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

Abstract

The invention relates to benzazepine derivatives with the formula to methods for their preparation and to medicinal products containing them. The compounds have such pharmacological properties that they are suitable for the treatment of sinus tachycardias of various origins and for the prevention and therapy of ischemic heart disease. 11 claims

Description

NEW BENZAZEPIN DERIVATIVES, THEIR PREPARATION AND

APPLICATION AS MEDICINAL PRODUCTS

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

It was discovered that new benzazepine derivatives with the general formula

(I)

They exhibit better pharmacological properties, namely, longer duration of action and fewer side effects, and show a stronger effect, especially on lowering the heart rate.

The subject of the present invention are the new benzazepine derivatives of the above general formula 1, their salts with inorganic or organic acids, methods for their preparation and the medicaments containing these compounds.

In the above general formula I stands for:

A - 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 with 1 to 3 carbon atoms and B - a methylene or carbonyl group or

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

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

G - 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 part 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 ₂ - an alkylenedioxy group is 1 or 2 carbon atoms.

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

R _s - hydrogen atom, alkyl, hydroxyl, alkoxy, amino.

alkylamino-, dialkylamino-, alkanoylamino-, alkoxycarbonylamino- or bis(alkoxycarbonyl)amino groups, in which the alkyl part may contain 1 to 3 carbon atoms, or one substituted trifluoromethyl group, methylamino- or ethylamino group, and

R _h - hydrogen atom, alkyl, phenylalkyl, alkanoyl and alkoxycarbonyl group, in which the _alkyl portion may contain 1 to 3 carbon atoms or an 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, we have in mind:

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

for R^ - hydrogen atom, methyl, ethyl, propyl, isopropyl, benzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, allylic, buten-2-yl, buten-3-yl, pentenyl, acetyl, propionyl, methoxycarbonyl,

BAD ORIGINAL

U.\ll propyl, 2-phenylethyl.

butsn-2-yl. buten-3-yl, acetyl, propionyl.

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

;a R _n - in·.>d<.tpt«den apium, methylova. etym»va. iz» >pr» »pil»'va. Beysilova, 1 -phenylethyl! 'va. phenylpropyl. allylic, pentenyl, formyl». 'va.

mepoxycarbonyl. ethoxycarbonyl. propoxycarbonyl or isopropoxy carbonyl group, for Rj together is R _? and/or R dioxy- or ethylenedioxy group, for E - ethylene. n-propylene. n-butylene, 1-methylethylene, 2-ethylethylene, 1-propylethylene, 1 -methyl-ppropylene, 2-methyl-p-propylene, 1-ethyl-p-propylene, 3-ethylp-propylene, 2-propyl-p-propylene, 2-methyl-p-butylene, 2hydroxy-p-propylene, 2-hydroxy-p-butylene or 3-hydroxy-p-butylene group for G butylidene. methylethylene, methylethylene group.

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

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

2-methylpropylidene,

-ethylethylene, propylidene, ethylene,

1-propylethylene or p12_

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-mshil-pnponu \cH'. Ήί or 2-vik|| ·”Κcu-n-npontιleš »lu pvna

G- McmuACiii’F’j. cmuAcii”lxi or 1-mstilsti.\enoVl group.

Rj - methyl.hydroxyl. benzyloxy- or alkoxygroup of 1 to 4 carbon atoms.

R.-, - Hydrogen apium. methyl. hydroxyl or mepoxy group. or Rj and R _? - methylenedioxy group.

R- ₅ - Hydrogen, fluorine, chlorine or bromine atom. trifluoromethyl. nitro-. alkyl or alkoxy group. having 1 to 4 carbon atoms,

R ₄ - Hydrogen, chlorine or bromine atom, methyl, methyl or cyano group or R ₁ and R ₄ together - methylenedioxy group.

R^ - Hydrogen apium, hydroxyl. mepuksi-. amino-. acetylamino-. epoxycar ^g 'onilzmin·..»-. biscepyoxycarbonyl.sh.shp»-.

dimeptylamino- or β.β.β-trifluoroethylamino group and

R ₍₎ - Hydrogen atom. Alkyl group with 3 to 6 carbon atoms. Alkyl. Benzyl. Acetyl or Epoxycarbonyl group.

and their salts, especially physiologically tolerable salts, obtained from organic or inorganic acids.

Particularly preferred compounds of the above general formula I are those which begin with:

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

SIι

With X pyia and B - carbonyl group or

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

E - n-propylene group.

G - ethylene group,

'BAD ORIGIN AL'

L—

' ! ‘ .! x Eve 4\ ι ¹ 1 - · 1 -11 λ 1. · J ι'· · ίχι. U .ί ί : ί ί ι ι ; \4'Hi Ί I! ρ·.ΊΊ.ι i ’ \.. :, ι ¹ ' ·4- ϊ ι 'pc : i'.i ' . pe u. . < . -p<. .: and . : ρ· ' 1 1 |· 1 D '· lx , · ' < ill' 'l< And- . re | . ι. !'·. Ή' > ?' ^ι ·..Κ ^; 1. X 44' i IX'- U i 4? Λ 1' Η 4 . e. e . ι, 1 -i I ' I l Γ\ tee 11 * - \ 1CI11UΛСΗ·..|I ί·. kx lb p e 11, i. !p - 1 ’ep rlden an··· ό. .o'' i;·i 'JJ meni ’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 .e. !'·:; and \ ·.·. U ··. '< ι . re Γι. 1. and theirs: Ι·ι .! 11 11 Λ ' 1!CHN i ’ JrUMU ell v HC'pC. .111114 i iu And \ ρ. .'No one km· Greeks ( ’! Λ :χΗ·. ' U'-?i’['CIUiCI iUCUU ’ u ’I'umc ci unions vC no. \e’ch .'Ril P · .••.ones : meth .'gu: .about B- .111 \ ί·. >gcii·...ml'uc h.i cue guiic’iue c o'4ii.am · ·.!·>rm\la

P

N H

The one who>

Au In are defined as In the beginning,

Rj' and RpredetA.lyavit one hydroxyl group. parts with -lirtsp radical, e.g. tri.methylsilyloxy-. acepy 'xi-. As]pyl·.'ke.i- and\i tri.hydro·'feranyl··'xisrup. or have the aipsliya pi RjiiRv given at the beginning. with a compound of the same formula

R'

R. ------ _T , .

k_;

/ 1' \ and

In which

'bad original'

L· . I ! I ! . I

!<. , c·.' ΐχ. Γ!·ίΛμ t • · Oh my!! ι '1 ’ CSO 1 VII· !r AND O! ' P'. 11 ! 1Щ' H i 1 l 1 ! . 3 Ci j fjtik .1 .. iMilj' ί.,ρ: 'UliZah IAN \· 1:· Ur 'U·. 1 /Ji Η 'ok<1'- U 41 IliClltp Л R ; and R _s and / - N'zh ·.··,.} 11 ,Ц.| ·.-11 years !!· -.j | •>a 11U • i ·. pa and l) ι.)·. 1 (III AND 1 ¹ μ ) 111 ι h ¹ ρ i’iOji. a,.| se Sh '3 1'1.1 Cat·.' X. ι '. CiiCH ai l μ 'M U 0.1 V State 3|1 · \. '1.0.1 n 1. 1! : 111 '. \ \ CH'SN. ι' p’' \1С’1 11' .1.1 llogCH alir.'M. X1c'ShaNsUlf·· Ί 111.X·. the.\ ' , l . ·. -. _Ί p 41U .sigh- or em”kv li- <elf·.'Nil·, «xi- group or with no :.·.Ή· ιΓιια . On dead ce possibly h the reaction mixture . ext. sieve parts 1 tic salt with . >general formula

C Rn 7

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

optionally followed by removal of the protecting group used.

The reaction is optionally carried out in a solvent or a mixture of solvents. e.g. in acetone, dimethylformamide. acetoacetate/dimethylformamide, dimethylsulfoxide or chlorobenzene and, if appropriate, depending on the reactivity of the radical Z, at temperatures between 1° and 150°C. preferably at the boiling point of the solvent used. The presence of an acid-binding agent is advantageous.

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

Any subsequent cleavage of the protecting group used takes place predominantly hydrolytically in an aqueous solvent, e.g.

Ik>ga, u :·.'ΐη·· ЧК11ЮЛ, B»>ga. tstrahydrofu'pail,.Water or girnkvaii IGga In the presence of an acid such as hydrochloric acid or sulfuric acid or In the presence of an a.al base such as sodium hydroxide or potassium hydroxide at temperatures between 1« and 1i<1 ^C C. preferably at the boiling temperature of the reaction mixture. The cleavage of the benzyl radical can be carried out hydrogenolytically e.g. with hydrogen In the presence of a catalyst such as platinum/carbon. In a solvent such as methanol. ethanol, ethyl acetate or acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 °C. preferably however at room temperature and a hydrogen pressure of oml to 7 bar, preferably however from 3 to 5 bar.

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

A compound with the general formula _ A (IV) reacts with a compound with the general formula

(V) in which

A, B, E and G are defined as at the beginning, and R ₅ ' each represents a hydroxyl group protected by a protective group.

BAD ORIGINAL

UCH Al.V’kvU- UAU

O radical, e.g. trimethylsilyl·. »kcu-. azp'oxy-, tetrahydrofuranyl*«oxy group or have the meanings of GC and R _s . mentioned at the beginning, one of the radicals U or V represents the R _M '-N1I-group, where R ₆ ' denotes hydrogen. alkeneL group with 3 to 5 carbon atoms, an alkyl or phenylalkyl group with 1 to 3 carbon atoms, the other of the radicals U or V represents a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulfonyloxy, orthotoluenesulfonyloxy or ethoxysulfonyloxy group or the radical U represents together with a β-positioned hydrogen atom of the radical E oxygen and V - an R^'-NH-apyna, where R ₆ ' is defined as above and optionally subsequent cleavage of the protective group used.

The reaction is conveniently 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 an excess of the compounds of general formula IV and/or V used and optionally in the presence of an acid-binding agent, e.g. an alcoholate such as potassium tert-butylate, an alkali hydroxide such as sodium or potassium hydroxide, an alkali carbonate such as potassium carbonate, an alkali amide such as sodium amide, an alkali hydroxide such as sodium hydride, a tertiary organic base such as triethylamine or pyridine, the latter of which can also serve as solvents, or in the presence of a reaction accelerator such as potassium iodide, depending on the reactivity of the nucleophilic replaceable radical, it is convenient to carry out the reaction at temperatures between 50 and 120 °C, e.g. at the boiling point of the solvent used. The reaction can also be carried out without a solvent. However, the reaction is particularly preferred.

I

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

The possible subsequent cleavage of the protective group used is preferably carried out hydrolytically 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 the boiling point of the reaction mixture. The cleavage of the benzyl radical can be carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as platinum/carbon, in a solvent such as methanol, ethanol, ethyl acetate or acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 °C, preferably however at room temperature and a hydrogen pressure of 0 to 7 bar, preferably however from 3 to 5 bar.

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

A compound with a general formula

N-E-H /

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

I<4

All· β which G u R ₄ go are defined kakm·. < β ιι.ι4.·.λ·,ίη·.> u R/ presktaVlyaVy hydrogen atom. alkenyl group with 5 to 5 carbon atoms, an alkyl or phenyl.gylovy group with 1 to 3 carbon atoms in the alkyl part.

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

It is particularly advantageous to carry out the 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 the general formula I in which R ₆ represents a hydrogen atom - in the presence of a hydrogenation catalyst, e.g. with hydrogen 6 in the presence of palladium/carbon at a hydrogen pressure of 5 bar. In this case, at the same time, any benzyl groups present can be cleaved off hydrogenolytically and/or the double bonds can be hydrogenated,

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

A compound with a general formula

BADORIG1N ^al £ > .

k/

N-E-N

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

(IX) in which R ₃ g or R ₅ and G are as defined at the beginning, however 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 conveniently carried out in a suitable solvent or solvent mixture such as methanol, ethanol, ethanol/ethyl acetate or dioxane at temperatures between 0 and 100 °C, preferably at temperatures between 20 and 80 °C.

It is particularly advantageous to carry out the 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 the general formula I in which R ₆ represents a hydrogen atom - in the presence of palladium/carbon at a hydrogen pressure of 5 bar. At the same time, any benzyl groups present can be cleaved off hydrogenolytically and/or the double bonds can be hydrogenated.

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

A compound with a general formula

H

CH ₂ —B— N—E'—

(X) in which

B and G are defined as in the beginning

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

Rj' and R ₄ ^{1 each} represent a hydroxyl group protected by a protecting radical, e.g. a trimethylsilyloxy, acetoxy, benzyloxy or tetrahydropyranyloxy group, or have the meanings of Rj and R ₄ mentioned at the beginning,

R ₅ represents a hydroxyl, amino or alkylamino group protected with a protecting radical or, with the exception of an amino or alkylamino group, has the meaning of R ₅ mentioned at the beginning and

R6” has, with the exception of hydrogen, the meaning of _R6 mentioned at the beginning 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 can be the same or different, always denotes a nucleophilic leaving group such as chlorine, bromine, an alkoxy group optionally substituted with a halogen atom having 1 to 3 carbon atoms or an imidazolyl-(2)-group, and optionally subsequent cleavage of the protective radical used.

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

The possible subsequent cleavage of the protective group used is preferably carried out hydrolytically 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 the boiling point of the reaction mixture. The cleavage of the benzyl radical can be carried out hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as platinum/carbon, in a solvent such as methanol, ethanol, ethyl acetate or acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 °C, preferably however at room temperature and a hydrogen pressure of 0 to 7 bar, preferably however from 3 to 5 bar.

f) For the preparation of compounds of general formula I, in which A represents a -C11-CH-,- group, Rj and R _? are not benzyloxyl groups, _R3 or _R4 are not a nitro group and _R6 does not represent a benzyl group or an alkenyl group of 3 to 5 carbon atoms:

Hydrogenation of a compound with the general formula

<-··. sn=sn R.· '7 \\ _R3 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 as defined at the beginning, with R ₃ or R ₄ not representing a nitro group if R ₅ represents an amino group.

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

g) A compound with the general formula

v ^R 3

X '••l

(ΧΗΐ) which

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

R ₆ -X (XIV) in which

R1 represents an alkyl group with 1 to 3 carbon atoms or also an alkenyl group with 3 to 5 carbon atoms when _R6 is a hydrogen atom, or also an alkyl group substituted with a phenyl group when R1 or _R2 is a hydroxyl group and/or _R6 is a hydrogen atom, and

X is a nucleophilic leaving group such as a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom, a methanesulfonyloxy, p-toluenesulfonyloxy or methoxysulfonyloxy group, or if at least one of the radicals R1 to _R5 represents a hydroxyl group, X together with the α-positioned hydrogen of the radical _R6 represent a diazo group, or also, if _R6 is a hydrogen atom or R6 is an amino or alkylamino group, they represent an oxygen atom.

The reaction is conveniently carried out in a solvent or 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, potassium tert-butylate or sodium hydroxide at temperatures between 0 and 150 °C, preferably however at temperatures between 20 and 120 °C.

If X represents a nucleophilic leaving group, the reaction is preferably carried out with an alkylating agent such as methyl iodide, dimethyl sulfate, ethyl iodide, diethyl sulfate, propyl bromide, allyl bromide, 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 a solvent.

If X together with the β-positioned hydrogen of the radical R ₆ represents a diazo 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 atom, the reaction is carried out 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 a -CH=CH - group, Rj is a chlorine or bromine atom and R ₅ is an amino or alkylamino group

A compound with the general formula (XV)

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

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

The reaction is carried out with a halogenating agent, e.g. chlorine, bromine, tribromophenol bromine or phenyliodide chloride, preferably in a solvent or a mixture of solvents, 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. Per mole of the compound of the general formula XV, which is used as a base or as a salt, e.g. mono-, di- or trihydrochloride, 1 or 2 moles or a small excess of halogenating agent are used. If a salt of a hydrohalic acid is obtained in the reaction, it can be isolated as such or, if desired, purified further using the base.

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

A compound with a general formula

(XVI) is oxidized, in which

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

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

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

And it's not -CH=CH- or

-C=No group

and R ₆ represent a benzyl or 1-phenylethyl group, the compound can be converted by catalytic hydrogenation into 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 1 or R ₄ represents a nitro group, it can be converted by reduction into 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 an amino group, this compound can be converted by acylation into the corresponding compound of general formula I, in which R ₀ represents an alkanoyl or alkoxycarbonyl group and/or R ₅ represents an alkanoylamino, alkoxycarbonylamino or bis(alkoxycarbonyl)amino group. the alkyl moiety always containing 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 carboxylic acid. R? and Rd do not represent a cyano group. it can be converted through ν. the corresponding diazonium salt into the corresponding compound of general formula I. in which R- is a hydrogen atom, a hydroxyl or alkoxy group or R ₅ is a hydrogen atom and R ₃ - a halogen atom or represent a cyano group.

The reduction that follows 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, or catalytic hydrogenation, is carried out in a solvent such as methanol, ethanol, ethyl acetate or acetic acid with hydrogen in the presence of a catalyst such as platinum or palladium/carbon at a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar and at temperatures between 0 and 75 °C, preferably 20 to 50 °C. The nitro and cyano groups present are also reduced at the same time.

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

The subsequent conversion of a diazonium salt, e.g. a fluoroborate, a hydrosulfate in sulfuric acid, a hydrochloride or a ,BAD ORIG]n _Al of xugpouogug, if necessary in the presence of copper or the corresponding copper(1) salt such as copper(1) chloride/hydrochloric acid, copper(1) bromide/hydrobromic acid or trisodium copper(1) tetracyanide is carried out at pH 7 and a slightly elevated temperature, e.g. at temperatures between 15 and 100 °C; The reaction with hypophosphorous acid is preferably carried out at -5 to 0 °C. The diazonium salt required for this purpose is expediently prepared in a suitable solvent, e.g. in water/hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric acid or dioxane/hydrochloric acid by diazotization of the corresponding amino compound with a nitrite, e.g. sodium nitrite or with a nitrous acid ester at low temperatures, e.g. at temperatures between -10 and 5 °C.

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

The compounds of the general formulae II to XVI, which are used as starting materials, are partly known in the literature and are prepared by known methods.

Thus, 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 a corresponding amine. The benzazepine of the general formula II required for this purpose is prepared by cyclization of the corresponding compound, for example by cyclization of a compound of the general formula

Ri...

X H

I

I N— CHo-CH

X...-·· 'sn ₂ ss/

OCH3

OCH3 (XVII)

or by ring closure of the corresponding o-amino compound and optionally subsequent catalytic hydrogenation and/or reduction of the 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 the general formula VI, which is used as a starting material, is prepared, for example, by reacting the corresponding benzazepine with the corresponding haloacetal and subsequent

hydrolysis.

A compound of general formula X, which is used as a starting material, is obtained, for example, by reduction of the corresponding nitro compound.

A compound of general formula XII, XIII, XV or XVI, which is used as a starting material, is preferably prepared by reacting the corresponding halogen compound with the corresponding amine and optionally subsequent cleavage of the protecting radicals which are used to protect the hydroxyl group.

As mentioned at the beginning, the new compounds of the general formula I and their physiologically tolerable salts with inorganic or organic acids exhibit valuable pharmacological properties, with limited side effects, e.g. with a weak antimuscarinic effect, they cause a sustained decrease in 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]-propanedihydrochloride,

B = 1-(7,8-guMem0kcu-1,3-guxugpo-2H-3-benzazepin-2-on-3-yl]-3[X-methyl-X-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane hydrochloride,

C = 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2dion-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- on-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]-propanehydrochloride,

F = 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on3-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-on-3-yl]-3[N-methyl-1-(2-(4-methoxyphenyl)-ethyl)-amino]-propane hydrochloride,

H = 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on3-yl]-3-[X-methyl-X-(2-(4-methoxyphenyl)-ethyl)-amino]-propanehydrochloride,

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

J = 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on3-yl]-3-(1\[-allyl-X-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propanehydrochloride and

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

Compared to

I... = l-[~.S-guanidino-1,2,3,4-tetrahydro-5H-2-benz-'pepin- 1-'H2-yl]-3-[N-methyl-N2-(3N-dimethylphenyl)-ethyl''-amino]-propane\lk|p<>\ V »pug uc investigated as follows:

1. Effect on heart rate in cats:

The effect of the test substance on heart rate was studied in ~ cats of both sexes with average weight

2.5 - 3.5 kg was given 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, was injected into the saphenous vein and duodenum, respectively.

The heart rate was recorded on a Grass polygraph before and after the administration of the substance, from the electrocardiogram (precordial lead) using a Grass tachograph.

The following table contains the values found:

substance dose mg/kg decrease in heart rate half-life (min) A 1.0 i.v. -55% >120 In 1.0 i.v. -45% >120 With 1.0 i.v. -44% >90 D 1.0 i.v. -41% 80 It is 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. Effect on atrial heart rate in guinea pigs:

Isolated spontaneously pulsating atria of guinea pigs of both sexes weighing 300-400 g were studied in Tyrode solution. The nutrient solution was supplied with carbogen (95 % O _? + 5 % CO2) and maintained at a constant temperature of 30 °C. Contractions were recorded isometrically using a strain gauge on a Grass polygraph. The studied substances were added in different concentrations for 60 min. to the physiological solution.

Concentration curves were constructed from the maximum effects and from them the concentrations that reduce the heart rate by about 30% ( = EC-6O ₃₀ ) were determined.

The following table contains the values found:

substance EC-60, _n [ _M g/ml] A 0.030 With 0.097 D 0.058 It is 0.066 F 0.014 G 0.014 H 0.0079 I 0.063 J 0.050 K 0.014

3. Acute toxicity:

The acute toxicity of the test substances was determined in mice (observation time 14 days) after intravenous or oral administration:

i Substance '______toxicity (BW _P ) '

I

I_______А___ί· ^ν ·______1350 mg/kg r.o. {

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

The dose required to achieve the desired effect is expediently 0.03 to 0.04 mg/kg body weight, preferably 0.07 to 0.25 mg/kg body weight, once or twice daily. The compounds of the general formula I prepared according to the invention, as well as the physiologically tolerable salts with inorganic or organic acids, optionally in combination with other active ingredients, together with one or more inert, customary carriers and/or diluents, e.g. with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, carboxymethyl cellulose or fat-containing substances such as hard fat, or suitable mixtures thereof, are processed into conventional pharmaceutical preparations such as tablets, dragees, capsules, powders, suspensions, drops, ampoules, juices or suppositories.

The following examples should explain the invention in more detail:

Preparation of the 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, 600 ml of thionyl chloride were added dropwise with stirring over 2 hours. After the gas evolution was complete (16 hours), the mixture was refluxed for another hour. After removal of the volatile components, the residue was distilled under vacuum.

Yield: 486 g (80.8% of theoretical value)

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 aminoacetaldehyde dimethyl acetal and 315 ml of triethylamine in 2.2 l of methylene chloride and stirred for another hour at 16-18 °C. It was then extracted repeatedly with water, dried over magnesium sulfate and evaporated. The resulting oil crystallized slowly.

Yield: 608 g (95% of theoretical value)

Melting point: 66-69 °C

c) 7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-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 standing for 17 hours at room temperature, the mixture was poured onto ice. The precipitated crystals were filtered, washed with water until neutral and dried.

Yield: 350 g (75.4% of theoretical value)

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-3benzazepin-2-one and 1.5 g of palladium/carbon (10%-ene) in 200 ml of glacial acetic acid was hydrogenated at 50 °C and a hydrogen pressure of 5 bar. After filtering off the catalyst, the solvent was evaporated under vacuum and the residue was dissolved in methylene chloride. After extraction with sodium bicarbonate solution and washing with water, it was dried over magnesium sulfate, concentrated and purified on silica gel with methylene chloride and then with increasing portions of methanol <to 1i /L7. , < /.

Yield: 12.6 g (57% of theoretical value).

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 was added dropwise a solution of 1.8 g of glacial acetic acid in 10 ml of dioxane, boiled for 3 hours under reflux. 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 theoretical value).

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) 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 were hydrogenated at 25 °C and 5 bar hydrogen pressure for 8 hours in the presence of 10% palladium/carbon. After removal of the catalyst, the solvent was distilled under vacuum.

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

Example E

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

2.0 g (0.007 mol) of N-(2,2-dimethoxyethyl)-2,5-dimethoxyphenylacetamide were poured into 3 ml of polyphosphoric acid and stirred for 60 min at 90 °C. Then it was mixed with ice water, the precipitated product was filtered and dried.

Yield: 0.98 g (64% of theoretical value).

Melting point: 188-191 °C.

Example F

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

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

Yield: 40.1% of theoretical 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 boiled under reflux for 6 hours.

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

Yield: 9.6 g (50% of theoretical value).

IR spectrum (methylene chloride): 3300 cm³/ ^l (NH)

2830 cm-ι (OSH _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 precipitate that formed was filtered off on a nutch filter, washed with glacial acetic acid, then with acetone/ether and dried.

Yield: 5.3 g (8% of theoretical value)

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-3benzazepine hydrobromide were dissolved in 100 ml of hot water, mixed with 1.3 g of anhydrous sodium acetate and heated for 1 hour at 90 °C. The reaction mixture was cooled, washed with cold water and dried.

Yield: 2.9 g (88% of theoretical value).

Melting point: 235 °C (decomposition)

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

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

Yield: 87% of theoretical value.

Melting point: 110 °C (decomposition)

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 ethyl acrylic acid ester was allowed to stand overnight at room temperature. The resulting addition product was dissolved in 40 ml of ether and added dropwise over 15 min, with stirring, to a suspension of 0.3 g (0.008 mol) of lithium aluminum hydride in 20 ml of ether. After 5 hours of refluxing, the mixture was cooled and then 30 ml of saturated aqueous sodium sulfate solution was added dropwise. The precipitate formed 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 theoretical value)

IR spectrum (methylene _chloride ): 3600, 3230 cm- ¹ (OH) m/e = 253 ( _C14H23HO3 : 253.35)

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

To 4 g of 3-[N-methyl-L-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]propanol were added 2.75 g of benzenesulfonic acid chloride. After standing for 1/2 hour, it was dissolved in methylene chloride, washed with

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

Yield: 1 g (17% of theoretical value)

_{C14H22C1NO2 ( 271.8} )

Calculated: C 61.86 I 8.15 N5.15

Found: C 62.00 N8.00 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)aminopropanol are 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 is added dropwise. After warming to room temperature, it is boiled under reflux for 2 hours. It is evaporated to dryness, then dissolved in methylene chloride and washed with 2 N sodium hydroxide and water. The organic phase is 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 another 40 min at 60-70 °C.

Yield: 1.8 g (48% of theoretical value).

Melting point: 175-180 °C.

Example L

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

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

Yield: 0.9 g (43.8 % of theoretical value)

Melting point: 162-163 °C.

Receiving the final products

Example 1

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

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

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, while cooling with ice water, to 7^ ml (0.72 mol) of 1-bromo-3-chloropropane in 30 ml of dimethyl sulfoxide. After a short time, the oily precipitate began to crystallize. The precipitate was filtered on a suction filter, dissolved in acetone, precipitated once more with water, filtered and dried.

Yield: 155.5 g (8 7.3 % of theoretical value).

Melting point: 101-103 °C

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

BAD ORIG* ^Nmu

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

Yield: 6.9 g (70.3% of theoretical value)

Melting point: 190-191 °C (dec.).

Example 2

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

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 3.6g (0.022 mol) N,N'-carbonyldiimidazole were boiled for 33 hours in 100 ml acetonitrile. The solvent was removed in vacuo and the residue was purified over Alumina WoelmN, Akt III, with methylene chloride and 15% acetone as eluent. The fractions were concentrated in vacuo, the residue was dissolved in acetone and precipitated with ethereal hydrochloric acid (ether saturated with hydrogen chloride).

Yield: 1.1 g (21.7% of theoretical value).

Melting point: 125-130 °C.

Example 3 with

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-1H-(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-on-3-yl)-3chloropropane with N-[2-(2-amino-3,5-dichlorophenyl)-ethyl]-methylamine. Oil

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

285 pt (0.14)

306 pt (0.10)

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

840 cm' ¹ O-CH ₃

655 spg 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-on-3-yl]-3-[N-methyl-N - (2 - (3,4-dimethoxyphenyl) -ethyl) - amino] propanedihydrochloride

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

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

Yield: 6.2 g (92% of theoretical value).

Melting point: 137 °C (decomposition).

When equimolar amounts of ethanolic hydrochloric acid are used, the hydrochloride is obtained with a mp of 165-168 °C.

Example 5

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

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

Obtained similarly to example 1a by reaction of 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one with 1-bromo-3-chloropropane (yield: 50% of theoretical value) or similarly to example 4 by catalytic hydrogenation of 1-(7,8-dimethoxy-1,3-dihydro-2H-3benzazepin-2-one-3-yl)-3-chloropropane (yield: 88% of theoretical value)

value).

Melting point: 84-85 °C

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

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

Yield: 75.2 % of theoretical value.

Melting point: 135-137 °C (dec.).

Example 6

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

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

Yield: 1.5 g (48.5% of theoretical value).

Melting point: 270-271 °C (dec.)

Example 7

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

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

Yield: 76.2 % of theoretical value)

Melting point: 139-142 °C

Example 8 1-[7,8-guMcmokcu-1,3,4,5-mempaxugpo-2H-3-6eH3a3enuH-2-oH-3-UA]-3-[Nmethyl->T(2-(4-methoxyphenyl)-ethyl)-amino]-propane hydrochloride

Prepared similarly to example 4 by catalytic hydrogenation of 1-[7,8-dimethoxy-1,3,-dihydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-X-(2-(4-methoxyphenyl)-ethyl)-amino]-propane.

Yield: 73.3 % of theoretical value.

Melting point: 175-177 °C.

with

Example 9

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

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

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

Yield: 72.1 % of theoretical value.

Melting point: 75-79 °C.

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

3-[N-methyl-A-(2-(3,4-dimepoxyphenyl)-ethyl)-amino]-propanehydrochloride

It was prepared similarly to Example 16 by reacting 1(7,8-methylenedioxy-1,3-dihydro-2H-benzazepin-2-on-3-yl)-3-chloropropane with N-methyl-N-2-(3,4-dimethoxyphenyl)-ethylamine.

Yield: 77.2 % of theoretical value.

Melting point: 185-187 °C.

BAD ORIGINAL

I

Example 10

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

Obtained pid-yun ? in example 4 by catalytic hydrogenation of 1-[7,8-methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-3-[Nmethyl-N)-2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane.

Yield: 77.3 % of theoretical value)

Melting point: 210-212 °C.

Example 11

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

To a solution of 0.22 g (0.5 mol) 1-[7,8-dimethoxy-1,3,4,5tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[β1-(2-(3,4dimethoxyphenyl)-ethyl)-amino]-propane, 0.5 ml 37% formalin solution, 2 ml acetonitrile and 0.1 g sodium cyanoborohydride were added at room temperature 0.05 ml glacial acetic acid. After two hours another 0.05 ml glacial acetic acid was added and stirred for 1/2 hour. The work-up was 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 through silica gel.

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

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

510 cm' ¹ (arom. C=C)

Melting point: 137 °C (decomposition).

BAD ORIGINAL

Example 12

1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[1methyl- N- (2- (3,4 -g imepoxyphenyl) - ethyl) - amino ] propanedihydrochloride g (0.075 mol) N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-propylmethylamine were heated with 7.2 g (0.036 mol) 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 and twice with water, dried over sodium sulfate and evaporated. The residue was purified by chromatography on silica gel. (particle size: 0.063-0.2 mm; eluent: methylene chloride/methanol = 10:1). The product thus obtained was dissolved in acetone and the dihydrochloride was precipitated with ethereal hydrochloric acid.

Yield: 8.0 g (45% of theoretical value).

Melting point: 135-136 °C (dec.).

Example 13

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[1H-methyl- N- (2-(4-acetylamino-3,5-dichlorophenyl)-ethyl)-amino]-propane g (0.0063 mol) 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-(4-amino-3,5-dichlorophenyl)ethyl)-amino]-propane in 50 ml chloroform and 0.7 g (0.007 mol) triethylamine were mixed in portions at boiling temperature with a total of about 0.8 ml acetyl chloride and boiled for several hours. After cooling to room temperature, it was washed with water. The aqueous phase was made strongly alkaline with 2 n sodium hydroxide solution. and extracted with methylene chloride. The separated organic phase was dried over sodium sulfate and evaporated. The crude product thus obtained was purified by chromatography on silica gel (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-on-3-yl]-3-[bH methyl-X-(2-(4-amino-3,5-dibromophenyl)-ethyl)-amino]-propane

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

Melting point: 105-110 °C.

Example 15

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

0.22 g (0.5 mmol) 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[1H-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]42propane are heated together with 0.2 ml of 37% formalin solution and 0.2 ml of 100% formic acid for 20 min to 90-100 °C. The processing continues 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-on-3-yl]-3-[N-methyl-X-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane

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

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-on-3yl]-3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane

To a solution of 2.77 g (10.0 mmol) of 3-(7,8-dimethoxy-1,3,4,5-trifluoro- ^2H -3- ^benzaldehyde and 1.95 g (10.0 mmol) of ^.1 -methyl-2-(3,4-dimethylphenyl)-ethylamine in 40 ml of methanol were added 1.26 g (20 mmol) of sodium cyanoborohydride, and the pH was maintained at 6- ^p by adding hydrochloric acid. At this pH value, the mixture 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 made alkaline, extracted 3 times with methylene chloride, the organic phase was concentrated and dried over silica gel. A weak 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-on-3-yl]-3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)amino]propanedihydrochloride ^a ) 1-(8-methoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane

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

Yield: 23% of theoretical 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

The process described in Example 4 was carried out by catalytic hydrolysis of 1-(6-methoxy-1,2-dihydro-3H-3-phenyl-3-methyl-5-yl)-3-chloro-3-methyl-1-methyl-3

Yield: '7 _of te·.'r. ip·· «ishkt.

IR-cnekmhp (methylene chloride.·: 1ό45 cm' ¹ <<'.·· in> 1-[8-methoxy-1,3.4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]3-[N-methyl-N-( 2-(3,4-dimethoxyphenylethyl)-amino]-propanedihydrochloride

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

Yield: 14% of theoretical value.

Melting point: 118-121 °C.

Example 19

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

Prepared similarly to Example 12 from N-[3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-(4-amino-3-chlorophenyl)-ethyl bromide. Oil.

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

1645 cm ¹ (C-O)

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-on-3-yl]-3-[Methyl-N- (2-(4-amino-3,5-dichlorophenyl)-ethyl)-amino]-propane

BAD ORIGINAL

Prepared similarly to example 12 om N-[3-(7,8-guMemokcu-1,3,4,5tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-ethylamine and 2-(4amino-3,5-dichlorophenyl)-ethyl chloride. Oil.

IR spectrum (methylene chloride): 3390, 3480 cm' ¹ (NH _? )

1650 ^cm'1 (CO)

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

Example 21 o

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

Prepared similarly to Example 12 from N-[3-(7,8-gamma-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-(4-amino-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-on-3-yl]-3-[N-methyl-N-(2-(4-amino-3,5-dibromophenyl)ethyl)amino]propane

Prepared similarly to Example 12 from N-[3-(7,8-gamma-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-propyl]-methylamine and 2-(4-amino-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-on-3-yl]-3-[1H-methyl-N-(2-(4-ethoxycarbonylamino-3,5-dichlorophenyl)-ethyl)-amino]propane

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

3,5-dichlorophenyl)-ethyl)-amino]-propane and ethyl ester of chloroformic acid. Oil.

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-on-3-yl]-3-[Nmethyl-N-(2-(4-bis-(ethoxycarbonyl)-amino-3,5-dichlorophenyl)-ethyl)aminopropane

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

3,5-dichlorophenyl)-ethyl)-amino]-propane and ethyl ester of chloroformic acid. Oil.

IR spectrum (methylene chloride): 1650 cm ¹ (CO-N<)

1730 cm' ¹ (CO-O-)

1760 cm'· ¹ (CO-O-)

1800 cm' ¹ (CO-O-)

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

Example 25

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-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-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[>1-methyl-1H-(2-(4-amino-3-cyano-5-fluorophenyl)-ethyl)-amino]-propane and ethyl chloroformate 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 with

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

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

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

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

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

Example 27

1-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-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-on-3-yl)-3-chloropropane and 2-(4-amino-3,5-dichlorophenyl)-N-methyl-ethylamine. Oil.

IR spectrum (methylene chloride): 3390, 3480 cm- ¹ (NH ₂ )

1655 ^cm'1 (CO)

UV spectrum (ethanol): λ max.: 238 nt (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-on-3-yl]-3-[N-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-on-3-yl)-3-[1-methyl-1H-(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-on-3-yl]-3-[1-ethyl- N-(2-(4-amino-3,5-dibromophenyl)-ethyl)-amino]-propane

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

3,5-dibromophenyl)-b1-mesyl-ethylamine. Oil.

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-on-3-yl]-3-[N-methyl-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-on-3-yl)-3-chloropropane and 2-(4-amino-

3,5-dichlorophenyl)-1-methyl-ethylamine.

Melting point: 94-104 °C.

Example 31

1-[7,8-dimepoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-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-on-3-yl)-3-chloropropane and 2-(4-amino-

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

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

IR spectrum (methylene chloride): 3390, 3480 cm' ¹ (NH ₂ )

1655 cm ¹ (C-O)

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-on-3-yl]-3-[N-methyl-N-(1-methyl-2-(4-amino-3,5-dichlorophenyl)-ethyl)-amino]-propanehydrochloride

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

3,5-Di([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-on-3-yl]-3-[]N-(2-(4-amino-3,5-dichlorophenyl)-ethyl)-amino]-propane hydrochloride

51'

Prepared similarly to Example 56 from 1-1,1-cymepyrene, xy-1,3,4,5-tetrahydro-2H-3-bsenza-epin-2-('H-3-yl1-3-x,1,3-propane) and 2-<4-amino·»-

3.5-dichlorophenyl ,·- 1-methyl-K-methyl-ethyl\shn.

Melting point: 236-241. °C.

Example 34

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

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

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

IR spectrum (methylene chloride): 3390, 3480 cm' ¹ (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-on-3-yl]-3-[N-methyl-N-(2-(3,5-dichloro-4-hydroxyphenyl)-ethyl)-amino]-propanehydrochloride

Prepared similarly to Example 56 from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-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-on-3-yl]-3-[N-methyl-1-(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-on-3-yl)-3-chloropropane and 2-(3-chloro-5fluoro-4-R,R,p-trifluoroethylaminophenyl)-l-methyl-ethylamine.

m/e = 545/547 (C ₂₆ H ₃₂ C 1 F ₄ N ₃ O ₃ ; 546.03)

Example 37

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

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

m/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-on-3-yl]-3-[N-methyl-N-(2-(4-amino-3-chloro-5-trifluoromethylphenyl)-ethyl)-amino]propane

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

IR spectrum (methylene chloride): 3410, 3510 cm' ¹ (NH ₂ )

1650 ^cm'1 (CO)

1610, 1520 cm- ¹ (C=C)

S'?

*· Lm/

2800 cm' ¹ (N-alkyl)

2830 ^cm'1 (OCH3)

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-on-3-yl]-3-[\C ........................................

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

IR spectrum (methylene chloride): 3400, 3490 cm' ¹ (NH ₂ )

2830 cm' ¹ (OHN ₃ )

2220 cm ⁴ (CN)

1650 ^cm'1 (CO)

Example 40

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

Prepared similarly to Example 16 from 1-(7,8-dimethoxy-1,3dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane and 2-(3,4dimethoxyphenyl)-b1-benzylethylamine.

Yield: 51% of theoretical value

Melting point: 102 °C (decomposition).

Example 41

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

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

Yield: 48% of theoretical value

Melting point: 160-162 °C.

is

Example 42

1-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl]-3-(>1benzylmethylamino)-propanhydrochloride

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

Yield: 92% of theoretical value

Melting point: 208-209 °C.

Example 43

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

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

Yield: 85% of theoretical value

Melting point: 162-164 °C.

Example 44

1-[8-Propoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-2-[M-methyl-M(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-ethane hydrochloride

Prepared similarly to Example 16 from 1-(8-propoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-2-chlorobutane and 1N-methyl-2-(3,4-dimethoxyphenyl)-ethylamine.

Yield: 31% of theoretical value

Melting point: 155-157 °C.

With Example 45

1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-4-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-butane hydrochloride Prepared similarly to example 16 from 1-[7,8-dimethoxy-1,3-dimethoxy-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-on-3-yl]-3-[\methyl-N-(2-(3,4-methylenedioxyphenyl)-ethyl)-amino]-propanehydrochloride

Obtained similarly to example 4 by catalytic hydrogenation of

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

Yield: 72% of theoretical value.

Melting point: 191-193 °C.

Example 47

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

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

Yield: 81% of theoretical value.

Melting point: 152-154 °C.

Example 48

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[>1allyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propanehydrochloride

3.1 g (0.007 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-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 residue obtained was purified over an alumina column (300 g neutral Aktivitgt III) (eluent: methylene chloride with 2% acetone). The hydrochloride was then precipitated.

Yield: 40% of theoretical value.

Melting point: 153-155 °C.

Example 49

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-propyl-?4-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propanehydrochloride

Prepared by example from 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[X-',2-{3,4-dimethylphenyl}-ethyl}-amino}-butane and 1-bromophenyl.

Yield: 53% of theoretical value.

Melting point: So °C (decomposition).

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

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

2-nitro-phenyl)-ethylamine.

Yield: 70% of theoretical value.

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

1510 and 1345 cm' ¹ (NO ₂ )

NMR spectrum (CDCy^O): δ = 8.10 ppm, d(J=9Hz), 2H (aromat.), (4-nitro-compound) δ = 7.83 ppm, d(J = 7Hz), 2H (aromat.), (2-nitro-compound)

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

3-UA]-3-[N-MemuA-N-(2-(2-aMUHO 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-benzazepine-2oH-3-uA)-3-[N-MemuA-N-(2-(2- and 4-nitrophenyl)-ethyl)-amino]-propane.

Yield: 34% of theoretical value.

Melting point: 100 °C (decomposition).

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

Calculated: C 64.34 H 7.65 N 9.38 Cl 7.91

Found: C 63.60 Η 7.20 N9.28 Cl 7.94

Example 52

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

1.8 g (0.004 mol) of an isomeric mixture of 1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-[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 acetic anhydride. It was 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-benzodi azepin-2-one-3-yl]3-[N-methyl-K-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane a j N-13-[N'-methyl-H'-(2-(3,4-dimethoxyphenyl)-ethyl)-alkyl]propyl]-2-(2-amino-4,5-dimethoxyphenyl)-ethylamine

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

Yield: 2.9 g (53% of theoretical value).

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-2-one-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 theoretical value).

Melting point: 116-117 °C.

Example 54

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

Prepared similarly to Example 16 by reacting 1-[

Yield: 24.2 % of theoretical value)

Melting point: 106 °C

Example 55

1- [7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-2-hydroxy-·> 3-[[n-methyl-H-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propav

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

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

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

Yield: 7.8 g (55.2 % of theoretical value).

IR spectrum (methylene chloride): 3600 cm' ¹ (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-dion-3-yl]-

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

3.5 g of selenium dioxide were added at 70 °C to 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-on-3-yl]-3-[X-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-amino]-propane hydrochloride. 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 methylene chloride + 1% ethanol as eluent. The fractions were concentrated in vacuo, the residue was dissolved in acetone and the hydrochloride was precipitated with ethereal hydrochloric acid.

Yield: 13.8 g (90.7 % of theoretical value).

Melting point: 196-197 °C.

Example 57

1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-2hydroxy-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-on-3-yl)-2-hydroxy3-[H-methyl-L-2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane, however, in ethanol at 50 bar and 70 °C with platinum oxide catalyst.

Yield: 37.5 % of meopem. value.

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

C _2Q H ₃ 6 ^N 2°6 (472.6)

Calcd.: 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-on-3-yl]-3-[N-methyl-N-(2-(4-nitrophenyl)-ethyl)-amino]-propanehydrochloride

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

Yield: 56.5 % of theoretical value.

Melting point: 182 °C.

Example 59

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[1H-methyl- N-(2-(3-nitro-4-acetylaminophenyl)-ethyl)-amino]-propanedihydrochloride

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

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

Yield: 230 mg (57.7% of theoretical value).

Melting point: 170 °C.

Example 60

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

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

Yield: 68.7 % of theoretical value.

Melting point: 203 °C.

Example 61

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

g (0.0045 mol) 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]propane were mixed with 15 ml of acetic anhydride 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 over alumina (neutral, activity II) with methylene chloride as eluent.

Yield: 1.5 g (68.5 % of theoretical value).

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

1640 cm' ¹ (CO) ^27^36^2^^6

Calculated: C 66.92 H 7.49 N 5.78

Found: C 66.75 H 7.44 N 5.80

Example 62

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

2.5 g (0.00565 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[1H-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]propane and 2.45 g (0.024 mol) of triethylamine were dissolved in 20 ml of methylene chloride. After addition of 2.6 g (0.024 mol) of ethyl chloroformate, the mixture 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 over alumina (neutral, activity II) with methylene chloride as eluent.

Yield: 1.5 g (51.6 % of theoretical value).

IR spectrum (methylene chloride): 1690, 1650 cm' ¹ (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-on-3-yl]-3-[Xmethyl-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-on-3-yl]-3-chloropropane with N-methyl-2-(2,6-dichlorophenyl)-ethylamine.

Yield: 70.5 % of theoretical value.

Melting point: 147 °C

Example 64

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

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

Yield: 57.6 % of theoretical value.

Melting point: 161 °C.

Example 65

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

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

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

Yield: 20% of theoretical value)

Melting point: 114 °C.

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

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

Yield: 72% of theoretical value.

IR spectrum (methylene chloride): 2830 cm' ¹ (CDCl3)

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=8Hz), 1H (olefin); 6.35, d(J=8Hz), 1H (olefin)

Example 66

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

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

Yield: 59% of theoretical value.

Melting point: 188-189 °C.

Example 67

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

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

Prepared similarly to example 1a by reacting 7,8-dimethyl-1-methyl-4-tetrahydro-2H-3-benzazepine-2,4-dione m.p.: 235 ^°C (100°C) with 1-chloro-3-chloropropane.

Yield: 26 A of theoretical value) IR spectrum (kVr): 1660 cm' ¹ (CO)

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

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

Yield: 35% of theoretical value.

Melting point: 163-164 °C.

Example 68

1-[7-benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on3-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-on-3yl)-3-chloropropane

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

BAD ORIGINAL

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

Point of p'11'pence: ^C C.

b 1 -1 -xug p* »k u u - 8 -bepz ylic si-1,3,4,5-memp axug ro-2 II - 3benzazepin-2-on-3-yl]-3-chl*>rpropane and 1-< 7-benzyl«»xy-8-hydr*xsi-

1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-chloropropane g (0.07 mol) 1-(7,8-goxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl)-3-chloropropane and 10.6 g potassium carbonate in 250 ml dimethyl sulfoxide were mixed with 19.5 g (0.154 mol) benzyl chloride. The mixture was stirred for 2 days at room temperature, 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 was carried out with silica gel and with methylene chloride and 3% acetone as eluent.

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

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-3benzazepin-2-on-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-on-3yl)-3-chloropropane with N-methyl-2-(3,4-dimethoxyphenyl)-ethylamine.

Yield: 75.4% of theoretical value.

Melting point: 128-129 °C.

'bad original'

Example 69

1-[7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-1-(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-on-3yl)-3-chloropropane with N-methyl-2-(3,4-dimethoxyphenyl)-ethylamine.

Yield: 47.2% of theoretical value.

Melting point: 157-158 °C.

Example 70

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

0.52 g (0.001 mol) of 1-[7-hydroxy-8-benzyloxy-1,3,4,5-tetrahydro2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-amino]-propane were 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 on a nutch 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 theoretical value).

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

1640 cm ¹ (CO) ^C 24 ^H 32 ^N 2°5 ^{x 1/2 H} 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-on3-yl]-3-[\-methyl-X-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]propane dihydrochloride

0.52 g (0.001 mol) of 1-[7-benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[H-methyl-\-(2-(3,4-dimethoxyphenyl;ethyl)-amino]-propane were dissolved in 30 ml of dimethylformamide and mixed with 50 mg of a 50% dispersion of sodium hydroxide (in oil). The mixture was heated for 30 minutes at 60 °C, mixed with 0.1 ml of dimethyl sulfate and heated for a further 2 hours at 60 °C. The dimethylformamide was distilled off in vacuo, the residue was dissolved in methylene chloride, the organic phase was washed with water and concentrated in vacuo. The resinous residue was purified with aluminum hydroxide (neutral, activity II) with methylene chloride as eluent. The oil obtained was dissolved in acetone and by mixing with ethereal hydrochloric acid the dichloride is precipitated.

Yield: 250 mg (41% of theoretical value.

Melting point: 117-120 °C.

with

Example 72

1-[7-methoxy-8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on3-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-on-3yl]-3-[1H-methyl-1H-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane with dimethyl sulfate.

Yield: 70% of theoretical value.

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

NMR spectrum (CDClyDoO): δ = 2.3 ppm. 3H(NCH^); 5.1 ppm, s, 2H (benzyl); 6.5-6.8 ppm, m, 5H (aromat.); 7.4 ppm, s, 5H (aromat.).

Example 73

1-[7-hydroxy-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3yl]-3-[1H-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propanehydrochloride

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

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

Yield: 45.2% of theoretical value.

IR spectrum (methylene chloride): 3530 cm' ¹ (OH)

2830 st' ¹ (OSH ₃ )

1655 ^cm'1 (CO)

^C 25 ^H 34 ^N 2°5 ^xHC1 ( ⁴⁷⁹⁰ )

Calculated: C 62.69 H 7.36

Found: C63.15 N 7.57

N5.85

N5.64

Example 74

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

Prepared similarly to Example 70 from 1-[7-methoxy-8-benzyloxy1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane by catalytic debenzylation.

Yield: 29.4% of meop. value.

IR spectrum (methylene chloride): 1640 cm' ¹ (CO)

C _{? 5H44N ? O5} (442.56)

Calcd.: C 67.85 H 7.74 N 6.33

Found: C 67.50 H 7.97 N 6.18

Example 75

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benz a3enuH-2-oH-3-UA]-3-[Nmethyl-H-(2-(3,4-dimethylphenyl)-ethyl)-amino]-propanedihydrochloride

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

Yield: 54.3 % of theoretical value.

Melting point: 170-172 °C.

Example 76

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-( ^N- methyl-N-(2-(4-tert-butylphenyl)-ethyl)-amino]propane dihydrochloride

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

Yield: 49.4 % of theoretical value.

Melting point: 146-149 °C.

Example 77

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

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

Yield: 55.3 % of theoretical value.

Melting point: 67-69 °C.

Example 78

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

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

Yield: 57.8 % of theoretical value.

IR spectrum (methylene chloride): 1650 cm' ¹ (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 C1 7.34

Example 79

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

a) 1-(7,8-dimethyl-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane ~3

Prepared similarly to example 1a by reacting ~.8dimethyl-1,3-dihydro-2H-3-benzazepin-2-one (melting point: 226-224 °C) with 1-bromo-3-chloropropane.

Yield: 99% of theoretical value.

Melting point: 62-64 °C.

b) 1-[7,8-Dimethyl-1,3-dihydro-2H-3-6enzazepin-2-on-3-yl]-3-[Mmethyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propanehydro,\oride

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

Yield: 70.9 % of theoretical value.

Melting point: 105-107 °C.

Example 80

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

Obtained similarly to example 4 by catalytic hydrogenation of

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

Yield: 83.8 % of theoretical value.

Melting point: 154-157 °C.

Example 81

1-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-2-methyl-3[P-methyl-l-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane χ .μ ψ·Γιρηη an.

Yield: ''7.5''7. in meop. cm·, shnost.

Melting point: 45-47 °C.

όι 1-[7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-2methyl-3-[H-methyl-\-'2-(3 _< 4-dimethoxyphenyl)-ethyl)-amino]-propane

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

Yield: 36% of theoretical value.

Melting point: 30-32 °C.

Example 82

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-2methyl-3-[N-methyl-1H-(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-on-3-yl)-3-[>N-methyl-N-(2-(3,4-dimethylphenyl)-ethyl)-amino]-propane.

Yield: 73.7 % of theoretical value.

Melting point: 99-101 °C.

Example 83

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

,ο

2.45 g (δ.005 mol) of 1-[7,8-dimethoxy-1,3,4,5-mempaxugpo-2H-36eH3a3enuH-2-oH-3-UA]-3-[N-MemuA-N-<2-( 3.4-dimepk'ksiphenyl *-ethyl)a.\n<']-pyr<'P311\pdrochloride were placed in 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 with silica gel and eluent - methylene chloride + 1% ethanol. The product thus obtained is dissolved in acetone and the hydrochloride is precipitated with ethereal hydrochloric acid.

Yield: 1.3 g (51.3 % of theoretical value).

Melting point: 197-198 °C.

Example 84

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

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

1.98 g (44.0 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[Γ<1-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)amino]-propanehydrochloride were suspended in 50 ml of acetic anhydride, 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 ammoniacal with conc. ammonia. The manganese dioxide precipitate was filtered on a nutch filter and the filtrate was extracted repeatedly with methylene chloride. The extract was dried over magnesium sulfate, concentrated in vacuo and purified by column chromatography with silica gel and methylene chloride + 1 % ethanol as eluent. The product thus obtained is dissolved in acetone and the hydrochloride is precipitated from ethereal hydrochloric acid.

Yield: 0.7 g (34.5% of theoretical value).

Melting point: 196-197 °C.

Example 85

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

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

Prepared similarly to example 1a by reacting 6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (melting point: 188-191 °C) with 1-bromo-3-chloropropane.

Yield: 27% of theoretical value.

Melting point: 97-99 °C.

c) 1-[6,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-3-[1-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-on-3-yl)-3-chloro-propane with N-methyl-2-(3,4-dimethoxyphenyl)-ethylamine.

Yield: 90% of theoretical value.

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

NMR spectrum (CDCl-^n^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-on-3-yl]-3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propanehydrochloride

Obtained similarly to example 4 by catalytic hydrogenation of

1-[6,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl,-3-[N-methyl1-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-pr'· 'Pan.

Yield: 85 ⁽ % of theoretical value.

Melting point: 76 °C.

Example 87

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

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

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

Yield: 45% of theoretical value.

Melting point: 67-71 °C.

c) 1-[8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-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-on-3-yl)-3-chloro-propane with N-methyl-2-(3,4-dimethoxyphenyl)-ethylamine.

Yield: 64% of theoretical value.

Melting point: 64-68 °C.

Example 88

1-[8,9-dimethoxy-1D4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[1-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propanehydrochloride

Obtained similarly to example 4 by catalytic hydrogenation of

1-[8,9-Dimepoxy-1,3-dihydro-21-1-3-bsenza]epin-2-one-3-yl1-3-(X-msylX-'. 2-<^; .4-dimeth· 'xyphenyl ι-ethyl >-ahgyn<'(-propane.

Yield: ”5 T of theoretical value.

Melting point: 13-133 °C.

Example 89

1-[7,8-dimepoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-(Xmethyl-N-(2-(3,4,5-trimethoxyphenyl)-ethyl)-amino]-propane dihydrochloride

Prepared similarly to Example 56 from 1-< ~,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-chloropropane and X-methyl-2(3,4,5-trimethoxyphenyl)-ethylamine.

Yield: 44% of theoretical value.

Melting point: 131 °C (decomposition).

Example 90

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

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

Yield: 72% of theoretical value.

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

Example 91

Isomeric mixture of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-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-yl3-[>1-methyl-N-(2-[2- and 4-nitrophenyl)ethylamino]-propane

Yield: 81% of theoretical value.

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

Example 92

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

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-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-on-3-yl)-3-[N-methyl-1H-(2-(2- and 4-aminophenyl)-ethyl)-4-amino]-propane with glacial acetic acid and acetic anhydride.

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

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

Example 93

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-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-on-3-yl]-3-[N-methyl-N-(2-(4-acetylaminophenyl)-ethyl)so

amino]-propane were stirred for 34 hours at 40 °C with 80 ml of methanolic hydrochloric acid. After concentration of 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 the resulting oil was then dried in vacuo at 50 °C.

Yield: 88% of theoretical 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 (aromat.).

Example 94

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-(4-chlorophenyl)-ethyl)-amino]-propanedihydrochloride

1.01 g (0.00245 mol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-(4-aminophenyl)-ethyl)-amino]propane were dissolved in 5 ml of semi-saturated hydrochloric acid and diazotized with 0.17 g (0.00245 mol) of sodium nitrite. The mixture was then stirred at 55 °C until the evolution of nitrogen ceased. The solution was made slightly alkaline, extracted with methylene chloride, dried and concentrated in vacuo. The resulting oil was purified by chromatography on alumina (200 g, neutral, activity II) (eluent: methylene chloride + 2% ethanol) and precipitated from acetone with ethereal hydrochloric acid.

Yield: 21% of theoretical value.

Melting point: 148-151 °C.

Example 95

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

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

2-oH-3-UA]-3-[N-MemuA-N-(2-(3.4-guMemokcu4>eHUA)-emuA)-aMUHo]propane are dissolved in 150 ml of absolute ether, mixed with lithium aluminum hydride and stirred for 2 hours at room temperature. While cooling with ice water, it is mixed with a 10% ammonium chloride solution, the precipitate is filtered on a nutch filter and the solvent is removed in vacuo. The oily residue is purified with aluminum oxide (neutral, activity II) with methylene chloride as eluent.

Yield: 1.6 g (72.7 % of theoretical value).

IR spectrum (methylene chloride): 2830 cm ^-1 (OCH 2 ).

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-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-N-[2-(4-hydroxyphenyl)-ethyl]-amino]-propanehydrochloride

1.1 g (2.67 mmol) of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[N-methyl-N-[2-(4-aminophenyl)-ethyl)-amino]propane were dissolved in 10 ml of semi-saturated sulfuric acid and diazotized at 0 °C with 0.18 g (2.67 mmol) of sodium nitrite. The solution was then heated on a steam bath for 20 minutes. , diluted with water, made slightly alkaline with sodium hydroxide, extracted with methylene chloride and dried. After concentration in vacuo, the resulting oil was purified with 100 g of alumina (neutral, activity II) with methylene chloride + 2% ethanol as eluent.

The hydrochloride is precipitated from acetone/etheric hydrochloric acid.

Yield: 0.17 g (15 % of meopem. value).

Melting point: 109-112 ^° C.

Example 97

1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-1-(2-(4-dimethylaminophenyl)-ethyl)-amino]-propanedihydrochloride

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

Yield: 40% of theoretical value.

Melting point: 193-196 °C.

Example 98

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

Prepared similarly to example 53a from N-[3-[N'-MemuA-N'-(2-(4-amino-3,5-dichlorophenyl)-ethyl)-amino]-propyl]-2-(2-amino-4,5-dimethoxy-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-2-one-3-yl]-3-[N-methyl-1H-(2-(4-amino-3,5-dichlorophenyl)-ethyl)-amino]propane

S3

Prepared similarly to Example 536 from N-[3-[N'-Meniu.\-N'-<2o4amino<>-3,5-dichlorophenyl)-ethyl)-amino]-propyl]-2-(2-amino-4.5dimethoxy-phenylethylamine hydrochloride and N.N'k ap6i >nyldiimidazole.

Melting point: 163-166 °C.

Example 99

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

3-[N-methyl-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-on-3-yl]-3-[bTmethyl-H-(2-(4-amino3,5-dichlorophenyl)-ethyl)-amino]-propane and selenium dioxide.

Melting point: 118-30 °C.

m/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-on-3-yl]-3-[1N-methyl-1-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propanedihydrochloride

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

Melting point: 136-137 °C.

Example 101

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

Prepared similarly to Example 100 from 7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and N-MemuA-N-(2-(3,4-gMemokcu(10 phenyl)-ethyl)-amino]-acetidine bromide.

Melting point: 137 °C.

Example 102

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

Prepared similarly to Example 12 by reaction of N-[3(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)propyl]methylamine and 2-(3-amino-4-chlorophenyl)ethyl chloride. Oil.

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

285 pt (0.13)

304 pt (0.06)

IR spectrum (dichloromethane): 3390 and 3480 cm' ¹ (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

Tablets of 10 mg 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[N-methyl-1-(2-(3,4-dimethoxyphenyl)ethyl)amino]-propanehydrochloride

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 receipt

The active substance, corn starch and polyvinylpyrrolidone are mixed and moistened with water. The moist mixture is passed through a 1.5 mm mesh sieve and dried at about 45 °C. The dry granulate is passed through a 1.0 mm mesh sieve and mixed with magnesium stearate. The finished mixture is compressed on a tablet press with a 7 mm diameter die to score-cut tablets.

Tablet weight: 120 mg

Example II

Dragee of 5 mg 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[(2-(3,4-dimethoxyphenyl)-hexyl)aminopropanehydrochloride dragee without 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 obtaining

The active substance, corn starch, lactose and polyvinylpyrrolidone are mixed well and moistened with water. The moist mixture is passed through a sieve with a mesh size of 1 mm and dried at about 45 °C. The granulate is then passed through the same sieve. After mixing with magnesium stearate, rounded dragees with a diameter of 6 mm are pressed on a tablet machine. The dragees thus obtained are coated in a known manner with a layer consisting mainly of sugar and talc. The finished dragees are polished with wax.

Weight of dragee: 130 mg

Example III

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

active substance sorbitol

5.0 mg

50.0 mg a for injection purposes ad

Method of obtaining

In a suitable container, the active substance is dissolved in water for injection and the solution is made 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

Suppositories of 15 mg of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[N-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)amino]-propane hydrochloride.

suppository contains:

active substance 0.015 t solid fat (e.g. Witepsol H 19 and W 45) ________1.685 g

1,700g

Method of receipt

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

Example V ©

Drops solution with 10 mg of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3benzazepin-2-on-3-yl]-3-[1H-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)aminopropanehydrochloride per 5 ml.

100 ml of solution contains:

active substance 0.2 g hydroxyethylcellulose 0.15 g tartaric acid 0. 1 g solution of sorbitol 70% dry in vol 30. 0 g glycerin 10. 0 g benzoic acid 0. 15 ' g distilled water ad 100 ml

Method of receipt

The water is heated to 70 °C. Hydroxyethylcellulose, benzoic acid and tartaric acid are dissolved in it while stirring. It is cooled to room temperature and the glycerin and sorbitol solution are added while stirring. At room temperature, the active substance is added and stirred until complete dissolution. Then, while stirring, it is vacuumed to deaerate.

Claims (11)

PATENT CLAIMS 1. Benzazepine derivatives with general formula: A. Kb N-E-N-G/ in (I) in which they mean: A - the group -CH ₂ -CH ₂ -, -CH=CH-, -NH-CO-, -CH ₂ -CO- or 5 5 _C^N-apyna in which R ₇ represents an alkyl group with 1 to 3 carbon atoms, and B - a methylene or carbonyl group or A- group -CO-CO-, and B - methylene group, E- an optionally substituted alkyl group having 1 to 3 carbon atoms, an ethylene, n-propylene or n-butylene group, a 2-position substituted hydroxyl group n-propylene group or a 2- or 3-position substituted hydroxyl group n-butylene group. G - 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 part may contain 1 to 3 carbon atoms, or one of the radicals Rj or R ₂ - also a hydrogen atom, or R1 together with R ₂ - an alkylenedioxy group with 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 with 1 to 4 carbon atoms, trifluoromethyl or cyano groups, or one of the radicals R ₄ or R ₄ - also a nitro group, or R together with R ₄ - an alkylenedioxy group with 1 or 2 carbon atoms. R _s - a hydrogen atom, an alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino or bis(alkoxycarbonyl)amino group, in which the alkyl part may contain 1 to 3 carbon atoms, or a methylamino or ethylamino group substituted with a trifluoromethyl group, and R ₆ - hydrogen atom, alkyl, phenylalkyl, alkanoyl or alkoxycarbonyl group, in which the alkyl part may contain 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms and their salts, especially their physiologically tolerable salts with inorganic and organic acids. 2. Benzazepine derivatives of general formula I, according to claim 1, in which they mean: A - 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 - -CO-CO-group and B - methylene group, E - ethylene, n-propylene, n-butylene, 2-methyl-n-propylene or 2-hydroxy-n-propylene group, G- methylene, ethylene or 1-methylethylene group, R-j - methyl, hydroxyl, benzyloxy or alkoxy group with 1 to 3 carbon atoms, BAD ORIGINAL Q R-, - hydrogen atom, methyl, hydroxyl or methoxy group. or Rj and R _? together - methylenedioxy group, R} - hydrogen, fluorine, chlorine or bromine atom, trifluoromethyl. nitro-, alkyl or alkoxy group is 1 to 4 carbon atoms, R ₄ - hydrogen, chlorine or bromine atom, methyl, methyloxy or cyano group or R ₃ and R ₄ together - methylenedioxy group, R^ - hydrogen atom, hydroxyl, methoxy-, amino-, acetylamino-, ethoxycarbonylamino-, bis(ethoxycarbonyl)amino-, dimethylamino- or β,β,β-trifluoroethylamino group and R ₆ - hydrogen atom, alkyl group with 3 to 6 carbon atoms, alkyl, benzyl, acetyl or ethoxycarbonyl group, and their salts, especially physiologically tolerable salts obtained with organic or inorganic acids. 3. Benzazepine derivatives of general formula I, according to claim 1, in which they mean: A - the group -CH2-CH2-, -CH=CH-, or —C=N-apyna and B - carbonyl group or A - -CH=CH-, -NH-CO- or -CO-CO-group and B - methylene group, $ E - n-propylene, G- ethylene, Rj - methoxy or hydroxyl group, R _? - methoxy group, or R j and R ₂ together - methylenedioxy group, R3 - methoxy or trifluoromethyl group, chlorine or bromine atom, R ₄ - methoxy group, GC - hydrogen atom, amino- or methoxy group and R 1 - hydrogen atom, methyl, ethyl, n-propyl or allyl group and their salts, especially physiologically tolerable salts obtained with organic or inorganic acids. 4. Benzazepine derivatives with general formula C (1a) in which they mean A - the group -CE^-CE^-, -CH=CH-, or CH ₃ I —C -N-group and B - carbonyl group or A - -NH-CO- or -CO-CO- group and B - methylene group, Rj and R ₂ - one methoxy group each, R _o - hydrogen atom, methyl or alkyl group, R ₃ - hydrogen atom or methoxy group in the 3rd position, R ₄ - methoxy group in the 4th position or R ₃ and R ₄ together - 3,4-methylenedioxy group and R ₅ - hydrogen atom, or R ₃ in the 3rd position - trifluoromethyl group, chlorine or bromine atom, R ₄ 65th position - chlorine or bromine atom and R ₅ in the 4th position - an amino group and its physiologically tolerable salts obtained with inorganic or organic acids. BAD ORIGINAL $ 5. 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3yl]-3-[X-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]-propane and its acid addition salts. 6. 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepine-1,2dion-3-yl]-3-[X-methyl-N-(2-(3,4-dimethoxyphenyl)-ethyl)-amino]propane and its acid addition salts. 7. 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3yl]-3-[N-methyl-N-(2-(4-amino-3,5-dichlorophenyl)-ethyl)-amino]-propane and its acid addition salts. 8. 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl]-3-[N-methyl-1-(2-(4-methoxyphenyl)-ethyl)-amino]-propane and its acid addition salts. 9. A pharmaceutical composition for the treatment of sinus tachycardia and ischemic heart disease, comprising a compound according to claims 1 to 8, together with one of a number of inert carriers or diluents. 10. Method for preparing benzazepine derivatives with the general formula (I) in which they mean: A - the group -CH ₂ -CH ₂ -, -CH=CH-, -NH-CO-, -CH ₂ -CO- or 5 5 R7 —C=N-2p?na in which _R7 represents an alkyl group with 1 to 3 carbon atoms and B - a methylene or carbonyl group or A- group -CO-CO-, and B - methylene group, E- an optionally substituted alkyl group having 1 to 3 carbon atoms, an ethylene, n-propylene or n-butylene group, a 2-substituted hydroxy-substituted p-propylene group or a 2- or 3-substituted hydroxy-substituted p-butylene group. G - 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 phenyl alkoxy groups, in which the alkyl part may contain 1 to 3 carbon atoms, or one of the radicals Rj or _R2 may be a hydrogen atom, or R1 together with _R2 - an alkylenedioxy group with 1 or 2 carbon atoms. R ₃ and R ₄ , which may be the same or different, are hydrogen or halogen atoms, hydroxyl groups, alkyl or alkoxy groups with 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 - an alkylenedioxy group with 1 or 2 carbon atoms. R ₅ - a hydrogen atom, an alkyl, hydroxyl, alkoxy, amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino or bis(alkoxycarbonyl)amino group, in which the alkyl part may contain 1 to 3 carbon atoms, or a methylamino or ethylamino group substituted with a trifluoromethyl group, and R^ - hydrogen atom, alkyl, phenylalkyl, alkanoyl or alkoxycarbonyl group, in which the alkyl part may contain 1 to 3 carbon atoms or an alkenyl group with 3 to 5 carbon atoms, as well as their salts, especially their physiologically acceptable addition salts obtained with inorganic or organic acids, characterized in that a) a compound with the general formula BAD ORIGINAL A N-H / . B UD in which A u B are defined as in the beginning, Ry and R ₇ ' each represent a hydroxyl group protected by a protecting radical or have the meanings for R j and R ₂ given at the beginning, reacts with a compound of general formula (III) in which R ₆ , E and G are defined as at the beginning, Ry and Ry each represent a hydroxyl group protected by a protecting radical or have the meanings for _R2 and _R5 mentioned at the beginning and Z - nucleophilic leaving group or its internal quaternary salt, possibly present in the reaction mixture, with the general formula (IIIa) in which E, G, Z, Ry go Ry and R ₆ are as defined at the beginning, and optionally subsequent cleavage 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 with 3 to 5 carbon atoms, an alkyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, a compound of general formula N—E-U interacts with a compound with the general formula R ₅ ' (V) in which A, B, E, and G are defined as at the beginning. Rj' and R^' each represent a hydroxyl group protected by a protecting radical or have the meanings of Rj and R ₅ mentioned at the beginning, one of the radicals U or V represents the R ₆ '-NH group, R ₆ ' denotes a hydrogen atom, an alkenyl group with 3 to 5 carbon atoms, an alkyl or phenylalkyl group with 1 to 3 carbon atoms, the other of the radicals U or V represents a nucleophilic leaving group, or the radical U represents together with a β-positioned hydrogen atom of the radical E - oxygen, and V - an R^'-NH group, R ₆ ' being defined as above, and optionally subsequent removal 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 with 3 to 5 carbon atoms, BAD ORIGINAL alkyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, a compound with 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 at the beginning, but in the radical E, two hydrogen atoms in one -CH ₂ - or CH ₃ -group of the radical are replaced by an oxygen atom, is reacted in the presence of a reducing agent with an amine of the general formula (VII) in which G and R ₃ to R ₅ are as defined at the beginning, and R ₆ ' represents a hydrogen atom, an alkenyl group with 3 to 5 carbon atoms, an alkyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, or d) for the preparation of compounds of general formula I, in which R^ represents a hydrogen atom, an alkenyl group with 3 to 5 carbon atoms, an alkyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, a compound of general formula (VIII) in which A, B, E, Rj and R _? are as defined at the beginning, and R ₆ ' means a hydrogen atom, an alkenyl group is 3 to 5 carbon atoms, an alkyl or phenylalkyl group with 1 to 3 carbon atoms in the alkyl part, is reacted in the presence of a reducing agent with a compound of the general formula Rs (IX) in which G and R ₃ or R ₅ are as defined at the beginning, but in the radical G two hydrogen atoms in one -CH ₂ - or CH 3 - 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 - optionally substituted with an alkyl group having 1 to 3 carbon atoms, an ethylene, n-propylene or n-butylene group, and R ₆ does not represent hydrogen, a compound of general formula group, (X) in which B and G are defined as in the beginning E' - optionally substituted with an alkyl group having 1 to 4 carbon atoms, ethylene, n-propylene or n-butylene BAD ORIGINAL L R( or R ₄ ' represent a hydroxyl group protected by a protecting radical, or have the meanings of R| and R ₄ mentioned at the beginning, R _s represents a hydroxyl, amino or alkylamino group protected with a protecting radical, or, with the exception of an amino or alkylamino group, has the meaning of R<^ mentioned at the beginning and R^' has, with the exception of hydrogen, the meaning of R ₆ mentioned at the beginning, 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, which may be the same or different, always represents a nucleophilic leaving group such as a chlorine or bromine atom, an alkoxy group optionally substituted with a halogen atom having 1 to 3 carbon atoms or an imidazolyl-(2)-group, and optionally subsequent cleavage of the protective radical used, or f) for the preparation of a compound of general formula I, in which A represents a -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 1 does not represent a benzyl group or an alkenyl group with 3 to 5 carbon atoms, a compound of general formula (XII) in which R ₁ go R^, B, E and G are defined as at the beginning, as R ₂ or R ₄ do not represent a nitro group, if R ₅ represents an amino group it is hydrogenated, or I'll I g) a compound with the general formula ^R i .. ,.-, . e- . A. 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 and G are defined as at the beginning, however at least one of the radicals Rj go R ₄ represents a hydroxyl group, or R _? - a hydroxyl group, an amino or alkylamino group with 1 to 3 carbon atoms, or R ^ must represent a hydrogen atom, reacts with a compound of the general formula (XIV) In which R ₆ represents an alkyl group with 1 to 3 carbon atoms or also an alkenyl group with 3 to 5 carbon atoms when R ₆ is a hydrogen atom, or also a phenyl-substituted alkyl group with 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 R1 to _R5 represents a hydroxyl group, X together with the α-positioned hydrogen of the radical _R1 represents a diazo group, or also if R2 is a hydrogen atom or R3 is an amino or alkylamino group they represent an oxygen atom, or h) for the preparation of compounds of general formula I, in which A is not -CH=CH- group, R ₃ is a chlorine or bromine atom and R^ is an amino or alkylamino group, a compound of 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, and G are defined as in the beginning, A' is an exception to the -CH=CH- group, has the meaning of A mentioned at the beginning and R ₅ represents an amino or alkylamino group with 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 - a methylene group and E - an optionally substituted alkyl group having 1 to 3 carbon atoms, an ethylene, n-propylene or n-butylene group, a compound of general formula (XVI) in which Rj go R, E and G are as defined at the beginning, is oxidized and optionally thereafter, the resulting compound of general formula I, in which B represents a carbonyl group, is converted by reduction into the corresponding compound of general formula I, in which B represents a methylene group, and/or the resulting compound of general formula I, in which And it's not -CH=CH- or 102 -C=N'apyna and R ₆ represents a benzyl or 1-phenylethyl group, is converted by catalytic hydrogenation into the corresponding compound <_ general formula I, in which R _o represents a hydrogen atom, and/or the resulting compound of general formula I, 6 in which R, or R ₄ represents a nitro group, is converted by reduction into the corresponding compound of general formula I, in which R ₅ represents an amino group, and/or the resulting compound of general formula I, in which R ₆ is hydrogen and/or R<; is an amino group, is converted by acylation β the corresponding compound of general formula 1. in which R _(i) represents an alkanoyl or alkoxycarbonyl group, and or R ₅ represents an alkanoylamino-. alkoxycarbonylamino- or bis(alkoxycarbonyl)amino group, the alkyl moiety always containing 1 to 3 carbon atoms, and/or the resulting compound of general formula I. in which 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 via the corresponding diazonium m'.\ into the corresponding compound of general formula I. in which R5 is a hydrogen atom, a hydroxyl or alkoxy group, or R$ is a hydrogen atom and Rj - a halogen atom, or denote a cyano group, and/or the resulting compound of general formula I can be converted into its salts obtained by addition with an acid, in particular into physiologically tolerable salts with inorganic or organic acids. 11. A method for preparing a medicament, characterized in that a compound of general formula I or a physiologically tolerable salt thereof is added in a non-chemical manner to one or more inert carriers and/or diluents.