IE56261B1 - Benzazepine and benzodiazepine derivatives - Google Patents

Abstract

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

Description

This invention relates to new bensasepine 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, Irish Patent Specification No. 45674 describes, j.nter alia, the compound of formula and the physiologically acceptable acid addition salts thereofp which has valuable pharmacological properties, i.e. in particular a selective heart10 rate lowering effect in addition to a mild hypotensive effect.

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

Thus, according to one feature of the present invention, we provide compounds of general formula X (I) Ivherein represents a hydrogen? fluorine? chlorine or bromine atom, a trifluoromethyl groups an alkoxy group with 1 to 3 carbon atoms or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution? be the same or different) and Ro represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 atoms, or k-j and together represent an alkylenedioxy group with 1 or 2 carbon atoms; represents a hydrogen? fluorine? chlorine or. bromine atom? a nitro or trif luoromethyl group or an alkyl or alkoxy group each having 1 to 3 carbon atoms and ft. represents a hydrogen atom? an amino group or an alkoxy? alkylamino or dialkylamino group (each alkyl moiety having 1 to 3 carbon atoms and the alkyl moieties in the dialkylamino group being the same or different)? or R3 and ft^ together represent an alkylenedioxy group with 1 or 2 carbon atoms? represents a hydrogen? chlorine or bromine atom? ftg represents a hydrogen atom? an alkyl group with X to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms? E represents an n-alkylene group with 2 fo carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms? B represents a thiocarbonyl? carbonyl or methylene group? G represents an n-alkylene group with 1 to carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms (wherein, so long as S 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", -CH«CH-, HNH-CO- ? -CH^-CO-, -ON-, -N«CH-, 5 5 OH ι -CHCO-, OH -ch-ck2 NOH II -C-CO-, NHR0 I 8 -OCO- or -CO-CO- (wherein 5 5 R? represents an alkyl group with 1 to 3 carbon atoms and Κθ 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 CHn-CH.

-CH»CH· NH-CO· , -CHj-CORn u * •ON~( (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 group with 1 fo 3 carbon toms? an η-alkylene group with 1 to 5 cabon 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 saethyXene~n«hydroxyalkylene group with 1 to carbon atoms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group Gf and/or and R^ ®ac^ represents a hydrogen atom or R^ represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and represents u hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms (except in the case of A representing a group, R^ and R^ representing methoxy groups in the 7- and 8- positions, '£ representing 15 an n~propylene group, Rg representing a methyl. group, G representing an ethylene group, Rg representing a hydrogen atom, and R3 and EG either both representing hydrogen atoms or representing respectively a 3-nitro and a 4-amino group, in which case B may represent a carbonyl group)ι (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 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 mefhylene-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 snd tt2&ch represents a hydrogen atom or represents & fluorine chlorine or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the ease of disubutitution. bs the same or different, and Rj 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-RO I I (» I 8 -N«CH-, "CH-CO-, -CH-CH^-, -C-CO- Or -CH-CO(wherein Rg is as hereinbefore defined), B represents a methylene group] and acid addition salts of the .aforementioned compounds.

The term 'acid addition salts4 as used herein refers to salts formed with organic and inorganic acids. Suitable acids include, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, lactic, citric, tartaric, succinic, maleic and fumaric acids.

For pharmaceutical use the acid addition salts will, of course, be physiologically acceptable acid addition salts, but other acid addition salts may find use, for example in the preparation of the compounds of general formula ϊ and their physiologically acceptable acid addition salts* The definitions given hereinbefore for the groups Rj to Rg, E and G include the following: may be a hydrogen, fluorine, chlorine or bromine atom, or a trifluoromethyl, methoxy, ethoxy, npropoxy, isopropoxy, amino, methylamino, ethylamino, n-propylamino, Isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamino, methylethylamino, methyl-n-propylamino, methyl-isopropylamino or ethyl-n-propylamino group, may represent a hydrogen, fluorine, chlorine or bromine atom, or a methoxy, ethoxy, n-propoxy or isopropoxy group or together with Rj may represent © methylenedioxy or ethylenedioxy group, r3 raay represent a hydrogen, fluorine, chlorine or bromine atom, or a nitro, trifluoromethyl, methyl, ethyl, n-propyl, methoxy, ethoxy, n-propoxy or isopropoxy group, Rg may represent a hydrogen atom, or a methoxy, ethoxy, n-propoxye isopropoxy, amino, methylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, di isopropylamino, methyl-ethylaminOp methyl-n-propylamino, methyl-isopropylamino or ethyl-n-propylamino group or together with may represent a methylenedioxy or ethylenedioxy group, &5 may represent a hydrogen, chlorine or bromine atom, R- may represent a hydrogen atom or a methyl, ethyl, n-propyl, isopropyl, allyl, n-buten~(2)yl or n-penten-(2)-yl group, Ry may represent a methyl, ethyl, n-propyl or isopropyl group, Rg may represent a hydrogen atom or a benzyl, 1-phenylethyl, 2-phenylethy1, 3-phenyIpropy18 2(^-methoxyphenyl)-ethyl, 2-(3„$~dimethoxyphenyl)ethyl, 3-(%-methoxyphenyI)-propyl or 3-(3,4-dimethoxy phenyl)-propyl group, E may represent an ethylene, n-propylene, n-butylene^ 1-aethyl-ethylene, 2-ethyI-eihyIsne, 1- propyl-ethylene, 1-methy1-n-propylene, 2-methyln-propylene, I-ethyl-n-propylene, 3-ethyI-n-propylene 2- propyl-n-propylene or ^-niethyX-n-butyXene group and G may represent a methylene, ethylidene, n-propylidene, n-butylidenee 2-methyl-propylidene, ethylenee 1-methy1-ethylene? 2-ethyl-ethylene? 1‘-propyl-ethylene, 2-methyl-ethylene? n-propylene, n-butylene? n-pentylene, 1-methyl-n-propylene? 1-methy1-butylene, 1-methyl-n-pentylene ? 1-ethyln-propylene, 2-ethyl-n-propylene, 1-methyl-n-butylene, methylenecarbonyl, ethylenecarbonyl? n-propylene10 carbonyl? n-butylenecarbonyl, carbonylmethylene? carbonylethylene, carbonyl-n-propylene, carbonyln-butylene, methylenecarbonylraethylene, ethylenecar bonylraethylene, 2-hydroxyethylene, 2-hydroxyn-propylene? 3-hydroxy-n-propylene, 2-hydroxy-n15 butylene? 3-hydroxy-n-butylene? 4-hydroxy-n-butylene or 2~hydroxy-n~pentylene group; the group R3 1S preferably in the 3- position, in the 4-position and Rc in the 5-position of the phenyl nucleus in question.

□ However, preferred compounds are compounds 23 of general formula la [wherein represents a hydrogen? chlorine or bromine &fom or a trifluoromethyl? methoxy, amino? methylamino or dimethylamino group, and R2r^Pr3S-n-s ® hydrogen, chlorine or bromine atom or a methoxy group? or and ^og^ther represent a methylenedioay group? a represents a hydrogen, fluorine, chlorine or bromine atom or a methyl, methoxy, trifluoromethyl or nitro group, end represents a hydrogen ©tom or an amino, methoxy, methylamino or dimethylamino group, or &3 ©nd together represent © methylenedioxy group? Rj represents a hydrogen, chlorine or bromine atom? R^ represents © hydrogen ©tom or a methyl or allyl group? B represents © 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 © group of formula -CH2-CH2-, OH OH WOH ι ι ~CH*CH-, ~N=CH-, -CH-CH,-, -CH-CO-, -C-CO-, 5 5 NH2 NH-CH2CH2·—O—CCH 3 -CH-CO-, -CH-CO- OCH3 or -COCO-; with the provisos that (i) when A represents a group of formula -CH2-CH2- or -CH®CH-V B represents a thiocarbonyl group, ©nd may also represent a carbonyl group when G represents ©n n-alkylene group with 3 fo 5 carbon ©toms, an n-alkylene group with 2 to 5 erbon atoms wherein a methylene group is replaced by a carbonyl group, or © methylene-n-hydroxyalkylene group with 1 to 3 carbon ©toms in the alkylene moiety, the methylene group being attached to the nitrogen atom to the left of the group G, and/or RjL and $ach represents a hydrogen atom or r^ represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and ^2 represents a hydrogen, chlorine or bromine atom or a methoxy group; (ii) when A represents a "CO-CO- group, 3 represents a methylene group and G represents an n-alkylene group with 3 to 5 carbon atoms, an n-alkylene group with 2 to 5 carbon atoms herein a methylene group is replaced by a carbonyl group, or a methylene-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^ represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and r2 represents a hydrogen, chlorine or bromine atom or a methoxy group? and (iii) when A represents a group of formula -N=CHOH OH -CH-CH2", -CH-CONOH H C-CO-, CH-CO- or -CH-COHOCH 2 och3 B represents a methylene group] and acid addition salts thereof » The compounds 1-(7,8-dimethoxy-X,3,^,5-tetrahydro2H-3-benzazepin-2-on-3"yl)-3-(N-methyl-N-(2-phenylethyl) -amino]-propane, and l-(7,8-dimethoxy-lP3,4,5tetrahydro-2H-3-bensazepin-2-on-3-yl)-3-(N-methylN-(2-H-amino-3-nitro-phenyl)-ethyl)-amino)-propane, acid addition salts of these compounds, are also preferred compounds of the invention» Particularly preferred are those compounds of general formula la above wherein A represents a -CH0CHo" & represents ft -CO- or -CS- group? represents a methoxy, amino, methylamino or dimethylamino group,and Ro represents a hydrogen atom or a methoxy group or R^ and together represent ft methylenedioxy group? R^ 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 IG together represent a methylenedioxy group? Rj represents a hydrogen, chlorine or bromine atom; Rg represents a methyl group? and G represents an n-alkylene group with 3 to OH I carbon atoms, a -CH^-CH- group, or (if 3 represents a -CS- group and/or ΚΊ represents an amino, methylamino Λ or dimethylamino group) a group, and acid addition salts thereof» Also mentioned as compounds of the invention 20 are those wherein and -ach represents a methoxy group; R3 represents a methoxy group or a hydrogen or chlorine atom; R^ represents a methoxy, amino or dimethylamino group? Rg represents a hydrogen or chlorine atom? Rg represents a methyl group? G represents a n-alkylene group with 3 to 5 OH carbon atoms or a -CH9~CH~ group or (if 0 represents a thiocarbonyl group or A represents a group of formula OH ι -CH-CO- ) a group? and either A represents a 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 I A represents a -CH-CO- group and B represents a methylene group, and acid addition salts of these compounds» The following compounds are specifically mentioned as examples of compounds of the invention? 1-(7,8-dimethoxy-l,3,4,5~tetr ahydro-2R-3benzasepin-2-on-3-yl)-3-[N-methyi-N-(3-(3?4-dimethoxyphenyl)-propyl)«amino)-propane, 1-(l-hydroxy-7,8-dimetho3ty-l,3,4? 5-tetrahydro2H-3-bensazepin-2-on-3~yl)-3-[N-methyl-N-(2-(3,4dimethoxy-phenyl)-ethyl)-amino]-propanee 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(4-amino3,5-dichloro-phenyl)-propyl)-amino]-propane, 1-(7,8-dimethoxy-l,3, 4,5-tetrahydro-2H-3benzagepin-2-on-3-yl)-3"[N-methyl-N-(2-pheny1-ethyl)amino]-propane, and 1-(7,B-dimethoxy-ly^,4,5-tetrahydro-2H-3bensazepin-2-on-3~yl) -3/lN-methyl-N^(2- (4-amino3-nitro-phenyl)-ethyl y-amino]-propane ? and acid addijzion salts of these compounds.

The compound/ of general formula I and their acid addition salts may, for example, be prepared by the following processes, which processes constitute further features of the present inventions a) reacting a compound of general formula with © compound of general formula XXX (wherein R2, ^3' 15 E end G cre as ^er-inb-£ore defined, R^1 each represents an amino or alkylamino group protected by © protecting group or they each have the meanings given for R^ and r. hereinbefore, one of the groups U and V represents an Rg-NH10 group wherein Rg is as hereinbefore defined, and the other group ϋ or V represents a nucleophilically exchangeable group such as, for example, a halogen atom or a sulphonyloxy group, eeg. a chlorine, bromine or iodine atom or a methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group), and optionally subsequently splitting off any protecting group used.

The reaction may conveniently be carried out in© solvent or mixture of solvents such as, for example, acetone, diethylether, methvlformamide, dimethylformamide, dimethylsulphoxide, benzene, chlorobenzene, tetrahydrofuran, bensene/tetr©hydrofuran or dioxan or in an excess of the compounds of general formula 11 and/or XXX used ©nd optionally in the presence of ©n acid-binding ©gent, e.g. an alkoxide such as potassium tert«butoxide, ©n alkali metal hydroxide such as sodium or potassium hydroxide, έΐη alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such ©s triethylamine or pyridine, whilst the latter may also serve as solvents at the seme time, or a reaction accelerator such as potassium iodide, and, depending on the reactivity of the nucleophilically exchangeable group, conveniently at temperatures of between 0 and 150°C, preferably at temperatures of between 50 and 120eC, e»g. at the boiling temperature of the solvent used. Howevere the reaction may also be carried out without a solvent» Xt is, however, particularly advantageous to perform the reaction in the presence of a tertiary organic base or an excess of the amine of general formula XIX used» The subsequent splitting off of a protecting group used is preferably effected hydrolytically in an aqueous solvent, e9ge in water, isopropanol/water, tefcrahydrofuran/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 hydroxide or potassium hydroxide at temperatures of between 0 and 100®C, preferably at the boiling temperature of the reaction mixture. However, a benxyl group may also be split off by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as, for example, palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures of between 0 and 50 ®C, but preferably at ambient temperature,- and under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar. b) Xn order to prepare compounds of general formula I wherein A represents a -CH-j-CH,-, -C53=CB-„ -HH-CO-, -COCO-, -CH,-CO-„ S 5 2 or group and 3 13 represents a -CH2 or -CO* groups Ί4 (XV) reacting a compound of general formula XV N—H » I B (wherein is as hereinbefore defined, Ae represents a -ΟΗ2-ΟΗ2"P -CH^CH-, -OT-COV? -COCO-, -CHo-CO~, -N-CH- or -C«N- group wherein 5 2 5 R? represents an alkyl group with 1 to 3 carbon atoms, Bg represents a -CH^- or -CO- group and RjJ represents an amino or alkylamino group protected by a protecting group or has the meanings given for Rj hereinbefore), with a compound of general formula V (wherein ^5* Ξ an<^ are as hereinbefore defined, r4* represents an amino or alkylamino group protected by a protecting group or has the meanings given for iG hereinbefore and * ft represents a nucleophilically exchangeable group such as, for example, a halogen atom or a sulphonyloxy group, Μ» a chlorine, bromine or iodine atom, or a me&haneeulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group)P and subsequently splitting off any protecting group used.

The reaction may optionally be carried out in a solvent or mixture of solvents, e.g. in acetone, dimethylformamide, acetone/dimethylformamide, diraethylsulphoxide or chlorobenzene, and conveniently, depending on the reactivity of the group 2, at temperatures of between 0 and 150eC, but preferably at the boiling temperature of the solvent usede 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 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 subsequent splitting off of a protecting group used is preferably effected hydrolytically in an aqueous solvent, e-grt in water, isopropanol/water, tetrahydrofuran/water or dioxan/water, in the presence of an acid &iuch as hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures of between 0 and 100°C, preferably at the boiling temperature of the reaction mixturge However, a benzyl group may also be split off by hydrogenolysis, with hydrogen in the presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as, for example, hydrochloric acid at temperatures of between 0 and 50®C, but preferably at ambient temperature, and under a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bar. c) In order to prepare compounds of general formula NH-Ra ι θ X wherein A does not represent a -CH-CO- or -CO-COgroups 5 reacting a compound of general formula VX (wherein Β, E, Rj and r7 are as hereinbefore defined but in the group E two hydrogen atoms in a -CH2~ or ~CHg group of the group E are replaced by an oxygen atom, and A represents a -CHj-CHj-, -CH«CH-? -NH-CO-P OH OH BOH 5 ' I H -CH--CO-, -N=CH-„ -CH-CO-j -CH-CH,-, -C-CO- or 5 5 5 5 5 ?7 -ON- group wherein K7 represents an 5 1 alkyl group with 1 to 3 carbon atoms), with an amine of general formula VII (wherein G and to Rg are as hereinbefore defined)e in the presence of a reducing agent» The reaction may conveniently be carried out in a suitable solvent or mixture of solvents such as, for example, methanol, ethanol, ethanol/ethyl acetate or dioxan at temperatures of between 0 and 100®C, but preferably at temperatures of between 20 and 80°Ce It is particularly advantageous to carry out the reductive amination in the presence of a complex metal hydride such as, for example, lithium or sodium cyanoborohydride, preferably at a pH of 5-7 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 in the presence of palladium/charcoal under a hydrogen pressure of 5 bar» Any double bonds present may be hydrogenatede d) In order to prepare compounds of general formula HN-Rfi ι a I wherein A does not represent a -CH-CO- or -CO-CO5 group: reacting a compound of general formula VIII (wherein Β, E, Rjp and Rg ©re as hereinbefore defined and A* represents a -CH2-CH2~, -CH®CH-, -NH-CO-, -CH0*CO-, 5 4 OH I -CH-COI -ON* group wherein R. 5 j represents an alkyl group with 1 to 3 carbon atoms) with a compound of general formula IX (IX) R H (wherein R3 to and G are as hereinbefore defined, but in the group G two hydrogen atoms in a or -CH^ group of the group G are replaced by an oxygen atom), in the presence of ε reducing agent.

The reaction may conveniently be carried out in a suitable solvent or mixture of solvents such as, for example, methanol, ethanol, ethanol/ethyl acetate or dioxan at temperatures of between 0 and X0OeC, but preferably at temperatures of between 20 and 0O®Ce It is particularly advantageous to carry out the reductive amination in the presence of a complex metal hydride such as lithium or sodium cyanoborohydride, preferably at a pH of 5 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 catalyst, e.g» with hydrogen in the presence of palladium/charcoal under a hydrogen pressure of 5 bax. Any double bonds present mey be hydrogenated» e) In order to prepare compounds of general formula a wherein A represents a group, B represents a methylene or carbonyl group and does not represent an alkenyl group with 3 to 5 carbon atoms: hydrogenating a compound of general formula X (wherein R^ to R*., E and G are as hereinbefore defined and B’ represents a methylene or carbonyl group)» The hydrogenation may be effected in a solvent or mixture of solvents such as, for example, methanol, ethanol, ethyl acetate or glacial acetic acid with catalytically activated hydrogen, e a g o w ith hydrogen in the presence of platinum or palladium/charcoal, under a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar, and at temperatures of between 0 and 75°C, but preferably at temperatures of between 20 and 50°Ce f) In order to prepare compounds of general formula I wherein 3 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 moietys reacting a compound of general formula XI ‘5 R.

A and S are as hereinbefore defined (wherein R1 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 methylenen-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety)P with a sulphur-introducing agent.

The reaction is carried out with a sulphurintroducing agent such as, for example, phosphorus pentasulphide or 5P4-bis-(4-methoxyphenyl)-1,3dithia-2,4-diphosphetane"2,4-disulphide, conveniently 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 ι ι I wherein A represents a -CH-CO- or -CH-CH9- group 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-nhydroxy-alkylene group with I to 4 carbon atoms in the alkylene moiety? reducing a compound of general formula XXI (XXX) (wherein Rj to R-, E and G are as hereinbefore defined)« The reaction is carried out in the presence of a suitable reducing agent such as, for example, a metal hydride, eeg. sodium borohydride, lithium aluminium hydride or diborane, in a suitable solvent such as, for example, water/methanol, methenol/ether, tetrahydrofuran, dioxan or ether/tetrahydrofuran at temperatures of between 0 and G0®C, but preferably at temperatures of between 15 and 40°C» Xn the reaction, any CO group present in the G group is also reduced to a CHOH group» h) ΐη order to prepare compounds of general formula X, wherein HN~R0 NOH 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 fo 3 carbon atoms or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moietys reacting a compound of general formula ΧΧΧϊ (wherein RS ®nd E as -^before defined ©nd Ge 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 methylenen-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety)e with a compound of general formula XXV (XIV) (wherein Rq represents a hydroxy group or has the meanings given for R0 hereinbefore), optionally with subsequent reduction.

The reaction may conveniently be effected in a solvent such as, for example,· ethanol, dioxan or glycol or in a melt at elevated temperatures, e.g. at temperatures of between 50 and 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 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 hydrasine/Raney nickel in a suitable 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 50eCe i) Xn order to prepare compounds of general formula I wherein A represents an group and R- represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atomss reacting a compound of general formula XV (XV) R .R (wherein R^ to &5, Β, Ξ and G are as hereinbefore defined and Rg9 represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms), with an orthoformic acid ester.

The reaction may preferably be carried out in a solvent such as, for example, ethanol, toluene, dimethoxyethane or in an excess of the orthoester used at temperatures of between 100 and 200°Co It may also be advantageous for any or groups present fo be protected by protecting groups, eag. acetyl, benzoyl, ethoxycarbonyl or benzyl groups, during the reaction.

Any protecting groups used during the reaction are subsequently split off, e»ge acyl groups are preferably removed hydrolytically in the presence of an acid or base whilst benzyl groups are preferably removed by hydrogenolysis, e.g. with hydrogen in the presence of a hydrogenation 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: Reducing a compound of general formula XVX (XVI) (wherein Rjl to Rg, B and E are as hereinbefore defined, Vs has the meanings given for A hereinbefore, with the exception of the -COCO- group, and represents a methylene-n-alkylene group, wherein the alkylene moiety contains 1 to 4 carbon atoms and a methylene group of the alkylene moiety is replaced by a carbonyl group).

The reduction is preferably carried out with a metal hydride such as, for example, sodium borohydride or lithium aluminium hydride, or with diborane, in a suitable solvent such as, for example, ethanol, ethanol/wster, methanol or isopropanol at temperatures of between 0 and 50°C, but preferably at temperatures of between 10 and 25°Ce k) in order to prepare compounds of general formula a wherein R^ represents a nitro group and represents an amino group: hydrolysis of a compound of general formula XVII (wherein Rx, R2r Rg» Rg, A, Β, E and G are as hereinbefore defined, and Acyl represents an acyl group such as, for example, an acetyl, ethoxycarbonyl or benzoyl group)e The acyl group used may preferably be split off by hydrolysis in an aqueous solvent, e.g* in water, isopropanol/water, tetrahydrofuran/weter or dioxan/water, in the presence of an acid such as, for example, hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide at temperatures of between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, the reaction is preferably carried out in the presence of an alcoholic acid, e.g. with methanollc or ethanolic hydrochloric acid. 1) In order to prepare compounds of general formula I wherein A represents a -CH^CH^-, -CH»CH-, -NH-CO-, ?7 -CH^-CO-, -N=CH-, -COCO- or -C=N- group and one of the groups r2, r3 or R^ represents an alkoxy, alkylamino or dialkylamino group or R- represents an alkyl or alkenyl groups reacting a compound of general formula XVIII (wherein R, to Rg, B and Ξ are as hereinbefore defined, but at least one of the groups R^ to R^ must represent © hydroxy group or R^ or must represent an amino or alkylamino group or R- must represent a hydrogen atom, A* represents © -CH^-CH^-, -CH=CH-, -NH-CO-, EU I / -CH^-CO-, -N=CH-, -COCO- or group wherein 2 5 5 represents an alkyl group with 1 to 3 carbon ©toms, ©nd Gw’ represents an n-alkylene group with 1 fo 5 carbon atoms optionally substituted by an ©Ikyl group with X to 3 carbon atoms, wherein a methylene group may be replaced by a carbonyl group), with a compound of general formula XXX R10 * X (XIX) (wherein R10 rePriSSents fin 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 iodine atom, a methanssulphonyloxy, p-toluenesulphonyloxy or methoxysulphonyloxy group or, if at least one of the groups Rx to R^ represents © hydroxy group, X together with a hydrogen atom in the α position of the group represents a diazo group or, if R- represents a hydrogen atom or Rx or represents an amino or alkylamino group, X may also represent an oxygen atom)« The reaction may conveniently be carried out in a solvent or mixture of solvents such as diethyl ether, methanol, acetone, tetrahydrofuran, dioxan, acetonitrile, pyridine or dimethylformamide, optionally in the presence of & base such as potassium carbonate, potassium hydroxide, potassium tert.butoxide or sodium hydride at temperatures of between 0 end 150°C, but preferably at temperatures of between 20 and 120eC.

If B represents a -CH^- or -CO- group end 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 p-toluenesulphonate in the presence of an acidbinding 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 c 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 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 110eC or with sodium cyanoborohydride at ambient temperature and at a pH of 6 to 7. m) In order to prepare compounds of general formula I wherein Ά represents a -COCO- group and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon Atoms wherein a «ethylene »y optionally be lieplaeedl by a (wherein to Rg, 2 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, glacial acetic acid, water/acetic acid or acetic anhydride at temperatures of between 0 and 100°C, preferably et temperatures of between 20 and 80eC. n) In order fo prepare compounds of general formula I wherein A represents a -CHo-CO- group and G represents 5 an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 fo 3 carbon atoms wherein a methylene group may optionally be replaced by β carbonyl group : oxidising a benzasepine of general formula XXI (XXI) (wherein R^ to Rg, B, S 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 is in the 7 position, A represents a "ch2ch2" 9rouP and B represents a -CO- group: cyclising a compound of general formula XXII (XXII) (wherein R, ° K5' 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).

Y may represent, for example, a carboxy or nitrile group, an ester group (such as a methoxycarbonyl, ethoxycarbonyX, n-propoxycarbonyl or bensyloxycarbonyl group), a thioester group (such as an ethylthiocarbonyl, phenylthiocarbonyl or pyridylthiocarbonyl group), an acyloxycarbonyl group (such as an acetoxycarbonyl or trifluoroacetylcarbonyl group) or an amide group (such as an aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or phenylaminocarbonyl group)» The reaction is optionally carried out in the presence of a suitable condensing agent and optionally in a pressure vessel in a solvent such as xylene, dimethyIglycol ether, tetralin or sulpholane at elevated temperatures, e»g. at temperatures 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,W·-dicyclohexylcarbodiimide, thionyl chloride, a phosphate such as diethyl chlorophosphonate or bis(o-nitrophenyl)-phenyIphosphonate, a phosporane such as (2,2,2-trifluoroethoxy)-triphenylphosphorane, an N-alkyl-pyridinium salt such as H-methyl-2-chloropyridinium iodide or H-methyl-2-fluoro-pyridinium tosylate, •-dicyclohexylcarbodiimlde/4-dimefchylaminopyridine, chlorosulphonyl isocyanate or N,W’carbonyldiimidazole.

It may also be advantageous for any HO, HH or groups present to be protected by means of protecting groups, e.g. acetyl, bensoy1, ethoxycarbonyl or benxyl groups, during the reaction.

If Y in a compound of general formula XXII represents a nitrile or amid® group, the reaction is preferably effected so that a corresponding compound is converted, by alkaline or acidic hydrolysis, e»gB by means of methanol/hydrochloric acid or ethanol/sodium hydroxide solution at the boiling temperature of the reaction mixture, into a corres31 ponding carboxy compound which is subsequently cyclised» Any protecting groups used during the reaction are subsequently split off, e.g* acyl groups are preferably removed by hydrolysis in the presence of an acid or base whilst benzyl groups are preferably removed by hydrogenolysis e.g. with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal or platinum.

The compounds of general formula I, initially obtained, may subsequently be converted info the acid addition salts thereof, for example by conventional methods such as reacting the compounds as bases with an acid in a suitable solvent» Acid addition salts of these compounds, initially obtained, may subsequently be converted info the corresponding compounds of general formula ϊ or into different acid addition salts thereof» The compounds of general formulae II to XXII used as starting materials are known from the literature in some cases or may be obtained by methods known se» Thus, for example, a starting compound of general formulae II and VIII may be obtained by reacting a corresponding benzazepine with a corresponding halogen compound and optionally subsequently reacting if with a corresponding ©mine» The benzazepine of general formula IV required for this is obtained by cyclising a corresponding compound, ®»g« by cyclising a compound of general formula ΧΧΪΙ1 or of general formula XXIV »*· / if Rj and R2not represent alkoxy groups? optionally followed by catalytic hydrogenation and/or reduction of the carbonyl group using sodium borohydride/glacial acetic acid, for example (see published European Patent Application No. 7070) and/or oxidation, e.g. with selenium dioxide.

A compound of general formula VI used as 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 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, Will, XX and XXI used as starting materials may preferably be obtained by reacting a corresponding halogen compound with a corresponding amine and subsequently splitting off any protecting groups used to protect the hydroxy groups.

A compound of general formula XXII used as starting material may be obtained, for example, by chloromethylation of a compound of general formula XXV (wherein Κχ, R2an® as hereinbefore defined ©nd W represents a protected hydroxy group, e.g. an acetoxy, benzoyloxy or 4-nitrobenzoyloxy group), further reacting it with an alkali metal cyanide, converting the group W into a suitable leaving group such as that of the chlorine, bromine or iodine atom or of the methylsulphonyloxy or 4-methylphenylsulphonyloxy group and subsequently reacting with an amine of general formula Vl'i (wherein R3 to Rg and G are as hereinbefore defined), with optional subsequent hydrolysis and/or esterification or amidation» As already mentioned hereinbefore, the new compounds of general formula X and the physiologically acceptable addition salts thereof have valuable pharmacological properties, more particularly a long-lasting heart rate lowering activity and the effect of reducing the requirement of the heart, with very few side effects, e.g. only a slight antimuscarinic effect» For example, the following compounds A « 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3bensazepin-2-on-3-yl)-3"[N-methyl-N-(3-(3,4dimethoxy-phenyl)-propyl)-amino]-propane hydrochloride, B * 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-fhion-3-yl)-N-[N-raethyl-N-(2(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane, C *' 1-(7, B-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl)-3-[N-methy1-N-(2-hydroxy2-(3,4-dimethosy-phenyl)-ethyl)-amino]-propane, D = 1-(l-hydroxy-7,8-dimethoxy-l,3,4,5-tefcrahydro2H-3-benzazepin-2-on-3-yl)-3-[N-raethyl-N~ (2-(3,4-d imethoxy-phenyl)-ethyl)-amino]-propane, E « l-(7,8"dimethoxy-l,3,4,5-tetrahydro-2H"3benzazepin-2-on-3-y1)-3-[N-methyl-N-(2-{4amino-3-nitro-phenyl)-ethyl)-amino]-propane hydrochloride, F « 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3benzasepin-2-on-3-yl)-3-[N-methyl-N-(4-(4dimethylamino-phenyl)-butyl)-amino]-propane hydrobromide, G « 1-(7,8-d imethoxy-1,3,4,5-tetrahydro-2H-3~ benxazepin-2~on-3-yl)-3-[N-methyl-N-(2-phenylethyl)-amino]-propane dihydrochloride H « 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2E-3bensasepin-2-on-3-yl)-3"[N-methyl-N-(5-(3,4dimethoxy-phenyl)-pentyl)-amino]-propane hydrochloride and ϊ « 1-(7,8-dimethoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl)-3-(N-methyl-N-(3-(4amino-3,5-dichlorophenyl)-propyl)-amino]propane have been tested by comparison with K * l"(7,8-dimethoxy-l,3,4,5-tetrahydro-5H-2benzazepin-l-on-2-yl)-3-fN-methyl-N-(2-(3,4dimethoxy-phenyl)-ethyl)-amino]-propane hydrochloride for their biological properties as follows: Effect on Heart Rate in Rats The effect of the test substances on heart rate was investigated in two rats with an average weight of 250 to 300 g for each dose. The rats were anaesthetised with pentobarbital (50 mg/kg i»p» and 20 mg/kg s.c.)» The test substances were injected in aqueous solution info the jugular vein (0.1 ml/100 g).

The blood pressure was measured using a cannula inserted in a carotid artery and the heart rate was recorded from an ECG (XXnd or XXXrd reading) obtained using needle electrodes. The heart rate of the animals in the control period was between 350 and 400 beats per minute (b/min)» The following table contains the values found: Reduction in heart rate measured minutes after administration of substance (b/rain).

Substance Dose (mg/kg) A 5.0 - 1S3 2.5 - 85 X.O ~ 51 B 5.0 - 255 2.5 - 134 1.0 - 73 C 5.0 - 173 2.5 - 137 D 5.0 - 117 2.5 - 73 1.0 - 83 E 5.0 ~ 130 F ' 5.0 - 123 2.5 - 91 1.0 - 94 G 5.0 - 135 2.5 - 110 1.0 - 80 H 5.0 - 75 X 5.0 - 175 K 5.0 - 18 The compounds prepared according to the invention do not have any toxic side effects of any kind when administered in therapeutic doses. Thus, for example, when substances A and 0 are administered intravenously to mice, even in a high dosage of 20 mg/kg, no toxic side effects can be detected.

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

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

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

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

Advantageously the compositions may be formulated as dosage units, each unit being adapted to supply a fixed dose of active ingredient, The dose required is conveniently from 0.03 to 0.4 mg/kg of body weight (preferably from 0.07 to 0.25 mg/kg of body weight) administered once or twice per day. Depending on the kind and the body weight of the patient to be treated, on the kind and the seriousness of the disease, on the type of preparation and on the route of administration as well as on the period or interval over which the administration takes place, it may however be necessary to deviate from the above dosages. Thus, it may be sufficient in some cases to administer less than the above5 mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient must be exceeded. The optimal dosage and type of administration of the active ingredients which are necessary in each case can easily be assessed by one skilled in the art.

The following non-limiting Examples are intended to illustrate the invention more fully: Preparation of the starting compounds Example A 1- (7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-bensazepin2- on-3-yl)-S-N-methyl^amino-propane-hydrochlorIde a) 1- (7,8-Pimethoxy-I,3-dihydro-2H~3_"benzazepin2-on-3-yl)-3-N-methyl-M-benzyl-amino-propane hydrochloride Prepared analogously to Example lb by reacting 1-(7,8-dimethoxy-l,3-dihydro-2H-3-benzazepin-2on-3-yl)-3-chloro-propane with N-methyl-benzylamine. Yields 92.1% of theory, Melting points 208-209°C. b) l-(7,8-Pimethoxy-l,3,4,5-tetrahydro-2H-3benzazepin-2-on-3Yl)-3-N-methyl-amino-propane hydrochloride Prepared analogously to Example 5 by catalytic hydrogenation of 1-(7,8-dimethoxy-l,3-dihydro-2H3- benzazepin-2-on-3-yl)-3-N-methyl-N-benzyl-aminopropane.

Yields 87% of theory Melting point: 110°C (decomposition).

Example B 1,3,4,5-Tetrahydro-2H-3-benzazepin-2-one a) N-(2-Phenyl-ethyl)-l-chloro-acetamide 38.7 ml (0.3 mol) of 2-phenylethylamine and 45.9 ml (0.033 mol) of triethylamine are dissolved in 30 ml of methylene chloride and mixed with 26.4 ml (0.33 mol) of chloroacetyl chloride, dissolved in 150 ml of methylene chloride, at 10eC. After 1 hour’s stirring at ambient temperature, the product is extracted with 1¾ acetic acid and with water, dried over magnesium sulphate and concentrated by evaporation in vacuo.

Yields 54*.2 g (91.4% of theory) M.p» 64-S5°C b) 1,3,4,5-Tetrahydro-2H-3-bensazepin2-one 54.0 g (0.373 mol) of '^-(2-phenyl-ethyl)l-chloroacetamlde ere mixed with 73.8 g (0.55 ml) of aluminium chloride and stirred for 13 hours 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 silica gel using methylene chloride plus 3% ethanol as eluant.

Yield: 8.22 g (14.1% of theory), Melting point: 158-160°C.

Example C 1— (7-Bromo-8-methoxy-l,3,4,5-tetrahydro-2H-3-benzazepin2- on~3yl) -3-chloro-propane a) 8-Methoxy-l,3,4,5-tetrahydro-2H-3-bengazepin2-one 56.8 g (0.3 mol) of 8-methoxy-l,3-dihydro2H-bensazepin-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 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 end neutralised with potassium carbonate. The precipitate was suction filtered, washed with water and dried.

Yields 51.1 g (89.1% of theory) Melting point: 160-l61*C b) 7-Bromo- and 9-bromo-8-methoxy-lg3P4,5-tet£ahydro2H-3-benzazepin-2-one .4 g " 2.03 ml (0.04 mol) of bromine were dropped into a solution of 7.4 g (0.04 mol) of 8-methoxy-l,3,4 e5-tetrahydro-2H-3-bensasepin-2one In 100 ml of 80% acetic acid at a temperature betwen 3® and 5®C whilst stirring. After 15 minutes. the reaction mixture was poured into ice-water and neutralized with potassium carbonate* The precipitate was suction filtered, washed with a little water and dried. The isomers were separated by means of chromatography over silica gel using ethyl acetate as eluant» Yields 5.7 g (52.8¾ of theory) of 9-bromo-isomer IR spectrum (methylene chloride)s 3,400 cm-1 (NH) 1,660 cm1 (CO) 4.1 g (38¾ of theory) of 7-bromo-isomer IR-spectrum (potassium bromide): 3,200 cm (NH) 1,665 cm1 (CO) c) 1-(7-Bromo-8-methoxy-l,3,4,5-tetrahydro-2H3-ben2azepin-2-on-3-vl) -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-benzazepin2-one in 15 ml of dimethylsulfoxide at room temperature After stirring at room temperature for 30 minutes 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 l-bromo-3-chloro-propane in 5 ml of dimethylsulfoxide» After stirring at room temperature for 2 hours, the mixture was poured into ice-water and extracted with methylene chloride four times.

The methylene chloride extracts were washed with water, dried and evaporated in vacuo. The obtained residue was purified over silica gel using ethyl acetate as eluant» fields 210 mg (12% of theory) Melting points 119-120°C Example D 7-Nitro-8-methoxy-l,3,4,5-°tetrahydro-2H-3-benzazepin35 2-one 765 mg (4 mol) of 8-methoxy-lc> 3,4,,5-tetrahydro2H-3"benzazepin-2-one were added to a mixture of 15 ml of concentrated nitric acid and of 1»5 ml of fuming nitric acid at a temperature between 3® and 5®C whilst stirring» After stirring et this temperature for further 30 minutes, the mixture was poured into ice-water end neutralised with potassium carbonate» The formed precipitate was suction filtered, washed with water and dried» The yellow crystals were purified over silica gel using ethyl acetate as eluant fo separate the corresponding 9-nitro- and 7,9-dinitro-isomers* Yields 400 mg (42.3% of theory) Melting points 204-205®C (decomp*) Preparation of the end products^ Example 1 1-(7,8-Dimethoxy-l ,3,4,5-tetrahydro-2H~3~benasagepin2^on-3yl)-3-(N-methyl-N-(3- (3,4-disaethoxv-phenyl) propyl)-amino]-propane hydrochloride a) 1- (7, 8-Pimethoxy-l, 3,4,5-tetr£ahydro-2H~3~ benzazepin-2-on-3-yl)-3-chloro-propane 1*1 g (0.005 mol) of 7,8~dimethoxy~I£.3,4tr5~ tetrahydro-2H-3-benzasepin-2-one are suspended in 15 ml of absolute dimethylsulphoxide and mixed with 0.67 g (0.006 mol) of potassium tert.butoxide with stirring. After 10 minutes, the suspension obtained is added dropwise fo 0«$4 ml (0.006 mol) of I-bromo-3-chloro-propane in 10 ml of dimethylsulphoxide, whilst cooling with ice water. After 1 hour the mixture is poured on fo waterθ After a short time the viscous precipitate begins to crystallise» The precipitate is suction filtered, dissolved in acetone, precipitated again with water, then suction filtered and dried.

Yield: 0»75 g (50.0% of theory) Melting points 84-85°C» b) 1-(7,8-Dimethoay-l,3,4 ,5-tetrahydro-2H~3~ benzazepin-2-on-3-vl)-3-[N-methvl-N-(3-(3,4dimethoxy-phenvl)-propyl)-amino]-propane hydrochloride .55 g (0.0106 mol) of l-(7,8~dimethoxy~l,3,4,5~ tetrahydro-2K*’3-benzazepin-2-on-3-yl)-3-chloropropane, 2.6 ml (0.0886 mol) of triethylamine and 3.9 g (0.0186 mol) of N-methyl-3-(3P4-dimethoxyphenyl)-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 obtained is purified over silica gel using methylene chloride plus 3% ethanol as eluant. The oily residue obtained Is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid» Yields 3.45 g (35.5¾ of theory).

Melting points 220«22IaC„ example 2 1- (7 ? S-Simethoay-1P 3,4,5r*tetrahvdro-2H-3-bensasepin2- on-yl)-3-[N-roefchyl-N-(2-pheny1-ethyl)-amino)~ propane .dihydrochlor ide Prepared analogously to Example lb by reacting 1(7 e8-dimethoxy-lp 3,4,5-tetrahydro-2H-3-benzasepin2- on-3-vl)-3-chloro-propane with N~raethyl-2-phenylethylamine* Yields 43»2% of theory, Melting points 155®C decomposition» Example 3 1-(1,3,4, 5-Tetrahydro-2H-3~benaa2epin-2~on-3-yl) 3- f'N-methy 1-^-(2-(3,, 4-dimethoxy-phenyl)-ethyl)20 amino)-propane hydrochloride a) 1- (1 p 3 P 4,5^-Tetr ahydro-2H-3-benzag®pin-2-on3-yl)-3-chloro-propane Prepared analogously to Example la by reacting 1,3ti4(?5-tefrahydro*=2H-3-bensagepin-2-on with X~ bromo-3-chloro«propane» Yields 13.4% of theory IR Spectrum (methylene chloride)s 1550 cm ~ (CO). b) 1- (1 g 3,4,5~Tetrahydro-2H~3~b®nssagepin-2-on 3-yl)-3-[N-methyl-N-(2-(3 34-cHmethoxy-phenyl)30 ethyl)-amino]-propane hydrochloride Prepared analogously to Example lb by reacting 1^(1,3,4,5-tetrchydro-2H-3-ben2azepin-2‘-on-3-yl)3-chloro-propane with N-»ethyl~B~(2-(3P4-diaefhoxyphenyl)-ethyl)-amine.

Yields 29.2% of theory.

Melting points 150-162°C.

Example 4 l^(7P8-Dimethoxy-lg3-dihydro-2H-3-ben£asePin-2on-3-yl)-3- [W-methyl-N- (5-(3,4-dimethoxy-phenyl) pentyl)-amino]-propane hydrochlor ide 5 a) 1-(7,8-Pimethoxylc 3-dihydro-2H-3-benzazepin2-on-3-yl)-3-chloro-Pfopane Prepared analogously to Example la by reacting 7?8-dimethoxy-l,3-dihvdro-2H-3-ben2asepin-2-one with !~bromo"3-chloro-propaneB Yields 87.3¾ of theory, Melting point? 101-103eC. b) 1- (7 g 8-Pimethoxy-le3-d ihydro-2H-bensagepin2-on-3°yl) -3- [N-methyl-N-(5-(3,4-dimethoxyphenyl)-pentyl)-amino]-propane hydrochlor ide 15 Prepared analogously to Example lb by reacting 1-(7,8-dimethoxy-l,3-dihydro-2H-3-bens&2epin-2on-3-yl)-3-chloro-propane with N-methy1-N-(5-(3,4dimethoxy-phenyl)-pentyl)-amine.

Yields 67.3¾ of theory, Melting points 158-160°C.

Example 5 1- (7 g 8-Pimethoxy-l,3,4,5-tetrahydro-2H-3-bensazepin2- on-3-yl)-3-[N-methyl-N-(5-(3e 4-dimethoxy-phenyl)25 pentyl)-amino]-propane hydrochloride. 3.23 g (0.0065 mol) of 1-(7,8-dimethoxy-l,3dihydro"2H-3-benga2epin-2"on«3-’yl)-3-[N-methy1N-(5-(3,4-dimethoxy-phenyl)-pentyl)-amino)-propane, dissolved in 30 ml of acetic acid? are hydrogenated at ambient temperature under a hydrogen pressure of 5 bar in the presence of 10% palladium/charcoal for 3Θ5 hours* The catalyst is filtered off, the filtrate is concentrated by evaporation in vacuo and the residue is taken up in methylene chloride/15% potassium carbonate solution* The organic phase is separated off, dried over magnesium sulphate and rotated in vacuo and the residue obtained is purified over silica gel using methylene chloride plus 4¾ ethanol as eluant, The residue obtained is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yields 2.1 g (50.3% of theory), Melting points 155-155®C Example S 1« (7 »8-Dimethoxv-l,3,4, 5-tetrahydro-2H-3-benzazepin« 2thion-3-yl)-3-rN-methyl-N-(2-(3,4-dimethoxy-phenyl)ethyl)-amino)-propane 2.28 g (0.005 mol) of l-(7P8-Diraethoxy~XP3,4,5tetrahydro-2H-3«bensasepin"2-on"3-yl)-3-SN-methylN-(2-(3 e4~d imethoxy-pheny1)-ethyl)-amino]«propane are dissolved in 10 ml of absolute toluene and refluxed for 50 minutes with 1.0 g (0.0025 mol) of 2,4-bis-(&=methoxy«pheny1)-1,3-dithi&"2,4«diphosphetane 2,4-disulphide. After the solvent has been rotated in vacuo0 the residue obtained is purified over aluminium oxide with methylene chloride plus 2% ethanol as eluant.

Yields X.45 g (51e4% of theory) ^26H3S^2°4® (472.5) Calcs C 56.07 H 7.68 N 5.93 S 5.78 Founds 55.10 7.71 5.55 5.75 Example 7 1- (7,8-Dimethoxy^l,3,4,5-tetrahydro-2H-3-bensagepin2- on-3-yl)-3-[N-methyl-N-(3,4-dimethoxy-benzoyl-methyl)amino]-propane hydrochloride Prepared analogously to Example lb by reacting 1-(7,8-d imethoxy^l,3,4,5™tetrahydro~2H-3~ bensazepin-2-on-3-vl)-3-N-methyl-amino-propane with c-bromo-3 P4-dimethoxy-acetophenone.

Yields 1.29 g (77,0% of theory), Melting points 190®C Bxample_8 1- (718-Pimethoxy-l,3,4,5-tetrahydro~2H3-bengagePin2- on3-yl)-3-[N-m®thyl-M-(2-hydrpxy-2-(3i74-dlmethoxypheny1)~e thy1)°aaino] -pr opane 0.92 g (0.002 mol) of 1-(7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazepin-2-on-3-yl)-3*· [K-methyl(3,4~dimethoxy-benzoyl"fflefchyl)-amino]-propane are dissolved in 6 ml of ethanol, mixed with 0.38 9 (0.01 mol) of sodium borohydride and stirred for 2 hours at 25°Ce After the solvent has been evaporated in vacuo, the mixture is dissolved In methylene chloride, extracted with water, dried over magnesium sulphate and concentrated by evaporation in vacuo and the residue obtained is purified over aluminium oxide using methylene chloride plus 1¾ ethanol as eluant.

Yields 0.5 g (54¾ of theory), _Ί IR spectrum (methylene chloride); 1855 cm (CO) C26H36M2°6 (*72-6> Calcs C 66.08 H 7.68 N 5.93 Found; 66.01 7.62 5.80 Example 9 l-[7g8-Pimethoxy-l-(2-(3,4-dimethoxy-phenyl)-ethyl^ amino)-lp3g4,5-tetrahydrO2H-3*bensa£epin-2-on-3* yl]-3-IN-methyl-W-(2-(3,4°dimethoxy-phenyl)-ethyl)amino]-propane dihydrochloride 2.45 g (5 mmol) of X-(7,8-dimethoxy-l,3,4p5t The fractions are concentrated by evaporation, the residue obtained is dissolved in 100 ml of methanol and hydrogenated for 6 hours at 50®C under a hydrogen pressure of 5 bar in the presence of 0.5 g of 10¾ palladium/charcoal. After the uptake of hydrogen has ended the catalyst is removed by suction filtering, the filtrate is concentrated by evaporation and the residue is purified over silica gel using methylene chloride and 5% ethanol as eluant. The residue obtained is dissolved in acetone and the dihydrochloride is precipitated with ethereal hydrochloric acid.

Yields 0.6 g (53.5% of theory), Melting points 222-224®C (decomposition).

Example 10 l-(l"Hydroxy-7,8-dimethoay-lg3,4,5-tetgahydro-2H3-bensagepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane 2.35 g (5 mmol) of 1-(7,8-dimethoxy-l,3,4p5tetr&hydro-2H-3-ben£asepin-l,2"dion-3-yl)-3-iN"methyX" N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane are dissolved in 100 ml of methanol and 5 ml of watere then 0.2 g of sodium borohydride are added in batches thereto, with stirring. After it has all been added, the mixture is stirred for a further 15 minutes, mixed with 10 ml of 2N hydrochloric acid, made alkaline with methanolic ammonia decolorised with fullerqs earth and then filtered and concentrated by evaporation in vacuo. The residue is dissolved in methylene chloride, any undissolved salts are filtered off and the filtrate is concentrated by evaporation.

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

-I IR spectrum (methylene chloride)$ 3400 cm * (OH) CoJa-^oO, 263626 Calcs Founds (472.59) C 66.08 H 7.68 N 5.93 Example 11 1— (7,_8_-Dimefchoay-lg3-dihydro~2H-3,5-benzodiagepln3-yl)-3-FN-methyl-N-(2"(3,4dimethoxy-phenyl) -ethyl) amino]-propane dihydrochloride 4.3 g (10 mmol) of N-[2-(2-amino~4,5-dimethosypheny1)-ethy1)-N8-methyl-N1- (2-(3,4-dimethoxy-pheny1)ethyl)-1,3-diaminopropane are refluxed for 18 hours in 30 ml of triethyl orthoformate, then concentrated by evaporation in vacuo and the residue is purified over silica gel with saethylene 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.

Yields 1.6 g (31.1% of theory), Melting point? 232-234°C.

Example 12 1°(7,8-Dimethoxy-l£3,4 e5-tetrahydro-2H-3-benzazepin~ 2- on-3°vl)-3-fW-methyl-N-(2- (4~amino-3-nltro-phenyl) ethyl)-amino]-propane hydrochlor ide 1.0 g (1«75 mmol) of 1-(7P8-Dimethoxy-1?3,4,5tetrahydro~2H-3-benzazepin-2"on~3-yl)-3-[N-methylN- (2- (4-acetamino-3"*nitro-phenyl) -ethyl) -amino] -propane is heated in 50 ml of methanolic hydrochloric acid for two hours to 45 to 50®Ca The reaction solution is concentrated by evaporation? dissolved in methylene chloride, washed with saturated sodium hydrogen carbonate solution and dried over magnesium sulphate and the solvent is distilled off in vacuo. After the residue has been purified over silica gel with methylene chloride and 5% ethanol as eluent, the hydrochloride is precipitated from acetone by the addition of ethereal hydrochloric acid.

Yields 0.4 g (43.1% of theory) Heltlng points 207-208*C (decomposition) Example 13 1- (l-Oxiininp-7p8-dlmethoKy«_l ,3P 4 ? 5-tetfahydro-2H3-benzgigepin-2-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxyphenvI) ~ethvl)-amino) -propane hydrochlor id® 3.6 g (6.8 mmol) of l-(7,8-dimethoxy-I,3,4,5tetrahydro-2H-3«benzasepin-lP 2-dIon-3-y1)-3-[N-methylN- (2-(3,4-6imethoxy-phenyl)-ethyl)-amino]-propane, 0.57 g of hydroxylamine hydrochloride end 0.87 g of sodium carbonate ©re refluxed for eight hours in 100 ml of ethanol. The solvent is distilled off in vacuo, the residue is dissolved in water/methylene chloride and the organic phase is separated off, dried over magnesium sulphate ©nd concentrated by evaporation. The residue is purified over silica gel using methylene chloride and 5% ethanol as eluent» The residue obtained is dissolved in acetone and the hydrochloride is precipitated by the addition of ethereal hydrochloric acid.

Yields 2.4 g (67.6% of theory) Melting points 156~158°C Example 14 1-(1-Amino-7, 3-dimethoxy-1,3,4,5-tetr©hydro~2H-3° bensazepin-2-on-3«y 1)-3- [N-methy 1-N- (2^ (3p4-dimethoxy25 phenyl)-ethyl)-amino]-propane dihydrochloride 1.6 g (3.3 mmol) of l-(l~oximino*7,8~diraethoxy1,3,4,5-tetrahydro-2H-3~benzasepin~2-on-3-yI) -3- (methyl¢3-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino]«propane are added to 150 ml of ethanol ©nd mixed with 1.5 ml of 98% hydrazine hydrate and 1 g of Raney nickel and the mixture is refluxed for seven hours. Xn order to complete the reaction, a further 1.5 ml of 98% hydrazine hydrate and 1 g of Raney nickel are added and the mixture is refluxed for a further three hours. The catalyst is removed by suction filtering, the solvent is distilled off in vacuo and the residue is purified over silica gel with methylene chloride and 10% methanol. The dlhydrochlorlde Is precipitated from an acetone solution by the addition of ethereal hydrochloric acid* Yields 0*8 g (44.5% of theory) Melting Points 232-234®C, m/e * 471.

Example 15 1- (7,8-Pimethoxy-l.3,4,S-tetrahydro^SH-S-bengazepin2- on-3-yl)-3-(N-methyl-N-(3-(4°dimethylamino-phenyl)propyl)-amino]-propane dihydrochloride .7 g (19.4 mmol) of l-(7,8-dimethoxy1,3,4,5-tetrahydro-2H~3~benzasepin-2-on-3-yl)-3-^methyl-amino-propane and 4.7 g (19.4 mmol) of 3-(4dimethylamino-phenyl)-propyl bromide are heated to 130°C for Xj hours after the addition of 3.3 ml of ethyldiisopropylamine» The reaction mixture is dissolved in chloroform and 25% sodium hydroxide solution, the organic phase is separated off, washed with water, dried over magnesium sulphate and concentrated by evaporation. After the residue obtained has been purified over silica gel with methylene chloride and 5% methanol as eluent, the dihydrochloride is precipitated from acetone with ethereal hydrochloric acid» Yield: 0.6 g (5.9% of theory) Melting point: 191-192®C (decomposition) Example 16 1- (7,8-Dimethoxy-l,3,4,5-tetrahydro2H-3-ben2azepin2- on-3-yl)-3-[N-methyl-N-(4-dimethylamino-phenyl) butyl) -amino) -propane-hydrobromide Prepared analogously to Example 15 from 1-(7,8dimethoxy- 1 >3,4,5-tetrahydro-2H-3-benzazepin2-on-3-yl)-3-N-methyl-amino-propane and 4-(4-diraethyl&minophenyl)-butyl bromide.

Yields 10.3% of theory Melting points 118~118°C.

Example 17 1- (l-rjydroxy^gS-dimgthoxy-?, 3P4 g5~tetrahydro-XH3-bensagepin-3-vl)~3-[N^roethyl-N- (2- (3t^4-dimethoxyphenyl)-ethyl)-amino]-propane dihydrochloyide 2.45 g (5 mmol) of l-(7,8-dimethoxy-i,3,4,5·5 tetrehydro-2H~3~benasasepin-l, 2-dion-3-yl) 3- [N-methylN-(2-(3, 4-dimethoxy-phenyl)-ethyl)-amino)-propane are dissolved in a mixture of 100 ml of ether and 50 ml of tetrahydrofuran and then 0.76 g of lithium aluminium hydride are added in batches, with stirring* The resulting mixture io refluxed for one hour? cooled with ice wafer 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 dissolved in acetone, the dihydrochloride is precipitated with methanolic hydrochloric acid.

Yields 2.2 g (82.7% of theory) Melting points 210-212°C.

Example 18 1- (7e8-Dimethoxy-lg3g4,5~tetrahydro-2H-3-bengazepin2- on-3-yl)-3- [N-methy1-N-(4- (4-amino-3, S-dibrOiao·^ phenyl)-amino]-propane hydrobromide Ϊ.1 g (3«6 mmol) of X~(7CI8-dimethosy25 1,3,4,5-tetrahydro-2H-3-ben;sasepin-2-on-3-yl)-3-Nmethyl-amino-propane and 1.4 g (3.5 mmol) of 4-(4araino-3,5-dibromo-phenyl)-butyl bromide are heated to 130°C for two hours in 3 ml of ethyl-dilsopropylamine» Then the excess amine is distilled off in vacuo and the residue obtained is purified over silica gel using methylene chloride &nd 2% ethanol &s eluant.

The fractions are combined In vacuo, the residue Is triturated with acetone and the precipitate formed is suction filtered.

Yields 0.5 g (27.9% of theory) Melting points 159-1510C Example 19 l^(7y3^oiffiethoay-l,3,4g5-tetrahydro-2H-3^benzazepin2-on-3-yl) -3- (N-methvl-N- (3-(3,4-dirnethoxy-phenyl) 2*6 g (5 mmol) of the sodium salt of [3-fNθmethyl-N1- (3-(3,4-dimethoxyphenyl)-propy1)-amino]propyl]-2-(2-carboxymethyl-4 P5-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 chloride. The organic extracts are washed twice with water, dried over magnesium sulphate and the solvent is concentrated by evaporation in vacuo.

The residue is dissolved In acetone and the hydrochloride Is precipitated by the addition of methanollc hydrochloric acid.

Yields 1.8 g (71% of theory) Melting points 220-221°C Example 20 1-(7 e8-Pimethoxy-l,3,4,5-tetrahydro-2H-3-benzazepinl,2-dion-3-yl-3-[N-methyl-w-(3-(3,4-dimethoxy-phenyl)propyl)-amino]-propane hydrochloride 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 water. After 15 minutes, 1.4 g of *Ce1ite and 6.9 g (0.0147 g) of l-(7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-bensasepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4dimethoxy-phenyl)-propyl)-amino]-propane are added and the resulting mixture is refluxed for 40 hours.

After cooling, the undissolved constituents are removed by suction filtering, the filtrate is rotated and the residue obtained is purified over silica gel with methylene chloride 4 4% ethanol as eluent.

The product is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acids, Yields 2.35 g (29.2% of theory) Melting points 189-192eC *Celite is a Trade Mark Example 21 1- (7£8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-bensasepin2- on-3-yl)-3-[N-methyl-N-(2-(4-amlnp-3ff5-dichlorophenyl)^2-hydroxy-ethyl)-amino]-propane Prepared from 1-(7,8-dimethoxy~Ii?3p4p5-tetr£ihyd£02H-3-bensasepIn-2-on-3-yl) -3- [N-methy 1-N- (4-amino3.5- dichloro-bengoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 3» Yield: 71.6% of theory Melting points 122-126ttC IR Spectrum (methylene chloride)s 3400 cm" 3<195 cra~l (KH,) 1550 csa-1 (CO) UV Spectrum (ethanol)s 240 nm (0.14) 290 nm (0.05) 314 nm (shoulder? 0.02) Example 22 1— (7 g8-Pj.methoxy-lp3?4? 5-tetr Bhydro-5H-3-benzazepin20 2-on-3-yl)-3-(N-methy1-N-(2-(2-amino-3g5-dichlorophenyl) ~2-hydroxy~ef_hyl) -amino]-propane Prepared from 1-(7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-on-3-yI)-3-[N-methyl-N-(2-smino3.5- dichlorO"bensoylmethyl)-amino]-prop&ne and sodium borohydride analogously to Example 8.

Yields 45% of theory, resin XR Spectrum (methylene chloride): 3360 cm , 3450 CM-1 (KH,) -Ί * 1550 cm Λ (Itsctam-CO) UV Spectrum (ethanol): 240 nm (0.13) 280-290 nm (0.045) 310 nm (shoulder? 0.03) Example 23 1-(7 ? 8-Dimethoxy-l,3,4? 5-tetgahydro-2H-3-bengagepin2- on=3-yl)-3° [N-mefchyl-W-(2- (3-aminp-4-chlor,o-phenyl) 2-hydroxy-ethyl)-amino]-propane Prepared from 1-(7,8-dimethoxy-l,3,4,5-tetrnhydro55 2H-3-bensazepin-2-on-3-yl)-3-[N-mefchyl-N-(3-amino4-chlofo~benzoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 8» Yield: 55% of theory, resin.

UV Spectrum (ethanol)s 1650 cm (lactam-CO) 236 nm (0.13) 282-292 nm (0.055) 310 nm (shoulder; 0.02) Example 24 1- (7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3-bensazepin2- on-3-vl)-3-[N-methyl-N-(2-(4-amino-3~chloro-5-fluorophenyl)-2-hydroxy-ethyl)-amino]-propane Prepared from 1-(7,8-dimethoxy-l,3,4,5-tetrahydro2H-3-benzazepin-2-on-3-yl)-3-[M-methyl-N-(4-amino3- chloro-5-fluoro-benzoyl-methyl)-amino]-propane and sodium borohydride analogously to Example 8.

Yield: 48% of theory, foam.

IR Spectrum (methylene chloride) 3390 ca\ 3480 UV Spectrum (ethanol) 1645 cm (lactam-CO) 238 nm (0.18) 282-292 nm (0.07) Example 25 1- (7,3-Dimethoxy-l,3,4,5-tefcrahydro-2H-3-benzazepin2- on-3-yl)-3-(N-methyl-M-(2-(4-amino-3-chloro-5-methylphenvl)-2-hydroxy-ethyl)-amino]^propane Prepared from 1-(7,8-dimethoxy-l,3,4,5-tetrahydro2K-3-bensazepin-2"On-3-yl)-3-(ft«methylefcl~(4-amino3~chloro-5-methyl-bensoyl-raethyl)-amino]-propane and sodium borohydride analogously to Example 8» Yield: 25% of theory, foam.

IR Spectrum (methylene chloride) 3380 cm , 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-Ig3,4,5-tetrahydro-2H-3-benzazepin-2on-3-yl)-3-[E-methyl-N-(3-(3,4-dimethoxy-phenyl)propyl)-amino]-propane hydrochlor ids, Melting point X72-I7S®C, X-(7-Methoxy-l,3 e4,5-tetrahydro-2H-3-bensasepin"2" on-3-yl)-3-[M-methylH&-{3-(4-amino-3,5-dichlorO"phenyl)propyl)-amino]-propane, 1- (7-Tr ifluoromethyl-1,3,4,5-tetrahydro-2H-3-bensa2epin2- on-3-yl)*3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)15 ethyl)-amino]-propane, 1- (7-Tr ifluoromethyl-1,3,4,5-tetrahydro-2H-3-benzEsepin2- on-3-yl)-3-[W-methyl-ft-(3-(3,4-dimethoxv-pheny1)propyl)-amino]-propane, 1-(7-Trifluoromethyl-1,3,4,5-tetrahydro-2H-3-bensazepin20 2-on-3-yl)-3-IW-methyl-^-(3-(4~amino-3,5-dichlorophenyl)-propyl)-amino]-propane, 1- (7-Methylamlno-XP3,4,5-tetrahydro-2H-3-bensazepin2- on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)ethyl)-amino]-propane 1-(7-MethylamIno-l,3,4,5-tetrahydro~2S-3-b®ngagepin2-on-3-vl)-3-[N-methyl-H-(3-(3,4-dimethoxy-phenyl)propyl)-amino]-propane - (7-Methylamino-X,3,4,5-tetrehydro-2H-3-bensa2epin2-on~3-yl)-3-[N-methy1-N- (3-(4-aminO"3P5"dichlorophenyl)-propyl)-amino]-propane , 1- (7-Diraethylamino-l,3,4,5-tetrahydro-2B~3bengazepin2- on-3-yl)-3-[N-»ethyl-S-(2-(3 3~dImethoxy-phenyX)ethyl)-amino]-propane? IR spectrum (methylene chloride): 1660 cnT1 2 (CO), 1- (7-Dimethylamino-l,3,4,5-tetrahydro~2H-3~benzasepin2- on-3-vl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)propyl)-amino]-propane 1- (7-Dimethylamino-l,3,4,5-fetrahydro-2H-3-benzazepin2- on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-dichlorophenyl)-propyl)-amino]-propane, 1- (7,8-Dichloro-l,3,4,5-tetrahydro-2H-3-benz&zepin2- 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-benzasepin2- on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)propyl)-amino]-propane, 1- (7,8-Dichloro-l,3,4,5"tetrahydro-2H-3-benzazepin~ 2- on-3-vl) -3-[N-methyl-N- (3- (4-amino-3,5-dichlorophenyl)-propyl)-amino]-propane, 1- (7,8-Dimethoxy-l,3,4,5-tefrahydro-2H-3-bensasepin2- on-3-yl)-3-[N-methyl-N-(2-hydroxy-3-(3,4-dimethoxyphenyl)-propyl)-amino]-propane Oil? ^-27^38^2θ5 (^86.6) Calcs C 66.64 S3 7.87 N 5.76 Founds 66.61 7.95 5.74 1- (7,8-Dimetho:ty-l,3,4,5-tetrahydro-2H-3-bensasepin2- on-3~yl)-3-(N~methyl~(2-hydroxy-3(4~amino~3,5~ dichloro-phenyl)-propyl)-amino)-propone. 1- (7,8-Dimethoxy-X,3,4,5-tetrahydro-2H-3-bensasepin5 2-on-3-yl)-3-[N-methyl-H-(3-hydroxy~3-(4-amino-3,S~ dichloro-phenyl)-propyl)-amino]-propane, l"(7,8-Oimethoxy-l,3,4,5*tefcrahydro-2H-3-ben2azepin2- on-3-yl) -3- [M-methyl-'$- (3-hydroxy-3- (3,4-dimethoxyphenyl)-propyl)«amino]-propane, 1-(7,8-Dimetboxy-X,3,4,5-tetrohydro-2H-3-benzasepin2- on-3=yl)-3-[H-methyl-H-(3-(4-amino-3,5-dichloro* phenyl)-propyl)-amino]-propane, Melting point; 92-93°C 1-(l-Hydroxy-7,8-d imethoxy-1,3,4,5-tetrahydro~2H15 3-bensasepin-2-on"3-yl)-3-[N-methyl-H-(3-(3,4-dimethoxy phenyl)-propyl)-amino]-propane, 1-(7-DimethylfiminO"8"me£hoxy-I,33,5-tetrahydro-2H3- benzasepin-2"On-3«yl)-3*(W-methyl-^-(3-(3,4-dimethoxy phenyl)-propyl)-amino)-propane, I-(7-Dimethylamino-8-methoxy-X,3,4,5-tetrahydro-2H" 3-benzasepin-2~on-3-yl) -3- [W-methyl-'$- (2- (3,4-dImethoxy phenyl)-ethyl)-amino]-propane IR spectrum (methylene chloride)s 1650 cm"^ (CO), 1-(7-Bromo-8-methoxy-I,3,4,5-tetrahydro«2H-'3-bensagepin 2-on-3-yl)~3- [£Maethyl-'$- (3- (3,4^dlmethoxy-phenyl) propyl)-amino]«propane hydrochloride, Melting points I98-X99°C (decomp.) 1- (7^Broao-8-iaethoxy-l, 3,4,5-tetr ahydro-lH-B-benwzepin 2- on-3-yl) -3~ I^-methyl-H- (2- (33-disaethoxy-phenyl) 30 ethyl)-amino]-propane NMR spectrum (CDC13): 7*2 ppm (1HP s, aromat.), 6.6 ppm (IH, s, ©romat.), 2.3 ppm (3H, s, N-CH^)» 1-(7-Chloro"8-metboxy-X,3,4,5-tetrahydro-2H"3-benzazepin 5 2-on-3~yl)-3-[N-methyl-W-(2-(3,4-dimethoxy-phenyl)propyl)-amino]-propane, 1— (7-ChIoro-8-methoxy-l,3,4,5-tetrahydro~2H-3"benzazepin 2- on-3~yl)-3-(N-methyl-N-(2-(3,4-dimethoxy-phenyl)ethyD^mino]-propane, 1-(7,8-Dimethoxy-l,3,4,5-*tetr&hydro-2H-3-bensazepin2-on-3-yl)-3-[W-(3-(3,4-dimethoxy-phenyl)-propyl)amino]-propane, IR spectrum (methylene chloride)s 1645 cm1 2 (CO) Melting point of the hydrochlorides 158-159°C, 1-(7,8-Dimethoxy-l,3,4,5"tetrahydro-2H-3-benzazepin2-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«benzzepin2- on-3-yX)-3-[N-(2-hydroxy-3-(3,4-dimethoxy-phenyl)20 propyl)-amino]-propane.

Example I Tablets containing 10 mg of l^(7g8-dimetho«y-lt3g4_f5tetrfjhydro-2H-3-ben2agepln-2-on-3-yl)-3-fN-roefchylN-(3-(3,4-dimefchoxy-phenyl)-propyl)-amino]-propane hydrochloride Compositions: Tablet contains: Active substance 10.0 mg Corn starch 57.0 mg Lactose 48.0 mg Polyvinylpyrrolidone 4.0 mg Magnesium stearate 1.0 mg fr- o e o mg Method The active substance, corn starch, lactose and polyvinylpyrrolidone ©re mixed together and moistened with water. The moist mixture is forced through a screen with a mesh size of 1.5 mm and then dried at about 45®C. The dry granulate Is passed through e LO biri mesh screen and mixed with magnesium stearate. The finished mixture is compressed in a tablet press with punches measuring 7 mm in diameter having a dividing slot, to form tablets.

Weight of tablets 120 mg Example Χϊ Coated tablets containing 5 mg of I-(7g8-dlmethoxy1,3,4,5-tetrahydro-2H~3-benzazepln~2-on~3~yl) methyl-N-(3-(3,4-dimethoay-phenyl)-propyl)-amino]propane hydrochloride Tablet core contains: Active substance 5.0 mg Corn starch 41.5 mg Lactose 30.0 mg Polyvinylpyrrolidone 3-0 sag Magnesium stearate 0.5 mg 80.0 mg Method The active substance, corn starch, lactose and polyvinylpyrrolidone are thoroughly mixed and moistened with water. The moist mass is forced through a screen with a mesh size of 1 mm, dried at about 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 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 Example ill Ampoules containing 5 mg of l-(7,8-dimethoxy-l,3,4,5tetrahydro-2H-3-benzazgpin-2~on-3-yl)-3-fN°methylN-(3-(3,4-diniethoxY-phenyl) -propyl) -amino] -propane hydrochloride Ampoule contains: Active substance 5.0 mg Sorbitol 50.0 mg Water for injection ad 2.0 ml Method In a suitable mixing vessel the active substance is dissolved in water for injections and the solution is made isotonic with sorbitol.

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

Example IV Suppositories containing 15 mq of 1-(7y8-dimethpxy1g 3 * 4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[Nmethy1-N-(3- (3;/4-dimethoxy-phenyl) -propyl)-amino]propane hydrochloride Suppository contains: Active 0.015 g Hard fat (e.g *Witepsol H 19 S. W 45) 1.685 g 1.700 g Method: The hard fat is melted. Xt 38°C the ground active substance is homogeneously dispersed in the melt. Xt is cooled to 35eC and poured into slightly chilled suppository moulds.

Example V Drops solution containing 10 mg of l-(7g8-dimethoxv1? 3 ? 4 p5-tetrahydro-2H-3-benzazepln-2-on-yl)-3-fNme thyl-N- (3- (3 y 4-d imethoiey-phenyl) -propyl) -amino]propane hydrochloride per 5 ml 100 ml of solution contain: Active substance 0.2 9 Hydroxyethyl cellulose 0.15 9 Tartaric acid 0.1 9 Sorbitol solution {70% dry content) 30.0 9 Glycerol 10.0 9 Benzoic acid 0.15 ι Distilled water ad 100 ml Method: Distilled water is heated to 70ftC. The hydroxyethyl cellulose, benzoic acid and tartaric acid are dissolved therein with stirring. The soXution is cooled to ambient temperature and the glycerol and sorbitol solution are added with stirring. At ambient temperature the active substance is 40 added and stirred until completely dissolved. Then the liquid is evacuated with stirring, to eliminate any air.

*Witepsol is a Trade Mark

Claims (77)

1. L Compounds of general formula I R. (X) (h [wherein r x represents a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, an alkoxy group with 1 to 3 carbon atoms or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and R 2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 fo 3 carbon atoms, or Η χ and R 2 together represent an alkylenedioxy group with 1 or 2 carbon atoms? r 3 represents a hydrogen, fluorine, chlorine or bromine atom, a nitro or trifluoromethyl group or an alkyl or alkoxy group each having 1 to 3 carbon atoms and R 4 represents a hydrogen atom, an amino group or an alkoxy, alkylamino or dialkylamino group (each alkyl moiety having 1 to 3 carbon atoms and the alkyl moieties in the dialkylamino group being the same or different), or R 3 and together represent an alkylenedioxy group with 1 or 2 carbon atoms? Rg 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 3 to 5 carbon atoms? E represents an n-alkylene group with 2 to 4 carbon atoms optionally substituted by an alkyl group with X to 3 carbon atoms? 3 represents a thiocarbonyl, carbonyl or 5 methylene group? G represents an n-alkylene group with X 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 -CH 2 ~CH 2 -, R 7 -CH«Ca~ p -NH-CO- „ -CH 9 -C0-, -C»‘N-, -n»ce~ p 5 5 5 5 OH -CHCO-, OH -ch-ch 2 - p NOH II -C-CO-, NHR I C—CO— or -CO-CO- (wherein R? 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 (1) when A represents a group of formula -CHj-CHj-,, -CH=CH- P -BH-CO-,-CH 2 -CO- p os: ~έ = Ν — (wherein a? is am hereinbefore defined) 3 may not represent a methylene or carbonyl group unless G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon toms, an n-alkylene group with 1 to 5 cabon atoms optionally substituted by an alkyl group with X to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety, the methylene group being attached fo the nitrogen atom fo the left of the group G, and/or » χ and R 2 each represents a hydrogen atom or R x represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms (which alkyl groups may, in the case of disubstitution, be the same or different) and r 2 represents a hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms (except in the case of A representing a ~CH 2 CH 2 -group, Β χ and R 2 representing methoxy groups in the and 8- positions, E representing an npropylene group, Rg representing a methyl group, G representing an ethylene group, R 5 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 represent a carbonyl group)? (ii) when A represents a -CO-CO- group, B represents a methylene group and G represents an n-alkylene group with 3 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms, an n-alkylene group with 1 to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms wherein a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety„ the methylene group being attached to the nitrogen atom to the left of the group G, and/or Β χ and & 2 each represents a hydrogen atom or represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or on 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 R 2 represents e hydrogen, fluorine, chlorine or bromine atom or an alkoxy group with 1 to 3 carbon atoms; and (iii) when X represents a group of formula OH OK NO3 n I ι W f 8 u -CH-CO-, ~CB-CH 2 - p -C-CO- or -CH-CO(wherein Rg is as hereinbefore defined), 3 represents a methylene group] and acid addition salts of the aforementioned compounds

2. Compounds as claimed in claim 1 wherein the 5 group Rj is in the 3-position, the group is in the 4-position and the group is in the 5-position of the respective phenyl nucleus.

3. » Compounds of general formula Ια ?0 [wherein represents a hydrogen, chlorine or bromine atom or a trifluoromethyl e methoxy, amino, methylamino or dimethylamino group; r 2 represents & hydrogen, chlorine or bromine ©tom or a methoxy group, or R^ and R 2 together represent a methylenedioxy group? R 3 represents & hydrogen, fluorine, chlorine or bromine atom or a methyl, methoxy, trifluoromethyl or nitro group? represents a hydrogen atom or an amino, methoxy, methylamino or dimethylamino group, or Rg and R^ together represent © methylenedioxy group; R 5 represents a hydrogen, chlorine or bromine ©tom? Rg represents a hydrogen atom or a methyl or allyl group? S represents a thiocarbonyl, carbonyl or methylene group; G represents an n-alkylene group with 2 to 5 carbon atoms (wherein, so long as 6 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 -CH 2 “CHp-, CH CH NOH I I II -CH e CH- f -N=CH-, -CH-CH 2 -, -CH-CO-, -C-CO-, 5 5 5 5 nh 2 mh-c H2 ch 2 -Q-och 3 -CH-CO-, -CH-CO- X OCH- or -COCO-? 5 5 J with the provisos that (ί) when A represents a group of formula -Ό3 2 -ΟΗ 2 “ or -CH=CH-, B represents a tbiocarbonyl 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 \ erbon atoms wherein & methylene group is replaced 68 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 & χ and R 2 each represents a hydrogen atom or R x represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and & 2 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 fo 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 Π χ and R 2 each represents a hydrogen atom or Rj, 20 represents a chlorine or bromine atom or a trifluoromethyl, amino, methylamino or dimethylamino group and R 2 represents a hydrogen, chlorine or bromine atom or a methoxy group? and (iii) when A represents a group of formula -S»CH25 OH OH -ch 2 -, -0h-co~, 5 5 3 represents a methylene group] 30 and acid addition salts thereof.

4. Compounds as claimed in claim 3, wherein A represents a -CH 2 -CH 2 - group? B represents a -CO- or -CS- group? represents a methoxy, amino, methylamino 35 or dimethylamino group, and R 2 represents a hydrogen atom or a methoxy group or Κ χ and & 2 together represent OT-CH 2 C h 2-Q NOH NH 9 ^-CO-, -CH-CO- or -^H-CO OCH OCH. a methylenedioxy group Rg represents a hydrogen, fluorine, chlorine or bromine atom or a methoxy or trifluoromethyl group,and R 4 represents a methoxy, amino, methylamino or dimethylamino group or Rg and R^ together represent 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 5. Carbon atoms, a “CH 2 -(!:h - group or (if B represents a -CS- group and/or R^ represents an amino, methylamino or dimethylamino group) a -CH 2 CH 2 - group.

5. Compounds as claimed in claim 3 wherein R^ and R 2 each represents a methoxy group? Rg represents a methoxy group or a hydrogen or chlorine atom? R^ represents a methoxy, amino or dimethylamino group? 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 group or (if 3 represents a thiocarbonyl group or A represents a group of OH formula -CH-CO~) a -CH o -CH 0 ~ group? &nfi 5 * either A represents a “ CH 2”^ R 2^ 9 rou P and represents © thiocarbonyl or (if G represents an n-alkylene group with 3 to 5 carbon atoms) a carbonyl group, or OH A represents a -CH -CO- group and 3 represents 5 a methylene group. S e l'’(7,0-Dimethoxy-l,3,4,5-tetrffihydro-2H-3benzasepin-2“On-3-yl) -3“(N-methyl~N~ (3-(3,4-dimethoxyphenyl)^propyl)-amino]-propane and acid addition 5 salts thereof»

6. 7» 1-(l-Hydroxy-7 ,

7. 8-d imethoxy-1,3,4,5-tetrahydro2H-3“bensasepin-2-on-3-yl)-3-(N-methyl-N-(2-(3,4dimethoxy-phenyl)-ethyl)~&mino]-propane and acid addition salts thereof. 10 8. l-(7,8-Dimethoxy-X,3,4p5-tetrahydro~2H~3bensasepin-2-on-3-yl)-3-[N-mefhyl-N-(3-(4-amino3,5-dichloro-phenyl)-propyl)-amino]-propane and acid addition salts thereof.

8. 9» 1-(7,8-Dimethoxy-l,3,4,5-tetrshydro-2K~3~ 15 benzazepin-2On-3-yl)-3-[N-methyl-N-(2-phenylethyl)amino]-propane and acid addition salts thereof.

9. 10. 1-(7,8-Dimethoxy-l,3,4,5-tetrahydro-2H-3~ bensagepin-2-on-3-yl)-3-[N-methyl~N-(2-(4-amino3-nitro-phenyl)-ethyl)-amino]-propane and acid 20 addition salts thereof»

10. 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.

11. 12® Physiologically acceptable acid addition salts of compounds as claimed in any one of claims 1 to 10«

12. 13. Compounds as claimed in claim 1 as herein 30 specifically described.

13. 14» Compounds as claimed in claim 1 as herein specifically described In any of Examples X to 25.

14. 15® A process for the preparation of compounds 35 as claimed in claim 1 which comprises rating a compound of general formula XI (XI) (Χϊϊ) are as defined (wherein R^, R^, R^, A, Β, E and G in claim 1, R| and R^ each represents an amino or alkylamino group protected by a protecting group or represent and R^ as defined in claim 1; one of the groups U and V represents an Rg-NHgroup wherein Rg is as defined in claim 1, and the other group ϋ or V represents a nucleophilically exchangeable group), an

15. 16 e A process as claimed in claim 15 wherein the nucleophilically exchangeable group XJ or V is a halogen atom or a sulphonyloxy group e

16. 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®

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

18. 19. A process as claimed in any one of claims 15 to 18 wherein the reaction is carried out at temperatures of between 0 and 150 e C.

19. 20 a 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 5 mixture.

20. 21« A process for the preparation of compounds as claimed in claim 1 wherein A represents & -CH^ *7 a CH«- P -CH=CH- P -OT-CO-, 2 5 -COCO-, -CH 0 -CO-, 5 z -C*ft· - or group and 5 5 B represents a °x -CO- group, which comprises reacting a compound of general formula (IV) (wherein Rj * s defined in claim 1, A' represents a -CH^-CH^-p ~CH»CH?7 -ftH-CO5 -COCO-, -CH o -CO-p or group wherein 5^ 5 represents an alkyl group with 1 to 3 carbon atoms, 0 y represents a -CH^- or -CO- group and represents an amino or alkylamino group protected by a protecting group or represents as defined in claim 1) with a compound of general (wherein R 3e Rg, Rg g £ and G are as defined in claim If R a ' represents an amino or alkylamino group protected by a protecting group or represents as defined in claim 1, and Z represents a nucleophilically exchangeable group) and optionally subsequently splitting off any protecting group used.

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

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

23. 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.

24. 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*

25. 26* A process as claimed in any one of claims 21 to 25 wherein the reaction is carried out in a solvent at the boiling temperature of the reaction mixture. 26. 27. A process for the preparation of compounds as claimed in claim 1 wherein A does not represent NH-R fi I 8 a —CH-CO- or -CO-CO- group, which comprises reacting 5 (wherein Β, B, R^ and defined in claim 1 but In the group E two hydrogen atoms In a -CH^ or -CH^ group of the group E are replaced by an 5 oxygen atom, and A” represents a ~CH 0 -CH 0 “? ~CH=CH-, -NH-CO-, A £> K OH OH NOH I I II -Cfly-CO-, -N=CH-, -CH-CO-, -CH-CH 0 -, -OCO- or 5 5 5^5 R-y I ' -C«N- group wherein R« represents an 5 10 alkyl group with 1 to 3 carbon atoms), with an amine of general formula VIX (VXI) (wherein G and R^ to R^ are as defined in claim 1), 15 in the presence of a reducing agent»

26. 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

27. 28 wherein the reaction is carried out in a solvent at temperatures of between 0 and 100°C®

28. 30* A process for the preparation of compounds as claimed in claim 1 ι 8 25 wherein A does not represent a -Ch-co- or ~CO~COgroup? which comprises reacting a compound of generi formula VXXX (VIII) (wherein S, Ε, R-p and Rg are as defined in claim 1 and A“ represents a -CH^-CH^-, -CH^CH-, -NH-CO-, OH OH NOH 5 1 1 * ΛΛ ~CH 0 -CO-, -N=CH-, -CH-CO-, -CH-CH 0 -, -C-CO- or 5 * 5 5 5^5 ?7 •C«N5 group wherein R? represents an alkyl group with 1 to 3 carbon atoms) e with a compound of general formula IX (IX) (wherein R^ to Rg and G are as defined in claim 1, but in the group G two hydrogen atoms in a ^2”“ or -CH^ group of the group G are replaced by an oxygen atom) in the presence of a reducing agent„

29. 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.

30. 32 e 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 3.00°C.

31. 33* A process for the preparation of compounds as claimed in claim 1 wherein A represents a group, 3 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 ^1 to 9 en< ^ G are tiS defined in claim 1, and 3 s represents a methylene or carbonyl group). 10

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

33. 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 e C. 35» A process as claimed in claim 35 wherein the temperatures are between 20 and 50°C»

34. 37. A process for the preparation of compounds 20 as claimed in claim 1 wherein 3 represents a -CSgroup 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 methylenen-hydroxy-alkvlene group with 1 to 4 carbon atoms 25 in the alkylene moiety, which comprises reacting a compound of general formula XX (JtX) (wherein a R x fo Rg, A and E are as defined in claim 1 and G’ represents an n-alkylene group with 1 ? to 5 carbon atoms optionally substituted by an alkyl group with 1 to 3 carbon atoms or e methylenen-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety) with a sulphur-introducing agent.

35. 38» A process as claimed in claim 37, wherein the sulphur-introducing agent is phosphorus pentasulphide or 2,4-bis-(4-methoxyphenyl)-1,3-difhia-2,4~diphosphetane2,4-disulphide.

36. 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.

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

38. 41» A process for the preparation of compounds OH as claimed in claim 1 wherein A represents a -CH-COOH 5 I or ~CH~CH 0 group 5 * and G represents an n-alkylene group with 1 to 5 carbon atoms optionally substituted by alkyl group with 1 to 3 carbon atoms or a methylene-nhydroxy-alkylene group with 1 to 4 carbon atoms in the alkylene moiety, which comprises reducing a compound of general formula 3CXX 4 (SID (wherein Rj to Rg, 2 and G are as defined in claim 1).

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

40. 43. A process as claimed in claim 42, wherein metal hydride used as reducing agent comprises sodium borohydride or lithium aluminium hydride.

41. 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.

42. 45* A process for the preparation of compounds 15 as claimed in claim 1 wherein HN-R a WOH 7 8 H 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 atoms or a methylene-n-hydroxyalkylene group with 20 1 to 4 carbon atoms in the alkylene moiety, which comprises reacting a compound of general formula Hill (wherein to Rg end 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 methylenen-hydroxyalkylene group with 1 to 4 carbon atoms in the alkylene moiety), with a compound of general formula XXV (XIV) (wherein Rg represents a hydroxy group or represents Rg as defined in claim 1) optionally with subsequent reduction

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

44. 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®Ce

45. 48» A process for the preparation of compounds as claimed in claim 1 wherein A represents an 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 B (XV) (wherein R^ to Rg, E and G are as defined in claim X and Rg 0 represents an alkyl group with 1 to 3 carbon atoms or an alkenyl group with 3 5 to 5 carbon atoms) with en orthoformic acid ester.

46. 49« A process as claimed in claim 48, wherein any -NH^ or 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.

47. 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*

48. 51. A process as claimed in any one of claims 48 fo 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*

49. 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 ! (wherein R, to R-z 3 and E are as defined in claim A v Ir A*· represents A as defined in claim 1 with the exception of the -COCO- group, and G w represents a methylsne-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)„

50. 53« A process as claimed in claim 52 wherein the reduction is carried out using a metal hydride or diborane as reducing agent.

51. 54. A process as claimed in claim 52 or claim 53 wherein the reduction is carried out in a solvent at temperatures of between 0 and 50°C.

52. 55. A process for the preparation of compounds as claimed in claim 1 wherein R^ represents a nitro group and R^ represents an amino group, which comprises hydrolysing a compound of general formula JCVxx (wherein Π χ , R^, Rg, Rg, A, 3, Ξ and G are as defined in claim 1, and Acyl represents an acyl group)« 55. A process as claimed in claim 55 wherein the acyl group is an acetyl, ethoxycarbonyl or benzoyl group. 57. A process as claimed in claim 55 or claim 56 wherein the acyl group is hydrolysed in an aqueous solvent in the presence of an acid or an alkali metal base at temperatures of between 0 and 100°C» 58. A process as claimed in claim 55 or claim

53. 56 wherein the hydrolysis Is carried out in methanollc or ethanolic hydrochloric acid.

54. 59. A process for the preparation of compounds 5 as claimed in claim 1 wherein wherein A represents a -ch 2 -ch 2 ~, -CH*CH~, -NH-CO-, -CH 0 -CO-, -ft’CH-, -COCO» or -Oft- group and one 5^5 5 of the groups Rp R 2 ' R 3 or R 4 represents an alkoxy, alkylamino or dialkylamino group or Rg represents 10 an alkyl or alkenyl group, which comprises reacting a compound of general formula XVXII (XVIXI) (wherein R, to B and E are as defined in claim l o 15 1 but at least one of the groups R^ to 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 -CK-CH-, -ftH-CO-, ?7 20 -CH-»C0~, *-ft«CH-, -COCO- or -Oft- qroup wherein 5 z 5 5 represents an alkyl group with 1 to 3 carbon atoms, and G'‘ l? represents an n-alkylene group with X to 5 carbon atoms optionally substituted by an ί 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 XXX R 10 - X (XIX) (wherein &10 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 P if at least one of the groups R 1 to R^ represents a hydroxy group, X together with a hydrogen atom in the a position of the group represents a diazo group or, if Rg represents a hydrogen atom or R n or R^ represents an amino or alkylamino qroup, X together with a hydrogen atom in the «position of the group R^ Q may also represent an oxygen atom). ? . t the group x in the compound of general formula XIX is a halogen atom or a sulphonyloxy group.

55. 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.

56. 62* A process as claimed in claim 61 wherein the alkylating agent used is methyl iodide, dimethyl sulphate, ethyl iodide, diethyl sulphate, propyl bromide, allyl bromide or isopropyl p-toluenesulphonate in the presence of an acid-binding agent.

57. 63. A process as claimed in any one of claims 59 to 61 wherein X together with a hydrogen atom in the α-position of the group R^ Q represents a diazo group and the reaction is carried out with a diazoalkane at temperatures of between 0 and 30°C.

58. 64. A process as claimed in any one of claims 59 to 61, wherein X together with a hydrogen atom in the «’position of the group represents an oxygen atom and the reaction is carried out in the presence uf a reducing agent at temperatures of between 0 and 120°C.

59. 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* 65» 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 ςεοπρ be !by * «rbonyl group, which comprises oxidising a compound of general formula XX 15 (wherein R^ to Rg, S and G are as defined in claim 1)«

60. 67. A process as claimed in claim 55 wherein the oxidation is carried out using potassium permanganate, selenium dioxide or sodium dichromate as oxidising agent. 20 S8, A process as claimed in claim 55 or claim 67 wherein the oxidation Is carried out in a solvent at temperatures of between 0 and 100°C*

61. 69. A process for the preparation of compounds as claimed in claim 1 wherein A represents a -CH^-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 (XXI) of general formula XXI (wherein to Rg, Β, E and G are as defined in claim 1). 5

62. 70* A process as claimed in claim 69 wherein the oxidation is carried out using ruthenium tetroxide, optionally produced in situ in the reaction mixture, as oxidising agent*

63. 71· A process as claimed In claim 69 or claim 10 70, wherein the reaction is carried out in a solvent and at temperatures of between 0 and 100°C.

64. 72* A process for the preparation of compounds as claimed in claim 1 wherein is in the /-position, to A represents a -CH^CH^- group and B represents 15 o -CO- group, which comprises cyclising a compound of general formula XXXI (wherein to Rg, G and Ξ 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).

65. 73. A process as claimed in claim 72 wherein Y in the compound of general formula XXIX represents 10 a carboiiy, nitrile, ester, thioester, acyloxycarbonyl or amide group.

66. 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

67. 75 s A process as claimed in any one of claims 72 to 74 wherein any HO-, -NH or groups present are protected by protecting groups during the cyclisation, the said protecting groups being subsequently split off after the reaction. 20

68. 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*

69. 77» A process as claimed in any one of claims 25 15 to 76, wherein a compound of general formula X, initially obtained, is subsequently converted into an acid addition salt thereof, or an acid addition salt of a compound of general formula initially obtained, is subsequently converted 30 into a compound of general formula X or Into a different acid addition salt the^of w 78® A process for the preparation of compounds as claimed in claim 1 substantially as herein described.

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

71. 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» i

72. 81« Compounds of general formula X as defined in claim 1 and physiologically acceptable acid 1C addition salts thereof for use in a method of preventing 1 or relieving ischaemic cardiac diseases or of relieving sinus tachycardia.

73. 82. Pharmaceutical compositions comprising, as active ingredient, at least one compound of general 15 formula Ϊ as defined in claim 1 or a physiologically acceptable acid addition salt thereof, in association with a pharmaceutical carrier or excipient.

74. 83. Pharmaceutical compositions as claimed in claim 82 in a form suitable for oral, rectal or 20 parenteral administration.

75. 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

76. 85» Pharmaceutical compositions as claimed in any one of claims 82 to 84 in the form of dosage units.

77. 86. Pharmaceutical compositions substantially as herein described. 30 87* Pharmaceutical compositions substantially as herein described in any of Examples I to V.