BG60412B2 - New benzazepine derivatives, methods for their preparation and their application as medicaments - Google Patents

Abstract

The invention relates to benzazepine derivatives having the formula (formula) to methods for their preparation and to medicaments containing them. The compounds have such pharmacological properties which make them suitable for the treatment of sinus tachicardias of different genesis and for the prophylaxy and therapy of the cardiac ischaemic disease.

Description

NEW GASKETS, PRODUCTS AND THEIR

ANNEX AS MEDICINAL PRODUCTS

In English Patent 1-546 844, which corresponds to DE-A-2 639 718, the structurally closest known compound is disclosed is 1 [7,8-dimethoxy-1,2,3,4-tetrahydro-5H-2- benzazepin-1-one-2-yl] -3- [Mmethyl-N4- (2- (3,4-dimethoxyphenyl) ethyl) amino] propane, and as the most valuable therapeutic compound, 1- [6,7- dimethoxy-3,4-dihydro2E1-isoquinolin-1-one-2-yl] -3- [N- [methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -amino] propane and their physiologically acceptable salts obtained by the addition of acids that exhibit valuable pharmacological properties and in particular lower blood pressure and pulse rate.

New benzazepine derivatives of the general formula were discovered

(I)

exhibit better pharmacological cBoucmBa, that is, with prolonged action and less side effects, they show a greater effect especially on lowering the pulse.

It is an object of the present invention to provide the new benzazepine derivatives of the above General Formula I, their salts with inorganic or organic acids, methods for their preparation and medicaments containing these compounds.

In the above general formula I mean:

A is the group -CH ₂ -CH ₂ -, -CH = CH-, -NH-CO-, -CH ₂ -CO-, or

C ' ^{5 -} C = N-apyr »a in which R? represents an alkyl group having 1 to 3 carbon atoms and B represents a methylene or carbonyl group, or

A is the -CO-CO- group and B is the methylene group,

E is - optionally substituted by an alkyl group having 1 to 3 carbon atoms, an ethylene, n-propylene or n-butylene group, one substituted in the 2 position by a hydroxyl group, a propylene group or substituted by a hydroxyl group in the 2 or 3 position of the n- butylene group.

G is an optionally substituted alkyl group having 1 to 3 carbon atoms, a methylene or ethylene group.

GC and R ₂ , which may be the same or different - hydroxyl groups, alkyl, alkoxy or phenylalkoxy groups, in which the alkyl moiety may contain 1 to 3 carbon atoms, or one of the radicals R 1 or R ₂ - also a hydrogen atom or R 1 together with R _? - one alkylenedioxy group is 1 or 2 carbon atoms.

R ₂ and R ₄ which may be the same or different are hydrogen or halogen atoms, hydroxyl groups, alkyl or alkoxy groups of 1 to 4 carbon atoms, trifluoromethyl or cyano groups, or one or more radicals R; or R ₄ - also one Humpoapvna. or R _; together is R ₄ - one alkylenedioxy group is 1 or 2 carbon atoms.

R _s is a hydrogen atom, alkyl, hydroxyl, alkoxy, amino.

alkylamino-. dialkylamino-. an alkanoylamine alkoxycarminylamino or bis (alkoxycarbonyl) amino group in which the alkyl moiety may contain 1 to 3 carbon atoms, or one substituted is a trifluoromethyl group of methylamino or ethylamino groups, and

R _h is a hydrogen atom, alkyl, phenylalkyl. alkanoyl, and alkoxycarbonyl; group, in which alkyl is _; that moiety may contain 1 to 3 carbon atoms or one alkenyl group is 3 to 5 carbon atoms.

For the meanings mentioned at the beginning in the definition of the radicals Rj go R ^, E and G mean:

for Rj - methyl, ethyl, propyl, isopropyl, hydroxyl. methoxy-, ethoxy-, propoxy-, isopropoxy-. benzyloxy-1-phenylethoxy or 3-phenylpropoxy, for R _? - hydrogen atom, methyl, ethyl, propyl. isopropyl, hydroxyl, methoxy-, ethoxy-, propoxy-, isopropoxy-, benzyloxy-, 1-phenylethoxy-, 2-phenylethoxy-, 2-phenylpropoxy- or 3-phenylpropoxy for R _; , respectively R ₄ , which may be the same or different - hydrogen, fluorine, chlorine, bromine or iodine atom, methyl, ethyl, propyl, isopropyl, n-butyl, hydroxyl, methoxy-, ethoxy-, propoxy-, isopropoxy-, n-butoxytrifluoromethyl or cyano or for one of the radicals R ₃ or R ₄ and a nitro group.

for R ^ is a hydrogen atom, methyl, ethyl, propyl, isopropyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, allyl, butene-2-yl, butene-3-yl, pentenyl, acetyl, propionyl, methoxycarbonyl,

BAD ORIGINAL

U.l. propyl, 2-phenylethyl.

butsn-2-silt. butene-3-yl, acetyl, propionyl.

ethoxycarbinyl, propoxycarb ·. h iu. \ t 4C il'Dpi4V'ake ipiH'HU.v> group.

; and R _n - in ·.> d <.tpt «den opium, methyl. etim »va. from »> pr» »saw» 'wa. benzyl, 1-phenylethyl! wa. phenylpropyl. allyl, pentyl, formyl ». wa.

mepxycarbonyl. ethoxycarb »» nil. propoxycarb * linyl or isopropox ir arbonyl hole, for Rj together is R _? and / or R is a dioxy or ethylenedioxy group, for E is ethylene. p-propylene. p-butylene, 1-methylethylene, 2-ethylethylene, 1-propylene, 1-methyl-propylene, 2-methyl-p-propylene, 1-ethyl-p-propylene, 3-ethyl-propylene, 2-propyl-p- propylene, 2-methyl-n-butylene, 2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-butylene group for G butylidene. methylene, methylene group.

Preferred compounds of the above general formula I are those in which:

A is the -CH.-CHy group. -CH = CH-. -NH-CO-. -CH ₂ -CO- or together with R ₄ - respectively methylenyls, methylene, ethylidene,

2-methylpropylidene,

-Ethylene, propylene, ethylene,

1-propylene or n12_

CH ₃ and B - methylene or carbonyl group or

A - -CO-CO-group and B - methylene group.

BAD ORIGINAL ft

CHlUACHoBa.

η-ηρ »tilen '> Ba. n G \ tilen · .Ί \ ι. 2-msil-pnponu \ cH '. Ήί or 2-vik || · ”Κcu-n-npontιлеш” lu pvna

G- McmuACiii'F'j. cmuAcii 'lxi or 1-mstyl. \ enOl group.

Rj - revenge. \ id »» xylene. benzyloxy or alkoxygroup v I go 4 Carbon atoms.

R.-, - Hydrogen opium. methyl. hydroxyl or mexyxy group. or Rj and R _? - methylenedioxy group.

R- ₅ - Hydrogen. fluorine, chlorine or bromine atom. trifluoromethyl. nitro-. an alkyl or an alkoxy group. which to them. »I to 4 Carbon atoms,

R ₄ - Hydrogen, chlorine or benzene atom, methyl. methanol cyano group or R _; and R ₄ together is a methylenedioxy group.

R ^ - Hydrogen opium, hydroxyl. mepxy-. amino-. acetylamino-. epiuxic ^r 'onilsmin · .. »-. bispyuxycarbonyl.

dimethylamino- or β.β.β-trifluoroethylethyl group and

R ₍₎ - Hydrogen atom. alkylCa group of 3 to ό Carbon atoms. alkyl. benzyl. acetyl or epoxycarbonyl group.

and salts thereof, especially the physiologically tolerated salts, are obtained organic or inorganic acids.

Particularly preferred compounds of the above Formula I are tags. In which they begin:

A is the -CIG-CEL- group. - (/ 14 = (.44-. Or

СИι

With X pyia and B the carbonyl group or

A is -644 = (/ (4-. -N44-CO- or -CO-CO-group and B is a methyl group,

E is a n-propylene group.

G is an ethylene group,

'BAD ORIGIN AL

L—

'! ' .! x Yves 4 \ ι ¹ 1 - · 1 -11 λ 1. · J ι '· · ίχι. In .ί ί: ί ί ι ι ; \ 4'Hi  Ί And! ρ · .ΊΊ.ι i ' \ ..:, ι ¹ '· 4- ϊ ι 'pc: i'.i'. pe u. . <. -p <. .: and. : ρ · ' 1 1 · 1 G '· lx, · '<ill'  'l <And-. re | . ι. ! '·. Ή '> ? ' ^ι · ..Κ ^; 1. X 44 'i IX'- U i 4? '1' Η 4 . ie. ι, 1 -ί I 'I l 11 \ tee 11 * - \ 1CI11UΛСΗ · .. | I ί ·. kx lb p e 11, i. ! p - 1 'Ep rlden an ··· ό. .o '' i; · and 'JJ menu' P u ρ η 'u R. - 1 » ί, ν. χ | ^ ρ · 4 | <'1ί .iH? a ;. JeHili ·· p.j. cl ilU.e ·· 'i'j. JU-p '·. . J and .f. ! '·:; and \ ·. ·. In ··. '<ι. re Γι. 1. and their: · · Ι.! 11 11 Λ '1! i 'JrUMU ell in HC'pC. .111114 and iu And \ ρ. .'A draw km · Hellenes ('! Λ : χΗ ·. ' In '-? I' ['CIUiCI iUCUU' u 'I'umc ci unions vC no. \ eh. ' P · . •• .one: met .'gu: .o B- .111 \ ί ·. > gcii · ... ml'uc h.i cue guiic'iue c o'4ii.am · ·.! ·> rm \ la

Ρ

Ν Η

Я koyap>

Au B are defined as In the beginning,

R 1 and R 4 are each hydroxyl upvna. chastity with a -lirspsp radical, e.g. tri.methylsilyloxy-. accept 'xi-. Ac] drank. 'Ke.i- and \ and tstra.hydr' 'ferranyl ··' xisrup. or have the pi RjiiRv aislips given to the beginning. with compound is a barking formula

R '

R. ------ _T ,.

k_;

/ 1 '\ u

Wherein

'bad original

L ·. And! And! . I

! <. , u ·. ' ΐχ. Γι! · ΊΛμ t • · About a !! ι '1' CSOs 1 VII · ! p AND O! 'P'. 11! 1H 'H i 1 l 1 ! . 3 Ci j fjtik .1.. iMilj ' ί., ρ: 'ELIZAH iAN \ · 1: · Ur 'B ·. 1 / Ji Η 'ok <1'- U 41 IliClltp L R; and R _s and / - H '· · ·,.} 11, C. | ·.-11 !! · -.j | •> a 11U • i  ·. pa and l) ι.) ·. 1 (III AND 1 ¹ μ) 111 ι h ¹ ρ i'iOji. a,. | se '3 1'1.1 cat ·. ' X. ι '. CiiCH ai l μ 'M U 0.1 In US 3 | 1 · \. '1.0.1 n 1. 1! : 111 '. \ \  H'SH. ι 'р' ' \ 1C'1 11 ' .1.1 llogCH alir.'M. X1s'ShaNsUulf ·· Ί 111.X ·. something. \ ', l. ·. -. _Ί p 41U .seat- or em ”kv li- <elf. 'neal,' xy-group or with no :. · .Ή · ιΓιιа . On shimmering ce possibly h the reaction mixture. ext sieves clear 1 tepid salt with . > formula

C Rn 7

'' X '' 1 \ r I 1 \ and! k '- · k, · R / an wherein E, G, Z, Rk go R _s ' and R ₆ are defined as ι in the beginning

any subsequent separation of the protecting group used.

The reaction is optionally carried out in a solvent or mixture of solvents. e.g. in acetone, dimethylformamide. acceptin / dimethylformamide, dimethyl sulfoxide or chlorobenzene and, as appropriate, depending on the reactivity of radical Z at temperatures between I &apos; and 150 &lt; 0 &gt; C. preferably at the reflux temperature of the solvent used. The presence of an acid binding agent is advantageous.

* such as an alcoholate such as sodium methylate, an alkali metal hydroxide such as sodium hydroxide, an alkaline carbonate such as potassium carbonate, an alkali amide such as sodium amide, an alkali metal hydride such as sodium hydride, or a tertiary organic base such as triethylamine or pyridine or an accelerator reaction. potassium iodide.

Any subsequent cleavage of the protecting group used becomes predominantly hydrolytic in an aqueous solvent, e.g.

Ik> ga, u: · .'ΐη ·· КK11UL, B »> ga. water or girnkvaii IGga in the presence of an acid such as hydrochloric acid or sulfuric acid, or in the presence of a depleting base such as sodium hydroxide or hydrochloride hydroxide at temperatures between 1 'and 1 and <1 ^C, preferably at boiling point of the reaction mixture. The cleavage of the benzyl radical can be carried out by hydrogenolytic e.g. with hydrogen in the presence of a catalyst such as platinum / carbon. In a solvent such as methanol. ethanol, acetic acid ethyl ester or acetic acid, optionally when acid is added as hydrochloric acid at temperatures between 0 and 50 ° C. however, preferably at room temperature and hydrogen pressure oml up to 7 bar, preferably from 3 to 5 bar.

b) For the preparation of compounds of general formula I wherein R ₆ represents a hydrogen atom, an alkenyl group having 3 to 5 carbon atoms, an alkyl or phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety:

One compound of general formula A (IV) is reacted with one compound of general formula

(V) in which

A, B, E and G are defined as in the beginning, R ₅ 'represents one hydroxyl group protected by a protected

BAD ORIGINAL

UCH Al.V'kvU- UAU

O radical, e.g. trimethylsilyl ·. »Kcu-. acxp'xy-, tetrahydrofuranyl * xygroup or having the values of HC and R _s . mentioned at the outset, one of the radicals D or V represents the R _M '-NlI group, where R ₆ ' represents a hydrogen opium. a carbonyl group of 3 to 5 carbon atoms, an alkyl or phenylalkyl group of 1 to 3 carbon atoms, the other of the radicals U or V being a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, e.g. chlorine, bromine or iodine atom, methanesulfonyloxy-, ptoluenesulfonyloxy- or ethoxysulfonyloxy group or radical U represents together with one β-positioned hydrogen atom of the radical E oxygen and V - one R ^ '- NH-apyna, as R ₆ ' is defined as above and any subsequent cleavage of the protecting group used.

The reaction is suitably carried out in a solvent or mixture of solvents such as acetone, diethyl ether, methylformamide, dimethylformamide, dimethylsulfoxide, benzene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or in excess of the compounds present or in general form with IV or compound of an acid-binding agent, e.g. an alcoholate such as potassium tert-butylate, an alkaline hydroxide such as sodium or potassium hydroxide, an alkaline carbonate such as potassium carbonate, an alkali amide such as sodium amide, an alkaline hydroxide such as sodium hydride, a tertiary organic base such as triethylamine or pyridines, such as the latter, and can serve , or in the presence of some reaction accelerator, such as potassium iodide, according to the reactivity of the nucleophilic substituent, it is appropriate to carry out the reaction at temperatures between 50 and 120 ° C, e.g. at the reflux temperature of the solvent used. The reaction can also be carried out without solvent. However, interaction is particularly preferred

I

1ί · to be carried out in the presence of tertiary organic again or in excess of the inserted amine is the general formula V.

Any subsequent cleavage of the protecting group used becomes predominantly hydrolytic in an aqueous solvent, e.g. 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 alkaline base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at reflux temperature. the reaction mixture. The cleavage of the benzyl radical can be carried out by hydrogenolytic e.g. with hydrogen in the presence of a catalyst such as platinum / carbon, in a solvent such as methanol, ethanol, acetic acid ethyl ester or acetic acid, optionally by adding acid as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature and hydrogen pressure oml up to 7 bar, but preferably from 3 to 5 bar.

c) For the preparation of compounds of general formula I wherein R ₆ represents a hydrogen atom, an alkenyl group having 3 to 5 carbon atoms, an alkyl or phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety:

A compound of the general formula

N-E-H /

B (VI) in which A, B, E, Rj and R ₂ are defined as in the beginning, but in radical E two hydrogen atoms in one -CH ₂ - or CH group of the radical are replaced by an oxygen atom, reacts in the presence of reducer with amine of the general formula ίί \ <.

4 <4

All · β which G u R ₄ go are defined by kakm ·. <β ιι.ι4. · .λ ·, ίη ·.> u R / pressed water <hh »atom atom. an alkenyl group of 5 to 5 carbon atoms, an alkyl or phenyl group of 1 to 3 carbon atoms in the alkyl moiety.

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

It is particularly advantageous to carry out reductive amination in the presence of a complex metal hydride such as lithium or sodium cyanoborohydride, preferably at pH 6-7 and at room temperature, or to obtain compounds of general formula I wherein R ₆ represents a hydrogen atom in the presence of a hydrogenation catalyst, e.g. with hydrogen 6 the presence of palladium / charcoal at a hydrogen pressure of 5 bar. However, at the same time, possibly the available benzyl groups may be cleaved hydrogenolitically and / or the double bonds may be hydrogenated,

d) For the preparation of compounds of general formula I, wherein R ₆ represents hydrogen, an alkenyl group of 3 to 5 carbon atoms, an alkyl or phenylalkyl group of 1 to 3 carbon atoms in the alkyl moiety:

A compound of the general formula

BADORIG1N ^al £>.

to /

N-E-N

... B ^k b '(VIII) in which A, B, E, R 1 and R ₂ are as defined above, and R ₆ represents a hydrogen atom, an alkenyl group of 3 to 5 carbon atoms, an alkyl or phenylalkyl group with 1 up to 3 carbon atoms in the alkyl moiety are reacted in the presence of a reducing agent with a compound of the general formula

(IX) in which R ₃ to R ₅ and G are defined as initially, but in the radical G, two hydrogen atoms in one -CH ₉ - or CH ₉ group of the radical are replaced by an oxygen atom.

The reaction is suitably carried out in a suitable solvent O or a mixture of solvents such as methanol, ethanol, ethanol / ethyl ester of acetic acid or dioxane at temperatures between 0 and 100 ° C, preferably at temperatures between 20 and 80 ° C.

It is particularly advantageous to carry out reductive amination in the presence of a complex metal hydride such as lithium or sodium cyanoborohydride, preferably at pH 6-7 and at room temperature, or to obtain compounds of general formula I wherein R ₆ represents a hydrogen atom in the presence of palladium / charcoal at hydrogen pressure 5 bar. However, at the same time, possibly the available benzyl groups can be cleaved hydrogenolitically and / or the double bonds are hydrogenated.

gi For the preparation of compounds of general formula I in which A represents an -NH-CO group, E is optionally substituted by an alkyl group having 1 to 3 carbon atoms, ethylene. a n-propylene or p-butylene group, and R ₆ is not hydrogen:

A compound of the general formula

N.

CH ₂ —B— N — E'—

(X) in which

B and G are defined as in the beginning

E '- optionally having an alkyl group of 1 to 4 carbon atoms substituted with an ethylene, n-propylene or p-butylene group,

R 1 'R ₄ ^{1 each} represent a hydroxyl group protected by a protective radical, e.g. trimetilsililoksi-, acetoxy-, benziloksiili tetrahidropiraniloksigrupa or have the meanings of Rj and R _4, mentioned in the introduction,

R ₅ represents a hydroxyl, amino or alkylamino group protected by a radical or, except for the amino or alkylamino group, the meaning of R ₅ mentioned at the beginning and

R6 ', with the exception of hydrogen, has the meaning of R ₆ mentioned above or represents a protecting group for an amino group, reacts with a carbonic acid derivative of the general formula

W-CO-W (XI) in which W may be the same or different always denote a nucleophilic leaving group such as chlorine, bromine, optionally having a halogen atom substituted by an alkoxy group being 1 to 3 carbon atoms or an imidazolyl- (2) group , and any subsequent cleavage of the protective radical used.

The reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, tetrachloromethane, benzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane or acetonitrile, preferably at temperatures between 0 and 150 ° C, but preferably at the boiling point of the solvent used. at temperatures between 40 and 100 ° C and optionally in the presence of an acid-binding agent such as potassium carbonate, sodium hydroxide, potassium hydroxide, pyridine or triethylamine, both of which may serve simultaneously as solvents. However, the reaction can also be carried out without solvent. If, in the compound of general formula XI incorporated, at least one of the radicals W represents an alkoxy group of 1 to 3 carbon atoms, the reaction is preferably carried out in excess of the solvent ester incorporated.

Any subsequent cleavage of the protecting group used becomes predominantly hydrolytic in an aqueous solvent, e.g. 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 alkaline base such as sodium hydroxide or potassium hydroxide at temperatures between 0 and 100 ° C, preferably at reflux temperature. the reaction mixture. The cleavage of the benzyl radical can be carried out by hydrogenolytic e.g. with hydrogen in the presence of a catalyst such as platinum / carbon, in a solvent such as methanol, ethanol, acetic acid ethyl ester or acetic acid, optionally by adding acid as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature and hydrogen pressure oml up to 7 bar, but preferably from 3 to 5 bar.

f) For the preparation of compounds of general formula I in which A represents -CIG-CH -, - group, R 1 and R _? are not benzyloxy groups, R ₃ or R ₄ are not a nitro group and R ₆ is not a benzyl group or the alkenyl group is 3 to 5 carbon atoms:

Hydrogenation of a compound of the general formula

<- ··. CH = CH R. · '7 \\ R ₃ i ! Ji N -E -Ν- // -G- <; > ι il / \ · / --- β \ R · R /

'Rs (XI) in which R ₁ to R ₅ , B, E and G are defined as in the beginning, with R ₃ or R ₄ not denoting a nitro group if R _s denotes an amino group.

The hydrogenation is carried out in a solvent or solvent mixture such as methanol, ethanol, acetic acid ethyl ester or acetic acid with catalytically excited hydrogen, e.g. hydrogen in the presence of platinum or palladium / carbon, at a hydrogen pressure of from 1 to 7 bar, preferably from 3 to 5 bar and at temperatures between 0 and 75 ° C, but preferably at temperatures between 20 and 50 ° C. If, in a compound of general formula XII, R ₆ represents a benzyl group, it is simultaneously replaced by a hydrogen atom during hydrogenation, or if R 1 and / or R 2 represent a benzyl group, they are always converted to a hydroxyl group upon hydrogenation.

g) One compound of general formula

in ^R 3

X '•• l

(ΧΗΐ) which

Rj go R ₆ , A, B, E and G are defined as initially, however, at least one of the radicals Rj go R ₄ represents a hydroxyl group, R ₅ is a hydroxyl group, an amino or alkylamino group having 1 to 3 carbon atoms or R ₆ must represent one hydrogen atom, reacted with a compound of the general formula

R ₆ -X (XIV) in which

R 4 represents an alkyl group of 1 to 3 carbon atoms or also an alkenyl group of 3 to 5 carbon atoms when R ₆ is a hydrogen atom or also a phenyl group substituted alkyl group when R 1 or R ₂ is a hydroxyl group and / or R ₆ is a hydrogen atom, and

X is a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, e.g. chlorine, bromine or iodine atom, methanesulfonyloxy-, p-toluenesulfonyloxy- or methoxysulfonyloxy group, or if at least one of the radicals Rj to R ₅ represents a hydroxyl group, X together with the a-positioned hydrogen of the radical R ₆ represent a diazgroup, or if R ₆ is a hydrogen atom or R 8 is an amino or alkylamino group, they represent an oxygen atom.

The reaction is suitably carried out in a solvent or a mixture of solvents such as diethyl ether, methanol, acetone, tetrahydrofuran, dioxane, acetonitrile, pyridine or dimethylformamide, optionally in the presence of a base such as potassium carbonate, potassium hydroxide or tert-butyl hydroxydate 0 and 150 ° C, but preferably at temperatures between 20 and 120 ° C.

If X is a nucleophilic leaving group, then the reaction is preferably carried out with an alkylating agent such as methyl iodide, dimethyl sulfate, ethyl iodide, diethyl sulfate. propyl bromide, allyl bromide, benzyl chloride, phenylethyl bromide or p-toluenesulfonic acid isopropyl ester in the presence of an acid-binding agent at temperatures between 20 and 80 ° C. However, the reaction can also be carried out without solvent.

If X together with the β-positioned hydrogen of the radical R ₆ represents a dia group then for the alkylation of a hydroxyl group, the reaction is preferably carried out with diazomethane or diazoethane at temperatures between 0 and 30 ° C, or if it represents an oxygen atom, then for the alkylation of the nitrogen the atom is reacted in the presence of a reducing agent at temperatures between 0 and 120 ° C, e.g. with formic acid at temperatures between 80 and 110 ° C or with sodium cyanoborohydride - at room temperature and pH value

6-7.

h) For the preparation of compounds of general formula I, in which A is not -CH = CH-group, R 1 is a chlorine or bromine atom and R ₅ is an amino or alkylamino group

A compound of the general formula (XV)

Rp R ₂ , R ₄ , R ₆ , B, E, and G are defined as in the beginning, A 'with the exception of the -CH = CH-group, has the meaning of A mentioned in the beginning and

R ₅ represents an amino or alkylamino group of 1 to 3 carbon atoms in each alkyl moiety, halogenated.

The reaction is carried out with a halogenating agent, e.g. chlorine, bromine, tribromophenol bromine or phenyldiodichloride, preferably in a solvent or solvent mixture, e.g. in 50 to 100% acetic acid or in tetrahydrofuran in the presence of a tertiary organic base, optionally in the presence of a heavy metal compound such as mercury (II) oxide and at temperatures between 0 and 50 ° C. On one mole of the compound of general formula XV which is incorporated as a base or as a salt, e.g. mono-, di- or trihydrochloride 1 or 2 mol or a small excess of halogenating agent are used. If the reaction produces a hydrochloric acid salt, it may be isolated as such or optionally further purified through the base.

i) For the preparation of compounds of general formula of general formula I, in which A represents a -CO-CO group, E is optionally an alkyl group of 1 to 3 carbon atoms, a substituted ethylene, propylene or n-butylene group and B - -CH ₂ -group:

A compound of the general formula

(XVI) is oxidized in which

R ₄ to R ₆ , E and G are defined as in the beginning.

The oxidation is preferably carried out with an oxidizing agent such as potassium permanganate, selenium dioxide or sodium dichromate in a suitable solvent or solvent mixture such as water, water / dioxane, glacial acetic acid, water / acetic acid or acetanhydride at temperatures between 0 and 100 ° C. preferably at temperatures between 20 and 80 ° C.

If a compound of the invention of general formula I is obtained in which B represents the carbonyl group, it can be reduced by reduction to the corresponding compound of general formula I, in which B represents a methylene group and / or if a compound with general formula I wherein

A is not -CH = CH- or

-C = No. group

and R ₆ represents a benzyl or 1-phenylethyl group, the compound can be converted by catalytic hydrogenation to the corresponding compound of general formula I, in which R ₆ represents a hydrogen atom and / or if a compound of general formula I is obtained, in which R ? or R ₄ represents a nitro group, it can be converted by reduction to the corresponding compound of general formula I, in which R ₅ represents an amino group and / or if a compound of general formula I is obtained, in which R ₆ is hydrogen and / or R 5 is amino group, this compound may be converted by acylation to the corresponding compound of general formula I, in which R ₀ represents an alkanoyl or alkoxycarbonyl group and / or R ₅ represents alkanoylamino-, alkoxycarbonylamino- or bis (alkoxycarbonyl) amino group. wherein the alkyl moiety always contains 1 to 3 carbon atoms, and / or if a compound of general formula I is obtained in which R _s

npeqcmab.vilia amino group. R. is not a vmcorous opium. R? and CD is not a cyano group. it can turn through ν. corresponding to the diazonium salt in the corresponding compound of general formula I. wherein R is a hydrogen atom, a hydroxyl or alkoxy group or R ₅ is a hydrogen atom and R ₃ is a halogen atom or denote a cyano group.

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

The subsequent reduction, respectively, of catalytic hydrogenation is carried out in a solvent such as methanol, ethanol, acetic acid ethyl ester or acetic acid with hydrogen in the presence of a catalyst such as platinum or palladium / charcoal at a hydrogen pressure of from 1 to 7 bar, but preferably from 3 to 5 bars and at temperatures between 0 75 ° C, but preferably at temperatures between 20 and 50 ° C. At the same time, the available nitro and cyano groups are reduced.

The acylation that follows is carried out e.g. with acetyl chloride, acetanhydride, propionic anhydride, or with the corresponding hydrochloric acid ester, e.g., hydrochloric acid ethyl ester, which may at the same time serve as a solvent, optionally in a solvent such as water / tetrahydrofuran, diethylene tetrahydrofuran, diethylene tetrahydrofuran, diethyl ether the presence of a base such as triethylamine or pyridine, wherein a tertiary organic base can serve simultaneously as a solvent, at temperatures between 0 and 100 ° C, preferably at room temperature. The conversion may also be carried out without solvent.

The conversion which follows of a diazonium salt, eg fluoroborate, hydrosulfate in sulfuric acid, hydrochloride or, BAD ORIG] n _Al to xugpouogug, optionally in the presence of copper or the corresponding copper (1 / salt as copper (1 ) chloride / hydrochloric acid, copper (1) bromide / hydrobromic acid or trisodium copper (1) tetracyanide is carried out at pH 7 and slightly elevated temperature, for example, at temperatures between 15 and 100 ° C; Reaction with hypophosphorous acid is carried out mainly at -5 to 0 C. The diazonium salt required for this purpose is obtained as appropriate but in a suitable solvent, eg in water / hydrochloric acid, methanol / hydrochloric acid, ethanol / hydrochloric acid or dioxane / hydrochloric acid by diazotizing the corresponding amino compound with nitrite, eg sodium nitrite or with nitric acid ester at low temperatures eg at temperatures between -10 and 5 ° C.

The compounds of the general Formula I obtained are further converted into their salts, especially their physiologically acceptable salts with inorganic or organic acids. As acids, we are referring to e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic or fumaric acid.

The compounds of general formulas II to XVI, which are used as starting materials, are partly known in the literature, respectively, obtained by known methods.

For example, a starting compound of the general formula IV or VIII is prepared by reacting the corresponding benzazepine with the corresponding halogen compound and optionally by further reacting with the corresponding amine. The benzazepine of the general formula II required for this purpose is obtained by cyclizing the corresponding compound, e.g. by cyclizing a compound of the general formula

Ri. . .

X H

I

I N— CHo-CH

X ...- ·· 'dream ₂ ss /

OCH3

OCH3 (XVII)

or by ring closure of the corresponding o-amino compound and optionally subsequent catalytic hydrogenation and / or reduction of a carbonyl group, e.g., with sodium borohydride / glacial acetic acid (see EP-A1 0 007 070) and / or oxidation e.g. with selenium dioxide.

A compound of general formula VI, which is used as a starting material, is prepared e.g. by reacting the corresponding benzazepine with the corresponding halogen acetal and subsequent

hydrolysis.

A compound of general formula X, which is used as starting material, is obtained e.g. by reducing the corresponding nitro compound.

A compound of general formula XII, XIII, XV or XVI, which is used as the starting material, is obtained preferably by reacting the corresponding halogen compound with the corresponding amine and optionally further cleaving the protective radicals used to protect the hydroxyl group.

As mentioned initially, novel compounds of the general Formula I and their physiologically acceptable salts with inorganic or organic acids exhibit valuable pharmacological properties, with limited side effects, e.g. with weak antimuscarinic effects, they cause a prolonged decrease in the heart rate as well as a decrease in the oxygen demand of the heart.

For example, the biological properties of compounds

A = 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-

3-yl] -3- (X-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride,

B = 1- (7,8-methylphenyl-1,3-hydroxy-2H -3-benzazepin-2-one-3-yl] -3 [X-methyl-X- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride,

C = 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dione-3-yl] -3- [X-methyl- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] propane hydrochloride,

D = 1- (7,8-dimethoxy-1,3,4,5-mempaxugpo-2H-1,3-benzodiazepine-

2-one-3-yl] -3- [X-methyl- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propane,

E = 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-

3-yl] -3- [X- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride,

F = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-yl] -3- [X-methyl-N- (2- (4-amino) -3,5-dichlorophenyl) ethyl) amino] propane,

G = 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3 [N-methyl- N - (2- (4-methoxyphenyl) -ethyl ) -amino] -propane hydrochloride,

H = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-yl] -3- [X-methyl-X- (2- (4-methoxyphenyl) ) -ethyl) -amino] -propanhydrochloride,

I = 1- (7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2on-3-yl] -3- [N-methyl-N- (2- (3,4 -Dimexyphenyl) -ethyl) -amino] propane hydrochloride,

J = 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-yl] -3- (1 '[- allyl-X- (2- (3 , 4-dimethoxyphenyl) -ethyl) -amino] -propane hydrochloride and

N = 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3 [N-methyl-N (2- (3,4-methylenedioxyphenyl) - ethyl) -amino] -propanhydrochloride

Comparison

I ... = 1- [~ .S-guoemino-1,2,3,4-tetrahydro-5H-2-yl] -p-epin-1-yl-2-yl] -3- [N-methyl- N2- (3-di-di-methyl ^ zsiphenyl> -ethyl '-shashno] -propane \ lk | p <> \ V »pug uc examined as follows:

1. Impact on the heart rhythm in cats:

The effect of the test substance on cardiac rhythm was examined as a medium-weight cat of both sexes.

2.5 - 3.5 kg was given in a single dose. The cats were anesthetized with Nembutal (30 mg / kg i.p.) and Chloralose-Urethan (40 mg / ml Chloralose + 200 mg / ml Urethan as needed). The test substance, in aqueous solution, is injected into the saphena vein, respectively into the duodenum.

The heart rate is recorded on a Grass polygraph before and after the substance is submitted by an electrocardiogram (precordial removal) using a Grass tachograph.

The following table contains the values found:

substance dose mg / kg anger. rhythm half-life (min) A 1.0 i.v -55% > 120 IN 1.0 i.v -45% > 120 P 1.0 i.v -44% > 90 D 1.0 i.v -41% 80 Well 1.0 i.v -45% > 90 F 1.0 i.v -51% > 120 L 1.0 i.v -8.2% 13

BAD ORIGINAL J.

2. Impact on guinea pig atrial heart rhythm:

Isolated spontaneously pulsating guinea pig atria of both sexes weighing 300-400 g were examined in a thyroid solution. The feed solution was fed with carbogen (95% _O? + 5% CO2) and maintained constant at 30 ° C. Contractions are recorded isometrically using a strain gauge on a Grass polygraph. The test substances were added at various concentrations for 60 min each. to saline.

From maximal effects are built concentration curves and their specific concentrations that reduce the heart rate by about 30% (= EU-6 O _zo)

The following table contains the values found:

substance EC-60, _n [ _M g / ml] A 0.030 P 0.097 D 0.058 Well 0.066 F 0.014 Mr 0.014 N. 0.0079 I 0.063 J 0.050 K. 0.014

3. Acute toxicity:

Acute toxicity of test substances was determined on mice (observation time 14 days) after intravenous or oral administration:

i resolving substance '______ toxicity (YSHT _II)'

I

I _______ A ___ ί · ^ν · ______ 1350 mg / kg p.o. {

Based on their pharmacological properties, the compounds prepared according to the invention are suitable for the treatment of sinus tachycardia of various origins and for the prevention and therapy of ischemic heart disease.

The dose required to achieve the corresponding action preferably contains from one to two times a day 0.03 to 0.04 mg / kg of weight, preferably 0.07 to 0.25 mg / kg of weight. The compounds of general formula I prepared according to the invention as well as the physiologically acceptable salts of inorganic or organic acids, optionally in combination with other active substances, together with one or more inert, conventional carriers and / or diluents, e.g. with corn starch, milk sugar, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, carboxymethyl, carboxymethyl, carboxymethyl containing fat such as solid fat, or suitable mixtures thereof, are processed into conventional medicines such as tablets, dragees, capsules, powders, suspensions, drops, ampoules, juices or suppositories.

The following examples should explain the invention in more detail:

Preparation of starting compounds

Example A

7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one

a) 3,4-dimethoxyphenylacetic acid chloride

To a suspension of 549.4 g of 3,4-dimethoxyphenylacetic acid In 600 ml of methylene chloride were added dropwise with stirring for 2 hours 600 ml of thionyl chloride. After completion of the gas separation (16 hours), boil for another hour under reflux. After removal of the volatile components, the residue is distilled in vacuo.

Yield: 486 g (80.8% of theory)

Boiling point: 134-136 ° C / 1.95 bar

b) N- (2,2-dimethoxyethyl) -3,4-dimethoxyphenylacetamide

Under ice-cooling, a solution of 485.2 g of 3,4-dimethoxyphenylacetic acid chloride in 1.1 l of methylene chloride was added dropwise at 15-20 ° C to a solution of 246.2 ml of amino acetaldehyde dimethylacetal and 315 ml of triethylamine in 2.2 l of methylene chloride and stirred. another hour at 16-18 ° C. It is then repeatedly extracted with water, dried over magnesium sulfate and evaporated. The resulting oil crystallizes slowly.

Yield: 608 g (95% of theory)

Melting point: 66-69 ° C

c) 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-one

A solution of 600.6 g of K (2,2-dimethoxyethyl) -3,4-dimethoxyphenylacetamide in 3 l of concentrated hydrochloric acid was reacted with 3 l of glacial acetic acid. After staying at room temperature for 17 hours, the mixture was poured onto ice. The precipitated crystals were filtered off, washed to neutral with water and dried.

Yield: 350 g (75.4% of theory)

Melting point: 234-237 ° C

Example B

7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one

A suspension of 21.9 g (0.1 mol) of 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one and 1.5 g of palladium / charcoal (10%) in 200 ml of glacial acetic acid is hydrogenated at 50 ° C and a hydrogen pressure of 5 bar. After filtration of the catalyst, the solvent was evaporated in vacuo and the residue was dissolved in methylene chloride. After extraction with sodium bicarbonate solution and washing with water, it is dried over magnesium sulfate, concentrated and purified apes silica gel with methylene chloride and then with increasing portions of methanol <1 / l7. , </.

Yield: 12.6 g (57% of theory).

Melting point: 188 - 191 ° C.

Example C.

7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepine

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

Yield: 1.1 g (92.7% of theory).

Melting point: 86 - 89 ° C.

Example D N- [3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propyl] -2 (2-amino-4,5-dimethoxyphenyl) -acetamide

33.3 g (0.07 mol) of X- [3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -amino] -propyl] -2- (2-nitro-4,5-dimethoxyphenyl) -acetamide,

BAD ORIGINAL

L ........

> 4 dissolved in 500 ml of methanol are hydrogenated at 25 ° C and a hydrogen pressure of 5 bar for 8 hours in the presence of 10% palladium / charcoal. After removal of the catalyst, the solvent was distilled in vacuo.

Yield: 31.5 g (100% of theory) of viscous oil.

Example E

6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one

2.0 g (0.007 mol) of (2,2-dimethoxyethyl) -2,5-dimethoxyphenylacetamide were poured into 3 ml of polyphosphoric acid and stirred for 60 minutes at 90 ° C. It is then mixed with ice water, the precipitated product is filtered off and dried.

Yield: 0.98 g (64% of theory).

Melting point: 188-191 ° C.

Example F

7.8-dimethyl-1,3-dihydro-2H-3-benzazepin-2-one

Obtained as Example E from N- (2,2-dimethoxyethyl) -3,4 dimethylphenylacetamide and polyphosphoric acid.

Yield: 40.1% of theory. value

Melting point: 220-224 ° C.

Example G

7.8-dimethoxy-5-methyl-1,3-dihydro-3,4-benzodiazepin-2-one

19.5 g (0.082 mol) of 2-acetyl-4,5-dimethoxyphenylacetic acid were suspended in 200 ml of ethanol, mixed with 8.2 ml of 98% hydrazine hydrate and refluxed for 6 hours.

The reaction mixture was evaporated in vacuo and purified on a silica gel column with methylene chloride and 1% ethanol as eluent.

Yield: 9.6 g (50% of theory).

IR spectrum (methylene chloride): 3300 cm ² (NH)

2830 cm-1 (BCH _h ) 1650 cm-1 (CO)

Example H

7,8-dimethoxy-1,3,4-tetrahydro-2H-3-benzazepine-2,4-dione

a) 7,8-dimethoxy-2-amino-4-bromo-1H-3-benzazepine hydrobromide

3.7 g (0.017 mol) of 3,4-dimethoxy-o-phenylene-diacetonitrile were suspended in 10 ml of acetic acid and mixed at 20 ° C with 12 ml of 30% hydrobromic acid in glacial acetic acid. The mixture was stirred at room temperature for 3 hours and the precipitated precipitate was filtered off with a suction filter, washed with glacial acetic acid, then with acetone / ether and dried.

Yield: 5.3 g (8% of theory)

Melting point: 210-211 ° C (dec)

b) 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-2,4-dione

5.3 g (0.014 mol) of 7,8-dimethoxy-2-amino-4-bromo-1H-3-benzazepine hydrobromide were dissolved in 100 ml of hot water, mixed with 1.3 g of anhydrous sodium acetate and heated to 90 ° C for 1 hour. . The reaction mixture was cooled, washed with cold water and dried.

Yield: 2.9 g (88% of theory).

Melting point: 235 ° C (dec)

Example I No. [3- (7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) propylmethylamine hydrochloride

Prepared as in Example B by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- (N-benzylmethylamino) -propane.

Yield: 87% of theory. value.

Melting point: 110 ° C (dec)

Example J

1-Chloro-3- [X-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propane

a) 3- [N-MemuA-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] propanol

A mixture of 2.1 g (0.011 mol) of X-methyl-2- (3,4-dimethoxyphenyl) ethylamine and 0.9 g (0.011 mol) of acrylic acid ethyl ester was allowed to stand at room temperature overnight. The resulting coupling product was dissolved in 40 ml of ether and added dropwise over 15 minutes, with stirring, to a suspension of 0.3 g (0.008 mol) of lithium aluminum hydride in 20 ml of ether. After refluxing for 5 hours, the mixture is cooled and then 30 ml of saturated sodium sulphate solution is added dropwise. The precipitated precipitate was filtered through silica gel and the filtrate was extracted with methylene chloride. The organic phase was dried over sodium sulfate and evaporated to dryness.

Yield: 3 g (89.7% of theory)

IR-spectrum (methylene chloride): 3600, 3230 cm ^'1 (OH) m / e = 253 (C ₁₄ N2zHO _3: 253.35)

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

2.75 g of benzenesulfonic acid chloride were added to 4 g of 3- [N-methyl-bT (2- (3,4-dimethoxyphenyl) -ethyl) -amino] propanol. After a period of 1/2 hour, it is dissolved in methylene chloride, washed with

30% solution of sodium hydroxide and water, dried over sodium sulfate and concentrated in vacuo. Purification through a silica gel column (eluent: methylene chloride / ethanol) gave a colorless oil.

Yield: 1 g (17% of theory)

C ₁₄ H ₂₂ C1NO ₂ (271.8)

Calculated: C, 61.86; 8.15; N5.15

Found: C 62.00 H 8.00 N4.63 ¢ / Example K

X-methylA- [2- (3,4-dimethoxyphenyl) -ethyl] -acetidine bromide g (0.011 mol) 3- [N -methylA- (2- (3,4-dimethoxyphenyl) -ethyl) amino-propanol was dissolved in 15 ml of methylene chloride and at 0-5 ° C a solution of 2 ml of phosphorus tribromide in 5 ml of methylene chloride was added dropwise. After warming to room temperature, boil for 2 hours at reflux. It was evaporated to dryness, then dissolved in methylene chloride and washed with 2 n sodium hydroxide and water. The organic phase was dried over sodium sulfate and evaporated to dryness.

After purification of the crude product through a silica gel column (eluent: methylene chloride / ethanol = 100: 5), the residue was heated for a further 40 minutes at 60-70 ° C.

Yield: 1.8 g (48% of theory).

Melting point: 175-180 ° C.

Example L

7,8-dimethoxy-2,3-dihydro-1H-3-benzazepine

A boiling suspension of 0.8 g of lithium aluminum hydride in 100 ml of absolute dioxane was mixed with 2.2 g (0.01 mol) of 7,8-dimethoxy-1,3 dihydro-2H-3-benzazepin-2-one and then heated for 3 hours under reflux condenser. When cooled with ice water, it is mixed with 10% ammonium chloride solution and the precipitate formed is filtered on a suction filter. The filtrate was concentrated in vacuo to a volume of about 20 ml, the precipitated precipitate was filtered off with suction and washed with a little dioxane.

Yield: 0.9 g (43.8% of theory)

Melting point: 162-163 ° C.

Getting the finished products

Example 1

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

a) 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane

131.5 g (0.6 mol) of 7,8-dimethoxy-3-dihydro-2H-3-benzazepin-2-one were suspended in 900 ml of dimethyl sulfoxide and mixed with stirring with 80.8 g (0.72 mol) of potassium tert-butylate. After 10 min. the resulting solution was added dropwise, with ice-water cooling, to 7 ml (0.72 mol) of 1-bromo-3-chloropropane in 30 ml of dimethyl sulfoxide. After a short time, the oily precipitate begins to crystallize. The precipitate was filtered off with a suction filter, dissolved in acetone, precipitated once more with water, filtered and dried.

Yield: 155.5 g (8 7.3% of theory).

Melting point: 101-103 ° C

b) 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-L1- (2- (3,4-dimethoxyphenyl) - ethyl) -amino] -hydrochloride

BAD ORIG * ^Nmu

5.9 g (0.02 mol) of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2on-3-yl)] - 3-chloropropane in 11.7 g (0.06 mol) of N-MemuA-2 - (3,4-dimethoxyphenyl) -ethylamine was heated for 3 hours at 100 ° C, cooled and dissolved in acetic acid / water ester, the organic phase separated, washed 3 times with 1% acetic acid and 2 times. extracted with 2 n hydrochloric acid. The hydrochloric extract is treated with ammonia and extracted with methylene chloride. The solvent of the extract was removed in vacuo, the residue dissolved in acetone and the hydrochloride precipitated with ether hydrochloric acid.

Yield: 6.9 g (70.3% of theory)

Melting point: 190-191 ° C (dec).

Example 2

1- [7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3,5-benzodiazepin-2,4-dione-yl] -3- [N-methyl-N- (2- (3 , 4-dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride

4.6g (0.01 mol) N- [3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -amino] -propyl] -2- (2-amino-4,5-dimethoxyphenyl) -acetamide and 3.6 g (0.022 mol) of N, N'-carbonyldiimidazole were boiled for 33 hours in 100 ml of acetonitrile. The solvent was removed in vacuo and the residue was purified through Alumina WoelmN, Akt III, with methylene chloride and 15% acetone as eluent. The fractions were concentrated in vacuo, the residue dissolved in acetone and precipitated with ether hydrochloric acid (ether saturated with hydrogen chloride).

Yield: 1.1 g (21.7% of theory).

Melting point: 125-130 ° C.

Example 3 with ·

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [1 H -methyl-1 H - (2- (2- amino-3,5-dichlorophenyl) -amino] -propane

Prepared according to Example 16 by reacting 1- (7,8 dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3chloropropane with N- [2- (2- amino-3,5-dichlorophenyl) -ethyl] -methylamine. Butter

UV spectrum (ethanol) λ max. 240 Fri (0.34)

285 pt (0.14)

306 Fri (0.10)

IR spectrum (dichloromethane): 2 810 cm-1 N-alkyl

840 cm @ ^-1 O-CH ₃

655 cmt ¹ C = O

520 and 1 620 cm ^'1 (C = C)

Example 4

1- [7,8-dimethoxy-1,3,4D-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Nmethyl-N- (2- (3,4-dimethoxyphenyl) - ethyl) -amino] propanhydrochloride

5.8 g (0.0127 mol) of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-

2-one-3-yl] -3- [N-methyl-N (2,3,4-dimethoxyphenyl) -ethyl) -amino] propane dissolved in 60 ml of acetic acid, at room temperature and pressure of 5 bar are hydrogenated in the presence of 10% palladium / charcoal for 5 hours. The catalyst was filtered off, the filtrate was concentrated in vacuo and the residue was dissolved in methylene chloride / semi-saturated potassium carbonate solution. The organic phase is treated with activated carbon / bleaching soil, filtered and concentrated in vacuo. The residue was then dissolved in acetone and guxugpt. The chloride precipitated was ethereal hydrochloric acid.

Yield: 6.2 g (92% of theory).

Melting point: 137 ° C (dec).

Using equimolar amounts of ethanol hydrochloric acid, hydrochloride of mp 165-168 ° C is obtained.

Example 5

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-] 81- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] propanhydrochloride

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

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

value).

Melting point: 84-85 ° C

b) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3 [N-methyl-N- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride

Prepared similarly to Example 16 by reacting 1 (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3chloropropane with N-methyl-2- (3,4-dimethoxyphenyl) -ethylamine.

Yield: 75.2% of theory. value.

Melting point: 135-137 ° C (dec).

Example 6

1- [7,8-dimethoxy-2,3,4,5-tetrahydro-1H-3-benzazepin-3-yl] -3- [Mmethyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] propanhydrochloride

2.7 g (6 mmol) of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N - (2- (3,4-Dimethoxyphenyl) -ethyl) aminopropane was dissolved in 100 ml absolute ether and 100 ml absolute tetrahydrofuran, mixed with 0.25 g lithium aluminum hydride and refluxed for 3.5 hours. After cooling and cooling, a 10% ammonium chloride solution was added, filtered on a suction filter and the filtrate was evaporated. The residue was purified on a silica gel column with methylene chloride. The fractions were concentrated, the residue dissolved in acetone and the dichloride precipitated with methanolic hydrochloric acid.

Yield: 1.5 g (48.5% of theory).

Melting point: 270-271 ° C (dec)

Example 7

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methylN- (2- (4-methoxyphenyl) -ethyl) -amino ] -propanhydrochloride

Prepared similarly to Example 16 by reacting 1- [7,8 dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3-chloropropane with Nmethyl-2- (4-methoxyphenyl) - ethylamine

Yield: 76.2% of theory. value)

Melting point: 139-142 ° C

EXAMPLE 8 1- [7,8-Dimethyl-1,2,4,5-mempaxugpo-2H-3-6 eH3a3enuH-2-oH-3-UA] -3- [Nmethyl-> T (2- (4-methoxyphenyl) - ethyl) -amino] -propanhydrochloride

Prepared similar to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3, -dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methylX- (2- (4-Methoxyphenyl) -ethyl) -amino] -propane.

Yield: 73.3% of theory. value.

Melting point: 175-177 ° C.

p

Example 9

1- [7,8-methylenedioxy-1,3, -dihydro-2H-3-benzazepin-2-one-3-yl] -3- [1,4methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl] ) -amino] -propane hydrochloride

a) 1- (7,8-methylenedioxy-1,3-dihydro-2H-benzazepin-2-one-3-yl) -3chloropropane

Prepared similarly to Example 1a by reaction of 7,8methylenedioxy-1,3-dihydro-2H-benzazepin-2-one. (melting point: 195 ° C (dec) with 1-bromo-3-chloropropane,

Yield: 72.1% of theory. value.

Melting point: 75-79 ° C.

b) 1- [7,8-methylenedioxy-1,3, -dihydro-2H-3-benzazepin-2-one-3-yl] -

3- [N-methylA- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride

Prepared similarly to Example 16 by reacting 1 (7,8-methylenedioxy-1,3-dihydro-2H-benzazepin-2-one-3-yl) -3chloropropane with No. methyl-2- (3,4-dimethoxyphenyl) ) -ethylamine.

Yield: 77.2% of theory. value.

Melting point: 185-187 ° C.

BAD ORIGINAL

I

Example 10

1- [. ^h- methylenediecane-1,3,4,5-tetrahydro-2H-3-benzazepin-2-op-3-yl] 3- [N-MenUA-N-t'2-i3.4-quMemokcu4 '' enuAj-einu / _k 'i-aMuil ·. »] ηροη anhydrous chloride

Received pid-yun? of Example 4 by catalytic hydrogenation of 1- [7,8-methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N) -2- (3.4- dimethoxyphenyl) ethyl) amino] propane.

Yield: 77.3% of theory. value)

Melting point: 210-212 ° C.

Example 11

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-51- (2 -) - 3,4- dimethoxyphenyl) ethyl) amino] propane

To a solution of 0.22 g (0.5 mol) of 1- [7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b1- (2- ( 3,4 dimethoxyphenyl) -ethyl) amino] -propane, 0.5 ml of 37% formalin solution, 2 ml of acetonitrile and 0.1 g of sodium cyanoborohydride were added at room temperature 0.05 ml of glacial acetic acid. After two hours, another 0.05 ml of glacial acetic acid was added and stirred for 1/2 hour. Processing is carried out by evaporation, dissolution in methylene chloride, washing with 2n sodium hydroxide and water. The organic phase dried over sodium sulfate was concentrated and purified over silica gel.

Yield: 104 mg (45.5% of theory), viscous oil.

IR spectrum (methylene chloride): 1 645 cm -1 (CO).

510 cm ^'1 (aroma. C = C)

Melting point: 137 ° C (dec).

BAD ORIGINAL

Example 12

1- (7,8-dimethoxy-1,3,4,5-getrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b] methyl-N- (2- (3,4-g imupyxyphenyl) -ethyl) -amino] propanhydrochloride g (0.075 mol) N- [3- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3-yl] -propylmethylamine was heated with 7.2 g (0.036 mol) of 2- (3,4-dimethoxyphenyl) -ethyl chloride for 20 hours at 140 ° C. After dissolving the reaction product in methylene chloride, the solution was washed once with 2n sodium hydroxide solution and 2 times with water, dried over sodium sulfate and evaporated The residue was purified by chromatography on silica gel (particle size: 0.063-0.2 mt; eluent: m tilenhlorid / methanol = 10: 1). The product thus obtained was dissolved in acetone and ethereal hydrogen chloride to precipitate the dihydrochloride.

Yield: 8.0 g (45% of theory).

Melting point: 135-136 ° C (dec).

Example 13

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [1Hmethyl-N- (2- (4-acetylamino-3 , 5-Dichlorophenyl) -ethyl) -amino] -propane g (0.0063 mol) 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] - 3- [N-methyl-N- (2- (4-amino-3,5-dichlorophenyl) ethyl) -amino] -propane in 50 ml of chloroform and 0.7 g (0.007 mol) of triethylamine are mixed in portions at reflux temperature. with a total of about 0.8 ml of acetyl chloride and boiled for several hours After cooling to room temperature, it is washed with water, the aqueous phase is made strongly alkaline with 2 n sodium hydroxide and extracted with methylene chloride. It was dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel (particle size: 0.063-0.2 mm; eluent: methylene chloride / methanol = 8: 1).

Melting point: 144-146 ° C.

Example 14

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [LH methyl-X- (2- (4-amino) -3,5-dibromophenyl) ethyl) amino] propane

To a solution of Ig (0.0025 mol) 1- [7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4aminophenyl) -ethyl) -amino] -propane in 20 ml of 95% acetic acid were added dropwise 0.8 g (0.005 mol) of bromine under stirring and room temperature. After 60 min, the solvent was removed with a rotary evaporator. The residue was partitioned between 2n sodium hydroxide and methylene chloride. The methylene chloride phase is washed once with water, dried over sodium sulfate and then evaporated in vacuo. The resulting oily residue was crystallized at room temperature and, to further purification, was crystallized from absolute ethanol.

Melting point: 105-110 ° C.

Example 15

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-L1- (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] -propane

0.22 g (0.5 mt) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [1 H- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] 42 propane was heated together with 0.2 ml of 37% formalin solution and 0.2 ml of 100% formic acid for 20 minutes to 90-100 ° C. The processing was continued analogously to Example 11. Viscous oil.

IR-spectrum (methylene chloride): 1645 cm ^'1 (CO)

1510 cm ' ¹ (arom. C = C)

Melting point of the dihydrochloride: 137 ° C (dec).

Example 16 is

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-X- (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] -propane

To a solution of 3.29 g (10.0 mmol) of N- [3- (7,8-fluoro-1, 3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -propyl] -methylamine hydrochloride and 1.8 g (10.0 mmol) of 2- (3,4-dimethoxyphenyl) -acetaldehyde in 40 ml of ethanol were added 1.26 g (20 mmol) of sodium cyanoborohydride while maintaining the pH at 6-7 by the addition of 2 n hydrochloric acid. At this pH, it was stirred for another 48 hours at room temperature. After evaporation of the solution in vacuo, residue Q was dissolved in dilute hydrochloric acid and extracted 2 times with ether. The aqueous phase was then basified, extracted 3 times with methylene chloride, the organic phase concentrated and dried over silica gel. Butter.

IR-spectrum (methylene chloride): 1645 cm ^'1 (CO)

1510 cm ' ¹ (arom. C = C)

Melting point of the dihydrochloride: 137 ° C (dec).

Example 17

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

To a solution of 2.77 g (10.0 mmol) 3- ( 7,8- dimethoxy-2H-3 1.3.4.5tstrahndro bin '' ^h '' ^{ld 1 Ί} ή *-yl) -propionaldehyde and 1.95 g (10.0 mmol). \ -methyl-2- (3,4-dimepiphenyl) -ethylamine in 40 ml of methanol was added 1.26 g (20 mmol) of sodium cyanoborohydride while maintaining the pH at 6- ^p by the addition of hydrochloric acid. At this pH, it was stirred for another 50 hours at room temperature. After evaporation of the solution in vacuo, the residue was dissolved in dilute hydrochloric acid and extracted 3 times with ether. The aqueous phase was then basified, extracted 3 times with methylene chloride, the organic phase concentrated and dried over silica gel. This results in a slightly yellowish viscous oil.

IR spectrum (methylene chloride): 1645 cm ^-1 (CO)

1510 cm ^'1 (arom. C = C) Melting point of the dihydrochloride: 137 ° C (dec).

Example 18

1- [8-Methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N - (2- (3,4-dimethoxyphenyl) a) ethyl (amino) propanhydrochloride ^a ) 1- (8-methoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane

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

Yield: 23% of theory. value.

IR-spectrum (methylene chloride): 1655 cm ^'1 (CO)

b) 1- (8-methoxy-1,3,4,5-tetrahydro-2H-3-benz azepin-2-one-3-yl) 3-chloropropane

Example 4 by Catalytic Hitzriller of 1- (6-Methoxy-1H-dihydro-3H-3-penchzepin-3-mn-5-yl. -3-chloro-1-yl) -pyrimidine .

Yield: '7 _of them · .'r. un ·· «ins.

IR-cnekmhp (methylene chloride ·: 1ό45 cm ′ ¹ << ’. ·· c> 1- [8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] 3 - [N-methyl-N- (2- (3,4-dimethoxyphenyl-ethyl) -amino] -propanhydrochloride

Prepared similar to Example 56 by reacting 1- (8methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with N-methyl-2- (3 , 4-dimethoxyphenyl) -ethylamine.

Yield: 14% of theory. value.

Melting point: 118-121 ° C.

Example 19

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [1Hmethyl-No. (2- (4-amino-3- chlorophenyl) ethyl) amino] propane

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

IR spectrum (methylene chloride): 3380, 3480 cm &lt; -1 ^&gt; (NH ₂ )

1645 cm ¹ (CO)

UV spectrum (ethanol): λ max .: 238 nm (0.16)

280-290 nm (0.05).

Example 20

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Methyl-N- (2- (4-amino-3 , 5-dichlorophenyl) -ethyl) -amino] -prop

BAD ORIGINAL

Obtained similarly to Example 12 om N- [3- (7,8-fluorobenz-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -propyl] -ethylamine and 2- <4amino -3,5-dichlorophenyl) ethyl chloride. Butter.

IR spectrum (methylene chloride): 3390, 3480 cm &lt; -1 ^&gt; (NH _? )

1650 cm ' ¹ (CO)

UV spectrum (ethanol): λ max .: 240 pt (0.13) 280-290 pt (0.05).

Example 21 about

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (4-amino-3 , 5-Dichlorophenyl) -ethyl) -amino] -propane

Obtained similarly to Example 12 from N- [3- (7,8-fluorocarbon-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -propyl] -methylamine and 2- (4amino) -3,5-dichlorophenyl) ethyl chloride.

Melting point: 94-104 ° C.

Example 22

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (4-amino-3 , 5-Dibromophenyl) -ethyl) -amino] -propane

Obtained similarly to Example 12 from N- [3- (7,8-methylacetyl-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -propyl] -methylamine and 2- (4amino) -3,5-dibromophenyl) ethyl chloride.

Melting point: 108-112 ° C.

Example 23

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [1Hmethyl-N- (2- (4-ethoxycarbonylamino-3 , 5-dichlorophenyl) -ethyl) -amino] propane

Prepared similarly to Example 13 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- [N-methyl-N- (2- (4-amino-

3,5-Dichlorophenyl) -ethyl) -amino] -propane and hydrochloric acid ethyl ester. Butter.

IR-spectrum (methylene chloride): 3410 cm ^'1 (NH)

1650 cm ' ¹ (CO-N <)

1735 cm ' ¹ (CO-O-)

1800 cm ' ¹ (CO-O-)

UV spectrum (ethanol): λ max .: 240 nm (arm 0.08)

Ο 280-290 nm (0.03).

Example 24

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Methyl-N- (2- (4-bis- ( ethoxycarbonyl-amino-3,5-dichlorophenyl-ethyl) amino-propane

Prepared similarly to Example 13 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- [N-methyl-No. (2- ( 4-amino-

3,5-Dichlorophenyl) -ethyl) -amino] -propane and ethyl chloric acid ethyl ester. Butter.

IR spectrum (methylene chloride): 1650 cm < ¹ & gt ^; (CO-N <)

1730 cm ' ¹ (CO-O-)

1760 cm '· ¹ (CO-O-)

1800 cm ' ¹ (CO-O-)

UV (ethanol): λ max .: 228 nm (arm 0.15) 282 nm (0.03).

Example 25

1- [7,8-dimethoxy-1,3,4> 5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-ethoxycarbonylamino) 3-cyano-5-fluorophenyl) -ethyl) amino] -propane

Prepared similarly to Example 13 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3 - [> 1-methyl-1 N - (2 - (4-Amino-3-cyan-5-fluorophenyl) -ethyl) -amino] -propane and hydrochloric acid ethyl ester in the presence of triethylamine.

IR spectrum (methylene chloride): 3400 cm @ ^-1 (NH)

2830 end (OCH ₃ ) 1730, 1650, 1510 cm ' ¹ (CO)

Example 26 p

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Kb] methyl-> E (2- (4-dimethylamino- 3,5-dichlorophenyl) -ethyl) -amino] -propane

Prepared similarly to Example 11 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3- [1,4-methyl-N- (2- (4-amino-

3,5-dichlorophenyl) -ethyl) -amino] -propane, paraformaldehyde and sodium cyanoborohydride in methanol. Butter.

IR spectrum (methylene chloride): 1650 cm &lt; -1 ^&gt; (CO)

UV (ethanol): λ max .: 227 pt (arm 0.16) © 280 nm (0.12).

Example 27

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-1- (2- (4-amino-3,5-dichlorophenyl) ) -ethyl) -amino] -propane

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (4-amino-3,5-dichlorophenyl) - N-methyl-ethylamine. Butter.

IR spectrum (methylene chloride): 3390, 3480 cm @ ^-1 (ΝΗ ₂ )

1655 cm ¹ (CO)

UV spectrum (ethanol): λ max .: 238 pt (arm 0.25)

280 pt (0.1).

303 pt (0.12).

Example 28

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [MM-methyl-4- (2- (4-amino-3 , 5-Dichlorophenyl) -ethyl) -amino] -propane

Prepared similarly to Example 4 from 1- (7,8-dimethoxy-1,3-dihydro2H-3-benzazepin-2-one-3-yl) -3- [L1-methyl-N- (2- (4-amino) -3,5-dichlorophenyl) -ethyl) -amino] -propane and hydrogen in the presence of palladium / carbon in glacial acetic acid.

Melting point: 94-104 ° C.

Example 29

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b] ethyl-N- (2- (4-amino-3 , 5-d ibromophenyl) -ethyl) -amino] -propane

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4D tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (4-amino-

3,5-dibromophenyl) -L-mesyl-ethylamine. Butter.

IR spectrum (methylene chloride): 3380, 3480 cm ¹ (NH ₂ )

1645 cm ' ¹ (CO)

UV spectrum (ethanol): λ max .: 240 pt (arm 0.13) 280-290 pt (0.04)

Example 30

1- [7,8-dimethoxy-1,3 4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Hmethyl-N- (2- (4-amino-3, 5-dichlorophenyl) -ethyl) -amino] -propane

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4,5 tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (4-amino-

3,5-dichlorophenyl) - N - methyl-ethylamine.

Melting point: 94-104 ° C.

Example 31

1- [7,8-Dimexy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Misopropyl-N- (2- (4-amino-3 , 5-Dichlorophenyl) -ethyl) -amino] -propane

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4,5 tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (4-amino-

3,5 - dichlorophenyl) -N-u isopropyl-ethyl amine.

Melting point of the hydrochloride: <90 ° C (firing after 70 ° C)

IR spectrum (methylene chloride): 3390, 3480 cm &lt; -1 ^&gt; (NH ₂ )

1655 cm ¹ (CO)

UV spectrum (ethanol): λ max .: 238 nm (0.13)

280-290 nm (0.05).

Example 32

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N- methyl-N- (1-methyl-2- (4 -amino-3,5-dichlorophenyl) -ethyl) -amino] -propanhydrochloride

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (4-amino-

3,5-dihydro-orphenyl) -1-methyl-X-methyl-ethylamine.

Melting point: 118-128 ° C.

Example 33

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

51 '

Obtained similarly to Example 56 from 1-yl, 2-cymepen. »Xi-1.3.4.5 tetrahydro-2H-3-benza-epin-2 - ('H-3-yl1-3-x. \ *» Propane and 2 - <4-amine · »-

3.5-dichlorophenyl, - - 1-methyl-N-methyl-ethyl.

Peep Point: 236-241. ° C.

Example 34

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b] methyl-No. (2- (4-amino-3-chloro- 5-methylphenyl) ethyl) amino] propane

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (4-amino- 3-chloro-5-methylphenyl) A-methylethylamine.

Melting point: 60 ° C (sintering, melting at 73 ° C)

IR spectrum (methylene chloride): 3390, 3480 cm &lt; -1 ^&gt; (NH ₂ )

1650 cm ' ¹ (CO)

UV spectrum (ethanol): λ max .: 237 nm (0.14)

280-290 nm (0.05).

Example 35

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (3,5-dichloro) -4-hydroxyphenyl) -ethyl) -amino] -propane hydrochloride

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (3,5-dichloro -

4-hydroxyphenyl) -N-methyl-ethyl amine.

Melting point: 225 ° C.

I ^SAD oronal $

Example 36

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-L1- (2- (3-chloro-5 -fluoro-4-3, P, p-trifluoroethylaminophenyl) ethyl) amino] -propane

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (3-chloro-5fluorine) -4-P, P, p-Trifluoroethylaminophenyl) -1H-methyl-ethylamine.

m / e = 545/547 (C ₂₆ H ₃₂ C1F ₄ N ₃ O ₃ ; 546.03)

Example 37

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (4-amino-3 -chloro-5-fluoro-phenyl) -ethyl) -amino] -propane

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (4-amino- 3chloro-5-fluoro-phenyl) -N-methylethylamine.

t / e = 463/465 (C ₂₄ H ₃₁ C1FN ₃ O ₃ ; 463.99)

Example 38

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (4-amino-3 -chloro-5-trifluoromethylphenyl) -ethyl) -amino] propane

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (4-amino-3-chloro -5-trifluoromethylphenyl) -N-methylethylamine.

IR spectrum (methylene chloride): 3410, 3510 cm &lt; -1 ^&gt; (NH ₂ )

1650 cm ' ¹ (CO)

1610, 1520 cm ^'1 (C = C)

S '?

* · Lm /

2800 cm ^'1 (N-alkyl)

2830 cm @ ^-1 (OCHj)

UV spectrum (ethanol): λ max .: 241 nm (0.33)

285 nm (0.10).

310 nm (0.08).

Example 39 1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3 - [C]. ...............................

Prepared similarly to Example 56 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and bTmethyl- (2 (4-amino) - 3-cyan-5-fluorophenyl-ethyl) -amine.

IR-spectrum (methylene chloride): 3400, 3490 cm ^'1 (ΝΗ ₂₎

2830 cm ' ¹ (OCH ₃ )

2220 cm ⁴ (CN)

1650 cm ' ¹ (CO)

Example 40

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

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (3,4-dimethoxyphenyl) -L-benzyl- ethylamine.

Yield: 51% of theory. value

Melting point: 102 ° C (dec).

Example 41

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methylN-t 2- (3,4-methylenedioxyphenyl) -ethyl) -amino] -propane hydrochloride

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 2- (3,4-dimethylenedioxy-phenyl) -N- methyl-ethylamine.

Yield: 48% of theory. value

Melting point: 160-162 ° C.

e

Example 42

1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3 - (> 1-benzylmethylamino) -prop anhydrochloride

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and Nmethylbenzylethylamine.

Yield: 92% of theory. value

Melting point: 208-209 ° C.

Example 43

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -4- [N-methylX- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -butanhydrochloride

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3-dihydro-2H3-benzazepin-2-one-3-yl) -4-chlorobutane and N-MemuA-2- (3,4dimethoxyphenyl) - ethylamine.

Yield: 85% of theory. value

Melting point: 162-164 ° C.

Example 44

1- [8-propoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2- [N-methyl-N (2- (3,4-dimethoxyphenyl) -ethyl) - amino] -ethanhydrochloride

Obtained similarly to Example 16 from 1- (8-propoxy-1,3-dihydro2H-3-benzazepin-2-one-3-yl) -2-chlorobutane and N-methyl-2- (3,4d propionate phenyl) -ethyl amine.

Yield: 31% of theory. value

Melting point: 155-157 ° C.

With Example 45

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -4- [N-methyl-N- (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] -butanhydrochloride Prepared similar to Example 16 of 1- [7,8-dimethoxy-1,3guxugpo-2H-3-6eH3a3enuH-2-oH-3-UAj-4- [N-MemuA-N - (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -butane.

Melting point: 192-194 ° C.

Example 46

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3 - [methyl-N- (2- (3,4- methylenedioxyphenyl) -ethyl) -amino] -propanhydrochloride

Prepared similar to Example 4 by catalytic hydrogenation of

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

Yield: 72% of theory. value.

Melting point: 191-193 ° C.

Example 47

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

Prepared similarly to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3- [N-benzyl N- (2 - ( 3,4-dimethoxyphenyl) ethyl) aminopropane.

Yield: 81% of theory. value.

Melting point: 152-154 ° C.

Example 48

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3 - [?] Allyl-N- (2- (3,4- dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride

3.1 g (0.007 mol) of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b4- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] propane were boiled with 1.0 g (0.007 mol) of potassium carbonate and 0.6 ml (0.007 mol) of allyl bromide for 21 hours in 100 ml of chloroform under reflux. The organic phase was then extracted with water, dried, concentrated in vacuo, and the resulting residue was purified through a column of aluminum oxide (300 g neutr. Activitt III) (eluent: methylene chloride with 2% acetone). The hydrochloride is then precipitated.

Yield: 40% of theory. value.

Melting point: 153-155 ° C.

Example 49

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mpropyl- 4- (2- (3,4- dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride

Examples of 1- [7,8-dimethoxy-1.3.4.5 tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [X- ', 2- | 3,4-dimethyloxyphenyl] N-ethyl) -amino | -butane and 1-pc.

Yield: 53% of theory. value.

Melting point: So ° C (dec).

Example 50 Isomeric mixture of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-yl] -3 - [N - methyl-X- (2- (2- and 4-nitrophenyl) - ethyl) -amino] -propane

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and N-methyl- (2- (4- and

2-nitro-phenyl) -ethylamine.

Yield: 70% of theory. value.

IR-spectrum (methylene chloride): 1655 cm ^'1 (CO)

1510 and 1345 cm ' ¹ (NO ₂ )

NMR (CDCl3) O: δ = 8.10 ppm, d (J = 9Hz), 2H (arom.), (4-nitro compound) δ = 7.83 ppm, d (J = 7Hz), 2H (arom. ), (2-nitro compound)

Example 51 Isomeric mixture of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-

3-UA] -3- [N-methyl-N- (2- (2-amino and 4-aminophenyl) -ethyl) -amino] propane hydrochloride

BAD ORIGINAL

Prepared similarly to Example 4 by catalytic reaction of an isomeric mixture of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2OH-3-uA) -3- [N-MemuA-N- ( 2- (2- and 4-nitrophenyl) -ethyl) -amino] -propane.

Yield: 34% of theory. value.

Melting point: 100 ° C (dec).

IR-spectrum (methylene chloride): 1660 cm ^'1 (CO) ^C 24 ^H 31 ^N 3 ° 35 ^{x HC1 (446} · °)

Calculated: C 64.34 Η 7.65 N 9.38 Cl 7.91

Found: C 63.60 Η 7.20 N9.28 Cl 7.94

Example 52

N-) 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3 - [N-methylN- (2- (2-acetylaminophenyl) -ethyl) - amino] -propane and 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3 - [N-methylN- (2- (2- acetylaminophenyl) ethyl) amino] propane

1.8 g (0.004 mol) isomeric mixture of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3- [N-methyl-No. (2- (2- and 4-aminophenyl-ethyl) -amino] -propane was stirred for 1 hour at room temperature in a mixture of 10 ml glacial acetic acid and 10 ml acetal anhydride. It is then mixed with water, neutralized with sodium carbonate and extracted with methylene chloride. After drying, the organic phase was concentrated in vacuo and the residue was chromatographed with alumina (200 g neutral, activity IV), (eluent: methylene chloride + 1% methanol).

Yield of 2-acetylamino compound: 0.24 g (14% of theory. Cm.) Melting point: 62-66 ° C.

Yield of 4-acetylamino compound: 0.5 g (28% of theory. Cm.) Melting point: 69-72 ° C.

Example 53

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H -1,3-benzodiazepin-2-one-3-yl] 3- [N-methyl-N- (2- ( 3,4-dimethoxyphenyl) -ethyl) -amino] -propane N, N -13- [N'-methyl-N '- (2- (3,4-methoxyphenyl) -ethyl] -yl) -acetyl] propyl] -2- (2-amino-4,5-dimethoxyphenyl) -ethylamine

4.5 g (0.01 mol) N- [3- [8 * N-methyl-1 N-2- (3,4-dimethoxyphenylmethyl) -amino] -propyl] -2- (2-amino-44-dimethoxyphenyl) - acetamide was dissolved in 100 ml of tetrahydrofuran and mixed under nitrogen atmosphere with 60 ml of 1-molar solution of diborane in tetrahydrofuran. The clear solution was allowed to stand at room temperature for 2 days and then digested with 20 ml of half-concentrated hydrochloric acid on cooling. The tetrahydrofuran is distilled off in vacuo and the remaining hydrochloric acid residue is made basic by cooling with concentrated sodium hydroxide. The fallen oil was dissolved in methylene chloride, the organic solution was separated, dried and concentrated in vacuo. The oily residue was purified on silica gel with methylene chloride and 1% methanol.

Yield: 2.9 g (53% of theory).

IR spectrum (methylene chloride): 2830 cm * ¹ (OCH ₃ )

2800 cm ^'1 (N-alkyl)

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

Prepared similarly to Example 2 by reacting N- [3- [N'methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propyl] -2- (2-amino-

4,5-dimethoxyphenyl) -ethylamine with N, N'-carbonyldiimidazole.

Yield: 0.9 g (61.6% of theory).

Melting point: 116-117 ° C.

Example 54

1- [7,8-dimethoxy-5-methyl-1,3-dihydro-2H-3,4-benzodiazepin-2-one-3yl] -3- [N-methyl-N- (2- (3,4- dimethoxyphenyl) -ethyl) -amino] propanhydrochloride

Prepared similarly to Example 16 by reacting 1-p-8-dimethoxy-5-methyl-1,3-dihydro-2H-3,4-benzodiazepin-2-one-3-yl] -3-chloropropane with N-methyl-2- ( 3,4-dimethoxyphenyl) -ethylamine

Yield: 24.2% of theory. value)

Melting point: 106 ° C

Example 55

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2-hydroxy-> 3 - [N-methyl-N- (2- (3 , 4-dimethoxyphenyl) -ethyl) -amino] -prop

a) 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2,3epoxypropane

Prepared similarly to Example 1a by reacting 7,8 dimethoxy-1,3-dihydro-2H-3,4-benzazepin-2-one with epichlorohydrin.

Yield: 94.5% of theory. value)

IR spectrum (methylene chloride): 2830 cm @ ^-1 (OCH ₃ )

1660 cm ' ¹ (CO)

b) 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2-hydroxy-3- [L1-methyl-No. (2- (3,4- dimethoxyphenyl) -ethyl) amino] propane

8.25 g (0.03 mol) of 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-

2-one-3-yl) -2,3-epoxypropane was dissolved in 8 100 ml of methanol, mixed with 5.85 g (0.03 mol) of N-methyl-2- (3,4-dimethoxyphenyl) -ethylamine and boiled for 3 hours under reflux. The methanol was distilled in vacuo and the residue was purified through a silica gel column with methylene chloride + 1% ethanol.

Yield: 7.8 g (55.2% of theory.).

IR spectrum (methylene chloride): 3600 cm &lt; -1 ^&gt; (OH)

1650 cm ' ¹ (CO) ^<-' 29 ^ 34 ^ 2θ6 (470.6)

Calculated: C 66.36 H 7.28 N 5.95

Found: C 66.16 H 7.26 N 5.S0

Example 56

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dione-3-yl] -

3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride

3.5 g of selenium dioxide are added at 70 ° C. I am a mixture of dioxane and 6 ml of water, stirred for 15 minutes and then mixed with 3 g of silica gel and 14.8 g (0.03 mol) of 1- [7,8-dimethoxy-1,3 , 4,5-tetrahydro2H-3-benzazepin-2-one-3-yl] -3- [X-methyl-N- (2- (3,4-dimethoxyphenyl) ethyl) -amino] -propanhydrochloride. The mixture was refluxed for 6 hours, cooled and filtered. The filtrate was concentrated in vacuo and the residue was purified through a silica gel column with eluent methylene chloride + 1% ethanol. The fractions were concentrated in vacuo, the residue dissolved in acetone and the hydrochloride precipitated with ether hydrochloric acid.

Yield: 13.8 g (90.7% of theory).

Melting point: 196-197 ° C.

Example 57

1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -2-hydroxy-3- [X-methyl-X- (2- (3 , 4-dimethoxyphenyl) -ethyl) -amino] propane

Prepared similarly to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2-hydroxy3- [H-methyl-LC2- However, (3,4-dimethoxyphenyl) -ethyl) -amino] -propane in ethanol at 50 bar and 70 ° C with a platinum oxide catalyst.

Yield: 37.5% om meopem. value.

IR-spectrum (methylene chloride): 3470 cm ^'1 (OH) 1635 cm' ¹ (CO)

C _2Q H ₃ 6 ^N 2 ° 6 (472.6)

Calculated: C 66.08 H 768 N 5. ⁽ '3

Found: C 66.22 H 757 N 5.85

Example 58

.¼

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b] methyl-N- (2- (4-nitrophenyl) -ethyl) -amino] -propanhydroch

Prepared similarly to Example 56 by reacting 1- (7,8 dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] chloropropane with N-methyl-2- (4-nitrophenyl) ) -ethylamine.

Yield: 56.5% of theory. value.

Melting point; 182 ° C.

Example 59

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [1Hmethyl- No. (2- (3-nitro-4- acetylaminophenyl) -ethyl) -amino] -propanhydrochloride

0.3 g (1.18 mmol) of N- [3- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -propyl] -methylamine and 0.34 g (1.3 mmol) 2- (3-nitro-4-acetylaminophenyl) -ethyl bromide is refluxed for 1 hour in 5 ml of chlorobenzene and 0.1 ml of pyridine. The reaction mixture was cooled and the precipitated pyridine hydrobromide was filtered on a suction filter. The filtrate was evaporated in vacuo and the residue was purified on alumina (neutral, activity II) with eluent

BAD ORIGINAL methylene chloride and 0.5% ethanol. The oil thus obtained was dissolved in acetone and the dihydrochloride precipitated with ether hydrochloric acid.

Yield: 230 mg (57.7% of theory.).

Melting point: 170 ° C.

Example 60

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (4-fluorophenyl) - ethyl) -amino] -dihydrochloride

O Obtained similarly to Example 56 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3chloropropane with N-methyl-2- ( 4-fluorophenyl) -ethylamine.

Yield: 68.7% of theory. value.

Melting point: 203 ° C.

Example 61

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Acetyl-L1- (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] -propane

g (0.0045 mol) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N- (2- (3,4- dimethoxyphenyl) -ethyl) amino] propane was mixed with 15 ml of acetanhydride and stirred for 1/2 hour at room temperature. The mixture was poured onto ice water, neutralized with sodium carbonate and then extracted with methylene chloride. The organic extract was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified on alumina (neutral, activity II) with methylene chloride eluent.

Yield: 1.5 g (68.5% of theory.).

IR spectrum (methylene chloride): 2830 cm &lt; -1 ^&gt; (OCH ₃ )

1640 cm ' ¹ (CO) ^ 27 ^ 36 ^ 2 ^^ 6

Calculated: C 66.92 Η 7.49 Ν 5.78

Found: C 66.75 Η 7.44 Ν 5.80

Example 62

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [No ethoxycarbonyl-No (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] -propane

2.5 g (0.00565 mol) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [1 H- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] propane and 2.45 g (0.024 mol) of triethylamine are dissolved in 20 ml of methylene chloride. After the addition of 2.6 g (0.024 mol) of hydrochloric acid ethyl ester was stirred for 30 minutes at room temperature, the solution was washed twice with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified on alumina (neutral, activity II) with methylene chloride eluent.

Yield: 1.5 g (51.6% of theory.).

IR spectrum (methylene chloride): 1690, 1650 cm &lt; -1 ^&gt; (CO) ^ 28 ^ 3δΧ2θ7 (484.6)

Calculated: C 65.30 H 7.44 N 5.44

Found: C64.19 H 7.14 N5.27

Example 63

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Hmethyl-N- (2- (2,6-dichlorophenyl) ) -ethyl) - aminopropanedihydrochloride

Prepared similarly to Example 56 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3-chloropropane with N-methyl-2- (2 , 6-dichlorophenyl) -ethylamine.

Yield: 70.5% of theory. value.

Melting point: 147 ° C

Example 64

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b] methyl-N- (2- (3,4-dichlorophenyl) ) -ethyl) -amino] -propanhydrochloride

Prepared similarly to Example 56 by reacting 1- (7,8 dimethoxy-1,3,4D-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3chloropropane with L-methyl-2- (3,4-dichlorophenyl) ) -ethylamine.

Yield: 57.6% of theory. value.

Melting point: 161 ° C.

Example 65

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2- [N-methylX- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -ethane

a) 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2-chloroethane

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

Yield: 20% of theory. value)

Melting point: 114 ° C.

b) 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2- [Mmethyl-N- (2- (3,4-dimethoxyphenyl) - ethyl) amino] ethane

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2-chloroethane and N-methyl-2 (3,4 dimethoxyphenyl) -ethylamine.

Yield: 72% of theory. value.

IR spectrum (methylene chloride): 2830 cm &lt; -1 ^&gt; (OSND

2790 cm ^'1 (N-alkyl) 1655 cm' ¹ (CO)

NMR spectrum (CDCl ₃ ): δ = 2.3 ppm, s, 3H (NCH ₃ ); 3.85 ppm, s, 12H (OCH ₃ ); 6.15 ppm, d (J = 8 Hz), 1H (olefin); 6.35, d (J = 8Hz), 1I (olefin)

Example 66

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -2- [No. methyl-No. (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] -ethanhydrochloride

Prepared similarly to Example 4 by catalytic hydrogenation of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2- [methylmethyl] (2- (3 , 4-dimethoxyphenyl) -ethyl) -amino] -ethane.

Yield: 59% of theory. value.

Melting point: 188-189 ° C.

Example 67

1- [7,8-dimethoxy-1,3,4D-tetrahydro-2H-3-benzazepin-2,4-dione-3-yl] 3- [N-methyl-No (2- (3,4-dimethoxyphenyl) -ethyl) -amino] prop anhydrochloride

a) 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione-3-yl) -3-chloropropane

Obtained similarly to Example 1a by reaction of 7,8dmethoxy-1,4-5-tetrahydro-2H-3-benzazepine-2.4-dione tm. m.p .: 235 ^to (ψΊ Μ. ρ 1-irom-H-chloropropane.

Yield: 26 And from theor. value) 1R spectrum (KBr): 1660 cm @ ^-1 (CO)

b) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2,4-dione-3-yl] -3- [X-methyl-Y- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] propanhydrochloride

Prepared similar to Example 56 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2,4-dione-3-yl) -3-chloropropane and N-methyl2 (3, 4-dimethoxyphenyl) -ethylamine.

Yield: 35% of theory. value.

Melting point: 163-164 ° C.

Example 68

1- [7-Benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-yl] -3- [N-methyl-X- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] -propane

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

8.9 g (0.03 mol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane was dissolved in 100 ml of methylene chloride and mixed at -6- ° C with 2.1 ml bortribromide. The reaction temperature was allowed to rise slowly to 20 ° C and then stirred for 10 hours. The resinous precipitate was crystallized by adding 100 ml of water and stirring for 1 hour. The precipitate was filtered off with a suction filter and washed with water and methylene chloride. For purification, the crystalline substance was stirred with acetone and filtered off. I L

BAD ORIGINAL

Yield: * 73 g D0.2 '' * ηη theory. value., ·.

Point at p'11'pence: ^C

b 1 -1 -xug p * »to uu - 8 -bepyl or si-1,3,4,5-memp axug ro-2 II - 3benzazepin-2-one-3-yl] -3-chl *> propane and 1- <7-benzyl "" xi-8-hydr * gsi-

1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3-chloropropane g (0.07 mol) 1- (7,8-guxugpo-1,3,4,5-tetrahydro- 2H-3-benzazepin-2-one-3-yl) -3-chloropropane and 10.6 g of potassium carbonate in 250 ml of dimethyl sulfoxide were mixed with 19.5 g (0.154 mol) of benzyl chloride. The mixture was stirred at room temperature for 2 days, poured onto ice water and extracted repeatedly with acetic acid ester. The organic extracts were washed 3 times with water, dried over magnesium sulfate and concentrated in vacuo. The separation of the isomers is carried out with silica gel and with eluent methylene chloride and 3% acetone.

Yield of 7-hydroxy compound: 6 g (23.8% of theory).

Melting point: 163-165 ° C.

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

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

Prepared similarly to Example 56 by reacting 1- (7-benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with N-methyl-2- (3,4-dimethoxyphenyl) -ethylamine.

Yield: 75.4% of theory. value.

Melting point: 128-129 ° C.

'Bad original

Example 69

1- [7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-yl] -3- [N-methyl-N - (2- (3,4- dimethoxyphenyl) ethyl) amino] propane

Prepared similarly to Example 56 by reacting 1- (7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane with No. methyl-2- ( 3,4-dimethoxyphenyl) -ethylamine.

Yield: 47.2% of theory. value.

Melting point: 157-158 ° C.

Example 70

1- [7,8-Dihydro-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Nmethyl-N- (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] -propane

0.52 g (0.001 mol) 1- [7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N - ( 2- (3,4-dimethoxyphenyl) ethyl) amino] -propane is hydrogenated for 5 hours at 20 ° C and 5 bar in 100 ml of methanol and 0.2 g of palladium / carbon. The catalyst was filtered off with a suction filter, the filtrate was concentrated in vacuo and the residue was purified with silica gel and eluent methylene chloride + 1% ethanol.

Yield: 0.2 g (43.9% of theory.).

IR spectrum (methylene chloride): 3520 cm @ ^-1 (OH)

1640 cm ¹ (CO) ^C 24 ^H 32 ^N 2 ° 5 ^{x 1/2 N} 2 ° ( ⁴⁵⁵ · ⁵ )

Calculated: C 63.28 H 7.74 N6.15

Found: C 63.44 H 7.77 N6.13

Example 71

1- [7-Benzyloxy-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-yl] -3 - [N-methyl-X- (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] propanhydrochloride

0.52 g (0.001 mol) 1- [7-benzyloxy-8-hydroxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-one-3-yl] -3- [N-methyl - N - (2- (3,4-dimethoxyphenyl; ethyl) -amino] -propane was dissolved in 30 ml of dimethylformamide and mixed with 50 mg of 50% sodium hydroxide dispersion (in oil). The mixture was heated at 60 ° C for 30 minutes, mixed. with 0.1 ml of dimethyl sulfate and heated for 2 hours at 60 ° C. The dimethylformamide was distilled in vacuo, the residue dissolved in methylene chloride, the organic phase washed with water and concentrated in vacuo. The resin residue was purified with aluminum hydroxide, activity II) with eluent me ilenhlorid. The resulting oil is dissolved in acetone by mixing with ethereal hydrochloric acid to precipitate the dichloride.

Yield: 250 mg (41% of theory).

Melting point: 117-120 ° C.

p

Example 72

1- [7-methoxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one3-yl] -3- [N-methyl-X- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] -propane

Prepared similarly to Example 71 by reacting 1- [7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [X-methyl-1H- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propane with dimethyl sulf.

Yield: 70% of theory. value.

IR-spectrum (methylene chloride): 1655 cm ^'1 (CO)

NMR Spectrum (CDClyDoO): δ = 2.3 ppm. 3H (NCH2); 5.1 ppm, s, 2H (benzyl); 6.5-6.8 ppm, m, 5H (arom.); 7.4 ppm, s, 5H (arom.).

Example 73

1- [7-hydroxy-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yl] -3- [N-methyl-N- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride

Prepared similar to Example 70 from 1- [7-benzyloxy-8-methoxy-

1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N (2- (3,4- by catalytic debenzylation).

Yield: 45.2% of theory. value.

IR spectrum (methylene chloride): 3530 cm &lt; -1 ^&gt; (OH)

2830 st ' ¹ (OCH ₃ )

1655 cm ¹ (CO)

^C 25 ^H 34 ^N 2 ° 5 ^xHC1 ( ⁴⁷⁹⁰ )

Calculated: C 62.69 H 7.36

Found: C63.15 H 7.57

N5.85

N5.64

Example 74

1- [7-Methoxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yl] -3- [N-methyl-No. (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] -propane

Prepared similarly to Example 70 from 1- [7-Methoxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-No. (2- (3,4dimethoxyphenyl) -ethyl) -amino] -propane by catalytic debenzylation.

Yield: 29.4% om meop. value.

IR spectrum (methylene chloride): 1640 cm &lt; -1 ^&gt; (CO)

C _{? 5} H ₄₄ N _? O ₅ (442.56)

Calculated: C 67.85 H 7.74 N 6.33

Found: C 67.50 H 7.97 N6.18

Example 75

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzane3H-2-oH-3-UA] -3- [Nmethyl-N- (2- (3,4- dimethylphenyl) ethyl) amino] propanhydrochloride

Prepared similarly to Example 56 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) -3chloropropane with No. methyl-2- (3, 4-dimethylphenyl) -ethylamine.

Yield: 54.3% of theory. value.

Melting point: 170-172 ° C.

Example 76

1- [7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- (b ^T methyl-N- (2- (4-tert -butylphenyl) -ethyl) -amino] propanhydrochloride

Prepared similarly to Example 56 by reacting 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3-chloropropane with N-methyl-2- (4 -tert-butylphenyl) -ethylamine.

Yield: 49.4% of theory. value.

Melting point: 146-149 ° C.

Example 77

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Nmethyl-N- (2- (4-p-butoxyphenyl) ) -ethyl) -amino] -propane

Prepared similarly to Example 56 by reacting 1- (7,8 dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3chloropropane with No. methyl-2- (4- butoxyphenyl) -ethylamine.

Yield: 55.3% of theory. value.

Melting point: 67-69 ° C.

Example 78

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [methyl-N- (2- (2,4, 6-trimethoxyphenyl) ethyl) amino aminopropane

Prepared similarly to Example 56 by reacting 1- (7,8 dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3chloropropane with No. methyl-2- (2, 4,6-trimethoxyphenyl) -ethylamine.

Yield: 57.8% of theory. value.

IR spectrum (methylene chloride): 1650 cm &lt; -1 ^&gt; (CO)

1520 cm ' ¹ (arom. C = C) ^C 27 ^H 38 ^N 2 ° 6 ^xHC1 ( ⁵²³ · ² )

Calculated: C 62.00 H 7.51 N5.35 C16.77

Found: C 61.75 H 7.52 N5.18 Cl 7.34

Example 79

1- [7,8-Dimethyl-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-No. (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propane hydrochloride

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

Obtained similarly to Example 1a by reacting .beta.-dimethyl-1,3-dihydro-2R-3-benzazspin-2-one (melting point: 226-224 ° C) with 1-bromo-3-chloropropane.

Yield: 99% of theory. value.

Melting point: 62-64 ° C.

b) 1- [7,8-dimethyl-1,3-dihydro-2H-3-6enzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (3,4-dimethoxyphenyl) - ethyl) -amino] -propanhydrochloride

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and N-methyl-2 (3,4 dimethoxyphenyl) -ethylamine .

Yield: 70.9% of theory. value.

Melting point: 105-107 ° C.

Example 80 [7,8-Dimethyl-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Methyl-N4- (2- (3,4-dimethoxyphenyl) ) -ethyl) -amino] propanhydrochloride

Prepared similar to Example 4 by catalytic hydrogenation of

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3- [N-methylN- (2- (3,4-dimethoxyphenyl) -ethyl] ) -amino] -propane.

Yield: 83.8% of theory. value.

Melting point: 154-157 ° C.

Example 81

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2-methyl-3 [N-methyl-L1- (2- (3,4- dimethoxyphenyl) -ethyl) -amino] -propane χ .μ ψ · ριρηη an.

Yield: '' 7.5 '7. and meop. cm ·, stitch.

Melting point: 45-47 ° C.

1- [7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -2-methyl-3- [N-methyl-N - '2- (3 _< 4-dimethoxyphenyl) -ethyl) -amino] -propane

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -2-methyl-3-chloropropane and methyl-2 (3,4- dimethoxyphenyl) -ethylamine.

Yield: 36% of theory. value.

Melting point: 30-32 ° C.

Example 82

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -2methyl-3- [N-methyl-1 H- (2- (3 , 4-dimethoxyphenyl) -ethyl) -amino] propanhydrochloride

Prepared similar to Example 4 by catalytic hydrogenation of 1- [7 _? 8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3 - [? TmethylN- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propane.

Yield: 73.7% of theory. value.

Melting point: 99-101 ° C.

Example 83

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dione-3-yl] 3- [N-MemuA-N- (2- (3, 4-dimethoxyphenyl) ethyl) aminopropanhydrochloride

, ο

2.45 g (ΰ.005 mol) 1- [7,8-dimethoxy-1,3,4,5-mempaxugpo-2H-36eH3a3enuH-2-oH-3-UA] -3- [N-MemuA-N- < 2- (3,4-Dimethoxyphenyl * -ethyl) - .beta. - .beta.-3beta.-tetrahydrofluoride is added to 50 ml of glacial acetic acid and mixed with 3 g of sodium bicarbonate x 2 H ₂ O. The mixture was stirred for 2 hours at room temperature, poured onto ice water, neutralized with potassium carbonate and shaken repeatedly with methylene chloride. The organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was purified through a column of silica gel and eluent methylene chloride + 1% ethanol. The product thus obtained was dissolved in acetone and the hydrochloride precipitated with ether hydrochloric acid.

Yield: 1.3 g (51.3% of theory.).

Melting point: 197-198 ° C.

Example 84

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dione-3-yl] -

3- [N-methyl-N (2- (3,4-dimethoxyphenyl) -ethyl) -amino] propanhydrochloride

1.98 g (44.0 mol) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N < 1 &gt; -methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) amino] -propanhydrochloride was suspended in 50 ml of acetanhydride, mixed with 2.5 g of potassium permanganate and stirred for 20 minutes at 20 ° C. The reaction mixture was poured onto ice water and made ammonia conc. ammonia. The manganese dioxide precipitate was filtered off with a suction filter and the filtrate was repeatedly extracted with methylene chloride. The extract was dried over magnesium sulfate, concentrated in vacuo and purified by a silica gel column and methylene chloride + 1% ethanol as eluent. The product thus obtained is dissolved in acetone and the hydrochloride precipitated is ethereal hydrochloric acid.

Yield: 0.7 g (34.5% of theory).

Melting point: 196-197 ° C.

Example 85

1- [6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methylN- (2- (3,4-dimethoxyphenyl) -ethyl) - amino] -propane

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

Obtained similar to Example 1a by reacting 6,9 dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (melting point: 188191 ° C) with 1-bromo-3-chloropropane.

Yield: 27% of theory. value.

Melting point: 97-99 ° C.

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

Prepared similarly to Example 16 by reacting 1- (6,9 dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with Nmethyl-2- (3,4 dimethoxyphenyl) ethylamine.

Yield: 90% of theory. value.

IR-spectrum (methylene chloride): 1658 cm ^'1 (CO)

NMR Spectrum (CDCl3- [delta] O): δ = 2.2 ppm; 3,7-3,8 ppm, 4s, 12H (OCH _3); 6.25 ppm, d (J = 9 Hz), 1H (olefin).

Example 86

1- (6,9-dimethoxy-1,3,4,5-tetrahydro-2H-t-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (3,4- dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride

Prepared similar to Example 4 by catalytic hydrogenation of

1- [6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl, -3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -pr '·' Mr.

Yield: 85 ⁽ b · Theoretical value.

Melting point: TK-76 ° C.

Example 87

1- [8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methylX- (2-DD-dimethoxyphenyl) -ethyl] -amino] -propane-hydrochloride

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

Prepared similar to Example 1a by reacting 8,9 dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (melting point: 165168 ° C) with 1-bromo-3-chloropropane.

Yield: 45% of theory. value.

Melting point: 67-71 ° C.

c) 1- [8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (3,4-dimethoxyphenyl) - ethyl) -amino] -propane hydrochloride

Prepared similarly to Example 1c by reacting 1- (8,9 dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl) -3-chloro-propane with Nmethyl-2- (3,4 dimethoxyphenyl) ethylamine.

Yield: 64% of theory. value.

Melting point: 64-68 ° C.

Example 88

1- [8,9-dimethoxy-1,1,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b] methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propane hydrochloride

Prepared similar to Example 4 by catalytic hydrogenation of

1- [8,9-dimpexy-1,3-dihydro-21-1-3-benzyl] epin-2-one-3-yl1-3- (X-methyl-X- '. 2- <^; .4-dimethyl ·' xiphenyl ι-ethyl> -ahgin <'(- propane.

Yield: 5 T of theory. value.

Melting point: 13-133 ° C.

Example 89

1- [7,8-dimepyuxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- (Hmethyl-N - (2- (3,4,5-trimethsulfonyl? -ethyl) -amino] -prop anhydrochloride

Prepared similarly to Example 56 from 1- <RTI ID = 0.0> 1- </RTI> 8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and X-methyl-2 (3,4,5 -trimethoxyphenyl) -ethylamine.

Yield: 44% of theory. value.

Melting point: 131 ° C (dec).

Example 90

Isomeric mixture of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [X-methyl-X- (2- (2- and 4-nitrophenyl) -ethyl) amino] -propane

Prepared similarly to Example 16 from 1- (7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl) -3-chloropropane and N-MemuA-2- (2i 4-Nitrophenyl) -ethyl amine.

Yield: 72% of theory. value.

IR-spectrum (methylene chloride): 1650 cm ^'1 (CO).

Example 91

Isomeric mixture of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [X-methyl-X- (2- (2- and 4-aminophenyl) -ethyl) propane

Prepared similarly to Example 4 by catalytic hydrogenation of an isomeric mixture of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3S '.

benzazepin-2-one-3-ylZ - [> 1-methyl-N- (2- * 2- and '4-nitrophenyl) ethylamino] -propane

Yield: 81% of theory. value.

IR-spectrum (methylene chloride): 1645 cm ^'1 (CO).

Example 92

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (2-acetylaminophenyl) - ethyl) -amino] -propane hydrochloride and

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Methyl-N- (2- (4-acetylaminophenyl) - ethyl) - aminopropane hydrochloride

Prepared similarly to Example 52 by reacting an isomeric mixture of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3-yl) -3- [N-methyl- N- (2- (2- and 4-aminophenyl) -ethyl) 4 amino] -propane with glacial acetic acid and acetanhydride.

Yield of the 2-acetylamine compound: 26% of theory. value. Melting point: 102-105 ° C.

Yield of 4-acetylamine compound: 49% of theory. value. Melting point: 89-93 ° C.

Example 93

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-N- (2- (4-aminophenyl) - ethyl) -amino] -propane

4.85 g (0.0107 mol) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3-yl] -3- [N-methyl-N - (2- (4-acetylaminophenyl) -ethyl) salt

amino] -propane was stirred 34 hours at 40 ° C with 80 ml of methanolic hydrochloric acid. After concentrating the solution, the residue was dissolved in methylene chloride, extracted with sodium bicarbonate solution and washed with water. The organic phase was dried, concentrated in vacuo and then the resulting oil was dried in vacuo at 50 ° C.

Yield: 88% of theory. value.

IR-spectrum (methylene chloride): 1645 cm ^'1 (CO)

NMR spectrum (CDCl3 / D2O): δ = 2.25 ppm; 3.8 ppm, s, 12H (OCH ₃ ); 6.9 ppm, d (J = 7 Hz), 2H (arom.).

Example 94

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [No. methyl-N- (2- (4-chlorophenyl) -ethyl) -amino] -propanhydrochloride

1.01 g (0.00245 mol) 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (4-aminophenyl) -ethyl) -amino] propane was dissolved in 5 ml of semi-saturated hydrochloric acid and diazotized with 0.17 g (0.00245 mol) of sodium nitrite. It was then stirred at 55 ° C until nitrogen was no longer released. The solution was made slightly alkaline, extracted with methylene chloride, dried and concentrated in vacuo. The resulting oil was purified by chromatography over alumina (200 g, neutral, activity II) (eluent: methylene chloride + 2% ethanol) and precipitated from acetone with ethereal hydrochloric acid.

Yield: 21% of theory. value.

Melting point: 148-151 ° C.

Example 95

1- [7,8-dimethoxy-2,3-dihydro-1H-3-benzazepin-3-yl] -3- [N-methyl-N- (2 (3,4-dimethoxyphenyl) -ethyl) -amino] propane

2.3 g (0.005 mol) of 1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepine-

2-oH-3-UA] -3- [N-MemuA-N- (2- (3.4-methylbenzoyl) -amino) -amino] propane was dissolved in 150 ml absolute ether, mixed with lithium aluminum hydride and stirred for 2 hours at room temperature. When cooled with ice water, it is mixed with 10% ammonium chloride solution, the precipitate is filtered off with a suction filter and the solvent is removed in vacuo. The oily residue was purified with alumina (neutral, activity II) with methylene chloride eluent.

Yield: 1.6 g (72.7% of theory).

IR spectrum (methylene chloride): 2830 cm @ ^-1 (OCH,).

2790 cm ¹ (N-alkyl) ^C 26 ^H 36 ^N ₂ ^O ₄

Calculated: C 70.88 H 8.24 N 6.36

Found: C 70.50 H 8.80 N6.22

Example 96

1- [7,8-dimethoxy-1,3,4,5-teparahydro-2H-3-benzazepin-2-one-3-yl] -3- [No methyl-No (2- (4-hydroxyphenyl) -ethyl) -amino] -propane hydrochloride

1.1 g (2.67 mmol) of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-No. (2- (4 -aminophenyl-ethyl) -amino] propane was dissolved in 10 ml of semi-saturated sulfuric acid and diazotized with 0.18 g (2.67 mmol) of sodium nitrite at 0 ° C. The solution was then heated in a steam bath for 20 minutes. water, basified slightly with sodium hydroxide, extracted with methylene chloride, and dried After concentration in vacuo, the resulting oil was purified with 100 g of aluminum oxide (neutral, activity II) with eluent - methylene chloride + 2% ethanol.

The hydrochloride precipitates from acetone / ether hydrochloric acid.

Yield: 0.17 g (15% OM).

Melting point: 109-112 C ^with

Example 97

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Pmethyl-L1- (2- (4-dimethylaminophenyl) - ethyl) -amino] -propanhydrochloride

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

Yield: 40% of theory. value.

Melting point: 193-196 ° C.

Example 98

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

a) X- [3- [N-methyl-N- (2- (4-amino-3,5-dichlorophenyl) -ethyl) -amino] propyl] -2- (2-amino-4,5-dimethoxyphenyl) -ethylamine hydrochloride

Obtained similarly to Example 53a from N- [3- [N'-MemuA-N '- (2- (4amino-3,5-dichlorophenyl) -ethyl) -amino] -propyl] -2- (2-amino-4 , 5dimethoxy-phenyl) -acetamide and lithium aluminum hydride.

Melting point: 182-188 ° C.

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

S3

Obtained similarly to Example 536 from N- [3- [N'-Mcniu. N-N '- <2O 4 amino] -3,5-dichlorophenyl) -ethyl) -amino] -propyl] -2- (2-amino- 4.5Dimethoxy-phenylTetylamine hydrochloride and N, N, and ap6i-nildiimidazole.

Melting point: 163-166 ° C.

Example 99

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dione-3-yl] -

3- [N-methyl-T1- (2- (4-amino-3,5-dichlorophenyl) -ethyl) -amino] -propane

Prepared similarly to Example 56 from 1- [7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b] methyl-N- (2- (4 -amino-3,5-dichlorophenyl) -ethyl) -amino] -propane and selenium dioxide.

Melting point: 118 ° C.

t / e = 493/495 (C ₂₄ H ₂₉ C1 ₂ N ₃ O ₄ : 494.43)

Example 100

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [1 H -methyl-N- (2- (3, 4-dimethoxyphenyl) -ethyl) -amino] -propanhydrochloride

1.1 g (5.0 mmol) of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one are suspended in 20 ml of dimethylsulfoxide and mixed with stirring with 0.6 g (5.3 mmol) of potassium tert- butylate. After 10 minutes, the solution was mixed with 2.0 g (7.4 mmol) of 1-fluoro-3- [methyl-1 N - (2- (3,4-dimethoxyphenyl) -ethyl) -amino] -propane. It is then stirred for another hour at 50 ° C, poured into water, extracted with ethyl acetate and the organic phase concentrated in vacuo. The residue was purified on silica gel with

Melting point: 136-137 ° C.

Example 101

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [b] methyl-N- (2- (3,4-dimethoxyphenyl) ) -Ethyl) -amino] - Propane Ichydrochloride

Prepared similarly to Example 100 from 7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-one and N-MemuA-N- (2- (3,4-guMenoxcu (io phenyl) - ethyl) -amino] -acetidine bromide.

Melting point: 137 ° C.

Example 102

1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [Mmethyl-No. (2- (3-amino-4- chlorophenyl) ethyl) amino] propane

Prepared similarly to Example 12 by reacting N- [3 (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) propylmethylamine and 2- (3- amino-4-chlorophenyl) ethyl chloride. Butter.

UV spectrum (ethanol): λ max. 238 pt (0.26)

285 pt (0.13)

304 Fri (0.06)

IR spectrum (dichloromethane): 3390 and 3480 cm &lt; -1 ^&gt; (NH ₂ )

1650 cm ' ¹ (CO)

2830 cm ⁴ (OCH ₃ )

2795 cm ^'1 (CH ₃ -N <) 1520 u 11620 cm' ¹ (C = C)

Example I

10 mg tablets of 1- [7,8-dimethoxy-1,3,4> 5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-L1- (2- (3 , 4-dimethoxyphenyl) -ethyl) amino] -propanhydrochloride

Composition:

1 tablet contains: active substance 10.0 mg cornstarch 57.0 mg milk sugar 48. 0 mg polyvinylpyrrolidone 4. 0 mg magnesium stearate 1. 0 mg

120.0 mg

Method of production

The active substance, corn starch and polyvinylpyrrolidone are mixed and moistened with water. The wet mixture was passed through a 1.5-mm mesh screen and dried at about 45 ° C. The dry granulate was passed through a 1.0-mesh mesh screen and mixed with magnesium stearate. The finished mixture was compressed into a tablet press with a 7-mm-diameter matrix to split tablets.

Tablet weight: 120 mg

Example II

5 mg dragee of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-one-3-yl] -3 - [(methyl-) - (2- (3, Uncoated 4-dimethoxyphenyl) -epyl) aminopropane hydrochloride coating contains:

active substance 5.0 mg cornstarch 41.5 mg milk sugar 30. 0 mg polyvinylpyrrolidone 3. 0 mg magnesium stearate 0. 5 mg

80.0 mg

Method of preparation

The active substance, maize starch, milk sugar and polyvinylpyrrolidone are all mixed well with water. The wet mixture was passed through a 1-mm mesh screen and dried at about 45 ° C. The granulate is then passed through the same sieve. After mixing with magnesium stearate, round tablets of 6 mm diameter are pressed on a tablet machine. The dragees thus obtained are in a known manner coated with a layer consisting essentially of sugar and talc. The finished dragees are polished with wax.

Dragee weight: 130 mg

Example III

5 mg ampoules of 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3 , 4-dimethoxyphenyl) -ethyl) amino] -propanhydrochloride ampoule contains:

the active substance is sorbitol

5.0 mg

50.0 mg a for injection purposes ad

Method of preparation

In a suitable vessel, the active substance is dissolved in water for injection and the solution is isotonic with sorbitol.

After filtration through a membrane filter, the solution is filled into cleaned and sterilized ampoules under nitrogen, which are autoclaved for 20 minutes in a stream of water vapor.

Example IV

15 mg suppositories of 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- ( 3,4-dimethoxyphenyl) -ethyl) amino] -propanhydrochloride.

suppository contains:

active substance 0.015 t solid fat (eg Witepsol H 19 and W 45) ________ 1.685 g

1.700 g

Method of production

The solid fat melts. At 38 ° C, the milled active substance disperses homogeneously in the molten fat. Cool to 35 ° C and pour into slightly pre-cooled spark plug forms.

Example V ©

10 mg dropwise solution 1- (7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N- (2- (3,4-dimethoxyphenyl) -ethyl) aminopropane hydrochloride in 5 ml.

100 ml solution contains:

active substance 0.2 Mr Rücker hydroxyethyl cellulose 0.15 Mr Rücker tartaric acid 0. 1 Mr Rücker sorbitol solution 70% dry in 30. 0 Mr Rücker glycerin 10. 0 Mr Rücker benzoic acid 0. 15 'Mr distilled water ad 100 ml

Method of production

The water was heated to 70 ° C. Hydroxyethyl cellulose, benzoic acid, and tartaric acid are dissolved therewith. Cool to room temperature and glycerol and sorbitol solution added with stirring. At room temperature, the active substance is added and stirred until complete dissolution. Then, with stirring, it is evacuated for aeration.

Claims (11)

Patent Claims 1. Benzazepine derivatives of the general formula: A. KB N-E-N-G / d (I) in which they mean: A is the group -CH ₂ -CH ₂ -, -CH = CH-, -NH-CO-, -CH ₂ -CO-, or In which R ₇ represents an alkyl group of 1 to 3 carbon atoms and B represents a methylene or carbonyl group, or A is the -CO-CO- group and B is the methylene group, E- optionally substituted by an alkyl group having 1 to 3 carbon atoms, an ethylene, n-propylene or n-butylene group, one substituted at the 2 position by a hydroxyl group, a propylene group or substituted by a hydroxyl group at the 2 or 3 position of the n- butylene group. G is an optionally substituted alkyl group having 1 to 3 carbon atoms, a methylene or ethylene group. Rj and R-. which may be the same or different - hydroxyl groups, alkyl, alkoxy or phenylalkoxy groups, in which the alkyl moiety may contain 1 to 3 carbon atoms, or one of the radicals R 1 or R ₂ is also a hydrogen atom, or R 1 together with R ₂ - an alkylenedioxy group having 1 or 2 carbon atoms. R _; u R ₄ kcunio μ ·. \ _ λιιι ga are the same or different - hydrogen or halogen atom, hydroxyl groups, alkyl or alkoxy groups of 1 to 4 carbon atoms, trifluoromethyl or cyano groups, or one of the radicals R ₄ or R ₄ - also one nitro group , or R together with R ₄ - an alkylenedioxy group of 1 or 2 carbon atoms. R _s is a hydrogen atom, an alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino or bis (alkoxycarbonyl) amino group in which the alkyl moiety may contain 1 to 3 carbon atoms, or carbon atoms, or with a trifluoromethyl group of a methylamino or ethylamino group, and R ₆ is a hydrogen atom, an alkyl, phenylalkyl, alkanoyl or alkoxycarbonyl group in which the alkyl moiety may contain 1 to 3 carbon atoms or one alkenyl group having 3 to 5 carbon atoms and their salts, especially their physiologically tolerable salts of inorganic and organic acids. Benzazepine derivatives of general formula I according to claim 1, in which: A is the group -CH ₂ -CH ₂ -, -CH = CH-, -NH-CO-, -CH ₂ -CO-, or CH ₃ -C-N-apyna and B-methylene or carbonyl group or A is a -CO-CO group and B is a methylene group, E is an ethylene, n-propylene, n-butylene, 2-methyl-propylene or 2-hydroxy-n-propylene group, G-methylene, ethylene or 1-methylene group, R 1 is a methyl, hydroxyl, benzyloxy or alkoxy group having 1 to 3 carbon atoms, BAD ORIGINAL Q R-, - a hydrogen atom, a methyl, hydroxyl or methoxy group. or Rj and R _? together, the methylenedioxy group, R1 is a hydrogen, fluorine, chlorine or bromine atom, trifluoromethyl. a nitro, alkyl or alkoxy group is 1 to 4 carbon atoms, R ₄ is a hydrogen, chlorine or bromine atom, methyl, mepxyxy or cyano, or R ₃ and R ₄ together are methylenedioxy, R ^ is a hydrogen atom, hydroxyl, methoxy-, amino-, acetylamino-, ethoxycarbonylamino-, bis (ethoxycarbonyl) amino-, dimethylamino- or β, β, β-trifluoroethylamino group and R ₆ is a hydrogen atom, an alkyl group of 3 to 6 carbon atoms, an alkyl, benzyl, acetyl or ethoxycarbonyl group, and their salts, especially the physiologically acceptable salts obtained with organic or inorganic acids. 3. Benzazepine derivatives of general formula I according to claim 1, in which they mean: A is the -CH2-CH2- group, -CH = CH-, or -C = N-apyna and B is a carbonyl group, or A is -CH = CH-, -NH-CO- or -CO-CO-group and B is a methylene group, $ E is n-propylene, G-ethylene, R1 is a methoxy or hydroxyl group, R _? - methoxy group, or Rj and R ₂ together, is methylenedioxy group, R3 is a methoxy or trifluoromethyl group, a chlorine or bromine atom, R ₄ is a methoxy group, HC is a hydrogen atom, an amino or methoxy group and R 4 is a hydrogen atom, a methyl, ethyl, n-propyl or allyl group and their salts, especially the physiologically acceptable salts obtained with organic or inorganic acids. 4. Benzazepine derivatives of general formula With (1a) in which denote A is the group -C 1 -C 5 -C 4 -, -CH = CH-, or CH ₃ I is a C-N group and B is a carbonyl group or A is a -NH-CO- or -CO-CO group and B is a methylene group, Rj and R ₂ - one methoxy group, R _o is a hydrogen atom, a methyl or alkyl group, R ₃ is a hydrogen atom or a methoxy group in the 3-position, R ₄ is a methoxy group in the 4th position or R ₃ and R ₄ together are 3,4 methylenedioxy group and R ₅ is a hydrogen atom, or R ₃ in the 3-position is a trifluoromethyl group, a chlorine or bromine atom, R ₄ 65th position - chlorine or bromine atom and R ₅ in the 4th position is an amino group and its physiologically tolerated salts obtained with inorganic or organic acids. BAD ORIGINAL $ 5. 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yl] -3- [X-methyl-N- (2- (3,4 -Dimethoxyphenyl) -ethyl) -amino] -propane and its salts obtained by acid addition. 6. 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl] -3- [X-methyl-N- (2- (3 , 4-dimethoxyphenyl) -ethyl) -amino] propane and its salts obtained by acid addition. 7. 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3yl] -3- [N-methyl-N- (2- (4-amino) -3,5-dichlorophenyl) -ethyl) -amino] -propane and its salts obtained by acid addition. 8. 1- [7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl] -3- [N-methyl-N - (2- (4 -methoxyphenyl) -ethyl) -amino] -propane and its salts obtained by acid addition. A medicament for treating sinus tachycardia and ischemic heart disease comprising a compound according to claims 1 to 8 together with one of the many inert carriers or diluents. 10. A process for the preparation of benzazepine derivatives of general formula (I) wherein: A is the group -CH ₂ -CH ₂ -, -CH = CH-, -NH-CO-, -CH ₂ -CO-, or 5 5 R7 -C = N-2p? Na in which R ₇ represents an alkyl group having 1 to 3 carbon atoms, and B - a methylene or carbonyl group or A is the -CO-CO- group and B is the methylene group, E is - optionally substituted by an alkyl group having 1 to 3 carbon atoms, an ethylene, n-propylene or n-butylene group, one substituted at the 2-position by a hydroxy group or a substituted by a hydroxyl group in 2 or 3 position p-butylene group. G is optionally substituted by an alkyl group having 1 to 3 carbon atoms, a methylene or ethylene group. Rj and R _? , which may be the same or different - hydroxyl groups, alkyl, alkoxy or phenyl alkoxy groups in which the alkyl moiety may contain 1 to 3 carbon atoms, or one of the radicals R 1 or R ₂ be a hydrogen atom or R 1 together with R ₂ - an alkylenedioxy group of 1 or 2 carbon atoms. R ₃ and R ₄ , which may be the same or different - hydrogen or halogen atom, hydroxyl groups, alkyl or alkoxy groups of 1 to 4 carbon atoms, trifluoromethyl or cyano groups, or one of the radicals R ₃ or R ₄ may be a nitro group , or R ₃ together with R ₄ is an alkylenedioxy group of 1 or 2 carbon atoms. R ₅ is a hydrogen atom, an alkyl, hydroxyl, alkoxy, amino, alkylamino, di alkylamino, alkanoylamino, alkoxycarbonylamino or bis (alkoxycarbonyl) amino group in which the alkyl moiety may contain 1 to 3 carbon atoms, or substituted by a trifluoromethyl group of a methylamino or ethylamino group, and R4 is a hydrogen atom, an alkyl, phenylalkyl, alkanoyl or alkoxycarbonyl group in which the alkyl moiety may contain 1 to 3 carbon atoms or one alkenyl group having 3 to 5 carbon atoms, and their salts, especially their physiologically tolerated salts, obtained by the addition of inorganic or organic acids, characterized in that (a) a compound of general formula BAD ORIGINAL A N-H / . B UD in which A u B are defined as in the beginning, Ry and R ₇ 'represent a hydroxy group protected with a protective group or have the meanings of Rj and R ₂ given in the beginning, is reacted with a compound of general formula (III) in which R ₆ , E and G are defined as in the beginning, Ry go Ry represent one hydroxyl group protected by a protected radical or have the meanings of R ₂ and R ₅ mentioned at the beginning and Z is a nucleophilic cleavage group, or an internal, quaternary salt of the general formula (IIIa) in which E, G, Z, Ry go Ry and R ₆ are as defined at the beginning and any subsequent cleavage, optionally present in the reaction mixture of the protecting group used or ό) for the preparation of compounds of general formula I, in which R ₆ is hydrogen, an alkenyl group of 3 to 5 carbon atoms, an alkyl or phenylalkyl group of 1 to 3 carbon atoms in the alkyl portion, a compound of general formula N-E-U is reacted with one compound of the general formula R ₅ '(V) in which A, B, E and G are defined as in the beginning. R 1 'and R 5' represent one hydroxyl group protected by a protected radical or having the meanings of R 1 and R ₅ mentioned at the outset, one of the radicals U or V represents the R ₆ '-NH group, wherein R ₆ ' denotes a hydrogen atom. alkenyl group of 3 to 5 carbon atoms, alkyl or phenylalkyl group of 1 to 3 carbon atoms, the other of the radicals U or V represents one nucleophilic leaving group, or the radical U represents together with one β-positioned hydrogen atom of the radical E - oxygen , and V is an R ^ '- NH group, with R ₆ ' being defined as above, and any further cleavage of the protecting group used, or c) for the preparation of compounds of general formula I in which R ₆ is a hydrogen atom, an alkenyl group having 3 to 5 carbon atoms, BAD ORIGINAL alkyl or phenylalkyl group having 1 to 3 carbon atoms in the alkyl moiety, one compound of the general formula ^R K .... \ · A il 1 Ί Ν-Ε-Η r ₂ - 1 / .., in (VI) in which A, B. E and R ₉ are defined as in the beginning, but in radical E, two hydrogen atoms in one -CH ₂ - or CH ₃ -group of the radical are replaced by an oxygen atom, reacts in the presence of of a reducer of an amine of general formula (VII) in which G and R ₃ to R ₅ are as defined above and R ₆ 'represents a hydrogen atom, an alkenyl group of 3 to 5 carbon atoms, an alkyl or phenylalkyl group of 1 to 3 carbon atoms in the alkyl moiety, or d) for the preparation of compounds of general formula I, in which R 1 represents a hydrogen atom, an alkenyl group of 3 to 5 carbon atoms, an alkyl or phenylalkyl group of 1 to 3 carbon atoms in the alkyl moiety, one compound of the general formula (VIII) in which AV, E, Rj and R _? are defined as in the beginning, and R ₆ 'represents a hydrogen atom, the alkenyl group is 3 to 5 carbon atoms, an alkyl or phenylalkyl group of 1 to 3 carbon atoms in the alkyl moiety, reacted in the presence of a reducing agent with a compound of the general formula R 5 (IX) in which G and R ₃ to R ₅ are defined as in the beginning, but in the radical G two hydrogen atoms in one -CH ₂ - or N-group of the radical are replaced by an oxygen atom, or e) for the preparation of compounds of general formula I, in which A represents an -NH-CO group, E is optionally substituted by an alkyl group having 1 to 3 carbon atoms, an ethylene, n-propylene or n-butylene group, a R ₆ does not represent hydrogen, a compound of the general formula group, (X) in which B and G are defined as in the beginning E 'is optionally substituted by an alkyl group having 1 to 4 carbon atoms, ethylene, p-propylene or p-butylene BAD ORIGINAL L i R (go R ₄ 'represents no one hydroxyl group protected by a protected radical, or have the meanings of R 1 and R ₄ mentioned at the beginning, R _s represents a protected radical protected hydroxyl, amino or alkylamino group, or with the exception of an amino or alkylamino group, the meaning of R < 2 &gt; R 6 ', with the exception of hydrogen, has the meaning of R ₆ mentioned in the beginning or is a protecting group for an amino group, reacted with a carbonic acid derivative of the general formula W-CO-W (XI) in which W, which may be the same or different, always denote a nucleophilic leaving group as a chlorine or bromine atom, optionally with a halogen atom substituted by an alkoxy group having 1 to 3 carbon atoms or imidazolyl- (2) a group, and any subsequent cleavage of the protecting radical used, or f) to obtain a compound of general formula I in which A represents -CH ₂ -CH ₂ -group, R ₄ and R ₂ are not benzyloxy groups, R ₃ or R ₄ are not a nitro group and R 4 is not a benzyl group or alkenyl a group of 3 to 5 carbon atoms, a compound of general formula (XII) in which R ₁ to R 4, B, E and G are defined as initially, such as R ₂ or R ₄ do not denote a nitro group if R ₅ means an amino group to be hydrogenated, or I'll I (g) a compound of the general formula ^R i .., .- ,. e- . А. R6 1 // N -E-N-G-V L / xr ₄ R? B 1 / 'r ₅ (XIII) in which Rj go R _0, A, B, E u G are as hereinbefore defined, with, however, at least one of the groups Rj go R ₄ represents a hydroxyl group, or _R? - a hydroxyl group, an amino or alkylamino group having 1 to 3 carbon atoms, or R1 must represent one hydrogen atom, reacted with a compound of the general formula (XIV) Wherein R ₆ represents an alkyl group of 1 to 3 carbon atoms or also an alkenyl group of 3 to 5 carbon atoms when R ₆ is a hydrogen atom or also a phenyl group substituted with an alkyl group of 1 to 3 carbon atoms when R 1 or R ₂ is a hydroxyl group and / or R ₆ is 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 the radicals Rj to R ₅ represents a hydroxyl group, X together with the a-positioned hydrogen of the radical R _fJ represent a diazo group, or also if R 4 is hydrogen. an atom or R8 is an amino or alkylamino group they represent an oxygen atom or h) for the preparation of compounds of general formula I wherein A is not -CH = CH-group, R ₃ is a chlorine or bromine atom and R 1 is an amino or alkylamino group, a compound of the general formula BAD ORIGINAL JOI R; A 'R, T _v ^R 4 N-E-N-G- (' ΰ / \ . IN - R5 " (XV) in which Rp R ₂ , R ₄ , R ₆ , B, E, u G are defined as in the beginning, A 'is an exception of the -CH = CH group, has the meaning of A mentioned at the beginning and R ₅ represents an amino or alkylamino group of 1 to 3 carbon atoms, is halogenated, or i) for the preparation of compounds of general formula I in which A represents a -CO-CO group, B is a methylene group and E is optionally substituted by an alkyl group having 1 to 3 carbon atoms, ethylene, n-propylene or n-butylene group, a compound of general formula (XVI) in which Rj go R, E and G are defined as in the beginning, oxidized and optionally thereafter, the resulting compound of general formula I, in which B represents a carbonyl group, is converted by reduction to the corresponding compound of general formula I, in which B represents a methylene group, and / or a compound of general formula I in which A is not -CH = CH- or 102 -C = N'apyna a R ₆ represents a benzyl or 1-phenylethyl group, converted by catalytic hydrogenation to the corresponding compound <EMI ID = 0.0> of general formula I, in which R _o represents a hydrogen atom, and / or a compound of general formula I, 6 obtained which R or R ₄ represents a nitro group is converted by reduction to the corresponding compound of general formula I in which R _s represents an amino group and / or a compound of general formula I in which R ₆ is hydrogen and / or R 1; is an amino group, converted by acylation β the corresponding compound is general formula 1. in which R _(i represents an alkanoyl or alkoxycarbonyl group, and or R _s represents an alkanoylamino- .alkoxycarbonylamino- or bis (alkoxycarbonyl) amino group, such as the alkyl moiety to the alkyl moiety 3 carbon atoms, and / or an obtainable compound of the general formula I. wherein R ^ represents an amino group, R ₆ is not a hydrogen atom. R ₄ and R ₄ do not represent a cyano group. is converted in the corresponding diazonium m '. \ to the corresponding compound is general formula I. wherein R5 is a hydrogen atom, a hydroxyl or alkoxy group, or R8 is a hydrogen atom and R1 is a halogen atom, or they represent a cyano group, and / or the compound obtained is a general formula I can be converted into its salts obtained by acid addition, especially to physiologically acceptable salts with inorganic or organic acids. A method for the preparation of a medicament, characterized in that a compound of general formula I or a physiologically tolerated salt thereof is added in a non-chemical manner to one or more inert carriers and / or diluents.