Note: Descriptions are shown in the official language in which they were submitted.
I 7
WOW
Chemical Compounds
This invention relates to new benzazepine
derivatives, to processes for their preparation,
TV pharmaceutical compositions containing them and
to the use of these compounds in the treatment
of disorders of heart-rate.
British Patent No. 1,548,844 describes, inter
alias the compound of formula
Ho CH2cH2cH2~-cH2cH2 ouch
and the physiologically acceptable acid addition
salts thereof, which has valuable pharmacological
properties, i.e. in particular a selective heart-
rate lowering effect in addition to a mild hypotensive
effect.
It has surprisingly now been found that the
compounds of the present invention have superior
pharmacological properties, namely, in particular,
a stronger heart-rate lowering effect with a longer
duration of activity and fewer side effects.
Thus according to one feature of the p event
invention, we provide compounds of general formula I
I
-- 2 --
EYING
wherein Al represents a hydrogen, fluorine, chlorine
or bromide atom, a trifluoromethyl group, an alkoxy
group with 1 to 3 carbon atoms or an amino group
optionally moo- or disubstituted by alkyd groups
each having 1 to 3 carbon atoms (which alkyd groups
may, in the case of disubstitution, be the same
or different) and R2 represents a hydrogen, fluorine,
chlorine or bromide atom or an alkoxy group with
an alkylenedioxy group with 1 or 2 carbon atoms;
R3 represents a hydrogen, fluorine, chlorine
or bromide atom, a Norway or tri1uoromethyl group
or an alkyd or alkoxy group each having 1 to 3
carbon atoms and R4 represents a hydrogen atom,
an amino group or an alkoxy, alkylamino or dialkylamino
group (each alkyd moiety having 1 to 3 carbon atoms
and the alkyd moieties in the dialkylamino group
being the same or different), or R3 and R4 together
represent an alkylenedioxy group with 1 or 2 carbon
atoms;
R5 represents a hydrogen, chlorine or bromide
atom;
6 represents a hydrogen atom, an alkyd group
with 1 to 3 carbon atoms or an alkenyl group with
US 3 to 5 carbon atoms;
E represents an n-alkylene group with 2 to
4 carbon atoms optionally substituted by an alkyd
group with 1 to 3 carbon atoms;
B represents a thiocarbonyl, carbonyl or
ethylene group;
G represents an n-alkylene group with 1 to
5 carbon atoms optionally substituted by an alkyd
lZlPlQ7
-- 3 --
group witch 1 to 3 carbon atoms (wherein so long
as B represents a ethylene or carbonyl group,
a ethylene group may optionally be replaced by
a carbonyl group), or a methylene-n-hydroxyalkylene
group with 1 to 4 carbon atoms in the alkaline
moiety, the ethylene group being attached to the
nitrogen atom to the left of the group G; and
A represents a group of formula -CH2-CH2-,
R7
-CH=CH-, NO , -SCHICK-, -CON-, NO
GO OH NO I
11
COO -CH-CH2-, -C-CO-, -C-CO- or -CO-CO- Wherein
R7 represents an alkyd group with 1 to 3 carbon
atoms and I represents a hydrogen atom or an alkyd
group with 1 to 3 carbon atoms substituted by a
phenol, methoxy-phenyl or dimethoxyphenyl group);
with the provisos that
(it when A represents a group of formula
R7
-SHAKER-, -CH=CH-, -NH-CO-,-C~2-CO- or CON t
(wherein R7 is as herein before defined)
B may not represent a ethylene or carbonyl
group unless
G represents an n-alkylene group with 3 Jo
5 carbon atoms optionally substituted by an alkyd
group with 1 to 3 carbon toys, an n-alkylene group
with 1 to 5 carbon atoms optionally substituted
by an alkyd group with 1 to 3 carbon atoms wherein
a ethylene group is replaced by a ~arbonyl group,
or a methylene-n~hydroxyalkylene group with 1 Jo
-- 4 --
4 carbon atoms in the alkaline moiety, the ethylene
group being attached to the nitrogen atom to the
left of the group G, and/or Al and each represents
a hydrogen atom or Al represents a fluorine, chlorine
or bromide atom, a trifluoromethyl group or an
amino group optionally moo- or disubstituted by
alkyd groups each having 1 to 3 carbon atoms (which
alkyd groups may, in the case of disubstitution,
by the same or different and I represents a hydrogen,
fluorine, chlorine or bromide atom or an alkoxy
group with 1 to 3 carbon atoms
except in the cave of A representing a
-CH2CH2- group; Al and R2 representing methoxy
groups in the 7- and 8- positions, E representing
an n-propylene group, R6 representing a methyl
group, G representing an ethylene group, R5 representing
a hydrogen atom, and R3 and I either both representing
hydrogen atoms or representing respectively a
nutria and a 4-amino group, in which case B may
represent a carbonyl group);
(ii) when A represents a -CO-CO- group, B
represents a ethylene group and
G represents an n-alkylene group with 3 to
5 carbon atoms optionally substituted by an alkyd
group with 1 to 3 carbon atoms, an n-alkylene group
with 1 to 5 carbon atoms optionally substituted
by an alkyd group with 1 to 3 carbon atoms wherein
a ethylene group is replaced by a carbonyl group,
or a methylene-n-hydroxyalkylene group with 1 to
3Q 4 carbon atom in the al~ylene moiety, the ethylene
group being attached Jo the nitrogen atom to the
left of the group G, and/or Al and R2 each represents
a hydrogen atom or Al represents a fluorine, chlorine
or hromine atom, a trifluoromethyl group or an
amino group optionally moo- or di~ubstituted by
alkyd groups each having 1 to 3 carbon atoms (which
alkyd groups may, in the case ox disubstitution,
-- 5 --
be the same or different) Rand R2 represents a hydrogen,
fluorine, chlorine or bromide atom or an alkoxy
group with 1 to 3 carbon atoms; and
lit when A represent a group of formula
OH OH NO HER
1 8
5 INCH -SCHICK -CH-CH2 , -C-CO- or -Chico-
wherein R8 is as here~nbefore defined),
represents a ethylene group]
and acid addition salts of the aforementioned compounds.
The term acid addition salts" as used herein
refers to salts formed with organic and inorganic
acids. Suitable acids include, for example hydrochloric,
hydrobromic, sulfuric, phosphoric, acetic, lactic,
citric, tartaric, succinic, malefic and fumaric acids.
For pharmaceutical use the acid addition
salts will, of course, be physiologically acceptable
acid addition salts, but other acid addition salts
may find use, lo example in the preparation of
the compound of general formula I and their physic-
logically acceptable acid addition salts.
The definitions given herein before for the
groups Al to R8, E and G include the following:
Al may be a hydrogen, fluorine, chlorine or bromide
atom or a tri1uoromethyl, methoxy, ethics, n-
propoxy, isopropoxy, amino, methyl amino, e~hylamino,n-propylamino, isopropyl amino, dimethylamino, deathly
amino di-n-propylamino, diisopropylamino, methyl-
ethyl amino, methyl-n-propylamino, methyl-isopropyl-
amino or ethyl n propylamino group,
R2 may represent hydrogen, fluorine, chlorine
or bromide atom or a methoxy, ethics, n-propcxy
Lo 7
-- 6 --
or isopropoxy group or together with Al may represent
a methylenedioxy or ethylenedioxy group,
X3 may represent a hydrogen, fluorine, chlorine
or brine atom, or a nitric, trifluoromethyl, methyl,
ethyl, n-propyl, methoxy, ethoxyr n-propoxy or
isopropoxy group,
R4 may represent a hydrogen atom, or a methoxy,
ethics, n-propoxy, isopropoxy, amino, methyl amino,
ethyl amino, n-propylamino, isopropyl amino, dlmethyl-
amino, diethylamino, di-n-propylamino, diisopropyl-
amino, methyl-ethylamino, methyl-n-propylamino,
methyl-isopropylamino or ethyl-n-propylamino group
or together with R3 may represent a methy].enedioxy
or ethylenedioxy group,
R5 may represent a hydrogen, chlorine or
bromide atom,
R6 may represent a hydrogen atom or a methyl,
ethyl n-propyl, isopropyl, ally, n-buten-(2j-
ye or n-penten-(~)-yl group,
R7 may represent a methyl, ethyl n-propyl
or isopropyl group,
R8 may represent a hydrogen atom or a bouncily,
l-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-
~4~methoxyphenyl)-ethyl, 2-(3,4-dimethoxyphenyl)-
ethyl, 3-(4-methoxyphenyl)-propyl or 3-~3,4-dimethoxy-
phenyl)-propyl group,
E may represent an ethylene, n-propylene,
n-butylene, l-methyl-ethylene, 2-ethyl-ethylene,
l-propyl-ethylene, l-methyl-n-pr~pylene, 2-methyl-
n-propylene, loethyl-n-propylene, 3-ethyl-n-propylene,
2-propyl-n-propylene or 2-methyl-n-butylene group
9LZ~
-- 7 --
and
G may represent a mel:hylene~ ethylidene,
n-propylidene, n-butylidene, 2 methyl-propylidene~
ethylene l-methyl-ethylene, 2-ethyl-ethylene,
1 propyloethylene, 2-methyl~ethylene~ n propylene
n~butylene~ n-pentylene, l-methyl-n-propylene,
l-methyl-butylene, l-methyl-n-pentylene, l-ethyl-
n-propylene, 2-ethyl-n-propylene, l-methyl-n-butylene,
methylenecarbonyl~ ethylenecarbonyl, n-propylene-
carbonyl~ n-butylenecarbonyl, carbonylmethylene,
carbonylethylene, carbonyl-n-propylen2, carbonyl-
n-butylene, methylenecarbonylmethylene, ethylene-
carbonylmethylene, 2-hydroxyethylene, 2-hydroxy-
n-propylene, 3-hydroxy-n-propylene, 2-hydroxy-n-
battalion, 3-hydroxy-n-butylene, 4-hydroxy-n-butylene
or 2 hydroxy-n-pentylene group; the group Al is
preferably in the B position, R2 in the 7 position,
R3 in the 3 position, R4 in the 4 position and
R5 in the 5 position of the phenol nucleus in question.
However, preferred compounds are compounds
of general formula It
Al l-CH2CH2CH2-N-G I (I )
wherein
Al represents a hydrogen, chlorine or bromide
atom or a trifluorome~hyl, methoxy, amino, methyl amino
or dimethy~amino group, and R2 represents a hydrogen,
chlorine or bromide atom or a methoxy group, or
Al and R2 together represent a methylenedioxy group;
UC37
R3 represents a hydrogen, fluorine, chlorine
or bromide atom or a methyl, methoxy, trifluoromethyl
or vitro group, and I represents a hydrogen atom
or an amino, methoxy, methyl amino or dlmethylamino
5 group, or R3 and R4 together represent a methylenedioxy
group;
R5 represents a hydrogen, chlorine or bromide
Tom;
R6 represents a hydrogen atom or a methyl
or ally group;
B represents a thiocarbonyl, ~arbonyl or
ethylene group;
G represents an n-alkylene group with 2 to
5 carbon atoms (wherein, so long as 8 represents
a ethylene or carbonyl group, a ethylene group
may optionally be replaced by a carbonyl group),
or a methylene-n-hydroxy-alkylene group with 1
to 3 carbon atoms in the alkaline moiety, the ethylene
group being attached lo the nitrogen atom to the
left of the group G; and
A represents a group of formula -C~2-Cff2-,
OH I NO
-CH-CH-, INCH -CH-CH2-, CHICO-, -C - CO-,
5 5 S S
NH2 NH-CH2CH2 OOZE
-CHICO-, -CHICO- . SHEA or -COO-;
5 5
with the provisos that
(i) when represents a group of formula
-C~2-C~2- or SCHICK-, B represents a ~hiocarbonyl
group and may also represent a carbonyl group
when
G represents an n-alkylene group with 3 to
5 carbon atoms, an n-alkylene group with 2 to 5
Ron atoms wherein a ethylene group is replaced
by a carbonyl group, or a methylene-n-hydroxyalkylene
group with 1 to 3 carbon atom in the alkaline
moiety; the ethylene group being attached to the
nitrogen atom to the left of the group G, and/or
Al and I each represents a hydrogen atom or Al
represents a chlorine or bromide atom or a trifler-
methyl, amino, methyl amino or dimethylamino group
and R2 represents a hydrogen, chlorine or bromide
atom or a methoxy group;
it when A represents a -CO-CO- group, B
represents a ethylene group and
G represents an n-alkylene group with 3 to
5 carbon atoms, an n-alkylene group with 2 to 5
carbon atoms herein a ethylene group is replaced
my a carbonyl group, or a methylene-n-hydroxyalkylene
group with 1 to 3 carbon atom in the alkaline
moiety, the ethylene group being attached to the
nitrogen atom to the left of the group G, and/or
Al and R2 each represents a hydrogen atom or Al
represents a chlorine or bromide atom or a truer-
methyl amino, methyl amino or dimethylamino group
and R2 represents a hydrogen, chlorine or bromide
atom or a methoxy group; and
lit when A represents a group of formula NO
OH ox NO lH2 N~-CH2CH2 OOZE
-CH-CH2-, -CHICO-, -C-CO-, -CHICO- or -CHICO- OUCH
5 5 5 5 5
B represents a ethylene group
and acid addition salts thereof.
The compounds 1-(7,8-dimethoxy--1,3,4,5-tetrahydro-
2H-3-~enzazepin-2-on 3-yl~-3-lN-methyl-N-(2-phenyl-
ethyl)-aminol-propane, and 1-(7,8-dimethoxy-1,3,4,5-
tetrahydro-2H-3-benzazepin-2-on-3-yl)-3~[N-methyl---
N-(2-(4-amino-3-nitro-phenyl)-ethyl)-amino]-propanno,
and acid addition salts of these compounds, are
also preferred compound of the invention.
Particularly preferred are those compounds
of general formula It above wherein
A represents a -C~2~CH2- group;
~21~
-- .10
B represents a -CO- or -US- group;
1 represents a methoxy, amino, methyl amino
or dimethylamino group and R2 represents a hydrogen
atom or a methoxy group or Al and R2 together represent
a methylenedioxy group;
R3 represents a hydrogen, fluorine, chlorine
or bromide atom or a methoxy or trifluoromethyl
group, and R4 represents a methoxy, amino methyl amino
or dimethylamino group or R3 and R4 together represent
lo a methylenedioxy group;
R5 represents a hydrogen, chlorine or Crimean
atom;
I represents a methyl group; and
G represents an n-alkylene group with 3 to
I
5 carbon atoms, a -CH2-CH- group, or (if B represents
a -US- group and/or Al represents an amino, methyl amino
or dimethylamino group) a -CH2CH2- group,
and acid addition salts thereof.
Also mentioned as compounds of the invention
are those wherein
Al and R2 each represents a methoxy group;
R3 represents a methoxy group or a hydrogen
or chlorine atom;
R4 represents a methoxy/ amino or dimethylamino
group
. R5 represents a hydrogen or chlorine Tom;
6 represents a methyl group;
G represents a n-alkylene group with 3 Jo 5
OH
30 carbon atoms or a -~H2-C~- group or (if represents
a thiocarbonyl group or A represent a group of formula
Lo 7
-OH CO ) a -Kiwi- group; and either A represents
a -CH2-CH2- group and B represents a thiocarbonyl
or if G represents an n-a'Lkylene group with 3
to 5 carbon atoms) a carbollyl group, or
OH
A represents a COO group and B represents
a ethylene group,
and acid addition salt of these compounds.
The following compounds are specifically
mentioned as examples of compounds of the invention:
1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2X-3-
benzazepin-2-on~3-yl~-3-TN~methyl-N-(3-(3,4-dimethholy-
phenyl)-propyl)-amino]-propane,
1-(1-hydroxy-7,8-dimethoxy-1,3,4,5-tetrahydro-
~H-3-benzaæepin-2-on-3-yl)-3-~N-methyl-N~(2-~3,4-
dimethoxy-phenyl)-ethyl)-amino]-propane,
1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-
benzazepin-2~on-3-yl)-3-[N-methyl-N-(3-(4-amino-
3,5-dichloro-phenyl)-propyl)-amino]-propane,
1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-
benzazepin-2-on-3-yl)-3-LN-methyl-N-(2-phenyl-ethyye)-
amino propane and
1-(7,8-dimethoxy-1,3,4,~-tetrahydro-2H-3-
benzazepin-2 on-3-yl)-3-[N-methyl-N~52-(4-amino-
3-nitro-phenyl~-ethyl)-amino]-propane,
and acid addition salts of these compounds.
The compounds of general formula I and their
acid addition salts may, for example, be prepared
by the following processes, which processes constitute
further features of the present invention:
a reacting a compound of general formula
II R2 -E-U
I 7
- 12 -
with a compound of general formula III
TV (III~
(wherein I R3, R5, A, B, E and G are as herein before
defined, Al and R4' each represents an amino oralkyla~ino group protected by a protecting group
or they each have the meanings given for Al and
R4 herein before,
one of the groups U and V represents an RUN
group wherein R6 is as herein before defined, and the other group U or V represents a nucleophilically
exchangeable group such as, for example, a halogen
atom or a sulphonyloxy group, e.g. a chlorine,
bromide or iodine atom or a methanesulphonyloxy,
p~toluenesulphonyloxy or ethoxysulphonyloxy group
and optionally subsequently splitting off any protecting
group used
The reaction may conveniently be carried
out in a solvent or mixture of solvents such as,
for example, acetone, diethylether, ~ethylformamide,
dimethylformamide, dimethylsulphoxide, Bunsen,
chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran
or dioxin or in an excess of the compounds of general
formula II and/or III used and optionally in the
presence of an acid-binding agent e.g. an alkoxide
ugh as potassium tert.butoxide, an alkali metal
hydroxide such as sodium or potassium hydroxide,
an alkali metal carbonate such as potassium carbonate,
an alkali metal aside such as sodium aside, an
alkali metal hydrides such as sodium hydrides a
tertiary organic base such as triethylamine or
13 -
pardon, whilst the latter may also verve as solvents
at the same time, or a reaction accelerator such
as potassium iodide and, depending on the reactivity
of the nucleophilically exchangeable group, conveniently
at temperature of between 0 and cry preferably
at temperatures of between 50 and 120C, e.g. at
the boiling temperature of the solvent used. However,
toe reaction may also be carried out without a
solvent. It is however, particularly advantageous
to perform the reaction in the presence of a tertiary
organic base or an excess of the amine of general
formula III used
The optional subsequent splitting off of
a protecting group used is preferably effected
hydrolytic ally in an aqueous solvent, e.g. in water,
lsopropanol/water, tetrahydrofuran/water or dioxan/water,
in the presence of an acid such as, for example,
hydrochloric or sulfuric acid or in the presence
of an alkali metal base such as, for example, sodium
hydroxide or potassium hydroxide at temperatures
of between 0 and 100C, preferably at the boiling
temperature of the reaction mixture. However,
a bouncily group may also be split off by hydrogenolysis,
e.g. with hydrogen in the presence of a catalyst
such as, for example, palladium/charcoal, in a
solvent such as methanol, ethanol, ethyl acetate
or glacial acetic acid, optionally with the addition
of an acid such as hydrochloric acid at temperatures
of between 0 and 50~C, but preferably at ambient
temperature, and under a hydrogen pressure of from
1 to 7 bar, preferably from 3 to 5 bar.
b) In order to prepare compounds of general formula
I wherein A represents a
CN2-CH~ HO NH-CO-, -COO-, -SCHICK-,
-CON- or NO group and
B represent a C~2- or -CO group-
I
- 14 -
reacting a compound of generic formula IV
Al
No (IV)
I B
(wherein
I is as here~nbefore defined,
R7
-COO-, -C~2-CO-, NO or -CON- group wherein
R7 represents an alkyd group with 1 to 3 carbon
atoms,
B' represents a -SHEA- or -CO- group and
Al' represents an amino or alkylamino group
protected by a protecting group or has the meanings
given for I herein before),
with a compound of general formula V
Z-E-N-G (~)
\~--R4
. I
(whereon
R3, R5, I E and G ore as herein before defined,
I represents an amino or alkylamino group
protected by a protecting group or has the meanings
given for R4 herein before and
I Z represents a nucleophilically exchangeable
group such as, for example, a halogen atom or a
sulphonyloxy group erg. chlorine, bromide or
iodine atom, or a methane~ulphonyloxy, p-toluenesulphonyl-
ox or ethoxysulph~nyloxy group), and optionally
I 7
subsequently splitting off any protecting group
used
The reaction may optionally be carried out
in a solvent or mixture of solvents, e.g. in acetone,
dimethylformamide, acetone/dimethylformamide, dim ethyl-
sulphoxide or chlorobenzene, and conveniently,
depending on the reactivity of the group Z, at
temperatures of Hun 0 and 150C, but preferably
at the boiling temperature of the solvent used.
It may be advantageous to work in the presence
of an acid-binding agent, for example, an alkoxide
such as sodium methoxide, an alkali metal hydroxide
such as sodium hydroxide, an alkali metal carbonate
such as potassium carbonate, an alkali metal aside
such as sodium aside, an alkali metal hydrides such
as sodium hydrides or a tertiary organic base such
as triethylamine or pardon, or a reaction accelerator
such a, for example, potassium iodide.
The optional subsequent splitting off of
a protecting group used is preferably effected
hydrolytic ally in an aqueous solvent, e.g. in water,
isopropanol/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 metal base such as sodium hydroxide or potassium
hydroxide at temperatures of between 0 and 100C,
preferably at the boiling temperature of the reaction
mixture. however, a bouncily group may also be split
off by hydrogenolysis, e.g. with hydrogen in the
presence of a catalyst such as palladium/charcoal,
in a solvent such as methanol, ethanol, ethyl acetate
or glacial acetic acid, optionally with the addition
of an acid such as, for example, hydrochloric acid
at temperatures of between 0 and 50C, hut preferably
at ambient emperor, and under a hydrogen pressure
of from 1 to 7 bar, but preferably from 3 to 5
bar.
I
- 16 -
c) In order to prepare compounds of general formula
NORWAY
I wherein A does not represent a -CHICO- or CO-CO-
group: 5
reacting a compound of general formula VI
Al
N-E-H
VOW)
(wherein
B, E, Al and R2 are as herein before defined
but in the group E two hydrogen atoms in a -C~2-
or SHEA group of the group E are replaced by an
oxygen atom, and
A" represents a -SHEA SHEA-, -CH=CH-, -NH-CO ,
OH OH NO 5
-SCHICK-, INCH -CHICO-, -CH-CH2-, -C-CO- or
R7
- ON- group wherein R7 represents an
alkyd group with 1 to 3 carbon atoms, with an
amine of general formula VII
R6 ~4R3 (VII)
(wherein G and R3 to R6 are a herein before defined),
in the presence of a reducing keynote.
AL 07
- 17 -
The reaction may conveniently be carried
out in a suitable solvent or mixture of Solvents
such as, for example, methanol, ethanol, ethanol/ethyl
acetate or dioxin at temperatures of between 0
and 100C, but preferably at temperatures of between
20 and 80C~
It is particularly advantageous to carry
out the reductive lamination in the presence of
a complex metal hydrides such as, for example, lithium
or sodium cyanoborohydride, preferably at a pi
of 6-7 and at ambient temperature or, in order
to prepare compounds of general formula I wherein
represents a hydrogen atom, in the presence
of a hydrogenation catalyst, e.g. with hydrogen
in the presence of palladium/~harcoal under a hydrogen
pressure of 5 bar. Any double bonds present may
be hydrogenated.
d) In order to prepare compounds of general formula
HO- R8
I wherein A does not represent a -CHICO- or -CO-CO-
group 5
reacting a compound of general formula VIII
Al -E-
¦ R6 VOW)
(wherein
By En R2 and R6 are as herein before defined
and
An represents a -CH2-CH2, -CH=CH-, -KIWI ,
~Z'1~ 7
OH OH NO or
SHEA CO , INCH -CHICO-, -CH-CH2-, CUD
I
-CON- group wherein R7 represents an alkyd
group with 1 to 3 carbon atoms with a compound
of general formula IX
(IX)
HUG R4
R5
(where in
R3 to R5 and G are as herein before defined,
but in the group G two hydrogen atoms in a -C~2-
or -SHEA group of the group G are replaced by an
oxygen atom), in the presence of a reducing agent.
The reaction may conveniently be tarried
out in a suitable solvent or mixture of solvents
such as, for example, methanol, ethanol, eShanol/ethyl
acetate or dioxin at temperatures of between 0
and Luke, but preferably at temperatures of between
20 and 80C.
It is particularly advantageous to carry
out the reductive lamination in the presence of
a complex metal hydrides such as lithium or sodium
cyanobcrohydride, preferably at a pi of 6 to 7
and at ambient temperature or in order Jo prepare
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 under a hydrogen pressure of
5 bar. Any double bonds present may be hydrogenated.
,
07
-- 19
e) on order to prepare compounds of general formula
I wherein A represents a -CH2~CH2- group, B represents
a ethylene or carbonyl group and I does not represent
an alkenyl group with 3 to 5 carbon atoms:
hydrogenating a compound of general formula X
I Go (X)
(wherein Al to R6 J E and G are as herein before
defined and B' represents a ethylene or carbonyl
group).
The hydrogenation may be effected 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
in the presence of platinum or palladium/charcoal,
under a hydrogen pressure of from 1 to 7 bar, preferably
from 3 to 5 bar, and at temperatures of between
0 and 75C, but preferably at temperatures of between
2Q and 50C.
f) In order to prepare compounds of general formula
I wherein B represents a -US- group and G represents
an n-alkylene group with 1 to 5 carbon atoms optionally
substituted by an alkyd group with 1 to 3 carbon
atoms or a methylene-n-hydroxyalkylene group with
1 to 4 carbon atoms in the alkaline moiety:
reacting a compound of general formula XI
Al ENNUI- 3 I
R2 R5
I 7
-- owe --
wherein
Al to R6, and E are as herein before defined
and
G' represents an n-alkylene group with 1
to 5 carbon atoms optionally substituted by an
alkyd group with 1 to 3 carbon atoms or a ethylene-
n-hydroxyalkylene group with 1 to 4 carbon atoms
in the alkaline moiety),
with a sulphur-introduciny agent.
The reaction is carried out with a Selfware-
introducing agent such as, for example, phosphorus
pentasulphide or 2,4-bis-(4-methoxyphenyl~-1,3-
dithia-2,4-diphosphetane-2,4 disulphide, conveniently
in a solvent such as, for example, Tulane or zillion
at temperatures of between 50 and 150C, e.g. at
the boiling temperature of the reaction mixture.
g) In order to prepare compounds of general formula
Ox OH
I wherein A represents a -SHEA- or -C~-CH~- group
5 5
and G represents an n-alkylene group with 1 to
S carbon atoms optionally substituted by an alkyd
group with 1 to 3 carbon atoms or a ethylene n-
hydroxy-alkylene group with 1 to 4 carbon atoms
in the alkaline moiety:
reducing a compound of general formula XII
NIGHING (ZOO)
9~2~
21 -
(wherein Al to R6l E and G are as herein before
defined.
The reaction is carried out in the presence
of a suitable reducing agent such as, for example,
a metal hydrides e.g. sodium bordered, lithium
aluminum hydrides or diborane, in a suitable solvent
such as, for example, water methanol methanol/ether,
tetrahydrofuranr dioxin or ether/tetrahydrofuran
at temperatures of between 0 and 80C, but preferably
at temperatures of between 15 and 40C. In the
reaction, any CO group present in the G group is
also reduced to a OH group.
h) In order to prepare compounds of general formula
I, wherein
HER NO
/ 8 I, .
A represents a I CO- or COO group and represents
an n-alkylene group with 1 to 5 carbon atoms optionally
substituted by an alkyd group with 1 to 3 carbon
atoms or a methylene-n hydroxyalkylene group with
1 to 4 carbon atoms in the alkaline moiety:
reacting a compound of general formula XIII
I 2 C 2 (XIII)
2 O -O
(wherein
Al to R6 and E are as herein before defined
and
I Do
22
G' represents an n-alkylene group with 1
to 5 carbon atoms optionally substituted by an
alkyd group with 1 to 3 carbon atoms or a ethylene-
n-hydroxyalkylene group with 1 to 4 carbon atoms
in the alkaline moiety),
with a compound of general formula XIV
-
N - Rug (XIV)
(wherein I represents a hydroxy group or has the
meanings riven for R8 herein before), optionally
with subsequent reduction.
The reaction may conveniently be effected
in a solvent such as, for example, ethanol, dioxin
or glycol or in a melt at elevated temperatures,
e.g. at temperatures of between 50 and 175C.
The optional subsequent reduction may be effected
with a reducing agent such as a complex metal hydrides
e.g. lithium aluminum hydrides with catalytically
activated hydrogen ego with hydrogen in the
presence of a hydrogenation catalyst such as platinum
or palladium/charcoal under a hydrogen pressure
of from 1 to 7 bar, but preferably from 3 to 5
bar, or with hydrazine/Raney nickel in a suitable
solvent such as, for example, methanol, ethanol,
ethyl acetate or glacial acetic acid at temperatures
of between 0 and 100C, but preferably at temperatures
of between 20 and 50C.
i) In order to prepare compounds of general formula
I wherein A represents an INCH group and R6 represents
an alkyd group with 1 to 3 carbon atoms or an ~lkenyl
group with 3 to 5 carbon atoms:
reacting a compound of general formula XV
- I -
Al R3 (XV)
R2 NIGHING R5
(wherein Al to R5, B, E and G are as herein before
defined and I represents an alkyd group with
1 to 3 carbon atoms or an alkenyl group with 3
to 5 carbon atoms r
with an orthoformic acid ester.
The reaction may preferably be carried out
in a solvent such as, for example, ethanol, Tulane,
dime~hoxyethane or in an excess of the orthoes~er
used at temperatures of between 100 and 200C.
It may also be advantageous for any -NH2
or No groups present to be protected by protecting
groups, e.g. acutely, bouncily, ethoxycarbonyl or
bouncily groups, during the reaction.
Any protecting groups used during the reaction
are subsequently split off, e.g. azalea groups are
preferably removed hydrolytic ally in the presence
of an acid or base whilst bouncily groups are preferably
removed by hydrogenolysis, ego with hydrogen in
the presence of a hydrogenation catalyst such as
palladium/charcoal or platinum.
Jo In order to prepare compounds of general formula
I wherein A does not represent a -COO- group and
G represents a methylene-n-hydroxyalkylene group.
Reducing a compound of general formula XVI
R3
R
2 E~N-Gn R5
I
- 24 -
(wherein
Al to R6, B and E are as herein before defined,
An' has the meanings given for A herein before,
with the exception of the -COO- group, and
G" represents a methylene-n-alkylene group,
wherein the alkaline moiety contains 1 to 4 carbon
atoms and a ethylene group of the alkaline moiety
is replaced by a carbonyl group).
The reduction is preferably carried out with
a metal hydrides such as, for example, sodium bordered
or lithium aluminum hydrides or with diborane,
in a suitable solvent such as for example, ethanol,
ethansl/water, methanol or isopropanol at temperatures
of between 0 and 50C, but preferably at temperatures
of between 10 and 25~.
k) In order to prepare compounds of general formula
I wherein R3 represents a vitro group and R4 represents
an amino group:
hydrolysis of a compound of general formula XVII
R
I
N -EGO ~XVIIj
B Nuzzle
R2 R5
(wherein
Al, I R5, R6, A, B, E and G are as herein before
defined, and
~%~
- 25
Azalea represents an azalea group such as, for
example, an acutely, ethoxycarbonyl or Bunnell group).
The azalea group used may preferably be split
off by hydrolysis in an aqueous solvent, e.g. in
water isopropanol/water, tetrahydrofuran~water
or dioxan/water, in the presence of an acid such
as, for example, hydrochloric or sulfuric acid
or in the presence of an alkali metal base such
as sodium hydroxide or potassium hydroxide at tempera-
lures of between 0 and Luke preferably at the boiling temperature of the reaction mixture However,
the reaction is preferably carried out in the presence
of an alcoholic acid, e.g. with methanolic or
ethanolic hydrochloric acid
1) In order Jo prepare compounds of general formula
I wherein A represents a -CH2-CH2-, -C~=CH-, -NH-CO-,
R7
SCHICK-, NO COCOS or -CON- group and one
g pus Al, R2, R3 or R4 represents an alkoxy~
alkylamino or dialkylamino group or R6 represents
an alkyd or alkenyl group:
reacting a compound of general formula XVIII
R
1 A' R6 I (xvIII)
R2 B -R5
(wherein
Al to I B and E are as herein before defined
but at least one of the groups Al to R4 must represent
a hydroxy group or Al or R4 must represent an amino
- 26 -
or alkylamino group or I nicety represent a hydrogen
atom,
A' represents a -C~2--CH2-, -CH=CH-, NO
R7- H2-CO-, INCH COCOS or -CON- group wherein
R7 represents an alkyd group with 1 to 3 carbon
atoms, and
Go' represents an n-alkylene group with 1
to 5 carbon atoms optionally substituted by an
alkyd group with 1 to 3 carbon atoms, wherein a
ethylene group may be replaced by a carbonyl group,
with a compound of general formula XIX
Rho - X SIX
Warren
Rio represents an alkyd group with 1 to 3
carbon atoms or, if I represents a hydrogen atom,
an alkenyl group with 3 to 5 carbon atoms and
X represents an nucleophilically exchangeable
group such as, for example, a halogen atom or a
sulphonyloxy group, e.g. chlorine, bromide or
iodine atom, a methanesulphonyloxy, p-toluenesulphonyl-
ox or methoxysulphonyloxy group or, if at least
one of the groups Al to R4 represents a hydroxy
group, X together with a hydrogen atom in the
position of the group Rio represents a Dow group
or, if R6 represent a hydrogen atom or Al or R4
represents an amino or alkylamino group, X may
also represent an oxygen atom).
The reaction may conveniently be carried
out in a solvent or mixture of solvents such as
deathly ether, methanol, acetone, tetrahydrofuran,
dioxin, acetonitrile~ pardon or dimethylformamide,
optionally in the presence of a base such as potassium
carbonate, potassium hydroxide, potassium tert.butoxide
~2,~1~07
_ I _
or sodium hydrides at temperatures of between 0
and 150C, jut preferably at temperatures of between
20 and 120~C.
If B represents a -SHEA- or -CO- group and
X represents a nucleophilically exchangeable group,
the reaction is preferably curried out with an
alkylating agent such as, for example methyl
iodide dim ethyl sulfite, ethyl iodide, deathly
sulfite, propel bromide, ally bromide or isopropyl
p-toluenesulphonate in the presence of an acid-
binding agent at temperatures of between 20 and
80C. However, the reaction may also be carried
out without a solvent.
If X together with a hydrogen atom in the
position ox the group Rio represents a dyes
group, in order to alkylate a hydroxy group the
reaction is preferably carried out with a diazoalkane
such as, for example,diazomethane or diazoethane
at temperatures of between 0 and 30C, or if X
represents an oxygen atom, in order to alkylate
the nitrogen atom the reaction is preferably carried
out in the presence of a reducing agent at temperatures
of between 0 and 120C, e.g. with formic acid at
temperatures of between 80 and 110C or with sodium
cyanoborohydride at ambient temperature and at
a pi ox 6 to 7.
m) In order to prepare compounds of general formula
I wherein A represents a -COO- group and G represents
an n-alkylene group with 1 to 5 carbon atoms optionally
substituted by an alkyd group with 1 to 3 carbon
Tess wherein a ethylene group Jay opt~oDally be
replaced by a ~rbonyl group:
oxidizing compound of general formula XX
I
- 28
4 OX
(wherein
Al to R6, E and are as herein before defined.
The oxidation may preferably be carried out
with an oxidizing agent such as, for example
potassium permanganate, selenium dioxide or sodium
dichromate in a suitable solvent or mixture of
solvents such as, for example, water, water/dioxan,
glacial acetic acid, water/acetic acid or acetic
android at temperatures of between 0 and 100C,
preferably at temperatures of between I and 80C.
n) In order to prepare compounds of general formula
I wherein A represents a -SCHICK- group and represents
an n-alkylene group with 1 to 5 carbon atoms optionally
substituted by an alkyd group with 1 to 3 carbon
atoms wherein a ethylene group Jay optionally be
replaced by a carbonyl group:
oxidizing a benzazepine of general formula XXI
DOW R4
R/ (XXI)
I
97
- 29
wherein Al Jo R6~ B, E and G are as herein before
defined).
The oxidation may be effected with ruthenium
tetroxide in a suitable solvent or mixture of solvents
such as chloroform/water, ethylene chloride/water
or carbon tetrachloride/water at temperatures of
between 0 and 100C, preferably at temperatures
of between 20 and 50C. however, the reaction
is preferably carried out in a two-phase system
such as ethylene chloride/water, chloroform/water
or carbon tetraehloride/water with a catalytic
quantity of ruthenium dioxide in the presence of
a suitable oxidizing agent such as, for example,
sodium peridot which produces ruthenium tetroxide
in situ.
o) In order to prepare compounds of general formula
I wherein Al is in the 7 position, A represents
a CH2CH2- group and B represents a -CO- group
cyclising a compound of general formula XXII
R~R2 - YE - EYING (XXII)
(wherein
Al to R5, G and E are as herein before defined,
I represents an alkyd group with 1 to 3
carbon atoms or an alkenyl group with 3 to 5 carbon
atoms and
Y represents a group suitable for cyclisation).
I
- 30 -
Y may represent, for example, a carb~xy or
nitrite group an ester group (such as a methoxycarbonyl,
ethoxycarbonyl, n-propoxycarbonyl or benzyloxycarbonyl
group), a thioester group (such as an ethylthiocarbonyl,
S phenylthiocarbonyl or pyridylthiocarbonyl group
an acyloxycarbonyl group such as an acetoxycarbonyl
or trifluoroacetylcarbonyl group) or an aside group
(such as an aminocarbonyl, methylaminocarbonyl~
dimethylaminocarbonyl or phenylaminocarbonyl group.
The reaction is optionally carried out in
the presence of a suitable condensing agent and
optionally in a pressure vessel in a solvent such
as zillion, dimethylglycol ether, tetralin or sulpholane
at elevated temperatures, e.g. at temperatures
of between 100 and 250C, but preferably at temperatures
of between 140 and 180C. However, the reaction
may also be carried out without a solvent.
Suitable condensing agents include, for example,
N,N'-dicyclohexylcarbodiimide, thinly chloride,
I a phosphate such as deathly chlorophosphonate or
bis(o-nitrophenyl)-phenylphosphonate, a phosporane
such as (2,2,2-trifluoroethoxy)-triphenylphosphorane,
an N-alkyl-pyridinium salt such as N-methyl-2-chloro-
pyridinium iodide or N-methyl-2-fluoro-pyridinium
tessellate N,N'-dicyclohexylcarbodiimide/4-dimethyl-
aminopyridine, chlorosulphonyl isocyanate or NUN'-
carbonyldiimidazole.
It may also be advantageous for any HO, No
or NH2 groups present to be protected by means
of protecting groups, e.g. acutely, bouncily, ethics-
carbonyl or bouncily groups, during the reaction.
If Y in a compound of general formula XXII
represents a nitrite or aside group, the reaction
is preferably effected so that a corresponding
compound is converted, by alkaline or acidic hydrolysis,
e.g. by means of methanol/hydrochloric acid or
ethanol/sodium hydroxide solution at the boiling
temperature of the reaction mixture, into a cores-
SWEDE
31 -
pounding car boxy compound which is subsequently
cyclised.
Any protecting groups used during the reaction
are subsequently split off eye. azalea groups are
5 preferably removed by hydrolysis in the presence
of an acid or base whilst bouncily groups are preferably
removed by hydrogenolysis e.g. with hydrogen in
the presence of a hydrogenation catalyst such as
palladium/charcoal or platinum
The compounds of general formula I, initially
obtained, may subsequently be converted into the
acid addition salts thereof, for example by conventional
methods such as reacting the compounds as bases
with an acid in a suitable solvent. Acid addition
lo salts of these compounds, initially obtained, may
subsequently be converted into the corresponding
compounds of general formula I or into different
acid addition salts thereof.
The compounds of general formulae II to XXII
used as starving materials are known from the literature
in some cases or may be obtained by methods known
_.
Thus, for example, a starting compound of
general formulae II and VIII may be obtained by
reacting a corresponding ~enzazepine with a corresponding
halogen compound and optionally subsequently reacting
it with a corresponding amine. The benzazepine
of general formula IV required for this is obtained
by cyclising a corresponding compound, ego by
cyclising a compound of general formula XXIII
1 H KOCH
R2 - -CH2-CH ( XII )
I
or of general formula XXIV
CH2CH2NHCCH2Cl (XXIV1
R2 0
if Al and R2 do not represent alkoxy groups, optionally
followed by catalytic hydrogenation and/or reduction
of the carbonyl group using sodium borohydride/glacial
acetic acid, for example see published European
Patent Application No. 7070) Andre oxidation,
e.g. with selenium dioxide.
A compound of general formula VI used as
starting compound may be obtained, for example,
by reacting a corresponding benzazepine with a
corresponding haloacetal with subsequent hydrolysis.
A compound of general formula XV used as
starting material may be obtained by reduction
of a corresponding vitro compound which is in turn
obtained by acylstion or alkylation of a corresponding
amine.
Compounds of general formulae X to XIII,
XVI to XVII, XVIII, XX and XXI used as starting
materials may preferably be obtained by reacting
a corresponding halogen compound with a corresponding
amine and optionally subsequently splitting off
any protecting groups used to protect the hydroxy
groups.
A compound of general formula XXII used as
starting material may be obtained, for example,
by chloromethylation of a compound of general formula XXV
~æ~ 7
- 33 -
COUCH
Al l
SCHICK- N\
W TV
R2
(wherein Al, R2 and E are as herein before defined
and W represents a protected hydroxy group, e.g.
an acetoxyt benzoyloxy or 4-nitrobenzoyloxy group)&
further reacting it with an alkali metal cyanide
converting the group W into a suitable leaving
group such as that of the chlorine, bromide or
iodine atom or of the methylsulphonyloxy or 4-methyl-
phenylsulphonyloxy group and subsequently reacting with an amine of general formula VII
H-~-G_~R3
R6 R4 VOW)
(wherein R3 to R6 and G are as herein before defined),
with optional subsequent hydrolysis and/or esterifi-
cation or amidation.
As already mentioned herein before, the new~ompounds of general formula I an the physiologically
acceptable addition salts thereof have valuable
pharmacological properties, more particularly a
I long-lasting heart rate lowering activity and the
effect of reducing the 2 requirement of the heart,
with very few wide effects/ e.g. only a iota
antimuscar~nic effect
Lo 7
- 34 -
For example, the following compounds
A = 1-(7,8-dimethoxy-1~3,4,5-tetrahydro-2~-3-
benzazepin-2 on-3-yl)-3-[N-methyl-N (3-~3,4-
dimethoxy-phenyl)-propyl3-amino] propane
S hydrochloride,
B - 1-(7~8-dimethoxy-1~3~4~5-tetrahydro-2H 3-
benzazepin-2-thion-3-yl)-N-[N-methyl-N-(2-
(3~4-dimethoxy-phenyl)-ethyl)-amino]-propane,
C = 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-~N-3-
benzazepin-2-on 3-yl~3~[N-methyl-N-(2-hydroxy-
2-(3,4-dimethoxy-phenyl)-ethyl)-amin~-propane,
D = l-(l-hydroxy-7,8-dimethoxy-1,3~4,5-~etrahydro-
2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-
(2-(3,4-dimethoxy-phenyl)-ethyl) amino propane
15 E = 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H~3-
benzazepin-2-on-3-yl)-3-1N-methyl-N-(2-(4-
amino-3-nitro-phenyl)-ethyl)-amino]-propane
hydrochloride,
F = 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2~-3-
benzazepin-2-on-3-yl)-3-[N-methyl-N-(4-(4-
dimethylamino-phenyl)-butyl)-amino]-propane
hydrobromide,
G 7,8-dimethoxy-1,3,4,5-tetrahydro-2~-3-
benzazepin-2-on-3-yl)-3-[N-methyl-N-(2 phenol-
ethyl)-amino]-propane dihydrochloride
(7 t 8-dimethoxy-1,3,4,5- etrahydro-2H-3-
benzazepin-2 on-3-yl)-3-[N-methyl-N-(5~(3,4-
dimethoxy-phenyl)-pentyl)-amino~-propane
hydrochloride and
I 7
I = 1-(7 9 8-dimethoxy-1,3,4,$-tetrahydro-2H-3~
benzazepin-2-on-3-yl)-3-~N-methyl-N~(3-(4-
amino-3,5-dichlorophenyl)-propyl~-amino]-
propane
have been tested by comparison with
K = 1-~7,8-dimethoxy-1l3,4,5-tetrahydro 5H-2-
benzazepin-1-3n-2-yl)-3-[N-methyl-N-(2-(3,4-
dimethoxy-phenyl)-ethyl~-ami.no]-propane hydra-
chloride
for their biological properties as follows:
Effect on Heart Rate in Rats
The effect of the test substances on heart
rate was investigated in two rats with an average
weight of 250 Jo 300 9 for each dose. The rats
were anesthetized with pentobarbital (50 mg/kg
imp. and 20 mg/kg sac.). The test substances were
injected in aqueous solution into the jugular vein
(0.1 ml~100 go.
The blood pressure was measured using a Connally
inserted in a carotid artery and the heart rate
was recorded from an HOG Wind or IIIrd reading)
obtained using needle electrodes. The heart rate
of the animals in the control period was between
350 and 400 beats per minute bin
The following table contains the values found:
SLY
- 36 -
Substance Dose Reduction in heart rate measured
/kg)20 minutes after administration
of substance bin
5.0 - 183
2.5 - 85
. 1.0 - 51
B 5.0 - 255
2.5 - 134
73
C 5.0 1~3
2.5 - 137
D 5.0 - 117
2.5 - 73
1.0 - I
E 5.0 - 130
F 5.0 - 123
2.5 - 91
1~0 94
G 5.0 - 135
2.5 - 110
1.0 o 80
H 5.0 75
I I - 175
R 5.0 - 18
The compounds prepared according to the invention
do not have any toxic side effects of any kind
when administered in therapeutic doses. Thus,
for example, when substances A and D are administered
intravenously to mice, even in a high dosage of
20 mg/kg, no toxic side effects can be detected.
In view of their pharmacological properties,
the compounds prepared according to the invention
are suitable for the treatment of Linus tachycardia
of various origins end for the propbylaxis and
therapy of isch~emic 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 herein before
defined or a physiologically acceptable acid addition
salt thereof in association with a pharmaceutical
carrier or excipient.
For pharmaceutical administration the compounds
of the invention may be incorporated into conventional
preparations in either solid or liquid form; optionally
together 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, tablets,
coated tablets, capsules, powders, suspensions,
drops, ampules, syrups and swoop tories.
The active ingredient may be incorporated
in inert carriers and/or delineates customarily employed
in pharmaceutical compositions, such as, for example,
corn starch, lactose; glucose, microcrystalline
cellulose magnesium Stewart, polyvinyl pyrollidone,
citric acid, tartaric acid, water, water/ethanol,
water/glycerol, water/sorbitol, water~polyethyleneglycol,
propyleneglycol, carboxymethyl cellulose, paraffin
derivatives, fatty substances of animal or vegetable
origin ego. hard photo various wetting, dispersing,
emulsifying, or preservative agents, or mixtures
thereof.
Advantageously the compositions may be formulated
as dosage units, each unit being adapted to supply
a fixed dose of active ingredient The dose required
is conveniently from 0.03 to 0.4 mg/kg of body
weight (preferably from 0.07 is 0.25 mg/kg of body
weight) administered once or twice per day. Depending
on the kind and the body weight of the patient
to be treated, on the kind and the seriousness
of the disease, on the type of preparation and
on the route of administration as well as on the
~21~ 7
- 38 -
period or interval over which the administration
takes place, it may however be necessary to deviate
from the above dosages. Thus, it may be sufficient
in some cases to administer less than the above-
mentioned amount of active ingredient, while another cases the above-mentioned amount of active
ingredient must be exceeded. The optimal dosage
and type of administration of the active ingredients
which are necessary in each case can easily be
assessed by one skilled in the art.
husk according to a still further feature
of the present invention, there is provided a method
of preventing or relieving ischaemic cardiac diseases,
or of relieving sinus tachycardia in a patient,
which comprises administering to the said patient
an effective amount of a compound of general formula
I as defined above or a physiologically acceptable
acid addition salt thereof.
The following non-limiting Examples are intended
to illustrate the invention more fully:
I
- 39
Preparation of the starting compounds
Example A
1-~7,8-Dimethoxy-1,3,4,5-tetrah~dro-2H-3-ben~azePitin-
2-on yule) 3-N-methyl-amino propane-hYdrochloride
a) 1-(7,8-Dimethoxy-1,3-dihydro-2H 3-benzazePin-
2-on-3-yl)-3-N-methyl-N-benzvl-amino-propane
hydrochloride
Prepared analogously to Example lb by reacting
1-~7,8-dimethoxy-1,3-dihydro-2H-3 ben~azepin-2~
on~3-yl)-3-chloro-propane with N-methyl-benzylamine.
Yield: 92.1% of theory,
Melting point: 208-209C.
b) l-~7,8-Dimethoxy-1,3,4,5-tetrahYdro-2H-3-
benzazepin-2-on-3-yl)-3-N-methyl-amino-propane
lo hydrochloride
Prepared analogously to Example 5 by catalytic
hydrogenation of 1-(7,8-dimethoxy-1,3-dihydro-2H
3~benzazepin-2-on-3-yl)-3 N-methyl-N-benzyl-amino-
propane.
Yield: 87~ of theory
Melting point: 110C (decomposition).
Example B
1,3,4,5-Tetrahydro-2H-3-benzazepin-2-one
a N-(2-Phenyl-ethyl)-l-chloro-acetamide
38.7 ml (0.3 molt of 2-phenylethylamine and
45.9 ml (0.033 molt of triethylamine are dissolved
in 30 ml of ethylene chloride and mixed with 26.4 ml
(0.33 molt of chloroacetyl chloride, dissolved
in 150 ml of ethylene chloride, at 10C. After
1 bourns stirring at ambient temperature, the product
is extracted with 1% acetic acid and with water,-
dried over magnesium sulfite and concentrated
by evaporation in vacua.
Yield: 54.2 9 (lo I Of theory)
Mop. 64-65C
,
~Z~1.1()7
- 40 -
b) 1,3,4L~Tetrahydro-2H-3-benzazepin-2-one
54.0 9 (0.373 molt of N-(2-phenyl-ethyl)-
l-chloroacetamide are mixed with 73~8 9 (0.55 ml)
of aluminum chloride and stirred for 13 hours
at 130-140C. After the aluminum chloride has
been destroyed with ice water, the product is extracted
with ethylene chloride, washed with water, dried
over magnesium sulfite, concentrated by evaporation
in vacua and the residue obtained is purified over
silica gel using ethylene chloride plus 3% ethanol
as eluant.
Yield: 6.22 9 (1401% of theory),
Melting point: 158-160C.
Example C
1-(7-Bromo-8-methox~-1,3,4,5-tetrahydro-2H-3-benzaaspen
2-on-3-yl)-3-chloro-pro~ane
a 8-Methoxy-1,3,4,5-tetrahydro-2H-3-benzazePin-
Z-one
56.8 9 (0.3 molt of 8-methoxy-1,3-dihydro-
2H-benzazepin-2-sne (melting point: 190-191C),
dissolved in 600 ml of glacial acetic acid, were
hydrogenated in the presence of 5 9 of 10% palladium/-
charcoal at a temperature of 80C under a hydrogen
pressure of 5 bar for 12 hours. After filtering
off the catalyst the solvent was removed in vacua.
The obtained residue was mixed with water and neutralized
wit potassium carbonate. The precipice was
suction filtered, washed with water and dried.
Yield: 51.1 9 (89.1% of theory)
Melting point: 160-161C
by Brigham and 9~bromo-8-methoxy-1,3,4,5-tetrahydro-
2~-3-benzaze~in-2-one
6.4 g -I 2.03 ml ~0.04 molt of bromide were
dropped into a solution of 7.4 9 (0.04 molt of
8-methoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-
one in 100 ml of 80% acetic acid at a temperature
between 3 and 5C whilst stirring. After 15 minutes,
~211~L~7
- 41 -
the reaction mixture was poured into ice-water
and neutralized with potassium carbonate The
precipitate was suction filtered, washed with a
little water and dried. The isomers were separated
by means of chromatography over silica gel using
ethyl acetate as eluantO
Yield: 5.7 9 (52.8% of theory) of 9-bromo-i~omer
IT spectrum (ethylene chloride 3,400 cm 1 NO
1,660 CO)
4.1 9 (38~ of theory) of 7-bromo-isomer
IR-spectrum (potassium bromide: 3,200 cm 1 NO
1,665 Cal (CO)
c) 1-(7 Bromo-8-methoxY-l~3~4~5-tetrahydro-2H~
3-benzazepin-2-on-3-yl2-3-chloro-PrOpane
15 0.24 9 of 55% sodium hydrides dispersion in
oil were added to a mixture of 1.35 9 (i molt of
Brigham methoxy-1,3,4,5-tetrahydro-~H-3-benzazepin-
2-one in 15 ml of dimethylsulfoxide at room temperature.
After stirring at room temperature for 30 minutes
and at a temperature between 35 and 40C for 10
minutes, the obtained solution was added to 0.79 9
(5.5 molt of 1-bromo-3~chloro-propane in 5 ml of
dimethylsulfoxide. After stirring at room temperature
for 2 hours, the mixture was poured into ice-water
and extracted with ethylene chloride four tomes.
The ethylene chloride extracts were washed with
water, dried and evaporated in vacua. The obtained
residue was purified over silica gel using ethyl
acetate a eluant.
Yield: 210 my (12% of theory)
Melting point: 119-120C
Example D
7-Nitro-8-methoxy-1,3 ! 4, 5-tetrahydro-2H-3-ben2aze~_n-
2-one
7~5 my (4 molt of 8-methoxy-1,3 9 4,5-tetrahydro-
2~-3-benzazepin-2-one were added to a mixture of
15 ml of concentrated nitric acid and of 1.5 ml
- I -
of fuming nitric acid at a temperature between
3 and 5C whilst stirring. After stirring at
this temperature for further 30 minutes, the mixture
was poured into ice-water and neutralized with
potassium carbonate. The formed precipitate was
auction filtered, washed with water and dried.
The yellow crystals were purified over silica gel
using ethyl acetate as eluant to separate the cores-
pounding nutria- and 7~9-dinitro-isomers.
Yield: 400 my (42.3% of theory)
Melting point: 204-205C (decomp.)
I: :
:: "
- 43 -
Preparation of the end_prolducts:
Example 1
1-(7,8-Dimethoxy-1,3,4~5-tetrahydro-2H-3-benzazepitin-
2-on-3-yl~-3-[N-methyl-N-~3-(3,4-dimethoxy-phenYl)))-
o~yl)-amino~-pr~pane hydrochloride
a 1 I ! 8-Dimethoxy-lc3,4,5-tetrahydro-2H-3-
benzazepin-2-oh 3-Yl)~3-chloro-Pro~2ne
1.1 g (0.005 molt of 7,8-dimetlloxy-1,3,4,5-
tetrahydro-2H-3-benzazepin-2-one are suspended
in 15 ml of absolute dimethylsulphoxide and mixed
with 0.67 g ~0.006 molt of potassium tert.butoxide
with stirring. After 10 minutes, the suspension
obtained is added drops to 0.64 ml (0.006 molt
of l-bromo-3-chloro-propane in 10 ml of dimethylsulph-
oxide, whilst cooling with ice water. After 1
hour the mixture is poured on to water. After
a short time the viscous precipitate begins to
crystallize. The precipitate is suction filtered,
dissolved in acetone, precipitated again with water,
then suction filtered and dried.
Yield: 0.75 9 (50.0% of theory)
Melting point: 84-85C.
b) 1~(7j8-Dimethoxy-1,3,4,5-tetrahydro~2H-3-
benzazepin-2-on-3-yl~-3 iN-methyl-N-~3-(3~4-
dimethoxy-phenyl)-prol~yl)-amino~ Propane
hydrochloride
5.55 9 (0.0186 molt of 1-(7,8-dimethoxy-1,3,4,5-
tetrahydro-2~-3-benzazepin-2-on-3 yl)-3-chloro-
propane, 2.6 ml (0.0886 molt of triethylamine and
3.9 9 (0.0186 molt of N-methyl-3-(3,4-dimethoxy-
phenyl)-pr~pylamine are heaved to 85~C for 4 hour,
then cooled and dissolved in ethylene chloride water
The organic phase it separated off extracted once
more with water, dried over magnesium sulfite,
concentrated by evaporation in vacua end the residue
obtained is purified over silica gel using ethylene
chloride ply I ethanol as eluant. The oily residue
I -
obtained is dissolved in acetone and the hydrochloride
is precipitated with ethereal hydrochloric acid.
Yield. 3.4S 9 ~36~6% of theory,
Melting point: 220-221C~
Example 2
1-(7,8-Dimethoxy-1~3l4,5-tetrahvdro 2~-3-benzazepin-
2 on-Yl?-3-[N-methvl-N-~2-phenyl-ethyl~-amino]-
propane dihydrochloride
Prepared analogously to Example lb by reacting
1-(7,8-dimethoxy-1,3,4~5-tetrahydro-2H-3-benzazepitin-
2-on-3-yl)-3-chloro-propane with N-methyl-2-phenyl-
ethyl amine.
Yield: 43.2% of theory,
Melting point: 165C decomposition.
Example 3
3~4,5-Tetrahydro-2H-3-benzazePin-2-on-3-yl)-
3-[N-methYl-N-(2-(3,4-dimethoxy-phenyl)-eth~l)-
amino]~ropane hydrochloride
a) 1-(1,3,4,5-Tetrahydro-2H-3-benzazepin-2-on-
3-Yl)-3-chloro-propane
Prepared analogously to Example lo by reacting
1,3,4,5-tetrahydro-2H-3-benzazepin-2-on with 1-
bromo-3-chloro-propane.
Yield: 13.4~ of theory
IT Spectrum (ethylene chloride: 1660 cm 1 (CO).
by 3,4,5-Tetrahydro-2H-3-benzazepin-2-on-
3-Yl~-3-[N-methyl-N-(2-(3~4-dimethoxy-phen
ethyl)-amino~-propane hydrochloride
prepared analogously Jo Example lb by reacting
1-(1,3,4,5-tetrahydro-2R-3-benzazepin-2 only)-
3-chloro-propane with N-methyl-N-(2-(3,4-dimethoxy-
phenyl)-ethyl)-amine.
Yield: 29.2% of theory
Melting point: kiwi
SLY 017
- 45 -
Example 4
1-~7,8-Dimetho~y-1,3-dihydro-2~ 3-benzazepin-2-
on-3-yl?-3-[N-methyl-N-(~-(3,4-dimethoxy-phenyll-
pentyl)-aminol propane hydrochloride
a) 1-(7~8-Dimethoxy-1,3 dihydro-2~-3-benzazepin-
2-on-3-yl)-~-chloro~roPane
Prepared analogously to Example lo by reacting
7,8-dimethoxy~1,3-dihydro-2H-3-ben2azepin-2-one
with l-bromo-3-chloro-propan~.
Yield: 8703~ of theory,
Melting point: 101-103C.
b) 1-~7~8-Dimethoxy-1,3-dihxdro-2H-benzazepin-
2-on-3-yl)-3-[N-methvl-N-~5-t3~4-dimethoxy-
phenyl)-pentyl~-amino3-propane hydrochloride
Prepared analogously to Example lb by reacting
1-(7,8-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-
- on-3-yl)-3-chloro-propane with N-methyl-~-(5~(3~4-
dimethoxy-phenyl)-pentyl)-amine.
Yield: 67.3~ of theory,
Melting point: 158-160C.
Example S
1-57,8-DimethoxY-1,3,4,5-tetrahydro-2H-3-benzazePitin-
2-on 3-yl)-3-tN-methyl-N-l5-(3~4-dimeth
pentyl~-aminol-proPane hydrochloride.
3.23 9 (0.0065 molt of 1-(7,8-dimethoxy-1,3-
dihydro-2~-3-benzazepin-2-on-3-yl)-3~[N-methyl-
N-(5-(3,4-dimethoxy-phenyl1-pentyl~-amirlo~-propanno,
dissolved in 30 ml of acetic acid, are hydrogenated
at ambient temperature under a hydrogen pressure
of 5 bar in the presence of 10% palladium/~harcoal
for 3.5 hours. The catalyst is filtered off, the
filtrate is concentrated by evaporation in vacua
and the residue it taken up in ethylene chloride/15%
potassium carbonate solution. The organic phase
is separated off, dried over magnesium sulfite
and rotated in vacua and the residue obtained is
Lo 7
- I -
purified over silica gel using ethylene chloride
plus I ethanol as eluant. The residue obtained
is dissolved in acetone and the hydrochloride is
precipitated with ethereal hydrochloric acid.
Yield: 2.1 9 ~60.3~ of theory),
Melting point: 165-166C
Example 6
1-(7.~ Dimethoxy~1,3~4c5-tetrahydro-2H-3-benzazepin-
thinly) 3 [N-methyl-N-t2-~3,4-dimethoxy-phenyl)-
ethyl amino propane
2.28 9 (0.005 molt of 1-(7,8-Dimethoxy-1~3,4,5-
tetrahydro-2H-3-benzazepin-2-on 3-yl)-3-[N-methyl-
N~(2-(3,4-dimethoxy-phenyl)-ethyl)-amino3-propane
are dissolved in 10 my of absolute Tulane and
reflexed for 50 minutes with 1.0 g (0.0025 molt
of2,4-bis-(4-methoxy-phenyl)-1,3-dithia-2,4~diphossphHutton-
2,4-di~ulphide. After the solvent has been rotated
in vacua, the residue obtained is purified over
aluminum oxide with ethylene chloride plus 2%
ethanol as eluant.
Yield: 1.45 g (61.4% of theory)
C26~36N24S (472.6)
Calm: C 66.07 H 7.68 N 5.93 S 6.78
Found: 66.10 7.71 5.56 6.76
Example 7
1-(7,8-Dimethoxy-1 Lo 4,5-tetrahydro-2H-3 benzazepin-
online methyl-N-(3,4 dimethoxY-benzoyl-methyl)-
amino] Prison hydrochloride
Prepared analogously to Example lb by
reacting 1-(7,8 dimethoxy-1,3,4,5-tetrahydro-2~-3-
~enzazepin-2-on-3 yl)-3-N-methyl-amino-propane with
~-bromo-3,4-dimethoxy-acetophenone.
Yield: 1.29 9 ~77.0~ of theory,
Melting print: 190C
- 47 -
Example
l-(7?8 Dimeth2xy-1,3,4~5-tetrahydro-2~-3-benzaze~
only 3-~N-methyl-N-(2-hydroxY-2-~3~4-dimethoxy
phenyl~-ethyl)~amino]-propane
0.~2 9 (0.002 molt of 1-(7j8-dimethoxy-1,3,4,~-
5tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl---
N-(3,4-dimethoxy-benzoyl~methyl)-amino]~propane
are dissolved in 6 ml of ethanol, mixed with 0.38 9
(0.01 molt of odium bordered and stirred for
2 hours at 25C. After the solvent has been evaporated
in vacua, the mixture is dissolved in ethylene
chloride, extracted with water, dried over magnesium
sulfite and concentrated by evaporation in vacua
and the residue obtained is purified over aluminum
oxide using ethylene chloride plus I ethanol
as eluant.
Yield- 0.5 9 (54% of theory),
IT spectrum (ethylene chloride), 1655 em 1 (CO)
C26H36N2O6 (472.6)
Cafe: C 66.08 7.68 N 5Og3
Found 66 r 01 7 62 5 I
Example 9
1-[7,8-Dimethoxy-1-(2-(3,4-dimethox~henYl)-ethyl-
amino~-1,3,4,5-~etrahydr~-2H-3-benzaze~in-2-on-3-
25 yl]-3-tN-methyl-N (2-(3/4-dimethox~y-Phenyl1-ethYl)
amino1-propane dihydrochloride
2.45 9 (5 Molly) of ~-(7,8-dime~hcxy-1,3,4,5-
tetrahydro-2~-3-benzazepin~1,2-dion-3-yl)-3-1N-metthy-
N-(2-(3,4-dimethoxy-phenyl)-ethyl)-amino~-propane
3Q and 2 g of 2-(3,4-dimethoxy-phenyl)-ethyl-amine are
heated to 150C for 3 hours. The reaction mixture
is purified over aluminum oxide N (activity II)
using ethylene chloride and I acetone AS eluant.
The fractions are concentrated by evaporation, the
residue obtained it dissolved in 100 ml of methanol
and hydrogenated for 6 hours at 50C under a hydrogen
pressure of 5 bar in the presence of 0.5 9 of 10%
palladium/charcoal. after the uptake of hydrogen
~LZ1~7
- 48 -
has ended the catalyst is removed by suction filtering,
the filtrate it concentrated by evaporation and the
residue is purified over silica gel using ethylene
chloride and I ethanol as eluant. The residue obtained
is dissolved in acetone and the dihydrochloride is
precipitated with ethereal hydrochloric acid.
Yield: 0.6 g (53.S~ of theory,
Melting point: 222-224C (decomposition).
Example 10
Hydroxy-~8-dimethoxy-1,3,4,5-tetrahydro-2H-
~-benzazePin-2-on-3-yl)-3-[N-methyl-N~l2-(3~4-dimeethics-
Phen~l)-ethyl)-amino]-Propane
2.35 9 (5 Molly of 1-(7,8-dimethoxy-1,3,4,5-
15tetrahydro-2~-3-benzazepin-1,2-dion-3-yl)-3-IN-metthy-
N-(2-~3,4-dimethoxy-phenyl)-ethyl)-amino~-propane
are dissolved in 100 ml of methanol and 5 ml of water,
then 0.2 9 of sodium bordered are added in batches
thereto, with stirring. After it has all been added,
the mixture is stirred for a further 15 minutes,
mixed with 10 ml of ON hydrochloric acid, made alkaline
with methanolic ammonia decolorised with ulcers
earth and then filtered and concentrated by evaporation
in assay. The residue is dissolved in ethylene
chloride, any undissolved salts are filtered off
and the filtrate is concentrated by evaporation.
Yield 1.65 g (69.9~ of theory), viscous oil.
IT spectrum (ethylene chloride 3400 cm 1 OH)
2840 cm 1 (methoxy)
2800 cm 1 (N-alkyl)
166D cm 1 (CO)
C26~36N2O6 (472.59)
Cowlicks 66.08 7.68 N 5.93
Phoned 7.75 5.73
I 7
- 49 -
Example_ 1
1-(7L8-Dimethoxy 113 dih~dro-2H-3,5-benzodiazepin-
3-Yl)-3-rN-met~ ,4-dimethoxy-phe~yl~-ethyl~-
aminoJ-E~opane dihydrochloride
4.3 9 (10 Molly) of N-[2-~2-amino~4,5-dimethoxy-
phenyl)~ethyl]-N'-methyl-N'-~2-(3,4-dimethoxy-phennil)-
ethyl)-1,3-diaminopropane are reflexed for 18 hours
in 30 ml of triethyl orthoformate, when concentrated
by evaporation in vacua and the residue is purified
over silica gel with ethylene chloride plus 3% methanol
as eluant. The residue obtained is dissolved in
acetone and the dihydrochloride is precipitated by
the addition of ethereal hydrochloric acid.
Yield: 1.6 y (31.1% of theory),
Melting point: 232-234C.
Example 12
1-(7,8-Dimethcxy-1,3,4~5-tetrahydro-2~-3-benzaze~ n-
2-on-3-yl)-3-[N-methyl-N-~2-(4-amino-3-nitro-phenyyule -
ethyl)--amino~-propane hydrochloride
1.0 g ~1.75 Molly of 1-(7,8-Dimethoxy-1,3,4,5-
tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-[N-methyl---
N-(2-(4-acetamino-3-nitro-phenyl)-ethyl)-amino]-prpropane
is heated in 50 ml of methanolic hydrochloric acid
for two hours to 45 to 50C. The reaction solution
is concentrated by evaporation, dissolved in ethylene
chloride washed with saturated sodium hydrogen carbonate
solution and dried over magnesium ~ulphate and the
solvent is distilled off in vacua After the residue
has been purified over silica gel with ethylene
chloride and So ethanol as fluent, the hydrochloride
it precipitated from acetone by the addition of ethereal
hydrochloric acid.
Yield: 0.4 g (43.1~ of theory)
I Melting point: 207-208C (decomposition)
I 7
- 50 -
Example 13
l-tl-Oximino-7,8-dimethoxy-1,3,4,5-tetrahydro-2H-
~henyl)-e~hyl)-amino]-~ropane hydrochloride
3~6 9 (6.8 Molly) of 1~7,8 dimethoxy-1,3,4,5-
tetrahydro-2H-3-benzazepin~ dion-3-yl)-3-[N-methyl-
N~(2-(3,4-dimethoxy-phenyl)-ethyl~-aminoJ-propane,,,
0.57 g of hydroxylamine hydrochloride and 0.87 9
of sodium carbonate are reflexed for eight hours
in 100 ml of ethanol. The solvent it distilled off
in assay, the residue is dissolved in water/methylene
chloride and the organic phase is separated off,
dried over magnesium sulfite and concentrated by
evaporation. The residue is purified over silica
gel using ethylene chloride and 5% ethanol us fluent.
The residue obtained is dissolved in acetone and
the hydrochloride is precipitated by the addition
of ethereal hydrochloric avid.
Yield: 2.4 9 (67.6% of theory)
Melting point: 156-158C
example 14
1-(1 Amino-7,8-dimethoxy-1,3,4,5-t_trah~dro-2H-3-
benzazepin-2-on-3-yl~-3-[N-methyl-N-~2-(3L4 dimethoxy-
phenyl)-ethyl) aminol-proeane dih~drochloride
1.6 g (3.3 Molly) of 1-~1-oximino-7,8-dimethoxy-
1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl~-3-~mmethyl-
N-~2-(3,4-dimethoxy-phenyl)-ethyl)-amino]-propane
are added to lS0 ml of ethanol and mixed with OWE ml
of 98~ hydrazine hydrate and 1 9 of Rangy nickel
and the mixture is reflexed for seven hours. In
order to complete the reaction, a further 1.5 ml
of 98% hydrazine hydrate and 1 9 of Rangy nickel
are added and the mixture is reflexed for a further
three hours. The catalyst is removed by union
filtering, the Convent it distilled off n vacua
and the residue is purified over silica gel with
ethylene chloride and 10% methanol. The dihydrochloride
is precipitated from an acetone solution by the addition
of ethereal hydrochloric acid.
Yield: 0.8 9 (44,6% of theory)
Melting Point: 232-234C, m/e = 471.
1-(?~8-Dimethoxy-1~3,4,5-tetrahydro 2H-3-benzaze~in-
2-on-3-yl)-3~N-methvl-N-~3-(4-dimethylamino-phenylif)-
~ropyl)-amino]-propane dihYdrochloride
5.7 9 (19~4 Molly) of 1-17,8~dimethoxy-phenyl-
1~3,4,5 tetrahydro-2H-3-benzazepin-2-on-3-yl)-3-N-
methyl-amino-propane and 4.7 9 ~19.4 Molly) of 3-(4-
dimethylamino-phenyl)-propyl brow de are heated to
1306C for I hours after the addition of 303 ml of
ethyldiisopropylamine. The reaction mixture is dissolved
in chloroform and 25% sodium hydroxide solution,
the organic phase is separated off, washed with water,
dried over magnesium sulfite and concentrated by
evaporation. After the residue obtained has been
purified over silica gel with ethylene chloride
and 5% methanol as elan, the dihydrochloride is
precipitated from acetone with ethereal hydrochloric
acid.
Yield: 0.6 g (5.9% of theory)
Melting point: 191-192C (decomposition)
example 16
1-(7!8-lDimethoxy-1,3,4,5-tetrahYdro-2R-3~benzazeppin
2-on-3-yl)-3-[N-methyl-N-(4-dimethYlamino-E~enyl~---
butyl)-amino]-propane-hydrobromide
Prepared analogously to Example 15 from 1-~7,8-
dimethoxy-phenyl-1,3,4,5-tetrahydro-2~-3-benzazepitin-
2-on-3-yl~-3-N-methyl-amino~propane and 4 (4-dimethylamino-
phenyl~-b~tyl bromide.
Yield: 10.3~ of theory
welting point: 116-118~C.
I
- 52 -
1 (1-Hydroxy-7~8-dimethoxy--2,~,4,5-tetrahYdro I
3-benzazepin-3-yl)-3-~N-methyl-N-(2 (3~4-dimethoxY-
phenyl)-ethyl)-amino]~propane dih~drochloride
2.45 9 I Molly) of 1 (7~8 dimethoxy-1,3~4~5-
tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-3-[N methyl
N (2-(3,4 dimethoxy-phenyl3-ethyl)-amino]-propane
are dissolved in a mixture of 100 ml of ether and
50 ml of tetrahydrofuran and then 0.76 9 of lithium
aluminum hydrides are added in batches, with stirring
I The resulting mixture is reflexed for one hour, cooled
with ice water and mixed with 15% amonium chloride
solution. The hydroxide precipitate is suction filtered
and washed with ether and the filtrate is concentrated
by evaporation. After the residue obtained has been
dissolved in acetone, the dihydrochloride is precipitated
with methanolic hydrochloric acid.
Yield: 2.2 9 (82.7~ of theory)
Melting point: 210-212C~
Example 18
1-(7,8-Dimethoxy-1,3~4,5-tetrahydro-2H-3-benzaze~nnun-
2 on-3-vlL~3-iN-methyl-N-(4-(4-amino-3,5-dibromo-
phenyl~aminol~ropane h~drobrom;de
1.1 9 (3.6 Molly of 1-(7,8-dimethoxy-phenyl-
1,3,4,5-tetrahydro-2H-3-benzazepin-2 online-
methyl-amino-propane and 1.4 9 (3~6 Molly) of 4-~4-
amino~3,5-dibromo-phenyl~-butyl bromide are heated
to 130C for two hours in 3 ml of ethyl-diisopropyl-
amine Then the excess amine is distilled off in
vacua and the residue obtained is purified over silica
gel using ethylene chloride and 2% ethanol as eluant.
The fractions are combined in vacua, the residue
is triturated with acetone and the precipitate formed
is suction filtered.
Yield: 0.6 9 t27.g% of theory)
Melting point: 159-lG1C
07
- 53
Example 1 9
1-(7,8-Dimethoxy-1~3,4,5-tetrahydro-2H-3-benzazepitin-
2-o -3-yl)-3-[N- ethyl-N-(3-_3/4-dimethoxy-Phenyl)
propyl)-amino]-pr~ane hydrochloride
2.6 9 (5 Moe) of the sodium salt of N-13~
5methyl-N'-(3-~3,4-dimethoxyphenyl)-propyl)-amino]---
propyl]-2-52-carboxymethyl-4,5-dimethoxyphenyl~-ettthylamine
are heated to 200~C in 30 ml of sulfolane for two
hours. After cooling, the mixture is diluted with
3 ml of water and extracted three times with ethylene
chloride. The organic extracts are washed twice
with water, dried over magnesium sulfite and the
solvent is concentrated by evaporation in Yoke.
The residue is dissolved in acetone and the hydrochloride
is precipitated by the addition of methanolic hydrochloric
acid.
Yield: 1.8 9 (71~ of theory)
Melting point: 220-221C
Example 20
2Q 1-(7,8-Dimeth_xy~ 3,4~5-tetrahydro-2H-3-benzazepin-
1,2-dion-3-,,~1-3-[N-methyl-N-(1-(3,4-dime',:hoxy---phenol)-
propyl)-amino]-propane hydrochloride
lr7 9 (0~0154 Molly) of selenium dioxide are
added at 70C to 70 ml of Dixon and 2.8 ml of
water. After 15 minutes, 1.4 9 of Celite~and 6.9 9
(0~0147 I of 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-
2~-3-benzazepin-2-on-3-yl)-3-[N-methyl-N-(3-(3,4-
dimethoxy phenol) propyl)-amino~-propane are added
and the resulting mixture it reflexed for 40 hours.
After cooling, the undissolved constituents are removed
by suction filtering the filtrate is rotated and
the residue obtained it purified over ilk gel
with ethylene chloride + 4% ethanol a fluent.
The product is dissolved in acetone and the hydrochloride
is precipitated with ethereal hydrochloric acid.
Yield: 2.36 g (29.2~ of theory)
Melting point: 189-192C
Jo
I role my k
- 54 -
Example 21
1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepitin-
2-on-3-yl)-3~[N-methyl-N-~2-(4-amino-3~5~dichloro---
phenyl~-2-hydroxy-ethyl)-amino]-pro~ane
Prepared from 1-(7,8--dimethoxy-1,3,4,5-tetrahydro-
2~-3-benzazepin-2-on-3-yl) 3-[N-methyl-N-(4-amino-
3,5-dichloro-benz~yl-methyl3-amino]-propane and sodium
bordered analogously to example 8.
Yield: 71.6% of theory
Melting point: 122-126C
It Spectrum (ethylene chloride): 3400 cm 1,
3495 cm 1 ~NH2)
1650 Cal KIWI)
W Spectrum (ethanol): 240 no (0.14)
290 no (0.061
314 no (shoulder; 0,02)
Example 22
1(7,8-Dim_thoxy-1,3,4,5-tetrahydro-2~-3-benzazepinn--
202-on-3-yl)-3-~N-methYl-N-(2-(2-amino-3,5-dichloro---
ennui -hydroxy-ethyl)-amino~-propane
Prepared from 1-(7~8-dimethoxy-1,3,4,5-tetrahydro-
2H-3-benzazepin-2-on-3-yl)-3-[N-methyl-N--(2-aminoox-
3,5-dichloro-benzoylmethyl3-aminol-propane and sodium
bordered analogously to Example 8.
Yield: 45% of theory, resin
IT Spectrum (ethylene chloride): 3360 cm 1,
3450 cm 1 NO
1650 Cal (lactam-CO)
3Q W Spectrum (ethanols 240 no (0.13)
280-290 no (0.045)
310 no shoulder; 0.03)
351(7,8-Dimethoxy__~3,4,5-tetrahydro-2~-3-benzaze~inn--
2-on-3-yl3-3-[N-methYl-N-(2-~3-amino~4-chloro-phenNoel
2-hydroxy-ethyl)-amino]-propane
Prepared from 1 (7,8-dimethoxy-1,3,4,5-tetrahydro-
sly
- 55 -
2H~3~benzazepin-2-on-3-yl)-3-[~-methyl Newman-
4-chloro-benzoyl~methyl)-amino]-prDpane and sodium
bcrohydride analogously to Example 8.
Yield: 55% of theory, resin.
5 IT Spectrum (ethylene chloride): 3380 cm l, 3470 cm 1
(NH23
1650 cm l(lactam-CO~
W Spectrum methanol): 236 no (0.13)
282-292 no (0.055)
310 no shoulder; 0.02)
Example 24
1-(7~8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepitin-
2-on-3-Yl)-3-[N-methyl-N-(2-~4-amino-3-chloro-5-flLowry-
I phenylJ-2-hydrox~-ethyl)-amino~-pro~ane
Prepared from 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-
2H-3-benzazepin-2-on-3-yl)-3-1N-methyl-N-(4-amino---
3-chloro-5-fluoro-benzoyl-methyl)-amino]-propane
and sodium bordered analogously to Example B.
Yield: 48% of theory, foam.
IT Spectrum (ethylene chloride) guy cm 1, 3480
cm 1 (No)
1645 cam ~lactam-CO~
W Spectrum (ethanol) 238 no ~0.18)
282-292 no (0.07)
Example 25
1-(7,8-Dimethoxy-1,3/4~5-tetrahydro-2H=3-benzazepitin-
2-on-3-yl)-3-EN-me~hyl-N-(2~4 amino-3-chloro-5-methYl-
E~enyl~-2-hvdroxy-ethyll-amino]-propane
Prepared from 1-(7,8-dimetho~y-1~3,4,5-tetrahydro-
2H-3-benzazepin-2-on-3~yl)-3-[N-methyl-N-~4-amino---
3-chloro-5-me~hyl-benzoyl-methyl)-amino~-propane
and sodium bordered analogously to Example 8.
Yield: 25% of theory, foam.
IT Spectrum (ethylene chloride) 3380 cm 1,
3470 cm 1 (NH2)
.
1650 cam (lactam-CO)
- 56 -
W Spectrum (ethanol 239 no (0 15)
280-290 no (0.05)
305 no (shoulder; 0.01)
The following compounds may be prepared analogously
to the preceding Examples:
1-(7-Methoxy-1/3,4,5-tetrahydro-2H-3-benzazepin-2---
on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)-
propyl)-amino]-propane hydrochloride,
Multilane point 172;~175C,
1-(7 MethQxy-1~3,4,5-tetrahydro-2~-3~benza~epin-2-
on-3-yl)~3-~N-methyl-N-(3-(4-amino-3j5-diohloro-phHoneywell)-
propyl)-amino]-propane,
1-(7-Trifluoromethyl-1,3,4,5-tetrahydro-2H-3-benzaAppian-
2-on-3-yl)-3-[N-methyl-~-(2 (3,4-dimethoxy-phenyl)-
ethyl)-amino~-propane,
1-(7-Trifluoromethyl-1,3 9 4~5-tetrahydro-2H-3-ben2azepin-
2-on-3-yl)-3-[N-methyl-N-(3-(3,4-dimethoxy-phenyl)))-
propyl)-amino]-propane,
1-(7-Trifluoromethyl-1,3,4,5-tetrahydro-2H-3-benzaaspen-
202-on-3-yl)-3-~N-methyl-N-(3-(4-amino-3,5dichloro---
phenyl)-propyl)-amino~-propane,
1-(7~Methylamino-1,3,4,5-tetrahydro-2H-3-benzazepitin-
2-on-3-yl)-3-[N-methyl-N (2-(3,4-dimethoxy-phenyl)-
ethyl)~aminoj-propane
251-(7-~ethylamino-1,3~4,5-tetrahydro-2H-3-benzazepitin-
2-on-3-yl)-3-~-methyl-N-(3-~3,4 dimethoxy-phehyl)-
propyl~-amino]-propane
I 7
- 57 -
1-(7-Methylamino-1,3,4,5-tetrahydro-2H-3 benzazepin-
2-on-3-yl3-3-[N-methyl-N-(3-(4-amino-3,5-dichloro---
phenyl)-propyl~-amino]-propane~
1-(7 Dimethylamino-1,3,4,5-tetrahydro-2E-3-benzazepin-
2-on-3 yl)-3-[N-methyl-N-(2-~3,4-dimethoxy-phenyl)-
ethyl)-amino]-propane IT spectrum ethylene chloride):
1660 Cal (KIWI
1-(7-Dimethylamino-1,3~4,5-tetrahydro-2H-3-benzazeepic-
2-on-3-yl)-3-~N-methyl-N-(3-(3,4 dimethoxy phenol)-
propyl)-amino]-propane
1-(7-Dimethylamino-1,3,4,5-tetrahydro-2H-3-benzazeepic-
2-on-3-yl~-3-[N-methyl-N-(3-~4-amino-3~5-dichloro---
phenyl~-propyl)-amino]-propane,
1-(7,8-Dichloro-1,3,4,5-tetrahydro-2H-3-benzazepinnun-
2-on-3-yl)-3-[N-methyl N-(2-(3,4-dimethoxy-phenyl)-
ethyl)-amino~-propane;
1-(7,8-Dichloro-1,3,4,5-tetrahydro-2H-3-benzazepinnun-
2-on-3-yl)-3-~N-methyl-N-~3 (3,4-dimethoxy-phenyl~-
propyl)-amino]-propane;
201-(7,8-Dichloro-1,3,4~5-tetrahydro-2H-3-benzazepinnun-
2-on-3-yl)-3-[N-methyl-N-(3-(4-amino-3,5-dichloro---
phenyl)-propyl)-amino~-propane,
1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2R-3-benzazepitin-
2-on-3 yl)-3-[N-methyl-N-(2-hydroxy-3-~3,4-dimethoxy-
25 phenyl)-propyl)~amino~-propane
Oil; C27H38N2G6 (486.6)
Cafe: C 66.64 7.87 N 5.76
Found: 66.61 7r95 5~74
- I -
1-(7,8-Dimethoxy-1,3~4,5-tetrahydro-2~-3-benz~zepitin-
online methyl-(2-hydroxy-3-(4-amino-3,5-
dichloro-phenyl~-propyl)-amino]-propane,
1-(7,8-Dimethoxy-1,3,4,~-tetrahydro 2H-3-benzazepin-
2~Gn~3-yl~-3-[N-methyl-N-(3 hydroxy~3-(4-amino-~,5-
dichloro-phenyl)-propyl)~amino]-propane,
1-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H~3-benzazepitin-
2-on-3~yl)-3-[N~methyl~N-(3-hydroxy-3-(3,4-dimethoox-
phenyl3-propyl)-amino]-propane~
101-(7,8-~imethoxy-1,3,4,5-tetrahydro-~H-3-benzazepitin-
2-on-3-yl)-3-1N-methyl-N~(3-(4-amino-3,5-dichloro---
phenyl)-propyl)-amino]-propane,
Melting point: 92-93C
l-(l-Hydroxy-7,8-dimethoxy 1,3,4,5-tetrahydro-2~-
3-benzazepin-2-on-3-yll-3-[N-methyl ~-(3-~3,4-dimethoxy-
phenyl)-propyl)-amino]-propane,
1-(7-Dimethylamino-8-methoxy-1,3,4,5-tetrahydro-2HHUH-
3-benza~epin 2-on-3-yl)-3-[N-methyl-N~(3-~3,4-dimethoxy-
phenyl)-propylj-amino]-propane,
1-(7 Dimethylamino-8-methoxy-1,3,4,5-tetrahydro-2H-
3-benzazepin-2 on-3-yl)-3-[N-methyl-~-(2-(3,4 dimethoxy-
phenyl)-ethyl)-amino]-propane
IT spectrum (ethylene chloride): 1650 cm 1 KIWI),
1-(7-Bromo-8-methoxy-1,3~4,~-tetrahydro-2~-3-benzaaspen-
2 on 3-yl)-3-[N-me~hyl-~-~3-(3~4-dime~hoxy-phe
propyl)-amino]-propane hydrochloride,
Melting point: 198-199C (decomp.)
1-~7-~romo-8~methoxy-1,3,4,5-tetrahydro-2~;3-benzaaspen-
2-on-3~yl)-3-EN-methyl-N-(2-(3,4-dimethoxy-phenyl333-
ethyl~-amino~-propane
-I so -
NO spectrum (CDC13~ 7.2 Pam (lo, I, aroma
6.6 Pam I s, aromat.3,
203 Pam I s, N-CB3~.
1-(7-Chloro-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzzzazepin-
52-on-3-yl)-3-[N-methyl-N-(2-(3,4-dimethoxy-phenyl)))-
propyl)~amino]-propane,
1-(7-Chloro-8-methoxy-1,3,4,5-tetrahydro-2H-3-benzzzazepin-
2~on-3-yl~-3-~N-methyl-N-(2-(3,4-dimethoxy-phenyl)))-
ethyl)-amino]-propane,
101-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepitin-
?-on-3-yl)-3-[N-(3-(3,4-dimethoxy-phenyl)-propyl)---
amino] propane,
IT spectrum (ethylene chloride: 1645 cm 1 (CO)
Melting point of the hydrochloride- 158-159C,
151-(7,8-Dimethoxy-1,3,4,5-tetrahydro-2~-3-benzazepitin-
2-on-3-yl)-3-[N-(3-(4-amino-3,5-dichloro-phenyl~-
propyl)-amino]~propane, and
I t 8-~imethoxy-1,3,4 ! 5-tetrahydro-2H-3-benzzepin-
2-on 3-yl)-3-[N-(2~hydroxy-3-~3,4-dimethoxyphenyl)-
propyl)-amino~-propaner
-- 6
Example I
Tablets containing 10 my of 1-~7~B-dimethox~1,3 r 4 e I
tetrahydro-2~-3-benæazepin-2-o I 3~IN-methyl-
Compositions:
1 Tablet contains:
Active substance 10.0 my
Corn starch 57.0 my
10 Lactose OR . O my
Polyvinylpyrrolidone 4.0 my
Magnesium turret 1.0 my
120.0 my
Method
The active substance, corn Starch, lactose and polyvinylpyrrolidone are mixed together and moistened
with waxer. The moist mixture is forced through
a screen with a mesh size of 1.5 em and then dried
at abut 45C. The dry granulate is passed through
a 1.0 mm mesh crown and mixed with magnesium turret.
The finished mixture is compressed in a tablet press
with punches measuring 7 mm in diameter having a
dividing slot, to form tablet.
Weight of tablet: 120 my
.
Coated tablet keynoting 5 my of 1-~7,8-dimethoxY-
3C 1,3,4,5-tetrahvdro-2~-3-ben~az
_ethYl-N-~3-(3~4-dimethsxY-phenvl~-~ropyl)-amino]---
1 Tablet Gore contain&:
A~tlv¢ substance 5.0 my
Corn trash 41.5 my
awaits -30.0 I
I 7
- 61 -
Polyvinylpyrrolid~ne 3,.0 my
magnesium Stewart 0.5 my
8Q.0 my
Method
. . . =
The active substance, corn starch, lactose
and polyvinylpyrrolidone are thrill mixed and
moistened with water. The moist mass forced through
a screen with a mesh size of 1 mm, tried it bout
45 and the granulate us then passed through the
tame screen. After the addition of magnesium Stewart,
convex tablet sores measuring 6 mm in diameter are
compressed on a tablet making machine. The table
sores thus produced are moated in known manner with
a coating consisting essentially of sugar and talc.
The finished coated tablets are poll hod with wax.
Weight of moated tablet: 130 my
Example It
joules containing 5 my of 1-~7,8-dimethoxY-~J3,4!5-
tetrahYdro-2E~-3-~
3-l3,4 dimeth~xy-phenYl)-ProE~ amino propane
hydrochloride
25 1 Ampule contains:
Active substance my
Sorbitol 50.0 my
water for injection
ad 2.0 ml
method
In a suitable ~ixlng vessel the active substance
it dissolved in water for injections end the solution
it jade tonic with ~osb~t~l.
After being filtered through a membrane filter,
the solution it txansferrea, under current of I
I 7
- 62 -
into clean ~terilised ampules end autoclave or
20 mines in current of water vapor.
Example IV
Suppositories oontainin~ Lo my of~lcllL~ by-
1,3,4,5-tetrahydr~-2H-3 benzazepin-2-on-3 3 1 -
methyl L3,4-dimethoxy-phenyl)-Proeyl~-aminol-
1 Suppository contains:
Active substance 0.015 9
Ward fat ego. Witepsol 19 W 45) 1 685 q
~0700 9
Method:
lo The hard fat it melted. At 38C the ground
active substance is homogeneously dispersed in the
melt. It is cooled to 35C and poured into slightly
chilled suppository mounds.
Example Drops solution containing 10 my of 1-(7~8-dimethoxy-
1,304,5-tetrahydro-2H-3-benzazePin-2-on~ ON
methyl-N-(3-(3,4-dimethoxy-phenyl~-ProPvl)-amino~---
E~ro~an~_~ydroc~5~æ~La~e~
25 100 ml of olutlon contain:
Active substance 0.2 9
~ydroxyethyl cellulose 0.15 9
Tartaric acid 0.1 9
Sorbitol solution (70~ dry content) 3~.0 9
Glycerol 10.0 9
~enzoic acid 0.15 9
Distilled water ad 100 ml
Mattel:
Distilled water it heated to 70^C. the hy~roxyethyl
cellulose, benzo~c I no tart~ric rid are dissolved
therein with tarring The solution it cooled to
Bennett temperature and the glycerol an ~orbi~ol
;Z~07
-- 63 --
Utahan ore added with Turin. At ambient 'temperature
the active substance us added and stirred ulltil completely
dissolved. Then the liquid is evacuated, Edith Turin,
to eliminate any air.
