Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
- l -
AK138-545
Chemical Compounds
This invention relates to new benzazepine derivatives,
to processes for their preparation and to pharmaceutical
compositions containing them.
In British Patent 1,548,844, there is described,
5. nter alia the compound of formula
ÇH~0 ~
CH30 ~ ~CH-CH-~H-N-CH2-CH2 ~ 3H3
and pysiologically compatible acid addition salts
thereof. ~hese substances possess valuable pharmacological
properties, i.e. not only a mild hypotensive effect,
10. but more particularly a selective heart rate reducing
effect.
Surprisingly, we have now found that compounds
of general formula I
R2 ~ A R6 ~ (I)
15.1' R2l ~3~ R4~ Rs~ R6~ A, B, E and G are
as defined below, and physiologically compatible acid
addition salts thereof have superior pharmacological
properties, and in particular a more powerful heart
rate reducing effect, with a longer duration of activity
20. and reduced side-effects.
Thus, according to one feature of the present
invention, there are provided compounds of general
formula I R
R1 N - E - N - G ~ ( )
B R~
3~3
-- 2 --
[wherein A represents a group of formula -CH2-CH2-,
l7
-CH=CH~, -NH-CO-, -CH2-CO- or -C=N-
(wherein R7 represents an alkyl group containing 1
to 3 carbon atoms) and B represents a methylene or
5- carbonyl group, or A represents a -CO-CO- group and
B represents a methylene group; E represents an ethylene,
n-propylene or n-butylene group (optionally substituted
by an alkyl group containing 1 to 3 carbon atoms),
and n-propylene group ~ubstituted at the 2-position
10. by a hydroxy group or an n-butylene group substituted
at the ~- or 3-position by a hydroxy group; G repre~ents
a methylene or ethylene group (optionally substitued
by an alkyl group containing 1 to 3 carbon atoms);
Rl and R2, which may be the same or diferent, each
15. represents a hydroxy group, an alkyl group containing
1 to 3 carbon atoms, or an alkoxy or phenylalkoxy
group (in each of which the alkyl part may contain
1 to 3 carbon atoms) or one of the radicals Rl or
R2 represen~s a hydrogen atom or Rl and R2 together
20. represent an alkylenedioxy group containing 1 or 2
carbon atoms; R3 and ~4 which may be the same or different,
- each represents a hydrogen or halogen atom, a hydroxy
group, an alkyl or alkoxy group each of which may
contain 1 to 4 carbon atoms, or a trifluoromethyl
25. or cyano group or one of the radicals R3 or R4 represents
a nitro group or R3 and R4 together represent an alkylene-
dioxy group containing 1 or 2 carbon atoms; R5 represents
a hydrogen atom, a hydroxy or amino group, an alkyl,
alkoxy or alkylamino group containing 1 to 3 carbon
30. atoms, a dialkylamino, alkanoylamino, alkoxycarbonyl-
amino or bis(alkoxycarbonyl)amino group, in each of
which the alkyl part may contain from 1 ~o 3 carbon
atoms, or a methylamino or ethylamino group substituted
by a trifluoromethyl group; and R6 represents a hydrogen
35. atom, an alkyl group containing from 1 to 3 carbon
atoms, or a phenylalkyl, alkanoyl or alkoxycarbonyl
-- 3 --
group, in each of which the alkyl part may contain
from 1 to 3 carbon atoms, or an alkenyl group containing
3 to 5 carbon atoms] and acid addition salts thereof.
It will be appreciated that, for pharmaceutical
5- ~se, the acid addition salts referred to above will
be physiologically compatible acid addition salts,
but other acid addition salts may find use, for example
in the preparation of the compounds of general formula
I and their physiologically compatible acid addition
10. salts. The term "acid addition salts~ used herein
includes salts formed with organic and inorganic acids.
In the definition of the group A in general
formula I a~ove, the symbol '5' indicates the site
of attachment to the phenyl nucleus.
15. Thus, in the compounds of formula I, Rl may,
for example, represent a methyl, ethyl, propyl, isopropyl,
hydroxy, methoxy, ethoxy, propoxy, isopropoxy, benzyloxy,
l-phenyl-ethoxy, 2-phenylethoxy or 3-phenylpropoxy
group; R2 may, for example, represent a hydrogen atom
20. or a methyl, ethyl, propyl, isopropyl, hydroxy, methoxy,
ethoxy, propoxy, isopropoxy, benzyloxy, l-phenylethoxy,
2-phenylethoxy, 2-phenylpropoxy, or 3-phenylpropoxy
group; R3 and R4, which may be the same or different,
may, for example, each represent a hydrogen, fluorine,
25. chlorine, bromine or iodine atom or a methyl, ethyl,
propyl, isopropyl, n-butyl, hydroxy, methoxy, ethoxy,
propoxy, isopropoxy, ~butoxy, trifluoromethyl or
cyano group or one of the radicals R3 or R4 may represent
a nitro group; R5 may, for example, represent a hydrogen
30. atom or a methyl, ethyl, propyl, isopropyl, hydroxy,
methoxy, ethoxy, propoxy, isopropoxy, amino, methylamino,
ethylamino, propylamino, isopropylamino, dimethylamino,
diethylamino, dipropylamino, methyl - ethylamino, ethyl-
propylamino, methyl-propylamino, formylamino, acetylamino,
35. propionylamino, methoxycarbonylamino, ethoxycarbonylamino,
propoxycarbonylamino, isopropoxycarbonylamino, bis(ethoxy-
carbonyl)-amino or ~ trifluoroethylamino group;
R6 may, for example, represent a hydrogen atom or
-- 4 --
a methyl, ethyl, propyl, isopropyl, benzyl, l-phenylethyl,
2-phenylethyl, 3 phenylpropyl, allyl, buten-2-yl,
buten-3-yl, pentenyl, formyl, acetyl, propionyl, methoxy-
carbonyl, ethoxycarbonyl, propoxycarbonyl or isopropoxy-
5. carbonyl group; Rl and R2 together and/or R3 and
R4 together may, for example, represent a methylenedioxy
or ethylenedioxy group; E may, for example, represent
an ethylene, n-propylene~ n-butylene, l-methyl-ethylene,
2-ethyl-ethylene, 1 propyl-ethylene, l-methyl-n-propylene,
10. 2-methyl-n-propylene, l-ethyl-n-propylene, 3-ethyl-
n-propylene, 2-propyl n-propylene, 2-methyl-n butylene,
2-hydroxy-n-propylene, 2-hydroxy-n-butylene or 3-hydroxy-
n-butylene group; and G may, for example, represent
a methylene, ethylidene, propylidene, n-butylidene,
15. 2~methyl-propylidene, ethylene, l-methyl-ethylene,
2-ethyl-ethylene, l-propyl-ethylene or 2-methyl-ethylene
group.
Preferred compounds of general formula I are
those wherein
A represents a group of formula -CH2-CH2-, -CH=CH-,
-NHCO-'-CH2-~O- or -C-N-
5 5 5
and B represents a methylene or carbonyl group
or
A represents a -CO-CO- group and B represents a methylene
25. group,
E represents an ethylene, n-propylene, n-butylene,
2-methyl-n-propylene or 2-hydroxy-n-propylene group,
G represents a methylene, ethylene or l-methyl-ethylene
group,
30. Rl represents a methyl, hydroxy or benxyloxy group
or an alkoxy group containing 1 to 3 carbon atoms,
R2 represents a hydrogen atom or a methyl, hydroxy
or methoxy group, or
Rl and R2 together represent a methylenedioxy group,
35. R3 represents a hydrogen, fluorine, chlorine or bromine
atom, a trifluoromethyl or nitro group or an alkyl
or alkoxy group each containing 1 to 4 carbon atoms,
dl~3~
-- 5 --
R4represe~ts a hydrogen, chlorine or bromine atom
or a methyl, methoxy or cyano group or
R3 and R~ together represent a methylenedioxy group,
R5 represents a hydrogen atom or a hydroxy, methoxy,
5. amino, acetylamino, ethoxycarbonylamino, bis(ethoxy-
carbonyl)-amino, dimethylamino or ~ triEluoroethyl-
amino group and
R6 represents a hydrogen atom, an alkyl group containing
l to 3 carbon atoms or an allyl, benzyl, acetyl
lO. or ethoxycarbonyl group.
Particularly preferred compounds of general
formula I are those wherein IH3
A represents a -CH2-CH2~, -CH=CH- or -C=N-group and
B represents carbonyl group, or A represents
15. a -C~=CH-, -N~-CO- or -CO-CO-
group and B represents a methylene group; E represents
an n-propylene group; G represents an ethylene group,
~l represen~s a methoxy or a hydroxy group; R2 represen~s
a methoxy group; R3 represents a methoxy or trifluoromethyl
20. group, or a chlorine or bromine atom and R4 represents
a methoxy group or a hydrogen, chlorine or bromine
atom, or R3 and R4 together represent a methylenedioxy
group; R5 represents a hydrogen atom or an amino or
methoxy group; and R6 represents a hydrogen atom or
25. a methyl, ethyl, n-propyl or allyl group.
Examples of particularly preferred compounds of general
formula I include compounds of formula Ia R3
R2 ~ N-CH -CHz~CH2~N~cHZ-cN2 ~ ~ (Ia)
CH3
wherein A represents a -CH2-CH2-, -CH=CH- or - C=N-
group and 8 represents a carbonyl group, or A represents
-- 6 -- .
an -NH-CO- or -CO-CO- group and B represents a methylene
S
group; Rl and R2 each represents a methoxy group;
R6 represents a hydrogen atom or a methyl or allyl
group; R~ represents a hydrogen atom or a methoxy
5. group at the 3-position, and R4 represents a methoxy
group at the 4-position, or R3 and R4 together represent
a 3,4-methylenedioxy group; and R5 represents a hydrogen
atom; or R3 at the 3-position represents a chlorine
or bromine atom, R4 at the 5-position represents a
10. chlorine or bromine atom, and R5 at the 4-position
represents an amino group.
The compounds of formula I may, for example, be
prepared by the following processes, which processes
constitute further features of the present invention:
15. a) Reaction of a comPound of general formula II
\
~ N - H (II)
R2 ~
[wherein A and ~ are as hereinbefore defined and Rl'
and R2' each represent a hydroxy group protected by
a protective radical (e.g. a trimethylsilyloxy, acetoxy,
20. benzyloxy or tetrahydropyranyloxy group), or represent
Rl and R2 as hereinbefore defined] with a compound
of general formula III R~'
R6
Z - ~ - N - G ~ R4~ ~III)
R5'
[wherein R6, E and G are as hereinbefore defined R3',
25. R4 and R5l each represents a hydroxy group protected
by a protective radical ~e.g. a trimethylsilyloxy,
acetoxy, benzyloxy or tetrahydropyranyloxy group)
or represents R3, R4 and R5 as hereinbefore defined,
,
;3r~
~ 7 --
and Z represents a nucleophilically exchangeable group
such as a halogen atom or a sulfonyloxy group (e.g.
a chlorine, bromine or iodine atom or a methanesulfonyloxy,
p-toluenesulfonyloxy or ethoxysulfonyloxy group)],
5- the corresponding internal quaternary salt of general
formula IIIa
R6 Z
~ 3~
(wherein E~ G, Z, R3', R4', R5' and R6 are as hereinbefore
lQo defined) optionally being present in the reaction
mixture, and optional subsequent cleavage of the protecting
group.
The reaction may optionally be carried out in a
solvent or mixture of solvents, e.g. acetone, dimethyl-
15. formamide, acetone/dimethylformamide, dimethylsulf
oxide or chlorobenzene, and depending on the reactivity
of the radical Z, the reaction is ~onveniently carried
out at temperatures between O and 150C, preferably,
however, at the boiling temperature of the solvent
20. used. It is advantageous to carry out the reaction
in the presence of an acid-binding agent, such as,
for example, an alcoholate such as sodium methylate,
an alkali metal hydroxide such as sodium hydroxide,
an alkali metal carbonate such as potassium carbonate,
25. an alkali metal amide such as sodamide, an alkali
metal hydride such as sodium hydride or a tertiary
organic base such as triethylamine or pyridine, or
a reaction accelerator such as, for example, potassium
iodide.
30. The cleavage of the protecting group, where
present, is preferably carried out hydro~ytically
in an aqueous solvent, e.g. in water, isopropanol/water,
-- 8 --
tetrahydrofuran/water or dioxan/water, in the presence
of an acid such as hydrochloric acid or sul~uric acid
or in the presence of an alkali base such as sodium
hydroxide or potassium hydroxide at temperatures between
5. 0 and 100C, preferably at the boiling temperature
of the reaction mixture. The cleavage of a benzyl
radical, however, may be carried out hydrogenolytically,
e.g. with hydrogen in the presence of a catalyst ~uch
as palladium/charcoal, in a solvent such as, for example,
10. methanol, ethanol, ethyl acetate or glacial acetic
acid, optionally with addition of an acid such as
hydrochloric acid at temperatures between 0 and 50C
(preferably room temperature~ and a hydrogen pressure
of 1 to 7 ~preferably 3 to 5) bar.
15. b) For the preparation of compounds of general formula
I wherein R6 represents a hydrogen atom, an alkenyl
group containing 3 to 5 carbon atoms, an alkyl group
containing 1 to 3 carbon atoms or a phenylalkyl group
containing 1 to 3 carbon atoms in the alkyl part:
20. Reaction of a compound of general formula IV
N - ~ - U (IV~
~ B
R2~
with a compound of general formula V
R3~
~ G - V (V)
X~/
R~ T
R5~
wherein A, B, E and G are as hereinbefore defined
25. Rl', R2', R3', R4' and R5' each represent a hydroxy
group protected by a protective radical (e.g. a trimethyl-
silyloxy, acetoxy, benzyloxy or tetrahydropyranyloxy
_ 9 _
group) or represent Rl, R2, R3, R4 and ~5 as hereinbefore
defined; one of the radicals U and v represents an
R~'-NH- group (wherein R6' represents a hydrogen atom,
an alkenyl group containing 3 to 5 carbon atoms, an
5. alkyl group containing 1 to 3 carbon atoms, or a phenylalkyl
group containing 1 to 3 carbon atoms in the alkyl
part), and the other of the radicals U and V represents
a nucleophilically exhangeable group such as a halogen
atom or a sulfonyloxy group, (e.g. a chlorine, bromine
10. or iodine atom or a methanesulfonyloxy, p-toluenesulfonyloxy
or ethoxysulfonyloxy group); or the radical U together
with a hydrogen atom at the ~-position of the radical
E represen~s an oxygen atom and V represents an R6'-
NH- group, wherein R6' is as hereinbefore defined,
15. with optional subsequent cleavage of the protective
radical, where present.
The reaction is conveniently carried out in
a solvent or mixture of solvents such as acetone,
diethyl ether, methylformamide, dimethylformamide,
20. dimethylsulfoxide, benzene, chlorbenzene, tetrahydrofuran,
benzene/tetrahydrofuran, dioxan or in an excess of
the compounds of general formulae IV and/or V used,
and optionally in the presence of an acid-binding
agent (e.g. an alcoholate such as potassium tert.butylate,
25. an alkali metal hydroxide such as sodium or potassium
hydroxide, an alkali metal carbonate such as potassium
carbonate, an alkali metal amide such as sodamide,
an alkali metal hydride such as sodium hydride, a
tertiary organic base such as txiethylamine or pyridine
whereby the last two may simultaneously serve as solvents)
or a reaction accelerator such as potassium iodide,
andr depending on the reactivity of the nucleophili-
cally exchangeable group, the reaction may conveniently
be carried out at temperatures from 0 to 150C, preferably
35- 50 to 120C, e.g. at the boiling temperature of the
solvent used. However, the reaction may also be carried
out without a solvent. It is, however, particularly
advantageous to carry out the reaction in the presence
3~
-- 10 --
of a tertiary organic base or an excess of the amine
of general formula V used.
The optional subsequent cleavage of a used protective
radical is preferably carried out hydrolytically in
5. an a~ueous solvent, e.g. in water, isopropanoi/water,
tetrahydrofuran/water or dioxan/water, in the presence
of an acid such as hydrochloric acid or sulfuric acid
or in the presence of an alkali base such as sodium
hydroxide or potassium hydroxide at temperature between
10. 0 and 100C, preferably at the boiling temperature
of the reaction mixture. The cleaYage of a benzyl
radical, however, may be carried out hydrogenolytically,
e.g. with hydrogen in the presence of a catalyst such
as palladium/charcoal, in a solvent such as methanol,
15. ethanol, ethyl acetate or glacial acetic acid optionally
with addition of an acid such as hydrochloric acid
at temperatures between 0 and 50C, preferably, however,
at room temperature, and a hydrogen pressure of 1
to 7, preferably 3 to 5, bar.
20. c) For the preparation of compounds of general formula
I wherein R6 represents a hydrogen atom, an alkenyl
group containing 3 to 5 carbon atoms, an alkyl group
containing 1 to 3 carbon atoms or a phenylalkyl group
containing 1 to 3 carbon atoms in the alkyl part:
25. Reaction of a compound of general formula VI
z ? ~ ~ ~ ~ (VI~
(wherein A, Bl E, Rl and R2 are as hereinbefore defined,
expect that in the radical E two hydrogen atoms of
a -C~2- or C~3- group are replaced by an oxygen atom)
3~. with an amine of general formula VII
R3
H - ~ G ~ R4 (VII~
R~ R
~ 11 -
whe~ein G, R3, R4 and R5 are as hereinbefore defined
and R6' represents a hydrogen atom, an alkenyl group
containing 3 to 5 carbon atoms, an alkyl group co~taining
1 to 3 carbon atoms or a phenylalkyl group containing
5. 1 to 3 carbon atoms in the alkyl part, in the presence
of a reducing agent.
The reaction is conveniently carried out in
a solvent or mixture of solvents such as for example,
methanol, ethanol, ethanol/ethyl acetate or dioxan
lOo at temperatures between 0 and 100C, preferably, however,
at temperatures between 20 and 80C.
It is particularly advantageous to carry out
the reductive animation in the presence of a complex
metal hydride such as lithium or sodium cyanoborohydride
15. preferably at pH 6 - 7 and at room temperature, or,
for the preparation of compounds of general formula
I wherein R6 represents a hydrogen atom, in the presence
of a hydrogenation catalyst, e.g. with hydrogen in
the presence of palladium/charcoal at a hydrogen pressure
20. of 5 bar. By this means, optionally present benzyl
groups may simultaneously be split off hydrogenolytically
and/or double bonds may be hydrogenated.
d) For the preparation of compounds of general formula
I wherein R6 represents a hydrogen atom, an alkenyl
25. group containing 3 to 5 carbon atoms, an alkyl group
containing 1 to 3 carbon atoms, or a phenylalkyl group
containing 1 to 3 carbon atoms in the alkyl part:
Reaction of a compound of general formula VIII
R1
\ ,~ H (VIII )
~ N - ~ - N R '
R2
(wherein A, B, E, Rl and R2 are as hereinbefore defined
and R6' represents a hydrogen atom, an alkenyl group
containing 3 to 5 carbon atoms, an alkyl group containing
1 to 3 carbon atoms or a phenylalkyl group containing
1 to 3 carbon atoms in the alkyl part) with a compound
D~ 3
- 12 -
of general formula IX
H - G ~ R3 (IX)
~ ~4
(wherein R3, R4, R5 and G are as hereinbefore defined,
except that in the radical G two hydrogen atoms of
5- a -CH2- or CH3- group are replaced by an oxygen atom)
in the presence of a reducing agent.
The reaction is conveniently carried out in a solvent
or mixture of solvents such as for example methanol,
ethanol, ethanol/ethyl acetate or dioxan at temperatures
lO. between 0 and lOO~C, preferably, however, 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
15. at pH 6 - 7 and at room temperature, or, for the preparation
of compounds of general formula I wherein R6 represents
a hydrogen atom, in the presence of a hydrogenation
catalyst, e.g. with hydrogen in the presence of palladium/
charcoal at a hydrogen pressure of 5 bar. By this
20. means, optionally present benzyl groups may simultaneously
be split off hydrogenolytically and/or double bonds
may be hydrogenated.
e) For the preparation of compounds of general formula
I wherein A represents a -NH-CO- group, E represents
25. an ethylene, n-propylene or n-butylene group (optionally
substituted by an alkyl group containing l to 3 carbon
atoms) and R6 does not represent a hydrogen atom:
Xeaction of a compound of general formula X
o -
'1 R~'
R ~ j~ CHz - B - N - ~' - N ~; ~ lX)
R5D
,
- 13 -
(wherein B and G are as hereinbefore defined, E' represents
an ethylene, n-propylene or n-butylene group optionally
substituted by an alkyl group containing 1 to 3 carbon
atoms,
5. Rl', R2 ~ R3' and R4' each represents a hydroxy group
protected by a protective radical (e.g. a trimethyl-
silyloxy, acetoxy, benzyloxy or tetrahydropyranyloxy
group) or represent Rl, R2, R3 and R4 as hereinbefore
defined, R5" represents a hydroxy, amino or alkylamino
10. group protected by a protective radical or has the
meanings mentioned before for R5 with the exception
of the amino or alkylamino group and R6" has the meanings
mentioned before for R6 with the exception of a hydrogen
atom or represents a protective group for an amino
15. group) with a carbonic acid derivative of general
formula XI
W - CO - W' (XI)
~wherein ~ and h", which may be the sa~e or different,
each ~e~resent a nucleophilically exchangeable
group such as, for example, a chlorine
or bromine atomt an alkoxy group containing 1 to 3
carbon atoms (optionally substitued by halogen atoms)
or an imidazolyl-(2) group] with optional subsequent
cleavage of a protective radical, where present.
~5- The reaction is conveniently carried out in
a solvent or mixture of solvents such as methylene
chloride, carbon tetrachloride, ben2ene, tetrahydrofuran,
benzene/tetrahydrofuran, dioxan or acetonitrile, conveniently
at temperatures between 0 and 150C, preferably, however,
30. at the boiling temperature of the solvent used (e.g.
at temperatures between 40 and 100C) and optiona31y
in the presence of an acid-binding agent such as,
for example, potassium carbonate, sodium hydroxide,
potassium hydroxide, pyridine or triethylamine, whereby
35. the last two may simultaneously serve as solvents.
However, the reaction may be carried out without a
solvent. If in a used compound of general formula
XI at least one of the radicals W and W' represents
an alkoxy group containing 1 to 3 carbon atoms, the
~A~
- 14 ~
reaction is preferably carried out in an excess of
the ester as solvent.
The optional subse~uent cleavage of a protective
radical is preferably carried out hydxolytically in
5. an aqueous solvent, e.g. water, isopropanol/water,
tetrahydrofuran/water or dioxan/water, in the presence
of an acid such as hydrochloric acid or sulfuric acid
or sulfuric acid or in the presence of an alkali base
such as sodium hydroxide or potassium hydroxide at
10. temperatures between 0 and 100C, preferably at the
boiling temperature of the reaction mixture. The
cleavage of a benzyl radical, however, may be carried
out hydrogenolytically, e.g. with hydrogen in the
presence of a catalyst such as palladium/charcoal,
15. in a solvent such as, for example/ methanol, ethanol,
ethyl acetate or glacial acetic acid optionally with
addition of an acid such as hydrochloric acid at temperatures
between 0 and 50C, preferably, however, at room temperature
and a hydrogen pressure of 1 to 7, preferably 3 to
20. 5, bar.
f) For the preparation of compounds of general formula
I wherein A represents a -CH2-CH2- group, Rl and R2
do not represent benzyloxy groups, R3 and R4 do not
represent nitro groups and R6 does not represent a
25. benzyl group or an alkenyl group containing 3 to 5
carbon atoms:
Hydrogenation of a compound of general formula
XII
R1 ~ ~6 ~ 3 (XII~
2 ~5
wherein Rl, R2, R3, R4, R5, B, E and G are as hereinbefore
30- defined, except that R3 or R4 may not represent a
nitro group if R5 represents ~n amino group.
- 15 -
The hydrogenation may be carried out in a solvent
or mixture of solvents such as, for example methanol,
ethanol, ethyl acetate or glacial acetic acid with
catalytically activated hydrogen, e.g. with hydrogen
5. in the presence of platinum or palladium/charcoal,
at a hydrogen pressure of 1 to 7 , preferably 3 to
5, bar, and at temperatures between 0 and 75C, preferably,
however, at temperatures between 20 and 50C. If
in a compound of general formula XII R6 represents
10. a benzyl group, this group may be replaced during
the hydrogenation by a hydrogen atom, or if Rl and/or
R~ represent a benzyloxy group, these radicals may
each be replaced by a hydroxy group during the hydrogenation.
g) Reaction of a compound of general form~la XIII
R2 ~ I - E - N - G ~ R3
15. 1' R2~ R3, R4, R5 to R6, A, B, E and G are
as hereinbefore defined, whereby, however, at least
one of the radicals Rl, R2, R3 and R4 must represent
a hydroxy group or R5 represents a hydroxy group,
an amino group or an alkylamino group containing 1
20. to 3 carbon atoms or R6 represents a hydrogen atom)
with a compound of general formula XIV
R8 ~ X ~XIV)
wherein R8 represents an alkyl group containing l
to 3 carbon atoms or (if R6 represents a hydrogen
25. atom) an alkenyl group containing 3 to 5 carbon atoms
or (if Rl or R2 represent a hydroxy group and/or R6
represents a hydrogen atom) an alkyl group containing
1 to 3 carbon atoms substitued by a phenyl group,
and X represents a nucleophilically exchangeable group
30- such as a halogen atom or a sulEonyloxy group, e.g.
a chlorine, bromine or iodine atom or a methanesulfonyloxy,
p-toluenesulfonyloxy or methoxysulfonyloxy group;
- 16 -
or, if at least one of the radicals Rl~ R2, R3~ R4 and Rs represents a
hydroxy group, X together wlth a hydrogen atom at the ~-position of the
radical R8 represents a diazo group, or also (if R6 represents a hydrogen
atom or R5 represents an ~mino or alkylamino group) an oxygen atom. For
example, the compound of formula XIV may he formaldehyde, being the compound
in which R8 is methyl and X together with a hydrogen atom at the ~- position
of R8 represents an oxygen atom.
The reaction is conveniently carried out in a solvent or mixture
of solvents such as diethyl ether, methanol, acetone, tetrahydrofuran,
lo dioxan, acetonitrile, pyridine or dimethylformamide optionally in the
presence of a base such as potassium carbonate, potassium hydroxide,
potassium tert.butylate or sodium hydride at temperatures between 0 and
150C, preferably, howe~er, at ~emperatures between 20 and 120C.
If X represents a nucleophilically exchangeable group, the reaction
is preferably carried out with an alkylating agent such as methyl iodide,
dimethyl sulfate, ethyl iodide, diethyl sulfate, propyl bromide, allyl
hromide, benzyl chloride, phenylethyl bromide or p-toluenesulfonic acid
isopropyl ester in the presence of an acid-binding agent at temperatures
between 20 and 80C. The reaction may, however, be carried out without a
solvent.
If X together with the hydrogen atom at the ~position of the
radical R8 represents a diazo group, the alkylation of a hydroxy group is
pre~erably carried out with diazomethane or diazoethane at temperatures
between 0 and 30C, or if it represents an oxygen atom, the alkylation of a
nitrogen atom may be carried out in the presence of a reducing agent at
,.~
;,'
- 16~1 -
temperatures between 0 and 1~0C, e.g. with formic acid at temperatures
between 80 and 110C or with sodium cyanoborohydride at room temperature
and pH 6 - 7.
h) For -the preparation of compounds of general formula I wherein A does
not represent a -CH= CH- group, R3 represents a chlorine or bromine atom
and R5 represents an amino or alkylamino group: Halogenation of a compound
of general formula XV
, , .
: .
~ 3
R2 ~ A' R6
R5nn
wherein Rl, R2, R4, R6, B, E and G are as hereinbefore
defined, A' represents A as hereinbefore defined with
the exception of a -CH=CH- group, and R5"" represents
5. an amino group or an alkylamino group containing 1
to 3 carbon atoms.
The reaction is carried out with a halogenating
agent, e.g. chlorine, bromine, tribromophenol/bromine
or phenyl iodide dichloride, preferably in a solvent
10. or mixture of solvents, e.g. in 50 to 100~ acetic
acid or in tetrahydrofuran in the presence of a compound
of a heavy metal such as mercuric oxide and conveniently
at temperatures between 0 and 50C.
The compound of general formula XV may be used
15. eitber as a base or a salt ~e.g. as its mono-, di-,
or trihydrochloride). Conveniently 1 or 2 moles (or
a slight excess) or halogenating agent per mole of
compound of formula XV or its salt may be used.
If a corresponding hydrogen halide salt is obtained
20. during the reaction, this may be direc~ly isolated
or, if desired, it may be further purified using a
base.
i) For the preparation of compounds of general formula
I wherein A represents a -COCO group, E represents
25. an ethylene, n-propylene or n-butylene group (optionally
substituted by an alkyl group containing 1 to 3 carbon
atoms) and B represents a -CH2- group:
Oxidation of a compound of general formula XVI
.
~c~l -co 16 ~ R4 (~VI)
R2 l 1 N - E - N - G ~
~/ \C~12 - C~12 \=~\ R5
wherein Rl, R2, R3, R4, R5, R6 and G are as hereinbefore defined, and E repre-
sents an ethylene, n-propylene or n-butylene group ~optionally substituted by an
alkyl group containing 1 to 3 carbon a~oms).
The oxidation is preferably carried out with an oxidizing agent such
as potassium permanganate, selenium dioxide or sodium dichromate in a solvent or
mixture of solvents such as, for example water, water~dioxan, 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 according to the invention a compound of general formula I is ob-
tained wherein B represents a carbonyl group, this may~ if desired, subsequently
- be converted by reduction into a corresponding compound of general formula I
wherein B represents a methylene group; and/or if a compound of general formula
I is obtained wherein IR7
A does not represent a -CM=CH- or -CaN- group and R6 represents a ben~yl or
l-phenylethyl group, this may, if desired, subsequently be converted by
catalytic hydrogenation into a corresponding compound of general formula I
wherein R6 represents a hydrogen atom; and/or if a compound of general formula I
is obtained wherein R3 or R4 represents a nitro group, this may, if desired sub-
~ 20 sequently be converted by reduction into a corresponding compound of general
; formula I wherein R5 represents an amino group; and/or if a compound of general
formula I wherein R6 represents a hydrogen atom and/or R5 represents an amino
group is obtained, this may, if desired, subsequently be converted by acylation
into a corresponding compound of general formula I wherein
',~ !'
19
R~ represents an alkanoyl or alkoxycarbonyl group
and/or R5 represents an alkanoylamino, alkoxycarbonylamino
or bis(alkoxycarbonyl)amino group, wherein each alkyl
part above may contain from 1 to 3 carbon atoms; and/or
if a compound of general formula I is obtained, wherein
R5 represents an amino group, R6 does not represent
a hydrogen atom, and neither R3 nor R4 represents
a cyano group, this may, if desired, subsequently
be converted via a corresponding diazonium salt into
10. a corresponding compound of general formula I wherein
R5 represents a hydrogen atom, or a hydroxy or alkoxy
group, or R5 represents a hydrogen atom and R3 represents
a halogen atom or a cyano group.
The subsequent reduction may preferably be carried
15. out with a metal hydride such as lithium aluminium
hydride or diborane in a solvent such as, for example,
diethyl ether, tetrahydrofuran or dioxan at temperatures
between 0 and lOO~C, preferably, however, at temperatures
between 30 and 85C.
20. The subsequent reduction or catalytic hydrogenation
may be carried out in a solvent such as, for example,
methanol, ethanol, ethyl acetate or glacial acetic
acid with hydrogen in the presence of a catalyst such
as platinum or palladium/charcoal at a hydrogen pressure
. of 1 to 7, preferably 3 to 5, bar and at temperatures
between 0 and 75C, preferably ~0 to 50C. By this
means, any nitro and cyano groups which are present
may be simultaneously reduced.
The subsequent acylation may be carried out
3~- with, for example, acetyl chloride, acetic anhydride,
propionic acid anhydride or a corresponding chloroformate,
e.g. ethyl chlorformate, which simultaneously may
serve as solvent, 3ptionally in a solvent such as,
for example, water/tetrahydrofuran, diethyl ether,
35- tetrahydrofuran or methylene chloride, optionally
in the presence of a base such as triethylamine or
pyridine, whereby a tertiary organic base simultaneously
may serve as solvent, at temperatures between 0 and
100~, preferably, however, at room temperature.
- 20 -
The reaction may, however, be carried out without
a solvent.
The subsequent reaction of a diazonium salt,
e.g. of the fluoroborate, the hydrosulfate in sulfuric
5. acid, the hydrochloride or the hydroiodide, may be
carried out, if desired, in the presence of copper
or a corresponding copper (I) salt such as copper
(I) chloride/hydrochloric acid, copper (I) bromide/hydro-
bromic acid or trisodium coppee (I) tetracyanide at
10. pH 7 at slightly elevated temperatures, e.g. at temperatures
between 15 and lOO~C; the subsequent reaction with
hypophosphorous acid is preferably carried out at
from -5 to 0C. The diazonium salt necessary for
this may be prepared in a solvent such as e.g. water-
15. /hydrochloric aicd, methanol/hydrochloric ac`id, ethanol-
/hydrochloric acid or dioxan/hydrochloric acid, by
diazotization of a corresponding amino compound with
a nitrite, e.g. sodium nitrite or an ester of nitrous
acid, at lower temperatures, e.g. at temperatures
20. betweeen -10 and 5C.
Further, the compounds of formula I prepared
as hereinbefore disclosed may optionally be converted
with inorganic or organic acids into their physiologically
compatible acid addition salts, for example by conventional
25. methods such as reacting the compounds as bases wi~h
a solution of the corresponding acids in a suitable
solvent.
-21-
Particularly preferred acids include, for example,
hydrochloric, hydrobromic, sulfuric, phosphoric, acetic,
lactic, citric, tartaric, ~uccinic, maleic and fumaric
acids.
5. The compounds of general formulae II to XVI
used as starting materials are partly known from the
literature, or may be obtained according to known
processes.
Thus, for example, compounds of general formulae
10. IV and VIII can be obtained, for example, by reaction
of a corresponding benzazepine with a corresponding
halogen compound and optional subse~uent reaction
with a corresponding amine. The benzazepine of general
formula II necessary for this can be obtained, for
example, by cyclisation of an appropriate compound,
e.g. by cyclisation of a compound of general formula
XVII
R2 ~ ~, X - CH2 C~--CCH
CH2~
-`-
-22-
or by ring closure of a corresponding o-amino compound
and optional subsequent catalytic hydrogenation and/or
reduction of the carbonyl group, for example with
sodium borohydride/glacial acetic acid (see, for example,
5. EP-A1 0.007.070) and/or oxidation, e.g. with selenium
dioxide.
Compounds of general formula VI can be obtained,
for example, by reaction of a benzazepine with an
appropriate halogen acetal and subsequent hydrolysis.
10. Compounds of general formula X can be obtained
for example, by reduction of a corresponding nitro
compound.
Compounds of general formulae XII, XIII, XV or XVI
can be obtained, for example by reaction of a halogen
15. compound with an appropriate amine and optional subsequent
cleavage of protective radicals, which are used for
the protection of hydroxy groups.
The compounds of general formula I and the physiologically
compatible acid addition salts thereof with inorganic
20. or organic acids possess valuable pharmacological
properties, particularly a long-lasting heart rate-
reducing effec~, and a reduction in the 2 requirement
of the heart, with only slight side-effects, e.g.
only a slight antimuscarinic effect.
25. For example the ~ollowing compounds have been
tested with regard to their biological properties
A = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-
2-one-3-yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-
phenyl)-ethyl)-amino]-propane dihydrochloride~
30. B = 1-[7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-
2-one-3-yl]-3-[N-methyl-N-(2-(3,4-dimethoxy-
phenyl)-ethyl)-amino]-propane hydrochloride,
C - 1-~7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-
1,2-dion-3-yl]~3-[N-methyl-(2-(3,4-dimethoxy-
35. phenyl)-ethyl)-amino~-propane hydrochloride,
-23
D = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-1,3-ben20-
d.iazepin-2-one-3-yl]-3-[N~methyl-(2-(3,4-dimethoxy-
phenyl)-ethyl)-amino] propane,
E = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3~benzazepin-
5. 2-one-3-yl]-3-[N-(2-(3,4-dimethoxy phenyl) ethyl)-
amino]-propane hydrochloride,
F = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-
2-one-3-yl]-3-[N methyl-N-(2-(4-amino-3,5-dichloro-
phenyl)-ethyl)-amino]-propane,
10. G = 1-[7~8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-
2-one-3-yl]-3-[N-methyl-N-(2-(4-methoxy-phenyl)-
ethyl~-aminol-propane hydrochloride,
H = 1-17,8-Dimethoxy-1,3,4,5-~etrahydro-2H-3-benzazepin-
2-one-3-yl]-3-[N-methyl-N-(2-(4-methoxy-phenyl)-
15. ethyl)-amino]-propane hydrochloride,
I = 1-[7,8-Methylenedioxy-1,3,4,5-tetrahydro-2H-
3-benzazepin-2-one-3-yl]-3-~N-methyl-N-(2-~3,4-
dimethoxy-phenyl)-ethyl-amino]-propane hydrochloride,
J = 1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-
20. 2-one-3-yl]-3-[N-allyl-N-(2-(3,4-dimethoxy-phenyl)-
ethyl)-amino]-propane hydrochloride and
K = 1-~7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-
2-one-3-yl]-3-[N-methyl~N-(2 (3,4-methylenedioxy-
phenyl)-ethyl)-amino]-propane hydrochloride,
25. in comparison with
L = 1-[7,8-Dimethoxy-1,2,3,4-tetrahydro-5H-2-benzazepin-
l-one-2-yl]-3-[N-methyl-N-(2 (3,4-dimethoxy-
phenyl)-ethyl)-amino]-propane hydrochloride
1. Efect on heart rate in cats:
-24-
The effect of the test substances on the heart
rate was investigated for each dose on 7 cats
of both sexes, with an average weight of 2.5
to 3.5 kg. ~o do this, the cats were anaesthetised
5. with Nembutal (30 mg/kg i.p.) and chloralose
urethane (40 mg/ml of chloralose + 200 mg/ml
oE urethane, as required). The substance to
be tested was injected in aqueous solution into
the vena saphena or into the duodenum.
10. The heart rate was recorded before and after the admin
istration of the substance by means of a Grass tachograph
from the electrocardiogram (taken from the chest wall)
on a Grass polygraph.
The results are shown in the following table:
. . _ .
15. Substance Dose Reduction in Half-life
_ mg!kg heart rate (minutes~
1.0 i.v. - 55 % ~ 120
B 1.0 ioV~ ~ 45 ~ ~ 120
C 1.~ i.v. - 44 % ~ gO
20. D 1.0 i.v. - 41 % 80
E 1.0 i.v. - 45 % ~ 90
F 1.0 i.v. - 51 ~ ~ 120
L 1.0 i.v. - 8. ~ 13
.
-25-
2. Effect on heart rate in quin a pig auricles:
Isolated, spontaneously beating auricles from guinea
pigs of both sexes~ with a body weight of 300 to 400
9, were tested in tyrode solution in an organ bath.
The nutrient solution was supplied with Carbogen t95
% 2 ~ 5 ~ CO2) and kept at a constant temperature
of 30C. The contractions were recorded isometrically
by means of a wire strain gauge on a Grass polygraph.
The substances to be tested were added to the organ
baths in various concentrations.
From the maximum effects, activity curves were
prepared and from them the concentration which
reduced the heart rate by 30% t= EC-6030) was
determined.
The results are shown in the following table:
Substance ~- EC 6030 [~g/ml]
. , ~
A 0.033
C 0.097
D 0.058
E 0.066
F 0.014
G 0O014
H 0.0079
I 0.063
J 0.050
K ____ 0.0l4
-26-
3. Acute toxicitY:
The acute ~oxicity of the test substance was determined
as a guide in mice (observation period: 14 days) after
intravenous administration:
.~
Substance Toxicity (LD50)
, ,..~
A 89 mg/kg i~v. 1,350 mg/kg p.o.
The compounds of general formula I are suitable for
the treatment of sinus tachycardia of various origins
and for the prophylaxis and treatment of ischaemic
cardiac diseases.
According to a yet further feature of the present
invention there are provided pharmaceutical compositions
comprising, as active ingredient, at least one compound
of general formula I as hereinbefore defined or a
physiologically compatible acid addition salt thereof,
in association with one or more pharmaceutical carriers
or excipients.
-27-
For phaLmaceutical administration the compounds
of general formula I or their physiologically compatible
acid addition salts may be incorporated into conventional
preparations in either solid or liquid form, optionally
in combination with other active ingredients. The
compositions may, for example, be presented in a form
suitable for oral, rectal or parenteral administration.
Preferred forms include, for example, plain tablet~,
coated tablets, powders, suppositories, suspensions,
drops, ampoules, capsules or juices.
The active ingredient may be incorporated in
excipients customarily employed in pharmaceutical
compositions such as, for example, corn starch, lactose,
polyvinyl pyrrolidone, tartaric acid, magnesium stearate,
cane sugar, citric acid, microcrystalline cellulose,
aqueous or non-aqueous vehicles, fatty substances
of animal or vegetable origin, paraffin derivatives,
glycols, various wetting, dispersing or emulsifying
agents and/or preservatives.
Suitable dosages for adults are from 0.03 to
0.4 mg, preferably 0.07 to 0.25 mg, of active ingredient
per kg of body weight, according to the invention~
Such dosages may, for example~ be administered 1 or
2 times daily. The total daily dosage may, however,
be varied according to the compound used, the subject
treated and the complaint concerned.
- 28 -
Advantageously the compositions may be formulated
as dosage units, each dosage unit being adapted to
supply a fixed dose of active ingredient.
According to a still further feature of the
5. present invention there is provided a method of treating
a patient suffering from or susceptible to disorders
of heart-rate, including sinus tachycardia and ischaemic
cardiac diseases, which comprises administering to
the said patient an effective amount of a compound
10~ of formula I, as hereinbefore defined, or a physiolgically
compatible acid addition salt thereof~
The following non-limiting examples serve to
illustrate the present invention.
-- 29 --
Preparation of the starting compounds
Example A
7,8-Dimethoxy-1,3-dihydro 2H-3-benzazepin-2-one
... .. ..
a) 3,4-Dimethoxyphenylacetic acid chloride
600ml of thionyl chloride were added dropwise to
a suspension of 549.4 9 of 3,4-dimethoxyphenylacetic
acid in 600ml of methylene chloride, with stirring,
over a period of 2 hours. After the development
of gas has ended (16 hours), the mixture was refluxed
for a further hour. After the volatile components
have been eliminated, the residue was distilled in
vacuo.
Yield: 436 9 (80.8 % of theory),
8p:134-136C/1.95 mbar
lS b) N-(2,2-dimethoxyethyl)-3,4-dimethoxyphenylacetamide
Whilst cooling with ice, a solution of 485.2g o
3,4-dimethoxyphenylacetic acid chloride in l.l litres
~f methylene chloride at 15 to 20C was added dropwise
to a solution of 246.2 ml of aminoacetaldehyde dimethyl
acetal and 315 ml of triethylamine in 2.2 litres
of methylene chloride and the mixture was stirred
for one hour at 16 to 18~C. Then it was extracted
with water several times, dried over magnesium sulphate
and concentrated by evaporation. The oil obtained
25 510wiy crystallised out.
Yield: 608 9 t95% of theory)
Melting point: 66-69~C
c) 7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one
A solution of 600.6 9 of N-(2,2-dimethoxyethyl)-3,4-
dimethoxy-phenylacetamide in 3 litres of concentrated
hydrochloric acid was mixed with 3 litres of glacial
acetic acid. After standing for 17 hours at ambient
temperature, the mixture was poured on to ice. The
crystals precipitated were suction filtered, washed
with water until neutral and dried.
Yield: 350 9 (75.4~ of theory)
.,
3~3
- 30 -
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-~H-3-benzazepin-2-one and 1.5 9 of 10%
palladium/charcoal in 200 ml of glacial acetic acid
was hydrogenated at 50C and at a hydrogen pressure
of 5 bar. After the catalyst had been filtered off,
~he solvent was evaporated in vacuo and the residue
was taken up in methylene chloride. After it has
been extracted with sodium bicarbonate sol~tion and
washed with water, it was dried over magnesium sulphate,
evaporated and purified over ~ilica gel with methylene
chloride and then with increasing amo~nts of methanol
(up to 10%).
Yield: 12.69 (57% of theory~
Melting point: 188-191C
Example C
7,8~Dimethoxy-2,3,4,5-tetrahYdro-lH-3-benzazepine
A solution of 1.5 9 of glacial acetic acid in 10
ml of dioxan was added dropwise to a suspension o~
1.3 g t6 mmol) of 7,8-dimethoxy-1,3,4,~-tetrahydro-
2H-3-ben~azepin-2-one and 1.1 9 (3 mmol) of sodium
borohydride in 20 ml of dioxan, the mixture was refluxed
for 3 ho~rs, concentrated by evaporation and mixed
wit~ water. The mixture was extracted twice by shaking
with methylene chloride, the extract was concentrated
by evaporation and the residue taken up in ether.
30 After fil~ering, the ether was eliminated in vacuo.
Yield: 1.1 9 (92.7 % of theory)
Melting point: 86-89C.
Example D
N-[3-[N'-Methyl-N'-(2-(3,4-dimethoxy-phenyl)-ethyl)-
amino~-propyl]~2-(2-amino-4~5-dimethoxy-phenyl)-acetamide
33.3g (0.07 mol) of N-[3-[N'-methyl-N'-(2-(3,4-dimethoxy-
_ 31 -
phenyl)-ethyl)-amino]-propyl]-2-(2-nitro~4,5-dimethoxy-
phenyl)-acetamide, dissolved in 500 ml of methanol,
were hydrogenated at 25C and at a hydrogen pressure
of 5 bar for 8 hours in the presence of 10% palladium/
charcoal. Rfter removal of the catalyst, the solvent
was distilled off in vacuo
__ .
Yield: 3l.59 ~100% of theory)~ viscous oil.
6,9-Dimetho~ dih~dro-2H-~-benzazePin-2-one
3 ml of polyphosphoric acid were poured on 2.0 g (0.007
mol) of N-(2~2 dimethoxyethyl)-2,5-dimethoxyphenyl acet-
amide and stirred for 60 minutes at 9OC. Subsequently
the reaction mixture was mixed with ice water9 the pre-
cipitated product was ~uction ~iltered and dried.
Yield: 0.98 g (64 % of theory),
M.p.: 188 - 191C.
.
Prepared analogously to Example E ~rom N-(2,2-dimethoxy-
2~ ethyl)-3,4-dimethyl-phenylacetamide and polyphosphoric
acid.
Yield: 40.1 % of theory,
M.p~: 220 - 224C.
- 32 -
.
8-DimethoxY-5-methyl-1,3-dihy~ro-3~4-benzodiazepin-2-one
1g.5 g (0.082 mol) of 2-acetyl-4,5-dimethoxyphenylacetic
acid were suspended in 200 ml of ethanol, mixed with 8.2 ml
of 98 % hydrazine hydrate and refluxed for 6 hours. The
reaction mixture was evaporated in vacuo and purified over
a silica gel column with methylene chloride and 1 % of
ethanol as elua~t.
Yield: 9.6 g ( 50 % of theory~,
IR-spectrum (methylene chloride): 3300 cm 1 (NH)
2830 cm` (OCH3)
1650 cm 1 (C0)
7~8-Dimethoxy-~l3~5-tetra~ydro-2H-3-benzaze;~n-2,4-dione
15 a)
3.7 g (0.017 mol) of 3,4-dimethoxy-o~phenylene-diacetQ
nitrile were suspended in 10 ml of glacial acetic acid
and mixed at 20C with 12 ml of 30 % hydrobromic acid in
glacial acetic acid. After stirring for 3 hours at room
temperature, the obtained precipitate was suction filtered,
washed with glacial acetic acid and subsequently with
acetone/ether and dried.
Yield: 5.3 g (82.8 % o~ theory),
M.p.: 210 - 211C (decomp.).
20 b) 7,8-Dimethox~-1~3,4,5-tetr
5.3 g (0.014 mol) of 7,8-dimethoxy-2-amino-4-bromo-1H-
~-benzazepine-hydrobromide were dissolved in 100 ml of
water heated to 85C, mixed with 1.3 g of anhydrous ~o-
dium acetate and heated for 1 hour up to 90C. The reac~
tion mixture was cooled, suction filtered9 washed with
cold water and dried.
Yield: 2.9 g (88 % of theory)9
M.p.~ 235C (decomp.).
- 33 -
~.~
N- ~ -(7,8-Dimethoxy-1,~,4,5-tetrahydro-2H-3-benzazepin-2-one-
Prepared analog~usly to Example B by catalytical hydrogenation
o~ 1-L7,8-dimethoxy-1,3-dihydro-2H-~-benzazepin-2-one-3-yl7-
3-(N-benzyl-methylamino)-propane.
Yield: 87 % of theory,
M.p.: 110C (decomp.).
Exam2le J
1-Chloro-3- ~ -methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-
amino7 ro ane
, P . P ~
a) 3- ~-Methyl-N-(2-~3,4-dimethoxy-phenyl)-ethyl)-aminQ7-
propanol ~ _
A mixture of 2.1 g (0.011 mol) of N-methyl-2-(3,4-di~
methoxyphenyl)-ethyl-amine and 0.9 g (0.011 mol~ of
methyl acrylate was allowed to rest over night at room
temperature. The addition product obtained hereby was
dissol~ed in 40 ml of ether and added dropwise with
stirring within 15 minutes to a suspension of 0.3 g
(0.008 mol3 of lithium aluminium hydride in 20 ml of
ether. After refluxing for 5 hours the reaction mixture
was cooled and subsequently 30 ml of saturated aqueous
sodium sulfate solution ~ere dropped thereto. The pre-
cipitate obtained was suction filtered over kieselguhr
and the filtrate was extracted with methylene chloride.
The organic phase was dried over sodium sulfate and
evaporated to dryness.
Yield: 3 g (89.7 % of theory),
IR-spectrum (methylene chloride): 3600, 3230 cm 1 (OH)
m/e = 25~ ~C14H23N03;
253.35).
- 3~ -
b) 1-Chloro-3 1R-methyl~N-(2~(3,4 dimethoxy-phenyl)-ethyl)-
amino7 ro ane
_ - !P
2.75 g of benzenesulfonic acid chloride were added to
4 g of ~- ~-methyl-N-(2-(~,4-dimethoxyphenyl~-ethyl)-
amino7propanol. After standing for 30 minutes the mix-
ture was dissolved ln methylene chloride, washed with
30 % sodium hydroxide solution and water, dried over
sodium sulfate and evaporated in vacuo. After purifying
o~er a silica g~l column (eluant: methylene chloride/
ethanol) a colourle~s oil was obtained.
Yield: 1 g (17 % o~ theory),
cl4H22clNo2 (271.8)
Calc.: C 61.86 H 8.15N 5.15
Found: 62.00 8.00 4.63
~ a~ ~
N-Meth~l-N- -(3~4-dim~ h_xy-phenyl)-ethyl7acetidinium-bromide
3 g (0~011 mol) of 3- ~ ~methyl-N-(2-(~,4-dimethoxy-phenyl)-
ethyl)~amin_7propanol were dissolved in 95 ~1 of methyle~e
chloride and at 0 - 5C a solution of 2 ml of phosphorus
tribromide in 5 ml of methylene chloride was dropped thereto.
A~ter heating to room temperature the reaction mixture was
refluxed for 2 hours, evaporated to dryness, subsequently
dissolved in methylene chloride, and washed with 2 n sodium
hydroxide and water. The organic phase was dried over sodium
sulfate and evaporated to dryness. After purlfying the crude
product o~er a silica gel column (eluant: methylene chloride/
ethanol = 100 : 5) the residue obtained was heated for 40 mi
nutes up to 60 - 70C.
Yield: 1.8 g (48 % of theory),
M.p.: 175 - 1B0C.
35 --
? 8-Dimethoxy-2,3-dih~dro-1H-~ benzazepine
A boiling suspension of 0. 8 g of lithium aluminium hydride
in 100 ml of absolute dioxan was reacted with 2.2 g (0.01 mol)
of 7,8-dimethoxy-1,3-dihydro-2H-~-benzazepin-2-one and subse-
quently refluxed for 3 hours. Ammonium chloride solution (10 %)
wa3 added whilst cooling with ice-water and the formed preci-
pitate was ~uction filtered. The filtrate was evaporated ixl
vacuo to a ~olume of approx. 20 ml 9 the obtained white preci-
pitate was suction filtered and washed with little dioxan.
Yield: 0.9 g (43.8 ~ of theory),
M.p.~ 162 - 163C.
'3
- 3~
Preparation of the end products
Example 1
1-[7~8-Dimethoxv-1~3-dihydro-2H-3-benzazepin-2-on
3~y1~-3-[N-methyl-N-(2-~3~4-dimethoxy-~hen~-eth
amino]-propane hydrochloride
a) l-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-
2~on-3-yl)-3-chloropropane
131.5 9 (0.6 mol) of 7,8-dimethoxy-1,3-dihydro-2H-
3-ben~azepin-2-one were suspended in 90~ ml sf dimethyl-
10 sulphoxide and mixed with 80.B 9 (0.72 mol) of potassium
tert.-butoxide, with stirring. After 10 minutes,
the solution obtained was added dropwise, whilst
being cooled with ice water, to 77 ml (0.72 mol)
of l-bromo-3-chloropropane in 300 ml of dimethyl-
sulphoxide. After one hour, the mixture was poured
on to ice water. After a short time, the glutinous
precipitate began to crystallize. The precipitate
was suction filtered, dissolved in acetone, precipitated
with water, then suction filtered and dried.
20 Yield: 15S.Sg (87.3~ of theory)
Melting point: 101-103C
b~ 7,8-Dimethoxy~1,3-dihydro-2~-3-benzazepin-
2-on-3-yl]-3-~N-methyl-N-12-(3,4-dimethoxy-phenyl)-
ethvl)-amino]-~roPane hvdrochloride
25 5.9 9 (0.02 mol) of 1-(7,8-dimethoxy-1,3-dihydro-
2H-3-benzazepin-2-on-3-yl)-3 chloropropane and 11.79
(0.06 mol) of of N-methyl-2-(3,4-dimethoxy-phenyl)-
ethylamine were heated to lOO~C for 3 hours, then
cooled and dissolved in ethyl acetate/water. The
organic phasé was removed, washed three times with
1% acetic acid and extracted by shaking twice with
2N hydrochloric acid. The hydrochloric acid extract
was made ammoniacal and extracted with methylene
chloride. The solvent of the extract was removed
in vacuo, the residue was dissolved in acetone and
the hydrochloride was precipitated out with ethereal
hydrochloric acid.
J~3~-3
- 37 -
Yield: 6.9 ~70.3% of theory)
Melting point: 190 191C (decomp.)
Example ?
1-[7,8-Dimethoxy-2,3,4,5-tetrahydro-lH-3,5-benzodlaze~ine-
2,4-dion-3-yl~ 3~[N-methyl-N-~2-t3,4-dimethoxy-phenyl)-
ethyl)-amino]-propane hydrochloride
4.6 9 ~0.0l mol) of N-[3-[N'-methyl-N'-(2-(3,4-dimethoxy-
phenyl)-ethyl)-amino]-propyl]-2-(2-amino-4,5-dimethoxy-
phenyl)-acetamide and 3.6 g (0.022 mol) of N,~'-carbonyl-
diimidazole were boiled in l00 ml o~ acetonitrilefor 33 hours. The solvent was removed in vac~o and
the residue purified over alumina (Woelm N, Act.
III) with methylene chloride and 15% acetone as eluant.
The fractions were concentrated by evaporation ln
vacuo, the residue was dissolved in acetone and precipitated
with ethereal hydrochloric acid.
Yield: l.lg (21.7~ of theory)
Melting point: l25-l30CC.
Example 3
2~ 1-/7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin 2-one-
3 yl7-3- ~ -methyl-N (2-(2-amino-3,5-dichloro-phenyl)-amin ~-
ro ane
P. ~ . _ _ __ _ , _
Prepared analogously to Example 1b by reaction of 1-t7,8-di-
methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-
3-chloro-propane with N- ~ -(2-amino-3,5-dichloro-phenyl)-
ethyl7methylamine. Oil.
UV-spectrum (ethanol): ~ max 240 nm (0,34)
285 nm (0.14)
~06 nm (0.10)
30 IR-spectrum (dichloromethane): 2810 cm 1 (N-alkyl)
2840 cm 1 (O-CH3)
1655 cm 1 (CcO)
1520 and 1620 cm 1 ~C=C)
~ 3
- 38 -
Example 4
1-[7,8-Dimethoxy-1,3,4,5-tetrahydro-2H 3-benzazepin-
2-on~3- 1]-3-[N-meth l-N-(2-(3,4-dimethoxv-phenyl)-
Y _ Y
ethyl~amino~-propane dihydrochl~ride
5.8 9 (0.0127 mol) of 1-[7,8-dimethoxy-1,3-dihydr~-
2H-3-benzazepin-~one~3-yl]-3-~N-methyl-~-(2-(3,4-
dimethoxy-phenyl)-ethyl~amino]-propane, dissolved
in 60 ml o~ glacial acetic acid, were hydrogenated
for 5 hours at ambient temperature and at a hydrogen
pressure of 5 bar in the presence o 10~ palladium/charcoal.
The catalyst was filtered off, the filtrate was concentrated
by evaporation _ vacuo and the resid~e taken up
in methylene chloride/semisaturated potassium carbonate
solution. The organic phase was treated with activated
15 charcoal/bleaching earth, filtered and evaporated in
vacuo. Subsequently, the residue was dissolved in ace-
tone and the dihydrochloride was precipitated with
ethereal hydrochloric acid.
Yield: 6.2 g (9~ ~ of theory)~
20 M.p.: 137C (decomp.).
When using an equimolar ~mount of ethanolic hydrochloric
acid the hydrochloride was obtained having a melting point
of 165 - 168C.
- 39 -
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro 2H-3-benzazepin-2-one-
3-yl7-3- ~ _methyl_N_(2-(~,4-dimethoxy-phenyl)-ethyl)-amino7
~ro ane dihvdrochloride
a) 1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
~-~l)-3-chloro=propane _ _ _ _
Prepared analogously to Example 1a by reaction of 7,8-di-
methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one with
1-bromo-3~chloropropane (yield: 50 % of theory) or ana-
logously to Example 4 by catalytic hydrogenation of1-~7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl)-
~chloro-propane (yield: 88 ~ of theory).
M.p.: 84 - 85C.
b) 1 ~ ,8-Dimethoxy-1,3,4~5-tetrahydro-2H-3-benzazepin-2-one-
15 ~-yl7-3- ~-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino7-
Prepared analogously to Example 1b by reaction of 1-(7,8-
dimethoxy-1,3,4,5-tetrahydro 2H-3-benzazepin-2-one-3-yl)-
3-chloro-propane with N-methyl 2-~3,4-dimethoxy-phenyl)-
ethylamineOYield: 75.2 % of theory,
M.p.: 135 - 137C (decomp.~.
r~ ~r~
-- ~10 --
Example 6
1-[7,8-~imethoxy-2,3,4,5-tetrahydro-lH-3-benzaze~in-
3-yl]-3-~N-methyl-N-(2-(3~4-dimethoxy-phenyl)-ethyl)
amino]-propane dihydrochloride
2.7 9 (6 mmol) of 1-[7,8-dimethoxy-1,3,4,5-tetrahydro-
2H-3-benzazepin-2-one-3-yl]-3-[N-methyl-N-(2-(3,4-
dimethoxy-phenyl)-ethyl)-amino~-propane ~ere dissolved
in 100 ml of absolute ether and 100 ml of absolute
tetrahydrofuran, then mixed with 0.25 9 of lithium
aluminium hydride and refluxed for 3.5 hours. After
cooling, a 10% ammonium chloride sol~tion was added,
whilst cooling was continued, then the mixture was
suction filtered and the filtrate concentrated by
evaporation. The residue was purified over a silica
gel col~mn with methylene chloride. The fractions
were concentrated by evaporation, the resid~e was
dissolved in acetone and the dihydro~hloride precipitated
with methanolic hydrochloric acid.
Yield: 1.59 (48.5~ of theory~,
Melting point: 270-271~C ~decomp.1.
1~7,8-Dimethoxy-1,3~dihydro 2H-3-benzazepin-2-one-3-y
3~ ~ -methyl-N-(2-(4~ethoxy-phenyl)-ethyl)-amino7propane
Prepared analogously to Example 1b by reaction of 1-(7,8-di-
methoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl)-~-chloro-
propane with N-methyl-2-(4-methoxy-phenyl)-ethylamine.
Yield: 76.2 % of theory,
M.p.: 139 - 142C.
,~?~g
Fxample 8
1- ~ ,8-Dimethcxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-y ~-3- ~ -methyl-N-(2-(4-methoxy-phenyl)-ethyl)-amino7-
nro~ane hvdrochloride
Prepared analogously to Example 4 by catalytical hydrogenation
of 1-~ ,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-y~ -
3- ~-methyl-N-(2-(4-methoxy-phenyl)-ethyl)-amino7propane.
Yield: 73.3 % of theory,
M.p.: 175 - 177C.
10 ExamPle 9
-
1- ~ ,8-Methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one 3-yl7-
3- ~-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino7propane
hvdrochloride
a) 1-(7,8-Methylenedioxy-1,3~dihydro-2H benzazepin-2-one-3-yl)
3-chloro-propane
Prepared analogously to Example 1a by reaction of 7,8-
methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one (m.p.:
~95C (decomp.)) with 1-bromo-3-chloropropane.
~ield: 72.1 % of theory,
M.p.: 75 - 79C.
..
b) 1- ~ ,8-Methylenedioxy-1,3-dihydro-2H-3-benzazepin-2-one-
3-yl7-3- ~-methyl-N-(2-(3,4 dimethoxy-phenyl~-ethyl)-
Prepared analogously to Example 1b by reaction o~
1-(7,8-methylenedioxy-1,3-dihydro-2H-benzazepin-2-one-3~yl)-
~-chloro-propane with N-methyl-2-(3,4-dimethoxy phenyl)-
ethylamine.
Yield: 77.2 % of theory,
M.p.: 185 - 187C.
- ~2 -
Example 10
1-~ ,8 Methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin
2-one-3-yl7-3- ~-methyl-N-(2~(~,4-dimethoxy-phenyl)-ethyl)-
amlno~ ropane hydrochloride _ ____
5 Prepared analogously to Example 4 by catalytical hydrogena-
tion of 1 ~ ,8-~ethylenedioxy-1,3-dihydro-2H-3-benzazepin-
2-one-3-yl7-3- ~ -methyl-N-(2~(3,4-dimethoxy-phenyl)-ethyl)-
amino7propane.
Yield: 77.3 % of theory,
lO M.p.: 210 - 212C.
1- ~ ,8-Dimethoxy-1,3,415-tetrahydro-2H-3-benzazepin-2-one-
3 yl7-3- ~ _methyl_N_(2_(394_dimethoxy-phenyl)-ethyl)-amino7-
~ro~ane
0.05 ml of glacial acetic acid were added at room temperature
to a mixture of 0.22 g ~0.5 mmol) of 1 ~ ,8-dimethoxy~1,3,4,5-
tetrahydro-2H-3-benzazepin-2-one-3-yl7-3- ~ -(2-(3,4-dimethoxy-
phenyl)-ethyl)-amino7propane, 0.5 ml of 37 % formali~ solution,
2 ml of acetonitrile and 0.1 g of sodium cyanoborohydride.
A~ter 2 hours 9 further 0.05 ml of glacial acetic acid were
added and the mixture was stirred for 30 minutes. The further
processing was carried out by evaporating, taking up in
methylene chloride, washing in 2 n sodium hydroxide solution
and water. The organic phase which was dried over sodium
sulfate was evaporated and purified over silica gel.
Yield: 104 mg (45.5 % of theory), viscous oil9
IR-spectr~m (methylene chloride): 1645 cm 1 (C0),
1510 cm 1 (aromatc C=C)
M.p. o~ the dihydrochloride: 137~C (decomp.).
- ~3 --
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3~ ~-methyl N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino7-
ro ane dihvdrochloride
5 22 g (0.075 mol) of N- ~ -(7,8-dimethoxy-1,3,4,5-tetrahydro-
2H-3-benza~epin-2 one-3-yl)-propy_7methylamin~ were heated
with 7.2 g (o.036 mol) of 2-(3,4-dimethoxy-phenyl)~ethyl-
chloride for 20 hours up to 140Co After dissolving the
reaction product in methylene chloride the solution was
washed twice with 2 n sodium hydroxide solution and twice
with water, dried over sodium sulfate and evaporated~ The
residue was purified by chromatography on silica gel (corn
size: 0.063 - 0.2 mm; eluant: methylene chloride/methanol
= 10 : 1). The product thus obtained was dissolved i~ acetone
and the dlhydrochloride was precipitated uith ethereal hydro~
chloric acid.
Yield: 8.0 g (45 % of theory),
M.p.: 135 - 136C (decomp.).
~e~
1- ~ ,fl-Dimethoxy-1,3,4,5-tetrahydro-2H ~-benzazepin-2-one-
3-yl7 3- ~-methyl N-(2-~4~acetylamino-3,5-dichloro-phenyl3-
ethyl)-amin ~ r~pane _ _ _ _ _ _
3 g (0~0063 mol) of 1- ~ ,8-dimethoxy-1,3,4,5-tetrahydro-2H-
3-ben~azepin-2-one-~-yl7-3- ~ -methyl~N-(2-(4-amino-3,5-di-
chloro-phenyl) ethyl)-~min_7propane in 50 ml of chloroform
and 0.7 g (0.007 mol) of triethylamine were mlxed ~t
boiling temperature in portions with altogether approx.
0.8 ml of acetyl chloride. After boiling for several hours,
the reaction mixture was cooled to room temperature and washed
with water. The aqueous phase was made stronyly alkali~e
by means of 2 n sodium hydroxide solution and extracted wlth
methylene chloride. The separated organic phase was dried
over ~odium sulfate and evaporated. The crude product thus
obtained was purified by chromatography on silica gel (corn
size~ 0.063 - 0.2 mm, eluant: methylene chloride/ methanol
= 8:1).
M.p.: 144-146C.
a ~ ~r~
- 4~ -
1-l7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3- ~_methyl~N_(2-(4-amino-3,5-dibromo-phenyl);ethyl)-
a~ino7~ro~ane
S 0.8 g (0.005 mol) of bromine were dropped at room temperature
with stirring to a solution of 1 g (0.0025 mol) of 1~ ~ ,8-di-
methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3~y~ -3- ~ -
methyl-N-(2-(4-aminophenyl)-ethyl)-amin_7propane in 20 ml of
95 % acetic acid. After approx. 60 minutes the solvent was
removed in a rotation evaporator and the residue was distri-
buted between 2 n sodium hydroxide solution and methylene
chloride. The methy'ene chloride phase was washed once with
water, dried over sodium sulfate and e~aporated in vacuo.
The obtained oily residue crystallized at room temperature
and was recrystallized from absolute ethanol for ~rther
purification.
M.p.: 105 - 110C.
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
20` ~-yl7-3-~ methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino7
0.22 g (0.5 mmol) of 1- ~ ,8-dimethoxy-1,3,4,5-tetrahydro-
2H-3-benzazepin-2-one-3-yl7-3- ~ -(2-(3,4 dimethoxy-phenyl~-
ethyl)-amino7propane were heated with 0.2 ml of 37 % formalin
solution and 0.2 ml of 100 % formic acid for 20 minutes up
to 90 - 100C. The further processing was carried out analo-
gously to Example 11. Viscous oil.
IR-spectrum (methylene chloride): 1645 cm 1 (C0),
1510 cm 1 (aromatic C=C)
3a M.p. of the dihydrochloride: 137C (decomp.).
hJq~33
- 45 -
1- ~ ,8~Dimethoxy-1,3,495-tetrahydro~2H~-benzazepin-2-one-
3 y~ -3- ~ -methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino7-
~ro~ane
1.26 g (20 mmol) of sodium cyanoborohydride were added to a
solution of 3.29 ~ (10.0 mmol) of N- ~ -(7,8-dimethoxy-1,3,495-
tetrahydro-2H-3~benzazepin-2-one-3-yl)-propyl7methylamine-
hydrochloride and 1.8 g (10.0 mmol) of 2-(3,4-dimethoxy-phenyl)-
acetaldehyde in 40 ml of ethanol, whereby a pH-value of 6 - 7
was kept by the addition of 2 n hydrochloric acid, and stirring
was continued for further 48 hours at room temperature, After
e~aporating the solution in vacuo, the residue was taken up
in diluted hydrochloric acid and extracted twice with ether.
Subsequently the aqueous phase was made alkaline, extrac-
ted thrice with methylene chloride, the organic phase wasevaporated ~nd purified over silica gel. Oil.
IR-spectr~m (methylene chloride~: 1645 cm 1 (CO)
1510 cm 1 (aromatic C=C)
M~pr of the dihydrochloride: 137C ~decomp.).
20 ~
1- ~,8-Dimethoxy-1,3,4 9 5-tetrahydro~2H-3-benzazepin-2-one-
3-yl7-3- ~ -methyl~N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amin ~-
~rODane
1.26 g (20 mmol) of sodium cyanoborohydride were added to a
solution of 2.77 g (10 mmol) of 3-~7,8 dimethoxy-1,3,4,5
tetrahydro-2H-3-benzazepin-2-one-3-yl)-propionaldehyde and
1.95 g (10 mmol) of N-methyl-2-(3,4-dimethoxy-phenyl)-ethyl-
amine in 40 ml of methanol, whereby a pH ~alue of 6 - 7 was
adjusted by the addition of hydrochloric acid, At this pH
3a value the reaction mixture was stirred for 50 hours at room
temperature. After evaporating the ~olution in vacuo, the
- 46 -
residue was taken up in diluted hydrochloric acid and
extracted ^thrice with ether. The aqueous phase was
made alkaline, extracted thrice with methylene chlori-
~de, the organic phase was evaporated and purified over
silica gel. Thereby a slight yellow, viscous oil was
obtained.
IR-spectrum (methylene chloride): 1645 cm 1 (C0)
1510 cm 1 (aromatlc C=C)
M.p. of the dihydrochloride~ 137C (decomp.~.
Example 18
1- ~ -Methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2 one~3-y~ -
3- ~ -methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amin ~ -propane
dihydrochloride _ _ _
a) 1-(8-Methoxy-1,3-dihydro-2H-3-benzazepin-2-one-3 yl)-
~
Prepared analogously to Example 1a by reaction of 8-meth-
oxy-1,3~dihydro-2H-3-benzazepin-2-one (m.p.: 189 - 190C)
with 1-bromo-3-chloropropane.
Yield: 23 % of theory,
IR-spectrum (methylene chloride): 1655 cm 1 (C0)
b) 1-~-Methoxy-1 9 3,4 9 5-tetrahydro-2H-3-benzazepin-2-one-
-3-chloropropane
Prepared analogously to Example 4 by catalytic hydro-
genation of 1-(8-methoxy-173-dihydro-2H-3-benzazepin-2-one-
3-yl) 3-chloropropane.
Yield: 67 % of theory,
IR-spectrum (methylene chloride): 1645 cm 1 (C0)~
c) 1- ~-Methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl7-
3- -methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl) -amino7-propane
dihYdrochloride _ _ _
Prepared analogously to Ex~mple 5b by reaction of 1-(8-
- 47 -
methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin~2-one~3-yl)-
3-chloropropane with N-methyl-2-(3,4-dimethoxy-phenyl)-
ethylamine.
Yield: 14 % of theory,
M.p.: 118 - 121C.
1- ~ ,8-Dimethoxy-1,3,4,5 tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3 ~-methyl-N-(2 (4-amino~3-chloro-phenyl)-ethyl)-amino7-
Prepared analogously to Example 12 from N- ~ -(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-propy ~-methyl-
amine and 2~(4~amino-3-chloro-phenyl)-ethylbromide. Oil.
IR-6pectrum (methylene chloride): ~380, 3480 cm 1 (NH2)
1645 cm (CO)
15 W~spectrum (ethanol): ~ max. 238 nm (0.16)
Z80 - 290 nm (0.05)
1- ~ y8-Dimethoxy-1,3,4~5-tetrahydro-2H-3-benzazepin-2-one-
3-y~ 3 ~-ethyl-N-(2-(4-amino-3 t 5~dichloro-phenyl)-ethyl)
amino7~roDane
Prepared ~nalogously to Example 12 from N- ~ -(7,8-dimethoxy-
1 9 3,4,5-tetrahydro-2H-3 benza2epin-2-one-3-ylj --propyl7-
ethylamine and 2-(4-amino-3,5-dichloro-phenyl)-ethylchloride.
Oil.
25 IR-spectrum (methylene chloride): 3390, 3480 cm 1 (NH2)
1650 cm 2 (CO)
W~spectrum (ethanol): ~ max: 240 nm (0.13)
280 - 290 nm (0.05)
1-~7t8-Dimethoxy~1,3,4,5-tetrahydro-2H-3 benzazepin-2-cne~
3-y ~3- ~ -methyl~N-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)-
min 7~ro~ane
Q ~
- 48 ~
Prepared analogously to Example 12 from N- ~ -(7,8-di-
methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)
. propyl7~ethylamine and 2-(4-amino-3,5-dichloro-phenyl)-
ethylchloride.
5 M.p.: 94 - 104C.
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2~one-
3-yl7-3- ~ _methyl_N_(2-(4-amino-3,5-dibromo-phenyl)-ethyl)-
amino ~ropane ~
lO Prepared analogously to Example 12 from N- ~ -(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-propyl7methyl-
amine and 2-(4-amino-3,5-dibromo-phenyl)-ethylchloride.
M.p.: 108 - 112C.
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-y ~ -3- ~ -methyl-N-(2-(4-ethoxycarbonylamino-3,5-dichloro-
Prepared analogously to Example 13 from 1- ~ ~8-dimethoxy-
1,3,4,5-tetrahydro-2H-~-benzazepin 2-one-3-y ~ -3-~-methyl-
20 N-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)-amino7propane and
ethyl chloroformate. Oil.
IR-spectrum (methylene chloride): 3410 cm 1 (NH)
1650 cm 1 (CO-N' )
1735 cm 1 (CO-O-)
1800 cm 1 (CO-O-)
W spectrum ~ethanol): ~ max: 240 nm (shoulder, O.08)
280 290 nm (0.03)
r ~' ~ y
~ 49 --
Example 24
1-~;7,8-Dimethoxy-1,3,4~5-tetrahy~ro-2H-3-benzazepin-2-one-
3-y;!7-3-~-methyl N-(2-(4-bis-(ethoxycarbonyl)-amino-3,5-di-
chlorophenyl~-ethyl~-amino7propane _ _
5 Prepared analogously to Example 13 from 1-~8-di~ethoxy-1~3
4,5-tetrahydro-2H-3~benzazepin-2 one-3-yl7-3-~i-methyl-
N-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)-amino7propane
and ethyl chloroformate. Oil,
IR-spectrum (methylene chloride): 1650 cm 1 (CO-N' )
1730 cm (CO-O-)
1760 cm 1 (CO-O-)
1800 cm 1 (CO-O-)
W-spectrum (ethanol): ~ max: 228 nm (shoulder~ 0.15)
282 nm (O.03)
15 ~
,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3-~-methyl-N-(2-(4-ethoxycarbonylamino-3-cyano-5-
Prepared analogously to Example 13 from 1-~,8-dimethoxy-
20 1,3,4,5-tetrahydro~ 2H-3-benzazepin-2-one-3-yl7-3~ methyl-
N (2-~4 amino-3-cyano-5-fluoro-phenyl)-ethyl)-amino7-propane
and ethyl chloroformate in the presence o:E triethylamine.
IR-spectrum (methylene chloride): 3400 cm 1 (NH)
Z830 cm ( 3) -2
1730, 1650, 1510 cm (CO)
- 50 -
Example 26
. 1-~7,8-Dimethoxy-1,3,4 9 5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7 3- ~ -methyl-N-(2-(4-dimethylamino-3,5-dichloro-phenyl)-
~,~,~
.
Prepared analogously to Example 11 from 1- ~ ,8-dimethoxy
1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-y ~-3- ~-methyl~
N-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)-amino7propane,
paraformaldehyde and sodium cy~noborohydride in methanol.
Oil~
IR-spectrum (methylene chloride): 1650 cm ~
W-spectrum (ethanol): ~ max: 227 nm (shoulder, 0 16)
280 nm (0.12)
Example 27
1- ~ ,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one 3-yl7-
3 ~ -methyl-N-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)-
Prepared analogously to Example lb from 1-(7,8-dimethoxy-
1,3-dihydro~2H-3-benzazepin-2-one-3-yl)-3-chloro-propane
and 2-(4-amino-3,5-dichloro-phenyl)-N-methyl-ethylamine. Oil.
20 IR-spectrum (methylene chloride): 3390, 3480 cm 1 (~H2)
1655 cm 1 (CO)
W -spectrum (ethanol): ~ max: 238 nm (sho~lder, 0 25)
. 280 nm (0.1)
303 nm (0.12)
25 a~
1- ~ ,8-Dimethoxy-1,3,4,5~tetrahydro 2M-3-benzazepin-2~one-
3 yl7-3-/~-methyl-N-(2-(4-amino-3,5-dichloro-phenyl)~ethyl)-
ne
Prepared analogously to Example 4 from 1- ~ ,8-dimethoxy-
30 1,3-dihydro-2H-3-benzazepin-2-one-3-yl7-3- ~-methyl-N-(2-
` (4-amino-3,5-dichloro-phenyl)-ethyl)-amin_7propane and
~A~3
- 51 -
hydrogen in the presence of palladium/coal in glacial
acetic acid.
M.p.: g4 - 104C.
1-~7,8-Dimethoxy-1,3,4 9 5-tetrahydro-2H-3-benzazepin-2-one-
3-y ~3- ~ -ethyl-N-(2-(4-amino-3,5-dibromo-phenyl)-ethyl)-
Prepared analogously to Example 5b from 1-~7,8 dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-3-chloro
propane and 2-(4-amino-3,~-dibromo-phenyl)-N-ethyl-ethyl-
amine. Oil.
IR-spectrum (methylene chloride): 3380, 3480 cm 1 (NH2)
1645 cm 1 (CO)
W -spectrum (ethanol): ~ max: 240 nm (shoulder, O.13)
280 - 290 nm (0.04)
~a~
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one~
3-yl7-3~ ~-methyl-N-(2-~4-amino-3,5-dichloro-phenyl)-ethyl)-
~0 Prepared analogously to Example 5b from 1-(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-3 chloro-
propane and 2-(4-amino-3,5-dichloro-phenyl)-N-methyl-ethyl-
amine,
M.p.: 94 - 104C.
- 52 -
Exa~ple 31
1-/7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3~benzazepin-2~one-
3-yl7-3- ~ _isopropyl-N-(2-(4-amino-3,5-dichloro-pheny1)-
Prepared analogously to Example 5b from 1-(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl) 3-chloro-
propane and 2-(4-amino-3,5-dichloro-phenyl)-N-isopropyl-
ethylamine.
M.p. of the hydrochloride: ~ 9~C (sintering from 70C~.
IR-spectrum (methylene chloride): 3390, 3480 cm 1 (NH2)
1650 cm 1 (C0)
W -spectrum ~ethanol): ~ max: 238 nm (0.13)
280 - 290 ~m (O.05)
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3- ~ -methyl-N-(1-methyl-2-(4-amino-3,5-dichloro-
Prepared analogously to Example 5b from 1-(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H 3-benzazepin-2-o~e-3-yl)-3-chloro-
propane and 2-(4-amino-3,5-dichloro-phenyl)-1-methyl-N
methyl-ethylamine.
M.p.: 118 - 128C (decomp.).
1~ ~ ,8~Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2~one-
3-yl7-3- ~ -(2-(4-amino-3,5-dichloro-phenyl)-ethyl)-amino7-
Prepared analogously to Example 5b from 1-~7,8-dimethoxy-
1,3,4,5~tetrahydro-2H-3 benzazepin-2-one-3-yl) 3-chloro-
- 53 -
propane and 2-~4-amino 3,5-dichloro-phenyl)-ethylamirle.
M~p.: 236 - 241C.
1-l7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-
2-one-3-yl7-3- ~-methyl-N-(2-(4-amino-3-chloro-5-methyl-
Prepared analogously to Example 5b from i-(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2 one-3-yl)-3-chloro-
propane and 2-(4-amino~3-chloro-5-methyl-phenyl)-N-methyl-
ethylamine.
M.p.: 60C (sin-tering, melting at 73C).
IR-spectr~m (methylene chloride): 3390, 3480 cm ~ (NH2)
1650 cm 1 (C0)
W -spectrum (ethanol): ~ max: 237 nm (0.14)
280-290 nm (O.05)
1- ~,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3- ~ -methyl N-(2-(~,5-dichloro-4-hydroxy phenyl)-
Prepared analogously to Example 5b from 1-(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2~one-3-yl)-3-chloro- .
propane and 2-(3,5-dichloro-4-hydroxy-phenyl)-N-methyl-ethrl-
amine.
M.p.: 225C.
- 5~ -
1 ~ ,8-Dimethoxy~1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3- ~-methyl-N-t2-(3-chloro-5-fluoro-4-B~B~B -trifluoro-
eth~lam~ henyl)-ethyl)-amino7propane _ _
Prepared analogously to Example 5b from 1-(7,8-dimethoxy-
1,3,4 9 5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-3-chloro-
propane and 2-(3-chloro-5-fluoro-4-B,B,B-tri~luoroethyl-
amino-phenyl)-N-methyl-ethylamine.
m/e c 545/547 (C26H32ClF4N303; 546.03)
Example 37
1- ~ ,~-Dimethoxy-~,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3- ~ -methyl-N-(2 (4-amino-3-chloro-5-fluoro-phenyl~-
Prepared analogously to Example 5b from 1-(7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-3-chloro-
propane and 2-(4-amino-3-chloro-5-fluoro-phenyl)-N-methyl-
ethylamine.
m/e = 463/465 ~C24H31ClFN303; 463.99)
1- ~ ,8rrDimethoxy 1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3 yl7-3- ~_methyl_N_(2-(4-amino-3-chloro-5-trifluoromethyl
Prepared analogously to Example 5b from 1-(7,8-dimethoxy-
1,3 9 4,5-tetrahydro-2H-3-benzazepin-2~one-3-yl)-3-chloro-
2s propane and 2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-
N-methyl-ethylamine. Oil,
3~:~
- 55 -
IR-spectrum (methylene chloride): 3410, 3510 cm 1 (NH2)
1650 cm 1 (C0)
1610, 1520 cm 1 (C=C)
2800 cm 1 (N-alkyl)
2830 cm (OCH3)
UV-spectrum (ethanol): ~ max: 241 nm (0.33)
285 nm (0.10
310 nm (0.08
~ ,,
1- ~ ,8-Dimethoxy-1,3,4,~-tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3- ~ _methyl_N_(2-(4 amino-3-cyano-5-fluoro-phenyl)-
ethyl?-amino7proPane
Prepared analogously to Example 5b from 1-(7S8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-3-chloro-
15 propane and N-methyl-(~ (4-amino-3-cyano-5-fluoro-phenyl)-
ethyl~-amine.
IR-spectrum (methylene chloride): 3400, 3490 cm 1 (NH2)
2830 cm~1 (OCH3)
2220 cm 1 (CN)
1650 cm 1 (C0)
1- ~ ,8~Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-y ~-
3- ~-benzyl-N-(2-(3,4-dimethoxy~phenyl)-ethyl)-amin~ -
25 Prepared analogously to Example 1b from 1-(7,8-dimethoxy-1,3-
dihydro-2H-3-benzazepin 2-one-3-yl)-3-chloro-propane and 2-
(3,4-dimethoxy-phenyl)-N-benzyl-ethylamine.
Yield: 51 % of theory,
M,p.: 102C (decomp.),
- 56 -
. 1- ~ ,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl7-
3- ~-methyl-N-(2-(3,4-methylenedioxy-phenyl~-e-thyl)-amino7-
~ro~ane hvdrochloride
Prepared analogously to Example 1b from 1-(7,8-dimethoxy-
1,3-dihydro-2H-3-benzazepin-2-one-3-yl~-3-chloro-propane
and 2-(3,4-methylenedioxy-phenyl)-N-methyl-ethylamine.
Yield: 48 % of theory,
M.p.: 160 - 162C.
10 ~
1 ~ ,8~Dimethoxy-1,3-dihydro-2H-~-benzazepin-2-one-3-yl7-
Prepared analogously to Example 1b from 1-(7,8-dimethoxy-
1,3-dihydro-2H-3-benzazepin-2-one-3-yl)-3-chloro-propane
and N-methyl-benzylamine.
Yield: ~2 % o~ theory,
.p.: 208 - 209C.
1~ ~ ,8-Dimethoxy-1,3~dihydro-2H~3-benzazepin-2-one-3-yl7-
4- ~-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino7-
butane hydrochloride ~
Prepared analogously to Example 1b from 1-(7,8-dimethoxy-
1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-4-chloro-butane
and N-methyl-2-(3,4-dimethoxy-phenyl)-ethylamine.
25 Yield: 85 % of theory,
M.p.: 162 - 164C,
- 57 -
~ Propoxy-1,3-dihydro~?H-3-benzazepin 2-o~e-3 y~-
2~ ~ -methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amin~-
Prepared a~alogously to Example 1b from 1 (8-propoxy-1,3~di-
hydro-2~-3-benzazepin-2-one-3-yl)-2-chloro-ethane and N-
methyl-2-(3,4-dimetho~y-phenyl)-ethylamine.
Yield: 31 % o~ theory,
M.P.: 155 - 157C.
10 Exam~le 4~
1- ~ ,8-Dimethoxy-1 9 3,4,5-tetrahydro-2H-3-be~zazepin-2 one-
3-yl7-4- ~-methyl-N-(2-(3,4-dimethoxy-phenyl~-ethyl)-ami~o7-
Prepared analogously to Example 4 by catalytic hydrogena-
tion of 1- ~ ,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-o~e-
3-yl7-4- ~-methyl-~-(2-(~,4-dimetho~y-phenyl)-ethyl j - Am ino7-
b~tane.
M,p.: 192 - 194C.
io 1-~ , 8-Dimetho~y-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one
3-yl7-3- ~ -~ethyl-N-(2-(3,4-methylenedio~y-phenyl~-ethyl~-
Prepared analogously to Example 4 by catalytic hydrogenation
o~ 1- ~ ,8-di~etho~y-1 3 3-dihydro-2H~3-benzazepin-2-one-3-yl7-
~ ethyl-N-(2-(3,4-methylenedio~y-phenyl)-ethyl)-amin ~-
propane.
Yield- 72 % of theory,
M.p.: 191 - 193 C.
~ 58 -
..,, ~
,8~Dimetho~y~1,3,4,5-tetrahydro-2H-3-ben2azepin-~-one-
3-yl7-3-~ -(2-(3,4-dimethoxy-phenyl)-ethyl~ amin_ 7propane
S Prepared analogously to Example 4 by catalytic hydrogena-
tio~ of 1- ~ ,~-dimethoxy-1,3-dihydro-2H-3~benzazepin 2-one-
3~yl7 ~- ~ -benzyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl) -ami~o7-
propane.
Yield: 81 % of theory,
M.p.: 152 - 154C.
~L~
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-be~zazepin-2-one-
3-y ~-3- ~ -allyl-N-(2-(3,4 dimetho~y-phenyl)-ethyl) -amino7-
~ro~ane hvdrochloride
3.1 g (0.007 ~ol) o~ 1- ~ ,8-dimetho~y-1i3,4,5-tetrahydro-2H-
3-~enzazepin-2-one-3-yl7-3- ~ -(2-(3,4-dimethoxy-phenyl)-ethyl~-
ami~o7-propane were reflu~ed for 21 hours with 1.0 g (0.007 mol)
of potassium carbonate and 0.6 ml (~.007 mol) o~ allyl bromide
i~ 100 ml of chloro~orm. Sub~equently the orga~ic phase was
e~tracted with water, dried, evaporated ln vacuo and the re-
sidue obtained was purified over an aluminiu~ oxide column
(300 g, ~eutral, act~vity III) with methylene chloride con-
tai~ing. 2 ~ of acetone as eluant.
Subsequently the hydrochloride was precipitated.
Yield: 40 % of theory,
M.p.: 153 - 155C.
- 59 -
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-y ~-3- ~-propyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amin ~-
~opane hydrochlorid
Prepared analogously to Example 48 from 1- ~ ,8-dimetho~y-
1,3,4,5-tetrahydro-2H-3~benzazepin-2-one-3~yl7-3- ~ -(2-
(3,4-dimethoxy-phenyl)-ethyl) - amin_7propane and 1-bromopropane.
Yield: 53 % of theory~
M.p.: 80C (decomp.).
10 ~
Mixture of isomer~ of 1- ~ ,8-dime~ho~y-1,3-dlhydro-2H-
3-benzazepin-2-o~e-3-yl7-3- ~ -methyl-N-(2-(2- and 4-nitro-
Prepared analogously to Example 1b from 1-~7,8-dimethoxy
1,3-dihydro-2H-3~benzazepin-2-one-3-yl)-3-chloro-propane
~nd N-methyl-2-~4- and 2-nitro-phenyl)-ethylamine.
Yield: 70 % of theory,
IR-spectrum (methylene chloride): 1655 cm 1 (C0)
1510 and 1345 cm 1 ~N02)
NMR-spectrum (CDCl3/D20): ~= 8.10 ppm, d(J~9~z)9 2H (arcmat.),
(4-nitro compoun~),
. 7.83 ppm, d(J-7Hz), 2H (~romat.),
(2-nitro co~pound).
t;,;~P~
- 60 -
~a~
Mixture of isomers of 1- ~ ,8-dimethoxy-1~3-dihydro-2H-
3-benzazepin-2 one-3-yl7-3- ~ -methyl-N-~2 (2-amino-
Prepared a~alog~usly to Example 4 by catalytic . reductionof a isomer mixture of 1- ~ ,8-dimethoxy-1,3-dihydro-2H-
3-benzazepln-2-o~e-3~yl7~- ~ -methyl-N-(2-(2- and 4-nitro-
phenyl)-ethyl )-~min_7propane .
Yield7 34 % of theory,
M.p.: 100C ~decomp.)
IR-spectrum (methylene chloride): 1660 cm 1 (C0
24 31 3 ~ (446.0)
Calc.: C 64.34 H 7.65 N 9~38 Cl 7.91
Foundo 63.60 7.20 9.28 7.94
15 ~
1- ~ ,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin 2-one-3-y ~-
3- ~ -methyl N-~2-(4-acetylamino-phenyl)-ethyl)-amin_7propane
and
1- ~ ,8-Di~ethoxy-1,3-dihydro-2H-3~be~zazepin-2-one-3-y ~ -
1.8 g (0.004 mol) of a isomer mixture of 1- ~ ,8-dimetho~y-
1,3-dihydro-2H-3-benzazepin-2-o~e-3-yl7-3- ~-methyl-N-(2-
(2- an~ 4-ami~o phenyl)-ethyl)-amin_7propa~e were stirred
at room temperature for 1 hour in a mi~ture o~ 10 ml of
glacial acetic acid and 10 ~l of acetic ~nhydride. Subseque~tly
water was added, the reaction mi~ture was neutralized with
sodium bicarbDnate a~d extracted with methylene chloride.
The organic phase was dried æn~ eTaporated ln vacuo and
the residue ~as chro~atographed over aluminium oxide (200 g,
neutral, activity IV) (eluant: methyle~e chloride ~ 1 % methanol).
61 -
Y.ield in 2-acetylamino compound: 0.24 g (14 % of theory),
M.p.: 62 - 66C.
Yield in 4-acetylamino compound: 0.5 g (28 ~ of theory),
~.p.: ~9 - 72C.
5 ~3~a~ ~
1- ~ ,8-Dimethoxy-1,394,5-tetrahydro-2H-1`~3-be~zodiazepin-2-one-
3-Yl7-3- ~ ~methyl N-(2-(3,4-dlmetho~y-phenyl)-ethyl)- amino7-
a) N- ~ -~ '-Methyl-N'-(2-(3,4-dime~hoxy-phenyl)-ethyl)-amino7-
~
4.5 g (0.01 ~ol3 o~ N- ~- ~ '-methyl ~'-(2-(3,4-dimetho~y-
phenyl)-ethyl) -amino7-propyl7-2- (2-amino-4,5-dimethoxy-
phe~yl)-acetamide were dissolved i~ 100 ml of tetrahydro-
fur~n and reacted under ~itrogen atmosphere with 60 ml of
a 7 Molar diborane solution in tetrahydrofur~n. The clear
solution was allowed to rest for 2 days at room temperature
~nd then mixed with 20 ml of ~emi-conc. hydrochloric
aoid with cooling. The tetrahydrofuran was distilled off
in YaCUO and the remaining hydrochloric residue ~as
made lkaline with oonc~ sodium hydroxide solution under
cooling. The precipitated oil ~a~ taken up i~ methylene
- - chloride, the organic solution wa~ separated, dried a~d
evaporated in vacuo. The oily residue was purified over
silica gel with methyle~e chloride Rnd 1 % of ~ethanol.
Y$eld: 2.9 g (67.2 % of theory),
IR-spectrum (methylene chloride): 2830 cm 1 (OCH3)
2~00 cm 1 (N-alkyl)
- 6~ -
b) 1- ~ ,8 Dimethoxy-1,3,4,5~tetrahydro-2H-1,3~benzodiazepin-
2-o~e-3-yl7-3-~ -methyl-(2-(3,4-dimethoxy-phenyl)-ethyl)-
amino7~ro~ane
Prepared a~alogou~ly to Example 2 by reaction of N- ~ -
~ '-methyl-N'-~2-(3 9 4-dimethoxy~phenyl)-ethyl)-amino7-
propy_7-2-(2-amino-4,5-dimethoxy-phenyl)-ethylamine with
N,N'-carbonyl diimidazole.
Yield: 0.9 g (61.6 % of theory),
M.p.: 116 - 117C.
10 ~
1- ~ ,8-Dimethoxy-5-methyl-1,3-dihydro-2H-~,4-benzodiazepi~-
2-one-3-yl7-3- ~-methyl-N-(2-(~,4 dimetho~y-phe~yl)-ethyl)-
amino7Pro~ane dihvdrochloride
Prepared analogously to Example 1b by reaction o~ 1-(7,8 di-
metho~y-5-methyl-1,3-dihydro~2H~,4-benzGd~azepin-2-one-3-yl)-
3~chloro-propane with N-methyl-2-(3,4-dimethoxy-phenyl)-ethyl~
a~ine~
Yield: 24.2 % of theory
M.p.: 106C.
2a
1- ~ ,8-Di~etho~y-1,3-dihydro~2~-3-benzazepin~2-one-~-yl7
2-hydroxy-3 ~ methyl-N-( 20 ~3,4-dlmetho~y-phenyl)-ethyl)-
amin o~ane
a) 1~(7,8-Dimethoxy-1, 3-dihydro-2H-3-be~zazepin-2- one-~-yl ) -
~
Prepared analogously to Example 1a by reaction of 7,8~dl-
b~ 3
- 63 -
methoxy-1,3-dihydro-2H-3 benzazepi~-2-one with ep~chloro-
hydrin.
Yield: 94.5 % of tbeory,
IR-spectrum (methylene chloride)~ 2830 cm 1 (OC~I3)
1660 cm ~CO)
b) 1~ ~ ,8-Dimethoxy 1,3-dihydro-2H 3-benzazepi~-2~o~e-3-y ~-
2-hydroxy-3 ~-methyl-N-~2-(3,4-dimethoxy-phenyl)-ethyl)-
8.25 g (0003 mol~ o~ 1-(798-dimethoxy-1,3-dihydro~2H-
3wbe~zazepi~-2-one-3-yl)-2,3-epo~y propane were di~-
solved in 100 ml o~ methanol, reacted with 5.85 g (0,0~
mol) of N-methyl-2-(~,4-dimethoxy-phe~yl)-ethylamine a~d
re~luxed for 3 hours. The methanol was distilled off in
vaGvo and the residue wa~ purified over a silica gel column
wi~h methylene chloride + 1 % of ethanol.
Yield: 7.8 g (55.2 % of theory),
IR spectrum (methylene chloride): 3600 cm ~ (OH)
1650 cm 1 ~CO)
C~6H34N206 (470.63
Calc.: C 66.36~ 7.28 ~ 5~95
~o~nd: 66c167.26 5.80
1- ~ ,8-Dimethoxy~ ,4~5-tetrahydro-2H-3 benzazepi~-1,2-dion-
3-yl7-3 ~-meth~l-N-(2-(3 9 4-d~methoxy-phenyl)-ethyl)-ami~o7-
To a mlxture of 150 ml of dio~an and 6 ml of water ~.5 g ofselenium dioxide were added at 70C, stirred for 15 ~inutes
and reacted with 3 g of kieselguhr and 14.~ g (0.03 mol) of
~ 8-di~ethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2 o~e~
3-yl7-3- ~-methyl-M-~2~(3,4-dimetho~y phenyl3-ethyl)-amino7-
propane ~ydrochloride. The mixture was re~luxed for 6 hours,
cooled and filtered. The filtrate was e~aporated i~ vacuo
; A .~ 3
- 64 -
and the residue was puri~ied over a silica gel column with
methyle~e chloride ~ 1 % of ethanol. The fractions were eva-
porated in vacuo, the residue wa~ dissolved in acetone and
the hydrochloride was precipitated with ethereal hydrochloric
acid.
Yield- 13.8 g (90.7 % of theory~,
M.p.: 196 - 197C.
~Z
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-y~-2-hydroxy-3- ~ -methyl-N-(2-(3,4-dimethoxy-phenyl3-
10 ~
Prepared a~alogously to Example 4 by catalytic hydroge-
natio~ of 1- ~ ,8 di~etho~y~ dihydro-2H-3-be~z~zepin-2 one-
3-yl7 2-hydroxy-3- ~-methyl-N-(2-(3,4-dimetho2y-phe~yl)-
ethyl~-amino7propane, however, in eth~ol at 50 bar a~d
15 70C with platinum o~ide as catalyst.
Yield: 37.5 % of theory,
XR~spectrum (~ethylene chloride): 347Q cm 1 (OH)
1635 cm 1 (C0)
C26~36N26 (472.6~
20 Calc.: C 66.08 H 7.68 N 5~93
Fou~d: 66.22 7~57 5.85
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-~H-3-benzaz2pin-2-one-
3-yl7-3- ~ ~methyl ~-(2-(4-nitro phe~yl)-ethyl)-amino7propane
25 h drochloride
Prepared analcgously to Example~5b by reaction of ~- ~,8-di
metho~y-1,3 9 4 , 5-tetrahydro 2~-3-be~zazepin-2-one-3-yl7
- 65
3-chloro-propane with N-methyl-2-(4-nitro-phenyl~-ethylamine.
Yield: 56.5 % o~ theory,
M p.: 182C.
5 1- ~ ,8-Dimethoxy-1 9 3 ~ 4,5-tetrahydro-2H-3-benzazepin-2-one~
3-yl7 3- ~-methyl-N-(2-(3-nitro-4-acetylami~o-phenyl)-ethyl)-
aminol~ropane dihydrochloride
0.3 g (1.18 mmol) of N- r-(7,8-dimethoxy-1,3,495-tetrahydro-
2H-3-ben~azepin-2-one-3 yl)-propyl7methylamine and 0.34 g
(1,3 ~mol) of 2-(3-~itro-4-acetylamino-phenyl)-ethylbromide
were refluxed for 1 hour i~ 5 ml of chlorobenzene and 0~1 ml
o~ pyridine. The reaction mi~ture was cooled and the pre-
cipitated pyridi~e hydrobromide w~s suctio~ filtered. The
filtrate was evaporated in vacuo and the residue was puri-
~ied over alumi~ium o~ide (nelltral, ~ctivity II~ with methy~lene ohlorlde a~d 0.5 % o~ ethanol as eluant. The oil thus
obtained was dissolved in acetone and the dihydrochloride
was precipitated with ethereal hydrochloric acid.
Yield: 230 mg (57.7 % of theory),
20 M~po~ 170C.
1 ~ ,8 dimethoxy-1,3,4,5-tetra~ydro 2H-3-benzazepin~2-o~e-
3-y ~ methyl-N-(2-(4-fluoro-phenyl)-ethyl) -ami~o7
25 Prepared analogously to E~ample 5b by reaction o~ 1-(798Odi-
~etho~y~ ,4,5-tetr~hydro-2H-3-be~zazepi~-2-o~e-3-yl)-
3-chloro-propane with N methyl-2~(4-~luoro-phenyl)-ethylamine.
Yield: 68.7 % of theory7
M.p.: 203C.
~ 66 -
.
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7-3- ~-acetyl-N-~2-(3 9 4-dimethoxy phenyl)-ethyl)-amino7-
nronane
2 g (0.004~ mol) of 1 ~ ,8-dimethoxy-1~3,4,5-tetrahydro-2H-
~-benzazepin-2-one~3-yl7-3- ~-(2-~3,4-dlmethoxy-phenyl)-
ethyl )~amin_7propane were reacted with 15 ml of acetic ~nhydride
and stirre~ for 30 mi~utes at room temperature. The mixture
was poured on ice water, neutralized wlth sodi~m bicarbonate
and subsequently extracted with methylene chloride. The organic
e~tract was dried over magnesium sulfate, filtered, and e~apo-
rated in vacuo. The residue was purified over alumi~ium oxide
(neutral 7 activity II) with methylene chlorlde as eluant.
Yield: 1.5 g (68.5 % of theory,
15 IR-spectrum (methyle~e chloride): 2830 c~ 1 (OCH3)
1640 cm 1 (C0)
C27H~6N26 (484.6)
Calc.: C 66.92 H 7.49 N 5,78
Fou~d: 66.75 7.44 5,80
20 ~
1 ~ ,8 Dim~tho~y-1,3,4,5-tetrahydro-2H-3-benzazepi~-2 one
3 yl7-3- ~-ethoxycarbonyl-N-(2-(3,4-di~ethoxy-phenyl)-ethyl)
.
2.5 ~ (0.00565 mol) of 1- ~ ,8-dl~etho~y-1,3,4,5-tetrahydro-
2H-3-benza~epin-2-one-3-yl7~ (2~3 7 4-d~metho~y-phenyl)-
ethyl) ami~o7propane and 2.45 g (0.024 mol) o~ trieth~lamine
were dissolved in 20 ml of methylene chloride. A~ter additio~
o~ 2.6 g (0.024 mol) o~ ethyl chloro~ormate stirring was
conti~ued for 30 m1nutes ~t room temperature, the solutio~
30 was washed twice with water, dried over magnesium sul~ate
and evaporated in vacuo. The residue was purified o~er
- 67 -
aluminium o~ide (~eutral, activity II) with methylene
chloride as eluant~
Yield: 1.5 g (51.6 % of theory)~
IR-spectrum (methylene chloride): 1690, 1650 om 1 (C0)
28 38 2 7 (514.6)
Calc.~ C 65.30 H 7.44 N 5.44
~ound: 64.19 7.14 5.27
1- ~ ,8-Dimethoxy-1,3,4~5-tetrahydro-2H-3-benzazepin-2-one-
i0 3 yl7-3- ~-methyl-N-(2-(2,6-dichloro-phenyl)-ethyl)-~mino7-
Prepared a~alogously to Example 5b by reactio~ of 1-(7,8-di~
metho~y-1,3,4,5-tetr~hydro-2H~3-be~zazepln-2-one-3-yl)-
~-chloro-propa~e with N-methyl-2-(2,6-dichloro-phe~yl)-
ethylami~e.Yield~ 70.5 % of theory,
M.p.: 147C.
1- ~ ,8-Dimetho~y-1,3 9 4,5-tetrahydro-2H-3-benzazepi~ 2~o~e-
3-yl/~- r-methyl-N-(2-~3~4-dichloro-phenyl)-ethyl~-ami~o7-
Prepared analogously to E~ample 5b by reaction of 1-(7,8-di-
methoxy-1,3,4,5-tetrahydro-2~-3-benzazepi~-Z one-3-yl)-3-
chloro-propane with N-methyl-2-(3,4-dichloro-phenyl)-ethyl-
amine.Yield: 57.6 % of theory,
M.p.: 161C.
- 68 -
1- ~ ,8-Dimethoxy-1,3-dihydro 2H-3-ben~azepin~2-one-3-yl7-
a) 1-(7,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-Qne 3-yl)-
S
Prepared analogously to Example 1a by reaction of
7,8-dimethoxy-193-dihydro-2H 3 benzazepin-2-one with
1-chloro-2~bromo-etha~eO
Yield: 20 % of theory9
M.p.: 114C.
b) 1- ~ ,8-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-
3-yl7-2- ~ -methyl-N (2-(3,4 dimethoxy-phe~yl)-ethyl)-
amino7ethane
Prepared analogously to Example 1b by reaction of
1-(798-dimethoxy-1,3 dihydro-2H-3-benzazepin-2-o~e=3-yl~-
2-chloro-etha~e with N-methyl 2-(394-dimethoxy phenyl)-
ethylamine.
Yield: 72 % o~ theory9
IR-spectrum (methylene chloride): 28~0 cm 1 (OCH3)
2790 cm 1 (N-alkyl)
1655 c~ 1 (CO~
NMR-spectrum (CDCl~): S 2 2.3 ppm, s, 3~ (NCH~); 3.85 ppm,
- s, 12H ~OCH3~; 6.15 ppm~ d(J=8Hz),
1H (olefin.); 6.35, d(J=8Hz),
lH (olefin.)O
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-y ~-2- ~-methyl-N (2-(3,4-dimethoxy-phenyl)-ethyl)-amino7-
Prepared analogously to Example 4 by catalytical hydrogenation
of 1-~9 8-dimetho~y~1,3-dihydro-2H-3-benzazepi~2-one-~-yl7-2-
-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amin ~ ethane.
Yield: 59 % of theory,
M.p.: 188 - 189C.
10 ~3~
1- ~,8~Dimethoxy-1,3,4,5-tetrahydro 2H-3-benzazepin-2,4-dione
3-~17-3-~ methyl-N-(2-(3,4-dimethoxy-phenyl) ethyl)-amino7-
a~ 1-(7,B-Dimetho~y-1,3,4,5 tetrahydro-2H-3-benza~epin-2,4-dion-
~
Prepared analogously to E~amplc 1a by reactio~ of 7 3 8-di-
metho~y-1,3,4,5 tetrahydro-2H-3-ben7azepin-2,4-dion
~m.p~: 235C (decomp.)) with 1-bromo-3-chloropropane.
Yield: 26 % o~ theory 7
IR-spectrum ~Br): 1660 cm 1 (C0)
b) 1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3 benzazepi~-2,4~dion-
3 yl7-3- ~ -methyl-N-(2-(3,4-dimetho~y-phenyl)-ethyl)-amino7-
~rooane hvdrochloride
PreparPd analo~ously to Example 5b by reaction o~ 1~(7,8-di-
methoxy-193,4,5-tetrahydro-2H 3-benzazepin-2,4~dion-3-yl)-
3-chloro-propane with N-~ethyl-2-(3~4 dimethoxy-phenyl~-
ethylamine~
Yield: 35 % of theory,
M.p.: 163 - 164C.
d ~ 43
- 70 -
~a~
~ Benzyloxy-8-hydroxy-1,3,4,5-tetrahydro-2H-~-ben~azepin
2-o~e-3-yl7-3- ~ methyl-N-(2-(3,4 dimethoxy-phenyl)-ethyl)-
amino7 ro ane
a) 1-(7,8-Dihydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
~ -chloro-nronane
8.9 g (0.03 mol) of 1-~7,8-dimethoxy-1,3,4,5-tetrahydro-
2H-3-benzazepin-2-one 3-yl)-~-chloro-propane were dissolved
in 100 ml of ~ethylene chloride and reacted at -60C with
2.1 ~l o~ boron tribromide. After removing the cooli~g bath
the reaction te~perature raised to 20C and at thi~ te~pera-
ture stirri~g was continued for 10 hours. The resinous pre-
cip~tate was ~ade crystalline by addition of
100 ml o~ water and subsequent ~tirri~g for 1 hour. The
precipitate was suction ~ltered and washed with water a~d
methyle~e chlorideO For puri~ication the crystalline product
was ~tirred with acetone and suctio~ filtered.
Yield~ 7.3 g (90.2 % of theory),
M.p.: 177 - 178Co
b) 1-(7-Hydroxy-8-benzyloxy-193,4,5-tetrahydro-2H-~-benzazepi~-
and
1-(7-Benzylo~y-8-hydroxy-1,3,4,5-tetrahydro-2H-3-benzazepin-
~~ ~
19 g (0.07 ~ol) of 1-(7,8-dihydroxy-1,3,4,5-tetrahydro-2H-
~-benzazepi~-2-o~e-3-yl)-3-chloro-propane and 10.6 g of
potas~ium carbonate in 250 ml of dimethyl sulfoxide ~ere
reacted with 19.5 g (0.154 ~ol) of benzyl chloride. The
mi~ture wa~ ~tirred for 2 days at room temperature, then
~ d ~3 1"3
. .
- 71 -
poured on ice water and extracted ~everal times with
ethyl acetate. The organic e~tracts were washed thrice
with water~ dried over magnesium sulfate and evaporated
in vacuo. The isomer ~eparation was carried out over
.
silica gel with methylene chloride and 3 % of acetone
as eluant.
Yield in 7-hydroxy compound: 6 g (23.8 % of theory),
M.p.: 163 - 165C,
Yield in 8-hydroxy compound: 4~5 g (17.9 % of theory),
M.p.: 185 - 186C.
c~ Benzylo~y-8-hydroxy-1~3 9 4,5-tetrahydro-2H-3-benzazepin-
2-o~e-3-y ~-3- ~~methyl-N-(2-~3,4-dimethoxy-phe~yl)-~thyl)
Prepared analogously to Exa~ple 5b by reactio~ of 1-(7-benz-
yloxy-8-hydroxy-1,3,4,5-tetrahydro-2X-3-be~zazepin-2-one-
~-yl)-3-chloro-propane with N-methyl-2-(3,4-d~me*hoxy-
phenyl)-ethylamine.
Yield: 75.4 % o theory,
M.p.: 128 - 129C.
~
1 ~ Hydroxy-8-be~zyloxy-1 9 3 9 4,5-tetrahydro-2H-3-benzazepi~-
2-one 3-Y17~3- ~-methyl-N ( 20 (3,4-d~methoxy-phenyl~-eth~l)-
amino7nro~ane
Prepared anal~gously to Example 5b by reaction of 1-(7-hydroxy-
8-ben~yloxy-1,3,495~tetrahydro-2H-3-benzazepi~-2-one-3-yl)-
3 chloro-propane with N methyl 2-(3,4 dimethoxy-phe~yl~-ethyl-
ami~e.
Yield: 47.2 % of theory,
M.p.: 157 ~ 158C.
- 72 -
1- ~ ,8-Dihydroxy-1,314,5-tetrahydro 2H 3~benzazepi~-2-one-
3-yl7~ methyl_N_~2-(3,4-dimetho~y-phenyl)~ethyl ) -amino7-
0.52 g (O.001 mol3 of 1- ~-hydroxy-8-benzyloxy-1,3,4,5-tetra-
hydro-2H-3 benzazepin-2-one-3-yl7-3- ~ -methyl-N~(2-(3,4-di-
metho~y-phenyl)-ethyl )-amino7propa~e were hydrogenated for
5 hour~ at 20C a~d 5 bar in 100 ml of methanol and 0.2 ~ of
palladium/charcoal (10 %). The catalyst was suctlon ~iltered,
the filtrate was evaporated in vacuo and the residue was
purified over silica gel with methylene chloride ~ 1 % of etha~
nol as eluant
Yield: 0.2 g (43.9 % o~ theory),
IR-spectrum (methylene chloride~: 3520 cm 1 (OH)
1640 cm 1 (co3
~24H32N25 x 1/2 H20 (45505)
Calc O C 63.28 H 7,74 N 6015
Found: 63.44 7.77 6.1~
1- ~-Ben2ylo2y-8~methoxy-1,39495-tetr~hydro-2H-3-benzazepin-
2-o~e-3-yl7-3- ~-methyl-N-(2-(3,4-dimethoxy-phenyl~-ethyl3~
0.52 g ~0~001 ~ol) o~ benzylo~y-~-hydroxy-1?3,495-tetra-
hydro~2H-~-be~zazepin~2 one-3~yl7-3-~ -methyl-N-(2-(3,4-di-
methoxy-phenyl)-ethyl)-amin ~-propane were dissolved in 30 ml
of dimethyl formamide and reacted with 50 mg of 50 % sodium
hydride dispersion (i~ oil). The mi~ture was warmed for
30 minut0s up to 60C, mi~ed with 0.1 ml of dimethyl ~ulfate and
warmed ~or further 2 hvurs up ts 60C. The dimethyl formamide
was distilled off in ~acuo, the residue was take~ up i~ methy-
lene chloride, the organic phase ~a washed with water, dried
aad evaporated in acuo. The resinous residue was purified
over alwminium oxide (~eutral, activity II) with methylene
chloride as eluant. The oil obtained was dissolved in acetone
s~
- - 73 -
and the dihydrochloride was precipitated by reaction with
ethereal hydrochloric acid.
Yield: 250 mg (41 % of theory),
M.p.: 117 120C~
5 ~a~a~
~ Methoxy 8-benzyloxy--1,3,4,5-tetrahydro-2H-3-benzazepin-
2-one-3-yl7~3- ~ -methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-
Prepared analogously to Example 71 by reactio~ of 1 ~-hydroxy-
lO 8-benzyloxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-y ~-
3- ~-methyl-N-(2-(3,4-dimethoxy~phenyl) ethyl) amino7-propane
with dimethyl sulfate.
Yield: 70 % of theory,
IR-spectrum (methylene chloride): 1655 cm 1 (C0)
15 NMR-spectrum (CDCl3/D20): ~ - 2.3 ppm, s, 3H (NCH3); 5~1 ppm,
~, 2H (benzyl.); 6.5 6.8 ppm,
m, 5H (aromat.); 7.4 ppm, s, 5H
(arom~t.~.
1- r-Hydroxy8-metho2y-1,3,4,~-tetrahydro-~H-3-benzazepin-
2-one-3-yl7-3~ ~-methyl-N-~-(3,4-dimethoxy-phenyl)-ethyl)-
~
Prepared analogously to Example 70 from 1- ~-benzyloxy-8-metho~y-
1,3,4 9 5-tetrahydro-2H-3-benzazepin-2-one-3-y ~ -~- ~ methyl N-
~2-(3,4~di~etho~y-phenyl)-ethyl)-ami~o7propane hydrochloride
by catalytic debenzylation.
- 7~ -
Yield: 45.2 % o~ theory,
IR-~pectrum (methylene chloride)- 3530 cm (OH)
2830 cm~1 (OCH~)
1650 cm 1 (CO)
5 C25~34N25 ~ HCl (479.0)
Calc.~ C 62.69 H 7.36 N 5.85
~ou~d: 63.15 7.57 5064
~ Methoxy 8-hydroxy-1,3~4,5-tetrahydro-2H-3-benzazepi~-
2-one-3-yl7-3- ~ -methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)-
Prepared a~alogously to Example 70 from 1 ~~methoxy-8-benzyl-
oxy~1,3 9 4,5-tetrahydro-2H-3-benza~epin-2-one-3-~l7-3- ~ -methyl-
N-(2-(~,4~dimethoxy-phenyl)-ethyl) amino7propane by catalytic
15 d~benzylationa
Yleld- 29.4 % of theory,
IR-spectrum ~methyle~e chloride): 1640 cm 1 ~CO)
C25~34N25 (442.5~)
Calc.: C 67.85 H 7.74 N 6.33
Found: 67.50 7-97 6.18
1- ~ ,8-Dimetho~y-1,3,4,5-tetrahydro-2H-3-benzazepl~-2-one-3-y ~-
3- ~ ~ethyl~N-(2-(3,4-dimethyl-phenyl)-ethyl)-amino7propa~e
Prepared analogously to Example 5b by reaction of 1-(7,8-di-
~etho~y-1 9 3,4,5-tetrahydro-2H-3-benzazepin-2-one-3;-yl)-3~chloro-
propane w~th N methyl-2-(3,4-dimethyl~phenyl)-ethyla~i~e.
Yield: 54.3 % o~ theory,
Mop~ 170 - 172C.
- 75 -
1- ~ ,8-Dimethoxy-1,3,4,5 tetrahydro-2H-3-benzazepin-2-one-
3-Yl7-3~ ~-methyl-N-(2-(4-tert.but~l-phenyl)-ethyl) amino7-
Prepared analogou~ly to Example 5b by reaction of 1-(7,8~di-
methoxy-1,3,4,5-tetrahydro-2H-~-benzazepin-2-one-~-yl)-3-chloro-
propane with N-methyl-2-(4-tert.butyl-phenyl)-ethylamine.
Yield: 49.4 ~ of theory,
M.p.: 146 - 149C.
10 ~
1- ~,8-Dimetho~y-1,3,4,5-tetrahydro-2H 3-benzazepin-2-one-
Prepared analogously tQ Example 5b by reactio~ of 1-(7,8-di-
~ethoxy 1,3,4,5-tetrahydrow2H-3-benzazepin 2one-3-yl)-3-chloro-
propane with N-methyl-2 (4-n-butoxy-phenyl)-ethylamine.
Yield: 55.3 % of theory,
M.p.: 67 ~ 69C.
1- ~ ,8-Dimethoxy-1~3,4~5 tetr~hydro-2H-3-benzazepin-2-one-3-yl7-
Prepared analogously to Example 5b by r2action of 1-(798-di-
methoxy-1,3,4,5-tetrahydro-2H-3~benzazepi~-2-one-3-yl)-~-chloro-
propane with N-methyl 2-(2,4,6~trimethoxy-phenyl)-ethylami~e.
Yield: 57.8 % of theory 9
- 76 -
IR-spectrum (methylene chloride): 1650 cm 1 (C0)
1520 cm 1 (aromat. C~C)
C27H38N26 x H~l (523.2)
Calc.: C 62.00 H 7.51 N 5.35 Cl 6.77
Found: 61.75 7.52 5.18 7.~4
1- ~ ,8-Dimethyl-1,3 dihydro-2H-3-ben~azepin-Z-o~e~3-y~-
3- ~ -~ethyl-N-(2-(3j4-dimethoxy-phenyl)-ethyl) amino7propane
~
a) 1-(7,8-Dimethyl-1,3-dihydro-2H-3-benzazepin-2-one-3-yl~-
Prepared analogously to Example 1a by reaction o~ 7,8-di
methyl-1,3-dihydro-2H 3~benzazepin-2-one (m.p.: Z20 - 224C)
with 1-bromo-3-chloropropane.
Yield: 99 % of theory,
~pO ~2 - 64C,
b) 1- ~ ,8-D~methyl-1,3-dihydro 2H-3-benzazepin~2-o~e-3-yl7-
3-~ methyl -N~ ~ 2- ( 3, 4-dimethoxy-pher~y~ ) - ethyl ) ~ o7propane
20 Prepared aYlalogou~ly to Example 1b by reaction o~ 1- (7 ~
dimethyl-113-dlhydro-~H 3-be~zazepi~-2-one-~-yl)-3-chloro-
propan~ with N-methyl~2 ~3,4 di~ethoxy-phenyl) ethyl~mine.
Yield: 70.9 % of theory,
M.p.: 1V5 - 107C.
_ Q
1-~7,8-Dimethyl-1,3,4,5-tetrahydro-2H-3~benzazepin-2-one-
3~yl7_3~ ~ -methyl-N-(2-(3,4-dimethoxy-phenyl~-ethyl)-amino7-
~ro~ane dihvdrochloride
Prepared analogou~ly to Example 4 by catalytical hydrogenation
o~ 1- ~ ,8-dimethyl 1,3 dihydro-2H-3-benzazepin-2-one-3-yl7-
3 ~-methyl-N-(2-(3,4~dimethoxy-phenyl~-ethyl)-amino7-propane.
Yield: 83.8 ~ o~ theory,
M.p.~ 154 - 157~C.
Example 81
1- ~ ,8 Dimetho~y-1,3-dihydro-2H-3-benza7epi~-2-o~e-3 yl7-
Z-methyl-3- ~-methyl-N-~2-(3,4~dimethoxy-phenyl)-ethyl)-amino7-
~) 1-(7,8-Dimetho~y-1,3-dihydro-2H-3-benzazepin-2-one-3~yl)-
~
Prepared analogously to Example 1a by reaction of 7,8-di-
~ethoxy-1,3 dihydro-2H-3-benzazepin-2-one with 1-bromo-
2-~ethyl-3 chloro-propane.
Yield: 97.5 % o~ theory,
M.p.: 45 - 47C.
b) 1- ~ ~8 Dimethoxy-1,3-dihydro-2H-3-benzazepin-2one~3-yl7
2-~ethyl-3- ~-methyl-N-(2-(3 9 4-dimethoxy-phenyl)-ethyl)-
Prepared analogously to Example 1b by reaction of 1~(7,~-di-
methoxy-1,3-dihydro-2H-3-benzazepin 2-o~e-3-yl)-2-methyl-
3-chloro~propane with N-methyl-2-(3,4-dimethoxy-phenyl)-
ethylamine.
Yield: 36 % o~ theory,
Mop~ 30 - 32C~
- 78 -
~Q~
1~ ~ ,8-Dimetho~y-1,3,4,5-tetrahydro-2H~3-benzazepin-2-one-
3-y ~-~-methyl-~ methyl-N (2-(3,4-dimethoxy-phenyl)-
Prepared a~alogously to Example 4 by catalytic hydroge~
nation of 1- ~,8 dimethoxy-1,3-dihydro-2H-3-benzazepin-
2-one-3-yl7-2-methyl-3- ~-methyl-N-(2-(3,4-dimethoxy-
phenyl)-ethyl)-amino7propane.
Yield: 73.7 % of theory,
M.p.: 99 - 101C.
1- ~ ,8-Dimethoxy-1,3,4~5-tetrahydro-2H-3-benzazepin-1,2-
dion-3-y ~-3- ~-methyl-N-(2-(3,4~dimethoxy phenyl)-ethyl)-
3 g of sodium dichromate x ~ H20 were given to 2.45 g~0.005 mol) of 1 ~ 98-dimethoxy-1,3,4~5~tetrahydro-2H-
3-ben2azepin-2-one-3-yl7-3-~R-methyl-N-(?-~3,4-dimethoxy-
phenyl~-ethyl~-amin_7propane hydrochloride in 50 ml of
glacial acetic acid. The mi~ture was stirred for 2 hours
20 at room temperature, poured o~ ice w~ter, ~eutralized with
potassium carbo~ate and e~tracted ~everal times with methy
lene chloride. The organic extracts were dried over mag~e-
sium.sulfate and evaporated in vacuo. The residue was puri-
fied over a silica gel column with methylene chloride ~ 1 %
25 of ethanol as eluant. The product thus obtained was dis-
~olved and the hydrochloride was precipitated wit~ ethereal
hydrochloric acid.
Yield~ g (51.3 % of theory),
M.p.: 197 - 198C.
~-3
- 79 -
1-/7,8-Dimethoxy-1,3,4,5~tetrahydro-2H-3-benzazepin
1,2-dion~3-y ~-3- ~methyl-N (2-(3,4-dimetho~y-phenyl)-
1.98 g (4.0 mmol) o~ 1- ~ ,8-dimethoxy-193,4,5-tetrahyAro-
2H-~-ben2azepin-2-one-3-yl7-3- ~ -methyl-N-(2-(3,4-dimethoxy-
phenyl)~ethyl)-amino7propane hydrochloride were suspended
in 50 ml of acetic anhydride t the suspension ~ixed with
2. 5 g of potassium permarlganate and stirred for 20 minu-
10 tes at 20C. The reaction mixture was poured on ice waterand made ammoniacal with conc. ammonia. The precipitated
manganese-dioxide was suction filtered and the filtrate was ex-
tracted se~eral times with methylene chlorideO The extract
was dried over magnesium ~ul~ate, evaporated in ~acuo and
the residue was purified over a silica gel column with
methylene chloride + 1 % of ethanol as eluant. The product
thus obtained was dissolved i~ acetone and the hydrochloride
was precipitated with ethereal hydrochloric acidO
Yield: 0.7 g (34.5 % of theory),
20 M.p.: 196 - 197C.
1- ~ ,9-Dimethoxy~ dihydro-2H~3-be~za~epin-2-o~e-3-y ~ -
a) 1-(6,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one~3-yl)
Prepared analogously to E~ample 1a by re~ction of 6,9-di-
~ethoxy-1,3-dihydro-2H-3 benzazepin-2-one (m.p.: 1~8 - 191C)
with 1-bromo-3-ohloro-propa~e.
Yield: 27 % o~ theory,
M.p.: 97 - 99C.
~ 80 -
b) 1-~9 9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl7-
Prepared analogously to Example 1b by reaction of 1-(6,9-
dimethoxy-1,3-dihydro-2H-3-benza2epin-2-one-3-yl)-3-chloro-
propane with N-methyl-2-(3,4-dimethoxy-phenyl)-ethylamine.
Yield: 90 ~ of theory,
IR-spectrum (methylene chloride): 1~58 cm 1 (CO)
NM~-spectrum (CDC13/D20): ~ - 2.2 ppm, s, 3H (NCH3);
3.7 - 3.8 ppm, 4s, 12H ~OCH3);
6.25 ppm, d tJ = 9HZ), 1H
(olefi~.).
B~
-
1- ~ ,9-Dimethoxy-1,3,4,5-tetrahydro-2H-benzazepin-2-one-3-yl7
~ methyl-N-(2-(~,4-dimethoxy-phenyl)-ethyl ) -amin~7propane
15 h~droohloride
Prepared analogously to Example 4 by catalytic hydrogenation
of 1- ~ ,9-dimethoxy-1,3-~ihydro-2H-3-benzazepin-2-one-3-yl7-
~ methyl-N-(2-(3~4-dimethoxy-phenyl)-ethyl)-amin ~propane.
Yield: 85 % of theory,
~.p.: 7~ 76C.
1- ~ ,9-Dimethoxy-1,3 dihydro 2H 3-benzazepin-2-one-3-y ~-
3- ~ methyl-N-~2-(3,4-dimethoxy-phenyl)-ethyl)~amino7-
ro ane h drochlorlde
a) 1 (8,9-Dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one-3-yl)-
chloro-propane _ _ _ _
Prepared analogously to Example 1a by reaction of 8,9-di-
methoxy-1,3-dihydro-2H-3-benzazepin-2-one (m.p.: 165 -
1~8C) with 1-bromo-3-chloroprop~ne.
Yield: 45 % of theory,
M.p.: 67 - 71C.
"?",3
-- 81 --
b) 1- ~ ,9-Dimethoxy-1,3-dihydro~2H-3~benzazepin-2-one-3-yl7-
3- ~ -methyl-N-(2-(~,4~dimethoxy-phenyl)-ethyl)-amino7-
Prepared analogously to Example 1b by reaction of 1-(8,9-
dimethoxy-1,3-dihydro-2H-3-benzazepin 2-one~3-yl)-3-chloro-
propane with N-methyl-2 (3,4-dimethoxy-phenyl)-ethylamine.
Yield- 64 % of theory~
M.p.: 64 - 68C~
lO 1- ~,9-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one~
3-y ~-~- r-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl) -amiao7-
Prepared analogously to Example 4 by catalytic hydroge~ation
of 1- ~ ,9-dimethoxy-1,3-dlhydro-2H-3-benzazepin-2-one-3-yl7-
3- ~methyl-N-(2-(3,4-dimetho~y-phenyl)-ethyl)-amin ~propane.
Yield: 75 % of theory t
M,p.: 131 - 13~C.
1- ~ ,8-Dimethoxy-1~3,4,5-tetrahydro-2H-3-benza?epi~-2~one-
3 y ~-3- ~ ~methyl~N-(2-(3,4,5-trlmethoxy-phenyl)-ethyl~-
Prepared analogously to Example 5b by reaction of 1-(7~8-di
~etho~y-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl)-3-
chloro-propa~e with N-methyl-2-(3,4,5-trimethoxy-phenyl~-
ethylamine.Yield: 44 % of theory,
M.p.: 131~C (decomp.).
- 82 -
Isomer ~ixture of 1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-
3-benzazepin-2-o~e 3-y ~-3- ~-methyl-N-(2-(2- and 4-nitro-
hen l~-eth l)~amino7 ro ane
S Prepared analogously to Example 1b from 1- ~ ,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benza~epin-2-one-3-yl7~3-chloro-
propane and N-methyl-2-(2- and 4-nitro-phe~yl)-ethylamine.
Yield: 72 % of theory,
IR-spectrum (methylene chloride): 1650 cm 1 (C0)
Isomer ml~ture ~f 1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro 2H~
3-benzazepin-2~one-3-y ~-3w ~ -methyl-N-(2-(2- and 4-amino-
hen l~-eth l~-amino7 ro ane
Prepared analogously to Example 4 by catalytic hydroge~ation
of a isomer mi~ture of 1- ~ ,8-dimethoxy-1,394,5-tetrahydro-
2H-3-be~zazepin-2-o~e-3-yl7-3- ~-methyl-N (2-(2- a~d 4-nitro-
phenyl~ ethyl)-amin ~propa~e.
Yield: 81 % of theory,
IR-spectrum (methylene chloride)- 1645 cm (C0).
~ 8
Example 2.2
1- ~ ,8-Dimethoxy-1,3,4,5~tetrahydro-2H-3-benzazepin-2-o~e-
~-yl7-3- ~-methyl-N-(2-(2-acetylamino-phe~yl)-ethyl)-amino7-
propane hydrochloride and
1~ ~ ,8-Dimethoxy-1,3,4,5-tetrahydro~2H-3-benzazepi~ 2-o~e-
3-y ~-3- ~-methyl-N-(2-(4-acetylamino-phenyl)-ethyl)-amin ~-
Prepared ~nalogously to Example 52 by reaction of a isomer
mixture of 1- ~ ,8-dimethoxy-1,394~5-tetrahydro-2H 3-benz-
azepin-2-one-3-y~ -~- ~-methyl-N-(2-(2- a~d 4-amino-phenyl)-
ethyl)-amin_7propane with glacial acetic acid a~d acetic anhydride.
Yield in 2-acetylamino compound: 26 % of theory,
M.p.: 102 - 105C (decomp.)
Yield in 4-acetylamino compou~d: 49 % o~ theory~
M.p.: 89 - 93C (decomp.).
1- ~ ,B-Dimethoxy-1,3,4,5-tetr~hydro-2H-3-benzazepin-2-one
4.85 g (0.0107 mol) o~ 1- ~ 78-dimethoxy-1,3,495-tetrahydro-2H-
3-benzazepin-2 one-3-yl7-3-~ -methyl N~(2-(4 acetylamino-phe~yl)~
ethyl)-amin_7pr~pane were stirred for 34 hours at 40C w~th
80 ml of ~etha~olic hydrochloric acid. After evaporating the
solution, the residue was dissolved in methylene chloride,
e~tracted with sodium bioarbonate solution and washed with water.
25 The organic phase was dried, evap~rated in vacuo and the oil
obtai~ed ~as subsequently dried at 50C in vacuo.
Yield: B8 % of theory,
IR spectrum (methylene chloride3: 1645 cm 1 (CO)
NMR-spectrum (CDSl3/D20): S - 2.25 ppm, s, 3H (NCH33; 3.8 ppm,
s, 1 H (OCH3); 6,9 ppm, d
(J~7Hz), 2H (aromat.).
- 84 -
1 ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin~2-one-
3-yl7 3-~ -methyl~N-(2-(4-chloro-phenyl)-ethyl)-amin ~-
~ropane dihydrochloride
1.01 g (0.00245 mol) of 1- ~ ,8-dimethoxy-1,3~4,5-tetrahydro-
2H-3-benzazepin-2-one-~-yl7-3-~ -methyl-N (2-~4-amino-phenyl~-
ethyl)-ami~_7propane were dissolved in 5 ml o~ semi-conc.
hydrochloric acid and diazotized with 0.17 g (~.00245 mol) of
sodium nitrite. Subsequently the solution was stirred at 55C
until no nitrogen escaped. The solution was made weakly
alkaline a~d extracted with methylene chloride. A~ter
drying and evaporating in vacuol the obtained oil was
puri~ied over aluminium oxide (200 g, neutral, activity II)
(eluant: methylene chloride ~ 2 % of ethanol) and the di-
hydrochloride was precipitated from acetone with etherealhydrochloric acid.
Yield: 21 % of theory
M.p.: 148 - 151C.
~a~
1- ~ ,8-Dimethoxy-2,~-dihydro-1H 3-benzazepin-3-yl7-3-
2.3 g (0.005 mol) of 1- ~ ,8-dimethoxy-1,3-dihydro-2~-3-
benzazepin-2-one-~-yl7-3- ~ -methyl-N-(2-(3,4-dimethoxy-
phe~yl)~ethyl )-amin_7propane were dissolved in 150 ml of
25 absolute ether, mixed with 0.6 g of lithium aluminium hydride
and stirred for 2 hours at room temperature. With ice cooling
10 % ammonium chloride ~olutio~ was added, the precipitate
was suction filtered and the solvent was removed in vacuo.
The oily residue was purified over aluminium oxide (neutral~
30 activity II) with ~ethylene chloride as eluant.
- 85 -
Yield: 1.6 g t72.7 % of theory),
IR-spectrum (methyle~e chloride): 2830 cm 1 (OCH3)
2790 cm 1 (N-alkyl)
C26~36N24 (440.6)
Calc.: C 70.88 H 8.24 N 6.36
5 Found: 70.50 8.~0 6.22
~2~
1- ~ ,8~Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2 one-
3 yl7-3- ~_methyl_N_(2 (4-hydroxy-phenyl)-ethyl~-amin
ro ane h drochloride
1.1 g (2.67 mmol) of 1- ~ ,8-dimethoxy-1,3,4,5-tetrahydro-2H-
3-benzazepin-2-one-3-yl7-3- ~-methyl-N-(2-~4-amino-phenyl)-
ethyl)-amino~7propane were dis~ol~ed in 10 ml of semi-conc.
sulfuric aoid and diazotized at 0C with 0.18 g (2.67 mmol)
of sodium nitrite. The solution was heated on the steam bath
15 for 20 minutes, diluted with water, made weakly alkaline
with sodiuffl hydroxide solution and ex~racted with methylene
chloride. A~ter drying and evaporating in VQCUO, the obtai~ed
oil W2S purified o~er 100 g of al~minium oxide (neutral,
activity II~ with methylene chloride + 2 ~ of ethanol as eluant.
20 The hydrochloride was precipîtated from acetone/ethereal hydro~
chloric acid.
Yield: 0.17 g (15 % of theory),
M~po 109 ~ 112C (decomp.~.
~2~
2S 1~ ~ ,8-Dimethoxy-1,394,5-tetrahydro-ZH-3~be~zazepi~-2-one~
3-y ~ 3- ~-methyl-N-(2-(4-dimethylamino-phenyl)-ethyl )-amino7-
ro ane dih drochloride
Prepared a~alogsu~ly to Example 11 by reaction of 1- ~,8-di-
methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-3-yl7-3- ~-
methyl-N-(?. (4-ami~o-phenyl)-ethyl)-amin_7propane with
- 86 -
37 % formali~ sslution and sodium cyanoborohydride.
Yield: 40 % of theory,
M.p.: 193 - 196C.
1-~5 8-Dimethoxy-1,3,4,5-tetrahydro 2H-1,3-benzodiazepin-
2-one-3-yl7-3 ~ -methyl-N-(2-(4-amino-3,5-dichloro-phenyl)-
a) N- ~ ~ Methyl-N'-(2-(4-amino-3,5-dichloro-phe~yl)-
ethyl )-amin_7-propy~1~7-2- (2-amino-4~5-dimethoxy-phenyl)-
ethylamine hydrochloride _ _
Prepared analogously to Example 53a from N- ~ ~ methyl-
N'-(2-(4-ami~o-3,5-dichloro-phenyl~-ethyl)-amino7-propy
2-(2-amino-4,5-dimethoxy-phe~yl)-acetamide and lithium
aluminium hydride.
M.p.: 182 - 188C (decomp.).
b) 1-r 8-Dimethoxy-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-
2-o~e-3~yl7-3- ~-methyl-N-(2-(4-~mino-3,5-dichloro-phe~yl)-
Prepared ~nalogously to Example 53b from N- ~ - ~ '-methyl-
N'-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)amino7-propy ~-
2-(2-amino-4,~-dimethoxy-phenyl)-ethylamine hydrochloride
and N,N'-carbonyl diimidazole.
M.p.: 16~ - 166C.
- 87 -
1- ~ ,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2 dion-
3~y~ -3- ~-methyl-N-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)-
-
Prepared analogously to Example 5b from 1- ~ 38-dimethoxy-
1,3,4p5-tetrahydro-2H-3-benzazepin-2-one-3-y ~ -3- ~ -methyl-
N-(2-(4-amino-3,5-dichloro-phenyl)-ethyl)-amin_7propane and
selenium dioxide.
M.p.: 11B - 130C,
m/~ = 493/495 (C2~H29Cl2N304; 494.43)
~'
1- ~ 98-Dimetho~y-1,~,4,5tetrahydro~ZH-3-benzazepin-~-one-
3 y ~-3 ~-methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl) -amino7
ro ane dihvdrochloride
1.1 g ~5.0 mmol) of 7,8-dimethoxy~1,3,4,5-tetrahydro-2H 3-
benzazepin-2~one were ~uspended i~ 20 ml of dimethyl sulfoxide
and mixed with stirring with 0.6 g (5.~ mmol) o~ potassium
tert.butylate. After 10 minutes the solutio~ w s mixed with
2.0 g (7.4 ~mol) of 1-chloro-3~ ethyl-N (2~(3,4-dimethoxy-
phenyl~-ethyl)-amln_7propaneg subsequently stirred ~or 1 hour
at 50C, poured on water~ extracted with ethyl acetate and
the organic phase was evaporated i~ ~acuo. The residue was
purifled over silica gel with methylene chloride + 10 %
of methanol as eluant and the dihydrochloride was precipitated
~rom acetone with ethereal hydrochloric acid.
M.p 7 136 - 137C.
- ~8 -
1-~9 8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one-
3-yl7~3- ~ -methyl-N-(2-(3,4-dimethoxy-phenyl)-ethyl)~amin ~ -
~ro~ane dihvdrochloride
Prepared analogously to E~ample 100 from 7,8-dimethoxy-
1,3,4~5-tetrahydro-2H-3-benzazepin-2-one and N-methyl-
N-(2-(3,4 dimethoxy-phenyl)-ethyl)-azetidinium bromide.
M.p : 137C.
1-L~,8-Dimethoxy-1,3,4,5-tetrahydr~-2H-3-benzazepin-2_one_
3 yl7-~- ~-methyl-N-(2-(3-amino-4-chloro-phenyl)-ethyl)-
-
Prepared analogously to Example 12 by reaction of N- ~-
(7,6-dimethoxy-1~3,4,5-tetrahydro-2H-3-benzazepin-2~one-
3-yl~-propy_7methylamins with 2-(3-~mino-4-chloro-phenyl)-
ethylchlorideO Oil.
W -spectrum (eth~nol): ~ max: 2~8 nm (0.~6)
285 nm ~0~19)
304 nm tO. 06)
IR-~pectrum (dichloromethane): 3390 and 3480 cm 1 (NH2)
1650 cm 1 (CO)
. 2830 cm 1 (OCH3)
2795 cm 1 (CH3 N~ )
1520 and 1620 cm 1 (C-C)
~ 3~3
-- 89 --
Tablets containing 10 mg of 1- ~ ,8-dimethoxy-1,3,475-tetra-
hydro-2H-3 benzazepin-2-one-3-yl7-3- ~ -methyl-N-(2-(3,4-di-
5 Composition:
1 tablet contains:
Active ingredient 10.0 mg
Corn starch 57.0 mg
Lactose 48.0 mg
10 Polyvi~yl pyrrolidone 4.0 mg
Magnesium stearate 1.O mg
120.0 mg
The sctive ingredient, corn starch, lactose and polyvinyl
15 pyrrolidine were mixed together and moistened with water.The moist mlxture was forced through a screen wlth a mesh
size of 1.5 mm and then dried at about 45C. The dry granu-
late was passed through a screen with a mesh size of 1.0 ~m
and then mi~ed with magnesium stear~te. The finished mixture
was compressed in a tablet press with punches 7 mm in dlameter
and marked with a notch, to ~orm tablets.
Weight of tablet: 120 mg
~a~ .
Coated tablets containing 5 mg of 1 ~ ,8-dimethoxy-193,495-
25 tetrahydro-2H-3-benz~zepi~-2-one 3-y ~-3- ~-methyl-N-(2-
1 Coated tablet core cont~i~s:
ActiYe ingredient 5.0 mg
Corn starch 41~5 mg
30 Lactose 30.0 mg
;3~
-- 90 --
Polyvinyl pyrrolidine 300 mg
Magnesium stearate 0.5 mg
80~0 mg
~}~
The active ingredient 9 corn starch, lactose and polyvinyl
pyrrolidone were thoroughly mixed and moistened with water.
The moist mass was forced through a screen with a mesh size
of 1 mm, then dried at about 45C and the granulate was then
passed through the same screen, After the addition of magne-
sium stearate, convex tablet core~ ~ith a diameter of 6 mmwere produced by compression in 3 tablet-making machine. The
tablet cores thus produced were coated i~ known manner with
a covering consisting es~entially of ~ugar and talc. The
finished ooated tablets were polished with wax.
15 Weight of coated tablet: 130 mg.
ple III
Ampoules containing 5 mg of 1- ~ ,B-dimetho~y-1,~9495-tetra-
hydro-2H-3-benzazepi~-2-one 3-yl7-3- ~ _methyl~N_(2 (3,4-di-
1 Ampoule co~tains:
Active ingredient 5.0 mg
Sorbitol 50.0 mg
Water for in~ection ad 2.0 ml
In a suitable container, the active ingredient was dissolvedln water for injection purposes and the solution was made
i~otonic with sorbitol~ After being filtered through a mem-
brane filter, the solution was deca~ted into clean, sterilized
ampoules u~der an N~ atmosphere and autoclaved for 20 ~i~utes
3~ in a current of steam.
Example IV
Suppositories containing 15 mg of 1- ~ ,8-dime-thoxy-1,3,4,5-
tetrahydro-2H-3-benzazepin-2-one-3-y ~ -~ methyl-N~(2-
(~ 2 4-dimethoxy~hen~l~-ethyl~ami_o7propane hydrochloride
5 1 Suppository contains:
Active ingredient 0.015 g
Hard fat (e.g. Witepsol H 19 and W 45) 1.685 g
1.700 g
The hard ~at was melted. At 38C the ground active ingredient
was homoge~eously disper~ed in the melt. It was cooled to
35C and poured into slightly pre-cooled supposltory moulds.
Drops solutio~ containing 10 mg of 1- ~ ,8-dimethoxy-1,3,4,5-
l5 tetrahydro-2H-3-benzazepin-2-one-3-y ~-3~ ~ -methyl-N-(2-(3,4-
100 ml of solution oontain-
Active ingredient 0.2 g
Hydroxy ethylcellulo~e 0.15 g
Tartaric acid 0.1
Sorbitol solution containing
70 % dry matter 30.0 g
Glycerine ~o.o g
Benzoic acid 0.15 g
25 Distilled water ad 100.0 ml
~L 3~
Distilled water was heated to 70C. The hydroxy ethyl-
cellulose, benzoic acid and tartaric acid were dissolved
therein with stirring. The mixture was cooled to ambient
temperature ~nd the glycerine and sorbitol solution were
added with stirring. At ambient temperature, the active
ingredient was added and stirred until completely dis-
solved. Then the mixture was evacuated, with stirring~
~n order to eliminate air from the liquid.
92 -
