DK156720B - METHOD OF ANALOGUE FOR THE PREPARATION OF BENZAZEPINE DERIVATIVES OR PHYSIOLOGICALLY ACCEPTABLE ACID ADDITION SALTS - Google Patents

Description

DK 156720 B

British Patent No. 1,548,844 discloses, inter alia, compounds of the formula:

CHjO

AA / = H3 / OCH3 in _ / V- CH30 q CH2-CH2-CH2-N-CH2-CH2 “V V- OCH3 10 and its physiologically acceptable acid addition salts, which compounds exhibit valuable pharmacological properties, namely a mild blood pressure lowering activity in particular a selective heart rate lowering activity.

It has now surprisingly been found that the novel benzazepine derivatives of the general formula I: W \ i6 / + vR "2 ^ A_b / \ = ^ r5 exhibit superior pharmacological properties in relation thereto, namely in connection with a longer duration of action and 25 minor side effects, notably a stronger heart rate-lowering activity.

The present invention therefore relates to an analogous process for the preparation of the novel benzazepine derivatives of the above general formula I, or their physiologically acceptable acid addition salts with inorganic or organic acids, the process of which is characterized by the characterizing part of claim 1.

In the above general formula I, the symbols have the following meanings: A is a group -CHO-CHO-, -CH = CH-, -NH-CO-, -CH9-CO- 5 h or -C = Nf where R- , is an alkyl group having 1-3 C-ato-5 '2

DK 156720 B

more, and B is a methylene or carbonyl group, or A is a group -CO-CO-, and B is a methylene group, E is an optionally substituted ethylene, n-propylene alkyl group having 1-3 C atoms. or n-butylene group, one substituted with a hydroxy group at 2-position n-propylene group or one with a hydroxy group 1 2- or 3-position substituted n-butylene group, G is optionally with an alkyl group having 1-3 C and atoms may be the same or different, is a hydroxy group, an alkyl, alkoxy or phenylalkoxy group, each alkyl part having 1-3 C atoms, or one of the the groups and R 5 may also be a hydrogen atom, or R 1 may together with R 2 form an alkylene dioxide group of 1 or 2 C atoms, R 3 and R 2 which may be the same or different, the drug or halogen atom, a hydroxy group, an alkyl or alkoxy group having 1-4 C atoms, a trifluoromethyl or cyano group, or one of the groups R3 and R4 may also may be a nitro group, or R 3 may together with R 1 form an alkylenedioxy group of 1 or 2 C atoms,

R 8 is a hydrogen atom, an alkyl, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkanoylairdino, alkoxycarbonylamino or bis (alkoxycarbonyl) amino group wherein each alkyl moiety has 1 -3 C atoms, or a methylamino or ethylamino group substituted by a trifluoromethyl group, and

Rg is a hydrogen atom, an alkyl, phenylalkyl, alkanoyl-ΙΟ or alkoxycarbonyl group wherein each alkyl moiety has 1-3 C atoms, or an alkenyl group having 3-5 C atoms. For example, for the meanings given in the definitions of groups R R to R,, E and G, the following is considered: 35 for R ^: a methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, benzyl oxy, 1-phenylethoxy, 2-phenylethoxy or 3-phenylpropoxy group,

DK 156720 B

3 for R 2 a hydrogen atom, a methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 2 phenylpropoxy or 3-phenylpropoxy group, for or R 2, which may be the same or different: a hydrogen, fluoro, chloro, bromo or iodo atom, a methyl, ethyl, propyl, isopropyl , n-butyl-7 hydroxy, methoxy, ethoxy, propoxy, isopropoxy-xy, n-butoxy, trifluoromethyl or cyano group or for one of the groups Rg and R4 also a nitro group, for R 2: a hydrogen atom, a methyl, ethyl, propyl, isopropyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino, ethylamino · no, propylamino -, isopropylamino, dimethylamino, diethylamino, dipropylamino, methylethylamino, ethylpropylamino, methylpropylamino, formylamino, acetylamino, propionylamino, methoxycarbonylamino, ethoxycarbonylamino, propoxylamino isopropoxycarbonylamino, bis (ethoxycarbonyl) amino or β, β, β-trifluoroethylamino group, for Rg: a hydrogen atom, a methyl, ethyl, propyl, isopropyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl , allyl, buten-2-yl, buten-3-yl, pentenyl, formyl, acetyl, propionyl, methoxycarbonyl, ethoxycarbonyl, propoxycycarbonyl or isopropoxycarbonyl group, for R R 2 and / or R 2 together with R 2: a methyl endioxy or ethylenedioxy group, for E: an ethylene, n-propylene, n-butylene, 1-6 methylethylene, 2-ethylethylene group. , 1-propyl-ethylene, 1-methyl-n-propylene, 2-methyl-n-propylene, 1-35 ethyl-n-propylene, 3-ethyl-n-propylene, 2-propyl · · n-propylene, 2-methyl-n-butylene, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-n-butylene group and

DK 156720 B

4 for G: a methylene, ethylidene, propylidene, n-butylidene, 2-methylpropylidene, ethylene, 1-methylethylene, 2-ethylethylene, 1-propylethylene or 2-methylethylene group.

Preferred compounds of the above general for flour I are those wherein: A is a group -CH 2 -CH 2 - / -CH = CH-, -NH-CO-, -CE 2 -CO- CH, 5 5 I 3 or - C = N- / and B is a methylene or carbonyl group or A is a group -CO-CO- and B is a methylene group, E is an ethylene, n-propylene, n-butylene, 2-methyl-n-propylene or 2-hydroxy-n-propylene group, G is a methylene, ethylene or 1-methylethylene group, R 1 is a methyl, hydroxy, benzyloxy or alkoxy group. pe having 1-3 C atoms, R 2 is a hydrogen atom, a methyl, hydroxy or methoxy group or R 2 and R 2 together form a methylenedioxy group, R 2 is a hydrogen, fluoro, chloro or bromine atom , a trifluoromethyl, nitro, alkyl or alkoxy group each having 1-4 C atoms, R 1 is a hydrogen, chloro or bromine atom, a methyl, methoxy or cyano group, or R 9 and R 2 form together a methylenedioxy group,

R 8 is a hydrogen atom, a hydroxy, methoxy, amino, acetylamino, ethoxycarbonylamino, bis (ethoxycarbonyl) amino, dimethylamino or β, β, β-trifluoroethyl amino group, and

Rg is a hydrogen atom, an alkyl group having 1-3 C atoms, an allyl, benzyl, acetyl or ethoxycarbonyl group, or their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids.

DK 156720 E

Particularly preferred compounds of the above general formula I are those wherein CHO in Δ A is a group -CH 2 -CE 2 -, -CH = CH- or -C = N-, and B is a carbonyl group, or A is a group -CH = CH-, -NH-CO- or -CO-CO-, and B is 5 is a methylene group, E is an n-propylene group, G is an ethylene group, is a methoxy or hydroxy group, R 2 is a methoxy group,

Rg is a methoxy or trifluoromethyl group, a chloro or bromine atom, R 4 is a methoxy group, a hydrogen, chloro or bromine atom, or Rg and R 2 together form a methylenedioxy group,

Rg is a hydrogen atom, an amino or methoxy group and

Rg is a hydrogen atom, a methyl, ethyl, n-propyl or allyl group, or their physiologically acceptable acid addition salts with inorganic or organic acids.

The compounds of this invention can be obtained by the following methods: a) Reaction of a compound of the general formula II; 25 R1 '| N - H (II)

V

Wherein: A and B are as defined above, R 1 and R 1 are each a hydroxy group protected with a protecting group, e.g. a trimethylsilyloxy, acetoxy, benzyloxy or tetrahydropyranyloxy group, or having the meanings given for R 1 and R 2 above, having a compound of the general formula III:

V

6

DK 156720 E

S - E - Μ6- (III)

V

where:

Rg, E and G are as defined above, R R to Rg1 each being one hydroxy group protected by a protecting group, e.g. a trimethylisilyloxy, acetotoxy, benzyloxy or tetrahydropyranyloxy group, or having the meanings given for R 1 to R 9 above, and Z is a nucleophilic eliminable group such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulfonyloxy, p-toluenesylphonyloxy or ethoxysulfonyloxy group, or having an optionally present quaternary site of general formula IIia:

Rg Z® Γΐ®- «ΟΤν 25 ER4 '

V

wherein: E, G, Z, Rg 'to R 2' and Rg are as defined above, and any subsequent cleavage of a protecting group used.

The reaction is optionally carried out in a solvent or solvent mixture, e.g. in acetone, dimethylformamide, acetone / dimethylformamide, dimethylsulfoxide or chlorobenzene, and suitably, depending on the reactivity of group Z, at temperatures between 0 ° and 150 ° C, preferably at the boiling temperature of

DK 156720B

7 the solvent used. The presence of a sewing-binding agent is advantageous, e.g. an alcoholate, such as sodium methylate, an alkali metal hydroxide, such as sodium hydroxide, an alkali metal carbonate, such as potassium carbonate, an alkali metal amide, such as sodium amide, an alkali metal hydride, such as sodium hydride, or a tertiary organic acid, or a reaction-promoting agent such as potassium iodide.

Preferably, the subsequent decomposition of a protecting group used is preferably hydrolytic in an aqueous solvent, e.g. water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid, such as hydrochloric or sulfuric acid, or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 ° and 100 ° C, preferably at the boiling temperature of the reaction mixture. However, the cleavage of a benzyl group may also be hydrogenolytic, e.g. with the hydrogen in the presence of a catalyst, such as palladium / 20 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 between 0 ° and 50 ° C, but preferably at room temperature, and a hydrogen pressure of 1-7 bar, preferably 3 to 5 bar.

B) For the preparation of compounds of the general formula I wherein R 9 is a hydrogen atom, an alkenyl group having 3 to 5 C atoms, an alkyl or phenylalkyl group having 1-3 C atoms in the alkyl moiety:

Reaction of a compound of general formula IV: 30

V> YN

| N - E - U (IV) 35 having a compound of general formula V:

DK 156720B

8 r3 * G - V (V) 5 R4, '^ V “~

V

wherein: A, B, E and G are as defined above, R 10 · 1 to R 1 are each one protected by a protecting group hydroxy group, e.g. a trimethylsilyloxy, aceto-toxic, benzyloxy or tetrahydropyranyloxy group, or having the meanings given for R 1 to R 2 above, one of the groups ü and V is a group R g'-NH- where R g * is a hydrogen atom, an alkenyl group having 3-5 C atoms, an alkyl or phenylalkyl group, each having 1-3 C atoms in the alkyl moiety, and the other of groups U and V is a nucleophilic eliminable group such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulfonyloxy, p-toluenesulfonyloxy or ethoxy sulfonyloxy group, or U together with a β-substituted hydrogen atom from group 25 E represents an oxygen atom and V is a group Rg'-NH - wherein Rg1 is as defined above and, optionally, the subsequent cleavage of an protecting group used.

The reaction is conveniently carried out in a solvent or solvent mixture such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethylsulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or in excess of the compounds used and or 35 V and optionally in the presence of an acid binding agent, e.g. an alcoholate, such as potassium tert-butylate, an alkali metal hydroxide, such as sodium or potassium hydroxide, an alkali metal carbonate, such as potassium carbonate, an alkali metal,

DK 156720B

9 metal amide, such as sodium amide, an alkali metal hydride, such as sodium hydride, a tertiary organic base, such as triethylamine or pyridine, the latter being simultaneously capable of serving as a solvent, or a reaction promoting agent, such as potassium iodide, and after reaction. the ability of the nucleophilic interchangeable group is conveniently at temperatures between 0 ° and 150 ° C, preferably at temperatures between 50 ° and 120 ° C, e.g. at the boiling temperature of the solvent used. The reaction can also be carried out without solvent. However, particularly advantageously, the reaction is carried out in the presence of a tertiary organic base or an excess of an applied amine of the general formula V.

Preferably, the subsequent decomposition of a protecting group used is preferably hydrolytic in an aqueous solvent, e.g. in water, iso-propanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid, such as hydrochloric or sulfuric acid, or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, at temperatures between 0 ° and 100 ° C, preferably at the boiling temperature of the reaction mixture. However, the cleavage of a benzyl group can also be hydrogenolytic, e.g. with hydrogen in the presence of a catalyst, such as palladium / carbon, 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 between 0 ° and 50 ° C, preferably at room temperature, and a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.

C) For the preparation of compounds of the general formula I wherein R 9 is a hydrogen atom, an alkenyl group having 3 to 5 C atoms, an alkyl or phenylalkyl group each having 1-3 C atoms in the alkyl moiety:

Reaction of a compound of general formula VI: 35

DK 156720 B

10 V \ I - E - H (VI) R 2 where: A, B, E, and R 2 are as defined above, however, in the group E, two hydrogen atoms in a group -CH 2 - or CH 2 - from the group E may be substituted with an oxygen atom / with an amine of the general formula VII: 15/3 / VR4 H - N - G - </ V (VII) V R5 where: G and R3 to Rg are as defined above and Rg ' is a hydrogen atom, an alkenyl group having 3-5 C atoms, an alkyl or phenylalkyl group each having 1-3 C atoms in the alkyl moiety, in the presence of a reducing agent.

The reaction is conveniently carried out in a suitable solvent or solvent mixture such as methanol, ethanol, ethanol / ethyl acetate or dioxane, at temperatures between 0 ° and 100 ° C, preferably at temperatures between 20 ° and 80 ° C.

It is particularly advantageous to effect the reductive amination in the presence of a complex metal hydride, such as lithium or sodium cyanoborohydride, preferably at a pH of 6-7 and at room temperature or 35, to prepare compounds with it. general formula I, wherein R 9 is a hydrogen atom, in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium / coal at a hydrogen pressure of 5 bar. Her- 11

DK 156720 B

if benzyl groups present may be simultaneously hydrogenolytically cleaved and / or double bonds dehydrogenated.

d) For the preparation of compounds of general formula I wherein R 9 is a hydrogen atom, an alkenyl group having from 3 to 5 C atoms, an alkyl or phenylalkyl group each having 1-3 C atoms in the alkyl moiety:

Reaction of a compound of general formula VIII:

R-L

As: 1H JN - E - N (VIII) r 2 where: A, B, E, R 2 and R 2 are as defined above and R 9 is a hydrogen atom, an alkenyl group having 3-5 C atoms, an alkyl or phenylalkyl group each having 1-3 C atoms in the alkyl moiety, with a compound of the general formula IX: h. g 25 R 1 R 5 where:

Rg to Rg and G are as defined above, however, in the group G, two hydrogen atoms in a group -CHg- or CHg- from the group G may be replaced by an oxygen atom, in the presence of a reducing agent.

The reaction is conveniently carried out in a suitable solvent or solvent mixture, such as methanol, ethanol, ethanol / ethyl acetate or dioxane, at temperatures between 0 ° and 100 ° C, preferably at temperatures between 20 ° and 80 ° C.

DK 156720B

12

It is particularly advantageous to carry out the reductive amination in the presence of a complex metal hydride, such as lithium or sodium cyanoborohydride, preferably at a pH of 6-7 and at room temperature, or to prepare compounds with it. general formula I, wherein R 9 is a hydrogen atom, in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium / coal at a hydrogen pressure of 5 bar. Hereby any benzyl groups present may simultaneously be hydrogenolytically cleaved and / or double bonds dehydrogenated.

e) For the preparation of compounds of general formula I wherein A is a group -NH-CO-, E is optionally substituted with an alkyl group of 1-3 C atoms, ethylene, n-propylene or n -butylene group, and Rg is not a hydrogen atom:

Reaction of a compound of general formula X:

V

20 nh2 r3 '

v-fc · Γ in V

- B - N - E '- H - G -e (x)

π II

R5 wherein: B and G are as defined above, E 'is optionally substituted with an alkyl group having 1-3 C atoms, ethylene, n-propylene or n-butylene group, R 1 is each a one-protecting group protected hydroxy group, e.g. a trimethylsilyloxy, acetoxy, benzyloxy or tetrahydropyranyloxy group, or having the meanings set forth for R 1 to R 2 above, R 1 is a hydroxy, amino or alkylamino group protected by a protecting group, or has with the exception of an amino or alkylamino group, the meanings given for R

DK 156720 B

13

With the exception of hydrogen, Rg has the meanings given for Rg or is a protecting group for an amino group, with a carbonic acid derivative of the general formula XI: 5 W - CO - W (XI) where: the W groups which may be the same or various, each being a nucleophilic eliminable group such as a chlorine or bromine atom, an optionally substituted alkoxy group having 1-3 C atoms or an imidazolyl (2) group, and optionally subsequent cleavage of an applied protecting group.

The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, carbon tetrachloride, benzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or acetonitrile, preferably at temperatures between 0 ° and 150 ° C, but preferably used at temperatures of 0 ° C and 150 ° C. solvent, e.g. at temperatures between 40 ° and 100 ° C, and optionally in the presence of an acid-binding agent such as potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine or triethylamine, the latter also being able to serve as a solvent. The reaction can also be carried out without solvent. If in a compound of general formula XI used, at least one of the groups W is an alkoxy group having 1-3 C atoms, the reaction is preferably carried out in excess of the ester used as the solvent.

Preferably, the subsequent decomposition of an protecting group used is preferably hydrolytic in an aqueous solvent, e.g. in water, iso-propanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid, such as hydrochloric or sulfuric acid, or in the presence of an alkali metal base, such as sodium hydroxide or potassium hydroxide, at temperatures between 14 ° C and 156720 °. 100 ° C, preferably at the boiling temperature of the reaction mixture. However, the cleavage of a benzyl group may also be hydrogenolytic, e.g. with the hydrogen in the presence of a catalyst, such as palladium / carbon, 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 between 0 ° and 50 ° C, but preferably at room temperature, and a hydrogen pressure of 1-7 bar, preferably 3-5 bar.

F) For the preparation of compounds of the general formula I wherein A is a group R R and R₂ is not a benzyloxy group, Rg or R ^ is not a nitro group and R R is not a benzyl group or an alkenyl group having from 3 to 5 C atoms: Hydrogenation of a compound of the general formula XII: R1 XVCH = CH \ '6 / "V" NENGV y (XII) 20 ^ v = j = / ^ R4 R2 R5 where: R ^ to Rg, B , E and G are as defined above, wherein R eller or R ^ is not a nitro group if R er is an amino group.

The hydrogenation is carried out in a solvent or solvent mixture, such as methanol, ethanol, ethyl acetate or glacial acetic acid, with catalytically activated hydrogen, e.g. with hydrogen in the presence of platinum or palladium / coal, at a hydrogen pressure of 1-7 bar, preferably at 3-5 bar, and at temperatures between 0 ° and 75 ° C, preferably at temperatures between 20 ° and 50 ° C.

If in a compound of the general formula XII Rg is a = 35 benzyl group, during hydrogenation it is simultaneously replaced with a hydrogen atom or if R 2 and / or R 9 is a benzyloxy group, these are transferred to a hydroxy group during hydrogenation. .

DK 156720 B

G) Reaction of a compound of the general formula XIII: E1 î6 5 N - E - N - G y (XIII) - R 4 R2 E5 - wherein: 10 R · to Rg, A, B, E and G are soin defined above, wherein at least one of the groups R- to R₂ must be a hydroxy group, Rg must be a hydroxy group, "an amino or alkylamino group having 1-3 C atoms, or Rg must be a hydrogen atom, having a compound of general formula XIV:

Rg - X (XIV) wherein: Rg is an alkyl group having 1-3 C atoms or an alkenyl group having 3-5 C atoms when Rg is a hydrogen atom, or is one having a phenyl group substituted alkyl group having 1- 3 C atoms when R 1 or R 2 is a hydroxy group and / or R 9 is a hydrogen atom and 25 X is a nucleophilic eliminable group such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulfonyloxy, p-toluene sulfonyloxy or methoxysulfonyloxy group, or X forms if at least one of the groups R 1 to R 9 is a hydroxy group, together with an α-positioned hydrogen atom from the group Rg is a diazo group, or if Rg is a hydrogen atom or Rg is an amino or alkylamino group, an oxygen atom.

The reaction is conveniently carried out in a solvent or solvent mixture such as diethyl ether, methanol, acetone, tetrahydrofuran, dioxane, acetonitrile, pyridine or dimethylformamide, optionally in the presence of a base such as potassium carbonate, potassium hydrogen.

DK 156720 E

16 droxide, potassium tert-butylate or sodium hydride, at temperatures between 0 ° and 150 ° C, preferably at temperatures between 20 ° and 120 ° C.

If X is a nucleophilic eliminable group, the reaction is preferably carried out with an alkylating agent, such as methyl iodide, dimethyl sulfate, ethyl iodide, diethyl sulfate, propyl bromide, allyl bromide, benzyl chloride, phenyl-ethyl bromide or p-toluenesulfonic acid amine propyl temperatures 10 between 20 ° and 80 ° C. However, the reaction can also be carried out without solvent.

If X together with an α-substituted hydrogen atom in the group Rg forms a diazo group, the reaction, for the alkylation of a hydroxy group, is preferably carried out with diazomethane or diazoethane at temperatures between 0 ° and 30 ° C, or if X is an oxygen atom the reaction, for alkylating the nitrogen atom, in the presence of a reducing agent at temperatures between 0 ° and 120 ° C, e.g. with formic acid at temperatures between 20 ° C and 110 ° C or with sodium cyanoborohydride at room temperature and a pH of 6-7.

h) For the preparation of compounds of general formula I in which A is not a group -CH = CH-, Rg is a chlorine or bromine atom and Rg is an amino or alkylamino group:

Halogenation of a compound of general formula XV: R1

Vva \ '6 30 R2-- NENG- ^ (XV) B / \ = / ^ Rg "" where: R ^, r2, R4, Rg, B, E and G are as defined above, 35 A * with the exception of the group -CH = CH- has the meanings given for A above, and r5 "" is an amino or alkylamino group having 1-3 C atoms in each alkyl moiety.

DK 156720 B

17

The reaction is carried out with a halogenating agent, e.g. with chlorine, bromine, tribromophenol bromine or phenyl iodine dichloride -, preferably in a solvent or solvent mixture, e.g. in 50-100% acetic acid or in tetrahydrofuran in the presence of a tertiary organic base, optionally in the presence of a heavy metal compound, such as mercury (II) oxide, and suitably at temperatures between 0 ° and 50 ° C. As a result of a compound of the general formula XV used as a base or also as a site / e.g. as mono-, di- or trihydrochloride, 1 or 2 moles of halogenating agent or a small excess is suitably used. If, during the reaction, a hydrogen halide acid site is formed, this can be directly isolated as such or, if desired, further purified over the base.

i) For the preparation of compounds of general formula I wherein A is a group -COCO-, E is optionally substituted with an alkyl group having 1-3 C atoms substituted ethylene, n-propylene or n-butylene group, and B is a group -CH 2 -: Oxidation of a compound of general formula XVI:

R1 R3 XV ch2-cox I6 / fv- R2-- N-E-N-G-V ^ (XVI) CH2 ~ CH2 ^ \ = S ^ R5 where: R ^ to Rg, E and G are as defined above.

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

In the present process, if a compound of general formula I wherein B is a carbonyl group is obtained, this may be reduced by a reduction to a corresponding compound of general formula I where B is

DK 156720E

18 is a methylene group, and / or is obtained a compound of general formula I, wherein 7 is not a group -CH = CH- or -C = N- and R 5 is a benzyl or 1-phenylethyl group, this may be by catalytic hydrogenation is transferred into a corresponding compound of formula I wherein R 9 is a hydrogen atom and / or is obtained a compound of general formula I, wherein R 9 or R 2 is a nitro group, this may be reduced by reduction in a corresponding compound of formula I wherein R 1 is an amino group and / or is obtained a compound of general formula I wherein R 9 is a hydrogen atom and / or R 9 is an amino group 15 a corresponding compound of formula I wherein R 9 is an alkanoyl or alkoxycarbonyl group and / or R 9 is an alkanoylamino, alkoxycarbonylamino or bis (alkoxycarbonyl) amino group, wherein each alkyl moiety has 1-3 C atoms and / or 20 is obtained a compound of general formula I wherein R 9 is an amino group, R 9 is not a hydrogen atom, and R 9 and R 2 is not each a cyano group, it may be transferred over a corresponding diazonium salt in a corresponding compound of formula I wherein R 9 is a hydrogen atom, 25 is a hydroxy or alkoxy group, or R 9 is a hydrogen atom and R 9 is a halogen atom or a cyano.

Said subsequent reduction is preferably carried out with a metal hydride, such as lithium aluminum hydride, or diborane, in a solvent such as di-ethyl ether, tetrahydrofuran or dioxane, at temperatures between 0 ° and 100 ° C, preferably at temperatures between 30 ° and 85 ° C.

..... -The following reduction or catalytic hydrogenation is carried out in a solvent, such as methanol, ethanol, ethyl acetate or glacial acetic acid, with hydrogen in the presence of a catalyst, such as platinum or palladium. / cool / at the hydrogen pressure of 1-7 "bar /" preferably 3-5 bar, and at temperatures between 0 ° and 75 ° C, preferably

DK 156720B

19 at temperatures between 20 ° and 50 ° C. Hereby, nitro and cyano groups present are simultaneously reduced.

Said subsequent acylation is carried out for example with acetyl chloride, acetanic anhydride, propionic anhydride or a corresponding chloroformic acid ester, e.g. chloromyric acid ethyl ester which may simultaneously serve as a solvent, optionally in a solvent such as water / tetrahydrofuran, diethyl ether, tetrahydrofuran or methylene chloride, optionally in the presence of a base such as triethylamine or pyridine, a tertiary base and can serve as a solvent, at temperatures between 0 ° and 100 ° C, preferably at room temperature. The reaction can also be carried out without solvent.

Said subsequent reaction of a diazonium salt, e.g. the fluoroborate, the hydrosulfate in sulfuric acid, the hydrochloride or hydroiodide, if necessary in the presence of copper or a corresponding copper (I) site, such as copper (I) chloride / hydrochloric acid, copper (I) bromide / hydrogen -bromic acid or trisodium-copper (I) -tetracyanide at pH 7 is carried out at slightly elevated temperature, e.g. at temperatures between 15 ° and 100 ° C, and the subsequent reaction with phosphorus subcirculation is preferably carried out at from -5 ° to 0 ° C. The necessary diazonium salt is suitably prepared in a suitable solvent, e.g. in water / hydrochloric acid, methanol / hydrochloric acid, ethanol / hydrochloric acid or dioxane / hydrochloric acid, by diazotizing a corresponding amino compound with a nitrite, e.g. sodium nitrite, or an ester of nitric acid, at lower temperatures, e.g. at temperatures between -10 ° and 5 ° C.

Further, the compounds of general formula I obtained can be transferred into their physiologically acceptable acid addition salts with inorganic or organic acids. As acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid can be obtained.

DK 156720 B

tartaric, succinic, maleic or fumaric.

The compounds used as starting materials of the general formulas II to XVI are partially known from the literature or can be obtained by methods known per se.

Thus, for example, starting compounds of general formulas IV and VIII are obtained by reacting a corresponding benzazepine with a corresponding halogen compound and, optionally, by subsequent reaction with a corresponding amine. The required benzazepine of the general formula II is obtained by cyclizing a corresponding compound, e.g. by cyclization of a compound of the general formula XVII: by cyclization of a corresponding o-amino compound and optionally subsequent catalytic hydrogenation and / or or reduction of the carbonyl group, for example, with sodium borohydride / glacial acetic acid (see EP-Al 0.007.070) and / or oxidation, e.g. with selenium dioxide.

A starting compound of general formula VI is obtained, for example, by reacting a corresponding benzazepine with a corresponding halogen acetal and subsequent hydrolysis.

For example, a starting compound used with the general formula X is obtained by reducing a corresponding nitro compound.

Preferably, a compound of formula XII, XIII, XV or XVI used as a starting material is obtained by reacting a corresponding halogen compound with a corresponding amine and optionally decomposing the protecting groups used to protect hydroxy groups.

21

DK 156720 B

As mentioned above, the novel compounds of general formula I and their physiologically acceptable acid addition salts with inorganic or organic acids exhibit valuable pharmacological properties, in particular, in connection with minor side effects, e.g. a small antimuscarinic activity, a prolonged heart rate-lowering activity, and a decrease in the C 1 requirement of the heart.

For demonstrating the heart rate-lowering activity of the compounds of the present invention as compared to those of the above-referenced British Patent Specification no.

1,548,844 known compounds, the activity of the test compound per dose determined in 2 rats with an average weight of 250-300 g. For this, the rats were anesthetized with pentobarbital (50 mg / kg i.p. and 20 mg / kg s.c.).

The test compounds were injected into aqueous solution in Vena jugularis (0.1 ml / 100 g).

Blood pressure was measured over a cannula bound in A. carotis and the heart rate was recorded from an ECG (II or III) lead derived from needle electrodes.

2Q The heart rate for the animals during the control period was between 350 and 400 beats / minute (S / min).

The values found are listed in the table below.

Compound Dose Heart Rate Low, Malt (Example (mg / kg) 20 minutes after drug use 25 no) _ (S / min) _ 1 5.0 -103 3 5.0 -168 4 5.0 -222 6 5.0 - 81 30 7 5.0 -170 8 5.0 -134

DK 156720 B

22

Compound Dose Heart Rate Low, Malt (Example (mg / kg) 20 minutes after drug use no.) _ (S / min) _ 5 10 5.0 ~ 108 13 5.0 * 82 14 5.0 -217 18 5.0 "72 19 5.0 _11 ° 10 20 2.5 -216 21 5.0 _315 25 5.0" 58 26 5.0 "136 27 5.0" 23 ° 15 29 5.0 -201 33. 2.5 ~ 143 35 5.0 - 71 36 5.0 -192 37 5.0 ~ i55 20 38 5.0 _ 26 ° 41 5.0 "23 ° 46 5.0" 197 47 5.0 -209 48 5.0 "268 25 49 5.0" 19 ° 53 5.0 -214 54 5.0 -138 56 5.0 "244 57 5.0 - 87 30 59 5.0 - 83 60 5.0 ~ 174 64 5.0 - * 168 67 5.0 - 78 68 5.0 -111 35 69 5.0 -112 70 5.0 - 75

DK 156720 S

23

Compound Dose Heart Rate Low, Malt (Example (mg / kg) 20 minutes after drug use no.) _ (S / min) _

71 5.0 "1U

5 75 5.0 "l2â 76 5.0" 169 77 5.0 -174 78 5.0 - 70 79 5.0 "233 10 80 5.0 -215 82 5.0 -116 86 5.0 - 75 93 5.0 -H ° 94 -5.0 -89 15 95 5.0 -148 96 5.0 "98 97 5.0" 229 98 5.0 -125 99 5.0 -129 20 102 5.0 -138 *

Acid Equation 5.0 - 48 * = 1- (6,7-Dimethoxy-3,4-dihydro-2H-isoquinolin-1-one-2-yl) -3- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride, (see Example 1 of GB 1,548,844).

Further, for example, the following compounds have been investigated for their biological activities, as further described below.

DK 156720B

24 A = 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 3,4-Dimethoxy-phenyl) -ethyl-amino] -propane dihydrochloride, B = 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-5-3-yl ] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride, C = 1- [7,8-dimethoxy-1,3,4 5-Tetrahydro-2H-3-benzazepine-1,2-dione-3-yl] -3- [N-methyl- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride , D = 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-1,3-benzodi-azepin-2-one-3-yl] -3- [N-methyl- ( 2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane, E = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one -3-yl] -3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride, F = 1- [7,8-dimethoxy-1,3, 4,5-Tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -ethyl amino] propane, G = 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-methoxy-phenyl) -ethyl) -amino] -propane hydrochloride, H = 1- [7,8-dime thoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-methoxy-phenyl) -ethyl) - amino] -propane hydrochloride, -1-1.5 = 1 [7,8-methylenedioxy-LA3, "4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3 - [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride, J = 1- [7,8-dimethoxy-1,3,4,5- tetrahydro-2H-3-benzazepine- * 2-ηη-3-γ1] -3- [N-allyl-N · - (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] - propane hydrochloride and K = 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3) , 4-methylenedioxy-phenyl) -e-thienylamino] -propane hydrochloride and by comparison: L = 1- [7,8-dimethoxy-1,2,3,4-tetrahydro-5H-2-benzazepine - 1-one-2-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

DK 156720 B

25 1. Cats heart rate activity.

The activity of the test compounds at heart rate was investigated per dose on 7 cats of both sexes and with an average weight of 2.5-3.5 kg. For this, the 5 cats were anesthetized with nembutal (30 mg / kg i.p.) and chloralose-urethane (40 mg / ml chloralose + 200 mg / ml urethane as needed). The test compound was injected into aqueous solution into vena saphena or duodenum.

The heart rate was recorded before and after substance ingestion by a Grass tachograph based on the electro-cardiogram (chest wall drain) on a Grass polygraph:

The values found are listed in the table below:

Connect Dose Heart Rate Half Life 12 mg / kg decrease (minutes) A 1.0 i.v. - 55%> 120 B 1.0 i.v. - 45%> 120 C 1.0 i.v. - 44%> 90 D 1.0 i.v. - 41% 80 20 E 1.0 i.v. - 45%> 90 F 1.0 i.v. - 51% ^ 120 L 1.0 i.v. - 8.2% 13 2. Heart rate activity with guinea pigs: 25 Isolated spontaneously striking guinea pigs of both cows with a body weight of 300-400 g were examined in an organ bath in thyroid solution. The nutrient solution was provided with the carbogen (95% + 5% CC 2) and kept constant at 30 ° C. The contraction was recorded isometrically with an extraction measuring strip on a Grass polygraph. The test compounds were added to the organ baths for 60 minutes at various concentrations.

From the maximum effects, concentration-activity curves were prepared, and from these, the concentration which reduced the stroke rate by 30% (= EC-6030) was determined.

26

DK 156720 B

The values found are listed in the table below:

Compound EC-603Q [yg / ml] A 0.030 5 C 0.097 D 0.058 E 0.066 P 0.014 G 0.014 10 H 0.0079 I 0.063 J 0.050 K 0.014 15 Acute toxicity:

The acute toxicity of the test compound was determined in mice (observation time: 14 days) following intra-venous and oral administration: 20

. Compound Toxicity {LDC / J

____DU_ A 89 mg / kg i.v. 1,350 mg / kg p.o.

Due to their pharmacological properties, the compounds of the present invention are suitable for the treatment of sinus tachycardias of various genesis and for the prevention and treatment of ischemic heart disease.

Conveniently, the dosage required to achieve a desired activity is one to twice daily, 0.03-0.4 mg / kg body weight, preferably 0.07-0.25 mg / kg body weight. For this purpose, the compounds in question with de.n. .alms .formels I as well as physiologically acceptable.

acid addition salts with inorganic or organic acids, optionally in combination with other active substances, together with one or more inert, usual carriers-to-f-fer and / or disinfectants, -f-ex. - with maize path— 35

DK 156720B

27 sugar, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerol, water / sorbit, water / polyethylene glycol, propylene glycol, carboxymethyl cellulose or fatty acids, fatty substances, - suitable mixtures thereof, are incorporated into conventional galenic formulations, such as tablets, dragees, capsules, powders, suspensions, drops, ampoules, juices or spells.

The method of the invention is described in more detail by the following examples.

Preparation of the starting compounds:

Example A

7,8-Dimethoxy-l, 3-dihydro-2H-3-benzazepin-2-one.

a) 3,4-Dimethoxyphenylacetic acid chloride.

To a suspension of 549.4 g of 3,4-dimethoxyphenylacetic acid in 600 ml of methylene chloride, 600 ml of thionyl chloride was added dropwise over a period of 20 hours.

After completion of gaseous development (16 hours), it was refluxed for an additional hour. After removing the slightly volatile components, the residue was distilled off in vacuo.

Yield: 486 g (80.8% of theory).

Bp: 134-136 ° C / 1.95 mbar.

28

DK 156720 B

b) N- (2,2-Dimethoxyethyl) -3,4-dimethoxyphenylacetamide.

Under ice-cooling, a solution of 485.2 g of 3,4-dimethoxyphenylacetic acid chloride in 1.1 liters of methylene chloride at 15-20 ° C was dripped to a solution of 246.2 ml of 5 aminoacetaldehyde dimethyl acetal and 315 ml of triethylamine in 2.2 liters of methylene chloride. and an hour was left at 16-18 ° C. Then it was extracted several times with water, dried over magnesium sulfate and evaporated. The oil obtained slowly crystallized.

Yield: 608 g (95% of theory).

Mp. 66-69 ° C.

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

To a solution of 600.6 g of N- (2,2-dimethoxyethyl) -3,4-dimethoxyphenylacetamide in 3 liters of concentrated hydrochloric acid was added 3 liters of glacial acetic acid. After standing for 17 hours at room temperature, the reaction mixture was poured on ice. The precipitated crystals were aspirated, washed neutral with water and dried. Yield: 350 g (75.4% of theory).

Mp: 234-237 ° C.

Example B

-3 = ,. 8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one.

A suspension of 21.9 g (0.1 mole) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine 2-one and 1.5 g of palladium / carbon (10%) in 200 ml of glacial acetic acid was hydrogenated at 50 ° C and a hydrogen pressure of 5 bar. After filtering off the catalyst, the solvent was evaporated in vacuo and the residue was taken up in methylene chloride. After extraction with sodium carbonate solution and washing with water, the residue was dried over magnesium Tumor sulfate, evaporated and purified over silica gel with methylene chloride and then with increasing methanol content (up to 10%). Yield: 12.6 g (57% of that theory.).

Mp: 188-191 ° C.

DK 156720 B

29

Example C

7.8- Dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine.

To a suspension of 1.3 g (6 mmol) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 1.1 g (3 mmol) of sodium borohydride in 20 ml dioxane was added a solution of 1.8 g of glacial acetic acid in 10 ml of dioxane, refluxed for 3 hours, evaporated and decomposed with water. The mixture was shaken twice with methylene chloride, the extract was evaporated and the residue was taken up in ether. After filtration, the ether was removed in vacuo.

Yield: 1.1 g (92.7% of theory).

Mp: 86-89 ° C.

Example D

N- [3- [Ν'-methyl- (2- (3,4-dimethoxyphenyl) ethyl) amino] propyl] -2- (2-amino-4,5-dimethoxy-phenyl) -acetamide .

33.3 g (0.07 mol) of N- [3- [Ν'-Methyl-N '- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyl] -2- (2 -nitro-4,5-20 dimethoxy-phenyl) -acetamide, dissolved in 500 ml of methanol, was hydrogenated at 25 ° C and a hydrogen pressure of 5 bar for 8 hours in the presence of 10% palladium / carbon. After removal of the catalyst, the solvent was distilled off in vacuo.

25 yield: 31.5 g (100% of theory), viscous oil.

Example E

6.9- Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one.

2.0 g (0.007 mol) of N- (2,2-Dimethoxyethyl) -2,5-dimethoxyphenylacetamide was poured with 3 ml of polyphosphoric acid and stirred for 60 minutes at 90 ° C. Then ice water was added and the precipitated product was filtered off and dried.

Yield yield: 0.98 g (64% of theory).

Mp: 188-191 ° C.

DK 156720 B

30

Example P

7,8-Dimethyl-l, 3-dihydro-2H-3-benzazepin-2-one.

Prepared analogously to Example E from N- (2,2-dimethoxyethyl) -3,4-dimethyl-phenylacetamide and polyphosphoric acid.

Yield: 40.1% of that theory.

Mp: 220-224 ° C.

Example G

7,8-Dimethoxy-5-methyl-1,3-dihydro-3,4-benzodiazepin-2-one.

19.5 g (0.082 mole) of 2-Acetyl-4,5-dimethoxyphenyl acetic acid were suspended in 200 ml of ethanol, 8.2 ml of 98% hydrazine hydrate was added and refluxed for 6 hours. The reaction mixture was evaporated in vacuo and purified over a silica gel column with methylene chloride and 1% ethanol as eluent.

Yield: 9.6 g (50% of theory).

IR Spectrum (Methylene Chloride): 3300 cm -1 (NH) 2830 cm -1 (OCH3) 1650 cm -1 (CO).

Example H

-7-, 8-Dimethoxy-1,3,4,5-tetrahydro-ZH-3-benzazepine-2,4-dione a) 7,8-Dimethoxy-2-amino-4-bromo-1H-3 -benzazepine hydro ~ bromide.

3/7 g (0.017 mol) of 3,4-Dimethoxy-o-phenylene-diaceto-hiTRX was suspended in 10 ml of glacial acetic acid and at 20 ° C 12 ml of 30% hydrogen bromic acid in glacial acetic acid was added. The mixture was stirred for 3 hours at room temperature, the precipitated precipitate was aspirated, washed with glacial acetic acid and then with acetone / ether, and dried.

Yield: 5.3 g (82.8% of theory).

Mp: 210-211 ° C (dec.).

B) 7,8-Dimethoxy-1,1,3,3,5-tetrahydro-2H = 3-benzazepine-2,4- * dione.

5.3 g (0.014 mol) of 7,8-Dimethoxy-2-amino-4-bromo-1

DK 156720 B

31 3-Benzazepine hydrobromide was dissolved in 100 ml of water at 85 ° C, 1.3 g of anhydrous sodium acetate was added and heated at 90 ° C for one hour. The reaction mixture was cooled, suctioned, washed with cold water and dried.

Yield: 2.9 g (88% of theory).

Mp: 235 ° C (dec.).

Example I

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

Prepared analogously to Example B by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benz-azepin-2-one-3-yl] -3- (N-benzyl-methylamino) propane.

Yield: 87% of that theory.

Mp: 110 ° C (dec.).

Example J

l-Chloro-3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

A) 3- [N-Methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propanol.

A mixture of 2.1 g (0.011 mole) of N-methyl-2- (3,4-dimethoxyphenyl) ethylamine and 0.9 g (0.011 mole) of acrylic acid methyl ester was allowed to stand overnight at room temperature. The resulting product thus obtained was dissolved in 40 ml of ether and, over 15 minutes, stirred to a suspension of 0.3 g (0.008 mol) of lithium aluminum hydride in 20 ml of ether. After 5 hours of refluxing, 30 ml of saturated aqueous sodium sulfate solution was cooled and then dripped. The precipitated precipitate was aspirated over diatomaceous earth and the filtrate was shaken with methylene chloride. The organic phase was dried over sodium sulfate and evaporated to dryness, Yield: 3 g (89.7% of theory).

IR Spectrum (Methylene Chloride): 3600, 3230 cm 2 (OH) m / e = 253 (c14 H23 NO3 '253.35).

32

DK 156720 B

b) 1-Chloro-3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

To 4 g of 3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) amino] propanol was added 2.75 g of benzenesulfonic acid chloride. After 1/2 hour standing, dissolved in methylene chloride, washed with 30% rs sodium hydroxide solution and water, dried over sodium sulfate and evaporated in vacuo. After purification over a silica gel column (eluent: methylene chloride / ethanol), a color 10 oil.

Yield: 1 g (17% of theory).

C14H22C1N02 (271 ^ 8)

Calculated: C: 61.86 H; 8.15 N: 5.15

Found: 62.00 8.00 4.63.

15

Example K

N-Methyl-N- [2- (3,4-dimethoxy-phenyl) -ethyl] -azetidinium bromide.

3 g (0.011 mol) of 3- [N-Methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propanol was dissolved in 15 ml of methylene chloride and at 0-5 ° C. a solution of 2 ml of phosphorus tribromide in 5 ml of methylene chloride was added dropwise.

After warming to room temperature, 2 hours was refluxed. It was evaporated to dryness, then dissolved in methylene chloride and washed with 2N sodium hydroxide and water. The organic phase was dried over sodium sulfate and evaporated to dryness. After purification of the crude product over a silica gel column (eluent: methylene chloride / ethanol = 100: 5), the residue was heated an additional 40 minutes at 60-70 ° C. Yield: 1.8 g (48% of theory).

Mp: 175-180 ° C.

Example L

7,8-Dimethoxy-2,3-dihydro-1H-3-benzazepine.

To a boiling suspension of 0.8 g of lithium aluminum hydride in 100 ml of absolute dioxane was added 2.2 g (0.01 mole) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2

DK 156720 B

33 on and then heated for 3 hours at reflux.

Under ice-water cooling, 10% ammonium chloride solution was added and the resulting precipitate was aspirated. The filtrate was evaporated in vacuo to a volume of ca.

5 to 20 ml, the precipitated white precipitate was aspirated and re-washed with a little dioxane. Yield: 0.9 g (43.8% of theory).

Mp: 162-163 ° C.

Manufacture of end products:

Example 1 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy) -phenyl) -ethyl) -amino] -propane hydrochloride.

a) 1- (7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane.

131.5 g (0.6 mol) of 7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one was suspended in 900 ml of dimethylsulfoxide and with stirring 80.9 was added. g (0.72 mole) of potassium tert.butylate. After 10 minutes, the obtained solution was cooled with ice-water cooling to 77 ml '(0.72 mole) of 1-bromo-3-chloropropane in 300 ml of dimethylsulfoxide. After an hour, poured on ice water. After a short time, the greasy precipitate began to crystallize. The precipitate was aspirated, dissolved in acetone, again precipitated with water, extracted and dried.

Yield: 155.5 g (87.3% of theory).

Mp: 101-103 ° C.

B) 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4- dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

5.9 g (0.02 mol) of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 11.7 g (0.06 mol) N-methyl-2- (3,4-dimethoxy-phenyl) -ethylamine was heated at 100 ° C for 3 hours, cooled and dissolved in ethyl acetate / water. The organic phase was separated, washed 3 times with 1% acetic acid and 2 times with 2N hydrochloric acid.

34

DK 156720 B

The hydrochloric acid extract was adjusted to ammonia and extracted with methylene chloride. The solvent of the extract was removed in vacuo, the residue was dissolved in acetone and the hydrochloride was precipitated with ethereal hydrochloric acid.

Yield: 6.9 g (70.3% of theory).

Mp: 190-191 ° C (dec.).

Example 2 1- [7,8-Dimethoxy-2,3,4,5-tetrahydro-1H-3,5-benzodiazepine-2,4-dione-3-yl] -3- [N-methyl N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

4.6 g (0.01 mole of N- [3- [N'-Methyl-N, - (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyl] -2- ( 2-Amino-4,5-dimethoxy-phenyl) -acetamide and 3.6 g (0.022 mol) of Ν, Ν'-carbonyldiimidazole were boiled in 100 ml of acetonitrile for 33 hours. in vacuo and the residue was purified over Alumina Woelm N, Akt.III, with methylene chloride and 15% acetone as eluent.

The fractions were evaporated in vacuo, the residue was dissolved in acetone and precipitated with ethereal hydrochloric acid. Yield: 1.1 g (21.7% of theory).

Mp: 125-130 ° C.

Example 3 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 2-amino-3,5-dichloro-phenyl) amino] propane.

Prepared analogously to Example 1b by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N - [2- (2-amino-3,5-dichlorophenyl) ethyl] methylamine. Oil.

UV Spectrum (Ethanol): Xmax. 240 nm (0.34) 285 nm (0.14) 306 nm (0.10) IR Spectrum (dichloromethane): 2810 cm 2 (N-alkyl) 2840 cm -1 (0-CH 3) 1655 cm -1 (C = 0) 1520 and 1620 cm -1 (C = C).

35

DK 156720 B

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

5.8 g (0.0127 mol) of 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane, dissolved in 60 ml glacial acetic acid, was hydrogenated for 5 hours at room temperature and a hydrogen pressure of 5 bar in the presence of 10% palladium. /coal.

The catalyst was filtered off, the filtrate was evaporated in vacuo and the residue was taken up in methylene chloride / semi-saturated potassium carbonate solution. The organic phase was treated with activated charcoal / bleaching soil, filtered and evaporated in vacuo. Then, the residue was dissolved in acetone and the dihydrochloride precipitated with ethereal hydrochloric acid.

Yield: 6.2 g (92% of theory).

Mp: 137 ° C (dec).

Using the equimolar amount of hydrochloric acid 20, the hydrochloride was obtained with m.p. 165-168 ° C.

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

a) 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane.

Prepared analogously to Example 1a by reacting 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one with 1-bromo-3-chloropropane (yield: 50% of theory or analogous to Example 4 by catalytic hydrogenation of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane (yield : 88% of that theory.).

Mp: 84-85 ° C.

35 36

DK 156720 B

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

Prepared analogously to Example 1b by reaction of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N -methyl-2- (3,4-dimethoxy-phenyl) ethylamine.

Exchanges: 15.2% of that theory.).

Mp: 135-137 ° C (dec.).

10

Example 6 1- [7,8-Dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy) phenyl) ethyl) amino] propane dihydrochloride.

2.7 g (6 mmol) of 1- [7,8-Dimethoxy-1,3,4,5-tetrahydid-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane was dissolved in 100 ml of absolute ether and 100 ml of absolute tetrahydrofuran added to 0.25 g of lithium aluminum hydride and boiled 3.5 for 20 hours. under reflux. After cooling, a 10% ammonium chloride solution was added, cooled, and the filtrate was evaporated. Evaporation residue was purified over a silica gel column with methylene chloride. The fractions were evaporated, the residue 25 was dissolved in acetone and the dihydrochloride was precipitated with methanolic hydrochloric acid.

Yield: 1.5 g (48.5% of theory).

Mp: 270-271 ° C (dec.).

Example 7 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 1b by reaction of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N-methyl-2 - (4-methoxy-phenyl) -ethylamine.

Yield: 76.2% of that theory.

Mp: 139-142 ° C.

DK 156720 B

37

Example 8 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) methoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benz-azepin-2-one-3-yl] -3- [N-methyl-N - (2- (4-methoxy-phenyl) -ethyl) -amino] -propane.

Yield: 73.3% of theory.

Mp: 175-177 ° C.

Example 9 1- [7,8-Methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy) (phenyl) -ethyl) -amino] -propane hydrochloride.

a) 1- (7,8-Methylenedioxy-1,3-dihydro-2H-benzazepin-2-one-3-yl) -3-chloro-propane.

Prepared analogously to Example 1a by reacting 7,8-methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one 20 (mp: 195 ° C (dec.)) With 1-bromo-3-chloropropane .

Yield: 72.1% of that theory.

Mp: 75-79 ° C.

b) 1- [7,8-Methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy) -phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 1b by reacting 1- (7,8-methylenedioxy-1,3-dihydro-2H-benzazepin-2-one-3-yl) -3-chloropropane with N-methyl-2- (3.4 -dimethoxy-phenyl-ethylamine.

Yield: 77.2% of that theory.

Mp: 185-187 ° C.

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

Prepared analogously to Example 4 by catalytic

DK 156720 B

38 hydrogenation of 1- [7,8-methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4- dimethoxy-phenyl) -ethyl) -amino] -propane. Yield: 77.3% of that theory.

Mp: 210-212 ° C.

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

To a mixture of 0.22 g (0.5 mmol) of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] - 3- [N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane, 0.5 ml of 37% formaldehyde solution, 2 ml of acetonitrile and 0.1 g of sodium cyanoborohydride were added at room temperature. added 0.05 ml of glacial acetic acid. After 2 hours, an additional 0.05 ml of glacial acetic acid was added and stirred for 1/2 hour. The work-up was by evaporation, absorption in methylene chloride, washing with 2N sodium hydroxide solution and water. The organic phase dried over sodium sulfate was evaporated and purified over silica gel.

Üdby'ifinge: 104 mg (45.5% of theory), viscous oil.

IR Spectrum (methylene chloride): 1645 cm45 ((CO), 1510 cm ^ ((aromat. C = C) m.p. of dihydrochloride: 137 ° C (dec.).

Example 12 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3 (4-Dimethoxy-phenyl) -ethyl) amino] -propane dihydrochloride.

22 g (0.075 mol) of N- [3- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) propyl] methylamine together with - 7-R 2 ~ g- (0, 3, 6 · moles) - 2 H - (37 4 - dimethoxy-phenyl ~) ----- ----- ethyl chloride heated for 20 hours at 140 ° C. After dissolving the reaction product in methylene chloride, the solution was washed once with 2N sodium hydroxide solution and twice with "water", drying over sodium sulphate and evaporated. The residue was purified by chromatography on silica gel.

DK 156720 B

39 cagel (grain size: 0.063-0.2 mm, eluent: methylene chloride / methanol = 10: 1). The product thus obtained was dissolved in acetone and the dihydrochloride precipitated with ethereal hydrochloric acid.

Exchanges: 8.0 g (45% of theory),

Mp: 135-136 ° C (dec.).

Example 13 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-10-one-3-yl] -3- [N-methyl-N- (2- 4-acetylamino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

To 3 g (0.0063 mol) of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl N- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane in 50 ml of chloroform and 0.7 g (0.007 mol) of triethylamine was added portionwise at boiling temperature for a total of approx. 0.8 ml of acetyl chloride and boiled for several hours. After cooling to room temperature, water was washed. The aqueous phase was adjusted strongly alkaline with 2N sodium hydroxide solution and extracted with methylene chloride. The separated organic phase was dried over sodium sulfate and evaporated. The crude product thus obtained was purified by chromatography on silica gel (grain size: 0.063-0.2 mm, eluent: methylene chloride / methanol) = 8: 1).

Mp: 144-146 ° C.

Example 14 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-30-on-3-yl] -3- [N-methyl-N- (2- ( 4-amino-3,5-dibromo-phenyl) -ethyl) -amino] -propane.

To a solution of 1 g (0.0025 mol) of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-amino-phenyl) -ethyl) -amino] -propane in 20 ml of 95% acetic acid was added dropwise 0.8 g (0.005 mol) of bromine at room temperature with stirring. . After approx. 60 minutes, the solvent was removed on rotary evaporator. The evaporation residue was partitioned between 2N

DK 156720 B

40 um hydroxide solution and methylene chloride. The methylene chloride phase was washed once with water, dried over sodium sulfate and evaporated in vacuo. The obtained oily evaporation residue crystallized at room temperature and was recrystallized from absolute ethanol for further purification.

Mp: 105-110 ° C.

Example 15 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

0.22 g (0.5 mmol) of 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N - (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane was heated together with 0.2 ml of 37% formaldehyde solution and 0.2 ml of 100% formic acid for 20 minutes at 90 DEG. 100 ° C. The work-up was analogous to Example 11. Viscous oil.

IR Spectrum (methylene chloride): 1645 cm -1 (CO), 1510 cm -1 (aromat. C = C)

Mp. of dihydrochloride: 137 ° C (dec.).

Example 16 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-25-3-yl] -3- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl-amino] -propane.

To a solution of 3.29 g (10.0 mmol) of N- [3- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -propyl] methylamine hydrochloride and 1.8 g (10.0 mmol) of 2-3Ό (3,4-dimethoxy-phenyl) -acetaldehyde in 40 ml of ethanol were added 1.26 g (20 mmol) of sodium cyanoborohydride , with the addition of 2N hydrochloric acid, ensuring that a pH of 6-7 was maintained. At this pH, the mixture was stirred for an additional 48 hours at room temperature. After evaporation of the solution in vacuo, the evaporation residue was taken up in dilute hydrochloric acid and extracted twice with ether. Then, the aqueous phase was adjusted alkaline, extracted three times with methylene chloride.

DK 156720 B

41, the organic phase was evaporated and purified over silica gel. Oil.

IR Spectrum (methylene chloride): 1645 cm -1 (CO) 1510 cm (aromat. C = C) m.p. of dihydrochloride: 137 ° C (dec.).

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

To a solution of 2.77 g (10 mmol) of 3- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -prox. pionic aldehyde and 1.95 g (10 mmol) of N-methyl-2- (3,4-dimethoxy-xy-phenyl) -ethylamine in 40 ml of methanol were added 1.26 g (20 mmol) of sodium cyanoborohydride, addition of hydrochloric acid was ensured to maintain a pH of 6 ”7. Then, at this pH, the mixture was stirred for an additional 50 hours at room temperature. After evaporation of the solution in vacuo, the residue was taken up in dilute hydrochloric acid and extracted three times with ether. Then, the aqueous phase was adjusted alkaline, extracted three times with methylene chloride, and the organic phase was evaporated and purified over silica gel.

A slightly yellowish, viscous oil was obtained.

IR Spectrum (methylene chloride): 1645 cm 3 (CO) 1510 cm (aromat. C = C)

Mp. of dihydrochloride: 137 ° C (dec.).

Example 18 1- [8-Methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -amino] propane dihydrochloride.

a) 1- (8-Methoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane.

Prepared analogously to Example 1a by reacting 8-methoxy-1,3-dihydro-2H-3-benzazepin-2-one (mp: 189-190 ° C) with 1-bromo-3-chloropropane.

Yield: 23% of that theory. , TD_Cy> / - »lr4 * vnm / mufur» nV> l ηνι \ · 1 Γ DK (b) 1- (8-Methoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2 -on-3-yl) -3-chloropropane.

Prepared analogously to Example 4 by catalytic hydrogenation of 1- (8-methoxy-1,3-dihydro-2H-3-benzaze-5-pin-2-one-3-yl) -3-chloropropane.

Yield: 67% of that theory.

Ï R Spectrum (methylene chloride): 1645 cm 2 (CO).

c) 1- [8-Methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4) (dimethoxy-phenyl) -ethyl) -amino] -propane dihydrochloride.

Prepared analogously to Example 5b by reacting 1- (8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with N-methyl-2- (3,4-dimethoxy-phenyl) -ethylamine.

Yield: 14% of that theory.

Mp: 118-121 ° C.

Example 19 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 4-amino-3-chloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 12 from N- [3- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) propyl] methylamine and 2 - (4-amino-3-chloro-phenyl) -ethylbromide. Oil.

IR Spectrum (methylene chloride): 3380, 3480 cm 2 (NH 3) 1645 cm -1 (CO) UV Spectrum (ethanol): Xmax: 238 nm (0.16) 280-290 nm (0.05).

30

Example 20 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-ethyl-N- (2- (4) amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 12 from N- [3- 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) propyl] ethylamine and 2 - (4-amino-3,5-dichloro-phe-nyl) ethyl chloride. Oil.

DK 156720 B

43 -1 IR Spectrum (Methylene Chloride): 3390, 3480 cm (NH 2) 1650 cm -1 (CO) UV Spectrum (Ethanol): Amax: 240 nm (0.13) 280-290 nm (0, 05).

5

Example 21 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 12 from N- [3- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) propyl] methylamine and 2- (4-Amino-3,5-dichloro-phenyl) -ethyl chloride.

Mp: 94-104 ° C.

15

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

Prepared analogously to Example 12 from N- [3- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) propyl] methylamine and 2- (4-amino-3,5-dibromo-phenyl'nyl) ethyl chloride.

Mp: 108-112 ° C.

25

Example 23 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -ethoxycarbonylamino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 13 from 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N - (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane and chloroformic acid ethyl ester. Oil.

IR Spectrum (methylene chloride): 3410 cm 2 (NH)

1650 cm -1 (CO-NO

1735 cm -1 (CO-O) 1800 cm-1 (CO-O) UV Spectrum (Ethanol): Amax: 240 nm (shoulder, 0.08) 280-290 nm (0.03).

DK 156720 B

44

Example 24 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -bis- (ethoxycarbonyl) -amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 13 from 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N - (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane and chloroformic acid ethyl ester. Oil.

-1 IR Spectrum (methylene chloride): 1650 cm (CO-N <) 1730 cm -1 (CO 0-) 1760 cm -1 (CO 0-) 1800 cm -1 (CO 0-) OV Spectrum (ethanol): axmax: 228 nm (shoulder, 0.15) 282 nm (0.03).

15

Example 25 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -ethoxycarbonylamino-3-cyano-amino-5-fluoro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 13 from 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N - (2- (4-amino-3-cyano-5-fluoro-phenyl) -ethyl) -amino] -propane and chloroformic acid ethyl ester in the vicinity of triethylamine.

IR spectrum (methylene chloride): 3400 cm (NH) 2830 cm -1 (OCH 3) 1730, 1650, 1510 cm -1 (CO).

Example 26 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 4-dimethylamino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 11 from 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -35 3- [N-methyl- N- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane, paraformaldehyde and sodium cyanoborohydride in methanol. Oil.

45

DK 156720 B

IR Spectrum (Methylene Chloride): 1650 cm (CO) UV Spectrum (Ethanol): axmax: 227 nm (shoulder, 0.16) 280 nm (0.12).

Example 27 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-amino) 3,5-dichloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 1b from 1- (7,8-10 dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (4-amino -3,5-dichloro-phenyl) -N-methyl-ethyl-amine. 01ie.

IR Spectrum (Methylene Chloride): 3390, 3480 cm 1 ((NI) 1655 cm "1 (CO) UV Spectrum (Ethanol): λmax: 238 nm (shoulder, 0.25) 280 nm (0.1) nm (0.12).

Example 28 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- [N-methyl-N- (2- ( 4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 4 from 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-Amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane and hydrogen in the presence of palladium / carbon in ice-vinegar.

Mp: 94-104 ° C.

Example 29 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-ethyl-N- (2- ( 4-amino-3,5-dibromo-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b from 1- (7,8-35 dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (4-amino-3,5-dibromo-phenyl) -N-ethyl-ethylamine. Oil.

DK 156720B

46 -1 IR Spectrum (Methylene Chloride): 3380, 3480 cm (NH 2) 1645 cm -1 (CO) UV Spectrum (Ethanol): Amax: 240 nm (shoulder, 0.13) 280-290 nm (0.04 ).

5

Example 30 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) amino-3,5-dichloro-phenyl) -ethy1) amino] propane.

Prepared analogously to Example 5b from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (4-amino-3,5-dichloro-phenyl) -N-me-thyl-ethylamine.

Mp: 94-104 ° C.

15

Example 31 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-isopropyl-N- (2- (4 amino-3,5-dichloro-phe-ny1) -ethy1) amino] propane.

Prepared analogously to Example 5b from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (4-amino-3,5-dichloro-phenyl) -N-isopropyl-ethylamine.

Mp. of hydrochloride: <90 ° C (sintering from 70 ° C).

IR Spectrum (Methylene Chloride): 3390, 3480 cm 1 NH (NH₂) 1650 cm ”1 (CO) UV Spectrum (Ethanol): Amax: 238 nm (0.13) 280-290 nm (0.05).

Example 32 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (1-methyl -2- (4-Amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 5b from 1- (7,8-35 dimethoxy-1,3,4,5-tetrahydro-2H-3-henzazepin-2-one-3-yl) -3-chloro-propane and 2- (4-amino-3,5-dichloro-phenyl) -1-methyl-N-methyl-ethylamine.

Mp: 118-128 ° C (dec.).

47

DK 156720 B

Example 33 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-2- (4-amino-3, 5-dichloro-phenyl) -ethyl-amino] -propane hydrochloride.

Prepared analogously to Example 5b from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (4-amino-3,5-dichloro-phenyl) -ethyl-amine.

Mp: 236-241 ° C.

10

Example 34 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) amino-3-chloro-5-methyl-phe nyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (4-amino-3-chloro-5-methyl-phenyl) -N-methyl-ethylamine.

Mp: 60 ° C (sintering, melting at 73 ° C).

IR Spectrum (Methylene Chloride): 3390, 3480 cm (((N 16) 1650 cm "1 (CO) UV Spectrum (Ethanol): λmax: 237 nm (0.14) 280-290 nm (0.05).

Example 35 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 3,5-dichloro-4-hydroxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 5b from 1- (7,8-30 dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (3,5-dichloro-4-hydroxy-phenyl) -N-methyl-ethylamine.

Mp: 225 ° C.

35

DK 156720 B

48

Example 36 1 "[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3 -chloro-5-fluoro-4-β, β, β-tri-fluoroethyl amino-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (3-chloro-5-fluoro-4-3,3,3-trifluoro-ethylamino-phenyl) -N-methyl-ethylamine. m / e = 545/547 (C26H32ClP4N3 ° 3, 546.03).

10

Example 37 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) amino-3-chloro-5-fluoro-phe nyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (4-amino-3-chloro-5-fluoro-phenyl) -N-methyl-ethylamine.

m / e = 463/465 (c24H31ClFN3O3, 463.99).

20

Example 38 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) amino-3-chloro-5-trifluoromethyl-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (4-amino-3-chloro-5-trifluoromethyl-pheny1) -N-methyl-ethylamine. 01ie.

IR Spectrum (methylene chloride): 3410, 3510 cm 2 (NH 2) 1650 cm -1 (CO) 1610, 1520 cm -1 (C = C) 2800 cm 1 (N-alkyl) 2830 cm -1 (OCH 3) UV Spectrum (ethanol): Amax: 241 nm (0.33) 285 nm (0.10) 310 nm (0.08).

49

DK 156720 B

Example 39 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) amino-3-cyano-5-fluoro-phe nyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and N- methyl- (2- (4-amino-3-cyano-5-fluoro-phenyl) -ethyl) -amine.

IR Spectrum (Methylene Chloride): 3400, 3490 cm ”'(NH₂) 2830 cm” 1 (OCH3) 2220 cm "1 (CN) 1650 cm”) (CO).

Example 40 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-benzyl-N- (2- (3,4- dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 1b from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (3.4 dimethoxy-phenyl) -N-benzyl-ethylamine. Yield: 51% of that theory.

Mp: 102 ° C (dec).

Example 41 1- (7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- methylenedioxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 1b from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 2- (3.4 methylenedioxy-phenyl) -N-methyl-ethyl-amine.

Yield: 48% of that theory.

Mp: 160-162 ° C.

35

DK 156720B

50

Example 42 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- (N-benzylmethylamino) -propane hydrochloride.

Prepared analogously to Example 1b from 1- (7,8-5 dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and N-methyl-benzylamine. Exchanges: 92% of that theory.

Mp: 208-209 ° C.

Example 43 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -4- [N-methyl-N- (2- dimethoxy-phenyl) -ethyl) -amino] -butane hydrochloride.

Prepared analogously to Example 1b from 1- (7,8-15 dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -4-chlorobutane and N-methyl-2- (3,4-dimethoxyphenyl) -ethyl-amine.

Exchanges: 85% of that theory.

Mp: 162-164 ° C.

20

Example 44 1- [8-Propoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) ) -ethyl) -amino] -ethane hydrochloride.

Prepared analogously to Example 1b from 1- (8- propoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2-chloro-ethane and N-methyl-2- (3 , 4-dimethoxy-phenyl) -ethylamine. yield; 31% of that theory.

Mp: 155-157 ° C.

30

Example 45 1- [7,8 -> - Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -4- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl-amino] -butane hydrochloride.

Prepared analogously to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benz-azepin-2-one-3-yl] -4- [N-methyl-N - (2- (3,4-dimethoxy-phenyl

DK 156720 B

51 (nyl) -ethyl) -amino] -butane.

Mp: 192-194 ° C.

Example 46 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 3,4-methylenedioxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benz-10-azepin-2-one-3-yl] -3- [N-methyl-N - (2- (3,4-methylenedioxy-phenyl) -ethyl) -amino] -propane.

Yield: 72% of that theory.

Mp: 191-193 ° C.

Example 47 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N- (2- (3,4- dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benz-azepin-2-one-3-yl] -3- [N-benzyl-N - (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane.

Yield; 81% of that theory.

Mp: 152-154 ° C.

25

Example 48 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-allyl-N- (2- (3 (4-Dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride, 3.1 g (0.007 mol) of 1 - [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H 3-Benzazepin-2-one-3-yl] -3- [N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane was combined with 1.0 g (0.007 mol) of potassium carbonate and 0.6 ml (0.007 mol) of allyl bromide boiled under reflux for 21 hours in 100 ml of chloroform.

The organic phase was then extracted with water, dried, evaporated in vacuo and the obtained evaporation residue was purified over an alumina column (300 g, neutral, Activity XII) (eluent; methylene chloride 52

DK 156720 B

with 2% acetone). The hydrochloride was then precipitated. Death rate: 40% of that theory.

Mp: 153-155 ° C.

Example 49 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-propyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 48 from 1- [7,8-10 dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -propane and 1-bromopropane.

Yield: 53% of that theory.

Mp: 80 ° C (dec).

15

Example 50

Isomer mixture of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (2- and 4- nitro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 1b from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and N-methyl-2- (4- and 2-nitro-phenyl) -ethylamine. Yield: 70% of that theory.

IR Spectrum (Methylene Chloride): 1655 cm -1 (CO) 1510 and 1345 cm -1 (NO2)

NMR Spectrum (CDClg / ÎÎO): δ = 8.10 ppm, d (J = 9Hz), 2H

(aromat.), (4-nitro compound), δ = 7.83 ppm, d (J = 7Hz), 2H (aromat.), (2-nitro compound).

Example 51

Isomer blend of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-35 benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (2-amino) and 4-amino-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 4 by catalytic reduction of an isomer mixture of 1- [7,8-dimethoxy-1,3- 53

DK 156720 B

dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (2-and-4-nitro-phenyl) -ethyl) -amino] -propane.

Yield: 34% of that theory.

Mp: 100 ° C (dec).

IR spectrum (methylene chloride): 1660 cm 3 (CO) C24H31N3 ° 3'HCl, (446'0)

Calculated: C: 64.34 H: 7.65 N: 9.38 Cl: 7.91 Found: 63.60 7.20 9.28 7.94.

Example 52 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-acetylamino phenyl) ethyl) amino] propane and 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -15 3- [N-methyl-N - (2- (2-acetylamino-phenyl) -ethyl-amino] -propane.

1.8 g (0.004 mol) isomer mixture of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- ( 2- (2- and 4-amino-phenyl) -ethyl) -amino] -propane was stirred for 20 hours in a mixture of 10 ml glacial acetic acid and 10 ml of acetanic anhydride at room temperature. Then water was added, neutralized with sodium bicarbonate and extracted with methylene chloride. After drying the organic phase, the residue was evaporated in vacuo and the residue was chromatographed on alumina (200 g, neutral, Activity IV) (eluent: methylene chloride + 1% methanol).

Yield of 2-acetylamino compound: 0.24 g (14% of theory).

Mp: 62-66 ° C.

Yield of 4-acetylamino compound: 0.5 g (28% of theory).

Mp: 69-72 ° C.

35 54

DK 156720 B

Example 53 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl} -amino] -propane.

A) N- [3- [Ν'-Methyl-N '- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyl] -2- (2-amino-4,5- dimethoxy-phenyl) -ethylamine.

4.5 g (0.01 mole) of N- [3- [N1-Methyl-N1- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyl] -2- (2-amino -4,5-dimethoxy-phenyl) -acetamide was dissolved in 100 ml of tetrahydrofuran and under a nitrogen atmosphere 60 ml of 1 M diborane solution in tetrahydrofuran was added. The clear solution was left to stand for 2 days at room temperature and then decomposed with 20 ml of semi-concentrated hydrochloric acid under cooling. The tetrahydrofuran was distilled off in vacuo and the hydrochloric acid evaporation residue was adjusted alkaline with concentrated sodium hydroxide solution upon cooling. The precipitated oil was taken up in methylene chloride and the organic solution was separated> 20 dried and evaporated in vacuo. The oily residue was purified over silica gel with methylene chloride and 1% methanol.

Yield: 2.9 g (67.2% of theory).

IR Spectrum (methylene chloride): 2830 cm30 ((OCHCH) 2800 cm 1 ((N-alkyl).

b) 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one-3-yl] -3- [N-methyl- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 2 by reaction of N- [3- [Ν'-methyl-N1- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propyl] -2- (2-amino -4,5-dimethoxy-phenyl) -ethylamine with N, N'-carbonyl diimidazole.

Yield: 0.9 g (61.5% of theory)

Mp: 116-117 ° C.

35

DK 156720 B

55

Example 54 1- [7,8-Dimethoxy-5-methyl-1,3-dihydro-2H-3,4-benzodiaze-pin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] propane dihydrochloride.

Prepared analogously to Example 1b by reacting 1- (7,8-dimethoxy-5-methyl-1,3-dihydro-2H-3,4-benzodi-azepin-2-one-3-yl) -3-chloro -propane with N-methyl-2- (3,4-dimethoxy-phenyl) -ethylamine.

Yield: 24.2% of that theory.

Mp: 106 ° C.

Example 55 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2-hydroxy-3- [N-methyl-N- (2- (3 (4-Dimethoxy-phenyl) -ethyl) -X-amino] -propane.

a) 1- (7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2,3-epoxy-propane.

Prepared analogously to Example 1a by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 20 epichlorohydrin.

Yield: 94.5% of that theory.

IR Spectrum (methylene chloride): 2830 cm30 ((OCH O) 1660 cm-1 (CO).

b) 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2-hydroxy-3- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

8.25 g (0.03 mole) of 1- (7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2,3-epoxy-propane were dissolved in 100 ml of methanol were added 5.85 g (0.03 mole) of N-methyl-2- (3,4-dimethoxy-phenyl) -ethylamine and boiled under reflux for 3 hours. The methanol was distilled off in vacuo and the residue was purified over a silica gel column with methylene chloride + 1% ethanol.

Yield: 7.8 g (55.2% of theory).

IR Spectrum (Methylene Chloride): 3600 cm 2 (OH) 1650 cm -1 (CO) C26H34N2 ° 6 <470'6>

DK 156720 B

56

Calculated: C: 66.36 H: 7.28 N: 5.95

Found: 66.16 7.26 5.80.

Example 56 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dione-3-yl] -3- [N-methyl-N- (2 - (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

3.5 g of selenium dioxide were added at 70 ° C to a mixture of 150 ml of dioxane and 6 ml of water, stirred for 15 minutes, 10 and then 3 g of silica and 14.8 g (0.03 mol) were added. - [7,8-dimethoxy-l, 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4- dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride. The mixture was refluxed for 6 hours, cooled and filtered. The filtrate was evaporated in vacuo and the residue was purified over a silica gel column with methylene chloride + 1% ethanol as eluent. The fractions were evaporated in vacuo, the residue was dissolved in acetone and the hydrochloride was precipitated with ethereal hydrochloric acid.

Yield: 13.8 g (90.7¾ of theory).

Mp: 196-197 ° C.

Example 57 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -2-hydroxy-3- [N-methyl-N- (2- (3,4-dimethoxy-phe nyl) -ethyl) -amino] -propane.

Prepared analogously to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benz-30-azepin-2-one-3-yl] -2-hydroxy-3- [N -methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane, but in ethanol at 50 bar and 70 ° C with platinum oxide as catalyst.

Yield: 37.5% of that theory.

IR Spectrum (Methylene Chloride): 3470 cm 2 (OH) 1635 cm -1 (CO) C26H36N2 ° 6 (472'6)

Calculated: C: 66.08 H: 7.68 N: 5.93

Found: 66.22 7.57 5.85.

DK 156720 8 57

Example 58 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -nitro-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 5b by reacting 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3-chloro-propane with N -methyl-2- (4-nitro-phenyl) -ethylamine.

Yield: 56.5% of that theory.

Mp: 182 ° C.

Example 59 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3 -nitro-4-acetylamino-phenyl) -ethyl) -amino] -propane dihydrochloride.

0.3 g (1.18 mmol) of N- [3- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) propyl ] -methylamine and 0.34 g (1.3 mmol) of 2- (3-nitro-4-acetylamino-phenyl) -ethyl bromide were refluxed in 5 ml of chlorobenzene and 0.1 ml of pyridine for one hour. The reaction mixture was cooled and the precipitated pyridine hydrobromide was aspirated. The filtrate was evaporated in vacuo and the residue was purified over alumina (neutral,

Activity II) with methylene chloride and 0.5% ethanol as eluent. The oil thus obtained was dissolved in acetone and the dihydrochloride precipitated with ethereal hydrochloric acid.

Yield: 230 mg (57.7% of theory).

Mp: 170 ° C.

30

Example 60 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -fluoro-phenyl) -ethyl) -amino] propane dihydrochloride.

Prepared analogously to Example 5b by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N -methyl-2- (4-fluoro-phenyl

DK 156720 B

58 nyl) -ethylamine.

Yield: 68.7% of that theory.

Mp: 203 ° C.

Example 61 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-acetyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

To 2 g (0.0045 mol) of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N - (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane was added 15 ml of acetanhydride and stirred for 1/2 hour at room temperature.

The mixture was poured into ice water, neutralized with sodium bicarbonate and then extracted with methylene chloride. The organic extract was dried over magnesium sulfate, filtered and evaporated in vacuo. The evaporation residue was purified over alumina (neutral, Activity II) with methylene chloride as the eluent. Yield: 1.5 g (68.5% of theory) 20 IR Spectrum (methylene chloride): 2830 cm30 ((OCH ^) 1640 cm "1 (CO) C27H36N2 ° 6 (484.6)

Calculated: C: 66.92 H: 7.49 N: 5.78

Found: 66.75 7.44 5.80.

25

Example 62 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-ethoxycarbonyl-N- (2- (3) , 4-dimethoxy-pheny3) -ethyl) -amino] -propane.

2.5 g (0.00565 mol) of 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [ N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane and 2.45 g (0.024 mol) of triethylamine were dissolved in 20 ml of methylene chloride. After adding 2.6 g (0.024 mole) of chloroformic acid ethyl ester 35, the mixture was stirred for 30 minutes at room temperature, the solution was washed twice with water, dried over magnesium sulfate and evaporated in vacuo. Evaporation residue was purified over alumina (neutral, Activity

DK 156720B

59 II) with methylene chloride as eluant. Yield: 1.5 g (51.6% of theory).

IR Spectrum (methylene chloride): 1690, 1650 cm 2 (CO) C 28 H 38 N 2 O 7 (514'6) 5 Calculated: C: 65.30 H: 7.44 N: 5.44 64.19 H: 7.14 , 27th

Example 63 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-10-3-yl] -3- [N-methyl-N- (2- ( 2,6-dichloro-phenyl) -ethyl) -amino] -propane dihydrochloride.

Prepared analogously to Example 5b by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-henzazepin-2-one-3-yl) -3-chloro-propane with N- methyl 2- (2,6-dichloro-phenyl) -ethylamine.

Exchanges: 70.5% of that theory.

Mp: 147 ° C.

Example 64 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3 , 4-dichloro-phenyl) -ethyl) -amino] propane dihydrochloride.

Prepared analogously to Example 5b by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N -methyl-2- (3,4-dichlorophenyl) -ethylamine. Exchanges: 57.6% of that theory.

Mp: 161 ° C.

Example 65 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2- [N-methyl-N- (2- (3,4- dimethoxy-phenyl) -ethyl) -amino] -ethane.

a) 1- (7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-35 yl) -2-chloro-ethane.

Prepared analogously to Example 1a by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 1-chloro-2-bromethane.

DK 156720B

60

Yield: 20% of that theory.

Mp: 114 ° C.

b) 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2- [N-methyl-N- (2- (3,4-dimethoxy) -phenyl) -ethyl) -5-amino] -ethane.

Prepared analogously to Example 1b by reacting 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2-chloroethane with N-methyl-2- (3 , 4-dimethoxy-phenyl) -ethylamine.

10 Yield: 72% of that theory.

IR Spectrum (methylene chloride): 2830 cm30 ((OCH ^) 2790 cm ^ ((N-alkyl) 1655 cm-1 (CO) NMR Spectrum (CDClg): δ = 2.3 ppm, s, 3H (NCH3), 3.85 ppm, s, 12H (OCH +), 6.15 ppm, d (J = 8Hz), 1H (olefin.), 6.35, d (J = 8Hz), 1H (olefin.).

Example 66 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -2- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] -ethane hydrochloride.

Prepared analogously to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benz-25-azepin-2-one-3-yl] -2- [N-methyl-N - (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -ethane.

Yield: 59% of that theory.

Mp: 183-189 ° C.

Example 67 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione-3-yl] -3- [N-methyl-N- (2 - (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

a) 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione-3-yl) -3-chloropropane.

Prepared analogously to Example 1a by reacting 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione (mp: 235 ° C (dec.)) With 1- bromo-3-chloropropane.

DK 156720B

61

Yield: 26% of that theory.

IR Spectrum (KBr): 1660 cm 2 (CO).

b) 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione-3-yl] -3- [N-methyl-N- (2- (3,4-Dimethoxy-phenyl-ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 5b by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione-3-yl) -3-chloro-propane with N-methyl-2- (3,4-dime-thoxy-phenyl) -ethylamine.

10 Yield: 35% of that theory.

Mp: 163-164 ° C.

Example 68 1- [7-Benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benz-azepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phe nyl) -ethyl) -amino] -propane.

a) 1- (7,8-Dihydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane.

8.9 g (0.03 mol) 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro -Propane was dissolved in 100 ml of methylene chloride and at -60 ° C 2.1 ml of boron tribromide was added. The reaction temperature was slowly allowed to rise to 20 ° C and stirred at this temperature for 10 hours. The resinous precipitate 25 was brought into crystalline form by adding 100 ml of water and then stirring for 1 hour. The precipitate was extracted and washed with water and methylene chloride. For purification, the crystallate was stirred with acetone and extracted.

Yield: 7.3 g (90.2% of theory).

Mp: 177-178 ° C.

b) 1- (7-Hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benz-azepin-2-one-3-yl) -3-chloro-propane and 1- ( 7-Benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane.

To 19 g (0.07 mol) of 1- (7,8-dihydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane and 10,6g

DK 156720 B

62 potassium carbonate in 250 ml of dimethyl sulfoxide was added 19.5 g (0.154 mol) of benzyl chloride. The mixture was stirred for 2 days at room temperature, poured into ice water and extracted several times with ethyl acetate. The organic extracts 5 were washed 3 times with water, dried over magnesium sulfate and evaporated in vacuo. Isomer separation took place over silica gel with methylene chloride and 3% acetone as eluent.

Yield of 7-hydroxy compound: 6 g (23.8% of theory), 10 mp: 163-165 ° C.

Yield of 8-hydroxy compound: 4.5 g (17.9% of theory), mp: 185-186 ° C.

c) 1- [7-Benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-Dimetho-xy-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b by reacting 1- (7-benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N-methyl-2- (3,4-dimethoxy-phenyl) -ethylamine.

Yield: 75.4% of that theory.

Mp: 128-129 ° C.

Example 69 1- [7-Hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benz-azepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phe nyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b by reacting 1- (7-Lydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N-methyl-2-30 (3,4-dimethoxy-phenyl) -ethylamine.

Yield: 47.2% of that theory.

Mp: 157-158 ° C.

Example 70 1- [7,8-Dihydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- 3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

0.52 g (0.001 mol) 1- [7-Hydroxy-8-benzyloxy]

DK 156720B

63 1,3,4,5-Tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) - ethyl) -amino] -propane was hydrogenated 5 hours at 20 ° C and 5 bar in 100 ml of methanol and 0.2 g of palladium / carbon (10% 1s). Catalyst 5 was aspirated, the filtrate was evaporated in vacuo and the residue was purified over silica gel with methylene chloride + 1% ethanol as eluent.

Yield: 0.2 g (43.9% of theory).

IR Spectrum (methylene chloride): 3520 cm20 ((OH) 1640 cm40 1 (CO) C24H32N2 ° 5'1 / 2 H2 ° <455'5)

Calculated: C: 63.28 H: 7.74 N: 6.15

Found: 63.44 7.77 6.13.

Example 71 1- [7-Benzyloxy-8-methoxy-1,3,4,5-tetrahydro-2H-3-benz-azepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane dihydrochloride.

0.52 g (0.001 mol) of 1- [7-Benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N- Methyl K- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane was dissolved in 30 ml of dimethylformamide and 50 mg of 50% sodium hydride dispersion (in oil) was added. . The mixture was heated for 30 minutes at 60 ° C, 25 ml of dimethyl sulfate was added and heated for 2 hours at 60 ° C. The dimethylformamide was distilled off in vacuo, the residue was taken up in methylene chloride, the organic phase was washed with water, dried and evaporated in vacuo. The resinous evaporation residue was purified over alumina (neutral, Activity II) with methylene chloride as eluant. The obtained oil was dissolved in acetone and the dihydrochloride was precipitated by the addition of ethereal hydrochloric acid.

Yield: 250 mg (41% of theory).

Mp: 117-120 ° C.

64

DK 156720B

Example 72 1- [7-Methoxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benz-azepin-2-one-3-yl] -3- [N-methyl-N- ( 2- (3,4-dimethoxy-phe nyl) -ethyl) -amino] -propane.

Prepared analogously to Example 71 by reacting 1- [7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N- methyl N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane with dimethyl sulfate.

Yield: 70% of that theory.

IR Spectrum (Methylene Chloride): 1655 cm -1 (CO) NMR Spectrum (CDCl 3 / D 2 O): δ = 2.3 ppm, s, 3H (NCH 3), 5.1 ppm, s, 2H (benzyl.) , 6.5-6.8 ppm, m, 5H (aromat.), 7.4 ppm, s, 5H (aromat.).

15

Example 73 1- [7-Hydroxy-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzaze-pin-2-one-3-yl] -3- [N-methyl-N- ( 2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 70 from 1- [7- benzyloxy-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl -N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride by catalytic debenzylation.

Yield: 45.2% of that theory.

IR Spectrum (Methylene Chloride): 3530 cm 2 (OH) 2830 cm -1 (OCH 3) 1650 cm (CO) C 25 H 34 N 2 ° 5'HCl (479 ° C) Calculated: C: 62.69 H: 7.36 N: 5.85

Found: 63.15 7.57 5.64.

Example 74 1- [7-Methoxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazpin-2-one-3-yl] -3- [N-methyl-N (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 70 from 1- [7-

DK 156720 B

65 methoxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy) -phenyl) -ethyl) -amino] -propane by catalytic debenzylation. Exchanges: 29.4% of that theory.

IR spectrum (methylene chloride): 1640 cm cm cm (CO) C 25 H 34 N 2 ° (442'56>

Calculated: C: 67.85 H: 7.74 N: 6.33

Found: 67.50 7.97 6.18.

Example 75 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-henzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 3,4-dimethyl-phenyl) -ethyl) -amino] propane dihydrochloride.

Prepared analogously to Example 5b by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N -methyl-2- (3,4-dimethyl-phenyl) -ethylamine.

Yield: 54.3% of that theory.

Mp: 170-172 ° C.

20

Example 76 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -t-butyl-phenyl) -ethyl) -amino] propane dihydrochloride.

Prepared analogously to Example 5b by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N -methyl-2- (4-tert-butyl-phenyl) -ethylamine.

Exchanges: 49.4% of that theory.

Mp: 146-149 ° C.

Example 77 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -n-butoxy-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N- methyl-2- (4-n-butoxy

DK 156720 B

66 phenyl) -ethylamine.

Yield: 55.3% of that theory.

Mp: 67-69 ° C.

Example 78 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 2,4,6-trimethoxy-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b by reacting 10- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N -methyl-2- (2,4,6-trimethoxy-phenyl) -ethylamine.

Yield: 57.8% of theory.

IR Spectrum (methylene chloride): 1650 cm50 ^ (CO) 1520 cm ^ ((aromat. C = C) C27H38N2 ° 6'HCl (523.2)

Calculated: C: 62.00 H: 7.51 N: 5.35 Cl: 6.77

Found: 61.75 7.52 5.18 7.34.

Example 79 1- [7,8-Dimethyl-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

a) 1- (7,8-Dimethyl-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane.

Prepared analogously to Example 1a by reacting 7,8-dimethyl-1,3-dihydro-2H-3-benzazepin-2-one (mp: 220-224 ° C) with 1-bromo-3-chloropropane.

Yield: 99% of that theory.

Mp: 62-64 ° C.

b) 1- [7,8-Dimethyl-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy) -phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 1b by reacting 1- (7,8-dimethyl-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N-methyl-2 - (3,4-dimethoxy-phenyl) -ethylamine.

Yield: 70.9% of that theory.

Mp: 105-107 ° C.

67

DK 156 72 0 B

Example 80 1- [7,8-Dimethyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3 , 4-dimethoxy-phenyl) -ethyl) -amino] propane dihydrochloride.

5 Analogously prepared Example 4 by catalytic hydrogenation of 1- [7,8-dimethyl-1,3-dihydro-2H-3-benz-azepin-2-one-3-yl] -3- [N-methyl-N - (2- (3,4-dimethoxy-phe nyl) -ethyl) -amino] -propane.

Yield: 83.8% of that theory.

Mp: 154-157 ° C.

Example 81 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2-methyl-3- [N-methyl-N- (2- (3 (4-Dimethoxy-phenyl) -ethyl) -amino] -propane.

a) 1- (7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2-methyl-3-chloro-propane.

Prepared analogously to Example 1a by reacting 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one with 20 l-bromo-2-methyl-3-chloro-propane.

• Yield: 97.5% of that theory.

Mp: 45-47 ° C.

b) 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2-methyl-3- [N-methyl-N- (2- (3) (4-Dimethoxy-phenyl) -ethyl-amino-propane.

Prepared analogously to Example 1b by reacting 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2-methyl-3-chloro-propane with N- methyl 2- (3,4-dimethoxy-phenyl) -ethylamine.

Yield: 36% of that theory.

Mp: 30-32 ° C.

Example 82 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -2-methyl-3- [N-methyl-N- ( 2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 4 by catalytic

DK 156720 B

68 hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benz-azepin-2-one-3-yl] -2-methyl-3- [N-methyl-N- (2 - (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

Yield: 73.7% of that theory.

Mp: 99-101 ° C.

Example 83 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-1,2-dione-3-yl] -3- [N-methyl-N- (2- (3,4-Dimethoxy-phenyl) -1-ethyl) -amino] -propane hydrochloride.

2.45 g (0.005 mol) of 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl -N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride was introduced into 50 ml of glacial acetic acid and 3 g of sodium dichromate, 2H2O was added. The mixture was stirred for 2 hours at room temperature, poured into ice water and neutralized with potassium carbonate and quenched several times with methylene chloride.

The organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified over a silica gel column with methylene chloride + 1% ethanol as the eluent. The product thus obtained was dissolved in acetone and the hydrochloride precipitated with ethyl hydrochloric acid.

Yield: 1.3 g (51.3% of theory).

Mp: 197-198 ° C.

Example 84 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dione-3-yl] -3- [N-methyl-N · - (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

1.98 g (4.0 mmol) of 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2H-3-yl] -3- [N -Methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride was suspended in 50 ml of acetanhydride, 2.5 g of potassium permanganate was added and stirred for 20 minutes at 20 ° C. ° C. The reaction mixture was poured into ice water and adjusted to concentrated ammonia with concentrated ammonia. The brown precipitate was aspirated and the filtrate was shaken several times with 69

DK 156720 B

methylene chloride. The extract was dried over magnesium sulfate, evaporated in vacuo and the residue was purified over a silica gel column with methylene chloride + 1% ethanol sorting eluent. The product thus obtained was dissolved in acetone and the hydrochloride precipitated with ethereal hydrochloric acid.

Yield: 0.7 g (34.5% of theory).

Mp: 196-197 ° C.

Example 85 1- [6,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4- dimethoxy-phenyl) -ethyl) -amino] -propane.

a) 1- (6,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane.

Prepared analogously to Example 1a by reacting 6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (mp: 188-191 ° C) with 1-bromo-3-chloro-propane.

Yield: 27% of that theory.

Mp: 97-99 ° C.

b) 1- [6,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy) phenyl) ethyl) amino] propane.

Prepared analogously to Example 1b by reaction of 1- (6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N-methyl-2 - (3,4-dimethoxy-phenyl) -ethylamine.

Yield: 90% of that theory.

IR Spectrum (Methylene Chloride): 1658 cm 2 (CO) NMR Spectrum (CDCl 3 / D 2 O): δ = 2.2 ppm, s, 3H (NCH 3), 3.7-3.8 ppm, 4s, 12H ( OCH3), 6.25 ppm, d (J = 9Hz), 1H (olefin.).

35

DK 156720 B

70

Example 86 1- [6,9-Dimethoxy-1,3,4,5-tetrahydro-2H-benzazepin-2-one · 3-yl] -3- [N-methyl-N- (2- (3, 4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 4 by catalytic hydrogenation of 1- [6,9-dimethoxy-1,3-dihydro-2H-3-benz-azepin-2-one-3-yl] -3- [N-methyl-N - (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane. Exchanges: 85% of that theory.

Mp: 73-76 ° C.

Example 87 1- [8,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy) -phenyl) -ethyl) -amino] -propane hydrochloride.

a) 1- (8,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane.

Prepared analogously to Example 1a by reacting 8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (mp: 165-168 ° C) with 1-bromo-3-chloropropane.

Exchanges: 45% of that theory.

Mp: 67-71 ° C.

b) 1- [8,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy) (phenyl) ethyl) amino] -propane hydrochloride.

Prepared analogously to Example 1b by reacting 1- (8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N-methyl-2- (3,4-dimethoxy-phenyl) -ethylamine.

30 exchange rates: 64% of that theory.

Mp: 64-68 ° C.

Example 88 1- [8,9-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3 , 4-dimethoxy-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 4 by catalytic

DK 156720B

71 hydrogenation of 1- [8,9-dimethoxy-1,3-dihydro-2H-3-benz-azepin-2-one-3-yl] -3- [N-methyl-N- (2- (3, 4-dimethoxy-phe nyl) -ethyl) -amino] -propane.

Yield: 75% of that theory.

Mp: 131-133 ° C.

Example 89 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3 , 4,5-trimethoxy-phenyl) -ethyl-amino-propane dihydrochloride.

Prepared analogously to Example 5b by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with N- methyl 2- (3,4,5-trimethoxy-phenyl) -ethylamine.

Yield: 44% of that theory.

Mp: 131 ° C (dec.).

Example 90

Isomer mixture of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 2- and 4-nitro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 1b from 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3-chloropropane and N-methyl-2 - (2- and 4-nitro-phenyl) -ethylamine.

Yield: 72% of that theory.

IR Spectrum (methylene chloride): 1650 cm50 ’(CO).

Example 91 Isomer mixture of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2 - (2- and 4-amino-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 4 by catalytic hydrogenation of an isomer mixture of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [ N-methyl-N- (2- (2- and 4-nitro-phenyl) -ethyl) -amino] -propane.

Yield: 81% of that theory.

IR spectrum (methylene chloride): 1645 cm 16 ”(CO).

DK 156720 B

72

Example 92 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (2 -acetylamino-phenyl) -ethyl) -amino] -propane hydrochloride and 5 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] 3- [N-methyl-N- (2- (4-acetylamino-phenyl) -ethyl) -amino] -propane hydrochloride.

Prepared analogously to Example 52 by reacting an isomer mixture of 1- [7,8-dimethoxy-1,3,4,5-tetra-10-hydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (2- and 4-amino-phenyl) -ethyl) -amino] -propane with glacial acetic acid and acetanhydride.

Exchanges of 2-acetylamino compound: 26% of theory.

Mp: 102-105 ° C (dec.).

15 exchange of 4-acetylamino compound: 49% of theory

Mp: 89-93 ° C (dec.).

Example 93 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 4-amino-phenyl) -ethyl) -amino] -propane.

4.85 g (0.0107 mol) 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N -Methyl-N- (2- (4-aceylamino-phenyl) -ethyl) -amino] -propane was stirred for 34 hours at 40 ° C with 80 ml of methanolic hydrochloric acid. After evaporation of the solution, the residue was dissolved in methylene chloride, extracted with sodium carbonate solution and washed with water. The organic phase was dried, evaporated in vacuo, and the oil obtained was then dried in vacuo at 50 ° C. Exchanges: 88% of that theory.

IR Spectrum (Methylene Chloride): 1645 cm (^ (CO) NMR Spectrum (CDClgA₂O): θ = 2.25 ppm, s, 3H (NCH ^), 3.8 ppm, s, 12H (OCH₂) l, 6.9 ppn, 35 d (J = 7Hz1, .2H (aromat,).

DK 156720 B

73

Example 94 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -chloro-phenyl) -ethyl) -amino] propane dihydrochloride.

1.01 g (0.00245 mol) of 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [ N-methyl-N- (2- (4-aminophenyl) ethyl) amino] propane was dissolved in 5 ml of semi-concentrated hydrochloric acid and diazotized with 0.17 g (0.00245 mol) of sodium nitrite. Then, 10 was stirred at 55 ° C until nitrogen was no longer eliminated. The solution was adjusted slightly alkaline, extracted with methylene chloride, dried and evaporated in vacuo. The oil obtained was purified over alumina (200 g, neutral, Activity II) (eluent: methylene chloride 15 + 1% ethanol) and the dihydrochloride precipitated with ethereal hydrochloric acid.

Yield: 21% of that theory.

Mp: 148-151 ° C.

Example 95 1- [7,8-Dimethoxy-2,3-dihydro-1H-3-benzazepin-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane.

2.3 g (0.005 mol) of 1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-Dimethoxy-phenyl) -ethyl) -amino] -propane was dissolved in 150 ml of absolute ether, with 0.6 g of lithium aluminum hydride added and stirred for 2 hours at room temperature. Under ice-water cooling, 10% ammonium chloride solution was added, suctioned from the precipitate and the solvent removed in vacuo. The oily residue was purified over alumina (neutral, Activity II) with methylene chloride as the eluent.

Yield: 1.6 g (72.7% of theory).

IR spectrum (methylene chloride); 2830 cm 2 (OCH 3) 2790 cm -1 (N-alkyl) C 26 H 36 N 2 ° 4 (440'6)

Calculated: C: 70.88 H: 8.24 N: 6.36

Found: 70.50 8.80 6.22.

DK 156720 B

74

Example 96 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -hydroxy-phenyl) -ethyl) -amino] -propane hydrochloride.

1.1 g (2.67 mmol) of 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [ N-methyl-N- (2- (4-amino-phenyl) -ethyl) -amino] -propane was dissolved in 10 ml of semi-concentrated sulfuric acid and diazotized at 0 ° C with 0.18 g (2.67 mmol) of sodium nitrite. The solution was then heated for 20 minutes in a steam bath, diluted with water, adjusted slightly alkaline with sodium hydroxide solution, extracted with methylene chloride and dried. After evaporation in vacuo, the recovered oil was purified over 100 g of alumina (neutral, Activity II) with 15 methylene chloride + 2% ethanol as eluent. The hydrochloride was then precipitated by acetone / ethereal hydrochloric acid.

Yield: 0.17 g (15% of theory).

Mp: 109-112 ° C (dec.).

20

Example 97 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4) -dimethylamino-phenyl) -ethyl) -amino] propane dihydrochloride.

Prepared analogously to Example 11 by reacting 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl N- (2- (4-amino-phenyl) -ethyl) -amino] -propane with 37% formaldehyde solution and sodium cyanoborohydride.

Yield: 40% of that theory.

Mp: 193-196 ° C.

Example 98 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one-3-yl] -3- [N-methyl-N- (2 - (4-Amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

DK 156720 B

A) N- [3- [Ν'-Methyl-N '- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propyl] -2- (2-amino- 4,5-dimethoxy-phenÿfi-ethylamine hydrochloride.

Prepared analogously to Example 53a from N- [3-5 [N1-methyl-N '- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propyl] -2- ( 2-amino-4,5-dimethoxy-phenyl) -acetamide and lithium aluminum hydride.

Mp: 182-188 ° C (dec.).

b) 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-1,3-benzodiaze-pin-2-one-3-yl] -3- [N-methyl-N- (2- (4-Amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 53b from N- [3- [N1-methyl-N1 - (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propyl] -2- (2- amino-4,5-dimethoxy-phenyl) -ethylamine 15-hydrochloride and N, N'-carbonyl diimidazole.

Mp: 163-166 ° C.

Example 99 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dione-3-yl] -3- [N-methyl-N- (2 - (4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 5b from 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-Amino-3,5-dichloro-phenyl) -ethyl) -25-amino] -propane and selenium dioxide.

Mp: 118-130 ° C, m / e = 493/495 (C24H29C12N3O4, 494.43).

Example 100 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] propane dihydrochloride.

1.1 g (5.0 mmol) of 7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one was suspended in 20 ml of dimethylsulfoxide, and with stirring, added 0.6 g (5.3 mmol) of potassium tert.butylate. After 10 minutes, 2.0 g (7.4 mmol) of 1-chloro-3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -amino] -propane) was added to the solution. then

DK 156720 B

76 O

was stirred for another hour at 50 ° C, poured into water, extracted with ethyl acetate, and the organic phase was evaporated in vacuo. The residue was purified over silica gel with methylene chloride + 10% methanol as eluent and the dihydrochloride was precipitated by acetone with ethereal hydrochloric acid.

Mp: 136-137 ° C.

Example 101 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 3,4-dimethoxy-phenyl) -ethyl) -amino] propane dihydrochloride.

Prepared analogously to Example 100 from 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and N-methyl-N- (2- (3,4-dimethoxy) phenyl) ethyl) -azatidinium bromide.

Mp: 137 ° C.

Example 102 1-J7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3 amino-4-chloro-phenyl) -ethyl) -amino] -propane.

Prepared analogously to Example 12 by reacting N- [3- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazpin-2-one-3-yl] propyl] - methylamine and 2- (3-amino-4-chloro-phenyl) -ethyl chloride.

UV Spectrum (Ethanol): λ max 238 nm (0.26) 285 nm (0.13) 304 nm (0.06) IR Spectrum (dichloromethane): 3390 and 3480 cm CO) 2830 cm -1 (OCH 3) 2795 cm -1 (CH 3 NO 1520 and 1620 cm 2 (C = C).

35

Claims (10)

1. Analogous Process for the Preparation of Benzazepine Derivatives of General Formula I: 2. Process according to claim 1, characterized in that the reaction is carried out in a solvent. 3. A process according to claim 1a, 1b, 1e or 2, characterized in that an applied protecting group is hydrolytically cleaved in the presence of an acid or base or a benzyl group used is hydrogenolytically cleaved. Process according to claim 1e, ld or 2, characterized in that, for the preparation of compounds of the general formula I, wherein Rg is a hydrogen atom, the reaction is carried out in the presence of hydrogen and a hydrogenation catalyst. Process according to claim 1e, ld or 2, characterized in that the reaction is carried out in the presence of a complex metal hydride, such as lithium or sodium anyanoborohydride, at a pH of 6-7 and at room temperature. 5 V k "JL E \ i6 // VR4 'CH - B - N - E' - N - G -y Λ (X) \ = ^ V 10 where: B and G are as defined above E1 is one optionally with a alkyl group having 1-3 C atoms substituted ethylene, n-propylene or n-butylene group, R 1 'to R 2' are each hydroxy group protected by a protecting group or have those of R 1 to R 2 R ^ "is a hydroxy, 20 amino or alkylamino group protected by a protecting group or, with the exception of an amino or alkylamino group, has the meanings given for R 1, and Rg" with the exception of hydrogen has the meanings given for Rg above or are a protecting group for an amino group are reacted with a carbonic acid derivative of the general formula XI: W - CO - W (XI) 3. wherein: The W groups which may be the same or different, each is a nucleophilic eliminable group such as a chlorine or bromine atom, an optionally substituted alkoxy group having 1-3 C atoms or an imidazolyl (2) group e, whereupon optionally a protecting group used is cleaved, or DK f) for the preparation of compounds of the general formula I wherein A is a group -CH 2 -CH 2 -, R 1 and R 2 are not a benzyloxy group, R 9 or R is not a nitro group and R 9 is not a benzyl group or an alkenyl group 5 having 3 to 5 C atoms, a compound of the general formula XII: R1 \ Λ CH = CH R. _ R2 R5 where: R ^ to Rg, B, E and G are so defined above, wherein Rg or R ^ may be a nitro group if Rg is an amino group, hydrogenated, or g) a compound of general formula XIII; 20 E1 i6 fVR3 N-E-N-G-V Λ) (XIII) - R2 is Rg where: R R to Rg, A, B, E and G are as defined above, however, at least one of the groups R ^ to R ^ must be a hydroxy group or Rg must be a hydroxy group, an amino - or alkylamino group having 1-3 C atoms, or Rg must be a hydrogen atom, reacted with a compound of general formula XIV: Rg - X (XIV) where: DK 156720 B Rg is an alkyl group having 1-3 C atoms or also an alkenyl group having 3-5 C atoms when Rg is a hydrogen atom, or also one having a phenyl group is substituted alkyl group having 1-3 C atoms when R R or R₂ is a hydroxy group and / or Rg is a hydrogen atom and X is a nucleophilic or nonminkable group such as a halogen atom or a sulfonyloxy group, or X means, if at least one of the groups R ^ to Rg is a hydroxy group, together with an α-positioned hydrogen atom from the group Rg, a diazo group or also if Rg is a hydrogen atom, or R ^ is an amino or alkylamino group, an oxygen atom, or h) for the preparation of compounds of general formula I wherein A is not a group -CH = CH-, R 9 is a chloro or bromine atom and R 9 is an amino or alkylamino group, a compound of general formula XV : View in RV 4 20 R2__ | N - E - N - G -V [y (XV) --► b '\ === / \ r5 "" where: R 2, R 2, R 2, R 9, B, E and G are as defined above, A 'with the exception of a group -CH = CH- has the meanings set forth for A above and Rg "" is an amino or alkylamino group having 1-3 C atoms, halogenated, or 30 i) for the preparation of compounds having the general formula I wherein A is a group -COCO-, B is a methylene group and E is an optionally substituted ethylene, n-propylene or n-butylene group optionally with 1-3 C atoms. , a compound of general formula XVI: wherein: to Rg, E and G are as defined above, oxidized and, if desired, then a won compound of the general formula I wherein B is a carbonyl group is reduced by a corresponding compound of the alpha-formula I wherein B is a methylene group and / or a won compound of the general formula I , f7 where A is not a group -CH = CH- or -C = N-, and Rg is a benzyl, or 1-phenylethyl group, by catalytic hydrogenation is transferred in a corresponding compound with 20 d a general formula I wherein R 9 is a hydrogen atom and / or a won compound of the general formula I wherein R 3 or R 4 is a nitro group is, by reduction, transferred to a corresponding compound of the general formula I wherein R 9 is a amino group, and / or a won compound of the general formula I wherein R 9 is a hydrogen atom and / or R 9 is an amino group, by acylation is transferred into a corresponding compound of the general formula I wherein R 9 is an alkanoyl or alkoxycarbonyl group and / or Rg is an alkanoylamino, alkoxycarbonylamino or bis (alkoxycarbonyl) amino group wherein each alkyl moiety has 1-3 C atoms and / or a compound of the general formula I wherein Rg is an amino group, Rg is not a hydrogen atom, Rg and R4 are each not a cyano group, over a corresponding diazonium salt is transferred in a corresponding compound of the general formula I wherein Rg is a hydrogen atom, a hydroxy or alkoxy group, or Rg is a hydrogen atom, and Rg is a halogen atom or the like is a cyano group, and / or 8.6 DK 156720 B or a won compound of general formula I is transferred into physiologically acceptable acid addition salts with inorganic or organic acids. 5 Rj R ^ ΚΊΓΑχ î6 r2 — Γ— Il N - E - N - G - (/ y (I) B '' \ = ^ RS 10 where: A is a group -CH, -CH., -, -CH = CH-, -NH-CO-, -CH.-CO- 5 z or -C = iN-, where R7 is an alkyl group of 1-3 C-ato-5 'mer and B is a methylene - or carbonyl group, or A is a group -CO-CO-, and B is a methylene group, E is an optionally substituted ethylene, n-propylene or n-butylene group with 1-3 C atoms, a n-propylene group substituted with a hydroxy group at 2-position or a n-butylene group substituted with a hydroxy group at 2 or 3 position, G is optionally substituted with an alkyl group having 1-3 C atoms, methylene or ethylene group, R 1 and R 2, which may be the same or different, is a hydroxy group, an alkyl, alkoxy or phenyl alkoxy group wherein each alkyl moiety has 1-3 C atoms, or one of the groups R and R 2 may also be a hydrogen atom or R 2 together with R 2 forms an alkylenedioxy group of 1 or 2 C atoms, 30, which may be the same or different, are a hydrogen or halogen atom, a hydroxy group, an alkyl or alkoxy group each having 1-4 C atoms, a trifluoromethyl or cyano group, or the one of the groups R 3 and R 4 may also be a nitro group, or R 3 forms together with R 1 an alkylenedioxy group having 1 or 2 C atoms, R 2 is a hydrogen atom, an alkyl, hydroxy, alkoxy, -, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino or bis (alkoxycarbonyl) amino group, wherein each alkyl moiety has 1-3 C atoms, or a methyl-amino or ethylamino group substituted with a trifluoromethyl group and R a hydrogen atom, an alkyl, phenylalkyl, alkanoyl or alkoxycarbonyl group wherein each alkyl moiety has 1-3 C atoms, or an alkenyl group having 3-5 C atoms, or their physiologically acceptable acid addition salts with inorganic or organic acids, characterized in that a) a compound of general formula II: Rn · Vy \ - H (II) V 20 where: A and B are as defined above, R 1 and R 21 are each a hydroxy group protected with a protecting group or have the meanings given for R 1 and R 2 above. , is reacted with a compound of the general formula III: Av Z - E - N - G "7 (III) where: Rg, E and G are as defined above, R 1 'to R 6' are each a hydroxy group protected with a protecting group or have those for R 1 to R 2. and Z is a nucleophilic eliminable group DK 156720 B or, optionally, present in the reaction mixture the internal quaternary sites of the general formula IIa: V 10 where: E, G, Z, 'to' and Rg are as defined above or, where appropriate, a protecting group used is cleaved, or b) for the preparation of compounds of the general formula I wherein R 9 is a hydrogen atom, an alkenyl group having 3-5 C atoms, an alkyl or phenylalkyl group having 1-3 C atoms in each alkyl moiety, a compound of general formula IV: 20 R 1 * N - E - U (IV) R2! is reacted with a compound of the general formula V: V · 30> g - v (v) VV 35 wherein: A, B, E and G are as defined above, DK 156720B R 1 'to R 2' each is one having a protecting group protected hydroxy group or have the meanings given for R 1 to R 9 above, one of U and V being a group R 9'-NH- wherein R 9 'is a hydrogen atom, an alkenyl group having 3-5 C atoms, a alkyl or phenylalkyl group having 1-3 C atoms in each alkyl moiety, the other of U and V is a nucleophilic eliminable group, or 10. together with a (3-position hydrogen atom from group E is an oxygen atom and V is a group Rg'-NH-, where Rg 'is as defined above, whereupon optionally a protecting group used is cleaved, or c) to prepare compounds of the general formula I wherein Rg is a hydrogen atom, an alkenyl group having 3- 5 C atoms, an alkyl or phenylalkyl group having 1-3 C atoms in each alkyl moiety, a compound of the general formula VI: R 1 Wherein: A, B, E, R 2 and R 2 are as defined above, however, in group E, two hydrogen atoms in a group -CE 2 - or 30 -CH 3 from group E are replaced by an oxygen atom, is reacted with an amine of the general formula VII: R3 R 4 H - N - G 7 (VII) v where: DK 156720 BG and Rg to Rg are as defined above and Rg 'is a hydrogen atom, an alkenyl group having 3-5 C atoms, an alkyl or phenylalkyl group with 1-3 C atoms in each alkyl moiety, 5. the presence of a reducing agent, or d) for the preparation of compounds of general formula I wherein R 9 is a hydrogen atom, an alkenyl group having 3-5 C atoms, a alkyl or phenylalkyl group having 1-3 C atoms in each alkyl moiety, a compound of the general formula VIII: - E - N (VIII) wherein R 2 is: A, B, E, R is defined as a hydrogen atom, an alkenyl group having 3 to 5 C atoms, an alkyl or phenylalkyl group having 1 to 3 C atoms in each alkyl moiety, reacted with a compound of the general formula IX: 25 Hg <3C R5 where: G and Rg to Rg are as defined above, however, in the group G two hydrogen atoms in a group -CHg- or 35 -CHg from the group G are replaced by an oxygen atom, in the presence of a reducing agent, or e) to preparation of compounds of general formula I wherein A is a group -NH-CO-, E is an optionally DK 156720 B having an alkyl group of 1-3 C atoms substituted with ethylene, n-propylene or n- butylene group, and Rg is not a hydrogen atom, a compound of the general formula X: Process according to claim 1g or 2, characterized in that the reaction with an aldehyde of general formula XIV is carried out in the presence of a reducing agent at temperatures between 0 ° and 120 ° C when Rg is a hydrogen atom and / or Rg. is an amino or alkylamino group. A process according to claim 1, characterized in that 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] is prepared]. -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane or acid addition salts thereof. 8. A process according to claim 1, characterized in that 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-1,2-dione-3 is prepared. yl] -3- [N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino] -propane or silicic acid salts thereof. Process according to claim 1, characterized in that 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3 - [N-methyl-N- (2- (4-amino-3,5-dichloro-phenyl) -ethyl) -amino] -propane or acid addition salts thereof. Process according to claim 1, characterized in that 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] is prepared. 3- [N-methyl-N- (2- (4-methoxy-phenyl) -ethyl) -amino] -propane or its acid addition salts.