Note: Descriptions are shown in the official language in which they were submitted.
-- 1 --
4-13010/12253/~
Derivatives of 3-amino-1,2-propanediol
The invention relates to novel derivatives of 3-amino-
1,2-propanediol, processes for the manufacture thereof,
pharmaceutical preparations that contain such compounds and
their use for the manufacture of pharmaceuticaI preparations
or as pharmacologically active compounds.
The compounds according to the invention correspond
to the formula
~ Rll OH
~COI~IH2
~J_o_C~I2-c~I-cH2-N-~lk- o ~J
O~I 'I
(I)
-- 2 --
in which
Rll represents polyhydroxy~lower alkyl,
cycloalkyl-lower alkoxy lower alkyl, lower
alkylsulphonylamino bonded in the 4-
position or l-lower alkylcarbamoyl-2-vinyl
bonded in the 4-position, and
alk represents a radical of the formula
-CH -CH - or CH
2 2 1 3
-C~-CH - .
The invention relates also to salts of such compounds.
The radicals and compounds designa~ed '~lower" in the
present description contain preferably up to 7, and espe-
cially up to 4, carbon atoms.
Cycloalkyl has 3 to 7, especially 3 to 5, carbon atoms
AS ring membersO Lower alkyl is, for example, methyl,
ethyl, n-propyl, isopropylt n~butylt isobutyl or tert.-
butyl. Polyhydroxy-lower alkyl can assume any of the
possible positions in the phenyl ring and is, for example,
di- or tri-hydroxy-lower alkyl, such as 1,2-dihydroxy- or
2,3-dihydroxy-lower alkyl, for example 1,2-dihydroxy- or
2,3-dihydroxy-propyl.
Cycloalkyl~lower alkoxy-lower alkyl can substitute
any of the pos~i~le posi~ions in the phenyl ring and is,
for example, cycloalkyl lower alkoxymethyl or 1- or 2-
~cycloalkyl lower alkoxy)-ethyl. Lower alkylsulphonylamino
corresponds to the formula lower alkyl-SO -N(R )-~ in
which R represents hydrogen or lower alkyl, and accord-
ingly represents, for example, ethylsulphonylamino and
espesially methylsulphonylamino, and also N~methyl-methyl-
sulphonylamino, l-lower alkylcarbamoyl-2-vinyl is, for
example, l-ethylcarbamoyl-2-vinyl and especially l-methyl
carbamoyl-2-vinyl.
The phenyl moiety carrying the amide group and the
hydroxy group is bonded to the rest of the molecule in such
a manner ~hat the latter is bonded in the 4-position of
the said phenyl moiety, i.e. in the para-position to the
-- 3 --
amide ~roup, and especially in the 5-position of the said
phenyl moiety (i.e. in the para-position to the hydroxy
group).
The novel compounds may be in the form of their salts,
such as their acid addition salts, and especially in the
form of their pharmaceutically acceptable, non-toxic acid
addition salts. Suitable salts are~ for example, those
with inorganic acids, such as hydrohalic acids, for example
hydrochloric acid or hydrobromic acid, sulphuric acid, or
phosphoric acid, or with organic acids, such as aliphatic,
cycloaliphatic, aromatic or heterocyclic carboxylic or sul-
phonic acids, for example formic, acetic, propionic, suc-
cinic, glycolic, lactic, màlic, tartaric, citric, maleic,
hydroxymaleic, pyruvic, ~umaric, benzoic, 4 aminobenzoic,
anthranilic, 4-hydroxybenzoic, salicylicl embonic, methane-
sulphonic, e~hane~ulphonic, 2-hydroxyethanesulphonic,
ethylenesulphonic, toluenesulphonic, naphthalenesulphonic
or sulphanilic acid, or with other acidic organic sub-
stances, such as ascorbic acid.
The novel compounds have valuable pharmacological
properties. In particular, they act in a specific manner
on ~-adrenergic receptors. This action, which is a property
common to all compounds of the formula I, can be attributed
~o their affinity to these receptors, which manifests itself
as a pure blockade when the inherent stimulating action is
absent or very ~light and as a blockade with simultaneous
ISA, i.e~ intrinsic sympathomimetric activity, when the
inherent stimulating action is slight to moderate.
The compounds of the formula I exhibit a blocking
action on adrenergic ~-receptors with pronounced cardio-
selectivity, which can be detected especially in the case
of those substances which are substituted in the 4-position
of the phenyl ring by lower alkylsulphonylamino, fcr example
methylsulphonylamino, or by l-lower alkylcarbamoyl 2-vinyl,
for example l-methylcarbamoyl-2-vinyl, while those
sub~tances of which the phenyl ring is substituted by
cycloalkyl-lower alkoxy-lower alkyl, for example
cyclopropylmethoxyethyl, have a l~ss pronounced
cardioselectivity. The compounds of the formula I also
effect a blockade of vascular ~-receptors, which can be
detected especially in the case of substances of whlch the
phenyl ring is subs~ituted by polyhydroxy-lower alkyl, for
example 2,3-dihydroxypropyl, or by cycloalkyl-lower alkoxy-
lswer alkyl, for example cyclopropylmethoxyethyl, a more
or less pronounced blockade of tracheal ~-receptors being
observed as an additional action both in the case of those
compounds and in the case of those carrying in the 4-
position of the phenyl ring a lower alkylsulphonylamino
group, for example a methylsulphonylamino group, or a 1-
lower alkylcarbamoyl-2-vinyl group, for example a 1-
methylcarbamoyl-2-vinyl group.
Compounds of the formula I having a polyhydroxy-lower
alkyl group; for example a 2~3-dihydroxypropyl group,
exhibit, furthermore, a more or less pronounced ISA, a
reduction of blood pressure being an additional effect.
This latter action can be de~onstrated also in compounds
having a lower alkylsulphonylamino group, for exampl~ a
me~hylsulphonylamino group9 in the phenyl ring.
The above information relating to pharmacolo~ical
propertieq is based on the results of appropriate pharma-
cological experiments in customary test procedures. Thus,
the novel ~-blocking compounds exhibit inhibition of tachy-
cardia induced by i oproterenQl in the isolated hearts of
guinea pi95 in a concentration range of from approximately
0.001 ~g/ml to approximately 3 ~g/ml, and in narcotised
cats treated beforehand with reserpine in a dosage range
of from approximately 0.001 mg/kg to approximately 10 mg/kg
in the case of intravenous administration~ The blockade
of vascular ~-receptors can be demonstrated in narcotised
cats treated beforehand with reserpine by the inhibition
of vasodilatation induced by isoproterenol in the vascular
region of the Arteria femoralis when adminis~ered intraven~
~-lY~Z'~
ously in a dosage range of from approximately 0.003 mg/kg
to approximately 30 mg/kg.
The blockade of tracheal ~-receptors effected by the
compounds of the formula I can be demonstrated by the
inhibition of relaxation induced by isoprenalin in the
isolated tracheae of guinea pigs in a concentration range
of from approximately 0.001 ~mole/litre to approximately
~mole~litre.
The ISA of the ~-blocking compounds of the formula
I is apparent from the increase in basal heart frequency
in narcotised cats treated beforehand with reserpine an~
can be demonstrated, for example in the case of intravenous
administration of 1-[2-(3-carbamoyl-4-hydroxyphenoxy~-
ethylamino] 3-[2-(2,3-dihydroxypropyl)-phenoxy]-2-propanol
in a dosage range of from approximately 0.001 mg/kg to
approximately 1 mg/kg.
In a dosage range of from approximately 0.03 mg/kg
to approximately 30 mg/kg i.v., the novel ~-blocking
compounds al50 effect a reduction in the arterial blood
pressure in narcotised cats.
The novel compounds of the formula I may accordingly
be used a , to ~ome extent cardioselective, ~-receptor-
~-blockers, for example, for the treatment of heart rhythm
disorders, Angina pectoris and hypertonia.
The compounds of the general formula I may also be
used as valuable intermediates for the manufacture of other
valuable, especially pharmaceutically active, compounds.
The invention relates especially to compounds of the
formula I in which R11 represents di- or tri hydroxy-lower
alkyl, cycloalkyl-lower alkoxy-lower alkyl having up to 4
carbon atoms in the lower alkyl moiety, lower alkylsul-
phonylamino or N-lower alkyl-lower alkylsulphonylamino each
bonded in the 4-position and having up to 4 carbon atoms in
each lower alkyl moiety, or l-lower alkylcarbamoyl-2-vinyl
bonded in the 4-position and having up to 4 carbon atoms
in the lower alkyl moiety, and alk represents a radical of
v~
-- 6 ~
the formula -CH2-C~2- or CH3 , or salts thereof,
-CH-CH2-
especially acid addition salts and more especially pharma-
ceutically acceptable, non-toxic acid addition salts.
The invention relates especially to compounds of the
formula I in which R represents 1,2-dihydroxy- or 2,3-
dihydroxy-lower alkyl, cycloalkyl-lower alkoxymethyl, or
1- or 2-(cycloalkyl-lower alkoxy)-ethyl, lower alkylsul-
phonylamino bonded in the 4-position and having up to 4
ca~bon atoms in the lower alkyl moiety, and wherein R12 is
hydrogen3or 1-ethylcarbamoyl-2-vinyl or l-methylcarbamoyl-
.2-vinyl, each bonded in the 4-position, and alk represents
a radical of the formula -CH2-CH2- or ~H3 , or salts
thereof, expecially acid addition salts and more
especially pharmaceutically acceptable, non-toxic acid
addition salts.
The invention relates especially to compounds of the
formula I in which Rll represents 1,2-dihydroxy- or 2,3-
dihydroxy-lower alkyl having up to 4 carbon atoms, for
example 1,2-dihydroxy~ or 2,3-dihydroxy-propyl, 1- or
2-(cycloalkyl-lower alkoxy)-ethyl having from 3 to 5 carbon
atoms in the cycloalkyl moiety, for example 1- or 2-(cyclo-
propylmethoxy)-ethyl, lower alkylsuIphonylamino bonded in
the 4-position and having up to 4 carbon atoms in the
lower alkyl moiety, and wherein R12 is hydrogen, for
example methylsulphonylamino, or l-methylcarbamoyl-2-vinyl,
and alk represents a radical of the formula -CH2-CH2- or
C~3 , or salts thereof, especially acid addition
-CH-CH2 -
salts and more especially pharmaceutically acceptable, non-
toxic acid addition salts.
~2~2~
The novel compounds of the formula I are prepared
in a manner known ~ e. They may be obtained, for
example, by reacting a compound of the formula
Rll
~ X1 tII)
O-CH2-C~-CH2 Zl
with a compound of the formula
n~
~ CON~2
Z2-alk-0 ~V~
(III~,
in which
one of the groups Z and Z represents a reac~ive
esterified hydroxy group and the other
represents the primary amino group, and
X represent~ hydroxy,
or in which
Xl and Z toge~her represent the epoxy group and
Z represents the primary amino group,
and, if desired, converting a resulting free compound into a
salt or a resulting salt into a free compound and/or, if
desired, separating a resulting isomeric mixture into its
isomers or a resulting racemate into its antipodes.
A reactive esterified hydroxy group Z or Z is
a hydroxy group e~terified by a strong acid, especially
a strong inorganic acid, such as a hydrohalic acid, espe-
- a -
cially hydrochloric, hydrobromic or hydriodic acid, or
sulphuric acid, or by a strong organic acid, especially
a strong organic sulphonic acid, such as an aliphatic or
aromatic sulphonic acid, for example methanesulphonic acid,
4-methylphenylsulphonic acid or 4 bromophenylsulphonic acid,
and i5 especially halogen, for example chlorine, bromine
or iodine, or aliphatically or aromatically substituted
sulphonyloxy, for example methylsulphonyloxy or 4-methyl-
phenylsulphonyloxy.
The above reaction is carried out in a manner known
se, wherein, especially wnen using a starting material
ha~ing a reactive esterified hydroxy group, the reaction
is carried out advantageously in the presence of a basic
medium, such as an inorganic base, for example an alkali
metal or alkaline earth metal carbonate or hydroxide, or
in the presence of an organic basic medium, such as an
alkali metal lower alkoxide, and/or an excess of the basic
reactant, and usually in the presence of a solvent or sol-
vent mixture, and, if necessary, while cooling or heating,
for example in a temperature range of from approximately
o o
-20 C to approximately 150 C, in an open or closed
ve~sel and/or in an inert gas atmosphere, for example a
nitrogen atmosphere.
Starting materials of the formula II are known or
can be prepared in a manner known ~ se.
Starting materials of the formula III may be obtained,
for example, by reacting a hydroxysalicylic amide with a
dihaloalkane corresponding to the meaning of alk, for
example a chloro-bromoalkane or dibromoalkane, in the pre-
sence of an alkaline condensa~ion agent, such as an alkali
carbonate. These reactions are carried out in the customary
manner, protecting groups at the hydroxy groups being
simultaneously or, as described hereinafter, subsequently,
split of~.
The compounds of the formula I may also be Manufac-
tured as follows: in a compound of the formula
_ 9 _
1 0-X4
O--CH2~ 2--N-alk--O ~r ~
X2 X3
(IV),
in which Rll has the meaning of Rll or represents lower
alkylsulphonylamino bonded in the 4~position and substituted
: at the nitrogen atom by a substituent that can be replaced
by hydrogen, X~, X3, X4 and X5 each represents hydrogen or
a substituent that can be replaced by hydrogen, or X2 and
X3 and/or X4 and X5 together represent a divalent radical
that can be replaced by two hydrogen atoms, with the proviso
that at least one of tbe radicals X2, X3, X4 and X5 is
different from hydrogen, or at least Rll represents lower
alkylsulphonylamino bonded in the 4-position and substituted
at the nitrogen atom by a substituent that can be repla~ed
:by hydrogen, or at least X2 and X3 toge~her or X4 and X5
together represent a divalent radical that can be replaced
by two.hydrogen a~oms, or in a salt thereof the 9rOUp5 X2,
X3, X4 and X5, or X2 and X3 toqether and/or X4 and X5
together that are different from hydrogen are split off and
replaced by hydrogen atoms, and/or a substituent that is
pre ent at the nitrogen atom of lower alkylsulphonylamino
R11 bonded in the 4-position and can be replaced by hydro-
gen is replaced by hydrogen and, if desired, the additional
process steps mentioned subsequently to the first process
are carried out.
: The splLtting off of the groups X2, X3r X4 or X5, or
X2 and X3 toge~her and/or X4 and X5 together, and of the
su~stituent present at the nitrogen atom in a 4-lower alkyl-
sulphonylamino group is effected by solvolysis, such as
-- 10 --
hydrolysis, alcoholysis or acidolysis, or by reduction,
including hydrogenolysis.
An especially suitable group X or X that can
be split off, or a protecting group bonded at the ni~rogen
atom in a 4-lower alkylsulphonylamino group, is especially
an -aryl-lowee alkyl group that can be split off by hydro-
genolysis, such as an optionally substituted l-polyphenyl-
lower alkyl group or a l-phenyl-lower alkyl group in which
substituents, especially of the phenyl moiety, may be, for
example, lower alkyl, such as methyl, or lower alkoxy, such
as me~hoxy, and especially benzyl. A group X and espe-
cially X2 and X4 and also a nitrogen protec~ing yroup in a
4-lower alkylsulphonylamino group may also be a radical
that can be split off by solvolysis, such as hydrolysis or
acidolysis, or also by reduction, including hydrogenolysis,
especially a corresponding acyl radical, such as the acyl
radical of an organic carboxylic acid, for example lower
alkanoyl, such as acetyl, or aroyl, such as benzoyl, the
acyl radical of a semi-ester of carbonic acid, such as lower
alkoxycarbonyl, for example methoxycarbonyl, ethoxycarbonyl
or tert.-butoxycarbonyl, 2-halo-lower alkoxycarbonyl, for
example 2,2,2-trichloroethoxycarbonyl or 2-iodoethoxycar-
bonyl, optionally substituted l-phenyl-lower alkoxycarbonyl,
for example benzyloxycarbonyl or diphenylmethoxycarbonyl,
or aroylmethoxycarbonyl, for example phenacyloxycarbonyl,
or an optionally substituted 1 polyphenyl-lower alkyl group
in whioh sub~tituents, especially of the phenyl moiety,
for example have the meaning given above, and represent
especially trityl.
A radical that can be split off and is formed by X
and X3 and/or X4 and X5 together is especially a group
that can be split off by hydrogenolysis, such as optionally
substituted l-phenyl-lower alkylidene, in which substi-
tuents, especially of the phenyl moiety, may be, for
example, lower alkyl or lower alkoxy, and especially benzyl
idene, and also a group that can be split off by solvolysis,
,',;1 ,41 ~Ar~ObY~?~
~ ~ ~7~ ~
especially by hydrolysis, such as lower alkylidene, for
example methylene or isopropylidene, or l-phenyl-lower
alkylidene of which the phenyl moiety is optionally sub-
stituted by lower alkyl~ such as methyl, or lower alkoxy,
such as methoxy, especially benzylidene, or cycloalkylidene,
for example cyclopentylidene or cyclohexylidene.
Starting materials that may be used in the form of
salts are used especially in the form of acid addition
salts, for example with mineral acids, and with organic
acids.
Radicals X2~ X3~ X4 an~/or X5 that can be split off by
hydrogenolysis, especially optionally substituted l-phenyl
lower alkyl groups, also suitable acyl groups, such as
optionally substituted l-phenyl-lower alkoxycarbonyl, and
optionally substituted l-phenyl-lower alkylidene groups
formed by the groups X2 and X3 and by X and X
together, and also protecting groups of this kind present
at the nitrogen atom in a 4-lower alkylsulphonylamino group,
can be split off by treating with catalytically activated
hydrogen, for example hydrogen in the presence of a nickel
catalyst, such as Raney nickel, or a suitable noble metal
catalyst.
Groups X~, X3, X4 and/or X5 that can be split oEf
by hydrolysis, such as acyl radicals of organic carboxylic
acids, for example lower alkanoyl, and of semi esters of
carbonic acid, for example lower alkoxycarbonyl, also for
example trityl radicals, and also lower alkylidene, 1-
phenyl-lower alkylidene ox cycloalkylidene groups formed
by the radicals X2 and X3 and/or X4 and X5 ~ogether, and
also the ni~rogen-protecting group of this kind present in
a 4-lower alkylsulphonylamino group, may, depending on
the nature of such radicals~ be spli~ of by treating wi~h
water under acidic or basic conditions, for e~ample in the
presence of a mineral acid7 such as hydrochloric acid or
sulphuric acid, or an alkali metal or alkaline earth metal
hydroxide or caebonate, or an amine, such as isopropylamineO
- 12 -
Radicals X2, X3, X~ and/or X5 and/or a nitrogen~
protecting group in a 4-lower alkylsulphonylamino group,
that can be split off by acidolysis are especially certain
acyl radicals or semi esters of carbonic acid, such as,
for example, tert.-lower alkoxycarbonyl or optionally sub-
stituted diphenylmethoxycarbonyl radicals, and also the
tertO lower alkyl radical; such radicals can be split off
by treating with suitable strong organic carboxylic acids,
such as lower alkanecarboxylic acid~ optionally substituted
by halogen, especially fluorine, or especially with tri- -
fluoroacetic acid (if necessary in the presence of an acti-
vating agent~ uch as anisole), and with formic acid.
Radicals X , X , X and/or X and/or a nitro-
2 3 4 5
gen-protecting group in a 4-lower alkylsulphonylamino group,
that can be split of by reduction shall also include those
groups which are split off when treated with a chemical
reducing agent (especially with a reducing metal or a reduc-
ing metal compound)O Such radicals are especially 2-halo-
lower alkoxycarbonyl or arylmethoxycarbonyl, which can be
split off, for example, by treating with a reducing heavy
metal, such as zinc, or with a reducing heavy metal ~alt,
such as a chromium(II) salt, for example chromium chloride
or a etate, usually in the presence of an organic car~oxylic
acid, such as formic acid or acetic acid, and water.
Nitrogen-protecting groups present at the nitrogen
atom in a 4-lower alkylsulphonylamino group Ri1 correspond
to the previously mentioned groups that can be split off
by means of the described methods and replaced by hydrogen,
such groups bein~ split off in the course of the described
process at the same time as other groups or subsequently in
a separate process step.
The above reactions are usually carried out in the
presence of a solvent, or a solvent mixture, wherein suit-
able reactants may also act simultaneou ly as such, and~
if necessary, while cooling or heating, for example in an
open or closed vessel, and/or in the atmosphere of an inert
- 13 -
gas, for example nitrogen.
The starting materials of the formula IV may be
obtained analogously to the process modifi~ations described
above, for exa~ple by treating a compound sf the formula
~Rll
~ OH
or a salt thereof, with a compound of the formula
O - X4
X -CH2 CH-CH2-N-alk- ~ \
X2 X3
(IVa)
in which X2 represents the group X2, wherein at least
one of the gro~ps X3 and X2 is different from hydrogen,
and X represent~ a reactive esterified hydroxy group, or
X2 and X to~ether represent a carbon-oxygen bond, or in
which X3 and X2 together represent a radical that can be
split off and replaced by two hydrogen atoms bonded to the
oxygen and nitrogen atoms, and X represents a reactive
esterified hydroxy group, or by treating a compound of the
formula
- 14
Rll
2 CH CH2 1 (IVb)
oX
with a compsund of the formula
_~4
~ CON
Y2-alk-o ~ \ H
(IVc)
o
in which X~ has the meaning given above for X2, and one
of the groups Y and Y represents a reactive esterified
hydroxy group and th~ other represents the group of the
formula -NH(X3), in which X has the meaning given
above, with the proviso that at least one of the ~roups X3
and X2 is different from hydrogen, or in which, X2 and
Y ~orm an oxygen-carbon bond and Y represents the
group of the formula -NH(X ) and X is different from
hydrogen. Tbe above reactions are carried out in a manner
known ~ se! for example as described under the first
process according to the invention.
Furthermore, the Schiff 15 base ormed by reacting
a compound of the formula
, . . .
- 15 -
R'
-CH2-1 -CH2-~2
~2
(IVd)
with a carbonyl compound of the formula
o-x4
R-O ~ CON \ X5 (IVe3
: ~ ~ in which R represents an alkyl radical corresponding ~o
the alkylene radical alk and containing a carbonyl group-
: ing that is separated from the oxygen atom by a carbon atom,
: and X4 and X5, or X4 and X5 together, represent one of the
: mentioned protecting groups, may be reduced, for example,
: ~ with a borohydride, for example sodium borohydride, to the
~ compound of the formula IV. The reduction can also be
I carried out by means of activated hydrogen in the presence
of a hydrogenation catalyst, for e~ample a platinum-on-
~ carbon catalyst.
: Carbonyl compounds of the formula (IVe) may in turn
: be obtained in the customary manner by reacting a compound
o the formula
.f~
O - X4
HO ~CON~ X5
~ IVf )
with a compound of the formula R-~al (IVg) in which R has
the ~eaning given above and represents~ for example, a halo-
ketone, for example chloroacetone.
The novel compounds of the formul~ I may likewise be
obt~ined as follows: in a compound of the formula
O -- X7
O-CH2 CH-x6_o i~ CO~I2
OX7
(~),
in which X6 is a reducible group of the formula
- CH - N - alk - (Va), or CH - N = alk - (Vb),
wherein alkl repres~nts an alkyl-ylidene radical corres-
ponding to the radical alk, and X represents hydrogen
or a radical that can be replaced by hydrogen under the
conditions for the reduction o~ X , Rll has the meaning
o~ Rl1 or represents lower alkylsulphonylamino bonded in
the 4-position and substituted on the nitrogen atom by a
substituent X7 ~hat can be replaced by hydrogen, wherein X7
has the meaning given abo~e, X always bei~g a reducible
group Va or Vb, this group is reduced, and simultaneously
the group X7 that is different from hydrogen is split
r~
-- 17 --
off and replaced by hydrogen and, if desired, the additional
process steps mentioned subsequently to the first process
are carried out.
A group X that can be split off by hydrogenolysis
is especially an -aryl-lower alkyl group, such as an
optionally substituted l-phenyl~lower alkyl group, in which
substituents of the phenyl moiety may be, for example, lower
alkoxy, such as methoxy, and more especially benzylO
Nitrogen-protecting groups X in a 4-lower alkylsul~
phonylamino group Rl1 correspond to the groups mentioned
previously for X that can be split off by the described
methods and replaced by hydrogen~ wherein such groups are
split off during the course o the described process at
the same time as other groups, or split off subsequently
in a separate process step.
Starting materials of the formula V having a group
X6 f the formula Vb may also be in the isomeric form of
ring tautomers of the formula
~ Ril
~ 2 ~ f-X7
o ~ ~
\ alk / ~ CONH2
(Vd)
in which
alk2 has the meaning of alk and the oxygen
and nitrogen atoms of the ring are bonded
to the same carbon atom.
An alkyl-ylidene group alk is, for example~ methine
or ethylylidene, whilst an alkylidene group alk repre-
sents, for example, methylene, ethylidene or l-methylethyli-
dene.
- 18 -
The reduction of the nitrogen-carbon double bond in
starting materials of the formula V ~hat contain a group
Va or Vb as X , whilst X has the meaning given under
formula V, to form the nitrogen~carbon single bond ca~ be
carried out in a manner known ~ s for example by
treating with catalytically activated hydrogen, such as
hydrogen in the presence of a suitable hydrogenatiGn
catalyst, for example a nickel, platinum or palladium
catalyst, wherein X7 groups that ca~ be split of by
hydrogenolysis are simultaneously split off an~3 replaced
by hydrogen; alternatively, the reaction i5 carried out
with a suitable hydride reducing agent, such as an alkali
metal borohydride, for example sodium borohydride~ When
using a hydride reducing agent, also acyl radicals of
carboxylic acids, such as, for example, acetic acid, that
are bonded to oxygen, may be present as X radicals and
may be split off in the same operation.
A starting material of the formula Y may be prepared
in a manner known ~ se, optionally in situ, that is to
say, under the conditions of the process described. Thus,
a compound of the form~la
~>,/ Ril '
C 2 1 CHo
(Ve)
OH
can be reacted with an amine of the formula
- 19 -
d~CONH2
H2N alk-o ~
(~f)
to form a starting product of the formula Y having the X
group of the formula Va.
By reactin~ a compound of the formula
-cH2-cH CH2-N~2
OH
with a carbonyl compound of the formula
o-x7
~C02~I2
= alkl- ~JJ ( Vi )
starting materials of the formula V havin~ a X group
of ~he formula (Vb) can be obtained . ~ modif ication of
these reactions consists in reacting a dibenzylamino com-
pound corresponding to a compound of ~he formula (Vh) with
- 20 -
the oxo compound of the formula (vi) under the reducing
conditions of the process. In this reaction the reducing
agent used is especially catalytically activated hydrogen,
for example hydrogen in the presence of a heavy metal hydro-
genation catalyst or a mixture thereof, such as a palladium
and/or platinum catalyst. ~nder these reaction conditions,
X groups that can be split off by hydrogenolysis, for
example benzyl groups, are split off, and at the same time
the nitrogen-carbon double bond is reduced to the corres-
ponding nitrogen-carbon single bond.
Oxo compounds of the formula (Vi) may in their turn
be obtained, for example, by reacting a compound of the
formula
~ CON~2
~VX)
with a haloalkanone compound of the above-mentioned formula
R - ~al (IVf), for example chloroacetone, in the presence
of an alkaline condensation agent, for example potassium
carbonate, or an organic base, such as triethylamine.
The novel compounds of the formula I may likewise
be obtained by reacting with ammonia (VII) a compound of
the formula
- 21 -
~ O-C~12-C~ 2-T-zllk-O ~ COO~
OH H
(VI),
in which Rll has the meaning of Rll or represents lower
alkylsulphonylamino bonded in the 4-position and option-
ally substituted at the nitrogen atom by a sub~tituent that
can be spli~ off by ammonolysis and replaced by hydrogen,
X represents hydrogen or a group that can be split off
by ammonolysis, or a reactive derivative of one of the
carboxylic acids defined in formula VI, and at the same
time splitting o~f optionally present radicals X or sub-
stituents present at the nitrogen atom of a 4-lower alkyl-
sulphonylamino group and replacing them by hydrogen and,
if desired, carrying out the additional process s~eps
mentioned subsequently to the first process.
Substituents and radicals X that can be split off
by ammonolysis are acyl radicals of organic carboxylic
acids, for example aroylt such as benzoyl, or lowe
alkanoyl, such as acetyl.
Reactive derivatives of the carboxylic acids defined
in formula ~I are, for example, the halides, such as the
chlorides or bromides, the azides, and also acid anhydrides,
especially mixed acid anhydrides with, for example, lower
alkanecarboxylic acids, such as acetic acid or propionic
acid, or lower alkoxyalkanecarboxylic acids, such as 2-
methoxyacetic acid. Reactive derivatives of carboxylic
acids of the formula VI are especially esters, for example
with lower alkanols, such as methanol, ethanol, isopropanol
or tert.-butanol, also with aryl-lower alkanols, for example
- 22 -
benzyl alcohol optionally substituted by lower alkyl, for
example methyl, or lower alkoxy, for example methoxy, or
with phenols that are optionally activated by suitable sub-
stituents, for example by halogen, for example 4-halo, such
as 4-chloro; lower alkoxy, for example 4-lower alkoxy, such
as 4-methoxy; 4-nitro; or 2,4-dinitro; for example 4-chloro-
phenol, 4-methoxyphenol, 4-nitrophenol or 2,4-dinitrophenol;
furthermore with cycloalkanols such as, for example, cyclo-
pentanol or cyclohexanol, which may optionally be substi-
tuted b~ lower alkyl, for example methyl~ The reaction
is carried out in a manner known ~ se~ usually in the
presence of an inert solvent, for example in a temperature
range of from approximately -10 to 50 C in a closed
vessel.
The starting materials of the formula IV may be
obtained in a manner known ~ by reacting a compound
of the formula (II), in which X and 21 together rPpre-
sent the epoxy group, with an amino compound of the formula
O-X8
~ COOH
H2N alk-O ~
tVIa)
in which X has the meaning already given, or with a
reactive derivative thereof.
The Schiff's base formed by reacting a compound of
the formula
~qæ~ ~
- 23 -
R"
/ 11
CH2--CH--CH2~2
OH ~VIb)
with a carbonyl compound of the formula
o Xp~
~ COOH
R-O ~ (VXc),
in which R represents the alkyl radical corresponding to
an alkylene radical aIk and containing an QX3 radical in
place of the free valency thereof~ may also be reduced with
a borohydride~ for example sodium borohydrideO The reduc-
tion can also be carried out by means of ac~ivated hydrogen
in the presence of a hydrogenation catalyst, for example
a platinum-on~carbon catalyst.
Carbonyl compounds of the formula (VIc) may in turn
be ob~ained in a manner known ~ se by reacting a compound
of the formula
- 2
p Xpj
~ COOH
HO
~/
(VId)
with a compound of the above.described formula
R - ~al (IVg~
in which ~al represents halogen, especially chlorine.
The novel compounds of the formula I may likewise
be obtained a follows: in a compound of the formula
R OH
~ ~C~
-CH~-fH-CH2-~-alk~O
OH E
(VIX),
in which one or all hydroxy groups and/or the secondary
nitrogen atom and/or the nitrogen atom o~ a lower alkyl-
sulphonylamino Rll bonded in the 4-position are option-
ally substituted by those groups that can be split off by
hydrolysis and replaced by hydrogen and which, under the
conditions of the process, are split off and replaced by
hydrogen, the -CN group is conver~ed by hydrolysis in~o
the -CON~ group and, at the same time, protecting groups
optionally present at the nitrogen atom of a lower alkylsul-
.,
- 25 -
phonylamino group bonded in the 4-position and/or at one or
all hydroxy groups and/or at the secondary nitrogen atom
are split off and seplaced by hydrogen and, if desired, the
additional process steps mentioned subsequently to the first
process are carried outO
The above reactions are carried out in a manner known
per se. The hydrolysis is effected in a basic or, advant-
ageously, in an acidic medium, especially in the presence
of concentrated aqueous mineral acid, such as, or example,
concentrated hydrochloric acid, and, if necessary, while
cooling or heating, for example in a temperature range of
from approximately 0 to 60 , preferably from approximately
40-50 , in an open or clo~ed vessel and/or in an inert
gas atmosphere, for example in a nitrogen a~mosphere.
The starting materials of the formula VII may be
obtained, for example, by reacting a compound of the formula
Rll
O-CH2-CH-CH~ NH2
(VII~
wi~h a compound of the formula
~H
~al-alX-o- I Irc~
~ ~VIIb),
~'t3Z2~l
- 26 -
in which Hal represents chlorine, bromine or iodine. The
reaction is advantageously carried out in the presence of
a basic medium in a manner known ~ se.
The compound VIIb may in t~rn be obtained by the
action of acetic anhydride on the oxime corxesponding to
the cyanide. This is expediently carried out by boiling
under reflux. The oxime may in its turn be prepared Erom
the corresponding aldehyde by boiling under reflux with
hydroxylamine hydrochloride in the presence of alcoholic
soda solution. The corresponding aldehyde may in turn be
prepared by reacting 2,4-dih~droxyben~aldehyde with an ~
dihalo-lower alkane, preferably in the presence of a basic
medium. Alternatively, however, a hydroxysalicylonitrile,
for example 2,4-dihydroxybenzonitrile lChem. Ber. 24, 3657
(1891)] or 2,5-dihydroxybenzonitrile (Hclv. Chim. Acta 30,
149, 153 (1947)] may be reacted in an analogous manner with
a non-geminal dihalo-lower alkane to form a compound of
the formula VIIb.
The novel compounds of the formula I, in which R
represents polyhydroxy-lower alkyl, for example 1,2~
dihydroxy- or 2,3-dihydroxy-lower alkyl, such as, for
example, 1,2-dihydroxy- or 2,3-dihydroxy-~ropyl, may be
obtained as follow~: in a compound of the formula
CONH2
2 1 -CH2~N alk-o _
OH
(VIII)
in which Rll represents a polyhydroxy-lower alkyl group,
for example one of those mentioned, wherein at least one
hydroxy group, or two hydroxy groups toyether each of which
- 27 -
is present at one of two adjacent carbon atoms, is or are
protected by a radical that can be split off and replaced
by hydrogen, or in a salt thereof, these protecting groups,
which can be identical or different, and other protecting
groups optionally present at the nitrogen atom and/or at
the oxygen atoms, are split off and replaced by hydrogen
and, if desired, the additional process steps mentioned
subsequently to the first process are carried out. Groups
that can be split off and replaced by hydrogen, for example,
by solvolysis, such as hydrolysis, alcoholysis or acidoly-
sis, or by reduction, including hydrogenolysis, for example
groups that can be split off as described above, are, for
example, the radicals X2 or X4 mentioned above. Radicals
X2 or X4 that can be split of~ by solvolysis, such as hydro-
lysis or acidolysis, are, for example 9 acyl radical~, such
as acyl radicals of organic carboxylic acids, for example
lower alkanoyl~ such as acetyl, or aroyl, such as benzoyl,
also, for example, lower alkoxycarbonyl 7 optionally substi-
tuted l-phenyl-lower alkoxycarbonyl, for example benzyloxy-
car~onyl, also an optionally substituted l-polyphenyl-lower
alkyl group, for example trityl, and furthermore, the tetra-
hydropyranyl radical. Protecting groups for two adjacent
hydroxy groups together are, for example, lower alkylidene,
for example methylene or isopropylidene, or l-phenyl-lower
alkylidene especially benzylidene, of which the phenyl
moiety is optionally substituted by lower alkyl, such as
methyl, or by lower alkoxy such as methoxy, or cycloalkyli-
dene, for example cyclopentylidene or cyclohexylidene, and
also the carbonyl group.
Groups of the type mentioned that can be split off
by hydrolysis, for example acyl radicals of organic carboxy-
lic acids, for example lower alkanoyl radicals~ and also,
for example, lower alkoxycarbonyl or trityl radicals, also
tetrahydropyranyl radicals, lower alkylidene, l-phenyl~
lower alkylidene or cycloalkylidene groups bonded at ~wo
hydroxy groups together, and optionally other protecting
,,
- ~8 -
groups of this type present at the nitrogen atom and/or
at the oxygen atoms may, depending on the nature of such
radicals, be split off by treating with water under acidic
or basic conditions, for example in the presence of a
mineral acid, such as hydrochloric or sulphuric acid, or
of an alkali metal or alkaline earth metal hy-Jroxide or
carbonate~ A carbonyl group present at two adjacent hydroxy
groups together is advantageously split off by means of
basic agents, for example an alkali hydroxide, such
as, for example, potassium hydroxide, or an alkali metal
alcoholate, such as sodium ethoxide or potassium tert.-
butoxide, while, for example, tetrahydropyranyl radicals
are split off by acidic agents, or example as sta~ed.
Radicals that can be split off by acidolysis are, for
example, those mentioned above for X2 and/or X~ and are, for
example, lower alkoxycarbonyl or alternatively tert.~lower
alkyl radicals. Such radicals may be split off, for example
as described above, by treating with suitable strong organic
carboxylic acids, such as lower alkanecarboxylic acids
optionally substituted by halog~n, especially fluorine,
especially with trifluoroacetic acid (if necessary, in the
presence of an activating agent, such as anisole) and with
formic acid. These reactions are carried out in a manner
known ~ se.
An e~pecially suitable hydroxy protecting group that
can be split off by hydrogenolysis is especially an a-aryl-
lower alkyl group that can be split off by hydrogenolysis,
such as an optionally substituted l-polyphenyl-lower alkyl
group or a l-phenyl-lower alkyl group, wherein substituents~
especially of the phenyl moiety, can be, for example, lower
alkyl, such as methyl, or lower alkoxy, such as methoxy,
and especially benzyl. A group that can be split off by
hydrogenolysis and is present at two adjacent hydroxy groups
together is, for example, optionally substituted l-phenyl-
lower alkylidene, wherein substituents, especially of the
phenyl moiety, can be, for example, lower alkyl, such as
- 29 -
methyl, or lower al~oxy, such as methoxyJ and is especially
benzylidene. Groups oE the type mentioned that can be ~plit
off by hydrogenolysis can be split of in customary manner
by treating with catalytically activated hydrogen, for
example with hydrogen in the presence of a nickel catalyst,
such as Raney nickel, or a suitable noble metal catalyst.
Protecting groups that can be split off by reduction
and are present at one or both hydroxy groups are, for
example, those which aEe split off when treated with a
chemical reducing agent, for example as described above,
for example 2-halo-lower alk~xycarbonyl or arylmethoxycar-
bonyl.
The splitting off is effected, for example, by means
of the methods described above, for example by means o~
zinc, or a chromium(II) salt~ or an vrganic carboxylic acid,
such as formic acid.
Other protecting groups optionally present at the
nitrogen atom and/or at the oxygen atoms correspond ~o
groups mentioned abo~e that can be split off by the
described methods and replaced by hydrogen, such groups
being split off in the course of the described process at
the same time as other groups or subsequently in a eparate
process step.
S~arting materials of the formula VIII in which R
represents a radical that can be converted into a poly-
hydroxy-lower alkyl group, such as a 1,2-dihydroxy- or 2,3-
dihydroxy-lower alkyl group, for example a 2,3-dihydroxy-
propyl group, can be obtained, for example, by reacting a
compound of the formula VIII optionally carrying protecting
groups at the nitrogen atom and/or at the oxygen atoms,
wherein Rll corresponds, for example, to a group of the
formula
,1 ~ Qi'~7~>~
--Rlo - CE - CH2 ~ Z3
ZA (VIIIa)
in which Rlo corresponds to a lower alkyl radical having
two fewer carbon atoms, and at least one of the groups
Z3 and Z4, which can be identical or different, represents
a reactive esterified hydroxy group, for example halogen,
such as chlorine and especially bromine, and the other
represents hydroxy, with a salt of a carboxylic acid, for
example an alkali metal salt, such as ~he potassium salt, of
a lower alkanecarboxylic acid, for example acetic acid, or
of an aromatic carboxylic acid, such as ben20ic acid, to
form the corresponding co~pound containing one or two acyl-
oxy groups in the ~roup VIIXa. Starting materials of the
formula VIII having a group VIIIa can in turn be obtained
by the addition of halo~en, for example bromin~, or a halo
compound of the ~ormula Hal-OH, for example hypochlorous
or hypobromous acid, to an alkenyl radical corresponding
to the group VIIIa. These reactions are carried out in
the customary manner~
Starting materials of the formula V~II, in which R
represents, for example, a group of the formula
Z~:~
- 31 -
10 ~ 1 2
xlo
(VIIIb)
wherein XlOrepresents a radical that can be split off
by hydrolysis, including alcoholysis or acidolysis, or by
redu~tion, including hydrogenolysis, for example one of
those mentioned above, and Rl~ has the meaning ~tated, can
be obtained, for example, by reacting a compound of the
formula
~L ~X /
(VIIIc~
with epichlorohydrin, and reacting the resulting compound
of the formula
2 \ /CH2 (VIIId)
i
22~
- 32 -
for example, with an optionally N-protected, such as N-
benzylated, 5-(2-aminoethoxy)salicylamide to form a com-
pound of the formula VIII in which Rli represents the group
VIIIb.
These reactions are carried out in the customary
manner, optionally while cooling or heating and in a
suitable solvent.
The novel compounds of the formula I in which R
represen~s a 4-lower alkylsulphonylamino group can likewise
be ob~ained by introducing the lower alkylsulphonyl group
into a compound of the formula
~12 OH
H~ OEI~-CH-C~2-N-alk-o ~ COM~2
O~ H
(IX),
in which R represents hydrogen or lower alkyl, and, if
desired, carrying out the additional process steps described
subsequently to the irst process. The introduction of a
lower alkylsulphonyl group is effected by reaction with a
corresponding lower alkanesulphonic acid, for example
methanesulphonic acid, op~ionally in the presence of a suit-
able condensation agent, for example N,N'-dicyclohexylcarbo-
diimide. Instead of a lower alkanesulphonic acid it is also
possible to use a reactive derivative thereof, for example
a halide, such as the chloride or bromide, also an azide, or
an acid anhydride, for example wi~h a lower alkanecarboxylic
acid, such as acetic acid. Reactive derivatives of lower
alkanesulphonic acids are especially also esters, ~or
example those with lower alkanols, such as methanol,
ethanol, isopropanol or tert.-butanol, and also with aryl-
- \
2~
- 33 -
lower alkanols, for example benzyl alcohol optionally sub-
stituted by lower alkyl, for example methyl, or by lower
alkoxy, for example methoxy, or with phenols that are
optionally activated by suitable substituents, such as 4-
halo, for example 4-chloro, 4-nitro or 4-methoxy, and accor-
dingly are, for example, 4-methoxy-, 4-nitro-, 2,4-dinitro-
or 4-chloro-phenol.
Advanta~eously, ~he secondary amino group located
in ~he side chain is present in a form having reduced reac-
~ivity, for example in protonated form, as a result of
carrying out the reaction in a pH range of approximately
4.0 - 5.0, for example in the presence of an acid, such
as acetic acid.
These reactions are carried out in a manner known per
se, for example at elevated or reduced temperature in the
absence or presence of a suitable solvent and optionally
in a protective gas atmosphere, for example under nitrogen.
Starting materials of the formula IX may be obtained
in the cuctomary manner, for example by reacting a compound
of the formula
2~ ~ ~ O \
O~CH2-CH - CH2
(IXa3
with a compound of the formula
~92~
- 3~ -
,~
~ CON~2
H2N-alk-O W
~IXb),
in which the primary amino group and/or the hydroxy group
can be protected by a group that can be split off by hydro-
g~nolysis and replaced by hydrogen, for example benzyl.
The starting material of the formula IX is obtained by sub-
sequently reducing the nitro group to the amino ~roup and
at the same time or in a separate reducing s~ep splitting
o~f a N- and~or O-protecting group present in the ~esult-
ing compound that can be split off by hydrogenolysis. These
reductions are carried out in customary manner, for example
by means of actlvated hydrogen, for example hydrogen in the
presence of a catalyst, such as nickel, or a noble metal
catalyst, such as platinum or palladiumr optionally on a
suitable carrîer, such as carbon.
Starting materials of the formula IX in which R12
represents lower alkyl may be obtained by reacting a com-
pound o the formula
R12
HN~L
OH
(IXc)
~q~
with a lower alkanesulphonic acid, or a reactive derivative
thereof, such as the chloride, reacting the resulting com-
pound of the Eormula
lower alkyl SO2-1 ~ OH
~IXd~,
in which ~1~ represents lower alkyl, with epichlorohydrin
to form the corresponding compound of the formula
lower alkyl-SO2-~ ~
-C~2~CH--CH2
(IXe)
and reacting this compound with a compound of the formula
IXb.
These reactions are carried out in a manner known
S
The novel compounds of the formula I may likewise
be obtained by reacting a compound of the formula
- 36 -
/Rll
~' (X~
~ OH
with a compound of the formula
~CO~H2
2 CX CH2 -N-alk_o ~ (XI~,
Xl H
in which Z5 represents a reactive esterified hydroxy
group and Xl is hydroxy, or in which Z5 and Xl together
represent the epoxy group, or with a corresponding cyclised
compound o the formula
n
X11' 1 I ~C0~2
-~-alk o ~
(XII),
37 -
in which Rll and alk each has the meaning stated, and Xll
represents hydrogen or a group that can be split off under
the conditions of the process and is capable of forming
the ether bond with the hydroxy group of a compound of the
formula X, and, i~ desired, carrying out the process steps
men-tioned subsequently to the first process. Groups Xll
that can be split off and are capable of forming the ether
bond in the manner cpecified above are, for example, aryl-
lower alkyl groups, wherein aryl represents, for example,
naphthyl, for example l-naphthyl, and especially phenyl
that is optionally substituted by lower alkyl, lower alkoxy
hydroxy, halogen, trifluoromethyl and/or nitro. Grou2s X
defined in the above sense are accordingly especially
ben~yl, and also lower alkoxymethyl, for example methoxy-
methyl.
A reactive esterified hydroxy group Z5 is a hydroxy
group esterified by a strong acid, especially a strong
inorganic acid, such as a hydrohalic acid, especially
hydrochloric, hydrobromic or hydriodic acid, or sulphuric
acid, or by a strong organic acid, especially a strong
organic sulphonic acid, such as an aliphatic or aromatic
sulphonic acid, for example methanesulphonic acid, 4-
methylphenylsulphonic acid or 4-bromophenylsulphonic acid,
and is especially halogen, for example chlorine, bromine,
or iodine, or aliphatically or aromatically substituted
sulphonyloxy, for example methylsulphonyloxy or 4-methyl-
phenylsulphonyloxy.
The reaction of a co~pound of the formula X with a
compound of the formula XI is effeGted in a manner known
se, wherein, especially when using a starting material of
the formula XI having a reactive esterified hydroxy group,
the reaction is carried out advantageously in the presence
of a basic medium, such as an inorganic base, for example
an alkali metal or alkaline earth metal carbonate or
hydroxide, or in the presence of an organic basic medium,
such as an alkali metal lower alkoxide, and/or an excess
3" ~ ~ d ~
of the basic reactant. The compound of the formula X may
also be in the form of a salt, for example an alkali salt,
for example the sodium salt.
The reaction of a compound of the formula X with a
compound of the formula XII is customarily carried out in
the presence of a basic catalyst, such as an alkali
hydroxide, such as potassium hydroxide, or an organic base,
such as triethylamine, or an acidic catalyst, such as tri
fluoroacetic acid.
These reactions are carried out in a manner known
se, usually in the presence of a solvent or solvent mixture
and, if necessary, while cooling or heating, for example
in a temperature range of from approximately 20 to
approximately 200 , preferably from approximately 100
to approximately 180 , in an open or closed vessel and/or
in an inert gas atmosphere, for example in a nitrogen
atmosphere~
Starting materials of the formula XI in which Z
ic a reactive esterified hydroxy group, for example
chlorine, and X represents hydroxy, can be obtained in
the customary manner by reacting an amine of the formula
~.~
d~ CONH
~-alk-o ~ 2
(XIa)
having an optionally protected hydroxy, with epichloro-
hydrin, while a starting material of the formula XI in which
Z5 and Xl together represent the epoxy group can be o~tained
from an amine of the formula XIa with epichlorohydrin in
the presence of a basic medium, for example an alkali or
~''3ZZ'~:~
- 39 -
alkaline earth hydroxide or carbonate, such as sodium
hydroxide or carbonate, or calcium hydroxide or carbonate.
A protected hydroxy group is a hydroxy group substituted,
for example by a group that can be split off by reduction,
including hydrogenolysisl and replaced by hydrogen, for
example an~ aryl-lower alkyl group, such as a l-phenyl-lower
alkyl group for example a benzyl group, optionally substi-
tuted, for example as stated above, or by a group that can
be split off by hydrolysis and replaced by hydrogen, for
example an acyl radical, such as a lower alkanoyl radic~l,
such as an acetyl group. Such protecting groups are split
off by reduction, including hydrogenolysis, or by hydroly-
sis, and replaced by hydrogen, in customary manner, simul-
taneo~sly or in a separate reaction step, for example as
described.
Starting materials of the formula XII may be obtained
in a manner known per se by reacting a compound of the
formula
20H
~11 - CH (XIIa),
in which the two hydroxy groups may preferably be in reac-
tive es~erified form, for example in the form of halogen,
such as chlorine~ or in the form of a sulphonyloxy group,
such as a methanesulphonylOXy group, with a compound of
the formuIa ~H
H2N-alk- ~ CONH2 (XIIb),
in which alk has the meaning as defined above and Xl1
is preferably different from hydrogen, and may be, for
example as described, an optionally substituted benzyl
group. These reactions are customarily carried out in a
solvent or solven~ mixture, and, if necessary, while
- 40 -
cooling or heating, for example in a temperature range of
from approximately -20C to approximately 150C, preferably
from approximately 60 to approximately 100, in an open or
closed vessel and/or in an inert gas atmosphere, for example
in a nitrogen atmosphere. If the group X11 in a starting
material of the formula XII thus obtained represents a
benzyl group optionally substituted, for example as stated,
this group can be split off in customary manner, for example
by means of catalytically activated hydrogen, such as hydro-
gen in the presence o a noble metal catalyst, such as a
palladium-on-carbon catalyst, and replaced by hydrogen,
yielding a starting material of the formula XII in which
Xll i5 hydrogen.
The reactions described above may be carried out
simultaneously or in succession, as desired, and also in
any sequenceO If necessary, they are carried out in the
presence of diluents, condensation agents and/or catalyti-
Gally active agents, at reduced or elevated temperature,
in a closed vessel under pressure and/or in an inert gas
atmosphere.
Dependina on the process conditions and the starting
materials, the novel compounds are obtained in free form
or in the form of their salts which is likewise included
in the scope of the invention, it being possible for the
novel compounds or salts thereof also to be~in the form
o hemi-, mono-, sesqui or poly-hydrates thereof. Acid
addition salts of the novel compounds can be converted into
the free compounds in a manner known ~ se, for example
by treating with basic agents, such as alkali metal
hydroxides, carbonates or bicarbonates, or ion exchangers.
On the other hand, resulting free bases may form acid addi-
tion salts with organic or inorganic acids, for example
with the mentioned acids, there being used for the manufac-
ture thereof especially those acids which are suitable for
the formation of pharmaceutically acceptable saltsO
These or other salt~, especially acid addition salts,
- 41 -
of the novel compounds, such as, for example, oxalates or
perchlorates, may a.Lso be used to purify the resulting free
bases, by converting the free bases into salts, separating
and purlfying ~hese, and liberating the bases from the salts
again.
Depending on the starting materials and procedures
chosen, the novel compounds may also be in the form of
optical antipodes or racemates or, if they contain at least
two asymmetric carbon atoms, also in the form of racemic
mixtures. The starting materials may also be used in the
form of specific optical antlpodes.
Resulting racemic mixtures may be separated on the
basis of the physical-chemical differences be~ween the dia-
stereoisomers, in known manner, for example by chromato-
graphy and/or fractional crystallisation~ into the two
stereoisomeric (diastereoisomeric1 racematesO
Resulting racemates can be resolved into the anti-
podes according ~o methods kno~n ~ se, for example by
recrystallisation rom an optically ac~ive solvent, by
treatment with suitable micro organisms or by reaction with
an optically active substance that forms salts with the
racemic compound, especially acids, and separating the salt
mixture obtained in this manner, for example on the basis
of differing solubility, into the diastereoisomeric salts
from which the free antipodes can be liberated by the action
of suitable agents. Especially customary optically active
acids are, for example, the D and L-forms of tartaric acid,
di-O,O'-(p-toluoyl)-tartaric acid, malic acid, mandelic
acid, camphorsulphonic acid, glutamic acid~ aspartic acid
or quinic acidO Advantageously~ the more active of the
two ~ntipodes is isolatedO
The invention relates also to those embodiments of the
process according to which a compound obtained as an inter
mediate at any stage of the process is used as starting
material and the remaining process steps are carried out, or
the procecs is discontinued at any stage, or in which a
~z~
- 42 -
starting ~aterial is formed under the reaction conditions,
or in which a reactant is optionally in the form of its
salts.
The starting materials used for carrying out the reac-
tions according to the invention are advantageously those
which result in the classes of end products given special
mention at the beginning and especially in those end pro-
ducts which are specifically described or emphasised.
The starting materials are known or, if new, can be
manufactured according to methods known ~ se, such as
those methods stated above, for example analogously to the
methods described in the Examples. The starting materials
of the formulae II ~o IX and XI to XII, which were developed
especially for the manufacture o the compound~ of the
formula I according to the invention, are also new and the
invention relates also to those starting materials.
The invention relates also to intermediates that can
be obtained according to the processO
The novel compounds may be used, for example, in the
form of pharmaceutical preparations which contain a phaxma-
cologically active amount of the active substance, option-
ally together with pharmaceutically acceptable carriers
whi~h are suitable $or enteral, for example oral, or paren-
teral administration, and may be inorganic or organic and
solid or liquid. Thus, tablets or gelatin capsules are
used which contain the active substance together with di-
luents, for example lactose, dex~rose, sucrose, manni~ol,
sorbitol, cellulose and/or glycerine and/or lubricants,
for example silica, talc, stearic acid or salts thereof,
such as magnesium or calcium stearate, and/or polyethylene
glycol. Tablets may also contain binders, for example mag-
nesium aluminium silicate, starches, such as corn, wheat,
rice or arrowroot starch, gelatin, tragacanth, methylcellu-
lose, sodium carboxymethylcellulose and/or polyvinyl pyrro-
lidone, and, if desired, disintegrators, for example
s~arches, agar, alginic acid or a salt thereof, such as
2~
- 43 -
sodium alginate, and/or effervescing mixtures, or adsor-
bents, colouring substances, flavourings and sweeteners.
The novel pharmacologically active compounds can also be
used in the form of parenterally administrable preparations
or infusion solutions. Such solutions are preferably iso-
tonic aqueous solutions or suspensions, it being possible
to manufacture these before use, for example in the case
of lyophilised preparations which contain the active sub-
stance alone or together with a carrier, for example manni-
tol. The pharmaceutical preparations can be sterilised
and/or contain adjuncts, for example preservatives, stabi-
lisers, ~etting agents and/or emulsifiers, solubilisers,
salts for regulating the osmotic pressure and/or buffers.
The present pharmaceutical preparations which may, if
desired, contain further pharmacologically active sub-
stances, are manuactured in a manner known per se, for
example by means of conventional mixing, granulating, coat-
ing, di~solving or lyophilising processes, and contain from
approximately Ool ~ to 100 %, especially from approximately
1 % to approximately 50 %, and, in the case of lyophili-
sates, up to 100 %, o the active substance.
The dosage may depend on various factors, such as
the manner of administration, the species, age and/or indi-
vidual condition. Thus, the daily doses of ~-receptor-
blockers of the formula I to be administered in one or
several, but preferably not more than 4, single doses in
the case of oral administration to warm-blooded animals
is between 0.03 my/kg and 3 mg/kg and for warm-blooded
animals of approximately 70 kg body weight preferably
between approximately 0.005 g and approximately 0.3 g.
The following Examples serve to illustrate the
invention: temperatures are given in degrees Centigrade.
f~;~
- 44 -
Example 1
A solution of 6.9 g of 1-[2-(3-carbamoyl-4-hydroxy-
phenoxy)-ethylamino]-3-[~2,2-dimethyldioxolan-4-yl)-methyl]-
phenoxy)-2-propanol in 165 ml of O.lN hydrochloric acid is
allowed to stand at 20 for 5 hours, and then washed twice
with ether; the aqueous phase is filtered and then concen-
trated ln vacuo at a bath temperature of 40 . The result-
ing aqueous solution is lyophilised yielding 1-[2-(3-
carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[2-(2,3-dihydroxy-
propyl)-phenoxy]-2-propanol hydrochloride in the form of
a colourless amorphous powder.
The starting material may be prepared in the following
manner:
la) A mixture of 76.8 g of 4-(2-hydroxybenzyl) 2,2-
dimethyl-1,3-dioxolane, 248 ml of epichlorohydrin and 63.7 9
of potassium carbonate is stirred at a bath temperature of
130 for 7 hours.
The reaction mixture is iltered and concentrated to
dryness in vacuo. The residue is dissolved in ether, the
solution is washed with 2N sodium hydroxide solution and
then with water, dried over sodium sulphate and then concen-
trated. The resulting crude 4-[2-~2,3-epoxypropoxy~-
benzyl~-2,2-dimethyl-1,3-dioxolane is further processed
as such.
lb) A mixture of 17~4 g of the resulting crude compound
and 17.1 g of 5-(2-benzylaminoethoxy)-~alicylamide in 60 ml
of dimethyl sulphoxide is stirred at a bath temperature of
for 20 hours. The reaction mixture is poured onto
ice and water and extracted with ethyl acetate. The organic
phase is diluted with ether and washed in succession with
O.lN hydrochloric acid (a~ pH 4-5~ and then with aqueous
saturated potassium carbonate solution and dried over sodium
sulphate. After concentration by evaporation there remains
an oil which is chromatographed over silica gel with
methylene chloride/methanol. After working up, l-[N [2-
(3-carbamoyl-4-hydroxyphenoxyl-ethyl]-benzylamino]~3-[2-
- 45 -
[(2,2-dimethyldioxolan-4-yl)-methyl]-phenoxy]-2-propanol is
obtained in the form of a thick oil.
lc) A solution of 23.5 g of the resulting compound in
240 ml of methanol is hydrogenated under nor~al conditions
with the addition of 2.4 g of palladium on-carbon catalyst.
The reaction product is disxolved in ethyl acetate and
caused to crystallise out by the addition of petroleum
ether. The crystals are again dissolved in ethyl aceta~e
and stirred with 4.5 g of silica gel for ~ hour. Petroleum
ether is added, in portions, to the filtered solution yield-
ing l-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[2-
[(2,2-dimethyldioxolan-4-yl)-methyl]-phenoxy]-2-propanol
having a melting point of 91 - 93 .
Example 2
After the addition of 205 g of Pd/C catalyst (5 ~),
a solution of 20.0 g of crude 1-[N-[2-(4-carbamoyl-3-
hydroxyphenoxy)-l-methylethyl]-benzylamino]-3-(4-methane-
sulphonylaminophenoxy)-2-propanol in 2~0 ml of methanol
is hydrogenated under normal conditions un~il debenzyla-
tion has ceased, (tested by TLC), for which purpose the
addition of a further 1.0 9 of catalyst is required.
The catalys~ is filtered off, the filtrate is con-
centrated by evaporation and the oil that remains is dis-
solved in a small quantity of hot isopropanol. After cool-
ing, crystalline l-L2-(4-carbamoyl-3-hydroxyphenoxy)-1~
methylethylamino]-3-(4-methanesulphonylaminophenoxy~-2-
propanol is obtained having a melting point of 147 - 150
(diastereoisomeric mixture).
The starting material is obtained in the following
manner:
2a) According to the method described by Irvine et. al.,
Synthesis 1972, 568, 2,4-dihydroxybenzamide is converted,
~sing an excess of acetone, into 2,3-dihydro-2,2-dimethyl-
7-hydroxy-4H-1,3-benæoxazin-4-one having a melting point
of 249 - 251 .
- 46 -
2b) From 168 9 of 2,3-dihydro-2,2-dimethyl-7-hydroxy-4~-
1/3-benzoxazin-4-one, 305 g of potassium carbonate and 88 ml
of chloroacetone in 1.2 litres of acetonitrile there is
obtained by boiling for 28 hours and subsequent working up,
2,3-dihydro-2,2-dimethyl-7-(2-oxopropoxy)-4~-1,3-benzoxazin-
4-one having a melting point of 160 - 162 (from isopro-
panol).
2c) A solution of 75 g of crude 2,3-dihydro-2,2-dimethyl-
7-(2-oxopropoxy~-4H-1,3-benzoxazin-4~one and 32 g of benzyl-
amine in 1000 ml of methanol is hydrogenated under normal
conditions with the addition of 0.75 g of concentrated sul-
phuric acid and 1.6 9 of Pt/C çatalyst (5 ~) until the
absorption of hydrogen has ceased. After filtering off the
catalyst and evaporating off the solvent, the oily residue
is partitioned between 300 ml of ethyl acetate and 500 ml
of 2N hydrochloric acid. From the aqueous phase there is
isolated, by the addition of concentrated ammonia (ice cool-
ing) and extraction with ethyl acetate, crude 2,3~dihydro-
2,2-dimethyl-7-[~2-benzylamino)-propoxy]-4H-1,3-benzoxazin-
4-one in the form of an oil which can be further used in
crude form.
2d) A mixture of 100 9 of crude 2,3-dihydro-2,2-dimethyl-
7-[(2-benzylamino)-propoxy]-4H-1,3-benzoxazin-4-one, 100 ml
of isopropanol and 100 ml of isopropylamine is boiled under
reflux for 1 hour and then concentrated by evaporation~
The oil that remains crystallises when triturated with
ether. The crystals are filtered off with suction and
washed with a small quantity of isopropanol. 4-~2-(benzyl-
amino)-propoxy]-salicylamide having a melting point of 121 -
123 is obtained.
2e) A solution o 19.0 9 of 4~[2-~benzylamino)-propoxy]-
salicylamide and 12.4 g of 4-(2,3~epoxypropoxy)-nitro- -
benzene in 300 ml of isopropanol is boiled under reflux
for 20 hours. After the addition of a further 1.2 9 of
4-(2,3-epoxypropoxy)-nitrobenzene, the solu~ion is heated
under reflux for a further 20 hours. Subsequently, the
- ~7 -
solvent is partially evaporated off, whereupon 1-[N-[2-
(4-carba~oyl-3-hydroxyphenoxy)-1-methylethyl]-ben~ylamino]-
3-~4-nitrophenoxy)-2-propanol having a melting point of
160 - 164 crystallises out (diastereoisomeric mixture).
2f) A solution of 19.0 g of the resulting compound in
380 ml oE dioxan is hydrogenated under nor~al conditions
with the addition of 18 9 of Raney nickel in 4 portions
until 3 molar equivalents of hydrogen have been absorbed.
After filtration and concentration of the filtrate by
evaporation, crude l-[N-[2-t4-carbamoyl-3-hydroxyphenoxy)-
l-methylethyl]~benzylamino]-3-(4-aminophenoxy)-2-propanol
remains behind in the form of an orange-brown oil which
is further processed without further purification.
2g) 16 g of the resulting compound are dissolved in 90 ~1
of anhydrous pyridine and, while cooling to 5 - 10 , 4.4 g
of methanesulphonic acid chloride are added dropwise
thereto. The reaction mixture i5 stirred at room tempera-
ture for 4 hours, the solvent is evaporated off and the
residue is parti~ioned between 400 ml of ethyl acetate and
50 ml of water. The organic phase is washed three times
using 50 ml of water each time, dried over magnesium sul-
phate, treated with carbon and concentrated by evaporation
yielding crude l-[N-[2-(4-carbamoyl-3-hydroxyphenoxy)-1-
methyle~hyl3-benzylamino]-3-(g-methanesulphonylamino-
phenoxy)-2-propanol in the form of an orange oil which is
further processed without further purification.
Example 3
A solution of 30 9 of crude 1-[N-[2-(3-carbamoyl-4-
hydroxyphenoxy) ethyl] benzylamino]-3-[4-[2-(cyclopropyl-
methoxy)-ethyl3-phenoxy]-2-propanol in 600 ml of methanol
is hydrogenated under normal conditions with the addition
of 4 g of Pd/C catalyst (5 %) until 1 molar equivalent of
hydrogen has been absorbed. The product that has already
crystallised out is made into a solution by adding dioxane
and heating, the catalyst is filtered off and ~he iltrate
- ~8 -
is concentra~ed by evaporation. After recrystallisation
from isopropanol and then from methanol, pure 1-[2 (3-
carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[2-(cyclo-
propylmethoxy)-ethyl]-phenoxy]-2-propanol having a melting
point of 149 ~ 150 is obtained.
The starting material is prepared in ~he following
manner:
3a) According to the method described by Irvine et. al.,
Synthesis 1972, 568, 2,5-dihydroxybenzamide is converted,
using an excess of acetone, into 2,3-dihydro-2,2--dimethyl-
6-hydroxy-4~-1,3 benzoxazin-4-one having a melting point
o~ 215 - 216 ~
3b) 70 g of 2,3-dihydro-2~2-dimethyl-6-hydroxy-4H-1,3-
benzoxazin~4-one in 400 ml of acetonitrile are stirred under
reflux with 100 g of potassium carbonate and 32 ml of
chloroacetone for 30 hours. After the addition of a further
3.2 ml o chloroacetone, the reaction mixture is heated
for a further 15 to 20 hours. The reac~ion mixture is fil-
tered while still warm, the residue is washed thoroughly
with acetone and the combined filtrate is concentrated by
evaporation. The crystalline residue is recrystallised
from toluene and yields 2,3-dihydro~2,2-dimethyl-6-(2-oxo-
propoxy)-4H-1,3-benzoxazin-4-one having a mel~ing point
of 125 - 126 .
3c) 74 g of the resulting 2,3-dihydro-2,2-dimethyl-6-~2
oxopropoxy)-4H-1,3-benzoxa~in-4-one are heated in a mix-
ture of 150 ml of dioxa~e and 450 ml of 2N hydrochloric
acid for 45 minutes on a water bath~ The solvent is
evaporated off and the crystalline residue is triturated
with water and then filtered with suction. Recrystallisa-
tion from isopropanol yields 5-(2-oxopropoxy)-salicylamide
having a melting point of 152 - 154 O
3d~ 55 g of benzylamine and 1.25 g of concentrated sul-
phuric acid are added to a solution of 104.5 9 of 5-(2-
oxopropoxy)-salicylamide in 1000 ml of methanol and the mix-
ture is hydrogenated under normal conditions in the presence
- 49 -
of 3.0 g of Pt/C catalyst until 1 equivalent of hydrogen has
been absorbed. The catalyst is filtered off, the solution
is stirred with approximately 10 9 of pulverulent calcium
carbonate, filtered again and concentrated by evaporation.
The oil that remains cxystallises from isopropanol.
Recrystallisation once more from isopropanol yields 5-~2-
(benzylamino) propoxy]-salicylamide having a melting point
of 102 - 104 .
3e) A solution of 14.3 9 of 1-[2-~cyclopropylmethoxy)-
ethyl]~ 2,3-epoxypropoxy) benzene (German Offenlegungs-
schrift 26 49 605) and 1~3 g of 5-[2-(benzylamino~-
propoxy~salicylamide in 200 ml of isopropanol is boiled
under reflux for 18 hour ~ After concentration of the
reaction mixture by evaporation, crude l-[N-[2-(3-carbamoyl-
4-hydroxyphenoxy)~thyl]-benzylamino]-3-[4-[2~cyclopropyl
methoxy)-ethyl]~phenoxy]-2-propanol is ob~ained in the form
of a brown oil which is further processed without further
purification~
Example 4
After the addition of 6 g of palladium-on carbon
catalyst (5 ~), a solution of 50 g of crude l~[N-12-(3-
carbamoyl-4 hydroxyphenoxy)-ethyl~-benzylamino3-3~(4
methanesulphonylaminophenoxy)-2-propanol in 550 ml of
methanol is hydrogenated under normal conditions until the
absorption of hydrogen has ceased. The product that has
already crystallised out is made in~o a solution by adding
dioxan and heating, the catalys~ is filtered off and ~he
filtrate is concentrated by evaporation. The crystalline
residue resulting from the concentration by evaporation is
recrystalli~ed from ethanol and then from methanol with
the addition of activated carbon to yield 1-[2-~3-carbamoyl-
4-hydroxyphenoxy)-ethylamino]-3-(4~methanesulphonylamino-
phenoxy)-2 propanol having a melting point oE 152 153 .
The starting material is prepared in the following
manner:
-- 50 --
4a) 19.5 g of 4-~2,3 epoxypropoxy)-nitrobenzerle and 28.6 g
of 5-(2-benzylaminoe~hoxy)-salicylamide are boiled under
reflux in 400 ml of isopropanol for 20 hours. The crude
l-[N-[2-(3-caebamoyl-4-hydroxyphenoxy)-ethyl]-benzylamino]-
3-(4-nitrophenoxy)-2-propanol, which is obtained in the
form of a viscous oil after concentration by evaporation
of the reaction mixture, is ~urther processed in that form.
4b) 50 g of the crude compound obtained according to
Example 4a) are dissolved in 500 ml of ethanol and hydro-
genated in the presence of 5 g of Raney nickel. It i9
necessary to make two additions of, in each case, 10 g of
~aney nickel until the calculated quantity (3 molar equi-
valents) of hydrogen is absorbed~ Af~er fil~ering and con-
centration of the filtrate by evaporation, crude 1- [N- [2-
(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylamino]-3-(4-
aminophenoxy)-2-propanol is obtained in the form oF a brown
oil.
4c) 44 g of the crude compound obtained according to
Example 4b) are dissolved in 300 ml of anhydrous pyridine
and, while stirring and cooling, 11.4 g of methanesulphonic
acid chloride are added dropwise at 10 - 20 . The reac-
tion mixture is stirred overnight a~ room ~emperature, con-
centrated by evaporation and partitioned between 500 ml
of ethyl acetate and 100 ml of water. The organic phase is
separated off~ washed twice using 100 ml of water each time,
dried over magnesium sulphate and c~ncentrated by evapora-
tion. The resulting crude [l-[N-12-~3-carbamoyl-4-hydroxy-
phenox~)-ethyl]-benzylamino]-3-(4-methanesulphonylamino-
phenoxy)-2 propanol, obtaine~ in the form of viscous oil,
is further processed without further purification.
Example 5
A mixture of 11.5 g of 4-(2,3-epoxypropoxy)-cinnamic
acid N-methylamide and 7.4 9 of 5-(2-aminoethoxy)-salicyl-
amide is dissolved in 50 ml of dimethyl sulphoxide heated
to approximately 80 , the solution is stirred for 1 hour
2~
- 51 ~
o o
at 75 - 85 and then poured onto SOO ml of water.
The resin like produc~ that is deposited is separated off
and stirred with 150 ml of ethyl acetate. The crystals
that are deposited are filtered off with suction and recry-
stallised from a small quantity of isopropanol yielding
4-[3-[2-(3-carbamoyl-4-hydroxyphenoxy~-ethylamino]-2-
hydroxypropoxy~-N- ethylcinnamic acid amide having a melting
point of 170 - 171 (sinters above 148 ).
Example 6
Analogously to Example 4, a solution of 41 g of crude
l-[N-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl~-benzylamino]-
3-[4-(N-methyl~methanesulphonylamino)-phenoxy]-2-propanol
in 410 ml of methanol is hydrogenated in the presence of
4 9 of palladium-on-carbon catalyst and worked up. After
recrystallisation from ethanol and methanol, 1-[2-(3-carb-
amoyl 4-hydroxyphenoxy)-ethylamino]-3-[4-(N-methyl-methane-
sulphonylamino)-phenoxy]-2-propanol having a melting point
of 120 - 121 is obtained.
The starting material is prepared in the following
manner:
6a) While stirring and cooling with ice, 77 ml of me~hane-
sulphonic acid chloride are added dropwise over a period
of approximately 30 minutes to a solution of 103.7 g of 4~
methylaminophenol sulphate in 330 ml of pyridine and 102 ml
of N,N-diisopropylethylamine and the mixture is stirred
overnight at room temperature. The volatile portions are
evaporated off and the residue resulting from concentration
by evaporation is partitioned between ethyl acetate and
water; the organic phase i~ separated off and concentrated
by evaporation and the crystalline resîdue is hea~ed on
a water bath ~ith 300 ml of 6N sodium hydroxide ~olution
until fully dissolved. The solution is filtered and the
pH is adjusted to 2 with concentrated hydrochloric acid.
On so doing, 4-~N-methylsulphonylamino)-phenol crystallises
out. The crystallisate is filtered off with suction and
~qJ~ ~
- 52 -
o o
dried at 80 in vacuo. Melting point 135 136 .
6b~ A mix~ure of 34.2 g of the compound obtained according
to Example 6a), 35.2 g of potassium carbonate and 125 ml
of epichlorohydrin is boiled under reflux, while stirring,
for 2 hours. The suspension is filtered, the filtrate i5
concentrated by evaporation, partitioned between ethyl
acetate and water and the organic phase is separated off,
dried over magnesium sulphate and concentrated by evapora-
tion . 4- (2,3-epoxypropoxy)~N-methyl-methanesulphonanilide
having a melting point of 96 100 is obtained (from
methanol).
6c) A solution of 19.0 g of the compound obtained accord-
ing to Example 6b) and 21.4 g of 5-(2-benzylaminoethoxy)-
salicylamide in 350 ml of isopropanol is boiled under reflux
for 5 hours. After concentration by evaporation, crude
l-[N-[2~t3-carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylamino]-
3-[4-(N-methyl-methanesulphonylamino)-phenoxy]-2-propanol
is obtained in the form of a viscous oil which is further
processed in that form.
Example 7
A mixture of 5 g of methanesulphonyl chloride, 5 g
of 1-[2-(3~carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-(4-
aminophenoxy)-2 propanol, 1.5 g of acetic acid and 100 ml
of water i5 heated~ while stirring, on a boiling water bath
for 15 minutes. After cooling, the pH of the mixture is
adjus~ed to 9.0 - 12.0 by the addi~ion of sodium hydroxide
solution and the mixture is extrac~ed exhaustively with
ethyl acetate. The ethyl acetate solution is washed with
water, dried over sodium sulphate and evaporated to dry-
ness. The residue resulting from concentration by evapora-
tion is recrystallised from ethanol and then from methanol
and yields 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-
3-(4-methanesulphonylaminophenoxy)-2-propanol having a melt
ing point of 152 .
The starting material may be prepared in ~he following
:,
;~9~
- 53 -
manner:
7a) After the addition of 0.5 g of palladium-on-carbon
catalyst (5 %), a solution of 10 g of the 1 [N-[2-(3-
carbamoyl-4-hydroxyphenoxy)-ethyl]-benzylamino]-3-(4-
aminophenoxy)-2-propanol obtained according to Exampl2 4b~
in 100 ml of ethanol is hydrogenated until the absorption
of hydrogen has ceased (1 molar equivalent). After filter-
ing off the catalyst, the fil~rate is evaporated ~o dryness
yielding 1 [2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-
3-(4-aminophenoxy)-2-propanol in the form of a crude product
which is further processed in that form.
Example 8
A mixture of 13.~ g of 1 (4-methanesulphonylamino-
phenoxy)-3-amino-2~propanol and 10.5 9 of 4-(2-oxopropoxy)-
salicylamide is boiled in a water ~eparator in 200 ml of
toluene with the addition of a few drops of acetic acid.
When the splitting off of water has ceased ~ 2 to 3 hours),
the solu~ion is concentrated by evaporation and the dark
red residue is dissolved in 300 ml of ethanol and a total
of 5.7 9 of sodium borohydride is added, in portions/ while
stirring. On so doing the temperature increases to 36 .
The reaction mixture is stirred at 20 to 30 for a further
2 hours and allowed to stand overnight. ~hile cuoling with
ice, the pH of the mixture is adjusted to 3 - 4 with
approximately 6N hydrochloric acid, filtered and concen-
trated by evapora~ion. The residue resulting from concen-
tration by evaporation is partitioned between 100 ml of
water and 100 ml of ethyl acetate and the aqueous phase
is separated c~f, rendered alkaline with concentrated
ammonia and extracted with 200 ml of ethyl acetate. After
washing the organic phase with water, drying over sodium
sulphate and evaporating off the solvent, 1-[2-(4-carbamoyl-
3-hydroxyphenoxy)-1-methylethylamino]-3-(4-me~hanesulphonyl-
aminophenoxy)-2-propanol is obt~ined in the form of a dia-
stereoisomeric mixture which is recrystallised from a small
- 54 -
quantity of hot isopropanol. Melting point 147 - 150 .
1-(4-methanesulphonylaminophenoxy)-3-amino-2-propanol,
which is required as starting material, is prepared as
follows^
8a) A mixture of 18.7 9 of 4-methanesulphonylaminophenol,
8.5 g of epichlorohydrin, 7 g of potassium carbonate and
70 ml of isopropanol is stirred at 90 for 2.5 hours.
The reaction mix~ure is filtered while hot, the residue
is washed with isopropanol and the filtrate is conc~ntrated
under reduced pressure and finally at 0.03 torr on a water
bath yieldingt as residue, 4-methanesulphonylamino-(2,3-
epoxypropoxy)-phenol.
A solution of approximately 2 9 of dry ammonia gas
in 110 ml of dioxane is added to a solution of 2~.3 g o
the resulting product in 170 ml of dioxane and the reac
tion mixture is allowed to stand in a closed flask for 24
hours at room temperature. After removing excess ammonia
and evaporating off the solvent under reduced pressure,
crude 1-~4-methanesulphonylaminophenoxy)-3-amino-2-propanol
is obtained and is further processed as such.
Example 9
A mixture a 50 ml of dioxane and 500 ml of concen-
trated ammonia solutîon is added to 23.2 g of 1-[2-(4-
methoxycarbonyl-3-hydroxyphenoxy)-1-methylethylamino]-3-
(4-methanesulphonylaminophenoxy)-2-propanol. The reaction
mixture i5 stirred for 1 to 2 hours and, as soon as it has
become homogeneous, allowed to stand for a further 3 days
at 20 - 30 . Concentration by evaporation yields crude
1-(4-carbamoyl~3 hydroxyphenoxy)-3-[2-(4-methanesulphonyl-
aminophenoxy~-l-methylethylamino]-2-propanol in the form
of a diastereoisomeric mixture. This is dissolved in a
small quantity of hot isopropanol and the solution is then
cooled yielding the pure compound having a melting point
of 147 - 150 .
The starting material may be obtained in the following
2~'~
~7
- 55
manner:
9a~ A solution of 2403 g of 4-(2,3-epoxypropoxy)~methane
sulphonylaminophenol and 30 g of 4-(2~benzylaminopropoxy)-
methoxycarbonyl~3-hydroxybenzene in 200 ml of isopropanol
is heated under reflux for 24 hoursO The crude product,
obtained after concentration by e~-aporation, is partitioned
between 2N hydrochloric acid and ether and the aqueous phase
is separated off and rendered alkaline with concentrated
ammonia solution~ Exhaustive extraction ~ith ethyl acetate,
washing the organic phase with water, drying over magnesium
sulphate and concentration by evaporation yields crude l-[N-
[2-t4-methoxycarbonyl-3-hydroxyphenoxy)-l-methylethyl]-
benzylamino]-3-(4-methanesulphonylaminophenoxy)-2-propanol
which is further processed as such in the following step.
9b) A solution of 46 g of 1-~N-[2-(4-methoxycarbonyl-3-
hydroxyphenoxy)-l-methylethyl`]-ben~ylamino]-3-(4-methane-
sulphonylaminophenoxy)-2-propanol in 500 ml of methanol
is hydrogenated under normal condi~ions with the addition
of 5 9 of palladium-on-carbon catalyst (5 ~) until l molar
equivalent of hydrogen has been absorbed. The catalyst
is filtered off and the filtrate is concentrated to dryness
yielding crude l-[2-(4-methoxycarbonyl-3-hydroxyphenoxy)-1-
methylethylamino]-3 (4-methanesulphonylaminophenoxy)~2-
propanol ~hich is further processed as such~
Example lO
A solution of 3.7 g of 1-[2-(3-cyano--4-hydroxyphen-
oxy)-ethylamino~-3-~4 methanesulphonylaminophenoxy]-2-
propanol in a mixture of lS ml of concentrated hydrochloric
acid and 25 ml of dioxane is stirred at a temperature of
20 - 25 for 15 hours. The reaction mixture is then con-
centrated by evaporation and rendered alkaline with lO
strength aqueous ammonia solution. The crude 1-[2-(3-
carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-methanesul-
phonylaminophenoxy~-2-propanol, depo~ited after standing
for several hours, i5 filtered off and recrystallised from
-
~9~"3Z'2~
- 56
ethanol and then from methanol. Melting point 152 - 153 .
1-[2-(3-cyano-4-hydroxyphenoxy)-ethylamino]-3-[4-
methanesulphonylaminophenoxy]~2-propanol, which is required
as starting material, may be obtained as follows:
lOa) A mixture of 6.5 9 of 5-(2~bromoethoxy)-2-hydroxy-
benzonitrile and 9.7 g of the 1-(4-methanesulphonylamino-
phenoxy)-3 amino-2-propanol obtained according to Example
8a) is melted in an oil bath at 100 and stirred magneti-
cally for 1 hour. The melt is then extrac~ed by boiling
with 100 ml of isopropanol, the solution is filtered and
the filtrate is concentrated by evaporation. The residue
resulting from concentration by evaporation is partitioned
between 400 ml of ethyl acetate and 50 ml of ~N potassium
bicarbonate solution and the organic phase is separated
off, washed with water, dried over magnesium sulphate and
concentrated by evaporation yielding crude l-[2-(3 cyano-4-
hydroxyphenoxy)-ethylamino]-3-[4-methanesulphonylaminophen-
oxy]-2-propanol which i5 further processed as such.
Example 11
2.3 9 of sodium metal are rea~ted with 45 ml of
methanol. When the reaction is complete, a solution of
19.2 g of 4-~2-cyclspropylmethoxyethyl)-phenol (German
Offenlegungsschrift 26 49 605) in 110 ml of methanol is
added and the mixture is hea~ed under reflux on a water
bath for 1 hour. The reaction mixture is subsequently con-
centrated to dryness by evaporation under reduced pressure
and the resulting sodium salt is made into a paste with
110 ml of dimethylformamide. To this there is added a solu-
tion of 28.85 9 of 5-[N-(3-chloro-2-hydroxypropyl)]-amino-
ethoxysalicylamide in 170 ml of dimethylformamide and the
mixture is heated, while stirring, on a boiliny water bath
for 3 hours. The solvent is removed under redu~ed pres-
sure and the residue is treated with 200 ml of water, fil
tered and the filter residue is recrystallised from isopro-
panol and then from methanol yieldirlg pure l-[2-(3-carb-
~g~
- 57 -
amoyl-4-hydroxyphenoxy)-ethylamino]-3-[4-[2-(cyclopropyl-
methoxy)-ethyl]-phenoxy]-2-propanol having a melting point
o~ 149 - 150 .
5-[N-(3-chloro-2-hydroxypropyl)]-aminoethoxysalicyl-
amide, which is re~uired as starting material, may be pre-
pared as follows:
lla) A mixture of 48.2 9 of 2,3-dihydro-2,2-dimethyl-6-
hydroxy-4H-1,3-benzoxazin~4-one, 70 g of potassium carbonate
and 250 ml oP 1,2-dibromoethane is boiled under reflux,
while stirring, for 4 hours. The paste-like reaction mix-
ture is extracted 3 or 4 times while hot using 1 litre of
methanol each time, the combined methanol extracts are co~
centrated by evaporation and the residue is recrystallised
from methanol. 6-(2-bromoethoxy)-2,3-dihydro-2,2-dimethyl-
4~-1,3-benzoxazin-4-one having a melting point of 190 -
195 is obtained.
llb) A mixture of 60 g of 6-~2-bromoethoxy3-2,3-dihydro-
2,2-dimethyl-4H-1,3-benzoxazin-4-one and 110 ml of benzyl-
amine is s~irred in a bath at 30 for 30 minutes. While
cooling with ice, the pH of the reaction mixture is adjusted
to 3 - 4 with concentrated hydrochloric acid and the mixture
is allowed to crystallise. After 2 to 4 hours, the crystals
are filtered off with suction, washed with 50 ml of water
and 50 ml of ethyl acetate, and dried. The resulting 5-12-
benzylaminoethoxy)~salicylamide hydrochloride melts at 214 -
o o
216 . The base liberated therefrom melts at 107 - 108
(from ethyl acetate/ether).
llc) 5-(2 aminoethoxy)-salicylamide may be prepared by
debenzylation of the corresponding N-benzyl compound
ob~ained according to Example llb), by means of hydrogen
in the presence of a Pd/C catalyst (5 ~) in methanol.
Melting point 140 .
lld) A solution of 19.6 g of 5 (2-aminoethoxy3-salicyl-
amide in 80 ml o methanol is slowly added to a solution
of 9.25 9 of epichlorohydrin in 30 ml of methanol and the
reaction mixture is stirred at 25 for 3 hours. Af~er
- 58 -
evaporating off the solvent, crude S-~N-(3-chloro-2-
hydroxypropyl)]-aminoethoxysalicylamide is obtained and
is further processed as such.
Example 12
0.4 9 of solid potassium hydroxide is added to a
mixture of 19.2 9 of 4-(2-cyclopropylmethoxyethyl)-phenol
and 25.2 g of 1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl]-
3-a etidinol and the mixture is heated at l5Q for 22
hours in a nitrogen atmosphereO A~ter cooling, the reac-
tion mixture is rendered neu~ral with 2~ hydrochloride acid~
extracted with 100 ml of ether and the ether phase is
separa~ed off and extracted with 2~ hydrochloric acidO
The aqueous phase is separated off, rendered neutral with
concentrated sodium hydroxide solution and the mixture is
extracted with methylene chloride. After washing the
organic phase wi~h water and evaporating off the solvent,
the resulting residue is recrystallised from isopropanol
and then from methanol yielding l-[2-(3-carbamoyl-4-
hydroxyphenoxy)-ethylamino]-3-[4 [2-(cyclopropylmethoxy)-
ethyl~-phenoxy]-2-propanol having a melting point of 149 -
150 .
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethyl~-3-
azetidinol, which is required as starting material, may be
obtained in the following manner:
12a) While stirring, a solution of 15~4 g of 2-benzyloxy-
1,3-dibromopropane in 95 % strength ethanol is added
dropwise, within a period of 1 hour, to a solution heated
to 80 of 40 ~ of 5-(2-aminoethoxy)-2-benzyloxybenzamide
in 250 ml of ~0 ~ strength ethanol and stirring is con-
tinued at ~he temperature stated for a further 12 hours.
The solvent is then substantially removed, the residue is
rendered alkaline with 2N sodium hydroxide solution and
the mixture is extracted with ethyl acetate. The ethyl
acetate solution is extracted with 2N hydrochloric acid
until acidic reaction; the organic phase is washed with
- 59 -
water, dried over magnesium sulphate and evaporated to
dryness yielding crude l-[2-(3-carbamoyl-4 benzyloxyphen-
oxy) ethylamino]-3-benzylazetidinol.
~ y hydrogenolysis by means of hydrogen in the pre-
sence of a palladium-on-carbon catalyst in methanolic solu-
tion until 2 molar equivalents of hydrogen have been
absorbed there is obtained from the above-mentioned compound
1-12-(3-carbamoyl-4-hydroxyphenoxy~ ethylamino]-3-azetidinol
which is further processed as such.
Example 13
Tablets containing 20 mg of active substance and
having the following composition are manufactured in custo-
mary manner:
Composition:
1-12-(3-carbamoyl-4-hydroxyphenoxy)-
ethylamino]-3-[4-[2-(cyclopropylmethoxy)-
ethyl]-phenoxy]-2-propanol 20 mg
wheat starch 60 mg
lactose 50 mg
colloidal silica 5 mg
talc 9 mg
magnesium stearate . 1 mg
145 mg
Manu~acture:
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino]-3-
[4-[2-(cyclopropylmethoxy)-ethyl]-phenoxy] 2-propanol is
- ~o -
mixed with a portion of the wheat starch, with the lactose
and the colloidal silica and the mixture is forced through
a sieve. A further portion of the wheat starch is made
into a paste with five times the quantity of water on a
water bath and the pulverulent mixture is kneaded with this
paste until a slightly plastic mass has been produced.
The plastic mass is pressed through a sieve having
a mesh wid-th of approximately 3 mm, dried and the resulting
dry granulate is again forced through a sieve. The remain-
der of the wheat starch, the talc and the magnesium stearate
are then mixed in and the mixture is pressed into tablets
having a breaking notch each weighing 145 mg.
Example 14
~ ablets containing 1 mg of active substance and having
the following composition are manufactured in the customary
manner:
Composition:
1-[2-(4-carbamoyl-3-hydroxyphenoxy)-
1-methylethylamino]-3-(4-methanesulphonyl-
aminophenoxy)-2-propanol 1 mg
wheat starch 60 mg
lactose 50 mg
colloidal silica 5 mg
talc 9 mg
magnesium stearate 1 mg
126 mg
~JL~,7fd~AO
Manufacture:
~ (4~carbamoyl-3-hydroxyphenoxy)-1-methylethyl-
amino]-3-t4-methanesulphonylaminophenoxy)-2-propanol is
mixed with a portion of the wheat starch, wi~h the lactose
and the colloidal silica and the mixture is forced through
a sieve. A further portion of the wheat starch is made
into a paste with five times the quantity of water on a
water bath and the pulverulent mixture is kneaded with this
paste until a slightly plastic mass has been produced.
~ he plastic mass is pressed through a sieve having
a mesh width of approximatel~ 3 mm, dried and the resulting
dry granulate is again forced through a sieve. The remain-
der of the wheat starch, the talc and the magnesium s~earate
are then mixed in and the mixture is pressed into tablets
having a hreaking notch each weighing 126 mg.
Example 15
Capsules containing 10 mg of active substance are
manufactured in customary manner as follows:
Composition:
1-[2-(3-carbamoyl-4-hydroxyphenoxy)-
ethylamino]-3-[2-[2,3-dihydroxypropyl)-
phenoxy]-2-propanol 2500 mg
talc 200 mg
colloidal ilica 50 mg
Manufacture:
The active substance is intimately mixed with the
talc and the colloidal silica/ the mixture is forced through
a sieve having a mesh width of 0.5 mm and is introduced,
in 11 mg'portions, into hard gelatin capsules of suitable
22:~
- 62 -
size.
Example 16
A sterile solution of 5~0 9 of 1-[2-(3-carbamoyl-4-
hydroxyphenoxy)-ethylamino]-3-[2-(2,3-dihydroxypropyl)-
phenoxy]-2-propanol hydrochloride in 5000 ml of distilled
water is introduced into ampoules of 5 ml capacity which
contain 5 mg of active substance in 5 ml of solution.
Example 17
Instead of the substances used as active substance~
in Examples 13 to 16, it is also possible to use the
following compounds of the formula I, or pharmaceutically
acceptable~ non-toxic acid addition salts thereof, as active
substances in tablets, dragees, capsules, ampoule solutions
and so on~ 2-(3-carbamoyl-4hydroxyphenoxy~-ethylaminoJ-
3-(4-methylsulphonylamino)-phenoxy-2-propanol; 4-[3-~2-(3-
carbamoyl-4-hydroxyphenoxy)-ethylaminoJ-2-hydroxypropoxy]-
N-methylcinnamic acid amide or 1-[2-(3-carbamoyl-4-hydroxy-
phenoxy) ethylamino]-3-[4-(N-methyl-methanesulphonylamino)-
phenoxy]-2-propanol.
