Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~2~Z~i36
-- 1 --
Chemical Compounds
This invention relates to new phenylalkylamines,
to processes $or their preparation and to pharmaceutical
compositions con~aining them, and to their use in the
treatment of disorders of the heart and circulation.
According to one feature of- the present invention
there are provided compounds of general formula I
1 ~ 1 ", R5 ,lI)
R
R
[wherein Rl represents a hydroxy aroup, an amino group
(optionally substituted by an alk~noyl group containing 1
to 3 carbon atoms or an alkoxycarbonyl group containing 2
to 4 car~on atoms~ or an alkylamino or dialkylamino group
in which each alkyl part may contain from 1 to 3 carbon
atoms and may each optionally be substituted by a phenyl
group;
R2 and R3, which may be the same or different, each
represents a halogen atom or a trifluoromethyl, cyano or
nitro group, or one of the radicals R2 or R3 represents
a hydrogen atom;
~0 R4 represents a hydrogen atom or an alkyl group containing
1 to 3 carbon atoms;
R5 represe~nts a hydrogen atom, a straight-cllained or branched
alkyl group containing 1 to 4 carbon atoms, a cycloalkyl
group containing 3.to 6 carbon atoms, an alkenyl group
containing 2 to 5 carbon atoms or an aralkyl group contain-
iny 7 to 10 carbon atoms;
A represents a methylene, ethylene or hydroxymethylene
group; and
B represents a group of formula
OZ636
-- 2 --
18 R6
-CH~(C~2)n-D ~
R7
or
~ r~ 6
R7
wherein R6 represents a hydrogen or halogen atom, a
hydroxy group, an alkoxy group containing l to 3-carbon atoms
optionally substituted by a phenyl group, or an alkyl-
sulfenyl or alkylsulfinyl group containing l to 3 carbon
atoms and R7 represents a hydrogen atom, a hydroxy group
or an alkoxy group containing 1 to 3 carbon atoms; or
R6 and R7 together represent a methylenedioxy group;
R8 represents a hydrogen atom or an alkyl group containing
l to 3 carbon atoms;
D represents an oxygen or sulfur atom, or a sulfinyl or
sulfonyl ~roup;
n is 1 or 2; and
E represents a straight-chained alkylene group containing
3 to 5 carbon atoms optionally subskituted bv one or two
alkyl groups containina l to 3 carbon atoms each, or (when
A represents a methylene or ethylene group, and/or Rl
represents an amino group substituted by an alkanoyl group
contalning l to 3 carbon a~oms or by an alkoxycarbonyl
group containing 2 to 4 carbon atoms, a hydroxy group or an
alkylamino or dialkylamino group in which each alkyl part
may contain ~rom l to 3 carbon atom and each may optionally
be substituted by a phenyl group, and/or R~ represents
a trifluoromethyl, cyano or nitro group, and/or R3
represents a fluorine atom, and/or ~4 represents an alkyl
group containing l to 3 carbon atoms, and/or R5 represents
an alkyl group containing l to 4 carbon atoms, a cycloalkyl
group conta~n~ng 3 to 6 carbon atoms, an alkenyl group
:~.. containing 2 to 5 carbon atoms, or an aralkyl group
~Z~ 263~
containing 7 to 10 carbon atoms, and/or R6 repr~sents a
fluorine or chlorine atom, or an alkylsulfenyl or alkyl-
sulfenyl or alkylsulfinyl aroup containin~ 1 to 3 carbon ato~s each)
E may further represent an ethylene qroup or (when A
s represents a methylene group) E may further represent a
group of formula
Rg
- CH CH~-
wherein Rg represents an alkyl group containin~ 1 to 3
carbon atoms] and acid addition salts thereo.
For pharmaceutical use, the acid addition salts
referred to above will of course be physiologically
compatible acid addition salts but other acid addition salts
may find use in the preparation of the compounds of formula
I and their physiologicallv compatible acid addition salts.
The term "acid addition salts" includes salts with oraanic
and inorganic acids.
It is to be understood that, although in the
above general formula I, no particular confiquration at
chiral centres is specified, various optical isomers are
possible, and the present invention includes within its
scope all possible racemic, enantiomeric and diastereoisomeric
forms of the compounds of formula I.
Rl may represent, for example, a hydroxy, amino, methyl-
amino, ethylamino, propylamino, isopropylamino, benzyl-
amino, l-phenylethylamino, 2-phenylethylamino, 3-
phenylpropylamino, dimethylamino, diethylamino, dipropyl-
amino, diisopropylamino, dibenzylamino~ di-(2-phenylethyl)-
amino, di-(3-phenylpropyl)-amino, methyl-ethylamino, methyl-
propylamino, methyl-isopropylamino, ethyl-isopropylamino,
methyl-benzylamino, ethvl-benzylamino, prop~-benzylamino,
pyrrolidino, piperidino, hexamethyleneimino, formylamino,
acetylamino, propionylamino, methoxycarbonylamino,
ethoxycarbonylamino, propoxycarbonylamino or
isopropoxycarbonylamino group;
:lZ~636
-- 4 --
R2 and R3, which may be the same or different, may each
repxesent, for examPle, a fluorine, chlorine, bromine or
iodine atom or a trifluorome~hyl, cyano or nitro group,
or one of R2 and R3 may represent a hydrogen atom;
R4 and R8, which may be the same or different, may each
represent, for example,a hydrogen atom, or a methyl, ethyl,
propyl or isopropyl group;
R5 may represent, for example, a hydrogen atom or a
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-
butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,allyl, crotyl, pententyl, benzyl, l-phenylethyl, 2-phenylethyl,
3-phenylpropyl or 4-phenylbutyl group;
R6 may represent, for example, a hydrogen, fluorine,
chlorine or bromine atom, or a hydroxy, methoxy, ethoxy,
propoxy, isopropoxy, methylsulfenyl, ethylsulfenyl,
methylsulf~nyl, propylsulfinyl, benzyloxy, 2-phenylethoxy
or 3-phenylpropoxy group;
R7 may represent, for example, a hydrogen atom or a hydroxy,
methoxy, ethoxy, propoxy, or isopropoxy group or R6 and
R7 together may represent a methylenedioxy group
Rg may represent, for example a methyl, ethyl, propyl
or isopropyl group; and
E may represent, for example, an ethylene, n-propylene,
n-butylene, n-pentylene, l-methyl-n-propylene, l-ethyl-n-
propylene, l-propyl-n-propylene, l,1-dimethyl~n-propylene,
l,l-diethyl-n-propylene, l,l-dipropyl-n-prop~lene, 1-
methyl-l-ethyl-n-propylene, l-methyl-l propyl-n-propylene,
l-ethyl-l-propyl-n-propylene, l-methyl-n-butylene, or
l-methyl-n-pentylene group.
Preferred compounds of general formula I are
those wherein P~l represents an amino group optionally
substituted by a benzyl group or an alkoxycarbonyl group
containing 2 to 4 carbon atoms or an alkylamino or
dialkylamino group, in which each alkyl part may contain
from 1 to 3 carbon atoms; R2 re~resents a hydrogen,
chlorine, bromine or iodine atom or a trifluoromethyl,
cyano or nitro group; R3 represents a fluorine, chlorine,
or bromine atom or a cyano group; R4 represents a hydrogen
atom or a methyl group; R5 represents a hydrogen atom,
~2~2636
an alkyl group containing 1 to 3 carbon atoms optionally
substituted by a phenyl group, or an allyl or cyclopropyl
group; A represents a methylene, ethylene or hydroxy-
methylene group; and B represents a group o formula
R8
S -CH-~H2)n-D ~ R7
or
R
wherein R8, D and n are as hereinbefore defined; R6 repre-
sents a hydrogen, fluorine or chlorine atom or a hydroxy,
methoxy, ethoxy, benzyloxy, methylsulfenyl or methylsulinyl.
group and R7 represents a hydrogen atom or a methoxy group;
or R6 and R7 together represent a methylenedioxy group; and
E represents an n-propylene, l-methyl-n-propylene, 1,1-
dimethyl-n-pr.opylene or n-butylene group or (when A repre-
sents a methylene or ethylene group; and/or Rl represents
an amino group optionally substituted by a benzyl group or
by an alkoxycarbonyl group containing 2 to 4 carbon atoms,
or an alkylamino or dialkylamino group in which each alkyl
part may contain from 1 to 3 carbon atoms; and/or R2 repre-
sents a trifluoromethyl, cyano or nitro group; and/or R3
represents a fluorine atom; and/o~ R5 represents an alkyl
group containing 1 to 3 carbon atoms optionally substituted
by a phenyl group, or an allyl or cyclopropyl group) E may
further represent an ethylene groupO
Especially preferred compounds of general formula
I are those wherein Rl represents an amino group optionally
substituted by an ethoxycarbonyl group, or an alkylamino cr
dialkylamlno group in which each alkyl part may contain
636
from 1 to 3 carbon atom~; R2 represents a hydrogen, chlorine
or bromine ato~ or a cyano group; R3 represents a fluorine
or chlorine atom or a cyano group; R4 repre~ents a hydrogen
atom or a methyl group; R5 represent~ a hydrogen ato~, an
alkyl group contalnl~g 1 to 3 carbon atom~ (optionally sub-
~tituted by a phenyl group) or an allyl or cyclopropyl group;
A repre~ents a methylene or hydrox~methylene group; and B re-
presents a group of formula
- E ~ ~ R6
R7
wherein E represents an n-propylene, 1-methyl-n-propylene,
1,1-dimethyl-n-propylene or n-butylene group, or (when R1
represent~ an ethoxycarbonylamino group and/or R2 repre~ents
a cyano group and/or R3 repre~ents a fluorine ~tom and/or R5
repre~ents an alkyl group cont~inlng 1 to ~ carbon atoms op-
tionally 3ub~tituted by a phenyl group, or an allyl or cyclo-
propyl group) E may ~urther represent an ethylene group;
R6 represents a hydrogen atom or a hydroxy or ~ethoxy group;
and R7 represents a hydrogen atom or a methoxy group.
The compounds of general ~ormula I may, for example, be prepa-
red by the following proces~e~, whlch processes con~tituted
further features of the present invention:
a) Reduction of a compound of general ~or~ula II
R2 ~ X - N ,(II)
R3
(wherein R1, R2, R3 and R5 are as hereinbefore de~ined),
B1 represents a group of formula
r~
6a -
636
-C-(CH2)k~ R7 and
X repre~ent~ 3 grollp of for~ula
R4
- A I n _ CH - or
B1 has the meanings ~entio~ed be~ore for B and
X repre~ents a group of ~orlaula
\
., j " ,~.
7 --
i36
R4 H R4
- CO - CH -, - CH - CH -,
O--ACY1
-CH - CO -, - An t ~ CO -,
Z R4 Z R4
- CH - CH - or - CH - CH2 - CH -
(wherein R4, R6 and R7 are as hereinbe~ore defined,Anl represents a methylene or ethylene group,
k repreaents the nu~bers 1, 2 or 3,
acyl repreaents an org~nic acyl group such a~ a~ acetyl,
propionyl or benzoyl group; a~d Z repre ent~ a reductively
cleavable group~ ~or example a broaine or iodine ato~ or a
carbonic ester radical, e.g~ a methoxycarbonyloxy or ethoxy-
carbo~yloxy group).
~r resp. B1,
Depending on the ~e~n~ng of the radical X to be reduced the
reductio~ may, for example, b~ carried out in a solvent such
a~ methanol, ~ethanol/water, ethanol, cthanol/water, i80-
propanol, trifluoroacetic acid, butanol, diethyl ether,
tetrahydro~uran, tetrahydrofuran/water 9 dioxan or hexa-
methyl-phosphoric acid tria~ide, and conveniently ~t tempe-
rature~ bet~ee~ -20C and the boiling point of the reactlon
mixture, c.g. at te~peratures between -20C a~d 100C.
Suitabl~ reducing agents include, for exa~ple, hydrides
aluminiu~ i~opropylate ln the pre~e~ce of a primary or
~econdary alcohol, catalytlcally activated hydrogen or
nascent hydrogen.
For the preparation of compound~ of general
36
formula It wherein A represents a hydroxymethylene group,
the reduc~ion is approprlately carried out~ for example,
wlth a complex metal hydride such as sodium borohydrlde or
lithium alu~inium hydride ln a solvent such as, for example,
methanol, methanol/water, diethyl ether or tetrahydrofuran
at -20C to 50C; wlth aluminium lsspropylate in isoproanol
convenlently at the bolling temperature, ~he acetone thus
formed being distilled off; with catalytically activated
hydrogen conveniently wlth hydro~en in the presence of a
catalyst such as for example platlnum9 palladlum, raney-
nlckel or raney-cobalt at room temperature and at a hydrogen
pressure of 1 to 5 bar; or with nascent hydrogen, e.g. from
actlvated metallic aluminlum and watex or zinc and hydxo-
chloric acid, at t~mperatures up to the boiling temperature
of the solvent used.
If in the compound of general formula II u~ed in
the above reduction, X represen~s a -CO-CH~4 group, the reac~
tion is conveniently carried out at temperatures between 0
and 50C, pre~erably at room temperature, e.g. with sodium
2 0 borohydride in methanol/water, ethanol/water or isopropanol
or with llthium alumlnium hydride in diethyl ~ther or tetra-
O-acyl
hydrofuran~ lf X represents the ~CH - CO- group, the reaction
( is preferably carried out with a hydrlde ln a solvent such
as, for example, ether, tetrahydrofuran or dioxan, e.g, wlth
diborane or lithium aluminium hydride in ~etrahydrofuran at
lower to slightly elevated temperatures, e.g. at tempera-
tures between 0 and 100C, and convenlently, at the bolllng
point of the reaction mixture,
For the preparation of compounds of general
formula Iy wherein A represents the methylene or ethylene
group, the reduction is appropriately carried out with, for
example, a hydride such as sodium borohydride, lithium
aluminlum hydrlde, sodium cyanoborohydride or pyridlne-
borane in a solvent 6uch as, for example, ethanol, iso-
propanol, tetrahydrofuran, dloxan, tr~fluoroacetic acid or
hex~methyl-pho~phoric acid triamide and conve~iently ~or
example at temperature~ betwe~n 0 and 100C.
If in the co~pound o~ general ~or~ula II u~ed in the aboYe
reduc~ion~ X repre~ent~ the -An '-C0-group or B1 r~pr~ent~
~C0-(CH2)k- ~ group,
the reaction i8 preferably carried out at eleY~ted temperatures,
e.g. with lithium alumlnium hydride i~ tetrahydro~uran at the
boiling temp2rature oi the reaction mixture; i~ X repre~ents
the hydroxy-ethylene group, thc reaction l~ pre~erably c~rrled
out with pyridin~-boran~ in trifluoroacetic acid at tempers-
tures between 25 a~d 100C, the reactio~ component~ havlng
been mixed ~t lower temperatur~s, e.g. at -10C; i~
. ,4 Z R4
X reprasent~ a -CH-CH- or CH CH2-CH- group, the reaction
i~ pre~erably carried out with ~odium borohydride, ~odiu~
cyanoborohydride or lithiu~ alu~i~ium hydride i~ a ~uitable
~olvent ~uch a~ 7 rOr exa~ple, i~oprop~nol, hexamethyl-pho~-
phoric 8cid tri~mide, tetr~hydro~ur~n or dio~a~ at t~mpera~
ture~ betwe~n 20 a~d 100C~
b) Reaction o~ a carbonyl compound (optionally formed in the
reaction mixture~ o~ general ~ormula III
K - L ,(III)
(wherein K -together with ~ neighbouring hydrogen ato~ in
the alkyl part o~ the r~dical L r~pre~ent~ an oxygen ato~; a~d
L ha3 one o~ the meaninga hereinbefore recited ~or ~ or (wlth
the exception of a hydrogen ato~) R5 or r~pre~ent~ a group of
~ormula
R4
- CH - A' ~ , R2
\~--R
R3
lZVZ636
-- 10 --
in which Rl, R2, R3 and R~ are as hereinbefore defined; and
A' represents a carbonyl, methylene or ethylene group~ or
an aldehyde hydrate thereof with an amine of general formula IV
M
~ _ ~ \ ,(IY)
(~erein M and Q, which are difL~ t, represent rjand ~ as herein-
before defined, or one of the radicals M or Q represents a
group of formula
- CH ~ R~
in which Rl, R2, R3, R~ and A are as hereinbefore defined)
and a reducing agent
The reaction is preferably carried out in a solvent
such as, for example, methanol, methanol/water, ethanol,
ethanol/water, butanol, diethyl ether, tetrahydrofuran or
- dioxan in the presence of a reducing agent at temperatures
between -20C and 50C, preferably, however, at tempera-
tures between 0 and 25C. Suitable reducing agents include,
for example, a complex metal hydride or catalytically
activated hydrogen.
Where the reaction is carried out with a secondary
arnine of general forrnula IV it is preferably carried out in
tetrahydrofuran as a solvent and with sodium cyanoboro-
hydride at pH ~7, e.g. at pH 6 - 6.5, and subsequently with
sodium borohydride at room temperature.
Where the reaction is carried out with a primary
;
.
`J2~36;
amine of general formula I~, the Schiff's base formed in the
reaction mixture is preferably reduced with a complex
metal .hydride such as sodium borohydride or lithium
aluminium hydride in a solvent such as, for example,
methanol, methanol/water, diethyl ether or tetrahydrofuran
at temperatures between -20C and the boiling point of the
used solvent, e.g. at -temperatures between 0 and 80C, or
with catalytically activated hydrogen, e.g. with hydrogen
in the presence of a catalyst such as, for example, platinum,
palladium, raney nickel, or raney cobalt, at temperatures
between 0 and 100C, preferably, however, at room tempera-
ture, and at a hydrogen pressure of 1 to 5 bar.
Methylation of an amine centre may a1so be carried out
using ~ormaldehyde and forrnic acid as the reducing agent at
elevated temperatures, e.g. at the boiling point of the
reaction mixture.
If the reaction is carried out with a compound of
general formula IV in which Rl represents an amino or alkyl-
amino group containing 1 to 3 carbon atoms, and with a car-
bonyl compound of general formula III, wherein L is as de-
ined for R5, the aforesaid Rl group can also be alkylated
at the nitrogen centre, especially when using an excess of
the carbonyl compound of general formula III.
c) Removal of one or more protective radicals from a com-
pound of general formula ~7
R2 A" - CX - N 5
~ , .
R1
~ 5 .
wherein R2, R3 and R4 are as hereinbefore defined; Rl' repre-
sents Rl as here.inbefore defined or represents a hydroxy or
amino group protected by a protective radical; Al' represents
A as hereinbefore defined or represents a hydroxymethylene
'1`2~:636
- 12 ~
group protected by a protective radical; R5' represents R5
as hereihbe~ore defined or represents a protective radical
for an amino group~ and B' represents B as hereinbefore de-
fined or represents a group ~f formula
R~
-CH-(CH2)n_D ~ R6'
R
or
- E ~ R63
~ R '
wherein ~8' D, E and n are as hereinbefore defined; and R6'
and R7', which may be the same or different, are as herein-
before defined for R6 and R7 respectively or representhydroxy groups protected by protective radicals, wherein at
least one of the radicals Rl', ~", R5' and B' represent or
must contain one of the above~mentioned protective radicals.
Suitable protective rA~;r~l~ inrl~ , for ex`ample, acyl
or alko~ycarkonyl rA~;c~l~ such as an ethoxycarbonyl, acetyl, propionyl
or benzoyl group or a benzyl group and for A" an acetyl,
methoxycarbonyl or ethoxycarbonyl group.
The cleavage of one or more of the above-mentioned
acyl and/or alkoxy carbonyl radicals is preferably carried
out hydrolytically in an a~ueous solvent, e.g. in water, iso-
propanol/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 temperatures between 0
and 100~, preferably at the boiling point of the reaction
mixture.
; The cleavage of a benzyl radical is preferably car-
ri~d out hydrogenolytically, e.g. with hydrogen in the pre-
sence of a catalyst such as, for example, palladium/charcoal,
263~
- 13 -
conveniently in a solvent such as methanol, ethanol, ethyl
acetate or glacial acetic acid and optionally under addition
of an acid such as hydroch.loric acid at temperatures between
0 and 50C, preferably, however, at r.oom temperature and at
a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.
d) For the preparation of compounds of general formula I,
wherein one of the radicals R2 or R3 represents a hydrogen
atom:
Dehalogenation of a compound of general formula VI
Nal ~ A - C~ - N 5 ,~VI)
Rl
R3
wherein Rl, R3, R4, R5, A and B are as hereinbefore defined
and Hal represents a chlorine, bromine or iodine atom.
The dehalogenation ~s preferably be carried
out in a solvent, e.g. with triphenyl phosphine in benzene
or toluene, with hydrogen in methanol, ethanol r ethyl
acetate or tetrahydrofuran and in the presence of a hydro-
genation catalyst or with a complex metal hyd.ride such as
lithium aluminium hydride or sodium diethoxy-aluminium
hyd~ide in tetrahydrofuran, dioxan or toluene. Depending on
the method used, the reaction may be carried out at room
temperature or at an elevated temperature, for example at
temperatures between 60C and 150C, and at a normal pres-
sure or a moderately elevated pressure. When using raney-
~ nickel or palladium~charcoal the dehalogenation may, for ex-
ample, be carried out at room temperature and at normal pres-
sure.
e) Alkylation of a compound of general formula VII
~21~ ;36
- 14 -
R4 ~ R n
Rz ~ A CH.~ N ,(V~I)
~ ~ B~
R1
R3
wherein Rl, R2, R3, R~ and A are as hereinbefore defined;
R5" is as hereinbefore defined for R5; and B" represents B
as hereinbefore defined provided that if R5" does not repre-
sent a hydrogen atom, at-least one of the radicals R6 or R7
must represent a hydroxy group or Rl must represent an amino
group optionally substituted by an alkyl group containing l
to 3 carbon atoms, which alkyl group may additionally be
substituted by a phenyl radical.
The reaction is preferably carried out in a sol-
vent e.g. in water/methanol, ethanol/water, tetrahydrofuran,
dioxan, acetone or dimethylsulfoxide, with an alkylating
agent such as, for example, methyl iodide, dimethyl sulfate,
ethyl bromide, diethyl sulfate, benzyl bromide, 2-phenyl-
ethyl bromide or methyl-p-toluene sul~onate, optionally in
the presence of a base such as sodium hydroxide or potassium
carbonate. Preferred temperatures are those between -10
and 50C, preferably between 0 and 30C. The reaction can,
however, be carried out without a solvent.
The alkylation of a nitrogen atom can also be car-
ried out using formaldehyde/~ormic acid at elevated tempera-
tures, e.g. at the boiling point of the reaction mixture, or
with a corresponding carbonyl compound and a complex metallic
hvdride, preferably with sodium cyanoborohydride at pH ~7,
e.g. at pH 6 to 6.5, in a solvent such as, for example,
water/methanol, ethanol, ethanol/water or tetrahydrofuran at
temperatures between 0 and 50C, preferably, however, at room
temperature.
~LZ~36
- 15 -
Moreover, the alkylation of a phenolic hydroxy
group can be carried out with, for example, a corresponding
diazo alkane in a solvent such as diethyl ether or tetrahydro-
furan. Preferred temperatures are those between 0 and 50C,
and preferably room temperature.
f) For the preparation of compounds of general formula I as
hereinbefoxe d~fined wherein Rl represents an amino group
substituted by an alkanoyl group containing 1 to 3 carbon
atoms or by an alkoxycarbonyl group containing 2 to 4 carbon
atoms,and R5 does not represent a hydrogen atom:
Acylation of a compound of general formula VIII
A - CH - N _____ R5 ,(VIII)
(wherein R2, R3, R4, R5, A and B are as hereinbefore defined)
with a compound of general formula IX
Y - CO - Rlo ,(IX)
(wherein Rlo represents a hydrogen atom, a methyl or ethyl
group or an alkoxy group cont~;n;ng 1 to 3 carbon atoms, and
Y represents a nucleophilically exchangeable group such as
for example a halogen atom, a nitrophenyl radical, an
imidazolyl group or a radical of formula -O-CORlo).
The reaction may, fo~ example, be carried out with
acetyl chloride, acetic anhydride, propionic acid anhydride
or a corresponding chloroformate, e.g. ethyl chloroformate,
which simultaneously may serveas asolvent. The reaction is
optionally effected in the presence of a solvent such as
water/tetrahydrofuran, diethyl ether, tetrahydrofuran or
~Z~Z63~;
- 16 -
methylene chloride, optionally in the presence of a base
such as triethylamine or pyridine (in which case the
tertiary organic base may optionally serve as a solvent), at
temperatures between 0 and 100C, preferably, however, at
room temperature. The reaction can also be carried out
without a solvent.
g) For the preparation of compounds of general formula I,
wherein D represents a sulfinyl or sulfonyl group:
Oxidation of a compound of general formula X
R2 A - CH - N R6
R ~ ~ C~ - (CH2)~ ~ Sm ~ R7
3 ,(X)
1' 2' R3, R4, R5, R6, R7, R8 A and n are as before
defined and m is 0 or 1.
The oxidation is preferably carried out in a sol-
vent, e.g. in water, water/pyridine, ethanol, methanol,
acetone, glacial acetic acid, formic acid, dilute sulfuric
acid or trifluoroacetic acid, depending on the oxidising
agent used and conveniently at ~emperatures between -80 and
100C.
For the preparation of sulfinyl compounds of
general formula I the oxidation is conveniently carried out
with an equimolar amount of the oxidising agent used. Suit-
able oxidising agents include, for example, hydrogen
peroxide in glacial acetic aci~, trifluoroacetic acid or
~ formic acid at 0 to 20C or in acetone at 0 to 60C; a
peracid such as performic acid in glacial acetic acid or tri-
fluoroacetic acid at 0 to 50C; m~chloroperbenzoic acid in
methylene chloride or chloroform at -20 to 60C; and sodium
metaperiodate in aqueous methanol or ethanol at 15 to 25C.
`: ,
~Z~2~36
- 17 -
For the preparation of sul~onyl compounds of gen-
eral formula I the oxidation is conveniently carried out
with one or with two or more moles of oxidising agent per
mole of compound of formula X. Suitable oxidising agents
include e.g. hydrogen peroxide in glacial acetic acid, tri-
fluoroacetic acid or formic acid at 20 to 100C or in
acetone at 0 to 60C; a peracid such as performic acid or
m-chloroperbenzoic acid in glacial acetic acid, trifluoro-
acetic acid, methylene chloride or chloroform at temperatures
between 0 and 60C; and potassium permanganate in glaclal
acetic acid, water/sul~uric acid or in acetone at 0 to 20C.
h) ~or the preparation of compounds of general formula I, as
hereinbe~ore defined, wherein D represents an oxygen or sul-
fur atom and .R5 does not represent a hydrogen atom:
Reaction of a compound of general formula XI
14 / R~
R2 ~ A 7H - (CH ) - V ,(XI)
R3
1' R2l R3, R4, R5, R8 and n are as hereinbefore
defined; V represents a nucleophilically exchangeable group
such as a halogen atom or a sulfonic acid ester radical, e.g.
a chlorine, bromine or iodine atom or a p-toluene sulfonyloxy
or methane sulfonyloxy group; and A"'represents a methylene
or ethylene group)
with a compound of general formula XII
H - D' ~ ,(XII )
lZ~ 3~
~ 18 -
(wherein R6 and R7 are as hereinbefore defined and D' repre-
sents an oxygen or sulfur atom) or an alkali metal salt or
alkaline earth metal salt thereof.
The reaction may, for example, be carried out in a
solvent such as chloroform, tetrahydrofuran, dioxan or
toluene, and preferably, in an anhydrous aprotic solvent such
as acetone, dime-thyl formamide or dimethyl sulfoxide,
optionally in the presence of an alkali base such as sodium
carbonate, potassium carbonate, sodium hydroxide, sodlum
hydride or potassium tert.-butoxide. Preferred temperatures
are those between -10C and the boiling point of the solvent,
e.g, at temperatures between -10C and 100C, and preferably,
at temperatures between 0 and 50C. The reaction can, how-
ever, also be carried out without a solvent.
The compounds of general formula I, which contain
one or more chiral centres, may subsequently be resolved
into their optical isomers, and diastereoisomeric racemates
and their optical isomers using known techniques.
Resolution of the racemates of a compound of
general formula I may conveniently be carried out by frac-
tional crystallisation of the diastereoisomeric salts formed
by the said compound and an optically active acid such as,
for example, D(-)-tartaric acid, L(+)-tartaric acid, diben-
zoyl-D-tartaric acid, dibenzoyl-L-tartaric acid, (+)-camphor-
10-sulfonic acid, L(-)-malic acid, L(+)-mandelic acid, d--
bromo-camphor-~-sulfonic acid or l-quinic acid and subsequent
isolation of the respective optically active base. Resolu-
tion of the racematesmay also be effected by column chroma-
tography over an optically active carrier, e.g. over acetyl
cellulose.
Purification of the diastereoisomeric racemates is
effected for example by fractional crystallization and/or
column chromatography over an inert carrier.
Further, the compounds of formula I
prepared as hereinbefore disclosed may optionally be con-
verted with inorganic or organic acids into their physiolo-
gically compatible acid addition salts, for example by
. .
~lZ4~Z636
~9 -
conventional methods such as reacting the compounds as
bases with a solution of the corresponding acids in a suit
able solvent.
Particularly preferred acids include, for example
hydrochloric, hydrobromic, sulfuric, phosphoric, fumaric,
succinic, lactic, citric, tartaric and maleic acids.
The compounds of general formulae II to XII used
as starting materials are known from the literature or may
be obtained according to known processes.
Thus, compounds of general formula II, wherein X
represents a -CO-CHR~ group, can be obtained, for example,
by reaction of an ~-halo-ketone with the corresponding
amine; compounds of genera] formula Il, wherein X represents
the -CH2-CO-group, can be obtained by reaction of a phenyl-
acetic acid derivative with the corresponding amine.
Compounds of general formula III, wherein A' re-
presents a carbonyl yroup and ~ represents a hydrogen atom,
can be obtained, for example, by selenium dio~ide oxidation
of the corresponding acetophenone; compounds of general
formula III, wherein A' represents a methylene or ethylene
group, can be obtained by converting a hydroxy compound into
the corresponding halogen compound, or by acylatin~ a hydroxy
compound with the corresponding chloroformate and subsequent reduction.
Compounds of general formula V can be obtained,
for example, by reaction of an ~-phenylalkyl halide with
the corresponding amine.
Compounds of general formulae VI, VII and VIII can
be obtained, for exarnple, by reduction of a carboxylic acid
amide or amino-actophenone.
Compounds of general formula X can be obtained, for
example, by alkylation of the corresponding mercapto com-
pound and optional subse~uent oxidation.
Compounds of general formula XI can be obtained,
for e~ample, by alkylation of the corresponding phenylalkyl-
amine.
The compounds of general formula I possess
~LZl~Z6i36
- 20 -
valuable pharmacological properties, and show
beneficial effects on heart and circulation, and especially
an activity on the blood pressure, an antiarrhythmic and/or
cardiotonic acti~ity; further, they show only a low toxicity
and slight side-effects.
For example the following compounds have been tes-
ted with regard to their biological properties:
A = 1-(4-Amino-3,5-dichloro-phenyl)-2~ (4-methoxy-phenyl)-
propy ~ amin ~ ethanol,
B = 1-(4-Amino-3-cya~o-5-fluoro-phenyl)-2- ~ - ~ (4-methoxy
phenyl)-propyl7methylamino7ethanol,
C - 1-(4-Amino-3,5-dichloro~phenyl)-2- ~ -(3-phenyl-propyl)-
~-propylamin ~ ethanol hydrochloride,
D - 1-(4-Amino-3,5-dichloro-phenyl)-2~ (4-hydroxy-phenyl)-
1-methyl-propy ~methylamin ~ ethanol,
E = N- r -Methyl-2-(4-amino-~,5-dichloro-phenyl)-ethyl7-N-
~ -(4-methoxy-phenyl)-propy ~ amine hydrochloride,
F = N- ~ -(4-Amino-3,5-dichloro-phenyl)-ethy ~ -N- ~ -(4-chloro-
phenyl)-propyl7isopropylamine,
G ~ N- ~ -(4-Chloro-phenyl)-propyl7-N- ~ (~95-dichloro-4~iso
propylamino-phenyl)-ethy ~ isopropylamine, and
H = N- ~ -(4-Amino-3-bromo-5-cyano-phenyl)-ethyl7-N- ~ -(4-meth-
oxy-phenyl)-but~_7methylami~e~
JI~ 63~
- 21 -
l. Determination of the contractility parameter
dp/dtma~ or heart frequency in narcotized cats
Male and ~emale cats having a body weight of
approx. 2 to 4 kg were narcotized with pentobarbital sodium
(40 mg/kg intraperitoneal) and anaesthesia was maintained by
continuously infusing pentobarbital sodium (8 mg/kg/h).
The animals breathed spontaneously.
The body temperature was kept at 38C by means of
a heating pad and a thermostat.
The pressure in the left ventricle was measured by
means of a pressure transducer (Millar PC 350), which was
introduced into the left ventricle via the right arteria
carotis. From the pressure signal the rate of pressure
rise (dp/dt) within the left ventricle was determined by
lS means of a differentiator.
The heart frequency was measured by means of a
Grass tachograph (model 7P4). ~s trigger signal either a
ECG or the left ventricular pressure curve was used. All
parameters were registered by a Grass polygraph. -
Al~ substances were injected into the V.saphena as
solution (water or polyethylene glycol 200). Each dose was
0.3 mg/kg i.v. The maximum activity and the time after
application at which the activity was reduced to half of the
maximum were measured.
The following tables show the results:
Table I:
Te~t Increase o~Half llfe time
dp/dtin minutes
compound max
%
A + 93 38
B + 124 ~140
~ + 83 112
D ~ ~ 105 ~100
* Trademark
'~
~Z~)~636
- 2~ -
Table II:
Test Decrease ofHalf life time
heart frequency in minu-te~
compound %
E - 27 39
F - 17 150
G - 13 ~ 90
H - 14 ~52
2. Acute toxicity:
The acute toxicity was determined in male and
female mice having a body weight of approx. 20 g after intra-
venous administration (V. saphena) of each test compound (0.1
or 0.2 ml/10 g of body weight) or by administration into the
stomach. After an observa-tion time of 14 days the LD50 was
determined according to the me-thods described by LITC~IFIELD
and WILCOXON:
Test LD50 mg/kg
compound i.v. p.o.
A 19 ~ 100
C 32 250
The compounds of general formula I are suitable
for the treatment of cardiovascular diseases such as e.g,
cardiac insufficiency (due to their positive inotropic
activity)~ and cardiac arrhythmias and coronary heart dis-
eases (due to their activity in lowering the heart frequency).
According to a yet further feature of the present
invention there are provided pharmaceutical compositions
36
- 23 -
comprising, as active ingredient, at least one compound of
general formula I as hereinbefore defined or a physiologi-
cally compatible salt thereof, in associationlwith one or
more pharmaceutical carri0rs or excipients.
For pharmaceutical A~m; n-i stration the compounds of
general formula I or their physiologically compatible 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
table~s, coated tablets, powders, suppositories, suspensions,
drops or ampoules, e.g. for injection.
The active ingredient may be incorporated in ex-
cipients customarily employed in pharmaceutical compositionssuch as, for example, corn starch, lactose, gelatine, mag-
nesium stearate, citric acid, aqueous or non-aqueous vehicles,
fatty substances of animal or vegetable origin, paraffin de-
rivatives, glycols, various wetting, dispersin~ or emulsify-
ing agents and/or preservatives.
Advantageously the compositions may be formulatedas dosage units, each dosage unit being adapted to supply a
fixed dose of active ingredient. Suitable single dosage
units for adults contain from 5 to 75 mg, preferably 10 to
50 mg, of active ingredient according to the invention. Such
dosage units may, for example, be A~m;n;stered 1 to 4 times
daily. The total daily dosage may, however, be varied
according to the compound used, the subject treated and the
complaint concerned.
According to a still further feature of the present
invention there is provided a method of treating a patient
suffering from or susceptible to cardiovascular diseases
which comprises ~m; n; stering to the said patient an effec-
tive amount of a compound of formula I, as hereinbefore de-
fined, or a physiologically compatible acid addition salt
thereof.
36
- 24 -
The following non~limiting examples serve to
illustrate the present invention.
.
636
- 2s -
Example 1
1-(4~Amino-3,5-dichloro-phenyl)-2- ~ - ~ -(4-methoxy-phenyl)-
propyl7methylamino7ethanol
0~5 g (13.5 m mol) of sodium borohydride were added irl portionB
5 to a solution of 3.45 g (9 m mol) of 4'-amino-3',5'-dichloro-
2- ~- ~ -(4~methoxy-phenyl)-propyl7methylamino7acetophenone in
40 ml of metha~ol and 15 ml of water, whereby the pH value
was kept between 3 and 6 by means of 2 N hydrochloric acid.
Af~er addition the reaction mixture was stirred for 30 minu-
lO tes and the solution was evaporated in a rotation evaporator.The residue obtained was distributed between 100 ml o~ ether
and 100 ml of 2 N ammonia solution. The ethereal phase was
washed with water, dried with sodium sulfate, and evaporated.
The remaining oil was chromatographed over silica gel with
1~ methyiene chloride : methanol = 19 : 1 as eluen~ (Macherey
and Nagel 70 - 23~ mesh ASTM). The fractions containin~
the desired compound were combined7 evaporated and in vacuo
the re~in;ng solvent wa~ removed from the oil at ~0~.
IR spectrum (methylene chloride): OH 3610 cm 1
MH2 3400 + 3490 cm 1
CH2 2850 + 2940 cm 1
OC~3 2830 c~~
N-alkyl 2800 cm 1
C=C 1610 cm 1
25 W spectrum (ethanol): ~ max: 243 nm (0.23)
280 nm (0.0~)
300 nm (0.08)
Example 2
1-(4-Amino-3,5-dichloro-phenyl)-2_ ~ -(3-phenyl-propyl)-methyl-
30 amino7ethanol hydrochloride
10 g (0.035 mol) of 4' amino-2-bromo-~',5'dichloro-acetophenone,
6.7 g (0.036 mol) of N-(3-phenyl-propyl)-ethylamine hydrochloride
* Trademark
`i,~ .j,
.. . _ . .. _ ... . . . -- . . _ .. _ . _ . _ _ . _ . _ .. .. .
:lLZ~ 6~6
and 10.5 ml (0.075 mol) o~ triethylamine were added to 250 ml
o~ methylene chloride. Thls mixture was refluxed for 6 hours
and subsequently allowed ts ~tand overnight at room temperature.
The mixture was then washed with water, dried over ~odium sulfate,
and evaporated in a rotation evaporator. The oily residue, which
consisted of 4'-amino-3'95'-dichloro-2~ -phenyl-propyl)-methyl-
amino7acetopheno~e, was dissolved in 100 ml o~ 90 % ethanol. Under
stirring and external cooling with water 5 g of sodium borohydride
were added in portions. A~ter st~n~1ng ~or 1 hour at room tempera-
ture the exce~s sodium borohydride was destroyed by means ofacetone. The reaction mixture was diluted with water and extracted
with methylene chloride. The methylene chloride phase was eparated,
washed with water, dried over sodium sul~ate, and eYaporated i~
~acuo in a rotation evaporator. The yellowish oily residue was
chromatographed over silica gel (eluent: methylene chloride :
ethyl acetate = 4 : 1). The ~ractions containing the de~ired
compound were evaporated. The remalnln~ olly re~idue wa3 dissolve~
in i~opropanol, acidi~ied with ethereal hydrochloric acid, and
mixed with ether until cry~tallization commenced. A colourlesc,
cryst~ ne product was obtai~ed.~
M.p.: from 85C (under sinteri~g).
Ex&mPle 3
1-(4-Amino-~,5-dichloro--phenyl) 2- r - ~ -(4-hydroxy-phenyl)-1-
methyl-pro~vl7methylamino7ethanol
0.2 mol of sodium borohydride were added in portions to a solutlon
of 0.1 mol of 4' amino-3',5'-dichloro-2~ (4-hydroxy-phenyl)-
1-methyl-propy_7methylami~_7acetophenone in 300 ml o~ tetrahydro;
~uran and 50 ml o~ water, which was cooled with ice-water. The
reaction solution was stirred for 60 minutes at r~om temperature7
and after acidi~ying wit~ 2 N hydrochloric acid, the tetrahydro-
~uran was ~istilled off i~ ~ rotation evaporator. ~he aqueous
acidic residue obtained was extracted twice ~ith each 250 ~l
o~ eth~r after additLon o~ 8.5 N a~monia until basic.
Subseq~entl~l the ~er extra~ts were washed
, .. . . . .. . .. . . .. . . . . . . . ~ . . ~, . ... ... .. .. . _ .. .. . .. . . . .. . .
Z~i36
- 27 -
twice with each.75 ml of water and dried with magnesium sulfate.
The filtrate was evaporated in a rotation evaporator and the
obtained evaporation residue was purified over silica gel 60
(Macherey and Nagel, 70 230 mesh- ASTM). As eluent a mixture
S of methylene chloride : methanol = 30 : 1 wa~ used. The
residue, which was obtained af-ter fractionation and eva~ora-
tion in a rotation evaporator, crystallized after addition of a sma~l
amount of previously prepared compound. The obtained diastereo-
isomeric crystals in a 1:1 mixture were recrystallized from methy-
lene chloride.
M.p.: 112 - 115C
Example 4
1-(4-kmino-3,5-dichloro-phenyl)-2- ~ - ~ -(4-methoxy-phenyl)-
1-methyl-propyl7methylamino7ethanol
0.02 mol of 1-(4-amino-~,5-dichloro-phenyl)-2- ~ - ~ -(4-hydroxy-
phenyl)-1-rnethyl-propyl7methylamino7ethanol were dissolved in
22 ml of 1 N sodium hydroxide solution and 10 ml of water. To
this solution were dropped under stirring and cooling with ice-
water 0.022 mol of dimethyl sulfate and the reaction solution
was stirred after addition of 50 ml of tetrahydro~uran for
20 hours at room temperature. Subsequently 9 100 ml of ether
were added, the organic phase was separated, washed with 50 ml
of 0.5 N sodium hydroxide solution and thrice with 75ml portions of
water, and dried over mag~esium sulfate. The organic phase was
evaporated i~ a rotation evaporator and the
residue was purified over silica gel 60 (Macherey and Nagel,~
70 - 230 mesh, ASTM) (eluent: methylene chlorlde : methanol
= ~0 : 1). The obtained oily evaporation residue was liberated
from the solvent residues in vacuo over sulfuric acid. T~e oil
obtàined was a 1:1 mixture of the diastereoisometric racemates,
* Trademark
- 2~ -
IR spectrum (methyle~e chloride): OH 3200 - 3500 cm 1 broad
(below NH2)
NH2 34~0 ~ ~390 c~ 1
CH2 2930, 2850 cm 1
OCH3 2830 cm 1
N-alkyl 2800 cm 1
C=C 1580, 1510, 1485 cm 1
C=C + NH2 deformation 1620 cm 1
W spectrum (ethanol): ~ max. 244 nm (0.27)
2~0 nm (0.08)
300 nm (0.08)
Example 5
1-(4-Ethoxycarbonylamino-3-cyano 5-~luoro-phenyl)-2~ ~- r -(4-metho~y-
phenyl)-propyl7amino7ethanol
0.5 g of celite and a~terwards 2.5 g (0.01 mol) o~ 4'-ethoxy-
carbonylamino-3'-cyano-5l-fluoro-~cetopheno~e were added in por-
tiong ~Q a solution o~ 1.16 g (0.01 mol) of ~elenium dioxide
in 12 ml of dioxa~ and 0.7 ml of water at 60C under stlrring.
Subsequently, the reaction mixture was re~luxed for 4 hours
and the undissolved~o]ids were filtered o~f. Into thi~ solutio~
were dropped a~ter cooling and external cooling with ice, 2.01 g
(0 01 mol) of 3-(4-methoxy-phenyl)-propylamine hydrochloride a~d
1.01 g (0.01 mol) of triethylamine, di3æolved in 12 ml oi ethanol.
The solution containlnE the crude 4'-ethoxycarbonylamino-3'-cyano~
5'-~luoro-phenyl-~lyoxylidene-3-(4-methoxy-phenyl)-propylamine,
was reacted in portions under stirring and. coolin~ w.~th ice wlth
1.5 g o~ sodium borohydride and allowed to $tand overnight at
room temperature. Subsequently, the exces~ sodium borohydride
was de~ o~ed with acetone, the reaction mixture was evaporated
in ~acuo to a small volume, mixed with water, and extracte~
with methylene chloride. The methylene chloride ~olution wa~ washed
wlth water, dried w.ith sodium ~ulfate, and evaporated in vacuo to
dryne~s. The rem~ n~ng oily re~idue was chromatographed over 200 g o~
~ilica g21 (eluent: methylene chloride : methanol ~ O : 1).
:12!~Z636
- 29 -
The fractio~s containing . the desired compound were evapo-
rated and a colourles orystalline product was obtained.
M.p.~ 112C.
Example 6
1-(4-Ethoxycarbonylamino-3-cyano-5-fluoro-phenyl)-2
~4-methoxy-phenyl)-propyl7methylamino7ethanol
15 g (0.06 mol) o~ 4'-ethoxycarbonylamino-3'-cyano-5'~1uoro-
acetophenone were added in portion~ at 60C to a solution of
6.6 g (0.06 mol) of selenium dioxide in 60 ml of dioxan and
2 ml of water whilst stirring. Sub~equently, the reactio~
mixture was refluxed ~or 4 hours, then diluted with 100 ml o~
tetrahydrofuran and filtered o~f from the undissolved solids.
~0.7 g (0.06 mol) of N- ~ -(4-methoxy phenyl)-propyl7methylamine,
dissolved in 100 ml o~ tetrahydrofuran, were added to this so-
lution o~ 4'-ethoxycarbonylamino-3'-cyano~5'-fluoro-phenylglyoxal
after cooling at room temperature. ~he solu~ion obtai~ed was
mixed in portions with 8 g (0~13 mol~ of sodium cyanoborohydrider
the solution beiny kept at pH 6 by dropwise addition of
2 N hydrochloric acid. The reaction mixture wa~ allowed to
overnight at room temperature, mixed with 5 g of sodium boro-
hydride and a~ain allowed tostand at room temperature for 5 hours.
After de~troying the exce~ sodium borohydride with
acetone, the reactio~ mixture was diluted with water and
extracted with ~ethylene chlor~de. The methylene chloride
solution was wa~hed with water 9 dried over sodium sulrate,
a~d evaporated in vacuo to dryness. The remaining oily re~i-
due was chromatographed over 700 g o~ ~llica gel ~ith ethyl
acetate as eluent. The ~ractiong containing the desired
co~pound were comblned, evaporated and in vaGuo ~ 40C
the rem~1n~n~ ~017ent wag removed from the oil obtained.
~`3~ 636
- 30 -
IR spectrum (methylene chlori.de): OH 3600 cm 1
NH 3400 cm 1
CH2 2930 cm 1
OCH3 2830 cm 1
N-alkyl 2800 cm 1
CN 2220 cm~1
NHCOOC2H5 1735 cm 1
W spectrum (ethanol): ~ max. 228 nm (shoulder; 0.19)
240 ~m (shoulder; 0.12)
285 ~m (0.06)
W spectrum (ethanol ~ KOH): ~ max. 223 nm (shoulder; 0.393
253 - 265 nm (shoulder; 0.1)
318 ~m (0.06)
Example 7
15 N- ~ -(4-~mino-3~bromo-phenyl~ethyl7-N- ~ -(4-metho~y-phenyl)
propyl7methylamine dihydrochlorlde
2,9 g (0.077 mol) o~ lithium aluminium hydride were suspended in
a ~itrogen atmosphere in 100 ml of absolute tetrahydro~uran. A
solution of 14.4 g (0~031 mol) of 4-amino-395-dibromo~N- ~ -(4-me-
20 thox~-phenyl)-prop~l7-N-methyl-phenylacetamide in loo ml
o~ ab301ute tetrahydrofuran was dropped thereto whilst stirring
at room temperature.,Subsequently, the reaction mixture wa3 re-
~luxed for 1 hour, the excess lit~.lum alumi~um hydride wa~ de-
compos~ with ethyl acetate and water, 10 N sodium hydroxide so-
25 lution was added dropwise until the i~organic material precipi-
tated a~ a granulateO The supernatant tetrahydrofuran phase was
decanted, dried over ~odium sul~ate, ~nd e~aporated i~ a rotation
evaporator. The e~apora-tion product was chromatographed over 8ili-
ca~gel (eluent: methyle~e chloride : methanol ~ 19 : 1) (Macherey
30 and Nagel, 70 ~ 230 me~ ASTM)~ The fraction~ oont~n~ng the de-
sired product were combi~ed a~d ev~porated~ The oil obt~ined was
dissolved in little sbsolute ethanol and by means of ethanolic
hydrochloric acid and a~d~tion of ether, the cryst~ ne di~ydro
chloride was prepared.
35 M.p.: 168 - 171C (decomp.).
~Z~36 - 31 -
Example 8
N~ ~ -(4-Amino-3,5-dibromo-phenyl)-ethy ~ -N- ~ -(4-~ethoxy-phenyl)-
butyl7methylamine
2.9 g (0.077 mol) of lithium ~luminium hydride were suspended,in
5 a nitrogen atmosphere~in 100 ml of absolute tetrahydrofuran. A
solution of 15.0 g (0.031 mol) of 4-amino-3,5-dibromo-N- ~ -(4-
met~oxy-phenyl)~buty ~ ~N-methyl~phenylacetamide in lO~ ml
o~ absolute tetrahydrofuran was added thereto whilst stirring at
room temperature. Subsequently, the reaction mixtu~ wa~ refluxed
10 ~or 1 hour, the excess lithium aluminium hydride was decomposed
with ethyl acetate and water, and 1~N sodium hydroxide ~olution
was added until the inorganic material precipitated as a gr~nulate.
The supernatant tetrahydrofuran phase wa~ decanted, dried over
sodium sulfate, and evaporated in a rotation evaporator. The eva-
15 poration product was chromatographed over silica gel (Machereyand Nagel, 70 - 230 meqh~ ASTM) with methylene chloride : meth~nol
~ 19 : 1 as eluent The ~ractions cont~ning the desired product
were combined and evaporated. The oil obtained was iiberated i~
vacuo at 40 C from the solvent residues.
20 IR spectrum (methylene chloride). NH2 3380 + 3470 cm '
N-alkyl 2790 cm
OCH3 2830 cm 1
aliphat. CH2 2850 ~ 293Q cm
C=C 1610 cm 1
25 UV spectrum ~ethanol):~ max. 246 ~m (0.24)
281 nm (0.08)
305 ~m (0.09).
3~ 32 -
Example g
N- ~ ~(4-Amino-3-chloro-5-cyano-phenyl)-ethy ~ -N- ~ -(4-methoxy-
phenyl)-prop~17methYlamine
6.6 g (0,014 mol) of 1-(ethoxycarbonyloxy)-1-(4-amino-3~chloro-
5 5-cyano-phenyl)-2- ~ - ~ -(4-methoxy-phenyl)-propy ~ methylamino7-
ethane were dis olved in 70 ml of isopropanol and stirred over~
night with 5.5 g (0,14 mol~ of sodium borohydride at room tempera-
ture. The solution obtained was evaporated to dryness and taken up
in 100 ml of water. The excess sodium borohydride was destroyed
lO with 50 ml of 2 N hydrochloric acid. Subsequently, the reaction
mixture was basified with 100 ml of 2 N ammonia, and ex-
tracted twice with 150 ml o~ ethyl acetate. The orga~ic phase
was dried with magnesium sulfate, and evaporated. The oil obtalned
was chromatographed over silica gel (Macherey and Nagel, 70 - 230
15 mesh, ASTM) with methylene chloride/methanol = 19 : 1 as eluent.
The fractions which contained the desired compound were combi-
ned, and evaporated. The oil obtained was liberated in vacuo at
40C ~rom the solvent residues.
IR ~pectrum tmethylene chloride): NH2 3400 + 3500 cm 1
N-alkyl 2800 cm 1
aliphat. CH2 2860 + 2940 cm 1
aromat. C~C 1600 cm 1
NH2 deformation 1625 cm~
UV spec-trum (ethanol): ~ max. 244 nm (0.23)
~78 nm (0.06)
330 nm (0~13).
Example 10
N- ~ -(4-Amino-3 chloro-5-cyano-phenyl)-ethy ~ -N- ~ -(4-methoxy-
phenyl)-~roPyl7methylamine
30 1,3 g (0.0027 mol) o~ 1-(4-amino-3-chloro-5-cyano-phenyl)-
2- ~ - ~ -(4-methoxy-phenyl)-propy ~ methylamin ~ ethyl iodide were
dissolved in 30 ml of hexamethyl phosphoric acid triamide. 0.25 g
9;2E;3~;
- 33 -
(O.004 mol) of sodium cyanoborohYdride were added thereto,
and the reaction solution was subsequently heated for 3 hours
up to 70C. After cooling, the reaction mixture was diluted with
100 ml of water, and e~tracted with ether. The ethereal solution
was washed with water; dried over sodium sulfate, and evaporated
to dryness in vacuo. The rem~in;ng oily residue was chromatographed
over silica gel (eluent: methylene chloride : methanol = 20 : 1).
The oily e~aporation residue obtained ,was liberated in vacuo from
the solvent resi~ues.
Mass spectrum. found M+ 357/59
Molecular weight: 357.8.
Exam~le 11
1-(4-Amino~3-~luoro-phenyl)-2- ~ - ~ -(4-methoxy-phenyl) -propyl7-
methylamino7ethanol
A solution of 3.9 g ~0.0095 mol) of 1-(4-amino-3-bromo-5 ~luoro-
henyl)-2~ (4-methoxy-phenyl)-propy ~ methy~amin ~ ethanol in
50 ml o~ met~anol was reacted with 2 g of 10% Palladium/charcoal ~ud
hydroge~ated in an autoclave at room temperature and a pre~sure
of 3.5 bar. When the theor~tically calculated amount of hydrogen had
20 been taken up, the ~atalyst was ~iltered o~f and the filtrate
was evaporated in a rotation evaporator. The 4 g o~ oil thus
obta~ned was chromatographed (Macherey and Nagel, 70 - 230 mesh,
ASTM) with chloroform : methanol = 19 : 1 as eluentO The fractions~
containing . the de~ired compound were combi~ed and evaporated.
The oil obtained wa~ dissolved in isopropanol and the hydrochlo-
ride was precipitated with isopropanolic hydrochloric acld and
ethyl acetate. The crystals were ~iltered o~ with suction, washed
with little cold isopropanol a~d dried in vacuo.
M.p.: 110C (decomp.).
6~6
- 34 -
Example 12
1-(4~Ethoxycarbonylamino~3-bromo-phenyl)-2~ ~ - ~ (4-methoxy-
phenyl)-but~l7methylamino7ethanol
1.5 ml (0.015 mol) of ethyl chloroformate were added under ice-
5 cooling at 0C to a ~olution of 5.1 g (0.0125 mol) o~ 1-(4-amino-
3-bromo-phenyl~-2- ~ ~ ~ -(4-methoxy-phenyl)-butyl7methylamin ~ -
ethanol in 40 ml of absolute pyridine. The solution obtained was
kept over night at +4C in the refrigerator~ 5ubsequently, the
pyridine was distilled off in a rotation evaporator at 50C. The
10 oil obtained was dissolved in 100 ml of methylene chloride, and
washed twice wlth 100 ml of water. The organic phase was dried
over sodium sulfate, filtered, and evaporatcd in a rotation evapo-
rator, The oil obtained was chromatographed over silica gel
(Macherey and Nagel, 70 - 230 mesh, ASTM) with methyle~e chloride
: methanol = 9 : 1 as eluent. The fractions contai~i~g the
desired compound were combined and evaporated. The oil obtai~ed
was liberated in vacuo at 40C from the solvent residues.
IR spectrum (methylene chloride): OH 3610 cm
NH 3400 cm
OCH3 2830 cm 1
N-alkyl 2800 cm 1
aliphat. CH2 2860 ~ 2940 cm 1
C~O 17~5 cm
aromat. C=C 1610 cm 1
2s W spectrum (ethanol): ~ maxl 224 nm (0.42)
2~0 ~m (0.29)
2~0 nm (0.04)
... . . _ .
~Z~'J~;36
- 35 -
Example 13
N- ~ -(4-Amino-3,5-dichloro-phenyl)-ethyl7-N- ~ -(4-hydroxy-
phenyl~ methyl-propyl7me-thylamine
O.012 mol of N- ~ -(4~amino-3,5-dlchloro-phenyl)-ethyl7~N-
~ -(4-hydroxy-phenyl)-1-methyl-propyl7amine were dissol~ed
in 13 ml of 1 N sodium hydroxide solution. Whilst cooling with
ice-water 0,014 mol of dimethyl sulfate were added dropwise to
this solution. After a short time an oily reaction product pre-
cipitated, which was dissolved by addition of 150 ml of tetra-
hydrofuran. The rsaction solution was stirred for 24 hours atroom temperature and subsequently extracted twice with 150 ml
porti~ of ether. The organic extracts were washed with water,
dried over m~gnesium sulfate and evaporated in vacuo. The evapo-
ration residue obtained was puri~ied over silica gel (Polygosill`
60 - 1525; Macher~y and Nagel~ with methylene chloride : methanol :
conc. ammonia = 19 : 1 : 0.1 as eluent. The oily evaporation re-
sidue was X~ed ~rom the solvent residues in vacuo over po-
tassium hydroxide.
IR spectrum (methylene chloride): OH 3580 cm 1
~H2 3480 + 3380 cm 1
CH2 2930, 2960, 2850 cm
N-alkyl 2790 cm
C=C 1580, 1510, ~480 cm
C=C ~ NH2 deformation 1610 cm
W spectrum (ethanol): ~ max. 240 nm (0.26; shoulder)
288 nm (0.08)
301 nm (0.08)
W spectrum (ethanol l KOH): ~ max. 241 nm (0.56)
299 nm (0.17).
* Trademark
,. r
~Z~Z~,36
- 36 -
Example 14
1-(4-Amino-3,5-dichloro phenyl)~2~ (4-methoxy-phenylsul-
finyl)-ethyl7methylamino7ethanol
7.0 g of 1-(4-amino-3,5-dichloro-phenyl)-2- ~ - ~ -(4-methoxy-
5 phenylsulfenyl)-ethyl7methylamin ~ ethanol were dissolved in
100 ml o~ glacial acetic acid and mixed with 2.0 g o~ 30 %
hydrogen peroxide whilst stirring at room temperature. Stirri~g
was continued overnight at the same temperature, and then the
solv~nt was evaporated in vacuo. The residue was taken up in
lO water and mixed with potassium carbonate until basic-
The reaction mixture w~s extracted with
dichloromethane, the organic phase was washed with water, dried
with magnesium sul~ate, and evaporated in vacuo~ The residue
was purified chromatographically (column: 40 x 200 mm~ silica
15 gel 60, of Messrs. E. Merck, grain size: 0.06 - 0.2 mm,
methylene chloride : methanol = 50 : 1). After evaporating the
desired fractions in vacuo, the title compound was obtained
as an oi 1.
IR spectrum (methylene chloride): NH2 ~390 ~ 3480 cm 1
CH2 2940 cm
OCH3 2840 cm 1
N-alkyl 2800 cm 1
C=C 1590, 1510 + 1480 cm 1
S=O 1040 cm 1 (shoulder)
25 W spectrum (ethanol): ~ max. ~44 nm (0.54)
300 nm (O.07; shoulder)
~.;2V~63~i
- 37 -
Example 15
1-(4-Amino-~,5-dichloro-phenyl)-2~ (4-methoxy-phenyl-
sulfonyl)-e~hyl7meth~lamino7ethanol
7.0 g of 1-(4-amino-3,5-dichloro~phenyl)-2- ~ - ~ -(4-methoxy-
phenylsulfenyl)-ethy ~methylamin ~ ethanol were converted to
the sulfinyl derivative as described in E~ample 14. The resi-
due (4.7 g) obtained a~ter e~aporating the dichloromethane
extract was dissolved ln 100 ml of dioxan and 30 ml of water
and mixed with 4,0 g o~ magnesium ~u~ate 2.5 g 0~ powdered
potassium permanganate were added in corresponding portions
under stirring. After the addition ~as finished, stirring was
continued ~or 2 hours and the insoluble sdids were ~iltered o~f
o~er celite. Aiter removing the dioxan in vacuo the r~idue
was distributed between dichlorometha~e and ~ater~ The evapora-
tion residue o~ the drled organic pha~e was purified twice bychromatography (1. column: 60 x 300 ~m, Al203 II neutral, methy-
le~ chloride : tetrahydrofuran - 5 : 1; 20 colu~n: 35 x 300 mm,
silica gel 60, Messrs. E. Merck, grai~ slze: 0.015 - 0.025 mmj
dichloromethane, 8,5 bar). A~ter evaporating the desired frac-
tions in vacuo the title compound was obtained as an oil.
IR spectrum (methylene chloride): NH2 3395 ~ 3480 cm 1
C~2 2940 cm
OCH3 2840 cm
N-alkyl 2800 cm^
C=C 15g5, 1520 ~
1495 cm '
S2 1150 + 1315 cm 1
W spectrum (ethanol): ~ max. 241 nm (0.59)
300 nm (O.og).
~1i21:1Z6~
- 3~ -
Example 16
1-(4-Amino-3,5-dichloro-phenyl)-2- ~ - ~ -(4-hydroxy-phenyl)-
propyl7methylamino7ethanol
9 2 g o~ 1-(4-amino-3,5-dichloro~phenyl)-2- ~ ~ ~ -(4-benzyloxy-
5 phenyl)~propyl7methylamin ~ ethanol were dissolved in 150 ml of
methanol. The solution was mixed with 1 g of 5 % palladium/
charcoal and hydrogenated at room temperature under a hydrogen
pressure of 5 bar. After taking up the calculated amount of
hydrogen, the catalyst was filtered off, the solution was evapo-
10 rated to dryness in a rotation evaporator, and the oily residuewas chromatographed over silica gel with methylene chloride :
methanol = 20 : 1 as eluenk. The ~ractions containing the
desired compound were combined, evaporated and the re~in~ng
oil was liberated from the solvent residues in vacuo at 40C.
IR spectrum (methylene chloride): OH 3580 cm 1
NH2 3395 + 3495 cm 1
N-alkyl 2800 cm 1.
Example 17
1-(4-Amino-3-bromo-phenyl)-2- ~ - ~ -(4-methoxy-phenyl)-butyl7-
20 methylamino7ethanol
3 g o~ 1-(4-acetamino-3-bromo-phenyl)-2- ~ - ~ -(4-methoxy-phenyl)-
butyl7methylamino7ethanol were refluxed in 100 ml o~ semi-concen~
trated hydrochloric acid for 1 hour. After cooling, the reaction
mixture was hasified with 10 N sodium hydroxide solution,
extracted with methylene chloride, the methylene chloride solution
was washed with water, dried over sodium sul~ate, and evaporated
in a rotation evaporator to dryness. The re~ln~ng oil was chro-
matographed over silica gel with methylene chloride : methanol
- 20 : 1 as eluent. From the fractions containiny the de-
sired compound, the title compound was obtained by evapora-
tion in vacuo at 40C. Oil.
~2163~
IR spectrum (methylene chloride): OH 3590 cm 1
NH2 3380 ~ 3470 cm 1
N-alkyl 2800 cm 1
OCH3 2830 cm 1
aliph. CH2 2850 ~ 2930 cm 1
aromat. C=C 1620 cm
W spectrum (ethanol)~ ~ max. 224 nm (0~20)
243 nm (0.14)
280 nm (0.0~)
300 ~m (0.04)
Example 18
1-(4-Amino-3-cyano 5-~luoro-phenyl)-2- ~ - ~ -(4-methoxy~phenyl)-
propyl7methylamino7ethanol
Prepared analogously to Example 1 ~rom 4'-amino-3 7 -cyano-5l-~luoro-
2~ (4-methoxyphenyl)propyl7methylamino7acetophenone and so-
dium borohydride in 90 % ~ethanol.
IR spectrum (~ethylene ch~oride): OH 3590 cm 1
` 3400 + 3490 cm ~
CH2 2850 ~ 2940 cm 1
OCH~ 2830 cm 1
N-alkyl 2800 cm 1
C--N 2210 cm ~
NH2 de~ormation 1635 cm 1
aroma~ C=C 1610 cm 1
W spectrum (ethanol): ~ max. 242 nm (0.3)
325 nm (0.14).
Example 19
~ -Amino-3-bromo-5-cyano-phenyl)-2~ (4-methox~-phenyl)-
prop~l7methylamino7ethanol
Prepared analogously to Example 1 ~rom 4'-amino--3'-bromo-5'
cyano-2- r - ~ (4 methoxy-phenyl)-propy_7methylamin ~ acetophenone
and ~odium borohydride ln 80 % methanol.
' ;
636
- so -
IR spectrum (methylene chloride): OH 3590 cm 1weak
NH2 3400 ~ ~480 cm 1
CH2 2850 + 2930 cm
C--N 2200 cm
C=C 1640 cm 1
W spectrum (ethanol): ~ max. 243 nm (0~20)
280 nm (0.04)
334 nm (0.12).
Example 20
10 1-(4-Amino-3,5-dibromo-phenyl)-2~ (4-methoxy-phenyl)-
propyl7methylamino~etha~ol
Prepared analogously to Example 1 ~rom 4'-amino-3~,5'-dibromo-
2- ~ - ~ -(4-methoxy-phenyl)-propy ~msthylamin_7acetophenone and
sodium borohydride in 80 % methanol.
15 IR spectrum (methylene chloride): OH 3590 cm 1
. NH2 3380 + 3460 cm 1
..
N-alkyl 2800 cm '
OCH3 2830 cm 1
aliphat. CH2 2850 ~ 2940 cm
C=C 1610 cm 1
W ~pectrum (ethanol): ~ max. 244 nm (0.16)
30~ nm (0.06).
Example 21
1-(4-Amino-3,5 dichloro-phenyl-2- ~ - ~ ,1-dimethyl-3-(4-methoxy-
25 pheny~ ropyl7amino7ethanol
Prepared analogousl~ to Exa~ple 1~ irom 1-~4-amino-3,5-dichloro-
phenyl)-2~ dimethyl-3-(4-hydro~phenyl)~propy_7amin ~
ethanol, tetrahydro~ura~, sodium hydroxide solution and di~ethyl-
sulfate. Oil.
30 IR spectrum (~ethyle~e chloride): 0~ 3600 cm 1
N~2 3390 + 3490 cm 1
CH2 2860 ~ 2960 cm
O~H3 2830 ~
C~C 1580 i 1620 c~-1
UY spectr~m (ethanol): ~ max. 243 nm (0.23)
280 nm (0.08)
300 ~m (0.08)
Example 22
5 1~(4-Ami~o-3,5~dichloro~phenyl) -2-1N- ~,1 -dimethyl-3-(4-m~thoxy-
phenvl)-prop~17methylamlno7etha~ol
Prepare8 analogously to Example 13 ~rom 1-(4-amino-3,5-dlchloro-
phenyl)-2- r ~ dimeth~ (4-hydroxyphe~yl )-propyl7amino-
ethanol7, tetrahydro~uran9 sodiu~ hydroxide solution9 and di-
lo methylsulfate. Oil.
Calc.: C 61.31 H 6.86 Cl 17.24 N 6.81
Found: 61.13 6.99 17.25 6.75
Example 23
1-(4-Amino-3-chloro-5-trifluoromethyl-phenyl) -2-LN-~- (4-methoxy-
15 phenyl)-proPY17methYlamino7ethanol
Prepared analogously to Example 1 from 4' amino-3'-chloro-5'-tri-
~luoromethyl-2- ~ - ~ -(4-methoxy-phenyl)-propyl7methy- ~r 1 n~-
acetophenone and sodium borohydride in 80 % methanol.
IR spectrum (methylene chloride): OH 3590 cm 1
NH2 3410 + 3510 cm 1
N-alkyl 2800 cm 1
OCH3 2830 cm 1
aliphat. CH~ 2850 ~ 2940 cm
-C,C 1630 cm
25 UV spectrum ~ethanol): ~ max. 225 nm (0.36)
245 nm (9.31)
280 nm (0005)
310 nm (0.1).
.,
.... . . . _ . . . . . . . . . . . ..
~ 26;~6 . ~2 -
~xample 24
1-(3,5-Dichloro-4-hydroxy~phenyl)-2- ~ - ~ -(4-methoxy-phenyl)-
propyl7methylam.ino7ethanol
Prepared analogously to Example 1 from 3',5' dichloro-4'-hydroxy-
2- ~ - ~ ~(4~methoxy~phenyl)-propyl7methylamin ~ acetophenone and
sodium borohydride in 80 % methanol.
M.p.: 156 - 157C.
Example 25
1-(3,5-Dibromo-4-hydroxy-phenyl)-2~ (4-methoxy-phenyl)-
1o propyl7meth~rlamirlo7ethanol
Prepared analogously to Example 1 from 3'~5'~dibromo-4'-hydroxy-
2~ (4-methoxy-phenyl)-propy_7methylamin_7acetophenone and
~odium borohydride i~ 80 % methanol.
M.p. of the hydrochloride: 159 - 162C,
15 Example 26
1-(4-Amino-3-bromo-5-~luoro-phenyl)-2~ (4-m~thoxy-phenyl)-
Propyl7methylamino7ethanol
Prepared analogously to Example 1 ~rom 4'-amino-3'-bromo-5'0~1uoro-
2- ~ - ~ (4-methoxyphenyl)-propy ~ methyl ~r ~ n~acetophenone a~d
20 sodium borohydride in 80 % methanol.
M.p. of the hydrochlorlde (amorphous): ~rom 60C.
Example 27
~ 4-Amino-3-chloro-5-fluoro-phenyl)-2- ~ - ~ -(4-methoxy-phenyl)-
prop~l7methylamino7ethanol
25 Prepared analogo~lsly to Example 1 from 4'-amino~3'-chloro-5l.-fluoro-
2~ (4-methoxy-phenyl)-propyl7methylamino7acetophenone and
.. . .. , . . . . .... .... .. ...... , .. . ,, . . _ . _ .. ... .... . . .. . . . ..
~2~Z636 ~. ~13
sodium borohydride in 80 % methanol.
M,p. o~ -~he hydrochloride: 103 ~ 108C (decomp.).
Example 28
1-(4-Amino-3-chloro-5~cyano-phenyl)-?- ~ -L3 (4-methoxy-phenyl)
5 propyl7methylamino7ethanol
Prepared analogously to Example 1 from 4'-amino-3'-chloro-5'-cyano-
2- ~ - ~ -(4 methoxy-phenyl)-propyl7methylamin_7acetoph~none and
sodium borohydride in 80 ~ of methanol.
IR spectrum (methylene chloride): OH 3590 cm 1
NH2 3400 ~ 3500 cm 1
N-alkyl 2800 cm 1
OCH3 2830 cm 1
aliphat~ CH2 2850 + 2940 cm 1
C-N 2210 cm 1
C~C ~625 cm 1
W spectrum (ethanol): ~ max. 245 nm (0.26)
278 nm (0~06~
332 nm (0.16).
Example 29
20 1~(4-Amino-.~-chloro 5-nitro-phenyl)-2- ~ - ~-(4-methoxy~phenyl)-
proprl7meth~lamino7ethanol
Prepared analogously to Example 1 from 4'-amino-3'-chloro-5'-r.itro-
2~ (4-methoxy-phenyl)-propy_7methylamin_7acetophenone and sod-
ium borohydride in 80 % methanol.
25 IR spectrum (methylene chloride): OH ~590 cm 1
NH2 3390 ~ 3500 cm 1
N--alkyl 2800 cm
OCH3 2830 cm
aliphat. CH2 28$0 ~ 2940 cm
C-C 1630 cm 1
N02 1330 ~ 1515 cm 1
:l`Z~Z636i
W spectrum (ethanol): ~ max. 227 nm (0,64)
280 nm (0.16)
400 nm (0.12)
Example 30
5 1 (4~Amino-3-chloro~phenyl)~2~ (4~methoxy phenyl)-propy ~ -
methylamino7ethanol
Prepared analogously to Example 1 from 4'-amino 3'-chloro 2 ~-
~3-(4-me-thoxy-phenyl)-propy ~ methylamin ~ acetophenone and sodium
borohydride in 80 ~ methanoll
10 IR spectrum (methylene chloride): OH 3600 cm 1
N~2 33~0 + 3470 cm 1
N-alkyl 2800 cm 1
OCH3 2830 cm 1
aliphatO CH2 2850 ~ 2940 cm 1
C-C 162Q cm
UV spectrum (ethanol): ~ max4 225 ~ (0-44)
243 nm (0.36)
280 nm (0.09)
295 nm (0.08)
20 ExamPle 31
1-(4-Amino-3-bromo-phenyl)-2- ~- ~ -(4-methoxy-phenyl)-propyl7-
methylamino7ethanol
Prepared analogously to Example 1 ~rom 4'-amino-3'-bromo-2- ~-
~ -(4-methoxy-phenyl)-propyl7methylamino7acetophenone and sodium
25 borohydride in 80 % methanol.
M~p. o~ the dihydrochloride: 137C (decomp.).
lL2~.~'263~i
- 45 -
Example 32
1 (4-Amino-3,5-dicyano~phenyl)-2 LN-~- (4-methoxy-phenyl) -propyl7-
meth~lamino7ethanol
Prepared analogously to Example 1 ~rom 4'-amino-3',5'-dlcyano-
2- ~ - ~ -(4-methoxy-p~enyl)-propyl7methylamino7acetophenone and
sodium borohydride in 80 % methanol.
M.p. of the hydrochloride: 167 - 170C.
Example ~3
1-(4-~mino-3 bromo-phenyl)-2- ~ - ~ -(4-methoxy-phenyl)-butyl7-
methylamino7ethanol
Prepared analogousl~ to Example 1 from 4' amino-3'-bromo-
2- ~ -L~-(4-metho~y-phenyl)-buty ~ methylamino7acetophenone and
sodlum borohydride in 80 % methanol.
IR spectrum (methylene chloride): OH 3590 cm 1
NH2 3380 + 347~ cm 1
N-alkyl 2800 cm 1
OCH3 2830 cm 1
aliphat. CH2 2850 + 2930 cm
C=C 1620 cm 1
W spectrum (ethanol): ~ max. 224 nm (0,44)
2~ nn (0.28)
280 nm (0.08)
300 ~m (o.06).
Example 34
1-(4 Amino-~-bromo-phenyl)-2-LN- ~ ;(4-methoxy-phe~yl)-ethy ~ -
me~hylamino7ethanol
Prepared analogously to Example 1 from 4'-amino-3'-bromo-2-
(4-methoxy-phenyl)-ethyl7methy1arin ~ acetophenone and
sodium borohydride in 80% met~a~
~ z~2636 ~16
IR spectrum (methylene chloride): OH 3590 cm 1
NH2 3380 ~ ~470 cm 1
N-alkyl 2800 cm
OCH3 2830 cm 1
aliphat. CH2 2840 + 2940 cm 1
C=C 1620 cm
W spectrum (ethanol): ~ max. 225 nm (0.4~)
243 nm (0.36)
280 nm (0.08)
296 nm (0~8).
Example ~5
1-(4-Am~no-3,5-dichloro-phenyl)-2~ (4-methoxy-phenyl)-
butyl7meth~1~m1no7ethanol
Prepared analogously to Example 1 from 4'-amino-3~5'-dichloro-
2- ~ -~ -(4-methoxy-phenyl)~buty_7methylamin ~ acetophenone a~d
sodium borohydride in 80 % methanol.
IR siectrum (methylene chloride): OH 3590 cm~1
NH2 3390 + 3490 cm 1
N-alkyl 2800 cm 1
OCH3 2830 cm
aliphat. CH2 2850 + 2930 cm
C=C 1610 cm 1
W spectrum (ethanol)~ ~ max. 245 nm (0.25)
320 nm (0.48).
Example 36
1-(4-~mino-3-bromo~5-cyano-phenyl)-2- ~ - ~ -(4-methoxy~phenyl)-
butyl7methylamino7ethanol
Prepared analogously to Example 1 from 4'-amino~3'-bromo-5'-cyano-
2- ~ - ~ -(4-methoxy-phenyl)-buty ~ methylamino7acetophenone and
sodium borohydride in 80 % metha~ol.
L` f~t~
,~f~U~'O~'v _ a~ 7
IR spectrum (methylene chloride): OH ~590 cm 1
~H2 3390 ~ 3490 cm 1
N al~yl 2800 cm 1
OCH3 2830 cm 1
aliphat~ CH2 2850 ~ 2930 cm 1
C-N 2210 cm
C=C 1620 cm 1
W spectrum (ethanol): ~ max. 245 ~m (0.27)
278 nm (0.08)
330 nm (0.15).
Example 37
1-(4-Amino-3-bromo 5-cyano-phenyl) -2-LN~- (4-methoxy-phe~yl)-
ethyl7methylamino7ethanol
Prepared analogously to Example 1 ~rom 4'-amino-3'-bromo-5'-cyano-
2- ~ - ~ -(4-methoxy-phenyl)-ethyl7methylamin ~ acetophenone and
sodium borohydride in 80 % methanol~
IR spectrum (methylene chloride): OH 3590 cm 1
NH~ -1
N-alkyl 2800 cm
OCH3 2~30 cm 1
aliphat. CH2 2850 ~ 2959 cm 1
C--N 2210 cm 1
C-~ 1620 cm 1
UV spectrum (ethanol): ~ max. 245 ~m (0.25)
277 nm (0.09)
~31 nm (0.10).
Example ~8
1-~(4-Amino-3,5-dichloro-pherlyl)-2- ~-L~-(4-methoxy-phe~yl)-ethyl7-
meth-ylamino7ethanol
Prepared analogously to Example 1 from 4' amino-3',59-dichloro-
2~ (4-methoxy-phenyl)-ethy_7methylamin_7acstophenone and
:lZOZ~3~ ~
sodium borohydride in 80 % methanol.
IR spectrum (methylene chloride): OH ~590 cm 1
NH2 3~ 1
N-alkyl 2800 cm
OCH3 2830 cm 1
aliphat. CH2 2850 ~ 2930 cm
C=C 1610 cm 1
Example 39
1-(4-Amino-3-chloro-5-cyano~phenyl) -2-LN-~ (4-methOXY-Phenr1 ) -
10 butyl7methylamino7ethanol
Prepared analogously to Example 1 from 4'-amino~3'-chloro-5'-cyano-
2- ~ - ~ -(4-methoxy-phenyl)-buty ~ methy~Am1no7acetopheno~e and
sodium borohydride in 80 % metha~ol.
IR spectrum (methylene chloride): OH 3590 cm 1
~5 NH2 3400 ~ 3500 cm
N-alkyl 2800 cm
OC~3 2830 cm 1
aliphat. CH2 2850 ~ 29~0 cm 1
C=N 2210 cm 1
C-C 1625 cm 1
W spectrum (ethanol): ~ max. 245 nm (0.23)
280 nm (0.05)
332 nm (0.13).
EX~mPl~ 4~-
25 1 (4-Amino-3-chloro-5-cyano-phenyl)-2- ~- r_(4_methoxy_phenyl)_
eth~l7methylamino7ethanol
Pre~pared analogously to Example 1 ~rom 4t~amino-3l-chloro-5!-cyano-
2- ~ - ~ -(4-methoxy-phenyl)-ethy ~ methyl~r ~ n_7aceto~h enon e and
sodium borohydride in 80 % methanol.
~2~Z~;36 - ~9 -
IR spectrum ~methylene chloride): OH 3590 cm 1
NH2 3390 ~ 3490 cm 1
N alkyl 2800 cm 1
OCH3 2830 cm 1
CH2 2850 + 2940 cm 1
C-N 2210 om 1
C=C 1620 cm 1
W ~pectrum (ethanol): ~ max. 245 nm (0.24)
280 nm (0.04)
3~2 nm (0.13)~
Example 41
1-(4-Amino 3,5-dichloro-phenyl)-2~ (4-methoxy-phenylsul-
fenyl)-eth~17methylamino7ethanol
Prepared analogou~ly to Example 1 from 4'-amino-3',5'-dichloro-
2- ~ - ~ -(4-methoxy-phenylsulfenyl)-ethy ~ methylamino7aceto-
phenone and so~ium borohydride in tetrahydro~ura~ : water :
methanoi - 25 : 5 : 10. Oil.
IR spectrum (methyle~e chloride): OH 3200 - 2500 cm 1
(below NH2)
NH2 3480 ~ 3390 cm 1
CH2 2940 cm
N-alkyl 2800 cm 1
OCH 2830 cm 1
C=C3 1580 ~ 1490 cm 1
25 W spectrum (ethanol): ~ max. 230 nm (0.58; shoulder~
245 nm (0.5~)
298 nm (0~14).
Example 42
1-(4-Amino-3,5-dichloro-phenyl)-2- ~ - ~ -(4-methoxy-phenoxy)-
ethyl7methylamino7ethanol
Prepared analogously to Example 1 from 4'-amino-3',5~-dichloro-
2- ~ - r -(4-methoxy-phenoxy)-ethy_7methyla~in ~ acetoph~none ~d
.. .. . . . ... . .... . .. . ...... ~ . .. . ......
~LZ~2~ i 5 o
sodium borohydride in tetrahydrofuran : water : methanol
15 : 5 : ~. Oil.
IR spectrum (methylene chloride): OH 3200 - 3500 cm 1
(below NH2)
NH2 3480 + 3~90 cm 1
CH2 2940 cm 1
N alkyl 2790 cm 1
OCH3 2830 cm 1
C-C 1580, 1505
~ 1485 cm 1
C-O-aryl 1250 cm 1
UV spectrum (ethanol): ~ max. 230 nm (0.32; shoulder)
244 nm (oJ26; shoulder)
294 nm (0.1~),
ExamPle 43
1-(4-Amino-3,5-dichloro-phenyl) -2-LN-~- (4-methoxy~phenyl)-
propyl7amino7propanol~(1)
Prepared analogously to Example 1 from 4'-amino-3',5'-dichloro-
2 ~ - ~ -(4-methoxy-phenyl)-propyl7amin ~propiophenone and
sodi~m borohydride.
M.p. of the hydrnchloride: 201 - 202C (decompl).
Example 44
1-(4-Amino-3,5-dichloro-phenyl)-2-lN- ~ -(4-methoxy phenyl)-
25 PropYl7-2~propvlamino7ethanol
P~epared analogously to Example 1 ~rom 4'-amino-3 ~.9 5'-dichloro-
2- ~ - ~ -(4-methoxy-phenyl)-propy ~ -2-propylamino7acetophenone
and ~odium borohydride. Oil~
IR spectrum (methylene chloride): OH ~600 cm 1
NH~ ~400 ~ 3490 cm 1
OCH3 2830 cm 1
W spectruM (ethanol): ~ max. 243 nm ~0.13)
280 nm (0.03)
300 nm. (0003)
.
.~Lr~ v ~v
- 51 -
Example 45
1-(4-Amino-3,5-dichloro-phenyl)-2~ (4-methoxy-phenyl)-
propyl7ethylamino7ethanol
Prepared analogously to Example 1 from 4'-amino ~',5'-dichloro-
2- ~ - ~ -(4-methoxy-phenyl)~propy ~ ethylamin ~ acetophenone and
sodium borohydride.
IR spectrum (methylene chloride): OH 3600 cm 1
NH2 3395 + 3490 cm 1
OCH~ 2830 cm
W spectrum (ethanol): ~ max. 243 nm (0^13)
280 nm (0.04)
300 ~m. (~.04)
Example 46
1-(4-Amino 3,5-dichloro-phenyl)-?~ (4-methoxy-phenyl)-
ProP~17propylamino7ethanol
Prepared analogously to Example 1 from 4'-amino-~',5'-dichloro-
2- ~ - ~ -(4-methoxy-phenyl)-propy ~ propylamino7acetophenone and
sodium borohydride. Oil.
IR spectrum (methylene chloride): OH 3600 cm 1
NH2 3395 ~ 3495 cm 1
OCH3 2850 cm
W spectrum (ethanol): ~ max. 245 nm (0010)
280 nm (0.03)
~00 nm. (0.03)
25 Example 47
1-(`4-Amino-3,5-dichloro-phenyl)-2~ (4-methoxy-phenyl)-
uroPY'17cYcloProPYlamino7ethanol
Prepared analogo~sly to Example 1 from 4'-amino-3',5'-dichloro-
2- ~ - ~ -(4-methoxy-pheny~ propya7cyclopropylamin-7acetophenone
;36
and sodium borohydride. Oil.
IR spectrl~ (methylene chloride): OH 3590 cm 1
NH2 3395 ~ 3495 cm 1
O~H3 2850 cm 1
5 W spectrum (ethanol): ~ max. 245 nm (0~12)
2~0 nm (O0O~)
300 nm. (V.04)
Example 48
1-(4-Amino-3,5-dichloro-phenyl)-2~ (4-methoxy~phenyl)-
lO Pro~yl7methylamino7ProPano~ Isomer B
Prepared analogously to Example 2 from N~ 4-methoxy-phenyl)
propyl7methylamine, 4'-amino-2-bromo-3'~5'-dichloro~propio-
phenone, triethylamine, and sodium borohydride. Oll.
IR spectrum (methylene chloride): OH 3600 ~ 3680 cm 1
` NH2 3390 + 3490 cm 1
OCH3 2835 ~ 2~40 cm 1
aromat 1510,
1585 ~ 1610 cm 1
W spectrum (ethanol): ~ max. 246 nm (0~14)
278 nm (0,08)
285 nm (0.0~)
~00 nm (~,08)
NMR spectrum (CDCl3/D20): signal of the proton at the carbon atom
1 of the propanol part: doublet at 4.1 ppm (J - 10 Hz).
25 Example 49
1-(4-Amino-3,5-dichloro-phenyl)-2- ~ - r -(4-methoxy-phenyl)-
propyl7methylamino7pronanol-(1), Isomer A
Prepared analngously to Example 2 from N- ~ -(4-methoxy-phenyl)-
propy ~ methylamine, 4'-amino-3',5'~dichloro-2~bromo-propiopherlone,
30 triethylamine, and ~odlum borohydr~de.
z~
- 53
M~p. of the hydrochloride: 178 181C.
NMR spectrl~m o~ the base (CDCl3/D20): signal of the proton at
the hydrogen atom 1 of the propanol part: doublet at 4.6 ppm
(J = 4.5 ~Z)-
5 Example 50
1-(4~Amino-3,5~dichloro-phenyl)-2 ~ - ~ -(4-etho~y-phenyl)-
propyl7methylamino7ethanol
Prepared ànalogously to Example 2 ~rom 4'-amino-3',5' dichloro-
2-bromo~acetophenone, 1-(4 ethoxy-phenyl)-3-methylamino-propane
10 hydrochloride, triethylamine, and sodium borohydride Oil.
IR spectrum (methylene chloride~: OH 3590 cm 1
NH2 3395 ~ 3495 ~m 1
N alkyl 2800 cm 1
W spectrum (ethanol): ~ m~x. 245 nm (0013)
~5 ~80 nm (0.04)
~00 nm. (0.0~)
Example 51
1 - (4~Amino~3 t 5-dichloro-phenyl)-2~ (4-benzyloxy-phenyl)-
propyl7methylamino7ethanol
20 Prepared analogously to Example 2 ~rom 4'-amino-3',5'-dichloro-
2-bromo-acetophenone, 1-(4-benzyloxy-phenyl)-~ methylamlno-pro-
pane hydrochloride, triethylamine, and sodium borohydride. Oil.
IR spectrum (methylene chloride): OH 3590 cm 1
NH2 3395 + 3495 cm 1
N-alkyl 2800 cm 1
3 ["A~O 2~;36
Example 52
1-(4-Amino~3-iodo-5 fluoro-phenyl)-2~ (4-methoxy-phenyl)-
propyl7methylamino7ethanol
Prepared a~alogously to Example 2 from 4'-amino-3'-iodo-5'-fluoro-
2-bromo-acetophenone~ 1-(4~methoxy-pherlyl)-3-methylamino-propane
hydrochloride, triethylamine, and sodium borohydride. Oil.
IR spectrum (methylene chloride): OH 3590 cm 1
NH2 3395 + 3495 cm 1
N-alkyl 2800 cm ~.
Example 53
1-(4-Amino-3-cyano-5-fluoro-phenyl)~-2~ (4-methoxy-phenyl)-
propyl7-2-propylamino7e-thanol
Prepared analo~ously to Example 2 ~rom 4'-amino-3'-cyano-5'~fluoro
2~bromo-acetophenone, 1-(4~methoxy-phenyl)-3-(2-propylamino)-
propane hydrochloride, and sodlum borohydride~
IR spectrum (methylene chloride~: OH 3600 cm 1
NH2 3395 ~ 3495 cm
OCH3 2830 om 1
N-alkyl 2800 cm
C--N 2220 cm 1
ExamPle 54
1~(4 Amino-3,5-dichloro-phenyl)-2~ (2-methoxy-phenyl)-
propyl7me-thylamino~etha~ol h~drochloride
Prepared analogously to Example 2 from 4'-amino-3',5'-dichloro-
2-bromo acetophenone, 1-(2-methoxy-phenyl)-3-methy1~m1no-propane
hydrochlorlde, triethylamlne~ and sodium borohydride.
M.p.: ~rom 75C (by sintering).
636
55 -
Example 55
1~4-~mino-3,5-dichloro-phenyl)-2-~R-L3- (3,4-dimethoxy-phenyl)-
propyl7methylamino7ethanol
Prepared analogously to Example 2 from 4'-amino-3',5'-dichloro-
2-bromo-acetophenone, 1-(3~4-dimethoxy-phenyl)-3-methylamino-
propane hydrochloride, triethylamine, and sodium borohydride.
IR spectrum (methylene chloride): OH 3600 cm 1
NH2 3390 ~ 3485 cm 1
OCH3 2830 cm 1
N-alkyl 2800 cm 1.
Example 56
1-(4-Amino-3-chloro-5 tri~luoromethyl-phenyl)-2- ~ - ~ (4-methoxy~
Phenyl)ethY17methylamino7ethanol
Prepared a~alogously to Example 1 ~rom 4'-amino 3'-chloro-5'-tri~
~luorome~hyl~2~ (4-methoxy-phenyl)-ethy ~methy1~ o7aceto-
phenone~ and sodium borohydride in 80 % methanol.
IR spectrum (methylene chloride): OH 3600 cm 1
NH2 3410 ~ 3510 cm 1
N-alkyl 2800 cm 1
0-CH3 2830 cm 1
aliphat~ CH2 2850 + 2940 cm 1
C.C 1630 cm
W spectrum (ethanol): ~ max. 225 nm (0.38)
244 nm (0.34)
280 nm (0.07)
307 nm (0.10).
~CJZ~36
- 56 -
Example 57
1 (4-Amino~3,5-dichloro-phenyl)-2~ (4-methoxy-phenyl)-
propyl7amino7ethanol hydrochloride
Prepared analogously to Example 1 from 4'-amino-3',5'-di-
chloro-2- ~ ~/3_(4-methoxy-phenylj-propy ~ amino7acetophenone and
sodium bQrohy~ride in 90 % ethanol.
M.p. of the hydrochloride: 185 - 186C (ethanol/ether)
Example 58
1-(4-Amino-3~5-dichloro-phenyl)-2- ~ -(3-phenyl-propyl)-2-propyl-
amino7ethanol hydrochloride
Prepared analogously to Examp]e 2 from 4'-amino-3',5'-dichloro-
2~bromo-acetophenone, 1-phenyl-3-(2-propylamino)-propane
hydrochloride, triethylamine, and sodium borohydride.
M.p.: 124 128C
Example 59
1~(4-Amino-3,5 dichloro-phenyl)-2- ~ - ~-(4-fluoro-phenyl)-propyl7-
methylamino7ethanol hydrochloride
Prepared analogously to Example 2 from 4~-amino-3',5'-dichloro-
2-bromo-acetophenone, 1-(4-fluoro-phenyl)-3-methylamino-propane
hydrochloride, triethylamine and sodium borohydride.
M.p.: 185 - 188C (decomp.).
Example 60
1-(4-Amino~3,5~dichloro-phenyl)-2- ~- ~-(4-hydroxy-phenyl)-
1-methyl ProP~l7amino7ethanol
Prepared analogou~ly to Example 4 from 4'-amino-3',5'dichloro-
2- ~ - ~ -(4~hydroxy-phenyl)-1-methyl-propyl7-~mino7acetophenone
and ~odium borohydride in aqueous tetrahydrofuran. As eluenk for
the chromatographic purufication over silica gel a mixture of
~lZ~263~
- 57 -
dichloromethane : methanol : co~c. ammonia = 19 : 1 : 0.05
was used.
(Oil~ 1 : 1 mixture o~ the diastereoisomeric racemates).
IR spectrum (KBr): OH 2300 - 3500 cm 1 (broad, as~ocia-
ted)
NH2 3460 + 3370 cm 1
CH2 2920 + 2960 cm 1
C=C 1580~ 1510 + 1480 cm 1
W spectrum (ethanol): ~ max. 244 nm (0.28)
280 ~m (0.08)
300 ~m (0.08)
UV spectrum (ethanol + KOH)- ~ max. 243 nm (0.54)
299 nm (0.15).
Example 61
1-(4-Amino-3,5-dichloro-phenyl)-2- ~ - ~ -(4-methoxy phenyl)-
1-methyl-propyl7amino7ethanol
Prepared anaiogously to Example 4. from 4'-amino-3',5'-dichloro-
2- ~ - ~ -(4-methoxy-phenyl~-1-methyl-propy_7~min_7acetophenone
and sodiumborohydride in aqueous tetrahydrofuran.
The compound was ~btained as a 1:1 mixture of the diastereoisome-
ric racemate.
IR 3pectrum (methylene chloride): OH 3600 cm 1
NH2 3480 + 3390 cm 1
CH~ ~930 cm
OCH3 2830 cm 1
C=C 15809 1510 ~ 1485 cm
W spectr~m (ethanol): ~ max. 244 nm (0.28)280 nm (0.08)
300 ~m (0.09).
Z63~i
- 5~ -
Example 62
1-(4-Amino-~ cyano-5-fluoro-phenyl)-2- ~ - ~ -(3,4-dimethoxy-
phenyl)~eth~l7amino7ethanol h~drochloride
Prepared analogously to Example 5 ~rom 4'-amino-3'-~luoro-
5'-cyano-acetophenone, selenium dioxide, 2-(3,4-dimethoxy-
phenyl)-ethylamine 9 and sodium borohydride.
M.p.: 196 - 197C (decomp.).
Example 63
1-(4-Amino-3-fluoro-5-iodo-phenyl)-2- ~ - ~ -(3 t 4-dimethoxy-phenyl)-
ethyl7amino7ethanol h~drochloride
Prepared analogously to Example 5 from 4'-amino-3'-~luoro-5'-iodo-
acetophenone, selenium dioxide, 2-(3 J 4-dimethoxy-phenyl)-ethylamine,
and sodium 40rohydride.
M.p.: 192 - 193C (decomp.).
,
ExamPle 64
1-(4-~mino-3-chloro-5-~luoro phenyl)-2- ~ - ~ -(3,4 dimethoxy-
phenyl)~ethyl7amino7ethanol hydrochloride
Prepared analogously to Example 5 ~rom 4'-amino-3'-chloro-
5'~luoro-acetophenone, selenium dioxide, 2--(3,4-dimetho~y-
phenyl)-ethylamine, and sodium borohydride.
M p.: 184 - 186C (decomp.).
Example 65
1-(4-Amino-3~bromo-5-fluoro-phenyl)-2- r - ~ (3,4-dimethoxy-phenyl)-
ethyl7amino7ethanol hydrochloride
Pr0pared analogously to Example 5 from 4~-amino-3~-bromo-5~-fluoro-
acetophe~one, selenium dioxide, 20 (3,4-dimethoxy-phenyl)-ethylami~e t
~Z~6;~6
- 59 -
and sodium borohydride.
M.p.~ 194 - 195C (flecomp.).
Example 66
1-(4-Amino-3-~luoro-5-cyano-phenyl)-2- ~ - ~ -(4-methoxy-phenyl)-
propyl7amino7ethanol
Prepared analogously to Example 5 ~rom 4'~amino~3'-fluoro-
5'-cyano-acetophenone, selenium dioxide, 3-~4 methoxy-phenyl)-
propylamine, and sodi~m borohydride.
M.p,: 119 - 121C.
~*~mple 67
. 1-(4-A~ino-3,5-dichloro-phenyl)-2-LR-(3-phenyl-pr~pyl)-amin ~ -
ethanol hydrochloride
Prepared ~nalogously to Example 5 from 4'-amino-3',5'-dichloro-
acetophenone, selenium dioxide, 3-phenyl-propylamine, and sodium
borohydride.
.p,: 180 - l81C (decomp.).
Example 68
1-(4-Amino-~-chloro-5-fluoro-phenyl) 2- ~-(1-methyl-2-phenoxy-
ethyl)-amino7ethanol dihydrochloride
Prepared analogously to Example 5 ~rom 4'-amino-3'~chloro-
5'-~luoro-acetophenone, selenium dioxide, 1~methyl-2~phenoxy-
ethylamine, and sodium borohydride.
~,p.: 158 ~ 160C (deco~p.).
~L2(~636
- 60 -
Exam~le 6~
1~(4-Amino-3-cyano 5-fluoro-phenyl)-2~ ~ -(1-methyl-2-phenoxy-
ethyl)-amino7ethanol hydrochloride
Prepared analogously to Example 5 from 4'-amino-3'-cyano-5'-fluoro-
5 acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylamine,
and sodium borohydride.
M.p,: 178 - 184C (decomp.).
Example 70
i-(4-Amino-3-bromo-5-fluoro-phenyl)-2- ~ methyl~2-phenoxy-
ethYl~ ami~o7ethanol dihydrochloride
Prepared analogously to Example 5 from 4'-amino-3'-bromo-5'-fluoro-
acetophenone, selenium dioxide, 1-methyl-2-phenoxy-ethylamine~
and sodium borohydride.
M.p,: 156 - 158C (decomp~).
ExamPle 71
N~ ~ -(4-Amino-3,5-dibromo-phenyl)-ethy ~ -N- ~ -(4-methoxy-phenyl)-
propyl7methylamine
Prepared analogously to Example 7 ~rom 4-amino-3,5-dibromo-N-
~-(4-methoxy-phenyl)~propy ~ -N-methyl-phenyl-acet~mide,
and lithium ~minium hydride.
M,p. o~ the hydrochloride: 149 - 153C~
Example 72
N- ~ -(4-Amino-3,5-dichloro-phenyl)-ethy ~ -N- ~ -(4-methoxy-phenyl)-
proP~rl7methyl~mine
Prepared analogously to Example 7 ~rom 4-amino-3,5 dichloro-
.
2ti3~i
N- ~ -(4-methoxy~phenyl)-propy ~ -N~methyl-phenyl-acetamide,
and lithium aluminium hydride.
M.p. of the hydrochloride: gO - 94C.
Example 73
N~ ~ ~(4-Amino-3,5-dichloro~phenyl)-ethy ~ -N- ~ -(4-methoxy-
phenvl~-eth~l7methylamine
Prepared analogously to Example 8 from 4-amino-3,5-dichloro-
N- ~ -(4-methoxy-phenyl)-ethy ~ -N-methyl-phenyl-acetamide,
and lithium aluminium hydride.
IR spectrum (methylene chloride): NH2 3380 ~ 3470 cm 1
N-alkyl 2780 cm
OCH~ 2830 cm 1
aliphat. CH2 2850 + 2930 cm
C=C 1610 cm 1
W spectrum (ethanol): ~ max. 245 nm (0.24)
281 nm (0.08)
. ~ 305 nm to-o7)-
Example 74
N- ~ -(4-Amino-3,5-dichloro-phenyl)-ethy ~ -N ~ ~(4-methoxy-phenyl)-
butyl7methylamine
Prepared analogously to Example 8 ~rom 4-amino-3~5-dichloro-
N- ~ -(4-methoxy-phenyl)-buty ~ ;N-m~thyl-phenyl-ace~amide,
and lithium alum;nium hydride.
IR spectrum (methylene chloride): NH~ 3380 ~ 3480 cm 1
O~H3 2830 cm
aliphat. CH2 2850 ~ 2930 cm 1
NH~ 2100 - 2500 cm 1
C C 1630 cm 1
W spectrum (ethanol): ~ max. 245 nm (0.22)
280 nm (0.07)
304 nm (0.08).
'~Z1~63~
- 62 -
Example 75
~ (4-Amino~3,5-dichloro-phenyl)-propyl7-2-(3,4-dimethoxy-
phenyl)-eth~lamine hydrochloride
Prepared analogously to Example 7 ~rom 3-(4-amino-3,5-dichloro-
5 phenyl)-N- ~ -(3,4-dlmethoxy-phenyl)-ethy ~propionamide,
and lithium aluminium hydride.
M.p.: 142 - 145C.
Example 76
N-L3-(4-Amino~3,5-dichloro-phenyl)-propyl7-N~ ,4-dimethoxy-
10~henyl)-ethyl7methYlamine
Prepared analogously to Example 8 ~rom 3-(4-amino-3,5-dichloro-
phenyl)-N- r -(3~4-dimet~oxy-phenyl)~ethyl7-N-methyl-propionamide~
and lithium aluminium hydride. Oil~
IR.spectrum (methylene chloride): NH2 , 3400 ~ 3500 cm 1
OCH3 2835 + 2960 cm 1
~CH3 2800 cm 1
aromat 1510 + 1590/
1615 cm 1
W spectrum (ethanol): ~ max~ 239 nm (shoulder)
281 ~m (0.11)
300 tlm (0~08)o
Example 77
N~ ~ -(4-Amino-3-bromo-phenyl)-propyl7-2-(~,4-dimethoxy-phenyl)-
ethylamine hYdrochloride
25 Prepared analogously to Example 7 ~rom 3-(4-amino-395-dibromo-
phenyl)~N- ~ -(3,4-dimethoxy-phenyl)-ethyl7propionamide,and
lithium aluminium hydride.
M.p.: 131 - 134C.
Z~36
- 63 -
Example 78
N- ~-(4~Amino-3,5-~ichloro-phenyl)-ethy~ r~(4 hydroxy-phenyl)~
1-methyl-proPY17amine
Prepared analogously to Example 8 ~rom 4-amino-3,5-dichloro-
N r- (4-hydro~y-phenyl)-1 ~methyl-propy ~ phe~yl-acetamide,
and lithium aluminium hydride in tetrahydrofuran. The
ohromatographic p~ri~ication was carried out by meanæ o~
medium pressure chromatography o~ silica gel (grai~ size:
0.015 - 00025 ~) With methylene chloride : methanol :
10 conc. ammonia , 19 : ~ : 0~1 a~ eluent a Foa~O
IR ~pectrum (meth~le~e chloride) a OH 3580 cm 1
NH2 ~4~0 ~ 3~85 e~ 1
C~2 2920 om 1
C=C 1580, 1510 1 1480 cm
W ~pectrum (ethanol): ~ max. 242 n~ (0.24; shoulder~
280 ~m (0.07)
303 nm (0.08)
UV spectrum (ethanol ~ KOH): ~ max. 242 nm to.53)
300 nm (0.16).
Example 79
N- ~ -(4-Amino-3,5-dichloro-phen~ ethy ~-N- ~ -(4-~ethoxy-phenyl)-
1 -meth~l-ProP~17amine
. Prepared analogou~ly to E~a~ple 8 ~rom 4-amino-3,5-diohloro-
N- ~ -(4~m~thoxy-phenyl) 1-methyl-propy ~phe~ylacetamide,
and :Lit~umaluminium hydride in tetrahydro~uran. Oil.
IR 3pectrum (~ethylene chloride): N~2 3480 ~ 3385 c~ 1
. C~2 2930 cm~
OC~3 2830 cm~1
C.C 1580 9 1510 ~ 1485 cm
UV ~pectrum (etha~ol~: ~ max. 242 ~ (0.25; shoulder)
280 nm (0.07)
30~ ~m (0.08).
~Z636
- 6~ -
Example 80
N~ ~ -(4-~mino-3,5-dichloro-phenyl)-ethy ~ -N ~ (4-benzyloxy-
phen~ prop~l7methylamine
Prepared analogou~ly to Example 8 from 4_~mino-3,5-dichloro-
5 ~ (4-benzylo~y~phe~yl)-propyl7-N ~ethyl-phenyla~ebamide,
and l1thium aluminium hydride. Oil.
IR spectrum (methyiene chloride): NH2 339 + 3490 cm 1
N-alkyl 2800 cm 1
UV spectrum (ethanol): ~ max. 245 nm (0.10~
280 nm (0.04)
300 nm. (0.04)
Example 81
N- ~ -(4-Ami~o 3,5~dichloro-phenyl)-ethyl7-N~ 3,4-dimethoxy-
phenyl)-propyl7methylamlne
15 Prepared analogou$ly to E~mple 8 irom 4-amin~-3,5-dichloro-
N- ~ -(3,4-dimethoxy~phenyl) -propy ~ -N-methyl-phe~ylacetamide,
and lithium aluminium hydride. Oil.
IR spectru~ (methylene chloride): NH2 3395 + 3495 cm 1
OC~3 2830 cm 1
N~alkyl 2800 cm 1
W spectrum (ethanol): ~ 2ax. 230 Dm (~houlder; 0.18)
245 ~m (~houlder; 0.12)
282 ~m (0.04)
` ~02 nm. (0.03)
25 ExamPle 82
N- ~-(4-A~i~o-3,5-dichloro-phenyl)-ethyl7-N- ~ -(2 ~etho~y~phenyl)-
prop~l7meth~lamine hYdrochloride
Prepared analogou~ly to Example 7 irom 4-a~i~o-3,5-dichloro-
636
- 65 -
N- ~-(2-methoxy~pheny~ propy~lJ-N-methyl-phenylacetami
and lithium aluminium hydride.
M.p.: 160 ~ 164C~
Example 83
5 N- ~ ~(4-~mino-3 9 5-dichloro-phe~yl)-ethy ~-N~(3-phenyl-propyl)-
methylamine
Prepared analogously to Example 8 ~rom 4-amino~3,5-dichloro-
N-(3-phenyl-propyl)-N-methyl-phenylacetamide, and
lithium aluminium hydride. Oil.
10 IR ~pectrum (me~hylene chloride): NH2 3390 + 3490 cm
N-alkyl 2800 cm
UV spectrum (ethanol): ~ max. 245 nm (0.12)
300 nm (0.~3)
Exsmple 84
15 M-r- ( 4~Amino-3,5-dichloro-phenyl)-ethyl7-N- ~ -(4 methoxy-phe~yl)-
propyl7~mine h~drochloride
Prepared a~alogously to Example 7 ~ro~ 4-amino-~,5-d~chloro-
N- ~ ~(4-methoxy-phenyl)-propy ~phe~ylacetami de, and
ltthium aluminium hydride.
20 ~.p.: ~03 - 205C.
Example 85
N- ~ -(4-A~i~o~3,5-dichloro-phenyl~-ethyl7-N- ~ -(4-~etho~y-phe~yl)-
prop~l7cv cloProPrlamlns
Prepared a~alogousl~ to ~xample 8 ~rom 4-a~i~o-3,5~dichl~ro-
25 N ~-(4-methoxy-phenyl)-propyl7-N-cyclopropyl~phenylacetamide,
and`lithiurn aluminium hydride. Oil.
IR ~p~ctrum tmethyle~e chloride): ~R2 3~90 ~ 3490 cm 1
.. OC~3 2830 o~~
~2~,~63~ii
- 66 -
W ~pectrum (eth~ol): ~ ma~. 245 nm (0.15~
280 n~ (0.04)
300 nm ~0.05)
Example 86
N-~(4-Ami~o 3,5-dichloro~phenyl)-ethyl7-N-~-(4-methoxy-
phenYl)-propyl7propylamine
Prepared analogously to Example 8 from 4-amino-3,5-dichloro~
N ~ (4-metho~y-phenyl)-propyl7N-propyl-phenylacetamide,
and lithium aluminium hydride. Oil.
0 IR spectrum (methyle~e chloride): N~2 3390 ~ 3490 cm 1
OCH3 28~0 cm 1
N-alkyl 2800 cm 1
UV spectrum (ethanol): ~ max. 243 ~m (0.13)
280 nm (~.04)
. 300 nm (0.04)
E~ample 87
~ (4-Amino-3~5-dlchloro-phe~yl)-ethy~-N-~-(4 methoxy-
Phe~yl )~proP~17eth~1amir~e
Prepared a~alogou~ly to Example 8 ~rom 4-ami~o-3,5 dichloro-
N-~ (4-me~hoxy-phenyl)-propy~-N-ethyl-ph~nylacetamider
and-lithium aluminium hydride. Oil.
IR æpectrum ~methylene chloride): NH2 3~90 ~ 3490 cm 1
oc~3 2830 cm 1
~-alkyl 2800 cm 1
UV ~pectru~ (etha~ol): ~ max. 243 nm (0.13)
280 n~ (0.04)
300 nm (0.04)
636
- 67 -
E~ample 88
N~ ~ (4-Ami~o-3~5-dichloro-phenyl)-ethy ~ -N-~ -(4-methoxy-
phenyl)-propyl7-2-propylamine
Prepared analogously to Example 8 ~rom 4-ami~o-3,5-dichloro-
5 N- ~ -(4-methoxy~phenyl)-propyl7-N-(2-propyl)-phenylacetamide,
and lithium aluminium hydride. Oil.
IR spectrum (methylene chloride): NH2 3390 + 3490 cm 1
oc~3 2830 cm 1
W ~pectrum (ethanol): ~ max. 243 nm (0.13)
28~ nm (0.04)
300 nm (0.04)
Example 89
N ~ -(4-Amino-3,5-dichloro phenyl)~ethy ~ -N-~ -(4-etho~y-
ph~yl~-propyl7methylamine
Prepared analogously to Example 8 ~rom 4~amino-3,5~dichloro-
N- ~ -(4-etho~y-phenyl)-propyl7~N-methyl-pheny~ace~amide,
and lithium aluminium hydride. Oil.
IR spectrum (~ethylene chloride): ~H2 3390 ~ 3490 c~ 1
OC~3 2830 cm 1
N-al~yl 2800 cm 1
~V spectrum (ethanol~: ~ max~ 245 n~ (0.1~)
280 nm (0003)
300 nm (0.04)
Exam~le ~0
~ (4-Amino~3,5-dichloro-phenylj-ethyl7-N- ~ -(4-methoxy-
phe~yl)D1 methyl-propyl7~ethY~ e
Prepared analo~ously to Example 9 fro~ 1-ethoxycarbonyloxy-1-
(4-amino-3,5-dichloro-phenyl)-2~ (4-methoxy-phenyl3-
1-methyl-propyl7methylami~ ~ ethane, a~d sodiu~ borohydride
in isopropanolO Oil.
~L~J~6~6
- 68 -
IR spectrum (methylene chloride): NH2 3480 ~ 3380 cm 1
CH2 2930 cm 1
N-alkyl 2790 cm 1
OCH3 2840 cm 1
C-C 1580, 1510 + 1480 cm 1
Example 91
N- r-(4-Ami~o-3-bromo-5-cyano-phenyl) ethy ~ (4-methoxy-
phenyl)-butyl7methyla~lne
Prepared analogously to Exa~ple 9 from 1-ethoxycarbonylo~y-1-
(4-amino-3-bromo-5-cyano-phenyl)-2- ~ - ~ ~(4-methoxy~phenyl)-buty ~ -
methylamino7ethane, and sodium borohydride.
Analysis:
Calc,: C 6006 H 6.3 Br 19.2 N 10.1
Found: 60~5 6.1 19.2 10.1
Ex~mPle 92
N- ~ (4-Amino-3-chloro-5-cyano-phenyl)-ethyl7-N~ 4-methoxy~
phenyl)-ethYl~meth~lamine
Prepared analogously to Example 9 ~rom 1-ethox~carbonylox~1
(4-a~i~o-3-chloro-5-cyano-phenyl)-2~ (4 methoxy-phe~yl)-
ethy ~ methylami~ ~ ethane, and sodium borohydride.
IR spectrum (methyle~e chloride): NH2 3400 ~ 3490 cm 1
N-alkyl 3790 cm 1
OCH3 2830 c~ 1
aliphat. CH2 2850 ~ 2940 cm 1
C~ 2210 cm~1
C-C 1620 c~ 1
W spectrum (ethanol): ~ max. 244 nm (0.26)
280 nm ~0.04)
335 nm (0.15).
2636
- 69 -
Exam~le 93
N~ ~ ~(4-Ami~o ~-bromo-5-cyano-phe~yl)-ethyl7-N ~-(4~methoxy-
phen~ propyl7methylamine
Prepared analogou~ly to Example 9 from 1-etho~yoarbo~ylo~y-1-
5 (4-amino~3-bromo-5-cya~o-phenyl)-2 ~ - ~-(4-methoxy-phenyl)-
propy ~methylamin ~ ethan~, and sodium borohydride.
IR spectrum (methylene chloride): NH2 3390 ~ ~490 c~ 1
N-alkyl 3790 cm 1
OCH3 3830 cm 1
aliphat. C~ 2850 + 2940 cm 1
CJN 2210 cm 1
C-C 1620 cm 1
UV ~pectrum (ethanol): ~ max. 244 Dm (0.20)
280 nm (0.04)
334 nm (0.13)-.
Exam~le 94
N- ~ ~4-Amino-3-chloro~5-cyano-phe~yl)-ethyl7-N- ~-(4-~ethoxy-
phenyl)-butY17methYlamine
~ Prepared analo~ously to Example 9 ~rom 1-etho~ycarbonyloxy-1-
(4-ami~o-~-chloro-5-oyano-phe~yl)-2- ~ ~ methox~-phenyl)-buty ~-
methylamin ~ eth~ne, a~d sodium borohydride.
A~alysi~:
Calc.: C 67.5 H 7.3 Cl ~.53 N 11.25
25 Found: 67.5 7.14 9.65 11.34
Example 95
1-(4-Amino-3-chloro-5-tri~luoromethyl-phenyl)-2- ~- ~-t4-methoxy
phe~vl~-butyl7methylami~o7ethanol
Prepared al:lalOgOUBly to Example 1 irom 4'-a~i~o-3'-chloro-5'-tri-
~zr3z636
- 70 --
fluorom~thyl 2- ~- ~ -(4-methoxy-phenyl)-buty ~ methylami~ ~ aceto-
phe~o~e~ and sod~um borohydride i.n 80 % methanol~
IR spectrum (met~ylene chloride~: OH 3590 cm 1
N~2 3410 ~ 3510 cm 1
N-alkyl 2800 cm 1
OCH3 2830 c~ 1
aliphat. CH2 2850 + 2930 c~ 1
aromat. C-C 1630 c~-
W spectrum (ethanol): ~ ma~. 225 nm (0.32)
245 ~m (0.31)
280 nm (0.06)
308 Dm (0.10).
Example 96
1-(4-~mi~o-3 cya~o-phenyl)~2- r ~ -(4-metho~y-phenyl)-propyl7-
15 meth~lamino7ethanol
P~epared a~alogously.to Example 11 ~rom 1-(4-ami~o 3-bromo-
5-cyano-phe~yl)-2- ~ - ~ -(4-meth~xy-phenyl)~propyl7methylamino~-
ethanol in the presence o~ palladium/charcoal a~d hydrogen.
IR spectrum (methylene chloride): OH 3610 cm 1
NH2 3400 ~ 3490 cm 1
N-alkyl 2800 cm 1
OCH3 2830 cm 1
C-N 2210 c~ 1
C=C 1630 cm 1
25 W spectru~ ~ethanol): ~ max. 251 nm (0.313
280 ~m (0.60)
328 n~ (0.12~.
Z636
- 71 -
Example 97
(4-Ami~o-~chloro-phenyl)-ethy ~ -N~ 4-benzyloxy-phenyl)-
propyl7methylamine
Prepared analogously to Example 11 from N ~ -(4 amino-3,5-dichloro-
S phenyl)=ethyl7-N- ~ -(4-benzyloxy-phenyl)-propyl7methylamine a~d
hydrogen. Oil.
IR ~pectrum (methylene chloride): N~I2 3390 + 3490 cm 1
N-alkyl 2790 cm 1.
E~ample 98
1o N-r- (4-Amino-3,5-dichloro-phe~yl~-ethyl7-N ~ -(4-hydroxy-phenyl3-
propyl7methylamine
Prepared analogou~ly to Example 16 ~rom N~ ~ -(4-amino-3,5-dichloro-
phenyl)-ethyl7-N- ~ -(4-benzyloxy~phenyl)-propyl7methylamine ~nd
hydro~en. Oil.
I~ ~pectrum (~ethyle~e chlor~de): OH 3580 cm 1
NH2 3390 ~ 3490 cm 1
N-alkyl 2800 cm 1.
Example 99
1-(4-Amino~3-~luoro-phenyl)-2- ~ -(1-methyl-2-pheno~y-ethyl)-
~20 amino7eth~nol tosylate
Prepar~d analogo~ly to Example 17 fro~ 1-(4-acetamino-3-~luoro-
ph~nyl)-2- r ~ methyl-2-pheno~y)-ethy_7amino-ethanol a~d ~odium
hydroxide.
M~po 124 - 128C.
iA~ Z 63 6
- 72
Example 100
N r~(4-Ami~o-3,5-dichloro-phenyl) ethy ~-N- ~ -(4~methoxy--
pheno~y~-prop~17methylamine
1~74 g (0.014 mol) of 4-met~oxy-phe~ol were dissol~ed in 60 ml
5 oi dry tetr~hydrofura~ the solutio~ was cooled to -5C and
under stirring 0.67 g (0.014 mol) o~ a 50 %suspension o~ 50dium
hydride ill oil were added thereto. Stirring was co~ti~ued fQr
2 hours at 0C a~d the reaction mixture was mi~ed dropwise ~ith
a ~ol~tion of 4.2 g o~ N- ~ -(4-~mino-395-dichloro-phenyl)-ethy 7-
10 N-(3-chloro-RrPYl)-methylamine in 50 ml o~ dry tetrahydro~uran
at the same temperature. After stirring for 18 hours at approx.
20C, the reaction mixture was evaporated i~ vacuo 9 a~d the evapo-
ratio~ re~idue was di~tributed between ether ~nd water. The phase~
were ~epar~ted and the aqueous layer wa3 e~tracted thrice with
15 ether. The ether e~tracts were wa~hed with water, combined, dried,
a~d evaporated i~ vacuo. The olly evaporatio~ re~idue ~a~ puri~ied
by chromatography ov~r a silica gel colu~n (eluent: ether), a~d
after evaporating the desired fract1o~s, ~he title com-
pound was obtained. as an oil
20 IR spectrum (methylene chloride): ~2 3390 ~ 34~0 cm 1
C~2 2950 cm 1
N-al~yl 2800 cm~~
C-C 1585 ~ 1560
1505 cm 1
25 W ~pectru~ (etha~ol): ~ ~ax. 230 nm (0.18; ~houlder)
246 ~m (OaO85; ~houlder)
295 ~lm (0~ 05) ~
-~Lo~u~v~
Example 101
1-~4-Amlno-3,5~dichloro-phenyl)~2- ~ -(3-phenyl propyl)-ethyl-
amino7ethanol hydrochloride
2 g of 1-(4~amino-3,5-dichloro-phe~yl) 2- r ~(3-phenyl-propy ~ amino7-
etha~ol hydrochloride were dissolved in 50 ml of ethanol. To
this solution 0.4 ml o~ acetaldehyde and subseque~tly whilst
stirring at room temperature 1.2 g of sodium cyanoborohydride
were added~ maintaining a pH value of 6 - 6. 5 by addi-
tion o~ 2 N hydrochloric acid. The mixture was stirred
~ra ~ther 2 hours at this p~ ~alue. The solutio~ was poured
into water and acidl~ied with Z N hydrochloric ~cid to destroy
the excess sodium cya~oborohydride. Then 2 N sodium hydroxide
solution was added until alkaline, the re~çtion mixture was extracted
extracted twice with methylene chloride, and the comhined methylene
chloride phases were washed with water, dried over sodium sul~ate,
and eYaporated in vacuo to dryne~ss. A ~early colourles~ oil was
obtained, which was dissolved in ethanol. This et~a~olic solutio~
wa~ acidi~ied with ethéreal hydroc~lorlc acid up to pH 5 and in
vacuo i~ a ro*atio~ eYaporator the solve~t was removed. The re-
r~nine oily residue was crystallised from ethyl acetate;~ourless crystals were obtained.
Mop~ 102 - 105C~
Example 102
1-(4-Ethoxycarbonylamino-~-cya~o-5-~luoro-Phenyl)-2- ~ - ~ -
(3,4-dimethoxy-phenyl)-eth~17a~ino7ethanol hvdrochloride
Prepared analogou~ly to Example 4 ~rom 4'-etho~ycarbonylamino-
3'-cyano-5'-fluoro-acetopheno~e, selenium dioxide, 2-(3,4-di-
methoxy-phen~ ethylamine, and sodium borohydride.
M,p.: 190 - 19~C (decomp.).
~3
- 74 -
E~mple 103
1-(4-~mino-3-cyano~5-fluoro-phe~yl) ~ 2- /R-~- ( 4-metho~y-phenyl)-
butyl7methylamino7ethanol
Prepared a~alogously to Example 1 ~rom 4'-amino-3'-cyano-5'-
5 ~luoro-2- r - ~-(4-methoxy-phenyl~-butyl7methylamin ~ aceto-
phenone and sodium borohydride in 80 % metha~ol.
IR ~pectrum (methylene chloride): OH 3590 cm 1
NH2 3400 ~ 3490 c~ 1
N-alkyl 2800 cm 1
OCH3 2830 cm 1
a1iphat. CH2 2850 + 2930 cm 1
C-N 2210 cm 1
C=C 1635 cm 1
W spectrum (ethanol): ~ max. 241 ~m (O.27)
280 Dm (0.07)
322 ~m (0.14).
Example 10~
1-(4-Ac~tami~o-3-bromo-phenyl)-2- ~ - ~ -(4-methoxy-phe~yl)-buty ~-
methylami~o7ethanol
20 Prepared analogously to Example 1 from 4'-acetamino-3'-bromo-
2- ~ - ~ -(4-metho~y-phenyl)-butyl7methylamLno7ac~tophe~one and
sodium borohydride in 80 % methanol.
IR spectrum (methylene chloride): OH 3590 cm 1
NH2 3410 cm 1
N-alkyl 2800 cm 1
OCH3 28~0 c~ 1
aliphat. CH2 2850 ~ 2930 cm 1
aromat. C~C 1610 cm 1
C~O 1700 cm 1
u~ide II 1510 cm 1
36
- 75 -
Example 105
Racemates A and B o~ 1-(4-amino-3,5-dichloro-phenyl~-2- ~ -
/~-(4~h~dro~y-phenyl)~1 meth~l-propyl7methylamino7eth~nol
36 g of 1 (4~ami~o-3,5 dichloro-phenyl)-2~ (4-hydro~y-
5 phenyl)~ ethyl-propyl7methylamln ~ ethanol (1:1 mlxture of
the dia~tereoiæomerie raoe~ates A a~d B) were ~ olved i~
ether and reacted with 0,5 equivalents o~ 3 N hydrogen
chloride in ether. The crude crystalline product of the
hydrochloride o~ the racemate A thus obtained was recrystallized
10 first from isopropanol and then by dissolving in a large quantity
of methanol and subsequent evaporation until ~rystallization began.
M.p. o~ the hydrochloride, 248 - 249C (deco~p.).
13C-NMR spectru~ o~ the base (CDC13/CD30D):
C~3
-CH2-CH2-CH- 37.50 ppm
CH
CH2 C~2 CH . 58.36 pp~
CH- ~ 13.91 ppm
,~,N-CH3 36.33 pp~.
~ N-C~2- 61.03 ppm
0~
-C - 68.89 ppm
The i30prs.panolic mother liquor wa~ evaporated and distributed
be-t~ee~ ether and 2 N ammonia. The ~vaporatio~ residue of the
25 dried org~ic phaRe was separated by means of HPLC~ the
Eacemate A being retained, to isolate the racemate B (sio2 60; Merck;
~IL`Z~Z~:i36
- 76 -
0.015 - 0.025 mm; ether : methanol = ~0 :1). The cryst~ ne
e~aporation residue was recrystallized from a quantity of ether
by concentrating at boLling temperatures.
M.p.: 128 ~ 131C.
5 13C~NMR spectru~ (CDCl3/CD30D):
CH~
2 _ 35.61 ppm
C,H3
-CH2-CH2-CH- 59.21 pp~
~ CH- ~ 14.56 ppm
- N- ~ 35.03 pp~
N-CH2- 63.11 ppm
QH
-CH- 69.08 ppm
l5 ExamPl~ 106
1-(4-A~tno-~-bromo-5-oya~o-phenyl)-2- ~ - ~ -(4-~ethoxy-phenyl)-
but~l7be~zylamino7ethznol hvdrochlorida
Prepared a~alogou~ly to E~a~ple 1 from 4'-a~i~o-3'-bro~o-
5~-c~a~o-2- ~ - ~ -(4-methoxy-phe~yl)-but~17benzylami~o7aceto-
20 phenone nnd ~odiu~ borohydride in 90 ~ ~tha~ol.
M.p. o~ the hydrochloride: 122 - 126C.
636
E~ample 107
1-(4-Amino-~-bromo-S-cyano-ph0nyl)-2~ (4-~ethoxy phenrl)~
butyl7allylamino7ethanol
Prepared analogously ts Example 1 from 4'~amino-3'-bromo-
5'-cyano-2 ~ - ~ -(4~metho~y-phenyl)-butyl7allylami~o7aceto-
pheno~e and sodium borohydride in 90 % methanol. Resin.
IR spectrum (methylene chloride): NR2 3390 + 3490 cm 1
oc~3 2830 ~ 2940 cm 1
CN 2210 cm 1
arGmat. c=c 1610 cm 1
W spectrum (ethanol): ~ ma~. 223 n~ (0.43)
244 n~ (~houlder, broad; 0.07)
330 ~m (broad; 0.05)
Example 108
1-(4-Amino-3~bromo-5-cya~o~phenyl)~ N- ~ -(4-metho2y-phenyl~-
butyl7isopropylami~o7ethanol hydrochloride
Prepared analogously to Example 1 ~ro~ 4'-~mi~o-3'-bromo-
5 ' -cyano-2-LN-~- (4-methoxy-phenyl)-buty ~ isopropyla~in ~ -
acetophenone and sodiu~ borohydride in 90 % metha~ol.
M.p. o~ the hydrochloride: sinterLng from 40C.
Calc.: C 55.60 H 6.29 Br 16.20 Cl 2.14 N 8.46
Fo~nd: 55.30 6.37 15.40 6.84 8.83
Example 109
1-(4-Ami~o-3-bro~o-5 cyano-phenyl)-2- ~ - ~ -(4-methoxy-phe~yl)-
butyl7-n-propylamino7ethanol hydrochl~ride
Prepared analogou~ly to Example 1 fro~ 4'-amino-3'-bromo-
5'-cyano-2-LN- ~ -(4-methoxy-phe~yl)-butyl7-~ propylaminQ7-
%636
- 7a -
acetopheno~e ~nd sodium borohydride in 90 % meth~ol.
M.p. of the hydrochloride. si~tering from 40C
Calc.: C 55~60 H 6.29 N 8.46
Found: 55.52 6.32 8.39
5 Example 110
1-(4-~mino-3-bromo-5-cyano-phenyl)~2-~N- ~ -(4-me~ho~y-phenyl)-
but~l7eth~lamino7ethanol h~drochloride
Prepared a~alogously to Ex2mple l ~rom 4'-amino~3'-bromo-
5'-cyano-2~ 4-me-thoxy-phenyl)-butyl7ethylami~o7aceto-
10 phenone and sodium borohydride in 90 % metha~ol.
M.p. of the hydrochloride: 139 - 142~C.
E~am~le 111
1-(4-Ami~o-3-bromo~5~tri~luorom~thyl~phe~yl)-2~ (4~metho~y-
phen~ propyl7methylamino7ethanol
l5 Prepared analogously to Example 1 ~rom 4'-amino~3'-brQmo-
5'-tri~luoro~ethyl-2- r - ~ -(4-methoxy-phenyl)-propy ~ methyl-
ami~ ~ acetophe~o~e and sodium borohydride i~ 90 ~ methanol. Oil.
IR spectru~ (methylene chloride~: NH2 3400 ~ 3490 cm 1
OC~ 2840 + 2940 cm 1
aro~at~ C=C 1610 cm 1
W ~pectru~ (etha~ol): ~ max, 22~ n~ (0.26)
24~ nm (0.10~
310 Dm (very broad; 0.04)
~2~Z~36
- 79 --
Example 112
1-(4-Amino-3-bromo~5-cya~o-phenyl~-2- ~ -(4 phe~yl-butyl)-
methylamino7ethanol hydrochloride
Prepared analogously to Exa~ple 1 ~rom 4 t- ~mino-3'-bro~o-
5'-cyano-2 ~ -(4-phenyl~butyl)-methylamin_7acetophenone and
sodium borohydride in ~0 % methanol.
M.p. o~ the hydrochloride. 153 - 155C.
E~ample 113
1-(4-Am~no-3-cya~o-5 ~luoro~phenyl)~2- ~/2 (4~methoxy-phenyl)-
10 ethYl7methylami2lo7ethanol ~Ydrochloride
Prep~red analogously to E~a~ple 1 ~rom 4 T ~a~i~o-3'-cyano-
5'-fluoro-2- ~ - ~ (4-metho~y phenyl)-ethyl7methyla~inQ7aceto-
phenone and sodium borohydride in 90 % methanol~
M.p. o~ the hyd~ochl~ride: sintering ~rom 68C.
Calc.: C 60.10 H 6.12 Cl 9.35 N 11.05
Found: 59.91 6.07 9.40 10.69
Ex~mple 114
1-(4-Amino-3,5-dichloro-phenyl)~-2-LN-~3-phenylsul~enyl-propyl)-
methylamino7ethanol
Prepared analogously to E~ample 2 ~ro~ 4'-a~ino~-bromo-3',
5'-dichloro-acetophe~o~e, N- ~ -(4-methoxy-phenylsulfe~yl) -propyl7-
methylami~e, and ~odium borohydride i~ 80 ~ me~thanol~ Oil~
IR spectrum (methylene chloride): ~H2 33~0 + 3490 cm 1
OH 3600 ~ 3680 c~ 1
W spectrum (ethanol): ~ ma~O 246 D~ (0.1~)
300 nm (0.05)
~2~ 636
-- ~o -
Example 115
1-(4-Amino-3,5--dichloro~phenyl)-2 ~ (4-hydroxy-phenyl)-
propy~7amino7ethanol
Prepared analogously to E~ample 3 from 4'~ami.~o-3',5'-dichloro-
2~ (4-hydroxy~ph0nyl)~prop~17ami~o7acetophenone a~d sodium
borohydride in aqueous tetra~ydro~ura~. Oll.
IR spectrum ~KBr~: OH7 ~i~2 3300 - 3600 cm 1
aromat. C-C 1615 cm 1
UV spectrum ~ethanol ~ KOH)~ ~ max; 244 nm (0.26)
29~ ~ (0.08)
E~ample 116
1-(4-Amino~3,5-dichloro-phenyl)-2~ (4-chlorop~e~
prop~l7amino7~thanol
Prepared aaalogou~ly to Example 3 ~rom 4'-~mino~3',~'-dichloro-
2- r - ~ -(4-chloro-phenyl)-propy_7ami~ ~ aoetopheno~e and sodiu~
borohydride in aqueous tetrahydrofuran.
M.p.: 103 - 106C.
E~ample 117
1-(4-Ami~o~3,5-~ichloro~phenyl)-2- ~- ~ (4-hydro~y-phe~yl)-
1-meth~ prop~l7i~opropylami~o7ethanol
Prepared a~alo~ou~ly to E~ample 3 ~ro~ 4'~ o-31,5'-dichloro-
2~ (4-hydro~-phe~yl)-1~methyl-propyl7i~oproprla~i~ ~ aceto-
phenone and sodlum borohydride. Oilo
Calc.: C G1.~1 R 6.86 Cl 17.24 N 6.81
Found: 6l.07 6.86 16.67 6.53
V26~6
- Sl -
Example 118
1-(4-Ami~o-3,5-dichloro-phenyl)~2D~N- ~ -(4-hydroxy-phenyl)-
1~methyl-propyl7ethylamino7etha~ol
Prepared analogously to Example 3 from 4l-amino-3',5'-dichloro-
2- ~ - ~ -(4-hydroxy-phenyl)-1-methyl-propyl7ethylamin ~ aceto-
phe~o~e a~d sodium borohydride. Oil.
Calc.. C 60.45 H 6.60 Cl 17.85 N 7.05
Fou~d: 60~45 6.76 17.70 6.~6
Example 11~
1o 1-(4-Methylamino-3,5-dichloro-phenyl)-2 r-r- (4-hydroxy-
phenyl)-~-methyl-propql7meth~1ami~o7etha~ol
Prepared analogou~ly to E~ample ~ from 4'-methylami~o-3',
5'~dichloro-2 ~ - ~ -(4~hydro~y-phe~yl)-1-methyl~propy ~ -
methylami~ ~ acetopheno~e a~d ~odiu~ borohydride. Oil.
Calc, C 60.45 ~ 6.60 Cl 17.85 N 7.05
Found: 60.58 6.73 17.50 6.71
Exam~le 120
1-(4-Dimethylamino-3,5-dichloro phe~ 2-r r- (4-hydroxy-
phen~l) 1-methyl-prop~17methyl ~Tn; no7eth~ol
Prepared analogou~ly to Ex~mple 3 ~rom 4'-dimethylami~o-3' t
5'-dichloro-2~ (4-hydro~y-phenyl)-1-methyl-propy ~ methyl-
amino7acetophc~one and ~odiu~ borohydride. Oil.
Calc.: C 6~.31 ~I 6.~6 Cl 17.24 ~ 6.81
~o~nd: ~1.28 6.57 16.80 6.42
:~Zt:);26;36
- 82 -
Example 121
1-(4-Acetylami~o-3,5-dichloro-phenyl)-2 ~-r- ~4-hydroxy~
phenyl)-1-meth~l-propyl7methylamino7ethanol
Prepared analogously to E~ample 3 from 4'-acetylamino-3',
5 5'-dichloro-2 ~- ~4~hydroxy-phenyl)-1-methyl-propyl7-
methylamin_7acetophenone and sodium borohydride. Foam.
IR ~peotrum (methylene chloride): OH 3580 cm
NH 3410 cm~~
N-alkyl 2800 cm 1
C,O 1700 cm 1
C~C 1610, 1595 cm 1
Amid~ II 1515 cm 1
UY spectrum (ethanol): ~ max. 230 nm ~0.30; shoulder)
280 nm (0.04)
(Etha~ol + EOH~: ~ max. 243 ~m (0~46)
294 nm (0.08)
Example 122
1-(4-Etho~ycarbonylami~o-3.5-dichloro-phenyl)-2- ~- ~-(4-hydroxy-
Phen~ meth~l-propyl7methylami~o7ethanol
20 Prepared a~alogously to Example 3 ~ro~ 4'-ethoxycarbo~ylamino-
3',5'-dichloro~2- ~ - ~ (4-hydro~y-phenyl)~ ethyl~propyl7-
methylamin~7acetophe~one and sodium borohydride. Oil.
Calc.: C 58.02 ~ 6.20 Cl 15.57 ~ 6.15
Found: 58.20 6.3Z 15.32 6.03
:~Z~Z636
- 83 -
Example 123
Racemates A and B of 1-(4-amino-3-cyano-5-fluoro-phe~yl)-
2-/N-/~-methyl-3-(4-h~drox~-phen~ propyl7methylaQino7ethanol
Prepared a~alogously to Example 3 from 4'-ami~o-3'-cyano-
5 5'-~luoro-2~ methyl-3-(4-hydroxy-phenyl)~proprl7methyl-
amin_7acetophenone and sodium borohydride. The obtained mixture
of the diastereoi~omeric racemates was separated by mean~ of
column chromatography (SiO2; methylene chloride : metha~ol :
co~c. ammonia = 50 : 1 : 0.1).
l0 Racemate A:
M.p.: 161 - 163C
13C-NMR spectrum (d6-dimethyl~ulfoxide):
CH3
-CH2-CH2-C~- 37017 ppm
CH~
-CH2~CH2~CH- 57.91 ppm
CH~ .26 ppm
N- ~ 35~74 ppm
\ N-CEI2 60.90 ppm
OEI
-CH - 69.21 ppm
~V2i636
- 84 -
Racemate B:
M.p.: 92 - 98C
13C-NMR spectrum (d6-dimethylsulfoxide):
CH3
-CH2-CH2-CH~ 36.52 ppm
CH3
-CH2-C~2-CH- 57.78 pp~
~CH-CH3 13.19 ppm
~ N-CH2 61.48 ppm
lO OH -
-C~ 69.02 ppm
Example 124
1-(4-A~i~o-3-cyano-5-~luoro-phenyl)-2- ~ - r -methyl-3-(4-meth-
oxy-phenyl~-prov~17amino7ethanol
15 Prepared a~alogou~ly to Example 3 from 4'-ami~o-3'-cya~o-
5'-~luoro-2- r - ~ -methyl-3-(4-methoxy-phe~yl)-propy_7amin ~ -
acetophe~one and ~odium borohydride.
M.p.: 108 - 110C.
- 85 -
Example 125
1 (4 Amino-3~cyano-5-fluoro-phenyl)-2~ methyl-3-(4-hydroxy-
phenyl~-propyl7amino7ethanol
Prepared analogously -to E~ample 3 ~rom 4'-ami~o-3'-cyaQo-
5'-~luoro-2 r- r~methyl-3~(4-hydroxy-phenyl)-propy_7amin ~ -
acetophenone and sodium borohydride.
M.p~: 162 - 164C.
Example 126
1~(4-Amino-~-cyano-5-~luoro-phenyl)-2- ~- ~-methyl-3-(4-~th-
1o ox~-phenyl)-propyl7meth~lamino7etha~ol
Prepared a~alogously to Example 4 ~rom 1-(4-ami~o~-cyano~
5.;fluoro-phenyl)-2- ~- r-methyl-3-(4-hydro~y phe~l) propy ~ -
methylamin ~ ethanol and dimethyl~ul~ate/1 N sodium hydroxlde ~ol~tion
i~ tetrahydrofura~. Oi~. -
IR ~pectrum (methylene chloride): NH2 3400 ~ 3500 cm 1
0-CH3 2830 cm 1
N-alkyl 2800 cm 1
C~N 2210 c~ 1
C-C 1580, 1510 c~ 1
C~C + NH2 de~ormation 1620 cm 1
UY spectrum (etha~ol): ~ max. 242 nm (0.27)
278 n~ (0.05)
286 nm (0.05)
324 ~m (0.12)
- ~6 -
E:xample 1 27
1-(4~Ami~o-3,5-dichloro~phenyl)-2~ methyl-2-rheno~y-
ethyl~-amino7ethanol ~ydrochloride
Prepared analogou~ly to Ex~mple 5 ~rom ~-ami~o-3',5'dichloro-
5 acetophenone, ~elenium dioxide; 1-methyl-2-p~e~oxy-ethylami~e,
a~d sodium borohydride. Amorphous hydrochloride.
IR spectrum (methyle~e chloride): NH2 3390 ~ 3490 cm 1
W s~ectrum (ethanol): ~ max 245 nm (0.15)
300 nm (0.04)
lO Example 128
1~(4~Ami~o-3,5-dichloro phenyl )-2-~R-r- (4-~luoro-phe~yl)-
propyl7amino7ethanol hydrochloride
Prepared analogously to Example 5 from ~-amî~o-3',5Ldichloro-aceto-
phe~one, sele~iu~ dioxide, 3-(4-fluoro-phe~yl)-propylamine, and
15 sodium borohydride.
M.p. of the hydrochloride: 185 - 187C (decomp.).
Example 129
1-(4-Amino-3,5-dichloro-phe~yl)-2- ~ -(3-phe~yl-1-methyl-propyl)-
methylami~o7ethanol
20 Prepared analogo~ly to EYample 5 ~ro~ 4'-amino-3',5'-dichloro~
acetophenone, sel~nium dioxide, 3-phe~yl-1-methyl-propylami~e,
~nd sodium borohydride. Oil.
IR spectrum (~ethylene chlor1de): NH2 3390 + 3490 om 1
~ 0~ 3600 + ~680 cm~1
25 UV spactrum (etha~ol): ~ ma~. 245 nm (0,18)
300 nm (0.06)
36
- 87 -
Example 130
1~(4~A~ino~3,5-dichloro-phenyl)-2~ me-thyl-2-phe~o~y-ethyl)-
am1~o7etha~ol hydrochloride
Prepared a~alogouæly to E2ample 5 Prom ~ami~o 3',5Ldichloro-
5 acetophe~one~ sele~ium dioxida, 1-methyl 2-pheno~y-et~yla~l~e,
a~d ~odium boroh~dride.
M.p. o~ the hydrochlorldes 122 - 125C.
Example 131
N- ~ (4-Ami~o-3-bromo-phe~yl)-prop~17 ~ (3,4~dimetho~y-
10 phen~ eth~17meth~1amine hydroc~loride
Prepared a~alogously to Example 7 from M-methyl~- r~(394 di-
metho~y-phe~yl)-ethy ~ -3-(4-~mino-3,5 dibromo-phenyl )~propionamide,
and li~hium aluminium hydride in absolute tetra-
hydro~ura~
15 Mop~ 0~ the hydrochloride: 70 - 120C (sinteri~g)
IR spectrum (~Br): N~ ~2500 - 2650 c~ 1
alkyl 28Q0 - 3000 cm 1
W ~pectrum (etha~ol3: ~max. 234 nm (0.17)
280 ~m (0.04)
300 nm (~houlder 9 0.03).
Example 132
N-/2-(4-Amino-3-chloro~phenyl)-ethy ~ -~ methyl-3-phenyl-
propyl)-i~opropylamîne
Prepared a~alogou~ly to Example 7 ~rom 4-amino-3,5~dichloro-
25 ~-lsopropyl-N (1-methyl ~-phenyl-propyl)-phenylacat amide
and lithium aluminium hydride in tetrahydrofuran. Oil.
IR ~pectrum (methylene chloride~: NH2 3390 ~ ~490 cm 1
W spectrum (ethanol): ~ ~ax. 241 Dm (0.15)
300 nm (0~03)
'7'0~L~
- ~8 -
~c~ple 1 33
~ ~ -(4 Amino~3,5-dichloro phenyl~eth~ ~-N~ mekhyl~3-p~e~yl-
pro~ o~ropylami~e
Prepared analogously to E~ample 7 ~rom 4-amlno~3,5~dichloro~
5 N-l~opropyl~N (1-methyl 3-phe~y~-propyl)-p~e~ylace~amide
and lithium aluminiumhydride in tetrahydrofuran. Oil.
IR ~pectrum (mcthylene chloride): ~H2 3~90 ~ 3490 cm
W spectrum (etha~ol)~ ~ max. 245 ~ (0.15)
302 n~ ~0.04).
1o E~ample 134
N- ~ -(4-Amino-3,5-dichloro-phenyl)-ethy ~ -3~(4 .~luoro-phenyl)-
propylamine h~drochlorid0
Prepared a~alogou~ly to Example 7 ~rom 4-ami~o-3,5.dichloro
N-~ -(4-~luoro-phenyl)-propy ~phe~ylacetamide and
15 :L:~hium ~uminium . hydride 1~ tetrahydrofuran.
M.p. o~ th0 hydrochloride: 205 - 206C.
E~ample 135
N- ~ -(4-Amino~3,5-dichloro phe~yl)-ethy ~ -N-(1 methyl-
3-phenyl-prop~ meth~lamine
20 Prepared analogously to Example 7 ~rom 4-amino~3,5-dichloro-
N-(l-methyl-3-phenyl-propyl)-phenylace-tamide and
llthium aluminium hydride in tetrahydro~uran. Oil.
IR spectrum (methylene chlorlde): N~2 3390 ~ 3490 c~
W spectrum (ethanol): ~ ma~. 243 nm (0014)
300 nm (0.0~)
r3'~63~
~9
Example 136
N- ~-(4-Ami~o~3,5-dichloro-phenyl) eth~ ~ -N- ~ ~(4 ~etho~y-
Phe~ sul~enyl)-pro~yl7methylamine
Prepared analogously to Example 7 ~rom 4-ami~o-395-dlchloro~
5 N- ~ -(4-metho~y-phenyl~ulfenyl)-propyl7-~-methyl-phe~ylacet-
amicle and lithium aluminium hydride in tetrahydrofuran oil.
IR spectrum (~ethyle~e chloride~: NH2 3390 ~ 3490 cm '
W spectrum (ethanol)- ~ max. 245 ~m (0.16)
300 ~m (0.0~)
10 Example 137
N-~2-(4-Amino-3-bromo-phenyl)-ethyl7~ (4-metho~y~phenyl)-
butvl7methylami~e
.Prepared analogou~ly to Example 8 fro~ 4-amino-3-bromo-N- ~ -
(4-metho~y-ph~yl)-but~ ~ -N-methyl-phenylac etamide
15 and lit~m ~uminium hydride i~ absolute tetrahydrofu~an.
IR spectrum (methylene chloride): N~2 3380 ~ 3470 cm 1
OCH3 2830 ~ 2930 cm 1
aromatO c=c 1620 cm 1
NMR ~pectrum (CDCl3/D20): aromat. H 6.4-7.3 ppm (m, 7H)
oc~3 3.7 ppm (s, 3H)
NC~3 2.2 ppm (s, 3H)
aliph. H 1.3-2.8 ppm (m, BH)
Example 138
N- ~ -(4-Ami~o-3-bromo-phenyl)-ethyl7-N- ~-(4-methoxy-phe~yl)-
25 et~Yl7methYlamine
Prepared analogcusly to Example 8 ~rom 4-amino-3 bromo-N- ~ -
(4-methoxy-phenyl)-ethyl7-N-methyl-phe~yl~ce~amide
- 9o -
and lithium ~luminium hydride in ab.solu-te tetrahydrofuran.
IR speotr~m (methrl2~e chloride): ~H2 3380 ~ 3480 cm 1
oc~3 2840 + 2940 cm 1
aromat. C~C 1620 cm 1
5 W spectrum (ethanol): ~ max~ 2Z4 ~m ~0.24)
242 ~m (0.15)
280 nm (broad; 0.03)
300 n~ (broad; 0.03)
Example 139
10 N- ~ -(4~A~ino-3-fluoro-phenyl)-ethy ~ ~M- ~ -(4-metho~y phe~yl)-
propyl7methvl~mi~e
Prepared a~alogouslg to E~ample 8 from 4~amino-3-~luoro-N~
r- (4-metho~y=phe~yl)-propy ~ N methyl-ph~nylacet~lide
and lithium aluminium hydride in absolute tetrahydrofuran.
15 Oil.
IR ~pectrum (methylene chloride): NH2 3390 t 3490 C~ 1
.OC~3 2840 ~ 2940 c~-
aromat. C=C 1610 cm
W spectrum (ethanol): ~ max. 227 ~m (0.30~
20279 ~m (0.06)
285 D~ (~.06)
E~ample 140
N- ~ -(4-Amino-3-chloro-phenyl)-ethyl7-N- ~ -(4-methoxy-phenyl)
Prop~17methylamine
25 Prepared analogou~ly to Example 8 ~rom 4-anino-3-chloro N-methyl-
N- ~ -(4-methoxy-phenyl)-propyl7phenylacetamide and lithium
aluminium hydride in absolute t~trahydro~uran. Resi~.
IR ~pectrul~l (m0thyle~e chlor:i.de ~ ~ N~ 3390 ~ 3470 c~ 1
OCH3 2840 ~ 2940 cm 1
aro~at0 C-C 1610
lJV spectrum (etha~ol)~ ~ max. 224 ~ ~0.25)
240 nm (0~18)
280 nDI (~. 0~
300 ~1 (0. 03) -
Example 1 41
N-~3 (4 Ami~o-3, 5~dichloro-pherlyl )-propyl7-N-~- (4-metho:~-
10 phenyl)-prop~17amirle h~drochloride
Prepared analogously to E:~ample 8 ~rom 3~ (4~ o-3, 5 dichloro-
phe~yl ) ~ (4-methoxy-phenyl ) -propy~7propion amide
and ]ithium ~lwninium hydrlde i~ ab~olute tetrahydro:~uran.
M~ p . of the hydrochloride: 138 - 1 42C .
15 ExamPle 142
N~ 4-Amino-3,5-dichloro-phenyl)-propy;!7-N~ (4-metho.~-
~henyl)-ethyl7methylami~e dih~drochloride
Prepared analogously to Ex~mple 8 ~rom 3-(4-amino-3 9 5-dichloro-
phenyl)-N-methyl-N- ~ ~(4-metho~y-phe~yl)-ethyl7propio~amide
20 and lithium alumini~m hydride in ab~olute t~trahydro~uran.
~,p. of the dih~droohloride: 147 - 157C.
- 92 -
E~am~le 14~
N~ 4-~mino-3,5-dichloro-phe~yl)-ethy ~ -N- ~ -(4-methoæy-
phen~ butyl~amin~ hydrochloride
Pr~pared a~alogou~ly to ~ample 8 from N~2-(4-ami~o-3,5~di-
5 chloro phe~yl)~ethy ~ -4-(4 metho~y phe~yl)~butyramide
~d li~hium aluminium hydride in ab~olute tetrahydro~ura~.
M.p~ o~ the hydrochloride: 186 - 189C.
Example 144
N-r~ (4-Amino-3,5-dichloro-phenyl)-ethyl7-N ~ ~(4 chloro-phenyl)-
lO propyl7ami~e hydrochloride
Prepared analogously to Example 8 ~rom 4-ami~o-3,5-dichloro-
N- ~ -(4-chloro-phenyl)-propyl7phe~ylacetamide and
lithium aluminium hydride i~ ab~olute tetrahydro~ura~.
M.p. o~ the hydrochloride: 186 ~ 190C.
15 Example 145
N- ~ -(4-Amino-3,5-dichloro-phenyl)-ethy ~ -N-lX (4-methox~-
Phen~ butyl7isopropylamine
Prepared a~alogously to E~ample 8 ~rom N-L2- (4-amino-3, 5-di-
chloro-phe~yl)-ethy ~ -N-isopropyl-4-(4-methoxy-phenyl) -butyramide
20 and lithium aluminium hydride in absolute tetrahydro-
~-~an. 0$1.
IR spectrum (methyle~e chloride): NH2 3390 -~ 3490 cm 1
OCH3 2850 ~ 2930 cm
aromat. CaC 1610 cm 1
25 W spectrum (ethanol). ~ max. 242 nm (0.12)
280 nm (~houlder; O.04)
30~ nm (0.0~)
- 93 -
Exampl~ 146
N- ~ -(4~minv~3,5~dichloro~phe~yl)-ethy~7~N- ~-(4-methoxy-
phe~yl~ethyl7i~opropyl~mine
Prepared an~logou~ly to Example B ~rom ~ ~ ~(4-ami~o-3,5~di-
5 chloro-p~enyl)-ethyl7~ opI~opyl-4-me~hox~phenylacetamide
and li-thium aluminium hydrlde in absolute tetra-
h~drofura~. Oil .
IR spectr~ (methyle~e chloride): N~2 3390 ~ 3490 c~ 1
OCH3 2830 ~ 2960 cm 1
aromat. C-C 1610 c~ 1
W spectrum (ethanol): ~ max. 244 ~ (~houlder;0.12)
280 Dm (~houlder; O~05)
~01 ~m (0.05)
Example 147
15 N~ 4-dmino-3,5~dichloro-phenyl)~thyl7-N- ~ ~(4-methoxy~
phenyl)-ethyl7amine h~drochloride
Prepared analogously to Example 8 ~rom 4~amino-3,5-dichloro-
N ~ -(4-me-thoxy-phenyl)-ethy ~phenylacetamide and
lithium aluminium hydride .in absolute tetrahydrofura~.
20 M,p. o~ the hydrochloride: 206 - 208C.
E~ample 148
N-L3-(4-Amino-3~5 dibromo-phenyl)-propy_7-N-~- (3,4-dimethoxy-
phenyl) ethyl7methylamine
Prepared analogously to Ex~mple 8 from N~methyl,N- ~ -(3,4-di-
25 metho~y~phenyl)-ethyl7~3-(4-amino-3,5-d.ibromo-phe~yl)-propio~amide
and lithium aluminium hydride in absolu-te te-trahydro-
furan. Oil.
- 94 -
IR ~pectrum (~etbLyl@~e chloride) ~ 3480 ~ 3380 om
0~3 2840 ~- Z940 cm~
NP~ ~pectrum (CDC13/D20~ ~3 4.85 ppm (s, 6~
N-C~3 2 ~ 25 pp~ ( ~ . 3~1)
aro~at. H 6075 ppla (d, 3~
7 . 2 ppm ( ~, 2H )
aliphat ~ 1~ 1 . 5 ~ 2. 9 ppm (~,
Example 1 49
10 N- ~ -(4-Amino~3,5-dichloro-phenyl)-ethy ~-3 phe~yl-propylamine
hvdrochloride
Prepared analogously to Ex~ple 8 ~rom 4-ami~o 3,5-dichloro-
N-(3-phenyl-propyl)-phenylacetamide and lithium aluminiu~
hydride in tetrahydrofuran.
15 M.p~ o~ the hydrochloride: 197 - 199C.
E~ample 150
N~ ~-(4~Ami~o-3~bromo-5-cyano-phe~yl)-ethy ~ -N- ~-(4-methoæ~-
phenyl)-butyl7benzvla~ine
Prepared analogously to Example 9 from 1-ethoxyoarbonylo~-
20 1-(4-amino-3-bromo-5-cyano-phe~yl)-2- ~ -L~-(4-methoxy phenyl)
buty ~benzyla~i~ ~ ethane a~d sodium borohydride i~ i30propan01
~il .
IR spectrum (methylene chloride): N~I2 3390 ~ ~490 cm~1
OCH3 2830 + 2930 cm 1
CN 2210 cm~1
aroma-t. C=C 1620 cm 1
W spectrum (ethanol): ~ max. 222 nm (0.42)
244 nm (~houlder; O.09)
335 nn (broad; O.05)
~ 3~6
-- 95 -
E~ample 151
N- ~ -(4 Amino-3~bromo-5-c~ano~phenyl) eth~l7-N~ metho~y-
phen~ but~l7all~1amine
Pr~pared a~alogou~ly to E~ample 9 .~rom 1-etho~ycarbo~ylo~y-
5 1~(4~ami~o~3~bromo~5cyano~phe~yl) 2 ~ ~ (4~metho~y-phe~yl)~
~ut~ ~ allylami~o7etha~e a~d ~odium borohydride in i~opropanol.
Oil.
IR ~pectrum (me-thylene shlori.de): NH2 3~90 -~ ~490 cm
OC~3 2830 ~ Z930 cm 1
lo CN 2210 cm~1
aromatO C-C 1620 cm 1
W spectrum (ethanol): ~ ma~. 222 nm (0.49)
244 nm (shoulder; O.1)
335 nm (broad; O.06)
15 E~ample 152
N ~ -(4 ~mino-~bromo 5-cyano-phe~yl)-ethyl7-N- ~ -(4-methoxy~
phenyl)~butyl7ethylamine
Prepared analogously to Example 9 ~rom l-etho~ycarbo~yloxy-1-
(4-amino 3-bromo-~-cya~o-phenyl)-2~ (4~methoxy-phenyl)-
20 buty ~ ethylamin ~ ethane and sodium borohydride in isopropa~ol.
Oil.
IR spectrum (methyle~e chloride): NH2 3390 + 3490 c~ ~
OCH 2~30 + 2960 cm 1
CN 3 2210 c~-1
aromat. C=C 1620 cm 1
W spectrum (ethanol): ~ max. 222 nm (0.49)
244 nm (shoulder; 0.08
333 nn (broad; 0.06)
V~636
-- 96 --
Example 153
N- ~(4~mi~o~3~bromo~5~cya~o~ph2~yl)~ethyl7 N~ ~w(4-methoxy-
phenyl)~but~l7i~opro~ylamine
Prepared analogously to Example 9 from 1-etho~ycarbonyloxy-
5 1-(4-ami~o 3-bromo~5-cyano~phenyl)~2 ~ ~ -(4-methogy-phenyl)-
buty ~ isopropy~a~ino7etha~e a~d ~odium borohydride in ~opro
p~ol. ~
IR spectrum (methylene ohloride). NM2 ~390 ~ 34gO cm 1
oc~3 2830 ~ 2960 cm 1
CN 2210 cm 1
aromatb c=c 1620 cm 1
W spectrum (ethanol): ~ max. 221 nm (0.53)
244 ~m (shoulder; 0.1)
330 nm (broad; 0.07)
15 Example ~ 5L~
N- ~ -(4-hmino-3-bromo-5-c7ano-phenyl)-ethy ~ -Nw ~(4 metho~y-
phenyl)butyl7 n-propylamine
Prepared analogou~ly to Example 9 from 1-ethox~carbonyloxy-
1-(4-amino-3-bromo-5-cyano-phenyl)-2~ (4-metho~y-phe~yl)-
20 bu-tyl7-n-propylamin ~ ethane and sodium borohydride in lsopro-
panol. Oil.
IR spectrum (methylene chloride): N~I2 3390 + 3490 cm 1
CN 2210 cm 1
OCH3 2830 ~ 2950 cm 1
aromat. C=C 1620 cm
UV spectrum (ethanol): ~ max. 222 r~ (0.46)
244 nm (~houlder; 0.08)
3~0 nm ~broad; O.05)
- 97 -
F.~ple 155
N~ 4-Amino~3~bromo-5~cya~o-phenyl)~e-~hy ~N-(4-phe~yl-
butyl)~methyla~i~e
Pr~par~ a~alogously to Example 9 from 1=ethog~carbo~ylo~y-
1~(4-a~ino-3 bromo-5~cy~o phenyl)-2~N~(4-phe~yl~butyl3-
~ethylamin ~ etha~0 a~d ~odiu~ boroh~dride i~ isopropanol. Oil,
NMR spectrum (CDC13): aro~at~ ~ 7.0 - 704 ppm (m, 7H)
~ 3 2.2 ppm (8, 3~)
aliphat. ~ 1.3 2.7 ppm ~m, 12H)
~amPle 156
N- ~ -(4-Amino~3~cyauo~5-~luoro~phenyl)~2thyl7-N- ~-(4 ~eth
o~y-phen~ eth~l7methyla~i~e
Prcpared analogously to ~ample 9 ~rom 1~etho~ycarbonylo~y-
1-(4-amino-3 cyano~5-~luoro-phe~yl)-2- ~ - ~ ~4-methoxy-phe~yl)~
ethyl7methyla~ino7ethane and ~odi~m borohydride i~ isopropanol.
Oiï .
~MR pec-tr~m (CDC13/C~OD)o aroma-t. H 6,7 712 pp~ (m, 6~)
OCH3 3~75 pp~ (3 9 3~)
NCH3 2.3 pp~ (~, 3H)
aliphat. ~ 2~4 - 2.7 pp~ (m, 8H)
E~ample ~57
N- ~ -(4~Ami~o-3-cya~o~5~1uoro-phenyl)-ethy ~ ~ (4-methoxy-
phen~ propyl7methylamine hydrochloride
Prepared analogously to Example 9 from 1-ethoxycarbo~ylo~-
1-~4 amino-3-cyano--5-fluoro-phenyl)-2- ~ - ~ -(4-metho~y-phenyl)-
prop~l,7m~thylamin ~ e-thane ~nd sodium borohydride in isopropanolr
~rdrochloride as resin.
3~
-- 9~3 --
NPqR spectrum (C1~13)~ aromat. E~ 6.7 7.2 ppm (m, 6~)
OC~; 3.75 pp~ , 3~I)
~CH3 2 0 8 pp~ ( 8 ~ 3~ )
aliphat. ~I 1 0 5 ~ 3. 5 pp~ (m, 10~)
5 Example 158
N~ (4~ o-3~cyano~5~fluoro~pheIlyl)-ethyl7~ ( 4 methoxy-
phen~ but~17methylamine
Prepared a~alo~sou~ly to E:s~ample 9 from 1-etho:~rcarbo2lylo~:y
1-(4-a~ o-3 c~ o-5-~lucro-phenyl)-2-~ L~- (4-methoxy-phen~rl)
10 buty~7methylami~37e tha~e a:nd 30dium borohydride in i~opropanol.
Resin .
N~ spec~um (CI~C13/D20): aromat. ~I 7.2 ppm (s, 2H)
6.85 ppm (q, 4H)
OCH~5 3 . 8 ppla ( s, 3H )
NC~3 ~^~5 l?Pm (s, 3H)
ali:phatO ~ 1 n 5 ~ 2~7 ppm ~(m, 12~I)
Example 159
N~ ~ -(4-Amino-~-chloro-5--tri~luoromethyl-phenyl)-~thy ~-
N-/~ (4-metho~y-phe~yl)~butyl7meth~1ami~e
Prepared analogou~ly to Example 9 ~rom 1-et~o~ycarbonylo~y~
1~(4-amino-~-chloro-5-tri~l~oromethyl-phenyl)-2-~N- ~-(4-meth-
oxy phenyl)-butyl7methyla~i~o7etha~e a~d sodium borohydride
in isopropa~ol.
.p.: 29C
~2~3~
-- '39 --
Ex~m~le 160
N~ ~ (4~A~ino~3~chloro~5~tri~1uorom~thyl~phe~yl)-ethy ~ -
N~ (4~methox~phe~yl~thyl7meth~1amiue
Prepared an~logou~ly to Example 9 ~rom 1 etho~ycarbonyloxy~
5 1-(4-amino~3-chloro-5~tri~1uo20me-thyl-phenyl)-2~ (4-~eth-
o~y phenyl)~e-thyl7methylami~o7ethane ~d ~od.ium borohydride in
isopropa~ol. Re~i~.
IR spectrum (m~thylene chloride)~ N~2 3400 -~ 3500 cm 1
OCH3 2840 + 2~So cm 1
lo aroma-t. C~C 1610 cm ~
W ~pec-tru~ (eth~ol): ~ ~ax. 228 nm (shoulder; 0010)
2L~ n~ (0,~0)
~10 ~m (0.03)
E~ample 161
15 N~ 4~Ami~o-3,5-dichloro-phe~yl) ethyl7~ 3-(4~luoro ~henyl)-
prop~,rl7meth~1 amine
Prepared analogou~ly to Example g from l-etho~ycarbonyloxy-
1 (4~amino-3,5-dichloro-phenyl)-2- ~ - ~ ~(4~1uoro-phe~yl) -propyl7-
methylamin ~ ethane a~d sodium borohydride in isopropanol. Oil.
IR spectrum (me-thylene chloride ) ~ NH2 3390 ~ 3490 cm
W spectr~ (ethanol): ~ ma~. 243 nm (0.13)
300 Ilm (O~03)
Example 162
1-(4-Amirlo-3-tri~luoromethyl-phenyl)-2~ (4-~ethoxy-
25 phenyl)-propyl7me-thylami~o7ethanol
Prepared analogously to Example 11 ~rom 1-(4--amino-3-bromo-5-tri-
~luoro~e-thylphenyl ) -2-LN-~- (4~metho~y phenyl)~propy ~ methyl-
amino7ethano:L and hyclrogen in the presence o~ palladium oxide
-- 100 -
on b~ium sulfat~ i~ methanol. Oil.
N~ ~pec-trum (CDCl~/D~0): aro~At~ H 6r 6 ~ 7~ 3 pp~ (m9 7~)
C~0~ 4,5 pp~ (t, 1~)
0~ 3-7 PP~ 3~)
~3 ~-~ PP~
alipha-t. H 202 - 2.7 ppm (m, 6H)
c~2~ ~8 pp~ (q, 2~)
Example 163
N- ~ (4-Acetamino-3 9 5~dichloro-phenyl)~propy~7~N~ ~ (3,4-di~
lO metho~y-phe~Yl)~ethYl~me~th~lamine
Prepared analogously to Example 12 from N~ ~(4~amino-3,5-dichloro-
phenyl)-propyl7-N- ~-(3,4~-dime-thoxy phenyl)-ethy ~methylami~e,
acetyl chlonde and triethyla~ine ln toluene. Oil,
IR spectru~ (m~thylene chloride)~ N~ 34Q5 cm
0~ 2830 ~ 2940 cm~~
C0 1700 cm
UV spectru~ ~ethanol~ ~ max. 228 ~m (shoulder; 0.17)
.2~0 ~m (0.04)
E~ample 164
20 1~(4 Annino~335 dich:loro-phen~l) 2 ~-L~ (4-hyclroxy-phenyl)-
1-meth~l-Propyl7allylamino7ethanol
Prepared analogou~ly to Example 13 ~rom 1~(4~airlo-3"5-di-
chloro-phenyl~2~ (4-hydroxy-phenyl)~1~methyl-propyl7-
amin ~ ethanol with ~llYl bromicle/sodium carbo~ate in absolute
25 ethanol. Oil.
IR spectrum (methylene chloride ): OH ~580 cm
NE12 3390 ~ 3480 cm 1
alipha-t. CH~ 1850 +~ 2930 cm
C~C 1615 cm 1
~2~i3~
-- :1 01 -
W ~p~ctrum (ethanol)o ~ ma~O 243 ~ (0.26)
282 nm (0.08)
300 nm (0.08)
(Ethanol ~ KOI~ max. 24~ ~m (0.47)
2~8 ~m (0.19
Example 165
I-(4~Ami~o 3 9 5 dichloro-phenyl)~2- ~ ~ (4~hydro~y-phe~yl)-
propyl7isopropylamino7etha~ol h~drochloride
Prep~red ~nalogously to Example 16 from 1 (4~amino-3l5-di-
lO chloro-phenyl)-2~ (4~be~zylo~y phenyl)~propy ~ i~opropyl-
ami~ ~ etha~ol a~d hydrogen in the prese~ce o~ palladium on
charcoal.
M.p. o~ the hydrochloride: 90 - 110C.
Example 166
15 1-(4-~mino-3-chloro-phenyl)-2~ hydro~y-phenyl ~-propyl7
ethylamino7e-thanol
Prepared analogou~ly to F~ample 16 ~rom 1 (4-amino-3,5 dichloro-
phenyl)~2- ~-L3-(4-benzylo~y-phe~yl~ propy ~ ~-thylamin ~ etha~ol
and hydrogen i~ the presence o~ palladium o~ charcoal. Re~in.
20 IR ~pectrum (methylene chloride)- OH 3595 cm
N~I2 3400 -~ 3490 cm 1
aliphat. C~ 2840 ~ 2940 c~
C=C 1625 cm 1
UV spectrum (ethanvl)- ~ ma~. 227 nm (0019)
244 ~m (0.17~
290 ~ (0.0~)
(Ethanol -~ KO~ max. 243 nm (O.32)
297 nm (0.08)
JL~ Z~36
- 1.(!2 -
Ex~ple 167
1~(4-Amino~3,5~dichloro-phenyl)~2~ (4~hydroxy-phe~yl)-
propyl7eth~1amino7etha~ol
Prepared analogously to Example 16 :f'rom 1-(4-ami~o~3,5-dichloro-
5 phe~yl)-2- ~- ~ (4-be~zyloxy-phenyl)~prop~¦eth~lamino7ethanol
and hydroge~ i~ the prese~e of palladiu~ on charcoal. Re~i~.
IR ~pectrum ~methylene chloride). OH 3590, 3620
3680 c~ 1
N~2 3390 -~ 3480 cm 1
aromat. C=C 1615 cm 1
W ~pectrum (ethanol~o ~ max. 244 ~m (0017)
28~ nm (~06)
200 ~ (0.05)
(E-tha~ol ~ KOH):~ ma~. 243 ~ (0,3l)
298 ~ ~000~)
E:cample 1 68
N~ (4-D~methylam o~3 9 5~dichloro phenyl)~propy~7-N- r -
(4-methox~-phenyl)-propyl7methylamine
Prepared analogou~ly to Example 101 ~rom N- ~ -(4-ami~o-3~5-di-
20 chloro-phenyl)~propy ~-N~ metho~y-phe~yl)-propy_ 7a~i~e,
para~ormaldehyde and sodium ~ya~oborohydride in ethanol. Oil.
IR ~pectrum (methylene chloride): OCH3 2830 ~ 2940 cm
~c~3 2790 cm-
NH2
aromat. C=C 1610 cm 1
MMR spectrum (C~Cl3/D20): aromat. H 7.0 ppm (q, 4H)
7.1 ppm (s, 2H)
. OCH3 3.75 pp~ (~, ~H)
N(C~3~2 2.85 ppm (s, 6~)
aliphat~ H 2.2 2.8 ppm (m,8H)
N~C~ 2.2 ppm (~, 3H)
-CH2- 1.6 - 1.8 ppm (q,4H)
63t~
-- I 03 -~
Exampl~ 1 6
N~L3~ (4~Ami~o~3 j 5~dlch~1.oro~1?henyl )~prop~ 7~ (4~ eths~
phe~yl ) ~propyl 71llethy1a~i:rle
Prepared a1tlalogou~Iy to Exa~pl~ 1 u1 ~rom N~L:3- (4-~ino~3, 5-di-
5 chloro-phenyl ~ - propy17~N ~ ~ 4~rse-l;ho~phe~lyl ) ~propyl7amine,
para.~ormaldehyde and ,~3diU~I/ ClrarlQbOrOh~-yd:~ lde i.n ethanol . Oil .
IR ~pec-krum ~m2-thyl2rle chloride ) ~ NtI~ 3390 ~ 3490 cm 1
I3 2830 ~ 2940 cm 1
aroma t . C=C 1610 cm
UV spectrum (etha~ol): A m~x. 230 nm (~houlder; 0.21 )
~42 .~m ~ O . 10 )
278 ~ Z85 (broad; O . (:)3 )
302 n~n (broad; O . 03 )
Example 1 70
N~ (4~Dimet:tlglamixlo~3 ~ 5~diohloirt) phenyl ) -tsth~l7~ (4~chloro-
phen~:L ~ ~propyl¦~eth~lamine
Prepareà analo~ously to E.~ample 1 0~l fro~l N~ amino~3, 5--di-
¢hloro-phenyl ) ~e-thyl7~ (4~chloro~phe:~yl ) -propyl7amine,
para:Eormaldehyde and ~odiL~ cyanoboroh~dride i~ ethanol. OilD
IR ~pectrum (me-thyle~e chloride), NCH3 2~90 cm
~I2
NH
UV ~pect~tlm ( etha~ol ): ~ max. 273 nm ~broad ; O ~ 04 )
3~
- 1 0~ --
Example 17 1
N~L2~(4~hino~,5-dichloro-phenyl) ethy~7-N L3 (4 chloro-
~hen~ prop~ll7~2-phe~lethvlamine hydrochloride
Px epared analogously to Exa~le 101 ~ro~ N~ ( 4 amino~3, 5-di-
5 chloro-phenyl ~ ethy~7-N~ (4-chloro-phenyl ) p:ropya7amine 9
phenylace taldehyde and sodi~am cyarloborohydride i~ ethalol .
M. p . of the hydrochloride: 158 - 161 C O
E2ample 1 72
M- ~ -(4-Ami~o-3,5-dichloro-phenyl)-ethy ~ N~ ~-(4-methoxy-
1o Phenyl)-b~tyl7ethylamine
Prepar~d analogously to Example 101 from M-L2~ (4-amino ~,5~di-
chloro-phenyl)~ethy ~ -N~ ~-(4-methoxy-phenyl)-buty~7ami~e,
acetaldehyde and sodium cyanoborohydride i~ ethanol. Oil.
IR spectrum (methylene chloride): 05H3 2860 + 29~0 cm 1
~roma-t. C-C 1610 cm 1
W ~pectr~m (ethanol): ~ max. 245 ~m (0~09)
278 nm (0.02)
282 n~ (0.0~)
300 nm (0.01)
20 F.xample 17~
N-~-(4-~mino-3,5-dichloro-phenyl) ethyl7-N-r3-(4~chloro-phenyl)-
propyl7benzwlami~e h~drochloride
Prepared analogously to Example 101 ~rom N-~-(4-amiuo-3,5-di~
chloro-phenyl)-e~hy~-N-~-(4-chloro-phe~yl)-propylamine, benz-
aldehyde a~d sodi~ cyanoborohydri.de in ethanol,
M. P . O.L the hydrochloride: 164 - 168C.
2~6
-- 105 --
Exam~l~ 174
N~ ~ -(4~mino-3,5-dichlQro-phenyl)-ethyl7-N- ~ ~(4~chloro-
phenyl)-~ropyl7isopropylamine
Prepared analogously to Example 101 from N~ ~(4-amino~
5 3,5~dichloro-phe~yl)-ethy ~ -N- ~ -(4-chloro~phenyl)-propy ~ ~
amine, acetone and sodium cya~oborohydride i~ ab olute methanol.
Oil.
IR spectr~m (methylene chloride): NH2
aromat. C~C 1615 cm
10 W spectr~ (ethanol): ~ max. 241 nm (0.13)
300 ~m (0.05)
Example 175
N- ~ -Methyl-2-(4~ami~o 3,5 dichloro-phenyl)~ethyl7-N- ~ -
(4-me-thox~phenyl)-propyl7amine h~drochloride
15 Prepared analogo~sly to E~ample 101 ~rom 1-(4'~amlno-3',5'-di-
chloro-phenyl)-aoetone, 3~(4-methoxyphenyl~~propylamine and
sodium cyanoborohydride in e-thanol.
M.p. of -the hydrochloride: 193 - 195Co
Example 176
20 N~ Amlno-3,5-dichloro-phenyl)-ethy ~N- ~ - ( 4 chloro-phenyl)-
prop~l7-~-propylamine
Prepared analogously to Example 101 ~rom N- ~ -(4-amino-3 7 5-di-
chloro-phenyl)-ethy ~ N-~ -(4-chloro-phenyl)-propy 7a~ine,
propio~aldehyde and sodium cyano~orohydride in ethanol. Oil.
25 IR speotrum (me~hylene chloride): NH 3380 + 3480 cm 1
aromat. C_C 1610 cm
W spectrum (ethanol): ~ max. 242 nm (0.13)
301 nm (0.05)
- 1 ~6 --
F.~am~le 1 77
N ~ (4~.4mino 3, 5~dichlox o pheny~ ethyl/~N~ (4-chloro ~phenyl ) -
prop ~17ethylam:Lne
Prepared analogously to :E3{ample 1 û1 .~`rom N lz- (4~ o-3, 5~
5 chloro-phenyl)-ethy~7~M-L3-(4-chloro~phenyl)-propy;~7amine, acet-
aldehyde and sodium cyanoborohydride ln etha~ol at p~l 6 - 6 l 5.
Oil .
IE~ spectru~ (me thyle~e ohloride ): NH;2 3390 t 3480 cm
aroma-t. C- C 1615 cm 1
UV spectrum (etha~o].)7 ~ Dlax. 242 n~ (0~14)
305 ma (0.04)
Example 1 78
N-,~- (4~mirlo-3 ~ 5~dlchloro-phenyl ) -ethy~J~N-~- (4-metho~
phen~rl )-ethlrl7ethy:Lamine
Prepared analogou~ly -to Example 101 :Erom N- ~(4-amino-3,5-di-
chloro~phenyl)~ethy ~ ~N-~2~(4-met,hoxy phenyl)-ethy ~ ami~e~
acetaldehyde and sodium cyanoborohydride in ethanol. Oil.
lR spectr~m (methylen~ chloride): NH~ 3890 ~ 3480 cm 1
OC~I3 2830 ~ 2940 cm 1
aromat. C--C 1620 cm 1
W spectr~ (ethanol): ~ max. 244 ~m (0.16)
284 ~m (shoulder; O.04)
300 nm ~0.04)
Example 17~
N~ ethyl-2-(4~amino 3,5-dichloro-phenyl)-ethyl7-N- ~ -(4-meth-
oxy-phenyl)-propyl~eth~lami~e
Prepared analogou~ly to Example 101 ~ro~ 1-(4'-amino-3',57-dichloro-
.phenyl)-acetone, 3-(4~metho~y~phenyl)-M-me-thyl~propylamine a~d
~2~ ;3~
- 1.07 -
so~llum cyanoborohydrid~ in ethanol. Oilo
IR SpeCtI~m (methylene chloride)o ~2 3390 + 3480 cm 1
oc~3 2840 + 2940 cm 1
aromatO c~c 1615 c~
5 W ~pectrum (ethanol): ~ maæ. 242 ~m (0,l4)
280 nm (shoulder; 0.04)
~0~ ~n (0.0
E~ampl~ 180
N~ ~-(4~Amino~3,5-dichloro-phe~yl)-ethy ~ -N~(3~phenylpropyl)-
lO isoprop~lamine h~drochloride
Prepared an logously to Example 101 fro~ N- ~ -(4-ami~o-3,5-di-
chloro-pheIlyl)-~thy ~ 3 phe~yl-propylamine, acetone~ ~clecular
sieve 3 ~ ~nd ~od.iu~ cy~oborohydride in absolute ~th2~ol. Foa~.
IR spectrum ~methylene chloride): NH 3390 ~ 3490 cm 1
l5N~ ~ . 2~00 - 2400 ~m 1
W ~pectr~ (ethanol): ~ max. 245 nm (0.12)
~02 ~ (0.04)
Example 181
1-(4~ o-3,5~dichloro-phenyl)-2~ methyl-3-phenyl-propyl)~-
20 methylamino7ethanol h~drochloride
Prepared analogously to Example 101 from 1-(4-amino~3,5-dichloro-
phe~yl)-2~ methyl-3-phenyl-propyl)-ami~ ~ ~thancl, para~orm-
aldehyde and sodium cyanoboro~ydride in ethanol. Oily hydrochlo-
ride.
25 IR spectrum (methylene chloride): NH2 3390 ~ 34gO cm 1
NH ~ 2300 ~ 2400 cm~
OH 35BO c~ 1
UV spectrum (ethanol): ~ max. 245 nm (0.12)
302 nm (0,03)
P~3~
- ~ o~ -
Example ~
1~(4~mirlo~3~5~dichloro-phe~lyl)~2~r~ m~-thyl-3-phe~yl-
pro~ methylami~o7etha~o1. h~drochloride
Prepared a~alogously to Example 101 from 1-(4~ami~o-3,5-di-
5 chlo~o~phenyl)-2 ~ ~ methyl~-phenyl-propylj~ami~ ~ ethanol
para~ormaldehyde and sodium cy~oborohydride i~ a~olute
ethanol.
Mop~ o~ the hydrochloride: l70 173C,
Example 183
10 1~(4-Amino-~,5-dichloro-phenyl)-2 ~ ~ methyl~3-phenyl
propyl)-~ropylami~o7ethanol h~drochloride
Prepared analogously to Example 101 from 1-(4-amino~,5-di-
chloro-phe~yl)-2~ ethyl 3-phenyl-propyl)~a~i~ ~ ethanol,
prvpionald~hyde and ~odium cyanoborohydride. Oily hydro-
l5 ch:Loride.
IR spectrum (methylene chloride): NH2 3390 ~ 3490 c~ 1
NH 2300 - 2400 cm 1
OH 3590 ~ 3680 cm 1
UV spectrum (ethanol): ~ max. 245 nm (0.12)
30~ nm (~.0~)
E~ample 184
N ~ -(4-Amino-3,5-dichloro~phenyl) ethy ~ ~N-(3-phenyl-propyl)-
n-pro~vlamine hydrochloride
Prepared analogously to Example 101 ~rom N-L2- (4-~mino-3 9 5-di-
chloro-phe~yl)-ethylt-3-phenyl~propylamine~ propionaldehyde
and ~o~ium cyanoborohydride in absolute ethanol. Oily hydro-
chloride.
IR spec-tr~ (me~hylene chloride): NH 3390 ~ 3490 cm 1
NH ~ 2300 -- 2400 cm 1
OH 3600 ~ 3650 cm 1
3~
-- ~ o~ --
WV spectrum (e-tha~ol): ~ ma~. 245 r~ (0.-17)
302 ~m (0.05)
Example 185
N- ~ -(4-A~ino-3,5-dichloro-phe~yl)-ethyl7~N-(3~phe~yl)~propyl)-
ethyla~ine hydrochloride
Prepared a~alogously -to Example 101 ~rom N~ ~ ~(4-a~ino 395-di-
chloro-phenyl)-ethy~7-3-phenyl-propylamine, acetaldehyde and
sodium cyanoborohydride i~ absolute eth~ol~ Oily hydro~hlnride.
IR spectrum (methylene chloride): NH~ 3390 ~ 3490 cm 1
N~ 2300 - 2400 cm 1
W spectrum (eth~ol): ~ max, 245 nm (0.123
302 n~ (0.0~)
Example 186
N-L2~(4-~mino~3,5~dichloro~phtnyl)-et~y ~ -N~ me-thyl-3-phenyl-
pro~yl)-ethylamine hydrochloride
Prepared analogously -to Example 101 ~rom N~L2- (4-amino-3,5-di-
chloro-phenyl3-ethyl7-N-(1-methyl-3-phenyl propyl7amine, acet-
aldehyde a~d sodium cyanoborohydride in absolute ethanol. Oily
hydrochloride.
20 IR spectrum (methylene chloride): NH2 3390 ~ 34gO cm
W spectrum (ethanol): ~ max. 243 nm (0.11)
300 nm (0.04)
Example 1 87
1-(4-~mino-3,5-dichloro-phenyl)-2- r -(1~me-thyl-2-phenoxy-e-thyl)-
ethylami~o7etharlol h~drochloride
Prepared analogously to Example 10~ ~rom 1-(4-amino-3,5-dichloro-
phenyl)-2- ~ -(1 methyl-2-phenoxy ethyl)-amin ~ ethanol) acetalde-
3~
J lo
hyde and sodium cya~oborohydride i~ ab~olute e-thanol. Oily
hydroc~lo~ideO
IR ~pectrum (methyle~e chloride): NH 3~90 ~ 3490 cm
N~ ~ 2320 - 2460 cm
OH 360Q ~ 3680 cm 1
W spectrum ~ethanol): ~ max. 248 n~ (0.12)
300 ~ (0.03)
Example 188
1-(4 Ami~o-3-cyano~5-fluoro~phenyl) 2 LR~ 3,4-dimetho~y-
lO phenyl~-ethyl7ethrlami~o7e-than
Prepared analogously to E~mple 101 .~rom t (4-amino~3-cya~o~
5~fluoro-phenyl)~2- ~-L2-(394-dimethoxy~phenyl)~ethy ~ amin ~ -
etha~ol~ acetaldehyde a~d ~odiu~ cy~noborohydride i~ ethanol.
Oil.
15 IR s~ectr~1 (methylene chloride)~ N~2 ~390 ~ 3~90 c~ 1
CN 220~ cm 1
W spectrum (e-thanol): ~ max~ 240 nm (~houlder; 0.16)
280 nm (0.0~)
325 ~m (0.06)
20 Example 189
~ Amino~-chloro~5-~luoro~phe~yl)-2~ (3~4-methylene-
dioxy-phenoxv)-1-me-thyl-ethyl7ethylami~o7ethanol h~drochloride
Prepared a~logously to Example 101 from l-(4-amino-3-chloro-
5~fluoro~phenyl) 2~ (3~4-~ethylenedioxy-phe~oxy)-1-methyl-
25 ethyl7amino7ethanol, acetaldehyde a~d sodium cyanoborohydride
ln absolute ethanol. Olly hydrochloride.
~2~6~6
IR spectrum ~methylene ohlorlde): NH 3390 + 34~0 cm 1
NH ~ 2300 2450 cm 1
OH ~600 ~ 36~0 cm 1
W ~pectrum ~ethanol)~ ~ max~ 243 nm (0.17)
2~7 D~ (O~07
Ex~mple 190
1~(4-Ami~o-3-bromo-5~ oro~phenyl)-2- ~ -(1~methyl~2-phenoxy-
ethyl)-ethylc~mino7ethanol
Prepared ~nalogously to E~ample 101 rom 1~-(4 amino-~ bromo-
10 5-fluoro-phenyl)-2~ methyl-2-phenoxy-ethyl)-amino~ethanol,
acetaldehyde and sodium cya~oborohydride i~ absolute ethanol. Oil.
IR spectrum (methylene chloride): N~2 3390 + 3490 cm 1
UV spectr~m (ethanol)~ x. 240 nm ~0.14)
280 ~ 290 Dm (O003)
15 Examp~e 191
1-(4 Amino~3-cya~o~5-~luoro-p1enyl)-2~ (4-methoxy phenyl)-
propyl7ethylami.no7ethanol hydrochloride
Prepared arlalogously -to Example 101 ~rom 1~ (4 c~mino-3-cyano-
5-fluoro-phenyl)~2~ ~ ~L3-(4-methoxy-phe~yl)-p~opy ~ amin ~ ethanol,
20 acetal~ehyde a~ ~odiwm cya~oborohydride in absolute ethanol.
Oily hydrochloxide.
IR spectr1lm (methy:Lene chloride): NH ~ 3390 + 3490 cm 1
NH 2300 - 2500 cm
CN 2205 cm 1
OH 3590 -~ 3680 cm 1
UV spectr~ (ethanol): ~ max. 248 nm (O.11)
280 n~ (0.03)
320 ~m (0.06)
ar -~ ~
36
- :1]2 -
Exa~lple 192
N- ~ -(4~mino~3,5~dic~10ro~phe~yl)~e~hy~L7 N~ (4-~luoro~
phenyl)~propyl7benzy.l.amix~e h.qdrochloride
Prepared a.nalogously to E~ample 101 ~rom N~ ~ (4-ami~o~395 di-
chloro~phenyl)~ethyl7-N~3-(4~luoro~phenyl)-propy ~ a~i~e9
be~zaldehyde ~.~d sodi~un cyanoborohydride in absolu^te ~tha~ol.
M.p. o~ khe hydrochloride~ 118 - 120C.
E~ample 193
N ~ ~(4-Amino-3,5 dichloro-phenyl) e~thyl7~N~ (4-~luoro
phenyl~-propyl7-rl -propylami~e hydrochloride
Propared arla:Lo~3ously to E:xample 101 from N-~-(4-amino-3,5-di-
chloro~phenyl ) - ethy~J-N ~ (4-~ I.uoro~phe~yl )~propyl7amine,
propionaldeh~de ~nd ~odi~m cyanoborohydride ln ab~olute
ethanol~ -
M.p. of the hydrochloride: 130 - ~33C.
Example 1g4
N- ~ -(4-Amino~3 9 5 d.ichloro~phenyl.~-ethy ~ -N~ ~-(4-~luoro-phe~yl)-
propyl7ethylamine hydrochloride
Prepared a~lalogously to Exa~ple 'l01 ~rom N~ ~ ~(4-amino-3,5-di-
chloro~phenyl)-ethyl7~N~3~(4 fluoro-phenyl)-propyl7amine,
acetaldehydep molecular sieve 3 ~ and sodium cganoborohydride
in ab~;o:! ute methano]. .
M.p. of the h~drochloride: i82 - 184C (decomp.)0
~ '3 ~ D ~
'U~ ~7~
Ll3 -
Exam~le 195
N~L2-(4-Ami~o 3,5~flichloro~phe~yl) ethyl7-N~ (4 fluoro-
phenyl)-propyl7isopropvl-amine hydrochloride
Prepared analogously to E~ample 101 ~rom N ~ ~ (4-amino ~
5 3,5-dichloro-phenyl)-ethy ~ -N- ~ -(4~luoro-phsnyl)-propy ~ -
amine, acetone9 molecular sieve 3 ~ and sodium cyanoborohydri-
de i~ absolute ~ethanol.
M.p. o~ the hydrochloride: 182 - 184C (decomp~),
Example 196
10 1~(4-Amino-3,5~dichlclro-phenyl)-2~ (4~fluoro--phenyl)-
propyl7-2-phenylethyl.amino7ethanol hydrochloride
Prepared analogou~ly to Exa~ple 101 from l~ amino-3 9 5-di-
chloro-phenyl.)-2~ (4-fluoro-phenyl)-propyl7ami~ ~ etha~ol,
phenylacetaldehyde a~d sodium cyanoborohydride i~ ab~olute
15 ethanol. Amorphous hydrochloride.
IR spectrum (methylene chloride): NH 3390 ~ 34gO cm 1
NH ~ 2300 - 2500 cm 1
OH 3590 ~ 3680 cm 1
W spectrum (ethanol): ~ max. 243 nm (0.11)
300 nm (0.04)
Example 197
1-(4-Amino-3,5-dichloro-phe~yl)-2-LR-L3-(4-~luoro-phe~yl)
pro~yl7benz~1amino7etha~ol hydrochloride
Preparecl analogously -to Example 101 from 1~(4-amino-3 9 5-di-
25 chloro-phenyl) 2- ~ - ~ -(4-fluoro-phenyl)-propy ~ amin ~ ethanol 7
benzaldehyde and sodium cyanoborohydride in absolute ethanol.
M.p. o~ the hydrochloride: 132 - 134C (decomp.)~
;3~
Example 19~
1-(4~mi~o 3,5-dichloro-phenyl)-2~r~ (4-fluoro-phe~yl)-
pro~yl7~n-propylamino7ethanol hydrochloride
Prepared analogously to E~ample 101 from 1-(4-amino-3,5-di-
5 chloro-phenyl)-2~ 3~(4 fluoro-phenyl)-propy ~ ami~o7~tha~ol,
propionaldehyde a~d sod1um cya~oborohydride in absolute
etha~ol.
M.p. o~ the hydrochloride: 136 - 13~C (decomp.).
E~ample 199
1o 1-(4-Ami~o-3,5-dichloro-phenyl)-2- ~ - ~ -(4-~luoro-phe~yl)-
pro~yl7ethylamino7ethanol h~drochloride
Prepared a~alogou31y to Example 101 from 1~(4-amino-3,5-dichloro
phenyl)-2- ~ - ~-(4-~luoro-phenyl) propy ~ amin ~ ethanol, acet-
aldehyde and sodium cyanoborohydride in absolute etha~ol.
15 M.p. o~ the hydrochloride~ 130 - 134C.
Example 200
1-(4-Amino-3,5-dichloro-phenyl)-2~ ~ -(3~phenyl-propyl)-2 phenyl-
ethylamino7ethanol hydrochloride
Prepared analogously to Example 101 ~rom 1-(4-ami~o-3 9 5-dichloro-
20 phe~yl)-2- ~ ~(3-phenyl~propyl~-amin ~ e-thanol, phenylacetaldehyde
and sodium cyanoborohydride in absolute e-thanol~ Amorphous hydro-
chloride.
IR spec-trum (methylene chloride): NH 3390 ~ 3490 cm 1
26~ 2300 - 250' cm 1
OH 3590 ~ 3690 cm 1
UV spectrum ~ethanol): ~ max. 243 nm (0.12)
300 nm (0004)
;3~
Example 201
1-(4-~mino~3,5~dichloro~phenyl)-2~ (4~fluoro-phenyl)~
propyl7isopropvlamino7eth~nol hydrochlorids
Prepared a~alogou~ly to Example 101 ~rom 1-~4~amino-3,5-di-
chlora~phenyl)-2~ ~ (4-fluoro phenyl)-propy ~ amin ~ ethanol
acetone, molecular sie~e 3 ~ and sodi~m cyanoborohydride $~
absolute methanol~
M.p~ o~ the hydrochloride: 80 - 85C (decomp.)~
Example 202
1o 1-(4~Ami~o~,5~dichloro-phenyl)-2~ methyl-~phe~yl ~ropyl)~
ethylamino7ethanol
Prepared ~alogou~ly to E~ample 101 ~rom 1~4~a~i~o-395~
chloro-phenyl)-2~ methyl-3~phenyl~propyl)~amino7ethanol,
acetaldehyde, molecular ~ieve 3 ~ and sodium cyanoborohydride
l5 in absolute ethanol. Oil.
IR spectr~m (methyle~e chloride) NH2 3390 + 3490 cm 1
UV spectrum (ethanol): ~ ma~O 245 nm (0.13)
300 nm (0.03)
E~ample 203
1-(4-Dimethylamino-~,5~dichloro-phenyl)-2- ~-(3-phenyl-1-methyl-
propyl)-methyl~mino7ethanol
Prepared analogou~ly to Example 101 ~rom 1-(4~a~s-3,5-di-
chloro-phenyl)-2~lN-(3-phenyl~1-methyl prop~ ami~ ~ ethanol,
formaldehyde and sodium cyanoborohydride ln absolute ~thanol,
Oi~.
IR spectrum (methylene chloride): OH 3600 + 3680 cm 1
N-alkyl 2800 cm
UV spectr~m (ethanol): ~ max. 275 nm (0.03)
2~i3~
- ]16 -
E~ample ?04
1~(4-~mino-375-dichloro~phenyl~-2- ~ ~(3-phenyl prop~yl)-
b~zyla~ino7etha~ol
Prepared a~alogously to Example 101 ~ro~ 1-(4~amino-3,5-di-
5 chloro-phenyl) 2~ ~-(3~phenyl-propyl) ~min ~ etha~ol, benæaldehyde
and sodium cqanoborohydride i~ absolute ethanol. Oil.
IR 3pec-trum (methylene chloride)~ ~2 ~3gO ~ 3490 cm 1
o~ 3600 + 3680 c~9
~V ~pectr~ (etha~ol) ~ ~ax. 245 .nm (0012)
300 ~m (0~03)
E~ample 205
1-(4-Ami~o~3,5-dichloro~p.henyl)-2 ~ ~ ~ ~(4-methylsul~i~yl-phenyl)-
propyl7amino7ethanol
1 . 5 g (0 0 0039 mol ) o~ (4-amino 3, 5~dichloro~pharlyl )-2~
15 (4-methylsul~er~ylpherLyl )~propy~7amino7ethallol and 639 mg
(0.0078 mol~ O:e anhydrous sodium acetate wer~ dissolved in 60 ml
oî 50 % acetic acid~ A solution o:e 622 mg (0. 0039 mol ) o~ bromine
in 3 ml of 50 % acetic acid was dropped slowly into -this solution
whilst st~rri~g at room temperature. ~he~ the addition was ~irli~hed
20 the llght-hrowrl solution was allowed tos tand for 1 lhour at room
temperature and the~ wa~ poured into water. The reac-tion mi~ture
was bas:ified w:ith c~ nonia up to pH 8.5 whils-t cooling
with ice and exhaustively e~ctracted with methylene chloride. The
combiI1ed methylene chlor.ide extracts were dried over sodium sul-
2s ~ate and in vacuo evaporalted to dr~ness. The residue wa~ re-
crystallized fro~ meth~nol/e-ther. Colourle~s cry~tals.
M~p.: i27 - 129C~
3~
:LI ~
Example 206
1~(4-~mi~o~3 9 S~diohloro-phenyl) 2~ ~ -L~-(4-~ethyl~ulfe~yl-
phenyl )-prop~17am.ino7ethanol
Pr~pared aaalogous~y to E~mple 5 from 4'-amino~3'95'-dichloro-
5 acetoph~no~e, selenium diox.ide~ 3 (4-~ethyl3ul~enylphenyl)~
propylami~e ~nd sodium bQrohydride.
M.p.: 128 - 130Co
E~ample 207
1 (4-A~ o-3,5 dichloro-phenyl)-2- ~ - ~-(4 ~thylsul~lnyl-
10 phen~ prop~17~eth~1ami~o7ethanol
Prepared a~alogously to Example 101 ~rom 1-~4 a~i~o~3,5-dichloro-
phenyl)-2~ ~-L~ (4-methylsul~in~1-phe~yl) propyl7a~i~o7~ -
ethanol, parafor~aldehyde and sodium cya~oborohydride ln methanol O
Foam.
15 IR ~pec-trum (methylene chlorlde): OH 3660 ~ 3600 cm 1
NH2 3490 ~ 3390 cm
SO 1050 cm~
W ~pect:rum ~etha~ol): ~ max. 242 nm (0.16)
300 nm ~0.03)
20 E~am~le Z08
1-~4 ~mlllo-3 9 5-dichloro phenyl)-2~ (4-methylsul~enyl ph~nyl)-
prcpyl7methylamino7eth~ol
Prepared analogously to Example 101 from 1-(4~ami~o-3,5-dichloro~
phenyl.)~2~ (4~methylsul~enyl-phenyl)-propyl7amin~ethanol,
25 para~ormaldehyde and sodium cyanoborohydride in methanolO Colour-
less oil.
IR spectrum (methylene chloride): OH 3690 ~ 3590 cm 1
N~2 3490 + 3~90 cm 1
36
UV 3p20tr~m (etha~ol~: ~ max~ 245 ~m (0.23)
~95 - 300 ~ (0.04)
E~am~le 209
1~(4 ~mino~3~5 dichloro-phenyl)-2~ ~ - ~ (4~chloro-phe~yl)-
5 propyl7-~-prop~lami~o7ethan
Prepared analogou~ly to ~xample 101 ~rom 1 (4~ o~3,5~di~
chloro-phenyl) 2~ (4 chloro~phenyl)-propyl7ami~ ~ etha~ol,
~pio~ ehyde ~d ~diu~ c~nob~ro~y~rid~ Oil.
IR ~pectrum (m~thylene chloride): N~2 3~90~ 3490 cm 1
aro~at. C=C 1620 cm 1
U~ ~pectrum (ethanol): ~ max. 243 nm (0.13)
3~0 ~m (0.~)
Example 210
1~(4-Dlmet~yla~ino-3,5-dichloro-phenyl)-~-methyl-2 ~ -~ -
l5 (l~-methox~-phen~ prop~l7methylamino7ethanol
Prepar~d analogou~ly to Example 101 ~rom 1-(4~ami~o-~,5-dichloro-
phenyl)-2-methyl 2-L~-L3-(4-metho~y-phenyl)-prop~ ~ amin ~ ethanol~
para~ormaldehyde and sodium cyanoborohydride .in ethanol at pH 3 to
7.50 Oil~
20 IR spec-trum (methylene chloride): OH ~590 cm 1
X10 NH, N~2
aromat. C=C 1610 cm 1
UV spectrum ~etha~ol): ~ max. 243 ~m (0.20)
278 nm (0.0~)
~ ~ p~
- :I l9 --
E~a~pl~ 211
1-(4~Ben2ylamino-3 ? 5-dichloro-phenrl)-2~ ~ ~ ~ (4~ohloro~
phenyl)-propyl7ami~o7etha~ol
Prepared a~alogou~ly to Example 101 ~rom 1-(4-am~o~3,5 di~
5 chloro~phenyl)-2~ ~ ~ (4 chloro-phe~yl)-propyl7amin ~ ethanol,
be~zaldehyde and sodium cya~oborohydride i~ eth~ol.
M.p. o~ the base: 85 -- 95C.
E~ample 212
1-(4-Amino-3,5~dichloro~phe~yl) 2~ (4~chloro-phe~yl)-
lO P~opyl7benzylamino7eth~nol hydrochloride
Prepared anal~gou~ly to Example 101 from 1-(4-amino~3,5-di-
ohloro-phenyl)-2~ (4-chloro~phenyl)~propy ~ ami~ ~ ethanol,
benzaldehyde and sodium cyanoborohydride ln e-tha~ol.
M~po o~ the hydrochloride: 110 - 114~C.
15 Example 213
1-(4~Am1no~3,5-dichloro-phenyl)-2 ~LN-~3- (4-chloro phenyl)-
prop~l7ethylamino7ethanol
Prepared analogously to ~2ample 101 from 1-(4-amino 3,5-dichloro-
phenyl)-2 ~- ~ -(4-chloro-phenyl~propy~7amin ~ ethanol, acet-
20 aldehyde a~d sodil~m cya~oborohydride in ethanolO Oil.
IR spectr~ (methylene chloricle): NH2 33gO, 3490 cm 1
aroma-t. C~C 1620 om 1
W spec~r~ (ethanol): ~ max. 244 nm (0.13)
300 nm (0.04)
36
- 120 -
Example 214
N- ~(4~Ami~o-~,5 dichloro~phenyl) e-thy~7~N-~-(4-chloro-
phenyl)-pro~yl7meth~1a~1ne
Prepared analogcusly to ~ample 101 .~rom N-~(4-amino-3,5-dil
5 chloro-phe~yl)-3-(4--chloro-phenyl)~propylamine, paraformaldehy-
de and sodium cyanoborohydride in methanol~ Oil,
IR ~pectrum (methylene chloride), NH2 3390, 3490 cm 1
aromat. C=C 1615 cm 1
W spec-trum (ethanol): ~ max. 241 nm (0~10)
300 nm (0.04)
E~ample 215
1 (4-Amino~3,5-dichloro=phenyl) ~2-LN=~ L3- (4-chloro-phenyl)-
prop~17~2-phen~lethylamino7ethanol hydrochloride
Prepared ~nalogously to Example 101 from 1-,(4-ami~o-3,5-di-
15 chloro-phenyl)~2~ (4-chloro-phenyl)-propy~7amin ~ethanol,
phenylacetaldehyde and sodium cyanoborohydride in ethanol,
M.p. o~ the hydrochloride: 103 - 10~C (decomp.).
E~ample 216
1-(4-Amino-3,5-dichloro-phenyl)-2-LR~-(4-chloro-phenyl~-propyi7-
~0 methylamino7ethanol hydrochloride
Prepared analogously to Example 101 from 1-(4 ami~o-3 9 5-dichloro-
phe~yl)-2- ~ ~-(4-chloro-phenyl)~propy~amino7ethanol, para-
~ormaldehyde and ~odium cyanoborohydride in ethanol.
M.p. o~ the hydrochloride: 85 - 100C (decomp.).
3~
- 12]. --
Example 217
1-(3-Chloro~4~piperidi~o phe~yl)-2~ 3 (4~methoxy phenyl)-
prop~l7meth~1a~1no7etha~ol h~drochloride
Prepared analogously to E~ample 1 ~rom 3' chloro-4'-piperidino~
5 ~ L3 (4~etho~y~phe~yl)~propyl7~ethylamin ~ acetopheno~e a~d
sodium borohydride i~ methanol. Oily hydrochloride.
IR spectrum (methylene c~loride): OH 3600 cm 1
OC~ 284() c~ 1
~ ~300 2700 cm 1
10 W spectrum (ethanol). ~ max, 258 nm (0.12)
28~ nm (shoulder; O.05)
Example 218
1-(4-Ami~o~3,5-dichloro-pheny~ 2~ (3-me^thoxy-phenyl)
propyl7amino7ethanol
15 Prepared analogously to Example 5 from 4'-a~ino-3'75'-dichloro-
acetophenone, æelenium diox:ide, 3-(3 metho~y-ph0nyl~-propylamine
and sodium borohydride.
~-P.: l24
Example 219
20 1-(4-~ino~3~5-dichloro-phenyl)-2~ t3-methoxy-phenyl)-
prop~17eth~1amino7ethanol
Prepar~d analogou~ly to E~ample 101 ~rom 1-(4~amino-3,5-dichlor~-
phen~yl)-~LN ~-(3-methoxy-ph~nyl)-propy ~ amin ~ ethanol, acet~
aldehyde and ~odi~m cya~loborohydride i~ methanol. Oil.
25 I~ spectrum (methylene chloride)- OH 3580 cm 1
NH? 3490 -~ 3390 cm 1
OCH~ 2830 cm 1
~ 3~
~ 122 -
W spectr~m (eth~ol)~ ~ ma.2. 247 ~m (O.06)
300 ~ ~0~0~)
Example 220
1-(4-Amino-3,5-dichloro~ph~yl)~2- ~ ~ (3-metho~y-phenyl)-
5 prop~l7methyla~i.no7etha~ol
Prepared analogously to Example 101 from 1-(4-amlno-3,5-dichloro
phenyl)~2~ (3-metho~y~phenyl) propy ~ aml~ ~ e~hanol, para-
~ormaldehyde and sodium cyanoborohydride in ~ethanolO Oil.
IR spectrum (methylene chloride)O 0~ 3680 ~ 3620 cm 1
NX~ 3490 + 3390 cm
OCH3 2840 cm
W spectrum (ethanol): ~ max. 246 rLm tO.15)
300 ~ (0,04)
Example 221
l5 1 (3,5-Dichloro~4~lsopropyl~mino-ph~nyl)~2~ (3~metho~y-
phenyl~-propyl7isopropylamino7ethanol
Prepared analogously to Example 101 from 1-(4-ami~o ~,5-di-
chloro~phcnyl)_2~ (3-metho~y~phenyl)-propy ~ amin ~ ethanol~
aceto~e and sodium cya~oborohydride in mçth~nol, Oil.
20 IR spectrum (methylene chloride): OH 3600 cm 1
NH 3350 cm 1
OCH3 2840 cm 1
UV spectrum (etha~ol): ~ max. 250 ~m (0.12)
278 ~ 280 nm (0,03)
.~u~63~
- 1~3 -
Example 222
1-(4-~mi.no-3,5-dichloro-phonyl) -2~r~- (4-chlorophenyl)-
propyl7i~opropylamino7ethanol
Prepared a~alogously to Example 10l ~rom 1-(4~amino-3,5-di-
5 chloro-phenyl) 2 ~ ~ ~(4 chloro-phenyl~-propyl7amin ~ ethanol 9
aceton~ ænd sodium cyanoborohydride in e-tha~ol. oll,
IR ~pectrum (methylene chloride): ~H2 3380 ~ 3480 cm 1
~romatO C=C 1615 cm
NMR spectrum (CDCl3/D20): aromat. ~ 7.0 7.4 ~pm (m,6~)
~CH~0~ 4.4 ppm (dd;1~)
-CH~ ~.0 ppm (dd;1H)
aliphat. CH2 2.3 - 2.7 ppm (m;6H)
1.6 - 2.0 ppm (m;2H)
isopropyl-CH3 0.8 - 1.2 ppm ~dd;6H)
15 Example 223
1--(4-Amino-3 9 5-dichloro~phenyl)-2- ~ ~ ~ ~(4 ~hlorophenyl)-propyl7-
allylamino7ethanol
Prepared analogously -to Example 13 from 1-(4-amino-3,5-dichloro-
phe~yl)~2~ (4-chloro-phellyl)-propy ~ amino7ethanol, allyl
20 bromide and triethylami~e. Oil.
IR spectr~ (methylene c~hloride)- NH2 3380 ~ 3480 cm 1
aromat. C=C 1610 cm 1
NMR spec.trum (CDCl3/D~O): aromat. H 7.0 - 704 ppm (m;6H)
olefinic H 5.5 - 6.1 ppm (~;1H)
5~0 - 5.3 ppm (m; 2H)
~CH-OH 4.3 - 4.'7 ppm (dd;1H)
` N-CH2- 2.8 - ~.5 ppm (m; 2H)
aliphat. CH2 232 - 2.7 ppm (m; 6H)
1.5 - 2.0 ppm (m; 2H)
~2~i;3~
-- l 2~ --
Example 224
N~- (4 Aml~o~ ~, 5~dic31loro~phenyl )~ethyl7~N~ (4-chloro-
phexlyl ) ~propyl7allylarniIle
Prepared analo~;ous1.y to F~cample 13 ~rom M~.2~(4~mino~3,5-di-
5 chloro-phenyl) eth~ 3- (4~c.hlorophe~yl) propyla~ e 9 allyl
bro~ide axld triet;hylami.neO Oil.
IR spec-trum (methylene chloride)- NH2 3380 ~ 34ao cm 1
aromat. C=C 1610 cm
N~ spectrum ~CDCl3/D20): aromat. H 6.9- 7.4 ppm (m; 6~I)
olefi~ic H 5. 6 - 6.1 ppm ~m; 1H)
5.0 - 5.3 ppm (m;~H)
~N-CH2~ 3.0 - 3.3 ppm (d; 2~I)
aliphat. CH2 2.7 - 3.3 ppm (m; 8H3
1 ~ 3 ~ 1 . 9 ppm (m; 2H)
l5~ Example 225
M-~- (4-Amino-~, 5-d:Lchloro-pherlyl ) -1 -methyl-ethy~7-N~ (4-methoxy-
phenyl ) -bll t;yl7methylamine
Prepared a~alogously to Example 101 from 4~-aDrlino-3 ~ ~ 5'-dichl-oro-
propiopheno~e, N~ ~ ~(4~me-thoxy~phenyl)-bu-ty ~ methylamine and
sodium cyanoborohy~ride~ Oil~
IR ~pectr~ (methylene chloride): NH2 33S0 ~ 3480 cm 1
aromat CYC 1610 cm 1
W spectrum (e-tha~ol): ~ max~ 245 ~m (0.13)
280 nm (broad 7 0, o4 )
300 ~m (broad; 0.04)
~2C~ 3~
~ 1 25 -
Exam~le 226
N~2~(4~Amino~ 5~dichlQro-phenyl)-ethy~7~N ~ methoxy-
phenyl ) ~1 me t;h~ prop~rl7{tt~ylami~e
Prepared analogously to Example 1~ ~rom N~ (4~amino = 3, 5-di-
5 chloro~phenyl ) -e-thyl7~ (4-hydro~cy-phe:nyl )-1 ~me-thyl-propy~7-
ethylarnine in tetrah~dro:~uLr~ wi th sodi~ hydroxide 801ution
and dimethyl ~ulfa~e~ The puri~lcation was carried out using
al~nin.i~l oxide ~neut:ral~ acti~i~,y step I) eluted with
ether : petroïeum e-ther ~ 1 : 1 . 5~ ()il .
1 0 Calc .: C 63 . 79 H 7 , 1 4 Cl 1 7 , 9L~ N 7 , 09
Found: 6~ ~1'7 7, 09 17. 90 7~15
Example 227
N-~2~4~Amlno-3,5~dichloro^p~enyl)-ethy~ dimethyl-
~(4~h~droxy~phenyl~-propvl7methylami~e
15 1~8 ~1 (00018 mvl~ O~ p~ridine bor~ne were added dropwise to
a ~olu-tlon of 3 g (0.0075 moL) o~ 1-(4-amino~3~5~dichloro~
phen~fl)-2~ dlmeth~l-3~(4 hydroxy-phe.nyl)-pr~py ~mcthyl-
am.i~ ~ ethanol in 12 nll o~ -trifluoroacetlc acid whil~t stirring
at -10Co After remo~ing -the cooling bath the reaction solution
20 warmsd up to room temperature with.in 30 minutes and was ~ubse-
quently heatecl on the steam bath for 60 minute~. A~ter e~apora-
ting the tri~luoroc-cetic acid in a rotatio~ e~aporator a-t 50C
in vacuo, the evapora-tion resi~ue was mixed with 40 ml of 2 N
sod.ium hydroxi.de sollltion and h~ated for 30 ~inutes at 120C.
25 After cooling the reaction mi~.tur~ was care~ully acidified with
hydrochloric scicl and mi.x~d with concentra~ed ammonia until
basic and subsequen-tly extracted twice with 75 ml
portions of e-ther. The e-ther eXt:x~cts obtained were washed twice
with each 50 ml o.~ water~ after combination dried with mag
30 nesium sul~`ate, and in vacuo in a rota-tion evaporator evapora-
ted to dr~ness~ The evaporation residue was first purifiedover silica gel 60 (Macherey and Nagel
~ "'P~ ~
~:~
-- ] 2 6
70 ~ 2~0 me~h 9 AS~ elue~ m~-~hylene chlorido/metha~o:L
~ 2 o 1. The fillal p~ ica-tion was carried out uslng aluminlum
o~ide (neu-kral, actlYity step ITI ) . The elue~lt used wa~ ether/
n~he:~a:rle ~ A.~te:r ~ ~hort tim~ the oily evaporat.ion re-
5 ~idue crys-tallized~
.p.~ 2 1~4C~
E~ample 2~s
N-~ (4~Am.i.no~3 ~ 5~dichlo:ro~phe:~yl )~ethy~7~N~ hyd:rox~
phenyl ) ~1 -methyl~prop~l7eth~ ine
10 Prepa:red ~a:l.ogou~ly to Example 227 :Erom 4 ~ ~amino-2-bromo-
3' ,5'~dichloro~acetophenone~ N-~-(4 hydro~y phenyl)-1-
methyl-propy~7ethylaminel sodium carbonate 1~L aqueou~ tetra-
hydrofura~ and subseq~ent reac~ion G~ the obtai~ed reaction
prodllct wi-th pyrid.ine~borane in trifluoroacetio acld. The
15 puri~ica-tion ~ earried Ollt over alumi.nlum oxide (~eutral,
acti.v.i ty s-tep III ~ . Elue:~?:t o ether/petro].eum ether - 2 ~ 1 .
. Oi:L~
IR spec tr~ (methylene chlori.de ): O~I 3590 cm
NH2 3480 ~ 3390 cm
2 0 CH 7, CEI3 2960 ~ 29~0
~ 2860 cm 1
N-alkyl 2810 c~ 1
C=C 1585 ~ 1510
-~ 1485 cm 1
W spectrum (ethano~ max. 241 nm (0. 28 ~hou:lder)
280 - 302 ~ O.08)
(Etha~ol -~ KOH): ~ max. 241 nm (0. 5~)
298 nm to. 17)
Example 2Z9
30 1-(4~Amillo~3,5 dichloro~phenyl)-2~ dimethyl-3-(4-hydroxy-
pheng~ pro~yl~ne thylamino7e~hanol
Prepared analogou:3ly to ~x~ple 3 ~rom 4 '-amino-2-bromo~3 ',
i3~
- ~27 -
5'-dichloro-aoetophenone, N~ dimethyl-3-(4-hydroxy-phenyl)-
propyl7methylami~c, sodium carbonate a~d subsequent re~ctlo~
~ith sod~um borohydride in aqueou~ tetrahydro~uran. The two
purificatlon stages were carried out using si~ica gel 60
5 (Macherey and Nagel, 70 - 230 me~h, ASTM). Eluents ether/
tetrahydrofuran = 3 ~ t~len methylene chloride/ meth~nol /
co~c. ammonia = 30 : 1 : 0~3.
M.p.: 155 - 15~C.
Exam~l~ 230
10 1-(4-Amino-3,5-dich10ro-phenyl)-2- ~ ~ ,1-dimethyl-3-
(4-hydroxy-phenyl)-prop~l7amino7ethanol
Prepared analogously to Example 2 from 4'-ami~o-2-bromo-3',
5'~dichloro-acetopheno~e, 1,1-dimethyl-3-(4-hydroxy-phenyl)-
propy]amine, sodi~ carbonate and reduc+ion with sodium boro-
15 hydride in aqueous tetrahydro~uran. The purification wa~ carriedout ~sln~J ~ ca gel 60 (~ac~erey and Nag~l7 70 - 2~0 mesh, ASTM).
Rluerlt: a mixtule of methylene chloride/methanol/conc. ammonia
= 25 o 1 : 0.2.
M.p.: 142 ~ 144C.
20ExamPle ~31
N- ~ -(4-Chlorophe~yl)-propy ~ -N- ~ -(3,5-dichloro~4-isopropyl-
amino~henyl)-ethyl7isopropyla~ine
Prepared analogou~ly to ~xample 101 ~rom N- ~ -(4-amino-3,5-di-
chlorophenyl)-ethyl7- ~ (4-chloro-phenyl)-propyl7amine, acetone
25and ~odi~ cyanoborohydride. Oil.
NMR spec-tr~ (CDCl3): aromat. H 7 7.~ ppm (m; 6H)
~CH- 3.5 - 4.1 ppm (m; 1H)
~CH- approx. 3 ppm (m; 1H)
alipha-t. H 2.3 - 2.7 ppm (m; 8H~
1.5 - 2.0 ppm (m; ZH)
0.9 - 1.3 ppm (dd, 12H)
.. ~
.,
2~;~6
l28 -
Example 232
N~2-(4-Amino-3~5-dlchloro-~phenyl)-ethy-7-N~ methyl-3
phenyl-pro~yl~-meth~lamin~
Prepared analogously to Example 101 from N- ~ -(4-amino-
3,5-dichloro-phenyl)-ethy ~ ~ methyl-3-phenyl-propyl)-
amine, paraformaldehyde and sodium cyanohoro~ydride. Oily
hydrochloride.
IR-spectrum (methylene chloride): N~2 3390 + 3490 cm 1
CH2 2930 cm
UV-spectrum (ethanol). ~ max. 243 nm (0.12)
300 nm (0.04)
Example 233
N-~- ( 4-Amlno~3,5-dichloro phenyl)-ethy ~ -N-(1-methyl-3-
phenyl-proDyl) n-propylamine
Prepared analogously to ~xample 101 from N-~2- (4-amino-
3,5-dichloro-phenyl)-ethy_7-N-(1-methyl-3-phenyl-propylJ-
~mine, propionaldehyde and sodium cyanoborohydride. Oily
hydrochloride.
IR spectrum (methylene chlorid~): NH2 3390 ~ 3490 cm
CH2 2930 cm 1
W -spectrum (ethanol), ~ max. 245 nm (0.11)
300 nm ~0~04)
,2~
- 129 -
Example A
Tablet~ conta;ning 25 mg o~ 1-(4~amino-3,5-dichloro-ph~nyl)-
2-/N-(4 phenvl-propyl)~2~prop~lamino7ethanol h~drochloride
COMPOSitiOn:
5 1 tablet contains:
Active ingredien-t 25.0 mg
Cor~ starch 30.0 mg
Lac~ose 61.5 mg
Gelatine 3.0 mg
10 Magnesium stearate 0.5 mg
120~0 mg
Method o~ preparation:
The active ingredient, corn starch and lactose were mi~ed,
homogeneously moi~tened with an aqueou~ gelatine solution
and ~ranulated. A~ter drying in a circulating drier and
screening (1.5 ~m ~esh size) the lubricant was mixed thereto.
The mixture thus obtained was pres~ed into tablets.
Form: biplanar with a dividing slot on one side
~nd a ~acet on both sides
20 Diameter~ 7 ~m
Weight: 120 mg.
Example B
Coa-ted tablets cont~ning 10 mg of 1-(4-amino-3,5-dichloro-
phenyl)-2-/R-(3-phen~l-propyl)-2-propylamino7ethanol hydrochloride
1 coated tablet core contains:
Active ingredient 10.0 mg
Corn starch 35.0 mg
Lactose 71.5 mg
Gelatine 3.0 mg
Magnesium stearate 0.5 mg
120.0 mg
63~
-- 130 --
M~thod o~ preparation:
Prepared analogously to Example A~
The mix-ture obtained was pressed into cores, which were then
coat~d with a sugar paste up to a weight o~ 160 mg~ an~ sub~
5 sequently c.oated with pure sugar syrup up to a weight o~
165 mg a~d polished.
Example C
Capsules con-tAin1n~ 20 mg o~ 1-(4-~mino-3,5-dichlororphenyl)-
2-~R-t3-phenyl-propyl)-2-propylamino7e-thanol hydrochloride
lO 1 Capsule con-tains
Ac-tive ingredient 20.0 mg
Lactose pulverized 11400 mg
Corn starch 60.0 mg
Soluble starch 5~0 mg
15 Magnesium stearate 1.O mg
200.0 ~g
Method or preparation-
The active lngredient was homogeneously mixed with the other
aux.iliary products and the mixture ~btained was ~illed into
20 gelatine capsules by means o~ a capsule filling machi~e.
Capsule sho t weigh-t: 200 mg O
6~3~
- 131-
Example D
Drops containing 20 mg/5 ml o~ 1-(4 amino-3,5-dichloro-phe~yl)-
2~N-(3-phenyl-propyl)-2-prop~lamino7ethanol hydrochloride
100 ml of drop solution contain:
5 Active ingredient 0.4 g
Hydroxyethyl cellulose 0015 g
Tartaric acid 0.1 g
Sorbite solution 70 % dry 30.0 g
Glycerine 10.0 g
10 Ben~oic acid 0.15 g
Water distilled ad 100.0 ml
Method of preparation:
The hydroxy~thyl cellulose, a~ well as the benzoic acid and
tartaric acid were dissolved whilst s-tirring in the water
15 hea~ted up to 70C. The solution obtained was cooled to room
tempera-ture and the glycerine and the sorbite solution were
added with stirring. The active ingredient was added at room
temperature, whereby ~tirring was continued until it was comple-
tely dissolved. The r~sultant ~uice wa~ deaerated in vacuo
20 under stirri~g.
Example ~
Suppositories containing 50 mg of 1-(4 amino-3,5-dichloro-phenyl)-
2-/N-(3-phenyl propyl)-2-propylam~no7ethanol h~drochloride
1 Suppository contains:
25 Active ingredien-t 0.05 g
Hard ~at (e.g. Witepsol W 45) 1.65 g
1~70 g
* Tradema rk
- ` '7
- 132 -
Me-thod o~ preparation
The hard fat was melted~ .At 38C the pulverized active ingreW
dien~ was dispersed i~ the melt. The liquid mixture thus for~
med was cooled -to 35C ~d poure~ into slightly pre~cooled suppo-
sitory moulds.
Welght of suppository: 1.7 g.
Example F
Ampoules cont~ining 20 mg of 1-(4~ami.~o-395-dichloro-phenyl)-
2~ (3-phenyl propyl)-2-propyla~ino7ethanol hydrochloride
10 1 Ampoule contains:
Active ingredient 20.0 mg
Citric acid 12.5 mg
Sodi~ monohydroge~l phosphate 37.5 mg
Sorbite 36.5 m~
15 Water for in~ection ad 5.0 ml
Method o.~ preparation:
The active ingredient, citric acid and sodi~ monohydrogen
phosphate and sorbite were successively dlssolved 1~ the ~ater
~or in~ectlon at room temperature.
20 A~ter filllng up ~o the calibration mark the solution was fil-
tered through a m~mbranous filter and ~llled into cleaned and
~terilized ampoules
Sterilisation: 20 minutes at 121C.
