DD215540A5 - PROCESS FOR THE PREPARATION OF BENZAZEPINE DERIVATIVES - Google Patents

Abstract

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

Description

Berlin, March 28, 1984 AP C 07 D / 256 756 63 066 12

Process for the preparation of benzazepine derivatives

Field of application of the invention

The invention relates to a process for the preparation of Benzazepinderivaten with valuable pharmacological properties, in particular with heart rate lowering effect. The compounds prepared according to the invention are used as medicaments, for example for the treatment of sinus tachycardias and for the prophylaxis or therapy of ischemic heart diseases.

Characteristic of the known technical solutions

In GB-PS 1 548 844 u. a. the compound of the formula

OH ₃ ,

CH ₂ CH ₂ CH ₂ N-CH ₂ CH ₂ '

and their physiologically acceptable acid addition salts, which has valuable pharmacological properties, namely, in addition to a mild hypotensive action, in particular a selective heart rate-lowering effect.

Object of the invention

The aim of the invention is the provision of new compounds

63 066 12

with superior pharmacological properties, in particular stronger heart rate lowering effect, longer duration of action and less side effects. ·. ' -

presentation; , of, we'sen, the invention;

The invention has for its object to find new benzazepine derivatives with the gewiinsohten properties and processes for their preparation ·

Surprisingly, it has now been found that the new benzazepine derivatives of the general formula

(I)

and 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-onf-3-yl) -3- / ΓH-methyl-H- (2-phenyl ethyl) amino J -propane and 1- (7,8-Dimethozy-1,3,4,5-tetrahydrρ-2H-3-benzazepin-2-on-3-yl) -3- £ "li ~ methyl -N- (2- (4-amino-3-nitrophenyl) -ethyl) -amino_7-propane have superior pharmacological properties, namely with a longer duration of action and fewer side effects, in particular a stronger heart rate-silencing effect

The present invention relates to processes for the preparation of the above novel benzazepine derivatives, their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids.

63 066 12

In the above general formula I means

A is -CH ₀ -OH ₀ -J-CH = Ch-J-IJH-CO-, -CH ₀ -CO- or R ^{2 2} 5 5 ²

5 5

-C = N-group, 5

in which R represents an alkyl group having 1 to 3 carbon atoms, and

B is the thiocarbonyl group or also when G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms n-alkylene group having 3 to 5 carbon atoms, an optionally substituted by an alkyl group having 1 to 3 carbon atoms n-alkylene group having 1 to 5 carbon atoms, in the a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group having 1 to 4 carbon atoms in the alkylene part, wherein the methylene group is linked to the nitrogen atom, or R ₁ and Rg is each a hydrogen atom or

R 1 represents a fluorine, chlorine or bromine atom, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms, the methylene or carbonyl group or _t

OH OH NOH ¹³ J ¹ "* ¹ ^

Il Il /

a -N = CH-, -CH-CO-, -CH-CH ₀ -, -C-CO- or -CH-CO- group; 5. 5 5 ^d 5 5

in which Rg represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms substituted by a phenyl, methoxyphenyl or dirnethoxyphenyl group, or also the -CO-CO- group, if G represents an n-substituted by an alkyl group having 1 to 3 carbon atoms. Alkylene group having 3 to 5 carbon atoms, one

63 066 12

optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms, in which a methylene group is replaced by an Oarbonylgruppe, or a methylene-h-hydroxyalkylengruppe having 1 to 4 carbon atoms in the alkylene part, wherein the methylene group with the Linked nitrogen atom " . is, or ^: · \ ·. '.' V '. '.. ·. R ₁ and E ₂ each represent a hydrogen atom or

R _{1 represents} a fluorine, chlorine or bromine atom, a trifluoromethyl group or an amino group mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms, and B represents the methylene group,

R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, an alkoxy group having 1 to 3 carbon atoms or an amino group which is mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms,

E is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group with 2 bis

4 carbon atoms,

G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group with 1 to

5 carbon atoms, in which a methylene group, when B represents a methylene or carbonyl group, may be replaced by a carbonyl group, or a methylene-n »hydroxyalkylene group having 1 to 4 carbon atoms in the alkylene part, wherein the methylene group is linked to the nitrogen atom .

R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, a

63 066 12

'.'"'- ⁵ -'^{;.: v::;...} · ^{·: Ν ;: ':' '': /} '.

Alkoxy group having 1 to 3 carbon atoms or, together with R _1, an alkylenedioxy group having 1 or 2 carbon atoms,

Ro is a hydrogen, fluorine, chlorine or bromine atom, a nitro, trifluoromethyl, alkyl or alkoxy group having in each case 1 to 3 carbon atoms,

R.sup.1 is a hydrogen atom, an alkoxy, amino, alkylamino or dialkylamino group having in each case 1 to 3 carbon atoms in each alkyl part or together with R.sup.1 an alkylenedioxy group having 1 or 2 carbon atoms,

Rc is a hydrogen, chlorine or bromine atom and

Rg is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 3 to 5 carbon atoms. ,

For in the definition of the radicals R ₁ to R ₈ , E and G mentioned above comes

R 1 is hydrogen, fluorine, chlorine or bromine, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, amino, methylamino, ethylamino, n-propylamino, isopropylamino, Dimethylamines, diethylamino, di-n-propylamino, diisopropylamino,

Methyl-ethylamino, methyl-n-propylamino, methylisopropylamino or ethyl-n-propylamino group,

for Rg that of the hydrogen, fluorine, chlorine or bromine atom, the methoxy, ethoxy, n-propoxy or isopropoxy group or together with R ₁ that of the methylenedioxy or ethylenedioxy group,

63 066 12

'..... ^. - 6 -

for R ₃ those of the hydrogen, fluorine, chlorine or bromine atom, the nitro, trifluoromethyl, methyl, ethyl, n-propyl, methoixy, ethoxy, n-propoxy or isopropoxy group,

for R * those of the hydrogen atom, the methoxy, ethoxy, npropoxy, isopropoxy, amino, ethylamino, ethylamino, n-propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, , Diisopropylamino, methylethylamino, methyl-n-propylamino, methylisoprbpylamino or ethyl-n-propylamino group or together with R-- that of the methylenedioxy or ethylenedioxy group,

for Rc that of the hydrogen, chlorine or bromine atom,

R 1 represents the hydrogen atom, the methyl, ethyl, n-propyl, isopropyl, allyl, n-buten (2) -yl or n-pentene (2) -yl group,

for Ry, the methyl, ethyl, n-propyl or isopropyl group,

for R ₈ those of the hydrogen atom, the benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2- (4-methoxyphenyl) ethyl, 2- (3,4-dimethoxyphenyl) ethyl, 3- (4-methoxyphenyl) propyl or 3- (3 »4-dimethoxyphenyl) propyl group,

for E, the ethylene, n-propylene, n-butylene, 1-methylethylene, 2-ethyl-ethylene, 1-propyl-ethylene, 1-methyl-n-propyl ene, 2-methyl ^ n-propyl, 1-ethyl-propylene, 3-ethyl-n-propylene, 2-propyl-n-propylene or 2-methyl-n-butylene and

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for G, the methylene, elihylidene, n-propylidene, n-butylidene, 2-methyl-propylidene, ethylene, 1-methylethylene, 2-ethyl-ethylene, 1-propyl-ethylene, 2 -Methyl-ethylene, n-propylene, n-butylene, n-pentylene, 1-methyl-n-propylene, 1-methyl-butylene, 1-methyl-n-pentylene, 1-ethyl-n- propylene, 2-ethyl-n-propylene, 1-methyl-n-butylene, methylenecarbonyl, ethylenecarbonyl, n-propylenecarbonyl, η-butylenecarbonyl, carbonylmethylene, carbonylethylene, carbonyl-n-propylene, Carbonyl-η-butylene, Methylencarbonylmethylen-, Ethylencarbonylme-ethylene, 2-hydroxyethyl, 2-hydroxyn-propylene, 3-hydroxy-n-propylene, 2-hydro-n-butylene, 3-hydroxy-n-butylene -, 4-hydroxy-n-butylene or 2-hydroxy-n-pentylene group, in this case 'is the radical R- preferably in the 8-position, Rp in the 7-, position, R ^ in the 3-position, R. in the 4-position and R ^ in the 5-position of the respective Phenylkems ·

However, preferred compounds are the compounds of the general formula

(Ia)

in the

A is a -CH ₂ -CH ₂ - or -CH = CH group and '

B the -CS group or also, if

G is an n-alkylene group having 3 to 5 carbon atoms, an n-alkylene group having 2 to 5 carbon atoms in which a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group

63 066 12

- β - '>.'. ' ι ^] \''- Ί V - "Λ V

with 1 to 3 carbon atoms in the alkylene part, wherein the methylene group is linked to the nitrogen atom, or E ₁ and Rg are each a hydrogen atom or

R _{1 represents} a chlorine or bromine atom, a trifluoromethyl, amino, methylamino #der dimethylamino group, the GO-örupp? »Or

OH OH I-OH HH ₀ A is a -NeGH-, -CH-OH ₀ -, -CH-CO -, - G-CO-, -CH-GO- or

: ,, '5' ,. _: - \ S '\ · 5,. 5 - .., δ. ;. ;. ..:, ·

Group or also the -COOO-group,

when β is an n-alkylene group having 3 to 5 carbon atoms, V is an n-alkylene group having 2 to 5 carbon atoms in which a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group having 1 to 3 carbon atoms in the alkylene moiety, the methylene group being i ^^ is, or

R ₁ and R ₂ 3e is a hydrogen atom or R _{1 is} a chlorine or bromine atom, a trifluoromethyl, amino,

Methylamino or dimethylamino group, and B is the -CHg group,

G is an n-alkylene group having 2 to 5 carbon atoms, in which a methylene group, when B represents a methylene or Garb - onylgruppe, may be replaced by a carbonyl group, or a methylene-n-hydrocyalkylene group having 1 to 3 carbon atoms in the alkylene moiety, where the methylene group is linked to the nitrogen atom,

63 066 12

";; "...". '. , - 9-: '.' : _R:; A "'i' · '' ^ β: ^[ '

R _{1 is} a hydrogen, chlorine or bromine atom, a trifluoromethyl, methoxy, amino, methylamino or dimethylamino group,

R _{2 is} a hydrogen, chlorine or bromine atom, a methoxy group or, together with R 1, the methylenedioxy group,

R is a hydrogen, fluorine, chlorine or bromine atom, a methyl, methoxy, trifluoromethyl or thio group,

R. a hydrogen torn, a methoxy, amino, methylamino or Dirnethylaminogruppe or together with IU the methylenedioxy group,

Rc is a hydrogen, chlorine or bromine atom and

Rg is a hydrogen atom, a methyl or allyl group, and 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-Bf -methyl-KC 2-phenyl ethyl) amino J-propane and 1- (7,8-dimethoxy-1 ^, ^ 'S-tetrahydro-'SH ^ -' ^ benzazepine 2-on-3-yl) - N-methyl-K- (2- (4-amino-3-nitrophenyl) -ethyl) amino-7-propane and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids

Particularly preferred compounds of the above general formula Ia are those in which

A is the -CHgCHg group,

B the -CO- or -CSH group,

R 1 is a trifluoromethyl, methoxy, amino, methylamino or dimethylamino group,

Rg a, hydrogen atom or a methoxy group or together with R ^ the methylenedioxy group,

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R is a hydrogen, fluorine, chlorine or bromine, a methoxy or trifluoroethylgrip,

R. a methoxy, amino, methyl-amino or dimethylamino group or together with R- the methylenedioxy group,

Rc is a hydrogen, chlorine or bromine atom, Rg is the methyl group and

G is an n-alkylene group having 3 to 5 carbon atoms or OH

the -CHg-CH group or even when B represents the -CS group and / or Rj represents a trifluoromethyl, amino, methylamino or dimethylamino group, the -CHgCHg group, and their physiologically acceptable acid addition salts with inorganic or organic acids.

Especially preferred are the following compounds:

1- (7,8-Pimethoxy-i, 3 * 4,5-1 yl) -3 N-methyl-Sr- (3- (3,4-dime thoxyphenyl) -propyl) -amino_7- and its physiologically acceptable acid addition

1- (1-hydroxy-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) ~ 3 - ^ "H" -ethyl-N- (2- (3 "4-dime thoxyphenyl) ethyl) amino-7-propane and its physiologically acceptable acid addition salts;

1 - (7,8-trimethoxy-1,3,4,4-tetrahydro-2H-3-benzazepine-2 * © n-3-yl) -3-N-methyl-N (3 ( 4-amino-3,5-dicyclo-phenyl) -propyl) amino-7-propane and its physiologically acceptable acid addition salts.

63 066 12

According to the invention, the novel compounds are obtained by the following processes:

a) reaction of a compound of the general formula

(II)

with a compound of the general formula

G-V (III)

in which

Each represent a Rg, R, Rc, A, B, E and G are as hereinbefore defined, R "V and R ¹ by a protecting group-protected amino or alkylamino group, or each have the meanings for R or R *, mentioned have one of the radicals U or V represents the Rg-NH group, wherein Rg is as defined above, and

the other of the radicals U or V is a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, z, "B" is a chlorine, bromine or iodine atom, the Methansulfonyloxy-, p-. Toluolsulfonyloxy- or Ethoxysulfonyloxy group, and optionally subsequent cleavage of a used protective moiety ·

; : ' - - ^: '; // .: ',. ', = ·.' , \ 63 o66 12

The reaction is expediently carried out in a solvent or solvent mixture such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethylsulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or in an excess of the compounds of the general formulas II and / or III used and, if appropriate, in Presence of an acid-binding agent, e.g. B is an alcoholate such as potassium tert-butylate, an alkali hydroxide such as sodium or potassium hydroxide, an alkali metal carbonate such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, the latter also serving as a solvent , or a reaction accelerator such as potassium iodide depending on the reactivity of the nucleophilically exchangeable radical expediently carried out at temperatures between 0 and 150 ⁰ C, preferably at temperatures between 50 and 120 ⁰ C, z · B · at the boiling temperature of the solvent used. However, the reaction can also be carried out without a solvent. However, the reaction is carried out particularly advantageously in the presence of a tertiary organic base or an excess of the amine of the general formula III used.

The optionally subsequent cleavage of a protective moiety used is preferably carried out hydrolytically in an aqueous solvent, for. In water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid 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 point of the reaction mixture. However, the removal of a benzyl radical can also be carried out by hydrogenolysis,

63 066 12

ζ · B * 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 and 50 ⁰ C, but preferably at room temperature, and a hydrogen pressure from 1 to 7 bar, but preferably from 3 to 5 bar ·

b) For preparing compounds of general formula I in which A is a -CH -CH _{0 0} -, -CH = CH-, -NH-CO-, -COCO-,

b ⁵

-CH ₀ -CO-, -Cs = N- or -N = CH- group and 5 * '5. '5

B is a -CH ₀ - or -CO- group represent: reacting a compound of general formula

R '

R ₂ K jf ^N H - H (IV)

in the ·

R "as defined above,

A. ^{1 is} -CH ₀ -CH ₀ -, -CH = CH-, -NH-CO-, -COCO-, -CH ₀ -CO-,

R5 ⁵

-N = CH- or -C = N-group, in which R _{7 is} an alkyl group

5 '

with 1 to 3 carbon atoms,

B ^{1 is} a -CHg- or -CO-group and

R ₁ ¹ represents a protecting group by a protected amino or alkylamino group, or has the groups mentioned for R ^ meanings, with a compound of general formula

63 066 12 - H -

6 r. \ ^ " R»

¹ / TX ³

^E 5

in the

R-, Rc, Rr, E and G are as defined above, R / ^{r is} a protected by a protecting group amino or alkylamino group or has the same meaning for R, and

Z is a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, e.g. B denotes a chlorine, bromine or iodine atom, the methanesulphonyloxy, p-toluenesulphonyloxy or ethoxysulphonyloxy group, and if appropriate subsequent removal of a protective residue used.

The reaction is optionally carried out in a solvent or solvent mixture, z · B # in acetone, dimethylformamide, acetone / dimethylformamide, dimethyl sulfoxide or chlorobenzene, and expediently ö® on the reactivity of the radical 2 at temperatures between 0 and 150 ⁰ C, but preferably at the boiling temperature The solvent used, carried out advantageous is the presence of an acid-binding agent, such as. B · an alcoholate, such as sodium methoxide, an alkali metal hydroxide, such as sodium hydroxide, of an alkali metal carbonate. such as potassium carbonate, an alkali metal amide such as sodium amide, an alkali metal hydride such as sodium hydride or a tertiary organic base such as triethylamine or pyridine, or a reaction accelerator such as potassium iodide ·

63 066 12

The optional subsequent cleavage of a protective moiety used is preferably carried out hydrolytically in an aqueous solvent, for example in water, isopropanol / water, tetrahydrofuran / WasBer or dioxane / water, in the presence of an acid such as hydrochloric acid 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 removal of a benzyl radical can also be effected by hydrogenolysis, for example 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, if appropriate with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ^° C., but preferably at room temperatures, and a hydrogen pressure of 1 to 7 bar, but preferably of 3 to 5 bar.

c) for the preparation of compounds of general formula I,

where A is not a -GH-CO group:

Reaction of a compound of the general formula

H-E-H (VI)

in the

B, E, R ₁ and R _{2 are} as defined above, but in the radical E two hydrogen atoms in a -CHg or CH ~ group of the radical E are formed by an oxygen atom.

63 066 12 - 16 -

are set, and A "is a -CH -CH _{0 0} -, -CH = CH-, -M-CO-, -CH ₀ -CO-, -N = CH-,

OH OH IJOH? 7

Represents -CH-CO-, -CH-CH ₀ -, -C-CO- or -C = N-group,

5 5. ^{for example} 5 '5

in which R _{7 is} an alkyl group having 1 to 3 carbon atoms, with an amine of the general formula

(VII)

in the

¹ W ^1. , ¹ ·.

G and R "to Rg are as defined above, in the presence of a reducing agent ·

The reaction is expediently 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., but preferably at temperatures between 20 and 80 ^° C.

The reductive amination is particularly advantageously in the presence of a complex metal hydride such as lithium or ITatriumeyanborhydrid preferably at a pH of 6 to 7 and at room temperature or for the preparation of compounds of general formula I, in which Rg represents a hydrogen atom, in the presence of a Hydrogenation catalyst, z * B. with hydrogen in the presence of palladium / carbon at a hydrogen pressure of 5 bar, carried out *

63 066 - 17 -

In this case, optionally present double bonds can be hydrogenated ·

d) For the preparation of compounds of general formula I,

HH-R ₈

where A is not a -CH-CO- group:

5.

Reaction of a compound of the general formula

(VIII)

in the

B, E, R ^, Rg and Rg are as defined above and A "is a -CH ₀ -CH ₂ -, -CH = CH-, -NH-CO-, -CH ₀ -CO-, -N = CH- , OH is OH NOH ^R 7) -, -CH-CH ₀ -, -C-CO- or -C = N-group,

5 5 ² 5 5

in which R 1 represents an alkyl group having 1 to 3 carbon atoms, with a compound of the general formula

H-G

(IX)

in the .

Ry to Rc and G are as defined above, but in the rest G two hydrogen atoms in a'r

63 066 12

or CH ^ group of the radical G are replaced by an oxygen atom, in the presence of a reducing agent *

The reaction is expediently 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., but preferably at temperatures between 20 and 80 ^° C.

Particularly advantageous is the reductive amination in the presence of a complex metal hydride such as lithium or sodium cyanoborohydride preferably at a pH of 6 to 7 and at room temperature or for the preparation of compounds of general formula I, in which Rg represents a hydrogen atöm, in the presence of a hydrogenation catalyst, such "-B · - with hydrogen in the presence of _v palladium / carbon bar at a hydrogen pressure of 5 performed · This can optionally present double bonds are rehydrated ·

e) For the preparation of compounds of the general formula I, in which A represents the -CHgCHg group, B the methylene or carbonyl group and Rg no alkenyl group having 3 to 5 carbon atoms:

Hydrogenation of a compound of the general formula

(X)

in the

R ₁ to Rg, E and G are as defined above and B 'represents the methylene or carbonyl group. «

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The hydrogenation is carried out in a solvent or solvent mixture such as methanol, ethanol, ethyl acetate or glacial acetic acid with catalytically excited hydrogen, z, B with hydrogen in the presence of platinum or palladium / carbon, at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, and at temperatures between 0 and 75 ⁰ O, but preferably carried out at temperatures between 20 and 50 ⁰ C, carried ·

f) For the preparation of compounds of the general formula I in which B is the -CS group and G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms or a methylene-n-hydroxy-alkylene group Represent 1 to 4 carbon atoms in the alkylene moiety:

Reaction of a compound of the general formula

CO '

(XI)

* 2

in the

R ₁ to Rg, A and E are as defined above and G * represents an n-alkylene group having 1 to 5 carbon atoms optionally substituted by an alkyl group having 1 to 3 carbon atoms or a methylene-n-hydroxyalkylene group having 1 to 4 carbon atoms in the alkyl moiety a sulfur-introducing agent «

The reaction is carried out with a sulfur introducing agent such as phosphorus pentasulfide or 2,4-bis (4-methoxyphenyl) -

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1,3-dithia-2,4-diphosphetane-2,4-disulfide is conveniently carried out in a solvent such as toluene or xylene at temperatures between 50 and 150 ^° C., eg at the boiling temperature of the reaction mixture.

g) For the preparation of compounds of general formula I,

OH OH t in the A is a -CH-CO- or -CH-CH ^- group and G is a

optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms or a methylene-n-hydroxy-alkylene group having 1 to 4 carbon atoms in the alkylene moiety:

Reduction of a compound of the general formula

in the R ₁ to

^CH 2 "" ^CH 2 \

N-E-N-G

E and G are as defined above

(XII)

pie reaction is conducted in the presence of a suitable reducing agent such as a metal hydrides such «B * sodium borohydride or lithium aluminum hydride, in a suitable solvent such as water / methanol, methanol / ether, tetrahydrofuran, dioxane or ether / Tetrahydföfüraii bsi -ieiape · - ^ n temperature between 0 and 80 ⁰ C, but preferably at temperatures between 15 and 40 ⁰ G,? '- Aue chgefiihrt.i in the reaction of an optionally present C0 ~ group in the radical G is added to the CHOH group mitreduziert ·,

63 066 12

h) For the preparation of compounds of general formula I,

HN-Rq'NOH

in the A is a -CH-OO- or -C-CO- group and G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms or a methylene * n-hydroxy-alkylene group with 1 to 4 carbon atoms in the alkylene part:

Reaction of a compound of the general formula

N-E

(XIII)

in the

R ₁ to Rg and E are as defined above and G ^{1 is} an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms or a methylene-n-hydroxyalkylene group having 1 to 4 carbon atoms in the alkylene part, with a Compound of the general formula

NO,

(XIV)

in the

Rq represents the hydroxy group or has the meanings mentioned for R _Q at the beginning »and optionally subsequent reduction ·

63 066 12 - 22 -

The reaction is conveniently carried out in a solvent such as ethanol, dioxane or glycol or in the melt at elevated temperatures, at temperatures between 50 and 175 ° C. The optionally subsequent reduction is carried out with a reducing agent such as a complex metal hydride, eg , lithium aluminum hydride, with catalytically promoted hydrogen, for example with hydrogen in the presence of a hydrogenation catalyst such as platinum or palladium / carbon at a hydrogen pressure of 1 to 7 bar, preferably however, from 3 to 5 bar, or with hydrazine / Raney-Michael in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid at temperatures between 20 and 50 ⁰ C, performed ·

i) For the preparation of compounds of the general formula I, in which A represents the -NeCH group and Rg represents an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 3 to "5 carbon atoms:

Reaction of a compound of the general formula

in the

R- to R, -, B, E and G are as defined above and Rg 'is an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 3 to 5 carbon atoms, with an orthoformic acid ester «

The reaction is preferably in a solvent

63 066 12

such as ethanol, toluene, dimethoxyethane or in an over. *., Shot of the orthoester used at temperatures between 100 and 200 ⁰ C, performed.

, Furthermore, it may be advantageous if any existing NHg or HH groups during the reaction by protecting groups, for. B · be protected by acetyl, benzoyl, ethoxycarbonyl or benzyl groups

The protective radicals which are optionally used during the reaction are then cleaved off again, for example acyl radicals preferably hydrolytically in the presence of an acid or base or benzyl radicals preferably hydrolytically, eg. With hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon or platinum.

k) For the preparation of compounds of the general formula I, in which A is not a -COCO group and G is a, methylene-n-hydroxyalkylene group:

^R 1

w-E-N-G "

Reduction of a compound of the general formula

^ ^R 4

(XVI)

in the

R ₁ to Rg, B and E are as defined above,

A " ¹ with the exception of the -COCO group has the meanings mentioned for A, and

G "represents a methylene-n-alkylene group, wherein the alkylene part contains 1 to 4 carbon atoms and a

63 066 12

Methylene group of the alkylene part is replaced by a carbonyl group ·

The reduction is preferably carried out with a metal hydride such as sodium borohydride in a suitable solvent such as ethanol, ethanol / water, methanol or isopropanol at temperatures between 0 and 50 ^° C., but preferably at temperatures between 10 and 25 ^° C.

1) For the preparation of compounds of general formula I,

in which R 1 is a methyl group and R is an amino group ^. represents: '·,'"'·"" ⁴ '.:: \ 'vv'/; C .-..;

Hydrolysis of a compound of the general formula

in the

R-, Rp, Rc, Rg, Aj B, E and G are as defined above

Acyl represents an acyl radical such as the acetyl, ethoxycarbonyl or benzoyl group.

The cleavage of an acyl radical used is preferably carried out hydrolytically in an aqueous solvent, eg, water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide Temperatures between 0 and 100 ⁰ C, preferably in the

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~ ²⁵ -

Boiling temperature of Reaktionsgemiscta.es. However, the reaction is preferably in the presence of an alcoholic acid, ζ. Β · with methanolic or ethanolic hydrochloric acid, carried out ·

m) For the preparation of compounds of general formula I in which A is a -CH -CO _{0 0} -, -CH = CH-, -NH-CO-, -CH ₀ -CO-,

^{d ά} 5 5 ^ά '

Η,

-N ^ CH-, -COCO- or -C = N- group and one of the radicals R ₁ ,

R ₂ , R or R represents an alkoxy, alkylamino or dialkylamino group or Rg represents an alkyl or alkenyl group:

Reaction of a compound of the general formula

R

(XVIII)

in the

R- to Rg, B and E are as defined above, but where at least one of R ^ to R, a hydroxy group or R ^ or R, an amino or alkylamino group or Rr must represent a hydrogen atom,

A ^{f is} -CH ₀ -CH ₀ -, CH = CH-, -NH-CO-, -CH ₀ -CO-, -N = CH-, ² _R ² 5 .5 ² 5

-COCO- or -C = N group in which R ^ is an alkyl group

5.

1 to 3 carbon atoms, and

G " ^{1 is} an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms, in which a methylene group by

63 066 12 - 26 -

a carbonyl group may be replaced with a compound of the general formula

R ₁₀ -X (XIX)

in the

R ^ q is an alkyl group having 1 to 3 carbon atoms or also, an alkenyl group having 3 to 5 carbon atoms when Rg represents a hydrogen atom, and X is a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, e.g. Example, a chlorine, bromine or iodine atom, a methanesulfonyloxy, p-toluenesulfonyloxy or Methoxysulfonyloxygruppe, or, if at least one of the radicals R to R * represents a hydroxy group, X together with an OC-hydrogen atom of the radical R _first Q is a diazo group or, if Rg is a hydrogen atom or R- or R * 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, Kaiiumhydroxid, potassium tert-butoxide or sodium hydride at temperatures between 0 and 150 ⁰ C, preferably However, at temperatures between 20 and 120 ⁰ C, carried out.

If B denotes a -CHp or -CQ group and X denotes a nucleophilic leaving 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 or isopropyl p-toluenesulfonate in

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waiting an acid-binding agent at temperatures zwisehen 20 and 80 ⁰ C performed · However, the reaction can also be carried out without solvent ·

Means X together with a "C-position hydrogen atom of the radical R-jq a diazo group, the reaction is preferably carried out with diazomethane or diazoethane at temperatures between 0 and 30 ⁰ O for the alkylation of a hydroxy group, or an oxygen atom, then alkylation of the Nitrogen atom, the reaction in the presence of a reducing agent at temperatures between'O and 120 ⁰ C, for example, with formic acid at temperatures between 80 and 110 ⁰ C or with Katriumcyanborhydrid at room temperature and a pH of 6 to 7 carried out.

n) For the preparation of compounds of general formula I in which A is the -COCO group and G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms, in which a methylene group replaced by a carbonyl group can represent:

Oxidation of a compound of the general formula

R-

_N -ENG

in the

R ₁ to Rg, E and G are as defined above.

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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 acetic anhydride at temperatures between 0 and 100 ⁰ C, preferably at temperatures between 20 and 80 ⁰ C, performed.

o) For the preparation of compounds of general formula I in which A is the -CHg-CO- group and G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms, in which a methylene group by a carbonyl group can be replaced, represent:

Oxidation of a benzazepine of the general formula

NESGT s% (XXI)

in the

R to Rg, B, E and G are as defined above.

The oxidation is carried out with ruthenium tetroxide in a suitable solvent or solvent mixture such as chloroform / water, methylene chloride / water or carbon tetrachloride / water at temperatures between 0 and 100 ⁰ C, preferably at temperatures between 20 and 50 ⁰ C, carried out preferably in a two-phase system such as methylene chloride / water, chloroform /

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Water or carbon tetrachloride / water with a catalytic amount of ruthenium dioxide in the presence of a suitable oxidizing agent, such as sodium periodate, which generates ruthenium tetroxide in situ.

p) For the preparation of compounds of the general formula I in which R _{1 is} in the 7-position, A represents the -CHgCHg group and B represents the CO group:

Cyclization of a compound of the general formula

I ⁶

CH ₀ - CH ₀ -HEUG 2 2,

⁴ (XXII)

in the

R- to Rc »G and E are as defined above, Rg ^{1 represents} an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 3 to 5 carbon atoms and Y represents a group suitable for ring closure ·

For example, Y is the carboxy or nitrile group, an ester group such as the methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl or benzyloxycarbonyl group, a thioester group such as the ethylthiocarbonyl, phenylthiocarbonyl or pyridylthiocarbonyl group, an acyloxycarbonyl group such as the acetoxycarbonyl or trifluoroacetylcarbonyl group or an amide group such as aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl or phenylaminocarbonyl group.

The reaction is optionally carried out in the presence of a

63 066 12 - 30 -

suitable condensing agent and optionally in a pressure vessel in a solvent such as xylene, thylglykoläther, tetralin or SuIfolan at elevated temperatures, for example, at temperatures between 100 and 250 ⁰ C, but preferably at temperatures between 140 and 180 ⁰ G. However, the reaction can also be carried out without a solvent.

As suitable condensing agents, for example, Hjl ^ -Dicyclohexyl-carbodiimide, thionyl chloride, a phosphate such as Diethylchlorphösphonat or bis (0-nitrophenyl) phenylphosphonate, a phosphorane such as (2,2,2-trifluoroethoxy) -triphenylphosphoran, an N-alkyl-pyridinium such N-methyl-2-chloro-pyridinium-iodide or K-methyl-2-fluoro-pyridinium-tosylate, N, W'-dicyclohexyl-carbodiimide / A-dimethylamino-pyridine, chlorosulfohyl isocyanate or ΪΓ, Ν ^1- carbonyldiimidazole in considered ·

Furthermore, it may be advantageous if any existing HO, HH or NH ^ groups during the reaction by protecting groups, for. By acetyl, benzoyl, ethoxycarbonyl or benzyl groups.

If Y in a compound of the general formula XXII denotes a uritrile or amide group, the reaction is preferably carried out in such a way that a corresponding compound is prepared by alkaline or acidic hydrolysis, using methanol / hydrochloric acid or ethanol / sodium hydroxide solution in each case Boiling temperature of the reaction mixture is converted into a corresponding carvoxy compound, which is subsequently cyclized

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The protective radicals which are optionally used during the reaction are then cleaved off again, for example acyl radicals preferably hydrolytically in the presence of an acid or base or benzyl radicals preferably by hydrogenolysis, for example with hydrogen in the presence of a hydrogenation catalyst such as palladium / carbon or platinum.

The resulting compounds of general formula I can be further converted into their acid addition salts, in particular in their physiologically acceptable acid addition salts with inorganic or organic acids. Examples of suitable acids are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid.

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

Thus, for example, a starting compound of the general formulas II and VII is 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 IV is obtained by cyclization of a corresponding compound, z, B by cyclization of a compound of the general formula

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OHgOO '

OH ₂ - CH

OCH.

OCH.

(XXIII)

or the general formula

(XXIV)

CH ₂ CH ₂ IIHCCh ₂ Cl 0

when R 1 and R _{2 are} not alkoxy groups, optionally subsequent catalytic hydrogenation and / or reduction of the carbonyl group, for example with sodium borohydride / glacial acetic acid (see EP-A1 O.OO7.O7O) and / or oxidation, for. With selenium dioxide ·

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

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

A compound of the general formulas X to XIII, XVI to XVII, XVIII, XX and XXI used as starting material is preferably obtained by reacting a corresponding halo.

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genverbindung with a corresponding amine and optionally subsequent cleavage of protective groups that are used to protect hydroxy groups ·

A compound of the general formula XXII used as starting material is obtained, for example, by chloromethylation of a compound of the general formula

COGH ₃

CH ₂ CH ₂ -IT.

E-W (XXV)

in the

R ₁ , R ₂ and E are as defined above and W is a protected hydroxy group, for example the acetoxy, benzoyloxy or 4-nitrobenzoyloxy group, further reaction with an alkali metal cyanide, conversion of the radical W into a suitable leaving group as in the Chloro, bromo or iodo, methylsulfonyloxy or 4-Methylphenylsulfonyloxygruppe and subsequent reaction with an amine of the general formula

f ³

S ₆ -BH- (S <Λ (VI)

in the

R ^ to R ^ and Q are as defined above, and given

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if subsequent hydrolysis and / or esterification or amidation · - "'^ - / ..., -.'," .- Z '' ¹ -... '/ /''., - ..' ·

As already mentioned, the novel compounds of the general formula I and their physiologically tolerated acid addition salts with inorganic or organic acids have valuable pharmacological properties, in particular with low side effects, for example a low antimuscarinic, a long-lasting heart rate-lowering action and a reduction of the Og need of the heart ·

For example, the compounds were

A s 1 - (. 7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- / N-methyl-N- (3 (3 "4-dime thoxy-phenyl) -propyl) -amino J7" "PiOpan hydrochloride,

B = 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2-thion-3-yl) -H-ZTlf-methyl-Ki 2- (3 »4- dime thoxy-phenyl) ethyl) -amino-7-propane »

C ss 1 - (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- £ N-methyl-N- (2 -hydroxy-2- (3,4-dime thoxyphenyl) ethyl) -amino J -propane,

Dβ 1- (1-Hydroxycy-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl) -3-ZTU-methyl-H- 2- (3,4-dimethylthio-phenyl) -ethyl) -amino-7-propane,

E it. 1- (7,8-dimethoxy-1,3,4 '5-tetrahydro-2H-3-benzazepin-2-on-3-yl) -3-ZTN-methyl-N- (2- (4-amino- 3-nitro-phenyl) -ethyl) -amino J ^ -propane hydrochloride,

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.P = 1- (7> 8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-Z-N-methyl-n- (4 - (4-dimethylamino-phenyl) butyl) -amino .7-propane-hydrobromide,

G a 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- / 1-l-methyl-IT- (2-phenyl -ethyl) -amino-7-propanedihydrochloride »

Hβ 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- ^ "N -methyl-N- (5- 3,4-dimethoxyphenyl) pentyl) amino-7-propane hydrochloride and ^

I s 1- (7,8-dimethoxy-1,3t4-5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- ^ TN-methyl-1- (3-amino-4-amino -3 ♦ 5-dichloro-phenyl) -propyl) -amino_7-propane

compared to

Kβ 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-5H-2-benzazepin-1-one-2-yl) -3-ZTK-methyl-N- (2- (3, 4-dimethoxyphenyl) -ethyl) amino-JZ-

examined for their biological properties as follows:

Effect on heart rate in rats;

The effect of the substances to be tested on the heart rate was examined per dose in 2 rats with an average weight of 250 to 300 g. For this purpose, the rats were anesthetized with pentobarbital (50 mg / kg i.p. and 20 rag / kg bc) The substances to be tested were injected in aqueous solution into the jugular vein (0.1 ml / 100 g).

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Blood pressure was measured by cannula attached to the carotid artery and the heart rate was recorded from an ECG (II or III lead) derived from needle electrodes. The heart rate of the animals in the control period was between 350 and 400 beats / minute (bpm). The following table contains the found values:

substance Dose (mg / kg) Heart rate reduction, measured 20 minutes after substance administration (bpm) A 5.0 - 183 2.5 -85 1.0 - 51 B 5,0,. - 255 2.5 - 134 1.0 - 73 5.0 - 173 2.5 - 137 D 5.0 - 117 2.5 - 73 1.0 , - 83 e 5.0 - 130 F 5.0 - 123 2.5 - 91 1 »0 - 94 G 5.0 - 135 2.5  - 110 1.0 - 80 H 5.0 - 75 I 5.0 - 175 K 5.0 - 18

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The compounds according to the invention have no toxic side effects at therapeutic doses. For example, no toxic side effects were observed in an intravenous administration of substances A and D even in a high dose of 20 mg / kg of mice.

Because of their pharmacological properties, the compounds according to the invention are suitable for the treatment of sinus tachycardias of various origins and for the prophylaxis and therapy of ischemic heart diseases.

The dosage required to achieve a corresponding effect is expediently once or twice daily 0.03 to 0.4 mg / kg of body weight, preferably 0.07 to 0.25 mg / kg of body weight. For this purpose, the compounds of the general formula according to the invention can be I and their physiologically tolerated acid addition salts with inorganic or organic acids, optionally in combination with other active substances, together with one or more inert conventional carriers and / or diluents, for. Corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinyl pyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerine, water / sorbitol, water / polyethylene glycol, propylene glycol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures , in usual Galenisohe preparations such as tablets, dragees, capsules, powders, suspensions, drops, ampoules, juices or suppositories incorporated.

embodiment

The following examples are intended to explain the invention in more detail: i

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Production of the starting compounds: Example A

- (7 * 8 * -Dime thö3cy «1.3» 4 .. »5-tetrahydro-2H-3-benzazepin-2-one-3

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

Prepared analogously to Example 1b by reacting 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl) -3-chloropropane with N-ethylbenzylaiolein. Calculated: 92.1 % of theory Melting point: 208 to 209 ⁰ G

b) 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3- yl) -3-methyl-aminopropane hydrochloride

Prepared analogously to Example 5 by catalytic hydrogenation of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-N-methyl-K-benzylamino propane · yield: 87% of theory melting point: 110 ⁰ C (dec.)

Example B

1 "3" 4 * 5-tetrahydro-2H-3-benzazepin-2-one

a) N'-2-phenyl-ethyl) -1-chloro-a-amide

38.7 ml (0.3 mol) of 2-phenylethylamine and 45.9 ml (0.333 mol) of triethylamine are dissolved in 30 ml of methylene chloride and with 26.4 ml (0.33 mol) of chloro-acetyl chloride, dissolved in

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150 ml of methylene chloride, at 10 ⁰ C added · After stirring for 1 hour at room temperature, extracted with 1 #iger acetic acid and with water, dried over magnesium sulfate and concentrated in vacuo · Yield: 54.2 g (91.4 % of theory) melting point : 64 to 65 ⁰ C

b) 1.3.4.5-Tetrahydro-2H-3-benzazepin-2-one

54.0 g (0.373 mol) of N- (2-phenyl-ethyl) -1-chloro-acetamide are with. 7-3.8 g (0.55 ml) of aluminum chloride and stirred at 130 to 140 ⁰ C for 13 hours. Each decomposition of the aluminum chloride with ice water is extracted with methylene chloride, washed with water, dried over magnesium sulfate, concentrated in vacuo and the residue obtained is purified on silica gel with methylene chloride + 3 % ethanol as eluent. Yield: 6.22 g (14.1 % of theory) melting point: 158 to I60 C ⁰

Example C

1- (7-Bromo-8-methoxy-1,3-4-5-tetrahydro-2H-3-benzazepin-2- on-3-yl) -3-chloro-propane

a) 8-Methoxy-1,3,5,5-tetrahydro-2H-3-benzazepin-2-one

56.8 g (0.3 mol) of 8-methoxy-T, 3-dihydro-2H-benzazepin-2-one (melting point 190 to 191 ^° C.) dissolved in 600 ml of glacial acetic acid are dissolved in the presence of 5 g of 10%. iger palladium carbon at 80 ⁰ C and 5 bar hydrogenated for 12 hours. The catalyst is filtered off with suction and the acetic acid is removed in vacuo.

63 066 12 - 40 -

distilled · The residue is mixed with water, neutralized with potassium carbonate, the precipitate filtered off with suction, washed with water and dried. Yield: 51.1 g (89.1 % of theory) Melting point: 160 to 161 ^° C.

b) 7-Bromo and 9-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3 ·· ' benzazepin-2-one

To 7.4 g (0.04 mol) ebenzazepin-2-one in 100 ml 80 S & Lger acetic acid at 3 to 5 ⁰ C under stirring 6.4 g = 2.03 ml (0.04 mol) of bromine in 10 ml Bisessig added dropwise · After 15 minutes, poured onto ice water, neutralized with potassium carbonate, the precipitate was filtered off with suction, washed with a little water and dried, pas obtained isomer mixture is chromatographically separated on a silica gel column ·, (eluent: ethyl acetate)

Yield: 5.7 g (52.8 % of theory) 9-bromine isomer IR spectrum (methylene chloride): 3400 cm (NH)

1660 cm " ¹ (0 = 0)

4.1 g (38 % of theory) of 7-bromo isomer

3200 cm "" ¹ (1 1665 cm " ¹ (CO)

IR spectrum (potassium bromide): 3200 cm ^-1 (NH)

c) 1- (7-Bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2- on-3-yl) -3-chloro-propane

To 1.35 g (5 mmol) of 7-bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one in 15 ml of dimethyl sulfoxide are added 0.24 g (5.5 mmol ) sodium hydride Pispersion in oil (55%) are added and ^1/2 hour at room temperature and 10 minutes

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stirred at 35 to 40 ⁰ O • The solution is added dropwise with stirring to 0.79 g (5 »5 mmol) of i-bromo-3-chloropropane in 5 ml Dimethyisulfoxid · Then stirred for 2 hours at room temperature, poured into ice water and extracted 4 times with methylene chloride. The methylene chloride extracts are washed several times with water, dried and concentrated in vacuo.

The residue is purified over a silica gel column using as eluent Essigester · Yield: 210 mg (12% of theory) Melting point: 119-120 ⁰ C.

Example D '. , ' ^: .''. / '·' -V.- '7-flitro-8-methoxy-1.3 "4 * 5-tetrahydro-2H-3-benzazepin-2-one

765 mg (4 mmol) of 8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin ~ 2-one are added in portions at 3 to 5 ⁰ C with stirring to a mixture consisting of 15 ml of concentrated and 1 , 5 ml fuming nitric acid added. Stirring is continued with further cooling for 30 minutes, poured onto ice water * truncated with potassium carbonate, filtered off, washed with water and dried. The yellow precipitate is to separate the corresponding 9-nitro isomer and the 7,9-dinitro compound over a silica gel column with Essigester purified as eluent.

Yield: 400 mg (42.3% of theory) Melting point: 204-205 ⁰ Q (dec.)

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Preparation of the end products: Example 1

1- (7,8-dimethoxy-1,3,4-> 5-tetrahydro-2H-3-benzazepine-2-on-3-yl) -3-ZTK-methyl-N- (3- (3,4 -dimethoxy-phenyl) -propyl) -amino_7- propane-hydrochloride

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

1.1 g (0.005 mol) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2EK3-benzazepin-2-one are suspended in 15 ml of absolute dimethyl sulfoxide and stirred with 0.67 g of CO, 006 mol After 10 minutes, the resulting suspension is added dropwise with cooling with ice water to 0.64 ml (0.006 mol) of 1-bromo-3-chloro-propane in 10 ml of dimethyl sulfoxide, After one hour, it is poured onto water · After a short time, the greasy precipitate begins to crystallize too much · The precipitate is filtered off with suction, dissolved in acetone, reprecipitated with water, filtered off with suction and dried.

Yield: 0.75 g (50.0 % of theory) Melting point: 84 to 85 ° C

b) 1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-N-methyl-N- (3- (3-yl) 3 »4-dimethoxy-phenyl) * -propyl) -amino-7-propane hydrochloride

' ^: . 5.55 g (0.0186 mol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3 Chloro-propane, 2.6 ml (0.0886 mol of triethylamine and 3.9 g (0.0186 mol) of N-methyl-3- (3,4-dimethoxy-phenyl) -propylamine are 4 hours at 85 ⁰ C.

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.43 -

heated, cooled and dissolved in methylene chloride / water · The organic phase is separated, extracted once more with water, dried over magnesium sulfate, concentrated in vacuo and the residue obtained on silica gel with methylene chloride + 3 % ethanol as eluent. The oily residue obtained is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 3.45 g (36.6% of theory) Melting point: 220 to 221 ⁰

Example 2 *

1- (7,8-Dimethoxy-1, 3,4,5 ^- tetrahydro-2H-3-benzazepin-2-one ~ 3-yl) -3- £ H-methyl-E- (2-phenyl) ethyl) -amino chloride. . · ...: · ·. ·, ·: · ·. ' :: - ^ - "-: -. · ' ·. '' -: "^; - ·

Prepared analogously to Example Ib by reaction of 1- (7 »8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl) - ^> 3-chloropropane with ¥ - methyl-2'-phenyl-ethylamine. Yield: 43.2 % of theory Melting point: 165 ° C decomposition

Example 3

1 - '(1,3,5,5-tetrahydro-2H-3-benzazepin-2-on-3-yl) -3-ZTK-methyl-N- (2- (3,4-dime thoxyphenyl ) -thyl) -amino ^ -p hydrochloride

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

Prepared analogously to Example 1a by reaction of

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1 »3» 4,5-Tetrahydro-2H-3-benzazepin-2-one with 1-bromo-3-chloro-propane

Yield: 13 »4% of theory

IR spectrum (methylene chloride): 1660 cm "(GO)

b) 1- (1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZT-methyl-2- (2- (3-4-dime thoxy-phenyl) -ethyl) -amino J7 "" propane hydrochloride

Prepared analogously to Example 1b by reacting ΤΟΤΟ3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl) -3-chloropropane with N-methyl-N- (2- (3,4-) dimethoxyphenyl) ethyl) amine ·

Yield: 29.2 % of theory Melting point: 160 to 162 ^° C.

Example 4

1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-2-on-3-yl) -3- £ 1-methyl-N- (5- (3, 4-dimethoxy-phenyl) - pentyl) amino J- [ propane-hydrochloride

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

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

Yield: 87.3 % of theory

Melting point: 101 to 103 ^° C.

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: '' '- 45 - ·'. .,:

b) 1- (7,8

-methyl-H- (5- (3 »4-dimethoxyphenyl) -pentyl) -amino_7- propane hydrochloride

Prepared analogously to Example 1b by reacting 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with IT-methyl-N- ( 5- (3 "4-dimethoxy-phenyl) -pentyl) -amine ·

Yield: 67 _t 3 % of theory

Melting point: 158 to 160 ^° C.

Example 5

1 - (7,8-Dimethoxy-1,3,4 »S -tetrahydro ^ H ^ -benzazepine -on-yl) -3- £" N-methyl-ir- (5- (3> 4-) dimethoxyphenyl) pentyl) amino J propane hydrochloride

3.23 g (0.0065 mol) of 1- (7,8-dimethoxy-1,3-dihydro ^ H ^ -benzazepin-2-one-3-yl) -3- ^ TN-methyl-N- ( 5- (3,4-dimethoxyphenyl) -pentyl) -amino_7-propane, dissolved in 30 ml of acetic acid, are hydrogenated at room temperature and a hydrogen pressure of 5 bar in the presence of 10% palladium / carbon for 3.5 hours. The catalyst is filtered off, the filtrate concentrated in vacuo and the residue taken up in methylene chloride / 15% potassium carbonate solution. The organic phase is separated, dried over magnesium sulfate, evaporated in vacuo and the residue obtained on silica gel with methylene chloride + 4 % ethanol as eluent · the resulting residue is dissolved in acetone, and ethereal, hydrochloric acid the hydrochloride precipitated · yield: 2.1 g (? 60.3% of theory) melting point: 165-166 ⁰ C.

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; , . ,; , ; ', -' - ^; ^ - V- -46 - '_''·.''^; ,

Example 6

1 - (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benz2-azepine-2-thion-3-yl) -3-N-methyl-N- (2- (3 , 4-dime thoxy-phenyl) -ethyl) -amino- 7-propane

2.28 g (0.005 mol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepiri-2-on-3-yl) -3- £ "N-methyl- K- (2- (3,4-dimethoxyphenyl) ethyl) amino J -propane are dissolved in 10 ml of absolute toluene and treated with 1.0 g (0.0025 mol) of 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide refluxed for 50 minutes Wake up of the solvent in vacuo, the residue obtained is purified over alumina with methylene chloride + 2% ethanol as eluent · Yield: 1, 45 g (61.4 % of theory)

^C 26 ^H 36 ^N 2 o ₄ s (472.6 ) H 7, 68 N 5 , 93 P. 6 , 78 Ber ·: C 66, 07 7, 71 5 , 56 6 , 76 Gef 66 10 example 7 - -

1- (7,8-dimethoxy-1,3,4,5-th-trahydro-2H-3-benzazepin-2-one-3-yl) -3-N-methyl-Ki- (3,4- dime-thoxy-benzoyl-methyl) -amino-Z- propane hydrochloride

Prepared analogously to Example 1b by reacting 1- (7, β-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-W-methyl-amino-propane with oc-bromo-3,4-dimethoxy-acetone and on. Yield: 1.29 g (77.0% of theory) Melting point: 190 ^° C.

63 066 12

Example 8

1- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- £ N-methyl-N- (2-hydroxy) 2- (3,4-dimethoxy-phenyl ) -ethyl) -amino-7-propane

0.92 g (0.002 mol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2-lfr-3-benzazepin-2-one-3-yl) -3--N-methyl-H- (3 * 4-dimethoxy-benzoylmethyl) -amino_7-propane are dissolved in 6 ml of ethanol, treated with 0.38 g (0.01 mol) of sodium borohydride and 2 hours at 25 ⁰ C After concentration of the solvent in vacuo in methylene chloride extracted, extracted with water, dried over magnesium sulfate, concentrated in vacuo and the residue obtained over alumina with methylene chloride + 1 % ethanol as eluant purified · Yield: 0.5 g (54 % of theory) iR spectrum (methylene chloride): 1655 cm (CO)

° 26 ^H 36 ^li 2 # 6 (472, 6) H 7 , 68 N 5 , 93 Ber ·: C 66 , 08 7 , 62 5 80 Found .: 66 , 01 example 9

1-Z ~ 7,8-dimethoxy-1- (2- (3,4-dimethoxy-phenyl) -ethyl-amino) -1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 3-yl_7-3- £ "N-methyl-N- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino-propan-y dihydrö chloride. _{m mmimm}

2.45 g (5 mmol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl) -3-ZTN-methyl- N- (2- (3,4-dimethoxyphenyl) ethyl) amino J'-propane and 2 g of 2- (3,4-dimethoxyphenyl) -ethyl-amine are heated at 150 ⁰ C for 3 hours. The

63 066 12

Reaction mixture is purified over alumina H (activity II) with methylene chloride and 5 % acetone as eluent. The fractions are concentrated by evaporation, the residue obtained is dissolved in 100 ml of methanol and hydrogenated at 50 ^° C. under a pressure of 5 bar in the presence of 0.5 g of 10% palladium carbon for 6 hours. After completion of the hydrogen absorption, the catalyst is filtered off with suction , the filtrate was concentrated and the residue was purified on silica gel with methylene chloride and 5 % ethanol as eluent. The residue obtained is dissolved in acetone and ethereal hydrochloric acid, the precipitated dihydrochloride · Ausbeuteϊ 0.6 g (53.6% of theory) Melting point: (decomp.) 222-224 C ⁰

Example 10

1- (1-hydroxy ~ 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin "2-on-3-yl) -3- £" N-methyl-N- (2 - (3,4-dimethoxy-phenyl ) -ethyl) -amino T'-propane

2.35 S (5 mmol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-1,2-dion-3-yl) -3- / TN-methyl N- (2- (3,4-dimethoxyphenyl) ethyl) amino-7-propane are dissolved in 100 ml of methanol and 5 ml of water, and 0.2 g of sodium borohydride are added in portions with stirring. After completion of the addition, stirring is continued for 15 minutes, mixed with 10 ml of 2N hydrochloric acid, made alkaline with methanolic ammonia, decolorized with bleaching earth and concentrated in vacuo after filtration. The residue is dissolved in methylene chloride, undissolved salts are filtered off and the filtrate is concentrated.

Yield: 1.65 g (69 _f 9% of theory) of viscous oil

63 066 12

IR spectrum (methylene chloride): 3400 cm ^-1 "(OH)

2840 cm.sup.- ¹ (methoxyl) 2800 cm.sup.- ¹ (N-alkyl) 1660 cm.sup.- ¹ (CO)

^C 26 ^H 36 ^N 2 ^O 6 ^ 72.59)

Calc .: C 66.08 H 7.68 Ii 5.93 F: 65.87 7.75 5.73

Example 11

1 - (7,8-dimethoxy-1,3-dihydro-2H-3,5-benzodiazepine-3-yl) -3-bis-1-methyl-1- (2- (3,4-dimethoxy-phenyl) -ethyl) -amino-7-propane dihydrochloride

4.3 g (10 mmol) of N- £ * 2- (2-amino-4 »5-dimethcxy-phenyl) -ethyl_7- -, N'-methyl-N ^l - (2- (3,4-dimethoxy- phenyl) -ethyl) -1,3-diaminopropane are refluxed in 30 ml triethyl orthoformate, concentrated in vacuo and the residue is purified on silica gel with methylene chloride + 3 % methanol as eluent of ethereal hydrochloric acid like the dihydrochloride

Yield: 1.6 g (31.1 % of theory) Melting point: 232 to 234 ⁰ C.

Example 12

1 - (7,8-Dimethoxy-1,3,4,5-t etrahydro-2H-3-benzazepin-2-one-3 · yl) -3-N-methyl-N- (2- (4 amino-3-nitro-phenyl) -ethyl) -amino- 7-propane-hydrochloride '

1 »g (1.75 mmol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-

"'. ^; 63 066 12

benz-azepin-2-on-3-yl) -3-ZTli-ethyl-N- (2- (4-acetamino-3-nitro-phenyl) -ethyl) -amino-7-propane is dissolved in 50 ml of methanolic hydrochloric acid for 2 hours heated to 45 ⁰ C to 50 ⁰ C. The reaction solution is concentrated, dissolved in methylene chloride, washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and the solvent distilled off in vacuo · Mach purification of the residue on silica gel with methylene chloride and 5% ethanol as the eluent from acetone by addition of ethereal hydrochloric acid, the hydrochloride like

Yield: 0.4 g (43.1 % of theory melting point; 207 to 208 ⁰ G (decomp.)

Example 13

1- (1-oximino-7,8-dimethoxy-1,3,4-> 5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- / 7n-methyl-N- (2- (3,4-dimethoxy-phenyl- ethyl) -amino-7-propane hydrochloride

3 »6 g (6.8 mmol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-1,2-dion-3-yl) -3-Z.sup N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) amino-7-propane, 0.57 g of hydroxylamine hydrochloride and 0.87 g of sodium carbonate are refluxed in 100 ml of ethanol for 8 hours. The solvent is distilled off in vacuo, the residue dissolved in water / methylene chloride, the organic phase separated, dried over magnesium sulfate and concentrated. The residue is purified on silica gel with methylene chloride and 5 % methanol as eluent. The residue obtained is dissolved in acetone and the hydrochloride is precipitated by addition of ethereal hydrochloric acid.

Yield: 2.4 g (67.6 % of theory) Melting point: 156 to 158 ^° C.

63 06612 - 51 -

Example 14

1- (1-amino-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZTH-methyl-1- (2-one) 3,4-dimethoxy-phenyl) -ethyl) -amino- T-propane-dihydrochloride

1 »6 g (3.3 mmol) of 1- (1-oximino-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- Methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino J7-propane are added in 150 ml of ethanol with 1.5 ml of 98% hydrazine hydrate and 1 g of Raney nickel and refluxed for 7 hours heated. To complete the reaction, another 1.5 ml of 98% hydrazine hydrate and 1 g of Raney nickel are added and heated under reflux for a further 3 hours. The catalyst is filtered off with suction, the solvent is distilled off in vacuo and the residue is purified on silica gel with methylene chloride and 10 % methanol. From an acetone solution, the dihydrochloride is precipitated by the addition of ethereal hydrochloric acid. Yield: 0.8 g (44.6 % of theory) Melting point: 232 to 234 ⁰ C m / e = 471

Example 15

1- (7,8-dimethoxy-1,3,4-s-tetrahydro-1H-benzazepine-1-yl) -3-N-methyl-W- (3- (4-dimethylamino-phenyl) -propyl) - amino 7-propane dihydrochloride,

5.7 g (19.4 mmol) of 1- (7,8-dimethoxyphenyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-N- Methyl-amino-propane and 4.7 g (19.4 mmol) of 3- (4-dimethylamino-phenyl) -propylbromid vverden after addition of 3.3 ml of ethyl diisopropylamine ¹ 1/2 hours at 130 ⁰ C heated. The reaction mixture is dissolved in chloroform

63 066 12

  ·; - 52 -. ,

form and 25% sodium hydroxide solution, the organic phase separated, washed with water, dried over magnesium sulfate and concentrated, after washing the residue obtained on silica gel with methylene chloride and 5 % methanol as Elutionsmittei from acetone with ethereal hydrochloric acid precipitated the Dihydrochiórid. .

Yield: 0.6 g (5.9% of theory) Melting point: 191 bia 192 ⁰ C (dec.)

Example 16

1 - (7,8-dimethoxy-1,3-4,5-t-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- / N-methyl-N- (4- (4-dimethylamino-phenyl) butyl) - amino-propan-* 7 hydrobromide '

Prepared analogously to Example 15 from 1- (7,8-dimethoxyphenyl-1,3,4,5-tetrahydro-2fi-3-benzazepin ~ 2-on-3-yl) -3-N-methylamino-propane and 4 - (4-dimethylamino-phenyl) -butylbromid · yield: 10.3% of theory melting point: 116 to 118 ⁰ C.

Example 17 ^v

1- (1-hydroxy-7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl) -3-ΖΓN-methyl-N- (2- (3,4- dime amino 7 ~ P ^ opane dihydrochloride

2.45 g (5 mmol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl) -3-zirconium methyl- II- (2- (3,4-dimethoxyphenyl) ethyl) -amino J- propane are dissolved in a mixture of 100 ml of ether and 50 ml of tetrahydrofuran and added in portions with stirring with 0.76 g of lithium aluminum hydride · It is then boiled for one hour under reflux,

63 066 12

Cools with ice water and mixed with 15% ammonium chloride solution. The hydroxide precipitate is filtered off with suction, washed with ether and the filtrate is concentrated. After dissolving the residue obtained in acetone, the dihydrochloride is precipitated with methanolic hydrochloric acid. Yield: 2.2 g (82.7 % of theory) Melting point: 210 to 212 ^° C. ',

Example 18

1- (7,8-dimethoxy-1,3,4,5-tetrahydΓO-2H-3-benzazepin-2-on-3-yl) -3-ZTN-methyl-K- (4- (4-amino- 3,5-dibromo-phenyl) -butyl) -amino- 7-propane-hydrobromide

1 »1 g (3.6 ml fol) of 1- (7,8-dimethoxyphenyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one ^ 3-yl) -3-N- methyl-amino-propane and 1.4 g (3T6 ramol) of 4- (4-amino-3,5-dibromo-phenyl) -butyl ^ bromide are heated in 3 ral ethyl-diisopropyl-amine for 2 hours at 130 ⁰ C. , The excess amine is then distilled off in vacuo and the residue obtained is purified on silica gel with methylene chloride and 2 % ethanol as eluent. The fractions are concentrated in vacuo, the residue triturated with acetone and the resulting precipitate is filtered off with suction. Yield: 0.6 g (27.9 % of theory) Melting point: 159 to 161 ° C

Example 19

1- (7,3-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3 C- N-methyl-N- (3- (3 »4 dimethoxy-phenyl) -propyl) -amino J ~ propane hydrochloride

2.6 g (5 mmol) U- £ 3-ZTN ^t -methyl-N ^t - (3- (3,4-dimethoxyphenyl) -

63 066 12

propyl) -amino_7 PiOpyl ~ ^ 7 ~ 2- (2-carboxymethyl-4,5-dimethoxyphenyl) ethylamine are heated in 30 ml Natriumsalζ SuIfolan 2 hours at 200 ⁰ C. After cooling, it is diluted with 300 ml of water and extracted 3 times with methylene chloride. The organic extracts are washed twice with water, dried over magnesium sulfate and the solvent is concentrated in vacuo. The residue is dissolved in acetone and the hydrochloride is precipitated by addition of methanolic hydrochloric acid.

Yield: 1.8 g (71 % of theory) Melting point: 220 to 221 ^° C.

Example 20

1- (7,8-dimethoxy-1,3-4-5-tetrahydro-2H-3-benzazepine-1,2-dione-3-yl) -3-ΖΓN-methyl-N- (3- (3) 4-dime-thoxy-phenyl) -propyl) -amino- 7-ProPa- ^n- hydrochloride

1.7 g (0.0154 mol) of selenium dioxide are added at 70 ⁰ C to 70 ml of 1,4-dioxane and 2.8 ml of water. After 15 minutes, 1.4 g of Celite and 6.9 g (0.0147 g) of 1- (7,8-dimethoxy-1,3-4,5-tetrahydro-2H-3-benzazepin-2-one are added. 3-yl) -3- / 7N-methyl-N- (3- (3,4-dimethylthiophenyl) propyl) amino-7-propane and refluxed for 40 hours. After cooling, the undissolved constituents are filtered off with suction, the filtrate is evaporated in a rotary evaporator and the residue obtained is purified on silica gel with methylene chloride + 4 % ethanol as eluent. The product is dissolved in acetone and the hydrochloride is precipitated with ethereal silicic acid

Yield: 2.36 g (29.2 % of theory) Melting point: 189 to 192 ^° C.

63 066 12 - 55 Example 21

1 - (7,8-Dimethoxy-1,3,4,5-th-trahydro-2H-3-benzazepin-2-one-3-yl) -3-Z "W-methyl-N- (2 - (4-amino-3,5-dichloro-phenyl) -2- hydroxy-ethyl) -amino-7-propane

Prepared from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzo-zepin-2-one-3-yl) -3-ZTN-methyl-N- (4-amino -3 "5-di-chloro-benzoyl-methyl) -amino_7" P ^ro pan and sodium borohydride analogous to Example 8 #

Yield: 71 »6 % of theory

Melting point: 122 to 126 ^° C.

IR spectrum (methylene chloride): 3400 cm ^-1 * 3495 cm ^-1 (NH ₂ )

1650 cm " ¹ '(CO)

UV spectrum (ethanol): 240 nm (0.14)

290 nm (0.06) 314 nm (shoulder; 0.02)

Example 22 _x

1- (7,8-dimethoxy-1,3,5,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZTN-methyl-N- (2- (2-amino) 3,5-dichloro-phenyl) -2- hydroxy-ethyl) -amino-7-propane

Prepared from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- "N-methyl-N- (2-amino -3,5-Dichlorobenzoyl-methyl) -amino_7-propane and sodium borohydride analogously to Example 8.

Yield: 45 % of theory, resin.

IR spectrum (methylene chloride): 3360 cm " ¹ , 3450 cm"" ¹ (NH ₀ )

-1

1650 cm (lactam-CO) UV spectrum (ethanol): 240 nm (0.13)

280-290 nm (0.045) 310 nm (shoulder; 0.03)

63 066 12

1- (7,8-diraethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZTN * methyl-N- (2- (3-amino) 4-chloro-phenyl) -2-h.-hydroxyethyl ) -amino-7-propane ,

Prepared from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3 "^> . Benzazepin-2-one-3-yl) -3-ZTIT-methyl-lir- (3-amino 4-chlorobenzoyl-methyl) -amino. J -propane and sodium borohydride analogously to Example Q ..

Yield: 55 % of theory, resin

IR spectrum (methylene chloride): 3380 cm ^-1 , 3470 cm ^-1 (HH ₀ )

1650 cm (lactam CO)

UV spectrum (ethanol) j 236 nm (0.13)

282 to 292 nm (0.055) 310 nm (shoulder; 0.02)

Example 24

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- £ "K-methyl-N- (2- (4- amino-3-chloro-5 <-f-fluorophenyl) -ζ- (hydroxyethyl ) -amino-7-propane

Prepared from 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-jCN-methyl-egg- (4-amino-3 -chloro-5-fluoro-benzoyl-methyl) -amino_7-propane and sodium borohydride analogous to Example 8

Yield: 48 % of theory, foam IR spectrum (methylene chloride): 3390 cm ^-1 , 3480 cm ^-1 (NH ³ )

I645 cm ^-1 (Iactam-CO) UV spectrum (ethanol): 238 nm (0.18)

\ 282 to 290 nm (0.07)

.'-. ..: ':''.:y'';'':'. : '. ' ⁶ 3 066 12

'.' · ^; , '':. : - 57-. V.-. ^: -.; ::. : ..; 'V: V'; · Example 25 ^:; ''; , . '^; .., · '''.^{; "; _-:;:...."} ''

1 - (7,8-dimethoxy-i, 3,4-5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZTN-methyl-N- (2- (4-amino 3-chloro-5-methylphenyl) -2-r -hydroxyethyl) -amino-7-propane

Prepared from 1- (7,8-dimethoxy-1, 3,4,5-tetrahydro-2H-3-benzo-2-quin-2-one-3-yl) -3- (2-methyl) -4- amino-3-chloro-5-methyl-benzoyl-1-methyl) -amino-7-propane and sodium borohydride analogously to Example 8,

Yield: 25 % of theory, foam

IR spectrum (methylene chloride): 3380 cm ^-1 , 3470 cm ** ¹ (MH ₂ )

I65O cm "" ¹ (Lactam-C0)

UV spectrum (ethanol): 239 mn (0.15)

280 to 292 nm (0.05) 305 nm (shoulder; 0.01)

Analogously to the above examples, the following compounds can be prepared:

1- (7-Methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-N-methyl-N- (3- (3,4-dimethoxy phenyl) propyl) amino ~ J- propan-hydrochloride melting point: 172 to 175 ⁰ C.

1- (7-Bfe thoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3: · 1 'Ηώ ^ ^ ^ ^ ( ^: ( ^: 3τ ( 4 ^ ίρϊηο; .- 3, S-dichlorophenyl ^ -propyl) -amine J ^

1- (7-irif luomethyl-1,3,4, S-tetrahydro ^ H ^ benzazepiri-O-on amino_7-propane "..;; '': ':' ':'. '' '-'; .'-... '.';. ·; '/: ·' :;: '/': ".

63 066 12

1- (7-trifluoromethyl-1,3,4,5-tetrahydro-2H-3-benzazepin ~ 2-on-3-yl) -3r8sr-methyl-3- (3,4-dimethoxy) -3- phenyl) -propyl) -

1- (7-Trifluoromethyl-1,3,4-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZTN-methyl-H- (3- (4-amino -3,5-dichloro-phenyl) propyl) propan--amino_7

1- (7-Methylamino-1,2,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- £ "N-methyl-2- (2- (3,4 -dimetlioxy-phenyl) -ethyl) -amino- J- propane

1 - (7-Methylamino-1,3 * 4, f-th-trahydro-2H-3-benzazepine-2-on-3-yl) -3-ZT ^N '- ^me ' ^t l ^{:] L} yl " N- (3- (3 ', 4-dime thoxyphenyl) -propyl) -amino-7-propane,

1 - (7-methylamino-1,3,4 »5-

yl) -3- "H-methyl-H" - (3- (4-amino-3,5-dichloro-phenyl) -propyl) -amino-J7-propane

1t (7-dimethylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZT "N-methyl-F ^ (2- (3,4-) dime thoxy-phenyl) -ethyl) -amino-7-propane,

IR spectrum (methylene chloride): 1660 cm ^-1 (GO)

1- (7-dimethylamino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZTN-ethyl-H- (3- (3,4-dimeoxy) -phenyl) -propyl) -amino-7-propane

1- (7-dimethylaraino-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZTlT-methyl-N- (3- (4-amino-3 , 5-dichloro-phenyl) -propyl) -amino-7-propane

63 066 12

1- (7,8-dichloro-i, 3,4,5-th-trahydro ^ H ^ -benzazepine-S-onyl) -3- / 7N-methyl-N- (2- (3 * 4-) dimethoxy-phenyl) -ethyl) propane--amino_7

1- (7,8-Dictoor-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one) 3-ZTR-methyl-N- (3- {3,4-dime-thoxy-phenyl) -propyl) - * amino_7 -'-propane ".... · : '- ". ; · ...! '^; . ·. · -. . ::;.. . ": '^;;:; · ..;: _; " :. · - ^ ^;

1- (7,8-dichloro-1,3,4-> 5-tetrahydro-2H-3-benzazepin-2-one-3-yl) · 3 - / 1-methyl-H- (3- (4- amino-3,5-dichloro-phenyl) -propyl) -amino- J- propane

1- (7,8-Dimethoxy-1,3f4 → 5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3 - / "N-methyl-J" - (2-rhydroxy-) - 3- (3, ^ -dimethoxyphenyl) -propyl) -aminoJ7-propane, oil

₂ O ₆ (486.6)

Ber · C 64.64 H 7.87 N 5.76

Gef .: 66.61 7.95 5.74

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-iC * N-methyl-N- (2-hydroxy- 3- (4-amino-3,5-di-chloro-phenyl) -propyl) -amino-7-propane

1- (7,8-dime thoxy-1,3 "4,5-tetrahydro-2H-3-benzazepin-2-one * -3-yl) -3-ZT ^ - ⁰ Ie thyl-N- (3- hydroxy-3- (4-amino-3,5-dichloro-phenyl) -propyl-amino-7-propane

1- (7,8-Dimethcxy-1,314,5-tetrahydro-2H-3-benzazepin-2-one-3-y1) -3- £ * N-methyl-N- (3-hydroxy-3- (3 ' 4-dimethoxy-phenyl) -propyl) -amino- J- propane

^; 63 066 12

    - 60 -

1 - (7.8 ~ dimethoxy-1,3,4 »5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-Zr ^ -methyl-K- (3- (4 -amino-3,5-dichloro-phenyl) -propyl) -amino-7-propane m.p .: 92 Ms 93 ⁰ C

1- (1-Hydroxy-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzaze-pin-2-one ~ 3-yl) -3- ^ N -neyl-N- (3- (3 "4-dime thoxy-phenyl) -propyl) -amino-7-propane

1- (7-Bimethylamino-8-methoxy-1,3,5,5-tetrahydro-2H-3-benzazepine-2-one-3-yl) -3- £ "H-methyl-N- ( 3- (3,4-dimethyl-phenyl) -propyl) -amino- J- propane

1- (7-dimethylamino-8-methoxy-1,3,4-> 5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-Z7I-methyl-U- (2- 3,4-dime thoxy-phenyl) ethyl) -amino J -propane IR spectrum (methylene chloride): 1650 cm ^-1 (CO)

1- (7-Bromo-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one 3-yl) -3-ωW-methyl-H- (3- (3, 4-dime thoxy-phenyl) -propyl) -amino_7-propane-hydroxymethane. Melting point: 198 to 199 ^ ⁰ C (dec.)

1 "- (7-bromo-8-methoxy-1,3,5,5-tetra-hydro-2H-3-benzazepin-2-one 3-yl) ~ 3 ~ £ TN-methyl-1- (2 - (3,4-dime thoxy-phenyl) -ethyl) -amino-7-propane

MR spectrometry (CDCl-): 7 »2 ppm (1H, see aromat ·), 6.6 ppm

(1H, see aromat.), 2.3 ppm (3H, 8, U)

1- (7-chloro-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-Z-α-ethyl-1- (2- 3,4-dime thoxyphenyl) -propyl) amino J7 ^OT propane

63 066 12 - 61 -

1- (7-chloro-8-methoxy) -1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- / 7N-methyl-1- (2- (3,4-dime-thoxy-phenyl) -ethyl) -amino_7-propane

-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-3- £ * W- (3- (3,4-dimethoxyphenyl) -propyl) -amino-7-propane IR spectrum (methylene chloride): 1645 cm ^"1 (CO) melting point of hydrochloride: 158 to 159 ⁰ C.

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl) -3- / ΓN- (3- (4-amino-3,5 dichloro-phenyl) -propyl) -amino-7-propane

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-Z - ^N - (2-hydroxy-3- (3, 4-dimethoxy-phenyl) -propyl) -amino-7-propane

Example I

Tablets to 10 mg of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-ZT ^1T -ethyl-N- (3 (3,4-dimethoxy- phenyl) -propyl) -amino-7-propane hydrochloride

Composition: active substance 10.0 mg 1 tablet contains: corn starch 57.0 mg lactose 48.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 1.0 mg

120.0 mg

63 066

- 62 Method of production:

The active substance, corn starch, lactose and polyvinylpyrrolidone are mixed and moistened with water · The moist mixture is forced through a sieve of 1.5 mm mesh width and dried at about 45 ⁰ · O · The dry granules through a sieve of 1.0 mm The mesh size was beaten and mixed with magnesium stearate. The finished mixture is pressed on a tablet press with punches of 7 mm diameter, which are provided with a partial notch, to tablets »tablet weight: 120 mg

Example II

Dragees to 5 mg of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benza-aepin-2-one-3-yl) -3-Z? W-methyl-U- (3 - (3 * 4-dimethoxyphenyl) propyl) -amino "7-propane-hydrochloride

1 DragSekem contains: Active substance 5.0 mg

Corn starch 41.5 mg

Lactose 30.0 mg

Polyvinylpyrrolidone 3 »0 mg

Magnesium stearate 0.5 mg

80.0 mg, manufacturing process:

The active ingredient, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mass is forced through a sieve with a 1 mm mesh size, dried at about 45 ^° C., and the granules are then beaten through the same sieve after mixing

63 066 12

- 63 -:

Magnesium stearate are pressed on a tableting machine curved Drageekerne with a diameter of 6 mm. The coated dragee cores are coated in a known manner with a layer consisting essentially of sugar and talc. The finished dragees are polished with wax.

Drag weight: 130 mg ^!

Example III

Ampoules of 5 mg of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-N-methyl-N- (3- (3-yl) 3,4-dimethoxy- phenyl-propyl) -amino-7-propane hydrochloride

1 ampoule contains: Active substance 5 »0 mg

Sorbitol 50.0 mg

Water for Injection

purposes ad 2,0 ml

Manufacturing process :.

The active ingredient is dissolved in water for injection purposes and the solution is made isotonic with sorbitol in a suitable preparation vessel. After filtration through a membrane filter, the solution is filled into purified and sterilized ampoules under inert gas sparging and autoclaved for 20 minutes in flowing steam.

  . ' , , ". -. ^! .-.

Example TV · '.. \; _; ; '. K ': \ ..-'. ^Λ ',;""".-. , : '''.

Suppositories to 15 mg of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-Z "NH-diethyl-N- (3- ( 3,4-dimethoxy-phenyl) -propyl) -amino 7-propane-hydrochloride '

63 066 - 64 - '.

1 suppository contains:

Active substance. 0.015 g

Hard grease (eg Witepsol H 19 and W 45) 1.685 g

1,700 g manufacturing process; .

The hard fat is melted. At 38 ⁰ G, the ground active substance in the melt is homogeneously dispersed. It is cooled to 35 ^° C. and poured into slightly pre-cooled suppository molds.

Beispiel.Y

Drop solution containing 10 mg of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-Z.n-methyl-1- (N-methyl) -li- 3- (3,4-dimethoxy- phenyl) -propyl) -amino-7-propane hydrochloride

100 ml solution contain:

Active substance 0.2 g

Hydroxyethylcellulose 0.15 g

Tartaric acid 0.1 g

Sorbitol solution 70 % dry substance 30.0 g

Glycerol 10.0 g

Benzoic acid 0.15 g

Dest. Water ad 100 ml

Production process :

Dest. Water is heated to 70 ^° C. Here, with stirring, hydroxyethylcellulose, benzoic acid and tartaric acid are dissolved.

63 066 12

It is cooled to room temperature and in this case the glycerol and the sorbitol solution are added with stirring. At room temperature, the active ingredient is added and stirred until complete dissolution. The mixture is then evacuated with stirring to vent the juice.

Claims (14)

in which R represents an alkyl group having 1 to 3 carbon atoms and B is the thiocarbonyl group or also, when G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms n-alkylene group having 3 to 5 carbon atoms, an optionally substituted by an alkyl group lnit 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms, in the a methylene group is replaced by a carbonyl group, or a methylene-nhydroxyalkylengruppe having 1 to 4 carbon atoms in the alkylene moiety »where the methylene group is linked to the nitrogen atom, or R ₁ and Rp is each a hydrogen atom or R _{1 is} a fluorine, chlorine or bromine atom, a trifluoromethyl group or an optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms amino group, the methylene or carbonyl group or 63 066 12 - 67 - OH OH NOH HNRs 1 IM "A is a -U = CH-, -CH-CO-, -CH-CH ₀ -, -C-CO or -CH-CO- group, 5 5 5 ^d 5 5 in the Rg. Represents hydrogen atom or a substituted by, a phenyl, methoxyphenyl or dimethoxyphenyl alkyl group having 1 to 3 carbon atoms, or the -CO-CO group, when G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group 3 to 5 carbon atoms, an n-alkylene group having 1 to 5 carbon atoms optionally substituted by an alkyl group having 1 to 3 carbon atoms in which a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group having 1 to 4 carbon atoms in the alkylene part, wherein the methylene group is linked to the nitrogen atom, or R-. and R _{2 is} each a hydrogen atom or R _{1 is} a fluorine, chlorine or bromiatome, a trifluoromethyl group or an amino group optionally mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms, and B is the methylene group, R _{1 is} a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl group, an alkoxy group having 1 to 3 carbon atoms or an amino group which is mono- or disubstituted by alkyl groups each having 1 to 3 carbon atoms, E is an optionally substituted by an alkyl group having 1 to carbon atoms substituted n-alkylene group having 2 to 4 carbon atoms, 63 066 12 G represents an optionally substituted by an alkyl group having 1 to carbon atoms n-alkylene group having up to 5 carbon atoms, in which a methylene group, when B represents a methylene or carbonyl group may be replaced by a carbonyl group, or a methylene-n-hydroxy-alkylene group 1 to 4 carbon atoms in the alkylene part, where the methylene group is linked to the nitrogen atom, R _{2 is} a hydrogen, fluorine, chlorine or bromine atom, an alkoxy group having 1 to 3 carbon atoms or together with R- an alkylenedioxy group having 1 or 2 carbon atoms,. R ~ is a hydrogen, fluorine, chlorine or bromine atom, a nitro, trifluoromethyl, alkyl or alkoxy group having in each case 1 to 3 carbon atoms, R is a hydrogen atom, an alkoxy, amino, alkylamino or dialkylamino group each having 1 to 3 carbon atoms in each alkyl moiety or together with R "is an alkylenedioxy group having 1 or 2 carbon atoms, Rc is a hydrogen, chlorine or bromine atom and Rg is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 3 to carbon atoms, and 1- (7,8-dimethoxy-1 »3» 4,5-tetrahydro-2H-3-benzazepin-2-one 3-yl) ^ - / fumedyl-II- (2-phenylethyl) amino-7-propane and 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2 -on-3-yl) -3-ir-methyl-H- (2- (4-amino-3-nitro-phenyl) -ethyl) -amino J-propane and their acid addition salts, in particular their physiologically acceptable acid addition salts anor- 63 066 12 ganic or organic acids, characterized in that a) a compound of the general formula (II) with a compound of the general formula G-V (III) in which R ₂ , IU, Rc, A, B, E and G are as defined above, R ^ ¹ and R, ^{f are} each an amino or alkylamino group protected by a protective radical or in each case the meanings mentioned above for R ₁ or R.sup.R have, one of the radicals ü or V represents the Rg-NH group, where R ^ is as defined above, and the other of the radicals U or V represents a nucleophilic leaving group such as a halogen atom or a sulphonyloxy group, and if appropriate subsequently a used protective radical is split off will or b) for preparing a compound of the general formula I in which A is a -CH -CH _{0 0} -, -CHsCH-, -NH-CO-, -COCO-, 2 2 ₅ 63 066 12 - 70 - -CH ₀ -CO-, -CsH- or -NaCH- group and B is a -CH ₀ - or ² 5 5 -CO group, a compound of the general formula (IV) in the R _{2 is} as defined above, A ^{1 is} a -CH ₀ -CH ₀ -, -CH = CH-, -KH-CO-, -COCO-, -CH ₀ -CO-, ^{2 2} 5 5 ² -ITsCH- or -C = N-group »in the R _{7 is} an alkyl group with 1 to 3 carbon atoms, B ^{1 represents} a -CHg- or -CO- group and
represents a protected by a protective amino or alkylamino group or has the meanings mentioned for R ₁ , with a compound of the general formula ^E 6 in the R ', Rc, Rg, E and G are as defined above, R / ^{1 is} a protected by a protective amino or alkylamino group or has the meanings mentioned for R ^ and, 63 066 12 Z is a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, reacted and, if appropriate, subsequently a protecting residue used is eliminated or c) for the preparation of a compound of general formula I, HH-R ₈ ''', where A is not a -CH-00 group, a compound 4's general formula (VI) in the B, E, R ₁ and R _{2 are} as defined above, but in the radical E two hydrogen atoms in a -CHp- or CH-, - group of the radical E are replaced by an oxygen atom, and A "is -CH ₀ -CH ₀ -, -CH = CH-J-IIH-CO-, -CH ₀ -CO-, -IT = OH-, 2 2 5 5 2 ₅ OH OH NOH R "I) represents ti | 7 -CH-CO-, -CH-CH ₀ -, -C-CO- or -C = N- group, 5 5 ^d 5 5 in which Ry is an alkyl group having 1 to 3 carbon atoms, with an amine of the general formula (VII) 63 066 12 in the G and R to Rg are as defined above, is reacted in the presence of a reducing agent or d) for preparing a compound of general formula I, HH-R ₈ where A is not a -CH-CO- group, one compound the general formula ^R 1 ν ^ Cv-A "H L> Jl · N-E-N <^ (VIII) />"V ~ -FR ₆ R ₂ in the B, E, R, Rg and Rg are as defined above and A "is -CH ₀ -CH ₀ -, -CH = CH-, -KH-CO-, -CH ₀ -CO-, -N = CH-, 2 2 _{5 5} 2 ₅ OH OH NOH R ₇ II II J '« Represents -CH-CO-, -CH-CH ₉ -, -C-CO- or ~ C = N-group, 5 5.5 5 wherein R _{7 represents} an alkyl group having 1 to 3 carbon atoms, with a compound of the general formula XX XX 63 066 12 in the R, to Rc and G are as defined above, but in the rest G two hydrogen atoms in a -CHg- or GH "- group of the radical G are replaced by an oxygen atom, is reacted in the presence of a reducing agent or e) for the preparation of a compound of the general formula I in which A represents the -CHg-CHg group, B the methylene or carbonyl group and Rg no alkenyl group of 3 to 5 carbon atoms, a compound of the general formula -CLOSELY in the RJ to R ^, E and G are as defined above and B ^{f represents} the methylene or carbonyl group is hydrogenated or f) for the preparation of a compound of the general formula I in which B is the -CS group and G is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms or a methylene-n-hydroxy-alkylene group 1 to 4 carbon atoms in the alkylene part, a compound of the general formula 63 066 12 - 74 - ? ⁶ -E-N- G '· R (XI) in the R * to Rr, A and £ are as defined above and G ^{1 is} an optionally substituted by, an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms or a methylene-n-hydroxy-alkylene group having 1 to 4 carbon atoms in Alkylene part is reacted with a sulfur-introducing agent or g) for the preparation of a compound of general formula I, OH OH in the A a -GH-CO or -CH-OHg group and G a optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms or a methylene-n-hydroxy-alkylene group having 1 to 4 carbon atoms in the alkylene, einö compound of the general formula N-B-N-G (XII) in the, R ₁ to Rg, E and G are as defined above, reduced will or 63 066 12 h) for preparing a compound of general formula I, HIf-R ₈ NOH in the A a -CH-CO- or -C-CO- group and G is a given 5 5 optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms or a methylene-n-hydroxy-alkylene group having 1 to 4 carbon atoms in the alkylene part, a compound of the general formula R. -NG ¹ (XIII) in the R- to Rg and E are as defined above and G * is an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms or a methylene-n-hydroxyalkylene group having 1 to 4 carbon atoms in the alkylene part, with a Compound of the general formula NO, (XIV) in the R represents the hydroxy group or has the meanings mentioned for Rg, reacted and, if appropriate, subsequently reducing a compound thus obtained or 63 066 12 -.76 - i) for the preparation of a compound of general formula I in which A represents the -NaCH group and Rg represents an alkyl group of 1 to 3 carbon atoms or an alkenyl group of 3 to 5 carbon atoms, a compound of the general formula IU -E - N "- G (XV) rr in the R- to Rc »B, E and G are as defined above and Rg 'is an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 3 to 5 carbon atoms, optionally present NEU or NH groups ge. can be protected, reacted with a Orthoameisensäureeeter and then an optionally used protective moiety is cleaved or k) for the preparation of a compound of the general formula I in which A is not a -GOCO group and G is a methylene-n-hydroxyalkylene group, a compound of the general formula (XVI) in the ', :' - " ; ' . •. ';-.' \ .- .. · ^.; "; · · ''. . ' -. ''. / R ₁ to Rg, B and E are as defined above, A ^MI except the -GOCO group has the meanings mentioned for A, and K-E-N - G " 63 066 12 - 77 - G "represents a methylene-n-alkylene group, wherein the alkylene part contains 1 to 4 carbon atoms and a methylene group of the alkylene part is replaced by a carbonyl group, is reduced or 1) for the preparation of a compound of the general formula I in which R, a nitro group and R 1 represents an amino group, a compound of the general formula (XVII) HH-Acyl in the R ₁ , R ₂ , Rc, Rg, A, B, E and G are as defined above and acyl represents an acyl radical, is hydrolyzed or m) for the preparation of a compound of general formula I in which A is a -CH ₂ -CH ₂ -, -CHsCH-, -NH-CO-, -CHg-CO-, -N = CH-, -COCO- or -C = N- group and one of the radicals R ₁ , 5 5 ^Ί R ₀ , Ro or R, an alkoxy, alkylamino or dialkylamino group or Rg represents an alkyl or alkenyl group, a compound of the general formula ^ß 3 R- I / rj-λ _R ¹ U - E - U - G "" J / "Λ ^A (XVIII) 63 066 12 in the R- to Rg, B and E are as defined above, but at least one of the radicals R to R * must represent a hydroxy group or R ₁ or R represents an amino or alkylamino group or R ₁ represents a hydrogen atom, A 'is -CH ₀ -CH ₀ -Z-CHeCH-, -NH-CO-, -CH ₀ -CO-, -N = CH-, 2 2 _{5 5} 2 ₅ -COCO- or -OsN- group in which R _{7 is} an alkyl group with 5 · ' 1 to 3 carbon atoms, and G " ^{1 represents} an optionally substituted by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms in which a methylene group may be replaced by a carbonyl group, with a compound of the general formula R ₁₀ - X (XIX) in the R ₁ Q is an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 3 to 5 carbon atoms, when Rg represents a hydrogen atom, and X is a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group or, if at least one of R ₁ to R * Represents hydroxy, X together with an oc-standing hydrogen atom of the radical R _{10 is} a penta group or also, if R g is a hydrogen atom or R ₁ or R ^, an amino or alkylamino group, an oxygen atom, is reacted or n) for the preparation of a compound of the general formula I in which A represents the -COCO group and G denotes an optionally substituted by an alkyl group having 1 to 3 carbon atoms. 63 066 12 Te n-alkylene group having 1 to 5 carbon atoms, in which a methyl group may be replaced by a carbonyl group, represent a compound of the general formula R. CH ₂ -CO CH ₂ -CH ₂ ' (XX) in the R- to Rg, E and G are as defined above, oxidized will or o) for the preparation of a compound of general formula I in which A is the -CH ^ -CO- group and G is an optionally. 5 ^d represented by an alkyl group having 1 to 3 carbon atoms substituted n-alkylene group having 1 to 5 carbon atoms in which a methylene group may be replaced by a carbonyl group, represent a benzazepine of the general formula E-K-G (XXI) in the R ₁ to Rg, B, E and G are as defined above, is oxidized with ruthenium tetroxide or p) for the preparation of a compound of general formula I in which R _{1 is} in the 7-position, A is the -CHg-CHg group and 63 066 12 B represents the CO group, a compound of the general formula CH ₂ - CH ₂ - I - EH ⁴ (XXII) in the Rj to Rc "G and B are as defined above, Rg ^{1 is} an alkyl group having 1 to 3 carbon atoms or an alkenyl group having 3 to 5 carbon atoms and Y is a ring-closing group, is cyclized and if desired, subsequently a compound of the general formula I thus obtained is converted into its acid addition salt, in particular into its physiologically tolerated acid addition salt. 2. The method according to item 1, characterized in that the reaction is carried out in a solvent · 3 · Process according to points 1a, 1b or 1p, characterized in that the reaction is carried out in the presence of an acid-binding agent · 4 · Process according to points 1a, 1b or 1p, characterized in that the removal of protective radicals takes place hydrolytically or hydrogenolytically Process according to points 1a, 1b, 2 and 3, characterized in that the reaction is carried out at temperatures between 0 and 150 ^° C., eg at the boiling point of the solvent used.   63 066 12 6. Process according to items 1c or 1d, characterized in that a complex metal hydride or hydrogen in the presence of a hydrogenation catalyst is used as the reducing agent. 7 - Method according to the points ic, 1d, 2 and 6, gekennzeicb. - - net in that the reaction at temperatures between 0 and 100 ⁰ C, but preferably at temperatures between 20 and 80 ⁰ G, durchgefi is performed. 8. The method according to the points te and 2, characterized in that the catalytic hydrogenation at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, and at temperatures between 0 and 75 ⁰ C, but preferably at temperatures between 20 and 50 ⁰ C, is performed. 9 · Method according to item 1f, characterized in that the reaction with phosphorus pentasulfide or 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetan-2,4-disulfide is performed. 10. The method according to items 1f, 2 and 9, characterized in that the reaction at temperatures between 50 and 150 ⁰ C, z. For example, at the Si «
mixed, is carried out « and 150 ^° C, z. At the boiling point of the reaction 11. The method according to the items 1g or 1k, characterized in that the reaction is carried out with a metal hydride such as sodium borohydride, lithium aluminum hydride or diborane. 63 066 12 12. The method according to points 1g, 2 and 11, characterized in that the reaction at temperatures between 0 and 80 ⁰ C, preferably at temperatures between 15 and 40 ⁰ O, is performed. 13 · Method according to points 1h and 2, characterized in that the reaction is carried out at temperatures between 50 and 175 ⁰ C. Process according to items 1h, 2 and 13, characterized in that the subsequent reduction is carried out with a complex metal hydride, with catalytically promoted hydrogen or with hydrazine / Raney-Hickel. 15 · Method according to points 1i and 2, characterized in that the reaction is carried out at temperatures between 100 and 200 ⁰ C. 1.6. Process according to items 1k, 2 and 11, characterized in that the reaction at temperatures between 0 and 50 ⁰ C, but preferably at temperatures between 10 and 25 ⁰ G, is performed. 17. Method according to items 11 and 2, characterized in that the hydrolysis is carried out in the presence of an acid or base, but preferably in the presence of alcoholic hydrochloric acid. 18. The method according to items 11, 2 and 17, characterized in that the reaction at temperatures between 0 and 100 ⁰ C, but preferably at the boiling temperature of the reaction mixture, is performed. , 63 06612 ·9 · Process according to items Im, 2 and 3 », characterized in that the reaction, when B represents the -OHg or -CO group, with an alkylating agent at temperatures between 0 and 150 ⁰ C, preferably at temperatures between 20 and 120 ⁰ G, is performed · 20. The method according to the items 1m and 2, characterized in that the reaction is carried out with a diazoalkane at temperatures between 0 and 30 ⁰ C · 21. The method according to the items 1m and 2, characterized in that the reaction is carried out in the presence of a reducing agent at temperatures between 0 and 120 ⁰ C. Process according to items 1n and 2, characterized in that the oxidation is carried out with potassium permanganate, selenium dioxide or sodium dichromate. Process according to items 1m, 1n and 2, characterized in that the oxidation is carried out at temperatures between 0 and 100 ⁰ C. 24. Method according to points 1p and 2, characterized. in that the cyclization is carried out in the presence of a condensing agent. . Process according to items 1p, 2 and 24, characterized in that the reaction is carried out at temperatures between 250 and 250 ^° C, but preferably at temperatures between 140 and 180 ^° C. 63 066 12 Method according to item 1, characterized in that benzazepine derivatives are prepared in which R _{1 is} in the 7-position, R ₂ in the 8-position, R, in the 3-position, R in the 4-position and Rc in the 5-position of the respective Phenylkems stands · Process according to item 1, characterized in that benzazepine derivatives of the general formula I ⁶
H-CH ₂ CH ₂ CH ₂ -HG- ^ J- R ₄ (Ia) be prepared, in which mean A is a -CHg-CHg or -CH = CH group and B is the -CS group or also, if G is an n-alkylene group having 3 to 5 carbon atoms, an n-alkylene group having 2 to 5 carbon atoms, in which a methylene group is replaced by a carbonyl group, or a methylene-n-hydroxyalkylene group having 1 to 3 carbon atoms in the alkylene part, wherein the Methylene group is attached to the nitrogen atom, or R ₁ and R ₂ each represents a hydrogen atom or R ". represents a chlorine or bromine atom, a trifluoromethyl, amino, methylamino or dimethylamino group, the CO group or OH OH H-OH HH ₂ A is a -H = CH-, -CH-CH ₂ -, -CH-CO-, -C-CO-, -CH-CO- or Group or also "the 63 066 12 - 85 - -GOCO group when G is an n-alkylene group having 3 to 5 carbon atoms, an n-alkylene group having 2 to 5 carbon atoms in which a methylene group is replaced by a carbonyl group, or a methylene-hydroxyalkylene group having 1 to 3 carbon atoms in the alkylene moiety, wherein the methylene group is linked to the nitrogen atom, or
RJ and Rg each represent a hydrogen atom or R 1 represents a chlorine or bromine atom, a trifluoromethyl, amino, methylamino or dimethylamino group, and
B the -CHg group, G is an n-alkylene group having 2 to 5 carbon atoms, in which a methylene group, when B represents a methylene or carbonyl group, may be replaced by a carbonyl group, or a methylene-nhydroxyalkylene group having 1 to 3 carbon atoms in the alkylene part, wherein the methylene group is linked to the nitrogen atom is R is a hydrogen, chlorine or bromine atom, a trifluoromethyl, methoxy, amino, methylamino or methylthio group, Rg is a hydrogen, chlorine or bromine atom, a methoxy group or together with R- the methylenedioxy group, R is a hydrogen, fluorine, chlorine or bromine atom, a methyl, methoxy, trifluoromethyl or nitro group, R is a hydrogen atom, a methoxy, amino, methylamino or dimethylamino group or together with R 0 the methylenedioxy group, 63 066 12 - 86 - Rc is a hydrogen, chlorine or bromine atom and Rg represents a hydrogen atom, a methyl or allyl group, and 1 ~ (7,8-methoxy-1,3,4,5-tetrahydro-2H ~ 3-benzazepin-2-one-3-yl) -3-Z ~ N-methyl-N- (2-phenylethyl) amino-7-propane and 1- (7,8-dimethoxy-1,3, 4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) - 3- ^ N-methyl-N- (2- (4-amino-3-nitro-phenyl) -ethyl) -amino J -propane and the acid addition salts, particularly the physiologically acceptable acid addition salts with inorganic or organic acids. Process according to item 1, characterized in that benzazepine derivatives of general formula Ia are prepared according to point 3, wherein A is the -CHg-CHg group, B is the -CO- or -CS-group, R-j is a trifluoromethyl, methoxy, amino, methylamino or dimethylamino group, Rg is a hydrogen atom or a methoxy group or, together with R, j is the methylenedioxy group, Ro is a hydrogen, fluorine, chlorine or bromine atom, a methoxy or trifluoromethyl group, R is a methoxy, amino, methylamino or dimethyl amino group or together with R, the methylenedioxy-V. group, -'. _{:; ;} ;: ' ^: . " ^y - \ ' ^r '"'::.'' ^:; · ' Rc is a hydrogen, chlorine or bromine atom, Rg is the methyl group and 63 066 12 G is an η-alkylene group having 3 to 5 carbon atoms or OH the -CHp-CH group or also when B represents the -CS group and / or R- a trifluoromethyl, amino, methylamino or dimethylamino group, the -CHgCHg group, and their physiologically acceptable acid addition salts with inorganic or organic acids. 29. The method according to item 1, characterized in that benzazepine derivatives of general formula Ia are prepared according to point 3, wherein A the -CHgOHg group and B is the -CS group or also, when G is an n-alkylene group having 3 to 5 carbon atoms, the -CO-group or OH ι,, A is the -CH-CO group and B the -CHg group, R ₁ and R ₂ de are a methoxy group, R-5 is a methoxy group, a hydrogen or chlorine atom, R. a methoxy, amino or dimethylamino group, Rc is a hydrogen or chlorine atom, Rg is a methyl group, G is an n-alkylene group having 3 to 5 carbon atoms or -CHp-CH group or else when B is the -CS group OH or A represents the -CH-CO- group, 5 63 066 12 the -CHgCHg group, as well as 1- (7,8-dimethoxy-1 »3» 4,5-th-trahydro-2H-3-benzo! 2epin-2-one ~ 3-yl) -3- ~ lime thyl- OPAN and 1- (7,8-dimethoxy-1,3 »4, 5 ⁱ tetrahydro-2H-3-benzazepin-2-one 3- (2-phenyl ethyl) amino J7""P3? yl) -3- / 7 H-methyl-H- (2- (4-amino-3-nitro-phenyl) -ethyl) amino- J- propane and their physiologically acceptable acid addition salts with inorganic or organic acids.