduction 5 of the carbonyl group using sodium borohydride/glacial acetic acid, for example (see New Zealand Patent No. 190,745) and/or oxidation, e.g. with selenium dioxide. 10 starting compound may be obtained, for example, by reacting a corresponding benzazepine with a corresponding haloacetal with subsequent hydrolysis. A compound of general formula XV used as starting material may be obtained by reduction 15 of a corresponding nitro compound which is in turn obtained by acylation or alkylation of a corresponding amine. Compounds of general formulae X to XIII, XVI to XVII, XVIII, XX and XXI used as starting 20 materials may preferably be obtained by reacting a corresponding halogen compound with a corresponding amine and optionally subsequently splitting off any protecting groups used to protect the hydroxy groups. 25 A compound of general formula XXII used as starting material may be obtained, for example, by chloromethylation of a compound of general formula XXV A compound of general formula VI used as 33 2 0 RJ-; : v *' c.s^ '\ji: tx# COCH 3 R 1 pr CH2CH2-\ E W (XXV) R. '2 (wherein R^, R2 and E are as hereinbefore defined and W represents a protected hydroxy group, e.g. 5 an acetoxy, benzoyloxy or 4-nitrobenzoyloxy group), further reacting it with an alkali metal cyanide, converting the group W into a suitable leaving group such as that of the chlorine, bromine or iodine atom or of the methylsulphonyloxy or 4-methyl-10 phenylsulphonyloxy group and subsequently reacting with an amine of general formula VII (wherein R^ to R^ and G are as hereinbefore defined), with optional subsequent hydrolysis and/or esterifi-15 cation or amidation. As already mentioned hereinbefore, the new compounds of general formula I and the physiologically acceptable addition salts thereof have valuable pharmacological properties, more particularly a 20 long-lasting heart rate lowering activity and the effect of reducing the 02 requirement of the heart, with very few side effects, e.g. only a slight antimuscarinic effect. R (VII) 5 For example, the following compounds 1-(7,8-d imethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3—(3,4— dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride, 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-thion-3-yl)-N-[N-methyl-N-(2-(3,4-d imethoxy-phenyl)-ethyl)-amino]-propane, 1-(7,8-d imethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-hydroxy- 2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, 1-(l-hydroxy-7,8-dimethoxy-l,3,4,5-tetrahydro- 2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N- (2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-y1)-3-[N-methyl-N-(2-(4-amino-3-nitro-phenyl)-ethyl)-amino]-propane hydrochloride, 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(4-(4-dimethylamino-phenyl)-butyl)-amino]-propane hydrobromide, 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-phenyl-ethyl)-amino]-propane dihydrochloride 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-y1)-3-[N-methyl-N-(5-(3,4-dimethoxy-phenyl)-pentyl)-amino]-propane hydrochloride and 2063 - 35 - I = l-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-dichlorophenyl)-propyl)-amino]-propane 5 have been tested by comparison with K = l-(7,8-dimethoxy-l,3,4,5-tetrahydro-5H-2- benzazepin-l-on-2-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane hydro-chlor ide 10 for their biological properties as follows: Effect on Heart Rate in Rats The effect of the test substances on heart rate was investigated in two rats with an average 15 weight of 250 to 300 g for each dose. The rats were anaesthetised with pentobarbital (50 mg/kg i.p. and 20 mg/kg s.c.). The test substances were injected in aqueous solution into the jugular vein (0.1 ml/100 g). 20 The blood pressure was measured using a cannula inserted in a carotid artery and the heart rate was recorded from an ECG (Ilnd or Illrd reading) obtained using needle electrodes. The heart rate of the animals in the control period was between 25 350 and 400 beats pier minute (b/min). The following table contains the values found: Substance Dose (mg/kg) A 5.0 - 183 2.5 - 85 1.0 - 51 B 5.0 - 255 2.5 - 134 1.0 - 73 C 5.0 - 173 ID . fM - 137 D 5.0 - 117 2.5 - 73 1.0 - 83 E 5.0 - 130 F 5.0 - 123 2.5 - 91 1.0 - 94 G 5.0 - 135 2.5 - 110 1.0 - 80 H 5.0 - 75 I o • in - 175 K 5.0 - 18 25 The compounds prepared according to the invention do not have any toxic side effects of any kind „ when administered in therapeutic doses. Thus, for example, when substances A and D are administered intravenously to mice, even in a high dosage of 30 20 mg/kg, no toxic side effects can be detected. In view of their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of sinus tachycardia of various origins and for the prophylaxis and 35 therapy of ischaemic cardiac diseases. / A /I 7 » . - 36 - Reduction in heart rate measured 20 minutes after administration of substance (b/min). 2063 According to a yet further feature of the present invention, there are provided pharmaceutical compositions comprising as active ingredient, at least one compound of general formula I as hereinbefore 5 defined or a physiologically acceptable acid addition salt thereof in association with a pharmaceutical carrier or excipient. For pharmaceutical administration the compounds of the invention may be incorporated into conventional 10 preparations in either solid or liquid form, optionally together with other active ingredients. The compositions may, for example, be presented in a form suitable for oral, rectal or parenteral administration. Preferred forms include, for example, tablets, 15 coated tablets, capsules, powders, suspensions, drops, ampoules, syrups and suppositories. The active ingredient may be incorporated in inert carriers and/or diluents customarily employed in pharmaceutical compositions, such as, for example, 20 corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinyl pyrollidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, carboxymethyl cellulose, paraffin 25 derivatives, fatty substances of animal or vegetable origin (e.g. hard fat), various wetting, dispersing, emulsifying, or preservative agents, or mixtures thereof. Advantageously the compositions may be formulated 30 as dosage units, each unit being adapted to supply a fixed dose of active ingredient. The dose required is conveniently from 0.03 to 0.4 mg/kg of body weight (preferably from 0.07 to 0.25 mg/kg of body weight) administered once or twice per day. Depending 35 on the kind and the body weight of the patient to be treated, on the kind and the seriousness of the disease, on the type of preparation and on the route of administration as well as on the 206305 - 38 - period or interval over which the administration takes place, it may however be necessary to deviate from the above dosages. Thus, it may be sufficient in some cases to administer less than the above-5 mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. The optimal dosage and type of administration of the active ingredients which are necessary in each case can easily be 10 assessed by one skilled in the art. Thus, according to a still further feature of the present invention, there is provided a method of preventing or relieving ischaemic cardiac diseases, or of relieving sinus tachycardia in a non-human 15 patient, which comprises administering to the said patient an effective amount of a compound of general formula I as defined above or a physiologically acceptable acid addition salt thereof. The following non-limiting Examples are intended 20 to illustrate the invention more fully: 2 t /" ^ ^ W' - 39 - Preparation of the starting compounds Example A 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-N-methyl-amino-propane-hydrochlor ide 5 a) 1-(7,8-Dimethoxy-l,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-N-methyl-N-benzyl-amino-propane hydrochlor ide Prepared analogously to Example lb by reacting 1-(7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-10 on-3-yl)-3-chloro-propane with N-methyl-benzylamine. Yield: 92.1% of theory, Melting point: 208-209°C. b) 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3- benzazepin-2-on-3-yl)-3-N-methyl-amino-propane 15 hydrochloride Prepared analogously to Example 5 by catalytic hydrogenation of 1-(7,8-dimethoxy-l,3-dihydro-2H- 3-benzazepin-2-on-3-yl)-3-N-methyl-N-benzyl-amino-propane. 20 Yield: 87% of theory Melting point: 110°C (decomposition). Example B 1,3,4,5-Tetrahydro-2H-3-benzazepin-2-one 25 a) N-(2-Phenyl-ethyl)-1-chloro-acetamide 38.7 ml (0.3 mol) of 2-phenylethylamine and 45.9 ml (0.033 mol) of triethylamine are dissolved in 30 ml of methylene chloride and mixed with 26.4 ml (0.33 mol) of chloroacetyl chloride, dissolved 30 in 150 ml of methylene chloride, at 10°C. After 1 hour's stirring at ambient temperature, the product is extracted with 1% acetic acid and with water, dried over magnesium sulphate and concentrated by evaporation jui vacuo. 35 Yield: 54.2 g (91.4% of theory) M.p. 64-65°C X fj - 40 - b) 1,3,4,5-Tetrahydro-2H-3-benzazepin-2-one 54.0 g (0.373 mol) of N-(2-phenyl-ethyl)-1-chloroacetamide are mixed with 73.8 g (0.55 ml) of aluminium chloride and stirred for 13 hours 5 at 130-140°C. After the aluminium chloride has been destroyed with ice water, the product is extracted with methylene chloride, washed with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and the residue obtained is purified over 10 silica gel using methylene chloride plus 3% ethanol as eluant. Yield: 6.22 g (14.1% of theory), Melting point: 158-160°C. 15 Example C 1-(7-Bromo-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-chloro-propane a) 8-Methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one 20 56.8 g (0.3 mol) of 8-methoxy-l,3-dihydro- 2H-benzazepin-2-one (melting point: 190-191°C), dissolved in 600 ml of glacial acetic acid, were hydrogenated in the presence of 5 g of 10% palladium/-charcoal at a temperature of 80°C under a hydrogen 25 pressure of 5 bar for 12 hours. After filtering off the catalyst the solvent was removed _in vacuo. The obtained residue was mixed with water and neutralised with potassium carbonate. The precipitate was suction filtered, washed with water and dried. 30 Yield: 51.1 g (89.1% of theory) Melting point: 160-161°C b) 7-Bromo- and 9-bromo-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one 6.4 g = 2.03 ml (0.04 mol) of bromine were 35 dropped into a solution of 7.4 g (0.04 mol) of 8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 100 ml of 80% acetic acid at a temperature betwen 3° and 5°C whilst stirring. After 15 minutes, 2 ^ .. ^ ^ - 41 - the reaction mixture was poured into ice-water and neutralized with potassium carbonate. The precipitate was suction filtered, washed with a little water and dried. The isomers were separated 5 by means of chromatography over silica gel using ethyl acetate as eluant. Yield: 5.7 g (52.8% of theory) of 9-bromo-isomer IR spectrum (methylene chloride) : 3,400 cm-"®" (NH) 1,660 cm"1 (CO) 10 4.1 g (38% of theory) of 7-bromo-isomer IR-spectrum (potassium bromide): 3,200 cm -1 (NH) 1,665 cm"1 (CO) c) 1-(7-Bromo-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane 15 0.24 g of 55% sodium hydride dispersion in oil were added to a mixture of 1.35 g (5 mol) of 7-bromo-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 15 ml of dimethylsulfoxide at room temperature. After stirring at room temperature for 30 minutes 20 and at a temperature between 35° and 40°C for 10 minutes, the obtained solution was added to 0.79 g (5.5 mol) of 1-bromo-3-chloro-propane in 5 ml of dimethylsulfoxide. After stirring at room temperature for 2 hours, the mixture was poured into ice-water 25 and extracted with methylene chloride four times. The methylene chloride extracts were washed with water, dried and evaporated iji vacuo. The obtained residue was purified over silica gel using ethyl acetate as eluant. 30 Yield: 210 mg (12% of theory) Melting point: 119-120°C Example D 7-Nitro-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-35 2-one 765 mg (4 mol) of 8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one were added to a mixture of 15 ml of concentrated nitric acid and of 1.5 ml 2063 - 42 - of fuming nitric acid at a temperature between 3° and 5°C whilst stirring. After stirring at this temperature for further 30 minutes, the mixture was poured into ice-water and neutralised with 5 potassium carbonate. The formed precipitate was suction filtered, washed with water and dried. The yellow crystals were purified over silica gel using ethyl acetate as eluant to separate the corresponding 9-nitro- and 7,9-dinitro-isomers. 10 Yield: 400 mg (42.3% of theory) Melting point: 204-205°C (decomp.) 2063 - 43 - Preparation of the end products: Example 1 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride 5 a) 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane 1.1 g (0.005 mol) of 7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-one are suspended in 15 ml of absolute dimethylsulphoxide and mixed 10 with 0.67 g (0.006 mol) of potassium tert.butoxide with stirring. After 10 minutes, the suspension obtained is added dropwise to 0.64 ml (0.006 mol) of l-bromo-3-chloro-propane in 10 ml of dimethylsulph oxide, whilst cooling with ice water. After 1 15 hour the mixture is poured on to water. After a short time the viscous precipitate begins to crystallise. The precipitate is suction filtered, dissolved in acetone, precipitated again with water, then suction filtered and dried. 20 Yield: 0.75 g (50.0% of theory) Melting point: 84-85°C. b) 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3- benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane 25 hydrochloride 5.55 g (0.0186 mol) of l-(7,8-dimethoxy-l,3,4,5 tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane, 2.6 ml (0.0886 mol) of triethylamine and 3.9 g (0.0186 mol) of N-methyl-3-(3,4-dimethoxy-30 phenyl)-propylamine are heated to 85°C for 4 hours, then cooled and dissolved in methylene chloride/water The organic phase is separated off, extracted once more with water, dried over magnesium sulphate, concentrated by evaporation in vacuo and the residue 35 obtained is purified over silica gel using methylene chloride plus 3% ethanol as eluant. The oily residue f0 6305 - 44 - obtained is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid. Yield: 3.45 g (36.6% of theory), Melting point: 220-221°C. 5 Example 2 1- (7/8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-yl)-3-[N-methyl-N-(2-phenyl-ethyl)-amino]-propane dihydrochloride 10 Prepared analogously to Example lb by reacting 1-(7/8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-chloro-propane with N-methyl-2-phenyl-ethylamine. Yield: 43.2% of theory, 15 Melting point: 165°C decomposition. Example 3 1-(1,3,4,5-Tetrahydro-2H-3-benzazepin-2-on-3-yl)- 3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-20 amino]-propane hydrochloride a) 1-(1,3,4,5-Tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane Prepared analogously to Example la by reacting l,3,4,5-tetrahydro-2H-3-benzazepin-2-on with 1-25 bromo-3-chloro-propane. Yield: 13.4% of theory IR Spectrum (methylene chloride): 1660 cm-1 (CO). b) 1-(1,3,4,5-Tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)- 30 ethyl)-amino]-propane hydrochlor ide Prepared analogously to Example lb by reacting 1-(1,3/4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-(2-(3,4-dimethoxy-phenyl) -ethyl)-amine. 35 Yield: 29.2% of theory, Melting point: 160-162°C. 206305 - 45 - Example 4 1-(7 ,8-Dimethoxy-l,3-d ihydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(5-(3,4-dimethoxy-phenyl)-pentyl)-amino]-propane hydrochlor ide 5 a) 1-(7,8-Dimethoxy-l, 3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane Prepared analogously to Example la by reacting 7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-one with l-bromo-3-chloro-propane. 10 Yield: 87.3% of theory, Melting point: 101-103°C. b) 1-(7,8-Dimethoxy-l,3-dihydro-2H-benzazepin-2-on-3-yl)-3-[N-methyl-N-(5-(3,4-dimethoxy-phenyl) -pentyl)-amino]-propane hydrochlor ide 15 Prepared analogously to Example lb by reacting 1-(7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-- on-3-yl)-3-chloro-propane with N-methyl-N-(5-(3,4-dimethoxy-phenyl)-pentyl)-amine. Yield: 67.3% of theory, 20 Melting point: 158-160°C. Example 5 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(5-(3,4-dimethoxy-phenyl)-25 pentyl)-amino]-propane hydrochloride. 3.23 g (0.0065 mol) of 1-(7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(5-(3,4-dimethoxy-phenyl)-pentyl)-amino]-propane, dissolved in 30 ml of acetic acid, are hydrogenated 30 at ambient temperature under a hydrogen pressure of 5 bar in the presence of 10% palladium/charcoal for 3.5 hours. The catalyst is filtered off, the filtrate is concentrated by evaporation _±n vacuo and the residue is taken up in methylene chloride/15% 35 potassium carbonate solution. The organic phase is separated off, dried over magnesium sulphate and rotated in vacuo and the residue obtained is - 46 - 206505 purified over silica gel using methylene chloride plus 4% ethanol as eluant. The residue obtained is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid. 5 Yield: 2.1 g (60.3% of theory). Melting point: 165-166°C Example 6 1-(7.8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-10 2-thion-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane 2.28 g (0.005 mol) of 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane 15 are dissolved in 10 ml of absolute toluene and refluxed for 50 minutes with 1.0 g (0.0025 mol) of 2,4-bis-(4-methoxy-phenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide. After the solvent has been rotated in vacuo, the residue obtained is purified over 20 aluminium oxide with methylene chloride plus 2% ethanol as eluant. Yield: 1.45 g (61.4% of theory) C26H36N2°4S (472.6) Calc: C 66.07 H 7.68 N 5.93 S 6.78 25 Found: 66.10 7.71 5.56 6.76 Example 7 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3,4-dimethoxy-benzoyl-methyl)-30 amino]-propane hydrochloride Prepared analogously to Example lb by reacting 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-N-methyl-amino-propane with a-bromo-3,4-dimethoxy-acetophenone. 35 Yield: 1.29 g (77.0% of theory), Melting point: 190°C - 47 - Example 8 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl) -3- [N-methyl-N- (2-hydroxy-2- (3,4-dimethoxy-phenyl) -ethyl)-amino]-propane 0.92 g (0.002 mol) of 1-(7,8-dimethoxy-l,3,4,5-5 tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3,4-dimethoxy-benzoyl-methyl)-amino]-propane are dissolved in 6 ml of ethanol, mixed with 0.38 g (0.01 mol) of sodium borohydride and stirred for 2 hours at 25°C. After the solvent has been evaporated 10 in vacuo, the mixture is dissolved in methylene chloride, extracted with water, dried over magnesium sulphate and concentrated by evaporation jji vacuo and the residue obtained is purified over aluminium oxide using methylene chloride plus 1% ethanol 15 as eluant. Yield: 0.5 g (54% of theory), IR spectrum (methylene chloride); 1655 cm-1 (CO) Example 9 1-[7,8-Dimethoxy-l-(2-(3,4-dimethoxy-phenyl)-ethyl-amino)-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-25 yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane dihydrochloride 2.45 g (5 mmol) of 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-l,2-dion-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane 30 and 2 g of 2-(3,4-dimethoxy-phenyl)-ethyl-amine are heated to 150°C for 3 hours. The reaction mixture is purified over aluminium oxide N (activity II) using methylene chloride and 5% acetone as eluant. The fractions are concentrated by evaporation, the 35 residue obtained is dissolved in 100 ml of methanol and hydrogenated for 6 hours at 50°C under a hydrogen pressure of 5 bar in the presence of 0.5 g of 10% palladium/charcoal. After the uptake of hydrogen 26 36 2 6 Calc: 20 Found: CocHocNoO (472.6) C 66.08 H 7.68 N 5.93 66.01 7.62 5.80 2062^5 48 has ended the catalyst is removed by suction filtering, the filtrate is concentrated by evaporation and the residue is purified over silica gel using methylene chloride and 5% ethanol as eluant. The residue obtained 5 is dissolved in acetone and the dihydrochloride is precipitated with ethereal hydrochloric acid. Yield: 0.6 g (53.6% of theory), Melting point: 222-224°C (decomposition). 10 Example 10 1-(l-Hydroxy-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl) -ethyl) -amino] -propane 15 tetrahydro-2H-3-benzazepin-l,2-dion-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane are dissolved in 100 ml of methanol and 5 ml of water, then 0.2 g of sodium borohydride are added in batches thereto, with stirring. After it has all been added, 20 the mixture is stirred for a further 15 minutes, mixed with 10 ml of 2N hydrochloric acid, made alkaline with methanolic ammonia decolorised with fuller's earth and then filtered and concentrated by evaporation in vacuo. The residue is dissolved in methylene 25 chloride, any undissolved salts are filtered off and the filtrate is concentrated by evaporation. Yield: 1.65 g (69.9% of theory), viscous oil. IR spectrum (methylene chloride): 3400 cm"1 (OH) 2.35 g (5 mmol) of 1-(7,8-dimethoxy-l,3,4,5- 30 2840 cm"1 (methoxy) 2800 cm"1 (N-alkyl) 1660 cm"1 (CO) u26n36"2u6 Calc: Found: CocH-J^N^O (472.59) C 66.08 H 7.68 N 5.93 65.87 7.75 5.73 206305 - 49 - Example 11 1-(7,8-Dimethoxy-l,3-dihydro-2H-3,5-benzodiazepin-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane dihydrochloride 5 4.3 g (10 mmol) of N-[2-(2-amino-4,5-dimethoxy- phenyl)-ethyl]-N'-methyl-N'-(2-(3,4-dimethoxy-phenyl)-ethyl)-1,3-diaminopropane are refluxed for 18 hours in 30 ml of triethyl orthoformate, then concentrated by evaporation iji vacuo and the residue is purified 10 over silica gel with methylene chloride plus 3% methanol as eluant. The residue obtained is dissolved in acetone and the dihydrochloride is precipitated by the addition of ethereal hydrochloric acid. Yield: 1.6 g (31.1% of theory), 15 Melting point: 232-234°C. Example 12 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3-nitro-phenyl)-20 ethyl)-amino]-propane hydrochloride 1.0 g (1.75 mmol) of 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4-acetamino-3-nitro-phenyl)-ethyl)-amino]-propane is heated in 50 ml of methanolic hydrochloric acid 25 for two hours to 45 to 50°C. The reaction solution is concentrated by evaporation, dissolved in methylene chloride, washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulphate and the solvent is distilled off ^n vacuo. After the residue 30 has been purified over silica gel with methylene chloride and 5% ethanol as eluent, the hydrochloride is precipitated from acetone by the addition of ethereal hydrochloric acid. Yield: 0.4 g (43.1% of theory) 35 Melting point: 207-208°C (decomposition) 206305 - 50 - Example 13 1-(1-Ox imino-7,8-dimethoxy-l,3,4,5-tetr ahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-d imethoxy-phenyl)-ethyl)-amino]-propane hydrochlor ide 5 3.6 g (6.8 mmol) of 1-(7,8-dimethoxy-l,3,4,5- tetrahydro-2H-3-benzazepin-l,2-dion-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, 0.57 g of hydroxylamine hydrochloride and 0.87 g of sodium carbonate are refluxed for eight hours 10 in 100 ml of ethanol. The solvent is distilled off in vacuo, the residue is dissolved in water/methylene chloride and the organic phase is separated off, dried over magnesium sulphate and concentrated by evaporation. The residue is purified over silica 15 gel using methylene chloride and 5% ethanol as eluent. The residue obtained is dissolved in acetone and the hydrochloride is precipitated by the addition of ethereal hydrochloric acid. Yields 2.4 g (67.6% of theory) 20 Melting point: 156-158°C Example 14 1-(l-Amino-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benza,zepin-2-on-3-y 1) -3- [N-methyl-N- (2- (3,4-dimethoxy-25 phenyl)-ethyl)~amino]-propane dihydrochloride 1.6 g (3.3 mmol) of l-(l-oximino-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane are added to 150 ml of ethanol and mixed with 1.5 ml 30 of 98% hydrazine hydrate and 1 g of Raney nickel and the mixture is refluxed for seven hours. In order to complete the reaction, a further 1.5 ml of 98% hydrazine hydrate and 1 g of Raney nickel are added and the mixture is refluxed for a further 35 three hours. The catalyst is removed by suction filtering, the solvent is distilled off ^n vacuo and the residue is purified over silica gel with methylene chloride and 10% methanol. The dihydrochloride - 51 - 206305 is precipitated from an acetone solution by the addition of ethereal hydrochloric acid. Yield: 0.8 g (44.6% of theory) Melting Point: 232-234°C, m/e = 471. 5 Example 15 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3-(4-dimethylamino-phenyl)-propyl)-amino]-propane dihydrochloride 10 5.7 g (19.4 mmol) of 1-(7,8-dimethoxy- 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-N-methyl-amino-propane and 4.7 g (19.4 mmol) of 3—(4— dimethylamino-phenyl)-propyl bromide are heated to 130°C for li hours after the addition of 3.3 ml of 15 ethyldiisopropylamine. The reaction mixture is dissolved in chloroform and 25% sodium hydroxide solution, the organic phase is separated off, washed with water, dried over magnesium sulphate and concentrated by evaporation. After the residue obtained has been 20 purified over silica gel with methylene chloride and 5% methanol as eluent, the dihydrochloride is precipitated from acetone with ethereal hydrochloric acid. Yield: 0.6 g (5.9% of theory) 25 Melting point: 191-192°C (decomposition) Example 16 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(4-dimethylamino-phenyl)-30 butyl)-amino]-propane-hydrobromide Prepared analogously to Example 15 from l-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)- 3-N-methyl-amino-propane and 4-(4-dimethylamino-phenyl) -butyl bromide. 35 Yield: 10.3% of theory Melting point: 116-118°C. \ - 52 - 206305 Example 17 1-(l-Hydroxy-7,8-dimethoxy-2,3,4,5-tetrahydro-lH-3-benzazepin-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl) -ethyl)-amino]-propane dihydrochloride 2.45 g (5 mmol) of 1-(7,8-dimethoxy-l,3,4,5-5 tetrahydro-2H-3-benzazepin-l,2-dion-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane are dissolved in a mixture of 100 ml of ether and 50 ml of tetrahydrofuran and then 0.76 g of lithium aluminium hydride are added in batches, with stirring. 10 The resulting mixture is refluxed for one hour, cooled with ice water and mixed with 15% amonium chloride solution. The hydroxide precipitate is suction filtered and washed with ether and the filtrate is concentrated by evaporation. After the residue obtained has been 15 dissolved in acetone, the dihydrochloride is precipitated with methanolic hydrochloric acid. Yield: 2.2 g (82.7% of theory) Melting point: 210-212°C. 20 Example 18 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(4-(4-amino-3,5-dibromo-phenyl)-amino]-propane hydrobromide 25 tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-N-methyl-amino-propane and 1.4 g (3.6 mmol) of 4-(4-amino-3,5-dibromo-phenyl)-butyl bromide are heated to 130°C for two hours in 3 ml of ethyl-diisopropyl-amine. Then the excess amine is distilled off in 30 vacuo and the residue obtained is purified over silica gel using methylene chloride and 2% ethanol as eluant. The fractions are combined in vacuo, the residue is triturated with acetone and the precipitate formed is suction filtered. 35 Yield: 0.6 g (27.9% of theory) 1.1 g (3.6 mmol) of 1-(7,8-dimethoxy-l,3,4,5- Melting point: 159-161°C 2 0 f: 2 " := - 53 - Example 19 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane hydrochlor ide 2.6 g (5 mmol) of the sodium salt of N-[3-[N'-5 methyl-N'-(3-(3 ,4-dimethoxyphenyl)-propyl)-amino]- propyl]-2-(2-carboxymethyl-4,5-dimethoxyphenyl)-ethylamine are heated to 200°C in 30 ml of sulfolane for two hours. After cooling, the mixture is diluted with 3 ml of water and extracted three times with methylene 10 chloride. The organic extracts are washed twice with water, dried over magnesium sulphate and the solvent is concentrated by evaporation jji vacuo. The residue is dissolved in acetone and the hydrochloride is precipitated by the addition of methanolic hydrochloric 15 acid. Yield: 1.8 g (71% of theory) Melting point: 220-221°C Example 20 20 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-1,2-d ion-3-yl-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane hydrochlor ide 1.7 g (0.0154 mmol) of selenium dioxide are added at 70°C to 70 ml of 1,4-dioxan and 2.8 ml of 25 water. After 15 minutes, 1.4 g of Celite and 6.9 g (0.0147 g) of 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane are added and the resulting mixture is refluxed for 40 hours. 30 After cooling, the undissolved constituents are removed by suction filtering, the filtrate is rotated and the residue obtained is purified over silica gel with methylene chloride + 4% ethanol as eluent. The product is dissolved in acetone and the hydrochloride 35 is precipitated with ethereal hydrochloric acid. Yield: 2.36 g (29.2% of theory) Melting point: 189-192°C 10 15 20630 - 54 - Example 21 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3,5-dichloro-phenyl)-2-hydroxy-ethyl)-amino]-propane Prepared from 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(4-amino-3,5-dichloro-benzoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 8. Yield: 71.6% of theory Melting point: 122-126°C IR Spectrum (methylene chloride): 3400 cm" -1 3495 cm -1 -1 (NH,) (CO) UV Spectrum (ethanol): 1650 cm 240 nm (0.14) 290 nm (0.06) 314 nm (shoulder; 0.02) Example 22 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-20 2-on-3-yl)-3-[N-methyl-N-(2-(2-amino-3,5-d ichloro-phenyl)-2-hydroxy-ethyl)-amino]-propane Prepared from 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-amino-3,5-dichloro-benzoylmethyl)-amino]-propane and sodium 25 borohydride analogously to Example 8. Yield: 45% of theory, resin IR Spectrum (methylene chloride) 3360 cm""1, 3450 cm -1 -1 30 UV Spectrum (ethanol): (NH2) 1650 cm-"1" (lactam-CO) 240 nm (0.13) 280-290 nm (0.045) 310 nm (shoulder; 0.03) Example 23 35 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3-amino-4-chloro-phenyl)-2-hydroxy-ethyl)-amino]-propane Prepared from l-(7,8-dimethoxy-l,3,4,5-tetrahydro- 206305 10 - 55 - 2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-amino-4-chloro-benzoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 8. Yield: 55% of theory, resin. IR Spectrum (methylene chloride) 3380 cm"1, -1 UV Spectrum (ethanol): 3470 cm (NH~) 1650 cm (lactam-CO) 236 nm (0.13) 282-292 nm (0.055) 310 nm (shoulder; 0.02) 15 20 25 Example 24 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3-chloro-5-fluoro-phenyl)-2-hydroxy-ethyl)-amino]-propane Prepared from 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(4-amino- 3-chloro-5-fluoro-benzoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 8. Yield: 48% of theory, foam. IR Spectrum (methylene chloride) 3390 cm"1, 3480 cm -1 UV Spectrum (ethanol) (NH,) 1645 cm (lactam-CO) 238 nm (0.18) 282-292 nm (0.07) Example 25 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3-chloro-5-methyl-30 phenyl)-2-hydroxy-ethyl)-amino]-propane Prepared from 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(4-amino- 3-chloro-5-methyl-benzoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 8. 35 Yield: 25% of theory, foam. IR Spectrum (methylene chloride) 3380 cm"1, 3470 cm 1650 cm -1 I -1 (NH2) (lactam-CO) - 56 - UV Spectrum (ethanol) 239 nm (0.15) 280-290 nm (0.05) 305 nm (shoulder; 0.01) The following compounds may be prepared analogously 5 to the preceding Examples: 1-(7-Methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride, Melting point 172-175#C, 10 1-(7-Methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2- on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-dichloro-phenyl) ■ propyl)-amino]-propane, 1-(7-Trifluoromethyl-1,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-15 ethyl)-amino]-propane, 1-(7-Trifluoromethyl-1,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane, 1-(7-Tr ifluoromethyl-1,3,4,5-tetrahydro-2H-3-benzazepin-20 2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-dichloro-phenyl) -propyl)-amino]-propane, 1-(7-Methylamino-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane 25 1-(7-Methylamino-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane - 57 - 1-(7-Methylamino-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-dichloro-phenyl) -propyl)-amino]-propane t 1-(7-Dimethylamino-l,3,4,5-tetrahydro-2H-3-benzazepin-5 2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane; IR spectrum (methylene chloride) 1660 cm""1 (CO) , 1-(7-Dimethylamino-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-10 propyl)-amino]-propane 1-(7-Dimethylamino-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-dichloro-phenyl) -propyl) -amino] -propane, 1-(7,8-Dichloro-l,3,4,5-tetrahydro-2H-3-benzazepin-15 2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, 1-(7,8-Dichloro-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane, 20 1-(7,8-Dichloro-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-d ichloro-phenyl)-propyl)-amino]-propane, 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(2-hydroxy-3-(3,4-dimethoxy-25 phenyl)-propyl)-amino]-propane Oil; C27H38N206 (486.6) Calc; C 66.64 H 7.87 N 5.76 Found: 66.61 7.95 5.74 2QCO ^ - 58 - 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-(2-hydroxy-3-(4-amino-3,5-dichloro-phenyl)-propyl)-amino]-propane, 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-5 2-on-3-yl)-3-[N-methyl-N-(3-hydroxy-3-(4-amino-3,5-dichloro-phenyl)-propyl)-amino]-propane, 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(3-hydroxy-3-(3,4-dimethoxy-phenyl )-propyl)-amino]-propane, 10 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-dichloro-phenyl) -propyl)-amino]-propane, Melting point: 92-93°C 1-(l-Hydroxy-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-15 3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl) -propyl)-amino]-propane, 1-(7-Dimethylamino-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-d imethoxy-phenyl)-propyl)-amino]-propane, 20 1-(7-Dimethylamino-8-methoxy-l,3,4,5-tetrahydro-2H- 3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl) -ethyl)-amino]-propane IR spectrum (methylene chloride): 1650 cm-1 (CO), 1-(7-Bromo-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-25 2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride, Melting point: 198-199°C (decomp.) 1-(7-Bromo-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-30 ethyl)-amino]-propane v\\ 63 OS - 59 - NMR spectrum (CDCI3): 7.2 ppm (1H, s, aromat.), 6.6 ppm (1H, s, aromat.), 2.3 ppm (3H, s, N-CH^). 1-(7-Chloro-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-5 2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane, 1-(7-Chloro-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin- 2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino] -propane, 10 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane, IR spectrum (methylene chloride): 1645 cm-1 (CO) Melting point of the hydrochloride: 158-159°C, 15 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-(3-(4-amino-3,5-dichloro-phenyl)-propyl)-amino]-propane, and 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzzepin- 2-on-3-yl)-3-[N-(2-hydroxy-3-(3,4-dimethoxy-phenyl)-20 propyl)-amino]-propane. $505 - 60 - Example I Tablets containing 10 mg of 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane 5 hydrochloride Compositions: 1 Tablet contains: Active substance 10.0 mg Corn starch 57.0 mg 10 Lactose 48.0 mg polyvinylpyrrolidone 4.0 mg Magnesium stearate 1.0 mg 15 120.0 mg Method The active substance, corn starch, lactose and polyvinylpyrrolidone are mixed together and moistened with water. The moist mixture is forced through 20 a screen with a mesh size of 1.5 mm and then dried at about 45®C. The dry granulate is passed through a 1.0 mm mesh screen and mixed with magnesium stearate. The finished mixture is compressed in a tablet press with punches measuring 7 mm in diameter having a 25 dividing slot, to form tablets. Weight of tablet: 120 mg Example II Coated tablets containing 5 mg of 1-(7,8-dimethoxy-30 1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-fN-methyl-N-(3-(3,4-d imethoxy-phenyl)-propyl)-amino]-propane hydrochloride 1 Tablet core contains: Active substance 5.0 mg 35 Corn starch 41.5 mg Lactose 30.0 mg 206305 - 61 - Polyvinylpyrrolidone 3.0 mg Magnesium stearate 0.5 mg 80.0 mg 5 Method The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is forced through 10 a screen with a mesh size of 1 mm, dried at about 45°C and the granulate is then passed through the same screen. After the addition of magnesium stearate, convex tablet cores measuring 6 mm in diameter are compressed in a tablet making machine. The tablet 15 cores thus produced are coated in known manner with a coating consisting essentially of sugar and talc. The finished coated tablets are polished with wax. Weight of coated tablet: 130 mg 20 Example III Ampoules containing 5 mg of 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride 25 1 Ampoule contains: Active substance Sorbitol Water for injection ad 30 Method In a suitable mixing vessel the active substance is dissolved in water for injections and the solution is made isotonic with sorbitol. 35 After being filtered through a membrane filter, the solution is transferred, under a current of N2, 5.0 mg 50.0 mg 2.0 ml 206305 - 62 - into clean sterilised ampoules and autoclaved for 20 minutes in a current of water vapour. Example IV 5 Suppositories containing 15 mg of l-(7,8-dimethoxy-1,3/4/5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-iN-methyl-N- (3- (3y 4-dimethoxy-phenyl) -propyl)-amino]-propane hydrochloride 1 Suppository contains: 10 Active substance 0.015 g Hard fat (e.g. Witepsol H 19 & W 45) 1.685 q 1.700 g Method: 15 The hard fat is melted. At 38®C the ground active substance is homogeneously dispersed in the melt. It is cooled to 35°C and poured into slightly chilled suppository moulds. 20 Example V Drops solution containing 10 mg of 1-(7,8-dimethoxy-ly 3/4 f 5-tetrahydro-2H-3-benzazepin-2-on-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride per 5 ml 25 100 ml of solution contain: Active substance 0.2 g Hydroxyethyl cellulose 0.15 g Tartaric acid 0.1 g Sorbitol solution (70% dry content) 30.0 g 30 Glycerol 10.0 g Benzoic acid 0.15 g Distilled water ad 100 ml Method: 35 Distilled water is heated to 70°C. The hydroxyethyl cellulose, benzoic acid and tartaric acid are dissolved therein with stirring. The solution is cooled to ambient temperature and the glycerol and sorbitol </div>

Claims

<div class="application article clearfix printTableText" id="claims"> - 63 - solution are added with stirring. At ambient temperature the active substance is added and stirred until completely dissolved. Then the liquid is evacuated, with stirring, to eliminate any air. 206305 - 64 - claims VftxnmWtiMls:. 1. Compounds of general formula I (I) [wherein represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, an alkoxy 5 group with 1 to 3 carbon atoms or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and Rj represents a hydrogen, fluorine, 10 chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms, or R^ and Rj together represent an alkylenedioxy group with 1 or 2 carbon atoms; R^ represents a hydrogen, fluorine, chlorine or bromine atom, a nitro or trifluoromethyl group 15 or an alkyl or alkoxy group each having 1 to 3 carbon atoms and R4 represents a hydrogen atom, an amino group or an alkoxy, alkylamino or dialkylamino group (each alkyl moiety having 1 to 3 carbon atoms and the alkyl moieties in the dialkylamino group 20 being the same or different), or R3 and R4 together represent an alkylenedioxy group with 1 or 2 carbon atoms; Rj represents a hydrogen, chlorine or bromine atom; 25 Rg represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms; 206305 - 65 - E represents an n-alkylene group with 2 to 4 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms; B represents a thiocarbonyl, carbonyl or 5 methylene group; G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms (wherein, so long as B represents a methylene or carbonyl group, 10 a methylene group may optionally be replaced by a carbonyl group), or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G; and 15 A represents a group of formula ?7 -CH=CH-, -NH-CO-, -CH2-C0-, -C=N-, -N=CH-, 5 5 5 5 OH OH NOH NHR0 I l li I ° -CH-CO-, -CH-CH,-, -C-C0-, -CH-CO- or -CO-CO- (wherein 5 5 5 5 Ry represents an alkyl group with 1 to 3 carbon atoms and Rg represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms substituted by a phenyl, methoxy-phenyl or dimethoxyphenyl group); with the provisos that (i) when A represents a group of formula -CH2-CH2-, -CH=CH-, -NH-CO-, -CHj-CO-, or -C=N- 20 25 (wherein is as hereinbefore defined) B may not represent a methylene or carbonyl group unless G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl - 66 - 206305 group with 1 to 3 carbon atoms, an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, 5 or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or and R2 each represents a hydrogen atom or R^ represents a fluorine, chlorine 10 or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, 15 fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms (except in the case of A representing a -CH2CH2- group, R^ and R2 representing methoxy groups in the 7- and 8- positions, E representing an n-20 propylene group, Rg representing a methyl group, G representing an ethylene group, R^ representing a hydrogen atom, and R^ and R^ either both representing hydrogen atoms or representing respectively a 3-nitro and a 4-amino group, in which case B may 25 represent a carbonyl group); (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl 30 group with 1 to 3 carbon atoms, an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 35 4 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R^ and R2 each represents; \ -s; \\ - 67 - 2QQ90S a hydrogen atom or R^ represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which 5 alkyl groups may, in the case of disubstitution, be the same or different) and R2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms; and (iii) when A represents a group of formula OH OH NOH HN-RQ i t II I o 10 -N=CH—, -CH-CO-, -CH-CH2-, -C-CO- or -CH-CO — (wherein RQ is as hereinbefore defined), O B represents a methylene group] and acid addition salts of the aforementioned compounds. 2. Compounds as claimed in claim 1 wherein the 15 group R^ is in the 3-position, the group R^ is in the 4-position and the group R,. is in the 5-position of the respective phenyl nucleus. 3. Compounds of general formula la Rg y 3 N-CH CH CH -N-Gf R< n p (la) 20 [wherein R^ represents a hydrogen, chlorine or bromine atom or a trifluoromethyl, methoxy, amino, methylamino or dimethylamino group; 206305 - 68 - 10 15 20 25 30 r2 represents a hydrogen, chlorine or bromine atom or a methoxy group, or R^ and R2 together represent a methylenedioxy group; R3 represents a hydrogen, fluorine, chlorine or bromine atom or a methyl, methoxy, trifluoromethyl or nitro group; R^ represents a hydrogen atom or an amino, methoxy, methylamino or dimethylamino group, or R^ and R4 together represent a methylenedioxy group; Rg represents a hydrogen, chlorine or bromine atom; Rg represents a hydrogen atom or a methyl or allyl group; B represents a thiocarbonyl, carbonyl or methylene group; G represents an n-alkylene group with 2 to 5 carbon atoms (wherein, so long as B represents a methylene or carbonyl group, a methylene group may optionally be replaced by a carbonyl group), or a methylene-n-hydroxy-alkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G; and A represents a group of formula oh oh noh „ 'in -ch=ch-, -n=ch-, -ch-ch2-, -ch-co-, -c co-, nh-I 2 -ch -co-, nh-ch2ch2 -ch-co- // v 5 och. och3 or -coco-; 5 5 with the provisos that (i) when A represents a group of formula -ch2-ch2- or -ch=ch-, b represents a thiocarbonyl group, and may also represent a carbonyl group when G represents an n-alkylene group with 3 to 5 carbon atoms, an n-alkylene group with 2 to 5 Car ben. fCjjfrbonf atoms wherein a methylene group is replaced 20C 69 by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or 5 R^ and R2 each represents a hydrogen atom or Rj represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and R2 represents a hydrogen, chlorine or bromine atom or a methoxy group; 10 (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 5 carbon atoms, an n-alkylene group with 2 to 5 carbon atoms wherein a methylene group is replaced 15 by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 3 carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or R^ and R2 each represents a hydrogen atom or R^ 20 represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and R2 represents a hydrogen, chlorine or bromine atom or a methoxy group; and 25 (iii) when A represents a group of formula -N=CH- 5 OH OH NOH i 2 , -CH-CO- or 5 -Q- -°ch3 OCH3, 5 5 5 5 30 B represents a methylene group] and acid addition salts thereof. 4. Compounds as claimed in claim 3, wherein A represents a -CH2-CH2~ group; B represents a -CO- or -CS- group; R^ represents a methoxy, amino, methylamino 35 or dimethylamino group, and R2 represents a hydrogen atom or a methoxy group or R^ and R2 together represent 206305 - 70 - a methylenedioxy group, R3 represents a hydrogen, fluorine, chlorine or bromine atom or a methoxy or trifluoromethyl group,and R4 represents a methoxy, amino, methylamino 5 or dimethylamino group or R^ and R^ together represent a methylenedioxy group, R^ represents a hydrogen, chlorine or bromine atom, Rg represents a methyl group and 10 G represents an n-alkylene group with 3 to OH 5 carbon atoms, a -CHj-^H - group or (if B represents a -CS- group and/or R^ represents an amino, methylamino or dimethylamino group) a -CH2CH2- group. 5. Compounds as claimed in claim 3 wherein 15 R^ and R2 each represents a methoxy group; R^ represents a methoxy group or a hydrogen or chlorine atom; R^ represents a methoxy, amino or dimethylamino group; 20 Rg represents a hydrogen or chlorine atom; Rg represents a methyl group; G represents an n-alkylene group with 3 to OH 5 carbon atoms or a -CH2-£h- group or (if B represents a thiocarbonyl group or A represents a group of OH 25 formula -C^H-CO-) a -CH0-CH0- group; and 5 2 2 either A represents a -CH2-CH2- group and B represents a thiocarbonyl or (if G represents an n-alkylene group with 3 to 5 carbon atoms) a carbonyl group, or OH A represents a -^H -CO- group and B represents 206305 " • - 71 - a methylene group. 6. 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl) -propyl)-amino]-propane and acid addition 5 salts thereof. 7. 1-(l-Hydroxy-7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane and acid addition salts thereof. 10 8. 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-dichloro-phenyl)-propyl)-amino]-propane and acid addition salts thereof. 9. 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3- 15 benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-phenylethyl)-amino]-propane and acid addition salts thereof. 10. 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(2-(4-amino-3-nitro-phenyl)-ethyl)-amino]-propane and acid 20 addition salts thereof. 11. Acid addition salts of compounds as claimed in any preceding claim formed with hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic and fumaric 25 acids. 12. Physiologically acceptable acid addition salts of compounds as claimed in any one of claims 1 to 10. 13. Compounds as claimed in claim 1 as herein 30 specifically described. 14. Compounds as claimed in claim 1 as herein specifically described in any of Examples 1 to 25. 15. A process for the preparation of compounds 35 as claimed in claim 1 which comprises reacting a compound of general formula II 4 363 206305 - 72 - (II) with a compound of general formula III 10 (wherein 1^, R^, R^, A, B, E and G are as defined in claim 1, R| and R^ each represents an amino or alkylamino group protected by a protecting group or represent R^ and R^ as defined in claim 1; one of the groups U and V represents an Rg-NH-group wherein Rg is as defined in claim 1, and the other group U or V represents a nucleophilically exchangeable group), and subsequently splitting off any protecting group used. 16. A process as claimed in claim 15 wherein 15 the nucleophilically exchangeable group U or V is a halogen atom or a sulphonyloxy group. 17. A process as claimed in claim 15 or claim 16 wherein the subsequent splitting off of a protecting group is effected hydrolytically or hydrogenolytically. 20 18. A process as claimed in any one of claims 15 to 17 wherein the reaction is carried out in the presence of an acid-binding agent or a reaction accelerator. 19. A process as claimed in any one of claims 25 15 to 18 wherein the reaction is carried out at \\ - 73 - 10 temperatures of between 0 and 150°C. 20. A process as claimed in any one of claims 15 to 19 wherein the reaction is carried out in a solvent at the boiling temperature of the reaction mixture. 21. A process for the preparation of compounds as claimed in claim 1 wherein A represents a -CH--CH.,-, -CH=CH-, -NH-CO-, -COCO-, -CH,-CO-, R 5 5 *7 —C=N- or -n=CH- group and 5 5 B represents a -CHj- or -CO- group, which comprises reacting a compound of general formula (iv) n-~h (iv) (wherein R2 is as defined in claim 1, 15 A' represents a -CH2~CH2-, -CH=CH-, -NH-CO- *7 -COCO-, ~CH~-CO-, -N=CH- or -C=N- group wherein 5 5 Ry represents an alkyl group with 1 to 3 carbon atoms, B' represents a -CH2- or -CO- group and ' represents an amino or alkylamino group protected by a protecting group or represents R^ as defined in claim 1) with a compound of general formula (V) z~e^g^C2C *3 20 R4 (V) R5 2 ^ ^ <sf> v ) s —CV • S , / , <j - 74 - (wherein R3, Rg, Rg, E and G are as defined in claim 1, r4* represents an amino or alkylamino group 5 protected by a protecting group or represents R^ as defined in claim 1, and Z represents a nucleophilically exchangeable group) and optionally subsequently splitting off any protecting group used. 10 22. A process as claimed in claim 21 wherein Z represents a halogen atom or a sulphonyloxy group. 23. A process as claimed in claim 21 or claim 22 wherein the optional subsequent splitting off of a protecting group is effected hydrolytically 15 or hydrogenolytically. 24. A process as claimed in any one of claims 21 to 23 wherein the reaction is carried out in the presence of an acid-binding agent or a reaction accelerator. 20 25. A process as claimed in any one of claims 21 to 24 wherein the reaction is carried out at temperatures of between 0 and 150°C. 26. A process as claimed in any one of claims 21 to 25 wherein the reaction is carried out in 25 a solvent at the boiling temperature of the reaction mixture. 27. A process for the preparation of compounds as claimed in claim 1 wherein A does not represent NH-Rq i 8 30 a -CH-CO- or -CO-CO- group, which comprises reacting 5 a compound of general formula VI N-E-H (VI) 20<r3 ^5 - 75 - (wherein B, E, and R2 are as defined in claim 1 but in the group E two hydrogen atoms in a -CH2- or —CH^ group of the group E are replaced by an 5 oxygen atom, and A" represents a -CH2-CH2~, -CH=CH-, -NH-CO-, OH OH NOH 5 I i li -CH--CO-, —N=CH-, -CH-CO-, -CH-CH--, -C-CO- or 5 Z 5 5 5 5 -C=N- group wherein R_ represents an 5 ' 10 alkyl group with 1 to 3 carbon atoms), with an amine of general formula VII (wherein G and R^ to Rg are as defined in claim 1), 15 in the presence of a reducing agent. 28. a process as claimed in claim 27, wherein a complex metal hydride or hydrogen in the presence of a hydrogenation catalyst is used as a reducing agent. 20 29. A process as claimed in claim 27 or claim 28 wherein the reaction is carried out in a solvent at temperatures of between 0 and 100°C. 30. A process for the preparation of compounds as claimed in claim 1 HN-RQ l 8 25 wherein A does not represent a -Ch-CO- or -CO-CO- group, which comprises reacting a compound of general formula VIII 20 «. 76 - R 1 (VIII) (wherein B, E, R^r r2 and Rg are as defined in claim 1 and 5 A" represents a -CH2-CH2-, -CH=CH-, -NH-CO- OH OH NOH 5 I I H -CH--CO-, -N=CH-, -CH-CO-, -CH-CH,-, -C-CO- or 5 5 5 5 5 group wherein R^ represents an alkyl group with 1 to 3 carbon atoms), with a compound 10 of general formula IX (wherein R^ to Rg and G are as defined in claim 1, but in the group G two hydrogen atoms in a -CH2-or -CH3 group of the group G are replaced by an 15 oxygen atom) in the presence of a reducing agent. 31. A process as claimed in claim 30, wherein a complex metal hydride or hydrogen in the presence of a hydrogenation catalyst is used as a reducing agent. 20 32. A process as claimed in claim 30 or claim 31, wherein the reaction is carried out in a solvent at temperatures of between 0 and 100°C. 33. A process for the preparation of compounds as claimed in claim 1 wherein A represents a -CH2-CH2— R (IX) wL0t3O5" - 77 - group, B represents a methylene or carbonyl group and Rg does not represent an alkenyl group with 3 to 5 carbon atoms, which comprises hydrogenating a compound of general 5 formula X (wherein R^ to Rg, E and G are as defined in claim 1, and B' represents a methylene or carbonyl group). 10 34. A process as claimed in claim 33, wherein the hydrogenation is effected with catalytically activated hydrogen. 35. A process as claimed in claim 33 or claim 34 wherein the hydrogenation is carried out under 15 a hydrogen pressure of 1 to 7 bar at temperatures of between 0 and 75°C. 36. A process as claimed in claim 35 wherein the temperatures are between 20 and 50°C. erepanxHVtrt 37. A process for the /pjrcparatiiy of compounds 20 as claimed in claim 1 wherein B represents a -CS — group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxy-alkylene group with 1 to 4 carbon atoms 25 in the alkylene moiety, which comprises reacting a compound of general formula XI 2 g « ^ - 78 - R 1 5 UD R 2 (wherein R^ to Rg, A and E are as defined in claim 1 and 5 G' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety) 10 with a sulphur-introducing agent. 38. A process as claimed in claim 37, wherein the sulphur-introducing agent is phosphorus pentasulphide or 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide. 15 39. A process as claimed in claim 37 or claim 38 wherein the reaction is carried out at temperatures of between 50 and 150°C. 40. A process as claimed in any one of claims 37 to 39 wherein the reaction is carried out in 20 a solvent at the boiling temperature of the reaction mixture. 41. A process for the preparation of compounds OH as claimed in claim 1 wherein A represents a -CH-CO- 5 OH I or —CH-CHj group 25 and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene-n-hydroxy-alkylene group with 1 to 4 carbon atoms in the alkylene moiety, which comprises reducing 30 a compound of general formula XII 5 206305 - 79 - (wherein to Rg, E and G are as defined in claim 5 1) . 42. A process as claimed in claim 41 wherein the reduction is carried out using a metal hydride or diborane as reducing agent. 43. A process as claimed in claim 42 wherein 10 the metal hydride used as reducing agent comprises sodium borohydride or lithium aluminium hydride. 44. A process as claimed in any one of claims 41 to 43 wherein the reduction is carried out in a solvent at temperatures of between 0 and 80°C. 15 45. A process for the preparation of compounds as claimed in claim 1 wherein HN-R0 NOH / o II A represents a -CH-CO- or -C-CO group and G represents 5 5 an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon 20 atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, which comprises reacting a compound of general formula XIII (XIII) 5 10 15 20 25 jl 0 6.3 0 b - 80 - (wherein R^ to Rg and E are as defined in claim 1 and G' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or a methylene n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety), with a compound of general formula XIV H N - R9 (XIV) (wherein Rg represents a hydroxy group or represents Rg as defined in claim 1) optionally with subsequent reduction . 46. A process as claimed in claim 45, wherein the optional subsequent reduction is effected using a complex metal hydride, catalytically activated hydrogen or hydrazine/Raney nickel as reducing agent. 47. A process as claimed in claim 45 or claim 46 wherein the reaction is carried out in a solvent or in a melt at temperatures of between 50 and 175°C. 48. A process for the preparation of compounds as claimed in claim 1 wherein A represents an -N=CH-group and Rg represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms, which comprises reacting a compound of general formula XV *2 (XV) - 81 - 20630S (wherein to R^, B, E and G are as defined in claim 1 and Rg1 represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 5 to 5 carbon atoms) with an orthoformic acid ester. 49. A process as claimed in claim 48, wherein any -NH2 or =NH groups in the compound of general formula XV is protected by protecting groups, the said protecting groups being subsequently split 10 off after the reaction. 50. A process as claimed in claim 49, wherein the protecting groups are selected from acetyl, benzoyl, ethoxycarbonyl and benzyl groups and the subsequent splitting off is effected hydrolytically 15 or hydrogenolytically. 51. A process as claimed in any one of claims 48 to 50, wherein the reaction is carried out in a solvent and/or in the presence of an excess of the orthoformic acid ester and at temperatures 20 of between 100 and 200°C. 52. A process for the preparation of compounds as claimed in claim 1, wherein A does not represent a -COCO- group and G represents a methylene-n-hydroxyalkylene group, which comprises reducing 25 a compound of general formula XVI - f6 J N-E-.N-G"-/' (XVI) 7 - 82 - (wherein R^ to Rg, B and E are as defined in claim 1, A"' represents A as defined in claim 1 with 5 the exception of the -COCO- group, and G" represents a methylene-n-alkylene group, wherein the alkylene moiety contains 1 to 4 carbon atoms and a methylene group of the alkylene moiety is replaced by a carbonyl group). 10 53. A process as claimed in claim 52 wherein the reduction is carried out using a metal hydride or diborane as reducing agent. 54. A process as claimed in claim 52 or claim 53 wherein the reduction is carried out in a solvent 15 at temperatures of between 0 and 50°C. 55. A process for the preparation of compounds as claimed in claim 1 wherein Rj represents a nitro group and R^ represents an amino group, which comprises hydrolysing a compound of general formula XVII 20 XiT^NH-Acyl <*VM> (wherein R^, R2, Rg, Rg* A, B, E and G are as defined in claim 1, and Acyl represents an acyl group). 56. A process as claimed in claim 55 wherein the acyl group is an acetyl, ethoxycarbonyl or 25 benzoyl group. 57. A process as claimed in claim 55 or claim 56 wherein the acyl group is hydrolysed in an aqueous solvent in the presence of an acid or an alkali metal base at temperatures of between 0 and 100°C. -Bass. A process as claimed in claim 55 or claim 56 wherein the hydrolysis is carried out in methanolic or ethanolic hydrochloric acid. 59. A process for the preparation of compounds 5 as claimed in claim 1 wherein wherein A represents a -CH2-CH2-, -CH=CH-, -NH-CO-, ft -CH9—CO—, -N=CH-, -COCO- or -C=N- group and one 5 5 5 of the groups R^, R2, R^ or R^ represents an alkoxy, alkylamino or dialkylamino group or Rg represents 10 an alkyl or alkenyl group, which comprises reacting a compound of general formula XVIII R4 (XVIII) (wherein R^ to Rg, B and E are as defined in claim 15 1 but at least one of the groups R^ to R^ must represent a hydroxy group or R^ or R^ must represent an amino or alkylamino group or Rg must represent a hydrogen atom, A* represents a -CH--CH--, -CH=CH-, -NH-CO-, * £ 5 *7 20 -CH--C0-, -N=CH-, -COCO- or -C=N- group wherein 5 * 5 5 r^ represents an alkyl group with 1 to 3 carbon atoms, and G"' represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an - 84 - 2063Q5 10 alkyl group with 1 to 3 carbon atoms, wherein a methylene group may be replaced by a carbonyl group), with a compound of general formula XIX R10 - X (XIX) 5 (wherein R10 rePresents an alkyl group with 1 to 3 carbon atoms or, if Rg represents a hydrogen atom, an alkenyl group with 3 to 5 carbon atoms, and X represents a nucleophilically exchangeable group or, if at least one of the groups R^ to R^ represents a hydroxy group, X together with a hydrogen atom in the a position of the group R^q represents a diazo group or, if Rg represents a hydrogen atom or R-^ or R^ represents an amino or alkylamino group, 15 X together with a hydrogen atom in the a position of the group R^q may also represent an oxygen atom). 60. A process as claimed in claim 59 wherein the group X in the compound of general formula XIX is a halogen atom or a sulphonyloxy group. 20 61. A process as claimed in claim 59 or claim 60 wherein B represents a methylene or carbonyl group and the reaction is carried out with an alkylating agent. 62. A process as claimed in claim 61 wherein the alkylating agent used is methyl iodide, dimethyl 25 sulphate, ethyl iodide, diethyl sulphate, propyl bromide, allyl bromide or isopropyl p-toluenesulphonate in the presence of an acid-binding agent. 63. A process as claimed in any one of claims 59 to 61 wherein X together with a hydrogen atom 30 in the a-position of the group R^ represents a diazo group and the reaction is carried out with a diazoalkane at temperatures of between 0 and 30°C. 64. A process as claimed in any one of claims 59 to 61, wherein X together with a hydrogen atom in 35 the a position of the group R-^q represents an oxygen^r-* r q% atom and the reaction is carried out in the presenpgr of 5 MAY 1986 ' ! - 85 - a reducing agent at temperatures of between 0 and 120°C. 65. A process as claimed in any one of claims 59 to 64 wherein the reaction is carried out in 5 the presence of a solvent. 66. A process for the preparation of compounds as claimed in claim 1 wherein A represents a -COCO-group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an 10 alkyl group with 1 to 3 carbon atoms wherein a ■ethylene group say optionally be replaced by a carbonyl group, which comprises oxidising a compound of general formula XX 15 (wherein R^ to Rg, E and G are as defined in claim 1). 67. A process as claimed in claim 66 wherein the oxidation is carried out using potassium permanganate, selenium dioxide or sodium dichromate as oxidising agent. 20 68. A process as claimed in claim 66 or claim 67 wherein the oxidation is carried out in a solvent at temperatures of between 0 and 100°C. 69. A process for the preparation of compounds as claimed in claim 1 wherein A represents a -CH2-CO— 25 group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group may be optionally replaced by a carbonyl group, which comprises oxidising a compound . - 86 - of general formula XXI (XXI) 10 15 (wherein to Rfit B, E and G are as defined in claim 1). 70. A process as claimed in claim 69 wherein the oxidation is carried out using ruthenium tetroxide, optionally produced situ in the reaction mixture, as oxidising agent. 71. A process as claimed in claim 69 or claim 70, wherein the reaction is carried out in a solvent and at temperatures of between 0 and 100°C. 72. A process for the preparation of compounds as claimed in claim 1 wherein R^ is in the 7-position, A represents a -CH2CH2- group and B represents a -CO- group, which comprises cyclising a compound of general formula XXII ,6 /rK ^h2-CH2-N-E-N-g-—_ > (XXII) 20&35s - 87 - (wherein to Rg, G and E are as defined in claim 1, Rg' represents an alkyl group with 1 to 3 5 carbon atoms or an alkenyl group with 3 to 5 carbon atoms and Y represents a group suitable for cyclisation). 73. A process as claimed in claim 72 wherein Y in the compound of general formula XXII represents 10 a carboxy, nitrile, ester, thioester, acyloxycarbonyl or amide group. 74. A process as claimed in claim 72 or claim 73 wherein the cyclisation is carried out in the presence of a condensing agent. 15 75. A process as claimed in any one of claims 72 to 74 wherein any HO-, =NH or -NH2 groups present are protected by protecting groups during the cyclisation, the said protecting groups being subsequently split off after the reaction. 20 76. A process as claimed in any one of claims 72 to 75 wherein the cyclisation is carried out in a solvent at temperatures of between 100 and 250#C. 77. A process as claimed in any one of claims 25 15 to 76, wherein a compound of general formula I, initially obtained, is subsequently converted into an acid addition salt thereof, or an acid addition salt of a compound of general formula I, initially obtained, is subsequently converted 30 into a compound of general formula I or into a different acid addition salt therof. 78. A process for the preparation of compounds as claimed in claim 1 substantially as herein described. * «I• * - 88 - % 06305 79. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any of Examples 1 to 25. 80. Compounds of general formula I as defined 5 in claim 1 and acid addition salts thereof when prepared by a process as claimed in any one of claims 15 to 79. 81. Compounds of general formula I as defined in claim 1 and physiologically acceptable acid 10 addition salts thereof for use in a method of preventing or relieving ischaemic cardiac diseases or of relieving sinus tachycardia. 82. Pharmaceutical compositions comprising, as active ingredient, at least one compound of general 15 formula I as defined in claim 1 or a physiologically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient. 83. Pharmaceutical compositions as claimed in claim 82 in a form suitable for oral, rectal or 20 parenteral administration. 84. Pharmaceutical compositions as claimed in claim 82 or claim 83 in the form of tablets, coated tablets, capsules, powders, suspensions, drops, ampoules, syrups and suppositories. 25 85. Pharmaceutical compositions as claimed in any one of claims 82 to 84 in the form of dosage units. 86. Pharmaceutical compositions substantially as herein described. 30 87. Pharmaceutical compositions substantially as herein described in any of Examples I to V. 88. A method of preventing or relieving ischaemic cardiac diseases or of relieving sinus tachycardia in a non-human patient, which comprises administering 35 to the said patient an effective amount of a compound of general formula I as defined in claim 1 or a physiologically acceptable acid addition 206305 - 89 - 89. Use of compounds as claimed in claim 1 in the treatment of sinus tachycardia and the prophylaxis and therapy of ischaemic cardiac diseases in non-human patients. B. { c. >'■ N & CAREY s*- ^ ATTORNEYS FOR THE APP$Qants' </div>